Primer On The Rheumatic Diseases 13th

Primer on the
Rheumatic Diseases
THIRTEENTH EDITION
Primer on the
Rheumatic Diseases
THIRTEENTH EDITION
Edited by
John H. Klippel, MD
John H. Stone, MD, MPH
Leslie J. Crofford, MD
Patience H. White, MD, MA
John H. Klippel, MD John H. Stone, MD, MPH
President and CEO Associate Physician
Arthritis Foundation Massachusetts General Hospital
Atlanta, GA, USA Deputy Editor for Rheumatology
UpToDate
Leslie J. Crofford, MD Boston, MA, USA
Gloria W. Singletary Professor of
Internal Medicine Patience H. White, MD, MA
Chief, Division of Rheumatology & Chief Public Health Officer
Womens Health Arthritis Foundation
University of Kentucky Atlanta, GA, USA
Lexington, KY, USA
Library of Congress Control Number: 2007925709
ISBN: 978-0-387-35664-8 e-ISBN: 978-0-68566-3
Printed on acid-free paper
Springer Science+Business Media, LLC. 2008

All rights reserved. This work may not be translated or copied in whole or in part without the written
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FOREWORD
The 13th edition of the Primer on the Rheumatic Diseases is an extraordinary hand-
book for clinical care. The Primer will educate trainees, update established clini-
cians, and help health care providers from all walks of the profession provide better
care for patients with arthritis and rheumatic diseases.
In achieving these purposes, the Primer continues a tradition of excellence dating
back more than 70 years. The Primer and its precursors have served as a major
learning tool for medical students, house officers, fellows, and allied health profes-
sionals since 1934, when the early publications of the American Committee for the
Control of Rheumatism included the Primer on Rheumatism: Chronic Arthritis in
1934. Since that work, which consisted of a 52-page brochure, the Primer has
evolved into a reference guide of nearly 90 chapters and 4 appendices.
The Primer is designed to provide up-to-date information about the major clini-
cal syndromes seen by primary care physicians, rheumatologists, orthopedic sur-
geons, as well as physician assistants, nurse practitioners, physical and occupational
therapists, and allied health professionals whose expertise contributes to patient
care. Emphasis on the evaluation of the patient, the physical examination including
musculoskeletal signs and symptoms, laboratory and imaging evaluations, and
current and novel therapeutic approaches are essential for all who work in this field.
Arthritis and other rheumatic diseases, which affect more than 46 million Ameri-
cans (including 300,000 children), remain a leading cause of disability and the most
common chronic illness in the United States.
I congratulate the editors on their superb work. In addition, the multiple con-
tributorsmany of whom are members of the American College of Rheumatology
should be thanked for their scholarly contributions to the Primer. Rheumatology
has never been more exciting than it is today, and there is no doubt that the 13th
edition of the Primer reflects this. I join clinicians and patients alike in thanking the
Arthritis Foundation for the continuing achievements of this book.
Michael E. Weinblatt, MD
Professor of Medicine
Harvard Medical School
Brigham and Womens Hospital
Boston, MA, USA
v
Preface
Students, residents, and fellows interested in learning about the rheumatic diseases
are faced with the daunting challenge of trying to integrate learning about a multi-
tude of fascinating and diverse clinical disorders with an ever-expanding and
complex body of basic science.
This need encapsulates the principal rationale for the major changes in the 13th
edition of The Primer on the Rheumatic Diseases. Although the first part of all
recent editions of The Primer have summarized succinctly the physiology of tissues
and cells that mediate inflammation and musculoskeletal disease, preparation of the
new edition resulted in the identification of two major problems with this tried-
and-true formula. First, for readers who really wished to understand the molecular
basis of rheumatic disease to the depth that would facilitate laboratory research and
improve patient care, the initial chapters no longer provided sufficient detail.
Second, for readers seeking an introduction or update within the clinical realm of
rheumatic disorders, the first part of The Primer bore virtually no relation to the
diseases described so engagingly in the rest of the book. In short, in this era of
increasing integration between the basic and clinical sciences, the preliminary
Primer chapters were at risk for becoming simply the pages thumbed through
quickly to get to the good stuff.
Therefore, in the 13th edition, the clinical descriptions that The Primer has
always done best have been augmented by including the clinically relevant basic
science components in the same sections. Thus, for each major rheumatic disease
for example, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and
idiopathic inflammatory myopathiesthe chapter describing the clinical and epide-
miological features is accompanied by another chapter devoted to Pathology and
Pathogenesis. This second chapter incorporates the appropriate (and updated)
elements from previous Primer chapters entitled Synovium, Articular Carti-
lage, The Complement System, and Muscle that are essential to understanding
a particular disease today.
Moreover, this fundamental change in the contents is only the beginning of the
improvements to the 13th edition. Other changes include:
New chapters on Clinical Immunology and Applied Genetics designed to

heighten the translational nature of the book.
Color figures that are particularly important for depicting cutaneous findings and
histopathology.
An expanded chapter on the cutaneous manifestations of disease, emphasizing
the types of disorders rheumatologists often see in consultation.
A section devoted entirely to juvenile inflammatory arthritis, with individual
chapters on Clinical Features, Pathology and Pathogenesis, Treatment and
Assessment, and Special Considerations.
Separate chapters on ankylosing spondylitis and the reactive and enteropathic
arthropathies, once lumped together (with psoriatic arthritis) as seronegative
spondyloarthopathies.
vii
v ii i P R E F A C E
A tripling of the text devoted to psoriatic arthritis, an acknowledgement of the

substantial treatment advances in that disorder.
Individual chapters (and more than doubling of the text) to the metabolic and
inflammatory myopathies, once included in the same chapter.
Reorganization of the vasculitis section along more rational and all-inclusive
lines, with a chapter entitled ANCA-Associated Vasculitis that addresses
together Wegeners granulomatosis, microscopic polyangiitis, and the Churg-
Strauss syndrome, disorders with striking similarities but important contrasts.
Now entering its eighth decade, The Primer has rejected strongly the notion that
If it aint broke, dont fix it. In view of the recent remarkable strides in under-
standing and treating rheumatic disease, students, trainees, and practicing clini-
cians all need a standard textbook that can change with the times and reflect
these advances. The Primer continues to fill that need. Read, learn, and enjoy.
John H. Klippel, MD
John H. Stone, MD, MPH
Patience H. White, MD, MA
CONTENTS
Foreword by Michael E. Weinblatt . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
1. Public Health and Arthritis: A Growing Imperative . . . . . . . . 1

Patience H. White and Rowland W. Chang
2. Evaluation of the Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
A. History and Physical Examination . . . . . . . . . . . . . . . . . . . 6

David B. Robinson and Hani S. El-Gabalawy
B. Laboratory Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Kerstin Morehead
C. Arthrocentesis, Synovial Fluid Analysis,

and Synovial Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Kenneth H. Fye
D. Imaging of Rheumatologic Diseases . . . . . . . . . . . . . . . . . . 28

William W. Scott, Jr., William J. Didie,
and Laura M. Fayad
3. Musculoskeletal Signs and Symptoms . . . . . . . . . . . . . . . . . . . 42
A. Monarticular Joint Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 42

H. Ralph Schumacher and Lan X. Chen
B. Polyarticular Joint Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Sterling West
C. Neck and Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

David Borenstein
D. Regional Rheumatic Pain Syndromes . . . . . . . . . . . . . . . . 68

Joseph J. Biundo, Jr.
E. The Fibromyalgia Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 87

Dina Dadabhoy and Daniel J. Clauw
4. Molecular and Cellular Basis of Immunity

and Immunological Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Kevin Elias, Richard Siegel, and John J. OShea
5. Genetics and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

James Kelley and Robert P. Kimberly
6. Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
A. Clinical and Laboratory Manifestations . . . . . . . . . . . . . 114

Christopher V. Tehlirian and Joan M. Bathon
ix
x CONTENTS
B. Epidemiology, Pathology, and Pathogenesis . . . . . . . . . . 122

Jean-Marc Waldburger and Gary S. Firestein
C. Treatment and Assessment . . . . . . . . . . . . . . . . . . . . . . . . 133

Alyce M. Oliver and E. William St. Clair
7. Juvenile Idiopathic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
A. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Daniel J. Lovell
B. Pathology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . 149

Patricia Woo

Philip J. Hashkes and Ronald M. Laxer
D. Special Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Carol B. Lindsley
8. Psoriatic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
A. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

Dafna D. Gladman
B. Pathology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 178

Christopher Ritchlin

Philip J. Mease
9. Ankylosing Spondylitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
A. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Dsire Van der Heijde

Juergen Braun

John C. Davis, Jr.
10. Reactive and Enteropathic Arthritis . . . . . . . . . . . . . . . . . . . . 217

Robert D. Inman
11. Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
A. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

Paul Dieppe

Francis Berenbaum
C. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Leena Sharma
12. Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

N. Lawrence Edwards
CONTENTS xi
B. Epidemiology, Pathology, and

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Hyon K. Choi
C. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Robert A. Terkeltaub
13. Calcium Pyrophosphate Dihydrate,

Hydroxyapatite, and Miscellaneous Crystals . . . . . . . . . . . . 263
Geraldine McCarthy
14. Infectious Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
A. Septic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

George Ho, Jr.
B. Viral Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

Leonard H. Calabrese
C. Lyme Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

Linda K. Bockenstedt
D. Mycobacterial, Fungal, and Parasitic

Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
Steven R. Ytterberg
E. Rheumatic Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

Stanford Shulman and Preeti Jaggi
15. Systemic Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . 303
A. Clinical and Laboratory Features . . . . . . . . . . . . . . . . . . . 303

Jill P. Buyon
B. Epidemiology, Pathology, and

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
David S. Pisetsky

Susan Manzi and Amy H. Kao
16. Antiphospholipid Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 339

Michelle Petri
17. Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

Maureen D. Mayes
B. Epidemiology, Pathology, and Pathogenesis . . . . . . . . 351

John Varga

Maya H. Buch and James R. Seibold
18. Idiopathic Inflammatory Myopathies . . . . . . . . . . . . . . . . . . 363

Robert L. Wortmann
x ii CONTENTS

Lisa G. Rider and Frederick W. Miller

Chester V. Oddis
19. Metabolic Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381

Alan N. Baer
20. Sjgrens Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

Troy Daniels
21. Vasculitides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
A. Giant Cell Arteritis, Polymyalgia Rheumatica,

and Takayasus Arteritis . . . . . . . . . . . . . . . . . . . . . . . . . . 398
Cornelia M. Weyand and Jrg J. Goronzy
B. Polyarteritis Nodosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410

Keith T. Rott
C. The Antineutrophil Cytoplasmic

AntibodyAssociated Vasculitides: Wegeners
Granulomatosis, Microscopic Polyangiitis, and
the ChurgStrauss Syndrome . . . . . . . . . . . . . . . . . . . . . . 416
John H. Stone
D. Immune ComplexMediated Vasculitis . . . . . . . . . . . . . 427

Philip Seo
E. Miscellaneous Vasculitis (Behets Disease, Primary

Angiitis of the Central Nervous System, Cogans
Syndrome, and Erythema Elevatum Diutinum) . . . . . . 435
Kenneth T. Calamia and Carlo Salvarani
F. Kawasakis Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444

Barry L. Myones
22. Relapsing Polychondritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451

Harvinder S. Luthra
23. Adult-Onset Stills Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455

John M. Esdaile
24. Periodic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460

John G. Ryan and Daniel L. Kastner
25. Less Common Arthropathies . . . . . . . . . . . . . . . . . . . . . . . . . . 470
A. Hematologic and Malignant Disorders . . . . . . . . . . . . . 470

Adel G. Fam
B. Rheumatic Disease and Endocrinopathies . . . . . . . . . . 479

Peter A. Merkel
C. Hyperlipoproteinemia and Arthritis . . . . . . . . . . . . . . . . 484

Robert F. Spiera
C O N T E N T S xi i i
D. Neuropathic Arthropathy . . . . . . . . . . . . . . . . . . . . . . . . . 488

Ann K. Rosenthal
E. Dermatologic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

Jeffrey P. Callen
F. Hypertrophic Osteoarthropathy . . . . . . . . . . . . . . . . . . . . 504

Manuel Martinez-Lavin
26. Complex Regional Pain Syndrome . . . . . . . . . . . . . . . . . . . . . 509

Geoffrey Littlejohn
27. Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514

Edward S. Chen
28. Storage and Deposition Diseases . . . . . . . . . . . . . . . . . . . . . . 523

Duncan A. Gordon
29. The Amyloidoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533

Pasha Sarraf and Jonathan Kay
30. Neoplasms of the Joint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543

Andrew J. Cooper, James D. Reeves, and Sean P. Scully
31. Heritable Disorders of Connective Tissue . . . . . . . . . . . . . . . 549

Reed Edwin Pyeritz
32. Bone and Joint Dysplasias . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559

William A. Horton
33. Osteonecrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565

Thorsten M. Seyler, David Marker, and Michael A. Mont
34. Pagets Disease of Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573

Roy D. Altman
35. Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576
A. Epidemiology and Clinical Assessment . . . . . . . . . . . . . 576

Kenneth G. Saag
B. Pathology and Pathophysiology . . . . . . . . . . . . . . . . . . . 584

Philip Sambrook
C. Treatment of Postmenopausal Osteoporosis . . . . . . . . 592

Nelson B. Watts
36. Rehabilitation of Patients with Rheumatic

Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
Thomas D. Beardmore
37. Psychosocial Factors in Arthritis . . . . . . . . . . . . . . . . . . . . . . . 609

Alex Zautra and Denise Kruszewski
38. Self-Management Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . 614

Teresa J. Brady
39. Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620

John B. Winfield
x iv C O N T E N T S
40. Therapeutic Injections of Joints and Soft Tissues . . . . . . . 628

Juan J. Canoso
41. Nonsteroidal Anti-Inflammatory Drugs . . . . . . . . . . . . . . . . 634

Leslie J. Crofford
42. Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644

Frank Buttgereit and Gerd-Rdiger Burmester
43. Operative Treatment of Arthritis . . . . . . . . . . . . . . . . . . . . . . 651

Joseph A. Buckwalter and W. Timothy Ballard
44. Complementary and Alternative Therapies . . . . . . . . . . . . 664

Erin L. Arnold and William J. Arnold
Appendix I. Criteria for the Classification and Diagnosis

of the Rheumatic Diseases . . . . . . . . . . . . . . . . . . . . 669
Appendix II. Guidelines for the Management of

Rheumatic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . 683
Appendix III. Supplement and Vitamin and

Mineral Guide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
CONTRIBUTORS
Roy D. Altman, MD Teresa J. Brady, PhD

Professor, Deparment of Medicine/Rheumatology and Senior Behavioral Scientist, Arthritis Program, Centers for
Immunology, University of California, Los Angeles, Los Disease Control and Prevention, Atlanta, GA, USA
Angeles, CA, USA
Juergen Braun, MD
Erin L. Arnold, MD Professor, Department of Rheumatology, Rheumazentrum
Partner/Rheumatologist, Illinois Bone and Joint Institute, Ruhrgebiet, Herne, Germany
The Center for Arthritis and Osteoporosis, Morton Grove,
IL, USA Maya H. Buch, MBchB, MRCP
Clinical Lecturer and Research Fellow, University of Michigan
William J. Arnold, MD Scleroderma Program, University of Michigan Health System,
Partner/Rheumatologist, Illinois Bone and Joint Institute, Ann Arbor, MI, USA; Academic Unit of Musculoskeletal
The Center for Arthritis and Osteoporosis, Morton Grove, Disease, University of Leeds, UK
IL, USA
Joseph A. Buckwalter, MS, MD
Alan N. Baer, MD Professor and Head, Orthopedic Surgery, Department of
Associate Professor, Department of Medicine, Chief, Section Orthopaedics and Rehabilitation, University of Iowa, Iowa
of Rheumatology, University at Buffalo, State University of City, IA, USA
New York, Buffalo, NY, USA
Gerd-Rdiger Burmester, MD
W. Timothy Ballard, MD Professor, Department of Rheumatology and Clinical
Director, Joint Replacement Center, Department of Immunology, Charit University Hospital, Berlin,
Orthopaedics, Memorial Hospital, Chattanooga, TN, USA Germany
Joan M. Bathon, MD
Frank Buttgereit, MD
Professor, Department of Medicine, Director, Johns Hopkins
Professor, Department of Rheumatology and Clinical
Arthritis Center, Johns Hopkins University School of
Immunology, Charit University Hospital, Berlin,
Medicine, Baltimore, MD, USA
Germany
Thomas D. Beardmore, MD, FACP, FACR
Chief, Department of Rheumatology, Rancho Los Amigos Jill P. Buyon, MD
National Rehabilitation Center, Downey, CA; Professor, Professor, Department of Medicine, Division of Rheumato-
Department of Medicine, Keck School of Medicine, The logy, New York University School of Medicine, New York,
University of Southern California, Los Angeles, CA, USA NY; Director, Lupus Clinic, New York University Hospital
for Joint Diseases, New York, NY, USA
Francis Berenbaum, MD, PhD
Professor, Department of Rheumatology, Saint-Antoine Leonard H. Calabrese, DO
Hospital; University Pierre & Marie Curie, Paris, France Professor, Department of Rheumatic and Immunologic
Diseases, Cleveland Clinic Lerner College of Medicine of
Joseph J. Biundo, Jr., MD Case Western Reserve University, Cleveland Clinic
Clinical Professor, Department of Medicine, Tulane Foundation, Cleveland, OH, USA
University School of Medicine, Kenner, LA, USA
Kenneth T. Calamia, MD
Linda K. Bockenstedt, MD Associate Professor, Department of Medicine, Division
Professor, Department of Internal Medicine, Yale University of Rheumatology, Mayo Clinic College of Medicine,
School of Medicine, New Haven, CT, USA Jacksonville, FL, USA
David Borenstein, MD Jeffrey P. Callen, MD

Clinical Professor of Medicine, The George Washington Professor, Department of Medicine (Dermatology); Chief,
University Medical Center; Arthritis and Rheumatism Division of Dermatology, University of Louisville School of
Associates, Washington, DC, USA Medicine, Louisville, KY, USA
xv
xvi CONTRIBUTORS
Juan J. Canoso, MD, FACP, MACR N. Lawrence Edwards, MD

Attending, American British Cowdray Medical Center, Professor and Vice Chairman, Department of Medicine,
Mexico City, Mexico University of Florida, Gainesville, FL, USA
Rowland W. Chang, MD, MPH Hani S. El-Gabalawy, MD, FRCPC

Professor of Preventive Medicine, Medicine, and Physical Professor, Department of Medicine, Arthritis Centre, Univer-
Medicine and Rehabilitation; Director, Program in Public sity of Manitoba, Winnipeg, Manitoba, Canada
Health, Northwestern University, Feinberg School of
Medicine, Chicago, IL, USA Kevin Elias, MD
Howard Hughes Medical Institute-National Institute of
Edward S. Chen, MD Health Research Scholar, Lymphocyte Cell Biology Section,
Assistant Professor, Department of Medicine, Division of National Institute of Arthritis, Musculoskeletal, and Skin
Pulmonary and Critical Care Medicine, Johns Hopkins Diseases, Bethesda, MD, USA
University School of Medicine, Baltimore, MD, USA
John M. Esdaile, MD, MPH
Lan X. Chen, MD, PhD
Scientific Director, Arthritis Research Centre of Canada;
Clinical Assistant Professor, Department of Medicine/
Professor, University of British Columbia, Vancouver, British
Rheumatology, University of Pennsylvania, Philadelphia, PA,
Columbia, Canada
USA
Hyon K. Choi, MD, MPH, DrPH, FRCPC Adel G. Fam, MD, FRCP(C), FACP
Associate Professor of Medicine and Mary Pack Arthritis Emeritus Professor of Medicine, Department of Medicine,
Society Chair in Rheumatology, Department of Medicine, Division of Rheumatology, Sunnybrook & Womens College
Division of Rheumatology, The University of British Health Sciences Centre, University of Toronto, Toronto,
Columbia, Vancouver, British Columbia, Canada Ontario, Canada
Daniel J. Clauw, MD Laura M. Fayad, MD

Professor, Department of Internal Medicine, Division of Assistant Professor, The Russell H. Morgan Department
Rheumatology, University of Michigan, Ann Arbor, MI, of Radiology and Radiological Science, Johns Hopkins
USA University School of Medicine, Baltimore, MD, USA
Andrew J. Cooper, MD Gary S. Firestein, MD

Resident, Department of Orthopaedic Surgery, University of Professor, Department of Medicine, Chief, Division of
Miami, Miami, FL, USA Rheumatology, Allergy and Immunology, University of
California San Diego, School of Medicine, La Jolla, CA, USA
Gloria W. Singletary Professor of Internal Medicine, Chief, Kenneth H. Fye, MD
Division of Rheumatology & Womens Health, University of Clinical Professor, Department of Medicine, University of
Kentucky, Lexington, KY, USA California, San Francisco, San Francisco, CA, USA
Dina Dadabhoy, MD
Dafna D. Gladman, MD, FRCPC
Clinical Lecturer, Department of Internal Medicine, Division
Professor, Department of Medicine/Rheumatology, University
of Rheumatology, University of Michigan, Ann Arbor, MI,
of Toronto; Senior Scientist, Toronto Western Research
USA
Institute; Director, Psoriatic Arthritis Program, University
Health Network, Toronto, Canada
Troy Daniels, DDS, MS
Professor, Schools of Dentistry and Medicine, University of
California, San Francisco, San Francisco, CA, USA Duncan A. Gordon, MD, FRCPC, MACR
Professor, Department of Medicine, University of Toronto;
John C. Davis, Jr., MD, MPH Rheumatologist, University Health Network, Toronto
Associate Professor, Department of Medicine, Division of Western Hospital, Toronto, Ontario, Canada
Rheumatology, University of California San Francisco, San
Francisco, CA, USA Jrg J. Goronzy, MD
Co-Director, Department of Medicine, Kathleen B. and
William J. Didie, MD Mason I. Lowance Center for Human Immunology, Emory
Fellow, Musculoskeletal Imaging, Department of Radiology, University School of Medicine, Atlanta, GA, USA
Johns Hopkins University, Baltimore, MD, USA
Philip J. Hashkes, MD, MSc
Paul Dieppe, MD Head, Section of Pediatric Rheumatology, Department of
Professor, Department of Social Medicine, University of Rheumatic Diseases, Cleveland Clinic Foundation, Cleveland,
Bristol, Bristol, UK OH, USA
C O N T R I B U T O R S x vi i
George Ho, Jr., MD Carol B. Lindsley, MD

Professor, Department of Internal Medicine, Division of Professor, Department of Pediatrics, Director of Pediatric
Rheumatology, Brody School of Medicine at East Carolina Rheumatology, University of Kansas Medical Center, Kansas
University, Greenville, NC, USA City, KS, USA
William A. Horton, MD Geoffrey Littlejohn, MD, MPH, MBBS[Hon], FRACP,

Director, Research Center/Molecular and Medical Genetics, FRCP(Edin)
Shriners Hospital for Children; Professor, Oregon Health and Director of Rheumatology and Associate Professor of
Science University, Portland, OR, USA Medicine, Department of Medicine, Monash University at
Monash Medical Centre, Melbourne, Australia
Robert D. Inman, MD
Professor, Department of Medicine, Division of Rheuma- Daniel J. Lovell, MD, MPH
tology, University of Toronto, Toronto Western Hospital, Joseph Levinson Professor of Pediatrics, Division of
Toronto, Ontario, Canada Rheumatology, Cincinnati Childrens Hospital Medical
Center, Cincinnati, OH, USA
Preeti Jaggi, MD
Assistant Professor, Department of Infectious Diseases, Harvinder S. Luthra, MD
Department of Pediatrics, Ohio State University, Columbus, John Finn Professor of Medicine, Department of
OH, USA Rheumatology, Mayo Clinic College of Medicine, Rochester,
MN, USA
Amy H. Kao, MD, MPH
Assistant Professor, Department of Medicine, Division of Susan Manzi, MD, MPH
Rheumatology and Clinical Immunology, University of Associate Professor, Department of Medicine, Division of
Pittsburgh School of Medicine, Pittsburgh, PA, USA Rheumatology and Clinical Immunology, University of
Pittsburgh School of Medicine, University of Pittsburgh
Daniel L. Kastner, MD, PhD Graduate School of Public Health, Pittsburgh, PA, USA
Chief, Genetics and Genomics Branch; Clinical Director and
Director of Translational Research, National Institute of David Marker, BS
Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Medical Student, Rubin Institute for Advanced Orthopedics,
MD, USA Sinai Hospital of Baltimore, Baltimore, MD, USA
Jonathan Kay, MD Manuel Martinez-Lavin, MD

Associate Clinical Professor, Department of Medicine, Chief, Department of Rheumatology, National Institute of
Harvard Medical School; Director of Clinical Trials, Cardiology, Mexico, DF, Mexico
Rheumatology Unit, Massachusetts General Hospital, Boston,
MA, USA Maureen D. Mayes, MD, MPH
Professor, Department of Internal Medicine, Division of
James Kelley, PhD Rheumatology and Immunogenetics, University of Texas-
Postdoctoral Fellow, Department of Medicine, Division of Houston Medical School, Houston, TX, USA
Clinical Immunology and Rheumatology, University of
Alabama at Birmingham, Birmingham, AL, USA Geraldine McCarthy, MD, FRCPI
Associate Professor/Consultant Rheumatologist, Division of
Robert P. Kimberly, MD Rheumatology, Department of Medicine, University College
Howard L. Holley Professor of Medicine and Director, Divi- Dublin, Dublin/Mater Misericordiae University Hospital,
sion of Clinical Immunology and Rheumatology, Senior Asso- Dublin, Ireland
ciate Dean for Research, Department of Medicine, University
of Alabama at Birmingham, Birmingham, AL, USA Philip J. Mease, MD
Head, Seattle Rheumatology Associates; Chief, Division of
John H. Klippel, MD Rheumatology Research, Swedish Medical Center; Clinical
President and CEO, Arthritis Foundation, Atlanta, GA, Professor, University of Washington School of Medicine,
USA Seattle, WA, USA
Denise Kruszewski, MS Peter A. Merkel, MD, MPH

Graduate Student/Research Assistant, Department of Associate Professor, Department of Medicine, Section of
Psychology, Arizona State University, Tempe, AZ, USA Rheumatology, Boston University School of Medicine,
Boston, MA, USA
Ronald M. Laxer, MD, FRCPC
Vice President, Education and Quality, The Hospital for Frederick W. Miller, MD, PhD
Sick Children; Professor, Department of Pediatrics and Chief, Environmental Autoimmunity Group, Office of
Medicine, The University of Toronto, Toronto, Ontario, Clinical Research, National Institute of Environmental Health
Canada Sciences, National Institutes of Health, Bethesda, MD, USA
x v ii i C O N T R I B U T O R S
Michael A. Mont, MD Ann K. Rosenthal, MD

Director, Rubin Institute for Advanced Orthopedics, Sinai Professor, Department of Medicine, Division of Rheumato-
Hospital of Baltimore, Baltimore, MD, USA logy, Medical College of Wisconsin/Zablocki VA Medical
Center, Milwaukee, WI, USA
Kerstin Morehead, MD
Assistant Clinical Professor, Department of Medicine, Keith T. Rott, MD, PhD
Division of Rheumatology, University of California, San Assistant Professor, Department of Medicine, Division of
Francisco, San Francisco, CA, USA Rheumatology, Emory University School of Medicine,
Atlanta, GA, USA
Barry L. Myones, MD
Associate Professor, Pediatric Rheumatology Center, Baylor John G. Ryan, MB, MRCPI
College of Medicine/Texas Childrens Hospital, Houston, TX, Clinical Fellow, Genetics and Genomics Branch, National
USA Institute of Arthritis and Musculoskeletal and Skin Diseases,
National Institutes of Health, Bethesda, MD, USA
Chester V. Oddis, MD
Professor, Department of Medicine, Division of Rheumato- Kenneth G. Saag, MD, MSc
logy and Clinical Immunology, University of Pittsburgh School Associate Professor, Director, Center for Education and Re-
of Medicine, Pittsburgh, PA, USA search on Therapeutics of Musculoskeletal Disorders, Division
of Clinical Immunology and Rheumatology, University of
Alyce M. Oliver, MD, PhD Alabama at Birmingham, Birmingham, AL, USA
Fellow in Rheumatology, Department of Medicine, Division
of Rheumatology and Immunology, Duke University Medical Carlo Salvarani, MD
Center, Durham, NC, USA Director, Division of Rheumatology, Hospital S. Maria
Nuova, Reggio Emilia, Italy
John J. OShea, MD
Scientific Director, National Institute of Arthritis and Muscu- Philip Sambrook, MD, FRACP
loskeletal and Skin Diseases; Chief, Molecular Immunology Professor, Department of Rheumatology, University of
and Inflammation Branch; Chief, Lymphocyte Cell Biology Sydney, Sydney, NSW Australia
Section, National Institutes of Health, Bethesda, MD, USA
Pasha Sarraf, MD, PhD
Michelle Petri, MD, MPH Fellow, Department of Medicine, Division of Rheumatology,
Professor, Department of Medicine, Johns Hopkins University Allergy and Immunology, Massachusetts General Hospital,
School of Medicine, Baltimore, MD, USA Boston, MA, USA
David S. Pisetsky, MD, PhD H. Ralph Schumacher, MD

Chief, Department of Medicine, Division of Rheumatology Professor, Department of Medicine/Rheumatology, Univer-
and Immunology, Duke University School of Medicine, sity of Pennsylvania; VA Medical Center, Philadelphia, PA,
Durham, NC, USA USA
Reed Edwin Pyeritz, MD, PhD William W. Scott, Jr., MD

Professor, Department of Medicine and Genetics, Hospital of Associate Professor, The Russell H. Morgan Department
the University of Pennsylvania, Philadelphia, PA, USA of Radiology and Radiological Science, Johns Hopkins
University School of Medicine, Baltimore, MD, USA
James D. Reeves, MD
Resident, Department of Orthopaedic Surgery, University of Sean P. Scully, MD, PhD
Miami, Miami, FL, USA Professor, Department of Orthopaedics, Miller School of
Medicine, University of Miami, Miami, FL, USA
Lisa G. Rider, MD
Deputy Chief, Environmental Autoimmunity Group, Office James R. Seibold, MD
of Clinical Research, National Institute of Environmental Professor, Department of Internal Medicine/Rheumatology,
Health Sciences, National Institutes of Health, Clinical Director, University of Michigan Scleroderma Program,
Research Center, Bethesda, MD, USA University of Michigan Health System, Ann Arbor, MI, USA
Christopher Ritchlin, MD Philip Seo, MD, MHS

Associate Professor, Department of Medicine, Division of Co-Director, Johns Hopkins Vasculitis Center, Division of
Allergy, Immunology and Rheumatology, University of Rheumatology, Johns Hopkins University School of Medi-
Rochester Medical Center, Rochester, NY, USA cine, Baltimore, MD, USA
David B. Robinson, MD, MSc, FRCPC Thorsten M. Seyler, MD

Associate Professor, Department of Medicine, Arthritis Center for Joint Preservation and Reconstruction, Rubin
Centre, University of Manitoba, Winnipeg, Manitoba, Institute for Advanced Orthopedics, Sinai Hospital of
Canada Baltimore, Baltimore, MD, USA
C O N T R I B U TO R S xi x
Leena Sharma, MD Jean-Marc Waldburger, MD, PhD

Professor, Department of Internal Medicine, Division of Post-Doctoral Scholar, Department of Medicine, Division
Rheumatology, Feinberg School of Medicine at Northwestern of Rheumatology, Allergy, and Immunology, University of
University, Chicago, IL, USA California San Diego School of Medicine, La Jolla, CA,
USA
Stanford Shulman, MD
Chief, Department of Infectious Diseases; Professor, Nelson B. Watts, MD
Department of Pediatrics, Northwestern University Feinberg Professor, Department of Internal Medicine, University of
School of Medicine/The Childrens Memorial Hospital, Cincinnati College of Medicine, Cincinnati, OH, USA
Chicago, IL, USA
Sterling West, MD
Richard Siegel, MD, PhD Professor, Department of Rheumatology, University of
Principal Investigator, Immunoregulation Group, National Colorado Health Sciences Center, Denver, CO, USA
Institute of Arthritis and Musculoskeletal and Skin Diseases,
National Institutes of Health, Bethesda, MD, USA Cornelia M. Weyand, MD
Co-Director, Kathleen B. and Mason I. Lowance Center for
Robert F. Spiera, MD Human Immunology, Department of Medicine, Emory
Adjunct Clinical Instructor, Department of Medicine/ University School of Medicine, Atlanta, GA, USA
Rheumatology, Mount Sinai School of Medicine, New York,
NY, USA Patience H. White, MD, MA
Chief Public Health Officer, Arthritis Foundation, Atlanta,
E. William St. Clair, MD GA, USA
Professor, Department of Medicine, Division of Rheuma-
tology and Immunology, Duke University Medical Center, John B. Winfield, MD
Durham, NC, USA Smith Distinguished Professor of Medicine Emeritus,
Department of Medicine, University of North Carolina,
John H. Stone, MD, MPH Chapel Hill, NC, USA
Associate Physician, Massachusetts General Hospital; Deputy
Editor for Rheumatology, UpToDate, Boston, MA, USA Patricia Woo, BSc, MBBS, PhD, MRCP, FRCP, CBE
Professor, Department of Immunology and Molecular
Christopher V. Tehlirian, MD Pathology, University College London, London, UK
Post-Doctoral Fellow, Department of Medicine, Division of
Clinical and Molecular Rheumatology, Johns Hopkins Robert L. Wortmann, MD, FACP, FACR
University School of Medicine, Baltimore, MD, USA Professor and C. S. Lewis, Jr., MD Chair of Medicine,
Department of Internal Medicine, The University of
Robert A. Terkeltaub, MD Oklahoma College of Medicine, Tulsa, OK, USA
Chief, Rheumatology Section, Department of Medicine,
Veterans Affairs Medical Center San Diego; Professor, Steven R. Ytterberg, MD
Department of Medicine, University of California San Diego Associate Professor, Department of Medicine, Division of
School of Medicine, San Diego, CA, USA Rheumatology, Mayo Clinic College of Medicine, Rochester,
MN, USA
Dsire Van der Heijde, MD, PhD
Professor, Department of Rheumatology, University Hospital Alex Zautra, PhD
Maastricht, The Netherlands Foundation Professor, Department of Psychology, Arizona
State University, Tempe, AZ, USA
John Varga, MD
Gallagher Professor of Medicine, Department of Medicine,
Division of Rheumatology, Northwestern University Feinberg
School of Medicine, Chicago, IL, USA
CHAPTER 1
Public Health and Arthritis:

A Growing Imperative
PATIENCE H. WHITE, MD, MA
ROWLAND W. CHANG, MD, MPH
Forty-six million people have doctor-diagnosed Public health focuses on the assessment and
arthritis and by 2030 it is projected to be 67 million, reduction of health burden in the population.
or 25% of the US population. Three types of prevention strategies can be applied
Arthritis is the number one cause of disability and costs to arthritis.
the United States an estimated 128 billion annually.
The Merriam-Webster Dictionary defines public health superior to the other. In fact, it is likely that arthritis
as the art and science dealing with the protection and patientphysician encounters will be more effective
improvement of community health by organized com- when arthritis public health efforts are successful and
munity effort and including preventive medicine and vice versa. It is this synergy for which both fields should
sanitary and social science. Until the mid-20th century, be striving.
the field of public health was primarily concerned
with the prevention and control of infectious diseases.
More recently, public health scientists and practitio-
ners have also been engaged in the prevention and RATIONALE FOR ARTHRITIS
control of chronic diseases. In the mid-19th century, PUBLIC HEALTH INITIATIVE
when the therapeutic armamentarium of physicians
was limited, the relationship between the fields of Arthritis and other rheumatic conditions are the lead-
public health and medicine was very close. Indeed, ing cause of disability in the United States (1), making
most public health professionals were physicians. it a major public health problem. Arthritis is one of the
However, as biomedical science led to more and more most common chronic diseases in the United States.
diagnostic and therapeutic strategies for physicians Forty-six million Americans, or one out of every five
in the 20th century, and as separate schools of adults, has doctor-diagnosed arthritis, and 300,000
medicine and public health were established in Ameri- children have arthritis (http://www.cdc.gov/arthritis/).
can universities, the fields have developed different Between 2003 and 2004, an estimated 19 million US
approaches to solving health problems. Medicine has adults reported arthritis-attributable activity limitation
been primarily concerned with the diagnosis and the and 8 million reported arthritis affected their work (2).
palliative and curative treatments of disease and the Arthritis is a large clinical burden, with 36 million
health of the individual patient. Public health has been ambulatory visits and 750,000 hospitalizations (3,4). In
primarily concerned with the prevention and control of 2030, due to the aging of the population and the
disease and the health of the population. The goal of growing epidemic of obesity, the prevalence of self-
this chapter is to illustrate the magnitude of the arthri- reported, doctor-diagnosed arthritis is projected to
tis public health problem in the United States and to increase to nearly 67 million (25% of the adult popula-
describe potential public health approaches to mitigate tion) and 25 million (9.3% of the adult population) will
this problem. In order to more clearly describe public report arthritis-attributable activity limitations (Table
health perspective, science, and intervention, contrasts 1-1) (5).
will be made with the medical approach, but this should In the future, this arthritis-related clinical and
not be interpreted to mean that one approach is health care system burden will require a planned
1
2 PATIENCE H. WHITE AND ROWLAND W. CHANG
TABLE 1-1. ESTIMATED US POPULATION AND PROJECTED PREVALENCE OF DOCTOR-DIAGNOSED ARTHRITIS AND
ACTIVITY LIMITATION FOR ADULTS AGES 18 AND OLDER IN THE UNITED STATES.
PROJECTED PREVALENCE OF PROJECTED PREVALENCE OF ARTHRITIS-
ESTIMATED US POPULATION DOCTOR-DIAGNOSED ARTHRITIS ATTRIBUTABLE ACTIVITY LIMITATIONS
YEAR IN THOUSANDS IN THOUSANDS IN THOUSANDS
2005 216,096 47,838 17,610
2015 238,154 55,725 20,601
2030 267,856 66,969 25,043
SOURCE: Hootman JM, Helmick CG, Arthritis Rheum 2006;54:226229, by permission of Arthritis and Rheumatism.
coordinated approach with increased need for more arthritis-related disability associated with the aging of
arthritis specialists, increased need for training of the US population. This is perhaps the most important
primary care providers in arthritis management, and reason to embrace an arthritis public health initiative:
increased availability of public health interventions to to have a greater impact on the health of the
improve quality of life through lifestyle changes and population.
disease self-management.
PUBLIC HEALTHS EMPHASIS ON

THE MEDICAL MODEL PREVENTION AND HOW IT
COMPARED WITH THE PUBLIC RELATES TO ARTHRITIS
HEALTH MODEL
Traditionally, public health has been concerned
There are several differences between medicine and with the prevention of disease and the prevention
public health, but perhaps the most important differ- of disease consequences (e.g., death and disability).
ence is that of perspective. Medicine focuses on the Three types of prevention have been described:
diagnosis and treatment of individuals, whereas public primary, secondary, and tertiary. Primary prevention
health focuses on the assessment and the reduction of is the prevention of the disease itself. In the infectious
health burden in the population. The diagnostic tools disease realm, this is made possible by the identifica-
of the physician includes history, physical examination, tion of the etiologic microorganism and the develop-
and a vast array of diagnostic tests including blood ment of a vaccine that will protect the host from
tests, imaging, and tissue sampling, all performed on developing the infection even when the host is exposed
the individual patient. Medical treatment includes to the microorganism. Primary prevention of a chronic
pharmaceuticals, surgery, and rehabilitation. The disease requires the identification of an etiologic factor
assessment tools of the public health professional associated with the disease and the successful inter-
include surveys and disease registries for defined popu- vention (lifestyle change and/or pharmacologic treat-
lations (local, state, and/or national). Public health ment) on the risk factor. For example, the reduction
intervention includes community health education of weight by dietary and physical activity intervention
and programs and advocacy for public policy reform. has been successful in the primary prevention of dia-
Medical research programs emphasize basic science, betes, and the pharmacologic treatment of hyperten-
drilling down to individual abnormalities at the sion has proven effective in the prevention of coronary
molecular and genomic level, whereas public health artery disease. An example of a primary arthritis
research programs emphasize epidemiology and the prevention trial showed that a vaccine for the spiro-
social sciences, searching out risk factors that pertain chete associated with Lyme disease reduced the risk
to a large proportion of the population. While medical for this disease in endemic areas (6). While several
science has undeniably improved the individual treat- etiologic factors associated with knee osteoarthritis
ment of some forms of arthritis (e.g., rheumatoid (most notably obesity) have been identified, no trials
arthritis), still much more needs to be done to deal have been performed to inform public health practice
with the coming increases in arthritis prevalence and regarding the primary prevention of this condition,
CHAPTER 1 PUBLIC HEALTH AND ARTHRITIS: A GROWING IMPERATIVE 3
although data will hopefully be available in the coming TABLE 1-2. THE NATIONAL ARTHRITIS ACTION
years. PLAN.
Secondary prevention involves the detection of
The overarching aims of the NAAP are:
1
disease in its preclinical (i.e., asymptomatic) phase to Increase public awareness of arthritis as the leading cause of
allow for early treatment and the prevention of impor- disability and an important public health problem.
tant consequences, such as death or disability. For Prevent arthritis whenever possible.
example, mammography has been shown to prevent Promote early diagnosis and appropriate management for
people with arthritis to ensure the maximum number of
breast cancerrelated death by detecting breast cancer
years of healthy life.
before clinical signs and symptoms develop such that Minimize preventable pain and disability due to arthritis.
early treatment can be initiated. Similarly, screening Support people with arthritis in developing and accessing the
for osteoporosis with dual-energy x-ray absorptiometry resources they need to cope with their disease.
(DXA) scanning has been shown to reduce fracture Ensure that people with arthritis receive the family, peer, and
community support they need.
rates and subsequent disability by allowing for early
detection and treatment of this common condition. The aims of the NAAP will be achieved through three major
Secondary prevention of rheumatoid arthritis is likely types of activities:
to be successful because of effective medical treatment Surveillance, epidemiology, and prevention research
Communication and education
that limits joint destruction and arthritis-related dis-
Programs, policies, and systems
ability. Studies have shown that the earlier the treat-
ment, the less the ultimate destruction and disability.
The challenge here is to identify a suitable screening
test.
Tertiary prevention involves the treatment of clinical
disease in order to prevent important consequences,
such as death or disability. Thus, tertiary prevention is
typically in the realm of medicine. However, public
health and public policy efforts to make medical, surgi-
National Arthritis Action Plan
cal, and rehabilitation treatment more effective and The National Arthritis Action Plan (NAAP) brought
more accessible are common public health tertiary pre- together over 40 partners to create a blueprint for popu-
vention interventions. lation-oriented efforts to combat arthritis. The NAAP
emphasizes four public health values: prevention, the
use and expansion of the science base, social equity, and
building partnerships. The NAAP is now widely utilized
ARTHRITIS PUBLIC HEALTH by other public health and professional organizations
as a model program for population-oriented efforts to
ACCOMPLISHMENTS combat a chronic disease (see Table 1-2 for the aims and
activities of NAAP). In 2000, the federal government
The Arthritis Foundation has focused its public health
funded the Arthritis Program at the Centers for Disease
activities by promoting the health of people with and at
Control (CDC) that provides the infrastructure for the
risk for arthritis through its leadership and involvement
program at the CDC, implementation of the arthritis
in the National Arthritis Act, the National Arthritis
public health plan through the establishment of
Action Plan, the arthritis section of Healthy People
arthritis programs in state health departments (see
2010, and the National Committee on Quality Assur-
http://www.cdc.gov/arthritis/), limited investigator-initi-
ance (NCQA) to develop an arthritis-related Health
ated grant program, and a peer-reviewed grant to the
Plan Employer Data and Information Set (HEDIS)
Arthritis Foundation. With this funding, the CDC
measure (2003).
Arthritis Program and the Arthritis Foundation have
created effective public education and awareness activi-
ties in both English and Spanish and have developed
evidence-based programs for people with arthritis,
National Arthritis Act including an arthritis-specific self-help course, an exer-
In 1974, the Arthritis Foundation joined in a partner- cise program, and a water exercise program (see the
ship that pushed the US Congress to pass the National Life Improvement Series descriptions at http://www.
Arthritis Act, which initiated an expanded response to arthritis.org).
arthritis through research, training, public education, The Arthritis Group at the Center for Disease
and treatment. The National Arthritis Act called for a Control have developed arthritis data collection
long-term strategy to address arthritis in the United plans through the Behavioral Risk Factor Surveillance
States. System (BRFSS), the National Health Interview Survey
4 PATIENCE H. WHITE AND ROWLAND W. CHANG
(NHIS), and the National Health and Nutrition Exami- evidence-based arthritis education as an integral
nation Survey (NHANES), and it has published an part of the management of their condition.
annual arthritis data report during Arthritis Month
in May.
Quality of Care Measures for
People with Arthritis
Healthy People 2010
The Arthritis Foundation Quality Indicators Project
Healthy People 2010 is the nations public health (AFQUIP) created indicators for treatment of rheuma-
plan that was created in consultation with the nations toid arthritis and osteoarthritis, and for analgesics and
health constituencies by the Department of Health pain use (7).
and Human Services. Healthy People 2010 has two These were used by the National Committee for
goals: (1) increase quality and years of life and (2) Quality Assurance (NCQA) to develop a HEDIS
eliminate health disparities. Healthy People 2010 con- measure for disease-modifying antirheumatic drugs
tains a separate chapter on Arthritis and Other Rheu- (http://www.ncqa.org). The osteoarthritis indicators
matic Conditions, including osteoporosis and back have been used by the American Medical Associa-
pain. The overall goal of this section of Healthy People tion (AMA) Physician Consortium for Performance
2010 is to prevent illness and disability related to Improvement.
arthritis and other rheumatic conditions, osteoporosis, Through a focus on public health goals, several
and chronic back conditions (www.healthypeople. organizations are cooperating and collaborating to
gov). lessen disability in the aging population, decrease
The general Healthy People 2010 arthritis objectives health disparities, and increase physical activity
are to: and reduce calorie intake in order to mitigate the
epidemic of obesity and its serious impacts on health.
Reduce the mean level of joint pain among adults The Arthritis Foundation and the CDC are actively
with doctor-diagnosed arthritis. forming partnerships with state public health depart-
Reduce the proportion of adults with doctor- ments, federal government agencies such as the
diagnosed arthritis who experience a limitation in National Institute of Arthritis and Musculoskeletal and
activity due to arthritis or joint symptoms. Skin Diseases at the National Institutes of Health, the
Reduce the proportion of adults with doctor- Agency for Orthopedic Surgery, community health
diagnosed arthritis who have difficulty in performing organizations, volunteer health organizations, other
two or more personal care activities, thereby preserv- volunteer organizations such as Research! America,
ing independence. and professional organizations such as the American
Increase health care provider counseling for persons College of Rheumatology and the American Academy
with doctor-diagnosed arthritis. of Healthcare Research and Quality to move this
Increase health care provider counseling about agenda forward.
weight loss among persons with doctor-diagnosed
arthritis.
Increase health care provider counseling for physical REFERENCES
activity or exercise for persons with doctor-diagnosed
arthritis. 1. Centers for Disease Control and Prevention. Prevalence of
Reduce the impact of doctor-diagnosed arthritis on disabilities and associated health conditions among adults:
employment. United States 1999. Morb Mortal Wkly Rep 2001;50:
Increase the employment rate among adults with 120125.
doctor-diagnosed arthritis in the working-aged 2. Centers for Disease Control and Prevention. Racial/ethnic
population. differences in the prevalence and impact of doctor diag-
Decrease the effect of doctor-diagnosed arthritis on nosed arthritis: United States, 2002. Morb Mortal Wkly
paid work. Rep 2005;54:119121.
3. Hootman JM, Helmick CG, Schappert SM. Magnitude and
Eliminate racial differences in the rate of total knee
characteristics of arthritis and other rheumatic conditions
replacements. on ambulatory medical visits, United States 1997. Arthritis
Increase the proportion of adults who have seen a Rheum 2002;47:571581.
health care provider for their chronic joint 4. Lethbridge-Cejku M, Helmick CG, Popovic JR. Hospital-
symptoms. izations for arthritis and other rheumatic conditions: data
Increase the proportion of persons with doctor- from the 1997 National Hospital Discharge Survey. Med
diagnosed arthritis who have had effective, Care 2003;41:13671373.
CHAPTER 1 PUBLIC HEALTH AND ARTHRITIS: A GROWING IMPERATIVE 5
5. Hootman JM, Helmick CG. Projections of US prevalence Disease Vaccine Study Group. N Engl J Med 1998;339:
of arthritis and associated activity limitations. Arthritis 209215.
Rheum 2006;54:226229. 7. MacLean CH, Saag KG, Solomon DH, Morton SC, Sampsel 1
6. Steere AC, Sikand VK, Meurice F, et al. Vaccination S, Klippel JH. Measuring quality in arthritis care: methods
against Lyme disease with recombinant Borrelia burg- for developing the Arthritis Foundations quality indicator
dorferi outer-surface lipoprotein A with adjuvant. Lyme set. Arthritis Rheum 2004;51:193202.
CHAPTER 2
Evaluation of the Patient

A. History and Physical Examination
DAVID B. ROBINSON, MD, MSC, FRCPC
HANI S. EL-GABALAWY, MD, FRCPC
The patient history and physical examination form The joint examination must include pattern, range of
the basis of diagnosis and monitoring the course of motion, signs of inflammation, stability, weakness,
rheumatic and musculoskeletal diseases. and deformity.
Attention is focused on signs and symptoms of both
joint and extra-articular features.
Musculoskeletal complaints are among the most Location and Symmetry

common problems in clinical medicine. It is therefore
important that all physicians are able to conduct The location of a musculoskeletal problem is often the
a basic screening evaluation that identifies the pres- most important clue in identifying the specific cause.
ence of pathology or dysfunction of musculoskeletal Musculoskeletal problems can broadly be categorized
structures. as regional or generalized, although there is often con-
siderable overlap between these two categories.
Regional syndromes typically affect a single joint or
RHEUMATOLOGICAL periarticular structure, or an entire extremity or body
region. A regional pain syndrome can be on a referred
HISTORY basis, and have little to do with the area where the pain
is experienced. Joints both immediately above and
A thoughtful and detailed history plays a critical role in below the painful area should be routinely examined for
determining the nature of the complaint and helps to pathology.
focus the clinical evaluation (1). The history should be Specific arthropathies have a predilection for involv-
structured to answer specific questions. ing specific joint areas (2). Involvement of the wrists and
the proximal small joints of the hands and feet is an
Questions for the Clinician important feature of rheumatoid arthritis (RA). In con-
trast, psoriatic arthritis (PsA) often involves the distal
to Address joints of the hands and feet. An acutely painful and
1. Is the problem regional or generalized, symmetric or swollen great toe is most likely caused by a gouty attack.
asymmetric, peripheral or central? An important aspect of the articular pattern of involve-
2. Is it an acute, subacute, or chronic problem? Is it ment is symmetry. Rheumatoid arthritis tends to involve
progressive? joint groups symmetrically, whereas the seronegative
3. Do the symptoms suggest inflammation or damage spondyloarthropathies and osteoarthritis (OA) tend to
to musculoskeletal structures? be asymmetrical in their articular patterns.
4. Is there evidence of a systemic process? Are there
associated extra-articular features?
5. Is there an underlying medical disorder which may
Onset and Chronology
predispose to a specific rheumatologic problem? The mode of onset and evolution of musculoskeletal
6. Has there been functional loss and disability? symptoms over time is very helpful in establishing a
7. Is there a family history of a similar or related diagnosis. For most chronic arthropathies such as RA,
problem? the onset is typically subacute, occurring over weeks to
6
CHAPTER 2 EVALUATION OF THE PATIENT 7
months rather than hours to days. Attacks of gout and important diagnostic clue. In addition, systemic rheu-
septic arthritis, on the other hand, have an acute onset, matic diseases are commonly associated with nonarticu-
reaching a crescendo within hours. The pain of fibromy- lar features that are of value in diagnosis. For example,
algia is often reported as being present for years with a history of recent genitourinary symptoms in associa-
episodic exacerbations. A temporally associated trau- tion with lower extremity asymmetric oligoarthritis is
matic event or history of repetitive use of a joint can be highly suggestive of reactive arthritis, whereas this same
a particularly good clue to diagnosing a regional mus- articular pattern in association with recurrent abdomi-
culoskeletal syndrome. nal pain and bloody diarrhea is more suggestive of the 2
arthropathy of inflammatory bowel disease. It is thus
important that the clinician perform a complete review
Inflammation and Weakness of systems and directly question the patient regarding
Articular pain and swelling can be on an inflammatory the presence of specific symptoms, such as rashes or skin
or non-inflammatory basis. When intra-articular inflam- changes, photosensitivity, Raynauds phenomenon,
mation is present, the process involves the synovial mouth ulcers, and dryness in the eyes and mouth.
membrane, and is termed synovitis. The swelling is
usually due to accumulation of fluid in the articular Functional Losses
cavity and/or infiltration and enlargement of the
synovium. Pain and swelling associated with the pres- Questioning regarding functional loss is essential for
ence of synovitis often occur at rest, whereas in degen- understanding the impact of a musculoskeletal disorder
erative disorders such as OA, these symptoms become and, in turn, developing a plan of management. The
more evident with joint use. In the presence of synovitis, questioning should span the spectrum of activities, from
the patient may also complain of difficulty moving the simple activities of daily living such as dressing and
joints after a period of immobility, a symptom referred grooming to more physically demanding activities such
to as stiffness. In inflammatory disorders such as RA, as sports. In some cases, the functional loss may be quite
this stiffness is most evident in the early morning. severe, impairing basic activities such as stair climbing
Indeed, the duration of morning stiffness, typically and gripping, while in others it may be quite subtle,
established by asking the patient, How long does it detectable only as a reduction in strenuous activities
take you before you are moving as well as you are going such as jogging.
to move for the day? is a semiquantitative measure of
the degree of articular inflammation. Family History
Complaints of limitation in joint motion, deformity,
and joint instability are usually caused by damage to A number of rheumatic diseases have a strong genetic
articular and periarticular structures. The patient should basis. Disorders such as ankylosing spondylitis are much
be carefully questioned to establish the circumstances more common in HLA-B27positive families than in
around which these symptoms were initiated, and the the general population. Questioning regarding family
types of movements that aggravate them. history should not be restricted only to ascertaining
Patients with musculoskeletal pathology often com- whether other family members have a similar arthritis,
plain of muscle weakness. This feeling of weakness may but should be as complete as possible regarding autoim-
be associated with pain, stiffness, and, in some cases, mune diseases, many of which (e.g., RA, thyroid disease,
parasthesia or other neurological symptoms. General- and diabetes) tend to cluster in families.
ized weakness may be in response to pain from articular
or periarticular inflammation, as in the case of RA and
polymyalgia rheumatica. Alternatively, weakness may PRINCIPLES OF
be caused by a primary neuropathic or myopathic RHEUMATOLOGICAL
process. In the case of myopathies, the weakness is typi-
cally symmetrical and involves proximal muscles most EXAMINATION
severely, whereas neuropathies more commonly affect
the distal musculature. Evaluation of musculoskeletal complaints involves
examination of the joints and their soft tissue support
structures, the bony skeleton, and the muscle groups that
Systemic and Extra-Articular move the skeletal structures (3). The joints, bones, and
muscles can be directly accessible to examination, as in
Features the extremities, or they may be inaccessible to direct
Constitutional symptoms of fatigue, weight loss, examination, as in the case of the spine and hip joints.
anorexia, and low grade fever can be associated with any All joint areas should be inspected from multiple
systemic inflammatory process, and their presence is an angles to assess for deformity (sometimes seen as loss
8 DAVID B. ROBINSON AND HANI S. EL-GABALAWY
of symmetry with the contralateral side), muscular A key part of the musculoskeletal evaluation involves
atrophy, swelling, erythema, or surgical scars. Extremity examination of the ligaments, tendons, menisci, and
joints should be palpated for warmth using the dorsum muscles. These structures may be the primary source of
of the hand. Superficial joints are normally slightly the pathology, or may be involved secondary to the
cooler than the surrounding soft tissue. The joint line articular pathology. Examination of individual muscle
and major bony and soft tissue structures should be groups requires a basic knowledge of the origin, inser-
palpated for tenderness. tion, and primary action of each muscle. Atrophy and
Functional joint motion should be tested both by weakness of the muscles surrounding a particular joint is
having the patient actively move the joint to its extremes an important indicator of chronic articular pathology.
and by having the examiner passively move the joint
through its range. Tenderness elicited by gentle stress A Screening Musculoskeletal
on the joint at its end range of motion (stress tender-
ness) is characteristic of joint pathology and may be
Exam
absent in pain syndromes such as fibromyalgia. Loss of The GALS (Gait, Arms, Leg, Spine) system has been
range of motion is seen both with acute articular inflam- devised to screen rapidly for musculoskeletal disease
mation and with chronic arthritis and damage. Joints (4). Initially, the patient is asked three basic questions:
should be assessed for the presence of swelling. The Have you any pain or stiffness in your muscles, joints,
cardinal signs of articular inflammation are warmth, or back?; Can you dress yourself completely without
joint line tenderness, pain on motion (particularly at the any difficulty?; Can you walk up and down stairs
extremes of the range of motion), and intra-articular without any difficulty?. Depending on the answers to
swelling or effusion. the questions, further questioning is undertaken to
Deformity caused by loss of alignment is a conse- explore specific areas.
quence of destructive arthropathies such as RA. The The examiner then systematically inspects the
damage is commonly associated with loosening of the patients gait, arms, legs, and spine, first with the patient
soft tissue support structures surrounding the joints. In standing still and then responding to instructions (Table
some cases, the joint may not exhibit any obvious defor- 2A-1). Abnormalities detected on this screening are fol-
mity, but may be unstable when put through its range lowed up with a more detailed regional or generalized
of motion or is mechanically stressed. musculoskeletal examination.
TABLE 2A-1. MAIN FEATURES OF THE GAIT, ARMS, LEG, SPINE (GALS) SCREENING INSPECTION.
POSITION/ACTIVITY NORMAL FINDINGS
Gait Symmetry, smoothness of movement; normal stride length; normal heel

strike, stance, toe-off, swing through; able to turn quickly
Inspection from behind Straight spine, normal symmetric paraspinal muscles, normal shoulder and
gluteal muscle bulk, level iliac crests, no popliteal cysts, no popliteal
swelling, no hindfoot swelling/deformity
Inspection from the side Normal cervical and lumbar lordosis, normal thoracic kyphosis
Touch your toes. Normal lumbar spine (and hip) flexion
Inspection from the front

Arms
Place your hands behind your head, elbows out. Normal glenohumeral, sternoclavicular, and acromioclavicular joint
movement
Place your hands by your side, elbows straight. Full elbow extension
Place your hands in front, palms down. No wrist/finger swelling or deformity, able to fully exend fingers
Turn your hands over. Normal supination/pronation, normal palms
Make a fist. Normal grip power
Place the tip of each finger on the tip of the thumb. Normal fine precision, pinch
Legs Normal quadriceps bulk/symmetry, no knee swelling or deformity, no
forefoot/midfoot deformity, normal arches, no abnormal callous
formation
Spine
Place your ear on your shoulder. Normal cervical lateral flexion
SOURCE: Modified from Doherty et al., Ann Rheum Dis 1992;51:11651169, with permission of Annals of Rheumatic Diseases.
EXAMINATION OF SPECIFIC and spread out the digits. Pincer function of the thumb
and fingers should be tested. The grip strength can be
JOINT AREAS estimated by having the patient squeeze two of the
examiners fingers. Individual hand joints should be pal-
The Hand and Wrist pated to determine the presence of joint line tenderness
and effusion, these being the most important indicators
A number of generalized arthropathies have distinctive of synovitis. The technique for palpating the DIP and
patterns of hand involvement, and the recognition of PIP joints is similar. The thumb and index finder of one 2
these patterns is highly valuable diagnostically. Exami- hand palpates in the vertical plane, while the thumb and
nation of the hands should be initiated with the patient index finder of the other hand palpates in the horizontal
sitting comfortably with the hands open and the palms plane (Figure 2A-1). Alternating gentle pressure
facing down. In this position, the examiner can inspect between the two planes will displace small amounts of
the alignment of the digits relative to the wrist and synovial fluid back and forth, allowing the examiner to
forearm. Atrophy of the intrinsic muscles of the hands detect effusions in these small joints. Likewise, tender-
can readily be appreciated as a hollowing out of the ness suggestive of synovitis can be elicited by this tech-
spaces between the metacarpals. The nails should be nique. The technique for palpating the MCP joints is
inspected for evidence of onycolysis or pitting sugges- somewhat modified because of the inability to directly
tive of psoriasis. Redness and telangiectasia of the nail palpate these joints from the horizontal plane. The
fold capillaries can by detected on close inspection, and thumbs are used to palpate the dorsolateral aspects of
is often indicative of a connective tissue disease such as the joint, while the index fingers palpate the palmar
systemic lupus erythematosus (SLE), scleroderma, or aspect.
dermatomyositis. Tightening of the skin around the Palpation of the wrist involves a similar technique to
digits, or sclerodactyly, is typical of scleroderma and is that used for the MCPs. The thumbs are used to palpate
usually both visible and palpable. The pulp of the digits the dorsum of the joint, while the index fingers palpate
should be examined for the presence of digital ulcers, the volar aspect (Figure 2A-2). Synovial thickening and
also seen most commonly in scleroderma. tenderness suggestive of wrist joint synovitis can usually
Articular swelling of the distal interphalangeal (DIP) be palpated on the dorsum of the joint. Particular atten-
and proximal interphalangeal (PIP) joints can represent tion should be paid to swelling and tenderness in the
bony osteophytes as in the case of Heberdens and area just distal to the ulnar styloid, where the extensor
Bouchards nodes in the DIP and PIP joints, respec- and flexor carpi ulnaris tendons are directly palpable.
tively, or can represent an intra-articular effusion This area is very commonly involved in early RA. Pain
associated with synovitis in the joint. Palpation will and tenderness confined to the radial aspect of the wrist
help in differentiating these. Swelling and redness of are most commonly due to either OA of the first carpo-
an entire digit, termed dactylitis, is highly suggestive of
a spondylarthropathy such as psoriatic arthritis or reac-
tive arthritis.
Swelling of the metacarpophalangeal (MCP) joints
can be visually appreciated as a fullness in the valleys
normally found between the knuckles (heads of the
metacarpal bones). In cases of RA where the MCP
synovitis has been longstanding, it is often associated
with ulnar subluxation of the extensor tendons, result-
ing in the ulnar drift of the digits that is typical of this
diagnosis. Swelling on the dorsum of the wrist area can
result from synovitis of the wrist or tenosynovitis of the
extensor tendons. Getting the patients to gently wiggle
the fingers helps differentiate these two findings in that
the swelling will tend to move with the tendons if it is a
result of tenosynovitis. Inspection of the palmar aspect
of the hands is important for identifying atrophy of the
thenar or hypothenar eminences, which can result either
from disuse due to articular involvement of the wrist FIGURE 2A-1
or, in the case of the thenar eminence, carpal tunnel
Technique for examining the small joints of the hands and feet.
syndrome. The thumb and index finger of the examiners hands are used
Global function of the hand should be evaluated by to gently ballot small amounts of intra-articular fluid back and
asking the patient to make a full fist and to fully extend forth to elicit evidence of joint line tenderness.
tis. With this maneuver, the bulge in the lateral recess

will tend to enlarge, becoming more tense due the
reduction in the internal dimension of the elbow in the
position of extension.
The synovial cavity and joint line can best be pal-
pated for swelling and tenderness in the area of the
lateral recess. This is also the site where arthrocentensis
of the elbow is performed. It should be noted that pain
in the lateral aspect of the elbow area is a common clini-
cal problem, and is usually due to lateral epicondylitis
or tennis elbow rather than elbow joint pathology. Ten-
derness directly palpable over the lateral epicondyle
and with stressing the wrist and finger extensors is sug-
gestive of this diagnosis.
FIGURE 2A-2 The Shoulder

The dorsum of the wrist joint is palpated for tenderness and Proper examination of the shoulder should always begin
swelling using the examiners thumbs. The wrist should be with appropriate visualization of the entire shoulder
examined in slight flexion to allow the joint line of the radiocar- girdle area, both from the front and the back. This
pal, intercarpal, and carpometacarpal joints to be optimally includes the sternoclavicular, glenohumeral, and acro-
palpated.
mioclavicular joints as well as the scapulothoracic
articulation. Comparison should be made with the con-
tralateral shoulder. Any asymmetry between the two
metacarpal joint, or to DeQuervains tenosynovitis. All sides should be noted. For example, patients with rotator
the joints of the hand and wrist should be evaluated for cuff tears often hold the affected shoulder higher than
stress tenderness. the other side. Atrophy of the shoulder girdle muscula-
ture is an important sign of chronic glenohumeral joint
pathology, as occurs in RA. This is most evident as
The Elbow squaring of the shoulder due to deltoid atrophy and
Flexion and extension of the forearm occur exclusively scooping out of the upper scapular area due to super-
at the elbow joint and involve the hinge type of articula- spinatus atrophy. Effusions in the shoulder joint are
tion between the proximal ulna and distal humerus. In visible anteriorly just medial to the area of the bicipital
examining the elbow, a number of surface landmarks groove, and if large enough are also evident laterally
need to be identified. These are the olecranon process, below the acromion. It should be noted that large
the medial and lateral epicondyles of the humerus, and amounts of fluid can accumulate in the glenohumeral
the radial head. A triangular recess is formed in the joint space without much visible evidence due to con-
lateral aspect of the joint between the olecranon process, siderable redundancy in the joint capsule.
the lateral epicondyle, and the radial head. This recess After inspecting the shoulder area in the resting posi-
is the point where the synovial cavity of the elbow is tion, the patient is asked to demonstrate the active
most accessible to inspection and palpation. range of motion of the shoulder. Abduction is observed
Examination of the elbow should be undertaken with as the patient moves both outstretched arms from their
the patient sitting comfortably and the entire arm being side in the lateral plane until the palms meet overhead.
well supported in order to eliminate muscle tension. The movement is evaluated for discomfort, symmetry,
Initially the joint should be inspected with forearm and fluid scapulohumeral coordination. Patients with
flexed to 90. Particular attention should be paid to the shoulder pathology will usually move the arm forward
lateral recess described above. Obvious bulging in this somewhat in order to complete the maneuver. External
area is highly suggestive of an effusion and synovitis. In rotation can then be tested by having the patient attempt
contrast, swelling directly over the olecranon process to touch the back of their head with the palm of the
is more suggestive of olecranon bursitis. Any process hand from the fully abducted position. If abduction is
that causes true synovitis of the elbow is typically associ- abnormal, active flexion should be tested by having the
ated with a reduction in the range of motion of the joint, patient lift the outstretched arm from their side directly
both in flexionextension and in supinationpronation. up in front of them. Active internal rotation and exten-
Having the patient extend the forearm as much as pos- sion is observed by having the patient reach behind
sible will detect the presence of a flexion contracture, their back and attempt to have their fingertips touch the
this being an almost invariant feature of elbow synovi- highest point possible on their scapula.
Palpation should include the entire shoulder girdle shoulder. The predictive value of these maneuvers is
area. The sternoclavicular joint is palpated, then the modest (5). Forced supination of the hand with the
fingers are walked laterally over the clavicle to the acro- elbow flexed at 90 will cause pain in the area of the
mioclavicular joint, which is palpated for tenderness and long head of the biceps in patients with bicipital tendi-
swelling. The subacromial space, containing the supra- nitis. Impingement of the subacromial bursa or supra-
spinatus tendon and subacromial bursa, lies directly spinatus tendon is suggested by pain with forced internal
below the acromion. Immediately below the acromio- rotation and flexion of the glenohumeral joint from a
clavicular joint, the coracoid process should be identi- position of 90 flexion with the elbow flexed at 90. 2
fied. The short head of the biceps inserts on this process. Supraspinatus tendinitis can be detected by having the
The long head of the biceps can be palpated lateral to patient position their outstretched arm at 90 of abduc-
this in the bicipital groove. The anterior aspect of the tion while maximally internally rotating the glenohu-
glenohumeral joint can be palpated between the cora- meral joint such that the thumb is pointing downward.
coid process and the long head of the biceps and follows The examiner then asks the patient to resist attempts to
the contour on the rounded anterior aspect of the push the arm down. In patients with superspinatus ten-
humeral head. Shoulder synovitis can be palpated in this dinitis, the maneuver will be associated with pain, and
area as joint line tenderness and/or boggy effusion. may result in the patient suddenly dropping the arm.
Passive range of shoulder motion is then evaluated.
The most informative parts of the range of motion are
internal/external rotation and abduction. When testing
The Hip
these movements it is very important to immobilize the Pain resulting from hip arthritis is typically experienced
scapula to prevent rotation at the scapulothoracic area. in the groin or, less commonly, the buttock. It tends to
In this way, glenohumeral motion can be isolated and radiate down the anteromedial aspect of the thigh, occa-
appropriately evaluated. One effective technique to sionally down to the knee. Pain in the lateral trochan-
achieve this is to firmly press down on the top of the teric area is most often indicative of bursitis involving
shoulder area with the palm of one hand, while the other the trochanteric bursa.
hand moves the arm through the range of motion (Figure Because the hip joint cannot be directly examined,
2A-3). Internal/external rotation should be tested with the examiner needs to glean important diagnostic clues
the arm by the patients side and with the arm abducted from observing the patients gait, buttock and thigh
to 90. Examination of the patient in the supine position musculature, and from evaluating passive range of
may aid in relaxing musculature in patients who are motion of the hip joint. As with all load bearing joints,
unable to fully relax during this maneuver. evaluation of functional joint motion needs to be
A large number of special maneuvers have been assessed under load with the patient walking and stand-
described that suggest specific clinical syndromes in the ing. Subtle hip pathology may be detected by having
the patient perform a squat. The patient with true hip
disease often walks with a coxalgic gait, tending to
quickly swing the pelvis forward on the affected side in
order to avoid weight bearing on the hip affected by
arthritis. If the hip arthritis is prolonged and severe, the
buttock musculature tends to atrophy, as does the thigh
musculature. In severe cases, the abductor muscles are
unable to hold the pelvis in a horizontal position when
the patient is asked to stand only on the affected hip.
This forms the basis of the Trendelenburg test, where
the patients pelvis tends to sag down on the contralat-
eral side when the patient is asked to hold their entire
weight on the affected leg.
With the patient in the supine position, passive range
of motion should initially be screened by log rolling the
entire extended leg. The leg is then flexed maximally to
assess completeness of this motion. With the knee flexed
FIGURE 2A-3 to 90 and the hip flexed to 90, internal and external
rotation of the hip are then tested. Care should be taken
Glenohumeral joint motion is best examined with the elbow that the hip movements are isolated, and that the
flexed to 90 and the upper arm in partial abduction. Internal
and external rotation of the shoulder are then examined in this
patients pelvis is not rotating to compensate for lost
position. Care should be taken to immobilize the scapula using a range of motion. Pain and loss of motion on internal
technique such as that shown. rotation are particularly sensitive indicators of hip
pathology. Flexion contracture of the hip tends to motion, the marks identifying this 10 cm segment nor-
accompany longstanding severe hip arthritis. mally expand to 15 cm or more, indicative of distraction
between the vertebrae. While reduction in this mea-
surement is not specific for any particular pathology, it
The Sacroiliac Joint can be used over time to follow disorders with progres-
Palpation of the sacroiliac (SI) joint is undertaken with sive loss of motion, such as ankylosing spondylitis.
the patient lying flat on their abdomen. With the palm Patients presenting with symptoms suggestive of a
of the examiners hand held around the iliac crest, the lumbar radiculopathy, such as pain and parasthesia
thumb tends to fall directly over the joint which extends shooting down the leg, need to undergo an examination
down below the dimples in the posterior pelvic area. To of the lumbosacral area and a detailed neurological
elicit tenderness in the SI joint, direct pressure is applied examination of the leg. Maneuvers that put traction on
with the thumb in this area. In addition to direct palpa- the lumbar spinal roots are used to provide further evi-
tion, the examiner can perform other maneuvers to dence of a radiculopathy. The most commonly used of
further establish the presence of sacroiliitis. Direct pres- these maneuvers is the straight leg raising test, where
sure over the sacrum will produce pain in an inflamed the patient lies in the supine position and the leg is pas-
SI joint. Gaenslens maneuver is performed by having sively raised by the examiner with the knee fully
the patient hyperextend their leg over the edge of the extended. A positive test requires that the patient expe-
examining table, thereby stressing the ipsilateral SI rience pain and parasthesia shooting down the leg to the
joint. level of the foot.
Cervical range of motion begins with the patient
upright and the examiner in front. The patient is asked
The Spine to flex, extend, laterally flex (patient attempts to touch
The spine should be examined initially with the patient their ear to their shoulder), and laterally rotate (patient
standing and the entire spine well visualized. The normal attempts to touch their chin to their shoulder) their
curvature of the spine, lumbar lordosis, thoracic kypho- head. Movements should be evaluated for symmetry,
sis, and cervical lordosis should be evaluated by observ- fullness of motion, and discomfort. Gentle passive range
ing the patient from the both the back and the side, and of motion may be attempted with the patient supine.
any loss or accentuation of these curves noted. If scolio- Spinous processes and surrounding musculature should
sis is noted with the patient standing upright, they should be palpated for spasm or tenderness. It should be noted
be asked to bend forward and flex the spine to evaluate that pain in the neck area often radiates down the arm,
the effects of this movement on the scoliosis. True sco- up the occiput, or down to the scapular area. The pain
liosis will be present irrespective of the state of spinal may be aggravated by particular parts of the range of
flexion, while a functional scoliosis due to leg length motion.
discrepancy will tend to decrease with spinal flexion.
The level of the iliac crests relative to the spine should
also be evaluated by observing the patient from the
The Knee
back, and the examiner sitting with their eyes at approxi- Examination of the knee starts with inspection of the
mately the level of the iliac crests. A tilted pelvis can be patients gait and with the patient standing. When
due to compensation for a primary scoliosis in the spine inspecting from the front, attention should first be paid
or, alternatively, due to a leg length discrepancy. to the areas above and below the knee. Atrophy of the
The range of motion of the entire spine should be quadriceps usually indicates chronic knee pathology.
examined in segments. The lumbar spine is assessed by Swelling due to synovial fluid accumulation or synovial
having the patient attempt to touch their toes and then infiltration and thickening is most readily appreciated
extend their back. Lateral flexion is assessed by having in the suprapatellar bursa. When a large effusion is
the patient reach their fingertips as far as possible down present, it can be seen to also cause bulging of both the
the lateral aspect of their leg. Lateral rotation, which lateral and medial compartments of the knee. Inspec-
involves both the lumbar and thoracic spine, is tested tion of the knee from the back with the patient standing
by having the patient turn their upper body with the up is the best way to evaluate the alignment of the
examiner holding the pelvis stable. femur relative to the tibia. Varus deformities of the
The Schober test is performed to specifically assess knee causing a bow-legged appearance most commonly
movement in the lumbar spine. With the patient stand- result from OA preferentially involving the medial
ing, a distance of 10 cm is measured up the lumbar spine compartment. Valgus deformities, causing a knock-
from the lumbosacral junction at the level of the sacral knee appearance are more commonly associated with
dimples. Marks are placed at both ends of this 10 cm RA. Posterior inspection is also important for detecting
segment. The patient is then asked to flex forward as far popliteal or Bakers cysts, which can be large enough to
as possible, attempting to touch their toes. With this track down the calf.
the medial and collateral ligaments. The cruciate liga-

ments are tested using the drawer sign, where antero-
posterior stress is placed on the upper tibia with the
knee in flexion. Instability of the ligaments will result in
the tibia moving back and forth relative to the femur,
much as a drawer would if pushed back and forth.
2
The Ankle and Hindfoot
The ankle and hindfoot should be examined as a unit,
because arthropathies often involve several structures
in this area. Valgus deformities of the ankle and hind-
foot can best be seen by inspecting the area from behind
with the patient standing. Swelling in the ankle area
eliminates the normal contours associated with the
malleoli.
FIGURE 2A-4 The joint line of the ankle is palpated anteriorly
The joint line of the knee is palpated on the medial and lateral (Figure 2A-5). Boggy swelling and tenderness in this
aspects for tenderness suggestive of synovitis. Stability of the area are typical of ankle synovitis. Tenderness and
cruciate ligaments can also be assessed in this position. Using swelling posteriorly at the insertion of the Achilles
the bulge sign or patellar tap sign, an effusion can be detected tendon usually indicates enthesitis, although this can
in the knee with the joint fully extended (see text for details).
also result from bursitis of the retrocalcaneal bursa.
Tenderness in the heel region can indicate plantar fas-
ciitis, another enthesitis associated with spondylar-
After inspecting the patient in the standing position, thropathies but also common in overuse injuries and
the knee is evaluated with the patient in the supine arch abnormalities.
position, and the joint fully extended. Flexion contrac- The ankle and hindfoot unit should be put through
tures should be noted. Loss of normal contours may the range of motion, isolating parts of the range associ-
suggest swelling. The knee should be palpated for ated with specific joints. The ankle proper, or talotibial
warmth. Bony and soft tissue landmarks should be pal- joint, is only capable of dorsi and plantar flexion. Pain
pated for tenderness, including the anserine bursaa and limitation in this part of the range is associated with
common nonarticular source of knee pain. The medial ankle synovitis. The subtalar joint, separating the talus
and lateral joint line are palpated for tenderness with and the calcaneus, can be tested by rocking the calca-
the knee in partial flexion (Figure 2A-4). neus laterally from side to side with one hand, while
Detection of synovial fluid in the knee is an impor-
tant diagnostic clue. Large amounts of fluid cause dis-
tention of the joint in the suprapatellar area, as well as
the medial and lateral compartment. The fluid can be
confirmed by firmly pushing the swelling in the supra-
patellar area down into the main compartment of the
knee with the palm of one hand. While maintaining
pressure over the suprapatellar area, the examiners
other hand is used to either ballot the fluid back and
forth between the medial and lateral compartments of
the knee, or alternatively to perform the patellar tap by
pushing the patella up and down against the femoral
condyles. Small amounts of fluid in the knee may be
detected using the bulge sign. The medial aspect of the
knee is stroked from the inferior aspect towards the
suprapatellar area in order to move the fluid into the
lateral compartment. The lateral aspect of the knee is
then stroked in a similar manner while the medial com-
partment is observed for the return of the fluid bulge. FIGURE 2A-5
While firmly supporting the joint with one hand (or Palpation for tenderness and swelling in the ankle is undertaken
by holding the foot in the examiners armpit area), varus medial and lateral to the extensor tendons on the anterior part
and valgus stress are gently applied to the joint to test of the joint below the malleoli.
holding the talus stable with the other. Talonavicular entire digit becomes swollen and inflamed, a process
motion is tested by stabilizing the talus and calcaneus termed dactylitis and referred to as a sausage digit.
and rotating the midfoot. Examining the plantar aspect of the forefoot is impor-
tant for identifying areas of callus formation. These
tend to occur in conjunction with subluxation of the
MTPJ, where the metatarsal head can be directly pal-
The Midfoot and Forefoot pated subcutaneously.
Observation of the patient in the standing position will
reveal abnormalities in the longitudinal arch and the
anterior part of the foot. Pes planus (flat foot, collapsed REFERENCES
arch) or pes cavus (high arch) will be most evident with
the patient standing. Hallux valgus deformities causing 1. Dieppe P, Sergent J. History. In: Klippel J, Dieppe P, eds.
bunions are some of the most commonly observed prob- Rheumatology. Mosby, London 1998:1.11.6.
lems in the joints. 2. Hubscher O. Pattern recognition in arthritis. In: Klippel J,
Swelling of the metatarsophalangeal joints (MTPJ) Dieppe P, eds. Rheumatology. Mosby, London 1998:3.1
causes a visible spreading of the toes referred to as the 3.6.
daylight sign. Direct pressure over each of the metatar- 3. Grahame R. Examination of the patients. In: Klippel J,
Dieppe P, eds. Rheumatology. Mosby, London 1998:2.1
sophalangeal joints will confirm the presence of tender-
2.16.
ness and swelling. In cases of advanced RA, subluxation 4. Doherty M, Dacre J, Dieppe P, Snaith M. The GALS
of the MTPJ results in a hammer toe deformity, which locomotor screen. Ann Rheum Dis 1992;51:11651169.
can cause skin breakdown on the dorsum of the toes 5. Calis M, Acgun K, Birtane M, Karacan I, Calis H, Fikret
from constant rubbing against the footwear. Inflamma- T. Diagnostic values of clinical diagnostic tests in subacro-
tion of the interphalangeal joints of the toes is more mial impingement syndrome. Ann Rheum Dis 2000;59:
common with spondylarthropathies. In some cases the 4447.
CHAPTER 2

B. Laboratory Assessment
KERSTIN MOREHEAD, MD
Laboratory testing is often valuable for screening for indication for additional investigations directed at
disease, confirming diagnoses, establishing disease identifying the precise autoantibody leading to the
stage, determining prognosis, gauging disease ANA pattern.
activity, and following responses to therapy. Among others, anti-Ro, -La, -Sm, and -RNP antibodies
The erythrocyte sedimentation rate (ESR) and C- may all result in a positive ANA. These autoantibod-
reactive protein (CRP) frequently correlate well with ies are associated with a range of different rheumatic
disease activity in inflammatory disorders. diseases.
Rheumatoid factor (RF) and anti-cyclic citrullinated Positive immunofluorescence assays for antineutro-
peptide (anti-CCP) anti-bodies are helpful in diagnos- phil cytoplasmic antibodies (ANCA) should be
ing rheumatoid arthritis. The specificity of RF for confirmed by enzyme immunoassays for antibodies
rheumatoid arthritis is poor. directed specifically against two antigens: proteinase-
Antinuclear antibodies (ANA) are found in many 3 and myeloperoxidase.
patients with rheumatic diseases and in essentially all Decreased serum complement levels usually indicate
patients with systemic lupus erythematosus (SLE) and a disease process mediated by immune complex
systemic sclerosis. Under the proper clinical condi- deposition within tissues.
tions, the finding of a positive ANA assay is an
Laboratory testing is an important part of the evalua- ERYTHROCYTE

tion for many patients with possible rheumatic diseases.
As the understanding of rheumatic disease progresses, SEDIMENTATION RATE
new biomarkers are developed and the utility of existing
ones is refined. Laboratory tests can be valuable guides Inflammatory stress alters hepatic synthesis of plasma
for screening, confirming diagnosis, establishing disease proteins. As a result, fibrinogen and immunoglobulin
stage, and prognosis, as well as for following disease levels increase during the acute phase response. When
activity and response to treatment. Because no single red blood cells (RBCs) interact with these proteins,
test can provide absolute certainty about diagnosis, they form clusters that sediment at a faster rate than
prognosis, or state of disease activity, however, results individual RBCs. In chronic states of inflammation,
must be interpreted in the context of the broader clini- decreased serum albumin and hematocrit levels also
cal picture. Sensitivity, specificity, positive and negative lead to increased rates of erythrocyte sedimentation.
predictive values, and likelihood ratios all warrant
careful consideration when interpreting the utility of
any test. Although laboratory testing has grown sub-
Method (Westergren)
stantially as an aid to clinical diagnosis and management Whole serum is anticoagulated with sodium citrate and
over the past several decades, treatment decisions are allowed to stand. After 1 hour, the distance in millime-
rarely based on the result of a single test alone. In addi- ters between the top of the tube and the erythrocyte
tion to appreciating the strengths and shortcomings of sediment is measured. The test is sensitive to handling
testing approaches, the clinician must also be aware of and temperature (1). Normal values are not adjusted for
the variability that often exists between different assay age or gender in most laboratories, yet these character-
methods and individual laboratories. In general, the istics have well-known (if erratic) influences on the ery-
most useful tests are those that are ordered to answer throcyte sedimentation rate (ESR). The ESR generally
well-defined questions. increases with age and is somewhat higher in women.
15
16 KERSTIN MOREHEAD
The upper limits of normal for a man is equal to the age does not exclude an inflammatory process. Moreover,
divided by 2; for a woman, add 10 to the age and divide other disease processes, including heart disease, infec-
by 2 (2). tion, and malignancy, can lead to CRP elevations, as can
obesity, diabetes, and cigarette smoking.
Interpretation
The ESR is sensitive for most types of inflammation,
but cannot distinguish if the underlying cause is infec- RHEUMATOID FACTOR
tious, inflammatory, or paraneoplastic (3). A normal
value may help to rule out inflammatory disease, but an Rheumatoid factor (RF) is an autoantibody that binds
increased ESR, especially if the increase is only moder- to the Fc region of human IgG. IgM is the most common
ate, can be confusing. In addition, the normalization of RF isotype, but IgG and IgA RF may also be detected
a high ESR often lags behind the resolution of inflam- in the serum (6).
mation, making it less than ideal for monitoring disease
activity. Along with normal elevation due to age and
gender, the ESR can be increased by any condition that Method
raises serum fibrinogen, such as diabetes, end-stage The latex fixation test measures only RF IgM by pre-
renal disease, and pregnancy. Conversely, the ESR can cipitating the antibody with IgG-coated latex particles
be lowered by congestive heart failure, sickled erythro- mixed with serial dilutions of serum. Titers greater than
cytes, and the presence of cryoglobulins. 1 : 20 are positive. Nephelometry and ELISA are able
to detect all three isotypes.
C-REACTIVE PROTEIN
The c-reactive protein (CRP) is an acute phase protein
Interpretation
synthesized in response to tissue injury. Serum CRP In established rheumatoid arthritis (RA), RF has a
levels change more quickly than the ESR; with sufficient sensitivity on the order of 70%. In early RA the sen-
stimulus, the CRP can increase within 4 to 6 hours and sitivity is somewhat lower, approximately 50%, as some
normalize within a week (4). The CRP is often measured patients seroconvert only after having clinical disease
simultaneously with (and sometimes in place of) the ESR for weeks or months. A positive RF assay, far from
as a general measure of inflammation. Although CRP specific for RA, can be found in many other autoim-
and ESR values tend to correspond with each other, mune diseases, mixed essential cryoglobulinemia (see
some patients disease processes appear to correlate cryoglobulinemia, below), chronic infections, sarcoid-
better with one measure or the other. osis, malignancy, and a small percentage of healthy
people. The IgA isotype has been linked to erosive
Method disease and to rheumatoid vasculitis, but its precise
clinical utility remains unclear. Higher titers of RF are
Specific antibodies to CRP allow direct quantification by
associated with more severe disease, but as a longitu-
a variety of means. Nephelometry uses antibodies to bind
dinal measure of disease activity RF fares poorly. CRP
target proteins and then measures the scatter of light by
values may be more reliable for monitoring disease
antigenantibody complexes. The enzyme-linked immu-
activity (7).
nosorbant assay (ELISA) uses coated plates to form
antigenantibody complexes. These complexes are
detected by addition of secondary antibodies labeled with
an enzyme that, when mixed with a substrate, produces ANTI-CYCLIC CITRULLINATED
color that is measured by spectrophotometry. Because PEPTIDE ANTIBODIES
the CRP is a stable serum protein and its measurement is
not affected by other serum components, it tends to be Anti-cyclic citrullinated peptide antibodies (ANTI-
less variable than the ESR. The CRP is affected by age CCP) are autoantibodies directed against the amino
and gender, as is the ESR (5). In general, levels <0.2 mg/ acids formed by the posttranslational modification of
dL are considered normal and levels >1 mg/dL are deemed arginine. Some investigators believe anti-CCP anti-
consistent with inflammation, but there is considerable bodies have a role in the pathogenesis of RA (8).
laboratory-to-laboratory variation.
Interpretation Method
Because a certain degree of injury is required before IgG anti-CCP are measured by ELISA using synthetic
CRP is synthesized, a normal or indeterminate value citrullinated peptides. Reference ranges vary (9).
Interpretation that is positive for staining and the pattern of the

stain.
Anti-cyclic citrullinated peptide antibodies have a sen-
sitivity for RA that is similar to that of RF, but anti-CCP
antibodies are much more specific. These test charac- Interpretation
teristics lend considerable usefulness to anti-CCP anti- Aninuclear antibody assays are nearly universally posi-
bodies in the setting of seronegative patients suspected tive in SLE, to the extent that ANA-negative lupus is
of having RA, patients with other forms of connective virtually nonexistent. Patients with systemic sclerosis 2
tissue disease who are RF positive, and patients with (scleroderma) and many other connective tissue dis-
hepatitis C or other infections that are often associated eases are also ANA positive with a very high frequency,
with RF positivity. Anti-CCP antibodies are often often in high titers. Depending on the exact technique
detectable in early RA and, in some cases, antedate the used, up to 30% of healthy people may have a positive
onset of inflammatory synovitis. Although anti-CCP titer (11). The prevalence of positive ANAs increases
antibodies may be a better predictor of erosive disease in women and older people. A positive ANA is not
than is RF, they do not correlate with extra-articular specific for SLE or autoimmune disease, especially if it
disease. A positive anti-CCP combined with a positive is transient or in low titer.
RF IgM correlates strongly with radiographic progres-
sion. Anti-CCP levels are not useful in the longitudinal
monitoring of disease activity (10). Specific Autoantibodies
Autoantibodies directed against individual antigens
have increased specificity for particular diseases. Some
ANTINUCLEAR ANTIBODIES of these autoantibodies also predict disease severity
(Table 2B-2) (12). These are ordered separately from
Antinuclear antibodies (ANA) are a diverse group of the ANA test.
autoantibodies that react with antigens in the cell
nucleus. Different patterns reflect different nuclear
components including nucleic acid, histones, and cen-
tromeres (Table 2B-1).
ANTINEUTROPHIL
CYTOPLASMIC ANTIBODY
Method Antineutrophil cytoplasmic antibodies (ANCA) are
Hep-2 cells (a human tumor cell line) are incubated autoantibodies that react with the cytoplasmic granules
with serial dilutions of serum. Using immunofluores- of neutrophils. Two general staining patterns, cyto-
cence microscopy, labeled antihuman IgG is used as plasmic (C-ANCA) or perinuclear (P-ANCA) can be
a stain. The result reflects the highest serum dilution detected by immunofluorescence. In forms of systemic
TABLE 2B-1. ANTINUCLEAR ANTIBODY PATTERNS.

PATTERN NUCLEAR ANTIGEN CLINICAL ASSOCIATIONS
Homogenous Double-stranded DNA Systemic lupus erythematosus
Diffuse Histone Drug reaction

Systemic lupus erythematosus
Topoisomerase I Systemic sclerosis
Speckled Extractable nuclear antigens (Sm, RNP) Mixed connective tissue disease
Ro-SSA/La-SSB Sjgrens syndrome
Other Poly/dermatomyositis
Various autoimmune diseases
Infection
Neoplasia
Nucleolar RNA-associated antigens Systemic sclerosis
Peripheral Double-stranded DNA Systemic lupus erythematosus
Centromere Centromere Limited systemic sclerosis

18 KERSTIN MOREHEAD
TABLE 2B-2. AUTOANTIBODIES IN RHEUMATIC DISEASES.

TYPE DESCRIPTION CLINICAL ASSOCIATION
Anti-dsDNA Antibodies to double-stranded DNA High specificity for SLE

Often correlates with more active, more severe disease
ELISA test is very sensitive and can be positive in other diseases,
normal people
Anti-histone Five major types exist SLE, drug-induced SLE, other autoimmune disease
SLE patients will likely be positive for other autoantibodies as well
Anti-ENA Sm (Smith) High specificity for SLE

RNP (ribonucleoprotein) Mixed connective tissue disease
RNAprotein complexes Higher prevalence in African American and Asian patients
Anti-SSA (Ro) Ribonucleoproteins SLE (especially subacute cutaneous lupus), neonatal lupus, Sjgrens
syndrome
Anti-SSB (La) Ribonucleoproteins Sjgrens syndrome, SLE, neonatal SLE
Anti-centromere Antibody to centromere/kinetochore region Limited scleroderma

of chromosome High rate of pulmonary hypertension
Primary biliary sclerosis
Anti-Scl 70 Antibodies to DNA topoisomerase 1 Diffuse scleroderma

Risk of pulmonary fibrosis
Anti-Jo-1 Antibody to histidyl tRNA synthetase Poly/dermatomyositis

Patients tend to have interstitial lung disease, Raynauds
phenomenon, mechanics hands, arthritis
Typically resistant to treatment
Anti-SRP Antibody to signal recognition protein Cardiomyopathy

Poor prognosis
Anti-PM-Scl Antibody to nucleolar granular component Polymyositis/scleroderma overlap syndrome
Anti-Mi-2 Antibodies to a nucleolar antigen of Dermatomyositis

unknown function Favorable prognosis
vasculitis, such as Wegeners granulomatosis, micro- One common laboratory approach is to screen with
scopic polyangiitis, and the ChurgStrauss syndrome, ethanol-fixed cells and to perform assays on formalin-
these patterns reflect autoantibodies to two lyzosomal fixed cells if immunofluorescence is observed on screen-
granule enzymes: serine protease-3 (PR3) and myelo- ing. Increasingly reliable ELISA assays for the detection
peroxidase (MPO), respectively. Upon immunofluores- of both PR3 and MPO have been available since the
cence testing of sera, many patients with other forms early 1990s. For optimal clinical utility, any positive
of inflammatory disease (e.g., SLE, autoimmune hepa- immunofluorescence assay should be confirmed by the
titis, inflammatory bowel disease) have positive ANCA performance of anti-PR3 and -MPO ELISAs.
assays. ELISA testing in such patients, however, reveals
antibody specificities for antigens other than PR3 and
MPO. ANCA directed against PR3 and MPO are
Interpretation
termed PR3-ANCA and MPO-ANCA, respectively. The combination of C-ANCA and PR3-ANCA has a
high positive predictive value for ANCA-associated
vasculitis, particularly Wegeners granulomatosis. Simi-
Method larly, the combination of P-ANCA and MPO-ANCA
To identify C- and P-ANCA patterns of immunofluo- has a high positive predictive value for microscopic
rescence, ethanol- or formalin-fixed human neutrophils polyangiitis. (For further discussion of the role of ANCA
are coated with the patients serum and stained with assays in these diseases and in the ChurgStrauss syn-
labeled anti-IgG. Formalin fixation is preferred because drome, please see Chapter 21C.)
the presence of antinuclear antibodies may cause a The more active and extensive the vasculitis, the
false-positive P-ANCA pattern on ethanol-fixed cells. more likely are ANCA assays to be positive. ANCA
titers often normalize with treatment but do not always indicate the presence of cryoglobulins. Unfortunately,
do so, even if clinical remissions are achieved. Some the correlations between changes in complement levels
data suggest that a persistent rise in ANCA titer or and disease activity are poor. In addition, hypocomple-
return of ANCA positivity heralds an increased risk of mentemia may also be secondary to nonrheumatic
recurrent disease, but neither persistently positive diseases, notably subacute bacterial endocarditis
ANCA tests nor rising ANCA titers provide reliable and poststreptococcal glomerulonephritis (15). Low or
information about the timing of a disease flare. Treat- undetectable CH50 may indicate a deficiency of one or
ment decisions in ANCA-associated vasculitis are never more complement components. Patients with genetic 2
based entirely ANCA assay result. Moreover, positive deficiencies of early complement components (C1C4)
ANCA tests may be caused by infection, drugs (particu- are at increased risk for developing immune-complex
larly thyroid medications such as propylthiouracil), and, diseases (16), particularly some forms of SLE.
as noted, other autoimmune diseases. Thus, under most
clinical circumstances, tissue biopsy remains the gold
standard for diagnosis (13). CRYOGLOBULINS
Cryoglobulins are immunoglobulins that precipitate
COMPLEMENT reversibly at cold temperatures. In a variety of diseases,
cryoglobulins often bind with complement proteins and
The complement cascade is a tightly regulated complex other peptides to form immune complexes. Based on
of proenzymes, regulatory proteins, and cell-surface their composition, cryoglobulins are classified into three
receptors that mediate and augment both of comple- types. Type I cryoglobulins are monoclonal immuno-
ment the humoral and cellular immune response. Acti- globulins, frequently of the IgM isotype. Type II cryo-
vation by antigenimmune complexes, bacterial surface globulins are a mixture of polyclonal IgGs and
proteins, and polysaccharides begins a fixed sequence monoclonal IgM. Type III cryoglobulins are a combina-
of reactions that lead to increased vascular permeabil- tion of polyclonal IgGs and polyclonal IgMs. In both
ity, chemotaxis, cell lysis, antigenimmune complex type II and type III cryoglobulinemia, the IgM compo-
clearance, and opsonization. The classical pathway (C1, nent has RF activity (i.e., it binds to the Fc portion of
C4, C2), the alternative pathway (factors B, D, and IgG), accounting for the fact that essentially all patients
properdin), and the mannose-binding lectin pathway all with these disorders are RF positive (often creating
share the final step of cleaving C3. The released product confusion in diagnosis with RA) (17).
(C3b) then induces formation of the terminal mem-
brane attack complex (C5C9) (14).
Method
For proper collection of cryoglobulins, careful attention
Method to detail and preparation in advance are required.
Serum levels of individual components such as C3 and Whole blood must be drawn and maintained at body
C4 are measured by ELISA and nephelometry. The temperature until it coagulates. The sample is then cen-
plasma total hemolytic complement assay, or CH50, trifuged and the clot removed. The remaining serum is
assesses the functional integrity of the classical pathway. allowed to stand at 4C for up to several days until
Serum is diluted and added to sheep antibodycoated precipitation is observed. The sample is spun again and
RBCs. The value reported is the reciprocal of the highest the cryocrit is measure in a calibrated tube. Isotype and
dilution able to lyse 50% of the RBCs. clonality are established by various immunochemical
techniques.
Interpretation
Decreased serum levels of individual components, espe-
Interpretation
cially C3 and C4, correlate with the increased consump- Cryoglobulins are not specific for any one disease. Type
tion observed in active immune complex mediated I cryoglobulins do not activate the complement cascade
disease, for example, SLE. In contrast, most inflamma- and are therefore associated with normal complement
tory disorders that are not associated with immune levels. They are linked to lymphoproliferative disor-
complex deposition demonstrate elevated levels of ders, malignancies, and hyperviscosity syndromes, and
complement because these proteins are acute phase often associated with sludging in the small vasculature
reactants. Hypocomplementemia, though useful in nar- of the extremities, eye, or brain. Type II and type III
rowing the differential diagnosis, is generally not spe- cryoglobulins, able to bind complement, are associated
cific for any particular disease. C4 levels that are with hepatitis C virus infections and a syndrome of
disproportionately low compared to those of C3 may small vessel vasculitis (see Chapter 21D) (18).
20 KERSTIN MOREHEAD
REFERENCES 9. Zendman AJW, Van Venroij, Pruijn GJM. Use and sig-
nificance of anti-CCP autoantibodies in rheumatoid
arthritis. Rheumatology 2006;45:2025.
1. Sox HC Jr, Liang MH. The erythrocyte sedimentation 10. Niewold TB, Harrison MJ, Paget SA. Anti-CCP antibody
rate: guidelines for rational use. Ann Intern Med 1986; testing as a diagnostic and prognostic tool in rheumatoid
104:515523. arthritis. QJM 2007;100:193201.
2. Miller A, Green M, Robinson D. Simple rule for calculat- 11. Tan E, Feltkamp TE, Smolen JS, et al. Range of antinu-
ing normal erythrocyte sedimentation rate. BMJ 1983; clear antibodies in healthy individuals. Arthritis Rheum
286:266. 1997;40:16121618.
3. Bridgen M. The erythrocyte sedimentation rate. Still a 12. Lyon R, Sonali N. Effective use of autoantibody tests in
helpful test when used judiciously. Postgrad Med 1998; the diagnosis of systemic lupus erythematosis. Ann N Y
103:257262. Acad Sci 2005;1050:217228.
4. Morley JJ, Kushner I. Serum C-reactive protein levels in 13. Bartunkova J, Tesar V, Sediva A. Diagnostic and patho-
disease. Ann N Y Acad Sci 1982;389:406418. genic role of antineutrophil cytoplasmic autoantibodies.
5. Wener MH, Daum PR, McQuillan GM. The influence of Rheumatology (Oxford) 2003;106;7382.
age, sex and race on the upper limit of serum C-reactive 14. Walport MJ. Advances in immunology: complement. N
protein concentration. J Rheumatol 2000;27:23512359. Engl J Med 2001;344:10581066, 11401144.
6. Johsson T, Valdimarsson H. Is measurement of rheuma- 15. Egner W. The use of laboratory tests in the diagnosis of
toid factor isotypes clinically useful? Ann Rheum Dis SLE. J Clin Pathol 2000;53:424432.
1993;52:161164. 16. Ratnoff WD. Inherited deficiencies of complement in
7. Witherington RH, Teitsson I, Valdimarsson H, et al. Pro- rheuamtologic diseases. Rheum Clin North Am 1996;22:
spective study of early rheumatoid arthritis. II Associa- 121.
tion of rheumatoid factor isotypes with fluctuations in 17. Brouet JC, Clauvel JP, Danon F, et al. Biological and
disease activity. Ann Rheum Dis 1984;43:679685. clinical significance of cryoglobulins: a report of 86 cases.
8. Vossenaar ER, Smeets TJ, Kraan MC, et al. The presence Am J Med 1974;57:775788.
of citrullinated proteins is not specific for rheumatoid 18. Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J Clin
arthritis. Arthritis Rheum 2004;50:34853494. Pathol 2002;55:413.
CHAPTER 2

C. Arthrocentesis, Synovial Fluid
Analysis, and Synovial Biopsy
KENNETH H. FYE, MD
When the diagnosis of an inflammatory arthropathy otherwise, and should be treated empirically
is unclear, synovial fluid should be evaluated for the with antibiotics until the results of culture are
three Cs: cell count, culture, and crystals. available.
Removal of infected synovial fluid is often a critical Microcrystalline disorders (gout and pseudogout)
adjunct to antibiotics in the treatment of a septic occasionally lead to synovial fluid neutrophil counts
joint. >100,000/mm3.
Careful preparation, appropriate assistance, and Examination of synovial fluid under polarized
planning of the approach to the joint enhance the microscopy is the only way of securing the diagnosis
likelihood of success in performing arthrocentesis. of a microcrystalline disease.
Synovial fluid neutrophil counts in excess of
100,000/mm3 spells an infection until proven
Despite the development of increasingly sophisticated may be present. Analyzing SF may yield information
serologic tests and imaging techniques, synovial fluid invaluable in making the diagnosis, determining prog-
(SF) analysis remains one of the most important diagnosis, and formulating appropriate therapy in patients
nostic tools in rheumatology (1). Normal SF lubricates with arthritis (4).
the joint and, along with blood vessels in subchondral
bone, supplies nutrients to the avascular articular carti-
lage. The majority of SF constituents originate in the
subsynovial vasculature, diffusing through the synovium
ARTHROCENTESIS
into the joint space. However, certain important mac-
romolecules, such as hyaluronic acid and lubricin, are
Indications
synthesized and secreted by synoviocytes (which line An acute, inflammatory, monarticular arthritis should
the joint). Plasma proteins not found in SF include probe considered either infectious or crystal-induced until
thrombin, fibrinogen, factor V, factor VII, antithrom- proven otherwise. Arthrocentesis is the only method of
bin, large globulins, and some complement components identifying infection or crystal-induced disease unequiv-
(2). ocally. Because acute bacterial infections can lead
Synovial fluid protein concentrations reflect the rapidly to joint and bone destruction, arthrocentesis
interplay between plasma concentration, synovial fluid must be performed immediately if there is any suspicion
blood flow, endothelial cell permeability, and lymphatic of infection. If preliminary analysis of the SF is compat-
drainage. There are few cells in normal SF. In arthritis, ible with infectionthat is, the white blood cell (WBC)
invading inflammatory cells produce additional proteins count is markedly elevated but no crystals are identi-
and release activated cytokines into SF. Elevated intra- fiedantibiotic therapy should be initiated pending
articular pressure due to increased amounts of SF leads definitive culture results. SF analysis can confirm the
to diminished perfusion of synovial microvasculature, presence of crystal-induced arthritis and enable the cli-
disrupting the process of diffusion that supplies synovial nician to identify the culprit crystal precisely. If a polar-
nutrients (3). In addition, offending substance such as ized microscope is used, the sensitivity of SF analysis for
microorganisms, foreign bodies, or abnormal crystals, identifying a crystal-induced arthropathy is 80% to 90%
21
22 KENNETH H. FYE
(4). Trauma can sometimes result in an acute monar- be used to swab the area to prevent an iodine burn.
ticular arthropathy. Analysis of joint fluid is the only Although it is wise to wear gloves during any procedure
way to distinguish posttraumatic hemarthrosis from involving exposure to potentially infected body fluids,
posttraumatic arthritis with bland synovial fluid. sterile gloves are generally not necessary. Sterile gloves
Arthrocentesis can also be useful in the evaluation should be used if the clinician anticipates having to
of chronic or polyarticular arthropathies. SF analysis palpate the target anatomy after preparation of the
enables the clinician to differentiate inflammatory arthrocentesis site using antiseptic technique.
and noninflammatory arthritides. The procedure is
often essential in distinguishing chronic crystal-induced
arthritide such as polyarticular gout or calcium pyro-
Local Anesthesia
phosphate dehydrate deposition disease from other Local anesthesia with 1% lidocaine without epineph-
arthropathies, such as rheumatoid arthritis (RA). rine significantly reduces discomfort associated with the
Although chronic mycobacterial or fungal infections procedure. One-quarter to 1 cc of lidocaine is usually
can sometimes be identified in SF, synovial biopsy is sufficient, depending on the joint being anesthetized.
frequently necessary to distinguish indolent infections A 25- or 27-gauge needle should be used to infiltrate
from other unusual chronic inflammatory processes, the skin, subcutaneous tissue, and pericapsular tissue.
such as pigmented villonodular synovitis. Because Larger caliber needles are more uncomfortable and can
people with chronic inflammatory arthropathies (e.g., lead to local trauma. Although many clinicians apply
RA) have an increased susceptibility to infection, acute ethyl chloride to the skin before injecting the anesthe-
monarticular arthritis in a patient whose disease is sia, others believe this practice is cumbersome and
otherwise well controlled is an indication for a diag- results in no clinically significant additional anesthesia.
nostic arthrocentesis. After the periarticular tissues have been anesthe-
The cellular and humoral components of inflamma- tized, a 20- or 22-gauge needle can be used to aspirate
tory SF can damage articular and periarticular tissues small- to medium-sized joints. An 18- or 19-gauge
(5). The activated enzymes in septic SF are highly needle should be used for aspirating large joints or
destructive to cartilage. Thus, in a septic joint, repeated joints suspected of infections, intra-articular blood, or
arthrocentesis may be necessary to minimize the accu- viscous, loculated fluid. Small syringes are easier to
mulation of purulent material (6). If purulent SF re- manipulate and provide greater suction than large
accumulates despite repeated arthrocenteses, surgical syringes, but must be changed frequently when aspirat-
arthroscopy with drain placement should be performed ing large joints with copious amounts of SF. When using
to ensure adequate drainage of the infected joint. For a large syringe to aspirate a significant amount of fluid,
joints that are noninfected but inflamed, drainage of as the suction in the syringe should be broken before use
much SF as possible removes inflammatory cells and and the plunger drawn. Excessive negative pressure can
other mediators, decreases intra-articular pressure, and suck synovial tissue into the needle and prevent an
reduces the likelihood of articular damage (7). Removal adequate joint aspiration. A Kelly clamp can stabilize
of inflamed fluid also increases the efficacy of intra- the hub of the needle while removing a full syringe.
articular corticosteroids. Finally, blood in a joint, Typical landmarks are often obscured around a
such as may occur in hemophilia, can lead quickly to swollen joint. Therefore, after a thorough physical
adhesions that inhibit joint mobility. When clinically examination and before sterilizing and anesthetizing the
indicated, therefore, therapeutic arthrocentesis may be skin, it is often helpful to mark the approach with a
prudent in a patient with hemarthrosis. When contem- ballpoint pen. If landmarks are still obscure, use sterile
plating such a procedure in a hemophiliac, careful con- gloves to maintain a clean field while using palpation to
sideration should be given to approaches to maximize identify an aspiration site for the target joint. Many
hemostasis (e.g., the use of clotting factor VIII concen- joints, such as the knee, ankle, and shoulder, are ame-
trate; see Chapter 25A) and prevent additional intra- nable to both medial or lateral approaches.
articular bleeding as a result of the procedure. In contrast to joint injection, aspiration is performed
most easily when a joint is in a position of maximum
intra-articular pressure. For example, injection of the
Techniques knee is best done with the knee in 90 flexion while the
patient is seated at an examining table with the foot
Sterile Procedures
dangling. This position allows gravity to open the joint
Infections caused by arthrocentesis are very rare. space, offering easy access to the intra-articular space
Nevertheless, preventive measures to minimize the from either side of the infrapatellar tendon. However,
likelihood of postarthrocentesis infection are prudent. this position decreases intra-articular pressure, thereby
Betadine or povidoneiodine should be applied to the decreasing the likelihood of a successful aspiration.
aspiration site and allowed to dry. Alcohol should then Conversely, therefore, the optimal positioning of the
TABLE 2C-1. ANATOMIC APPROACH TO ASPIRATION.

JOINT POSITION OF JOINT LOCATION OF APPROACH
Knee Extended Medial or lateral under the patella
Shoulder Neutral adduction, external Anterior: inferolateral to coracoid

rotation Posterior: under the acromion
Ankle Plantar flexion Anteromedial: medial to extensor hallucis longus

2
Anterolateral: lateral to extensor digiti minimi
Subtalar Dorsiflexion to 90 Inferior to tip of lateral malleolus
Wrist Midposition Dorsal into radiocarpal joint
First carpometacarpal Thumb abducted and flexed Proximal to base of metacarpal
Metacarpophalangeal Finger slightly flexed Just under extensor mechanism dorsomedial or dorsolateral
or interphalangeal
Metatarsophalangeal Toes slightly flexed Dorsomedial or dorsolateral

or interphalangeal
Elbow Flexed to 90 Lateral in triangle formed by lateral epicondyle, radial head, and
olecranon process
patient for aspiration of the knee is lying supine with the porting structures. If bone is encountered, slight with-
knee fully extended, thereby maximizing intra-articular drawal of the needle followed by redirection and another
pressure. Although most joints can be aspirated without attempt at aspiration is indicated. In unsuccessful aspi-
radiologic assistance, some joints, such as the hips, sac- ration attempts, the needle may be outside the joint
roiliac joints, or zygoapophyseal joints, should be aspi- space, blocked by synovium or SF debris, or too small
rated using computed tomography guidance. Aspirations for the degree of SF viscosity.
should generally not be done through areas of infection,
ulceration, or tumor, or obvious vascular structures.
Table 2C-1 lists suggestions for optimal anatomic
approaches for aspirating or injecting specific joints. SYNOVIAL FLUID ANALYSIS
If corticosteroids are to be injected after aspiration
is complete, the drug should be prepared in a separate The four general classes of SF, defined by differences in
syringe ahead of time so that the aspirating needle gross examination, total and differential WBC count,
already in the joint can be used for the injection. If dif- the presence or absence of blood, and the results of
ficulties arise during the procedure, the needle should culture are shown in Table 2C-2. SF characteristics of
not be manipulated aggressively because of the risk of arthritic conditions can be extremely variable and may
damaging the cartilage, capsule, or periarticular sup- change with therapy. Therefore, the classes of SF are
TABLE 2C-2. CLASSES OF SYNOVIAL FLUID.

CLASS I (NONINFLAMMATORY) CLASS II (INFLAMMATORY) CLASS III (SEPTIC) CLASS IV (HEMORRHAGIC)
Color Clear/yellow Yellow/white Yellow/white Red
Clarity Transparent Translucent/opaque Opaque Opaque
Viscosity High Variable Low NA
Mucin clot Firm Variable Friable NA
WBC count <2,000 2,000100,000 >100,000 NA
Differential <25% PMNs >50% PMNs >95% PMNs NA
Culture Negative Negative Positive Variable
ABBREVIATIONS: PMN, polymorphonuclear leukocytes; NA, not applicable.

24 KENNETH H. FYE
TABLE 2C-3. DIAGNOSIS BY SYNOVIAL CLASS.

CLASS I CLASS II CLASS III CLASS IV
Osteoarthritis Rheumatoid arthritis Septic arthritis Trauma

Traumatic arthritis Systemic lupus erythematosus (bacterial) Pigmented
Osteonecrosis Poly/dermatomyositis villonodular
Charcots arthropathy Scleroderma synovitis
Systemic necrotizing vasculitides Tuberculosis
Polychondritis Neoplasia
Gout Coagulopathy
Calcium pyrophosphate deposition disease Charcots arthropathy
Hydroxyapatite deposition disease
Juvenile rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Reactive arthritis
Chronic inflammatory bowel disease
Hypogammaglobulinemia
Sarcoidosis
Rheumatic fever
Indolent/low virulence infections (viral, mycobacterial, fungal,
Whipples disease, Lyme disease)
intended only as a general guide in the diagnosis of break down hyaluronan. The string formed by inflam-
arthritis (Table 2C-3). matory SF may be only 5 cm or less. Extremely viscous
fluid with a very long string is suggestive of hypothy-
roidism (9). One can also determine the integrity of
Gross Examination hyaluronic acid by placing a few drops of SF into 2%
Certain characteristics of SF provide the clinician with acetic acid. Normal SF will form a stable clump of hyal-
valuable clues as to the nature of an arthropathy. Clarity uronateprotein complex called a mucin clot. Inflamma-
reflects the density of particulate matter in SF. Normal tory SF fluid forms a mucin clot that will fragment easily,
SF or that from patients with osteoarthritis is colorless reflecting the loss of integrity of hyaluronan.
and clear. In contrast, the SF of systemic lupus erythe-
matosus (SLE) or mild rheumatoid arthritis may be
translucent, and the SF from a septic joint will be
Cell Count
opaque. Generally, the number of WBCs determines The WBC count and differential are among the most
the opacity of inflammatory SF (8). The xanthochromia valuable diagnostic characteristics of SF. Normal SF
that sometimes characterizes SF from patients with contains fewer than 200 cells/mm3. SF from noninflam-
arthritis is caused by the breakdown of heme from red matory arthropathies may have WBC counts of up to
blood cells that leak into the joint space from diseased 2000 cells/mm3 (9). Noninfectious inflammatory arthrop-
synovium. Gross, fresh bleeding due to trauma, hemo- athies have WBC counts that vary widely, ranging from
philia, pigmented villonodular synovitis, or other patho- 2000 to 100,000 cells/mm3 (10). Although the autoim-
logic processes will result in red or bloody SF. Other mune arthropathies generally present with WBC counts
materials that can opacify SF include lipids, crystals of 2000 to 30,000 cells/mm3, cell counts of 50,000/mm3
(such as calcium pyrophosphate dehydrate, monoso- or higher are not unusual in RA. Patients with crystal-
dium urate, or hydroxyapatite), and debris that accumu- induced arthritis, such as acute gout, usually have WBC
lates in destructive forms of arthritis (such as severe RA counts of greater than 30,000 cells/mm3 and counts of
or Charcots arthropathy). 50,000 to 75,000 calls/mm3 are common. The closer the
Normal joint fluid is viscous due to the presence of WBC count gets to 100,000 cells/mm3, the greater the
hyaluronan. Enzymes present in inflammatory arthrop- likelihood of a septic arthritis. Although a rare patient
athies digest hyaluronic acid, resulting in a decrease in with crystal-induced arthropathy, RA, or even a sero-
fluid viscosity. When a single drop of normal SF is negative arthropathy may have a WBC count greater
expressed from a syringe, a tail or string of fluid should than 100,000 cells/mm3, such patients should be treated
stretch approximately 10 cm before surface tension is empirically for a septic joint until microbiologic data
broken. The greater the degree of inflammation within exclude infection.
a joint, the higher the number of inflammatory cells and A WBC count of less than 100,000 cells/mm3 does
the greater the concentration of activated enzymes that not preclude the possibility of infection. Patients with
chronic inflammatory arthritides due to RA, SLE, or pigmentation derives from hemosiderin accumulated
psoriatic arthritis have an increased risk of joint sepsis from recurrent hemorrhage. The SF from patients with
secondary to both the structural joint damage caused tuberculosis is often hemorrhagic, as is that associated
by chronic inflammation and the immunosuppressive with local or metastatic tumors. Patients with con-
effects of many of the drugs used to treat those diseases. genital, metastatic, or hemorrhagic disorders, such
Moreover, many disease modifying agents in such as EhlersDanlos syndrome, pseudoxanthoma elasti-
diseases, including methotrexate, cyclosporine, lefluno- cum, sickle cell disease, or scurvy, may also develop
mide, azathioprine, cyclophosphamide, or other cyto- hemarthrosis. 2
toxic agents, may blunt the WBC response to infection
and cause spuriously low WBC counts within the SF. In
comparison with bacterial infections, more indolent
Crystals
processes such as tuberculosis or fungal infection are Although crystals can be identified in SF that is a few
associated with lower WBC counts; SF counts <50,000/ days old, optimal examinations for crystals are per-
mm3 are typical. formed on fresh SF prepared immediately after aspira-
The differential WBC count can provide valuable tion (12). If the SF is to be anticoagulated before
information (11). SF from a septic joint usually contains examination, only sodium heparin and EDTA are
greater than 95% polymorphonuclear leukocytes acceptable; lithium heparin and calcium oxalate may
(PMNs). Frequently, more than 90% of the WBC in the both form birefringent crystals that can confound the
SF from patients with crystal-induced arthropathies or fluid examination. In addition, a clean slide and cover
RA will be PMNs, as well. On the other hand, the dif- slip should be used, because talc, dust, or other debris
ferential WBC count of noninflammatory SF character- may mimic crystalline materials.
istically contains less than 50% granulocytes. Although monosodium urate crystals can be seen
Examination of a wet preparation is particularly with ordinary light microscopy (13), an adequate crystal
helpful in assessing SF for its cellular and crystalline examination requires a polarized light microscope with
content. The wet preparation is best done on SF applied a red compensator (14). The lower polarizing plate (the
directly from the syringe to a slide, but SF anticoagu- polarizer), inserted between the light source and the
lated with sodium heparin or EDTA can also be used. study specimen, blocks all light waves except those that
Ragocytes, which are PMNs with refractile inclusions vibrate in a single direction. The second polarizing plate
containing immune complexes and complement, can be (the analyzer) is positioned between the study specimen
observed on wet-preparation examination of SF from and the observer and is oriented 90 from the polarizer.
patients with RA. SF from patients with SLE may No light passes through to the observer, who sees only
contain lupus erythematous (LE) cells. Cytologic exam- a dark field through the microscope. Birefringent mate-
ination may reveal malignant cells in the SF of patients rial will bend light waves that have passed through the
with synovial metastases. polarizer, so they can pass through the analyzer to the
observer, who now sees a white object against a dark
field. If a first order red compensator is placed between
Blood the polarizer and the analyzer, the background field
The presence of blood in a joint is usually the result of becomes red and a birefringent crystal becomes yellow
acute trauma. If arthocentesis reveals a hemarthrosis, or blue, depending on its identity and orientation to the
the bloody fluid should be evacuated to prevent syno- direction of the slow-vibration axis of the light passing
vial adhesions that could decrease the range of motion through the red compensator.
of the injured joint. Hemarthrosis is sometimes seen in Light passing through the red compensator is
Charcots arthropathy because of chronic trauma to the refracted into two vibration waves, a fast wave and a
affected joint. In the absence of a history of trauma, slow wave, which are perpendicular to each other. The
bloody SF could represent a traumatic aspiration. The identical phenomenon occurs with light passing through
blood seen in a traumatic aspiration is not homoge- a birefringent crystal. The fast-wave vibration of mono-
neous throughout the sample and usually appears only sodium urate, which is a birefringent crystal, is oriented
after the clinician encounters difficulty with the proce- along the long pole of the needle-shaped crystal. When
dure. If the procedure was not traumatic, the presence the long pole of a monosodium urate crystal is parallel
of bloody SF should alert the clinician to several possi- to the slow-wave axis marked on the red compensator,
bilities. Recurrent hemarthrosis is common in people a color-subtraction interference pattern of fast and slow
with severe coagulation disorders such as hemophilia, vibration occurs, resulting in a yellow color. A crystal
von Willebrands disease, and platelet disorders, and that is yellow when its long pole is parallel to the slow
in patients on anticoagulation therapy. The SF from axis of vibration of the red compensator is, by conven-
patients with pigmented villonodular synovitis is virtu- tion, considered to be negatively birefringent. If
ally always hemorrhagic or xanthochromic. In fact, the the slow wave of vibration of a birefringent crystal is
26 KENNETH H. FYE
parallel to its long pole when the long pole of the crystal use the air to blow the fluid in the needle onto a slide.
is parallel to the slow axis of the red compensator, This is a particularly valuable technique when looking
an addition pattern of slow-plus-slow vibration will for monosodium urate crystals in podagra.
result in a blue color. By convention, a birefringent
crystal that is blue when the long pole is parallel to the
slow axis of vibration of the red compensator is consid-
Culture
ered to be positively birefringent. Calcium pyrophos- An inflammatory monarticular arthritis should be con-
phate dehydrate crystals, for example, are positively sidered infectious until proven otherwise. In most bac-
birefringent. Birefringence can be strong, meaning the terial infections, Gram stain and culture and sensitivity
birefringent crystal is bright and easy to see, or weak, yield valuable diagnostic information and are crucial
meaning the birefringent crystal is muted and difficult components of analysis. Generally, SF need only be
to detect. collected in a sterile culture tube and transported to the
Crystals are identified by a combination of shape laboratory for routine analysis. Unfortunately, some
and birefringence characteristics. Monosodium urate important infectious agents are difficult to culture, so
crystals are needle shaped and have strong, negative negative Gram stains and cultures do not necessarily
birefringence (see Figure 12A-7). In contrast, calcium preclude an infection. For example, SF cultures are
pyrophosphate dehydrate crystals are short and rhom- negative in more than two-thirds of people with gono-
boid, and show weak, positive birefringence. Calcium coccal arthritis, even if chocolate agar is used as the
oxalate crystals, which can be seen in primary oxalosis culture medium. In addition, tuberculosis is often diffi-
or in chronic renal failure, are rod or tetrahedron shaped cult to culture from SF, and special techniques and
and positively birefringent. Cholesterol crystals are flat culture media are required for anaerobic or fungal
and boxlike, tend to stack up, and often have notched pathogens. Sometimes mycobacterial (17) or fungal
corners. Spherules with birefringence in the shape of a (18) infections can be detected only on synovial biopsy
Maltese cross generally represent lipid. However, it has material. Because bacterial infections can lead rapidly
been suggested that some forms of urate or apatite may to joint destruction, early antibiotic therapy is essential.
take this shape (15,16). Hydroxyapatite is usually diffi- Antibiotic therapy should be initiated based on the
cult to recognize in SF, partly because it is not birefrin- results of WBC count, WBC differential, and Gram
gent. However, sometimes it forms clumps large enough stain, and adjusted later if necessary, based on the
to be seen when stained with alizarin red S. Finally, results of culture and sensitivity.
glucocorticoid crystals injected into the joint as a thera-
peutic measure are birefringent and may be misinter-
preted by the unwary observer. SYNOVIAL BIOPSY
The presence of intracellular crystals is virtually
diagnostic of a crystal-induced arthropathy. However, Arthroscopy has greatly facilitated the clinicians ability
a superimposed infection must be excluded even if to obtain synovial tissue for analysis. At one time,
crystals are identified. In addition, a patient may have synovial tissue could only be obtained by open arthrot-
more than one crystal-induced disorder. For example, omy or blind needle biopsy (19). Advances in the tech-
up to 15% of patients with gout also have calcium nology of arthroscopy have led to the development of
pyrophosphate dihydrate deposition disease. It is small, flexible instruments that allow direct visualiza-
important to make that determination, because it will tion and biopsy of synovium (20). In certain clinical
affect therapy. A patient with chronic gout may require settings, synovial biopsy can add significant diagnostic
only ongoing hypouricemic therapy (and perhaps pro- information.
phylactic colchicine). In contrast, a patient with both The granulomatous diseases are frequently difficult
gout and calcium pyrophosphate dihydrate deposition to diagnose by SF analysis alone. SF acid-fast smears
disease may require continued nonsteroidal anti- and cultures are negative in a significant number of
inflammatory therapy in addition to ongoing hypouri- patients with tuberculosis. The diagnosis of tuberculous
cemic therapy. arthritis is often based on histologic demonstration of
Attempts to aspirate inflammatory joints are not caseating granulomata and acid-fast stain or culture evi-
always successful. For example, aspiration of an inflamed dence of Mycobacterium tuberculosis in synovial tissue.
first metatarsophalangeal joint is difficult. However, if Atypical mycobacterial and fungal arthropathies can be
the clinician keeps negative pressure on the syringe as indolent, inflammatory, oligoarticular infections that
the needle is withdrawn from articular or periarticular cannot be diagnosed without obtaining synovial tissue
tissues, there is almost always enough interstitial fluid for histologic and microbiologic analysis (18). In patients
in the needle to allow adequate polarized-light exami- without pulmonary involvement, the diagnosis of sarcoid
nation for crystals. Simply remove the needle from the arthropathy may rest on the demonstration of noncase-
syringe, fill the syringe with air, reattach the needle, and ating granulomata in synovial tissue.
Malignant infiltrations of the synovium can be seen 3. Gaffney K, Williams RB, Jolliffe VA, Blake DR. Intra-
in synovial sarcomas, lymphomas, metastatic disease, articular pressure changes in rheumatoid and normal
and leukemias. The diagnosis of synovial osteochon- peripheral joints. Ann Rheum Dis 1995;54:670673.
dromatosis can be made based on the presence of foci 4. Shmerling RH. Synovial fluid analysis. A critical appraisal.
Rheum Dis Clin North Am 1994;20:503512.
of osteometaplasia or chondrometaplasia on synovial
5. Chapman PT, Yarwood H, Harrison AA, et al. Endo-
biopsy. Sometimes cytologic examination of SF reveals
thelial activation in monosodium urate monohydrate
a malignancy. However, the diagnosis of a malignant
arthropathy is generally based upon histologic demon-
crystal-induced inflammation. Arthritis Rheum 1997;40: 2
955965.
stration of malignant cells in synovial tissue. Therefore, 6. Sack KE. Joint aspiration and injection: a how-to guide.
synovial biopsy is indicated if there is a suspicion of J Musculoskel Med 1999;16:419427.
articular malignancy. 7. Zuber TJ. Knee joint aspiration and injection. Am Fam
The diagnosis of some infiltrative nonmalignant Physician 2002;66:14971507.
processes depends on the histologic or microscopic 8. Pasqual E, Jovani V. Synovial fluid analysis. Best Pract
evaluation of synovial material. A diagnosis of amyloid Res Clin Rheumatol 2005;19:371386.
arthropathy can be made if apple green birefringence is 9. Dorwart BB, Schumacher HR. Joint effusions, chondro-
calcinosis and other rheumatic manifestations in hypothy-
observed in Congo redstained synovial biopsy material
roidism. A clinicopathologic study. Am J Med 1975;
examined under polarized light. Hemochromatosis is
59:780790.
characterized by the deposition of golden brown hemo- 10. Krey PR, Bailen DA. Synovial fluid leukocytosis. A study
siderin in synovial lining cells. Hydroxyapatite deposits of extremes. Am J Med 1979;67:436442.
in synovial tissue appear as clumps of material that stain 11. Trampuz A, Hanssen AD, Osmon DR, et al. Synovial
with alizarin red S and have a typical appearance on fluid leukocyte count and differential for the diagnosis
electron micrography. The synovium of patients with of prosthetic knee infection. Am J Med 2004;117:556
multicentric reticulohistiocytosis is filled with multinu- 562.
cleated giant cells and histiocytes with a granular 12. Kerolus G, Clayburne G, Schumacher HR. Is it manda-
ground-glass appearance. The SF from patients with tory to examine synovial fluids promptly after arthrocen-
ochronosis has a ground-pepper appearance due to pig- tesis? Arthritis Rheum 1989;32:271278.
13. Gordon C, Swan A, Dieppe A. Detection of crystals in
mented debris. The synovial biopsy from these patients
synovial fluid by light microscopy: sensitivity and reliabil-
contains shards of ochronotic pigment that is diagnostic.
ity. Ann Rheum Dis 1989;48:737742.
In Whipples disease, foamy macrophages containing 14. Joseph J, McGrath H. Gout or pseudogout: how to dif-
periodic acid-Schiff (PAS)positive material can be ferentiate crystal-induced arthropathies. Geriatrics 1995;
seen on synovial biopsy. Pigmented villonodular syno- 50:3339.
vitis is defined by the presence of giant cells, foamy 15. McCarty DJ, Halverson PB, Carrera GF, Brewer BJ,
cells, and hemosiderin deposits in synovial tissue. Kozin F. Milwaukee shoulderassociation of micro-
The ease of direct biopsy of target tissues that has spheroids containing hydroxyapatite crystals, active col-
resulted from advances in arthroscopic techniques has lagenase, and neutral protease with rotator cuff defects.
not changed the clinical indications for synovial biopsy. Arthritis Rheum 1981;24:464473.
Biopsy should be done only if the diagnosis cannot be 16. Beaudet F, de Medicis R, Magny P, Lussier A. Acute
apatite podagra with negatively birefringent spherulites in
made using traditional, less invasive procedures.
the synovial fluid. J Rheumatol 1993;20:19751978.
17. Sequeira W, Co H, Block JA. Osteoarticular tuberculosis:
current diagnosis and treatment. Am J Ther 2000;7:393
REFERENCES 398.
18. Kohli R, Hadley S. Fungal arthritis and osteomyelitis.
1. Swan A, Amer H, Dieppe P. The value of synovial fluid Infect Dis Clin North Am 2005;19:831851.
assays in the diagnosis of joint disease: a literature survey. 19. Schumacher HR, Kulka JP. Needle biopsy of the synovial
Ann Rheum Dis 2002;61:493498. membraneexperience with the Parker-Pearson technic.
2. Gatter RA, Schumacher HR Jr. A practical handbook of N Engl J Med 1972;286:416419.
joint fluid analysis, 2nd ed. Philadelphia: Lea & Febiger; 20. Gerlag D, Tak PP. Synovial biopsy. Best Pract Res Clin
1991. Rheumatol 2005;19:387400.
CHAPTER 2

D. Imaging of Rheumatologic
Diseases
WILLIAM W. SCOTT, JR., MD
WILLIAM J. DIDIE, MD
LAURA M. FAYAD, MD
Conventional radiographs are the initial imaging High resolution CT of the lungs is an essential
agent of choice for most rheumatic conditions. For adjunct to the evaluation of many inflammatory
most forms of arthritis, no additional imaging studies rheumatic diseases, for example, systemic sclerosis,
are required. systemic vasculitis, and other disorders associated
Trabecular bone and small bone erosions are with signs of interstitial lung disease.
visualized well by conventional radiography. Magnetic resonance imaging (MRI), which has
Weight-bearing views of the knees are important in superior imaging capabilities of soft tissue and bone
the evaluation of significant knee osteoarthritis. marrow lesions, is the study of choice for a host of
Computed tomography (CT) is superior to conven- musculoskeletal diagnoses, including meniscal tears
tional radiographs in the assessment of certain joint of the knee, spinal disc herniations, osteonecrosis,
conditions, including many cases of tarsal coalition, osteomyelitis, skeletal neoplasms, and others.
sacroiliitis, osteonecrosis, and sternoclavicular joint Bone densitometry plays a crucial role in the diagno-
disease. sis and treatment of osteopenia and osteoporosis.
Imaging techniques may aid in making diagnoses, permit which individual structures are visualized), radiation
objective assessments of disease severity and response dose to the patient, availability, and specific uses in
to treatment, and promote new understandings of assessing musculoskeletal signs and symptoms.
disease processes. Imaging modalities that are valuable
in rheumatology include conventional radiography,
computed tomography (CT), magnetic resonance
imaging (MRI), ultrasound, radionuclide imaging, CONVENTIONAL RADIOGRAPHY
arthrography, bone densitometry, and angiography.
A basic knowledge of the merits and limitations of Conventional radiographs are the starting point for
these techniques is essential in selecting the most appro- most imaging evaluations in rheumatic disorders, even
priate and cost-effective imaging. In the discussion to when studies such as MRI are expected to follow. The
follow, high spatial resolution will indicate excellent cost is low and spatial resolution is very high, permitting
ability of an imaging modality to demonstrate fine bone good visualization of trabecular detail and tiny bone
detail and to detect small calcifications. High contrast erosions. When necessary, resolution can be enhanced
resolution will indicate excellent ability to distinguish further by magnification techniques and filmscreen
different soft tissue structures. Techniques such as combinations optimized for detail. However, contrast
conventional radiography have good spatial resolution. resolution is poor compared to that obtainable with CT
MRI generally has best contrast resolution among and MRI. This limitation is especially noticeable when
current imaging techniques. This chapter reviews the trying to evaluate soft tissues. Although plain radiogra-
basic imaging techniques with regard to their spatial phy is a useful tool to assess the effect of a soft tissue
and contrast resolution (which determine the degree to mass on nearby bone and to detect calcification within
28
soft tissue, other techniques should be employed if atrophy, and evaluate the state of the biceps tendon and
optimal soft tissue imaging is required. articular cartilage in such cases.
Examination of peripheral structures, such as the Knee radiographs are useful in cases of advanced
hands and feet, delivers a low radiation dose to the arthritis, when they may demonstrate complete loss of
patient. Serial studies of the extremities can be per- knee joint cartilage and bone-on-bone contact. This
formed without concern about excessive radiation marks the end point for useful arthroscopic and medical
exposure. Studies of central structures, however, such treatment of knee arthritis and time to consider joint
as the lumbar spine and pelvis, expose patients to high replacement. Weight-bearing views are necessary 2
radiation doses. Close proximity to the gonads and to because hyaline cartilage loss is deduced from the
bone marrow increases the potentially detrimental degree of apposition of the bony surfaces. In this
effects to the patient. Whenever possible, the pelvic regard, the flexed posterioranterior (PA) standing
region of pregnant or potentially pregnant women radiograph is often more useful than an anterior
should not be exposed to x-rays, and radiation to posterior (AP) view in full extension, as the flexed
children should be minimized stringently. When such view images the portion of the articular surface subject
studies are necessary in these patients, radiation physi- to the greatest wear (Figure 2D-5). However, for earlier
cists can calculate the minimum radiation dose required stages of arthritis, MRI is important for detection of
for the imaging study. These same basic principles apply small focal articular cartilage defects that may poten-
to all other x-ray imaging techniques. tially be treated with recently developed surgical
Conventional radiography is widely available and techniques.
convenient. Moreover, a vast fund of knowledge about
plain radiographic findings in various rheumatic dis-
eases is available (Figures 2D-12D-3). In many cases, DIGITAL RADIOGRAPHY
simple, low cost imaging may provide all the informa-
tion necessary to make clinical decisions. If the plain Computed radiography uses a photosensitive phosphor
radiograph of the shoulder shows upward subluxation plate to create a digital image, rather than the analog
of the humeral head so that it contacts the undersurface image of conventional radiography. At present, com-
of the acromion, one can be quite certain that the rotator puted radiography images are utilized at most centers.
cuff is torn with atrophic musculature, and likely very The resolution is adequate for many routine joint
difficult to repair (Figure 2D-4). This may argue against evaluations and can be improved by magnification,
a decision to undertake surgery. If surgery is contem- if necessary for special tasks. The radiation dose is
plated, however, then MRI can confirm the large size of approximately the same as for conventional radiogra-
the rotator cuff tendon tear, the extent of muscle phy. Soft tissue is better visualized than on conven-
tional radiographs.
Direct radiography is a technique whereby digital
images are created at the time of x-ray exposure. The
advantages of digital images, whether digitized con-
ventional radiographs, computed radiography, or direct
radiography, include the ability to manipulate images
electronically and to display images simultaneously in
several remote areas. Image manipulation permits
technically excellent final images to be obtained under
adverse circumstances. For this reason, computed radi-
ography is currently popular in emergency departments
and intensive care units, locations where it is often
difficult to obtain optimal radiographic exposures.
The ability to manipulate digital data is also useful to
researchers wishing to make automated measurements
on radiographs and to clinicians wishing to send images
via the Internet.
The resolution of computed radiography can be
improved and conventional high resolution radiographs
FIGURE 2D-1 can be converted into digital format. CT, MRI, and
ultrasound images are also acquired in digital form, and
Typical radiographic findings in osteoarthritis of the hand
showing asymmetric joint narrowing with osteophyte formation.
are easily transported and manipulated. Digital imaging,
The distal interphalangeal joints, proximal interphalangeal joints, now widely utilized, has the advantages of rapid trans-
and first carpometacarpal joint are most commonly involved. mission, cost-effective storage, and easy retrieval.
30 WILLIAM W. SCOTT, JR., WILLIAM J. DIDIE, AND LAURA M. FAYAD
C D
FIGURE 2D-2
(A) Severe rheumatoid arthritis in an elderly woman showing erosive changes and marked
cartilage narrowing of wrist, intercarpal, metacarpophalangeal, and proximal interphalangeal
joints. The joints involved are typical for rheumatoid arthritis. Alignment abnormalities with ulnar
deviation of the metacarpals and osteoporosis are also typical. (B) Coronal short time inversion
recovery (STIR) image of the wrist in a different patient showing multiple osseous erosions and
synovial thickening, characteristic findings of rheumatoid arthritis. (C) T1 weighted coronal image
showing more extensive erosions (arrows) with areas of synovial thickening. (D) Axial postcon-
trast fat-saturated image depicting tenosynovitis, with fluid distention of the tendon sheaths
(arrow).
FIGURE 2D-3
A 57-year-old woman with systemic lupus erythematosus (SLE)

shows striking alignment abnormalities without erosions as well as
periarticular osteoporosis. Similar changes are seen in the arthropa-
thy associated with rheumatic fever (Jaccouds arthropathy). The
cartilage destruction and synovial proliferation of rheumatoid
arthritis is lacking. Early in the disorder, the alignment abnormalities
can be corrected by passive positioning.
A B
FIGURE 2D-4
(A) An 80-year-old woman with weakness and pain in the

right shoulder. Radiograph shows superior subluxation of
the humeral head and markedly decreased space
between humeral head and acromion. (B) Oblique
coronal STIR MRI image shows similar decreased distance
between the acromion and humeral head, as well as a
complete rotator cuff tendon tear. (C) Sagittal oblique T1
weighted image demonstrating a significant degree of
atrophy of the supraspinatus, infraspinatus, and subscapu-
laris muscles. MRI findings could have been predicted
from the plain radiograph and the clinical history.
However, in this case the MRI provides an accurate
estimation of the size of the rotator cuff tear, as well as
commonly associated findings such as the status of the
long head of the biceps tendon and articular cartilage.
These soft tissue abnormalities cannot be assessed by
plain radiography.
C
A B
FIGURE 2D-5
(A, B) Standing anteroposterior (A) and standing flexed posteroanterior (B) views of the right
knee. In (A), no significant narrowing of the joint is identified although osteophytes and subchon-
dral sclerosis, indicative of osteoarthritis, are evident. In (B), however, the standing flexed view
demonstrates complete articular cartilage loss in the lateral compartment.
COMPUTED TOMOGRAPHY myelography and CT with intravenous contrast enhance-

ment are used to evaluate disc disease and other spinal
Compared with radiography, CT offers superior con- processes. In general, MRI is preferred over CT for
trast resolution, but spatial resolution of CT remains investigating disc disease (following plain radiography).
inferior. CT is especially useful in specific locations dif- For cases in which MRI is contraindicated, CT is an
ficult to evaluate by radiography, such as the sacrum. acceptable alternative and may be useful in circum-
Although relatively expensive, CT is less costly than stances where additional information about osteophytes
MRI. With the advent of multidetector technology is important. Elsewhere in the musculoskeletal system,
capable of producing CT datasets with isotropic resolu- CT is useful for evaluating structures in areas of complex
tion, the spatial resolution of CT is comparable or supe- anatomy where overlying structures obscure the view
rior to that of MRI, but its contrast resolution is inferior. on conventional radiographs. Examples include tarsal
Consequently, CT is not as sensitive as MRI for defining coalitions not visible on plain radiographs (Figure
bone marrow or soft tissue abnormalities. 2D-6) (1); sacroiliitis, especially that of infectious origin
Computed tomography is an excellent technique for (Figure 2D-7); and articular collapse of the femoral
evaluating degenerative disc disease of the spine and head following osteonecrosis, indicating the need for
possible disc herniations in older patients, in whom joint replacement rather than a core procedure. The
radiation dose is less critical than in young patients. CT sternoclavicular joint, which is notoriously difficult to
see on conventional radiography, is quite visible with

CT.
The radiation dose from CT is relatively high com-
pared with a single plain radiograph of the same region,
but the radiation doses between these imaging tech-
niques are comparable when several conventional
radiographic views of the same area are required.
If the correct initial data are obtained by appropri-
2
ately adjusting the thickness of the collimation used and
the thickness of the reconstructed slice width, images
can be reconstructed satisfactorily in any plane,
especially with the advent of advanced multidetector
technology capable of isotropic resolution datasets.
In addition to multiplanar reconstructions, three-
dimensional images can be obtained, which may aid in
evaluating abnormalities of the pelvis and other areas
of complex anatomy. Using multidetector technology,
including multiplanar reformatting, better images of
joints affected by respiratory motion, such as the shoul-
der, can be acquired rapidly during a single breath,
minimizing motion artifact.
High resolution (thin cut) CT of the lung may reveal
details of disease not seen on thicker CT slices of the FIGURE 2D-7
thorax. Thin cut CT scans have the additional advan-
tage of not requiring intravenous contrastoften a Woman with left hip and back pain. Plain radiographs demon-
strated no abnormalities. CT scan shows marked erosion and
concern in patients with rheumatic disease who have widening of the left sacroiliac joint, consistent with sacroiliitis.
tenuous renal status. The interstitial lung disease that Note relative osteopenia on the adjacent sacral side, indicating
hyperemia.
occurs in many patients with a variety of rheumatic

conditions (systemic sclerosis, rheumatoid arthritis,
inflammatory myopathy, microscopic polyangiitis) is
characterized well by high resolution CT. The demon-
stration of ground glass infiltrates connotes an active
process that may respond to treatment, but unfortu-
nately this finding does not distinguish between infec-
tion, inflammation, and other conditions (2).
Multidetector spiral CT is now used increasingly as
a means of excluding pulmonary emboli, a complication
to which many patients with rheumatic disorders (sys-
temic lupus erythematosus, primary antiphospholipid
antibody syndrome, Wegeners granulomatosis) are
susceptible. For pulmonary thromboembolism detec-
tion, the chest is scanned rapidly following a bolus intra-
venous injection of contrast medium, timed so that the
pulmonary arteries are opacified to optimal effect.
MAGNETIC RESONANCE
IMAGING
FIGURE 2D-6
A 50-year-old woman with suspected tarsal coalition. CT scan

Because of its ability to image soft tissue structures not
shows the non-osseous talocalcaneal coalition between the visible on conventional radiographs, MRI has brought
sustentaculum of the calcaneus and the talus above. significant advances to musculoskeletal imaging. The
technique derives structural information from the Magnetic resonance imaging is free of the hazards of
density of protons in tissue and the relationship of these ionizing radiation, a major advantage in examining
protons to their immediate surroundings. central portions of the body. The technique does pose
Magnetic resonance imaging involves changing the some unique potential hazards, however. For example,
strength and timing of magnetic field gradients, as well the strong magnetic field can move metal objects such
as altering radiofrequency pulses and sampling the as surgically implanted vascular clips and foreign metal
emitted energy. By altering these factors appropriately, in the eyes, cause pacemaker malfunction, heat metal
varying amounts of T1 and T2 weighting are imparted objects, and draw metal objects into the magnet. Metal-
to the images. T1 reflects the time constant for spins to lic objects in the vicinity of the magnetic field can also
align themselves with the main magnetic field of the compromise the quality of MRI images. Because of
equipment and T2 reflects the time constant for loss of these risks and the adverse effect on imaging quality,
coherence among spins, resulting in decay of the com- operators must screen patients and visitors carefully.
ponent of magnetization perpendicular to the main Patients suffering from claustrophobia may be unable
magnetic field. These relaxation times are different in to tolerate the procedure, which is performed with the
different tissues, permitting optimal imaging of differ- patient positioned in a hollow tube. More open configu-
ent tissues by selection of an appropriate mix of T1 and rations for the magnet can circumvent this problem, but
T2 weighting. the quality of images produced by these devices varies.
As a result, MRI highlights different types of tissue MRI c gadolinium is contraindicated in patients with
and metabolic states. Altering these parameters can significant renal dysfunction, because of the risk of
produce radically different images of the same anatomic inducing nephrogenic systemic fibrosis (3). Finally,
site. CT images, which basically map the density of because MRI instruments can be noisy, hearing protec-
tissues in a manner similar to conventional radiographs, tion should be provided for the patient.
are intuitively easier to grasp than are MR images. Spatial resolution using the latest MRI equipment is
Magnetic resonance imaging is more expensive than similar to spiral CT, but contrast resolution in soft tissues
most other imaging approaches, largely because of the as well as bone marrow is superior among imaging
cost of equipment and the time required to perform the modalities. Intra-articular soft tissue structures, such as
studies. In the future, more attention will probably be the menisci and cruciate ligaments of the knee, are dem-
given to tailored, limited imaging sequences, which onstrated clearly by MRI (Figure 2D-8). In fact, tiny liga-
potentially could lower the cost. Newer, faster imaging mentous structures in the wrist or ankle can be assessed
sequences continue to be developed, which may reduce quite readily (4). The synovium can be imaged, espe-
the time and cost of MRI, as well as provide dynamic cially using intravenous gadolinium. Joint effusions,
studies of joint motion. popliteal cysts, ganglion cysts, meniscal cysts, and bursi-
FIGURE 2D-8
(A) Sagittal proton density images of the knee, depicting vertical tear of the posterior horn of the
medial meniscus. (B) Sagittal proton density images of the knee. Bucket-handle tear of the medial
meniscus, with double Posterior Cruciate Ligament sign.
A B
tis can be imaged clearly (Figure 2D-9), and the integrity

of tendons assessed accurately as well (5). One limitation
of MRI is in the detection of calcifications, which present
as signal voids and are therefore not as well seen by MRI
as by radiographic images. For example, chondrocal-
cinosis, important to the diagnosis of calcium pyro-
phosphate dehydrate deposition disease (CPPD), is
demonstrated more reliably by plain radiography (Figure 2
2D-10). Otherwise, MRI remains the modality of choice
for evaluating potential internal joint derangements.
Magnetic resonance imaging has specific utility in the
assessment of:
Imaging Cartilage. MRI has a negative predictive

value close to 100% for the presence of meniscal
tears in the knee. MRI is also a sensitive method for
diagnosing labral tears of the shoulder and triangu-
lofibrocartilage tears in the wrist.
Alterations in articular hyaline cartilage are visible
on MRI. Although direct observation with arthros-
copy is more sensitive to small superficial changes,
refinements are being made that improve the ability FIGURE 2D-10
of MRI to detect small articular cartilage defects (6). Chondrocalcinosis in the hand: 58-year-old man with chondro-
With recent improvements in therapy for cartilage calcinosis in triangular fibrocartilage and lunotriquetral ligaments
defects, MRI provides a useful noninvasive method (arrows). Note MCP joint degenerative changes, a typical location
for CPPD arthropathy. First carpometacarpal (CMC) joint also
for quantifying cartilage loss as well as evaluating the
shows moderate degenerative change.
success of surgical repair. In addition, MRI is the
study of choice for evaluating osteochondritis disse-
cans when information is needed about whether the Recent studies have suggested that MRI may have
osteochondral fragment is loose or detached. a role in assessing responses to therapy in arthritis.
For example, in rheumatoid arthritis, MRI can quan-
tify the volume of enhancing inflammatory tissue (7).
In ankylosing spondylitis, MRI may be used to assess
changes over time in spinal inflammation (8). MRI
has been established as the most sensitive modality
for the detection of bony erosions (Figure 2D-11) (9),
although its specificity for early erosive changes has
been reported to be low. Healthy subjects can occa-
sionally demonstrate imaging findings suggestive of
mild synovitis or erosions, indistinguishable from
early rheumatoid arthritis (10). Finally, as bone
marrow edema and synovitis can precede frank ero-
sions, MRI may have a predictive role, and thus
affect patient management early in the disease course
(11).
Detecting Bony Abnormalities. MRI is extremely
sensitive to subtle bony abnormalities. In fact, micro-
fractures due to trauma or stressoften referred to
as bone bruiseswere essentially unknown before
MRI. Now, recognizing their presence is quite impor-
tant. The pattern of bone bruises is also closely
related to ligamentous injuries (12). Similarly, much
FIGURE 2D-9 of the pain accompanying some acute meniscal tears
Adolescent with knee pain. Coronal proton density fat-saturated
may be caused by associated bone marrow edema.
image shows horizontal cleavage tear of the lateral meniscus, When the edema subsides, the pain disappears,
with associated parameniscal cyst (arrow). despite the persistent meniscal tear. This finding
Diagnosing Disc Herniation. Following plain radiog-

raphy, MRI is an excellent study of the spine and its
contents in cases of suspected disc herniation, par-
ticularly in young patients, because it does not employ
ionizing radiation.
Localizing Muscle Abnormalities, Including
Inflammation-Associated Edema in Inflammatory
Muscle Disease. MRI is indicated in the assessment
of muscle abnormalities for detection of potential
tears and contusions. The activity of different muscles
during joint motion can also be studied by noting
signal changes that occur with muscle activity. In
inflammatory myopathies (polymyositis, dermato-
myositis, inclusion body myositis), MRI demonstrates
characteristic (albeit not diagnostic) edema, and may
be useful in identifying sites to biopsy and following
disease activity.
FIGURE 2D-11
SCINTIGRAPHIC TECHNIQUES
MRI images of a patient treated with corticosteroids. T1 Scintigraphy following intravenous administration of
weighted image of hips demonstrates characteristic serpentine agents such as 99m technetium methylene diphospho-
foci of low signal intensity within the femoral heads bilaterally,
consistent with osteonecrosis.
nate (99mTc MDP) for bone scans, 99mTc sulphur colloid
for bone marrow scans, 67 gallium citrate (67Ga citrate),
and leukocytes labeled with 111 indium [111In-labeled
white blood cells (WBCs)] are useful for evaluating a
variety of musculoskeletal disorders (Figure 2D-12).
could have important implications for therapy. One These studies, similar in cost to CT, deliver a radiation
should possibly wait for the edema to resolve before dose similar to a CT scan of the abdomen. Scintigraphy
attempting surgical intervention to repair or remove is quite sensitive for detecting many disease processes,
the meniscus. In some cases intervention might be and has the advantage of imaging the entire body at
unnecessary. MRI studies of the knee in older people once. The technique is nonspecific, however, because
often reveal asymptomatic meniscal tears. These a number of processes may cause radionuclide accumu-
individuals may have had pain at the time of the tear lation. When areas of increased uptake are detected,
which resolved with the edema and did not cause additional studies such as radiography are often neces-
them long-term disability. sary to define the type of abnormality further. In clini-
Diagnosing Osteonecrosis. MRI is the study of choice cal situations where the presence of skeletal disease is
for diagnosing osteonecrosis (Figure 2D-11). Early uncertain, a bone scan can be useful in excluding
in the course of disease, plain radiographs show no disease.
abnormalities.
Evaluating Musculoskeletal Neoplasms. MRI is also
the best method for evaluating the extent of a mus-
culoskeletal neoplasm. Plain radiographs are still the Localization of Scintigraphic
mainstay for detecting bone neoplasms.
Identifying Bone Infections. MRI is highly sensitive
Imaging Agents
to the presence of bone infection because of altera- 99m Technetium methylene diphosphonate, the most
tions in the marrow signal. Osteomyelitis cannot be commonly used radionuclide, accumulates in areas of
detected on radiography until approximately 30% to bone formation, calcium deposition, and high blood
40% bone destruction has occurred. Thus, MRI is the flow. 99mTC sulphur colloid localizes in the reticuloen-
study of choice for the early detection of osteomyeli- dothelial system (liver, spleen, and bone marrow).
67
tis (13). Small studies have shown variable results for Gallium citrate accumulates in inflammatory and
MRI in differentiating osteomyelitis and neuropathic certain neoplastic processes, and 111In-labeled WBCs
arthropathy, which is very difficult with other imaging localize in inflammatory sites, especially acute inflam-
techniques. matory processes.
A B
FIGURE 2D-12
(A) An 82-year-old woman with a history of breast cancer and recent onset of lower back pain.
Metastases were suspected. 99mTc MDP bone scan shows increased uptake in the sacrum and
right pubic ramus, typical of insufficiency fractures rather than metastatic cancer. (B) Computed
tomography scan in the same 82-year-old woman. This test demonstrates the linear nature of
the healing fracture in the sacrum, adjacent to the right sacroiliac joint, lending specificity to the
diagnosis suggested by the radionuclide scan.
Using Radionuclide Imaging to Other Uses of Radionuclide Imaging

Diagnose Osteomyelitis Bone scans are a reasonable alternative for early detec-
tion of osteonecrosis if MRI is not available. Bone scans
The 99mTc MDP triple-phase bone scan is commonly used can also detect stress injuries such as shin splints, tendon
for early detection of osteomyelitis. Images are obtained avulsions, insufficiency fractures, and stress fractures,
in the early vascular phase (during bolus injection of the which sometimes mimic arthritis symptome (Figure
radionuclide), intermediate blood pool phase (5 minutes 2D-12).
postinjection), and late bone phase (3 hours postinjec-
tion). A fourth phase (24 hours postinjection) can be
added to accentuate areas of increased bone uptake, ULTRASOUND
during which time soft tissue background is decreased,
although delayed imaging is not widely used because of Ultrasound provides unique information by creating
its inconvenience. If necessary, the specificity of scanning images based on the location of acoustic interfaces in
can be increased by also using 67gallium citrate or 111In- tissue. It is relatively inexpensive, widely available, and
labeled WBCs. The 111In-labeled WBC scan is especially free of the hazards of ionizing radiation. Spatial resolu-
useful when osteomyelitis is suspected to be superim- tion is similar to CT and MRI, but this depends on the
posed on a healing fracture or surgical incision because transducer. However, resolution is limited by the depth
uptake of 99mTc MDP is increased at these sites even in of tissue being studied; resolution is much higher for
the absence of infections. 111In-labeled WBC scans may superficial structures.
also be useful in diagnosing osteomyelitis of the foot in One limitation of ultrasound is dependence on the
people with diabetes. In suspected osteomyelitis of the operator. It is not always possible for one investigator
hematopoietic bone marrow, the combination of 99mTc to reproduce the results of another. Furthermore,
MDP and 111In-labeled WBC appears to be an effective because ultrasound has no cross-sectional orientation,
diagnostic technique. Spatial localization of bone scans it may be difficult for individuals who were not actually
can be improved with single-photon emission computed present during the study to interpret the images later.
tomography (SPECT), and radiographs of scan-positive In some centers, ultrasound has proved accurate
areas can be used to increase specificity. in detecting rotator cuff tears. It is also excellent for
assessing fluid collections, such as joint effusions, pop- containing contrast medium and sometimes air. The
liteal cysts, and ganglion cysts, and can therefore be cost is less than that of CT or MRI, and the procedure
used to guide aspiration of fluid. Superficially located can be performed wherever fluoroscopy is available.
tendons, such as the Achilles tendon and patellar The possibility of introducing bacteria into a joint or
tendon, can be studied for tears. encountering reactions to the local anesthetic or con-
Ultrasound is excellent for differentiating thrombo- trast medium must be considered, but these complica-
phlebitis from pseudothrombophlebitis. With real-time tions are very rare.
compression ultrasonography, venous thrombosis and One of the major reasons for developing arthrogra-
popliteal cysts can be identified. phy was to examine structures within the joint, such as
Ultrasound, similar to MRI, has been shown to be the menisci of the knee, which were not visible on con-
much more sensitive than radiography in detection of ventional radiographs. Now these structures can be
erosions in rheumatoid arthritis (14). With amplitude imaged noninvasively by MRI. However, certain impor-
color Doppler (ACD), it can demonstrate synovial hyper- tant roles remain for arthrography.
emia in active disease. The technique requires a skilled Conventional arthrography, using iodine-containing
operator and is more effective in the examination of the contrast medium either alone or combined with air,
metacarpophalangeal (MCP) and interphalangeal (IP) accurately detects full-thickness rotator cuff tears
joints than the intercarpal joints, but is relatively inex- (Figure 2D-13). CT scanning can be added to the air
pensive and convenient. It avoids the potentially uncom- contrast arthrogram (CT arthrography), providing an
fortable positioning that may be necessary with MRI. excellent study of the glenoid labrum that can be an
Finally, although ultrasound has been reported to be alternative to MRI in selected patients (15).
useful in the diagnosis of temporal arthritis, there is an Knee arthrography can confirm the diagnosis of a
absence of blinded studies confirming its utility for this popliteal cyst, and permits injection of corticosteroids
purpose. at the same time. It is an alternative for evaluating the
menisci in patients who are claustrophobic or whose
size precludes MRI examination (Figure 2D-14).
ARTHROGRAPHY Wrist arthrography is excellent for evaluating the
integrity of the triangular fibrocartilage, ligaments
Arthrography involves injecting a contrast agent into between the scaphoid and lunate, and ligaments between
the joint followed by radiography. In conventional the lunate and triquetrum (16). Some clinicians prefer
arthrography, the joint cavity is filled with an iodine- arthrography to MRI in this situation.
FIGURE 2D-13
(A) Single contrast arthrogram of a normal shoulder. (B) Single contrast shoulder arthrogram of a
66-year-old man with a painful shoulder and history of injury in distant past. Contrast media fills
not only the shoulder joint [as in Figure 2D-11(A)] but has filled the subdeltoidsubacromial
bursa superiorly, a finding diagnostic of full-thickness rotator cuff tear.
A B
A B
FIGURE 2D-14
(A, B) A 40-year-old woman, too large to fit in the MRI scanner, was suspected of having a
popliteal cyst. Double contrast arthrogram demonstrated popliteal cyst and also a torn medial
meniscus. Ultrasonography would have been an appropriate alternative approach to making this
diagnosis.
Magnetic resonance arthrography is performed by are available for lumbar spine and proximal femur,
distending a joint with a dilute solution of a gadolinium- which are the most widely studied.
containing contrast medium. This technique, not widely Quantitative computed tomography scans several
studied, probably increases the diagnostic accuracy of lumbar vertebrae while simultaneously scanning a
glenoid and acetabular labral tears, as well as rotator phantom containing different concentrations of bone-
cuff tears (17). equivalent material. A standard curve is constructed
from the concentration values versus CT attenuation,
and then the bone density at any location scanned is
BONE DENSITOMETRY determined from the standard curve. The cost of this
study is moderate and the radiation dose fairly low,
Bone densitometry is used primarily for evaluating although not as low as that for DXA. One purported
osteoporosis. Two precise, accurate, and widely avail- advantage of this technique is that trabecular bone in
able techniques are dual-energy x-ray absorptiometry the middle of the vertebrae can be evaluated because
(DXA) and quantitative computed tomography overlying cortical bone and posterior elements of the
(QCT) (18). vertebrae are not measured. Trabecular bone, which
Dual-energy x-ray absorptiometry scans with a has tremendous surface area, is more rapidly affected
narrow x-ray beam that alternates energy (kilovoltage during bone loss than is cortical bone.
peak; KVP). A sensitive receptor detects the fraction of
the x-ray beam that traverses the body at each point
along the scan path. Because the absorption character- ANGIOGRAPHY
istics of bone and soft tissue vary at different x-ray
energies, the amount of radiation absorbed by bone Angiography is useful in the primary diagnosis of rheu-
can be calculated. From this, the amount of bone in the matologic disorders with vascular components. In poly-
path of the x-ray beam at any point along the scan is arteritis nodosa, for example, demonstration of multiple
determined. small aneurysms in medium-sized arteries may be
Dual-energy x-ray absorptiometry is relatively inex- diagnostic. Similarly, in Takayasus arteritis, the long,
pensive and delivers very little radiation to the patient. smooth tapering of involved vesselsmost often the
It is thus a good choice for studies that must be repeated. subclavian arteriesis highly characteristic. Aortogra-
Any part of the body can be studied. Standard values phy with central aortic pressure measurement is also
important in patients with Takayasus disease, whose REFERENCES

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2
CHAPTER 3
Musculoskeletal Signs and

Symptoms
A. Monarticular Joint Disease
H. RALPH SCHUMACHER, MD
LAN X. CHEN, MD, PHD
Pain or swelling of a single joint merits prompt Analyzing synovial fluid is a helpful way to delineate
evaluation to rule out infectious causes and to identify the cause of monarthritis.
patients in need of urgent and aggressive care.
The underlying causes of monarthritis are divided
into two groups: inflammatory diseases and mechan-
ical or infiltrative disorders.
Pain or swelling of a single joint merits prompt evalua- arthritic symptoms wax and wane with physical activity.
tion to identify patients in need of urgent and aggressive Morning stiffness lasting more than an hour suggests an
care (1). Although there are many minor and easily inflammatory disease.
managed causes of monarthritis, infectious arthritis A history of previous episodes provides support for
with its risk of prolonged morbidity (and even mortal- a crystalline or other noninfectious cause, such as pal-
ity, if untreated) requires that this very serious problem indromic rheumatism (3). Patients with established
always be considered. The underlying causes of monar- rheumatoid arthritis (RA) who develop a dramatic
thritis are divided into two groups: inflammatory dis- monarthritis should always be evaluated for superim-
eases (Table 3A-1) and mechanical or infiltrative posed septic arthritis or crystal-associated disease (4).
disorders (Table 3A-2). Triage into one of these catego- Patients with antecedent joint disease or surgery should
ries is the first step in the differential diagnosis of raise the clinicians concern about infection. In patients
monarthritis. with a prosthesis in the involved joint, loosening of the
implant should also be investigated.
Monarticular arthritis is occasionally the first symp-
DIAGNOSIS OF MONARTICULAR tom of polyarticular disease, such as reactive arthritis,
inflammatory bowel disease, psoriatic arthritis, or RA.
JOINT DISEASE A history of fever, chills, tick bites, sexual risk factors,
travel outside the country, and intravenous drug use (5)
History can contribute clues to infectious causes. Symptoms
It is important to determine the course and duration of such as rash, diarrhea, urethritis, or uveitis might suggest
symptoms, although patients frequently have difficulty reactive arthritis. Weight loss can suggest malignancy or
establishing the exact time of onset, duration, and the other serious systemic disease.
rate of evolution. Acute problems or sudden onset of A history of trauma suggests fracture or an internal
monarthritis often require immediate evaluation and derangement, but minor trauma can also precipitate
therapy. The course of symptoms may provide critical acute gout or psoriatic arthritis, or can introduce infec-
information. Bacterial infection tends to increase in tion. Occupations involving repetitive use of the joint
severity until treated. Viral monarthritis often resolves favor osteoarthritis. Concurrent illnesses and medica-
spontaneously. Fungal or tuberculous (TB) arthritis can tion use may also provide important clues; in addition,
be chronic and can elude diagnosis for years (2). Osteo- they can affect test results and influence the choice or
42
CHAPTER 3 MUSCULOSKELETAL SIGNS AND SYMPTOMS 43
TABLE 3A-1. SOME INFLAMMATORY CAUSES OF passive motion of the joint in all planes usually indicates
MONARTHRITIS. joint involvement. Pain limited to one movement or
tenderness on only one side of the joint suggests a peri-
Crystal-induced arthritis
Monosodium urate (gout) articular problem.
Calcium pyrophosphate dihydrate In any patient with acute monarthritis, it is important
Hydroxyapatite to look for extra-articular signs that might provide clues
Calcium oxalate to specific causes. For example, mouth ulcers may occur
Liquid lipid microspherules
in Behcets syndrome, reactive arthritis, and systemic
Infectious arthritis lupus erythematosus (SLE). Small patches of psoriasis
Bacteria may be found in the anal crease or behind the ears. The
Fungi keratoderma blennorrhagicum of reactive arthritis can
Lyme disease or disease due to other spirochetes
Mycobacteria
be subtle and often affects only the feet. Erythema 3
Virus (HIV, hepatitis B, others) nodosum may occur in sarcoidosis and inflammatory
bowel disease. Skin ulcerations can be a source of
Systemic diseases presenting with monarticular involvement infection.
Psoriatic arthritis
Reactive arthritis
Rheumatoid arthritis
Systemic lupus erythematosus SYNOVIAL FLUID ANALYSIS
Arthrocentesis should be performed in almost every
patient with monarthritis, and it is obligatory if infection
is suspected. Virtually all the important information
outcome of therapy. Because some monarticular dis- from synovial fluid analysis is obtained through the
eases are inherited, family history can be helpful. gross examination, total leukocyte and differential
count, cultures, Gram staining, and examination of a
wet preparation for crystals and other microscopic
PHYSICAL EXAMINATION abnormalities (6). All these studies can be performed
with only 1 to 2 mL of synovial fluid. Even a few drops
The clinician must first distinguish arthritis, which may be adequate for culture, Gram staining, and wet
involves the articular space, from problems in periar- preparations. Cloudy synovial fluid is likely to be caused
ticular areas, such as bursitis, tendinitis, osteomyelitis, by inflammatory arthritis and is confirmed by a leuko-
or cellulitis. In arthritis, the swelling and tenderness cyte count (see also Chapter 7C).
tend to surround the joint. If normal joint motion is Normally, synovial fluid contains fewer than 200
retained, true arthritis is unlikely. Painful limitation of leukocytes/mm3, most of which are mononuclear
cells. In general, the leukocyte count and the suspicion
of infection should rise at the same ratethe higher
the count, the greater the suspicion. Effusions with
more than 100,000 leukocytes/mm3 are considered
TABLE 3A-2. SOME NON-INFLAMMATORY CAUSES septic until proved otherwise. However, leukocyte
OF MONARTHRITIS.
counts vary widely in both sterile and septic inflam-
Amyloidosis matory arthritis. Synovial fluid should be cultured if
there is any suggestion of infection. Special stains and
Osteonecrosis
cultures for mycobacteria and fungi are sometimes
Benign tumor appropriate.
Osteochondroma Careful examination for crystals in synovial fluid can
Osteoid osteoma
Pigmented villonodular synovitis
establish a diagnosis early and avoid unnecessary hos-
pital admissions for the treatment of suspected infec-
Fracture tious arthritis. A tentative diagnosis can be made by
Hemarthrosis
standard light microscopy. Monosodium urate crystals
are needle or rod shaped, and calcium pyrophosphate
Internal derangement dihydrate (CPPD) crystals are usually short rods,
Malignancy squares, or rhomboids. Polarized light examination can
confirm the nature of these crystals. Individual apatite
Osteoarthritis crystals, which cause acute monarthritis or periarthritis,
Foreign bodies are visible only on electron microscopy. However,
masses of these crystals look like shiny, nonbirefringent
44 H. RALPH SCHUMACHER AND LAN X. CHEN
clumps that resemble cell debris. Special stains such as culture of synovial tissue may be more informative than
alizarin red S can confirm that these clumps are masses a synovial fluid culture in certain settings, such as when
of calcium crystals. gonococcal or mycobacterial disease is suspected or
The presence of crystals does not exclude infection, when no fluid is available for culture. Biopsies can iden-
however, especially because antecedent joint disease tify infiltrative diseases, such as amyloidosis, sarcoid-
such as gout may coexist with or predispose to septic osis, pigmented villonodular synovitis, or tumor. The
arthritis (7). Large fat droplets in synovial fluid suggest polymerase chain reaction and immunoelectron micro-
a fracture involving the bone marrow space. Small lipid scopy may help identify DNA sequences from many
droplets may also indicate fracture or pancreatic fat organisms including mycobacteria (10), Borrelia
necrosis. burgdorferi, Neisseria gonorrhoeae, chlamydia, and
ureaplasma (11).
LABORATORY TESTS INITIAL TREATMENT

Synovial fluid cultures may be negative in some infec-
Management decisions often must be made before all
tious arthritis. This is especially true for gonococcal
test results are available. For example, a patient with
arthritis, as only about 25% of patients have positive
synovial fluid indicating a highly inflammatory process,
synovial fluid cultures. For this reason, cultures and
a negative Gram stain, and no obvious cause or source
Gram stains of blood, skin lesions or ulcers, cervical or
of infection requires antibiotic coverage while testing
urethral swabs, urine, or any other possible sources of
proceeds. Try to obtain several cultures before initiating
microorganisms should be ordered in suspected infec-
treatment.
tious arthritis. Tests for human immunodeficiency virus
Suspected crystal-induced arthritis in a patient whose
(HIV) antibodies and Lyme antibodies may also be
course is uncomplicated can be treated with full doses
appropriate. However, no single serologic test can
of nonsteroidal anti-inflammatory drugs (NSAIDs) with
establish the cause of any arthritis. For example, rheu-
tapering as the inflammation subsides. Oral cortico-
matoid factor can be positive in many diseases besides
steroids or occasionally colchicine are also effective in
RA, including sarcoidosis and subacute bacterial endo-
gout and pseudogout. NSAIDs are an acceptable initial
carditis. Similarly, an elevated serum uric acid does not
symptomatic treatment in other unexplained inflamma-
mean a patient has gout, and normal urate levels can be
tory arthritis. Acetaminophen may be used during the
seen during the acute phase of gouty arthritis.
evaluation of non-inflammatory arthritis. However,
because NSAIDs and acetaminophen can mask fever
patterns and delay diagnosis, propoxyphene or codeine
RADIOGRAPHS might be preferred in some instances. Acutely swollen
joints can safely be rested, but should not be casted
Radiologic findings are typically unremarkable in most unless a fracture is proved.
patients with acute inflammatory arthritis, other than
showing soft tissue swelling. However, x-ray studies can
help exclude some causes and can provide a useful base-
line for future comparisons. Radiographs of the involved
SPECIFIC TYPES OF
joint may show fractures, tumors, or signs of antecedent MONARTHRITIS
chronic disease such as osteoarthritis. Chondrocalcino-
sis in the involved joint suggests, but does not prove, Infection
that the arthritis is caused by CPPD crystals. X-rays or Between 80% and 90% of nongonococcal bacterial
ultrasound can show calcific peri-arthritis. Magnetic infections are monarticular. Most joint infections
resonance imaging (MRI), although often overused, can develop from hematogenous spread. The discovery of a
localize an infectious or inflammatory process to the primary site of infection can be an important clue to the
joint, its surrounding tissue, or bone (8). MRI can also infectious agent involved. By far the most common
identify meniscal tears and ligament damage. agents are Gram-positive aerobes (approximately 80%)
(12), with Staphylococcus aureus accounting for 60%.
Gram-negative bacteria account for about 18% of infec-
SYNOVIAL BIOPSY tions, and anaerobes are increasingly common causes as
a result of parenteral drug use and the rising number of
Needle biopsy of the synovial membrane or a biopsy immunocompromised hosts. Anaerobic infections are
obtained during arthroscopy may be critical in patients also more common in patients who have wounds of an
with monarthropathy that remains undiagnosed (9). A extremity or gastrointestinal cancers.
N. gonorrhoeae remains a common cause of septic monarticular disease. Penetrating injuries from thorns,
arthritis. It is often preceded by a migratory tendinitis wood fragments, or other foreign materials can cause
or arthritis. Mycobacterial infection may cause monoar- monarthritis (16).
thritis or may involve several joints. The disease is more
likely to be chronic, but acute mycobacterial arthritis Hemarthrosis
has been reported and may even cause podagra (13).
Atypical mycobacterial infections can involve the The most common causes of hemarthrosis, or bleeding
synovium and should be considered in the differential into a joint, are clotting abnormalities due to anticoagu-
diagnosis, especially in immunocompromised hosts and lant therapy or congenital disorders such as hemophilia.
in patients whose joints have been injected frequently Hemarthrosis can also result from scurvy. Fracture of
with corticosteroids. Fungal arthritis is usually indolent, the joint should always be considered in patients with
but cases of acute monarthritis due to blastomycosis hemarthrosis, especially if the synovial fluid is bloody 3
or Candida species have been reported. Acute monar- and contains fat.
thritis associated with herpes simplex virus, Coxsackie
B, HIV, parvovirus, and other viruses has also been Systemic Rheumatic Diseases
described (14).
The joint symptoms of Lyme disease range from Many systemic diseases may present as acute monarticu-
intermittent arthralgias to chronic monarthritis (most lar arthritis, but this is decidedly uncommon and should
often in the knee) to oligoarthritis. Monarthritis can not be emphasized in the differential diagnosis. RA,
also rarely be caused by other spirochetes, such as SLE, arthritis of inflammatory bowel disease, psoriatic
Treponema pallidum. arthritis, Behets disease, and reactive arthritis can all
begin as acute monarthritis. Other causes include sar-
coidosis, serum sickness, hepatitis, sickle cell disease,
Crystal-Induced Arthritis hyperlipidemias, and malignancies. Persistence in evalu-
ating patients for underlying systemic diseases can some-
Gout, which is caused by monosodium urate crystals, is
times lead to an early diagnosis of systemic disease.
the most common type of inflammatory monarthritis.
In a substantial number of patients with synovial
Typically, gout initially involves one first metatarsopha-
fluid findings indicative of inflammatory arthritis, the
langeal (MTP) joint, ankle, midfoot, or knee. However,
cause cannot be determined. Many of these patients
acute attacks of gout can occur in any joint. Later attacks
have transient monarthritis with no recurrences (17).
may be monarticular or polyarticular. Accompanying
Guidelines for the initial evaluation of patients with
fever, although less common with monarticular than
acute musculoskeletal symptoms have been published
with polyarticular gout, can mimic infection.
and include aspects of evaluation of monarthropathy
Calcium pyrophosphate dihydrate crystals can cause
(see Appendix II) (18).
monarthritis that is clinically indistinguishable from
gout and thus is often called pseudogout. Pseudogout is
most common in the knee and wrist, but it has been REFERENCES
reported in a variety of other joints, including the first
MTP joint. Among other crystals known to cause acute 1. Baker DG, Schumacher HR. Acute monarthritis. N Engl
monarthritis are apatites, calcium oxalate, and liquid J Med 1993;329:10131020.
lipid crystals. Apatites have also been recognized as a 2. Pinals Robert S. Sarahs knee: a famous actress with
cause of goutlike podagra. chronic, inflammatory monoarthritis. J Clin Rheumatol
2004;10:1315.
3. Schumacher HR. Palindromic onset of rheumatoid arthri-
Osteoarthritis, Osteonecrosis, tis: clinical, synovial fluid, and biopsy studies. Arthritis
Trauma, and Foreign Body Rheum 1982;25:366369.
4. VanLinhoudt D, Schumacher HR. Acute monosynovitis
Reactions or oligoarthritis in patients with quiescent rheumatoid
Although osteoarthritis is primarily a chronic and slowly arthritis. J Clin Rheumatol 1995;1:4653.
progressive disease, it may present with suddenly wors- 5. Ross JJ, Shamsuddin H. Sternoclavicular septic arthritis:
review of 180 cases. Medicine (Baltimore) 2004;83:139
ening pain, swelling, and even erosions in a single joint
148.
(15). New pain in the knee is often due to an effusion 6. Gatter RA, Schumacher HR, eds. A practical handbook
as a result of overuse or minor trauma. Spontaneous of synovial fluid analysis. Philadelphia: Lea & Febiger;
osteonecrosis, especially of the knee, is seen in elderly 1991:1423.
patients and can lead to pain in a single joint with or 7. Yu KH, Luo SF, Liou LB, et al. Concomitant septic and
without effusion. Trauma to a joint leading to internal gouty arthritis: an analysis of 30 cases. Rheumatology
derangement, hemarthrosis, or fracture can also lead to (Oxford) 2003;42:10621066.
46 H. RALPH SCHUMACHER AND LAN X. CHEN
8. Hoving JL, Buchbinder R, Hall S, et al. A comparison of 13. Boulware DW, Lopez M, Gum OB. Tuberculosis podagra.
magnetic resonance imaging, sonography, and radiogra- J Rheumatol 1985;12:10221024.
phy of the hand in patients with early rheumatoid arthri- 14. Rivier G, Gerster JC, Terrier P, Cheseaux JJ. Parvovirus
tis. J Rheumatol 2004;31:663675. B19 associated monarthritis in a 5 year old boy. J Rheu-
9. Schumacher HR, Kulka JP. Needle biopsy of the synovial matol 1995;22:766777.
membrane: experience with the Parker-Pearson technic. 15. Punzi L, Ramonda R, Sfriso P. Erosive osteoarthritis.
N Engl J Med 1972;286:416419. Best Pract Res Clin Rheumatol 2004;18:739758.
10. van der Heijden IM, Wilbrink B, Schouls LM, et al. Detec- 16. Stevens KJ, Theologis T, McNally EG. Imaging of plant
tion of mycobacteria in joint samples from patients with thorn synovitis. Skeletal Radiol 2000;29:605608.
arthritis using genus specific PCR and sequence analysis. 17. Schumacher HR, Habre W, Meador R, Hsia EC. Predic-
Rheumatology 1999;38:547553. tive factors in early arthritis: long-term follow-up. Semin
11. Rahman MU, Cheema S, Schumacher HR, Hudson AP. Arthritis Rheum 2004;33:264272.
Molecular evidence for the presence of chlamydia in the 18. American College of Rheumatology Ad Hoc
synovium of patients with Reiters syndrome. Arthritis Committee on Clinical Guidelines. Guidelines for
Rheum 1992;35:521529. the initial evaluation of the adult patient with acute
12. Goldenberg DL, Reed JI. Bacterial arthritis. N Engl J musculoskeletal symptoms. Arthritis Rheum 1996;39:
Med 1985;312:764771. 18.
CHAPTER 3
Musculoskeletal Signs
and Symptoms
B. Polyarticular Joint Disease
STERLING WEST, MD
Polyarticular joint pain can be caused by problems complaints are a thorough history and physical
within the joint, around the joint (such as tendons examination.
and adjacent bone), and from psychogenic factors. Onset and course of symptoms, pattern of joint
The two most important diagnostic tools in the involvement, and pain characteristics separate
evaluation of a patient with polyarticular joint inflammatory from non-inflammatory causes.
Polyarticular joint pain can be caused by problems tion of the pattern of joint involvement is a key to the
within the joint (arthritis), from adjacent bone (peri- diagnosis of polyarthritis. However, it is important to
ostitis, osteonecrosis), from surrounding soft tissues understand that all patients will not fit the expected
(bursa, tendon, muscle, nerve), or from psychogenic patterns, and atypical presentations frequently occur.
factors (depression). Arthritis generally causes diffuse Despite the lengthy list of diseases that cause
joint pain that is aggravated by movement. The polyarthritis, a few disorders explain most cases. In one
purpose of this chapter is to discuss the diagnostic study of over 200 patients with early inflammatory
approach and differential diagnosis of acute and chron- synovitis, 60% were diagnosed with either rheumatoid
ic polyarthritis. The two most important diagnostic arthritis (RA) or a spondyloarthropathy at presenta-
tools in the evaluation of a patient with polyarticular tion or during the following year (5). In another study
joint complaints is a thorough history and skillful phys- of 566 patients with early arthritis followed for 2 years,
ical examination (14). Laboratory and radiographic 30% were diagnosed with RA and 46% were given
studies or, rarely, tissue biopsy can support or confirm another diagnosis (crystalline-induced arthritis, sar-
the diagnostic impression formulated after the initial coidosis, reactive arthritis, and psoriatic arthritis) (6).
examination. Following a correct diagnosis, more Among patients with a non-inflammatory polyarthritis,
effective therapy can be prescribed and prognosis osteoarthritis is overwhelmingly the most common
discussed. diagnosis.
CLASSIFICATION OF DIAGNOSTIC APPROACH

POLYARTICULAR
JOINT DISEASE History
The history and physical examination are critical in nar-
There are two main categories of polyarticular rowing the differential diagnosis in a patient presenting
joint disease: inflammatory (Table 3B-1) and non- with polyarthritis. The evaluation should focus on the
inflammatory (Table 3B-2). Both groups can be further time course of the joint symptoms and whether or not
subdivided by characteristic mode of presentation inflammatory signs are present. Additionally, the
(acute vs. chronic) and pattern of joint involvement number and distribution of joint involvement and the
(polyarticular vs. oligoarticular; symmetric vs. asym- presence of any extra-articular manifestations are criti-
metric; with or without axial involvement). Recogni- cal components to consider.
47
48 STERLING WEST
TABLE 3B-1. CLASSIFICATION OF POLYARTICULAR INFLAMMATORY JOINT DISEASE.

SYMMETRIC POLYARTICULAR ASYMMETRIC OLIGOARTICULAR
Infectious arthritis Infectious arthritis

Viral Gonococcal/meningococcal
Parvovirus Lyme disease (late phase)
Hepatitis B and C Fungal and mycobacterial
Others: HIV, EBV, rubella Bacterial endocarditis
Whipples disease
Postinfectious or reactive arthritic Postinfectious or reactive arthritic

Rheumatic fever Rheumatic fever
Poststreptococcal arthritis (PSA) Poststreptococcal arthritis
Reactive arthritis
(Enteric, urogenital)
Palindromic rheumatism Enteropathic arthritis of IBD
Juvenile idiopathic arthritis (Polyarticular) Juvenile idiopathic arthritis (Pauciarticular)
Rheumatoid arthritis Undifferentiated spondyloarthritis
Psoriatic arthritis Psoriatic arthritis
Systemic rheumatic disease Systemic rheumatic disease

Systemic lupus erythematosus Relapsing polychondritis
Sjgrens syndrome Behets disease
Systemic sclerosis Crystal-induced
Poly/dermatomyositis Gout
Mixed connective tissue disease Pseudogout (calcium pyrophosphate
Stills disease (juvenile, adult) deposition disease)
Relapsing seronegative symmetrical synovitis Basic calcium phosphate
with pitting edema (RS3PE) Other systemic illnesses
Polymyalgia rheumatica Familial Mediterranean fever
Systemic vasculitis Carcinomatous
Relapsing polychondritis Pancreatic diseaseassociated arthritis
Hyperlipoproteinemia
Sarcoidosis (chronic)
Multicentric reticulohistiocytosis
Other systemic illnesses

Celiac disease
Sarcoidosis (acute type)
Acute leukemia (children)
Peripheral arthritis with axial involvement

Enteropathic arthritis associated with
inflammatory bowel disease (IBD)
Psoriatic arthritis
Reactive arthritis (enteric, urogenital)
SAPHO (synovitis, acne, pustulosis, hyperostosis,
osteitis)
Whipples disease
Time Course of Joint Symptoms has an insidious onset may have an acute onset in some
patients.
Polyarticular joint symptoms may have an acute or
insidious onset. Acute polyarthritis, especially when ac-
Pattern of Joint Involvement
companied by fever, is always due to an inflammatory
disease and requires immediate evaluation to rule out Particular attention should be given to the pattern
infection or crystalline arthritis (7,8). Alternatively, of joint involvement, which can be additive, migratory,
there are both inflammatory and non-inflammatory or intermittent. The additive pattern is most common
causes of polyarthritis with an insidious onset. Varia- but least specific. It refers to recruitment of new
tions, however, may occur, and a disorder that typically joints while previously involved joints remain involved
TABLE 3B-2. CLASSIFICATION OF NON- Pain Characteristics

INFLAMMATORY POLYARTICULAR JOINT DISEASE.
Inflammatory joint pain involves the joints diffusely and
ASYMMETRIC is present at rest and with normal use. Nocturnal pain
SYMMETRIC POLYARTICULAR OLIGOARTICULAR
may interfere with sleep. This joint pain is associated
Osteoarthritis Osteoarthritis with prolonged stiffness for greater than 30 to 60 min-
Primary generalized Localized utes, which is worse in the morning or after inactivity
Erosive (gelling). Fatigue is common, may be severe, and typi-
cally occurs by early afternoon after stiffness has
Crystal-induced Crystal-induced
CPPD (pseudo-RA type) CPPD (pseudo-OA type) improved. Patients with non-inflammatory joint pain
Basic calcium phosphate Hematologic have pain with activity that is relieved by rest. Although
Hemoglobinopathies they may have stiffness or gelling after inactivity, it typi-
Hemophilia cally lasts less than 15 minutes, and systemic fatigue is
3
Hereditary metabolic Peripheral arthritis with axial not common.
Hemochromatosis involvement
Wilsons disease
Gauchers disease Number and Distribution of
Endocrine Osteoarthritis
Joint Involvement
Myxedematous arthropathy Diffuse idiopathic skeletal Polyarthritis refers to involvement of five or more
hyperostosis (DISH)
Ochronosis
joints. The joint distribution typically is symmetric,
although distribution may go through an initial asym-
Hematologic Spondyloepiphyseal dysplasia metric phase. A wide variety of inflammatory disorders
Amyloid arthropathy may present as acute or chronic polyarthritis and may
Hemoglobinopathies
be recognized by their presenting pattern of arthritis.
Hypertrophic osteoarthropathy The most common identifiable cause of a self-limited
disorder causing acute symmetric polyarthritis involv-
ing the small joints of the hands and wrists is parvovirus-
associated arthritis. The most common cause of a
chronic inflammatory polyarthritis that involves small
and is commonly seen in RA and other systemic rheu- and large joints bilaterally and symmetrically in the
matic diseases. A migratory pattern refers to symptoms upper and lower extremities is RA. The metacarpopha-
being present in certain joints for a few days and then langeal (MCP) joints and proximal interphalangeal
remit, only to reappear in other joints. This pattern is (PIP) joints of the fingers, metatarsophalangeal (MTP)
most characteristic of rheumatic fever, the early phases joints of the feet, and wrists are commonly affected,
of Neisserial infection and Lyme disease, and acute while the distal interphalangeal (DIP) joints, lumbar
childhood leukemia. An intermittent pattern is typified spine, and sacroiliac joints are spared. Inflammatory
by repetitive attacks of acute polyarthritis with com- arthritis in an RA pattern but also involving the DIP
plete remission between attacks. A prolonged period joints of the fingers should always suggest psoriatic
of observation may be necessary to establish this arthritis or multicentric reticulohistiocytosis. Any
pattern. Palindromic rheumatism, crystal-induced dis- patient with inflammatory arthritis involving both ankles
eases, familial Mediterranean fever, and Whipples predominantly should be evaluated for acute sarcoid
disease can intermittently affect joints for a few to arthropathy.
several days at a time, followed by asymptomatic A number of non-inflammatory disorders may cause
periods of varying length over a number of years. RA, a chronic polyarthritis. The most common of these is
relapsing seronegative symmetrical synovitis with primary generalized osteoarthritis, which typically
pitting edema (RS3PE syndrome), systemic lupus ery- involves the DIPs, PIPs, and first carpometacarpal
thematosus (SLE), sarcoidosis, and Stills disease can (CMC) joint of the fingers, hips, knees, and first MTP.
also appear episodically, particularly early in their Hemochromatosis and calcium pyrophosphate disease
disease course. The seronegative spondyloarthropa- (CPPD) should be considered in a patient with chronic
thies may have an intermittent course, but the articular non-inflammatory polyarthritis involving the MCPs,
symptoms in these diseases last for weeks (not days) wrists, shoulders, and ankles, which are joints not typi-
at a time before resolving. The self-limited nature of cally involved with osteoarthritis.
these intermittent arthritides are a valuable discrimi- Oligoarticular arthritis refers to arthritis at two to
nating feature used to narrow the differential four separate joints. The joint distribution is typically
diagnosis. asymmetric. The most common causes of an acute or
50 STERLING WEST
chronic inflammatory oligoarticular arthritis are the uveitis, which may indicate a reactive arthritis or other
seronegative spondyloarthropathies. An asymmetric spondyloarthropathy.
oligoarthritis involving scattered DIP and PIP finger A review of a patients concomitant medical condi-
joints characterizes psoriatic arthritis. The lower extrem- tions, medications, travel, and social history is impor-
ity inflammatory oligoarthritis involving knees and an- tant. Certain disorders, like renal insufficiency, obesity,
kles asymmetrically is typical of an HLA-B27associated and alcoholism, or use of medications such as diuretics
reactive arthritis or an enteropathic arthritis due to and cyclosporine, among others, are associated with
inflammatory bowel disease (IBD). Dactylitis due to gouty arthritis, while hyperparathyroidism and hemo-
inflammation of the small joints of the toes and enthesi- chromatosis are associated with chondrocalcinosis and
tis due to inflammation at sites of ligament/tendon inser- pseudogout. The sexual history should be elicited to
tion into bone are frequently seen in reactive arthritis. help exclude reactive arthritis, gonococcal arthritis, and
Some diseases, such as septic arthritis and crystalline human immunodeficiency virus (HIV) exposures. A
disease, that characteristically present as a monoarticu- history of blood transfusions or intravenous drug use
lar inflammatory arthritis may have an oligoarticular puts patients at risk for hepatitis B, hepatitis C, HIV, or
onset. The most common cause of a non-inflammatory septic arthritis. The use of certain medications, such as
asymmetric oligoarthritis is osteoarthritis. procainamide, hydralazine, and minocycline, can cause
Axial involvement of the spine in a patient present- drug-induced lupus. Travel history or a history of a tick
ing with peripheral polyarthritis is an important clue to bite in an endemic area may indicate Lyme disease.
the diagnosis. Up to 25% of patients with ankylosing Frequent exposure to children may predispose to par-
spondylitis may present with hip or knee oligoarthritis, vovirus infection and rheumatic fever. Tobacco abuse
but eventually all will have evidence of inflammatory may indicate lung cancer in a patient with hypertrophic
sacroiliitis and spondylitis characterized by night pain osteoarthropathy.
and prolonged morning stiffness that improves with
exercise. Patients with psoriatic arthritis, reactive arthri-
tis, or enteropathic arthritis associated with IBD can
Demographics and Family History
have evidence of inflammatory sacroiliitis/spondylitis in The sex, age, and ethnicity of the patient may help
25% of cases. Apart from the sacroiliac joints and spine, narrow the differential in a patient with polyarthritis.
centrally located joints, such as the sternoclavicular and Juvenile idiopathic arthritis occurs in children under
manubriosternal joints, and chest wall can also be age 16 years. Young adult women are the most likely
involved. The most common non-inflammatory cause of group to develop disseminated gonococcal arthritis,
polyarthritis affecting both peripheral joints and the parvovirus, rubella arthritis, and SLE, and rarely
spine simultaneously is osteoarthritis. develop gout unless they have an underlying metabolic
disorder. Young adult men are more likely to develop
Associated Extra-Articular Symptoms and ankylosing spondylitis, reactive arthritis, HIV- and hep-
atitis C-related arthritis. RA and osteoarthritis of the
Medical Conditions fingers are most frequently seen in middle-aged women,
The presence of past or current extra-articular manifes- whereas gout and hemochromatosis are more common
tations may provide important clues to the etiology of in middle-aged men. Individuals 55 to 60 years of age
polyarticular arthritis (Table 3B-3). Fever suggests a are more likely to have primary generalized osteoarthri-
subset of illness including infection (viral, bacterial), tis, CPPD disease, and polymyalgia rheumatica. African
postinfectious (rheumatic fever, reactive arthritis), Americans have a high prevalence of SLE and sarcoid-
systemic rheumatic diseases (RA, SLE, Stills disease, osis, while Asians have more gout. Caucasians are more
vasculitis, IBD), crystal-induced diseases (gout, pseudo- likely to develop a seronegative spondyloarthropathy,
gout), and miscellaneous diseases (malignancy, sarcoid- polymyalgia rheumatica, hemochromatosis, and celiac
osis, mucocutaneous disorders) (7). Night sweats and disease. Certain regions of the world have a higher
weight loss may also be important. Rashes such as prevalence of specific diseases, such as Lyme disease in
psoriatic plaques, erythema migrans (Lyme disease), southern New England, the mid-Atlantic states, upper
erythema nodosum (IBD, sarcoidosis), erythema mar- Midwest, and northern California. Rheumatic fever is
ginatum (rheumatic fever), and butterfly malar rash more likely to occur in various South American and
(SLE), among others, can be particularly useful in the Asian nations, while Behets disease is more frequent
diagnosis. Other potentially important diagnostic clues in Japan and the eastern Mediterranean. Family history
are a history of Raynauds disease, serositis, oral ulcers is important but can be difficult to obtain accurately. It
(IBD, Behets disease), or involvement of the lungs, may be especially important in a patient with oligo- or
heart, kidney, or liver (Table 3B-3). Other important polyarthritis who has a family history of gout, pseudog-
associated symptoms include a history of diarrhea, out, psoriasis, ankylosing spondylitis, rheumatoid arthri-
abdominal pain, urethral discharge, low back pain, and tis, or SLE.
TABLE 3B-3. SYSTEMIC AND ORGAN INVOLVEMENT ASSOCIATED WITH POLYARTHROPATHY.

ORGAN INVOLVEMENT
DISORDER Fever Lungs Eye Gastrointestinal system or liver Heart Kidney
Amyloidosis
Bacterial arthritis
Bacterial endocarditis
Behets disease
Crystal-induced arthritis 3
Erythema nodosum
Familial Mediterranean fever
Hemochromatosis
Hypertrophic osteoarthropathy
Inflammatory bowel disease
Juvenile idiopathic arthritis
Leukemia
Lyme disease
Polymyositis/dermatomyositis
Reactive arthritis
Relapsing polychondritis
Rheumatic fever
Sarcoidosis
Seronegative spondyloarthropathy
Sjgrens syndrome
Stills disease
Systemic sclerosis
Systemic vasculitis
Viral arthritis
Whipples disease
Physical Examination adenopathy, parotid enlargement, oral and genital

ulcers, eye disease (conjunctivitis, uveitis, scleritis, kera-
The physical examination should be used to verify the toconjunctivitis sicca, funduscopic abnormalities), heart
presence of historical features as well as additional find- murmurs (subacute bacterial endocarditis [SBE], rheu-
ings the patient may have not reported. Vital signs can matic fever), bruits, pericardial or pleural friction rubs,
help determine the severity of the illness with fever fine inspiratory rales due to interstitial lung disease,
being most important. Other findings on general exami- hepatosplenomegaly, muscle weakness (polymyositis),
nation that suggest a systemic disorder include lymph- and any neurologic abnormalities (vasculitis). Particular
52 STERLING WEST
attention should be given to the skin and nails, looking may be useful in a patient with a suspected undifferenti-
for characteristic rashes or nodules (rheumatoid, tophi, ated spondyloarthropathy.
or, rarely, xanthomas or amyloid masses). An elevated erythrocyte sedimentation rate (ESR)
In addition to symptomatic joints, all 66 joint areas and C-reactive protein (CRP) are not specific but are
should be examined. Particular attention should be elevated in over 90% of patients with an inflammatory
given to the spine examination to rule out an underlying cause for their polyarthritis. Unfortunately, patients
axial arthritis. Upon examination of the symptomatic with non-inflammatory arthritides may have an ele-
joints, the presence or absence of synovitis should be vated ESR/CRP because of another problem such as
documented. The detection of synovitis limits the dif- diabetes, dysproteinemia, or occult malignancy. Spe-
ferential diagnosis to an inflammatory arthritis and is cific antibody tests can identify exposure to potential
characterized by diffuse involvement of the joint with pathogens such as Group A streptococcus (antistrep-
tenderness, soft tissue swelling, warmth over the joint, tolysin O antibody), parvovirus B19, hepatitis B and C,
and possibly a joint effusion. Significant erythema EpsteinBarr virus, and Borrelia burgdorferi (Lyme
should suggest an infectious or crystalline arthropathy. disease) and should be ordered when these diseases
Active and passive range of motion will be limited in all are suspected clinically.
planes. Crepitus may be heard or felt as the joint is put Autoantibodies, including rheumatoid factor and
through a range of motion. Fine crepitus can arise from antinuclear antibodies (ANA), can be seen in a variety
synovitis, while more medium crepitus can arise from of diseases. Rheumatoid factor should be ordered in
grating of roughened cartilage surfaces or from bone patients suspected to have RA but can also be present
rubbing against bone. The examination of symptomatic in high titers in patients with other diseases which can
joints in patients with a non-inflammatory arthritis typi- cause a polyarthritis resembling RA, such as SLE, sub-
cally shows diffuse involvement with tenderness, bony acute bacterial endocarditis, and hepatitis C. The ANA
enlargement or spurs, minimal if any warmth, and no test has high sensitivity but low specificity for SLE. A
erythema. An effusion, particularly in the knee, may be negative ANA rules out SLE whereas a positive ANA
demonstrated. Range of motion is limited, both pas- with specific antibodies to double-stranded DNA or
sively and actively, in all planes, and medium or coarse Smith (Sm) are virtually diagnostic of SLE in a patient
crepitus may be felt. with polyarthritis.
The musculoskeletal examination may reveal other Synovial fluid should be obtained for total white
characteristic findings to help narrow the diagnostic blood cell count, crystal examination, and cultures when
possibilities. Tenosynovitis causes tenderness and swell- the diagnosis remains uncertain after history, physical
ing along the track of the tendon between joints; it is a examination, and standard laboratory tests. Synovial
characteristic feature of RA, gout, reactive arthritis, and fluid is only diagnostic in patients with infections, gout,
gonococcal arthritis, being distinctly uncommon in other and pseudogout. Otherwise, synovial fluid analysis
causes of polyarthritis. Diffuse bilateral hand edema can only classify the polyarthritis as inflammatory
can be seen in the RS3PE syndrome, mixed connective (>2000 WBC/mm3) or non-inflammatory based on the
tissue disease, scleroderma, polymyalgia rheumatica, synovial fluid WBC count.
RA, and, rarely, psoriatic arthritis. Diffuse swelling of
all fingers is seen in hypertrophic osteoarthropathy and
thyroid acropachy. Painful thickening of the palmar
Radiographic Studies
area of the hands with contractures of the fingers may In an appropriate clinical setting, plain radiographs
occur in association with neoplastic conditions such as may be supportive of a particular diagnosis. The find-
ovarian cancer. ings of chondrocalcinosis and osteoarthritic changes
suggest, but do not prove, these diagnoses without
corresponding synovial fluid analysis. In acute polyar-
Laboratory Studies thritis, radiographs lack specificity and usually only
A limited number of laboratory tests are helpful in the show soft tissue swelling and intra-articular fluid. In
evaluation of polyarthritis. A complete blood count, chronic inflammatory polyarthritis, marginal joint
biochemical tests of renal and liver function, and a uri- erosions are seen earliest in the small joints of the
nalysis may help to identify patients with a systemic hands, wrists, and feet in patients with RA. Chronic
illness. Serum uric acid levels are usually elevated gout can also cause erosions with an overhanging
in gout but can be normal, particularly in patients edge that typically involve small peripheral joints
with a polyarticular onset. Additional tests should be such as the first MTP joint. Radiographs of the axial
ordered, depending on the clinical suspicion. For skeleton may show sacroiliitis early in the course
example, iron studies should be ordered in a patient of ankylosing spondylitis or other seronegative spon-
suspected of having hemochromatosis who has osteoar- dyloarthropathies. Syndesmophytes are seen in more
thritis affecting atypical joints, while an HLA-B27 test longstanding disease. Magnetic resonance imaging is
more sensitive than plain radiographs in demonstrat- Acute Inflammatory Polyarthritis

ing erosions early in the course of RA or sacroiliitis
in patients with a recent onset of a seronegative Viral Arthritis
spondyloarthropathy. A common cause of acute inflammatory polyarthritis is
parvovirus B19associated arthritis. It occurs most com-
Tissue Biopsy monly in young women with frequent exposure to young
children. This self-limited polyarthritis resembles acute
Rarely will a diagnosis of polyarthritis depend on a RA with morning stiffness and symmetric involvement
biopsy of synovium or other tissues. However, tissue of the hands and wrists, often lasting for weeks. The
biopsy may be helpful in establishing a diagnosis of typical viral exanthem may be absent. The diagnosis is
Whipples disease, Lyme disease, sarcoidosis, amy- confirmed serologically. A similar arthritis can be seen
loidosis, hemochromatosis, leukemia, and multicentric with hepatitis B, HIV, EpsteinBarr virus (EBV), and 3
reticulohistiocytosis. rubella. Hepatitis Bassociated arthritis precedes other
signs of hepatitis and is often accompanied by an urti-
carial rash. Acute HIV and EBV can resemble SLE
DIFFERENTIAL DIAGNOSIS with fever, rash, polyarthritis, hematologic abnormali-
ties, and a positive ANA.
In addition to polyarthritis, there are several other dis-
orders that need to be considered in the patient present-
ing with polyarticular pain. These patients may complain Rheumatic Fever
of joint pain, but the joint examination will be normal
with full passive range of motion and no evidence of Acute rheumatic fever in children typically presents with
synovitis. The most common disorder causing polyar- fever and a migratory arthritis that involves several
ticular symptoms is fibromyalgia manifested as diffuse joints simultaneously but persists in each joint for only
pain, characteristic tender points in periarticular areas, a few days. In adults, the arthritis is typically less acute,
and normal joint examination, laboratories, and radio- additive, of longer duration, and has been termed post-
graphs. Another important cause of diffuse pain is streptococcal reactive arthritis. Large joints of the lower
depression. Patients with psychogenic factors contri- extremities are most commonly involved. Carditis, ery-
buting to their joint pain typically have pain that does thema marginatum, and chorea, which can occur in
not change with rest and activity and may have severe childhood, are rare in adults. Streptococcal pharyngitis
fatigue. Their joint examination, however, will be is commonly asymptomatic. Therefore, serologic evi-
normal. A common cause of oligoarticular pain is mul- dence should be sought in all patients with polyarthritis
tiple areas of tendinitis or bursitis. This manifests as and fever. The fever usually fluctuates without return-
localized joint pain in specific areas that may cause limi- ing to normal for a week or more. In children, the fever
tation of active range of motion in only one plane with and arthritis respond well to high dose aspirin therapy,
preserved passive range of motion. Other less common while in adults the response is less dramatic.
but important disorders causing polyarticular pain
include muscle disorders, neuropathies, hypothyroid-
ism, primary bone diseases (osteomalacia, Pagets Rheumatic Diseases
disease, osteonecrosis, stress fractures), myeloma, Adult and juvenile rheumatoid arthritis and psoriatic
metastatic cancer, vasculitis, vaso-occlusive diseases arthritis can present as acute polyarthritis but typically
(emboli), and malingering. have a more insidious onset. Both children and adults
can develop Stills disease, which is characterized
by high spiking fevers, polyarthritis, pericarditis, an
SPECIFIC DISEASES CAUSING evanescent truncal rash, neutrophilic leukocytosis,
POLYARTHRITIS and the absence of a rheumatoid factor and ANA.
The fever characteristically spikes up to 104F once or
The preceding discussion emphasizes that the key to the twice a day and returns to normal or below normal
correct diagnosis of polyarticular pain is an accurate between fever spikes. The synovitis may be intermit-
history and physical examination supported by labora- tent initially, but a persistent polyarthritis develops
tory and radiographic tests. What follows is an abbrevi- in most patients.
ated discussion of the most common diseases causing Systemic lupus erythematosus may present with acute
certain patterns of polyarthritis. Notably, several of polyarthritis that can be additive, migratory, or inter-
these diseases may have more than one presentation, mittent and may occur with fever. Characteristic rashes,
may change their articular pattern over time, or may other extra-articular manifestations, and a positive
have an atypical course. ANA support the diagnosis. Relapsing seronegative
54 STERLING WEST
symmetrical synovitis with pitting edema (RS3PE) is may be present. Pseudogout as a presentation of CPPD
associated with marked joint stiffness and symmetric favors the wrist and knee, and occurs primarily in elderly
polysynovitis involving the hands and feet. The onset is patients. In each disease, demonstration of appropriate
abrupt. Profound pitting edema of the hands may lead crystals in the synovial fluid confirms the diagnosis.
to carpal tunnel syndrome, and large joints can be Radiographs may show typical erosions in chronic gout
involved. It is typically seen in patients over the age of or chondrocalcinosis in CPPD disease.
60 and is more common in men. Patients with polymy-
algia rheumatica can have a similar presentation. Rheumatic Diseases
Reactive arthritis due to prior enteric or genitourinary
Other Systemic Illnesses infection may present with fever and an acute sterile
Acute leukemia in children may cause recurrent acute lower extremity oligoarticular arthritis. Dactylitis,
episodes of arthritis and bone pain. Acute sarcoid arthri- inflammatory back pain, and extra-articular manifesta-
tis usually is accompanied by fever, erythema nodosum, tions of conjunctivitis, uveitis, oral ulcers, or character-
and hilar adenopathy. Marked periarticular swelling istic rashes support the diagnosis. A similar large joint
and erythema in both ankles is characteristic of this oligoarticular arthritis may occur in patients with active
disease. inflammatory bowel disease. It usually remits when the
bowel disease is suppressed. Palindromic rheumatism
causes recurrent attacks of acute synovitis in one to five
Acute Inflammatory joints at a time with irregular, symptom-free intervals
Oligoarthritis between attacks. The pattern of joints involved tends to
be the same in an individual patient. Attacks are sudden
Infectious Arthritis
and pain intense, often reaching a peak within a few
Bacterial septic arthritis usually presents as a monoar- hours. In some patients, this presentation may be the
thritis, but in 10% to 20% of adults can involve two or earliest manifestation of RA or SLE, particularly if they
more large joints. Risk factors for this presentation have positive serologies.
include immunosuppression, intravenous drug use,
and preexisting joint disease such as RA. In contrast,
Other Systemic Diseases
gonococcal and meningococcal arthritis frequently
involve more than one joint and may present with Familial Mediterranean fever is characterized by irregu-
a migratory pattern. Vesiculopustular skin lesions on lar attacks lasting 1 to 3 days of fever, abdominal pain,
the extremities may provide an important diagnostic and arthritis with onset in childhood. Arthritic attacks
clue. Tenosynovitis frequently is found in the wrist typically involve one or more lower extremity joints.
and ankle extensor tendon sheaths. Synovial fluid cul- Although pain is severe, joint erythema and warmth are
tures are usually sterile early in the course, but blood notably absent. Carcinomatous polyarthritis is a seroneg-
cultures may be diagnostic. Fungal and mycobacterial ative, lower extremity large joint arthritis with an explo-
infections typically cause a chronic monarthritis but in sive onset that occurs in close temporal relationship
immunosuppressed patients can rarely cause an acute with the diagnosis of a malignancy. The arthritis
oligoarticular arthritis. Bacterial endocarditis may pre- improves with treatment of the underlying cancer. Epi-
sent with fever, back pain, and arthralgias. A minority sodic arthritis and periarthritis have been described in
of the patients have large joint oligoarticular arthritis, some types of hyperlipoproteinemia.
usually of the lower extremities. Synovial fluid cultures
are sterile, and rheumatoid factor may be Chronic Inflammatory
positive. Endocarditis should be suspected in anyone
with a heart murmur and fever. Blood cultures will be Polyarthritis
confirmatory. Patients with inflammatory polyarthritis and oligoartic-
ular arthritis of less than 3 months duration are the most
Crystalline Arthritis difficult to classify accurately. The most important factor
is to identify patients who are likely to have persistent
Crystal-induced arthritis is generally monoarticular but arthritis that might cause joint injury. Recently, a pre-
may present as an acute oligoarticular arthritis, often diction model based upon data from over 500 patients
with fever. Typically, joint pain comes on suddenly and with early arthritis demonstrated that a combination of
reaches a maximum intensity within hours. The joints clinical, laboratory, and radiographic data could predict
are warm and erythematous, and swelling extends to the which patients were at risk for developing persistent
soft tissues well beyond the joint. Gouty arthritis usually and/or erosive disease (6). The seven most important
affects the feet, especially the first MTP joint, and tophi features included: (1) symptoms lasting over 12 weeks;
(2) morning stiffness lasting over 1 hour; (3) demon- on radiographs, even in patients with a deforming
strable synovitis in three or more joint areas; (4) pain arthritis. Drug-induced lupus presents with a symmetric
with metatarsal compression; (5) positive rheumatoid polyarthritis associated with systemic manifestations
factor; (6) positive anti-cyclic citrullinated protein such as fever and serositis. Other systemic rheumatic
(CCP) antibodies; and (7) erosions on radiographs of diseases can have an inflammatory polyarthritis, includ-
the hands or feet. Not surprisingly most of these patients ing mixed connective tissue disease and systemic sclero-
have or will develop RA. However, many patients with sis. Patients with these diseases will also have Raynauds
early inflammatory polyarthritis have only a couple of disease and skin thickening. Patients with polymyositis
these features yet will manifest a persistent arthritis that and dermatomyositis may have a polyarthritis accompa-
defies classification. Two recent studies have empha- nied by proximal muscle weakness and/or a character-
sized that 25% to 30% of patients presenting with early istic rash.
synovitis continue to have an undifferentiated polyar- 3
thritis even after 1 to 2 years of follow-up (6,9). This is
an important group, as up to 42% have progressive
Other Systemic Illnesses
disease that will need therapy (9).
The remainder of this section will discuss causes Hepatitis C viral infection may be associated with a
of chronic inflammatory polyarthritis that can be chronic polyarthritis resembling RA. These patients
classified. may have a high titer rheumatoid factor but negative
anti-CCP antibodies and no erosions on radiographs.
Cryoblobulinemia, hypocomplementemia, and vasculi-
Rheumatoid Arthritis tis may be seen. Any patient with polyarthritis and
Adult and juvenile rheumatoid arthrtis is the most elevated liver-associated enzymes should be evaluated
common cause of a chronic inflammatory polyarthritis. for hepatitis C infection. Multicentric reticulohistio-
Approximately 30% to 40% of patients presenting to cytosis can also cause a destructive arthritis that mimics
an early polyarthritis clinic have RA (5,6). Patients RA. Involvement of the DIP joints and the presence
classically present with a symmetric polyarthritis that of periungual nodules should help define the
usually affects MCPs, PIPs, wrists, and MTPs. Other diagnosis.
patients may have an additive pattern with an oligoar-
ticular onset. Prolonged morning stiffness upon awak-
ening and gelling after periods of inactivity are common. Chronic Inflammatory Oligoarticular
Proliferative synovitis of symptomatic joints may lead
to deformities and erosions on radiographs. Extra- Arthritis with or Without Axial
articular manifestations include subcutaneous nodules Involvement
(25%), pleural effusions, episcleritis, and vasculitis,
among others. Rheumatoid factor is positive in 70% to
Seronegative Spondyloarthropathies
85% of patients, while anti-CCP is positive in only 50% This group includes ankylosing spondylitis, psoriatic
to 60% of patients, but is more specific (95%). arthritis, reactive arthritis, and enteropathic arthritis
related to IBD. These diseases are the most common
cause of an asymmetric oligoarticular inflammatory
Psoriatic Arthritis arthritis. Dactylitis and enthesopathy are common find-
Psoriatic arthritis can have several presentations. The ings. The sacroiliac joints and spine are frequently
typical onset is as an oligoarticular arthritis that may involved. Ankylosing spondylitis may present with
evolve into a symmetric small and large joint polyarthri- peripheral arthritis (25%), typically of the hips, shoul-
tis resembling RA. The involvement of the DIP joints, ders, and knees. Some may also develop an acute ante-
presence of psoriatic plaques, and the absence of rheu- rior uveitis, while all will eventually have inflammatory
matoid factor support the diagnosis. low back pain and stiffness leading to bilateral sacroili-
itis and possibly syndesmophytes on radiographs. This
disease occurs primarily in Caucasian males less than
Systemic Rheumatic Disease age 40 and has a strong association with HLA-B27.
Systemic lupus erythematosus frequently presents as Psoriatic arthritis most commonly presents with an oli-
a symmetric polyarthritis that may be confused with goarticular upper extremity arthritis with DIP involve-
RA if other extra-articular manifestations have not yet ment, while reactive arthritis and enteropathic arthritis
appeared. The arthritis may be migratory or inter- associated with IBD cause a lower extremity oligoartic-
mittent and extremely painful. Synovial proliferation ular arthritis involving knees, ankles, and toes. Sacroi-
is not as evident as with RA but can lead to RA-like liitis can be present in 25% and characteristically is
deformities. Notably, articular erosions are not present unilateral or asymmetric on radiographs.
56 STERLING WEST
Juvenile Idiopathic Arthritis Patients with hand osteoarthritis often have a strong
family history.
The pauciarticular form of juvenile idiopathic arthritis Erosive inflammatory osteoarthritis is localized to the
occurs most commonly in young girls less than age 5. It DIP, PIP, and first CMC joints of the hands. It causes
presents with involvement of one to four joints, typi- more pain, tenderness, and soft tissue swelling than
cally including the knee. There is a striking association does typical nodal osteoarthritis. Patients with this
with a positive ANA and chronic uveitis, which can lead variant experience rapid loss of motion from joint
to blindness. destruction that may lead to bony ankylosis. Other
patients with osteoarthritis have only one to a few
Infectious Arthritis joints involved. This localized form of osteoarthritis
is the most common cause of an asymmetric non-
The late phase of Lyme disease, fungal, and mycobacte- inflammatory polyarthropathy.
rial infections typically cause a chronic inflammatory
large joint monarticular arthritis, usually involving the
knee. Occasionally more than one joint can be involved. Osteoarthritis in Atypical Joints
Whipples disease is a chronic infection caused by Tro-
phermyma whippleii, which may cause enteritis and oli- When patients present with osteoarthritis in atypical
goarticular or migratory arthritis. Multiple organ joints, such as MCPs, wrists, elbows, shoulders, or the
involvement may suggest the diagnosis, which is con- ankles, secondary causes for osteoarthritis must be
firmed by intestinal, lymph node, or synovial biopsies. ruled out. Calcium-containing crystals can cause osteo-
arthritis in atypical joints. CPPD crystal deposits can
cause progressive degeneration of numerous joints, fre-
Other Systemic Illnesses quently in a symmetric pattern, in elderly patients. The
In Behets disease, recurrent oral and genital ulcer- knees are most commonly involved, followed by the
ations often are accompanied by skin, eye, and neuro- wrists, MCPs, shoulders, and ankles. Chondrocalcinosis
logic manifestations. About half of these patients have is most commonly found in the knees and wrists on
arthritis at some time during the course of the disease. radiographs. Basic calcium phosphate crystals are
Relapsing polychondritis presents with extra-articular responsible for a shoulder osteoarthritis in the elderly.
manifestations, including inflammation and destruction The hips and lateral compartment of the knees can also
of cartilaginous tissues in the nose, ear, and upper be involved. This arthritis has been called the Milwau-
airway. Recurrent oligoarticular arthritis is a frequent kee shoulderknee syndrome.
early or late finding. Sarcoidosis can cause a chronic Hemochromatosis may present in 30% of cases as a
oligoarticular arthritis, typically involving the knee. symmetric non-inflammatory polyarthritis, typically
Most patients have other manifestations of sarcoidosis. involving the MCPs, wrists, knees, and ankles. Other
If the diagnosis is in doubt a synovial biopsy will show extra-articular manifestations may be absent. This most
noncaseating granulomas. commonly occurs in middle-aged Caucasian males and
can be misdiagnosed as seronegative RA. Radiographs,
however, show typical osteoarthritic changes and no
Non-Inflammatory erosions. Iron studies will be abnormally elevated.
Patients with ochronosis lack the enzyme to metabolize
Polyarthropathy homogentisic acid. The polymers of this acid deposit in
Osteoarthritis cartilage, causing it to develop a gray or black discolor-
ation. The cartilage becomes brittle, leading to degen-
Osteoarthritis is the most common cause of an asym-
erative arthritis, particularly in the spine. Multiple levels
metric non-inflammatory polyarthropathy as well as an
of calcified discs can be seen on radiographs of the spine
asymmetric oligoarticular arthritis with or without axial
and should suggest the diagnosis if found in a young
involvement. Primary generalized nodal osteoarthritis
adult.
is an asymmetric non-inflammatory arthritis character-
ized by Bouchards nodes in the PIP joints and
Heberdens nodes in the DIP joints of the hands. Other
joints characteristically involved are the first CMC, cer-
Other Systemic Diseases
vical and lumbar spine, hips, knees, and first MTP joints. Amyloidosis can be primary or secondary to multiple
Pain is aggravated by weight bearing and motion. On myeloma. Arthritis is due to amyloid deposits around
examination, bony enlargement from osteophytes and the joints. Shoulder involvement may be impressive,
crepitus from roughening of articular cartilage may be causing the shoulder pad sign. Hand swelling and
detected. Non-inflammatory synovial fluid may be deformity may resemble patterns seen in RA. Monoclo-
detected as an effusion, particularly in the knees. nal immunoglobulins or light chains usually are found
in the serum or urine. Patients receiving hemodialysis make the diagnosis in the majority of patients present-
may have amyloid deposits derived from beta-2 micro- ing with acute or chronic polyarthritis. Evaluation must
globulin in articular tissues, resulting in chronic arthritis be timely and complete to arrive at the correct diagnosis
and carpal tunnel syndrome. and initiate appropriate treatment.
Hypertrophic osteoarthropathy is a syndrome that
may be caused by carcinoma of the lung as well as other
disorders. The main features are clubbing of the fingers,
osteoarticular pain, and radiographic evidence of peri-
REFERENCES
ostitis. Some patients have symmetric joint swelling,
1. Pinals RS. Polyarticular joint disease. In: Klippel JH, ed.
warmth, and effusions suggesting an inflammatory Primer on the rheumatic diseases, 12th ed. Atlanta: Arthri-
arthritis, but synovial fluid analysis fails to show inflam- tis Foundation; 2001:160165.
mation. Pancreatic diseaseassociated arthropathy can 2. Hbscher O. Pattern recognition in arthritis. In: Hochberg 3
cause an arthritis of the knees and ankles. It is typically MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH,
associated with panniculitis on the extremities, fever, eds. Rheumatology, 3rd ed. London: Mosby; 2003:191
and eosinophilia. Synovial fluid is non-inflammatory but 197.
creamy in color due to lipid droplets caused by fat 3. Sergent JS. Polyarticular arthritis. In: Harris ED, Budd
necrosis from high circulating serum lipase levels RC, Firestein GS, et al., eds. Kelleys textbook of rheuma-
released from the diseased pancreas. tology, 7th ed. Philadelphia: Elsevier Saunders; 2005:514
521.
Hemophilia causes recurrent episodes of pain and
4. McCarty DJ. Differential diagnosis of arthritis: analysis of
swelling due to intra-articular and periarticular hemor- signs and symptoms. In: Koopman WJ, Moreland LW, eds.
rhage. The attacks start in childhood and usually affect Arthritis and allied conditions, 15th ed. Philadelphia: Lip-
only one or two joints at a time. In the absence of factor pincott, Williams & Wilkins; 2005:3749.
VIII replacement therapy, a deforming polyarthritis 5. El-Gabalawy HS, Duray P, Goldbach-Mansky R. Evaluat-
may develop. Sickle cell disease, which also begins in ing patients with arthritis of recent onset: studies in patho-
childhood, often involves bones and joints. Monoarticu- genesis and prognosis. JAMA 2000;284:23682373.
lar or oligoarticular joint swelling can occasionally be 6. Visser H, le Cessie S, Vos K, et al. How to diagnose rheu-
seen. matoid arthritis early: a prediction model for persistent
(erosive) arthritis. Arthritis Rheum 2002;46:357365.
7. Pinals RS. Polyarthritis and fever. N Engl J Med 1994;
330:769774.
SUMMARY 8. American College of Rheumatology Ad Hoc Committee
on Clinical Guidelines. Guidelines for the initial evaluation
There are multiple etiologies for polyarticular symp- of the adult patient with acute musculoskeletal symptoms.
toms ranging from osteoarthritis to rheumatoid arthri- Arthritis Rheum 1996;39:18.
tis. On the basis of the history and physical examination 9. Jansen LM, van Schaardenburg D, von der Horst-
and with support from selected laboratory and radio- Bruinsma IE, Dijkmans BA. One year outcome of undif-
graphic studies, the astute clinician should be able to ferentiated polyarthritis. Ann Rheum Dis 2002;61:700703.
CHAPTER 3
and Symptoms
C. Neck and Back Pain
DAVID BORENSTEIN, MD
Low back pain is one of the most common symp- For most people with low back pain, radiographs and
toms, being second only to the common cold. laboratory tests are not necessary.
The role of the physician is to separate mechanical
from systemic causes of neck and low back pain.
Low back and neck pain are second only to the common patients symptoms and physical signs help differentiate
cold as the most common affliction of mankind. Approx- mechanical from systemic causes of axial pain. The
imately 10% to 20% of the US population has back or initial diagnostic evaluation includes a history and phys-
neck pain each year (1). Low back pain is the fifth most ical examination with complete evaluation of the mus-
common reason for visiting a physician, according to a culoskeletal system, including palpation of the axial
US National Ambulatory Care Survey (2). skeleton and assessment of range of motion and align-
The symptom of axial skeleton pain is associated ment of the spine. Neurologic examination to detect
with a wide variety of mechanical and systemic disor- evidence of spinal cord, spinal root, or peripheral nerve
ders (Table 3C-1) (3). Mechanical disorders of the axial dysfunction is essential. In most patients, radiographic
skeleton are caused by overuse (muscle strain), trauma, and laboratory tests are not necessary. Plain radiographs
or physical deformity of an anatomic structure (herni- and erythrocyte sedimentation rate (ESR) are most
ated intervertebral disc). Systemic disorders that cause informative in patients who are 50 years or older, who
spine pain are associated with constitutional symptoms, have a previous history of cancer, or who have consti-
disease in other organ systems, and inflammatory or tutional symptoms (5).
infiltrative disease of the axial skeleton. Mechanical dis- The initial evaluation should eliminate the presence
orders cause the vast majority of low back or neck pain of cauda equina syndrome and cervical myelopathy,
episodes. Characteristically, mechanical disorders are which are rare conditions that require emergency inter-
exacerbated by certain physical activities and are ventions. Cauda equina compression is characterized
relieved by others, and most of these disorders resolve by low back pain, bilateral motor weakness of the
over a short period of time. More than 50% of all lower extremities, bilateral sciatica, saddle anesthesia,
patients will improve after 1 week, and up to 90% may and bladder or bowel incontinence. The common
improve by 8 weeks. However, a recurrence of spinal causes of cauda equina compression include central
pain occurs in up to 75% of people over the next year. herniation of an intervertebral disc, epidural abscess or
Back pain will persist for 1 year and longer in 10% of hematoma, or tumor masses. In the cervical spine,
the spinal pain population (4). myelopathy with long tract signs (e.g., spasticity, clonus,
positive Babinskis sign, incontinence) indicate com-
pression of the spinal cord. The common causes of
INITIAL EVALUATION myelopathy include disc herniation and osteophytic
overgrowth. If cauda equina syndrome or cervical
In the initial evaluation of patients with spinal pain, the myelopathy is suspected, radiographic evaluation is
physician must separate individuals with mechanical mandatory. Magnetic resonance imaging (MRI) is the
disorders from those with systemic illnesses. The most sensitive radiographic technique for visualizing
58
TABLE 3C-1. DISORDERS AFFECTING THE LOW BACK AND/OR NECK.

Mechanical Infectious
Muscle strain Vertebral osteomyelitis
Herniated intervertebral disc Meningitisa
Osteoarthritis Discitis
Spinal stenosis Pyogenic sacroiliitisb
Spinal stenosis with myelopathya Herpes zoster
Spondylolysis/spondylolisthesisb Lyme disease
Adult scoliosisb
Whiplasha Neoplastic/Infiltrative
Benign tumors
Rheumatologic Osteoid osteoma
Reactive arthritis
Osteoblastoma
Giant cell tumor
3
Psoriatic arthritis Aneurysmal bone cyst
Osteochondroma Hemangioma
Enteropathic arthritis Eosinophilic granuloma
Rheumatoid arthritisa Gauchers diseaseb
Diffuse idiopathic skeletal hyperostosis Sacroiliac lipomab
Vertebral osteochondritisb Malignant tumors
Polymyalgia rheumatica Skeletal metastases
Fibromyalgia Multiple myeloma
Behets syndromeb Chondrosarcoma
Whipples diseaseb Chordoma
Hidradenitis suppurativab Lymphomab
Osteitis condensans iliib Intraspinal lesions
Behcets syndromeb Metastases
Whipples diseaseb Meningioma
Vascular malformations
Endocrinologic/Metabolic Gliomas
Osteoporosisb Syringomyeliaa
Osteomalaciab
Parathyroid diseaseb Hematologic
Microcrystalline disease Hemoglobinopathiesb
Ochronosisb Myelofibrosisb
Fluorosisb Mastocytosisb
Heritable genetic disorders
Referred Pain
Neurologic/Psychiatric Vascular
Neuropathic arthropathyb Abdominal aortab
Neuropathies Carotida
Tumors Thoracic aortaa
Vasculitis Gastrointestinal
Compression Pancreas
Psychogenic rheumatism Gallbladder
Depression Intestine
Malingering Esophagusa
Genitourinary
Miscellaneous Kidney
Pagets disease Ureter
Vertebral sarcoidosis Bladder
Subacute bacterial endocarditisb Uterus
Retroperitoneal fibrosisb Ovary
Prostate
SOURCE: Modified from Borenstein DG, Wiesel SW, Boden SD. Low back and neck pain: comprehensive diagnosis
and management. Philadelphia: Saunders; 2004.
a
Neck predominant.
b
Low back predominant.
60 DAVID BORENSTEIN
the spine. If the clinicians suspicion is confirmed, sur- strate stiffness in all planes of spinal motion. Plain
gical decompression of the compromised neural ele- radiographs of the lumbosacral spine are helpful for
ments is indicated with best results with surgery within identifying early changes, loss of lumbar lordosis, joint
48 hours of onset of symptoms (6). erosions in the lower one third of the sacroiliac joints,
and squaring of vertebral bodies. More costly radio-
graphic tests are not necessary to identify skeletal
SYSTEMIC DISORDERS abnormalities in patients with spondylitis.
The majority of people with spinal pain and systemic Localized Bone Pain
illnesses can be identified by the presence of one or
more of the following: fever or weight loss; pain with Spinal pain localized to the midline over osseous struc-
recumbency; prolonged morning stiffness; localized tures is associated with disorders that fracture or expand
bone pain; or visceral pain. bone. Any systemic process that increases mineral loss
from bone (osteoporosis), causes bone necrosis (hemo-
globinopathy), or replaces bone cells with inflammatory
Fever and Weight Loss or neoplastic cells (multiple myeloma) weakens verte-
bral bone to the point that fractures may occur sponta-
In people with a history of fever or weight loss, spinal
neously or with minimal trauma. Patients with acute
pain frequently is caused by an infection or tumor (7).
fractures experience sudden onset of pain. Bone pain
Vertebral osteomyelitis causes pain that is slowly pro-
may be the initial manifestation of the underlying
gressive, may be either intermittent or constant, is
disorder. On physical examination, palpation of the
present at rest, and is exacerbated by motion. Tumor
affected area produces pain. Plain radiographs may
pain progresses more rapidly. Plain radiographs gener-
reveal alterations but do not show microfractures. Scin-
ally are not helpful unless more than 30% of the bone
tigraphy can detect increased bone activity soon after a
calcium has been lost in the area of the lesion. Bone
fracture occurs, and a CT scan may identify the abnor-
scintigraphy is a sensitive but nonspecific test for
mality. However, locating the lesion is not sufficient to
bone lesions. Areas of bony involvement and soft tissue
define the specific cause of the bony changes. Labora-
extension are identified best by computed tomography
tory tests including ESR, serum chemistries, and com-
(CT) or MRI, respectively.
plete blood count are most helpful in differentiating
between metabolic and neoplastic disorders that cause
Pain with Recumbency localized bone pain.
Tumors, benign or malignant, of the spinal column or

spinal cord are the prime concern in patients with noc- Visceral Pain
turnal pain or pain with recumbency (8). Compression Abnormalities in organs that share segmental innerva-
of neural elements by expanding masses and associated tion with part of the axial skeleton can cause referred
inflammation accounts for the pain. Physical examina- back pain. Viscerogenic pain may arise as a result of
tion demonstrates localized tenderness, and if the spinal vascular, gastrointestinal, or genitourinary disorders.
cord or roots are compressed, neurologic dysfunction. The duration and sequence of back pain follows the
MRI is the most sensitive method to detect bony abnor- periodicity of the diseased organ. Colicky pain is associ-
malities, spinal cord or root compromise, and soft tissue ated with spasm in a hollow structure, such as the ureter,
extension of neoplastic lesions. colon, or gallbladder. Throbbing pain occurs with vas-
cular lesions. Exertional pain that radiates into the left
arm in a C7 distribution may be associated with angina
Morning Stiffness and coronary artery disease. Back pain that coincides
Morning stiffness lasting an hour or less is a common with a womans menstrual cycle may be related to
symptom of mechanical spinal disorders. In contrast, endometriosis.
morning stiffness of the lumbar or cervical spine last- Physical examination of the abdomen may reveal
ing several hours is a common symptom of seronega- tenderness over the diseased organ. Laboratory tests
tive spondyloarthropathy. Bilateral sacroiliac pain is as- are useful to document the presence of an abnor-
sociated with ankylosing spondylitis and enteropathic mality in the genitourinary (hematuria) or gastrointes-
arthritis, while reactive arthritis and psoriatic spondyli- tinal (amylase) systems. Radiographic tests are helpful
tis may have unilateral sacroiliac pain, or spondylitis for diagnosing some visceral disorders. For example,
without sacroiliitis. Women with spondyloarthropathy a CT of the aorta can show abdominal aneurysm
may have neck pain and stiffness with minimal low back and a barium swallow test can reveal esophageal
pain. On physical examination, these patients demon- diverticulum.
MECHANICAL DISORDERS OF The Agency for Health Care Policy and Research
published an evidence-based review of the effective
THE LUMBOSACRAL SPINE therapies for acute low back pain in 1994 (Table 3C-3)
(10). Therapy that combines controlled physical
Mechanical disorders are the most common causes of activity with nonsteroidal anti-inflammatory drugs
low back pain. They include muscle strain, herniated (NSAIDs) and muscle relaxants can help resolve acute
nucleus pulposus, osteoarthritis, spinal stenosis, spon- low back pain (11).
dylolisthesis, and adult scoliosis. The clinical character-
istics of these disorders are listed in Table 3C-2.
Lumbar Disc Herniation
Intervertebral disc herniation causes nerve impinge-
Back Strain ment and inflammation that results in radicular pain
Back strain is preceded by some traumatic event that (sciatica). Herniation occurs with sudden movement,
3
can range from coughing or sneezing to lifting an object and frequently is associated with heavy lifting. Sciatica
heavier than can be supported by the muscles and liga- is exacerbated by activities that increase intradiscal
ments of the lumbosacral spine (9). The typical history pressure, such as sitting, bending, or Valsalvas maneu-
of muscle strain is acute back pain that radiates up the ver. On physical examination, any movement that
ipsilateral paraspinous muscles, across the lumbar area, creates tension in the affected nerve, such as the straight-
and sometimes caudally to the buttocks without radia- leg raising test, elicits radicular pain. Neurologic exami-
tion to the thigh. Physical examination reveals limited nation may reveal sensory deficit, asymmetry of reflexes,
range of motion in the lumbar area, with paraspinous or motor weakness corresponding to the damaged spinal
muscle contraction. No neurologic abnormalities are nerve root and degree of impingement (Table 3C-4).
present. An MRI is the best technique to identify the location
TABLE 3C-2. MECHANICAL LOW BACK PAIN.

SPINAL STENOSIS BACK STRAIN HERNIATED NUCLEUS PULPOSUS OSTEOARTHRITIS
Age at onset >60 2040 3050 >50
Pain Pattern
Location Back Back/leg Back Leg
Onset Acute Acute Insidious Insidious
Upright I D I I
Sitting D I D D
Bending I I D D
SLR test + +(exertion)
Plain x-ray + +
CT/myelogram + +/ +
MRI + +/ +
SPONDYLOLISTHESIS ADULT SCOLIOSIS
Age at onset 2030 2040
Pain Pattern
Location Back Back
Onset Insidious Insidious
Upright I I
Sitting D D
Bending I I
SLR
Plain x-ray + +
CT/myelogram +
MRI +/ +/
ABBREVIATIONS: I, increase; D, decrease; SLR, straight leg raising test.

62 DAVID BORENSTEIN
TABLE 3C-3. AHCPR GUIDELINE FOR ACUTE LOW

BACK PAIN TREATMENT.
Patient Education
Natural history of rapid recovery and recurrence
Safe and effective methods of symptom control
Activity modifications
Limit recurrences
Special investigations required when systemic disorders
suspected
Risks of common diagnostic tests
Treatment recommendations for persistent symptoms
Medications
Acetaminophen
NSAIDs: decision based on comorbidities, toxicities, cost,
patient preferences
Physical Treatments
Spinal manipulation in the first month in the absence of
radiculopathy (efficacy short term)
Activity Modification
Bed rest no more than 4 days
Gradual return to normal activities
Low-impact aerobic exercise
SOURCE: From Agency for Health Care Policy and Research. Acute low back
problems in adults, clinical practice guideline. Rockville, MD: Agency for FIGURE 3C-1
Health Care Policy and Research; 1994. Publication no. 95-0642.
Magnetic resonance scan sagittal view of a 45-year-old man
with right leg radicular pain. The scan reveals herniated discs at
the L3 to L4 and L4 to L5 levels.
of disc herniation and nerve impingement, but is signifi-
cant only when correlated with clinical symptoms
(Figures 3C-1 and 3C-2) (12). Large disc fragments that
enhance with gadolinium during MRI examination are
Lumbosacral Spondylosis
more likely to resorb spontaneously without the need Osteoarthritis of the lumbosacral spine may cause local-
for surgical excision (13). Electromyography (EMG) ized low back pain. As the intervertebral disc degener-
and nerve conduction tests may document abnormal ates, intersegmental instability and approximation of
nerve function after impingement has been present for the vertebral bodies shift the compressive forces across
8 weeks or longer. the zygapophyseal joints. The transition of these facet
Therapy for disc herniation includes controlled phys- joints from nonweight-bearing to weight-bearing joints
ical activity, NSAIDs, and epidural corticosteroid injec- leads to zygapophyseal osteoarthritis (lumbosacral spon-
tion. For most patients, radicular pain resolves in a dylosis). As a result, patients develop lumbar pain that
12-week period. Only 5% or fewer of patients with a increases at the end of the day and radiates across the
herniated disc require surgical decompression (14). low back. The disorder may progress, causing increased
TABLE 3C-4. RADICULAR SYMPTOMS AND SIGNS.

PAIN DISTRIBUTION SENSORY LOSS MOTOR LOSS REFLEX LOSS
Lumbar
4 Anterior thigh to medial leg Medial leg to medial malleolus Anterior tibialis Patellar
5 Lateral leg to dorsum of foot Lateral leg to dorsum of foot Extensor hallucis longus (Posterior tibial)
S1 Lateral foot Lateral foot sole Peroneus longus and brevis Achilles
Cervical
5 Neck to outer shoulder, arm Shoulder Deltoid Biceps, supinator
6 Outer arm to thumb, index finger Thumb, index fingers Biceps, wrist extensors Biceps, supinator
7 Outer arm to middle finger Index, middle fingers Triceps Triceps
8 Inner arm to ring, little fingers Ring, little fingers Hand muscles None
pain that is persistent, regardless of the patients posi-

tion. The physical examination may be unrevealing
unless the patient exercises to the point of developing
symptoms. Sensory, motor, and reflex examination
during the episode of pain reveals abnormal function
that reverses when the pain disappears. Motor weak-
ness is present in one third of patients, and one half
have reflex abnormalities. Plain radiographs of the
lumbar spine may demonstrate degenerative disc disease
with zygapophyseal joint narrowing, even in patients
who are asymptomatic. Thus, radiographic alterations
are significant only if the patient has corresponding 3
symptoms. A CT scan can identify the presence of zyg-
apophyseal joint disease, trefoil configuration of the
spinal canal, and reduced dimensions of the canal. An
MRI can document the location of neural compression
(see Figure 3C-1).
Prescribing NSAlDs and teaching patients appropri-
FIGURE 3C-2 ate spinal biomechanics are the initial therapies for
osteoarthritis and spinal stenosis (16). Facet joint injec-
Magnetic resonance scan axial view of L4 to L5 disc space
demonstrating an extruded herniated disc (white arrow).
tions should be considered when conservative medical
therapy does not provide enough relief. People with
spinal stenosis may benefit from epidural corticoste-
narrowing of the spinal canal that results in spinal steroid injections given every 2 to 3 months. Surgical de-
nosis and compression of neural elements (spinal steno- compression is reserved for patients who are totally
sis). The clinical manifestation of spinal stenosis is incapacitated by pain. Most people with spinal stenosis
neurogenic claudication. Physical examination reveals do not require surgery. In patients of any age who have
that pain worsens with extension of the spine, and no no serious comorbid illness, the first decompression
neurologic deficits are present. Pain radiates into the
posterior thigh and is exacerbated by ipsilateral bending
to the side with the osteoarthritic joints (facet syn-
drome). Oblique views of the lumbar spine demonstrate
facet joint narrowing, periarticular sclerosis, and osteo-
phytes (Figure 3C-3). These findings have significance
only with clinical correlation with historical and physi-
cal factors (15).
Lumbar Spinal Stenosis

Spinal stenosis is secondary to the growth of osteo-
phytes, redundancy of the ligamentum flavum, and pos-
terior bulging of the intervertebral discs. Lumbar
stenosis may be located in the center of the canal, the
lateral recess, or the intervertebral foramen, and may
occur at single or multiple levels. The pattern of radia-
tion depends on the location of nerve compression.
With central canal stenosis, pain in one or both legs
occurs with walking. Unlike vascular claudication, leg
pain appears after walking variable distances. Individu-
als with vascular claudication must stop walking to gain
relief of pain, whereas those with neurogenic claudica-
tion must sit or flex forward, which increases room in
the spinal canal and restores blood flow to the spinal
roots to decrease pain. FIGURE 3C-3
Lateral stenosis causes unilateral leg pain with stand- Lateral radiograph of the lumbar spine demonstrating traction
ing. Stenosis of the intervertebral foramen causes leg osteophytes at the superior endplate of L5 and L4.
64 DAVID BORENSTEIN
operation for spinal stenosis has the greatest chance for Scoliosis
an excellent outcome.
Scoliosis, a lateral curvature of the spine in excess
of 10, most commonly begins to develop in adolescent
girls (18). In the lumbar spine, a curve greater than
Spondylolisthesis 40 generally leads to a constant rate of progression
of 1 per year. Patients complain of increasing back
Spondylolisthesis is the anterior displacement of a ver-
pain that is relieved with bed rest. Neurologic exami-
tebral body in relation to the underlying vertebra. Spon-
nation reveals findings of nerve compression in more
dylolisthesis usually is secondary to degeneration of
severely affected patients. Plain radiographs allow the
intervertebral discs and reorientation of the plane of
clinician to measure the degree of scoliosis by Cobbs
motion of the zygapophyseal joints. The process also
method.
may occur as a developmental abnormality with separa-
In people with scoliosis of 40 or less, exercises,
tion of the pars interarticularis (spondylolysis) (17).
braces, and NSAIDs are effective in reducing pain and
People with spondylolisthesis complain of low back
maintaining function. Surgical fusion and placement of
pain that is exacerbated with standing and is relieved
Harrington rods are reserved for patients with progres-
with rest. Individuals with severe subluxation also have
sive scoliosis who are at increased risk for pulmonary
leg pain. Physical examination reveals increased lor-
compromise (19).
dosis with a step off. The neurologic examination
reveals no abnormality. Plain radiographs are adequate
to demonstrate the lytic lesions in the pars interarti-
cularis, and lateral x-rays demonstrate the degree of
subluxation. An MRI can detect the entrapment and
direct impingement of spinal nerve roots associated
MECHANICAL DISORDERS OF
with this disorder. THE CERVICAL SPINE
Treatment of spondylolisthesis includes flexion
strengthening exercises, NSAIDs, and orthopedic Mechanical disorders of the cervical spine are less
corsets. Fusion surgery is useful for patients with greater common than lumbar spine disorders, tend to be less
than grade II slippage and persistent symptoms of disabling, and result in fewer physician consultations
neural compression. (Table 3C-5).
TABLE 3C-5. MECHANICAL NECK PAIN.

HERNIATED
NUCLEUS
NECK STRAIN PULPOSUS OSTEOARTHRITIS MYELOPATHY WHIPLASH
Age at onset
(years) 2040 3050 >50 >60 3040
Pain Pattern
Location Neck Neck/arm Neck Arm/leg Neck
Onset Acute Acute Insidious Insidious Acute
Flexion I I D D I
Extension D I/D I I I
Plain x-ray + +
CT/myelogram + +/ +
MRI + +/ +
ABBREVIATIONS: I, increase; D, decrease.

Neck Strain unstable. Increased instability results in osteophyte for-

mation in the uncovertebral and zygapophyseal joints,
Neck strain causes pain in the middle or lower part of and local synovial inflammation (cervical spondylosis).
the posterior aspect of the neck. The area of pain may Neck pain is diffuse and may radiate to the shoulders,
be unilateral or bilateral and may cover a diffuse area. suboccipital areas, interscapular muscles, or anterior
Pain may radiate toward the head and shoulder, sparing chest. Involvement of the sympathetic nervous system
the arms. Neck strain, which rarely is associated with a may cause blurred vision, vertigo, or tinnitus. Physical
specific trauma, typically is triggered by sleeping in an examination of most patients reveals little, other than
awkward position, turning the head rapidly, or sneezing. midline tenderness. Plain radiographs of the cervical
Physical examination reveals local tenderness in the spine are adequate to show the intervertebral narrow-
paracervical muscles, with decreased range of motion ing and facet joint sclerosis (Figure 3C-3). The presence
and loss of cervical lordosis (20). Muscles most com- of abnormalities is not necessarily associated with clini- 3
monly affected include the sternocleidomastoid and the cal symptoms.
trapezius. No abnormalities are found on shoulder or Conservative therapy is effective for cervical spondy-
neurologic examination, laboratory tests, or radio- losis. NSAIDs and local injections may diminish neck
graphic studies. and referred pain. The appropriate amount of immobi-
Treatment of neck strain includes controlled phys- lization is controversial, however. The use of cervical
ical activity, limited use of cervical orthoses, NSAIDs, orthoses may increase neck stiffness and pain. Patient
and muscle relaxants. Injections of anesthetic and cor- education should stress the importance of balancing the
ticosteroid are helpful to decrease local muscle pain, need to restrict neck movement with a cervical collar
and isometric exercises should be prescribed to main- and to maintain neck flexibility with range-of-motion
tain strength in the neck. Modifications in the body exercises. Most people with cervical spondylosis have a
mechanics while the patient is at work may help prevent relapsing course, with recurrent exacerbations of acute
recurrences. neck pain.
Cervical Disc Herniation Myelopathy

Intervertebral disc herniation in the cervical spine The most serious sequelae of cervical spondylosis is
causes radicular pain (brachialgia) that radiates from myelopathy. This disorder occurs as a consequence of
the shoulder to the forearm to the hand (21). The pain spinal cord compression by osteophytes, ligamentum
may be so severe that the use of the arm is limited. Neck flavum, or intervertebral disc (spinal stenosis). Cervical
pain is minimal or absent. Cervical herniation occurs spondylotic myelopathy is the most common cause of
with sudden exertion and frequently is associated with spinal cord dysfunction in individuals older than 55
heavy lifting. Physical examination reveals increased years (22). With disc degeneration, osteophytes develop
radicular pain with any maneuver that narrows the posteriorly and project into the spinal canal, compress-
intervertebral foramen and places tension on the ing the cord and its vascular supply. Symptoms may
affected nerve. Spurlings sign (compression, extension, occur with or without movement. The size of the spinal
and lateral flexion of the cervical spine) causes radicular canal is the important static component. Stenosis is
pain. Neurologic examination may reveal sensory deficit, associated with an anteroposterior diameter of 10 mm
reflex asymmetry, or motor weakness corresponding to or less. Dynamic stenosis, which is secondary to insta-
the damaged spinal nerve root and degree of impinge- bility, causes compression of the spinal cord with
ment (Table 3C-3). An MRI is the best tool to identify flexion or extension of the neck. Protruding structures
the location of disc herniation and nerve impingement. that are located anterior to the spinal cord can com-
An EMG and nerve conduction tests may document press the posterior and lateral columns. Compression
abnormal nerve function. of the anterior spinal artery in the lower cervical spine
Therapy includes controlled physical activity, cervi- is another mechanism of spinal cord injury (23). Neck
cal orthoses, NSAIDs, and cervical traction. The pain pain is mentioned by only one third of people with
typically subsides within 3 months; only 20% or fewer myelopathy.
of patients require surgical decompression. Clinical symptoms include a history of peculiar sen-
sations in the hands, associated with weakness and
uncoordination. In the lower extremities, this disorder
Cervical Spondylosis can cause gait disturbances, spasticity, leg weakness,
Osteoarthritis of the cervical spine produces a clinical and spontaneous leg movements. Older patients may
syndrome similar to that in the lumbosacral spine. As describe leg stiffness, foot shuffling, and a fear of
the disc degenerates and the articular structures are falling. Incontinence is a late manifestation. Physical
brought closer together, the cervical spine becomes examination reveals weakness of the appendages in
66 DAVID BORENSTEIN
association with spasticity and fasciculations. Sensory 3. Borenstein DG, Wiesel SW, Boden SD. Low back and
deficits include decreased dermatomal sensation and neck pain: comprehensive diagnosis and management, 3rd
loss of proprioception. Hyperreflexia, clonus, and posi- ed. Philadelphia: Saunders; 2004.
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JTM, Bouter LM. The prognosis of low back pain in
ties. Plain radiographs reveal advanced degenerative
general practice. Spine 1997;22:15151521.
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osteophytes. 15151522.
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mise. Surgical intervention works best before severe
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neurologic deficits are present.
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from the rear causes accelerationdeceleration injury to ville, MD: Agency for Health Care Policy and Research;
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3
CHAPTER 3
and Symptoms
D. Regional Rheumatic Pain
Syndromes
JOSEPH J. BIUNDO, JR., MD
Regional rheumatic pain syndromes typically result Although medications may be useful in the treatment
from injuries related to a specific activity or event. of regional pain syndromes, a more comprehensive
Injuries leading to regional rheumatic pain syn- management approach that takes into consideration
dromes may be caused by a single episode or be the etiology of the complaintoften leading to
the result of repetitive overuse. In either case, activity modificationis a critical part of effective
abnormal body position or mechanics is usually therapy.
present. Nonsteroidal anti-inflammatory drugs are prescribed
This chapter reviews 62 different regional rheumatic frequently for these conditions.
pain syndromes, involving the shoulder, elbow, wrist Local injections and physical therapy also can be
and hand, hip, knee, and ankle and foot. useful components of treatment.
The regional rheumatic pain syndromes, because of cially when abnormal body position or mechanics is
their prevalence, complexity, and lack of diagnostic present. Tendons become less flexible and elastic with
laboratory tests, present a challenge to the clinician. Yet aging, making them more susceptible to injury. Also
success in diagnosis and treatment is most gratifying. with aging and with disuse atrophy, the muscles become
The conditions discussed in this chapter include disor- weaker and exhibit less endurance and bulk, resulting
ders involving muscles, tendons, entheses, joints, carti- in a decreased muscle absorption of mechanical forces
lage, ligaments, fascia, bone, and nerve. A working otherwise transmitted to joints, tendons, ligaments, and
knowledge of regional anatomy and an approach utiliz- entheses. A musculotendinous unit shortened from lack
ing a regional differential diagnosis helps lead to specific of stretching is more prone to injury. Tendon syndromes
diagnoses and problem-focused therapies (1). are basically overuse injuries. Tendinitis may occur
A precise history is needed to identify the conditions when the tendon repeatedly bears more load than it can
present; more than one syndrome can occur concomi- withstand. This may result from excessive high loads
tantly. A complete neuromusculoskeletal examination across normal tendons, or from normal loads across
should be performed emphasizing careful palpation, degenerated tendons.
passive range of motion (ROM), and active ROM alone Any site of tendinitis may result in a calcific tendini-
and, sometimes, with resistance. tis, which usually produces more inflammation with
pain and swelling. The calcification may be detected by
plain x-ray. Magnetic resonance imaging (MRI) and
CAUSATIVE FACTORS ultrasonography are helpful in confirming a diagnosis of
tendinitis. Even though the term tendinitis is used
Many syndromes of the neuromusculoskeletal system throughout this chapter, the term tendinosis might be
are the result of injury from a specific activity or event, more appropriate, as these conditions exhibit degenera-
ranging from one episode to repetitive overuse, espe- tive changes and few inflammatory cells (2). Tendino-
68
pathy is also an acceptable terminology. Tenosynovitis of an area of nonspecific muscle tenderness with a cor-
and peritendinitis refer to an inflammatory response of ticosteroid preparation should be discouraged.
the tenosynovium or peritenon. In addition to the Basic principles of intralesional injections include
overuse, degenerative and inflammatory causes, there aseptic technique and use of small needles (25-gauge
appears to be a genetic predisposition to certain regional 5/8 or 1 or a 22-gauge 1). The use of separate
syndromes, resulting from variations in anatomy and syringes for lidocaine and corticosteroid avoids mixing
abnormal biomechanics. Unfortunately, causative of the two substances, and permits infiltration of lido-
factor(s) often are not identified. caine beginning intracutaneously with a small wheal
and continuing to the site of the lesion. This method
makes the injection relatively painless. When the needle
GENERAL CONCEPTS reaches the desired site, the syringe is changed with the
needle left in place, and the corticosteroid is then 3
OF MANAGEMENT injected. This technique helps avoid possible subcutane-
ous and skin atrophy secondary to corticosteroid use.
Drug Therapy When injecting a tendon sheath, the needle should
Oral medications, including nonsteroidal anti-inflam- be placed parallel to the tendon fibers and not into
matory drugs (NSAIDs) and analgesics, play a role in the tendon itself. Using a more water-soluble cortico-
management of regional musculoskeletal disorders. The steroid may lessen the possibility of corticosteroid-
NSAIDs help reduce inflammation and pain. For addi- induced tendon weakness or postinjection flare in some
tional pain relief, analgesics such as acetaminophen, or patients.
tramadol, and propoxyphen alone or in combination
with acetaminophen can be added. Tricyclic antidepres-
sants, such as amitriptyline, may also be useful in chronic
Physical Therapy
pain and neurogenic or myofascial pain. The goals of therapeutic exercise are to increase flexibil-
Comprehensive management of these regional syn- ity by stretching, increase muscle strength by resistive
dromes should be undertaken rather than relying on exercises, and improve muscle endurance by some
oral medications alone. The causative aspects should be repetitive regimen. The physician should become knowl-
evaluated, and activity modification advised, as needed. edgeable about exercise prescriptions for the various
Local injections and physical therapy also can be useful conditions (4). For example, older women tend to have
components of treatment and will be described below. tight calf muscles, which predispose to calf cramps,
Some guidelines for the management of these condi- Achilles tendon problems, or other ankle and foot dis-
tions are provided in Table 3D-1. orders. Tight quadriceps, hamstring, and iliopsoas
muscles are related to problems in the low back, hip,
and knee regions. Exercise to stretch these muscles can
Intralesional Injections be taught by the physician. Instruction for quadriceps
After specific diagnosis of a regional rheumatic pain strengthening, especially by straight leg raising from the
syndrome, local injection with lidocaine, corticosteroids, sitting position, and for pelvic tilt exercise can be given
or both is often of benefit (3). In fact, the immediate in the office (5). Heat or cold modalities provide pain
pain relief from a properly directed injection into a relief and muscle relaxation and serve as a prelude to
tendon sheath, bursa, enthesis, or nerve area for a spe- an exercise regimen. They are of doubtful benefit when
cific problem further validates the diagnosis. Injection used alone over an extended period.
TABLE 3D-1. GUIDELINES FOR MANAGEMENT OF REGIONAL RHEUMATIC PAIN SYNDROMES.

1. Exclude systemic disease and infection by appropriate methods. Diagnostic aspiration is mandatory in suspected septic bursitis.
Grams stain and culture of bursal fluid provide prompt diagnosis of a septic bursitis.
2. Teach the patient to recognize and avoid aggravating factors that cause recurrence.
3. Instruct the patient in self-help therapy, including the daily performance of mobilizing exercises.
4. Provide an explanation of the cause of pain, thus alleviating concern for a crippling disease. When the regional rheumatic pain
syndrome overlies another rheumatic problem, the clinician must explain the contribution each disorder plays in the symptom
complex and then help the patient deal with each one.
5. Provide relief from pain with safe analgesics, counterirritants (heat, ice, vapocoolant sprays), and, if appropriate, intralesional
injection of a local anesthetic or anesthetic with depository corticosteroid agent.
6. Provide the patient with an idea of the duration of therapy necessary to restore order to the musculoskeletal system.
7. Symptomatic relief often corroborates the diagnosis.
70 JOSEPH J. BIUNDO, JR.
DISORDERS OF THE SHOULDER appearing round or oval and several centimeters in

length. These deposits may resolve spontaneously over
REGION a period of time. A true subacromial bursitis may also be
present when calcific material ruptures into the bursa.
Rotator Cuff Tendinitis The more typical chronic rotator cuff tendinitis mani-
fests as an ache in the shoulder, usually over the lateral
Rotator cuff tendinitis, or impingement syndrome, is the deltoid, and occurs on various movements, especially on
most common cause of shoulder pain. Tendinitis (and abduction and internal rotation. Other symptoms in-
not bursitis) is the primary cause of pain, but secondary clude difficulty in dressing oneself and night pain due
involvement of the subacromial bursa occurs in some to difficulty in positioning the shoulders. Tenderness on
cases (Table 3D-2). The condition may be acute or palpation and some loss of motion may be evident on
chronic and may or may not be associated with calcific examination. The initial movement to detect rotator
deposits within the tendon. The key finding is pain in the cuff tendinitis is to determine whether pain is present
rotator cuff on active abduction, especially between 60 on active abduction of the arm in the horizontal posi-
and 120, and sometimes when lowering the arm. In tion. Passive abduction is then carried out. Usually less
more severe cases, however, pain may begin on initial pain is present on passive abduction than active abduc-
abduction and continue throughout the ROM. In acute tion. Conversely, pain may be increased on active
tendinitis, pain comes on more abruptly and may be abduction against resistance. The impingement sign is
excruciating. Such cases tend to occur in younger patients nearly always positive. This maneuver is performed by
and are more likely to have calcific deposits in the supra- the examiner using one hand to raise the patients arm
spinatus tendon insertion (Figure 3D-1). The deposits in forced flexion while the other hand prevents scapular
are best seen on roentgenogram in external rotation, rotation (6). A positive sign occurs if pain develops at
TABLE 3D-2. REGIONAL RHEUMATIC SYNDROMES.

Shoulder Hip
1. Rotator cuff tendinitis 1. Trochanteric bursitis
2. Rotator cuff tear, complete and incomplete 2. Iliopsoas bursitis (iliopectineal)
3. Proximal bicipital tendinitis 3. Ischial bursitis (ischiogluteal)
4. Tear of proximal bicipital tendon 4. Piriformis syndrome
5. Adhesive capsulitis (frozen shoulder) 5. Meralgia paresthetica
6. Suprascapular neuropathy 6. Coccydynia
7. Long thoracic nerve paralysis
8. Brachial plexopathy Knee
9. Thoracic outlet syndrome 1. Popliteal cysts (Bakers cysts)
2. Anserine bursitis
Elbow 3. Prepatellar bursitis
1. Olecranon bursitis 4. Medial plica syndrome
2. Lateral epicondylitis (tennis elbow) 5. Popliteal tendinitis
3. Medial epicondylitis (golfers elbow) 6. PellegriniStieda syndrome
4. Distal biceps tendinopathy 7. Patellar tendinitis
5. Distal biceps rupture, complete and incomplete 8. Quadriceps tendon and patellar tendon rupture
6. Cubital bursitis 9. Peroneal nerve palsy
7. Triceps tendinitis 10. Patellofemoral pain syndrome
8. Triceps tendon rupture
9. Ulnar nerve entrapment Ankle and foot
1. Achilles tendinitis
Wrist and hand 2. Achilles tendon rupture
1. Ganglion 3. Subcutaneous Achilles bursitis
2. de Quervains tenosynovitis 4. Retrocalcaneal bursitis
3. Intersection syndrome 5. Plantar fasciitis
4. Tenosynovitis of the wrist 6. Posterior tibialis tendinitis
5. Pronator teres syndrome 7. Posterior tibialis tendon rupture
6. Anterior interosseous nerve syndrome 8. Peroneal tendon dislocation and tendinitis
7. Radial nerve palsy 9. Bunionette
8. Posterior interosseous nerve syndrome 10. Hammer toe
9. Superficial radial neuropathy (cheiralgia paresthetica) 11. Metatarsalgia
10. Carpal tunnel syndrome 12. Pes planus
11. Ulnar nerve entrapment at the wrist 13. Pes cavus
12. Volar flexor tenosynovitis 14. Mortons neuroma
13. Dupuytrens contracture 15. Tarsal tunnel syndrome
beneficial; however, the most frequent treatment is

injection of a depot corticosteroid into the subacromial
bursa, the floor of which is contiguous with the rotator
cuff (7).
Rotator Cuff Tear

An acute tear of a rotator cuff after trauma is easily
recognized. The trauma may be superimposed on an
already degenerative and possibly even partially torn
cuff. In trauma resulting in a ruptured cuff, especially
falls, fractures of the humeral head and dislocation of 3
the joint should also be considered. However, at least
one half of patients with a tear recall no trauma. In these
cases, degeneration of the rotator cuff gradually occurs,
resulting in a complete tear. Rotator cuff tears are clas-
sified as small (1 cm or less), medium (13 cm), large
(35 cm), or massive (>5 cm) (8). Shoulder pain, weak-
ness on abduction, and loss of motion occur in varying
degrees, ranging from severe pain and mild weakness to
no pain and marked weakness. A positive drop-arm sign
FIGURE 3D-1 with inability to actively maintain 90 of passive shoul-
der abduction may be present in large or massive tears.
Right shoulder of a 44-year-old man illustrating massive
Surgical repair is indicated in younger patients.
calcareous deposits in the supraspinatus tendon (white arrow)
and subdeltoid bursa (black arrow). Less easily diagnosed is the smaller, chronic com-
plete (full thickness) tear of the rotator cuff or a partial
(incomplete or nonfull thickness) tear. Pain on abduc-
tion, night pain, weakness, loss of abduction, and ten-
or before 180 of forward flexion. Another useful test derness on palpation can be present in both of these
to confirm rotator cuff disease is the impingement test, types of tears. A small complete tear, however, can exist
performed by injecting 2 to 5 mL of 2% lidocaine into despite fairly good abduction. Tears of the rotator cuff
the subacromial bursa. Pain relief on abduction follow- may also occur as a result of the chronic inflammation
ing the injection denotes a positive impingement test. in RA, and is often present with cystic swelling around
The same test can be used in another way to determine the shoulder.
whether apparent shoulder weakness is due to pain. Magnetic resonance imaging has become the most
Once pain is eliminated with the injection, the arm is expeditious imaging technique to determine a tear (9).
retested for weakness. If the weakness is still present, Diagnostic ultrasonography can also be used. The most
the result is again considered positive. definitive diagnosis of a ruptured rotator cuff is estab-
The causes of rotator cuff tendinitis are multifacto- lished by an abnormal arthrogram showing a com-
rial, but relative overuse, especially from overhead munication between the glenohumeral joint and the
activity causing impingement of the rotator cuff, is com- subacromial bursa. In a partial tear, in which an intact
monly implicated. Compression of the rotator cuff layer of rotator cuff tissue still separates the joint space
occurs above by the edge and undersurface of the ante- from the subacromial bursa, a small ulcerlike crater is
rior third of the acromion and the coracohumeral liga- seen on the arthrogram. Small complete tears and
ment and below by the humeral head. There is also incomplete tears of the rotator cuff are treated conser-
age-related decrease in vascularity and degeneration of vatively with rest, physical therapy, and NSAIDs.
the cuff tendons and reduction of strength of the cuff Although their role has not yet been established by
muscles due to aging or decline in use. Osteophytes on careful studies, subacromial injections of a corticoste-
the inferior portion of the acromioclavicular joint or roid may relieve pain.
acute trauma to the shoulder region contribute to devel-
opment of tendinitis. An inflammatory process such as
rheumatoid arthritis (RA) can also cause rotator cuff Bicipital Tendinitis and Rupture of
tendinitis independent of impingement.
Treatment consists of rest and modalities such as hot
the Proximal Bicipital Tendon
packs, ultrasound, or cold applications, with specific This condition is manifested by pain, most often in the
ROM exercises as soon as tolerated. NSAIDs are often anterior region of the shoulder and occasionally more
diffusely. The pain may be acute, but is usually chronic Suprascapular Neuropathy
and is related to impingement of the biceps tendon by
the acromion. Tenosynovitis of the long head of the The suprascapular nerve, which innervates the supra-
biceps is present, and the tendon may be frayed and spinatus and infraspinatus, may be damaged by trauma,
fibrotic. Palpation over the bicipital groove reveals overactivity of the shoulder, local ganglion, or a frac-
localized tenderness. The patients response should be ture of the scapula. The nerve may be compressed at
compared with palpation of the opposite side, as this the suprascapular notch. The condition is marked by
tendon has normal tenderness. Pain may be reproduced weakness on abduction and external rotation. In
over the bicipital tendon in some cases by supination of chronic cases, atrophy of the supraspinatus and infra-
the forearm against resistance (Yergasons sign), shoul- spinatus muscles may be seen. Electrodiagnostic studies
der flexion against resistance (Speeds test), or by exten- help confirm the diagnosis. Treatment generally con-
sion of the shoulder. Bicipital tendinitis and rotator cuff sists of physical therapy and may include a local corti-
tendinitis may occur at the same time. Treatment of costeroid injection into the area of the suprascapular
bicipital tendinitis consists of rest, hot packs, ultrasound, notch. In some chronic cases, surgical decompression
and, as pain subsides, passive then active ROM exer- is needed.
cises. NSAIDs may be helpful, and occasionally a small
amount of corticosteroid carefully injected in the tendon Long Thoracic Nerve Paralysis
sheath may be of benefit.
Rupture of the proximal tendon occurs at the su- Injury to the long thoracic nerve produces weakness of
perior edge of the bicipital groove. Full rupture of the the serratus anterior muscle, resulting in a winged
long head of the tendon produces a characteristic bul- scapula. Pain may be felt along the base of the neck and
bous enlargement of the lateral half of the muscle belly. downward over the scapula and deltoid region, along
Generally, this condition is treated conservatively. with fatigue on elevation of the arm. The winging of the
scapula becomes apparent when the patient pushes
against the wall with arms outstretched. Trauma and
Adhesive Capsulitis diabetes seem to be common causes of this disorder, but
Known also as frozen shoulder or pericapsulitis, adhesive it is often idiopathic and usually self-limited.
capsulitis is associated with generalized pain and tender-
ness with severe loss of active and passive motion in all Brachial Plexopathy
planes. It is rare before age 40 and may be secondary to
any type of shoulder problem. Muscle atrophy may occur Brachial plexopathy presents with a deep, sharp shoul-
early in the course. Every stiff and painful shoulder, der pain of rapid onset made worse by abduction and
however, is not necessarily adhesive capsulitis. Inflam- rotation and followed by weakness of the shoulder
matory arthritis and diabetes may also be causes of girdle. An electromyogram helps confirm this diagnosis
adhesive capsulitis. Additional factors such as immobil- by demonstrating positive sharp waves and fibrillations
ity, low pain threshold, depression, and neglect or in the involved muscles. Recovery may take from 1
improper initial treatment also favor the development of month to several years. Brachial plexopathy can result
a frozen shoulder. Many cases, however, are idiopathic. from trauma, tumor, radiation, inoculation neuritis, dia-
The joint capsule adheres to the anatomic neck, and the betes, infection, or median sternotomy done for cardiac
axillary fold binds to itself, causing restricted motion. surgery, or it can be idiopathic.
The capsule becomes thickened and contracted.
Arthrography helps confirm this diagnosis by showing
a decrease in volume of the shoulder joint capsule with
Thoracic Outlet Syndrome
loss of the normal axillary pouch and often the absence The thoracic outlet syndrome includes a constellation of
of dye in the biceps tendon sheath. The joint may accept symptoms resulting from compression of the neurovas-
as little as 0.5 to 3.0 mL of dye or occasionally up to cular bundle, where the brachial plexus and subclavian
10 mL, whereas a normal shoulder joint has a capacity artery and vein exit beneath the clavicle and subclavius
of 28 to 35 mL. A frozen shoulder is best treated with a muscle. The neurovascular bundle is bordered below by
comprehensive program involving NSAIDs and corti- the first rib, anteriorly by the scalenus anterior muscle,
costeroid injections into the glenohumeral joint and the and posteriorly by the scalenus medius muscle. The
subacromial bursa (10). Physical therapy consists of ice clinical picture depends on which component is com-
packs, ultrasound, transcutaneous electrical nerve stim- pressedneural, vascular, or both. Neurologic symp-
ulation, and gentle ROM exercisesbeginning with toms predominate in most patients. Pain, paresthesia,
pendulum exercises and wall climbing with the fingers and numbness are the principal symptoms, radiating
and finally active ROM and strengthening exercises. from the neck and shoulder down to the arm and hand,
Manipulation under anesthesia may be needed in rare especially distributing to the ring and little fingers.
resistant cases. Symptoms are worsened by activity. Weakness and
atrophy of intrinsic muscles may appear as a late finding. alysis. With septic olecranon bursitis, localized erythema
Vascular symptoms consist of discoloration, tempera- and warmth over the bursa are the major clues. Pain
ture change, pain on use, and Raynauds phenomenon. and a positive culture are also frequently present. The
A careful neurologic examination and evaluation for condition is treated by aspiration, drainage, and the
arterial and venous insufficiency and postural abnor- administration of appropriate antibiotics. Surgical exci-
malities should be done. The Adson test, in which the sion is occasionally needed.
patient holds a deep breath, extends his neck, and then
turns his chin toward the side being examined, is posi-
tive when the radial pulse becomes extremely weak or
Lateral Epicondylitis
disappears. Many normal people have this finding, but Lateral epicondylitis, or tennis elbow, is a common con-
if the maneuver reproduces the patients symptoms, it dition in those who overuse their arms. Localized ten-
is more significant. With the hyperabduction maneuver, derness directly over or slightly anterior to the lateral 3
the radial pulse is monitored when the patient raises an epicondyle is the hallmark of this disorder. Pain may
arm above the head. A reduction in the radial pulse occur during handshakes, lifting a briefcase, or other
strength may indicate arterial compression. Again, this similar activities. Probably less than 10% of patients
test may be positive in normal people. A chest roent- actually acquire lateral epicondylitis through playing
genogram should be obtained to look for a cervical rib, tennis; job and recreational activities, including garden-
an elongated transverse process of C7, or healing frac- ing and other athletics, are the usual causes. Pathologi-
tures or exostoses. Because of the difficulty in measur- cally, the condition consists of degeneration of the
ing nerve conduction velocity of the involved nerves, common extensor tendon, particularly of the extensor
results of these tests have been somewhat inconsistent, carpi radialis brevis tendon. Because of the degenerative
but in capable hands they furnish additional supporting findings, rather than inflammation, the term angiofibro-
information. Somatosensory evoked potentials have blastic tendinosis has been proposed by Nirschl (12).
also been used successfully. An angiogram or venogram Treatment is aimed at altering activities and prevent-
can be obtained in cases of suspected arterial or venous ing overuse of the forearm musculature. Ice packs, heat,
compression. and NSAIDs are of some benefit. A forearm brace can
In general, management of thoracic outlet syndrome also be used. A local corticosteroid injection with a 25-
is conservative. Good posture is emphasized. Stretching gauge needle over the lateral epicondyle often produces
of the scalene and pectoral muscles, together with satisfactory initial relief. Isometric strengthening is
scapula mobilization and strengthening of the shoulder important as the initial part of a rehabilitation program.
girdle musculature, is beneficial. A local anesthetic Alvarez and Canoso reviewed the treatment of lateral
injection into the scalene anticus muscle, if a trigger epicondylitis in an evidence-based report (13).
point is present, may be helpful as well. In resistant or Evaluation of chronic cases should include a roent-
severe cases of thoracic outlet syndrome, the first rib genogram to check for calcification, exostosis, or other
and the scalene muscle may be resected. bony abnormalities. Tendon tears may sometimes be
the cause of chronic cases. Entrapment of the radial
nerve at the elbow, which is called radial tunnel syn-
DISORDERS OF THE ELBOW drome, can also cause discomfort and a vague aching at
that site. Weakness of extension of the middle finger
REGION may be seen. Forced forearm supination against resis-
tance seems to aggravate the symptoms of a neural
Olecranon Bursitis entrapment more than the symptoms of lateral epicon-
The subcutaneous olecranon bursa is frequently involved dylitis, in which resisted wrist extension aggravates the
with bursitis, either secondary to trauma or as an idio- pain.
pathic condition. The bursa is characteristically swollen
and tender on pressure, but pain may be minimal and
generally no motion is lost. Aspiration may yield clear
Medial Epicondylitis
or blood-tinged fluid with a low viscosity, or grossly Medial epicondylitis, or golfers elbow, which mainly
hemorrhagic fluid. Aspiration alone and protection involves the tendon attachment of the flexor carpi radia-
from trauma are generally sufficient to resolve the con- lis, is less common and less disabling than lateral epi-
dition. A small dose of corticosteroid may be injected, condylitis. Local pain and tenderness over the medial
but there is a possibility of secondary infection, skin epicondyle are present, and resistance to wrist flexion
atrophy, or chronic local pain that apparently results exacerbates the pain. This condition results from work
from subclinical skin atrophy (11). Inflammatory olec- or leisure activities but may also result from sport par-
ranon bursitis may be due to gout, RA, or calcium pyro- ticipation, including golf and throwing. Although not
phosphate deposition disease. Olecranon bursitis has usually needed for diagnosis, MRI shows thickening
also been seen in uremic patients undergoing hemodi- and increased signal intensity of the common flexor
tendon on both T1 and T2 weighted images (14). and elbow, especially in such activities as throwing and
Alteration of activities and use of NSAIDs usually hammering and also may occur as a result of direct
alleviate the problem, although occasionally a local trauma. Treatment is conservative. Rupture of the tri-
corticosteroid injection is required at the medial epi- ceps tendon at the insertion in the olecranon is rare and
condyle site. usually is the result of trauma, although a few cases have
been in association with corticosteroid injections into
the olecranon bursa, and also with heavy use of anabolic
Tendinopathy, Complete and Partial steroids. Acute pain occurs, and there is weakness of
Rupture of the Distal Biceps elbow extension against gravity. Swelling, tenderness,
Insertion and a palpable gap in the tendon may be noted. Surgical
repair is usually indicated.
Tendinopathy of the distal insertion of the biceps (lac-
ertus fibrosus) may cause dull pain throughout the
antecubital fossa of the elbow (15). Palpation of the Ulnar Nerve Entrapment
distal biceps tendon confirms the source of pain, and Entrapment of the ulnar nerve at the elbow produces
mild swelling may be present. Resisted elbow flexion numbness and paresthesia of the little finger and adja-
and resisted supination may increase pain. Heat, cent side of the ring finger as well as aching of the
NSAIDs, rest, and, occasionally, a local injection of medial aspect of the elbow. Hand clumsiness can be
corticosteroid generally are beneficial in this condition. present. Tenderness may be elicited when the ulnar
Complete rupture of the distal biceps tendon is uncom- nerve groove, located on the posteroinferior surface of
mon, and, when seen, it is in a middle-aged male who the medial epicondyle, is compressed. The little finger
experiences a sudden forced extension against an may have decreased sensation and weakness on abduc-
actively contracting biceps muscle (16). A popping sen- tion and flexion. Elevating the hand by resting the
sation may occur, with the onset of sudden pain and forearm on the head for 1 minute may produce pares-
weakness of elbow flexion and supination. A bulbous thesia. In longstanding cases, atrophy and weakness of
deformity proximal to the insertion and ecchymosis the ulnar intrinsic muscles of the hand occur. A positive
may be seen. A palpable tendon defect is present. An Tinels sign, elicited by tapping the nerve at the elbow,
MRI confirms the diagnosis and surgical repair is is often present. Similar symptoms may result from sub-
usually indicated. In partial rupture of the distal biceps luxation of the nerve.
tendon there is acute pain, some weakness of elbow Ulnar nerve entrapment has many causes, including
flexion and forearm supination, but the tendon is still external compression from occupation, compression
palpable and no ecchymosis or swelling is seen. Con- during anesthesia, trauma, prolonged bed rest, earlier
servative treatment may be of help, but sometimes sur- fractures, and inflammatory arthritis. A nerve conduc-
gical repair is necessary. tion test that shows slowing of ulnar motor and sensory
conduction and prolonged proximal latency aids in con-
Cubital Bursitis firming the diagnosis. Avoiding pressure on the elbow
and repetitive elbow flexion may be all that is necessary
Cubital bursitis (bicipitoradial bursitis) is manifest by a for improvement, but in severe persistent cases, surgical
swelling of the antecubital fossa and sometimes tender- correction is needed.
ness with some restriction of pronation. It is more often
seen in RA or other inflammatory arthritis conditions,
but also can be secondary to trauma or overuse. It may
also be seen in association with a partial tear of the
DISORDERS OF THE WRIST
distal biceps tendon. An MRI or diagnostic ultrasound AND HAND
may confirm the diagnosis. This condition may be
treated conservatively, including an image-guided aspi- Ganglion
ration and corticosteroid injection. A ganglion is a cystic swelling arising from a joint or
tendon sheath that occurs most commonly over the
Triceps Tendinitis and Triceps dorsum of the wrist. It is lined with synovium and con-
tains thick jellylike fluid. Ganglia are generally of
Tendon Rupture unknown cause but may develop secondary to trauma
In triceps tendinopathy pain is present in the posterior or prolonged wrist extension. Usually, the only symptom
elbow which may be worse by extension and even more is swelling, but occasionally a large ganglion produces
by resisted extension. Tenderness of the insertion of the discomfort on wrist extension. Treatment, if indicated,
tendon may be noted as well as some swelling. This consists of aspiration of the fluid, with or without injec-
syndrome occurs as a result of overuse of the upper arm tion of corticosteroid. Use of a splint may help prevent
recurrence. In severe cases, the whole ganglion may be carpi radialis, flexor carpi ulnaris, flexor digitorum
removed surgically. superficialis, and flexor digitorum profundus.
The findings vary depending on which tendon is
involved. Localized pain and tenderness are usually
De Quervains Tenosynovitis present, and there is sometimes swelling. Pain on resisted
De Quervains tenosynovitis may result from repetitive movement is often seen. The tenosynovitis may be mis-
activity that involves pinching with the thumb while interpreted as arthritis of the wrist.
moving the wrist. It has been reported to occur in new This problem may be due to repetitive use, a trau-
mothers as a complication of pregnancy. In the past it matic episode, inflammatory arthritis, or may be idio-
was thought to be from repetitive diapering using pathic. The treatment consists of avoiding overuse,
safety pins, but also may be a result of injury of the splinting, and NSAIDs. A local corticosteroid injection
wrist area from lifting of the baby (17). The symptoms into the tendon sheath, avoiding direct injection into the 3
are pain, tenderness, and, occasionally, swelling over tendon itself, is usually of benefit.
the radial styloid. Pathologic findings include inflam-
mation and narrowing of the tendon sheath around the Pronator Teres Syndrome
abductor pollicis longus and extensor pollicis brevis. A
positive Finkelstein test result is usually seen; pain An uncommon condition, pronator teres syndrome may
increases when the thumb is folded across the palm be difficult to diagnose because some features are
and the fingers are flexed over the thumb as the exam- similar to carpal tunnel syndrome. In this case, however,
iner passively deviates the wrist toward the ulnar side. the median nerve is compressed at the level of the pro-
This test, however, may also be positive in osteoarthri- nator teres muscle. The patient may complain of aching
tis (OA) of the first carpometacarpal (CMC) joint and in the volar aspect of the forearm, numbness in the
must be differentiated. Treatment involves splinting, thumb and index finger, weakness on gripping with the
local corticosteroid injection, and NSAIDs as indicated thumb, and writers cramp. The most specific finding is
(13,18). Accuracy of the injection may be improved tenderness of the proximal part of the pronator teres,
with use of guided imagery such as ultrasound. Rarely, which may be aggravated by resistive pronation of the
surgical removal of the inflamed tenosynovium is forearm. Pronator compression often produces pares-
needed. thesia after 30 seconds or less. In some patients, a posi-
tive Tinels sign is found at the proximal edge of the
pronator teres. Unlike carpal tunnel syndrome, noctur-
Intersection Syndrome nal awakening and numbness in the morning are absent.
The intersection syndrome, which is less common than Pronator teres syndrome is thought to result from
de Quervains syndrome, must be differentiated from it overuse by repetitive grasping or pronation, trauma, or
as both occur in the radial side of the wrist. This condi- a space-occupying lesion.
tion involves the site of the intersection and crossing of Electrodiagnostic studies may reveal signs of dener-
the extensor carpi radialis longus and brevis with the vation of the forearm muscles supplied by the median
abductor pollicis longus and the extensor pollicis brevis, nerve but sparing the pronator teres; however, they
which is about 4 cm from the wrist. Pain is present and often fail to localize the lesion. If the condition does not
worse with radial or twisting motions. Swelling and ten- improve with alteration of activities and with time,
derness of this site is present and crepitus may be pal- exploratory surgery may be undertaken to look for
pated. It results from overuse in many types of activities, fibrous or tendinous bands or a hypertrophied pronator
including racket sports, skiing, canoeing, and weight muscle.
lifting. If a diagnosis is uncertain, MRI is very helpful
(19). Conservative treatment is usually successful and Anterior Interosseous Nerve
includes relative rest with possibly a thumb splint,
NSAIDs, ice, and a local steroid injection.
Syndrome
Compression of the anterior interosseous nerve near its
bifurcation from the median nerve produces weakness
Tenosynovitis of the Wrist of the flexor pollicis longus, flexor digitorum profundus,
Tenosynovitis occurs in other flexor and extensor and pronator quadratus muscles. Sensation is not af-
tendons of the wrist in addition to those involved in de fected, but a person with this syndrome cannot form an
Quervains tenosynovitis and the intersection syndrome O with the thumb and index finger because motion is
(20). The individual tendons on the extensor side that lost in the interphalangeal (IP) joint of the thumb and
may be vulnerable are the extensor pollicis longus, the distal interphalangeal (DIP) joint of the index finger.
extensor indicis proprius, extensor digiti minimi, and Electromyography may help confirm the diagnosis.
extensor carpi ulnaris, and on the flexor side, the flexor Repetitive overuse, trauma, and fibrous bands are the
principal causes of this syndrome. Protection from Tight wrist restraints from handcuffs or watch bands
trauma usually results in improvement; if not, surgical are well-known causes. Trauma to the area, repetitive
exploration may be undertaken. wrist motion, diabetes, ganglion cyst, venipuncture, and
local surgical procedures are other possible etiologies.
The neuropathy may resolve with time. Treatment con-
Radial Nerve Palsy sists of splinting, NSAIDs, local corticosteroid injection,
The most common type of radial nerve palsy is the or surgical neurolysis in some cases.
spiral groove syndrome, or bridegroom palsy, in which
the radial nerve is compressed against the humerus. Carpal Tunnel Syndrome
The most prominent feature is a wrist drop with flexion
Carpal tunnel syndrome is the most common cause of
of the metacarpophalangeal (MCP) joints and adduc-
paresthesias and numbness in the hands. The median
tion of the thumb. Anesthesia in the web space and
nerve and flexor tendons pass through a common tunnel
hypesthesia from the dorsal aspect of the forearm to
at the wrist, whose rigid walls are bounded dorsally and
the thumb, index, and middle fingers may be present.
on the sides by the carpal bones, and on the volar aspect
If the radial nerve is compressed more proximally
by the transverse carpal ligament (Figure 3D-2). Any
through improper use of crutches or prolonged leaning
process encroaching on this tunnel compresses the
of the arm over the back of a chair (Saturday night
median nerve, which innervates the thenar muscles (for
palsy), weakness of the triceps and brachioradialis
flexion, opposition, abduction); the radial lumbricales;
muscles may also occur. Compression injuries generally
and the skin of the radial side of the palm, thumb,
heal over a period of weeks. Splinting the wrist during
second and third fingers, and the radial half of the fourth
this recovery time prevents overstretching of the para-
finger.
lyzed muscles and ligaments. Electrodiagnostic studies
are helpful in determining the specific point of Symptoms are variable, but episodes of burning pain
compression. or tingling in the hand are common, often occurring
during the night and relieved by vigorous shaking or
movement of the hand. Numbness commonly affects
Posterior Interosseous Nerve the index and middle fingers, radial side of the ring
fingers, and occasionally the thumb. Some patients
Syndrome experience only numbness without much pain. Numb-
Posterior interosseous nerve entrapment in the radial ness may also occur with activities such as driving or
tunnel produces discomfort in the proximal lateral holding a newspaper or book. The patient may have a
portion of the forearm. The fingers cannot be extended sensation of hand swelling when in fact no swelling is
at the MCP joints. The posterior interosseous nerve, visible. Occasionally the pain spreads above the wrist
a branch of the radial nerve, is primarily a motor into the forearm or, rarely, even above the elbow and
nerve, so sensory disturbances are rare. Occupational up the arm. Bilateral disease is common.
or recreational repetitive activity with forceful supina- A positive Tinels sign or Phalens sign may be
tion, wrist extension, or radial deviation against represent. Phalens test is performed by holding the wrist
sistance may be a factor. Direct trauma and such flexed at 90 for 1 minute. Loss of sensation may be
nontraumatic conditions as a ganglion also have been
implicated. Interestingly, this syndrome has been seen FLEX. DIGITORUM
SUBLIMIS MEDIAN NERVE
in RA due to synovial compression of the nerve and, TRANSVERSE
ULNAR CARPAL LIGAMENT
therefore, must be distinguished from a ruptured exten- N. & A.
sor tendon (21).
Superficial Radial Neuropathy

(Cheiralgia Paresthetica)
A lesion of this sensory nerve is more common than
previously thought and causes symptoms of a burning FLEX. DIGITORUM
PROFUNDUS
or shooting pain and sometimes numbness and tingling FLEX. POLLICIS
LONGUS
over the dorsoradial aspect of the wrist, thumb, and
index fingers. Hyperpronation and ulnar wrist flexion FIGURE 3D-2
may be provocative. Decreased pinprick sensation and Cross-section of wrist illustrating the position of the transverse
a positive Tinels sign may be seen. Electrodiagnostic carpal ligament (flexor retinaculum) and the structures occupying
studies are helpful in the diagnosis. the osseousfibrous carpal tunnel.
demonstrated in the index, middle finger, or radial side nerve at the hook of the hamate may cause tingling or
of the fourth finger. Weakness and atrophy of the pain. Atrophy of the hypothenar and intrinsic muscles
muscles of the thenar eminence may gradually appear can occur. Clawing of the ring and little fingers may be
in chronic cases. Confirmation of the diagnosis can be seen, resulting from weakness of the third and fourth
obtained by demonstrating prolonged distal latency lumbricales. Loss of sensation occurs over the hypo-
times during electrodiagnostic studies. thenar area.
A variety of disorders may cause carpal tunnel syn- If the superficial branch alone is involved, then only
drome, including edema from pregnancy or trauma, numbness, pain, and loss of sensation occur. Entrap-
osteophytes, ganglia related to tenosynovial sheaths, ment of the deep branch produces only motor weakness
lipomata, and anomalous muscles, tendons, and blood of the ulnar innervated muscles. The sites of motor
vessels that compress the median nerve. Carpal tunnel weakness depend on the exact location of nerve com-
syndrome has been observed in various infections such pression. For example, if the compression is distal to the 3
as tuberculosis, histoplasmosis, sporotrichosis, coccidi- superficial branch but proximal to the branch of the
oidomycosis, and rubella. Rheumatoid arthritis, gout, hypothenars, then the hypothenar muscles and intrin-
pseudogout, and other inflammatory diseases of the sics may be spared, causing weakness and atrophy of
wrist can cause compression of the median nerve. only the adductor pollicis, deep head of the flexor pol-
Amyloid deposits of the primary type or in association licis brevis, and first dorsal interosseous muscles. The
with multiple myeloma can occur at this site, and carpal causes of ulnar neuropathy at the wrist include trauma,
tunnel syndrome may be the initial manifestation of the ganglia, bicycling, inflammatory arthritis, flexor carpi
disease. The syndrome has also been reported to occur ulnaris hypertrophy, fractures, neuroma, lipomata, and
in myxedema and acromegaly. In many cases, however, diabetes.
no obvious cause can be found or a nonspecific tenosyn- The diagnosis is assisted by electrodiagnostic studies,
ovitis is evident. Many idiopathic cases may be due to indicating a prolonged distal latency of the ulnar nerve
occupational stress. at the wrist and denervation of the ulnar innervated
In milder cases, splinting the wrist in a neutral posi- muscles. Treatment includes rest from offending activ-
tion may relieve symptoms (22). Local injections of cor- ity, splinting, or a local corticosteroid injection; how-
ticosteroids into the carpal tunnel area, using a 25-gauge ever, surgical exploration and decompression may be
needle, are helpful for nonspecific or inflammatory necessary.
tenosynovitis. The benefit may be only temporary,
depending on the degree of compression and the revers-
ibility of the neural injury. When conservative treat- Trigger Finger (Volar Flexor
ment fails, surgical decompression of the tunnel by
release of the transverse carpal ligament and removal
Tenosynovitis)
of tissue compressing the median nerve is often benefi- Inflammation of the tendon sheaths of the flexor digi-
cial. Even with surgery, however, symptoms may some- torum superficialis and flexor digitorum profundus
times recur. tendons in the palm is extremely common but often
unrecognized. Pain in the palm is felt on finger flexion,
but in some cases the pain may radiate to the proximal
Ulnar Nerve Entrapment at interphalangeal (PIP) and MCP joints on the dorsal
side, thus misleading the examiner. The diagnosis is
the Wrist made by palpation and identification of localized ten-
The ulnar nerve can become entrapped at the wrist derness and swelling of the volar tendon sheaths. The
proximal to Guyons canal, in the canal itself, or distal middle and index fingers are most commonly involved,
to it (23). Guyons canal is roughly bounded medially but the ring and little fingers can also be affected. Often
by the pisiform bone, laterally by the hook of the a nodule composed of fibrous tissue can be palpated in
hamate, superiorly by the volar carpal ligament (piso- the palm just proximal to the MCP joint on the volar
hamate ligament), and inferiorly by the transverse side. The nodule interferes with the normal tendon
carpal ligament. Because the ulnar nerve, on entering gliding and can cause a triggering or locking (trigger
the canal, bifurcates into the superficial and deep finger), which may be intermittent and may produce an
branches, the clinical picture may vary, with only uncomfortable sensation. Similar involvement can occur
sensory, only motor, or both sensory and motor at the flexor tendon of the thumb. Volar tenosynovitis
findings. may be part of inflammatory conditions, such as RA,
The complete clinical picture includes pain, numb- psoriatic arthritis, or apatite crystal deposition disease.
ness, and paresthesias of the hypothenar area, clumsi- It is seen frequently in conjunction with OA of the
ness, and a weak hand grip, including difficulty using the hands. It is important to point out that volar flexor
thumb in a pinching movement. Pressure over the ulnar tenosynovitis occurs in the absence of triggering. The
actual trigger finger may be a late phase of the process. dure, but if the disease remains active, recurrence is
The most common cause of volar flexor tenosynovitis is likely.
overuse trauma of the hands from gripping with in-
creased pull on the flexor tendons. Injection of a long-
acting steroid into the tendon sheath usually relieves the
problem (24,25), although surgery on the tendon sheath
DISORDERS OF THE HIP
may be needed in unremitting cases. REGION
Infection of the tendon sheaths in the hand requires
drainage and antibiotics. People with drug addictions Trochanteric Bursitis
and diabetes may be at increased risk for such infec-
Although common, trochanteric bursitis frequently
tions. Atypical mycobacterium or fungal infections also
goes undiagnosed. It occurs predominantly in middle-
cause a chronic tenosynovitis in the hands. Mycobacte-
aged to elderly people, and somewhat more often in
rium marinum, which is found in infected fish, barnacles,
women than men. The main symptom is aching
fish tanks, and swimming pools, is a common culprit
over the trochanteric area and lateral thigh. Walking,
(26).
various movements, and lying on the involved hip
may intensify the pain. Onset may be acute, but more
Dupuytrens Contracture often is gradual, with symptoms lasting for months.
In chronic cases the patient may fail to adequately
In Dupuytrens contracture, a thickening and shorten-
locate or describe the pain, or the physician may fail
ing of the palmar fascia occurs. In established cases
to note the symptoms or interpret them correctly.
the diagnosis is obvious with typical thick, cordlike
Occasionally the pain may have a pseudoradiculopathic
superficial fibrous tissue felt in the palm causing a
quality, radiating down the lateral aspect of the thigh.
contracture, usually of the ring finger. The fifth, third,
In a few cases the pain is so severe that the patient
and second fingers are involved in decreasing order of
cannot walk and complains of diffuse pain of the entire
frequency. Initially, a mildly tender fibrous nodule in
thigh.
the volar fascia of the palm may be the only finding,
The best way to diagnose trochanteric bursitis is to
leading to confusion with volar flexor tenosynovitis.
palpate over the trochanteric area and elicit point ten-
Dimpling or puckering of the skin over the involved
derness. In addition to specific pain on deep pressure
fascia helps identify the early Dupuytrens contracture.
over the trochanter, other tender points may be noted
The initial nodules probably result from a contraction
throughout the lateral aspect of the thigh muscle. Pain
of proliferative myofibroblasts, which are the product
may be worse with external rotation and abduction
of fibrogenic cytokines inducing fibroblasts (27). The
against resistance. A positive Trendelenburg sign is
tendon and tendon sheaths are not implicated, but the
often present. Although bursitis is generally named as
dermis is frequently involved, resulting in fixation to
the principal problem, the condition more likely arises
the fascia. Progression of the disease varies, ranging
at the insertions of the gluteus medius and gluteus
from little or no change over many years to rapid pro-
minimus tendons (28). Local trauma and degeneration
gression and complete flexion contracture of one or
play a role in the pathogenesis. In some cases calcifica-
more digits.
tion of the trochanteric bursa is seen. Conditions that
The cause of this condition is unknown, but a hered-
may contribute to trochanteric bursitis, apparently by
itary predisposition appears to be present. Some
adding stress to the area, include OA of the lumbar
patients also have associated plantar fasciitis, knuckle
spine or of the hip, leg length discrepancy, and scoliosis.
pads, and fibrosis in the shaft of the penis. The disorder
Treatment consists of local injection of depot cortico-
is about five times more frequent in men, occurs pre-
steroid using a 22-gauge, 3 needle to ensure that the
dominantly in Caucasians, and is more common in
bursal area is reached (29). The use of fluoroscopic
Europe. A gradual increase in incidence of the disease
guidance with injection of radiopaque contrast increases
occurs with age. Associations exist between Dupuy-
the accuracy of the injections. NSAIDs, weight loss,
trens contracture and chronic alcoholism, epilepsy,
and strengthening and stretching of the gluteus
and diabetes.
medius muscle and iliotibial band help in overall
Treatment depends entirely on the severity of the
management.
findings. Heat, stretching, ultrasound, and intralesional
injection of corticosteroids may be helpful in early
stages. When actual contractures occur, surgical inter-
vention may be desirable. Limited fasciectomy is effec-
Iliopsoas (Iliopectineal) Bursitis
tive in most instances, but more radical procedures, The iliopsoas bursa lies behind the iliopsoas muscle,
including digital amputation, may rarely be necessary. anterior to the hip joint and lateral to the femoral
Palmar fasciotomy is a useful and more benign proce- vessels. It communicates with the hip in 15% of ilio-
psoas bursitis cases. When the bursa is involved, groin Meralgia Paresthetica
and anterior thigh pain are present. This pain becomes
worse on passive hip hyperextension and sometimes on The lateral femoral cutaneous nerve (L2L3) innervates
flexion, especially with resistance. Tenderness is pal- the anterolateral aspect of the thigh and is a sensory
pable over the involved bursa. The patient may hold nerve. Compression of the nerve causes a characteristic
the hip in flexion and external rotation to eliminate intermittent burning pain associated with hypesthesia
pain and may limp to prevent hyperextension. The and sometimes with numbness of the anterolateral
diagnosis is more apparent if a cystic mass, which is thigh. Extension and abduction of the thigh or pro-
present in about 30% of cases, is seen; however, other longed standing and walking may make symptoms
causes of cystic swelling in the femoral area must be worse, whereas sitting may relieve the pain. Touch and
excluded. A bursal mass may cause femoral venous pinprick sensation over the anterolateral thigh may be
obstruction or femoral nerve compression. As with decreased. Pain can be elicited by pressing on the ingui- 3
most bursitis, acute or recurrent trauma and inflamma- nal ligament just medial to the anterior superior iliac
tory conditions like RA may be a cause. The diagnosis spine. This syndrome is seen more commonly in people
is confirmed by plain roentgenogram and injection of who have diabetes, are pregnant, or are obese. Direct
a contrast medium into the bursa, or by computed trauma, compression from a corset, or a leg length dis-
tomography, ultrasonography, or MRI. Iliopsoas bur- crepancy may also be factors. Nerve conduction velocity
sitis generally responds to conservative treatment, studies help confirm the diagnosis. Weight loss, heel
including corticosteroid injections under guided im- correction, and time generally alleviate the problem.
agery. With recurrent involvement, excision of the Because entrapment of the nerve often occurs just
bursa may be necessary. medial to the anterior superior iliac spine, a local injec-
tion of a corticosteroid at that site may help.
Ischial (Ischiogluteal) Bursitis Coccydynia

Ischial bursitis is caused by trauma or prolonged sitting Coccydynia is manifest by pain in the coccyx area when
on hard surfaces as evidenced by the name, weavers pressure is applied to the area. This most notably occurs
bottom. Pain is often exquisite when sitting or lying upon sitting. The patient squirms from buttock to
down. Because the ischiogluteal bursa is located super- buttock to relieve the pressure and consequent pain,
ficial to the ischial tuberosity and separates the gluteus and often chooses to sit on a cushion. The symptoms
maximus from the tuberosity, the pain may radiate may be chronic and severe. The condition may relate to
down the back of the thigh. Point tenderness over the a fall on the coccyx or to dropping to a hard chair upon
ischial tuberosity is present. MRI and ultrasonography sitting, or to some related trauma to the coccyx.
may be used to confirm the diagnosis. Use of cushions However, at times no obvious cause can be detected.
and local injection of a corticosteroid are helpful. Women are much more frequently affected. Perhaps
this is due to the lordosis often occurring in women,
which exposes the coccyx to more trauma. The diagno-
Piriformis Syndrome sis is confirmed by finding localized tenderness over the
Piriformis syndrome is not well recognized and is incom- coccyx on palpation. A plain x-ray can be obtained to
pletely understood, even though it was first described in exclude a fracture or dislocation of the coccyx. Treat-
1928 (30). The main symptom is pain over the buttocks, ment with a local injection of a long-acting corticoste-
often radiating down the back of the leg as in sciatica. roid and 2 mL of 2% lidocaine is usually very effective
A limp may be noted on the involved side. Women are (32). The exact nature of the pathology of coccydynia
more often affected, and trauma plays a major role. has not been studied but is presumed to be a bone
Diagnosis is aided by tenderness of the piriformis muscle bruise.
on rectal or vaginal examination. Pain in the involved
buttock is evident on hip flexion, adduction and internal
rotation (FAIR) (31). Another maneuver is performed DISORDERS OF THE KNEE
by having the patient lie on the uninvolved side with the
upper knee resting on the table. Buttock pain occurs
REGION
when the knee of the involved side is lifted several
inches off the table. Pain and weakness have also been
Popliteal Cysts
noted on resisted abduction and external rotation. A Popliteal cysts, also known as Bakers cysts, are not
carefully done local injection of lidocaine and cortico- uncommon, and the clinician should be well aware of
steroid, under fluoroscopic guidance, into the piriformis the possibility of dissection or rupture. A cystic swelling
muscle may help. with mild or no discomfort may be the only initial
finding. With further distention of the cyst, however, a cases of dual involvement, anserine bursitis is the prin-
greater awareness and discomfort is experienced, par- cipal source of pain.
ticularly on full flexion or extension. The cyst is best
seen when the patient is standing and is examined from Prepatellar Bursitis
behind. Any knee disease having a synovial effusion
can be complicated by a popliteal cyst. A naturally Manifested as a swelling superficial to the kneecap, pre-
occurring communication may exist between the knee patellar bursitis results from trauma such as frequent
joint and the semimembranosusgastrocnemius bursa, kneeling, leading to the name housemaids knee. The
which is located beneath the medial head of the gas- prepatellar bursa lies anterior to the lower half of the
trocnemius muscle. A one-way valvelike mechanism patella and upper half of the patellar ligament. The pain
between the joint and the bursa is activated by pressure is generally slight unless pressure is applied directly
from the knee effusion. An autopsy series has shown over the bursa. The infrapatellar bursa, which lies
that about 40% of the population has a knee joint between the patellar ligament and the tibia, is also
bursa communication. subject to trauma and swelling. Chronic prepatellar bur-
Popliteal cysts are most common secondary to sitis can be treated by protecting the knee from the
RA, OA, or internal derangements of the knee. irritating trauma.
There are a few reported cases secondary to gout and Septic prepatellar bursitis should also be considered
reactive arthritis. A syndrome mimicking thrombo- when swelling is noted in this area. Generally, erythema,
phlebitis may occur, resulting from cyst dissection heat, and increased tenderness and pain are present.
into the calf or actual rupture of the cyst. Findings When obtained, the history may include trauma to the
include diffuse swelling of the calf, pain, and some- knee with puncture or abrasion of the skin overlying the
times erythema and edema of the ankle. An arthro- bursa is obtained. The bursal fluid should be aspirated
gram of the knee will confirm both the cyst and the and cultured, and treatment with appropriate antibiot-
possible dissection or rupture. Ultrasound is now ics should be instituted if infection is demonstrated.
used more often to make a diagnosis and monitor the
course. History of a knee effusion is often a hint that Medial Plica Syndrome
a dissected Bakers cyst is the cause of the patients
A plica is a synovial fold in the knee joint, and infrapa-
swollen leg. A Doppler ultrasound can also exclude the
tellar, suprapatellar, and medial plicae have been iden-
possibility of concomitant thrombophlebitis. A cyst
tified. The medial plica can sometimes cause knee
related to an inflammatory arthritis is treated by inject-
symptoms (33). Patella pain may be the predominant
ing a depot corticosteroid into the knee joint and pos-
complaint, and snapping or clicking of the knee, a sense
sibly into the cyst itself, which usually resolves the
of instability, and possible pseudolocking of the knee
problem. If the cyst results from OA or an internal
may be seen. The plica become symptomatic through
derangement of the knee, surgical repair of the under-
any traumatic or inflammatory event in the knee. Diag-
lying joint lesion is usually necessary to prevent recur-
nosis and treatment are made by arthroscopy, in which
rence of the cyst.
a thickened, inflamed, and occasionally fibrotic medial
patella plica, leading to a bowstring process, is seen.
Anserine Bursitis
Seen predominantly in overweight, middle-aged to Popliteal Tendinitis
elderly women with big legs and OA of the knees, Pain in the posterolateral aspect of the knee may occur
anserine bursitis produces pain and tenderness over the secondary to tendinitis of the popliteal tendons (ham-
medial aspect of the knee about 2 below the joint string and popliteus). With the knee flexed at 90, ten-
margin. Pain is worsened by climbing stairs. The pes derness on palpation may be found. Straight leg raising
anserinus (Latin for goose foot) is composed of the with or without palpation may cause pain. Running
conjoined tendons of the sartorius, gracilis, and semi- downhill increases the strain on the popliteus and can
tendinosus muscles. The bursa extends between the lead to tendinitis. Rest and conservative treatment are
tendons and the tibial collateral ligament. The diagnosis indicated; occasionally a corticosteroid injection may be
is made by eliciting exquisite tenderness over the bursa beneficial.
and by relieving pain with a local lidocaine injection.
The treatment is rest, stretching of the adductor and
quadriceps muscles, and a corticosteroid injection into
PellegriniStieda Syndrome
the bursa. PellegriniStieda syndrome consists of calcification of
Anserine bursitis is often overlooked as it frequently the medial collateral ligament of the knee. This syn-
occurs concomitantly with OA of the knee, which when drome generally occurs in men, is thought to result from
present is the assumed cause of pain; however, in some trauma and is followed by an asymptomatic period.
Later, the symptomatic stage of medial knee pain and the deep peroneal nerve (which supplies the dorsiflex-
progressive restriction of knee movement coincides ors of the foot and toes). An electromyogram is helpful
with the beginning of calcification of the medial collat- in demonstrating slowing of nerve conduction veloci-
eral ligament, typically appearing as an elongated, ties. Treatment consists of removing the source of com-
amorphous shadow on roentgenogram (34). The pain is pression, if there is one, and use of an anklefoot
self-limited, and improvement usually occurs within orthosis if necessary. Occasionally, surgical exploration
several months. is needed.
Patellar Tendinitis Patellofemoral Pain Syndrome

Patellar tendinitis, or jumpers knee, is seen predomi- This syndrome consists of pain and crepitus in the
nantly in athletes engaging in repetitive running, patellar region (36). Stiffness occurs after prolonged 3
jumping, or kicking activities. Pain and tenderness are sitting and is alleviated by activity; overactivity involv-
present over the patellar tendon. Diagnostic ultraso- ing knee flexion, particularly under loaded conditions
nography adds to confirmation of diagnosis (35). Treat- such as stair climbing, aggravates the pain. On exami-
ment consists of rest, NSAIDs, ice, knee bracing, and nation, pain occurs when the patella is compressed
stretching and strengthening of the quadriceps and against the femoral condyle or when the patella is dis-
hamstring muscles. Corticosteroid injections are usually placed laterally. Joint effusions are uncommon and
contraindicated due to risk of tendon rupture. In some usually small. The symptoms of patellofemoral pain
chronic cases surgery is needed. syndrome are often bilateral and occur in a young age
group. This syndrome may be caused by a variety of
patellar problems, such as patella alta, abnormal quad-
Rupture of Quadriceps Tendon and riceps angle, and trauma. The term chondromalacia
Patellar Tendon patellae has been used for this syndrome, but patello-
femoral pain syndrome is preferred by many. Treat-
When the tendons around the patella rupture, the quad- ment consists of analgesics, NSAIDs, ice, rest, and
riceps tendon is involved about 50% of the time; other- avoidance of knee overuse. Isometric strengthening
wise, the patellar tendon is involved. Quadriceps tendon exercises for the quadriceps muscles are of benefit. In
rupture is generally caused by sudden violent contrac- some patients, however, surgical realignment may be
tions of the quadriceps muscle when the knee is flexed. tried.
A hemarthrosis of the knee joint may follow. Rupture
of the patellar tendon has been associated with a spe-
cific episode of trauma, repetitive trauma from sporting DISORDERS OF THE ANKLE AND
activities, and systemic diseases. Patients with chronic
renal failure, RA, hyperparathyroidism, gout, and sys- FOOT REGION
temic lupus erythematosus patients on steroids have
been reported to have spontaneous ruptures of the Achilles Tendinitis
quadriceps tendon. The patient experiences a sudden Usually resulting from trauma, athletic overactivity, or
sharp pain and cannot extend the leg. Roentgenograms improperly fitting shoes with a stiff heel counter, Achil-
may show a high riding patella, and the diagnosis may les tendinitis can also be caused by inflammatory condi-
be confirmed by MRI or ultrasonography. The tendon tions such as ankylosing spondylitis, reactive arthritis,
is generally found to be degenerated, and surgical repair gout, RA, and calcium pyrophosphate dihydrate crystal
is necessary. deposition disease (CPPD). It also has been associated
with treatment with fluoroquinolones. Pain, swelling,
and tenderness occur over the Achilles tendon at its
Peroneal Nerve Palsy attachment and in the area proximal to the attachment.
In peroneal nerve palsy, a painless foot drop with a Crepitus on motion and pain on dorsiflexion may be
steppage gait is usually evident. Pain sensation may be present. Ultrasonography aids in the diagnosis. Man-
slightly decreased along the lower lateral aspect of the agement includes NSAIDs, rest, shoe corrections, heel
leg and the dorsum of the foot. Direct trauma, fracture lift, gentle stretching, and sometimes a splint with slight
of the lower portion of the femur or upper portion of plantar flexion. Because the Achilles tendon is vulner-
the tibia, compression of the nerve over the head of able to rupture when involved with tendinitis, it was felt
the fibula, and stretch injuries are all causes of this in the past that treatment by a corticosteroid injection
palsy. Generally, the common peroneal nerve is com- could worsen this possibility. However, this view is
pressed, affecting the muscles innervated by the super- being challenged and fluoroscopic guided steroid injec-
ficial peroneal nerve (which supplies the everters) and tions have been successfully performed (37).
Achilles Tendon Rupture ity, such as athletics, prolonged walking, using improper
shoes, or striking the heel with some force. Plantar fas-
Spontaneous rupture of the Achilles tendon is well ciitis may be idiopathic; it also is likely to be present in
known and occurs with a sudden onset of pain during younger patients with spondyloarthritis. The pain char-
forced dorsiflexion. An audible snap may be heard, fol- acteristically occurs in the morning upon arising and is
lowed by difficulty in walking and standing on toes. most severe for the first few steps. After an initial
Swelling and edema over the area usually develop. improvement, the pain may worsen later in the day,
Diagnosis can be made with the Thompson test, in especially after prolonged standing or walking. The pain
which the patient kneels on a chair with the feet extend- is burning, aching, and occasionally lancinating. Palpa-
ing over the edge, and the examiner squeezes the calf tion typically reveals tenderness anteromedially on the
and pushes toward the knee. Normally this produces medial calcaneal tubercle at the origin of the plantar
plantar flexion, but in a ruptured tendon no plantar fascia. Treatment includes relative rest with a reduction
flexion occurs. Achilles tendon rupture is generally due in stressful activities, NSAIDs, use of heel pad or heel
to athletic events or trauma from jumps or falls. The cup orthoses, arch support, and stretching of the heel
tendon is more prone to tear in those having preexisting cord and plantar fascia. A local corticosteroid injection,
Achilles tendon disease or in those on corticosteroids. using a 25-gauge needle, is often of help.
Orthopedic consultation should be obtained, and immo-
bilization or surgery may be selected, depending on the
situation. Posterior Tibial Tendinitis
Pain and tenderness just posterior to the medial malleo-
Subcutaneous Achilles Bursitis lus occur in posterior tibial tendinitis. This can be due
to trauma, excessive pronation, RA, or spondyloar-
A subcutaneous bursa superficial to the Achilles tendon thropathy. Extension and flexion may be normal, but
may become swollen in the absence of systemic disease. pain is present on resisted inversion or passive eversion.
This bursitis, known as pump-bumps, is seen predomi- The discomfort is usually worse after athletic events,
nantly in women and results from pressure of shoes, and swelling and localized tenderness may be present.
although it can also result from bony exostoses. Other Treatment usually includes rest, NSAIDs, and possibly
than relief from shoe pressure, no treatment is a local injection of corticosteroid. Immobilization with
indicated. a splint is sometimes needed.
Retrocalcaneal Bursitis Posterior Tibialis Tendon

The retrocalcaneus bursa is located between the pos- Rupture
terior surface of the Achilles tendon and the calcaneus.
The bursas anterior wall is fibrocartilage where it The rupture of the posterior tibialis tendon, which is not
attaches to the calcaneus, whereas its posterior wall commonly recognized, is a cause of progressive flat foot
blends with the epitenon of the Achilles tendon. Mani- (38). Trauma, chronic tendon degeneration, or RA may
festations of bursitis include pain at the back of the cause it. An insidious onset of pain and tenderness may
heel, tenderness of the area anterior to the Achilles be noted along the course of the tendon just distal to
tendon, and pain on dorsiflexion. Local swelling is the medial malleolus, along with swelling medial to the
present, with bulging on the medial and lateral aspects hind foot. The unilateral deformity of hind foot valgus
of the tendon. Retrocalcaneal bursitis, also called sub- and forefoot abduction is an important finding. The
Achilles bursitis, may coexist with Achilles tendinitis; forefoot abduction can best be seen from behind; more
distinguishing the two is sometimes difficult to do clini- toes are seen from this position than would be seen
cally. However, ultrasonography and MRI are most normally. The result of the single heel rise test is posi-
helpful. This condition may be secondary to RA, spon- tive when the patient is unable to rise onto the ball of
dylitis, reactive arthritis, gout, or trauma. Treatment the affected foot while the contralateral foot is off the
consists of administration of NSAIDs, rest, and a local floor. Orthopedic consultation should be obtained to
injection of a corticosteroid carefully directed into the determine whether the rupture should be treated con-
bursa. servatively with NSAIDs and casting or with a surgical
repair.
Plantar Fasciitis
Peroneal Tendon Dislocation
Plantar fasciitis, which is seen primarily in persons
between 40 and 60 years of age, is characterized by pain
and Peroneal Tendinitis
in the plantar area of the heel. The onset may be gradual Dislocation of the peroneal tendon may occur from a
or may follow some trauma or overuse from some activ- direct blow, repetitive trauma, or sudden dorsiflexion
with eversion. Sometimes a painless snapping noise is arthritis, stress fracture, foot surgery, or a foot with a
heard at the time of dislocation. Other patients report high longitudinal arch. Flattening of the transverse arch
more severe pain and tenderness of the tendon area that and weakness of the intrinsic muscles occur, resulting in
lies over the lateral malleolus. The condition may be a maldistribution of weight on the forefoot. Treatment
confused with an acute ankle sprain. Conservative treat- is directed at elevating the middle portion of the trans-
ment with immobilization is often satisfactory because verse arch with an orthotic device, strengthening of the
the peroneal tendon usually reduces spontaneously. If intrinsic muscles, weight reduction, and use of metatar-
the retinaculum supporting the tendon is ruptured, sal pads or metatarsal bar.
however, surgical correction may be needed. Peroneal
tendinitis can also occur and be manifested as localized
tenderness over the lateral malleolus. Conservative
Pes Planus
treatment is usually indicated. Pes planus, or flat foot, is often asymptomatic, but may 3
cause fatigue of the foot muscles and aching with intol-
erance to prolonged walking or standing. There is loss
Hallux Valgus of the longitudinal arch on the medial side and promi-
In hallux valgus, deviation of the large toe lateral to the nence of the navicular and head of the talus. The calca-
midline and deviation of the first metatarsal medially neus is everted (valgus), and out-toeing can be seen on
occurs. A bunion (adventitious bursa) on the head of ambulation. The tendency for this condition is largely
the first metatarsophalangeal (MTP) joint may be inherited and is seen with generalized hypermobility. A
present, often causing pain, tenderness, and swelling. Thomas heel, firm shoes, and grasping exercises to
Hallux valgus is more common in women. It may be strengthen the intrinsic muscles are helpful. A shoe
caused by a genetic tendency or wearing pointed shoes, orthosis may be needed for more cases. The asymptom-
or it can be secondary to RA or generalized OA. atic flat foot is left untreated.
Stretching of shoes, use of bunion pads, or surgery may
be indicated. Metatarsus primus varus, a condition in
which the first metatarsal is angulated medially, is seen
Pes Cavus
in association with or secondary to the hallux valgus In contradistinction to pes planus, pes cavus, or claw
deformity. foot, is characterized by an unusually high medial arch,
and in severe cases, a high longitudinal arch, resulting
in shortening of the foot. These abnormally high arches
Bunionette further result in shortening of the extensor ligaments,
A bunionette, or tailors bunion, is a prominence of the causing dorsiflexion of the PIP joints and plantar flexion
fifth metatarsal head resulting from the overlying bursa of the DIP joints, giving a clawlike appearance to the
and a localized callus. The fifth metatarsal has a lateral toes. The plantar fascia may also be contracted. Gener-
(valgus) deviation. ally, a tendency to pes cavus is inherited, and in a high
percentage of cases an underlying neurologic disorder
is present. Although pes cavus can cause foot fatigue,
Hammer Toe pain, and tenderness over the metatarsal heads with
In hammer toe, the PIP joint is flexed and the tip of the callus formation, it may also be asymptomatic. Calluses
toe points downward. The second toe is most commonly generally develop over the dorsum of the toes. Use of
involved. Calluses may form at the tip of the toe and metatarsal pads or a bar is helpful, and stretching of the
over the dorsum of the interphalangeal joint, resulting toe extensors is usually prescribed. In severe cases sur-
from pressure against the shoe. Hammer toe may be gical correction may be needed.
congenital or acquired secondary to hallux valgus and
may result from improper footwear. When the MTP
joint is hyperextended, the deformity is known as
Mortons Neuroma
cocked-up toes. This may be seen in RA. Middle-aged women are most frequently affected by
Mortons neuroma, an entrapment neuropathy of the
interdigital nerve occurring most often between the
Metatarsalgia third and fourth toes. Paresthesia and a burning, aching
Pain arising from the metatarsal heads, known as meta- pain are experienced in the fourth toe. The symptoms
tarsalgia, is a symptom resulting from a variety of condi- are made worse by walking on hard surfaces or wearing
tions. Pain on standing and tenderness on palpation of tight shoes or high heels. Tenderness may be elicited by
the metatarsal heads are present. Calluses over the palpation between the third and fourth metatarsal
metatarsal heads are usually seen. The causes of meta- heads. Occasionally, a neuroma is seen between the
tarsalgia are many, including foot strain, high-heeled second and third toes. Compression of the interdigi-
shoes, everted foot, trauma, sesamoiditis, hallux valgus, tal nerve by the transverse metatarsal ligament and
possibly by an intermetatarsophalangeal bursa or syno- local swelling in Tietzes syndrome but not in costo-
vial cyst may be responsible for the entrapment. Treat- chondritis (40).
ment usually includes a metatarsal bar or a local steroid Tietzes syndrome is much less common than costo-
injection into the web space. Ultimately, surgical exci- chondritis and is of unknown etiology. Its onset may be
sion of the neuroma and a portion of the nerve may be gradual or abrupt with swelling usually occurring in the
needed. second or third costal cartilage. Pain, which ranges from
mild to severe, may radiate to the shoulder and be
aggravated by coughing, sneezing, inspiration, or by
Tarsal Tunnel Syndrome various movements affecting the chest wall. Tenderness
In tarsal tunnel syndrome, the posterior tibial nerve is is elicited on palpation, and approximately 80% of
compressed at or near the flexor retinaculum. Just dis- patients have a single site.
tally, the nerve divides into the medial plantar, lateral Costochondritis is more common and is associated
plantar, and posterior calcaneal branches. The flexor with pain and tenderness of the chest wall, without
retinaculum is located posterior and inferior to the swelling. Tenderness is often present over more than
medial malleolus. Numbness, burning pain, and pares- one costochondral junction, and palpation should dupli-
thesias of the toes and sole extend proximally to the cate the described pain. In one study of 100 patients
area over the medial malleolus. Nocturnal exacerba- with noncardiac chest pain, 69% were found to have
tion may be reported. The patient gets some relief by local tenderness on palpation and in 16% the palpation
leg, foot, and ankle movements. A positive Tinels sign elicited the typical pain (41). Other names attached to
may be elicited on percussion posterior to the medial costochondritis include anterior wall syndrome, cos-
malleolus, and loss of pinprick and two-point discrimi- tosternal syndrome, parasternal chondrodynia, and
nation may be present. Women are more often affected chest wall syndrome. Some individuals with chest wall
than men. Trauma to the foot, especially fracture, pain are found to have fibromyalgia or localized myo-
valgus foot deformity, hypermobility, and occupational fascial pain. Chest wall pain can also complicate heart
factors may relate to development of tarsal tunnel syn- or lung disease, so its presence does not exclude more
drome. An electrodiagnostic test may show prolonged serious problems.
motor and sensory latencies and slowing of the nerve Xiphoid cartilage syndrome or xiphoidalgia, also
conduction velocities. In addition, a positive tourniquet known as hypersensitive xiphoid or xiphodynia, is char-
test and pressure over the flexor retinaculum can acterized by pain over the xiphoid area and tenderness
induce symptoms. A newer test is reported to be of on palpation. Pain may be intermittent and brought on
value in which the ankle is passively maximally everted by overeating and various twisting movements.
and dorsiflexed while all of the MTP joints are maxi- These three conditions are often self-limiting. Treat-
mally dorsiflexed. The position is held for 5 to 10 ment consists of reassurance, heat, stretching of chest
seconds, and in a positive test, numbness and/or pain wall muscles, or local injections of lidocaine, corticoste-
are produced and tenderness is intensified (39). Shoe roid, or both.
corrections and steroid injection into the tarsal tunnel In addition, a number of other disorders may
may be of benefit, but often surgical decompression is produce chest wall pain. Sternocostoclavicular hyper-
needed. ostosis is manifested by a painful swelling of the clavi-
cles, sternum, or ribs and may be relapsing. It is
associated with an elevated erythrocyte sedimentation
rate, pustules on the palms and soles, and progression
DISORDERS OF THE ANTERIOR to ossification of the chest wall lesions. Condensing
CHEST WALL osteitis of clavicles is a rare, benign condition of
unknown etiology, occurring primarily in women of
Chest wall pain of a musculoskeletal origin is fairly child-bearing age. It is characterized by sclerosis of the
common. It must be differentiated from chest pain medial ends of the clavicles without involvement of
of a cardiac nature, which is the usual main concern, the sternoclavicular joints. Pain and local tenderness
or from pain due to pulmonary or gastrointestinal are present.
disease. Pain can also radiate to the chest as a Any condition involving the sternoclavicular joint,
result of cervical or thoracic spine disease. The muscu- including spondyloarthropathy, OA, and infection, can
loskeletal syndromes usually associated with chest cause chest wall pain. Stress fracture of the ribs, cough
wall pain are Tietzes syndrome and costochondritis. fracture, herpes zoster of the thorax, and intercosto-
Both conditions are characterized by tenderness of brachial nerve entrapment are other causes of chest
one or more costal cartilages and the terms have some- pain.
times been used interchangeably. The two disorders, Thorough palpation of the chest wall must be done,
however, are generally separated by the presence of including the sternoclavicular joint, costochondral junc-
tions, sternum, and chest wall muscles. Maneuvers such 16. Hamilton W, Ramsey ML. Rupture of the distal tendon
as crossed-chest adduction of the arm and backward of the biceps brachii. U Penn Orthop J 1999;12:2126.
extension of the arm from 90 of abduction help in elu- 17. Skoff HD. Postpartum/newborn deQuervains tenosyn-
cidating whether chest pain is of a musculoskeletal ovitis of the wrist. Am J Orthop 2001;30:428430.
18. Anderson BC, Manthey R, Brouns MC. Treatment of de
origin. Imaging studies may include plain roentgeno-
Quervains tenosynovitis with corticosteroids. Arthritis
gram of the ribs, special roentgenogram of the sterno-
Rheum 1991;34:793798.
clavicular joint, tomogram, and bone scan. A computed 19. Costa CR, Morrison WB, Carrino JA. MRI features of
tomography scan or MRI provides the most detail of intersection syndrome of the forearm. AJR Am J Roent-
the sternoclavicular joint. genol 2003;181:12451249.
20. Stern PJ. Tendinitis, overuse syndromes, and tendon inju-
ries. Hand Clinics 1990;6:467475.
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CHAPTER 3
and Symptoms
E. The Fibromyalgia Syndrome
DINA DADABHOY, MD
DANIEL J. CLAUW, MD
Fibromyalgia (FM) is a soft tissue pain syndrome that Patient education about FM is a fundamental part of
affects 4% of the population of the United States. the treatment process. A variety of Internet-based
American College of Rheumatology (ACR) criteria for Web sites are available for patients.
the classification of FM include a history of chronic Exercise is a crucial element of therapy. A
widespread pain involving all four quadrants of the regular exercise program should be considered
body and the axial skeleton, plus the presence of 11 to be a full part of the pharmacological
of 18 tender points on physical examination. armamentarium.
A variety of nonspecific symptoms are often present Tricyclic antidepressant (TCA) agents, such as cyclo-
in FM. These include fatigue (often worsened by benzaprine and amitriptyline, are usually the first-line
physical activity), paresthesias, irritable bowel pharmacologic treatment.
complaints, migraine headaches, and deficits of
attention and memory.
Fibromyalgia (FM) is the most common cause of In performing the history, particular attention should
chronic, widespread pain in the United States. The dif- be focused on the onset and character of the pain,
ferential diagnosis of FM is lengthy because diffuse pain accompanying symptoms, and exposures that could
may also occur in a number of other settings (Table be causing the symptoms. Both prescription and over-
3E-1). The diagnostic evaluation of an individual with the-counter medications are particularly important in
diffuse pain varies depending on the duration of symp- this regard. Red flags in the history indicating the need
toms, as well as the findings in the history and physical for further investigation include a family history of
examination. Diffuse pain that has been present for myopathies, a personal history of cancer, unexplained
years is likely to be due to FM, especially if there are symptoms of weight loss or associated fevers, or symp-
symptoms of fatigue, memory difficulties, and sleep dis- toms suggesting joint inflammation (true morning stiff-
turbance, and if the physical examination reveals ten- ness, swelling, redness, and warmth).
derness to palpation at soft tissue sites. In this setting, The examination should be detailed with a focus on
minimal workup is necessary. In contrast, an individual the musculoskeletal and neurological exam. Signs of
whose symptoms are of only a few weeks or months inflammation (e.g., synovitis) or neurological abnor-
duration requires a more extensive evaluation for auto- malities (e.g., objective weakness) are not consistent
immune, endocrine, and neurological conditions. with FM and imply other possible etiologies.
87
88 DINA DADABHOY AND DANIEL J. CLAUW
At a minimum, individuals who present with Fibromyalgia

chronic, widespread pain should have a complete 1990 American College of
Rheumatology Criteria
blood count, liver and kidney function tests, thyroid
stimulating hormone level, erythrocyte sedimenta- Chronic widespread pain
tion rate, and C-reactive protein measured. Careful in all four quadrants of
history-taking and physical examination generally ob- the body and the axial
skeleton
viate the need for extensive radiological evaluations
and other tests. Radiographs, cross-sectional imaging 11/18 tender points
studies, nuclear medicine tests, electromyography, and (patient experiences pain
nerve conduction velocities should be obtained spar- with 4 kg of pressure)
ingly, and only when they are designed to address
specific clinical issues raised by the history or physical
examination.
FIGURE 3E-1
EPIDEMIOLOGY 1990 American College of Rheumatology classification criteria

for fibromyalgia syndrome. (Reference 1).
Fibromyalgia affects up to 4% of the population. To

fulfill the classification criteria for FM published by an
American College of Rheumatology (ACR) committee
in 1990, an individual must have both a history of

chronic widespread pain involving all four quadrants
of the body (and the axial skeleton), and the presence
TABLE 3E-1. DIFFERENTIAL DIAGNOSIS OF DIFFUSE of 11 of 18 tender points on physical examination
PAIN AND/OR FATIGUE. (Figure 3E-1) (1). These criteria were never intended
for application as diagnostic criteria to individual
Mechanical overuse
patients; at least half of the individuals who have clini-
Drugs cal diagnoses of FM do not fulfill the ACR classifica-
Statins and fibrates tion criteria.
Antimalarials
Endocrinopathies
Hypothyroidism
Hyperparathyroidism
CLINICAL FEATURES
Cushings syndrome
Diabetes mellitus The defining features of FM are chronic, widespread
Neurological
pain and tenderness. The pain of FM frequently waxes
Multiple sclerosis and wanes, and may be migratory. In some instances
Myasthenia gravis patients will present with aching all over, whereas in
Malignancy other instances patients experience several areas of
chronic regional pain. In this setting, regional muscu-
Infections
Hepatitis C
loskeletal pain typically involves the axial skeleton
Human immunodeficiency virus (HIV) and/or tender point regions, and may be diagnosed ini-
Lyme disease tially as a local problem (e.g., low back pain, lateral
Rheumatologic diseases epicondylitis).
Rheumatoid arthritis Tender points at defined anatomic sites throughout
Systemic lupus erythematosus the body are considered present when an individual
Sjgrens syndrome complains of pain when 4 kg of pressure are applied
(approximately the amount of pressure required to
Polymyalgia rheumatica
Inflammatory myopathies blanch the examiners nail). Since the publication of the
ACR criteria, much has been learned about tender
Metabolic myopathy
points. Research has shown that individuals with FM
Osteomalacia are not only tender at discrete localized areas, but have
Tapering of steroids tenderness extending throughout their body (2). In
Regional pain syndrome addition, women with chronic widespread pain are more
likely to have more tender points on examination than
are their male counterparts. Whereas tender points Although individuals with FM may present with
have been shown to be associated with psychological symptoms that can be seen early in the course of auto-
factors such as distress, tenderness (as measured through immune disorders, serologic assays such as antinuclear
objective testing paradigms) is not. Therefore, rigidly antibodies (ANA) and rheumatoid factor should gener-
adhering to the ACR criteria in clinical practice skews ally be avoided unless there is strong evidence for an
the diagnosis of FM towards identifying females with autoimmune disorder. Such tests have very low predic-
high levels of distress. tive values in the setting of nonspecific symptoms.
In addition to pain and tenderness, most individuals
with FM also report a high lifetime and current preva-
lence of a variety of nonspecific symptoms that seem to OVERLAP WITH AUTOIMMUNE
defy any current organic explanation (Figure 3E-2). DISORDERS
Fatigue, often worse with activities, is one of the most 3
common such symptoms. Paresthesias following a non- The overlap between FM and autoimmune disorders
dermatomal distribution and neurological symptoms, deserves special mention. Symptoms that can be seen in
particularly those related to attention and short-term both FM and autoimmune disorders include not only
memory, are also common. arthralgias, myalgias, and fatigue, but also morning stiff-
The clustering of somatic symptoms associated with ness and a history of subjective swelling of the hands
FM can give rise to a number of identifiable overlapping and feet. In addition, symptoms suggestive of Raynauds
syndromes, including the chronic fatigue syndrome, irri- phenomenon (characterized, in contrast to true Ray-
table bowel syndrome, and multiple chemical sensitiv- nauds phenomenon, by paleness or erythema of the
ity. There is also frequently overlap with other chronic entire hand rather than only specific digits), malar flush-
pain conditions, such as tension headaches, migraines, ing (in contrast to a fixed malar rash), and livedo reticu-
and temporomandibular disorders. laris are all common in FM, and can mislead the
Except for the finding of tender points, the physical practitioner to suspect an autoimmune disorder.
examination is generally unremarkable in FM. As stated Persons with established autoimmune disorders also
previously, the tenderness is diffuse, and not confined commonly exhibit comorbid symptoms of FM. Studies
to tender points. The former concept of control points, have suggested that up to 25% of persons with systemic
previously described as areas of the body that should inflammatory disorders, such as systemic lupus erythe-
not be tender, has been abandoned. Laboratory testing matosus (SLE), rheumatoid arthritis (RA), and anky-
should be highly focused on the exclusion of FM mim- losing spondylitis, also meet ACR criteria for FM.
ickers that appear to be legitimate possibilities (Table Because both inflammatory and non-inflammatory
3E-1). Fishing expeditions with laboratory tests are mechanisms cause symptoms in this setting, FM should
strongly discouraged. be suspected when an individual with an autoimmune
FIGURE 3E-2
Overlapping regional syndromes and

symptoms.
Tension/migraine headache
Cognitive difficulties
Multiple chemical sensitivity, ENT complaints (sicca sx., vasomotor

allergic symptoms rhinitis, accommodation problems)
Vestibular complaints
Esoplageal dysmotility
Temporomandibular
joint syndrome Neurally mediated hypotension, mitral
valve prolapse
Non-cardiac chest pain, dyspnea due to
respiratory mm. dysfunction
Irritable bowel
syndrome Interstitial cystitis,
female urethral syndrome,
Nondermatomal vulvar vestibulitis, vulvodynia
paresthesias
disorder has persistent complaints despite normal input plays a role in central pain amplification in some
inflammatory indices, or when symptoms are unre- individuals with FM. This may have some bearing on
sponsive to anti-inflammatory regimens. FM symptoms why so many patients with autoimmune disorders
may become particularly prominent when individuals develop FM.
are being tapered from high doses of glucocorti- Investigators are examining the pain processing path-
coids (perhaps due to an effect of glucocorticoids on ways to understand the neuropathology involved in
the sleep cycle), a phenomenon previously termed augmented central pain. Just as the immune system con-
pseudo-rheumatism. tains pro- and anti-inflammatory cytokines, pain pro-
cessing systems contain compounds and pathways that
are generally pronociceptive (i.e., increase the gain on
pain processing systems) or antinociceptive.
ETIOLOGY AND PATHOGENESIS Biochemical studies performed on samples from FM
patients have supported the notion that the pathology
Genetic and Environmental might be due to high levels of pronociceptive com-
Influences pounds, low levels of antinociceptive compounds, or
both. Four studies have identified much higher levels of
Increasing evidence supports the existence of a genetic substance P in the cerebrospinal fluid (CSF) of patients
predisposition to FM. First-degree relatives of individu- with FM versus normal subjects (5). Substance P is a
als with FM display an eightfold higher risk of FM than pronociceptive peptide stored in the secretory granules
the general population (3) Although no absolute links of sensory nerves and released upon axonal stimulation.
have been ascertained, polymorphisms in the serotonin Elevated substance P is not specific for FM because it
5-HT2A receptor (T/T phenotype), the serotonin trans- occurs in other chronic pain states, and appears to be a
porter, the dopamine 4 receptor, and the catecholamine biological marker for the presence of chronic pain.
o-methyl transferase enzyme have been detected at Alternatively, there are data suggesting that FM
higher frequencies in patients with FM (4) Notably, could be related to a decrease in the activity of descend-
these polymorphisms all affect the metabolism or trans- ing antinociceptive pathways (6). Beginning in the
port of monoamines, compounds that have a critical limbic forebrain structures or subcortical structures and
role in both sensory processing and the human stress passing either directly or indirectly to the spinal cord,
response. these antinociceptive pathways exert a tonic effect,
In addition to the genetic associations, factors exter- inhibiting the upward transmission of pain in normal
nal to the patient can enhance symptom expression. For conditions.
many patients, certain stressors have strong temporal The two principal descending antinociceptive
associations with the development of either FM or pathways in humans are the opioidergic and mixed
chronic fatigue syndrome: physical trauma (especially serotonergicnoradrenergic pathways. Current evi-
involving the axial skeleton and trunk); certain infec- dence suggests that the opioidergic systems are acti-
tions (e.g., hepatitis C virus, EpsteinBarr virus, parvo- vated to a maximum extent in groups of individuals with
virus, and Lyme disease); emotional stress; and other FM. Consequently, the deficiency may be in the other
regional pain conditions or autoimmune disorders. antinociceptive pathway, the serotonergicnoradrener-
gic pathway. Drugs that inhibit the reuptake of norepi-
nephrine and serotonin are effective in FM. In contrast,
Abnormalities in Pain and no randomized controlled trials have confirmed efficacy
for opiates in this condition.
Sensory Processing
Once a susceptible individual has symptoms of FM, the HypothalamicPituitary and
most consistently detected objective abnormalities
involve the pain and sensory processing systems. Numer-
Autonomic Dysfunction
ous experimental pain studies have demonstrated that Substantial data imply alterations in the hypothalamic
FM patients cannot detect electrical, pressure, or thermal pituitary axes and the autonomic nervous system in
stimuli at lower levels than normal subjects, but the subsets of persons with FM and related disorders (7).
point at which these stimuli cause pain or unpleasant- Although the findings generally indicate a hyperactivity
ness is lower. The aberrant pain perception is likely of both the hypothalamicpituitary adrenal axis as well
multifactorial, but one key factor is central pain, or as the sympathetic nervous system, there are inconsis-
enhanced nociceptive sensation due to augmented tencies in these studies results. Recent work suggests
central pain processing. Because peripheral pain (e.g., that these abnormalities create a milieu in which the
that caused by injury or inflammation) can lead to somatic symptoms may occur, rather than triggering the
central pain amplification, it is possible that peripheral symptoms directly themselves.
Psychological and TREATMENT

Behavioral Factors
Progress in the understanding of FM has led to improved
There has been a longstanding debate over the role therapeutic options for patients with this condition.
of psychiatric, psychological, and behavioral factors Clinic-based evidence advocates a multifaceted program
in FM. Population-based studies have demonstrated emphasizing education, certain medications, cognitive
that distress can lead to pain, and pain to distress. In behavioral therapy, and exercise (Figure 3E-3).
this latter instance, pain and other symptoms of FM
may cause individuals to function less well in their
various roles. They might have difficulties with family Consider Diagnosis Label
members and coworkers, which exacerbate symptoms Once an individual with the diagnosis of FM is identi-
and lead to maladaptive illness behaviors such as fied, the practitioner must consider whether or not 3
cessation of pleasurable activities and reductions in labeling the patient at that juncture is wise. For the
activity and exercise. In the worst cases, patients majority of patients, having a name to apply to their
become involved with disability and compensation disorder helps them understand their symptoms and the
systems, a decision that almost ensures they will not most appropriate treatment. On the other hand, for
improve. The psychosocial factors that influence the some individuals the diagnostic label may prove detri-
experience of pain are not, however, unique to FM, but mental (10). The practitioner must make this decision
have a prominent role in symptom expression in all on a case-by-case basis.
rheumatic diseases. The practitioner should schedule a prolonged visit,
Given the biopsychosocial nature of FM, several or series of visits. This upfront time can be extremely
groups have identified positive psychological and cogni- useful for both patients and providers. It helps the phy-
tive factors might actually buffer neurobiological factors, sician understand precisely what is bothering the patient,
leading to pain and distress. These psychological and and assists the patient in understanding the goals and
cognitive factors, postulated to work by affecting the rationale of treatment.
supraspinal pain modulatory pathways, include an inter-
nal locus of control (i.e., patients feel that they are
empowered to do something about their pain) or low
Education
catastrophizing (a negative, pessimistic view of their For all patients with FM, education about the nature of
pain) (8). The findings stress the value of positive coping this disorder is critical. Some patients who present with
responses and give insight into why psychological inter- milder symptoms of FM want only to be told that this
ventions such as cognitive behavioral therapy (CBT) is a benign, nonprogressive condition. At a minimum,
may be efficacious in improving physical and psycho- the physician should describe this condition in terms
logical functioning in FM (9). they feel most comfortable with, and then refer the
FIGURE 3E-3
Evaluation and treatment paradigm for

fibromyalgia syndrome.
patient to reputable sources of information, such as the these types of symptoms. Due to its sedative properties,
Arthritis Foundation, several national patient support giving a proportionally higher dose at night in the
organizations (e.g., the National Fibromyalgia Associa- context of a three times a day schedule leads to better
tion, the American Fibromyalgia Syndrome Associa- medication tolerance and has the additional benefit of
tion, and the Fibromyalgia Alliance of America), or improving sleep. Clonazepam, another anticonvulsant
current, reputable Web sites. agent, and dopamine agonists, such as pramipexole,
may also be helpful in this condition, particularly if
patients suffer from the comorbid condition or restless
Pharmacologic Therapies leg syndrome.
Tricyclic compounds (tricyclic antidepressants; TCA), Compounds with more prominent noradrenergic
notably amitriptyline and cyclobenzaprine, have been and/or dopaminergic mechanisms, such as buproprion,
studied most extensively; these demonstrate the strong- nefazadone, and pemoline, may have some clinical
est evidence for efficacy in the treatment of FM (9). To utility, especially if given during the day to patients with
increase the tolerance of cyclobenzaprine and amitrip- prominent fatigue or cognitive complaints. Other drugs
tyline, these compounds should be administered several may be useful for treating certain symptoms of FM,
hours before bedtime, beginning at low doses (10 mg or without necessarily leading to a globally beneficial
less) and increasing slowly (10 mg every 12 weeks) effect. For example, tramadol is an effective analgesic
until the patient reaches the maximally beneficial dose in this disorder. For treating insomnia in persons intol-
(up to 40 mg of cyclobenzaprine, or 50100 mg of erant to tricyclic compounds, bedtime doses of traza-
amitriptyline). done and zolpidem may be of benefit. In persons with
Because of the side effects of tricyclics, recent studies symptoms suggestive of autonomic dysfunction, such as
have examined the efficacy of better-tolerated com- orthostatic intolerance, vasomotor instability, or palpi-
pounds, specifically serotonin reuptake inhibitors tations, increased fluid and sodium/potassium intake,
(SSRIs) and dual receptor inhibitors [serotonin and/or low doses of beta blockers, might be of benefit.
norepinephrine and norepinephrineserotonin re-
uptake inhibitors (SNRIs and NSRIs)]. Many experts
believe that drugs targeting both the serotonin and nor- Cognitive Behavioral Therapy
epinephrine pathways may be more beneficial than drugs
Cognitive behavioral therapy refers to a structured edu-
that are purely serotonergic. The SSRI evaluated most
cation program that focuses on teaching individuals
carefully to date is fluoxetine. Aggregate data suggest
skills that they can utilize to improve their illness. CBT,
that fluoxetine is most efficacious at higher doses, perhaps
shown to be effective in improving patient outcomes in
because it partially inhibits reuptake of norepinephrine
nearly every chronic medical illness (including FM),
as well as serotonin at high doses, and that the use of
must be tailored to the specific condition. The skills
fluoxetine is synergistic with a TCA taken at bedtime.
most commonly associated with CBT for pain include
The currently available SNRIs include venlafaxine
relaxation training, activity pacing, pleasant activity
and duloxetine. There is one randomized, controlled
scheduling, visual imagery techniques, distraction strat-
trial of venlafaxine for FM, but data from open trials
egies, focal point and visual distraction, cognitive
indicate that higher doses than that employed in that
restructuring, problem solving, and goal setting.
trial (i.e., in the range of one 75 mg extended release
tablet twice daily) may be necessary. Because of nausea
early in the use of this class of drugs, they should be
begun at a low dose (i.e., 37.5 mg/day) and escalated
Aerobic Exercise
slowly. Duloxetine, studied in multicenter trials, is effec- Aerobic exercise improves FM outcomes, particularly
tive in improving pain, fatigue, and overall well-being those related to function. In designing aerobic exercise
with either 60 mg daily or 60 mg twice daily. The impact programs, careful planning is required to enhance toler-
of duloxetine on symptoms were independent of the ability and ensure long-term compliance. Especially in
medications effect on the mood of the patient, suggest- illnesses such as FM, patients may experience a worsen-
ing that the analgesic and other positive effects of this ing of symptoms immediately after exercise, and thus
class of drugs in FM are not simply due to the treatment fear that any form of exercise will exacerbate their con-
of depression. dition. To reduce the pain associated with exercise, low-
Anticonvulsant medications are also being evaluated impact exercises, such as aquatic exercise, walking,
for the treatment of FM. Recent trials have shown swimming, or stationary cycling, are recommended. Just
the effectiveness of pregabalin (especially at doses of as with medication, a start low, go slow approach
450 mg/day) in improving pain, fatigue, sleep, and mood. appears to be most effective, with a gradual progression
Anecdotal evidence suggests that gabapentin, not yet in exercise intensity and a focus on adherence to a long-
tested in randomized, controlled trials, also improves term program.
Complementary Therapies REFERENCES

There are several different types of complementary 1. Wolfe F, Smythe HA, Yunus MB, et al. The American
therapies that are used to treat FM. Some of these are College of Rheumatology 1990 Criteria for the Classifica-
physical modalities, such as trigger point injections, tion of Fibromyalgia. Report of the Multicenter Criteria
myofascial release therapy (or other hands-on tech- Committee. Arthritis Rheum 1990;33:160172.
niques), acupuncture, and chiropractic manipulation, 2. Granges G, Littlejohn G. Pressure pain threshold in pain-
each of which has some data supporting efficacy. Many free subjects, in patients with chronic regional pain syn-
others, however, including most nutritional supple- dromes, and in patients with fibromyalgia syndrome.
ments, diets, and devices, are to be avoided. Arthritis Rheum 1993;36:642646.
Because few controlled trials of these complemen- 3. Arnold LM, Hudson JI, Hess EV, et al. Family study of
fibromyalgia. Arthritis Rheum 2004;50:944952.
tary therapies are available to guide the practitioner, a
4. Buskila D, Neumann L. Genetics of fibromyalgia. Curr 3
general approach is suggested. The practitioner should
Pain Headache Rep 2005;9:313315.
first evaluate the safety of the proposed treatment, and 5. Russell IJ, Orr MD, Littman B, et al. Elevated cerebro-
indicate any potential harmful effects. The physician spinal fluid levels of substance P in patients with the fibro-
should then consider whether this treatment is reinforc- myalgia syndrome. Arthritis Rheum 1994;37:15931601.
ing a maladaptive belief, for example, a treatment pro- 6. Julien N, Goffaux P, Arsenault P, Marchand S. Wide-
gram of prolonged bed rest, or of isolation, which in the spread pain in fibromyalgia is related to a deficit of endog-
end will be harmful to the patient. If the treatment is enous pain inhibition. Pain 2005;114:295302.
neither harmful nor maladaptive, then the practitioner 7. Crofford LJ. Neuroendocrine abnormalities in fibromyal-
may suggest that the patient conduct the equivalent of gia and related disorders. Am J Med Sci 1998;315:359
a clinical trial on himself or herself (as is done in n of 366.
1 trials). In this setting, the patient begins a single 8. Gracely RH, Geisser ME, Giesecke T, et al. Pain catastro-
phizing and neural responses to pain among persons with
treatment (keeping all other variables constant) and
fibromyalgia. Brain 2004;127:835843.
determines if the treatment is beneficial. If the patient 9. Goldenberg DL, Burckhardt C, Crofford L. Management
judges the treatment helpful, then the treatment should of fibromyalgia syndrome. JAMA 2004;292:23882395.
be discontinued to determine if the symptoms worsen. 10. Hadler NM. Fibromyalgia, chronic fatigue, and other iat-
If the treatment withstands this test of efficacy, a placebo rogenic diagnostic algorithms. Do some labels escalate
effect cannot be excluded, but in clinical practice, it is illness in vulnerable patients?. Postgrad Med 1997;102:161
difficult to argue with success. 166, 171.
CHAPTER 4
Molecular and Cellular Basis of

Immunity and Immunological
Diseases
KEVIN ELIAS, MD
RICHARD SIEGEL, MD, PHD
JOHN J. OSHEA, MD
The immune system can be divided into innate and The adaptive immune response depends on antigen
adaptive subsystems whose inappropriate activation recognition by T and B cells, whose cell surface
leads to autoinflammatory and autoimmune diseases, receptors are highly variable to respond to environ-
respectively. Many rheumatic diseases are a combi- mental insults. Normally, adaptive immune cells are
nation of both processes. tolerant to self.
The innate immune system is activated by specific Different subsets of T lymphocytes, including T-
receptors that recognize patterns associated with helper, cytotoxic T cells, and T-regulatory cells,
pathogens, which activate a program of inflamma- modulate the immune response to effectively combat
tion involving hundreds of genes. pathogens yet limit autoimmunity. Dysregulation of
Cells of the innate immune system, including den- T-cell function is seen in autoimmune disease.
dritic cells, natural killer (NK) cells, mast cells, eosino- Antibody-producing B lymphocytes recognize and
phils, and basophils, activate and modulate the present soluble antigens. Autoantibodies contribute
adaptive immune response, directly combat patho- significantly to autoimmune diseases.
gens, and respond to allergens.
The vertebrate immune system protects the host OVERVIEW OF THE

from a wide variety of pathogens, including bacteria,
viruses, fungi, and parasites. However, this remarkable IMMUNE SYSTEM
versatility comes at the cost of autoimmune and
autoinflammatory diseases that affect approximately 1 The immune system can be divided into innate and
in 30 individuals. This chapter briefly reviews the cardi- adaptive subsystems (Figure 4-1). Innate immunity
nal molecular and cellular features of the immune includes physical barriers such as skin and mucosa,
system, including the molecular basis of recognition and phagocytic cells of the myelomonocytic lineage, natural
response to pathogens, mechanisms of tolerance, and killer (NK) lymphocytes, and serum constituents such
immunological memory. Knowledge of the immune as complement proteins. The innate immune system is
system is critical to understanding rheumatologic hard wired to recognize pathogens through receptors
disease. While the detailed pathophysiology of major that have evolved over hundreds of millions of years. In
autoimmune diseases remains elusive, genetic immune contrast, adaptive immune cells, namely T and B lym-
disorders and the effects of new biologic targeted treat- phocytes, display receptors derived from gene segments
ments provide insights into many of the mechanisms of that are shuffled through the action of recombinase and
immunological disease. somatic mutation enzymes. Both arms of the immune
94
CHAPTER 4 IMMUNITY AND IMMUNOLOGICAL DISEASES 95
Innate Immunity Adaptive Immunity
Epithelial Cells Complement
CD8+ T Cell
Th1 IFN-gamma
Neutrophil Natural Killer Cell Th2 IL4, IL5, IL-13
Th17 IL-17, IL-6, IL-22
nTreg Foxp3
4
iTreg Foxp3
CD4+ T cell
Macrophage Dendritic Cell
B Cell Immunoglobulins
Eosinophil Mast Cell
FIGURE 4-1
For discussion purposes, the cells of the immune system may be divided into the innate and the
adaptive immune subsystems. Innate immunity includes epithelial cells, complement, phagocytic
cells, and granulocytes. Innate immune cells have pattern recognition molecules that allow them
to respond quickly to pathogens. Signals from the innate immune system activate the adaptive
immune system, made up of T cells and B cells. T cells in turn may be divided into CD8+ T cells
(cytotoxic T lymphocytes) and CD4+ T cells (T-helper cells). CD4+ T cells are subdivided into
lineages of T-helper cells based on their unique cytokine and transcription factor profiles. B cells
secrete immunoglobulin.
system coordinate host defense and can be responsible cells. B cells mature in the bone marrow, T cells mature
for immune-mediated disease. When the adaptive in the thymus, and monocytes develop at varying sites
immune system causes pathology through T and B cell in the periphery. Lymphoid organs include the thymus,
mediated effects, this is termed autoimmune disease. spleen, lymph nodes, gut-associated lymphoid tissue
The innate immune system can also inappropriately (GALT), and mucosa-associated lymphoid tissue
trigger inflammation without activation of the adaptive (MALT) (Figure 4-2). The spleen, the major site where
immune system; this is termed autoinflammatory disease. lymphocytes encounter blood-borne antigen, also clears
As will be described, many rheumatic diseases are a the circulation of senescent red blood cells and foreign
combination of both processes. substances.
Stem cells of the immune system arise from the fetal Ultimately, immune function depends on the ability
yolk sac and populate the bone marrow, spleen, and of cells to localize within specific tissues and to interact
liver. In the adult, bone marrow is the predominant with each other in a coordinated fashion. During normal
source of lymphocytic and myelomonocytic progenitor homeostasis and inflammation, chemotactic cytokines
96 KEVIN ELIAS, RICHARD SIEGEL, AND JOHN J. OSHEA
pathogens by using pathogen-associated molecular

patterns (PAMPs). PAMPs, such as viral RNA and
lipopolysaccharide (LPS), are essential molecules for
microbial survival, which restricts major changes in
their structure. Cells recognize PAMPs using pathogen-
recognition receptors (PRRs), such as Toll-like recep-
tors (TLRs), an evolutionarily ancient mechanism that
is conserved in plants and animals (1,2). Other PRRs
include NLRs (NOD-like receptors), and RLRs (RIG-
I-like receptors) (Table 4-1).
The engagement of PRRs leads to the activation of
signaling pathways that activate inflammation. The NF-
kB signaling pathway can be activated by most TLRs
and culminates in the transcriptional activation of hun-
dreds of pro-inflammatory genes, including many pro-
inflammatory cytokines such as interleukin (IL)-1, IL-6,
tumor necrosis factor (TNF), and chemokines, such as
IL-8, that attract more innate immune cells. Activation
of NLRs leads to the formation of a proteolytic signal-
FIGURE 4-2
ing complex denoted the inflammasome, which pro-
Immune system tissues are found throughout the body. They cesses a subset of these cytokines, leading to the
include large organs, such as the spleen and bone marrow, as secretion of IL-1 and IL-18 (3).
well as aggregates of lymphatic tissue lining mucosal surfaces.
The importance of proinflammatory cytokines in
rheumatic disease is exemplified by the effectiveness
of TNF-alpha receptor antagonists like etanercept,
(chemokines) and their cognate receptors provide a flex- infliximab, and adalimumab in the treatment of
ible code for facilitating this cell trafficking. Limiting rheumatoid arthritis (RA). Conversely, dominant
lymphocyte migration through pharmacological target- mutations in one of the TNF receptors (TNFR1) result
ing of chemokines or their receptors is one strategy for in an autoinflammatory disorder termed TRAPS
immunosuppression. One drug that acts in this manner is (TNFR-associated periodic syndrome). Mutations in
fingolimod, a sphingosine 1-phosphate receptor agonist. constituents of the inflammasome give rise to diseases
such as familial Mediterranean fever (FMF) and neona-
tal onset multiorgan inflammatory disorder (NOMID)
INNATE IMMUNITY (4). The latter disorder can be effectively treated
with the IL-1 receptor antagonist anakinra. Mutation
Innate immunity provides the bodys initial encounter of proteins that recognize intracellular pathogens such
with pathogens. Phagocytic cells, that is, macrophages, as the NLR NOD2/CARD15 is associated with Crohns
dendritic cells (DCs), and neutrophils, recognize disease.
TABLE 4-1. PATTERN RECOGNITION RECEPTORS (PRRs) IDENTIFIED IN EXPERIMENTAL ANIMALS AND HUMANS.a
PRR FAMILY FAMILY MEMBERS EXAMPLES OF PAMPs EXAMPLES OF ASSOCIATED IMMUNE DISEASES
Toll-like receptors (TLRs) TLR1-13 Zymosan, lipopolysaccharide, Leprosy, atherosclerosis, asthma, inflammatory
CpG oligonucleotides bowel disease
NOD-like receptors (NLRs) NOD 15, NALP 114, Low intracellular potassium, Crohns disease, MuckleWells syndrome,
CIITA, IPAF, NAIP monosodium urate, pseudogout, Familial Mediterranean fever
peptidoglycan
RIG-I-like receptors (RLRs) RIG1, MDA5, LGP2 Double-stranded RNA Increased susceptibility to RNA viruses
a
Dozens of pattern recognition receptors (PRRs) have been identified in experimental animals and in humans. Although the pathogen-associated molecular
pattern (PAMP) that each of these receptors recognizes has not been elucidated, mutations in PRRs have been linked to several human diseases. These include
genetic mutations that lead to hyperactivation of the inflammasome (e.g, NALP3 and MuckleWells syndrome) and increased susceptibility to chronic inflam-
mation (e.g., NOD2 and Crohns disease). Chronic stimulation of the innate immune system through PRRs appears to be important in the chronic inflammation
of rheumatic diseases. This is the rationale behind arthritis therapy with the drug etanercept, which blocks the action of TNF-alpha, a PRR signaling pathway
target cytokine.
Innate Immune Cells IFNs are critical for host defense against viruses, but
overproduction of IFN is a feature of rheumatic diseases,
The release of pro-inflammatory cytokines activates such as systemic lupus erythematosus (SLE).
other components of the innate and adaptive immune Natural killer cells are a lymphocyte subset that can
systems, and DCs are key to this connection (Figure 4-3) be included in the innate immune system because NK
(5). Although derived from the bone marrow, DCs reside cells lack rearranging antigen receptors. Among the
in the periphery. Most organs are thought to possess receptors NK cells do express, some can sense stressed
their own DC populations, where they act as sentinels or damaged cells. For example, NK cells can lyse virus-
for pathogens. Upon activation, they migrate to the infected cells and tumors that lack major histocompati-
lymph nodes and the spleen, where they present their bility class (MHC) I molecules. NK cells also produce
antigens to T cells in the context of costimulatory mole- significant quantities of cytokines, such as IFN-gamma,
cules. Adjuvants increase the antigenicity of vaccines that can influence the development of T cells. NKT cells
through their ability to activate DCs and other phago- are a unique subset of T cells with properties of NK cells
cytes. DCs produce an array of cytokines, including IL- that recognize lipid antigens presented by the molecule
12 and IL-23, that activate and regulate lymphocytes. CD1d via a restricted set of T-cell receptors. NK T cells
Conversely, DCs and other phagocytic cells are activated appear to be vital for combating certain fungal, proto-
by the products of lymphocytes, such as the cytokine zoan, bacterial, and viral infections (7). 4
interferon (IFN) gamma. A subset of DCs, plasmacytoid Eosinophils, basophils, and mast cells are cellular
DCs, is the bodys major producer of type I IFNs (6). components of the innate immune system that are often
FIGURE 4-3
Dendritic cells (DC) reside inside peripheral tissues where they survey the environment for
pathogens. After contact with a pathogen, a DC migrates to the regional lymph node to activate
the adaptive immune response. DCs sense pathogens in one of several ways. One method is
activation of intracellular and extracellular pattern recognition receptor (PRR) signaling pathways
by pathogen-associated molecular patterns (PAMPs). Dendritic cells also ingest pathogens and
break them down into peptides that are then presented to T cells in the context of major
histocompatibility complex (MHC) molecules. In addition, complement can bind to the surface of
pathogens, and phagocytes will recognize the complementpathogen aggregates through
complement receptors. After antigen recognition, the DC activates cells of the adaptive immune
response either via direct cell contact at the immune synapse or through cytokine signaling. T
cells and B cells in turn secrete cytokines that offer feedback to the dendritic cells, altering the
DC cytokine secretion profile and regulating DC survival. Adaptive immune cells also signal to
one another as well as engage in autocrine stimulation.
associated with allergic diseases, but these cells are also are also immunodeficient. Patients with C4 deficiency
active participants in other aspects of immunity (8). are the most susceptible to SLE and related autoim-
Eosinophils, important for host defense against gastro- mune diseases, perhaps due to a failure to properly
intestinal parasites, secrete cytokines that regulate B regulate the effects of immune complexes on adaptive
cells and T cells, and exhibit strong effects on mucosal immune cells.
surfaces. Basophils and mast cells both express high
affinity IgE receptor and release histamine. Basophils
influence CD4+ T cells via the release of IL-4 and IL-13 ANTIGEN PRESENTATION AND
and activate B cells via CD40 ligand. Mast cells are
long-lived cells that undergo terminal differentiation
MAJOR HISTOCOMPATIBILITY
and ultimately reside in well-vascularized tissues. They CLASS MOLECULES
express TLRs, secrete pathogen-fighting toxins, respond
to allergens, and secrete cytokines that influence CD4+ An antigen can be defined as a substance that generates
T-cell activity. Though mast cells are known to be an immune response. What distinguishes adaptive
involved in the pathogenesis of allergies and asthma, immune cells from innate immune cells is the ability of
they also appear to be critical in the development of B cells and T cells to express unique, highly antigen-
arthritis. specific receptors on their plasma membranes. Engage-
ment of these receptors causes an individual B or T cell
to expand into a clonal population of lymphocytes
COMPLEMENT directed against the antigen-bearing pathogen. Expan-
sion of lymphocytes that recognize host antigens rather
The complement system consists of more than 30 serum than pathogenic antigens is one mechanism of autoim-
and cell surface proteins that function as soluble innate mune disease.
immune receptors and amplifiers of antibody responses. Although T and B cells use a similar strategy to
Components of the complement system, such as C1q, produce their antigen-specific receptors, they recognize
C3, and mannan binding lectin (MBL), bind cellular antigen very differently. B cells recognize soluble pep-
and subcellular components of microbes as well as tides, proteins, nucleic acids, polysaccharides, lipids,
DNA, RNA, and membrane fragments released by and small synthetic molecules. These antigens bind
endogenous cell death. The classic complement pathway directly to the B-cell antigen receptor (BCR), a mem-
begins with the activation of C1q by immunoglobulin- brane-associated form of immunoglobulin. Conse-
containing immune complexes, and the alternative quently, B cells have no need for antigen-presenting
complement pathway begins with the thioester activa- cells. In contrast, T cells need antigen to be presented,
tion of C3. Complement coats the surface of microor- that is, the T-cell antigen receptor (TCR) recognizes
ganisms. Receptors on phagocytic cells can then bind fragments only when they are bound to MHC molecules
the complement, prompting ingestion of the microor- on the surface of other cells.
ganisms (opsonization). Complement also induces The two types of MHC molecules, class I and class
phagocytic cells to secrete cytokines through activation II, are the most polymorphic human proteins, and
of the complement receptors and influences TLR signal expression of different MHC alleles correlates with sus-
transduction. Additionally, the inflammatory cascade ceptibility to autoimmune disease. In humans, the MHC
initiated by complement binding recruits more phago- [also termed histocompatibility locus antigen (HLA)]
cytes and mast cells to sites of tissue injury and pro- comprises a 3.6 Mbp DNA sequence on chromosome
motes cytokine production that activates the adaptive 6p. It is the single most gene-dense region of the human
immune response. Another complement function is the genome. HLA alleles associated with specific diseases
direct lysing of microorganisms through formation of include HLA-B27 with spondyloarthropathy and
the membrane attack complex (MAC), made up of HLADRB1 with rheumatoid arthritis.
C5-C9. The three-dimensional structure of both classes of
Interestingly, mutations in complement and comple- MHC creates a cleft, or groove, in which peptides are
ment regulatory protein gene deficiencies have been bound and can be recognized by T cells. Each MHC
linked to several autoimmune and inflammatory dis- molecule binds a single peptide, but the total pool of
eases, including SLE (9). Complement H deficiency MHC molecules can bind an array of peptides. The
increases susceptibility to hemolytic uremic syndrome association of peptides with MHC molecules is deter-
and macular degeneration. Deficiency of C1 inhibitor mined by MHC molecule primary and secondary struc-
causes hereditary angioedema. C3 deficiency results in tures. The types of antigens that each MHC class binds
severe susceptibility to microbial pathogens, and defi- are distinct: MHC class I molecules most often present
ciency of C5-C9 is associated with selective susceptibil- endogenous peptides, while the MHC class II molecules
ity to Neisseria species. Patients with mutations of MBL present exogenous peptides. Class I molecules are con-
stitutively expressed on nearly all cells except neurons of proteases and HLA-DM. Endosomes containing the
and red blood cells, whereas class II molecules are ingested extracellular peptides then fuse with MHC
limited to B cells, macrophages, DCs, activated T cells, class IIcontaining vesicles exported from the Golgi.
and activated endothelial cells. Cells that present antigen This action allows processed, extracellularly derived
to T cells in the context of MHC class II are called antigen to bind to class II molecules. The T-cell acces-
antigen presenting cells (APCs). sory molecule, CD4, binds to class II molecules; there-
Although most T cells recognize peptides, gamma fore, CD4+ T cells are class II restricted. The bare
delta T cells, representing about 5% of peripheral blood lymphocyte syndrome (BLS) is a primary immunodefi-
T cells, can recognize nonpeptide antigen, such as prenyl ciency resulting from the absence of MHC class II
pyrophosphate derivatives of mycobacteria. A subset of expression.
these cells, known as Vdelta2+ T cells, do not need
APCs to recognize antigen and may act as APCs them-
selves to direct other T-cell responses. T CELLS
The T-Cell Receptor and
MAJOR HISTOCOMPATIBILITY Antigen Recognition 4
CLASS CLASS I Antigen-recognition and signal-transducing elements
aggregate at the plasma membrane to form the T-cell
Major histocompatibility class class I molecules are syn- receptor (TCR) complex. Four TCR genes encode the
thesized and assembled within the endoplasmic reticu- subunits responsible for antigen recognition: alpha,
lum (ER). Two proteins comprise the MHC class I beta, gamma, and delta. These TCR genes are members
molecule. The alpha chain, encoded by genes within the of the immunoglobulin superfamily. Like other immu-
HLA locus (HLA-A, -B, and -C), associates with a noglobulin genes, the TCR genes undergo DNA rear-
nonMHC-encoded protein, beta2 microglobulin. Class rangement of variable (V), diversity (D), joining (J),
I molecules bind peptides that are 9 to 11 amino acids and constant (C) region segments. Recombination of
in length. Peptides from pathogens in the cytosol, such gene segments is generated by the action of several
as viruses, as well as normal cellular proteins are enzymes, including the recombinase-activating genes
degraded in the proteasome and then transferred to the RAG-1 and RAG-2. The rearranged genes are then
ER by the TAP transporter molecules, also encoded transcribed and translated to produce protein subunits.
within the MHC locus. Within the ER, these endoge- Heterodimers of these subunits come together to create
nous peptides bind the nascent MHC class I molecules. either the alpha beta or gamma delta receptors, which
In addition, mechanisms allow certain exogenous anti- function as the T cells antigen-recognition units. The
gens to be cross-presented by class I, such as fusion of majority of T cells in peripheral blood, lymph nodes,
endosomes with the ER. This occurs most efficiently in and spleen express alpha beta receptors.
activated DCs. The MHC I moleculepeptide com- Diversity-generating mechanisms allow humans to
plexes translocate to the plasma membrane, where they produce 1016 possible antigen-specific alpha beta T-cell
engage T cells. The T-cell accessory molecule, CD8, receptors. V-region gene segments are highly polymor-
binds to class I molecules; thus, CD8+ T cells are class phic, and recombinant assembly of the different V, D,
I restricted. and J segments allows for a wide array of possible
antigen receptors. The enzyme terminal deoxytransfer-
ase further expands the receptor repertoire by inserting
MHC CLASS II random nucleotides at the junctions between the gene
segments.
Major histocompatibility class class II molecules bind T-cell receptor genes show allelic exclusion, that is,
extracellular peptides. Class II molecules are composed if one chromosome undergoes rearrangement and pro-
of two chains that are products of different MHC genes duces a functional receptor chain, the genes on the
(HLA-DR, -DQ, and -DP) than MHC class I. Antigen other chromosome are prevented from rearranging.
processing by MHC class IIexpressing APCs occurs in Hence, each T-cell clone expresses only one antigen
three steps: extracellular antigens are ingested, inter- receptor, and antigen-specific T cells develop in unim-
nalized, and proteolyzed (Figure 4-3). MHC class II munized or naive individuals independent of exposure
molecules are synthesized and assembled in the ER, but to antigen. Subsequent antigen exposure leads to clonal
they are prevented from binding endogenous antigens selection or expansion of lymphocytes with the appro-
because the class II complex associates with a molecule priate antigen receptors. Clonal selection improves the
called the invariant chain. After export from the Golgi efficiency of the immune response and produces immu-
complex, the invariant chain is removed by the action nological memory.
Mutations in the genetic machinery for V(D)J recom- T-Cell Receptor Signal
bination have been linked to a variety of severe com-
bined immunodeficiency (SCID) conditions in humans
Transduction
(10). Deficiency in RAG-1 or RAG-2 leads to a virtual T-cell receptor alpha beta or gamma delta subunits
lack of all mature T and B lymphocytes, whereas impair- provide an elegant solution to the problem of antigen
ment of RAG-1 and RAG-2 without total loss of func- recognition, but these subunits do not transmit activa-
tion leads to a distinct phenotype called Omenn tion signals. The antigen-recognizing subunits associate
syndrome. Mutations in another recombination gene, with nonpolymorphic signaling subunits called the
ARTEMIS, cause RS-SCID, a condition with absence invariant chains, which include the CD3 family of mol-
of mature B cells and T cells, normal NK cells, and ecules (gamma, delta, and epsilon) and the zeta chain
increased radiosensitivity. Rearrangement of the (Figure 4-4). These subunits contain domains called
TCR genes requires double-stranded breaks in the immune tyrosine-based activation motifs (ITAMs),
genome, and the kinase ataxia telangiectasia mutated domains that are also present on B-cell and Fc recep-
(ATM) regulates this potentially hazardous action. tors. The ITAMs are phosphorylated by protein tyrosine
ATM deficiency leads to ataxiatelangiectasia (A-T), an kinases (PTKs) and serve to recruit other signaling mol-
autosomal recessive genomic instability syndrome. ecules. Some lymphocyte receptors have motifs called
FIGURE 4-4
A CD4+ T cell and an APC interact at the immune synapse. The T-cell receptor, comprised of the
alpha beta subunits, CD3 invariant chains, and CD4 coreceptor, contacts the MHCpeptide
complex. Costimulatory signals are transmitted through a series of molecules, including CD28
and CD40L. Engagement of peptide in the context of MHC brings the CD4-linked tyrosine kinase
Lck into proximity with the beta alpha subunits and CD3, while excluding the phosphatase
CD45. Lck phosphorylates immune tyrosine-based activation motifs (ITAMs) on CD3. This triggers
a phosphorylation cascade that ultimately activates the transcription factors, including NFAT and
NF-B, which bind the DNA and modulate gene expression. APCs also activate T cells through
cytokines, particularly via the JAK/STAT signaling pathway. Drugs that block the activation of T
cells are shown in italics.
C H A P T E R 4 I M M U N I T Y A N D I M M U N O L O G I C A L D I S E A S E S 1 01
immunoreceptor tyrosine-based inhibitory motifs (13). T cells that only receive a TCR signal can become
(ITIMs), which recruit phosphatases and attenuate sig- anergic or unable to achieve full activation. Receptors
naling. In the resting T cell, a kinetic balance between that provide costimulation include: CD28, ICOS (induc-
PTKs and tyrosine phosphatases keeps TCR signaling ible costimulator), PD-1, and adhesion molecules
through the ITAMs at a low basal level. (CD11a/CD18, CD2, and others). Mutation of ICOS is
When the TCR engages the MHCantigen complex one cause of common variable immunodeficiency
of an APC, rearrangement of the plasma membrane (CVID). A number of receptors in the TNF-receptor
surrounding the TCR changes the relative distribution family also function as lymphocyte costimulators.
of PTKs and tyrosine phosphatases near the cell surface; The counter-receptors for CD28 are CD80 and CD86,
this redistribution of signaling molecules is referred to which are expressed on APCs. Interruption of CD28-
as the immune synapse (Figure 4-4) (11). The first step dependent costimulation with the drug abatacept is effi-
in TCR signaling is tyrosine phosphorylation of recep- cacious in treating rheumatoid arthritis. A CD28-related
tor subunits and adapter molecules such as LAT (linker molecule, CTLA-4, which also binds CD80 and CD86,
of activated T cells) and SLP-76. This is mediated by a downregulates immune responses; its deficiency is asso-
series of PTKs including Lck (a PTK bound to the CD4+ ciated with lethal autoimmune disease in mice.
and CD8+ molecules), Zap-70 (zeta-associated protein
of 70 kDa), and members of the Tec family. This in turn 4
leads to the elevation of intracellular calcium, which
T-Cell Development
activates the phosphatase calcineurin. Calcineurin Precursor T cells originate in the bone marrow from
dephosphorylates NFAT (nuclear factor of activated T hematopoietic stem cells and migrate to the thymus. As
cells), allowing the translocation of this transcription they mature, T cells move from the thymic cortex to the
factor to the nucleus. The immunosuppressive drugs medulla. The most immature T cells, known as double-
cyclosporine and tacrolimus work by inhibiting calci- negative (DN) T cells, lack the surface markers CD4
neurin and NFAT activation; conversely, mutations that and CD8; these cells do not express a mature TCR but
inhibit calcium channel function are a cause of primary do express the preT-cell receptor, which comprises the
immunodeficiency. TCR signaling also activates other beta chain, an invariant protein called pre-T alpha,
transcription factors such as NF-B, Fos, and Jun, which CD3, and zeta proteins. These cells mature into double-
modulate the expression of genes encoding cytokines, positive (DP) T cells, which express CD4 and CD8 and
receptors, and other proteins that carry out T-cell undergo alpha chain rearrangement to form TCR alpha
functions. beta heterodimers. DP thymocytes mature to become
T cells are also activated by cytokines, some of which single-positive (SP) thymocytes, which express either
are made by other cells, and some of which are made by CD4 or CD8, as well as a complete TCR. Mature SP T
T cells themselves. Many, but not all, cytokines bind to cells migrate out from the thymic medulla to populate
receptors that are members of a cytokine receptor super- the peripheral lymphoid tissues.
family that signals via Janus kinases (JAKs). An impor- The development of T cells depends on signals from
tant class of substrates for JAKs are the STATs (signal the thymic stroma, which direct multipotent cells
transducers and activators of transcription), a family of towards the T-cell fate. Forkhead box N1 (FOXN1) is
seven transcription factors with distinct but critical func- a transcription factor that is essential for thymic organo-
tions in host defense. Cytokine signaling is negatively genesis and the attraction of hematopoietic stem cells
regulated by inhibitors of cytokine signal transduction, to the thymus. Mutations of FOXN1 result in the nude
including SH2-containing phosphatases (SHP), protein phenotype in mice and humans, characterized by
inhibitors of activated STATs (PIAS), and suppressors athymia and hairlessness. Another important stromal
of cytokine signaling (SOCS). Absence of SHP1, SOCS1, signal is Notch1 signaling; mutation of Notch1 results in
or SOCS3 is associated with systemic autoimmune developmental arrest of T cells.
disease in mouse models. Conversely, patients with The vast majority of T cell precursors generated in
mutations of JAK3, or its associated receptor subunit the thymus die there. Much of the T-cell death that
the common gamma chain, have SCID due to failure in occurs in the thymus is due to programmed cell death
signaling by IL-2, IL-4, IL-7, IL-15, and IL-21. Pharma- (apoptosis). To survive, potential T cells must first
cological targeting of JAK3 is being studied as a new produce TCRs at the DP stage that can recognize self-
class of immunosuppressant drugs (12). MHC molecules, a process called positive selection.
Cells lacking an appropriate receptor undergo death
by neglect, that is, they do not receive further matura-
Costimulation tion signals from the thymic stroma. Of the SP thymo-
Occupancy of the T-cell receptor alone does not lead to cytes that do develop, some recognize self-MHC
T-cell activation; occupancy of other costimulatory mol- molecules and self-peptides with high avidity. These
ecules is necessary to provide a full activation signal potentially autoreactive T cells are also eliminated, a
process called negative selection or clonal deletion. The cytokines. So-called Th17 cells produce IL-17, IL-6,
removal of potentially harmful T cells in the thymus is IL-22, G-CSF (granulocyte-colony stimulating factor),
termed central tolerance. Of course, not all potential and TNF-alpha (16). Th17 cell differentiation and main-
self-peptides are expressed in the thymus. This problem tenance is promoted by transforming growth factor
is addressed by a transcription factor, autoimmune reg- (TGF)-beta 1, IL-6, and IL-23, and it is inhibited by both
ulator (AIRE), which induces the ectopic transcription IFN-gamma and IL-4. Th17 cells are abundant in the
of organ-specific non-thymic peptides in thymic epithe- lamina propria of the small intestine in mice and seem to
lium (14). Patients with mutations in AIRE have an be important in host defense against extracellular bacte-
autoimmune disorder called APECED (autoimmune ria. IL-17 is overproduced in many autoimmune and
polyendocrinopathy-candidiasis-ectodermal dystrophy) autoinflammatory disorders, in which it appears to play
syndrome, which results from failure of negative selec- a major pathogenic role. In addition, although individual
tion of T cells responsive to tissue-specific antigens. mouse T cells tend to produce cytokines related to one
of the above subsets, human T cells can produce a wider
variety of cytokines and are not as easily classified by the
CD4+ T-Cell Differentiation above criteria.
CD4+ T cells are also known as T-helper cells because
of their role in promoting the function of other immune Regulatory T Cells and Maintenance
cells. Classically, CD4+ cells have been thought to dif-
ferentiate into one of two primary effector cell types:
of Peripheral Tolerance
T-helper 1 (Th1) and T-helper 2 (Th2) cells (Figure Another set of CD4+ cells, dubbed T regulatory (Treg)
4-1). Precisely how T-helper cell lineage differentiation cells, is essential for limiting immune responses; as such,
occurs is the subject of intense study, but cytokines it is critical for peripheral tolerance (17). Tregs have the
produced by DCs and macrophages are clearly impor- remarkable ability to suppress proliferation and cyto-
tant in the outcome. Macrophages and dendritic cells kine production by effector T cells through mechanisms
promote differentiation of naive CD4+ cells into Th1 that are at present not well understood. The transcription
cells by secreting IL-12. In addition, T-cell transcription factor FoxP3 (forkhead box P3) is both necessary and
factors, such as Stat6, GATA-3, Stat4, and T-Bet are sufficient for Treg function. Natural Tregs (nTregs),
also critical (15). arising in the thymus, express molecules such as CD25
T-helper 1 cells secrete cytokines that promote and GITR that are usually restricted to activated T cells.
cell-mediated immunity. The key Th1 cytokine is IFN- In addition, naive T cells can be driven to differentiate
gamma, which enhances the ability of macrophages to into induced or iTregs under the influence of the cyto-
kill ingested microorganisms, upregulates MHC class I kine TGF-beta1. Mutation of FoxP3 produces the scurfy
expression on many cell types, and suppresses Th2 phenotype in mice and IPEX (immune dysregulation,
responses. Mutations that affect the IL-12/IFN-gamma polyendocrinopathy, enteropathy, X-linked) syndrome
axis cause susceptibility to intracellular microorgan- in humans, both of which are manifested by T-cell attack
isms, especially atypical Mycobacteria. Mutation of on multiple organs and autoantibody production.
Tyk2, the Jak kinase responsible for signaling by IL-12 Though important, Treg cells are not the only media-
and type I IFNs, is one cause of primary immunodefi- tors of peripheral tolerance. Another mechanism is
ciency known as HyperIgE syndrome (HIES). elimination of activated T cells through repetitive stim-
T-helper 2 cells are essential for defense against hel- ulation. Repeatedly stimulated CD4+ T cells can undergo
minth infections and the host response to allergens. IL-4 autocrine cell death through interactions between the
promotes the differentiation of naive CD4+ T cells into TNF-ligand FasL and its receptor Fas/CD95. Auto-
Th2 cells, which produce IL-4, IL-5, IL-10, and IL-13. immune lymphoproliferative syndrome (ALPS), charac-
These cytokines promote humoral and allergic-type terized by lymphadenopathy, accumulation of an
responses. IL-4 inhibits macrophage activation, blocks unusual subset of CD4CD8 double-negative periph-
the effects of IFN-gamma, promotes mast cell growth, eral T cells, and frequent autoimmune disease, is caused
and induces B cells to produce IgE. IL-5 induces eosino- in most cases by dominant negative germline mutations
philia, and IL-10 inhibits macrophage antigen presenta- in the gene coding for Fas. Naive T cells activated
tion and decreases expression of MHC I molecules. The through the TCR without appropriate costimulation
importance of IL-10 is underscored by the finding that can also become anergic, a more temporary form of
IL-10 knockout mice develop severe autoimmune peripheral immune tolerance. Because of positive selec-
disease. tion towards self-MHC, it is thought that most periph-
The simple dichotomy between Th1 and Th2 cells has eral T cells are constantly receiving low levels of
recently been called into question with the discovery of activation signals from self-peptide MHC complexes in
other types of CD4+ cells that produce neither IFN- the periphery, and this may modulate T-cell responses
gamma nor IL-4, but rather produce other inflammatory as well.
CD8+ T Cells events producing the memory phenotype are unknown,

cytokines including IL-2, IL-7, and IL-15 are important
CD8+ T cells, also known as cytotoxic T lymphocytes for CD8+ memory cell generation and maintenance
(CTLs), recognize antigen in the context of MHC I (15). Lack of CD4+ help or IL-2 during primary stimula-
molecules. Because MHC I molecules present antigens tion of CD8+ T cells can promote the expression of
synthesized by the target cell, CTLs play a prominent molecules like PD1, which negatively regulates prolif-
role in defense against intracellular pathogens, particu- eration, or TRAIL, which induces apoptosis and blocks
larly viruses, protozoa, and bacteria, as well as cancer. effective memory cell formation. This can occur in
During primary infection, antigen-specific CTL clones chronic infections such as human immunodeficiency
expand rapidly, and at the peak of response can repre- virus (HIV).
sent a substantial fraction of all T cells. After the infec- Cytotoxic T lymphocytes have several strategies for
tion is cleared, this initial burst is followed by a rapid mediating cell killing. Like NK cells, CTLs kill target
depletion of these cells, probably due to the cells out- cells directly using perforin and granzymes. Perforin, a
growing their cytokine supply (Figure 4-5). A small homologue to the complement component C9, disrupts
number of CD8+ T cells then become memory T cells, the plasma membrane through pore formation. This
allowing the host rapid, heightened responses to future allows the CTL to insert granules containing granzymes,
infections with a specific pathogen. Although the exact which are proteases that rapidly activate apoptosis in 4
FIGURE 4-5
The immune response begins when the cells of the innate immune system and complement
engage pathogens. As the pathogens are neutralized, innate immune cells secrete cytokines that
increase the number of phagocytes at the site of infection. APCs also migrate to the lymphatic
tissue, where they stimulate the clonal expansion of B cells and T cells. As the immune response
progresses, the specificity of the reaction increases. B cells refine their immunoglobulins through
isotype/class switching and somatic hypermutation. CD8+ T cells lyse infected cells, and CD4+ T
cells direct the B-cell response as well as increase the ability of phagocytes to neutralize
pathogens. As the infection clears, there is attenuation of the immune response accomplished by
the apoptosis of clonal T cells and decreased activation of innate immune cells. Memory cells
develop, allowing a rapid response to any future encounters with pathogens. Failure to resolve
the initial immune response produces chronic inflammation, a state of continued innate cell
activation and adaptive cell reaction.
the target cells. CTLs also direct secretion of FasL, epithelial surfaces and, when secreted, is associated
which binds the apoptosis-inducing receptor Fas on with a secretory fragment.
target cells. CTLs secrete cytokines such as TNF-alpha
and IFN-gamma, which can attract phagocytes to sites
of infection. Viruses can evade CD8+ T cells by down-
B-Cell Development and
regulating MHC class I molecules; fortunately, the loss Immunoglobulin Gene
of MHC molecules is a signal that activates NK cells. Rearrangement
CTLs may also regulate themselves through cytotoxic
activity. This is evident in patients with familial hemo- Like other hematopoietic cells, B cells first develop in
phagocytic lymphohistiocytosis, a fatal autosomal reces- the fetal liver but later are produced in the bone marrow;
sive disorder caused by mutations in perforin or other like T cells, the cytokine milieu is important for the
molecules involved in cytotoxic granule formation. proliferation of stem cells and B-cell progenitors. As
These patients have uncontrolled activation of CTLs with T-cell development, successful B-cell development
and overproduction of inflammatory cytokines. is dependent upon immunoglobulin gene rearrange-
ment and the formation of a functional antigen recep-
tor. As in T cells, B-cell development requires the
B CELLS AND recombination of V, D, and J genes that are separate
IMMUNOGLOBULINS from one another in the germline; a proper B-cell recep-
tor repertoire is dependent upon the recombinase
Another major component of the adaptive immune machinery. B-cell precursors first assemble heavy chain
response is a class of lymphocytes termed B cells. Gen- (chromosome 14) D and J genes, with subsequent
erated in the bone marrow, B cells produce immuno- joining of a V region to the DJ complex, forming a mu
globulins or antibodies. B cells can also function as chain. H-chain rearrangements then cease. B-cell pre-
antigen-presenting cells and share some features with cursors that have not yet initiated immunoglobulin rear-
innate immune cells. Immunoglobulins function as rangement are called pro-B cells, whereas precursors
antigen receptors on B cells, but are also secreted and that express an H chain are called pre-B cells. In pre-B
have major functions in host defense. Additionally, cells, the mu chains are mostly intracellular, but some
immunoglobulins are major contributors to immune- are expressed on the cell surface in association with
mediated disease. surrogate L chain to form the preB-cell receptor
Immunoglobulin molecules consist of four polypep- complex. This receptor signals the pre-B cell to prolifer-
tide chains: two identical light (L) chains and two identi- ate and to rearrange the V and J regions of one of its L
cal heavy (H) chains, both of which have variable and chain genes (kappa and lambda loci on chromosomes 2
constant regions. Structurally, the four chains assemble and 22, respectively). Once a B-cell precursor success-
to form a Y-shaped molecule. The variable regions bind fully rearranges an H and L gene, the process stops, and
antigens, which, unlike in T cells, encompass many types the cell expresses surface immunoglobulin; it then is
of molecules, including proteins, lipids, carbohydrates, termed an immature B cell. Mature B cells express both
nucleic acids, or even drugs. The constant regions of the membrane IgM and IgD.
H chain form what is called the Fc region of the immu- Combinatorial rearrangement of H and L chain
noglobulin molecule. Many of the effector functions of genes allows for 1011 possible antigen receptors and
immunoglobulins, such as binding complement and immunoglobulin molecules. Many precursor cells fail
receptors on phagocytic cells (Fc receptors), depend on to make successful rearrangements or fail to express
the constant region of H chain. a functional preB-cell receptor, which results in
There are two types of immunoglobulin L chains apoptosis. In general, any mutation that impairs H-
kappa and lambdaand five types of H chainsmu, chain rearrangement or expression will block B-cell
gamma, delta, epsilon, alpha. The five different classes development.
or isotypes are designated IgM, IgG, IgD, IgE, and IgA,
respectively. There are also subclasses of IgG (gamma B-Cell Activation and
l, gamma 2, gamma 3, and gamma 4) and IgA (alpha 1
and alpha 2). The antigen receptor on B cells is a mem-
Differentiation
brane-bound form of IgM or IgD. After encounter with The B-cell receptor (BCR) signals similarly to the TCR,
antigen and with the help of T cells, B cells proliferate but unlike the TCR it has two functions. It initiates
and secrete immunoglobulins of different classes, a signals that activate B cells to proliferate but also binds
process known as heavy chain class or isotype switching. and internalizes antigens. The antigens are processed,
The secreted form of IgM molecules is a multimer of loaded onto class II molecules, and presented to CD4+
five Y-shaped immunoglobulin monomers joined by a J T cells. Structurally, the BCR consists of membrane-
chain. IgA molecules form a dimer, which functions at bound IgM associated with two transmembrane pro-
teins: Ig-alpha and Ig-beta Similar to the TCR-associated tion produces short-lived oligoclonal proliferative foci
molecules, Ig-alpha and Ig-beta have ITAMs, which are (each derived from several B cells). Many of the B cells
phosphorylated by PTKs such as Lyn, Blk, and Fyn. This in these foci secrete IgM and undergo isotype switching,
leads to the activation of additional PTKs, including Syk and IgM antibodies of a given antigen specificity can be
and Brutons tyrosine kinase (Btk), which activate down- converted to IgG, IgA, or IgE. These events depend on
stream pathways. Mutations of Btk underlie the disorder direct costimulatory signals from T cells, such as CD40
X-linked agammaglobulinemia. The B-cell trans- ligand/CD40 interactions and T-cellderived cytokines
membrane protein CD19 enhances BCR signaling, and such as IL-2, IL-4, IL-6, L-10, and IL-21. Mutations of
deficiency of this molecule is a cause of common variable CD40 or CD40L (TNF/TNFR members on T cells and
immunodeficiency (CVID). These patients, who make B cells, respectively) underlie hyper-IgM syndromes.
inadequate amounts of immunoglobulin, can be treated These patients lack germinal centers and have impaired
with replacement intravenous immunoglobulin. class switch recombination in B cells owing to a lack of
Once a B-cell precursor expresses surface immuno- T cell stimulation. Interference with the CD40/CD40L
globulin, it can respond to exogenous and self-antigens. interaction is being studied as a means of treating auto-
However, binding of antigens to the BCR on immature immune disorders.
B cells does not trigger cellular activation; rather, Some B cells migrate from these proliferative foci to
binding induces a cellular response that leads to self- primary follicles and enter the germinal-center pathway. 4
tolerance. Multivalent self-antigens tend to induce pro- Within a primary follicle, an oligoclonal expansion of B
grammed cell death, whereas oligovalent self-antigens cells forms the dark zone. Eventually, these cells migrate
render immature B cells refractory to further stimula- into a region called the light zone, where they interact
tion. Such a cell may escape anergy by rearranging with helper T cells and follicular dendritic cells that
another L-chain immunoglobulin gene, changing its have trapped and localized antigen on their surfaces.
BCR specificity, and losing its self-reactivity; this process Under these conditions, antibody affinity is further
is known as receptor editing. altered by the introduction of mutations in B-cell
A subset of B cells, B1 cells, is produced early in variable gene segments, a process known as somatic
ontogeny and is present predominantly in the perito- hypermutation, which does not occur in T-cell receptor
neal cavity. They have limited diversity of their antigen variable genes. As a consequence of random hypermu-
receptors. Most of the circulating IgM comes from B1 tation, B cells possessing high affinity BCRs are selected
cells and is specific for carbohydrate products of for survival, whereas those that do not possess this affin-
bacteria. ity die. B cells in which somatic mutations generated an
Mature B cells with nonself-reactive BCRs enter autoreactive BCR also are eliminated.
secondary lymphoid tissues, such as the spleen and Passage through the germinal center leads to the for-
lymph nodes, where they may encounter foreign anti- mation of plasma-cell precursors and memory B cells;
gens. B-cell antigens are divided broadly into thymus- few antibody-secreting cells remain within the germinal
dependent (TD) and thymus-independent (TI) antigens. center. Plasma cells lose their membrane immunoglob-
TD antigens are typically soluble protein antigens that ulin and many of the markers that identify B cells,
require MHC class IImediated T-cell help for antibody including CD20, the target for the drug rituximab (18).
production, whereas TI antigens do not require such Instead, plasma cells uniquely express high levels of
help. TI antigens often are multivalent, for example, CD38. Plasma cells secrete large amounts of immuno-
bacterial polysaccharides. In general, TI responses gen- globulin. They are generally short-lived cells and need
erate poor immunological memory, induce minimal ger- constant replenishment to sustain high antibody levels,
minal-center formation (see below), and trigger IgG2 although a population of long-lived plasma cells can be
secretion. B cells responding to TI antigens have a dis- maintained in the bone marrow. These may account for
tinct phenotype and localize in the marginal zone of memory immunoglobulin persistence (19). Memory B
the spleen. Dependence on these splenic B cells for cells are long-lived cells, carry somatically mutated V
responses to TI antigens may account for the poor genes, and are morphologically distinct from naive B
responses to polysaccharide antigens seen in splenecto- cells. They can be restimulated to rapidly generate a
mized individuals and in infants, because marginal zone secondary antibody response.
B cells do not mature until about 2 years of age. For Together, the extrafollicular and germinal-center
vaccines, this deficit can be overcome by coupling poly- pathways of B-cell differentiation lead to a coordinated
saccharides to a carrier protein, which triggers a TD humoral response that provides the very rapid produc-
response. tion of low affinity antibodies, the subsequent production
In the spleen, antigen-activated B cells migrate to T of high affinity antibodies, and the potential for a
cellrich zones in the periarteriolar lymphoid sheath rapid recall response. Cytokines such as IL-2, IL-10, IL-6,
searching for T-cell help. Failure to find this help likely and IL-21 promote differentiation into plasma cells,
results in anergy, but successful B-cell/T-cell collabora- whereas CD40/CD40L interactions promote memory-
cell formation and inhibit plasma-cell generation. Cyto- autoantibodies attack particular tissues, while others are
kines also contribute to isotype switching. IL-4 enhances clearly limited to the innate immune system, such as
switching to IgE and IgG4; IL-10 to IgG1, IgG3, and IgA; gout and the inherited periodic fevers. Most fall between
and TGF-beta 1 to IgA. The enzyme activation-induced these two extremes and can be thought of as resulting
cytidine deaminase (AID), which participates in recep- from pathological positive feedback between innate and
tor editing, class switching, and somatic hypermutation, adaptive immune mechanisms. For example, in rheuma-
is key to the diverse B-cell response. AID deficiency is toid arthritis, macrophages secrete cytokines, such as
another cause of hyper-IgM syndromes. TNF and metalloproteinases, that help destroy the joint
structure, but these cells depend on cytokines and cel-
lular signals provided by T cells that are co-infiltrating
AUTOIMMUNITY AND THE the synovium. To complete the feedback loop, activated
macrophages produce cytokines such as IL-12 that rein-
PATHOGENESIS OF IMMUNE- force the production of T-cellderived cytokines such as
MEDIATED DISEASE IFN-gamma. Rheumatoid factorcontaining immune
complexes present in the rheumatoid joint produced by
A fundamental aspect of the immune response is that autoreactive B cells can then amplify innate inflamma-
pathogen-derived and MHC-disparate foreign antigens tory responses through complement and Fc receptors on
are recognized and eliminated, but the host generally innate immune cells. Such an integrated model could
does not attack its own tissues. This unresponsive state is explain why therapies directed against both the innate
referred to as self-tolerance, but as discussed, self/non- (e.g., anticytokine) and adaptive (e.g., anticostimula-
self recognition occurs on many levels. Innate immune tory, antiB cell) immune systems are effective in this
cells recognize non-self through PRRs; similarly, the disease. The extraordinary therapeutic advances that
alternative complement pathway also recognizes micro- have been made recently in the treatment of rheumato-
bial products. Cross-reactivity to self-antigens by PRRs logic disorders through the targeting of specific mole-
could be an evolutionary hard-wired aspect of auto- cules with biologic agents have the added potential
immunity. For example, recognition of certain mamma- benefit of providing mechanistic insights that should
lian DNA or RNA sequences may be important in permit even better therapies in the future.
targeting autoantibodies to these ubiquitous molecules.
Similarly, the repertoire of antigens recognized by adap-
tive immune cells, T and B cells, is immense and highly SUMMARY
specific but the inherent self-reactivity of T cells and
somatic mutation of B cells requires additional mecha- The human immune response is composed of highly
nisms, such as Tregs, to maintain peripheral immune tol- antigen-specific cells that work in concert with cells
erance. Fas-mediated deletion of activated T cells is involved in innate immunity. Ordinarily, this orches-
another homeostatic mechanism that contributes to self- trated process efficiently rids the host of pathogenic
tolerance. In addition, cytokines like IL-10 and TGF-beta organisms, but not always. Immunological disease can
1 help damp immune responses. Negative regulatory occur as a consequence of dysregulation of many dif-
molecules also inhibit most immune activation events, for ferent parts of the immune system. Immunopathology
example, pyrin in inflammasome activation, CTLA4 in also can occur as a byproduct of immune responses to
T-cell activation, and SOCS proteins in cytokine signal- foreign pathogens or tissue damage. Unlike rare single-
ing. Genetic ablation of many of these negative regulatory gene disorders that are illustrative of the role of par-
proteins in mice or mutations in humans results in autoim- ticular molecules in the immune system, a variety of
mune or autoinflammatory disease. mutations or polymorphisms in an array of separate
Classically, immune-mediated diseases have been immune system genes likely contribute to the genetic
characterized based on their predominant immuno- susceptibility to common rheumatologic diseases, and
pathologic lesion. These categories are: immediate these loci are now being identified. The challenge for
hypersensitivity due to production of IgE (e.g., allergies the future will be to use these insights into the immune
and anaphylaxis); antibodies against circulating or fixed system to design better therapies for rheumatic
cells (e.g., autoimmune thrombocytopenia, Good- diseases.
pastures syndrome); immune-complex disease (e.g.,
SLE, vasculitis); and delayed type hypersensitivity.
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Some autoimmune diseases can be classified as medi- trinity of pathogen sensors that co-operate in innate
ated by adaptive immunity, such as diseases in which immunity. Trends Immunol 2006;27:352357.
2. Akira S, Uematsu S, Takeuchi O. Pathogen recognition 14. Villasenor J, Benoist C, Mathis D. AIRE and APECED:
and innate immunity. Cell 2006;124:783801. molecular insights into an autoimmune disease. Immunol
3. Ogura Y, Sutterwala FS, Flavell RA. The inflammasome: Rev 2005;204:156164.
first line of the immune response to cell stress. Cell 2006; 15. Laky K, Fowlkes BJ. Receptor signals and nuclear events
126:659662. in CD4 and CD8 T cell lineage commitment. Curr Opin
4. Stojanov S, Kastner DL. Familial autoinflammatory dis- Immunol 2005;17:116121.
eases: genetics, pathogenesis and treatment. Curr Opin 16. Weaver CT, Harrington LE, Mangan PR, Gavrieli M,
Rheumatol 2005;17:586599. Murphy KM. Th17: an effector CD4 T cell lineage with
5. Steinman RM, Bonifaz L, Fujii S, et al. The innate func- regulatory T cell ties. Immunity 2006;24:677688.
tions of dendritic cells in peripheral lymphoid tissues. Adv 17. Kronenberg M, Rudensky A. Regulation of immunity by
Exp Med Biol 2005;560:8397. self-reactive T cells. Nature 2005;435:598604.
6. Stetson DB, Medzhitov R. Type I interferons in host 18. Edwards JC, Cambridge G. B-cell targeting in rheuma-
defense. Immunity 2006;25:373381. toid arthritis and other autoimmune diseases. Nat Rev
7. Brigl M, Bry L, Kent SC, Gumperz JE, Brenner MB. Immunol 2006;6:394403.
Mechanism of CD1d-restricted natural killer T cell activa- 19. Kalia V, Sarkar S, Gourley TS, Rouse BT, Ahmed R.
tion during microbial infection. Nat Immunol 2003;4:1230 Differentiation of memory B and T cells. Curr Opin
1237. Immunol 2006;18:255264.
8. Prussin C, Metcalfe DD. IgE, mast cells, basophils, and 4
eosinophils. Allergy Clin Immunol 2006;117(Suppl):S450
S456. Suggested Reading
9. Wen L, Atkinson JP, Giclas PC. Clinical and laboratory
evaluation of complement deficiency. J Allergy Clin Abbas AK, Lichtman AH, Bell E, Bird L, eds. Cellular and
Immunol 2004;113:585593. molecular immunology. 5th ed. Philadelphia, PA: Saun-
10. Kovanen PE, Leonard WJ. Cytokines and immunodefi- ders; Nature, 2005;435:583627.
ciency diseases: critical roles of the gamma(c)-dependent Janeway C. Immunobiology: the immune system in health and
cytokines interleukins 2, 4, 7, 9, 15, and 21, and their sig- disease. 6th ed. New York: Garland Science; 2005.
naling pathways. Immunol Rev 2004;202:6783. Diamond B, Davidson A. Autoimmune diseases. N Engl J
11. Davis SJ, van der Merwe PA. The kinetic-segregation Med 2001;345:340350.
model: TCR triggering and beyond. Nat Immunol 2006;7: McGonagle D, McDermott MF. A proposed classification
803809. of the immunological diseases. PLoS Med 2006;3:e297.
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253. immunity/index.html.
CHAPTER 5
Genetics and Disease

JAMES KELLEY, PHD
ROBERT P. KIMBERLY, MD
Most rheumatic disease are caused by a combination be used to identify disease-causing variants and
of genes and environment, with genetic variation provide information on recombination, population
predisposing or protecting and environmental factors structure, and evolutionary pressures.
initiating and maintaining a disease state. Association of genes with disease can be performed
Variations in genes can occur as single nucleotide using linkage studies or association studies. Associa-
polymorphisms in coding or noncoding regions and tion studies can determine the odds ratio of a
leading to different alleles. Point mutations are rare particular gene variant being associated with a
variations occurring at less than 1% minor allele particular disease, but require large numbers of
frequency. Deletion, insertion, repeated sequences of samples from affected and unaffected individuals.
different lengths, and copy number polymorphisms Linkage studies are most useful for monogenic traits
are also responsible for differences in genes. with high penetrance where extended family infor-
Haplotypes, blocks of polymorphisms inherited mation is available. If a particular gene has only a
together more often than expected by chance, can subtle effect, linkage studies are limited in use.
Relationships between genes and diseases have long set of genetic variants (2). The relative contributions of
been hypothesized. The association of a disease with a genetic and environmental factors to disease can be
gene dates back in Western medicine as far as Hip- thought of in terms of a sliding scale (Figure 5-1). On
pocrates, who hypothesized epilepsy was caused by a one side of the scale, some conditions could be attrib-
singular hereditary unit of biological material. How- uted almost entirely to the environment, for example, a
ever, with technological advances and the completion car accident. On the other end of the spectrum, there
of the human genome sequence (1), scientists can now are primarily genetic disorders, such as cystic fibrosis or
associate specific genetic variations with clinical condi- hemoglobinopathy. Most clinical conditions, though,
tions. Genetic associations provide informative clues ranging from heart disease to rheumatoid arthritis (RA)
for developing new diagnostic and therapeutic tech- to the common cold, involve some causal component
niques to improve patient care. Understanding the prin- from both an individuals genetic background and envi-
ciples that underlie genetic studies will become an ronment. For example, genes may predispose an indi-
essential skill for clinicians if we are to appreciate the vidual to develop type II diabetes mellitus; however,
complexity of genetic contributions to disease and its diet and exercise habits ultimately lead to disease.
treatment (Table 5-1). Remembering this paradigm is important for appreciat-
ing both the advantages and limits of applying genetic
research to the understanding of both health and illness.
THE CAUSE OF DISEASE Neither genetics nor environmental factors should be
evaluated alone.
In most cases, diseases are not caused by either genes When determining the genetic contribution to the
or the environment but by a combination of the two. cause of disease, the question arises: does one gene or
Genetic variation confers a susceptible or protective many lead to illness? Mendelian, or monogenic, dis-
effect towards an illness for a specific person when com- eases, such as Huntingtons disease or cystic fibrosis, can
pared with a population. In this paradigm, genetic varia- be associated with a single genetic variant. Most dis-
tions predispose an individual towards a particular eases, however, are complex diseases because they
outcome while environmental factors, such as infectious derive their genetic components from a combination of
agents, chemicals, tobacco smoke, and diet, actually ini- genetic variants, each providing subtle, additive, and
tiate and maintain a disease state in the presence of a personalized effects. The varying genetic components
108
C H A P T E R 5 G E N E T I C S A N D D I S E A S E 1 09
TABLE 5.1. GLOSSARY OF SELECTED GENETIC TERMS.

TERM DEFINITION
Admixture Amount of genetic variation present in an individual due to descending from a particular population
Allele One of the genetic forms possible at a specific locus, when variation at that locus occurs
Ancestry informative marker Polymorphism occurring at varying allele frequencies between different populations
Complex (disease or trait) Involving more than one gene
Haplotype Group of polymorphisms that are inherited together and are observed together more often than
expected by chance
Linkage disequilibrium (LD) Likelihood that two or more polymorphisms will be inherited together as part of a haplotype
Locus (loci) Defined position within the genome
Minor allele frequency (MAF) The frequency of the less common allele in a population
Penetrance Tendency for a trait to be expressed
Polymorphism Many bodies, genetic variation
Population structure Background genetic variation common within and unique to a group due to a similar and isolated
evolutionary history
5
Recombination Rearrangement of alleles that is due to the nuclear sequence breaking and recombining during the
crossing-over phase of meiosis
of complex diseases explain the different possible clini- TYPES OF GENETIC VARIATION
cal manifestations present in one condition, such as the
11 defined possible criteria for patients with systemic The genetic component of disease can be attributed to
lupus erythematosus (SLE), of which only four are genetic variations present (or lacking) in affected indi-
required for diagnosis (3). viduals of the population. Genetic variation is found by
sequencing the genomes of several individuals from a
population to detect the most frequent allele and any
variants at that specific locus. Single nucleotide poly-
morphisms (SNPs), the most common type of genetic
variant, occur when more than one nucleotide is present
at a single position. Nonsynonymous SNPs are those
present in coding regions that change the proteins
sequence. Synonymous SNPs are those present in exons
that do not alter protein sequence. SNPs present in
untranslated regions and introns can also affect protein
function by altering splicing sites, affecting transcription
factor binding, changing promoter sites, and influencing
gene expression.
Point mutations are rare variants occurring at a single
basepair locus with less than 1% minor allele frequency
(MAF). (SNPs occur at greater than 1% MAF.) Point
mutations are much more difficult to associate with
disease than SNPs without larger sample sizes, which
are logistically difficult to collect (2). The frequency at
FIGURE 5-1 which a variant appears in the population is important
Relative contributions of genetic and environmental factors to
because a disease found in a high proportion of the
disease. Each disease is caused by varying degrees of genetic population should be associated with a genetic variant
and environmental factors. also occurring in a high proportion of the population.
110 JAMES KELLEY AND ROBERT P. KIMBERLY
This idea, the common diseasecommon variant hypoth- Assigning polymorphisms to a haplotype, when pos-
esis (4), directs researchers to which polymorphisms are sible, requires experimental data. About half the
more likely to influence a disease. genome contains variants that cannot be placed in hap-
Deletion/insertion polymorphisms (DIPs or indels) lotypes (8). Sequencing multiple samples from a popu-
result from the removal or incorporation of nucleotides lation identifies the combinations and frequencies of
into the genome sequence. While most DIPs occur polymorphisms possible in that population, which
outside exons, they are likely to be important in complex allows researchers to predict which polymorphisms are
traits and diseases, due to their potential for influencing inherited together and belong in a common haplotype.
gene expression. Haplotypes are defined based on statistical predictions,
Repeated sequences, or repeat elements, are another not absolute certainties. Therefore, polymorphisms
form of genetic variation. Interspersed repeat sequences, assigned to the same haplotype may not be inherited
which account for almost half of the human genome together in all individuals, even though it is likely that
sequence (1), are sections of DNA copied and distrib- they will.
uted randomly throughout the genome. Tandemly The probability that polymorphisms assigned to the
duplicated elements, such as microsatellites (e.g., same haplotype will occur together is called linkage
CACACACACA), are repeat sequences that, at their disequilibrium (LD). In complete or strong LD, these
time of origin, were copied in a unique pattern and linked alleles are inherited together within one segment
then translocated immediately near their original of genomic information. Therefore, any evolutionary
sequence. However, once present, tandemly duplicated pressure or association with disease for one linked allele
elements are generally inherited through generations in will inadvertently be observed as present in all polymor-
a stable manner. These unique patterns of tandemly phisms of the same haplotype. In weak LD, variants are
duplicated elements provide genetic markers that are inherited independently, due to recombination, and a
both specific and consistent to a population or group of genetic event influencing one allele will not affect the
descendants. other.
Copy number polymorphisms arise when an entire Linkage disequilibrium is most commonly measured
gene or gene segment has been duplicated or when a with the statistics D and r2. The values of these
gene is absent in some individuals. Entire gene duplica- measures range from 0 to 1, with 0 showing weak
tions allow new genes with new functions to evolve LD and 1 referring to strong or complete LD.
while keeping a functional, backup copy of the original, Generally, polymorphisms within a defined haplo-
ancestral gene (5). Examples of copy number poly- type will have a correlation coefficient or r2 value of
morphisms are found in natural killer cell receptor at least 0.8. To illustrate how LD is determined
gene families and in the major histocompatibility and haplotypes are defined from experimental data,
complex (MHC) (6), both regions important in clinical an equation for calculating D between two loci is seen
immunology. below.
D = PAB (PAXPB) Dmax = PAB D= |D/Dmax|

RELATIONSHIPS BETWEEN D = 1 Complete LD
VARIANTS: HAPLOTYPES AND The measure D is equal to the probability of both poly-
LINKAGE DISEQUILIBRIUM morphisms occurring together in an individual (PAB)
minus the product of the probabilities that only one of
Haplotypes are blocks of polymorphisms that are the polymorphisms will occur in an individual (i.e., PA
inherited together more often than expected by chance. is the probability that only polymorphism A will occur).
These blocks of genetic variants are often separated by Please note that the probabilities mentioned above are
regions of high recombination. Haplotypes are useful equivalent to the appropriate allele frequencies deter-
in identifying disease-causing variants in association mined from the sequencing data experimentally
studies and can provide information on recombination, obtained. For example, if both polymorphisms occur
population structure, and evolutionary pressures. together in 80% of samples and each polymorphism is
Because haplotypes define groups of polymorphisms observed individually in 10% of samples, then D = 0.8
that occur together, experimentally obtaining informa- (0.1 0.1) = 0.79. D is equal to the absolute value of
tion about one polymorphism also provides information dividing D by Dmax. Dmax equals the probability that both
on the other polymorphisms in the haplotype. There- polymorphisms occur in the same sample. Again, in this
fore, when attempting to associate genetic variants with instance, D = | 0.79/0.8 | = 0.9875, showing that strong
disease, testing one or a selection of polymorphisms LD is present between these two loci. Strong LD in the
per haplotype, in a process called haplotype tagging, can above situation is intuitive because both variants occur
save time and resources (7). together in 80% of samples.
POPULATION STRUCTURE: which do not necessarily produce a phenotypic effect,

distributed throughout the genome to detect regions
CONSIDERING ETHNIC that may contain a variant influencing disease. Such
DIFFERENCES studies rely on LD between these markers and a disease-
associated variant. Linkage studies have proven most
Factors causing genetic variation do so in response to the useful in detecting monogenic diseases, such as Hun-
development, migration, and structure of populations. tingtons disease and cystic fibrosis.
Due to human history, each population has been exposed While linkage studies provided early insight into the
to different environments, likely creating different evo- genetic component of complex diseases, association
lutionary pressures to preserve or delete genetic variants studies are used with increasing frequency to identify
in their genomes (9). Cross-population studies on the variants involved in complex disorders, such as SLE,
genomic organization of polymorphisms have shown that RA, and other autoimmune conditions. They compare
Yoruban Africans (Nigeria) have shorter haplotypes the frequency of a variant in an appropriate number of
and more variants than do Europeans and Asians (8). patients with the disease to the frequency in unrelated,
The wider range of genetic diversity in Africans occurs yet matched, controls. Matched controls have similar
because humans originated there and only a subgroup of ages, ethnicities, and backgrounds to affected patients
the ancestral human population (and therefore subgroup in an effort to reduce errors from population structure.
of genetic variants) migrated to other continents, leaving While such studies associate the likelihood of a variant
more genetic diversity in Africa to evolve. occurring simultaneously with a phenotype, they do not
Genetic variations common to a population but not to necessarily provide information on any functional dif-
the whole species is known as population structure. These ference leading to disease (12). During an association 5
population-specific variants can create phenotypic alter- study, genome-wide polymorphism scans can detect spe-
ations, including some associated with disease. Ethnic cific polymorphisms that are more common in disease
differences in allele frequencies at disease-associated loci groups than in healthy cohorts. Using high capacity tech-
and in disease prevalence are commonly reported, such nology, this approach evaluates a panel of thousands of
as the increased presence of SLE in patients of African common polymorphisms for differences in allele fre-
ancestry or an increase in RA in Native Americans when quencies between affected individuals and controls. A
compared with Caucasians. Due to the presence of ethnic- smaller scale technique for association studies is to select
specific genetic contributions, matching cases and con- and test candidate genes for association. Candidate gene
trols by ethnicity can help prevent any false genetic selection suggests a physiological reason for a genes
associations created by population structure (10). possible relationship with a particular disease, thereby
In addition to self-identification, samples segregated focusing which genes and variants to study (13).
by population can be tested empirically for population Statistical measures facilitate the interpretation and
admixture. Population admixture is the measurement of design of association studies. Relative risk (RR) mea-
the number of discrepancies in allele frequencies be- sures the likelihood that an individual who possesses the
tween two populations that have been historically iso- genetic variant will (or will not) develop the associated
lated. Therefore, admixture quantifies the proportion of disease (i.e., the risk an individual possessing the variant
an individuals genome that is unique and attributable to has of getting the disease relative to those without the
an ethnic background (i.e., 20% European ancestry). variant). A RR of 1.5 means an individual with the
Population structure varies greatly among groups whose associated variant is 1.5 times more likely to express
immediate ancestors no longer remained in isolation, the phenotype. RR can be estimated in association
such as Latin Americans and African Americans. Ad- studies with a statistic, the odds ratio (OR). The OR can
mixture can be measured by comparing evolutionarily be calculated with the equation: (A x B)/(C x D), where
stable microsatellites, which are exclusive to a particu- A equals the number of samples with the variant and
lar population (11), or by evaluating ancestry informa- the disease, B equals the number of samples without
tive markers (AIMs). AIMs are polymorphisms (or the either the variant or the disease, C equals the number
genes containing such polymorphisms) that vary dis- of samples with the variant but not the disease, and D
tinctly in allele frequencies between populations. equals the number of samples with the disease but not
the variant (see Figure 5-2). Basically, the OR measures
the ratio of the presence or absence of both disease and
DETERMINING GENETIC variant against the appearance of either of the two
COMPONENTS OF DISEASE exclusively.
Statistical power, in association studies, refers to the
Two main types of studies are used to identify disease- probability of finding a genetic association when it is in
causing genes: linkage studies and association studies. fact true. Power is a function of the number of samples
Linkage studies use standardized genetic markers, tested, the MAF of the variant, the presence of genetic
112 JAMES KELLEY AND ROBERT P. KIMBERLY
FIGURE 5-2
Associating a genetic variant with disease. Samples taken from a group of affected cases and a
group of matched controls are used to determine which allele each individual in the study
possesses. Note that not all individuals with disease have the studied variant and not all
individuals with the variant have the disease. In this case, the variant is the G allele at position
6. By counting the number of times the variant occurs in each group, it is possible to determine
the likelihood that having the variant will correlate with having the disease. This correlation is
based on calculating the odds ratio (OR).
features (e.g., dominant/recessive allele), and the OR present in each group. Keeping these issues in mind is
required to convince scientists the association is mean- important when interpreting genetic studies because
ingful. This OR is arbitrarily set depending on the many false positives may be in the literature due to a
disease and the level of effect researchers hope to positive publication bias; that is, studies demonstrating
observe. A study that tests too few samples can likely an association are more likely to be published than
lead to false-positive results, especially when testing a studies that fail to find an association (14).
low frequency variant.
There are advantages and weaknesses of both linkage
and association studies. Linkage studies are more useful MAJOR HISTOCOMPATIBILITY
in situations where samples are available from extended COMPLEX
families to detect a monogenetic trait with high pene-
trance. When a variant only contributes a subtle pheno- While scientists have found that genetic variants from
typic effect, linkage studies are limited in use. In this all over the genome contribute to complex disease, one
case, association studies should better detect an associa- region of the genome has been associated with more
tion; however, the large sample sizes necessary for sta- diseases, including rheumatic diseases, than any other:
tistical inference of association with disease can be the MHC (6). A selection of genetic associations of
challenging to obtain. Phenotypes tested in association rheumatic diseases with MHC-encoded genes is listed
studies often vary, especially in rheumatic diseases, in Table 5-2.
complicating interpretation of results. For example, in The MHC is a dense cluster of over 260 genes on
SLE, patients can present a variety of symptoms; there- chromosome 6p21.3 containing a high percentage of
fore, the genetic variants contributing to one individu- immune-related genes, in particular the highly polymor-
als disease may differ from the next patient. Therefore, phic human leukocyte antigen (HLA) genes involved
association studies should consider well-defined clinical in antigen presentation. The MHC is genomically orga-
subgroups during analysis to prevent missing a positive nized into multiple regions. From the telomere to cen-
association. Replication, which is finding a positive tromere, they are: extended class I region, class I region
association in another collection of samples or another (HLA-A, HLA-B, HLA-C, etc.), class III region (C4,
population, also can confuse interpretation of associa- TNF, LTA, etc.), class II region (HLA-DR, HLA-DQ,
tion studies results. During replication studies, positive HLA-DP, etc.), and the extended class II region. The
associations can be lost when larger sample sizes are class IV, or inflammatory region, is located within the
tested or when testing other populations due to the dif- class III region and contains a concentration of genes
ferent evolutionary histories and other genetic variants encoding inflammatory-mediating molecules (see
TABLE 5.2. SOME RHEUMATIC DISEASE ASSOCIATIONS become more understood and as new genetic-based
WITH THE MAJOR HISTOCOMPATIBILITY COMPLEX. technologies are translated into the clinic. Understand-
ing the genetic contribution to a clinical condition,
GENE DISEASE
both in the MHC and throughout the genome, will
HLA Systemic sclerosis allow physicians and researchers the ability to find
new markers for detecting and preventing an illness, to
HLA-B Ankylosing spondylitis
develop new diagnostic measures for evaluating poten-
HLA-B Behcets disease tial success of drug therapies, and to predict biological
malfunctions underlying a disease.
HLA-B Sarcoidosis
MICA Behcets disease
MICA Rheumatoid arthritis

References
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structure, differential bias and genomic control in a large-
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CHAPTER 6
Rheumatoid Arthritis
A. Clinical and Laboratory
Manifestations
CHRISTOPHER V. TEHLIRIAN, MD
JOAN M. BATHON, MD
Rheumatoid arthritis affects all ethnic groups, with Physical findings are most notable for joint-centered
females 2.5 times more likely than males to develop swelling, deformities, and painful or reduced joint
the disease and an overall prevalence of 1% to 2% motion. Extra-articular disease occurs in seropositive
of the population. patients and includes rheumatoid nodules, Sjgrens
Most common mode of onset is insidious fatigue, syndrome, interstitial lung disease, and vasculitis.
morning stiffness, and joint pain and swelling Laboratory tests that support a diagnosis of rheuma-
involving small distal joints [wrists, metacarpophalan- toid arthritis include elevated erythrocyte sedimenta-
geal (MCP), proximal interphalangeal (PIP), metatarso- tion rate and C-reactive protein, positive rheumatoid
phalangeal (MTP)] in symmetrical fashion. factor, positive anti-cyclic citrullinated peptide (CCP)
In most cases, rheumatoid arthritis is a chronic antibody. Further evidence of chronic inflammation
progressive disease that, if left untreated, can cause includes anemia and hypoalbuminemia. Radiographs
joint damage and disability. Factors that predict poor may reveal periarticular osteoporosis, joint space
outcome include severity of disease, seropositivity, narrowing, erosions, and deformities. Magnetic
low socioeconomic and educational status, and poor resonance imaging and ultrasound may be more
functional status. sensitive in early disease.
Rheumatoid arthritis (RA) is a chronic systemic autoim- involved, and any variance in symptoms according to
mune inflammatory disease that affects all ethnic groups time of day. It is important to remember that RA is
throughout the world. Females are 2.5 times more likely a systemic disease and individuals may therefore
to be affected than males. The onset of disease can occur present with symptoms such as fever, weight loss, and
at any age but peak incidence occurs within the fourth fatigue; however, joint symptoms are usually the most
and fifth decades of life. The average annual incidence prominent.
of RA in the United States is 0.5 per 1000 persons per Most commonly, the onset of symptoms of joint pain
year (1). The overall prevalence of RA is 1% to 2%, and and swelling is insidious, occurring over weeks to months
it steadily increases to 5% in women by the age of 70 (2). (4). However, a minority of patients may present with
However, there are differences in prevalence rates of an abrupt explosive onset polyarthritis. Still others may
RA in various ethnic groups, ranging from 0.1% in rural present with transient self-limited episodes of mono- or
Africans to 5% in Pima or Chippewa Indians (3). Many polyarthritis lasting days to weeks. This presentation is
factors contribute to the risk of developing RA and are known as palindromic rheumatism. Approximately 50%
reviewed in the following chapter (see Chapter 6B). of patients with palindromic rheumatism will go on to
develop (i.e., fulfill criteria for) RA, and only 15%
remain symptom-free after 5 years. Occasionally RA
PATIENT HISTORY may present as a monoarthritis; however, infectious and
crystalline etiologies should always be ruled out first
A detailed history of the articular symptoms is of when inflammation affects a single joint.
the utmost importance, with particular focus on the Rheumatoid arthritis is the most common form of
mode of onset (gradual vs. acute), the pattern of joints inflammatory arthritis that affects diarthrodial joints. In
114
C H A P T E R 6 R H E U M A T O I D A R T H R I T I S 1 15
early disease, the wrists, metacarpophalangeal (MCP) rated into the Revised 1987 American Rheumatism
joints, proximal interphalangeal (PIP) joints of the Association (now the American College of Rheumatol-
fingers, interphalangeal joints of the thumbs, and meta- ogy) Criteria for the classification of RA (Table 6A-1).
tarsalphalangeal (MTP) joints are most commonly In addition to articular symptoms, patients with early
affected. As the disease progresses, larger joints such as RA frequently have constitutional symptoms such as
the ankles, knees, elbows, and shoulders frequently low grade fevers, fatigue, malaise, myalgias, decreased
become affected. In contrast, involvement of the tem- appetite, and weight loss that are due to systemic inflam-
poromandibular and sternoclavicular joints and cervical mation. In some individuals, constitutional symptoms
spine are relatively uncommon, and the distal interpha- may even overshadow the articular symptoms. Organ
langeal (DIP) joints and thoracolumbar spine are nearly involvement other than the joints tends to occur in long-
always spared. standing disease and includes firm nontender bumps
Joint involvement is classically symmetrical in nature, (rheumatoid nodules) that occur most commonly on the
and morning stiffness lasting more than an hour is a elbows, Achilles tendons, and fingers; shortness of
hallmark symptom of RA. Frequently patients with breath or chest pain due to pleuropulmonary involve-
newly diagnosed RA arise from bed 1 to 2 hours earlier ment; orbital redness and pain due to scleritis; and dry
than usual to allow time in order to loosen up, and will eyes (keratoconjunctivitis sicca) and dry mouth (xero-
often describe the need for a warm shower or for soaking stomia) due to secondary Sjgrens syndrome. Extra-
their hands in warm water in order to enhance early articular symptoms are present in approximately 40%
morning function. Pain with turning door knobs, opening of RA patients. Other organ systems involved will be
jars, and buttoning shirts is commonly reported due to described later in this chapter.
pain and swelling in the wrists and small joints of the In most cases, RA is a chronic progressive disease
hands. Pain in the ball of the foot (metatarsalgia) upon that, if left untreated or inadequately treated, can cause
arising from bed, and widening of the forefoot necessi- extensive joint damage and chronic pain. A number of
tating an increase in shoe size, are frequently reported prognostic variables that predict a poor outcome have
and are due to inflammation of the metatarsalphalan- been identified and include female sex, strong family
geal joints. Neck pain and stiffness tend to occur later in history, human leukocyte antigen-DR4 cluster suscep- 6
disease and may signal tenosynovitis of the transverse tible genes (the so-called shared epitopes; see Chapter
ligament of C1, which stabilizes the odontoid process of 6B), a high number of swollen/tender joints, a high
C2. The symmetry, bilaterality, and predilection for score on a patient-rated instrument for measuring dis-
small joints (especially early in disease) are incorpo- ability (the Health Assessment Questionnaire or HAQ),
TABLE 6A-1. THE 1987 REVISED CRITERIA FOR THE CLASSIFICATION OF RHEUMATOID ARTHRITIS
(TRADITIONAL FORMAT).a
CRITERION DEFINITION
1. Morning stiffness Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement.
2. Arthritis of three or more At least three joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth
joint areas alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee,
ankle, and MTP joints.
3. Arthritis of hand joints At least one area swollen (as defined above) in a wrist, MCP, or PIP joint.
4. Symmetric arthritis Simultaneous involvement of the same joint areas (as defined in item 2) on both sides of the body
(bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry).
5. Rheumatoid nodules Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxta-articular regions,
observed by a physician.
6. Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result
has been positive in <5% of normal control subjects.
7. Radiographic changes Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs,
which must include erosions or unequivocal bony decalcification localized in or most marked
adjacent to the involved joints (osteoarthritis changes alone do not qualify).
SOURCE: From Arthritis and Rheumatism, 1988;31:315324, with permission.

a
For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least four of these seven criteria. Criteria 1 through
4 must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designation as classic, definite, or probably rheumatoid
arthritis is not to be made.
116 CHRISTOPHER V. TEHLIRIAN AND JOAN M. BATHON
high titer of rheumatoid factor (RF), high titer of anti-

cyclic citrullinated peptide (anti-CCP) antibodies, low
socioeconomic status, low educational status, psychoso-
cial problems, and the presence of erosions on joint
radiographs. Several studies have demonstrated the
highest predictor of disability at 5 years after diagnosis
to be a high score on the HAQ at 1 year after initial
diagnosis. Additional predictors of poor outcomes
include elevated erythrocyte sedimentation rate (ESR)
and C-reactive protein (CRP), persistently high scores
on the HAQ, and persistent pain.
PHYSICAL EXAMINATION
FIGURE 6A-2
Patients with suspected or confirmed RA should
undergo a thorough initial physical exam to gauge the Ulnar deviation and subluxation of the metacarpophalangeal
joints are present in the hand on the left. Muscle atrophy is also
extent of articular and extra-articular involvement.
evident in the dorsal musculature of both hands. (From the ACR
Patients should be followed every 2 to 4 months hence- slide collection on the rheumatic diseases, 3rd ed. Slide 19
forth to monitor disease activity and response to treat- (#9105030), with permission of the American College of
ment, the frequency depending upon the severity of the Rheumatology.)
disease and the medication regimen.
warmth, mild erythema, and swelling of the joints
becomes more apparent. Joint swelling is usually con-
Joint Examination fined within the joint capsule (in contrast to gout, e.g.,
Not surprisingly, the articular manifestations of RA are which can also cause considerable periarticular edema).
the most common findings on physical exam. Symmetri- It is important to record the location, symmetry, and
cal swelling and tenderness of the joints is invariably degree of swelling in each joint at the initial evaluation,
observed. Careful palpation of the joint line is necessary and to repeat this examination at subsequent visits in
in order to feel joint space fullness (swelling) and syno- order to gauge response to treatment. The examiner
vial bogginess in order to differentiate those features should also identify the joints that are painful on active
from joint enlargement secondary to the bony hypertro- and/or passive motion, the range of motion of each joint,
phy (osteophytes) of primary or secondary osteoarthri- and any deformities of the joints. The presence of joint
tis. Frank synovitis can sometimes be subtle and difficult swelling is indicative of active synovitis, whereas joint
to confirm early on but, as the disease progresses, deformity, decreased range of motion, malalignment, or
frank dislocation is indicative of joint damage.
Fusiform swelling of the proximal interphalangeal
joints (PIP) is one of the earliest findings (Figure 6A-1),
whereas deformities of the hands occur later in disease
and include ulnar deviation of the fingers, dorsal sub-
luxation of the MCP joints, and hyperextension (Swan
neck) or hyperflexion (boutonniere deformity) at the
proximal interphalangeal joints (Figure 6A-2). Swelling
of the wrists and elbows is common and is easily palpa-
ble as both joints are superficial. Loss of extension at
the elbows and wrists may result from active synovitis
or from loss of cartilage; treatment should restore exten-
sion in the former, but not the latter instance. Compres-
sive ulnar neuropathy may develop as a complication of
synovitis in the elbow, whereas compressive median
neuropathy (carpal tunnel syndrome) can result from
FIGURE 6A-1 synovitis in the wrist. Thus, a careful neurologic exami-
nation is important if sensorymotor symptoms are elic-
Swelling of the proximal interphalangeal joints in a patient with
early rheumatoid arthritis. (From the ACR slide collection on the
ited during the history taking.
rheumatic diseases, 3rd ed. Slide 17 (#9105020), with permis- Synovitis in the shoulder is more difficult to assess by
sion of the American College of Rheumatology.) physical examination because the joint is deep and the
joint capsule is not very distensible. If there is a com- TABLE 6A-2. ORGAN SYSTEMS INVOLVED IN
plete tear in the rotator cuff, an effusion in the glenohu- RHEUMATOID ARTHRITIS.
meral joint may extravasate into the subacromial space
Skin Rheumatoid nodules (25%50%)
and become more visible. Painful synovitis in the shoul-
der can result rather rapidly in loss of range of motion Hematologic Normocytic normochromic anemia (25%
due to contracture of the joint capsule and should be 30%), thrombocytosis,
thrombocytopenia,a lymphadenopathya
aggressively and proactively treated. Hip involvement
in RA occurs in only 20% of patients. This joint, like the Feltys syndrome Splenomegaly with neutropenia, large
shoulder, is deep and therefore difficult to palpate or granular lymphocytes,
visualize on physical exam; thus, it is particularly impor- thrombocytopeniaa
tant to ask about symptoms. Synovitis in the hip typically Hepatic Nonspecific transaminitis
causes groin, thigh, buttock, low back, or referred ipsi-
lateral knee pain, but early hip involvement may be Pulmonary Pleural thickening, pleural effusions,
pulmonary nodules, diffuse interstitial
asymptomatic. Knee involvement is quite common in lung disease, BOOP, Caplans syndrome,
RA and effusions are easily detected on physical exam. cricoarytenoid arthritis (pulmonary
Large knee effusions may herniate posteriorly, creating arteritis, PAH, shrinking lunga)
a popliteal (Bakers) cyst that can dissect or rupture into
Cardiac Pericarditis, accelerated atherosclerotic
the calf, causing calf pain, swelling, pitting edema, and disease, valvulitisa
bruising around the ankle (the so-called crescent sign).
These symptoms may also be suggestive of a deep venous Ophthalmologic Keratoconjunctivits sicca (10%15%),
episcleritis, scleritis, uveitis,a ulcerative
thrombosis but ultrasonography can differentiate the
keratitisa
two entities. Synovitis in the ankle may be due to inflam-
mation in the tibiotalar joint (which mediates flexion Neurologic Peripheral entrapment neuropathy, cervical
and extension) or in the joints of the hind foot (which myelopathy due to cervical spine
subluxation
mediate inversion and eversion of the ankle). Range of
motion of the tibiotalar joint is usually fairly well pre- Muscular Muscle atrophy, inflammatory myositisa
6
served early on, while diminished inversion and eversion
Renal Low grade membranous glomerular
are more common. Synovial hypertrophy in the ankle nephropathy, reactive amyloid
can compress the tarsal tunnel, causing a compressive
neuropathy. Tenosynovitis and frank rupture of the pos- Vascular Small vessel vasculitis, systemic vasculitisa
terior tibialis tendon (inferomedial to the medial malle- a
Less than 5%.
olus) is common in patients with RA, resulting in Percentage range of rheumatoid arthritis patients reported to have this
disabling heel valgus and chronic pain. Physical exami- organ system involvement is presented in parentheses.
nation of the MTPs in early disease reveals tenderness,
a widened and puffy forefoot, and frequently splaying
of the toes. In more chronic disease, dorsal subluxation
of the MTPs resulting in cock-up toe deformities, and to new symptoms. The most common extra-articular
hallux valgus (bunion) are commonly seen. manifestation of RA is Sjgrens syndrome, manifested
Early symptoms of cervical spine involvement consist by dry eyes (keratoconjunctivitis sicca) and dry mouth
primarily of neck stiffness due to tenosynovitis of the (xerostomia), and occurring in approximately 35% of
transverse ligament of C1, which stabilizes the odontoid patients. Rheumatoid nodules are also relatively
process of C2. With persistent inflammation, erosion of common, with a reported frequency of approximately
the odontoid process and/or attrition and rupture of the 25%. Rheumatoid nodules develop over pressure areas
transverse ligament may occur, leading to cervical of the body such as the elbows, Achilles tendons, fingers,
myelopathy. The amount of neck pain does not corre- scalp, and ischial tuberosities (Figure 6A-3). The nodules
late with the severity of myelopathy. Therefore, a careful are firm, nontender, and are frequently adherent to the
neurologic exam is helpful in uncovering significant underlying periosteum. Nodules are usually associated
myelopathy as abnormalities of cervical spine joints are with seropositivity for rheumatoid factor. Up to 50% of
neither visible nor palpable. RA patients will have pleural thickening on autopsy, but
this is usually asymptomatic. Pleural effusions and pleu-
risy can be bilateral in up to 25% of the cases. The
Extra-Articular Examination pleural fluid typically exhibits a low to modestly elevated
Because extra-articular manifestations can be seen in white blood cell count, low glucose, high lactate dehy-
almost 50% of all RA patients at some point during the drogenase, and high protein concentration. Up to 30%
course of their illness (Table 6A-2) (5), an organ-specific of RA patients will have parenchymal lung disease
evaluation should be done periodically and in response including pulmonary nodules (usually asymptomatic)
that may limit the use of hepatically cleared medications

such as methotrexate or leflunomide. Likewise, renal
insufficiency will preclude the use of nonsteroidal anti-
inflammatory medications. In some individuals, high
levels of systemic inflammation are associated with
depressed hepatic synthesis of albumin (hypoalbumin-
emia) and increased gamma globulin production by B
cells (hypergammaglobulinemia), leading to elevated
serum levels of nonalbumin protein (so-called protein
gap or gamma gap). It is important in these cases to rule
out a monoclonal gammopathy. Most often in RA a
broad-based polyclonal increase in gamma globulins
will be observed on serum protein electrophoresis.
Approximately 25% of RA patients will have a normo-
FIGURE 6A-3 cytic normochromic anemia as a result of chronic inflam-
mation. If iron deficiency anemia is found, further
A large subcutaneous nodule is located on the extensor surface workup is warranted to evaluate for gastrointestinal
of the forearm near the elbow. (From the ACR slide collection on
blood loss, especially if the patient chronically uses non-
the rheumatic diseases, 3rd ed. Slide 37 (#9105190), with
permission of the American College of Rheumatology.) steroidal anti-inflammatory medications. Rarely, RA
patients may exhibit leucopenia or thrombocytopenia,
which can be due to Feltys syndrome (splenomegaly
and/or diffuse interstitial lung disease that resembles and neutropenia associated with longstanding severe
idiopathic pulmonary fibrosis, obliterative bronchiolitis, RA) or due to medications.
bronchiectasis, or bronchiolotis obliterans organizing The most commonly used inflammatory biomarkers
pneumonia (BOOP). From a cardiac standpoint, peri- in clinical practice are the ESR and CRP. These markers
carditis is the most common manifestation of RA and, are usually, but not always, elevated in RA patients with
as with pleural disease, is generally asymptomatic and active disease and decline with treatment. Thus, the two
found on autopsy. Patients with RA also have a higher inflammatory markers can be followed along with the
incidence of fatal and nonfatal cardiovascular events patients symptoms and joint examination to monitor
(myocardial infarction and stroke) than the general disease activity over time. High ESR and CRP at the
population, presumably due to accelerated atheroscle- onset of disease are predictive of more aggressive
rosis from chronic systemic and/or vascular inflamma- disease and potentially worse prognosis.
tion. Hematologically, most RA patients are anemic. In addition to the routine bloodwork discussed above,
The most common cause is due to inflammation-induced two autoantibodies should be assessed in patients sus-
anemia of chronic disease but iron deficiency anemia pected of having RA. These are the RF and anti-CCP
due to gastrointestinal blood loss from nonsteroidal antibodies. RFs are antibodies against the Fc portion of
anti-inflammatory agents also occurs (see Chapter 41). IgG and can be of any immunoglobulin subclass (IgA,
Small vessel vasculitis is relatively uncommon and is IgG, and IgM) but are most commonly IgM. The cutoff
generally restricted to the digits and nailfold areas but value for a positive RF varies depending on the meth-
may also cause peripheral neuropathy and/or mononeu- odology used in the local laboratory, but a common
ritis multiplex presenting as wrist or foot drop. cutoff point is greater than 45 IU/mL by enzyme-linked
immunoabsorbent assay (ELISA) or laser nephelome-
try, or greater than a titer of 1 : 80 by latex fixation.
LABORATORY FINDINGS Similarly, the cutoff point for a positive anti-CCP test
varies according to the assay used, but greater than or
Routine laboratory studies at baseline are important in equal to 80 IU/mL is commonly used.
assessing the degree of systemic inflammation, in ruling Rheumatoid factor is detectable during the course of
out other potential confounding conditions, and in disease in approximately 75% to 85% of patients with
guiding the use of therapies that have known organ- RA. Approximately 50% are positive in the first 6
specific toxicities. These should include a comprehen- months of illness and 85% become positive over the first
sive metabolic panel, a complete blood count with 2 years. A low level of RF can also be associated with
differential, and inflammatory biomarkers such as the a number of other chronic inflammatory infectious
ESR and/or C-reactive protein. The serum electrolytes, and noninfectious conditions as well (such as bacterial
liver function, and renal function are usually normal in endocarditis, hepatitis C with cryoglobulinemia, aging,
patients with RA. Abnormal liver function tests usually primary biliary cirrhosis), whereas a high level of RF is
signal the presence of a concomitant disease process more likely indicative of RA. In RA patients, high levels
of RF are also predictive of more aggressive erosive with high titer RF and extra-articular manifestations of
articular disease and poorer long-term function, and are the disease. In contrast to systemic lupus erythemato-
associated with more extra-articular disease such as sus, in which complement levels are low, complement
rheumatoid nodules and lung involvement. The sensi- levels in RA are usually normal or increased because
tivity and specificity of RF for the diagnosis of RA are complement is an acute phase reactant.
roughly 66% and 82%, respectively. Synovial fluid analysis can also be useful in the assess-
Anti-cyclic cirullinated peptide antibodies are also ment of patients suspected of having RA. Although
found in the sera of many patients with RA and are there is no pathognomonic finding in RA, analysis of
directed against the citrullinated residues of proteins. the synovial fluid is useful to rule out infectious and
Citrulline is a non-naturally occurring amino acid gener- crystalline processes. RA patients are at an increased
ated by deimination of arginine residues on proteins by risk of developing septic joints (streptococcal and staph-
enzymes called peptidylarginine deiminases. Deiminated ylococcal infection most commonly), which can be diag-
recombinant fillagrin protein in cyclic form is a particu- nosed based on Gram stain and culture of the synovial
larly useful substrate to detect these auto antibodies. fluid. A total white blood cell count in the synovial fluid
The sensitivity of the anti-CCP antibody test for RA is above 2000 cells/mm3 is indicative of an inflammatory
similiar (70%), but specificity is superior (95%) to RF. process. A total white blood cell count greater than
Moreover, 35% of patients with a negative RF at pre- 50,000 cells/mm3 should be worrisome for an infectious
sentation will test positively for anti-CCP antibody (6). process. The differential on the white blood cell count
Thus, diagnostic yield is enhanced by measuring both in the rheumatoid joint (whether infected or not) usually
RF and anti-CCP in a patient suspected of having RA. demonstrates a neutrophilic predominance. The pres-
Like RF, the higher the level of anti-CCP antibody, the ence of crystals or bacteria in the synovial fluid speak
higher the correlation with erosive joint disease, func- to an alternate diagnosis. Synovial biopsy is not rou-
tional disability, and extra-articular disease. tinely recommended unless a chronic infectious process
Interestingly, anti-CCP and RF have been demon- such as tuberculosis is suspected.
strated in sera up to 10 years before the onset of articu-
lar symptoms in some patients who later develop RA, 6
and anti-CCP antibodies appear somewhat earlier than RADIOLOGICAL FINDINGS
RF (Figure 6A-4) (7). This important observation has
potential implications for screening individuals who are Radiographic abnormalities are very helpful in the diag-
at high risk for developing RA, as well as the potential nosis and treatment of RA. The earliest change on
for instituting preventive therapy in the preclinical stage radiographs of the small joints of the hands and feet is
of disease. These types of innovative approaches are periarticular osteopenia; however, this is variable, non-
under discussion in academic centers. specific, and nondiagnostic. More typical changes of RA
A small portion of RA patients will remain seronega- are juxta-articular bony erosions and symmetrical joint
tive throughout the course of their disease. Antinuclear space narrowing. These changes can be evident in the
antibody (ANA) can be present in 20% to 30% of first 6 to 12 months of disease and accumulate over time
patients with RA. ANA is more common in RA patients if effective control of disease activity is not achieved.
60 FIGURE 6A-4
Cumulative percentages of patients

50 with one or more positive test results
49.4%
Percentage of positive patients
for IgM rheumatoid factor (IgM-RF),

anti-cyclic citrullinated peptide (anti-
40 CCP), and IgM-RF and/or anti-CCP
before the onset of symptoms of
40.5% IgM-RF or anti-CCP rheumatoid arthritis. (From Nielen M,
30 anti-CCP van Schaardenburg D, Reesink H, et
IgM-RF al. Arthritis Rheum 2004;50:380
386, by permission of Arthritis and
20
Rheumatism.)
27.8%
10
0
15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
Years before the start of symptoms
Erosions typically appear at the margins of the joints, anti-CCP reactivity, and the presence of antinuclear
both medially and laterally, and on both apposing bones. (and other) antibodies will help to differentiate these
Late radiographic findings include subluxation and loss diseases from RA. It should be noted that RF can be
of joint alignment, due not only to bone and cartilage present in most connective tissue diseases and occurs
destruction, but also due to laxity or frank rupture of with particularly high frequency in Sjgrens syndrome.
the ligaments and tendons surrounding the joint. Radio- Patients with connective tissue diseases who have
graphs in advanced disease may also show degenerative erosive arthritis should be considered to have an overlap
changes such as osteophytes. While not specific for RA, syndrome (e.g., rupus as an overlap of RA and sys-
the findings of erosions, symmetric joint space narrow- temic lupus).
ing, and/or subluxation indicate the presence of an Hepatitis Cassociated polyarthritis with cryoglobu-
inflammatory arthritis that requires urgent assessment linemia can present a more challenging diagnostic
and treatment. Radiographs of the hands, wrists, and dilemma because cryoglobulins frequently have reactiv-
feet should be obtained at baseline in patients with RA, ity in the RF assay. For this reason, it is particularly
and can be repeated periodically to ensure that addi- important to consider hepatitis C risk factors in evaluat-
tional damage is not occurring in the face of apparently ing patients with rheumatoidlike arthritis and a positive
effective treatment. Radiographs of the hands, feet, and RF. The distribution of joint involvement in patients
wrists are more informative for following disease pro- with parvovirus B19associated polyarthritis is gener-
gression than radiographs of large joints because of the ally very similar to RA but the intensity of inflammation
numerous joints available for assessment; furthermore, is considerably less; furthermore, this arthritis resolves
because the bone is thinner in these joints, erosions are spontaneously in weeks to months in most individuals
identified earlier and visualized more easily than in without treatment. The presence of IgM-specific parvo
larger joints such as the knees. B19 viral antibodies will confirm the diagnosis.
Magnetic resonance imaging (MRI) and ultrasound Psoriatic skin involvement most commonly occurs
have proven to be more sensitive methods for detecting before the onset of the arthritis, thus providing a clue
early joint erosions; in addition, because these methods to the diagnosis of psoriatic arthritis. Furthermore,
also image soft tissues, inflammation (tenosynovitis) unlike RA, psoriatic arthritis typically involves the DIP
and integrity (rupture) of the tendons can be evaluated, joints and is less symmetrical. Other causes of inflam-
and cartilage volume can be measured by MRI. In matory arthritis that are less symmetrical and typically
patients suspected of having early RA in whom the oligo- or monoarthritic in presentation include the
articular exam is particularly difficult (e.g., in the obese crystalline arthropathies (gout and pseudogout), septic
individual), MRI can also be very helpful in confirming arthritis, and the human leukocyte antigen (HLA)-
the presence of synovial effusion and hypertrophy. MRI B27associated spondyloarthropathies. In patients pre-
and ultrasound has largely replaced arthrography, par- senting with an inflammatory monoarthritis, the process
ticularly for confirmation of ruptured popliteal cysts in should be assumed to be septic until proven otherwise.
the knee. Joint aspiration should be performed and the fluid
sent for Gram stain, culture, and crystal examination.
Usually patients with bacterial infectious arthritis will
DIFFERENTIAL DIAGNOSIS appear septic and erosions may be present on radio-
graphs, depending on the duration of infection within
A comprehensive initial evaluation of the patient, the joint. Monoarthritis that is more chronic and
including demographic characteristics, characterization accompanied by radiographic damage should evoke
of articular and extra-articular complaints, and careful the possibility of mycobacterial or fungal infection; in
physical examination, will guide the construction of the this case, a synovial biopsy for culture may be needed
differential diagnosis and subsequent laboratory and in order to expose the infection. Arthritis caused by
radiological testing. The most common causes of disseminated Neisseria gonorrhea should be consid-
symmetrical inflammatory polyarthritis that may be ered, particularly in younger female patients; skin
confused with RA are the other systemic connective lesions (pustules, blisters, vasculitic lesions) can provide
tissue disorders, psoriatic arthritis, and viral-induced a clue to the diagnosis along with history of vaginal
arthritis (in particular, parvovirus B19 and hepatitis discharge. If suspected, vaginal and oral cultures should
Cassociated arthritis). be obtained along with synovial fluid cultures. In
Other connective tissue disorders that can cause patients presenting with oligoarthritis, the spondyloar-
polyarthritis with a rheumatoidlike distribution include thropathies should be considered. These include anky-
systemic lupus erythematosus, systemic sclerosis, mixed losing spondylitis, psoriatic arthritis (discussed above),
connective tissue disease, and Sjgrens syndrome. In reactive arthritis, and arthritis associated with inflam-
most cases, the presence of extra-articular features such matory bowel disease. Features common to these dis-
as Raynauds phenomenon and rash, the absence of eases include involvement of the sacroiliac joints,
asymmetric peripheral joint involvement, uveitis, and Making the diagnosis of RA early in the course of
Achilles tendonitis. Lyme-associated arthritis is also, in disease is imperative so that effective treatment can be
essence, a reactive arthritis, occurring weeks to months initiated in a timely manner. The goals of treatment are
after the acute infection. Lyme arthritis tends to occur reduction of pain and inflammation and prevention of
in the knee and/or ankle as a monoarthritis or oligoar- long-term disability and extra-articular morbidity and
thritis. Patients should be queried about tick bites and mortality (see Chapter 6C).
Lyme antibody testing should be obtained if suspected.
Gout and pseudogout commonly present with an
intense inflammation and subcutaneous edema and can
be confused with cellulitis. If inadequately treated, REFERENCES
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arthritis or osteoarthritis, should not be confused rence of rheumatoid arthritis in the United Kingdom:
results from the Norfolk Arthritis Register. Br J Rheuma-
with RA as they do not exhibit prolonged morning
tol 1994;33:735739.
stiffness, and swelling of the joints is relatively uncom- 3. Hochberg M, Spector T. Epidemiology of rheumatoid
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checking a serum protein electropheresis. Certain met- 155163.
abolic disorders such as hypo- or hyperthyroidism can 7. Nielen M, van Schaardenburg D, Reesink H, et al. Specific
cause polyarthralgias. Also, hyperparathyroidism and autoantibodies precede the symptoms of rheumatoid
other causes of hypercalcemia predispose to the devel- arthritis: a study of serial measurements in blood donors.
opment of pseudogout. Arthritis Rheum 2004;50:380386.
CHAPTER 6
B. Epidemiology, Pathology,
and Pathogenesis
JEAN-MARC WALDBURGER, MD, PHD
GARY S. FIRESTEIN, MD
Genetic factors, including the human leukocyte T cells are involved in RA pathogenesis due to their
antigen (HLA) shared epitope, hormonal factors, and presence in the synovium, association with HLA,
environmental exposures such as tobacco smoke or presence of T-cell cytokines, and efficacy of antiT
infectious agents may predispose to the development lymphocyte treatment strategies.
of rheumatoid arthritis (RA). Cytokines are critical to RA pathogenesis. Proinflam-
The primary target organ in RA is the synovial matory cytokines tumor necrosis factor alpha (TNF-
membrane. Changes include increased cellularity, alpha), interleukin (IL) 1, and IL-6 have proved to be
increased vascularity, and infiltration with immune important as treatments, though many others may
inflammatory cells. also play essential roles.
Autoantibodies in RA include rheumatoid factor Mechanisms that result in destruction of cartilage and
and anti-cyclic citrullinated peptide (CCP) antibodies. bone lead to joint deformities and disability.
Importance of humoral immunity is demonstrated
by the efficacy of antiB lymphocyte treatment
strategies.
Rheumatoid arthritis (RA) is one of the most common EPIDEMIOLOGY AND RISK
inflammatory arthritides. Affected patients suffer from
chronic articular pain, disability, and excess mortality. FACTORS OF RHEUMATOID
It primarily affects the small diarthrodial joints of the ARTHRITIS
hands and feet, although larger weight-bearing and
appendicular joints can also be involved. Extra-articular
manifestations and systemic symptoms also occur, but The prevalence estimates for RA are between 0.5% and
in a minority of patients. RA is a heterogeneous disease 1.0% in European and North American populations.
of variable severity and unpredictable response to The disease has a worldwide distribution but studies in
therapy. Genetic and environmental factors are clearly Asia, including China and Japan, suggest a somewhat
implicated in its etiology and pathogenesis. Transla- lower rate in those regions (0.2%0.3%). Some Native
tional research efforts have led to novel targeted thera- American populations have a remarkably high preva-
pies, although the treatment of RA remains a significant lence (more than 5%) that is likely related to as yet
unmet medical need. poorly defined genetic factors.
122
Genetic Factors an uncharged citrulline, thereby permitting the antigen

to be loaded onto the MHC and presented to autoreac-
Genetic background contributes disease susceptibility tive T cells. Given this functional role, it is of interest
in RA, and the risk of developing the disease in first- that one of the four isoforms, PADI 4, has been impli-
degree relatives of a rheumatoid patient is 1.5-fold cated in RA, although the association with RA appears
higher than the general population. The concordance to be mainly in Asian populations rather than Western
rate is markedly higher for monozygotic twins com- Europeans.
pared with dizygotic twins (12%15% vs. 3.5%, respec-
tively), which supports a critical role of genes in addition
to shared environmental influences between siblings. Other Genetic Risk Factors
The overall heritability of RA has been estimated from
Polymorphisms in several other genes may contribute
twin studies to reach about 50% to 60%.
incremental risk for RA that is quantitatively lower
than the MHC itself. Many genes have been implicated,
The Role of HLA-DR and the Shared although the data vary widely. Some of the putative
Epitope Hypothesis associations relate to cytokines, chemokines, and their
receptors.
The most potent genetic risk for RA is conveyed by The analysis of the genetic predisposition to RA has
certain major histocompatibility complex alleles (MHC, recently been expanded using genomewide scans (2).
or HLA for human leukocyte antigen; see Chapter 4). An example of a newly described susceptibility gene
Early studies of MHC associations relied on serologic discovered by this approach is a functional variant
or cellular HLA typing, which only identified a fraction (R620W) of the intracellular protein tyrosine phospha-
of the allelic variability. Increased prevalence of RA tase N22 (PTPN22). The risk of developing RA is about
was reported to be associated with a subset of DR4 twofold higher in heterozygotes and fourfold higher
alleles in most Western European populations or a in homozygotes who carry this polymorphism. The
subset of DR1 alleles in other populations such as PTPN22 variant is also associated with other autoim-
Spanish, Basque, and Israeli cohorts. Current HLA 6
mune diseases, including type I diabetes and systemic
typing can discriminate allelic variants at the nucleotide lupus erythematosus. The product of this gene is an
level and reveals that a conserved amino acid sequence intracellular tyrosine phosphatase that negatively regu-
is over-represented in patients with RA. This sequence lates T-cell activity. The R620W allele results in a gain
maps in the third hypervariable region of DR beta of enzymatic function that alters the threshold for T-cell
chains from amino acids 70 to 74. The shared epitope receptor (TCR) signaling. Theoretically, the defect in
(SE) (1) is glutamine-leucine-arginine-alanine-alanine TCR signaling caused by R620W could generate auto-
(QKRAA), and presence of the SE is associated with immunity by modulating negative selection in the
increased susceptibility to and severity of RA. thymus. PTPN22 could also regulate other cell types
Different models have been proposed to explain the because it is expressed in myeloid cells and B cells.
role of the shared epitope in RA. Susceptibility alleles
could (1) bind efficiently to arthritogenic peptides, such
as those either derived from a self-antigen or a micro- Nongenetic Risk Factors
bial pathogen, (2) lead to the positive or negative selec-
tion of autoimmune T cells in the thymus, (3) lead to
Influence of Sex
inadequate numbers of regulatory T cells, (4) become Women are two to three times more likely to develop
the target of T cells themselves due to molecular mimicry RA than men. Hormonal factors like estrogen and pro-
between QKRAA and pathogens implicated in RA, gesterone could potentially explain some of the gender
such as Escherichia coli DnaJ or EpsteinBarr virus effect. Estrogen might have detrimental effects through
(EBV) peptides. its ability to decrease apoptosis of B cells, potentially
A recent alternative hypothesis suggests that the permitting the selection of autoreactive clones. Hor-
association is not necessarily between the SE itself and mones also have a complex influence on the balance
the development of RA, but instead between the SE of T-cell subsets with distinct cytokine profiles. For
and the production of certain autoantibodies, especially instance, administration of estrogen in animal models
anti-cyclic citrullinated peptide (CCP) antibodies. This can enhance or suppress T-helper (Th) 1-mediated
model implies that anti-CCP antibodies rather than the immunity, depending on the timing and the dose used.
SE is responsible for the genetic link. One possible In murine collageninduced arthritis, exogenous admin-
explanation is that the SE confers a positive charge to istration of estrogen is protective primarily by inhibiting
the peptide binding cleft on the class II MHC that pre- Th1 immunity. However, the precise explanation for
vents the binding of peptides containing arginine. Pep- the greater prevalence of RA in females and the role of
tidylarginine deiminases (PADIs) convert arginine to hormones remains uncertain.
124 JEAN-MARC WALDBURGER AND GARY S. FIRESTEIN
The situation during pregnancy exemplifies complex as peptidoglycans, are also present in RA joints in the
influence that sex has on RA. Seventy-five percent of absence of active infection. Bacterial peptidoglycans,
pregnant women with RA experience spontaneous like prokaryotic DNA, can activate Toll-like receptors
remission, although the disease typically flares within (TLR) and stimulate synovial innate immune responses.
weeks after delivery. Soluble mediators released by the Even nonspecific bacterial products could thus play a
placenta like transforming growth factor (TGF) beta, role in synovitis by activating cytokine networks or
IL-10, or alpha-fetoprotein might contribute to this acting enhancing adaptive autoimmune responses. Such
effect. Alternatively, the immune system in pregnant phenomena are well described in animal models where
women displays a shift towards a Th2 bias, which could arthritis can be induced and/or enhanced by injecting
suppress the characteristic Th1 profile of RA (see T-cell purified bacterial products, in particular lipopolysaccha-
subsets p. 127). ride (LPS) or extracts of mycobacteria. Importantly,
The presence of fetal cells in the maternal circulation LPS shares a common signaling pathway with IL-1 and
that contain potentially alloreactive, paternal HLA can substitute for this cytokine in a mouse model of
molecules has been implicated in immune modulation antibody-mediated arthritis.
during pregnancy. Generation of alloantibodies to the
MHC or competition of fetal peptides with maternal
autoantigens for MHC binding could potentially modu-
Viruses
late the disease. In one study, most pregnant women Several viruses have been implicated as possible etio-
experiencing RA remission had maternalfetal dispar- logic factors in RA. A relationship between RA and
ity in HLA class II molecules, whereas HLA mismatch EBV was suggested by several observations. For
was less common in pregnancies that did not show RA instance, EBV is a polyclonal activator of B lympho-
improvement. This association was not observed in a cytes and increases the production of rheumatoid factor
second study, so the immunological effects of a mater- (RF). Rheumatoid arthritis patients have an increased
nalfetal HLA mismatch remains to be clearly EBV load, and their synovium can expresses viral RNA.
established. The viral gp110 protein is also one of the many xeno-
proteins that contains the QKRAA sequence also found
in the SE. Such proteins might trigger autoimmune
Tobacco
responses by a process known as molecular mimicry,
Exposure to various environmental factors increase the leading to an inappropriate immune response directed
risk for RA, and cigarette smoke is one of the best against a similar endogenous protein. Parvovirus B19
characterized. Of interest, smoking also enhances the has also been suggested as an etiologic agent in RA. B19
risk of developing anti-CCP positive RA in patients DNA is more often found in RA joints than in controls,
with the SE (3). The mechanism of anti-CCP antibody although only about 5% of newly diagnosed RA patients
generation from inhaled smoke probably relates to have evidence of recent parvovirus infection. The mech-
inflammation and activation of innate immunity in the anisms of B19induced synovitis, when it does occur,
airway, which then induces peptide citrullination. In a could include increased invasive properties of infected
susceptible host, such as someone carrying the SE and fibroblastlike synoviocytes.
with genetically determined immune hyperreactivity, Based on current data, the bacterial products or viral
these repeated insults followed by chronic exposure to nucleic acids detected in RA joints are not likely to
citrullinated peptides could lead to the production of be part of an active infectious process. Even so, these
anti-CCP antibodies and other antibodies like rheuma- products could still participate indirectly to arthritis
toid factors. While the link between autoantibody proin genetically susceptible individuals by stimulating
duction and the onset of RA is not always exact, this their innate immune system, which can amplify adaptive
situation could enhance the synovial inflammatory immunity.
response when innate immunity in the joint is activated
by unrelated stimuli.
SYNOVIAL PATHOLOGY
Bacteria and Their Products The synovium is the primary site of inflammation in
Infectious agents have long been considered prime can- RA. Morphological and functional studies of this target
didates as initiating factors for RA, although the search tissue have led to improved understanding of RA
for a specific etiologic agent has been unrewarding. through systematic comparison of rheumatoid samples
Bacterial DNA is present in synovial tissue by sensitive with other joint diseases and normal tissue. Serial biop-
polymerase chain reaction techniques, but the species sies are also used increasingly in clinical studies, thus
are not unique and have also been identified in many providing insight into pathogenic mechanisms at the
other arthropathies. Other microbial components, such molecular level.
The Normal Synovium underlying cartilage and bone where the proliferating
tissue is called pannus. In the synovial sublining region,
The normal synovium consists of an intimal lining layer edema, blood vessel proliferation, and increased cellu-
that is usually discontinuous, one to two cell layers larity lead to a marked increase in tissue volume.
thick, and lacks an underlying basal membrane. The T and B lymphocytes, plasma cells, interdigitating
sublining below the intima contains blood vessels, lym- and follicular dendritic cells (IDC and FDC), and
phatics, nerves, and adipocytes distributed within a less natural killer cells (NK cells) accumulate in rheumatoid
cellular, fibrous matrix. The intimal lining layer com- synovium and can be distributed diffusely throughout
prises roughly equal proportions of two different cell the sublining or organized into lymphoid aggregates.
types, macrophagelike synoviocytes or type A synovio- The dominant cells, CD4+ T cells, are mostly of the
cytes, and fibroblastlike synoviocytes (FLS) or type B memory CD45RO+ and display the chemokine recep-
synoviocytes. The latter are responsible for the synthe- tors CXCR3 and CCR5 characteristic of Th1 cells.
sis of extracellular matrix proteins including collagen, CD4+ T cells are especially enriched in aggregates,
fibronectin, hyaluronic acid, and other molecules that whereas CD8+ T cells are present in the periphery of
facilitate the lubrication and function of cartilage sur- the aggregates or scattered throughout the sublining. In
faces. Type A cells are phagocytic and express numer- about 15% to 20% of patients, structures typical of
ous markers of the monocytemacrophage lineage. secondary lymphoid follicles can be found. T- and B-cell
infiltrates are not specific to RA and can be found in
The Synovium in many chronic inflammatory arthropathies.
The complex histological architecture of the synovial
The Synovial Fluid in
tissue in RA is the result of a dynamic process involving Rheumatoid Arthritis
coordinated molecular signals (chemokines, adhesion Normal joints contain a small amount of synovial fluid
molecules, cytokines, and growth factors) and cellular to lubricate articular surfaces. The volume of synovial
events (apoptosis, proliferation, cell migration, and 6
fluid can increase dramatically in RA due to increased
survival). Increased numbers of both type A and B leakage from the synovial microvasculature. Neutro-
synoviocytes augment the depth of the lining layer, phils (polymorphonuclear leukocytes, or PMNs) are the
sometimes to 10 cell layers, and mononuclear cells infil- predominant cell type, although lymphocytes, macro-
trate the sublining (Figure 6B-1). The lining is the phages, NK cells, and fibroblasts are also present. PMNs
primary source of inflammatory cytokines and prote- are drawn into the articular cavity by a gradient of che-
ases, thus participating in joint destruction in concert mokines and other chemotactic factors, such as C5a and
with activated chondrocytes and osteoclasts. Villous leukotriene B4. The dramatic influx of neutrophils into
projections protrude into the joint cavity, invading the joint effusions might be due, in part, to low expression
of adhesion molecules on PMNs that would retain these
cells within the synovial tissues compared with mono-
nuclear cells. The former can readily migrate out of the
tissue while the latter are retained. PMNs in the syno-
vial fluid are activated by factors such as immune com-
plexes and cellular debris. They degranulate, generate
products of oxygen metabolism, metabolize arachidonic
acid, and release proteinases and cytokines. The lym-
phocyte population in synovial effusions differs from
the synovium, with a higher number of CD8+ T cells
in the fluid compared with CD4+ T-cell predominance
in the tissue.
AUTOIMMUNITY AND
AUTOANTIBODIES IN
FIGURE 6B-1 RHEUMATOID ARTHRITIS
Synovium in rhuematoid arthritis. Only modest synovial lining
hyperplasia is present in this example, although sublining
The role of autoimmunity in RA was first suggested by
mononuclear cell infiltration, lymphoid aggregates, and vascular the discovery of autoantibodies like rheumatoid factor
proliferation are prominent. in the sera of patients, which suggests that autoreactive
B cells are generated. Risks conveyed by the SE also genic driven B-cell selection. In contrast, RFs produced
serve as an argument for a pathogenic role of adaptive by healthy individuals have avidity for the Fc portion of
immunity. The advent of B- and T-celldirected thera- IgG several orders of magnitude lower than in RA and
pies provide compelling evidence that adaptive immune contain mostly germline-derived sequences.
processes are involved in RA (see Chapter 6C).
Anti-Cyclic Citrullinated Peptide
B-Cell Autoimmunity and Antibodies
Autoantibodies Anti-cyclic citrullinated peptide antibodies are another
key autoantibody system in RA. Anti-CCP testing has
Antibodies directed against joint-specific and systemic
a sensitivity of up to 80% to 90% and a specificity of
autoantigens are commonly detected in the blood of
90% for RA, which increases to >95% specificity if com-
RA patients. Autoantibodies are also found in immune
bined with the presence of IgM RF (see Chapter 6A).
complex deposits in rheumatoid joints and probably
Anti-CCP antibodies are occasionally produced in other
contribute to the local inflammation by activating com-
inflammatory diseases, such as psoriatic arthritis, auto-
plement. In mouse models of arthritis, synovitis can be
immune hepatitis, and pulmonary tuberculosis (TB).
induced by injecting purified antibodies directed against
Similar to RF, anti-CCP antibodies are a risk factor
joint-specific proteins like type II collagen or against
for more aggressive disease and are produced early in
ubiquitous proteins that localize to joint tissue by non-
disease.
specific interactions with cartilage. Although antibodies
The process of citrullination involves conversion of
can be arthritogenic, the arthritis generated by injection
arginine to citrulline by PADIs. Of the four isoforms,
of antibodies is generally transient, whereas active
PADI 2 and PADI 4 are most abundant in the inflamed
production of autoantibodies and persistent disease
synovium. In RA, citrullination occurs in the inflamed
requires T-cell help. The concept that autoantibodies
synovium and the antibodies produced by resident B
and immune complexes are pathogenic fostered the
cells. A variety of citrullinated proteins are present in
development of targeted B-cell depletion in RA (see
the rheumatoid joint, including fibrinogen, collagen,
Chapter 6C) (4).
and fibronectin. The precise pathogenic role of the
autoantibodies in RA is not well defined. However,
Rheumatoid Factors anti-CP antibodies bind to intra-articular antigens in
Rheumatoid factors (RFs) are autoantibodies directed mice with collagen-induced arthritis and can enhance
against the Fc portion of IgG (5). They were first joint damage.
detected in the sera of patients in 1940 and fostered the
concept that humoral autoimmunity contributes to the Other Autoantibodies
pathogenesis of RA. IgG and IgM RFs are found in up Many other autoantibodies can be detected in RA sera,
to 90% of RA patients. Testing for IgM RF is about indicating that aberrant immune responses can be
70% sensitive and 80% specific for RA. However, these directed against a broad range of autoantigens. Anti
autoantibodies can also be produced during chronic type II collagen antibodies are especially interesting
infections, malignancy, and in a variety of inflammatory because they are pathogenic in a mouse model of arthri-
and autoimmune syndromes. RFs are also detectable in tis. Synovial B cells in RA produce anticollagen anti-
1% to 4% of healthy individuals, and up to 25% of bodies that fix complement. However, elevated serum
healthy individuals over the age of 60 years. They can titers are found in only a minority of patients.
be detected in the blood up to 10 years before the onset
of RA, with an increasing incidence in the period imme-
diately before clinical symptoms develop (see Chapter
T-Cell Autoimmunity
6A). Therefore, the mere presence of RF is not suffi- T cells have been implicated in RA due to their pres-
cient to cause arthritic symptoms. The presence of RF ence in the synovium and the class II MHC association.
in RA, however, has prognostic significance. Seroposi- Synovial T cells isolated from patients respond to some
tive patients have more aggressive disease while sero- cartilage-specific proteins as well as ubiquitous antigens
negative patients tend to experience less severe arthritis like heat-shock peptides. In animal models, T cells con-
with fewer bone erosions. tribute at various levels to the development and pro-
B cells isolated from RA synovium can secrete RF, gression of experimental arthritis. Several models rely
indicating that the autoantibody is produced locally in on active immunization protocols against joint antigens
the joint. The variable domains of the RF light chain such as type II collagen, which requires T-cell help. In
from RA patients contain somatic mutations that encode one mouse model, a mutation in a signal transduction
high affinity antibodies, which are a hallmark of anti- protein linked to TCR signaling causes arthritis through
abnormal thymic selection of arthritogenic T cells. matrix. IL-17 has been detected in the synovium of
Despite evidence implicating T cells in RA, the results patients with RA, although its functional role in vivo
of early targeted therapies were disappointing. More remains to be determined.
recently, a biologic agent that blocks T cell costimula- Th2 cytokines, such as IL-4 and IL-10, have also been
tion (CTLA4-Ig; abatacept) demonstrated efficacy and examined in RA, in part because they tend to antago-
has renewed the interest in targeting T cells to treat RA nize Th1 cells and are effective treatments when admin-
(see Chapter 6C) (6). istered in animal models of arthritis. Levels of Th2
cytokines are generally very low in RA, perhaps reflect-
T-Cell Subsets ing the Th1 bias of the synovium. Of the Th2 factors
present, IL-10 has been most consistently detected;
Naive CD4+ T cells can be differentiated into multiple
however, a clinical trial of IL-10 in RA did not demon-
effector types, including Th1 and Th2 phenotypes.
strate significant benefit.
Experimental systems have shown that precursor cells
can be polarized towards one of these phenotypes
depending on the nature of the antigen, characteristics MACROPHAGE AND FIBROBLAST
of the antigen-presenting cells, and the cytokine milieu.
Th1 cells are involved in the defense against intracellu-
CYTOKINES IN RHEUMATOID
lar pathogens and have been implicated in many auto- ARTHRITIS
immune diseases. Th2 cells participate in host defense
against parasitic worms but can also contribute to allergy Cytokine Networks
and asthma. Each subtype is induced by cytokines
Macrophages and fibroblasts are the primary sources of
present in the milieu (mainly IL-12 for Th1 cells, IL-4
cytokines in the rheumatoid synovium. Synovial macro-
for Th2 cells) and secretes characteristic effector cyto-
phages and fibroblasts produce a plethora of proinflam-
kines (IFN-gamma and IL-2 by Th1 cells, IL-4 and IL-
matory factors in the joint involved in the cytokine
10 by Th2 cells). IL-4 and IL-10 inhibit Th1 cells, while
network (Figure 6B-2), including IL-1, IL-6, IL-8, IL-12,
IFN-gamma suppresses Th2 function.
IL-15, IL-16, IL-18, IL-32, TNF-alpha, granulocyte- 6
Additional subsets have also been defined, including
macrophage colony-stimulating factor (GM-CSF), and
Th3 cells that produce TGF-beta and Th17 cells that
multiple chemokines (7). These cytokines can partici-
produce IL-17 after precursor cells are exposed to IL-6
pate in paracrine and autocrine networks that enhance
and TGF-beta or IL-23. Another subset, regulatory T
and perpetuate synovial inflammation. For instance,
cells (Tregs) can suppress arthritis in several experi-
macrophages and fibroblasts in the intimal lining can
mental models of autoimmunity. Tregs co-express the
activate adjacent cells that, in turn, can produce media-
surface markers CD25 and CD4 and inhibit T-cell
tors that can stimulate their neighbors. The concept of
responses by poorly defined cell-contact mechanisms.
cytokine networks dominated by synovial lining cells
In RA, CD4+CD25+ regulatory T cells isolated from
played a major role in the advent of anticytokine therapy
patients might be functionally compromised, and anti
in RA.
TNF-alpha therapy appears to this defect.
Although proinflammatory cytokines can be coun-
terbalanced by the suppressive cytokines (IL-10, TGF-
T-CellDerived Cytokines beta), soluble receptors (TNF-alpha), binding proteins
CD4+ T cells infiltrating the synovium primarily display (IL-18), and naturally occurring receptor antagonists
the Th1 phenotype. Nevertheless, levels of Th1 cyto- (IL-1Ra), all of which are produced by macrophages
kines in the rheumatoid synovium are surprisingly low. and fibroblasts in the synovial intima, the concentra-
IFN-gamma can be detected in most patients, but its tions are below those required to suppress inflamma-
concentration is much less than in other Th1-mediated tion. Although the cytokine network can be highly
diseases. Another prototypic Th1 cytokine, IL-2, is also redundant, disease control can be achieved in many
quite low in RA. However, cytokines that enhance Th1 patients by inhibiting a single cytokine. TNF-alpha
differentiation, such as IL-12, can be readily detected in antagonists are the most salient example, in which one
the rheumatoid joint. third to one half of patients have dramatic clinical
Of the T-cell cytokines implicated in RA, IL-17 may responses to cytokine blockade (see Chapter 6C).
be especially important. This cytokine synergizes with Some of the key cytokines produced by macrophages
IL-1 and TNF-alpha in vitro to induce inflammatory and fibroblasts in RA are discussed below. This is by no
cytokine production by fibroblasts and macrophages means a complete list, and the network becomes more
and enhance osteoclast activation. In animal models of complex with each passing year. In some cases, the con-
arthritis, IL-17 deficiency or blockade markedly decrease tribution of more recently described proinflammatory
clinical arthritis and destruction of the extracellular cytokines has not been defined.
FIGURE 6B-2
Cytokine networks. Macrophages (M),

fibroblastlike synovioctyes (FLS), and
T
synovial and T cells produce proinflam-
matory cytokines (denoted with +) that + IL-17 IFN-
can activate either themselves (autocrine IL-18 +
loops, blue arrows) or their adjacent cells IL-12 IL-4 IL-10
within the joint (paracrine loops, orange
arrows). They also secrete inhibitory
cytokines (denoted by -) that only FGF
IL-10 IL-1 TGF-
partially suppress the inflammation. IL-1Ra IL-18
Cytokines also stimulate osteoclasts, the sTNF-R TNF- +
MF FLS
main cell type responsible for bone
destruction. RANKL produced by FLS and
+ +
T cells (not shown in the figure) activate
IL-15 IL-6 +
osteoclasts in the rheumatoid joint.
GM-CSF IL-8
M-CSF GM-CSF
+
TNF- + IL-6
OPG
IL-1 RANKL
TNF- M-CSF
M-CSF
OC
Tumor Necrosis Factor or defective tumor immune surveillance represent

potential adverse effects of antiTNF-alpha agents.
Superfamily
Tumor necrosis factor alpha is a pro-inflammataory
cytokine that is synthesized as a membrane-bound Interleukin 1 Family
protein and released after proteolytic cleavage by Interleukin 1
TNF convertase (TACE). It is the eponymous mem-
ber of a larger group of related cytokines known as Interleukin 1 exhibits many properties that can contrib-
the TNF superfamily, many of which are also produced ute to inflammation in RA, including increased synthe-
in the rheumatoid joint. Some members of the family sis of IL-6, chemokines, GM-CSF, prostaglandin and
regulate the subsynovial microarchitecture (lymph- collagenase. It also plays a pivotal role in many animal
otoxins and LIGHT) while others participate in models of inflammatory arthritis. Of the two forms of
apoptosis (TRAIL, Fas ligand) or osteoclast activation IL-1, IL-1 beta is secreted, whereas IL-1 alpha is
(RANKL, receptor activator of NF-B ligand). expressed within cells and associated with cell mem-
In RA, TNF-alpha is mainly produced by synovial branes. The bioactive form of IL-1 beta is cleaved from
macrophages. The stimulating signals have not been a precursor protein by the cysteine protease caspase-1,
defined but could involve TLRs, a family of receptors also known as interleukin 1 converting enzyme (ICE).
that recognize specific molecular patterns and activate IL-1 acts via the type I IL-1 receptor (IL-1R1), whereas
the innate immune system, and other cytokines like IL-1R2 is a decoy receptor that does not transduce an
IL-15. TNF-alpha can then bind to two ubiquitously intracellular signal. Macrophages are the main source
expressed receptors (TNF-RI and TNF-RII) to induce of IL-1 in the rheumatoid synovium. A variety of inflam-
the release of other cytokines and metalloproteases by matory factors induce IL-1 production in RA, including
fibroblasts, decrease the synthesis of proteoglycans by TNF-alpha, GM-CSF, immunoglobulin Fc fragments,
chondrocytes, and promote the differentiation of mono- collagen fragments and, to a lesser extent, immune
cytes to osteoclasts in the presence of RANKL. TNF- complexes.
alpha inhibitors improve signs and symptoms of RA
and also decrease the progression of bone erosions due
to effects on other cytokines and osteoclasts. In addition
Interleukin 18
to its role in RA, TNF-alpha is an important molecule Interleukin 18 is another proinflammatory member of
in the host response to certain infectious agents. Oppor- the IL-1 family and induces the production of IFN-
tunistic infections, including reactivation of latent TB, gamma, IL-8, GM-CSF, and TNF-alpha by synovial
macrophages. IL-18 also biases the immune responses M-CSF and GM-CSF, are produced by both macro-
of T cells toward the Th1 phenotype. It is expressed phages and fibroblasts in the intimal lining and can
mainly by synovial fibroblasts and macrophages in enhance osteoclast differentiation and macrophage
response to TNF-alpha and IL-1 stimulation. IL-18 inhi- activation, respectively.
bition significantly attenuates collagen-induced arthritis
in the mouse. A human IL-18 binding protein blocks
IL-18 activity in vitro and is a potential therapeutic MECHANISM OF JOINT
agent.
DESTRUCTION
Interleukin 1 Receptor Angiogenesis and Cell Migration
Antagonist Protein The generation of new blood vessels is required to
Interleukin 1 receptor antagonist protein is a natural provide nutrients to the expanding synovial membrane
inhibitor of IL-1 present in the RA joint, but at con- and is an early event in the development of synovitis.
centrations too low to counteract IL-1 activity. Admin- The expanding tissue can ultimately outstrip angiogen-
istration of exogenous IL-1Ra is very effective in esis in RA; synovial fluid oxygen tension is quite low
IL-1dependent diseases such as systemic onset juvenile and is associated with low pH and high lactate levels.
idiopathic arthritis, adult Stills disease, or familial cold Hypoxia is a potent stimulus for angiogenesis in the
autoinflammatory syndrome. IL-1Ra, along with other synovium, and factors that promote blood vessel
IL-1 directed approaches like caspase-1 inhibitors and growth, such as vascular endothelial growth factor
engineered IL-1 binding proteins, have modest efficacy (VEGF), IL-8, angiopoietin-1, and many others, are
in RA (see Chapter 6C). Taken together, these data expressed in RA. Several anti-angiogenesis approaches
suggest that IL-1 might not be a central cytokine regu- can markedly attenuate arthritis in animal models. For
lating synovial inflammation in this disease. instance, targeting the integrin alpha-v beta-3 expressed
by proliferating blood vessels in the synovium or treat- 6
ing with antibodies to the type 1 VEGF receptor
Interleukin 6 Family (VEGF-R1) suppress clinical and histologic evidence of
Interluekin 6 has pleiotropic effects and influences disease.
systemic inflammation through its actions on hemato- Proinflammatory cytokines induce the expression of
poiesis and many cell types of the immune system. specialized receptors on capillaries and postcapillary
IL-6 is perhaps the major factor that induces acute venules that regulate the migration of the inflammatory
phase proteins like CRP by the liver. Very high levels cells into the synovium. E- and P-selectins, which
of IL-6 are present in the synovial fluid of RA patients mediate leukocyte rolling, and vascular cell adhesion
and type B synoviocytes are the major source. IL-6 molecule-1 (VCAM-1) and intercellular adhesion mol-
is also implicated in the activation of the endothelium ecule-1 (1-IAM), which control immobilization and
and contributes to bone erosion by stimulating the ingress of cells into tissue, are adhesion molecules iden-
maturation of osteoclasts. In RA, IL-6 levels decrease tified on the inflamed synovial endothelium in RA.
dramatically after treatment with TNF inhibitors. Once leukocytes have migrated into the tissue, they
Clinical trials of IL-6 inhibitors show a degree of effi- adhere to the matrix through surface receptors and their
cacy that is similar to TNF-alpha antagonists (see survival and proliferation is stimulated by the cytokine
Chapter 6C). milieu.
Other Key Cytokines The Role of Fibroblastlike

The number of additional cytokines and growth factors
Synoviocytes
produced by macrophages and fibroblasts in RA is Activated type-B synoviocytes are a major source of
extensive and a complete description is beyond the inflammatory mediators and metalloproteinases in RA.
scope of this chapter. For instance, many C-C and Synoviocytes can be grown in vitro to study signal
C-X-C chemokines are produced by the synovium that transduction systems that relay information from the
recruit mononuclear cells and PMNs into the joint. IL- environment to the nucleus and activate gene expres-
15 is a macrophage-derived cytokine that activates T sion. Several intracellular pathways have distinctive
cells and can increase endogenous TNF-alpha produc- but overlapping functions, including NF-B, mitogen-
tion. Certain macrophage products, like IL-12, can activated protein kinases (MAPK), and signal trans-
influence T-cell differentiation and bias cells towards ducers and activators of transcription (STATs). For
the Th1 phenotype. Colony stimulating factors, such as instance, p38 MAPK regulate production of IL-6 by
synoviocytes, while c-Jun N-terminal kinase (JNK) is a is improved in patients treated with chronic low dose
critical MAPK that induces collagenase expression and methotrexate.
regulates joint destruction in experimental arthritis.
These studies have contributed to the notion that tar-
geting signaling molecules that regulate synoviocyte
Bone Destruction
and macrophage activation might have therapeutic Focal bone erosions are a hallmark of RA that can
potential in RA. occur early in the disease and cause significant morbid-
Fibroblastlike cells derived from the synovium of RA ity due to subchondral and the cortical bone damage.
patients exhibit some unique aggressive properties. RA is also associated with periarticular bone loss adja-
Unlike synovial fibroblasts from normal or osteroarthri- cent to inflamed joints and generalized osteopenia,
tis donors, RA synoviocytes transferred to severe com- leading to increased risk of fracture in both the appen-
bined immunodeficient (SCID) mice invade and destroy dicular and axial skeleton.
human cartilage explants. Insufficient synoviocyte apo- The cellular and molecular mechanisms underlying
ptosis in RA probably contributes to intimal lining cartilage destruction and focal bone erosions are dis-
hyperplasia of the synovium due to several mechanisms, tinct. Synoviocytes, chondrocytes, and neutrophils are
including low expression of anti-apoptotic genes and probably the major effectors of the former. Bone ero-
abnormal function of tumor suppressor genes like p53. sions are mainly caused by osteoclasts, which are derived
RA synoviocytes also express a variety of oncogenes from macrophage precursors (8). They accumulate at
and display some evidence of de-differentiation, as the pannusbone interface and the subchondral marrow
demonstrated by expression of the want family of space.
embryonic genes. Receptor activator of NF-B (RANK) and its
ligand RANKL form the most important receptor
ligand pair that modulates bone resorption in RA.
RANK is expressed by osteoclasts and modulates
Extracellular Matrix Damage their maturation and activation. Expression of the
RANKL on T cells and fibroblastlike synoviocytes
Cartilage Destruction is promoted by cytokines such as TNF-alpha, IL-1,
Aggressive synoviocytes at sites of pannus overgrowth, and IL-17. The RANKRANKL system is antagonized
cytokine-activated chondrocytes, and PMNs are major by a soluble decoy receptor, osteoprotegerin (OPG),
cell types responsible for destruction of the cartilage in that binds to RANKL. Injection of OPG or deletion
RA. They release destructive enzymes in response to of the RANKL gene in animal models inhibits bone
IL-1, TNF-alpha, IL-17, and immune complexes. Once destruction but does not suppress inflammation. Of
the cartilage is compromised, mechanical stress works interest, antiTNF-alpha agents can slow the progres-
as an accelerating factor to enhance destruction. A sion rate of bone erosions in RA, even in patients
variety of enzymes participate in extracellular matrix without clinical improvement. Therefore, the inflam-
degradation of the joint, such as matrix metalloprotein- matory and destructive mechanisms in RA can be
ases (MMPs; collagenases, gelatinases, and stromely- distinct.
sin), serine proteases (trypsin, chymotrypsin), and
cathepsins (see Chapter 11B). Reversible loss of proteo-
glycans occurs early, most likely due to the catabolic
effect of cytokines and the production of stromelysins CONCLUSION
and aggrecanases. Cleavage of native type II collagen
by collagenases is an irreversible step that permanently The pathogenesis of RA is highly complex and involves
damages the cartilage. interconnected cellular and molecular pathways ulti-
Protease inhibitors are also present in the RA mately causing joint inflammation and damage (9).
joint; like endogenous cytokines antagonists, they Interaction between innate and adaptive immunity
are overwhelmed by massive production of degra- explain many aspects of RA (Figure 6B-3). Basic
dative enzymes. In addition to protecting the matrix, research and clinical studies have not clearly established
serine protease inhibitors can also prevent the a hierarchy among the different pathogenic pathways
activation of MMPs through limited proteolytic because therapies that target cytokines, T cells, or B
digestion. Tissue inhibitors of metalloproteinases cells exhibit a similar efficacy. The self-perpetuating
(TIMPs) inhibit the active form of MMPs and are mechanisms of RA are resistant to current treatments
expressed by intimal lining and sublining synovial because established disease usually relapses when
cells. The relative balance between MMPs and TIMPs therapy is discontinued, even if a full remission had
is unfavorable in RA compared with osteoarthritis and been achieved. A better understanding of these unre-
Antigen presentation
Cytokine networks
Autoantibodies
Osteoclast activation
Environment
Immune complexes
Genetics B Activation of innate immunity
DC
Activation of
PMN
innate immunity MF
Antigen loading T
Inflammatory cell FLS

recruitment
DC OC
MF FLS
Synovlum
Migration to central Central lymphoid organs

lymphoid organs
T T
Migration to joint
T
DC T
B
Antigen presentation
T cell activation 6
B cell help
Autoantibody production
FIGURE 6B-3
Innate and adaptive immunity both contribute to the pathogenesis of RA. Genetic predisposition
places individuals at risk for RA, perhaps due to abnormal T-cell selection, elevated cytokine
production, or enhanced propensity to protein citrullination. Stochastic events, such as environ-
mental exposures, might enhance immune reactivity and permit a breakdown of tolerance.
Nonspecific inflammation due to environmental exposures or endogenous ligands, such as
stimulation of the TLR, can also directly induce cytokine production, activate synoviocytes and
macrophages that secrete chemokines, and recruit lymphocytes that can respond to local
antigens. Self-antigens derived from the inflamed tissues can be processed by tissue dendritic
cells, which migrate to central lymphoid organs and activate T cells. B cells and T cells activated
in the central tissues can subsequently migrate back to the joint. At later stages, local cytokine
networks amplify and maintain a self-sustained inflammatory loop within the joints and perhaps
lead to local antigen presentation and the formation of secondary lymphoid aggregates. The
activation of enzymes that degrade the matrix and osteoclasts can cause irreversible joint
destruction.
solved issues will hopefully lead to improved diagnostic 2. Gregersen PK. Pathways to gene identification in rheuma-
and prognostic tools that are needed to achieve early toid arthritis: PTPN22 and beyond. Immunol Rev 2005;
disease control in RA before irreversible joint damage 204:7486.
has occurred. 3. Klareskog L, Stolt P, Lundberg K, et al. A new model for
an etiology of rheumatoid arthritis: smoking may trigger
HLA-DR (shared epitope)-restricted immune reactions to
autoantigens modified by citrullination. Arthritis Rheum
REFERENCES 2006;54:3846.
4. Cambridge G, Edwards JC. B-cell targeting in rheumatoid
1. Gregersen PK, Silver J, Winchester RJ. The shared epitope arthritis and other autoimmune diseases. Nat Rev Immunol
hypothesis. An approach to understanding the molecular 2006;6:394403.
genetics of susceptibility to rheumatoid arthritis. Arthritis 5. Dorner T, Egerer K, Feist E, Burmester GR. Rheumatoid
Rheum 1987;30:12051213. factor revisited. Curr Opin Rheumatol 2004;16:246253.
6. Kremer JM. Selective costimulation modulators: a novel 8. Walsh NC, Crotti TN, Goldring SR, Gravallese EM. Rheu-
approach for the treatment of rheumatoid arthritis. J Clin matic diseases: the effects of inflammation on bone.
Rheumatol 2005;11(Suppl):S55S62. Immunol Rev 2005;208:228251.
7. Arend WP. Physiology of cytokine pathways in rheuma- 9. Firestein GS. Evolving concepts of rheumatoid arthritis.
toid arthritis. Arthritis Rheum 2001;45:101106. Nature 2003;423:356361.
CHAPTER 6
C. Treatment and Assessment
ALYCE M. OLIVER, MD, PHD
E. WILLIAM ST. CLAIR, MD
Ongoing assessment of rheumatoid arthritis (RA) Disease-modifying drugs, such as methotrexate,

should include evaluation of tender and swollen should be initiated within the first 3 to 6 months of
joints, acute phase reactants [erythrocyte sedimenta- disease and, in most cases, effective control of
tion rate (ESR), C-reactive protein (CRP)], subjective disease activity will require more than one
evaluation of pain and overall disease activity, medication.
functional limitations, and radiographs. If RA cannot be controlled with one or more conven-
The treatment goal in RA is early and effective tional therapies, biologic treatments such as anti
control of synovitis to prevent joint damage, disabil- tumor necrosis factor (TNF) drugs should be used.
ity, and secondary consequences of chronic inflam- Knowledge of drug toxicities and institution of
mation such as cardiovascular disease. appropriate monitoring is required to effectively
Symptomatic relief of pain and swelling can be manage RA patients.
achieved using nonsteroidal anti-inflammatory drugs
(NSAIDs) and glucocorticoids.
ASSESSMENT OF ing, and tested for impaired range of motion. Inflamed

joints are typically tender and swollen, with visible effu-
RHEUMATOID ARTHRITIS sions. Synovitis may also be reflected by impaired or
painful joint motion. Other findings, such as subcutane-
The assessment of patients with rheumatoid arthritis ous rheumatoid nodules on extensor surfaces, are asso-
(RA) incorporates multiple domains, which include ciated with positive rheumatoid factor (RF) and
clinical, functional, biochemical, and imaging parame- antibodies to cyclic citrullinated peptide (CCP) and
ters. The history and physical examination are vital for should also be documented.
ongoing evaluation of any patient with a diagnosis of Several patient-reported measures may be used in
RA. The history should document the location of the clinical practice to evaluate the activity of disease. The
affected joints, and presence of joint pain and swelling. duration of morning stiffness often exceeds 1 hour in
Morning stiffness of the joints is an important symptom patients with active synovitis and tends to correlate with
that should be documented as well. While RA predomi- the amount of inflammation (e.g., more prolonged stiff-
nantly affects the joints, it also may lead to systemic ness associated with more active disease). Patient self-
manifestations, including fatigue, Raynauds phenome- reported pain and fatigue may be quantified using a
non, dry eyes and mouth (secondary Sjgrens syn- visual analog scale. The Health Assessment Question-
drome), interstitial lung disease, pleuritis, pericarditis, naire Disability Index (HAQ-DI) measures a patients
peripheral nervous system involvement, and vasculitis, functional ability by asking questions in different cate-
to name a few. Therefore, the history must be complete gories of functioning and can be useful in monitoring
to evaluate for possible extra-articular disease. In addi- the patients course and response to therapy.
tion, the medical history is important to assess the
patients extent of disability, including the effect of the
disease on daily activities, family life, recreational pur-
suits, and work.
Laboratory Studies
During the musculoskeletal examination, each joint Once the diagnosis of RA is established and seropositiv-
is carefully palpated for tenderness, inspected for swell- ity has been determined, testing for RF and anti-CCP
133
134 ALYCE M. OLIVER AND E. WILLIAM ST. CLAIR
to follow disease activity is not useful. Acute phase TREATMENT OF

reactants, such as the erythrocyte sedimentation rate
(ESR) and C-reactive protein (CRP), are measures of RHEUMATOID ARTHRITIS
systemic inflammation. The finding of an elevated ESR
or serum CRP level is usually indicative of active disease There has been a growing emphasis on diagnosing and
and, if repeatedly elevated over the disease course, por- treating RA early and intensively due to the recognition
tends a greater risk of disease progression. that disability and damage rapidly accrue during the
first several years of the disease. This more intensive
approach has been made possible in light of the expand-
Radiographic Studies ing therapeutic armamentarium over the past decade.
Serial radiographs of the hands and feet may be used to The classes of drugs used for the treatment of RA in-
monitor disease progression and the effectiveness of clude: nonsteroidal anti-inflammatory drugs (NSAIDs)
treatment. The accumulation of erosions or worsening and selective cyclooxygenase-2 (COX-2) inhibitors,
of joint space narrowing implies an inadequate response DMARDs, biologics, and corticosteroids. NSAIDs and
to disease-modifying antirheumatic drugs (DMARDs) COX-2 inhibitors are utilized primarily for symptomatic
or biologics and may warrant a change in medical man- relief of pain and are useful cotherapies because of their
agement. In fact, scoring systems (e.g., van der Heijde anti-inflammatory and analgesic effects (see Chapter
modification of the Sharp score) to quantify the extent 41). DMARDs are a diverse group of therapeutic agents
of joint damage have been developed to assess radio- that reduce the signs and symptoms of RA as well as
graphic progression in clinical trials of DMARDs and retard radiographic progression of joint damage. This
biologics. Magnetic resonance imaging (MRI) and class of drugs is central to the control of RA, and is part
ultrasonography have been increasingly utilized in of nearly every patients treatment regimen. The ability
patients with early RA because they are imaging modal- of a drug to slow disease progression or produce a
ities that can detect erosions with greater sensitivity disease-modifying effect is that property which defines
than plain radiographs and uniquely visualize the it as a DMARD. The biologics are structurally engi-
synovium and adjacent soft tissue structures. However, neered versions of natural molecules (e.g., monoclonal
they are mostly used as research tools, and are not yet antibodies) designed to specifically target pathogenic
validated for routine use. mediators of joint inflammation and damage. In
general, biologics are also considered to be DMARDs
when they have been shown in large clinical trials to
Disease Activity Indices significantly inhibit the progression of joint damage.
The assessment of disease activity in RA is drawn from Corticosteroids are versatile agents with potent anti-
a composite of clinical, laboratory, and radiographic inflammatory effects that represent yet another class of
measures. In clinical practice, the number of tender and drugs (see Chapter 42). They are prescribed in a variety
swollen joints is the dominant variable that drives the of clinical situations to control disease activity, but their
overall assessment of disease activity. However, treat- use is limited by significant long-term toxicity. These
ment decisions are not strictly dependent on the joint different classes of drugs are frequently combined in a
count and may be influenced by other factors. For multidrug regimen to afford optimal suppression of
example, large joints with synovitis may assume more disease activity for the individual patient.
importance in treatment decisions because of their dis- Several overarching principles guide the treatment of
proportionately greater impact on physical dysfunction. RA. Most importantly, treatment decisions are based
Individual patient factors, such as age and occupation, on accurate assessment of disease activity. There are no
are also frequently taken into account to ensure an specific standards for optimal care of RA, but the
appropriate balance of risk and benefit. A patients outcome measures described above provide a frame-
overall rating of pain, degree of functional disability, work for determining if patients need a change in
serum levels of acute phase reactants, and extent of therapy or have achieved an adequate therapeutic
radiographic progression of disease also influence the response. Treatment decisions are shaped by experi-
assessment of disease activity. A formula incorporating enced clinical judgment and balanced by the possibility
selected clinical and laboratory variables has been of improving disease control with the risks of drug toxic-
derived to produce a disease activity score (DAS28), ity. The goals of therapy are to reduce or eliminate joint
which is calculated from the number of tender and pain and swelling, prevent joint damage, minimize dis-
swollen joints (28-joint count), patient self-assessment ability, and maintain employability. Presently, treat-
of disease activity (visual analog scale), and ESR or ment decisions are largely made on empiric grounds
serum CRP level. This formula has been applied in given the lack of reliable biomarkers that can tailor
clinical practice to monitor disease activity and guide therapies to the individual patient. Thus, the same drugs
treatment decisions and is increasingly being used as an are generally employed for the treatment of all patients
endpoint in clinical trials. with RA.
Treatment with Disease-Modifying binations of DMARDs have been tested in patients

with RA and found to be more effective than MTX
Antirheumatic Drugs therapy alone. For example, a popular DMARD com-
The initiation of DMARD therapy within the first 3 to bination is the triple therapy of MTX combined with
6 months of disease onset is now the standard of care HCQ and SSZ (1). MTX is also frequently combined
for RA. The most common DMARD of choice in this with a tumor necrosis factor alpha (TNF-alpha) blocker,
setting is methotrexate (MTX) because of its proven such as etanercept, infliximab, or adalimumab. Many
clinical benefits and well-understood long-term efficacy other DMARD combinations with MTX as the anchor
and toxicity profile. Moreover, MTX may be combined drug have proven to be more effective than MTX alone.
effectively with most other DMARDs, making it a It is also important to realize that complete remission,
highly adaptable drug. Alternatively, sulfasalazine while desirable, is often not attainable despite treat-
(SSZ) and hydroxychloroquine (HCQ) may be employed ment with an optimal, empirically derived regimen
for the treatment of patients with milder forms of RA. given the current available agents.
In early disease, corticosteroids may be used to provide An empiric approach to the treatment of RA is the
rapid control of the signs and symptoms of RA and so-called step-up method in which DMARDs are added
serve as a bridge between the initiation of DMARD in sequential fashion until the signs and symptoms of
therapy and its onset of action, which is often delayed RA are adequately controlled to reach the desired
by a few months. outcome (Figure 6C-1). As MTX is often the initial
While remission is the ultimate goal of therapy, it is DMARD used for the treatment of RA, it is usually
usually not achievable with standard DMARD mono- continued as other DMARDs or biologics are added to
therapy. Thus, many different two- and three-drug com- enhance clinical benefit. In some cases, MTX may be
Active RA FIGURE 6C-1

6
Algorithm for treating active RA. In general,
patients with moderate-to-severe RA are
initially treated with methotrexate (MTX)
Moderate-to-Severe therapy. Alternatively, patients with milder
forms of RA may be treated initially with
Mild disease Consider low hydroxychloroquine (HCQ) or sulfasalazine
dose prednisone (SSZ), and if necessary, advanced to MTX
(510 mg/d) therapy depending on clinical response and
disease progression. The MTX dose may be
Begin increased from 10 to 25 mg/week, as toler-
MTX ated, to afford optimal control of disease
activity. DMARD combinations are employed
HCQ or SSZ Inadequate for those patients with an inadequate
Inadequate
response response response to MTX therapy. If patients fail to
achieve any clinical benefits from MTX
therapy, or are intolerant of this drug, they are
Escalate MTX up usually switched from MTX to another
to 25 mg/week1 DMARD, such as leflunomide or an anti-TNF
blocker (not shown in the figure).
Inadequate 1
If inadequate response to oral weekly MTX
response
therapy, consider switching from oral to
subcutaneous route of administration to
Add other DMARD MTX + anti-TNF improve bioavailability.
Inadequate MTX + abatacept

response
MTX + leflunomide
Switch to other
DMARD
combination MTX + HCQ + SSZ
MTX + rituximab
withdrawn if the patient fails to achieve even a partial safety of induction regimens continues to be a focus of
clinical response or suffers intolerable side effects. Con- investigation.
versely, a step-down method may be employed in which Successful treatment of RA depends on a detailed
two to three DMARDs are initiated simultaneously in knowledge of the different drugs, including their phar-
combination to produce a maximal clinical effect at the macokinetics, interactions with other drugs, side effects,
outset of disease. The disadvantage of this approach is and monitoring (Tables 6C-1 and 6C-2). A full discus-
that some patients with a favorable prognosis may be sion of this information is beyond the scope of this
overtreated and exposed to unnecessary side effects. chapter but some of the most important aspects of the
Following this paradigm, patients achieving a sustained individual DMARDs and biologics are described
clinical response are then weaned from some of their below. In clinical trials of DMARD therapy for RA,
medications to a less intensive regimen that maintains treatment responses are usually defined according to
disease control. This approach is also referred to as the American College of Rheumatology (ACR) criteria
induction therapy and is based on a theory that early, for improvement. These criteria are based on a compos-
intensive treatment may alter the natural history of the ite set of disease measures, including the number of
disease, an appealing feature of this strategy. To this tender and swollen joints, patient self-reported assess-
point, a 52-week study investigated the use of SSZ (2 g/ ment of pain, patient and physician assessment of overall
day), prednisolone (60 mg/day), and MTX (7.5 mg/week) disease severity, patient self-assessment of functional
in patients with early RA. Those receiving this combi- disability, and serum levels of acute phase reactants
nation regimen had significantly less joint damage at the (ESR or CRP). For example, an ACR20 response is
end of 52 weeks than those receiving SSZ alone (2). defined as a 20% improvement in the number of tender
Interestingly, the inhibition of disease progression was and swollen joints plus 20% improvement in at least
maintained in those patients receiving the combination three of the five other disease measures. The ACR20
regimen for up to 5 years (2,3). The clinical efficacy and response is a minimum amount of improvement that has
TABLE 6C-1. DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDs) FOR THE TREATMENT OF RHEUMATOID
ARTHRITIS: SIDE EFFECTS, MONITORING, AND OTHER CONSIDERATIONS.
CLINICALLY IMPORTANT OTHER WARNINGS AND
DMARD SIDE EFFECTS SCREENING/MONITORING CONSIDERATIONS
Methotrexate Nausea, diarrhea, stomatitis, fatigue, CBC, renal function, liver Viral hepatitis B and C screening;
alopecia, elevated liver enzymes, enzymes every 812 weeks contraindicated in renal disease
myelosuppression, pneumonitis, (creatinine 2 mg/dL), teratogenic
increased risk of infection
Leflunomide Nausea, diarrhea, rash, alopecia, CBC, renal function, liver Screening for viral hepatitis B and C;
elevated liver enzymes enzymes every 812 weeks teratogenic
Hydroxychloroquine Nausea, rash, skin hyperpigmentation, Yearly ophthalmologic exama Adjusted dose in renal insufficiency
retinopathy (rare)
Sulfasalazine Nausea, abdominal bloating, rash, CBC, liver enzymes every Screen for G6PD deficiency; reduce
granulocytopenia 812 weeks dose in renal or hepatic
insufficiency
Injectable gold Stomatitis, proteinuria, CBC, urinalysis prior to each

myelosuppression dose
Oral auranofin GI upset, stomatitis, proteinuria, CBC, urinalysis every 812

myelosuppression weeks
Minocycline Skin hyperpigmentation, rash, nausea, Avoid sun exposure

drug-induced lupus
Cyclosporine Nausea, abdominal pain, CBC, renal function Cyclosporine levels increase with
nephrotoxicity, hypertension, concomitant use of ketoconazole,
hypertrichosis, paresthesias, tremor, calcium antagonists, and H2
gum hyperplasia, increased risk of blockers; decreased levels with use
infection of anticonvulsants and rifampicin;
contraindicated in renal insufficiency
ABBREVIATIONS: CBC, complete blood count; G6PD, glucose 6-phosphate dehydrogenase.

a
American Academy of Ophthalmology recommends annual eye exams for individuals older than 50 years.
TABLE 6C-2. BIOLOGICS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS: SIDE EFFECTS, MONITORING AND
OTHER CONSIDERATIONS.
BIOLOGIC CLINICALLY IMPORTANT SIDE EFFECTS MONITORING OTHER WARNINGS AND CONSIDERATIONS
TNF antagonists Injection site reaction, infusion reaction, Periodic CBC Question about prior history of TB exposure and
Etanercept reactivation of latent TB, increased risk of screen with tuberculin skin testing; avoid in
Infliximab serious bacterial and opportunistic infection, NYHA class IIIIV heart failure
Adalimumab possible increased risk of lymphoma, rare
occurrence of demyelinating disorders and
lupuslike syndromes
Kineret Injection site reaction, neutropenia, increased Screen with tuberculin skin testing
risk of serious bacterial infection
Abatacept Infusion reaction, increased risk of serious Screen with tuberculin skin testing; use with
bacterial infection caution in individuals with COPD because of an
increased risk of adverse events and serious
infections in this group; avoid live vaccines
Rituximab Infusion reaction, increased risk of infection Periodic CBC Screen for viral hepatitis B infection
ABBREVIATIONS: CBC, complete blood count; COPD, chronic obstructive pulmonary disease; NYHA, New York Heart Association; TB, tuberculosis.
been shown to distinguish between an effective drug to 15 mg weekly and may be escalated to a maximum
and placebo. Compared with an ACR20 response, dose of 25 mg weekly to yield maximal disease control.
ACR50 and ACR70 responses correspond to 50% and Weekly MTX therapy has been shown in randomized,
70% improvement in these same disease measures, and controlled trials to reduce the signs and symptoms of
are viewed as more robust levels of improvement with RA and slow its rate of radiologic progression (4,5). 6
greater clinical relevance. When used alone, MTX therapy is associated with an
ACR20 response rate of nearly 60% (6), which com-
pares favorably with the other most effective DMARDs.
METHOTREXATE MTX also has been shown to reduce the rate of radio-
logical progression of disease. Importantly, women of
As indicated above, the mainstay of DMARD therapy childbearing age must use appropriate contraceptive
for RA is methotrexate (MTX). MTX inhibits dihydro- measures because of the known teratogenic effects of
folate reductase, an enzyme needed for DNA synthesis. MTX. Because MTX is partially eliminated through the
Its therapeutic action was originally thought to be due kidney, this DMARD is generally avoided in patients
to suppression of lymphocyte proliferation. However, with a serum creatinine of greater than 2.0 mg/dL. Sup-
MTXs mechanism of action is most likely due to its pression of bone marrow occurs more commonly if
anti-inflammatory effects, although the specific mecha- renal insufficiency is present. In addition, MTX may
nisms remain unclear. Inside cells, MTX is converted cause an increase in serum transaminases and, rarely,
to a polyglutamated form that inhibits the enzyme 5- liver fibrosis. Periodic laboratory monitoring of com-
aminoimidazole-4-carboxamidoribonucleotide (AICAR) plete blood counts and liver enzymes are recommended
transformylase. This enzymatic block leads to the intra- in all patients taking MTX (see Appendix II).
cellular accumulation of AICAR and, in turn, extracel-
lular adenosine release. Adenosine binds to specific
receptors on the surface of lymphocytes, monocytes, LEFLUNOMIDE
and neutrophils, and downregulates inflammatory path-
ways. MTX also has been reported to inhibit neovascu- Leflunomide was approved in 1997 for the treatment of
larization, neutrophil activity and adherence, interleukin RA, and represents an alternative oral agent to MTX.
(IL) 1 and IL-8 production by stimulated peripheral It inhibits an enzyme involved in pyrimidine synthesis,
blood mononuclear cells, and TNF production by stimu- orotic acid dehydrogenase. Leflunomide is taken once
lated peripheral T cells. a day orally, in doses of 10 or 20 mg. Leflunomides
Methotrexate can be taken orally or by subcutaneous active metabolite has a long half-life of 15 to 18 days,
injection. Generally, the oral form of MTX is initiated which is a notable feature of its pharmacokinetics. In a
for convenience, but may be switched to the subcutane- double-blind, randomized trial, leflunomide was clini-
ous route to improve gastrointestinal tolerability as well cally superior to placebo and showed ACR20 response
as bioavailability. Initial doses of MTX range from 7.5 rates similar to MTX or SSZ (7,8). Leflunomide also has
been proven to reduce structural damage. Its use is cyclines exert their ameliorating effects are unknown,
limited to some extent by gastrointestinal side effects but they have been shown in vitro to inhibit collagenase
and potential for teratogenicity. Similar to MTX, leflu- activity and nitric oxide production. In addition, mino-
nomide therapy has been associated with elevated cycline upregulates the synthesis of IL-10, an anti-
serum transaminases and should be monitored by inflammatory cytokine. Minocycline and doxycycline
regular liver enzyme testing. have been shown to decrease the signs and symptoms
of RA, but their effects on radiographic progression
remain unclear (12).
HYDROXYCHLOROQUINE AND Gold compounds are seldom used now because of
their frequent toxicity and the availability of other
SULFASALAZINE agents with better tolerability. There are two parenteral
gold formulations, gold sodium malate and myochrys-
Hydroxychloroquine and SSZ have been both shown in
ine, and an oral compound, auranofin. Treatment with
clinical trials to reduce the signs and symptoms of RA.
injectable gold and methotrexate produce similar
They are typically used to treat milder forms of RA and
response rates in clinical trials but gold therapy has
in combination with other DMARDs. The mechanism
higher rates of drug discontinuation due to toxicity (13).
of action of HCQ is not well understood but may, in
Auranofin has fewer side effects than gold injections,
part, be due to the fact that it concentrates inside cells,
but has had limited use in clinical practice due to slow
principally within acidic cytoplasmic vesicles. In lyso-
onset of action, lack of sustained clinical efficacy, and
somes, accumulation of HCQ raises the intravesical pH
poor gastrointestinal tolerability.
and may thereby interfere with the processing of auto-
In clinical trials, cyclosporine has been shown to
antigenic peptides (9). The clinical efficacy of HCQ
reduce the signs and symptoms of RA, as well as slow
therapy has been shown in a randomized, controlled
the development of joint erosions. Cyclosporine has
trial of patients with relatively mild disease of less than
been shown to produce incremental clinical benefit in
5 years duration (10). To date, no studies have shown
combination with MTX therapy (14,15). The micro-
that HCQ alone can decrease the rate of structural
emulsion-based formulation of cyclosporine (NeoralTM)
damage in RA.
has higher oral bioavailablitiy and more predictable
Sulfasalazine was initially designed as a drug that
absorption than the standard form. Cyclosporines
linked an antibiotic, sulfapyridine, with an anti-
effectiveness may be due to its biologic activities of
inflammatory agent, 5-aminosalicyclic acid (5-ASA),
inhibiting IL-2 production and the proliferation of acti-
which was based on a belief many decades ago that RA
vated T cells. Its renal side effects have been a major
was an infectious disease. Approximately 30% of SSZ
limiting factor in long-term use.
is absorbed from the gastrointestinal (GI) tract. The
remainder is degraded in the gut to sulfapyridine and
5-ASA. Whereas the bulk of the sulfapyridine is TUMOR NECROSIS FACTOR
absorbed from the gut, most 5-ASA is excreted in the
feces. SSZ suppresses various lymphocyte and leuko-
ANTAGONISTS
cyte functions and, like MTX, inhibits AICAR transfor-
Etanercept, infliximab, and adalimumab are TNF inhib-
mylase, resulting in extracellular adenosine release (11).
itors approved for the treatment of RA. These biologic
In a randomized, double-blind, placebo-controlled trial,
agents have revolutionized the treatment of RA because
an ACR20 response was achieved by 56% of patients
of their substantial benefits on the signs and symptoms
receiving SSZ after 24 weeks of treatment, compared
of this disease, as well as their ability to significantly
with a 29% response rate for placebo-treated subjects
retard the radiographic progression of joint damage.
(8). SSZ also has been shown to reduce the develop-
These drugs were engineered to specifically inhibit
ment of joint damage.
TNF, which is a critical mediator of joint inflammation.
TNF has been shown to be a pivotal proinflammatory
cytokine that regulates the production of other proin-
OTHER ANTIRHEUMATIC flammatory cytokines, such as IL-1 and IL-6 (see
MEDICATIONS Chapter 6B). TNF also activates endothelium, upregu-
lates the expression of adhesion molecules, promotes
Several well-designed controlled trials attest to the clin- the release of matrix metalloproteinases, and stimulates
ical efficacy of minocycline and doxycyline for the treat- osteoclastogenesis. All of these pathways are believed
ment of RA, but they appear to be suited primarily for to be important in the pathogenesis of RA.
mild disease. Large trials have not been performed Etanercept is a soluble receptor fusion protein that
using these agents, and they are not approved drugs for binds to soluble TNF, neutralizing its biologic activities.
the treatment of RA. The mechanisms by which tetra- Infliximab is a chimeric monoclonal antibody that binds
to both soluble and membrane-bound TNF, whereas In trials, the SIR increases to 2.6 and 3.8 with the use
adalimumab is a fully human monoclonal antibody with of infliximab and etanercept, respectively (19). Based
binding properties similar to infliximab. Etanercept and on trial data, a meta-analysis has shown that infliximab
adalimumab are administered as a subcutaneous injec- and adalimumab therapy has a pooled odds ratio of 3.3
tion while infliximab is administered as an intravenous for malignancies, including nonmelanoma skin cancers,
infusion. Clinical trials indicate that all of these TNF suggesting a possible relationship between TNF block-
blockers, when added to MTX, produce incremental ers and an increased risk for solid tumors (19).
ACR20 response rates of approximately 50% to 70%. Other rare side effects of note include demyelinating
These agents have also been studied in patients with disorders and drug-induced lupus reactions. The
early RA and when used in combination with MTX, anti-TNF agents should not be used in patients with
produce ACR50 response rates of 40% to 50%. New York Heart Association (NYHA) class III to V
Although etanercept and adalimumab can be used as heart failure because these drugs may exacerbate heart
monotherapy, the combination of MTX and a TNF failure.
blocker appears to be the most effective regimen for
preventing radiographic progression of disease.
While TNF blockers have proven to be clinically effi-
cacious in RA, their use has been associated with side
ANAKINRA
effects, some of which may have serious consequences.
Anakinra is a human recombinant antiIL-1 receptor
Etanercept and adalimumab have caused injection site
antagonist that has been approved for the treatment of
reactions but they are rarely severe enough to limit
RA. It is administered as a daily 100 mg subcutaneous
therapy. Infliximab has been associated with infusion
injection and has been shown to improve the signs and
reactions, which can range from rash to urticaria and
symptoms of RA. However, in a randomized, controlled
fever, and rarely to anaphylaxis. Neutralizing antibodies
trial the ACR20 response rates using this drug were
can develop in infliximab-treated individuals that may
only 38% (20). Modest reductions in radiographic pro-
inhibit the efficacy of the drug and predispose to infu-
sion reactions. There is also an increased risk of serious
gression of joint disease were also seen using this drug 6
compared to controls (21). Overall, the clinical benefits
bacterial and opportunistic infections, especially reacti-
of anakinra are less than those of the TNF blockers. For
vation of latent tuberculosis. A long-term study of etan-
this reason, the use of anakinra in RA has been limited
ercept therapy for RA showed that the rate for serious
to selective patients with refractory disease.
infection was 4.2 per 100,000 patient years, which
remained relatively stable throughout the time period
(16). The German Biologics Registrar showed a relative
risk of 3.0 for serious infection in patients receiving inf- ABATACEPT AND RITUXIMAB
liximab (17). Additionally, recent meta-analysis of trial
data found a twofold increased risk for serious infec- Abatacept and rituximab are among the recent addi-
tions in RA subjects treated with anti-TNF antibodies tions to the biologics available for the treatment of
(18). Data from the FDA in 2001 revealed 8.2 cases of moderate-to-severe RA. They are currently approved
tuberculosis (TB) in the United States for every 100,000 for patients with active RA who have had an inadequate
patient years of etanercept or infliximab therapy, response to other DMARDs or have failed treatment
although more cases of reactivated TB have been with an anti-TNF agent. Abatacept (CTLA-4Ig) is a
reported with infliximab therapy. There have also been recombinant fusion protein consisting of the extra-
cases of TB reported with the use of adalimumab. cellular domain of human CTLA-4 and the Fc domain
Because of the increased risk for reactivation of latent of human IgG1. Abatacept binds to CD80/CD86 on
TB, it is now standard practice to screen individuals for the surface of antigen-presenting cells, thus preventing
prior TB exposure and with skin testing before starting their binding to CD28 on T cells. Blockade of CD28
a TNF antagonist. The rate of TB infection while using binding prevents the so-called second signal of T-cell
TNF antagonists appears to be declining due in large activation. A randomized, double-controlled trial has
part to this routine screening. shown that abatacept therapy produces an ACR20
Use of anti-TNF agents may also confer an increased response of 50% in patients with active RA who had
risk for lymphoproliferative disorders, namely lym- previously failed an anti-TNF drug, compared to placebo
phoma. The strength of this link remains unclear because rate of 19% (22). Abatacept has also been shown to be
of the fact that RA itself is associated with an increased effective in patients with an inadequate response to
risk of lymphoma and that the magnitude of this risk MTX therapy. Moreover, in those taking a combination
appears to rise with increasing disease severity. Patients of both abatacept and methotrexate, radiographic
with RA have an increased risk of lymphoma, corre- progression was reduced in comparison to controls
sponding to a standardized incidence ratio (SIR) of 1.9. (22).
Initially approved in 1997 for non-Hodgkins lym- cholesterol-lowering medications prescribed as needed.
phoma, rituximab is a chimeric anti-CD20 monoclonal Other CV risk factors, such as hypertension, diabetes,
antibody now approved for the treatment of moderate- and obesity, should be treated according to usual
to-severe RA. Rituximab depletes B cells that have recommendations.
CD20 on their surface. Its mechanism of action is incom-
pletely understood but may involve inhibition of T-cell
activation through reduction of antigen presentation SUMMARY
by B cells or reduction of B-cell cytokines. Despite the
depletion of peripheral B cells by more than 97%, The assessment of RA demands a careful history and
immunoglobulin levels usually remain within the normal examination, with a detailed joint count to determine
range. RF may decline; however, clinical improvement disease activity. The level of clinical disease activity
often starts before the RF titers decline. Rituximab is largely determines the need for therapy. DMARDs are
infused at a dose of 1000 mg and repeated 2 weeks central to the control of disease activity and resulting
later. joint damage. The availability of an expanding array of
Initial studies of rituximab therapy were performed DMARDs and biologics has created new opportunities
in patients who had failed MTX therapy. In one study, to effectively intervene in this condition. The standard
they were treated for 24 weeks with MTX alone, ritux- of care for RA continues to evolve with increasing evi-
imab alone, MTX and rituximab, and rituximab and dence that persistent joint inflammation leads to irre-
cyclophosphamide. An ACR20 was achieved by 38%, versible damage and disability. As a result, combination
65%, 73%, and 76%, respectively (23). To reduce the DMARD regimens are being employed to afford
likelihood of infusion reactions, intravenous methyl- optimal disease control in order to avert permanent
prednisolone was given with the infusion followed by joint injury.
tapering doses of oral prednisone. A subsequent study
has found that such corticosteroid therapy has no effect
on efficacy, but that methylprednisolone given at the REFERENCES
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matoid arhtritis with methotrexate alone, sulfasalazine
uals, B cells remain depleted for greater than 3 months.
and hydroxychloroquinne, or a combination of all three
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and repopulation occurs preferentially with naive B 2. Boers M, Verhoeven AC, Markusse HM, et al. Randomised
cells (25). Repeated rituximab dosing appears to be comparison of combined step-down prednisolone, metho-
effective in restoring disease control. Remarkably, trexate and sulphasalazine with sulfasalzine alone in early
rituximab therapy has been generally well tolerated rheumatoid arthritis. Lancet 1997;350:309338.
except for infusion reactions of mild-to-moderate sever- 3. Landew RB, Boers M, Verhoeven AC, et al. COBA
ity, although little is known about the long-term risks of combination therapy in patients with early rheumatoid
repeated rituximab dosing. arthritis: long-term structural benefits of a brief inter-
vention. Arthritis Rheum 2002;46:347356.
4. Andersen PA, West SG, ODell JR, et al. Weekly pulse
methotrexate in rheumatoid arthritis. Clinical and immu-
COMORBIDITIES nologic effects in a randomized, double-blind study. Ann
Intern Med 1985;103:489496.
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result from both the disease itself and the use of corti- of drug therapy on radiographic progression of rheuma-
costeroids. Most patients are routinely advised to toid arthritis. Results of a 36-week randomized trial com-
take calcium and vitamin D to prevent osteoporosis. paring methotrexate and auranofin. Arthritis Rheum
Bone densitometry should be performed in patients 1993;36:613619.
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for a bisphosphonate or a selective estrogen receptor parison of etanercpt and methotrexate in patients with
blocker. early rheumatoid arthritis. N Engl J Med 2000;343:1586
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7. Strand V, Cohen S, Schiff M, et al. Treatment of active
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rheumatoid arthritis with luflunomide compared with
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ences this risk, though available data suggest that MTX 25422550.
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Low dose aspirin should be considered in patients over of leflunomide compared with placebo and sulphasalazine
the age of 50 years as primary prevention for CV disease. in active rheumatoid arthritis: a double-blind, randomised,
Cholesterol levels should be regularly monitored and multicentre trial. Lancet 1999;353:259266.
9. Fox RI. Mechanism of action of hydroxychloroquine as 18. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF
an antirheumatic drug. Semin Arthritis Rheum 1993;23: antibody therapy in rheumatoid arthritis and the risk of
8291. serious infections and malignancies. JAMA 2005;295:
10. Clark P, Casas E, Tugwell P, et al. Hydroxychloroquinne 22752285.
compared with placebo in rheumatoid arhtritis. A ran- 19. Wolf F, Michaud K. Lymphoma in rheumatoid arthritis:
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10671071. therapy in 18,572 patients. Arthritis Rheum 2004;50:1740
11. Gadangi P, Langaker M, Naime D, et al. The anti-inflam- 1751.
matory mechanism of sulfasalazine is related to adenosine 20. Cohen SB, Moreland LW, Cush JJ, et al. A multicentre,
release at inflamed sites. J Immunol 1996;156:19371941. double blind, randomised, placebo controlled trial of
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arthritis. Rheum Dis Clin North Am 1998;24:489499. antagonist, in patients with rheumatoid arthritis treated
13. Lehman AJ, Esdaile JM, Klinkhoff AV, et al. A 48-week, with background methotrexate. Ann Rheum Dis 2004;63:
randomized, double-blind, double-observer, placebo- 10621068.
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13601370. placebo-controlled trial. J Rheumatol 2004;31:1103
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A monotherapy versus cyclosporin A and methotrexate rheumatoid arthritis. N Engl J Med 2004;350:25722581.
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Arthritis Rheum 2005;52:34033412. Rheum 2006;54:613620.
CHAPTER 7
Juvenile Idiopathic Arthritis

A. Clinical Features
DANIEL J. LOVELL, MD, MPH
Juvenile idiopathic arthritis (JIA) is the most common Diagnosis requires a combination of data from
form of childhood arthritis and one of the more history, physical examination, and laboratory testing.
common chronic childhood illnesses. For the vast majority of patients with JIA, the immu-
JIA is an umbrella term that refers to a group nogenetic associations, clinical course, and functional
of disorders that have in common chronic outcome are quite different from adult-onset rheuma-
arthritis. toid arthritis.
Juvenile idiopathic arthritis (JIA) is the most common reported that 50% of JIA patients have active disease
form of childhood arthritis and one of the more common that persists into adulthood (5). Many of the published
chronic childhood illnesses. As the term indicates, the prevalence studies have not included adult-age JIA
cause is unknown. In fact, JIA is an umbrella term that patients, resulting in an underestimation. The incidence
refers to a group of disorders that have in common ranges between 7 to 21 per 100,000 people in studies of
chronic arthritis. Diagnosis requires a combination of US- and Northern Europeanbased populations (1,9,10).
data from history, physical examination, and laboratory All the incidence and prevalence estimates have wide
testing. For the vast majority of patients with JIA, the confidence intervals because of the relative rarity of JIA
immunogenetic associations, clinical course, and func- and the small number of actual cases detected in even
tional outcome are quite different from adult-onset the largest studies. This leads to enormous differences
rheumatoid arthritis (RA). However, approximately between the lower and upper estimates of actual JIA
5% to 10% of those with JIA (those classified as poly- cases. The most commonly cited figure is 70,000 to
arthritis rheumatoid factor positive) have a disease that 100,000 cases (active and inactive) of JIA in the US
resembles adult-onset RA much more than other types population under age 16 (1). Using Andersson-Gre
of JIA. The JIA nomenclature has in most instances and Fasths report on disease persisting into adulthood,
replaced the older classification for chronic idiopathic an estimated 35,000 to 50,000 people over age 16 have
arthritis in childhoodjuvenile rheumatoid arthritis active JIA in the United States (5).
(JRA). The differences and similarities in the two Juvenile idiopathic arthritis affects a much smaller
classifications will be discussed below. In fact, this is portion of the US population than adult-onset RA.
the first edition in which the term juvenile idiopathic However, compared to other pediatric-onset chronic
arthritis is being used in the Primer on the Rheumatic illnesses, JIA is relatively common, affecting approxi-
Diseases. mately the same number of children as juvenile diabe-
tes, at least four times as many children as sickle cell
anemia or cystic fibrosis, and at least 10 times as many
EPIDEMIOLOGY as hemophilia, acute lymphocytic leukemia, chronic
renal failure, or muscular dystrophy (6).
The prevalence of JIA has been estimated to be between
57 and 220 per 100,000 children younger than 16 years
in population-based studies (18). In a meta-analysis CLINICAL FEATURES
including both practitioner- and clinic-based studies, a
prevalence of 132 per 100,000 [95% confidence interval The criteria for JIA require disease onset before the
(95% CI), 119,145] was reported (9). In a population- 16th birthday, persistent objective arthritis in one or
based study from Sweden, Andersson-Gre and Fasth more joints for at least 6 weeks, and exclusion of other
142
C H A P T E R 7 J U V E N I L E I D I O P A T H I C A R T H R I T I S 14 3
causes of childhood arthritis (7,11,12). Misdiagnosis Juvenile idiopathic arthritis is subdivided into seven
often results when one or more of the following four categories: systemic, polyarthritis rheumatoid factor
key points are missed: (1) objective arthritis must be positive, polyarthritis rheumatoid factor negative, oli-
present and is defined as swelling, effusion, or the pres- goarthritis (subcategories of persistent and extended),
ence of two or more of the followinglimitation of psoriatic arthritis, enthesitis-related arthritis and undif-
motion, tenderness, pain on motion, or joint warmth ferentiated arthritis (11,12; Table 7A-1). These subtypes
(i.e., arthralgia alone is not sufficient); (2) the arthritis demonstrate unique clinical presentations, immunoge-
must be consistently present for at least 6 weeks; (3) netic associations, and clinical courses (Table 7A-2).
more than 100 other causes of chronic arthritis in chil- The categories of JIA are meant to be mutually exclu-
dren must be excluded; and (4) no specific laboratory sive so that the inclusion criteria for one classification
or other test can establish the diagnosis of JIA, that is, are also used as exclusion criteria for the other cate-
it is a diagnosis of exclusion. gories. For those patients who fit into more than one
TABLE 7A-1. CLASSIFICATION CRITERIA FOR JUVENILE IDIOPATHIC ARTHRITIS, SECOND REVISION, EDMONTON, 2001.
PERCENTAGE OF JIA
CLASSIFICATION DESCRIPTION POPULATION
Systemic Arthritis with or preceded by daily fever of at least 2 weeks duration, documented 2%17%
to be quotidian for at least 3 days, and accompanied by at least one of the
following: rheumatoid rash, generalized lymphadenopathy, hepato- or
splenomegaly and serositis
Exclusions: a,b,c,d
Oligoarthritis, Arthritis in four joints at any time during the onset or course of the disease 12%29%
subcategory persistent Exclusions: a,b,c,d,e
Oligoarthritis, subcategory Arthritis in four joints in first 6 months of disease but affecting a cumulative total 12%29%
extended of five joints after the first 6 months
Exclusions: a,b,c,d,e
Polyarthritis rheumatoid Arthritis affecting five joints during first 6 months with negative tests for 10%28% 7
factor negative rheumatoid factor
Exclusions: a,b,c,d,e
Polyarthritis rheumatoid Arthritis affecting five joints during first 6 months and positive test for 2%10%
factor positive rheumatoid factor at least twice at least 3 months apart
Exclusions: a,b,c,e
Enthesitis-related arthritis Arthritis and enthesitis or arthritis or enthesitis plus any two of the following: 3%11%
Sacroiliac joint tenderness and/or inflammatory lumbosacral pain
Positive HLA-B27
Physician-diagnosed HLA-B27associated disease in first- or second-degree relative
Symptomatic anterior uveitis
Male > 6 years old at onset of arthritis or enthesitis
Exclusions: a,d,e
Psoriatic arthritis Arthritis and psoriasis or arthritis and at least two of the following: 2%11%
Physician-diagnosed psoriasis in first-degree relatives
Dactylitis
Nail abnormalities (pitting or onycholysis)
Exclusions: b,c,d,e
Undifferentiated Arthritis but does not fulfill any of the above categories or fits into more than one 2%23%
category
Exclusions: Not applicable
SOURCE: Data from Petty RE, Southwood TR, Manners P, et al. J Rheumatol 2004;31:390392, Journal of Rheumatology.
Exclusion criteria:
(a) Psoriasis or a history of psoriasis in the patient or a first-degree relative.
(b) Arthritis in an HLA-B27positive male beginning after the 6th birthday.
(c) Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiters syndrome, or acute anterior uveitis, or a history of
one of these disorders in a first-degree relative.
(d) The presence of IgM rheumatoid factor on at least two occasions at least 3 months apart.
(e) The presence of systemic JIA in the patient.
144 DANIEL J. LOVELL
TABLE 7A-2. JUVENILE IDIOPATHIC ARTHRITIS CATEGORY CHARACTERISTICS.

oJIA, oJIA,
CHARACTERISTIC sJIA poJIA RF+ poJIA RF PERSISTENT EXTENDED pJIA eJIA uJIA
Number of joints Variable 5 5 4 5 Variable Variable Variable

with arthritis at
onset
Sex ratio (F:M) 1:1 3:1 3:1 4:1 4:1 1:1 1:7 1:1
Frequency of 0%2% 3%10% 3%10% 30%50% 15%20% 5%20% 25% (acute)

uveitis (% of
patients in that
JIA category)
Frequency of +RF 0% 100% 0% 0% 0% 0% 0% 3%5%

on at least two
occasions in
first 6 months
of disease (%
of patients in
the JIA category)
Frequency of 5 50% 100% 100% 0% 100% 655% 50%

joints involved
during course
of disease (%
of patients in
the JIA category)
Percentage in 33%80% 0%15% 23%46% 43%73% 12%35%

clinical remission
at last F/Ua
Percentage in 0%65% 5%38% 3%41% 0%7% 36%43%

Steinbrocker
functional class
III or IV at last
F/Ua
Percentage with 14%75% 75%77% 40%43% 5%27% 25%33%

radiographic
evidence of
joint damage
at last F/Ua
ABBREVIATIONS: eJIA, enthesis-related JIA; F/U, last follow-up visit in published studies; JIA, juvenile idiopathic arthritis; oJIA, oligoarticular JIA; pJIA, psoriatic JIA;
poJIA, polyarthritis JIA; RF, rheumatoid factor; sJIA, systemic JIA; uJIA, undifferentiated JIA.
a
Data taken from meta-analysis of outcome studies in JIA and JRA populations.17
category or who do not satisfy all the inclusion criteria category will be indicated using the letter of the criteria
for one of the other categories, the undifferentiated in this listing:
arthritis category is to be used. In both the older JRA
criteria, and even more so with the JIA criteria, the (a) psoriasis in the patient or a first-degree relative;
concept is that these systems are classifying within a (b) arthritis in a human leukocyte antigen (HLA)-B27
single umbrella term different forms of chronic arthritis positive male with arthritis onset after 6 years of age;
(11,12). The JIA classification was intended to have (c) anklyosing spondylitis, enthesitis-related arthritis,
ongoing validation by both clinical and immunogenetic sacroiliitis with inflammatory bowel disease, reac-
methods to assess the homogeneity and stability of the tive arthritis, or acute anterior uveitis in a first-
diagnostic categories and, if necessary, change the cat- degree relative;
egories on the basis of published data (12). (d) presence of IgM rheumatoid factor on at least two
In addition to the inclusion criteria, for each of the occasions more than 3 months apart;
JIA categories the relevant exclusion criteria for that (e) presence of systemic JIA in the patient.
JUVENILE IDIOPATHIC Approximately 2% to 10% of all children with JIA have

polyarthritis juvenile idiopathic arthritis rheumatoid
ARTHRITIS, SYSTEMIC CATEGORY factor positive (poJIA RF+) and 10% to 28% have
polyarthritis juvenile idiopathic arthritis rheumatoid
Approximately 2% to 17% of children with JIA have factor negative (poJIA RF) (12). poJIA RF+ patients
systemic juvenile idiopathic arthritis (sJIA) (12). Clas- are almost always girls with later disease onset (at least
sification as systemic JIA requires that the child dem- 8 years old) who are usually HLA-DR4 positive, have
onstrate daily fever of at least 2 weeks duration that for symmetric small joint arthritis, and are at greater risk
at least three of those days is documented to be quotid- for developing erosions, nodules, and poor functional
ian (defined as a daily recurrent fever that rises to 39C outcome compared with RF patients. poJIA RF+
once a day and returns to 37C or below between fever resembles adult-onset RA more than any other JIA
spikes) and at least one of the following: (a) an evanes- subset. Clinical manifestations and outcome of both
cent, nonfixed, erythematous rash; (b) generalized poJIA categories are highly variable, and include fatigue,
lymph node enlargement; (c) hepatomegaly and/or anorexia, proteincaloric malnutrition, anemia, growth
splenomegaly; (d) serositis (pericardial, pleural or peri- retardation, delay in sexual maturation, and osteopenia.
toneal). Systemic JIA is excluded if criteria a, b, c, or d poJIA may develop at any age less than 16 years, and
from the list of exclusion criteria are present. girls with poJIA outnumber boys with this form 3 to 1.
The characteristic rash is pale pink, blanching, tran-
sient (lasting minutes to a few hours), nonpuritic in 95%
of cases, and characterized by small macules or macu- JUVENILE IDIOPATHIC
lopapules. Children with sJIA often have growth delay, ARTHRITIS, OLIGOARTHRITIS
osteopenia, diffuse lymphadenopathy, hepatospleno-
megaly, pericarditis, pleuritis, anemia, leukocytosis, To be characterized as having oligoarthritis juvenile
thrombocytosis, and elevated acute-phase reactants. idiopathic arthritis (oJIA), a child must have arthritis in
Positive rheumatoid factor (RF) and uveitis are rare. four or more joints during the first 6 months of the
The extra-articular features are usually mild to moder- disease. Relevant exclusion criteria are a, b, c, d, and e.
ate in severity and almost always self-limited. Most sys- oJIA patients are divided into two subcategories: per-
temic features will resolve when the fevers resolve; sistent and extended. Persistent oJIA patients never
however, sJIA patients can develop pericardial tampon- have a cumulative total of more than four joints with
ade, severe vasculitis with secondary consumptive coag- arthritis during the course of the disease and extended 7
ulopathy, and macrophage activation syndrome, all of oJIA patients demonstrate a cumulative total during the
which require intense steroid therapy. course of the disease of arthritis in five or more joints
The long-term prognosis for sJIA is determined by after the first 6 months of the disease. oJIA is the most
the severity of the arthritis, which usually develops con- frequent of the JIA categories (24%58% of all JIA
currently with the fever and systemic features, but in patients) (12). Persistent oJIA has the best overall artic-
some patients does not develop for weeks or months ular outcome of all JIA categories. Up to half of the
after the onset of the fever. sJIA may develop at any persistent oJIA patients will demonstrate monoarticu-
age <16 years, but the peak age of onset is 1 to 6 years lar involvement in a knee joint (13). The severity of joint
old. Boys and girls are equally affected. symptoms in these patients is usually very mild and it is
not uncommon for these children to present with normal
or near normal overall physical function, joint swelling,
JUVENILE IDIOPATHIC and loss of motion in the knee. Up to 50% of oJIA cases
will evolve to the extended subcategory and 30% will
ARTHRITIS, POLYARTHRITIS do so in the 2 years after disease onset. Risk factors in
RHEUMATOID FACTOR POSITIVE the first 6 months of disease onset for developing oJIA,
extended subcategory (i.e., more extensive and severe
AND RHEUMATOID FACTOR articular involvement), are arthritis in the wrist, hand or
NEGATIVE CATEGORIES ankle; symmetric arthritis, arthritis in more than one
joint; elevated erythrocyte sedimentation rate (ESR)
To be characterized as having polyarthritis juvenile and positive antinuclear antibodies (ANA) (13). Patients
idiopathic arthritis (poJIA), a child must have arthritis with oJIA are commonly younger (15 years old at
in five or more joints during the first 6 months of the onset), are more likely to be girls (girls outnumber boys
disease. To be classified as poJIA, exclusion criteria a, 4 to 1), are often ANA positive, and have the greatest
b, c, and e must be absent. To be considered RF+, the risk for developing chronic eye inflammation (7). Eye
patient must have at least two positive results for RF at involvement occurs in 30% to 50% of oJIA patients
least 3 months apart during the first 6 months of disease. (7,13). The inflammatory process primarily involves the
TABLE 7A-3. AMERICAN ACADEMY OF PEDIATRICS exclusion criteria are b, c, d, and e. In the JIA criteria,
GUIDELINES FOR SCREENING EYE EXAMINATIONS dactylitis is defined as swelling of one or more digits,
ADAPTED FOR JUVENILE IDIOPATHIC ARTHRITIS. usually in an asymmetric distribution, that extends
DISEASE SUBGROUP FREQUENCY OF SCREENING beyond the joint margin and nail pitting is defined as a
minimum of two pits on one or more nails at any time.
Any JIA category except sJIA, Every 34 months for 4 years, Onycholysis is not specifically defined in the JIA criteria
6 years old at JIA onset, then every 6 months for 3 but refers to the partial loosening or complete detach-
ANA+ years, then annually
ment of the nail from the nail bed. pJIA accounts for 2%
Any JIA category except sJIA, Every 6 months for 4 years, to 11% of all JIA cases (12).
6 years old at JIA onset, then annually In the vast majority of cases of pJIA, the arthritis is
ANA peripheral, asymmetric, and often involves the knees,
Any JIA category except sJIA, Every 6 months for 4 years, ankles, and small joints of the hands and feet. The dac-
7 years old at JIA onset, then annually tylitis (sausage digit) involves inflammation of not
ANA+/ only the small joints of the toes or fingers but also the
sJIA Annually
tendon sheath. The dactylitis is often surprisingly
asymptomatic despite obvious swelling and loss of
SOURCE: Adapted from Cassidy J, Kivlin J, Lindsley C, Nocton J, Pediatrics motion in the digit. At onset, about 70% of the pJIA
2006;117:18431845, by permission of Pediatrics. patients have arthritis in four or more joints. In longi-
ABBREVIATIONS: JIA, juvenile idiopathic arthritis; sJIA, systemic JIA.
tudinal studies, during the course of the disease, about
40% (range, 11%100%) of pJIA patients demon-
strated involvement of the sacroiliac joint (7).
anterior chamber of the eye and is associated with
Asymptomatic chronic anterior chamber uveitis clin-
minimal, if any, symptoms in more than 80% of affected
ically indistinguishable from that seen in oJIA develops
children. Because severe, irreversible eye changes,
in up to 20% of these patients (7,13). Accordingly, fol-
including corneal clouding, cataracts, glaucoma, and
lowing the usual recommendations for routine slit lamp
partial or total visual loss, can occur, patients should be
of the eyes, as described in Table 7A-3, is required in
screened at regular intervals and treated by experienced
pJIA.
eye specialists (Table 7A-3).
The risk for persistent articular disease is very differ-
ent for the oJIA subtypes. In one study, 75% of the
patients with persistent oJIA achieved remission by JUVENILE IDIOPATHIC
adulthood compared to only 12% of those with extended ARTHRITIS, ENTHESITIS RELATED
oligoarticular JIA (13).
This category addresses the fact that in children the
JUVENILE IDIOPATHIC axial manifestations of spondyloarthropathy may not
become evident for many years. Children are classified
ARTHRITIS, PSORIATIC as enthesitis juvenile idiopathic arthritis (eJIA) if they
ARTHRITIS have both arthritis and enthesitis or have either arthritis
or enthesitis with any two of the five following manifes-
In contrast to the JRA criteria, patients demonstrating tations: (1) sacroiliac tenderness and/or inflammatory
arthritis in association with psoriasis are included in the lumbosacral pain; (2) positive HLA-B27; (3) onset of
JIA classification. Patients manifesting chronic arthritis arthritis in a male 6 years old; (4) acute (symptomatic)
in association with psoriasis with an onset at or before anterior uveitis; and (5) presence in a first-degree rela-
the age of 16 are said to have psoriatic juvenile idiopathic tive of ankylosing spondylitis, enthesitis-related arthri-
arthritis (pJIA). However, the classic psoriatic rash may tis, inflammatory bowel disease with sacroiliitis, reactive
not appear for many years after the onset of the arthritis. arthritis or acute anterior uveitis. The relevant exclu-
In published studies, 33% to 62% of the patients will not, sion criteria are a, d, and e. About 10% of all JIA
in the past or at the time the arthritis develops, demon- patients are classified as eJIA (12).
strate any of the dermatologic manifestations. Only Enthesitis refers to inflammation at the insertion of
about 10% of children have the onset of the rash and the the tendon, ligament, joint capsule, or fascia into the
arthritis at the same time. In the rest of the patients bone. The most frequent manifestations are pain and
(33%67%), the rash comes first (7). Accordingly, the tenderness at the enthesis but swelling is also seen at
JIA criteria allow for children to be classified as having the site. Enthesitis is not specific for pJIA and is some-
psoriatic arthritis if they have arthritis and at least two times seen in other JIA categories, systemic lupus ery-
of the following three criteria: dactylitis, nail pitting or thematosus (SLE), and healthy active children (7). The
onycholysis, and psoriasis in a first-degree relative. The most common sites for enthesitis include the superior
psoriasis has to be diagnosed by a physician. The relevant curve of the patella, infrapatellar at the tibial tuberosity,
attachment of the Achilles tendon, back of the foot patient fulfills criteria for more than one category. In
(attachment of plantar fascia to the calcaneous), and the published series, 2% to 23% of all JIA patients were
sole of the foot at the metatarsal heads (7). classified as uJIA. In those classified as uJIA, 60% failed
In contrast to the JRA criteria, patients with arthritis to demonstrate characteristics that fulfilled the eligibil-
in association with inflammatory bowel disease can be ity criteria for one of the other JIA categories and 40%
classified as eJIA if the inclusion and exclusion criteria demonstrated criteria from more than one JIA category
are satisfied. In patients with inflammatory bowel (12). In those fitting more than one category, the overlap
disease, the articular involvement may precede the gas- was most commonly between the poJIA RF category
trointestinal (GI) inflammation by months to years. and either the eJIA or the pJIA categories. Some chil-
Clues to the presence of GI involvement include fatigue, dren overlapped the oJIA category with either the eJIA
weight loss, growth failure, nocturnal bowel movement, or pJIA categories (12). Longitudinal studies need to be
mouth ulcers, erythema nodosum, pyoderma gangreno- performed to determine the eventual diagnoses in the
sum, and anemia (more severe than normally seen in patients placed in the uJIA category to see how many
association with the extent of the arthritis). will remain as uJIA and how many will evolve to fulfill
Patients with eJIA may also demonstrate involve- the criteria for one of the other JIA categories or dis-
ment in other areas. Acute uveitis characterized by eases other than JIA.
intermittent episodes of red, photophobic, painful
ocular inflammation (usually unilateral) may occur in
up to 25% of eJIA patients. Aortic involvement with OCULAR INVOLVEMENT
aortic valve insufficiency has been rarely reported in
children with eJIA (7).
IN JUVENILE IDIOPATHIC
At disease onset, the articular involvement includes ARTHRITIS
peripheral arthritis in approximately 80% of eJIA
patients and only 25% will have symptoms or physical A unique manifestation of JIA is chronic uveitis. A
findings involving the sacroiliac or lumbar spine areas. meta-analysis of 21 published studies on uveitis in chil-
In about 85% of the patients, the arthritis will involve dren with JIA with a combined 4598 JIA patients (13).
four or more joints. Because the eJIA criteria are rela- The data demonstrated that there are obvious differ-
tively new and the axial manifestations can evolve very ences in the incidence of uveitis in JIA patients based
slowly, no publications provide longitudinal data specific on geographic distribution. In Scandinavian studies,
to eJIA. Data from older related diagnostic categories 18.5% of patients demonstrated uveitis, in studies from 7
can be used to give some insight as to the risk for axial the United States 14.5% of patients demonstrated
involvement over time. In children diagnosed as having uveitis, and in studies from East Asia only 4.5% of
seronegative enthesitis and arthritis syndrome (SEA patients demonstrated uveitis. The frequency of uveitis
syndrome), after 11 years of follow-up, 65% had evolved varies by JIA subtype12% of children with oJIA,
to have clinically important axial involvement. In those 4.3% of poJIA, and 1.8% of sJIA patients developed
diagnosed with juvenile ankylosing spondylitis, over chronic uveitis. Other studies have documented that up
90% eventually manifest clinically important lumbar to 20% of children with pJIA will develop chronic
spine and/or sacroiliac (SI) joint involvement (7). uveitis identical to the chronic uveitis associated with
In eJIA, tests for ANA and RF are negative, and plain oJIA in terms of manifestations, chronicity, and ocular
radiographs often do not show the characteristic changes outcomes (7).
in the SI or lumbosacral spine for many years. Bone scans Uniform adoption of early and routine screening
are seldom helpful because radioisotope uptake is typi- guidelines have been developed and recently updated
cally increased in the SI joints and the lumbar spine in (2006) by the American Academy of Pediatrics Sections
all children as a consequence of skeletal growth. Com- of Ophthalmology and Rheumatology for children with
puted tomography (CT) and magnetic resonance imaging JRA (Table 7A-3) (14). The recommendations were
(MRI) scans can be useful studies if interpreted by a based on factors known to be associated with an
radiologist familiar with axial imaging of children. There increased frequency of developing uveitis in children
are no pathognomonic laboratory tests. with JRA: articular features, age at onset of the arthri-
tis, duration of disease, and presence of ANA. These
same factors relate to the uveitis risk for JIA categories
and should be applied as shown in Table 7A-3. Despite
JUVENILE IDIOPATHIC general adoption of routine screening for uveitis and
ARTHRITIS, UNDIFFERENTIATED rapid institution of treatment, the outcome for chronic
uveitis in children with JIA is still associated with an
Patients are placed in the undifferentiated juvenile idio- unacceptably high frequency of serious complications.
pathic arthritis (uJIA) category if the manifestations do In this meta-analysis, in the JIA patients with uveitis,
not fulfill the inclusion criteria for any category or the 20% developed cataracts, 19% developed glaucoma,
and 16% developed band keratopathy (13). The identi- the JIA categories has characteristic manifestations,
fication of effective treatments for JIA-associated uveitis complications, and outcomes. Familiarity with the
that are able to avoid or minimize the eye damage asso- different types of JIA will facilitate earlier diagnosis,
ciated with chronic steroid treatment and chronic awareness of potential problems, and, initiation of
inflammation of the eyes is an important and unsolved proper treatment.
problem at this time.
REFERENCES
OUTCOME
1. Singsen BH. Rheumatic diseases of childhood. Rheum
In a recent meta-analysis of outcome studies in children Dis Clin North Am 1990;16:581599.
with chronic idiopathic arthritis, only 2 of the 21 studies 2. Towner SR, Michet CJJ, OFallen WM, Nelson AM. The
reviewed used the JIA classification criteria (15). In a epidemiology of juvenile arthritis in Rochester, Minne-
summary of published outcome studies, more than 30% sota. Arthritis Rheum 1983;26:12081213.
of people with childhood-onset idiopathic chronic 3. Hochberg MC, Linet MS, Sills EM. The prevalence and
arthritis (most frequently classified as having one of the incidence of juvenile rheumatoid arthritis in an urban
black population. Am J Public Health 1983;73:1202
JRA subtypes) had significant functional limitations
1203.
after 10 or more years of follow-up (16). Twelve percent 4. Andersson-Gre BA, Fasth A. Epidemiology of juve-
were in Steinbrocker classes III (limited self-care) or IV nile chronic arthritis in Southwestern Sweden5-year
(bed or wheelchair bound) 3 to 7 years after disease prospective population study. Pediatrics 1992;90:950
onset, but 48% were classified in class III or IV 16 or 958.
more years after disease onset (7). Active synovitis can 5. Andersson-Gre BA, Fasth A. The natural history of
be detected in 30% to 55% of the patients 10 years after juvenile chronic arthritis: a population based cohort study.
disease onset (16). In a longitudinal study of JRA II. Outcome. J Rheumatol 1995;22:308319.
patients referred to a pediatric rheumatologist within 6. Gortmaker S. Chronic childhood disorders. Prevalence
the first 6 months of disease onset, 28% of the pJRA, and impact. Pediatr Clin North Am 1984;31:318.
54% of the poJRA, and 45% of the sJRA patients dem- 7. Cassidy JT, Petty RE, Laxer RM, Lindsley CB. Textbook
of pediatric rheumatology, 5th ed. Philadelphia: Elsevier
onstrated either erosions or joint-space narrowing on
Saunders; 2005.
standard radiographs during follow-up (16). In an anal- 8. Borchers AT, Seemi C, Chema G, Keen CL, Sheonfeld
ysis of outcome studies published after 1994 that are Y, Gershwin ME. Juvenile idiopathic arthritis. Autoim-
thought to reflect the positive impact of at least some mune Rev 2006;5:279298.
of the recent therapeutic advances, only 40% to 60% of 9. Oen KG, Cheang M. Epidemiology of chronic arthritis in
the JIA patients demonstrated either inactive disease or childhood. Semin Arthritis Rheum 1996;26:575591.
remission, and on average 10% demonstrated severe 10. Berntson L, Andersson-Gre B, Fasth A, et al. Incidence
functional limitation (Steinbrocker functional class III of juvenile idiopathic arthritis in Nordic countries. A
or IV) (17). population based study with special reference to the valid-
Mortality estimates have ranged from 0.29 to 1.10 per ity of ILAR and EULAR criteria. J Rheumatol 2003;30:
100 patients. These estimates represent a mortality rate 22752282.
11. Petty RE, Southwood TR, Manners P, et al. International
3 to 14 times greater than the standardized mortality
League of Associations for Rheumatology classification
rate for a similarly aged US population (16). of juvenile idiopathic arthritis: second revision, Edmon-
The outcome for JRA patients with uveitis has sig- ton, 2001. J Rheumatol 2004;31:390392.
nificantly improved over the past several decades, but 12. Hofer M, Southwood TR. Classification of childhood
is still associated with an unacceptably high rate of arthritis. Best Pract Res Clin Rheumatol 2002;16:379
ocular complications. In the most recent study of ocular 396.
outcomes, at a mean follow-up of 9.4 years since onset 13. Weiss JE, Ilowite NT. Juvenile idiopathic arthritis. Pediatr
of eye disease, 85% of patients had normal visual acuity Clin N Am 2005;52:413442.
but 15% had significant visual loss, including 10% who 14. Cassidy J, Kivlin J, Lindsley C, Nocton J. Ophthalmologic
were blind in at least one eye (7). examination in children with juvenile rheumatoid arthri-
tis. Pediatrics 2006;117:18431845.
15. Adib N, Silman A, Thomson W. Outcome following onset
of juvenile idiopathic inflammatory arthritis: I. Frequency
SUMMARY of different outcomes. Rheumatology 2005;44:9951001.
16. Levinson JE, Wallace CA. Dismantling the pyramid.
Juvenile idiopathic arthritis is the most common chronic J Rheumatol 1992;19:610.
arthritis in children, the most common inflammatory 17. Ravelli A. Toward an understanding of the long-term
rheumatic disease in children, and still a cause of sig- outcome of juvenile idiopathic arthritis. Clin Exp Rheum
nificant morbidity and increased mortality. Each of 2004;22:271275.
CHAPTER 7

B. Pathology and Pathogenesis
PATRICIA WOO, BSC, MBBS, PHD, MRCP, FRCP, CBE
Juvenile idiopathic arthritis (JIA) is an umbrella term Gene variations in the human leukocyte antigen
for a heterogeneous group of childhood onset, (HLA) region of chromosome 6 are associated with
inflammatory forms of arthritis. different types of subtypes of JIA except systemic-
T-cell and cytokine profiles vary according to the JIA onset JIA.
subtype.
Juvenile idiopathic arthritis (JIA) is the umbrella term cells and the cytokines produced between the JIA
for a heterogeneous group of childhood onset arthriti- subtypes.
des lasting more than 6 weeks. The current interna- The immunohistochemistry of the synovial mem-
tional classification system proposed by International branes of a mixed group of JIA patients were examined
League of Associations for Rheumatology (ILAR) for cytokine production by T cells and a type 1 immune
(1) defines clinical differences between the groups. response was found (2). Furthermore, the analysis of
However, within each group there is also a clinical spec- synovial fluid (SF) T-cell markers has shown that the
trum of disease duration and severity. Some of this may difference between T cells in PO and EO is the presence
be defined by genetic markers/susceptibility genes. This of regulatory T cells in the milder PO, consistent with
chapter aims to describe common and discriminative the current hypothesis that there is a better balance of
features between the groups from the pathological and the immune system in the milder disease (3).
genetic points of view.
Laboratory Findings
OLIGOARTICULAR JUVENILE In monoarthritis and mild PO patients, there is often
no sign of acute phase response in the serum, such as
IDIOPATHIC ARTHRITIS a raised erythrocyte sedimentation rate (ESR) or
C-reactive protein (CRP). In the more severe cases and
Children with oligoarticular JIA have four or fewer in EO patients, the ESR and CRP are raised. Rheuma-
joints affected at the onset of disease. There are two toid factor is not present, but low titer antinuclear anti-
recognizable clinical subtypes with different disease bodies (ANA) are frequently seen. There are no other
courses: persistent oligoarthritis (PO) and extended oli- autoantibodies.
goarthritis (EO). Oligoarthritis patients have milder
disease and many have spontaneous remission. In addi-
tion, all patients in this group can have anterior Uveitis
uveitis. The anterior uveitis that is found in JIA patients is
particularly indolent and predominantly affects the
anterior uveal tract, with cells visible in the anterior
The Synovium and Synovial Fluid chamber of the eye on slit lamp examination. The
There is no distinction in the histology of the synovial pathogenesis is not clear and there are differences
tissues in inflamed joints, whether adult onset or between the clinical nature of the inflammation in this
childhood onset; that is, there is infiltration of lympho- and the other types of uveitis, such as sarcoid, Behets,
cytic and monocytic cells as well as abundant neutro- and infection-related types. Studies reported that a
phils. However, there are differences in the types of T positive ANA was a risk factor/associated marker, but
149
150 PATRICIA WOO
when using more sensitive tests for ANA, such as the the associated genes mentioned above are likely to con-
use of Hep2 cells in the test, the correlation is less tribute to pathology by modifying adaptive immunity
strong. responses. These consist of the presentation of protein
fragments to the effector arm of the immune system (T
Inflammatory Cytokines and and B lymphocytes) via these HLA molecules, causing
the lymphocytes to become activated, divide and multi-
Joint Damage ply, and differentiate into further subtypes. Further
There have been many studies that measure various linkage analyses of the ASP have confirmed the contri-
inflammatory and anti-inflammatory cytokines in the bution of genes in this region of the chromosome, as
serum and synovial fluid of oligoarticular JIA, and these well as many other possible regions (7).
studies have often been limited by the technical prob- Nonhuman leukocyte antigen genetic polymorphisms
lems of sample collections and the assays themselves. associated with oligoarticular JIA include protein tyro-
For example, interleukin 1 (IL-1) and tumor necrosis sine phosphatase N22 (PTPN22) (8), a TNF haplotype
factor (TNF) are easily degraded ex vivo and levels of (9), SLC11A1 (10), and a genetic variant of macrophage
IL-6 and TNF are often increased during the blood clot- inhibitory factor (MIF) that may determine levels of
ting procedure. There are some consistent findings, MIF production (11). IL-10 is a cytokine that suppresses
however. TNF and its natural inhibitor, soluble TNF the expression of proinflammatory cytokines and its
receptors (TNFR), are usually found in synovial fluid, production is genetically determined by a particular
along with IL-6 and IL-18 and a number of chemo- genetic variant of IL-10. Crawley and colleagues showed
tactic factors, such as macrophage inhibitory protein-1 the association of this genetic variant of IL-10 with the
alpha (MIP-1 alpha), all of which will attract lympho- more severe EO subtype (12) and also showed that low
cytes, monocytes, and neutrophils to the synovium. Joint IL-10 production is inherited from the parents in the
damage is less in the PO versus polyarticular JIA and EO patients (13). Thus, a complex inheritance pattern
one current hypothesis is that insufficient inhibition of is emerging of genes that confer different levels of risk
proinflammatory cytokines can prolong disease, thus to the child and which may lead to differing disease
leading to more damage. Consistent with this hypothesis course and severity.
is the observation in the study of Rooney and colleagues
(4), where the authors showed a higher sTNFR/TNF
ratio (sTNFR is a natural inhibitor of TNF) in the SF of Cause of the Disease
the PO patients versus polyarticular JIA patients. The prevailing hypothesis is that given a specific autoim-
Damage to cartilage and bone erosion are both seen mune genetic background, diverse stimuli can trigger the
in JIA, but the rate and degree of damage, as seen on disease. Indeed, many JIA patients will have a history of
radiological imaging, is less in PO. There is often uneven upper respiratory infections or, sometimes, vaccinations
local acceleration of growth of epiphyses in the inflamed preceding the onset of arthritis. The composite genetic
area, leading to growth deformities. background in the individual will determine the severity
of the arthritis. The true extent of the contribution of
Genetic Predisposition different areas of the genome is still being characterized.
There is no single microorganism that has been impli-
There is good evidence that there is a strong genetic cated to be the cause of oligoarticular JIA.
component to oligoarticular JIA. In the biggest collec-
tion of affected siblings with JIA, known as affected
sibling pairs (ASP), a high proportion of the ASP show SYSTEMIC JUVENILE IDIOPATHIC
concordance of disease onset type (53% of the ASPs
were concordant for the oligoarticular onset type). In ARTHRITIS
addition, there is a strong autoimmune disease back-
ground in the family history of the ASP. These observa- This group of patients represents approximately 10% of
tions suggest a strong genetic background to this group all JIA in Caucasian series. Its proportion is reported to
of diseases (5). Approximately 17% of the risk of a be greater in other ethnic groups, such as the Japanese
sibling developing JIA has been estimated to be due to and Chinese. There is a wide spectrum of disease
the influence of a region on chromosome 6 (6p), where severity.
the HLA are found (5). There was significant sharing of
HLA-DR alleles (6) in the ASPs with respect to onset
type and disease course in the oligoarticular group. The
Laboratory Findings
HLA genes are classically found significantly associ- There are no specific laboratory tests for systemic JIA
ated with autoimmune diseases, and the replication of (sJIA), but there are characteristic patterns of labora-
disease association in different populations shows that tory abnormalities. There is typically a very high level
of CRP, high ESR, neutrophilia, thrombocytosis, and a On the other hand, non-HLA genes, such as the
hypochromic, microcytic anemia. Liver enzymes and gene encoding macrophage migration inhibitory factor
coagulation screen might be abnormal in the more (MIF), have been shown to be associated with JIA as
severe cases and in the complication often seen in severe a whole (10), but in particular, a MIF single nucleotide
sJIA, macrophage activation syndrome (MAS). The variant that correlated with higher MIF levels in serum
factors that have the most specificity in the diagnosis of and synovial fluids has been found to be associated with
MAS, as distinct from a flare of sJIA, have been identi- sJIA (21). Another non-HLA genetic variant, the 174G-
fied to be decreased platelet count, fibrinogen, high fer- allele of IL-6, found to correlate with significantly
ritin, raised liver enzymes, and decreased white blood higher serum IL-6 levels, has been confirmed as a sus-
cell count (14). Confirmation of MAS with a bone ceptibility gene for sJIA by family studies (22,23).
marrow aspirate, or trephine biopsy makes the diagno- These genes code for proteins that can be grouped
sis. There are no autoantibodies or rheumatoid factor broadly as proinflammatory according to their effects
(RF) detectable in JIA serum and complement levels and many hypothesize that such genetic variants pre-
are normal or high. Immunological abnormalities dispose the patient to a more than usually vigorous
include the presence of polyclonal hypergammaglobu- inflammatory response to stimuli, such as infectious
linemia, raised proinflammatory cytokines, such as IL-1, agents. Secretion of IL-1 beta, another major proin-
IL-6, IL-18, and TNF, as well as chemokines, such as flammatory cytokine, has also been found to be high in
IL-8 (CXCL8) in the serum or plasma (1517). Occa- patients with sJIA (24). Open-label pilot trials of bio-
sionally a fulminant presentation of sJIA can take the logic agents blocking the signaling of IL-1 and IL-6
form of MAS and polyarthritis with aneurysms in have shown highly encouraging results (2426). Such
medium-sized arteries, demonstrable by angiography. putative genetic imbalances echo the more recent
Apart from severe joint destructions in patients at discovery of genetic defects in innate immunity and
the more severe end of the spectrum, secondary com- anti-inflammatory pathways in the autoinflammatory
plications include MAS, generalized osteoporosis, syndromes. Examples of these autoinflammatory syn-
growth retardation/failure, and amyloidosis. All of these dromes are familial Mediterranean fevers (FMF),
features suggest generalized and systemic inflammation hyperIgD or familial Dutch fevers, Muckle-Wells syn-
affecting all parts of the body, not just the joints. drome (MWS), chronic infantile neurological cutane-
ous arthropathy syndrome (CINCA, also known as
NOMID), and familial Hibernian fever or tumor necro-
Pathogenesis sis receptorassociated periodic fever syndromes 7
Infectious agents have often been reported as having (TRAPS). sJIA can also be regarded as an autoinflam-
triggered the onset of the disease, but there is no single matory syndrome from the clinical picture of general-
agent that can be identified as the culprit in microbio- ized inflammation, as well as its association with certain
logical and virological examinations. In fact, by defini- pro- and anti-inflammatory gene variants.
tion, sJIA is not an infectious disease because a negative
septic screen is necessary for diagnosis. The frequent
association of the complication MAS with severe sJIA
is unusual and research, so far, shows reversible defects POLYARTICULAR JUVENILE
in natural killer (NK) cell activity, as well as reversible IDIOPATHIC ARTHRITIS
expression of the perforin gene on NK cells (18,19).
These defects may be part of the pathology of sJIA and These are usually chronic and severe conditions that
triggering of disease flares by infectious agents would require disease-modifying therapies. There are two
suggest that the mechanisms for ridding the child of subgroups as defined by ILAR: RF negative and RF
these agents are defective, NK cell function being one positive.
of them. Rheumatoid factor positive polyarticular JIA is
There is some evidence that genetic predisposition to similar to adult-onset rheumatoid arthritis (RA) with
sJIA comprises at least part of the etiology of sJIA. severe widespread erosive joint disease. The similarities
There are very few sibling pairs with this type of JIA in between juvenile- and adult-onset RA include the pres-
a large sibling pair cohort from North America (5). ence of rheumatoid factor, as well as other more special-
Despite earlier reports of associations with different ized antibodies, such as anti-cyclic citrullinated peptides
HLA alleles in small cohorts, these results were not (anti-CCP) and anti-Bip, and association with certain
replicated in other case control studies. Furthermore, HLA genes. Caution has to be made in the diagnosis of
there is no association between HLA and sJIA in a this in children, because RF can be transiently raised
larger cohort of UK Caucasians, in sharp contrast with due to infection. The ILAR definition clearly stipulates
other types of JIA, where there are multiple reports of that the classification is made only if there are two posi-
disease association with HLA (20). tive results found at least 3 months apart.
152 PATRICIA WOO
Rheumatoid factor negative polyarticular JIA is by inflammatory disease and pathological and genetic
far the most common and is heterogeneous in terms of studies, so far, suggest that this may be better classified
age of onset as well as disease course. Many of the as an autoinflammatory syndrome, with genetic varia-
younger patients also have anterior uveitis, similar to tions in genes within the inflammation networks that
oligoarticular JIA patients and, similarly, it is often predispose the patient to a proinflammatory state.
associated with a positive ANA. The histology of the
synovium is similar to oligoarthritis, but there may be
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6. Prahalad S, Ryan MH, Shear ES, Thompson SD, Giannini
These arthritides are classified using clinical criteria EH, Glass DN. Juvenile rheumatoid arthritis: linkage to
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in late teenage or adult years. Many of these will have wide scan for juvenile rheumatoid arthritis in affected
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the reason for the differences in the clinical spectrum. Woo P. Polymorphic haplotypes of the interleukin-10 5
Modifying influences from non-HLA genes also con- flanking region determine variable interleukin-10 tran-
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Prakken BJ. Simultaneous detection of 30 soluble media- Role of interleukin-1 (IL-1) in the pathogenesis of sys-
tors in plasma and synovial fluid of patients with JIA. Clin temic onset juvenile idiopathic arthritis and clinical
Exp Rheumatol 2004;22:538. response to IL-1 blockade. J Exp Med 2005;201:1479
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17. Woo P. Cytokines and juvenile idiopathic arthritis. Curr proof of principle of the efficacy of IL-6 receptor blockade
Rheumatol Rep 2002;4:452457. in this type of arthritis and demonstration of prolonged
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Reduced perforin expression in systemic juvenile idio- R1288.
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plantation. Rheumatology (Oxford) 2003;42:375379. efficacy of humanized recombinant anti-interleukin-
19. Grom AA, Villanueva J, Lee S, Goldmuntz EA, Passo 6 receptor antibody in children with systemic-onset juve-
MH, Filipovich A. Natural killer cell dysfunction in nile idiopathic arthritis. Arthritis Rheum 2005;52:818
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292296. on a theme. Curr Mol Med 2004;4:2130.
20. Thomson W, Barrett JH, Donn R, et al. Juvenile idio- 28. Brown MA, Brophy S, Bradbury L, et al. Identification of
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11831189. 29. Timms AE, Crane AM, Sims AM, et al. The interleukin 7
21. De Benedetti F, Meazza C, Vivarelli M, et al. Functional 1 gene cluster contains a major susceptibility locus for
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onset juvenile idiopathic arthritis. Arthritis Rheum 2003; 30. Korendowych E, McHugh N. Genetic factors in psoriatic
48:13981407. arthritis. Curr Rheumatol Rep 2005;7:306312.
CHAPTER 7

PHILIP J. HASHKES, MD, MSC
RONALD M. LAXER, MD, FRCPC
Most patients with juvenile idiopathic arthritis (JIA) do Evidence-based guidelines are available for the
not achieve a remission and require long-term treatment of some subtypes of JIA.
treatment. Assessment tools have improved the documentation
Discovery and use of new therapies such as metho- of individual and clinical trial outcome.
trexate and biologics have improved the outcome of
JIA.
RATIONALE OF CURRENT 40% of patients have significant long-term functional

disabilities including unemployment, and between
TREATMENT APPROACH 25% to 50% need major surgery, including joint replace-
ment (2).
The medical treatment of juvenile idiopathic arthritis Juvenile idiopathic arthritis is associated with a mor-
(JIA) has changed dramatically over the past 15 years. tality rate of 0.4% to 2%, about three times the stan-
This change has been related to data showing that most dardized mortality rate for the US population. Most
children never achieve a long-term remission, and thus deaths are in patients with systemic arthritis, with amy-
the burden of disease to the patient, family, and, ulti- loidosis (almost exclusively in Europe) and the macro-
mately, society is enormous. Until 1990, treatment was phage activation syndrome being the main causes (1).
based on the pyramid approach beginning with various The outcome of uveitis has improved significantly
nonsteroidal anti-inflammatory drugs (NSAIDs) and in recent years, but there is still a high prevalence of
corticosteroids and gradually advancing to other medi- ocular complication and vision loss. Five to 16% of
cations. Studies in the late 1980s indicated that previous patients have significant visual deficits, and even blind-
assumptions on the course and outcome of JIA were ness, and 16% to 26% develop cataracts, 14% to 24%
incorrect. Radiologic joint damage, previously thought develop glaucoma, and 11% to 22% develop band
to develop late in the disease course, occurs in most keratopathy (4).
patients with systemic and polyarthritis within 2 years Several predictors of a poor outcome can help deter-
and in oligoarthritis within 5 years (1). Early cartilage mine patients requiring early aggressive therapy.
damage, often in the first year of disease, was demon- Patients with polyarthritis and positive rheumatoid
strated using magnetic resonance imaging (MRI). factor (RF), antibodies to cyclic citrullinated peptides
The assumption that JIA will usually resolve by anti-CCP), the presence of human leukocyte (HLA)-
adulthood also was found to be incorrect. Studies DR4, nodules, and early-onset symmetric small joint
have shown that between 50% to 70% of patients with involvement have a worse prognosis. Patients with
poly- or systemic arthritis and 40% to 50% of patients systemic arthritis who are corticosteroid dependent
with oligoarthritis will continue to have active disease for control of systemic symptoms and have a platelet
in adulthood. Only a few patients seem to achieve long- count >600,000 after 6 months of disease have a worse
term, medication-free remission (13). Between 30% to outcome.
154
MEDICAL TREATMENT OF resulted in other NSAIDs replacing aspirin in treating

JIA.
JUVENILE IDIOPATHIC Serious gastrointestinal (GI) adverse effects are rare,
ARTHRITIS although many children develop GI symptoms. In order
to prevent these symptoms, NSAIDs should be admin-
Nonsteroidal Anti-Inflammatory istered with food. GI symptoms can be treated by
changing NSAIDs or by using H2 blockers or proton
Drugs pump inhibitors. Mild elevations of liver enzymes are
Only about 25% to 33% of JIA patients, mainly those common. Other adverse effects include pseudopor-
with oligoarthritis, respond well to NSAIDs (5). A 4- to phyria, most often associated with the use of naproxen
6-week trial of an individual NSAID is necessary to in fair-hair Caucasians, and central nervous system
assess its efficacy. Because NSAIDs do not alter the effects, including headaches and disorientation, espe-
disease course or prevent joint damage, they are used cially from indomethacin. Renal adverse effects are
more to treat pain, stiffness, and the fever associated uncommon in children, but are more frequent during
with systemic arthritis. No individual NSAID has been concurrent use of more than one NSAID. The issue of
shown to have a clear advantage over others in treating cardiovascular adverse effects has not been formally
arthritis. Some patients not responsive to one NSAID studied but there are no case reports of these events in
may respond to another (Tables 7C-1 and 7C-2). children with JIA treated with NSAIDs.
Nonsteroidal anti-inflammatory drugs approved by
the Food and Drug Administration (FDA) for JIA and
currently available on the market in the United States
Corticosteroids
include naproxen, ibuprofen, meloxicam, and tolmetin Due to many deleterious effects, especially the effect on
sodium. Liquid preparations are available for the bone and growth, the use of systemic corticosteroids for
former three. For reasons of compliance it is preferable JIA should be minimized. There is no evidence that sys-
to use an NSAID which is administered only once or temic corticosteroids are disease modifying. The main
twice per day. Thus, the need to administer aspirin three indications for systemic use of corticosteroids are uncon-
times per day, to monitor serum levels, and the associa- trolled fever, serositis, and the macrophage activation
tion of aspirin with the Reye syndrome have largely syndrome in systemic arthritis. Another indication
7
TABLE 7C-1. MAJOR MEDICATIONS AND INDICATIONS FOR TREATMENT OF JUVENILE IDIOPATHIC ARTHRITIS.
MEDICATION ARTHRITIS SUBTYPE INDICATION
NSAIDs All types Symptomatic: pain, stiffness
Intra-articular corticosteroids All types, mainly oligoarthritis Injection of few swollen joints
Systemic corticosteroids Systemic, polyarthritis Fever, serositis, bridging medication, macrophage

activation syndrome
Methotrexate All types, less effective in systemic Disease modifying
Sulfasalazine Oligoarthritis, polyarthritis, enthesitis-related Disease modifying
Leflunomide Polyarthritis Disease modifying
Cyclosporine A Systemic Macrophage activation syndrome, steroid sparing
Thalidomide Systemic Possibly anti-TNF
Anti-TNF (etanercept infliximab, Polyarthritis, enthesitis-related (less effective Biologic modifying

adalimumab) in systemic)
AntiIL-1 (anakinra) Systemic Biologic modifying
AntiIL-6 (tocilizumab) Systemic Biologic modifying (currently not available outside

studies)
IVIg Systemic Steroid sparing
ABBREVIATIONS: IL, interleukin; IVIg, intravenous immunoglobulin; NSAIDs, nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factor.
Hydroxychloroquine, gold, and penicillamine not effective in JIA. Abatacept, rituximab, and minocycline not studied in JIA.
156 PHILIP J. HASHKES AND RONALD M. LAXER
TABLE 7C-2. DOSES AND ADVERSE REACTIONS OF MAJOR MEDICATIONS USED TO TREAT JUVENILE
IDIOPATHIC ARTHRITIS.
MEDICATION DOSE MAIN ADVERSE REACTIONS
NSAIDs GI, liver enzymes, headaches, interstitial nephritis
Naproxen 7.510 mg/kg (max 500 mg) twice daily As above, pseudoporphyria
Ibuprofen 1015 mg/kg (max 800 mg) 34 times daily As above
Meloxicam 0.250.375 mg/kg (max 15 mg) once daily As above
Methotrexate 1015 mg/m /week (parenteral if >12.5 mg/m )

2 2
GI, mouth sores, liver enzymes, cytopenia
Sulfasalazine 1525 mg/kg (max 1500 mg) twice daily GI, rashes, cytopenia
Leflunomide <20 kg: 10 mg every other day GI, liver enzymes

2040 kg: 10 mg/day
>40 kg: 20 mg/day
Etanercept 0.4 mg/kg (max 25 mg) SC injection twice weekly Injection site reaction, UR symptoms, infections
2
Adalimumab 24 mg/m (max 40 mg) SC injection every other Injection site reaction, UR symptoms, infections
week
Infliximab 36 mg/kg, intravenously at weeks 0, 2, and 6, Infusion reactions (allergic), infections

then every 68 weeks
Anakinra 12 mg/kg/day (max 100 mg) SC injection Injection site reaction, UR symptoms, infections
Triamcinolone hexacetonide For large joints 1 mg/kg (max 40 mg) IA injection Subcutaneous atrophy
ABBREVIATIONS: GI, gastrointestinal; IA, intra-articular; NSAIDs, nonsteroidal anti-inflammatory drugs; SC, subcutaneous; UR, upper respiratory.
is use as a bridging medication until other medications Several controlled studies, including a study of simul-
become effective. In some patients, periodic intravenous taneous injections of bilateral inflamed joints in
pulses of corticosteroids (30 mg/kg/dose, maximal 1 g) individual patients, have found that the long-acting
are used instead of high dose daily oral corticosteroids, triamcinolone hexacetonide was more effective and had
although there are no controlled studies showing fewer a longer effect than other forms of injectable corticoste-
adverse effects of this modality in children. roids (8). Younger children and children needing mul-
There is excellent evidence for the efficacy of intra- tiple joint injections usually require sedation during the
articular injections of corticosteroids, mainly in patients procedure.
with oligoarthritis. Several studies have shown that as
many as 70% of patients with oligoarthritis do not have
reactivation of disease in the injected joint for at least
Methotrexate
1 year and in 40% for more than 2 years (6). MRI The use of methotrexate (MTX) is the cornerstone of
studies have shown a marked decrease in synovial the medical management plan for most patients with
volume after injection without a deleterious effect on JIA and polyarthritis (9). The initial dose is 10 mg/m2/
the cartilage. One study reported significantly fewer week given orally or parenterally. If not effective the
patients with leg length discrepancies when intra-articu- MTX dose should be increased to 15 mg/m2/week and
lar corticosteroid injections are used early (7). The effi- given parenterally (10). There is no additional advan-
cacy is less in other JIA subtypes, especially systemic tage in giving higher doses.
arthritis. The efficacy of MTX differs by the subtype of JIA,
There are few adverse effects associated with these with the greatest efficacy seen in patients with extended
injections. One that can be seen is the development of oligoarthritis, while less effective in systemic arthritis
periarticular subcutaneous atrophy. This may be pre- (11). MTX may slow the radiologic damage progression
ventable by injecting small amounts of saline while rate as demonstrated in two small series.
withdrawing the needle following the injection and by Because food decreases the bioavailability of MTX,
applying pressure to the injection site. Repeated injec- it is advised to give MTX on an empty stomach. MTX
tions over time to an individual joint have not been at doses 12 mg/m2 should be given parenterally, because
found to be associated with joint or cartilage damage. oral MTX is not absorbed well at those doses.
In order to decrease adverse effects of nausea, oral the treatment of arthritis in patients with systemic
ulcerations, and perhaps liver enzyme abnormalities, arthritis and may be especially effective in patients with
MTX should be administered with folic acid (1 mg/day) the macrophage activation syndrome. Thalidomide may
or folinic acid, 25% to 50% of the MTX dose, given 24 be effective in the treatment of refractory systemic
hours after MTX administration. arthritis, both for systemic features and arthritis. In
Nausea and other GI symptoms are frequent. Strate- addition to the teratogenic effect, careful observation
gies to decrease the severity of these phenomena include for the development of peripheral neuropathy is neces-
taking MTX before bed, switching the mode of admin- sary (17).
istration (oral to parenteral) and using anti-emetics. Most controlled studies in children did not find
Some children develop a psychologic aversion to MTX hydroxychloroquine, oral gold, D-penicillamine, or aza-
that can be alleviated by teaching relaxation or self- thioprine to be effective in the treatment of JIA (5).
hypnosis techniques. There are no controlled studies of minocycline use
The collective long-term experience of MTX use for or of combination disease-modifying antirheumatic
JIA remains one of remarkable safety. Tests to monitor drugs (DMARD) therapy with or without MTX in
for MTX toxicity, complete blood counts, liver enzymes, JIA.
and renal function are recommended at least every 3
months (12). While mild elevations of liver enzymes
occur frequently through the course of treatment, no Biologic-Modifying Medications
cases of severe, irreversible liver fibrosis have been
reported in JIA. Thus, routine liver biopsies are not
Anti-Tumor Necrosis Factor Medications
recommended (13). Pulmonary toxicity and severe Recent studies have shown these medications to be
infections are extremely rare in children. Children highly effective in patients with polyarthritis, including
should avoid live vaccinations while using MTX but patients who failed MTX. There are three anti-tumor
other vaccinations can be given and seasonal influenza necrosis factor (TNF) medications: etanercept, a soluble
vaccine is recommended. If possible, children should TNF receptor, and two anti-TNF antibodies, infliximab,
receive varicella vaccine prior to starting MTX. MTX based on a mouse protein, and adalimumab, a human-
should be skipped during an acute infection, especially ized protein. Trials of all three medications have shown
EpsteinBarr virus (EBV; see below). While rare case similar efficacy, but currently etanercept is the only
reports of lymphoma have been reported, current data drug approved by the FDA (18). More than 50% of
do not suggest that the rate of malignancies is greater patients have a response greater than the American 7
than in the general child population. Some of the lym- College of Rheumatology (ACR) Pediatric 70 level for
phomas developed in association with EBV infection. all three medications. Anti-TNF medications also
appear to be highly effective in enthesitis-related arthri-
tis (juvenile spondyloarthropathy) but are significantly
Other Disease-Modifying less effective in systemic arthritis (19). Infliximab is
Antirheumatic Drugs and more effective than etanercept for JIA-related uveitis
(20,21). It is still not clear whether the combination of
Immunosuppressive Medications anti-TNF and MTX is more effective than either alone
Sulfasalazine and leflunomide may be alternatives to but initial data support the use of combination therapy.
methotrexate. A controlled study showed that sulfasala- Anti-TNF medications may slow radiologic damage
zine is effective in the treatment of oligo- and polyar- progression and may increase bone density.
thritis; the effect may persist for years after sulfasalazine Adverse effects of etanercept are generally mild,
is discontinued (14). Sulfasalazine may also slow the mainly injection site inflammation for etanercept and
progression of radiologic damage (15). Sulfasalazine adalimumab and infusion-related allergic reactions for
seems to be most effective in older males with oligoar- infliximab. To prevent or minimize infliximab allergic
thritis, representing, perhaps, children with enthesitis- reactions, premedication with acetaminophen, diphen-
related arthritis. Adverse reactions were frequently hydramine, and, occasionally, hydrocortisone are some-
reported, especially rashes, GI symptoms, and leuko- times needed. Other common mild adverse effects
penia, frequently necessitating discontinuation of sul- include upper respiratory infections and headaches.
fasalazine. Adverse effects may be especially severe in However, some patients develop severe adverse effects
patients with systemic arthritis. Leflunomide was shown including neurologic (demyelinating diseases), psychi-
to be effective in polyarthritis, although in a controlled atric, severe infectious (especially related to varicella),
study significantly more responders were found in cutaneous vasculitis, pancytopenia, and development
patients receiving MTX (16). of other autoimmune diseases (18,19). One case of
Cyclosporine A may be more beneficial for fever each of tuberculosis and histoplasmosis have been
control and corticosteroid dose reduction than for reported in the use of anti-TNF medications for JIA.
No cases of malignancy have been reported in children. EVIDENCE-BASED GUIDELINES

Adult screening guidelines for tuberculosis, at a
minimum using purified protein derivative (PPD) skin FOR THE TREATMENT OF
testing prior to anti-TNF therapy, are adopted in pedi- JUVENILE IDIOPATHIC
atric practice.
ARTHRITIS SUBTYPES
Other Biologic-Modifying Drugs Suggested treatment guidelines were published based
on a systematic review of the controlled studies done in
Interleukin (IL)-1 Receptor Antagonists JIA (25). Thirty-six controlled trials were identified, 30
Initial very promising results using anakinra, an IL-1 of them were double blind. This brief summary of the
receptor antagonist, for systemic arthritis have been recommendations emphasizes that the treatment plan
reported for both the systemic and articular compo- needs to be individualized based on the arthritis
nents, including patients not responsive to anti-TNF subtype.
medications. IL-1 appears to be a major mediator
of inflammation in systemic arthritis (22). Anakinra
is less effective for polyarthritis than anti-TNF Oligoarthritis
medications. Only a minority of patients respond completely to
NSAIDs. In those not responsive or patients presenting
with flexion contractures, intra-articular corticosteroid
Anti-Interleukin-6 Receptor Antibody injections, especially triamcinolone hexacetonide, are
Interleukin 6 is also an important cytokine in the patho- effective for most patients. Patients not responsive to
genesis of systemic arthritis. Two open series of 29 corticosteroid injections or with extended oligoarthritis
patients with systemic arthritis given intravenous tocili- or small joint involvement should be treated as patients
zumab, an anti-IL6 receptor antibody, reported signifi- with polyarthritis.
cant improvements in the majority of the patients as
soon as after the second dose (23). Tocilizumab is still
under study. Polyarthritis
Nonsteroidal anti-inflammatory drugs are mostly
not effective as disease-modifying medications and
Intravenous Immunoglobulin are used mostly as symptomatic treatment. MTX
Two controlled studies did not find intravenous immu- should be started early, initially at 10 mg/m2/week,
noglobulin (IVIg) to be effective in the treatment of the and if not effective increased to 15 mg/m2/week, given
arthritis component of systemic and polyarthritis JIA. parenterally. Alternatives include sulfasalazine and
There may be more benefit for IVIg for the treatment leflunomide. If not effective, anti-TNF medications
of the systemic features of systemic arthritis. should be used.
Other Medications Systemic Arthritis

There are no reports or studies in JIA of new medica- There is a particular lack of evidence for systemic
tions found to be effective in rheumatoid arthritis, arthritis. NSAIDs and systemic corticosteroids are
including rituximab (anti-CD20 mature B-cell anti- often needed for symptomatic (fever, serositis) relief.
bodies) or abatacept (anti-CD28, T-cell co-stimulator Intra-articular corticosteroid injections, MTX, and
antibodies). anti-TNF medications appear to be less beneficial
than in other JIA subtypes, both for the systemic
and arthritis components. Among the medications
Autologous Stem-Cell currently available there may be an advantage to using
anakinra as a first-line corticosteroid-sparing medica-
Transplantation tion. IVIg may have some benefit as a corticosteroid-
In patients with longstanding and unresponsive systemic sparing effect on the systemic component. Treatment
and polyarthritis JIA there may be a role for autologous for the macrophage activation syndrome includes
stem-cell transplantation (ASCT) (24). However, there high dose intravenous corticosteroids pulses and if
is a significant mortality rate associated with ASCT not rapidly effective cyclosporine should be added.
(15%), thus ASCT must still be regarded as an experi- Tocilizumab, still available only in research trials, shows
mental procedure in JIA. initial promise.
Enthesitis-Related Arthritis motion and muscle strengthening exercises, splints,

orthotics, and various modalities to decrease pain.
Sulfasalazine may be beneficial, particularly for older Aquatic exercise is often tolerated more than land exer-
males with peripheral arthritis. Anti-TNF medications cises, especially in patients with significant lower extrem-
are highly effective. ity arthritis. Splints are used for knee flexion contractures.
Some patients with persistent knee contractures may
Psoriatic Arthritis benefit from serial casting. Orthotics are often used for
ankle or subtalar arthritis or for foot deformities in order
There are no studies of the treatment of psoriatic arthri- to decrease pain when walking, improve gait, as an arch
tis in children. The presentation of psoriatic arthritis can support for flatfoot, and to minimize pressure on meta-
be as oligo-, poly-, and enthesitis-related arthritis and tarsal heads, thus preventing the formation of callus or
until other evidence is reported should be treated as the subluxations of the toes. Patients with leg length discrep-
parallel JIA subset. ancy occasionally need shoe lifts in the shorter leg.
The role of occupational therapy is to maintain and
improve the normal life function. Techniques used
Uveitis include hand exercises; wrist, hand and finger splints;
The treatment of uveitis should be directed by ophthal- teaching joint protection techniques; and fitting various
mologists with experience in treating this disorder with aids for daily activities. These depend on the extent of
the guidance of pediatric rheumatologists experienced the disease and include aids for writing, dressing (also
in managing immunosuppressive and biologic-modify- shoes), eating utensils, adapting bathrooms and other
ing medications. Usually, initial treatment consists of household equipment for patients with arthritis, and
topical corticosteroid drops. Subtenon corticosteroid mobility aids, if needed (canes, walkers, wheelchairs).
injections may also be beneficial. Immunosuppresive Heat pads or bottles, bathing, and paraffin baths may
therapy should be started early in patients with severe help decrease morning stiffness.
uveitis or in those who become corticosteroid depen- Dietary consultation may be needed because some
dent. MTX is the most common medication used (21,26). patients with significant arthritis have anorexia and lack
For patients not responsive to MTX, infliximab, but not adequate growth from several factors, including active
etanercept, appears to be effective (19,20). disease, arthritis of the temporomandibular joint, and
various medications (NSAIDs, methotrexate). Dietary
consultation is also important for patients treated with 7
OTHER FACETS OF TREATING corticosteroids in preventing excessive weight gain,
hypertension, and bone loss, and includes advice on
JUVENILE IDIOPATHIC adequate calcium and vitamin D intake.
ARTHRITIS Physical activity is encouraged but should be tailored
by the degree of arthritis and the joints involved.
The medical treatment of JIA, while most important, is Children are encouraged to set their own limits but
only one facet of JIA therapy. A multidisciplinary should not persist in an activity that causes pain in
team incorporating pediatric rheumatologists, ophthal- an arthritic joint. In general, activities that are less
mologists, orthopedic surgeons, dentists, physical and weight bearing, such as swimming and cycling, are pre-
occupational therapists, dietitians, social workers, psy- ferred, but most sports that do not involve significant
chologists, and educational and vocational counselors contact (football, hockey, wrestling, boxing) are toler-
are involved in treating patients with JIA. ated. Patients with neck arthritis need to limit activities
Many patients continue to have pain despite adequate that can result in cervical spine damage (diving, certain
disease control with modern medications and often pain types of jumping).
is not adequately treated. Patients should receive ade- It is important to discuss school issues with the
quate pain medications, including narcotics if necessary. patients, family, and, if needed, school officials. In
Other pain modalities should be considered, including general, patients with JIA attain similar school achieve-
physical therapy, physical measures like heat or cold, ments as healthy students. However, JIA patients are
splints, orthotics, acupuncture and massage, and various often absent due to flares, infections, and visits to physi-
behavioral and stress-reducing techniques. cians and other therapists. Patients may arrive late to
A critical part of the treatment regimen is physical school due to morning stiffness. Gym performance,
therapy. The main purposes of physical therapy are to moving from class to class, and writing may be affected.
maintain range of motion of the affected joints, improve Children with uveitis may need adjustments due to visual
muscle strength, prevent deformities, and to correct or difficulties. Common school adjustments include allow-
minimize damage and loss of function. Methods used ing elevator use, more time to get from class to class,
include guided and home exercise programs for range of stretching in class, more time to write tests, computer
use, having a second set of books, and gym modifica- TABLE 7C-3. ASSESSMENT AND OUTCOME MEASURE
tions. In the United States, the Americans with Disabil- TOOLS FOR JUVENILE IDIOPATHIC ARTHRITIS.
ity Act (504 plan) mandates allowing for every child to
DOMAIN ASSESSMENT TOOLS
receive education in the least restrictive environment. In
more severe cases a formal individualized educational Disease activity Active joint count, acute phase
plan (IEP) can be employed (see Chapter 7D). reactants
As in any chronic disease, especially one with chronic
Global assessment Physician, patient visual analog scale
medication use, psychological support is often needed.
Patients and families should be encouraged to seek Functional assessment Childhood Health Assessment
support early before a crisis occurs. This support is often Questionnaire (CHAQ), Juvenile
Arthritis Functional Assessment
needed to deal with medication issues such as body Report (JAFAR), Juvenile Arthritis
image changes from corticosteroids, nausea from meth- Functional Status Index (JASI)
otrexate, or to increase compliance with the medication
regimen (see Chapter 7D for a discussion of adherence). Quality-of-life assessment Childhood Health Questionnaire
(CHQ), Peds-Quality of Life (QOL)
Social workers can assist with the financial burden rheumatology subset, pain visual
caused by the disease and the cost of medications. analog scale
An important issue is the transition to adulthood,
including transition of medical care to adult rheuma- Radiologic damage Poznanski, Dijkstra scores
tologists, education, and vocational planning. These Disease-related Juvenile Arthritis Damage Index
issues should start to be discussed and planned well in irreversible damage (JADI)
advance of the youths 18th birthday. Data show that
Clinical trial outcome American College of Rheumatology
transition to adult health care results in improved out- measures (ACR) Pediatric 30, criteria for
comes if the transition is planned and the disease is well inactive disease or clinical
controlled at the time of the transfer to the adult rheu- remission
matologist (27). A transition policy has been adopted
by the major primary care physician groups (American
Academy of Pediatrics, American Academy of Family
Physicians, and the American College of Physicians)
(28) and there are special medical issues for the young
adult who has grown up with JIA.
Patient advocacy groups, such as the Juvenile acute phase reactants, for example, the erythrocyte
Arthritis Alliance, sponsored by the Arthritis Founda- sedimentation rate (ESR) and C-reactive protein
tion, can also give support. The Arthritis Foundation (CRP). It is important to note, however, that many
supports regional and national meetings, arthritis patients with active arthritis have normal acute phase
camps, educational materials, newsletters, and discus- reactants. Subjective, but well-validated global assess-
sion forums on JIA (http://www.arthritis.org). Other ment tools include visual analog scales used by physi-
important sources of educational material on JIA cians and parents.
include the American College of Rheumatology (http:// Several functional assessments tools have been devel-
www.rheumatology.org) and the Pediatric Rheumatol- oped (29). These include the Childhood Health Assess-
ogy International Trials Organization (PRINTO; http:// ment Questionnaire (CHAQ), Juvenile Arthritis
www.printo.it). The latter site has information on JIA Functional Assessment Report (JAFAR), and Juvenile
in more than 30 languages. Arthritis Self-Report Index (JASI). These tools have all
been validated, and are reliable, sensitive to change,
include items applicable to all children with JIA at all
TOOLS TO ASSESS JUVENILE ages, and are easy to use and score (except the JASI,
which is limited to children >8 years old and is very
IDIOPATHIC ARTHRITIS lengthy). Most are completed by parents and/or patients.
OUTCOMES These tools provide an overall functional assessment by
a composite score and also enable determination of
Several assessment tools have been developed for the particular functional deficits. The CHAQ, translated
purposes of following individual patients as well as for and validated in more than 30 languages, is the most
clinical trials and outcome studies (Table 7C-3). These commonly used. Various studies did not find significant
tools assess various domains of JIA. A validated com- differences between the measures, thus all appear valid
prehensive global disease activity scale has not been for use in clinical practice and trials. There are several
developed yet. Disease activity tools commonly used problems with the functional assessment tools, espe-
include active joint count (joints with swelling or tender/ cially a ceiling effect in patients with mild oligoarthritis
pain on motion), joints with limitation of motion, and and minimal functional problems.
Most functional tools do not address issues of overall significantly faster than patients treated later in the
quality of life (QOL), especially general health and psy- disease course. However, recent sobering studies have
chosocial issues related to JIA (29). These are most shown our inability to induce long-term, medication-
commonly assessed in JIA by use of the Juvenile Arthri- free remission in most patients. There also is a lack of
tis Quality of Life Questionnaire (JAQQ) and the evidence-based medicine in the treatment of some JIA
Childhood Health Questionnaire (CHQ). The CHQ subtypes. Controlled studies for new medications for
also allows comparisons between diseases for research systemic arthritis, including antiIL-6 receptor antibod-
studies. It has been translated and validated in more ies, new antiIL-1 medications, and thalidomide or
than 30 languages and is the most used tool. In the other combinations are necessary. Studies of new medi-
United States, there is also widespread use of the Pedi- cations shown to be effective in rheumatoid arthritis,
atric Quality of Life generic questionnaire and the rheu- such as abetacept and rituximab, need to be studied in
matology module (PedsQL-RM). polyarthritis.
Until recently the only radiologic assessment tool A high priority for investigation should be the early
was the Poznanski scale that looked at wrist damage by effect of aggressive therapy on the disease course,
comparing the ratio of the length of the carpus bones including the potential use of remission induction
to the length of the second metacarpal bone. A more therapy that could include combining various methods
comprehensive scale was recently developed and vali- of administering corticosteroids with MTX and a bio-
dated by the Dutch JIA Study Group (15). The Dijkstra logic-modifying medication to be followed with step-
composite score is based on inflammation (swelling, down maintenance therapy in both poly- and systemic
osteopenia), damage (joint space narrowing, cysts, ero- arthritis. While intuitively logical in the short term,
sions), and growth abnormality subscores for 19 joints these protocols need to be validated for long-term
or joint groups. effects as well as for potential increases in adverse reac-
Most recent clinical trials for JIA have used the well- tions. The results of these studies should fill gaps in
validated ACR Pediatric 30 scale as the primary outcome evidence-based guidelines in order to assure quality
measure of responsiveness (30). This scale, developed in care of children with arthritis. New outcome tools will
1997, defines patients as responders or nonresponders. enable us to study the long-term disease-modifying
This scale was modified for defining disease flares neces- effects of MTX and biologic-modifying medications on
sary for some clinical trials of rapidly acting biologic- remission rates, radiologic changes, functional capabili-
modifying medications utilizing a withdrawal design, ties, and the prevention of irreversible articular and
that is, patients defined as responders in the open phase extra-articular damage. 7
of the trial were randomized to continue the medication
or to receive placebo. Due to the advent of potent bio-
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CHAPTER 7

D. Special Considerations
CAROL B. LINDSLEY, MD
Youth with juvenile idiopathic arthritis (JIA) educational, organizational, and behavioral
require special attention to managing growth approaches
abnormalities, both local and general, as well as Management of youth with JIA should take in
osteopenia. account the psychological, educational, and
Adherence to medical regimens is often suboptimal transition to adulthood issues to maximize their
and can be improved by paying attention to outcome.
Many rheumatic diseases that occur in adults also affect motion is critical. A single swollen digit may be the only
children, albeit less frequently. Additionally, some dis- sign of arthritis.
eases such as systemic-onset or pauciarticular pattern of Most school-aged children like to actively participate
juvenile rheumatoid arthritis occur predominantly in in the examination, particularly if they are in comfort-
children. In all of these diseases, the clinical manifesta- able clothing such as T-shirt and shorts. It is generally
tions are often impacted by the childs growth and best to examine any painful area last, after completing
development. the general and remainder of the musculoskeletal
examination. In addition to joint examination, careful
attention should be paid to gait, leg length, and muscle
EXAMINATION strength. Having a child perform a sit-up or climb a few
stairs can be a helpful screen for muscle weakness.
Performing a valid and complete examination on a child In adolescents, the examination itself is not difficult
who is ill or in pain can be difficult. Yet an accurate but relating to the patient can be. It is again important
exam is necessary if the correct diagnosis is to be made. that the patient is as comfortable as possible and that
Children at different ages and developmental levels rapport is established with the adolescent, not just the
respond differently to examination. Rheumatic disease parent. In situations where the parent continues to
manifestations can also vary with age. It may be helpful dominate the interactions, it may be helpful to ask to
to keep certain guidelines in mind. Height and weight speak to the adolescent alone. The examination should
should be obtained at each visit and these growth include a scoliosis screen as part of the musculoskeletal
parameters plotted on an appropriate growth chart. examination.
Inadequately controlled disease or medication side
effects can impair normal growth.
In infants and toddlers, observation skills are particu- GROWTH
larly important. By looking for movements that cause
pain or irritability as well as lack of movement of any Juvenile rheumatoid arthritis (JRA) is a chronic disease
joint, one can ascertain much before the patient is ever and has long been known to affect growth of the child.
examined. Using toys, talking, and keeping eye contact Historically, this clinical effect was noted by Still in 1897
with the child may help alleviate the childs fear. Having and later described by Kuhns in 1932. Its cause is multi-
the child sit on the parents lap and even having the factorial, including not only the disease itself but medica-
parent assist with the examination may make a more tion side effects, nutrition, and mechanical problems. The
thorough examination possible. Swelling can be subtle roles of growth hormone and insulin-like growth factors
in a chubby child and careful attention to range of are gradually being elucidated, as described below.
163
164 CAROL B. LINDSLEY
General have a low level of adverse effects (5). (3) Micrognathia

and malocclusion are known as common sequelae of
It is clear that the onset subtype of JRA is important, JRA. Unilateral disease may lead to chin deviation.
with little or no general adverse effect on growth seen Sixty-nine percent of youth with polyarticular and sys-
in the pauciarticular group. However, this group may temic disease had orthodontic abnormalities (6). Poly-
have severe local growth disturbances at the sites of articular patients often have small, short facies with
inflammation, particularly leg length discrepancy and underdeveloped mandibles. These consequences of
mandibular asymmetries. temporomandibular joint (TMJ) arthritis are difficult to
Patients with polyarticular and systemic disease who treat. Magnetic resonance imaging (MRI) may detect
have never received corticosteroid therapy may have early changes. Orthodontic consultation is recom-
general growth retardation, generally related to the mended. Corticosteroid injection may be helpful in
severity and duration of disease. In one study, one selected patients and costochondral grafts have been
fourth of both disease groups lost greater than 1 height used in severely affected patients. (4) Other sites fre-
Z score over the 14-year follow-up period (1). [Z score quently involved include the wrist, with undergrowth of
= (X1 X2)/SD, where X1 = subjects measurement, the ulnar head, and the vertebrae, with undergrowth of
X2 = mean of the reference population for age and the cervical spine.
gender, and SD = standard deviation of the mean for
the reference population.] Growth impairment was
generally not severe except in a small number of sys-
temic patients. Height velocity during puberty was Osteopenia and Osteoporosis
especially vulnerable. The degree of catch-up growth Osteopenia is low bone mass for age and the child with
was unpredictable. JRA is at great risk for failure to achieve adequate
In another study with 64 prepubertal children postpubertal bone mass. The introduction of dual-
with primarily mild pauciarticular and polyarticular energy x-ray absorptiometry (DXA) has enabled assess-
JRA, growth velocity decreased in the first year of ment of osteopenia and has led to realization of the
disease postdiagnosis and then increased to normal magnitude of the problem. Both the cortical appendicu-
range with treatment and 4-year follow-up. The greatest lar skeleton and the axial trabecular bone are affected,
effect on velocity was seen in children with more but the cortical to a greater degree (7). Osteopenia
severe polyarticular disease. There were only two appears to correlate with disease activity and severity
systemic patients in the study (2). A long-term follow- (7). Other factors, including decreased physical activity,
up study of adults who had JRA and had received immobility, decreased sun exposure, and decreased
corticosteroids showed reduced final height and dietary intake of calcium and vitamin D, are additional
arm-span (3). contributing factors. Peak bone mass is normally
reached during adolescence and this achievement is
important to minimize future risk for osteoporosis and
Local fractures. Often in JRA the bone density fails to
Local growth disturbances occur as a result of inflam- undergo expected pubertal increase. Significant axial
mation and the accompanying increase in vascularity, osteopenia of lumbar spine and femoral neck was found
which may result in either over- or undergrowth of the in patients with polyarticular disease (8). In a 2-year
affected bone. Examples of local growth abnormalities prospective, controlled study in early juvenile idio-
are the following: (1) The hip is a frequently involved pathic arthritis (JIA; includes JRA, psoriatic arthritis,
joint in JRA and occasionally this leads to a small and ankylosing spondylitis), moderate reduction of
femoral head within a larger acetabulum. This was bone mass gain, bone turnover, and total lean body
noted in five patients undergoing hip arthroplasty. The mass was observed (9).
small size was thought to be secondary to destruction of Therapy includes weight-bearing exercise, appropri-
the articular cartilage (4). Of note, all patients had ate nutrition, calcium and vitamin D supplementation,
disease onset prior to age 3. (2) The knee is the most and, most importantly, adequate disease control with
frequently involved joint in JRA and persistent synovi- suppression of inflammation. Early study of bisphos-
tis, particularly in an asymmetric fashion, can lead to phonate therapy in children with rheumatic disease has
significant leg length discrepancy. The distal femoral been encouraging but not without adverse effects (10).
epiphysis accounts for approximately 70% of femoral Behavioral intervention may also be helpful in increas-
growth, so persistent inflammation leads to overgrowth ing calcium intake (11).
on the involved side in a child whose epiphyses have not In addition to generalized osteopenia, involved joints
yet closed. Often the medial side predominates, leading often show local juxta-articular demineralization even
to additional knee valgus. Increased use of intra- on early radiographs. Patients may benefit from DXA
articular steroids may reduce this risk and appears to monitoring at selected intervals.
Endocrine Factors Growth Hormone Therapy

Osteocalcin In one study, 14 children with JRA on corticosteroid
therapy received 1.4 IU rGH/kg/week with a partial
Low levels of osteocalcin, along with decreased bone
response. The mean height velocity increased from 1.9
mineral content, were found in children with active
to 5.4 cm/year with an accompanying 12% increase in
inflammation but both parameters were normal in
lean body mass. However, at the end of 1 year the
children with inactive disease (12). Osteocalcin levels
height velocity decreased to pretreatment levels (18).
in patients with heights less than the third percentile
In another study, rGH increased height velocity
were below normal, suggesting decreased osteo-
during the year of therapy (mean, 3.1 cm/year) but the
blast activity (13). In this study, osteocalcin levels
long-term effect was unknown. There was no correla-
correlated with decreased insulin-like growth factor 1
tion between growth hormone secretion and rGH
(IGF-l) levels. However, these patients were also on
therapy response, raising the question of a target cell
corticosteroid therapy, which can decrease osteocalcin
defect or peripheral defect regarding growth hormone
levels.
mediation. Fifty percent of the children in this study had
borderline or poor caloric intake (13). Growth hormone
therapy may be beneficial in some patients but the
Insulin-like Growth Factor 1 response is unpredictable. In a 4-year study of growth
Insulin-like growth factor 1 is a peptide produced in the hormone therapy in children with polyarticular or sys-
liver and is the main periperal mediator of growth temic disease receiving corticosteroids, improvement
hormone. It promotes collagen formation. Serum levels of 1 SD was seen in bone mineral content compared to
of this peptide have been reduced in most JRA studies, controls (19).
especially in systemic disease (14). Levels appear to
correlate with the degree of inflammation as measured
by acute phase reactants. Levels returned to normal
Thyroid Disease
with recombinant growth hormone (rGH) therapy in Other endocrine disease may affect both symptoms and
one study (13). growth. Stagi and colleagues found an increased preva-
lence of autoimmune thyroiditis, subclinical hypothy-
roidism, and celiac disease in children with JIA (20). In
Interleukin 6 (IL-6) a separate study, antithyroid antibodies were found in 7
a higher frequency in children with arthritis, especially
This cytokine is markedly elevated in systemic disease pauciarticular disease, than in the general population
and appears to correlate with the degree of inflamma- (21). These findings suggest that careful monitoring of
tion. Studies in transgenic mice show that IL-6 mediates thyroid function in children with arthritis is indicated.
a decrease in IGF-1 production, which might represent
a mechanism by which chronic inflammation affects
growth (15). Nutrition
Adequate nutrition, both caloric and protein, are criti-
cal to optimize growth in children with JRA. Up to 30%
Vascular Endothelial Growth Factor of children with JRA have some growth abnormality
This factor is a mitogen for vascular endothelial cells (22). Using anthropometric measurements, up to 40%
and a mediator of vascular permeability. Serum levels have poor nutritional status and muscle mass is
correlate with disease activity in polyarticular JRA and frequently low. Protein stores as well as specific nutri-
may play a role in inflammation that could affect growth ents such as iron, selenium, vitamin C, and zinc have
(16). been reported as low (23). In a recent study, undernutri-
tion was present in 16% of the children with arthritis,
including those with pauciarticular disease (24).
Inflammatory cytokines, such as IL-1, IL-6, and tumor
Growth Hormone necrosis factor (TNF) likely modulate some of the nutri-
Children with JRA and short stature have low human tional abnormalities. In addition, some patients have
growth hormone (hGH) secretion and some had inad- mechanical feeding problems related to jaw or upper
equate or no response to exogenous hGH administra- extremity disease. Aggressive early therapy and use of
tion, suggesting an additional defect in the response newer biologic agents, such as anti-TNF agents, can
pathway or growth hormone insensitivity (17). Other dramatically improve individual patients nutritional
studies have shown levels not significantly different status and growth. However, long-term studies are not
from controls (13). yet available.
Monitoring of serial weights during clinic visits should differentiate between complete nonadherence and
be routine. Dietary logs, nutrient analysis, and consulta- periodic nonadherence.
tion with a dietitian is needed for a child with continued The consequences of nonadherence are multiple, not
poor weight gain. Nutritional supplementation may be only for the patient but also for the health care system.
beneficial, as may behavioral therapy. The patients risk for disease complications and long-
term sequelae are generally increased with noncompli-
ance. Poor or dishonest communication between patient
EYE DISEASE and physician or health care provider also stresses the
relationship and may lead to needless changes of medi-
Inflammatory eye disease, especially uveitis, occurs with cation or unnecessary testing. All of these are inefficient
increased frequency in children with arthritis. Reported and lead to increased health care costs.
incidence varies from 5% to as high as 50%, but recent
studies show an incidence of 12% to 25% (25,26). The
known risk factors include age <6 years at disease onset,
Factors Affecting Adherence
pauciarticular pattern of disease, and antinuclear anti- Many factors may impede adherence. These can gener-
body (ANA) positivity. Current guidelines for fre- ally be grouped into three categories: (1) factors relat-
quency of ophthalmologic examination are available ing to the disease; (2) factors related to the patient
(27). As uveitis can develop after the onset of arthritis, and family; and (3) those related to the regimen itself.
ongoing monitoring is important. Long-term outcome There is no typical noncompliant patient and no consis-
for adult patients with childhood-onset uveitis is still tent correlations with obvious demographic factors.
poor, with visual acuity impaired in 40%, poor in 20%, However, certain states that lead to noncompliance
and lost in 10% (28). Current arthritis therapeutic regi- have been reported (33) and are included in Tables
mens, especially methotrexate and anti-TNF agents, 7D-1 and 7D-2.
appear effective in uveitis. Therefore, the outcome of
uveitis with onset in the past 5 to 10 years will likely be
much better than the existing reports (see Chapter 7A
Factors Related to
for more information) (29). Treatment Regimen
The health care provider can increase the likelihood of
good adherence by making the treatment regimen as
ADHERENCE simple as possible and by anticipating some of the
Optimal treatment of pediatric rheumatic disease often

requires complex therapeutic strategies that can be
both confusing and time consuming to patients and
their families. Strategies often involve a coordinated TABLE 7D-1. ADHERENCE: FACTORS RELATING TO
list of activities, including taking regular medication, PATIENT/FAMILY.
complex exercise regimens, dietary modifications, 1. Negative reactions from the child, including complaints,
regular clinic visits and laboratory tests for monitoring refusal, discomfort, or embarrassment, or more general
the patient, and, in some children, wearing of thera- oppositional behavior.
peutic splints. This is complicated by the fact that there 2. Lack of understanding of the disease and treatment,
is often delayed benefit for good compliance. It is easy especially in younger children.
to understand why adherence to these regimens is
3. Misunderstanding of the disease and treatment.
often compromised. In fact, estimates are that only
50% to 54% of patients with chronic pediatric disease 4. Lack of patient autonomy and low self-esteem.
adhere adequately with their recommended therapy
5. Dissatisfaction with the provider or the therapeutic
(30). In JRA, the medication adherence was found to intervention.
be of similar frequency, ranging from 38% to 59%
(31). In a study of prednisone therapy in children with 6. Inadequate family resources.
systemic lupus erythematosus (SLE) or dermatomyosi- 7. Language barriers.
tis, compliance ranged from 33% to 78%, which is
similar to that reported in pediatric cancer patients 8. Family instability or disagreement.
(32). Surprisingly in the prednisone study, two thirds 9. Other family demands, for example, parental illness.
of patients overmedicated themselves, possibly when
they felt poorly. Adherence with exercise regimens are 10. Parental resentment or anger over the illness.
likely to be lower than with medication, ranging from 11. Familys coping abilities and strategies.
47% to 67% by parent report (33). One must also
TABLE 7D-2. ADHERENCE: FACTORS RELATED TO cognitive abilities. It is important not to overwhelm the
DISEASE. family early in the process.
Organizational strategies include counseling, increas-
1. Duration, often prolonged with unpredictable exacerbations
compliance tends to decrease over time. ing supervision, decreasing complexity, decreasing costs,
and increasing palatability of medication. The regimens
2. Age of onsetyounger patients are less compliant. should fit into the family daily routine as much as pos-
3. Asymptomatic periods. When a patient is asymptomatic or in sible. Therapeutic exercise and play can often be
remission, there is often a temptation to discontinue combined.
medication because the patient feels well. This is enhanced Behavioral strategies can include self-management
by a commonly seen delay in therapeutic response of days training to increase self-esteem, training for parents to
to weeks and also by the delay in occurrence of negative
effects (recurrence of symptoms) with missed medication.
deal with oppositional behavior, and monitoring adher-
ence and using reinforcement or a reward system for
4. Severity of diseaseno clear correlation with compliance. good adherence. Reinforcement programs are time
consuming and require parental training but can
improve adherence (33). Reward systems where tokens
are exchanged for privileges can be successful. The
known negative factors, including bad-tasting medica- childs responsibilities for the treatment regimen should
tion, dosing frequency, forgetting (exercise vs. medica- increase as the child gets older but parents should not
tion), high cost, complexity, delay in therapeutic completely withdraw their supervision.
response, and transportation concerns. Exercise regi- Regular clinic visits are important to re-educate and
mens may be especially problematic because the child reinforce adherence strategies and adapt treatment.
may experience discomfort and express anger or resent- They also help build and maintain a cooperative and
ment toward the parent. trusting relationship between clinician and patient.
Children with chronic disease may be asked to alter Visits should allow enough time for adherence discus-
their lifestyle in a way that restricts their sports interests sion and reinforcement. Good documentation is also
or peer-related social activity or reduces their leisure important to facilitate monitoring of adherence. The
time. Such changes are especially difficult for active clinician must relate to the child, who needs to be an
children and adolescents. Parental supervision and active partner in his or her treatment program. Judg-
appropriate involvement are critical in providing the mental attitudes are not helpful. A multidisciplinary
children with needed support. Delay in receiving or lack team approach is optimal. Further studies are needed 7
of subspecialty care and implementation of appropriate to identify children and families at high risk for nonad-
therapeutic regimens may also contribute to poor func- herence, further define successful family coping mecha-
tional outcomes. nisms that can be taught and reinforced, and to evaluate
strategies for improving compliance.
Assessment of Adherence
Assessment of adherence can be direct or indirect. Indi- PSYCHOSOCIAL AND
rect means include parental observation, self-report, EDUCATIONAL ISSUES
medication diary, prescription renewals, and presence
of predictable side effects. Direct means include pill Chronic disease has a major impact on the development
count, measurement of laboratory parameters such as and daily functioning of a child as well as on the family.
drug levels, and electronic devices that record and store Unfortunately, there are few and often contradictory
the time and date a pill container is opened (34). studies on the nature of the impact and the contributing
factors. Different assessment methods, varying popula-
tion size, and a mixture of disease subtypes, particularly
Improving Adherence with JRA, contribute to the different conclusions. Some
Strategies used to improve compliance can be catego- epidemiological studies concluded that there is more
rized into three types: educational, organizational, and risk for psychosocial problems in JRA patients (35),
behavioral. These can be used singly or in combination others less (36). A controlled study used self-report
(33). questionnaires combined with personal interviews to
Educational strategies include providing informa- study children (age 711) and adolescents (age 1216)
tion, helping prioritize, re-education, written handouts, with arthritis (37). Self-esteem, perceived competence,
reminder systems, community and national resources, and body image were similar to healthy controls. The
positive feedback, and appropriate discipline tech- arthritis patients did have less energy to participate in
niques. Information should be age, culture, and lan- social activities and adolescents received more emo-
guage appropriate and take into account the childs tional support from family, peers, and professionals.
The amount of support received correlated positively adherence with physical therapy and the presence of
with disease severity. Other studies showed that chil- psychological problems but not with age or duration of
dren with chronic illness do not have a higher incidence illness (43). School problems for children with arthritis
of psychiatric disease nor is there any correlation include handwriting, opening doors, lateness to class,
between psychological test scores and disease functional physical education participation, carrying books, fati-
measurements (38). gue, absences, and inadequate understanding by teach-
ers and peers. School success is critical to the normal
development of the child and school status and educa-
Family Impact tional progress should be assessed regularly at clinic
Long-term psychosocial outcome appears to be favor- visits. In a controlled study of 44 adults with JRA sur-
able overall. Chronic family difficulties predicted psy- veyed 25 years after disease onset, there were equiva-
chosocial functioning in patients with JRA in a 9-year lent levels of educational achievement, income, and
follow-up study, without correlation with disease activ- insurance coverage but lower rates of employment,
ity (39). The most frequent psychiatric disturbance on daily energy levels, and exercise tolerance (44).
follow-up was anxiety disorder. No children had depres- During the past decade, the overall prognosis for
sive disorder and 15% had mild-to-moderate impair- children with rheumatic disease has steadily improved.
ment in psychosocial functioning (39). However, for optimal treatment and outcome attention
Positive family factors may play an important role in must be given to their special needs.
the childs ability to cope with chronic illness. In one
study a highly cohesive family structure correlated with
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CHAPTER 8
Psoriatic Arthritis
DAFNA D. GLADMAN, MD, FRCPC
Psoriatic arthritis (PsA) occurs in approximately 26% Other musculoskeletal features include dactylitis
of patients with psoriasis, leading to prevalence in (sausage digit), tenosynovitis, and enthesitis.
the population of 0.3% to 1%. Patients with PsA may also have iritis, urethritis,
There are multiple clinical subsets of PsA reflecting nonspecific colitis, and cardiovascular manifestations.
variable clinical patterns including: distal joint Diagnosis is made on clinical grounds in patients
disease, arthritis mutilans, oligoarthritis (less than or with psoriasis having skin, scalp, or nail changes.
equal to four joints), rheumatoid arthritis (RA)-like Rheumatoid factor should be negative.
polyarthritis, and spondylitis.
Psoriatic arthritis (PsA) is an inflammatory arthritis EPIDMEMIOLOGY OF

associated with psoriasis (1). Psoriasis is an inflamma-
tory skin condition that presents with a red scaly rash PSORIATIC ARTHRITIS
often on the extensor surfaces but may also affect the
scalp and flexural areas as well as palms and soles (2). Prevalence of Psoriatic Arthritis
It commonly affects the nails with either pits or ony-
cholysis. Up to one third of patients with psoriasis may The exact prevalence of PsA is unknown. Estimates
develop an inflammatory arthritis presenting with pain have varied from 0.1% to over 1% of the population
and stiffness in the affected joints. Both psoriasis and (5,6). This variation may be related to the fact that there
PsA affect men and women equally. PsA was distin- are no valid diagnostic criteria for the disease and
guished from rheumatoid arthritis (RA), the prototype various studies have used different case definitions.
inflammatory arthritis, in the middle of the past century Moreover, some studies used administrative databases,
with the discovery of rheumatoid factor (RF). Whereas some used population surveys, and others used clinical
85% of patients with RA are RF positive, patients with observations within hospital admissions or clinic attend-
psoriatic arthritis are usually seronegative for RF. ees. The incidence of PsA has also varied and its true
Earlier studies using the latex fixation test suggested value remains unknown.
that up to 15% of patients with PsA were seropositive The prevalence of PsA among patients with psoriasis
(3), but more recent studies using either nephelometry has varied from 6% in the Mayo Clinic (7) study to 30%
or enzyme-linked immunosorbent assay (ELISA) tests in the European survey (Table 8A-1) (8). It should be
reveal a prevalence of only 4% to 5% (4). noted that the Mayo Clinic study was based on an
Several other features distinguish PsA from RA, administrative database and accepted the database
including the equal gender frequency, the pattern of diagnosis of psoriasis, whereas the European survey was
joint involvement, the presence of spinal involvement, administered to members of a psoriasis association. A
and specific radiologic features. Because of the seroneg- recent survey performed through the National Psoriasis
ative RF, the spinal involvement, and other extra-artic- Foundation in the United States identified an overall
ular features seen among patients with PsA, as well as prevalence of PsA among patients with psoriasis at
the association with human leukocyte antigen (HLA)- 11%, but this value increased to 56% when the extent
B27, PsA has been classified among the seronegative of psoriasis exceeded 10 palms (9). An Italian study that
spondyloarthropathies. was based at a clinic where dermatologists and rheuma-
170
C H A P T E R 8 P S O R I A T I C A R T H R I T I S 17 1
TABLE 8A-1. FREQUENCY OF PSORIATIC ARTHRITIS AMONG PATIENTS WITH PSORIASIS.

AUTHOR (YEAR; REFERENCE) CENTER NUMBER OF PATIENTS STUDIED PERCENTAGE PSA
Leczinsky (1948) (64) Sweden 534 7
Vilanova (1951) (65) Barcelona 214 25
Little (1975) (66) Toronto 100 32
Leonard (1978) (67) Rochester 77 39
Green (1981) (68) Cape Town 61 42
Scarpa (1984) (10) Naples 180 34
Stern (1985) (69) Boston 1285 20
Zanelli (1992) (70) Winston-Salem 459 17
Falk (1993) (71) Kautokeino 35 17
Barisic-Drusko (1994) (72) Osijek region 553 10
Salvarani (1995) (73) Reggio-Emilia 205 36
Shbeeb (2000) (7) Mayo Clinic 1056 6.25
Brockbank (2001) (74) Toronto 126 31
Alenius (2002) (75) Sweden 276 48
Zachariae (2003) (8) Denmark 5795 30
Gelfand (2005) (9) United States 601 11
tologists see patients together, identified 33% of the CLINICAL FEATURES OF

patients as having psoriasis (10). As can be seen in
PSORIATIC ARTHRITIS 8
Table 8A-1, the frequency estimates for PsA among
patients with psoriasis average 26%. If the prevalence
of psoriasis is 1% to 3% of the population, then the true Clinical Subsets of Psoriatic Arthritis
prevalence of PsA is more likely between 0.3% and 1%.
A definite prevalence figure awaits valid diagnostic cri- Psoriatic arthritis affects both peripheral joints and the
teria for this disease. axial skeleton. Wright and Moll described the clinical
patterns of PsA (1). These include (1) a predominantly
distal joint disease, which they identified in about 5%
Classification Criteria of their patients, and which have been variably recog-
Several sets of classification criteria for PsA have been nized by other groups (3,10,1321); (2) arthritis muti-
proposed, although only one was derived from clinical lans, a very destructive form of arthritis, which they
data (11). Taylor and colleagues (12) compared several identified in 5% of the patients, but which may be more
classification criteria sets for PsA. Most criteria sets frequent; (3) oligoarthritis, affecting four or fewer joints,
were highly sensitive and specific, but the Fournie often in an asymmetric distribution which they observed
criteria (11) require HLA typing and therefore 24% in 70% of the patients; (4) polyarthritis, indistinguish-
of patients could not be classified. The CASPAR able from RA, which they detected in 15% of the
(Classification of Psoriatic Arthritis) group, an interna- patients; (5) spondyloarthritis, which occurs alone in
tional group gathered to develop classification criteria about 5% of the patients, but may be associated with
for PsA, recently completed its study of the classifica- one of the other forms in about 40% of the patients. It
tion of PsA (4). It proposed a new set of criteria for has now been recognized that while these patterns may
classification of PsA which were 99% specific and 92% be helpful at disease onset, they do not stay stable over
sensitive for PsA (Table 8A-2). time (17,22,23). Moreover, it has been recognized that
172 DAFNA D. GLADMAN
TABLE 8A-2. CASPAR CRITERIA.

INFLAMMATORY ARTICULAR DISEASE (JOINT, SPINE, OR ENTHESEAL)
With 3 or more points from the following:
1. Evidence of psoriasis (one of a, b, c) (a) Current psoriasisa Psoriatic skin or scalp disease present today as judged by a
rheumatologist or dermatologist
(b) Personal history A history of psoriasis that may be obtained from patient, family
of psoriasis doctor, dermatologist, rheumatologist, or other qualified health
care provider
(c) Family history of A history of psoriasis in a first- or second-degree relative according
psoriasis to patient report
2. Psoriatic nail dystrophy Typical psoriatic nail dystrophy including onycholysis, pitting, and
hyperkeratosis observed on current physical examination
3. A negative test for rheumatoid factor By any method except latex but preferably by ELISA or
nephelometry, according to the local laboratory reference range
4. Dactylitis (one of a, b) (a) Current Swelling of an entire digit

(b) History A history of dactylitis recorded by a rheumatologist
5. Radiological evidence of juxta-articular Ill-defined ossification near joint margins (but excluding osteophyte
new bone formation formation) on plain x-rays of hand or foot
SOURCE: The CASPAR Study Group, Arthritis Rheum 2006;54:26652673, with permission of Arthritis and Rheumatism.
Specificity, 98.7%; sensitivity, 91.4%.
a
Current psoriasis scores 2, whereas all other items score 1.
the symmetry is a function of the number of joints with RA (25). This has practical implications both in
involved (24). Indeed, with established disease most terms of recognizing the presence of arthritis by the
patients with PsA present with polyarthritis (3,6). patients and physicians, and therefore the ability to
We have recorded the patterns according to distal, diagnose the condition, and in terms of recognizing the
oligoarthritis, polyarthritis alone or in combination with need for therapy. Many patients present with deformity
spinal disease, as well as isolated spinal disease (3,19). and joint damage, not having perceived any pain during
Because arthritis mutilans could occur within any of the inflammatory phase of their disease. The presence
these groups it has not been identified as an isolated of a bluish/purplish discoloration over the inflamed joint
group. This classification was found to be 97% sensitive is typical for seronegative disease, including PsA, and
and 99% specific for PsA (12). A review of 705 patients may help differentiate PsA from RA even in the absence
followed prospectively at the University of Toronto of obvious psoriasis (26). The distribution of the affected
PsA Clinic reveals that at presentation, 3.7% have pre- joints is another typical feature of PsA. Whereas RA
dominantly distal joint disease but over 50% of the tends to involve joints along the same level (all meta-
patients have distal joint involvement in association carpophalangeal joints, all proximal interphalangeal
with another pattern. Arthritis mutilans, defined as at joints) in a symmetric distribution, PsA affects all the
least one totally destroyed joint, was detected in 19.5%, joints of one digit, in a ray pattern, giving the asym-
whereas five or more totally destroyed joints were metric distribution typical for the disease. Thus, the
detected in 8.2% of the patients (Table 8A-3). presence of distal joint inflammation as well as the ray
pattern are key features in PsA (Figure 8A-1).
Peripheral Arthritis in Psoriatic Spondyloarthritis

Psoriatic Arthritis Spinal involvement in PsA includes inflammation in
The arthritis of PsA is inflammatory in nature, present- both the sacroiliac joints and the apophyseal joints of
ing with pain, swelling, and stiffness in the affected the spine. The distribution in PsA tends to be asym-
joints. Any joint may be affected. Early in the disease metric, with only one sacroiliac joint involved and the
course the arthritis tends to be oligoarticular, but may other being spared, or with a different degree of involve-
become polyarticular as more joints are accrued over ment noted on sacroiliac radiographs. Likewise, the
time. There are several clinical characteristics of the spinal involvement tends to be asymmetric, and with
peripheral arthritis in PsA regardless of the clinical skip lesions (Figure 8A-2). Nonetheless, all levels of the
pattern. Patients with PsA are not as tender as patients spine may be involved (2730). The prevalence of spinal
TABLE 8A-3. PATTERNS OF PSORIATIC ARTHRITIS.a

Number of patients 705
Age at onset skin (mean [SD]) 28.8 (14.4)
Age at onset joints 36.1 (13.2)
Gender 57% male, 43% female
Age at presentation 43.7 (13.3)
Number of inflamed joints 10.2 (9.6)
Number of damaged joints

Clinical 3.2 (7.5) FIGURE 8A-2
Radiological 4.8 (8.1)
Asymmetric sacroiliitis, skip syndesmophytes.
AT PRESENTATION LAST VISIT
PATTERN (%) (%)
Distal 3.7 1.6

involvement in PsA has been variable, partly due to the
Oligoarthritis 14.7 8.5 definition used by the investigators. If radiographs are
Polyarthritis 39.3 30.6
performed on each patient, then sacroiliitis may be
detected quite frequently. In one study it was reported
Back alone 2.4 1.4 in 78% of the patients (30). After 10 years of observa-
Back plus distal 2.6 1.1
tion, some 50% of the patients in the University of
Toronto PsA Clinic have demonstrated evidence of
Back plus oligoarthritis 7.4 10.1 spinal involvement defined by the presence of sacroili-
Back plus polyarthritis 29.9 45.7 itis and/or syndesmophytes. However, only a portion of
these patients have clinical complaints of either pain or
Remission 0 1.1 morning stiffness. Indeed, patients with psoriatic spon-
Arthritis mutilans dylitis do not complain of as much pain, and do not
1 joint with stage 4 19.5 36.4 exhibit as much spinal limitation as patients with idio-
radiological damage pathic ankylosing spondylitis (31). This may be the
5 joints with stage 4 8.2 18.2 result of the generalized lower pain threshold noted
radiological damage
among these patients, as well as from the fact that the
a
Data from the University of Toronto Clinic, Toronto, Ontario, Canada.
disease itself may not be as severe, because fewer
patients with psoriatic spondyloarthritis present with 8
grade 4 sacroiliitis and they have fewer syndesmophytes
than patients with ankylosing spondylitis (31).
OTHER ARTICULAR
MANIFESTATIONS IN
PSORIATIC ARTHRITIS
Dactylitis
Dactylitis, or sausage digit, is a typical feature of PsA.
It refers to inflammation of the whole digit. It likely
results from both synovitis in the joints of the digit, as
well as tenosynovitis, particularly in the flexor tendons
(32,33). Dactylitis most commonly affects the toes, but
fingers are affected as well (34). Joints within digits that
demonstrated acute dactylitis were more likely to
FIGURE 8A-1 develop erosions than those in digits without dactylitis,
Ray distribution peripheral arthritis. Note the involvement of the suggesting that the presence of dactylitis is prognostic
second, third, and fifth digits on the left hand, while the third for disease progression (34). It should be noted that
right digit is totally spared. dactylitis may become chronic, such that it is no longer
painful or red, but remains as a chronically swollen The relationship between skin and joint disease is
digit, which may not respond to therapeutic interven- variable (39,40). There may be a stronger association in
tion. Helliwell and colleagues (35) proposed a method patients whose skin and joint manifestations began
for assessing dactylitis that may be useful in clinical simultaneously (40). It has been noted that in clinical
trials and in clinical observational cohort studies. trials for PsA the degree of skin disease is not as high
Recently, swelling of the extremity has been recognized as it is in clinical trials in psoriasis patients. Nail lesions
as a feature of PsA (36). The exact mechanism of this have been observed in a higher frequency among
peripheral edema is unclear but both lymphedema and patients with PsA compared to uncomplicated psoriasis
tenosynovitis may play a role (37). (41). These may be associated with distal interphalan-
geal joint disease.
Tenosynovitis
Tendonitis or tenosynovitis occurs frequently among Other Extra-Articular
patients with PsA. Inflammation may affect the flexor Manifestations
tendons of the fingers, as well as the extensor carpi
Iritis is an extra-articular feature common to all spon-
ulnaris, sites that are commonly affected in RA. Achil-
dyloarthropathies and is also seen among patients with
les tendonitis is commonly seen, as is plantar fascitis.
PsA. Some 7% of patients with PsA present with iritis,
These may interfere with function and may lead to dis-
and it can also be seen among patients with psoriasis
ability. In PsA, tendonitis may be associated with tendon
without arthritis (3,41).
nodules and significant functional limitation.
Urethritis is also a feature of seronegative disease. It
is less common in PsA than in the other members of the
Enthesitis spondyloarthritis group.
Inflammation of the enthesis, site of insertion of tendon Bowel involvement may occur in patients with PsA
into bone, is another typical feature of PsA. Enthesitis and is usually nonspecific colitis (42,43).
may occur at any tendon insertion site, but most com- Cardiac abnormalities have been reported among
monly affects the plantar fascia, Achilles tendon inser- patients with PsA, including dilatation of the base of
tion, insertion of tendons at the knee and shoulder, as the aortic arch which occurs in ankylosing spondylitis.
well as the pelvic bones. It has been suggested that More recently it has been recognized that patients
enthesitis alone in the presence of psoriasis may be with PsA are at risk for cardiovascular disease (44).
sufficient for the diagnosis of PsA (38). Indeed, the This may be related to the metabolic abnormalities
CASPAR criteria require the presence of any inflam- associated with PsA, including hyperlipidemia, hyper-
matory musculoskeletal features, including enthesitis, uricemia, as well as lifestyle factors such as obesity and
together with three other features to classify a patient smoking (44,45).
as having PsA (4).
DIAGNOSING PSORIATIC
EXTRA-ARTICULAR ARTHRITIS
FEATURES OF PSORIATIC
The diagnosis of PsA should be considered in any
ARTHRITIS patient who presents with an inflammatory arthritis in
the presence of psoriasis. However, not all patients with
Skin Disease psoriasis presenting with arthritis have PsA. PsA must
Skin psoriasis is a prerequisite for the diagnosis of pso- be distinguished from RA. Because psoriasis occurs in
riatic arthritis. There are several clinical presentations of 1% to 3% of the population and RA occurs in about
psoriasis (2). Psoriasis vulgaris is the most common type 1%, the chance of a patient having both RA and psoria-
and the most commonly associated with psoriatic arthri- sis is 1 : 10,000. If a patient with psoriasis and inflamma-
tis. If affects the extensor surfaces, particularly elbows tory arthritis has rheumatoid nodules, they are more
and knees. Psoriasis vulgaris may also affect the scalp, likely to have coexistence of RA with psoriasis. On the
the gluteal folds, as well the anal cleft. Psoriasis may other hand, if they are RF negative, have distal inter-
affect flexural areas primarily, in which case it would be phalangeal joint disease, and have nail lesions, they are
hidden unless the patients are asked about it, or are much more likely to have PsA even if they present with
totally undressed for the physical examination. Guttate a symmetric polyarthritis. The presence of spinal disease
psoriasis may also be associated with psoriatic arthritis, also tips the balance towards PsA. Because of the
but is less common than psoriasis vulgaris (6). The most involvement of distal joint disease, PsA must be distin-
severe form of psoriasis is the erythrodermic type. guished from osteoarthritis. Osteoarthritis is primarily
not an inflammatory disease. Therefore, if the distal ated with male gender and less active and severe disease
interphalangeal joints are inflamed with redness and at presentation to clinic.
swelling, especially in the context of nail lesions, the
patient is much more likely to have PsA. In patients
with mono- or oligoarticular presentation, PsA must be Quality of Life in Psoriatic Arthritis
differentiated from gout. Because patients with PsA
may have an elevated serum uric acid, it is important to Patients with PsA demonstrate reduced quality of life
obtain synovial fluid for crystal analysis to determine and function compared to the general population
the underlying pathophysiology. (55,56). Indeed, quality of life among patients with PsA
Patients with PsA who present with inflammatory was similar to that of patients with RA (57). Patients
spinal disease must be differentiated from other spon- with PsA exhibited more vitality, but also more bodily
dyloarthropathies. Because psoriasis may be associated pain than patients with RA (58). While 28% of the
with Crohns disease, with the latter being associated patients did not demonstrate disability over a 10-year
with spondylitis, it may be difficult to differentiate. period, female sex and older age were associated with
However, as noted above, the spinal involvement in more disability, while longer disease duration was asso-
PsA tends to be asymmetric, whereas in ankylosing ciated with no change in disability (59).
spondylitis and inflammatory bowel disease the spinal
disease tends to be symmetric. The presence of nail
lesions suggests the diagnosis of PsA (46). Mortality in Psoriatic Arthritis
Patients with PsA are at an increased risk of death
compared to the general population (60). While the
causes of death are similar to those seen in the general
COURSE AND OUTCOME IN population, disease activity and severity at presentation
PSORIATIC ARTHRITIS are predictive of early mortality in patients with PsA
(61). Survival in PsA seems to have improved in the past
In the past, patients with PsA were thought to have a 30 years, with the most recent standardized mortality
milder disease than patients with rheumatoid arthritis ratio reducing from 1.62 to 1.36 (62). It is possible that
(47). However, over the past 20 years it has become more aggressive therapeutic approaches have helped
clear that the disease is more severe than previously improve survival (63). A recent study demonstrated
thought. A study of 220 patients with PsA demonstrated that there is no increased malignancy risk among
that 67% of the patients had erosive disease at presenta- patients with PsA followed over 25 years.
tion to clinic, and 20% of the patients had a very severe
form of arthritis, similar to what had been reported for
RA (3). More recently, 47% of the patients with PsA 8
seen in clinic within 5 months of onset were found to SUMMARY
have erosive disease by 2 years (48). Patients with PsA
demonstrate disease progression over time, with more Psoriatic arthritis is an inflammatory arthritis associated
patients developing polyarthritis and an increase in with psoriasis, usually seronegative for RF. It presents
joint damage both clinically and radiologically (23,49). in a number of clinical patterns. PsA may be severely
While progression of damage may be determined first disabling and is associated with an increased mortality
by radiographs, clinical damage may be observed at risk. Patients with PsA should be diagnosed early and
each clinic visit and should be recorded (50). treated promptly and aggressively in order to prevent
these untoward outcomes.
Predictors for Disease Progression

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CHAPTER 8
Psoriatic Arthritis
CHRISTOPHER RITCHLIN, MD
Psoriatic arthritis (PsA) histopathology differs from Cellular immunity and cytokines, including tumor
rheumatoid arthritis (RA), with the most striking necrosis factor alpha (TNF-alpha), are important
difference in the characteristic of the synovial mediators of PsA.
vasculature. Osteoclasts are important mediators of dysregulated
Psoriatic arthritis is triggered by interaction between bone remodeling in PsA.
genetic and environmental factors with initiating
events occurring in the skin and/or gut.
Psoriatic arthritis (PsA) is an inflammatory arthritis vial vasculature displayed endothelial cell swelling,
associated with psoriasis that is usually negative for inflammatory cell infiltration, and marked thickening of
rheumatoid factor (RF). Inflammation can target a the vessel wall (2). Monocytoid cells infiltrate the sub-
range of musculoskeletal structures, including the axial synovium but in PsA the numbers are less than in RA.
skeleton, peripheral joints, attachment sites of liga- Immunopathologic features observed more commonly
ments, tendons or joint capsules onto bone (entheses), in PsA compared to RA were increased vascularity,
and tendon sheaths. Joint manifestations may be highly prominent neutrophil infiltration, and increased expres-
localized and mild in some patients, while others may sion of the mature monocyte marker CD163 by subsy-
experience widespread inflammation and damage that novial monocytes (3). Infiltrating CD4+ lymphocytes
results in significant functional decline. Moreover, as predominate in the synovial tissue, whereas CD8+ T
discussed in the previous chapter, several clinical subsets cells are present in the synovial fluid (4,5). Ectopic
of PsA have been described (symmetric polyarthritis, lymphoid aggregates have been noted in psoriatic
asymmetric oligoarticular arthritis, spondylitis, arthritis synovium. No significant pathologic differences were
mutilans, and predominant distal interphalangeal dis- found between oligo- or polyarticular PsA and the pso-
ease) and it is not known whether these distinct clinical riatic synovial histology was more similar to other forms
entities are orchestrated by the same disease mecha- of spondyloarthropathies (SpA) than to RA (6).
nisms. Joint dysfunction can arise not only as a result of The inflamed synovial membrane or pannus, com-
bone resorption and cartilage degradation, but also from prised of fibroblastoid cells and activated macrophages,
diffuse soft tissue inflammation (dactylitis) and new is invasively destructive. Fibroblastoid cells release
bone formation in the form of ankylosis or periostitis. metalloproteinases (MMP)-1, 2, and 3, which degrade
cartilage, while MMP-9 is localized to vessel walls (7).
Osteoclasts are present in deep resorption pits at the
PATHOLOGY bonepannus junction. Biopsies of entheseal inflamma-
tion sites revealed CD8+ T cells in the underlying sub-
The histologic changes in the peripheral joints are chondral bone and macrophages infiltrating the tendon
similar to those observed in rheumatoid arthritis (RA) (8,9). Studies of bone and synovium from patients with
but important distinctions have been noted. One of the axial PsA have not been performed, but imaging studies
most prominent features is a striking increase in syno- suggest an entheseal-based pathology with prominent
vial vascularity, characterized at the macroscopic level osteitis in the underlying bone (Figure 8B-1) (10).
by dilated and tortuous blood vessels that contrast Dactylitis is most likely a form of flexor tenosynovitis,
sharply with the linear pattern observed in RA (1). At although pathologic studies of involved digits have not
the histologic and ultrastructural level, psoriatic syno- been published.
178
is slightly weaker than in psoriasis. A smaller propor-

tion of cases have an association with HLA-B27, chiefly
in patients with predominant spinal disease. HLA-B27
in the presence of HLA-DR7 and HLA-DQw3 in the
absence of HLA-DR7 predict progression, while HLA-
B22 is protective. Other reports noted an association
with HLA-B38 and -B39, as well as with other alleles in
linkage disequilibrium. The presence of HLA-DR*04
shared epitope is associated with worse radiological
damage (12,13).
Major histocompatibility complex class I molecules
could promote PsA by presenting arthritogenic pep-
FIGURE 8B-1
tides to CD8+ lymphocytes or by selection of a T-cell
Fat-suppressed T2 weighted magnetic resonance imaging (MRI) repertoire that is autoreactive in skin and joints. Another
scans in PsA and RA. In the left panel, a psoriatic knee demon- mechanism recently described indicates that natural
strates extensive bone marrow edema in three areas: the
killer (NK) cell activity is controlled through interac-
anterior patella (straight arrow), superior insertion of the posterior
cruciate ligament (S), and marked subchondral bone marrow tions between killer immmunoglobulinlike receptors
edema in the tibial plateau, especially at the patellar tendon (KIR) and MHC class I genes, particularly Cw6. PsA
insertion (curved arrow) and the inferior insertion of posterior patients have a genetic profile of KIR alleles that lower
cruciate ligament (*). In the right panel, a rheumatoid knee the threshold for NK activations (14). Two recent
shows a joint effusion (E) and focal increased signal limited to
reports have also found associations of PsA with inter-
vessels behind the femur. (Modified from McGonagle D et al.,
Arthritis Rheum 1998;41:694700, with permission of Arthritis leukin 1 (IL-1) and tumor necrosis factor (TNF) alleles
and Rheumatism and Wiley Periodicals, Inc.) (15,16).
It should be emphasized that the great majority of
these studies have been performed in cases or families
ascertained by the presence of psoriasis. Thus, to dissect
PATHOGENESIS disease associations specific to arthritis, two separate
cohorts of psoriasis patients (with and without arthritis)
In the current paradigm, PsA is triggered by a complex must be characterized and genotyped. Furthermore, the
interaction between genetic and environmental factors. finding that relevant HLA class I MHC alleles occur in
Given the temporal relationship with psoriasis, it is less than 50% of PsA patients may reflect involvement
likely that the initiating events involve both innate and of non-HLA genes in the causal pathway.
acquired immune responses that arise in the skin and
spread to the joint in susceptible individuals. Recent
studies have underscored the central role of inflamma-
Environmental Factors 8
tory cytokines in joint inflammation and destruction. Compelling evidence suggests that trauma and infection
Treatment interventions directed at these molecules play a role in the etiologic pathway of PsA. Koebner
have provided effective treatment options and uncov- phenomenon, described as psoriatic lesions arising at
ered novel disease mechanisms. sites of trauma, occurs in 24% to 52% of psoriasis
patients (17). The development of PsA following trauma
to a joint, with the suggested name of the deep Koebner
phenomenon, has also been reported in the Toronto
Genetic Basis of Psoriatic Arthritis longitudinal observational cohort, where 50 of 203
Moll and Wright found that 5.5% of first-degree (24.6%) patients reported a traumatic event prior to the
relatives of PsA probands developed inflammatory diagnosis of PsA (18). Subclinical trauma may also con-
arthritisan inheritability risk that is greater than tribute to the distal interphalangeal (DIP) joint arthri-
observed in psoriasis (11). Several genetic loci have tis, dactylitis, and enthesitis, although this relationship
been implicated in the predisposition to psoriasis and has not been formally studied. It is also important to
PsA, but the strongest effect has been linked to alleles note that a history of trauma has been reported in only
in the major histocompatibility complex (MHC). Earlier a minority of PsA patients.
association studies in PsA focused attention on HLA- Some studies suggest involvement of bacterial agents
Cw6, in addition to HLA-B13 and -B17 (B57). These in psoriasis and possibly PsA. A strikingly high associa-
associations reflect the strong linkage disequilibrium tion between guttate psoriasis and preceding strepto-
between HLA-Cw6 and HLA-B57, and HLA-Cw6 and coccal pharyngitis and tonsillitis exists in children (19).
HLA-B13, which extends into the MHC class II region. The link between Gram-positive infection and PsA was
In individuals with PsA, the association with HLA-Cw6 suggested by high levels of circulating antibodies to
180 CHRISTOPHER RITCHLIN
microbial peptidoglycans and elevated levels of group

A streptococcus 16S RNA in the peripheral blood of
PsA patients (20). Both streptococcal and staphylococ-
cal superantigens promote inflammation and upregula-
tion of keratinocyte TNF in noninvolved psoriatic skin,
but not other inflammatory dermatoses, elucidating the
potential importance of this novel immune pathway in
psoriasis (21).
Cellular Activation and Cytokine

Pathways in Psoriatic Arthritis
Recent evidence indicates that cells of the innate
immune system may direct the early events in psoriatic
joint inflammation. The effector cells of the innate
FIGURE 8B-2
response are keratinocytes, dendritic cells, neutrophils,
monocytes/macrophages, and NK cells. In a mouse Representative images of CD3+ and CD68+ immunohistochemi-
model of PsA, targeted keratinocyte deletion of JunB cal staining and TUNEL assay in psoriatic synovial tissues at
and c-Jun, components of the AP-1 transcription factor baseline and 48 hours after initiation of infliximab therapy.
A significant decline in infiltrating CD3+ T cells and CD68+
that is involved in cellular differentiation and prolifera- macrophages was noted. Therapy was not associated with
tion, resulted in psoriasiform skin lesions and subse- increased apoptosis as measured by the TUNEL assay. (From
quent arthritis with features of joint destruction and Goedkoop AY et al., Ann Rheum Dis 2004;63:769773, with
new bone formation (22). This model demonstrated permission of Annals of the Rheumatic Diseases.)
that disruption of keratinocye function could promote
an inflammatory response in the skin that spreads to the
joint via mechanisms that involve T cells and TNF sig- The role of the acquired immune response in psori-
naling pathways. Activated plasmacytoid and monocy- atic joint disease is not well understood but the strong
toid dendritic cells (DC) have been detected in the association of psoriatic arthritis with MHC class I mol-
dermis of psoriasis plaques and both of these DC subsets ecules suggests that CD8+ T lymphocytes may be pivotal
were isolated from PsA joint fluid (23). As previously in pathogenesis. Immunohistologic studies on psoriatic
mentioned, prominent neutrophil and monocyte infil- synovial membranes, however, revealed a predomi-
trates are present in psoriatic skin and synovium. The nance of CD45RO+ memory T cells in the synovial
role of NK cells in PsA has not been elucidated, but the lining mononuclear cell infiltrate (30). In contrast, CD8+
finding that specific alleles associated with NK cell T cells are the principal lymphocytes in synovial fluid,
receptor are associated with susceptibility to psoriasis some of which demonstrate oligoclonal expansion of T-
and PsA suggests that they may contribute to the patho- cell receptor (TCR) B chains, suggesting the presence
genesis (14). Moreover, cytokines involved in the innate of an antigen-driven response (5). Additional support
immune response have been detected in psoriatic for T-lymphocyte involvement came from studies on
synovium, including IL-1, IL-8, IL-15, and TNF-alpha psoriatic synovial explant tissues which produced higher
(24). levels of the helper-T-lymphocyte (Th1) cytokines IL-2
Several lines of evidence demonstrate that TNF- and interferon gamma (INF-gamma) protein than
alpha is a pivotal cytokine in psoriatic joint inflamma- explants similarly cultured from osteoarthritis and rheu-
tion. First, elevated levels of TNF-alpha have been matoid patients (24). In contrast, IL-4 and IL-5 were not
detected in joint fluid and in psoriatic synovial superna- identified in psoriatic explants. This Th1 profile has been
tants (24). Second, immunohistochemical studies dem- observed in both psoriasis and RA. A similar pattern of
onstrated upregulation of TNF-alpha in the psoriatic cytokine production in psoriatic synovium was shown
synovial membrane and skin (25,26). Third, histopatho- using immunohistochemical techniques (25).
logic analysis of synovial specimens from PsA patients
treated with anti-TNF agents revealed decreased vascu- Dysregulated Bone Remodeling
larity, synovial lining thickness, and mononuclear cell
infiltration following treatment (Figure 8B-2) (27,28).
in Psoriatic Arthritis
Fourth, clinical trials revealed that anti-TNF agents sig- In regard to bone, psoriatic joint biopsies demonstrate
nificantly lessen inflammation in the psoriatic plaque, large multinucleated osteoclasts in deep resorption pits
entheses, flexor tendons, and the axial skeleton (see at the bonepannus junction (31). Osteoclastogenesis
Chapter 8C) (29). (differentiation of osteoclasts) is a contact-dependent
process directed by osteoblasts and stromal cells in the in psoriatic joints (31). In addition, OCP, derived from
bone marrow (Figure 8B-3) (32). These cells release circulating CD14+ monocytes, were markedly elevated
two different signals necessary for differentiation of an in the peripheral blood of PsA patients compared to
osteoclast precursor (OCP), derived from the CD14+ healthy controls. Treatment of PsA patients with anti-
monocyte population, into an osteoclast. The first, TNF agents significantly decreased the level of circulat-
macrophage-colony stimulating factor (M-CSF) and the ing OCP, thus supporting a central role for TNF-alpha
second, receptor activator of NF-B ligand (RANKL), in the generation of this precursor population.
a member of the TNF superfamily, bind to RANK The mechanisms responsible for new bone formation
on the surface of OCP and osteoclasts. This ligand in the psoriatic joint are poorly understood. Transform-
receptor interaction stimulates proliferation and differing growth factor (TGF) beta and vascular endothelial
entiation of OCP and activation of osteoclasts. Because growth factor (VEGF) may be pivotal in this process
permissive quantities of M-CSF are constitutively given that TGF-alpha is strongly expressed in synovial
expressed in the bone microenvironment, it has been tissues isolated from ankylosing spondylitis patients and
proposed that the relative expression of RANKL synergizes with VEGF to induce bone formation in
and its natural antagonist osteoprotegerin (OPG) animal models (33,34). Male DBA/1 mice caged together
ultimately control osteoclastogenesis. Interestingly, develop an ankylosing enthesitis remarkably similar to
RANKL is also expressed by infiltrating T cells and lesions in PsA and bone morphogenetic proteins (BMP)
synovial fibroblastoid cells in the synovial lining of 2 and 7 are upregulated in regions of pathologic new
inflamed joints. bone formation (35). In addition, expression of phos-
In psoriatic synovial tissues, marked upregulation of phorylated Smad 1 and Smad 5, important signaling
RANKL protein and low expression of OPG was molecules in the downstream BMP signaling pathway,
detected in the adjacent synovial lining. Osteoclasts was markedly increased in regions of new bone forma-
were also noted in cutting cones traversing the subchon- tion taken from the calcaneous in a patient with Achil-
dral bone supporting a bidirectional attack on the bone les tendonitis and periostitis.
Before After FIGURE 8B-3
Osteoclast differentiation. RANKL is

expressed by osteoblasts and stromal
cells in response to a variety of stimuli. In
the inflamed joint, RANKL is expressed by
fibroblastoid lining cells and infiltrating T
CD3
lymphocytes. RANKL binds to the RANK
receptor expressed on OCP and OC. In
the presence of M-CSF and RANKL, OCP 8
mature into OC capable of resorbing
bone. OPG, a physiologic decoy molecule,
can bind to RANKL and inhibit OC
differentiation and activation. Abbrevia-
tions: RANKL, receptor activator of NF-B
ligand; OCP, osteoclast precursor; M-CSF,
monocyte colony stimulating factor; OPG,
osteoprotegerin.
CD68
TUNEL
Pathogenesis of Extra-Articular psoriasis is viewed as a systemic disease that involves

different anatomical sites in the same patient (37).
Psoriatic Arthritis Taken together, the evidence suggests that trauma or
Gut and eye involvement are present in a subset of PsA infection in a genetically susceptible individual triggers
patients. Subclinical gut inflammation was noted in 16% PsA and that the initial inciting event probably occurs
of 64 PsA patients on ileocolonoscopy, and this finding in the skin, resulting in activation of monocytes and T
was limited to patients with oligoarthritis or spinal cells (Figure 8B-4). In the subset with spondylitis, the
disease but not those with polyarthritis (36). Further- early events may arise in the gut. In some patients with
more, PsA patients have an increased risk of inflamma- psoriasis, local events in the joint promote angiogenesis
tory bowel disease compared to controls. Uveitis, both followed by mononuclear cell activation accompanied
unilateral and bilateral, can occur in PsA patients, par- by increased expression of TNF-alpha and RANKL.
ticularly in the subset with axial disease. Furthermore, Circulating OCP enter the joint after binding to acti-
both uveitis and bowel inflammation often respond to vated endothelial cells and undergo osteoclastogenesis
anti-TNF therapy. These clinical observations suggest a and resorb bone. Elevated production of BMP and
link between bowel inflammation, spondylitis, and eye VEGF contribute to new bone formation, while MMPs
disease in a subset of PsA patients that may be medi- released by synovial lining cells degrade cartilage
ated in part by TNF. An alternative view has been pro- and engage in blood vessel remodeling. Presumably,
posed based on the concept of psoriatic disease in which perpetual release of proinflammatory cytokines,
FIGURE 8B-4
PsA pathogenesis model. The major events in PsA begin in the skin (step 1) and spread to the
joint (step 2). The genetic factors associated with skin or joint disease may not be identical. In
step 1, DC are triggered by trauma, infection, or other signals to activate T cells. Activated T cells
promote entry of monocytes into the dermis and release of TNF and other cytokines that lead to
keratinocyte hyperplasia and PMNs infiltration. In step 2, activated monocytes and T cells leave
the skin and enter the joint that has been subjected to trauma or infection, after binding to
primed ECs. Vascular remodeling is directed by VEGF, MMP-9, and ang-2. TNF and other
cytokines released by these infiltrating cells drive synovial cell hyperplasia. The lining cells
promote osteoclastogenesis and subsequent bone resorption via RANKL expression and they
release MMPs which mediate cartilage degradation. Inflammatory events in the subchondral
bone foster enthesitis and osteitis. Activation of BMPs leads to new bone formation. Abbrevia-
tions: EC, endothelial cell; M, monocyte/macrophage; MHC, major histocompatibility complex;
MMP: metalloproteinase; ang-2, angiopoietin 2; VEGF, vascular endothelial growth factor; PMN,
neutrophils; BMP, bone morphogenetic protein; KIR, killer immunoglobulin receptor.
Skin
Genetic Factors
Step 1 T cell activation by DC CW6 (other MHC
TNF release activates EC and non MHC
alleles?)
Influx of M, PMNs
Keratinocyte hyperplasia
Vascular factors
EC activation (TNF)
Step 2
Environmental factors Vascular remodeling (MMP-9,
Gut VEGF, ang-2)
Trauma, Infection
Activated T cells, PMNs, M
bind to EC
Joint
Infiltration of synovium,
entheses and tendons by T cells,
M, PMNs
Genetic factors
Release of IL-1, TNF and other
B17, B38, 39, Cw6
cytokines
Upregulation of RANKL, BMP, KIR alleles, IL-1, TNF
VEGF alleles
Bone resorption and new bone

formation
particularly TNF, leads to persistent synovitis, enthesi- shared epitope on the clinical characteristics and radio-
tis, and progressive matrix degradation. The events that logical outcome of psoriatic arthritis. J Rheumatol 2003;
drive the chronic influx of mononuclear cells into the 30:96101.
joint and sustained release of proinflammatory cyto- 14. Martin MP, Nelson G, Lee JH, et al. Cutting edge: sus-
ceptibility to psoriatic arthritis: influence of activating
kines have not been elucidated.
killer Ig-like receptor genes in the absence of specific
HLA-C alleles. J Immunol 2002;169:28182822.
15. Rahman P, Sun S, Peddle L, et al. Association between
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CHAPTER 8
Psoriatic Arthritis
PHILIP J. MEASE, MD
Multiple instruments are available for assessment of Destructive arthritis should be managed by tradi-
skin, joints, and quality of life in psoriasis and tional disease-modifying drugs or biologic therapies.
psoriatic arthritis (PsA). Tumor necrosis factor (TNF) inhibitors have shown
Management of skin and arthritis can often be the greatest efficacy to date in PsA.
accomplished with similar agents.
The framework for the treatment of psoriatic arthritis and therapy, exercise, nutrition, psychological counsel-
(PsA) is constituted by proper diagnosis and assessment ing, physical and occupational therapy, and orthopedic
of severity of the domains of disease activity involved surgery. There have been few studies of these modali-
in PsA: peripheral arthritis, enthesitis, dactylitis, spine ties in PsA per se, although there has been extensive
inflammation, and skin and nail lesions, which may research on their value and utility in the management
be differentially active. The degree of disease activity of arthritis in general and RA specifically, from which
in these domains, along with background contextual we can extrapolate regarding their value and utility in
factors for the individual (age, gender, psychological PsA. A key role for the rheumatologist and rheumatol-
and socioeconomic factors, comorbidities, etc.) deter- ogy office staff is to serve as a central triage point for
mine the impact of disease on quality of life, function, such adjunct therapy.
and life expectancy.
Typically, a patient will be aware of having the skin
condition psoriasis long before the associated arthritis ASSESSMENT OF DISEASE
occurs. In just 15% to 25% of patients will the arthritis
manifest simultaneously or subsequently (1,2). Thus,
ACTIVITY AND THERAPY
many patients will be under the care of a dermatologist OUTCOME
or primary care physician (PCP) for management of
skin lesions and, as such, are in an ideal position to be Determination of disease severity and effectiveness of
queried about symptoms of musculoskeletal pain and therapies in clinical trials and in practice requires assess-
stiffness. PsA can occur in up to 30% of patients with ment tools that have generally been adapted from similar
psoriasis, depending on method of ascertainment and measures used in assessment of RA and psoriasis (Table
severity of psoriasis (see Chapter 8A). Because other 8C-1) (49). These have been used in clinical trials and
forms of arthritis may occur in a patient with psoriasis, clinical registries of PsA patients. These measures have
such as osteoarthritis, rheumatoid arthritis (RA), other been shown to effectively assess peripheral joint and
spondyloarthritides, and gout (see Chapter 8A), it may skin symptoms and signs, function, quality of life, and
be prudent for the dermatologist or PCP to obtain fatigue, as well as distinguish treatment from placebo.
a rheumatology consult to help clarify what type of Approaches to assessment of enthesitis, dactylitis, and
arthritis condition is present, supplement education for spine involvement are still in development. Adaptation
the patient and family, and strategize about treatment of RA methodologies to assess change of radiographs in
approaches based on the diagnosis and severity (3). PsA has occurred in a number of recent clinical trials
Although this review will focus on pharmacotherapy (7,8), suggesting that such approaches are appropriate
of PsA, it must be recognized that optimal therapy also in PsA despite its differences from RA. Several studies
comprises nonpharmacotherapy approaches, including have documented the effectiveness of ultrasound
patient and family education about the disease process and magnetic resonance imaging (MRI) in detecting
185
186 PHILIP J. MEASE
TABLE 8C-1. PSORIATIC ARTHRITIS OUTCOME all administered parenterally, based on successful
MEASURES USED IN CLINICAL TRIALS. clinical trials of the antitumor necrosis factor (anti-
TNF) agents etanercept, infliximab, and adalimumab
Arthritis response
American College of Rheumatology Response Criteria (1820) and the T-cell modulating agents, alefacept and
(including DIP and CMC joints) efalizumab (21,22). Etanercept, infliximab, and efali-
Psoriatic Arthritis Response Criteria (PsARC) zumab have been approved in the United States and
Disease Activity Score (DAS, DAS 44, DAS 28) Europe for psoriasis and alefacept has been approved
Radiographic assessment for use in the United States. Clinical studies and clinical
Modified (for PsA) Sharp experience, including safety and tolerability issues, with
Modified (for PsA) van der Heijde/Sharp these agents in psoriasis have been extensively reviewed
Skin response
elsewhere (9,10,13,17,2325). The first biologic agents
Psoriasis Area and Severity Index (PASI) approved in the United States were the T-cell modula-
Target Lesion score tory agents alefacept and efalizumab, based on the key
Physician Global Assessment (PGA) of Psoriasis role played by T lymphocytes in psoriasis pathogenesis
Quality of life/function improvement
(26). Both block T-cell stimulation; alefacept promotes
Short-Form 36 Health Survey (SF-36) apoptosis of memory T cells and efalizumab inhibits
Health Assessment Questionnaire (HAQ) Disability Index migration of lymphocytes to the site inflammation. Both
Dermatology Life Quality Index (DLQI) show clinically meaningful reductions in skin lesional
Functional Assessment of Chronic Illness Therapy (FACIT) activity and improved quality of life. A typically greater
and more rapid improvement of psoriasis has been seen
SOURCE: Data from references 4 through 9.
ABBREVIATIONS: CMC, carpometacarpal; DIP, distal interphalangeal. with the anti-TNF agents, along with correlated improve-
ments of fatigue and quality of life and return to normal
work and social life. These drugs offer an alternative to
other systemic therapies or time-consuming UV light or
inflammation in the joints and enthesium of SpA topical therapies.
patients, as well as the extent of structural damage (8).
PSORIASIS MANAGEMENT PSORIATIC ARTHRITIS

MANAGEMENT
The patients individual experience with psoriasis thera-
pies, prior to development of PsA, will have depended Nonsteroidal Anti-Inflammatory
on the severity of skin disease. Milder disease, for
example, involving less than 5% body surface area
Drugs in Psoriatic Arthritis
(BSA), showing less severe induration and scale, and Nonsteroidal anti-inflammatory drugs (NSAIDs) are a
not involving important functional or cosmetic areas cornerstone of therapy for most PsA patients with mus-
such as the hands, scalp, or other visible areas, may be culoskeletal pain symptoms, either used alone in mild
treated with topical corticosteroid and/or vitamin D or disease or in combination with other therapies. Typi-
A analogues, as well as ultraviolet (UV) light therapy cally a patient may have already tried an over-the-
(1012). Patients with moderate-to-severe skin disease counter formulation, such as ibuprofen and naprosyn,
may have been treated with systemic therapies, such as so will have a sense of their relative effectiveness and
methotrexate, cyclosporine, and acitretin, as well as UV tolerability. Switching among choices of NSAIDs may
light therapy, often in a cyclic fashion to maximize ther- be indicated to try to achieve maximum convenience,
apeutic effect while minimizing treatment side effects effectiveness, and tolerability. There is scant trial expe-
(1017). When psoriasis clears it does not leave residual rience with NSAIDs in PsA documenting efficacy (27),
damage, so dermatologists typically treat till clear and so support for their use is primarily derived from trials
then withdraw therapy until lesions return. A number in rheumatoid arthritis (RA) and osteoarthritis (OA) as
of strategies have been developed for intermittent as well as clinical experience. There are isolated case
well as combination therapy, based on assessment of reports of psoriasis exacerbation related to NSAID use,
skin lesion severity, to achieve optimal results (17). It is but this has not been felt to be of significant conse-
important to take into account previous tolerability and quence (27).
effectiveness of systemic medicines used for psoriasis Nonsteroidal anti-inflammatory drugs have been
when considering therapeutic options for inflammatory found to be efficacious for the treatment of spinal pain
arthritis when it develops. in ankylosing spondylitis, on which evidence it is rea-
In recent years, there has been extensive uptake of sonable to extrapolate efficacy in management of PsA
the biologic response modifier medications in psoriasis, spondylitis (28).
Glucocorticoids in Psoriatic Arthritis show any difference in radiologic progression scores in

the two groups (31). Patients on chronic MTX therapy
Episodic intra-articular steroid injections can be symp- must have regular blood monitoring (blood counts, liver
tomatically helpful, especially for patients with mono- function tests, and creatinine). Significant elevation of
articular PsA, oligoarticular disease, or a situation liver tests or drop in blood counts should lead to adjust-
wherein a polyarticular patient has one or a few joints ment of dose or cessation of therapy. A further consid-
inadequately controlled by systemic therapy. Enthesitis eration is that based on older liver biopsy studies, the
and tendonitis may also be helped by selective steroid suggestion has been made that there is greater proclivity
injection. Results tend to be short lived, thus of limited to MTX hepatotoxicity in a psoriasis population than in
long-term use if inflammation is recurrent in that site. patients with RA (32). Thus, there is often a preference
However, if the inflammation is transient in that site, by the dermatologist to limit overall use of MTX, or, if
then local injection therapy can be quite helpful. Sys- continued, to assess for liver toxicity by periodic liver
temic glucocorticoids should be used more judiciously biopsy (33). This is in contrast to the rheumatology
than in other inflammatory arthritides because of the experience wherein liver function tests are periodically
chance that psoriasis skin lesions will severely flare assessed, but not liver biopsies, and MTX is used con-
upon withdrawal of therapy (27). tinuously and often in combination with other medica-
tions (34). Nevertheless, the practice of routine liver
biopsies based on MTX dose has been questioned in the
Traditional Disease-Modifying literature as more data are acquired (3335).
Antirheumatic Drugs in Although the combination of MTX and TNF inhibi-
Psoriatic Arthritis tors has in RA been shown to be superior in all clinical
parameters of efficacy, including inhibition of structural
Utilization of systemic disease-modifying drugs in PsA damage (30), this has not been assessed in PsA. Thus,
has generally been modeled after their use in psoriasis in the treatment of PsA in clinical practice, MTX may
and RA. Those that are considered traditional include sometimes be discontinued after initiation of biologic
the oral agents methotrexate, sulfasalazine, and cyclo- therapy and only reinitiated if the patient experiences
sporine. Injectable and oral gold and azathioprine would inadequate control of disease with biologic monother-
also be considered in this group, but have been infre- apy. Response of spinal joints has not been assessed in
quently used and, in the case of injectable gold therapy, PsA. In ankylosing spondylitis, MTX has not been
have generally fallen out of favor. shown to benefit spinal measures of disease activity
Leflunomide, a pyrimidine antagonist approved for (28,36).
the treatment of RA, is typically considered along with
this group of agents.
Sulfasalazine
The largest number of controlled trials of traditional 8
Methotrexate
DMARD therapy has been conducted with sulfasala-
Methotrexate (MTX) is one of the most commonly used zine (27). In the largest of these, 221 PsA patients
systemic medications in PsA, yet controlled trial evi- were treated with sulfasalazine, 2 g/day, for 36 weeks
dence for its effectiveness is scant. In 1984, Willkens (37). Although a composite arthritis score showed
published a small controlled trial using dosages of the statistically significant improvement in the treatment
drug that were then considered potentially appropriate group, the only individual measure within the responder
in the treatment of inflammatory arthritis, 7.5 mg and index to do so was the patient global assessment, indi-
15 mg per week (29). In this trial, only the physician cating that the effect was not strong. Further, there was
global assessment of arthritis showed statistically signifi- no benefit to the skin and gastrointestinal intolerability
cant improvement, and not the tender and swollen joint was an issue. As with MTX, spine response was not
count. Skin improvements were modest. However, clin- assessed and controlled trials with this agent in ankylos-
ical experience with standard doses in the 15 to 20 mg ing spondylitis have not shown efficacy in the spine
per week range would suggest that the drug can be domain (28).
efficacious in many patients and it remains one of the
most commonly used disease-modifying antirheumatic
drugs (DMARDs).
Cyclosporine
Increasingly it has been recognized that MTX only Although cyclosporine can achieve rapid improvement
partially inhibits the progression of structural damage of the skin lesions of psoriasis, its effectiveness in PsA
in RA (30). This has not been prospectively assessed in has been minimally studied other than showing some
PsA, but a 2-year retrospective analysis of matched PsA effectiveness in open trials (27). Its utility is limited by
patients who were either on or off MTX therapy did not concerns regarding the adverse effects of hypertension
188 PHILIP J. MEASE
and renal insufficiency. Regarding the combination of progression of joint space narrowing and erosions was
cyclosporine with MTX, 72 patients with incomplete shown, with 1 unit of modified total Sharp score (mTSS)
response to MTX were randomized to placebo or progression in the placebo group and none (0.03 units)
addition of cyclosporine (38). At 48 weeks, significant in the etanercept group (p = 0.001). In the open label
improvements in tender and swollen joint count, C- extension of this study, at 2 years, effectiveness was
reactive protein (CRP), psoriasis area and severity maintained in joint response, and skin response further
index (PASI), and synovial ultrasound score occurred improved to a PASI 75 response in 38%. Originally
in the combination group, but statistical differentiation placebo patients achieved a similar degree of effective-
between the combination and MTX-alone group ness in joints and skin as well as inhibition of further
occurred just in PASI and ultrasound score. structural damage (45). The drug was well tolerated and
no safety issues emerged apart from those seen in clini-
cal trial and general clinical experience with etanercept
Leflunomide in RA.
Leflunomide, a pyrimidine antagonist approved in RA
at a dose of 20 mg/day, was assessed in 188 PsA patients. Infliximab
The Psoriatic Arthritis Response Criteria (PsARC)
response, the primary endpoint, was met by 59% of Infliximab is a chimeric monoclonal anti-TNF antibody
leflunomide-treated patients compared with 29.7% of now approved in RA, Crohns, PsA, psoriasis, and
placebo-treated patients (p < 0.0001). American College ankylosing spondylitis. A phase III study of infliximab
of Rheumatology (ACR) 20 response was achieved by in 200 PsA patients (IMPACT II) showed significant
36.3% and 20%, respectively (p = 0.0138), and PASI 75 benefit (46). Baseline demographic and disease activity
response by 17.4% and 7.8%, respectively (p = 0.048) characteristics were similar to those of the etanercept
(39). As with MTX, liver function test abnormalities phase III trial. At week 14, 58% of infliximab patients
may be noted and need to be monitored. Leflunomide and 11% of placebo patients achieved an ACR20
did not benefit the spine in AS (28,36). response (p < 0.001). Presence of dactylitis and enthesi-
tis, assessed by palpation of the Achilles tendon and
plantar fascia insertions, decreased significantly in the
Tumor Necrosis Factor Alpha infliximab group (46). In skin evaluation, at 24 weeks,
Inhibitors in Psoriatic Arthritis PASI 75 was achieved by 64% of the evaluable treat-
ment group and 2% of the placebo group (p < 0.001).
The antitumor necrosis factor alpha (TNF-alpha) Utilizing the van der Heijde-Sharp scoring method
compounds, etanercept (Enbrel) (40), infliximab (hands and feet), modified for PsA, infliximab-treated
(Remicade) (41), and adalimumab (Humira) (42) are patients showed inhibition of radiographic disease pro-
approved for use in PsA as well as psoriasis skin disease. gression at 24 weeks, although PsA-specific radiographic
features, including pencil-in-cup deformities and gross
osteolysis, did not differ between the treatment groups,
Etanercept as has been observed in other antiTNF-alpha trials,
Etanercept is a soluble receptor for TNF, administered presumably due to the more fixed nature of theses
subcutaneously in a dose of 25 mg twice a week or 50 mg changes (47). HAQ score improved for 59% of inflix-
once a week for PsA, now approved in RA, PsA, pso- imab patients, compared with 19% of placebo patients,
riasis, and ankylosing spondylitis. In the placebo- while both the physical and mental components of SF-
controlled portion of the phase III etanercept trial in 36 scores improved for patients receiving infliximab.
PsA (n = 205), utilizing 25 mg administered subcutane- Improvement was sustained at 1 year (46).
ously twice a week, ACR20 response was achieved by
59% of etanercept treated patients versus 15% in the
Adalimumab
placebo group (42% and 41% on background MTX,
respectively; p < 0.0001; 43). Skin response, as measured Adalimumab is a fully human antiTNF-alpha mono-
by the PASI score in patients with BSA involvement clonal antibody administered subcutaneously, 40 mg,
3%, showed a 75% improvement in 23% and 3%, every other week or weekly and is approved for RA
respectively, at 24 weeks (p = 0.001). A change of 0.51 and PsA. It was studied in a phase III study (n = 313),
units of the Health Assessment Questionnaire (HAQ), the Adalimumab Effectiveness in Psoriatic Arthritis
a measure of physical function, was noted in the etan- Trial (ADEPT) (48). At 12 weeks, 58% of patients
ercept group, both statistically significant and clinically receiving adalimumab 40 mg every other week achieved
meaningful (44). Improvement in quality of life, as mea- ACR20 response compared with 14% of patients
sured by the Short Form 36 (SF-36) questionnaire, was receiving placebo (p < 0.001). This response rate did
also demonstrated in the treatment group. Inhibition of not differ between patients taking adalimumab in
combination with MTX (50% of patients) and those Other Biologic Agents
taking adalimumab alone, similar to observations made
in the etanercept and infliximab trials. Mean improve- Alefacept
ment in enthesitis and dactylitis was greater for patients Alefacept is a fully human fusion protein that blocks
receiving adalimumab, but this result did not achieve interaction between LFA-3 on the antigen-presenting
statistical significance. PASI 75 was achieved by 59% cell and CD2 on the T cell, or by attracting natural
in the adalimumab-treated group and 1% in the placebo killer lymphocytes to interact with CD2 to yield
group (p < 0.001) in those evaluable for PASI scoring. apoptosis of particular T-cell clones (53). It is approved
Radiographic progression of disease was significantly for treatment of psoriasis (21,54) and is administered
inhibited by adalimumab, as evaluated by x-rays of weekly as a 15 mg intramuscular injection, in an alter-
hands and feet, using a modified Sharp score (48). nating 12 weeks on, 12 weeks off regimen in order to
Mean change in TSS was 0.2 for patients receiving allow return of depleted CD4 cells in the off period. A
adalimumab and 1.0 for patients receiving placebo phase II controlled trial of alefacept in PsA (n = 185)
(p < 0.001). Mean change in HAQ was 0.4 for showed that 54% of patients given a combination of
adalimumab patients and 0.1 for placebo patients alefacept and MTX had an ACR20 response as com-
(p < 0.001). Mean change in the physical component of pared to 23% in the MTX alone group (p < 0.001) at
the SF-36 was 9.3 for the treatment group and 1.4 for week 24. PASI 75 results were 28% and 24%, respec-
the placebo group (p < 0.001). tively (55).
Spine disease was not assessed in these trials, due to
variability of expression of this domain in this patient
group. However, significant efficacy of anti-TNF treat- Efalizumab
ment of axial symptoms and signs has been demon-
Efalizumab is a humanized monoclonal antibody to the
strated in a closely related disease, ankylosing spondylitis
CD11 subunit of LFA-1 on T cells, which inteferes with
(28,36,49). Relative inefficacy of methotrexate, sul-
its coupling with ICAM-1 on antigen-presenting and
fasalazine, and leflunomide has been noted in ankylos-
endothelial cells. It interferes with activation of T lym-
ing spondylitis, suggesting preference for use of the
phocytes and migration of cells to the site of inflamma-
anti-TNF agents in this domain. It is unknown if the
tion. It is administered subcutaneously, once per week
same holds true in PsA, although extrapolation of this
and is approved for use in psoriasis (22). In a 12-week
experience to PsA seems reasonable.
trial of efalizumab in patients with PsA, 28% of patients
In summary, the antiTNF-alpha medications have
achieved an ACR20 response versus 19% in the placebo
shown the greatest efficacy of any treatment to date in
group (p = 0.2717). Because this response was not sta-
the various clinical aspects of PsA. Their efficacy in
tistically significant, it is not recommended for treat-
joint disease activity, inhibition of structural damage,
ment of arthritis (56).
function, and quality of life are similar. There may
be some differentiation in efficacy in the skin and 8
enthesium, but all have excellent effects in these Abatacept
domains. These agents tend to be well tolerated and
patients generally acclimate to their parenteral admin- Abatacept (CTLA4-Ig) is a recombinant human fusion
istration, especially when they experience significant protein that binds to the CD80/86 receptor on an
efficacy. Safety concerns are present, such as risk for antigen-presenting cell, thus blocking the second signal
infection, but no new concerns have arisen in the PsA activation of the CD28 receptor on the T cell. It is
population compared to the more extensively studied administered intravenously once per month and has
RA patient experience (see Chapter 6C). Recent studies been approved for use in RA (57). A phase II trial for
have also demonstrated the cost-effectiveness of anti use in psoriasis has been conducted (58). It is antici-
TNF-alpha therapy in PsA (5052). New antiTNF- pated that this drug will be evaluated in PsA.
alpha agents are being developed for use in PsA,
including cimzia and golimumab, each with advantages
of infrequent subcutaneous administration. Experience
Other Potential Treatments
in management of RA with currently available anti- A pilot trial of anti-interleukin (IL) 15 compound has
TNF agents suggests that when a clinician switches shown efficacy in PsA (59). An IL-1 antagonist, anakinra,
from one of these agents to another, if the first has has not shown significant efficacy (60). A monoclonal
not had or has lost efficacy, or caused side effects, that antibody to the IL-6 receptor (MRA) is in phase III
a substantial percentage of patients will respond to development for the treatment of RA, and will likely
another medication in this class. Anecdotally, a similar be tested in PsA (61). Several inhibitors of IL-12 are
experience has been noted in the management of PsA being evaluated in psoriasis, with good success (62), and
patients. will likely be assessed in PsA.
190 PHILIP J. MEASE
CONCLUSION 7. van der Heijde D, Sharp J, Wassenberg S, et al. Psoriatic

arthritis imaging: a review of scoring methods. Ann
Rheum Dis 2005;64(Suppl 2):ii61ii64.
A number of systemic treatments for PsA, such as 8. Mease P, van der Heidje D. Joint damage in psoriatic
inhibitors of TNF-alpha, have demonstrated significant arthritis: how is it assessed and can it be prevented? Int J
benefit for all disease domains, including inflammation Adv Rheumatol 2006;4:3848.
in the joints, enthesium, and skin, inhibition of joint 9. Mease PJ, Menter MA. Quality-of-life issues in psoriasis
damage as assessed by radiographic progression, and and psoriatic arthritis: outcome measures and therapies
improved quality of life and functional status. Tradi- from a dermatological perspective. J Am Acad Dermatol
tional immune-modulating drugs can beneficially affect 2006;54:685704.
many of these domains as well. Agents that block the 10. Lebwohl M. A clinicians paradigm in the treatment of
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11. Lebwohl M, Ting P, Koo J. Psoriasis treatment: tradi-
tion of the effectiveness of these agents has helped elu-
tional therapy. Ann Rheum Dis 2005;64(Suppl 64):ii83
cidate the pathogenesis of PsA and psoriasis which, in ii86.
turn, may lead to more novel and effective interven- 12. Koo JY. New developments in topical sequential therapy
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Development of targeted therapies has also increased agement of severe plaque form of psoriasis. Am J Clin
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15. Norris DA. Mechanisms of action of topical therapies and
dermatologist or PCP is in an ideal position to educate
the rationale for combination therapy. J Am Acad Der-
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CHAPTER 9
Ankylosing Spondylitis
DSIRE VAN DER HEIJDE, MD, PHD
Ankylosing spondylitis (AS) is the prototypical form of Sacroiliitis, the most common initial feature, causes
seronegative spondyloarthropathies, a group of pain in the buttocks, typically alternating in severity
disorders that involves chronic inflammation of the between the left and right sides.
sacroiliac joints and spine as well as extraspinal When synovitis is present, the hips, knees, ankles,
lesions involving the eye, bowel, and heart. and metatarsophalangeal joints are affected most
The prevalence of AS ranges from 0.1% to 6.0% commonly.
across different populations, with figures for most Acute anterior uveitis, characteristically unilateral, is
populations near the lower end of that range. the typical ocular lesion. Patients present with a red,
Human leukocyte antigen (HLA)-B27 is a strong painful, photophobic eye.
genetic risk factor for AS. However, this gene is A sizable minority (10%15%) of patients with AS
neither necessary nor sufficient to cause the disease. have full-blown inflammatory bowel disease.
The principal musculoskeletal lesions associated Conventional radiographs of the sacroiliac joints are
with AS are sacroiliitis, synovitis, and enthesitis usually the most helpful diagnostic test. In earlier
(inflammation at the site of tendinous insertions cases, findings on magnetic resonance imaging may
into bone). also be diagnostic.
Ankylosing spondylitis (AS) is a chronic inflammatory the United Kingdom and United States, to around 6%
disease of the sacroiliac joints and spine that may be in the Haida Native Americans in Northern Canada.
associated with a variety of extraspinal lesions involving The prevalence generally, but not exclusively, reflects
the eye, bowel, and heart. AS usually begins in young the prevalence of human leukocyte antigen (HLA)-B27
adulthood. The natural history of AS involves progres- in the different populations. Because few population
sive stiffening of the spine, with ankylosis (fusion of some surveys have been undertaken, much of the available
or all spinal joints) occurring after some years of disease data have been drawn from selective hospital-based
in about two thirds of the patients. Patients with long- surveys and from information on other related
standing severe disease are at increased risk of prema- spondyloarthritides.
ture death, but overall the life span of individuals with Ankylosing spondylitis is more common in men, with
AS appears to be normal. AS shares many features with a male : female ratio of approximately 2 : 1. Expression
the arthritides associated with psoriasis, inflammatory of disease may vary slightly between men and women,
bowel disease, and reactive arthritis. Together, these but earlier reports exaggerated this disparity to the
conditions comprise the spondyloarthritis family and are under-estimation of women with AS, many of whom
sometimes termed the seronegative spondyloarthropa- experienced unnecessary delays in diagnosis (2). Some
thies (seronegative because they are not associated investigators have suggested that the true sex ratio is
with rheumatoid factor) (1). Typical spondylitis may be closer to unity if based on population data.
present in each of the other spondyloarthritides.
ETIOLOGY
EPIDEMIOLOGY
In spite of dramatic advances in recent years, the etiol-
The prevalence of AS in different populations varies ogy of AS remains unclear. A strong multigenic inher-
from 0.1% in some African and Eskimo populations, ited component is evident, although HLA-B27 remains
through 0.5% to 1.0% among white populations in the strongest association in almost all populations (3).
193
194 DSIRE VAN DER HEIJDE
Animal and laboratory studies suggest that the HLA- by impaired sleep caused by pain and stiffness. Other
B27 molecule itself plays a key role, and that involve- constitutional features may include fever and weight
ment of class I major histocompatibility complex (MHC) loss. Overt or subclinical depression, accompanied by a
antigens in the presentation of microbial peptides is loss of libido and reduced capacity for work, also may
central to the pathogenic mechanism (4). contribute to lack of well-being.
Infective mechanisms also have been proposed. Spinal discomfort and stiffness typically ascend the
However, aside from the occurrence of spondylitis in spine over a period of years, producing progressive
some patients with another form of spondyloarthropa- spinal pain and restriction. One of the first clinical signs
thyreactive arthritisno clear evidence implicates is the disappearance of the lumbar lordosis. This pro-
infection in the etiology of AS. Klebsiella aeruginosa gression affects the costovertebral joints, reducing
has been implicated on the basis of molecular mimicry respiratory excursion, and the cervical spine, limiting
with HLA-B27 and clinical studies, although its true neck movement. Thoracic spine involvement may be
significance remains unclear. Subclinical mucosal inflam- associated with anterior chest pain and sternal/costal
mation in the large and small bowel undoubtedly is cartilage tenderness, which can be particularly distress-
present in many individuals with AS; this finding could ing for patients. Osteoporosis (which may be prevented
provide the basis for an immune or infective mechanism by appropriate therapy) may lead to vertebral and other
for the spinal disease. fractures later in life (6). Spinal fractures are more
common in patients who have severe involvement with
rigidity. Aseptic spondylodiscitis may occur in patients
CLINICAL FEATURES with AS, especially in the thoracic spine.
The principal musculoskeletal lesions associated with
AS are enthesitis and synovitis, with sacroiliitis also Enthesitis
involving adjacent bone. Inflammatory eye lesions, myo-
The central feature of AS is inflammation at entheses,
cardial changes, gut mucosal lesions, and skin lesions are
the sites where tendons and ligaments attach to bone.
inconsistent but characteristic features of AS.
These inflammatory lesions initially lead to radiographic
appearances of osteopenia or lytic lesions, but subse-
PRESENTING FEATURES quently reactive bone forms a new, more superficial
enthesis, which develops into a radiologically detectable
Spinal features of AS seldom appear before the age of bony overgrowth or spur (7). In the spine, enthesitis
16 to 18 years. Before this age, children and teenagers occurs at capsular and ligamentous attachments and
may develop oligoarthritistypically a swollen knee or discovertebral, costovertebral, and costotransverse
metatarsophalangeal (MTP) jointsometimes associ- joints, with involvement also at bony attachments of
ated with iritis and/or enthesitis (5). Juvenile AS is interspinous and paravertebral ligaments.
remarkable because it does not involve the spine. For Enthesitis accounts for much of the pain, stiffness,
many, symptoms begin early in the third decade of life; and restriction at sacroiliac and other spinal joints. The
the average age at onset is 26 years. Although the phenomenon also occurs at extraspinal sites, producing
disease rarely begins after the age of 40 years, it is not potentially troublesome symptoms. Such lesions most
uncommon for the diagnosis to be made only years commonly affect the plantar fascia and Achilles tendon
later, well after that age. Earlier symptoms often are insertions to the calcaneus, leading to disabling heel
mild, ignored, or not recognized as being part of AS. pain. Plantar fasciitis typically leads to the formation of
The usual presenting symptom is inflammatory back fluffy calcaneal spurs visible on heel radiographs after
pain that is insidious in onset, persistent for more than 6 to 12 months. Similar lesions may occur around the
3 months, worsened by rest and improved by exercise. pelvis, costochondral junctions, tibial tubercles, and
Night pain is a frequent symptom. Sacroiliitis, the most elsewhere, causing marked local tenderness. More
common initial feature, causes pain in the buttocks, widespread diffuse lesions lead to insidious stiffness and
typically alternating between right and left in severity. generalized discomfort. Sternal and costochondral pain
This pain sometimes radiates down the thighs but never also reflect a combination of local enthesitis and referred
below the knee. Although clinical examination is unreli- pain from the thoracic spine. This development fre-
able as a means of diagnosing sacroiliitis, pain in the quently produces chest pain that must be distinguished
buttocks may be elicited in some patients by pushing from myocardial ischemia.
firmly with both hands on the sacrum when the patient
is prone. A minority of patients present with oligoar-
thritis or enthesitis that particularly affects the heel, or
Sacroiliitis
hip pain due to aggressive synovitis. Fatigue, a common Inflammation of the sacroiliac joints develops most fre-
and troublesome symptom, may be caused in large part quently in the late teens or in the third decade of life,
C H A P T E R 9 A N K Y L O S I N G S P O N D Y L I T I S 1 95
producing bilateral or occasionally, unilateral buttock

pain, usually worse after inactivity and sometimes
aggravated by weight bearing. Changes principally
affect the lower anterior (synovial) portion of the sac-
roiliac joints and are associated with juxta-articular
osteopenia and osteitis. This condition leads to radio-
graphic appearances of widening of the sacroiliac
joint. Endochondral ossification as a consequence of
the osteitis gives the radiographic appearance of
erosion along the lower part of the sacroiliac joints.
Osteitis appears as increased water content of adjacent
bone, as seen on magnetic resonance imaging (MRI).
MRI is a valuable imaging modality for assessment
of inflammation in both the sacroiliac joints and the
spine. This can frequently be an important aid in es-
tablishing an early diagnosis. Capsular enthesopathy
also occurs over the anterior and posterior aspect of
the joint throughout its length, leading to sheets of
ossification that ultimately obscure the joint completely FIGURE 9A-1
on standard radiographs, depicted as ankylosis of the Acute anterior uveitis in AS, typically unilateral and associated
sacroiliac joint. with redness, pain, and photophobia.
Synovitis
Peripheral synovitis in AS is distinctive because of by to considerable scarring, irregularity of the pupil, and
the distribution of joints affected rather than because of visual impairment. Red, sore, gritty eyes or blurring of
distinct histological changes. Synovitis is indistinguish- vision in a patient with AS require urgent ophthalmo-
able histologically and immunohistochemically from logic examination.
typical rheumatoid disease. Peripheral joint synovitis
may precede, accompany, or follow the onset of spinal
symptoms. Hips, knees, ankles, and MTP joints are Inflammatory Bowel Disease
affected most commonly. With the exception of the
Sacroiliitis occurs in 6% to 25% of people with Crohns
shoulders, upper limb joints are almost never involved
disease or ulcerative colitis. Patients with Crohns
in AS, particularly in the absence of psoriasis. In further
disease or ulcerative colitis frequently have unilateral
contrast to rheumatoid arthritis, peripheral joint syno-
sacroiliitis, and may also suffer from peripheral arthritis
vitis usually is oligoarticular, often asymmetrical, and
and enthesitis. Similarly, inflammatory bowel disease
frequently episodic rather than persistent. Joint ero-
may be present or develop in people with preexisting
sions, especially at the MTP joints, may lead to sublux-
ation and deformity. Peripheral joint involvement is
AS. Indeed, approximately 60% of people with AS 9
have subclinical changes in the small or large bowel (8).
indistinguishable from that seen in the other spondylo-
There is speculation that these changes may relate to
arthritides. Temporomandibular joints may be affected,
the pathogenesis of AS, but their true significance is
leading to reduced mouth opening and discomfort on
unknown. Even though some AS lesions closely resem-
chewing. Dactylitis may lead to pain in one or more toes
ble those of Crohns disease, the great majority of such
that lasts many months.
lesions never become symptomatic. Only about 10% to
15% of the patients with AS have overt ulcerative colitis
or Crohns disease. The link between AS and inflamma-
Eye Lesions tory bowel disease appears to be indirect, as variations
Acute anterior uveitis (iritis) develops at some time in inflammatory activity of each disease appear to occur
during the course of the disease in approximately one independently. However, in a patient with AS altered
third of patients with AS, and may be recurrent (Figure bowel habits with diarrhea and abdominal discomfort,
9A-1). The typical pattern is alternating, unilateral eye with or without passage of blood or mucus, requires
inflammation associated with pain, redness, lacrimation, investigation.
photophobia, and blurred vision. The occurrence of In a minority of people with colitis and peripheral
uveitis typically does not coincide with flares of arthritis. arthritis, peripheral joint disease may diminish substan-
Untreated or inadequately treated iritis may lead rapidly tially after total colectomy. Conversely, however, many
patients complain of a disorder resembling fibromyalgia IMAGING

that produces mild but widespread discomfort after col-
ectomy. Active inflammatory bowel disease increases Radiographic damage of the spine and axial joints is a
the risk and severity of osteoporosis. Crohns disease key characteristic of patients with AS. By definition, all
with extensive small bowel involvement also may lead patients fulfilling the modified New York criteria show
to impaired vitamin D absorption and osteomalacia, signs of sacroiliitis on radiographs. However, about
producing ill-defined musculoskeletal pain and diffi- 30% of the patients do not develop damage of the spine
culty with walking. visible on radiographs. If patients show no spinal damage
after a certain disease duration (about 10 years), it is
unlikely that the patient will develop radiographic
Cardiovascular Involvement abnormalities of the spine at all. On the other hand,
Cardiac conduction abnormalities and myocardial dys- patients who have spinal damage are prone to develop
function have been recorded in a significant minority more damage.
of people with AS (9). Aortitis with dilatation of the The most widely used imaging technique is conven-
aortic valve ring and aortic regurgitation has been tional radiography. However, MRI and ultrasound are
demonstrated in approximately 1% of patients. The being used more frequently. Characteristic features on
risk of occurrence of aortic insufficiency and cardiac radiographs of the sacroiliac joints are pseudowidening
conduction abnormalities increase with age, disease of the joint space, sclerosis, erosions, and ankylosis
duration, presence of HLA-B27, and peripheral joint (Figure 9A-2). At late stages, there is complete ankylo-
involvement. sis of the joint. The sacroiliac joint has a complicated,
irregular anatomy; computed tomography (CT), which
provides views through slices of the joint space, can be
Pulmonary Involvement helpful when the presence of sacroiliitis is in question.
Many AS-related changes can be seen in the spine;
Approximately 1% of patients develop progressive
squaring of the vertebrae, sclerosis, erosions, syndesmo-
upper lobe fibrosis of the lungs (10). Rigidity of the
phytes, bony bridging, and spondylodiscitis are the most
chest wall results in the inability to extend the
relevant (Figures 9A-3 and 9A-4).
chest fully and to mild restrictive lung function im-
Syndesmophytes are characterized by axial growth
pairment, but rarely leads to ventilation insufficiency
that may lead to bridging phenomena. For making a
due to the compensation by increased diaphragmatic
diagnosis, conventional radiography is still the preferred
contribution.
option. However, if the radiographs are persistently
normal in the setting of high disease suspicion, MRI of
Neurologic Lesions the sacroiliac joints and spine can add information. In
contrast to conventional radiographs, MRI has the
Neurologic deficits are associated most often with cord potential to demonstrate inflammation, not merely
or root lesions following spinal fracture. Nerve root the end results of inflammation on bone. Among MRI
pain may arise from the cervical spine, especially when
there is marked flexion deformity. Long-tract signs,
including quadriplegia, may follow spinal fracture dis-
location after relatively minor trauma and complicate
spontaneous atlantoaxial subluxation. Subluxation also
may lead to severe occipital headache. Weakness of the
legs occasionally occurs in association with a cauda
equina syndrome. This syndrome is particularly associ-
ated with the development of dural ectasia demonstra-
ble on MRI.
Skin Involvement
In various series, between 10% and 25% of the patients
with typical AS have concomitant psoriasis lesions.
FIGURE 9A-2
Renal Consequences
Anteroposterior radiographs of the pelvis showing complete
Although rarely seen today, secondary amyloidosis ankylosis of both sacroiliac joints and syndesmophyte formation
caused by longstanding AS is well described. in the lower lumbar vertebrae.
FIGURE 9A-3 FIGURE 9A-5
Radiograph of the lateral cervical spine, demonstrating the Short tau inversion recovery (STIR) image of the sacroiliac joints
formation of extensive bridging syndesmophytes that involve revealing extensive inflammation (white) involving both the
almost the entire cervical spine. sacral and iliac sides of the joints bilaterally.
techniques for delineating inflammation, the short tau

inversion recovery (STIR) technique is preferred (Figure
9A-5). MRI is also useful in visualizing enthesitis, for
MAKING THE DIAGNOSIS
example, of the heel or Achilles tendon insertion.
As in many other diseases in which the etiology is not
clearly defined (e.g., by the isolation of a specific caus-
ative pathogen), the diagnosis of AS must rest on the
combination of clinical features, radiological findings,
and laboratory results. There are no established diag-
nostic criteria for AS. On the other hand, classification
criteria, used for the purpose of categorizing patients in
research studies, are available. The most widely used
classification criteria for AS are the modified New York
criteria (Table 9A-1) (11). Although the New York
criteria are useful in established disease, their heavy
reliance on the demonstration of radiographic sacroili-
itis diminishes their applicability in patients with early
disease. 9
TABLE 9A-1. MODIFIED NEW YORK CRITERIA FOR

ANKYLOSING SPONDYLITIS.
Criteria
1. Low back pain for at least 3 months duration improved by

exercise and not relieved by rest.
2. Limitation of lumbar spine motion in sagittal and frontal
planes.
3. Chest expansion decreased relative to normal values for age
and sex.
4a. Unilateral sacroiliitis grade 34.
4b. Bilateral sacroiliitis grade 24.
Definite ankylosing spondylitis if (4a OR 4b) AND any clinical

FIGURE 9A-4 criterion (13)
Radiograph of the lateral lumbar spine with squaring of L1 and SOURCE: From Van der Linden et al., Arthritis Rheum 1984;27:361368, with
syndesmophyte formation from L3 to L5. permission of Arthritis and Rheumatism.
Classification criteria for spondyloarthritis, although TABLE 9A-3. THE EUROPEAN

clearly not intended for diagnostic purposes, are used SPONDYLARTHROPATHY STUDY GROUP CRITERIA.
frequently in clinical practice aids to the identification
Inflammatory spinal pain
of atypical or undifferentiated cases. Amors criteria
(Table 9A-2) (12) and the European Spondyloarthropa- OR
thy Study Group criteria (Table 9A-3) (13) are often Synovitis (asymmetric, predominantly in lower extremities)
employed in this manner. Ongoing studies are designed
to evaluate the use of classification criteria for the AND one or more of the following:
purpose of diagnosis when applied to patients at early Family history: first- or second-degree relatives with ankylos-
ing spondylitis, psoriasis, acute iritis, reactive arthritis, or
stages of disease. inflammatory bowel disease
The optimal role of HLA-B27 in establishing the Past or present psoriasis, diagnosed by a physician
diagnosis of AS remains under investigation. For Past or present ulcerative colitis or Crohns disease, diag-
many years, HLA-B27 was not recommended for nosed by a physician and confirmed by radiography or
use as a diagnostic test. In certain clinical situations, endoscopy
Past or present pain alternating between the two buttocks
Past or present spontaneous pain or tenderness at examina-
tion of the site of the insertionthe Achilles tendon or
TABLE 9A-2. AMORS CLASSIFICATION CRITERIA FOR plantar fascia (enthesitis)
SPONDYLOARTHRITIS. Episode of diarrhea occurring within 1 month before onset of
arthritis
A CLINICAL SYMPTOMS OR HISTORY OF SCORING
Nongonococcal urethritis or cervicitis occurring within 1
month before onset of arthritis
1 Lumbar or dorsal pain at night or morning 1
Bilateral grade 24 sacroiliitis or unilateral grade 3 or 4
stiffness of lumbar or dorsal pain
sacroiliitis [grades are 0, normal, 1, possible, 2, minimal, 3,
2 Asymmetrical oligoarthritis 2 moderate, 4, completely fused (ankylosed)]
3 Buttock pain 1 SOURCE: From Dougados M et al., Arthritis Rheum 1991;34:12181230, by

If alternate buttock pain 2 permission of Arthritis and Rheumatism and Wiley Periodicals, Inc.
4 Sausagelike toe or digit 2
5 Heel pain or other well-defined enthesopathy 2 however, when moderate to high suspicion of spondy-
loarthritis exists, HLA-B27 testing may play an im-
6 Iritis 1
portant role (14). At present, only radiographic
7 Nongonococcal urethritis or cervicitis within 1 1 sacroiliitis is included in the various criteria sets.
month before the onset of arthritis However, MRI studies confirming the presence of
8 Acute diarrhea within 1 month before the 1 inflammation even before the occurrence of radio-
onset of arthritis graphically evident joint damage may contribute to
earlier diagnosis.
9 Psoriasis, balanitis, or inflammatory bowel 2
disease (ulcerative colitis or Crohns disease)
B RADIOLOGICAL FINDINGS REFERENCES

10 Sacroiliitis (bilateral grade 2 or unilateral 3
1. Khan MA. An overview of clinical spectrum and hetero-
grade 3)
geneity of spondyloarthropathies. Rheum Dis Clin N Am
C GENETIC BACKGROUND 1992;18:110.
2. Kidd B, Mullee M, Frank A, et al. Disease expression of
11 Presence of HLA-B27 and/or family history of 2 ankylosing spondylitis in males and females. J Rheumatol
ankylosing spondylitis, reactive arthritis, 1988;15:14071409.
uveitis, psoriasis, or inflammatory bowel 3. Wordsworth P. Genes in the spondyloarthropathies.
disease
Rheum Dis Clin North Am 1998;24:845863.
D RESPONSE TO TREATMENT 4. Gonzalez S, Martina-Barra J, Lopez-Larrea C. lmnumo-
genetics. HLA-B27 and spondyloarthropathies. Curr
12 Clear-cut improvement within 48 hours after 2 Opin Rheumatol 1999;11:257264.
NSAIDs intake or rapid relapse of the pain 5. Burgos-Vargas R, Vasquez-Mellado J. The early recogni-
after their discontinuation tion of juvuenile onset ankylosing spondylitis and its dif-
ferentiation from juvenile rheumatoid arthritis. Arthritis
SOURCE: From Amor B et al., Rev Rheum Mal Ostoart 1990;57:8589, by Rheum 1995;38:835844.
permission of Revue du rheumatisme et des maladies osto-articulaires.
ABBREVIATIONS: NSAIDs, nonsteroidal anti-inflammatory drugs.
6. Will R, Palmer R, Bhalla A, et al. Osteoporosis in early
A patient is considered as suffering from a spondylarthropathy if the sum ankylosing spondylitis: a primary pathological event?
is 6. Lancet 1989;2:14831485.
7. Vernon-Roberts B. Ankylosing spondylitis; pathology. In: posal for modification of the New York criteria. Arthritis
Klippel JH, Dieppe PA, eds. Rheumatology. 2nd ed. Rheum 1984;27:361368.
London: Mosby; 1998:6.18.16.18.6. 12. Amor B, Dougados M, Mijiyawa M. Critres de classifica-
8. Leirisalo-Repo M, Repo H. Gut and spondyloarthrop- tion des spondylarthropathies. Rev Rhum Mal Ostoart
athies. Rheum Dis Clin North Am 1992;18:2335. 1990;57:8589.
9. ONeill TW, Bresnihan B. The heart in ankylosing spon- 13. Dougados M, Van der Linden S, Juhlin R, et al. The
dylitis. Ann Rheum Dis 1992;51:705706. European Spondylarthropathy Study Group preliminary
10. Rosenow E, Strimlan CV, Muhm JR, et al. Pleuropulmo- criteria for the classification of spondyloarthropathy.
nary manifestations of ankylosing spondylitis. Mayo Clin Arthritis Rheum 1991;34:12181230.
Proc 1977;52:641649. 14. Rudwaleit M, van der Heijde D, Kahn A, et al. How to
11. Van der Linden SM, Valkenburg HA, Cats A. Evaluation diagnose axial spondyloarthritis early? Ann Rheum Dis
of diagnostic criteria for ankylosing spondylitis: a pro- 2004;63:535543.
9
CHAPTER 9
JUERGEN BRAUN, MD
Human leukocyte antigen (HLA)-B27 is the major spondyloarthritides. In contrast, only 5% to 15% of
genetic risk factor for ankylosing spondylitis (AS), the general population is HLA-B27 positive.
reactive arthritis, psoriatic arthritis, spondyloarthropa- The contribution of HLA-B27 to AS susceptibility is
thy associated with inflammatory bowel disease, and estimated to be 30%.
isolated acute anterior uveitis. Fewer than 5% of HLA-B27positive individuals
These diseases are linked by the frequency of develop SpA.
inflammation involving the entheses (the sites where Among the HLA class B molecules that determine the
tendons and ligaments join to bones) and the axial antigen binding cleft, HLA-B27 has a unique B pocket
skeleton, and the common finding of micro- or that likely influences the peptide repertoire.
macroscopic gut inflammation, even in patients The subtypes of HLA-B27, of which there are more
without overt gastrointestinal symptoms. than 30, differ in part only by single amino acids.
HLA-B27 transgenic rats develop a Only a few HLA-B27 subtypes are associated with AS.
spondyloarthropathy. Intracellular misfolding of HLA-B27 may lead to aber-
HLA-B27 is present in >90% of patients with AS, as rant expression of B27 homodimers on the cell surface,
well as 50% to 75% of patients with other forms of with possible influences on antigen presentation.
Ankylosing spondylitis (AS) and other spondyloar- SpA. The following points are explored in further detail
thritides (SpA) are characterized by inflammation and in this chapter:
new bone formation in the axial skeleton and entheses.
Peripheral joints and other organs, such as the eye, skin, 1. Among the HLA class B molecules that determine
heart, and gut, may also be involved. Details of the the antigen binding cleft, HLA-B27 has a unique B
pathogenesis of AS and other SpA remain unresolved, pocket that likely influences the peptide repertoire.
but much has been learned in the three decades since 2. There are more than 30 subtypes of HLA-B27, which
the discovery of HLA-B27, a major histocompatibility differ in part only by single amino acids. Only a few
complex (MHC) class I allele that is the major genetic HLA-B27 subtypes are associated with AS.
factor in these interrelated diseases. HLA-B27 is present 3. Intracellular misfolding of HLA-B27 may lead to
not only in most patients with AS, but also in many with aberrant expression of B27 homodimers on the
other forms of SpA: reactive arthritis (ReA), psoriatic cell surface, with possible influences on antigen
SpA, inflammatory bowel disease (IBD)associated presentation.
SpA, and isolated acute anterior uveitis. 4. HLA-B27 itself can be presented by HLA class II as
Some important considerations related to the origin of an autoantigen, and could be recognized by CD4+ T
AS and related diseases stem from clinical observations. cells.
First, the entheses and the axial skeleton are affected 5. HLA-B27 transgenic rats develop an SpA-like
much more strongly in patients with SpA than in other disease.
rheumatic diseases. Second, microscopic and macro- 6. Data suggest that intracellular handling of microbes
scopic gut inflammation are more frequent in patients by HLA-B27 transfected cell lines is altered.
with SpA than in other rheumatic diseases (1). The gas-
trointestinal immune response to pathogens and even Both genetic and nongenetic factors contribute to
normal flora may play a role in causing these disorders. AS. In addition to HLA-B27 and other MHC-related
Several interesting features of the HLA-B27 mole- genetic factors, current hypotheses implicate both innate
cule itself may contribute to disease pathogenesis in the and adaptive immune responses. Chlamydia, Yersinia,
200
Salmonella, and other species contribute directly to the of patients with AS, as well as 50% to 75% of patients
etiology of ReA, for example, and autoantigens such as with other forms of SpA. In contrast, only 5% to 15%
the G1 domain of aggrecan have been linked to AS. of the general population is HLA-B27 positive, with
variations based on ancestry. The overall contribution
of HLA-B27 to AS susceptibility is estimated to be
Human Leukocyte Antigen-B27 30%, but the gene is neither necessary nor sufficient to
cause the disease. Fewer than 5% of HLA-B27positive
The discovery of the link between HLA-B27 and AS individuals develop SpA, but the individual risk is higher
was a major contribution to understanding the patho- in the setting of a positive family history of SpA (Figure
genesis of this disease (2). HLA-B27 is present in >90% 9B-1) (3). The dominant effect of HLA-B27 in AS
FIGURE 9B-1
Unique intracellular and extracellular functions of HLA-B27 that may affect susceptibility to
spondyloarthritis. (a) The HLA-B27 heavy chain is transcribed off ribosomes in macrophages, and
retained in the endoplasmic reticulum (ER) by the molecular chaperone calnexin and ERp57. The
latter is a protein disulfide isomerase that reduces and oxidizes disulfide bonds. HLA-B27 is then
folded into its tertiary structure and bound to beta-2-microglobulin. Calnexin releases the
complex, which becomes associated with calreticulum, which in turn chaperones the formation
of the peptide loading onto the complex of heavy chain, beta-2-microglobulin and antigenic
peptide, via the TAP proteins and tapasin. Thence the trimolecular peptide complex (HLA-B27
heavy chain, beta-2-microglobulin, and peptide) travels to the cell surface, where the antigenic
peptide is presented either to CD8+ T lymphocytes or to natural killer (NK) cells. (b) The HLA-B27
heavy chain misfolds in the endoplasmic reticulum, forming B27 homodimers and other
misfoldings, where they either (b1) accumulate causing an proinflammatory ER stress response;
or (b2) migrate to the cell surface, where they become antigenic themselves or present peptide
to receptors on other inflammatory cells. (c) Intracellular impairment of peptide processing or
loading into HLA-B27 by viruses or intracellular bacteria causes a selective impairment of the
immune response. (d) Either the trimolecular complex presents processed peptide to CD4+ T
lymphocytes, or free HLA-B27 heavy chains or HLA-B27 homodimers are recognized as antigenic
by the T-cell receptor thence, or processed antigenic fragments of HLA-B27 are presented to the
T-cell receptor of CD4positive T lymphocytes.
CD4 Positive
T Iymphocyte
CD8 Positive Natural Killer
T Iymphocyte (NK) Cell
ab d
T cell receptor
KIR Receptor
b2 9
HLA-class II
free B27 HLA-B27 homodimers
(DR, DQ, DP)
heavy chain at cell surface
HLA-B27: B2 microglobulin: presenting
a1 peptide trimolecular complex HLA-B27
peptide a2
Golgi
Endoplasmic Reticulum
ER stress
B27 misfolding, response
b c HLA-B27: B2M: peptide trimolecular
homodimerization b1 complex transported to the cell
surface via the Golgi apparatus
Tapasin
B27 folding, assembly and loading of peptide
B27 heavy chain (HC) ERp57 B2 microglobuin
HC
B27 HC folding (B2m) loading peptide loading Macrophage
ribosome calreticulum
a calnexin B1P B2m
TAP 1,2
viral, bacterial proteolytic degradation
or tumor protein within proteasome peptide fragments
202 JUERGEN BRAUN
makes this disease rather unique among rheumatic con- TABLE 9B-1. OVERVIEW OF THE FOUR MAIN
ditions. It is clear, however, that other genes also con- THEORIES ON THE PATHOGENESIS OF
tribute to the risk of AS. SPONDYLOARTHRITIDES RELATED TO HLA-B27.
Human leukocyte antigen-B27 is an MHC class I The Arthritogenic Peptide Hypothesis
molecule and, as such, participates in antigen presenta- HLA-B27 binds a unique set of antigenic peptides, bacterial or
tion. HLA-B27 binds an accessory moleculebeta-2 self, which gives rise to an HLA-B27restricted cytotoxic T-cell
microglobulinthat helps the heavy chain maintain its response to such peptides which are presented by disease-
associated HLA-B27 subtypes but not by other HLA class I
proper conformation. Genetic evidence from humans
molecules.
and data from animal models suggest that HLA-B27 has
one or more unique characteristics that can promote Self-Association of the HLA-B27 Molecule
inflammation. Among individuals with HLA-B27, the A unique property of HLA-B27 is that its heavy chains can form
homodimers in vitro that are dependent on disulfide binding
protein is expressed ubiquitously but most abundantly
through their cysteine-67 residues in the alpha-1 domain.
on antigen-presenting cells such as macrophages and These homodimers occur as a result of B27 misfolding within
dendritic cells (DC). HLA-B27 expression is upregu- the endoplasmic reticulum. The accumulation of misfolded
lated by proinflammatory stimuli. The peptides dis- protein may result in a proinflammatory intracellular stress
played by HLA-B27 and related MHC class I molecules response. Alternatively, B27 homodimers can migrate to the
cell surface where they either become antigenic themselves or
are normally derived from self-proteins, but when cells
present peptide to other inflammatory cells.
are infected with microbes such as viruses or other intra-
cellular pathogens, foreign peptides are presented. Alteration of Intracellular Handling of Microbes Due to
Peptide-loaded MHC class I molecules are recog- HLA-B27
HLA-B27 leads to a less effective elimination of microbes, such
nized by receptors on several different types of immune as salmonella, in conjunction with an upregulated production
cells. T-cell receptors (TCRs) on cytotoxic CD8+ T cells of cytokines.
recognize MHC class I complexes. The ability of TCRs
on CD8+ T cells to recognize MHC class I molecules Recognition of HLA-B27 as an Autoantigen
HLA-B27 itself can be recognized by CD4+ T cells, when
and distinguish different alleles or different peptides presented by HLA class II (DR, DQ, and DP) heterodimers as
displayed by the same allele (e.g., viral vs. self-peptide) an autoantigen. This was also part of the classic molecular
plays a critical role in the adaptive immune response to mimicry hypothesis, wherein homology of peptides from the
viruses. HLA-B27 molecule shared striking sequence homology with
Hypotheses about the role of HLA-B27 in AS can those from bacterial sources.
be considered in terms of two distinct paradigms: one
invokes immunological recognition of HLA-B27
expressed on the cell surface, either as classic trimo-
lecular complexes of heavy chain/peptide/beta-2 micro- of HLA-B27 are the main causes of the chronic inflam-
globulin, or beta-2-microglobulin free forms of the mation. HLA-B27-restricted CD8+ T-cell clones with
heavy chain that exist as dimers or perhaps monomers. specificity for bacteria or possibly self-peptides have
The other paradigm posits that intracellular effects of been detected in both the synovial fluid and peripheral
HLA-B27 are responsible for influences on bacterial blood of patients with ReA and AS. With regard to
killing, either due to HLA-B27 misfolding (4) or some ReA, several HLA-B27binding Yersinia- and Chla-
other as yet unrecognized consequence of its expres- mydia-derived peptides have been identified in synovial
sion (Table 9B-1). Potential links to pathogenesis from fluid that may account for the CD8+ T-cell response.
misfolding include endoplasmic reticulum (ER) stress Whether these immune responses are beneficial or det-
and activation of the unfolded protein response, while rimental to the patient remains unclear. Autoreactive
enhanced bacterial survival may lead to persistent self-peptides that might be targeted by these T cells
infection. These concepts also differ in terms of whether have not been defined.
the fundamental abnormality is one of adaptive (arthri- Indirect evidence that antigens might be driving the
togenic peptides) or innate immunity (immune recep- inflammation comes from analyses of the TCR beta
tor recognition, misfolding, altered bacterial survival). chain (TCRB) repertoire using TCRB CDR3 size spec-
tratyping: HLA-B27+ twin pairs who were concordant
for AS exhibited increased T-cell oligoclonality in both
Arthritogenic Peptides CD8+ and CD4+ T-cell subsets, suggesting a role for
The basis for this concept is essentially that of molecular conventional T-cell antigens in AS pathogenesis.
mimicry; that is, self-peptides displayed by folded HLA- Although triggering bacterial infections have as yet
B27 heavy chain/beta-2 microglobulin complexes are not been identified in AS, several HLA-B27binding
targeted by autoreactive CD8+ T cells because they candidate peptides have been studied. The peptide
resemble microbial peptides (5). In this model, the cyto- LRRYLENGK, for example, known to be part of both
toxic T cells and the unique peptide binding specificity the HLA-B27 heavy chain and proteins from entero-
bacteriae, was recognized more often by HLA-B27 binding of the heavy chain to the ER chaperone BiP.
restricted CD8+ T cells from AS patients compared to Misfolding has not been seen in other MHC class I
controls. alleles. HLA-B27 misfolding and cell surface dimeriza-
tion are distinct processes.
The tendency of HLA-B27 to misfold is a conse-
Aberrant Cell Surface Heavy Chains quence of residues that comprise the B pocket of the
Human leukocyte antigen-B27 heavy chains exist in peptide-binding groove. The B pocket renders HLA-
aberrant forms on the cell surface. Purified HLA-B27 B27 inefficient at loading peptides because of resistance
molecules can refold in vitro without beta-2 microglob- to the peptide-induced conformational change that pro-
ulin, for which the formation of disulfide-linked dimers motes folding. Prolonged retention of the HLA-B27
through the unpaired Cys 67 residue (Cys67) is func- heavy chain in the ER in an unfolded conformation
tional. Such dimers form when cell surface heavy chains results in aberrant disulfide bond formation, with possi-
lose beta-2 microglobulin and undergo endosomal recy- ble involvement of the unpaired Cys at position 67
cling. Furthermore, relatively stable monomeric HLA- (Cys67). Aberrant disulfide bond formation may contrib-
B27 heavy chains exist on the cell surface (6). Thus, ute to the accumulation of heavy chains bound to BiP.
MHC class I receptors on leukocytes might recognize The amino acid residue in HLA-B27 most detrimental
aberrant forms of HLA-B27 in a specific manner, to efficient folding, not surprisingly, is Glu45 in the B
leading to modification of leukocyte function. The pocket. Some proteins that misfold are not eliminated
extent to which other alleles form cell surface dimers is efficiently and may lead to stress in the ER by activating
less clear. a process known as the unfolded protein response.
Enhanced Bacterial Survival Human Leukocyte Antigen-B27:

The strong relationship between HLA-B27 and ReA A Causative Factor for Disease in
leads to the question of whether HLA-B27 might influ- Animal Models
ence the invasion and the handling of intracellular bac-
The immunologic function of HLA-B27 is to bind pep-
teria. Enhanced survival of intracellular Salmonella has
tides derived from proteins degraded in the cytosol and
been reported in monocytic cells and fibroblasts that
display them on the cell surface, where they can be
express HLA-B27 after DNA transfection. The effect
recognized by CD8+ T cells. In transgenic animal
of HLA-B27 seems to depend on the Glu45 residue,
models, HLA-B27 and human beta-2-microglobulin
which may be a major determinant of HLA-B27 mis-
were expressed in mice without producing inflamma-
folding. Data on this point are not conclusive, however,
tory joint disease. In other HLA-B27 transgenic mice
as other experiments have failed to demonstrate an
models, a higher frequency of ankylosing enthesopathy
effect of HLA-B27 expression on synoviocytes on the
was reported, but this phenotype occurs also in wild-
clearance of Salmonella.
type mice.
The strongest experimental evidence that HLA-B27
Protein Misfolding and Endoplasmic plays a direct role in disease pathophysiology comes
Reticulum Stress from transgenic rats, where overexpression of HLA- 9
B27 and human beta-2-microglobulin results in sponta-
Evidence of abnormalities in HLA-B27 folding was first neous inflammation in the gastrointestinal tract and
reported a few years ago. HLA-B27 heavy chains, even joints (7). The skin and nail lesions in this transgenic rat
those expressed under normal physiologic conditions, model resemble those seen in psoriasis HLA-B27/
were described as undergoing ER-associated degrada- human beta-2-microglobulin transgenic (B27-Tg) rats,
tion (ERAD) shortly after synthesis. ERAD is a quality which develop colitis initially and subsequently mani-
control pathway that cells use to dispose of proteins that fest inflammation in other locations. Expression of the
do not fold efficiently. Abnormally folded HLA-B27 disease phenotype depends on the specific genetic back-
complexes have been found in the ER, with abnormali- ground of the rat. When raised under entirely germ-free
ties relating to aberrant inter- and intrachain disulfide conditions, B27-Tg rats do not develop disease. Coloni-
bonds. zation of the gastrointestinal tract with normal gut flora,
In normal cells, the dimers that form in the ER do however (e.g., Bacteroides sp.), is sufficient to trigger
not contribute to the cell surface population. About inflammation. B27-Tg rats do not provide a precise phe-
25% of newly synthesized HLA-B27 heavy chains form nocopy of human AS because they do not develop
disulfide-linked complexes in the ER, whereas only ankylosis of the axial skeleton. Further, the colitis
about 6% become disulfide-linked on the cell surface. observed in the B27-Tg rats is more prominent than that
Another critical feature of misfolding is prolonged which occurs in human AS patients.
204 JUERGEN BRAUN
THE ROLE OF MICROBES AND B27 SPECIFIC

LYSINE B2701
THE GUT B pocker
Several gastrointestinal or genitourinary pathogens have B2703 B2702

B2717
been implicated as triggers of HLA-B27associated 45
B2708
ReA in humans, including Campylobacter, Chlamydia,
Salmonella, and Shigella. DNA from these organisms
B2712
can be detected by polymerase chain reaction (PCR) in 70 74 77 80 82
59 81
synovial samples, and the lipopolysaccharide (LPS) of 83
97 B2704
Salmonella, Yersinia, and Shigella has also been found. 116 B2715
The presence of bacterial products in joints provides a 114
potential link between gut infection and joint inflamma- 113 B2706
152 B2721
tion in ReA (1). More than two thirds of patients with 172
B2728
SpA have microscopic lesions of the gut: polymorpho- 163 B2709
N
nuclear infiltration of ileal villi and crypts, and granulo-
cytes, lymphocytes, and plasma cells in the lamina B2707, 2711, 2720, 2724
131
B2710
propria. Patients who develop overt inflammatory bowel
disease are more likely to have symptoms of active AS, FIGURE 9B-2
and SpA patients with gut inflammation have a higher
risk of developing AS. The crystallized HLA-B27 molecule, indicating positions of amino
acid substitutions in selected HLA-B27 subtypes.
In juvenile AS patients without gastrointestinal
symptoms, radionuclide labeling of lymphocytes indi-
cate homing to the gut in almost half of the patients. marily in Sardinia and regions of mainland Italy,
Positive scans are in patients with active joint disease -B*2706 is common in native Indonesians. Although
and correlate with nonspecific mucosal inflammatory neither -B*2709 nor -B*2706 appears to be associated
changes on biopsy. Thus, subclinical gut inflammation with AS, B*2709 has been reported in patients with
may be important in disease pathogenesis. In this regard, undifferentiated forms of SpA (uSpA).
CD163+ macrophages are overrepresented in the gut Variations in the clinical phenotype associated with
mucosa of patients with SpA and Crohns disease, but HLA-B27 subtypes likely relate to amino acid differ-
not ulcerative colitis. These findings have underscored ences in the B pocket of the antigen binding cleft, which
the close relationship between gut inflammation and could alter the nature of the peptides presented by these
arthritis in the SpA. HLA-B27 subtypes. The only xdifference between these
subtypes and the major AS-associated subtypes is the
exchange at position 116 of an aspartate for a histidine
Human Leukocyte Antigen-B27 residue. Position 116, located within the peptide binding
SUBTYPES groove at the floor of the F pocket, plays a pivotal role
in anchoring the C-terminal peptide residue. Other sub-
Human leukocyte antigen-B27 constitutes the greatest types of HLA-B27 are too rare to have had their clinical
known risk factor for AS. However, HLA-B27 is not associations established, but cases of AS have occurred
just one molecule: more than 30 different subtypes have in carriers of -B*2701, *2703, *2704, *2707, *2708, *2710,
now been described (http://www.ebi.ac.uk/imgt/hla/). *2714, *2715, and *2719.
Most of these subtypes only differ by a few amino acids, Until recently, the only known differences between
but these differences may be sufficient to alter the these subtypes was their peptide binding specificity,
peptide binding properties of the molecule. which has been used to support the concept that disease
Human leukocyte antigen-B*2705, found in all popu- pathogenesis is a consequence of peptide display differ-
lations, appears to be the original or parent HLA-B27 ences. For the VIP1R400408 peptide, this is clearly not
molecule. Most of the other subtypes have probably the case because it is presented by both -B*2705 and
evolved from three pathways, defined by the pattern of -B*2709. However, there are interesting differences
amino acid substitutions in the first (alpha-1) and second between -B*2706 and other disease-associated alleles.
(alpha-2) domains (Figures 9B-2 and 9B-3). The finding Comparing -B*2704, -B*2705, -B*2706, and -B*2709,
of particular HLA-B27 subtypes in populations tends to -B*2706 is the only subtype that does not interact appre-
have strong geographic patterns. The most common ciably with the peptide loading complex (8). The -
subtypesHLA-B*2705, -B*2702, -B*2704, -B*2707 B*2706 heavy chain also folds faster than other sub-
are clearly associated with SpA. types. This raises the possibility that the -B*2706 heavy
The HLA-B27 subtypes are distributed unevenly chain might show a diminished capacity to misfold and
around the world. Whereas HLA-B*2709 is found pri- cause ER stress because mutations that enhance the
a1 a2 Group
B*2713 0 0 Caucasian
HLA-B*2705
a1 a2 Group
B*2718 9 0 Asian
a1 a2 Group a1 a2 Group a1 a2 Group

B*2703 1 0 African B*2704 1 1 Asian B*2709 0 1 Caucasian
B*2717 1 0 Unknown B*2715 1 2 Asian B*2710 0 1 Caucasian
B*2701 3 0 Cauc/Afr B*2706 1 3 Asian B*2728 0 2 Unknown
B*2702 3 0 Caucasian B*2725 1 3 Asian B*2727 0 3 Unknown
B*2716 3 0 Caucasian B*2721 1 4 Unknown B*2714 0 3 Caucasian
B*2708 4 0 Caucasian B*2711 1 5 Asian B*2719 0 3 Middle East
B*2726 4 0 African B*2720 1 5 Asian B*2707 0 5 South Asia
B*2712 7 0 Caucasian B*2724 1 7 Asian
B*2723 7 0 Caucasian
FIGURE 9B-3
Possible evolutionary pathway of HLA-B27 subtypes from the parent HLA-B*2705. The three
major families of HLA-B27 subtypes are denoted in relationship to the parent subtype HLA-
B*2705 (HLA-B*2713 and B*2718 are assumed to have evolved separately). The numbers of amino
acid substitutions from B*2705 in the first (alpha-1) and second (alpha-2) domains are indicated,
as well as the predominant ethnic group in which the subtype was described. For example, HLA-
B*2704 differs from HLA-B27 by one amino acid substitution in the alpha-1 and one amino acid
substitution in the alpha-2 domain. Of note, at the time of this writing, we are unable to find the
sequences of four HLA-B27 subtypes that have been described only in the past few months
(B*2729B*2732).
rate of -B*2705 folding reduce misfolding. If this is NONMAJOR

responsible for the lack of association with disease, then
another explanation would be necessary for -B*2709. HISTOCOMPATIBILITY COMPLEX
GENES AND ANKYLOSING
OTHER MAJOR SPONDYLITIS SUSCEPTIBILITY
HISTOCOMPATIBILITY COMPLEX
GENES AND ANKYLOSING The strength of the association of B27 and of the linkage 9
of the MHC with AS has obscured the role of other
SPONDYLITIS SUSCEPTIBILITY genetic factors for decades. The concordance rate for
B27-positive dizygotic (DZ) twin pairs (23%), consider-
Human leukocyte antigen-B27 constitutes only part of ably lower than that of monozygotic (MZ) twin pairs
the overall risk for SpA. Fewer than 5% of HLA-B27 (63%), points clearly to the presence of non-B27 sus-
positive individuals in the general population develop an ceptibility factors (9).
SpA. In contrast, up to 20% of HLA-B27positive rela- The total number of genes involved in susceptibility
tives of AS patients will develop an SpA in time. Family to AS is unknown, but family recurrence risk modeling
studies have shown that HLA-B27 contributes less than suggests that the number is limited. The reduction of
40% of the overall genetic risk for SpA. The entire effect disease concordance with distant relatives of patients is
of the MHC, on the other hand, is about 50%. determined by the number and the interactions of the
Identifying other MHC genes that may be involved involved genes. In AS, an oligogenic model appears to
in AS susceptibility is generally complicated because of be operative, with multiplicative interactions between
the tight linkage disequilibrium found within the MHC. loci.
However, there is some evidence from studies of indi- Non-major histocompatibility complex genetic effects
vidual MHC genes that other non-B27 MHC genetic appear to also have significant influence on disease
effects are present in patients with AS. These genes are severity, as demonstrated by a complex segregation
listed in Table 9B-2. study (10). A high degree of familiality was observed
206 JUERGEN BRAUN
TABLE 9B-2. GENES POSSIBLY INVOLVED IN THE 1RA), along with six other homologous genes named
PATHOGENESIS OF ANKYLOSING SPONDYLITIS. IL-1F510. These cytokines, all strong candidates for
involvement in inflammatory diseases, lie directly below
Major histocompatibility complex (MHC)
HLA-B27 the 2q peak found in AS linkage studies. The agreement
HLA-B60 of some large studies implicates IL-1A/B variants
HLA-B38,-B39 strongly in the etiology of AS, but key variants remain
MICA to be identified. Observational studies of IL-1 inhibition
MHC class II alleles including HLA-DRB1*01 and DRB1*04
with anakinra in patients with AS have shown conflict-
TAP alleles
Low molecular weight proteosome (LMP) -2 and -7 ing results. Based on the results of genetic studies to
Tumor necrosis factor (TNF) alpha (TNF-308 polymorphism) date, however, rigorous investigations of this therapy in
AS would seem appropriate.
Nonmajor histocompatibility complex
Interleukin 1 complex
Interleukin 6
Interleukin 10
HISTOPATHOLOGY IN
Transforming growth factor (TGF) beta ANKYLOSING SPONDYLITIS
Alpha/beta T-cell receptor (TCR)
Cytochrome P450 gene debrisoquine 4-hydroxylase (CYP2D6)
The most common sites of inflammation in AS include
CARD15
Vascular endothelial growth factor (VEGF) polymorphisms sacroiliac joints, entheses, vertebral bodies adjacent to
TLR4, CD14, NFKB1, MMP3, PTPN22, alpha-1-antitrypsin, intervertebral disks, peripheral joints, gastrointestinal
secretor status, and immunoglobulin allotypes tract, and the eye. Many of these lesions are poorly
Ank (extracellular inorganic pyrophosphates) accessible, so information on their histopathology is
limited. In immunohistologic studies on early sacroiliitis
in SpA, synovitis with myxoid-appearing bone marrow,
pannus formation, and granulation tissue have been
described. CD4+ and CD8+ T cells and CD68+ macro-
for disease activity and function, with heritability esti- phages are accompanied by proliferating fibroblasts and
mated at 51% and 68%, respectively. High heritability neovascularization. Overexpression of tumor necrosis
of radiographic severity was demonstrated. The herita- factor alpha (TNF-alpha) and expression of transform-
bility observed was clearly due to non-B27 factors ing growth factor beta (TGF-beta) mRNA were found.
because all patients in the study were HLA-B27 Destroyed bone is partly replaced, and endochondral
positive. ossification results in bony ankylosis.
Genomewide linkage studies in AS and SpA have In studies of peripheral synovitis (not restricted to
detected strong suggestions of linkage at chromosome patients with AS), increased vascularity, endothelial cell
16q (11). Other regions achieving moderate evidence of activation, and expression of adhesion molecules and
linkage have been identified on chromosomes 3, 10, and chemotactic factors have been observed. Infiltrating
19. On chromosome 3, peak linkage was seen at 202 cM, cells include activated T lymphocytes, with CD4+ T
and on chromosome 10, at 127 cM. Loci previously asso- cells often predominating over CD8, natural killer
ciated with AS on chromosome 2q (the IL-1 gene (NK) cells, B lymphocytes, and CD68+ macrophages.
cluster) and 22q (CYP2D6) had nominal linkage in a Although the total numbers of CD68+ macrophages are
meta-analysis (12), providing further statistical support similar in SpA, macrophages expressing the hemoglo-
for their involvement in susceptibility to AS. bin scavenger receptor CD163 are increased in both
In a genomewide study of 151 affected sibling pair synovial tissues and the colonic mucosa of patients with
families, linkage with disease activity was observed on SpA. The cell surface expression of CD163 defines a cell
chromosomes 11q, 16p, 18p, and 20q, with age of symptom population that produces more TNF-alpha and less IL-
onset on chromosome 11q, and with function on chromo- 10, indicating a T-cell helper (Th1) response.
some 2q (12). Five regions on chromosomes 3p, 11p and Enthesitis, a hallmark of SpA, is characterized by
11q, 16p and 18p were linked to more than one phenotype erosive, inflammatory lesions associated with an abun-
studied, making the likelihood of chance findings low. dance of osteoclasts and infiltration of the bone marrow.
MHC genes were associated with susceptibility to SpA, Lymphocytic infiltration of CD8+ and CD4+ T cells is
but not with disease severity or age of onset. found in established disease. In earlier enthesitis, CD68+
Association studies in different populations have macrophages predominate.
shown that implicated variations in IL-1 gene family With regard to joint inflammation, there are more
members are associated with susceptibility to AS. The similarities than differences between the SpA and other
interleukin 1 complex on chromosome 2 includes the forms of inflammatory arthritis. Macrophages appear to
genes encoding IL-1 alpha, IL-1 beta, and their natu- play an important role in early disease, but T cells are
rally occurring inhibitor, IL-1 receptor antagonist (IL- clearly involved. Both innate and adaptive immune
responses may have a role in SpA. The observation that onic endochondral bone formation in a spontaneous
TNF-alpha is overexpressed in sacroiliac joints provided model of arthritis in DBA/1 mice. Bone morphogenetic
a strong rationale for the use of TNF inhibitors, which protein (BMP) signaling is a key molecular pathway
are very efficacious in SpA. involved in this pathology. Systemic gene transfer of
noggin, a BMP antagonist, is effective both as a preven-
tive and a therapeutic strategy in this mouse model,
CYTOKINE EXPRESSION IN interfering with enthesial progenitor cell proliferation
ANKYLOSING SPONDYLITIS (14). Immunohistochemical staining for phosphorylated
smad1/5 in entheseal biopsies of SpA patients reveals
The inflammation associated with AS and SpA has also active BMP signaling in similar target cells. This sug-
been examined by assessing cytokine production. gests a role for BMPs in the pathogenesis of AS.
Enzyme-linked immunosorbent assay (ELISA) tech- Ankylosing spondylitis patients frequently are
niques have been used to measure serum cytokine treated with nonsteroidal anti-inflammatory drugs
levels, and fluorescent-activated cell sorting (FACS) (NSAIDs), including selective cyclooxygenase (COX)-
technology to assess the percentage of cells producing 2 inhibitors. COX-2 is an inducible enzyme that con-
cytokines in peripheral blood. Serum cytokines are dif- verts arachidonic acid to prostaglandin E2, a modulator
ficult to measure because their half-lives are short and of bone metabolism. The inhibition of radiographic
differ between cytokines. Although the measurement of progression by continuous intake of NSAIDs may be
TNF-alpha serum levels does not seem useful in clinical explained by the inhibition of prostaglandins by
practice, IL-6 levels are increased in AS patients, cor- NSAIDs. Several animal and in vitro studies demon-
relate with other measures of disease activity, and reflect strated impaired bone healing in the presence of
responses to therapy. NSAIDs. The steps involved in bone healing include an
Studies examining T cells in SpA have mostly shown inflammatory response, bone resorption, and new bone
a decrease in Th1 cytokine-producing cells. The T cells formation. Prostaglandins have been shown to elicit and
of HLA-B27+ patients with AS and healthy HLA-B27+ participate in inflammatory responses, enhance osteo-
individuals produce less TNF-alpha and interferon clast activity and subsequent bone resorption, and
gamma (IFN-gamma) than do those of healthy HLA- increase osteoblast activity and new bone formation. By
B27+ controls. An impaired Th1 response could hinder inhibiting COX and the subsequent production of pros-
elimination of intracellular pathogens and lead to a taglandins, NSAIDs act in an anti-inflammatory mode
chronic infection. However, a primary Th1 deficit in all and may inhibit new bone formation simultaneously.
HLA-B27+ individuals seems unlikely, and its presence
in the majority of active SpA patients is unclear. The
presumed Th1 deficit improved after treatment with REFERENCES
certain TNF inhibitors, but not others (13).
Cytokine production by antigen-presenting cells, 1. Mielants H, Veys EM, Goemaere S, et al. Gut inflam-
mation in the spondyloarthropathies: clinical, radiologic,
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biologic and genetic features in relation to the type of
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One important recognition system is the family of Toll- 1551.
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tion such as TNF-alpha and IL-6 by activation of NF-B. spondylitis and HL-A 27. Lancet 1973;1:904907.
Thus, TLRs sit at the crossroads of innate and adaptive 3. Van der Linden SM, Valkenburg HA, de Jongh BM, et
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nonspecific to antigen-specific inflammatory responses. B27 positive individuals. A comparison of relatives of
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Rheum 1984;27:241249.
4. Mear JP, Schreiber KL, Munz C, et al. Misfolding of
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The remodeling of bone leading to the squaring of thropathies. J Immunol 1999;163:66656670.
5. Scofield RH, Kurien B, Gross T, et al. HLA-B27 binding
the vertebral bodies in AS is the result of acute and
of peptide from its own sequence and similar peptides
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the destruction and simultaneous rebuilding of both the Lancet 1995;345:15421544.
cortex and the spongiosa of the vertebral bodies. The 6. Allen RL, OCallaghan CA, McMichael AJ, et al. HLA-
development of square vertebral bodies is based on a B27 can form a novel beta-2-microglobulin-free heavy
combination of a destructive osteitis and repair. The chain homodimer structure. J Immunol 1999;162:5045
process of joint ankylosis partially recapitulates embry- 5048.
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7. Hammer RE, Maika SD, Richardson JA, et al. Spontane- 11. Brown MA. Non-major-histocompatibility-complex
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HLA-B27 and human b2-m: an animal model of HLA- Rheumatol 2006;20:611621.
B27-associated human disorders. Cell 1990;63:10991112. 12. Brown MA, Brophy S, Bradbury L, et al. Identification of
8. Brown MA, Wordsworth BP, Reveille JD. Genetics of major loci controlling clinical manifestations of ankylos-
ankylosing spondylitis. Clin Exp Rheumatol 2002;20(Suppl ing spondylitis. Arthritis Rheum 2003;48:22342239.
28):S43S49. 13. Zou J, Rudwaleit M, Brandt J, et al. Upregulation of the
9. Brown MA, Kennedy LG, MacGregor AJ, et al. Suscep- production of tumour necrosis factor alpha and interferon
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HLA, and the environment. Arthritis Rheum 1997;40: ment with etanercept. Ann Rheum Dis 2003;62:561564.
18231828. 14. Lories RJ, Derese I, Luyten FP. Modulation of bone mor-
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Arthritis Rheum 2001;44:13961400. 15711579.
CHAPTER 9
JOHN C. DAVIS, JR., MD, MPH
Multiple modalities for the therapy of ankylosing Physical therapy and stretching exercises are corner-
spondylitis (AS) are available, including physical stones of AS treatment, regardless of which other
therapy and patient education, nonsteroidal anti- therapies are employed.
inflammatory drugs (NSAIDs), glucocorticoids, disease- Indomethacin is the most commonly prescribed
modifying antirheumatic drugs (DMARDs), and NSAID for AS treatment, but other NSAIDs are
antitumor necrosis factor (TNF) agents. comparable to indomethacin in efficacy and safety.
Combination approaches to therapy are often Tumor necrosis factor inhibitors (etanercept, inflix-
required to relieve symptoms, improve function, and imab, and adalimumab) demonstrate striking efficacy
potentially modify disease progression. in the majority of patients with AS.
In assessing patient outcomes in clinical trials, For patients with AS and concomitant inflammatory
disease activity is measured by the Bath Ankylosing bowel disease, a monoclonal antibody approach to
Disease Activity Index (BASDAI), which includes six the inhibition of TNF (i.e., either infliximab or adalim-
patient-oriented questions based on fatigue, overall umab) is preferred.
back and hip pain, peripheral arthritis, entheses, and
the duration and intensity of morning stiffness.
Ankylosing spondylitis (AS) is the prototype of chronic DISEASE ACTIVITY AND

inflammatory diseases of the spine known as the
spondyloarthropathies (SpA). Patients present with CLINICAL ASSESSMENT
significant inflammatory back pain and may progress,
in severe forms, to fusion of the entire spine. AS Other than a complete medical history and physical
may also involve peripheral joints, entheses, and non- examination, a core set of domains and instruments has
articular structures (such as the gut and anterior been recommended by the Assessments in Ankylosing
chamber of the eye). Accordingly, these manifestations Spondylitis Working group (ASAS) for monitoring
should be taken into account when assessing and patients in the clinical setting (Table 9C-2) (1). These
treating the patient. Recently, the treatment goal in include measures of physical function, pain, spinal
AS has evolved from providing only symptomatic mobility, patients global assessment, duration of
relief to inducing major clinical responses and poten- morning stiffness, involvement of peripheral joints and
tially disease-modifying benefits. Multiple modalities entheses, acute phase reactants, and fatigue. Overall
are available, including physical therapy and patient disease activity should be measured by the Bath Anky-
education, nonsteroidal anti-inflammatory drugs losing Spondylitis Disease Activity Index (BASDAI),
(NSAIDs), glucocorticoids, disease-modifying antirheu- which includes six patient-oriented questions based on
matic drugs (DMARDs), and antitumor necrosis factor fatigue, overall back and hip pain, peripheral arthritis,
(TNF) agents (Table 9C-1). No single modality treats entheses, and the duration and intensity of morning
all manifestations of a patient with AS. Combination stiffness (Table 9C-2). In addition, a physician global
approaches to therapy are often required to relieve assessment, taking into account available clinical, labo-
symptoms, improve function, and potentially modify ratory, and imaging data, should be performed using
disease progression. either a visual analog scale or a numeric ranking scale.
209
210 JOHN C. DAVIS, JR.
TABLE 9C-1. SUMMARY OF THERAPIES FOR motion and kyphosis of the spine are significant con-
ANKYLOSING SPONDYLITIS. tributors to morbidity, and a regular, individualized
exercise program is important for maintenance of func-
TREATMENT EFFICACY
tion and posture. Extended periods of immobility,
NSAIDs Provide symptom relief, may reduce including car and plane travel, should be minimized and
inflammation interrupted with breaks to permit frequent stretching.
May influence radiographic progression Sleeping with a thin pillow and lying in a straight
Muscle relaxants May reduce stiffness, but not evaluated in position are preferred. Deep breathing exercises and
clinical trials avoidance or discontinuation of smoking should be
emphasized. Patient support groups such as the Spon-
Glucocorticoids Oral: useful for treatment of peripheral
arthritis
dylitis Association of America (http://www.spondylitis.
lnjected glucocorticoids may be useful for org) are of tremendous benefit in terms of education
spine disease, enthesitis, and peripheral and additional resources available to patients.
arthritis
Topical: effective in AAU
MTX Limited/no evidence of efficacy
SSZ Limited effectiveness, decrease in ESR and TABLE 9C-2. ASSESSMENT OF DISEASE ACTIVITY.
morning stiffness; peripheral arthritis
possible benefit ASAS CORE SET FOR DAILY PRACTICE
Thalidomide Provides clinical improvement in small Domain Recommended instrument

clinical trials
Physical function BASFI or Dougados Functional Index
Pamidronate Provides clinical improvement in small
clinical trials Pain VAStotal back pain and nocturnal back
pain over the past week
Etanercept Supported by clinical trials, may impact
disease progression; MRI/DXA Spinal mobility Chest expansion, Schober Test, occiput to
wall, and lateral lumbar flexion
Infliximab Supported by clinical trials, may impact
disease progression; MRI/DXA Patient global VASover the past week
assessment
Adalimumab Supported by clinical trials, impact on disease
progression under study Stiffness Duration of morning stiffness over last
week
Leflunomide No evidence of efficacy
Peripheral joints Number of swollen joint counts, enthesitis
Anakinra No evidence of efficacy
and entheses score such as developed in San
Francisco, Maastricht, or Berlin
ABBREVIATIONS: AAU, acute anterior uveitis; DXA, dual-energy x-ray absorp-
tiometry; ESR, erythrocyte sedimentation rate; MRI, magnetic resonance Acute phase ESR or CRP
imaging; MTX, methotrexate; NSAIDs, nonsteroidal anti-inflammatory drugs;
reactants
SSZ, sulfasaliazine.
Fatigue VAS or fatigue question on BASDAI
BASDAI Calculated by averaging questions 5 and

6 and then averaging this sum with
questions 14
PHYSICAL THERAPY, EXERCISE, VAS overall level of fatigue/tiredness
AND PATIENT EDUCATION VAS overall level of AS neck, back, or hip
pain
VAS overall level of pain/swelling in
The cornerstone of therapy for all patients includes joints other than neck, back, or hips
physical therapy, exercise, and patient education in con- VAS overall discomfort from any areas
junction with any pharmacologic intervention. There tender to touch or pressure
are, however, limited and conflicting data on which VAS overall level of morning stiffness
from time of awakening
specific approach is most appropriate (2). In a meta- Duration and intensity of morning
analysis, group exercise in a hospital setting was reported stiffness from time of awakening (up to
to be more effective than a home-based program (3). 120 minutes)
Spa therapy programs used in addition to standard
medications and group physical therapy programs have ABBREVIATIONS: ASAS, Assessments in Ankylosing Spondylitis Working
Group; BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI); CRP,
been reported to add additional benefit in terms of clini- C-reactive protein; ESR, erythrocyte sedimentation rate; VAS, visual analog
cal response and cost savings (4,5). Decreased range of scale (VAS can be replaced with a numeric rating scale).
PHARMACOLOGIC MODALITIES cant morbidities, including osteoporosis and vertebral

fracture. Intravenous methylprednisolone (either
Tricyclic Antidepressants and 375 mg/day or 1000 mg/day) for 3 days has been reported
to produce improvement in morning stiffness, back
Muscle Relaxants pain, and spinal mobility for up to 21 months, but trials
Sleep disturbances and fatigue are common symptoms to date have been uncontrolled and no difference in
of AS. Amitriptyline was studied over a 2-week period response has been noted between the two doses (9,10).
in a small randomized trial (6). The authors reported Local glucocorticoid injections of joints and, less fre-
improvement in sleep and reduced disease activity, quently, entheses can provide temporary relief of symp-
with minimal side effects. Patients with a significant toms but may cause side effects such as tendon rupture.
degree of stiffness and muscle spasm may respond to (Glucocorticoid injections of tendons are not advised.)
a combination of NSAIDs (see below), analgesics, and Injections are preferable to systemic glucocorticoids for
muscle relaxants, particularly when initiating physical treatment of oligo- or monoarticular arthritis. Fluoro-
therapy. scopic or computer tomography (CT)-guided glucocor-
ticoid injections of the sacroiliac joints was shown to
provide symptomatic relief in a double-blind study (11).
Acute anterior uveitis (AAU) is the one manifestation
Nonsteroidal Anti-Inflammatory of AS that responds effectively to topical glucocorti-
Drugs coids. Prompt evaluation and treatment of AAU with
a combination of glucocorticoid eyedrops and a mydri-
Nonsteroidal anti-inflammatory drugs, commonly pre- atic agent are critical for the prevention of ocular
scribed as first-line therapy, have been proven effective sequelae (synechiae formation between the iris and
in relief of axial and peripheral symptoms (including lens).
arthritis and enthesitis). A rapid response to NSAIDs
(within 48 hours) has also been included in classification
criteria for SpA. Indomethacin is the most commonly
prescribed NSAID for AS treatment, but other NSAIDs Pamidronate and Thalidomide
are comparable to indomethacin in efficacy and safety. Pamidronate is an intravenously administered
(As is true with the use of NSAIDs in other disorders, bisphosphonate. Several studies reported the effects
patients may develop individual choices regarding which of bisphosphonates on bone metabolism, inflamma-
NSAID is most effective for them.) A randomized trial tion, and immune regulation (1214). In both open-
of the cyclooxygenase-2 (COX-2) selective agent cele- label and blinded studies, monthly infusions of
coxib showed similar efficacy to the nonselective agent pamidronate decreased disease activity and produced
ketoprofen and superiority to placebo in both global improvement in the functional, outcomes global
and spinal pain measurements (7). In addition, a post measures, and spinal mobility (15,16). The most
hoc analysis of patients in this study treated with con- common side effects of therapy were musculoskeletal
tinuous versus on-demand celecoxib reported a small complaints following the first infusion and transient
decrease in radiographic progression (8). Adequate lymphopenia.
doses of at least two different NSAIDs should be tried Thalidomide is a glutamic acid derivative that pro- 9
for several weeks before concluding that a patients duces anti-inflammatory and immunomodulatory
response to NSAIDs has been suboptimal. For patients effects, including a reduction in TNF production (17).
with moderate-to-severe disease, the high frequency of Early reports of its use in AS came from a study from
adverse effects and a lack of efficacy in limiting disease France demonstrating reductions in clinical symptoms
progression may require that other agents be used in and a reduction in acute phase reactants (18). Two open-
conjunction with NSAIDs. Selective COX-2 inhibitors label studies reported on a total of 43 patients (19,20).
should be reserved for those who have contraindica- In a year-long study of 30 patients, 80% showed a clini-
tions to conventional NSAIDs and no cardiovascular cal response (20% in several parameters) (20). Second-
risk factors. ary outcomes, including reductions in acute phase
reactants, were also observed. Maximum beneficial
effects of thalidomide were observed following 6 to 12
months of therapy, and relapse occurred 3 months after
Glucocorticoids discontinuation. In a 6-month study of patients with
Oral glucocorticoids have limited efficacy in the treat- severe, refractory AS, 4 of 10 patients achieved signifi-
ment of AS. Both axial and peripheral joint pain and cant improvement and 4 of 10 patients achieved a
swelling may respond in the short term to oral gluco- moderate response (19). The tolerability and side effects
corticoids, but long-term use is associated with signifi- of thalidomide vary significantly between studies and
may represent differences in dosing regimens. Com- BIOLOGIC AGENTS

monly reported side effects include drowsiness, consti-
pation, dizziness, headache, nausea/vomiting, and There is no evidence that the conventional therapies
paresthesias. Peripheral neuropathy (often irreversible) discussed so far actually modify disease progression. In
is an important long-term concern with thalidomide. contrast, there is a growing body of evidence that dem-
onstrates the clinical efficacy of TNF blockade. Multiple
Sulfasalazine studies have demonstrated that TNF-alpha appears
to play a key role in promoting inflammation in AS.
Sulfasalazine (SSZ), a salicyclic acid derivative created Increased TNF-alpha expression is found in the sacro-
by covalent linkage of 5-amino-salicyclic acid (5-ASA) iliac joints, peripheral synovial tissue, and serum of
to sulfapyridine, is cleaved by bacteria in the colon. patients with AS (2731). Following a series of ran-
The 5-ASA absorption is limited to the colonic wall, domized, controlled clinical trials, three TNF inhibitors
where the drug is effective in inflammatory bowel are either approved for the treatment of AS or the
disease. The sulfapyridine moiety, absorbed through subject of ongoing studyetanercept, infliximab, and
the gastrointestinal wall, acts as systemic effects in adalimumab.
several autoimmune diseases (21). A meta-analysis of
five randomized, controlled trials involving a total of
272 patients was published in 1990 (22). Doses ranged
Etanercept
from 2 to 3 g/day for 3 to 11 months. Benefit was dem- Etanercept is a soluble fusion protein containing an Fc
onstrated in clinical and laboratory parameters, includ- fragment of human IgG1 fused to two extracellular
ing the severity and duration of morning stiffness and domains of the p75 TNF receptor. The medications
the severity of pain. General well-being, acute phase mechanism of action is to bind soluble forms of TNF-
reactants, and spinal mobility measurements showed alpha, thereby preventing attachment of the cytokine
nonsignificant trends in favor of SSZ. Only one of the to cell surface receptors. Etanercept is given in doses
five trials in this meta-analysis evaluated response rates of 50 mg subcutaneously per week (alternatively 25 mg
in axial versus peripheral symptoms, with a nonstatisti- twice weekly). The efficacy of etanercept in AS was
cally significant trend favoring response of peripheral demonstrated in a double-blind, placebo-controlled
symptoms (23). trial of 40 patients with active spondylitis (32). Patients
had moderate-to-severe disease despite stable doses of
NSAIDs, DMARDs, or glucocorticoids. Patients ran-
METHOTREXATE domized to the etanercept group demonstrated a rapid
and sustained response in four primary outcome mea-
The limited studies of methotrexate (MTX) available sures: duration of morning stiffness, nocturnal pain,
have shown little benefit in the treatment of AS, in patients global assessment, and functional index. A
contrast to the proven long-term efficacy and tolerabil- number of secondary outcomes also improved, includ-
ity in rheumatoid arthritis and psoriatic arthritis. In an ing spinal and chest range of motion, enthesitis, and
open-label study of MTX (7.515 mg once a week), 9 of acute phase reactants. The most frequent side effects
11 patients who had previously demonstrated inade- were injection-site reactions and minor infections,
quate response to either NSAIDs or sulfasalazine were which did not differ statistically between the two
evaluated at 24 weeks. The small study reported a groups. These results were confirmed in a larger ran-
reduction in the number of swollen joints in patients domized, placebo-controlled trial in patients with
with a predominance of peripheral arthritis (24). Two moderate to severe disease (33). A significant percent-
patients with significant extra-articular disease (both age of patients achieved the primary outcome, defined
with enthesitis and iridocyclitis) discontinued MTX due by the ASAS Working Group 20% improvement cri-
to continued disease activity. A randomized, placebo- teria (ASAS20) compared to placebo at both 12 and
controlled trial of MTX in AS failed to demonstrate 24 weeks. These results were sustained through 2
significant benefit in either axial or peripheral arthritis, years (34).
but there was a trend toward a reduction in peripheral Early evidence of the benefit of etanercept by MRI
symptoms (25). A more recent small study evaluated was published in an uncontrolled study of 10 patients
MTX in a dose of only 7.5 mg/week in patients with AS with active spondylitis (35). Repeated MRIs demon-
treated for 24 weeks (26). This study reported a com- strated a 86% reduction or resolution in acute inflam-
posite response rate of over 50% (n = 17) in those matory bone lesions over 24 weeks. Moreover, no new
receiving MTX, compared with 17% in the placebo bone lesions were identified over this period. These
group (despite the relatively low dose of MTX used in results were confirmed by a larger MRI substudy of the
the study). Long-term data in MTX-treated patients are large randomized study that demonstrated significant
not available. reduction in inflammatory lesions (36).
Infliximab many secondary outcome measures when adalimumab

was administered over a 24-week period (41).
Infliximab is a chimeric monoclonal IgG1 antibody that
binds both soluble and cell bound forms of TNF-alpha.
In AS, infliximab is usually given at a slightly higher TREATMENT
dose than in rheumatoid arthritis patients. Dosing for
AS is 5 mg/kg intravenously at baseline, week 2, week RECOMMENDATIONS AND BEST
6, and then every 6 weeks thereafter. In an early study, PRACTICE GUIDELINES
a 3-month randomized study compared infliximab in
doses of 5 mg/kg intravenously to placebo in AS patients A systematic literature review and Delphi exercise was
with active disease (37). A larger proportion of patients performed on all treatment modalities for AS and
experienced a response in terms of the BASDAI than recently published (Table 9C-3) (42). In addition, treat-
placebo. This has been shown to be sustained to 3 years ment recommendations for the use of anti-TNF agents
(38). These results have been confirmed by a larger have been published by the ASAS and modified for use
randomized placebo-controlled trial over 24 weeks (39). in the United States by the Spondyloarthritis Research
A significantly larger proportion of patients achieved and Treatment Network (SPARTAN) (Table 9C-4)
an ASAS20 compared to placebo over the 24 weeks. (4345). Patients who are symptomatic, regardless of
MRI results also demonstrated a significant decrease in their predominant manifestation (peripheral arthritis,
inflammatory lesions. axial arthritis, enthesitis) should be given a trial of at
least two NSAIDs. Patients with moderate disease
activity or greater [BASDAI score of 4 or above and a
Adalimumab physician global score of at least 2 (range, 04)], should
Adalimumab is a fully humanized IgG1 monoclonal be given additional therapy. For patients with pro-
antibody that inhibits. The usual dose is 40 mg, admin- nounced peripheral symptoms, a trial of SSZ or MTX
istered subcutaneously every other week. Results from should be considered. For patients with purely axial
a small open-label trial in which AS patients were manifestations, no trial of SSZ or MTX is required and
treated with adalimumab showed significant improve- an anti-TNF agent should be prescribed. For those with
ment in disease activity, acute phase reactants, pain, concomitant inflammatory bowel disease, a monoclonal
and morning stiffness (40). Results from a large, ran- antibody is preferred. Strict adherence to screening
domized, placebo-controlled study demonstrated a sig- and treatment of latent tuberculosis infection is
nificant clinical response in the ASAS20 as well as required prior to the initiation of anti-TNF therapy. In
TABLE 9C-3. SUMMARY OF APPROVED ANTITUMOR NECROSIS FACTOR AGENTS USED IN THE TREATMENT OF
PATIENTS WITH ANKYLOSING SPONDYLITIS.
AGENT DESCRIPTION DOSING CLINICAL RESPONSE DISEASE-MODIFYING PROPERTIES
9
Etanercept Dimeric fusion protein of the Subcutaneous injection ASAS 20/50/70 DXA improvement in lumbar spine
TNF-alpha receptor linked to of 50 mg once a BASDAI 50 Reduction in acute MRI changes
the Fc portion of human IgG1 week or 25 mg twice ASAS 5/6 Limited plain radiographic data
weekly Partial remission
Infliximab Monoclonal IgG1 anti-TNF Intravenous infusion ASAS 20/50/70 DXA improvement in lumbar spine
antibody with a mouse of 5 mg/kg at 0, 2, BASDAI 50 and hip
variable region and 6 weeks and ASAS 5/6 Improvement in cartilage and bone
then every 6 weeks Partial remission metabolism measures
Reduction in acute MRI changes
Limited radiographic data
Effective in patients with IBD
Adalimumab Fully humanized monoclonal Subcutaneous injection ASAS 20/50/70 Reduction in acute MRI changes
antibody directed against of 40 mg every BASDAI 50 Limited data on efficacy in patients
TNF-alpha other week ASAS 5/6 with IBD
Partial remission
ABBREVIATIONS: ASAS, Assessments in Ankylosing Spondylitis Working Group; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; DXA, dual-energy x-
ray absorptiometry; IBD, inflammatory bowel disease; MRI, magnetic resonance imaging; TNF, tumor necrosis factor.
Data from References 33 and 39.
TABLE 9C-4. BEST CLINICAL PRACTICE GUIDELINES FOR THE USE OF ANTITUMOR NECROSIS FACTOR AGENTS IN
ANKYLOSING SPONDYLITIS.
Patient acceptance including and understanding of risk and benefits of long-term or potentially lifelong anti-TNF therapy and unknown
effects on pregnancy/lactation.
Diagnosis and/or associated features

Modified NY Criteria or other evidence of SpA, including inflammatory back pain, persistently elevated acute phase reactants, baseline
radiographic damage and/or rapid radiographic progression, spinal inflammation on imaging modality including MRI and ultrasound.
Suggested disease activity

BASDAI Score of 4 (010).
Physician global assessment of at least moderate disease activity based upon either a score of 2 on a Lickert scale (04) or VAS score
of 4 (010).
Clinical presentation and extra-articular features

Three clinical presentations: axial, peripheral arthritis (excluding hip), and entheseal. Predominant feature guides the previous treatment
requirements.
For axial, peripheral, and entheseal presentationsfailure of at least two NSAIDs either due to inefficacy or toxicity.
For peripheral featuresarthritis or ethesitis: NSAID failure and failure of methotrexate or sulfasalazine at maximally tolerated doses for
3 months.
For axial predominance: NSAID failure and no DMARD failure required.
Intra-articular or entheseal injections of glucocorticoids as clinically indicated.
Response
Reduction in BASDAI score and physician global score of at least 50%.
Timing of response
Response expected within 12 weeks of initiation of treatment.
Agents
Etanercept 50 mg/wk sq
Infliximab 5 mg/kg at 0, 2,and 6 weeks, then every 6 weeks intravenously.
Adalimumab 40 mg every other week sq
Precautions/contraindications
Active or recurrent infection including untreated evidence of latent TB or recent TB exposure.
SLE or MS symptom/history.
Other per package insert.
ABBREVIATIONS: BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; DMARD, disease-modifying antirheumatic drug; MRI, magnetic resonance imaging;
MS, multiple sclerosis; NSAIDs, nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus; SpA, spondyloarthropathies; TB, tuberculosis; TNF,
tumor necrosis factor; VAS, visual analog scale.
Data from References 43 through 45.
addition, if during treatment there are signs/symptoms Acknowledgment. This work supported by the Rosa-
of infection or recent contact, screening and evaluation lind Russell Medical Center for Arthritis Research, The
should be pursued. University of California San Francisco.
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CHAPTER 10
Reactive and Enteropathic Arthritis

ROBERT D. INMAN, MD
In reactive arthritis (ReA), exposure of the host to Enthesopathy (inflammation at the sites of insertion
infectious agents leads to the development of an of tendons and ligaments into bone) and anterior
inflammatory arthritis and other manifestations of uveitis are often found in ReA, as in other seronega-
systemic disease in the absence of an ongoing tive spondyloarthropathies.
infectious process. Cutaneous manifestations of ReA include: kerato-
Approximately 50% of ReA and undifferentiated derma blenorrhagicum, a papulosquamous rash
oligoarthritis cases can be attributed to a specific affecting the palms and soles; nail dystrophy;
pathogen by a combination of culture and serology. circinate balanitis, characterized by shallow ulcers on
The predominant organisms are Chlamydia, Salmo- the glans or the shaft of the penis; and oral ulcers,
nella, Shigella, Yersinia, and Campylobacter species. typically painless.
The annual incidence of ReA, found to be Enteropathic spondyloarthritis is the inflammatory
28/100,000 individuals in one study, may exceed arthritis that often accompanies ulcerative colitis or
that of rheumatoid arthritis. Crohns disease.
In a study of 91 individuals exposed to food-borne The peripheral arthritis of enteropathic spondyloar-
Salmonella enteritidis, 17 (19%) individuals developed thritis is typically pauciarticular, asymmetric, and
ReA. Other studies have estimated the frequency of migratory. It has a predilection for joints of the lower
ReA following exposure to potential etiologic agents extremities.
to be on the order of 10%. The axial disease of enteropathic spondyloarthritis is
Reactive arthritis characteristically involves the joints indistinguishable clinically from that of primary
of the lower extremities in an asymmetric, oligoar- ankylosing spondylitis.
ticular pattern.
A dactylitis (sausage digit) pattern in the feet is
typical of ReA.
REACTIVE ARTHRITIS test, however, critically depends on the prevalence of

positives in the healthy population at large (1), and this
The role of infection as a triggering factor in the patho- is an important consideration in the case for causality
genesis of the various forms of spondyloarthritis (SpA) in ReA.
is implicated with varying degrees of certainty among
the SpA subcategories. The very definition of reactive
arthritis (ReA)a sterile synovitis following an extra-
Epidemiology
articular infectionclearly implicates infection in its Studies on the epidemiology of ReA have provided
defining features, and ReA occupies the conceptual insight into the frequency of this complication of enteric
ground somewhere between septic arthritis and the infections. Data indicate that approximately 50% of
classic autoimmune rheumatic diseases, such as rheu- ReA and undifferentiated oligoarthritis cases can be
matoid arthritis (RA). An etiologic classification has attributed to a specific pathogen by a combination of
fueled the search for definitive links between particular culture and serology. The predominant organisms are
pathogens and ReA. Many of these studies are based Chlamydia, Salmonella, Shigella, Yersinia, and Campy-
on guilt by association, in that the demonstration of a lobacter species (2). Species-specific analysis of sero-
particular immune response profile by serology or cel- logical responses to pathogens might increase this
lular responses leads to identification of the causative detection rate further (3). A prospective study of the
pathogen even when there is no direct demonstration annual incidence of inflammatory joint disease in
of the organism or its antigens in synovial tissues or Sweden found that the annual incidence of ReA
fluid. The predictive power of a diagnostic microbiology (28/100,000) exceeded that of RA (24/100,000), empha-
217
218 ROBERT D. INMAN
sizing the importance of ReA in the overall burden of chlamydial urethritis) or can be an extra-articular
rheumatic diseases (4). Studies on both sporadic (5) and feature of postdysenteric ReA. The distinction is impor-
outbreak-related (6) Salmonella typhimurium infections tant because there may be great concern on the part of
have provided further support for the role of Salmonella the patient about a possible sexually transmitted disease
spp in triggering ReA. The frequency of ReA in this when genital symptoms occur, and a discussion with the
context has generally been in the range of 10% (6), but patient (and often the spouse) becomes a key element
in a study of 91 individuals exposed to food-borne Sal- in care. Oral ulcers on the hard palate or tongue are
monella enteritidis, 17 individuals developed ReA, indi- typically painless, so the patient may be unaware of
cating that this might be more frequent than previously their presence in the mouth. Acute anterior uveitis
thought (7). In a population-based study, it was deter- occurs in 20% of patients at some point during the
mined that ReA is common after campylobacter infec- course of ReA. As in the case of evolution into AS,
tions, with an annual incidence of 4.3/100,000 (8). These whether the uveitis is triggered by the antecedent infec-
incidence figures are no doubt strongly influenced by tion or is a feature of a common genetic predisposition
the unique aspects of a particular population under has not been resolved.
study: ReA appears to be more prevalent in Alaskan
Eskimo populations (9), for example, and the incidence
of ReA after a salmonella outbreak appears to be lower
in children than adults (10).
Pathogenesis of Reactive Arthritis
With respect to ReA, the most common triggering uro-
genital agents are urogenital (Chlamydia spp) and
Clinical Features of enteric (Shigella, Salmonella, Yersinia, and Campylo-
bacter spp) pathogens (11). Substantial regional differ-
Reactive Arthritis ences are evident, however, particularly with regard to
Reactive arthritis is characteristically a lower extremity, the enteric pathogens (12). Chlamydia spp are regarded
asymmetric oligoarthritis. The pattern may be additive. as the most common causative agents in ReA. Chla-
Hip disease is uncommon and exclusively upper extrem- mydia DNA, mRNA, rRNA, and intact Chlamydia-like
ity involvement is extremely rare. The joints are typi- cells have been found in synovial tissues and peripheral
cally warm, swollen, and tender, and can mimic a septic blood of ReA patients (13,14). The mechanisms account-
arthritis, reminding that aspiration of synovial fluid and ing for the persistence of Chlamydia and the thwarting
cultures are mandatory when assessing such patients. A of host immune defenses have been studied from several
dactylitis pattern in the feet is not uncommon. perspectives. In chronic disease, altered regulation of
Enthesitis (inflammation at sites of ligamentous specific Chlamydia genes is apparent, with reduced
attachment to bone) is a characteristic feature of ReA. expression of the major outer membrane protein and
Achilles tendonitis and plantar fasciitis are the most increased expression of heat shock protein (HSP) and
common sites, but pain in the iliac crests, ischial tuber- lipopolysaccharide (LPS). Chlamydia spp can also
osities, and back can be seen. This aspect of the disease downregulate the expression of major histocompatibil-
can be disabling, with marked restriction in weight ity complex (MHC) antigens on the surface of infected
bearing and ambulation. cells. Chlamydia spp may induce T-cell apoptosis by
Low back pain and buttock pain, reflecting sacroiliac stimulating the local production of tumor necrosis factor
joint inflammation, occurs in up to 50% of cases, but (TNF) (15). There is also evidence that Chlamydia spp
progression to ankylosing spondylitis (AS) is uncom- can alter host response to the organisms by inhibition
mon. The latter event is strongly associated with human of host cell apoptosis, by reducing the release of cyto-
leukocyte antigen (HLA)-B27. chrome C, and by sequestering protein kinase C delta
The extra-articular features of ReA can often be in the membrane of the organisms vacuoles (16). Newer
helpful in diagnosis, particularly in circumstances when analytic techniques are being used to probe synovial
it is difficult to identify a triggering infection. Kerato- fluids and tissues for evidence of prior or current
derma blenorrhagicum is a papulosquamous rash most microbes (17,18).
commonly affecting palms and soles. The lesions can be Serological studies have previously provided sugges-
indistinguishable clinically and histopathologically from tive evidence that certain Gram-negative bacteria,
pustular psoriasis. Nail dystrophy can occur with ReA, notably Klebsiella pneumoniae, contribute to the patho-
further highlighting the clinical overlap of some fea- physiology of AS. The implication of such studies is that
tures with psoriatic arthritis. Circinate balanitis presents AS may be a form of ReA. One recent analysis, however,
as shallow ulcers on the glans or the shaft of the penis, which addressed both humoral and cellular host immune
and is plaquelike and hyperkeratotic. Dysuria and responses, found no evidence to support the notion that
pyuria present an interesting clinical feature because K. pneumoniae has a pathogenic role in AS (19). LPS
urethritis can be the clue to the inciting infection (as in in synovial tissue is a potent macrophage stimulator and
C H A P T E R 1 0 R E A C T I V E A N D E N T E R O P A T H I C A R T H R I T I S 21 9
this could set the stage for persistence of activated mac- class Irestricted CD8+ CTLs as having a role in the
rophages within the synovium and for ensuing chronic pathogenesis of these diseases. CD8+ T cells in synovial
inflammation. One unresolved issue is the mechanism fluid can express a heterogeneous array of natural killer
by which antecedent infection can induce inflammation (NK) cell receptors (27), which might modulate their
and erosions in a joint in the absence of viable organ- cytotoxicity and contribute to disease pathogenesis. An
isms. Synovial fibroblasts might have an intermediary analysis of the specificity of T-cell clones demonstrated
role in this sequence of events. In laboratory models, that target cells pulsed with Yersinia HSP60, but not
synovial fibroblasts infected with S. typhimurium with other Yersinia proteins, were successfully lysed by
mediate osteoclast differentiation and activation (20). CTLs, and that this killing was controlled by B27 (28).
A single nonamer derived from Yersinia HSP60 was the
dominant epitope in this recognition event. Using a
Human Leukocyte Antigen-B27 and computer-generated algorithm that incorporated HLA-
Direct HostPathogen Interactions B27 binding motifs and proteosome-generated motifs,
an approach has been undertaken to identify immuno-
The conventional role ascribed to class I HLA mole-
dominant peptides from C. trachomatis (29). Nine
cules such as HLA-B27 is the presentation of processed
peptides identified using this method proved to be stim-
peptides to CD8+, cytotoxic T lymphocytes (CTL). It
ulatory for CD8+ T cells, and many of these same pep-
has been difficult to demonstrate that such CTL mediate
tides were recognized by CD8+ T cells derived from
the chronic inflammation that is the hallmark of SpA,
patients with ReA. A recent study successfully used
however. Two points related to HLA-B27 may be rele-
HLA-B27 tetramers to identify low frequency antigen-
vant. First, HLA-B27positive cells kill Salmonella less
specific T cells in Chlamydia-induced reactive arthritis
efficiently than do control cells (21). Second, LPS stimu-
(30). Such cells could be expanded ex vivo, suggesting
lation results in a more pronounced increase in nuclear
a functional capability that might contribute to the
factor B activation and TNF secretion in HLA-B27
arthritis.
positive cells (22).
This phenomenon of more permissive intracellular
replication of Salmonella might depend on the unique Molecular Mimicry
characteristics of the HLA-B27 B pocket, in particular
Whether microbial peptides share functional homology
the glutamic acid residue at position 45 (23). In contrast,
with self-proteins such as HLA-B27 itself remains
some investigators have found that HLA-B27 expres-
unknown. There is some supportive evidence for this
sion alters neither the rates of infection nor the rate
notion of molecular mimicry in SpA (31). This theory
of replication of C. trachomatis in cell lines (24).
postulates that an autoimmune process can ensue after
Using synoviocytes harvested from HLA-B27positive
an infection if there is some degree of cross-reactivity
patients, it was observed that HLA-B27 had no direct
in host and microbial antigens. But several important
role in either the internalization of S. typhimurium or
questions need to be addressed. For example, the target
in the kinetics of intracellular killing (25). A biochemi-
organ specificity of seronegative spondyloarthropathies
cal approach has been used to examine endogenously
remains unexplained, as does the apparent frequency of
labeled HLA-B27bound peptides by mass spectrome-
homologous sequences, even among bacteria not com-
try (26). This technique allows investigators to radiola-
monly thought to be arthritogenic on clinical grounds.
bel peptides that are specifically bound to the HLA-B27
An immunodominant epitope from the S. typhimu-
molecule, and thereafter to isolate these peptides for
rium GroEL chaperonin molecule (a member of the
characterization. Using this approach, there was no evi-
HSP60 protein family) was recognized by CTLs after
dence of significant changes in the range of peptides
natural infection in mice (32). These CTLs cross-reacted
that were bound by the HLA-B27 molecule after infec-
with peptides derived from mouse HSP60. A dodecamer 10
tion of the target cells with S. typhimurium. Although
derived from the intracytoplasmic tail of HLA-B27 was
this does not exclude a role for altered CTL recognition
found to be a natural ligand for disease-associated
of infected HLA-B27positive target cells, harvesting
HLA-B27 subtypes, but not for nondisease-associated
arthritogenic peptides using such a biochemical approach
subtypes. This peptide showed striking homology to a
will be an extremely challenging undertaking using
region of the DNA primase from C. trachomatis, indi-
current methods.
cating that some molecular mimicry exists between
HLA-B27derived and chlamydial peptides (33). In a
Human Leukocyte Antigen-B27 and study investigating CTL recognition in B27-transgenic
animals (34), it was observed that these animals are
Host Immune Responses tolerant to immunization with B27 DNA, but if spleno-
The strong association between HLA-B27 and SpA has cytes from these animals are exposed to Chlamydia
indirectly implicated microbial antigen-specific, MHC spp in vitro, then autoreactive B27-specific CTLs are
220 ROBERT D. INMAN
generated. This indicates a dynamic interrelationship placebo-controlled trial of azithromycin in ReA were
between the pathogen and host B27 that might have reported (40). Azithromycin, given orally for 13 weeks,
important implications for the pathogenesis of ReA. was ineffective in ReA, based on the data from 152
These interactions might result in a break in self-toler- patients who were analyzed for a response.
ance, or perhaps an impaired clearance of the organism
on the basis of impaired recognition of the organism as
non-self. ENTEROPATHIC
SPONDYLOARTHRITIS
Therapy for Reactive Arthritis The arthritis accompanying the inflammatory bowel dis-
First-line treatment of ReA includes nonsteroidal anti- eases (IBDs)Crohns disease (CD) and ulcerative
inflammatory drugs (NSAIDs), which in most cases colitis (UC)is included in the family of spondyloar-
prove adequate for control of the acute synovitis and thritis because so many clinical features of this arthritis
enthesitis. Intra-articular corticosteroid injections can are shared with other members of this family of disor-
be useful for a monoarthritis. Second-line agents for ders. In contrast, the arthritis associated with Whipples
persistent synovitis have included sulfasalazine and disease and celiac disease, albeit enteropathic by defini-
methotrexate, but there are few controlled trials to tion, are generally not considered part of the spondylo-
objectively evaluate efficacy. Because the triggering arthritis spectrum. Arthritis occurs in 10% to 22% of
event in ReA is infection, there has been particular patients with IBD, with a higher prevalence in CD than
interest in the role of antibiotics in the treatment of in UC. Arthritis may precede the gastrointestinal (GI)
ReA. Some studies to date indicate that only Chla- symptoms by lengthy periods of time, and the patients
mydia-induced ReA is responsive to antibiotic treat- may be regarded as undifferentiated SpA until the IBD
ment, raising the question of fundamental differences declares itself. The studies of Mielants and Veys have
between ReA induced by this pathogen and disease provided evidence that patients with undifferentiated
triggered by enteric pathogens. The cellular basis for spondyloarthropathies (uSpA) and even AS may have
such differences, if genuine, are not clear. subclinical bowel inflammation that plays an important
A 3-month, double-blind, randomized, placebo-con- role in triggering and perpetuating joint inflammation
trolled study found no benefit of ciprofloxacin treat- (41). One 20-year follow-up study of patients with IBD
ment in patients with ReA and undifferentiated reported musculoskeletal features in 30% (42). Another
oligoarthritis (35). In subgroup analysis, however, cip- study, employing computed tomography scans, detected
rofloxacin was better than placebo in Chlamydia- sacroiliitis in 45% of patients with CD complaining of
induced ReA, but not in Salmonella- or Yersinia-induced back pain (43). Magnetic resonance imaging (MRI) is
ReA. A subsequent report showed that lymecycline the most sensitive means of detecting sacroiliitis in IBD
therapy decreased the duration of acute arthritis in patients. Asymptomatic sacroiliitis may occur in 14% of
Chlamydia-induced ReA, but not in patients with ReA patients with IBD (44). HLA-B27positive patients
induced by other pathogens (36). Of 17 patients fol- with CD have a high likelihood of progressing to frank
lowed for 10 years in this study, 1 patient had AS, 3 AS. Enteropathic arthritis can occur in a peripheral,
had radiographic sacroiliitis, and 3 had radiographic axial, or mixed pattern.
changes in peripheral joints, but long-term lymecycline
treatment did not change the natural history of the
disease.
Peripheral Arthritis
A 3-month trial of doxycycline for chronic SpA The arthritis is typically pauciarticular and asymmetric,
showed this drug to be no better than placebo for reduc- and may occur in a migratory pattern in some patients.
ing pain or improving functional status, but the caus- In one study, 6% of uSpA patients developed CD 2 to
ative organism was only identified in a few patients (37). 9 years after the onset of arthritis (45). The arthritis is
In a group of patients with undifferentiated SpA, it was typically nonerosive, occurring in intermittent attacks
reported that a combination of doxycycline and rifampin lasting up to 6 weeks (46). There is a predilection for
was superior to doxycline alone, although no placebo lower extremity joints. Dactylitis and enthesitis reiter-
was included in the design (38). In a 4- to 7-year follow- ate the close relationship to the SpA family. The activ-
up of an earlier ReA trial, it was noted that chronic ity of the peripheral arthritis generally correlates well
arthritis developed in 41% of patients initially treated with the degree of active bowel inflammation, particu-
with placebo, in contrast to 8% of patients initially larly in UC. Indeed, colectomy performed for control
treated with ciprofloxacin, suggesting that long-term of UC can be associated with a complete arthritis
prognosis might be favorably influenced by antibiotic remission. The same is not true of surgical interven-
treatment (39). Recently the results of a 3-month, tions for CD.
Axial Arthritis found no significant relationship between CARD15 and

SpA and indicate no enhanced risk for primary AS
The axial pattern of enteropathic arthritis is indistin- associated with this gene. However, CARD15 muta-
guishable clinically and radiographically from primary tions may be found more commonly among patients
AS, although some studies have observed that severity, with CD complicated by sacroiliitis (49).
defined by spinal mobility impairment, is enhanced in
IBD-related spondylitis in comparison with primary AS
(47). Unlike the peripheral arthritis, axial disease in Treatment
IBD does not parallel the activity of the bowel disease,
Therapies for enteropathic arthritis follow the same
and may precede it. Similarly, surgical therapy of UC
principles as those guiding treatment of SpA in general.
or CD has no impact on the associated spondylitis. An
NSAIDs are first-line treatment for joint inflammation
association with HLA-B27 is seen in axial but not in the
in both axial and peripheral disease. The cautionary
peripheral form of enteropathic arthritis.
note in these patients, however, is that NSAIDs may
exacerbate underlying IBD, particularly UC. NSAID-
Nonarticular Complications of related adverse events may also mimic a flare of IBD
Inflammatory Bowel Disease and complicate management. Decisions on NSAID use
should be undertaken jointly by the rheumatologist and
Skin lesions can be seen in up to 25% of patients. Ery- the gastroenterologist.
thema nodosum tends to mirror the activity of the Sulfasalazine, which has a role in the treatment of
bowel disease and can often parallel the activity of the colonic inflammation in IBD, has been effective in
peripheral arthritis. Pyoderma gangrenosum, with treating peripheral, but not axial, arthritis in these
painful deep skin ulcerations, is a more serious skin patients. Studies that address the efficacy of methotrex-
manifestation but is less common. Acute anterior uveitis ate in the peripheral form of enteropathic arthritis are
can be seen in up to 11% of patients and is usually the lacking. Intra-articular glucocorticoid injections can be
unilateral, transient pattern of eye inflammation char- used for flares of the peripheral arthritis. Budesonide,
acteristic of SpA patients. CD may also be associated a glucocorticoid with first-pass hepatic metabolism and
with a granulomatous uveitis that is more chronic. fewer systemic side effects as a result, has been used
Recurrent oral ulcerations may reflect the activity of increasingly for CD flares, but there are no studies to
underlying CD. date addressing the effect of this steroid on enteropathic
arthritis. In RA, budesonide has not found to be supe-
Diagnostic Studies rior to prednisone therapy (50).
Anti-tumor necrosis factor therapies have had a
Anemia is common in enteropathic SpA, reflecting major impact on the therapeutic approach to IBD and
both the anemia of chronic disease and GI blood to the associated joint diseases. Striking differences in
loss. C-reactive protein and erythrocyte sedimentation IBD are apparent between different modes of TNF
rate are usually elevated when the disease is active. inhibition, however, with infliximab (a monoclonal anti-
Rheumatoid factors and antinuclear antibodies are body) showing efficacy for many patients with IBD
absent in most patients. Radiographic studies of periph- particularly CDbut etanercept (a soluble fusion
eral joints generally do not reveal erosive changes, but protein) being ineffective. Etanercept can control the
a destructive process in the hip can occur. Imaging of arthritis associated with CD while having no effect on
the sacroiliac joints and spine are usually similar to the bowel disease itself (51). Infliximab mediates the
primary AS, although a higher frequency of asymmetric healing of fistulas in CD and also helps maintain disease
sacroiliitis and zygapophyseal joint ankylosis has been control. Recent studies have demonstrated that inflix-
reported (48).
10
imab is as effective for both axial and peripheral arthri-
tis associated with CD as it is for primary AS (52).
Genetics
The peripheral arthritis of IBD is not associated with
HLA-B27, whereas the axial form of arthritis is,
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lonoscopy and bowel histology in patients with HLA-B27 63:688695.
related arthritis. J Rheumatol 1985;12:294298. 51. Marzo-Ortega H, McGonagle D, OConnor P, Emery P.
42. Veloso FT, Carvalho J, Magro F. Immune-related mani- Efficacy of etanercept for treatment of Crohns-related
festations of inflammatory bowel diseasea prospective spondyloarthroarthritis but not colitis. Ann Rheum Dis
study of 792. J Clin Gastroenterol 1988;83:703709. 2003;62:7476.
43. Steer S, Jones H, Hibbert J, et al. Low back pain, sacroi- 52. Rispo A, Scarpa R, Di Girolamo E, et al. Infliximab in the
liitis and the relationship with HLA-B27 in Crohns treatment of extra-intestinal manifestations of Crohns
disease. J Rheumatol 2003;30:518522. disease. Scand J Rheumatol 2005;34:387391.
10
CHAPTER 11
Osteoarthritis
PAUL DIEPPE, MD
Osteoarthritis (OA) is the most common form of joint The symptoms of OA are pain, short-lasting stiffness,
disease in humans. cracking of joints, joint swelling, fatigue, and func-
The most commonly affected are apophyseal tional limitation.
joints of the cervical and lumbar spine, Osteoarthritis is characterized on physical exam by
interphalangeal joints of the hand, the thumb firm swelling around the joint line, crepitus, and
base, the first metatarsophalangeal joint, the hips, restricted range of motion.
and the knees. Diagnosis of OA can usually be made by history and
Osteoarthritis is strongly age related. Additional risks physical exam, but radiographs demonstrating joint
include family history, female sex, obesity, and space loss, osteophytes, and changes in the subchon-
trauma. dral bone are diagnostic.
Osteoarthritis (OA) is the most common form of joint OA in some of their joints (although they may remain
disease in humans. Our ancestors skeletons show that asymptomatic).
it has been with us for many centuries. However, it was The most important risk factors for OA are shown
only differentiated from other forms of arthritis about in Table 11A-1. But, as indicated, some risk factors are
100 years ago (1), when a combination of pathological more important for OA of a particular joint than others.
and radiographic studies made it clear that there were For example, OA of the knee is strongly associated with
two quite distinct types of synovial joint damage: atro- women and obesity, and is more common in blacks than
phic arthritis, in which there is periarticular osteoporo- whites, whereas hip OA has a more equal sex incidence,
sis and erosive changes, in addition to cartilage loss; and a less strong association with obesity, and is rare in
hypertrophic arthritis, in which the cartilage loss is Chinese people.
accompanied by an increase in bone density and bone
formation around the joint.
The atrophic subset was subsequently differentiated CLINICAL FEATURES
into a variety of infectious and inflammatory conditions,
including rheumatoid arthritis (RA). Hypertrophic Osteoarthritis is, by definition, a disorder of synovial
arthritis is what we now know as OA. It is clear that this joints. It can affect any one of the 200 or so synovial
too includes a variety of different conditions, but we joints in the body, but whereas it is common in some, it
have made less progress in our understanding of this rarely affects others. The most frequently affected sites
group, and the differentiation of distinct entities has are the apophyseal joints of the cervical and lumbar
proved elusive. Osteoarthritis, then, is a term that des- spine, the interphalangeal joints of the hand, the thumb
cribes a heterogeneous group of common conditions, base, the first metatarsophalangeal joint, the knee and
with similar pathological and radiographic features. the hip. Shoulders, ankles, and metacarpophalangeal
joints are amongst the less common sites of OA.
Osteoarthritis is also a focal disease of joints. Unlike
EPIDEMIOLOGY inflammatory arthropathies, it does not always affect
the whole joint. For example, in the knee the most
Osteoarthritis is a strongly age-related disorder. It is common parts to be affected are the medial tibiofemo-
uncommon before the age of 40, but its prevalence ral and lateral patellofemoral compartments, and the
rises rapidly with age thereafter, such that most people superior pole of the hip is the most likely area of that
over the age of 70 have the pathological changes of joint to be damaged.
224
C H A P T E R 1 1 O S T E O A R T H R I T I S 2 25
TABLE 11A-1. RISK FACTORS FOR OSTEOARTHRITIS. getting started after sitting down for a while. It is not
known what causes this. People may present with a
Increasing age (all sites)
variety of other symptoms, including cracking of joints
Female sex or gender (some sites, particularly knee and hand) (audible crepitus), joint locking, swelling, fatigue, and,
of course, difficulty with daily activities.
Race or ethnicity (variable at different joint sites)
Genetic predisposition (all sites)
Obesity (most sites, but more marked for the knee than other
PHYSICAL EXAMINATION
joints)
The osteoarthritic joint generally has evidence of mild-
Trauma, and some occupations involving repetitive activities to-moderate firm swelling around the joint line, palpa-
(specific sites)
ble creaking on movement (crepitus), and restricted
range of motion with pain at the end of the range. The
swelling is usually due to the formation of chondro-
phytes or osteophytes at the joint margin, and these may
How can we explain this? If the OA process is driven be tender. There may also be tenderness over the joint
by mechanical factors, one plausible hypothesis is that line itself. In some cases there is evidence of mild inflam-
it is an age-related disorder of evolution (2). Our mus- mation, with some warmth over the joint line and an
culoskeletal system evolved to suit our ancestors, who effusion. Other common signs include weakness and
walked around on four legs and did not have a prehen- wasting of the muscles acting on the joint, and areas of
sile grip. In evolutionary terms, we stood up and started periarticular tenderness. In advanced cases, deformities
to grip things between fingers and thumbs a relatively and instability of the joints are seen.
short time ago, so that the skeleton has not had time to
adapt to these changes in posture and joint use. One
result of this is that the shape of certain parts of our INVESTIGATIONS
joints, such as the superior pole of the hip, are not well
suited to the mechanical stresses that our everyday In the majority of cases, OA can and should be diag-
activities submit them to. nosed from the history and clinical signs alone, without
recourse to any investigations. It is a localized disorder,
without any systemic features, so blood tests are all
HISTORY normal [with the caveat that small increases in serum
C-reactive protein (CRP) can occur]. Joint images,
Despite the fact that OA is described as a heteroge- including x-rays and magnetic resonance imaging
neous group of disorders, shared clinical features bind (MRI), are abnormal, reflecting the joint pathology.
the group together. The two cardinal symptoms of OA The plain radiograph is the investigation most fre-
are use-related pain, and relatively short-lasting stiff- quently used to confirm the clinical diagnosis, and for
ness or gelling of the joints after inactivity. the definition of the condition for research studies. The
We know surprisingly little about OA paineither main radiographic features of OA are narrowing of the
about the patient experiences of pain or about its patho- joint space (due to loss of articular cartilage), osteo-
genesis. Most people describe pain that is exacerbated phytes, and a variety of changes in the subchondral
by use of the joint, but the discomfort often continues bone, including cysts, sclerosis, shape changes, and loss
for some time after activity ceases, wearing off slowly. of bone volume (Figure 11A-1) (3).
Some people experience particularly severe but short- If synovial fluid is aspirated from a joint with OA, it
lasting bouts of pain on a particular movement or activ- is generally relatively viscous and translucent in com-
ity, and some experience such bouts spontaneously. In parison with that from a patient with RA, which tends
others pain can occur at night, disrupting sleep. A wide to be thinner and more opaque due to the higher number
variety of adjectives are used to describe the pain or of cells related to a greater degree of intra-articular
discomfort. The amount of pain experienced obviously inflammation. 11
depends on what people do, and to what extent they There is a great deal of current interest in another
avoid particular activities or movements that are most type of laboratory investigation in OAthe search for
likely to exacerbate it, making the assessment of pain in so-called biochemical markers of the disease process,
OA problematic. products of abnormal breakdown or synthesis of
Similarly, gelling of joints is a somewhat mysterious connective tissue components in the joint, but such
symptom. The most common phenomenon seems to be investigations have proved to be of limited value as yet,
difficulty initiating joint movement after inactivity, epit- even as a research tool, and they have no clinical
omized by the problems older people with OA have in relevance.
226 PAUL DIEPPE
However, a concern is that we have not, as yet, found

the most important features of the condition on which
to attempt the distinction of subsets. Those of us who
are natural splitters of diseases like to talk about distinct
subsets when we see patients with OA, such as general-
ized inflammatory OA, secondary OA of the knee, or
pyrophosphate arthropathy, as if these were clear enti-
ties. But there is a great deal of evidence to suggest that
such patients represent the extremes of the spectrum,
rather than distinct disorders. For example, the chances
of someone getting secondary knee OA after injury or
meniscectomy are dependent on the same set of local
and systemic risk factors associated with primary or
sporadic cases of knee OA (4). Similarly, most patients
with OA and effusions have some crystals in their joint
fluid; this is just rather more obvious in some, such as
those that we might label as having the condition pyro-
phosphate arthropathy.
Genetic investigations may help sort out this problem.
For example, families who inherit an abnormality in the
FIGURE 11A-1
articular cartilage, such as those with the well-described
Plain radiograph of a typical patient with moderate osteoarthritis abnormality of the COL2A1 gene, or those with alkap-
of the knee joint. Note the loss of joint space, particularly tonuria, have an uncommon OA phenotype character-
marked in the medial compartment, caused by loss of articular ized by the involvement of joints not usually affected by
cartilage, the sclerosis of the underlying subchondral bone, and
the osteophyte formation at the joint margin.
sporadic or generalized OA (such as the shoulder) and
by more involvement of the lateral than the medial side
of the tibiofemoral joint. Similarly, some forms of epiph-
yseal dysplasia, which can result in an unusual, prema-
ture OA phenotype, have been associated with genetic
DISEASE PATTERNS defects of cartilage components, such as COL9A3 (5).
AND SUBSETS This suggests that most sporadic OA may not be caused
by intrinsic abnormalities of articular cartilage.
It has proved difficult to pin down clear disease subsets The typical patient with OA is a middle-aged or
within what is clearly a spectrum of disorders. This is a older person presenting with the gradual onset of dis-
major problem for OA research, as the current explosion comfort and stiffness in a knee or hip, often accompa-
of interest in the genotype is unlikely to prove valuable nied by some back pain, in whom one or both hips or
until we can describe the phenotype properly. knees are the major sites of joint damage. In some of
The main factors that have been considered as indic- these cases there is evidence of previous injury or abnor-
ative of possible subsets have included: mality in the worst affected joint(s).
However, in routine clinical practice, there are a
1. The presence or absence of an obvious cause (primary number of other quite different patient archetypes seen,
or secondary OA). who also get labeled as having OA. These include:
2. The distribution between joints and numbers of joints
affected (localized or generalized OA). 1. Menopausal, inflammatory, nodal, generalized (or
3. The amount of bone formation around the joints, or, erosive) OA. As indicated, this condition, which may be
conversely of bone attrition (hypertrophic or atro- a distinct entity, has been given many different names
phic OA), and the related presence or absence of over the years. It occurs most often in women, begin-
diffuse idiopathic skeletal hyperostosis (DISH). ning around the time of the menopause, and is charac-
4. The presence of absence of overt inflammation terized by the development of pain, swelling, and
(inflammatory OA). inflammation in interphalangeal joints of the hand
5. The presence or absence of chondrocalcinosis (Figure 11A-2). One or more joints come up at a time
(pyrophosphate arthropathy) or of basic calcium and are often red. After a while the pain and inflamma-
phosphate crystal deposition (apatite-associated tion in them settles, leaving the joint swollen, sometimes
arthropathy). deformed, and stiff. Bony erosions may develop in the
6. The rate of progression (rapidly progressive joints, and cystic swellings full of hyaluronan can also
osteoarthritis). appear. These features have led many people to specu-
the foot being the principle site affected) or syringomy-

elia (when the shoulder is the joint most often affected)
are now the common causes. So-called Milwaukee
shoulder syndrome or apatite associated destructive
arthritis may be a variant of this condition (see Chapter
25D).
4. Rapidly progressive hip or knee OA. As outlined
below, the natural history of OA is usually slow.
However, in a minority of cases there a rapidly progres-
sive phase of joint damage, often accompanied by more
inflammation than is usual, and severe pain. Such cases
often come to joint replacement. The cause of this rapid
progression is unknown.
DIFFERENTIAL DIAGNOSIS
The diagnosis of OA is easy. The main problem does
not come with diagnosing the presence or absence of
joint pathology characteristic of OA, it comes in
knowing whether the pain and disability is due to those
pathological changes or not. As already noted, many
people with advanced pathology are asymptomatic, and
FIGURE 11A-2 OA pathology in joints is so common as to be almost
normal in older people. So we cannot assume that all
Clinical photograph of a patient with nodal, generalized those that are symptomatic have pain that is a direct
osteoarthritis showing the typical swellings of the distal
result of their OA pathology. The pain may be referred,
interphalangeal joints (Heberdens nodes) and of the proximal
interphalangeal joints (Bouchards nodes), as well as squaring of it may be due to periarticular problems (such as tro-
the thumb base due to OA and subluxation of the carpometa- chanteric bursitis around the hip or anserine bursitis
carpal joint. (From Womens Health Services, University of around the knee), or it may be the result of pain sensi-
Maryland Medical School, with permission.) tization, causing abnormal sensations with normal
activities. Psychological factors, such as anxiety and
depression, as well as social problems, such as isolation
late that it is an inflammatory type of arthritis, and to and coping strategies, are all known to be determinants
try disease-modifying drugs of the sort used in RA to of pain in people with OA (7).
treat the patients. However, the condition nearly always
settles on its own after a few years, and there is no good
evidence for the effectiveness of these drugs. Further-
more, the condition does seem to be strongly related to COURSE, PROGNOSIS, AND
the presence of ordinary OA in the knees and other OUTCOME
joints.
2. Diffuse idiopathic skeletal hyperostosis (DISH). Osteoarthritis is generally thought of as a slowly pro-
This condition is characterized by the formation of gressive condition. Its association with age, as well as
bridging enthesophytes in the spine, as well as entheso- the loss of articular cartilagea very obvious pathologi-
phytes and osteophytes in peripheral joints, and people cal featurehas led to it being called degenerative joint
with it often have OA (6). The affected joints often disease and to all the negativity that goes with such a
stiffen up with a marked reduction in the range of name, including the concept that it inevitably gets worse
motion. DISH is associated with metabolic syndrome and that the joints wear out. This is not the case. 11
and occurs principally in older, obese men or The idea that OA is a spectrum disorder, with rela-
diabetics. tively distinct clinical entities seen at the ends of the
3. Neuropathic arthropathy (Charcots joints). spectrum, including a progressive form, has already been
Denervation of joints, or loss of pain sensation, can mentioned. Rapidly progressive joint damage is clearly
result in the development of a destructive form of OA uncommon. Epidemiological data make it is obvious
with extensive new bone formation around the joints. that most OA must stabilize: some 40% of older people
This used to be seen mostly in the context of late syphi- have x-ray evidence of significant OA in their hips or
lis (with knee disease), but diabetic neuropathy (with knees, and yet less than 5% of older people will ever
228 PAUL DIEPPE
as the joint anatomy is changing pain is generated, along

with a change in pain sensitization both in the periphery
DEVELOPING OA and centrally, in which case normal movements may
PROGRESSIVE OA
(painful) become painful, and this activity-related pain (due to
(painful)
sensitization of the pain system) may persist even when
the process has become quiescent. If this is the case, it
may help us explain the discordance between x-rays and
symptoms, as outlined in Figure 11A-3.
Osteoarthritis, then, is not necessarily a progressive
IDENTICAL
disorder, and the prognosis is not inevitably a bad one.
STABLE OA RADIOGRAPHS However, OA is a disease affecting older people, in
(painless) whom a combination of advancing years and comorbidi-
ties are taking their toll on health. For these reasons,
manyperhaps mostpeople with OA do get worsen-
ing of disability over the years, making it appear that
FIGURE 11A-3 their OA has deteriorated. But the comorbidities may
Diagram summarizing an hypothesis about OA x-rays and be much more important than the OA. For example,
disease progression. This hypothesis, outlined in the text, in people with OA, walking speed may be as depen-
considers OA to be a phasic disease process that is a response dent on the presence of a cataract as it is on the joint
to abnormal joint biomechanics and an attempt at joint repair. disease.
While the disease is active, changing joint anatomy, it can cause
direct nocioceptive pain. Pain sensitization may also occur, in
which case pain may persist when the disease process has
ceased to be active. The plain radiograph, the most frequently REFERENCES
used investigation in OA, will look the same whether the disease
is evolving, inactive, or progressing, and whether the pain is due 1. Nichols E, Richardson F. Arthritis deformans. J Med Res
to direct nocioception, to periarticular problems, or results from 1909;21:149221.
peripheral or central pain sensitization.
2. Lim K, Rogers J, Shepstone L, Dieppe P. The evolution-
ary origins of osteoarthritis: a comparative study of
hand disease in two primates. J Rheumatol 1995;22:2132
2134.
need a joint replacement. It follows that either the joint 3. Watt I, Doherty M. Plain radiographic features of osteo-
arthritis. In: Brandt K, Doherty M, Lohmander S, eds.
damage and/or the symptoms cannot progress in the
Osteoarthritis. 2nd ed. Oxford, England: Oxford Univer-
majority. Most cases stabilize after a period of change in sity Press; 2003.
joint anatomy, some progress, and a small minority 4. Englund M, Lohmander S. Risk factors for symptomatic
improve spontaneously (especially hip OA) (8). knee osteoarthritis fifteen to twenty-two years after meni-
It seems likely that OA is a pathological process sectomy Arthritis Rheum 2004;50:28112819.
characterized by phases of activity within the joint, 5. Nakashima E, Kitoh H, Maeda K, et al. Novel COL9A3
interspersed with periods in which the process is quies- mutation in a family with multiple epiphyseal dysplasia.
cent (9). Perhaps relatively minor degrees of change in Am J Med Genet A 2005;132:181184.
biomechanics trigger the process. The process itself can 6. Sarzi-Puttini P, Atzeni F. New developments in our under-
be seen as an attempt of the joint to repair damage; standing of DISH (diffuse idiopathic skeletal hyperosto-
thus, the formation of osteophytes and thickening of the sis). Curr Opin Rheumatol 2004;16:287292.
7. Steultjens M, Dekker J, Bijlsma J. Coping, pain and dis-
capsule can be seen as the attempt of the joint to splint
ability in osteoarthritis. J Rheumatol 2001;28:10681072.
itself, and the changes in the subchondral bone, which 8. Perry G, Smith M, Whiteside C. Spontaneous recovery of
alter joint shape, can be seen as an attempt to normalize the joint space in degenerative hip disease. Ann Rheum
load bearing. These processes, which are accompanied Dis 1979;31:440448.
by cartilage loss (within this hypothesis cartilage is the 9. Kirwan J, Elson C. Is the progression of osteoarthritis
innocent bystander) inevitably lead to x-ray changes, phasic? Evidence and implications. J Rheumatol 2000;
but not to symptoms. However, it is also probable that 27:834836.
CHAPTER 11
Osteoarthritis
FRANCIS BERENBAUM, MD, PHD
Changes in articular cartilage and subchondral bone cartilage-degrading enzymes. Other mediators
are the characteristic histopathological changes of of inflammation including prostaglandins and
osteoarthritis (OA). reactive oxygen species also contribute to OA
Osteoarthritis results from a failure of chondrocytes pathogenesis.
to maintain the balance between degradation and Mechanical factors are essential for maintaining
synthesis of extracellular matrix. normal cartilage homeostasis and mechanical stress
Increased breakdown of cartilage involves protein- contributes significantly to disease initiation and
ases such as matrix metalloproteinase. progression.
Proinflammatory cytokines synthesized by chondro-
cytes and synoviocytes may drive production of
PATHOLOGY Passage of Normal Cartilage to

Aging Cartilage
Osteoarthritis (OA) can be defined as a gradual loss
of articular cartilage, combined with thickening of the Fissures that develop in cartilage during aging are due
subchondral bone, bony outgrowths (osteophytes) at mainly to stress fractures of the collagen network.
joint margins, and mild, chronic nonspecific synovial Several structural and biochemical changes involving
inflammation. The difference between physiologic aging the noncollagenous component of the matrix occur
of the cartilage and OA cartilage is not sharp. However, during aging. These changes alter biomechanical prop-
three cartilage stages can be identified: stage I, normal erties of the cartilage that are essential for the
cartilage; stage II, aging cartilage; and stage III, OA distribution of forces in the weight-bearing zone.
cartilage. Glycosaminoglycans are modified qualitatively; they
become shorter as the cartilage ages. The concentration
of type 6 keratan sulfate (KS) increases during aging, to
Normal Cartilage the detriment of type 4 KS. Also, an age-related reduc-
Normal cartilage has two main components. One is the tion in total proteoglycan synthesis after skeletal matu-
extracellular matrix, which is rich in collagens (mainly ration has been reported. This reduction could be due,
types II, IX, and XI) and proteoglycans (mainly aggre- at least in part, to a reduction in chondrocyte numbers
can). Aggrecan is a central core protein bearing numer- with advancing age. These quantitative and qualitative
ous glycosaminoglycan chains of chondroitin sulfate changes in proteoglycan reduce the capacity of the mol-
and keratan sulfate, all capable of retaining molecules ecules to retain water. A prominent feature of aging is
of water. The second component consists of isolated the modification of proteins by nonenzymatic glycation
chondrocytes, which lie in the matrix. The matrix leading to the accumulation of advanced glycation end
components are responsible for the tensile strength products (AGEs). Once they are formed, AGEs cannot
and resistance to mechanical loading of the articular be removed from the collagens, and, therefore, they
cartilage. accumulate in articular cartilage. The accumulation of
229
230 FRANCIS BERENBAUM
AGEs in cartilage leads to inferior mechanical proper- disease progression. Specific changes in the architecture
ties. Moreover, chondrocytes can express receptors that of the subchondral trabecular bone are due to acceler-
are capable of binding AGEs and can modulate cell ated bone turnover.
function. The best characterized AGE receptor is called
the receptor for advanced glycation end products
(RAGE). Thus, AGEs trigger RAGE on chondrocytes, PATHOGENESIS
leading to increased catabolic activity and therefore to
cartilage degradation (1). In conclusion, aging cartilage The physiologic homeostasis of the articular cartilage is
contains less water, which alters the biochemical prop- driven by chondrocytes, which synthesize collagens,
erties of the cartilage, less chondrocytes, which decreases proteoglycans, and proteinases. Osteoarthritis result
the capacity of cartilage to synthesize matrix, and altered from a failure of chondrocytes within the joint to syn-
collagens. thesize a good quality matrix, in terms of resistance and
elasticity, and to maintain the balance between synthe-
sis and degradation of the extracellular matrix.
Osteoarthritic Joints The change in the quality of the matrix synthesized
Osteoarthritic joints have abnormal cartilage and bone, is due to alterations in the differentiation process of
with synovial and capsular lesions (2). Macroscopically, chondrocytes (3). Chondrocyte hypertrophy can con-
the most characteristic elements are reduced joint space, tribute to the progression of OA via effects including
formation of osteophytes (protrusions of bone and car- dysregulation of matrix repair through reduced expres-
tilage) mostly at the margins of joints, and sclerosis of sion of collagen II and aggrecan, increased expression
the subchondral bone. These changes are the result of of type X collagen, upregulation of matrix metallopro-
several histologic phases. teinase 13 (MMP-13), and promotion of pathologic
calcification. OA cartilage typically develops foci of
maturation of cells to hypertrophic differentiation (4).
Phase 1: Edema and Microcracks A recapitulation of embryonic skeletal development
also occurs in the deep and calcified zones where the
The first recognizable change in OA is edema of the
hypertrophic chondrocyte-specific type X collagen is
extracellular matrix, principally in the intermediate
expressed, and in the upper middle zone where type III
layer. The cartilage loses its smooth aspect, and micro-
collagen expression is detected. Chondrocyte dediffer-
cracks appear. There is a focal loss of chondrocytes,
entiation has also been described. The main evidence
alternating with areas of chondrocyte proliferation.
of chondrocyte dedifferentiation in OA is the presence
of types I and III collagens, and the chondroprogenitor
Phase 2: Fissuring and Pitting splice variant type IIA collagennone of which usually
are present in adult articular cartilageand the pro-
The microcracks deepen perpendicularly in the direc- duction of greater than normal amounts of type VI
tion of the forces of tangential cutting and along fibrils collagen.
of collagen. Vertical clefts form in the subchondral bone The imbalance between synthesis and degradation of
cartilage. Clusters of chondrocytes appear around these the extracellular matrix is caused by increasing synthe-
clefts and at the surface. sis of proteinases that breakdown collagens and aggre-
cans, and decreased synthesis of natural inhibitors of
these proteinases, the tissue inhibitor of metalloprotein-
Phase 3: Erosion ases (TIMPs). This abnormal chondrocyte synthesis is
Fissures cause fragments of cartilage to detach and the result of tissue activation by cytokines, lipid media-
fall into the articular cavity, creating osteocartilagi- tors (mainly prostaglandins), free radicals (NO, H2O2),
nous loose bodies and uncovering the subchondral and constituents of the matrix itself, such as fibronectin
bone, where microcysts develop. The loose bodies cause fragments. Activated chondrocytes become capable of
the mild synovial inflammation of OA. The resulting synthesizing certain proteinases and proinflammatory
synovial inflammation often is more focal, though often mediators. Although the role of the chondrocyte seems
just as intense, than inflammation that occurs in rheu- to be fundamental, the synovial tissue helps perpetuate
matoid synovitis. Histologically, OA synovitis is charac- chondrocyte activation. Synovial cells phagocytize the
terized by nonspecific lymphoplasmocytic and histiocytic fragments of cartilage released into the joint, which
infiltration. causes synovial inflammation. Then, OA synovial cells
There is sclerosis of the subchondral bone, due to the become capable of producing a range of mediators that
apposition of small strips of new bone. Osteophytes are released in the cavity, such as MMPs and cytokines,
form around this zone, their surface covered with fibri- which in turn can alter the cartilage matrix and activate
lar cartilage. Subchondral sclerosis increases with chondrocytes. Finally, the subchondral bone may
contribute to the degradation of cartilage. Osteoblasts CYTOKINES

isolated from subchondral OA bone demonstrate an
altered phenotype. In comparison to normal osteoblasts, Although OA is often classified as a non-inflammatory
they produce more alkaline phosphatase, osteocalcin, disease, numerous studies have shown that inflamma-
insulinlike growth factor (IGF)-1, and urokinase. tory cytokines provide essential biomechanical signals
OA osteoblast phenotype contributes to cartilage that stimulate chondrocytes to release cartilage-
degradation by inhibiting cartilage matrix component degrading enzymes. Proinflammatory cytokines synthe-
synthesis and by increasing MMP synthesis by articular sized by chondrocytes and synoviocytes bind to specific
chondrocytes (5). receptors on chondrocytes. These bound cytokines
cause transcription of the MMP genes, and the genes
products are exported from the cell in an inactive form.
It is generally accepted that interleukin (IL) 1 is the
Enzymes Involved in pivotal cytokine released during inflammation of the
Cartilage Degradation osteoarthritic joint (8). Other cytokines are released,
The main proteinases involved in the destruction of including chemokines (IL-8, GRO alpha, MIP-1 alpha
cartilage in OA are the MMPs (6). There are at least 18 and MIP-1 beta). Some of these cytokines and chemo-
members of this gene family of neutral Zn2+ metallopro- kines may be regulatory [e.g., IL-6, IL-8, lymphocyte
teinases. Because they are active at neutral pH, the inhibitory factor (LIF)], or inhibitory (e.g., IL-4, IL-10,
MMPs can act on the cartilaginous matrix at some dis- IL-13, interferon gamma). IL-1 receptor antagonist, IL-
tance from the chondrocytes. They can be synthesized 4, IL10, and IL-13 prevent the secretion of some MMPs
by chondrocytes and synoviocytes under the influence and may increase the synthesis of TIMPs. In a more
of cytokines. general way, IL-4 and IL-13 counteract the catabolic
Aggrecanase, the enzyme that cleaves the Glu373- effects of IL-1. Finally, IL-1 alters the quality of the
Ala374 bond of the interspherical domain of aggrecan, cartilage matrix by causing synthesis of type II and IX
also plays a major role in the degradation of the matrix. collagens to decrease, while increasing the synthesis of
Two aggrecanases have been cloned. They belong to the type I and type III collagens.
MMP family, specifically the ADAMTS (disintegrin A new family of cytokines, called adipokines (for
and metalloproteinases with thrombospondin motifs) cytokines produced by adipose tissue), has been recently
family. They are called aggrecanase 1 (or ADAMTS-4) implicated in the pathophysiology of OA. Adipokines
and aggrecanase 2 (or ADAMTS-11). such as leptin, adiponectin, and resistin are detected
The activities of MMPs are strictly controlled by both in the plasma and in the synovial fluid obtained
stoichiometric inhibition with specific inhibitors, from OA patients. Various tissues obtained from human
TIMP1-4. Therefore, the balance between the amounts OA-affected joints, including synovium, infrapatellar
of MMPs and TIMPs in cartilage determines if carti- fat pad, meniscus, cartilage, and bone, release leptin and
lage is degraded (7). MMPs produced by the chondro- adiponectin. The roles of adopokines in OA pathophys-
cyte and released into the extracellular matrix are iology remain largely unknown.
activated by an enzyme cascade involving serine pro-
teinases (plasminogen activator, plasminogen, plasmin), Lipid Mediators
free radicals, cathepsins, and some membrane-type
MMPs. This enzymatic cascade is regulated by natural The eicosanoids also can take part in chondrocyte
inhibitors, including the TIMPs and the inhibitors of activation (9). Prostaglandins, produced after activation
the plasminogen activator. MMP-13 is elevated in OA of phospholipases A2, cyclooxygenases (mainly the
joint tissues, particularly in articular cartilage, and cyclooxygenase-2 isoform) and prostaglandin synthases
colocalizes with type II collagen cleavage epitopes in (mainly the microsomal prostaglandin E synthase-1) by
regions of matrix depletion in OA cartilage. The other proinflammatory cytokines can favor the synthesis of
enzymes that can degrade type II collagen and proteo- MMPs by activating the cell via specific cellular or/and
glycans are the cathepsins. They are active only at low nuclear prostaglandin receptors. Among eicosanoids,
pH and include the aspartate proteinases (cathepsin D) prostaglandin E2 seems to be the main lipid mediator 11
and cysteine proteinases (cathepsins B, H, K, L, and produced by synovial cells, chondrocytes, and sub-
S) that are stored in chondrocyte lysosomes and chondral osteoblasts and involved in cartilage degrada-
released into the pericellular microenvironment. tion in OA.
Glycosidases also may be important, because proteo-
glycans are very rich in carbohydrate chains. Although
hyaluronidases are not present in cartilage, other
Reactive Oxygen Species
glycosidases may contribute to the degradation of Reactive oxygen species (ROS) play a crucial role in the
proteoglycans. regulation of a number of basic chondrocyte activities,
such as cell activation, proliferation, and matrix remod- 5 beta 1, alpha 10 beta 1), laminin (alpha 6 beta 1), and
eling. However, when ROS production exceeds the vitronectin and osteopontin (alpha V beta 3). Some
antioxidant capacities of the cell, an oxidative stress of these receptors are sensitive to prolonged changes
occurs, leading to structural and functional cartilage in pressure (mechanoreceptors). Injurious static or
damages like cell death and matrix degradation (10). dynamic compression stimulates depletion of proteo-
Nitric oxide (NO) is a gas synthesized by way of the glycans and damage to the collagen network and
oxidation of L-arginine by the NO synthases (NOS). decreases the synthesis of cartilage matrix proteins,
Chondrocytes produce large amounts of NO after whereas low intensity dynamic compression increases
upregulation of the iNOS gene by cytokines. Most in matrix synthetic activity. Certain types of mechanical
vitro studies indicate that NO is partly responsible for stress and cartilage matrix degradation products are
the blocking of glycosaminoglycan and collagen synthe- capable of stimulating the same signaling pathways as
sis by IL-1, and may contribute to the activation of the those induced by IL-1 and tumor necrosis factor alpha
latent forms of MMPs. NO also may mediate the IL-1 (TNF-alpha). These pathways involve cascades of
stimulated synthesis of MMP mRNA and protein, and kinases, including the stress-activated protein kinases
may contribute to chondrocyte cell death by interfering (SAPKs), also termed c-Jun N-terminal kinases (JNKs)
with survival signals from the extracellular matrix. and p38 MAP kinase, IB kinases, and phosphati-
However, NO may have anabolic and anticatabolic dylinositol-3-kinase (PI-3K) and NF-B. Because these
effects in cartilage under certain conditions. Therefore, pathways may also induce the expression of the genes
the actual role of NO in the degradative process of OA encoding these cytokines, it remains controversial
is not clear (11). whether inflammatory cytokines are primary or second-
ary regulators of the progressive cartilage destruction
in OA.
Matrix Degradation Products
The products of matrix degradation, such as fibronectin
fragments, can activate chondrocytes through intergrin- Attempts to Repair Cartilage
type receptors, causing the synthesis of MMPs. These
There is evidence of attempted repair of the
products can stimulate or activate other factors, such
OA-damaged joint, particularly of the cartilage and
as catabolic cytokines, that amplify the damage. The
subchondral bone, at least in the early stages of OA
damage, in turn, enhances the concentrations of the
(13). Growth factors involved in the physiological
degradation products themselves, as in a positive feed-
matrix synthesis, such as platelet-derived growth factor,
back loop.
IGF-1, and transforming growth factor beta (TGF-
beta), are produced in excess by OA chondrocytes,
subchondral bone, and synovial tissues. TGF-beta,
Mechanical Stress IGF-I, and basic fibroblast growth factor have anabolic
Along with chemical mediators, biophysical mediators effects in matrix synthesis, can inhibit the effects of the
could also be directly involved in chondrocyte activa- proinflammatory cytokines, and possess mitogenic
tion in OA. Compressive, but also shear and stretch, properties for the chondrocyte. These growth factors
stresses occur on cartilage. Interestingly, there is con- also have a high affinity for matrix. When they are syn-
siderable evidence that interactions between biome- thesized they become trapped in the cartilage, which
chanical factors and proinflammatory mediators are acts as a reservoir for these factors. The factors are
involved in the initiation and the progression of OA released when the matrix is broken down, and tend to
(12). In vivo studies have shown increased concentra- repair lesions.
tions of inflammatory cytokines and mediators in the There is considerable interest in the role of subchon-
joint in mechanically induced models of osteoarthritis. dral bone in this attempted repair. The metabolism of
In vitro explant studies confirm that mechanical load is subchondral bone is increased during OA, which leads
a potent regulator of matrix metabolism, cell viability, to the production of growth factors, such as the bone
and the production of proinflammatory mediators such morphogenic protein 2 (BMP-2). Experiments have
as NO and prostaglandin E2. Chondrocytes have recep- shown that this protein can repair a cartilaginous defect.
tors for responding to mechanical stress and can respond However, attempted repair of cartilage defects is in
to direct biomechanical perturbation by upregulating vain for the following reasons: (1) Alterations in the
synthetic activity or inflammatory cytokines, which are differentiation process of the chondrocytes results
also produced by other joint tissues. Chondrocytes in the synthesis of a matrix with poor biomechanical
express several members of the integrin family, and properties. (2) Not enough growth factors and TIMPs
these can serve as receptors for fibronectin (alpha 5 are produced to counteract the effect of cytokines and
beta 1), types II and VI collage (alpha 1 beta 1, alpha proteinases. (3) The bioavailability of certain growth
factors is decreased (e.g., IGF-I activity is reduced Epidemiological studies on the prevalence of OA in
because of excess IGF-binding proteins and receptor women after menopause suggest that one or more hor-
desensitization). monal factors are involved in the initiation of OA.
Chondrocytes bear estrogen receptors, and stimulation
of these receptors triggers the synthesis of growth
Initiation of Osteoarthritis factors. The plasma concentration of estrogens decreases
The initiation of OA is not well understood. It involves after menopause, which could result in decreased syn-
local, systemic, genetic, and environmental factors. thesis of growth factors by chondrocytes. This theory is
Numerous mechanical factors can directly or indirectly being examined, particularly in OA of the hand and
increase cartilage vulnerability. Experimentally, knee, two sites more frequently affected in this
increased pressure on cartilage alters the matrix archi- population.
tecture, which probably explains the high incidence of
knee OA in obese people. The ligaments around the
joints become more lax with age, leading to instability CONCLUSION
and injury. With age, strength gradually decreases and
peripheral neurologic responses that protect the joints The simple hypothesis that a passive deterioration of
slow. All these factors contribute to an abnormal distri- cartilage is the main cause of OA has given way to a
bution of pressure on the cartilage, resulting in shear more exciting view (Figures 11B-1, 11B-2). It is clear
stress. that the pathogenesis of OA is due to altered chondro-
Osteoarthritis also may be triggered by changes in cyte phenotype mediated by different autocrine and
the structure of the subchondral bone. This hypothesis paracrine signals, leading to the synthesis of many medi-
is based on the observation that sclerosis of subchondral ators of inflammation and degradation that alter the
bone precedes cartilaginous defects in some patients. matrix. Moreover, recent experimental studies empha-
Repeated microtraumas affecting the joint could size the predominant role of mechanical stresses on
provoke microfractures of the subchondral bone that, chondrocyte activation. It is quite likely that research
in turn, may modify the biomechanical qualities of the carried out over the next decade will result in increased
cartilage in the environment of these microfractures. understanding of the interaction between biomechanics
These changes would cause the bone to synthesize and molecular biology of chondrocytes, and of the inter-
growth factors that can result in the production of action between bone and cartilage in the pathogenesis
osteophytes and osteosclerosis. of OA.
FIGURE 11B-1
Modulation of chondrocyte activation by catabolic pathways. Signaling pathways are activated by

the binding of catabolic mediators on specific receptors. Activation of these signaling cascades
lead to transcription and post-transcriptional modifications of a set of genes [MMPs, aggrecanases
(ADAMTS), cytokines, NO, and prostaglandins]. Some of them may feedback/regulate or amplify
these responses. These catabolic factors include biochemical [proinflammatory cytokines, reactive
oxygen species (ROS), prostaglandins, ligands for the receptor of advanced glycation end products
(RAGE), extracellular matrix (ECM) components] and biophysical factors (mechanical stresses).
Mechanical
stress Interaction Cytokines (including chemokines, adipokines)
Ligands/specific receptors Prostaglandins
Reactive oxygen species
RAGE ligands
Extracellular matrix components
MAPK
NF-kB
11
Others
Transcriptional and MMPs

post-transcriptional regulation ADAMTS
Cytokines
Reactive oxygen species
Prostaglandins
FIGURE 11B-2 RISK FACTORS AGING CARTILAGE

Excess weight Cartilage fissure
Hypothetical model for initiation and Injury and occupation Shorter GAG Reversible
perpetuation of osteoarthritis. Accumula- Developmental deformities Increased KS6 conc. / decreased KS4 conc.
Joint laxity Decrease in chondrocyte number
tion of risk factors on aging cartilage Accumulation of AGEs
triggers the initiation of the osteoarthritic Decrease in water concentration
process. For didactic reasons, two phases
are described, early OA and late OA, but
the passage from one to the other is INITIATION
progressive and generally lasts many Deleterious mechanical stresses
Genetic factors (unknown)
years. Structural treatment of OA should Hormonal factors?
be more efficient at the early stage when
chondrocytes keep a high metabolic
EARLY OSTEOARTHRITIS
activity rather than at the late stage Increased chondrocyte proliferation
when chondrocytes lose their ability to Increased synthesis of matrix by chondrocytes
synthesize matrix. Abbreviations: KS, Alteration in collagen synthesis (decrease in type II/type I
collagen ratio)
keratan sulfate; AGE, advanced glycation Chondrocyte dedifferentiation
end products. Increased synthesis of proteinases by chondrocytes
Increased synthesis of cytokines by chondrocytes
Subchondral bone demineralization with microfractures
Inflamed synovial tissue
LATE OSTEOARTHRITIS Irreversible

Decreased chondrocyte proliferation
Chondrocyte apoptosis
Hypertrophic differentiation of chondrocytes
Osteophyte formation
Bone sclerosis
Persistence of proteinases and cytokines synthesis
REFERENCES 7. Dean DD, Martel-Pelletier J, Pelletier JP, Howell DS,

Woessner JF Jr. Evidence for metalloproteinase and
1. Loeser RF, Yammani RR, Carlson CS, et al. Articular metalloproteinase inhibitor imbalance in human osteoar-
chondrocytes express the receptor for advanced glycation thritic cartilage. J Clin Invest 1989;84:678685.
end products: potential role in osteoarthritis. Arthritis 8. Jacques C, Gosset M, Berenbaum F, Gabay C. The Role
Rheum 2005;52:23762385. of IL-1 and IL-1Ra in joint inflammation and cartilage
2. Pritzker KPH. Pathology of osteoarthritis. In: Brandt KD, degradation. Vitam Horm 2006;74:371403.
Doherty M, Lohmander S, eds. Osteoarthritis. New York: 9. Goldring MB, Berenbaum F. The regulation of chondro-
Oxford University Press; 1998;5061. cyte function by proinflammatory mediators: prostaglan-
3. Goldring MB. The role of the chondrocyte in osteoarthri- dins and nitric oxide. Clin Orthop 2004;(Suppl):S37S46.
tis. Arthritis Rheum 2000;43:19161926. 10. Henrotin Y, Kurz B, Aigner T. Oxygen and reactive
4. Cecil DL, Johnson K, Rediske J, Lotz M, Schmidt AM, oxygen species in cartilage degradation: friends or foes?
Terkeltaub R. Inflammation-induced chondrocyte hyper- Osteoarthritis Cartilage 2005;13:643654.
trophy is driven by receptor for advanced glycation end 11. Abramson SB, Attur M, Amin AR, Clancy R. Nitric oxide
products. J Immunol 2005;175:82968302. and inflammatory mediators in the perpetuation of osteo-
5. Lajeunesse D, Hilal G, Pelletier JP, Martel-Pelletier J. arthritis. Curr Rheumatol Rep 2001;3:535541.
Subchondral bone morphological and biochemical altera- 12. Guilak F, Fermor B, Keefe FJ, et al. The role of biome-
tions in osteoarthritis. Osteoarthritis Cartilage 1999;7:321 chanics and inflammation in cartilage injury and repair.
322. Clin Orthop 2004;1726.
6. Cawston T. Matrix metalloproteinases and TIMPs: prop- 13. van der Kraan PM, van den Berg WB. Anabolic and
erties and implications for the rheumatic diseases. Mol destructive mediators in osteoarthritis. Curr Opin Clin
Med Today 1998;4:130137. Nutr Metab Care 2000;3:205211.
CHAPTER 11
Osteoarthritis
C. Treatment
LEENA SHARMA, MD
Nonpharmacologic treatments of osteoarthritis (OA) Pharmacologic approaches to treatment include non-

include education, weight management, and appro- narcotic analgesics such as acetaminophen and
priate exercise, which may delay disease progression, nonsteroidal anti-inflammatory drugs (NSAIDs).
reduce symptoms, and improve function. Intra-articular injection of glucocorticoids or hyaluro-
Nutritional supplements such as glucosamine nan may be useful for isolated joint involvement.
and chondroitin sulfate have been studied in Surgical joint replacement, especially at the hip and
OA, may benefit some patients, and have low knee, can reduce pain and improve function in
toxicity. appropriate candidates.
It is estimated that 12% of Americans between ages NONPHARMACOLOGIC

25 and 75 years have clinical signs and symptoms of
osteoarthritis (OA). The increase in the prevalence of THERAPY
symptomatic OA with age, the inadequacy of current
symptom-relieving treatments, and the lack of disease- An array of nonpharmacologic interventions for OA
modifying treatment each contribute to the overall has been described, each in various stages of develop-
burden of OA. Given the frequency of periarticular ment, investigation, and application. Interventions from
syndromes that mimic OA symptoms, it is important to this burgeoning field take advantage of gains in under-
establish, as much as is possible, that the given symp- standing of causes of symptoms, disease progression,
toms are a result of the OA itself (see Chapter 11A). function loss, and disability in persons with OA. The
The variation in responsiveness to standard treatments category of nonpharmacologic therapy in OA encom-
may be explained by the heterogeneity of OA as a clini- passes physical activity, exercise, weight loss, education,
cal syndrome and the several other potential sources of inserts, footwear, bracing, therapeutic ultrasound, and
pain. pulsed electromagnetic field therapy. For many of these
Four sources of guidelines for the management interventions, further investigation is necessary to better
of lower-limb OA include recommendations for define their place in OA management.
nonpharmacological therapy and pharmacological For knee OA in particular, results from ongoing
therapy: the American College of Rheumatology studies suggest that interventions targeting knee laxity,
(ACR; Table 11C-1) (1); the task force of the European symptoms of knee instability, proprioceptive acuity,
League Against Rheumatism Standing Committee muscle function, agility, self-efficacy, and specific com-
for International Clinical Studies Including Thera- binations of nonpharmacologic therapies may be espe-
peutics (EULAR; Table 11C-2) (2,3); Algorithms cially effective and should be further developed and
for the Diagnosis and Management of Musculos- tested.
keletal Complaints (4); and the Institute for Clinical Some nonpharmacologic interventions for OA may
Systems Improvement (5). Pencharz and colleagues ultimately be shown to contribute to secondary preven-
provide a critical appraisal of some of these sets of tion, that is, prevention of disease progression. At
guidelines (6). present, these approaches are applied predominantly to
235
236 LEENA SHARMA
TABLE 11C-1. RECOMMENDATIONS (2000) FOR THE endurance, cardiovascular fitness, and self-efficacy and
MANAGEMENT OF KNEE OSTEOARTHRITIS FROM THE reduction in excess body weight, depression, and
AMERICAN COLLEGE OF RHEUMATOLOGY. anxiety. The reviews of Van Baar and colleagues (7)
Nonpharmacologic therapy for patients with osteoarthritis and of Baker and McAlindon (8) suggest that the effec-
Patient education tiveness of isolated strengthening exercise is less than
Self-management programs (e.g., Arthritis Foundation Self- more comprehensive interventions that include aerobic
Management Program) exercise, pain modalities, and education. A small
Personalized social support through telephone contact
number of studies suggest that proprioceptive acuity
Weight loss (if overweight)
Aerobic exercise programs may be improved by exercise or by orthoses as simple
Physical therapy as a neoprene sleeve.
Range-of-motion exercises There is abundant epidemiologic evidence to suggest
Muscle-strengthening exercises that excess body weight increases the risk of incident
Assistive devices for ambulation
knee OA. Less is known about the impact of body
Patellar taping
Appropriate footwear weight on OA progression and there is a paucity of trial
Lateral-wedged insoles (for genu varum) data concerning the discrete effects of weight reduction
Bracing on OA outcomes. Nevertheless, there is a strong
Occupational therapy
Joint protection and energy conservation
Assistive devices for activities of daily living (ADL)
Pharmacologic therapy for patients with osteoarthritis

Oral
Acetaminophen TABLE 11C-2. RECOMMENDATIONS (2003) FOR THE
COX-2-specific inhibitor MANAGEMENT OF KNEE OSTEOARTHRITIS FROM A
Nonselective NSAID plus misoprostol or a proton pump TASK FORCE OF THE EULAR STANDING COMMITTEE
inhibitor FOR INTERNATIONAL CLINICAL STUDIES INCLUDING
Nonacetylated salicylate THERAPEUTICS (ESCISIT).
Other pure analgesics (tramadol, opioids) The optimal management of knee OA requires a combination of
Intra-articular nonpharmacological and pharmacological treatment
Glucocorticoids modalities.
Hyaluronan
Topical The treatment of knee OA should be tailored according to:
Capsaicin Knee risk factors (obesity, adverse mechanical factors, physical
Methylsalicylate activity)
General risk factors (age, comorbidity, polypharmacy)
SOURCE: From Altman RD, et al. Arthritis Rheum 2000;43:19051915, by Level of pain intensity and disability
permission of Arthritis and Rheumatism. Sign of inflammation, e.g., effusion
Location and degree of structural damage
Nonpharmacological treatment of knee OA should include

regular education, exercise, appliances (sticks, insoles, knee
bracing), and weight reduction.
treat symptoms and maintain or improve functioning.
Many nonpharmacologic interventions are low cost, Paracetamol is the oral analgesic to try first and, if successful,
the preferred long-term oral analgesic.
incorporate self-management approaches, and are home
based, and, as such, may ultimately have substantial Topical applications (NSAID, capsaicin) have clinical efficacy and
public health impact. Some specific suggestions are are safe.
offered in Table 11C-3. NSAIDs should be considered in patients unresponsive to
It is well documented that regular physical activity paracetamol. In patients with an increased gastrointestinal
and exercise benefit symptoms, function, and quality of risk, nonselective NSAIDs and effective gastroprotective
life, and they are crucial components of OA manage- agents, or selective COX-2 inhibitors should be used.
ment. Exercise for OA should address range of motion, SYSADOA (glucosamine sulphate, chondroitin sulphate, ASU,
flexibility, aerobic conditioning, and muscle function. diacerein, hyaluronic acid) have symptomatic effects and may
Muscle performance can be enhanced not only by modify structure.
strengthening exercise but also by functional exercise to
Intra-articular injection of long-acting corticosteroid is indicated
improve muscle endurance and motor control. The for flare of knee pain, especially if accompanied by effusion.
daily exercise regimenparticularly exercises targeting
muscle strengthshould take into consideration the Joint replacement has to be considered in patients with
local joint pathology and impairments such as malalign- radiographic evidence of knee OA who have refractory pain
and disability.
ment and laxity. In theory, exercise and activity benefits
on pain and function in OA may be mediated through SOURCE: From Jordan KM, et al. Ann Rheum Dis 2003;62:11451155, with
a variety of routes, including improvement in strength, permission from Annals of the Rheumatic Diseases.
TABLE 11C-3. SPECIFIC SUGGESTIONS FOR program. The Arthritis Self-Management Program
NONPHARMACOLOGIC INTERVENTION IN (ASMP), taught by trained lay leaders at weekly ses-
OSTEOARTHRITIS. sions, includes patient education regarding disease pro-
Address psychosocial factors cesses, medication side effects, exercise, as well as
Enhance self-efficacy, using individualized approaches + cognitivebehavioral techniques, and a communication
arthritis self-management courses exercise in which participants learn to elicit support
Educate about OA from family and friends (11). A body of literature sug-
Improve coping skills
gests that the ASMP leads to improvement in symp-
Prevent/treat anxiety and depression
Improve social support toms, psychological well-being, perceived helplessness,
levels of physical activity, use of cognitive pain manage-
Improve/maintain aerobic capacity, conditioning, strength, and ment techniques, use of self-management behaviors
ADL performance
such as exercise, communication with physicians, with
Increase physical activity
Promote home exercise (aerobic + resistance) long-term retention of initial gains. ASMP sessions are
Refer for physical and occupational therapy sponsored and/or organized by the national Arthritis
Provide assistive devices Foundation in the United States and other organiza-
Address local factors
tions in Canada and the United Kingdom. A major
Adjust footwear mechanism of the beneficial effect of the ASMP is
Refer for inserts/insoles enhanced self-efficacy, a key determinant of physical
Promote resistance exercise cognizant of individual pathologic functioning over time in epidemiologic studies.
anatomy (i.e., physical therapy referral to learn optimal Varus alignment substantially increases the likeli-
exercises for malaligned or unstable knee)
Refer for agility training
hood of progression of subsequent medial tibiofemoral
OA. For years, wedge osteotomy has been undertaken
Provide weight loss program for those who are overweight with the goal of reducing forces in the medial compart-
ment in varus knees. Conservative approaches have also
emerged. The use of a lateral wedge insole orthosis is
rationale that weight reduction in persons with knee believed to lower medial compartment load and reduce
OA who are overweight may delay disease progression, lateral tensile forces by enhancing valgus correction of
reduce symptoms, improve function, and lower the the calcaneus, whether or not varus deformity at the
impact of comorbidities. knee is lessened. A small number of controlled trials
Several nutritional products are available and touted have been reported, most of which suggest a beneficial
as beneficial for OA, but few have undergone rigorous effect on knee symptoms. Larger trials of longer dura-
testing. Among these, glucosamine and chondroitin tion are ongoing.
sulfate have been evaluated in clinical trials, most of Kerrigan and colleagues found that wearing high-
which received some manufacturer support. A meta- heeled shoes leads to a striking increase in forces across
analysis suggested efficacy for symptoms, but also the medial and patellofemoral compartments (12).
described evidence of publication bias, suggesting that Although long-term effects of this footwear have not
the magnitude of the beneficial effect may be less than been elucidated, it seems prudent to minimize the
what has been reported (9). Studies of glucosamine pub- wearing of high-heeled shoes.
lished since the meta-analysis have had mixed results, The goal of the valgus unloading brace in medial
with some trials suggesting no or very modest difference knee OA is to produce an abduction moment to shift
between treatment and placebo. A recent report from the joint contact force away from the stressed medial
an National Institutes of Healthfunded multicenter compartment. Most studies suggesting a beneficial effect
trial suggests that glucosamine and chondroitin (alone on symptoms were uncontrolled or inadequately con-
or in combination) were not better than placebo in trolled. Systematic reviews suggest that there is insuffi-
reducing pain in the overall group of patients with knee cient evidence as yet to advocate either therapeutic
OA, but that the combination may be effective in persons ultrasound or pulsed electromagnetic field therapy in
with moderate-to-severe knee pain (10). the management of OA.
There is some epidemiologic evidence that dietary 11
intake of vitamin C and vitamin D may be associated
with a reduced risk of knee OA progression and a trial SYSTEMIC PHARMACOLOGIC
of vitamin D in knee OA is ongoing. Data are insuffi- THERAPY
cient at present to support a therapeutic dose of vita-
mins C or D for prevention or treatment of OA. Pharmacologic treatment categories for OA are typi-
Patient education is highly recommended in the cally set up to designate whether drugs are symptom
management of OA. OA patient education may have relieving or disease modifying. However, there is insuf-
a specific focus, for example, relaxation, cognitive pain ficient evidence as yet that any drug has a disease-
management, or exercise, or may be a multicomponent modifying effect in OA.
238 LEENA SHARMA
Non-Narcotic Analgesic of cyclooxygenase (COX), which is essential for the

production of prostaglandins. Two isoforms of this
Medication enzyme exists, with the COX-2 isoform being most
The most recent ACR guidelines for the medical man- important for synthesis of prostaglandins that cause
agement of OA suggest acetaminophen as an effective pain and inflammation. All NSAIDs inhibit COX-2,
initial approach for mild-to-moderate pain. In keeping while the nonselective NSAIDs inhibit both COX-1 and
with this, the most recent EULAR guidelines suggest COX-2. The effect of both nonselective and selective
paracetamol as the initial approach as well as the best NSAIDs on symptoms may relate to their analgesic as
long-term choice. While some studies have shown that well as their anti-inflammatory effects.
the effect of acetaminophen and nonsteroidal anti- For both nonselective and COX-2selective NSAIDs,
inflammatory drugs (NSAIDs) is comparable, others it is recommended that a patient be started on the lowest
have revealed that NSAIDs may be more efficacious therapeutic dose and that the dose be gradually increased
and preferred by patients. The ACR guidelines suggest until the response is satisfactory, the maximal recom-
NSAIDs as an alternative approach in those with mended dose is reached, or the patient experiences an
moderate-to-severe pain and signs of inflammation. adverse effect. If the response is inadequate at the full
However, given the superior safety profile for acet- dose of a given NSAID, it may be beneficial to try other
aminophen, its over-the-counter availability and low NSAIDs. Efficacy does not differ substantially between
cost, and concerns about the potential cardiovascular nonselective and COX-2selective NSAIDs in clinical
and gastrointestinal effects of NSAIDs, it seems trials. However, different NSAIDs may be more or less
reasonable to initiate therapy with regularly dosed effective in individual patients. The use of two or more
acetaminophen. NSAIDs simultaneously does not improve efficacy but
Doses of acetaminophen should not exceed 4000 mg/ does increase the risk of toxicity. NSAIDs and
day and the minimally effective dose should be used. acetaminophen may be used concurrently, and this
As acetaminophen may increase the half-life of warfa- combination may be more effective than using either
rin sodium, warfarin dosage may need to be adjusted medication alone.
in persons who start high dose acetaminophen. Acet- Monitoring for possible occult side effects during
aminophen-associated hepatic toxicity is rare in persons the regular use of any NSAIDs is recommended. This
on doses used in the setting of OA but may be more should include the following: at 2 weeks or so after the
likely in those with liver disease or who abuse institution of therapy, an examination of blood pres-
alcohol. sure, a complete blood cell count, and laboratory tests
of hepatic and renal function; every 4 to 6 months,
blood pressure, a complete blood cell count, hepatic
Narcotic Analgesic Medication and renal function tests, urinalysis, and a stool occult
blood test. With routine use of NSAIDs in patients
Narcotic analgesic medication should be reserved for with OA, there is an increased risk of upper gastroin-
persons with severe OA and pain that is refractory to testinal toxicity (e.g., gastric and duodenal ulcers) and
regularly dosed non-narcotic analgesia coupled with gastrointestinal bleeding, though this risk may be
nonpharmacologic measures. A central goal of pain reduced with COX-2selective NSAIDs. The 2000
management is to provide a sufficient level of symptom ACR guidelines for the medical management of OA
improvement to allow healthy levels of physical activity recommend either misoprostol or a proton-pump
and exercise that, in turn, may help to prevent function inhibitor with a nonselective NSAID in a patient at
loss and disability. Given the potential negative conse- increased risk for an adverse gastrointestinal effect.
quences of undertreating or overtreating OA pain, the Gastroprotective therapy is not felt to be necessary in
involvement of a multidisciplinary pain service should those with a low risk for adverse gastrointestinal
be considered, especially in the management of persons effects.
with severe OA who are ineligible for or who have Renal toxicity (e.g., renal insufficiency, fluid reten-
opted against total joint replacement. tion, hyperkalemia) also occurs with all NSAIDs. Only
nonselective NSAIDs are associated with disrupted
platelet function, a function of COX-1 inhibition.
Nonsteroidal Anti-Inflammatory Certain COX-2selective NSAIDs have been associ-
ated with an increased risk for serious cardiovascular
Drugs events. However, new labeling requirements are in
If treatment with a non-narcotic analgesic is not effec- place regarding cardiovascular effects for all NSAIDs
tive, therapy with a nonselective NSAID or a cyclooxy- to emphasize the possibility that all these drugs may be
genase-2 (COX-2)selective NSAID may be initiated associated with risk. Given the toxicity issues associated
(see Chapter 41). NSAIDs inhibit the enzymatic activity with nonselective and COX-2selective NSAIDs, it
seems most prudent to individualize this aspect of phar- With advances in prosthetic design and fixation, the
macological management of OA depending upon typical number of years during which loosening is very
comorbidities and individual risks. rare has increased. However, given the probable life
span of most prostheses and implantation techniques,
and the fact of a greater likelihood of complications
LOCALIZED PHARMACOLOGIC with revision surgery, total joint replacement is avoided
in younger individuals.
THERAPY In theory, osteotomy could help to unload a stressed
compartment in a malaligned knee without severe OA,
Intra-articular administration of corticosteroids may and thereby prevent disease progression. However, spe-
result in pain reduction in OA joints, an effect that may cific indications for osteotomy in the joint with mild-to-
be more likely in joints that show signs of inflammation. moderate OA are not clear, and this is made more
The duration of a beneficial effect may be only a few complex by the concept that removal of periarticular
days but may last for a few months. Such therapy should bone stock may make future joint replacement for that
not be repeated more than three times into the same knee more complex. Recent findings suggest that
joint in 1 year. A greater frequency is discouraged arthroscopic meniscal debridement may not improve
based predominantly on animal model data suggesting outcome in OA knees (13). Whether there are catego-
that intra-articular therapy may accelerate cartilage ries of meniscal pathology in OA knees that should be
loss. Intra-articular steroid did not accelerate radio- debrided remains to be elucidated.
graphic knee OA progression in one study. The effect
of instilled steroid on OA progression by magnetic
resonance imaging (MRI) has not been reported. Cor- REFERENCES
ticosteroid injection therapy should not be considered
as a primary or scheduled form of therapy, but rather 1. Altman RD, Hochberg MC, Moskowitz RW, Schnitzer
as an adjunct to other pharmacologic and nonpharma- TJ. Recommendations for the medical management of
cologic treatment. osteoarthritis of the hip and knee: 2000 update. Arthritis
Intra-articular hyaluronan may result in a modest Rheum 2000;43:19051915.
improvement in symptoms. The response appears to be 2. Jordan KM, Arden NK, Doherty M, et al. EULAR rec-
slightly better in knees at earlier stages of OA. Avail- ommendations 2003: an evidence-based approach to the
able preparations are instilled weekly for 3 to 5 weeks. management of knee osteoarthritis: report of a task force
of the Standing Committee for International Clinical
A potential adverse effect is the development of syno-
Studies Including Therapeutic Trials (ESCISIT). Ann
vitis and effusion after the injection.
Rheum Dis 2003;62:11451155.
Topical capsaicin has some pain-relieving effect in 3. Zhang W, Doherty M, Arden N, et al. EULAR evidence-
osteoarthritic knees and hands. The best effect is associ- based recommendations for the management of hip osteo-
ated with adherence to the recommended schedule, that arthritis: report of a task force of the EULAR Standing
is, application three to four times per day to the painful Committee for International Clinical Studies Including
joint. Burning at the applied site diminishes with regular Therapeutics (ESCISIT). Ann Rheum Dis 2005;64:669
use. Capsaicin may be highly irritating to mucous mem- 681.
branes; careful hand washing after application helps to 4. Algorithms for the diagnosis and management of muscu-
prevent mucous membrane contact. loskeletal complaints. Am J Med 1997;103:3S6S.
5. Lee JA. Adult degenerative joint disease of the knee:
maximizing function and promoting joint health: Institute
for Clinical System Integration. Postgrad Med 1999;
SURGERY 105:183197.
6. Pencharz JN, Grigoriadis E, Jansz GF, Bombardier C. A
Surgical options should be considered for patients with critical appraisal of clinical practice guidelines for the
symptoms and functional loss refractory to nonsurgical treatment of lower-limb osteoarthritis. Arthritis Res 2002;
pharmacologic and nonpharmacologic therapies. In 4:3644.
patients with advanced OA coupled with severe pain 7. van Baar ME, Assendelft WJJ, Dekker J, Oostendorp 11
and reduced function, total joint replacement is a RAB, Bijlsma WJ. The effectiveness of exercise therapy
in patients with osteoarthritis of the hip or knee. Arthritis
highly effective intervention in the vast majority of
Rheum 1999;42:13611369.
patients, especially when the involved joint is the hip 8. Baker K, McAlindon T. Exercise for knee osteoarthritis.
or the knee. Total joint replacement at other joint sites Curr Opin Rheumatol 2000;12:456463.
is at present less predictable than at the hip or the 9. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glu-
knee. Successful outcome hinges not only on operative cosamine and chondroitin for treatment of osteoarthritis;
factors and prevention of medical complications but on a systematic quality assessment and meta-analysis. JAMA
the quality of physical therapy before and after surgery. 2000;283:14691475.
240 LEENA SHARMA
10. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chon- 12. Kerrigan DC, Todd MK, ORiley PO. Knee osteoarthritis
droitin sulfate, and the two in combination for painful and high-heeled shoes. Lancet 1998;351:13991401.
knee osteoarthritis. N Engl J Med 2006;354:795808. 13. Moseley JB, OMalley K, Petersen NH, et al. A controlled
11. Lorig K, Holman HR. Arthritis self-management studies: trial of arthroscopic surgery for osteoarthritis of the knee.
a 12 year review. Health Educ Quarterly 1993;20:1728. N Engl J Med 2002;347:8188.
CHAPTER 12
Gout
N. LAWRENCE EDWARDS, MD
Gout is caused by the deposition of The onset of a gouty attack usually is heralded by
monosodium urate crystals in and around the the rapid development of warmth, swelling,
tissues of joints. erythema, and pain in the affected joint.
The course of classic gout passes through three The joint most commonly affected first by gout is the
distinct stages: asymptomatic hyperuricemia, acute first metatarsophalangeal joint. This condition is
intermittent gout, and advanced gout. known as podagra.
The incidence of gout increases with age as well as Fevers of higher than 38C are seen in approximately
with the degree of hyperuricemia. 30% of gout patients during the early phases of
The vast majority of people with hyperuricemia acute attacks.
never develop symptoms associated with uric acid Advanced gout (sometimes referred to as chronic
excess, such as gouty arthritis, tophi, or kidney tophaceous gout) usually develops after 10 or more
stones. years of acute intermittent gout, although patients
In men, the first attacks usually occur between the have been reported with tophi as their initial clinical
fourth and sixth decades of life. In women, the age manifestation.
of onset is older and varies with several factors, The development of tophaceous deposits of
including the age of menopause and the use of monosodium urate is a function of the duration and
thiazide diuretics. severity of hyperuricemia.
Gout is a clinical disease associated with hyperuricemia Asymptomatic Hyperuricemia

and caused by the deposition of monosodium urate
(MSU) crystals in and around the tissues of joints. Hyperuricemia is a common biochemical abnormality
Symptomatic crystal deposition includes attacks of that can be defined in either epidemiologic or physio-
acute inflammatory arthritis, a chronic destructive logic terms. In extracellular fluids, 98% of uric acid is in
arthropathy, and soft tissue accumulation of MSU crys- the form of urate ion at pH 7.4. Clinical laboratories
tals. The nonarticular (soft tissue) clinical manifesta- define hyperuricemia as a serum urate level that is
tions of gout include the development of tophi (Figure greater than two standard deviations above the mean
12A-1) and the precipitation of crystals in the renal col- value in a gender- and age-matched healthy population.
lecting ducts, leading to urolithiasis. Using this standard, the upper limit for normal serum
urate frequently is listed as 8.0 to 8.5 mg/dL. In physio-
logic terms, however, any level above 6.8 mg/dL is
hyperuricemia because it exceeds the soluble concen-
STAGES OF CLASSIC GOUT tration of MSU in body fluid. Serum urate levels in
children are relatively low (2.04.0 mg/dL). In men, this
The course of classic gout passes through three distinct value increases dramatically around the time of puberty
stages: asymptomatic hyperuricemia, acute intermittent to reach the level they will maintain throughout adult-
gout, and advanced gout (Figure 12A-2). The rate of hood. In women, serum urate levels gradually increase
progression from asymptomatic hyperuricemia to ad- throughout early adulthood and do not reach maximum
vanced gout varies considerably from one person to levels until after menopause. This difference in the
another and is dependent on numerous endogenous and duration of urate elevations is the main reason gout is
exogenous factors. a male-predominant disease.
241
242 N. LAWRENCE EDWARDS
Acute Intermittent Gout

The initial episode of acute gout usually follows decades
of asymptomatic hyperuricemia. Thomas Sydenham,
the famous 17th-century physician who wrote of his
personal experiences with gout, eloquently described
the initial hours of an acute attack:
He goes to bed and sleeps well, but about Two a Clock

in the Morning, is waked by the Pain, seizing either his
great Toe, the Heel, the Calf of the Leg, or the Ankle;
this Pain is like that of dislocated Bones, with the
Sense as it were of Water almost cold, poured upon
the Membranes of the part affected; presently shivering
and shaking follow with a feverish Disposition; the
Pain is first gentle, but increased by degrees-till dash
towards Night it comes to its height, accompanying
FIGURE 12A-1 itself neatly according to the Variety of the bones of the
The hands of a patient with advanced gout reveal large tophi Tarsus and Metatarsus, whose Ligaments it seizes,
over all digits as well as the right fifth metacarpophalangeal sometimes resembling a violent stretching or tearing of
joint and both wrists. those ligaments, sometimes gnawing of a dog, and
sometimes a weight; more over, the Part affected has
such a quick and exquisite Pain, that it is not able to
bear the weight of the cloths upon it, nor hard walking
in the Chamber (2).
The incidence of gout increases with age as well as
with the degree of hyperuricemia. In the Normative
Aging Study, the cumulative incidence of gouty arthritis This classic description captures the intense pain fre-
among subjects with uric acid levels between 7.0 and quently associated with acute gouty arthritis, and it is
8.0 mg/dL was 3%, and subjects with urate levels of this clinical picture most commonly evoked by the term
9.0 mg/dL or more had a 5-year cumulative incidence gout.
of 22% (1). However, the vast majority of people with In men, the first attacks usually occur between the
hyperuricemia never develop symptoms associated fourth and sixth decades of life. In women, the age of
with uric acid excess, such as gouty arthritis, tophi, or onset is older and varies with several factors, including
kidney stones. the age of menopause and the use of thiazide diuretics.
The onset of a gouty attack usually is heralded by the
rapid development of warmth, swelling, erythema, and
pain in the affected joint. Pain escalates from the faint-
est twinges to its most intense level over an 8- to 12-hour
period. The initial attack usually is monarticular and, in
one half of patients, involves the first metatarsophalan-
INTENSITY OF PAIN
geal (MTP) joint. Involvement of the first MTP joint,

which occurs eventually in 90% of individuals with gout,
is known as podagra (from the Greek for foot-trap;
Figure 12A-3). Other joints that frequently are involved
in this early stage are the midfoot, ankles, heels, and
knees, and less commonly, the wrists, fingers, and
elbows. The intensity of pain characteristically is very
YEARS severe, but may vary among subjects. As Sydenham
observed, patients find walking difficult or impossible
ASYMPTOMATIC ACUTE INTERMITTENT CHRONIC
HYPER- GOUT TOPHACEOUS when lower extremity joints are involved.
URICEMIA GOUT
Systemic symptoms, such as fever, chills, and malaise
FIGURE 12A-2 may accompany acute gout. Fevers of higher than 38C
are seen in approximately 30% of gout patients during
The three stages of disease progression in classic gout. The the early phases of acute attacks (3). The cutaneous
period of asymptomatic hyperuricemia lasts decades, followed
by acute intermittent gout with painless intercritical segments,
erythema associated with the gouty attack may extend
leading to advanced gout with progressive background pain and beyond the involved joint and resemble bacterial cellu-
joint destruction in untreated patients. litis (Figure 12A-3). The natural course of untreated
C H A P T E R 1 2 G O U T 24 3
(see Figure 12A-2). Clinically evident tophi may or may

not be detected on physical examination during the first
few years of this stage of gout. However, periarticular
tophi detected by magnetic resonance imaging (MRI)
(6) and synovial microtophi discovered through the
arthroscope certainly are present early in this stage of
gout and may in fact be present during the earlier acute
intermittent phase of gout. Polyarticular involvement
becomes much more frequent during this time. With
diffuse and symmetric involvement of small joints in the
hands and feet, chronic tophaceous gout can occasion-
ally be confused with the symmetrical polyarthritis of
rheumatoid arthritis.
The development of tophaceous deposits of MSU is
a function of the duration and severity of hyperuricemia
(7). Hench found that untreated patients developed
FIGURE 12A-3
tophi 11.7 years after the onset of acute gout, on average
Acute gouty arthritis involving the first metatarsophalangeal (8). In a study of 1165 people with primary gout, those
joint. without tophi had serum uric acid levels of 10.3 1.3 mg/
dL and those with extensive deposits had levels of
11.0 2.0 mg/dL. Other factors associated with the
acute gout varies from episodes of mild pain that resolve development of tophi include early age of gout onset,
in several hours (petit attacks) to severe attacks that long periods of active but untreated gout, an average of
last 1 to 2 weeks. Early in the acute intermittent stage, four attacks per year, and a greater tendency toward
episodes of acute arthritis are infrequent, and intervals upper extremity and polyarticular episodes (9). In
between attacks sometimes last for years. Over time, untreated patients, the interval from the first gouty
the attacks typically become more frequent, longer in attack to the beginning of advanced arthritis or the
duration, and involve more joints. development of visible tophi is highly variable, ranging
Intercritical periods of acute intermittent gout are from 3 to 42 years, with an average of 11.6 years (10).
just as characteristic of this stage as are the acute attacks. The subcutaneous tophus is the most characteristic
Previously involved joints are virtually free of symp- lesion of advanced gout (Figure 12A-3). Tophi may be
toms. Despite this, MSU crystals often can be identified found anywhere over the body, but occur most com-
in the synovial fluid. In one study, these crystals were monly in the fingers, wrists, ears, knees, olecranon
found in the synovial fluids of 36 of 37 knees that previ- bursa, and such pressure points as the ulnar aspect of
ously had been inflamed. Synovial fluids containing the forearm and the Achilles tendon. In people with
crystals also had a higher mean cell count than those nodal osteoarthritis, tophi have a propensity for forming
with no crystals, 449 cells/mm3 versus 64 cells/mm3 (4). in Heberdens nodes. Tophi also may occur in connec-
These subtle differences may reflect ongoing subclinical tive tissues at other sites, such as renal pyramids, heart
inflammation. valves, and sclerae. Similar appearing nodules are
observed in other rheumatic conditions, such as rheu-
matoid arthritis and multicentric reticulohistiocytosis
Advanced Gout (11,12). Before antihyperuricemic agents were avail-
Advanced gout (sometimes referred to as chronic topha- able, as many as 50% of patients with gout eventually
ceous gout) usually develops after 10 or more years of developed clinical or radiographic evidence of tophi.
acute intermittent gout, although patients have been Since the introduction of allopurinol and the uricosuric
reported with tophi as their initial clinical manifestation agents, the incidence of tophaceous gout has declined.
(5). The transition from acute intermittent gout to Much of the knowledge about sequential develop-
chronic tophaceous gout occurs when the intercritical ment of the mature, multilobulated gouty tophus comes
periods no longer are free of pain. The involved joints from the classic histopathologic descriptions of Sokoloff
become persistently uncomfortable and swollen, al- (13) and Schumacher (14), and the more recent immu-
though the intensity of these symptoms is much less nohistochemical studies of Palmer and colleagues (15).
than during acute flares. Gouty attacks continue to Figure 12A-4 represents a theoretical sequence of how
occur against this painful background, and without a noncrystalline, cellular locus (macrophage acinus) 12
therapy, they may recur as often as every few weeks. progresses through stages of crystal precipitation,
The amount of background pain also steadily increases coronal hypertrophy, and finally, crystal coalescence
with time if appropriate intervention is not started and cellular atrophy, to eventually form the clinically
central amorphous material is believed to be detritus

A B from a collection of monocytes that conjugates at the
locus in response to some inciting event.
Some time after the acinus is formed, a small, eccen-
tric collection of radially arranged MSU crystals form
C in the amorphous core of monocyte-derived material
150 mm [Figure 12A-4(B)]. The macrophages do not phagocy-
150 mm
tize the MSU crystal, but as the crystalline mass expands
and contacts the surrounding cells, this shell that is 1- to
D
2-cells thick proliferates to form a tightly packed, 8- to
10-cell-thick corona [Figure 12A-4(C)]. As the tophus
matures, this corona is lost and replaced by fibrous
1 1.5 mm
septae [Figure 12A-4(D)] that contain some fibroblastic
cells and occasional multinucleated giant cells. Adja-
cent crystalline deposits coalesce to form multilobu-
E lated tophi [Figure 12A-4(E)] measuring 1 to 10 cm in
3 4 mm diameter, interlaced with fibrous strands containing
few cells and encapsulated by a sometimes tenuous
and sometimes thick fibrous tissue. The cellular and
crystalline components of a gouty tophus are easily
demonstrated by magnetic resonance imaging (Figure
12A-5).
1 5 cm
UNUSUAL PRESENTATIONS
FIGURE 12A-4
Early-Onset Gout
The stages of development of a gouty tophus. (A) The crystal-
free macrophage acinus is the earliest organized phase of a Between 3% and 6% of patients with gout have
gouty tophus. (B) The amorphous center of the acinus fosters symptom onset before age 25. Early-onset gout repre-
urate crystal formation. (C) As the crystalline mass expands, the sents a special subset of cases that generally have a
surrounding corona of macrophages likewise undergoes genetic component, show a more accelerated clinical
hypertrophy. (D) Further crystallization results in a thinning of
course, and require more aggressive antihyperuricemic
the corona until only fibrous septae separate one nidus of
crystal formation from another. (E) A fully mature tophus. therapy. In large epidemiologic studies of classic gout,
a family history of gout and/or nephrolithiasis is present
in 25% to 30% of cases. In early-onset gout, the inci-
observable subcutaneous tophus (7). The macrophage dence of family history is approximately 80%. In this
acinus (Figure 12A-4A) is the earliest structure observed younger group, detailed questioning about the kindred
by light microscopy in tophus development. The acinus over several generations may yield enough information
has a core of noncrystalline, amorphous material sur- to suggest a mode of inheritance (X-linked or auto-
rounded by a rosette of mononuclear phagocytes. The somal dominant or recessive).
FIGURE 12A-5
(Left) Midline sagittal section magnetic

resonance image of a finger with
advanced tophaceous deformities.
(Right) T1 weighted, spin echo
technique with gadolinium contrast
reveals the deep soft tissue anatomy.
The heterogeneous composition of
the tophus dorsal to the proximal
interphalageal joint and distal
phalanx is clearly revealed. The
central crystalline deposit remains
low intensity, but surrounding tissue
enhances.
C H A P T E R 1 2 G O U T 24 5
Like classic gout, early-onset gout may be caused by the acute intermittent stage is only 1 to 4 years in trans-
overproduction of urate or reduced renal clearance of plant recipients, but it may last 8 to 15 years in classic
uric acid. Diseases associated with overproduction of gout. Because organ transplant recipients use other
urate in children and young adults include enzymatic medications, such as systemic corticosteroids and aza-
defects in the purine pathway, glycogen storage dis- thioprine, their gouty symptoms frequently are more
eases, and hematologic disorders, such as hemo- atypical and less dramatic than those of patients with
globinopathies and leukemias. The complete deficiency classic gout.
of hypoxanthine-guanine phosphoribosyltransferase
(HGPRT) is an X-linked inherited inborn error of
purine metabolism with a characteristic clinical presen-
Gout in Women
tation known as the LeschNyhan syndrome. These Unlike most other rheumatic conditions, gout is less
boys, who have severe neurologic abnormalities, common in women than in men. In most large reviews,
develop gout and kidney stones in the first decade of women account for no more than 5% of all people with
life if not treated early with allopurinol. The partial gout (19). Ninety percent of women are postmenopausal
deficiency of HGPRT (the KelleySeegmiller syn- at the time of their initial attack. Postmenopausal gout
drome) results in early-onset gout or uric acid nephro- is similar clinically in presentation and course to classic
lithiasis and also is also an X-linked trait. People with gout, except that the age of onset is later in women than
this syndrome have minor or no neurologic problems. in men. Conditions that are much more commonly asso-
Glycogen storage disease types I, III, V, and VII, ciated with gout in postmenopausal women than with
inherited as autosomal recessive diseases, are associ- gout in men include diuretic use (95%), hypertension
ated with early-onset gout. Sickle cell disease, beta- (73%), renal insufficiency (50%), and preexisting joint
thalassemia, and nonlymphocytic leukemias may be disease, such as osteoarthritis (20).
complicated by gouty arthritis in the young adult Premenopausal gout has a strong hereditary compo-
years. nent. Most women who develop gout before menopause
Conditions associated with uric acid underexcretion have hypertension and renal insufficiency. The rare
in young patients include a specific renal tubular disor- woman with premenopausal gout and normal renal
der known as familial juvenile hyperuricemic nephro- function should be evaluated for the autosomally inher-
pathy (16). This autosomal dominant disorder causes ited familial juvenile hyperuricemic nephropathy (16)
hyperuricemia from a very young age, before any evi- or the even more rare nonX-linked inborn errors of
dence of renal insufficiency. The condition may lead to purine metabolism (20).
progressive renal failure and end-stage kidney disease
by age 40. Other nephropathies associated with early-
onset gout include polycystic kidney disease, chronic
Normouricemic Gout
lead intoxication, medullary cystic disease, and focal The most frequent explanations for apparent gout with
tubulointerstitial disease. normal levels of uric acid are that (1) gout is not the
correct diagnosis or (2) the patient actually is chroni-
Gout in Organ Transplantation cally hyperuricemic but the serum urate is normal at the
time it is measured (for a potential explanation of this
Patients phenomenon, see below).
Hyperuricemia develops in 75% to 80% of heart trans- Several articular conditions can mimic gout closely,
plant recipients who routinely take cyclosporine to including crystalline arthropathies of calcium pyrophos-
prevent allograft rejection (17). A slightly lower fre- phate dehydrate (pseudogout), basic calcium (apatite),
quency (approximately 50%) of kidney and liver trans- and liquid lipid (21). Other causes of acute monoar-
plant recipients develop hyperuricemia, presumably thropathies, such as infection, sarcoidosis, and trauma,
because lower doses of cyclosporine are used in these also should be considered (22). The clinical suspicions
individuals. Whereas asymptomatic hyperuricemia proof gout should be confirmed by crystal analysis of
gresses to clinical gout in only 1 in 30 subjects in the synovial fluid. Without this confirmation, the diagnosis
general population, cyclosporine-induced hyperurice- remains in question.
mia leads to gout in 1 in every 6 patients (18). Other Misunderstanding the definition of hyperuricemia
differences between primary and cyclosporine-induced also can contribute to misdiagnosis of normouricemic
gout include the marked shortening of the asymptom- gout. A sustained serum urate level above 7.0 mg/dL
atic hyperuricemia and acute intermittent gout stages, provides a permissive environment for MSU crystal for-
with the rapid appearance of tophi. The stage of asymp- mation, but people with acute and chronic gout may 12
tomatic hyperuricemia lasts for 20 to 30 years in classic have urate values below this biochemical definition of
gout, but is present for only 6 months to 4 years in hyperuricemia. In fact, as many as one third of people
cyclosporine-induced disease. Similarly, the duration of presenting with acute gout to have a serum urate below
7.0 mg/dL during the episode of severe pain (23). This (the word saturnine, meaning of or relating to lead, is
condition probably results from uricosuric effects of derived from the belief of the ancients that this metal
ACTH release and adrenal stimulation, which are comprised the planet Saturn). The ingestion of any form
caused by the stress of the painful process. Normaliza- of ethanol can raise uric acid production acutely by
tion of serum urate values during acute gouty flares may accelerating the breakdown of intracellular adenosine
be more common in alcoholics than in nondrinkers. triphosphate (25). Beer consumption has an added
Aside from such standard urate-lowering agents as impact on gout because it contains large quantities of
allopurinol, probenecid, and sulfinpyrazone, high dose guanosine, which is catabolized to uric acid (26).
salicylates, angiotensin II receptor blockers, fenofibrate, Drugs may precipitate gout by rapidly raising or low-
glucocorticoids, warfarin, glycerol guaiacholate, and x- ering urate levels. Thiazide diuretics selectively interfere
ray contrast agents also may lower serum urate values with urate excretion at the proximal convoluted tubule.
in people with gout and lead to the false impression of Low dose aspirin (less than 2 g/day) also can raise serum
normouricemic gout. urate levels, but higher doses have a uricosuric effect
Yu reported that 1.6% of 2145 gout patients had and may lower the serum urate concentration. A rapid
sustained normouricemia months after discontinuing increase or reduction in the serum urate level can provoke
use of allopurinol or uricosuric agents (24). In most of gouty attacks; allopurinol is the drug most often respon-
these cases, hyperuricemia eventually returned, although sible for this effect. The mechanism for this paradoxic
several patients with very mild gouty symptoms re- response appears to be the destabilizing of microtophi in
mained normouricemic over a prolonged period. the gouty synovium when the urate concentration of the
synovial fluid is changed rapidly. As the microtophi
break apart, crystals are shed into the synovial fluid and
PROVOCATIVE FACTORS OF the gouty episode is initiated (27).
ACUTE ATTACKS
Why crystals form in some hyperuricemic fluids and not
CLINICAL ASSOCIATIONS
in others is unclear. When synovial fluids are balanced
for urate concentrations, the fluids from gouty patients
Renal Disease
have a far greater propensity for promoting crystal for- The only consistent visceral damage caused by hyper-
mation than similar fluids from people with osteoarthri- uricemia is its effect on the kidneys. Three forms of
tis or rheumatoid arthritis. A number of synovial fluid hyperuricemia-induced renal disease are recognized,
proteins have been reported to function as promoters including (1) chronic urate nephropathy, (2) acute uric
or inhibitors of crystal nucleation. The current list of acid nephropathy, and (3) uric acid nephrolithiasis.
physiologically important nucleators is short, with the Chronic urate nephropathy is a distinct entity caused
leading contenders being type I collagen and a gamma by deposition of MSU crystals in the real medulla and
globulin subfraction (10). pyramids and is associated with mild albuminuria.
The degree of hyperuricemia correlates positively Although chronic hyperuricemia is thought to be the
with the overall risk of acquiring gout. However, rapid cause of urate nephropathy, this form of kidney involve-
increases or decreases in the concentration of synovial ment is essentially never seen in the absence of gouty
fluid urate are related more closely to actual precipita- arthritis. Progressive renal failure is common in people
tion of the acute gouty attack. A rapid flux in urate level with gout, but the attribution of renal failure to chronic
is a triggering mechanism in gout induced by trauma, urate nephropathy itself is often difficult owing to the
alcohol ingestion, and drugs. frequent confluence of multiple comorbid conditions in
Trauma frequently is reported to be an inciting event patients with gout. As described in further detail below,
for acute gouty episodes. The trauma may be as minor the hypertension, diabetes, obesity, and ischemic heart
as a long walk and may not have caused pain during the disease that often accompany gout are also risk factors
activity, but it caused intra-articular swelling. When the for renal dysfunction. To a large extent, the role of
joint is allowed to rest, there is a relatively rapid efflux hyperuricemia as a single factor in chronic parenchymal
of free water from the joint fluid. This results in a sudden disease of the kidney remains controversial. Other
increase in synovial fluid urate concentration, which chronic effects of hyperuricemia on the kidney may not
may allow precipitation of urate crystals and a gout be caused by crystal deposition but rather by the direct
attack. This mechanism may explain why gouty attacks action of the soluble uric acid molecule on the afferent
commonly occur at night. arteriolar vessels of glomeruli (28).
Alcohol ingestion may predispose to gout through Acute renal failure can be caused by hyperuricemia in
several mechanisms. The consumption of lead-tainted the acute tumor lysis syndrome, which occurs in patients
moonshine results in chronic renal tubular damage that given chemotherapy for rapidly proliferating lympho-
leads to secondary hyperuricemia and saturnine gout mas and leukemias. With massive liberation of purines
C H A P T E R 1 2 G O U T 24 7
during cell lysis, uric acid precipitates in the distal tubules

and collecting ducts of the kidney. Acute uric acid
nephropathy can result in oliguria or anuria. This form
of acute renal failure can be distinguished from other
forms by a ratio of uric acid to creatinine greater than 1.0
in a random or 24-hour urine collection.
Uric acid renal stones occur in 10% to 25% of all
people with gout. The incidence correlates strongly with
the serum urate level, and the likelihood of developing
stones reaches 50% when the serum urate is above
13 mg/dL. Symptoms of renal stones precede the devel-
opment of gout in 40% of patients. Calcium-containing
renal stones occur 10 times more frequently in gouty
subjects than in the general population.
Hypertension
Hypertension is present in 25% to 50% of people with
gout, and 2% to 14% of people with hypertension have
gout. Because serum urate concentration correlates
directly with peripheral and renal vascular resistance,
reduced renal blood flow may account for the associa-
FIGURE 12A-6
tion between hypertension and hyperuricemia. Factors
such as obesity and male gender also link hypertension Radiographic changes of advanced gout include the typical
and hyperuricemia (29,30). gouty erosions with overhanging edge (white arrows) and soft
tissue swellings of gouty tophi.
Obesity
Hyperuricemia and gout correlate highly with body The bony erosions of gout are radiographically dis-
weight for both men and women, and individuals with tinct from the erosive changes of other inflammatory
gout commonly are overweight, compared with the arthritides. Gouty erosions usually are slightly removed
general population. Obesity may be a factor linking from the joint, but rheumatoid erosions typically are in
hyperuricemia, hypertension, hyperlipidemia, and the immediate proximity of the articular surface (Figure
atherosclerosis. 12A-6). The characteristic gouty erosion has features
that are both atrophic and hypertrophic, leading to ero-
sions with an overhanging edge. The joint space is pre-
Hyperlipidemia served in gout until very late in the disease process.
Serum triglycerides are elevated in 80% of people with Juxta-articular osteopenia, a common and early finding
gout. The association between hyperuricemia and serum in rheumatoid arthritis, is absent or minimal in gout.
cholesterol is controversial, although serum levels of
high density lipoprotein generally are decreased in
patients with gout. These abnormalities of serum lipids LABORATORY FEATURES
likely reflect overindulgence rather than a genetic link. AND DIAGNOSIS
An elevated serum urate level has long been considered
RADIOGRAPHIC FEATURES a cornerstone in the diagnosis of gout. In reality, this labo-
ratory finding is of limited value in establishing the diag-
The radiographic findings of gout often are unremark- nosis. The vast majority of hyperuricemic subjects will
able early in the disease course. In acute gouty arthritis, not develop gout, and serum urate levels may be normal
the only finding may be soft tissue swelling around the during gouty attacks (31). Far too many patients are diag-
affected joint. In most instances, bone and joint abnor- nosed with gout based on the clinical triad of an acute
malities develop only after many years of disease and monoarthritis, hyperuricemia, and a dramatic improve- 12
are indicative of the deposition of urate crystals. Most ment of articular symptoms in response to treatment. A
frequently, the abnormalities are asymmetric and seen diagnosis by these parameters is presumptive only, and
in the feet, hands, wrists, elbows, and knees. the physician should remain alert to other possibilities.
one of the diseases associated with rapid cellular turn-

over, such as the myelo- or lymphoproliferative disor-
ders. Certain drugs, contrast dyes, and alcohol interfere
with urinary uric acid measurements and should be
avoided for several days before the study.
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1. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic
hyperuricemia: risks and consequences in the Normative
Aging Study. Am J Med 1987;82:421426.
2. Sydenham T. The whole works of that excellent practical
physician, Dr. Thomas Sydenham. 7th ed. Pechey J. trans.
London: Feales; 1717:17.
FIGURE 12A-7 3. Ho G, DeNuccio M. Gout and pseudogout in hospitalized
Polarized microscopic view of typical needle-shaped MSU patients. Arch Intern Med 1993;153:27872790.
crystals in synovial fluid from an acutely inflamed joint. 4. Pascual E. Persistence of monosodium urate crystals and
low-grade inflammation in the synovial fluid of patients
with untreated gout. Arthritis Rheum 1991;34:141145.
5. Wernick R, Winkler C, Campbell S. Tophi as the initial
A clinical response to treatment, for example, nonsteroi- manifestation of gout: report of six cases and review of
dal anti-inflammatory agents or glucocorticoids, fre- the literature. Arch Intern Med 1992;152:873876.
quently is observed with other types of arthritis, including 6. Popp JD, Bidgood WD, Edwards NL. Magnetic reso-
calcium pyrophosphate pseudogout and basic calcium nance imaging of tophaceous gout in the hands and wrists.
phosphate (hydroxyapatite) tendonitis. Serum urate Semin Arthritis Rheum 1996;25:282289.
determinations are helpful and necessary in following the 7. Popp JD, Bidgood WD, Edwards NL. The gouty tophus.
effects of antihyperuricemic therapy. Rheumatol Rev 1993;2:163168.
8. Hench PS. The diagnosis of gout and gout arthritis. J Lab
The definitive diagnosis of gout is possible only by
Clin Med 1936;22:4855.
aspirating and inspecting synovial fluid or tophaceous 9. Nakayama DA, Barthelemy C, Carrera G, et al. Topha-
material and demonstrating characteristic MSU crystals ceous gout: a clinical and radiographic assessment. Arthri-
(Figure 12A-7). The crystals usually are needle or rod tis Rheum 1984;27:468471.
shaped. On compensated polarized microscopy, they 10. McGill NW, Dieppe PA. The role of serum and synovial
appear as bright, birefringent crystals that are yellow fluid components in promotion of urate crystal formation.
when parallel to the axis of slow vibration (marked on J. Rheumatol 1991;18:10421045.
the first-order compensator) and blue when perpendic- 11. Ziff M. The rheumatoid nodule. Arthritis Rheum 1984;27:
ular to this axis. The crystals usually are intracellular 468471.
during acute attacks, but small, truncated, extracellular 12. Campbell DA, Edwards NL. Multicentric reticulohistio-
crystals commonly appear as the attack subsides and cytosis: systemic macrophage disorder. Clin Rheumatol
1991;5:301318.
during the intercritical periods.
13. Sokoloff L. The pathology of gout. Metabolism 1957;6:
The synovial fluid findings are consistent with 230/243.
moderate-to-severe inflammation. The leukocyte count 14. Schumacher HR. Pathology of the synovial membrane in
usually falls between 5000 and 80,000 cells/mm3, with gout. Arthritis Rheum 1975;18(Suppl):771782.
the average count between 15,000 and 20,000 cells/mm3. 15. Palmer DG, Highton J, Hessian PA. Development of the
The cells are predominantly neutrophils. Synovial fluid gout tophus. A hypothesis. Am J Clin Pathol 1989;91:
should be sent for culture, as well, as bacterial infection 190195.
can coexist with gouty crystals. 16. Moro F, Ogg CS, Simmonds HA, et al. Familial juvenile
A 24-hour urine uric acid measurement is not gouty nephropathy with renal urate hypoexcretion pre-
required of all people presenting with gout. This mea- ceding renal disease. Clin Nephrol 1991;35:263269.
surement is useful for patients being considered for uri- 17. Burack DA, Griffith BP, Thompson ME, et al. Hyperuri-
cemia and gout among heart transplant recipients receiv-
cosuric therapy (probenecid or sulfinpyrazone) or when
ing cyclosporine Am J Med 1992;92:141146.
the cause of marked hyperuricemia (>11 mg/dL) is being 18. Howe S, Edwards NL. Controlling hyperuricemia and
investigated. On a regular diet, urinary uric acid excre- gout in cardiac transplant recipients. J Musculoskel Med
tion of more than 800 mg in 24 hours suggests a problem 1995;12:1524.
of urate overproduction. In children and young adults, 19. Lally EV, Ho G, Kaplan SR. The clinical spectrum of
this overproduction may be caused by enzymatic defects. gouty arthritis in women. Arch Intern Med 1986;146:
In older patients, this level of urinary uric acid suggest 22212225.
C H A P T E R 1 2 G O U T 24 9
20. Puig JG, Michan AD, Jimenez ML, et al. Female gout: 26. Choi HK, Atkinson K, Karlson EW, et al. Alcohol intake
clinical spectrum and uric acid metabolism. Arch Intern and risk of incident gout in men and a prospective study.
Med 1991;151:726732. Lancet 2004;363:94179420.
21. Reginato AJ, Schumacher HR, Allan DA, et al. Acute 27. Popp JD, Edwards NL. New insights into gouty arthritis.
monoarthritis associated with lipid liquid crystals. Ann Contemp Intern Med 1995;7:5564.
Rheum Dis 1985;44:537543. 28. Mazzali M, Kanellis J, Han L, et al. Hyperuricemia induces
22. Baker DG, Schumacher HR Jr. Acute monoarthritis. a primary renal arteriopathy in rats by a blood pressure-
N Engl J Med 1993;329:10131020. independent mechanism. Am J Physiol Renal Physiol
23. Urano W, Yamanaka H, Tsytani H, et al. The inflamma- 2002;282:F991F997.
tory process in the mechanism of decreased serum uric 29. Feig DI, Johnson RJ. Hyperuricemia in childhood primary
acid concentrations during acute gouty arthritis. J Rheu- hypertension. Hypertension 2003;42:247252.
matol 2002;29:19501953. 30. Feig DI, Nakagawa T, Karumanchi SA, et al. Hypothesis:
24. Yu TF. Diversity of clinical features in gouty arthritis. uric acid, nephron number, and the pathogenesis of essen-
Semin Arthritis Rheum 1984;13:360368. tial hypertension. Kidney Int 2004;66:281287.
25. Puig JG, Fox IH. Ethanol-induced activations of adenine 31. Schlesinger N, Baker DG, Schumacher HR Jr. How well
nucleotide turnover. Evidence for a role of acetate. J Clin have diagnostic tests and therapies for gout been evalu-
Invest 1984;74:936941. ated? Curr Opin Rheumatol 1999;11:441445.
12
CHAPTER 12
Gout
and Pathogenesis
HYON K. CHOI, MD, MPH, DRPH, FRCPC
The prevalence of gout, which occurs predominantly synthetase genes can result in overactivity of the
among men and postmenopausal women, is approxi- pathway, leading to increased rate of PRPP,
mately 2.7%. purine nucleotide, and urate production. Mutations
The incidence of primary gout has doubled over the in the gene encoding hypoxanthine-guanine
past 20 years in both sexes. phosphoribosyl transferase (HPRT) are associated
Gout prevalence rises with advancing age, reaching a with a spectrum of disease in children that ranges
level of 9% in men older than 80 years of age, and from hyperuricemia alone to hyperuricemia with
6% in women. profound neurological and behavioral dysfunction
There appears to be a higher prevalence of gout (LeschNyhan syndrome).
among individuals of lower family income levels, likely Ethanol administration increases uric acid production
reflecting a greater number of risk factors for goutfor by net adenosine triphosphate (ATP) degradation to
example, obesity, hypertension, and a Western dietary adenosine monophosphate (AMP), which is rapidly
pattern with a greater red meat component. degraded to uric acid, leading to hyperuricemia.
Two major genetic mutations are known to result in Alcohol consumption, uric acid levels, and risk of
gout, urolithiasis, and other disturbances: Mutations gout have a strong doseeffect relationship.
in the 5-phosphoribosyl 1-pyrophosphate (PRPP)
Gout is a form of inflammatory arthritis triggered by the mately 2.7%. The prevalence rises with advancing age,
crystallization of uric acid within the joints (1). Acute reaching a level of 9% in men older than 80 years of
gout, characteristically intermittent, is one of the most age, and 6% in women.
painful conditions experienced by humans. Chronic Serum urate concentrations in men are about
tophaceous gout develops usually after years of acute 1 mg/dL higher on average than in women (2), but after
intermittent gout. Beyond the morbidity associated menopause the serum levels of uric acid in women tend
with gout itself, the disease is associated with important to approach those in men. The sex differences in uric
medical conditions including the insulin resistance syn- acid levels may stem from the effects of estrogen on the
drome, hypertension, nephropathy, alcohol abuse, and renal tubular handling of uric acid; premenopausal
disorders associated with increased cell turnover. Gout levels of estrogens in women may promote more
is often associated with hyperuricemia. efficient renal clearance of urate (2). The prevalence
appears to be higher among African Americans than
among Caucasians, possibly reflecting the increased
EPIDEMIOLOGY prevalence of hypertension among African Americans
(3). Once termed the patrician malady, gout has been
Gout occurs predominantly among men and postmeno- considered a disease of the affluent, primarily observed
pausal women. The disease rarely occurs in men before in middle-aged men of wealthy status. Recent epidemi-
adolescence or in women before menopause. According ologic data, however, suggest a higher prevalence of
to the Third National Health and Nutrition Examina- gout among individuals of lower family income levels,
tion Survey (19881994), the prevalence of self-reported, likely reflecting a greater number of risk factors for
physician-diagnosed gout among US adults is approxi- goutfor example, obesity, hypertension, and a Western
250
C H A P T E R 1 2 G O U T 25 1
dietary pattern with a greater red meat componentin to occur in osteoarthritic joints (because such joints
lower socioeconomic classes. contain nucleating debris); and (3) the frequency of
The incidence of primary gout, defined as the occur- nocturnal onset (the result of intra-articular dehydra-
rence of this disease in the absence of a clear cause (e.g., tion that may occur at night) (1).
the LeschNyhan syndrome or diuretic use) has doubled
over the past 20 years in both sexes (4). Diet and life-
style trends, increasing frequencies of obesity, meta-
Urate Metabolism
bolic syndrome, hypertension, organ transplantation, The amount of urate in the body depends on the balance
and increasing use of certain medications (e.g., low dose between dietary intake, synthesis, and excretion of this
salicylate and diuretics) may explain the increasing inci- molecule. Hyperuricemia results from the overproduc-
dence of gout. tion of urate (10%), underexcretion of urate (90%), or
often a combination of the two. The purine precursors
come from exogenous (dietary) sources or endogenous
PATHOGENESIS OF metabolism (synthesis and cell turnover).
HYPERURICEMIA AND GOUT The dietary intake of purines makes a substantial
contribution to the blood uric acid. For example, sub-
Humans are the only mammals who are known to develop stitution of an entirely purine-free formula diet over a
gout spontaneously, probably because hyperuricemia period of days can reduce blood uric acid of healthy
only commonly develops in humans (1). In most fish, men from an average of 5.0 mg/dL to 3.0 mg/dL (1). The
amphibians, and nonprimate mammals, uric acid gener- bioavailable purine content of particular foods depends
ated from purine metabolism undergoes oxidative deg- on their relative cellularity as well as the transcriptional
radation via the uricase enzyme, producing the more and metabolic activity of their cellular content. Little is
soluble compound allantoin. In humans, the uricase gene known, however, about the precise identity and quan-
is crippled by two mutations that introduce premature tity of individual purines in most foods, especially when
stop codons (1). The absence of uricase, combined with cooked or processed (1,7). Ingested purine precursors
extensive reabsorption of filtered urate, results in urate go though steps in digestion, including (1) the break-
levels in human plasma that are approximately 10 times down of nucleic acids into nucleotides by pancreatic
than those of most other mammals (0.51.0 mg/dL). nucleases; (2) breakdown of oligonucleotides into
Urates role as the primary antioxidant in human blood simple nucleotides by phosphodiesterases; and (3)
may account for its evolutionary advantage (1). removal of phosphate and sugar groups from nucleo-
tides by pancreatic and mucosal enzymes. The addition
of dietary purines to purine-free dietary protocols has
Solubility of Urate revealed a variable increase in blood uric acid, depend-
Uric acid is a weak acid (pKa = 5.8) that exists largely ing on the formulation and dose of purines administered
as urate, the ionized form, at physiological pH. In (1,7). For example, RNA has a greater effect than an
general, the risk of supersaturation and crystal forma- equivalent amount of DNA; ribomononucleotides a
tion rises in parallel with the concentration of urate in greater effect than nucleic acid; and adenine a greater
physiologic fluids. Population studies indicate a direct effect than guanine.
correlation between serum urate levels and risk of A large prospective study showed that men in the
future gout (5). Conversely, lowering uric acid levels is highest quintile of meat intake had a 41% higher risk
associated with a substantially lower risk of recurrent of gout compared with those in the lowest quintile, and
gout, confirming the causal relation between uric acid that men in the highest quintile of seafood intake had a
levels and risk of gouty arthritis (6). The solubility of 51% higher risk compared with those in the lowest
urate in joint fluids is influenced by other factors as quintile (7). In a representative sample of US men and
well, however, including temperature, pH, cation con- women, higher levels of meat and seafood consumption
centration, articular hydration state, and the presence were associated with higher serum uric acid levels. The
of nucleating agents around which urate crystals may variation in the risk of gout associated with different
coalesce (e.g., nonaggregated proteoglycans, insoluble purine-rich foods may be explained by varying amounts
collagens, and chondroitin sulfate). and type of purine content and their bioavailability for
Variation in these factors may account for some of purine to uric acid metabolism. At the practical level,
the difference in the risk for gout associated with a these data suggest that dietary purine restriction in
given elevation in urate level. Moreover, these risk patients with gout or hyperuricemia (8) may be appli-
factors may explain several of the interesting clinical cable to purines of animal origin but not to purine-rich 12
features of gout: (1) predilection for the first metatar- vegetables, which are excellent sources of protein, fiber,
sophalangeal joint, that is, podagra (caused by the lower vitamins, and minerals. Similarly, implications of these
temperature at this peripheral body site); (2) tendency findings for dietary recommendation for patients with
252 HYON K. CHOI
FIGURE 12B-1
Dietary influences on the risk for gout White rice,

and their implications within a Healthy Use Sparingly white
Eating Pyramid. Data on the relationship bread,
Red potatoes,
between diet and the risk for gout are meat & pasta, &
primarily derived from the recent Health butter sweets
Professionals Follow-Up Study. Upward Dairy or calcium supplement
solid arrows denote an increased risk for 1 to 2 servings Multiple Vitamins
gout, downward solid arrows denote a For Most
(Low-fat dairy products
decreased risk, and horizontal arrows High-fat diary products (Vitamin C )
)
denote no influence on risk. Broken Alcohol in moderation
arrows denote potential effect but without Fish , poultry and eggs Unless Contraindicated
prospective evidence for the outcome of (wine ,
0 to 2 servings
gout. (Adapted from Choi HK, et al. Ann beer
Intern Med 2005;143:499516, with liguor )
Nuts and legumes
permission from Annals of Internal
1 to 3 servings
Medicine.)
Vegetables Fruit
in abundance 2 to 3 servings
Plant oils (olive, canola, soy, sunflower,

Whole grain foods
peanut, & other vegetable oils)
At Most Meals
At Most Meals
DAILY EXERCISE AND WEIGHT CONTROL
hyperuricemia or gout are generally consistent with a ing HPRT are associated with a spectrum of disease that
new Healthy Eating Pyramid, except for fish intake ranges from hyperuricemia alone to hyperuricemia
(Figure 12B-1) (1). The use of plant-derived omega-3 with profound neurological and behavioral dysfunction
fatty acids or supplements of eicosapentaenoic acid and (LeschNyhan syndrome) (2,7,9) Hypoxanthine cannot
docosahexaenoic acid in place of fish consumption could be reutilized without HPRT, and can only be degraded
be considered to provide the benefit of these fatty acids to urate. Both the underutilization of PRPP and decrease
without increasing the risk of gout. in inosine monophosphate and guanosine monophos-
phate levels in the salvage pathway contribute to hyper-
uricemia by feedback inhibition on de novo purine
Urate Production Pathways and synthesis (Figure 12B-2) (2,7,9). Because both of these
enzyme defects are X-linked traits, homozygous males
Inborn Errors of Metabolism are affected. In addition, postmenopausal gout and
The steps in the urate production pathways implicated urinary tract stones can occur in carrier females. Hyper-
in the pathogenesis of hyperuricemia and gout are dis- uricemia in prepubertal boys always suggests one of
played in Figure 12B-2. The vast majority of patients these enzymatic defects (2).
with endogenous overproduction of urate have the con-
dition as a result of salvaged purines arising from
increased cell turnover in proliferative and inflamma-
tory disorders (e.g., hematologic malignancies and pso-
Alcohol and Gout
riasis); pharmacologic intervention resulting in increased Conditions associated with net adenosine triphosphate
urate production (e.g., chemotherapy); or tissue hypoxia. (ATP) degradation lead to accumulation of adenosine
Only a small fraction of those with urate overproduc- diphosphate (ADP) and adenosine monophosphate
tion (10%) have an inborn error of metabolism such (AMP), which can be rapidly degraded to uric acid,
as superactivity of 5-phosphoribosyl 1-pyrophosphate leading to hyperuricemia (Figure 12B-2, Table 12B-1).
(PRPP) synthetase or deficiency of hypoxanthine- Examples of this include acute, severe illnesses such as
guanine phosphoribosyl transferase (HPRT; Figure the adult respiratory distress syndrome, myocardial
12B-2) (2,7,9). infarction, or status epilepticus, in which tissue hypoxia
Mutations in the PRPP synthetase genes can result impairs the mitochondrial synthesis of ATP from ADP.
in overactivity of the pathway. Superactivity of PRPP Another example relates to alcohol consumption.
synthetase leads to increased rate of PRPP, purine Ethanol administration increases uric acid production
nucleotide, and urate production, in association with by net ATP degradation to AMP. Decreased urinary
gout and urate urolithiasis. Mutations in the gene encod- excretion associated with dehydration and metabolic
C H A P T E R 1 2 G O U T 25 3
DE NOVO SYNTHESIS
Ribose-5-P+ ATP
+
PRPP synthetase
PRPP Inbom Errors of Metabolism

Ethanol
Fructose Intolerance or
Infusion Severe Tissue Hypoxia n
itio
Glycogen Storage Diseases + in hib
(Type I, III, V, and VIII) ATP ck GTP
d ba
fee
AMP IMP GMP

SALVAGE PATHWAYS
5 5
5
nucleotidase nucleotidase
nucleotidase
Inosine HPRT
APRT Adenosine Guanosine
+ PRPP adenosine PNP + PRPP
PNP PNP
deaminase
Adenine Hypoxanthine Guanine

xanthine
oxidase
Xanthine
xanthine
oxidase
Urate
FIGURE 12B-2
Urate production pathways implicated in the pathogenesis of hyperuricemia and gout. The de
novo synthesis starts with 5-phosphoribosyl 1-pyrophosphate (PRPP), which is produced by
addition of a further phosphate group from adenosine triphosphate (ATP) to the modified sugar
ribose-5-phosphate. This step is performed by the family of PRPP synthetase (PRS) enzymes. In
addition, purine bases derived from tissue nucleic acids are reutilized through the salvage
pathway. The enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT) salvages
hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine monophosphate
(GMP). Only a small proportion of patients with urate overproduction have the well-characterized
inborn errors of metabolism, such as superactivity of PRS and deficiency of HPRT. Furthermore,
conditions associated with net ATP degradation lead to the accumulation of adenosine diphos-
phate (ADP) and adenosine monophosphate (AMP), which can be rapidly degraded to uric acid.
These conditions are displayed in left upper corner. Plus sign denotes stimulation, and minus
sign denotes inhibition. Abbreviations: APRT, adenine phosphoribosyl transferase; PNP, purine
nucleotide phosphorylase. (Adapted from Choi HK, et al. Ann Intern Med 2005;143:499516,
with permission from Annals of Internal Medicine.)
acidosis also may contribute to the hyperuricemia asso- Adiposity, Insulin Resistance,
ciated with ethanol ingestion. A prospective study con-
firmed the doseresponse relationships between ethanol
and Hyperuricemia
consumption, uric acid levels, and risk of gout (9). An increased adiposity and the insulin resistance syn-
The same study found that the risk of gout varies drome are both closely associated with hyperuricemia
according to type of alcoholic beverage: beer confers a (10). Whereas body mass index, waist-to-hip ratio, and
larger risk than liquor, whereas moderate wine drinking weight gain are all associated with gout in men (11),
did not increase the risk (9). These findings suggest that weight reduction is associated with a decline in urate
certain nonalcoholic components within alcoholic bev- levels and risk of gout. Weight reduction leads to lower
erages play an important role in urate metabolism. The de novo purine synthesis and lower serum urate levels.
effect of purines ingested from beer on blood uric acid Exogenous insulin can reduce the renal excretion of 12
may be sufficient to augment the hyperuricemic effect urate in both healthy and hypertensive subjects, thus
of alcohol itself, producing a greater risk of gout than providing an additional link between adiposity, insulin
liquor or wine (9). resistance, type II diabetes, and gout. Insulin may
254 HYON K. CHOI
TABLE 12B-1. CAUSES OF HYPERURICEMIA AND RENAL TRANSPORT

URATE-LOWERING AGENTS.
OF URATE
Causes of hyperuricemia
Uric acid overproduction Renal urate transport follows a four-component model:

Inherited enzyme defects (1) glomerular filtration, (2) nearly complete reabsorp-
HGRT deficiency, PRPP synthetase overactivity
tion of the filtered urate, (3) subsequent secretion, and
Increased cell turnover
Myeloproliferative and lymphoproliferative disorders, (4) postsecretory reabsorption in the remaining proxi-
polycythemia vera, malignant diseases, hemolytic diseases, mal tubule (1). The molecular target for uricosuric
psoriasis agents, an anion exchanger responsible for the reab-
Purine-rich foods sorption of filtered urate by the renal proximal tubule,
Obesity
was identified recently (1,11). The authors searched the
Accelerated ATP degradation
Ethanol, fructose, severe tissue hypoxemia or muscle exertion, human genome database for novel gene sequences
glycogen storage diseases (types I, III, V, and VII) within the organic anion transporter (OAT) gene family
Urate Increasing Agents and identified URAT1 (SLC22A12), a novel transporter
Cytotoxic drugs, warfarin, vitamin B12 (patients with pernicious expressed at the apical brush border of the proximal
anemia), ethylamino-1,3,4-thiadiazole, 4-amino-5-imidazole
nephron (11). Urateanion exchange activity similar to
carboxamide riboside
that of URAT1, initially described in brush border
Uric acid underexcretion membrane vesicles (BBMV) from urate-reabsorbing
Clinical disorders associated with uric acid underexcretion species such as rats and dogs, was subsequently con-
Renal failure, hypertension, metabolic syndrome, obesity
Certain nephropathy
firmed in human kidneys (1). Xenopus oocytes injected
Lead nephropathy, polycystic kidney disease, medullary cystic with URAT1-encoding RNA transport urate and exhibit
kidney disease, familial juvenile hyperuricemic nephropathy pharmacological properties consistent with data from
Agents increasing urate reabsorption through trans-stimulation human BBMV (11). These and other experiments
of URAT1 indicate that uricosuric compounds (e.g., probenecid,
Pyrazinamide, salicylate (low dose), nicotinate, lactate, beta-
hydroxybutyrate, acetoacetate
benzbromarone, sulfinpyrazone, and losartan) directly
Agents decreasing renal urate excretion, maybe through inhibit URAT1 from the apical side of tubular cells
URAT1 or other mechanisms (cis-inhibition). In contrast, anti-uricosuric substances
Diuretics, ethambutol, insulin, beta-blockers (e.g., pyrazinoate, nicotinate, lactate, pyruvate, beta-
Urate Lowering Agents
hydroxybutyrate, and acetoacetate) serve as the
Inhibition of xanthine oxidase exchanging anion from inside cells, thereby stimulat-
Allopurinol, febuxostat ing anion exchange and urate reabsorption (trans-
Uricase stimulation) (Table 12B-1).
Agents decreasing urate reabsorption through direct inhibition Urate transporter-1 is crucial for urate homeostasis:
of URAT1
Probenecid, sulfinpyrazone, benzbromarone, losartan, salicylate
a handful of patients with renal hypouricemia were
(high dose) shown to carry loss-of-function mutations in the human
Uricosuric agents, maybe through inhibition of URAT1 or other SLC22A12 gene encoding URAT1, indicating that this
mechanisms exchanger is essential for the proximal tubular reab-
Amlodipine, fenofibrate, vitamin C, estrogen, angiotensin II, sorption (12). Furthermore, pyrazinamide, benzbroma-
parathyroid hormone
rone, and probenecid failed to affect urate clearance in
ABBREVIATIONS: ATP, adenosine triphosphate; HGRT, hypoxanthine-guanine subjects with homozygous loss-of-function mutations in
phosphoribosyl transferase; PRPP, 5-phosphoribosyl 1-pyrophosphate; SLC22A12, indicating that URAT1 is essential for the
URAT1, urate transporter-1. effect of both anti-uricosuric and uricosuric agents.
Anti-uricosuric agents exert their effect by stimulat-
ing renal reabsorption rather than inhibiting tubular
secretion (1). The mechanism appears to involve a
priming of renal urate reabsorption, via the Na+-
enhance renal urate reabsorption via stimulation of dependent loading of proximal tubular epithelial cells
urateanion exchanger URAT1 (12) and/or the Na+- with anions capable of a trans-stimulation of urate reab-
dependent anion cotransporter in brush border mem- sorption. A transporter in the proximal tubule brush
branes of the renal proximal tubule. Some investigators border mediates Na+-dependent reabsorption of pyr-
have suggested that leptin and increased adenosine azinoate, nicotinate, lactate, pyruvate, beta-hydroxybu-
levels may contribute to hyperuricemia. The epidemic tyrate, and acetoacetate, all of which are monovalent
of obesity and the insulin resistance syndrome thus anions that are also substrates for URAT1 (1). Increased
presents a substantial challenge in the prevention and plasma concentrations of these antiuricosuric anions
management of gout. result in their increased glomerular filtration and greater
C H A P T E R 1 2 G O U T 25 5
reabsorption by the proximal tubule. The augmented The tophus represents the most characteristic lesion
intra-epithelial concentrations, in turn, induce the reab- of gout and can be found in the synovium as well as
sorption of urate by promoting the URAT1-dependent elsewhere (13). Crystals in the tophi in synovium and
anion exchange of filtered urate (trans-stimulation). elsewhere are needle shaped and often are arranged
Urate reabsorption by the proximal tubule thus radially in small clusters. The histopathology of tophi
exhibits a form of secondary Na+ dependency, in that shows foreign body granulomas surrounding a core of
Na+-dependent loading of proximal tubular cells stimu- amorphous mass or monosodium urate (MSU) crystals
lates brush border urate exchange. Urate itself is not by mono- and multinucleated macrophages, fibroblasts,
a substrate for the Na+anion transporter. The molec- and lymphocytes. Other components of tophi include
ular identity of the relevant Na+-dependent anion lipids, mucopolysaccharides, and plasma proteins. At
cotransporter(s) remains unclear. However, a leading least in some cases, tophi in the synovium have been
candidate gene is SLC5A8, which encodes a Na+- observed at the time of first gouty attack (13). These
dependent lactate and butyrate cotransporter (1). The synovial tophi often lie near the joint surface and are
SLC5A8 protein may also transport both pyrazinoate weakly encapsulated so that minor trauma or changes
and nicotinate, potentiating urate transport in Xenopus in the crystal equilibrium within the tophus would likely
oocytes that co-express URAT1 (1). allow release of crystals into the joint to precipitate
The anti-uricosuric mechanism explains the long- attacks (13).
standing clinical observations that hyperuricemia is
induced by increases in beta-hydroxybutyrate and ace-
toacetate in diabetic ketoacidosis, lactic acid in alcohol
URATE CRYSTALINDUCED
intoxication, or nicotinate and pyrazinoate in niacin INFLAMMATION
and pyrazinamide therapy, respectively (Table 12B-1).
Urate retention is provoked also by a reduction in Urate crystals in joint fluid at the time of the acute
extracellular fluid volume and by excesses of angioten- attack may derive from rupture of preformed synovial
sin II, insulin, and parathyroid hormone. URAT1 and deposits or precipitate de novo (2). However, the finding
the Na+-dependent anion cotransporter(s) may be of crystals in synovial fluids of asymptomatic joints
targets for these stimuli (Table 12B-1). illustrates that factors other than the presence of crys-
Certain anions that interact with URAT1 have tals are important in modulating the inflammatory reac-
the dual potential to either increase or decrease renal tion (14).
urate excretion, through either trans-stimulation or cis- Urate crystals initiate, amplify, and sustain intense
inhibition of apical urate exchange in the proximal inflammatory attacks by stimulating the synthesis and
tubule (1). For example, a low concentration of pyr- release of humoral and cellular mediators (1,2). Urate
azinoate stimulates urate reabsorption through trans- crystals interact with the phagocyte through two broad
stimulation. A higher concentration, in contrast, reduces mechanisms. First, they activate the cells through opso-
urate reabsorption via extracellular cis-inhibition of nized and phagocytosed particles, eliciting a stereotypi-
URAT1. Biphasic effects on urate excretion, that is, cal phagocyte response of lysosomal fusion, respiratory
anti-uricosuria at low dose and uricosuria at high dose, burst, and release of inflammatory mediators. The other
are also well described for salicylate (1). Salicylate cis- mechanism involves the particular properties of the urate
inhibits URAT1, explaining the high dose uricosuric crystal to interact directly with lipid membrane and pro-
effect; low anti-uricosuria reflects a trans-stimulation of teins via cell membrane perturbation and cross-linking
URAT1 by intracellular salicylate, which is evidently a of membrane glycoproteins in the phagocyte. This inter-
substrate for the Na+pyrazinoate transporter. action leads to the activation of several signal trans-
duction pathways including G proteins, phospholipase
C and D, Src tyrosine kinases, the mitogen-activated
PATHOLOGY OF GOUT protein kinases ERK1/ERK2, 9c-Jun N-terminal kinase,
and p38 mitogen-activated protein kinase (1,2). These
Neutrophilic synovitis is the hallmark of acute gouty steps are critical for crystal-induced interleukin (IL) 8
attack. Acute gouty synovitis shows diffuse superficial expression in monocytic cells, which plays a key role in
and perivascular infiltration with polymorphonuclear the neutrophil accumulation (1,2). Recently, innate
leukocytes in the synovium, as well as exudate con- immune responses involving Toll-like receptors (TLR) 2
taining polymorphonuclear neutrophilic leukocytes and 4 have been implicated in the chondrocyte and
and fibrin adhering to the synovial surface (13). Some macrophage signaling (14). Furthermore, induction of
proliferation of synovial cells and infiltration of triggering receptor expressed on myeloid cells 1 (TREM- 12
lymphocytes, macrophages, and occasional plasma 1) has been implicated as another potential mechanism
cells have also been observed during the acute gouty for the early, induced innate immune response to ampli-
synovitis. fication of acute gouty inflammation (15).
256 HYON K. CHOI
Animal models of gout indicate that whereas mono- apoptosis and other apoptotic cell clearance represent
cytes and mast cells participate during the early phase a fundamental mechanism in the resolution of acute
of inflammation, neutrophilic infiltrates occur later (1). inflammation. Transforming growth factor beta, abun-
Macrophages from noninflamed joints may contain dant in acute gouty synovial fluid, inhibits IL-1 recep-
urate crystals (1). The state of differentiation of mono- tor expression and IL-1driven cellular inflammatory
nuclear phagocytes determines whether or not the responses (1). Furthermore, urate crystals can induce
crystals will trigger an inflammatory response. In undif- peroxisome proliferator-activated receptor-gamma
ferentiated monocytes, induction of proinflammatory receptor (PPAR-gamma) expression in human mono-
cytokines [tumor necrosis factor alpha (TNF-alpha), cytes, promoting neutrophil and macrophage apoptosis.
IL-1 beta, IL-6, IL-8, and cyclooxygenase-2 (COX-2)] Similarly, upregulation of IL-10 expression has been
and endothelial cell activation occur after urate crystal shown to limit experimental urate-induced inflamma-
phagocytosis. In contrast, well-differentiated macro- tion and may function as a native inhibitor of gouty
phages failed to induce these cytokines or activate inflammation. Inactivation of inflammatory mediators
endothelial cells. These findings suggest that monocytes by proteolytic cleavage, cross-desensitization of recep-
play a central role in stimulating an acute attack of gout. tors for chemokines, release of lipoxins, IL-1 receptor
Conversely, differentiated macrophages play an anti- antagonist, and other anti-inflammatory mediators may
inflammatory role, helping to terminate acute attacks all facilitate the resolution of the acute gout. The entry
and restore the asymptomatic state (1). Furthermore, of large molecules such as apolipoprotein B and E, and
animal models of gout suggest that mast cells are other plasma proteins into the synovial cavity due to
involved in the early phase of crystal-induced inflamma- increased vascular permeability also would contribute
tion. In response to C3a, C5a, and IL-1, mast cells to the spontaneous resolution (1).
release histamine and other inflammatory mediators Chronic gouty arthritis typically occurs after years of
(1). The vasodilatation, increased vascular permeabil- gout. Cytokines, chemokines, proteases, and oxidants
ity, and pain so characteristic of gout are also mediated involved in urate crystalinduced inflammation also
by kinins, complement cleavage peptides, and other contribute to the chronic inflammation, leading to
vasoactive prostaglandins. chronic synovitis, cartilage loss, and bone erosion (1).
Neutrophilicendothelial cell interaction leading to Low rade synovitis may persist in involved joints with
neutrophilic influx, a central event in gouty inflamma- ongoing intra-articular phagocytosis of crystals by leu-
tion, provides the basis for the pharmacologic effect of kocytes even during the remissions of acute flares (13).
colchicine. Neutrophil influx is believed to be promoted Tophi on the cartilage surface observed through arthros-
by endothelialneutrophil adhesion, triggered by IL-1, copy may contribute to chondrolysis despite adequate
TNF-alpha, IL-8, the neutrophil chemoattractant treatment of both hyperuricemia and acute gouty attacks
protein-1 (MCP-1), and other cytokines and chemo- (1). Adherent chondrocytes phagocytize microcrystals
kines (1). Neutrophil migration involves neutrophilic and produce active metalloproteinases. Furthermore,
endothelial interaction mediated by cytokine-induced crystalchondrocyte cell membrane interactions can
E-selectin clustering on endothelial cells. Colchicine trigger chondrocyte activation, gene expression of IL-1
interferes with the interactions by altering the number beta and inducible nitric oxide synthase, nitric oxide
and distribution of selectins on endothelial cells and release, and matrix metalloproteinases, leading to
neutrophils (15). cartilage destruction (17). The crystals can also suppress
Once in the synovial tissue, the neutrophils follow the 1,25-dihydroxycholecalciferolinduced activity of
concentration gradients of chemoattractants such as alkaline phosphatase and osteocalcin. Thus, crystals can
C5a, leukotriene B4, platelet activating factor, IL-1, and alter the osteoblast phenotype by reducing their ana-
IL-8 (1). Among these factors, IL-8 and growth-related bolic effects that may contribute to damage to the juxta-
gene chemokines play a central role in neutrophil inva- articular bone (1).
sion (16). For example, IL-8 alone accounts for approxi-
mately 90% of the neutrophil chemotactic activity of
human monocytes in response to urate crystals. Neu-
tralization of IL-8 or its receptor therefore offers a REFERENCES
potential therapeutic target in gout. Several other neu-
1. Choi HK, Mount DB, Reginato AM. Pathogenesis of
trophil chemotactic factors, including the calgranulin
Gout. Ann Intern Med 2005;143:499516.
family members S100A8 and S100A9, are also involved 2. Terkeltaub RA. Epidemiology, pathology, and pathogen-
in neutrophil migration induced by urate crystals. esis. In: Klippel JH, ed. Primer on the rheumatic diseases,
Several processes contribute to the self-limited nature 12th ed. Atlanta: Arthritis Foundation; 2001:307312.
of acute gout. Clearance of urate crystals by differenti- 3. Hochberg MC, Thomas J, Thomas DJ, et al. Racial dif-
ated macrophages in vitro has been linked to inhibition ferences in the incidence of gout. The role of hyperten-
of leukocyte and endothelial activation. Neutrophil sion. Arthritis Rheum 1995;38:628632.
C H A P T E R 1 2 G O U T 25 7
4. Arromdee E, Michet CJ, Crowson CS, OFallon WM, 12. Schumacher HR. Pathology of the synovial membrane in
Gabriel SE. Epidemiology of gout: is the incidence rising? gout. Light and electron microscopic studies. Interpreta-
J Rheumatol 2002;29:24032406. tion of crystals in electron micrographs. Arthritis Rheum
5. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic 1975;18:771782.
hyperuricemia. Risks and consequences in the Normative 13. Pascual E, Batlle-Gualda E, Martinez A, Rosas J, Vela P.
Aging Study. Am J Med 1987;82:421426. Synovial fluid analysis for diagnosis of intercritical gout.
6. Shoji A, Yamanaka H, Kamatani N. A retrospective study Ann Intern Med 1999;131:756759.
of the relationship between serum urate level and recur- 14. Liu-Bryan R, Terkeltaub R. Evil humors take their toll as
rent attacks of gouty arthritis: evidence for reduction of innate immunity makes gouty joints TREM-ble. Arthritis
recurrent gouty arthritis with antihyperuricemic therapy. Rheum 2006;54:383386.
Arthritis Rheum 2004;51:321325. 15. Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin
7. Choi HK, Atkinson K, Karlson EW, Willett WC, Curhan RI, Weissmann G. Colchicine alters the quantitative and
G. Purine-rich foods, dairy and protein intake, and the qualitative display of selectins on endothelial cells and
risk of gout in men. N Engl J Med 2004;350:10931103. neutrophils. J Clin Invest 1995;96:9941002.
8. Emmerson BT. The management of gout. N Engl J Med 16. Terkeltaub R, Baird S, Sears P, Santiago R, Boisvert W.
1996;334:445451. The murine homolog of the interleukin-8 receptor
9. Choi HK, Atkinson K, Karlson EW, Willett WC, Curhan CXCR-2 is essential for the occurrence of neutrophilic
G. Alcohol intake and risk of incident gout in mena inflammation in the air pouch model of acute urate
prospective study. Lancet 2004;363:12771281. crystal-induced gouty synovitis. Arthritis Rheum 1998;
10. Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, 41:900909.
weight change, hypertension, diuretic use, and risk of gout 17. Liu R, Liote F, Rose DM, Merz D, Terkeltaub R.
in menThe Health Professionals Follow-Up Study. Proline-rich tyrosine kinase 2 and Src kinase signaling
Arch Intern Med 2005;165:742748. transduce monosodium urate crystal-induced nitric
11. Enomoto A, Kimura H, Chairoungdua A, et al. Molecular oxide production and matrix metalloproteinase 3 ex-
identification of a renal urate anion exchanger that regu- pression in chondrocytes. Arthritis Rheum 2004;50:
lates blood urate levels. Nature 2002;417:447452. 247258.
12
CHAPTER 12
Gout
C. Treatment
ROBERT A. TERKELTAUB, MD
The three major considerations on comprehensive Colchicine (generally 0.6 mg once or twice daily) is an
gout therapy include: (1) the treatment of acute appropriate therapy for prophylaxis against recurrent
flares; (2) management of the complications of gout flares.
chronic tophaceous gout; and (3) prophylaxis through The two standard urate-lowering therapies are
urate-lowering agents designed to prevent disease allopurinol (most popular) and the uricosuric agents,
flares and long-term sequelae. for example, probenecid.
In the absence of contraindications, nonsteroidal anti- Asymptomatic hyperuricemia does not require
inflammatory drugs (NSAIDs) are considered first-line treatment.
therapy for acute gout. The dose of allopurinol must be decreased in the
Systemic glucocorticoids, also effective therapy for setting of renal insufficiency.
acute gout, are very useful for patients in whom Febuxostat, a relative newcomer to gout therapy,
NSAIDs are contraindicated. also achieves its effects through the inhibition of
Intra-articular glucocorticoid injections may be xanthine oxidase, albeit through a different mecha-
effective if only one or two joints are affected by nism than allopurinol.
acute gout.
Gout management involves two primary components: Nonsteroidal Anti-Inflammatory

(1) treatment and prophylaxis of acute joint and bursal
inflammation and (2) lowering of serum urate levels
Drugs and Other Analgesic Agents
with the objectives of avoiding recurrent, painful The primary goal in treatment of acute gout is rapid,
inflammatory flares, suppressing progression of joint safe resolution of pain and functional incapacity.
damage, and preventing the occurrence of urolithiasis. Because acute gout attacks are self-limited, results of
All too often, current strategies for treating gouty clinical trials for this condition warrant careful con-
arthritis and lowering urate levels are based more on sideration. Nonsteroidal anti-inflammatory drugs
practitioner preferences than on evidence-based medi- (NSAIDs) typically produce major symptom reduction
cine (1). within 24 hours. In the absence of contraindications,
NSAIDs are considered first-line therapy for acute gout.
No specific NSAID has clear superiority over others in
MANAGEMENT OF ACUTE the treatment of gout. Ibuprofen in full doses (e.g.,
GOUTY ARTHRITIS 800 mg q.i.d.), for example, is as likely to be effective as
indomethacin (50 mg t.i.d.). Unfortunately, NSAID gas-
Choices for both anti-inflammatory and antihyperuri- trointestinal and renal toxicity are major concerns in
cemic therapy in gout are reviewed below. many patients. The comparable efficacy of etoricoxib
258
C H A P T E R 1 2 G O U T 25 9
and indomethacin in a head-to-head comparison in press an attack and the narrow therapeutic window and
acute gout (2) suggests that selective cyclooxygenase-2 high potential for serious toxicities associated with
(COX-2) inhibition provides an alternative approach intravenous colchicine. In nearly all patients, NSAIDs,
when nonselective COX inhibitors are contraindicated glucocorticoids, or ACTH provide better options for
in the acute setting. However, cardiac safety of selective the treatment of acute gout. As discussed below, colchi-
COX-2 inhibitors remains controversial. Opiates are cine continues to play a major role in the prophylaxis
useful adjuncts for analgesia early in acute gout treat- against gout attacks.
ment, though this has not been evaluated in controlled
clinical trials (1). Prophylactic Therapy for Acute
Gouty Arthritis
Glucocorticosteroids and
Low dose colchicine (i.e., 5 or 6 mg p.o. once or twice
Adrenocorticotrophic Hormone daily) is a highly appropriate choice for prophylaxis of
Glucocorticosteroids (systemic or local) and adreno- recurrent acute gout (1). Although colchicine is not a
corticotrophic hormone (ACTH) are reliably effective potent anti-inflammatory agent, the medication is par-
second-line treatments for acute gout. These drugs also ticularly effective for prophylaxis against gout and
are limited by the potential for toxicity, particularly the calcium pyrophosphate dehydrate deposition disease
exacerbation of hyperglycemia. Relatively large doses (CPPD) crystal-induced inflammation. Even low con-
of systemic glucocorticosteroids often are required to centrations of colchicine modulate neutrophil adhesion
treat acute gout effectively, particularly when the arthri- to the endothelium (3). High concentrations of colchi-
tis is polyarticular or when it affects a large joint such cine suppress urate crystal-induced activation of the
as the knee. A typical regimen in such a scenario would NALP3 inflammasome (4). It is less clear that low dose
be prednisone, initiated at 30 to 60 mg/day (perhaps in NSAIDs work reliably for gout prophylaxis.
divided doses), with a steady taper to discontinuation Gouty arthritis is a particularly common event in the
over 10 to 14 days. The use of a tapering oral methyl- first few months after initiation of uric acidlowering
predisolone dose package regimen has not yet been treatment. Standard clinical practice is to prescribe
systematically evaluated for acute gout. The effective- daily oral colchicine (0.6 mg p.o. bid in patients with
ness of intra-articular injection of a depot glucocortico- intact renal function) for the first 6 months of antihy-
steroid ester for gout affecting one or two large joints peruricemic therapy. The dosage of low dose prophy-
has been supported by small, open-label studies (1). lactic colchicine should be lowered in the presence of
Synthetic ACTH appears to be effective within hours renal dysfunction and with age over 70 (1). Even so,
for acute oligoarticular and polyarticular gout and was caution is needed, as low dose daily colchicine may be
superior to indomethacin in acute gout treatment in associated with severe toxicities, including neuromyop-
one controlled clinical trial (1). A controlled study of athy and bone marrow suppression. Concurrent treat-
patients with acute gout suggested that systemic anti- ment with erythromycin, statin drugs, gemfibrozil, and
inflammatory doses of glucocorticosteroids and ACTH cyclosporine predispose to colchicine toxicity by alter-
have comparable effectiveness (1). Peripheral anti- ing colchicine elimination (1). Because colchicine is not
inflammatory effects of ACTH mediated by melanocor- dialyzable, it should not be employed in dialysis-depen-
tin receptor 3 activation, preceding induction of adrenal dent renal failure (1).
glucocorticosteroid release, could be responsible for the
rapidity of ACTH efficacy in acute gout. ACTH is rela- Uric Acid Lowering Approaches
tively expensive, however, and is not universally avail-
able. Primary treatment of acute gout with systemic The decision to initiate antihyperuricemic therapy in
glucocorticosteroids or ACTH also can be associated gout requires thoughtful consideration, as antihyperur-
with rebound arthritis flares. Therefore, initiation of cemic agents have multiple potential drug interactions
low dose prophylactic colchicine simultaneously with and toxicities. Gout does not always progress in the
systemic glucocorticosteroids or ACTH is often useful absence of urate-lowering therapy, and in some patients
as an adjunctive treatment. serum urate levels can be normalized through lifestyle
changes, without antihyperuricemic drugs. Lifestyle
alterations that may affect urate levels include cessation
Colchicine of alcohol abuse, weight reduction, and the replacement
Colchicine, administered either orally or intravenously, of thiazide diuretics with another class of antihyperten-
was once a standard approach to the treatment of acute sive agent. Conventional purine-restricted diets are un- 12
gout attacks. Colchicine is no longer recommended for palatable and only modestly effective in lowering serum
the treatment of acute gout flares, however, because of urate. A palatable, calorie-restricted, low carbohy-
the length of time required for oral colchicine to sup- drate diet tailored to improve insulin sensitivity appears
260 ROBERT A. TERKELTAUB
to diminish hyperuricemia by 15% to 20% (5). Other level of urate solubility in physiologic solutions in vitro.
dietary measures, such as specifically limiting beer con- Standard clinical practice is to achieve this level of
sumption and increasing low fat dairy product consump- serum urate lowering via gradual escalation of anti-
tion, merit further direct investigation. hyperuricemic drug dosages over the first few months
of therapy (1). However, lowering serum urate to levels
Pharmacologic Antihyperuricemic above 6.0 mg/dL is associated with at least partial
clinical efficacy in many patients. Allopurinol and uri-
Treatments cosuric therapy promote shrinkage of tophi at similar
The two major indications for chronic uric acid rates when serum urate is also diminished to a similar
lowering therapy in gout are macroscopic subcutane- level.
ous tophi and unacceptably frequent attacks of gouty Allopurinol is the most frequently used antihyperuri-
arthritis (e.g., three or more per year). Standard prac- cemic agent among practitioners, due to the convenient
tice is to delay initiating uric acidlowering treatment single daily dosing and the generally predictable
until resolution of the inflammatory phase of acute efficacy of allourinol irrespective of etiology of the
gout. This practice is due to concern that antihyperuri- hyperuricemia in gout (1). The usual starting dose of
cemic therapy could worsen acute gout by mobilizing allopurinol for most patients should be on the order of
urate crystals from remodeling microscopic and macro- 100 mg/day (lower for patients with renal insufficiency,
scopic tophi. Precipitation of acute gout through this possibly higher for young patients with normal renal
mechanism is a common side effect in the first few function). This dose is titrated upward over a period of
months after initiation of antihyperuricemic therapy several weeks according to the serum uric acid level.
(1,6). Doses of up to 300 mg/day and even higher may be used.
The currently available pharmacotherapies for serum A broad issue limiting effective allopurinol use appears
urate lowering are: (1) allopurinol, a xanthine oxidase to be poor patient compliance, which challenges practi-
inhibitor, which reduces uric acid production; or (2) tioners to educate patients better regarding the long-
uricosuric agents (exemplified by probenecid), which term objectives of antihyperuricemic therapy.
increase renal uric acid excretion. Probenecid and other Side effects of allopurinol include minor hypersensi-
uricosurics act through inhibition of the organic anion tivity reactions such as pruritus and dermatitis, which
exchanger URAT1 in the proximal renal tubule, thereby occur in approximately 2% of patients (1). Approxi-
inhibiting urate reabsorption. mately half of the patients with such minor reactions
In traditional evaluations of gout, patients were have been reported to be desensitized successfully in
divided into two groups on the basis of 24-hour urine small, open-label studies (1). However, allopurinol tox-
uric acid exretion results: uric acid overproducers icity, including hepatic damage and major hypersensen-
and underexcreters. Overproducersthe great major- sitivity reactions, can become severe. A mortality rate
ity of gout patientshave been defined as those gout of ~20% is seen with the allopurinol major hypersensi-
patients whose daily urinary uric acid excretion exceeds tivity syndrome, which is dose dependant and typically
800 mg. Unfortunately, such urine collections are incon- manifests as severe dermatitis, accompanied by features
venient to patients, prone to inaccuracy, and may fail including vasculitis, fever, eosinophilia, hepatic and
to identify combined uric acid overproduction and renal dysfunction (1). Renal insufficiency and possibly
underexcretion. Moreover, 24-hour urine collections concomitant thiazide therapy are predisposing factors
fail to identify uric acid overproduction reliably in for the severe allopurinol hypersensitivity syndrome. In
subjects with creatinine clearances <60 mL/min. Mea- Han Chinese, human leukocyte antigen (HLA)-B5801
surement of uric acid in spot urine samples does is strongly linked to severe allopurinol cutaneous hyper-
not distinguish reliably between uric acid overproduc- sensitivity (7). Fortunately, major allopurinol hypersen-
tion from underexcretion (1). Thus, in practice, the sitivity syndrome is uncommon and it is believed that
usual approach to therapy once the need for urate- adjusting the initial daily dose of allopurinol in direct
lowering therapy is determined is allopurinol, regard- proportion to creatinine clearance may reduce the risk
less of the 24-hour uric acid excretion measurement. of developing this drug toxicity (1). Overly aggressive
Twenty-fourhour urine uric acid collections may be attempts to bring serum urate below 6.0 mg/dL with
used to screen for uric acid overproduction in the allopurinol may be hazardous in subjects with advanced
absence of an obvious cause of hyperuricemia such as renal insufficiency because of dose-dependent toxicities
renal failure, diuretic use, or myeloproliferative disease. of allopurinol.
This test is particularly useful in subjects presenting When a uricosuric agent is required (e.g., in the
with gout before the age of 30 or with gout and a setting of allopurinol hypersensitivity), probenecid is
history of urolithiasis. The optimal target level for usually the agent of choice. Probenecid increases renal
serum urate reduction is held to be below 6.0 mg/dL, uric acid clearance and can be employed effectively for
given that this is approximately 1 mg/dL lower than the patients with substantially decreased renal uric acid
C H A P T E R 1 2 G O U T 26 1
excretion but creatinine clearance 60 mL/min (1). Uri- Gout in the Patient with
cosuric agents require good renal function in order to
be effective. Probenecid is started at a dosage of 500 mg
Organ Transplantation
twice daily and titrated upward to a maximum dosage A striking example of refractory gout is provided by
of 1 g twice daily (or until the target serum uric acid patients with major organ transplantation. In such
level is achieved). Subjects taking probenecid are at patients, cyclopsporine or tacrolimus are critical to the
increased risk for uric acid urolithiasis and should be success of the allograft (1). In this condition, nephro-
compliant and able to consume at least 2 L of fluid orally pathic and renal urate transportaltering effects of
on a daily basis to reduce urolithiasis risk. Low dose cyclosporine or tacrolimus drive the potential for
acetylsalicylic acid, which reduces renal uric acid marked hyperuricemia and remarkably accelerated
excretion, does not appear to significantly block the tophi development. Consequently, the diagnosis of
antihyperuricemic activity of probenecid. Other potent transplantation-associated gout nearly always calls
uricosuric agents include sulfinpyrazone and benzbro- for the institution of antihyperuricemic therapy. Low
marone, but these drugs are limited by toxicity and are dose cyclosporine microemulsion regimens and on-
not universally available (1). Less potent uricosuric going development of cyclosporine-free immunosup-
agents include the angiotensin 1 (AT1) receptor antago- pression regimens for major organ transplant recipients
nist losartan, and the lipid-lowering agents atorvastatin should diminish the scope and extent of this iatrogenic
and fenofibrate. Among these three agents, fenofibrate condition.
has the greatest capacity to decrease serum urate levels.
The uricosuric effect of losartan appears to have limited
sustainability. Use of losartan, atorvastatin, and fenofi- Treatment of Refractory Gout
brate as a serum urate-lowering primary or adjunctive Patients: Current Options and Drugs
approach may have potential for selected patients with
moderate hyperuricemia associated with gout and
in Advanced Development
comorbid conditions such as hypertension, metabolic Limitations in antihyperuricemic therapy often become
syndrome, and hyperlipidemia. However, the place in a major clinical problem in subjects. The most common
management of these agents is not yet established and issues are intolerance to allopurinol, renal insufficiency
uric acid urolithiasis is a risk as with other uricosuric or urolithiasis (rendering uricosuric agents ineffective
modalities. or contraindicated), and extensive tophi. Several poten-
tial new agents for the treatment of goutoxypurinol,
febuxostat, and uricaseare discussed below.
Considerations Regarding Limitations of allopurinol are not confined to
Comorbidities in Patients with hypersensitivity and other forms of drug intolerance.
Gout and Asymptomatic The major active metabolite of allopurinol, oxypurinol,
binds to the reduced form of xanthine oxidase with very
Hyperuricemia high affinity but does not efficiently bind and inhibit the
Implicit in the medical management of gout patients oxidized form of xanthine oxidase. This may contribute
is recognition and appropriate therapy of medical to lack of efficacy of allopurinol seen in some patients
conditions commonly associated with gout that may at doses as high as 300 mg daily (6). Oxypurinol is toler-
affect both urate levels and longevity. These conditions ated in some allopurinol-hypersensitive patients, but
include the metabolic syndrome, hyperlipidemia, hyper- the oral absorption of oxypurinol is poor relative to that
tension, alcohol abuse, renal disorders, and myelopro- of allopurinol, and oxypurinol doses may need extended
liferative diseases. Asymptomatic hyperuricemia alone titration to achieve satisfactory reduction of serum
does not appear to cause clinically significant renal urate. Cross-reactivity with allopurinol and dependence
disease. However, hyperuricemia is both an indepen- on intact renal function for efficient elimination of oxy-
dent risk factor for atherosclerosis and a powerful pre- purinol may further limit the utility of oxypurinol in the
dictor of adverse outcomes of ischemic cardiovascular treatment of refractory gout in allopurinol-intolerant
diseases (8). Serum urate positively correlates with patients.
blood pressure in children, and extensive studies in Febuxostat, which inhibits xanthine oxidase through
rodents have suggested that hyperuricemia exerts a different mechanism than allopurinol and oxypurinol,
direct, deleterious and pro-atherogenic effects on arte- blocks substrate access to xanthine oxidase by occupy-
rial endothelial and smooth muscle cells, as well as ing a channel in the enzyme leading to the active site
toxic effects on the glomerular microvasculature, renal (9). This leads to the potent inhibition of both the oxi- 12
function, and systemic blood pressure (8). There is no dized and reduced forms of xanthine oxidase, but has
evidence basis to support treatment of asymptomatic minimal effects on other enzymes involved in purine
hyperuricemia at this time. and pyrimidine metabolism. Furthermore, unlike the
262 ROBERT A. TERKELTAUB
currently available xanthine oxidase inhibitors, febuxo- intolerant or unresponsive to other forms of antihyper-
stat is metabolized primarily by hepatic glucuronide uricemic therapy.
formation and oxidation and is excreted in approxi-
mately equal amounts in stool and urine. The efficacy
of febuxostat (80 and 120 mg daily) in serum uratelow-
ering in gout patients with starting serum urate levels of REFERENCES
8.0 mg/dL was superior to that of allopurinol 300 mg
daily in a phase III study in which the primary endpoint 1. Terkeltaub RA. Clinical practice. Gout. N Engl J Med
was the percentage of patients with serum urate level 2003;349:16471655.
<6.0 mg/dL (6). Nevertheless, after 1 year of treatment, 2. Rubin BR, Burton R, Navarra S, et al. Efficacy and safety
reductions in the incidence of gout flares and in the size profile of treatment with etoricoxib 120 mg once daily
of tophi were seen in similar fractions of subjects in all compared with indomethacin 50 mg three times daily in
treatment groups (6). acute gout: a randomized controlled trial. Arthritis Rheum
The hepatic enzyme uricase, the expression of which 2004;50:598606.
is lacking in human beings, oxidizes relatively insoluble 3. Cronstein BN, Terkeltaub R. The inflammatory process
uric acid in a reaction that generates highly soluble of gout and its treatment. Arthritis Res Ther 2006;8(suppl
1):S3.
allantoin, and also generates the oxidant hydrogen
4. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J.
peroxide as well as reactive intermediates of uric acid Gout-associated uric acid crystals activate the NALP3
oxidation. Uricase has the capacity to lower serum inflammasome. Nature 2006;440:237241.
urate levels profoundly and to promote accelerated 5. Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokg-
tophus dissolution (debulking). Recombinant unmodi- adi J. Beneficial effects of weight loss associated with
fied Aspergillus flavus uricase (Rasburicase) is US Food moderate calorie/carbohydrate restriction, and increased
and Drug Administrationapproved for prevention of proportional intake of protein and unsaturated fat on
the hyperuricemia-mediated tumor lysis syndrome. serum urate and lipoprotein levels in gout: a pilot study.
However, this form of uricase is highly immunogenic Ann Rheum Dis 2000;59:539543.
and can trigger severe and potentially lethal side effects 6. Becker MA, Schumacher HR Jr, Wortmann RL, et al.
including anaphylaxis. Administration of unmodified Febuxostat compared with allopurinol in patients with
hyperuricemia and gout. N Engl J Med 2005;353:2450
uricase beyond a single, short-term course is limited by
2461.
hypersensitivity reactions and development of uricase- 7. Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele
neutralizing antibodies. Reduced antigenicity and pro- as a genetic marker for severe cutaneous adverse reac-
longed half-life of uricase activity are being optimized tions caused by allopurinol. Proc Natl Acad Sci U S A.
via mutation of specific amino acids in uricase and by 2005;102:41344139.
polyethyleneglycol (PEG) modification of the recombi- 8. Kanellis J, Feig DI, Johnson RJ. Does asymptomatic
nant enzyme (10). PEGylated uricase has appeared hyperuricaemia contribute to the development of renal
promising in studies of gout patients, though intrave- and cardiovascular disease? An old controversy renewed.
nous infusion may be superior to subcutaneous injec- Nephrology 2004;9:394399.
tion with respect to immunogenicty (10). However, 9. Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF,
uricase-induced injection or infusion reactions are a Nishino T. An extremely potent inhibitor of xanthine oxi-
doreductase. Crystal structure of the enzyme-inhibitor
concern, as is redox stress. In this context, uricase can
complexandmechanismofinhibition.JBiolChem2003;278:1848
induce hemolysis and methemoglobinemia, most 1855.
predictably so in patients with glucose-6-phosphate 10. Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS.
dehydrogenase (G6PD) deficiency. Therefore, the Control of hyperuricemia in subjects with refractory gout,
therapeutic niche for modified uricases in the treatment and induction of antibody against poly(ethylene) glycol
of gout will most likely be for the short-term induction (PEG), in a phase I trial of subcutaneous PEGylated urate
of tophus de-bulking in carefully selected patients oxidase. Arthritis Res Ther 2005;8:R12.
CHAPTER 13
Calcium Pyrophosphate Dihydrate,

Hydroxyapatite, and Miscellaneous
Crystals
GERALDINE MCCARTHY, MD, FRCPI
The incidence and prevalence of calcium pyrophos- rheumatoid arthritis, pseudoneuropathic arthropathy,
phate dihydrate (CPPD) are unknown, though there is and asymptomatic chondrocalcinosis (lanthanic CPPD).
an increasing prevalence of radiographic chondrocal- Diagnosis is made by identifying CPPD crystals in
cinosis with age, and trauma may predispose to the synovial fluid of affected joints.
disease. Several metabolic diseases are associated There is no practical way to remove calcium pyro-
with CPPD. phosphate crystals from the joints and symptomatic
Overproduction of extracellular pyrophosphate in treatment is with nonsteroidal anti-inflammatory
abnormal cartilage matrix contributes to CPPD. drugs (NSAIDs), colchicines, and local or systemic
Acute pseudogout is the inflammatory host response glucocorticoids.
to CPPD crystals shed from cartilaginous tissues. Basic calcium phosphate crystals (BCP) frequently
Because of the common occurrence of these crystals deposit in articular tissues and may involve dysregu-
in osteoarthritic cartilage, there is a strong associa- lation of extracellular pyrophosphate homeostasis.
tion of pseudogout with osteoarthritis (OA). BCP crystals can cause diverse clinical conditions
There are multiple clinical manifestations of CPPD, including destructive arthritis (Milwaukee shoulder)
including pseudogout, pseudo-osteoarthritis, pseudo and calcific periarthritis/tendonitis.
Calcium pyrophosphate dihydrate (CPPD) and hydro- ate between CPPD crystal deposition disease and other
xyapatite crystals are the most common calcium- inflammatory and degenerative arthritides. The term
containing crystals associated with joint and periarticular chondrocalcinosis generally refers to the characteristic
disorders. Deposition of these crystals is frequently radiographic features of CPPD deposition in articular
asymptomatic or can be intermittently symptomatic. cartilage. Calcium-containing crystals other than CPPD
However, common clinical manifestations of calcium may also deposit in articular cartilage, producing
crystal deposition include acute or chronic inflammatory radiographically detectable densities in cartilage as well
and degenerative arthritides, and certain forms of peri- as joint inflammation or degeneration. Deposition of
arthritis. In addition to these, a number of other crystal- CPPD crystals is not limited to articular cartilage. Less
line materials have been identified less commonly in frequently, CPPD crystals are deposited in synovial
synovial or bursal fluid. These include calcium oxalate, lining, ligaments, tendons, and, on rare occasions, peri-
cholesterol, lipids, and synthetic corticosteroid crystals. articular soft tissue, much like gouty tophi.
Calcium pyrophosphate dihydrate crystal deposition
disease may be asymptomatic or may manifest in a
CALCIUM PYROPHOSPHATE variety of ways. The term pseudogout refers to the
acute, goutlike attacks of inflammation that occur in
DIHYDRATE DEPOSITION some individuals with CPPD deposition disease. CPPD
DISEASE deposition may also cause symptoms similar to septic
arthritis, polyarticular inflammatory arthritis (which
Specific identification of calcium pyrophosphate dihy- can be mistaken for rheumatoid arthritis), or osteoar-
drate (CPPD) crystals (Ca2P2O7.H2O) in synovial fluid thritis (OA). The incidence and prevalence of clinically
(SF) or articular tissue allows the clinician to differenti- important CPPD deposition disease are unknown.
263
264 GERALDINE McCARTHY
Radiographic surveys show a steadily increasing pre- TABLE 13-1. CONDITIONS ASSOCIATED WITH
valence of chondrocalcinosis with age. Data from CALCIUM PYROPHOSPHATE DIHYDRATE CRYSTAL
the Framingham study showed an overall prevalence DEPOSITION DISEASE.
of radiographic chondrocalcinosis of 8.1% in the Strongly associated
population over the age of 63, showed prevalence rates Age
of 20% in knee joints of patients over the age of 60, Previous joint surgery
and rates as high as 50% in patients over the age of 90 Osteoarthritis
Trauma
(1).
Gout
Hyperparathyroidism
Hemochromatosis
Classification Hypophosphatasia
Categorization based on etiology results in four patient Hypomagnesemia
groups: hereditary, sporadic/idiopathic, associated with Weakly associated
a metabolic abnormality, or post-traumatic. Although Hypothyroidism
most cases of CPPD deposition disease are nonfamilial,
Potentially associated
many multicase families with CPPD deposition disease Wilsons disease
have been reported in the literature. Most familial cases Acromegaly
appear to be inherited in an autosomal dominant Hyaluronidase deficiency
manner, with early onset and varying severity (2). Sus- X-linked hypophosphatemic rickets
ceptibility to familial CPPD deposition disease has been Familial hypocalciuric hypercalcemia
Ochronosis
most commonly localized to the short arm of chromo-
some 5. Of particular interest is the gene located at the
CCAL2 locus on chromosome 5p, the ANKH gene. The
ANKH gene codes for the multipass transmembrane
protein AHKH, which transports inorganic pyrophos-
phate (PPi) from the cell. Gain-of-function mutations Pathogenesis of Inflammation and
in ANKH causes familial autosomal dominant CPPD
deposition, of which several variants have been reported.
Cartilage Degeneration
Other genetic conditions are associated with chondro- Acute pseudogout is believed to represent a dose-
calcinosis. Gitelmans and Bartters diseases are both related inflammatory host response to CPPD crystals
associated with CPPD deposition, possibly due to their shed from cartilaginous tissues contiguous to the syno-
association with chronic hypomagnesemia. Magnesium vial cavity. Phagocytosis of crystals by neutrophils, as
is a cofactor of alkaline phosphatase, and it is postulated invariably demonstrated by compensated polarized
that these conditions lead to mild functional hypophos- light microscopy in fluids removed from acutely inflamed
phatasia. Iron and copper overload, associated with joints of patients with pseudogout, results in the release
haemochromatosis and Wilsons disease, respectively, of lysosomal enzymes and cell-derived chemotactic
are thought to favor calcium crystal nucleation as well factors. Phagocytosis by synovial-lining cells leads to
as inhibiting alkaline phosphatase activity. Genetic cell proliferation and release of prostaglandins, cyto-
factors could also participate in so-called sporadic cases, kines, and matrix metalloproteases capable of matrix
as a familial pattern has been identified in some case degradation, such as collagenase and stromelysin.
series of apparently sporadic CPPD deposition disease. The relationship between OA and CPPD deposition
However, the late onset of the arthritis phenotype is complex. A study of SF sampled at the time of knee
makes family studies of CPPD deposition disease replacement demonstrated that 60% of 53 unselected
difficult. patients with a preoperative diagnosis of OA contained
A number of metabolic disease and physiologic either CPPD or hydroxyapatite or both (3). It has been
stresses, such as aging and trauma, have been associated suggested that most SF from patients with OA may
with CPPD crystal deposition (Table 13-1). Only aging contain CPPD or hydroxyapatite too small or too infre-
and previous joint surgery have been proven to be asso- quent to detect by routine microscopy. The frequency
ciated. Nonetheless, circumstantial evidence suggests of association of CPPD crystal deposits may result from
that many of these other associations are valid. There- the biological effects of CPPD crystals as they interact
fore, the routine study of a patient newly diagnosed with with fibroblasts or mononuclear synovial lining cells.
CPPD crystal deposition should include evaluation of These include a well-documented mitogenic response,
serum calcium, ferritin, magnesium, phosphorus, alka- resulting in tissue hypertrophy. Stimulated lining cells
line phosphatase, and thyroid-stimulating hormone. secrete proteolytic enzymes and cytokine release. Pro-
Further studies should be obtained if abnormal values teolytic enzymes may damage cartilage and other artic-
are found. ular structures and cytokine release can enhance further
C H A P T E R 1 3 C P P D , H Y D R O X Y A P A T I T E , A N D M I S C E L L A N E O U S C R Y S T A L S 2 65
protease production by synovial lining cells or chondro- swelling in the affected joint. Signs include swelling
cytes. Such effects have been demonstrated for CPPD with variable erythema and warmth. Systemic manifes-
crystals in vitro. tations during an attack may include a fever of 99F to 13
103F, leukocytosis of 12,000 to 15,000 cells/mm3 and
elevated erythrocyte sedimentation rate (ESR) and
Pathogenesis of Crystal Deposition serum acute phase reactants. Compared to true gout,
pseudogout attacks may take longer to reach peak
Overproduction of extracellular PPi, the anionic com- intensity, and are often considerably longer lasting
ponent of the crystal, contributes to CPPD crystal than gout attacks, as symptoms can last 3 to 120 days
deposition (4). Synovial fluid PPi concentration is ele- despite therapy (6). Pseudogout is more common in
vated in most joints with CPPD deposition, in contrast large than in small joints. The knee is the most com-
to plasma and urinary excretion levels. Furthermore, monly involved joint, followed by the wrist, ankle,
chondrocytes from CPPD-containing cartilage produce elbow, toe, shoulder, and hip. As with gout, pseudo-
more extracellular PPi than normal and OA control gout attacks can occur spontaneously or can be pro-
cartilages. Articular chondrocytes likely contribute to voked by trauma, surgery, or postparathyroidectomy
SF PPi because they liberate PPi, an effect which can or severe illness, such as stroke or myocardial infarc-
be enhanced by transforming growth factor beta (TGF- tion. Patients are usually asymptomatic between epi-
beta), ascorbate, retinoic acid, and thyroid hormones. sodes. Differentiation from gout or septic joint may be
PPi may be made de novo by chondrocyte ectoen- difficult and requires arthrocentesis followed by culture
zymes, which hydrolyze nucleoside triphosphates. In and examination of the SF for crystals. About 25% of
addition, intracellular PPi may be transported across people with CPPD deposition exhibit the pseudogout
cell membranes by the multipass transmembrane pattern of disease.
protein ANK or other proteins. Calcium is also neces-
sary for CPPD crystal formation and calcium concen-
trations are increased in cartilages from patients with Pseudo-Osteoarthritis
CPPD. Most patients with clinically apparent CPPD crystal
Changes in the pericellular matrix and matrix vesi- deposition have an unusually severe, oddly distributed,
cles (MV) of articular cartilage have been implicated degenerative arthritis resembling OA. They present
in CPPD crystal formation. MV are small membrane- with the gradual onset of joint pain and stiffness,
bound extracellular organelles that bud off chondro- typically involving knees, wrists, metacarpophalangeal
cytes which, when isolated from articular cartilage, can (MCP) joints, hips, shoulders, spine, elbows, and ankles.
produce CPPD crystals in vitro. CPPD crystals are Half of these patients will have acute attacks superim-
formed in areas of abnormal pericellular matrix, but not posed on their chronic symptoms. Flexion contractures
in normal matrix. Affected cartilage matrix contains of the affected joints and deformities of the knees are
damaged collagen type II fibers and increased calcium- common. Valgus knee deformities are especially sug-
binding matricellular proteins. Type I collagen, not gestive of underlying CPPD crystal deposition. This
usually present in normal cartilage, is found in increased type of presentation can be difficult to differentiate
quantities in CPPD-containing cartilage and fewer large from OA and consequently may be significantly under-
proteoglycans are present. Current data also supports a recognized. In one series, 30% of patients diagnosed
role for transglutaminases, which post-translationally with OA had CPPD crystals in their affected joints at
modify extracellular matrix proteins in CPPD crystal the time of total knee replacement (3).
formation.
PseudoRheumatoid Arthritis
Clinical Features and Diagnosis About 5% of patients with CPPD deposition manifest
At least five clinical presentations have been associated multiple joint involvement with symmetric distribution
with articular CPPD (5). and low grade inflammation. Accompanying morning
stiffness, fatigue, synovial thickening, flexion contrac-
tures, and elevated ESR often lead to a misdiagnosis of
rheumatoid arthritis. In addition, 10% of individuals
Pseudogout with CPPD crystal deposits have low titers of rheuma-
Acute pseudogout is an inflammatory process manifest toid factor, which provide further diagnostic confusion.
by joint effusions and symptoms and signs of articular The presence of high titer rheumatoid factor, anti-cyclic
inflammation in one or more joints. These self-limited citrullinated peptide (anti-CCP) antibodies, and radio-
attacks can be as abrupt in onset and as severe as acute graphic evidence of typical rheumatoid bony erosions
gout. Patients typically experience pain, stiffness, and favor the diagnosis of true rheumatoid arthritis.
PseudoNeuropathic Arthropathy TABLE 13-2. REVISED DIAGNOSTIC CRITERIA FOR

CALCIUM PYROPHOSPHATE DIHYDRATE CRYSTAL
Some patients with CPPD deposition disease have a DEPOSITION DISEASE.
severe destructive monoarthritis similar to that seen in
Criteria
neuropathic joints. These patients have no neurologic
I. Demonstration of CPPD crystals in tissue or synovial fluid by
abnormalities and yet present with a painful monoar- definitive means (e.g., characteristic x-ray diffraction or
thritis, associated with dramatic destructive radiographic chemical analysis)
changes. The natural history of patients with this type II. (a) Identification of monoclinic or triclinic crystals showing
of CPPD deposition disease is not well described. weakly positive or no birefringence by compensated
polarized light microscopy
(b) Presence of typical radiographic calcification
Lanthanic III. (a) Acute arthritis, especially of knees or other large joints.
(b) Chronic arthritis, especially of knee, hip, wrist, carpus,
Some individuals with radiographic or pathologic elbow, shoulder, or metacarpophalangeal joint, especially
evidence of articular chondrocalcinosis have no clini- if accompanied by acute exacerbations. The following
features help differentiate chronic arthritis from
cally apparent arthritis. This finding has been termed
osteoarthritis:
lanthanic CPPD deposition and is of uncertain signifi- 1. Uncommon sitewrist, metacarpophalangeal, elbow,
cance. These patients have not been rigorously studied and shoulder
to see if they develop signs and symptoms of clinical 2. Radiographic appearanceradiocarpal or patellofemo-
arthritis with a greater frequency than the unaffected ral joint space narrowing, especially if isolated (patella
wrapped around the femur)
population.
3. Subchondral cyst formation
Calcium pyrophosphate dihydrate crystals are not 4. Severity of degenerationprogressive, with subchon-
commonly found in tissue other than cartilage. Even in dral bony collapse and fragmentation with formation
synovium, CPPD crystals typically form in areas of of intra-articular radiodense bodies
chondometaplasia. Tophaceous CPPD crystal deposits 5. Osteophyte formationvariable and inconstant.
6. Tendon calcifications, especially triceps, Achilles,
are well described and can cause nerve compression
obturators
syndromes. Neurologic manifestations of CPPD deposi-
tion in the axial skeleton can occur. Spinal ligaments Categories
seem particularly prone to CPPD crystal deposition. A. Definite disease: Criteria I or II(a) plus II (b) must be fulfilled
B. Probable disease: Criteria II (a) or II (b) must be fulfilled
Affected patients may present with myelopathy. Almost
C. Possible disease: Criteria III (a) or III (b) should alert the
25% of patients undergoing decompressive laminec- clinician to the possibility of underlying CPPD crystal
tomy for lumbar spinal stenosis had CPPD crystal deposition
deposits in their ligamenta flava. Clinically, patients
with CPPD crystals had more acute onset of symptoms
than those without CPPD crystals.
Diagnosis of CPPD-associated disease is most com- crystals render them more difficult to discern than
monly and accurately made by identifying CPPD crys- monosodium urate (MSU) crystals. They can be quite
tals by polarizing light microscopy in the SF of affected sparse in number. SF characteristics can vary from
joints (Figure 13-1). The weak birefringence of CPPD inflammatory to non-inflammatory in CPPD deposition
disease. In pseudogout, SF may be turbid, watery, or
hemorrhagic. Average white cell counts are in the region
of 12,000 cells/mm3 in pseudogout. Histologic examina-
tion of cartilage or synovial biopsies can be helpful as
long as tissue preparation methods preserve crystals.
Diagnostic criteria for CPPD deposition disease have
been established (Table 13-2).
Radiographic Features
The typical appearance of punctate and linear densities
in hyaline or fibrocartilagenous tissues is helpful diag-
nostically (Figure 13-2). The most characteristic sites of
crystal deposition include knee articular cartilage and
FIGURE 13-1 menisci, acetabular labrum of hip joint, fibrocartilage-
Rod-shaped calcium pyrophosphate dihydrate (CPPD) crystals in
nous symphysis pubis, triangular cartilage of the wrist,
synovial fluid analyzed by compensated polarized light and the annulus fibrosis of intervertebral discs. When
microscopy. the deposits are typical and unequivocal, the radio-
result in resorption of CPPD crystal deposits. Acute

attacks in large joints can be treated through aspira-
tion alone or aspiration combined with injection of 13
corticosteroids. Nonsteroidal anti-inflammatory drugs
(NSAIDs) are recommended for most patients. The
effectiveness of oral colchicine is less predictable in
pseudogout than in gout, but the number and duration
of acute attacks are reduced significantly by colchicine
taken on a daily basis for prophylaxis. Corticotropin or
systemic corticosteroid therapy has been used success-
fully in patients with gout or pseudogout. Phosphoci-
trate is a promising agent that inhibits CPPD crystal
formation and cellular responses to CPPD, but it is not
currently clinically available.
FIGURE 13-2
Chondrocalcinosis involving lateral meniscus of left knee. Apatite/Basic Calcium Phosphates

Basic calcium phosphate crystals (BCP), consisting
of carbonate-substituted hydroxyapatite, octacalcium
phosphate, and, rarely, tricalcium phosphate, frequently
graphic appearance is reasonably specific, but interpre- deposit in articular tissues, but may also be found in
tation of atypical or faint deposits often is difficult. skin, arteries, breast, and other tissues. In the musculo-
Calcific deposits also may appear in the articular capsule, skeletal system, crystals may be found in tendons, inter-
ligaments, and tendons. Although the earliest calcific vertebral discs, joint capsule, synovium, and cartilage.
deposits occur in radiographically normal cartilage, Studies have suggested that dystrophic tendon calcifica-
degenerative changes often supervene. An individual tion occurs as a consequence of local trauma, ischemia,
can be screened for CPPD deposits with four radio- and necrosis of tendons. Some evidence suggests that
graphs: an anterposterior (AP) view of both knees calcifying tendonitis is an active, cell-mediated process
(preferably not standing), an AP view of the pelvis for in which local vascular and mechanical changes result
visualization of the symphysis pubis and hips, and a in focal transformation of tendinous tissues into fibro-
posteroanterior (PA) view of each hand to include the cartilagenous material containing chondrocytes. This is
wrists. If these views show no evidence of crystal depos- followed by local deposition of hydroxyapatite crystals
its, it is most unlikely that further study will prove within extracellular matrix vesiclelike structures derived
fruitful. from these chondrocytes. The mechanism of intra-
Changes in the metacarpophalangeal joints, such as articular BCP crystal deposition is incompletely under-
squaring of the bone ends, subchondral cysts, and stood but likely involves matrix vesicles and local
hooklike osteophytes, are characteristic features of the dysregulation of extracellular PPi homeostasis. PPi is a
arthritis associated with hemochromatosis (see Chapter potent inhibitor of apatite crystal nucleation.
28), but are also found in patients with CPPD deposi-
tion alone. These changes occur more frequently in
patients with CPPD crystal deposits and hemochroma- Basic Calcium Phosphate
tosis than in those with only crystal deposits. In addition
to the difference in pattern of affected joints, the finding
Crystal Identification
of isolated patellofemoral joint space narrowing or iso- Although BCP crystals are common, particularly in
lated wrist degeneration differentiates CPPD from OA. OA, their presence in SF is recognized infrequently
Such differences may provide helpful clinical clues and because of the lack of a simple, reliable test for detec-
are incorporated into the proposed diagnostic criteria tion. Polarized light microscopy, which effectively iden-
given in Table 13-2 (7). tifies MSU and CPPD crystals, is unable to detect BCP
crystals, which are too small to be resolved by light
microscopy (20100 nm). Despite the small size of indi-
Treatment vidual crystals, they tend to aggregate into larger masses
In contrast to monosodium urate crystals in gout, there that occasionally may be observed by light microscopy
is no practical way to remove CPPD crystals from joints. as refractile shiny coins up to 5 mm in diameter. The
Treatment of associated diseases, such as hyperparathy- larger BCP aggregates have been detected by Alizarin
roidism, hemochromatosis, or myxedema, does not red S staining, but this method lacks sensitivity and
There is no known therapy for prevention or removal

of BCP crystals from joints or for interfering specifically
with the biological effects of BCP crystals.
Large Joint Destructive Arthritis/Milwaukee

Shoulder Syndrome
A distinctive type of destructive arthropathy of the
shoulder has been described in elderly individuals (10).
Typically, these patients are elderly women and mani-
fest large, non-inflammatory synovial effusions, severe
radiographic damage, and large rotator cuff tears.
Patients typically have pain on shoulder use and also
pain at night. There is reduced active and passive range
FIGURE 13-3 of motion, sometimes associated with pronounced joint
instability. Marked bone-on-bone crepitus is typical.
Alizarin redstained clumps of apatite in joint fluid. The rotator cuff is generally completely destroyed. Joint
effusion may be massive and typically yields 5 to 130 mL
of SF that is frequently blood tinged and has a low,
predominantly mononuclear cell count. BCP crystals
specificity (Figure 13-3). Techniques that are more spe- are identified in most fluids. Some contain CPPD crys-
cific for BCP crystal identification include x-ray diffrac- tals in addition. Radiographs typically show upward
tion, scanning or transmission electron microscopy with subluxation and deformity of the humeral head and
energy dispersive analysis, electron microprobe, Raman calcification of the tendinous rotator cuff (Figure 13-4).
spectroscopy, atomic force microscopy, and a binding as- Treatment is generally unsatisfactory. A conservative
say utilizing [14C]ethane-1-hydroxy-1,1-diphosphonate. approach, including analgesics and NSAIDs and
Unfortunately, these methods typically are unavailable repeated shoulder aspirations with or without steroid
or too costly for the handling of routine clinical injections, has sometimes controlled symptoms satisfac-
specimens (8). torily. Surgical intervention is sometimes successful.
Pain may subside with time alone.
Clinical Features
Osteoarthritis
Concurrence of BCP crystals and OA is well established
(9). The incidence of BCP crystals in SF from patients
with knee OA is at least 30% to 60%. Indeed, it has
recently been suggested that many OA fluids contain
clusters of BCP crystals that are too small or too few in
number to be identified by conventional techniques.
Ample data supports the role of BCP crystals in carti-
lage degeneration as their presence correlates strongly
with severity of radiographic OA, and larger joint effu-
sions are seen in affected knee joints when compared
with joint fluid from OA knees without crystals. Fur-
thermore, in vitro studies of BCP crystal-induced cell
activation support the active role of BCP in OA patho-
genesis as they have numerous biologic effects, includ-
ing the ability to induce mitogenesis in and matrix FIGURE 13-4
metalloproteases and prostaglandin synthesis by syno- Anteroposterior radiograph of the shoulder joint affected by
vial fibroblasts and chondrocytes. Although the basis of hydroxyapatite-associated destructive arthritis (Milwaukee
cartilage damage by crystals has been the subject of shoulder). The extensive destruction of the periarticular tissues,
numerous investigations, there are ongoing controver- including the rotator cuff, has led to instability of the shoulder
with upward subluxation of the humerus. Note the associated
sies concerning the relationship between calcium- glenohumeral degeneration and soft tissue evidence of joint
containing crystals and OA and whether the crystals effusion. Periarticular calcific deposition is noted at the acromio-
cause damage or are present as a result of joint damage. clavicular joint.
Calcific Periarthritis masses can be observed around the shoulders, hips, and
elbows. They may be uni-or multifocal. Complications
Periarticular calcifications are occasionally observed
on shoulder or other radiographs (Figure 13-4). The
include skin ulceration with secondary infection, drain- 13
ing sinus, cachexia, and amyloidosis.
most common site of calcification is the rotator cuff.
Most calcifications remain asymptomatic. If a patient
has chronic shoulder pain, the radiographic finding of MISCELLANEOUS CRYSTALS
a calcification in the supraspinatus tendon or another
tendon in the rotator cuff supports a diagnosis of Oxalate Crystals
chronic calcific tendinitis. In a few cases, particularly
those with large calcific deposits, a severe attack of joint To date, oxalates have been described in joints of
pain is precipitated by dispersal of crystals into sur- patients with overt renal failure only. Acute or chronic
rounding tissues, the subdeltoid bursa, or the shoulder arthritis resulting from oxalate deposition can occur in
joint. These crystals elicit a major local inflammatory a variety of joints, with the most frequently involved
response. Patients present with severe pain and joint being the knees and hands. There are also reports of
swelling, with warmth and erythema. The diagnosis is involvement of wrists, ankles, feet, tendon sheaths, and
suspected upon radiographic observation of a rotator bursae. Joint fluid leukocyte counts are generally less
cuff calcification. Other diagnoses are likely to be con- than 2000/mm3. Definitive diagnosis is by crystal identi-
sidered, including sepsis, trauma, fracture, gout, or fication in joint fluid or biopsy of joints, bones, or other
pseudogout. The radiographic features may evolve over tissues. SF crystals can be pleomorphic but characteris-
time, with the calcific deposit becoming smaller, frag- tically include at least some with bipyramidal or envelo-
menting, or disappearing. Needle aspirate of the calcific pelike shapes. Sizes range from 5 to 30 m. Most crystals
deposit may yield chalky material, and, in the case of are brightly birefringent although some of the smaller
the shoulder, may shorten the attack. Improvement rod-shaped crystals could be confused with CPPD.
also occurs following administration of NSAIDs or Oxalate accumulation in hemodialysis patients may be
local corticosteroid injection. Ultrasound has been sug- slowed by avoiding use of vitamin C, which is metabo-
gested as a method of breaking up calcific deposits. lized to oxalate.
Untreated, the involved area may remain symptomatic
for a few days or for several weeks. Smaller joints, such
as the first metatarsal of the foot (hydroxyapatite pseu-
Depot Corticosteroid-Induced
dopodagra) and small joints of the hand, may undergo Iatrogenic Inflammation
similar inflammatory attacks, particularly in younger Iatrogenic inflammation typically occurs during the first
women. 8 hours following steroid injection. It appears more
common following triamcinolone hexacetonide injec-
tion than with other preparations. Diagnosis can be sup-
Acute Arthritis
ported by aspiration and identification of pleomorphic
In rare situations, BCP crystal may cause acute inflam- crystals that include irregular shaped rods and squares
mation in joints. BCP crystal have been found in finger with intense positive or negative birefringence. Relief
joints that exhibit inflammation and erosive changes. can be expedited by use of local ice packs.
BCP crystal may have a role in inflammatory OA, a
subgroup of OA associated with erythema, synovial
thickening, and severe radiographic damage in proxi- Other Crystals with Possible
mal and distal interphalangeal joints of the hands. Pathogenic Potential
These include liquid lipid crystals, cholesterol, other
Calcinosis/Idiopathic Tumoral Calcinosis lipids, and foreign bodies. Management of inflamma-
tory episodes related to these less common crystals
Calcinosis is the soft tissue deposition of BCP crystals. generally involves NSAIDs when the clinical situation
A wide variety of diseases has been associated with permits. Foreign bodies are best managed by removal.
dystrophic calcification. Some of these conditions
include the connective tissue diseases (limited sclero-
derma, myositis, systemic lupus erythematosus), calcifi- REFERENCES
cation following following severe neurologic injury,
and calcification following triamcinolone hexacetonide 1. Felson DT, Anderson JJ, Naimark A, Kannel W, Meenan
injection of joints. Idiopathic tumoral calcinosis is a rare RF. The prevalence of chondrocalcinosis in the elderly
syndrome characterized by the presence of irregular and its association with knee osteoarthritis: the Framing-
calcifying masses in periarticular soft tissue. These ham Study. J Rheumatol 1989;16:12411245.
2. Zaka R, Williams CJ. Genetics of chondrocalcinosis. sis. In: McCarty D, ed. Arthritis and allied conditions.
Osteoarthritis Cartilage 2005;13:745750. Philadelphia: Lea and Febiger; 1985:15151546.
3. Derfus BA, Kurian JB, Butler JJ, et al. The high preva- 8. Rosenthal AK, Mandel N. Identification of crystals in
lence of pathologic crystals in pre-operative knees. J synovial fluids and joint tissues. Curr Rheumatol Rep
Rheumatol 2002;29:570574. 2001;3:1116.
4. Kirsch T. Determinants of pathological mineralization. 9. OShea FD, McCarthy GM. Basic calcium phosphate
Curr Opin Rheumatol 2006;18:174180. crystal deposition in the jointa potential therapeutic
5. McCarty DJ. Calcium pyrophosphate dihydrate crystal target in osteoarthritis. Curr Opin Rheumatol 2004;16:
deposition disease1975. Arthritis Rheum 1976;19:275 273278.
286. 10. McCarty DJ, Halverson PB, Carrera GF, Brewer BJ,
6. Masuda I, Ishikawa K. Clinical features of pseudogout Kozin FK. Milwaukee shoulder: association of micro-
attack. a survey of 50 cases. Clin Orthop 1988;173181. spheroids containing hydroxyapatite crystals, active col-
7. Ryan LM, McCarty DJ. Calcium pyrophosphate crystal lagenase, and neutral protease with rotator cuff defects, I:
deposition disease; pseudogout; articular chondrocalcino- clinical aspects. Arthritis Rheum 1981;24:464473.
CHAPTER 14
Infectious Disorders
A. Septic Arthritis
GEORGE HO, JR., MD
Septic joints signal the presence of a potentially life- be initiated pending culture result of the
threatening infection. For nongonococcal joint fluid.
infections, the mortality rate among adults ranges Cell count, differential, Gram stain, culture, and
from 10% to greater than 50%. examination for crystals are the crucial tests to be
The most common pathway to a septic joint is performed on synovial fluid. This boils down to the 3
through hematogenous seeding from an extra- Cs: cell count, culture, and crystals.
articular site of infection, for example, pneumonia, In the setting of nongonococcal septic arthritis, Gram
pyelonephritis, or skin infection. stains of infected synovial fluid are positive only 60%
The causes of adult nongonococcal septic arthritis are to 80% of the time. Blood cultures are positive in
Gram-positive cocci (75%80%) and Gram-negative approximately 50% of patients.
bacilli (15%20%). Staphylococcus aureus is most In cases of suspected septic arthritis, antibiotic
common organism in both native and prosthetic joint treatment should begin immediately once proper
infections. samples for microbiologic studies have been
Arthrocentesis and synovial fluid analysis are the collected.
cornerstones for the diagnosis of septic arthritis. Selection of the initial antibiotic approach is guided
If the synovial fluid white blood cell (WBC) count by the result of the synovial fluid Gram stain and the
is extremely high (e.g., >100,000/mm3), organisms most likely to be responsible for the
treatment for presumed septic arthritis should infection, based upon the clinical scenario.
Nongonococcal bacterial infections are the most serious and skin infection (1). Compared to diseased or
infections affecting the joints. Normal joints, diseased prosthetic joints, normal joints are very resistant to
joints, and prosthetic joints are all vulnerable to bacte- infection. An important predisposing factor to septic
rial infection. The fact that septic joints signal the pres- arthritis is an impaired immune system. RA, liver
ence of a potentially life-threatening infection cannot cirrhosis, chronic renal failure, and malignancies are
be overemphasized, nor can the importance of early often present among patients with septic arthritis.
diagnosis and prompt, effective therapy. Mortality rates Hemodialysis patients and intravenous drug abusers
among adults range from 10% to greater than 50%. Full are predisposed to bacterial joint infections at axial
recovery is possible, but poor outcomes are common skeleton sites such as the sternoclavicular joint and
among those with preexisting arthritis, especially rheu- the sacroiliac joint. Other susceptible hosts are
matoid arthritis (RA). This chapter discusses acute non- patients with acquired immunodeficiency syndrome,
gonococcal bacterial arthritis in adults. Septic arthritis hemophilia, organ transplantation, or hypogammaglob-
in children, gonococcal joint infection, and septic bursi- ulinemia (2).
tis are also briefly discussed.
PATHOGENESIS
RISK FACTORS
The most common pathway to a septic joint is bactere-
Independent risk factors for acute nongonococcal mic seeding of the affected joint from an extra-articular
septic arthritis are age greater than 80 years, diabetes site of infection such as pneumonia, pyelonephritis, or
mellitus, preexisting RA, the presence of a prosthetic skin infection. Direct inoculation of the pathogen into
joint in the knee or the hip, recent joint surgery, a joint is much less common. A cat bite can introduce
271
272 GEORGE HO, JR.
Pasteurella multocida into a finger joint, however, and TABLE 14A-1. CONDITIONS THAT MAY PRESENT AS
the piercing of a nail through the sole of a sneaker may PSEUDOSEPTIC ARTHRITIS.
lead to a Pseudomonas aeruginosa infection of the foot.
Septic arthritis resulting from arthrocentesis or joint
injection occurs at a rate 0.0002% from such occur- Juvenile rheumatoid arthritis
rences. Penetrating foreign body injury or any surgery Gout
on the joint, including total joint replacement, can result
in infection. Attention to technique, environment, and Pseudogout
perioperative antibiotic prophylaxis have minimized Apatite-related arthropathy
the rate of early prosthetic joint infections. Late infec-
tions, occurring a year or more after joint replacement, Reiters syndrome
result from contamination at the time of the implant Psoriatic arthritis
surgery or bacterial seeding during transient bactere-
mia. Patients with this uncommon complication com- Systemic lupus erythematosus
plain of pain in a previously painless total joint Sickle cell disease
replacement. Aseptic loosening of a prosthetic joint
must be distinguished from infection causing prosthesis Dialysis-related amyloidosis
failure, because the infection must be eradicated before Transient osteoporosis synovitis of the hip
undertaking revision arthroplasty.
Plant thorn synovitis
Metastatic carcinoma
MICROBIOLOGY Pigmented villonodular synovitis
Hemarthrosis
Among nongonococcal causes of acute bacterial
arthritis, the Gram-positive cocci are the major Neuropathic arthropathy
pathogens. The causes of adult nongonococcal
septic arthritis are Gram-positive cocci (75%80%)
and Gram-negative bacilli (15%20%). Staphylococcus
Arthrocentesis and synovial fluid analysis are the
aureus is the most common organism in both native
cornerstones for the diagnosis of septic arthritis. If the
and prosthetic joint infections. Staphylococcus epider-
synovial fluid white blood cell (WBC) count is extremely
midis occurs commonly in prosthetic infections but
high [e.g., >100,000/mm3 white blood cells (WBC)],
is rare in native joint infections. Anaerobic infections
treatment for presumed septic arthritis should be initi-
also occur in this setting. Anaerobic infections and
ated pending culture result of the fluid. Pseudoseptic
coagulase-negative staphylococci are more common in
arthritisan extremely inflammatory arthritis not due
prosthetic joint infections. In the elderly, the Gram-
to bacterial infection (Table 14A-1)can only be diag-
negative microorganisms may be more common because
nosed when one is confident that infectious causes have
of the many comorbidities that predispose them to
been excluded (3). In this regard, negative synovial fluid
systemic Gram-negative bacillary infections. Underly-
cultures should be corroborated by negative blood cul-
ing joint diseases are also more prevalent among the
tures and by negative results of tests, such as polymerase
elderly.
chain reaction (PCR), for bacterial DNA in the synovial
fluid.
Polyarticular infection occurs more commonly in
CLINICAL FEATURES patients with preexisting arthritis and may portend a
less favorable outcome (4). S. aureus is again the major
Septic arthritis is more often monoarticular (80% pathogen. RA patients with polyarticular septic arthritis
90%) than polyarticular (10%20%). The predilection had a mortality rate of greater than 50% (5). More than
is for a single large joint, typically the knee. Thus, in one joint should be aspirated when infection in multiple
the evaluation of a patient with an acute monoarthritis, joints is suspected.
septic arthritis is always a consideration, especially if
the patient is febrile, appears toxic, or has an extra-
articular site of bacterial infection. In the patient Laboratory Findings
with underlying RA, an acute exacerbation of joint
inflammation, whether monoarticular or polyarticular, The synovial fluid of septic arthritis typically reflects
must raise the suspicion of superimposed infection purulent inflammation, with extremely high WBC
complicating rheumatoid disease. counts and a preponderance of polymorphonuclear
C H A P T E R 1 4 I N F E C T I O U S D I S O R D E R S 27 3
cells. Although typically >50,000 WBCs/mm3 and often the results of the Gram stain and the organisms most
>100,000 WBCs/mm3, the cell count range is wide, likely to be responsible for the infection based upon the
depending on the timing or arthrocentesis, pretreat- clinical scenario. For hospitalized patients with indwell-
ment with antibiotics, and other factors. Gram stains of ing vascular catheters or patients on hemodialysis, for
infected synovial fluid are positive only 60% to 80% of example, coverage for Staphylococci and Streptococci
the time. A cell count, a Gram stain, and a wet prepara- may be appropriate, in addition to other organisms.
tion examination for crystals under polarized micros- Narrow antibiotic coverage may be appropriate if sus-
copy are essential immediate tests after joint aspiration. picion for a specific organism is validated by Gram stain 14
Culturing the fluid for bacteria and any unusual patho- (e.g., Gram-positive cocci in clusters or chains). On the
gens under suspicion (e.g., acid-fast bacilli, fungi) is also other hand, if the Gram-stained smear is inconclusive
critical. Blood cultures are positive in approximately and there are no clinical clues after searching for an
50% of the patients with nongonococcal septic arthritis. extra-articular source of infection in an elderly debili-
In addition to attempts to increase the sensitivity and tated patient, then broad antibiotic coverage (against
yield of positive cultures, technological advances, such both Gram-positive cocci and Gram-negative bacilli)
as PCR assays, can aid in the diagnosis and management should be given initially. In a healthy person who
of many infectious diseases (6). One shortcoming of engages in high-risk sexual practice and presents with
PCR assays is their extreme sensitivity and the substan- tenosynovitis and migratory arthritis, initiating mono-
tial risk of false-positive results. therapy against gonococcal infection may be appropri-
The coexistence of crystal-induced inflammation ate after culturing and Gram staining all portals of
and bacterial infection must not be overlooked. Fever possible infection. (The drugs of choice for gonococcal
can be due to acute crystal-induced synovitis or acute infectionssecond-generation cephalosporinshave
flare of rheumatoid arthritis without infection. But broad antimicrobial activity beyond Gram-negative
when fever is present, it must not be attributed to the diplococci.) Once the identity and the sensitivities of the
underlying RA without a diligent search for complicat- microorganism are known, therapy should continue
ing bacterial infection in the inflamed joint. with the most efficacious agent that has the best safety
profile and the lowest cost.
Drainage of the infected joint space must be ade-
THERAPY quate in order to relieve pain, eradicate the infection,
and hasten recovery of lost function. During the initial
Therapeutic approaches to different kinds of joint infec- few days, immobilization of the affected joint and
tions are shown in Table 14A-2. Prompt treatment effective analgesic medication helps ensure patient
eradicates the infection with less morbidity and hastens comfort. Physical therapy should be instituted as soon
recovery. Once septic arthritis is suspected and the as the patient can tolerate mobilization of the inflamed
proper samples for microbiologic studies are collected, joint.
antibiotic treatment should begin immediately. The Repeated needle aspirations may be adequate in
choice of which antibiotic agent(s) to use depends on some patients if sterilization of the joint space can be
TABLE 14A-2. EMPIRIC ANTIBIOTIC REGIMENS FOR PATIENTS WITH POTENTIALLY SEPTIC JOINTS.
SYNOVIAL FLUID GRAM-STAIN FINDINGS INITIAL ANTIBIOTIC REGIMEN
Gram-positive
Gram-positive cocci in clusters (presumptive Staphylococcus) Nafcillin or oxacillin (aminoglycoside should be added if patient is an
injection drug user)
Gram-positive cocci in chains (presumptive Streptococcus) Nafcillin or oxacillin
Gram-negative
Gram-negative bacilli Nafcillin or oxacillin/aminoglycosidea
Gram-negative diplococci (presumptive gonococcus)b Ceftriaxone or cefotaxime
a
All patients with prosthetic joints, intravenous line placement, or recent hospitalization are at risk for infection with methicillin-resistant Staphylococcus species
and should receive vancomycin until culture results are available, regardless of Gram-stain results.
b
In the absence of definitive Gram-stain results, a reasonable empiric regimen for the adult with possible septic arthritis is the combination of nafcillin or oxa-
cillin with a cephalosporin, such as ceftriaxone or ceftizoxime or cefotaxime. An aminoglycoside should be added in the injection drug user. Vancomycin
should be substituted for nafcillin/oxacillin if methicillin-resistant Staphylococcus is a possibility.
274 GEORGE HO, JR.
achieved rapidly. Tidal lavage to wash out the joint and Although evidence-based data are lacking, intuition
arthroscopic procedures are intermediate steps that tells us that these considerations may improve
may benefit some patients and avoid the morbidity of the outcome of those with unfavorable prognostic
arthrotomy. Under a variety of circumstances, however, factors.
surgical drainage may be necessary. Such circumstances
include: (1) if when needle aspiration is technically dif-
ficult or does not provide thorough drainage of the
joint; (2) if sterilization of the joint fluid is delayed; (3) PREVENTION
if the infected joint has is already been damaged by
preexisting arthritis; or (4) if infected synovial tissue Opportunities to prevent septic arthritis are limited but
or bone needs debridement (7). Involving the orthope- should be kept in mind in patients with underlying
dic surgeon and the physical therapist early in the arthritis, especially RA, and or patients with total joint
course of treatment will facilitate the best choice of replacements. For most patients who have undergone
drainage procedure and result in the best functional total joint replacements, antibiotic prophylaxis is not
outcome. indicated routinely before dental procedures. How-
The optimal duration of antibiotic treatment has ever, in 2003 the American Dental Association and
not been studied prospectively. For uncomplicated American Academy of Orthopedic Surgeons modified
native joint infections, antibiotic treatment can be as an earlier advisory statement regarding the use of anti-
brief as 2 weeks (but more often 4 weeks) if the organ- biotic prophylaxis before invasive dental procedures
ism is highly susceptible to the antibiotic selected. (9). It states that antibiotic prophylaxis is not routinely
This treatment duration is typically more prolonged, indicated for most dental patients with total joint
between 4 and 6 weeks, for more serious infections in replacements. However, all patients with a total joint
the compromised host. For prosthetic joint infections, replacement within 2 years of the implant proce-
the antibiotic course is usually quite protracted. For dure and some immunocompromised patients with
most cases of infected joint replacement, the prosthesis total joint replacements are at high risk for hemato-
is removed and antibiotic treatment is continued until genous infections should be considered for antibiotic
the site is sterile before reimplantation is considered. prophylaxis before invasive dental procedures. The re-
Antibiotic-impregnated cement or beads are some- commended antibiotic agents are based on an empiric
times employed in the reimplantation, either during regimen directed against the most common microorgan-
multistaged procedures or during an exchange arthro- isms responsible for late prosthetic joint infections
plasty. On rare occasions, antibiotic treatment is con- (S. epidermidis).
tinued indefinitely in the patient in whom the risk of The issue of the cost effectiveness of antibiotic pro-
removing the infected prosthesis is deemed too great phylaxis to prevent late infections in prosthetic joints
and the microorganism responsible for the infection remains extremely controversial due to the lack of reli-
can be reasonably suppressed by the use of an oral able data. No long-term observational studies or pro-
antibiotic agent. spective trials have been done.
The incidence of late infection of a prosthetic joint
as a result of procedure-related bacteremia appears to
be extremely low, perhaps between 10 to 100 cases per
OUTCOME 100,000 patients with total joint replacement per year.
Until future studies provide definitive data on cost
Retrospective observations indicate that factors por- effectiveness, the decision regarding the use of antibi-
tending a poor outcome include young age, old age, otic prophylaxis must be based on the physicians esti-
virulent microorganisms, delay in the diagnosis mation of the potential risks, the possible benefits for
and/or initiation of treatment, presence of underlying individual patients, and discussions between patient and
joint disease, and infection of particular joints (e.g., doctor.
the shoulder or hip). But a prospective study con- Any local or systemic bacterial infections must
firmed that only old age, preexisting joint diseases be treated promptly to minimize the possible spread of
such as RA, and the presence of a prosthetic joint con- the infection to the artificial joint. When confronted
stituted poor prognostic factors (8). with an elective procedure that is likely to lead to tran-
Avoiding delays in diagnosis, ensuring adequate sient bacteremia (any degree of bleeding at a site that
decompression to prevent avascular necrosis willing- is not normally sterile), the opportunity for antibiotic
ness to consider alternative drainage methods when prophylaxis should be discussed and the final decision
progress is not evident, and being proactive with is made in consultation with the patient (Table
rehabilitation are within the control of the clinician. 14A-3).
TABLE 14A-3. COUNSELING PATIENTS WITH A TOTAL isms are important pathogens in the neonate and young
JOINT REPLACEMENT REGARDING ANTIBIOTIC infant. Candida and Gram-negative bacilli are usually
PROPHYLAXIS BEFORE AN INVASIVE PROCEDURE acquired in the hospital or in another health care
THAT LEADS TO TRANSIENT BACTEREMIA. setting.
(1) You have (this condition, these conditions, or no condition) With the decline in H. influenzae septic arthritis in
that may make you more susceptible to infections. children less than 5 years old, microorganisms such as
Kingella kingae account for a greater percentage of
(2) The procedure that you are about to undergo may cause
patients. Gonococcal infection must always be consid- 14
these kinds of bacteria to enter your bloodstream briefly. This
normally results in no problems. (Brushing your teeth or ered in the sexually active adolescent with migratory
moving your bowels may result in a small number of bacteria arthritis and pustular skin lesions.
entering your bloodstream briefly in a similar manner.) Septic arthritis and osteomyelitis can coexist or
(3) Taking this antibiotic drug beforehand may reduce the complicate each other in the very young child because
likelihood of the bacteria causing problems in the replaced the metaphyseal and epiphyseal blood vessels commu-
joint. But there is no proof or guarantee that this preventive nicate and the metaphyses of some long bones are
step is 100% effective. within the joint capsule. Avascular necrosis of the
(4) The antibiotic medication is not very expensive. But taking it femoral head is unique to septic arthritis of the hip in
is associated with a slight risk of unpredictable side effects, children. Early surgical decompression to reduce the
similar to ones that what you may encounter with taking high intra-articular pressure will restore blood flow to
other medications (skin rash, nausea, vomiting, joint pain). the femoral head. The outcome of treatment of septic
(5) The risk of total joint replacement infection as the result of arthritis in children is more favorable than in adults.
the procedure is very small (estimated to be between 1 in Leg length discrepancy, limitation of joint mobility, and
10,000 and 1 in 10,000), and taking an antibiotic before- secondary degenerative joint disease are late sequelae
hand may reduce the risk even further, but it will not reduce in 25% of cases.
the chance to zero.
(6) If the artificial joint becomes infected, it usually means that it

has to be removed and the infection has to be treated until it
is cured, and then another total joint replacement procedure GONOCOCCAL JOINT DISEASE
can be considered.
Migratory arthritis and tenosynovitis with or without
(7) In my opinion (recommend one of the three choices): a, b, or c
(a) You most likely do not need to take an antibiotic before skin lesions in a sexually active adult should raise the
this procedure. suspicion of disseminated gonococcal infection (DGI).
(b) Even though taking an antibiotic before your procedure is Joint infections caused by Neisseria gonorrhoeae differ
associated with a small risk, I believe that assuming this from nongonococcal disease. In contrast to patients
small risk would be worthwhile in your case because of
with nongonococcal arthritis, who are often elderly or
the significant implications of a joint infection and the
possibility (however small) that such an infection might have serious underlying illnesses, individuals with gono-
occur. coccal (GC) arthritis are typically young, healthy adults.
(c) I believe that taking the antibiotic beforehand is worth- Women are more susceptible to DGI than men. Positive
while in your case. GC cultures at extra-articular sites, for example, geni-
I would be happy to review any of these points with you again tourinary tract, rectum, and throat, can help confirm the
before you make your decision. diagnosis because the synovial fluid Gram stain and
culture are typically negative.
Prompt response to antibiotic therapy is the rule and
residual problems in the affected joint are uncommon.
Resistance to penicillin is on the rise and it is wise to
use a third-generation cephalosporin as the initial treat-
SEPTIC ARTHRITIS ment for DGI.
IN CHILDREN
Septic arthritis in children is monoarticular more SEPTIC BURSITIS
than 90% of the time. Knee and hip joints account
for about two thirds of all cases. Children less than The bursae throughout the body facilitate joint mobility
2 years old are more susceptible to septic arthritis and many are located in close proximity to the synovial
than older children. Signs of joint disease in the neonate joints. The superficial bursae are more susceptible to
and infant may be minimal or absent. After S. aureus, bacterial infection than the deep bursae (10). The
group B streptococcus and Gram-negative microorgan- most common sites of septic bursitis are the olecranon
276 GEORGE HO, JR.
and the prepatellar bursa. The pathogenesis of septic REFERENCES

bursitis is the direct extension of a superficial skin
infection into the adjacent bursa. Some of the activities 1. Kaandorp CJE, Van Schaardenburg D, Krijnen P, et al.
that cause trauma to the superficial bursae are carpet Risk factors for septic arthritis in patients with joint
laying, mining, plumbing, roofing, gardening, wrestling, disease: a prospective study. Arthritis Rheum 1995;38:
gymnastics, and hemodialysis. S. aureus is the most 18191825.
common pathogen, responsible for greater than 80% of 2. Franz A, Webster AD, Furr PM, et al. Mycoplasmal
all cases. arthritis in patients with primary immunoglobulin defi-
Extensive cellulitis surrounding the bursa and distal ciency: clinical features and outcome in 18 patients. Br J
Rheumatol 1997;36:661668.
edema on the affected limb are common. A careful
3. Ho G Jr. Pseudoseptic arthritis. R I Med 1994;77:79.
search for skin lesions as the portal of bacteria invasion 4. Dubost J, Fis I, Denis P, et al. Polyarticular septic arthri-
is often rewarding. A bursal effusion or fluctuance of tis. Medicine 1993;72:296310.
the bursal sac on physical examination should lead to 5. Epstein JH, Zimmermann B, Ho G Jr. Polyarticular septic
aspiration of the content. arthritis. J Rheumatol 1986;13:11051107.
The bursal fluid is usually inflammatory and the 6. Post JC, Ehrlich GD. The impact of the polymerase
Gram stain is positive for Gram-positive cocci. A chain reaction in clinical medicine. JAMA 2000;283:
bactericidal antistaphylococcal agent is the initial 15441546.
drug of choice. In mild infections, an oral agent 7. Ho G Jr. How best to drain an infected joint: will we ever
will suffice with outpatient follow-up and adequate know for certain? J Rheumatol 1993;20:20012003.
drainage. If the infection is severe and the patient 8. Kaandorp CJE, Krijnen P, Moens HJB, et al. The outcome
of bacterial arthritis: a prospective community-based
appears toxic, admission to the hospital for parenteral
study. Arthritis Rheum 1997;40:884892.
antibiotic treatment is advisable. In draining the bursa, 9. American Dental Association/American Academy of
a large bore needle is necessary when the content is Orthopaedic Surgeons. Advisory statement: antibiotic
thick or contains particulate matter. Surgical drainage prophylaxis for dental patients with total joint replace-
or bursectomy is rarely necessary. The outcome of ments. J Am Dent Assoc 2003;134:895899.
treatment of septic bursitis of the superficial bursae is 10. Zimmermann B III, Mikolich DJ, Ho G Jr. Septic bursitis.
usually excellent. Semin Arthritis Rheum 1995;24:391410.
CHAPTER 14
B. Viral Arthritis
LEONARD H. CALABRESE, DO
Three general patterns of virus-associated illness are joint symptoms out of proportion to physical find-
observed in rheumatic disease: acute, self-limited ings; intermittent mono- and oligoarticular arthritis;
illness; chronic infection; and latent infection, with and symmetrical polyarthritis involving small joints
potential for reactivation. and resembling RA.
Parvovirus B19 can cause a polyarticular, small-joint The majority of patients with hepatitis C virus
arthritis that mimics rheumatoid arthritis (RA). infections are rheumatoid factor positive, often in
The slapped cheek rash characteristic of parvovirus high titer. This frequently leads to diagnostic
B19 infections in children is seen rarely in adults. confusion.
In contrast to RA, the duration of joint symptoms in Acute hepatitis B infections are associated with
B19 infections almost never persists beyond 1 the sudden onset of an inflammatory polyarthritis
month, and the joint disease is never erosive. and often with an urticarial or maculopapular
Rubella infections are associated with fever, constitu- rash.
tional symptoms, cervical and posterior occipital The arthritis of hepatitis B generally precedes the
lymphadenopathy, and a characteristic maculopapu- onset of jaundice by days to weeks, then subsides
lar rash. once jaundice begins.
Hepatitis C can be associated with a variety of Human immunodeficiency virus (HIV) infection should
rheumatic complaints, none of which are associated be considered in individuals who present with
ultimately with joint erosions: A nonerosive, nonpro- features of reactive arthritis, psoriatic arthritis, or
gressive arthritis associated with tenosynovitis and unusual inflammatory joint complaints.
The potential relationships between many viral infec- This chapter focuses on viral pathogens associated
tions and rheumatic syndromes are confounded by the with the first two of these clinical disease patterns, as
ubiquity of viral agents, and by the fact that all individu- the acute (but self-limited) and chronic infection pat-
als are afflicted intermittently by viral infections of terns are most likely to cause articular complaints. Table
some kind. Three patterns of viral illness are useful 14B-1 provides a full list of viral infections known to
when considering the possibility of a virus-associated produce clinically significant forms of arthritis (1).
rheumatic disease:
Acute but self-limited illness. The pathogen produces PARVOVIRUS B19
a short-lived infection and survives by moving on to
the next host. Many respiratory viruses, e.g., parvo- Parvovirus B19, a small DNA virus, is the cause of fifth
virus B19 and rubella, fit this pattern. disease, also known as erythema infectiosum, which is
Chronic infection. The viral agents establish ongoing principally a disease of childhood. In addition, B19 can
infections following the primary stage in all or only cause a polyarticular, small-joint arthritis that mimics
some of the patients whom they infect. Examples of rheumatoid arthritis (RA). B19 occurs in outbreaks and
viruses known to lead to chronic infections include is spread by respiratory secretions. The secondary trans-
hepatitis B (HBV), hepatitis C (HCV), and the mission rate to adults is about 50%. Up to 50% of
human immunodeficiency virus (HIV). healthy adults are positive for anti-B19 IgG antibodies
Latent infection, with potential for re-activation. In but negative for IgM directed against this virus, indicat-
this pattern, typified by herpesviruses such as Vari- ing previous exposure to this agent and (in most cases)
cella zoster, the primary infection may be either asymptomatic infection at some point in the past.
apparent or subclinical. Seronegative individuals in contact with school-aged
277
278 LEONARD H. CALABRESE
TABLE 14B-1. COMMON VIRAL INFECTIONS WITH rarely necessary. The essential elements of treatment
PROMINENT JOINT INVOLVEMENT. are recognizing the self-limited nature of the condition
and not confusing it with RA. Treatment is generally
MOST CHARACTERISTIC
PATHOGEN ARTICULAR MANIFESTATIONS symptomatic, though in rare cases of chronic arthritis
following acute B19 infection the administration of
Parvovirus B19 Rheumatoid arthritislike illness intravenous immunoglobulin has been reported to
lasting days to weeks after efficacious (3).
infection
Rubella virus Morbilliform rash and self-limited

polyarthritis following natural
RUBELLA
infection or vaccination
Rubella, a small RNA virus, is spread by airborne drop-
Hepatitis C virus Chronic polyarthralgias or lets. Two or three weeks after the infection, rubella
polyarthritis; mimic of
rheumatoid arthritis
produces an exanthemous illness characterized by fever,
constitutional symptoms, cervical and posterior occipi-
Hepatitis B virus Acute polyarthritis in prodromal tal lymphadenopathy, and a characteristic maculopapu-
phase of hepatitis; chronic lar rash. Before the widespread application of vaccines,
polyarthritis with systemic
vasculitis
rubella occurred in epidemic patterns every 6 to 9 years.
Since the introduction of aggressive immunization pro-
Human immunodeficiency Changing patterns of rheumatic grams, the rates of new infections have become a mere
virus (HIV) morbidity in modern era of HIV fraction of those previously seen. Thus, many clinicians
therapy
overlook rubella in the differential diagnosis of acute
arthritis (1).
In the course of natural infection with rubella, sym-
children or with an actively infected individual are
metrical arthralgias or arthritis associated with morning
at highest risk. Eliciting a history of such contacts is
stiffness may mimic RA. A more migratory pattern of
essential in the evaluation of patients with an acute
joint involvement may occur, as well. Periarthritis, teno-
polyarthritis (2).
synovitis, and carpal tunnel syndrome have also been
Articular symptoms in adult B19 infection generally
reported. The articular phase of the illness is self-limited
include the acute onset of polyarthralgias or, less com-
and generally lasts less than 2 weeks (4). Antirubella
monly, polyarthritis. Although the ultimate pattern of
IgM antibodies appear within a few weeks of infection
joint involvement is similar to classic RA, the arthritis
and persist for 4 to 6 months; thus their detection in the
of B19 infection may start in one or a few joints and
appropriate clinical setting is diagnostic.
spread with an additive pattern. For the purposes of
Rubella can be prevented by vaccination. Postvacci-
diagnosis in adults, unfortunately, the striking slapped
nation rheumatic symptomatology, however, including
cheek rash so often evident in children is seen rarely.
arthralgias, arthritis, myalgias, and paresthesias, have
The median duration of joint symptoms is about 10
lessened overall enthusiasm for universal vaccination.
days, but pain and stiffness may persist for longer and
The vaccine is a live attenuated virus that has under-
may recur (3). In contrast to RA, however, the dura-
gone modification in recent years in the interest of
tion of joint symptoms almost never persists beyond
diminishing arthritogenicity. Despite these modifica-
1 month in B19 infections, and the joint disease is
tions, adult immunization is associated with arthropathy
never erosive.
in about 15% of individuals. These generally occur 2
Most patients with parvovirus B19 arthropathy lack
weeks after immunization and last less than a week.
rheumatoid factor, although occasional patients have
Children undergoing immunization may develop a
been noted to have positive rheumatoid factors, anti-
peculiar lumbar radiculoneuropathy that produces pop-
nuclear antibodies (ANAs), anti-DNA, and other auto-
liteal pain, dubbed catchers crouch, upon arising in
antibodies. Other rheumatic syndromes have also been
the morning. This may occur 1 to 2 months following
described including a lupus-like syndrome, vasculitis,
immunization and generally resolves without therapy.
and cytopenias.
Rubella arthritis is managed conservatively with anal-
The diagnosis of B19-associated arthritis depends on
gesics and nonsteroidal anti-inflammatory agents.
a high degree of clinical suspicion, often driven by the
critical medical history of exposure to sick children, the
appropriate clinical picture, and the detection of anti- HEPATITIS C VIRUS
B19 IgM antibodies. The presence of anti-B19 IgG is
insufficient, as this merely indicates past infection. The Hepatitis C virus is the major cause of post-transfusion
detection of B19 DNA in serum by polymerase chain and community acquired non-A, non-B chronic hepati-
reaction (PCR) can also secure the diagnosis, but this is tis. The natural history of HCV is generally one of a
subclinical infection followed by chronicity in 70% to TABLE 14B-3. ESTIMATED PREVALENCE OF

80% of individuals. The incidence of HCV is 150,000 SEROLOGIC ABNORMALITIES IN PATIENTS WITH
new cases each year in the United States, resulting in HEPATITIS C VIRUS INFECTION.
93,000 cases of chronic hepatitis C. Hepatitis C, cur- SEROLOGIC FINDING PREVALENCE
rently estimated to infect 3.5 million people nationwide,
is transmitted predominantly by parenteral routes. Most Rheumatoid factor 50%60%
patients never develop progressive liver disease, but in
about 20% of cases cirrhosis or hepatocellular carci-
Cryoglobulins 30%40% 14
noma ensues over two to three decades. HCV is associ- Antinuclear antibody 10%40%
ated with a wide variety of extrahepatic manifestations, Monoclonal gammopathy 10%15%
many of which are rheumatic and immunologically
driven (Table 14B-2) (5). Antithyroid antibodies 5%10%
Articular disease manifested by painful joints is Antiphospholipid antibodies 20%
common in the setting of HCV infection. Remarkably
little is known or agreed upon with regard to the articu- Antismooth muscle antibody 7%20%
lar manifestations of HCV: their clinical features, patho- Antineutrophil cytoplasmic antibody (ANCA)* 10%
genesis, natural history, or optimal therapy. Data on the
prevalence of articular symptoms in HCV infection vary SOURCE: Adapted from Vassilopoulos D, Calabrese LH. Curr Rheumatol Rep
markedly among studies, probably due to major differ- 2003;5:200204, with permission of Current Rheumatology Reports.
* ANCA is hepatitis C virus infection is not directed against proteinase or
ences in design (e.g., reliance upon questionnaires as myeloperoxidase.
opposed to detailed physical examinations). Whereas
studies utilizing physical examination suggest arthritis as
a complication of HCV in less than 5% of patients, those manifestations of autoimmunity (Table 14B-3). The
employing questionnaire methodology describe joint high proportion of HCV-infected patients who are posi-
complaints in up to 30% of infected individuals (1). tive for RF is explained in part by the high prevalence
Whether HCV is associated with a distinct form of of cryoglobulins among HCV-infected individuals. (The
inflammatory joint disease is still unsettled, though a IgM component of mixed cryoglobulinemia has RF
growing number of observational reports suggest it is. activity; i.e., reacts with the Fc portion of the IgG com-
One syndrome recently described depicts a nonerosive, ponent; see Chapter 21E.)
nonprogressive arthritis associated with tenosynovitis Although the presence of RF does not correlate with
and joint symptoms out of proportion to physical find- articular symptoms, it has led to much confusion in dif-
ings. Others have found an RA-like picture, as well as ferentiating articular syndromes in HCV infection from
an intermittent mono- and oligoarticular arthritis, all true RA. Antibodies to CCP are of higher diagnostic
without erosive changes. On physical examination, joint sensitivity than is RF for the diagnosis of RA (6). RA
tenderness is common but frank synovitis less so. Joint patients also tend to have much more in the way of
effusions are distinctly rare. objective joint changes (i.e., frank synovitis) than
One of the most frequent challenges in the HCV- patients with HCV infection, in whom arthralgias are
infected population is differentiating true RA from the more common. Finally, HCV-associated joint disease is
polyarthritis of HCV infection. The differential diagno- not associated with erosive changes. Evidence of joint
sis is complicated by the fact that HCV-infected indi- destruction or bone erosions invoke other diagnoses.
viduals have a high prevalence of rheumatoid factor The management of HCV-associated articular mani-
(RF; 50%60%) activity as well as other laboratory festations remains problematic. A recent uncontrolled
study of interferon-based therapy suggested that HCV-
related articular manifestations may respond to aggres-
sive antiviral therapy, but controlled trials and better
TABLE 14B-2. AUTOIMMUNE CONDITIONS clinical definitions of disease and response are needed
ASSOCIATED WITH HEPATITIS C VIRUS INFECTION.
(7). Given the potential for exacerbation of the underly-
Cryoglobulinemic vasculitis ing hepatic disease, all therapies must be administered
Autoantibody production
with caution.
Autoimmune cytopenias
Membranoproliferative glomerulonephritis HEPATITIS B INFECTION

Sicca-like syndrome Hepatitis B virus (HBV) is an enveloped, partially
Arthralgias and arthritis double-stranded DNA virus. HBV is transmitted by
both parenteral and sexual routes. With an estimated
280 LEONARD H. CALABRESE
one third of the worlds population having histories of invariably fatal diseasea chronic illness, albeit one
HBV infection (self-limited in the majority of cases) that is complex in management.
and 5% to 10% remaining chronically infected, HBV is In the pre-HAART era, severe cases of reactive
the most common viral illness worldwide. HBV can arthritis and psoriatic arthritis were observed in the
cause cirrhosis and hepatocellular carcinoma, as well as HIV population. In addition, atypical forms of joint
a variety of extrahepatic manifestations (8). inflammation not fitting any particular pattern, often
Acute HBV infection is associated with an inflamma- referred to as HIV-associated arthritis, were also
tory polyarthritis that is clinically important to recog- described. Although relatively uncommon, these condi-
nize, for it may mimic the onset of classic RA. Often tions were often clinically dramatic and at times difficult
associated with the articular phase of this infection is an to manage (9).
urticarial or maculopapular rash. The arthritis, usually Today, these entities should be considered in indi-
sudden in onset, involves the wrists, knees, and ankles viduals with documented HIV infection or risk factors
as well as the small joints of the hands in a symmetrical for HIV infection who develop features of reactive
fashion. The arthritis generally occurs in the prodromal arthritis, psoriatic arthritis, or unusual inflammatory
phase of viremia and subsides after the appearance of joint complaints. Clues to the presence of these condi-
jaundice, which it precedes by days to weeks. tions in HIV include the propensity for overlapping
The pathogenesis of this illness is believed to be sec- features (e.g., clinical features of reactive arthritis in the
ondary to immune complex deposition in small blood presence of psoriasis vulgaris) and a sparing of the axial
vessels. No specific therapy is required for the arthritis spine.
other than supportive care because the condition is self- Acquiring precise data on incidence of these forms
limited. The condition should be suspected in any patient of arthritis has been problematic, with multiple studies
with the acute onset of polyarthritis, and heightened using different methodologies yielding disparate results
when risk factors for HBV acquisition are evident. (9). Since the introduction of HAART in 1997, these
The vast majority of patients with HBV-associated syndromes have been reported with diminishing fre-
arthritis have some liver enzyme abnormalities at the quency in Western countries but in sub-Saharan Africa,
time of arthritis onset. The presence of IgM directed where access to such therapies is unfortunately rare,
against HBV surface antigen or the detection of HBV these disorders are widely seen (1,10).
DNA in serum is diagnostic. Recognizing the underly- With the changing patterns of overall morbidity in
ing etiology (and avoiding inappropriate therapy for HIV disease have come changing patterns of rheumatic
other joint disorders) is critical (1). Persistent polyar- complications, including the descriptions of an immune
thritis lasting more than a few weeks should raise the reconstitution syndrome following the institution of
suspicion for transformation to a systemic vasculitic HAART (10). In this disorder, following initiation of
state (i.e., polyarteritis nodosa; see Chapter 21B). HAART in patients with advanced forms of immuno-
deficiency, the new onset or exacerbation of previously
mild or unrecognized autoimmune disease such as sar-
coidosis, RA, systemic lupus erythematosus, or autoim-
HUMAN IMMUNODEFICIENCY mune thyroid disease may be seen weeks to months
VIRUS later. A similar syndrome is well recognized to occur
with immune reconstitution to occult infections with
Human immunodeficiency virus (HIV-1), a lentivirus, is organisms such as mycobacteria, fungi, viruses, bacteria,
the etiologic agent of acquired immunodeficiency syn- and parasites. In general, most immune reconstitution
drome (AIDS). HIV disease has been reported in virtu- syndromes are self-limited, but their recognition is vital
ally every part of the world and is a major global public to plan an appropriate course for management. HAART
health problem. By the end of this decade, there will be need not be interrupted or discontinued. Immunosup-
100 million individuals infected with HIV. HIV disease pressive therapy can be employed as necessary in indi-
is a chronic illness with a mean life expectancy after viduals with the immune reconstitution syndrome,
infection of approximately 10 years. The virus preferen- although aiming for the minimal effective doses in con-
tially infects CD4 lymphocytes and through a variety trolling inflammation is obviously desirable.
of mechanisms leads to progressive CD4 lymphocyte
depletion, progressive immunodeficiency, and opportu-
nistic infection or malignancy. In recent years, the intro- OTHER FORMS OF VIRAL
duction of combination antiretroviral therapy (highly ARTHRITIS
active antiretroviral therapy; HAART) has dramati-
cally changed the natural history of the disease for those Articular symptoms consisting of polyarthralgias are
individuals with access to drugs. For many of these observed commonly in the course of many common
patients, HIV disease has becomerather than an viral syndromes that are rarely diagnosed in clinical
practice and are so self-limited that they rarely receive chronic viral infections: hepatitis C, hepatitis B, and HIV
rheumatologic attention. A variety of far less common infection. Ann Rheum Dis 2004;63(Suppl 2):ii18ii24.
viral infections can also be associated with arthritis, 4. Smith CA, Petty RE, Tingle AJ. Rubella virus and arthri-
including the alphaviruses such as Chikungunya, tis. Rheum Dis Clin North Am 1987;13:265274.
5. Vassilopoulos D, Calabrese LH. Rheumatic manifesta-
Onyong-nyong and Igbo viruses, and Ross River,
tions of hepatitis C infection. Curr Rheumatol Rep 2003;
Sinbis, and Mayaro viruses, which are found worldwide,
5:200204.
especially in Asia and the Pacific, South America, and
Scandinavia. All of these agents should be considered
6. Sene D, Ghillani-Dalbin P, Limal N, et al. Anti-cyclic 14
citrullinated peptide antibodies in hepatitis C virus associ-
in the differential diagnosis of unusual forms of arthritis ated rheumatological manifestations and Sjogrens syn-
with or without fever and other constitutional symp- drome. Ann Rheum Dis 2006;65:394397.
toms given the appropriate epidemiologic history (10). 7. Zuckerman E, Keren D, Rozenbaum M, et al. Hepatitis
Infection with HTLV-1, an endemic retrovirus in the C virus-related arthritis: characteristics and response to
Pacific and Caribbean now increasingly seen in intrave- therapy with interferon alpha. Clin Exp Rheumatol 2000;
nous drug users in the United States, is also associated 18:579584.
with a number of rheumatic syndromes, including an 8. Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis
B. Lancet 2003;362:20892094.
illness that resembles RA in its presentation (10).
9. Vassilopoulos D, Calabrese L. Rheumatic aspects of
human immunodeficiency virus infection and other immu-
nodeficiency states. In: Hochberg M, Silman A, Smolen J,
REFERENCES Weinblatt M, Weisman M, eds. Rheumatology. 4th ed. St.
Louis: Mosby; 2006:26.126.9.
1. Calabrese LH, Naides SJ. Viral arthritis. Infect Dis Clin 10. Calabrese L, Kirchner E, Shrestha R. Rheumatic compli-
North Am 2005;19:963980. cations of human immunodeficiency virus (HIV) infection
2. Young NS, Brown KE. Parvovirus B19. N Engl J Med in the era of highly active antiretroviral therapy (HAART):
2004;350:586597. emergence of a new syndrome of immune reconstitution
3. Calabrese LH, Zein N, Vassilopoulos D. Safety of antitu- and changing patterns of disease. Semin Arthritis Rheum
mor necrosis factor (anti-TNF) therapy in patients with 2005;35:166174.
CHAPTER 14
C. Lyme Disease
LINDA K. BOCKENSTEDT, MD
Lyme disease is a tick-borne zoonosis caused by The hallmark of disseminated Lyme disease is the
spirochetes of the genus Borrelia burgdorferi sensu lato. appearance of multiple EM lesions. These arise in
The majority of Lyme disease cases are localized to about 50% of untreated patients with early localized
endemic foci in the United States, Europe, and Asia. disease. Secondary lesions are similar to the primary
In the United States, more than 90% of cases occur lesion, although are generally smaller in size and can
in only nine states: New York, Connecticut, New appear anywhere on the body.
Jersey, Pennsylvania, Massachusetts, Maryland, Fever, malaise, myalgias, and arthralgias generally
Rhode Island, Wisconsin, and Minnesota. accompany dissemination of the Borrelia infection.
B. burgdorferi species are transmitted by hard-shelled Cardiac involvement in Lyme disease occurs in 4% to
ticks of the Ixodes complex, for example, Ixodes 10% of untreated patients, usually as varying
scapularis in the northeastern and north central degrees of atrioventricular heart block.
United States. Acute peripheral nervous system disease may take
Upon infecting humans, B. burgdorferi replicates in the several forms in Lyme disease: cranial nerve palsies
skin and then disseminates via the bloodstream to (unilateral or bilateral seventh nerve palsy is the
other organs, leading to extracutaneous disease most common neurological manifestation), senso-
manifestations. rimotor radiculopathies, and mononeuritis multiplex.
Seventy to eighty percent of Lyme disease patients Late manifestations of Lyme disease may occur in
develop a characteristic skin rash, erythema migrans the joints, nervous system, and skin. At this stage,
(EM), at the site of tick feeding. The rash usually joint involvement usually presents as an intermittent,
appears within days to weeks of the tick bite (range, oligoarticular arthritis. The knee is most commonly
330 days). affected.
Lyme disease is a tick-borne zoonosis caused by spiro- organism from tissues and body fluids confirmed the
chetes of the genus Borrelia burgdorferi sensu lato (1). spirochetal etiology of the disorder.
The disease was first recognized in 1976 with evaluation
of a clustering of children with presumed juvenile rheu-
matoid arthritis in the area around Lyme, Connecticut. EPIDEMIOLOGY
The onset of arthritis was often heralded by a charac-
teristic skin rash, erythema migrans (EM), which had Lyme disease is widespread, with the majority of cases
been linked previously to the bite of Ixodes ricinus ticks localized to specific endemic foci in the United States,
in Europe and the subsequent appearance of neurologic Europe, and Asia (2). In each of these locations, B.
abnormalities (Bannworths syndrome). With time, it burgdorferi species are transmitted by hard-shelled
became apparent that arthritis was one manifestation of ticks of the Ixodes complex: Ixodes scapularis in the
a multisystem disorder that involved the skin, heart, northeastern and north central United States, I. pacifi-
joints, and nervous system. In 1981, Willy Burgdorfer cus along the United States west coast, I. ricinus in
isolated the causative agent that bears his name, Bor- Europe, and I. persulcatus in Asia. The B. burgdorferi
relia burgdorferi, from Ixodes scapularis ticks collected species transmitted by Ixodes ticks differs among conti-
on Long Island. The subsequent demonstration of anti- nents, with exclusively B. burgdorferi sensu stricto in
bodies to B. burgdorferi in the sera of patients with North America, and B. burgdorferi sensu stricto, B.
Lyme disease along with the eventual culture of the afzelii, and B. garinii in Europe and Asia. Although
282
similar in genetic make-up, these Borrelia species are CLINICAL MANIFESTATIONS

not identical and disease manifestations resulting from
infection can vary across species. Arthritis is more The clinical manifestations of Lyme disease largely
common after B. burgdorferi sensu stricto infection. reflect the biology of B. burgdorferi as it replicates in
Neurologic disease is associated more strongly with B. the skin and then disseminates via the bloodstream to
garinii, and chronic skin disease with B. afzelii (see other internal sites where disease can be seen. Typically
below). signs and symptoms appear in overlapping stages as
Lyme disease is the most common vector-borne 14
early localized disease, early disseminated infection, or
disease in the United States, with 19,804 cases reported late disease (1,4).
in 2004 to the Centers for Disease Control (CDC) (3).
The incidence of Lyme disease parallels the prevalence
of infected ticks, with more than 90% of cases originat-
ing from just nine states: New York, Connecticut, New
Jersey, Pennsylvania, Massachusetts, Maryland, Rhode
Early Localized Disease
Island, Wisconsin, and Minnesota. The seasonal varia- Within days to weeks of the tick bite (range, 330 days),
tion of Lyme disease relates to the 2-year life cycle and 70% to 80% of infected individuals develop a charac-
feeding patterns of Ixodes ticks. In the northeast, larval teristic skin rash, erythema migrans (EM), at the site of
ticks first acquire B. burgdorferi by feeding on small tick feeding [Figure 14C-1(A)]. As ticks preferentially
rodent reservoir hosts (especially the white-footed feed in skin folds or where clothing grips the skin,
mouse), then molt into nymphs, the predominant vector common sites are the axilla, popliteal fossa, groin, and
for human disease. The peak incidence of Lyme disease abdomen. EM typically begins as a single painless ery-
occurs during the late spring and summer, when nymphal thematous macule or papule that expands rapidly (2
ticks feed, as adult ticks prefer to feed on white-tailed 3 cm/day), with some lesions more than 70 cm in diameter
deer. Transovarial transmission of B. burgdorferi from (most, however, are on the order of 5 cm). These fea-
infected adult female tick to egg does not occur, so a tures distinguish EM from reactions to the tick bite
competent reservoir host, such as the white-footed itself, which usually begins within hours and is associ-
mouse, is required to maintain B. burgdorferi in nature. ated with significant pruritis.
This may explain the paucity of cases of Lyme disease Although classically reported as a bulls eye rash,
in warmer climates, where larvae preferentially feed on EM more commonly appears as an expanding macular
noncompetent reservoirs such as lizards. Although the lesion, occasionally with a vesicular or necrotic center.
primary reservoir for B. burgdorferi is mammals, the It is unusual for EM to produce local symptoms other
organism can also survive in birds. than tingling and burning or occasionally mild pruritis.
FIGURE 14C-1
(A) Erythema migrans rash with central clearing on the shoulder of a patient. Note the central
hyperpigmentation at prior tick bite site (punctum). Borrelia burgdorferi was isolated from a biopsy
culture performed at the periphery of the lesion. (B) Multiple erythema migrans lesions on the
back of a patient whose primary lesion is depicted in (A). Note absence of central papule or
postinflammatory skin change. (From Nadelman RE, Wormser GP, Am J Med 1995;98:16S, with
permission from Excerpta Medica, Inc.)
A B
284 LINDA K. BOCKENSTEDT
EM can be associated with systemic viral-like symptoms system disease occurs most commonly above the bundle
including malaise, fever, headache, stiff neck, myalgia, of His and involves the atrioventricular node, but can
and arthralgia. These latter symptoms without EM involve multiple levels. Although myopericarditis can
can be the presenting manifestation in up to 18% of rarely occur, acute valvular disease and congestive heart
patients, and can be distinguished from other viral failure are not found in Lyme carditis, distinguishing B.
syndromes by the absence of upper respiratory or burgdorferi infection from acute rheumatic fever or
gastrointestinal involvement. Histopathology of EM viral myopericarditis. Lyme carditis resolves without
lesions reveals mononuclear and lymphoplasmacytic specific therapy, but in some cases temporary pacemak-
infiltrates. ers are required.
Erythema migrans must be distinguished from Lyme disease can affect both the peripheral and the
another EM-like rash associated with the bite of the central nervous systems. Neurologic involvement, once
lone star tick, Amblyomma americanum, found in the seen in 10% to 15% of untreated patients, has declined
southeastern and south-central states. Patients with with earlier recognition and treatment of Lyme disease.
Southern tick-associated rash illness (STARI) develop Acute peripheral nervous system disease results in
a bulls eye rash but are seronegative for Lyme disease cranial nerve palsies, sensorimotor radiculopathies, and
(5). A noncultivable spirochete, Borrelia lonestari, has mononeuritis multiplex. Unilateral or bilateral seventh
been identified in A. americanum ticks, and one patient nerve palsy is the most common neurological manifesta-
has been described in whom B. lonestari DNA was tion in the United States. Even in endemic areas,
detected in a skin biopsy of the rash and in the biting however, Lyme disease accounts for only about 25% of
tick. cases of seventh nerve palsies arising during the periods
Another recognized but rare skin manifestation seen of nymphal tick feeding (spring/summer). Acute central
in European Lyme disease is borrelial lymphocytoma, nervous system involvement presents as a lymphocytic
which typically presents on the earlobe or nipple as a meningitis and rarely encephalomyelitis, the latter more
solitary bluish-red nodule. It arises with EM or some- commonly seen in Europe. Cerebrospinal fluid exami-
what later, but may persist for months or more than a nation of patients with isolated seventh nerve palsy can
year, in contrast with EM, which usually disappears reveal an asymptomatic lymphocytic pleocytosis, but
without specific therapy within weeks. given the favorable outcome with oral antibiotic regi-
mens that penetrate the central nervous system (CNS),
performance of lumbar puncture is not generally rec-
ommended in the absence of suggestive signs and symp-
Early Disseminated Infection toms of meningitis or encephalomyelitis.
Weeks to months after the onset of infection, spiro- Disseminated B. burgdorferi infection can result in
chetes can disseminate to internal organs, with disease abnormalities in other organ systems, including the eye
primarily seen in the skin, joints, heart, and nervous (keratitis), the liver (hepatitis), the spleen (necrosis),
system. The hallmark of disseminated Lyme disease is and subcutaneous tissue (panniculitis). Disease in these
the appearance of multiple EM lesions [Figure 14C- organ systems is rare and generally associated with
1(B)], which arise in about 50% of untreated patients more classic manifestations of Lyme disease. Routine
with early localized disease. Secondary lesions are screening for Lyme disease in the absence of other sug-
similar to the primary lesion, although are generally gestive signs of B. burgdorferi infection in this setting is
smaller in size and can appear anywhere on the body. unwarranted.
Patients generally are ill during this phase, with fever,
malaise, myalgias, and arthralgias.
Musculoskeletal involvement in Lyme disease is
Late Disease
common at all stages of infection, but inflammatory A minority of patients develops late manifestations of
arthritis appears in <10% of infected individuals and is Lyme disease, principally confined to the joints, nervous
considered a manifestation of late disease (see below). system, and the skin. At this stage, joint involvement
Fleeting migratory pains in muscles, joints, and periar- may present as an intermittent, oligoarticular arthritis.
ticular structures, lasting only hours to days, can be seen The knee is most commonly affected, followed by the
in both early localized infection as well as in acute shoulder, the elbow, the temporomandibular joint, and
disseminated disease. Although myalgia is a com- the wrist. Joint effusions can be quite large (50100 cc
mon symptom, true myositis with elevation in muscle in the knee) but not particularly painful. Synovial fluid
enzymes and abnormalities on muscle biopsy is rare. is inflammatory; cell counts average 25,000/mm3, with a
Cardiac involvement in Lyme disease occurs in 4% neutrophil predominance. Periarticular symptoms such
to 10% of untreated patients, and typically manifests as as bursitis and tendonitis can also be seen. Patients with
varying degrees of atrioventricular heart block. Electro- Lyme arthritis can experience recurrent attacks of joint
physiology studies have demonstrated that conduction inflammation with the frequency and duration of attacks
diminishing with time. Lyme arthritis can mimic other required for mammalian infection. The immunomodu-
causes of mono- or pauciarticular arthritis, including the latory properties of Ixodes tick saliva promote the initial
seronegative spondyloarthropathies and juvenile rheu- survival of spirochetes within the mammal. As an extra-
matoid arthritis. Low back pain and spinal involvement cellular pathogen, spirochetes evade host defense
is rare in Lyme disease, however. Less than 10% of mechanisms through several features, including (1)
patients with recurrent Lyme arthritis evolve a pattern inhibition of complement through erp and CRASP gene
of chronic unremitting synovitis involving a single joint, products that bind factor H and factor H-like protein I
especially the knee. In these individuals, the spirochete and (2) by defeating antibody-mediated clearance 14
DNA can no longer be detected by polymerase chain through antigenic variation, especially of the vlsE gene.
reaction (PCR) of joint fluid and synovial specimens, B. burgdorferi also expresses proteins that promote
and further treatment with antibiotics does not alter the establishment of infection in the extracellular matrix
time to resolution, which generally occurs within 5 and dissemination through the vasculature. These
years. include the fibronectin-binding protein BBK32, decorin-
Late neurologic manifestations of Lyme disease binding proteins A and B, the integrin-binding protein
include encephalomyelitis, peripheral neuropathy, and p66, and the glycosaminoglycan-binding protein Bgp.
encephalopathy. Encephalomyelitis is primarily seen in A characteristic feature of Lyme disease is that symp-
Europe and presents as a slowly progressive, unifocal toms can be severe despite a paucity of organisms in
or multifocal disease involving the white matter. A lym- tissues; much of the pathology is believed to be due to
phocytic pleocytosis, elevated protein, and normal the host immune response to spirochete components.
glucose are characteristic cerebrospinal fluid (CSF) fea- Highly inflammatory B. burgdorferi lipoproteins acti-
tures. Magnetic resonance imaging of the brain reveals vate innate immune cells through the Toll-like receptor
contrast-enhancing areas of inflammation with increased (TLR) family of pattern recognition receptors, princi-
signal on T2 imaging. The peripheral neuropathy of late pally TLR2/1 and TLR2/6 heterodimers. TLR stimula-
Lyme disease presents with intermittent paresthesias in tion results in a cascade of immune events, including
a stocking-glove distribution, occasionally associated production of inflammatory cytokines and chemokines,
with radicular pain. Reduced vibratory sensation can be upregulation of adhesion molecules on endothelial cells,
found on physical examination, and electrophysiology and priming of the adaptive T- and B-cell response.
studies are consistent with mononeuritis multiplex. Late Macrophages expressing TLRs readily ingest and kill B.
encephalopathy presents with mild impairment in cog- burgdorferi, but human polymorphonuclear leukocytes
nitive function and memory testing that is demonstrable (PMNs) require opsonization of spirochetes for efficient
on neuropsychology testing. CSF examination in this phagocytosis. PMNs produce the zinc-binding protein
rare manifestation of Lyme disease is generally normal. calprotectin, which inhibits B. burgdorferi growth in
Brain imaging is either normal or reveals minor, non- vitro at concentrations of calprotectin found within
specific abnormalities. inflamed joints.
In Europe, B. afzelii infection can result in a chronic Humoral immunity is a key host defense against B.
skin lesion, acrodermatitis chronica atrophicans. This burgdorferi infection. Antibodies that arise in the
skin lesion first appears as an erythematous hyperpig- absence of T-cell help are sufficient to resolve inflam-
mented lesion that evolves to a chronic stage of hypo- mation and prevent challenge infection in the mouse
pigmentation and atrophic, cellophane-like skin. model of Lyme borreliosis. Sera from patients with late
Acrodermatitis chronica atrophicans responds to antibi- Lyme disease contain protective antibodies. Immune
otics if treated during the inflammatory phase. Because complexes, found in the serum of patients with Lyme
B. afzelii is not found in North America, acrodermatitis disease, are concentrated in the joints of those with
chronic atrophicans is not a manifestation of Lyme Lyme arthritis. Analysis of plasma cells derived from
disease acquired on that continent. the synovium of patients with treatment-resistant Lyme
arthritis reveals evidence of expansion of the antibody
a response, but the driving antigens have not been
PATHOGENESIS identified.
B. burgdorferi infection primes both CD4+ and
Lyme disease begins when spirochetes are transmitted CD8+ T cells and the predominance of T-helper 1type
to humans serving as incidental bloodmeal hosts for responses correlates with more severe arthritis. The
infected ticks. B. burgdorferi resides in the midgut of synovium of Lyme arthritis patients resembles rheuma-
unfed ticks and migrates to the salivary glands during toid synovium, with mononuclear cell infiltration and
the first 24 hours of tick feeding. During this period, pseudolymphoid follicles formed by T cells, B cells,
spirochetes bind host plasminogen to disseminate within and plasma cells. There is an association between T-
the tick, downregulate outer surface protein (Osp) A, and B-cell responses to Osp A and the development
a midgut adhesin, and upregulate Osp C, a protein of chronic antibiotic-resistant Lyme arthritis (6).
HLADRB1*0401, 0101 and related alleles are more two-tiered approach is recommended, using an enzyme-
commonly found in patients with this form of arthritis, linked immunosorbent assay (ELISA) to measure serum
and it has been proposed that in these individuals, Osp IgM and IgG reactivity to B. burgdorferi as a screening
A immune responses are perpetuated through molecu- tool, followed by immunoblot (Western blot) to confirm
lar mimicry with host proteins after B. burgdorferi has specificity (Table 14C-1). IgM reactivity usually appears
been cleared. Although an Osp A T-cell epitope reac- within 2 to 3 weeks of infection and should be used to
tive with a human LFA-1 peptide has been identified, support a diagnosis of Lyme disease in patients with
available evidence points away from this self-peptide as signs and symptoms present for less than 4 weeks. IgG
a driving force for persistent inflammation. Because responses are detectable after 1 month of illness and
even treatment-resistant Lyme arthritis subsides with should be positive in patients with a clinical history of
time (within 5 years), the immune responses detected longer duration; IgG reactivity alone should not be used
may be appropriate and directed toward eliminating for diagnosis in these individuals. A persistently positive
persisting antigens rather than viable organisms. Pro- IgM response without IgG seroconversion is consistent
longed arthritis may also be due to the persistence of an with a false-positive test. Both rheumatoid factor and
abnormal immune regulatory state after the pathogen antinuclear antibodies can give rise to positive Lyme
and its inflammatory products have been eliminated. serology by ELISA. An IgM and IgG immunoblot of B.
The pathogenesis of neurologic disease is more enig- burgdorferi antigens separated by molecular weight
matic. Peripheral neuropathy has been associated with should be used to confirm antibody specificities for all
a vasculopathy resembling endarteritis obliterans, which positive or equivocal ELISA samples, but should not be
may secondarily lead to nerve ischemia, mononeuritis routinely performed on negative ELISA samples.
multiplex, and other manifestations of nerve dysfunc- Patients with Lyme disease may test negative within the
tion. Patients with Lyme disease rarely develop persis- first 1 to 2 weeks of infection. A synthetic C6 peptide
tent neurologic abnormalities, most notably subtle ELISA, which measures antibodies to a constant region
cognitive changes with radicular pain or distal paresthe- of the VlsE protein, may be useful in the early diagnosis
sias. These symptoms are not responsive to antibiotics of Lyme disease. The high specificity (99%) and sensitiv-
and may represent sequelae from irreversible tissue ity (74% in acute Lyme disease to 100% in late Lyme
injury. disease) of this assay are particularly helpful when
patients present with only viral-like symptoms in the
absence of EM. In the case of Lyme meningitis, intrathe-
DIAGNOSIS cal antibodies to B. burgdorferi can be detected. Evi-
dence of an elevated CSF to serum IgG ratio is supportive
The diagnosis of Lyme disease should be suspected in of CNS infection. Positive serologic tests must be inter-
individuals who have an appropriate clinical history and preted in the clinical setting; the rate of seropositivity in
a reasonable risk of exposure to B. burgdorferiinfected asymptomatic individuals may be as high as 4% in
ticks (7). The hallmark skin lesion EM is a diagnostic endemic areas. The vast majority of patients with dis-
criterion for early Lyme disease and is sufficiently disseminated infection are seropositive; in those with ini-
tinctive to warrant treatment without further testing. tially negative or equivocal tests, a follow-up convalescent
In contrast, other manifestations require supporting titer 2 weeks after the first sample will often be positive,
laboratory evidence to secure the diagnosis. Although even with antibiotic therapy. Once positive, IgM and
culture is a gold standard for many bacterial infections,
B. burgdorferi is only rarely detected by this method
from diseased sites, the exception being the leading
TABLE 14C-1. CRITERIA FOR WESTERN BLOT
margin of EM lesions. Routine laboratory tests are non- INTERPRETATION IN THE SEROLOGIC CONFIRMATION
specific, with occasional elevation in the white blood OF LYME DISEASE.
cell count, erythrocyte sedimentation rate, and mild
ISOTYPE TESTED CRITERIA FOR POSITIVE TEST
abnormalities of liver function tests. As noted above,
analysis of synovial fluid from patients with Lyme IgM Two of the following three bands are
arthritis reveals an inflammatory infiltrate (cell counts present: 23 kDa (OspC), 39 kDa (BmpA),
ranging from 3,000100,000/mm3; mean, 25,000/mm3) and 41 kDa (Fla)
and the synovial histopathology is indistinguishable IgG Five out of 10 bands are present: 18 kDA,
from that of rheumatoid arthritis or reactive arthritis. 21 kDa, 28 kDa, 39 kDa, 41 kDa, 45 kDa,
CSF examination in patients with CNS disease reveals 58 kDa (not GroEL), 66 kDa, and 93 kDa
lymphocytic pleocytosis, but oligoclonal bands are not
present. SOURCE: Adapted from Centers for Disease Control and Prevention, Recom-
mendations for test performance and interpretation from the Second
Serologic tests are the mainstay of diagnosis because National Conference on Serologic Diagnosis of Lyme Disease, MMWR 1995;
they provide evidence of B. burgdorferi exposure. A 44:590591.
IgG antibody titers may remain elevated for months to evidence of co-infection with A. phagocytophilum or
years after treatment and should not be used to monitor Babesia microti, particularly if there is associated unex-
response to therapy. plained leucopenia, thrombocytopenia, or anemia.
Other methods for detecting B. burgdorferi infection Patients with Lyme arthritis who fail to respond com-
include PCR amplification of spirochete DNA targets pletely to oral therapy should receive a second course
from tissues and body fluids. This technique has been of either oral or intravenous therapy. If arthritis persists
used with variable success to detect B. burgdorferi DNA and PCR analysis of synovial tissue or fluid is negative
in synovial fluid and CSF specimens from patients with for B. burgdorferi DNA, then treatment with nonsteroi- 14
Lyme disease. Up to 85% of synovial fluid specimens dal anti-inflammatory drugs, intra-articular corticoste-
may test positive, whereas B. burgdorferi DNA could roid injections, or disease-modifying antirheumatic drug
be detected in less than 40% of CSF specimens from (DMARD) therapy with plaquenil may be considered.
patients with Lyme meningitis. Other tests, such as a Synovectomy for chronic Lyme arthritis can be curative.
urine antigen test and blood microscopy for borrelia Individuals with late neurologic abnormalities may not
have not been validated. respond completely to antibiotic therapy because of
Imaging modalities for CNS disease can provide sup- irreversible tissue injury. Re-treatment of this subgroup
porting evidence of neurologic abnormalities, but no of patients is not generally recommended unless there
imaging findings are diagnostic of CNS Lyme disease. is objective evidence of relapse or progression of disease.
Magnetic resonance imaging of the brain is generally Serologies and intrathecal antibody production are not
normal, but 25% of patients with encephalopathy may useful to assess response to therapy as successfully
have white matter lesions. Absence of oligoclonal bands treated patients may have positive tests that persist for
in the CSF helps distinguish patients with CNS Lyme years.
disease from those with multiple sclerosis, in whom oli- Treatment of Lyme disease in pregnancy follows
goclonal bands are typically present and serologic tests the same recommendations as for the nonpregnant
for Lyme disease are negative. state except that doxycycline should be avoided. While
maternalfetal transmission of B. burgdorferi can occur,
there is no evidence that B. burgdorferi infection results
in fetal abnormalities or demise in cases where the
TREATMENT AND PROGNOSIS mother has received recommended antibiotic therapy.
B. burgdorferi infection cannot be transmitted by inges-
Recommendations for treatment of Lyme disease, tion of breast milk.
recently revised, are summarized in Table 14C-2 (8). About 10% of patients may experience a Jarisch
Doxycycline, amoxicillin, and cefuroxime axetil are Herxheimer reaction within 24 to 48 hours of initiation
effective therapies for early localized or early dissemi- of antibiotic therapy. This condition is self-limited; sup-
nated Lyme disease in the absence of neurologic portive care with reassurance and nonsteroidal anti-
manifestations or high degree atrioventricular block. inflammatory agents may help relieve symptoms. Most
Doxycycline is the preferred antibiotic because it is also patients with Lyme disease respond to the recom-
effective against another tick-borne pathogen, Ana- mended courses of antibiotics without significant objec-
plasma phagocytophilum, which causes human granulo- tive sequelae, but a minority may complain of persistent
cytic anaplasmosis. Macrolides are not as effective as fatigue, musculoskeletal pain, and cognitive dysfunc-
the other antimicrobials and should not be used as first- tion. Objective findings are generally lacking. In a study
line therapy. First generation cephalosporins are inef- of these individuals with a previously well-documented
fective. Most manifestations of Lyme disease can be history of Lyme disease, an extended course of antibiot-
managed with oral therapy, the exceptions being any ics (30 days of intravenous ceftriaxone followed by 60
neurologic involvement other than isolated cranial days of oral doxycycline) had no effect on symptoms
nerve palsy, cardiac disease with advance atrioventricu- when compared to a placebo group (9). The conclusion
lar block, and recurrent arthritis after oral therapy. regarding these subjective complaints is that Lyme
In general, the response to therapy correlates with disease may result in a post-Lyme syndrome similar to
duration of signs and symptoms, with late manifesta- fibromyalgia or chronic fatigue syndrome. There are,
tions requiring weeks to months for improvement or however, numerous reports of patients with chronic
resolution. Antibiotic therapy may not hasten the reso- subjective complaints in whom serologic tests are nega-
lution of cranial nerve palsies or carditis, which resolve tive yet who receive extended courses of antibiotics for
without therapy, but patients should be treated to avoid Lyme disease (10). Many of these individuals report a
other complications from Lyme disease. Individuals partial response rate to therapy, which may be a placebo
with early Lyme disease who present with more severe effect or due to anti-inflammatory properties of the
viral-like symptoms or who have persistent fever after antibiotics themselves that are unrelated to anti-
48 hours of antibiotic therapy should be evaluated for microbial actions. When evaluated at academic medical
TABLE 14C-2. RECOMMENDED TREATMENT OF LYME DISEASE.a,b

MANIFESTATION DRUG ADULT DOSAGE PEDIATRIC DOSAGE DURATION (RANGE)
Erythema migrans Doxycyclinec 100 mg po b.i.d. <8 years, not recommended 14 days (1021 days)
(Recommended) 8 years, 4 mg/kg/day in two
divided doses (max 100 mg/dose)
Amoxicillin 500 mg po t.i.d. 50 mg/kg/day in three divided doses 14 days (1021 days)
Cefuroxime axetil 500 mg po b.i.d. 30 mg/kg/day in two divided doses 14 days (1021 days)
Erythema migrans Azithromycin 500 mg po q.i.d. 10 mg/kg q.i.d. (max 500 mg/day) 710 days
(Alternative)d Clarithromycin 500 mg po b.i.d 7.5 mg/kg b.i.d. 1421 days
Erythromycin 500 mg po q.i.d. 12.5 mg/kg q.i.d. (max 500 mg/dose) 1421 days
Acute neurologic disease

Cranial nerve palsye Same as oral regimens for erythema migrans 14 days (1021 days)
Meningitis or Ceftriaxone 2 g IV q.i.d. 5075 mg/kg IV q.i.d. in single dose 14 days (1028 days)
radiculopathyf (max 2 g/day)
(Alternative IV) Cefotaxime 2 g IV q8h 15020 mg/kg/d IV in three to four
divided doses (max 6 g/day)
Penicillin G 1824 million units 200,000400,000 U/kg/day divided
q4h (max 1824 million U/day)
Cardiac diseaseg Same as for erythema migrans or 14 days (1021 days)

IV regimen as for neurologic disease 14 days (1021 days)
Late disease
Arthritis without Same as for erythema migrans 28 days (28 days)
neurologic
Recurrent arthritis Repeat oral regimen or
after oral regimen IV regimen as for neurologic disease 14 days (1428 days)
Central or peripheral IV regimen as for acute neurologic disease 14 days (1428 days)
nervous system
disease
SOURCE: Adapted from Wormser GP, et al., Clin Infect Dis 2006;43:10891134, by permission of Clinical Infectious Diseases.
a,b
Complete response to treatment may be delayed beyond the treatment period, regardless of the clinical manifestation, and relapse may recur. Patients with
objective signs of relapse may need a second course of treatment.
c
Tetracyclines are relatively contraindicated in pregnant or lactating women and in children <8 years of age.
d
Due to their lower efficacy, macrolides are reserved for patients who are unable to take or who are intolerant of tetracyclines, penicillins, and
cephalosporins.
e
Patients without clinical evidence of meningitis may be treated with an oral regimen. The recommendation is based on experience with seventh cranial nerve
palsy. Whether oral therapy would be as effective for patients with other cranial neuropathies is unknown; the decision between oral and parenteral therapy
should be individualized.
f
For nonpregnant adult patients intolerant of beta-lactam agents, doxycycline 200400 mg/day orally (or IV if unable to take oral medications) in two divded
doses may be adequate. For children 8 years of age, the dosage of doxycycline for this indication is 48 mg/kg/day in two divided doses (maximum daily
dosage of 200400 mg).
g
A parenteral antibiotic regimen is recommended at the start of therapy for patients who have been hospitalized for cardiac monitoring; an oral regiment
may be substituted to complete a course of therapy or to treat outpatients. A temporary pacemaker may be required for patients with advanced heart
block.
centers, the majority of such patients do not have objec- ing, topical application of DEET-containing insect
tive evidence of B. burgdorferi exposure or infection. repellents, and daily personal surveillance to remove
Some have other treatable diseases. ticks can reduce the risk of infection. For individuals
bitten by Ixodes ticks that have been attached for 36
hours, a single 200 mg dose of doxycycline (or 4 mg/kg
PREVENTION for children 8 years of age) is effective at preventing
Lyme disease, but no data are available regarding other
The most effective strategy to prevent Lyme disease is tick-borne diseases. This therapy is not recommended
to limit potential exposure to infected ticks through unless the tick was acquired in an area where the tick
environmental and personal protective measures. Elim- infection rate is 20%. A recombinant Osp Abased
inating brushy areas and spraying properties with in- Lyme disease vaccine received US Food and Drug
secticides can reduce the local tick population. For Administration approval and was briefly available for
individuals in endemic areas, wearing protective cloth- prevention of Lyme disease. Although phase I to III
studies demonstrated that the vaccine was safe and 80% 5. James AM, Liveris D, Wormser GP, et al. Borrelia lones-
effective at preventing Lyme disease after three doses, tari infection after a bite by an Amblyomma americanum
it was withdrawn in part because of public concern for tick. J Infect Dis 2001;183:18101814.
potential vaccine-related side effects, especially Osp 6. Steere AC, Falk B, Drouin EE, et al. Binding of outer
surface protein A and human lymphocyte function-associ-
Aassociated arthritis.
ated antigen 1 peptides to HLA-DR molecules associated
with antibiotic treatment-resistant Lyme arthritis. Arthri-
REFERENCES
tis Rheum 2003;48:534550. 14
7. Aquero-Rosenfeld ME, Wang G, Schwartz I, et al.
Diagnosis of Lyme borreliosis. Clin Microbiol Rev 2005;
1. Steere AC, Coburn J, Glickstein L. The emergence of 18:484509.
Lyme disease. J Clin Invest 2004;113:10931101. 8. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clini-
2. Dennis DT, Hayes EB. Epidemiology of Lyme borrelio- cal assessment, treatment, and prevention of lyme disease,
sis. In: Kahl O, Gray JS, Lane RS, Stanek G, eds. Lyme human granulocytic anaplasmosis, and babesiosis: clinical
borreliosis: biology, epidemiology and control. Oxford: practice guidelines by the Infectious Diseases Society of
CABI Publishing; 2002:251280. America. Clin Infect Dis 2006;43:10891134.
3. Lyme disease statistics. Centers for Disease Control Web 9. Klempner MS, Hu LT, Evans J, et al. Two controlled trials
site. Available at: http://www.cdc.gov/ncidod/dvbid/lyme/ of antibiotic treatment in patients with persistent symp-
ld_statistics.htm. toms and a history of Lyme disease. N Engl J Med
4. Bockenstedt LK. Lyme disease. In: Imboden JB, 2001;345:8592.
Hellmann DB, Stone JH, eds. Current diagnosis and 10. Cairns V, Godwin J. Post-Lyme borreliosis syndrome: a
treatment in rheumatology. 2nd ed. New York: McGraw- meta-analysis of reported symptoms. Int J Epidemiol
Hill. 2007:372382. 2005;34:13401345.
CHAPTER 14
D. Mycobacterial, Fungal,
and Parasitic Arthritis
STEVEN R. YTTERBERG, MD
Osteoarticular involvement occurs in about 5% of The syndrome of erythema nodosum leprosum,

patients with tuberculosis (TB), with estimated manifested as crops of subcutaneous nodules, fever,
percentage ranging from about 2% of all TB cases in and arthralgia or arthritis, occurs in patients with
the United States to more than 6% in developing lepromatous leprosy.
countries. Valley fever (or desert rheumatism) are terms used for
Potts disease (spinal tuberculosis) is the most an immune complexmediated syndrome associated
common form of osteoarticular infection with with cocciodiomycosis infection. This syndrome,
Mycobacterium tuberculosis. which is self-limited, is characterized by joint
Articular TB is usually due to reactivation of a complaints, fever, rash, erythema nodosum,
hematogenously seeded focus and need not be erythema multiforme, eosinophilia, and hilar
associated with active disease elsewhere; it can also adenopathy.
spread from adjacent osteomyelitis. Sporotrichosis, which usually presents as a
Lengthy delays in diagnosison the order of 3 to 4 painful erythematous nodule at the site of a skin
yearsare reported. wound. Inoculation of the organism Sporothrix
Poncets disease is a form of reactive arthritis schenckii into the skin through gardening or
occurring during active TB. landscape exposures to soil or plant material is the
Mycobacterium marinum infection is often associated mode of pathogenesis (the classic exposure is to a
with such aquatic exposures as fish tank water, fish rose thorn).
hook lacerations, skin punctures by fish spines, and
cuts from boat motor propellers.
Mycobacteria, fungi, and parasites are unusual causes MYCOBACTERIA

of musculoskeletal infections. Infections with these
organisms are seen with growing frequency in the Mycobacterium Tuberculosis
United States, however, for two major reasons: (1)
increasing numbers of persons who are immunosup- Infection with M. tuberculosis, usually acquired by inha-
pressed because of the presence of debilitating diseases, lation, begins as nonspecific pneumonitis, followed by
medical therapy, advanced age, or human immunodefi- lymphatic and hematogenous spread to upper lobes of
ciency virus (HIV) infection; and (2) greater immigra- the lung and other organs. In immunocompetent hosts,
tion from developing countries endemic for these infection is limited by cellular immunity. Reactivation
infections. These agents should be considered in patients may occur during a period of diminished host immunity,
with chronic monoarticular arthritis, but they may with multiplication of bacilli in dormant foci, and spread
present with other manifestations, including osteomy- via lymphatics or blood. Osteoarticular involvement
elitis, spondylitis, tendonitis, and erythema nodosum occurs in about 5% of patients with tuberculosis (TB),
(Table 14D-1). Definitive diagnosis usually depends on with estimated percentages ranging from about 2% of
identification of the responsible organism in pus, syno- all TB cases in the United States to more than 6% in
vial fluid, or tissue. Some agents, however, may cause developing countries (1). In children, bone infection
inflammatory disease without direct infection, resem- typically occurs via hematogenous seeding during
bling reactive arthritis. primary pulmonary infection. In contrast, in adults,
290
TABLE 14D-1. TYPICAL PRESENTATIONS OF Spinal Tuberculosis

OSTEOARTICULAR INFECTIONS CAUSED BY
MYCOBACTERIA AND FUNGI. Potts disease is the most common form of osteoarticu-
lar infection with M. tuberculosis (2). Thoracic verte-
Mycobacteria
brae are involved most frequently, followed by lumbar,
Tuberculosis Spondylitis (Potts disease) and, less commonly, cervical and sacral vertebrae. In
Monarticular arthritis of large weight- regions endemic for TB, spinal TB is primarily a disease
bearing joints of children and young adults. In the United States and 14
Osteomyelitis and dactylitis
Europe, most cases are in adults, occurring by reactiva-
Bursitis and tenosynovitis
Reactive arthritis (Poncets disease) tion of dormant foci (3).
Infection characteristically begins in the anterior
BCG treatment Migratory arthritis or arthralgia portion of the vertebral bodies, with subsequent disc
Atypical Arthritis or tendonitis of hand or wrist involvement, disc space narrowing, destruction of ver-
mycobacteria Multifocal bone, joint, or tendon infection tebral end plates, and collapse of the anterior portion
of the vertebral body, causing the characteristic gibbus
Leprosy Polyarthritis with erythema nodosum
leprosum
deformity (Figure 14D-1) (1,4). Infection often extends
Destructive arthritis of small bones and to adjoining discs or vertebrae, or to distant sites. Local-
joints of hands and feet ized soft tissue inflammation, for example, paraverte-
Neuropathic arthritis of wrists or ankles bral or psoas abscesses or sinus tracts may ensue,
Fungi
accompanied by neurologic injury.
Spinal TB can mimic vertebral osteomyelitis (spon-
Candidiasis Polyarthritis with osteomyelitis in dylodiskitis) caused by pyogenic bacteria, but usually
seriously ill infants has a longer duration of symptoms. Fever is less common
Monarticular arthritis of knee in seriously
ill patients past infancy
in Potts disease (5). Back pain and tenderness are
present in most patients. Neurologic manifestations
Coccidioidomycosis Polyarthritis with erythema nodosum from compression of spinal cord or roots occur in 12%
Monarticular arthritis of knee
to 50% of patients. Active pulmonary TB may be absent,
Osteomyelitis
but there is often evidence of past disease.
Sporotrichosis Monarticular arthritis of knee, wrist, or Radiographs typically show disc space narrowing
hand with vertebral collapse and paraspinous abscess (4).
Polyarthritis with disseminated cutaneous
Computerized tomography (CT) can define the bony
lesions
anatomy and paraspinal masses. Magnetic resonance
Blastomycosis Osteomyelitis imaging (MRI) can reveal the extent of inflammation
Spondylitis and impingement of neural structures. The differential
Monarticular arthritis of weight-bearing
diagnosis is broad, including other infections, neoplasm,
joints with lung and cutaneous lesions
and sarcoidosis; bacteriologic confirmation is required.
Cryptococcosis Osseous infection Diagnosis is best made by CT-guided or open biopsy.
Spondylitis Therapy is complicated by the increase in drug-
Rare monarticular arthritis
resistant TB. Six to nine months of combination chemo-
Histoplasmosis Polyarthritis with erythema nodosum therapy including rifampin is recommended (6). The role
of surgery is not clearly defined. Indications for surgery
ABBREVIATION: BCG, Bacillus Calmette-Guerin. have included the presence of motor deficits, spinal
deformity, a nondiagnostic needle biopsy, and noncom-
pliance with or lack of response to medical therapy.
However myelopathy and functional impairment can
bone infection usually occurs from either a quiescent resolve with chemotherapy alone (6). Although adjunc-
pulmonary focus or an extrapulmonary site. Tuberculin tive glucocorticoids are recommended for some extra-
skin tests are positive in most patients with osteoarti- pulmonary manifestations of TB, such treatment is not
cular TB, but chest radiographs are often normal. The recommended for musculoskeletal involvement (6).
definitive diagnosis is made by the demonstration of M.
tuberculosis in tissue or synovial fluid.
Tuberculous Arthritis
The classic presentation of osteoarticular infection is
spinal TB, or Potts disease. Infections at peripheral Tuberculous arthritis occurs mainly as monoarticular
sites, especially weight-bearing joints, tendons, bursae, arthritis affecting a hip or knee, but may involve other
or bones, also occur. Reactive arthritis (Poncets disease) joints (1,7,8). Most patients are middle-aged or older,
has been reported (see below). often with underlying medical disorders. The onset is
292 STEVEN R. YTTERBERG
A, B C
FIGURE 14D-1
Tuberculous spondylitis (Potts disease). (A) A lateral radiograph of the thoracic spine shows
destruction of adjacent vertebral endplates of the T10 and T11 vertebrae with disc space
narrowing and vertebral collapse, resulting in a gibbus deformity. (B) A lateral T2 weighted
magnetic resonance imgaing (MRI) scan of the thoracic spine in the same patient demonstrates
inflammation in the area of collapse and extension anteriorly. (C) An anterioposterior T2
weighted MRI image of the thoracic spine of the same patient demonstrates a multilocular soft
tissue mass extending above and below the area of vertebral collapse. (Courtesy of Dr. Timothy
Maus, Mayo Clinic, Rochester, MN.)
typically insidious. Joint pain and swelling are usually smears are positive in about 20% of cases, and culture
present, but signs of inflammation may be limited. is positive in up to 80%. The diagnosis of tuberculous
Lengthy delays in diagnosison the order of 3 to 4 arthritis is best made by histologic and microbiologic
yearsare reported. Articular TB is usually due to examination of synovium. Synovial cultures are positive
reactivation of a hematogenously seeded focus and in over 90% of cases. Histology may demonstrate case-
need not be associated with active disease elsewhere; it ating or noncaseating granulomas.
can also spread from adjacent osteomyelitis. Tubercu- Tuberculous arthritis usually responds to combina-
lous osteomyelitis can occur without joint involvement. tion chemotherapy (1,6,8). Surgery may be needed
In adults, a single lesion is most common, usually infor synovectomy, debridement, joint stabilization, or
volving the metaphysis of a long bone. In children, the removal of infected prostheses.
hands and feet may be involved, causing tuberculous
dactylitis. Poncets Disease
Characteristic radiographic findings of tuberculous
arthritis are juxta-articular osteoporosis, marginal ero- Poncets disease is a form of reactive arthritis occurring
sions, and gradual joint space narrowing (Phemisters during active TB (10). Polyarticular arthritis typically
triad). Similar changes can occur in other forms of infec- involves the hands and feet. Joint fluid and tissue
tion or rheumatoid arthritis. Compared with pyogenic samples are sterile. Symptoms abate with antitubercu-
joint infections, however, joint space is preserved early lous treatment.
in TB arthritis. Additional radiographic findings that
may be present include soft tissue swelling, subchondral Mycobacterium Bovis and Bacillus
cysts, bony sclerosis, periostitis, and calcifications.
The synovial fluid white blood cell count is generally
Calmette-Guerin
elevated, usually with a predominance of neutrophils Mycobacterium bovis infection is now rare, but muscu-
but occasionally of lymphocytes (9). The glucose in the loskeletal symptoms have been related to attenuated M.
synovial fluid is usually low. Synovial fluid acid-fast bovis as a component of Bacillus Calmette-Guerin
(BCG) (11). Intravesicular BCG instillation for bladder are resistant to antituberculous drugs to some degree.
cancer has been associated with fever, malaise, and Combination chemotherapy is required for most.
migratory polyarticular arthralgia or arthritis in a minor-
ity of patients. Symptoms worsen with repeated treat- Mycobacterium Leprae
ments and can be prevented by isoniazid. Considerable
debate exists within the literature about whether the Leprosy can cause several forms of arthritis (13,14).
inflammation is an immune-mediated response, or Erythema nodosum leprosum occurs in patients with
whether it represents a manifestation of active BCG lepromatous leprosy. Manifestations include crops of 14
infection. Some musculoskeletal complications of this subcutaneous nodules, fever, and arthralgias or arthri-
therapy, for example, monoarticular arthritis accompa- tis. The joint symptoms usually are mediated by an
nied by the isolation of M. bovis from joints, are clearly immunologic mechanism, but septic arthritis with M.
related to active infection. Reactive arthritis and leprae in synovial fluid occurs infrequently. Chronic
Sjgrens syndrome have also been reported. erosive arthritis of large and small joints resembling
rheumatoid arthritis, which improves with treatment of
the leprosy, is also described. In late stages of leprosy,
Atypical Mycobacteria Charcot joints may develop due to sensory neuropathy
Musculoskeletal involvement with atypical (nontuber- and repeated trauma.
culous) mycobacteria can mimic TB and include bone,
joint, tendon, and bursal infection. Infections are indo- FUNGI
lent, with insidious onset. The peak age incidence is 40
to 69 years, with a male-to-female ratio of 3:1 (12). The Most fungal musculoskeletal infections have an insidi-
majority of infections are caused by M. marinum, M. ous onset, an indolent course, and generally mild inflam-
kansasii, and M. avium complex. Various other myco- mation. Other than positive cultures, laboratory findings
bacterial species are identified in the remaining cases. are nonspecific.
A history of prior trauma, surgery, or intra-articular
injection is usual, but occasionally hematogenous
seeding occurs. Glucocorticoid use and underlying
Candida
arthritis are additional risk factors. M. marinum infec- Candida species are commensal organisms in humans.
tion is often associated with such aquatic exposures as They are the most common cause of opportunistic infec-
fish tank water, fish hook lacerations, skin punctures by tion among fungi, but rarely cause joint infection (15).
fish spines, and cuts from boat motor propellers. Fungi, most commonly Candida albicans, cause only
Any joint, bursa, or tendon sheath may be infected, 1% of infected prosthetic joints (16). Arthritis can arise
but the hands are most frequently involved, followed by from direct inoculation or hematogenous spread of
the wrists and knees. Polyarticular involvement occurs organisms (16,17). Intra-articular inoculation may occur
in less than one fourth of patients. The most common during joint surgery or arthrocentesis. Infection is typi-
presentation is joint swelling, followed by joint pain and cally indolent, monarticular, and chronic. Symptoms
limited motion. Carpal tunnel syndrome may arise from may not develop until 2 years after surgery. Loosening
synovitis involving the flexor tendons of the wrist. A of prosthetic components is seen radiographically.
slowly healing cutaneous wound may be present. Con- When related to arthrocentesis, infection is usually
stitutional symptoms, such as fever, chills, weight loss, caused by species other than C. albicans.
and malaise are infrequent. Hematogenous spread of C. albicans to joints can
Radiographs of affected joints are often normal. If occur during disseminated candidiasis. Disseminated
abnormalities are present, they are usually soft tissue candidiasis is associated with drug abuse; among non
swelling, effusion, bony erosion, or joint destruction. A drug abusers, it is seen in seriously ill patients receiving
pattern of preservation of the central joint space with intensive medical care, notably hospitalized infants. In
marginal erosion containing sclerotic borders of adja- infants, Candida arthritis is usually polyarticular and
cent bone has been described. associated with local osteomyelitis. Older patients with
Synovial fluid may be noninflammatory or markedly disseminated candidiasis typically have a serious illness
inflammatory. Pathology typically demonstrates nonca- treated with antibiotics, chemotherapy, and/or immu-
seating granulomas, but the absence of granulomas does nosuppressive agents. The clinical course may be acute,
not exclude the diagnosis. Diagnosis is made by demon- with marked synovitis, or milder and more indolent.
stration of mycobacteria in synovial fluid or tissue. Arthritis is monarticular in about 75% of cases. Septic
Negative cultures do not rule out infection, as these bursitis may occur.
organisms can be difficult to cultivate. The diagnosis is made by culture of synovial fluid or
Treatment of atypical mycobacterial joint infections tissue. Treatment with systemic or intra-articular ampho-
involves a combination of antituberculous therapy and tericin B has been successful. 5-Fluorocytosine may be
surgery. Most strains of nontuberculous mycobacteria helpful as an adjunct to amphotericin B, but should not
be used alone because of resistance. Ketoconazole and itis, or granulomatous myositis (19). Cutaneous findings
fluconazole have been successful in treating candidal are present in most patients with musculoskeletal
infection, but the Candida species causing infection must disease. The arthritis, usually chronic, may be monoar-
be identified, as some nonalbicans species are resistant ticular or polyarticular, involving the knees, wrists,
(18). Treatment of infected prosthetic joints usually small joints of the hands, ankles, and elbows. Dissemi-
requires removal of the prosthesis and debridement. nated sporotrichosis is rare, usually occurring in immu-
nosuppressed or systemically ill patients. Most patients
with disseminated sporotrichosis have bone or joint
Coccidioidomycosis involvement or both. Radiographs show lytic lesions
Coccidioidomycosis is caused by Coccidioides immitis, with minimal periostitis.
a soil fungus endemic in semi-arid areas of the south- Synovial pathology demonstrates chronic, noncaseat-
western United States, Central America, and South ing granulomatous inflammation. Diagnosis is based on
America. Osteoarticular involvement can occur during culture of organisms from joint fluid or tissue. Ampho-
primary or disseminated infection. tericin B with or without surgical debridement is often
Primary infection is often asymptomatic, but about curative, but prolonged treatment may be necessary
40% of patients develop self-limited symptoms that (15,18). Azole antifungal agents and intra-articular
range from flulike complaints to pneumonia. Valley amphotericin B have been reported to be effective.
fever or desert rheumatism are terms used for a self-
limited, immune complexmediated syndrome of
arthralgias or arthritis that can occur during primary
Blastomycosis
infection. Fever, rash, erythema nodosum, erythema Blastomyces dermatitidis is endemic in the Ohio and Mis-
multiforme, eosinophilia, and hilar adenopathy may sissippi River valleys and in the mid-Atlantic portion of
occur. The arthritis, usually polyarticular and migra- the United States. Primary pulmonary infection occurs
tory, resolves within 4 weeks without treatment (15). after inhalation of infectious spores; other sites are
Chronic pulmonary infection occurs in about 2% of seeded by hematogenous or lymphatic spread. Skeletal
patients and disseminated disease is seen in about 0.2%. infection occurs in up to 60% of patients (19). Osteomy-
Arthritis and osteomyelitis can occur during dissemi- elitis is most common, involving vertebrae, ribs, tibiae,
nated infection. The most frequent articular manifesta- and skull. Vertebral infection mimics TB. Arthritis is
tion is chronic arthritis of one knee. Nodular cutaneous typically monoarticular but can be polyarticular (15).
lesions and draining sinuses may be present (19). Radio- Patients with blastomycosis usually have constitutional
graphs show lytic lesions and bony erosions. Delay in symptoms and their arthritis tends to be acute in onset,
diagnosis averages over 4 years. Osteomyelitis occurs in characteristics that lead generally to quicker diagnoses
10% to 20% of patients with disseminated disease, most compared with other fungal causes of arthritis. A knee
often involving ends of long bones, the skull, vertebrae, is most frequently involved, followed by an ankle or
and ribs. elbow. Articular disease may arise from hematogenous
Synovial fluid samples rarely yield C. immitis. The spread or from extension from nearby osteomyelitis.
diagnosis is best made by demonstration of organisms Stains of synovial fluid may reveal organisms, but
in tissue. Treatment involves surgical drainage of pus, definitive diagnosis requires culture. Blastomycosis can
debridement, or synovectomy, and chemotherapy with be treated with amphotericin B, ketoconazole, or itra-
amphotericin B. Early infections have been treated with conazole. Surgery may be required for patients who fail
azole antifungal agents, but infection may recur after treatment with these drugs.
stopping therapy (15,18). Intra-articular amphotericin
B has been reported to be useful.
Cryptococcosis
Inhalation of Cryptococcus neoformans can cause clini-
Sporotrichosis cally silent or overt pulmonary infection. Hematoge-
Sporotrichosis, caused by Sporothrix schenckii, is usually nous spread may seed other organs, notably the central
limited to cutaneous disease, presenting as a painful nervous system. Most clinically apparent disseminated
erythematous nodule at the site of a skin wound. Inocu- cases occur in immunosuppressed patients. Osseous
lation of the organism into the skin through gardening infection occurs in 5% to 10% with dissemination,
or landscape exposures to soil or plant material is the involving the long bones, vertebrae, ribs, tarsals, and
mode of pathogenesis (the classic exposure is to a rose carpals with a subacute or chronic course (19). Verte-
thorn). Infection is spread by lymphatic drainage or bral infection may mimic TB. Radiographs show lytic
local extension. lesions with little periosteal reaction. Cryptococcal
Extracutaneous disease primarily affects musculo- arthritis is infrequent, usually due to direct extension of
skeletal structures, causing arthritis, tenosynovitis, oste- adjacent osteomyelitis (15,19). The diagnosis is made by
demonstration of organisms in synovial fluid or tissue. usually benign and often resolve with treatment of the
Treatment is usually with amphotericin B, with or underlying infestation. Arthralgia is more common than
without 5-fluorocytosine. Fluconazole may be sufficient arthritis, but the frequency of joint involvement is not
for immunocompetent hosts. clearly known (20).
Among protozoa, Giardia lamblia has been reported
Histoplasmosis as a cause of acute-onset, mild, recurrent seronegative
arthritis, similar to reactive arthritis. Other protozoa
Histoplasmosis, caused by Histoplasma capsulatum, is
associated with arthralgia and arthritis include Ent- 14
endemic in the Mississippi and Ohio River valleys of the
amoeba histolytica, Trichomonas vaginalis, and Toxo-
United States. Most infections are subclinical and self-
plasma gondii.
limited. During primary infection, acute self-limited
Several helminths have been associated with joint
migratory polyarthritis or arthralgias may occur, with or
symptoms (20). Dracunculosis can produce arthralgia,
without erythema nodosum or erythema multiforme.
as well as acute or chronic monarticular arthritis due to
Arthritis in these cases is immunologically mediated
joint invasion or death of the worm in situ near a joint.
(15,19). Dissemination occurs in less than 0.1%, usually
Among patients with filariasis, monoarticular arthritis,
in elderly or immunosuppressed patients (19). Arthritis,
often involving knee or ankle may occur. Reactive
osteomyelitis, tenosynovitis, and carpal tunnel syn-
arthritis and sacroiliitis have been described with Stron-
drome are rarely described in disseminated histoplas-
gyloides stercoralis and schistosomiasis. Echinococcus
mosis. Diagnosis is based on the culture of H. capsulatum
granulosus, which causes hydatid cysts, can lead to cystic
from tissue or histologic demonstration of organisms.
infection of bone and pathologic fractures.
Successful treatment has been accomplished with
amphotericin B, itraconazole, and fluconazole, but sur-
gical debridement may be required. REFERENCES
Other Fungal and Related 1. Leonard MKJ, Blumberg HM. Musculoskeletal tubercu-
Organisms losis. In: Schlossberg D, ed. Tuberculosis & nontuber-
culous mycobacterial infections. 5th ed. New York:
A variety of other fungi have been reported rarely as McGraw-Hill; 2006:242263.
causes of infectious arthritis (19). Invasive Aspergillus 2. Martini M, Ouahes M. Bone and joint tuberculosis: a
infection can involve a variety of organs, most often the review of 652 cases. Orthopedics 1988;11:861866.
lungs and sinuses. Direct extension of infection can 3. Cormican L, Hammal R, Messenger J, Milburn HJ.
result in osteomyelitis of vertebrae, ribs, or skull. Ver- Current difficulties in the diagnosis and management of
tebral involvement can mimic Potts disease. Articular spinal tuberculosis. Postgrad Med J 2006;82:4651.
4. Ridley N, Shaikh MI, Remedios D, Mitchell R. Radiology
involvement is rare (15,19). Paracoccidioidomycosis
of skeletal tuberculosis. Orthopedics 1998;21:12131220.
is caused by Paracoccidioides brasiliensis, endemic to 5. Perronne C, Saba J, Behloul Z, et al. Pyogenic and tuber-
South America. The organism may disseminate and culous spondylodiskitis (vertebral osteomyelitis) in 80
cause osteomyelitis with extension to joints (14). adult patients. Clin Infect Dis 1994;19:746750.
Maduromycosis, or mycetoma, is a chronic infection 6. Blumberg HM, Burman WJ, Chaisson RE, et al. Ameri-
of skin, subcutaneous tissue, and bone, most often can Thoracic Society/Centers for Disease Control and
involving the foot (14). Maduromycosis is caused by a Prevention/Infectious Diseases Society of America: treat-
variety of organisms, including true fungi and actinomy- ment of tuberculosis. Am J Respir Crit Care Med 2003;
ces (which are actually bacteria). Infection begins with 167:603662.
subcutaneous inoculation of organisms and local exten- 7. Garrido G, Gomez-Reino JJ, Fernandez-Dapica P,
sion, with eventual development of granule-draining Palenque E, Prieto S. A review of peripheral tuberculous
arthritis. Semin Arthritis Rheum 1988;18:142149.
sinus tracts.
8. Malaviya AN, Kotwal PP. Arthritis associated with tuber-
culosis. Best Pract Res Clin Rheumatol 2003;17:319343.
PARASITES 9. Allali F, Mahfoud-Filali S, Hajjaj-Hassouni N. Lympho-
cytic joint fluid in tuberculous arthritis. A review of 30
Parasites are organisms that live on or in a host organ- cases. Joint Bone Spine 2005;72:31921.
10. Dall L, Long L, Stanford J. Poncets disease: tuberculous
ism and derive their nourishment from the host. Some
rheumatism. Rev Infect Dis 1989;11:105107.
parasites may persist in the host for extended periods. 11. Tinazzi E, Ficarra V, Simeoni S, Artibani W, Lunardi C.
Parasites can be grouped as protozoa, helminths, and Reactive arthritis following BCG immunotherapy for
arthropods. Immune responses induced by parasitic urinary bladder carcinoma: a systematic review. Rheuma-
infections can cause tissue injury and musculoskeletal tol Int 2006;26:481488.
manifestations, including hypersensitivity reactions and 12. Yangco BC, Espinoza CG, Germain BF. Nontuberculous
immune complex deposition. Such manifestations are mycobacterial joint infections. In: Espinosa L, Goldenberg
D, Arnett F, Alarcon G, eds. Infections in the rheumatic 17. Cuende E, Barbadillo C, Isasi C, Trujillo A, Andreu
diseases. Orlando: Grune & Stratton; 1988:139157. JL. Candida arthritis in adult patients who are not
13. Gibson T, Ahsan Q, Hussein K. Arthritis of leprosy. Br J intravenous drug addicts: report of three cases and review
Rheumatol 1994;33:963966. of the literature. Semin Arthritis Rheum 1993;22:224
14. McGill PE. Geographically specific infections and arthri- 241.
tis, including rheumatic syndromes associated with certain 18. Perez-Gomez A, Prieto A, Torresano M, et al. Role of the
fungi and parasites, Brucella species and Mycobacterium new azoles in the treatment of fungal osteoarticular infec-
leprae. Best Pract Res Clin Rheumatol 2003;17:289307. tions. Semin Arthritis Rheum 1998;27:226244.
15. Kohli R, Hadley S. Fungal arthritis and osteomyelitis. 19. Cuellar ML, Silveira LH, Citera G, Cabrera GE, Valle R.
Infect Dis Clin North Am 2005;19:831851. Other fungal arthritides. Rheum Dis Clin North Am
16. Silveira LH, Cuellar ML, Citera G, Cabrera GE, Scopeli- 1993;19:439455.
tis E, Espinoza LR. Candida arthritis. Rheum Dis Clin 20. Peng SL. Rheumatic manifestations of parasitic diseases.
North Am 1993;19:427437. Semin Arthritis Rheum 2002;31:228247.
CHAPTER 14
E. Rheumatic Fever
STANFORD SHULMAN, MD
PREETI JAGGI, MD
Acute rheumatic fever (ARF) is most frequent among needed before a host develops the immune mecha-
5 to 15 year olds, with a declining incidence in nisms required to develop ARF.
adults. With the exception of chorea, the latent period
It is extremely rare in children under age 3, prompt- between the inciting GAS infection and symptoms of
ing some speculation that more than one group A ARF is approximately 3 weeks.
streptococcal (GAS) respiratory tract infection is
EPIDEMIOLOGY Major Clinical Criteria

Arthritis occurs in approximately 75% of patients with
The global prevalence of ARF has been estimated to
ARF. The arthritis is characteristically migratory, which
be approximately 15.6 million cases, with 282,000 new
is in contrast to poststreptococcal reactive arthritis. Left
cases per year and 233,000 deaths (mostly from chronic
untreated, the affected joint becomes inflamed and
rheumatic heart disease) per year (1). It is estimated
then resolves spontaneously, but the migrating pattern
that the annual incidence of ARF among children aged
of polyarthritis persists for 1 to 4 weeks. The arthritis
5 to 14 years is highest in sub-Saharan Africa (5.7 cases
mainly affects larger joints, including knees, ankles,
per 1000), the Pacific and indigenous populations of
wrists, and elbows, but can also less frequently affect
Australia and New Zealand (2.2 cases per 1000), and
the smaller joints of the hands and feet; the axial skele-
south central Asia (2.2 cases per 1000) (1). Rates in the
ton is rarely involved. Inflamed joints are often red, hot,
United States and most of Western Europe are much
swollen, and exquisitely tender, and classically even
lower, <1 case per 100,000.
minimal contact with the affected joint can cause exqui-
site pain. Another characteristic strongly suggestive of
the arthritis of ARF is a dramatic response to salicy-
CLINICAL FINDINGS lates, so much so that a lack of response to salicylate
therapy within 48 hours should prompt the clinician to
Diagnostic Criteria doubt the diagnosis of ARF and to explore other
The diagnostic criteria for ARF are based on T. Duckett diagnoses.
Jones proposed guidelines, derived from clinical obser- Carditis occurs in approximately 50% to 60% of
vation of hundreds of patients with ARF. The guide- ARF cases and accounts for significant morbidity and
lines were originally proposed in 1944 and have been even mortality. When rheumatic fever affects the heart,
revised several times, the last being in 1992 (2). The it usually involves the endocardium, myocardium, and
current Jones criteria are shown in Table 14E-1, and it pericardium to varying degrees. Endocarditis is the hall-
is of note that they apply only to first attacks of ARF. mark, and this is manifested by mitral and/or aortic
Exceptions to these criteria include patients presenting valvulitis; the tricuspid and pulmonary valves are rarely
with pure chorea or with indolent carditis; in these affected. In resultant chronic rheumatic heart disease,
patients the antistreptococcal antibody levels usually valvular regurgitation can evolve to valvular stenosis.
have returned to normal by the time the patient pres- The revised Jones criteria for ARF require auscultation
ents, and no other rheumatic symptoms may be of a new valvular murmur in order to meet the criterion
present. of carditis; echocardiographic findings of valvular
297
298 STANFORD SHULMAN AND PREETI JAGGI
TABLE 14E-1. MODIFIED JONES CRITERIAa FOR Subcutaneous nodules occur in fewer than 1%
DIAGNOSIS OF ACUTE RHEUMATIC FEVER. of cases of ARF, most often in those with severe
carditis. The nodules are firm, nontender, and are
Major criteria
Carditis usually less than 2 cm in diameter. They are typically
Polyarthritis located over bony prominences or tendon sheaths.
Chorea Nodules usually resolve spontaneously without perma-
Erythema marginatum nent sequelae.
Subcutaneous nodules
Minor criteria
Fever
Minor Clinical Criteria
Arthralgia The fever in ARF is usually greater than 39.0C. It is
Elevated acute phase reactant (C-reactive protein or
usually present at the onset of illness and resolves over
erythrocyte sedimentation rate)
Prolonged PR interval on electrocardiogram several weeks, even without treatment. Arthralgia may
fulfill a minor criterion in the revised Jones criteria, but
Supporting evidence of antecedent Group A streptococcal only in the absence of polyarthritis. Arthralgia may be
infection
Positive throat culture or rapid antigen test
migratory, and pain may be severe, even without objec-
Elevated or rising streptococcal antibody titer tive signs of arthritis.
a
Diagnosis requires two major criteria or one major and two minor criteria,
plus supporting evidence of antecedent group A streptococcal infection. DIAGNOSTIC TESTS
Approximately one third of patients presenting with
ARF have no history of a recent symptomatic pharyn-
geal infection, and, therefore, it is necessary to find
regurgitation without a murmur do not fulfill this crite- laboratory evidence of a recent streptococcal infection.
rion. Myocarditis manifests as tachycardia that is dis- This can be done either by (a) obtaining history of a
proportionate to the degree of fever and is best assessed throat culture or a GAS rapid antigen test positive for
during sleep. Pericarditis is the least common finding in GAS from a throat swab, or by (b) documenting an
rheumatic carditis. It usually manifests as a pericardial elevated or rising serum antistreptococcal antibody
effusion and/or friction rub. Myocarditis and/or pericar- titer. It is important for the clinician to recognize that
ditis in the absence of valvular involvement is very normal values of antistreptococcal antibodies in the
unlikely to be due to ARF, and in this circumstance, general population vary by patient age, geographic loca-
other diagnoses should be explored. tion, and season of the year, with highest values observed
Sydenham chorea (St. Vitus dance) is the manifesta- in 10 to 12 year olds and at the end of the streptococcal
tion of central nervous system involvement in ARF and season (late spring) (4). The use of normal ranges estab-
occurs in 10% to 15% of patients. It is usually a later lished for adults for interpretation of pediatric values is
manifestation of ARF, occurring several months after misleading.
the inciting streptococcal infection. Cross-reactive The antistreptolysin O (ASO) titer is the most com-
immune responses that affect the basal ganglia neurons monly used streptococcal antibody test to establish a
are thought to be the etiology. The characteristic fea- recent streptococcal infection. An ASO titer of 240
tures of chorea are purposeless involuntary movements Todd units or higher in adults or in excess of 320 Todd
(but not stereotyped like a tic), incoordination, diffi- units in children is considered modestly elevated. ASO
culty with handwriting, facial grimacing, and emotional titers above 500 Todd units are uncommon in healthy
lability. In one recent pediatric series, hemichorea was individuals and therefore more reliably serve as evi-
seen in 29% of patients (3). Chorea is a self-limited dence of a recent streptococcal infection (4).
illness, and full recovery takes several months. Rarely, Because ASO titers can be normal in approximately
symptoms can occur over years and are exacerbated by 20% of ARF patients, other streptococcal antibody
stress, pregnancy, oral contraceptives, and intercurrent tests are useful to help establish a recent GAS infection;
illnesses. these include antideoxyribonuclease B (anti-DNase B),
Erythema marginatum occurs in fewer than 2% antistreptokinase, and antihyaluronidase. If all anti-
of patients. It is characteristically an erythematous, streptococcal antibody titers are normal on initial pre-
serpiginous macular rash with pale central clearing. sentation and ARF remains a clinical concern, it is
The rash usually occurs on the trunk and extremities highly advisable to repeat these tests a few weeks later
and characteristically spares the face. The rash waxes to see if the antibody titers have risen because a single
and wanes, may be transient and is exacerbated by low antistreptococcal antibody titer does not exclude
warmth. the diagnosis of ARF.
SPECIAL TESTS molecular mimicry (Figure 14E-1). Only a small per-

centage of individuals with untreated GAS pharyngitis
Synovial fluid analysis of the arthritis of ARF reveals a go on to develop ARF. ARF is not considered a sequela
sterile inflammatory fluid typically with 10,000 to 100,000 of cutaneous GAS infection (5). Recent evidence sup-
white blood cells/mm3 (with a predominance of neutro- ports the conclusion that ARF has declined markedly
phils), normal glucose level, and a protein concentra- in the United States over the past four decades because
tion of approximately 4g/dL. of a decline in rheumatogenic types of GAS causing
pharyngitis (6). 14
The nonclinical (laboratory) minor criteria of the
revised Jones criteria include an increased PR interval Host genetic factors appear to influence the suscep-
on electrocardiogram (which does not per se indicate tibility to ARF. Observational studies in the 19th century
carditis) and elevated acute phase reactants (C-reactive recognized familial tendencies to develop ARF, and in
protein and/or erythrocyte sedimentation rate). Acute the early 1940s, studies showed familial clustering of the
phase reactants are almost always greatly elevated in disease, with greatest risk occurring in children if both
ARF patients presenting with polyarthritis or acute car- parents had rheumatic heart disease (7). Genetic sus-
ditis, but are often normal in patients presenting with ceptibility to develop ARF has been characterized as
chorea alone. autosomal recessive or autosomal dominant with vari-
able penetrance and has been linked with human leu-
kocyte antigen (HLA) types. Significant increases in the
DIFFERENTIAL DIAGNOSIS frequency of DRB1*0701, DR6, and DQB1*0201 confer
susceptibility to ARF in several international studies
Other than ARF, the most frequently encountered dis- (8). However, monozygotic twins usually do not both
eases in the differential for acute polyarticular arthritis develop ARF, clearly indicating that there are also
include juvenile rheumatoid arthritis, systemic lupus important environmental factors involved in the patho-
erythematosus (SLE), serum sickness, and gonococcal genesis of the disease (9).
arthritis. Choreiform movements can occur in SLE,
neoplasms involving the basal ganglia, Wilsons disease,
and Huntingtons disease. Chorea can occasionally be TREATMENT
encountered in pregnancy (chorea gravidarum).
Treatment of ARF requires anti-inflammatory treat-
PATHOGENESIS ment, prevention of future streptococcal infections, and
symptomatic care (Table 14E-2). Upon diagnosis, a
The pathogenesis of ARF is not completely understood, dose of intramuscular benzathine penicillin or 10 days
but it appears to involve immune responses to GAS of oral penicillin or erythromycin (for penicillin-allergic
antigens that then cross-react with human tissue through patients) is recommended regardless of streptococcal
FIGURE 14E-1
Pathogenesis of acute rheumatic fever

(proposed).
TABLE 14E-2. TREATMENT OF ACUTE RHEUMATIC FEVER.

CONDITION ANTI-INFLAMMATORY TREATMENT
Mild or no carditis Aspirin 50100 mg/kg/day in four divided doses for 24 weeks, then taper over 46 weeks
Moderate or severe carditis Prednisone 2 mg/kg/day in two doses for 24 weeks, then taper over about 4 weeks, with
addition of aspirin when prednisone is 0.5 mg/kg/day.
Primary antistreptococcal therapy 1.2 million units of benzathine penicillin G IM or oral penicillin or erythromycin for 10 days
Prophylaxis of GAS infection 1.2 million units benzathine penicillin G IM q.i.d. 4 weeks or sulfadiazine 500 mg po q.i.d.
( 27 kg) or 1.0 g po q.i.d. ( 27 kg) or penicillin V 250 mg po b.i.d
Medications to control cardiac Diuretic, angiotension-converting enzyme inhibitor, and/or cautious use of digoxin
symptoms (if needed)
Medications to control chorea (if needed) Haloperidol or phenobarbitol
Infective endocarditis prophylaxis As recommended by the American Heart Association
throat culture results. Anti-inflammatory treatment penicillin and sulfa allergic. The recommendations for
includes oral salicylates (50100 mg/kg/day) in four daily the duration of secondary prophylaxis of streptococcal
doses. This is continued for 2 to 4 weeks, then is gradu- infection are based upon likelihood of recurrence and
ally tapered over 4 to 6 weeks. Corticosteroid treatment years since last ARF episode. The current American
should be reserved for those patients with congestive Heart Association recommendations for duration of
heart failure or at least moderate cardiomegaly on chest antimicrobial prophylaxis of ARF are listed in Table
radiograph. Corticosteroids are tapered slowly over 14E-3 (10). In addition, patients with rheumatic heart
about 6 weeks; during the taper of corticosteroids, salic- disease should receive infective endocarditis pro-
ylates are added. Supportive care for cardiac dysfunc- phylaxis as recommended by the American Heart
tion includes diuretics, antihypertensives, or digoxin. Association.
For patients with Sydenham chorea, haloperidol or phe-
nobarbital may be of some benefit.
Prevention of GAS infection is of utmost importance PROGNOSIS
to prevent recurrent attacks of ARF that can be associ-
ated with increased severity of cardiac disease or with The only long-term manifestation of ARF is that of
development of cardiac disease not previously present. rheumatic heart disease, and the prognosis of patients
All patients with ARF should receive antimicrobial pro- with ARF is generally attributable to the degree of
phylaxis with intramuscular benzathine penicillin G cardiac involvement, to consequences of infective endo-
every 4 weeks or twice daily oral penicillin, or once daily carditis, and to the risk of recurrent ARF secondary to
sulfadiazine if penicillin allergic, or erythromycin if recurrence of GAS pharyngitis. Patients presenting
only with chorea or polyarthritis may develop rheu-
matic heart disease if they develop recurrent ARF,
thus emphasizing the importance of prophylactic
TABLE 14E-3. RECOMMENDATIONS OF DURATION OF
ANTIMICROBIAL PROPHYLAXIS IN PATIENTS WITH antibiotics.
ACUTE RHEUMATIC FEVER.
CONDITION TREATMENT DURATION
POSTSTREPTOCOCCAL
Patients with rheumatic At least 10 years since last episode REACTIVE ARTHRITIS
fever with carditis and and at least until age 40,
residual heart disease sometimes lifelong prophylaxis
General Considerations
Rheumatic fever with 10 years or well into adulthood,
carditis but no residual whichever is longer Those patients who do not fulfill the diagnostic criteria
heart disease (no valvar for ARF but who develop arthritis after a streptococcal
disease) infection are deemed to have poststreptococcal reactive
arthritis (PSRA). This arthritis is predominantly associ-
Rheumatic fever without 5 years or until age 21 years,
carditis whichever is longer ated with GAS infections but has also been reported
after infection with group C and G streptococci. There
appears to be a bimodal age distribution of PSRA, with TABLE 14E-4. PROPOSED DIAGNOSTIC CRITERIA FOR
peak incidence at ages 8 to 14 years and 21 to 37 years. DIAGNOSIS OF POSTSTREPTOCOCCAL REACTIVE
In Caucasians, PSRA is associated with the class II ARTHRITIS.
HLA antigen DRB1*01 (11,12). A. Characteristics of arthritis
1. Acute in onset, symmetric or asymmetric, usually
nonmigratory
Clinical Findings 2. Persistent or recurrent symptoms
The arthritis of PSRA is generally acute and nonmigra- 3. Lack of a dramatic response to nonsteroidal anti- 14
inflammatory drugs
tory and predominantly affects the large joints of the
lower limbs, occasionally causing tenosynovitis. It may B. Evidence of an antecedent group A streptococcal infection
be mono- or polyarticular, and symmetrical or asym- (previous positive throat culture or rapid antigen test positive
for GAS, or elevated or rising antistreptolysin O and/or anti-
metrical. The axial skeleton is affected in about 20% of
DNase B titers)
patients. During the antecedent GAS infection, fever
with or without a scarlatiniform rash may be present, C. Does not fill the modified Jones criteria for acute rheumatic
but they are not usually when arthritis has manifested. fever
The interval between the inciting streptococcal infec-
tion and the onset of arthritis (onset usually 314 days
after infection) is generally shorter than that of ARF. that prophylaxis should be discontinued after 1 to 2
The symptoms of PSRA resolve slowly over a few weeks years if no evidence of carditis is found. Penicillin is
to several months (mean of 2 months). Characteristi- recommended as first-line therapy, and erythromycin is
cally, PSRA patients have a gradual response to non- appropriate for penicillin-allergic patients. Some experts
steriodal anti-inflammatory drug (NSAID) therapy in suggest that the same prophylaxis recommendations for
contrast to ARF patients, who typically have a dramatic ARF patients also should apply to those with PSRA
and prompt response to NSAIDs (11,13,14). Recur- because the time of onset of documented carditis can
rences have been reported after subsequent streptococ- be widely variable, but this recommendation has not
cal pharyngitis episodes. The most concerning possible been endorsed by the AHA or other organizations.
sequela is that of late-onset carditis; in the original
description of PSRA, this occurred in 4 of 13 (31%)
patients with PSRA who did not meet the criteria for REFERENCES
and did not have a clinical history of ARF; these patients
developed evidence of cardiac disease 1 to 18 years after 1. Carapetis JR, Steer AC, Mulholland EK, Weber M. The
their original diagnosis. Substantially lower rates of global burden of group A streptococcal diseases. Lancet
development of late carditis have been observed in Infect Dis 2005;5:685694.
more recent series. Other possible extra-articular mani- 2. Guidelines for the diagnosis of rheumatic fever. Jones
festations of PSRA include glomerulonephritis (which Criteria, 1992 update. Special Writing Group of the Com-
is very rare with ARF) and uveitis in the minority of mittee on Rheumatic Fever, Endocarditis, and Kawasaki
patients. Disease of the Council on Cardiovascular Disease in the
Young of the American Heart Association. JAMA
1992;268:20692073.
Diagnostic Criteria 3. Zomorrodi A, Wald ER. Sydenhams chorea in western
Pennsylvania. Pediatrics 2006;117:e675e679.
The diagnostic criteria for PSRA are not clearly defined, 4. Kaplan EL, Rothermel CD, Johnson DR. Antistreptoly-
but the criteria proposed by Ayoub and colleagues (15) sin O and anti-deoxyribonuclease B titers: normal values
are detailed in Table 14E-4. for children ages 2 to 12 in the United States. Pediatrics
1998;101:8688.
5. Stollerman GH. Rheumatic fever in the 21st century. Clin
Treatment Infect Dis 2001;33:806814.
Patients with PSRA generally respond much less dra- 6. Shulman ST, Stollerman G, Beall B, Dale JB, Tanz RR.
matically to aspirin or other NSAIDs than do those with Temporal changes in streptococcal M protein types and
classic ARF, but these agents can be used to treat this the near-disappearance of acute rheumatic fever in the
United States. Clin Infect Dis 2006;42:441447.
form of arthritis. Some experts recommend both a base-
7. Wilson M, Schweitzer, MG, Lubschez R. The familial
line echocardiogram and a follow-up echocardiogram 1 epidemiology of rheumatic fever. J Pediatr 1943;22:
to 2 years later because of the concern of occult carditis. 461491.
The American Heart Association (AHA) currently rec- 8. Guedez Y, Kotby A, El-Demellawy M, et al. HLA class
ommends that patients with PSRA should be followed II associations with rheumatic heart disease are more
while receiving antistreptococcal prophylaxis for 1 to 2 evident and consistent among clinically homogeneous
years to assess for evidence of cardiac involvement, and patients. Circulation 1999;99:27842790.
9. Taranta A TS, Metrakos JD. Rheumatic fever in mono- 12. Ahmed S, Ayoub EM, Scornik JC, Wang CY, She JX.
zyogotic and dizygotic twins. Circulation 1959;20:778792. Poststreptococcal reactive arthritis: clinical characteristics
10. Dajani A, Taubert K, Ferrieri P, Peter G, Shulman S. and association with HLA-DR alleles. Arthritis Rheum
Treatment of acute streptococcal pharyngitis and preven- 1998;41:10961102.
tion of rheumatic fever: a statement for health profession- 13. Herold BC, Shulman ST. Poststreptococcal arthritis.
als. Committee on Rheumatic Fever, Endocarditis, and Pediatr Infect Dis J 1988;7:681682.
Kawasaki Disease of the Council on Cardiovascular 14. Shulman ST, Ayoub EM. Poststreptococcal reactive
Disease in the Young, the American Heart Association. arthritis. Curr Opin Rheumatol 2002;14:562565.
Pediatrics 1995;96:758764. 15. Ayoub EM, Ahmed S. Update on complications of group
11. Mackie SL, Keat A. Poststreptococcal reactive arthritis: A streptococcal infections. Curr Probl Pediatr 1997;27:
what is it and how do we know? Rheumatology (Oxford) 90101.
2004;43:949954.
CHAPTER 15
Systemic Lupus Erythematosus

A. Clinical and Laboratory Features
JILL P. BUYON, MD
Systemic lupus erythematosus (SLE) is a common of autoantibodies may help to predict clinical
autoimmune disorder occurring predominantly in manifestations. Antidouble-stranded DNA
women during reproductive years and having strong antibodies are useful, along with changes in
minority representation. complement levels, for predicting disease flares
The hallmark of SLE is its diversity of presentation in some patients.
with accumulation of manifestations over time and Special attention during pregnancy may help
undulating disease course. to avoid disease flares and adverse fetal
Essentially any organ system can be affected by SLE outcome.
with constitutional symptoms, mucocutaneous, Many drugs can trigger a lupuslike illness associated
musculoskeletal, renal, and central nervous system with autoantibodies, but typically with fewer disease
(CNS) being most common. manifestations and temporal association with the
Presence of autoantibodies, the unifying manifesta- offending agent.
tion of SLE, is useful for diagnosis and the pattern
In sharp distinction to organ-specific autoimmune dis- applied in a practice setting, or reserved only for formal
eases such as thyroiditis, diabetes, or myasthenia gravis, academic studies, they do facilitate a methodologic
systemic lupus erythematosus (SLE) is a constellation approach to evaluate a patient.
of signs and symptoms classified as one nosologic entity. As one reviews the clinical descriptions, it will become
Indeed, it is the diversity of presentation, accumulation apparent that not only is just about every bodily part
of manifestations over time, and undulating disease potentially targeted by lupus, but in each organ differ-
course that challenge the most astute of clinicians. With ent structural components can be involved with varying
rare exception, the unifying laboratory abnormality is frequencies, as exemplified in evaluating a large Cana-
the presence of circulating antinuclear antibodies dian cohort (Figure 15A-1) (3). In addition, nonspecific
(ANA). Acknowledging the complexity of this disease, constitutional features of SLE, some of which dominate
its broad differential diagnosis, and the need to develop the clinical picture, are fatigue, fever, and weight loss.
better and more specific therapies, the American Demographic characteristics, such as overwhelming
College of Rheumatology (ACR) has designated 11 female predominance (approximately 9:1), typical onset
diagnostic criteria (presented in Table 15A-1) (1,2). during the reproductive years, and strong minority rep-
These criteria reflect the major clinical features of the resentation, are helpful clues to diagnosis. Factors to
disease (mucocutaneous, articular, serosal, renal, neu- consider that might precipitate the onset or exacerba-
rologic) and incorporate the associated laboratory find- tion of systemic disease or isolated organ involvement
ings (hematologic and immunologic). The presence of include recent sun exposure, emotional stress, infection,
four or more criteria is required for diagnosis. They certain drugs, such as sulfonamides, and surgery.
need not necessarily present simultaneously: a single Happily, over 90% of SLE patients survive at least 2
criterion such as arthritis or thrombocytopenia may years after diagnosis compared to about 50% three
recur over months or years before the diagnosis can be decades ago (4). Recent data support an 80% to 90%
confirmed by the appearance of additional features. survival at 10 years (5). A bimodal mortality curve is
While there is incomplete agreement among rheuma- prevalent in SLE (6,7). Patients who die within 5 years
tologists as to whether these criteria need to be strictly of diagnosis usually have active disease requiring high
303
304 JILL P. BUYON
TABLE 15A-1. THE REVISED CRITERIA FOR THE DIAGNOSIS OF SYSTEMIC LUPUS
ERYTHEMATOSUSa
1. Malar rash Fixed erythema, flat or raised, over the malar eminence, tending to
spare the nasolabial folds
2. Discoid rash Erythematous raised patches with adherent keratotic scaling and
follicular plugging; atrophic scarring may occur in older lesions
3. Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient

history or physician observation
4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a

physician
5. Arthritis Nonerosive arthritis involving two or more peripheral joints,

characterized by tenderness, swelling or effusion
6. Serositis (a) Pleuritis; convincing history of pleuritic pain or rub heard by

physician or evidence of pleural effusion
OR
(b) Pericarditis; documented by electrocardiogram or rub or
evidence of pericardial effusion
7. Renal disorder (a) Persistent proteinuria > 500 mg per day or > 3+ if quantitation
not performed
OR
(b) Cellular casts: may be red cell, hemoglobin, granular, tubular or
mixed
8. Neurologic disorder (a) Seizures: in the absence of offending drugs or known meta-
bolic derangement; e.g., uremia, ketoacidosis, or electrolyte
imbalance
OR
(b) Psychosis: in the absence of offending drugs or known
metabolic derangement; e.g., uremia, ketoacidosis, or electro-
lyte imbalance
9. Hematologic disorder (a) Hemolytic anemia: with reticulocytosis

OR
(b) Leukopenia: < 4000/mm3 total
OR
(c) Lymphopenia: < 1500/mm3 on two or more occasions
OR
(d) Thrombocytopenia: < 100,000/mm3 in the absence of
offending drugs
10. Immunologic disorderb (a) Anti-DNA: antibody to native DNA in abnormal titer
OR
(b) Anti-SM: presence of antibody to SM nuclear antigen
OR
(c) Positive finding of antiphospholipid antibodies based on (1) an
abnormal serum level of IgG or IgM anticardiolipin antibodies,
(2) a positive test result for lupus anticoagulant using a
standard method, or (3) a false-positive serologic test for
syphilis known to be positive for at least 6 months and
confirmed by Treponema pallidum immobilization or fluorescent
treponemal antibody absorption test
11. ANA Abnormal titer of ANA by immunofluorescence or equivalent assay

at any point in time, in the absence of drugs known to be associ-
ated with drug-induced lupus syndrome
SOURCE: From Tan EM, Cohen AS, Fries JF, et al. (1), by permission of Arthritis Rheum.
a
This classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person must
have SLE if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation
(1).
b
The modifications to criterion number 10 were made in 1997 (2).
C H A P T E R 1 5 S Y S T E M I C L U P U S E R Y T H E M A T O S U S 3 05
FIGURE 15A-1
Frequency of manifestations at onset and

at any time during the course of systemic
lupus erythematosus, in a large Canadian
cohort (3). The frequency at onset is
based on 376 patients diagnosed at
Lupus Clinic (University of Toronto), and
frequency at point is for 750 patients
registered prior to July 1995. Estimates of
the frequency of each manifestation differ
in some studies; therefore, in the body of
the text of this chapter, frequencies are
reported that may be at variance with the
above cohort. The reader is referred to 15
two major books on systemic lupus
erythematosus (50,51).
doses of corticosteroids, intense immunosuppression, acutebased strictly on clinical appearance and dura-
and concomitant infections. In contrast, late deaths are tion, without considering the extracutaneous manifesta-
often the result of cardiovascular disease. This latter tions or laboratory features of the overall disease.
point has received major attention at both the bench The most common form of chronic disease is discoid
and bedside. While SLE is not considered curable, lupus [DLE; 15%30%; Figure 15A-2(A)], which can
patients can enjoy periods of extended remission with occur as part of the systemic disease or exist in isolation
virtually no clinical activity and even the disappearance in the absence of any autoantibodies (2%10% will
of antinuclear antibodies. develop SLE). DLE lesions are discrete plaques, often
erythematous, covered by scale that extends into dilated
hair follicles. These lesions most typically occur on the
MORE COMMONLY INVOLVED face, scalp, in the pinnae, behind the ears, and neck.
They can be seen in nonsun-exposed areas. The lesions
ORGAN SYSTEMS can progress, with active indurated erythema at the
periphery. Central atrophic scarring is very characteris-
Mucocutaneous tic. Irreversible alopecia can result from follicular
Clearly, the cutaneous system is one of the most com- destruction. Albeit rare, prominent dermal mucin accu-
monly affected, approaching 80% to 90%. In parallel mulation in the early course of DLE can result in the
with the myriad of signs and symptoms of SLE itself, the succulent, edematous lesions of tumid lupus. Lupus
skin and mucous membranes can be involved in a variety panniculitis-lupus profundus is a less common form of
of ways (8). Notably, 4 of the 11 formal criteria can be chronic disease. These lesions spare the epidermis and
fulfilled in this system alone. SLE-specific skin lesions represent involvement of the deep dermis and subcuta-
are classified into three typeschronic, subacute, and neous fat. The lesions of lupus panniculitis are firm
306 JILL P. BUYON
FIGURE 15A-2
Cutaneous manifestations of systemic

lupus erythematosus. (A) Discoid
lesions are present on the face and
in the pinnae. (B, C) Examples of the
lesions of subacute cutaneous lupus
erythematosus on the back and arm.
(D) Classic malar rash. (E) Extensive
acute perforating ulcer on the upper
palate. (F) Erythematous lesions
consistent with cutaneous vasculitis
on the digits. (Photographs provided
by Dr. Andrew Franks, Associate
Professor of Clinical Dermatology,
New York University School of
Medicine.)
nodules generally without surface changes. In time, the hypopigmentation. Generally, both forms are non-
overlying skin becomes attached to the subcutaneous scarring. Antibodies to SSA/Ro ribonucleoproteins are
nodular lesions and is drawn inward, resulting in deep commonly found in patients with SCLE.
depressions. Perhaps the most classic of all the rashes in SLE is
Subacute cutaneous lupus erythematosus (SCLE) the malar or butterfly rash, which is categorized among
lesions are seen in 7% to 27% of patients [Figure 15A- the acute rashes [Figure 15A-2(D)]. It occurs in 30% to
2(B,C)]. SCLE primarily affects Caucasian females. 60% of all patients. This erythematous and edematous
The lesions are typically symmetric, widespread, super- eruption simulates the shape of a butterfly with its body
ficial, and nonscarring, and are most often present in bridging over the base of the nose and wings spreading
sun-exposed areas, for example, the shoulders, extensor out over the malar eminences. At times the same rash
surfaces of the arms, upper chest, upper back, and neck. can be seen on the forehead and chin but classically
The lesions begin as small, erythematous, scaly papules spares the nasolabial folds. The absence of discrete
or plaques that can evolve into papulosquamous (pso- papules and pustules distinguishes it from acne rosacea.
riasiform) or annular polycyclic forms. The latter often The rash is abrupt in onset and can last for days. Postin-
coalesce to produce large confluent areas with central flammatory changes are common, particularly in patients
with pigmented skin. The butterfly rash is often initiated areas, the scalp, pinnae, behind the ears, palate, finger-
and/or exacerbated by exposure to sunlight. However, tips, and palms.
patients can have a photosensitive erythematous rash
elsewhere on the body in the absence of a butterfly rash.
The criteria for photosensitivity and butterfly rash are MUSCULOSKELETAL SYSTEM
thus independent of each other albeit coexistent in the
majority of patients. The Systemic Lupus Erythemato- Painful joints are the most common presenting symptom
sus International Cooperating Clinics (SLICC), a group of SLE, with frequencies reported between 76% to
of internationally recognized experts in SLE, are working 100%. In some cases the pain is more characteristic of
on a revision of the ACR classification criteria, and the arthralgia because it is unaccompanied by the tradi-
assignment of photosensitivity based on history alone tional signs of inflammation. In others the classical signs
may likely prove to be an insensitive parameter. A more of a true arthritis, such as swelling, erythema, heat, and 15
widespread, morbilliform or exanthemous eruption is decreased range of motion, are present. Notably, the
another acute cutaneous manifestation of SLE. patients complaint of pain may be out of proportion to
Alopecia associated with SLE may be diffuse or the degree of synovitis present on physical examination.
patchy, reversible or permanently scarring as a result of Although arthritis can affect any joint, it is most often
discoid lesions in the scalp. The breakage of hairs at the symmetrical with involvement of the small joints of the
templesso-called lupus frizzcan be observed. hands (proximal interphalangeal and metacarpal pha-
Mucosal lesions are also part of the clinical spectrum langeal), wrists and knees, but sparing the spine. The
of SLE and can affect the mouth (most commonly), arthritis can be evanescent, resolving within 24 hours, or
nose, and anogenital area. While oral lesions can be more persistent. Many of these features account for the
seen on the buccal mucosa and tongue, sores on the initial diagnostic consideration of early rheumatoid
upper palate are particularly characteristic [Figure 15A- arthritis (RA) in some patients. In contrast to RA, the
2(E)]. They are typically described as painless but need arthritis in SLE is nonerosive and generally nondeform-
not be. Central depression often occurs and painful ing. In those patients that do appear to have deforming
ulcerations develop. features, such as ulnar deviation, hyperflexion, and
Vasculitis is another component of skin disease in hyperextension, the deformities are generally reducible
SLE. It may be manifest as urticaria, palpable purpura, (Figure 15A-3). These hypermobile digits with reducible
nailfold or digital ulcerations, erythematous papules of deformities are secondary to involvement of para-
the pulps of the fingers and palms, or splinter hemor- articular tissues, such as the joint capsule, ligaments, and
rhages [Figure 15A-2(F)]. tendons, and are referred to as Jaccoud-like arthropa-
Because the skin can be an important marker thy. Exceptions are certainly possible and, when present,
of disease activity in SLE, the physical examination erosions may be clinically difficult to distinguish from
should always include inspection of often overlooked RA; however, they are usually nonprogressive and
FIGURE 15A-3
(A) Swan neck deformity of the second and third digits. (B) Hyperextension of the first interpha-
langeal joint. (Courtesy of Dr. Harry Fischer, Beth Israel Medical Center, New York, NY.)
A B
308 JILL P. BUYON
likely result from capsular pressure and an altered Generalized myalgia and muscle weakness, fre-
mechanical situation caused by subluxation. quently involving the deltoids and quadriceps, can be
Effusions tend to be modest. The synovial fluid is accompanying features of disease flares. Overt myositis
clear to slightly cloudy with good viscosity and mucin with elevations of CPK occurs in <15% of patients.
clot, reflecting the absence of major inflammation. Anti- Electromyogram (EMG) and muscle biopsy findings
nuclear antibodies can be present. White blood cell range from normal to those seen in dermato/polymyo-
counts are usually <2000/mm3 with a predominance of sitis. Exceptionally high levels of creatine kinase (CPK)
mononuclear cells. The fluid can be transudative or exu- are rare. Patients with SLE can develop myopathy as a
dative. The serum/synovial fluid ratios of complement, consequence of glucocorticoids or antimalarials.
total protein, and IgG can all be 1, indicating a propor-
tional escape of proteins into the joint space, or >1 for
complement levels only, indicating local consumption,
Renal
not simply a reflection of decreased serum complement. The kidney is considered by many to be the signature
Larger effusions with warmth should prompt the con- organ affected by SLE. Essentially all studies of prog-
sideration of septic arthritis. Rheumatoid nodules can nosis have identified lupus nephritis as an important
occur in SLE accompanied by the presence of rheuma- predictor of poor outcome. Renal disease is present in
toid factor, but this is not common. one half to two thirds of patients and, with rare excep-
Rheumatic complaints localized to the hips should tion, is diagnosed based on the presence of proteinuria
raise serious consideration of osteonecrosis, the fre- (dipstick 2+, >500 mg/24 hour). There is a spectrum of
quency of which has been reported to be 5% to 10%. renal injury that can be assessed, in part on clinical
Although the femoral head is the most common site of grounds, and more definitively by biopsy (9). Initial
involvement, other sites include the femoral condyles, categories of lupus nephritis were based on classifica-
talus, humeral head, and, occasionally, the metatarsal tion by the World Health Organization as assessed by
heads, radial head, carpal bones, and metacarpal bones. histology and location of immune complexes (Table
Bilaterality is frequent but not necessarily simultane- 15A-2) (10). Recently, this classification has been
ous. Most cases are associated with the use of cortico- revised by the International Society of Nephrology and
steroids, but causality has also been attributed to Renal Pathology Society (ISN/RPS; Table 15A-3) (11).
Raynauds, small vessel vasculitis, fat emboli, or the The important difference is that this new classification
presence of antiphospholipid antibodies. Typically, is an attempt to stratify proliferative lesionsfocal and
patients with osteonecrosis complain of persistent diffuse (class III and IV, respectively)as active versus
painful motion localized to a single joint, and symptoms chronic scarring, with the concept that the former is
are relieved by rest. treatable. Furthermore, diffuse proliferative nephritis
TABLE 15A-2. WORLD HEALTH ORGANIZATION CLASSIFICATION OF LUPUS NEPHRITIS

CLINICAL CLUESa
SITE OF IMMUNE
COMPLEX Proteinuria Serum Blood
CLASS PATTERN DEPOSITION Sediment (24 h) creatinine pressure Anti-dsdna C3/C4
I Normal None Bland <200 mg Normal Normal Absent Normal
II Mesangial Mesangial only RBC or 200500 mg Normal Normal Absent Normal

bland
III Focal and Mesangial, RBC, WBC 5003500 mg Normal to mild Normal to Positive Decreased
segmental subendothelial, elevation elevated
proliferative subepithelial
IV Diffuse Mesangial, RBC, WBC, 1000>3500 mg Normal to High Positive Decreased

proliferative subendothelial, RBC dialysis- to high
subepithelial casts dependent titer
V Membranous Mesangial, Bland >3000 mg Normal to mild Normal Absent to Normal

subepithelial elevation modest
titer
SOURCE: From Appel GB, Silva FG, Pirani CL (10), by permission of Medicine.
ABBREVIATIONS: RBC, red blood cells; WBC, white blood cells.
a
These are only guidelines, and parameters may vary, substantiating the need for biopsy when precise diagnosis is required.
TABLE 15A-3. INTERNATIONAL SOCIETY OF tion) would each be an unusual reflection of lupus
NEPHROLOGY/RENAL PATHOLOGY SOCIETY (ISN/RPS) nephritis in the absence of proteinuria (unless pathol-
CLASSIFICATION OF LUPUS NEPHRITIS. ogy is limited to the mesangium in the case of red blood
Class I Minimal mesangial lupus nephritis cells and interstitium in case of white blood cells). An
elevated creatinine without concomitant proteinuria is
Class II Mesangial proliferative lupus nephritis unexpected unless advanced renal insufficiency is
Class III Focal lupus nephritis present. While renal disease is frequently insidious,
III (A): Active lesions: focal proliferative lupus symptoms which occur with progressive activity include
nephritis swollen ankles, puffy eyes upon waking in the morning,
III (A/C): Active and chronic lesions and frequent urination. A low serum albumin is an indi-
III (C): Chronic inactive lesions with scars
cator of persistent proteinuria. Isolated hypertension
Class IV Diffuse lupus nephritis outside of the norms for age, race, and gender should 15
IV-S (A): Active lesions: diffuse segmental raise suspicion of underlying renal disease.
proliferative lupus nephritis Biopsies are not required to diagnose lupus nephritis
IV-G (A): Active lesions: diffuse global
proliferative lupus nephritis
but are extremely helpful in certain settings because
IV-S (A/C): Active and chronic lesions clinical parameters are not absolute. Given the impor-
IV-G (A/C): Active and chronic lesions tance of identifying pathologic features suggestive of
IV-S (C): Chronic inactive lesions with scars more aggressive disease, such as crescents, some clini-
IV-G (C): Chronic inactive lesions with scars cians believe kidney biopsy to be the fulcrum for thera-
Class V Membranous lupus nephritisa peutic decisions. Thus, treatment with alkylating agents,
such as cyclophosphamide, which can result in prema-
Class VI Advanced sclerotic lupus nephritis
ture ovarian failure, becomes readily justified in circum-
SOURCE: Adapted from Weening JJ, DAgati VD, Schwartz MM, et al. (11), by
stances where the clinical picture may have suggested
permission of J Am Soc Nephrol. a more favorable histology. For example, there are
a
Class V may occur in combination with class II or IV, in which case both patients who have rapidly rising titers of anti-dsDNA
will be diagnosed.
and falling complements but only modest proteinuria
(400 mg1 g), bland sediment, normal creatinine, and no
other systemic manifestations to warrant intense immu-
was divided into those cases with predominantly seg- nosuppression. Other patients may have nephrotic-
mental lesions and those with predominantly global range proteinuria and an active sediment yet serologic
lesions. To date it is not clear whether this histologic parameters are normal. Renal biopsies in these some-
division will have clinical and prognostic impact. Class what ambiguous situations can be quite informative. In
V/membranous is now purely membranous, and if there contrast, the decision to withhold aggressive therapy is
is evidence of a proliferative lesion, both classes are also important and may be appropriate for irreversible
specified, for example, V + III or V + IV. late-stage sclerotic disease. Renal biopsies should be
Renal biopsy is abnormal in most patients, especially performed when the result will make a clear difference
when tissue is evaluated by electron microscopy and in the approach and/or is required as part of a research
immunofluorescence. Diffuse proliferative nephritis study. Renal ultrasound is another helpful guide to
and progressive forms of focal proliferative nephritis therapy because the chances of successful treatment
are associated with a poorer prognosis than membra- become smaller with decreased size and increased echo-
nous or mesangial disease. genicity of the kidneys.
Clinical evaluation initially includes urine dipstick Urine protein is a critical measurement of ongoing
and microscopic analysis. A baseline 24-hour urine for renal lupus activity. While new proteinuria of 500 mg is
measurement of protein and creatinine, even in the significant, patients with membranous nephropathy, in
presence of 1+ dipstick, is common practice, especially particular, can have continued proteinuria between
in a patient with antibodies to double-stranded DNA 500 mg and 2 g and still be considered stable. In such
(dsDNA) and low complement levels. Given the incon- cases, an exacerbation is best defined as at least a dou-
venience of obtaining a 24-hour urine collection, many bling of baseline proteinuria. It is essential to monitor
physicians utilize the spot protein/creatinine ratio to blood pressure because hypertension can be a reflection
gauge the extent of proteinuria. The sediment can be of renal disease activity and, as such, accelerates func-
bland (consistent with mesangial or membranous) or tional impairment.
active containing red blood cell casts (consistent with Renal transplantation in lupus has been successful.
proliferative lesions). Persistent hematuria with >5 red However, lupus nephritis can recur (10%), even in the
blood cells per high power field (in the absence of other absence of clinical or serologic evidence of active SLE
causes such as menstruation) and/or pyuria with >5 (12) but is not always associated with allograft loss.
white blood cells per high power field (excluding infec- Clinical and serological activity in SLE may improve in
310 JILL P. BUYON
patients who have end-stage renal disease (13), although hypertension is also included in the case definition of
this paradigm has recently been challenged (14). headache. The term lupoid sclerosis has been used to
describe a rare condition in which patients exhibit
complex neurologic deficits similar to those observed in
Nervous System multiple sclerosis. Myelopathy and aseptic meningitis
Approximately two thirds of patients with SLE have are rare. Chorea, albeit infrequent, is the most common
neuropsychiatric manifestations. The pathophysiology movement disorder observed in SLE. This and cerebro-
of this broad clinical category is not well understood, vascular accidents have been related to the presence of
which probably reflects the inaccessibility of the tissue antiphospholipid antibodies.
involved. Proposed mechanisms include vascular occlu- Disturbances of the cranial nerves can result in visual
sion due to vasculopathy, leukoaggregation or throm- defects, blindness, papilledema, nystagmus or ptosis,
bosis, and antibody-mediated neuronal cell injury or tinnitus and vertigo, and facial palsy. Peripheral neu-
dysfunction (15). Neuropsychiatric systemic lupus ropathy may be motor, sensory, mixed motorsensory,
includes neurologic syndromes of the central, periph- or mononeuritis multiplex. Transverse myelitis present-
eral, and autonomic nervous systems, and psychiatric ing with lower extremity paralysis, sensory deficits, and
disorders in which other causes have been excluded. loss of sphincter control has been observed in a limited
These manifestations may occur as single or multiple number of patients. An acute inflammatory demyelinat-
events in the same person. Symptoms can be present ing polyradiculoneuropathy (GuillainBarre syndrome)
concomitantly with activity in other systems, or exist in has been described.
isolation. While the formal ACR criteria for neuropsy- Examination of the cerebrospinal fluid is useful to
chiatric lupus include only seizures and psychosis, it has rule out infection. However, with regard to neuropsy-
become increasingly clear that further descriptors might chiatric lupus, often the findings are nonspecific with
be important in diagnosis. In an effort to expand the elevated cell counts, protein levels, or both, found in
criteria, an ACR Ad Hoc Committee has developed only about one third of patients. The fluid may be com-
reporting standards, recommendations for laboratory pletely normal in the face of acute disease. Computer-
and imaging evaluation, and case definitions for 19 neu- ized tomography is sufficient for the initial diagnosis of
ropsychiatric syndromes observed in SLE (16). most mass lesions and intracranial hemorrhages. The
A variety of psychiatric disorders are reported findings of magnetic resonance imaging (MRI) reflect
and include mood disorders, anxiety, and psychosis. the histopathologic findings of vascular injury and may
Unequivocal attribution to lupus is difficult because involve the white or gray matter (17). Abnormalities on
such disorders may be related to the stress of having a MRI are more likely with focal findings. Unfortunately,
major chronic illness, or be due to drugs, infections, or the correlation between MRI findings and clinical pre-
metabolic disorders. Patients can demonstrate signifi- sentation is low.
cant cognitive defects, such as attention deficit, poor
concentration, impaired memory, and difficulty in word
finding. These abnormalities are best documented by
Cardiovascular System
neuropsychological testing and a decline from a higher A variety of cardiac complications are seen in SLE but
former level of functioning. Another syndrome of certainly the most common is pericarditis, occurring in
diffuse neurologic dysfunction is termed acute confu- 6% to 45%. The clinical picture is usually typical with
sional state and defined as disturbance of consciousness the patient complaining of substernal or pericardial pain,
or level of arousal with reduced ability to focus, main- aggravated by motion such as inspiration, coughing,
tain, or shift attention, accompanied by cognitive dis- swallowing, twisting, and bending forward. Symptoms
turbance and/or changes in mood, behavior, or affect. may either be severe and last for weeks, or mild and last
The syndrome often develops over a brief time frame, for hours. A pericardial rub may or may not be present
fluctuates over the day, and covers a wide spectrum and can be heard in an asymptomatic patient. Although
ranging from mild alterations of consciousness to the electrocardiogram may show the typical T-wave
coma. abnormalities, echocardiography is the best diagnostic
Inclusive in the neurologic manifestations of the test. Most effusions are small to moderate. The pericar-
central nervous system are seizures, which may be focal dial fluid is straw-colored to serosanguinous, exudative,
or generalized. Headache is a common complaint in and can have a high white blood cell count with a pre-
patients but there is still debate as to whether this is a dominance of neutrophils. LE cells can be seen in the
unique feature attributable to SLE. The lupus headache centrifuged cell sediment. Cardiac tamponade is rare as
has been operationally defined as severe, disabling, is constrictive pericarditis. Importantly, when a young
persistent, and not responsive to narcotic analgesics. woman presents with shortness of breath and pleuritic
However, severe migraine in the absence of lupus may chest pain, the differential diagnosis must include SLE,
have these same characteristics. Benign intracranial and the patient should be tested for ANA.
Primary myocardial involvement in SLE is uncom- with SLE, plaque was independently associated with
mon, <10%. The patient may have fever, dyspnea, pal- age, longer disease duration, higher damage index, and
pitations, heart murmurs, sinus tachycardia, ventricular less frequent use of cyclophosphamide and antimalarial
arrhythmias, conduction abnormalities, or congestive drugs, as well as a lower prevalence of anti-Sm anti-
heart failure. Percutaneous endomyocardial biopsy may body. Asanuma and colleagues (24) used electron beam
be helpful. It is now well recognized that hemodynami- computer tomography (EBCT) to evaluate 65 patients
cally and clinically significant valvular disease occurs with SLE and 69 controls. Patients with SLE had higher
and may require prosthetic valve replacement. Aortic coronary calcium scores, independent of other athero-
insufficiency represents the most commonly reported sclerotic risk factors. Furthermore, on analysis within
lesion and may be the result of multiple factors, includ- age strata, patients with SLE were found to have coro-
ing fibrinoid degeneration, distortion of the valve by nary artery calcification at younger ages than controls.
fibrosis, valvulitis, bacterial endocarditis, aortitis, and 15
LibmanSacks endocarditis. LibmanSacks atypical
verrucous endocarditis, the classic cardiac lesion of
Pleura and Lungs
SLE, is comprised of verrucous vegetations ranging The lungs and contiguous structures involved in normal
from 1 to 4 mm in diameter, initially reported to be respiration are commonly affected in SLE, but are gen-
present on the tricuspid and mitral valves. Interestingly, erally not as life threatening as the renal and central
it has been noted that neither the usual clinical and nervous system complications. Over 30% of patients
immunologic markers of lupus activity, nor its treat- have some form of pleural disease in their lifetime,
ment, are temporally related to the presence of or either as pleuritis with chest pain or frank effusion.
changes in valvular disease (18). Prophylactic antibiot- Pleurisy is a more common feature of serositis than
ics for surgical and dental procedures have been recom- pericarditis. The pain of pleuritis can be quite severe
mended for all SLE patients. and must be distinguished from pulmonary embolus or
Accelerated atherosclerosis has received consider- infection. Pleural rubs are less common than either
able attention and is an important cause of morbidity clinical pleurisy or radiographic abnormalities. Pleural
and mortality in SLE. It has been established that the effusions are most often small and bilateral. The fluid is
proportionate mortality from myocardial infarction is usually clear, exudative with increased protein, normal
approximately 10 times greater in patients with SLE glucose, white blood cell count <10,000, a predominance
than in the general age- and sex-matched population of neutrophils or lymphocytes, and decreased levels of
(6,7,19). Autopsy studies support the clinical data, as complement.
severe coronary artery atherosclerosis is present in up Pulmonary involvement includes pneumonitis, pul-
to 40% of patients with SLE, compared with 2% of monary hemorrhage, pulmonary embolism, pulmonary
control subjects, matched for age at the time of death hypertension, and shrinking lung syndrome. The term
(20). Studies have identified hypercholesterolemia, acute lupus pneumonitis has been applied to individuals
hypertension, and lupus itself as risk factors in these with an abrupt febrile pneumonitic process in whom
patients (21). Glucocorticoid therapy contributes to the infection has been ruled out. Prominent features are
elevation of plasma lipids, while antimalarials may pleuritic chest pain, cough with hemoptysis, and dyspnea.
result in a reduction of plasma cholesterol, low-density Diffuse alveolar hemorrhage is considered a manifesta-
lipoprotein (LDL), and very low-density lipoprotein tion of acute lupus pneumonitis and associated with
(VLDL). Coronary arteritis is rare and may coexist with a 50% mortality rate. It can occur in the absence of
atherosclerotic heart disease. Studies of clinical out- hemoptysis and is suggested by a falling hematocrit and
comes for atherosclerotic disease, including angina and pulmonary infiltrates. Rare patients (<10%) develop a
myocardial infarction, have shown a prevalence of 6% more chronic syndrome characterized by progressive
to 12% in a number of SLE cohorts (6,7,21). More dyspnea, nonproductive cough, basilar rales, and diffuse
sensitive investigations, including carotid plaque and interstitial lung infiltrates.
intima-media thickness (IMT) measured by B-mode Pulmonary hypertension should be suspected in
ultrasound, revealed that 40% of 175 women with SLE patients complaining of progressive shortness of breath
had focal plaque (22). and in whom the chest radiograph is negative and pro-
Two recent articles further link SLE and premature found hypoxemia is absent. Pulmonary function studies
atherosclerosis. Roman and colleagues (23) performed show a restrictive pattern with a reduction in the diffus-
carotid ultrasonography, echocardiography, and assessing capacity for carbon monoxide. Doppler ultrasound
ment for risk factors for coronary artery disease (CAD) studies and cardiac catheterization confirm the diagno-
in a cross-sectional study of 197 patients with SLE and sis. Frequently, these patients also have Raynauds
197 controls. Atherosclerosis occurred prematurely in phenomenon. Intrapulmonary clotting and/or multiple
patients with SLE and was independent of traditional pulmonary emboli must be addressed, especially in the
risk factors for cardiovascular disease. Among patients setting of antiphospholipid antibodies. Recent studies
312 JILL P. BUYON
suggest that pulmonary hypertension is gradually pro- Cytoid bodies refer to the histologic features of the
gressive over time and related to an increase in pulmo- cotton wool spot.
nary resistance (25).
LABORATORY FEATURES
LESS COMMONLY INVOLVED Hematologic Abnormalities
ORGAN SYSTEMS
Each of the cellular elements of the blood can be
Gastrointestinal Tract and Liver affected in SLE. Accordingly, the complete blood count
is a critical part of the initial and continued evaluation
Involvement of the gastrointestinal tract can, as in other of all lupus patients. In the absence of offending medi-
organ systems, be quite varied, but for most patients is cations, the penias are generally secondary to periph-
not the source of any diagnostic criteria. The perito- eral destruction, and not marrow suppression.
neum is the least likely of the serosal linings to be Autoimmune hemolytic anemia is present in <10%
affected in SLE. Symptoms include rebound tender- of patients. A Coombs test can be positive (both direct
ness, fever, nausea, vomiting, and diarrhea. Unfortu- and indirect) without active hemolysis. A nonspecific
nately, confusion with serious abdominal pathology or anemia reflecting chronic disease is present in up to
infection can prompt surgical intervention. Abdominal 80% of patients. Leukopenia is seen in over 50% of
pain in SLE can also be caused by pancreatitis and patients. Absolute lymphopenia is more common than
bowel vasculitis. Rectal bleeding can be present in neutropenia. Unfortunately, the criterion for lympho-
mesenteric vasculitis. Protein-losing enteropathy is penia (<1500/mm3) is not very stringent and in most
quite uncommon but should be considered in the face laboratories is not highlighted as abnormal. While leu-
of low serum albumin, pedal edema, and the absence of kopenia does represent some degree of disease activity
proteinuria. and has been described as a signal of more systemic
Parenchymal liver disease as a result of SLE is rare. activity, there are clearly patients whose low white
However, elevated transaminases can be encountered blood cell counts do not associate with disease flares in
during periods of active disease and/or following the use other organs and do not predispose them to infection.
of many medications prescribed to treat lupus, such as Thrombocytopenia can be modest (platelet counts of
nonsteriodal anit-inflammatory drugs (NSAIDs), aza- 50,000100,000/mm3), chronic and totally asymptom-
thioprine, and methotrexate. In the absence of known atic, or profound (<20,000/mm3) and acute, with gum
offending drugs, persistent signs of hepatitis may require bleeding and petechiae. In some cases, thrombocytope-
a liver biopsy. The term lupoid hepatitis was coined by nia is the sole manifestation of disease activity at a given
Bearn in 1956 and initially believed to be a manifesta- point in time. Moreover thrombocytopenia can be the
tion of SLE. However, an individual need not have initial presentation of SLE, antedating the development
lupus; it is defined serologically and histologically and of other symptoms or signs by years. Any young woman
is a subset of chronic, active hepatitis. It is seen in less presenting with idiopathic thrombocytopenia should
than 10% of patients who fulfill the ACR criteria for be evaluated for SLE. Fortunately, there are rarely
SLE. qualitative defects in the platelets and therefore life-
threatening bleeding is unusual. Analogous to the other
cell lines, antiplatelet antibodies may be present without
Ocular System thrombocytopenia.
The erythrocyte sedimentation rate is frequently
With regard to the eye itself, cotton wool spots in the
elevated in SLE and is generally not considered a reli-
retina are generally cited as being the most common
able marker of clinical activity. A rise in the C-reactive
lesion, followed in frequency by corneal and conjuncti-
protein may be an indicator of infection, but this has not
val involvement, with only rare patients exhibiting
proven to be absolute.
uveitis or scleritis. Although also quite uncommon,
retinal damage from antimalarials used in treating SLE
is probably a greater cause of visual loss than is retinal Hallmark Autoantibodies
involvement occurring in the natural course of the
disease. Cotton wool spots (an ophthalmologic term)
and Complement
are not pathognomonic for lupus and result from focal Measurement of the so-called serologic parameters is an
ischemia. They occur preferentially in the posterior part integral part of the baseline evaluation and follow-up of
of the retina and often involve the optic nerve head. patients with SLE. The term simply refers to those tests
Each spot appears as a grayish-white soft, fluffy exudate, performed using the serum component of whole blood,
averaging about one third of a disc diameter in width. although testing for antibodies, but not functional assays
of complement, can be obtained using plasma. For The frequency of various autoantibodies and their clini-
example, testing the ability of serum complement to cal relevance are summarized in Table 15A-4. A very
lyse sheep red blood cells in the CH50 test (see below) recently described autoantibody in the sera of about
cannot be done using plasma, because it is generally 30% of lupus patients is directed against an epitope of
accepted that complement activation does not proceed the glutamate/N-methyl-D-aspartic acid (NMDA)
in EDTA- and citrate-plasma because of calcium chela- receptor subunits NR2a and NR2b (highly expressed in
tion by EDTA and citrate. human brain) (26). Albeit not unambiguously proven,
The presence of a positive ANA is clearly one of the access of this antibody across the bloodbrain barrier
most important abnormalities to identify at presenta- may result in neuropsychiatric abnormalities.
tion because it establishes that the differential diagnosis Complement proteins, the bullets of the antibodies
includes autoimmunity. However, a positive ANA, par- and intrinsic components of immune complexes, can be
ticularly in young women, can be detected in about 2% measured both functionally (CH50) and antigenically 15
of normals. This test should be considered a valuable (C3, C4). Most laboratories measure the C3 and C4
guide but by no means diagnostic. Once documented, because they are stable and do not require special han-
the continued measurement of the ANA is not useful dling as does the CH50. The CH50 reflects the function
as a gauge of disease activity. In contrast, the presence of serum complement to lyse sheep red blood cells
of antibodies to dsDNA [not single-stranded DNA (RBCs); its value is the reciprocal of the dilution of
(ssDNA)] is not only of major diagnostic significance serum that lyses 50% of antibody-coated sheep RBCs.
but in select patients, particularly those with renal A reduction of the CH50 occurs when individual com-
involvement (see below), a valuable means of predict- plement component(s) are deficient or consumed. In
ing and assessing disease activity. Anti-Sm antibodies, fact, none of these traditional measures of the comple-
which recognize determinants on proteins associated ment system discriminate between accelerated con-
with small ribonucleoproteins involved in processing of sumption of complement or decreased synthesis. Such
messenger RNA, are of diagnostic importance but do distinction requires measurement of the complement
not track disease. Antibodies reactive with SSA/Ro and split products (e.g., C3a), which is still considered a
SSB/La ribonucleoproteins, the latter involved in tran- research tool and is not readily available in most com-
scription termination, also do not correlate with activ- mercial laboratories.
ity, but are often seen in patients who may have one or A challenge in the management of patients with SLE
more of the following: photosensitivity, dry eyes and dry is to identify parameters that will stratify those at risk
mouth (secondary Sjgrens syndrome), subacute cuta- for disease flares, particularly flares which might lead to
neous lesions, risk of a child with neonatal lupus. Anti- permanent damage in major organs. The presumption
SSA/Ro antibodies, depending on the methodology is that earlier treatment in the high-risk patient might
used for screening, can stain the cytoplasmic component have an impact on subsequent morbidity and mortality.
of the cell and therefore account for some ANA- Interest in measurements of the complement system
negative lupus. While ANA-negative lupus is consid- and anti-DNA antibodies to evaluate lupus patients
ered, it is difficult to conceptualize a situation whereby originates from the longstanding observation that
an individual is said to have SLE, a prototypic autoim- decreased complement levels and rising titers of anti-
mune disease, yet has no detectable autoantibodies. DNA are often associated with severe disease (27).
TABLE 15A-4. AUTOANTIBODIES AND CLINICAL FEATURES

ANTIBODIES FREQUENCY CLINICAL ASSOCIATIONS RELATIONSHIP TO DISEASE ACTIVITY
ANA > 90% Nonspecific For diagnostic purposes only
Anti-dsDNA 40%60% Nephritis May predict disease flare and associates with flare
Anti-RNP 30%40% Raynauds, musculoskeletal Does not track disease
Antiribosomal P 10%20% Diffuse CNS, psychosis, major depression Does not track disease
Anti-SSA/Ro 30%45% Dry eyes and mouth, SCLE, neonatal lupus, Does not track disease
photosensitivity
Anti-SSB/La 10%15% Dry eyes and mouth, SCLE, neonatal lupus, Does not track disease
photosensitivity
Antiphospholipid 30% Clotting diathesis Varied
ABBREVIATIONS: CNS, central nervous system. SCLE, subacute cutaneous lupus erythematosus.
314 JILL P. BUYON
FIGURE 15A-4
Longitudinal clinical and autoantibody

profile in a patient with a lupus flare. This
patient demonstrates concordance of
clinical and serologic activity with regard
to anti-dsDNA and complements. Note
that despite changes in disease activity,
titers of anti-Ro/La (elevated throughout)
and anti-Sm/RNP (absent throughout)
remain stable.
These findings are linked to the notion that immune endothelial protein C receptor (sEPCR), a protein that
complexes result in complement activation products promotes both procoagulant and proinflammatory
that are present locally or in the circulation, and are responses (33,34).
capable of stimulating inflammatory cells with resultant
vascular injury.
Measurements of anti-DNA antibodies and comple- SPECIAL CONSIDERATIONS
ment are an essential part of baseline evaluation, but
treatment is dictated by the clinical picture, not neces- Systemic Lupus Erythematosus
sarily the serologic one. Over time it should become
obvious in an individual patient whether these parame-
and Pregnancy
ters do predict and accompany disease flares. It is well Sterility and fertility fates for women with SLE are
appreciated that in certain patients low complements comparable to control groups without disease. However,
and elevated anti-DNA antibodies persist despite rela- increased disease activity can be associated with sec-
tive clinical quiescence. In contrast, there are patients ondary amenorrhea. Moreover, menstrual irregularities
who repeatedly demonstrate concordance of clinical have been noted in patients taking high doses of gluco-
and serologic activity (an illustrative case is provided in corticoids, and age-dependent premature ovarian failure
Figure 15A-4). In these individuals treatment may be occurs in those receiving cyclophosphamide. Women
considered solely on the basis of change in serologic with SLE have a higher rate of spontaneous abortion,
parameters in advance of overt clinical disease, thus intrauterine fetal death, and premature birth compared
preventing relapse (28). These issues have been recently to otherwise healthy women.
addressed in a prospective clinical trial to evaluate sero- In contrast to the rule of remission during pregnan-
logically active, clinically stable patients and determine cies in women with RA, the influence of pregnancy on
whether anti-DNA, C3, C4, or the complement split SLE disease activity is variable. There are two principal
product C3a are predictive of flare, and whether a short areas of concern. The first is that the clinical and sero-
trial of glucocorticoids can avert major disease (29). logic expression of SLE may be adversely altered by
Albeit a relatively small study, it appeared that preemp- pregnancy. The second is that the placenta and fetus
tive therapy with glucorticoids did prevent flares. At the may become targets of specific attack by maternal auto-
very least it is probably prudent to increase the fre- antibodies, resulting in a generalized failure of the preg-
quency of simple dipstick analysis of the urine in a nancy or specific syndromes of passively acquired
patient with rising titers of anti-DNA and falling com- autoimmunity, such as neonatal lupus (see below).
plement levels. It has been suggested that antinucleo- Pregnancy outcome is optimal when disease is in
some antibodies constitute a selective biologic marker complete clinical remission for 6 to 12 months (35,36).
of active SLE, specifically for lupus nephritis (30). Not unexpectedly, the most recent study to address the
Current studies are aimed at evaluating specific bio- effect of SLE clinical status on pregnancy outcome
markers in the urine that might predict onset and type identified that high lupus activity in the first and second
of glomerulonephritis. Recently published candidates trimesters led to a threefold increase in pregnancy loss
include adiponectin, an adipocyte-derived cytokine (miscarriages and perinatal mortality) (37). Whether
that has anti-inflammatory properties (31); monocyte flare rates increase during or after pregnancy is still
chemoattractant protein (MCP-1), a key chemokine unsettled, because individual patient series vary in the
involved in monocyte chemotaxis (32); and soluble characteristics of patients accepted for study and in the
definitions of flare. Current definitions of flare are changes and heavier proteinuria in the past. Addition-
imprecise, and accepted instruments used to measure ally reassuring are the results of a recent Canadian
disease activitysuch as the Systemic Lupus Erythe- study comparing 53 pregnant and 78 nonpregnant
matosus Disease Activity Index (SLEDAI), British patients with lupus nephritis, which found that changes
Isles Lupus Activity Group (BILAG), and Systemic in renal disease activity and progression were similar in
Lupus Activity Measurement (SLAM)do not account the two groups (42).
for the physiologic adaptations of pregnancy and have
not been validated for pregnant lupus patients (38).
Suggestions for valid criteria attributable to a flare are
Neonatal Lupus
characteristic dermatologic involvement, arthritis, fever This illness of the fetus and neonate is considered a
not secondary to infection, lymphadenopathy, leukope- model of passively acquired autoimmunity, in which
nia, alternative-pathway hypocomplementemia, and immune abnormalities in the mother lead to the produc- 15
rising titers of antibodies to DNA. In contrast, invalid tion of anti-SSA/Ro-SSB/La antibodies that cross the
markers of disease activity include alopecia, facial or placenta and presumably injure fetal tissue (43). The
palmar blush, arthralgia, musculoskeletal aching, mild most serious manifestation is damage to the cardiac
anemia, and fatigue, each of which may be present as conducting system resulting in congenital heart block
part of the normal physiologic changes of pregnancy. (CHB), which is most often third degree although less
Additionally, thrombocytopenia and proteinuria advanced blocks have been observed. CHB is generally
emerge in the setting of preeclampsia and cannot be identified between 16 and 24 weeks of gestation. The
attributed unambiguously to active lupus. In one major mortality rate is 20% and the majority of children
study comparing pregnant and nonpregnant women require pacing. Cutaneous involvement (erythematous
with SLE, the flare rates for both groups were similar and often annular lesions with a predilection for the
(39). Despite a high overall flare rate in one series eyes, face and scalp, frequently photosensitive) and, to
approaching 60% (35), recorded flares were usually a lesser extent, hepatic and hematologic involvement
not severe. In general, if all possible abnormalities are are also associated with maternal anti-SSA/Ro-SSB/La
presumed due to SLE, disease exacerbation occurs in antibodies and are grouped under the heading of Neo-
approximately 25%, and if only SLE-specific abnor- natal Lupus Syndromes. Neonatal lupusso termed
malities are considered, disease exacerbation occurs in because the dermatologic lesions of the neonate resem-
<13% (40). bled those seen in SLEis a misnomer in that less than
In counseling a patient about the maternal risks of a a third of mothers of affected children actually have
prospective pregnancy, major issues include the pres- SLE (many are asymptomatic) and the neonatal disease
ence of active nephritis and/or deterioration of renal is frequently only manifest as heart block, a problem
function, neither likely in the absence of prior involve- rarely reported in adults with lupus. To date, complete
ment. However, newly diagnosed lupus nephritis in the block is irreversible. In contrast, the noncardiac mani-
first trimester is associated with a poor fetal outcome. festations are transient, resolving at about 6 months of
In a patient with established membranous nephritis, the life coincident with the disappearance of maternal auto-
normal increase in glomerular filtrate rate may result antibodies from the neonatal circulation.
in protein excretion greater than 300 mg/24 hours, the The incidence of neonatal lupus in an offspring of a
upper limit accepted for an otherwise normal preg- mother with anti-SSA/Ro antibodies is estimated at 1%
nancy. In some cases there will be coexistent hyperten- to 2%. No serologic profile is unique to mothers of
sion which then must be differentiated (if possible) from affected children, but compared with mothers of healthy
preeclampsia, especially if it first becomes evident in the children, anti-SSA/Ro antibodies are usually of high
third trimester. In other patients, proteinuria will more titer (frequently anti-52kD SSA/Ro positive by immu-
clearly represent an exacerbation of lupus nephritis as noblot) and associated with anti-SSB/La antibodies
suggested by cellular casts in the urinary sediment. Acti- (44). Reports of discordant dizygotic and monozygotic
vation of the alternative complement pathway with a twins, and relatively low recurrence rates of CHB [in
concomitant decrease in CH50 accompanies disease our series, 18 of 101 (18%) next pregnancies following
flares in SLE, a laboratory finding that may be useful in the birth of a child with CHB] indicate that factors
distinguishing active lupus nephritis from preeclampsia (likely fetal) in addition to anti-SSA/Ro and SSB/La
or pregnancy-induced hypertension (41). The presence antibodies contribute to the development of neonatal
of active lupus nephritis and/or preeclampsia increases lupus (45). A Research Registry for Neonatal Lupus
the risk for pre-term delivery and fetal death. Encour- was established in 1994; with its current enrollment of
agingly, women in whom renal disease is stable (serum 361 mothers and their 423 affected children, this data-
creatinine <1.5 and 24-hour protein <2 g) prior to preg- base (along with available serum and DNA) provides a
nancy can experience an uncomplicated course during valuable resource for basic researchers and clinicians
pregnancy, despite a history of severe histopathologic (43,45).
316 JILL P. BUYON
Antiphospholipid Antibody clotting in an in vitro system which is not corrected by

mixing studies. The latter test is paradoxical because the
Syndrome readout is the inability to form a clot due to interference
Antiphospholipid antibodies, ascertained by a variety with proper assembly of the clotting factors, yet in vivo
of different assays, are associated with the risk of clot- these antibodies are thrombogenic. Experimental data
ting. The clinical consequences include venous and arte- suggest that antiphospholipid antibodies are not
rial thromboses and placental insufficiency resulting in directed against anionic phospholipids, as initially
recurrent fetal loss. Except for manifestations of active hypothesized, but are part of a larger group of autoan-
SLE, lupus patients with antiphospholipid antibodies tibodies that recognize phospholipid-binding proteins.
do not appear to have different pregnancy courses than At present, the best-characterized antigenic target is
patients with the primary antiphospholipid syndrome. beta2-glycoprotein I (beta 2GPI) (48), which has been
Paradoxically, thrombocytopenia can also be part of the shown to possess multiple inhibitory functions in coagu-
clinical spectrum because the surfaces of activated lation pathways. Although the measurement of antiphos-
platelets display the anionic phospholipid target anti- pholipid antibodies by ELISA is now well standardized,
gens. Patients who have antiphospholipid antibodies these new observations on beta 2GPI will require large-
and one of the above clinical features in the absence of scale testing, the outcome of which may substantially
any other manifestations of SLE are classified as having alter current recommendations.
primary antiphospholipid syndrome (APS), as outlined
in Table 15A-5; 46,47). Alternatively a patient can have Drug-Related Lupus
these antibodies in the context of SLE (secondary
APS). The term drug-related lupus (DRL) refers to the devel-
Currently, assessment of antiphospholipid antibodies opment of a lupuslike syndrome which follows exposure
is done by enzyme-linked immunosorbent assay (ELISA) to chlorpromazine, hydralazine, isoniazid, methyldopa,
to measure reactivity with cardiolipin, or by prolonged minocycline, procainamide, or quinidine. In addition to
these definitively associated drugs, there is a long list of
TABLE 15A-5. PRELIMINARY CLASSIFICATION other potential offending agents, such as diphenylhy-
CRITERIA FOR ANTIPHOSPHOLIPID SYNDROME (APS)* dantoin, penicillamine, and gold salts (49). There are no
specified ACR criteria for DRL, but in general these
CLINICAL CRITERIA
patients present with fewer than four SLE criteria. A
Vascular thrombosis temporal association (generally a matter of weeks or
1 arterial, venous, or small-vessel thrombosis in any tissue months) between ingestion of an agent and develop-
or organ, ment of symptoms is required. Following removal of the
AND offending agent, there should be rapid resolution of the
Confirmation by imaging or Doppler studies or histopathol-
ogy (not SVT)
clinical features although autoantibodies may persist for
6 months to a year. Drugs capable of causing DRL
Pregnancy morbidity: do not seem to aggravate idiopathic SLE. The demo-
1 unexplained death(s) of normal fetus at 10 weeks
graphic features of DRL tend to reflect those of the
gestation,
OR diseases for which the offending drug has been pre-
1 premature birth(s) of normal neonate at 34 weeks scribed. Accordingly, DRL occurs more frequently in
gestation due to severe preeclampsia or placental insufficiency, the elderly, occurs only slightly more frequently in
OR females than males, and is more common in Caucasians
3 unexplained consecutive spontaneous abortions < 10
than African Americans.
weeks gestation (exclude anatomic, hormonal, or chromo-
somal abnormality) Drug-related lupus patients frequently present with
constitutional symptoms such as malaise, low grade
LABORATORY CRITERIA fever, and myalgia, which may occur acutely or insidi-
ously. Articular complaints are present in over 80%,
Anticardiolipin antibody of IgG and/or IgM isotype
medium or high titer (1580 GPL, 650 MPL)

with arthralgia being more common than arthritis. Pleu-
on 2 occasions at least 6 weeks apart
ropulmonary disease and pericarditis are present most
measured by standard ELISA for beta2-glycoprotein

often in procainamide-related lupus. Other clinical
I-dependent anticardiolipin antibodies manifestations of idiopathic SLE, such as dermatologic,
OR
renal, and neurologic, are rare in DRL. ANAs should
Lupus anticoagulant (LAC)
on 2 occasions at least 6 weeks apart

be present in order to diagnose DRL. However, the
development of an ANA without accompanying clinical
SOURCE: Adapted from Derksen RH, Khamashta MA, Branch DW (46), by features is insufficient for the diagnosis and not reason
permission of Arthritis Rheum. by itself to discontinue medication. Typically the ANA
ABBREVIATION: APS, antiphospholipid syndrome.
*APS considered definite if at least one clinical and one laboratory criteria
is a diffuse-homogenous pattern, which represents
are met. binding of autoantibodies to chromatin that consists of
DNA and histones. Anti-dsDNA and anti-Sm are not 10. Appel GB, Silva FG, Pirani CL. Renal involvement in
characteristic of DRL. systemic lupus erythematosus (SLE): a study of 56 patients
emphasizing histologic classification. Medicine 1978;75:
371410.
CONCLUSIONS 11. Weening, JJ, DAgati VD, Schwartz MM, et al. Classifica-
tion of glomerulonephritis in systemic lupus erythemato-
Systemic lupus erythematosus is a composite of clini- sus revisited. J Am Soc Nephrol 2004;15:241250.
cally unrelated manifestations often accumulated over 12. Stone JH, Millward CL, Olson JL, Amend WJ, Criswell
LA. Frequency of recurrent lupus nephritis among ninety-
time which are unified, with rare exception, by the pres-
seven renal transplant patients during the cyclosporine
ence of antibodies directed against one or more self era. Arthritis Rheum 1998;41:678686.
components of the nucleus, cytoplasm, and/or cell 13. Nossent HC, Swaak TJG, Berden JHM. Systemic lupus
membrane. Greater awareness of the clinical features erythematosus: analysis of disease activity in 55 patients 15
and advances in the laboratory evaluation of autoanti- with end-stage renal failure treated with hemodialysis or
bodies have facilitated diagnosis and eliminated much continuous ambulatory peritoneal dialysis. Am J Med
of the frustration previously experienced both by the 1990;89:169174.
patient and physician. In many patients flares are 14. Krane NK, Burjak K, Archie M, ODonovan R. Persistent
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CHAPTER 15

and Pathogenesis
DAVID S. PISETSKY, MD, PHD
Systemic lupus erythematosus (SLE) is primarily a Autoantibodies in lupus may be driven by self-
disease of young women, though it can be seen in antigens implicating a more generalized immune
both pediatric and older patients where the sex ratio cell dysfunction. which promotes B-cell
is more balanced. hyperactivity.
The pathologic findings of SLE occur throughout the Genetic susceptibility to lupus is likely polygenic, as
body and are manifested by inflammation, blood exemplified by multiple types of genes associated
vessel abnormalities that encompass bland with lupuslike diseases in mice.
vasculopathy and vasculitis, and immune-complex Triggering events for disease initiation and flares
deposition. may include may environmental exposures, such as
Autoantibodies can occur in the absence of clinical hormones, infectious agents, diet, sunlight, toxins
lupus, but pathogenic autoantibodies are important (including drugs), and others.
contributors to tissue damage in the kidney as well
as in other involved organs.
EPIDEMIOLOGY IMMUNOPATHOLOGY
Systemic lupus erythematosus (SLE) is a prototypic The pathologic findings of SLE occur throughout the
autoimmune disease with diverse clinical manifesta- body and are manifested by inflammation, blood vessel
tions in association with autoantibodies to components abnormalities that encompass bland vasculopathy and
of the cell nucleus. SLE primarily is a disease of young vasculitis, and immune-complex deposition. The best-
women, with a peak incidence between the ages of 15 characterized pathology involves the kidney, which dis-
and 40 and a female:male ratio of 6 to 10 : 1. The age at plays increases in mesangial cells and mesangial matrix,
onset, however, can range from infancy to advanced inflammation, cellular proliferation, basement mem-
age; in both pediatric- and older-onset patients, the brane abnormalities, and immune-complex deposition.
female:male ratio is approximately 2 : 1. In a general These deposits are comprised of IgM, IgG, and IgA, as
outpatient population, SLE affects approximately one well as complement components. On electron micros-
in 2000 individuals, although the prevalence varies with copy, the deposits can be seen in the mesangium and
race, ethnicity, and socioeconomic status (1). the subendothelial and subepithelial sides of the glo-
Like other autoimmune diseases, SLE can display merular basement membrane (Figure 15B-l). Renal
familial aggregation, with a higher frequency among pathology is classified according to two systems to
first-degree relatives of patients. The disease occurs provide information for clinical staging (see Chapter
concordantly in approximately 25% to 50% of monozy- 15A) (2,3). With either system, lupus nephritis exhibits
gotic twins and 5% of dizygotic twins. Moreover, in marked variability, differing in severity and pattern
extended families, SLE may occur with other autoim- among patients, as illustrated in Figure 15B-2.
mune conditions, such as hemolytic anemia, thyroiditis, Skin lesions in SLE demonstrate inflammation and
and idiopathic thrombocytopenia purpura. Despite the degeneration at the dermalepidermal junction, and the
influence of heredity, most cases of SLE appear basal or germinal layer is the primary site of injury. In
sporadic. these lesions, granular deposits of IgG and complement
319
320 DAVID S. PISETSKY
even in the absence of clinically significant manifesta-

tions. Verrucous endocarditis, known as LibmanSacks
endocarditis, is a classic pathologic finding of SLE and
is manifested by vegetations, most frequently at the
mitral valve. These vegetations consist of accumulations
of immune complexes, inflammatory cells, fibrin, and
necrotic debris.
Occlusive vasculopathy with venous and arterial
thrombosis is a common pathologic finding in SLE.
Although coagulation can result from inflammation,
autoantibodies also may trigger thrombotic events.
FIGURE 15B-1
These autoantibodies represent a spectrum of specifici-
Immune deposits in lupus nephritis. This electron micrograph ties designated as antiphospholipid antibodies, anticar-
illustrates large granular subendothelial immune deposits, as diolipin antibodies, or lupus anticoagulants (4). Although
well as smaller subepithelial and intramembranous deposits. some of these antibodies bind lipid antigens, others are
Broadening and fusion of the foot processes also are present.
(Reprinted from the Revised Clinical Slide Collection on the
directed to the serum protein beta2-glycoprotein 1, a
Rheumatic Diseases, with permission of American College of protein that can form complexes with lipids. Vessel
Rheumatology.) abnormalities in SLE may also result from increases in
endothelial cell adhesiveness by a mechanism analo-
gous to the Schwartzman reaction triggered by Gram-
components occur in a bandlike pattern as observed by negative bacteria.
immunofluorescence microscopy. Necrotizing vasculitis Other pathologic findings prominent in SLE have
also may cause skin lesions. Other organ systems an uncertain relationship to inflammation. Patients,
affected by SLE usually display nonspecific inflamma- including women without the usual risk factors for car-
tion or vessel abnormalities, although pathologic find- diovascular disease, frequently develop accelerated ath-
ings sometimes are minimal. For example, despite the erosclerosis and have an increased risk of stroke and
severity of central nervous system (CNS) involvement, myocardial infarction. It is unclear whether these lesions
the typical findings are cortical microinfarcts and a result from corticosteroid-induced metabolic abnormal-
bland vasculopathy with degenerative or proliferative ities, hypertension, or vascular changes caused by a
changes; inflammation and necrosis indicative of vascu- chronic burden of inflammation. Similarly, osteonecro-
litis are found only rarely. sis, as well as neurodegeneration in people with chronic
The heart may show nonspecific foci of inflammation severe disease, may arise from vasculopathy, drug side
in the pericardium, myocardium, and endocardium, effects, or persistent immunologic insults.
FIGURE 15B-2
(Left) Signs of active lupus nephritis showing glomerular proliferation, crescents, abundant
inflammatory cell infiltration, and interstitial cell infiltrates (hematoxylineosin stain). (Right) Signs
of chronic lupus nephritis showing glomerular cirrhosis, vascular thickening, tubular atrophy,
and interstitial fibrosis (periodic acid, Schiff stain).
IMMUNOPATHOGENESIS OF Among ANA specificities in SLE, two appear unique

to this disease. Antibodies to double-stranded (ds)
ANTINUCLEAR ANTIBODIES DNA and a nuclear antigen called Sm are essentially
found only in people with SLE, and are included as
The central immunologic disturbance in SLE is autoan- serologic criteria in the classification of SLE (see Appen-
tibody production. These antibodies are directed to a dix I). Although both anti-DNA and anti-Sm are sero-
host of self-molecules found in the nucleus, cytoplasm, logic markers, they differ in their pattern of expression
or surface of cells. In addition, SLE sera contain anti- and clinical associations. Whereas anti-DNA levels can
bodies to such soluble molecules as IgG and coagulation fluctuate markedly over time, anti-Sm levels remain
factors. Because of the wide range of its antigenic more constant. The anti-Sm and anti-DNA responses
targets, SLE is classified as a disease of generalized also differ in the nature of their target antigens. The Sm
autoimmunity. antigen is designated an snRNP (small nuclear ribonu- 15
Among autoantibodies found in patient sera, those cleoprotein) and consists of uridine-rich RNA mole-
directed against components of the cell nucleus (anti- cules complexed with proteins. In contrast to anti-DNA
nuclear antibodies, or ANA) are the most characteristic antibodies, which react to a nucleic acid determinant,
of SLE and are found in more than 95% of patients (5). anti-Sm antibodies target snRNP proteins and not
These antibodies bind DNA, RNA, nuclear proteins, RNA.
and protein/nucleic acid complexes (Table 15B-1). As a Perhaps the most remarkable feature of the anti-
group, the molecules targeted by ANA are highly con- DNA response is its association with immunopathologic
served among species, serve important cellular func- events in SLE, especially glomerulonephritis. This role
tions, and exist inside cells as part of complexes (e.g., has been established by correlating anti-DNA serum
nucleosomes). Furthermore, these molecules, depend- levels with disease activity, isolating anti-DNA in
ing upon context (e.g., presence in immune complexes), enriched form from glomerular eluates of patients with
display intrinsic immunological activity. This activity active nephritis, and inducing nephritis by administer-
results from stimulation of the innate immune system ing anti-DNA antibodies to normal animals. The rela-
via receptors known as the Toll-like receptors (TLR). tionship between levels of anti-DNA and active renal
The TLRs can recognize a diverse array of foreign and disease is not invariable; some patients with active
self-molecules, with DNA, single-stranded RNA and nephritis may lack serum anti-DNA, and others with
double-stranded RNA all TLR ligands (6). high levels of anti-DNA are clinically discordant and
Antibodies to certain nuclear antigens (e.g., DNA escape nephritis (7).
and histones) frequently occur together, a phenomenon The occurrence of nephritis without anti-DNA may
known as linkage. Linkage suggests that a complex, be explained by the pathogenicity of other autoanti-
rather than the individual components, serves as the body specificities (e.g., anti-Ro or anti-Sm). The con-
target of autoreactivity, as well as its driving antigen. verse situation of clinical quiescence despite serologic
TABLE 15B-1. PRINCIPLE ANTINUCLEAR ANTIBODIES IN SYSTEMIC LUPUS ERYTHEMATOSUS.

SPECIFICITY TARGET ANTIGEN FUNCTION
Native DNA dsDNA Genetic information
Denatured DNA ssDNA Genetic information
Histones H1, H2A, H2B, H3, H4 Nucleosome structure
Sm snRNP proteins B, B, D, E Splicesome component, RNA processing
U1RNP snRNP proteins, A, C, 70K Splicesome component, RNA processing
SSA/Ro 60- and 52-KDa proteins, complexed with Y1-Y5 RNAs Unknown
SSB/La 48-kDa protein complexed with various small RNAs Regulation of RNA polymerase-3 transcription
Ku 86- and 66-kDa proteins DNA binding
PCNA/cyclin 36-kDa protein Auxillary protein of DNA polymerase alpha
Ribosomal RNP 38-, 16-, 15-kDa phosphoproteins, associated with ribosomes Protein synthesis
SOURCE: Modified from Tan EM, Adv Immunol 1989;44:93151, with permission of Advances in Immunology.
ABBREVIATIONS: ss, double-stranded; ss, single-stranded; snRNP, small nuclear ribonucleoprotein.
activity suggests that only some anti-DNA provoke by elevated anti-DNA levels with a depression of total
glomerulonephritis. Antibodies with this property are hemolytic complement. Because anti-DNA shows pref-
denoted as pathogenic or nephritogenic. Features erential renal deposition, these findings suggest that
promoting pathogenicity may include isotype, charge, DNA/anti-DNA immune complexes are a major patho-
ability to fix complement, and capacity to bind glo- genic species. DNA in these complexes likely is in the
merular preparations (7). In this regard, anti-DNA form of nucleosomes, suggesting that antibodies to
antibodies appear to be a subset of pathogenic anti- other components of this structure may participate in
bodies that bind to nucleosomes, the likely form of immune-complex formation.
DNA in the circulation as well as in immune deposits. Although immune complexes may provoke renal
Unless the full range of antinucleosomal antibodies is injury in SLE, the amounts of such complexes in the
assessed, the presence of nephritogenic antibodies may serum appear limited. This finding has suggested that
be missed. complexes may form in situ, rather than within the
In addition to their direct role in nephritis, antibodies circulation. According to this mechanism, immune
to DNA may promote immune system disturbances that complexes assemble in the kidney on DNA or other
potentiate inflammation systemically as well in the nucleosomal components adherent to the glomerular
kidney. Thus, immune complexes containing DNA can basement membrane. Another mechanism for nephritis
promote the expression of interferon alpha (IFN-alpha) in SLE is the direct interaction of autoantibodies with
by a specialized population of dendritic cells known as glomerular antigens. Many anti-DNA antibodies are
plasmacytoid dendritic cells. This response requires the polyspecific and interact with molecules other than
presence of both antibody and DNA in an immune DNA. The binding of anti-DNA to these molecules
complex and depends upon Fc receptors. While the could activate complement and inciting inflammation.
basis of this response is not well understood, stimulation The pathogenesis of other SLE manifestations is less
may involve the TLRs as well as other non-TLR signal- well understood, although immune-complex deposition
ing systems that respond to internalized nucleic acids. at relevant tissue sites generally has been considered a
Antibodies to other nuclear antigens, including RNP likely mechanism. Indeed, the frequent association of
complexes, can also stimulate this response, raising the depressed complement levels and signs of vasculitis
possibility that immune complexes, in addition promot- with active SLE suggests that immune complexes are
ing organ damage, can contribute to the overall distur- important agents for initiating or exacerbating organ
bance in the immune system in patients (8). damage. These considerations do not exclude the
In addition to anti-DNA, other autoantibodies may possibility that tissue injury results from either cell-
have a clinical impact because of effects on organ- mediated cytotoxicity or direct antibody attack on target
specific manifestations. Associations of other auto- tissues. Consistent with the operation of such a mecha-
antibodies with disease events include antibodies to nism, a cross-reactive population of antibodies to the
ribosomal P proteins (anti-P) with neuropsychiatric NMDA receptor may CNS disturbances by inducing
disease and hepatitis; antibodies to Ro with neonatal excitotoxic damage (10).
lupus and subacute cutaneous lupus; antibodies to phos-
pholipids with vascular thrombosis, thrombocytopenia,
and recurrent abortion; and antibodies to blood cells
with cytopenias. DETERMINANTS OF DISEASE
The contribution of ANAs to clinical events in SLE SUSCEPTIBILITY
has been difficult to understand because the intracellular
location of the target antigens should protect them from Studies of patients suggest that SLE is caused by geneti-
antibody interactions. The location of these antigens cally determined immune abnormalities that can be
may not be fixed, however, and some antigens may triggered by exogenous or endogenous factors. Although
translocate to the membrane and become accessible to the predisposition to disease is hereditary, it is likely
antibody attack either during development or during multigenic and involves different sets of genes in differ-
apoptosis. Thus, during cardiac development, a molecule ent individuals (see Chapter 5). Analysis of genetic sus-
bound by anti-Ro appears on the surface of myocytes ceptibility has been based primarily on the search for
and, in the presence of complement, lead to local inflam- gene polymorphisms occurring with greater frequency
mation and damage to the conducting system (9). in people with SLE than in control populations. The
Because of the impact of kidney disease on morbidity study of genetic factors predisposing to SLE also has
and mortality, nephritis has been the clinical event in involved genomewide scans of siblings with SLE or
SLE most intensively studied mechanistically. Clinical multiplex families. Although this approach has led to
observations strongly suggest that SLE renal disease the identification of chromosomal regions that contain
results from the deposition of immune complexes con- genes potentially relevant to pathogenesis, the identi-
taining anti-DNA, because active nephritis is marked ties of these genes are not yet known definitively. Fur-
thermore, the regions associated with disease may differ is illustrated by the features of mice in which C1q
depending upon racial and ethnic group (11). has been eliminated by genetic knockout techniques.
Of genetic systems that could predispose to autoim- C1q-deficient mice have elevated anti-DNA levels,
munity, the major histocompatibility complex (MHC) glomerulonephritis, and increased apoptotic cells in
has been most intensively scrutinized for its contribu- the tissue (13). Impairment of other aspects of the
tion to human SLE. Using a variety of MHC gene clearance system (e.g., IgM and DNase) can also
markers, population-based studies indicate that the sus- provoke immune system abnormalities, including the
ceptibility to SLE, like many other autoimmune dis- stimulation of interferon by dead and dying cells and
eases in humans, involves class II gene polymorphisms. their constituents.
An association of human leukocyte antigen (HLA)-
DR2 and HLA-DR3 (and various subspecificities) with
SLE has been commonly observed, with these alleles
producing a relative risk of disease that ranges approxi- GENETICS OF MURINE SYSTEMIC 15
mately from 2 to 5. This analysis of MHC gene associa- LUPUS ERYTHEMATOSUS
tions is complicated by the existence of extended HLA
haplotypes in which class II genes are in linkage dis- Several strains of inbred mice with inherited lupuslike
equilibrium with other potential susceptibility genes. disease have been studied as models to elucidate the
Because the MHC is rich in genes for immune-system human disease. These mice mimic human SLE in ANA
elements, the association of disease with a class II production, immune complex glomerulonephritis,
marker does not denote a specific functional abnormal- lymphadenopathy, and abnormal B-cell and T-cell func-
ity promoting pathogenesis. tion. These strains differ in the expression of certain
Among other MHC gene systems, inherited comple- serologic and clinical findings (e.g., anti-Sm, hemolytic
ment deficiencies can influence disease susceptibility. anemia, and arthritis), as well as in the occurrence of
Like class I and II molecules, complement components, disease among males and females. Among various lupus
in particular C4a and C4b, show striking genetic poly- strains described (NZB, NZB/NZW, MRL-lpr/lpr,
morphism, with a deficiency of C4a molecules (null BXSB, and C3H-gl/lgld), the development of a full-
alleles) a common occurrence in the population. As blown lupus syndrome requires multiple unlinked genes
many as 80% of people with SLE have null alleles irre- (11).
spective of ethnic background, with homozygous C4a In mice, single mutant genes (lpr, gld, and Yaa) can
deficiency conferring a high risk for SLE. Because C4a promote anti-DNA production and abnormalities in the
null alleles are part of an extended HLA haplotype with number and function of B and T cells. In lpr and gld
the markers HLA-B8 and HLA-DR3, the influence of mice, these abnormalities result from mutations in pro-
these class I and class II alleles of disease susceptibility teins involved in apoptosis. Apoptosis plays a critical
may reflect linkage disequilibrium with complement role in the development of the immune system, as well
deficiency. SLE also is associated with inherited defi- as in the establishment and maintenance of tolerance.
ciency of Clq, Clr/s, and C2 (12). The lpr mutation leads to the absence of Fas, a cell-
An association of SLE with inherited complement surface molecule that triggers apoptosis in lymphocytes,
deficiency may seem surprising because of the promi- and gld affects a molecule that interacts with Fas, the
nence of immune-complex deposition and complement Fas ligand. These gene defects appear to operate in
consumption during disease. However, a decrease in peripheral, in contrast to central, tolerance and allow
complement activity could promote disease susceptibil- the persistence of autoreactive cells. Among humans,
ity by impairing the clearance of foreign antigen or while mutations of Fas can lead to lymphoproliferation
apoptotic cells. Apoptosis, or programmed cell death, is and autoantibody production, clinical and serologic
associated with the breakdown of DNA, the rearrange- findings of SLE are uncommon, suggesting that in
ment of intracellular constituents, and the release DNA humans, as in the mouse, SLE requires more than one
and RNA into external milieu where these molecules, gene.
alone or in the context of immune complexes, could The interaction of genes in SLE also occurs in New
stimulate the immune system by the TLRs. Zealand mice. NZB/NZW F1 mice develop an SLE-like
As shown in in vitro and in vivo systems, the clear- illness that results from genes contributed by both NZB
ance of apoptotic cells, a process called efferocytosis, and NZW parents. Among these genes, an interferon
involves diverse cellular and humoral pathways, includ- inducible gene called Ifi202 contributes powerfully to
ing the complement system. Clq, for example, binds to the development of autoimmunity, providing additional
apoptotic cells, initiating complements role in clear- evidence between the link between the interferon
ance. In the absence of complement, apoptotic cells system and SLE (8). In the NZM2410 model, extensive
may persist and stimulate immune responses. The genetic studies have shown that genes that can promote
importance of complement deficiency to autoimmunity as well as suppress autoimmunity. Individually, genes
that promote autoimmunity (denoted sle1, sle2, sle3) related molecular techniques, peripheral blood cells of
lead to distinct immune disturbances, including expres- SLE patients demonstrate patterns of gene expression
sion of ANA. When these genes are co-expressed consistent with stimulation by IFN-alpha. Furthermore,
because of genetic crosses, the clinical and serologic this signature appears to be associated with antibodies
features of SLE occur. Importantly, other genes can to DNA or RNP antigens, consistent with stimulation
suppress the development of SLE in mice, indicating of this cytokine by the nucleic acid components of
complexity in the genetic predisposition for disease immune complexes impacting on Toll-like receptors
(11). (TLR) or other receptors (see Chapter 4) (16,17). In
Among lupus mice, New Zealand strains have an view of the broad effects of the type I interferons on the
MHC-linked deficiency in the expression of the proin- immune system, a host of nonspecific functional abnor-
flammatory cytokine tumor necrosis factor alpha (TNF- malities could result from the presence of high levels of
alpha). This deficiency may be pathogenic because this cytokine.
administration of TNF-alpha to mice with low endoge- Although nonspecific immune activation can provoke
nous production ameliorates disease. In humans, TNF certain ANA responses, it does not appear to be the
blockers have not been extensively used to treat patients major mechanism for inducing pathogenic autoantibod-
because of concerns that it can potentiate autoreactiv- ies, especially anti-DNA. Levels of these antibodies far
ity; in small clinical trials, however, such therapy did not exceed the extent of hyperglobulinemia. In addition,
exacerbate disease (14). A role of TNF-alpha in the anti-DNA antibodies have features indicative of in vivo
pathogenesis of autoimmunity is also suggested by the antigen selection by a receptor-driven mechanism.
development of anti-DNA antibodies in patients with These features include variable-region somatic muta-
rheumatoid arthritis treated with TNF blockers, tions that increase DNA binding activity and specificity
although the full development of SLE is very uncom- for dsDNA. The generation of such responses also may
mon in this setting. be affected by the composition of the pre-immune rep-
A variety of new SLE models have been created ertoire and the content of precursors that can be mutated
using molecular genetic techniques. These models under influence of self-antigen drive.
reflect aberrant patterns of gene expression that occur The ability of DNA to drive autoantibody produc-
in mice in which specific genes are eliminated by knock- tion in SLE contrasts with the poor immunogenicity of
out techniques or enhanced by transgene expression. mammalian DNA when administered to normal animals.
Studies of these mice suggest that a variety of genetic This discrepancy suggests that SLE patients either have
abnormalities may predispose to autoimmunity and a unique capacity to respond to DNA or are exposed to
genes regulating immune cell life span or signaling DNA in a form with enhanced immunogenicity (e.g.,
threshold may lead to autoantibody production. These surface blebs on apoptotic cells or nucleosomes).
genetic defects may affect the establishment of toler- Although serologic profiles of people with SLE and
ance or the persistence of autoreactive cells. mice with murine models of SLE point to nucleosomes
as the driving antigen, bacterial or viral DNA may stim-
ulate this response. Bacterial DNA, because of charac-
IMMUNE CELL DISTURBANCES teristic sequence motifs, can stimulate a TLR directly
and has potent adjuvant properties. As a result, bacte-
Autoantibody production in SLE occurs in the set- rial DNA is immunogenic and may be able to elicit
ting of generalized immune cell abnormalities that anti-DNA autoantibodies in a genetically susceptible
involve the B cell, T cell, and monocyte lineages. These host (18).
immune cell disturbances appear to promote B-cell The specificity of ANA directed to nuclear proteins
hyperactivity, leading to hyperglobulinemia, increased supports the hypothesis that these responses are antigen
numbers of antibody-producing cells, and heightened driven, because these antibodies bind multiple indepen-
responses to many antigens, both self and foreign. dent determinants found in different regions of these
Another consequence of B-cell and T-cell disturbance proteins. The pattern of ANA binding minimizes
in SLE may be abnormal tolerance. In healthy indi- the possibility that molecular mimicry is the exclusive
viduals, anti-DNA precursors are tolerated by anergy etiology for autoimmunity in SLE. This type of cross-
or deletion; however, people with SLE or animals reactivity has been hypothesized for many different
with SLE models may retain such precursors, which autoimmune diseases, and it has been suggested for
can be stimulated to generate high affinity autoanti- SLE because of the sequence similarity between certain
body responses (15). nuclear antigens and viral and bacterial proteins.
While these immune cell disturbances can affect mul- However, if SLE autoantibodies resulted from molecu-
tiple cell types and lineages, the appearance of an inter- lar mimicry, they would be expected to bind self-antigen
feron signature is a prominent feature in peripheral only at sites of homology with foreign antigen, rather
blood cells of patients. As shown using microarray and than throughout the entire molecule. While self-antigen
can sustain ANA production, a cross-reactive response

to a foreign antigen can initiate it. A role of infection in REFERENCES
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are infected more commonly with EpsteinBarr virus 1. Ward MM, Pyun E. Studenski S. Long-term survival in
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Among these potential influences are infectious agents, 10. Huerta PT, Kowal C, DeGiorgio LA, et al. Immunity and
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which can provoke neuroendocrine changes affecting 11. Lauwerys BR, Wakeland EK. Genetics of lupus nephritis.
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immunogenicity of self-antigens; and physical agents, tosus. Ann Rev Immunol 2004;22:431456.
13. Botto M, DellAgnola C, Bygrave AE, et al. Homozygous
such as sunlight, which can cause inflammation and
C1q deficiency causes glomerulonephritis associated
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remission. temic lupus erythematosus: an open-label study. Arthritis
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cal abnormalities years in advance of clinical disease 15. Yurasov S, Wardemann H, Hammersen J, et al. Defective
manifestations (20), mechanistically, disease may B cell tolerance checkpoints in systemic lupus erythema-
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induction gene expression signature in peripheral blood
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NZB/NZW mice by immunization with bacterial DNA. J 20. Arbuckle MR, McClain MT, Rubertone MV, et al. Devel-
Clin Invest 1995;95:13981402. opment of autoantibodies before the clinical onset of
19. James JA, Kaufman KM, Farris AD, Taylor-Albert E, systemic lupus erythematosus. N Engl J Med 2003;349:
Lehman TJA, Harley JB. An increased prevalence of 14991500.
Epstein-Barr virus infection in young patients suggests a
CHAPTER 15

SUSAN MANZI, MD, MPH
AMY H. KAO, MD, MPH
Global management of systemic lupus erythematosus dal anti-inflammatory drugs (NSAIDs), corticosteroids,
(SLE) importantly includes education, photoprotection, and antimalarials.
maintaining good physical conditioning, appropriate Treatment of severe organ involvement typically
immunization, and identifying and treating risk requires immunosuppressive agents.
factors for cardiovascular disease. Targeted biologic therapies are under development
Many traditional treatments are available for the that may change treatment algorithms in the future.
nonorgan manifestations of SLE, including nonsterio-
The significant improvement in survival and quality of highway, primarily the Internet. It is the duty of the
life in patients with systemic lupus erythematosus (SLE) physicians and health care providers to clarify the con-
is the result of major advances over the past half century fusion and alleviate the fear caused by learning about
in the management of SLE. Milestones in the treatment the worst-case scenarios of SLE through the means of
of lupus include the discovery and use of corticosteroids Internet, friends, and family members.
in the 1950s, renal dialysis in the 1960s, and cyclophos- Fatigue is very common in patients with SLE. The
phamide in the 1970s. However, there has been a cause may be multifactorial, and include other comor-
drought of almost 40 years when it comes to new thera- bid conditions, such as hypothyroidism, depression,
peutic agents for lupus. Corticosteroids, hydroxychloro- fibromyalgia, and deconditioning from chronic illness.
quine, and aspirin are the only three drugs currently Thus, therapy relies on identifying the underlying eti-
approved by the US Food and Drug Administration ologies. Patients with photosensitivity can also develop
(FDA) for treatment of SLE. Novel therapeutics with fatigue and disease flare following exposure to ultravio-
more specific targets directed toward the autoimmune let light. Photoprotection includes avoidance of excess
aspects of SLE are on the horizon. The goals of therapy sunlight during mid-day, routine sunscreen/sunblock,
are the reduction of both autoimmunity and target and photoprotective clothing. Window films and fluo-
organ damage from inflammation and injury. In addi- rescent light shields reduce ultraviolet light exposure
tion, side effects of therapy must be addressed as part and can minimize the risk of lupus flare due to photo-
of the management of SLE. It is crucial to recognize the sensitivity. Patients also need to be cautioned regarding
wide spectrum of clinical manifestations in SLE. The drug-induced photosensitivity, commonly seen with
treatment should be tailored based on the clinical mani- antibiotics. Sedentary lifestyle resulting from chronic
festations in an individual patient because SLE mani- illness, depression, or fibromyalgia is another promi-
fests a unique disease profile in everyone afflicted. nent feature in patients with SLE. This problem can
lead to obesity and poor physical and cardiac health.
SLE patients have been found to have diminished
GENERAL MANAGEMENT aerobic capacity (1). Low impact aerobic exercise, such
as aquatic therapy, and walking exercise should be
Patient education directed toward understanding of the considered part of the nonpharmacologic regimen in
disease and therapy is fundamental in management of patients with SLE.
any chronic illness. Many patients may already have Infections are common in SLE due to the intrinsic
begun their own investigation through the information immune dysregulation and chronic immunosuppressive
327
328 SUSAN MANZI AND AMY H. KAO
use. Patients should be advised to seek medical atten- serositis, and headaches. The choice of NSAID is deter-
tion for unexplained fevers and not immediately attri- mined by cost, effectiveness, and side effects. The effec-
bute these fevers to lupus flares. Judicious use of tiveness of these agents varies among individual patients
corticosteroids and immunosuppressive agents and and also can change in the same patient over time. In
appropriate immunization with influenza and pneumo- patients with renal impairment from lupus nephritis,
coccal vaccines can minimize the risk of infection. both selective and nonselective NSAIDs should be
Patients with SLE are at increased risk of premature avoided because the inhibition of cyclooxygenase
cardiovascular disease (CVD). It is important to reduce (COX) by NSAIDs can further impair the renal blood
modifiable risk factors including tobacco use, obesity, flow and the maintenance of tubular transport through
sedentary lifestyle, dyslipidemia, and hypertension. The the reduction of both prostaglandins and prostacyclins.
disease and its treatment can exacerbate these known Side effect profiles for renal, hepatic, and central nervous
CVD risk factors. Smoking cessation, weight reduction system (CNS) toxicities are similar in nonselective COX
by dietary and exercise modalities, good blood pressure inhibitors and selective COX-2 inhibitors. These side
control, and annual monitoring of fasting lipid profiles effects may be confused with SLE activity. Mild and
are ways that may reduce the CVD risk in SLE patients. reversible increases in hepatic enzymes are common
Similarly, osteoporosis is quite common, especially in side effect of NSAIDs. Similarly, aseptic meningitis,
patients that require prolonged corticosteroid therapy. headache, confusion, cognitive dysfunction, and even
Several studies have demonstrated that the heightened psychosis may be seen in patients using NSAIDs. Selec-
risk of bone loss in lupus is seen in all ethnicities, includ- tive COX-2 inhibitors reduce the gastrointestinal side
ing African American women, who are normally less effects, namely peptic ulcers and bleeding. However,
susceptible. Calcium plus vitamin D supplementation due to the increased risk of cardiovascular events in
and antiresorptive agents (bisphosphonate) should be selective COX-2 users, these agents should generally be
instituted appropriately. The safety of bisphosphonates avoided in patients with known coronary heart disease.
in young individuals and those in childbearing age Only one selective COX-2 inhibitor (celecoxib) remains
remains unclear. Because of recent evidence to support in the current market. The antiplatelet effect of nonse-
a high prevalence of vitamin D deficiency in SLE, it is lective COX inhibitors can increase the risk of bleeding
advisable to check levels of 25-hydroxy vitamin D as a during surgical procedures and with concomitant use
part of routine health maintenance. of anticoagulants; thus, nonselective COX inhibitors
Women with SLE may be at increased risk for cervi- should be discontinued prior to surgery and should be
cal dysplasia and cervical cancer, in part due to the used judiciously in the setting of anticoagulation.
chronic infection from human papilloma virus. Simi- NSAIDs should be discontinued towards the third tri-
larly, a recent international collaborative study reported mester in pregnant patients, due to the risk of prema-
an increased risk of malignancy, particularly non-Hodg- ture closure of ductus arteriosus.
kins lymphoma, in patients with lupus (2). Whether this
increased risk is related to the underlying disease or the
drugs used to treat lupus is unclear. Age-appropriate
Corticosteroids
health maintenance, including gynecological and breast Corticosteroids are effective in the treatment of various
examination, and colonoscopy is recommended. inflammatory rheumatic diseases; they can also provide
immediate relief of many manifestations of SLE. Topical
corticosteroids are frequently used for local treatment
CURRENT THERAPY of mucocutaneous disease. Systemic corticosteroids
ranging from 5 mg to 30 mg equivalent dose of predni-
The key to selecting appropriate therapies relies on the sone in single or divided doses given daily are effective
careful assessment of the organ involvement and the in treatment of mild-to-moderate SLE disease, includ-
severity of lupus disease activity. Because most medica- ing cutaneous disease, arthritis, and serositis. More
tions have potential adverse reactions, Table 15C-1 out- severe organ involvement, specifically nephritis, pneu-
lines the strategies for toxicity monitoring of medications monitis, hematologic abnormalities, CNS disease, and
commonly used in SLE. systemic vasculitis, require high dosages of corticoste-
roids in oral or parental preparations in equivalent
dosages of prednisone of 1 to 2 mg/kg/day. Intravenous
Nonsteroidal Anti-Inflammatory pulse methylprednisolone (1 g) can be given for three
consecutive days when these severe manifestations of
Drugs SLE are life threatening.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are Systemic corticosteroids can act as bridging therapy
effective in pain relief and are widely used in patients for the slower-acting immunomodulatory agents (dis-
for diverse manifestations including arthritis, myalgia, cussed later). Corticosteroids can then be tapered when
TABLE 15C-1. RECOMMENDED MONITORING FOR TOXICITIES OF DRUGS USED IN SYSTEMIC LUPUS ERYTHEMATOSUS.
MONITORING
DRUG ADVERSE REACTIONS PREGNANCY Baseline evaluation Routine evaluation Annual evaluation
NSAIDs GI bleeding, hepatotoxicity, Discontinue in third CBC, creatinine, urinalysis, Creatinine, AST, ALT every CBC
nephrotoxicity, hypertension, trimester AST, ALT 6 months
headache, aseptic meningitis
Corticosteroids Cushingoid features Safe but keep to the Fasting lipid profile, DXA, Blood pressure, glucose DXA and fasting lipid profile
(hypertension, dyslipidemia, lowest dose glucose, blood pressure
hyperglycemia), cataracts,
osteonecrosis, osteoporosis
Antimalarials Retinopathy, GI complaints, Safe Eye exam in patients over Fundoscopic and visual
rash, myalgia, headache; 40 years old or with field exams every 612
hemolytic anemia in patients previous eye diseases; months
with G6PD deficiency G6PD level in high risk
patients;
Dapsone Hemolytic anemia in patients Discontinue 4 weeks CBC, platelets, creatinine, CBC and platelet every
with G6PD deficiency; before delivery AST, ALT; G6PD level in 12 weeks with changes
methemoglobinemia high-risk patients in dose (every 13
months afterwards)
Azathioprine Myelosuppression, hepatatoxicity, Safe CBC, platelets, creatinine, CBC and platelet every 12 Pap test and age-appropriate
lymphoproliferative disorders AST, ALT, hepatitis B weeks with changes in routine health maintenance
and C serology dose and then AST, ALT
every 13 months
afterwards
Methotrexate Mucositis, myelosuppression, Teratogenic CBC, platelets, creatinine, CBC and platelet, AST, ALT, Pap test and age-appropriate
hepatatoxicity, cirrhosis, AST, ALT, hepatitis B albumin, creatinine routine health maintenance
pneumonitis, pulmonary and C serology every 12 months
fibrosis
Mycophenolate Myelosuppression, GI complaints, Limited data (avoid) CBC, platelets, creatinine, CBC and platelet, AST, ALT, Pap test and age-appropriate
mofetil myalgia AST, ALT, hepatitis B albumin, creatinine routine health maintenance
and C serology every 12 months
Cyclosporine Myelosuppression, gingival Safe CBC, platelets, creatinine, CBC and platelet, AST, ALT, Fasting lipid profile; Pap test
hypertrophy, hepatotoxicity, AST, ALT, hepatitis B albumin, creatinine, and age-appropriate routine
nephrotoxicity, dyslipidemia, and C serology, urinalysis every 12 health maintenance
hyperuricemia urinalysis months
Cyclophosphamide Myelosuppression, hemorrhagic Teratogenic CBC, creatinine, AST, ALT, CBC and platelet, AST, ALT, Urine cytology; Pap test and
cystitis, lymphoproliferative hepatitis B and C creatinine, urinalysis age-appropriate routine
disorders, malignancy, infertility serology, urinalysis monthly health maintenance
ABBREVIATIONS: ALT, alanine transaminases; AST, aspartate transaminases; CBC, complete blood cell count; DXA, bone densitometry; G6PD, glucose-6-phosphate dehydrogenase; GI, gastrointestinal; Pap,
Papanicolaou.
15
the immunomodulator begins to take effect. Once the or 400 mg/day (56.5 mg/kg/day). The response of HCQ
disease activity is under control, corticosteroids are is very slow and typically occurs after 6 weeks; its peak
tapered to none or minimal daily (prednisone 5 mg/ efficacy may not be reached for 4 months. Hydroxychlo-
day) or alternate-day dosing for maintenance therapy. roquine demonstrated clinical efficacy in a randomized
The goal of successful tapering of the corticosteroids is withdrawal trial when patients who discontinued HCQ
to reduce the numerous potential but common side were 2.5 times more likely to develop mild lupus flare
effects of prolonged corticosteroid therapy while than those who maintained the treatment (3). Long-
avoiding disease relapse or exacerbation. Common side term follow-up of this study suggested a trend towards
effects of systemic corticosteroids include emotional reduction in flares in those who remained on HCQ,
lability, glaucoma, cataracts, peptic ulcer disease, osteo- although this reduction was not statistically significant
porosis, osteonecrosis, increased infection risk, and (4). In addition, HCQ use appeared to predict renal
Cushingoid features (central obesity, striae, hyperten- remission within 1 year in lupus patients treated with
sion, diabetes mellitus, and dyslipidemia). mycophenolate mofetil for membranous glomerulone-
phritis (5). Two studies have shown that cigarette
smoking may interfere with the efficacy of antimalarials
Topical Agents in treating patients with discoid lupus and subacute
Similar to minimizing the use of systemic corticoste- cutaneous lupus (6,7). Smokers were found to be less
roids, topical corticosteroids can be tapered to discon- responsive to the antimalarial therapy than nonsmokers
tinuation or on an as-needed basis once the slower-acting with a dose effect, meaning patients who smoked the
immunomodulators or immunosuppressive agents are most had the least response to antimalarials (7). In addi-
instituted. Clobetasol (high potency) in the preparation tion, improvement of skin lesions occurred once the
of solution or foam can be used to treat alopecia caused patients stopped smoking while remaining on antima-
by SLE-associated rashes. The use of high potency or larial therapy.
fluorinated topical corticosteroids should be avoided on Chloroquine is used at 250 mg/day (3.5 mg/kg/day)
the face and intertriginous areas due to the increased with effects seen within 3 to 4 weeks, sooner than that
risk of developing skin atrophy and telangiectasias. In of HCQ. Quinacrine, which has a rapid onset of action
addition, topical corticosteroids should not be used similar to chloroquine, is usually dosed at 100 to 200 mg/
continuously due to the development of tachyphylaxis. day (2.5 mg/kg/day). Combination therapy with HCQ
Typically, patients can apply the topical corticosteroids (or chloroquine) and quinacrine is commonly used with
on weekdays and none on weekends. Other steroid- success when one agent alone is not effective.
sparing topical agents, such as tacrolimus or pimecroli- Gastrointestinal side effects are the most common.
mus, can be given during steroid-drug holidays. They are often transient and reduced by lowering the
Intralesional triamcinolone may be administered in dose of the antimalarials or administering brand rather
hypertrophic lupus lesions. Both topical tacrolimus and than generic. Most common complaints include crampy
pimecrolimus ointments are FDA approved for atopic abdominal pain, nausea, vomiting, bloating, or diarrhea.
dermatitis. They inhibit T-cell proliferation and release Chloroquine less frequently causes gastrointestinal
of cytokines. Unlike corticosteroids, they do not affect reactions followed by hydroxychloroquine and quina-
keratinocytes, endothelial cells, and fibroblasts, and crine. Chloroquine has a higher incidence of retinal
thus do not induce skin atrophy. Topical retinoids, toxicity causing visual field defects than HCQ. There-
including tretinoin and tazarotene, have both anti- fore, HCQ and chloroquine should be used together
inflammatory and immunosuppressive effects and have with caution because the risk of retinopathy is high with
been used successfully for the treatment of chronic cuta- this combination. Other visual symptoms include
neous lupus. Common side effects include local skin blurred distance vision, difficulty in reading, photopho-
irritation. bia, and flashing lights. The risk of retinal toxicity can
be minimized when the total daily recommended dose
of HCQ is kept 6.5 mg/kg/day, chloroquine 3 to
Antimalarials 4 mg/kg/day, and quinacrine 2.5 mg/kg/day. A long-
Antimalarial agents are the most common background term follow-up study demonstrated a very low incidence
therapy for SLE. Hydroxychloroquine (HCQ) is the of HCQ-related retinopathy (0.5%) in 400 patients
agent most frequently prescribed in the United States, who were treated with the recommended dosages for >6
followed by chloroquine and quinacrine. The antima- years (8). Despite the rarity of retinal toxicity, patients
larials are commonly used as the first-line immunomod- receiving antimalarials should have ophthalmologic
ulatory agents in the treatment of mild SLE disease evaluations at baseline and then at 6- to 12-month inter-
manifestations, including constitutional, cutaneous, and vals. This evaluation should include a fundoscopic
musculoskeletal. HCQ is usually initiated at 200 mg/day examination, visual field, and visual acuity testing.
dosage and eventually increased to 200 mg twice daily Antimalarials may cause hyperpigmentation on nails,
anterior legs, face, and, rarely mucous membranes, pre- Another serious adverse effect is bone marrow suppres-
dominantly on sun-exposed areas. Bluish-gray to dark sion, which appears to be an idiosyncratic reaction to
purple discoloration is associated with HCQ therapy, dapsone that is exacerbated by the concomitant use of
while yellow discoloration with quinacrine. Hypopig- a folate antagonist. Similar to antimalarials, patients
mented lesions that involve mainly the hair or lentigines with G6PD deficiency are at increased risk of develop-
may occur with chloroquine therapy. These cutaneous ing hemolytic anemia while taking dapsone. Although
lesions can gradually resolve after discontinuation of dapsone is not teratogenic, it can increase the risk of
the drug. Rare but serious cardiotoxicity from HCQ and methemoglobinemia and cyanosis in neonates as
chloroquine with the presentation of myocardial dys- observed in adults (16). Discontinuation of dapsone
function has been reported, although less than half of therapy 1 month before the expected date of delivery
the cases were biopsy proven (912). Histologic findings to minimize the theoretical risk of kernicterus is recom-
of the endomyocardial biopsy may reveal myeloid and mended (17). Breastfeeding by mothers taking dapsone 15
curvilinear bodies (lipid-rich structures representing should be cautioned because this drug is secreted in
abnormal lysosomes) with variable myofiber atrophy breast milk and can place the infants at risk of develop-
and necrosis (13). Older women with long duration of ing hemolytic anemia.
antimalarial therapy appeared to be in greater risk for
this cardiotoxicity. Drug-induced myopathy from HCQ
has also been reported with the presence of curvilinear
Azathioprine
bodies in skeletal muscle biopsy. Azathioprine (22.5 mg/kg/day) is frequently used as a
Hydroxychloroquine has hypoglycemic properties steroid-sparing agent in patients with mild-to-moderate
that could improve glycemic control in patients with disease activity, and as an alternative maintenance
poorly controlled type 2 diabetes (14). In addition, therapy to cyclophosphamide in patients with lupus
HCQ may lower the insulin requirement in patients nephritis and other organ-threatening manifestations.
with type 2 diabetes on insulin therapy, thereby placing This agent is a purine analog and a mercaptopurine
these patients at greater risk for hypoglycemic events. immunosuppressant that inhibits nucleic acid synthesis
Thus, patients should be aware of the hypoglycemic and thus affects both cellular and humoral immune
effects of HCQ. Another precaution of antimalarials is function. Azathioprine can be used during pregnancy in
the risk of hemolytic anemia in patients with glucose-6- women who may require an immunomodulator stron-
phosphate dehydrogenase (G6PD) deficiency. G6PD ger than the antimalarials can provide. Azathioprine
deficiency is more common in the Mediterranean passes into breast milk; thus mothers on azathioprine
regions, Middle East, Africa, and the Indian subconti- should not breastfeed their infants.
nent. Physicians need to be aware of this increased risk The main adverse reaction of azathioprine is acute
in patients of these descents. HCQ has been shown to myelotoxicity, manifesting as pancytopenia in patients
be safe during pregnancy (15). No retinal toxicity or who are deficient in the enzyme thiopurine methyltrans-
otoxicitiy in children born to women on HCQ has been ferase (TPMT) that inactivates azathioprine. Drug
reported. The safety of HCQ, chloroquine, and quina- interaction between azathioprine and allopurinol (used
crine in breastfeeding has not been established. in the treatment of gout) can also cause acute pancyto-
penia. This combination should be avoided. The other
common side effect is gastrointestinal toxicity similar to
Dapsone the antimalarials. Azathioprine requires regular moni-
Dapsone is a sulfone antibiotic used in the treatment of toring of renal and liver functions because of the hepatic
leprosy and for the prophylaxis of Pneumocystis jirovec- metabolism and renal excretion. Dosage should be
cii pneumonia (previously known as Pneumocystis adjusted in patients with renal or hepatic dysfunction.
carinii pneumonia). Dapsone has additional immuno-
modulatory properties, particularly effective against
neutrophil-mediated processes, and is used to treat
Methotrexate
various bullous disorders, erythema nodosum, pyo- Methotrexate has been the standard therapy of rheuma-
derma gangrenosum, Sweets syndrome, cutaneous toid arthritis, with extensive data demonstrating its effi-
vasculitis, and cutaneous lupus. Dapsone (100 mg/day) cacy and safety in this disease. However, there are only
alone or in combination with systemic corticosteroids/ a few prospective randomized trials of methotrexate
antimalarials, is the drug of choice for bullous SLE as therapy for SLE, with conflicting results. Numerous case
well as for cutaneous lesions involving the small dermal series and few retrospective studies have demonstrated
vessels, such as leukocytoclastic vasculitis. success in the treatment of active cutaneous and/or artic-
The most serious but rare side effect is the hyper- ular involvements, allowing corticosteroid taper.
sensitivity syndrome, characterized by fever, rash, Methotrexate is an analog of dihydrofolic acid,
lymphadenopathy, hepatitis, and hepatosplenomegaly. which inhibits dehydrofolate reductase, and has
immunomodulatory effects at low doses without the Most side effects are dose dependent and reversible.
cytotoxic or antiproliferative effects seen in the very They include hypertension, elevations in serum creati-
high doses that are typically given in chemotherapy. nine and hepatic enzymes, tremor, hypertrichosis,
Side effects are common and include gastrointestinal gingival hypertrophy, parathesis, gastrointestinal com-
complaints, mucositis, alopecia, hepatic enzyme eleva- plaints, and infections. Cyclosporine can also cause
tions, and infections, especially when the dosage is high. hyperkalemia, dyslipidemia, and worsen hyperuricemia
These side effects may be minimized if the methotrex- that can lead to a gouty flare. Although cyclosporine
ate is given in the range of 7.5 to 15 mg/week. Addition appears to be effective in treatment of refractory
of daily folate or weekly folinic acid supplementation nephrotic syndrome or membranous glomerulonephri-
may alleviate the common side effects of oral ulcers and tis (WHO class V), long-term therapy can result in
alopecia. Injectable administration of methotrexate can structural changes in the kidneys, such as interstitial
improve the bioavailability of this medication and may fibrosis and tubular atrophy. Therefore, regular moni-
also minimize the gastrointestinal complaints (nausea, toring of renal function and blood pressure are
vomiting, diarrhea, and abdominal cramps). Abnormal advised.
liver function tests are of concern if the elevations
persist; however, they are often poor predictors of the
severity of hepatotoxicity by histopathology. Patients
Cyclophosphamide
taking methotrexate should be advised against regular Cyclophosphamide is an alkylating and cytotoxic agent,
alcohol consumption because the combination of meth- which cross-links DNA and DNA-associated proteins.
otrexate and alcohol can further increase the risk of It is reserved for the treatment of severe SLE, including
hepatotoxicity. A rare but potentially life-threatening lupus nephritis, central nervous system disease, pulmo-
pulmonary complication is methotrexate-induced pneu- nary hemorrhage, and systemic vasculitis. The results of
monitis. This adverse reaction can develop early as well the landmark randomized trial by the National Insti-
as late in the course of the treatment and needs to be tutes of Health (NIH) in 1986 set the gold standard
distinguished from infectious pneumonia and lupus for treatment of patients with diffuse proliferative
pneumonitis. Discontinuation of methotrexate is war- glomerulonephritis (21). In this study, patients treated
ranted when either pneumonia or methotrexate-induced with corticosteroids and intermittent cyclophosphamide
pneumonitis is suspected. The teratogenicity of metho- (intravenous bolus regimens of 0.51 g/m2 body surface
trexate is well established. Methotrexate should there- area) had significantly better renal survival than those
fore be discontinued 6 months prior to pregnancy, treated with corticosteroids alone. However, no signifi-
regardless of the patients gender. cant difference in renal survival was found between this
regimen and the one with azathioprine. The traditional
cyclophosphamide regimen for diffuse proliferative glo-
Cyclosporine merulonephritis is 6 to 7 monthly pulse of cyclophos-
Cyclosporine primarily inhibits the proliferation of T phamide alone or with pulse methylprednisolone in the
lymphocytes and selectively inhibits T-cellmediated induction, and then quarterly pulse cyclophosphamide
responses, such as interleukin 2 (IL-2), IL-3, and inter- for 2 years. The intravenous administration of cyclo-
feron gamma (IFN-gamma), and other cytokines at the phosphamide has the advantage over oral formulations
transcriptional level from naive T cells. Although SLE in that the bladder can be protected by intravenous
has been thought to arise from B-cellmediated autoim- infusion of mesna (mercapto-ethanesulphonic acid)
munity with autoantibody production and immune- along with rigorous hydration to prevent hemorrhagic
complex formation, there is evidence that indicates a cystitis and bladder cancer from acrolein, a toxic metab-
primary role for T cells. In murine models of SLE, olite of cyclophosphamide. Variations of shorter dura-
depletion of CD4+ T cells prevents disease onset (18) tion and/or lower dose of cyclophosphamide therapy
and athymic mice do not develop SLE (19). Dosages of have been studied with varying results; however, due to
cyclosporine ranging from 2.5 to 5 mg/kg/day are gener- the toxicity of an extended cyclophosphamide regimen,
ally well tolerated, with reduction of corticosteroid attempts to reduce exposure by changing to alternate
dosage and improvement in disease activity, protein- treatments are an active area of investigation.
uria, leukopenia, thrombocytopenia, and complement Adverse effects of cyclophosphamide include nausea
levels (20). Limited pregnancy data primarily from the and vomiting, alopecia, bone marrow suppression,
transplant patients showed no increased in adverse out- increased risk of infections, and bladder carcinoma.
comes in pregnancy. This medication is not teratogenic Cyclophosphamide has been associated with increased
in animals. Cyclosporine can be continued in pregnant risk for cervical dysplasia and cervical intraepithelial
patients with SLE if the benefits outweigh the risks. neoplasia (22,23). Nausea and vomiting can be pre-
Mothers taking cyclosporine are advised against breast- vented with anti-emetic drugs such as ondansteron and
feeding because cyclosporine passes into breast milk. dolasetron, given on a regular schedule during the first
24 hours and then as needed afterwards. A dose- spective studies are needed to provide more informa-
dependent nadir leukocyte count should be checked 8 tion on the efficacy and safety of leflunomide in
to 12 days after intravenous cyclophosphamide therapy. treatment of SLE.
Infertility due to gonadal toxicity from cyclophospha- The most common adverse reaction is diarrhea, which
mide is one of the most concerning side effects. The two is usually transient or improves with dose reduction.
key factors associated with the risk of ovarian failure Other common side effects include elevation in hepatic
in women are older age at the start of treatment and enzymes, hypertension, and transient leukopenia. Sub-
higher cumulative dose of cyclophosphamide. Use of acute cutaneous lupus precipitated by leflunomide has
cyclophosphamide during pregnancy and lactation is been reported (27). Leflunomide is teratogenic. Because
prohibited. the half-life of leflunomide is quite long (15 days) due
to enterohepatic circulation, its use is contraindicated in
Mycophenolate Mofetil patients who are pregnant or who plan to have a child. 15
Breastfeeding is not advised while taking leflunomide.
Mycophenolate mofetil (MMF) is an inactive prodrug Before pregnancy is considered, plasma concentration
of mycophenolic acid (MPA), which inhibits inosine of its active metabolite (A77 1726) should be <0.2 mg/L
monophosphate dehydrogenase, lymphocyte prolifera- on two occasions 2 weeks apart. In the event of preg-
tion, and both T- and B-cell function. MMF has been nancy or toxicity, leflunomide can be eliminated by
widely used to prevent renal allograft rejection. Many administering 8 g cholestyramine three times daily for 11
case series and small controlled trials have suggested days. Therefore, use of leflunomide may not be recom-
the effectiveness of MMF in treatment of lupus nephri- mended in young SLE patients of childbearing age.
tis. A recent randomized, open-label, noninferiority
trial supports the notion that MMF appeared to be as
effective as intravenous cyclophosphamide in inducing
Hormonal Therapy
short-term remission of lupus nephritis with a better Dehydroepiandrosterone (DHEA) is an adrenal steroid
safety profile (24). The role of MMF in improving long- with mild androgenic activity that has shown some
term outcomes of lupus nephritis remains unknown. promise for the treatment of mild-to-moderate SLE
An ongoing larger, multicenter, randomized, controlled disease activity in several clinical trials. Preliminary
trial will examine effectiveness of MMF compared to results from a recent randomized, controlled trial showed
intravenous cyclophosphamide during induction, and that prasterone (DHEA) preserved bone mineral
MMF compared to azathioprine during the mainte- density (BMD) and significantly improved the BMD in
nance phase. MMF is a promising addition to the arma- women with SLE receiving chronic corticosteroids (28).
mentarium of treatment of lupus nephritis, particularly However, the findings were not considered robust
in young women of childbearing potential when there enough for approval by the FDA. This drug is well toler-
are concerns of infertility. Pregnancy safety data of ated, with acne being the most frequent adverse effect.
MMF is limited; thus, it should be avoided during preg- Another hormonal therapy studied in SLE is bromocrip-
nancy and lactation. tine, a dopamine analog and a selective inhibitor of
Mycophenolate mofetil is generally well tolerated at anterior pituitary secretion of the immune-stimulatory
the dosing range from 500 mg to 1500 mg twice daily. hormone prolactin. Bromocriptine has shown benefit
Side effects include gastrointestinal complaints (nausea, in improving disease activity in SLE patients with and
bloating, and diarrhea), cytopenias, and increased risk without hyperprolactinemia (29). However, bro-
of infections. The gastrointestinal reactions can be mini- mocripine therapy remains experimental. Danazol, a
mized with gently escalating dosing of MMF or the use weak androgen, has been shown to be effective in the
of a preparation that comes in 250 mg capsules. treatment of autoimmune cytopenias, particularly
thrombocytopenia and hemolytic anemia (30).
Leflunomide
Leflunomide is effective in the treatment of rheumatoid
Thalidomide
arthritis. It inhibits dihydro-orotate dehydrogenase, a Much of the controversy associated with the use of tha-
key enzyme in de novo pyrimidine synthesis, and thus lidomide concerns its well-recognized teratogenicity.
decreases T- and B-cell proliferation. A few small Thalidomide is an immunomodulator with anti-
studies of short duration showed that leflunomide was angiogenic effects. It is highly effective at dosage ranging
well tolerated in patients with SLE (25,26). Due to the from 50 to 400 mg/day for treatment of refractory chronic
relative lack of renal toxicity, and mainly hepatic and cutaneous lupus although the precise mechanism
gastrointestinal metabolism, leflunomide appears to be remains unclear. There is a high rate (68%) of relapse
more favorable than cyclosporine or methotrexate in off the drug (31). Another common adverse effect is
those with renal impairment. Larger and long-term pro- peripheral neuropathy, reported in up to 50% of patients,
although there is a wide range of incidence rates (32). to rescue bone marrow of the patient with autologous
The neuropathy is not felt to be dose related and can be stem cell transplantation after receiving a high mye-
irreversible if the drug is not discontinued or the dose is loablative dose of cyclophosphamide. In addition, a
not reduced promptly. An important complication of high dose cyclophosphamide regimen is purported to
thalidomide is deep venous thrombosis, which occurs in reset the naive immune response in the bone marrow
up to 30% of patients with malignancy and has also been stem cells by destroying the autoreactive lymphocytes.
reported in patients with SLE (33,34). In the retrospective analysis of 53 patients with refrac-
tory SLE who underwent immunoablation and autolo-
Intravenous Immunoglobulin gous stem cell transplantation, a European group found
a remission rate based on a reduction of SLE disease
High dose intravenous immunoglobulin (IVIG) has activity index (SLEDAI) to less than 3 in 66% of these
been used in the treatment of hypogammaglobulinemia, patients (35). However, 1-year transplant related
refractory thrombocytopenia, and Kawasakis disease. mortality was high at 12%. A recent open-label study
The mechanisms of action are thought to include the demonstrated a reduction in disease activity by nonmy-
blockade of Fc receptors, complement inhibition, and eloablative autologous hematopoietic stem cell trans-
immunomodulation of T- and B-cell functions. Improve- plantation in patients with refractory SLE (36). There
ment in thrombocytopenia, arthritis, nephritis, and is a heightened infection and mortality risk associated
immunologic parameters have been reported after treat- with immunoablation therapy.
ment with IVIG. Because IVIG provides protection
against infections in immunodeficient patients, it is a
favorable treatment alternative in acutely ill patients
Immunoablation Without Stem
with SLE when there is a concern for a commitment Cell Transplantation
infection. IVIG can be administered in the usual dose High dose cyclophosphamide without stem cell trans-
of 2 g/kg, divided into 2 to 5 daily doses. Common side plantation is another approach that can lead to rapid
effects of IVIG include fever, myalgia, arthralgia, and hematopoietic reconstitution through granulocyte cell
headache. Rarely, aseptic meningitis and thromboembo- stimulating factor (G-CSF) therapy and clinical improve-
lism can occur. Patients with IgA deficiency will develop ment in patients with refractory SLE. Durable complete
serious anaphylactic reactions to IVIG infusion; thus, its remission of SLE has been reported in some patients
use is contraindicated in these patients. Quantitative with treatment-refractory moderate-to-severe disease
immunoglobulins should be checked for IgA deficiency (37). These studies are not randomized and thus are still
prior to the IVIG therapy. Patients with a hypercoagu- preliminary. These approaches require further valida-
lable state, such as antiphospholipid syndrome, should tion by controlled randomized studies.
be cautioned against the use of IVIG therapy due to the
increased risk of thromboembolism.
Renal Dialysis and Transplantation
Plasmapheresis The availability of renal dialysis and transplantation has
improved survival of patients with SLE. Aside from an
Plasma exchange or plasmapheresis is an effective but increased risk of infection, SLE patients generally do
costly therapy to rapidly remove circulating autoanti- well with dialysis. For those patients who undergo renal
bodies and immune complexes. It also comes with the transplantation, long-term patient and renal graft sur-
price of heightened risk of infection and anaphylaxis. vival are similar to those transplant patients without
The most common indications for plasmapheresis in SLE (38). However, the risk for thrombotic complica-
SLE include thrombotic thrombocyptopenic purpura tions, such as early graft thrombosis, may be greater in
(TTP), catastrophic antiphospholipid syndrome, pul- SLE patients, particularly those with positive antiphos-
monary hemorrhage, cryoglobulinemia, and hypervis- pholipid antibodies. The outcome of kidney transplan-
cosity syndrome. Other life-threatening complications tation largely depends on the clinical condition at the
of SLE may also be treated with plasmapheresis if con- time of transplantation. The risk of recurrence of lupus
ventional therapy has failed. nephritis in the transplanted kidneys ranges between
2% and 30% (39).
Immunoablation with Autologous
Stem Cell Transplantation NOVEL THERAPIES
In severe cases of SLE, cyclophosphamide is the
mainstay of therapy with its dose limited by myelosup- Moving away from global immunosuppression by tradi-
pression. The rationale behind immunoablation with tional drug therapies for SLE, designed therapeutics of
cyclophasmide followed by stem cell transplantation is the future provide improved efficacy and lower toxicity
B-cell depletion Inhibition of B-cell survival FIGURE 15C-1

Anti-CD20 CD22
Anti-BLvs
Anti-CD22 BAFF-R Targets for novel therapies in systemic
Anti-BAFF
CD20 TACI lupus erythematosus. Abbreviations: BCR,
BCMA
B-cell receptor; BAFF-R, B-cell activating
LJP
factor receptor; TACI, transmembrane
B-cell toleragen
394 BCR B cell activator and cyclophilin ligand interactor;
Inhibition of co-stimulatory BCMA, B-cell maturation activator; IL,
interactions interleukin; TNF, tumor necrosis factor;
CTLA4-Ig, cytotoxic T-lymphocyte
am CD80/CD86 CD40 Anti-CD40L
stre e
Cytokine
CTLA4-lg antigen-4 Ig.
o wn ckad receptor
CD40L
D Blo
CTLA4-lg CD28
CD80/CD86
15
T cell
Cytokine Inhibition
IL-6 Dendritic cell
IL-10 Cytokine
TNF- receptor
IFN-
IFN-_
Cytokine
receptor
by targeting specific steps in the pathogenesis of SLE zumab will validate its safety and efficacy in patients
while preserving immunocompetence. Many of the with SLE.
novel therapeutics are being developed and studied
currently in clinical trials. Some of the promising novel B-CellSpecific Toleragen
therapies are discussed in the following overview.
Figure 15C-1 depicts the specific targets for the novel Abetimus sodium (LJP 394) is a tetramer of double-
therapies. stranded oligonucleotides that can bind to DNA-
reactive B cells and induce B-cell anergy or apoptosis,
resulting in reduction of circulating double-stranded
B-Cell Depletion DNA antibodies. Results of a clinical trial in SLE
Rituximab and epratuzumab are two antibody- patients with renal disease showed that abetimus was
based agents, which target a specific cell-surface well tolerated and potentially effective in preventing
antigen on B cells and result in B-cell depletion. renal flares in a subset of patients with sustained reduc-
Rituximab is a chimeric monoclonal antibody that tions in antidouble-stranded DNA (anti-dsDNA)
binds CD20 on the surface of B cells. It is the first antibodies.
monoclonal antibody therapy approved by the FDA
for the treatment of non-Hodgkins lymphoma. Ritux- Inhibition of B-Cell Survival
imab is currently approved for use in rheumatoid
arthritis that is refractory to antitumor necrosis factor B-cell activating factor (BAFF)/B-cell stimulator (BlyS)
(TNF) alpha therapy. In small anecdotal and clinical modulates B-cell survival and maturation, and is a
studies, rituximab has been shown to be beneficial in member of the TNF superfamily. Belimumab is a human
the treatment of patients with SLE. Various dosing BAFF monoclonal antibody that recognizes BlyS and
regimens have been used to achieve complete B-cell reduces B-cell proliferation and differentiation in animal
depletion. A multicenter, randomized, placebo- models. A phase II clinical trial failed to demonstrate
controlled (phase II/III) trial has begun to study the efficacy. However, in a subset of SLE patients with ele-
efficacy of rituximab in patients with moderate-to- vated anti-dsDNA antibodies and low serum C3, there
severe lupus flares. Another similar phase III trial will was a significant reduction in disease activity. Thus, a
study the efficacy of rituximab in the treatment of phase III trial may be needed for further validation.
lupus nephritis in adult patients.
Epratuzumab is a human monoclonal antibody Inhibition of Costimulatory
that targets CD22 on B cells. In an open-label phase
II trial, epratuzumab showed efficacy in patients
Interactions
with SLE, despite causing only modest B-cell deple- Dendritic or antigen presenting cells link innate to
tion. Two ongoing phase III clinical trials of epratu- adaptive immunity and thus play an important role in
both initiating and maintaining inflammatory and developed antibodies to the murine monoclonal
immune responses. These cells also possess costimula- antibodies.
tory potential, sufficient to activate naive T cells. Abata- Interleukin 6 (IL-6) is another proinflammatory
cept is a fusion protein of CTLA4-Ig that binds to B7 cytokine secreted predominantly by macrophages
molecules (CD80/CD86) on dendritic cells and blocks and T cells and has a wide range of biologic
the binding of costimulatory molecules CD80 and CD86 activities that mediate immune regulation and inflam-
with CD28 on T cells, thereby interrupting signals mation in autoimmune diseases like SLE. It also
required for the activation of naive T cells and their induces terminal differentiation of B lymphocytes
downstream effects on B-cell activation. This drug has into antibody-forming plasma cells and the differentia-
been approved by the FDA for the treatment of rheu- tion of T lymphocytes into effector cells. IL-6 is highly
matoid arthritis. Multicenter clinical trials of two avail- expressed in lupus nephritis (42). In murine models,
able compounds, abatacept and RG2077, are currently IL-6 promotes disease activity whereas IL-6 blockade
under way in SLE. delays the development of lupus nephritis (43). Tocili-
The interaction of CD40 on B cells and CD40 zumab is a humanized monoclonal antibody against
ligand (CD40L) on T cells is also essential for B-cell IL-6 receptor (IL-6R) that suppresses IL-6 signaling
activation and antibody production. The therapeutic mediated by both membranous and soluble IL-6R. An
blockade of the CD40CD40L interaction has open-label trial of IL-6 blockade is currently under
been studied extensively in animal models. How- way.
ever, clinical trials of two such monoclonal anti- Elevated serum levels of IFN-alpha are found in
bodies (IDEC-131 and BG9588) against CD40L that patients with SLE. IFN-alpha has been associated with
interrupts the CD40CD40L interaction revealed B-cell lymphopenia, germinal center differentiation,
disappointing results. IDEC-131 was shown to be safe generation of antibody-forming plasma cells, and acti-
but ineffective, whereas BG9588 was associated with a vation of dendritic cells, findings relevant to the immu-
high incidence of thromboembolic events unacceptable nologic characteristics of SLE. The concept of disease
for clinical use, despite limited data demonstrating pathogenesis by IFN-alpha is supported by the finding
potential efficacy. of patients with lupuslike illness on IFN-alpha therapy.
More recent studies showed a striking IFN-alpha signa-
ture on gene expression in peripheral blood mononu-
Cytokine Blockade clear cells of patients with SLE compared with those of
Tumor necrosis factor alpha inhibitors (etanercept, inf- controls (44). IFN-alpha modulation may be another
liximab, and adalimumab) have been very successful in promising therapeutic target for use in the treatment
treatment of rheumatoid arthritis and psoriatic arthritis. of SLE.
A small open-label study of infliximab in SLE showed This is an exciting time for drug development in
significant improvement in patients with refractory SLE, and several of these novel biologic agents appear
nephritis, despite a parallel increase in levels of anti- to be promising. The complexity of lupus and the wide
dsDNA antibodies (40). However, antiTNF-alpha range of severity in different organ systems will likely
therapy has been associated with autoantibody produc- translate into the need for a variety of therapeutic
tion, specifically anti-dsDNA antibodies, in patients options.
with various autoimmune conditions. Although this
autoantibody production may be common in RA
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CHAPTER 16
Antiphospholipid Syndrome
MICHELLE PETRI, MD, MPH
An acquired cause of hypercoagulability; 50% of Antiphospholipid syndrome predisposes to mis-

antiphospholipid syndrome (APS) patients have carriage and other pregnancy morbidity.
systemic lupus erythematosus (SLE). Antiphospholipid syndrome may cause
Antiphospholipid syndrome predisposes to both thrombocytopenia.
venous and arterial thrombosis. The most common Antiphospholipid syndrome is diagnosed by per-
venous thrombosis is deep venous thrombosis; the sistent antiphospholipid antibody: lupus anticoagu-
most common arterial thrombosis is stroke. lant; anticardiolipin; and antibeta 2 glycoprotein I.
Antiphospholipid antibodies (aPL) are autoantibodies with the lupus anticoagulant is 50% by 20 years after
directed against negatively charged phospholipid/ diagnosis.
plasma proteins. The most common plasma protein
target is beta 2 glycoprotein I. The three most im-
portant antiphospholipid antibodies are the lupus CLINICAL FEATURES
anticoagulant, anticardiolipin, and antibeta 2 glyco-
protein I. The most common cutaneous finding in APS patients is
Antiphospholipid syndrome (APS) is one of the most livedo reticularis, a purplish lacelike reticular pattern,
common acquired causes of hypercoagulability. Fifty especially apparent on the extremities. Other cutaneous
percent of APS patients have systemic lupus erythe- signs include splinter hemorrhages, superficial thrombo-
matosus (SLE). APS presents in two major ways: phlebitis, cutaneous necrosis, digital gangrene, and leg
thrombosis (venous or arterial) and pregnancy loss. ulcers (4).
Thrombocytopenia, present in about 20% of cases, can Venous thrombosis in APS usually presents as a deep
be an important clue. venous thrombosis of the lower extremities. Other pos-
sible sites of venous thrombosis include pulmonary em-
boli, BuddChiari syndrome, and dural sinus thrombosis.
EPIDEMIOLOGY The most common site of arterial thrombosis is the
brain. Although strokes can occur from in situ throm-
Antiphospholipid antibodies (aPL) occur in 1% to 6% bosis, about one third of patients with primary APS
of the general population (1). The estimated relative have cardiac valve vegetations or valve thickening that
risk of venous thromboembolism with anticardiolipin is can lead to emboli. Rarely, a destructive valvulitis
2 and with the lupus anticoagulant is 10 (2). APL also occurs requiring valve replacement. Other sites of arte-
increase the risk of an initial myocardial infarction, rial thrombosis include myocardial infarction, retinal
initial stroke, recurrent stroke, and death. In patients thromboses, renal artery thrombosis, glomerular capil-
presenting with a deep venous thrombosis, up to 30% lary thrombi, and digital gangrene. Pregnancy losses
will have the APS. In a person under age 50 with a from APS can occur in the first trimester or as late fetal
stroke, up to 46% will have APS. deaths. Severe placental insufficiency can occur. HELLP
If APS occurs in a patient without SLE or other syndrome (hemolysis, elevated liver enzymes, low plate-
connective tissue disease, it is termed primary APS. lets) has been reported in APS, as well, but the true
About 8% of primary APS patients later develop relationship between the HELLP syndrome and APS is
SLE (3). In SLE patients, about 30% have anticar- unclear.
diolipin and about 25% have the lupus anticoagulant. Some nonthrombotic neurologic presentations of
The term secondary APS is used for SLE patients APS include chorea and transverse myelitis.
who have aPL and have had thrombosis or pregnancy Approximately 20% of APS patients have thrombo-
losses. The risk of venous thrombosis in a SLE patient cytopenia, usually in the range of 50 to 140,000/mm3.
339
340 MICHELLE PETRI
TABLE 16-1. CLASSIFICATION CRITERIA FOR 1. A sensitive screening test must show prolongation
ANTIPHOSPHOLIPID SYNDROME (SYDNEY REVISION). of the clotting time. A sensitive activated partial throm-
One clinical criterion boplastin time (aPTT) or the dilute Russell viper venom
Thrombosis Arterial time (dRVVT) is recommended for screening. No single
or screening test can detect all LAs.
Venous 2. Prolongation of the clotting time must be due to
or
Vasculopathy
an inhibitor (rather than a factor deficiency). This is
pregnancy morbidity 3 or more first trimester losses confirmed by demonstrating that the prolonged clotting
or time does not correct with a 1 : 1 or 4 : 1 mix with normal
1 or more late fetal losses plasma.
or 3. Phospholipid dependence of the coagulation test
Severely preterm birth due to placental
insufficiency
abnormality must be demonstrated. This can be accom-
plished in several ways, including a platelet neutraliza-
One laboratory criterion: persistent over 3 months tion procedure.
Lupus anticoagulant
or
Moderate/high titer IgG or IgM anticardiolipin Anticardiolipin
or
Moderate/high titer IgG or IgM antibeta 2 glycoprotein I Anticardiolipin (aCL) is actually an antibody directed
against negatively charged phospholipids bound to beta
SOURCE: From Miyakis S, et al. J Thromb Haemost 2006;4:295306, by 2 glycoprotein I. Only medium-to-high titers of the IgG
permission of Journal of Thrombosis and Haemostasis.
or IgM isotype are accepted for the classification
criteria.
Thrombosis can occur even in the presence of throm- AntiBeta 2 Glycoprotein I

bocytopenia in APS. Catastrophic APS is a rare presen-
International criteria for anti-beta 2 glycoprotein I
tation with multiorgan thrombi (5). Precipitants of
(anti-beta 2 GPI) assays do not yet exist. However,
catastrophic APS include infection, surgery, pregnancy,
multiple valid commercial assays are in use. It is unusual
exogenous estrogen, and cessation of anticoagulation.
for an APS patient to be negative for both LA and aCL.
In the evaluation of APS, it is necessary to exclude
Thus, anti-beta 2 GPI is rarely necessary to make the
genetic and acquired causes of hypercoagulability (6).
diagnosis/classification of APS.
Genetic causes include Factor V Leiden, the G20210A
prothrombin mutation, deficiency of antithrombin III,
Protein C or Protein S, and hyperhomocysteinemia.
PATHOLOGY
Thrombotic events in APS are bland; that is, in the
CLASSIFICATION CRITERIA absence of a coexisting condition, there is no evidence
of vasculitis.
Classification criteria for APS have been revised multi-
ple times, most recently in 2006 (Table 16-1) (7). Classi-
fication requires a clinical criterion (thrombosis or
pregnancy morbidity) plus evidence of persistence
PATHOGENESIS
(present twice over 3 months) of the lupus anticoagu-
The pathogenesis of APS is complex and multifactorial,
lant, medium or high titer IgG/IgM anticardiolipin, or
reflecting the fact that aPL bind to plasma proteins and
medium-to-high titer IgG/IgM antibeta 2 glycoprotein
to endothelial cells involved in multiple steps in coagu-
I antibodies.
lation. APL interfere with the activated Protein C
complex and also bind to platelets. They bind to endo-
thelial cells, leading to upregulation of cytokines and
LABORATORY FEATURES tissue factor.
A murine model of APS pregnancy loss has shown
Lupus Anticoagulant that aPL lead to complement activation. Complement
The lupus anticoagulant (LA) is a double misnomer, deficiency or inhibition of complement activation is pro-
because only 50% of patients with LA have lupus. tective against pregnancy loss and thrombosis in this
Moreover, the LA behaves as a procoagulant in vivo. model (8). In addition, the benefit of heparin in the
To confirm the presence of an LA, three criteria are animal model is due to its anti-inflammatory effect, not
required: to anticoagulation.
C H A P T E R 1 6 A N T I P H O S P H O L I P I D S Y N D R O M E 3 41
Antiphospholipid syndrome (APS) complications tional Normalized Ratio (INR) in the high intensity
happen to only a minority of patients with aPL. Several range (3.04.0) was required, two subsequent random-
features are thought to increase the risk of thrombosis, ized clinical trials (11,12) have proven that normal
including the lupus anticoagulant (over aCL), high titers intensity anticoagulation (2.03.0) is both sufficient and
of aCL, persistence of aPLs for longer than 6 months, safer in the long term.
and comorbid factors including estrogen, thalidomide, The APS patient with thrombosis and thrombocyto-
nephrotic syndrome, bed rest, surgery, pregnancy, and penia is of special concern. Thrombocytopenia does not
the postpartum period. protect the APS patient from thrombosis. Most throm-
bocytopenia in APS is mild, in the range of 90 to 140,000.
Profound thrombocytopenia, however, would greatly
TREATMENT increase the risk of bleeding with anticoagulation. The
platelet count should be stable at above 50,000 before
Asymptomatic Antiphospholipid chronic anticoagulation is begun, and the INR goal
Antibodies would be 2.0 in such a patient.
One clinical trial found no difference in outcome in
Patients with aPL but no history of thrombosis or preg-
stroke patients with aPL randomized to aspirin or to
nancy loss should avoid medications that might contrib-
warfarin. Stroke patients in this trial had aPL measured 16
ute to hypercoagulability, including oral contraceptives
at baseline, but were not shown to be persistently posi-
and hormone therapy. Other risk factors for hyperco-
tive, a requirement for the classification of APS.
agulability should be minimized. Low dose aspirin can
Many experts believe that APS patients with arterial
be considered as a prophylactic therapy, but efficacy has
thrombosis should be maintained on both low dose
not been proven in clinical trials.
aspirin and warfarin anticoagulation, because platelets
are involved in the pathogenesis of arterial thrombi.
Asymptomatic Antiphospholipid However, the addition of aspirin does increase the risk
Antibodies in Systemic Lupus of bleeding.
Erythematosus
In addition to low dose aspirin, hydroxychloroquine can Catastrophic Antiphospholipid
be considered as a possible prophylactic intervention in Syndrome
SLE patients. The benefit of hydroxychloroquine has
Based on analysis of a large case series, catastrophic
been confirmed in an animal model and in several
APS is treated by heparin, plasmapheresis or intrave-
observational cohort studies in SLE.
nous immunoglobulin, and high dose methylpredniso-
lone (the latter likely calms the cytokine storm produced
Pregnancy Loss by the intense endothelial cell activation) (5). Cyclo-
The preferred regimen to prevent pregnancy loss is pro- phosphamide is not recommended as initial therapy
phylactic doses of unfractionated or low-molecular- because of the increased risk of infection. Mortality of
weight heparin plus low dose aspirin (81 mg) (9). This catastrophic APS, even with intensive treatment in
regimen causes less maternal morbidity (diabetes mel- major academic centers, remains 50%.
litus, cataracts) and less pregnancy morbidity (pre-
eclampsia, preterm birth) than the older regimens of Experimental Treatments
prednisone and aspirin. Unfortunately, the heparin and
aspirin regimen is successful in only 75% of pregnan- Statins have benefit for APS in animal models and
cies. If unsuccessful, there is some scientific rationale to reduce thrombosis in clinical studies of non-APS
the addition of intravenous immunoglobulin in the next patients. However, they cannot be used in pregnancy
pregnancy. and have not been studied formally in APS.
Rituximab depletes B cells, including B cells that
Thrombosis make aPL. However, the period of B-cell depletion is
variable, and long-lived plasma cells make aPL survive.
The treatment of an acute thrombotic event (throm- Further studies are needed before it can be recom-
bolysis and/or heparin) is not changed by knowledge mended for APS.
that the patient has an aPL. Because of the high risk of
recurrence of thrombosis in APS, a strong case can be
made for life-long anticoagulation after a first throm- REFERENCES
botic event. If anticoagulation is stopped after 6 months,
there is a recurrence rate of 20% or more (10). Although 1. Petri M. Epidemiology of the antiphospholipid syndrome.
a past retrospective series suggested that an Interna- In: Asherson RA, Cervera R, Piette J-C, Shoenfeld Y, eds.
342 MICHELLE PETRI
The antiphospholipid syndrome. Boca Raton, FL: CRC 8. Holers VM, Girardi G, Mo L, et al. Complement C3 acti-
Press; 1996:1328. vation is required for antiphospholipid antibody-induced
2. Bates SM, Ginsberg JS. Clinical practice. Treatment of fetal loss. J Exp Med 2002;195:211220.
deep-vein thrombosis. N Engl J Med 2004;351:268277. 9. Cowchock FS, Reece EA, Balaban D, Branch DW,
3. Gomez-Puerta JA, Martin H, Amigo MC, et al. Long-term Plouffe L. Repeated fetal losses associated with antiphos-
follow-up in 128 patients with primary antiphospholipid pholipid antibodies: a collaborative randomized trial com-
syndrome: do they develop lupus? Medicine (Baltimore) paring prednisone with low-dose heparin treatment. Am
2005;84:225230. J Obstet Gynecol 1992;166:13181323.
4. Frances C, Niang S, Laffitte E, Pelletier F, Costedoat N, 10. Schulman S, Svenungsson E, Granqvist S, the Duration of
Piette JC. Dermatologic manifestations of the anti- Anticoagulation Study Group. Anticardiolipin antibodies
phospholipid syndrome: two hundred consecutive cases. predict early recurrence of thromboembolism and death
Arthritis Rheum 2005;52:17851793. among patients with venous thromboembolism following
5. Asherson RA, Cervera R, de Groot PG, et al. Catastrophic anticoagulant therapy. Am J Med 1998;104:332338.
antiphospholipid syndrome: international consensus state- 11. Crowther MA, Ginsberg JS, Julian J, et al. A comparison
ment on classification criteria and treatment guidelines. of two intensities of warfarin for the prevention of recur-
Lupus 2003;12:530534. rent thrombosis in patients with the antiphospholipid anti-
6. Nachman RL, Silverstein R. Hypercoagulable states. Ann body syndrome. N Engl J Med 2003;349:11331138.
Intern Med 1993;119:819827. 12. Finazzi G, Marchioli R, Brancaccio V, et al. A randomized
7. Miyakis S, Lockshin MD, Atsumi T, et al. International clinical trial of high-intensity warfarin vs. conventional
consensus statement on an update of the classification antithrombotic therapy for the prevention of recurrent
criteria for definite antiphospholipid syndrome (APS). thrombosis in patients with the antiphospholipid syndrome
J Thromb Haemost 2006;4:295306. (WAPS). J Thromb Haemost 2005;3:848853.
CHAPTER 17
Systemic Sclerosis
MAUREEN D. MAYES, MD, MPH
Systemic sclerosis (scleroderma; SSc) is divided further The fibrosing process results in thickened skin,
into limited cutaneous disease and diffuse cutaneous pulmonary parenchymal disease, and gastrointestinal
disease on the basis of the extent of skin thickening. dysmotility.
Limited disease is defined as skin thickening that Tendon friction rubs, caused by an inflammation in
only affects the extremities below the elbows and/or the tendon sheath, are usually palpable on
below the knees. Diffuse cutaneous disease is examination and sometimes cause pain with motion.
defined as skin thickening proximal to the elbows A variety of autoantibodies occur in SSc, including
and/or knees in addition to distal extremity those antitopoisomerase III antibodies and
involvement. Truncal skin may also be involved in anticentromere antibodies.
diffuse cutaneous systemic sclerosis (dcSSc). Raynauds phenomenon, usually the first
The face can be involved in both forms and has no manifestation of SSc, may precede the development
bearing on subset designation. of other features by months to years.
The clinical manifestations of SSc may be considered Pulmonary disease is now the leading cause of death
the result of three pathological processes: (1) a small in SSc. Pulmonary fibrosis occurs in many SSc
vessel non-inflammatory obliterative vasculopathy; patients, with 20% ultimately requiring supplemental
(2) the pathological accumulation of collagen in skin oxygen.
and other organs (fibrosis); and (3) autoimmunity. Scleroderma renal crisis, the most common cause of
The obliterative small vessel vasculopathy is death in SSc prior to the introduction of angiotensin-
responsible for Raynauds phenomenon, scleroderma converting enzyme (ACE) inhibitors, remains an
renal crisis, and pulmonary artery hypertension. important source of patient morbidity in SSc.
From a clinical point of view, scleroderma is usually disease occurring in the same patient, this is a rare event
divided into two main forms, localized scleroderma and and the two conditions should be thought of as two
systemic scleroderma or systemic sclerosis (Figure 17A- separate diseases with very different clinical pictures
1). Localized scleroderma includes the disease entities of and prognosis.
morphea (one or more patches of thickened skin), linear For rheumatologists, scleroderma is synonymous
scleroderma (a line of thickened skin affecting one or with systemic disease. Only SSc will be considered in
more extremities), and scleroderma en coup de sabre, the remainder of this chapter. In broad terms, the clini-
which is a distinct subset of linear disease that affects the cal manifestations of SSc may be considered the result
forehead and face [for review, see Piette (1)]. Although of three pathological processes: (1) a small vessel non-
atrophy of the subcutaneous tissue underlying the lesions inflammatory obliterative vasculopathy; (2) the patho-
typically occurs in localized scleroderma, there is usually logical accumulation of collagen in skin and other organs
no associated internal organ or systemic involvement. (fibrosis); and autoimmunity (3). The mechanisms by
Systemic sclerosis (SSc), on the other hand, almost which these three processes are linked are unclear.
always has an element of internal organ disease (2). SSc
is divided further into limited cutaneous disease (lcSSc)
and diffuse cutaneous disease (dcSSc) on the basis of VASCULOPATHY
the extent of skin thickening. The terms limited sclero-
derma and localized scleroderma cause linguistic confu- The obliterative small vessel vasculopathy is responsible
sion, but these terms refer to very different conditions. for Raynauds phenomenon, scleroderma renal crisis,
In spite of a few reported cases of localized and systemic and pulmonary artery hypertension. In contrast, the
343
344 MAUREEN D. MAYES
FIGURE 17A-1
Scleroderma is usually divided into two

main forms, and then further subdivided.
fibrosing process results in thickened skin, pulmonary Thus, digital ulcers or gangrene should not result from
parenchymal disease, and gastrointestinal dysmotility. primary Raynauds phenomenon.
Some patients have an associated inflammatory com- Secondary Raynauds phenomenon due to SSc, on
ponent manifested by tendon friction rubs and syno- the other hand, frequently results in irreversible tissue
vitis. Other features such as calcinosis are less well loss. In addition to the cold-induced vasospasm that
understood. occurs in such patients, the caliber of the blood vessels
Raynauds phenomenon is caused by vasospasm of at baseline becomes narrowed by a vasculopathy.
the small vessels of the hands on cold exposure. This Chronic ischemia leads to reduction of the finger pad
vasospasm, in turn, results in blanching, cyanosis, and substance with consequent tapering of the fingers.
then reactive hyperemia (rubor) as the affected area Tender digital pitting scars are the result of more isch-
rewarms (4). An episode of Raynauds phenomenon can emia, leading to losses of small areas of tissue. Digital
be triggered by emotional stress, but the association ulcers and digital gangrene are caused by even more
with cold exposure must be present to make the diag- severe degrees of ischemia [Figure 17A-2(A,B)]. Ulcers
nosis. Of the three phasespallor, cyanosis, and rubor that spontaneously occur on the fingertips are due
rubor is the least frequent. The diagnosis is usually made almost exclusively to ischemia, whereas those over the
on the basis of a compelling history rather than on extensor surfaces of the proximal interphalangeal (PIP),
attempts to recreate an episode under observation. This metacarpophalangeal (MCP), ulnar styloid, and elbow
condition is common in the general population; approxi- joints are due to a combination of poor perfusion in
mately 5% to 10% or more of American adults will areas of stretched skin and repeated minor trauma
experience episodes of Raynauds phenomenon (5,6). (Figure 17A-3).
Most of these individuals have primary Raynauds Raynauds phenomenon, usually the first manifesta-
disease, not with a connective tissue disease. Primary tion of SSc, may precede the development of other
Raynauds disease does not result in tissue damage. features by months to years. In some cases, the delay
FIGURE 17A-2
(A, B) Digital ulcers and digital gangrene are caused by severe degrees of ischemia.
A B
C H A P T E R 1 7 S Y S T E M I C S C L E R O S I S 3 45
tion to distal extremity involvement. Truncal skin may

also be involved in dcSSc. The face can be involved in
both forms and has no bearing on subset designation.
Limited cutaneous disease (lcSSc) typically begins
with Raynauds phenomenon, followed by the gradual
development of other scleroderma-associated signs and
symptoms including heartburn on a frequent, often
daily, basis; tender digital pitting scars or ulcers; and
thickening of the skin of the fingers, which may progress
to include the dorsum of the hands and forearms. Later
features include dyspnea related to pulmonary fibrosis;
telangiectasias (initially on the hands and face); and,
much later, the development of dyspnea related to pul-
monary arterial hypertension.
In contrast, dcSSc has a more rapid onset, with skin
FIGURE 17A-3 changes shortly after or coincidental with the onset of
Metacarpophalangeal ulcers are due to poor perfusion in areas Raynauds phenomenon, and with internal organ
of stretched skin or in areas of repeated minor trauma. involvement occurring during the first 2 years of disease.
Skin involvement usually progresses over the first 1 to
5 years, then stabilizes, and can gradually improve but
in diagnosis is due to the absence of full-blown SSc seldom totally resolves. Even if the extent and severity 17
manifestations. In others, the diagnosis is delayed by the of skin disease recede with time, the designation of
failure to realize that mild sclerodactyly (skin thicken- diffuse disease remains relevant because the course of
ing limited to the fingers), gastroesophageal reflux, and the internal organ involvement does not parallel skin
other symptoms or signs of SSc are incipient indications improvement. Fibrosis in the pulmonary, cardiac, and
of a broader systemic illness. Antinuclear antibodies gastrointestinal (GI) systems fibrosis does not resolve.
(ANA) are usually present at the time of Raynauds Individuals with dcSSc are at risk for progressive
phenomenon onset. Indeed, the finding of a positive involvement in these organs. In addition, early dcSSc
ANA in a patient with Raynauds phenomenon sug- patients, especially in the phase of skin worsening, are
gests the need for further scrutiny of a possible connec- at the highest risk of developing scleroderma renal crisis
tive tissue disorder. (SRC).
The 1980 classification criteria for SSc, established by Inflammatory features are also prominent in this
the American Rheumatism Society (now the American group of patients with early, diffuse disease. Such fea-
College of Rheumatology), consist entirely of clinical tures include inflamed, reddened, and intensely pruritic
features (7). The single major criterion is the presence skin, tendon friction rubs, and synovitis (which may be
of thickened skin proximal to the MCP joints. There are difficult to appreciate due to the thickened overlying
three minor criteria, including sclerodactyly, permanent skin). Although prednisone can provide symptomatic
ischemic changes of the fingertips (loss of finger pad relief, doses of 15 mg per day or higher have been linked
substance, digital pitting scars, or digital ulcers), and to the development of SRC.
bibasilar pulmonary fibrosis. Classification of SSc is In general, poor prognostic factors include diffuse
considered correct if proximal skin thickening is skin involvement, late age of disease onset, African- or
present, or if two of the three minor criteria are met. Native-American race, a diffusing capacity <40% of the
These classification criteria have a specificity of 98% predicted value, the presence of a large pericardial effu-
and a sensitivity of 97%. However, this system may miss sion, proteinuria, hematuria, renal failure, anemia, ele-
individuals who clearly have SSc by our current under- vated erythrocyte sedimentation rate, and abnormal
standing. For example, individuals with only the CREST electrocardiogram (9,10).
features (calcinosis, Raynauds phenomenon, esopha- Autoantibody status is also helpful in considering
geal dysmotility, sclerodactyly, and telangiectasias) do prognosis (11). Nearly all SSc patients are ANA posi-
not meet this definition (8). tive. Those with a centromere pattern ANA usually have
The division of SSc into limited cutaneous or diffuse limited disease and a relatively good prognosis but are
cutaneous disease subsets has important prognostic at an increased risk of developing pulmonary arterial
implications and can be accomplished in a straightfor- hypertension, primary biliary cirrhosis, and severe digital
ward, clinically applicable approach. Limited disease is ischemia. Antitopoisomerase antibodies (also known as
defined as skin thickening that only affects the extremi- antiScl 70) identify individuals with an increased risk
ties below the elbows and/or below the knees (8). of severe pulmonary fibrosis. Antibodies to RNA-
Diffuse cutaneous disease (dcSSc) is defined as skin polymerase (not to be confused with anti-RNP antibod-
thickening proximal to the elbows and/or knees in addi- ies) are associated with increased risk of SRC.
TABLE 17A-1. KEY CLINICAL FEATURES OF SYSTEMIC and-pepper appearance, caused by maintenance of
SCLEROSIS. pigment at the base of hair follicles but the loss of
Diffuse cutaneous systemic sclerosis (dcSSc) pigment in the surrounding skin. As time progresses,
Proximal skin thickening involving the trunk, upper arms and areas of pigment loss coalesce and may become quite
thighs, in addition to symmetrical involvement of the fingers, extensive over the hands, face, and chest.
hands, arms, and face/neck Telangiectasias most commonly occur over the
Rapid onset of disease following the appearance of
Raynauds phenomenon
fingers, palms, dorsum of the hands, and face (Figure
Significant visceral disease: lungs, heart, gastrointestinal, and/ 17A-4). By definition, telangiectasias blanch with pres-
or kidneys sure. The lesions, initially 1 mm in diameter, can enlarge
Absence of anticentromere antibodies over time and affect the upper extremities and trunk, as
Variable disease course but overall poor prognosis, with well as the vermilion border of the lips and oral mucosa.
survival 40% to 60% at 10 years
For reasons that are not clear, telangiectasias rarely
Limited cutaneous systemic sclerosis (lcSSc) affect the lower extremities. These lesions are cosmeti-
Symmetrical skin thickening limited to the areas below the cally disturbing for many patients. When telangiectasias
elbows and knees and involving the face/neck
involve the GI tract extensively, they may be associated
Progression of disease typically months or years after the
onset of Raynauds phenomenon with significant blood loss. Otherwise, telangiectasias do
Later and less severe development of visceral disease not cause clinical problems.
Late development of pulmonary arterial hypertension Digital tip pitting scars, ulcers, and gangrene caused
Association with anticentromere antibodies by ischemia are invariably painful. Ulcers over bony
Relatively good prognosis with survival >70% at 10 years
prominences (PIPs, MCPs, elbows, malleoli) are due to
Overlap syndromes a combination of stretched and thickened skin, poor
Diffuse or limited systemic sclerosis with typical features of circulation in the microvasculature, and repetitive minor
one or more of the other defined connective tissue diseases trauma. Although infection is not the primary cause of
Mixed connective tissue disease: features of systemic lupus
these ulcers, the areas can become secondarily infected
erythematosus, systemic sclerosis, and polymyositis in the
presence of anti-U1 RNP antibodies due to their chronicity. Digital tip gangrene can occur
suddenly and may require surgical intervention. When-
ever possible from the standpoint of pain management,
Table 17A-1 provides a summary of key clinical fea- however, unsalvageable digital tissue should be allowed
tures of the subsets of SSc. Although the recognition of to undergo autoamputation rather than surgical
limited and diffuse disease subsets is useful, SSc is a
highly variable disorder. Severe internal organ disease
can occur even in those in the lcSSc group.
SKIN MANIFESTATIONS
The hallmark feature of SSc is thickened skin. However,
skin manifestations also include swollen hands (and
sometimes feet), pruritus, hyper- and/or hypopigmenta-
tion, telangiectasias, calcinosis, dermal ulcers, digital tip
pitting scars, and digital tip gangrene (12). Frequently,
the first symptom following the onset of Raynauds phe-
nomenon is that of puffy hands; patients find that their
rings no longer fit. This is followed by thickening of the
skin beginning distally and progressing proximally,
affecting the upper extremities more than the lower.
Pruritus, a common feature, usually affects those with
early diffuse disease and frequently predates clinically
apparent skin thickening. Occasionally patients com-
plain of sharp fleeting pains and superficial skin tender-
ness. Both the pruritus and the skin pain tend to be
early symptoms and usually improve as the fibrosis
becomes well established.
Diffuse hyperpigmentation is believed to be due to FIGURE 17A-4
chronic inflammation in the skin. In time, the skin may Telangiectasias most commonly occur over the fingers, palms,
develop a spotty hypopigmentation known as a salt- dorsum of the hands, and face.
pressure of the gastroesophageal sphincter, but only a

few develop severe GI dysmotility to the extent that
hyperalimentation is required.
Gastrointestinal symptoms are related to dysmotility
which, in turn, is related to smooth muscle atrophy and
fibrosis. One current theory regarding SSc in the GI
tract attributes gut dysfunction to early neural involve-
ment with secondary muscular atrophy. In this scenario,
fibrosis is a repair mechanism rather than the primary
process (15).
Initially, there is incoordination of peristaltic waves
in the esophagus. Over time, the esophagus may become
totally aperistaltic. The sensation of dysphagia can occur
on the basis of an esophageal stricture due to chronic
FIGURE 17A-5
reflux, or on the basis of disordered peristalsis such that
food hangs up in one area, requiring several swallows
Calcinosis can occur in the hands as well as in the forearms, to clear the material.
elbows, knees, and legs. Chronic GERD can lead to mucosal erosions, dyspla-
sia, stricture formation, and reactive airway disease due
removal, as surgical interventions generally lead to the to nocturnal aspiration. GAVE, which is seen on upper
loss of more tissue. endoscopy, is due to the thinning of the gastric mucosa 17
Calcinosis cutis, usually a late manifestation of SSc, such that the underlying parallel blood vessels in the
occurs more frequently in limited disease but can occur antrum resemble the stripes of a watermelon. This
in late diffuse disease, as well. Calcinosis can occur in condition, sometimes associated with blood loss, is
the hands as well as in the forearms, elbows, knees, and amenable to endoscopic laser coagulation. Mucosal
legs (Figure 17A-5). These deposits can erupt through telangiectasias, which late in disease can develop
the skin, become secondarily infected, and pose major throughout the GI tract, sometimes lead to occult,
problems in management. difficult-to-control blood loss.
Although more than 95% of SSc patients have evi- Gastroparesis and small bowel dysmotility leads to
dence of skin thickening, a small proportion will have early satiety, bloating, and flatulence. Bacterial over-
scleroderma sine sclerosis, characterized by Raynauds growth in the small intestine may cause malabsorption
phenomenon, typical GI signs and symptoms, positive and diarrhea, requiring intermittent or rotating anti-
autoantibodies, and/or telangiectasias (13). The progno- biotics. Decreased motility in the large bowel is associ-
sis for these individuals, who have an increased risk for ated with constipation, which can be severe. Radio-
pulmonary arterial hypertension late in their course, is graphic contrast studies demonstrate wide-mouthed
similar to those with limited cutaneous SSc. The diagno- diverticuli as well as pneumotosis cystoides intestinalis.
sis of SSc is usually quite delayed for this subtype due These latter two features are rarely of clinical conse-
to the lack of thickened skin. quence. Decreased pressure of the anal sphincter can
also be seen in SSc, leading to stool incontinence.
Primary biliary cirrhosis (PBC) occurs in a small pro-
portion of patients but at a rate that is greater than
GASTROINTESTINAL expected in the general population (16).
MANIFESTATIONS
Next to skin involvement, the GI system is most com- PULMONARY AND PULMONARY
monly affected (14). Depending on the extent of involve- VASCULAR DISEASE
ment, signs and symptoms can include frequent
heartburn, dysphagia, esophageal stricture formation, Pulmonary disease is now the leading cause of death in
mucosal dysplasia (Barretts esophagus), erosive esoph- SSc (9). Pulmonary fibrosis occurs in many SSc patients,
agitis, gastritis, gastric antral vascular ectasia (GAVE or with 20% ultimately requiring supplemental oxygen.
watermelon stomach), postprandial bloating, early Patients with dcSSc are at higher risk of developing
satiety, weight loss, constipation, flatulence, and malab- significant lung fibrosis compared to those with lcSSc.
sorptive diarrhea. However, this distinction is not absolute, and pulmonary
The severity of GI tract disease is highly variable function test (PFT) monitoring is recommended for both
among individual patients. Most have some evidence of groups. Early lung disease is frequently asymptomatic.
gastroesophageal reflux disease (GERD) due to lowered Dry cough, a later symptom, is not specific for lung
disease and may be related to chronic GERD. Dyspnea fibrosis and PAH is similar to that of patients with iso-
on exertion may be a consequence of multiple factors. lated PAH and worse than those with pulmonary fibro-
Pulmonary function test that show a restrictive sis alone (17).
pattern is the most sensitive test for pulmonary paren- The prevalence of PAH in the SSc patient population
chymal disease. Periodic testing is suggested. Decreases when measured by right heart catheterization is 8% to
in the vital capacity, lung volumes, and/or diffusing 12% (18,19). The prevalence of PAH by echocardio-
capacity for carbon monoxide (DLCO) are indicative gram alone is more than double this figure (20) and
of restrictive changes. An isolated decrease in DLCO emphasizes the point that right heart catheterization is
may also indicate pulmonary hypertension. necessary to confirm the diagnosis.
Computed tomography (CT) scans of the lung are As echocardiography is being done more frequently in
more sensitive than radiographs for the detection of the SSc population, it is becoming clear that this condition
early fibrotic changes. High resolution CT views are is more common than believed previously, and that it can
required to detect a ground glass appearance, which is affect both lcSSc and dcSSc patients. Risk factors for pro-
believed to represent inflammation or alveolitis. Bron- gression to severe pulmonary hypertension include older
choalveolar lavage (BAL) showing neutrophils and/or age, limited skin disease, and elevated pulmonary artery
eosinophils is suggestive of active inflammation. Patients pressures at the time of initial evaluation (21).
who are positive for antitopoisomerase antibodies are
at an increased risk for clinically significant pulmonary CARDIAC INVOLVEMENT
fibrosis, but this complication is not confined solely to
this autoantibody subgroup. If cardiac involvement in SSc is defined as any change
Pulmonary hypertension can occur on the basis of in the electrocardiogram (EKG), pericardium, or cardiac
two main pathologic processes: (1) those primarily function, then heart disease in SSc is common (22).
involving destruction or obliteration of lung vascula- However, clinically apparent cardiac disease, usually a
ture, such as pulmonary fibrosis, recurrent thromboem- late finding associated with a poor prognosis, is rela-
bolic disease, or scleroderma vasculopathy; or (2) those tively uncommon. When present, SSc cardiac disease is
associated with decreased cardiac output, for example, manifested by disturbances in the conduction system of
diastolic dysfunction, congestive heart failure, or valvu- the heart, arrhythmias, left ventricular or global heart
lar disease. Pulmonary arterial hypertension (PAH) is a failure, and pericarditis. Patchy fibrosis throughout the
term used to describe the first group of conditions. myocardium is the typical histological picture in SSc.
As noted, PFTs in patients with PAH show an isolated Contraction band necrosis, characteristic of ischemia/
decrease in DLCO with other parameters being normal, reperfusion injury, has been described.
or a DLCO that is decreased out of proportion to the Asymptomatic small or moderate-sized pericardial
other measures. An echocardiogram is helpful in making effusions are frequently found, but tamponade is rare.
the diagnosis, particularly if the right ventricular systolic Large pericardial effusions, however, are associated
pressure and/or the velocity of the regurgitant jet of the with a poor prognosis (23).
tricuspid valve are high. However, the echocardiogram
is less reliable in borderline cases. In addition, the echo-
cardiogram does not provide a measure of pulmonary RENAL DISEASE AND
capillary wedge pressure. Right heart catheterization SCLERODERMA RENAL CRISIS
should therefore be performed in patients suspected of
PAH to confirm the diagnosis and obtain an accurate Scleroderma renal crisis (SRC) was the most common
measurement of both the pulmonary artery and pulmo- cause of death in SSc prior to the introduction of angio-
nary capillary wedge pressures. Chronic thromboem- tensin-converting enzyme (ACE) inhibitors (24). SRC
bolic disease must be excluded in patients with PAH. still occurs, typically in the setting of early diffuse disease
In terms of symptoms, PAH is initially silent. Early (<4 years from onset). In SRC, malignant hypertension
symptoms can be nonspecific, for example, a sense of can occur suddenly in individuals with previously normal
generalized weakness on exertion. Dyspnea is a later blood pressure values. Clinical signs and symptoms are
symptom and can be attributed to multiple other factors. those of severe hypertension and can include headaches,
PAH in SSc typically develops late in the course of stroke, and heart failure. The creatinine is elevated and
patients with lcSSc. Many SSc patients with PAH are urinalysis shows proteinuria and microscopic hematu-
anticentromere antibody positive. However, in individ- ria. Changes of microscopic angiopathy can be seen
uals with restrictive lung disease of mild or moderate with anemia and thrombocytopenia, which resolve on
severity, it is difficult to distinguish which patients have normalization of the blood pressure. If treated early and
PAH secondary to their lung fibrosis and which patients aggressively with ACE inhibition (combined if neces-
have a combination of scleroderma lung disease with sary with other antihypertensives), the outcome is
scleroderma pulmonary vasculopathy. The mortality favorable, with return to normal or near normal renal
risk in SSc patients with the combination of pulmonary function within several days of blood pressure normal-
ization. Good outcomes are dependent on lowering of muscle weakness, elevation of CPK, and typical electro-
the blood pressure to truly normal levels. myographic changes of inflammatory muscle disease.
Factors predictive of SRC include diffuse skin disease, True myositis usually responds to immunosuppression.
rapid progression of skin involvement, disease duration Osteolysis or bone resorption of the digital tufts, seen
<4 years, anti-RNA polymerase III antibody, new in 40% to 80% of patients, is believed to be on the basis
anemia, new cardiac events, and antecedent high dose of chronic ischemia. Osteolysis of other bones is also
corticosteroid usage. In addition, prior use of cyclospo- seen but is much less common than digital tuft resorp-
rine has been linked to SRC. tion. These sites include the ribs, the mandible, the distal
Poor prognostic factors in SRC include a creatinine clavicle, the humerus and the cervical spine.
level >3 mg/dL at the time of diagnosis of SRC, delay in Inflammatory synovitis of the peripheral joints, par-
blood pressure normalization >3 days, male sex, older ticularly those of the hands and wrists, is a frequent
age, and presence of congestive heart failure. In one finding early in the disease course. Joint swelling can be
study, 55% of patients who initially required dialysis difficult to appreciate under the thickened and taut
were able to discontinue dialysis at a mean of 8 months. scleroderma skin. The arthritis of SSc is nonerosive,
It is therefore important to continue ACE inhibition and usually responsive to anti-inflammatory agents (includ-
blood pressure control even after dialysis is initiated. ing methotrexate), and can resolve after several months.
Normotensive renal crisis, characterized by a slow In contradistinction to the above situation, some
rise in creatinine in the absence of significant blood patients have an overlap of SSc and rheumatoid arthritis
presssure elevation and without a microangiopathic with positive rheumatoid factor, erosive joint disease,
picture, also has been described in SSc. Other causes for and progressive articular destruction. Treatment is
renal failure must be investigated thoroughly, and ACE the same as the treatment of idiopathic rheumatoid 17
inhibitors employed empirically. arthritis.
The most common compression neuropathy in SSc is
carpal tunnel syndrome. This frequently occurs in the
MUSCULOSKELETAL DISEASE edematous phase of early disease. Other compression
neuropathies, such as ulnar neuropathy, can occur as
Characteristics of musculoskeletal involvement include the skin becomes thickened and taut and as flexion
joint contractures, tendon friction rubs, myopathy, myo- contractures develop.
sitis, bone resorption, cutaneous calcifications, synovitis,
and compression neuropathies (25).
In the absence of inflammatory synovitis, joint con- SCLERODERMA-LIKE DISORDERS
tractures are due to involvement of overlying skin that
restricts motion. The degree of contractures reflects the Several SSc-like disorders have been described (27).
extent of skin involvement. The hands, wrists, and The most clinically relevant today include nephrogenic
elbows are the most commonly affected joints. Upper systemic fibrosis (NSF, previously called nephrogenic
extremity involvement can interfere with normal hand fibrosing dermopathy), eosinophilic fasciitis, sclere-
and arm activities. Range of motion may also be reduced dema, and scleremyxedema.
at the shoulders, hips, knees, and ankles. Lower extrem- Nephrogenic systemic fibrosis (NSF) occurs in the
ity involvement can lead to marked gait impairment. setting of chronic renal insufficiency, usually but not
Tendon friction rubs, caused by an inflammation in always affecting individuals on dialysis (28). Features
the tendon sheath, are usually palpable on examination that distinguish this from SSc are the following: The
and sometimes cause pain with motion. If a patient com- fibrosis affects the lower extremities more than the upper
plains of pain over the tendon with joint motion and no extremities, occurs relatively rapidly, and tends to spare
rub is palpated, it can usually be heard with the stetho- the hands. Raynauds phenomenon is not associated
scope. The most commonly affected tendon sheaths are with NSF, and renal transplantation has been reported
those of the ankle dorsiflexors, the finger extensors, and to cause regression of this disease. Although the mecha-
the knee extensors. Tendon friction rubs may also be nism is not fully established, it is thought that circulating
detected around the shoulders, wrists, and other joints. fibrocytes, derived from the bone marrow, are recruited
In SSc, both a myopathy and a myositis can occur. to the skin, become activated and result in fibrosis.
Scleroderma myopathy is characterized by a relatively Eosinophilic fasciitis (Shulmans disease) is charac-
nonprogressive course; mild proximal muscle weakness; terized by fairly rapid onset of skin and fascial thicken-
normal or slight elevations of creatine phosphokinase ing with the early development of flexion contractures,
(CPK); and poor response to corticosteroids (26). particularly at the elbow. The skin has an orange peel
Muscle biopsy shows replacement of muscle fibers with or puckered appearance, sparing the hands and fingers.
fibrosis, and lymphocytic infiltrates (if present) are A deep biopsy that extends to the underlying fascia
scanty. In contrast, true myositisa less common clini- needs to be done in order to make the diagnosis. An
cal findingis characterized by progressive proximal eosinophilic infiltrate is seen on biopsy affecting the
fascia which is thickened. Peripheral eosiniphilia, 11. Cepeda EJ, Reveille JD. Autoantibodies in systemic scle-
unusual to any substantial degree in SSc, is common in rosis and fibrosing syndromes: clinical indications and
eosinophilic fasciitis. relevance. Curr Opin Rheumatol 2004;16:723732.
Scleredema (or scleredema diabeticorum) occurs, as 12. Clements PJ, Medsger TA Jr, Feghali CA. Cutaneous
involvement in systemic sclerosis. In: Clements PJ, Furst
its name suggests, as a complication of diabetes mellitus
DE, eds. Systemic sclerosis. Philadelphia: Lippincott
and causes induration and thickening of the skin of the
Williams & Wilkins; 2004:129150.
neck, shoulder girdle area, proximal upper extremities, 13. Poormoghim H, Lucas M, Fertig N, Medsger TA Jr.
and back. The distribution is contrasts with the distal Systemic sclerosis sine scleroderma: demographic,
involvement of SSc and there is no Raynauds phenom- clinical, and serologic features and survival in forty-eight
enon. A biopsy shows excess mucin as well as collagen. patients. Arthritis Rheum 2000;43:444451.
Scleredema can also be associated with a paraprotein 14. Weinstein WM, Kadell BM. The gastrointestinal tract in
or with multiple myeloma. Paraproteins are usually not systemic sclerosis. In: Clements PJ, Furst DE, eds. Systemic
demonstrated in the skin. sclerosis. Philadelphia: Lippincott Williams & Wilkins;
Scleromyxedema, on the other hand, is characterized 2004:293308.
by a more generalized cutaneous induration than that 15. Goldblatt F, Gordon TP, Waterman SA. Antibody-
mediated gastrointestinal dysmotility in scleroderma.
seen in scleredema. Scleromyxedema can involve the
Gastroenterology 2002;123:11441150.
hands but there is also the presence of mucinous papules
16. Mackey RI. Autoimmunity and primary biliary cirrhosis.
and nodules. This condition is also associated with a Baillieres Best Pract Res Clin Gastroenterol 2000;14:519
paraprotein. It can be distinguished by the presence of 533.
folded and pendulous skin, rather than the tight, hide- 17. Chang B, Wigley FM, White B, Wise RA. Scleroderma
bound character of SSc skin. patients with combined pulmonary hypertension and
interstitial lung disease. J Rheumatol 2003;30:23982405.
18. Hachulla E, Gressin V, Guillevin L, et al. Early detection
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sis: a French nationwide prospective multicenter study.
1. Piette WW. Morphea or localized scleroderma. In: Arthritis Rheum 2005;52:37923800.
Clements PJ, Furst DE, eds. Systemic sclerosis. 19. Mukerjee D, St George D, Coleiro B, et al. Prevalence and
Philadelphia: Lippincott Williams & Wilkins; 2004:2937. outcome in systemic sclerosis associated pulmonary arte-
2. Medsger TA Jr. Classification, prognosis. In: Clements PJ, rial hypertension: application of a registry approach. Ann
Furst DE, eds. Systemic sclerosis. Philadelphia: Lippincott Rheum Dis 2003;62:10881093.
Williams & Wilkins; 2004:1728. 20. Wigley FM, Lima JAC, Mayes M, McLain D, Chapin JL,
3. Korn JH. Pathogenesis of systemic sclerosis. In: Koopman Ward-Able C. The UNCOVER study: prevalence of
WJ, Moreland LW, eds. Arthritis and allied conditions. undiagnosed pulmonary arterial hypertension in subjects
Philadelphia: Lippincott Williams & Wilkins; 2005:1621 with connective tissue disease at the secondary health-
1632. care level of community-based rheumatologists. Arthritis
4. Boin F, Wigley FM. Understanding, assessing and treating Rheum 2005;52:21252132.
Raynauds phenomenon. Curr Opin Rheumatol 2005;17: 21. Chang B, Wigley FM, White B, Wise RA. Scleroderma
752760. patients with combined pulmonary hypertension and
5. Fraenkel L, Zhang Y, Chaisson CE, et al. Different factors interstitial lung disease. J Rheumatol 2006;33:269274.
influencing the expression of Raynauds phenomenon in 22. Follansbee WP, Marroquin OC. Cardiac involvement in
men and women. Arthritis Rheum 1999;42:306310. systemic sclerosis. In: Clements PJ, Furst DE, eds. Systemic
6. Suter LG, Murabito JM, Felson DT, Fraenkel L. The inci- sclerosis. Philadelphia: Lippincott Williams & Wilkins;
dence and natural history of Raynauds phenomenon in 2004:195220.
the community. Arthritis Rheum 2005;52:12591263. 23. Smith JW, Clements PJ, Levisman J, Furst D, Ross M.
7. Subcommittee for Scleroderma Criteria of the American Echocardiographic features of progressive systemic scle-
Rheumatism Association Diagnostic and Therapeutic rosis (PSS): correlation with hemodynamic and postmor-
Criteria Committee: preliminary criteria for the classifica- tem studies. Am J Med 1979;66:2833.
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1980;23:581590. In: Clements PJ, Furst DE, eds. Systemic sclerosis. Phila-
8. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma delphia: Lippincott Williams & Wilkins; 2004:279292.
(systemic sclerosis): classification, subsets, and pathogen- 25. Pope JE. Musculoskeletal involvement in scleroderma.
esis. J Rheumatol 1988;15:202205. Rheum Dis Clin North Am 2003;52:391405.
9. Steen VD, Medsger TA Jr. Severe organ involvement in 26. Clements PJ, Furst DE, Campion DS, et al. Muscle disease
systemic sclerosis with diffuse scleroderma. Arthritis in progressive systemic sclerosis: diagnostic and therapeu-
Rheum 2000;43:24372444. tic consideration. Arthritis Rheum 1978;21:6271.
10. Bryan C, Knight C, Black CM, Silman AJ. Prediction of 27. Mori Y, Kahari VM, Varga J. Scleroderma-like cutaneous
five-year survival following presentation with scleroderma: syndromes. Curr Rheumatol Rep 2002;4:113122.
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factors at first visit. Arthritis Rheum 1999;42:26602665. update. Curr Rheumatol Rep 2006;8:151157.
CHAPTER 17
Systemic Sclerosis
and Pathogenesis
JOHN VARGA, MD
Systemic sclerosis (SSc) is a chronic, multisystem arterioles, combined vascular and interstitial fibrosis
disease of unknown etiology characterized by in target organs. In patients with established SSc,
autoimmunity and inflammation, functional and these lesions occur in the absence of inflammation.
structural abnormalities in small blood vessels, and In relatively early-stage disease, perivascular cellular
progressive fibrosis of the skin and visceral organs. infiltrates are detected in many organs prior to the
Estimates of its incidence in the United States range appearance of fibrosis.
from 9 to 19 cases per million per year. The only The organs most prominently affected by obliterative
community-based survey of SSc yielded a prevalence vasculopathy are the heart, lungs, kidneys, and
of 286 cases per million population. intestinal tract.
SSc is more common in females, with women-to-men Fibrosis is prominent in the skin, lungs, gastrointesti-
ratios of 3 to 5 : 1. nal tract, heart, tendon sheath, perifascicular tissue
African Americans have a higher incidence than surrounding skeletal muscle, and in some endocrine
whites, and disease onset occurs at an earlier organs, such as the thyroid gland.
age. Furthermore, African Americans are more Multiple cell types and their products interact in the
likely to have the diffuse cutaneous form of the processes that underlie the diverse clinical manifesta-
disease with interstitial lung involvement and tions of SSc.
worse prognosis. An integrated view of the pathogenesis of SSc must
Some SSc patients (1.6%) have a first-degree relative incorporate the development of vasculopathy,
with the disease [relative risk (RR) = 13], indicating an activation of the cellular and humoral immune
important genetic contribution to disease responses, and progressive fibrosis of multiple
susceptibility. organs.
Among environmental factors, infectious agents Autoimmunity, altered endothelial cell function, and
(particularly viruses), exposure to environmental and vascular reactivity may be the earliest manifestations
occupational toxins, and drugs have been suspected of SSc, leading to Raynauds phenomenon years
of playing a role in the etiology of SSc. before other disease features are present. Complex
The distinguishing pathological hallmark of SSc is an interplay among these processes initiates, amplifies,
obliterative vasculopathy of small arteries and and sustains aberrant tissue repair and fibrosis.
Systemic sclerosis (SSc) is a chronic, multisystem disease EPIDEMIOLOGY

of unknown etiology characterized by autoimmunity
and inflammation, functional and structural abnormali- Systemic sclerosis, an acquired, sporadic disease with
ties in small blood vessels, and progressive fibrosis of worldwide distribution, affects all races. Estimates of its
the skin and visceral organs. The pathogenesis of SSc incidence in the United States range from 9 to 19 cases
is highly complex and incompletely understood. Multi- per million per year. Prevalence rate estimates range
ple cell types and their products interact in the pro- from 28 to 253 cases per million. The only community-
cesses that underlie the diverse clinical manifestations based survey of SSc yielded a prevalence of 286 cases
of SSc. per million population (1). It is estimated that some
351
352 JOHN VARGA
100,000 people in the United States have SSc, although focused on polymorphisms of candidate genes, particu-
this number may be significantly higher if patients who larly those involved in regulation of immunity and
may have milder disease and do not meet formal clas- inflammation, vascular function, and connective tissue
sification criteria are also included. There does not homeostasis. Weak associations of single nucleotide
appear to be a difference in incidence between warmer polymorphisms (SNPs) with SSc have been reported in
and colder climates within the United States. Studies genes encoding angiotensin-converting enzyme (ACE),
from England, Australia, and Japan have shown lower endothelin 1, nitric oxide synthase, B-cell markers
rates compared to the United States (2). (CD19), chemokines (monocyte chemoattractant
Age, gender, and ethnicity are important factors protein 1) and chemokine receptors, cytokines (inter-
determining disease susceptibility. Like other connec- leukin 1 alpha, IL-4, and tumor necrosis factor alpha),
tive tissue diseases, SSc is more common in females, growth factors and their receptors (connective tissue
with women-to-men ratios of 3 to 5 : 1. The female pre- growth factor [CTGF] and transforming growth factor
dominance, most striking among patients aged 15 to 40 beta [TGF-beta]), and extracellular matrix proteins
years, declines after menopause. The most common age (fibronectin, fibrillin, and SPARC). The list continues
of onset is in the 30 to 50 years range, and in contrast to grow.
to localized forms of scleroderma, SSc is rare in chil-
dren. African Americans have a higher incidence than
whites, and disease onset occurs at an earlier age. Fur- ENVIRONMENTAL FACTORS
thermore, African Americans are more likely to have
the diffuse cutaneous form of the disease with intersti- The relatively low rates of twin concordance for SSc
tial lung involvement and worse prognosis. Increased suggest the importance of environmental factors in
disease severity and mortality of SSc in African Ameri- disease susceptibility. Infectious agents (particularly
cans may be related to the greater frequency of severe viruses), exposure to environmental and occupational
disease subtypes and subtype-specific autoantibodies toxins, and drugs have been suspected. Patients with
such as those directed against topoisomerase I (Scl-70) SSc have increased serum antibodies to human cyto-
and U3-RNP (3). megalovirus (hCMV), and antitopoisomerase I autoan-
Associations of SSc with specific human leukocyte tibodies recognize antigenic epitopes that are present
antigen (HLA) haplotypes are generally weak. In con- on the hCMV-derived UL94 protein. Because anti-
trast, specific autoantibodies are associated with partic- bodies to UL94 induce endothelial cell apoptosis and
ular HLA alleles. For instance, antitopoisomerase I activation of dermal fibroblaststwo of the pathophy-
antibodies show strong association with the HLA- siologic hallmarks of SScmolecular mimicry may be a
DRB1*1101-1104 alleles in white and black Americans, possible mechanistic link between hCMV infection and
and with DRB1*1502 in Japanese. Certain antibody SSc. Other studies have implicated hCMV infection
HLA associations differ among different ethnic groups. in the allograft vasculopathy that follows solid organ
Among whites with SSc, the HLA-DQB1 molecule is transplantation. This vasculopathy is characterized by
associated with anticentromere antibodies. vascular neointima formation and smooth muscle pro-
liferation, reminiscent of the obliterative vasculopathy
of SSc. Demonstration that hCMV can directly induce
GENETIC FACTORS CTGF production in infected fibroblasts lends further
rationale to the hypothetical connection between hCMV
Systemic sclerosis is not inherited in a Mendelian and SSc. Human parvovirus B19 infection has also been
fashion. Furthermore, monozygotic and dizygotic twin postulated to have a link with SSc.
pairs show a similarly low rate of disease concordance Several reports of apparent geographic clustering of
(4). On the other hand, 1.6% of SSc patients have a SSc cases suggest shared environmental exposures, but
first-degree relative with the disease [relative risk (RR) careful investigations have failed to substantiate these
= 13], indicating an important genetic contribution to clusters. In the past two decades, two epidemics of
disease susceptibility. The risk of other autoimmune multisystemic illnesses reminiscent of SSc have been
diseases, including systemic lupus erythematosus (SLE) reported. One of these, the toxic oil syndrome, was
and rheumatoid arthritis, is also increased in first- linked to contaminated rapeseed cooking oils in Spain.
degree relatives of SSc patients. Among Choctaw Native The other, eosinophiliamyalgia syndrome, was caused
Americans from Oklahoma, the prevalence of SSc may by the ingestion of a dietary supplement (L-tryptophan)
be as high as 4690 per million. Moreover, affected indi- in the United States. Both of these apparently novel
viduals in the Choctaw population display striking syndromes, each of which affected more than 10,000
homogeneity of disease phenotype, with diffuse cutane- individuals, were characterized by chronic scleroderma-
ous involvement, pulmonary fibrosis, and antitopoisom- like skin fibrosis. Yet both showed clinical and patho-
erase I antibodies. Genetic investigations in SSc have logical features that clearly distinguished them from
SSc. Some observers have noted an increased incidence

of SSc among men with occupational exposure to silica,
such as miners. Other occupational exposures tenta-
tively linked with SSc include polyvinyl chloride, epoxy
resins, and aromatic hydrocarbons (e.g., toluene and
trichloroethylene). Drugs implicated in SSc-like ill-
nesses include bleomycin, pentazocine, cocaine, and
appetite suppressants (primarily derivatives of fenflura-
mine) associated with pulmonary hypertension. The
occurrence of SSc in some women with silicone breast
implants raised concern regarding a possible associa-
tion, but careful epidemiologic investigations found no
evidence of increased risk of SSc (5).
PATHOLOGY
Figure 17B-1
The distinguishing pathological hallmark of SSc is an
obliterative vasculopathy of small arteries and arteri- Inflammation and fibrosis in the skin. This skin lesion from a
oles combined with interstitial fibrosis in target organs. patient with early systemic sclerosis shows a focal perivascular
In patients with established SSc, these lesions occur in infiltrate composed on monocytes and lymphocytes, surrounded
by densely packed collagen fibers in the deep layer of the
17
the absence of inflammation. In relatively early-stage dermis. Adnexal structures are encased by connective tissue.
disease, however, perivascular cellular infiltrates are (Hematoxylin and eosin). (From Varga J, Abraham D. Systemic
detected in many organs prior to the appearance of sclerosis: a prototypic multisystem fibrotic disorder, by permis-
fibrosis. Cutaneous infiltrates are composed primarily sion of J Clin Invest 2007 117:55767.)
of CD4+ T lymphocytes (6). In addition, CD8+ T cells,
monocytes/macrophages, plasma cells, mast cells, and
occasionally B cells are detected. In contrast to skin, the is generally spared. The lower esophagus is frequently
majority of T cells infiltrating the lungs are CD8+. Evi- involved, with prominent fibrosis of the lamina propria
dence of eosinophil degranulation is found in lesional and submucosa, characteristic vascular lesions, and
skin and lungs in the absence of intact eosinophils. atrophy of the muscular layers. Lower esophageal
The vascular lesion of SSc, characterized by bland dysfunction leads to gastroesophageal reflux in a high
intimal proliferation in the small and medium-sized percentage of patients. Chronic reflux is associated
arteries, results in luminal narrowing. The organs most with esophageal inflammation, ulcerations, and stric-
prominently affected by obliterative vasculopathy are ture formation, and may lead to Barretts esophagus.
the heart, lungs, kidneys, and intestinal tract. Fibrosis is Replacement of the normal intestinal tract architecture
prominent in the skin, lungs, gastrointestinal tract, results in disordered peristaltic activity, dysmotility, and
heart, tendon sheath, perifascicular tissue surrounding small bowel obstruction.
skeletal muscle, and in some endocrine organs, such as In the lungs, patchy infiltration of the alveolar walls
the thyroid gland. SSc-associated fibrosis is character- with CD8+ lymphocytes, macrophages, and eosinophils
ized by homogeneous-appearing connective tissue is prominent in early disease. With disease progression,
composed of type I collagen, fibronectin, proteoglycans, fibrosis and vascular damage dominate the pathological
and other structural macromolecules. The process leads picture in diffuse SSc, often coexisting within the same
to progressive replacement of normal tissue, disruption lesions. In patients with limited cutaneous disease, vas-
of architecture, functional impairment, and (frequently) cular lesions predominate with little or no fibrosis.
organ failure. In the skin, fibrosis is preceded by inflam- Intimal thickening of the pulmonary arteries, best seen
matory cell accumulation. This causes massive dermal with elastin stain, underlies pulmonary hypertension.
expansion with obliteration of the hair follicles, sweat At autopsy in such cases, multiple pulmonary emboli
glands, and other appendages (Figure 17B-1). Collagen and evidence of myocardial fibrosis are often found.
accumulation is most prominent in the reticular dermis, Pulmonary fibrosis is characterized by expansion of the
and the fibrotic process invades the subjacent adipose alveolar interstitium, with accumulation of collagen and
layer with entrapment of fat cells. The epidermis is atro- other connective tissue proteins. This pattern is classi-
phic, and the rete pegs are effaced. fied histopathologically as nonspecific interstitial pneu-
Pathological changes can be found in any part of the monitis (NSIP). Progressive thickening of the alveolar
gartrointestinal tract, from the mouth to the rectum. septae results in obliteration of the air spaces and hon-
The striated muscle in the upper third of the esophagus eycombing, as well as loss of pulmonary blood vessels
354 JOHN VARGA
Autoimmunity, altered endothelial cell function, and

vascular reactivity may be the earliest manifestations of
SSc, leading to Raynauds phenomenon years before
other disease features are present. Complex interplay
between these processes initiates, amplifies, and sustains
aberrant tissue repair and fibrosis (7).
ANIMAL MODELS OF DISEASE

No animal model reproduces all three cardinal features
of human SSc (vascular damage, autoimmunity, and
fibrosis), but some models recapitulate selected disease
characteristics. The tight skin mouse (Tsk1/+) is a natu-
Figure 17B-2 rally occurring model of SSc characterized by spontane-
ous development of scleroderma-like skin changes. The
Pulmonary artery. There is thickening of the intimal layer of a
small pulmonary artery, leading to occlusion of vascular lumen. mutation responsible for the mouse phenotype, an in-
(Hematoxylin and eosin). frame duplication in the gene responsible for Marfans
disease (fibrillin-1), results in defective matrix assembly
and altered TGF-beta activation. However, correspond-
ing mutations have not been found in human SSc. A
chronic condition with fibrosis in the skin and lungs can
(Figure 17B-2). This process impairs gas exchange and be induced in mice by chemical exposure (bleomycin
contributes to worsening pulmonary hypertension. injections) or by transplantation of HLA-mismatched
The heart is frequently affected, with prominent bone marrow or spleen cells (sclerodermatous graft
involvement of the myocardium and pericardium. The versus host disease). Increasingly, manipulation of mice
characteristic arteriolar lesions of intimal proliferation via mutagenesis or targeted genetic modifications such
and luminal narrowing are accompanied by contraction as knockout models or transgenesis have created new
band necrosis, reflecting ischemia-reperfusion injury, approaches to studying SSc and dissecting the roles of
and patchy myocardial fibrosis. The electrical system of individual molecules in the underlying processes. For
the heart (bundle of His, Purkinje fibers) may be instance, genetic targeting of Smad3, an intracellular
involved, leading to conduction disturbances. mediator for TGF-beta, and of the chemokine MCP-1,
In the kidneys, lesions of the interlobular arteries both resulted in mice that were resistant to bleomycin-
predominate. Glomerulonephritis is not characteristic induced scleroderma.
of SSc. Chronic renal ischemia is associated with
shrunken glomeruli. Patients with scleroderma renal
crisis show dramatic changes in small renal arteries: VASCULOPATHY
reduplication of elastic lamina, marked intimal prolif-
eration and narrowing of the lumen, and often throm- Vascular involvement is widespread in SSc and has
bosis and microangiopathic hemolysis. The renal lesion important clinical implications. Raynaud phenomenon,
in scleroderma renal crisis may be identical histopatho- an early disease manifestation, is characterized by an
logically to that of thrombotic thrombocytopenic altered blood flow response to cold challenge. This
purpura. Other organs may also be affected. Synovitis initially reversible abnormality is due to alterations in
may be found in patients with early SSc, but with pro- the autonomic and peripheral nervous systems, with
gression the synovium becomes fibrotic, as do tendon impaired production of neuropeptides, such as calcito-
sheaths and fascia, producing audible tendon friction nin gene-related peptide (from sensory afferent nerves)
rubs. Inflammatory myositis and muscle fibrosis are and heightened sensitivity of alpha 2-adrenergic recep-
common findings. tors (on vascular smooth muscle cells). While primary
Raynauds phenomenon is a relatively benign, nonpro-
gressive condition, in SSc irreversible morphological
PATHOGENESIS and functional changes in the circulation develop,
leading to endothelial injury. Within the endothe-
An integrated view of the pathogenesis of SSc must lium, there is altered production of and responsiveness
incorporate the development of vasculopathy, activa- to endothelium-derived factors that mediate vasodi-
tion of the cellular and humoral immune responses, and latation (nitric oxide and prostacyclin) and vasocon-
progressive fibrosis of multiple organs (Figure 17B-3). striction (endothelin 1). Microvessels show increased
Vascular Injury
Endothelial dysfunction
Endothelial cell activation
Endothelin-1 release
Platelet activation
Vascular damage
Neointima formation
Leukocyte Activation, recruitment Medial hypertrophy
Activated Th2 cells (CD4+ CD8+) Peri-adventitial fibrosis
Monocytes/macrophages Luminal narrowing
Activated B cells Thrombosis
TGF-
Obliterative Vasculopathy
Autoantibodies Th2 cytokines
CTGF, PDGF
Chemokines
Tissue Hypoxia
Fibroblast activation
Collagen accumulation
17
ECM molecule deposition
Myofibroblast differentiation Adhesion, matrix
remodeling, contraction Defective vasculogenesis
Pericyte differentiation
Bone-marrow derived
mesenchymal progenitor cells
Collagen accumulation
Extracellular matrix reorganization
Impaired matrix degradation
Fibrosis
FIGURE 17B-3
Schematic representation of the complex pathogenesis of systemic sclerosis. Initial vascular injury
in genetically susceptible individuals leads to functional and structural vascular alterations,
inflammation, and the generation of autoimmunity. The inflammatory and immune responses
then initiate and sustain fibroblast activation and differentiation, resulting in pathological
fibrogenesis and irreversible tissue damage. CTGF, connective tissue growth factor; PDGF,
platelet-derived growth factor; ECM, extracellular matrix.
permeability, enhanced transendothelial leukocyte hands and kidneys of patients with late-stage disease
diapedesis, activation of coagulation and fibrinolytic cas- reveal a striking absence of blood vessels. Damaged
cades, and platelet aggregation. These processes culmi- endothelium promotes platelet aggregation and release
nate in thrombosis. Endothelial cells show increased of thromboxane, a potent vasoconstrictor, and platelet-
expression of intercellular adhesion molecule 1 (ICAM- derived growth factor (PDGF). Vascular compromise is
1) and other surface adhesion molecules. Vasculopathy aggravated further by defective fibrinolysis. Oxidative
affects capillaries, arterioles, and even large vessels in stress due to ischemia-reperfusion is associated with
many organs. Smooth muscle cell-like myointimal cells generation of free radicals that further contribute to
proliferate, the basement membrane is thickened and endothelial damage through peroxidation of membrane
reduplicated, and adventitial fibrosis develops. lipids. Paradoxically, the process of revascularization
Progressive vascular luminal occlusion due to intimal that normally re-establishes blood flow to ischemic
and medial hypertrophy and adventitial fibrosis, com- tissue appears to be defective in SSc. Failure of vascu-
bined with persistent endothelial cell damage and apo- logenesis occurs in the setting of elevated levels of
ptosis, establish a vicious cycle. Angiograms of the angiogenic factors, such as vascular endothelial growth
356 JOHN VARGA
factor (VEGF). In patients with SSc, the number of induce its own production, as well as that of CTGF (also
bone marrowderived CD34+ CD133+ endothelial pro- termed CCN2) and other cytokines, TGF-beta estab-
genitor cells circulating in the system is reduced mark- lishes sustained autocrine/paracrine loops for activation
edly; moreover, their differentiation in vitro into mature of fibroblasts and other effector cells. DNA microarray
endothelial cells is impaired (8). Thus, widespread oblit- studies of global gene expression in CD8+ T cells in
erative vasculopathy and failure to replace damaged bronchoalveolar lavage fluids from patients with SSc
vessels are hallmarks of SSc. have demonstrated an activated Th2 pattern of gene
expression, characterized by increased levels of IL-4
and IL-13, and reduced production of interferon gamma
CELLULAR AND HUMORAL (IFN-gamma). Th2 cytokines promote collagen synthe-
AUTOIMMUNITY sis and other profibrotic responses. IFN-gamma inhibits
collagen synthesis and blocks cytokine-mediated fibro-
blast activation.
In the early stages of the disease, activated T cells and
Circulating autoantibodies are detected in virtually
monocytes/macrophages accumulate in lesional skin,
all patients with SSc. These mutually exclusive autoan-
lungs, and other affected organs. Infiltrating T cells
tibodies are highly specific for SSc, and show strong
express activation markers such as CD3, CD4, CD45,
association with individual disease phenotypes and
and HLA-DR, and display restricted receptor signa-
genetically determined HLA haplotypes. Autoantibody
tures indicative of oligoclonal expansion in response to
levels correlate with disease severity and their titers
unknown antigens. Circulating CD4+ T cells also have
fluctuate to some degree with disease activity, albeit the
elevated levels of chemokine receptors and express
precise temporal relationships between antibody titer
alpha 1 integrin (an adhesion molecule), accounting for
and disease activity is imperfect. Some SSc-specific
their enhanced ability to bind to endothelium and to
autoantibodies are antinuclear and directed against pro-
fibroblasts. Endothelial cells express ICAM-1 and other
teins involved in mitosis, such as topoisomerase I and
adhesion molecules that facilitate leukocyte diapedesis.
the RNA polymerases. Others are directed against cell
Activated macrophages and T cells show a Th2-
surface antigens or secreted proteins. The concordance
polarized response, and secrete interleukin 4 and inter-
rates for positive ANA in twin pairs in which one sibling
leukin 13. Both of these Th2 cytokines can induce
has SSc are 85% (monozygotic) and 60% (dizygotic),
TGF-beta, a powerful modulator of immune regulation
indicating a major role for genetics in the SSc-specific
and matrix accumulation (Table 17B-1). Because it can
immune response.
Although autoantibodies have well-established clini-
cal utility as diagnostic and prognostic markers, their
role in clinical manifestations of SSc remains uncertain.
TABLE 17B-1. SOLUBLE MEDIATORS OF FIBROBLAST Topoisomerase I autoantibodies in SSc patients can
ACTIVATION ELEVATED IN SYSTEMIC SCLEROSIS.
directly bind to fibroblasts, and autoantibodies to fibro-
MOLECULE CELLULAR SOURCE blasts, endothelial cells, fibrillin-1, and matrix metallo-
proteinase enzymes have all been described. Some of
TGF-beta Inflammatory cells, platelets,
these autoantibodies may have direct pathogenic roles
fibroblasts
as mediators of tissue damage. Multiple potential
PDGF Platelets, macrophages, mechanism(s) have been proposed to account for auto-
fibroblasts, endothelial cells antibody generation in SSc. According to one theory, in
CTGF Fibroblasts SSc patients specific self-antigens undergo novel modi-
fications, such as structural alterations due to proteolytic
Insulinlike growth factor 1 Fibroblasts cleavage, increased expression level, or changes in sub-
IL-4, IL-13 Th2 lymphocytes, mast cells cellular localization, resulting in their recognition by the
immune system. For example, cytotoxic T cells release
IL-6 Macrophages, B cells, T cells,
the protease granzyme B, which cleaves autoantigens,
fibroblasts
generating novel fragments with potential neo-epitopes
Chemokines (MCP-1, MCP-3) Neutrophils, epithelial cells, that break immune tolerance. Recent studies implicate
endothelial cells, fibroblasts B cells in both autoimmunity and fibrosis in SSc. In addi-
Fibroblast growth factor Fibroblasts tion to their well-recognized role in antibody produc-
tion, B cells can present antigen, produce cytokines,
Endothelin 1 Endothelial cells such as IL-6 and TGF-beta, and modulate T-cell and
dendritic-cell function. B cells from SSc patients show
ABBREVIATIONS: CTGF, connective tissue growth factor; IL, interleukin; PDGF,
platelet-derived growth factor; TGF-beta, transforming growth factor beta. intrinsic abnormalities, with elevated expression of the
MCP, monocyte chemotactic protein. CD19 B-cell receptor, expansion in the naive B-cell
compartment, and reduced numbers of memory B cells ing and scar formation. Dysregulated fibroblast activa-
and early plasma cells (9). Gene expression profiling of tion and matrix accumulation are the fundamental
SSc skin biopsies has identified mRNA expression sig- pathogenetic alterations underlying tissue fibrosis in
natures characteristic of activated B cells. SSc.
In addition to locally derived connective tissue fibro-
blasts, circulating mesenchymal progenitor cells of bone
FIBROSIS: CELLULAR AND marrow origin also participate in fibrogenesis. Periph-
MOLECULAR COMPONENTS eral blood mononuclear cells expressing CD14 and
CD34 have been shown to differentiate into collagen-
producing alpha-smooth muscle actin-positive fibro-
Fibrosis affecting multiple organs is a prominent hall-
cytes in vitro. This process is enhanced by TGF-beta
mark, distinguishing SSc from other connective tissue
(10). The factors that regulate the production of mes-
diseases. Fibrosis is thought to be a consequence of
enchymal progenitor cells in the bone marrow and their
autoimmunity and vascular damage. The process is
trafficking from the circulation into lesional tissue,
characterized by progressive replacement of normal
and promote their differentiation in situ into matrix-
tissue architecture with dense acellular connective
producing adhesive and contractile fibrocytes, remain
tissue, and accounts for substantial morbidity and mor-
unknown. Epithelial to mesenchymal cell transition
tality in SSc.
(EMT), a process implicated in the development of
Fibroblasts and related mesenchymal cells are nor-
fibrosis following injury in the lungs and kidney, may
mally responsible for the functional and structural
also be involved in organ fibrosis in SSc. Fibroblasts can
integrity of connective tissue in parenchymal organs.
When activated by TGF-beta and related cytokines
differentiate into smooth musclelike myofibroblasts. 17
Both EMT and myofibroblast differentiation are medi-
(Table 17B-2), fibroblasts proliferate, migrate, elabo-
ated by TGF-beta. Although myofibroblasts can be
rate collagen and other matrix macromolecules, secrete
transiently detected during normal wound healing, their
growth factors and cytokines and express surface recep-
persistence in tissue, possibly due to apoptosis resis-
tors for them, and differentiate into myofibroblasts.
tance, indicates dysregulated repair during pathological
Together, these fibroblast responses facilitate effective
fibrogenesis. Myofibroblasts contribute to scar forma-
repair of tissue injury. Under physiologic conditions,
tion via their ability to produce collagen and TGF-beta,
the fibroblast repair program is self-limited, terminating
and to generate contractile forces on the surrounding
upon completion of healing. In pathological fibrotic
matrix, converting it into dense scar.
responses however, fibroblast activation is sustained
Fibroblasts explanted from lesional SSc tissues
and amplified, resulting in exaggerated matrix remodel-
display an abnormal phenotype indicative of autono-
mous activation. Compared to normal fibroblasts, SSc
fibroblasts in culture are characterized by variably
increased rates of type I collagen gene transcription.
TABLE 17B-2. PROFIBROGENIC ACTIVITIES OF Furthermore, they have smooth muscle actin stress
TRANSFORMING GROWTH FACTOR BETA fibers, enhanced synthesis of various extracellular matrix
POTENTIALLY IMPORTANT IN SYSTEMIC SCLEROSIS. molecules, expression of chemokine receptors and cell
Recruits monocytes surface adhesion molecules, secretion of PDGF, Akt-
mediated resistance to apoptosis, and autocrine TGF-
Stimulates fibroblast synthesis of collagens, extracellular matrix, beta signaling. This abnormal scleroderma phenotype
inhibitors of proteolytic enzymes; suppresses matrix metallopro-
teinase enzymes
persists during serial passage in vitro. The mechanisms
underlying the acquisition of the autonomously acti-
Stimulates fibroblast proliferation, chemotaxis vated phenotype are unknown; persistent fibroblast
Induces fibrogenic cytokine production: CTGF; autoinduction; activation via autocrine stimulatory loops involving
blocks synthesis and activity of interferon gamma TGF-beta, selection of activated fibroblast subpopula-
tions driven by hypoxia or immune factors, intrinsic
Induces fibroblast mitogenic responses to PDGF
abnormalities in SSc fibroblasts, and altered cellmatrix
Promotes fibroblastmyofibroblast differentiation interaction are some of the mechanisms under investi-
gation. Recent reports indicate that intracellular block-
Promotes monocytefibrocyte differentiation
ade of TGF-beta signaling can abrogate the activated
Promotes epithelialmesenchymal transition phenotype in SSc lesional fibroblasts, resulting in their
partial normalization. Autocrine TGF-beta signaling,
Inhibits fibroblast apoptosis
therefore, contributes to the persistence of the fibro-
ABBREVIATIONS: CTGF, connective tissue growth factor; PDGF, platelet-derived genic phenotype of SSc fibroblasts. Results from
growth factor. global transcriptome analyses of SSc fibroblasts show
358 JOHN VARGA
differential expression of many ECM genes, including 2. Mayes MD, Lacey JV Jr, Beebe-Dimmer J, et al. Preva-
collagens, fibronectin, and fibrillins (11). A majority of lence, incidence, survival, and disease characteristics of
the abnormally expressed genes could be mechanisti- systemic sclerosis in a large US population. Arthritis
cally linked to TGF-beta responses, but other fibrogenic Rheum 2003;48:22462255.
3. Kuwana M, Kaburaki J, Arnett FC, Howard RF, Medsger
signaling pathways also operate in SSc.
TA Jr, Wright TM. Influence of ethnic background on
Autocrine/paracrine TGF-beta and its intracellular
clinical and serologic features in patients with systemic
signaling pathways play pivotal roles in the initiation sclerosis and anti-DNA topoisomerase I antibody.
and propagation of the fibrotic response in SSc. Intra- Arthritis Rheum 1999;42:465474.
cellular TGF-beta signaling is a complex and cell type 4. Feghali-Bostwick C, Medsger TA Jr, Wright TM. Analy-
specific process involving multiple primary and accessory sis of systemic sclerosis in twins reveals low concordance
receptors, stimulatory and inhibitory members of the for disease and high concordance for the presence of anti-
Smad family of signal transducer proteins and other nuclear antibodies. Arthritis Rheum 2003;48:19561963.
transcriptional factors, coactivators and repressors. 5. Janowsky EC, Kupper LL, Hulka BS. Meta-analyses of
Lesional fibroblasts secrete TGF-beta and exhibit TGF- the relation between silicone breast implants and the risk
beta hyper-responsiveness due to elevated expression of connective-tissue diseases. N Engl J Med 2000;342:781
790.
of TGF-beta receptors and activation of latent TGF-
6. Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding
beta. Inappropriate activation of the intracellular TGF-
P. Sequential dermal microvascular and perivascular
beta signal transduction pathways due to constitutive changesinthedevelopmentofscleroderma.JPathol1992;166:255
Smad3 phosphorylation and defective Smad-7depen- 263.
dent negative feedback loops have been described in 7. Abraham DJ, Varga J. Scleroderma: from cell and molec-
SSc. The nuclear coactivator protein p300 facilitates ular mechanisms to disease models. Trends Immunol
Smad-mediated collagen transcription and is an impor- 2005;26:587595.
tant locus of integration for multiple extracellular signals 8. Kuwana M, Okazaki Y, Yasuoka H, Kawakami Y, Ikeda
modulating fibroblast function. The cellular abundance Y. Defective vasculogenesis in systemic sclerosis. Lancet
of p300 appears to control the magnitude of its response 2004;364:603610.
to TGF-beta (12). Abnormalities in the expression, 9. Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered
blood B lymphocyte homeostasis in systemic sclerosis:
function, and interactions of Smads, p300, and other
expanded naive B cells and diminished but activated
cellular proteins account for the persistence and pro-
memory B cells. Arthritis Rheum 2004;50:19181927.
gression of the scleroderma fibrogenic process by mod- 10. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN.
ulating target gene transcription. Peripheral blood fibrocytes: differentiation pathway and
migration to wound sites. J Immunol 2001;166:75567562.
11. Whitfield ML, Finlay DR, Murray JI, et al. Systemic and
cell type-specific gene expression patterns in SSc skin.
REFERENCES Proc Natl Acad Sci U S A. 2003;100:1231912324.
12. Bhattacharyya S, Ghosh AK, Pannu J, et al. Fibroblast
1. Maricq HR, Weinrich MC, Keil JE, et al. Prevalence of expression of the coactivator p300 governs the intensity
scleroderma spectrum disorders in the general population of profibrotic response to transforming growth factor
of South Carolina. Arthritis Rheum 1989;32:9981006. beta. Arthritis Rheum 2005;52:12481258.
CHAPTER 17
Systemic Sclerosis
MAYA H. BUCH, MBCHB, MRCP
JAMES R. SEIBOLD, MD
Systemic sclerosis (SSc; scleroderma) targets several important roles in selected patients with pulmonary
aspects of disease pathophysiology: vascular features arterial hypertension.
that are currently highly treatable; inflammatory Early recognition of scleroderma renal crisis (SRC) and
features that are currently partly amenable to prompt treatment with angiotensin-converting
therapy; fibrotic features for which therapies of enzyme (ACE) inhibitors has improved outcomes in
modest efficacy (at best) exist; and atrophic, end SRC dramatically.
organ damage for which only supportive therapy is Cyclophosphamide is a cornerstone of
available. interstitial lung disease treatment in SSc, but the
The extent of skin involvement is neither a robust therapeutic gains from this agent are relatively
primary outcome measure for clinical trials nor a small.
reliable guide to the therapy of individual patients. Long-term proton-pump inhibition is highly
Regular pulmonary function testing is a cornerstone effective in treating the gastroesophageal reflux.
of assessment. High doses, sometimes two to three times the
Continuous intravenous epoprostenol, subcutaneous normal therapeutic dose, are required to alleviate
or intravenous treprostinil, and bosentan all have symptoms.
Systemic sclerosis (SSc, scleroderma) has one of the ASSESSMENT OF DISEASE

highest mortality rates among all connective tissue dis-
orders. To date, no effective therapy that addresses the The extent of skin involvement is the basis for SSc
underlying disease process exists. Significant strides subset classification and a major indicator of risk for
have been made in improving survival, however, largely certain internal organ complications. Unfortunately,
through therapies directed at the treatment of specif- skin involvement is neither a robust primary outcome
ic organ complications. State-of-the-art management measure for clinical trials nor a reliable guide to the
entails organ-based therapy with particular attention to therapy of individual patients. Monitoring for lung
lung and renal involvement, the major causes of mor- involvement with regular pulmonary function testing is
bidity and mortality. This strategy emphasizes the role a cornerstone of assessment, particularly in patients with
of early detection of internal organ involvement, and early diffuse scleroderma. Reduction in forced vital
the timely implementation of treatment. In simple capacity suggests the presence of interstitial lung disease,
terms, SSc includes vascular features that are eminently which is usually confirmed then by the demonstration of
treatable; inflammatory features that are at least partly reticular or alveolar parenchymal disease on high resolu-
amenable to therapy, as well; fibrotic features for which tion computed tomography (CT) of the chest.
therapies of modest efficacy (at best) exist; and atro- Isolated or disproportionate reduction in diffusing
phic, end organ damage for which only supportive capacity suggests pulmonary vascular pathology;
therapy is available. namely, pulmonary arterial hypertension (PAH).
359
360 MAYA H. BUCH AND JAMES R. SEIBOLD
Doppler echocardiography can provide estimates of The natural tendency for skin involvement to improve
pulmonary artery pressures and is useful in serial follow- by the second to third year complicates the assessment
up, but right heart catheterization remains the gold of treatment efficacies. Therapeutic strategies have
standard for confirmation of that diagnosis (1). evolved rapidly in recent years, but still permit rela-
Measures of renal function and blood pressure serve tively few evidence-based approaches (see Figure 17C-
as prime indicators of scleroderma renal crisis in early 1). The next sections focus in turn on treatments of the
diffuse disease. Creatinine phosphokinase and aldolase vascular, inflammatory, and fibrotic components of
levels are sensitive indicators of myositis/myopathy. scleroderma.
Specific serologies, including antitopoisomerase and
anti-U1RNP antibodies, predict diffuse disease. In con- Vascular Therapy
trast, anticentromere antibodies predict limited SSc.
Complications of scleroderma that result clearly from
Not all patients with scleroderma are positive for one
vascular dysfunction include PAH, scleroderma renal
of these autoantibodies (see Chapter 17A).
crisis (SRC), and Raynauds phenomenon (RP). Treat-
ment approaches to these disease manifestations are
evolving rapidly (2).
TREATMENT
Pulmonary Arterial Hypertension
When treating individual complications, a core set of
principles applies, regardless of patients subset and The endothelial dysfunction of PAH leads to increased
stage. Certain targeted treatment approaches may also endothelin and reduced nitric oxide and prostacyclin.
address individual organ system components of disease. Continuous intravenous epoprostenol (Flolan) and sub-
Disease subset and stage, however, are key in guiding cutaneous or intravenous treprostinil (Remodulin),
initial treatment. Progression of skin changes in early, both US Food and Drug Administration (FDA)
diffuse SSc signals the need for aggressive management approved therapies, are consensus first-line treatments
to limit internal organ damage. The precise choice of for PAH patients with World Health Organization
therapy depends upon the specific organ system (WHO) class IV disease. The delivery systems (indwell-
manifestations. ing catheters), associated risks (line infection), and
FIGURE 17C-1
A summary of organ-directed treatment in limited and diffuse scleroderma. Treatments in bold:

FDA-approved. Cyclophosphamide*: Confirmed efficacy over placebo in a randomized, double-
blind study in patients with interstitial lung disease. MMF: No controlled studies. Abbreviations:
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CTGF,
connective tissue growth factor; GAVE, gastric antral venous ectasia; GERD, gastroesophageal
reflux disease; MCP-1, macrophage chemoattractant protein 1; MMF, mycophenylate mofetil;
MTX, methotrexate; NTG, nitroglycerin; OT/PT, occupational therapy/physical therapy; PAH,
pulmonary arterial hypertension; PDE-5, type 5 phosphodiesterase; RP, Raynauds phenomenon;
SRC, scleroderma renal crisis; SSRI, specific serotonin receptor uptake inhibitor; Stem cell Tx, stem
cell transplantation; TGF-, transforming growth factor beta.
ORGAN-BASED THERAPY IN SYSTEMIC SCLEROSIS
GENERAL SYMPTOMATIC VASCULAR IMMUNE/FIBROTIC

MEASURES
Arthritis RP PAH SRC

Tendonitis
Myositis/myopathy
OT/PT Calcium channel Bosentan ACEI Cyclophosphamide* Experimental
Gastrointestinal blocker
BP control MMF* Broad
Nutrition GERD Sildenafil
Stricture SSRI Stem cell Tx
MTX Targeted
Fitness GAVE inhaled Iloprost
Diarrhea ACEI/ARB Anti-TGF-b
Emotional support iv Epoprostenol Anti-CTGF
Topical NTG Anti-MCP-1
sc Trepostinil Imatinib
PDE-5 inhibitor
Pirfenidone
Bosentan
other side effects (infusion site pain) have forced a strongly advised to several layers of clothing over their
search for alternative therapies. entire bodies, particularly during cold months.
The selectivity of prostacyclins effects on pulmonary Calcium-channel blockers, such as amlodipine, nife-
vasculature provided the rationale behind the develop- dipine, or felodipine, are the initial medical treatment
ment of inhaled therapy for PAH, which have the added for RP. Low dose selective serotonin reuptake inhibi-
potential advantage of avoiding some systemic side tors (SSRIs) are also used because of their allegedly
effects. Repeated inhalation of iloprost (Ventavis) has salubrious effects on platelet aggregation and activa-
been shown to improve function and hemodynamics, tion. Among the SSRIs, fluoxetine (Prozac; Symbyax;
and to slow the rate of clinical decline. The role of Sarafem) is the best studied. Despite their striking
endothelin 1 in idiopathic PAH and SSc-PAH patho- effectiveness in SRC, ACE inhibitors and ARBs are not
physiology has led to the development of endothelin particularly effective for RP.
receptor antagonists (ERA). Bosentan (Tracleer), an Digital ischemia and ulceration are often managed
oral, nonselective ERA, is considered a first-line therapy with intermittent intravenous iloprost, particularly
in WHO class III patients. Regular monitoring is during the winter months. In addition, therapies intro-
required for possible abnormal liver function. duced originally for the management of PAH now are
Other ERA therapies are under investigation. Type being applied to the treatment of recalcitrant RP. Two
V phosphodiesterase (PDE-5) metabolizes cyclic large, multicenter, controlled trials of bosentan con-
guanine monophosphate (cGMP). Inhibition of cGMP firmed a reduction in the development of new digital
metabolism with the PDE-5 inhibitor sildenafil (Viagra) ulcers compared to placebo (4). Case series and reports
enhances pulmonary vasodilation. Side effects include have suggested improved RP control with the use of
axial muscle cramps. To date, long-term studies examin- sildenafil. Despite the improved options for the treat- 17
ing mortality as the primary outcome are not available ment of RP now, therapy is expensive, access often
for any agent. Combination therapies using agents limited, and the responses (albeit dramatic in some
from each of the different classes are under active patients) frequently inconsistent.
investigation.
Anti-Inflammatory Treatments
Scleroderma Renal Crisis In addition to the vascular nature of some scleroderma-
Development of accelerated to malignant hypertension related problems, other manifestations of this disease,
with microangiopathic hemolytic anemia is the defini- for example, interstitial lung disease and myositis, have
tion of SRC. Until the availability of angiotensin- clear inflammatory components. At the present time,
converting enzyme (ACE) inhibitors, the treatment of anti-inflammatory therapies for scleroderma are less tar-
SRC was extraordinarily difficult despite the use of other geted than are those for vascular problems. An approach
antihypertensive approaches, and the onset of SRC involving the use of nonspecific, broadly immunosup-
nearly always signaled a terminal phase of the illness. pressive agents assumes that immunological activation
Early recognition of SRC and the prompt institution influences both the fibrotic and vascular components.
of ACE inhibition (at the maximum tolerable dose) has
improved outcomes in SRC dramatically. Deaths from Cyclophosphamide
SRC are now decidedly rare, and fewer than 50% of Cyclophosphamide (CYC) has been used as the primary
patients in SRC progress to end-stage renal disease
therapeutic agent for interstitial lung disease in sclero-
(ESRD) (3). If patients do progress to ESRD, ACE
derma. In a recent controlled trial (5), cyclophospha-
inhibition should be continued into the phase of dialy-
mide improved forced vital capacity (FVC) by only
sis; some patients demonstrate renal recovery even after
2.9% compared to placebo. Although the demonstra-
several months of dialysis.
tion of a modest benefit of CYC supports its continued
For patients with diffuse sclerodermathe subset at
use, the small effect suggests the need for a more tar-
highest risk for SRCprophylactic treatment with an
geted approach.
ACE inhibitor is advisable. Although not yet tested in
a rigorous fashion, angiotensin receptor blockade
(ARB) therapies are also probably efficacious in SRC.
Autologous Stem Cell Transplantation
Immunoablation with immune reconstitution using
autologous peripheral stem cells has been considered
Raynauds Phenomenon
for severe diffuse scleroderma. Pilot studies have sug-
A growing number of treatments are now available for gested robust effects on skin and patient function and
RP. A cornerstone of the therapy of this complication, neutral effects on internal involvement (6). Ongoing
however, is the maintenance of a warm core body tem- studies comparing stem cell transplantation with CYC
perature. In addition to gloves, handwarmers, and other treatments will determine the appropriateness of this
approaches to warming the extremities, patients are strategy.
362 MAYA H. BUCH AND JAMES R. SEIBOLD
Methotrexate octreotide, a somastatin analogue. Abdominal bloating

and/or diarrhea suggest small bowel bacterial over-
A randomized, controlled trial evaluating efficacy of growth. This is treated with antibiotics, often rotating
methotrexate in early diffuse scleroderma suggested courses, to circumvent antibiotic resistance. One- to two-
greater disease stability compared with placebo (7). The week courses of metronidazole (250 mg t.i.d.) or cipro-
precise advantages conferred in clinical practice remain floxacin (500 mg q.d.) are usually prescribed. Advanced
uncertain. Methotrexate use is reserved generally for scleroderma involvement of the gastrointestinal tract
early diffuse cases with features limited to skin and may be dominated by fecal incontinence and constipa-
musculoskeletal systems, including myositis. tion. Antidiarrheal agents and behavioral therapy in the
form of biofeedback is undertaken to manage inconti-
Mycophenolate Mofetil nence. Stool bulking and softening agents are the main-
stay of treatment in addressing constipation.
Mycophenolate mofetil has not been studied in any con-
trolled trials. Current anecdotal evidence suggests it
may be effective in early diffuse disease, including cases CONCLUSION
complicated by interstitial lung disease (8).
Modern management of scleroderma is characterized
most appropriately as organ-based therapy. Specific
Antifibrotic Therapy gains in the treatment of scleroderma renal crisis and
Despite the fact that fibrosis is a central component to pulmonary hypertension have unequivocally improved
the pathophysiology of scleroderma, no agent designed overall outcome and survival. Continued progress in
to prevent fibrosis has been proven effective to date. our understanding of the disease will lead to more tar-
Nonspecific agents, including D-penicillamine (9) and geted, effective treatments.
recombinant human relaxin, have failed in clinical trials.
The importance of transforming growth factor beta
(TGF-beta) expression in the pathogenesis of sclero- REFERENCES
derma has prompted the evaluation of agents that either
trap or block TGF-beta. Although the use of an anti 1. McGoon M, Gutterman D, Steen V, et al. Screening, early
TGF-beta antibody has been suggested in early studies detection, and diagnosis of pulmonary arterial hyperten-
sion: ACCP evidence-based clinical practice guidelines.
to be safe, clinical benefit remains to be observed. Other
Chest 2004;126:11S34S.
anticytokine therapies, all of which remain unvalidated 2. Farber HW, Loscalzo J. Pulmonary arterial hypertension.
in scleroderma, are included in Figure 17C-1. N Engl J Med 2004;351:16551665.
3. DeMarco PJ, Weisman M, Seibold JR, et al. Predictors and
outcome of scleroderma renal crisis. The high-dose versus
Other Organ-Specific Therapies low-dose D-penicillamine in early diffuse systemic sclerosis
Aside from therapies directed against disorders of the trial. Arthritis Rheum 2002;46:29832989.
lung, kidneys, and peripheral vasculature in scleroderma, 4. Korn JH, Mayes M, Matucci-Cerinic M, et al. Digital
the gastrointestinal tract is a common focus for organ- ulcers in systemic sclerosisprevention by treatment with
bosentan, an oral endothelin receptor antagonist. Arthritis
specific therapy. Long-term proton-pump inhibition is
Rheum 2004;50:39853993.
highly effective in treating gastroesophageal reflux, 5. Tashkin DP, Elashoff R, Clements PJ, et al. The Sclero-
often a chronic problem leading to significant complica- derma Lung Study: oral cyclophosphamide versus placebo
tions in scleroderma. High doses, sometimes two to three for the treatment of scleroderma-related interstitial lung
times the normal therapeutic dose, are required to alle- disease. N Engl J Med 2006;354:26552666.
viate symptoms. Dilatation of esophageal strictures is 6. McSweeney PA, Nash RA, Sullivan KM, et al. High-dose
undertaken where indicated. Watermelon stomach, also immunosuppressive therapy for severe systemic sclerosis:
known as gastric antral venous ectasia (GAVE), is now initial outcomes. Blood 2002;100:16021610.
considered the most common cause of gastrointestinal 7. Pope JE, Bellamy N, Seibold JR, et al. A randomized
bleeding in scleroderma. GAVE is diagnosed and treated controlled trial of methotrexate versus placebo in early
with endoscopy and laser photocoagulation. diffuse scleroderma. Arthritis Rheum 2001;44:13511358.
8. Stratton RJ, Wilson H, Black CM. Pilot study of anti-
With regard to gut function, smooth muscle atrophy
thymocyte globulin plus mycophenolate mofetil in
results in gastroparesis and small bowel hypomotility. recent-onset diffuse scleroderma. Rheumatology (Oxford)
Prokinetic agents, including metoclopramide and dom- 2001;40:8488.
peridone (the latter not available in the United States), 9. Clements PJ, Furst DE, Wong W-K, et al. High-dose versus
are used with variable effects. Intestinal pseudo-obstruc- low-dose D-penicillamine in early diffuse systemic sclero-
tion may be managed cautiously with subcutaneous sis. Arthritis Rheum 1999;42:11941203.
CHAPTER 18
Idiopathic Inflammatory
Myopathies
ROBERT L. WORTMANN, MD, FACP, FACR
Idiopathic inflammatory myopathies (IIM) is a Increased serum muscle enzymes, muscle biopsy,
heterogeneous group of disorders characterized by electromyography (EMG), and magnetic resonance
chronic inflammation of striated muscle and skin. imaging (MRI) can assist in the diagnosis.
Painless proximal muscle weakness with or without
rash is the hallmark feature.
The idiopathic inflammatory myopathies (IIM) are a Despite the fact that patients with an IIM share the
heterogeneous group of disorders characterized by sym- stated features, the presentations of the different myo-
metric proximal muscle weakness and elevated serum sitis syndromes vary considerably from patient to
levels of enzymes derived from skeletal muscle. These patient. The usual presentation is insidious, progressive
include creatine phosphokinase (CPK), aldolase, aspar- painless symmetric proximal muscle weakness which
tate, and alanine aminotransferases (AST and ALT), develops over 3 to 6 months before the patient seeks
and lactate dehydrogenase (LDH). In addition, electro- medical attention. However, some patients (especially
myography (EMG), magnetic resonance imaging (MRI), children and young adults with dermatomyositis) expe-
and muscle histology show changes indicative of non- rience a more acute onset with symptoms developing
supparative inflammation (Table 18A-1) (1). rapidly over the course of several weeks. In that case,
Today several diseases are included among the IIM constitutional features such as low-grade fever and
(Table 18A-1). The term polymyositis refers to patients fatigue tend to be more common. Myalgias occur in
characterized by the criteria listed above. The term der- some patients, but are rare. Finally a subset of patients
matomyositis refers to patients who fulfill the criteria exists where weakness evolves slowly over 1 to 10 years
for polymyositis but also have a rash. When this occurs before a diagnosis is made. This presentation is most
in children, the term juvenile dermatomyositis (JDM) is likely in patients with IBM.
employed (2). Further, there is a subset of patients who Other findings include pitting edema of the extremi-
have the cutaneous manifestations of dermatomyositis ties, periorbital regions, or eyelids, as well as hoarseness,
but are otherwise normal (good strength and normal dysphagia, nasal regurgitation of liquids, aspiration
enzymes, EMG, and histology), a condition termed pneumonia, and dyspnea. Distinctive cutaneous mani-
amyopathic dermatomyositis. The findings of polymyo- festations are often the initial findings in dermatomyo-
sitis or dermatomyositis can be seen in patients with sitis and may be present for months before muscle
another collagen vascular disease, such as systemic lupus weakness develops (4).
erythematosus (SLE) or scleroderma, or associated
with a malignancy. Inclusion body myositis (IBM) occurs
in the elderly and is characterized by a polymyositislike
CLINICAL FEATURES
presentation (although the specific muscles involved are
more variable) and a characteristic histology which
Constitutional
includes rimmed vacuoles. Patients with an IIM can be Fatigue, fever, and weight loss may occur with any IIM.
further categorized by the presence or absence of a cir- Weight loss may result from poor caloric intake associ-
culating myositis-specific autoantibody (MSA) (3). ated with pharyngeal striated muscle dysfunction or
363
364 ROBERT L. WORTMANN
TABLE 18A-1. IDIOPATHIC INFLAMMATORY Skin

MYOPATHIES.
The skin rash of dermatomyositis may precede, develop
CRITERIA SUBSETS simultaneously with, or follow symptoms of myopathy
1. Symmetric proximal muscle Polymyositis
(4). Gottrons papules and the heliotrope rash on eyelids
weakness are considered pathognomonic features. Gottrons
papules are scaly, erythematous, or violaceous papules
2. Muscle biopsy evidence of Dermatomyositis and plaques located over bony prominences, particu-
myositis
larly over the small joints of the hands, elbows, knees,
3. Increase in serum skeletal Myositis with an associated and ankles. Gottrons sign is a macular erythema that
muscle enzymes collagen vascular disease occurs in the same distribution. Photosensitivity with
4. Characteristic Cancer-related myositis rash on the face or anterior chest, termed the V sign,
electromyographic pattern Juvenile dermatomyositis may also be seen. Pruritus is common, particularly in the
scalp. Other cutaneous changes include a rash located
5. Typical rash of Inclusion body myositis
over the upper back and across both shoulders (the
dermatomyositis
shawl sign), rash on the lateral surface of the thighs and
hips (holster sign), erythroderma, cuticular hypertrophy,
and periungual erythema. Capillary changes are
often present proximal to the cuticles in patients with
esophageal dysmotility and dysphagia. If weight loss Raynauds phenomenon. Cracking, fissuring, or both, of
persists or is severe, an associated malignancy should be the lateral and palmar digital skin pads is termed
considered. mechanics hands. Later in the disease course, skin
lesions may become shiny, atrophic, and hypopigmented
with telangiectasias. Characteristic changes seen in JDM
Skeletal Muscle that are rare in adults include cutaneous necrosis, lipo-
Typically, skeletal muscle involvement develops insidi- dystrophy, and subcutaneous calcifications.
ously, is bilateral and symmetric in distribution, affects
proximal muscles much more than distal muscles, and is Joints
painless. An exception is IBM, in which an asymmetric
distribution, distal weakness, or atrophy can occur alone Arthralgias or arthritis, if they occur, usually develop
or in combination with proximal weakness. In polymyo- early in the disease course. They tend to be rheumatoid-
sitis and dermatomyositis, the lower extremity (pelvic like in distribution and are generally mild. Joint findings
girdle) is often affected causing difficulty walking up are more common with overlap syndromes and in child-
steps or arising from a seated position. Walking on level hood dermatomyositis.
ground may be fairly normal, but the patients are prone
to falls. Upper extremity (shoulder girdle) symptoms,
which may lag behind those of the lower extremity,
Lung
include difficulty raising their arms overhead or combing The lung is the most common extramuscular target in
their hair. Neck flexor weakness may also occur. When IIM (5,6). Dyspnea may result from interstitial lung
myalgias are present, they are more common with exer- disease as well as nonparenchymal problems, such as
cise. Proximal dysphagia, with nasal regurgitation of ventilatory (diaphragmatic and intercostal) muscle
liquids and pulmonary aspiration, is a poor prognostic weakness or cardiac dysfunction. Pulmonary function
sign and indicates pharyngeal striated muscle involve- testing reveals restrictive physiology, with reduced lung
ment. Pharyngeal weakness also results in hoarseness or volumes, for example, total lung capacity and forced
dysphonia and a nasal quality voice. Ocular or facial vital capacity and a parallel decrease in the diffusion
muscle weakness is very uncommon in IIM, and their capacity for carbon monoxide.
presence should prompt consideration of another The presence of a ground glass appearance on
diagnosis. high resolution computed tomography (CT) indicates
Physical examination using manual muscle testing alveolitis, a potentially treatment-responsive inflamma-
confirms weakness of individual muscles or muscle tory condition with a more favorable prognosis. In
groups. In JDM, the Childhood Myositis Assessment contrast, the presence of honeycombing usually indi-
Scale has been shown to be reliable and valid for assess- cates fibrosis (7). The progression of interstitial lung
ing physical function, muscle strength, and endurance. disease is unpredictable but the more favorable
Muscle atrophy and joint contractures are sequelae of histologies include nonspecific interstitial pneumonitis
disease damage and are late findings in chronic muscle (NSIP) and the organizing pneumonias. In contrast, the
inflammation. finding of usual interstitial pneumonitis (UIP) or diffuse
C H A P T E R 1 8 I D I O P A T H I C I N F L A M M A T O R Y M Y O P A T H I E S 3 65
alveolar damage (DAD) portends a more ominous INVESTIGATIONS

course.
Patients with progressive interstitial lung disease can Serum Muscle Enzymes
develop secondary pulmonary arterial hypertension.
Diffuse alveolar hemorrhage with pulmonary capillari- Enzymes that leak into the serum from injured skeletal
tis and pneumomediastinum are rare associations. muscle include the CK, aldolase, AST, ALT, and
LDH (12,13). Which enzymes are elevated and which
one is the best to follow varies from patient to patient.
Heart Some feel that the CK is the most reliable enzyme to
Cardiac involvement is common in IIM but is seldom use in routine patient care and best reflects disease
symptomatic (8). The most common finding is a rhythm activity. The CK is elevated at least at some time during
disturbance. More ominous complications, such as con- the course of illness in patients with an IIM. Lower
gestive heart failure and pericardial tamponade, are values are often seen late in the disease course, in IBM,
quite rare. and in cancer-related myositis. The myocardial fraction
of CK (CK-MB) may be increased in myositis without
any cardiac involvement because this isoform is also
Gastrointestinal Tract released from regenerating myoblasts.
Swallowing problems (upper dysphagia) manifest as dif- In contrast, elevated CK levels do not necessarily
ficulty in the initiation of deglutition or nasal regurgita- evidence active inflammation. Previously damaged
tion of liquids. If severe, aspiration of oral contents leads muscle membranes may remain permeable to CK after
to chemical pneumonitis. Cricopharyngeal muscle dys- the disease has been controlled, resulting in elevated
function is more common in inclusion body myositis, but serum levels. In addition, many nondisease-related
also occurs in other IIM. This can also cause dysphagia, factors, such as race, may cause an elevated CK (see
with the complaint of a blocking sensation with swal- Chapter 18C for more information on CPK).
lowing. Patients note a retrosternal sticking sensation
on swallowing bread or meat and heartburn (reflux) Electromyography 18
with esophageal body and gastroesophageal sphincter Electromyography is a sensitive but nonspecific method
involvement, respectively. Gastrointestinal mucosal of evaluating muscle for evidence of inflammation. Of
ulceration and hemorrhage are rare. the 90% of patients with active myositis who have an
abnormal EMG, about half show the classic findings of
Malignancy and Myositis inflammation of fibrillation potentials, complex repeti-
tive discharges, positive sharp waves, and complex motor
There has been considerable controversy regarding the unit potentials of low amplitude and short duration. In
validity and magnitude of the relationship between addition to aiding in the diagnosis, EMG is helpful in
malignancy and inflammatory myopathy (9). Recent the selection of a site for muscle biopsy. When this is the
reports strongly support an increased risk of cancer in case, the study should be performed unilaterally and a
patients with polymyositis and an even greater risk with contralateral muscle chosen for biopsy to avoid confu-
dermatomyositis. Amyopathic dermatomyositis patients sion with inflammation artifact that can result from
also have an increased risk of malignancy (10). Pa- injury caused by the needle.
tients with pulmonary fibrosis, circulating myositis- Later in the course, EMG examination may be helpful
specific autoantibodies, or an associated connective for the detection of low grade myositis in the setting of
tissue disease have a decreased likelihood of cancer. chronic damage from fibrosis or fatty infiltration. It may
The overall risk of cancer is greatest in the first 3 years also be useful in differentiating active inflammation
after the diagnosis of myositis, but an increased risk of from steroid myopathy.
malignancy persists through all years of follow-up,
emphasizing the importance of continued surveillance.
In general, the sites of origin of malignancy are typical
Muscle Biopsy
for the age of the patient (11). The strongest asso- Muscle histology remains the gold standard for confirm-
ciations are with ovarian, lung, pancreatic, stomach, ing the diagnosis of an IIM (14). Despite the character-
and colorectal cancer and with non-Hodgkins lym- istic features described below, some patients with active
phoma. However, many other types of cancer occur myositis have a normal biopsy. Because the disease is
with myositis, including genitourinary malignancies and patchy in distribution, sampling error precludes 100%
melanoma. Ovarian cancer is over-represented in sensitivity. Furthermore, the changes in some biopsies
some series. Asian and Chinese patients with dermato- may be too nonspecific.
myositis have a clear increase in nasopharyngeal The most characteristic changes in polymyositis
carcinoma. include degeneration and regeneration of muscle fibers
366 ROBERT L. WORTMANN
and CD8+ T lymphocytes invading non-necrotic fibers. Pulmonary function testing is useful in assessing a
In dermatomyositis, CD4+ T cells and B cells predomi- variety of potential problems. Reduced ventilatory
nate in the perivascular areas and perifascicular atrophy, muscle strength is determined by measuring inspiratory
related to capillary depletion and dropout, is noted. The pressures at the mouth. Impaired function results in a
histology of IBM is characterized by the presence of weak cough and an increased risk of aspiration. A forced
lined or rimmed vacuoles. Otherwise IBM may appear vital capacity of less than 55% of normal predicts carbon
identical to that of polymyositis, be essentially normal, dioxide retention that can result when ventilatory muscle
or show triangulated cells with fiber-type grouping, function is compromised and interstitial disease is absent.
changes considered to be indicative of a neuropathic Interstitial lung disease also causes restrictive physiol-
process. In chronic myositis, macrophages are seen ogy on pulmonary function testing but is typically accom-
phagocytosing necrotic fibers and muscle is replaced by panied by pulmonary fibrosis. More sensitive indicators
fibrous connective tissue or fat (see Chapter 18B for a of compromised gas exchange include a reduction in the
more detailed discussion of the muscle pathology). diffusing capacity for carbon monoxide and a decrease
in the alveolararterial oxygen gradient with exercise.
Magnetic Resonance Imaging
Magnetic resonance imaging techniques add an impor-
Heart
tant dimension to our approach to patients with myopa- Clinically significant cardiac findings are uncommon in
thy (15). MRI is noninvasive and can be used to visualize IIM. However, electrical disturbances are not uncom-
large areas of muscle. T1-weighted images provide mon. These include nonspecific ST-T segment changes
excellent anatomic detail, with clear delineation of and conduction system abnormalities. Using sensitive
various muscle groups and are useful in assessing cardiac scintigraphic techniques, increased technitium-
changes resulting from damage and chronicity. T2- 99m pyrophosphate uptake and indium-labeled anti-
weighted images with fat suppression or STIR (short myosin binding have been reported.
tau inversion recovery) sequences can identify edema,
which is indicative of active inflammation. Accordingly, Intestine
MRI can be used to document myositis or a disease
flare, distinguish chronic active from chronic inactive When pharyngeal muscles are involved, a barium
myositis, and noninvasively direct the site of biopsy. swallow may show cricopharyngeal muscle spasm, poorly
coordinated motion of the pharyngeal musculature, val-
lecular pooling of the dye, and, occasionally, aspiration
Skin of barium into the trachea (18). Cinesophagrams and
The characteristic cutaneous histopathologic findings of manometry are best for evaluation of distal dysphagia
dermatomyositis include vacuolar alteration of the epi- resulting from distal esophageal hypomotility.
dermal basal layer, necrotic keratinocytes, vascular dila-
tation, and a perivascular lymphocytic infiltrate (4). The Serum Autoantibodies
pattern is similar to that seen with systemic lupus
erythematosus and closely resembles those of chronic Antinuclear or anticytoplasmic antibodies are present
graft-versus-host reaction. Vasculitis or vasculopathy in the majority of patients with IIM, with the exception
may be found in small cutaneous vessels. Capillary of IBM, where the frequency is low. Patients with myo-
changes proximal to the cuticles are often seen in patients sitis and an associated collagen vascular disease will
with Raynauds phenomenon (see Chapter 18B for a manifest the antibodies characteristic of that disease
more detailed discussion of the skin pathology in IIM). [i.e., antidouble-stranded DNA (dsDNA) antibodies
and SLE, antiScl 70 and scleroderma, etc]. In addition,
some antibodies are termed myositis-specific autoanti-
Lung bodies (MSAs) because they are found exclusively in
Chest radiographs may show fibrotic changes in patients patients with features of an inflammatory myopathy (3).
with interstitial lung disease, but they are insensitive Although a few patients have more than one serum
compared with high resolution CT (HRCT) (16,17). autoantibody, several MSAs are rarely detected in the
HRCT findings include ground-glass opacities typical of same patient. A negative antinuclear antibody (ANA)
alveolitis and/or consolidation, subpleural lines or bands, test does exclude an MSA, as the latter antigens are
traction bronchiectasis, and honeycombing indicating cytoplasmic in location and the immunofluorescence
fibrosis. The most common HRCT pattern is a combina- staining pattern may be subtle. Testing for serum auto-
tion of reticular and/or ground glass opacities with or antibodies can both solidify the diagnosis of myositis in
without consolidation and without honeycombing. patients with atypical clinical features and provide prog-
When honeycombing is present on the initial HRCT, the nostic information regarding the likelihood of future
prognosis is generally poor. clinical complications.
Although the MSAs are relatively insensitive markers REFERENCES

for myositis, the presence of one suggests that the
patient will have certain associated features (see Table
18C-1). AntiJo 1 antibodies are directed against histi- 1. Bohan A, Peter JB. Polymyositis and dermatomyositis. N
Engl J Med 1975;292:344347, 403407.
dyl-tRNA synthetase. AntiJo 1 is the most common
2. Lindsley CB. Juvenile dermatomyositis update. Curr Opin
MSA and is one of a group of antiaminoacyl-tRNA
Rheumatol 2006;8:174177.
synthetases. The clinical associations of the antisynthe- 3. Targoff IN. Myositis specific autoantibodies. Curr Opin
tase antibodies have been termed the antisynthetase Rheumatol 2006;8:196206.
syndrome. The muscle involvement in this syndrome is 4. Santmyire-Rosenberger B, Dugan EM. Skin involvement
often severe with multiple exacerbations, requiring in dermatomyositis. Curr Opin Rheumatol 2003;15:714
immunosuppressive agents in addition to corticoste- 722.
roids. Antibodies against signal recognition particle 5. Kang EH, et al. Interstitial lung disease in patients with
(anti-SRP) identify patients with polymyositis who may polymyositis, dermatomyositis and amyopathic dermato-
have cardiomyopathy and who often have severe, refrac- myositis. Rheumatology 2005;44:12821286.
tory disease. AntiMi 2 is an antinuclear antibody that 6. Schnabel A, Hellmich B, Gross WL. Interstitial lung
disease in polymyositis and dermatomyositis. Curr Rheum
is almost always associated with dermatomyositis and a
Rep 2005;7:99105.
good response to immunosuppression.
7. Bonnefoy O, et al. Serial chest CT findings in interstitial
lung disease associated with polymyositis-dermatomyosi-
NATURAL HISTORY tis. Eur J Radiol 2004;49:235244.
8. Yazici Y, Kagen LJ. Cardiac involvement in myositis. Curr
AND PROGNOSIS Opin Rheumatol 2002;14:663665.
9. Buchbinder R, Hill CL. Malignancy in patients with
The clinical course is quite variable among patients with inflammatory myopathy. Curr Rheum Rep 2002;4:415
IIM (19). In some, the illness is brief and is followed by 426.
remission that does not require continued treatment. 10. Whitmore SE, et al. Dermatomyositis sine myositis:
That is more common in dermatomyositis than in poly- association with malignancy. J Rheumatol 1996;23:101 18
105.
myositis and most common in patients with an associ-
11. Chen Y-J, Wu C-Y, Shen J-L. Predicting factors of malig-
ated collagen vascular disease. Other patients with
nancy in dermatomyositis and polymyositis: a case-control
theses diseases experience exacerbations and remissions study. Br J Dermatol 2001;144:825831.
or persistent disease activity, necessitating chronic use 12. Sultan SM. Clinical assessment in adult onset idiopathic
of immunosuppressive drugs, with the frequency of clin- inflammatory myopathy. Curr Opin Rheumatol 2004;16:
ical and biochemical relapse varying from 34% to 60% 668672.
in different series. Patients with IBM do not respond to 13. Targoff I. Laboratory testing in the diagnosis and manage-
any known medications. This disease is characterized by ment of idiopathic inflammatory myopathies. Rheum Dis
a slow and gradual decline in muscle strength, although Clin North Am 2002;28:859890.
the level of weakness can plateau for some. 14. Grundtman C, Lundberg IE. Pathogenesis of idiopathic
As long as the myositis is active, there is the potential inflammatory myopathies. Curr Opin Rheumatol 2006;8:
188195.
for absolute loss of muscle mass and strength (20). In
15. Scott DL, Kingsley GH. Use of imaging to assess patients
general, the best functional outcomes occur in derma-
with muscle disease. Curr Opin Rheumatol 2004;16:678
tomyositis, whereas the worst are seen in IBM, myositis 683.
with anti-SRP antibody, cancer-related myositis, and 16. Arakawa H, et al. Nonspecific interstitial pneumonia asso-
patients with interstitial lung disease. In JDM, predic- ciated with polymyositis and dermatomyositis: serial high-
tors of chronic active myositis include delay in diagno- resolution CT findings and functional correlation. Chest
sis, failure to regain normal muscle strength after 4 2003;123:10961103.
months of corticosteroid treatment, continued increased 17. Tansey D, et al. Variations in histological patterns of inter-
serum muscle enzyme beyond 3 months, increased stitial pneumonia between connective tissue disorders and
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of treatment, and anasarca with hypoalbuminemia. 585596.
18. Marton K, et al. Evaluation of oral manifestations and
Factors associated with poor survival include older
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age, malignancy, delayed initiation of corticosteroid
matomyositis. J Oral Pathol Med 2005;34:164169.
treatment, pharyngeal dysphagia with aspiration pneu- 19. Ponyi A, et al. Disease course, frequency of relapses
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tions of corticosteroid or immunosuppressive treatment. tomyositis. Clin Exp Rheum 2005;23:5056.
Additional adverse risk factors for survival among 20. Ponyi A, et al. Functional outcome and quality of life in
patients with JDM are gastrointestinal vasculitis and adult patients with idiopathic inflammatory myositis.
sepsis. Rheumatology 2005;44:8388.
CHAPTER 18
Myopathies
LISA G. RIDER, MD
FREDERICK W. MILLER, MD, PHD
Major pathology consists of focal inhomogeneous Etiology is still unclear but selected environmental
inflammation with injury, death, and repair of muscle exposures in genetically predisposed hosts have
cells. been found.
Each subgroup of myositis has characteristic changes
on microscopy and immunochemistry.
PATHOLOGY AND performed at the site of an electromyogram (EMG),

due to artifactual changes from the EMG. In inclusion
IMMUNOPATHOLOGY body myositis (IBM), the inclusions are not always
apparent, either because of their patchy nature or
The characteristic skeletal muscle pathology in the because they may appear later in the course of illness.
idiopathic inflammatory myopathies (IIM) consists of Paraffin processing also dissolves the vacuoles, so that a
chronic inflammation with infiltration by mononuclear Gomori trichrome stain is needed for detection.
cells, including lymphocytes, plasma cells, macrophages A muscle biopsy should be performed, processed,
and dendritic cells, in the endomysium (between myo- and evaluated by persons experienced in these proce-
cytes), perimysium (within fascicles), or perivascular dures because careful attention to selection of the biopsy
(vessels in interstitium surrounding muscle fibers) areas site, to collection of the tissue, and to rapid freezing and
(Figure 18B-1). The muscle fibers (myocytes), which appropriate histochemistry is needed to obtain the most
may be necrotic or non-necrotic, show evidence of informative biopsies. Standard procedure should include
degeneration and regeneration, fiber hypertrophy or hematoxylin and eosin and Gomori trichrome stains
atrophy, and replacement by fibrosis or fat, and are to highlight the cellular infiltrates as well as muscle
often accompanied by increased connective tissue or architecture. Alkaline phosphatase positive connective
fibrosis in the interstitial areas around the muscle tissue, even in the absence of cellular infiltrates, can also
cells (1). aid in the diagnosis of myositis. A portion of the frozen
These features collectively are characteristic of myo- tissue block should be saved for enzymatic and meta-
sitis, but each feature may be seen as part of the pathol- bolic stains, as well as immunohistochemistry or detec-
ogy of other muscle disorders, particularly muscular tion of muscle sarcolemmal proteins if needed for
dystrophies. Macrophages may infiltrate to scavenge diagnosis (1).
necrotic muscle as a secondary inflammatory process in Each subgroup of myositis has somewhat character-
dystrophies and other myopathies. Some features of istic changes on routine microscopy and immunohisto-
other neuromuscular disorders, such as small angulated chemistry. In dermatomyositis (DM), the mononuclear
fibers, may also be present in myositis. A muscle biopsy cells are focused more along the vessel walls of perimy-
is not always diagnostic of myositis. First, the inflamma- sial arterioles and venules, with such changes more
tion is often focal and inhomogeneous. Inflammation is prominent in the juvenile form of DM (2,3). Vessel
also diminished after the initiation of immunosuppres- thrombosis may also occur. Infarcts from the peri-
sive therapy. A muscle biopsy should also not be fascicular region to the center of the fascicle are
368
B
18
C D
E F
FIGURE 18B-1
Muscle pathology and immunopathology by light microscopy. Cross-sectional views of muscle

biopsies showing characteristic changes in IIM. (A) Endomysial mononuclear cell infiltrates
surrounding and invading myocytes in a patient with polymyositis (hematoxylin and eosin stain).
(B) Similar findings are present in inclusion body myositis, with the exception of typical multiple
reddish-rimed vacuoles in myocytes on trichrome staining that define the inclusion bodies
(trichrome stain). (C) Dermatomyositis and juvenile dermatomyositis show more prominent
vascular changes, including perivascular mononuclear cell infiltration and vessel thrombosis, as
well as perifascicular atrophy. (From Rider LG, Targoff IN. In: Lahita RG, Chiorazzi N, Reaves WH,
eds. Textbook of autoimmune diseases. Philadelphia: Lippincott Raven; 2000.) (D) Immunohisto-
chemistry demonstrating staining for CD8+ cells that are surrounding myocytes in polymyositis.
(From Figarella-Branger D et al., Muscle Nerve 2003;28:659.) (E) Positive immunostaining for B
cells in dermatomyositis. (From Figarella-Branger D et al., Muscle Nerve 2003;28:659.) (F) Staining
for the C5C9 membrane attack complex on capillaries and myocytes in dermatomyositis.
(Courtesy of Dr. J.T. Kissel.)
370 LISA G. RIDER AND FREDERICK W. MILLER
particularly present in juvenile DM and less frequently and serosal layers (3). A chronic endarteropathy char-
in adult DM (3). Perifascicular atrophy with small fibers acterized by narrowing or complete occlusion of multi-
at the external rim of a fascicle is also characteristic of ple small and medium-sized arteries, subintimal foam
DM. In contrast, in polymyositis (PM) and IBM, the cells, fibromyxoid neointimal expansion, and significant
inflammatory cells invade non-necrotic muscle fibers in luminal compromise and infiltration of macrophages
a primarily endomysial distribution (4,5). through the muscle layers into the intima may also be
Immunohistochemistry also implicates different path- seen. The pathology of the interstitial lung disease most
ogeneses in the various forms of myositis. In DM, more commonly is that of nonspecific interstitial pneumonitis
frequent in the juvenile than adult form, the earliest (NSIP), but occasionally diffuse alveolar damage, usual
changes include activation of the complement cascade interstitial pneumonitis (UIP), and bronchiolitis obliter-
through C3, deposition of the complement C5b-9 mem- ans organizing pneumonia (BOOP) may be present.
brane attack complex on the endomysial vasculature, The myocardium may demonstrate myocarditis with
with resultant capillary destruction, muscle ischemia, subsequent fibrosis.
and dilatation of the remaining capillaries (high endo-
thelial venule formation) (68). This leads to resulting
inflammation, with the infiltrating cells consisting mainly PATHOGENESIS
of B lymphocytes and CD4+ helper T cells in perimysial
areas around the muscle fascicles and small blood While the etiology and pathogenesis of the IIM remain
vessels. MHC class I antigen and intracellular adhesion unclear, a number of lines of investigation have sug-
molecule (ICAM) are upregulated on the cell surfaces gested possible ways in which selected environmental
of damaged fibers or in perivascular areas, respectively exposures in genetically susceptible individuals may
(9). In PM and IBM, the weight of evidence suggests a lead to chronic immune activation and the ultimate
predominant cytotoxic T lymphocytemediated process immunologic attack on muscle and other involved
with CD8+ T cells, accompanied by smaller numbers of tissues (Figure 18B-2). A number of these mechanisms,
macrophages, surrounding and invading otherwise which include upregulation of MHC class I on muscle
normal-appearing myocytes in endomysial areas (10). fibers, immune activation, and activation of the endo-
MHC class I antigen is upregulated on the surface of plasmic reticulum stress response, are processes common
the majority of muscle fibers, even those not affected by to other myopathies besides myositis. While some of the
inflammation, although this is not specific to myositis mechanisms are found in all forms of myositis, others
(1). Necrotic muscle fibers may be scattered in the are likely unique to selected groups.
biopsy, particularly in PM.
In IBM, in addition to these inflammatory findings,
there are vacuolated myofibers occurring in the center
Genetic Factors
or periphery of muscle fibers, with wide variation in The finding of families in which two or more blood rela-
myofiber size, including scattered atrophic fibers, and tives have myositis and associations of myositis with
prominence of central muscle nuclei. The vacuoles are particular genes support the hypothesis that myositis is
rimmed by granular eosinophilic material, which on at least in part inherited. Polymorphic alleles in the
Gomori trichrome stains purple-red and on Congo red major histocompatibility locus (MHC) are the major
staining reveals amyloidlike deposits, including phos- immunogenetic risk and protective factors identified for
phorylated tau, ubiquitin, beta-amyloid, and presinilin 1 the IIM. The A1-B8-Cw07-DRB1*0301-DQA1*0501
(9). Diffuse inflammatory infiltrates and ragged red ancestral haplotype is the major immunogenetic risk
fibers are sometimes seen. In IBM-characteristic tubu- factor for PM, as well as adult and juvenile DM in Cau-
lofilaments, 15 to 18 nm in diameter and seen most often casians, with the risk factor likely in the class II HLA
in the cytoplasm and less often in the nuclei, are often region at or near human leucocyte antigen (HLA)
visible by electron microscopy (1). DRB1*0301. For IBM, DRB1*0301 and its linked allele
In terms of the pathologic features of other organs, DQA1*0501 are risk factors along with the class I
the skin in DM demonstrates interface dermatitis, often Cw*14 allele. HLA DQA1*0201 is protective for all
with basement membrane thickening and mucin deposi- forms of myositis, and other DRB1 or DQA1 alleles are
tion. Many of the changes in muscle, including the types protective for specific clinical groups (11). In the class
of infiltrating cells and the predominance of perivascu- III MHC region, the tumor necrosis factor alpha (TNF-
lar inflammation, are also evident in the skin. In the alpha)-308A allele is a risk factor for adult and juvenile
gastrointestinal tract, ischemic ulceration is a potentially DM and PM in Caucasians, and may also be a severity
life-threatening manifestation and may include a non- factor, perhaps related to photosensitive rashes and the
inflammatory acute endarteropathy with arterial and development of calcinosis. DMA*0103 and DMB*0102
venous intimal hyperplasia and occlusion of intestinal are possible risk factors for juvenile DM. Outside the
vessels by fibrin thrombi in the submucosa, muscularis, HLA region, the IL1 receptor antagonist VNTR A1
18
FIGURE 18B-2
Possible pathogenic mechanisms in IIM. All forms of myositis appear likely to involve immune
activation following specific exposure to environmental risk factors in genetically susceptible
individuals. Common immune activation processes in muscle and other tissues include upregula-
tion of MHC expression and IL-1 alpha and beta, leading to autoantibody production prior to
clinical disease onset. Following this, myocyte-directed cytotoxic T-cell mechanisms predominate
in PM and IBM, while complement-mediated endothelial damage, leading to CD4, B-cell, and
dendritic-cell infiltrations, predominate in DM and JDM. Other general mechanisms may involve
hypoxia, activation of the endoplasmic reticulum stress response, and cleavage of autoantigens,
resulting in cytokine and chemokine release and positive feedback loops that lead to further
immune activation. Later processes include muscle regeneration, angiogenesis, and repair, and in
some cases fibrotic changes and other damage in affected tissues.
allele is a risk factor for juvenile DM in Caucasians. The Caucasian patients. MHC class II alleles DRB1*0701
Gm allotypes, serologic markers on the heavy chains of and DQA1*0201 are risk factors for Mi 2 autoantibodies.
IgG, rather than HLA alleles, are genetic risk or protec- DQA1*0301 is a risk factor for p155, a myositis-associ-
tive factors for myositis in Koreans and Mesoamericans, ated autoantibody common in adult and juvenile DM.
suggesting that genetics likely varies among ethnic
groups (12).
Human leukocyte antigen risk factors are more
Environmental Factors
strongly associated with specific autoantibodies (13). The temporal association of exposure to a number of
The ancestral haplotype A1-B8-Cw07-DRB1*0301- infectious and noninfectious agents prior to the onset of
DQA1*0501 is a strong risk factor for patients the IIM in certain individuals, as well as reports docu-
with antisynthetase autoantibodies, including Jo1, in menting temporal, seasonal, or geographic clustering of
IIM cases suggest a role for environmental factors in ated with IIM. Similarly, although there is no epidemio-
initiation of disease (12). logic evidence from population studies confirming an
Epidemiologic investigations have also suggested a association between silicone exposure and myositis,
number of environmental factors which may be impor- Caucasian women who develop myositis following sili-
tant in the development of IIM. Most are not proven cone implants do not have the characteristic genetic
environmental risk factors, but for some exposures, features seen in IIM, but rather have an increased fre-
case-controlled epidemiologic studies, cases of de- quency of HLA DQA1*0102. Temporal associations of
challenge and re-challenge, and biomarker assays onset of the IIM with certain other drugs (including
strengthen the association with illness onset. Of the lipid-lowering agents, zidovudine, leuprolide, and local
infectious agents, Group A streptococcus and influenza anesthetics), biologic therapies (such as interferon alpha
have the strongest evidence of association with onset of and interleukin 2), and vaccines have been reported, but
juvenile IIM and toxoplasmosis with adult DM from additional evidence is needed to confirm their potential
case-controlled epidemiologic studies. With Group A associations (12). Certain alum-containing vaccines
streptococcus, peripheral blood T lymphocytes from have also been associated with the distinct entity of
juvenile DM patients react with streptococcal M5 macrophagic myositis, in which macrophages are the
protein and a myosin peptide with homology to M5. The predominant infiltrating cell.
evidence is mixed for coxsackie B virus, with reports of
isolation of the virus from some affected muscles but a Cytotoxic Mechanisms in
case-controlled study not supporting an association with
onset of juvenile DM. Echoviruses, however, have been Polymyositis and Inclusion
clearly associated with a DM-like illness in patients with Body Myositis
agammaglobulinemia. Other infections temporally asso-
Many lines of evidence suggest that cytotoxic mecha-
ciated with onset of IIM which are not yet defined as
nisms play a more important role in PM and IBM than
definite risk factors for IIM include retroviruses, hepa-
adult or juvenile DM (15). First, as is the case for the
titis viruses, Borrelia burgdorferi, and Trypanosoma
quantitation of subsets of lymphocytes in the affected
cruzi. Parvovirus B19 is not associated with onset of
muscle, studies of peripheral mononuclear cells demon-
juvenile DM in a case-controlled study. A search for
strate that PM and IBM are virtually indistinguishable
viral genomes by sensitive molecular methodology in
in showing higher numbers of circulating activated T
DM and PM biopsies has failed to identify consistently
cells. Second, peripheral blood cells from PM patients
any viral nucleic acid, suggesting that known viruses are
have an increased proliferative response to, and demon-
not contributing to the persistent inflammation (12).
strate cytotoxicity to, autologous muscle tissue in vitro.
Noninfectious agents, including ultraviolet light,
Third, T cells in PM and IBM contain perforin and
physical exertion, psychological stress, medications, and
granzyme granules that are directed towards the surface
vaccines have been suggested as possible triggers for
of the myofibers and that, on release, induce pores in
some forms of IIM. Growing evidence suggests a role
the myocyte membranes (10). Fourth, based on restricted
for ultraviolet radiation (UV) in the onset of DM. DM
T-cell receptor usage, there is clonal expansion of
patients have a number of photosensitive rashes and,
muscle-infiltrating T cells selected for certain gene fami-
anecdotally, illness may exacerbate following sun expo-
lies in PM and IBM, implying an antigen-driven process,
sure. Adult DM patients also have increased sensitivity
in contrast to a more polyclonal pattern of T-cell recep-
to UVB as demonstrated by an abnormally low minimal
tor usage in DM. Additionally, the CD8+ cells found in
erythema UVB dose. An increase in the proportion of
PM and IBM appear to preferentially target MHC class
DM relative to PM and an increase in the proportion of
Iexpressing myocytes, which would be required for
patients with the DM-associated Mi 2 autoantibody in
their antigen-specific recognition of cellular targets.
areas of the world with higher surface UV radiation
These findings, taken together, suggest that in PM and
suggest that UV light exposure may modulate the clini-
IBM, subpopulations of T cells are selected and
cal and immunologic expression of myositis. Keratino-
expanded in response to as yet uncharacterized antigens
cytes damaged by UV radiation also undergo apoptosis,
and may explain some of the T-cellmediated pathology
with increased autoantigen expression on the surface of
seen in these diseases.
such cells.
Case-controlled studies support a role for psycho-
logical stress, muscular exertion, and collagen implants Humoral and Endothelial
in the onset of adult DM or PM (14). Exposure to D- Mechanisms in Adult and Juvenile
penicillamine may induce myositis in 1% to 2% of
patients and this has been associated with HLA B18,
Dermatomyositis
B35, and DR4 in Caucasians but with DQw1 in patients Humoral and endothelial mechanisms appear to be
from India, which are genes distinct from those associ- more important for adult and juvenile DM compared to
PM and IBM (15). First, higher numbers of circulating and CCR2B) are also upregulated in myositis, thus
B and CD4+ T lymphocytes are present in the periphery attracting monocytes, macrophages, and T lymphocytes
as well as in the affected muscle. Second, immunoglobu- to the inflammatory sites. The molecules that facilitate
lin and the terminal portion of complement are depos- leukocyte migration from the vasculature into the
ited on blood vessels in the earliest phases of illness (6), tissues, including intercellular adhesion molecule 1
resulting in a decrease in the number of capillaries and (ICAM-1), vascular cell adhesion molecule 1 (VCAM-
muscle injury, including ischemia. From microarray 1), CD142, and CD31 (which facilitate dendritic cell
experiments, in some cases confirmed by immunohis- migration), have also been found to be increased in the
tochemistry or real-time polymerase chain reaction muscle tissue of myositis patients compared to controls.
(PCR), a number of promoters and inhibitors of angio- ICAM-1 is upregulated on perimysial or perivascular
genesis are overexpressed in the affected muscle tissue areas in DM and on endomysial vessels in PM and IBM.
(16,17). There is also increased expression of genes pro- Other studies demonstrate increased expression of
moting endothelial differentiation and activation, as interferon alpha/betainducible genes as one of the
well as classical and alternative complement pathway major features differentiating adult and juvenile DM
regulators that facilitate angiogenesis in the muscle from PM and IBM. Furthermore, an investigation of
tissue of adult DM patients (16). In juvenile DM, a serial muscle biopsies from three DM and four IBM
number of angiostatic ELR-chemokines are increased patients, before and after treatment with intravenous
in expression and correlate with the degree of capillary immunoglobulin, suggested decreases in selected che-
loss (17). Upregulation of leucocyte adhesion molecules, mokine and ICAM-1 genes in those DM patients who
particularly ICAM-1 on the muscle arterioles and responded to therapy (20).
venules in juvenile DM and somewhat in adult DM, The cytokines present in the muscle biopsies of myo-
results in the infiltration of B and CD4+ T lymphocytes, sitis subjects may be involved in regulating immune
dendritic cells, and macrophages (9). Proinflammatory responses, but they may also have direct effects on
cytokines result in damage and further infiltration of muscle and other target tissues (9). For example, TNF-
cells. alpha has been shown to induce many changes in muscle
Immune dysregulation is also a key part of the patho- from accelerated catabolism to contractile dysfunction. 18
genesis, with upregulation of interferon alpha/beta IL-1 alpha may play a role in direct myotoxicity via its
inducible genes and genes upregulated in a type I inter- influence on insulinlike growth factor, thereby leading
feron response, as well as genes involved in antigen to metabolic disturbances in nutrition supply, and by
presentation, suggesting either viral initiation of disease suppressing myoblast proliferation and fusion. Differ-
or activation of plasmacytoid dendritic cells (18,19). ences in methodology and patient populations under
Some of these factors are also angiostatic. study, however, have made it difficult to determine if
any of these signaling molecules are playing a primary
Cytokines, Chemokines, and or secondary role in pathogenesis and if there are criti-
cal differences in cytokine patterns in the different
Related Factors forms of IIM.
A growing number of signaling molecules have been
discovered to be important in regulating the movement Major Histocompatibility Complex
of immune cells from the circulation into different
tissues and in altering their subsequent function (9).
Overexpression and Sequelae
Immunohistochemistry and array studies have sug- Increased MHC class I antigen expression occurs on
gested an increased expression of many types of these scattered myocytes in all forms of IIM, and MHC class
signaling molecules in the form of cytokines, chemo- I molecules are present even on myocytes far removed
kines, chemokine receptors, and related proteins in from inflammation, suggesting that this may be an early
muscles of myositis patients. Cytokines frequently found event in pathogenesis (1). How specific this process is
in inflammed muscle include: proinflammatory cyto- to IIM remains unclear because myocytes in muscle
kines, such as interleukin (IL) 1 and tumor necrosis biopsies from some muscular dystrophies also show
factor alpha (TNF-alpha); cytokines involved in T-cell MHC class I expression. Nonetheless, additional evi-
differentitation, including interferons (IFNs), IL-2, IL-5, dence that overexpression of MHC class I may be
and IL-10; and cytokines involved in fibrotic processes, related to myositis comes from an animal model where
such as transforming growth factor beta (TGF-beta). directed transgenic upregulation in skeletal muscle led
Chemokinesespecially macrophage inflammatory to muscle inflammation as well as decreased muscle
protein-1 alpha (MIP-1 alpha, CCL3), monocyte che- strength, even before detectable histological damage in
moattractant protein-1 (MCP-1, CCL2) and CCL5 the skeletal muscles of these mice (21). The increased
(RANTES)as well as CXC-chemokine ligands (CXCL MHC class I not only renders muscle a possible target
9 and 10) and chemokine receptors (CCR1-5, CCR2A, for the recognition by cytotoxic T cells, but it may also
negatively impact cellular metabolism. When there is an 9. Figarella-Branger D, Civatte M, Bartoli C, Pellissier JF.
imbalance between the load of proteins in the endoplas- Cytokines, chemokines, and cell adhesion molecules in
mic reticulum (ER) and the cells ability to process that inflammatory myopathies. Muscle Nerve 2003;28:659682.
load, signaling pathways are activated that adapt cells 10. Goebels N, Michaelis D, Engelhardt M, et al. Differential
expression of perforin in muscle-infiltrating T cells in
to ER stress. This process is called the ER stress response
polymyositis and dermatomyositis. J Clin Invest 1996;
and it can be provoked by a variety of conditions, includ-
97:29052910.
ing ischemia, viral infections, mutations that impair 11. OHanlon TP, Carrick DM, Arnett FC, et al. Immunogenetic
protein folding, and excess accumulation of proteins in risk and protective factors for the idiopathic inflammatory
the ER. The assembly and folding of MHC class I mol- myopathies: distinct HLA-A, -B, -Cw, -DRB1 and -DQA1
ecules in the ER involves a highly regulated process to allelic profiles and motifs define clinicopathologic groups in
assure their proper conformation and to prevent accu- Caucasians. Medicine (Baltimore) 2005;84:338349.
mulation of unfolded proteins. When excess MHC class 12. Reed AM, Ytterberg SR. Genetic and environmental risk
I molecules are present, this system can be overloaded factors for idiopathic inflammatory myopathies. Rheum
to result in many cellular changes, including activation Dis Clin North Am 2002;28:891916.
of the NF-B pathway, as has been demonstrated in 13. OHanlon TP, Carrick DM, Targoff IN, et al. HLA-A, -B,
-DRB1 and -DQA1 allelic profiles for the idiopathic
both IIM and the transgenic upregulated MHC class I
inflammatory myopathies: distinct immunogenetic risk
animal model (22,23). This finding suggests that excess
and protective factors distinguish European American
production of MHC class I molecules may lead to the patients with different myositis autoantibodies. Medicine
ER stress response, which may play a role in IIM patho- 2006;85:111127.
genesis via activtaion of NF-B, resulting in the induc- 14. Lyon MG, Bloch DA, Hollak B, Fries JF. Predisposing
tion of a number of cytokines, chemokines, adhesion factors in polymyositis-dermatomyositis: results of a
molecules, and further MHC upregulation, thus initiat- nationwide survey. J Rheumatol 1989;16:12181224.
ing a self-sustaining positive feedback loop. 15. Dalakas MC. Mechanisms of disease. Signaling pathways
and immunobiology of inflammatory myopathies. Nat
Clin Pract Rheumatol 2006;2:219227.
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Ann Neurol 1984;16:209215. of therapy with IVIG and biological validation of clini-
5. Engel AG, Arahata K. Mononuclear cells in myopathies: cally relevant genes. Brain 2005;128:18871896.
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antigen-specific cell-mediated cytotoxicity in some dis- regulation of MHC class I in skeletal muscle leads to
eases, and implications for the pathogenesis of the differ- self-sustaining autoimmune myositis and myositis-specific
ent inflammatory myopathies. Hum Pathol 1986;17:704 autoantibodies. Proc Natl Acad Sci U S A 2000;97:9209
721. 9214.
6. Kissel JT, Mendell JR, Rammohan KW. Microvasculature 22. Nagaraju K, Casciola-Rosen L, Lundberg I, et al. Activa-
deposition of complement membrane attack complex in tion of the endoplasmic reticulum stress response in auto-
dermatomyositis. N Engl J Med 1986;314:329334. immune myositis: potential role in muscle fiber damage
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Ann Neurol 1990;27:343356. H, Askanas V. Homocysteine-induced endoplasmic reticu-
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Hum Pathol 1992;23:888895. 14911499.
CHAPTER 18
Myopathies
CHESTER V. ODDIS, MD
Precise diagnosis is essential and muscle Steroids are the main pillar of therapy with immuno-
biopsy may identify myositis not responsive suppressive drugs, such as methotrexate and azathio-
to therapy. prine, utilized as steroid-sparing agents.
Autoantibodies define heterogeneous clinical A core set of measures has been developed for
subsets. assessing disease activity.
ASSESSMENT OF Routine Assessment Tools

INFLAMMATORY MYOPATHY Serum Muscle Enzymes
Given the rarity of idiopathic inflammatory myopathies Serum creatine kinase (CK) is generally the most
(IIM) and the heterogeneity of the myositis syndromes, reliable muscle enzyme test to use in the routine care
their management is difficult. There are few well- of adult myositis. It tends to predict clinical events as
controlled clinical trials in IIM and many of the reported serum CK levels often increase weeks before overt
studies have not adequately distinguished muscle weak- muscle weakness develops during disease flares. Con-
ness as secondary to irreversible disease damage (muscle versely, the CK often decreases to normal prior to an
atrophy with fatty infiltrate and fibrosis) or disease objective improvement in muscle strength. There are
activity (reversible inflammation) so that assessing treat- exceptions, as some patients with active biopsy-proven
ment response in such reports is problematic. A system- myositis (DM > PM and children > adults) have a normal
atic approach to the assessment and treatment of IIM is CK. It has been suggested that in children with juvenile
essential. This begins with accurately establishing the DM (JDM) the combination of lactate dehydrogenase
diagnosis of an immune-mediated myopathy and exclud- (LDH) and aspartate aminotransferase (AST) are the
ing the various mimics of myositis. This is especially best predictors of disease flare (4). There is considerable
important in polymyositis (PM), which lacks the hall- racial variation in CK concentrations as persons of
mark cutaneous features of dermatomyositis (DM) that Afro-Caribbean descent have an upper limit of normal
make the latter disease easier to diagnose. A consortium CK that is higher compared to other ethnic subsets (5).
of myositis experts, the International Myositis Assess- Any form of exercise (anaerobic or aerobic) or trauma
ment and Clinical Studies Group (IMACS), has been (sharp or blunt) can raise CK levels. Many medications
organized to address many of these concerns. Recent and drugs (statins, alcohol, colchicine, cocaine, etc.) can
efforts from this group include the (1) development of cause increases. Finally, at different times, as many as
core set measures for assessing disease activity in myo- 30% of people may have an asymptomatic hyper-
sitis trials (1); (2) proposal of a preliminary definition of CK-emia which is of no clinical significance.
improvement in adult and juvenile myositis clinical trials In addition to the CK, other serum enzyme activity
(2); and (3) development of an international consensus levels that may be elevated in myositis include the trans-
document on the conduct of therapeutic trials in adult aminases, alanine aminotransferase (ALT) and aspar-
and juvenile myositis (3). The systematic assessment of tate aminotransferase (AST), lactate dehydrogenase
the inflammatory myopathies will first be discussed and (LDH), and aldolase. When the CK is normal any one
then a treatment approach will be outlined. or a combination of these enzymes may be elevated and
375
376 CHESTER V. ODDIS
useful in following disease activity. Elevation of the AST thy is noted. Occasionally, overt vasculitis is found in
and ALT can often lead to an erroneous diagnosis DM. The characteristic cutaneous histopathologic find-
of liver disease because these enzymes are also re- ings of DM include vacuolar degeneration of the epi-
leased with hepatic injury. A muscle source should be dermal basal layer, vascular dilatation, and a perivascular
considered when the alkaline phosphatase and gamma- lymphocytic infiltrate. This interface dermatitis may be
glutamyl transferase (GGT) activity levels are concomi- similar to that seen with systemic lupus erythematosus
tantly normal. From a practical standpoint, if ALT and (SLE). Microvascular injury is again mediated by the
AST levels do not fall with the CK during treatment, terminal components of complement as in the case of
then investigations for hepatic disease should occur. The muscle (see Chapter 18B for more detailed discussion
serum aldolase, although helpful in some patients, is not on muscle and skin pathology).
as specific as the CK. Aldolase is widely distributed and
found in more tissue than CK and may be elevated with
liver disease, hematologic and other disorders, and with
Radiographic Assessment of Myositis
specimen hemolysis. The availability of magnetic resonance imaging (MRI)
adds another assessment tool to adult and juvenile myo-
sitis. (6). MRI is noninvasive, which makes it particularly
Electromyography useful in children where electromyography is painful
Although electrical testing is a sensitive but nonspecific and poorly tolerated. Large areas of muscle (e.g., the
method of evaluating muscle inflammation, it allows for thighs) can be studied and the results used to increase
several muscle groups to be examined. The typical elec- the diagnostic yield of muscle biopsy. The T1-weighted
tromyographic features of myofibril irritability include image provides excellent anatomic detail as normal
fibrillation potentials, complex repetitive discharges, tissue is homogeneously dark with a low signal, while
and positive sharp waves on needle insertion. Due to its fat (subcutaneous tissue and bone marrow) appears
sensitivity nearly all patients with active myositis will bright. Although muscle is darker on T2-weighted
have an abnormal electromyography (EMG) such that images, inflammation is bright on both T1 and T2 images.
a normal study indicates inactive disease. Electromyo- Utilizing techniques of fat suppression with short tau
graphy is often used in the selection of a muscle for inversion recovery (STIR) sequencing with T2 imaging
biopsy and it should be performed unilaterally to avoid improves the detection of muscle inflammation by
confusion with inflammation artifact resulting from the enhancing its bright signal and decreasing the darker fat
needle itself. Due to disease symmetry, a contralateral signal. The indications for MRI include (1) documenta-
muscle that is abnormal by EMG should be chosen for tion of myositis or disease flare in a patient with normal
biopsy. Although corticosteroid myopathy is often dif- muscle enzymes or a normal EMG and biopsy; (2) con-
ficult to clinically distinguish from active inflammatory firmation of amyopathic dermatomyositis in a patient
disease, the presence of fibrillation potentials suggests with normal serum enzymes, dermatologic features, and
active inflammation due to the disease process. no apparent muscle involvement; (3) distinguishing
chronic active disease from chronic inactive myositis
(i.e., damage) where both groups of patients may have
Muscle and Skin Biopsy muscle weakness but the fat-suppressed technique will
Muscle histology can confirm the diagnosis of IIM, but distinguish fatty changes from inflammation; (4) direct-
patchy changes within muscle or choosing the wrong ing the site of muscle biopsy particularly in PM where
muscle to biopsy can limit diagnostic sensitivity. Degen- mimics are more of a diagnostic problem; and (5) dis-
eration and regeneration of myofibrils is the most tinguishing PM from IBM as some useful distinguishing
common finding, while a chronic inflammatory infiltrate features have been noted in IBM (7). Limitations of
in the perivascular and interstitial area is more specific MRI include the expense of the procedure and the non-
for immune-mediated myositis. PM and inclusion body specificity of edema (even with STIR sequences and T2
myositis (IBM) is histologically distinct from DM. The imaging) that may be found in other inflammatory pro-
pathognomonic feature of PM (and occasionally IBM) cesses, toxic myopathies, or dystrophic conditions.
is lymphocytic (cytotoxic T cell) invasion of non-necrotic
myofibers. T-helper cells may also be found in the peri-
vascular and perimysial areas but the vasculature is
Extramuscular Organ Assessment
often spared. In contrast, B cells and the terminal com- Idiopathic inflammatory myopathies are systemic con-
ponent of complement (C5C9, membrane attack nective tissue disorders and affect patients in ways well
complex) are found in the perivascular area in DM beyond the musculoskeletal system. Lung disease can
along with CD8+ and CD4+ T cells. The vasculature is be particularly devastating and patients with antibodies
commonly targeted in DM and perifascicular myofibril to the aminoacyl-transfer RNA synthetases (see Serum
atrophy, likely secondary to an ischemic microangiopa- Autoantibodies section) are at risk for interstitial lung
disease (ILD). Involvement of the respiratory muscula- IBM patients in one European cohort had identifiable
ture is less common but can occur in severe cases of antibodies (10). A negative antinuclear antibody test
muscle weakness. In the latter instance, reduced ventila- does not exclude MSA because the antigens targeted by
tory muscle strength is determined by measuring inspi- these autoantibodies may be cytoplasmic in location.
ratory pressures at the mouth. ILD, however, shows Testing for serum autoantibodies is helpful and can
restrictive physiology on pulmonary function testing solidify the diagnosis of myositis in patients with atypi-
and is accompanied by radiographic evidence of pulmo- cal clinical features and provide prognostic information
nary fibrosis. Compromised gas exchange leads to a because of the known clinical associations.
reduction in the diffusing capacity for carbon monoxide AntiJo-1 is the most common MSA but the clinical
and a decrease in the alveolararterial oxygen gradient features of the various antisynthetase antibodies are
(desaturation) with exercise. The chest radiograph is similar, and have been described as comprising the
insensitive compared with high-resolution CT (HRCT) antisynthetase syndrome characterized by fever,
scanning, which reveals ground glass opacities (alveo- mechanics hands, Raynauds phenomenon, inflam-
litis), consolidation, subpleural lines or bands, traction matory arthritis, ILD, and myositis. Patients with an
bronchiectasis, and honeycombing (fibrosis). Biopsy antisynthetase autoantibody may not manifest all fea-
and autopsy studies of patients with myositis show tures of the syndrome and some will never develop
an interstitial infiltrate of predominantly CD8+ T cells, myositis. For example, antiPL-12 antibody-positive
while bronchoalveolar lavage (BAL) yields mostly patients are more likely to have ILD without myositis.
CD8+ cells and a minor B-cell component (8). Clinically Antibodies against signal recognition particle (anti-
significant cardiac involvement is uncommon in IIM SRP) comprise a separate subgroup of MSAs targeting
although autopsy studies detect a higher frequency of a ribonucleoprotein involved in protein translocation.
myocarditis. Electrical disturbances are commonly Most patients have PM with severe, refractory disease
reported, including nonspecific ST-T segment changes and the muscle biopsy often does not demonstrate the
and various conduction system abnormalities that can characteristic lymphocytic endomysial inflammation
be monitored by electrocardiography. The myocardial (11) that is commonly found in PM. Mi-2 is a multi-unit
fraction of CK (CKMB) is increased in patients with protein complex involved in transcription and, unlike 18
active myositis as regenerating myoblasts release this the cytoplasmic location of the synthetases and SRP,
enzyme. However, cardiac troponin I is not influenced anti-Mi-2 is an antinuclear antibody. In general, anti
by skeletal muscle injury and elevations indicate myo- Mi-2 is associated with the rash of DM and a good
cardial damage. In myositis patients with proximal or response to therapy but it has been observed in PM
distal dysphagia, the barium swallow may demonstrate patients as well as JDM and in malignancy, where the
cricopharyngeal hypertrophy or spasm in the case of rash can be severe (12).
IBM or poorly coordinated motion of the pharyngeal Antipolymyositis-Scl is an antinucleolar antibody
(striated) musculature, vallecular pooling, or aspiration associated with a good prognosis that can be seen in PM
of barium into the trachea in the case of severe PM or or DM alone, systemic sclerosis alone, or in patients with
DM. Distal dysphagia reveals distal esophageal (smooth overlap syndromes. AntiU1-RNP antibodies should be
muscle) hypomotility on the cinesophagram or manom- suspected in patients with a high-titer speckled pattern
etry, and occurs most frequently in patients with myosi- on routine antinuclear antibody testing and occur in
tis in overlap with another connective tissue disorder. patients with an overlap syndrome of mixed connective
tissue disease where clinical findings include Raynauds
phenomenon and variable features of SLE, myositis,
Serum Autoantibodies
and/or systemic sclerosis. Antibodies to Ro/SSA are
Antinuclear or anticytoplasmic autoantibodies are seen in at least 10% of myositis, especially those with
found in up to 90% of patients with PM or DM and are antibodies to the aminoacyl-tRNA synthetases.
useful in defining clinically homogeneous subsets of
patients (9). Myositis-specific autoantibodies (MSAs)
Malignancy and Myositis
have been previously reported to occur exclusively in
IIM but the presence of MSAs without evidence of an Recent reports strongly support an increased risk of
inflammatory myopathy have being reported (10). It is cancer in patients with PM and DM with the greatest
rare for myositis patients to have more than one MSA. risk in DM. In a pooled study from Sweden, Denmark,
Autoantibodies seen in other connective tissue diseases and Finland, 618 cases of DM were identified, 198 of
may also be found in patients with myositis and are whom had cancer (13). Fifty-nine percent of the 198
termed myositis-associated autoantibodies. Both groups patients developed a malignancy after the diagnosis of
of autoantibodies and their clinical associations are DM was made and the most common cancers were
summarized in Table 18C-1. Although the frequency of ovarian, lung, pancreatic, stomach, colorectal, and non-
autoantibody positivity is low with IBM, 18% (7/38) of Hodgkins lymphoma. A lower but statistically increased
TABLE 18C-1. SERUM AUTOANTIBODIES IN POLYMYOSITIS AND DERMATOMYOSITIS.

FREQUENCY IN
IDIOPATHIC
INFLAMMATORY
AUTOANTIBODY ANTIGENIC TARGET MYOPATHIES (%) CLINICAL ASSOCIATIONS
MYOSITIS-SPECIFIC AUTOANTIBODIES
Jo-1 Histidyl-tRNA synthetase 20 Antisynthetase syndrome (fever, interstitial

lung disease, arthritis, Raynauds and
mechanics hands and poor response to
Rx)
PL-7 Threonyl-tRNA synthetase 2 Antisynthetase syndrome
PL-12 Alanyl-tRNA synthetase 2 Antisynthetase syndrome; lower frequency of

myositis
OJ Isoleucyl-tRNA synthetase 1 Antisynthetase syndrome
EJ Glycyl-tRNA synthetase 1 Antisynthetase syndrome; DM > PM
KS Asparaginyl-tRNA synthetase <1 Rare; most patients have ILD
Mi-2 Nuclear helicase 510 DM (good response to Rx); PM only when

ELISA used
SRP Signal recognition particle 5 PM (with cardiomyopathy and unresponsive

to Rx); rare cases of overlapping CTD
MYOSITIS-ASSOCIATED AUTOANTIBODIES
PM-Scl Exosome proteins; multiprotein 510 Overlap with limited systemic sclerosis;
complex myositis less severe
U1RNP U1 small nuclear ribonucleoprotein 510 MCTD or overlapping myositis syndromes
Ku DNA binding complex 1 PM-SSc overlapping; occasionally SLE
Ro/SSA Ro60 and Ro52 1020 Sjgrens; seen with antisynthetases
ABBREVIATIONS: CTD, connective tissue disease; DM, dermatomyositis; ILD, interstitial lung disease; MCTD, mixed connective tissue disease; PM, polymyositis;
SSc, systemic sclerosis.
risk of cancer was seen with PM and several case reports TREATMENT OF
note that amyopathic DM may also be associated with
malignancy. The overall risk of cancer is greatest in the INFLAMMATORY MYOPATHY
first 3 years after the diagnosis of myositis, but an
increased risk of malignancy continues, emphasizing the General Rehabilitative Measures
importance of ongoing surveillance. Serum CA-125
screening may be useful in women with DM. The pres- After confirming the diagnosis, assessing for systemic
ence of myositis-associated or specific serum auto- involvement and defining the relative contribution of
antibodies and/or another connective tissue disease disease activity and damage treatment should com-
decreases the likelihood of cancer. A cancer screening mence. Although the timing and aggressiveness of phys-
evaluation of high-risk patients may increase early ical therapy is controversial, the overall goal is to
detection and reduce mortality. In addition to a careful improve and preserve existing muscle function and
history and physical examination (including a gyneco- prevent atrophy and muscle contractures. Patients with
logic evaluation in women) with routine laboratory acute, severe muscle weakness should receive passive
testing, it is appropriate to complete an age-specific exercises including a stretching program to prevent con-
malignancy evaluation given the distribution of tumors tractures. As muscle strength improves to near 50% to
noted above. This would include chest, abdominal, and 60% normal then an active, assisted program can be
pelvic CT scans, along with colonoscopy and mammog- instituted including an isotonic and isometric compo-
raphy (see Chapter 18A for further discussion of malig- nent involving resistive bands of varying elasticity.
nancy and myositis). A more aggressive approach with free weights and
resistive machines can later be incorporated. Controlled a reconsideration of that diagnosis. Methotrexate or
studies utilizing strength training programs in patients azathioprine are often the first IS, steroid-sparing agents
with active but stable disease have shown that muscle chosen and their combination has proven efficacious in
enzymes do not increase and an improvement in muscle refractory myositis (15). Methotrexate can be used in
strength and well-being results. synthetase-positive patients if pulmonary function is
carefully monitored. Cyclosporine is useful in both adult
and childhood IIM in prospective and retrospective
Pharmacologic Therapy reports and another calcineurin inhibitor, tacrolimus,
Very few well-designed trials in IIM have been com- has efficacy for both myositis and ILD, particularly in
pleted over the past 20 years. Although there are only Jo-1positive patients (16). Mycophenolate mofetil has
a handful of randomized, blinded, and controlled been increasingly reported in both PM and DM as well
studies, a pharmacologic approach can be recommended as the ILD associated with connective tissue diseases
(14). including myositis. The use of alkylating agents is con-
troversial and should be reserved for refractory disease
or severe systemic complications. In patients presenting
Corticosteroids with significant extramuscular manifestations or severe
Although fraught with side effects, corticosteroids (CS) disease a CS-sparing agent should be concomitantly
remain the agents of choice for the initial empiric treat- administered initially with prednisone. Immunosup-
ment of inflammatory myopathy. The dosing depends on pressive (IS) regimens in IBM have generally not been
the disease severity and risk factors for toxicity because beneficial and treatment expectations with IBM patients
some patients with milder (i.e., overlapping syndromes) should be different than with PM or DM given the
disease may benefit from lower CS doses. In general, greater damage at the time of diagnosis. Studies
patients should begin on daily, oral, divided-dose CS suggest that the inflammatory response in IBM may play
equivalent to 60 mg/day of prednisone. After normaliza- a secondary role in disease pathogenesis and although
tion of the serum CK (often within 13 months), the corticosteroid treatment results in a decrease in inflam-
prednisone can be consolidated to a once-daily dose and mation in muscle biopsies and improved serum CK 18
tapered by approximately 20% to 25% of the existing levels, muscle strength continues to deteriorate (17).
dose every 3 to 4 weeks to a daily morning dose of 5 to
10 mg. This dose should be maintained for several
Intravenous Immune Globulin
months depending on the clinical course, but patients
often flare, necessitating an increase of CS to a previ- Although the mechanism of action is unknown, several
ously effective (but not necessarily initial) dose. To prospective trials of intravenous immune globulin
evaluate treatment response, patients should be seen at (IVIG) have been efficacious in PM, DM, and IBM
least monthly with measurement of serum muscle (18). This agent is often used in JDM early in the disease
enzymes and an assessment of manual muscle testing course in combination with CS and/or another IS agent.
and functional status. With severe myositis or life-threat- It can be utilized as bridge therapy but is unlikely to be
ening extramuscular manifestations such as ILD, intra- helpful without concomitant disease-modifying therapy.
venous pulse methylprednisolone should be instituted It is also useful in the infected myositis where IS agents
to effect more rapid disease control. In IBM the use of are contraindicated. IVIG can be administered for 2
steroids is controversial but in a patient with new-onset consecutive days per month in conventional doses for 3
disease an acceptable regimen might include predni- months and with a positive response, therapy may be
sone at 40 to 60 mg/day for 2 to 3 months. A favorable continued for 6 months. Limitations include its expense
response would include a clear increase in muscle and availability.
strength with or without a decrease in the serum CK
because it is well known that the CK will drop in IBM
Other Therapies
without any clinical benefit. If improvement occurs,
another immunosuppressive agent may be considered Tumor necrosis factor alpha antagonists are anecdotally
as a CS-sparing agent. However, assessing a response in helpful and may be considered in the refractory patient
IBM is difficult as the disease progresses insidiously and but caution should be exercised as alveolitis has been
no studies in IBM have ever established the efficacy of reported with these agents in other rheumatic disease
any therapies. populations. Rituximab has been reported as effective
in a small pilot study of DM (19) as well as other iso-
lated cases of both PM and DM. Although one might
Other Immunosuppressive Agents
postulate its improved efficacy in B cell-mediated DM,
Most myositis patients at least partially respond to CS it is being studied in the largest clinical trial to date in
and a complete lack of response in PM should prompt adult and juvenile DM as well as PM.
Extramuscular Manifestations 4. Guzman J, Petty RE, Malleson PN. Monitoring disease

activity in juvenile dermatomyositis: the role of von Will-
Pulmonary manifestations significantly contribute to ebrand factor and muscle enzymes. J. Rheumatol
the morbidity and mortality of myositis patients and the 1994;21:739743.
most worrisome complication is rapidly progressive 5. Johnston JD, Lloyd M, Mathews JA, et al. Racial variation
diffuse alveolitis manifesting as ground glass on HRCT in serum creatine kinase levels. J Roy Soc Med 1996;89:
of the lung. This may rapidly decompensate into adult 462464.
6. Scott DL, Kingsley GH. Use of imaging to assess patients
respiratory distress syndrome, which caries a poor prog-
with muscle disease. Curr Opin Rheumatol 2004;16:
nosis and an often fatal outcome. The treatment of ILD
678683.
in such patients is empiric and often unsatisfactory but 7. Dion E, Cherin P, Payan C, et al. Magnetic resonance
initial therapy should include pulse solumedrol therapy imaging criteria for distinguishing between inclusion body
(1 g daily for 3 consecutive days) followed by daily, myositis and polymyositis. J Rheumatol 2002;29:1897
divided-dose corticosteroids (6080 mg) and a second IS 1906.
agent such as cyclophosphamide, azathioprine, cyclo- 8. Schnabel A, Hellmich B, Gross WL. Interstitial lung
sporine, or tacrolimus. Joint symptoms in IIM often disease in polymyositis and dermatomyositis. Curr Rheum
resolve with corticosteroids but the rheumatoidlike Rep 2005;7:99105.
disease that may occur with Jo-1positive patients 9. Targoff IN. Idiopathic inflammatory myopathy: autoanti-
requires other disease-modifying agents. The rash of body update. Curr Rheum Rep 2002;4:434441.
10. Brouwer R, Hengstman GJ, Egberts WT, et al. Autoanti-
DM can be difficult to treat and its course and response
body profiles in the sera of European patients with myo-
to treatment may be discordant with the muscle disease.
sitis. Ann Rheum Dis 2001;60:116123.
Hydroxychloroquine (200400 mg/day) is often effec- 11. Kao AH, Lacomis DH, Lucas M, et al. Anti-signal recogni-
tive, but quinacrine (100 mg/day), isotretinoin (0.5 tion particle autoantibody in patients with and patients
1.0 mg/kg/day), topical tacrolimus, methotrexate, myco- without idiopathic inflammatory myopathy. Arthritis
phenolate mofetil, or any of the other IS agents should Rheum 2004;50:209215.
be considered in treating the rash of DM. Subcutaneous 12. Hengstman GJ, Brouwer R, Egberts WT, et al. Clinical and
or soft tissue calcification is unusual in adults but serological characteristics of 125 Dutch myositis patients.
common in JDM. The soft tissue inflammatory response Myositis-specific autoantibodies aid in the differential
to calcinosis often responds to oral colchicine and other diagnosis of the idiopathic inflammatory myopathies. J
agents anecdotally reported to benefit calcinosis include Neurol 2002;249:6975.
13. Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of
low-dose warfarin, aluminum hydroxide, probenecid,
specific cancer types in dermatomyositis and polymyositis:
bisphosphonates, and diltiazem. However, most clini-
a population-based study. Lancet 2001;357:96100.
cians believe that no treatment effectively treats 14. Baer AN. Advances in the therapy of idiopathic inflam-
calcinosis. matory myopathies. Curr Opin Rheumatol 2006;18:
236241.
15. Villalba L, Hick JE, Adams EM, et al. Treatment of refrac-
tory myositis: a randomized crossover study of two new
REFERENCES cytotoxic regimens. Arthritis Rheum 1998;41:392399.
16. Wilkes MR, Sereika SM, Fertig N, et al. Treatment of
1. Miller FW, Rider LG, Chung YL, et al. Proposed prelimi- antisynthetase-associated interstitial lung disease with
nary core set measures for disease outcome assessment in tacrolimus. Arthritis Rheum 2005;52:24392446.
adult and juvenile idiopathic inflammatory myopathies. 17. Barohn RJ, Amato AA, Sahenk Z, et al. Inclusion body
Rheumatology 2001;40:12621273. myositis: explanation for poor response to immunosup-
2. Rider LG, Giannini EH, Brunner HI, et al. International pressive therapy. Neurology 1995;45:13021304.
consensus on preliminary definitions of improvement in 18. Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial
adult and juvenile myositis. Arthritis Rheum 2004;50:2281 of high-dose intravenous immune globulin infusions as
2290. treatment for dermatomyositis. N Engl J Med 1993;329:
3. Oddis CV, Rider LG, Reed AM, et al. International con- 19932000.
sensus guidelines for trials of therapies in the idiopathic 19. Levine TD. Rituximab in the treatment of dermatomy-
inflammatory myopathies. Arthritis Rheum 2005;52:2607 ositis: an open-label pilot study. Arthritis Rheum 2005;52:
2615. 601607.
CHAPTER 19
Metabolic Myopathies
ALAN N. BAER, MD
The metabolic myopathies are a heterogeneous Secondary types occur with abnormal production of
group of diseases characterized by impaired skeletal parathyroid, thyroid, and cortisol production and
muscle energy production. vitamin D deficiency.
Primary metabolic myopathies are associated Symptoms occur mainly during or shortly after exercise
with genetic defects in glycogen and lipid and include pain, weakness, and cramping, and can
metabolism. result in myoglobinuria due to muscle necrosis.
The metabolic myopathies are a heterogeneous group undue fatigue and dyspnea during low levels of exer-
of diseases characterized by impaired skeletal muscle tion, including moderate activities of daily living.
energy production. Primary metabolic myopathies The diagnosis of a metabolic myopathy should be
are associated with genetically determined defects in suspected in a patient with muscle symptoms that
glycogen and lipid metabolism and in mitochondrial develop during or after exercise, particularly if associ-
oxidative phosphorylation. These include the muscle ated with myoglobinuria. These diseases should also be
glycogenoses and the lipid and mitochondrial myopa- included in the differential diagnosis of slowly progres-
thies. Other metabolic myopathies arise from endocrine sive proximal or truncal muscle weakness. Support for
or electrolyte abnormalities and therapy with specific the diagnosis of certain metabolic myopathies can be
drugs. A classification of the primary metabolic myopa- gained from the measurement of organic and amino
thies is presented in Table 19-1. acids in the blood and urine and exercise testing, includ-
The symptoms of a metabolic myopathy develop pre- ing the ischemic forearm exercise test and cycle ergome-
dominantly during or shortly after muscle exertion, and try (Table 19-1). Confirmation of the diagnosis usually
include muscle weakness, pain, stiffness, and cramping, requires muscle biopsy and/or molecular genetic testing
sometimes culminating in myoglobinuria due to muscle (1).
fiber necrosis. Patients with metabolic myopathies may
also develop fixed proximal muscle weakness, generally
mild in severity, and be misdiagnosed as having poly- PRIMARY METABOLIC
myositis. While the symptoms of a metabolic myopathy
are usually first experienced in childhood or early adult-
MYOPATHIES
hood, they may also develop later in adult life.
The type of exercise intolerance varies in relation to
Muscle Glycogenoses
the defect in muscle bioenergetics (Figure 19-1). Patients The glycogen storage diseases arise from inherited
with muscle glycogenoses develop muscle pain and defects in glycogen degradation, glycogen synthesis, or
cramps early during strenuous exertion, at a time when glycolysis. Eleven defects in glycogen metabolism affect
muscle energy is derived from glycogen. Patients with skeletal muscle, either alone or together with other
defects of lipid metabolism experience similar muscle organs and are known as muscle glycogenoses (2). The
symptoms during or shortly after prolonged lower- classic clinical manifestation of a muscle glycogenosis is
intensity exercise or during fasting, reflecting the depen- exercise intolerance. Patients develop painful cramps
dence of muscle on free fatty acids as their primary and swelling of the exercising muscles, sometimes asso-
energy source during these conditions. Patients with ciated with myoglobinuria. The symptoms are relieved
mitochondrial myopathies have impaired muscle oxygen by rest. In some muscle glycogenoses, progressive muscle
utilization, as a result of defects in oxidative phosphory- weakness is the predominant clinical presentation
lation. With exercise, there is an exaggerated circulatory (Table 19-1).
and ventilatory response to overcome the block in The most common muscle glycogenosis is myophos-
muscle oxygen utilization. As a result, patients note phorylase deficiency (McArdles disease), with an
381
TABLE 19-1. KEY FEATURES OF THE PRIMARY METABOLIC MYOPATHIES.
382 ALAN N. BAER
ENZYME OR
BIOCHEMICAL OTHER CLINICAL
BIOCHEMICAL CLASS DEFECT GENETICS MUSCLE SYMPTOMS FEATURES LABORATORY FEATURES DIAGNOSTIC TESTING
Defects in glycogenolysis or Myophosphorylase AR Exercise intolerance Second wind Variable serum CK Abnormal FIET
glycolysis (glycogenoses) phenomenon
Phosphofructokinase AR Exercise intolerance; Out of wind phenomenon serum CK, uric acid Abnormal FIET
proximal myopathy Hemolytic anemia, Gout
(late onset)
Phosphorylase b kinase AR Myopathy in Hepatomegaly, Fasting serum CK
childhood hypoglycemia
AR(?XR) Exercise intolerance, serum CK
myoglobinuria
Phosphoglycerate mutase AR Exercise intolerance, Most often in African serum CK Abnormal FIET
myoglobinuria Americans
Lactate dehydrogenase AR Exercise intolerance, LDH does not rise in Abnormal FIET with
myoglobinuria proportion to serum CK elevated pyruvate/
lactate ratio
Phosphoglycerate kinase XR Exercise intolerance, Hemolytic anemia CNS Variable serum CK Abnormal FIET
myoglobinuria dysfunction
Debrancher (adult AR Generalized or distal Hepatomegaly, Left or
patients) weakness biventricular
hypertrophy
Brancher AR Progressive myopthy Cardiomyopathy,
Hepatomegaly
Aldolase AR Exercise intolerance Hemolytic anemia
Weakness
Acid maltase (nonclassical AR Progressive myopathy Respiratory insufficiency Deficient alpha-glucosidase Myotonic discharges
forms) in leucocytes and muscle on EMG
Defects in fatty acid transport Carnitine deficiency AR Facial and proximal Hypoketotic hypoglycemia, Total serum carnitine <5% Reduced muscle
(primary systemic) myopathy Encephalopathy, normal carnitine
Cardiomyopathy
Carnitine deficiency AR Progressive myopathy Normal serum carnitine Muscle carnitine levels
(primary myopathic) levels; variable serum <25% normal
CK
Carnitine palmitoyltrans- AR Exercise intolerance, Serum CK normal between
ferase II myoglobinuria attacks
Defects in fatty acid Multiple acyl coA Progressive myopathy Increased urinary glutaric
beta-oxidation dehydrogenase acid Increased plasma
acyl-carnitine
Very-long-chain acyl coA Exercise intolerance,
dehydrogenase (adult myoglobinuria
phenotype)
Trifunctional protein Myoglobinuria Peripheral neuropathy Increased urinary DCAs
enzyme
Defects in respiratory chain Mutations in mtDNA or Maternal Exercise intolerance, Axonal neuropathy, Ataxia Elevation of resting, fasting Abnormal cycle
function (mitochondrial nDNA genes that Mendelian ptosis, external Seizures, Pigmentary blood lactate ergometry
myopathy) determine mitochon- Sporadic ophthalmoplegia retinopathy, Sensorineu-
drial respiratory chain ral hearing loss
function
Defects in purine nucleotide Myoadenylate deaminase AR None Abnormal FIET

cycle
SOURCE: Data from References 1, 2, 12, 14, 15, 16.

ABBREVIATIONS: CK, creatine kinase; FIET, forearm ischemic exercise test; AR, autosomal recessive; XR, X-linked recessive; DCA, dicarboxylic acid; EMG, electromyography; mtDNA, mitochondrial DNA; nDNA, nuclear
DNA.
C H A P T E R 1 9 M E T A B O L I C M Y O P A T H I E S 3 83
19
384 ALAN N. BAER
Glycogen
Glycogen metabolism
Vigorous isometric exercise (anaerobic)
Initial hour of moderate to high intensity Glucose
Long-chain fatty acids
exercise (aerobic)
Fatty acid transport and oxidation
Lactate Pyruvate Sustained (>1 hour) moderate exercise
anaerobic
aerobic conditions
conditions
Fatty acyl CoA
Short- and
CPT1 medium-chain
fatty acids
CPT2
Pyruvate
FA (n2) CoA
Acetyl CoA
FA CoA
-oxidation
TCA
cycle ATP
ADP + Pi
NADH V
FADH2
III IV
I II
flow
ctron
Ele
Oxidative phosphorylation
Mitochondrion
FIGURE 19-1
Skeletal muscle bioenergetics. The primary muscle fuels are glucose and free fatty acids. At rest,
muscle utilizes predominantly fatty acids. During a sudden, vigorous bout of exertion, energy is
derived from anaerobic glycolysis. Glucose, derived primarily from the breakdown of muscle
glycogen, is metabolized by the glycolytic pathway to yield pyruvate. In anaerobic conditions,
the pyruvate is converted to lactate. During submaximal exercise, the utilization of muscle fuels
depends on its relative intensity and duration. At higher intensities, aerobic metabolism of
glycogen is an important source of energy. Pyruvate derived from glycolysis enters mitochondria
and is metabolized by the tricarboxylic acid (TCA) cycle. At lower intensities, muscle energy is
derived from both blood glucose and free fatty acids. With longer durations of low intensity
exercise, free fatty acids become the primary fuel source. The free fatty acids enter the mitochon-
dria, either via the carnitine shuttle (long-chain fatty acids) or by passive diffusion (short and
medium chain fatty acids). The carnitine shuttle transports fatty acids into mitochondria as their
acylcarnitine derivatives and involves the enzymatic activities of the carnitine palmitoyltransfer-
ases, CPT1 and CPT2. Within the mitochondria, the fatty acids are converted to their coenzyme
A (CoA) derivative and then undergo successive cycles of beta-oxidation, their acyl chains
shortening by two carbons with each cycle. Acetyl CoA, NADH, and FADH2 are produced during
each cycle of beta-oxidation; the acetyl CoA is then metabolized in the TCA cycle, yielding
additional molecules of NADH and FADH2. Electrons derived from these reduced flavoproteins
are passed along the respiratory chain, releasing energy that is stored as a proton gradient
across the mitochondrial inner membrane. This energy is used by the last component of the
respiratory chain, adenosine triphosphate (ATP) synthase, to produce ATP from adenosine
diphosphate (ADP) and phosphate.
estimated prevalence of 1 case per 100,000 persons (3). Acid maltase (lysosomal alpha-1,4-glucosidase) defi-
Symptoms develop during intense isometric exercise, ciency has three modes of clinical presentation (8). The
such as weight lifting, and during the initial minutes of classic form, known as Pompes disease, is characterized
moderately intense exertion, such as walking uphill (2). by a hypertrophic cardiomyopathy, progressive myopa-
Most affected persons are well at rest and can function thy, and death by the age of 2 years. The nonclassic
without difficulty at low levels of exertion. Symptoms forms are dominated by skeletal muscle involvement
often begin during childhood, but significant problems, (9). A childhood variant is characterized by severe prox-
such as severe cramping or exercise-induced rhabdomy- imal, truncal, and respiratory muscle weakness. Affected
olysis, may not develop until the teenage years. Patients individuals usually die of respiratory insufficiency in
with myophosphorylase deficiency may first present in their second or third decade of life. Acid maltase defi-
mid-adult life with a history of slowly progressive proxi- ciency may also present in young adults with slowly
mal muscle weakness. Patients commonly describe a progressive proximal muscle weakness, simulating poly-
second wind phenomenon. With the initial onset of myositis and limb-girdle muscular dystrophy. In contrast
exercise-induced symptoms, they must stop or reduce to other muscle glycogenoses, there are no exercise-
the level of exercise, but are often able to resume the related muscle symptoms. A minority of adult patients
same level of exercise with better endurance after a few presents with respiratory insufficiency, manifested by
minutes of rest. The second wind occurs as a result of dyspnea on exertion, excessive daytime somnolence, or
increased availability of blood glucose and free fatty morning headaches. Respiratory involvement eventu-
acids derived from nonmuscle sources. ally occurs in all adults and is the usual cause of death.
Serum creatine kinase (CK) levels are commonly CK levels are usually elevated. Adult acid maltase defi-
increased in the muscle glycogenoses. Electromyogra- ciency causes characteristic electromyographic changes
phy (EMG) may be normal or show nonspecific myo- of intense electrical irritability and myotoniclike dis-
pathic changes. The forearm ischemic exercise test is a charges in the absence of clinical myotonia. Muscle
useful screening test for most of these disorders (4). In biopsy shows a glycogen storage vacuolar myopathy.
one version of the test, the patient squeezes a ball repeat- The diagnosis can be confirmed by demonstrating defi-
edly for 2 minutes or to the point of exhaustion while cient alpha-glucosidase activity in muscle, leucocytes, or
arterial blood flow to the exercising arm is occluded by fibroblasts.
a blood pressure cuff inflated to above systolic blood Management of patients with a muscle glycogenosis
pressure (5). The blood pressure cuff is then released. includes modification of their exercise and dietary regi-
Levels of lactate and ammonia are measured in blood mens. A high-protein, low-carbohydrate diet is gener- 19
obtained from the antecubital vein of the exercising arm, ally recommended for patients with myophosphorylase
both at baseline and then 2 minutes after the cessation deficiency because branched chain amino acids may be
of the anaerobic exercise. In individuals with a muscle an alternative to glycogen as a fuel source. Ingestion of
glycogenosis (except in those with acid maltase, brancher sucrose before exercise can markedly improve exercise
enzyme, or phosphorylase b kinase deficiencies), plasma tolerance (3). Vitamin B6 and creatine supplementation
levels of ammonia increase at least threefold while those may also be beneficial. Patients with phosphofructoki-
of lactate do not rise. False-positive results may result if nase deficiency should avoid high-carbohydrate diets
the patient does not exercise with sufficient vigor to because these may provoke decreased exercise capacity,
increase lactate production. The characteristic abnor- the so-called out-of-wind phenomenon (10).
mality on muscle biopsy is PAS (periodic acid Schiff)-
positive deposits of glycogen in the periphery of muscle
fibers. The putative diagnosis can be confirmed by spe-
Disorders of Lipid Metabolism
cific enzyme analysis of muscle tissue whenever it is The disorders of lipid metabolism in muscle result from
suspected based on histology or ischemic exercise testing. various biochemical defects in mitochondria. Some are
Molecular genetic tests for the mutations that account caused by defective transport of fatty acids into the
for up to 90% of cases of myophosphorylase deficiency mitochondria and others by defects in their subsequent
can also be performed using whole blood, thereby obvi- beta-oxidation. The mitochondrial myopathies result
ating the need for muscle biopsy (6). from defects in oxidative phosphorylation. Disorders of
Adult-onset myopathies may occur in debrancher fatty acid transport and oxidation share common fea-
deficiency. Four different clinical phenotypes are recog- tures. They present most commonly in the neonatal
nized: a generalized myopathy that may resemble poly- period or infancy with hypoketotic hypoglycemia and
myositis, a distal myopathy involving calves and peroneal liver dysfunction. Older children and young adults
muscles, a selective myopathy of respiratory muscles, typically present with exercise intolerance and
and mild weakness accompanying severe liver involve- myoglobinuria.
ment (7). Childhood hepatomegaly is an important his- Carnitine is an amino acid that is required for the
torical feature. transport of long-chain fatty acids into mitochondria.
386 ALAN N. BAER
Carnitine deficiency causes a lipid storage myopathy. rhabdomyolysis or, often, after prolonged exercise or
Primary and secondary types are distinguished. One fasting. Molecular genetic testing, using whole blood,
primary form, inherited as an autosomal recessive trait, can detect known mutant alleles in approximately 80%
is related to mutations in OCTN2, an organic cation of affected patients (1). The diagnosis may also be estab-
transporter (11). It affects multiple tissues and usually lished by assaying muscle tissue for enzyme activity.
presents with a progressive cardiomyopathy in children Management of CPT2 deficiency includes avoidance
between the ages of 2 and 4 years, with or without skel- of prolonged fasting and of exercise lasting more
etal muscle weakness. Some affected children present at than 30 minutes. Consumption of small low-fat, high-
a younger age with recurrent episodes of hypoketotic carbohydrate meals throughout the day may reduce the
hypoglycemia and hepatic encephalopathy, resembling frequency of attacks. If sustained exercise is anticipated,
Reyes syndrome. Another primary form affects skeletal carbohydrate loading may prevent attacks. Dietary sup-
muscle only (12). It presents in late childhood and plementation with medium chain triglycerides may be
through the early adult years as a progressive myopathy beneficial.
affecting the proximal limbs and occasionally the facial Defects in fatty acid beta-oxidation are rare causes
and respiratory muscles. The molecular basis for this of myopathies. Late-onset forms of very-long-chain
form has not been defined. Carnitine deficiency may acyl-coenzyme A dehydrogenase deficiencies may share
also occur in the setting of other metabolic disorders the same clinical features as CPT2 deficiency (14). The
(fatty acid oxidation disorders, organic acidemias), preg- multiple acyl-coenzyme A dehydrogenase deficiencies
nancy, long-term hemodialysis, end-stage cirrhosis, myx- may present in late childhood or adulthood as lipid
edema, adrenal insufficiency, and chronic treatment storage myopathies. One form, responsive to riboflavin
with valproate or pivampicillin. supplementation, is characterized predominantly by
Carnitine deficiency may be confused with polymyo- respiratory and neck muscle weakness (14). Patients
sitis because serum CK concentrations may be increased with mitochondrial trifunctional protein enzyme defi-
and EMG may reveal myopathic changes. Measurement ciency typically have episodic rhabdomyolysis and a
of carnitine levels in muscle and plasma is required to peripheral neuropathy.
establish the diagnosis. In the systemic form of primary
carnitine deficiency, both plasma and tissue carnitine
levels are markedly reduced, while in the myopathic
Mitochondrial Myopathies
form, only carnitine levels in the muscle are reduced. The mitochondrial myopathies are a clinically heterog-
The carnitine deficiency syndromes can be treated effec- enous group of disorders that arise due to defects in
tively with pharmacologic doses of oral carnitine. mitochondrial respiratory chain function. Their varied
Two distinct carnitine palmitoyltransferases (CPT) clinical features and multisystemic nature reflect
serve to transport long-chain fatty acids into mitochon- dysfunction of organs that are highly dependent on
dria. CPT1 is located on the inner surface of the outer oxidative metabolism, such as skeletal muscle, brain,
mitochondrial membrane and CPT2 is located on the peripheral nerve, organ of Corti, heart, retina, endo-
inner side of the inner mitochondrial membrane. Defi- crine glands, and renal tubules. Clinical features of
ciencies of both CPT1 and CPT2 occur, but muscle these disorders include a proximal myopathy, strokelike
disease is confined to the latter. CPT2 deficiency is an episodes, seizures, ataxia, cognitive decline, axonal neu-
autosomal recessive disorder with clinical presentations ropathy, sensorineural hearing loss, hypertrophic car-
in juvenile or adult life (myopathic form), in infancy diomyopathy, pigmentary retinopathy, diabetes mellitus,
(hepato-cardio-muscular form) and at birth (hepatic short stature, and renal tubular acidosis. A number of
form) (13). The myopathic form of CPT2 deficiency is diverse syndromes are characterized by specific combi-
the most common cause of hereditary recurrent myo- nations of these clinical features (15). Predominant
globinuria. It occurs most often in young men aged 15 involvement of one organ system can also occur. The
to 30 years. Women are affected far less frequently, age at onset of symptoms ranges from birth to late life,
usually later in life and with a milder form of the disease. but is usually childhood or early adult life (16). Most
Paroxysmal rhabdomyolysis is the primary clinical mitochondrial myopathies are caused by mutations in
feature of CPT2 deficiency and is usually precipitated mitochondrial DNA (mtDNA) genes that encode poly-
by sustained exercise, ranging in vigor from strolling to peptide subunits of the respiratory chain or transfer or
mountain hiking (13). Other precipitants include fasting, ribosomal RNAs that mediate the synthesis of entire
infection, or exposure to cold. Stiffness, pain, and weak- mitochondrial proteins (15). These mtDNA mutations
ness of the exercising muscles are commonly experi- are usually inherited through maternal transmission and
enced following prolonged exercise. True cramps do not are thus expressed in a heteroplasmic fashion in cells
occur. Muscle weakness is not present between attacks. and tissues. A minority of mitochondrial myopathies
Serum CK concentrations, EMG, and muscle histology are caused by mutations of genes in the nuclear DNA
are normal, except during episodes of symptomatic that encode functional subunits or ancillary proteins of
the respiratory chain, as well as factors involved in vidual with this deficiency has muscle weakness, myalgia,
intergenomic communication. These nuclear DNA or fatigue, another diagnosis should be sought to explain
defects are inherited as autosomal recessive or domi- these symptoms. Patients with primary myoadenylate
nant traits. Mitochondrial diseases have an estimated deaminase deficiency have normal serum CK concen-
prevalence of 10 to 15 cases per 100,000 persons (15). trations, EMG, and muscle histology. However, the
Muscle involvement is present in the majority of forearm ischemic exercise test is abnormal. In contrast
mitochondrial diseases and varied in its clinical presen- to the muscle glycogenoses, levels of lactate, but not
tation. Chronic progressive external ophthalmoplegia those of ammonia, increase several-fold in the blood
and eyelid ptosis often precede or accompany the skel- after ischemic exercise.
etal muscle disease (16). Mild weakness of the proximal
limb musculature is usually present and is made
worse by exertion. Patients often note myalgias and SECONDARY METABOLIC
premature fatigue during exercise. Headache and nausea MYOPATHIES
may occur during strenuous activity. More severe defects
of oxidative phosphorylation result in a disparity
Proximal muscle weakness is the primary feature of the
between oxygen delivery and oxygen utilization and a
myopathies that may accompany Cushings syndrome,
hyperdynamic cardiopulmonary response to exercise
hypothyroidism, hyperthyroidism, vitamin D deficiency,
(17). Patients thus experience marked tachycardia and
acromegaly, and hyperparathyroidism. Hypothyroidism
exertional dyspnea when they engage in submaximal
may be associated with elevation of the serum CK and
exercise.
be misdiagnosed as polymyositis. Disorders that cause
Serum CK levels are normal or only mildly elevated.
abnormally high or low concentrations of sodium, potas-
Electromyography usually shows mild myopathic or
sium, calcium, magnesium, or phosphorus can also cause
neuropathic changes, or a combination of both. An ele-
weakness, fatigue, myalgias, or cramps. Zidovudine may
vated resting and fasting lactate level (>2.5 mmol/L) in
induce a mitochondrial myopathy.
the blood has high specificity but only modest sensitivity
for the diagnosis (18). Exercise testing using a cycle
ergometer typically shows a reduction in maximal whole
body oxygen consumption due to a reduction in periph-
REFERENCES
eral oxygen extraction and a disproportionately greater
1. Vladutiu GD. The molecular diagnosis of metabolic
production of carbon dioxide relative to oxygen con- myopathies. Neurol Clin 2000;18:53104. 19
sumption (18). Muscle biopsy is required for specific 2. DiMauro S, Lamperti C. Muscle glycogenoses. Muscle
diagnosis. The characteristic findings include ragged red Nerve 2001;24:984999.
fibers, evident with the modified Gomori trichrome 3. Vissing J, Haller RG. The effect of oral sucrose on exercise
stain, and/or muscle fibers with reduced or absent cyto- tolerance in patients with McArdles disease. N Engl J
chrome c oxidase activity. Electron microscopy may Med 2003;349:25032509.
also show mitochondria in increased numbers or with 4. Livingstone C, Chinnery PF, Turnbull DM. The ischaemic
abnormal morphology or inclusions. Identification of lactate-ammonia test. Ann Clin Biochem 2001;38:304
the responsible mitochondrial defect requires biochem- 310.
5. Wortmann RL, DiMauro S. Differentiating idiopathic
ical assessment of respiratory chain function in muscle
inflammatory myopathies from metabolic myopathies.
tissue, often coupled with molecular genetic studies Rheum Dis Clin North Am 2002;28:759778.
(19). 6. Greenberg SA, Walsh RJ. Molecular diagnosis of inher-
itable neuromuscular disorders. Part II: application of
genetic testing in neuromuscular disease. Muscle Nerve
Myoadenylate Deaminase 2005;31:431451.
7. Kiechl S, Kohlendorfer U, Thaler C, et al. Different clinical
Deficiency aspects of debrancher deficiency myopathy. J Neurol
Myoadenylate deaminase deficiency is the most common Neurosurg Psychiatry 1999;67:364368.
genetic abnormalitiy of skeletal muscle, affecting up to 8. Amato AA. Acid maltase deficiency and related myopa-
2% of the population. The affected biochemical pathway thies. Neurol Clin 2000;18:151165.
9. Winkel LP, Hagemans ML, van Doorn PA, et al. The
normally metabolizes adenosine monophosphate
natural course of non-classic Pompes disease; a review of
(AMP), generated via the adenylate kinase reaction, to 225 published cases. J Neurol 2005;252:875884.
inosine monophosphate and ammonia. This serves to 10. Haller RG, Lewis SF. Glucose-induced exertional fatigue
buffer increases in AMP that occur during strenuous in muscle phosphofructokinase deficiency. N Engl J Med
exertion. Individuals with this deficiency do not have a 1991;324:364369.
measurable impairment in exercise energy metabolism 11. Wang Y, Ye J, Ganapathy V, Longo N. Mutations in the
(20) and are almost always asymptomatic. If an indi- organic cation/carnitine transporter OCTN2 in primary
388 ALAN N. BAER
carnitine deficiency. Proc Natl Acad Sci USA 1999;96: 17. Taivassalo T, Jensen TD, Kennaway N, DiMauro S,
23562360. Vissing J, Haller RG. The spectrum of exercise tolerance
12. Cwik VA. Disorders of lipid metabolism in skeletal in mitochondrial myopathies: a study of 40 patients. Brain
muscle. Neurol Clin 2000;18:167184. 2003;126:413423.
13. Deschauer M, Wieser T, Zierz S. Muscle carnitine palmitoyl- 18. Tarnopolsky MA, Raha S. Mitochondrial myopathies:
transferase II deficiency: clinical and molecular genetic fea- diagnosis, exercise intolerance, and treatment options.
tures and diagnostic aspects. Arch Neurol 2005;62:3741. Med Sci Sports Exerc 2005;37:20862093.
14. Olpin SE. Fatty acid oxidation defects as a cause of neu- 19. Taylor RW, Schaefer AM, Barron MJ, McFarland R,
romyopathic disease in infants and adults. Clin Lab 2005; Turnbull DM. The diagnosis of mitochondrial muscle
51:289306. disease. Neuromuscul Disord 2004;14:237245.
15. DiMauro S, Schon EA. Mitochondrial respiratory-chain 20. Tarnopolsky MA, Parise G, Gibala MJ, Graham TE,
diseases. N Engl J Med 2003;348:26562668. Rush JW. Myoadenylate deaminase deficiency does not
16. Nardin RA, Johns DR. Mitochondrial dysfunction and affect muscle anaplerosis during exhaustive exercise in
neuromuscular disease. Muscle Nerve 2001;24:170191. humans. J Physiol 2001;533:881889.
CHAPTER 20
Sjgrens Syndrome
TROY DANIELS, DDS, MS
Primary Sjgrens syndrome (pSS) is a systemic production, leading to xerostomia and a predilection
autoimmune disease with early and gradually for dental caries.
progressive lacrimal and salivary dysfunction. Extraglandular manifestations of SS include
Secondary SS occurs in association with other arthralgias, thyroiditis, renal involvement (leading to
autoimmune disorders, the most common of which is renal tubular acidosis), peripheral neuropathy,
rheumatoid arthritis. cutaneous vasculitis, and lymphoma.
Minor salivary glands and lacrimal glands in SS The risk of lymphoma in pSS is approximately 5%.
exhibit a particular pattern of periductal lymphocytic Most patients with SS develop increased circulating
infiltration known as focal lymphocytic sialadenitis. polyclonal immunoglobulins and autoantibodies.
About 90% of patients with SS are women. These autoantibodies include two fairly specific
Sjgrens syndrome is very common, with a antibodies directed against the Ro (SS-A) and La (SS-B)
community prevalence of pSS ranging from 0.1% to antigens.
0.6% of all individuals. Anti-Ro and -La antibodies may be associated with
The major eye problem in SS is keratoconjunctivitis fetal heart block during the pregnancies of women
sicca, leading to xerophthalmia. The principal oral with SS.
manifestation of SS is decreased salivary gland
Primary Sjgrens syndrome (pSS) is a systemic autoim- ment that addresses all of the diverse manifestations of
mune disease with gradually progressive lacrimal and this disease.
salivary dysfunction, which can be symptomatic or
asymptomatic and include a variety of extraglandular
conditions. Secondary Sjgrens syndrome (sSS) occurs EPIDEMIOLOGY
when lacrimal and salivary dysfunction develop in
patients with another autoimmune connective tissue Women comprise the great majority (>90%) of patients
disease (ACTD), most commonly rheumatoid arthritis. with pSS. The mean age at onset is 45 to 55 years of age,
Because of the persistence and progression of secretory but the disease affects a broad age range of individuals,
dysfunction, patients with either form of SS often expe- including small numbers of children.
rience significant misery. The community prevalence of The prevalence and incidence of SS are defined rather
pSS, using current diagnostic criteria, ranges from 0.1% poorly because reliable indicators of the disease for
to 0.6%, depending on the study design. Affected organs epidemiologic studies are not available and the various
in patients with SS exhibit a particular pattern of chronic currently used diagnostic criteria give widely differing
inflammation that is gradually progressive and uncom- results (discussed below). Based on the widely used
monly undergoes transformation to lymphoma. Patients 1993 Preliminary European Community (EC) diagnos-
with SS produce a variety of circulating autoantibodies, tic criteria, the prevalence of pSS was estimated to be
but no combination of these has yet been established as high as 1% to 2% of the general population. However,
as a satisfactory classification criterion for pSS, which more recent prevalence estimates of pSS range from
requires multisystem diagnostic tests. Treatment of SS 0.1% to 0.6%, based on the 2002 AmericanEuropean
requires effective management of both ocular and oral Consensus criteria for pSS (1). There are traditional
secretory dysfunction, the prevention or treatment of estimates that about 50% of patients with SS have the
disease sequelae, and therapy for any extraglandular secondary form of the disease (sSS) and, in rheuma-
conditions that occur. There is currently no single treat- tology clinics, approximately 25% of patients with
389
390 TROY DANIELS
rheumatoid arthritis (RA) or systemic lupus erythema- and most patients with pSS do not have serological evi-
tosus (SLE) have objective evidence of sSS. dence of HCV infection. A recent multicenter study
concluded that HCV infection should be considered as
a cofactor in the development of a subset of patients
ETIOLOGY with SS (4). The true relationship between HCV and SS
(or a subset of SS patients), if any, requires further
The etiology of SS, also called autoimmune exocrinopa- definition.
thy, remains unknown. There is evidence of both genetic
and nongenetic contributions. Families have been
reported in which there is clustering of SS with other IMMUNOPATHOLOGY
autoimmune diseases. There are also reports of similar-
ity of specific SS phenotypes among affected twin pairs. Histopathology
Various associations between specific class II human
leukocyte antigen (HLA)-DR and -DQ alleles, haplo- Minor salivary glands and lacrimal glands in SS exhibit
types, and patients with SS have been found, but regional a particular pattern of periductal focal lymphocytic infil-
and racial differences occur. More recently, the associa- tration in otherwise normal-appearing glands. The
tion between HLA and SS was found to be restricted to severity of this inflammation, called focal lymphocytic
those patients with circulating anti-SS-A and/or -SS-B sialadenitis, can be estimated by a semiquantitative
antibodies, while no such association was apparent in SS focus score (described below), which correlates with
patients without those antibodies (2). the diagnosis and severity of keratoconjunctivitis sicca
For many years, the possibility that a virus partici- (5). This pattern must be distinguished from other com-
pates in the pathogenesis of SS has been considered, monly occurring patterns of chronic inflammation that
either in the context of an infectious agent inducing are not associated with SS.
chronic inflammation, a source of exogenous antigen
that triggers autoimmunity, or a molecular mimic of the Cellular Immunopathology
candidate autoantigen. Viruses that have been consid-
ered include EpsteinBarr virus (EBV), Coxsackie The earliest lymphocytic infiltrates in salivary glands are
virus, human immunodeficiency virus (HIV), and hepa- composed of T cellsmostly of the CD45RO primed
titis C virus (HCV). The DNA of EBV, a highly preva- memory T-helper phenotypeand CD20+ B cells. Later,
lent virus latent in the majority of humans, has been CD27+ (memory) and CD79a+ B cells join the infil-
identified in major and minor salivary glands. Latent trates. Clusters of CD38+ plasma cells are present in
EBV may serve as a cofactor in SS by contributing to normal salivary glands and at the periphery of T/B-cell
chronic inflammation in salivary glands, but an etiologic infiltrates in SS (6). These infiltrates also may exhibit
role for this virus has not been established. RNA lymphoid follicle formation in various stages of devel-
from Coxsackie virus B4 was found in minor salivary opment, including mostly CD20+ B cells and CD21+
glands from pSS patients, but not from sSS patients and follicular dendritic cells with a few CD4+ helper T cells,
controls (3). This suggestion of an environmental trigger and immunoglobulin deposits (7).
role for Coxsackie virus in pSS has not been T-helper (Th) cell infiltrates in SS elaborate both Th1
confirmed. and Th2 cytokines. Th2 cytokines [interleukin (IL)-4, -5,
Because HIV-infected adult patients occasionally and -13] predominate in early stages of SS, but shift
present with mild salivary hypofunction, bilateral towards a Th1 profile (interferon gamma and IL-2) in
parotid enlargement, and focal lymphocytic infiltrates in patients with more advanced disease (8). A newly iden-
minor salivary glands, HIV and other retroviruses have tified B-cell activating factor (BAFF; also known as B
been theorized to have pathogenic roles in some cases lymphocyte stimulator, BLyS) promotes the survival
of SS. In contrast to primary SS, however, salivary infil- and maturation of B cells. BAFF regulated by interferon
trates in patients with HIV are composed of CD8+ lym- gamma, is implicated in polyclonal activation of B cells.
phocytes, not memory CD4+ T cells and B cells (see BAFF levels are elevated in SS serum, correlate with
below). Further, recent clinical trials of antiretroviral the levels of circulating autoantibodies (9), and may
drugs in pSS patients did not show any significant have a long-term role in development of lymphoma.
changes in either the clinical or histopathological fea-
tures of SS.
Because some HCV-infected patients develop clini-
Autoantibodies
cal features similar to SS, an association of HCV with Most patients with SS develop increased circulating
SS has been considered since the early 1990s. The SS- polyclonal immunoglobulins and autoantibodies. These
like clinical and immunological profiles of HCV patients autoantibodies include the highly nonspecific rheuma-
are different from those of patients with pSS, however, toid factor and antinuclear antibodies, and the more
C H A P T E R 2 0 S J G R E N S S Y N D R O M E 39 1
specific anti-Ro (SS-A) and anti-La (SS-B) antibodies, TABLE 20-1. DRY EYE SYMPTOMSDIFFERENTIAL
which are more highly associated with pSS and SLE. DIAGNOSIS.
The roles of anti-Ro and anti-La antibodies in the
Sjgrens syndrome (keratoconjunctivitis sicca)
pathogenesis of pSS itself remain unclear. In women
who are pregnant, anti-Ro and anti-La antibodies Conjunctival cicatrization:
may lead to particular pregnancy complications: after StevensJohnson syndrome
Ocular cicatricial pemphigoid
the 20th week of gestation, these antibodies may cross
Drug-induced pseudopemphigoid
the placenta can cause inflammation within the conduc- Trachoma
tion system of the fetal heart, leading in 1% to 2% of Graft-vs.-host disease
cases to congenital heart block. The likelihood of con-
Anticholinergic drug effects
genital heart block is higher in fetuses of women who
have previously given birth to children with heart AIDS-associated keratoconjunctivitis sicca
block.
Trigeminal or facial nerve paralysis
Antibodies against alpha-fodrin, a protein in the
cytoskeleton of most eukaryotic cells, are more preva- Vitamin A deficiency (xerophthalmia)
lent than anti-Ro. Antifodrin antibodies are present
in almost all pSS patients diagnosed by the San Diego SOURCE: Whitcher J, Gritz D, Daniels T. Int Ophthalmal Clin 1998;38:2337,
by permission of International Ophthalmology Clinics.
diagnostic criteria (the most restrictive set), but are ABBREVIATION: AIDS, acquired immunodecifiency syndrome.
found in fewer patients diagnosed by the EC criteria.
Antifodrin antibodies have been proposed as a specific
diagnostic marker for pSS, but this remains
controversial. Clinical signs of KCS, best observed at the slit lamp,
Antibodies against the M3 muscarinic acetylcholine include scanty or absent tear meniscus, decreased tear
receptor (M3R) have been identified in sera from breakup time, and characteristic staining of the cornea
patients with pSS. A possible role of anti-M3R in with fluorescein and conjunctiva with lissamine green.
decreasing lacrimal and salivary secretions was sup- Fluorescein dye provides the basis for measuring tear
ported by experiments showing that pSS sera inhibit breakup time, which assesses stability of the tear film
aquaporin AQP-5 (a transmembrane protein affecting and reveals corneal changes by the location and pattern
water transport in acinar cells) (10). The effects of anti- of its staining. Lissamine green or rose bengal dyes can
M3R on the receptor remain unclear, but in theory assess surface changes to the air-exposed conjunctiva,
slowed gastric emptying and decreased bladder muscle which are characteristic of KCS (Figure 20-1) (11). The
contractility seen in pSS patients may relate at least in use of lissamine green is preferred oral rose bengal,
part to the effects of this antibody. however, because rose bengal staining is painful to the
patient in direct proportion to the severity of their
KCS. 20
CLINICAL FEATURES The quantity of tear production can be estimated
with an unanesthetized Schirmer test (Schirmer I test)
AND ASSESSMENT using sterile filter paper strips. Results of 5 mm in 5
minutes indicate abnormal tear production; however,
Ocular such a result is not specific to KCS and can be caused
The ocular component of SS, called keratoconjunctivitis by other unrelated conditions.
sicca (KCS), was first described by Henrik Sjgren in
1933. KCS causes a prolonged but slowly progressive
decrease in tear production and qualitative changes in
OralSalivary
the tear film, leading to decreased tear film stability. The salivary and oral components of SS are character-
This, in turn, causes repeated dehydration of the ocular ized by decreased saliva production and qualitative
surface epithelium and ultimately results in keratiniza- changes in the saliva and oral flora, called salivary hypo-
tion. Bacterial infection, usually by Staphylococcus function or dysfunction. Early in the course of SS, most
aureus, is an occasional result of KCS. The most charac- patients complain of symptoms of dry mouth (xerosto-
teristic symptoms of KCS are insidious onset of ocular mia; Table 20-2). Others complain of difficulty chewing
foreign body sensation, burning, pain, inability to tear, or swallowing food, difficulty wearing a lower denture,
or photophobia (Table 20-1). However, some patients or oral burning symptoms (usually associated with
with KCS are asymptomatic. The term xerophthalmia is chronic candidiasis). The onset of these symptoms is
occasionally, but inappropriately, used for SS because usually insidious. However, some patients with signifi-
the term refers to the ocular manifestations of vitamin cant signs of salivary dysfunction do not complain of
A deficiency, which are not the same as KCS. oral symptoms. The late stages of this salivary change in
392 TROY DANIELS
FIGURE 20-1
Lissamine green staining (arrows) of air-exposed conjunctiva, lateral to the cornea, in patients
with mild (left) and severe (right) keratoconjunctivitis sicca. (Courtesy of Dr. K. Kitagawa.)
SS are similar to those experienced by patients undergo- About 20% to 30% of pSS patients experience pro-
ing radiation therapy to the head and neck for an oro- longed bilateral enlargement of the parotid or subman-
pharyngeal cancer. dibular glands, which are usually firm and nontender to
The clinical signs of salivary dysfunction in SS include palpation (Table 20-3). When examined by biopsy, these
a reduced or absent salivary pool in the mouth floor, tumors are usually diagnosed as lymphoepithelial lesion
reduced mucosal lubrication, and a particular pattern of (or lymphoepithelial sialadenitis), which is a benign
progressive dental decay. Dental caries in SS are located reactive process. However, these chronic tumors may
on the necks of teeth (next to the gingiva), the incisal transform into MALT (mucosa-associated lymphoid
edges of the anterior teeth, or the cusp tips of posterior tissue) lymphomas, which are usually indolent for many
teeth, patterns unusual for common diet-associated years but may later give rise to rapidly growing high-
caries. Thickened or cloudy-appearing saliva may be grade, large-cell lymphomas.
expressible from the parotid or submandibular ducts.
About one third of SS patients develop signs of chronic
erythematous candidiasis (i.e., loss of filiform papillae
from the dorsal tongue and symmetrical areas of mucosal
erythema, with or without angular cheilitis; Figure
20-2).
TABLE 20-2. DRY MOUTH SYMPTOMS

DIFFERENTIAL DIAGNOSIS.
Chronically administered drugs (e.g., antidepressants,
parasympatholytics, neuroleptics)
Sjgrens syndromea
Sarcoidosis,a tuberculosis
HIVa or hepatitis C infection
Uncontrolled diabetes
FIGURE 20-2
Amyloidosis
Chronic erythematous candidiasis in a 64-year-old woman,
Therapeutic radiation to head and neck before (left) and after (right) treatment with an antifungal drug,
accompanied by significant improvement in oral symptoms. The
Graft-vs.-host disease dorsal tongue (left) illustrates characteristic features: atrophy of
filiform papillae, erythema, and fissuring, accompanied by
ABBREVIATION: HIV, human immunodeficiency virus. intraoral areas of symmetrically distributed mucosal erythema
a
May also cause bilateral major salivary gland enlargement. and by angular cheilitis.
TABLE 20-3. BILATERAL SALIVARY GLAND tenderness or swelling in multiple peripheral joints.
ENLARGEMENTDIFFERENTIAL DIAGNOSIS. Raynauds phenomenon was noted in 13% to 62% of
patients.
Sjgrens syndromea (lymphoepithelial lesion)
Autoimmune thyroiditis was identified in 10% to
Viral infections (mumps, CMV, HIV,a Coxsackie) 24% of pSS patients, usually in the form of Hashimotos
Granulomatous diseasesa (e.g., sarcoidosis)
thyroiditis, characterized by goiter and the presence of
antithyroglobulin antibodies. SS patients with thyroid
Sialadenosisb (associated with diabetes mellitus, acromegaly, disease are usually hypothyroid or euthyroid, and only
gonadal hypofunction, hyperlipoproteinemia, hepatic cirrhosis, rarely hyperthyroid.
anorexia/bulimia, or pancreatitis)
Renal involvement, usually in the form of distal renal
Recurrent parotitis of childhood tubular acidosis (dRTA), has been reported in 5% to
33% of pSS patients. Risk factors for the development
ABBREVIATIONS: CMV, cytomeglovirus; HIV, human immunodeficiency virus. of dRTA include high levels of serum gamma globulin
a
Associated with chronic salivary hypofunction.
b
Affects parotid glands only; symmetrical enlargement that is soft and and beta 2 microglobulin. Glomerulonephritis occurs
nontender to palpation; no symptoms or signs of salivary hypofunction; uncommonly in pSS.
diagnosis by clinical presentation; biopsy unnecessary. Hepatic disease, usually in the form of autoimmune
hepatitis or primary biliary cirrhosis, has been identified
in 2% to 4% of pSS patients. In a recent study of pSS
The most disease-specific assessment of the salivary patients selected for liver biopsy, 47% had autoimmune
component of SS is from a labial salivary gland (LSG) hepatitis, 35% primary biliary cirrhosis, and 18% non-
biopsy. This office procedure consists of local anesthetic specific chronic or acute hepatitis (14).
infiltration, a 1.5 to 2.0 cm incision just through the Symptoms of peripheral nerve dysfunction, such as
lower lip mucosal epithelium, and careful dissection of paresthesias, numbness, or motor defects of the upper
4 or 5 minor salivary glands, one at a time, from the or lower limbs, have been reported in 2% to 38% of
subepithelial connective tissue (12). A LSG biopsy is pSS patients. Central nervous system disease was
not necessary for patients who have objective evidence reported in some patients with pSS, but it has not been
of KCS and serum anti-Ro or anti-La antibodies. In established whether this occurs at a higher rate than in
patients with KCS and signs of salivary hypofunction the general population.
who lack serum anti-Ro/La antibodies, however, a LSG Pulmonary disease, reported in 7% to 35% of pSS
biopsy demonstrating focal lymphocytic sialadenitis and patients, may include persistent cough and/or dyspnea
a focus score 1 focus/4 mm2 is required for the diagno- with chronic diffuse interstitial infiltrates, a restrictive
sis of pSS. pattern on pulmonary function studies, and evidence of
Salivary function is assessed most easily by measur- pulmonary alveolitis or fibrosis.
ing whole unstimulated salivary flow for 5 to 10 minutes. Cutaneous vasculitis occurs in 9% to 32% of pSS
This can also be accomplished by sequential salivary patients. This usually takes the form of palpable purpura, 20
scintigraphy, but at greater expense. Functional assess- urticarial lesions, or erythematous maculopapules. On
ments of salivary flow can quantify patients salivary biopsy, most lesions are shown to involve only small-
production as a severity measure or an assessment of sized blood vessels with a leucocytoclastic vasculitis
disease progress. Various means of imaging salivary (albeit lymphocytes sometimes predominate, as well).
glands (e.g., contrast sialography, magnetic resonance Involvement of medium-sized blood vessels in pSS-
imaging, ultrasound, or combinations of those) have associated cutaneous vasculitis is unusual (15).
been proposed to diagnose the salivary component of Patients with pSS have a substantially higher risk of
SS, but do not assess function and are not yet suffi- developing non-Hodgkins lymphoma than the general
ciently disease-specific to replace LSG biopsy. population. Patients undergoing malignant transforma-
tion of their disease may exhibit monoclonal immuno-
globulins and/or loss or reduction of circulating
Extraglandular autoantibodies. Tumors, which may occur in the salivary
Symptoms and signs of various diseases and conditions glands, gastrointestinal tract, or lungs, often begin as B-
affecting other organ systems are observed in patients cell MALT lymphomas, or in lymph nodes as marginal
with pSS at higher rates than in the general population. zone lymphomas. Over time, either of these indolent
Many of these conditions also have autoimmune mech- tumors can progress to rapidly growing, high-grade
anisms. The following descriptions of extraglandular large-cell lymphomas. Risk factors for development of
conditions associated with pSS are derived from the lymphoma include hypocomplementemia, particularly
comparisons of 10 pSS cohorts (13). low C4 levels, presence of palpable purpura, and
Arthralgias or signs of arthritis have been noted in prolonged salivary gland enlargement. Meta-analysis
25% to 85% of pSS patients, usually in the form of of five cohort studies, including a total of 1,300 pSS cases
394 TROY DANIELS
in which lymphoma had developed, found a pooled stan- TABLE 20-4. AMERICANEUROPEAN CONSENSUS
dardized incidence rate of 18.8 (16). GROUP CLASSIFICATION CRITERIA FOR SJGRENS
SYNDROME.
Laboratory Features I. Ocular symptoms: a positive response to at least one of the

following questions:
Sjgrens syndrome patients often exhibit polyclonal 1. Have you had daily, persistent, troublesome dry eyes for
increases in serum immunoglobulins and a variety of more than 3 months?
2. Do you have a recurrent sensation of sand or gravel in the
autoantibodies, consistent with chronic B-cell activa-
eyes?
tion. The erythrocyte sedimentation rate is increased in 3. Do you use tear substitutes more than 3 times a day?
SS, usually in proportion to increased gamma globulins.
In a multicenter report of 400 pSS patients diagnosed II. Oral symptoms: a positive response to at least one of the
following questions:
according to the European Community Preliminary
1. Have you had a daily feeling of dry mouth for more than
Criteria (1993), serology identified anti-Ro antibodies 3 months?
in 40%, anti-La antibodies in 26%, antinuclear antibod- 2. Have you had recurrently or persistently swollen salivary
ies in 74%, and rheumatoid factor in 38% (13). Hema- glands as an adult?
tological abnormalities (anemia, 20%), leukopenia 3. Do you frequently drink liquids to aid in swallowing dry
food?
(16%), and thromombocytopenia (13%) were also
present in sizeable portions of the cohort (17). In pSS III. Ocular signs: a positive result for at least one of the follow-
patients diagnosed using the recent AmericanEuro- ing two tests:
pean Consensus Criteria, hypocomplementemia was 1. Schirmer I test, performed without anesthesia 5 mm in 5
minutes)
detected in 24%, including low levels of C3, C4, and/or 2. Rose bengala score or other ocular dye score (4 on the
CH50 activity (18). van Bijstervled scale)
IV. Histopathology: In minor salivary glands (obtained through

normal-appearing mucosa) focal lymphocytic sialadenitis,
DIAGNOSIS evaluated by an expert histopathologist, with a focus score
1, defined as a number of lymphocytic foci (which are
Diagnosing pSS is more difficult than sSS because adjacent to normal-appearing mucous acini and contain
patients usually present with the three most common more than 50 lymphocytes) per 4 mm2 of glandular tissue.
symptoms (dry eyes, dry mouth, and musculoskeletal V. Salivary gland involvement: a positive result for at least one
pain) to different specialists. Furthermore, patients of the following tests:
developing pSS are more likely not to be receiving 1. Unstimulated whole salivary flow 1.5 mL in 15 minutes)
regular medical attention during their gradual symptom 2. Parotid sialography showing the presence of diffuse
onset, in contrast to patients with underlying connective sialectasis (punctate, cavitary, or destructive pattern),
without evidence of major duct obstruction
tissue disorders, who normally are in periodic contact 3. Salivary scintigraphy showing delayed uptake, reduced
with a rheumatologist when SS symptoms develop. Each concentration, and/or delayed excretion of tracer
pSS symptom has its own differential diagnosis, and a
specialist dealing with one SS complaint may not be VI. Autoantibodies: presence in the serum of the following:
1. Antibodies to Ro(SS-A) or La(SS-B) antigens, or both
familiar with common considerations relating to the
others. When a patient has any of these symptoms, SS Rules for Classification
must be considered along with the probability that other For primary SS: In patients without any potentially associated
disease
organ systems are involved. Regardless of which special-
a. Presence of any 4 of the 6 items indicates pSS as long as
ist patient sees the patient first, interdisciplinary consul- either item IV (histopathology) or VI (serology) is positive
tation early in the course of the disease is appropriate. b. Presence of any 3 of the 4 objective criteria items (i.e.,
Unfortunately, delay in diagnosis and failure to appreci- items III, IV, V, VI)
ate the full extent of patients organ involvement remains c. The classification tree procedure (best used in clinical
epidemiological surveys)
the rule. A survey of more than 3000 SS patients reported
For secondary SS: patients with a potentially associated disease
that the average time between occurrence of their first (e.g., another well-defined connective tissue disease), the presence
symptoms and diagnosis of SS was 6.5 years (19). of item I or item II plus any 2 from among items III, IV and V.
Exclusion criteria: Past head and neck radiation treatment;

Classification/Diagnostic Criteria hepatitis C infection; acquired immunodeficiency syndrome
(AIDS); preexisting lymphoma; sarcoidosis; graft-vs.-host disease;
Since 1965, at least 10 diagnostic/classification criteria use of anticholinergic drugs (since a time shorter than fourfold
have been proposed for SS. Each uses different combi- the half-life of the drug)
nations of tests, therefore diagnosing different numbers
SOURCE: From Vitali C, Bombardieri, Jonsson R, et al. Ann Rheum Dis
of patients who have different clinical features. For
2002;61:544558, by permission of Annals of the Rheumatic Diseases.
example, the least restrictive (and most widely used) a
Rose bengal has now been replaced by lissamine green for this test.
criteriathe European Community Preliminary Crite- pattern of dental caries (described above) in direct pro-
ria (20)diagnose pSS in about five times as many portion to the severity of their hypofunction. Appropri-
patients as the most restrictive criteria (21). Subsequent ate dental care is therefore essential. The dentist must
analysis of the European Community Preliminary Cri- treat and prevent this pattern of caries in its early stages
teria has led to several revisions, the most current of because once it begins to progress, arresting the process
which are the AmericanEuropean Consensus Group is extremely difficult. Loss of the affected tooth is the
Classification Criteria (Table 20-4) (22). common result. When many teeth are affected concur-
rently, the results can be devastating because, among
other negative outcomes, patients with severe salivary
TREATMENT hypofunction are often unable to wear a lower denture.
To prevent further dental caries, the dentist will include
No cure for SS is available and no single treatment dietary control of sucrose, personal and professional
modality addresses the diverse symptoms of SS. oral hygiene procedures, regular topical fluoride appli-
However, a number of medications provide symptom cations in proportion to the patients risk for decay (e.g.,
relief and help prevent complications of many individ- fluoride mouth rinse, home applications of fluoride gel
ual organ system manifestations of SS. Treatment in custom fitted trays, office applications of fluoride
requires separately managing the ocular and oral secre- varnish), and control of oral flora that are particularly
tory dysfunction, preventing or treating their sequelae, cariogenic through focused antibiotic therapy.
and treating extraglandular conditions as they occur. Reducing oral symptoms and improving oral func-
Rheumatologists must develop and maintain therapeu- tion are often managed by the attending physician
tic collaborations with other specialists in caring for through increasing salivary secretion, selective use of
patients with pSS or sSS. saliva substitutes, and monitoring patients systemic
drugs to eliminate, if possible, those with significant anti-
cholinergic effects.
Ocular
The treatment provided by ophthalmologists for patients Patients with mild salivary dysfunction may benefit
with SS expands with increasing severity of the patients from regular gustatory stimulation with sugar-free
KCS. Primary ocular treatment for all patients with lozenges. For other patients, prescription of cevime-
KCS includes the use of preservative-free artificial tears line (30 mg t.i.d.) or pilocarpine (5 mg t.i.d. or q.i.d.)
during the day and preservative-free ointments at night. should be considered. The side-effect profiles of these
The selection of these and their frequency of use should drugs are usually mild.
be established by the ophthalmologist. Frequent sips of water are helpful, but if too frequent
For patients with advanced disease, the ophthalmolo- can reduce the mucus film in the mouth and actually
gist may consider occlusion of the lacrimal puncta. The increase symptoms. If water consumption continues
performance of this procedure should be withheld until up to bedtime, it may initiate a pattern of sleep dis- 20
a patients tear production has become sufficiently low ruption from nocturia.
that the patient will not experience tearing after closure Saliva substitutes (particularly a glycerate polymer
of the puncta. Systemic cholinergic drugs, such as pilo- preparation) can be helpful for patients with moder-
carpine (5 mg t.i.d. to q.i.d.) or cevimeline (30 mg t.i.d.) ate-to-severe dysfunction, mainly when awakening at
may provide supplemental benefit but do not serve as night, by using a small amount of substitute, in lieu
primary treatment. The intermittent use of topical anti- of water when awakening from sleep, to reduce oral
biotics for intermittent bacterial infections, topical symptoms and prevent nocturia. Current saliva sub-
mucolytic agents, and autologous serum eye drops may stitutes are seldom helpful for patients with only mild
be useful on an as-needed basis. Weak solutions of dysfunction.
cyclosporine (0.05%) have had mixed results in reliev-
ing patient discomfort in severe cases of KCS. About one third of patients with chronic salivary
dysfunction develop chronic erythematous candidiasis,
as described above. In such patients, who have observ-
Oral able saliva production (i.e., by noting pooled saliva in
The oral treatment for patients with SS includes the mouth floor or examining the parotid or subman-
treating and preventing dental caries, reducing oral dibular duct orifice while applying gentle pressure to the
symptoms, improving oral function, and diagnosing and corresponding gland), fluconazole (100 mg q.d.) can be
treating oral sequelae, such as chronic erythematous prescribed for 2 to 4 weeks. The treatment endpoint is
candidiasis. resolution of mucosal erythema, return of filiform papil-
Patients with chronic salivary hypofunction from SS, lae on the dorsal tongue, and resolution of any oral
or from any other cause, are susceptible to a particular mucosal burning symptoms. In those patients with
396 TROY DANIELS
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terase levels in saliva from pSS patients (which may sicca. Analysis of 618 patients with suspected Sjgrens
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chapter. and healthy subjects. Scand J Immunol 2005;61:98107.
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10. Li J, Ha Y, Ku N, et al. Inhibitory effects of autoantibod-
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described risk factors for developing lymphoma, there drome. Assessment as a diagnostic criterion in 362 cases.
is higher mortality. Lymphoma development in SS is Arthritis Rheumatol 1984;27:147156.
relatively uncommon but as noted occurs at a much 13. Garcia-Carrasco M, Ramos-Casals M, Rosas J, et al.
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ity rate of patients with sSS would be the same as disease patterns in a cohort of 400 patients. Medicine
2002;81:270280.
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340347.
20
CHAPTER 21
Vasculitides
A. Giant Cell Arteritis, Polymyalgia
Rheumatica, and Takayasus
Arteritis
CORNELIA M. WEYAND, MD
JRG J. GORONZY, MD
Giant cell arteritis (GCA) and Takayasus arteritis (TA) accompanied or preceded by a systemic inflamma-
are prototypes of large vessel vasculitis, tending to tory process.
involve the aorta and its branches. Visual loss is the most feared complication of GCA.
Giant cell arteritis predominantly affects the second- Visual loss may occur through the syndrome of
to fifth-order aortic branches, often in the extracranial anterior ischemic optic neuropathy, caused by
arteries of the head. narrowing of the posterior ciliary artery and other
Giant cell arteritis occurs exclusively among individu- vessels to the eye.
als who are 50 years of age or older. The mean age The diagnosis of GCA is made usually by biopsy of
at diagnosis onset is approximately 72. the temporal artery.
In TA, the aorta and its major branches are the prime Polymyalgia rheumatica (PMR), a syndrome of muscle
disease targets. pain and stiffness in the neck, shoulders, and hips,
Both GCA and TA are associated with granulomatous often occurs with GCA but can occur independently.
inflammation within the blood vessel wall. Glucocorticoids are the cornerstone of treatment for
In both GCA and TA, clinical symptoms of vascular GCA, TA, and PMR. Isolated PMR requires a lower
inflammation and vascular insufficiency are usually dose of prednisone for disease control.
Despite the spatial closeness of blood vessels and rheumatica (PMR), a syndrome of muscle pain and
inflammatory cells, blood vessel walls are infrequently stiffness in the neck, shoulders, and hips. PMR can
targeted by inflammation. Giant cell arteritis (GCA) accompany, precede, or follow GCA, but it also occurs
and Takayasus arteritis (TA) are characterized by independently. In a subset of PMR patients, GCA is
inflammation directed against the vessel wall. GCA and present but not clinically evident.
TA display stringent tissue tropism and affect defined
vascular territories in a preferential manner. GCA pre-
dominantly affects the second- to fifth-order aortic
branches, often in the extracranial arteries of the head.
GIANT CELL ARTERITIS
The aorta itself may also be affected in GCA, albeit less
often than other regions. In contrast, in TA, the aorta
Epidemiology
and its major branches are the prime disease targets. Giant cell arteritis is the most common primary form of
In both GCA and TA, clinical symptoms of vascular vasculitis among adults in the United States and Europe.
inflammation and vascular insufficiency are usually The disease occurs almost exclusively in individuals
accompanied or preceded by a systemic inflammatory aged 50 years and older, and its incidence increases
process not localizable to a single tissue or organ. Sys- progressively with age (1). Women are more likely to be
temic inflammation is also characteristic of polymyalgia affected than men. The prevalence is highest in Scandi-
398
C H A P T E R 2 1 V A S C U L I T I D E S 39 9
navian countries and in regions settled by people of the intima becomes hyperplastic, compromising or
Northern European descent, with incidence rates reach- occluding the arterial lumen. Although the vessel lumen
ing 15 to 25 cases per 100,000 persons aged 50 years and may become critically narrowed, thrombosis is not the
older. GCA occurs much less frequently in Southern central event. Hyperplasia of the intimal layer with scar-
Europeans (6 cases per 100,000 individuals) and is ring in the media and fragmentation of the elastic lamina
rare in blacks and Hispanics (12 cases per 100,000 are irreversible changes that persist beyond the stages
individuals). of active arterial inflammation.
Fibrinoid necrosis is rare and should raise the suspi-
cion for other forms of vasculitis. Polyarteritis nodosa,
The Vasculitic Lesion microscopic polyangiitis, and Wegeners granulomatosis,
The histological hallmark of GCA is a mononuclear cell for example, are known to affect the temporal artery as
infiltrate dominated by T lymphocytes and macrophages. well as other more typical vascular beds. When these
The inflammatory infiltrate penetrates all layers of the forms of vasculitis affect the temporal artery, their first
arterial wall (Figure 21A-1). The infiltrates can be gran- pathological manifestations may be lymphoplasmacytic
ulomatous with the accumulation of histiocytes and infiltrates within the adventitia, indistinguishable at an
multinucleated giant cells. Granuloma formation is most early stage from GCA.
likely to be observed in the media. Although the pres-
ence of multinucleated giant cells inspired the name of
the disease, they are often absent, and the mononuclear Pathogenesis
infiltrates lack a complex organization. If present, giant
The Immune Response in the Arterial Wall
cells lie in close proximity to the fragmented internal
elastic lamina. Their presence correlates with increased Experimental evidence supports a T-cellmediated
risk for ischemic complications. GCA can also present immunopathology of GCA (2). Humoral immunity does
with perivascular cuffing of vasa vasorum or T cellmac- not appear to be important: B cells are not found within
rophage infiltrates in the adventitia, sometimes arranged the arterial wall; no pathognomic antibodies have been
along the external elastic lamina. This finding is consis- identified; and hypergammaglobulinemia is absent. T
tent with recent studies suggesting that the adventitia is cells enter the vessel wall from the vasa vasorum in the
a critical site in the disease process. adventitia, not from the macroendothelium. Recruit-
The inflammation causes a series of structural changes ment and activation of tissue-invading T cells is con-
to the arterial wall. Among the first pathologic changes trolled by dendritic cells (DCs) in the adventitia. DCs
observed is the finding of a lymphoplasmacytic infiltrate are an indigenous cell population in normal medium-
in the adventitia. With progress of the inflammatory sized and large vessels. In the adventitia, they are typi-
process, the media of the arterial wall becomes thinner. cally localized at the outside of the external elastic
As the medial smooth muscle cell layer loses thickness, lamina, close to the adventitiamedia junction. Evi-
dence suggests that these vascular DCs utilize Toll-like
receptors (TLRs) to scan their environment for signs of
infection, specifically for pathogen-related molecules.
In GCA and PMR, such adventitial DCs are strongly
activated, produce chemokines, and express T-cell stim- 21
ulatory ligands. This model is supported by experiments
in human artery mouse chimeras. In these experiments,
human temporal arteries from GCA patients are
implanted into severe combined immunodeficiency
mice. Depletion of either T cells or DCs from the
implanted vascular lesions terminates the inflammatory
response, with subsequent clearing of the inflammatory
infiltrate. In contrast, administration of TLR ligands to
chimeras implanted with normal temporal arteries fol-
lowed by the adoptive transfer of T cells is sufficient to
induce the initial steps of vasculitis (3).
Based on these studies, it has been proposed that the
FIGURE 21A-1 vessel wall, in its physiologic state, is an immunoprivi-
leged site. In GCA, activation of vascular DCs by micro-
Histomorphology of giant cell arteritis. A typical temporal artery
biopsy specimen is shown. Characteristic changes include a bial products can break this immunoprivilege and lead
panmural mononuclear infiltrate, destruction of the internal and to the recruitment and stimulation of T cells. The nature
external elastic laminae, and concentric intimal hyperplasia. of the peptide antigens recognized by these T cells is
400 CORNELIA M. WEYAND AND JRG J. GORONZY
undetermined, but it may be that common self-antigens active secretory cells, producing molecular mediators
are sufficiently immunogenic when DCs are activated. relevant in structurally changing the arterial wall. The
Macrophage function in GCA is known to be multi- presence of giant cells in GCA corresponds with the
faceted, with specific commitments of these cells linked presence of high adventitial levels of IFN-gamma (6).
closely to their topographical arrangements within the
cell wall (4). Interferon (IFN) gamma, a T-cell cytokine, The Artery Is an Active Collaborator
regulates both macrophages and giant cells. Macro-
in Arteritis
phages in the adventitia, intermingling with activated T
cells, produce interleukin (IL)-1, IL-6, and transforming The assumption that all pathogenic mechanisms in
growth factor (TGF) beta. Macrophages in the medial inflamed arteries are mediated by tissue-infiltrating
layer are specialized in the production of metallopro- immune cells is simplistic. T cells and macrophages in
teinases, and also contribute to oxidative damage. End the arterial wall do not live and function in isolation,
products of lipid peroxidation, a cell injury mechanism but rather closely interact with stromal components of
driven by oxygen radicals, are typically found on medial the blood vessel in a bidirectional pattern (7). The major
smooth muscle cells (5). Macrophages recruited to the vascular abnormality leading to clinical disease is a non-
intimal layer are committed to the production of nitric thrombotic luminal occlusion, caused by rapid and con-
oxide synthase-2. Nitric oxide is suspected to be involved centric growth of the intima. These structural alterations
in tissue injury, cellular activation, and vascular remod- result from the response to injury elicited in arterial
eling. Multinucleated giant cells, once assumed to func- cells (Figure 21A-2). Intimal hyperplasia is generated
tion in the removal of indigestible debris, are actually by the mobilization of smooth muscle cells, their directed
FIGURE 21A-2
Schematic diagram of the sequence of pathogenetic events in giant cell arteritis. (1) Mononuclear
cells enter the adventitia via the vasa vasorum, where T cells recognize antigens and produce
IFN-gamma. (2) The infiltrate advances to the media, where macrophages and giant cells
undergo differentiation and exert tissue-injurious effector functions. (3) The artery responds with
neoangiogenesis and intimal hyperplasia.
migration towards the lumen, and their proliferation are associated with increased disease risk. Several allelic
and matrix deposition. This process is under the control variants of HLA-DR4 are enriched among patients.
of growth factors. Platelet-derived growth factor Selective binding of antigenic peptides has been pro-
(PDGF), a factor with the capability of supporting the posed as the mechanism underlying this genetic associa-
outgrowth of the hyperplastic intima, is present in tion. In contrast to other HLA-DR4associated diseases
inflamed arteries. PDGF derives from macrophages and such as rheumatoid arthritis, HLA polymorphisms do
multinucleated giant cells. Patients with low PDGF pro- not correlate with clinical phenotypes and disease sever-
duction have no or minimal lumen-occlusive intimal ity. Many other genetic risk factors have been suggested,
proliferation. In contrast, those with excessive PDGF but none have been proven to date.
production are at a risk for ischemic complications (8).
A second pathway of the arterial injuryresponse
program relates to the formation of new capillaries. The
Clinical Features
media and intima of normal arteries are avascular, but The diagnostic category of GCA encompasses multiple
intense neoangiogenesis is induced in GCA (9). Vascu- variants (Figure 21A-3). Each of these subtypes has
lar endothelial growth factor (VEGF) is critical in characteristic clinical features (11); however, the clinical
driving the generation of neovessels in the media and manifestations of the different subtypes overlap sub-
intima. VEGF, like PDGF, originates from macrophages stantially, and none of the clinical symptoms is unique
and multinucleated giant cells. The arterial response for any one of the variants. Increased awareness of
pattern initiated by the production of PDGF and VEGF GCA, a growing population of individuals older than 50
leads to profound structural arterial abnormalities with years of age, and improvement in diagnostic procedures
subsequent stenosis and tissue ischemia, emphasizing (e.g., the availability of magnetic resonance angiogra-
that the immune system coerces the artery toward a phy to image the aorta and its branches) have led to
counterproductive pattern of reaction. However, the increased detection of cases formerly considered to be
inflammation also leads to the induction of protective atypical presentations.
response patterns that are aimed at healing and tissue Giant cell arteritis presents with two major symptom-
repair. An example is the upregulation of the enzyme, atic complexes, signs of vascular insufficiency resulting
aldose reductase (10), which metabolizes and detoxifies from impaired blood flow and signs of systemic inflam-
end products of oxidative damage. mation. In general, vascular changes are those of occlu-
sion; arterial wall dilatation only occurs when the aorta
is involved.
The Systemic Inflammatory Response
The activation of vascular DCs as an early step in the
Cranial Giant Cell Arteritis
pathogenesis of GCA has two major implications: (1)
Inflammation and immune activation are not limited to Giant cell arteritis, also known as temporal arteritis, has
vascular lesions; and (2) a systemic component of a predilection for involving the extracranial branches of
GCA is an independent dimension of the disease the carotid arteries. The temporal artery, which courses
process and not simply a spillover from vessel wall just below the skin over the temple region, is the vessel
inflammation. Further evidence for this systemic com- most amenable to biopsy. In 80% to 90% of patients,
ponent is the activation in GCA patients of circulating histopathology of vasculitis is detected in the extracra- 21
monocytes, which produce IL-1 and IL-6. Elevated nial arterial tree, most often in the superficial temporal
levels of IL-6, a potent inducer of acute phase responses, artery; the vertebral, ophthalmic, and posterior ciliary
are characteristic of GCA. In this model, GCA is a sys- arteries; and, less frequently, the internal and external
temic inflammatory disease, with vasculitis of medium carotid and central retinal arteries.
and large arteries as a consequence of the disease Patients complain of throbbing, sharp, or dull head-
process. aches that are usually severe enough to prompt clinical
evaluation. The headaches may or may not be associ-
ated with scalp tenderness. In classic cases, the patients
Risk Factors notice temporal tenderness when wearing glasses,
Age is the major risk factor for GCA. No other envi- grooming, or lying on a pillow. On physical examination,
ronmental risk factors, including a variety of infectious involved vessels may be thickened, tender, and nodular.
agents, have been demonstrated convincingly to play Pulses may be reduced or absent. Abnormalities are
important roles in this disease. The high incidence rates most frequent in the temporal arterial branches, but
of GCA in all geographical regions settled by people of they can also be detected in the occipital arteries or
Scandinavian ethnicity strongly suggest inherited risk other superficial scalp vessels. In one third of the patients
factors (1). The best available information is for human with biopsy-proven GCA, the temporal arteries are
leukocyte antigen (HLA) genes. HLA-DR4 haplotypes normal on physical examination.
FIGURE 21A-3
Clinical spectrum of the giant cell arteritis/

polymyalgia rheumatica syndrome.
Focal arteritic lesions in the ophthalmic artery being recognized and can be expected in 20% to 30%
produce the most feared complication of GCA: vision of patients. True intraparenchymal CNS vasculitis in
loss. The disease is an ophthalmological emergency, GCA is rare, but reported.
because prompt recognition and treatment can prevent Occult presentations of GCA are common. GCA is
blindness. Ischemia anywhere along the visual pathway the cause of fever of unknown origin in up to 15% of
can lead to visual loss, but anterior ischemic optic neu- elderly individuals, for example. Nonspecific symptoms
ropathy is the most common cause. Visual loss is sudden, of pain in the face, neck, or throat are other warning
painless, and usually permanent. Amaurosis fugax, signs of possible GCA. Chronic nonproductive cough
reported as fleeting visual blurring with heat or exercise can be an initial presentation of GCA. The involvement
or posture-related visual blurring and diplopia, may of cough receptors (present throughout the repiratory
precede partial or complete blindness. On ophthalmo- tree) by the vasculitic process is believed to be the cause
logic examination, anterior ischemic optic neuropathy of cough in GCA.
is recognized by optic disc edema, eventually followed
by sectoral or generalized optic atrophy with optic disc
cupping. Besides optic neuropathy, the spectrum of oph- Giant Cell Arteritis Manifesting as
thalmic complications is wide, ranging from pupillary
defects to orbital ischemia and from ocular motor is-
Fever of Unknown Origin
chemia to anterior and posterior segment ischemia. Symptoms related to systemic inflammation are fre-
A relatively disease-specific manifestation of GCA quently present. Laboratory abnormalities are detect-
that is present in about half of the patients is jaw clau- able in more than 90% of patients. In a subset of patients,
dication: pain in the masseter or temporalis muscles the disease process is dominated by a systemic inflam-
caused by compromised blood flow in the extracranial matory syndrome. Fever of unknown origin with spiking
branches of the carotid artery. Prolonged talking and temperatures and chills usually leads to diagnostic eval-
chewing produce pain in the muscles of mastication. The uations designed to exclude infections and malignan-
onset of jaw claudication following the initiation of cies. In less dramatic cases, malaise, anorexia, weight
chewing is surprisingly swift. Cases of trismus have been loss, low-grade fever, and fatigue eventually become
described. Claudication of the tongue is less frequent, severe enough to prompt medical attention. Physical
but tongue infarctions have been reported. Vaso- examination of the scalp arteries is often negative, and
occlusive disease of the carotid and vertebrobasilar symptoms of vascular insufficiency can be absent. Tem-
arteries results in ischemia of the central nervous system poral artery biopsy, even if the artery is normal on clini-
(CNS), manifesting as transient ischemic attacks or cal examination, remains the diagnostic procedure of
infarcts. Neurologic manifestations are increasingly choice.
Large Vessel Giant Cell Arteritis Even the most specific findings for history, physical
examination, and routine laboratory testing have sensi-
In at least 10% to 15% of patients, GCA involves the tivities of only (at best) 50%. In view of the fact that
large arteries in a clinically evident manner. (The per- rendering the diagnosis of GCA commits a patient to
centage of cases with subclinical large vessel disease long-term course of glucocorticoid therapy, confirma-
may be substantially higher.) Preferred vascular beds tion of the diagnosis by temporal artery biopsy is essen-
are the carotid, subclavian, and axillary arteries. Vascu- tial whenever possible. True negative results are expected
litis of the femoral arteries is infrequent. The major in more than 50% to 70% of all patients undergoing
clinical presentation is that of aortic arch syndrome, biopsies at most institutions. False-negative biopsies,
producing claudication of the arms, absent or asym- which occur as frequently as 10% of the time, can be
metrical pulses, paresthesias, and (rarely) symptoms of minimized by taking a sufficient length of biopsy, by
digital ischemia. Patients with the large vessel variant of examining serial sections, and by removing the contra-
GCA often lack evidence of cranial involvement; they lateral temporal artery when the first biopsy is free of
do not complain about headaches, have normal tempo- arteritis. Short-term glucocorticoid treatment (up to 2
ral arteries on examination, and almost 50% of tempo- weeks, or even significantly longer) is unlikely to inter-
ral artery biopsies are negative for vasculitis (12). fere with the results of a temporal artery biopsy. Pred-
Aortitis in GCA can coexist with cranial arteritis. nisone should therefore not be withheld if a biopsy
Whether the patient subset with subclavianaxillary cannot be performed immediately.
GCA is distinct from the subset progressing to aortic
involvement is not known. Overall, the risk of patients
with GCA to develop thoracic aortic aneurysm is Laboratory Testing
increased 17-fold (13). The elastic membranes support- A pathognomic laboratory test for GCA does not exist.
ing the aortic wall are destroyed and replaced by fibrotic Specific autoantibodies have not been identified. Highly
tissue. The resulting histopathology can be indistinguish- elevated acute phase responses are typical for GCA but
able from that of TA. Most cases of aortitis have been are not present in all patients. Although a high erythro-
diagnosed several years after the initial diagnosis of cyte sedimentation rate (ESR) is usually considered a
GCA, raising the possibility that smoldering aortitis is hallmark of GCA, in a recent study 25% of all patients
more common than previously expected (14). The spec- with positive temporal artery biopsies had normal ESRs
trum of clinical manifestations ranges from silent aneu- before the initiation of glucocorticoid therapy (16).
rysm to aortic dissection and fatal rupture. Other markers of acute phase response, particularly C-
reactive protein (CRP), may be more sensitive than
ESR in some patients, but studies have not demon-
Diagnosis strated this consistently. Some evidence indicates that
In 1990, the American College of Rheumatology (ACR) the most sensitive serum marker for ongoing systemic
formulated classification criteria for GCA. These crite- inflammation in GCA (both before and after glucocor-
ria, not intended for the purposes of establishing a clini- ticoid therapy) is IL-6. IL-6, a strong inducer of acute
cal diagnosis of GCA, are shown in Appendix I. phase reactants, probably functions upstream in the
The diagnosis of GCA should be considered in disease process. Unfortunately, reliable IL-6 measure-
patients aged 50 years and older with recent onset of ments are not widely available, and knowledge about 21
unexplained headache, signs of tissue ischemia in the how (or if) to adjust therapy in the context of changing
extracranial vascular territory, loss of vision, symptoms IL-6 levels remains incomplete. There is currently no
of limb or jaw claudication, or polymyalgia rheumatica. evidence that treatment decisions should be predicated
Laboratory evidence of an acute phase response height- upon the results of laboratory testsESR, CRP, or IL-
ens concern about GCA. The diagnostic procedure of 6in the absence of clinical symptoms.
choice is the histological verification with the superficial Other laboratory abnormalities in GCA include
temporal artery. In a recent meta-analysis, positive clini- mild-to-moderate normochromic or hypochromic
cal predictors of a positive biopsy were jaw claudication, anemia. Elevated platelet counts are common. Liver
diplopia, and abnormalities of the temporal artery function tests, particularly alkaline phosphatase, can be
biopsy on physical examination (15). All other symp- abnormal.
toms, including vision loss, elevated sedimentation rate,
headaches, and constitutional symptoms, were not par-
ticularly helpful in predicting the results of temporal
Imaging Studies
artery biopsies (i.e., in diagnosing GCA). The presence Precise mapping of the vaso-occlusive process still
of synovitis was a negative predictor of GCA, indicative requires angiography. Angiography is also essential for
of the fact that most patients with true arthritis have patients with significant stenoses in vessels to all four
another diagnosis, such as rheumatoid arthritis. extremities, for the purpose of measuring central aortic
pressure directly. Alternatives to conventional angiog- disease reactivation, the dose of prednisone generally
raphy, however, have made great strides in recent years can be tapered by 10% every 1 to 2 weeks.
(17). Magnetic resonance angiography (MRA) permits So far, the use of glucocorticoid-sparing agents to
evaluation of vessel wall thickness and perivascular allow a more rapid taper has been unsuccessful (17).
edemasignificant advantages over conventional angio- Initial positive results with methotrexate could not be
grams, which evaluate only the vascular lumen. In the confirmed in a subsequent study (20). A recent random-
proper clinical context, therefore, certain MRA findings ized, controlled trial of tumor necrosing factor (TNF)
may be diagnostic of large vessel vasculitis. The nonin- alpha blockade found this therapy to be ineffective as a
vasive nature of MRA also lends important advantages glucocorticoid-sparing medication (21). A recent study
in serial monitoring. Unfortunately, the appropriate suggests that a more aggressive induction therapy at the
interpretations of some MRA findings, for example, onset of the disease, including three daily pulses of 1 gram
enhancement of the vessel wall following gadolinium of methylprednisolone, may allow for a rapid tapering of
administration and the presence of vessel wall edema, glucocorticoids and, in particular, a discontinuation of
remain uncertain and require additional longitudinal glucocorticoids in the second year of disease (22).
studies. Aspirin is an important adjunctive treatment for
Computed tomography angiography, another prom- GCA patients without contraindications. Retrospective
ising technique, has not been evaluated thoroughly in studies have indicated strong reductions in the risks of
large vessel vasculitis. Position emission tomography visual loss and central nervous system ischemic events
(PET) with 18F-fluorodeoxyglucose also holds promise among patients taking aspirin for other reasons at the
for the assessment of the degree of disease activity in time their GCA was diagnosed (23). The mechanism of
large arteries, but has not yet been validated for general aspirins efficacy in this setting is not entirely clear, but
clinical use. Other noninvasive vascular studies, includ- the medication may exert its effect through the selective
ing fluorescein angiography, transcranial Doppler flow suppression of interferon gamma production (17).
studies, and Doppler ultrasonography, are useful in Although the optimal dose of aspirin has not been
assessing certain vascular beds, for example, the retinal, established, doses ranging from 81 mg/day to 325 mg/day
vertebral, or subclavian arteries. These techniques only may be beneficial.
identify vascular insufficiency in cases with pronounced,
lumen-stenosing disease, however, and do not provide
specific information useful from the standpoint of diag-
Prognosis
nosis. Although Doppler ultrasound was once hypothe- The most significant morbidity of GCA relates to
sized to be useful in the diagnosis of GCA, the value of reduced blood flow to the eye and optic nerve as well
identifying a hyperechoic halo on ultrasound in the as hypoperfusion of the brain (19). If diagnosed and
temporal artery has not been confirmed in subsequent treated promptly, progression of the downstream effects
studies (18). of arterial wall inflammation, in particular lumen occlu-
sion with tissue ischemia, can be prevented. Side effects
of high doses of glucocorticoids given over a prolonged
Treatment period of time can be serious, especially in patients
Glucocorticoids are explicitly effective in suppressing older than 50 years, and treatment should therefore only
clinical manifestations of GCA. Since the introduction be initiated if the diagnosis is confirmed. In the majority
of glucocorticoids, the rate of GCA-related blindness of patients, GCA does not enter remissions that are
has declined, documenting the effectiveness of this sustained indefinitely after discontinuation of glucocor-
immunosuppressive approach. In almost all patients, ticoids. In a prospective study of 25 patients with biopsy-
glucocorticoids induce relief within 12 to 48 hours. The proven GCA, all of the patients responded to 60 mg
excellent response of the disease to this therapy has prednisone with disappearance of clinical signs of the
been suggested by some as a diagnostic criterion. disease (16). However, 60% of patients had disease
In view of the severity of GCA-related morbidity, relapses that occurred throughout the course of treat-
initial doses of 60 mg prednisone or equivalent have ment. Typically, reactivation of the disease produced
been recommended. Glucocorticoids cannot reverse symptoms of systemic inflammation or polymyalgic
intimal hyperplasia but may help attenuate the ischemic symptoms, but no vascular complications were seen.
insult by reducing tissue edema. In ophthalmologic
emergencies (e.g., amaurosis fugax occurring in sus-
pected GCA), pulse glucocorticoids may be appropriate POLYMYALGIA RHEUMATICA
(19). Initial doses should be maintained until reversible
manifestations of the disease have responded and the Polymyalgia rheumatica is diagnosed in patients pre-
systemic inflammatory syndrome is suppressed. Subse- senting with pain and stiffness in the muscles of the
quently, under close monitoring for clinical signs of neck, shoulder girdle, and pelvic girdle of at least 4
weeks duration (24). The myalgias are combined with although in lower quantities than in GCA. Of note, IFN-
signs of systemic inflammation manifesting clinically as gamma is absent in PMR, but abundant in GCA (25).
malaise, weight loss, sweats, and low-grade fever. Most A subset of PMR patients develops inflammation of
patients have laboratory abnormalities such as elevated periarticular structures, for example, bursae. Whether
ESR, elevated CRP, and anemia, which are indicative of these patients comprise a different subset from those
a systemic inflammatory syndrome. Upregulation of susceptible to developing frank vasculitis remains
acute phase reactants is helpful in distinguishing PMR unclear.
from other pain syndromes, yet (as in GCA and TA) not
all patients with active disease have elevated markers
of inflammation within their serum. No pathognomic
Clinical Features
test for PMR is available; exclusion of other diseases Patients complain about aching and pain in the muscles
with similar clinical presentations is essential. The sys- of the neck, shoulders, lower back, hips, thighs, and occa-
temic inflammatory syndrome associated with PMR is sionally the trunk. In typical cases, the onset is abrupt
exquisitely sensitive to glucocorticoid therapy, such that and the myalgias symmetrical; they usually affect the
prompt improvement of clinical symptoms with gluco- shoulders first. Often the patients have pain during the
corticoid therapy has been proposed as a diagnostic night and have difficulties rising and dressing them-
criterion. The pathophysiology of PMR is related closely selves. Weight loss, anorexia, malaise, and depression are
to those of GCA. PMR is now often considered a form common. Fever and chills should raise the suspicion of
of GCA that lacks fully developed vasculitis. fully developed GCA. PMR is frequently difficult to
distinguish from forms of seronegative polyarthritis. In
particular, male patients can present with proximal
Epidemiology aching and diffuse edema of the hands and feet that is
Because PMR remains a clinical diagnosis, epidemio- highly glucocorticoid-responsive.
logical studies are difficult. PMR affects the same patient Polymyalgia rheumatica includes patients with mild
population as GCA, but occurs approximately two to disease that is promptly responsive to therapy and
three times more frequently (24). Women are affected remits within a few months (26). In many patients,
more often than men, and the diagnosis is extremely however, reactivation of myalgias occurs when gluco-
unlikely in individuals younger than 50 years of age. In corticoid doses are tapered. Some patients require
high-risk populations, such as Scandinavians and other higher initial doses of glucocorticoids than are usually
peoples of Northern European descent, annual inci- considered to be effective in PMR.
dence rates have been estimated at 20 to 53 per 100,000 Patients with PMR must be carefully evaluated for
persons over the age of 50 years. In low-risk popula- possible GCA. A negative temporal artery biopsy does
tions, such as Italians, the annual incidence rates for not exclude the possibility of large vessel vasculitis tar-
individuals aged 50 years and older are only 10 cases geting primarily the subclavian and axillary arteries and
per 100,000. the aorta. Signs of vascular insufficiency, including
claudication in the extremities, bruits over arteries, and
discrepant blood pressure readings should alert the phy-
Pathogenesis sician to the possibility of GCA (12). MRA can be
Although the sudden onset of intense inflammation is helpful in confirming the concomitant diagnosis of large 21
suspicious for an infectious etiology, no causative agent vessel vasculitis.
has been identified. Most pathogenic abnormalities in In PMR patients with inflammation of periarti-
PMR patients are reminiscent of those in GCA, sup- cular structures, the most prominent findings are
porting the concept that PMR is a variant of GCA char- subdeltoid and subacromial bursitis (27). Biceps ten-
acterized by the dominance of the systemic inflammatory donitis and glenohumeral synovitis may also be present.
over the vascular component. Ultrasonography reveals fluid accumulation in the
Human leukocyte antigen polymorphisms that are bursae; T2-weighted MRI shows thickening and edema.
genetic risk factors for GCA are also associated with These involved areas show increased uptake on PET
PMR. There is no evidence that the HLA has a role in scans.
determining whether the disease process will remain The clinical symptoms of PMR can be mimicked by
limited to PMR or progress to fully developed GCA. a number of arthropathies, shoulder disorders, inflam-
Polymyalgia rheumatica appears to be associated matory myopathies, hypothyroidism, and Parkinsons
with a global activation of the innate immune system, disease. The differential diagnosis also includes malig-
including circulating monocytes that produce IL-1 and nancies and infections. No clear guidelines have been
IL-6. Activated DCs render arteries susceptible to vas- developed to determine whether patients with PMR
culitis. In many patients with PMR, in situ cytokine pro- should be screened for occult malignancies. Lack of the
duction can be demonstrated in biopsy specimens, typical and impressive improvement upon initiation of
therapy can provide a clue towards reevaluating the tation and aneurysm in about 25%. Complete occlusion
diagnosis of PMR. of upper extremity arteries results in the loss of palpable
pulses, which is why TA is also termed the pulseless
disease. The preference for the aorta and its primary
Treatment branches is signified in another alternative name, aortic
Polymyalgia rheumatica is dramatically responsive to arch syndrome. The ACR has developed a set of criteria
glucocorticoid therapy. Currently there are no data to distinguish TA from other vasculitic syndromes (see
documenting glucocorticoid-sparing effects of other Appendix I).
medications. However, almost all patients with PMR
can be safely managed with glucocorticoids; doses for
long-term treatment are low and unlikely to cause
Epidemiology
serious side effects. Takayasus arteritis is a rare disease that primarily
A critical decision in treating PMR is the dose of affects adolescent girls and young women. The diagnos-
glucocorticoids required for successful suppression of tic criteria include an age of less than 40 years at disease
symptoms and inflammation. The glucocorticoid require- onset; however, TA can start later in life, particularly in
ments may differ quite markedly among patients. Two Asians (29). (In addition, the diagnosis is often not
thirds of patients can be expected to respond with remis- made until the patient is older than 40, but symptoms
sion of pain and stiffness when started on 20 mg/day or may have begun years before the diagnosis.) Incidence
less prednisone (25). Some patients will need doses as rates are highest in Asia (Japan, Korea, China, India,
high as 40 mg/day for complete clinical control. Such and Thailand), with estimates of approximately 1 case
patients may be at higher risk of full-blown GCA. per 1 million persons annually. TA can occur in all races
Patients initially controlled on 20 mg/day of prednisone and geographic regions, but South American countries
can usually taper the dose by 2.5 mg every 10 to 14 days. have recently been recognized as additional areas of
More protracted tapering may be necessary once daily relatively high incidence. An international survey among
doses of 7 to 8 mg prednisone are attained. Dose adjust- 20 countries has indicated differences in the clinical
ments should be based mainly on clinical evaluation, spectrum of TA in different ethnic groups.
not exclusively on laboratory abnormalities. In many
patients, PMR can go into long-term remission, and
prednisone can be discontinued. Occasionally, success-
Pathogenesis
ful suppression of recurrent myalgias and stiffness may Takayasus arteritis is a granulomatous polyarteritis.
only be achieved by giving very low doses of prednisone The adventitia is characterized by striking thickening,
over an extended period. Patients should be warned often with intense perivascular infiltrates around the
about the potential of PMR progressing to GCA and vasa vasorum. Granuloma formation and giant cells are
should be monitored for vascular complications, partic- predominantly found in the media of the large elastic
ularly when discontinuing glucocorticoid therapy. arteries. The medial elastic smooth muscle cell layer is
destroyed in a centripetal direction and replaced by
fibrotic tissue, leading (in the aorta) to vessel wall dilata-
Prognosis tion and aneurysm formation. Smooth tapering, narrow-
The prognosis of patients with PMR is good. In the ing, or complete occlusion of the vascular lumen results
majority of patients, the condition is self-limited. A pro- from proliferation of the intima, occasionally with
portion of patients will eventually present with typical thrombosis.
symmetrical polyarthritis, fulfilling the criteria for the The etiology of TA remains unknown. In view of the
diagnosis of seronegative rheumatoid arthritis. Such systemic features of the syndrome, microbial infections
patients may require disease-modifying antirheumatic have been implicated, but no conclusive evidence for
drug (DMARD) therapy. infectious organisms has been provided. CD8 T cells are
a major component of vascular infiltrates, setting TA
apart from GCA. Cytotoxic activities of tissue infiltrat-
TAKAYASUS ARTERITIS ing CD8 T cells, mediated by the release of the pore-
forming enzymes perforin and granzyme B, have been
Takayasus arteritis is a vasculitis of the large elastic suspected of contributing to smooth muscle cell damage
arteries, specifically the aorta and its main branches. The (30).
disease may also affect the coronary and pulmonary Support for a role of CD8 T-cellmediated cytolytic
arteries (28). Inflammatory injury to the vessel wall tissue injury has come from the observation that selected
leads to patchy disappearance of the elastica and smooth HLA class I molecules, specifically HLA-B52, are over-
muscle layer and subsequent intimal hyperplasia, result- represented among TA patients (31). CD8 T cells rec-
ing in vascular stenosis in virtually all patients and dila- ognize antigens when bound to HLA class I molecules.
The role of CD4 T-cell responses and the contribution sions of the brachiocephalic and subclavian arteries
of macrophage effector functions in the vascular lesions impair blood flow to the upper extremities, presenting
are not understood. The focus of lymphocytic infiltrates as arm claudication, pulselessness, and discrepant blood
on the adventitia and accumulation of T cells around pressures. The detection of bruits can be helpful in
vasa vasorum makes it less likely that the macroendo- making the diagnosis.
thelium has major involvement in the pathogenesis of Cardiac disease, including ischemic coronary disease,
TA. arrhythmia, and congestive heart failure, can be related
to aortitis of the ascending aorta or severe hypertension.
Aortic regurgitation, a serious complication requiring
Clinical Features prompt clinical attention, is a consequence of aortic
A generalized inflammatory syndrome with fever, night dilatation. Coronary arteries can be involved directly or
sweats, malaise, anorexia, weight loss, and diffuse myal- indirectly, producing classical symptoms of myocardial
gias often dominates initial manifestations of TA. These ischemia. Progressively enlarging aneurysms and possi-
symptoms are frequently misdiagnosed as infection. The ble rupture are a major concern in patients with TA of
clinical pattern of ischemic complications that emerge the aortic arch and the descending thoracic aorta.
often years laterdirectly reflect the vascular territory Patients from India, China, and Korea often have lesions
targeted by the disease (Figure 21A-4). in the abdominal aorta and its branches (particularly the
Involvement of the carotid and vertebral arteries renal arteries, causing renovascular hypertension). The
leads to neurologic and ophthalmologic symptoms, proximal ends of mesenteric arteries are less frequently
including dizziness, tinnitus, headaches, syncope, stroke, affected, but gastrointestinal symptoms, such as nausea,
and visual disturbances. Atrophy of facial muscles and vomiting, and ischemic bowel disease can be seen in
jaw claudication are mostly late manifestations. Occlu- patients with TA.
FIGURE 21A-4
Clinical spectrum of Takayasus arteritis in relationship to vascular bed involvement.
Vascular bed Dominant clinical symptoms Frequency of involvement
Common carotid Visual defects, strokes, TIA , syncope
Vertebral Dizziness, visual impairment
Subclavian Arm claudication, pulselessness
Aortic arch / root Aortic insufficiency, congestive heart failure

21
Pulmonary Dyspnea, chest pain
Coronary Myocardial infarction, angina
Celiac axis Abdominal angina
Superior mesenteric Abdominal angina
Renal Hypertension
Abdominal aorta Claudication, hypertension, abdominal angina
Iliac Claudication
0 20 40 60 80 100
Patients presenting (%)
Diagnosis must be tailored to the individual patient. Low-dose

aspirin or other antiplatelet agents should complement
A combination of vaso-occlusive disease and systemic glucocorticoid therapy. Methotrexate, given in weekly
inflammation in a young patient should immediately doses of up to 25 mg, has shown promise in improving
raise suspicion for TA. Typically, the diagnosis is made remission rates and sparing glucocorticoids (35), but has
by characteristic findings on vascular imaging (32). never been tested in a randomized trial (the same is true
Tissue is rarely available. The findings on conventional for all other potential steroid-sparing agents). Azathio-
angiography can be diagnostic for TA in the proper prine, mycophenolate mofetil, cyclosporine, and TNF-
clinical setting. Angiography reveals long, smooth taper- alpha blockers have been used with reported success in
ings of involved vessels, with a remarkable web of col- individual patients, but controlled studies are required.
lateral blood vessels in advanced cases. As in GCA, Contrary to other vasculitides, cyclophosphamide does
conventional angiography is essential in many patients not play a major role in this disease because of its toxic-
with TA in order to measure accurately the central ity and uncertain efficacy.
aortic blood pressure. Stenotic lesions are irreversible. Surgical manage-
Several noninvasive imaging techniques are informa- ment and angioplasty or stent placement have a role in
tive for assessing progression of occlusive disease, but selected patients, but for most patients revascularization
currently lack standardization and are subject to inves- attempts of vessels to the extremities are not necessary
tigator bias and experience. Far more problematic than because of the exuberant collateralization that develops
assessing the degree of stenosis within a given blood in TA. When revascularization is necessary, bypass grafts
vessel is the reliable assessment of inflammatory activity are generally successful, while stenting appears to have
by imaging. MRI/A has largely replaced conventional a high rate of reocclusion (33). Angioplasty is reserved
angiography for serial assessments of the distribution for short stenotic segments. Treatment of hypertension
and degree of vessel involvement, and also permits eval- secondary to renal artery stenosis may or may not
uations of the vessel wall as well as the lumen. MRI/A benefit from revascularization, depending on the loca-
is particularly important in the longitudinal monitoring tion of the lesion leading to renovascular hypertension.
of TA although, as noted, the correct interpretation of Decisions about whether or not to attempt revascular-
all MRI/A findings is not always clear. MRI/A has clear ization should be undertaken in consultation with
utility in monitoring the progress or stability of vascular experts accustomed to the management of complex
stenoses, provided that serial studies are compared care- hypertension cases.
fully for changes. Doppler ultrasound provides a good
assessment of cervical vessels. Computed tomography
angiography can be used to survey the aorta and proxi- Prognosis
mal vessels, but rigorous serial studies of its use in TA
For much of the past several decades, TA has been
remain to be performed. The role of PET scanning in
viewed as an inevitably devastating disease. The diagno-
gauging the degree of ongoing inflammation (as opposed
sis was seldom made before damage from prolonged
to uptake that might be related to a process of healing
vascular inflammation was already extensive. More
or fibrosis) has not been established.
recently, the potential for earlier diagnosis, effective
immunosuppressive therapy, and astute surgical man-
Treatment agement have led to an improved prognosis for many
patients. Long-term follow up of almost 1000 Japanese
Although some patients with TA have disease that patients found stable clinical conditions in two thirds of
appears to burn out, becoming quiescent after years the patients and serious complications occurring in only
of active disease, most patients have progressive or 25% of affected individuals. Cardiac complications,
relapsing/remitting disease and require long-term immu- including congestive heart failure and ischemic heart
nosuppressive treatment (33). Glucocorticoids are the disease, have become the most common cause of death
therapy of choice for management of TA. Recommenda- in Japanese patients with TA. Acceleration of athero-
tions of initial doses have varied, but 40 to 60 mg of sclerotic disease emerges as a critical factor in long-term
prednisone may be necessary to control vascular as well outcome.
as systemic inflammation. Monitoring of acute phase
reactants (ESR, CRP) is only helpful in a subset of
patients. In a National Institutes of Health (NIH) cohort, REFERENCES
50% of patients had active progressing disease despite
nonelevated acute phase reactants (34). Prednisone 1. Hunder GG. Giant cell arteritis and polymyalgia rheu-
doses are tapered as clinically indicated and tolerated, matica. Med Clin North Am 1997;811:195219.
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CHAPTER 21
Vasculitides
B. Polyarteritis Nodosa
KEITH T. ROTT, MD, PHD
Polyarteritis nodosa (PAN) primarily affects medium- small-sized muscular arteries, sparing large arteries,
sized arteries that supply the skin, gut, nerve, and capillaries, and the venous system. The inflammation
kidney, but may involve multiple organs. leads to fibrinoid necrosis, but is not associated with
Microaneurysms of arteries to or within the kidneys, granulomatous features.
liver, or gastrointestinal tract are highly characteristic High-dose glucocorticoids are the mainstay of
of PAN. therapy in PAN. In cases that are rapidly
Polyarteritis nodosa is not associated with progressive or life- or organ-threatening, however,
antineutrophil cytoplasmic antibodies (ANCA) directed cyclophosphamide is added to glucocorticoid
against either proteinase-3 or myeloperoxidase. treatment.
Mononeuritis multiplex, an asymmetric sensory and Most cases of idiopathic PAN do not recur once
motor neuropathy due to ischemia and infarction of a sound remission has been achieved with 6 to
peripheral nerves, occurs frequently in PAN. 12 months of therapy.
In mononeuritis multiplex, nerve conduction studies A minority of PAN cases (now >10%) are
of peripheral nerves reveal a distal, asymmetric, associated with acute hepatitis B infection. Cases
axonal neuropathy involving both motor and sensory associated with hepatitis B are treated with
nerves. regimens emphasizing antiviral therapy and only
Polyarteritis nodosa is characterized pathologically by short courses of immunosuppression and
patchy, transmural inflammation in medium- and plasmapheresis.
Polyarteritis nodosa (PAN) is a vasculitis affecting pre- tumors up to the size of poppy and hemp seeds)
dominantly medium-sized arteries. Clinically, PAN often throughout medium-sized arteries, conspicuously
presents insidiously with nonspecific, constitutional sparing both the venous circulation and the lungs.
symptoms. The disease has a predilection for medium- Before the delineation of vasculitis subsets and the
sized arteries supplying skin, gut, nerve, and kidney, but formulation of definitions based principally on vessel
may involve multiple organs. The majority of PAN cases size (3), PAN was used to describe two now-distinct
have no known cause, but cases secondary to hepatitis forms of vasculitis: the classic PAN described by
B virus infection have been reported. Kussmaul and Maier, and microscopic PAN (now
Described by Kussmaul and Maier in 1866 (1,2), PAN called microscopic polyangiitis). According to current
is often regarded as the first reported form of systemic convention, and as described in this text, PAN is a vas-
vasculitis. In fact, earlier descriptions of Behcets disease, culitis affecting medium-sized arteries. PAN is also
Takayasus arteritis, HenochSchnlein purpura, and not associated with antineutrophil cytoplasmic anti-
even PAN itself exist in the medical literature. For nearly bodies (ANCA), at least not those directed against
a century after the case reported by Kussmaul and proteinase-3 (PR3) or myeloperoxidase (MPO) that
Maier, however, most forms of systemic vasculitis were are such a distinctive feature of the majority of cases of
termed periarteritis nodosa, and forms of vasculitis Wegeners granulomatosis, microscopic polyangiitis,
recognized later were contrasted and classified in com- and, to a lesser extent, the ChurgStrauss syndrome.
parison to PAN. The patient described by Kussmaul Although patients may be P-ANCA-positive on immu-
and Maier was a 27-year-old male with fever, weight nofluorescence testing, enzyme immunoassays for
loss, abdominal pain, and a polyneuropathy that pro- PR3- and MPO-ANCA are negative in PAN. Further,
gressed over the period of 1 month to paralysis. An in contrast to the ANCA-associated vasculitides (see
autopsy revealed microaneurysms (whitish small Chapter 21C), PAN does not involve either the lungs or
410
blood vessels as small as the renal glomeruli (which are TABLE 21B-1. SELECTED CLINICAL AND DIAGNOSTIC
essentially capillaries). FEATURES OF PAN AND THEIR FREQUENCY.
Polyarteritis nodosa affects men and women approxi- Clinical Features
mately equally and has a broad age range of patients. Myalgias, general weakness, or leg muscle tenderness 69%
Although the incidence of PAN varies according to the Weight loss 4 kg 67%
population studied, it is rare in all populations, with Mononeuropathy or polyneuropathy 65%
Azotemia (BUN > 40 mg/dL or Cr > 1.6 mg/dL) 40%
annual incidence rates generally ranging from 2 to 9 cases Hypertension (diastolic blood pressure >90 mm Hg) 37%
per million. Higher rates have been reported in popula- Testicular pain or tenderness 29%
tions with a high burden of hepatitis B virus infection, but Skin ulcers, infarction, or peripheral gangrene 27%
with the availability of a vaccine, hepatitis B virus infec- Livedo reticularis 25%
tion now accounts for less than 10% of PAN cases in Abdominal angina or ischemic perforation 24%
developed countries (4). PAN has also been reported to Diagnostic Features
occur in conjunction with hairy cell leukemia. Visceral arteriogram with aneurysm or occlusion 73%
Biopsy of small-or medium-sized artery with granulocytes 48%
Abnormal arteriogram or characteristic biopsy 92%
CLINICAL FEAURES SOURCE: From Lightfoot RW, et al. Arthritis Rheum 1990;33:10881093, by
permission of Arthritis and Rheumatism.
Polyarteritis nodosa can present with nonspecific con- ABBREVIATIONS: BUN, serum urea nitrogen; Cr, creatinine.
stitutional symptoms such as fever, fatigue, malaise,
myalgias, and arthralgias. This phase of the illness can
last weeks or months. The more specific clinical mani- in hypertension due to renal ischemia; hypertension is
festations of PAN are the direct results of inflammation mediated by the reninangiotensin system. Renal insuf-
in medium- and small-sized muscular arteries. PAN ficiency, another common manifestation of PAN, is due
often has cutaneous involvement, a feature it shares to ischemia resulting from the involvement of arteries
with small vessel vasculitides such as the ANCA- the size of renal arteries and smaller. Microaneurysms,
associated disorders. This differentiates it from large detectable by angiography [Figure 21B-1(A,B)], are a
vessel vasculitis (e.g., giant cell arteritis and Takayasus hallmark of PAN.
arteritis), in which skin disease is very rare. However, The gastrointestinal (GI) tract is involved in up to
unlike the ANCA-associated vasculitides, PAN is not 50% of patients. Postprandial periumbilical pain, or
associated with glomerulonephritis or pulmonary intestinal angina, is the result of mesenteric ischemia.
involvement. Common clinical features of PAN and More severe disease can result in bowel infarction and
their frequency are listed in Table 21B-1 (5). perforation. Other GI symptoms can include nausea,
In autopsy studies, the most frequently involved vomiting, diarrhea, and bleeding. While the small intes-
organ in PAN is the kidney. Involvement of the medium- tine is most commonly involved, rare presentations
sized arteries supplying the renal parenchyma can result involving ischemia of the gallbladder or appendix have
FIGURE 21B-1
Microaneurysms detected by angiography in polyarteritis nodosa. (A) Renal microaneurysms. 21

(B) Mesenteric vessel microaneurysms. (Courtesy of Dr. John Stone.)
A B
412 KEITH T. ROTT
been described (6). Moderately elevated hepatic trans-

aminases often betray liver involvement. Asymptomatic
mircoaneurysms within the liver are common; these
occasionally rupture.
Involvement of the peripheral nervous system is seen
in 50% to 75% of patients, usually as an asymmetric
sensory and motor neuropathy due to ischemia of
peripheral nerves (7). Infarction of named nerves results
in mononeuritis multiplex (Figure 21B-2). Progressive
sensory neuropathy has been described less frequently.
Central nervous system involvement is much less
common, but has been reported in the form of cerebro-
vascular accidents.
Polyarteritis nodosa can have multiple cutaneous
manifestations: livedo reticularis, nodules, ulcerations
FIGURE 21B-3
(Figure 21B-3), and frank ischemia of digits (8). A small
group of patients have a form of disease termed cutane- Cutaneous ulcerations over both medial malleoli in polyarteritis
ous PAN, a variant limited ostensibly to the skin. These nodosa. (Courtesy of Dr. John Stone.)
patients develop nodules and ulcerations, primarily of
the lower legs, which can occur in crops and can be very mon, and coronary involvement is usually only seen at
painful. However, as with any other vasculitis, cutaneous autopsy. Contraction band necrosis, indicative of seg-
manifestations should prompt a thorough evaluation for mental ischemia, is a common finding in the myocar-
evidence of systemic disease. dium at autopsy, attesting to the presence of vasculitis
As with Kawasakis disease, the other medium vessel below the resolution of conventional angiography. PAN
vasculitis described in this text, PAN can also involve can involve other organs, such as the testicle, ovary,
the coronary arteries. Clinical proof of coronary disease breast, and eye.
during life is difficult. Myocardial infarction is uncom-
PATHOLOGY
Polyarteritis nodosa is characterized pathologically by
patchy, transmural inflammation in medium- and small-
sized muscular arteries, sparing large arteries, capillar-
ies, and the venous system. There is a pleomorphic
cellular infiltrate and fibrinoid necrosis in the vessel, but
no features of granulomatous inflammation. Disruption
of the elastic laminae of the vessel wall can lead to
aneurysmal dilatation at the site of the lesion. PAN has
a predilection for certain organs: arteries to the kidney
are estimated to be involved 70% to 80% of the time,
the GI tract is involved in 50% of cases, the peripheral
nerves are involved in 50% of cases, and the central
nervous system is involved in 10% of cases (9).
DIAGNOSIS
Polyarteritis nodosa is diagnosed based on characteris-
tic symptoms, physical examination findings, and com-
patible laboratory, angiographic, and pathologic data.
Because PAN is a rare disease and its treatment can
result in serious adverse events, the diagnosis should be
supported with either abdominal angiography or biopsy
whenever possible. PAN must be differentiated from
FIGURE 21B-2
other forms of vasculitis, such as the ANCA-associated
Mononeuritis multiplex. (Courtesy of Dr. John Stone.) disorders, cryoglobulinemia, and Buergers disease.
TABLE 21B-2. AMERICAN COLLEGE OF Imaging

RHEUMATOLOGY CRITERIA FOR CLASSIFICATION OF
PAN. Imaging in a patient with suspected PAN should be
guided by symptoms. In patients with abdominal pain,
At least 3 of 10 criteria:
1. Weight loss 4 kg
abdominal arteriography often reveals characteristic
2. Livedo reticularis strictures and aneurysms (beading) of the mesenteric
3. Testicular pain or tenderness vessels [see Figure 21B-1(B)]. Similar findings can be
4. Myalgias, weakness, or leg tenderness seen in the renal vasculature.
5. Mononeuropathy or polyneuropathy
6. Diastolic blood pressure >90 mm Hg
7. Elevated serum nitrogen urea (>40 mg/dL) or creatinine Biopsy
(>1.5 mg/dL)
8. Hepatitis B virus infection
As with imaging, biopsy should be guided by organ
9. Arteriographic abnormality involvement. Blind biopsy of an asymptomatic organ,
10. Biopsy of small- or medium-sized artery containing such as muscle or testicle, is not recommended. Skin
polymorphonuclear neutrophils biopsy is often the easiest way to confirm this diagnosis,
with a biopsy from the center of a nodule or the edge of
SOURCE: From Lightfoot RW, et al. Arthritis Rheum 1990;33:10881093, by
permission of Arthritis and Rheumatism.
a vasculitic ulcer. Routine punch biopsy of involved skin
reveals leukocytoclastic vasculitis and fibrinoid necrosis
within the blood vessel wall. Because punch biopsy
samples include only epidermis and superficial dermis,
Common vasculitis mimics, such as viral hepatitis, bacte-
they do not capture medium-sized, muscular-walled
rial endocarditis, or other embolic diseases, should be
arteries whose inflammation is characteristic of PAN.
excluded. Undiagnosed connective tissue diseases, such
When PAN is suspected and skin biopsy is indicated, a
as systemic lupus erythematosus, rheumatoid arthritis,
full thickness skin biopsy that includes some subcutane-
or systemic sclerosis, must be ruled out, as such diseases
ous fat should be performed (arteries within the fat
can be associated with systemic vasculitis or widespread
lobules of subcutaneous tissue are often involved.)
vascular dysfunction that involves multiple organs.
Another option for confirming the diagnosis of PAN
Atrophie blanche, a thrombotic disorder that may lead
is a peripheral nerve biopsy. The sural nerve is biopsied
to lower extremity ulcerations, must be differentiated
most often because it does not mediate motor function.
from PAN by skin biopsy.
Whenever the sural nerve is biopsied, a muscle biopsy
The American College of Rheumatology criteria for
(of the gastrocnemius) should be performed simultane-
the classification of PAN are listed in Table 21B-2 (5).
ously. Because of the highly vascular nature of muscle,
The criteria were developed through the selection of
biopsies of this organ may yield proof of vasculitis even
clinical findings that identify PAN and distinguish it
in the absence of clinical indications of muscle involve-
from other forms of vasculitis. Although the criteria are
ment (Figure 21B-4).
useful for classifying patients in clinical studies, they
were not intended for use in diagnosing individual
patients (10).
Laboratory Studies 21
Routine laboratory studies are often abnormal but
nonspecific, such as elevated inflammatory markers
(erythrocyte sedimentation rate or C-reactive protein),
anemia, and thrombocytosis. The patient may have mild
renal insufficiency, with an elevated blood urea nitrogen
and creatinine. Non-nephrotic range proteinuria and
mild hematuria are also seen, but active urine sediments
are not a feature of PAN.
As not, PAN is not associated with ANCA. Indeed,
there is no characteristic autoantibody for PANa fact FIGURE 21B-4
that creates one of the diagnostic challenges in this
disease. Electromyography/nerve conduction velocity Muscle biopsy showing fibrinoid necrosis within the wall of a
(EMG/NCV) studies may be very useful in confirming medium-sized muscular artery. Although the patient had clinical
symptoms of a neuropathy and nerve conduction studies were
patterns of nerve dysfunction consistent with mononeu- consistent with a mononeuritis multiplex, the nerve biopsy was
ritis multiplex; namely, a distal, asymmetric, axonal neu- negative. The diagnosis of polyarteritis was confirmed by the
ropathy involving both motor and sensory nerves. muscle biopsy. (Courtesy of Dr. John Stone.)
414 KEITH T. ROTT
PROGNOSIS cyclophosphamide. Although many clinicians still prefer

daily oral cyclophosphamide to monthly pulsed intrave-
Untreated PAN has a high mortality, with an estimated nous cyclophosphamide, a meta-analysis comparing the
5-year survival of 13% prior to the introduction of glu- two regimens in ANCA-associated vasculitis showed
cocorticoids. With current treatment, survival is greatly little difference (13). Therapy should be tailored to the
improved, approximately 80% at 5 years. In a popula- individual patients circumstances.
tion of 278 patients enrolled in prospective trials for Most cases of idiopathic PAN do not recur after
PAN, MPA, and ChurgStrauss syndrome, approxi- remission has been achieved and the patient has received
mately 75% of the deaths occurred during the first 18 6 to 12 months of cyclophosphamide. Current regimens
months after the diagnosis was made and treatment generally emphasize shorter courses of cyclophospha-
initiated. Of the patients who died, 26% died from pro- mide, with durations of therapy closer to 6 months than
gression of their vasculitis, while 13% died of infectious to 12. After treatment with 6 months of cyclophospha-
complications related to treatment. No major differ- mide, patients in remissionthe great majorityshould
ences were seen among the three vasculitides studied be switched to another immunosuppressive agent for
(11). remission maintenance. As with the ANCA-associated
Not surprisingly, more severe disease is associated vasculitides, azathioprine or methotrexate is often used.
with increased mortality. A Five Factor Score has been After a total treatment length of approximately 18
used to classify disease severity (12). The five factors are months, the remission maintenance agent can often be
(1) proteinuria >1 g/day, (2) renal insufficiency (Cr > stopped, with a low relapse rate. Patients should con-
1.6 mg/dL), (3) cardiomyopathy, (4) gastrointestinal tinue to be monitored for evidence of recurrence.
symptoms, and (5) CNS involvement. A Five Factor Much potential morbidity in PAN relates to adverse
Score of 0 is associated with a 5-year mortality of only events from inappropriate (or overly aggressive)
13% (with not all deaths caused directly by PAN). Five treatment. Conversely, poor outcomes also result
Factor Scores of 1 and 2 or more are associated with from undertreatment, for example, failure to employ
mortalities of 26% and 46%, respectively (12). cyclophosphamide in a patient clearly failing high-
dose glucocorticoids. An important aspect of treatment
is avoiding known side effects of agents used.
This includes the use of calcium and vitamin D supple-
TREATMENT mentation in all patients on glucocorticoids, along with
use of a bisphosphonate in those at high risk for bone
The treatment of PAN is guided by both the etiology of loss and monitoring of bone density. Patients on
the disease (if known) and its severity. PAN cases associ- cyclophosphamide should have routine monitoring for
ated with hepatitis B are treated with a short course of cytopenias and hematuria and receive trimethoprim/
prednisone (1 mg/kg/day) to suppress the inflammation. sulfamethoxazole for prevention of Pneumocystis jir-
Patients begin 6-week courses of plasma exchange oveci (formerly carinii) pneumonia. Patients receiving
(approximately three exchanges per week) simultane- pulsed intravenous cyclophosphamide are also candi-
ously with the start of glucocorticoids. The dose of pred- dates for MESNA (sodium-2-sulfanyl ethanesulfonate)
nisone is tapered rapidly (over approximately 2 weeks), for prevention of hemorrhagic cystitis. Premenopausal
followed by the initiation of antiviral therapy (e.g., lami- females on cyclophosphamide are candidates for leup-
vudine 100 mg/day). rolide to suppress the GnRH axis and prevent prema-
For idiopathic PAN, the mainstay of treatment is glu- ture ovarian failure; males may opt to bank sperm.
cocorticoids, with an initial dose of approximately 1 mg/ Finally, as a teratogen, patients should not become
kg daily of prednisone. Intravenous glucocorticoids can pregnant or father children on cyclophosphamide.
be used in patients with difficulty taking oral medica-
tions due to GI involvement. Pulse doses (e.g., methyl-
prednisolone 1 g intravenously each day times three)
may be used in severe disease. Glucocorticoids alone REFERENCES
may be enough to treat milder cases. Approximately
half of all patients with PAN may be cured with gluco- 1. Kussmaul A, Maier R. Ueber eine bisher nicht bes-
corticoids alone. chriebene eigenthumliche arterienerkrankung (periar-
teritis nodosa), die mit morbus brightii und rapid
In cases of PAN that are rapidly progressive or life-
fortschreitender allgemeiner muskellahmung einhergeht.
or organ-threatening, cyclophosphamide is added to Dtsch Arch Klin Med 1866;1:484518.
glucocorticoid treatment. Cyclophosphamide should be 2. Matteson EL. Polyarteritis nodosa: commemorative trans-
considered for any patient with a Five Factor Score of lation of the 130-year anniversary of the original article
1 or greater. In addition, severe peripheral neuropathy by Adolf Kussmaul and Rudolf Maier. Rochester, MN:
or mononeuritis multiplex is also a strong indication for Mayo Foundation; 1996.
3. Jennette J, Falk R, Andrassy K, et al. Nomenclature of 9. Conn DL. Polyarteritis. Rheum Dis Clin North Am 1990;
systemic vasculitides. Proposal of an international consen- 16:341362.
sus conference. Arthritis Rheum 1994;37:187192. 10. Hunder GH, Arend WP, Bloch DA, et al. The American
4. Stone JH. Polyarteritis nodosa. JAMA 2002;288:1632 College of Rheumatology 1990 criteria for the classifica-
1639. tion of vasculitis. Arthritis Rheum 1990;33:10651067.
5. Lightfoot RW, Michel BA, Bloch DA, et al. The Ameri- 11. Gayraud M, Guillevin L, Le Toumelin P, et al. Long term
can College of Rheumatology 1990 criteria for the classi- follow up of polyarteritis nodosa, microscopic polyangiitis
fication of polyarteritis nodosa. Arthritis Rheum 1990;33: and Churg-Strauss syndrome. Analysis of four prospec-
10881093. tive trials including 278 patients. Arthritis Rheum 2001;44:
6. Levine SM, Hellman DB, Stone JH. Gastrointestinal 666675.
involvement in polyarteritis nodosa (19862000): presen- 12. Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors
tation and outcomes in 24 patients. Am J Med 2002; in polyarteritis nodosa and Churg-Strauss syndrome. A
112:386391. prospective study in 342 patients. Medicine (Baltimore)
7. Tervaert JWC, Kallenberg C. Neurologic manifestations 1996;75:1728.
of systemic vasculitides. Rheum Dis Clin North Am 1993; 13. De Groot K, Adu D, Savage COS. The value of pulse
19:913940. cyclophosphamide in ANCA-associated vasculitis: meta-
8. Gibson LE, Su WP. Cutaneous vasculitis. Rheum Dis Clin analysis and critical review. Nephrol Dial Transplant
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21
CHAPTER 21
Vasculitides
C. The Antineutrophil Cytoplasmic
AntibodyAssociated Vasculitides:
Wegeners Granulomatosis,
Microscopic Polyangiitis, and the
ChurgStrauss Syndrome
JOHN H. STONE, MD, MPH
Many patients with Wegeners granulomatosis (WG), saddle-nose deformity, erosive sinusitis, and subglot-
microscopic polyangiitis (MPA), or the ChurgStrauss tic stenosis. The CSS is often associated with allergic
syndrome (CSS) have antineutrophil cytoplasmic rhinitis, nasal polyposis, or sinusitis, but is rarely
antibodies (ANCA) within their serum. associated with destructive lesions.
As a result, these three disorders are termed the A host of ocular lesions may occur in the AAV,
ANCA-associated vasculitides (AAV), even though not all including episcleritis, scleritis, peripheral ulcerative
patients with these conditions have ANCA. keratitis, and orbital pseudotumor.
Multiple antibodies may lead to positive immunofluo- Lung disease is common in the AAV and ranges from
rescence testing for ANCA in either perinuclear (P- asthma (in CSS) to nodular lesions with a tendency to
ANCA) or cytoplasmic (C-ANCA) patterns. However, cavitate (in WG) to interstitial lung disease (MPA) to
only antibodies to myeloperoxidase (MPO) and alveolar hemorrhage (all forms of AAV).
proteinase-3 (PR3) are associated with the AAV. Segmental, necrotizing glomerulonephritis commonly
Wegeners granulomatosis may be associated with accompanies the AAV, particularly WG and MPA.
destructive upper respiratory tract disease, including Eosinophilia is the sine qua non of CSS.
In 1954, Godman and Churg observed that Wegeners Anticytoplasmic antibodies directed against neutro-
granulomatosis (WG), microscopic polyangiitis (MPA), phils (i.e., ANCA) were reported in association with
and the ChurgStrauss syndrome (CSS) share certain segmental necrotizing glomerulonephritis in the early
pathological similarities despite their clinical distinc- 1980s. In 1985, the presence of diffuse cytoplasmic
tions (1). These diseases, Godman and Churg noted, staining of neutrophils was reported in patients with
group themselves into a compass, (ranging from) nec- WG (2). In studies of patients with WG, MPA, or
rotizing and granulomatous processes with angiitis . . . to renal-limited vasculitis, Falk and Jennette (3) noted
vasculitis without granulomata. Validation of the path- another pattern of immunostainingperinuclear fluo-
ological links between these disorders became clear rescence of alcohol-fixed neutrophils. The two types of
three decades later with the discovery of antineutrophil antibodies associated with AAV are those directed
cytoplasmic antibodies (ANCA) and the finding that against (1) proteinase-3 (PR3) and (2) myeloperoxidase
most patients with WG, MPA, and (to a lesser extent) (MPO). PR3 and MPO, both serine proteases, are
CSS have ANCA in their serum. These diseases are constituents of the primary granules of neutrophils
commonly termed ANCA-associated vasculitides and monocytes. Antibodies directed against these
(AAV), even though not all patients with these diseases antigens are known, respectively, as PR3-ANCA and
have detectable ANCA (Table 21C-1). MPO-ANCA.
416
TABLE 21C-1. THE 1990 AMERICAN COLLEGE OF RHEUMATOLOGY CLASSIFICATION CRITERIA FOR WEGENERS
GRANULOMATOSIS AND CHURGSTRAUSS SYNDROME.
WEGENERS GRANULOMATOSIS CHURGSTRAUSS SYNDROME
Nasal or oral inflammation Asthma
Painful or painless oral ulcers or purulent or bloody nasal discharge Wheezing or high-pitched rales
Abnormal chest radiograph Eosinophilia
Nodules, fixed infiltrates, or cavities >10% of white blood cell differential
Urinary sediment Mononeuropathy or polyneuropathy
Microhematuria or red cell casts Mononeuropathy, multiple mononeuropathies, or

polyneuropathy attributable to vasculitis
Granulomatous inflammation on biopsy specimen Pulmonary infiltrates, nonfixed
Granulomatous inflammation within the wall of an artery or in the Migratory or transitory pulmonary infiltrates
perivascular area Paranasal sinus abnormality
Acute or chronic paranasal sinus pain, tenderness, or
radiographic opacification
Extravascular eosinophils
Biopsy of artery, arteriole, or venule showing accumulations
of eosinophils in extravascular areas
SOURCE: From Leavitt RY et al. Arthritis Rheum 1990;33:11011107, and Masi AT et al. Arthritis Rheum 1990;33:10941100, by permission of Arthritis and
Rheumatism.
CLASSIFICATION CRITERIA EPIDEMIOLOGY

AND DEFINITIONS A population-based study from Norfolk, England,
reported incidences of 8.5 cases per million for WG, 3.6
The 1990 American College of Rheumatology classifi-
cases per million for MPA, and 2.4 cases per million for
cation criteria for WG and the CSS (Table 21C-1) (4,5)
the CSS (8). In two large U.S. cohorts of patients with
were developed to ensure the inclusion of uniform
WG (9,10), whites comprised more than 90% of all
disease populations in research studies (6). These crite-
cases, whereas African Americans, Hispanics, and Asians
ria did not address the utility of ANCA for classification
together represented 1% to 4% of cases. The mean age
or the difference between polyarteritis nodosa and
at diagnosis is about 55 years, but cases involving octo-
MPA. These limitations were addressed by the Chapel
genarians are not unusual.
Hill Consensus Conference (Table 21C-2) (7). To date,
widely accepted diagnostic criteria for these diseases
have not been developed.
21
TABLE 21C-2. THE CHAPEL HILL CONSENSUS CONFERENCE DEFINITIONS OF THE ANTINEUTROPHIL CYTOPLASMIC
ANTIBODIESASSOCIATED VASCULITIDES.
Wegeners granulomatosis
Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small- to medium-sized vessels
(e.g., capillaries, venules, arterioles, and arteries). Necrotizing glomerulonephritis is common.
Microscopic polyangiitis
Necrotizing vasculitis, with few or no immune deposits, affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotizing
arteritis involving small- and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary
capillaritis often occurs.
ChurgStrauss syndrome
Eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small- to
medium-sized vessels, associated with asthma and eosinophilia.
SOURCE: Jennette JC, et al. Arthritis Rheum 1994;37:187192, by permission of Arthritis and Rheumatism.
418 JOHN H. STONE
TABLE 21C-3. CLINICAL FEATURES OF THE PRIMARY ANTINEUTROPHIL CYTOPLASMIC ANTIBODIESASSOCIATED

VASCULITIDES.
MICROSCOPIC CHURGSTRAUSS
FEATURE WEGENERS GRANULOMATOSIS POLYANGIITIS SYNDROME
ANCA positivity 80%90% 70% 50%
ANCA antigen specificity PR3 > MPO MPO > PR3 MPO > PR3
Fundamental histology Leukocytoclastic vasculitis; necrotizing, Leukocytoclastic vasculitis; no Eosinophilic tissue infiltrates
granulomatous inflammation (rarely seen granulomatous and vasculitis; granulomas
in renal biopsy specimens) inflammation have eosinophilic necrosis
Ear/nose/throat Nasal septal perforation; saddle-nose Absent or mild Nasal polyps; allergic rhinitis;
deformity; conductive or sensorineural conductive hearing loss
hearing loss; subglottic stenosis
Eye Orbital pseudotumor, scleritis (risk of Occasional eye disease: Occasional eye disease:
scleromalacia perforans), episcleritis, scleritis, episcleritis, uveitis scleritis, episcleritis, uveitis
uveitis
Lung Nodules, infiltrates, or cavitary lesions; Alveolar hemorrhage Asthma; fleeting infiltrates;
alveolar hemorrhage alveolar hemorrhage
Kidney Segmental necrotizing glomerulonephritis; Segmental necrotizing Segmental necrotizing

rare granulomatous features glomerulonephritis glomerulonephritis
Heart Occasional valvular lesions Rare Heart failure
Peripheral nerve Vasculitic neuropathy (10%) Vasculitic neuropathy (58%) Vasculitic neuropathy (78%)
Eosinophilia Mild eosinophilia occasionally None All
SOURCE: Reproduced with permission from Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med 2004;117:3950.
ABBREVIATIONS: ANCA, antineutrophil cytoplasmic antibody; MPO, myeloperoxidase; PR3, proteinase 3.
CLINICAL FEATURES
There is substantial overlap in many of the clinical fea-
tures of the AAVs. In some cases, distinguishing among
two or more of these diseases on the basis of clinical
features alone is difficult (Table 21C-3).
Upper Respiratory Tract and Ears

Although patients with the CSS or MPA may experi-
ence substantial ear, nose, or sinus disease, this pattern
of involvement is most characteristic of WG. More than
90% of patients with WG eventually develop upper
airway or ear abnormalities. The nasal symptoms of WG
include nasal pain and stuffiness, rhinitis, epistaxis, and
brown or bloody crusts. Nasal inflammation may lead
to septal erosions, septal perforation, or, in many cases,
nasal bridge collapsethe saddle-nose deformity
(Figure 21C-1). The distinction between active WG in
the sinuses and secondary infections in the sinuses may
be challenging (see Nonmedical Interventions section).
In 60% to 70% of patients with the CSS, allergic
FIGURE 21C-1
rhinitis is the earliest disease manifestation, typically
appearing years before the development of full-blown Saddle-nose deformity in Wegeners granulomatosis.
Lungs
In WG, the pulmonary manifestations range from asymp-
tomatic lung nodules and fleeting (or fixed) pulmonary
infiltrates to fulminant alveolar hemorrhage. The
nodules are usually multiple, bilateral (Figure 21C-2),
and often cavitary. Infiltrates are often misdiagnosed
initially as pneumonia.
Pulmonary capillaritis, equally likely to occur in WG
and MPA, may lead to lung hemorrhage, hemoptysis,
and rapidly changing alveolar infiltrates (Figure 21C-3).
Patients with MPA may also develop interstitial fibrosis
of the lungs.
Obstructive airway disease and fleeting pulmonary
infiltrates are the hallmarks of the CSS. The majority of
FIGURE 21C-2 patients report the new onset of asthma months to years
before the appearance of overt vasculitis. Following
Multifocal cavitary nodules in Wegeners granulomatosis.
resolution of the vasculitic phase with treatment, many
patients with CSS suffer from steroid-dependent
asthma.
systemic vasculitis. Rhinitis may be severe and may Kidneys

require serial polypectomies to relieve obstruction
and sinusitis. Nasal crusting and conductive hearing loss The most feared clinical presentation of renal disease
(due to serous otitis or granulomatous middle ear among the AAVs is rapidly progressive glomerulone-
inflammation) may also occur in the CSS. phritis. More than 75% of patients with WG will eventu-
Two principal categories of ear diseaseconductive ally develop renal involvement. The progression of the
and sensorineural hearing lossare typical of WG. The disease often appears to accelerate once kidney involve-
most common cause of conductive hearing loss may ment is apparent. In MPA, renal disease may have a
be Eustachian tube dysfunction due to nasopharyngeal more indolent course, and renal biopsies typically dem-
disease. Inner ear disease in WG may be associated with onstrate more sclerosis and fibrosis than do specimens
sensorineural hearing loss, vestibular dysfunction, or from patients with WG. Severe renal disease in CSS is
both. In contrast to middle ear disease, the mechanism very rare. Renal-limited vasculitis is pauci-immune
of inner ear disturbances in WG is poorly understood. glomerulonephritis (see Pathology section) associated
with ANCA, usually directed against MPO, without evi-
dence of disease in other organs. ANCA-associated
Trachea and Bronchi
Subglottic stenosis and stenotic lesions of the bronchi
are potentially serious complications of WG. Subglottic 21
involvement, often asymptomatic initially, becomes
apparent as hoarseness, pain, cough, wheezing, or stridor.
Thin-cut computed tomographic scans and often direct
laryngoscopy are useful in assessing these airway
narrowings.
Eyes
Scleritis may lead to necrotizing anterior scleritis (scle-
romalacia perforans) and blindness. Peripheral ulcer-
ative keratitis may cause the corneal melt syndrome.
Other ocular manifestations of AAV include conjuncti-
vitis, episcleritis, and anterior uveitis. In WG, orbital
masses termed pseudotumors occur in a retrobulbar
location in 10% to 15% of patients, causing proptosis,
FIGURE 21C-3
diplopia, or visual loss. Nasolacrimal duct obstruction is
most typical of WG. Alveolar hemorrhage in microscopic polyangiitis.
420 JOHN H. STONE
renal disease may lead to fibrotic crescents and other Nervous System
scarring within the kidney. Subsequent disease flares
and progression of renal dysfunction through hyperfil- Vasculitic neuropathy may lead to a devastating mono-
tration may lead to end-stage renal disease. neuritis multiplex or a disabling sensory polyneuropa-
thy. Mononeuritis multiplex occurs more commonly in
the CSS [up to 78% of patients (11)] and MPA (up to
Arthritis/Arthralgias 58%) than in WG. Central nervous system abnormali-
ties occur in approximately 8% of patients with WG,
Inflammatory joint complaints, often migratory and oli- usually in the form of cranial neuropathies, mass lesions,
goarticular in nature, occur in at least 60% of patients or pachymeningitis. The frequency of parenchymal brain
with AAV. Joint problems are frequently the presenting involvement in AAV, though not yet known with cer-
complaint, but the diagnosis is seldom made until other tainty and generally regarded as rare, has been reported.
symptoms are manifest. The combination of joint com- Central nervous system disease generally occurs only
plaints, cutaneous nodules (frequently mistaken for when more typical disease manifestations are present
rheumatoid nodules), and the high frequency of rheu- elsewhere.
matoid factor positivity among patients with AAV
(approximately one third are rheumatoid factor posi-
tive) often lead to the misdiagnosis of rheumatoid
Heart
arthritis early in the disease course. Arthralgias are The CSS is the type of AAV that is most likely to
more common than frank arthritis. The recurrence of involve the heart, usually in the form of rapid-onset
musculoskeletal complaints in a patient in remission heart failure. Cardiac complications in WG and MPA
often marks the start of a disease flare. are both less common and more difficult to attribute
with certainty to the underlying disease. Focal cardiac
valvular lesions, valvular insufficiency, pericarditis, and
Skin coronary arteritis have been described in WG.
In both the CSS and WG, cutaneous nodules may occur
at sites that are also common locations for rheumatoid Gastrointestinal Tract
nodules, particularly the olecranon region (Figure Eosinophilic gastroenteritis often precedes the frank
21C-4). Skin findings in the AAVs also include all of vasculitic phase of the CSS. Among patients with either
the potential manifestations of cutaneous vasculitis: the CSS or MPA, unexplained abdominal pain occurs in
palpable purpura, vesiculobullous lesions, papules, up to one third of patients and may lead to ischemic
ulcers, digital infarctions, and splinter hemorrhages. bowel. Gastrointestinal involvement is less common in
WG.
Blood
Eosinophilia (before treatment) is a sine qua non of the
CSS. Eosinophil counts are usually sensitive markers of
disease flares, but respond very quickly (within 24 hours)
to treatment with high doses of glucocorticoids. Tissue
infiltration by eosinophils, however, may remain. Mild
eosinophilia (rarely more than 15% of the total white
blood cell count) may also occur in WG. Most patients
with CSS also have elevated serum immunoglobulin E
levels. In addition to ANCA, nonspecific autoantibodies,
such as antinuclear antibodies and rheumatoid factor,
also occur in high percentages of patients with AAV.
Other
Antineutrophil cytoplasmic antibodies-associated vas-
FIGURE 21C-4 culitides rarely affect the parotid gland, pulmonary
artery, breast, or genitourinary organs. Involvement of
ChurgStrauss granulomas, that is, cutaneous extravascular
necrotizing granulomas, occurring over the elbow. These lesions
these organs by AAV is usually an unexpected finding
may occur in both the ChurgStrauss syndrome and Wegeners on biopsies performed to exclude other diseases, par-
granulomatosis, mimicking rheumatoid nodules. ticularly cancer and infection.
PATHOLOGY The interstitial lung disease of MPA resembles usual

interstitial pneumonitis (UIP), with the exception that
Fibrinoid necrosis, a pathological hallmark of AAV, necrosis of the alveolar septae and areas of hemorrhage
may be found in a variety of vasculitic (and nonvascu- can occur. More characteristic findings in MPA,
litic) conditions, such as polyarteritis nodosa, sclero- however, reveal nonspecific infiltrates or alveolar hem-
derma renal crisis, systemic lupus erythematosus, and orrhage. Vasculitis of the pulmonary capillaries may be
malignant hypertension. Both vasculitic and necrotizing difficult to prove.
granulomatous features, which do not invariably coexist, Renal disease in the AAVs is associated with focal,
may be confirmed in lung biopsy specimens. In addition, segmental lysis of glomerular tufts, disruption of the
pulmonary WG frequently demonstrates an extensive, basement membrane, and accumulation of fibrinoid
nonspecific inflammatory background. Coalescence of material (i.e., fibrinoid necrosis). Crescents in Bowmans
such neutrophilic microabscesses leads to extensive space develop as a result of spillage of inflammatory
regions of geographic necrosis. Palisading granulo- mediators across the ruptured glomerular capillaries,
mas, scattered giant cells, and poorly formed granulo- accumulation of macrophages, and epithelial cell prolif-
mas may also be found in WG. eration. Thrombotic changes in the glomerular capillary
ChurgStrauss syndrome typically evolves through loops are among the earliest histologic changes. Acute
three phases, with corresponding pathological findings. tubular necrosis and tubulointerstitial nephritis are
In the first phase, allergy, asthma, and other atopic also seen commonly. Immunofluorescence studies of
symptoms predominate. In the second, eosinophilic renal biopsy specimens demonstrate scant deposition of
infiltration occurs in the lung and other organs immunoglobulin and complement, hence the term
(eosinophilic pneumonia, eosinophilic gastroenteritis; pauci-immune glomerulonephritis.
Figure 21C-5). In the third phase, vasculitis ensues. Tissue samples from involved areas of the upper
Curiously, at the time the vasculitic phase begins, respiratory tract (nose, sinuses, and subglottic region) in
patients asthma often improves significantly. The his- WG often reveal only acute and chronic inflammation.
topathological findings in CSS in the lung include eosin- Nevertheless, these biopsies are easier to obtain than are
ophilic infiltrates; extensive areas of necrosis (reminiscent biopsies of the lung and kidney. Moreover, the combina-
of the geographic necrosis in WG); a granulomatous tion of these pathological findings (nondiagnostic in and
vasculitis of small arteries and veins, associated with of themselves) and compatible clinical features (e.g.,
striking eosinophilic infiltration. In contrast to WG and pulmonary nodules and PR3-ANCA) may yield the
MPA, lymphadenopathy (with overwhelming eosino- diagnosis in some cases. Upper respiratory tract biopsies
philic infiltration into the lymph nodes), is frequently are therefore worth undertaking in patients with signifi-
found in CSS. cant upper respiratory involvement.
FIGURE 21C-5
Eosinophilic infiltration of a salivary gland in a patient with the ChurgStrauss syndrome. The
arrows in panel B indicate the formation of a Churg-Strauss granuloma, with multinucleated
giant cells, palisading histiocytes, and scattered eosinophils.
21
422 JOHN H. STONE
ANTINEUTROPHIL CYTOPLASMIC is associated most strongly with WG. The P-ANCA

pattern, which usually corresponds to the presence of
ANTIBODIES MPO-ANCA in vasculitis patients, occurs in approxi-
mately 10% of patients with WG, but is more typical of
The Antigens MPA, the CSS, and renal-limited vasculitis. The great
Proteinase-3, a 29-kDa serine protease, is found in the majority of patients with drug-induced AAVs are
azurophilic granules of neutrophils and peroxidase-pos- P-ANCA positive, often with very high titers of
itive lysosomes of monocytes. MPO, which constitutes MPO-ANCA.
nearly 5% of the total protein content of the neutrophil, Regardless of the immunofluorescence pattern, posi-
is localized to the same cellular compartments as PR3. tive immunofluorescence assays should be confirmed
The protein is a covalently linked dimer with a molecu- by the performance of enzyme immunoassays for the
lar weight of 140 kDa. The autoantibodies directed specific antibodies associated with vasculitis: PR3- and
against PR3 and MPO are directed against multiple MPO-ANCA. Even for C-ANCA, the positive predic-
epitopes. Sera from different patients may recognize tive value for WG is only in the range of 45% to 50%
different epitopes. All ANCA, however, recognize (12,13).
restricted epitopes of PR3 involving its catalytic site.
Clinical Utility of Antineutrophil
Cytoplasmic Antibody Serologies
Clinical Testing for Antineutrophil
Despite advances in ANCA testing techniques, the
Cytoplasmic Antibodies cornerstone of diagnosis in WG remains the rigorous
Two types of assays for ANCAimmunofluorescence interpretation of histopathological specimens within the
and enzyme immunoassayare now in common use. overall clinical context. When biopsy specimens are
Capture enzyme immunoassays may offer some advan- nondiagnostic, ANCA assays provide an important
tages over the more widely available tests, but are cur- adjunct to diagnosis (Table 21C-4).
rently performed only in specialty centers. In the proper clinical setting, a positive ANCA assay
With immunofluorescence, three principal patterns greatly increases the likelihood that a form of AAV is
of fluorescence are recognized: the cytoplasmic (C- present. Most series indicate that up to 10% to 20% of
ANCA), perinuclear (P-ANCA), and atypical pat- patients with active, untreated WG are ANCA nega-
terns. In patients with vasculitis, the C-ANCA pattern tive. For patients with limited WG, 30% or more of
usually corresponds to the detection of PR3-ANCA by patients lack ANCA. Approximately 70% of patients
enzyme immunoassay. The combination of a C-ANCA with MPA and 50% of those with CSS (higher in some
pattern on immunofluorescence testing and PR3-ANCA series) have ANCA.
TABLE 21C-4. CLINICAL UTILITY OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODY TESTING.

Positive ANCA serologies are extremely useful in suggesting the diagnosis in the proper clinical setting.
Positive immunofluorescence assays without confirmatory enzyme immunoassays for anti-PR3 or anti-MPO antibodies are of limited
utility.
Histopathology remains the gold standard for diagnosis in most cases.
Negative ANCA assays do not exclude ANCA-associated vasculitis because between 10% and 50% of patients with ANCA-associated
vasculitis (depending on the particular disease) may be ANCA-negative.
Persistence of ANCA in the absence of clinical indications of active disease does not indicate a need for continued treatment.
In a patient who was ANCA-positive during active disease, persistent ANCA-negativity provides reassurancebut no guaranteethat the
disease is not active. If disease flares occur in such patients, they are usually limited.
A patient who becomes ANCA-positive again following a period of clinical quiescence associated with negative ANCA assays may be at
an increased risk for a disease flare. The temporal correlation between the return of ANCA and a disease flare, however, is poor.
Treatment of ANCA-associated vasculitis should never be predicated upon ANCA serologies or titers alone.
ABBREVIATIONS: ANCA, antineutrophil cytoplasmic antibody; MPO, myeloperoxidase; PR3, proteinase 3.

Utility of Antineutrophil temic necrotizing vasculitis (16). In humans, the evi-

dence is indirect. Propylthiouracil is known to accumulate
Cytoplasmic Antibody Assays within neutrophil granules and may lead to a drug-
following Disease Activity and induced AAV (17), possibly by increasing the immuno-
in Predicting Flares genicity of MPO (leading to the characteristically high
titers of MPO-ANCA seen in this disease).
In general, ANCA titers have imperfect correlations In addition to ANCA, multiple other elements of the
with disease activity. In one study, the positive predictive immune system participate in the pathophysiology of
value of a rise in ANCA titers as measured by immuno- these diseases. If the autoantibody response leading to
fluorescence was only 57% in a prospective study, ANCA production follows the exposure of a cryptic
compared with 71% for enzyme immunoassay (14). epitope, epitope spreading may then generalize the anti-
Moreover, among patients with an elevation of ANCA body response to the rest of the molecule. This hypoth-
titers measured by enzyme immunoassay, only 39% suf- esis implies a prominent role for the T cell in the
fered disease flares within 6 months. A more recent pathogenesis of the AAVs. Moreover, most patients with
prospective study (15) showed that increases in PR3- AAVs produce isotype-switched IgG ANCA, implying
ANCA levels did not predict disease relapses. The pro- a secondary immune response driven by T cells. Growing
portion of patients who relapsed within 1 year following evidence, particularly data from clinical studies (18),
an increase in ANCA levels was only 40%. Although now also implicates B cells as important participants in
some studies suggest that a rise in ANCA titer is a risk the inflammation of AAV. As the precursors of plasma
factor for a flare, the temporal relationship between a cells (which produce ANCA), B cells now seem a logical
rise in ANCA titers and the development of disease therapeutic target in AAV. In addition to disrupting
activity requiring treatment is very poor, with months ANCA production, however, interference with B-cell
to years between these two events. Thus, the adjustment function may also ameliorate AAV by disabling critical
of immunosuppressive medications based solely on the B cell/T cell interactions, by removing the antigen
rise or fall of ANCA titers is never justified. presenting function of B cells, and perhaps other mecha-
nisms. B-cell depletion is the focus of ongoing random-
ized trials involving patients with WG and MPA.
PATHOPHYSIOLOGY The pathophysiology of CSS likely bears many simi-
larities to that of WG and MPA, albeit ANCA are less
The AAVs are complex disorders mediated by the common in CSS. In the CSS, however, relatively little
immune system in which tissue injury results from the is currently understood about the special role played by
interplay between an initiating inflammatory event and the eosinophil in that disease.
a highly specific pathogenic immune response (i.e., the
production of ANCA) to previously shielded epitopes
of neutrophil granule proteins. ANCAs produce tissue DIFFERENTIAL DIAGNOSIS
damage via interactions with primed neutrophils and
endothelial cells. The hypothesis, supported strongly by Because of their multiorgan system nature, the differ-
in vitro evidence, is that the antibodies induce a necro- ential diagnosis of AAV is lengthy. One frequently chal-
tizing vasculitis by inciting a respiratory burst and lenging task is the differentiation of these diseases from 21
degranulation of leukocytes (neutrophils and mono- other forms of vasculitis. Indeed, clear distinctions are
cytes), leading to endothelial injury. The initial events in often impossible between WG and MPA, because gran-
the process require the priming of leukocytes by cyto- ulomatous inflammation is not detected on all biopsy
kines and perhaps other stimuli, leading to the expres- specimens from patients with WG. Distinguishing the
sion of PR3 and MPO on the cell surface. The effects AAVs from other forms of vasculitis is often more criti-
of ANCAs are determined by the state of neutrophil cal because the specific treatments differ according to
activation. ANCAs may constitutively activate primed diagnosis. In addition, the AAVs must be distinguished
neutrophils and promote binding of the primed neutro- from a host of other disorders associated with inflam-
phils to the vascular endothelium, degranulation, and mation and multiorgan system dysfunction. The differ-
the release of neutrophil chemoattractants, hence creat- ential diagnosis of AAV is shown in Table 21C-5.
ing an autoamplifying loop. ChurgStrauss syndrome has an additional major
There is now substantial evidence that ANCAs are branch of its differential diagnosis because of the eosin-
directly involved in the widespread tissue damage that ophilia associated with the disease. Allergic bronchopul-
is the hallmark of the AAVs. Recombinant activating monary aspergillosis, chronic eosinophilic pneumonia,
gene 2 (RAG-2)deficient mice that receive anti-MPO eosinophilic gastroenteritis, eosinophilic fasciitis, the
antibodies develop clinical features consistent with hypereosinophil syndrome, and eosinophilic leukemias
AAV, including crescentic glomerulonephritis and sys- must all be excluded.
424 JOHN H. STONE
TABLE 21C-5. DIFFERENTIAL DIAGNOSIS OF adjusted for renal dysfunction (20)] for 3 to 6 months.
ANTINEUTROPHIL CYTOPLASMIC ANTIBODY Some experts prefer intermittent (intravenous) regi-
ASSOCIATED VASCULITIS. mens of cyclophosphamide (e.g., 500750 mg/m2 every
Another form of ANCA-associated vasculitis month). No data yet available strongly endorse one
Wegeners granulomatosis, ChurgStrauss syndrome, cyclophosphamide regimen over another. Remission
microscopic polyangiitis, drug-induced ANCA-associated induction with cyclophosphamide is usually followed by
vasculitis, or renal-limited vasculitis longer periods of remission maintenance therapy with
Another form of vasculitis. Typical vasculitic mimickers: either azathioprine (11) or methotrexate (21).
Polyarteritis nodosa, HenochSchnlein purpura, For patients who demonstrate propensities to flare,
cryoglobulinemia, antiglomerular basement membrane long-term use of the least toxic drug for the mainte-
disease nance of remission may be appropriate. This may include
Systemic inflammatory disorders associated with autoimmunity methotrexate or azathioprine and, for patients with
Systemic lupus erythematosus, sarcoidosis, inflammatory recurrent disease flares, low doses of prednisone (e.g.,
bowel disease, relapsing polychondritis 5 mg/day). The optimal length of treatment with metho-
Infection
trexate or azathioprine is not clear, but continuation of
Endocarditis, sepsis, deep fungal infections, mycobacteria these medications for at least 1 year after remission is
(Mycobacterium tuberculosis and Mycobacterium avium- reasonable in most patients. Tumor necrosis factor inhi-
intracellulare), actinomycosis, syphilis bition (or at least etanercept) does not appear to be
Malignancy
effective in WG (22), and its use in combination with
Lymphomatoid granulomatosis, lymphoma, Castlemans cyclophosphamide may heighten the risk of solid malig-
disease, lung tumors nancies substantially (23).
Among patients with limited WG, remission is
Hypereosinophilic disorders
Allergic bronchopulmonary aspergillosis, chronic eosinophilic induced in approximately three fourths of patients with
pneumonia, eosinophilic gastroenteritis, eosinophilic fasciitis, the use of methotrexate (up to 25 mg/week) and gluco-
hypereosinophil syndrome, eosinophilic leukemia corticoids alone. Patients treated with methotrexate and
glucocorticoids must be observed carefully for break-
Miscellaneous
Idiopathic pulmonary alveolar hemorrhage, illicit drug use through disease, particularly glomerulonephritis.
(intranasal cocaine, smoking of crack)
ABBREVIATION: ANCA, antineutrophil cytoplasmic antibody.

Other Potential Medical
Treatments in Antineutrophil
Cytoplasmic AntibodyAssociated
TREATMENT Vasculitis
Current choices for treatment in WG are based on the The use of trimethoprimsulfamethoxazole as a treat-
classification of patients into the categories of either ment for WG has fallen increasingly into disfavour. The
severe or limited disease (19). Severe WG constitutes use of trimethoprimsulfamethoxazole alone for the
an immediate threat either to the function of a vital treatment of active WG is not appropriate. The medica-
organ or to the patients life. Conversely, limited WG tion may have some role in remission maintenance for
consists of disease manifestations that do not pose such patients with upper respiratory tract disease, however,
threats. The practical distinction between severe and its efficacy is uncertain and its mechanism of action
limited disease is that under the current standard of care unclear. A wide array of other therapies, such as plasma-
the diagnosis of severe WG mandates the use of cyclo- pheresis, intravenous immunoglobulin, mycophenolate
phosphamide, whereas milder therapeutic approaches mofetil, and leflunomide, have been employed in small
may be appropriate and should be considered for limited numbers of patients, but so far there are insufficient data
disease. The treatment of MPA parallels very closely to judge their efficacy. Rituximab and other strategies
that of severe WG. Because of the propensity of MPA for B-cell depletion are now being tested. Interferon-
to involve major organs (lungs, kidneys, peripheral alpha has been reported to have some benefit for CSS.
nerves) in a severe fashion, limited forms of the disease
are recognized less often. Some cases of CSS can be
treated with glucocorticoids alone, but those with vas-
Nonmedical Interventions
culitic neuropathy, life-threatening pulmonary involve- Once scarring and fibrosis are well established in the
ment, and other sobering organ involvement require subglottic region, airway narrowing may be due to the
cyclophosphamide from the outset of therapy. progression of scar tissue rather than to WG-related
In treating severe AAV, the standard approach now inflammation. In such cases, subglottic stenosis responds
is to employ cyclophosphamide [e.g., 2 mg/kg/day, poorly to immunosuppressive therapy, and the most
effective therapeutic approach to this problem is laryn- in the WGET had sustained at least one item of damage
goscopic dilatations of the airway, augmented by intra- from the disease or treatment within 1 year of enroll-
lesional corticosteroid injections (24). Serial procedures ment (26). The most common items of damage recorded
are often required. If severe subglottic stenosis pre- were hearing loss (26%) and proteinuria (19%).
cludes a safe dilatation procedure, a patent airway Much of the morbidity in the AAVs relates to pro-
should first be secured by a tracheostomy. WG often longed courses of immunosuppression, particularly the
leads to chronic nasosinus dysfunction. Regardless of need to re-treat patients who suffer multiple relapses.
disease activity, most patients require multiple daily In the 1229 patient-years of follow-up in the NIH series,
saline irrigations to minimize the accumulation of secre- only 46% of these years were spent in remission. Serious
tions and crusts, and to reduce the incidence of second- infections occurred in 46%. Other morbidities included
ary infections. Persistent or recurrent infections may drug-induced cystitis caused by cyclophosphamide
require surgical drainage. Distinguishing between wors- (43%), increased risk of malignancy (particularly
ening sinus disease caused by active WG and superin- bladder cancer, leukemia, and lymphoma), infertility
fection may be difficult. In the absence of a prompt (57% of women with childbearing potential), and
response to antibiotics, surgical drainage and biopsy are a host of side effects related to the use of
often required for a more definitive diagnosis. glucocorticoids.
COURSE AND PROGNOSIS REFERENCES

In contrast to the situation in the first 40 years follow- 1. Godman G, Churg J. Wegeners granulomatosis: pathology
ing the descriptions of the AAVs, these diseases are and review of the literature. Arch Pathol Lab Med 1954;
now highly treatable. Unfortunately, disease relapses 58:533.
are a major threat. MPA and the CSS are somewhat less 2. Van der Woude FJ, Rasmussen N, Lobatto S, et al. Auto-
likely than WG to flare after the achievement of remis- antibodies against neutrophils and monocytes: tool for
sion. The percentages of patients with those diseases diagnosis and marker of disease activity in Wegeners
who suffer disease flares after appropriate courses of granulomatosis. Lancet 1985;1:425429.
3. Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoan-
treatment have been estimated to be about 25% to
tibodies with specificity for myeloperoxidase in patients
40%. with systemic vasculitis and idiopathic necrotizing and
Even with therapy, mortality and morbidity are sub- crescentic glomerulonephritis. N Engl J Med 1988;318:
stantial. In a cohort of 158 patients followed at the 16511657.
National Institutes of Health (NIH) from the late 1960s 4. Leavitt RY, Fauci AS, Bloch DA, et al. The American
through the early 1990s (9), 12% of deaths were due to College of Rheumatology 1990 criteria for the classifica-
either the disease or complications of treatment, and tion of Wegeners granulomatosis. Arthritis Rheum 1990;
86% suffered permanent disease-related morbidity, 33:11011107.
including chronic renal insufficiency (42%), end-stage 5. Masi AT, Hunder GG, Lie JT, et al. The American College
renal disease requiring dialysis (10%), hearing loss of Rheumatology 1990 criteria for the classification of
(35%), nasal deformity (28%), tracheal stenosis (13%), Churg-Strauss syndrome (allergic granulomatosis and
angiitis). Arthritis Rheum 1990;33:10941100.
and visual loss (8%). Many patients incurred more than
6. Hunder GG, Bloch DA, Michel BA, et al. The American
21
one type of permanent morbidity. In a more recent ret- College of Rheumatology 1990 criteria for the classifica-
rospective study of 246 patients with ANCA-associated tion of giant cell arteritis. Arthritis Rheum 1990;33:
renal vasculitis (25), cumulative patient survival at 5 11221128.
years was 76%. There was an 18% mortality rate at 1 7. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of
year, however, with infections as a major cause of death. systemic vasculitides. Proposal of an international consen-
In this cohort, mortality was associated with age older sus conference. Arthritis Rheum 1994;37:187192.
than 60 years, the development of end-stage renal 8. Watts RA, Carruthers DM, Scott DG. Epidemiology of
failure, and an initial serum creatinine level greater than systemic vasculitis: changing incidence or definition?
2.26 mg/dL. Semin Arthritis Rheum 1995;25:2834.
In the Wegeners Granulomatosis Etanercept Trial 9. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegeners gran-
ulomatosis: an analysis of 158 patients. Ann Intern Med
(WGET) (22), although >90% of all patients achieved
1992;116:488498.
at least a transient disease activity score of zero, fewer 10. Stone JH for the WGET Research Group. Limited versus
than 50% of patients achieved and maintained these severe Wegeners granulomatosis: baseline data on
disease remissions over the mean 22-month course of patients in the Wegeners granulomatosis etanercept trial.
follow-up on treatment. Thus, although remissions are Arthritis Rheum 2003;48:22992309.
achieved in most patients with WG, relapse remains a 11. Hoffman GS, Specks U. Antineutrophil cytoplasmic anti-
major threat. Furthermore, 89% of the patients enrolled bodies. Arthritis Rheum 1998;41:15211537.
426 JOHN H. STONE
12. Stone JH, Talor M, Stebbing J, et al. Test characteristics 20. Jayne D, Rasmussen N, Andrassy K, et al. A randomized
of immunofluorescence and ELISA tests in 856 consecu- trial of maintenance therapy for vasculitis associated with
tive patients with possible ANCA-associated conditions. antineutrophil cytoplasmic autoantibodies. N Engl J Med
Arthritis Care Res 2000;13:424434. 2003;349:3644.
13. Boomsma MM, Stegeman CA, van der Leij MJ, et al. Pre- 21. Langford CA, Talar-Williams C, Barron KS, et al. A
diction of relapses in Wegeners granulomatosis by mea- staged approach to the treatment of Wegeners granulo-
surement of antineutrophil cytoplasmic antibody levels: a matosis: induction of remission with glucocorticoids and
prospective study. Arthritis Rheum 2000;43:20252033. daily cyclophosphamide switching to methotrexate for
14. Finkielman JD, Merkel PA, Schroeder D, et al. Antineu- remission maintenance. Arthritis Rheum 1999;42:2666
trophil cytoplasmic antibodies against proteinase 3 do not 2673.
predict disease relapses in Wegeners granulomatosis. 22. The WGET Research Group. Etanercept in addition to
Ann Intern Med 2007, (in press). standard therapy in patients with Wegeners granuloma-
15. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplas- tosis. N Engl J Med 2005;352:351361.
mic autoantibodies specific for myeloperoxidase cause 23. Stone JH, Holbrook JT, Tibbs A, et al. Solid malignancies
glomerulonephritis and vasculitis in mice. J Clin Invest in the Wegeners granulomatosis Etanercept trial. Arthri-
2002;110:955963. tis Rheum 2006;54:16081618.
16. Choi HK, Merkel PA, Walker AM, et al. Drug-associated 24. Hoffman GS, Thomas-Golbanov CK, et al. Treatment of
antineutrophil cytoplasmic antibody-positive vasculitis: subglottic stenosis, due to Wegeners granulomatosis,
prevalence among patients with high titers of antimyeloper- with intralesional corticosteroids and dilation. J Rheuma-
oxidase antibodies. Arthritis Rheum 2000;43:405413. tol 2003;30:10171021.
17. Keogh KA, Ytterberg SR, Fervenza FC, et al. Rituximab 25. Booth AD, Almond MK, Burns A, et al. Outcome of
for refractory Wegeners granulomatosis: report of a pro- ANCA-associated renal vasculitis: a 5-year retrospective
spective, open-label pilot trial. Am J Respir Crit Care study. Am J Kidney Dis 2003;41:776784.
Med 2006;173:180187. 26. Seo P, Min Y-I, Holbrook JT, et al. Damage from
18. Wung PK, Stone JH. Therapeutics for Wegeners granu- Wegeners granulomatosis and its treatment: prospective
lomatosis. Nat Clin Pract Rheumatol 2006;2:192200. data from the Wegeners Granulomatosis Etanercept
19. WGET Research Group. Design of the Wegeners Gran- Trial. Arthritis Rheum 2005;52:21682178.
ulomatosis Etanercept Trial (WGET). Control Clin Trials
2002;23:450468.
CHAPTER 21
Vasculitides
D. Immune ComplexMediated
Vasculitis
PHILIP SEO, MD, MHS
Pathogenic immune complexes formed between medications (e.g., penicillins, sulfonamides, or

antigen and antibodies tend to occur during periods cephalosporins) or infections.
of antigen excess. When the immune complexes Cryoglobulinemic vasculitis is usually caused by
precipitate into the tissues, they fix complement, hepatitis C infections. The antigens involved in
leading to an intense immune reaction. cryoglobulinemic vasculitis are portions of the
In immune complex vasculitis, immune complexes hepatitis C virus (HCV) virion. The relevant antibodies
deposit in the vascular endothelium or in capillary are both IgG and IgM, leading to the designation
beds, such as those found in the skin, kidneys, or mixed cryoglobulinemia.
lungs. HenochSchnlein purpura is associated
The most common skin manifestation of small vessel strongly with IgA deposition within blood vessel
vasculitis is palpable purpura. walls.
Hypersensitivity vasculitis is characterized by immune Hypocomplementemic urticarial vasculitis has many
complex deposition in capillaries, postcapillary features that overlap with systemic lupus
venules, and arterioles. The usual causes are either erythematosus.
Exposure to a foreign antigen activates an adaptive several examples of immune complexmediated vascu-
immune response that leads to the production of litis and highlights some common themes.
antigen-specific antibodies. The combination of anti-
body with antigen creates immune complexes that neu-
tralize the foreign antigen, and allow it to be cleared PATHOPHYSIOLOGY
safely by the reticuloendothelial system. This complex
system, however, contains within it the potential for In 1903, Maurice Arthus noted that intradermal injec-
failure. If the antibody response is just right, these tion of a rabbit with horse serum resulted in a cutaneous
immune complexes may escape early detection, and inflammatory reaction that evolved into localized tissue
instead imbed themselves into joints and blood vessels. necrosis (2). The reaction was faster, he observed, if the
These immune complexes can then activate comple- animal had been previously exposed to horse serum.
ment, leading to local inflammation. Immune complexes This response, now known as the Arthus reaction, forms
deposited in the kidneys, for example, create glomeru- the basis of our understanding of immune complex
lonephritis (1). Those deposited in the synovium lead to mediated diseases. In the Arthus model, injection of the
arthritis. If the immune complexes are found in the horse serum leads to immune complex formation that
blood vessels, vasculitis is the result. initiates complement activation and an influx of inflam-
In pathology, the word vasculitis describes inflamma- matory cells. In the areas of most intense inflammation,
tion within blood vessel walls. This process frequently in situ thrombosis formation can lead to tissue ischemia
leads to cellular destruction, damage to the vascular and hemorrhagic infarction.
structures, and compromise of blood flow to organs sup- In general, immune complexes are not pathogenic.
plied by the involved vessels, resulting in organ compro- Their immunogenicity is governed by a large number of
mise. Several forms of vasculitis are the direct result of factors, including antigen load, antibody response, the
immune complex deposition. This chapter outlines efficiency of the reticuloendothelial system in the clear-
427
428 PHILIP SEO
ance of immune complexes, physical properties of the In 1990, the American College of Rheumatology pro-
blood vessels (including flow dynamics and previous posed the following five criteria for the classification of
endothelial damage), and the solubility of the immune hypersensitivity vasculitis in an adult (3):
complexes themselves.
Immune complex solubility is determined by the ratio Age >16 years
of antibody to antigen. When antibody and antigen are Use of a possible offending medication in temporal
present in equal proportion, large immune complexes relation to the symptoms
are formed, which are identified easily and removed by Palpable purpura
the reticuloendothelial system. When there is an excess Maculopapular rash
of antibody, small immune complexes are formed, which Biopsy of a skin lesion showing neutrophils around
remain in solution, and do not elicit an immune response. an arteriole or venule
When there is a slight excess of antigen, however,
the immune complexes precipitate from solution, and The presence of three or more criteria has a sensitiv-
become trapped in characteristic areaseither the cap- ity of 71% and specificity of 84% for the diagnosis of
illary beds (such as those found in the skin, kidneys, or hypersensitivity vasculitis.
lungs), or the endothelium of medium-sized blood Hypersensitivity vasculitis that occurs without sys-
vessels previously damaged by turbulent blood flow. temic manifestations is sometimes referred to as cutane-
When the immune complexes precipitate into the ous vasculitis or cutaneous leukocytoclastic angiitis. The
tissues, they fix complement, leading to an intense term serum sickness, on the other hand, is reserved to
immune reaction. Complement fixation and local inflam- describe a systemic illness, including rash and arthral-
mation recruit neutrophils, which attempt to engulf the gias, which occurs 1 to 2 weeks after exposure to a drug
immune complexes. During this process, the neutrophils or foreign antigen.
degranulate, releasing lysosomal enzymes and oxygen
free radicals that cause tissue necrosis. Clinical Presentation
The inciting antigen can be from numerous sources.
Most patients with hypersensitivity vasculitis will
In infective endocarditis, the antibody response, formed
develop cutaneous manifestations, the most common
against bacterial antigens, can lead to painful cutaneous
of which is purpura (Figure 21D-1). These lesions are
lesions known as Osler nodes. In systemic lupus erythe-
matosus (SLE), antibodies form against nuclear compo-
nents (e.g., DNA and histones) that are released during
tissue injury. Certain forms of malignancy can be associ-
ated with immune complex formation, with antibodies
directed against tumor-associated antigens. Immune
complexes may also form in response to a large number
of drugs, including penicillin and sulfonamides.
CLINICAL SYNDROMES
Hypersensitivity Vasculitis
Definition
Hypersensitivity reactions were first noted in patients
who were treated with antitoxin derived from horse
serum. Such patients developed an antibody response
to the horse antigens, which led to a characteristic syn-
drome of fever, joint pain, and rash now known as serum
sickness.
Hypersensitivity vasculitis refers to a heterogeneous
group of syndromes (including serum sickness and drug-
induced vasculitis) characterized by immune complex
deposition in capillaries, postcapillary venules, and
arterioles. This is the most common form of vasculitis.
Although multiple agents have been implicated, includ- FIGURE 21D-1
ing penicillins, sulfonamides, and cephalosporins, the Palpable purpura in a patient with hypersensitivity vasculitis.
inciting agent cannot always be identified. (Courtesy of Dr. John Stone.)
distributed usually in a symmetric fashion over depen- Prognosis

dent regions of the body, particularly the lower legs
(and, in recumbent patients, over the buttocks) because The prognosis for patients with hypersensitivity vascu-
of the increased hydrostatic pressure in such areas. Pur- litis depends on the nature of the inciting agent. In the
puric lesions are not always palpable to the touch. The case of drug-induced vasculitis, multiple agents may
term palpable purpura is essentially synonymous with need to be discontinued and re-introduced gradually.
small vessel vasculitis, but does not necessarily imply an Approximately half of cases of isolated cutaneous angi-
immune complexmediated pathophysiology; pauci- itis do not have an obvious cause. Many such cases are
immune forms of vasculitis, such as Wegeners granulo- associated with a relapsing and remitting course, but
matosis, microscopic polyangiitis, and the ChurgStrauss remain restricted to the skin and do not mandate aggres-
syndrome, for example, may present with identical skin sive immunosuppressive therapy.
findings (see Chapter 21C).
Diagnosis
Cryoglobulinemic Vasculitis
Definition
Biopsy is the diagnostic method of choice. Cutaneous
biopsies are associated with low morbidity, and are gen- In 1933, Wintrobe and Buell noted that when serum
erally sufficient to confirm ones clinical suspicion. Light from a patient with a hyperviscosity syndrome due to
microscopy examination of a hematoxylin and eosin multiple myeloma was held at temperatures less than
(H&E) preparation will demonstrate an inflammatory 37C, a protein precipitate formed (4). In 1947, this
infiltrate primarily composed of mononuclear or poly- cold precipitable serum globulin was referred to for
morphonuclear cells, as well as telltale signs of small the first time as a cryoglobulin. Cryoglobulins are
vessel vasculitis: leukocyte diapedesis, karyorrhexis, immune complexes that are characterized by their ten-
and leukocytoclasis. Although H&E preparations are dency to precipitate from serum under conditions of
adequate for confirming the presence of vasculitis, they cold. Cryoglobulins, detectable to a varying degree in a
often provide insufficient data for a precise diagnosis. wide array of inflammatory conditions, are not invari-
In cases of immune complexmediated vasculitis, ably pathogenic. In some patients, however, cryoglobu-
direct immunofluorescence (DIF) studies on the biopsy lins deposit in the small- and medium-sized blood vessels
demonstrate the types of immunoreactants (i.e., and activate complement, leading to cryoglobulinemic
immunoglobulin and complement proteins) present at vasculitis (5).
the site of disease. Although direct immunofluorescence Three major types of cryoglobulinemia are recog-
requires a biopsy of a second cutaneous site, this proce- nized, defined by the specific kinds of immunoglobulins
dure is critical in many cases to differentiating the array with which they are associated. Type I cryoglobulinemia,
of conditions associated with cutaneous vasculitis. characterized by a monoclonal gammopathy (generally
Biopsy is especially useful to exclude other causes of IgG or IgM), can be associated with Waldenstrms
vascular injury, including embolism and hypercoagula- macroglobulinemia or, less frequently, multiple
bility states, which may demonstrate evidence of eryth- myeloma. Type I IgA cryoglobulinemia has also been
rocyte extravasation but not immune complex deposition. described, although this is quite rare. In contrast to the
Of course, the presence of small vessel vasculitis does monoclonal nature of type I cryoglobulinemia, type II 21
not always confirm the presence of a primary autoim- and type III cryoglobulinemias are known as mixed
mune disease; malignancy, for example, can also be asso- cryoglobulinemias because they are comprised of
ciated with leukocytoclastic vasculitis. All biopsies, both IgG and IgM. In most cases of type II cryoglo-
therefore, must be evaluated in the appropriate clinical bulinemia, more than 90% of which are caused by
context. hepatitis C infections, the cryoproteins consist of
monoclonal IgM and polyclonal IgG. Cases of type II
cryoglobulinemia not associated with hepatitis C
Therapy infections are sometimes termed mixed essential
Removal of the inciting agent is the only reliable therapy. cryoglobulinemia. Such cases may be associated with a
In patients who have been exposed to multiple medica- still undefined viral infection. Type III cryoglobuline-
tions, determining the inciting agent may be difficult, mia, typically associated with polyclonal IgG and
and may require withdrawal of multiple agents simulta- polyclonal IgM, is associated with many forms of chronic
neously until the syndrome clears, typically in 1 to 2 inflammation, including infection and autoimmune
weeks. Immunosuppression with glucocorticoids should disease. Not every form of cryoglobulinemia fits
be reserved for patients with particularly fulminant neatly into this classification system; cryoglobulins
disease, and may be discontinued usually within several can, for example, have an oligoclonal antibody
weeks. component.
430 PHILIP SEO
Clinical Presentation
Type I cryoglobulinemia rarely presents with signs and
symptoms of vasculitis. When symptomatic, type I cryo-
globulinemia may be associated with a hyperviscosity
syndrome that can lead to serious neurologic manifesta-
tions, including dizziness, confusion, headache, and
stroke. Type I cryoglobulinemia can also be associated
with other evidence of vascular stasis, including livedo
reticularis, acrocyanosis, and digital gangrene (Figure
21D-2).
Type II and type III cryoglobulinemias often present
with a triad of signs and symptoms: purpura, arthralgias,
and myalgias. The purpura may be extensive and con-
fluent, and sometimes involves the trunk, upper extrem- FIGURE 21D-3
ities, and even the face (albeit in most cases the rash is
confined to the lower extremities). Other common Proliferative glomerulonephritis associated with type II cryoglob-
ulinemia. (Courtesy of Dr. Mark Haas.)
organ system involvement, more common in type II
than in type III cryoglobulinemia, includes membrano-
proliferative glomerulonephritis (Figure 21D-3), periph-
eral neuropathy, and cutaneous ulcerations (the result
of medium vessel vasculitis, in contrast to the small- Renal biopsies from patients with glomerulonephritis
sized vessel involvement that leads to purpura). caused by cryoglobulinemia reveal a membranoprolif-
erative glomerulonephritis that must be distinguished
Diagnosis from lupus nephritis (another disorder in which immune
complexes play a major role).
Biopsy of an affected organ (such as the skin or kidney) If biopsy is impractical or impossible, serologic testing
may be the most straightforward method of confirming may be helpful. The most directly relevant test is a
the diagnosis. Light microscopy of purpuric lesions serum cryoglobulin assay, which can give a direct sense
demonstrates leukocytoclastic vasculitis. Direct immu- of the burden of disease. The serum is allowed to remain
nofluorescence studies reveal various types of immu- at 4C for several days before interpretation. The per-
noglobulin and complement deposition, depending on centage of the serum occupied by the cryoprecipitate is
cryoglobulinemia type. In type II cryoglobulinemia, for commonly referred to as the cryocrit, and may be useful
example, direct immunofluorescence reveals IgG and for following such patients longitudinally.
IgM deposition, as well as complement components. Serum cryoglobulin tests are, unfortunately, notori-
ously difficult to obtain, largely because the collection
apparatus must be prewarmed and the blood must be
allowed to clot at 37C before processing. False-
negative assays for cryoglobulins are common, particu-
larly in laboratories not experienced in the collection
and processing of samples.
For patients with type II and type III cryoglobuline-
mia, nonspecific serologic testing may also heighten
suspicion. First, a strong clue to the presence of mixed
cryoglobulinemia is an extremely low (to almost unde-
tectable) level of C4. For reasons that are not entirely
clear, C4 levels are lowered out of proportion to the
decrease observed in C3. Second, the monoclonal com-
ponent of type II cryoglobulins almost invariably has
rheumatoid factor activity (i.e., binds to the Fc portion
of IgG). Thus, essentially all patients with type II cryo-
globulinemia are rheumatoid factor-positiveusually
FIGURE 21D-2 strikingly so. In many cases, rheumatoid factor tests are
Acrocyanosis and digital necrosis in type I cryoglobulinemia a more reliable screening test for type II cryoglobuline-
associated with multiple myeloma. (Courtesy of Dr. John Stone.) mia than are assays for cryoglobulins themselves.
Although rheumatoid factor titers correlate with immu- HenochSchnlein Purpura

noglobulin burden in such patients and can be used in
longitudinal follow-up in a manner similar to the cry- Definition
ocrit, the level of clinical symptomatology often corre- HenochSchnlein purpura (HSP) is an immune
lates poorly with both rheumatoid factor level and complexmediated form of small vessel vasculitis that
cryocrit. Once patients have achieved a state of disease is associated strongly with IgA deposition within blood
quiescence following treatment, both rheumatoid factor vessel walls. Many cases of HSP are reported to occur
levels and cryocrit often remain elevated. Neither should after upper respiratory tract infections. Group A strep-
be used as a gauge of therapy for most patients. Finally, tococci, mycoplasma, EpsteinBarr virus, varicella, and
acute-phase reactants such as the erythrocyte sedimen- other infectious agents have all been implicated in the
tation rate and the C-reactive protein are elevated in pathogenesis of this disease, but the true etiology
many patients with cryoglobulinemia. In patients with remains unknown.
type I cryoglobulinemia, for example, the erythrocyte In 1990, the American College of Rheumatology pro-
sedimentation rate may be even higher than anticipated posed the following criteria for the classification of HSP
because of the excess circulating immunoglobulin. (6):
Therapy Palpable purpura

Age 20 years at disease onset
Treatment of the underlying cause of the cryoglobulins Bowel angina
is the only approach that may lead to long-term response. Granulocytes in arteriole or venule walls on biopsy
Immunosuppression alone will not be sufficient to treat
a cryoglobulinemic vasculitis that is driven by malig- Meeting two of four criteria is associated with a
nancy or chronic infection. In the case of hepatitis C sensitivity of 87% and a specificity of 88% for this
associated cryoglobulinemic vasculitis, for example, the diagnosis.
optimal therapy consists of the effective control of the
underlying viral infection (typically with interferon-
alpha and ribavirin). In patients who experience severe
consequences of cryoglobulinemia (such as mononeuri- Clinical Presentation
tis multiplex, glomerulonephritis, or other forms of The hallmarks of HSP include an upper respiratory
tissue necrosis), immunosuppression with high dose glu- tract infection followed by a syndrome characterized by
cocorticoids and cyclophosphamide may be necessary a purpuric rash, arthralgias, abdominal pain, and renal
to prevent further damage. In patients with rampant disease. HSP is usually viewed as a disease of childhood
systemic vasculitis, anecdotal evidence suggests that the and, indeed, the majority of cases affect children younger
systemic inflammation should be controlled first with than 5 years of age. Adults, however, can also be affected
glucocorticoids and other immunosuppressive agents, as by HSP, and have a greater tendency toward prolonged
appropriate, before the institution of antiviral therapy. disease courses (with recurrent bouts of purpura) than
In some cases of flagrantly active vasculitis, the intro- do children (7). Colicky abdominal pain, presumably
duction of antiviral therapy first is believed to have secondary to gastrointestinal vasculitis, is a common
triggered disease exacerbation through an unfavorable characteristic of HSP, and frequently occurs within a 21
alteration of the antigen/antibody ratio. week after the onset of rash. Occasionally the abdomi-
nal pain in HSP occurs before the onset of purpura, and
Prognosis may be difficult to distinguish from an acute abdomen.
Endoscopy may demonstrate purpura in the upper
The prognosis of patients with cryoglobulinemia gener- or lower intestinal tract. Mild glomerulonephritis is
ally depends on the underlying cause. The outcome of common and generally self-limited, although some
type I cryoglobulinemia relates closely to the efficacy in patients will develop end-stage renal disease.
treating the cause of the cryoglobulin. Type II cryo-
globulinemia secondary to hepatitis C may be treated
effectively if the viral infection is responsive to therapy.
Diagnosis
If patients do not tolerate antiviral therapy well or if the In children with mild manifestations, the clinical history
treatment is ineffective, however, some patients may alone may be sufficient to confirm the diagnosis. In
require low-to-moderate doses of prednisone to control more serious cases or when there is sufficient doubt
the disease. Type III cryoglobulinemia is frequently a about the diagnosis, biopsy of an involved organ is
response to an inflammatory event (such as infection), essential. Unlike other forms of immune complexmedi-
and may not require specific therapy. ated disease, however, direct immunofluorescence will
432 PHILIP SEO
reveal florid IgA deposition. In the proper clinical ity vasculitis in which the principal skin manifestation is
setting, this finding is diagnostic of HSP. Other forms of urticaria. Normocomplementemic urticarial vasculitis
small vessel vasculitis may have small quantities of IgA tends to be self-limited, as is the case with hypersensitiv-
within blood vessels, but IgA is not the predominant ity vasculitis. In contrast, urticarial vasculitis associated
immunoreactant in such cases. with hypocomplementemia is much more likely to con-
stitute a significant and persistent clinical problem.
Two categories of urticarial vasculitis associated with
Therapy hypocomplementemia are recognized. The distinctions
In mild cases of HSP, no specific therapy is necessary. between these two categories are not always sharp, and
Even for patients with glomerulonephritis, it has been both categories also share a number of features with
difficult to demonstrate that treatment with glucocorti- systemic lupus erythematosus. The first category, known
coids or immunosuppressive agents significantly alters simply as hypocomplementemic urticarial vasculitis,
outcomes. Despite this, it may be prudent to treat ag- refers to cutaneous vasculitis associated with low levels
gressive renal involvement with an immunosuppres- of serum complement (C3 and C4). The diagnosis of
sive regimen, including high-dose glucocorticoids and hypocomplementemic urticarial vasculitis is predicated
another immunosuppressive agent such as cyclophos- upon the exclusion of other disorders that may present
phamide, azathioprine, or mycophenolate mofetil, in a similar fashion, particularly cryoglobulinemia and
depending on disease severity (8). In patients with renal SLE. The second categorya more specific but still
involvement, anecdotal evidence suggests that plasma- loosely defined entity known as the hypocomplement-
pheresis and intravenous immunoglobulin may also be emic urticarial vasculitis syndrome (HUVS)consists
beneficial, particularly in patients who are refractory to of the constellation of low complement levels and urti-
standard immunosuppressive regimens. caria for a period of at least 6 months, as well as some
or all of the following: arthritis, glomerulonephritis,
uveitis, angioedema, chronic obstructive pulmonary
Prognosis disease, pleurisy, or pericarditis.
Recurrences of skin disease, often comprised of multi-
ple episodes occurring over many months, are not Clinical Presentation
unusual. Generally, however, even in patients with
recurrent disease, the rule is for the disorder to subside Although the lesions associated with chronic urticaria
and to resolve completely over a few months to a year. and urticarial vasculitis are similar in appearance, certain
In a minority of patients, some evidence of permanent differences help differentiate these two conditions. In
renal damage persists in the form of proteinuria and urticarial vasculitis, the urticaria typically have a purpu-
hematuria. Only a small minority, probably well under ric quality, indicative of small blood vessel damage and
5%, develop renal failure as a result of HSP. red blood cell extravasation (Figure 21D-4). Unlike
common urticaria, the lesions of urticarial vasculitis are
frequently associated with moderate pain, burning, and
Hypocomplementemic Urticarial
Vasculitis Syndrome
Definition
The study of urticaria is hampered by multiple terms
that sound similar but describe different types of dis-
eases. The word urticaria is most frequently used to
describe acute urticaria, an IgE-mediated hypersensitiv-
ity reaction to a variety of stimuli, including medica-
tions, infection, and other triggers. Acute urticaria
manifests as pruritic wheals that resolve days after the
allergen is removed. Chronic urticaria is an autoimmune
condition that is probably driven by an autoantigen.
This form of urticaria may require immunosuppressive
therapy in addition to antihistamines to prevent recur-
rence (9).
Urticarial vasculitis describes a form of small vessel
vasculitis that is characterized by the appearance of
FIGURE 21D-4
urticarial wheals. Normocomplementemic urticarial vas-
culitis is most often simply an example of hypersensitiv- Urticarial vasculitis. (Courtesy of Dr. John Stone.)
tenderness, in addition to pruritus. Whereas common nosis based not only on the presence of urticarial vas-
urticaria typically resolve completely within 24 to 48 culitis but also the occurrence of typical features in
hours, the lesions of urticarial vasculitis may take days extracutaneous organ systems.
to resolve completely and often worsen without therapy.
Arthralgias and myalgias are common in urticarial vas- Therapy
culitis. As noted above, patients with HUVS may also
develop glomerulonephritis, pulmonary manifestations Some cases of hypocomplementemic urticarial vas-
(particularly obstructive airway disease), and other find- culitis respond to therapies commonly used for the
ings. Gastrointestinal, cardiovascular, and neurologic treatment of SLE, including low-dose prednisone,
manifestations are uncommon, but have been reported. hydroxychloroquine, dapsone, or other immunomodu-
There is striking overlap between HUVS and SLE, and latory agents. There is anecdotal evidence that anti-
patients will frequently have characteristics of both, histamines, calcium channel antagonists, doxepin,
although angioedema and COPD are more common in methotrexate, indomethacin, colchicine, and pentoxifyl-
HUVS. line are effective in some cases. Serious cases, particu-
larly those presenting with glomerulonephritis or other
forms of serious organ involvement, may require treat-
Diagnosis ment with high doses of glucocorticoids and cytotoxic
Biopsy of an urticarial wheal in UV will demonstrate agents. Both chronic obstructive pulmonary disease
evidence of leukocytoclastic vasculitis, including injury (COPD) and cardiac valvular abnormalities are associ-
to the endothelial cells of the postcapillary venules, ated with HUVS, and may require specific treatment as
erythrocyte extravasation, leukocytoclasis, fibrin deposi- well.
tion, and a perivascular neutrophilic (or less commonly,
lymphocytic) infiltrate. Direct immunofluorescence Prognosis
demonstrates immune complex deposition around
blood vessels in the superficial dermis and striking The prognosis of HUVS is frequently linked to the dis-
deposition of immunoglobulins and complement along order with which it is associated. SLE, COPD, angio-
the dermalepidermal junction (Figure 21D-5). The edema, and valvular abnormalities are all known to
interface dermatitis is identical to that observed in occur in association with this disorder, and in such cases,
lupusa histopathological finding termed the lupus may strongly influence both quality and quantity of
band test. In the proper setting, these findings (interface life.
dermatitis as well as immunoreactant deposition within
blood vessels) are diagnostic of hypocomplementemic
urticarial vasculitis. HUVS, in contrast, is a clinical diag-
SUMMARY
The immune complexmediated vasculitides are a clini-
cally heterogeneous group of disorders linked by inef-
ficient, defective, or dysregulated clearance of immune
complexes by the reticuloendothelial system. Biopsy of
an involved organ is frequently helpful in establishing
the diagnosis. Direct immunofluorescence studies of 21
involved blood vessels demonstrate characteristic pat-
terns of immunoglobulin and complement deposition,
which may be particularly useful in distinguishing these
diseases. The prognosis of patients with immune
complexmediated vasculitis is tied closely to the ability
to identify and to treat the underlying cause of the
immune response.
REFERENCES
FIGURE 21D-5 1. Nangaku M, Couser WG. Mechanisms of immune-deposit
Direct immunofluorescence of a skin biopsy in urticarial formation and the mediation of immune renal injury. Clin
vasculitis. The immunostaining shows immunoreactant deposi- Exp Nephrol 2005;9:183191.
tion within small blood vessels in the superficial dermis, and 2. Arthus M. Injections repetees de serum de cheval cuez le
florid deposition along the dermalepidermal junction. (Courtesy lapin. Seances et Memoire de la Societe de Biologie 1903;
of Dr. John Stone.) 55:817825.
434 PHILIP SEO
3. Calabrese LH, Michel BA, Bloch DA, et al. The American tion of Henoch-Schnlein purpura. Arthritis Rheum 1990;
College of Rheumatology 1990 criteria for the classifica- 33:11141121.
tion of hypersensitivity vasculitis. Arthritis Rheum 1990;33: 7. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V,
11081113. Garcia-Fuentes M, Gonzalez-Gay MA. Henoch-Schonlein
4. Wintrobe MM, Buell MV. Hyperproteinemia associated purpura in adulthood and childhood: two different express-
with multiple myeloma: with report of a case in which ions of the same syndrome. Arthritis Rheum 1997;40:859864.
an extraordinary hyperproteinemia was associated with 8. Flynn JT, Smoyer WE, Bunchman TE, Kershaw DB,
thrombosis of the retinal veins and symptoms suggesting Sedman AB. Treatment of Henoch-Schonlein purpura glo-
Raynauds disease. Bulletin Johns Hopkins Hosp 1933; merulonephritis in children with high-dose corticosteroids
52:156. plus oral cyclophosphamide. Am J Nephrol 2001;21:128
5. Ferri C, Mascia MT. Cryoglobulinemic vasculitis. Curr 133.
Opin Rheumatol 2006;18:5463. 9. Davis MD, Brewer JD. Urticarial vasculitis and hypocom-
6. Mills JA, Michel BA, Bloch DA, et al. The American plementemic urticarial vasculitis syndrome. Immunol
College of Rheumatology 1990 criteria for the classifica- Allergy Clin North Am 2004;24:183213.
CHAPTER 21
Vasculitides
E. Miscellaneous Vasculitis
(Behets Disease, Primary Angiitis
of the Central Nervous System,
Cogans Syndrome, and Erythema
Elevatum Diutinum)
KENNETH T. CALAMIA, MD
CARLO SALVARANI, MD
The prevalence of Behets disease is highest in The diagnosis of primary angiitis of the central
countries of the eastern Mediterranean, the Middle nervous system should never be made on the basis
East, and East Asia. of an angiogram alone.
Aphthous oral ulcers are usually the first and most Patients with benign angiopathy of the central
persistent clinical feature of Behets disease. Aph- nervous system are predominantly female, tend to
thous ulcers also occur frequently on the genitals present acutely with headache (with or without focal
(e.g., the scrotum or vulva). symptoms), and have normal or near normal
Uveitiseither anterior or posterioris common in cerebrospinal fluid.
Behets disease and a source of major morbidity. Cogans syndrome refers to the association of
Many forms of central nervous system disease may inflammation in both the eyes and ears: specifically,
occur in Behets disease. These include aseptic the occurrence of nonsyphilitic interstitial keratitis
meningitis and white matter lesions in the and immune-mediated inner ear disease, resulting in
brainstem. audiovestibular dysfunction.
Human leukocyte antigen (HLA)-B51 is a strong risk Any type of ocular inflammation may occur in
factor for Behets disease. Cogans syndrome (e.g., scleritis, uveitis, orbital
The diagnosis of primary angiitis of the central pseudotumor). The inner ear disease associated with
nervous system is predicated upon either biopsy this condition often leads to deafness.
evidence of vasculitis or angiographic findings In erythema elevatum diutinum, skin lesions consist of
suggestive of vasculitis in the setting of other purple, red, or brown plaques and often have an annular
compelling features, for example, strokes demon- or nodular appearance. The skin lesions have a predilec-
strated by magnetic resonance imaging or the tion for the extensor surfaces of the distal extremities
findings of a cerebrospinal fluid pleocytosis. and often overlie joints, but may be generalized.
BEHETS DISEASE disease. The disease tends to be more severe in areas

where it is more common. Prevalence rates in all areas
Behets disease (BD) is a chronic inflammatory disor- of the world are increasing, probably because of
der of unknown cause. Its manifestations are thought improved recognition and reporting.
to be caused by an underlying vasculitis. Although this Behets disease occurs primarily in young adults.
disease is recognized worldwide, the prevalence is The mean age at onset is between 25 and 30 years. The
highest in countries of the eastern Mediterranean, the incidence of disease in males and females with the
Middle East, and East Asia, thus the name Silk Road disease is approximately equal along the Silk Road, but
435
436 KENNETH T. CALAMIA AND CARLO SALVARANI
in Japan, Korea, and Western countries the disease

occurs more frequently in women. Familial aggregation
and juvenile cases are not common. Case confirmation
can be challenging because many patients labeled as
having Behets disease have oral ulcers as the primary
or sole manifestation.
Clinical Manifestations
Aphthous oral ulcers are usually the first and most per-
sistent clinical feature of BD. Lesions occur in crops and
some patients may have them during most of the course
of the disease. Aphthae occur as ulcers that are 2 to
12 mm or larger. These are discrete, painful, round or
oval red-rimmed lesions that affect mainly the nonke- FIGURE 21E-2
ratinized mucosa of the cheeks, the border of the tongue,
Ulcers on the scrotum in a patient with Behets disease.
the soft palate, and the pharynx (Figure 21E-1). Oral (Courtesy of J.D. ODuffy, MB.)
ulcers are identical to the lesions of recurrent aphthous
stomatitis. The severity and behavior of the oral ulcers
in BD often fit the description of complex aphthosis, in
and may result in scarring, but vaginal ulcers may be
which multiple, recurrent, or persisting lesions result in
asymptomatic or only produce a discharge. Perianal
a severe syndrome that may include perianal or genital
ulcers may occur.
ulceration.
Skin lesions are common in BD. The International
Genital ulcers resemble oral aphthae but occur less
Study Group (ISG) criteria for the diagnosis of BD
frequently. They occur as single or multiple lesions of
(Table 21E-1) (1) include the presence of erythema
the vulva and in the vagina, or on the scrotum or penile
nodosum, pseudofolliculitis, papulopustular lesions,
shaft (Figure 21E-2). Genital lesions are usually painful
or acneform nodules. Nodular lesions should be distin-
guished from superficial thrombophlebitis. A neutro-
philic vascular reaction characterizes lesions typical of
TABLE 21E-1. INTERNATIONAL STUDY GROUP

CRITERIA FOR BEHETS DISEASE.
Recurrent oral Minor aphthous, major aphthous, or
ulceration herpetiform ulceration observed by
physician or patient, which recurred at
least 3 times in one 12-month perioda
Plus 2 of:
Recurrent genital Aphthous ulceration or scarring,

ulceration observed by physician or patienta
Eye lesions Anterior uveitis, posterior uveitis, or cells

in vitreous on slit lamp examination;
or retinal vasculitis observed by
ophthalmologist
Skin lesions Erythema nodosum observed by

physician or patient, pseudofolliculitis,
or papulopustular lesions; or acne-
form nodules observed by physician
in postadolescent patients not
receiving corticosteroid treatmenta
Positive pathergy test Read by physician at 24 to 48 hours

FIGURE 21E-1
SOURCE: From International Study Group for Behets Disease. Lancet
Oral aphthous ulceration in Behets disease. (Courtesy of J.D. 1990;335:10781080, by permission of Lancet.
ODuffy, MB.) a
Findings applicable only in the absence of other clinical explanations.
to episodes of retinal occlusion and areas of ischemia,

may be followed by neovascularization, vitreous hemor-
rhage and contraction, glaucoma, and retinal detach-
ment. The earliest findings of retinal vasculitis may be
detected with fluorescein angiography. Isolated optic
disk edema in BD suggests cerebral venous thrombosis
rather than ocular disease, but papillitis may occur with
ocular inflammation and central nervous system disease.
Cranial nerve palsies may result from brain stem lesions,
and visual field defects may also be caused by intracra-
nial disease involving the optic pathways.
With cerebral venous thrombosis, patients usually
present with symptoms of intracranial pressure: head-
ache, visual obscurations, and papilledema. Magnetic
FIGURE 21E-3 resonance imaging may be used to demonstrate acute
or recent clot in the larger dural sinuses, but magnetic
Hypopyon in the anterior chamber of a patient with Behets
resonance venography is more reliable for recognizing
disease, caused by anterior uveitis.
clot in the cerebral venous system, especially in the
smaller veins and older thromboses.
Central nervous system symptoms in BD may be due
BD. A neutrophilic infiltrate is typical of other derma- to aseptic meningitis or parenchymal lesions, resulting
toses occasionally seen with the disorder, including pyo- in focal or diffuse brain dysfunction. An increased
derma gangrenosum and Sweets syndrome. protein concentration and lymphocytic pleocytosis in
Pathergy is an excessive skin response to trauma, the cerebrospinal fluid (CSF) is supportive of the diag-
reflecting neutrophil hyperreactivity, and is highly spe- nosis. The clinical combination of stroke, aseptic menin-
cific for BD. Pathergy is suggested if there is a history gitis with CSF pleocytosis, and mucocutaneous lesions
of red papules, pustules, or sterile abscesses after thera- can be diagnostic of BD. Focal or multifocal nervous
peutic injections, at intravenous catheter sites, or after system involvement reflects the predilection of the
minor skin trauma. Testing for pathergy can be done disease for diencephalon, midbrain, and brainstem
with a sterile 20-gauge needle, used to penetrate the (Figure 21E-4). In contrast to multiple sclerosis, there is
cleansed skin perpendicularly to a depth of approxi-
mately one quarter of an inch, rotated briefly on its axis,
and then removed. After 48 hours, the appearance of an
erythematous papule or pustule at the puncture site
constitutes a positive test. The volar forearm is usually
chosen for the test and sensitivity is greater when three
needle punctures are made. The positivity of the test
may vary during the course of the disease and is more
likely to be positive at times of active disease. The sen- 21
sitivity of the test is lower in Western countries than in
Silk Road countries, but a positive test adds great
support for the diagnosis of BD.
Ocular inflammation typically follows mucocutane-
ous symptoms by a few years, but it often progresses
with a chronic, relapsing course affecting both eyes. The
ocular finding in Behets original patients was anterior
uveitis associated with a hypopyon [the accumulation of
an inflammatory cell infiltrateessentially pusin the
anterior chamber (Figure 21E-3)]. Anterior uveitis that
is not treated promptly with a mydriatic agent may
result in synechiae formation between the iris and the
lens and permanent papillary distortion. The ocular
manifestations of Behets disease may also include a
panuveitis, however, with posterior chamber involve-
FIGURE 21E-4
ment and retinal vasculitis, the complications of which
may extend to visual loss. Retinal vasculitis, which leads Brainstem involvement in a patient with Behets disease.
no preference for the periventricular structures (2). drome [mouth and genital ulcers with inflamed carti-
Isolated headaches in BD are common but the cause is lage]) likely represents the simultaneous occurrence of
not well understood. These may represent secondary two disorders.
migraine or may not be related to the disease. No laboratory abnormality is diagnostic of BD.
Large vessel involvement, which occurs in about one Acute-phase reactants may be increased, especially in
fourth of patients with BD, is a major cause of morbidity patients with large vessel vasculitis, but they may be
and mortality (3). Patients with vascular disease often normal in other patients, even those with active eye
have multiple lesions and involvement of both the arte- disease. The histocompatibility antigen HLA-B51 is
rial and venous systems (4). Deep venous thrombosis associated with BD in areas of high prevalence and in
(DVT) is the most common large vascular lesion. patients with ocular disease.
Patients with recurrent DVTs are at risk for chronic
stasis changes in the legs. Occlusions of the vena cava, Diagnosis
hepatic, and portal veins, other recognized thrombotic
The multiple manifestations of BD in the same patient
complications in BD, are associated with an increased
may be separated in time, occasionally by several years.
risk of mortality. Chest wall, abdominal, and esophageal
For definitive diagnosis, the manifestations must be
varices may occur from deep-seated venous thrombosis.
documented or witnessed by a physician. The ISG
Right ventricular thrombi have been reported, usually
criteria for the classification of BD (Table 21E-1) (1)
in association with pulmonary vasculitis. No primary
are not meant to replace clinical judgment regarding the
abnormality of the coagulation, anticoagulation, or fibri-
diagnosis in individual cases. For patients in Western
nolytic system explaining the thrombotic tendency in
countries, large vessel disease or acute central nervous
BD has been identified consistently.
system infarction in the setting of aphthosis should
Arterial complications occur in up to 7% of patients
suggest the diagnosis (7).
with BD (5). Stenoses, occlusions, and aneurysms occur
The diagnosis of BD in patients with complex aph-
in the systemic circulation or the pulmonary arterial
thosis requires the presence of other characteristic
bed. Arterial aneurysms, caused by vasculitis of the vasa
lesions and the exclusion of other systemic disorders.
vasorum, involve the aorta or its branches. The risk
Inflammatory bowel disease, sprue, cyclic neutropenia
of rupture is high. Pulmonary artery aneurysms (6) may
or other hematologic disorders, herpes simplex infec-
lead to fistulae between the pulmonary artery and
tion, and acquired immune deficiency syndrome may
bronchi, presenting with hemoptysis. Anticoagulant
cause similar lesions. Other disorders responsible for
treatment for presumed pulmonary emboli can result in
orogenital/ocular syndromes include erythema multi-
massive hemorrhage and death. Clinically apparent
forme, mucous membrane pemphigoid, and the vulvo-
cardiac vascular involvement is unusual, but may result
vaginalgingival form of erosive lichen planus. The
in myocardial infarction.
differential diagnosis can be clarified with the aid of an
Gastrointestinal symptoms in BD include melena
experienced dermatologist and biopsy findings. In Reit-
and abdominal pain. Colonoscopic lesions appear as
ers disease, mucocutaneous lesions are nonulcerative
single or multiple ulcerations involving primarily the
and painless, and the uveitis is usually limited to the
distal ileum and cecum. Gastrointestinal lesions have
anterior chamber. Similarities between BD and Crohns
a tendency to perforate or to bleed. The lesions in
disease include gastrointestinal lesions, fever, anemia,
BD should be differentiated from those of Crohns
oral ulcers, uveitis, arthritis, thrombophlebitis, and ery-
disease and those due to the use of nonsteroidal anti-
thema nodosum. Granuloma formation in intestinal
inflammatory drugs.
lesions is not typical in BD, and in Crohns disease the
An intermittent, symmetric oligoarthritis of the
iritis is typically confined to the anterior chamber.
knees, ankles, hands, or wrists affects one half of the
Genital ulcerations and central nervous system disease
patients with BD; arthralgia is also common. An erosive
are rare in Crohns disease.
or destructive arthropathy is unusual. Inflammatory
cells of the synovium and synovial fluid are primarily
polymorphonuclear leukocytes.
Disease Activity
Epididymitis occurs in about 5% of affected patients. Frequent ophthalmologic examinations are essential for
Glomerulonephritis and peripheral neuropathy occur patients with ocular disease, and periodic monitoring of
much less frequently in BD than in other forms of sys- the eyes is recommended for all patients. A careful history
temic vasculitis. AA-type amyloidosis, presenting as and examination, with attention to the vascular and neu-
nephrotic syndrome, can accompany BD. The occa- rologic systems, should be part of the physicians assess-
sional association of the disorder with ankylosing spon- ment. Standardized forms for scoring disease activity and
dylitis [in human leukocyte antigen (HLA)-B27-positive ocular inflammation have been developed for use in
patients] or relapsing polychondritis (MAGIC syn- clinical trials and the care of individual patients (8).
Management of BuddChiari syndrome has included anticoagulants

or antiaggregants, colchicine, and glucocorticoids. Por-
Aphthous lesions are treated with topical or intrale- tocaval shunting should be considered if the inferior
sional corticosteroids. An empiric trial of dapsone or vena cava is patent.
methotrexate may be appropriate in difficult cases. Col-
chicine is used in the treatment of mucocutaneous mani- Pathogenesis
festations and as an adjunct in the treatment of more
serious manifestations (0.6 mg three times daily may be In many geographic areas, genetic studies have shown a
required to achieve a therapeutic effect; many patients strong association with HLA-B51, but the exact role of
suffer gastrointestinal intolerance of the drug at that this gene in the development of BD is uncertain. Neu-
dose). The effectiveness of colchicine has been demon- trophilic hyperfunction is recognized in BD, in normal
strated for genital ulcers and erythema nodosum in subjects with HLA-B51, and in HLA-B51 transgenic
females and for arthritis in both sexes (9). Thalidomide mice (13). Evidence also exists for antigen-driven
has been used for the treatment of mucosal and follicu- immune mechanisms in the pathogenesis of BD. Cyto-
lar lesions, but toxicity is a major concern. Short courses kine analysis and cellular characterization suggest a T-
of prednisone are useful in the management of muco- helper cell (Th1) response by lymphocytes in BD.
cutaneous disease in some patients. In others, low-dose Molecular techniques have identified herpes simplex
prednisone as maintenance therapy is required. viral RNA and DNA in cells from patients with BD, and
Cyclosporine can be effective for the control of streptococcal antigens have been proposed as triggers
uveitis. A controlled study has demonstrated the value of active disease. Activated gamma-delta T cells are
of azathioprine at a dose of 2.5 mg/kg per day in limiting increased in the circulation and in mucosal lesions, but
the progression of ocular disease and preventing new the precise role of these cells in the pathogenesis of BD
eye disease in males. Combination treatment with cyclo- is uncertain. Peptides from mycobacterial heat shock
sporine and azathioprine can been used when single- protein (HSP) and homologous human peptides have
agent treatment has failed. Azathioprine can have a been found to stimulate gd+ T cells from patients with
beneficial effect on mucosal ulcers, arthritis, deep venous BD in a specific fashion (14). Cross-reactivity and
thrombosis, and long-term prognosis (10). Because molecular mimicry between peptides from streptococ-
young males are at the greatest risk for severe disease, cal or viral HSP, homologous human HSP, and mucosal
especially uveitis, aggressive treatment is warranted in antigens may result in selection of autoreactive T cells
this disease subset. In open trials, interferon-alpha has (15). More recently, similarities between BD and inflam-
been found useful for treating mucocutaneous lesions matory disorders associated with autoimmunity have
and arthritis and is emerging as an effective treatment been recognized (16).
for ocular disease (11). Etanercept, a tumor necrosis
factor inhibitor, was shown to be beneficial for mucocu-
taneous manifestations in a controlled study (12). PRIMARY ANGIITIS OF THE
Reports of uncontrolled experience with infliximab for CENTRAL NERVOUS SYSTEM
eye inflammation have been positive, but controlled
data are lacking. Immunosuppression with chlorambucil Primary angiitis of the central nervous system (PACNS)
or cyclophosphamide is used for uncontrolled ocular is a rare form of vasculitis limited to the brain and spinal 21
disease, central nervous system disease, and large vessel cord. The term granulomatosis angiitis of the central
vasculitis, including recurrent deep venous thrombosis. nervous system was previously applied because of the
Glucocorticoids are useful in suppression of inflamma- histopathologic findings observed in arteries from early
tion in acute phases of the disease, but these agents are reported cases. However, an analysis of a larger number
insufficient by themselves to treat such severe disease of cases supports varied mononuclear cell infiltrates,
manifestations as posterior uveitis or parenchymal brain with fewer than 50% of cases showing granulomatous
disease. inflammation (17). Anatomically, the angiitis is multifo-
Because of the high risk of rupture, surgical treat- cal and segmental in distribution and involves the small
ment is indicated for systemic arterial aneurysms. Glu- leptomeningeal and intracerebral arteries. In general,
cocorticoids and alkylating agents should also be used the arteries are involved much more frequently than the
to minimize the high risk of anastomotic recurrences or veins.
continued disease. Pulmonary arterial aneurysms may
respond to these same medications, but uncontrolled
bleeding requires percutaneous embolization or surgi-
Clinical Manifestations
cal treatment. Cerebral venous thrombosis is treated The disease predominantly affects males. Most patients
with anticoagulation and corticosteroids. The treatment are young or middle-aged, although patients of a broad
age range are affected. Cases of PACNS in children

have also been described. The clinical manifestations of
PACNS are not distinctive. The most common symptom
is headache. Because virtually every anatomic area of
the central nervous system may be affected by the vas-
culitis, a wide range of neurologic presentations and
deficits may be seen, including transient ischemic attacks
(TIAs), cerebral infarction, paraparesis, quadriparesis,
hemiparesis, ataxia, seizures, aphasia, and visual field
defects, among others. Decreased cognitive function or
fluctuating levels of consciousness are not uncommon.
Progressive multifocal symptoms over time in a younger
patient should suggest the possibility of PACNS, partic-
ularly in the absence of other risk factors. The spinal
cord may occasionally be involved. Presentations with
subarachnoid or intracerebral hemorrhage are rare.
Diagnosis
Timely diagnosis of PACNS is critical, before the occur-
rence of massive brain damage. Preliminary diagnostic
criteria for PACNS have been proposed (18) but never FIGURE 21E-5
validated. The diagnosis of PACNS is usually predicated Cerebral angiogram in a patient with central nervous system
upon either biopsy evidence of vasculitis or angiographic vasculitis. The angiogram reveals multiple segmental stenoses of
findings suggestive of vasculitis in the setting of other the A1 and A2 segments of the anterior cerebral artery and the
compelling features, for example, strokes demonstrated distal segments of the middle cerebral artery.
by magnetic resonance imaging or the findings of a cere-
brospinal fluid pleocytosis (17). Histologic confirmation
remains the most specific diagnostic procedure for
PACNS, but the sensitivity of brain biopsy is limited
because of the focal segmental distribution of the the setting of biopsy-proven active disease. Cerebrospi-
disease. A negative biopsy does not exclude the diagno- nal fluid (CSF) analysis, however, is an essential part of
sis of PACNS, but may be essential to excluding other the diagnostic workup of PACNS. The CSF findings are
disorders that mimic PACNS clinically. abnormal in 80% to 90% of cases documented patho-
In the absence of histologic confirmation, a cerebral logically. CSF findings are characterized by a modest
angiogram typical of vasculitis in the appropriate clini- pleocytosis and elevated protein levels. CSF analysis
cal settings is frequently used to establish the diag- should include appropriate stains, cultures, and sero-
nosis of PACNS. Suggestive angiographic findings logic tests to exclude for CNS infections.
include segmental narrowing, dilatation, or occlusion Magnetic resonance imaging (MRI) is the most
affecting multiple cerebral arteries in the absence of sensitive imaging study in the evaluation of PACNS.
proximal atherosclerotic changes (Figure 21E-5). The Only rare cases have no MRI abnormalities. The most
findings of narrowing are, however, highly nonspecific, common findings are multiple, bilateral, supratentorial
and can be caused by a host of nonvasculitic causes. infarcts distributed in the cortex, deep white matter,
Angiographic findings compatible with vasculitis are and/or leptomeninges, but the findings lack specificity.
commonly encountered in conditions such as vaso- Magnetic resonance angiography (MRA) is limited in
spasm, central nervous system infection, cerebral arte- sensitivity in most cases of PACNS. Angiographically
rial emboli, intravascular lymphomatosis, and demonstrable lesions are often beyond the resolution of
atherosclerosis. Furthermore, the sensitivity of angiog- current MRA technology. Thus, a normal MRA does
raphy is limited if small vessels beyond its resolution are not rule out the disorder.
primarily involved. Cerebral angiography has been
normal in some biopsy-proven cases.
General laboratory tests, including acute-phase reac-
Management and Outcome
tants such as C-reactive protein and the erythrocyte Primary angiitis of the central nervous system is consid-
sedimentation rate, are not useful in the diagnosis of ered a progressive disorder with a fatal course unless
PACNS. In addition to being nonspecific, in fact, acute- treated vigorously with a combination of high-dose glu-
phase reactants are known often to be normal even in cocorticoids and a cytotoxic agent (usually cyclophos-
phamide). There are no controlled treatment trials on

which to base this standard. The optimal duration of
therapy is unknown, but in view of the substantial side
effects associated with cyclophosphamide and the suc-
cessful use of shorter courses of therapy in other forms
of vasculitis, a 6-month course of cyclophosphamide fol-
lowed by an additional 1 year of azathioprine appears
reasonable. Prednisone should be discontinued in a
tapering fashion over 6 to 9 months.
Benign Angiopathy of the Central

Nervous System
The presence of a subset of patients with some features FIGURE 21E-6
suggesting PACNS but demonstrating a more benign
course has been suggested (19). This subset of patients Nonsyphilitic interstitial keratitis in a patient with Cogans
syndrome. Retroillumination image of the cornea with the slit
is considered to have a disease entity known as benign lamp reveals a patchy, deep, granular corneal infiltrate charac-
angiopathy of the central nervous system (BACNS). teristic of early Cogans syndrome in the cornea. (Courtesy of Dr.
BACNS patients are predominantly female, primarily Thomas J. Liesegang, Mayo Clinic College of Medicine.)
present acutely with headache, with or without focal
symptoms, and have normal or near normal CSF analy-
bilateral, shows a downsloping pattern on audiograms,
sis. The diagnosis in these cases has been established
and is often progressive and profound. Vestibular testing
angiographically and appeared to have a monophasic
shows bilateral cochlear dysfunction, helping to distin-
course with a favorable neurologic outcome. Most of
guish this disorder from Mnires syndrome. In com-
these patients recover after only short-term glucocorti-
parison to Mnires syndrome, the damage to hearing
coid treatment, often supplemented by a calcium
from Cogans syndrome is typically more unremitting.
channel blocker to mitigate against vasospasm. Cyto-
Scleritis, uveitis, or other inflammatory conditions of the
toxic agents are not required for patients with
eye (Figure 21E-7) may be present initially but often
BACNS.
patients will subsequently develop interstitial keratitis
The etiology of the vascular disease in this benign
if not present initially. Systemic manifestations include
form has not been defined clearly, but could be the
headache, fever, arthralgia, and vasculitis, with or
result of arteritis or reversible vasospasm. The existence
without aortitis. The critical evaluation and monitoring
of a benign, angiographically defined subset, however,
remains controversial (20). Recently, we identified a
subset of patients presenting with evidence of promi-
nent leptomeningeal enhancement on MRI (21). These
patients were characterized by normal cerebral angiog-
raphy, brain biopsy evidence of vasculitis predominantly
affecting the small leptomeningeal vessels, and a good
21
response to corticosteroids and/or immunosuppressive
therapy with a favorable neurologic course.
COGANS SYNDROME
Cogans syndrome refers to the association of nonsyphi-
litic interstitial keratitis (Figure 21E-6) and immune-
mediated inner ear disease, resulting in audiovestibular
dysfunction. The disorder affects men and women FIGURE 21E-7
equally at any age, but typically in their third and fourth
decade. Presenting manifestations include sudden Localized corneal edema in Cogans syndrome. Direct corneal
view of classic ocular Cogans syndrome in an advanced stage.
hearing loss, Mnires-like vertigo and tinnitus, and
There is localized peripheral corneal edema, mild lipid infiltrate,
ocular inflammation, alone or in any combination (22). and moderate vascularization extending from the corneal
Other features of the disease, if not present initially, limbus. (Courtesy of Dr. Thomas J. Liesegang, Mayo Clinic
usually follow within several months. Hearing loss is College of Medicine.)
affects both men and women in middle age. Individual

lesions consist of purple, red, or brown plaques that
often have an annular or nodular appearance. The skin
lesions of EED have a predilection for the extensor
surfaces of the distal extremities and often overlie joints,
but may be generalized. Older lesions may be dense and
coalesce (Figure 21E-8). Erupting lesions may be associ-
ated with stinging, burning, or tenderness, and may be
accompanied by systemic symptoms. In early lesions, the
pathology of EED is one of a leukocytoclastic vasculitis
with a perivascular neutrophilic infiltrate. More mature
lesions demonstrate perivascular or onion-skin
like fibrosis. Capillary proliferation and cholesterol-
containing histiocytes may also be seen. The differential
diagnosis includes other neutrophilic dermatoses, pri-
marily Sweets syndrome.
Erythema elevatum diutinum has been recognized to
occur in association with infections diseases, including
human immunodecifiency virus infection, hematologic
disorders (particularly IgA gammopathies), and several
immune-mediated inflammatory diseases, including
rheumatoid arthritis. Treatment of any associated disor-
der may benefit EED. Dapsone (100 mg/day) has been
FIGURE 21E-8 reported to be successful in some patients.
Erythema elevatum diutinum.
REFERENCES
of Cogans patients requires the expertise and collabo-
1. International Study Group for Behets Disease. Criteria
ration of the treating rheumatologist, otolaryngologist, for diagnosis of Behets disease. Lancet 1990;335:1078
and ophthalmologist (23). 1080.
There are no controlled studies on the treatment of 2. Kural-Seyahi E, Fresco I, Seyahi N, et al. The long-term
Cogans syndrome. Glucocorticoids are used topically mortality and morbidity of Behcet syndrome: a 2-decade
for anterior eye disease and systemically for audioves- outcome survey of 387 patients followed at a dedicated
tibular manifestations, unremitting ocular disease, or center. Medicine (Baltimore), 2003;82:6076.
when the disorder is complicated by vasculitis or signifi- 3. Calamia KT, Schirmer M, Melikoglu M. Major vessel
cant systemic manifestations. These agents should be involvement in Behcet disease. Curr Opin Rheumatol
started as soon as the disorder is recognized, in ade- 2005;17:18.
4. Le Thi Huong D, Wechsler B, Papo T, et al. Arterial
quate doses (at least 1 mg/kg/day), and for a sufficient
lesions in Behets disease. A study in 25 patients. J Rheu-
duration to initially control the disease or for relapse.
matol 1995;22:21032113.
Documented improvement in 2 to 3 weeks supports a 5. Hamuryudan V, Er T, Seyahi T, et al. Pulmonary artery
therapeutic response and can be followed by gradual aneurysms in Behcet syndrome. Am J Med 2004;117:
tapering of the dose and use of immunosuppressive 867870.
agents if necessary for maintenance. The prognosis for 6. Borhani Haghighi A, Pourmand R, Nikseresht AR.
hearing in these patients has been poor (22), but cochlear Neuro-Behcet disease. A review. Neurologist 2005;11:
implants are used successfully in these patients with 8089.
bilateral deafness. 7. Schirmer M, Calamia KT. Is there a place for large vessel
disease in the diagnostic criteria for Behets disease?
J Rheumatol 1999;26:25112512.
8. Kaklamani VG, Vaiopoulos G, Kaklamanis PG. Behets
ERYTHEMA ELEVATUM Disease. Semin Arthritis Rheum 1998;27:197217.
9. Yurdakul S, Mat C, Tuzun Y, et al. A double-blind trial
DIUTINUM of colchicine in Behets syndrome. Arthritis Rheum
2001;44:26862692.
Erythema elevatum diutinum (EED) is an extremely 10. Hamuryudan V, Ozyazgan Y, Hizli N, et al. Azathioprine
rare, chronic, recurrent vasculitis with distinctive clini- in Behets syndrome: Effects on long-term prognosis.
cal and histopathologic features (24,25). The disorder Arthritis Rheum 1997;40:769774.
11. Ktter I, Zierhut M, Eckstein A, et al. Human recombi- literature, and proposal for diagnostic criteria. Medicine
nant interferon alfa-2a for the treatment of Behets (Baltimore) 1988;67:2039.
disease with sight threatening posterior or panuveitis. Br 19. Calabrese LH, Gragg LA, Furlan AJ. Benign angiopathy:
J Ophthalmol 2003;87:423431. a distinct subset of angiographically defined primary angi-
12. Melikoglu M, Fresco I, Mat C, et al. Short-term trial of itis of the central nervous system. J Rheumatol 1993;20:
etanercept in Behcets disease: a double blind, placebo 20462050.
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function of peripheral blood neutrophils from patients benign? Neurology 1998;51:183188.
with Behets disease and from HLA-B51 transgenic 21. Salvarani C, Hunder GG. Primary central nervous system
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14. Hasan A, Fortune F, Wilson A, et al. Role of gamma delta Arthritis Rheum 2005(52 supplement):S650.
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Lancet 1996;347:789794. drome: a retrospective review of 60 patients throughout a
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Int Rev Immunol 1997;14:2132. drome. In Hoffman GS, Weyand C, eds. Inflammatory
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21
CHAPTER 21
Vasculitides
F. Kawasakis Disease
BARRY L. MYONES, MD
Kawasakis disease (KD), once known as mucocutane- Attempts to link KD definitively to some
ous lymph node syndrome, is a systemic inflamma- types of infection, particularly ones associated
tory disorder occurring in children that is with superantigens, have thus far been
accompanied by vasculitis and a risk of coronary unsuccessful.
artery aneurysms. High dose aspirin and intravenous immune
Other typical features of KD include spiking fevers, globulin (IVIG) are the cornerstones of therapy in KD.
cervical lymphadenopathy, conjunctivitis, erythema- IVIG is essential to the prevention of coronary
tous changes on the lips and in the oral cavity, aneurysms.
dryness and cracking of the lips, a strawberry Years after KD has occurred during childhood years,
appearance to the tongue, and a polymorphous rash. some cases of myocardial infarction caused by
Eighty percent of KD cases occur in children less than thrombosis of coronary aneurysms have been
5 years of age. reported.
Kawasakis disease (KD) is a form of systemic vasculitis was the site of hemorrhage into the pericardium.
that occurs in young children and may be associated Although the microscopic appearance of the disease
with the development of coronary arteritis and aneu- was typical of periarteritis nodosa (i.e., PAN; see
rysm formation (Figure 21F-1). KD is the leading cause Chapter 21B), no hepatic or renal infarctions were
of acquired heart disease of children in the United present. Indeed, among the internal organs the heart
States. This illness, first recognized to be a new entity by alone was involved. The childs death was attributed to
Tomasaku Kawasaki in Japan in 1967 (1,2), was termed an atypical case of infantile periarteritis nodosa, now
for mucocutaneous lymph node syndrome (MCLNS) recognized as KD.
until KD became the accepted designation for this dis-
order (3). Although the disorder was named after Kawa-
saki, at least one previous case exists in the medical
literature (4). This case, recounted in detail below, is CLINICAL FEATURES
classic in its clinical features of KD.
A 5-year-old girl presented with a sore throat, a Kawasakis disease strikes quickly, runs a furious course
fever to 105F, and an erythematous rash over her over a few weeks, and then apparently resolves. In all
trunk, appearing desperately and acutely ill (4). Oro- 50 of the patients described initially by Kawasaki, the
pharyngeal lesions included an aphthous stomatitis, symptoms resolved without sequelae within 1 month. In
erythematous lesions of the hard palate, and prominent subsequent years, however, mortality from cardiac com-
lingual papillae. On the fifth hospital day the hectic plications (usually coronary artery thrombosis) was
fevers ceased, but low-grade fevers and tachycardia to reported (5,6). Cardiac complications of KD result from
140 beats per minute persisted. The skin of her fingers a severe panvasculitis, leading to narrowing of the
desquamated, but over the ensuing weeks she improved coronary lumina by the migration of myointimal cells
steadily. One month after admission, however, she from the media through the fragmented internal elastic
developed acute chest pain, shortness of breath, and lamina. Although catastrophic heart complications
expired. A postmortem examination revealed blood occur in only a small minority of patients (<5%), the
and clots in the pericardial space, and several large preponderance of patients with KD appear to have at
aneurysms along the epicardial vessels. One aneurysm, least some cardiac involvement. Heart lesions may
the size of a large ripe cherry in the left coronary artery, include myocarditis, pericarditis, aneurysmal dilatation
444
FIGURE 21F-1
FIGURE 21F-2
Coronary and peripheral aneurysms in Kawasakis disease (KD).
Magnetic resonance angiogram in an infant with KD, revealing Coronary artery thrombosis leading to death in Kawasakis
irregularities of the subclavian, axillary, and proximal brachial disease. [Reproduced with permission from the American College
arteries, as well as fusiform dilatation of the right common iliac of Rheumatology collection, slide 124 (#9406010).]
and right proximal internal iliac arteries. There is also a focal
aneurysm of the left internal iliac artery.
and thrombosis of the coronary arteries (Figure 21F-2), plete KD has been applied to any patient felt to have
and myocardial infarction. The tropism of the vascular KD but who did not fulfill classical criteria. These are
inflammation for coronary arteries and its unusual often diagnosed by echocardiogram findings of coro-
propensity to cause aneurysm formation remain nary aneurysms and often occur in the older children or
unexplained. young infants (10,11). Coronary aneurysms, in fact, are
In addition to the cardiac findings, KD is associated most likely to occur in infants <6 months of age. Because
with a number of other dramatic clinical findings (Table 21
21F-1). Spiking fevers may last for 5 days or more. The
TABLE 21F-1. PRINCIPAL CRITERIA FOR THE
conjunctivae, generally inflamed in a nonpurulent DIAGNOSIS OF KAWASAKIS DISEASE (5 OUT OF
manner, are accompanied by erythematous changes on 6 CRITERIA MET).a
the lips and in the oral cavity [Figure 21F-3(A)]. The
Fever lasting 4 days or more
lips become dry and cracked [Figure 21F-3(B)], with a
diffuse reddening of the oropharyngeal area and a Bilateral nonpurulent conjunctival injection
strawberry appearance to the tongue (Figure 21F-4). A
Changes of the lips and oral cavity (including dry, fissured lips,
polymorphous rash typically involves the trunk [Figure strawberry tongue, diffuse reddening of the oropharyngeal
21F-3(A)], and there may be extensive lymphadenopa- mucosa)
thy in the neck region. The palms and soles become
Polymorphous rash primarily on the trunk
erythematous and indurated, followed by desquamation
in the skin of these areas during the healing phase Acute nonpurulent swelling of a cervical lymph node to >1.5 cm
(79).
Changes of the peripheral extremities (including reddening of
The term atypical KD has been used to describe both
palms and soles, indurative edema of hands and feet,
older children and young infants presenting outside the membranous desquamation from the fingertips)
typical age range of 2 to 5 years, as well as those present-
ing with features other than the classical criteria. Incom- a
Illness not explained by any other known disease process.
446 BARRY L. MYONES
A B
FIGURE 21F-3
Oral and cutaneous manifestations of Kawasakis disease. (A) Erythema of the lips and an
erythematous, annular rash on the skin. (B) Cracking and desquamation of the lips in a patient
with Kawasakis disease. [Reproduced with permission pending from the American College of
Rheumatology slide collection. (A) Slide 93 (#9106110). (B) Slide 92 (#9106131).]
of confusion (and often inappropriate use) surrounding

disease terminology, there have been sentiments among
KD experts to phase out the term atypical and to expand
the term incomplete. Unusual disease features known to
occur in KD include sterile pyuria and urethritis, arthral-
TABLE 21F-2. REVISED GUIDELINES FOR THE

DIAGNOSIS AND TREATMENT OF KAWASAKIS DISEASE.
Expanded epidemiologic case definition includes fever of at least
4 days and 4 principal criteria (Table 21F-1) without other
explanation OR fever and <4 principal criteria if coronary
artery abnormalities are detected by echocardiogram or
coronary angiography
An echocardiogram should be performed in any patient 6

months of age if fever persists 7 days without other
explanation and with laboratory measures of inflammation,
even in the absence of any principal clinical criteria
The following laboratory parameters may be used to help with

diagnosis and determine disease severity: CRP 3.0 mg/dL, ESR
40 mm/h, albumin 3.0 g/dL, anemia for age, ALT, platelets
after 7 days 450,000, WBC 15,000, urine microscopic
10 WBC/high-powered field
FIGURE 21F-4 SOURCE: From the scientific statement by the American Heart Association
(AHA) Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease.
Strawberry tongue in Kawasakis disease. [Reproduced with Circulation 2004;110:27472771 and Pediatrics 2004;114:17081733.
permission pending from the American College of Rheumatol- ABBREVIATIONS: ALT, alanine aminotransferase; CRP, C-reactive protein; ESR,
ogy slide collection, Slide 95 (#9106120).] erythrocyte sedimentation rate; WBC, white blood cell count.
gia and arthritis, aseptic meningitis, diarrhea, abdomi- TABLE 21F-4. KAWASAKIS DISEASE: RECOMMENDED
nal pain, pericardial effusion, obstructive jaundice, and THERAPY.
hydrops of the gallbladder.
Acute Stage
Intravenous immune globulin (IVIG), a critical Aspirin 80100 mg/kg/day in 4 divided doses until the 14th day
medication in the treatment of KD, is a limited resource of illness
in many parts of the world because of its expense. +
The American Heart Association (AHA), concerned IVIG 2 g/kg in 1 dose over 1012 hours
about both the potential for overuse of IVIG as well Convalescent Stage (>14th illness day; afebrile patient)
as the failure to employ this medication in a timely ASA at 35 mg/kg/day in a single dose
manner in appropriate patients, issued guidelines on Discontinue 68 weeks after onset of illness after verifying that
the diagnosis and treatment of KD (Tables 21F-2 no coronary abnormalities are present by echocardiography
through 21F-4) (12,13). In these guidelines, the epide- Acute Coronary Thrombosis
miologic case definition of KD included fever of at Prompt fibrinolytic therapy with streptokinase, urokinase, or
least 4 days and four or more principal criteria (Table tissue plasminogen activator by a tertiary care center under
21F-1) without other explanation; or fever and less the supervision of a cardiologist
than four principal criteria if coronary artery abnor- Chronic Treatment for Patients with Coronary Aneurysms
malities are detected by echocardiogram or coronary ASA 35 mg/kg/day in a single dose
angiography. Some physicians add dipyridamole in selected patients deemed
at high risk
Some physicians use warfarin or heparin in combination with
antiplatelet therapy in patients with severe coronary findings
EPIDEMIOLOGY or past evidence of coronary thrombosis
In Japan, the illness appears in late winter and spring. SOURCE: From the scientific statement by the American Heart Association
The peak age is 6 to 12 months, with 80% of cases occur- (AHA) Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease.
Circulation 1993;87:17761780 and Pediatrics 1979;63:175179.
ring in patients younger than 5 years of age. The male:
female ratio is 1.5:1. Except for three major pandemics
(1979, 1982, 1985/6), the cases have reached a plateau <14 years old per year include 23.0 in Asians, 2.3 in
of 5000 to 6000 per year. The endemic annual incidence African Americans, and 1.6 in Caucasians and Hispan-
is 67/100,000 children <5 years old, with a recurrence ics (1417).
rate of 6%.
In the United States, there is also a seasonal variation
in most places. The peak age is 18 to 24 months, and the ETIOLOGY
illness accounts for 3000 hospitalizations/year. The
recurrence rate is 1% to 3%. Data from Hawaii from The epidemiology of KD is consistent with an infectious
19711980 show ethnic incidence rate/100,000 children cause: clinical features that resemble infection (fever,
<8 years old per year of 33.6 in Japanese, 11.1 in Chinese, lymphadenopathy), time/space clusters, epidemic occur-
9.2 in Hawaiians, 2.9 in Filipinos, 2.8 in Caucasians. In rences, and alleged proximity of case foci to bodies of
Los Angeles from 19801983, rates per 100,000 children water. To date, however, no infectious etiology has
been proven. There has been no culture or serologic 21
evidence for conventional viral agents, Mycoplasmae,
Rickettsiae, or bacterial agents (Streptococcus, Staphy-
TABLE 21F-3. ECHOCARDIOGRAM CRITERIA lococcus). Molecular biologic techniques have provided
INCLUDE ANY OF THE FOLLOWING THREE. support, however, for a Propionibacterium acnes variant,
1. LADa or RCAb z score 2.5 retroviruses, Rickettsiae, parvovirus B19, EpsteinBarr
virus, and coronavirus, as well as for the participation
2. Japanese Ministry of Health Criteria (coronary artery diameter
of the S. aureus toxin TSST-1 and other superantigens
>3 mm in children <5 year or >4 mm in children 5 years,
lumen diameter 1.5 an adjacent segment, coronary lumen (e.g., Yersinia pseudotuberulosis).
is clearly irregular) Support exists for a superantigen-mediated process
both from clinical studies (1822) and from a murine
3. 3 suggestive features: (perivascular brightness, lack of
model for coronary arteritis stimulated by Lactobacillus
tapering, left venticular function, mitral regurgitation,
pericardial effusion, LAD or RCA z scores = 22.5) casei cell wall extracts (23). This hypothesis proposes
that the etiologic agentswhich may differ across
SOURCE: From the scientific statement by the American Heart Association geographic sites throughout the worldare capable
(AHA) Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease. of evoking immunologic responses via T-cell receptor
Circulation 2004;110:27472771 and Pediatrics 2004;114:17081733.
a
Left anterior descending coronary artery. V beta restriction. An oligoclonal response is supported
b
Right coronary artery. by the discovery of IgA-secreting plasma cells within
448 BARRY L. MYONES
the walls of the affected arteries. This finding lends (31). No patients in the IVIG arm developed giant coro-
credence to the hypothesis that the respiratory or gas- nary artery aneurysms. In contrast, 6% of the aspirin-
trointestinal tract may be the portal of entry for the only group suffered this occurrence. This study
inciting organism, and that the process is antigen-driven established IVIG as the standard of care. Several years
(24,25). later, a follow-up trial compared a single dose of IVIG
(2 g/kg) to the traditional 0.4 mg/kg/day 4 schedule,
confirming the superiority (a further lowering of the
PATHOGENESIS coronary aneurysm rate) of the single-dose regimen
(32). Thereafter, the single-dose regimen became the
The pathogenesis is characterized by immune activa- standard of care recommendation by the AHA (Table
tion. A host of immunologic irregularities have been 21F-4) (9,33).
described in KD, not all of which have been confirmed The use of glucocorticoids in KD is, surprisingly, con-
consistently: endothelial cell activation [particularly troversial. One retrospective study assessed the out-
human leukocyte antigen (HLA)-DR expression on comes of five different treatment regimens, including
coronary endothelial cells]; autoantibody formation aspirin alone, aspirin plus prednisolone, prednisolone
(e.g., anti-endothelial cell antibodies); complement acti- alone, prednisolone plus warfarin, and no treatment
vation and immune complex formation; abnormalities aside from background antibiotic therapy (which all
of immunoregulation (lymphocyte infiltration, activated other treatment groups received, as well). Although
CD4+ and B cells, activated monocyte/macrophages, T aspirin alone reduced the aneurysm rate from 20% to
lymphopenia, polyclonal B-cell activation); adhesion 11% compared with the no-treatment group, treatment
molecule upregulation (soluble P-, E-, and L-selectins); with prednisolone was associated with an increase in the
increased vascular endothelial growth factor; and percentages of patients who developed aneurysm to
marked cytokine production with high levels of inter- 67% (34). Of note, the seven patients treated with
feron-gamma, interleukins-1, -4, -6, and -10, and tumor aspirin plus prednisolonenone of whom developed
necrosis factor (TNF)-alpha (18,2628). In severe cases, aneurysmwere not emphasized in the discussion. In
this cytokine storm results in a macrophage activation addition, the patients in the prednisolone-only group
syndrome (MAS). were perhaps the most ill at baseline (and hence were
treated with glucocorticoids, presumed empirically to be
the most powerful therapy).
TREATMENT After the publication of this studys results, glucocor-
ticoids for the treatment of KD fell into disfavor among
Following the initial recognition of KD, this illness was pediatricians and in fact were viewed as contraindicated
treated with salicylates, using the same doses of aspirin for this disease. More recent case series, evaluating the
employed in the treatment of rheumatic fever. Because use of pulse methylprednisolone as rescue therapy for
of the potential for impedance of aspirin absorption IVIG nonresponders, have been more encouraging with
caused by vasculitic involvement of the gastrointestinal regard to the potential for a beneficial effect of gluco-
tract, however, the use of aspirin must be monitored corticoids (3537). Initial results from a multicenter trial
carefully in this setting. If aspirin doses are too high (38) indicate no worsening in the coronary aneurysm
(e.g., 100150 mg/kg/day), improvement of intestinal rate among patients treated with glucocorticoids, and a
absorption with therapy may lead to symptoms of toxic- decrease in fever, inflammatory markers, length of hos-
ity. In Japan, doses of 30 to 50 mg/kg/day have been pital stay, and IVIG side effects.
employed because of the high incidence of the slow- A consensus conference at the National Institutes
acetylator gene in the Japanese population. A combined of Health (18) was prompted by the recognition of an
US and Japanese multicenter study demonstrated that ongoing immune activation at microvascular levels in
30 to 50 mg/kg of aspirin plus IVIG (see below) was patients treated adequately by the current therapies.
effective at preventing aneurysm formation in most Outcome data from Japan with long-term (1015 year)
cases (29). Current AHA guidelines, however, endorse follow-up demonstrated persistence of disease in some
aspirin doses of 80 to 100 mg/kg/day, in four divided cases, with intravascular ultrasound and ultrafast com-
doses (Table 21F-4). puted tomography studies demonstrating lingering cor-
Furusho studied the use of aspirin alone versus the onary aneurysms and/or wall fibrosis. Of greatest alarm
combination of aspirin plus IVIG (0.4 mg/kg/day 4 was the finding of such abnormalities in areas of the
days), using a protocol then in use for immune throm- vasculature previously documented as normal by echo-
bocytopenic purpura (30). A multicenter study demon- cardiogram and even coronary angiography. Electron
strated a decrease in the incidence of coronary artery microscopy studies of endomyocardial biopsies up to 23
abnormalities: only 4% (3 of 68) in the IVIG group, years after the KD episode showed ongoing microaneu-
compared with 33% (38 of 119) in the aspirin-only arm rysms and small vessel coagulopathy. In a small number
of young adults who have experienced myocardial 6. Kato H, Ichinose E, Kawasaki T. Myocardial infarction in
infarctions in the absence of known cardiac risk factors, Kawasaki disease: clinical analyses in 195 cases. J Pediatr
angiograms have revealed giant coronary artery aneu- 1986;108:923927.
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guideline of Kawasaki disease. Tokyo: Japan Kawasaki
in such patients, if any, as opposed to the clinical sequelae
Disease Research Committee; 1984.
occurring in arteries damaged years before, is not
8. American Heart Association Committee on Rheumatic
clear. Fever, Endocarditis, and Kawasaki Disease. Diagnostic
Newer treatment modalities have been utilized in guidelines for Kawasaki disease. Am J Dis Child 1990;
selected patients and patient populations. Small studies 144:12181219.
and anecdotal reports of treatment with the antiglyco- 9. Dajani AS, Taubert KA, Gerber MA, et al. Diagnosis
protein IIb/IIIa monoclonal antibody (abciximab) or and therapy of Kawasaki disease in children. Circulation
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thelial cell remodeling. Noninvasive imaging modalities, plete Kawasaki disease with coronary artery involvement.
such as magnetic resonance imaging studies of the chest J Pediatr 1987;110:409413.
11. Rosenfeld EA, Corydon KE, Shulman ST. Kawasaki
and abdomen, have identified the extracardiac arterial
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126:524529.
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49:17581766. Kawasaki syndrome. Lancet 1993;342:13851388.
450 BARRY L. MYONES
22. Abe J, Kotzin BL, Jujo K, et al. Selective expansion of T 33. Dajani AS, Taubert KA, Takahashi M, et al. Guidelines for
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drome. N Engl J Med 1991;324:16331639.
CHAPTER 22
Relapsing Polychondritis
HARVINDER S. LUTHRA, MD
Relapsing polychondritis (RP) is a rare disease that cartilage, and laryngotracheal cartilage. Nonerosive
occurs worldwide in all age groups and affects men arthritis, ocular inflammation, vestibular symptoms,
and women equally. and involvement of the heart and kidney also occur.
An associated rheumatologic or hematologic disorder Diagnosis is made on clinical grounds, though
is seen in over 30% of patients with RP. Inflamma- cartilage biopsy may be useful.
tion of cartilaginous structures with lymphocytic Treatment with nonsteriodal anti-inflammatory drugs
infiltration and association with anticollagen (NSAIDs) or corticosteroids may control inflammation,
antibodies are consistent with an autoimmune but immunosuppressive and biologic treatments may
pathogenesis. be required for severe disease.
The characteristic clinical findings are acute painful Laryngotracheal involvement is a serious complica-
swelling and redness of the external ear, nasal tion that may require tracheostomy.
Relapsing polychondritis is a recurring inflammatory nized with type II collagen (10). These observations are
disorder of unknown etiology causing inflammatory consistent with the thought that autoimmune mecha-
reactions in the cartilaginous structures of the nose, nisms are involved in this disease.
ears, trachea, and the joints. It is considered an auto-
immune disorder. It was first described by Jaksch-
Wartenhorst (1), in a patient with systemic illness
OTORHINOLARYNGEAL
characterized by external ear swelling, collapse of the
One of the hallmarks of this disease and the presenting
nasal bridge, fever, and arthritis. Pearson and colleagues
feature in 40% of the patients is acute painful swelling
(2) first coined the term relapsing polychondritis (RP),
and redness of the external ear (Figure 22-2). This may
and described, in detail, the clinical features of several
occur spontaneously or following minor injury, and
of their own patients along with those in the literature.
even though it is unilateral initially, most patients
Since then, this disorder has been described worldwide
develop it bilaterally. Ultimately 80% of the patients
and occurs in all age groups, although it peaks in the
experience this swelling (Table 22-1). The lobule of the
fifth decade. Over 30% of patients have an associated
external ear is characteristically spared. Recurrent
disorder, usually autoimmune or hematologic. These
inflammatory episodes lead to destruction of the exter-
include systemic vasculitis syndromes, systemic lupus
nal ear cartilage, resulting in either a soft flopped ear or
erythematosus (SLE), Sjgrens syndrome, overlap
a firm fibrotic knobby ear. In rare cases the cartilage of
connective tissue disorders, rheumatoid arthritis (RA),
the ear may calcify. The nasal bridge may be similarly
spondyloarthropathies, dysmyelopoietic syndromes,
involved and can cause nasal bridge collapse. The exter-
Hodgkins disease, diabetes mellitis, and psoriasis vul-
nal auditory canal may be stenosed by the inflammatory
garis (3). It is a rare disease occuring in 3.5 persons per
swelling and cause conductive deafness. About one
million (Michet, personal communication). The 5-year
third of the patients experience vestibular or auditory
survival is decreased to approximately 74%. The
abnormalities of varying degrees from vasculitis of the
male : female ratio is equal (4).
internal auditory artery (11).
The pathology shows destructive changes in the
fibrocartilagenous junction by mononuclear cells (Figure
22-1). These cells have been found to be CD4+ lympho- RESPIRATORY
cytes (5). Evidence of local complement activation has
been observed (6,7). Elevated levels of anticollagen Hoarseness, cough, wheezing, and dyspnea are com-
antibodies and cell-mediated immunity to cartilage monly observed. The severity of these depends upon
components have been observed (8,9). Recently, similar the severity of the inflammation of the tracheal carti-
changes have been observed in transgenic mice immu- lages. Tenderness of the thyroid cartilage and trachea
451
452 HARVINDER S. LUTHRA
TABLE 22-1. Clinical manifestations of relapsing

polychondritis.
MANIFESTATION INITIAL (%) TOTAL (%)
Auricular chondritis 40 85
Nasal cartilage 20 50
Hearing loss 9 30
Arthritis 35 50
Ocular 20 50
Larynotrachealbronchial 26 48
Laryngotracheal stricture 15 23
FIGURE 22-1
Systemic vasculitis 3 10
Histology of the fibrocartilagenous junction of the ear in a
Valvular dysfunction 0 6
patient with relapsing polychondritis. Inflammatory mononuclear
cells infiltrate this region with occasional polymorphonuclear
SOURCE: Adapted from Isaak BL, Liesegang TJ, Michet CJ Jr. Ophthalmology
leukocytes with damage to the cartilage. Hemotoxylin and eosin
1986;93:681689, by permission of Ophthalmology.
stain. Original magnification, 200. (Courtesy of Dr. Lestor E.
Wold.)
can be a clue to this involvement. Narrowing of the ratory symptoms of varying degree may be observed in
trachea, either localized or generalized, leads to inabil- up to 50% of patients (12).
ity to clear the throat, choking spells, and respiratory
infections. These symptoms should be taken seriously
because this is a potentially lethal complication. Respi- CARDIOVASCULAR
Vasculitis of various varieties can be observed in about
10% of the patients. Small vessel involvement leading
to a leukocytoclastic vasculitis, medium size vessel
disease of the polyarteritis variety, and large vessel
disease of the Takayasus arteritis variety occur. Signs
and symptoms depend upon the type of involvement as
well as the associated disease. Inflammation of the root
of the aorta can cause aortic valve dysfunction, includ-
ing aortic incompetence. Myocarditis may manifest as
arrhythmias or even heart block (13).
OCULAR
The ocular involvement is very variable with both intra-
and extraocular disease. Intraocular changes seen
include iridocyclitis and retinal vasculitis. Extraocular
disease manifests as periorbital edema, extraocular
muscle palsy, conjunctivitis, keratitis, scleritis, and
episcleritis. Proptosis is observed rarely (11).
MUSCULOSKELETAL
Figure 22-2 A seronegative episodic inflammatory oligo- or polyar-
Acutely inflamed ear with sparing of the noncartilageneous thritis can be observed in anywhere from 30% to 75%
lobule. of the patients. This is generally nonerosive and nonde-
C H A P T E R 2 2 R E L A P S I N G P O L Y C H O N D R I T I S 4 53
forming, affecting both the small and large joints. Artic- or leprosy need to be kept in mind. Local trauma may
ular cartilage damage can cause symmetrical joint space cause inflammatory changes that mimic chondritis.
narrowing and costal cartilage damage may lead to a Nasal cartilage damage leading to collapse of the bridge
pectus excavatum deformity (14). can occur from trauma, infections, granulomatous dis-
eases like Wegeners granulomatosis, as well as from
neoplastic diseases. Vasculitis of large and small blood
OTHER FEATURES vessels from other connective tissue diseases should be
considered.
Segmental proliferative glomerulonephritis may be
observed in approximately 10% of patients (15). Sys-
temic features, including fever, weight loss, and fatigue,
are commonly seen. Several cases of myelodysplastic
MANAGEMENT
syndrome have been described (16).
The management of patients with RP depends upon the
manifestations of the disease. If the patients have mild
DIAGNOSIS disease with fever, ear cartilage and/ or nasal cartilage
inflammation with arthalgias, then nonsteriodal anti-
McAdam and colleagues (17) proposed that the diagno- inflammatory drugs (NSAIDs) may be adequate. If,
sis of RP require three or more of the following clinical however, the symptoms are severe or resistant to
criteria: (1) bilateral auricular chondritis, (2) nonerosive, NSAID therapy, then low-to-moderate doses of corti-
seronegative inflammatory polyarthritis, (3) nasal chon- costeroids may be necessary. Presence of respiratory
dritis, (4) ocular inflammation (conjunctivitis, keratitis, symptoms, renal disease, or vasculitis require high-dose
scleritis/episcleritis, uveitis), (5) respiratory tract chon- corticosteroids. As the disease is better controlled the
dritis (laryngeal and/or tracheal cartilages), and (6) steroid dose can be reduced. Immunosuppressives may
cochlear and/or vestibular dysfunction (neurosensory be necessary as steroid-sparing agents. Other drugs,
hearing loss, tinnitus, and/or vertigo), and a compatible for example, dapsone and cyclosporine, have been
biopsy. The need for a biopsy has not been necessary in reported to be helpful in small numbers of patients and
retrospective studies (4) and is not necessary in clinical so have immunosupressive drugs, including azathio-
practice if the patient has chondritis of both ears, or chon- prine, methotrexate, chlorambucil, and cyclophospha-
dritis at multiple sites. If, however, the history is recent mide. Recently, anti-CD4 antibodies and antitumor
and the clinical picture unclear or confusing, a biopsy (see necrosis factor (TNF) agents have been used with mixed
Figure 22-1) may be essential to make a diagnosis. success. Because of the rarity of this illness, no con-
As with other inflammatory diseases there can be trolled studies have been done. Involvement of the
anemia of chronic disease, elevated sedimentation rate, trachea is a serious complication and necessitates
and hypergammaglobulinemia. If macrocytosis is aggressive management, including tracheostomy, use of
observed, the possibility of associated myelodysplasia stents if there is tracheal collapse, high-dose corticoste-
should be investigated. An abnormal urinalysis gener- roids, and immunosuppressives (21). Infection from
ally reflects renal involvement and the possibility of respiratory compromise and immunosuppressed state,
glomerulonephritis should be investigated. as well as systemic vasculitis have been increasingly
Respiratory involvement is always a serious compli- common causes of death. Aortic valve disease can be
cation and may go undiagnosed until complications successfully treated by surgery (22).
develop. Thus, all patients should undergo pulmonary
function tests, as well as inspiratory and expiratory flow
volume curves (12). Radiologic assessment by tomogra- REFERENCES 22
phy or computed tomography (CT) scan (3,1820) has
been helpful in delineating the inflammatory changes of 1. Jaksch-Wartenhorst R. Polychondropathia. Wien Arch F
the trachea and the bronchial tree and the presence of Inn Med 1923;6:93100.
stricture/s (localized or diffuse) and calcification can be 2. Pearson CM, Kline HM, Newcomer VD. Relapsing poly-
accurately assessed. chondritis. N Engl J Med 1960;263:5158.
Echocardiogram may help assess involvement of the 3. Kent PD, Michet CJ, Luthra HS. Relapsing polychondri-
tis. Curr Opin Rheumatol 2004;16:5661.
cardiac valves and CT/magnetic resonance angiography
4. Michet CJ Jr, McKenna CH, Luthra HS, OFallon WW.
(MRA) may be necessary to look for large vessel Relapsing polychondritis; survival and predictive role of
disease. Other investigations depend upon the associ- early disease manifestations. Ann Int Med 1986;104:
ated disease. 7478.
When faced with a patient with early RP, one is 5. Riccieri V, Spadaro A, Taccari E, Zoppini A. A case of
obligated to consider other diagnosis. Chondritis due to relapsing polychondritis: pathogenetic considerations
streptococcal infection, local fungal infections, syphilis, Clin Exp Rheumatol 1988;6:9596.
454 HARVINDER S. LUTHRA
6. Homma S, Matsumoto T, Abe H, Fukuda Y, Nagano M, 15. Chang-Miller A, Okamura M, Torres VE, et al. Renal
Suzuki M. Relapsing polychondritis: pathological and involvement in relapsing polychondritis. Medicine 1987;
immunological findings in an autopsy case. Acta Pathol 66:202217.
Jpn 1984;34:11371146. 16. Myers B, Gould J, Dolan G. Relapsing polychondritis and
7. McKenna CH, Luthra HS, Jordan RE. Hypocomplement- myelodysplasia: a report of two cases and review of the
emic ear effusion in relapsing polychondritis. Mayo Clin literature. Clin Lab Haematol 2000;22:4548.
Proc 1976;51:495497. 17. McAdam LP, OHanlon MA, Bluestone R, Pearson
8. Foidart J, Abe S, Martin GR, et al. Antibodies to type II CM. Relapsing polychondritis: prospective study of 23
collagen in relapsing polychondritis. N Engl J Med 1978; patients and a review of the literature. Medicine
299:12031207. 1976;55:193215.
9. Herman JH, Dennis MV. Immunopathologic studies in 18. Booth A, Dieppe PA, Goddard PL, Watt I. The radiologi-
relapsing polychondritis. J Clin Invest 1973;52:549558. cal manifestations of relapsing polychondritis. Clin Radiol
10. Taneja V, Griffiths M, Behrens M, Luthra HS, David CS. 1989;40:147149.
Auricular chondritis in NOD.DQ8.A beta o (A(g7-/-)) 19. Mendelson DS, Som PM, Crane R, Cohen BA, Spiera H.
transgenic mice resembles human relapsing polychondri- Relapsing polychondritis studied by computed tomogra-
tis. J Clin Invest 2003;112:18431850. phy. Radiology 1985;157:489490.
11. Isaak BL, Liesegang TJ, Michet CJ Jr. Ocular and sys- 20. Davis SD, Berkmen YM, King T. Peripheral bronchial
temic findings in relapsing polychondritis. Ophthalmology involvement in relapsing polychondritis: demonstration
1986;93:681689. by thin-section CT. AJR Am J Roentgenol 1989;153:953
12. Krell WS, Staats BA, Hyatt RE. Pulmonary function in 954.
relapsing polychondritis. Am Rev Respir Dis 1986;133: 21. Eng J, Sabanathan S. Airway complications of
11201123. relapsing polychondritis. Ann Thorac Surg 1991;51:686
13. Delrosso A, Petix NR, Pratesi M, et al. Cardiovascular 692.
involvement in relapsing polychondritis. Semin Arthritis 22. Buckley LM, Ades PA. Progressive aortic valve
Rheum 1997;26:840844. inflammation occuring despite apparent remission of
14. OHanlon M, McAdam LP, Bluestone R, Pearson CM. relapsing polychondritis Arthritis Rheum 1992;35:812
The arthropathy of relapsing polychondritis. Arthritis 814.
Rheumatism 1976;19:191194.
CHAPTER 23
Adult-Onset Stills Disease

JOHN M. ESDAILE MD, MPH
Diagnosis is one of exclusion and is suggested by the tumor necrosis factor (TNF) alpha have been reported
characteristic febrile pattern, evanescent rash, in persons with active adult Stills disease and
organomegaly, elevated white blood cell count, and therapy against these cytokines is an active area of
a markedly elevated serum ferritin, serum IL-18 when investigation.
available, and a reduced glycosylated fraction of Most have a chronic course with morbidity arising
ferritin. from a polyarthritis.
A predominance of T-helper cell (Th1) cytokines such
as interleukin (IL)-2, IL-6, IL-18, interferon gamma,
ADULT STILLS DISEASE Clinical, Laboratory, and

Radiographic Findings
The clinical features of adult Stills disease resemble
the systemic form of juvenile rheumatoid arthritis. The The clinical manifestations and laboratory findings of
disorder is rare, affects both genders equally, and exists adult Stills disease (2,7) are summarized in Table 23-1.
worldwide. The majority of patients are 16 to 35 years Usually the initial symptom is sudden onset of a high
of age (1). spiking fever. The fever spikes once daily (rarely, twice
daily), usually in the evening, and the temperature
returns to normal in 80% of patients untreated with
Pathogenesis antipyretics. Arthralgia and severe myalgia are univer-
The etiology of adult Stills disease is unknown. Studies sal. Arthritis is almost universal but may be mild and
of linkage to human leukocyte antigens (HLA) have overlooked by a physician whose attention is drawn to
been inconclusive (2). It has been suggested that immune more dramatic manifestations. Initially the arthritis
complexes play a pathogenic role, but this suspicion has affects only a few joints but may then evolve into poly-
not been confirmed (1,2). The principal hypothesis is articular disease. The most commonly affected joints
that Stills disease results from a virus or other infec- are the knee (84%) and wrist (74%). The ankle, shoul-
tious agent, but study results lack consistency (1). Preg- der, elbow, and proximal interphalangeal joints are
nancy or use of female hormones have not been involved in one half of patients and the metacarpopha-
associated with the development of Stills disease (3). langeal joints are involved in one third of patients.
The possible role of stress as an inducing phenomenon Involvement of the distal interphalangeal joints in one-
has been raised, but lacks confirmation (3). fifth of patients is notable (2,8). Stills rash, present in
A predominance of T-helper (Th1) cytokines have more than 85% of patients, is almost pathognomonic.
been reported in the blood and tissues of persons The rash is salmon pink, macular or maculopapular,
with active adult Stills disease (4). Increased levels of frequently evanescent, and often occurs with the evening
interleukin (IL)-2, IL-6, IL-18, interferon gamma, and fever spike. Because the rash may not be noticed by the
tumor necrosis factor (TNF) alpha have been described patient, a check during evening rounds can lead to the
(1,46). Alterations in cytokines may be important detection of this almost diagnostic finding. The rash is
in the pathogenesis of the disorder and in its future most common on the trunk and proximal extremities,
treatment. but is present on the face in 15% of patients. It can be
455
456 JOHN M. ESDAILE
TABLE 23-1. CLINICAL MANIFESTATIONS AND LABORATORY TESTS IN ADULT

STILLS DISEASE.a
CHARACTERISTICb PATIENTS POSITIVE/PATIENTS TOTAL PERCENTAGE
Clinical manifestations
Female 145/283 51
Childhood episode (15 years) 38/236 16
Onset 1635 years 178/233 76
Arthralgia 282/283 100
Arthritis 249/265 94
Fever 39C 258/266 97
Fever 39.5C 54/62 87
Sore throat 57/62 92
JRA rash 248/281 88
Myalgia 52/62 84
Weight loss 10% 41/54 76
Lymphadenopathy 167/264 63
Splenomegaly 138/265 52
Abdominal pain 30/62 48
Hepatomegaly 108/258 42
Pleuritis 79/259 31
Pericarditis 75/254 30
Pneumonitis 17/62 27
Alopecia 15/62 24
Laboratory tests
Elevated ESR 265/267 99
WBC 10,000 cells/mm3 228/248 92
WBC 15,000 cells/mm3 50/62 81
Neutrophils 80% 55/62 88
Serum albumin < 3.5 g/dL 143/177 81
Elevated hepatic enzymesb 169/232 73
Anemia (hemoglobin 10 g/dL) 159/233 68
Platelets 400,000/mm3 37/60 62
Negative antinuclear antibody test 256/278 92
Negative rheumatoid factor 259/280 93
ABBREVIATIONS: ESR, erythrocyte sedimentation rate; JRA, juvenile rheumatoid arthritis; WBC, white blood cell.
a
Data from Pouchot and colleagues(2), including patients reviewed by Ohta and colleagues (J Rheumatol
1987;14:11391146). Data for fever 39.5C, sore throat, myalgia, weight loss, abdominal pain, pneumonitis,
alopecia, WBC 15,000 cells/mm3, neutrophils, and platelets are from Pouchot and colleagues only, as these data
were likely underreported in early studies.
b
Any elevated liver function test.
precipitated by mechanical irritation from clothing, in the wrist, including nonerosive narrowing of the car-
rubbing (Koebners phenomenon), or a hot bath. The pometacarpal and intercarpal joints, which progresses
rash may be mildly pruritic. to bony ankylosis (2,10,11).
An elevated erythrocyte sedimentation rate is uni-
versal. Leukocytosis is present in 90% of cases, and in
80% the white blood cell count is 15,000/mm3 or more.
The liver function tests may be elevated in up to three
Diagnosis
fourths of patients (1,2,9). Anemia, sometimes pro- Although several sets of diagnostic criteria have been
found, is common. Rheumatoid factor and antinuclear proposed (8,12,13), the criteria of Cush and colleagues
antibody tests are generally negative and, if present, are (8) are a practical guide (Table 23-2). It is important to
of low titer. Synovial and serosal fluids are inflamma- note that most patients do not present with the full-
tory with a predominance of neutrophils (2). blown syndrome. Fever is the most common first mani-
Radiographic findings at presentation are nonspe- festation, and other features develop over a period of a
cific. Early in the disease course, soft tissue swelling and couple of weeks or occasionally months. A patient with
periarticular osteoporosis may be found. With time, car- high daily fever spikes, severe myalgia, arthralgia,
tilage narrowing or erosion develop in most patients. arthritis, Stills rash, and leukocytosis (frequently in
Characteristic radiographic findings are typically found combination with other manifestations outlined in Table
C H A P T E R 2 3 A D U L T - O N S E T S T I L L S D I S E A S E 45 7
TABLE 23-2. CRITERIA FOR THE DIAGNOSIS OF with adult Stills disease were lower than in other chronic
ADULT STILLS DISEASE. rheumatic diseases. Educational attainment, occupa-
tional prestige, social functioning, and family income
A diagnosis of adult Stills disease requires the presence of all of
the following: did not differ between the Stills patients and the con-
Fever 39C (102.2F) trols (16). The results suggest that patients with Stills
Arthralgia or arthritis disease are remarkably resilient in overcoming handi-
Rheumatoid factor < 1 : 80 caps. However, premature death may be slightly
Antinuclear antibody < 1 : 100
increased above that expected. Causes of fatality include
In addition, any two of the following are required: hepatic failure, disseminated intravascular coagulation,
White blood cell count 15,000 cells/mm3 amyloidosis, and sepsis, all of which were likely due to
Stills rash the Stills disease (1,2,7,8).
Pleuritis or pericarditis
Hepatomegaly or splenomegaly or generalized
lymphadenopathy Treatment
SOURCE: From Cush JJ, Medsger TA Jr, Christy WC, et al. Arthritis Rheum Acute Disease
1987;30:186194, by permission of Arthritis and Rheumatism.
Nonsteroidal anti-inflammatory drugs (NSAIDs),
including aspirin, are first-line treatment. Response to
23-1) is unlikely to have anything other than adult Stills NSAIDs may be slow but responders usually have a
disease. Thus, this diagnosis should top the differential good prognosis (2).
diagnosis list (Table 23-3). Most other diagnoses can be A major concern with NSAID therapy has been
excluded on clinical grounds or by simple diagnostic severe hepatotoxicity. Liver function test abnormalities,
tests. Recently, a markedly elevated serum ferritin and a common finding on presentation, are likely an integral
a reduced glycosylated fraction of ferritin has been part of the disease and may return to normal despite
proposed as suggesting Stills disease (12,14,15). The continued NSAID therapy (2). However, frequent
elevated ferritin likely results from the increased inflam-
matory cytokines and it has been suggested that IL-18
may be a better marker. TABLE 23-3. DIFFERENTIAL DIAGNOSIS OF ADULT
STILLS DISEASE.
Disease Course and Outcome Granulomatous disorders

Sarcoidosis
Approximately one fifth of patients with Stills disease Idiopathic granulomatosis hepatitis
experience long-term remission within 1 year. One- Crohns disease
third of patients have a complete remission followed by Vasculitis
one or more relapses. The timing of relapse is unpre- Serum sickness
dictable, although relapse tends to be less severe and Polyarteritis nodosa
Wegeners granulomatosis
of shorter duration than the initial episode (2,8). The
Thrombotic thrombocytopenic purpura
remaining patients have a chronic disease course. The Takayasus arteritis
principal problem is chronic arthritis, and some patients
with severe involvement of the hips and, to a lesser Infection
Viral infection (e.g., hepatitis B, rubella, parvovirus, Coxsackie
extent, the knees have required total joint replacement
virus, EpsteinBarr, cytomegalovirus, human immunodefi-
(2,8). ciency virus)
The presence of polyarthritis (four or more joints Subacute bacterial endocarditis
involved) or root joint involvement (shoulders or hips) Chronic meningococcemia
has been identified as markers for a chronic disease Gonococcemia
Tuberculosis
course in a number of studies (2,8). A prior episode in
Lyme disease
childhood (which occurs in about 1 of 6 patients) and a Syphilis
need for more than 2 years of therapy with systemic Rheumatic fever 23
corticosteroids may also be poor prognostic markers
Malignancy
(8).
Leukemia
Overall, the prognosis is good. A recent controlled Lymphoma
study noted that an average of 10 years after diagnosis, Angioblastic lymphadenopathy
patients with adult Stills disease had significantly higher
Connective tissue disease
levels of pain, physical disability, and psychologic dis-
ability than their unaffected siblings of the same gender. Mixed connective tissue disease
However, the levels of pain and disability in patients
458 JOHN M. ESDAILE
monitoring of liver function, even after hospital dis- therapists, psychologists, or arthritis support groups
charge, is mandatory for patients receiving NSAIDs. may all be needed to care for individual patients. A
NSAIDs may also increase the risk of intravascular knowledgeable, caring physician can make a tremen-
coagulopathy. dous difference. It is important to realize that Stills
In patients who fail to respond to NSAIDs and those disease can remit even years after onset and that the
with severe disease require systemic intravascular coag- vast majority of patients are leading remarkably full
ulopathy, rising values on liver function tests during lives a decade after the onset of the disease.
NSAID treatment, and individuals who do not respond
to NSAIDs may require corticosteriod treatment. Gen-
erally, prednisone in a dose of 0.5 to 1.0 mg/kg/day is REFERENCES
needed initially, but relapse can occur with tapering and
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patients. Medicine 1991;70:118136.
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for adult Stills disease. J Rheumatol 1996;23:20492054.
No controlled studies of second-line agents for the 4. Chen DY, Lan JL, Lin FJ, Hsieh TY, Wen MC. Predomi-
treatment of Stills disease have been published. The nance of Th1 cytokine in peripheral blood and pathologi-
most common cause of chronicity is arthritis. Low-dose cal tissues of patients with active untreated adult onset
weekly methotrexate in doses similar to that used in Stills disease. Ann Rheum Dis 2004;63:13001306.
adult rheumatoid arthritis has been used to control both 5. Hoshino T, Ohta A, Yang D, et al. Elevated serum
chronic arthritis and chronic systemic disease (1,17,18). interleukin 6, interferon-gamma, and tumor necrosis
While methotrexate is potentially hepatotoxic, this factor-alpha levels in patients with adult Stills disease.
agent is being used increasingly. Approximately two J Rheumatol 1998;25:396398.
thirds of patients will respond to methotrexate (17). 6. Kawashima M, Yamamura M, Taniai M, et al. Levels
of interleukin-18 and its binding inhibitors in the blood
Mild chronic systemic disease (e.g., fatigue, fever, rash,
circulation of patients with adult-onset Stills disease.
serositis) may also respond to hydroxychloroquine and Arthritis Rheum 2001;44:550560.
this agent can be combined with methotrexate. Increased 7. Ohta A, Yamaguchi M, Tsunematsu T, et al. Adult Stills
toxicity with sulfasalazine has been reported, thereby disease: a multicenter survey of Japanese patients.
limiting its use (19). J Rheumatol 1990;17:10581063.
Immunosuppressive agents, including azathioprine, 8. Cush JJ, Medsger TA Jr, Christy WC, Herbert D, Co-
cyclophosphamide, and, most recently, cyclosporin A operstein LA. Adult-onset Stills disease: clinical course
(20), have been used in resistant cases. Intravenous and outcome. Arthritis Rheum 1987;30:186194.
immunoglobulin (21) has been used, alone (21) or in 9. Esdaile JM, Tannenbaum H, Lough JO, Hawkins D.
combination with mycophenolate mofetil (22), but its Hepatic abnormalities in adult Stills disease. J Rheuma-
use is controversial. tol 1979;6:673679.
10. Medsger TA Jr, Christy WC. Carpal arthritis with anky-
Elevated serum levels of cytokines including TNF
losis in late onset Stills disease. Arthritis Rheum 1976;19:
alpha, IL-6, interferon gamma, and especially IL-18 232242.
(1,46), although nonspecific, have suggested the possi- 11. Bjorkengren AG, Pathria MN, Sartoris DJ, et al. Carpal
ble benefit of anticytokine therapies. TNF-alpha block- alterations in adult-onset Stills disease, juvenile chronic
ing treatments, especially infliximab, appear effective arthritis and adult-onset rheumatoid arthritis: a compara-
(23,24), although a recent report noted that they were tive study. Radiology 1987;165:545548.
not continued in 17 of 20 patients because of adverse 12. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary
effects or loss of efficacy (25). Anakinra (100 mg subcu- criteria for classification of adult Stills disease. J Rheu-
taneous daily) shows great promise as a treatment. It matol 1992;19:424430.
has been reported in a small number of cases to have 13. Masson C, Le Loet X, Liote F, et al. Comparative study
dramatic benefits (1,26,27). A decade after disease of 6 types of criteria in adult Stills disease. J Rheumatol
1996;23:495497.
onset, approximately one half of patients require
14. Fautrel B, Le Moel G, Saint-Marcoux B, et al. Diagnostic
second-line agents, and one third of these require low value of ferritin and glycosylated ferritin in adult onset
dose corticosteroids (16). Stills disease: J Rheumatol 2001;28:322329.
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a time when they are completing their education, start- and low glycosylated ferritin may also be a marker of
ing a career, or starting a family, which can make it excessive macrophage activation. J Rheumatol 2003;30:
particularly devastating. Physiotherapists, occupational 10271028.
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16. Sampalis JS, Esdaile JM, Medsger TA Jr, et al. A con- ment with intravenous immunoglobulins and mycopheno-
trolled study of the long-term prognosis of adult Stills late mofetil. Rheumatology 2004;43:795799.
disease. Am J Med 1995;98:384388. 23. Kokkinos A, Iliopoulos A, Greka P, Efthymiou A, Katsi-
17. Fujii T, Akizuki M, Kameda H, et al. Methotrexate treat- lambros N, Sfikakis PP. Successful treatment of refractory
ment in patients with adult onset Stills disease retro- adult-onset Stills disease with infliximab. A prospective,
spective study of 13 cases. Ann Rheum Dis 1997;56:144 non-comparative series of four patients. Clin Rheumatol
148. 2004;23:4549.
18. Fautrel B, Borget C, Rozenberg S, et al. Corticosteroid 24. Husni ME, Maier AL, Mease PJ, et al. Etanercept in the
sparing effect of low dose methotrexate treatment in adult treatment of adult patients with Stills disease. Arthritis
Stills disease. J Rheumatol 1999;26:373378. Rheum 2002;46:11711176.
19. Jung JH, Jun JB, Yoo DH, et al. High toxicity of sulfasala- 25. Fautrel B, Sibilia J, Mariette X, Combe B. Tumour necro-
zine in adult-onset Stills disease. Clin Exp Rheumatol sis factor alpha blocking agents in refractory adult Stills
2000;18:245248. disease: an observational study of 20 cases. Ann Rheum
20. Marchesoni A, Ceravolo GP, Battafarano N, Rossetti A, Dis 2005;64:262266.
Tosi S, Fantini F. Cyclosporin A in the treatment of adult 26. Fitzgerald AA, LeClercq SA, Yan A, Homik JE, Din-
onset Stills disease. J Rheumatol 1997;24:15821587. arello CA. Rapid response to anakinra in patients with
21. Vignes S, Wechsler B, Amoura Z, et al. Intravenous refractory adults Stills disease. Arthritis Rheum 2005;52:
immunoglobulin in adult Stills disease refractory to non- 17941803.
steroidal anti-inflammatory drugs. Clin Exp Rheumatol 27. Vasques Godinho FM, Parreira Santos MJ, Canas da
1998;16:295298. Silva J. Refractory adult onset Stills disease successfully
22. Bennett AN, Peterson P, Sangle S, et al. Adult onset Stills treated with anakinra. Ann Rheum Dis 2005;64:647
disease and collapsing glomerulopathy: successful treat- 648.
23
CHAPTER 24
Periodic Syndromes
JOHN G. RYAN, MB, MRCPI
DANIEL L. KASTNER, MD, PHD
Hereditary periodic fever syndromes are autoinflam- flammatory syndrome (FCAS), MuckleWells
matory diseases characterized by episodes of fever syndrome (MWS), and neonatal-onset multisystem
with serosal, synovial, and/or skin inflammation. inflammatory disease (NOMID) are dominantly
Familial Mediterranean fever (FMF) and hyperimmu- inherited.
noglobulinemia D with periodic fever syndrome Colchicine and biologic therapies such as tumor
(HIDS) are inherited in an autosomal recessive necrosis factor alpha (TNF-alpha) and interleukin
manner and tumor necrosis factor receptorassoci- 1 beta (IL-1 beta) receptor agonists are successful in
ated periodic syndrome (TRAPS), familial cold autoin- the treatment of some of these inherited diseases.
Several forms of arthritis may present with patterns of have identified four genes underlying these six clinical
exacerbation and remission that may be considered entities.
periodic. This chapter focuses on six clinically distinct It should be noted at the outset that there are a
illnesses in which underlying genes have been identified, number of patients with unexplained recurrent fevers
and in addition a group of disorders of unclear who do not have demonstrable mutations in these four
etiology. genes, and who may not meet clinical criteria for any of
the six disorders described below. In children, the syn-
drome of periodic fever with aphthous stomatitis, phar-
HEREDITARY PERIODIC yngitis, and cervical adenopathy (PFAPA) is relatively
FEVER SYNDROMES common (2). In addition to the cardinal manifestations
making up the acronym, abdominal pain and arthralgia
are also sometimes seen. Mutations in the known peri-
This group of diseases is characterized by episodes of
odic fever genes are an exclusion criterion, and this
fever with serosal, synovial, and/or cutaneous inflamma-
condition almost uniformly abates in late adolescence
tion. Unlike the commonly recognized autoimmune
or early adulthood.
diseases, there is a lack of either high titer autoantibod-
ies or self-reactive T cells, and hence these conditions
are sometimes referred to as autoinflammatory diseases
(1). Based on clinical findings and patterns of inheri-
Familial Mediterranean Fever
tance, at least six distinct disorders have been grouped Familial Mediterranean fever is a recessively inherited
among the hereditary periodic fever syndromes (Table disease most frequently observed in Jewish, Armenian,
24-1). Two of these illnesses, familial Mediterranean Arab, Turkish, and Italian populations (3), with a
fever (FMF) and the hyperimmunoglobulinemia D with modest male predominance (4). FMF (entry 249100 of
periodic fever syndrome (HIDS), are inherited in an Online Mendelian Inheritance in Man, OMIM, at http://
autosomal recessive manner. The other diseases, tumor www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM) is
necrosis factor (TNF) receptorassociated periodic caused by mutations in MEFV (MEditerranean FeVer),
syndrome (TRAPS), familial cold autoinflammatory a 10-exon gene encoded on the short arm of chromo-
syndrome (FCAS), MuckleWells syndrome (MWS), some sixteen (5,6). To date, over 70 disease-associated
and neonatal-onset multisystem inflammatory disease MEFV mutations have been described, many clustered
(NOMID, also known as chronic infantile neurologic in exon 10. The online database of periodic fever muta-
cutaneous and articular syndrome, or CINCA), are tions, INFEVERS (http://fmf.igh.cnrs.fr/infevers/),
dominantly inherited. Advances in molecular genetics provides an updated listing of MEFV mutations and
460
TABLE 24-1. THE HEREDITARY PERIODIC FEVER SYNDROMES.
TNF RECEPTOR NEONATAL
FAMILIAL ASSOCIATED FAMILIAL COLD ONSET MULTISYSTEM
CLINICAL MEDITERRANEAN HYPER IGD PERIODIC AUTOINFLAMMATORY MUCKLEWELLS INFLAMMATORY
FEATURES FEVER SYNDROME SYNDROME SYNDROME SYNDROME DISORDER/CINCA
Mode of inheritance Autosomal recessive Autosomal recessive Autosomal dominant Autosomal dominant Autosomal dominant Autosomal dominant
Underlying gene MEFV, encoding pyrin MVK, encoding TNFRS1A, encoding CIAS1, encoding CIAS1, encoding CIAS1, encoding
(marenostrin) mevalonate kinase p55 TNF receptor cryopyrin (NALP3) cryopyrin cryopyrin (NALP3)
Usual ethnicity Turkish, Armenian, Dutch, other north Any ethnicity Mostly European Mostly European Any ethnicity
Arab, Jewish, Italian European
Duration of attacks 1272 hours 37 days Days to weeks 1224 hours 23 days Continuous, with flares
Abdominal pain Sterile peritonitis, Severe pain, vomiting, Peritonitis, diarrhea, Nausea Abdominal pain, Can occur
constipation diarrhea, rarely or constipation vomiting, diarrhea
peritonitis
Pleural Common Rare Common Not seen Rare Rare
Arthropathy Monoarthritis; rarely Arthralgia, symmetric Arthritis in large Polyarthralgia Polyarthralgia, Epiphyseal overgrowth,
protracted arthritis polyarthritis joints, arthralgia oligoarthritis, contractures,
in knee or hip clubbing intermittent or chronic
arthritis, clubbing
Cutaneous Erysipeloid erythema on Diffuse maculopapular Migratory rash with Cold-induced urticarial Urticarialike rash Urticaria-like rash
lower leg, ankle, foot rash, urticaria underlying myalgia rash
Ocular Rare Uncommon Periorbital edema, Conjunctivitis Conjunctivitis, Progressive visual loss,
conjunctivitis episcleritis uveitis, conjunctivitis
Neurologic Rarely aseptic Headache Controversial Headache Sensorineural Headache, sensorineural

meningitis deafness deafness, chronic
aseptic meningitis,
mental retardation
Lymphatic Splenomegaly, Painful cervical Splenomegaly, Not seen Rare Hepatosplenomegaly,

occasional lymphadenopathy occasional lymphadenopathy
lymphadenopathy in children lymphadenopathy
Vasculitis HenochSchenlein Cutaneous vasculitis HSP, lymphocytic Not seen Not seen Occasional
purpura (HSP), common, rarely HSP vasculitis
polyarteritis nodosa
Systemic Risk depends on MEFV Rare Occurs in 15%, risk Rare Occurs in 25% May develop in some
amyloidosis and SAA genotypes, increased with patients, usually in
more common in cysteine mutations adulthood
Middle East
Treatment Daily colchicine Anti-TNF, statins Corticosteroids, Anakinra (anti-IL1 Anakinra (anti-IL1 Anakinra (anti-IL1
prophylaxis investigational etanercept receptor antagonist) receptor antagonist) receptor antagonist)
C H A P T E R 2 4 P E R I O D I C S Y N D R O M E S 46 1
ABBREVIATIONS: TNF, tumor necrosis factor.
24
462 JOHN G. RYAN AND DANIEL L. KASTNER
polymorphisms. Carrier frequencies in high risk popula- serosal attacks, with large effusions, extreme pain, and
tions can be as high as 1 in 3. inability to bear weight. Synovial fluid may appear
MEditerranean FeVer is expressed in polymorpho- septic, with as many as 100,000 polymorphonuclear
nuclear leukocytes, the major cell found in FMF inflam- leukocytes/mm3, but is sterile. Nevertheless, erosive
matory infiltrates, as well as activated monocytes and changes rarely develop. In the precolchicine era, up to
synovial and peritoneal fibroblasts. MEFV codes for a 5% of patients developed chronic hip arthritis, with
781 amino acid protein called pyrin (5), also known as secondary osteoarthritis or osteonecrosis, requiring
marenostrin (6). The N-terminal 90 amino acids of pyrin joint replacement. Chronic sacroiliitis may also occur
are the prototype for a motif termed the pyrin domain, in FMF, regardless of human leukocyte antigen (HLA)-
or PYD, found in over 20 human proteins involved in B27 status or use of colchicine. Arthralgia is common
the regulation of inflammation and apoptosis. Through in FMF, but nonspecific.
its PYD, pyrin associates with the apoptosis-associated The most characteristic cutaneous lesion of FMF is
specklike protein with a caspase recruitment domain erysipeloid erythema, a sharply demarcated, erythema-
(ASC), and thereby may regulate interleukin 1 beta tous, tender swollen area occurring on the dorsum of
(IL-1 beta) processing and leukocyte apoptosis (7). It is the foot, ankle, or lower leg. FMF patients may rarely
likely that pyrin variants in FMF lead to accentuated experience febrile myalgia, with excruciating muscle
innate immune responses, and may have been selected pain lasting up to several weeks; histologic features are
by an as-yet unknown infectious agent. suggestive of vasculitis. Other forms of vasculitis, includ-
ing HenochSchnlein purpura and polyarteritis
nodosum, are seen at increased frequency. Aseptic
Clinical and Laboratory Features
meningitis has been reported in FMF; however, a causal
Familial Mediterranean fever is characterized by epi- relationship has not been established.
sodes of fever, usually lasting 1 to 3 days, with or without The most serious complication of FMF is systemic
serositis, synovitis, or skin rash. Young children may amyloidosis (AA type), due to the deposition of a
present with fever alone. The first clinical episode product of the acute phase reactant, SAA, in the kidneys,
usually occurs in childhood or adolescence, and 80% to adrenal glands, intestine, spleen, lung, and testes. Risk
90% of patients experience their first episode by age 20. factors for amyloidosis include M694V homozygous
The time between attacks can vary for an individual MEFV genotype (8), male gender, a positive family
patient, and may range from days to years. The magni- history for amyloidosis, and the SAA1 alpha/alpha geno-
tude of fever and type of attack (abdominal, pleural, or type. Before the use of colchicine, renal failure due to
arthritic) may vary over time for any patient. During amyloidosis was the most common cause of death.
attacks, laboratory abnormalities in FMF include leuko- Amyloid deposition in the intestine may result in mal-
cytosis and elevated acute-phase reactants, including absorption. Cardiac involvement, neuropathy, and
the erythrocyte sedimentation rate (ESR), C-reactive arthropathy are uncommon in the amyloidosis of FMF.
protein (CRP), fibrinogen, haptoglobin, and serum Amyloidosis may rarely be the first manifestation of
amyloid A (SAA). FMF (phenotype II). Urinalysis for protein is a rapid
Attacks comprised of fever and abdominal pain occur and inexpensive screen for amyloidosis. In patients with
at some time in nearly all FMF patients. Abdominal persistent proteinuria, amyloidosis can be evaluated
pain may range from a dull ache to full-blown peritoni- directly by examination of a Congo redstained rectal
tis, with rigid abdomen, absent bowel sounds, and or renal biopsy specimen under polarized light.
rebound tenderness. Patients often undergo exploratory In patients from high-risk ethnic groups with typical
laparoscopy, which may reveal neutrophil-laden exu- symptoms and a therapeutic response to colchicine,
dates. Repeated episodes of peritonitis may lead to genetic testing is usually not considered necessary to
adhesions. Constipation is common during attacks. confirm the diagnosis. Genetic testing may be a useful
Pleuritic episodes may occur without fever, and are adjunct in atypical cases, or for physicians not familiar
usually unilateral. Other forms of serositis may occur. with FMF and related syndromes. Nevertheless, a sig-
Pericarditis is uncommon; there have been rare reports nificant fraction of patients with typical clinical findings
of tamponade. Unilateral acute scrotal pain occurs in of FMF have only one demonstrable MEFV mutation,
5% of prepubertal boys, due to inflammation of the rather than two, as would be expected in a recessive
tunica vaginalis, an embryological remnant of the peri- condition, and a small number of patients with clinical
toneal membrane. FMF may have no demonstrable mutations. These
Joint involvement in FMF is particularly common in observations raise the possibility that there is a second
those with the M694V homozygous genotype (8). FMF gene, or that MEFV mutations exist that are not
Acute monoarticular arthritis is most characteristic in accessible to current screening methods. Interpretation
FMF, particularly affecting the knee, ankle, or hip. of genetic tests may be further complicated by the exis-
These episodes of arthritis tend to last longer than tence of complex alleles, where more than one mutation
is identified on a single carrier chromosome, which at in addition to features seen in HIDS. Current hypothe-
times appear sufficient to cause symptoms with a second ses on the pathogenesis of HIDS are based on the pos-
normal allele. Thus, even in the era of molecular diag- sible effects of isoprenoid deficiency or excess mevalonic
nostics, clinical judgment maintains a central role in the acid on innate immune function. Elevated serum IgD is
diagnosis of FMF. not thought to play a primary role in pathogenesis.
Treatment Clinical and Laboratory Findings

Daily oral cochicine therapy is the mainstay of treat- The first attack usually starts in infancy, often precipi-
ment; it prevents both acute attacks and the develop- tated by childhood immunizations. The duration of
ment of amyloidosis. Over 75% of adults experience attacks is between 3 and 7 days. Episodes may occur
near-complete improvement in symptoms. The usual once or twice a month in childhood and adolescence,
daily dose is 1.2 to 1.8 mg for adults, with children over and may become less frequent or severe when the
5 years of age requiring similar doses. In younger chil- patient reaches adulthood. Minor infections, trauma,
dren, lower doses may be sufficient. In patients with surgery, and menses may act as triggers.
amyloidosis, therapy should be aimed at reducing SAA The attacks of HIDS often begin with chills and
levels below 10 mg/L. Diarrhea is a common side effect headache. In children diffuse tender lymphadenopathy
of colchicine, but may be minimized by starting at a low is common, and is considered a characteristic finding of
dose and gradually titrating upwards, by dividing the HIDS. Abdominal pain is often present, but peritoneal
daily dose, and by taking appropriate measures should irritation is less common than in FMF or TRAPS.
lactose intolerance develop. Neuropathy and myopathy Attacks are often accompanied by vomiting and diar-
are rare complications observed mainly in the elderly rhea. A number of cutaneous manifestations have
and those with renal impairment. There may be a slightly been described, including diffuse painful erythematous
increased risk of trisomy 21 in the offspring of parents macules, urticaria, and a morbilliform rash. Unlike FMF
taking colchicine at the time of conception. The use of there is no predilection for the lower limbs and the rash
intravenous colchicine to abort acute episodes may does not migrate. In as many as 70% of patients, HIDS
cause severe toxicity in those taking daily oral colchi- may be associated with arthralgia or arthritis, and joint
cine. Patients with breakthrough attacks may benefit symptoms sometimes coincide with abdominal attacks.
from subcutaneous interferon alpha, the IL-1 beta In contrast with the monoarticular arthritis of FMF,
receptor antagonist anakinra, or biologic therapies tar- HIDS arthritis tends to be polyarticular. Large joints
geted at TNF-alpha, although all of these approaches are usually affected, synovial fluid shows a predomi-
remain investigational. FMF patients with Henoch nance of granulocytes, and x-rays do not usually show
Schnlein purpura or protracted febrile myalgia may erosions. Systemic amyloidosis is uncommon in HIDS.
require corticosteroids, and those with polyarteritis During inflammatory attacks, HIDS patients present
nodosa may require cyclophosphamide and high-dose with leukocytosis and elevated acute-phase reactants.
corticosteroids. Prior to the identification of the underlying gene, HIDS
was defined by polyclonal elevation of serum IgD
Hyperimmunoglobulinemia D with (100 U/mL or >10 mg/dL) on two occasions at least 1
month apart in patients with a compatible history. While
Periodic Fever Syndrome most MVK mutation-positive patients with recurrent
Hyperimmunoglobulinemia D with periodic fever syn- fevers meet these criteria, a small percentage of muta-
drome (OMIM 260920) is a recessively inherited auto- tion-positive patients have normal IgD levels despite
inflammatory disorder described primarily in patients of clinical symptoms (HIDS sine hyperimmunoglobu-
Dutch or north European origin (9). In 1999, HIDS was linemia D). Serum IgD levels do not correlate with
shown to be caused by mutations in MVK, the gene severity or frequency of attacks. Over 80% of patients
encoding mevalonate kinase, an enzyme involved in also have elevated serum IgA levels (9). Urinary levels
cholesterol and nonsterol isoprene biosynthesis (10,11). of mevalonic acid are markedly increased during attacks.
As of this writing, over 50 disease-associated MVK The diagnosis of HIDS can be confirmed in patients
mutations are listed on the INFEVERS website. HIDS with a typical history, with or without an elevated serum
mutations leave low levels of residual function of the IgD, by finding increased urinary mevalonic acid during
enzyme, and lead to increased levels of the substrate, attacks or two mutations in MVK on genetic analysis.
mevalonic acid, in the urine, especially during febrile Patients with typical symptoms and increased serum
attacks. Serum cholesterol levels are in the lownormal IgD but without mutations or increased urinary meval- 24
range. MVK mutations leading to complete loss of enzy- onate are sometimes said to have variant HIDS. It is
matic activity cause mevalonic aciduria, a rare disease likely that this latter category represents an etiologically
with mental retardation, cataracts, and failure to thrive, heterogeneous group of patients.
Treatment African-American and Caucasian populations, respec-

tively, and are associated with a broader spectrum of
There has been no proven treatment for HIDS. Nonste- clinical findings than cysteine mutations.
riodal anti-inflammatory drugs (NSAIDs) and intra- When TNFRSF1A mutations were first described,
articular steroids may be of benefit in HIDS arthritis. mechanistic studies suggested that TRAPS might be
Corticosteroids, cyclosporine, and intravenous immu- caused by a failure to shed mutant TNF receptors from
noglobulin are not generally effective in HIDS. A the cell surface (1). Ordinarily, p55 receptors are cleaved
modest benefit from HMGCoA reductase inhibitors by metalloproteases from leukocyte cell membranes
such as simvastatin has been described (12). A study of upon cellular activation, thereby preventing repeated
etanercept, a TNF-alpha inhibitor, in two patients dem- TNF signaling and creating a pool of soluble receptors
onstrated marked improvement. Anecdotal evidence that might compete for ligand with membrane-bound
would suggest that some patients benefit from treat- receptors. TRAPS patients have lower than normal
ment with the IL-1 beta receptor antagonist, anakinra, levels of soluble p55 in the serum, and studies of leuko-
or the leukotriene inhibitor montelukast. HIDS does cytes from three patients with the C52F mutation dem-
not seem to have a major effect on longevity and attacks onstrated impaired ectodomain cleavage upon activation.
tend to ameliorate after adolescence. While this shedding defect was subsequently corrobo-
rated in patients with at least some other TNFRSF1A
Tumor Necrosis Factor Receptor mutations, a number of other functional abnormalities
in TRAPS-mutant receptors have been identified. These
Associated Periodic Syndrome include reduced binding to TNF, decreased signaling for
Tumor necrosis factor receptorassociated periodic apoptosis, and impaired trafficking in the cell. This
syndrome (OMIM 142680) is a dominantly inherited latter abnormality may lead to ligand-independent cel-
autoinflammatory disease caused by mutations in lular activation through multiple pathways, and may
TNFRSF1A, a gene on the short arm of chromosome account for the dominant inheritance of the TRAPS
12 that encodes the p55 receptor for TNF (1). Patients phenotype. It is interesting to note that, to date, it has
with TRAPS tend to have inflammatory episodes longer been difficult to identify any effect of the R92Q
than those seen in FMF or HIDS, often lasting at least TNFRSF1A variant on leukocyte function.
1 week and sometimes as long as 4 to 6 weeks. Prior to
the identification of causative TNFRS1A mutations,
case reports described this condition under a number of
clinical names, including familial Hibernian fever (13) In common with the other hereditary recurrent fever
and benign autosomal-dominant familial periodic fever. syndromes, TRAPS is characterized by episodes of fever
The recognition that this disorder may be seen in a wide and localized inflammation (14). Although there is a
range of ancestries has led to the introduction of the great degree of variability, attacks may last more than 1
ethnically neutral TRAPS nomenclature, which empha- month at a time. The cutaneous manifestations can be
sizes the pathogenesis of the disorder. quite distinctive, the most characteristic of which is a
The TNFRSF1A protein, also known as the p55 TNF migratory macular area of erythema that can occur on
receptor, has four highly conserved extracellular cys- the torso (Figure 24-1), or on the limbs and migrate dis-
teine-rich domains, a transmembrane domain, and an tally, with myalgia in the underlying muscle groups.
intracellular death domain. Five of the first six muta- Magnetic resonance imaging has demonstrated inflam-
tions identified were single-nucleotide differences matory changes extending into the muscle compartments
causing amino acid substitutions at cysteines that par- (Figure 24-1). Ocular involvement is quite common in
ticipate in disulfide bonds that maintain the receptors TRAPS, presenting with periorbital edema or conjunc-
three-dimensional conformation. Other subsequently tivitis but rarely uveitis. The combination of prolonged
identified mutations have been shown to interfere with attacks, characteristic rash, and ocular involvement, with
hydrogen bonding or to add or delete amino acids in the more pronounced response to corticosteroids than to
extracellular domains of the receptor. To date, over 50 colchicines, are all suggestive of TRAPS.
mutations in the TNFRSF1A gene have been catalogued Attacks of TRAPS are associated with a marked
on the INFEVERS website, about half of which involve acute-phase response. Systemic AA amyloidosis may
substitutions at conserved extracellular cysteine resi- develop in approximately 15% of patients with TRAPS
dues. Thus far no patients have been identified with (Figure 24-1) and can result in renal failure. The risk of
transmembrane or intracellular mutations, null muta- amyloidosis may be somewhat higher among those with
tions (in which the protein is not expressed), or muta- a positive family history of amyloidosis and those with
tions in the p75 TNFRSF1B receptor, encoded on mutations causing substitutions at cysteine residues. The
chromosome 1. Two particular TNFRSF1A variants, diagnosis of TRAPS should be considered in all patients
P46L and R92Q, are found at high frequency in the with unexplained inflammatory episodes even when no
family history has been elicited, as de novo TNFRS1A

mutations have been reported. To make a diagnosis of
TRAPS, the patient should have a documented
TNFRS1A mutation and history suggestive of the
disease. Patients with TRAPS-like illnesses who do not
have mutations in TNFRSF1A have been described, but
the molecular basis of their illness(es) remains unknown.
Although TRAPS attacks are debilitating, they are self-
limited. The prognosis of TRAPS is largely dependent
on whether the patient develops amyloidosis.
Treatment
Daily colchicine neither prevents acute attacks nor pre-
vents the development of amyloidosis. NSAIDs may be
used in mild attacks, with corticosteroids reserved for
more severe cases. Patients on corticosteroids frequently
require increasing doses over the course of their illness
with attendant increased adverse effects. Studies using
etanercept, the p75 TNF receptor fusion protein, suggest
a favorable response in clinical and laboratory parame-
ters. It has been suggested that modifying the etaner-
cept dose in response to normalized SAA levels may be
important to prevent the development or progression
of amyloidosis in patients at increased risk. Apropos of
recent data suggesting a ligand-independent pathophys-
iology of TRAPS, there are anecdotal data indicating
that TRAPS patients who cannot tolerate etanercept
may respond to the IL-1 beta receptor antagonist,
anakinra.
Cryopyrinopathies
The cryopyrinopathies include FCAS (OMIM 120100)
(15), MWS (OMIM 191900) (16), and NOMID/CINCA
(OMIM 607115) (17). These three disorders comprise a
clinical spectrum, with FCAS the mildest and NOMID/
CINCA the most severe, caused by dominantly inher-
ited mutations in CIAS1 (cold-induced autoinflamma-
tory syndrome 1) (18,19). The protein encoded by
CIAS1, denoted cryopyrin or NALP3, has an N-termi-
nal PYD, thus establishing a relationship with the FMF
protein pyrin, a central NACHT domain thought to be
involved in nucleotide-binding and oligomerization,
and a C-terminal leucine-rich repeat domain that may
interact with microbial products. Nearly all of the over
50 disease-associated mutations in cryopyrin listed in
FIGURE 24-1 the INFEVERS database reside in the NACHT domain,
encoded by exon 3 of CIAS1.
Clinical features of the tumor necrosis factor (TNF) receptor
associated periodic syndrome (TRAPS). (Top) Typical migratory The cryopyrin protein forms a macromolecular
erythematous rash on the trunk of a patient with the T50M complex called the inflammasome, which activates
mutation. (Center) Magnetic resonance image of a person with caspase-1 and thereby cleaves IL-1 beta from its 31 kDa
TRAPS (T50M) with skin rash and myalgia of the left thigh. The precursor to the biologically active 17 kDa fragment. 24
biopsy demonstrated fasciitis and panniculitis, but no myositis.
Cryopyrin-deficient mice exhibit a number of immuno-
(Bottom) Photomicrograph demonstrating amyloidosis in the kidney
of a TRAPS patient with the C52F mutation. The kidney section was logic abnormalities, most notably the inability to
stained with Congo red and viewed under polarizing light. produce active IL-1 beta in response to certain bacteria
or bacterial products. Leukocytes from patients with the complete remission of all disease symptoms. In a trial
cryopyrinopathies exhibit accentuated IL-1 beta pro- involving 18 patients with NOMID/CINCA who had
duction at baseline or in response to various stimuli. failed to respond to either corticosteroids or TNF block-
ers (20), treatment with daily subcutaneous injections
of anakinra resulted in disappearance of rash and con-
Clinical and Laboratory Features junctivitis within 3 days. In the 12 patients for whom
Patients with the cryopyrinopathies usually present very cerebrospinal fluid (CSF) could be obtained, intracra-
early in life with fever, an urticarialike skin rash, and an nial pressure, protein, and white cell counts decreased
intense acute-phase response. The rash is not true urti- significantly. Vision remained stable in all patients, and
caria, in that there are infiltrates of granulocytes and hearing actually improved in one third. Complete remis-
lymphocytes rather than mast cells. The severity of joint sion of inflammation occurred in 10 of the 18 symptoms
and neurological involvement, along with the risk of after 6 months of treatment. Magnetic resonance
amyloidosis, helps to distinguish among the three clini- imaging demonstrated marked reduction in cochlear
cal disorders, although there is considerable overlap. and leptomeningeal enhancement. These findings
Familial cold autoinflammatory syndrome has a clear suggest that CNS as well as peripheral manifestations
episodic quality, with attacks of rash, fever, polyarthral- of NOMID/CINCA are mediated by an excess of IL-1
gia, and constitutional symptoms occurring 1 to 2 hours beta, and that these symptoms can be ameliorated by
after generalized cold exposure. Amyloidosis is rare, the administration of anakinra. The discontinuation of
and patients usually have normal life expectancy. In anakinra led to a relapse of symptoms within days, and
MWS, attacks occur with no clear relationship to cold re-treatment led to rapid improvement, thus supporting
exposure, and are manifested by fever, urticarial skin the need for continuous use of anakinra in NOMID/
rash, limb pain, arthralgia, or arthritis, and sometimes CINCA. Longer term follow-up will be required to
abdominal pain, conjunctivitis, or episcleritis. Sensori- determine whether IL-1 inhibition will prevent the
neural hearing loss occurs in most patients, and AA intellectual sequelae of NOMID/CINCA, or the devel-
renal amyloidosis may develop in about one quarter. opment of amyloidosis.
Patients with NOMID/CINCA usually present in
infancy with nearly continuous clinical findings. These
include fever, urticarial skin rash, and constitutional IDIOPATHIC INTERMITTENT
symptoms. Chronic aseptic meningitis also occurs, which ARTHROPATHIES
can lead to headache, increased intracranial pressure,
and intellectual impairment. Sensory organ involve- In contrast to the hereditary periodic fever syndromes,
ment includes sensorineural hearing loss, conjunctivitis, which are systemic diseases, these disorders primarily
and uveitis, sometimes leading to deafness and/or blind- affect joints and adjacent structures (Table 24-2), and
ness. NOMID/CINCA patients may also develop a dis- genetics appears to play a less important role.
tinctive arthropathy with overgrowth of the epiphyses
of the long bones. Untreated, about 20% die before
reaching adulthood, and amyloidosis may occur later in Palindromic Rheumatism
life. Although all three disorders are dominantly inher- Initially described in 1944, palindromic rheumatism
ited, NOMID/CINCA was not initially recognized as a (PR) describes intermittent, relatively brief episodes of
genetic disease because of decreased reproductive typically monoarticular arthritis or periarthritis (inflam-
fitness in patients carrying the diagnosis. mation of the soft tissues adjacent to the joint). The
Genetic testing usually focuses on sequencing exon prevalence is roughly 20-fold less than that of rheuma-
3 of CIAS1. As is the case for FMF, TRAPS, and HIDS, toid arthritis (RA). The mean age of onset is approxi-
there are patients who meet clinical criteria for the cryo- mately 45 years, with a relatively even gender balance.
pyrinopathies who do not have identifiable mutations. Occasional families have been reported with multiple
This is particularly the case for NOMID/CINCA, where cases of PR, or in which PR and RA have occurred
only about half of the patients carrying the clinical diag- together. Recent series suggest increased prevalence of
nosis have demonstrable CIAS1 mutations. Neverthe- the shared epitope DRB-0401 and DRB-0404 alleles in
less, the availability of genetic testing has markedly PR relative to controls (21). In the absence of laboratory
increased the awareness of these disorders. and radiographic clues to the diagnosis, it is likely that
PR represents a heterogeneous group of disorders.
Treatment
Promising results have been obtained with the IL-1 beta
receptor antagonist, anakinra, in all three cryopyrinopa- In PR, attacks occur suddenly, initially affect one joint,
thies. Patients with FCAS and MWS exhibit almost and last from hours to days. Recurrences can occur over
TABLE 24-2. IDIOPATHIC PERIODIC SYNDROMES.

FEATURE PALINDROMIC RHEUMATISM INTERMITTENT HYDRARTHROSIS EOSINOPHILIC SYNOVITIS
Attacks 2 days; monoarticular arthritis 35 days, monoarticular arthritis, 12 weeks, monoarthritis triggered
or periarticular soft tissue large effusions by trauma
inflammation
Joints involved MCPs, PIPs, wrists, shoulders, Knee to hip, ankle, elbow Knee, MTP
MTPs, ankles
Associated conditions Familial aggregation with RA Episodes may coincide with Personal or family history of atopy,
menses; heterozygous MEFV dermatographism
mutations?
Prognosis 50% persistent palindromic Attacks often occur at predictable Self-limited episodes, benign
rheumatism, 33% develop intervals; sometimes prognosis
RA spontaneous remissions
Treatment Injectable gold, antimalarials, NSAIDs, colchicine, intra-articular Symptomatic

sulfasalazine steroids, synovectomy
ABBREVIATIONS: MCP, metacarpophalangeal joint; MTP, metatarsophalangeal joint; NSAID, nonsteriodal anti-inflammatory drug; PIP, proximal interphalangeal
joint; RA, rheumatoid arthritis.
irregularly spaced intervals. The joints affected include been no large randomized, controlled trials in the treat-
the interphalangeal joints of the hands and feet, the ment of PR.
wrists, shoulders, and ankles (22). Tender periarticular
swelling, 2 to 4 cm in diameter, may accompany an
attack, or occur independently. Small, sometimes painful
Intermittent Hydrarthrosis
subcutaneous nodules may develop near the elbows, Intermittent hydrarthrosis is characterized by
wrists, or knees, with a particular predilection for the periodic episodes of monoarticular or pauciarticular
fingers. Periarticular swelling and nodule formation are arthritis. Constitutional symptoms are rare. Attacks
usually transient. are notable for the periodicity of their nature, such
During attacks, there is a mild-to-moderate accelera- that patients can accurately predict their next attack.
tion of the ESR (22). Antibodies to cyclic citrullinated Spontaneous remission occurs in some cases (24).
peptide (anti-CCP) and rheumatoid factor (RF) are Prevalence data are not available; however, it is a rela-
positive in about half of patients with PR. Antinuclear tively rare condition. The usual age of onset is between
antibodies are negative with normal complement levels. 20 and 50, with a relatively even gender balance. There
Synovial biopsies and fluid taken during an attack dem- are cases in which attacks began at menarche, coin-
onstrate polymorphonuclear leukocytes. Biopsies of cided with menses, and remitted during pregnancy and
subcutaneous nodules demonstrate inflammatory cells, following menopause. Generally, familial clustering of
and notably lack the areas of fibrinoid necrosis and this condition does not occur. Recently, three cases of
palisading mononuclear cells seen in rheumatoid intermittent hydrarthrosis with heterozygous MEFV
nodules. mutations were reported from Spain, raising the
Longitudinal data on patients with PR demonstrated intriguing possibility that this disorder might be a
that 33% eventually develop RA, the conversion her- forme fruste of the more well-recognized autoinflam-
alded by conversion to seropositivity for RF, and devel- matory diseases.
opment of more aggressive disease (22). A retrospective
study identified RF positivity, female gender, and
involvement of the wrist in proximal phalangeal joints
as the greatest risk factors for the development of RA Attacks involve episodes of pain, swelling, and limita-
(23), and more recent data suggest that antibodies to tion of movement, usually affecting a single joint,
CCP may be a better predictor than RF. although occasionally more than one joint may be
affected. In most cases, attacks last 3 to 5 days, with
massive joint effusions but no erythema or warmth. In 24
Treatment
an individual patient, a limited number of joints may be
Anecdotal evidence suggests a role for NSAIDs, inject- affected, the most commonly affected being the knee,
able gold, antimalarials, or sulfasalazine. There have with the hip, ankle, and elbow less frequently involved.
Laboratory findings during attacks demonstrate a REFERENCES

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present on synovial biopsy (24). Radiographs demon- mutations in the extracellular domains of the 55 kDa TNF
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This rare condition is described in individuals with a 5. International FMF Consortium. Ancient missense muta-
history of atopy. Both genders are affected equally, and tions in a new member of the RoRet gene family are likely
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normal, although some patients have elevated IgE gene encoding mevalonate kinase cause hyper-IgD and
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(25). CharcotLeyden crystals (bipyramidal, hexagonal- encoding mevalonate kinase, cause hyperimmunoglobu-
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Numerous conditions are associated with synovial macol Ther 2004;75:476483.
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24
CHAPTER 25
Less Common Arthropathies

A. Hematologic and Malignant
Disorders
ADEL G. FAM, MD, FRCP(C), FACP
Recurrent hemarthrosis is the primary clinical mani- vessel occlusion in the bone marrow by sickled
festation of hemophilia. red cells.
Hemophilia A (classic hemophilia) is a heritable, Osteomyelitis in patients with Hb SS disease is due
X-linked recessive disorder of blood coagulation, to a combination of ischemic bone infarction and
occurring almost exclusively in males. The disorder is impaired host immunity. Salmonella is the most
associated with a deficiency of factor VIII. common organism.
Hemophilia B (Christmas disease), somewhat rarer Thalassemia is a group of inherited hemoglobin
but essentially indistinguishable clinically from disorders characterized by defects in the synthesis of
hemophilia A, is caused by factor IX deficiency. one or more of the alpha or beta subunits of Hb.
Sickle-cell hemoglobinopathies associated with In beta-thalassemia, the reduced or absent produc-
chronic hemolytic anemia and rheumatic manifestation of beta chains leads to the production of an
tions include both homozygous sickle-cell anemia (Hb imbalance between the numbers of alpha and beta
SS) and the heterozygous states: sickle-beta thalasse- chains. This leads, in turn, to unstable Hb molecules,
mia, sickle-C (S-C) disease, and sickle-D (S-D) disease. precipitation of the unaffected chains during erythro-
Sickle-cell disease results from a single nucleotide poiesis, and hemolysis.
substitution of valine for glutamic acid in the beta Mechanisms by which cancer can cause musculoskel-
globin gene. etal symptoms include direct tumor invasion of
In SS disease, the painful crises, osteonecrosis, bones and joints, hemorrhage into the joint, second-
and dactylitis are the result of small blood ary gout, and paraneoplastic syndromes.
Musculoskeletal manifestions of hematologic and malig- of tissue factorbearing cells. Factor Xa and factor IXa,
nant disorders are reviewed in this chapter. A list of formed in the initial reaction, then play a role in factor
these conditions is shown in Table 25A-1. VIII activation, generation of thrombin on platelet sur-
faces, and blood clotting. Factor VIII is a 340,000 Da
coagulant protein that activates factor X in the intrinsic
NONMALIGNANT HEMATOLOGIC coagulation pathway (1). In hemophilia, the extrinsic
tissue-dependent pathway remains intact, and is proba-
DISORDERS bly the major hemostatic regulatory system. Gene dele-
tions, insertions, or rearrangements have been implicated
Hemophilia in the chromosomal abnormalities leading to hemo-
Hemophilia A is a heritable, X-linked recessive dis- philia. These various genetic abnormalities lead to a
order of blood coagulation, occurring almost exclusively range of disease severities in hemophilia. Identification
in males (1 in 500010,000 male births). Hemophilia A of the gene for factor VIII, located on the X chromo-
(classic hemophilia) is due to factor VIII deficiency, some, facilitates both prenatal diagnosis of hemophilia
whereas hemophilia B (Christmas disease) is caused by and carrier detection for genetic counseling.
factor IX deficiency. Tissue factorfactor VIIa complex In mild hemophilia, the levels of factor VIII are
is important in initiating coagulation by activating small 6% to 36% of normal, and bleeding generally occurs
amounts of both factors X and IX in the environment in response to minor trauma. In a moderately severe
470
C H A P T E R 2 5 L E S S C O M M O N A R T H R O P A T H I E S 4 71
TABLE 25A-1. LESS COMMON ARTHROPATHIES. mity, instability, and secondary osteoarthritis. Chronic
HEMATOLOGIC AND MALIGNANT DISORDERS. arthritis is less frequent and less severe in Christmas
Nonmalignant hematologic disorders
disease. 25
Hemophilic arthropathy Hemophilic arthropathy is thought to be due to
Hemoglobinopathy-associated arthropathies repeated intra-articular bleeding and excessive iron
Sickle-cell disease deposition in both the synovial membrane and articular
Thalassemia cartilage. Because prothrombin and fibrinogen are
Malignant disorders absent in normal synovial fluid, the blood remains as a
Metastatic (tumor invasion of joints) liquid. Plasma gradually resorbs while the remaining
Metastatic carcinomatous arthritis red cells are phagocytosed by synovial lining macro-
Leukemic arthritis phages. Hemosiderin deposition in both synovial lining
Lymphomatous arthritis
cells and subsynovial supporting tissue is associated
Angioimmunoblastic T-cell lymphomaassociated arthritis
Myelomatous arthritis with chronic proliferative synovitis and pannus for-
Waldenstroms macroglobulinemia mation. The synovitis results in the production of
Nonmetastatic (paraneoplastic) lysosomal enzymes, collagenase, catabolic cytokines
Hypertrophic osteoarthropathy (see Chapter 25F) [interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-
Carcinoma polyarthritis
alpha)], superoxide anions, and hydroxyl radicals that
Amyloid arthritis
Secondary gout can lead to cartilage breakdown and osteoarthritis.
Miscellaneous: dermatomyositis, paraneoplastic vasculitis Radiographs often show increased periarticular soft
tissue swelling due to extensive iron deposition in the
synovium. Widening or premature fusion of the epiphy-
ses, enlargement of the femoral and humeral intercon-
hemophilia, the level ranges from 2% to 5% of normal. dylar notches (Figure 25A-1), squaring of the inferior
In severe hemophiliatwo thirds of all patientsthe patella, expansion of the radial head at the elbow, and
level is 1% or less. Plasma levels of factor VIII of <5% secondary osteoarthritis may occur in later stages. Com-
of normal are associated with spontaneous hemarthro- puted tomography (CT) scans are helpful in delineating
sis. The diagnosis of hemophilia can be confirmed by a the bone and soft tissue lesions. Magnetic resonance
coagulation screen, including bleeding time, platelet imagaing (MRI) is useful in demonstrating intra-
count, prothrombin time, plasma thromboplastin time, articular hemorrhage, subsynovial or muscle hemato-
and determinations of the levels of factors VIIl and mata, and chronic synovial hypertrophy.
IX. Bleeding into muscles occurs less frequently and
Christmas disease (hemophilia B), due to factor IX can lead to large bloody collections or hemophilic
deficiency, is less common than hemophilia A. The gene pseudotumors associated with muscle necrosis, cyst
for factor IX is also located on the X chromosome. formation, and, sometimes, compartment syndromes.
Hemophilia B, which occurs in approximately 1 in Compression femoral neuropathy may result from a
30,000 to 100,000 male births, produces a clinical picture retroperitoneal or psoas hematoma. Subperiosteal hem-
that is largely indistinguishable from that of hemophilia orrhage can result in a bone pseudotumor.
A. Factor IX is a 60,000 Da proenzyme that is converted Septic arthritis is a rare complication of hemophilic
to an active protease (factor IXa) by the tissue factor arthropathy. Staphylococcus aureus is the most common
VIIa complex. Factor IXa, in combination with acti- organism; coincidental human immunodeficiency virus
vated factor VIII, subsequently activates factor X (2). (HIV) infection appears to be an important contribut-
In rare circumstances, deficiency of factors XI, VII, V, ing factor in this complication. Septic arthritis is sus-
X, or II may be associated with hemarthrosis. pected when an episode of hemarthrosis fails to respond
Recurrent hemarthrosis is the most common bleed- promptly to treatment with factor VIII and joint immo-
ing manifestation of hemophilia A, occurring in up to bilization, particularly in the presence of fever or
two thirds of patients (3). This may occur spontaneously leukocytosis.
or following minor trauma. The onset is rapid with pain,
swelling, local tenderness, and limitation of joint move-
ments. The rising intra-articular pressure eventually
Treatment
terminates bleeding, but resolution of the clot occurs Since the 1960s, the widespread use of human donor
slowly. The knee, elbow, and ankle are the most fre- plasma products, concentrated with factor VIII, includ-
quently affected joints. Bleeding into the hip joint can ing cryoprecipitate, has improved the care of patients
lead to osteonecrosis of the femoral head. Patients with with hemophilia by reducing the severity and frequency
factor VIII levels <5% of normal, who are inadequately of the bleeding episodes and by permitting surgical pro-
treated, may develop a chronic arthritis with intermit- cedures. Between 1980 and 1985, however, these prod-
tent pain, stiffness, persistent synovial swelling, defor- ucts also led to the spread of HIV and viral hepatitis
472 ADEL G. FAM
FIGURE 25A-1
Elbow radiograph in a patient with

chronic hemophilia A showing widening
of the intercondylar notch and second-
ary osteoarthritis with joint space
narrowing, marginal osteophytes, and
intra-articular osseous bodies. Note
increased periarticular swelling and
density due to iron deposition in the
synovium (arrows).
(hepatitis B and C) among hemophiliacs. Donor screen- lead to side effects. For subacute and chronic arthritis,
ing and purification of factor VIII concentrates with nonsteroidal anti-inflammatory drugs (NSAIDs)not
monoclonal antifactor VIII antibody and heat lyophi- including aspirinare relatively safe and beneficial.
lization markedly reduced these infectious complica- Physical therapy is useful in preventing joint contrac-
tions. The advent of recombinant factor VIII has tures and deformities (3).
completely eliminated the risk of infection. Replace- Surgical synovectomy reduces the chronic synovitis
ment recombinant factor VIII therapy is administered and subsequent joint damage, but is associated with
prophylactically to children with severe hemophilia 1 to significant morbidity. Arthroscopic synovectomy, also
3 years of age in order to maintain plasma factor levels effective, has fewer complications. Both chemical
>1% (3). This serves to reduce the frequency of spon- synovectomy (by injecting intra-articular osmic acid,
taneous bleeding and prevent joint damage. Desmo- rifampicine, or other sclerosing agent) and radiation
pressin (DDAVP), a synthetic analog of vasopressin, synovectomy (using intra-articular radioisotope injec-
stimulates a transient increase in factor VIII levels, and tions such as colloidal P 32 chromic-phosphate, 90-
can provide an alternative therapy for patients with yttrium, or 186-rhenium) may be effective in the short
mild or moderate hemophilia A (3). Inhibitor IgG anti- term. The long-term efficacies of both chemical and
bodies to factor VIII develop in 5% to 10% of young radiation synovectomy, however, are less favorable (3).
patients with hemophilia A, but are less common in Total joint replacement is indicated for advanced osteo-
Christmas disease. Therapeutic options in these patients arthritis of the hip, shoulder, elbow, or ankle. Promising
include plasmapheresis and treatment with oral gluco- preliminary results with gene therapy have been
corticoids, azathioprine, cyclophosphamide, or porcine reported in a small number of patients with severe
factor VIII concentrate. Factor IX is not present in hemophilia.
cryoprecipitate or in factor VIII concentrates. Fresh
frozen plasma is an effective therapy, but carries with it
some risk of blood-borne infections. Virally inactivated Hemoglobinopathy-Associated
factor IX concentrate and recombinant factor IX are Musculoskeletal Manifestations
preferred.
Acute hemarthrosis is treated with immobilization,
Sickle-Cell Disease
ice packs, and prompt administration of factor VIII con- Sickle-cell hemoglobinopathies associated with chronic
centrate or recombinant factor VIII for approximately hemolytic anemia and rheumatic manifestations include
48 hours. If the joint effusion is unusually tense or if both homozygous sickle-cell anemia (Hb SS) and the
infection is suspected, joint aspiration is recommended, heterozygous states: sickle-beta thalassemia, sickle-C
preferably following factor VIII replacement. Short- (S-C) disease, and sickle-D (S-D) disease. SS disease
term use of intra-articular or oral glucocorticoids may occurs mostly in Africans, but also in southern Italy,
confer some additional benefit, but repeated use can Greece, Turkey, Saudi Arabia, and India (4).
Sickle cell disease results from a single nucleotide

substitution of valine for glutamic acid in the beta globin
gene. The diagnosis can be confirmed by cellulose 25
acetate Hb electrophoresis showing 76% to 100% Hb
SS. Deoxygenation (hypoxia) results in polymerization
of HbS, forming liquid crystals. This deforms the red
cells from biconcave discs into elongated, rigid, cres-
cent-shaped sickle cells, causing occlusion of the micro-
circulation and breakdown of red cells (hemolysis),
leading in turn to further tissue hypoxia and sickling.
Polymerization of HbS is influenced by intracellular
concentrations of HbS, HbF, and HbC; blood oxygen
saturation; and pH and temperature.
Once a sufficient number of rigid sickle cells is
formed, microvascular occlusion will result. Hypoxia of FIGURE 25A-2
tissues causes a secondary inflammatory reaction medi- Radiograph of the hips, showing bilateral osteonecrosis.
ated by histamine, bradykinin, and prostaglandins,
resulting in increased intramedullary pressure and bone
pain (4). The painful crises, osteonecrosis, and dactylitis
are the result of small blood vessel occlusion in the bone arthritis, but there is a high rate of perioperative com-
marrow by sickled red cells. These manifestations, most plications and mechanical loosening (7).
frequent in homozygous (SS) sickle-cell disease, may Dactylitis typically occurs in children, and is charac-
also occur under certain circumstances in the milder terized by acute, painful, nonpitting swelling of the
heterozygous sickle hemoglobinopathies such as HbS/ hands and feet (hand and foot syndrome) (4,6). Fever
beta-thalassemia (sickle-thal disease) and S-C disease. and leukocytosis, which may be the initial disease mani-
Individuals with sickle-cell trait (HbAS), healthy carri- festations, occur in S-S, S-C, and S-thalassemia disease.
ers of the gene mutation, are free from musculoskeletal Radiographs may show soft tissue swelling, periosteal
symptoms. Pure HbC disease, caused by substitution of new bone formation, or intramedullary sclerotic infarcts
lysine for glutamic acid in the beta chain, produces of the phalanges, metacarpals, and metatarsals. Scintig-
hemolysis. In contrast, Hb S-C disease results in fea- raphy and MRI are more sensitive in detecting bone
tures of both sickling and hemolysis (4). Recurrent infarcts. Symptoms usually resolve within 7 days, but
painful crises mainly affect the juxta-articular areas of recurrences are frequent. Osteonecrosis of the epiphy-
long bones, joints, spine, and ribs (5,6). The pain is often ses can lead to digital shortening. Osteopenia, stress
associated with local swelling and tenderness. The crises fractures, vertebral collapse, and growth abnormalities
can be triggered by infection, dehydration, acidosis, may also occur in sickle-cell disease (6).
cold exposure, traveling at high altitudes, and stress. Osteomyelitis in patients with Hb SS disease is due
The duration of crises is variable but usually no longer to a combination of ischemic bone infarction and
than 2 weeks. The pain rate (number of painful epi- impaired host immunity. Salmonella is the most common
sodes per year) correlates with early death in patients organism, followed by Staphylococcus aureus and Gram-
with SS anemia. Hydroxyurea, which increases the negative bacilli. Osteomyelitis usually follows an episode
levels of fetal Hb, reduces the pain rate and may ulti- of painful crisis and may affect multiple sites. Chronic
mately improve survival (5,6). sickling of the intestinal microvasculature may predis-
Sickle-cell arthropathy, caused by microvascular pose the devitalized bowel to invasion by Salmonella
ischemia and synovial infarctions, often affects large and other enteric bacteria. Osteomyelitis should be sus-
joints. Reaction to juxta-articular bone infarcts may also pected if symptoms of a painful crisis fail to respond
contribute to joint pain. Small, non-inflammatory syno- after 1 to 2 weeks. The diagnosis is confirmed by radi-
vial effusions are common. ography, bone scanning, and by cultures from the blood
Osteonecrosis (Figure 25A-2) affects the femoral or bone (obtained through a CT-guided aspiration).
head in approximately 33% of patients and the humeral MRI is more accurate in delineating the lesions. Septic
head in 25%. Multiple joints, including the spine, may arthritis is caused by the same organisms as osteomyeli-
be involved (7). In the spine, the bony infarcts result in tis, often occurring in association with osteonecrosis or
the characteristic biconcave or Lincoln log vertebrae. a painful vaso-occlusive crisis involving the same joint.
The risk of osteonecrosis is highest in those with A high index of suspicion and synovial fluid cultures are
frequent painful crises and in patients with Hb SS- essential for early recognition.
alpha-thalassemia. Total replacement arthroplasty is Gout is a rare complication of sickle-cell disease.
recommended for those with advanced secondary osteo- Hyperuricemia results from enhanced erythropoiesis
474 ADEL G. FAM
secondary to chronic hemolysis, increased nucleic acid beta-thalassemia often have HbA2 and features of both
sythesis, and overproduction of uric acid. In addition, SS disease and beta-thalassemia. beta-Thalassemia
cumulative renal damage occurring by the third decade minor (trait) is a relatively common disorder that is
of lifethe result of renal ischemia and microinfarc- rarely associated with clinical manifestations.
tionscan lead to sustained hyperuricemia and gout. Blood transfusions are the main supportive treat-
Severe sickle-cell anemia is treated by blood transfu- ment of beta-thalassemia major, but transfusion hemo-
sions and folic acid supplements (15 mg folic acid/day) siderosis is a common problem and chelation therapy
(4). Enhanced erythropoietic activity secondary to with deferoxamine is often required (10). Splenectomy
chronic hemolysis may lead to folate deficiency through is indicated if 40% or greater increase in the transfusion
the depletion of folate stores. Measures to prevent requirements occur during a 1-year period. Allogeneic
painful crises include avoidance of stress, alcohol, over- bone marrow (stem cell) transplantation and gene
exertion, swimming, and high altitudes. Treatment of transfer is a promising new treatment in children.
the painful crises consists of acetaminophen or NSAIDs
for mild episodes, and codeine or oxycodone for more
severe attacks (4). Oral controlled-release morphine is MUSCULOSKELETAL SYMPTOMS
as effective as continuous intravenous morphine for AND CANCER
the management of painful episodes in children (8).
Hydroxyurea enhances the production of HbF, which
Malignant disease is associated with a number of mus-
in turn reduces polymerization of Hb SS (9). Treatment
culoskeletal manifestations (Table 25A-2) (11). Mecha-
with hydroxyurea has been shown to be both cost-
nisms by which cancer can cause musculoskeletal
effective and beneficial in reducing the rate of painful
symptoms include: (1) direct tumor invasion of bones
crises in adults with SS (9). Favorable results have been
and joints (skeletal metastases, metastatic carcinoma-
reported with bone marrow (stem cell) transplantation
tous arthritis, leukemic synovitis and lymphomatous
in children with SS disease.
arthritis); (2) hemorrhage into the joint (leukemia); (3)
secondary gout (leukemia, polycythemia, lymphoma,
Thalassemia myeloma, carcinoma); and (4) through remote, non-
Thalassemia is a group of inherited hemoglobin disor-
ders characterized by defects in the synthesis of one or
more of the alpha or beta subunits of Hb. (Normally, TABLE 25A-2. CANCER AND RHEUMATIC DISEASE.
alpha-globin proteins are equal to beta-globin proteins.)
Direct tumor invasion of joints
The reduced or absent production of beta chains in
Metastatic carcinomatous arthritis
beta-thalassemia, for example, subunit leads to the pro- Leukemic arthritis
duction of an imbalance between the numbers of alpha Lymphomatous arthritis
and beta chain, unstable Hb molecules, and precipita- Myelomatous arthritis
tion of the unaffected chains during erythropoiesis,
Nonmetastatic paraneoplastic rheumatic syndromes
resulting ultimately in hemolysis and the formation of Articular
Heinz bodies. In beta-thalassemia, the precipitated Hypertrophic osteoarthropathy (Chapter 25F)
alpha-globin chains are particularly toxic, damaging red Carcinomatous polyarthritis
cell membranes and causing hemolysis, marrow ery- Amyloid arthritis
Secondary gout
throid hyperplasia, and often hypersplenism. In com-
Muscular
pensation for the decreased beta subunits, levels of both Dermatomyositis and polymyositis
HbF and HbA2 are often elevated in these patients LambertEaton myasthenic syndrome
(10). Cutaneous
Thalassemia is especially common in persons of Palmar fasciitis and arthritis
Panniculitis and arthritis
Mediterranean background. beta-Thalassemia major
Eosinophilic fasciitis
(also known as Cooleys anemia) is one of the most Vascular
severe forms of congenital hemolytic anemia. These Paraneoplastic vasculitis
patients are typically transfusion-dependent and rarely Erythromelalgia
survive into adulthood. Only beta-thalassemia major is Miscellaneous
Multicentric reticulohistocytosis
associated with musculoskeletal manifestations. These
result from expansion of the erythroid marrow, and Malignancy developing in a preexisting connective tissue disease
include osteoporosis with wide medullary spaces, coarse Lymphoma developing in Sjgrens syndrome
trabeculae, and pathologic fractures. Epiphyseal de-
Malignancy as a complication of therapy for rheumatic disorders
formities and leg shortening may also occur, but oste- Myelodysplastic syndrome after cyclophosphamide therapy
onecrosis is not a feature. Patients with HbS and
metastatic effects of the tumor (paraneoplastic syn-

dromes), such as hypertrophic osteoarthropathy. There
is an increased incidence of lymphoma in patients with 25
Sjgrens syndrome, rheumatoid arthritis (RA), and
systemic lupus erythematosus. Treatment of rheumatic
disorders with immunosuppressive drugs may also result
in malignancy. Conversely, chemotherapeutic drugs
used in the treatment of neoplasms may cause rheu-
matic syndromes.
Direct Tumor Invasion of Joints

Metastatic Carcinomatous Arthritis
Metastatic carcinomatous arthritis, due to direct inva- FIGURE 25A-4
sion of the joint or adjacent bones by metastases, is a
rare form of arthritis (11,12). The arthritis may be the Acute lymphoblastic leukemia, leukemic arthritis: cytocentrifuge
initial manifestation of malignant disease. Broncho- preparation of synovial fluid from left elbow showing a cALLA-
positive lymphoblast by immunocytology (Wrights stain, original
genic carcinoma is the most common primary tumor. magnification 1000).
Other sources include carcinoma of the breast, prostate,
thyroid, kidney, and colon. The arthritis is often mono-
articular and commonly affects the knee, hip, shoulder,
elbow, or ankle. Metastases distal to the elbows and
other sites. Carcinomatous invasion of the synovium
knees are uncommon and involvement of the joints of
can be demonstrated by arthroscopic or percutaneous
the hands and feet is rare.
needle synovial biopsy. Treatment with chemotherapy
Severe bone and joint pain, worse at night and with
and radiotherapy is often palliative.
movements, is common. Joint effusions are commonly
hemorrhagic and often re-accumulate rapidly after aspi-
ration. The fluids are non-inflammatory with low cell Leukemic Arthritis
counts characterized by mononuclear predominance.
Joint manifestations occur in about 14% of patients
Using cytomorphologic techniques, tumor cells may be
with leukemia (13,14). These are more common in acute
identified in synovial effusions (Figure 25A-3) (12).
leukemia, particularly acute lymphoblastic leukemia in
Radiographs commonly show juxta-articular osteolytic
children. Known mechanisms of arthritis in patients
lesions and bone scanning may reveal metastases at
with leukemia include leukemic arthritis caused by
direct invasion of articular tissues and juxta-articular
bones by leukemic cells, joint infection, intra-articular
hemorrhage, and gouty arthritis.
Leukemic arthritis is an asymmetric, painful polyar-
thritis of large joints, such as the knee, shoulder, or
ankle. It may precede other manifestations of leukemia.
Nocturnal bone pains and severe joint pains, often dis-
proportionate to the apparent degree of arthritis, are
characteristic. Hematologic and bone marrow abnor-
malities are inevitably present in leukemic arthritis.
Radiographic findings include metaphyseal rarefaction,
osteolytic lesions, and sometimes periosteitis. The diag-
nosis can be confirmed by demonstration of leukemic
cells in synovial fluid and/or synovium (Figure 25A-4)
(13,14). Immunocytological techniques employing indi-
rect immunofluorescence and a panel of early B-cell and
myeloid antigens (e.g., cALLA or acute lymphoblastic
FIGURE 25A-3 leukemia antigen) have been used to identify leukemic
cells in joint effusions and in the synovium (13,14). Leu-
Metastatic carcinomatous arthritis of right shoulder: synovial
fluid cytology showing malignant cells (carcinoma of lung) with
kemic arthritis usually occurs in patients with wide-
pleomorphic, eccentric, hyperchromatic nuclei and large irregular spread disease and the response to therapy is generally
nucleoli. poor.
476 ADEL G. FAM
Lymphoma and Arthritis amyloid arthropathy. The arthritis typically affects the
shoulder, wrists, and knees. It is often symmetrical and
Musculoskeletal symptoms occur in up to 25% of relatively painless, but may mimic RA. Amyloid infil-
patients with non-Hodgkins lymphoma. Bone pain is tration of the synovium of the shoulders produces the
the most common manifestation. Mechanisms of arthri- characteristic shoulder-pad sign. Synovial effusions
tis in patients with lymphoma include lymphomatous are non-inflammatory with low total leukocyte counts
arthritis, hypertrophic osteoarthropathy (see Chapter (<2000 106/L). Spun synovial fluid sediments often
25F), joint infection, and secondary gout (15). Lympho- contain amyloid bodies. These are synovial villi, laden
matous arthritis, due to invasion of juxta-articular bone with amyloid. Using Congo red stains, amyloid deposits
or synovial tissue by lymphoma, is rare. Both polyarticu- in both the synovium and synovial fluid sediment dem-
lar and monoarticular presentations have been described. onstrate apple-green birefringence under polarized
Lymphoma is suspected in patients in whom severe con- light. Other manifestations of AL amyloid in patients
stitutional symptoms appear out of proportion to the with myeloma include peripheral neuropathy, carpal
severity of arthritis, and in those with periarticular tunnel syndrome, subcutaneous amyloid deposits, mac-
osteolytic lesions. The diagnosis can be confirmed by roglossia, cardiomyopathy, nephropathy, and hepato-
bone or synovial biopsy. A symmetric polyarthritis with splenomegaly. The diagnosis of amyloid arthritis can be
fever has been described in patients with the rare intra- confirmed by bone marrow examination, serum and
vascular lymphoma (intravascular lymphomatosis). urine protein immunoelectrophoresis showing an M-
protein, and by biopsy of the synovium, abdominal sub-
Angioimmunoblastic T-Cell cutaneous fat, or rectum. Management consists of
LymphomaAssociated Arthritis therapy for the underlying myeloma, and symptomatic
treatment of the arthritis with NSAIDs.
Angioimmunoblastic T-cell lymphoma (AITL), previ- Osteosclerotic myeloma is a rare form of myeloma
ously termed angioimmunoblastic lymphadenopathy, characterized by osteosclerotic rather than osteolytic
is a rare type of non-Hodgkins T-cell lymphoma solitary or multiple bone lesions (18). Other features
characterized by fever, weight loss, lymphadenopathy, include an indolent chronic course, polyneuropathy,
hepatosplenomegaly, urticaria or other skin eruption, organomegaly, endocrinopathy, M-protein, and skin
vasculitis, serositis, hemolytic anemia, and polyclonal changes (POEMS syndrome). Skin thickening, abnor-
hypergammaglobulinemia (16). mal pigmentation, and, sometimes, a sclerodermatous
A nonerosive, nondeforming, symmetric, seronega- appearance are common. Weight loss, fever, thrombo-
tive polyarthritis may occur as initial manifestation of cytosis, and arthritis may also occur.
the disease or concurrent with other features. Joints of
the hands are commonly affected. Synovial biopsies
Waldenstroms Macroglobulinemia
may show typical features of AITL. Synovial fluid leu-
kocytosis with decreased number of CD8 lymphocytes Waldenstroms macroglobulinemia is a neoplastic lym-
may occur. The diagnosis is confirmed by lymph node phoproliferative disorder associated with serum mono-
biopsy showing proliferation of small blood vessels and clonal IgM, lymphadenopathy, hepatosplenomegaly,
replacement of normal lymph node architecture by purpuric skin lesions, and symptoms of hyperviscosity
plasma cells, immunoblasts, and eosinophils. Response (headaches, visual changes). Direct tumor invasion of
to chemotherapy is often poor and only 30% of indi- juxta-articular bone and joints is rare, but light chain
viduals survive 2 years (16). amyloidosis and amyloid arthritis may occur (17).
Multiple Myeloma and Arthritis Paraneoplastic Rheumatic

Myeloma is a malignant bone marrow plasma cell tumor,
Syndromes
occurring most commonly in the fifth and sixth decades. Paraneoplastic symptoms, often bearing an only indi-
It is often associated with bone pains (particularly in the rect relationship to tumor mass, are present at diagnosis
back and ribs), pathologic fractures, monoclonal serum in about 10% of patients with cancer. Up to 50% of
protein abnormalities, and BenceJones proteinuria. patients with cancer develop paraneoplastic syndromes
Generalized osteopenia due to myeloma-secreted cyto- at some time during the course of their illness. One third
kines (IL-1 beta, TNF-beta, and IL-8) occurs in about of these are endocrine in nature; the remainder usually
a third of patients. Myelomatous arthritis, caused by comprise hematological, rheumatic, and neuromuscular
invasion of the articular and juxta-articular bones by disorders. Among the paraneoplastic rheumatic syn-
myeloma cells, is rare (17). More commonly, about dromes, hypertrophic osteoarthropathy, carcinoma
15% of patients with myeloma develop monoclonal polyarthritis, myositis, and vasculitis are the most fre-
light chain (AL amyloid) amyloidosis, associated with quent (Table 25A-2). These disorders may coincide or
follow the diagnosis of primary malignancy, but may by myalgias and migratory arthralgias of hands, feet,
precede the onset of cancer by as long as 2 years (11). knees, and ankles, occurring in some patients with
The clinical course of a paraneoplastic musculoskel- carcinoma of the breast, ovary, or non-Hodgkins 25
etal syndrome generally parallels that of the primary lymphoma, 1 to 3 months after treatment with cyclo-
tumor. Thus, radical treatment of the primary neoplasm phosphamide, 5-fluorouracil, or methotrexate.
usually, but not invariably, results in regression of the Gout is rare in patients with solid tumors until the
paraneoplastic syndrome. Conversely, recurrence of the tumor metastasizes widely. Clinically, secondary gout
tumor can lead to re-appearance of the musculoskeletal differs from idiopathic gout in that women are more
symptoms. Paraneoplastic manifestations may be mis- commonly affected and a family history of gout is less
taken for metastatic disease, leading to inappropriate frequent. In hematologic malignancies, gout may occur
therapies. On the other hand, symptoms of true metas- secondary to massive tumor lysis following the institu-
tases may be attributed to a paraneoplastic syndrome, tion of chemotherapy. In many protocols, allopurinol is
thereby delaying therapy. used routinely to prevent this complication of cancer
therapy.
Erythromelalgia is an intense pain and erythema
Carcinomatous Polyarthritis
afflicting the palms and soles (palms > soles), typically
Carcinomatous polyarthritis is an inflammatory, sero- in patients with either polycythemia vera or essential
negative arthritis that may herald the presence of malig- thrombocythemia. Erythromelalgia is exquisitely sensi-
nancy (11). Although its clinical presentation is variable, tive to aspirin, usually in doses not exceeding 325 mg/
certain features suggest the possibility of an underlying day. Miscellaneous paraneoplastic conditions include
malignancy and serve to distinguish this form of polydermatomyositis (see Chapter 18A), paraneoplastic
arthritis from RA. These include a late age of onset; an vasculitis, and panniculitis (11).
explosive onset of asymmetric oligoarthritis or polyar-
thritis; predominant involvement of the joints of the
lower extremities; frequent sparing of the wrists and
joints of the hands; and the absence of erosions, defor-
REFERENCES
mities, rheumatoid factor, nodules, or family history of
1. Peake I. The molecular basis of haemophilia A. Haemo-
RA. On rare occasions, the arthritis is symmetrical and
philia 1998;4:346349.
may mimic RA. 2. Lillicup D. The molecular basis of haemophilia B. Hae-
The temporal relationship between the onset of car- mophilia 1998;4:350357.
cinomatous polyarthritis and diagnosis of the tumor is 3. Hilgartner MW. Current treatment of hemophilic arthrop-
usually a close onetypically less than 1 year. Exclu- athy. Curr Opin Pediatr 2002;14:4649.
sion of hypertrophic osteoarthropathy or metastatic 4. Ballas SK. Sickle cell disease: clinical management. Bail-
invasion of the synovium or periarticular bone is critical lieres Clin Hematol 1998;11:185214.
for establishing the appropriate therapeutic approach. 5. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in
The arthritis typically occurs in women with carcinoma sickle cell disease. Rates and risk factors. N Engl J Med
of the breast, and in men with carcinoma of the lung. 1991;325:1116.
Synovial effusions are mildly inflammatory and the 6. Almeida A, Roberts I. Bone involvement in sickle cell
disease. Br J Haematol 2005;129:482490.
erythrocyte sedimentation rate (ESR) is often elevated.
7. Vichinsky EP, Neumayr LD, Haberkern C, et al. The
There are no distinctive pathologic or radiographic perioperative complication rate of orthopedic surgery in
abnormalities (11). sickle cell disease: report of the national sickle cell surgery
The pathogenesis of carcinoma polyarthritis is poorly study group. Am J Hematol 1999;62:129138.
understood. Broad possible mechanisms include: (1) an 8. Jacobson SJ, Kopecky EA, Joshi P, Babul N. Randomized
immune complexmediated synovitis; (2) cross-reactiv- trial of oral morphine for painful episodes of sickle-cell
ity of antigenic determinants on the synovium and neo- disease in children. Lancet 1997;350:13581361.
plastic tissue; and (3) an abnormality of cell-mediated 9. Moore RD, Charache S, Terrin ML, et al. Cost-effective-
immunity, leading to the expression of both neoplasia ness of hydroxyurea in sickle cell anemia. Am J Hematol
and connective tissue disease. The most convincing evi- 2000;64:2631.
dence that carcinoma polyarthritis is a true paraneo- 10. Perrine SP, Boosalis V. Thalassemia. In: Rakel RE, Bope
ET, eds. Conns current therapy. Philadelphia: Saunders
plastic disorder is the frequent resolution of the arthritis
(Elsevier); 2006:488492.
following resection of the underlying neoplasm, and 11. Fam AG. Paraneoplastic rheumatic syndromes. Baillieres
its reappearance with recurrence of the cancer. The Clin Rheumatol 2000;14:515533.
arthritis may respond to NSAIDs and intra-articular 12. Fam AG, Kolin A, Lewis AJ. Metastatic carcinomatous
glucocorticoids. arthritis and carcinoma of the lung. A report of two cases
Postchemotherapy rheumatism is a rare, self- diagnosed by synovial fluid cytology. J Rheumatol 1980;
limited syndrome of unknown etiology, characterized 7:98104.
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13. Evans TL, Nercessian BM, Sanders KM. Leukemic Case report and literature review. J Clin Rheumatol 2005;
arthritis. Semin Arthritis Rheum 1994;24:4856. 11:326328.
14. Fam AG, Voorneveld C, Robinson JB, Sheridan BL. 17. Roux S, Fermand J-P, Brechignac S, et al. Tumoral joint
Synovial fluid immunocytology in the diagnosis of leuke- involvement in multiple myeloma and Waldenstroms
mic synovitis. J Rheumatol 1991;18:293296. macroglobulinemia report of 4 cases. J Rheumatol
15. Dorfman HD, Siegeel HL, Perry MC, Oxenhandler R. 1996;23:11751178.
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rheumatoid arthritis. Arthritis Rheum 1987;30:155161. Study of a patient with proteinuria, microangiopathic
16. Tsochatzis A, Vassilopoulos D, Deutsch M, et al. Angi- glomerulopathy and renal enlargement. Arthritis Rheum
ommunoblastic T-cell lymphoma-associated arthritis. 1986;29:233241.
CHAPTER 25

B. Rheumatic Disease and
Endocrinopathies
PETER A. MERKEL, MD, MPH
Musculoskeletal signs and symptoms frequently occur elevation; thyroid acropachy; and drug-induced
in endocrinopathies. vasculitis associated with antineutrophil cytoplasmic
A number of syndromes of limited joint mobility antibodies (ANCA), usually caused by propylthiouracil.
occur in people with diabetes mellitus, including Hypothyroidism may be associated with polyarthral-
diabetic hand syndrome (diabetic cheiroarthropathy), gias, carpal tunnel syndrome, and proximal myopa-
adhesive capsulitis (frozen shoulder, periarthritis), thy, with serum CK elevation.
Dupuytrens contractures, trigger finger (flexor Hyperparathyroidism may cause osteoporosis,
tenosynovitis), diffuse idiopathic skeletal hyperostosis osteitis fibrosa cystica, chondrocalcinosis, and
(DISH syndrome), neuropathic arthritis (Charcot joints, pseudogout.
diabetic osteoarthropathy), and diabetic muscle Other endocrinopathies that may lead to
infarction. musculoskeletal complaints are hypoparathyroidism,
Hyperthyroidism may be associated with proximal acromegaly, and glucocorticoid-induced Cushings
myopathy, usually without serum creatine kinase (CK) syndrome.
Most endocrine disorders are associated with systemic established autoimmune diseases. Such findings have
manifestations caused by changes in the quantity or led to the investigation of pathophysiologic links
activity of various hormones. Musculoskeletal signs and between autoimmune and endocrine diseases.
symptoms are among the more frequent clinical sequelae
of endocrinopathies. In some cases, the first clinical
signs or symptoms of endocrine disease are rheumatic. RHEUMATIC SEQUELAE OF
Some rheumatic symptoms, such as myalgias, can be
seen in a variety of different endocrinopathies; other
SPECIFIC ENDOCRINE DISEASES
rheumatic manifestations, such as Raynauds phenom-
enon, are indicative of only one or two certain diseases.
Diabetes Mellitus
Various endocrinopathies also may be associated with Diabetes mellitus is associated with a wide variety of
specific rheumatic diseases. musculoskeletal problems, some of which are unique to
Understanding the associations between endocrine the disease (1,2). The spectrum of rheumatologic syn-
and rheumatic diseases is important for several reasons. dromes seen in people with diabetes is outlined in Table
First, appreciating these clinical connections will help 25B-1. The nomenclature of these conditions can be
clinicians avoid misdiagnoses of primary rheumatic confusing, with some having more than one name in
disease and can lead to prompt treatment of a primary the medical literature. Some of these manifestations are
endocrine disorder. Second, many of these rheumatic secondary to the microvascular disease, neuropathic
syndromes respond, in full or in part, to treatment of complications, or proliferation of connective tissue seen
the underlying endocrinopathy. Third, some of the asso- in diabetes. These rheumatic syndromes affect people
ciations are sufficiently common or striking to justify with either type I or type II diabetes, especially those
screening for specific endocrine diseases when patients with evidence of organ damage.
manifest certain rheumatic symptoms or signs. Finally, A number of syndromes of limited joint mobility
endocrine disorders may affect the disease activity of occur in people with diabetes (3). Diabetic hand syn-
479
480 PETER A. MERKEL
TABLE 25B-1. RHEUMATOLOGIC MANIFESTATIONS condition that is the consequence of peripheral neu-
OF DIABETES MELLITUS. ropathy, most commonly affects the foot (5). Despite
the resulting joint obliteration, ankylosis, and deformi-
Syndromes of limited joint mobility
Diabetic hand syndrome (diabetic cheiroarthropathy) ties, patients usually have little or no pain, and the
Adhesive capsulitis (frozen shoulder, periarthritis) diagnosis is based on radiographic appearance. Plain
Trigger finger (flexor tenosynovitis) radiography, bone scintigraphy, and magnetic reso-
Dupuytrens contractures nance imaging are useful imaging modalities for diag-
Osteoporosis nosing diabetic osteoarthropathy and documenting the
extent of disease. Similarly, the peripheral neuropathy
Diffuse idiopathic skeletal hyperostosis (DISH) of diabetes increases the incidence of foot infections
Neuropathies and foreign body reactions, in which patients may be
Neuropathic arthritis (Charcot joints, diabetic osteoarthripathy) unaware of injury due to anesthetic feet; both of these
Carpal tunnel syndrome conditions may lead to septic arthritis.
Diabetic amyotrophy The incidence of carpal tunnel syndrome, a median
Reflex sympathetic dystrophy (multiple synonyms)
Various other neuropathies
nerve neuropathy, is increased in people with diabetes
and may occur bilaterally. Similarly, reflex sympathetic
Diabetic muscle infarction dystrophy (causalgia) is more common among people
with diabetes. Diabetic amyotrophy is characterized by
painful, often bilateral, muscle weakness resulting from
a mononeuropathy with non-inflammatory atrophy of
drome (diabetic cheiroarthropathy) is a condition stem- type II muscle fibers (6). Spontaneous improvement
ming from alterations in the soft tissue of the hands and may occur. Other neuropathies that can occur among
fingers, resulting in stiff, waxy skin and joint contrac- people with diabetes may be central or peripheral, and
tures. This condition can be confused with arthritis and include such conditions as mononeuritis multiplex
the sclerodactyly seen in systemic sclerosis. Cheiro- and radiculopathies that mimic other musculoskeletal
arthropathy is demonstrated when patients are asked to conditions.
oppose the palmar surfaces of their hands and fingers Diabetic muscle infarction is a rare but increasingly
(the prayer sign), and they are unable to fully touch these recognized syndrome of acute infarction of multiple
surfaces. Adhesive capsulitis (frozen shoulder, periar- muscle areas in people with diabetes and organ damage
thritis) is a similar condition that leads to shoulder joint (7). This condition usually occurs with severe pain in
contractures, which often are severe. This condition fre- one extremity. Diabetic muscle infarction can be con-
quently is bilateral and sometimes is accompanied by fused with pyomyositis or venous thrombosis. Magnetic
calcific deposits in the surrounding soft tissues (4). Physi- resonance imaging (MRI) can be diagnostic, although
cal therapy appears to be helpful, and spontaneous reso- biopsy may be needed in some cases. Although self-
lution may occur over months to years. Dupuytrens limited, this condition can recur. The etiology of dia-
contractures and trigger finger (flexor tenosynovitis) are betic muscle infarction is unclear but may be related to
frequent, annoying, and potentially disabling conditions microvasculopathy and microthrombosis.
that are more common among people with diabetes. Improved glycemic control may not reverse the con-
These finger problems may respond to glucocorticoid ditions outlined in Table 25B-l, but may help prevent
injection or surgical correction. future episodes. When these syndromes are present
Two other common musculoskeletal diseases with without an obvious explanation, it is appropriate to
an increased prevalence and generally younger age of consider screening patients for undiagnosed diabetes
presentation in people with diabetes are osteoporosis mellitus by testing fasting glucose and glycosylated
and diffuse idiopathic skeletal hyperostosis (DISH syn- hemoglobin levels.
drome). Insulin-like growth factors are thought to play
a pathogenic role in these diseases. Although the asso-
ciation between diabetes and osteoporosis has been
Thyroid Disease
questioned, the link between hyperostosis and diabetes Thyroid disease frequently is accompanied by various
is established more firmly. DISH is accompanied by musculoskeletal problems (Table 25B-2) (8,9). Hyper-
ossification and calcification of spinal ligaments, but does thyroidism, hypothyroidism, and thyroxine replacement
not necessarily cause significant clinical problems. therapy, in particular, are associated with rheumatic
Patients with diabetes mellitus may encounter several disease. Some studies report that thyroid abnormalities
types of neuropathies that result in musculoskeletal are more common among people with various auto-
symptoms or that may mimic rheumatic diseases. Neu- immune syndromes, including rheumatoid arthritis,
ropathic arthritis (Charcot joints, diabetic osteoarthrop- systemic lupus erythematosus, and systemic sclerosis.
athy; see Chapter 25D), a destructive bone and joint However, these associations have been questioned, and
TABLE 25B-2. RHEUMATOLOGIC MANIFESTATIONS by the literature. However, the evidence is compelling
OF THYROID DISEASE. that propylthiouracil and related thionamides used in
Hyperthyroidism
the treatment of hyperthyroidism can cause vasculitis 25
Osteoporosis syndromes associated with antineutrophil cytoplasmic
Myopathy antibodies (11).
Periarthritis
Acropachy
Hypothyroidism
Hypothyroidism
Arthralgias Hypothyroidism in children or fetuses results in multiple
Symmetrical polyarthritis skeletal abnormalities, as well as severe developmental
Joint laxity problems. In adults, hypothyroidism can cause a series
Carpal tunnel syndrome
of musculoskeletal problems. Given the high prevalence
Chondrocalcinosis and pseudogout
Hyeruricemia and gout of hypothyroidism in adults, this diagnosis must be con-
Myopathy sidered in all patients presenting with the syndromes
described in this section. The discovery of previously
undiagnosed thyroid deficiency among people present-
ing with rheumatic symptoms is common.
the perceived increased prevalence of thyroid disorders Joint symptoms are extremely common among
among patients with these autoimmune diseases may be patients with hypothyroidism, and range from vague
confounded by the fact that thyroid diseases are common arthralgias to a symmetric polyarthritis that may be con-
among women, and women account for 75% to 90% of fused with rheumatoid arthritis. The joint effusions seen
people with these autoimmune diseases. Musculoskele- in hypothyroidism are non-inflammatory. Additionally,
tal problems may be the first, and sometimes only, clini- an increased incidence of joint laxity has been noted
cal sign of thyroid disease. among people with myxedema. Carpal tunnel syndrome
Because thyroid diseases are easily diagnosed and is associated with hypothyroidism and may be bilateral.
highly responsive to treatment, screening for thyroid When a euthyroid state is attained, these rheumatologic
dysfunction among people with various rheumatic symptoms often remit fully.
symptoms is essential. Achieving a euthyroid status There is an increased incidence of hypothyroidism
improves many, but not all, of these conditions. among patients with crystal-induced arthritis. In par-
ticular, asymptomatic chondrocalcinosis and clinical
pseudogout are associated with hypothyroidism. Simi-
Hyperthyroidism larly, there are reports linking hypothyroidism to asymp-
Hyperthyroidism is an important, reversible, and easily tomatic hyperuricemia and gout.
detected cause of osteoporosis. Administration of levo- Myopathy is a common feature of hypothyroidism
thyroxine as replacement therapy or for suppression of and can include myalgias and weakness (especially
thyroid nodules may lead to osteoporosis (10). proximally). The weakness usually is mild to moderate
Thyrotoxicosis often causes a proximal myopathy in severity and is accompanied by abnormal findings on
that may be severe. Most patients with this myopathy electromyography. In contrast to the myopathy seen in
do not have elevated creatinine kinase levels but do hyperthyroidism, serum creatinine kinase levels are
have electromyographic abnormalities. This myopathy elevated in most patients with muscle disease associated
almost always is reversible upon attainment of a euthy- with hypothyroidism. Muscle bulk is not changed appre-
roid state. All patients presenting with weakness must ciably, and biopsy specimens may demonstrate evidence
be screened for thyrotoxicosis. of degeneration and regeneration of muscle fibers
A shoulder periarthritis (often bilateral) may be seen without inflammation. The myopathy reverses with
in people with hyperthyroidism. treatment of the underlying thyroid disorder.
Thyroid acropachy, an unusual late manifestation of
Graves disease, involves painful soft tissue swelling of
hands, fingers, and toes, with clubbing and periostitis.
Parathyroid Disease
Although similar to hypertrophic osteoarthropathy, Table 25B-3 outlines the rheumatologic manifestations
most patients with acropachy already have established of parathyroid disease.
exophthalmos, pretibial myxedema, and measurable
levels of long-acting thyroid stimulator in the serum.
Hyperparathyroidism
Acropachy usually presents after treatment of hyperthy-
roidism and is thought to have an immunologic basis. A wide variety of bone and joint abnormalities have
Although many drugs have been associated with vas- been associated with hyperparathyroidism. Some of
culitis, some of these associations are poorly supported these conditions have become less common due to the
482 PETER A. MERKEL
TABLE 25B-3. RHEUMATOLOGIC MANIFESTATIONS parathyroidism are associated with unusual bony abnor-
OF PARATHYROID DISEASE. malities and ectopic calcification of subcutaneous tissue
and paraspinal ligaments.
Hyperparathyroidism
Osteoporosis Myopathies also have been reported.
Osteitis fibrosa cystica
Erosive arthritis
Joint laxity Acromegaly
Chondrocalcinosis and pseudogout
Acromegaly, a rare disorder of pituitary hypersecretion
Hyperuricemia and gout
Myopathy of growth hormone, usually is caused by an adenoma
and is associated with a large variety of musculoskeletal
Hypoparathyroidism abnormalities. The syndrome illustrates the protean
Ectopic calcification
effects of growth hormone on human physiology (13).
Myopathy
In children whose epiphyses have not yet closed, growth
hormone excess causes gigantism and presents a set of
problems different from those seen in adults with acro-
earlier detection and treatment of hyperparathyroid- megaly. Growth hormone exerts many of its actions
ism. Nevertheless, rheumatologic manifestations of via the production of insulin-like growth factors (IGF
hyperparathyroidism commonly are the presenting fea- or somatomedins). In particular, IGF-I and growth
tures of disease. This section outlines the rheumatologic hormone itself promote proliferation of soft tissues and
problems encountered in primary hyperparathyroidism. bone. Tissues affected by acromegaly include synovium,
A series of similar disorders can result from secondary cartilage, bursae, and muscle.
hyperparathyroidism associated with renal failure or Table 25B-4 outlines the rheumatic manifestations of
malabsorption. acromegaly and categorizes them as articular, bone,
Osteoporosis is a direct consequence of excess para- neuromuscular, or miscellaneous problems.
thormone and can cause severe, irreversible bone loss. The musculoskeletal manifestations of acromegaly
Bone loss associated with hyperparathyroidism is usually are present long before the underlying endo-
greater in cortical than in cancellous regions. crinopathy is diagnosed. Treatment, through a com-
Osteitis fibrosa cystica is a syndrome of multiple bination of surgical resection of the adenoma and
bony abnormalities associated with severe hyperpara- administration of octreotide, can prevent worsening of
thyroidism. Due to earlier detection, this disorder is some aspects of the disease and a few of its complica-
rarely seen in areas with comprehensive medical care. tions. In view of the potential for this disease to cause
Osteitis fibrosis cystica involves unique radiographic significant deformities, morbidity, and mortality, early
findings, including bone cysts and subperiosteal ero- detection is a key factor to improving the lives of people
sions. Diffuse bone pain can be present, and an erosive, with acromegaly.
noneffusive arthritis has been reported. Increased joint
laxity, tendon laxity and ruptures, and ectopic calcifica-
tions also are associated with hyperparathyroidism. TABLE 25B-4. RHEUMATOLOGIC MANIFESTATIONS
Chondrocalcinosis and pseudogout commonly occur OF ACROMEGALY.
in people with hyperparathyroidism and may be pre- Articular
senting features of disease (12). A non-inflammatory Arthralgias
polyarthritis also has been reported. An increased prev- Bursal enlargement
Osteoarthritis
alence of hyperuricemia and gout is seen among people
Joint laxity
with hyperparathyroidism secondary to nephrocalcino- Cartilage hypertrophy and degeneration
sis. These crystal-induced diseases persist even after Pseudogout (possibly)
correction of excess parathormone production. Tendinous and capsular calcification
Although people with hyperparathyroidism com-
Bone
monly report vague myalgias and malaise, a reversible Back pain
proximal myopathy is unusual and is associated only Osteoporosis
with severe disease. Ectopic calcifications, including Bone hypertrophy and resorption
intravascular lesions, occasionally may result in various
Neuromuscular
neuropathies. Myopathy and muscle hypertrophy
Compression neuropathy, especially carpal tunnel syndrome
Ischemic neuropathy
Hypoparathyroidism
Miscellaneous
Hypoparathyroidism and the related disorders of Raynauds phenomenon
pseudohypoparathyroidism and pseudopseudohypo-
Articular problems that occur in acromegaly are due Glucocorticoid deficiency (Addisons disease) can
to a combination of cartilage hypertrophy, synovial pro- cause myalgias, arthralgias, and flexion contractures.
liferation, and osteophytosis. Vague arthralgias, joint These problems are responsive to glucocorticoid 25
space widening, joint laxity, and non-inflammatory effu- replacement therapy. Reported rheumatologic manifes-
sions may be followed by degenerative joint disease and tations of the carcinoid syndrome include arthralgias,
clinical osteoarthritis. Whether chondrocalcinosis and muscle wasting, bony erosions, and retroperitoneal
pseudogout are associated with acromegaly remains a fibrosis (15).
controversial issue.
Back pain is quite common and may be due to hyper-
trophy of the vertebral bodies and discs. Patients often REFERENCES
exhibit spinal hypermobility. Osteoporosis may develop
secondary to the hypogonadism that often occurs. 1. Pastan RS, Cohen AS. The rheumatologic manifestations
Because increased bone thickness can occur, bone of diabetes mellitus. Med Clin North Am 1978;62:
density measurements can be difficult to interpret. 829839.
Many of the articular, soft tissue, and bone abnor- 2. Crisp AJ, Heathcote JG. Connective tissue abnormalities
malities in acromegaly result in characteristic radio- in diabetes mellitus. J R Coll Phys Lond 1984;18:132
141.
graphic features, including joint space widening, heel
3. Schulte L, Roberts MS, Zimmerman C, Ketler J, Simon
pad hypertrophy, and terminal phalanx enlargement. LS. A quantitative assessment of limited joint mobility
Once bone and joint problems occur, treatment in patients with diabetes. Goniometric analysis of upper
of acromegaly does not appear to reverse musculoskel- extremity passive range of motion. Arthritis Rheum 1993;
etal manifestations and may not prevent damage 36:14291443.
progression. 4. Mavrikakis ME, Drimis S, Kontoyannis DA, Rasidakis A,
The neuromuscular problems seen in acromegaly Moulopoulou ES, Kontoyannis S. Calcific shoulder peri-
also are secondary to tissue hypertrophy, including arthritis (tendinitis) in adult onset diabetes mellitus: a
compression and ischemic neuropathies. Carpal tunnel controlled study. Ann Rheum Dis 1989;48:211214.
syndrome is especially common and often is bilateral. 5. Sinha S, Munichoodappa CS, Kozak GP. Neuro-arthropa-
This complication of acromegaly usually remits with thy (Charcot joints) in diabetes mellitus (clinical study of
101 cases). Medicine (Baltimore) 1972;51:191210.
proper treatment of the endocrinopathy. Although
6. Krendel DA. Costigan DA, Hopkins LC. Successful treat-
muscle hypertrophy can occur, some patients develop ment of neuropathies in patients with diabetes mellitus
proximal muscle weakness and fatigue. The myopathy [see comments]. Arch Neurol 1995;52:10531061.
may not remit with treatment of the growth hormone 7. Grigoriadis E, Fam AG, Starok M, Ang LC. Skeletal
excess. muscle infarction in diabetes mellitus. J Rheumatol 2000;
Octreotide, a somatostatin analog used to treat acro- 27:10631068.
megaly, occasionally causes neuromuscular weakness. 8. Bland JH, Frymoyer JW. Rheumatic syndromes of myx-
Octreotide also may cause hypothyroidism, leading to edema. N Engl J Med 1970;282:11711174.
the rheumatic problems discussed previously. 9. Bland JH, Frymoyer JW, Newberg AH, Revers R, Norman
R. Rheumatic syndromes in endocrine disease. Semin
Arthritis Rheum 1979;9:2365.
Miscellaneous Endocrine Disorders 10. Wartofsky L. Levothyroxine therapy and osteoporosis.
An end to the controversy? Arch Intern Med 1995;155:
Glucocorticoid excess (Cushings syndrome) from 11301131.
primary adrenal hyperproduction, pituitary stimulation 11. Merkel P. Drugs associated with vasculitis. Curr Opin
(Cushings disease), or exogenous administration can Rheumatol 1998;10:4550.
cause a variety of musculoskeletal problems. Osteopo- 12. Alexander GM, Dieppe PA, Doherty M, Scott DG. Pyro-
rosis is a particular problem with these disorders and phosphate arthropathy: a study of metabolic associations
can lead to pathologic fractures. Osteonecrosis can and laboratory data. Ann Rheum Dis 1982;41:377381.
occur in Cushings disease but is associated more com- 13. Bluestone R, Bywaters EG, Hartog M, Holt PJ, Hyde S.
monly with exogenous corticosteroid administration Acromegalic arthropathy. Ann Rheum Dis 1971;30:243
258.
(14). The so-called steroid myopathy can occur with any
14. Phillips KA, Nance EP Jr, Rodriguez RM, Kaye JF.
form of glucocorticoid excess. This proximal muscle Avascular necrosis of bone: a manifestation of Cushings
weakness is non-inflammatory, not associated with ele- disease. South Med J 1986;79:825829.
vated serum creatinine kinase levels, and resolves with 15. Plonk JW, Feldman JM. Carcinoid arthropathy. Arch
correction of the hormone imbalance. Intern Med 1974;134:651654.
CHAPTER 25

C. Hyperlipoproteinemia
and Arthritis
ROBERT F. SPIERA, MD
Several recognized heritable disorders of lipid Osseous xanthomas, observed occasionally in

metabolism result in a variety of clinical phenotypes, type III hyperlipoproteinemia, can predispose
each of which may be associated with distinct patients to pathologic fractures, particularly in
musculoskeletal manifestations. long bones.
Tendinous xanthomas are associated most often with An episodic, acute, migratory inflammatory arthritis
the type II and type III hyperlipoproteinemias, known occurs in up to 50% of homozygotes with type II
respectively as familial hypercholesterolemia and hyperlipoproteinemia. The joints are erythematous,
familial dysbetalipoproteinemia. warm, and swollen, and acute-phase reactants are
Tendinous xanthomas characteristically occur on the elevated.
dorsum of the hands over the digit extensor tendons, Gout can be associated with hypertriglyceridemia in
or on the heels at the Achilles tendon insertions. types I, IV, and V hyperlipoproteinemia.
Musculoskeletal problems can occur in association with XANTHOMAS

hyperlipoproteinemia, a condition in which underlying
genetic defects lead to overproduction or impaired Xanthomas can occur in any of the inherited hyper-
removal of lipoproteins. The abnormalities, related lipoproteinemias. Tendinous xanthomas are associated
either to the lipoprotein or its receptor, results in ele- most often with the type II and type III hyperlipopro-
vated levels of lipoprotein that contribute to the devel- teinemias, known respectively as familial hypercho-
opment of premature atherosclerosis. Recognition of lesterolemia and familial dysbetalipoproteinemia (1).
these syndromes facilitates both the proper diagnosis Tendinous xanthomas characteristically occur on the
and management of the musculoskeletal problem, and dorsum of the hands over the digit extensor tendons, or
the appropriate treatment of a condition that poses sig- on the heels at the Achilles tendon insertions (2). They
nificant long-term cardiovascular threats. have been described at other extensor surfaces as well,
Several recognized heritable disorders of lipid metab- including the triceps, olecranon, or quadriceps inser-
olism result in a variety of clinical phenotypes (Table tions. Achilles tendon xanthomas are more strongly
25C-l) (1), each of which may be associated with distinct associated with type III hyperlipoproteinemia (1).
musculoskeletal manifestations. Hyperlipidemia also Although patients with polygenic hypercholesterolemia
can occur secondary to other clinical contexts (e.g., the can have similar lipid profiles, xanthomata are not seen
nephrotic syndrome, primary biliary cirrhosis, cigarette in these patients.
smoking). Arthritis and hyperlipidemia also may be Tendinous xanthomas often are noticeable but not
linked because of a common risk factor (e.g., obesity necessarily symptomatic. Tendinitis or tenosynovitis can
as a risk factor for both osteoarthritis and hyperlipid- occur, however, particularly in the Achilles tendon,
emia). In this section, we will focus on musculoskeletal where the mass effect of the xanthoma contributes to
syndromes believed to be related directly to local irritation by overlying footwear. Radiographic find-
hyperlipidemia. ings can include calcifications within the xanthomas, or
484
TABLE 25C-1. CLASSIFICATION OF HYPERLIPIDEMIA.

LIPOPROTEIN
PHENOTYPE ABNORMALITY LIPID ABNORMALITY MUSCULOSKELETAL MANIFESTATION
25
Type I Chylomicrons increased Markedly increased triglycerides Eruptive xanthomas
Type IIa LDL increased Increased cholesterol Tendinous, tuberous xanthomas; migratory,
episodic polyarthritis; Achilles tendonitis
Type IIb LDL and VLDL increased Increased cholesterol and triglycerides Tendinous, tuberous xanthomas, migratory,
episodic polyarthritis; Achilles tendonitis
Type III Chylomicrons and VLDL Increased cholesterol; increased to Tendinous, tuberous, and plane xanthomas
remnants increased markedly increased triglycerides
Type IV VLDL increased Increased triglycerides Eruptive tendinous and tuberous xanthomas;
arthralgias
Type V Chylomicrons and VLDL Increased cholesterol, markedly Eruptive xanthomas

increased increased triglycerides
SOURCE: Modified from Fredrickson DS, Levy RI, Lees RS. N Engl J Med 1967;276:3442, ff., by permission of New England Journal of Medicine.
ABBREVIATIONS: LDL, low-density lipoprotein, VLDL, very low-density lipoprotein.
even periarticular cortical erosions, presumably second- as the second decade. Another disorder associated with
ary to pressure effects of the enlarged tendons (3). tendinous xanthomas is beta-sitosterolemia, an autoso-
Tendinitis preceding xanthoma formation or even spon- mal recessive disorder in which there is hyperabsorption
taneous tendon ruptures are rare, but have been of cholesterol and plant sterols from the intestine (9).
described in type IIa hyperlipoproteinemia (4,5). The These disorders should be considered when a patient
tendinous xanthomas reside within the tendon fibers and presents with tendinous xanthomas, particularly at a
move in conjunction with the tendon. Pathologic exami- young age, in the absence of marked elevation of serum
nation of such xanthomas reveals infiltrates of foam cells cholesterol. Xanthomata also can be seen in the second-
that seem to be macrophages congested with remnants ary hypercholesterolemia associated with cholestatic
of ingested (endocytosed) circulating lipoproteins. liver disease, such as primary biliary cirrhosis.
Osseous xanthomas, observed occasionally in type
III hyperlipoproteinemia, can predispose patients to
pathologic fractures, particularly in long bones. Other ARTICULAR DISEASE
locations include the small bones of the hands, skull,
spine, and pelvis. Such xanthomas have the radiological There is some controversy about the association of
appearance of well-defined, round, or oval lucencies (6). articular disease with familial hyperlipoproteinemias.
In a patient with type V hyperlipidemia, pathologic Some arthropathies purported to be linked with hyper-
evaluation of a cystic femoral lesion revealed foamy lipidemia based on descriptive case series (5,10,11) have
histiocytes with granulomatous reaction around choles- not been borne out in all controlled studies (12,13),
terol clefts (7). although some associations do appear to have been con-
Tuberous xanthomas are subcutaneous masses gen- firmed (14,15). Certain musculoskeletal presentations,
erally found over extensor surfaces, including the however, are well-recognized. An episodic, acute,
elbows, knees, hands, or buttocks. They can be observed migratory inflammatory arthritis occurs in up to 50% of
in types II, III, and IV hyperlipoproteinemias. Xantho- homozygotes with type II hyperlipoproteinemia (16,17).
mas on the palmar surfaces (xanthoma striata palmaris) This condition primarily affects large peripheral joints,
occur in type III hyperlipoproteinemia (1). such as knees and ankles, but the small joints of the
Although xanthomas generally are associated with hands and feet can be involved. The joints are ery-
heritable disorders of lipid metabolism, other, rarer thematous, warm, and swollen, and acute-phase reac-
causes are recognized. Cerebrotendinous xanthomato- tants, such as sedimentation rate and plasma fibrinogen,
sis is a rare autosomal recessive disorder in which accu- are elevated. Distinction of this entity from acute rheu-
mulation of cholestanol or dihydrocholesterol in neural matic fever can be difficult, particularly because some
tissue or tendons results in clinical manifestations of of those patients may have valvular disease as a down-
disease, including ataxia, paresis, dementia, and tendon stream effect of atherosclerosis. The presence of tendi-
xanthomas (8). These manifestations can appear as early nous xanthomas, a markedly elevated cholesterol, and
486 ROBERT F. SPIERA
the absence of antecedent Streptococcal infection helps (NSAIDs) can be helpful, but recent concerns regarding
distinguish the entities. Generally, episodes are self- the potential cardiovascular consequences of long-term
limited and resolve within 2 weeks. This pattern of NSAID use, particular with selective cyclooxygenase 2
arthritis is seen much less commonly (approximately inhibitors, must be considered in this high-risk group of
4%) in heterozygotes. patients (21). Treating the underlying dyslipidemia can
Self-limited episodes of acute mono- or oligoarthri- lead to regression of tendinous xanthomas. Surgical
tis, often of the knee or ankle, can be seen in familiar excision also can be beneficial, particularly in the Achil-
hypercholesterolemia. In type IV hyperlipoprotein- les tendon, where mechanical irritation by footwear
emia, a more chronic arthritis can occur. Patients com- can cause pain and debility. Recurrences can occur.
plain of morning stiffness and a bland, often asymmetric, The arthropathy associated with type IV hyperlipid-
polyarticular arthritis. Both large and small joints may emia seems to wane with improved control of serum
be involved, including proximal interphalangeal joints, lipid levels.
metacarpophalangeal joints, wrists, knees, shoulders,
and tarsophalangeal and metatarsophalangeal joints
(18). Synovial fluid analysis reveals minimally inflam-
matory or non-inflammatory fluid, without crystals.
REFERENCES
Synovial biopsy has been described as revealing moder-
1. Fredrickson DS, Levy RI, Lees RS. Fat transport in lipo-
ate synovial hyperplasia, with a modest infiltrate of proteins: an integrated approach to mechanisms and dis-
mononuclear cells and foam cells. There may be a rela- orders. N Engl J Med 1967;276:3442, 94103, 148156,
tionship between serum triglyceride level and joint 215225, 273281.
complaints. 2. Fahey JJ, Stark HH, Donovan WE, Drennan DB. Xan-
Even xanthomata, the hallmark physical finding in thoma of the Achilles tendon. J Bone Joint Surg Am
hyperlipoproteinemias, can be mistaken for other enti- 1973;55A:11971211.
ties, such as gouty tophi in a person with oligoarthritis, 3. Yaghami I. Intra- and extraosseous xanthomata associ-
or rheumatoid nodules in a person with polyarthritis. ated with hyperlipidemia. Radiology 1978;128:4954.
Clinicians caring for people with musculoskeletal com- 4. Shapiro R, Fallat RW, Tsang RC, Glueck CJ. Achilles
plaints must therefore be aware of these hyperlipo- tendinitis and tenosynovitis. Am J Dis Child 1974;128:
486490.
proteinemia-related musculoskeletal syndromes and
5. Glueck CJ, Levy R, Fredrickson DS. Acute tendinitis and
distinguish them from more common arthropathies. arthritis. A presenting symptom of familial type II hyper-
lipoproteinemia. JAMA 1968;206:28952897.
6. Bardin T, Kuntz D. Primary hyperlipidemias and xantho-
CRYSTAL DISEASE matosis. In: Klippel JH, Dieppe P (eds). Rheumatology.
London: Times Mirror International Publishers Limited;
Gout, an eminently treatable form of arthritis related 1994;27.127.4.
to hyperuricemia, can be associated with hypertriglyc- 7. Siegelman SS, Schlossberg I, Becker NH, Sachs BA.
eridemia in types I, IV, and V hyperlipoproteinemia. Hyperlipoproteinemia with skeletal lesions. Clin Orthop
When the clinical scenario is compatible with a micro- 1972;87:228232.
crystalline disease, examination of the synovial fluid for 8. Truswell AS, Pfister PJ. Cerebrotendinous xanthomato-
sis. Br Med J 1972;1:353354.
crystals is essential. The presence of cholesterol crystals
9. Shulman RS, Bhattacharyya AK, Connor WE, Fredrick-
has been associated with a worse outcome for a joint son DS. Beta-sitosterolemia and xanthomatosis. N Engl J
affected by degenerative or inflammatory arthritis, and Med 1976;294:482483.
has been shown to maintain the inflammatory reaction 10. Rooney PJ, Third J, Madkour MM, Spencer D, Dick WC.
in experimental animals (19). In people with primary Transient polyarthritis associated with familial hyperbetal
hyperlipoproteinemia, however, cholesterol crystals lipoproteinemia. Q J Med 1978;47:249259.
have not been specifically implicated in acute or chronic 11. Mathon G, Gagne C, Brun D, Lupien PJ, Moorjani S.
arthrititis. Crystals were found in a retrocalcaneal bursa Articular manifestations of familial hypercholesterolemia.
adjacent to a xanthoma in a patient with type II hyper- Ann Rheum Vis 1985;44:599602.
lipoproteinemia, but the significance of these crystals 12. Welin L, Larsson B, Svardsudd K, Tibblin G. Serum
has not been determined (20). lipids, lipoproteins and musculoskeletal disorders among
50- and 60-year-old men. Scand J Rheumatol 1977;1:
712.
13. Struthers GR, Scott DL, Bacon PA, Walton KW. Muscu-
MANAGEMENT loskeletal disorders in patients with hyperlipidemia. Ann
Rheum Dis 1983;42:519523.
The acute migratory polyarthritis or oligoarthritis 14. Wysenbeek AJ, Shani E, Beigel Y. Musculoskeletal mani-
associated with type II hyperlipoproteinemia tends to festations in patients with hypercholesterolemia. J Rheu-
be self-limited. Nonsteroidal anti-inflammatory drugs matol 1989;16:643645.
15. Klemp P, Halland AM, Majoos FL, Steyn K. Musculo- 19. Lazarevic MB, Skosey JL, Vitic J, et al. Cholesterol crys-
skeletal manifestations in hyperlipidemia: a controlled tals in synovial and bursal fluid. Semin Arthritis Rheum
study. Ann Rheum Dis 1993;52:4448. 1993;23:99103. 25
16. Khachadurian AK. Migratory polyarthritis in familial 20. Schumacher HR, Michaels R. Recurrent tendinits and
hypercholesterolemia (type II hyperlipoproteinemia). Achilles tendon nodule with positively birefringent crys-
Arthritis Rheum 1968;11:385393. tals in a patient with hyperlipoprotenemia. J Rheumatol
17. Rimon D, Cohen L. Hypercholesterolemic (type II hyperli- 1989;16:13871389.
poproteinemic) arthritis. Rheumatology 1989;16:703705. 21. Solomon DH, Avorn J, Strmer T, Glynn RJ, Mogun H,
18. Buckingham RB, Bole GG, Bassett DR. Polyarthritis Schneeweiss S. Cardiovascular outcomes in new users of
associated with type IV hyperlipoproteinemia. Arch coxibs and nonsteroidal antiinflammatory drugs. Arthritis
Intern Med 1975;135:286290. Rheum 2006;54:13781389.
CHAPTER 25

D. Neuropathic Arthropathy
ANN K. ROSENTHAL, MD
Neuropathic arthropathy, also known as a Charcot erythema, and variable amounts of pain in the
joint, is a destructive arthritis characterized by affected joint.
fracture, subluxation, and dislocation of the articular Two consistent clinical features of neuropathic
structures in the setting of neurologic damage to the arthropathy are the presence of a significant sensory
involved joint or limb. deficit and a degree of pain that is less than would
Both central (upper motor neuron) and peripheral be expected considering the amount of joint
(lower motor neuron) lesions may lead to the destruction evident on radiographs.
development of neuropathic arthropathy. The differential diagnosis of neuropathic
Diabetic neuropathy is now the most common cause arthropathy includes osteomyelitis and other deep
of neuropathic arthropathy. Neuropathic arthropathy tissue infections, fracture, gout, calcium
occurs in 7.5% of diabetic patients. pyrophosphate dihydrate deposition disease,
The pathologic features of Charcot arthropathy Milwaukee shoulder/knee syndrome, osteonecrosis,
include cartilage destruction, bone eburnation, and osteoarthritis.
osteophytosis, and loose body formation. Plain radiographs are extremely helpful in making
Two major theories have been proposed to explain the diagnosis of neuropathic arthropathy.
the development of neuropathic arthropathy: the Categorizing the disease into three clinical stages
neurovascular theory and the neurotraumatic theory. acute, subacute, and remodelingis a useful way to
Neuropathic arthropathy typically presents as an organize approaches to therapy.
acute or subacute monoarthritis with swelling,
Neuropathic arthropathy is a destructive arthritis char- 25D-1). In the pre-penicillin era, neuropathic arthropa-
acterized by fracture, subluxation, and dislocation of thy was most commonly seen in the setting of tabes
the articular structures in the setting of neurologic dorsalis from tertiary syphilis. Diabetic neuropathy is
damage to the involved joint or limb. The concept of an now the most common cause of neuropathic arthropa-
association between sensory neurologic lesions and thy. Neuropathic arthropathy occurs in 7.5% of diabetic
arthritis was described elegantly by Jean-Martin Charcot patients, with prevalence rates rising to 29% among
in 1868 (1). Consequently, the terms Charcot arthropa- diabetic patients with neuropathy (2). Syringomyelia,
thy, neurotrophic arthropathy, and neuroarthropathy spina bifida, and spinal cord injuries may also result in
are used synonymously with neuropathic arthropathy. neuropathic arthropathy. Less commonly encountered
causes of neuropathic arthropathy include inflamma-
tory or neoplastic lesions of the spinal cord or periph-
EPIDEMIOLOGY eral nerves, congenital neurologic abnormalities, and
alcoholic neuropathies. Rarely, cases occur in which no
Accurate figures on the incidence and prevalence of
neurologic abnormality is identifiable (3).
neuropathic arthropathy in the general population are
difficult to ascertain. The presence of sensory neuropa-
thy is the only established risk factor for neuropathic PATHOLOGY
arthropathy. Both central (upper motor neuron) and
peripheral (lower motor neuron) lesions may lead to the The pathologic changes of neuropathic arthropathy
development of neuropathic arthropathy. are similar to those of advanced osteoarthritis: cartilage
The neurologic diseases associated with neuropathic destruction, bone eburnation, osteophytosis, and loose
arthropathy have radically changed with time (Table body formation. The presence of detritic synovium,
488
TABLE 25D-1. NEUROLOGIC CONDITIONS ization of the affected limb may precede the develop-
ASSOCIATED WITH NEUROPATHIC ARTHROPATHY. ment of neuropathic arthropathy (4). In contrast, the
Diabetes mellitus
observation that injury often accelerates or initiates 25
neuropathic arthropathy supports the neurotraumatic
Syringomyelia hypothesis (5). Elements of both theories are probably
Spina bifida
correct.
Brain or spinal cord trauma
Peripheral nerve trauma CLINICAL FEATURES

Syphilis
Neuropathic arthropathy typically presents as an acute
Multiple sclerosis or subacute monoarthritis with swelling, erythema, and
variable amounts of pain in the affected joint. The two
CharcotMarieTooth disease
most consistent clinical features of neuropathic arthrop-
RileyDay syndrome athy are the presence of a significant sensory deficit and
Pernicious anemia
a degree of pain that is less than would be expected
considering the amount of joint destruction evident on
Congenital insensitivity to pain radiographs. Abnormal sensation can be accurately
Alcoholism
detected with the SemmesWeinstein monofilament
test. When slowly progressive, neuropathic arthropathy
Amyloidosis often resembles osteoarthritis. When rapidly progres-
Thalidomide exposure sive and acute in onset, it mimics osteomyelitis. Initial
examinations show swelling, erythema, effusions, and
Polyneuropathy of DejerineSottas variable amounts of tenderness. With time, the neuro-
Leprosy pathic joint becomes deformed with large effusions,
palpable osteophytes, and loss of range of motion. Cat-
Yaws egorizing the disease into three clinical stagesacute,
Neurofibromatosis subacute, and remodelingis a useful way to organize
approaches to therapy (see Management section, below)
(6).
The pattern of joint involvement in neuropathic
arthropathy depends on the location of the neurologic
defined as fragments of cartilage and bone embedded impairment and may involve small as well as large joints.
in the synovium, is characteristic of neuropathic arthrop- In diabetes, the foot is most commonly involved. In
athy, but is also seen in severe osteoarthritis (3). As spina bifida, the knee, hip, ankle, and lumbar spine are
reflected radiographically, neuropathic arthropathy can affected. Patients with syringomyelia typically demon-
cause exuberant bone and cartilage overgrowth as well strate upper extremity involvement.
as joint destruction. Usually both processes are seen,
but one process often predominates.
Neuropathic Arthropathy in
PATHOPHYSIOLOGY the Diabetic Foot
Neuropathic arthropathy of the diabetic foot deserves
Two major theories have been proposed to explain the special consideration. It typically occurs after the fifth
development of neuropathic arthropathy. The neuro- decade of life in patients with longstanding diabetes,
vascular theory postulates that joint denervation pro- and may follow minor trauma or surgery. It is unilateral
duces physiologic changes, such as increased blood in 80% of patients. Five anatomic patterns have been
flow from loss of sympathetic regulation, and upsets described, including involvement of the toe joints, the
the balance between bone resorption and formation. tarsometatarsal joints, the midfoot, ankle, and calca-
The neurotraumatic theory proposes that repeated epi- neus. Midfoot involvement is particularly common
sodes of minor trauma to joints unprotected by the (Figure 25D-1) (2). During the acute stage, patients
usual response to pain cause damage through further present with a swollen foot or ankle. Concurrent skin
trauma and inadequate repair. The neurovascular ulcers are common. The onset of symptoms and rate of
hypothesis is supported clinically by reports of neuro- destruction may be acute and dramatic with radio-
pathic arthropathy in patients at bedrest who could not graphic evidence of joint dissolution occurring within
have sustained trauma and the finding that demineral- weeks (7). Involvement of the midfoot may result in
490 ANN K. ROSENTHAL
from those of infection, where involved bone surfaces

are indistinct. In neuropathic arthropathy of the dia-
betic foot, destruction with prominent fragmentation
and loose body formation typically occurs in the tarsal
bones, while absorptive changes may predominate in
the metatarsals and forefoot (Figure 25D-2). In the
spine, multilevel thoracic and lumbar involvement is
common.
Bone scintigraphy with technetium 99m-MDP and
indium-111labeled WBC scans (8) demonstrate
increased uptake of radiolabeled technetium in neuro-
pathic arthropathy; unfortunately, uncomplicated neu-
ropathy as well as infection both can produce similar
findings (9). Magnetic resonance imaging should be
interpreted with caution as bony changes in osteomyeli-
tis can be difficult to differentiate from those of neuro-
pathic arthropathy. A combined approach using multiple
FIGURE 25D-1
imaging techniques with or without bone cultures is
Neuropathic arthropathy of the foot in a patient with diabetes. often necessary to differentiate infection from neuro-
Note the midfoot collapse resulting in a rocker bottom pathic arthropathy.
deformity. (Courtesy of Dr. Daniel Toutant.) Synovial fluid is typically non-inflammatory in
neuropathic arthropathy. Fifty percent of synovial
fluids from affected joints are hemorrhagic or xantho-
chromic. Effusions may be very large. CPPD crystals
reversal of the curve of the metatarsal arch and rocker and basic calcium phosphate crystals have been
bottom deformity. The possibility of osteomyelitis or identified in these joint effusions and may contribute
soft tissue infection in the feet must always be consid- to joint damage.
ered in diabetic patients.
DIAGNOSIS
The diagnosis of neuropathic arthropathy can be made
clinically. Helpful diagnostic tests include plain radio-
graphs, bone scans, and indium-111labeled white blood
cell (WBC) scans. The differential diagnosis of neuro-
pathic arthropathy includes osteomyelitis and other
deep tissue infections, fracture, gout, calcium pyrophos-
phate dihydrate deposition (CPPD) disease, Milwaukee
shoulder/knee syndrome, osteonecrosis, and osteoar-
thritis. The differentiation between osteomyelitis and
acute neuropathic arthropathy in the diabetic foot is
particularly challenging.
Plain radiographs are extremely helpful in making
the diagnosis of neuropathic arthropathy (3). Early
features include demineralization, joint space narrow-
ing, and osteophyte formation. In established disease,
bone fragmentation, periarticular debris formation,
and joint subluxation occur (Figures 25D-1, 25D-2).
Bone absorption, bone shattering, sclerosis and massive
soft tissue swelling are seen in some patients. Neuro- FIGURE 25D-2
pathic joints are often described radiographically as
disorganized, with chaotic bone destruction and Neuropathic arthropathy of the foot in a patient with diabetes.
There is involvement of the forefoot and the midfoot. The
repair. The presence of sharply defined articular sur- typical combination of both resorptive and reparative processes
faces in neuropathic arthropathy is helpful in differen- results in a disorganized appearance of the involved bones.
tiating radiographic changes of neuropathic arthropathy (Courtesy of Dr. Daniel Toutant.)
MANAGEMENT References
There are no specific therapies for neuropathic arthrop- 1. Gupta A. A short history of neuropathic arthropathy. Clin 25
athy. The prognosis of affected patients is variable and Orthop 1993;296:4349.
depends on the severity of the condition and the re- 2. Lee L, Blume P, Sumpio B. Charcot joint disease in dia-
sponse to treatment. betes mellitus. Ann Vasc Surg 2003;17:571580.
Standard management strategies for the acute phase 3. Resnick D. Neuropathic osteoarthropathy. In: Resnick D,
ed. Diagnosis of bone and joint disorders. 3rd ed. Phila-
(6) of neuropathic arthropathy include joint immobili-
delphia: Saunders; 1995:34133442.
zation, usually achieved by casts, braces, orthotics, and 4. Sinacore D, Withrington N. Recognition and manage-
restricted weight bearing. With immobilization, the ment of acute neuropathic (Charcot) arthropathies of the
average time to healing in neuropathic arthropathy of foot and ankle. J Orthop Sports Phys Ther 1999;29:736
the diabetic foot is approximately 6 months (4). With 746.
early diagnosis and bracing, risks for amputation are 5. Fishco W. Surgically induced Charcots foot. J Am Podiatr
2.3%, but 23% will require bracing for 18 months, and Med Assoc 2001;91:288293.
50% will have recurrent ulcers (10). There is some pre- 6. Eichenholtz S. Charcot joints. Springfield: Thomas; 1966.
liminary evidence for the efficacy of bisphosphonates in 7. Sloman-Kovacs S, Braunstein E, Brandt K. Rapidly pro-
the early destructive phase of the disease (2). gressive Charcot arthropathy following minor joint trauma
Surgical treatments, another mainstay of therapy, are in patients with diabetic neuropathy. Arthritis Rheum
1990;33:412417.
generally recommended in the remodeling phase of the
8. Lipman B, Collier B, Carrera G, et al. Detection of osteo-
disease (2). Goals are to improve pain, joint stability, myelitis in the neuropathic foot: nuclear medicine, MRI,
and alignment, and to prevent or treat overlying skin and conventional radiography. Clin Nucl Med 1998;23:
ulceration. Arthrodesis is useful in the spine, foot, ankle, 7782.
and knee. Removal of exostoses may restore some 9. Palestro C, Mehta H, Patel M, et al. Marrow versus infec-
motion and decrease joint pain in patients with severe tion in the Charcot joint: indium-111 leukocyte and tech-
rocker bottom deformities of the foot. With current netium-99m sulfur colloid scintigraphy. J Nucl Med 1998;
techniques, joint replacement may also be effective for 39:346350.
selected patients. 10. Saltzman C, Hagy M, Zimmerman B, Estin M, Cooper R.
Prevention is perhaps the best therapy. Prompt atten- How effective is intensive nonoperative intial treatment
tion to any minor trauma to the diabetic foot or ankle of patients with diabetes and Charcot arthropathy of the
feet? Clin Orthop 2005;435:185190.
may prevent the development of neuropathic arthropa-
thy. Good control of blood glucose levels in diabetics
decreases the incidence of neuropathy and thereby
reduces the risk of neuropathic arthropathy.
CHAPTER 25

E. Dermatologic Disorders
JEFFREY P. CALLEN, MD
Many rheumatologic diseases have prominent pyoderma gangrenosum), panniculitis (e.g.,

cutaneous findings. erythema nodosum), the sclerosing/fibrosing
Careful examination of the skin may lead to prompt diseases (e.g., morphea and scleromyxedema),
diagnoses, relatively noninvasive means of defining pustular conditions, and a variety of cutaneous
systemic disorders, and possibly better outcomes. conditions with possible implications for rheumatic
Entities discussed in this chapter include the disease.
neutrophilic dermatoses (Sweets syndrome,
The skin often reflects the presence of disease involving have arthralgias or arthritis. The process is more
internal organs. Consequently, careful examination of common in women. The disease may be classified
the skin may lead to prompt diagnoses, relatively non- further based upon its potential associations with
invasive means of defining systemic disorders, and pos- malignancy, inflammatory disorders, infections, drugs,
sibly better outcomes. Many rheumatologic diseases or a group of miscellaneous conditions. In approxi-
have prominent cutaneous findings. This chapter pro- mately 15% to 20% of patients with Sweets syndrome,
vides an overview of a group of conditions in which skin myeloid malignancy or preleukemia occurs. Solid
findings are a major component of systemic disease. tumors are very rare in these patients. The diagnosis is
confirmed by excluding other diseases, particularly cel-
lulitis. Patients with Sweets syndrome demonstrate
NEUTROPHILIC DERMATOSES pathergythe occurrence of the characteristic skin
lesions following minor trauma.
The neutrophilic dermatoses are noninfectious disor- Patients with Sweets syndrome often have antineu-
ders characterized by infiltration of the skin by poly- trophil cytoplasmic antibodies (ANCA) by immuno-
morphonuclear leukocytes (Table 25E-1) (1). Some of fluorescence testing, but the ANCA specificity is not
these disorders may be angiocentric, but typically they directed against either myeloperoxidase or proteinase-3
are not associated with the type of vessel wall destruc- (the specificity observed in microscopic polyangiitis,
tion observed in vasculitis. The neutrophilic dermatoses Wegeners granulomatosis, and related vasculitides).
include Sweets syndrome, pyoderma gangrenosum, No laboratory findings are pathognomonic of Sweets
neutrophilic dermatosis of the dorsal hands, rheuma- syndrome. Patients with Sweets syndrome secondary
toid neutrophilic dermatosis, and the bowel-associated to myelodysplasia or leukemia, however, are frequently
dermatosisarthritis syndrome. anemic or thrombocytopenic. Although generally con-
Sweets syndrome (2), originally termed acute febrile fined to the skin, extracutaneous neutrophilic infiltra-
neutrophilic dermatosis, is characterized by painful, tion occurs in a small percentage of Sweets syndrome
erythematous plaques on almost any body surface patients, potentially affecting any organ (most com-
(Figure 25E-1). The surface of the lesions, frequently monly the lungs). Osteolytic bone lesions have also
tender, may be so edematous that the lesions appear been reported. The entity known as multifocal sterile
vesicular. Subcutaneous nodules and dermal nodules recurrent osteomyelitis might represent an orthopedic
are unusual manifestations of Sweets syndrome. The variant of Sweets syndrome.
characteristic histopathological findings of Sweets syn- Therapy for Sweets syndrome is directed toward
drome are shown in Figure 25E-2. The patients are any identified underlying condition, including cessation
usually febrile, have a leukocytosis, and frequently of drugs with the potential to trigger this condition.
492
TABLE 25E-1. ASSOCIATIONS WITH NEUTROPHILIC DERMATOSES.

BOWEL-ASSOCIATED
PYODERMA RHEUMATOID DERMATOSIS NEUTROPHILIC
25
SWEETS GANGRENOSUM NEUTROPHILIC ARTHRITIS DERMATOSIS OF
DERMATOSIS SYNDROME (PG) DERMATOSIS SYNDROME THE DORSAL HANDS
Inflammatory bowel Some 20%25% No Yes Occasional

diseaseCrohns disease
and ulcerative colitis
Rheumatoid arthritis Occasional 10% for superficial Yes, occasionally No, but joint disease Occasional
forms, less for seronegative may simulate RA
classical PG
Hematologic malignancies 25%30% 15% for the No No 15%

superficial forms
Solid tumors Rare Rare No No Rare
Sjgrens syndrome Possible No Possible No Possible
Drug-induced Occasionally No No No Possible
Pregnancy Occasionally No No No No
Medications known to be associated with Sweets syn- Pyoderma gangrenosum (PG) is a form of ulcerative
drome include granulocyte-monocyte colony-stimulat- skin disease. There are at least four clinical variants of
ing factor (GMCSF), granulocyte colony stimulating PG: classical, atypical, peristomal, and mucosal (3). The
factor (GCSF), bortezomib, imatinib, minocycline, classical lesion is a rapidly progressing, painful ulcer,
hydralazine, and oral contraceptives. For acute disease, most often on the leg, with a violaceous, undermined
a short course of oral prednisone tapered over 2 weeks (overhanging) border (Figure 25E-3). Atypical PG
is often sufficient. For recurrent disease without an asso- occurs as a more superficial lesion, often on the dorsal
ciated condition, glucocorticoid-sparing agents such as hands (Figure 25E-4), extensor forearms, or face. The
dapsone, thalidomide, immunosuppressive agents, and border of atypical PG may appear bullous, leading to
tumor necrosis factor alpha (TNF-alpha) antagonists clinical confusion with Sweets syndrome. Peristomal
are often used. In patients with acute, idiopathic disease, PG occurs as a deep ulcer near the site of a stoma,
the prognosis is generally good; many have only episode. usually created after gastrointestinal or genitourinary
However, the course of patients with underlying leuke- surgery. Finally, mucosal PG is associated with ulcer-
mia or myelodysplasia follows that of the associated ations that can resemble simple aphthae or vegetative
disease. Absent disease remission or a cure, recurrences lesions. Mucosal PG must be differentiated from
are common. Behets disease.
FIGURE 25E-1 FIGURE 25E-2
Sweets syndrome. Histopathological findings in Sweets syndrome.

494 JEFFREY P. CALLEN
PG. Prednisone (1 mg/kg/day) is generally the first line

of therapy for idiopathic PG. Infliximab (35 mg/kg
every 6 weeks following two initial doses 2 weeks apart)
is also an effective therapy for PG, even in the absence
of inflammatory bowel disease. Other therapies
employed in PG include dapsone [100200 mg/day
(assuming normal levels of glucose-6-phosphate dehy-
drogenase; G6-PD)], thalidomide (100 mg/day), cyclo-
sporine (5 mg/kg/day), azathioprine [2 mg/kg/day,
assuming normal levels of thiopurine methyltransfer-
ase; (TPMT)], and mycophenolate mofetil (1.0.5 g
b.i.d.).
Neutrophilic dermatosis of the dorsal hands (NDDH)
(4), considered by some to be a separate disease entity,
is regarded more commonly as a variant of either
Sweets syndrome or atypical PG. NDDH is associated
FIGURE 25E-3 with the same underlying conditions as Sweets syn-
Pyoderma gangrenosum in a patient without an associated drome and atypical PG, and the management consider-
disease. ations are identical.
Rheumatoid neutrophilic dermatosis, an unusual
complication of RA, is characterized by symmetrical
Patients with PG also demonstrate pathergy. Thus, erythematous papules and plaques on the dorsal hands,
this condition has been reported following a variety of elbows, and extensor surfaces of the forearms (5).
surgical procedures, for example, thoracotomy or fasci- Patients generally have active and often severe RA, but
otomy. The systemic associations vary depending on the the condition has been reported in at least two patients
type of PG. Classical disease and peristomal PG are with seronegative RA. In terms of histopathology, rheu-
associated more frequently with inflammatory bowel matoid neutrophilic dermatosis resembles Sweets syn-
disease and/or arthritis. Careful evaluation for inflam- drome. Treatments that have been suggested include
matory bowel disease is warranted in cases of peristo- glucocorticoids, dapsone (100200 mg/day), and colchi-
mal PG, even when the stoma was created for other cine (0.6 mg b.i.d.); however, spontaneous resolution
reasons (e.g., following cancer surgery). In contrast, has been reported to occur.
atypical pyoderma gangrenosum is found more fre- Bowel-associated dermatosisarthritis syndrome was
quently in the setting of myelocytic leukemia or pre- first recognized in the 1970s following gastric bypass
leukemic conditions. surgery for morbid obesity. Fortunately, because of
The diagnosis of PG is one of exclusion. Although major alterations in surgical technique, this syndrome is
biopsies should be performed to exclude other condi-
tions, PG does not have a distinctive histopathology.
Because of the importance of excluding disease mimick-
ersparticularly infectionsbiopsy is almost always
performed as part of the evaluation, despite the possi-
bility that the ulcer will extend through pathergy.
Culture of the lesions following skin biopsy is essential.
Infectious mimickers are not common but include deep
fungal infections; for example, blastomycosis, sporotri-
chosis, histoplasmosis, and coccidioidomycosis; as well
as nocardiosis, tuberculosis, atypical mycobacteria; and
herpes simplex virus. Following diagnosis, appropriate
studies should be undertaken to exclude inflammatory
bowel disease, rheumatoid arthritis (RA), systemic vas-
culitis, paraproteinemia, and other hematologic disor-
ders. As with Sweets syndrome, neutrophilic infiltration
of organs other than the skin may sometimes occur in
PG.
For cases of PG associated with an underlying disease FIGURE 25E-4
(e.g., inflammatory bowel disease or RA), treatment of Atypical pyoderma gangrenosum, also known as neutrophilic
the primary condition often leads to improvement in dermatosis of the dorsal hands.
rarely observed today. The former procedure involved traceptive use, inflammatory bowel disease, and sar-
the creation of a blind intestinal loop that frequently led coidosis are other common causes of erythema nodosum.
to bacterial overgrowth, presumed responsible for the In sarcoidosis, erythema nodosum typically occurs in 25
clinical manifestations. The bowel-associated dermato- the setting of arthritis and hilar adenopathy, a syndrome
sisarthritis syndrome was initially called bowel bypass known as Lfgrens syndrome. Lfgrens syndrome,
syndrome until recognition of the fact that similar self-limited in two thirds of cases, usually requires symp-
changes occurred in patients with ulcer surgery that tomatic treatment only.
created a blind loop. Joint inflammation may accompany erythema
The skin lesions of the bowel-associated dermato- nodosum, but at times the inflammatory reaction on the
sisarthritis syndrome are characterized by pustular legs surrounds the joints, creating a periarthritis but
lesions or erythematous papules and/or plaques. Lesions not a true synovitis. Patients with erythema nodosum
that simulate NDDH (see above) have also been should be evaluated with a careful history and physical
reported. The joint manifestations consist of a symmet- examination. Skin biopsies are required only for atypi-
rical, nondeforming arthropathy, most often involving cal presentations or persistent disease. Additional eval-
the small joints of the hands and feet. These patients uation should include throat cultures, a streptozyme
often respond to antibiotic therapy, including tetracy- titer, and a chest radiograph. Treatment is often sup-
cline or metronidazole. portive, including gradient support stockings, elevation
of the legs, and nonsteroidal anti-inflammatory agents.
Other therapies that have been reported to be effective
PANNICULITIDES in single cases or small case series include potassium
iodide, dapsone, antimalarial agents, colchicine, gluco-
Panniculitis refers to inflammation of the subcutaneous corticoids, immunosuppressive agents, and TNF-alpha
fat (6,7). The process probably evolves from neutro- antagonists.
philic infiltration through lymphocytic and histiocytic The existence of WeberChristian disease as a dis-
infiltration to fibrosis. The classification of panniculiti- tinct entity is controversial. The condition is character-
des is controversial, but several clear-cut entities are ized by recurrent, often multiple, tender subcutaneous
defined here. nodules accompanied by fever. In contrast to erythema
Erythema nodosum, perhaps the most common form nodosum (a septal panniculitis), WeberChristian
of panniculitis, is characterized histologically by septal disease is a lobular panniculitis. With regard to nomen-
inflammation (8). Erythema nodosum is most often clature, the issue is whether the lobular panniculitis
characterized by red, tender subcutaneous nodules on associated with WeberChristian disease occurs as a
the anterior leg (Figure 25E-5). The disorder is believed primary disorder or as a complication of another under-
to be a reactive process commonly triggered by infec- lying illness. For example, a lobular panniculitis is
tions in the upper respiratory tract and/or lungs. The known to occur in alpha-1-antitrypsin deficiency, pan-
most common association is streptococcal pharyngitis, creatic disease-associated panniculitis, and a wide array
but tuberculosis, coccidioidomycosis, and psittacosis are of other inflammatory disorders. Systemic involvement
other common infectious causes. Pregnancy, oral con- due to inflammation of fatty tissues other than the sub-
cutis has also been reported in cases labeled Weber
Christian disease. There is no specific therapy for this
entity, but suggested therapies include those for chronic
erythema nodosum (see above).
Lupus panniculitis (also known as lupus profundus),
a rare manifestation of systemic lupus erythematosus
(SLE), is a form of chronic cutaneous lupus erythema-
tosus. The histopathology of lupus profundus reveals
both lobular and septal inflammation, sometimes dem-
onstrating an interface dermatitis (deposition of immu-
noreactants such as immunoglobulins and complement
proteins at the dermal/epidermal junction) that is char-
acteristic of cutaneous lupus. Hydroxychloroquine
[6.5 mg/kg (ideal body weight)/day in single or divided
doses] is usually an effective first approach to therapy.
Lipodermatosclerosis, also known as sclerosing
panniculitis, is characterized by tender, subcutaneous
FIGURE 25E-5
nodules most often over the medial malleolus, accom-
Erythema nodosum. panied by hyperpigmentation, telangiectases, tortuous
each other aside from the finding of skin induration that

may be localized or generalized.
Localized scleroderma, one subtype of which is
morphea, is more common in children and women (11).
Localized scleroderma is differentiated from systemic
sclerosis by the lack of Raynauds phenomenon, sclero-
dactyly, and the absence of internal organ involvement.
The term morphea is synonymous with localized sclero-
derma, of which there are at least five subtypes: (1)
guttate morphea refers to patients with small drop-
like lesions; (2) morphea profundus refers to deep
lesions that involve the panniculus along with the
dermis; (3) bullous morphea; (4) generalized morphea
(Figure 25E-7) encases the body in hard skin within
contrast to systemic sclerosissparing of the acral areas,
face, and nipples; and (5) linear scleroderma (Figure
FIGURE 25E-6 25E-8). When linear scleroderma occurs on the face
Lipodermatosclerosis. and/or scalp, the term en coup de sabre (blow of the
saber) is used. The ParryRomberg syndrome, associ-
ated with facial hemiatrophy, is usually accompanied by
linear scleroderma. In the ParryRomberg syndrome,
however, there is atrophy of the underlying bony struc-
veins, edema, and a woody induration (Figure 25E-6)
tures, muscles and, in some instances, even the contigu-
(9). Women older than 40 years of age are affected
ous nervous system.
most commonly by this condition. The histopathology
Most patients with any form of morphea improve
includes inflammation of the panniculus in addition to
over time, with softening of the sclerotic skin lesions.
dermal sclerosis. This process, occasionally diagnosed
However, there may be residual dyspigmentation, limb
incorrectly as localized scleroderma or as an inflamma-
atrophy or deformity, or joint contracture. Therapy
tory type of panniculitis, is in fact simply a long-term
includes topical glucocorticoids or calcipotriene for
complication of venous insufficiency. The most effective
localized disease. Methotrexate with or without pulse
therapy is the application of support stockings with a 30
methylprednisolone has been used for widespread
to 40 mm Hg gradient.
disease. Phototherapy with ultraviolet (UV)A-1 light
Calcifying panniculitis is a variant of calciphylaxis
has also been reported to be successful in patients with
(more properly termed calcific uremic arteriolopathy).
localized scleroderma.
This process most often occurs in people with renal
Lichen sclerosus is a superficial dermatosis that has
failure, frequently on dialysis. The management of these
recently been linked to circulating autoantibodies
patients involves a control of their serum calcium and
directed against extracellular matrix protein 1 (12). The
phosphate levels and, when present, treatment of sec-
disease is manifested by induration and superficial, atro-
ondary hyperparathyroidism.
phic, hypopigmented patches or plaques that resemble
Cytophagic histiocytic panniculitis, an entity associ-
cigarette paper (Figure 25E-9). These same changes are
ated with tender subcutaneous nodules, fever, hepato-
observed in some patients with morphea and may also
splenomegaly, pancytopenia, and serositis (10), is
occur in patients with chronic graft-versus-host disease
believed now to be a manifestation of subcutaneous
(Figure 25E-10). In some cases the disease affects only
panniculitislike T-cell lymphoma. The disorder fre-
the genitalia and in women may be associated with a
quently masquerades as an undefined connective tissue
risk of malignant transformation. Potent topical gluco-
disease until its progression allows the proper diagnosis.
corticoids are the treatment of choice for lichen
Treatment of this condition is directed at the underlying
sclerosus.
lymphoma.
Scleromyxedema is characterized by a generalized
papular and sclerodermatous eruption often described
as waxy papules. The distribution of the skin lesions
SCLEROSING/FIBROSING in scleromyxedema is over the head, neck, arms, and
DISEASES upper trunk. Papular lesions are often situated on
thickened, indurated skin. On biopsy, these lesions
Several skin conditions are associated with cutaneous demonstrate mucin deposition, fibrosis, and fibroblast
thickening and varying levels of systemic disease (Table proliferation on biopsy. Patients are often misdiagnosed
25E-2). These disorders are not necessarily related to as having systemic sclerosis (scleroderma). Thyroid
TABLE 25E-2. DERMATOLOGICAL CONDITIONS ASSOCIATED WITH SCLERODERMOID AND/OR FIBROSING ALTERATIONS.
CUTANEOUS SYSTEMIC
DISEASE MANIFESTATIONS MANIFESTATIONS EVALUATION MANAGEMENT COMMENTS
Morphea (and guttate Indurated plaques. Sometimes the Rare involvement, but ANA, Anti-ssDNA, antihistone Topical glucocorticoids, topical Positive serology is
morphea) borders are violaceous. Surface esophageal dysfunction, antibodies, PFTs. calcipotriene, UVA-1, predictive of a more
changes of lichen sclerosus may pulmonary fibrosis have methotrexate. prolonged course.
coexist. been reported.
Linear scleroderma Indurated linear lesions on the Same as morphea Same as morphea Same as morphea
arms, legs or face [en coup de
sabre (Figure 25E-7)]. Facial
lesions may be accompanied by
atrophy of underlying bone,
soft tissues and nervous system.
Surface changes of lichen
sclerosus may coexist.
Generalized morphea Generalized indurated plaques, Same as morphea Same as morphea Topical therapy is adjunctive to
often with sparing of the nipples systemic therapies or
(Figure25E-8). Surface changes phototherapy.
of lichen sclerosus may coexist.
Lichen sclerosus Cigarette paperlike changes on None Antibodies to extracellular Superpotent topical glucocorticoids Elevated risk of cancer
the surface (Figure 25E-9). May matrix 1 protein have for localized disease. in patients with genital
be present on trunk or been recently observed in Methotrexate or UV lesions.
extremities. Genital lesions, patients with lichen phototherapy for extensive
particularly in girls, may be sclerosus, suggesting that disease.
mistaken for abuse because it is an autoimmune
bleeding into the lesion is disorder.
common.
Scleredema Indurated, erythematous plaque Often complicates diabetes Biopsy reveals deposition of There is no known effective Occassional monoclonal
usually on the upper back. mellitus. May occur post amorphous material that therapy. gammopathy is
streptococcal infection. stains positive with mucin present.
stains. SPEP should be
done.
(continued)
25
TABLE 25E-2. Continued
CUTANEOUS SYSTEMIC
DISEASE MANIFESTATIONS MANIFESTATIONS EVALUATION MANAGEMENT COMMENTS
Scleromyxedema Linear flesh-colored papules are Monoclonal gammopathy Biopsy reveals increase in Stem-cell transplant has resulted in
an early change, but eventually and plasma cell dyscrasia mucin in the dermis. SPEP, complete responses in patients
induration occurs. is common. IEP, bone marrow with plasma cell dyscrasia.
aspiration or biopsy. Systemic glucocorticoids or
cytotoxic agents are used in
patients without plasma cell
dyscrasia.
Nephrogenic fibrosing Acute onset of induration often Renal disease of some sort Tests of renal function. Renal transplantation may improve The process may be
dermopathy/ follows anasarca. Usually affects is almost always present. Monoclonal protein is process. Other therapies that preceded by a surgical
nephrogenic the arms [Figure 25E-11(B)] and Pulmonary fibrosis absent. Biopsy looks have been reported to be procedure, particularly
systemic fibrosis forearms, or the legs. Decrease may occur. Calcifications identical to effective include thalidomide, vascular revision of
in the range of motion of the may also compromise scleromyxedema. photopheresis, plasmapheresis, hemodialysis shunt, or
hands [Figure 25E-11(A)] and the process. methotrexate, phototherapy, IVIG. by a thrombotic event.
feet lead to limitations of the
patients ability to function.
Graft-versus-host Acute disease is associated with a Hepatic dysfunction and/or There is no test to determine Topical superpotent glucocorticoids
disease (GVHD) morbilliform eruption. As the bowel dysfunction. whether a patient has and/or calcineurin inhibitors for
process becomes more chronic, GVHD. Biopsy in the late localized disease. Phototherapy,
lichen planuslike lesions may stages simulates morphea thalidomide, immunosuppressive
develop. Eventually sclerotic or lichen sclerosus, but agents for widespread or
lesions, often with superficial there is often an interface systemic disease.
features of lichen sclerosus dermatitis as well.
occur. (Figure 25E-10).
ABBREVIATIONS: ANA, antinuclear antibodies; Anti-ssDNA, antisingle-stranded DNA; IEP, immunoelectrophoresis; IVIG, intravenous immune globulin; PFT, pulmonary function tests; SPEP, serum protein electro-
phoresis; UV, ultraviolet.
25

Generalized morpheathis patient has widespread disease on Lichen sclerosus. Note the cigarette paperlike changes on the
her trunk and proximal extremities. Note the sparing of surface. Hemorrhage within the lesions is quite characteristic.
scleroderma on the nipples, which is a common feature of
generalized morphea.
in scleromyxedema. Features that separate this entity
from scleromyxedema are the lack of a monoclonal
disease must also be excluded. Monoclonal gammopa- gammopathy and the presence of renal disease. Since its
thies, particularly IgG lambda, are common in sclero- initial description, systemic fibrosis (particularly affect-
myxedema, which may also be associated with multiple ing the lungs) has been described in many patients,
myeloma and amyloidosis. Treatment of patients with leading to debate over the appropriate name of the
scleromyxedema is often difficult. Therapies that have condition. Many patients improve with renal transplan-
been used include cytotoxic agents, including melpha- tation, while others have been treated with thalidomide,
lan, thalidomide, and, most recently, autologous stem methotrexate, TNF antagonists, plasmapheresis, and
cell transplantation (13). photopheresis with variable success. NSF is now known
Nephrogenic systemic fibrosis (NSF; also termed to be associated strongly with the administration of
nephrogenic fibrosing dermopathy or nephrogenic gadolinium, a contrast agent used in magnetic resonance
fibrosing systemic disorder) is a recently described imaging, to patients with renel insufficiency.
process characterized by a rapid onset of skin thickening
[14; Figure 25E-11(A,B)]. The process is accompanied
by limited range of motion, particularly of the feet and
hands. The biopsy is identical to the changes observed
FIGURE 25E-10
Graft-versus-host disease (GVHD). Patients with chronic GVHD

FIGURE 25E-8 often have cutaneous manifestations. This patient demonstrates
the widespread nature of the disease which simulates both
Linear scleroderma. morphea and lichen sclerosus.
A B
FIGURE 25E-11
(A, B) Nephrogenic systemic fibrosis in a patient with acute renal failure who underwent a
magnetic resonance imaging study with gadolinium dialysis.
PUSTULAR CONDITIONS infliximab is useful. Pustular lesions of the palms and

soles are difficult to treat and can cause disability.
The following disease entities, characterized by pustular SAPHO syndrome is a rare disorder characterized
lesions, demonstrate substantial overlap. by synovitis, acne, pustulosis of the palms and soles,
Generalized pustular psoriasis is a rare phenomenon, hyperostosis of one of the bones of the chest wall, and
but pustular psoriasis localized to the palms and soles sterile osteitis (16). These patients may also have pso-
(Figure 25E-12) is relatively common. These diseases riasis vulgaris or accompanying inflammatory bowel
may be induced by various medications, including the disease. The synovitis may involve either peripheral or
withdrawal of systemic glucocorticoids in the case of axial joints. The osteitis is similar to chronic recurrent
generalized pustular psoriasis and the use of TNF antag- sterile osteomyelitis. The prevalence of human leuko-
onists in the case of palmoplantar pustular psoriasis cyte antigen (HLA)-B27 is increased among patients
(15). Generalized pustular psoriasis, a highly labile form with the SAPHO syndrome, leading some authorities
of psoriasis, can be accompanied by systemic symptoms. to classify this entity as a spondyloarthropathy. SAPHO
Control with oral retinoids, methotrexate, or possibly syndrome has considerable overlap with the other pus-
tular conditions discussed in this section, however, as
well as with the neutrophilic dermatoses discussed
above. The pathogenetic mechanisms of all of these
conditions remain incompletely defined. Treatment of
SAPHO is often difficult. Drugs that have been
reported to be effective in individual cases or small
case series include nonsteriodal anti-inflammatory
drugs (NSAIDs), colchicine, glucocorticoids, sulfasala-
zine, methotrexate, infliximab, and second generation
bisphosphonates.
The PAPA syndrome is the occurrence of sterile
pyogenic arthritis, pyoderma gangrenosum, and acne.
Usually the acne is nodulocystic. The differentiation of
this syndrome from SAPHO may be difficult.
Hidradenitis suppurativa is a disorder of apocrine
glands. Patients present with pustules and draining sinus
tracts in the axilla, under the breasts, within inguinal
folds, and on the buttocks. Women appear to be affected
more frequently than men. Hidradenitis may be associ-
FIGURE 25E-12 ated with Crohns disease in some patients. Oral antibi-
Palmoplantar pustulosisnote the crusts accompanied by both otics are frequently prescribed but often not fully
large and small pustules on the palms of this patient. effective. Oral isotretinoin is often suggested, but in this
authors opinion, it is rarely effective. Recent case

reports and case series have documented responses to
infliximab. Definitive therapy with surgical exenteration 25
of the involved areas is curative.
Acne fulminans is a severe form of acne that is
accompanied by systemic symptoms (17). It is explosive
in its onset and most often occurs in adolescent boys.
The face, chest, and upper back are the most common
sites. The lesions may begin as mild typical acne, but
they rapidly become markedly inflamed and coalesce
into painful and oozing friable plaques with hemor-
rhagic crusts. Systemic involvement includes fever,
arthralgia, myalgia, hepatosplenomegaly, and severe
prostration. Erythema nodosum may occur in some
patients with acne fulminans. Osteolytic bone lesions
have also been reported. There is no specific laboratory
abnormality associated with this process, but elevation FIGURE 25E-14
of the erythrocyte sedimentation rate, leukocytosis, and Livedoid vasculopathy (also known as atrophie blanche).
anemia may occur. Therapy with oral glucocorticoids
and isotretinoin is helpful. Oral dapsone has also been
utilized as an adjunctive therapy. Residual scarring is
common. Occasionally scurvy may masquerade as small vessel
vasculitis. Reintroduction of vitamin C into the diet
leads to resolution of the process.
MISCELLANEOUS Livedoid vasculopathy, also known as segmental
DERMATOLOGICAL CONDITIONS hyalinizing vasculopathy, livedoid vasculitis, atrophie
blanche, and livedo reticularis with summer ulcerations,
WITH POSSIBLE is a clinical entity manifested by painful ulcerations of
RHEUMATOLOGIC the distal legs, more commonly over the medial malleo-
lus (Figure 25E-14). This process is not an inflammatory
CONSEQUENCES disease. On biopsy, the characteristic change is fibrin
deposition within the vessel lumina. The process may
Scurvy, caused by vitamin C deficiency, frequently pres- represent an end result of a number of coagulation dis-
ents with purpura or ecchymoses and bone pain. It is orders, including cryofibrinogenemia, Factor V Leiden
more common in alcoholics. The purpuric lesions tend mutation, and other inherited thrombophilic conditions,
to be perifollicular (Figure 25E-13). Careful examina- and the antiphospholipid syndrome (18). Livedoid vas-
tion reveals corkscrew hairs that are also characteristic. culopathy may mimic vasculitis or stasis dermatitis clini-
cally. Therefore, a biopsy is helpful in directing the
evaluation. Therapy should include smoking cessation
and prevention of trauma, in addition to addressing any
underlying coagulation disorder. Various platelet inhib-
itors and anticoagulants have been reported to be effec-
tive in individual cases or small case series.
Granuloma annulare is a relatively common
cutaneous disease not generally associated with sys-
temic conditions. The findings of granuloma annulare
are flesh-colored or erythematous lesions that are
annular (Figure 25E-15) and may occur on any surface
of the body. The histopathology of granuloma annulare
is a necrobiotic granulomaessentially the same histo-
pathological finding that occurs in necrobiosis lipoidica
and rheumatoid nodules. Biopsies are frequently read
as rheumatoid nodules by general pathologists; patients
FIGURE 25E-13 are then referred inappropriately for rheumatologic
Scurvy. Perifollicular purpura with corkscrew hairs. (Courtesy of evaluations. Treatment of granuloma annulare with
Kenneth E. Greer, MD, Charlottesville, VA.) intralesional injections of triamcinolone acetonide in
Granuloma annulare on the dorsal hands. Acute, acral granuloma annulare. This patient had disease which
clinically mimicked Sweets syndrome, but the histopathology
demonstrated a necrobiotic granuloma.
dilute concentrations usually leads to resolution of the
disorder.
Two variants of granuloma annulare are worth men-
tioning: the subcutaneous variant (19) and a recently Cutaneous extravascular necrotizing granulomas are
described acute acral variant (20). Subcutaneous granu- known as the ChurgStrauss granulomas. The term pali-
loma annulare often presents on the feet or hands and saded neutrophilic and granulomatous dermatitis with
may be slightly tender (Figure 25E-16). Acute acral arthritis, rheumatoid papules, superficial ulcerating
granuloma annulare is a process associated with the rheumatoid necrobiosis, and interstitial granulomatous
sudden onset of tender acral erythematous lesions, dermatitis with arthritis have also been used to describe
usually on the hands and fingers (Figure 25E-17). The this entity (21). Whether this is a distinct entity is con-
acral variant, which often occurs in patients with a troversial and the exact relationship to arthritis has
history of various forms of arthritis, is managed with been questioned. Patients present with symmetrical,
topical glucocorticoids, oral antimalarial agents, oral annular, erythematous lesions, often favoring intertrigi-
dapsone, or (rarely) oral glucocorticoids. nous sites. Recently multiple drugs have been linked to
the development of interstitial granulomatous dermati-
tis, but even when a drug has appeared to trigger the
cutaneous disease, it is likely that the patient has an
underlying rheumatologic disease, particularly SLE,
RA, Wegeners granulomatosis, or the Churg-Strauss
syndrome. Treatment involves discontinuation of a drug
in an appropriate setting and treatment of the associ-
ated condition.
Lichen planus is a common cutaneous disease char-
acterized by pruritic, purple, polygonal papules and
plaques (Figure 25E-18). The surface scale, when exam-
ined closely demonstrates a reticulated pattern known
as Wickham striae. Common areas of involvement
include the wrists and mouth but any surface may be
involved. Erosive oral and/or genital disease may lead
to malignancy. Lichen planus is frequently associated
with hepatitis C. A variant of lichen planus is caused by
drugs and has occurred more commonly in patients
FIGURE 25E-16 treated with gold or penicillamine. Lichen planuslike
Subcutaneous granuloma annulare. This patient was misdiag-
lesions may be a manifestation of acute graft-versus-
nosed as having rheumatoid arthritis after her initial biopsy was host disease. The disease is self-limited but may be
interpreted as a rheumatoid nodule. treated with topical or systemic glucocorticoids.
25
A B
FIGURE 25E-18
Lichen planus lesions on the wrist (A) and in the mouth (B).
REFERENCES 11. Zulian F, Vallongo C, Woo P, et al. Localized scleroderma

in childhood is not just a skin disease. Arthritis Rheum
1. Callen JP. Miscellaneous disorders that commonly affect 2005;52:28732881.
both skin and joints. In: Sontheimer RD, Provost TT, eds. 12. Oyama N, Chan I, Neill SM, et al. Development of
Cutaneous manifestations of rheumatic diseases. 2nd ed. antigen-specific ELISA for circulating autoantibodies to
Philadelphia: Lippincott Williams & Wilkins; 2004:221 extracellular matrix protein 1 in lichen sclerosus. J Clin
241. Invest 2004;113:15501559.
2. Cohen PR, Kurzrock R. Sweets syndrome revisited: a 13. Donato ML, Feasel AM, Weber DM, et al. Scleromyx-
review of disease concepts. Int J Dermatol 2003;42:761 edema: role of high-dose melphalan with autologous stem
778. cell transplantation. Blood 2006;107:463466.
3. Jackson JM, Callen JP. Pyoderma gangrenosum. 14. Cowper SE, Boyer PJ. Nephrogenic systemic fibrosis: an
An expert commentary. Int J Dermatol 2006;41:916 update. Curr Rheumatol Rep 2006;8:151157.
918. 15. Sfikakis PP, Iliopoulos A, Elezoglou A, Kittas C, Stratigos
4. Walling HW, Snipes CJ, Gerami P, Piette WW. The rela- A. Psoriasis induced by anti-tumor necrosis factor therapy:
tionship between neutrophilic dermatosis of the dorsal a paradoxical adverse reaction. Arthritis Rheum 2005;52:
hands and sweet syndrome: report of 9 cases and compari- 25132518.
son to atypical pyoderma gangrenosum. Arch Dermatol 16. Suei Y, Taguchi A, Tanimoto K. Diagnostic points and
2006;142:5763. possible origin of osteomyelitis in synovitis, acne, pustu-
5. Brown TB, Fearneyhough PF, Burruss JB, Callen JP. losis, hyperostosis and osteitis (SAPHO) syndrome: a
Rheumatoid neutrophilic dermatitis in a woman with radiographic study of 77 mandibular osteomyelitis cases.
seronegative rheumatoid arthritis. J Am Acad Dermatol Rheumatology (Oxford) 2003;42:13981403.
2001;45:596600. 17. Mehrany K, Kist JM, Weenig RH, Witman PM. Acne
6. Requena L, Yus ES. Panniculitis. Part I. Mostly fulminans. Int J Dermatol 2005;44:132133.
septal panniculitis. J Am Acad Dermatol 2001;45:163 18. Hairston BR, Davis MDP, Pittelkow MR, Ahmed I. Live-
183. doid vasculopathy: further evidence for procoagulant
7. Requena L, Sanchez Yus E. Panniculitis. Part II. Mostly pathogenesis. Arch Dermatol 2006;142:14131418.
lobular panniculitis. J Am Acad Dermatol 2001;45:325 19. McDermott MB, Lind AC, Marley EF, Dehner LP. Deep
361. granuloma annulare (pseudorheumatoid nodule) in chil-
8. Requena L, Requena C. Erythema nodosum. Dermatol dren: clinicopathologic study of 35 cases. Pediatr Dev
Online J 2002;8:4. Pathol 1998;1:300308.
9. Bruce AJ, Bennett DD, Lohse CM, Rooke TW, 20. Brey NV, Malone J, Callen JP. Acute-onset, painful acral
Davis MD. Lipodermatosclerosis: review of cases evalu- granuloma annulare: a report of 4 cases and a discussion
ated at Mayo Clinic. J Am Acad Dermatol 2002;46: of the clinical and histologic spectrum of the disease. Arch
187192. Dermatol 2006;142:4954.
10. Ma L, Bandarchi B, Glusac EJ. Fatal subcutaneous pan- 21. Chu P, Connolly MK, LeBoit PE. The histopathologic
niculitis-like T-cell lymphoma with interface change and spectrum of palisaded neutrophilic and granulomatous
dermal mucin, a dead ringer for lupus erythematosus. dermatitis in patients with collagen vascular disease. Arch
J Cutan Pathol 2005;32:360365. Dermatol 1994;130:12781283.
CHAPTER 25

F. Hypertrophic Osteoarthropathy
MANUEL MARTINEZ-LAVIN, MD
Hypertrophic osteoarthropathy is characterized by a significant internal illness, often a pulmonary

abnormal proliferation of skin and bone at the distal malignancy or inflammatory disease of the
parts of the extremities. lung.
Clinical features include bulbous deformity of the Abnormal vascular endothelial growth factor
tips of the digits (conventionally known as expression may play a central role in the
clubbing) and periostosis of the tubular bones. pathogenesis of this condition.
The development of hypertrophic
osteoarthropathy may indicate the presence of
Hypertrophic osteoarthropathy (HOA) or acropachy is diogenic HOA frequently have circulating macrothrom-
a syndrome characterized by excessive proliferation of bocytes with distorted volume distribution curves. Such
skin and bone at the distal parts of the extremities. Its abnormalities concur with the notion that normally
most conspicuous feature is a unique bulbous deformity megakaryocytes rupture in the highly dichotomized pul-
of the tips of the digits, conventionally known as club- monary vascular bed. It has been proposed that in
bing (Figure 25F-1). In advanced stages, periosteal pro- patients with right-to-left shunts, large platelet frag-
liferation of the tubular bones and synovial effusions ments gain direct access to the systemic circulation and
become evident. The classification of HOA is shown in reach its most distal sites on axial streams. In the distal
Table 25F-1 (1). In most instances, HOA appears as a microcirculation abnormally large platelets interact
consequence of an internal illness, often localized to the with endothelial cells, leading to the release of growth
chest. Nevertheless, there are cases of primary HOA. factor(s) and the induction of acropachy (Figure 25F-2)
This subgroup affects mostly males and demonstrates a (3). The finding of elevated levels of von Willebrand
familial predisposition. factor antigen in HOA further supports the notion of
enhanced platelet/endothelial cell activation.
Vascular endothelial growth factor (VEGF) may be
PATHOLOGY AND involved in the pathogenesis of HOA. This growth
PATHOGENESIS factor, a potent angiogenic stimulus and osteoblast-
differentiation agent, is derived from platelets and
Clubbing develops as a result of edema and excessive induced by hypoxia. A variety of malignant tumors also
collagen deposition. In addition, endothelial cell activa- produce VEGF, fostering their uncontrolled growth.
tion and vascular hyperplasia are prominent features. People with primary HOA and HOA associated with
At the tubular bone level, there is vascular hyperplasia lung cancer have elevated levels of VEGF in their
with proliferation of the periosteal layers (2). plasma (2,4). Immunohistochemistry studies show
Any proposed scheme for the pathogenesis of HOA increased VEGF deposition in the stroma of clubbed
must explain how a group of diseases as diverse as those digits (5). Overproduction of VEGF may explain how
listed in Table 25F-1 could induce the unique connec- diverse hypoxic or neoplastic pathologies induce HOA,
tive tissue abnormalities of HOA. Cyanotic heart dis- and may also explain how diseases with prominent
eases are excellent models for studying the pathogenesis endothelial cell involvement, such as infective endocar-
of this syndrome, because practically all patients with ditis, Graves disease, or mesothelioma, lead to acro-
such conditions develop clubbing, and more than one pachy. More studies are needed to elucidate the
third display fully developed HOA. Patients with car- pathogenesis of HOA.
504
features. The increased volume of soft tissue molds the

fingernail into a watch-crystal convexity. The nailbed
rocks when palpated. Toes are also affected, but early 25
changes are more difficult to discern due to the normal
splaying of the toes. The digital index is a practical
bedside method to measure clubbing. With a string, the
circumference of each finger is measured at the nailbed
(NB) and at the distal interphalangeal joint (DIP). If
the sum of the 10 NB/DIP ratios is more than 10, club-
bing is most likely present (6).
When the complete features of HOA are evident,
bone thickening may be appreciated in areas of the
extremities not covered by muscles, such as ankles and
wrists. These areas can be tender to palpation. Effusions
FIGURE 25F-1 in large joints may be present but do not produce detect-
A clubbed finger (left) is compared with a normal finger. able synovial hypertrophy on examination. Range of
motion of the affected joint may be slightly decreased.
Arthrocentesis yields a clear, viscous fluid with few
inflammatory cells; the leukocyte count is typically less
than 1000 cells/mm3. These findings indicate that HOA
CLINICAL FEATURES does not cause inflammatory or proliferative synovial
disease, but rather the effusions are most likely a reac-
Many people with HOA are asymptomatic and unaware tion to the adjacent periostosis (7).
of the deformity of their digits (Figure 25F-1). However, Particular types of HOA are associated with pecu-
other patients, particularly those with pulmonary liar clinical findings. Thyroid acropachy (see Chapter
malignancies, suffer incapacitating bone pain (4). Char- 25B) is distinguished by an exuberant periosteal pro-
acteristically, this pain is deep-seated and often more liferation that principally involves the small tubular
prominent in the legs. bones of the hands and feet. In thyroid acropachy,
The diagnosis of HOA is based primarily on physical clubbing usually coexists with exophthalmos and pre-
examination and the finding of characteristic radiologic tibial myxedema. Other forms of HOA are localized to
TABLE 25F-1. CLASSIFICATION OF HYPERTROPHIC OSTEOARTHROPATHY.

DIGITAL CLUBBING
HYPERTROPHIC OSTEOARTHROPATHY
Secondary
Localized
Patent ductus
Primary Generalized Hemiplegia Aneurysm Infective arteritis arteriosus
Pulmonary Cardiac Hepatic Intestinal Mediastinal Miscellaneous
Cystic fibrosis Congenital cyanotic Cirrhosis Crohns disease Esophageal Graves disease
diseases carcinoma
Pulmonary fibrosis Infective endocarditis Carcinoma Ulcerative colitis Thymoma Thalassemia
Chronic infections Chronic infections Achalasia Diverse malignancies
Cancer: primary or metastatic Laxative abuse POEMS syndrome
Arterio-venous fistulae Polyposis Others
Mesothelioma Malignant tumors

506 MANUEL MARTINEZ-LAVIN
Megakar yocyte
Growth
factors
(VEGF?)
Large
fragments
Cancer
of the
lung
In tetralogy
Fibroblast
Growth
factor
(VEGF?)
Osteoblast Large
proliferation Endothelial platelet
Finger clubbing edema cell
periostosis
FIGURE 25F-2
The theoretical pathogenesis of hypertrophic osteoarthropathy.
one or two extremities. Such cases usually occur as a reach the extreme of cutis verticis gyrata, which is the
response to prominent endothelial injury to the most advanced stage of cutaneous hypertrophy. In
involved limb, for example, damage caused by aneu- addition, these patients often demonstrate glandular
rysms or infective endarteritis. Alternatively, they may dysfunction of the skin that is manifested as hyperhi-
be associated with patent ductus arteriosus and rever- drosis, seborrhea, or acne (7).
sal of the physiologic direction of blood flow. People
with primary HOA may display a generalized skin
hypertrophy called pachyderma (Figure 25F-3). This LABORATORY FEATURES
skin overgrowth roughens the facial features and can
AND IMAGING
There are no distinctive clinical laboratory test abnor-
malities associated with HOA. However, an array of
biochemical alterations that reflect the underlying illness
may be found. Longstanding clubbing produces a prom-
inent bone remodeling of the distal phalanges.
Periostosis evolves in an orderly manner, with sym-
metrical bone changes. Initially, periostosis affects the
distal parts of the lower extremities and then evolves in
a centripetal fashion (8). When mild it involves only few
selected bones (usually the tibia and fibula). Moreover,
periosteal apposition is limited to the diaphysis in mild
cases, and has a monolayer configuration [Figure 25F-
4(A)]. In contrast, severe periostosis affects all tubular
bones, spreads to the metaphyses and epiphyses, and
generates irregular configurations [Figure 25F-4(B)].
Typically, the joint space is preserved, and there are no
FIGURE 25F-3 erosions or periarticular osteopenia. Radionuclide bone
Generalized skin hypertrophy in hypertrophic osteoarthropathy, scanning is a sensitive method for demonstrating peri-
known as pachyderma. Note also the clubbed fingers. osteal involvement.
25
A B
FIGURE 25F-4
Radiograph of the bones of the distal lower extremities in hypertrophic osteoarthropathy in mild
(A) and severe (B) cases.
DIAGNOSIS cate infective endocarditis. Similarly, clubbing in a

patient with polyneuropathy of recent onset should lead
When HOA is fully expressed, the drumstick fingers to the suspicion of POEMS (polyneuropathy, organo-
are so unique that recognition poses no dilemma. The megaly, endocrinopathy, M-protein, and skin changes)
symptoms of HOA can be subtle. Nevertheless, in some syndrome (see Chapter 25B) (9).
patients with lung cancer, painful arthropathy may be
the initial manifestation, occurring before clubbing is
detectable. Such patients are sometimes misclassified as
TREATMENT
having an inflammatory arthritis. Patients with the exu-
Apart from the disfigurement, clubbing is usually
berant skin hypertrophy of HOA may be misdiagnosed
asymptomatic and does not require therapy. Painful
as having acromegaly.
osteoarthropathy generally responds to analgesics or
The diagnosis of HOA requires the combined pres-
nonsteroidal anti-inflammatory drugs. Several uncon-
ence of clubbing and periostosis of the tubular bones
trolled case reports have described that pamidronate,
(1). Synovial effusion is not essential for the diagnosis.
an inhibitor of osteoclastic bone resorption, relieves the
An important feature that distinguishes HOA from
pain in cases of resistant painful osteoarthropathy (10).
inflammatory types of arthritis is that in HOA the
Interestingly, pamidronate and other biphosphonate
pain involves not only the joint, but also the adjacent
compounds are potent VEGF inhibitors. Correction of
bones.
a heart defect, removal of a lung tumor, or successful
If a previously healthy individual develops any of the
treatment of endocarditis produce rapid regression of
manifestations of HOA, a thorough search for underly-
the syndrome.
ing illness should be undertaken. Primary HOA should
be diagnosed only after careful clinical scrutiny fails
to disclose any of the internal illnesses listed in Table REFERENCES
25F-1. In an individual with a previous diagnosis of
pulmonary fibrosis, cystic fibrosis, liver cirrhosis, or 1. Martnez-Lavn M, Matucci-Cerinic M, Pineda C, et al.
inflammatory bowel disease, the development of club- Hypertrophic osteoarthropathy: consensus on its defini-
bing is usually a poor prognostic sign. Clubbing in a tion, classification, assessment and diagnostic criteria.
person with known rheumatic heart disease may indi- J Rheumatol 1993;20:13861387.
508 MANUEL MARTINEZ-LAVIN
2. Silveira L, Martnez-Lavn M, Pineda C, Navarro C, 6. Vazquez-Abad D, Martnez-Lavn M. Digital clubbing: a

Fonseca MC, Nava A. Vascular endothelial growth factor numerical assessment of the deformity. J Rheumatol 1989;
in hypertrophic osteoarthropathy. Clin Exp Rheumatol 16:518520.
2000;18:5762. 7. Martnez-Lavn M, Pineda C, Valdz T, et al. Primary
3. Vazquez-Abad D, Martnez-Lavn M. Macrothrombo- hypertrophic osteoarthropathy. Semin Arthritis Rheum
cytes in the peripheral circulation of patients with cardio- 1988;17:156162.
genic hypertrophic osteoarthropathy. Clin Exp Rheumatol 8. Pineda C, Fonseca C, Martnez-Lavn M. The spectrum of
1991;9:5962. soft tissue and skeletal abnormalities in hypertrophic
4. Olan F, Portela M, Navarro C, Gaxiola M, Silveira V, osteoarthropathy. J Rheumatol 1990;17:773778.
Martinez-Lavin M. Circulating vascular endothelial 9. Martnez-Lavn M, Vargas AS, Cabr J, et al. Features of
growth factor concentrations in a case of pulmonary hypertrophic osteoarthropathy in patients with POEMS
hypertrophic osteoarthropathy. Correlation with disease syndrome. A metaanalysis. J Rheumatol 1997;24:2267
activity. J Rheumatol 2004;31:614616. 2268.
5. Atkinson S, Fox SB. Vascular endothelial growth factor 10. Guyot-Drouot MH, Solau-Grvais E, Cortet B, et al.
(VEGF)-A and platelet-derived growth factor (PDGF) Rheumatologic manifestations of pachydermoperiostosis
play a central role in the pathogenesis of digital clubbing. and preliminary experience with bisphosphonates. J
J Pathol 2004;203:721728. Rheumatol 2000;27:24182423.
CHAPTER 26
Complex Regional Pain Syndrome

GEOFFREY LITTLEJOHN, MD, MPH, MBBS[HON], FRACP, FRCP(EDIN)
Complex regional pain syndrome is an uncommon Current emphasis on pain sensitization mechanisms
but long recognized and high-impact regional and earlier clinical recognition is facilitating manage-
musculoskeletal pain disorder. ment and improving outcomes.
Complex regional pain syndrome (CRPS) is a disorder had two or more features of CRPS at 9 weeks and 62%
of the musculoskeletal system that primarily relates to still had residual features at 6 months (3). Between 1
abnormal functioning of the sensory, sympathetic, and in 20 and 1 in 200 people presenting to a trauma unit
motor nerves. The clinical picture is varied, but the develop CRPS. Before intense mobilization of patients
main components are those of regional pain and tender- with myocardial infarction and hemiplegia became stan-
ness disproportionate to any inciting event and com- dard treatment, it was estimated that between 5% and
monly coupled with vasomotor (swelling and color 20% would develop CRPS (4,5).
change), sudomotor (sweating), or motor abnormality
(stiffness, weakness, tremor, or dystonia). There are a
number of clinical presentations of CRPS, with milder CLINICAL FEATURES
forms being fairly common and having a good progno-
sis, but less common and more severe CRPS often Trauma precedes CRPS in around 50% of cases. Another
responding poorly to treatment and being more persis- 25% is associated with a variety of miscellaneous medical
tent. Pain, emotional distress, and disability character- disorders. These include diseases of the central nervous
ize this disorder. system, such as hemiplegia, cerebral tumor, or meningi-
tis, or disorders of the peripheral nerves, such as nerve
injury from herpes zoster, nerve root impingement, or
EPIDEMIOLOGY peripheral neuropathy. Medications, particularly barbi-
turates and isoniazide, as well as pregnancy, metastatic
Criteria to define CRPS continue to evolve (1). Cur- tumors, and prolonged immobilization of a limb, are
rently, most CRPS may be subclassified as CRPS type also associated with CRPS. About 25% of CRPS occurs
I, formerly called reflex sympathetic dystrophy, but when for no apparent reason. In this setting there may be a
major nerve damage triggers the syndrome (around background history of overt or subtle psychosocial dis-
10% of cases) it is subclassified as CRPS type II, for- tress (6). Distress-associated psychological factors are
merly called causalgia. Both types are clinically identi- also seen in individuals with the specific triggering factors
cal. CRPS occurs in all races and geographical regions. named above. The link between psychological distress
It affects both sexes and may occur at any age, but most and the onset of CRPS remains unclear as the persistent
commonly between 40 and 60 years. In the adult pre- pain of the disorder may result in emotional distress as
sentation men slightly outnumber women but in the part of the individuals adjustment to the disorder.
adolescent age group females predominate. Triggering Whether cause or effect, emotional distress is a charac-
factors associate with different age and sex distribution. teristic clinical feature of CRPS.
For instance, CRPS following fall and fracture of the Chronic regional pain syndrome usually affects a
distal radius often occurs in osteoporotic women in the distal limb component, for example, patella, digit, hand,
sixth decade. or foot, with the key symptom of being pain out of
The prevalence of CRPS is unclear (2). Minor forms proportion to any tissue damage in the region (7). The
are common after injury and might blend with clinical majority have persistent spontaneous pain often
features which are part of the normal response to injury. described as tearing or burning in quality. Lancinating
Of 109 unselected patients with Colles fracture, 25% pain occurs in one third and activity-induced pain is
509
510 GEOFFREY LITTLEJOHN
little used due to poor correlation with mechanisms and

outcomes (8).
Variants of CRPS include transient regional osteo-
porosis, which often affects the hip. Fairly rapid onset
of pain and restricted movement, without cutaneous
features, are characteristic and a combination of appro-
priate clinical assessment, plain x-ray, bone scan, and
magnetic resonance imaging (MRI) are usually diagnos-
tic (9). The duration of symptoms is shorter, possibly
because mobilization is easier, and there is usually an
absence of precipitating trauma. Good outcome is
expected but there is a propensity for recurrent epi-
sodes as well as involvement of multiple regions, often
termed regional migrating osteoporosis.
FIGURE 26-1 LABORATORY FEATURES

Chronic regional pain syndrome (CRPS) affecting left hand
showing diffuse swelling, dusky discoloration, and shiny skin. There are no specific abnormal features on investigation
and clinical features remain the most important con-
tributors to diagnosis (10). Acute-phase reactants are
present in all. Many describe the painful area as numb. not elevated. Routine radiological imaging in the first
Pain is associated with abnormal cutaneous sensitivity, weeks to months may show patchy osteopenia affecting
manifesting as allodynia (whereby otherwise innocuous adjacent bones in the involved region or diffuse osteo-
stimuli, such as touch, induce pain), and hyperalgesia penia later. This has only moderate diagnostic predic-
(whereby pain perception is increased to a given painful tive value. Fine-detailed radiography will show some
stimulus, such as a pinprick). Unless there is a triggering degree of cortical bone resorption in around 80%. MRI
nerve lesion, neurological examination of the painful shows more clear-cut abnormality with regional or
and abnormally tender region will only show variable diffuse bone loss and increased T2 bone signal affecting
dysesthesia in a non-neuroanatomical distribution. many adjacent bony areas. Three-phase technetium
The most severe discomfort and allodynia is present bone scans are abnormal in around 75% of patients with
distally, but the majority have abnormal tenderness established CRPS, with regional change in blood flow in
present in the entire quadrant of the involved limb, the early phase and increase in bone uptake in the late
including the low back or neck, as the case may be. The phase (Figure 26-2) (11). Diminished flow and uptake
relevant spinal region is often stiff. Frozen shoulder
may be a CRPS variant. In around 25% of cases, the
opposite limb also develops similar but less marked
clinical features.
Swelling of the involved area is common, usually
diffuse and often associated with reticular or lividoid
appearance over the skin of the involved part (Figure
26-1). Alteration in peripheral sympathetic tone may
lead to other changes in skin color (cyanotic, pale, or
red). Temperature may be decreased or increased, as
may be sweatingthere is no specific pattern. The distal
involved limb of adolescents with CRPS tends to be
cooler and those of adults warmer, but both may have
temperature fluctuation over days and weeks. Finally,
many patients have disorders of muscle function that
might include peripheral weakness, proximal co-con-
traction and tightness, dystonia, spasm, tremor, or
myoclonus. Tendon reflexes are usually normal or brisk.
As time passes trophic changes may occur, but they are FIGURE 26-2
uncommon. Changes include unilateral differences in Technetium bone scan of patient with left forearm/hand chronic
growth (more or less) of hair or nails and thinning of regional pain syndrome (CRPS) showing altered (increased) blood
skin. A staging system for the progress of CRPS is now flow into involved part in early phase of study.
C H A P T E R 2 6 C O M P L E X R E G I O N A L P A I N S Y N D R O M E 51 1
are more commonly seen in children and adolescents Thus, movement and touch, which otherwise would be
than in adults. Thermography may show significant innocuous, activate pain and account for the key feature
changes compared to the unaffected side. of allodynia. The pain transmission neurons are modu-
lated by other inputs, including descending pathways
from the mid-brain which involve the neurotransmitters
PATHOPHYSIOLOGY norepinenephrine and serotonin. These pathways link
in turn to higher cortical centers, including those that
The exact cause of CRPS remains unclear. However, relate to the emotional part of the brain. Other brain 26
the key pathophysiological abnormality lies in the changes in CRPS include expansion of pain-related
change in function of peripheral sensory, autonomic, limb areas, implying plasticity and significant functional
and motor nerves in the symptomatic region. This changes within the cerebral cortex (12,13).
relates to both peripheral and central mechanisms. Where there is a painful triggering cause for the
Increased activity in the two afferent nociceptor fiber CRPS it is likely that the nociceptive pain input to
types (the small diameter nonmyelinated C-fibers and the dorsal horn will activate the sensitization process.
myelinated A-delta fibers), the proprioception afferents The resultant emotional response to the pain and the
(the large myelinated A-beta-fibers), and the sympa- injury predicament may both increase sympathetic tone
thetic efferents appear to be mediators of many of the and also impact on spinal cord sensitization through a
peripheral features (Table 26-1). change in spinal cord pain modulation, as described
Enhanced sympathetic fiber activity, likely through above. Thus, a mixture of peripheral and central inter-
release of norepinephrine will promote sensitization of actions, of differing degrees in different patients, may
peripheral nociceptors, decreasing threshold to mechan- sensitize the spinal cord. The resultant cascade of down-
ical and chemical stimuli. This may result in the hyper- stream events leads to the typical clinical features.
algesia. In a minority subset of patients with CRPS,
blockage of sympathetic nervous system inputs to the
painful area will significantly modify clinical features, TREATMENT
including pain. Release of proinflammatory neuropep-
tides, such as substance P, by activated C-fibers will Appropriate management of CRPS requires early diag-
likely contribute to regional neurogenic inflammation nosis. The key clinical predictors for the problem are
with increase in blood flow, edema, and other features regional pain occurring in an emotional context, partic-
such as synovitis and regional osteoporosis. The sensory ularly after injury. Pain which seems out of keeping with
peripheral nerves link to deeply placed pain transmis- the original injury, particularly where it becomes more
sion neurones located in the dorsal horn. In CRPS there diffuse and persistent, coupled with swelling and vaso-
is increased spontaneous activity of these neurones, motor change are the usual early features. Not all people
called central sensitization. As a result of this process get all components of the syndrome. In others, the origi-
the large myelinated afferent A-beta fibers, which can nal injury triggering the problem may still be present
also access these neurons, will now translate sensory and might require independent treatment and investiga-
mechanoreceptor function inputs into pain sensation. tion. Preventive strategies thus include identification of
clinical situations where this syndrome has been shown
to be common. Early mobilization after myocardial
TABLE 26-1. MECHANISMS OF CHRONIC REGIONAL infarction, cerebrovascular accident, hand surgery, or
PAIN SYNDROME CLINICAL FEATURES. mild peripheral injury is essential. Appropriate reassur-
FEATURE MECHANISM ance and explanation of all patients in the post-trau-
matic setting is a part of routine treatment. Addressing
Spontaneous pain Peripheral nociceptor sensitization anxiety and sleep disturbance with explanation, physi-
Allodynia, movement Mechanoreceptor input to sensitized
cal therapy, or medication is essential (14).
dorsal horn transmission neuron Chronic regional pain syndrome is a pain syndrome
and hence holistic management is required. This should
Swelling Neuropeptide release from C-fibers, include a team of individuals, including relevant family
sympathetic neural effects
members and health professionals, which could include
Sudomotor changes an occupational therapist, physiotherapist, psycholo-
gist, and doctor, among others. Patient education about
Vasomotor changes
the nature of the problem and the expected good prog-
Bone, synovial changes Neuropeptide and sympathetic effects nosis is essential.
In milder CRPS, particularly in children, exercise
Dystrophy Altered neural input to dermal
structures programs that include hydrotherapy can be very helpful.
To achieve good exercise, adequate analgesia may be
512 GEOFFREY LITTLEJOHN
TABLE 26-2. MANAGEMENT PRINCIPLES OF inconsistent or lacking. There is little evidence to suggest
CHRONIC REGIONAL PAIN SYNDROME. specific benefits from NMDA-receptor antagonists,
opioids, or nonsteroidal anti-inflammatory agents,
Anticipate high-risk situations
although these and other potentially neuromodulating
Ensure accurate diagnosis and careful explanation drugs are often used empirically (17). Bisphosphonates
Indicate expected good outcome
may help prevent bone loss and help pain (18,19). Cal-
citonin, alpha blockers (prazocin), beta blockers (pro-
Identify and manage psychosocial stressors panolol), or calcium channel blockers (nifedipine) may
Seek psychological advice sometimes help. Appropriate trials for all these agents
Encourage activity are lacking. In severe cases of this disorder, advice from
Involve physical therapist a pain management center may be required and, rarely,
more invasive neuromodulation therapies, such as
Plan resumption of normal activities
dorsal horn stimulation, have been used (20).
Provide analgesia (acetaminophen, NSAIDs, opioids) Response to treatment in CRPS is unpredictable.
Generally, earlier diagnosis and intervention result in
Consider transcutaneous nerve stimulation, hydrotherapy
better outcomes. Most patients have CRPS of mild-to-
Consider topical agents (capsaicin, DMSO) moderate severity that responds well to treatments.
Use tricyclic drugs early (e.g., low-dose mid-evening
Adolescents are typical of this group (14). Some patients
amitriptyline) have more severe and persistent symptoms with resul-
tant high impact on activities of daily living. A positive
Trial of other drugs, more so in adults approach to treatment outcomes is appropriate for the
Oral corticosteroids, pregabalin, clonidine, bisphosphonates,
many others
majority (Table 26-2).
Review response each 2 to 4 weeks; adjust therapy if not

improving
Consult anesthesiologist/pain management team

REFERENCES
Sympathetic nerve blocks
Other strategies 1. Harden RN, Bruehl SP. Diagnostic criteria: the statistical
derivation or the four criterion factors. In: Wilson PR,
Use various combinations of above according to response Stanton-Hicks M, Harden RN, eds. CRPS: current diag-
nosis and therapy. Seattle: IASP Press; 2005:4579.
ABBREVIATIONS: DMSO, dimethylsulfoxide; NSAIDs, nonsteriodal anti-inflam- 2. Wilson P, Bogduk N. Retrospection, science and epidemi-
matory drugs.
ology of CRPS. In: Wilson PR, Stanton-Hicks M, Harden
RN, eds. CRPS: current diagnosis and therapy. Seattle:
required with the use of oral analgesics ranging from IASP Press; 2005:1941.
acetaminophen to more potent opioid medication at 3. Atkins RM, Duckworth T, Kanis JA. Algodystrophy
appropriate dosage for the patients age. Where CRPS following Colles fracture. J Hand Surg [Br] 1989;14:161
occurs in the context of medicolegal and similar safety- 164.
net deliberations, these need to be addressed as quickly 4. Kozin F. Reflex sympathetic dystrophy syndrome. Bull
Rheum Dis 1986;36:18.
as possible as they may act as significant stressors and
5. Davis SW, Petrillo CR, Eichberg RD, et al. Shoulder-
negate response to otherwise appropriate therapy. hand syndrome in a hemiplegic population: a 5-year ret-
The role of sympathetic blocks remains unclear (15). rospective study. Arch Phys Med Rehabil 1977;58:353
In some patients temporary interruption of the sympa- 356.
thetic efferent nerve supply to the symptomatic region 6. Geertzen JH, de Bruijn-Kofman AT, de Bruijn HP, et al.
gives benefit. There are many ways to produce nerve Stressful life events and psychological dysfunction in
block and an anesthesiologist or pain management team complex regional pain syndrome type I. Clin J Pain 1998;
approach is required. 14:143147.
Medication approaches include the use of low-dose 7. Littlejohn G. Complex regional pain syndrome [algodys-
tricyclic medications, such as amitriptyline in doses of trophy, reflex sympathetic dystrophy syndrome]. In:
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book of Rheumatology. 3rd ed. Oxford: Oxford Medical
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Publications; 2004:11951200.
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such as prednisone 25 to 50 mg per day over a few drome: present status as a diagnostic and therapeutic
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CRPS (16). 9. Toms AP, Marshall TJ, Becker E, et al. Regional migra-
Membrane-stabilizing drugs, such as gabapentin or tory osteoporosis: a review illustrated by five cases. Clin
pregabalin, may have benefit, but controlled trials are Radiol 2005;60:425438.
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10. Rommel O, Habler H-J, Schurmann M. Laboratory tests 16. Kozin F, McCarty DJ, Sims J, et al. The reflex sympathetic
for complex regional pain syndrome. In: Wilson PR, dystrophy syndrome. I. Clinical and histologic studies:
Stanton-Hick M, Harden RN, eds. CRPS: current diagno- evidence for bilaterality, response to corticosteroids and
sis and therapy. Seattle: IASP Press; 2005:139159. articular involvement. Am J Med 1976;60:321331.
11. Shehab D, Elgazzar A, Collier BD, et al. Impact of three- 17. Quisel A, Gill JM, Witherell P. Complex regional pain
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CHAPTER 27
Sarcoidosis
EDWARD S. CHEN, MD
Systemic inflammatory disorder with noncaseating organ involvement, confirmatory biopsy, and
granulomatous inflammation in affected organs, response to therapy.
commonly involving the lungs, eyes, skin, joints, When treatment is indicated, glucocorticoids remain
lymph nodes, and upper respiratory tract. the only recognized effective therapy for active
Diagnosis attained via consensus between the clinical sarcoidosis.
presentation and natural history, pattern of major
Sarcoidosis is a systemic inflammatory disorder charac- Genetic and Familial Associations

terized by the presence of noncaseating granulomatous
inflammation in affected organs (1). The etiology of
in Sarcoidosis
sarcoidosis remains undetermined, the clinical manifes- Reports of families with more than one case of sarcoid-
tations of this disease are protean, and a diagnosis of osis support a genetic basis for this disease. The recently
sarcoidosis is often made by the exclusion of other pro- completed multicenter study in the United StatesA
cesses. What helps distinguish sarcoidosis from other Case Control Etiologic Study of Sarcoidosis (ACCESS)
systemic disorders is a consideration of clinical presen- estimated the relative risk for sarcoidosis to be
tation and natural history, confirmatory biopsy, and approximately 5 among first-degree relatives of patients
appropriate response to therapy. Although this disease with sarcoidosis (8). In contrast to the higher annual
most commonly affects the lungs, virtually any part of incidence of sarcoidosis among African Americans
the body may be affected, and the presence and behav- (35.5 per 100,000) compared with Caucasians (10.9 per
ior of characteristic extrapulmonary manifestations 100,000) (8), the relative risk of sarcoidosis among first-
may assist in supporting a diagnosis of sarcoidosis. degree relatives of Caucasian patients may be sub-
stantially higher than that of first-degree relatives of
African-American patients.
EPIDEMIOLOGY Many genetic associations have linked sarcoidosis
with genes within the major histocompatibility complex
The worldwide prevalence varies widely and has been (MHC) locus (9). Most recently, the novel gene BTNL2
reported to be 1 to 10 cases per 100,000 population in a (butyrophilinlike) (2) has been associated with sarcoid-
diverse array of countries (Denmark, Belgium, Japan, osis in a genomewide linkage analysis using a cohort of
Korea, Czechoslovakia). In Sweden, for reasons that Caucasian patients (10). This finding was confirmed in
are not clear, the prevalence is estimated to be between a separate linkage analysis using a cohort of African-
60 to 80 per 100,000 (2,3). In the United States, the American patients from the Sarcoidosis Genetic
prevalence of sarcoidosis has been estimated to be 10 Analysis (SAGA) consortium (11,12).
to 40 per 100,000. Studies using mass screening through
chest radiography identify a significant number of
asymptomatic patients with sarcoidosis (4,5). Other
methods of case detection, for example, autopsy reports, CLINICAL FEATURES
generally conclude even higher rates of disease (6,7).
Sarcoidosis tends to be diagnosed in younger adults Sarcoidosis typically involves more than one organ. The
(ages 2040) although a second peak may be appreci- frequency of involvement by organ system is shown
ated in Caucasian women over age 50. In the United in Table 27-1. Alternative diagnoses must always be
States, the highest incidence of sarcoidosis is observed excluded when considering rare and unusual presenta-
in young African-American women. tions of sarcoidosis (13).
514
C H A P T E R 2 7 S A R C O I D O S I S 51 5
TABLE 27-1. CLINICAL FEATURES OF SARCOIDOSIS. occur either at rest or with activity, may be related to
the presence of bulky mediastinal adenopathy. Most
FREQUENCY OF CLINICALLY
patients with mediastinal adenopathy, however, do not
ORGAN SYSTEM RELEVANT DISEASE (%)
experience chest pain. The chest pain does not respond
Lung 7090 well to glucocorticoids, and the exclusion of cardiac,
gastroesophageal, and musculoskeletal etiologies is
Skin 2030
important.
Sinus and upper respiratory tract 510 Pulmonary hypertension is a rare complication (<5%)
of pulmonary sarcoidosis, usually found in patients with
Eye 2030
advanced lung disease (stage III or IV). Pulmonary
Musculoskeletal 1020 hypertension is associated with higher rates of mortal-
Abdominal 1020
ity. As with atypical chest pain, other potential con- 27
tributors to pulmonary hypertension, for example,
Hematological 2030 sleep apnea and thromboembolic disease, should be
excluded.
Salivary/parotid 510
Cardiac 510
Chronic Cutaneous Sarcoidosis
Neurological 510
Skin lesions of various appearances may occur in up to
one third of patients with sarcoidosis. The most common
sarcoidosis skin lesions are hyperpigmented nodules,
violaceous plaques, hypopigmented macules, and sub-
cutaneous nodules (Figure 27-1). Such lesions most
Acute Sarcoidosis commonly occur over the extensor surfaces of the arms
Two acute presentations associated with eponyms are and legs and tend to resolve with scarring and retrac-
worth noting. First, Lfgrens syndrome consists of tion. Lupus pernioa confusing name because the
fever, erythema nodosum, bilateral hilar adenopathy, condition has nothing to do with systemic lupus
symmetric polyarthritis, and uveitis. Lfgrens syn- erythematosusrefers to a particular type of sarcoid-
drome is more common among Scandinavians. In most osis lesion that occurs on the face and scalp. Lupus
patients, the erythema nodosum and arthritis resolve pernio lesions (Figure 27-1) appear as violaceous
after several weeks, often without specific therapy. plaques found on the nose, nasal alae, malar areas,
Nonsteriodal anti-inflammatory drugs (NSAIDs) or eyelids, hairline, and scalp. They are indolent, but often
low-dose glucocorticoids may be necessary in some difficult to treat.
patients. Once resolved, Lfgrens syndrome recurs in
less than 30% of cases (14). Sinuses and Upper
Second, lacrimal and salivary gland involvement
causing glandular enlargement and the sicca syndrome Respiratory Tract
may be a feature of an acute presentation of sarcoidosis, Upper respiratory tract disease is common in sarcoid-
known as Heerfordts syndrome (uveoparotid fever). osis. Symptoms include severe nasal congestion and
Heerfordts syndrome is a constellation of fever, granu- sinus pain. Hoarseness and stridor requires prompt
lomatous inflammation of the lacrimal and parotid evaluation by an otolaryngologist to document laryn-
glands, uveitis, bilateral hilar adenopathy, and cranial geal involvement. A saddle-nose deformity may result
neuropathies. from chronic disease or repeated surgical interventions.
Mucocutaneous involvement is associated with other
Pulmonary Sarcoidosis indolent manifestations, such as lupus pernio.
Lung involvement is detectable through chest radio-

graphs in up to 90% of sarcoidosis patients. The most
Ocular
common symptoms include dyspnea and dry cough. A significant percentage of patients has ocular involve-
Sputum production and hemoptysis are associated with ment. Nodular sarcoidosis lesions can involve all major
fibrocystic pulmonary sarcoidosis and bronchiectasis. compartments of the eye. Granulomatous conjunctivitis
The physical examination is often unremarkable, with and conjunctival nodules are common findings that are
wheezes or crackles heard in less than 20% of sometimes accessible for biopsy. Intraocular sarcoidosis
patients. occurs more frequently in the anterior segment and can
A minority of patients may present with atypical result in nodules on the pupillary margin, the surface of
chest pain. The etiology of this chest pain, which may the iris, and the trabecular meshwork. Granulomatous
516 EDWARD S. CHEN
A B
FIGURE 27-1
Chronic cutaneous sarcoidosis. This manifestation of sarcoid-

osis can occur with a variety of appearances and include
hyperpigmented nodular lesions (A) and hypopigmented
macules (B). Cutaneous lesions most commonly occur over
the extensor surfaces of the arms and legs and tend to
resolve with scarring and retraction. Violaceous nodular
lesions of lupus pernio are often indolent and more difficult
to treat than other sarcoidosis skin lesions (C). (Figure 27-C,
Adrienne Rencioc, MD, PhD, DermAtlas; http://www.
C DermAtlas.org.)
uveitis of the anterior chamber can lead to keratic Musculoskeletal

precipitates on the posterior surface of the cornea
Joint
which, on slit-lamp examination, have the appearance
of mutton-fat droplets. Intermediate uveitis can lead As noted, frank arthritis tends to occur in patients with
to suspended snowball or string of pearl vitreous acute presentations of sarcoidosis (Lfgren syndrome).
opacities, also characteristic of sarcoidosis. Posterior Arthralgias occur commonly in patients with chronic
segment uveitis is often associated with superficial active sarcoidosis. Chronic sarcoid arthritis is a rare
candle wax exudates and deeper chorioretinal lesions manifestation (<1%) that can result in joint deformities,
that may require fluorescein angiography for detection. and is associated with other chronic manifestations such
Posterior uveitis can be associated with neurological as cutaneous sarcoidosis (15). Arthrocentesis reveals
involvement, that is, optic neuritis, in up to one quarter mild elevations in white blood cell counts (2505000/
of cases, which may be difficult to distinguish from pos- mL) with a mononuclear cell predominance. Synovial
terior uveitis. Both kinds of posterior eye involvement biopsy may reveal noncaseating granulomatous inflam-
can result in abrupt blindness. Rare extraocular mani- mation. Frank tenosynovitis and periarticular inflam-
festations include involvement of the lacrimal gland, mation occur less frequently than arthralgias or arthritis,
tear duct system (dacrocystitis), ocular orbit (often uni- but periarthritis (inflammation around a joint rather
lateral), cornea, and scleritis. The range and potentially than in it, sometimes difficult to discern from true syno-
insidious nature of ocular findings in sarcoidosis make vitis) is well described in sarcoidosis. Other articular
regular ophthalmologic evaluations an important part manifestations of sarcoidosis would include dactylitis,
of care. characterized by a violaceous swelling involving the
granulomatous hepatitis may progress to cirrhosis,

however, particularly if severe and left untreated (17).
The constellation of hepatosplenomegaly, abdominal
adenopathy, hepatosplenomegaly, and hypercalcemia
(and often bone marrow involvement) is often referred
to as abdominal sarcoidosis.
Involvement of the gastrointestinal tract is rare. It is
often associated with pain and dysmotility and does not
respond well to glucocorticoids. In patients where this
is the sole or principal manifestation of sarcoidosis, then
other causes of inflammatory bowel disease (Crohns
disease, ulcerative colitis) should be excluded. 27
FIGURE 27-2
Other Important Manifestations
Osseous sarcoidosis. A 45-year-old woman with a 2- to 3-year
history of cough, fevers, exertional dyspnea, and recurrent A wide range of hematological manifestations may be
swelling and stiffness in both hands. A diagnosis of sarcoidosis found in up to one third of patients with sarcoidosis
was established by bronchoscopy. This plain film of the hand
(18). Peripheral adenopathy occurs commonly at time
reveals multiple punched-out lesions that are characteristic of
osseous sarcoidosis. (Johns Hopkins Arthritis Website, http:// of disease presentation, and bulky adenopathy may
www.hopkins-arthritis.org., S. Levine, MD and W. Scott, MD.) persist in ~10% of cases. Massive splenomegaly may
be present in 5% of cases. Anemia, lymphopenia, and
leucopenia may be observed in 30% to 50% of all cases
second or third fingers, sacroiliitis, and bilateral heel and is more common than thrombocytopenia. A poly-
pain. clonal gammopathy is also frequently seen (~25%) in
many patients with active sarcoidosis. Common vari-
able immunodeficiency (CVID) should be suspected in
Bone
patients who lack elevations in serum globulin fraction
Cystic, punched-out lesions and lacey reticulations are or develop an increased frequency of infections, both of
commonly observed on plain radiographs or other which are unusual in sarcoidosis (19).
imaging studies, often as incidental findings (Figure Cardiac sarcoidosis is a rare but important manifesta-
27-2). Such lesions, typically located in the bones of the tion that can lead to heart block, malignant arrhythmias,
hands and feet, can also be found in the skull and ver- and cardiomyopathy. Autopsy series suggest that the
tebrae. Lesions involving the pelvis may be associated incidence of cardiac sarcoidosis may be as high as 25%,
with pain that mimics sacroiliitis (16). Bone biopsies but clinical diagnoses of this condition are made in
may be necessary in osseous sarcoidosis to exclude <10% of patients. Endomyocardial biopsy detects gran-
infections or cancers that may result in similar radio- ulomatous inflammation in less than 25% of cases (20).
graphic findings. The diagnosis is frequently rendered indirectly in a
patient with biopsy-proven sarcoidosis at other sites and
a compatible myocardial imaging study, such as nuclear
Myositis medicine stress test, cardiac MRI with gadolinium con-
Random muscle biopsies may reveal granulomas in trast, or positron emission tomography (PET).
50% to 80% of cases, but muscle involvement in sar- Presentations of neurosarcoidosis can be placed into
coidosis is often asymptomatic. Muscle inflammation three major groups. The most common form would be
can also be detected incidentally by radiographic imag- neuropathies involving cranial nerves II (optic neuritis),
ing using gallium scanning and magnetic resonance V, VII, IX, or XII. Cranial neuropathies, usually associ-
imaging (MRI). Glucocorticoid-induced myopathy ated with an aseptic basilar meningitis, tend to recur
should be considered in patients who develop acute- intermittently. A second presentation of neurosarcoid-
onset weakness following the initiation of treatment. osis is encephalopathy or myelopathy associated with
either a mass or an enhancing lesion on MRI. Such
patients benefit from prolonged courses of immuno-
Abdominal suppression. Finally, the third presentation of neuro-
Granulomatous inflammation may be detected in more sarcoidosis is peripheral neuropathy. This complication
than 50% of liver biopsies in sarcoidosis, but clinically is potentially disabling and often unresponsive to gluco-
significant liver disease is present in not more than 10% corticoids. A small fiber neuropathy has been impli-
of all cases. Elevated liver enzymes often resolve spon- cated recently as a significant cause of chronic pain and
taneously or with therapy with glucocorticoids. Chronic fatigue in sarcoidosis (21).
518 EDWARD S. CHEN
RADIOGRAPHIC FEATURES LABORATORY FEATURES

Chest radiographs detect abnormalities in ~ 90% of all Routine bloodwork consisting of comprehensive meta-
patients with sarcoidosis (22). Chest radiograph abnor- bolic panel and complete blood count is useful to screen
malities are assigned a category (stage) according to the for abnormalities (renal function, kidney function,
Scadding system: 0, normal; I, bilateral hilar lymphade- anemia, lymphopenia, hypercalcemia, hypergamma-
nopathy (BHL); II, BHL + interstitial infiltrates; III, globulinemia) associated with extrapulmonary sarcoid-
interstitial infiltrates only; IV, fibrocystic lung disease osis. No biomarkers are useful in predicting outcomes
(Figure 27-3). Computed tomography scans of the chest or guiding treatment decisions. Serum levels of angio-
reveal that the pulmonary infiltrates of sarcoidosis tensin-converting enzyme and the active form of vitamin
are typically nodular in appearance, and tend to dis- D (1,25-dihydroxy vitamin D3) are elevated in some
tribute themselves along bronchovascular structures patients with active sarcoidosis, but these test results
(Figure 27-4). have poor specificity and little utility in either the diag-
The presence of inflammation suggesting active sar- nosis or management of sarcoidosis (23).
coidosis can be identified in the brain, cranial nerves,
spinal cord, heart, or other soft tissue organs using MRI
with gadolinium contrast or PET scanning. Cardiac PATHOLOGY
sarcoidosis can also be inferred from gated thallium
scanning. Classic findings associated with sarcoidosis Sarcoidosis is associated with well-formed epithelioid
revealed by 67-gallium scanning include uptake in the granulomas in the absence of other known causes of
parotid and lacrimal glands (panda sign) and uptake granulomatous disease, such as infection and malig-
in bilateral hilar and right paratracheal lymph nodes nancy. These granulomas are typically noncaseating,
(lambda sign). Although these radiographic findings although fibrinoid necrosis can occasionally be seen. In
are highly typical of sarcoidosis, a biopsy is still required the lung, the granulomas tend to occur along broncho-
to confirm diagnosis. vascular structures.
FIGURE 27-3
Pulmonary sarcoidosis (A, B). Chest radiograph (A) compatible with Scadding stage I, demonstrat-
ing bilateral hilar and right paratracheal adenopathy without significant parenchymal infiltrates.
This patient presented with constitutional symptoms (fevers, unintentional weight loss), arthral-
gias, and a cough. A transbronchial biopsy revealed noncaseating granulomatous inflammation.
In another patient (B), the presence of both adenopathy and pulmonary infiltrates signifies a
Scadding stage III radiograph.
A B
27
A B
C D
FIGURE 27-4
(AC) Pulmonary sarcoidosis. Computed tomography scans of the chest, revealing patchy, diffuse
reticulonodular infiltrates predominantly involving the upper and middle lung fields with a
bronchovascular distribution. If observed on a chest radiograph, such findings would be
comparable with a Scadding stage II (Scadding stages are based upon radiographs, not com-
puted tomography scans).
PATHOGENESIS Oligoclonal expansion of T cells bearing a limited set of

T-cell receptors in the lung, skin, and other sites of
The cause of sarcoidosis remains uncertain. The active disease support the hypothesis that sarcoidosis involves
granulomatous inflammation of sarcoidosis is associ- an antigen-driven response (25). The most compelling
ated with a dominant expression of T-helper (Th)1 cyto- example of this is the over-representation of T cells
kines [interferon gamma (IFN-gamma), interleukin bearing the V alpha 2.3 T-cell receptor subunit reported
(IL)-12, IL-18] and tumor necrosis factor (TNF) (24). in a significant portion of Scandinavian patients (26).
520 EDWARD S. CHEN
One prevailing hypothesis is that an exposure, possibly tangible endpoints (pulmonary function tests, chest
of microbial origin, triggers the development of sarcoid- radiograph, bloodwork, MRI studies) rather than sub-
osis. Recent laboratory studies suggest that sarcoidosis jective symptoms (fatigue, cough, localized pain) is
may be associated with a previous exposure to microbial essential to good therapeutic decision making. Although
antigens (27,28), although sarcoidosis does not repre- sarcoidosis is often considered a restrictive lung disease
sent an active infection. The large multicenter ACCESS (low forced vital capacity or total lung capacity), changes
study failed to identify a dominant environmental or in airway obstruction (FEV1) and/or diffusion capacity
occupational exposure associated with an increased risk (DLCO) may herald clinical deterioration in some
for developing sarcoidosis (29). patients with lung involvement.
For patients who require systemic therapy, glucocor-
ticoids remain the only uniformly effective medication
TREATMENT for active inflammation. Topical glucocorticoids
(inhaled, ointment) are ineffective except for some
Clinical Course and Prognosis instances of ocular involvement. In general, patients
should be treated for an initial period of 8 to 12 months
Nearly all patients with sarcoidosis experience one of before attempting to discontinue glucocorticoids (taper-
two clinical courses: (1) sustained clinical remission or ing of the daily dose to a tolerable level, however, is
(2) chronic active disease that does not remit. Thus, essential). Patients with Lfgren syndrome generally
sarcoidosis differs from many rheumatological diseases have a good prognosis and earlier attempts to curtail
in that waxing and waning courses with intermittent systemic glucocorticoids can be considered. Patients
flares and remissions are unusual. The major exception who have chronic active disease should be treated with
to this rule is the neurosarcoidosis presentation of optic a stable maintenance regimen of low-dose glucocorti-
neuritis and cranial neuropathies, which may recur coids rather than repeated aggressive tapering regimens
several years after apparent remission. on and off glucocorticoids. End-stage changes (scar-
Most patients who achieve remission do so within the ring) are not amenable to any treatment. Most patients
first 2 to 3 years of diagnosis. Acute sarcoidosis (Lfgren demonstrate a lower limit for prednisone dosing, below
syndrome) is associated with a high rate of remission which their disease will flare.
(>70%). Unremitting, chronic active disease is associ- Untreated patients initially require higher doses of
ated with a greater burden of lung disease (stage III or glucocorticoids (prednisone 2040 mg/day) to control
IV), sinus and upper respiratory tract involvement, active disease, which can be tapered gradually after the
lupus pernio, neurosarcoidosis, cardiac involvement first month, by 5-mg intervals every 2 weeks down to
organ system manifestations characterized by indolent 20 mg/day, then more gradually below this dose with
presentations. Careful follow-up for at least several smaller increments (2.5 mg) and longer intervals (12
years (>23) is necessary to confirm whether a patient months). If symptoms recur or pulmonary function dete-
has remitting or chronic active sarcoidosis. Long-term riorates with interval dose reduction, the patient should
follow-up is also important to ensure that patients with resume the previously effective dose of prednisone and
chronic active disease receive adequate treatment to the addition of a steroid-sparing agent should be consid-
minimize progressive impairment of organ function ered. The average maintenance dose of sarcoidosis for
from chronic inflammation. most patients tends to be 5 to 15 mg/day. Patients with
Although sarcoidosis is a systemic disorder, the neurosarcoidosis or cardiac sarcoidosis may benefit from
extent of organ involvement is largely defined at pre- even higher doses of glucocorticoids in combination
sentation. The recent ACCESS study found that less with steroid-sparing immunosuppressants.
than 25% of patients developed new organ involvement
within 2 years of follow-up (30).
Steroid-Sparing Agents
A variety of steroid-sparing immunosuppressants and
Therapy immunomodulating agents are recommended to help
The first step in deciding upon a treatment course is to minimize the maintenance dose of glucocorticoids
exclude the presence of immediately life-threatening (ideally 15 mg/day). However, most potential steroid-
disease manifestations. In patients with limited cutane- sparing agents have not been tested rigorously in ran-
ous disease or the Lfgren syndrome, NSAIDs may be domized clinical trials. In contrast to glucocorticoids,
sufficient to control symptoms. Local steroid injections which induce responses within several days to a few
may be considered for isolated skin lesions. Patients weeks, steroid-sparing agents may require a few months
with critical organ involvement (heart, central nervous of therapy (26) before any clinical benefit is evident.
system) should be treated aggressively with high doses Antimalarial drugs (hydroxychloroquine, chloro-
of systemic glucocorticoids. In all cases, the selection of quine) and synthetic tetracyclines (minocycline, doxycy-
cline), medications with few serious side effects, are sis (SAGA) study. Sarcoidosis Vas Diffuse Lung Dis 2005;
used primarily to help control mucocutaneous disease. 22:115122.
Pentoxifylline and thalidomide may be useful in a small 12. Rybicki BA, Walewski JL, Maliarik MJ, Kian H, Iannuzzi
subset of patients, but may have more significant side MC. The BTNL2 gene and sarcoidosis susceptibility in
African Americans and Whites. Am J Hum Genet 2005;
effects. Other immunosuppressive agents (metho-
77:491499.
trexate, mycophenolate mofetil, azathioprine, cyclo-
13. Moller DR. Rare manifestations of sarcoidosis. In: Drent
phosphamide) have been used in conjunction with M, Costabel U, eds. Sarcoidosis. Vol 10. Wakefield, UK:
glucocorticoids to treat more severe manifestations of European Respiratory Society Journals, Ltd.; 2005:233
sarcoidosis that cannot be managed with lower doses of 250.
glucocorticoids alone or when intolerable glucocorti- 14. Gran JT, Bohmer E. Acute sarcoid arthritis: a favourable
coid-related side effects occur. A recently completed outcome? A retrospective survey of 49 patients with
phase II trial demonstrated that patients treated with review of the literature. Scand J Rheumatol 1996;25: 27
infliximab, a monoclonal antibody targeted against TNF, 7073.
experienced mild improvement in pulmonary function 15. Kaplan H. Sarcoid arthritis. A review. Arch Intern Med
(31). Etanercept, a soluble TNF inhibitor, was shown to 1963;112:924935.
16. Wilcox A, Bharadwaj P, Sharma OP. Bone sarcoidosis.
be ineffective in a randomized clinical trial (32). Further
Curr Opin Rheumatol 2000;12:321330.
evaluation is necessary to determine the role of anti-
17. Kennedy PT, Zakaria N, Modawi SB, et al. Natural history
TNF agents such as infliximab (and an analogous agent, of hepatic sarcoidosis and its response to treatment. Eur
adalimumab) in the treatment of sarcoidosis. J Gastroenterol Hepatol 2006;18:721726.
18. Lower EE, Smith JT, Martelo OJ, Baughman RP. The
anemia of sarcoidosis. Sarcoidosis 1988;5:5155.
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Society/European Respiratory Society/World Association 20. Ardehali H, Howard DL, Hariri A, et al. A positive endo-
of Sarcoidosis and other Granulomatous Disorders. Sar- myocardial biopsy result for sarcoid is associated with
coidosis Vas Diffuse Lung Dis 1999;16:149173. poor prognosis in patients with initially unexplained car-
2. Kitaichi M. Prevalence of sarcoidosis around the world. diomyopathy. Am Heart J 2005;150:459463.
Sarcoidosis Vas Diffuse Lung Dis 1998;15:1618. 21. Voorter CE, Drent M, Hoitsma E, Faber KG, van den
3. Siltzbach LE, James DG, Neville E, et al. Course and Berg-Loonen EM. Association of HLA DQB1 0602 in
prognosis of sarcoidosis around the world. Am J Med sarcoidosis patients with small fiber neuropathy. Sarcoid-
1974;57:847852. osis Vasc Diffuse Lung Dis 2005;22:129132.
4. Nelson RS. Sarcoidosis in the armed forces. Am J Med 22. Johns CJ, Michele TM. The clinical management of
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guchi M, Selroos O. The frequency of sarcoidosis in 23. Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest
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6. Hagerstrand I, Linell F. The prevalence of sarcoidosis in coidosis. In: Baughman R, ed. Sarcoidosis. Vol 210. New
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7. Reid JD. Sarcoidosis in coroners autopsies: a critical Moller DR. Selective activation and accumulation of
evaluation of diagnosis and prevalence from Cuyahoga oligoclonal V beta-specific T cells in active pulmonary
County, Ohio. Sarcoidosis Vas Diffuse Lung Dis 1998; sarcoidosis. J Clin Invest 1994;94:15331542.
15:4451. 26. Grunewald J, Janson CH, Eklund A, et al. Restricted V
8. Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, alpha 2.3 gene usage by CD4+ T lymphocytes in bron-
Iannuzzi MC. Racial differences in sarcoidosis incidence: choalveolar lavage fluid from sarcoidosis patients corre-
a 5-year study in a health maintenance organization. Am lates with HLA-DR3. Eur J Immunol 1992;22:129135.
J Epidemiol 1997;145:234241. 27. Song Z, Marzilli L, Greenlee BM, et al. Mycobacterial
9. Schurmann M, Reichel P, Muller-Myhsok B, Schlaak M, catalase-peroxidase is a tissue antigen and target of the
Muller-Quernheim J, Schwinger E. Results from a adaptive immune response in systemic sarcoidosis. J Exp
genome-wide search for predisposing genes in sarcoidosis. Med 2005;201:755767.
Am J Respir Crit Care Med 2001;164:840846. 28. Ebe Y, Ikushima S, Yamaguchi T, et al. Proliferative
10. Valentonyte R, Hampe J, Huse K, et al. Sarcoidosis is response of peripheral blood mononuclear cells and levels
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Nat Genet 2005;37:357364. rium acnes DNA expression library in Japanese patients
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522 EDWARD S. CHEN
29. Newman LS, Rose CS, Bresnitz EA, et al. A case control 31. Baughman RP, Drent M, Kavuru M, et al. Infliximab
etiologic study of sarcoidosis: environmental and occupa- therapy in patients with chronic sarcoidosis and pulmo-
tional risk factors. Am J Respir Crit Care Med 2004;170: nary involvement. Am J Respir Crit Care Med 2006;174:
13241330. 795802.
30. Judson MA, Baughman RP, Thompson BW, et al. Two 32. Utz JP, Limper AH, Kalra S, et al. Etanercept for the
year prognosis of sarcoidosis: the ACCESS experience. treatment of stage II and III progressive pulmonary sar-
Sarcoidosis Vas Diffuse Lung Dis 2003;20:204211. coidosis. Chest 2003;124:177185.
CHAPTER 28
Storage and Deposition Diseases

DUNCAN A. GORDON, MD, FRCPC, MACR
Some unusual arthropathies are caused by deposition In Gauchers disease, Fabrys disease, Farbers
of normal material, such as metal ions, or storage of disease, and multicentric reticulohistiocytosis,
abnormal material, such as lipids. rheumatic manifestations result from cellular storage
Hemochromatosis, ochronosis, and Wilsons disease of abnormal lipids.
are characterized by cellular deposition of the normal
metal ions: iron, calcium, and copper, respectively.
This chapter covers a number of unusual arthropathies The gene for hemochromatosis (HFE, HLA-H) was
that are caused by deposition of normal material, such discovered in 1996 by positional cloning methods near
as metal ions, or storage of abnormal material, such as the human leukocyte antigen (HLA)-A locus on chro-
lipids (1). Hemochromatosis, ochronosis, and Wilsons mosome 6 (4). More than 90% of typical patients possess
disease are characterized by cellular deposition of the the C282Y mutation of the HFE gene. Homozygous and
normal metal ions: iron, calcium, and copper, respec- heterozygous genotypes correlate with major or minor
tively. In the case of Gauchers disease, Fabrys disease, disease expression, respectively. The association of
Farbers disease, and multicentric reticulohistiocytosis, hemochromatosis with arthritis is most common in
rheumatic manifestations result from cellular storage homozygotes with the heaviest iron overload. The
of abnormal lipids. In hemochromatosis, arthralgias C282Y mutation is most common in whites, and most
may be the first indication of a systemic disorder, C282Y homozygotes have elevations in serum ferritin
but arthritis evolves as a predominant feature in levels and transferrin saturation. However, the absence
ochronosis, Gaucherss disease, and multicentric of C282Y mutation does not account for high mean
reticulohistiocytosis. serum ferritin levels and transferrin values in nonwhites
(5).
Prolonged excessive iron ingestion and repeated
HEMOCHROMATOSIS blood transfusion in chronic hypoproliferative anemia
and thalassemia may also result in iron deposition. If
Hemochromatosis is a common inherited autosomal iron overload occurs without tissue damage, the disor-
recessive disorder affecting as many as 5 per 1000 white der is known as hemosiderosis. With tissue damage, it is
persons of European extraction. It is characterized by called secondary hemochromatosis. The iron deposition
excessive body iron stores and the deposition of hemo- in macrophages in secondary hemochromatosis is asso-
siderin, which cause tissue damage and organ dysfunc- ciated with less tissue damage and end-organ dysfunc-
tion (2). The disorder rarely appears before age 40 tion compared with the idiopathic form.
unless there is a family history, and men are affected 10 Yersinia septic arthritis or septicemia is an
times more frequently than women, who are protected unusual complication that may occur in people with
by menstruation. Increased intestinal iron absorption hemochromatosis because of a microbial requirement
and visceral deposition can lead to the phenotypic for an iron-rich environment. Hepatitis B and C viral
features of hepatic cirrhosis, cardiomyopathy, diabetes infection may accelerate liver damage in people with
mellitus, pituitary dysfunction (including hyogonadism), hemochromatosis (6).
sicca syndrome, and skin pigmentation mostly of melanin
(2). In a survey of 2851 patients with hemochromatosis,
symptoms had been present for an average of 10 years
Clinical Features
before the diagnosis was made. Arthralgia (44%) Chronic progressive arthritis, predominantly affecting
was among the most common and most troublesome the second and third metacarpophalangeal (MCP) and
complaints (3). proximal interphalangeal (PIP) joints, is the presenting
523
524 DUNCAN A. GORDON
less osteophytosis. Ulnar styloid erosion may suggest

rheumatoid diseases, but the irregular joint narrowing
and sclerotic cyst formation are more indicative of a
degenerative process. Although the distal interphalan-
geal joints may be affected, the carpometacarpal
joint changes of generalized osteoarthritis are not a
feature. Somewhat similar MCP changes can occur in
calcium pyrophosphate dehydrate crystal deposition
without hemochromatosis. Some degree of diffuse
osteoporosis may be present, presumably due to hypo-
gonadism, but a direct effect of iron on bone is also
possible. Chondrocalcinosis is characteristic of the
arthropathy and is a late complication in about 50% of
patients; it may be the sole abnormality (7). The hyaline
cartilage of the shoulder, wrist, hip, and knee, and the
fibrocartilage of the triangular ligament of the wrist
and symphysis pubis may be affected. Superimposed
attacks of calcium pyrophosphate dihydrate crystal
synovitis occur in these cases. The finding of chondro-
calcinosis should always suggest the possibility of
hemochromatosis.
FIGURE 28-1
Radiograph of hand with hemochromatosis. Note the joint space

Laboratory Features
narrowing, cystic subchondral lesions, joint space irregularity, Synovial fluid has good viscosity, with leukocyte counts
mild subluxation, bony sclerosis, and small osteophytes in the
below 1000 cells/mm3. During acute episodes of pseudo-
metacarpophalangeal joints. Chondrocalcinosis is present in the
ulnar carpal joint, and soft tissue has calcified around the gout, synovial fluid leukocytosis with calcium pyrophos-
interphalangeal joint of the thumb. (Courtesy of Dr. H.R. phate crystals can be found. Except for such episodes,
Schumacher, Jr.) the erythrocyte sedimentation rate is usually normal. In
patients with chronic liver disease, rheumatoid factor
tests may be positive.
The diagnosis may be suspected by a raised serum
feature in about one half of cases (Figure 28-1). Involve- iron and high ferritin concentration with increased satu-
ment of the MCP joints is typically the most common ration of the plasma iron-binding protein transferrin (2).
rheumatologic feature at the time of diagnosis (7). The The latter, however, is more specific and should be
dominant hand may be solely or more severely affected. regarded as the cornerstone test for diagnosis (2). For
The finger joints and wrists are mildly tender with population screening, the simpler unbound iron binding
limited motion. Larger joints, such as the shoulders, hips, capacity (UIBC) showed higher sensitivity and fewer
and knees, may also be affected. Hemochromatotic false positives. Needle biopsy of the liver provides
arthropathy of the hips or shoulders may, at times, be definitive evidence of iron overload in hemochromato-
rapidly progressive. True morning stiffness is not a sis, but nowadays it is usually reserved for cases in
feature of hemochromatosis. diagnostic doubt, or more often to assess the severity of
Individuals heterozygous for the C282Y HFE muta- liver damage associated with fibrosis, cirrhosis, or
tion may be at increased risk for hand osteoarthritis (8). hepatoma.
Therefore the detection of an osteoarthritislike disease In idiopathic hemochromatosis, iron deposits affect
that involves MCP and wrist joints, particularly in men parenchymal hepatic cells, whereas reticuloendothelial
during the fifth and sixth decade of life, should signal cells are most affected in secondary forms. In hemo-
the possibility of underlying hemochromatosis. Arthrop- chromatosis, synovial biopsy shows iron deposition in
athy may also be seen in juveniles and may affect indi- the type B synthetic lining cells of synovium. In rheu-
viduals as young as 26 before any other manifestations matoid arthritis, traumatic hemarthrosis, hemophilia,
of the disease develop. and villonodular synovitis, deposits are in the deeper
layers or in the phagocyte type A lining cells. Hemosid-
erin deposits may also be found in the chondrocytes.
Radiographic Features Further evidence of iron may be found in biopsies of
The radiologic changes of hemochromatosis resemble skin and intestinal mucosa, or in bone marrow, buffy
osteoarthritis, except that in hemochromatosis there is coat, or urine sediment. The amount of iron excreted in
C H A P T E R 2 8 S T O R A G E A N D D E P O S I T I O N D I S E A S E S 5 25
the urine after administration of the iron-chelating the human HGO gene and established that it is the gene
agent deferoxamine correlates with the presence of responsible for AKU (10). This HGO gene harbors
parenchymal hepatic iron in hemochromatosis. Where misuse mutation(s) that represent a loss of function.
available, direct noninvasive magnetic measurements of This defect causes accumulation of homogentisic acid, a
hepatic iron stores provide a quantitative method for normal intermediate in the metabolism of phenylala-
early detection of iron overload or rapid evaluation of nine and tyrosine, which is excreted in the urine.
treatment. Alkalization and oxidation of this acid cause the urine
The pathogenesis of the arthritis is unknown, as to turn black. The homogentisic acid retained in the
degenerative joint changes do not necessarily develop body is deposited as a pigmented polymer in the carti-
in relation to synovial iron. The low frequency of chon- lage and, to a lesser degree, in skin and sclerae. The
drocalcinosis in people with hemophilia and rheuma- darkening of tissues parts by this pigment is designated
toid arthritis weighs against synovial hemosiderin as a ochronosis.
cause of chondrocalcinosis. It is speculated that ionic The pigment, which is found in the deeper layers of
iron might inhibit pyrophosphatase activity and lead to the articulator cartilage, is bound to collagen fibers,
a local concentration of calcium pyrophosphate in the causing this tissue to lose its normal resiliency and
joint. The deposition of calcium in cartilage appears to become brittle and fibrillated. The erosion of this
predispose to inflammatory and degenerative joint abnormal cartilage leads to denuding of subchondral 28
disease (2). bone and the penetration of tiny shards of pigmented
cartilage into the bone, synovium, and joint cavity (11).
It is likely that these pigmented cartilage fragments
Treatment become a nidus for the formation of osteochondral
Following the diagnosis of hemochromatosis in any bodies.
patient, it is imperative to obtain biochemical screening
of at least first-degree relatives for medical preventive
reasons. Screening may be done by measuring serum
Clinical Features
iron-binding transferrin or the UIBC test. Genotyping A progressive degenerative arthropathy develops, with
for the C282Y mutation of the HFE gene is a useful symptoms usually beginning in the fourth decade of life
diagnostic aid and helpful in counseling and predicting (9). Features include arthritis of the spine (ochronotic
the risk of disease in healthy relatives (2). However, it spondylosis) and larger peripheral joints, with chondro-
gives no indication of iron stores or prognosis. calcinosis, formation of osteochondral bodies, and syno-
Aggressive phlebotomy therapy promotes longevity vial effusions (ochrontonotic peripheral arthropathy).
and can prevent or reverse much organ damage. Weekly Initially, the spinal column is affected with pigment
phlebotomies are generally needed until iron is depleted found in the annulus fibrosus and nucleus pulposus of
and mild anemia is present. Venesection may not prevent the intervertebral discs (Figure 28-2). Later, the knees,
the progression of arthritis in hemochromatosis, but in shoulders, and hips deteriorate; the small peripheral
some cases arthritis may improve after this therapy. It joints are spared. In adults, the first sign of spondylosis
has been suggested that prophylactic phlebotomy should may be an acute disc syndrome. Eventually, it clinically
be considered on the basis of genetic predisposition. resembles ankylosing spondylitis, with progressive
Iron-chelating therapy with intravenous deferoxamine lumbar rigidity and loss of stature.
is generally effective but impractical because of the Disability is common and severe, with stiffness
expense and the need for intravenous administration. and loss of joint mobility predominant and pain less
Arthritis symptoms may be difficult to control even with prominent (9). Knee effusions, crepitus, and flexion
nonsteroidal anti-inflammatory drugs (NSAIDs). Agents contractures are common, but other signs of articular
requiring hepatic metabolism, such as diclofenac or inflammation are ordinarily lacking. Fragments of darkly
nabumetone, should be avoided. Prosthetic hip, knee, pigmented cartilage can occasionally be found floating
and shoulder arthroplasties can be performed when in the joint fluid. Osteochondral bodies, which form in
required. response to the deposition of cartilaginous fragments in
the synovium, are often palpable in and around the
knee joint and may reach several centimeters in
ALKAPTONURIA (OCHRONOSIS) diameter.
Nonarticular features of ochronosis include bluish
Alkaptonuria (AKU), a rare autosomal recessive inher- discoloration and calcification of the ear pinnae, trian-
ited disorder, results from a complete deficiency of the gular pigmentation of the sclera, and pigmentation over
enzyme homogentisic acid oxidase (HGO) (9). In six the nose, axillae, and groin. Prostatic calculi are common
reported pedigrees it was mapped to chromosome 3q2. in men, and cardiac murmurs may develop from valvu-
Since then a Spanish group has reported the cloning of lar pigment deposits.
Laboratory Features
The diagnosis of AKU is suspected when the patient
gives a history of passing dark urine, or when fresh urine
turns black on standing or on alkalinization. In individu-
als lacking this history, the diagnosis is made only after
the detection of a false-positive test for diabetes melli-
tus or the onset of arthritis. Dark pigmented synovium
may be seen on arthroscopy. A specific enzymatic
method permits quantitation of homogentisic acid in
urine and blood and molecular cloning of the HGO
gene makes detection of heterozygotic carriers possible
(10).
Synovial fluid is usually clear, yellow, and viscous and
does not darken with alkalinization. At times the fluid
may be speckled with many particles of debris resem-
bling ground pepper (Figure 28-3). Leukocyte counts of
a few hundred cells are predominantly mononuclear.
Occasionally, the cytoplasm of mononuclear and poly-
morphonuclear cells contains dark inclusions of phago-
cytosed ochronotic pigment.
Centrifugation and microscopic examination of syno-
vial fluid sediment may show fragments of pigmented
cartilage. Effusions may contain calcium pyrophosphate
dihydrate crystals and show no inflammation. Pigmented
cartilage fragments are embedded in synovium and are
often surrounded by giant cells (11).
No effective treatment is available for the underly-
ing metabolic disorder, but the herbicide nitisinone,
an enzyme inhibitor, can deplete and markedly reduce
FIGURE 28-2 urinary excretion of homogentisic acid in persons with
Part of a lumbar vertebral column of a 49-year-old woman with
alkaptonuria who died of real failure (ochronotic nephrosis).
Blackened intervertebral discs are thin and focally calcified. This
patient had incapacitationg pain since age 36, with progressive
limitation of back motion. Microscopic examination of the discs,
which splintered easily, revealed nonrefractile granular pigment.
(Reprinted from Cooper J, Moran TJ. Studies on ochronosis. I.
Report of case with death from ochronotic nephrosis. Arch
Pathol 1957;61:4653.)
The earliest features visible on roentgenograms are
multiple vacuum discs of the spine. Eventually, the
entire spine shows ossification of the discs with narrow-
ing, collapse, and fusion. Chondrocalcinosis may affect
the symphysis pubis, costal cartilage, and ear helix. In
contrast to ankylosing spondylitis, the sacroiliac and FIGURE 28-3
apophyseal joints are not affected. The roentgeno- Ochronosis: synovial fluid and synovium (gross and microscopic).
graphic appearance of the peripheral joints resembles On the left, the synovial fluid reveals numerous dark particles
that in primary osteoarthritis, with loss of cartilage and shards having the appearance of ground pepper. On the
space, marginal osteophytes, and eburnation of the sub- right, a low-power microscopic view of the synovium shows
fragments of darkly pigmented cartilage (hemotoxylin and eosin
chondral bone. Unlike primary osteoarthritis, however, stain). (Reprinted with permission from Hunter T, Gordon DA,
degeneration of the shoulders and hips is more severe, Ogryzlo MA. The ground pepper sign of synovial fluid: a new
and osteochondral bodies are seen. diagnostic feature of ochronosis. J Rheumatol 1974;1:4553.)
AKU. Limited trials with low doses of it suggest the observed in patients with Wilsons disease, light and
possibility of preventing joint destruction and providing transmission electron microscopy have failed to detect
relief of pain. However, side effects may preclude its crystals containing calcium in synovial fluids or in carti-
long-term use (12). Surgical removal of osteochondral lage and synovial biopsies. Copper has been found in
loose bodies from the knee joint is warranted when the articular cartilage by elemental analysis of a few
these interfere with motion. Prosthetic joint replace- patients with Wilsons disease and could theoretically
ment may be helpful. cause tissue damage mediated by oxygen-derived free
radicals (14). Although the arthropathy is generally
milder than that seen in hemochromatosis, its cause may
WILSONS DISEASE be similar and it may involve deposition of calcium
pyrophosphate dehydrate and the development of
Wilsons disease (hepatolenticular degeneration) is a chronic arthritis.
rare metabolic disorder in which deposition of copper
leads to dysfunction of the liver, brain, and kidneys.
It is inherited as an autosomal recessive trait
affecting about 1 in 30,000 persons in most populations. Radiologic features may include subchondral cysts, joint
It becomes symptomatic for individuals aged 6 to 40 space narrowing, sclerosis, marked ostophyte formation, 28
years. A defective gene and related mutations mapped to and multiple calcified loose bodies, especially at the
chromosome 13 provide some explanation for the wide wrist. Unlike hemochromatosis, involvement of the hip
phenotypic variation seen in Wilsons disease (13). and MCP joints is uncommon.
Periostitis at the femoral trochanters and other
tendinous insertions, periarticular calcifications, and
Clinical Features chondrocalcinosis have been reported. Changes in the
Total body copper is increased. The accumulation of spine are seen mainly in the mid-thoracic to lumbar
copper in the liver leads to cirrhosis; in the cornea, to areas and include squaring of the vertebral bodies,
characteristic KayserFleischer rings; in the basal intervertebral joint space narrowing, osteophytes, and
ganglia, to lentricular degeneration and movement dis- osteochondritis.
orders; in the kidneys, renal tubular damage (13). An Skeletal manifestations of Wilsons disease include
arthropathy may develop in as many as 50% of affected generalized osteoporosis in as many as 50% of patients.
adults, but arthritis is rare in children (14). Patients The osteoporosis is usually asymptomatic, unless spon-
usually develop hepatic or neurologic symptoms in taneous fractures occur (14). Osteomalacia, Milkman
childhood or adolescence. Liver disease is the most pseudofractures, and renal rickets have been reported.
common presentation between ages 8 and 16, with Some cases are from areas where nutritional deficien-
symptoms of jaundice, nausea, vomiting, and malaise. cies may also affect skeletal abnormalities.
Acute hepatic failure may rarely develop. Neurologic
symptoms are rare before age 12. Dysarthria and
decreased coordination of voluntary movements are the
Laboratory Features
most common complaints. Other presenting symptoms Although KayserFleischer corneal rings are pathogno-
include acute hemolytic anemia, arthralgias, renal stones, monic of Wilsons disease, the diagnosis is established
and renal tubular acidosis. The arthropathy is character- by laboratory investigations. Low serum copper and
ized by mild premature osteoarthritis of the wrists, MCP decreased serum ceruloplasmin levels occur in most
joints, knees, or spine. Occasionally, joint hypermobility cases, and in symptomatic patients urinary copper excre-
also may be found (14). Ossified bodies of the wrists tion is increased. Biliary excretion of copper is also
may be associated with subchondral cysts. Chondroma- markedly decreased. Microchemical evidence of copper
lacia patellae, osteochondritis dissecans, or chondrocal- deposition may be obtained from needle biopsy of the
cinosis of the knee may be associated with mild knee liver, but histochemical methods are unreliable. In
effusions. Arthropathy tends to be mild in patients doubtful cases, specialized studies with radioactive
treated early in life, but it may be more severe in patients copper may be necessary.
with untreated disease of longer duration. A few patients Synovial biopsies show hyperplasia of synovial lining
show acute or subacute polyarthritis that resembles cells with mild inflammation. Neither calcium pyrophos-
rheumatoid arthritis and may be associated with a posi- phate nor copper are seen by standard methods. Limited
tive rheumatoid factor. These seropositive cases are pos- data are available concerning morphologic changes in
sibly a result of penicillamine therapy. joints. Microvilli formation, initial cell hyperplasia,
The pathogenesis of the arthropathy is unclear, and chronic inflammatory infiltrates, and vascular changes
its presence does not correlate with neurologic, hepatic, have been reported in synovium. Joint fluids have had
or renal disease. Although chondrocalcinosis has been low leukocyte counts.
Treatment Type 2, infantile, is a fulminating disorder with severe

brain involvement and death within the first 18 months
Copper chelation with penicillamine along with dietary of life. Type 3, the intermediate or juvenile form, begins
copper restriction is the treatment of choice. Whether in early childhood and shows many features of the
penicillamine can control the arthropathy is unclear, chronic form, with or without central nervous system
but contemporary series suggest that the arthropathy dysfunction.
is milder because of earlier diagnosis with more inten- Skeletal involvement is characteristic of type 1 and
sive chelation therapy. Side effects from penicilamine to a lesser extent type 3, but not type 2 disease. Muscu-
reported in people with Wilsons disease rarely include loskeletal involvement occurs in the adult and juvenile
acute polyarthritis, polymyositis, or a syndrome resem- forms, but it is rarely the first symptom. Patients usually
bling systemic lupus erythematosus. Trientine or tetra- present with lymphadenopathy, hepatosplenomegaly,
thiomolybate are chelating agents available for patients or signs and symptoms of hypersplenism. Nevertheless,
intolerant of penicillamine. Liver transplantation is the rheumatic complaints may appear early in the disease
only treatment option available for acute hepatic failure course. Pain in the hip, knee, or shoulder is caused by
or longstanding cirrhosis where penicillamine or trien- disease of adjacent bone. In young individuals, the most
tine are not options. Otherwise, symptomatic measures common complaint is chronic aching around the hip or
suffice to control arthritis symptoms. proximal tibia. This may last a few days but is usually
recurrent. Another complaint is excruciating pain (bone
GAUCHERS DISEASE crisis) involving the femur and tibia with tenderness,
swelling, and erythema. Monoarticular hip or knee
Gauchers disease is a lysosomal glycolipid storage degeneration is typical, and unexplained migratory
disease in which glucocerebroside accumulates in the polyarthritis sometimes occurs. Bony pain tends to
reticuloendothelial cells of the spleen, liver, and bone lessen with age. Other skeletal features include patho-
marrow (15). It is an autosomal recessive disorder logic long bone fractures, vertebral compression, and
caused by subnormal activity of the hydrolytic enzyme osteonecrosis of the femoral or humeral heads or proxi-
glucocerebrosidase. The gene for Gauchers disease is mal tibia. The osteonecrosis can develop slowly, or can
located on chromosome 1 in the q21 region. Modern appear rapidly with bone crisis. These crises usually
DNA technology has led to the cloning of the glucocer- affect only one bone area at a time. Because acute-
ebroside genes and identification of their mutations. All phase reactants and bone scans are usually positive, the
the cells of the body are deficient in glucocerebroside clinical picture of acute osteomyelitis is mimicked
activity in Gauchers disease, but it is the glycolipid- (pseudo-osteomyelitis). Surgical drainage in these cases
engorged macrophages that account for all the non- commonly leads to infection and chronic osteomyelitis.
neurologic features of the disease. Due to this increased susceptibility to infection, conser-
Fortunately, the most severe forms of Gauchers vative management of bony lesions is recommended.
disease are extremely rare, whereas milder forms are
encountered frequently, particularly in the Jewish popu- Radiographic Features
lation. Gauchers disease has been classified into clinical
subdivisions. Type I, the most common form, is the adult Asymptomatic radiologic areas of rarefaction, patchy
or chronic type that accounts for more than 99% of sclerosis, and cortical thickening are common. Osteone-
cases. It is a common familial disorder in Ashkenzi Jews crosis of bone, particularly of the hips, and pathologic
while other types occur in all ethnic groups. It is defined fractures of the femur and vertebrae are the most serious
by the lack of neurologic involvement, and affected and deforming features of Gauchers disease. Involve-
adults present with accumulation of glucocerebroside in ment of the femur is thought to be a barometer of
the reticuloendothelial system causing organomegaly, bone symptoms. Widening of the distal femur with the
hypersplenism, conjunctival pingueculae, skin pigmen- radiologic appearance of an Erlenmeyer flask is a fre-
tation, and osteoarticular disease. It has the best prog- quent finding, but flaring of the bones can occur in the
nosis, but may be mistaken for juvenile rheumatoid tibia and humerus as well.
arthritis.
Laboratory Features
Clinical Features When bone pain or other articular symptoms appear,
Some patients with type I disease have few or no clinical the serum acid phosphatase and the angiotensin-
manifestations. In these cases the condition may be converting enzymes are usually elevated. However, the
discovered only when bone marrow is examined for most reliable method for diagnosing Gauchers disease
some other reason, or if mild thrombocytopenia is is the determination of leukocyte beta-glucosidase.
investigated. Diagnosis has been confirmed by examination of bone
marrow aspirate for the Gaucher cell, a large lipid alpha-galactosidase A. The gene and its mutations
storage histiocyte. This cell should be differentiated responsible for expression of this enzyme have been
from globoid cells of another lysosomal storage disor- localized to the middle of the long arm of the X
der, Krabbes disease (galactocerebrosidosis). However, chromosome.
histologic diagnosis of Gauchers disease is unnecessary
and can be misleading. Moreover, bone biopsy is not
recommended because of the risk of secondary infec-
Clinical Features
tion. Needle biopsy of the liver for assay of glucocere- As a slowly progressive disorder predominately affect-
broside may be performed, but washed leukocytes and ing males, clinical features are widespread and non-
extracts of cultured skin fibroblasts are easily obtained specific; thus, diagnosis is often missed or delayed. In
for glucocerebrosidase testing. These assays may also be childhood, the deposition is particularly marked in and
used to detect heterozygous carriers. Amniocentesis has around blood vessels, giving rise to the characteristic
been used for the prenatal detection of diseased fetuses. rash of dark blue or red angiokeratomas or angiectases
When the diagnosis is established, genetic counseling around the buttocks, thighs, and lower abdomen. When
for family members or prospective parents is recom- diffuse, it is referred to as angiokeratoma corgoris
mended. Although enzyme assays are useful for genetic diffusum and is almost always associated with
screening, DNA analysis using the polymerase chain hypohydrosis. 28
reaction is much more precise (15). The kidneys are the main target organ and protein-
uria gradually develops in childhood or adolescence,
with abnormal urinary sediments including birefringent
Treatment lipid crystals (Maltese crosses). Progressive renal disease
Until recently, therapy of Gauchers disease was mostly leads to renal failure. Cardiovascular and cerebrovascu-
symptomatic, based on control of pain and infection. lar deposition of the sphingolipid parallels the renal
In adults, splenectomy may control hypersplenism, but disease, with vascular insufficiencies such as cryptogenic
bone disease may then accelerate. Bisphosphonates stroke or death in young persons. Ocular changes are
have been effective in treating bone disease in Gau- severe. A characteristic corneal opacity seen by slit-
chers disease. Intermittent intravenous pamidronate lamp examination occurs early and can be helpful in
with oral calcium has been effective in the treatment of diagnosis even in heterozygous women.
a few patients with type I Gauchers disease with severe Some patients experience the insidious development
bone involvement. Partial splenectomy has been recom- of polyarthritis with degenerative changes and flexion
mended as protection against postsplenectomy infec- contractures of the fingers, particularly of the distal
tion, and for its hepatic and bone-sparing effect. interphalageal joints. Foam cells have been described in
Arthroplasty and complete joint replacement is often the synovial vessels and connective tissues. Radiographs
necessary, but loosening of prostheses occurs more often may show infarctlike opacities of bone and osteoporosis
than in other disorders. Bleeding can be an operative of the spine. Osteonecrosis of the hip and talus have
problem. been described. Eighty percent of children or young
With the commercial availability of replacement adults undergo painful crises of burning paresthesias of
enzyme, the modified glucocerebroside (Ceredase), the hands and feet and later of whole extremities. These
effective but costly treatment of Gauchers disease has attacks are associated with fever and elevations of the
become a reality, but not without its limitations (16). erythrocyte sedimentation rate.
Periodic intravenous infusions of the enzyme over many Genetic counseling should be offered to affected
months commonly results in regression of the features families. Measurement of alpha-galactosidase to alpha-
of Gauchers disease (15). However, alternatives to galactosidase activity ratios in leukocytes and fibroblasts
enzyme replacement therapy include substrate reduc- provide reasonable discrimination between carriers and
tion, active site-specific chaperone therapy, and gene noncarriers. Identification by DNA studies is reserved
therapy (17). The latter involves using retroviral vector for subjects showing equivocal results.
constructs for coding the gene for glucocerebrosidase
into hematopoietic progenitors.
Treatment
Treatment has not been satisfactory. However, the pros-
FABRYS DISEASE pect of effective gene therapy using recombinant
adenovirus AxCAG alpha-gal to provide enzyme
Fabrys disease is a lysosomal lipid storage disease in replacement has been reported in a randomized, con-
which glycosphingolipids accumulate widely in nerves, trolled trial (18). Antiplatelet medication may suppress
viscera, skin, and osteoarticular tissues. It is a sex-linked vascular damage. Burning paresthesias may benefit
inherited disease caused by a deficiency of the enzyme from phenytoin or carbamazepine. Without dialysis or
transplantation most affected males succumb to renal

failure before age 50.
FARBERS DISEASE
Farbers disease is a lysosomal lipid storage disease in
which a glycolipid ceramide accumulates widely in many
tissues, including the skin and musculoskeletal system
(19). It is an autosomal recessive disorder caused by a
deficiency of the enzyme acid ceramidase. Affected chil-
dren show disease manifestations by the age of 4 months FIGURE 28-4
and die before the age of 4 years. The fingers of a 16-year-old girl (left) with multicentric reticulo-
A hoarse cry from thickened vocal cords or swollen histiocytosis reveal multiple, reddish-brown, tender papulonod-
painful joints may be the first feature. The appearance ules that are periungual in distribution. On the right is another
of tender, subcutaneous nodules follows and the early patient with multiple nodules in the fingers. These nodules are
firm, can fluctuate in size, and may disappear spontaneously.
occurrence of nodules correlates with shortened sur-
(Reprinted from Revised Clinical Slide Collection on the Rheu-
vival. All the extremities may be swollen and tender, but matic Diseases, with permission of the American College of
this gives way to more localized joint swelling with Rheumatology.)
nodules around the fingers, wrists, elbows, and knees.
Joint contractures, especially affecting the fingers and
wrists, develop later. The gastrointestinal, cardiovascu-
lar, and nervous systems gradually become involved, Clinical Features
and death results from respiratory disease. Diagnosis Disease onset is insidious and is characterized by poly-
can be confirmed by demonstrating a deficiency of arthritis, skin nodules, and, in many cases, xanthelasma.
ceramidase both in leukocytes and fibroblasts. Small papules and beadlike clusters around the nail-
folds are characteristic, with skin nodulation of the face
and hands. Varying sizes of skin nodules are yellowish,
LIPOCHROME HISTIOCYTOSIS purple, and occur over the hands (Figure 28-5), elbows,
face, and ears. Oral, nasal, and pharyngeal mucosa
Lipochrome histiocytosis is an extremely rare lysosomal
storage disease associated with pulmonary infiltrates,
splenomegaly, hypergammaglobulinemia, polyarthritis,
and increased susceptibility to infection (20). The disor-
der is familial. Histiocytes show lipochrome pigment
granulation and peripheral blood leukocytes exhibit
impaired activity.
MULTICENTRIC
RETICULOHISTIOCYTOSIS
Multicentric reticulohistiocytosis is a rare dermatoar-
thritis of unknown cause or familial association. It is
characterized by the cellular accumulation of glycolipid-
laden histocytes and multinucleated giant cells in skin
and joints (21). The most common presentation is a
painful destructive polyarthritis resembling rheumatoid
arthritis, for which affected persons may be mistakenly
treated. The joint manifestations precede the appear- FIGURE 28-5
ance of skin lesions in most patients, but the appearance
and location of the skin nodules are not entirely char- Photomicrograph of synovium (knee) from a 54-year-old woman
with multicentric reticulohistiocytosis shows numerous histio-
acteristic of rheumatoid arthritis (Figure 28-4). Although
cytes and multinucleated giant cells that contain large amounts
a self-limited form may be seen in childhood, adult of periodic acid-Schiff (PAS)-positive material. (Reprinted from
multicentric reticulohistiocytosis predominantly affects McCarthy DJ, Koopman WJ. Arthritis and allied conditions.
middle-aged women. Philadelphia: Lea & Febiger; 1993.)
involvement sometimes with ulceration is seen in one been reported, but patients may be left with severe joint
fourth of patients. Various visceral sites may also be disability.
affected.
Symmetric polyarthritis resembles rheumatoid
disease when PIP joints are affected, and psoriatic
Treatment
arthritis when involvement of distal interphalangeal Spontaneous remission of skin and arthritis occurs in
joints predominates. Tenosynovial involvement may some cases, especially in childhood. In the remainder,
also occur. Remission of polyarthritis may be seen after corticosteroids or topical nitrogen mustard may improve
many years of progressive disease. the skin lesions. In cases with severe skin and joint disease
Early radiographs early on show punched out bony combinations of corticosteroid, methotrexate (MTX)
lesions resembling gouty tophi. Severe joint destruction plus cyclophosphamide or cyclosporine, and bisphos-
will be seen in later radiographs. Spinal involvement phonates have been effective. Low-dose MTX alone has
with erosions and subluxations including atlanto-axial shown prolonged effect, and MTX plus hydroxychloro-
damage may occur. quine has also been beneficial. The presence of synovial
TNF-alpha in the disease indicates that, in addition to
MTX, dramatic clinical and serologic improvement may
Laboratory Features occur with TNF-alpha inhibition (23). 28
No specific laboratory abnormality has yet been dem-
onstrated, and the diagnosis is established by examina-
tion of biopsies of affected tissues. Both the skin and REFERENCES
synovium (Figure 28-5) are infiltrated by large, multi-
nucleated giant cells. The cytoplasm has a ground glass 1. Rooney PJ. Hyperlipidemias, lipid storage disorders, metal
appearance and stains positively for lipids and glycopro- storage disorders and ochronosis. Curr Opin Rheumatol
teins with periodic acid-Schiff stain (PAS positive). 1991;3:166171.
Definitive analysis of these cell contents has not been 2. Pietrangelo A. Hereditary hemochromatosisa new look
made, but it is probably a glycolipid. Triglycerides, cho- at an old disease. N Engl J Med 2004;350:23832397.
lesterol, and phosphate esters appear to be present in 3. McDonnell SM, Preston BL, Jewell SA, et al. A survey
of 2,851 patients with hemochromatosis: symptoms and
the lesion, suggesting either that histiocytes are stimu-
response to treatment. Am J Med 1999;106:619624.
lated to produce these substances or that this is a form 4. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class
of lipid storage disease. A lymphocytic origin for the I-like gene is mutated inpatients with hereditary hemo-
giant cells has been proposed because of the presence chromatosis. Nat Genet 1996;13:399408.
of T-cell markers, but multicentric reticulocytosis cells 5. Adams PC, Reboussin DM, Barton JC, et al. Hemochro-
also stain for macrophage markers (21). A monocyte/ matosis and iron-overload screening in a racially diverse
macrophage origin for these cells has also been sug- population. N Engl J Med 2005;352:17691778.
gested because of the detection of macrophage- 6. Piperno A, Fargion S, DAlba R, et al. Liver damage in
activated cytokines of IL-1 beta, IL-12, and tumor Italian patients with hereditary hemochromatosis is highly
necrosis factor alpha (TNF-alpha). The distribution of influenced by hepatitis B and C virus infection. J Hepatol
TNF-alpha appears similar to that for rheumatoid syno- 1992;16:364368.
7. Mathews JL, Williams HJ. Arthritis in hereditary hemo-
vial cell proliferation. Synovial fluid leukocyte counts
chromatosis. Arthritis Rheum 1987;30:11371141.
range from 220 to 79,000 cells/mm3, with mononuclear 8. Ross JM, Kowalchuk RM, Shaulinsky J, et al. Association
cells predominating. Scanning the synovial fluid Wright- of heterozygous hemochromatosis C282Y gene mutation
stained smear or wet preparation may reveal giant cells with hand osteoarthritis. J Rheumatol 2003;30:121125.
or large, bizarre macrophages. 9. Perry MB, Suwannarat P, Furst GP, et al. Musculoskeletal
The foregoing specific histologic picture of multicen- findings and disability in alkaptonuria. J Rheumatol 2006;
tric reticulohistiocytosis is quite different from the 33:22802285.
myofibroblast cells in a collagen matrix characteristic 10. Fernandez-Canon JM, Grandadino B, Beltram-Valero
of the cutaneous nodules and polyarthritis of fibroblas- de Bernabe D, et al. The molecular basis of alkaptonuria.
tic rheumatism (22). Nat Genet 1996;14:1924.
Although the pathogenesis is unknown, hidden 11. Gaines JJ, Tom GD, Khan Khanian N. The ultrastructural
and light microscopic study of the synovium in ochronotic
malignancy and tuberculosis have been implicated.
arthropathy. Hum Pathol 1987;8:11601164.
Rheumatoid factor does not occur. Some patients 12. Suwannarat P, Obrien K, Perry MB, et al. Use of nitisinone
develop positive reactions to tuberculin (PPD positive). in patients with alkaptonuria. Metabolism 2005;54:719
There are case descriptions with associated Sjgrens 728.
syndrome and polymyositis. Multicentric reticulohistio- 13. Gow PJ, Smallwood RA, Angust PW, et al. Diagnosis
cytosis has also been implicated with a variety of malig- of Wilsons disease: an experience over three decades.
nancies (21). Death due to the disease itself has not Gut 2000;46:415419.
14. Memerey KA, Eider W, Brewer GJ, et al. The arthropa- 19. Chanoki M, Ishii M, Fukaik, et al. Farbers lipogranulo-
thy of Wilsons disease: clinical and pathologic features. matosis in siblings: light and electron microscopic studies.
J Rheumatol 1988;15:331337. Br J Dermatol 1989;121:779785.
15. Pastores GM, Meere PA. Musculoskeletal compli- 20. Rodey GE, et al. Defective bacteriocidel activity of
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Gaucher disease and Hurler-Scheie syndrome (mucupoly- Am J Med 1970;49:322327.
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7078. centric reticulohistiocytosis: case report with immuno-
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hereditary metabolic storage disorders. Rejuvenation Res blastic rheumatism. Arthritis Rheum 1997;40:183187.
2006;9:237244. 23. Shannon SE, Schumacher HR, Self S, Brown AN. Multi-
18. Schiffmann R, Kopp JB, Austin HA 3rd, et al. Enzyme centric reticulohistiocytosis responding to tumor necrosis
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trolled trial. JAMA 2001;285:27432749. J Rheumatol 2005;32:565567.
CHAPTER 29
The Amyloidoses
PASHA SARRAF, MD, PHD
JONATHAN KAY, MD
The prevalence of amyloid diseases varies in Clinical manifestations vary according to the type of
different geographic areas. Alzheimers disease is the amyloid disease.
most common form of localized amyloidosis, while Diagnosis is made by recognition of deposits with a
AL amyloidosis is the most common systemic characteristic apple green birefringence under
form of amyloidosis in the United States, while AA polarizing microscopy and the specific subunit protein
amyloidosis is the most common form worldwide. by immunohistochemistry.
Amyloid fibrils resemble a woven cable and are Treatment is directed toward reducing production of
deposited in tissues depending of the specific aberrant proteins or surgical removal of amyloid
causative protein. Amyloid deposits do not cause an deposits or affected organs.
inflammatory reaction, but interfere with the function
of surrounding tissues.
The amyloid diseases involve a wide variety of proteins quent acidification. Because this pattern of staining was
that share in common the property of forming fibrils (1). characteristic of plant cellulose, Virchow concluded that
Deposition and accumulation of these fibrils in various the corpora amylacea was composed of a celluloselike
tissues, ultimately interfering with normal organ func- substance that he labeled amyloid. The term amyloid,
tion, results in the clinical entity known as amyloidosis. derived from the Greek word amylon, refers to
The amyloidoses can occur either as isolated localized materials that contain or resemble starch. This is a
processes or as systemic disorders involving multiple misnomer, however, as it now is known that amyloid
organ systems. Furthermore, amyloidosis may occur as deposits contain mainly protein, even though some
a primary disease process or as a secondary consequence carbohydrate-containing substances may associate with
of other diseases. Both light and heavy chain (formerly the proteins. The study of amyloid has focused mainly
known as primary) amyloidosis and familial amyloidosis on its protein composition.
belong to the former group, whereas serum amyloid A The understanding of the protein structure of amyloid
protein and beta2-microglobulin (dialysis-associated) has been advanced by the observation that Congo red,
amyloidosis belong to the latter group. In the United an aniline textile dye, stains amyloid deposits. Congo
States, primary (idiopathic) amyloidosis is the most red molecules deposit and align perpendicular to the
common form of amyloid disease, while serum amyloid long axis of amyloid fibrils, markedly enhancing the
A-associated amyloidosis occurs more commonly in anisotropy of these fibrils and appearing as apple
other countries. Alzheimers disease and prion deposi- green birefringence under polarizing microscopy.
tion disease are the only forms of localized amyloid Independent of their protein of origin, by definition, all
fibril deposition which often lead to serious illness; other amyloid proteins share three common characteristics: a
forms of localized amyloid deposition usually lead only cross-beta-pleated sheeted structure, an organized fibril-
to mechanical interference and generally are considered lar ultrastructure, and congophilia producing apple
to be benign. green birefringence.
The name amyloidosis is preserved in deference to Amyloid deposits are amorphous and consist of a
Rudolph Virchow, who first used histochemical stains in number of components (3). The wide array of proteins
1854 to characterize amyloid deposits in pathologic that may result in amyloidosis are not derived from
specimens of brain (2). Whereas all other structures in common precursors and do not have any particular
his brain sections stained yellow after the application of genetic homology. However, each protein, in the proper
iodine and sulfuric acid, the corpora amylacea stained setting, can form amyloid fibrils. Other components of
pale blue with iodine and brilliant violet upon subse- amyloid deposits include the serum amyloid P compo-
533
534 PASHA SARRAF AND JONATHAN KAY
nent and proteoglycans which, although not part of the vitro, but only a limited repertoire of molecules form
fibrils themselves, may contribute to amyloid formation detectable deposits of amyloid in vivo. The reasons for
in situ. this discrepancy are unknown, but likely are related
Amyloid nomenclature is based on the name of the to modifying influences of the affected individual.
primary subunit protein: all amyloid fibril proteins are These include, but are not limited to, the presence and
named protein A- with a suffix that identifies the specificity of endoproteolytic enzymes, the presence of
specific subunit protein (e.g., protein AL for light chain inherited single nucleotide polymorphisms that coun-
amyloidosis and protein AA for serum amyloid A teract the effect of the amyloidogenic mutation, and the
amyloidosis). Both the amyloid type and the resulting amount of amyloidogenic protein synthesized. Factors
disease are named for the protein. Thus, AA amyloidosis such as these determine the timing of disease onset and
replaces the label secondary amyloidosis, and AL amy- the rapidity of its progression.
loidosis replaces the names primary amyloidosis and The presence of detectable amyloid is the sine qua
myeloma-associated amyloidosis. Currently, 24 amyloid non for expression of disease in patients. Although
proteins that can cause clinically apparent amyloidosis the extent and rapidity of organ damage and disease
have been identified. However, most of these types expression varies between patients, even in those
of amyloidosis are quite rare and occur primarily with similar types of amyloid proteins, the whole body
as hereditary diseases with clustering of cases in burden of amyloid correlates directly with the extent
families. of disease. Thus, reducing the total amount of amyloid
may stabilize or improve clinical manifestations of
disease.
PATHOGENESIS Amyloid deposits do not elicit a significant inflamma-
tory reaction in vivo. This is consistent with the observa-
The structure of an amyloid fibril resembles that of a tion that amyloid fibrils prepared ex vivo do not induce
woven cable, in which three to six filaments wrap around a systemic acute-phase response or an inflammatory
one another to form a fibril (4). Individual filaments reaction when administered to experimental animals.
have a lamellar beta sheet structure that is composed In the absence of significant inflammation, it might be
of thousands of individual, noncovalently associated assumed that amyloid fibrils result in clinical disease
peptide subunits. This higher ordered structure facili- because of a direct cytotoxic effect on surrounding
tates the binding of certain small molecules, such as cells. In Alzheimers disease, oligomers of amyloid-beta
Congo red, and macromolecules, such as proteoglycans protein interfere with cognition in experimental animals
and serum amyloid P component. by causing cytopathic changes in neurons. However,
The initiation and progression of amyloidogenesis there is no evidence that other amyloid proteins are
is entirely dependent on the causative protein, but directly cytopathic to surrounding tissues in vivo. Rather,
generally follows one of three pathogenetic processes: the clinical course of amyloidosis suggests that physical
overproduction and deposition of wild-type protein, interference of amyloid deposits with normal organ
deposition of a mutated variant of a protein, or deposi- function is the primary mechanism of disease pathogen-
tion of protein fragments that have been generated by esis. In cardiac amyloidosis, the intrinsic contractility of
aberrant endoproteolytic cleavage. The first scenario heart muscle is not affected by amyloid deposition;
results in AA or senile ATTR amyloidosis, in which instead, amyloid fibril deposition in the myocardium
serum amyloid A protein or transthyretin is overpro- alters the elastic properties of cardiac muscle and causes
duced and deposited. The second scenario, in which a a restrictive cardiomyopathy with reduced filling. Simi-
mutation destabilizes the wild-type protein and confers larly, retinal cells are not affected by transthyretin depo-
amyloidogenic properties on the new variant protein, sition in the vitreous humor, as years of blindness can
results in hereditary types of amyloidosis such as famil- be reversed by replacing the vitreous fluid. Further-
ial ATTR or AGel amyloidosis. The third scenario is more, patients with familial amyloidosis who undergo
illustrated by AL amyloidosis, in which normal immu- organ transplantation to restore function of failing
noglobulin light chains undergo limited proteolysis that organs do not exhibit recurrent organ dysfunction until
yields the amyloidogenic form. The unfolded proteolytic many years after transplantation, when amyloid depos-
cleavage products then self-associate by a mechanism its once again become clinically evident. These obser-
known as seeded polymerization to form a superstruc- vations suggest that the clinical manifestations of the
ture called a seed, the formation of which is rate- amyloid diseases result from interference with normal
limiting. Once produced, the seed acts as a template for organ and tissue architecture that causes predictable
the rapid addition of new monomers, thus accelerating patterns of progressive organ dysfunction over time.
the assembly of an amyloid fibril. Thus, it is critical to intervene to inhibit amyloid for-
Amyloid fibrillogenesis can occur both in vivo and in mation and deposition, as quickly as possible, so as to
vitro. Virtually any protein can form amyloid fibrils in prevent disease progression.
C H A P T E R 2 9 T H E A M Y L O I D O S E S 53 5
EPIDEMIOLOGY TABLE 29-1. SYSTEMIC AMYLOIDOSIS.

HC IMMUNOHISTOLOGY
The prevalence of the amyloid diseases varies in differ-
ent geographic locations (5). Although in the United TYPE ASSOCIATION CR SAP l/k SAA b2M TTR
States and throughout the world, Alzheimers disease is
AL Plasma cell + + +
the most frequent form of amyloidosis, this chapter will
dyscrasia
focus primarily on the most commonly encountered
systemic forms of the disease. In the United States, AL AA Chronic + + +
is the most common form of systemic amyloidosis. The inflammation
stable population of Olmstead County, Minnesota, has A2M Chronic dialysis + + +
provided reliable data regarding the disease prevalence
between 1950 and 1989, suggesting that approximately ATTR Familial + + +
1 in 100,000 people will develop AL amyloidosis (6). Of
ABBREVIATIONS: /, lambda and kappa light chains; 2M, beta2-
the Mayo Clinic patients with AL amyloidosis, 18% had microglobulin; CR, Congo red; HC, histochemistry; SAA, serum amyloid A
a diagnosis of multiple myeloma and 16% had a prior protein; SAP, serum amyloid P component; TTR, transthyretin.
diagnosis of monoclonal gammopathy of unknown sig- This table illustrates the histochemical and immunohistochemical properties
of the main systemic amyloidoses. Tissue may be stained with Congo red
nificance. Among all patients with multiple myeloma, (CR) to demonstrate presence of amyloid deposits and may subsequently
approximately 20% will develop AL amyloidosis. be immunostained for the specific amyloid subunit protein to determine the
Worldwide, AA is the most common form of systemic specific type of the amyloid deposit.
Listing of the human amyloidoses and their precursor proteins. The amyloid
amyloidosis. In industrialized countries, inflammatory diseases and their subunit proteins have been divided broadly into systemic
conditions are the leading cause of AA amyloidosis, and localized disease. It should be noted that some of the proteins may 29
whereas systemic or chronic infections are responsible have overlapping disease presentations: for example, AL amyloidosis may
present in a localized form, as well as in a systemic form (see text), and
for the majority of cases of AA amyloidosis in develop- AGel amyloidosis may present in a systemic form as a neuropathy, as well
ing countries. as in a localized form. This has been indicated by L (localized ) or S (sys-
Of the hereditary forms of amyloidosis, those due to temic) under the heading: Main Clinical Setting.
transthyretin (TTR) mutations occur most frequently,

causing either systemic ATTR amyloidosis or isolated
senile cardiac amyloidosis. The TTR mutation V122I
is the most common amyloid-associated TTR variant systemic amyloid diseases (AL, AA, ATTR, and A2M)
worldwide and occurs in 3.9% of African Americans are reviewed.
and in over 5% of the population in some areas of
Western Africa. TTR V122I is the most frequently iden- AL Amyloidosis
tified subunit protein in patients with isolated senile
cardiac amyloidosis. The clinical manifestations of AL amyloidosis are
protean (7). The kidney, heart, and liver are the organs
that are most frequently and most prominently involved;
however, all organs other than the central nervous
CLINICAL FEATURES system may be affected. In the kidney, AL amyloid
deposits primarily in the glomerulus, causing nephrotic
Amyloidosis can present as either a systemic or a local- syndrome that usually manifests as proteinuria with
ized disease. There are four classes of systemic amyloi- initial daily urine protein excretion of more than 2 g.
dosis: AL, AA, ATTR, and A2M (Table 29-1). Numerous Not infrequently, in more advanced disease, daily urine
forms of localized amyloidosis have been identified. protein excretion may be as high as 5 to 15 g.
Alzheimers disease and isolated laryngeal and urinary Cardiac involvement develops insidiously. By the
tract amyloid deposits are the most common forms of time most patients with AL amyloidosis present with
localized amyloidosis. clinically apparent cardiac disease secondary to amy-
With the exception of Alzheimers disease, where loidosis, significant myocardial damage already has
direct cellular cytotoxicity in the brain is observed, the occurred. Supraventricular tachyarrhythmias may occur
clinical presentation of the other amyloidoses is caused as a result of atrial enlargement. The restrictive cardio-
by mechanical disruption of normal physiologic func- myopathy can result in significant orthostatic hypoten-
tion as previously described. The clinical presentation sion due to restricted ventricular filling, compounded by
of amyloidosis depends on the amyloid subunit protein autonomic dysfunction caused by peripheral nervous
involved. Table 29-2 summarizes the amyloid proteins, system involvement.
their associated clinical syndromes, and the distribution Bleeding and motility disorders are the most common
of organ involvement in the localized amyloid diseases. presentations of AL amyloid deposition in the gastro-
In the following sections, the most common acquired intestinal tract. Early satiety, caused by delayed gastric
TABLE 29-2. HUMAN AMYLOIDOSIS: PROTEINS, PRECURSORS, AND DISEASE.

TYPE FIBRIL PROTEIN MAIN CLINICAL SETTING
Systemic Acquired AL, Ig light chain Plasma cell disorder

AH, Ig heavy chain Plasma cell disorder
ATTR, transthyretin Familial amyloidosis
AA, (apo) serum amyloid A Inflammation associated
A2M, beta2-microglobulin Dialysis associated
Hereditary AFib, Fibrinogen alpha chain Familial systemic amyloidosis
AAPOAI, Apolipoprotein AI Familial systemic amyloidosis
AAPOAII, Apolipoprotein AII Familial systemic amyloidosis
ALys, Lysozyme Familial systemic amyloidosis
Localized CNS A, beta-protein precursor Alzheimers, Downs

APrP, Prion disease CreutzfeldtJacob disease, Gertsmann
StrausslerScheinker disease
ACys, Cystatin C Herediatry cerebral hemorrhage
with amyloidosis (Icelandic)
ABri ABriPP precursor protein Familial dementia (British/Danish)
Ocular AGel, Gelsolin Familial amyloidosis (Finnish)
ALac, Lactoferrin Familial corneal amyloidosis
AKer, Keratoepithelin Familial corneal amyloidosis
Endocrine-related ACal, (pro) Calcitonin Medullary thyroid carcinoma
AIAPP, Amylin (islet amyloid polypeptide) Insulinoma, type 2 diabetes
AIns, insulin Insulinoma, type 2 diabetes
APro, Prolactin Pituitary amyloid
AANF, Atrial natriuretic factor Cardiac/atrial amyloid
Other AKep, Keratin (keratoepithelin) Cutaneous amyloidosis
AMed, Medin (lactadherin) Aortic amyloidosis in the elderly
emptying, is also a frequent symptom. Bacterial stiffness of the lungs and restrictive pulmonary physiol-
overgrowth with significant malabsorption may cause ogy. Infrequently, AL amyloid may deposit locally in
diarrhea and may result in deficiencies of vitamin B12, laryngeal and tracheal tissue, resulting in hoarseness
folic acid, and carotene deficiency. Hemorrhage may and, sometimes, significant upper airway obstruction.
occur in any part of the gastrointestinal tract, although Hematological abnormalities of AL amyloidosis
the stomach and small intestine are more frequently include purpura and thrombosis. Amyloid infiltration of
affected. AL amyloid often deposits in the liver, although blood vessel walls causes the vessels to become fragile.
it rarely produces symptoms. Disruption of cutaneous capillaries results in extra
Peripheral nervous system involvement, which can vasation of red blood cells and purpura. In a patient
occur months to years before visceral involvement, with AL amyloidosis, periorbital purpura can result
occurs in as many as 20% of patients with AL amyloi- from maneuvers as innocuous as rubbing the eyes or
dosis. It may manifest as either or both a sensorimotor keeping the head facing downwards for a prolonged
neuropathy and an autonomic neuropathy. Paresthesias period, leading to the characteristic raccoon eyes
develop first in the lower extremities and, over time, appearance. Factor X deficiency occurs in this disorder
may extend proximally. Motor nerve involvement, and is believed to result from absorption of this clotting
although rare, may be severe and may result in foot drop factor by large amyloid deposits in the spleen, as well as
and gait abnormalities. Autonomic neuropathy occurs from protein loss in the setting of nephrotic syndrome.
commonly in patients with AL amyloidosis, often result- This, in addition to abnormalities in the plasminogen
ing in gastrointestinal dysmotility, impotence, and ortho- system, results in an increased incidence of venous
static hypotension. thrombosis.
There are two predominant pulmonary manifesta- Although AL amyloidosis is the most prevalent form
tions of AL amyloidosis. Occasionally, AL amyloid may of amyloidosis that involves skin, skeletal muscle, and
present as a tumorlike mass in the lung parenchyma, the tongue, its soft tissue and articular manifestations
often with concomitant enlargement of hilar and occur infrequently. Carpal tunnel syndrome, often bilat-
peritracheal lymph nodes. Although these masses eral, may be caused by amyloid deposits in the wrist
may enlarge progressively, they generally are not life- compressing the median nerve and may occur years
threatening. Alternatively, there may be diffuse inter- before the full clinical presentation of systemic disease.
stitial infiltration of the lung parenchyma, causing Amyloid infiltration of skeletal muscle, typically involv-
ing the tendons and capsular structures of the shoulders, choice (10). In patients with more advanced disease,
may result in pseudohypertrophy (shoulder pad sign) intermediate-dose melphalan with stem cell rescue may
in a patient who is otherwise very cachectic. Amyloid provide a better tolerated alternative therapy (10).
deposits in bone, such as in the femoral neck, may Among patients who are eligible for and receive
appear as cystic lucencies on radiographs and may com- treatment with bone marrow transplantation, mean
promise the tensile strength of bone, resulting in patho- survival is extended to 40 months, whereas it remains
logic fractures. Although uncommon, macroglossia may 18 months in those patients who are ineligible for
develop in patients with AL amyloidosis. The enlarged transplantation.
tongue is firm to palpation and may cause problems
with speech and deglutition and produce the sensation
of choking.
AA Amyloidosis
AL amyloidosis results from the abnormal and clonal Serum amyloid A (SAA) protein is a member of the
expansion of B-cell lymphocytes. However, although acute-phase protein family (11). The normal plasma
necessary for the elaboration of this disease, it is concentrations of SAA range between 1 and 3 g/mL.
not sufficient to have monoclonal cell expansion and During an acute-phase response, concentrations rapidly
light or heavy chain synthesis. AL amyloidosis may increase 200- to 300-fold and, upon its resolution, return
develop in the setting of Waldenstroms macroglobulin- to the normal range within days. Amyloidosis due to
emia, multiple myeloma, monoclonal gammopathy of SAA is the most common form of systemic amyloidosis
unknown significance, or benign B-cell expansion. The worldwide. Any inflammatory stimulus that turns on
amount of protein produced by these clones seems the SAA gene can induce AA amyloidosis. The most
unimportant, as between 10% and 20% of patients with common cause of AA amyloidosis is tuberculosis but, 29
AL amyloidosis have no monoclonal protein detectable in industrialized nations, rheumatologic diseases such
in serum or urine. The primary structure of light chains as rheumatoid arthritis, juvenile rheumatoid arthritis,
appears to be particularly important to the develop- spondyloarthritides, and autoinflammatory syndromes
ment of this condition because normal serum ratios of are the leading causes of AA amyloidosis. AA amyloid
light chains are reversed and lambda chains are found fibrils may be detected in biopsy specimens from asymp-
in AL amyloid deposits far more frequently than are tomatic individuals, preceding any signs of systemic
kappa chains. Certain lambda chain subtypes have a amyloidosis by many years.
greater propensity to form fibrillar deposits than do The most important manifestation of AA amyloido-
others. Furthermore, AL amyloid fibril subunit sis is renal disease, which generally presents as nephrotic
proteins almost always contain the variable segment syndrome. This may occur after 10 to 20 years of inflam-
(VL) of the immunoglobulin light chain, either in its matory arthritis and may occur in patients in whom the
entirety or as a segment. However, the reasons for selec- underlying primary inflammatory disease has subsided.
tive organ involvement and for differential rates of Thus, AA amyloidosis may be confused with the presen-
disease progression among affected individuals remain tation of other pathologic processes involving the kidney,
unclear. such as gold-induced nephropathy. Furthermore, acute
AL amyloidosis is the most serious of the amyloid inflammatory triggers may accelerate the occurrence of
diseases, with survival following tissue diagnosis of only systemic AA amyloidosis in patients who previously
18 to 24 months (8,9). An initial presentation with have been exposed to inflammatory insults, such as
carpal tunnel syndrome or peripheral neuropathy fre- tuberculosis or other chronic infections. Therefore,
quently connotes a better prognosis than does an initial nephrotic syndrome may develop over the course of
presentation with cardiac involvement. Multiple several weeks in patients with new active tuberculosis,
myeloma may appear after the diagnosis of AL amyloi- perhaps because preexisting foci of localized amyloid
dosis in a small proportion of patients, emphasizing the deposits may accelerate the progression of systemic AA
importance of continued follow-up and appropriate amyloidosis.
testing. Gastrointestinal hemorrhage may occur in patients
The treatment of AL amyloidosis is directed with AA amyloid. Deposition of protein AA along
towards reducing the aberrant plasma cell clone with blood vessel walls leads to decreased distensibility and
medications, such as melphalan and prednisone (8,9). increased fragility, with episodic vessel rupture and
Occasionally, chemotherapeutic agents, such as cyclo- bleeding. Although described in the literature, clinically
phosphamide or chlorambucil, are also used. Vinca alka- significant involvement of the heart, nerves, skeletal
loids or adriamycin should be used with great caution, muscle, or tongue is very unusual in AA amyloidosis. It
as they may be especially toxic to those patients who is important to consider the diagnosis of AA amyloido-
have established neuropathy or cardiomyopathy. For sis in patients who present with nephrotic syndrome,
eligible patients, high-dose intravenous melphalan with even in those with no history of an inflammatory or
autologous stem cell transplantation is the treatment of infectious disease. This presentation occurs in patients
with familial Mediterranean fever (FMF) who have ATTR Amyloidosis

subclinical elevation of SAA and other acute-phase
reactants, but who are otherwise asymptomatic. These The hereditary amyloidoses are caused by a variety of
patients eventually may progress to systemic amyloido- unrelated proteins (Table 29-2). These syndromes
sis. Because many of these patients with FMF have lived exhibit autosomal dominant inheritance with varying
in developing countries, environmental exposures, such degrees of penetrance. Even though the gene mutation
as endemic infections, may potentiate this presentation is present at birth, clinical features of disease usually do
by causing chronic inflammation, thereby increasing not manifest until after the third decade of life. These
their risk of developing AA amyloidosis. syndromes share clinical features, typically presenting
Serum amyloid A, a highly conserved acute-phase with cardiomyopathy, nephropathy, and polyneuropa-
protein, is produced primarily in the liver. There are thy. However, each amyloidogenic protein should be
four SAA genes: saa1 and saa2 are under acute physio- considered to cause a discrete disease entity, with other
logic regulation, saa3 is a pseudogene and is not unique clinical features. The vast majority of the heredi-
expressed, and saa4 is expressed at a continuous basal tary amyloidoses are caused by deposition of trans-
level. Although each SAA protein has been identified thyretin (TTR) variants, with more than 100 mutations
as an apolipoprotein component of the high-density having been identified (13). TTR is also known as pre-
lipoprotein (HDL) particle, only the SAA4 protein albumin, because it runs faster than does albumin on gel
appears to function in this capacity, under physiological electropheresis. Transthyretin is a plasma protein that
conditions, and does not appear to be involved in the carries about 20% of thyroxine in plasma, as well as
pathogenesis of amyloid disease. SAA1 and SAA2, vitamin A associated with retinol binding protein. TTR
which are mainly responsible for the pathogenesis of is synthesized in the liver as a single polypeptide and, in
AA amyloidosis, also can be found in the HDL particle plasma, forms a tetramer that consists of four identical
at low levels. However, serum levels of both of these monomers. The wild-type protein has significant beta
proteins increase dramatically in response to gluco- sheet structure; a single amino acid substitution contrib-
corticoids and to proinflammatory cytokines, such as utes to its aggregation and fibril formation.
interleukin 1 and interleukin 6. Therefore, the broad Not all TTR-related amyloidosis is due to mutations
conservation of these proteins across species and the in TTR. Fragments of wild-type TTR may form amyloid
tightly regulated acute control of their expression fibrils that deposit in the heart, causing senile cardiac
suggest a more important role for these SAA proteins amyloidosis. This nonheritable disorder affects about
in the control of inflammation. Thus, it is thought that 25% of individuals over the age of 80 years.
chronic inflammation results in continuous overproduc- Most TTR-related amyloidoses present initially with
tion of these proteins, which, over time, lead to form peripheral neuropathy. This often is a sensorimotor neu-
amyloid fibrils and deposit in tissues. ropathy involving the distal lower extremities that pro-
Full-length SAA1 and SAA2, each 104 amino acids, gresses proximally to involve the proximal extremities.
are cleaved at their N-termini by endoproteases in the Carpal tunnel syndrome may be the initial presentation
liver to produce fragments of 76 amino acids. Both the in 20% of cases, with ATTR amyloid deposits compress-
full-length proteins and the cleaved products are found ing the median nerve. Autonomic neuropathy can cause
in serum and in AA amyloid deposits. In AA amyloido- gastrointestinal symptoms, such as alternating constipa-
sis, both SAA1 and SAA2 can form amyloid fibrils; tion and diarrhea, or genitourinary symptoms, such as
however, SAA1 usually contributes much more to fibril incontinence or impotence.
formation than does SAA2. The reason for this is Although peripheral nervous system disease is associ-
unclear. Furthermore, the saa1 gene has single nucleo- ated with significant morbidity, cardiomyopathy and
tide polymorphisms that define three haplotypes: 1.1 renal disease are the predominant causes of mortality
(1.alpha), 1.2 (1.beta), and 1.3 (1.gamma). Caucasian among patients with ATTR amyloidosis. The majority
patients with the 1.1/1.1 (1.alpha/1.alpha) genotype (60%) of deaths are due to cardiomyopathy, whereas
have a three- to sevenfold increased risk of developing renal disease accounts for only 5% to 7% of deaths.
AA amyloidosis (12). Vitreous amyloid deposits occur in 20% of patients with
Treatment of AA amyloidosis is directed towards ATTR amyloidosis. These are thought to arise from TTR
controlling the underlying inflammatory disease process. that is secreted by the choroid plexus and that forms
The clinical outcome of AA amyloidosis is more favor- amyloid fibrils, which accumulate in the vitreous.
able when the serum SAA concentration remains below ATTR amyloidosis is diagnosed by using genetic
10 mg/L (11). For more advanced disease, renal trans- techniques to identify TTR mutations: the majority of
plantation effectively restores renal function in patients mutations in ATTR occur in exons 2 through 4. The
with AA amyloidosis. However, unless the underlying use of polymerase chain reactions to identify restric-
inflammatory process is suppressed, AA amyloid may tion fragment length polymorphisms has become
deposit in the transplanted kidney. commonplace to diagnose affected patients and to
identify carriers of the mutant gene among their family in number and enlarge with time. Pathologic fractures,
members. especially of the femoral neck, may occur through areas
ATTR amyloidosis is treated by replacing the liver of bone weakened by amyloid deposits.
and other affected organs. Liver transplantation results Visceral deposits of A2M amyloid also have been
in synthesis of wild-type (normal) TTR, with rapid dis- identified in patients receiving long-term dialysis, most
appearance of the variant transthyretin from the circu- for 10 years or longer. Although gastrointestinal tract
lation. Combined liver/kidney transplantation has been and cardiovascular complications have been reported,
performed in patients with ATTR amyloidosis with visceral A2M amyloid deposits usually do not cause
significant renal involvement. In patients affected by symptoms.
ATTR amyloidosis, it is important to intervene before Beta2-microglobulin, the subunit protein in A2M
severe malnutrition or cardiomyopathy develops, amyloidosis, is the light chain of class I major histocom-
because transplant survival declines rapidly in those patibility antigens. Normally present in most biologic
affected individuals. Amyloid deposition may continue, fluids, it is filtered by glomeruli and catabolized after
even after organ transplantation, perhaps related to the proximal tubular reabsorption. Because the rate of
presence of small deposits of abnormal protein that beta2-microglobulin synthesis exceeds the rate of its
serve as a nidus for the subsequent deposition of normal removal by different dialysis modalities, serum beta2-
proteins. Because of this, patients with earlier presenta- microglobulin levels are elevated up to 60-fold in
tions of ATTR amyloidosis may require repeat organ patients undergoing dialysis.
transplantation. Current theories regarding the pathogenesis of A2M
amyloidosis implicate the role of advanced glycation
Ab2M Amyloidosis end product (AGE) modification of proteins, which 29
confers on the proteins resistance to proteolysis,
A2M amyloid deposits predominantly in osteoarticular increased affinity for collagen, and the ability to stimu-
tissue (14). The presence of shoulder pain, carpal tunnel late activated mononuclear leukocytes to release pro-
syndrome, and irreducible flexion contractures of the inflammatory cytokines such as tumor necrosis factor
fingers in a patient undergoing long-term hemodialysis alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and
is highly suggestive of A2M (beta2-microglobulin or interleukin 6 (IL-6). AGE-modified proteins are poorly
dialysis-related) amyloidosis. Signs and symptoms of cleared by dialysis modalities (14,15). Thus, patients
A2M amyloidosis are infrequently observed in patients undergoing dialysis have elevated levels of these modi-
with chronic renal failure who have not yet received fied proteins, as compared with individuals with normal
dialysis treatment. renal function or functioning renal allografts. AGE-
Axial skeletal involvement, which occurs in about modified beta2-microglobulin has been identified in
10% of patients undergoing long-term hemodialysis, amyloid deposits of patients receiving long-term hemo-
presents as a destructive spondyloarthropathy, the dialysis and may play a significant role in the develop-
radiographic features of which include narrowing of the ment of A2M amyloidosis. The propensity for A2M
intervertebral disk spaces and erosion of the vertebral amyloid to deposit in osteoarticular tissue may be due
endplates without appreciable formation of osteophyte. to the enhanced binding of AGE-modified proteins to
The lower cervical spine is most often affected; however, collagen. Surgery may be necessary for symptomatic
similar changes may also occur in the dorsal and lumbar patients with large deposits of A2M amyloid. Over the
spine. Cystic deposits of A2M amyloid within the odon- past decade, hemodialysis with newer, more permeable
toid process and the vertebral bodies of the upper cervi- membranes appears to have postponed the onset of
cal spine and peri-odontoid soft tissue masses of A2M carpal tunnel syndrome and bone cysts and reduced the
amyloid, termed pseudotumors, have also been demon- incidence of A2M amyloidosis. A2M amyloid deposits
strated. Although neurologic compromise occurs infre- do not progress and may regress in patients who have
quently, significant myelopathy has resulted from A2M undergone successful renal transplantation. Patients
amyloid deposits in the cervical and lumbar spinal canal, with A2M amyloidosis who undergo successful renal
especially in patients who have received hemodialysis transplantation experience a marked reduction in joint
for 20 years or longer. pain and stiffness. Thus, early renal transplantation in
Cystic bone lesions may develop in the appendicular appropriate candidates, before significant A2M amyloid
skeleton of patients undergoing long-term hemodialysis. deposition has occurred, may be the most effective pre-
Subchondral amyloid cysts, most commonly found in ventive measure currently available for this condition.
the carpal bones, may also occur in the acetabulum and
in long bones, such as the femoral head or neck, the
humeral head, the distal radius, and the tibial plateau.
Localized Amyloidosis
Unlike brown tumors of hyperparathyroidism, these The localized forms of amyloidosis can involve many
bone cysts typically occur adjacent to joints and increase organ systems including the eye, the genitourinary tract,
the endocrine system, and the respiratory tract (Table DIAGNOSIS

29-2). With the exception of Alzheimers disease, these
types of amyloidosis are rare and challenging to diag- Imaging
nose. The pathophysiologic principles governing disease
expression in the localized forms of amyloidosis are Scintigraphy using 123I-serum amyloid P component has
similar to those for the systemic forms. The most fre- been used to identify the systemic distribution of
quently occurring forms of localized amyloidosis affect amyloid deposits (17). Serial imaging has demonstrated
the genitourinary and respiratory tracts (13). both progression and regression of amyloid deposition.
Localized genitourinary amyloidosis may involve the However, this technique is limited in that it exposes
entire tract, but more frequently involves the bladder patients to radioactive allogeneic protein and it is avail-
and urethra and causes hematuria or signs of obstruc- ability only in specialized centers.
tion. The responsible amyloid subunit protein often is The only widely available imaging technique that
immunoglobulin light or heavy chain, but occasionally yields information specific for the diagnosis of systemic
may be SAA. The localized finding of AL or AH amyloid amyloidosis is echocardiography (18,19). Specific
deposits may prompt an exhaustive search for systemic echocardiographic features of amyloidosis include atrial
disease, often with negative results. However, localized enlargement, reduced left ventricular size, biventricular
AL or AH amyloidosis usually is self-limited and does and atrial septal thickening, and increased myocardial
not portend a severe prognosis. Treatment consists of echogenicity. In more advanced disease, restrictive filling
excision of the localized amyloid deposits. patterns become more evident. Unfortunately, by the
In the respiratory tract, AL amyloid deposition often time a patient has echocardiographic manifestations of
produces localized forms of disease. Three forms of amyloidosis, median survival is only 6 months. Also,
localized amyloidosis affect the respiratory tract: tra- echocardiography does not demonstrate regression of
cheobronchial amyloidosis, which accounts for half of amyloid disease, even after successful therapy.
cases, nodular parenchymal amyloidosis, which accounts Cardiac magnetic resonance imaging (MRI) is a
for about 45% of cases, and diffuse parenchymal amy- rapidly advancing field and has supplemented echocar-
loidosis, which accounts for about 5% of cases. In tra- diography in the diagnosis of cardiac amyloidosis (20).
cheobronchial amyloidosis, there is either localized or Cardiac MRI, using gadolinium enhancement, provides
diffuse involvement of the tracheobronchial tree with high spatial resolution (approximately 2 mm) and tissue
submucosal deposition of amyloid. Computed tomogra- contrast, differentiating diseased tissue from normal
phy (CT) scanning demonstrates nodules or plaques of myocardium. In patients with amyloid involving the
amyloid, sometimes with calcification, or circumferen- heart, cardiac MRI demonstrates qualitative global and
tial thickening of the trachea, main bronchus, and lobar subendocardial enhancement after intravenous admin-
or segmental bronchi with luminal narrowing. In nodular istration of gadolinium. Although there are no sine qua
parenchymal amyloidosis, CT scanning demonstrates non MRI findings for cardiac amyloidosis, future studies
nodules with sharp and lobulated margins in a periph- may elucidate a combination of noninvasive tools that
eral, subpleural location. The nodules vary in size from could be used to select patients for definitive, more inva-
micronodular to up to 15 cm in diameter; calcification is sive, endomyocardial biopsy, as well as to follow the
seen in half of the cases. In diffuse parenchymal or natural history of cardiac amyloid disease.
alveolar septal amyloidosis, amyloid deposition is wide- Because there are no findings specific for systemic
spread, involving both small vessels and the parenchy- amyloidosis, imaging should be used as an adjunct to
mal interstitium; multifocal small nodules of amyloid physical examination and appropriate laboratory testing
also may be present. High-resolution CT scanning dem- to evaluate symptomatic patients. Although the gastro-
onstrates abnormal reticular opacities, interlobular intestinal tract is almost always involved in systemic
septal thickening, small (24 mm diameter) nodules, and amyloidosis, radiographic manifestations of gastrointes-
confluent consolidated opacities predominantly in the tinal amyloidosis are infrequently seen. Ischemia and
subpleural regions (16). This pattern of localized amy- resulting edema, due to amyloid deposition in vessels,
loidosis sometimes is indistinguishable from systemic may cause symmetrical thickening of mucosal folds that
amyloidosis. Patients with this form of diffuse parenchy- appear as target lesions on abdominal CT scanning.
mal pulmonary amyloidosis are more likely to die from Ultrasound or CT scanning may reveal enlargement
respiratory failure than are patients with tracheobron- of the kidneys in early stages of amyloidosis. Ultra-
chial or nodular parenchymal amyloidosis.. sonography usually demonstrates diffusely increased
Localized amyloid deposition limited to the respira- echogenicity of the renal parenchyma with preservation
tory tract may be excised to cure this form of limited of the corticomedullary contrast, because the cortical
amyloidosis. Other amyloid subunit proteins may also architecture remains grossly normal in early disease. As
deposit in the respiratory tract, but these are rare and disease progresses, the kidneys may appear contracted
generally do not result in significant pathology. with substantial cortical thinning.
Histopathology deposits renders sural nerve biopsy less sensitive than

biopsy of other involved organs.
Once amyloidosis is suspected, its diagnosis is confirmed Three points are essential to consider in the diagnosis
by a biopsy that demonstrates the characteristic apple of the amyloid diseases (23). (1) The pretest probability
green birefringence under polarizing microscopy and of a biopsy for amyloid is determined by the patients
the specific subunit protein by immunohistochemistry. clinical presentation. To determine pretest probability,
The biopsy may be taken from either an involved or an it is critical to consider the patients history (including a
uninvolved organ. The latter approach usually is pre- thorough family history), in the context of a complete
ferred because of the high risk of complications and physical examination and laboratory evaluation that
discomfort associated with biopsy of internal organs. includes a serum and urine protein electrophoresis and
Three types of screening biopsies typically are per- urinalysis to assess for proteinuria. (2) Immunohisto-
formed to diagnose amyloidosis: gastrointestinal tract chemistry should always be performed on tissue speci-
(rectal or gastroduodenal) biopsy, subcutaneous abdom- mens that are being evaluated for amyloid deposits to
inal fat aspiration, and labial salivary gland biopsy (5). identify the specific amyloid subunit protein. Occasion-
Rectal biopsy, performed by sigmoidoscopy or proc- ally, a patient with an inflammatory disorder may develop
toscopy, is the preferred gastrointestinal tract biopsy AL disease or a patient with a serum monoclonal protein
because of the accessibility of this site (5). The biopsy may develop AA amyloidosis. Because the treatment of
specimen must include submucosal blood vessels, which these diseases differ dramatically, it is imperative to
are more likely to contain amyloid deposits than are establish a definite diagnosis. (3) Deposits of AA amyloid
those in the mucosa or muscularis layers. Although the in abdominal fat are not uncommon in patients with
data are most robust for rectal biopsy, gastric or duode- inflammatory diseases, such as rheumatoid arthritis or 29
nal biopsies can be diagnostic of amyloidosis if the tissue ankylosing spondylitis. However, even after long-term
specimen contains blood vessels of the appropriate follow-up, most of these patients do not have evidence
size. of organ dysfunction. Thus, not all patients who have
Abdominal fat aspiration was first performed after it AA amyloid deposits have AA amyloid disease; biopsy
was observed that specimens taken at autopsy of patients results should be interpreted with caution.
with amyloidosis often contained amyloid deposits
around adipocytes; the highest density of amyloid
deposits was in the adipose tissues isolated from the SUMMARY
scalp and the abdominal wall (21). The reported sensi-
tivity of abdominal fat aspiration varies between 55% Rheumatologists play an important role in the recogni-
and 75%, but is similar to that of rectal biopsy. This tion and treatment of the amyloid diseases. The amyloi-
technique is useful for the diagnosis of AA, AL, and doses occur and progress insidiously, taking years to
ATTR amyloidosis; however, because of the limited cause clinically apparent organ damage. Delay in diag-
organ distribution of A2M amyloid deposits, abdomi- nosis may result in an increased burden of amyloid
nal fat aspiration cannot reliably be used to diagnose fibrils and may reduce the opportunity to effectively
A2M amyloidosis. deliver therapy and improve prognosis. Each of the
Labial salivary gland biopsy samples the accessory amyloidoses presents with a unique constellation of
salivary glands in the labial mucosa (22). Previously, findings which, although not pathognomonic, may lead
gingival biopsy had been used to detect amyloid deposi- an astute physician to follow appropriate diagnostic
tion, but was found to be of low sensitivity. In AA, algorithms and intervene expeditiously in the disease
ATTR, and AL amyloidosis, labial salivary gland biopsy process. Finally, although the amyloid diseases are very
has sensitivity comparable to that of rectal biopsy or heterogeneous, the clinical approach to their diagnosis
abdominal fat aspiration. and treatment is straightforward and an earnest under-
If the suspicion for amyloidosis is high and one of the standing of the pathogenetic principles that contribute
above techniques does not yield a positive finding, an to disease expression should guide the rational manage-
involved organ should be biopsied. In the setting of ment of the patient.
renal involvement, a kidney biopsy usually provides
diagnostic information. The organs predominantly
involved in ATTR and AL amyloidosis, the heart and REFERENCES
the bone marrow, should be biopsied in these forms of
the amyloidosis to confirm the diagnosis. Although the 1. Sipe JD, Cohen AS. Review: history of the amyloid fibril.
sural nerve may be involved in the amyloid diseases, J Struct Biol 2000;130:8898.
sural nerve biopsy is less desirable because it usually is 2. Majno G, Joris I. Extracellular pathology. In: Cells,
painful and slow to heal and may leave a residual sensory tissues, and disease: principles of general pathology.
deficit. Furthermore, the patchy distribution of amyloid Oxford: Oxford University Press; 2004:250267.
3. Pepys MB. Amyloidosis. Annu Rev Med 2006;57:223 14. Kay J. 2-microglobulin amyloidosis. Int J Exp Clin Invest
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4. Merlini G, Bellotti V. Mechanisms of disease: molecular 15. Miyata T, Inagi R, Iida Y, et al. Involvement of beta 2-
mechanisms of amyloidosis. N Engl J Med 2003;349: microglobulin modified with advanced glycation end
583596. products in the pathogenesis of hemodialysis-associated
5. Buxbaum J. The amyloidoses. In: Klippel JH, Dieppe PA, amyloidosis. Induction of human monocyte chemotaxis
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6. Kyle RA, Linos A, Beard CM, et al. Incidence and natural 16. Georgiades CS, Neyman EG, Barish MA, Fishman EK.
history of primary systemic amyloidosis in Olmsted Amyloidosis: review and CT manifestations. Radiograph-
County, Minnesota, 1950 through 1989. Blood 1992;79: ics 2004;24:405416.
18171822. 17. Hawkins PN, Lavender JP, Pepys MB. Evaluation of sys-
7. Kyle RA, Gertz MA. Primary systemic amyloidosis: clin- temic amyloidosis by scintigraphy with 123I-labeled serum
ical and laboratory features in 474 cases. Semin Hematol amyloid P component. N Engl J Med 1990;323:508513.
1995;32:4559. 18. Shah KB, Inoue Y, Mehra MR. Amyloidosis and the
8. Skinner M, Anderson J, Simms R, et al. Treatment of heart: a comprehensive review. Arch Intern Med 2006;166:
100 patients with primary amyloidosis: a randomized trial 18051813.
of melphalan, prednisone, and colchicine versus colchi- 19. Falk RH, Plehn JF, Deering T, et al. Sensitivity and speci-
cine only. Am J Med 1996;100:290298. ficity of the echocardiographic features of cardiac amyloi-
9. Kyle RA, Gertz MA, Greipp PR, et al. A trial of three dosis. Am J Cardiol 1987;59:418422.
regimens for primary amyloidosis: colchicine alone, mel- 20. Maceira AM, Joshi J, Prasad SK, et al. Cardiovascular
phalan and prednisone, and melphalan, prednisone, and magnetic resonance in cardiac amyloidosis. Circulation
colchicine. N Engl J Med 1997;336:12021207. 2005;111:186193.
10. Comenzo RL. Amyloidosis. Curr Treat Options Oncol 21. Westermark P, Stenkvist B. A new method for the diag-
2006;7:225236. nosis of systemic amyloidosis. Arch Intern Med 1973;132:
11. Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins 522523.
PN. Amyloid load and clinical outcome in AA amyloido- 22. Hachulla E, Janin A, Flipo RM, et al. Labial salivary
sis in relation to circulating concentration of serum gland biopsy is a reliable test for the diagnosis of primary
amyloid A protein. Lancet 2001;358:2429. and secondary amyloidosis. A prospective clinical and
12. Booth DR, Booth SE, Gillmore JD, Hawkins PN, Pepys immunohistologic study in 59 patients. Arthritis Rheum
MB. SAA1 alleles as risk factors in reactive systemic AA 1993;36:691697.
amyloidosis. Amyloid 1998;5:262265. 23. Comenzo RL, Zhou P, Fleisher M, Clark B, Teruya-
13. Benson MD. Amyloidosis. In: Koopman WJ, Moreland Feldstein J. Seeking confidence in the diagnosis of sys-
LW, eds. Arthritis and allied conditions: a textbook temic AL (Ig light-chain) amyloidosis: patients can have
of rheumatology. Philadelphia: Lippincott Williams & both monoclonal gammopathies and hereditary amyloid
Wilkins; 2005:19331960. proteins. Blood 2006;107:34893491.
CHAPTER 30
Neoplasms of the Joint

ANDREW J. COOPER, MD
JAMES D. REEVES, MD
SEAN P. SCULLY, MD, PHD
The most common primary neoplasms of the joint intracapsular chondromas, and synovial
are pigmented villonodular synovitis and synovial chondrosarcomas.
chondromatosis and a diagnosis is best made Secondary neoplasms of the joint are synovial
using magnetic resonance imaging (MRI). sarcoma and giant cell tumors.
Other primary lesions are rare and include The malignancies that metastasize to bone also
lipoma arborescens, synovial hemangiomas, may invade the articular space.
Although some neoplasms originate in the joint, others The typical presentation is a 20- to 40-year-old patient
penetrate or metastasize to it. Pigmented villonodular who complaints of a traumatic swelling of a single joint
synovitis and synovial chondromatosis are the most (49). The knee is involved 80% of the time. Some
common proliferative disorders arising from within the patients may experience pain, warmth, and stiffness in
joint. Other primary lesions are rare and include lipoma the joint (7,8,10). Mechanical symptoms, such as locking
arborescens, synovial hemangiomas, intracapsular and instability, may develop, particularly if the joint
chondromas, and synovial chondrosarcomas. Synovial contains a large pedunculated nodule (11). The symp-
sarcoma and giant cell tumors are neoplasms that tend toms typically are episodic or slowly progressive (7).
to extend into the joint. The malignancies that metasta- Results of laboratory studies, such as a complete blood
size to bone also may invade the articular space. count and erythrocyte sedimentation rate, are within
normal limits and can help exclude infection and rheu-
matoid arthritis. Aspiration of the joint reveals a brown,
PRIMARY NEOPLASMS red, or yellow fluid (7,9,12).
During the initial stages, plain radiographs reveal
OF THE JOINT periarticular synovial swelling, absence of synovial cal-
cification, normal bone density, and preservation of the
Pigmented Villonodular Synovitis cartilage space (13). Bone changes develop in the later
Pigmented villonodular synovitis (PVNS) is a rare pro- stages. Recent evidence suggests that tissue expression
liferative disorder of unknown etiology that affects the of matrix metalloproteinases in PVNS contributes to
synovial lining. PVNS does not exhibit cellular atypia, the destruction of bone and cartilage often seen in
but there is recent evidence of cytogenetic abnormali- PVNS (14). In joints with small synovial volumes (e.g.,
ties. Yet the presence of synovitis suggests an inflamma- the hip), the synovial villi may abut the bone and cause
tory process. The etiology of PVNS remains unresolved. subtle erosions. As the villi grow, pressure within the
Regardless, it is characterized by inflammation and joint capsule increases. The villi then invade the bone
deposition of hemosiderin in the synovium (1). It occurs and juxta-articular cysts appear (15,16). If the disorder
in three forms: an isolated lesion involving the tendon is not diagnosed and treated, joint destruction can
sheaths (giant cell tumor of the tendon sheath); a soli- ensue.
tary intra-articular nodule (localized PVNS); and a Due to deposition of hemosiderin, a magnetic reso-
diffuse villous and pigmented lesion involving synovial nance image (MRI) typically will show nodular foci of
tissue (diffuse PVNS) (2,3). This section focuses on the decreased signal on both T1 and T2 images (Figures
latter two forms. 30-1, 30-2) (12). Additionally, low signal on fast field
543
544 ANDREW J. COOPER, JAMES D. REEVES, AND SEAN P. SCULLY
A B
FIGURE 30-1
(A) T2 magnetic resonance imaging (MRI) sequence of heterogeneous mass anteriorly in the
knee consistent with nodular PVNS. (B) T1 MRI of pigmented villonodular synovitis (PVNS)
showing extensive involvement posteriorly with hypointense areas consistent with hemosiderin.
echo (FFE) sequences are helpful in the diagnosis of If the diagnosis remains in question, an arthroscopic
PVNS. Joint effusions will be present, and commonly exam can show the gross appearance of the lesion. In
bone erosions will be identified in PVNS of the hip, its localized form, PVNS appears as a solitary yellow,
ankle, elbow, and wrist (17). In cases of localized PVNS, pedunculated nodule. The surface often is lobulated
the MRI will show the single nodular mass (6). It also and cuts with a buttery feel. It often occurs on the
may show the extent of the disease, which helps the anterior aspect of the knee and is similar in appearance
surgeon plan an appropriate treatment. to giant cell tumor of the tendon sheath (6,8). In the
diffuse form, the thickened synovium contains folds of
villi and sessile or pedunculated nodules. The entire
joint appears to be covered with brown and orange
seaweed. The nodules have been described as grape-
like masses protruding in the joint cavity. They typi-
cally are friable and bleed with minimal trauma. Some
of the villi contain bulbous ends and give the appear-
ance of a straggly beard. Other villi possess fine points
and look like ferns. The villi may invade bone or, less
commonly, extend beyond the joint capsule and into
the extra-articular soft tissue (46,18). A biopsy can
confirm the diagnosis of PVNS. All three forms of
PVNS share a similar histology, characterized by hyper-
cellular subsynovial connective tissue (19). The syno-
vial lining is one to three layers thick and outlines the
nodules and villi. In some areas, the ends of the villi
fuse to form clefts. Histologically, the subsynovial
stroma contains collagen-producing fibroblast and
FIGURE 30-2 phagocytic histiocytes. These cells are polyhedral and
Magnetic resonance image showing extensive synovium and contain pale nuclei and abundant cytoplasm. They tend
nests of cartilaginous loose bodies. to proliferate and may be visualized in their mitotic
C H A P T E R 3 0 N E O P L A S M S O F T H E J O I N T 5 45
stage. Some histiocytes will phagocytize hemosiderin; loose areolar tissue, and then protrude into the joint
some will fuse to form multinucleated cells; and others cavity that is covered only by the synovial lining. Even-
will form foam cells. The hemosiderin-laden macro- tually, the cartilaginous nests are extruded and form
phages give PVNS its rusty brown color and are more loose bodies (Figure 30-2). Nourished by the synovial
common in the diffuse form. The lipid-filled foam cells fluid, the chondroblasts continue to multiply. As the
account for the yellow color that dominates the local- loose body enlarges, its central portion loses contact
ized form. The foam cells and hemosiderin-laden mac- with the nutritional source and dies. The necrotic area
rophages tend to localize to the periphery, and giant then calcifies (22).
cells tend to be scattered throughout the areolar tissue On gross exam, the synovial lining appears swollen
(Figure 30-1) (19). because it contains multiple nodules of hyaline carti-
Good clinical outcomes can be obtained with local lages (Figure 30-3). These masses are of various sizes
excision of a solitary nodule (6). However, once diffuse and are of a translucent whitish-gray color. The micro-
pigmented villonodular synovitis is diagnosed in a young scope shows the cartilage nests to be in different stages
patient, a total synovectomy is recommended (9,12). If of maturity. Occasionally, a capillary may invade some
the MRI shows the lesion to be accessible by arthros- of these areas and allow endochondral ossification to
copy, arthroscopic resection may be worthwhile, as it is occur (22).
associated with relatively low morbidity (12). However, Synovial chondromatosis occurs in three phases (23).
an open synovectomy may be necessary because lesions During the initial phase, there are no loose bodies, but
typically extend beyond the reach of the arthroscope metaplastic activity occurs within the synovium. Loose
(2,3,9). In the past, synovectomy has been associated bodies appear during the intermediate phase. During
with recurrence rates as high as 40%. An incomplete the final phase, metaplastic activity ceases, but multiple
synovectomy has been cited consistently as the main loose bodies persist.
cause (2,7,9,16). Similar conclusions are found when The disease most often afflicts those in their third or
arthroscopic synovectomy is performed. The level of fourth decades and occurs twice as often in men. It is
synovectomy for diffuse PVNS is critical in reducing the almost always monarticular, and only rarely is it isolated
recurrence (20). Following open synovectomies via an to a bursa or tendon sheath. It affects the knee joint more 30
anterior and posterior approach in knees with PVNS, than 50% of the time, although the hip, elbow, shoulder,
an 8% recurrence rate and minimal morbidity was noted ankles, and other joints may be involved (22,24). Swell-
(9). If diffuse PVNS is diagnosed in an older patient ing, discomfort, and decreased range of motion are the
with degenerative joint disease, an arthroplasty can give most common symptoms. As the disease progresses,
excellent results. In a young patient, arthrodesis may be such mechanical symptoms as locking and giving way
considered as a savage procedure. may develop (24,25). Eventually, the pedunculated car-
Radiation therapy has been advocated as an adjuvant tilaginous masses and loose bodies can destroy the joint
to surgery to control this disease process. In a pro- surfaces and lead to more severe symptoms.
spective study, external-beam radiation combined with During the early stages, plain radiographs may show
partial (anterior) arthroscopic synovectomy approached a nonspecific soft tissue mass, due to the presence of
success rates of total synovectomy. The authors recom-
mend the use of adjuvant external-beam radiation at
anti-inflammatory doses of 2600 cGy for treatment of
diffuse PVNS of the knee when subtotal synovectomy
is performed (21). Intra-articular injection of yttrium 90
has been used to treat diffuse PVNS. Studies regarding
its effectiveness are inconclusive, and its use remains
experimental. It may prove useful as an adjunct to sub-
total excision in extensive lesions in which complete
excision would result in unacceptable morbidity. Prior
to its use, patients ought to be informed that it can
impair tissue healing, exacerbate stiffness, and possibly
cause sarcomatous degeneration (7,9).
Synovial Chondromatosis
Synovial chondromatosis is a benign metaplastic disor-
der that occurs when subsynovial mesenchymal cells
mature into chondroblasts instead of fibroblasts. Rather FIGURE 30-3
than producing collagen, these cells form nodules of Gross photograph of cartilaginous loose bodies with surrounding
cartilage. These nodules initially expand within the synovium seen in synovial chondromatosis.
nonmineralized cartilage. Bony erosions may be seen,

secondary to focal pressure. During the second and
third stages, multiple juxta-articular calcifications or
loose bodies are seen (Figure 30-4). These nodules
typically are of a similar size and uniformly scattered.
Joint space narrowing, osteophytes, sclerosis, and
abundant calcified loose bodies represent end-stage
disease (26).
If osteonecrosis, rheumatoid arthritis, post-traumatic
arthritis, or degenerative arthritis is noted, a diagnosis
of secondary synovial chondromatosis must be consid-
ered. This diagnosis is especially likely if the presence
of the disorder preceded the diagnosis of chondromato-
sis. In contrast to the primary form, secondary synovial
chondromatosis shows fewer ostechondral bodies, which
vary more in size, and does not recur or show histologic
atypia (11,26,27).
Magnetic resonance imaging can help define the
location of the cartilaginous nodules and is the best
noninvasive study to confirm a diagnosis of syno-
vial chondromatosis. An intermediate density on T1
sequences and an intermediate-to-high density on T2 FIGURE 30-5
sequences characterize the immature nodules (Figure A lateral radiograph demonstrating a radiolucency involving the
30-5). Calcified and ossified areas appear hypointense distal femoral epiphysis. Biopsy demonstrated tissue consistent
on both T1 and T2 images. The exception occurs when with a giant cell tumor of bone.
a loose body contains marrow fat, which appears as a
hyperintense area on T1 (2629).
Synovial chondromatosis is treated by removal of
the loose bodies and excision of all abnormal synovium. reported as high as 11% after open treatment. In rare
Stiffness may occur, and recurrence rates have been cases, the lesion may transform into a chondrosarcoma
(2527). Synovial chondromatosis of the hip can be
treated arthroscopically assisted. The use of the arthro-
scope to address the intra-articular component of the
disease avoids dislocation of the hip and is less invasive.
Arthroscopically assisted synovectomy and removal of
loose bodies has been shown effective by some surgeons
(30). Similarly, arthroscopy for chondromatosis of the
shoulder has been used with anticipated advantages of
more complete removal of loose bodies, decreased post-
operative pain, and enhanced rehabilitation (31). Dys-
regulation of the hedgehog signaling pathway has been
implicated in the many benign cartilaginous tumors.
Increased expression of the hedgehog transcription
factor in mice recreates synovial chondromatosis.
Medication-induced blockage of the hedgehog signaling
pathway may be a future treatment option (28).
Other Primary Joint Tumors

A solitary intra-articular lipoma may occur but is
extremely rare. More commonly, excessive intra-articu-
lar adipose tissue is due to lipoma arborescens. This
entity involves fatty synovial villi and often is associated
FIGURE 30-4 with osteoarthritis, rheumatoid arthritis, and trauma. It
Plain radiograph of synovial chondromatosis showing calcified usually occurs in the knee and causes joint swelling and
cartilage in the hip joint. pain (29). Synovectomy often is curative.
C H A P T E R 3 0 N E O P L A S M S O F T H E J O I N T 5 47
Synovial hemangiomas usually occur in children and SYT-SSX2 is the fusion product of translocation
young adults and almost exclusively involve the knee. (X,18) found in a vast majority of synovial cell sarco-
Plain films often show the pathognomonic phleboliths. mas. The fusion product has now been identified to
Histologically, it is identical to the soft tissue hemangio- regulate beta-catenin recruitment to the nucleus which
mas. Both the localized and diffuse forms can cause pain subsequently regulates cell adhesion. Identification of
and hemarthrosis. This benign vascular neoplasm is the fusion product by molecular diagnostics in synovial
treated by surgical excision (29,32). sarcoma is becoming a standard (36).
Intracapsular solitary chondromas, like extra-articu- Once synovial sarcoma is diagnosed, wide surgical
lar chondromas, are benign cartilaginous neoplasms resection with removal of any affected lymph nodes is
that may calcify. They may present as firm intra-articu- indicated (32). Although adjuvant radiation and chemo-
lar mass. therapy have improved the overall prognosis, the risk
Synovial chondrosarcomas are exceptionally rare of regional and pulmonary metastasis remains high.
and may be primary or secondary to synovial chondro- Reports have shown the 5- and 10-year survival rates
matosis. Treatment is wide surgical resection (27). to be 55% and 40%, respectively (37). Increased age,
tumor size greater than 5 cm, and 10 or more mitotic
figures per 10 high-powered fields are thought to
SECONDARY JOINT NEOPLASMS increase the risk of metastasis and/or death (33).
Synovial Sarcoma
Synovial sarcoma is an uncommon, highly malignant
Giant Cell Tumor
tumor involving mesenchymal cells. It typically occurs Giant cell tumor is a benign, but locally aggressive,
near tendon and fascial planes, although, on rare occa- tumor of unknown origin that most commonly affects
sions, it may arise within or adjacent to a joint (22,33). 20- to 40-year-olds. This lesion involves the knee (distal
The lower extremities are affected most frequently and femur and proximal tibia) 50% of the time (32), and the
the incidence is highest among those between the ages distal radius and proximal humerus are the next most
of 15 and 40 years (32). Although synovial sarcoma sug- common sites. Plain radiographs show a purely lytic 30
gests a relationship to normal synovium, the disease is lesion that begins in the epiphysis and abuts the articu-
rarely found intra-articularly. However, there have lar surface (22). It frequently extends into the joint
been case reports of solely intra-articular involvement (Figure 30-6) (36), tends to recur, and, 1% to 2% of the
of synovial sarcoma (34). time, it will become malignant and metastasize to the
Patients typically present complaining of a slowly lungs. The addition of phenol, bone graft, and methyl-
growing soft tissue mass. Approximately 50% of the methacrylate to marginal resection can decrease the
time, the lesion is described as painful. Plain radio- recurrence rate and allow the joint to be preserved. The
graphs often reveal a large, lobulated, juxta-articular use of a high speed burr also can decrease the rate of
mass. Calcification is seen in up to one third of cases
and often has a diffuse speckled appearance. MRI shows
nonspecific characteristics, but can narrow the diagnosis
and define the lesions anatomic location (29).
A biopsy often is required to confirm the diagnosis
and will show the sarcoma to be one of the three types.
The biphasic form is the most common and involves
obvious epithelial and mesenchymal differentiation.
The plump cuboidal or tall columnar epithelial cells line
mucin-filled clefts and cystlike spaces. The round and
oval epithelial cells form nests and cords. The fibro-
blasts are spindle-shaped and may be arranged in a
manner similar to that seen in fibrosarcoma. Sometimes
the field is dominated largely by either the epithelial cell
(rarely) or the fibroblast (more commonly). The lesion
then is categorized as monophasic. The monophasic
form can be confused with other neoplasms of fibrous
or epithelial origin and is thought by some to carry a
worse prognosis. A rare, poorly differentiated type, rep- FIGURE 30-6
resented histologically by numerous mitotic round cells, A sagittal fast spin echo (FSE) image of the distal femur demon-
also has been described. Rapid growth and a very poor strating a distal femoral giant cell tumor of bone extending into
prognosis characterize this form (22,32,35). the articular space along the cruciate ligaments.
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and joints. Philadelphia: Lea and Febiger; 1958. 32. Campanacci M. Bone and soft tissue tumors. New York:
12. Michael RH. Pigmented villonodular synovitis. Orthop Springer-Verlag; 1981:99135, 11091126, 12431252,
Nurs 1997;16:6668. 12891306.
13. Lewis RW. Roentgen diagnosis of pigmented villonodular 33. Kaakaji Y, Valle DE, McCarthy KE, Nietzschman HR.
synovitis and synovial sarcoma of knee joint. Radiology Case of the day. Case 4: synovial Sarcoma. AJR Am J
1947;49:26. Roentgenol 1998;171:868870.
14. Uchibori M, Nishida Y, Tabata I, et al. Expression of 34. Namba Y, Kawai A, Naito N, Morimoto Y, Hanakawa
matrix metalloproteinases and tissue inhibitors of metal- S, Inoue H. Intraarticular synovial sarcoma confirmed
loproteinases in pigmented villonodular synovitis suggests by SYT-SSX fusion transcript. Clin Orthop 2002:221
their potential for joint destruction. J Rheumatol 2004; 226.
31:110119. 35. Machen KS, Easley KA, Goldblum JR. Synovial sarcoma
15. Schwartz HS, Unni KK, Pritcherd DJ. Pigmented villo- of the extremities. A clinicopathologic study of 34 cases,
nodular synovitis. A retrospective review of affected large including semi-quantitative analysis of spindles, epithelial,
joints. Clin Orthop 1989;247:243255. and poorly differentiated areas. Am J Surg Pathol 1999;
16. Scott PM. Bone lesions in pigmented villonodular synovi- 23:268275.
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17. Cheng XG, You YH, Liu W, Zhao T, Qu H. MRI features Eid JE. The synovial sarcoma translocation protein SYT-
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North Am 1988;26:13271347. Louis: Mosby; 1988:638688, 861881.
CHAPTER 31
Heritable Disorders of
Connective Tissue
REED EDWIN PYERITZ, MD, PHD
The genes that specify the hundreds of proteins Phenotypes used: (1) disorders of fibrous elements,
involved in connective tissue have been such as osteogenesis imperfecta and Marfans
mapped. syndrome, (2) disorders of proteogylcan metabolism,
The heritable disorders of connective tissue such as mucopolysaccharidoses, (3) dysostoses and
(HDCT) show both considerable variability osteochondrodysplasias, such as achondroplasia,
within and among families and genetic and (4) inborn errors of metabolism, such as
heterogeneity. homocystinuria.
The molecular composition and organization of con- and (4) inborn errors of metabolism that secondarily
nective tissue, known as the extracellular matrix, are affect connective tissue, such as homocystinuria and
extraordinarily complex. Much remains unknown about alkaptonuria. However, most of the features of Marfan
the number, structure, map location, and regulation of syndrome, one of the preeminent disorders of a fibrous
genes that control synthesis, organization, and metabo- element, are now recognized as due to dysregulation
lism of this ubiquitous tissue. However, the genes that of signaling because of impaired interaction between
specify several hundred proteins involved in connective the latent transforming growth factor beta (TGF-beta)
tissue metabolism and skeletal development have been complex and the extracellular microfibril.
mapped (1). Mutations in the genes for these proteins
cause a variety of disorders. The heritable disorders of
connective tissue (HDCT) follow Mendels laws, but MARFAN SYNDROME
like many such disorders, show both considerable vari-
ability within and among families and genetic heteroge- People with Marfan syndrome (MFS) have abnormali-
neity (2,3). ties in multiple organs and tissues, especially the skele-
Some common disorders, such as osteoarthritis, tal, ocular, cardiovascular, pulmonary, and central
osteoporosis, and aortic aneurysms, involve predomi- nervous systems. Diagnosis is based primarily on clini-
nantly connective tissue and are mendelian in occa- cal features and the autosomal dominant inheritance
sional families. For the majority of cases, however, pattern (6). The basic defect in all cases studied is in
multiple genes and other factors likely are important in fibrillin 1, the principal constituent of extracellular
cause and pathogenesis (4). microfibrils (7). The locus (FBN1) for this protein maps
The phenotypic characterization of the HDCT, crude to 15q21. Microfibrils are ubiquitous, 10 to 14 nm struc-
as it sometimes is, still outstrips biochemical or genetic tures that, in conjunction with tropoelastin, form elastic
understanding (5). More than 200 conditions are called fibers. Thus, fibrillin is a functionally important mole-
HDCT. The more familiar ones have prevalences of 1 in cule in any organ containing elastic fibers, such as arter-
3000 to 1 in 50,000; many are less prevalent. More refined ies, ligaments, and lung parenchyma. In other tissues,
classification of the HDCT is unsatisfactory, and ulti- such as the zonular fibers of the eye, at the epidermal
mately must be based on pathobiology. But several phe- dermal junction, and in the perichondrium, microfibrils
notypic groupings traditionally are used: (1) disorders are not associated with elastin. Thus, defective fibrillin
of fibrous elements, such as osteogenesis imperfecta; is consistent with the pleiotropic manifestations of
(2) disorders of proteoglycan metabolism, including the MFS.
mucopolysaccharidoses; (3) dysostoses and osteochon- In the past few years, considerable progress
drodysplasias, such as achondcoplasia (see Chapter 35); was made to understand the molecular and cellular
549
550 REED EDWIN PYERITZ
pathogenesis of each manifestation in MFS, and to therapy has been used occasionally in young girls, but
understand the cause and pathogenesis of other dis- rarely in boys. Most patients do not dislocate joints,
orders related to MFS. Autosomal dominant ectopia but in those who do, the patella is the most common
lentis, autosomal dominant aortic aneurysm, and auto- dislocation. People with MFS may be predisposed to
somal dominant tall stature are caused by mutations in develop degenerative arthropathy and osteoporosis in
FBN1 in the absence of MFS (8). Congenital contrac- middle age. Women with MFS are at increased risk of
tural arachnodactyly is due to mutations in FBN2 on aortic dissection and rupture during pregnancy; an
chromosome 5, a locus that specifies another member aortic root diameter greater than 40 mm is a contrain-
of the fibrillin family of proteins. Many of the features dication to pregnancy.
of MFS in a mouse model engineered with a human The mouse model of MFS responds in strikingly posi-
FBN1 mutation are due to overexpression of TGF- tive ways to the drug losartan, which in addition to its
beta during both development and growth (9,10). The angiotensin receptor blocking action interferes with the
latent TGF-betabinding complex is held in check by action of TGF-beta (17). Clinical trials of losartan are
normal microfibrils; mutant fibrillin 1 leads to dysregu- underway in humans.
lation. Ectopia lentis may be the one feature that is
indeed due to an abnormality of tensile strength of
microfibrils. HOMOCYSTINURIA
Skeletal manifestations of MFS include excessive
stature (11); abnormal body proportions with a long Homocystinuria usually refers to an inborn error in the
arm span and an abnormally low ratio of the upper metabolism of methionine due to deficient activity
segment to the lower segment (dolichostenomelia); of the enzyme cystathionine beta-synthase. Clinical
elongated digits (arachnodactyly); anterior thoracic features are similar superficially to those of MFS and
deformity (pectus excavatum, carinatum, or an asym- include ectopia lentis, tall stature, dolichostenomelia,
metric combination); abnormal vertebral column curva- arachnodactyly, and anterior chest and spinal deformity
ture (scoliosis, excessive kyphosis, or loss of thoracic (18). Generalized osteoporosis, tight joints, arterial
kyphos resulting in straight back); hyperextensibility and venous thrombosis, malar flush, mental retardation,
or, less often, congenital contractures of appendicular and autosomal recessive inheritance are features of
joints; protrusio acetabulae; and pes planus with a long, homocystinuria not consistent with MFS, whereas aortic
narrow foot. Most patients have myopia, and approxi- aneurysm and mitral prolapse are not features of homo-
mately half have subluxation of the lenses (ectopia cystinuria. Back pain and vertebral collapse due to
lentis). The ascending aorta, beginning in the sinuses of osteoporosis occur in some patients. Most patients have
Valsalva, gradually dilates in association with fragmen- no specific arthropathy.
tation of the medial elastic fibers; aortic regurgitation The pathogeneses of the three cardinal manifesta-
and dissection result and are the main causes of death. tionsmental retardation, connective tissue disorder,
Mitral valve prolapse occurs in a majority and leads to and thrombosisare not understood. One hypothesis
severe mitral regurgitation in some, occasionally in holds that sulfhydryl groups of homocysteine and
childhood. Hernias are frequent; apical bullae lead to methionine interfere with collagen cross-linking. If true,
pneumothorax in 5%; and striae atrophicae over the this is a form of thiolism such as occurs from prolonged
pectoral, deltoid, and lumbar areas are a helpful diag- administration of penicillamine, a compound structur-
nostic sign. Dural ectasia producing erosion of lower ally similar to homocysteine. Fibrillin is rich in cysteine,
lumbar and sacral vertebrae usually is an incidental and intra- and interchain disulfide bonds are crucial to
finding on computed tomography (CT) or magnetic the formation and function of microfibrils. Some of the
resonance imaging (MRI), but may lead to pelvic menin- phenotypic resemblance of homocystinuria to MFS may
goceles or radicular problems (12,13). be due to disruption of microfibrils by the reactive sulf-
Management is both palliative and preventive. The hydryl moiety of homocysteine (19).
size of the ascending aorta should be followed by echo- Approximately one half of patients respond bio-
cardiography. beta-Adrenergic blockade is advisable to chemically and clinically to large doses of vitamin B6
reduce stress on the aortic wall, and repair of the aortic (usually more than 50 mg pyridoxine per day), an obli-
root should be undertaken when the aortic diameter is gate cofactor for cystathionine beta-synthase. Adequate
greater than 50% expected (about 4550 mm in the levels of folate and vitamin B12 are required for thera-
adult) (14,15). Scoliosis should be managed aggres- peutic and biochemical response. Preexisting mental
sively with bracing in the child and adolescent; when retardation and ectopia lentis are not reversed by pyri-
curvature exceeds about 40, surgical stabilization doxine treatment in patients who show biochemical cor-
should be considered (16). Hormonal advancement of rection, emphasizing the need for early diagnosis and
pubarche can modulate excessive stature and reduce therapy. Early diagnosis is feasible because many states
the time when vertebral curvature can worsen; this include testing for elevated blood methionine as part of
C H A P T E R 3 1 H E R I T A B L E D I S O R D E R S O F C O N N E C T I V E T I S S U E 5 51
newborn screening. Unfortunately, some pyridoxine tend to occur only in specific types of EDS. Six main
responders may escape detection in the typical screen- EDS types are accepted, based on phenotypic and
ing protocols. In pyridoxine nonresponders, a low inheritance characteristics (Table 31-1), but numerous
methionine diet and oral betaine therapy (to stimulate other clinical types occur (23). Within individual
remethylation of homocysteine to methionine) are the types, however, biochemical studies have demonstrated
usual treatments; this approach can be successful if the considerable heterogeneity. Extensive phenotypic
diet and vitamin are tolerated. and biochemical characterization nonetheless fails the
clinician as often as it helps; approximately one half of
patients who have at least one cardinal feature defy
STICKLER SYNDROME categorization.
Stickler syndrome is a relatively common, autosomal

dominant condition with severe, progressive myopia;
EhlersDanlos, Classical Type
vitreal degeneration; retinal detachment; progressive People with classical type EDS (formerly, types I and
sensorineural hearing loss; cleft palate; mandibular II) have generalized hyperextensibility of joints and
hypoplasia; hyper- and hypomobility of joints; epiphy- skin; bruisability and fragility of the skin, with gaping
seal dysplasia; and potential disability from joint pain, wounds from minor trauma; and poor retention of
dislocation, or degeneration (20). This condition, also sutures. Congenital dislocation of the hips in the
called progressive arthroophthalmopathy, is underdiag- newborn, habitual dislocation of joints in later life, joint
nosed, in part due to patients often not having the full effusions, clubfoot, and spondylolisthesis are all conse-
syndrome and in part due to the clinicians failure to quences of loose jointedness. Hemarthrosis and hem-
obtain a detailed family history that might suggest a arthritic disability have been described and are
hereditary condition. The diagnosis should be strongly analogous to the bruisability of the skin in this syn-
considered in any infant with congenitally enlarged drome. Scoliosis sometimes is severe. This type of EDS
(swollen) wrists, knees, or ankles, particularly when is inherited as an autosomal dominant trait with wide
associated with the Robin anomalad (hypognathia, cleft variability. Management of classical EDS stresses pre-
palate, and glossoptosis); any young adult with degen- vention of trauma and great care in treating wounds.
erative hip disease; and anyone suspected of MFS who Pregnancies of fetuses with EDS are prone to prema-
has hearing loss, degenerative arthritis, or retinal detach- ture rupture of membranes. This form of EDS is geneti-
ment. The Stickler syndrome can be caused by muta- cally heterogenous, with mutations in COL5A1 and 31
tions in at least four genes, three of which have been COL5A2 causing the phenotype in one half of cases
identified (21). Mutations in the alpha l(II) or the alpha (24). Heterozygosity for mutations in COL1A1 can
1(XI) procollagen loci (COL2A1 and COL11A2, cause a classic EDS phenotype, often with mild features
respectively) cause classic Stickler syndrome. These two of osteogenesis imperfecta. Rare individuals with muta-
genes are expressed in cartilage and the vitreous, in tions in both COL1A1 alleles have classic EDS with
which both types II and XI collagen are prominent. A severe cardiovascular involvement.
form of Stickler syndrome in which ocular features are
absent is due to mutations in alpha 2(XI) procollagen
(COL11A2); this protein is a component of type XI
EhlersDanlos, Hypermobility Type
collagen only in cartilage and not in the vitreous. About Hypermobility type EDS (formerly type III) has less
two thirds of patients have mutations in COL2A1, typi- marked skin involvement than the classical form; joint
cally ones that cause premature chain termination. hyperextensibility ranges from extreme to moderate.
Some families show genetic linkage to none of these Many people with mild joint laxity and without joint
three genes. Variability in clinical features among fami- instability are labeled as having this type, particularly if
lies is much more extensive than within a family, which relatives show a similar manifestation (25). In some
likely reflects the genetic heterogeneity. cases, such labeling does more harm than good, unless
it is made quite clear that little disability, if any, is likely.
A wide variety of biochemical and molecular abnor-
EHLERSDANLOS SYNDROMES malities, including in type I and III collagen and tenas-
cin-X, have been reported in patients with this broad
The EhlersDanlos syndromes (EDS) are a group of phenotype (26).
disorders whose wide phenotypic variability is due
largely to extensive genetic heterogeneity. The cardinal
features relate to the joints and skin: hyperextensibility
EhlersDanlos, Vascular Type
of skin, easy bruisability, increased joint mobility, and Vascular type EDS (formerly type IV) is by far the most
abnormal tissue fragility (22). Internal manifestations serious type because of a propensity for spontaneous
TABLE 31-1. EHLERSDANLOS SYNDROMES.

FORMER OMIM
TYPE NAME CLINICAL FEATURESa INHERITANCE NUMBER(S)b MOLECULAR DEFECT
Classical ESD I and II Joint hypermobility; skin hyperex- AD 130000 (ESD I) Structure of type V
tensibility; atrophic scars; collagen (EDS I)
smooth, velvety skin; subcuta-
neous spheroids
Hypermobility EDS III Joint hypermobility; some skin AD 130010 ? COL5A1, COL5A2 (EDS II),
hyperextensibility; smooth (EDS II) TNXB
and velvety skin 130020
Vascular EDS IV Thin skin; easy bruising; pinches AD 130050 Deficient type III collagen
nose; acrogeria; rupture of large (225350)
and medium caliber arteries, (225360)
uterus, and large bowel
Kyphoscoliotic EDS VI Joint hypermobility; congenital, AR 225400 PLOD

progressive scoliosis; scleral
fragility with globe rupture;
tissue fragility; aortic dilatation;
MVP
Arthrochalasia EDS VIIA and Joint hypermobility, severe with AD 130060 No cleavage of N-terminus
VIIB subluxations; congenital hip of type I procollagen 2
dislocation; skin hyperextensibil- mutations in COL1A1 or
ity; tissue fragility COL1A2
Dermatosparaxis EDS VIIC Severe skin fragility; decreased AR 225410 No cleavage of N-terminus
skin elasticity; easy brusing; of type I procollagen 2
hernias; premature rupture of deficiency of ADAMTS2
fetal membranes
Unclassified types EDS V Classic features XL 305200 ?

EDS VIII Classic features and periodontal AD 130080 ?
disease
EDS X Mild classic features, MVP ? 225310 ?
EDS XI Joint instability AD 147900 ?
EDS IX Classic features; occipital horns XL 309400 Allelic to Menkes syndrome
ABBREVIATIONS: AD, autosomal dominant; AR, autosomal recessive; XL, X-linked; MVP, mitral valve prolapse; OMIM, Online Mendelian Inheritance in Man; ?,
unknown.
a
Listed in order of diagnostic importance.
b
Entries in Online Mendelian Inheritance in Man (1).
rupture of arteries and bowel (27). The unifying patho- EhlersDanlos, Kyphoscoliosis Type
genetic theme is abnormal production of type III colla-
gen. A variety of mutations have been described in the Kyphoscoliosis type EDS (formerly type VI) is charac-
COL3A1 gene. Skin involvement is variable: thin, nearly terized by fragility of the ocular globe, marked joint and
translucent skin is present in some, and mildly hyperex- skin hyperextensibility, a propensity to severe scoliosis,
tensible skin is the only feature in others. Joint laxity and autosomal recessive inheritance. Collagen in skin
also varies, but may be limited to the digits. Inheritance contains little hydroxylysine because of a deficiency of
usually is autosomal dominant, and many cases are spo- the enzyme that hydroxylates selected lysyl residues in
radic occurrences in their pedigree, suggesting they are the nascent collagen chains (PLOD). Vitamin C is a
heterozygous for a new mutation. The majority of necessary cofactor of lysyl hydroxylase, and pharmaco-
patients with the vascular type of EDS have a relative logic doses may be beneficial.
deficiency of type III collagen, compared with type I
collagen, and this deficiency is detectable in cultured
dermal fibroblasts. Because this test is relatively straight-
EhlersDanlos, Arthrochalasia Type
forward to conduct, and because the results are highly Arthrochalasia type EDS (formerly type VIIA and
specific for this condition, the diagnosis often is con- VIIB) is typified by profound loose jointedness, congeni-
firmed biochemically (27). tal dislocations, moderately short stature, and variable
skin involvement. The underlying defect is an inability involvement. Classification is based on inheritance
to cleave the N-propeptide from type I procollagen, a pattern and clinical criteria (Table 31-2).
process that is necessary for conversion to mature colla-
gen. Mutations at the cleavage site of alpha 1(I) and
alpha 2(1) procollagens can cause this phenotype; the
Type I Osteogenesis Imperfecta
procollagen defects behave as dominant traits. Type I is the most common form of OI. It is autosomal
dominant and is associated with considerable intrafa-
EhlersDanlos, Dermatosparaxis milial variability. One patient might be markedly short
Type of stature, with frequent fractures and much disability,
while an affected relative leads an unencumbered, vig-
Dermatosparaxis type EDS (formerly type VIIC) is a orous life. Defects in the genes for both alpha 1(I) and
recessive condition due to deficiency of the N-propep- alpha 2(I) procollagen can cause this syndrome. Muta-
tidase that cleaves type I procollagen (ADAMTS2). The tions in COL1A1 are more often associated with blue
disorder affects primarily skin and fascia, and joints are sclera while mutations in COL1A2 result in shorter
affected little (28). stature (31).
JOINT INSTABILITY SYNDROMES Type II Osteogenesis Imperfecta

The cardinal manifestation of familial joint instability, Type II encompasses the classic congenital variants,
which once was classified as an EhlersDanlos type, is nearly all of which are lethal in infancy, if not in utero.
instability of numerous appendicular joints. Recurrent Most cases arise as the result of a new mutation (the
dislocation, especially of the shoulder or patella, is the phenotype being dominant transmissable, if the patient
usual presenting complaint (29). Joint hyperextensibil- lived and reproduced) in either alpha 1(I) or alpha 2(I)
ity is variable but usually mild, and skin involvement is procollagen. A dominant-negative model explains
uncommon. This syndrome is not rare and often is asso- the severe phenotype produced by a heterozygous
ciated with considerable disability. Autosomal domi- mutation. Rare patients have affected siblings and
nant inheritance with marked variability within a family normal parents; in some of these cases, a parent has
is the rule, emphasizing the need for a comprehensive been shown to have the mutation at low level in the
family history, including examination of close relatives gonads, resulting in the potential for multiple affected
if possible. The biochemical defect is unknown. offspring. 31
Larsen syndrome is characterized by congenital dis-
locations; a characteristic facies of prominent forehead, Type III Osteogenesis Imperfecta
depressed nasal bridge, and widely spaced eyes; joint
dislocations; and skeletal dysplasia. Dislocation occurs Type III comprises severe skeletal deformity, kypho-
at the knees (characteristically, anterior displacement scoliosis, short stature, and variable fractures. It usually
of the tibia on the femur), hips, and elbows. The meta- occurs sporadically, suggesting new mutations, or auto-
carpals are short, with cylindrical fingers that lack the somal recessive inheritance.
usual tapering. Cleft palate, hydrocephalus, abnormali-
ties of spinal segmentation, and moderate-to-severe Type IV Osteogenesis Imperfecta
short stature have occurred in some. Several instances
of multiple affected siblings with normal parents are Type IV is similar phenotypically and genetically to
known, suggesting autosomal recessive inheritance; type I, only less common, not associated with blue
however, parentchild involvement also occurs, consis- sclera, and having fewer fractures, on average.
tent with dominant inheritance. The recessive form is
associated more often with severe short stature and Natural History
neurologic complications of spinal deformity. The gene
for the dominant form has been mapped to chromo- The natural histories of skeletal involvement among
some 3p21.1-p14.1. these types bear similarities. Brittle bones are a unify-
ing theme; sometimes fractures occur in utero, parti-
cularly in type II, and permit radiographic antenatal
OSTEOGENESIS IMPERFECTA diagnosis. In such cases, the limbs are likely to be short
SYNDROMES and bent at birth, and multiple rib fractures give a char-
acteristic beaded appearance on radiographs. Other
Several phenotypically distinct osteogenesis imper- patients with types I or IV have few or no fractures,
fecta (OI) syndromes exist (2,5,30). The disorders although the presence of blue sclerae, opalescent teeth,
share osseous, ocular, dental, aural, and cardiovascular or hearing loss indicates the presence of the mutant
TABLE 31-2. OSTEOGENESIS IMPERFECTA SYNDROMES.

TYPE CLINICAL FEATURES INHERITANCE OMIM NUMBERa BASIC DEFECTS
I Fractures variable in number; little deformity; AD 166200 Typically, one nonfunctional COL1A1
stature normal or nearly so; blue sclerae; allele
hearing loss common but not always
present; DI uncommon
II Lethal in utero or shortly after birth; many AD 166210 COL1A1 or COL1A2: typically substitu-
fractures at birth involving ribs (may appear tion of glycyl residues; occasionally,
beaded) and other long bones; little deletions of a portion of the triple-
mineralization of calvarium; pulmonary helical domain
hypertension AR 259400 Deletion in COL1A2 plus nonfunctional
allele
III Fractures common, but long bones progres- AD 259420 One (single amino acid substitution) or
sively deform starting in utero; stature rarely two mutations in COL1A1
markedly reduced; sclerae often blue but and/or COL1A2
become lighter with age; ID and hearing loss
common
IV Fractures common; stature usually reduced; AD 166220; 166240 Point mutations in COL1A1 or COL1A2;
bone deformity common but rarely severe; exon skipping mutations in COL1A2
scleral hue normal to grayish; hearing loss
variable; DI common
V Similar to type IV, but with hyperplastic callus AD ? No mutations in COL1A1 or COL1A2
formation, decreased supination and
pronation of the forearms; no DI
VI Similar to type IV, but with earlier and more ? Increased serum alkaline phosphatase;
frequent fractures; no DI; decreased no mutations in COL1A1 or COL1A2
mineralization but no defect of mineral
metabolism
ABBREVIATIONS: AD, autosomal dominant; AR, autosomal recessive; DI, dentinogenesis imperfecta; OMIM, Online Mendelian Inheritance in Man.
a
Entry in Online Mendelian Inheritance in Man (1).
gene. Brittleness and deformability result from a defect The differential diagnosis of OI includes idiopathic
in the collagenous matrix of bone. The skeletal aspect juvenile osteoporosis, HajduCheney syndrome (osteo-
of OI is, therefore, a hereditary form of osteoporosis. porosis, multiple wormian bones, acroosteolysis), pyc-
Codfish vertebrae (scalloping of the superior and nodysostosis (dwarfism, brittle bones, absent mandibular
inferior vertebral bodies by pressure from the expansile ramus, persistent cranial fontanelles, acroosteolysis),
intervertebral disc) or flat vertebrae are observed, par- and hypophosphatasia. In one family, susceptibility to
ticularly in older patients in whom senile or postmeno- osteoporosis was found to be due to a mutation in type
pausal changes exaggerate the change, or in young I collagen. This emphasizes that the ability to identify
patients who are immobilized after fractures or ortho- mutations in a particular gene does not necessarily facil-
pedic surgery. itate clinical diagnosis. Furthermore common problems
Frequency of fractures usually decreases at puberty that are not thought to be syndromic may be due to
for patients with types I, III, and IV. Pseudoarthrosis defects in one or another of the components of the
occurs in some patients due to nonunion of fractures. extracellular matrix.
Hypertrophic callus occurs frequently in patients with A variety of hormonal and pharmacological appro-
OI and may be difficult to distinguish from osteosar- aches to therapy have been tried. Calcium supplemen-
coma. Debate continues as to whether the risk of true tation, calcitonin, and vitamin D are ineffective unless
osteosarcoma is increased in any form of OI; regardless, clear deficiency is present. Treatment with oral or
the risk is not great, but worthy of consideration when- injected bisphosphonates has had considerable success
ever skeletal pain occurs in the absence of fracture, in young patients in reducing fractures and improving
particularly in an older patient. Joint laxity sometimes skeletal growth (32,33). However, the overall quality
is striking in type I; dislocation of joints can result from of the bone may not be improved and the issues of how
deformity secondary to repeated fractures, lax liga- long to treat children and whether to treat adults
ments, or rupture of tendons. remain unresolved (34). Bone marrow transplantation,
to provide normal mesenchymal stem cells, has shown MUCOPOLYSACCHARIDOSES

some promise (35), and studies of gene therapy in
autologous mesenchymal stem cells are ongoing. The mucopolysaccharidoses (MPS) are the result of
inborn errors of proteoglycan catabolism (41). Although
phenotypically diverse, the individual disorders share
mucopolysacchariduria and deposition of catabolites of
PSEUDOXANTHOMA ELASTICUM proteoglycan in various tissues. Numerous distinct types
of MPS can be distinguished, based on combined phe-
The cardinal features of pseudoxanthoma elasticum notypic, genetic, and biochemical analysis (Table 31-3).
occur in the eyes, blood vessels, and skin (36). Although Relative short stature is the rule in all forms of MPS,
the most easily recognized finding in the ocular fundus and can be profound in type IH (Hurler syndrome), II
is the angioid streak, due to a break in Bruchs mem- (Hunter syndrome), IV (Morquio syndrome, a proto-
brane, progressive visual loss occurs from retinal hem- type of short-trunk dwarfism), and VI (Maroteaux
orrhages. The media of muscular arteries develop Lamy syndrome). Radiologically, the skeletal dysplasia
degeneration of the elastic fibers and a histologic is quite similar in character in all but MPS type IV, dif-
pattern similar to Mnckeberg arteriolosclerosis. fering among the others largely in severity. Although
Peripheral pulses gradually are lost, and intermittent the term dysostosis multiplex has been used, it is not
claudication is common. Myocardial infarction, stroke, specific for the MPS because similar changes occur in a
and gastrointestinal hemorrhage are complications of variety of storage disorders. The chief radiologic fea-
vascular involvement and the leading causes of death. tures are a thick calvaria; an enlarged, J-shaped sella
The condition gets its name from characteristic skin turcica; a short and wide mandible; biconvex vertebral
lesions that develop in regions of flexural stress and bodies; hypoplasia of the odontoid; broad ribs; short
resemble plucked chicken skin. The skeleton and joints and thick clavicles; coxa valga; metacarpals with
usually are not involved. Elastic fibers throughout widened diaphyses and pointed proximal ends; and
the body show calcification. Inheritance is autosomal short phalanges.
recessive in most cases due to mutations in ABCC6, Survival to adulthood without severe retardation
which encodes an ATP-dependent membrane trans- occurs with types IS (Scheie syndrome), II mild, IV, and
port protein expressed primarily in the liver and kidney VI. In these forms, progressive arthropathy and trans-
(37). This raises the likelihood that the effects on the verse myelopathy secondary to C1-C2 subluxation
extracellular matrix are due to some circulating metab- account for considerable disability. Joint replacement, 31
olite that is dysregulated because of the transport particularly of the hips, has been beneficial in several
defect (38). forms, especially type IS. Cervical fusion should be con-
sidered whenever upper motor neuron signs appear; a
particular concern in types IH, IV, and VI. Stiff joints
are a more-or-less striking feature of all except type IV.
FIBRODYSPLASIA OSSIFICANS Like other somatic features, such as coarse facies,
PROGRESSIVA reduced joint mobility is less striking in type III. In type
IS, stiff hands, hip arthropathy, and clouding of the
Fibrodysplasia ossificans progressiva (FOP) is charac- corneae produce the main disabilities. Carpal tunnel
terized by progressive ossification of ligaments, tendons, syndrome contributes to disability in all types. The
and aponeuroses (39). An inexorable course begins in major life-threatening problems in types II mild, IV,
the first year or so of life, usually with a seemingly and VI are valvular heart disease and progressive nar-
inflammatory process and nodule formation on the rowing of the middle and lower airways. The latter
back of the thorax, neck, or scalp. Local heat, leuko- frequently presents as obstructive sleep apnea or com-
cytosis, and elevated sedimentation rate are observed plications with general anesthesia.
at this stage, and acute rheumatic fever sometimes is Genetic disturbances of mucopolysaccharide metab-
diagnosed. A valuable clue to the correct diagnosis is olism without mucopolysacchariduria include the muco-
a short great toe with or without a short thumb; FOP lipidoses (42). Type II, a severe disorder similar to
is the leading cause of congenital hallux valgus. Most Hurler syndrome, also is called I-cell disease because of
cases of this autosomal dominant disorder are the con- conspicuous inclusions in cultured cells. Type III, also
sequence of new mutation. Life expectancy is reduced called pseudo-Hurler polydystrophy, has stiff joints,
considerably, with progressive restriction in lung capac- cloudy corneae, carpal tunnel syndrome, short stature,
ity contributing to respiratory insufficiency and termi- coarse facies, and, sometimes, mild mental retardation,
nal pneumonia. The cause of FOP is mutations in and is compatible with survival to adulthood. Neither
ACVR1, a receptor for bone morphogenic protein type type shows mucopolysacchariduria, despite lysosomal
I (40). storage of mucopolysaccharide and a demonstrable
TABLE 31-3. MUCOPOLYSACCHARIDOSES.
DISORDER OMIM
NUMBERa EPONYM CLINICAL MANIFESTATIONS GENETICS URINARY MPS ENZYME DEFICIENCY LOCUS
MPS I 252800 AR Dermatan sulfate; alpha-L-iduronidase; 4p16.3

heparin sulfate IDUA
MPS IH Hurler Coarse facies; severe DM; clouding of

cornea; progressive MR; death usually
before 10 years
MPS IS Scheie Stiff joints; cloudy cornea; aortic valve

disease; normal intelligence; survival
to adulthood
MPS IH/S Intermediate phenotype

HurlerScheie
MPS II 309900 XL Dermatan sulfate; Iduronate 2-sulfatase; IDS Xq28

heparin sulfate
Hunter, severe No corneal clouding, otherwise similar

to MPS IH; death before 15 years
Hunter, mild Stiff joints; survival to 30 s60 s; fair

intelligence
MPS IIIA 252900 Mild physical features and DM; severe AR Heparan sulfate Heparan N-sulfatase 17q25.3
Sanfilippo A progressive MR (sulfamidase)
MPS IIIB 252930 Indistinguishable from MPS IIIA AR Heparan sulfate N-acetyle-alpha-D- SGSH
Sanfilippo B glucosamindase; 17q21
NAGLU
MPSIIIC 252930 Indistinguishable from MPS IIIA AR Heparan sulfate Acetyl-CoA-alpha- 14

Sanfilippo C glucosaminide; N-
acetyltransferase;
MPS3C
MPS IIID 252940 Indistinguishable from MPS IIIA AR Heparan sulfate N-acetylglucosamine-6- 12q14
Sanfilippo D sulfate sulfatase; GNS
MPS IVA 253000 Severe, distinctive bone changes; cloudy AR Keratan sulfate Galactosamine-6-sulfate; 16Q24.3
Morquio A cornea; aortic regurgitation; thin GALNS
enamel
MPS IVB 253010 Mild bone changes; cloudy cornea; AR Keratan sulfate beta1-galactosidase; GLB1 3p21.33
Morquio B hypoplastic odontoid; normal enamel
(OBrienArbisser)
MPS V No longer used
MPS VI 253200 AR Dermatan sulfate Arylsufatase B (N- 5q11q13

MaroteauxLamy acetyl-galactosamine
4-sulfatase
Severe Severe DM and corneal clouding;

valvular heart disease; striking WBC
inclusions; normal intellect; survival
to 20 s
Intermediate Same spectrum as severe, but milder
Mild Same spectrum as severe, but mild
MPS VII 253230 DM; progressive MR; WBC inclusions; AR Dermatan sulfate; beta1-glucuronidase; 7q21.11
hepatosplenomegaly heparin sulfate GUSB
MPS VIII 253230 No longer used
MPS IX 601492 Short stature; progressive soft tissue AR Hyaluroran Hyaluronidase; HYAL1 3p21.3
and periarticular accumulations of p21.2
hyaluroran
ABBREVIATIONS: AD, autosomal dominant; AR, autosomal recessive; DM, dysostosis multiplex; MR, mental retardation; OMIM, Online Mendelian Inheritance in
Man; WBC, white blood cell; XL, X-linked.
a
Entry in Online Mendelian Inheritance in Man (1).
defect in degradation of mucopolysaccharides. Both are study of the fibrillin-1 gene FBN1 because of suspected
autosomal recessive and genetically heterogeneous. Marfan syndrome. Arch Intern Med 2001;161:24472454.
The basic biochemical defect is an enzyme responsible 8. Pyeritz RE. Marfan syndrome and other disorders of
for posttranslational modification of lysosomal enzymes. fibrillins. In: Rimoin DL, Connor JM, Pyeritz RE, Korf B,
eds. Principles and practice of medical genetics. 5th ed.
This defect results in multiple enzyme deficiencies and
New York: Elsevier; 2007, Chapter 149.
accumulation in tissues of both mucopolysaccharides
9. Neptune ER, Frischmeyer PA, Arking DE, et al.
and mucolipids. Dysregulation of TGF-beta activation contributes to
Mucopolysacchariduria can be identified by one of pathogenesis in Marfan syndrome. Nat Genet 2003;33:
several standard screening tests, at least one of which is 407411.
part of the standard battery performed when a meta- 10. Ng CM, Cheng A, Myers LA, et al. TGF-beta-dependent
bolic screen is ordered. Fractionation and characteriza- pathogenesis of mitral valve prolapse in a mouse model
tion of the urinary mucopolysaccharides are useful in of Marfan syndrome. J Clin Invest 2004;114:15431546.
separating the several types of disorders, but enzymatic 11. Erkula G, Jones KB, Sponseller PD, Dietz HC, Pyeritz
assay may be needed for diagnostic confirmation. Pre- RE. Growth and maturation in Marfan syndrome. Am J
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12. Pyeritz RE, Fishman EK, Bernhardt BA, Siegelman SS.
methods is possible.
Dural ectasia is a common feature of the Marfan syn-
Like other lysosomal disorders, the mucopolysaccha-
drome. Am J Hum Genet 1988;43:726732.
ride and mucolipid disorders have distinctive character- 13. Foran JR, Pyeritz RE, Dietz HC, Sponseller PD. Charac-
istics: (1) intracellular storage occurs; (2) storage material terization of the symptoms associated with dural ectasia
is heterogeneous because the degradative enzymes are in the Marfan patient. Am J Med Genet A 2005;134:
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the disorders are clinically progressive. Therapy by aortic root in patients with Marfans syndrome. N Engl J
replacing the enzyme that is deficient is possible, but Med 1999;340:13071313.
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marrow transplant is effective in the disorders lacking patients with the Marfan syndrome. J Thorac Cardiovasc
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16. Sponseller PD, Hobbs W, Riley LH III, Pyeritz HE. The
investigated in patients with mental retardation (43).
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Enzyme replacement therapy is available for MPS type Surg Am 1995;77:867876.
I (44) and is in clinical trials for several other types. 17. Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 31
antagonist, prevents aortic aneurysm in a mouse model of
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CHAPTER 32
Bone and Joint Dysplasias

WILLIAM A. HORTON, MD
Chondrodysplasias are inherited disorders of difficulties, and psychological issues due to short
cartilage that affect its function as a template for stature.
bone growth. The osteochondroses are a heterogeneous group of
Problems common to many chondrodysplasias are disorders in which localized non-inflammatory
respiratory distress, osteoarthritis of the weight- arthropathies result from regional disturbances of
bearing joints, dental crowding, obesity, obstetrical skeletal growth.
Bone dysplasias are a broad group of conditions in The chondrodysplasias result from mutations in
which skeletal development and function are disturbed. genes that encode the structural proteins of cartilage
They include the chondrodysplasias and osteochondro- matrix and proteins that regulate growth plate function,
ses discussed in this chapter, as well as osteodysplasias, including growth factors, receptors, and transcription
such as osteogenesis imperfecta syndromes (discussed factors. These proteins, which contribute to different
in Chapter 31), and many others that are either aspects of endochondral ossification, are required for
extremely rare or of little relevance to rheumatology. bone growth to proceed in a normal fashion (4,5).
Although poorly understood, the different types of
chondrodysplasias reflect the functional consequences
CHONDRODYSPLASIAS of disturbances in these proteins with regard to bone
growth and other clinical manifestations.
The term chondrodysplasialiterally, abnormal (dys)
cartilage (chondro) growth (plasia)is used to desig-
nate inherited disorders of cartilage that affect its func-
Classification
tion as a template for bone growth (1). The clinical Well over 100 clinical forms of chondrodysplasia are
picture is typically dominated by varying degrees of currently recognized. Based on their differences in clini-
dwarfism and bone and joint deformities. However, cal presentation, characteristic appearances of skeletal
because the genes that harbor chondrodysplasia muta- radiographs, growth plate histology, and pattern of
tions are often not specific to bone growth, the clinical inheritance, these disorders have been grouped over the
manifestations frequently extend to other cartilages, past decade into classes which correspond in many
such as articular cartilage, and to other tissues (13). instances to a common gene that is mutated (1,6). A
well-defined chondrodysplasia class, such as the achon-
droplasia or spondyloepiphyseal dysplasia (SED) class,
Pathogenesis typically contains a group of disorders ranging in sever-
Most bones develop and grow through the process of ity from lethal at or around birth to very mild, often
endochondral ossification, in which cartilage serves as a blending into the normal (nonchondrodysplasia) popu-
template for bone formation. In postembryonic growing lation. The current classification scheme is based pri-
bone, ossification occurs in the growth plate residing marily on molecular genetics, but the genetic basis of
near the ends of bones (4). Growth plates have a leading many disorders has yet to be determined. Consequently,
and trailing edge. In essence, template cartilage is syn- the scheme continues to evolve.
thesized de novo at the leading edge, whereas it is
degraded and replaced by an expanding front of bone
at the trailing edge. Endochondral ossification accounts
Diagnosis
for linear bone growth from mid-gestation through the A few conditions, such as achondroplasia, can be
end of puberty. diagnosed simply by seeing a patient. However, the
559
TABLE 32-1. SALIENT FEATURES OF SELECTED CHONDRODYSPLASIAS.
OVERALL
CLASS AND DISORDER OMIM INHERITANCE GENE LOCUS SEVERITY RHEUMATOLGIC COMPLICATIONS
Achondroplasia
Thanatophoric dysplasia 187600/187610 AD FGFR3 Lethal
Achondroplasia 100800 AD FGFR3 ++/+++ Arthralgias
Hypochondroplasia 146000 AD FGFR3 +
Spondyloephiphyseal dysplasia (SED)
Achondrogenesis type II 200610 AD COL2A1 Lethal
Hypochondrogenesis 14600 AD COL2A1 Lethal
SED congenita 183900 AD COL2A1 +++ Precocious OA
Kniest dysplasia 156550 AD COL2A1 +++ Contractures, precocious OA
Stickler dysplasia 108300 AD COL2A1 ++ Precocious OA
Stickler-like dysplasia 184840 AD COL11A1 ++ Precocious OA
Stickler-like dysplasia 184850 AR COL11A2 ++ Precocious OA
SED late onset AD COL2A1 + Precocious OA
SED tarda 313400 XLR SEDL + Precocious OA
Multiple epiphyesal dysplasia (MED)/pseudoachondroplasia
MED 600969 AD COMP +++ Arthralgias, precocious OA
Pseudoachondroplasia 177170 AD COMP +++ Arthralgias, precocious OA
Diastrophic dysplasia
Achondrogenesis type 1B 600972 AR DTDST Lethal
Ateleosteogenesis type II 256050 AR DTDST Lethal
Diastrophic dysplasia 222600 AR DTDST +++ Precocious OA, contractures
Metaphyseal chondrodysplasia
Jansen type 156400 AD PTHR1 +++ Contractures
Schmid type 156500 AD COL10A1 ++
McKusick type 250250 AR RMPR +++
Metatropic dysplasia
Metatropic dysplasia 250600 AD Unknown +++ Contractures
Chondrodysplasia punctata
Rhizomelic type 215100 AR ACDPA Lethal Contractures
X-linked recessive type (CDPX1) 302950 XLR ARSE +++
X-linked dominant type (CDPX2) 302960 XLD EBP ++/+++ Contractures
Brachyolmia
Hobaek type 271530 AR Unknown ++ Arthralgia, stiffness in hip, back
Maroteaux type AR Unknown ++ Arthralgia, stiffness in hip, back
Autosomal dominant type 113500 AD Unknown ++ Arthralgia, stiffness in hip, back
ABBREVIATIONS: ACDPA, acetyl-CoA dihydroxyacetone phosphate acetyltransferase; AD, autosomal dominant; AR, autosomal recessive; ARSE, arylsulfatase E;
COL10A1, type X collagen alpha l chain; COL11A1, type XI collagen alpha l chain; COL11A2, type XI collagen alpha 2 chain; COL2A1, type II collagen alpha l
chain; COMP, cartilage oligomeric matrix protein; DTDST, diastrophic dysplasia sulfate transporter; EBP, delta(8)-delta(7) sterol isomerase emopamil-binding
protein; FGFR3, fibroblast growth factor receptor 3; OA, osteoarthritis; PTHR1, parathyroid hormonerelated protein receptor 1; RMPR, RNA component of
mitochondrial RNA processing endoribonuclease; XLD, X-linked dominant; XLR, X-linked recessive.
OMIM refers to Online Mendelian Inheritance of Man, which provides extensive references (http://www.ncbi.nlm.nih.gov/omim).
C H A P T E R 3 2 B O N E A N D J O I N T D Y S P L A S I A S 56 1
diagnosis is usually based on recognizing a unique com- prominent forehead and hypoplasia of the mid-face.
bination of clinical, radiographic, and genetic features Most joints are hyperextensible, especially the knees,
(13,7). Because the clinical features typically evolve but elbow mobility is limited. The most serious prob-
over time, the natural history must be taken into account lems are related to a small spinal canal, especially at the
when patients are evaluated. The most useful informa- foramen magnum level. This anomaly contributes to
tion usually comes from skeletal radiographs; specific hypotonia, failure to thrive, developmental delay, apnea,
radiologic diagnostic criteria have been developed (7 and even quadriparesis and sudden death in some
10). Like the clinical picture, radiographic characteris- infants. Common childhood problems include middle-
tics change with age. Films taken before puberty are ear infections, dental crowding, and bowing of the
usually more informative because the radiographic hall- legs.
marks of many disorders disappear after closure of the The lifespan is normal in the absence of life-threat-
epiphyses. In fact, it is often difficult to make a specific ening neurologic problems in early life. In adulthood,
diagnosis from postpubertal radiographs. Because many men reach an average height of 132 cm (about 45
patients are the first and only known case in a family, a inches) and women, 124 cm (about 40 inches). Pain is
pedigree may be of little help as the inheritance pattern common in weight-bearing joints, probably due to mis-
cannot be determined. Nevertheless, a family history alignment of bones aggravated by physical activity and
sometimes provides critical clues toward a diagnosis. by obesity, which is common. However, people with
Historically, laboratory tests have not been useful in achondroplasia rarely develop osteoarthritis. Stenosis
diagnosing chondrodysplasias. However, as the muta- of the lumbar spine may cause paresthesias, claudica-
tions are being better defined, genetic testing may be tion and numbness of the legs, and bowel and bladder
helpful in disorders caused by a recurrent mutation in dysfunction.
the population, as is the case with achondroplasia and Pregnant women with achondroplasia need to be
perhaps in some forms of late-onset SED associated monitored carefully and delivered by cesarean section.
with precocious osteoarthritis. Although histologic Because of the high prevalence of heterozygous achon-
evaluation of growth plate specimens often reveals droplasia in the short-stature community, people with
characteristic changes, biopsy is seldom warranted as this condition often marry; their offspring have a 25%
the diagnosis can usually be made by other means. risk for inheriting the much more severe homozygous
Salient features of the more common chondrodyspla- achondroplasia.
sias are summarized in Table 32-1 (6), and additional
information can be found in several recent reviews
(1,2,5,7,11). The most up-to-date information and refer-
Hypochondroplasia
ences are available through the Online Mendelian Not usually recognized until mid- to late childhood,
Inheritance in Man, developed by McKusick and col- patients with hypochondroplasia appear to have mild
leagues (http://www.ncbi.nlm.nih.gov/omim/). achondroplasia with short limbs (mostly the proximal
segments), a stocky build, and a normal or slightly 32
enlarged head. The natural history is usually unremark-
CLASSIFICATION OF able other than for mild short (approximately 5 or less)
stature. The true incidence of hypochondroplasia is
CHONDRODYSPLASIAS unknown; because its features are mild, it may often
escape detection.
Achondroplasias
This class of autosomal dominant disorders includes the
following: thanatophoric dysplasia, the most common
Spondyloepiphyseal Dysplasias
chondrodysplasia lethal in the perinatal period; achon- Spondyloepiphyseal dysplasia (SED) is a large, diverse
droplasia, by far the most common nonlethal chondro- class of autosomal dominant disorders with clinical
dysplasia; and hypochondroplasia. Although the three features that reflect varying degrees of dysfunction of
differ substantially in severity, the features of each are type II collagen, the principal structural protein of
qualitatively similar. Heterozygous mutations of the cartilage. In severe forms, many types of cartilage and
gene encoding fibroblast growth factor receptor 3 other tissues containing type II collagen are affected,
(FGFR3) have been identified in all three conditions. whereas in milder forms, only articular cartilage is
involved.
Achondroplasia
Spondyloepiphyseal Dysplasia Congenita
The prototype of short-limb dwarfism, achondroplasia
is recognizable at birth by a long narrow trunk, short This form of dysplasia is the prototype of short trunk
limbs (especially proximally), and a large head with dwarfism. Neonates with SED congenita have a short
562 WILLIAM A. HORTON
neck, a short barrel-shaped trunk, and sometimes cleft Multiple Epiphyseal Dysplasia and
palate and club foot. The proximal limbs are short, but
the hands, feet, head, and face appear to be normal in
Pseudoachondroplasia
size. The shortening becomes more prominent with Multiple epiphyseal dysplasia (MED) and pseudo-
time. Scoliosis commonly develops in childhood and achondroplasia are classified together because muta-
may cause respiratory compromise. Odontoid hypopla- tions in the cartilage oligomeric matrix protein (COMP)
sia may predispose to cervicomedullary instability and gene have been found in both disorders.
spinal cord compression, but sudden death is uncom- The Fairbank type of MED is usually diagnosed in
mon. Osteoarthritis, especially of the hips and knees, childhood because of moderately short limbs, a wad-
typically appears in the third decade. Severe myopia is dling gait, and painful joints. Radiographs show gener-
common, and retinal detachment may occur in older alized epiphyseal involvement. The Ribbing type of
children and adults. Adults range in height from 95 to MED may not be detected until adolescence. Because
128 cm (about 35 to 50 inches). involvement is typically restricted to the proximal
femurs, the Ribbing type is often confused with bilateral
LeggCalvPerthes disease. Both types of MED are
Kniest Dysplasia associated with moderately short stature (145170 cm)
At birth, infants with Kniest dysplasia have a short and osteoarthritis of weight-bearing joints.
trunk and limbs and a flat face with prominent eyes. Pseudoachondroplasia typically presents in the
Their fingers are long and knobby, and many have club second or third year of life with a dramatic slowing of
foot and cleft palate. The most debilitating aspect is the bone growth accompanied by a waddling gait and gen-
progressive enlargement of joints during childhood, eralized joint laxity. The head and face appear normal,
which is associated with painful contractures and, even- but the hands are short and broad, and ulnar deviation
tually, with osteoarthritis. Hearing loss is common, as occurs. The growth deficiency worsens with age. Major
is severe myopia that is often complicated by retinal complications are related to excessive joint mobility,
detachment. most notably involving the knees, where it produces
various deformities. Osteoarthritis of the hips and knees
is common.
Stickler Dysplasia
The clinical picture of Stickler dysplasia is dominated
Diastrophic Dysplasia
by ocular problems. Severe myopia is usually present at Diastrophic dysplasia is usually apparent at birth.
birth, together with cleft palate and a small jaw. Retinal Infants display very short extremities and distinctive
detachment may occur during childhood, as may cho- hands with short digits and proximal displacement of
roidoretinal and vitreous degeneration. Sensorineural the thumb (hitchhiker thumb). There may be bony
hearing loss often develops during adolescence. Osteo- fusion of metacarpophalangeal joints producing sym-
arthritis typically begins during the second or third phalangism and ulnar deviation of the hands. Cleft
decade of life. Short stature is not a feature of Stickler palate and club foot are common. The external ears
dysplasia; indeed, some patients exhibit a Marfan-type often become inflamed soon after birth; healing results
habitus and joint laxity. A dysplasia similar to Stickler in small, fibrotic ears (cauliflower deformity). Scoliosis
dysplasia may arise from mutations of genes encoding and multiple joint contractures usually begin during
type XI collagen. childhood and are typically progressive and severe.
Adult height varies from 105 to 130 cm (4044 inches).
Late-Onset Spondyloepiphyseal Dysplasia Metaphyseal Chondrodysplasias

Some type II collagen mutations manifest primarily as The metaphyseal chondrodysplasias (MCDs) are a het-
precocious osteoarthritis of weight-bearing joints. erogeneous group of disorders that share radiographic
Radiographs usually reveal subtle changes of SED, but involvement of the metaphyses. However, studies have
many of these patients are of normal stature and have shown that they do not share a common genetic basis.
no other abnormalities. The term familial (or autosomal
dominant) osteoarthritis is sometimes used to describe
Jansen Metaphyseal Chondrodysplasias
this syndrome. Recurrent mutations of the type II col-
lagen gene have been observed in a few instances of Severely shortened limbs, prominent forehead, and
familial osteoarthritis. Mutations of an X-linked gene small jaw are present at birth. Some infants have club
encoding a protein termed sedlin can produce a foot and hypercalcemia. Joints enlarge and become
similar but distinct clinical picture in males, which is restricted during childhood. Flexion contractures at the
called SED tarda. hips and knees often result in a bent-over posture.
C H A P T E R 3 2 B O N E A N D J O I N T D Y S P L A S I A S 56 3
Schmid Metaphyseal Chondrodysplasias Rhizomelic Chondrodysplasia Punctata

This disorder usually becomes apparent at age 2 to 3 At birth, rhizomelic CDP is evidenced by severe and
years because of mild shortening of the limbs, especially symmetric shortening of limbs, multiple joint contrac-
the legs (which are bowed), a waddling gait, and some- tures, cataracts, ichthyosiform rash, absent hair, micro-
times hip pain. Adults are of mildly short stature and cephaly, and flat face with hypoplasia of the nasal tip.
have few problems. These infants fail to thrive and usually die during the
first year.
McKusick Metaphyseal Chondrodysplasias
X-Linked Chondrodysplasia Punctata
Also called cartilagehair hypoplasia, the McKusick
type MCD manifests at age 2 to 3 years as growth defi- Chondrodysplasia punctata may be X-linked dominant
ciency. It is characterized by short limbs, bowed legs, or recessive. The recessive form, CDPX1, is symmetric
and flaring of the lower rib cage. Hands and feet are and severe, whereas the dominant form, CDPX2 is rela-
short and broad, and fingers are short and stubby. Liga- tively mild and asymmetric in distribution. Varying
mentous laxity is marked. The hair tends to be blond degrees of contractures, cataracts, skin rash, and hair
and thin, and the skin is lightly pigmented. Some patients loss are found in CDPX2. The asymmetry may worsen
have associated problems, including immune deficiency, and scoliosis may develop over time, but patients with
anemia, Hirschsprungs disease, and malabsorption. CDPX2 usually have a normal life span.
Adults exhibit marked dwarfism and are predisposed to
certain infections and malignancies of the skin and lym-
phoid tissue.
Brachyolmia
Three types of brachyolmia are recognized, all of which
have similar clinical features (Table 32-1). They present
Metatropic Dysplasia in early to mid-childhood with mildly short stature
Newborn infants with metatropic dysplasia have short mainly involving the trunk. Back and hip pain typically
limbs and a long narrow trunk. Kyphoscoliosis, which arise during adolescence and continue into adulthood.
starts during late infancy or early childhood, may cause Back stiffness is common and some patients develop
cardiorespiratory problems. Odontoid hypoplasia is scoliosis.
common. Most joints become large and have restricted
mobility, and contractures often develop at the hips and
knees. JUVENILE OSTEOCHONDROSES
The juvenile osteochondroses summarized in Table
Chondrodysplasia Punctata 32-2 are a heterogeneous group of disorders in which 32
Disorders classified as chondrodysplasia punctata localized non-inflammatory arthropathies result from
(CDP) share the radiographic finding of stippled epiph- regional disturbances of skeletal growth (12,13). Chil-
yses, but specific features differ substantially. dren may present with painless limitation of movement
TABLE 32-2. JUVENILE OSTEOCHONDROSES.

REGION AFFECTED EPONYM TYPICAL AGE AT PRESENTATION SEX PREDILECTION
Capital femoral epiphysis LeggCalvPerthes disease, 312 years Male

coxa plana
Tibial tubercle OsgoodSchlatter disease 1016 years None
Os calcis Severs disease 610 years None
Head of second metatarsal Freibergs disease 1014 years None
Vertebral bodies Scheuermanns disease Adolescence Male
Medial aspect of proximal tibial epiphysis Blount disease, tibia vara Infancy or adolescence None
Subchondral areas of diarthroidal joints Osteochondritis dissecans 1020 years Male

(particularly knee, hip, elbow and ankle)
564 WILLIAM A. HORTON
of affected joints (such as in LeggCalvPerthes dis- groups, such as the Little People of America and the
ease and Scheuermanns disease) or with local pain Human Growth Foundation, and from publications
and sometimes tenderness and swelling (such as in directed to the lay population (11). Useful lay informa-
Freibergs disease, OsgoodSchlatter disease, and tion is also available through websites such as http://
osteochondritis dissecans). Bone growth may be altered www.lpaonline.org/.
to produce deformities, such as bowing of the tibia in
Blounts disease.
The diagnosis of juvenile osteochondrosis can usually REFERENCES
be confirmed radiographically, and magnetic resonance
imaging is sometimes useful to define the lesions. The 1. Horton WA, Hecht JT. The chondrodysplasias: general
pathogenesis is thought to involve ischemic necrosis of concepts and diagnostic and management considerations.
primary or secondary endochondral ossification centers. In: Royce PM, Steinman B, eds. Connective tissue and its
Some cases may be related to stress and injury. Most of heritable disorders. 2nd ed. New York: Wiley-Liss; 2002:
these disorders occur sporadically, but familial forms 641676.
2. Rimoin D, Lachman R, Unger S. Chondrodysplasias. In:
have been described.
Rimoin DS, Connor JM, Pyeritz RE, Korf BR, eds. Emery
and Rimoins principles and practice of medical genetics.
4th ed. London: Churchill Livingstone; 2002:40714115.
MANAGEMENT OF BONE AND 3. Sponseller PD, Ain MC. The skeletal dysplasias. In
JOINT DYSPLASIAS Morrissy RT, Weinstein SL, eds. Lovell & Winters pedi-
atric orthopaedics. 6th ed. Philadelphia: Lippincott Wil-
liams & Wilkins; 2006:205250.
No definitive treatment is available to counter defective
4. Morris NP, Keene DR, Horton WA. Biology of extra-
bone growth for any of the bone and joint dysplasias. cellular matrix: cartilage. In Royce PM, Steinman B, eds.
Consequently, management is directed at prevention Connective tissue and its heritable disorders. 2nd ed. New
and correction of skeletal deformities and preventing York: Wiley-Liss; 2002:4166.
nonskeletal complications. Management is guided by 5. Horton WA. Molecular genetic basis of the human chon-
knowledge of the natural history of these disorders, so drodysplasias. Endocrinol Metab Clin North Am 1996;25:
that disorder-specific problems can be anticipated and 683697.
treated early. 6. Hall CM. International nosology and classification of con-
A number of problems are common to many chon- stitutional disorders of bone (2001). Am J Med Genet
drodysplasias, including respiratory distress, osteoar- 2002;113:6577.
thritis of weight-bearing joints, dental crowding, 7. Spranger J, Maroteaux P. The lethal osteochondrodyspla-
sias. Adv Hum Genet 1995;19:1103.
obesity, obstetrical difficulties, and psychological prob-
8. Spranger JW, Brill PW, Poznanski A. Bone dysplasias, an
lems related to short stature. General recommenda- atlas of genetic disorders of skeletal development. 2nd ed.
tions can be made to address these problems (1,3). For New York: Oxford University Press; 2002.
example, most patients with a chondrodysplasia should 9. Wynne-Davies R, Hall CM, Apley AG. Atlas of skeletal
avoid contact sports and other activities that trauma- dysplasias. Edinburgh: Churchill Livingstone; 1985.
tize or stress joints. Joint replacement is often neces- 10. Tabyi H, Lachman RS. Radiology of syndromes, meta-
sary for progressive osteoarthritis. Dietary control bolic disorders, and skeletal dysplasias. 4th ed. St. Louis:
should be instituted during childhood to prevent obesity Mosby; 1996.
in adulthood. Dental care should be started in early 11. Scott CI Jr, Mayeux N, Crandall R, Weiss J. Dwarfism,
childhood to manage crowding and misalignment effec- the family and professional guide. Irvine, CA: Short
tively. Because of their small pelvic bones, pregnant Stature Foundation & Information Center, Inc.; 1994.
12. Sharrard WJW. Abnormalities of the epiphyses and limb
women with most chondrodysplasias should be managed
inequality. In: Paediatric orthopaedics and fracture. 3rd
in high-risk prenatal clinics and, in many instances, ed. Oxford: Blackwell Scientific Publications; 1993:719
have their babies delivered by cesarean section. Intel- 814.
ligence is usually normal in the nonlethal chondrodys- 13. Herring JA, ed. Disorders of the knee/Disorders of the
plasias, but because patients are so easily recognized leg/Disorders of the foot [three chapters]. In: Tachdjians
as being different from their peers, they and their pediatric orthopedics, 3rd ed. Philadelphia: Saunders;
families often benefit from support provided by lay 2002:789838, 839890, 8911038.
CHAPTER 33
Osteonecrosis
THORSTEN M. SEYLER, MD
DAVID MARKER, BS
MICHAEL A. MONT, MD
Osteonecrosis or vascular necrosis refers to the final A variety of non-operative treatment interventions
result of a number of different pathways leading to are available at some centers, including vasodilators,
bone death and ultimately to joint destruction. The lipid-lowering agents, prostacyclin analogues, various
femoral head is the most common site of types of anticoagulants, bisphosphonates, hyperbaric
osteonecrosis. oxygen therapy, and extracorpeal shock wave
Osteonecrosis develops bilaterally in more than 80% therapy. Rigorous data on the efficacy of these
of cases. Besides the hip, the most common sites for approaches are currently not available.
necrosis are knees, shoulders, ankles, and elbows. There are currently four general categories of
The most common risk factors for osteonecrosis are operative treatment options aimed toward preserving
glucocorticoid use, excessive alcohol consumption, the femoral head and delaying (or preventing) total
and cigarette smoking. arthroplasty: (1) core decompression; (2) osteotomy;
The first symptom associated with the disease is (3) nonvascularized bone grafting; and (4) vascular-
typically a deep, throbbing groin pain. This pain, ized bone grafting.
usually intermittent and of gradual onset, occasion- Many patients eventually undergo total joint arthro-
ally appears abruptly. plasty or resurfacing arthroplasty.
Osteonecrosis (ON), also often termed avascular operative treatments and ultimately required surgical
necrosis, is a disease that leads pathologically to dead intervention. However, a number of new non-operative
bone. There are many direct and indirect causes of approaches have shown early success rates, confirming
ON, which may be multifactorial and lead to joint the importance of early diagnosis. The following section
destruction. ON of the femoral head, the most common details the risk factors and pathophysiology of ON. We
location for this disease, is the focus of this chapter. In then describe the staging of this disease in relationship
more than 10% of cases, symptomatic ON of the hip to the latest non-operative and operative treatment
also involves the knee and shoulder. In approximately methods.
3% of patients, more than three anatomic sites are
involved. Between 10,000 and 20,000 patients are
diagnosed with this disease each year, and approxi- RISK FACTORS AND
mately 10% of the hip replacements performed in the PATHOGENESIS
United States are related to ON. The disease usually
occurs in the fourth decade of life, but the age range of Recent advances in the understanding of ON have led
patients is wide. Because of the relative youth of many to identification of a number of risk factors for this
patients with ON, joint replacements in many cases disease. The most common ones include: glucocorticoid
are unlikely to last the full life expectancy of the patient. use, excessive alcohol consumption, and cigarette
Thus, much effort has been aimed at preserving the smoking. Other risk factors and associated conditions
femoral head. are shown in Table 33-1. In approximately 15% of
Rheumatologists are often the first medical practitio- patients, the occurrence of ON must still be considered
ners to encounter these patients, whose major risk idiopathic, as no clear cause may be identified. Risk
factor is frequently long-term glucocorticoid use. The factors for ON are not mutually exclusive. Each increases
key to joint preservation in ON is early diagnosis. ON the likelihood of establishing the appropriate pathologi-
was previously a disease that inevitably failed non- cal milieu for ischemic bone events and subsequent bone
565
566 THORSTEN M. SEYLER, DAVID MARKER, AND MICHAEL A. MONT
TABLE 33-1. RISK FACTORS AND CLINICAL Arterial and venous abnormalities are relatively
CONDITIONS ASSOCIATED WITH OSTEONECROSIS. common in cases of ON. In the case of venous abnor-
malities, it remains unclear whether they are causative
Direct causes
Fracture or simply a result of the ON. Studies on a rat model of
Dislocation ON showed that LeggCalvePerthes disease led to sec-
Pregnancy ondary mechanical instability of the femoral epiphyseal
Radiation plate, collapse of this segment, and ultimately to blood
Chemotherapy
supply compromise in a manner similar to that of trau-
Organ transplantation
Hypersensitivity reactions matic-induced ischemia (4).
Myeloproliferative disorders (Gauchers disease, leukemia) Mechanical occlusion of vessels can also be caused
Sickle-cell disease by embolic events. These emboli may be composed of
Coagulation deficiencies (thrombophilia, fat, sickled red blood cells, or nitrogen bubbles (in the
hypofibrinolysis)
context of caisson disease or dysbarism). Thrombo-
Gauchers disease philia, hypofibrinolysis, and heritable coagulation disor-
Thalassemia ders are more common among patients with ON than
Dysbarism among controls (5).
Liver dysfunction Other disorders strongly associated with ON are Gau-
Gastrointestinal disorders
chers disease (see Chapter 28), leukemia, and myelo-
Caisson disease
proliferative disorders. These disorders are linked to
Indirect causes intraosseous marrow displacement and increased pres-
Glucocorticoids sure in the bony compartment of the femoral head and
Alcohol
neck (6). Because it cannot expand, the bone involved
Smoking
Idiopathic cannot compensate for increased pressure, resulting in
Genetic factors vascular collapse, ischemia, and cell damage.
Another direct cause of ON is cellular toxicity caused
by radiation, chemotherapy, and thermal injuries. In
necrosis to occur. The location of these physiological each of these cases, the external stimulus results in
abnormalities can be either intra- or extraosseous, and osteocyte and marrow cell damage or death, and ulti-
also either intra- or extravascular. The pathogenic mately in ON. Although even moderate amounts of
mechanisms associated with these etiological factors can alcohol are toxic to osteocytes, no in vitro studies have
be grouped into two categories, direct and indirect. indicated direct cytotoxic effects of alcohol when con-
sumed at physiologically tolerated concentration. Simi-
larly, although glucocorticoids have been shown to
Direct Causes increase fat accumulation and result in bone cell death,
Direct causes of ON include trauma, nitrogen bubbles animal models have been unsuccessful in demonstrating
(caisson disease, a consequence of deep-sea diving), collapse that is similar to the human conditions associ-
various myeloproliferative disorders that lead to an ated with ON.
expanded bone marrow, sickle cell disease, and patho-
logical entities leading to direct bone cell injury (e.g.,
radiation). The cause-and-effect relationship between
Indirect Causes
trauma and ON is readily apparent in cases involving Although glucocorticoid use, alcohol consumption, and
dislocations or fractures of the hip. In one study, ON was smoking are found in more than 80% of ON cases, the
associated with 16% of nondisplaced subcapital frac- pathogenic mechanism for these risk factors is not clear.
tures and 27% of displaced subcapital fractures (1). For glucocorticoids, doses of >2 g of prednisone (or its
Traumatic occlusion of vessels is the most direct equivalent) within 2 to 3 months are considered to raise
cause of bone ischemia. Fractures and dislocations may the risk of ON (7). The onset of ON following the start
directly injure both intra- and extraosseous vessels sup- of glucocorticoid use has been documented as being
plying blood to a specific bone such as the hip. Although between a mean of 3 and 5 months (8). For both alcohol
the initial injury leads to ON, the healing process itself and cigarette smoking, the risk of ON rises with the
may also exacerbate the problem. Results of animal level of exposure.
studies are consistent with the hypothesis that ON of A mutation in a type II collagen gene was identified
the femoral head stems from the failed attempt to in three families demonstrating autosomal dominant
replace dead bone with new tissue (2). Similarly, arte- inheritance of femoral head ON (9). Other genetic
riographic studies reveal extraosseous blockage of the studies have reported an association between ON and
superior retinacular arteries and poor revascularization certain polymorphisms involving alcohol-metabolizing
in weight-bearing regions, suggesting that occlusion enzymes and the drug transport protein P-glycoprotein.
does not fully occur until after the healing process (3). Further studies of genetic risk factors are needed, but
C H A P T E R 3 3 O S T E O N E C R O S I S 56 7
this approach may serve one day as a tool for identifying relatively asymptomatic despite advanced radiographic
patients at high risk for ON. This, in turn, may have changes. As patients reach end-stage clinical symptoms,
implications for non-operative treatment to delay dis- however, the pain worsens and range of motion becomes
ease progression. increasingly limited. The time course for ON varies
according to individual patients, ranging from months
to years between initial symptom onset and the devel-
PATHOLOGY opment of end-stage ON.
Despite all the different causes and associated factors
with this disease, the pathology is similar in all cases. A RADIOGRAPHIC STAGING
number of factors, including the size and location of the
ON lesion, may influence the rate of progression. In some Patients at risk for ON who have any groin pain should
cases, small lesions may be stabilized by the healing be evaluated radiographically as soon as possible.
response. More than 90% of patients with ON, however, Patients diagnosed with ON should also be evaluated
demonstrate ineffective repair and progression of the for potential bilateral presentation of the disease, as
disease (6). Early lesions typically demonstrate histologi- well as the involvement of other joints. ON develops
cal signs such as hemorrhage and necrosis, surrounded bilaterally in more than 80% of cases. Besides the hip,
by areas of normal fatty marrow. Loss of hematopoietic the most common sites for necrosis are knees, shoul-
elements and microvesicular changes of the marrow adi- ders, ankles, and elbows.
pocytes are evident. The lesions then progress and lead The most accurate imaging modalities for diagnos-
to extensive necrosis of the hematopoietic and fatty bone ing ON are roentgenograms and magnetic resonance
marrow elements. This necrosis is accompanied by his- imaging (MRI). Other modalities such as bone scans,
tiocytic phagocytosis of debris. Without revasculariza- bone biopsies, computed tomography (CT) scans, and
tion, the necrotic zone remains acellular and the positron emission tomography (PET) scans are not nec-
surrounding tissue alternates between repair and necro- essary for the diagnosis of this disease and for formulat-
sis. Larger lesions cannot be repaired and progress to ing a treatment plan. One major obstacle to studying
more advanced stages of ON. Advanced stages are char- ON is the absence of a universally accepted method for
acterized by a wedge or conically shaped area of dead classifying disease severity and determining prognosis.
bone that contains disorganized trabeculae and fatty Authors classify the stages of ON variably, according to
tissue, later replaced by granular, reticular, or amor- institutional practice, confounding comparisons of data
phous tissue. This region, known as the sequestrum, is across studies. Sixteen major classification systems are
characterized by an osteochondral fracture beneath the used currently to describe the various radiographic
subchondral plate. This fracture ultimately leads to the findings of ON. Four of these systemsthe Ficat and
death of the medullary bone, marrow, and cortex. Arlet, University of Pennsylvania, ARCO (Association
When healing is unsuccessful, revascularization and Research Circulation Osseous), and Japanese Ortho-
repair are prevented as fibrous scar tissue forms and paedic Association classificationsaccount for more
separates the necrotic bone from healthy tissue. After than 85% of all published studies since 1985 (10). The
the formation of this scar, the lesion often progresses stages for each system are shown in Table 33-2. In a
and the mechanical stability of the necrotic region systematic analysis of classification systems (10), the
becomes compromised. Stress-induced fractures of the following parameters were found to be the most useful 33
necrotic trabeculae lead to collapse of the subchondral for uniform data collection:
bone, cartilage disintegration, and deformity of the
With regard to the femoral head, lesions should be
femoral head. Collapse of the femoral head leads to
classified by pre- or postcollapse status. Precollapse
substantial cartilage breakdown and induces additional
lesions have better prognoses.
degenerative changes to the joint.
The size of the necrotic segment must be assessed.
Smaller lesions have better prognoses.
CLINICAL PRESENTATION The amount of femoral head depression must be
assessed. Lesions with <2 mm of depression have
The clinical manifestations of ON may follow the incit- more favorable outcomes.
ing injury or pathological conditions by months or years. Acetabular involvement, if present, should be char-
The first symptom associated with the disease is typi- acterized. Any sign of osteoarthritis will limit treat-
cally a deep, throbbing groin pain. This pain, usually ment options.
intermittent and of gradual onset, occasionally appears The presence or absence of a crescent sign (Figure
abruptly. This pain may correlate with movement and 33-1), indicative of femoral head collapse, should be
weight bearing, but later may advance to rest pain. The noted.
relationship between symptom manifestations and Diffuse sclerosis and the presence of cysts should be
radiologic findings is imperfect. Some patients remain noted.
TABLE 33-2. RADIOGRAPHIC CLASSIFICATION OF OSTEONECROSIS OF THE

FEMORAL HEAD.
STAGE DESCRIPTION
Ficat and Arlet

I Normal
II Sclerotic or cystic lesions, without subchondral fracture
III Crescent sign (subchondral collapse) and/or step-off in contour of subchondral bone
IV Osteoarthritis with decreased articular cartilage, osteophytes
University of Pennsylvania System of Staging

I, II First two stages are the same as Ficat and Arlet
III Crescent sign only
IV Step-off in contour of subchondral bone
V Joint narrowing or acetabular changes
VI Advanced degenerative changes
Each lesion is divided into A, B, and C depending on the magnetic resonance imaging
(MRI) size of the lesion (small, moderate, large)
ARCO
0 None
1 X-ray and computed tomography (CT) normal; at least one other technique is positive
2 Sclerosis, osteolysis, focal porosis
3 Crescent sign and/or flattening of articular surface
4 Osteoarthritis, acetabular changes, joint destruction
Japanese Investigation Committee

1 Demarcation line
Subdivided by relationship to weight-bearing area (from medial to lateral)
1A
1B
1C
2 Early flattening without demarcation line around necrotic area
3 Cystic lesions
Subdivided by site in the femoral head
3A (Medial)
3B (Lateral)
FIGURE 33-1
Anteroposterior (A) and lateral (B) radiographs demonstrating advanced osteonecrosis of the
femoral head. The lateral view (B) delineates a crescent sign (arrow) that is the result of a
subchondral fracture, indicating biomechanical compromise of the femoral head.
A B
TABLE 33-3. PHARMACOLOGICAL TREATMENT OPTIONS AND REPORTED CLINICAL OUTCOMES.

PHARMACOLOGICAL FOLLOW-UP
AGENTS AUTHOR YEAR (MONTHS) CLINICAL OUTCOME
Lipid-lowering drugsa Pritchett (15) 2001 90 (60132) Three (1%) out of 284 patients taking high-dose glucocorticoids
as well as statins developed osteonecrosis
Bisphosphonatesb Agarwala (16) 2005 12 (360) Six (10%) out of 60 patients had disease progression and
required surgery
Lai (17) 2005 >24 Two (7%) out of 29 hips demonstrated loss of femoral head
integrity which required further intervention
Prostacyclin analoguesc Disch (18) 2005 25 (1137) All 17 patients demonstrated improvement in Harris hip scores,
range of extension, flexion and rotation, pain reduction, and
patient satisfaction
Anticoagulantsd Glueck (19) 2005 161 (108216) In 19 (95%) out of 20 hips, disease progression was retarded
a
Reduce elevated lipid levels associated with diseases such as systemic lupus erythematosus and osteonecrosis.
b
Decrease osteoclastic resorption of bone and promote new bone growth.
c
Inhibit platelet aggregation and alleviate hypertension to further enhance vascularization of ischemic bone areas.
d
Reverse coagulation pathologies associated with hypofibrinolysis and/or thrombophilia.
NON-OPERATIVE TREATMENT results of related studies using some of these novel

drugs. Additional clinical work is necessary to deter-
OPTIONS mine the true effectiveness of these measures.
The concept of hyperbaric oxygen treatment is based
Osteonecrosis diagnosed in the early stages may be
on the notion that increased oxygenation will prevent
amenable to non-operative treatment modalities, but
any additional bone necrosis and promote healing.
the precise stages at which specific interventions may be
Pulsed electromagnetic field therapy, direct current
successful have not been established yet. Historically,
electrical stimulation, and shock wave therapy are all
non-operative treatment options consisted largely of
designed to stimulate osteoblast activity and lead to new
assisted weight-bearing modalities such as canes or
bone growth, in the theory that this will prevent collapse
crutches. The rationale for these approaches was that
and promote healing. Among these modalities, extra-
the reduced stress would slow the progression of the
corpeal shock wave therapy appears the most promis-
disease enough to allow for procedures that might pre-
ing. Conflicting studies of pulsed electromagnetic field
serve the femoral head. This approach has proven
therapy and direct current electrical stimulation promote
unsuccessful: more than 80% of cases progressed to
continued skepticism by some experts.
femoral head collapse by 4 years after diagnosis (11).
In response to the poor prognosis of previous
non-operative treatment options, several non-operative
OPERATIVE TREATMENT 33
treatment modalities are under study. The most common
of these modalities are pharmacological measures, OPTIONS
hyperbaric oxygen treatment, extracorporeal shock
wave therapy, and various types of electrical stimulation Multiple operative treatment options are available to
(direct current, pulsed electromagnetic field therapy). treat ON prior to collapse of the femoral head. Some
The basic requirement for all of these treatment options surgeons have begun to use these procedures in con-
is that they must be administered prior to biomechani- junction with non-operative modalities described above.
cal collapse of the femoral head (evidence of collapse The impetus for these strategies is the poor prognosis
with a crescent sign). for patients treated with protected weight-bearing
Pharmacological measures are intended to amelio- alone. There are currently four general categories of
rate one or more pathophysiological features of ON operative treatment options aimed toward preserving
while allowing revascularization and bone growth. The the femoral head and delaying (or preventing) total
most common drugs employed for this purpose are arthroplasty: (1) core decompression; (2) osteotomy;
vasodilators, lipid-lowering agents, prostacyclin ana- (3) nonvascularized bone grafting; and (4) vascularized
logues, various types of anticoagulants, and bisphos- bone grafting. Some of these methods can also be com-
phonates. Table 33-3 lists these pharmacological agents bined with each other; for example, core decompression
with their desired physiological outcomes and provides may be combined with ancillary bone grafting.
Core Decompression TOTAL JOINT REPLACEMENT

Core decompression appears to preserve the femoral
Despite early operative and non-operative modalities,
head in many cases when ON is diagnosed at early
many patients eventually progress to advanced stages
stages (before femoral head collapse). Some authors
of ON. Total joint replacement remains a standard
have reported femoral head salvage rates of 70% to
treatment for these advanced cases. Up to 10% of all
90% at follow-ups ranging from 5 to 10 years (12).
total joint replacements are performed because of ON.
Techniques for core decompression continue to evolve
In addition to standard total hip arthroplasty, other
(13). Preferences among different surgeons vary as
arthroplasty alternatives, such as limited femoral resur-
to what procedure follows drilling of the initial core
facing and metal-on-metal resurfacing, exist.
tract. Some surgeons leave the site alone, while others
Historically, the results of standard total hip arthro-
prefer to fill it with bone graft. There is also interest
plasty in patients with ON have been poorer compared
in using various bone growth factors, stem cells, and
to those of the total hip arthroplasty population overall.
pro-osteogenic mediators simultaneously with the core
Recent advances in design and surgical technique have
decompression to enhance the long-term outcome of
allowed for improved survival rates. Despite these
the procedure.
results, the downside to standard total hip arthroplasty
is that it sacrifices bone and decreases the options for
Osteotomy future operations. This is an important consideration
due to the younger age of ON patients and the likeli-
Proximal femoral osteotomies, technically challenging hood that they will require a revision at some point in
to perform, have shown poor-to-moderate success with their life.
the exception of studies in Japan. This difference may
be in part due to differences in the pattern of vascular
anatomy found in the specific patient populations. The RESURFACING ARTHROPLASTY
objective of an osteotomy is to redistribute forces to
healthy bone by moving necrotic tissue away from areas Limited resurfacing or hemi-resurfacing of the femoral
which are weight-bearing. To increase the effectiveness head utilizes a cemented femoral head prosthesis that
of this procedure, surgeons have begun utilizing bone conforms to the patients original femoral head, simu-
growth factors. lating the coupling of the native femoral head to the
patients undamaged acetabulum. By fitting the pros-
thesis in this manner, the chance for dislocation follow-
Nonvascularized Bone Grafting ing surgery decreases. This procedure also conserves
bone stock and readily allows for conversion to a total
The purpose of bone grafts is to provide structural hip replacement in the future. Metal-on-metal resurfac-
support to the subchondral bone and articular cartilage. ings are more comprehensive than limited resurfacings,
Grafts harvested from healthy bone are remodeled to providing better functional results, more effective pain
the site of necrotic bone. The graft may be inserted relief, and improved range of motion. First introduced
through a trap door window in either the femoral head in the middle of the last century, metal-on-metal resur-
or neck. Surgeons have also begun to use growth and facings were discounted initially as a viable arthroplasty
differentiation factors to improve the outcome of this because of the unacceptably high number of cases with
procedure. component loosening and failure. New technology cre-
ating improved bearing surfaces has triggered renewed
interest in this technique. One recent study of 42 patients
Vascularized Bone Grafting with ON reported a 5-year joint survival rate of 95% for
Vascularized bone grafting was suggested as an alterna- metal-on-metal total hip resurfacing (14).
tive to nonvascularized bone grafting after initial results
suggested there was not adequate vascularization fol-
lowing the procedure. Similar to nonvascularized bone
PROPOSED TREATMENT
grafting, growth factors and osteogenic factors may ALGORITHM AND PROGNOSIS
increase the effectiveness and improve the long-term
outcome of vascularized bone grafting. The downside Many patient-specific factors must be considered when
to this procedure is that it is technically difficult, time- developing a treatment plan for ON, including overall
intensive, and associated with higher donor-site mor- health, age/life expectancy, comorbidities, and activity
bidity. Furthermore, this procedure requires two teams: level. Total joint arthroplasty and other major surgical
one team must prepare the femur while the other har- procedures are likely inappropriate for patients with
vests the fibula. chronic disease or short life expectancies. Conversely,
FIGURE 33-2
Symptoms?
Proposed treatment algorithm for
Asymptomatic Symptomatic osteonecrosis. MOM, metal-on-
metal.
Radiographs? Radiographs?
Normal Positive MRI Normal Positive MRI
Observation Pharmacologic Reconsider Collapse?

Treatment or Diagnosis
Core Decompression
Postcollapse Precollapse
Depression Size? Core Decompression and

Optional
Bone Grafting
> 2mm < 2mm Pharmacologic Treatment
Ancillary use of growth
factors
Acetabular Involvement Bone Grafting or
Osteotomy
Yes No
MOM Resurfacing or Limited Femoral

Total Joint Arthroplasty Resurfacing
young or active patients should be considered as can- 6. Mont MA, Hungerford DS. Non-traumatic avascular
didates for procedures that delay total joint arthro- necrosis of the femoral head. J Bone Joint Surg Am 1995;
plasty, such as bone grafts or bone preserving operations 77:459474.
such as metal-on-metal resurfacing. Because of their 7. Mont MA, Jones LC, Hungerford DS. Nontraumatic
osteonecrosis of the femoral head: ten years later. J Bone
increased life expectancy, younger patients are more
Joint Surg Am 2006;88:11171132.
likely to require a revision. Figure 33-2 provides a
8. Koo KH, Kim R, Kim YS, et al. Risk period for develop-
simple algorithm based on symptoms and radiographic ing osteonecrosis of the femoral head in patients on
features to determine the appropriate treatment of ON steroid treatment. Clin Rheumatol 2002;21:299303.
with regard to disease stage. In the future, more non- 9. Liu YF, et al. Type II collagen gene variants and inherited
operative methods may be available for successful hip osteonecrosis of the femoral head. N Engl J Med 2005;
preservation. 352:22942301.
10. Mont MA, Marulanda GA, Jones LC, et al. Systemic analy-
sis of classification systems of osteonecrosis of the femoral
REFERENCES head. J Bone Joint Surg Am. 2006;88(Suppl 3):126130.
33
11. Mont MA, Carbone JJ, Fairbank AC. Core decompres-
1. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld sion versus nonoperative management for osteonecrosis
Y, Gershwin ME. Pathogenesis and natural history of ON. of the hip. Clin Orthop 1996:169178.
Semin Arthritis Rheum 2002;32:94124. 12. Mont MA, Tomek IM, Hungerford DS. Core decompres-
2. Levin D, Norman D, Zinman C, Misselevich I, Reis DN, sion for avascular necrosis of the distal femur: long term
Boss JH. Osteoarthritis-like disorder in rats with vascular followup. Clin Orthop 1997:124130.
deprivation-induced necrosis of the femoral head. Pathol 13. Mont MA, Ragland PS, Etienne G. Core decompression
Res Pract 1999;195:637647. of the femoral head for osteonecrosis using percutaneous
3. Atsumi T, Kuroki Y, Yamano K. A microangiographic multiple small-diameter drilling. Clin Orthop 2004:131
study of idiopathic ON of the femoral head. Clin Orthop 138.
1989:186194. 14. Mont MA, Seyler TM, Marker DR, Marulanda GA,
4. Kikkawa M, Imai S, Hukuda S. Altered postnatal expres- Delanois RE. Use of metal-on-metal total hip resurfacing
sion of insulin-like growth factor-I (IGF-I) and type X for osteonecrosis of the femoral head: an analysis of 42
collagen preceding the Perthes disease-like lesion of a rat hips compared to osteoarthritis. J Bone Joint Surg Am.
model. J Bone Miner Res 2000;15:111119. 2006;88(Suppl 3):9097.
5. Jones LC, Hungerford DS. Osteonecrosis: etiology, diag- 15. Pritchett JW. Statin therapy decreases the risk of osteo-
nosis, and treatment. Curr Opin Rheumatol 2004;16:443 necrosis in patients receiving steroids. Clin Orthop 2001:
449. 173178.
16. Agarwala S, Jain D, Joshi VR, et al. Efficacy of alendro- 18. Disch AC, Matziolis G, Perka C, et al. The management
nate, a bisphosphonate, in the treatment of AVN of of necrosis-associated and idiopathic bone-marrow
the hip. A prospective open-label study. Rheumatology oedema of the proximal femur by intravenous iloprost.
(Oxford) 2005;44:352359. J Bone Joint Surg Br 2005;87:560564.
17. Lai KA, Shen WJ, Yang CY, et al. The use of alendronate 19. Glueck CJ, Freiberg RA, Sieve L, et al. Enoxaparin pre-
to prevent early collapse of the femoral head in patients vents progression of stages I and II osteonecrosis of the
with nontraumatic osteonecrosis. A randomized clinical hip. Clin Orthop 2005:164170.
study. J Bone Joint Surg Am 2005;87:21552159.
CHAPTER 34
Pagets Disease of Bone

ROY D. ALTMAN, MD
Pagets disease affects 1% of the US population over Bone pain, fracture, and nerve impingement can
the age of 40 years and is a chronic disorder of adult occur due to enlarging and poorly constructed bone
skeleton characterized by increased resorption and matrix.
deposition of bone resulting in replacement of the Potent and generally safe suppressive agents have
normal matrix with softened and enlarged bone. been developed and have resulted in a more
Most adults with Pagets disease are asymptomatic aggressive approach to therapy.
and diagnosis is found on x-ray of the bones.
Pagets disease is a chronic disorder of the adult skele- and may worsen at night. The enlarging bones may
ton characterized by increased resorption and deposi- compress nerves, adding to the pain. Sometimes Pagets
tion of bone resulting in replacement of the normal disease leads to the development of painful osteoarthri-
matrix with a softened and enlarged bone. Initially, tis in contiguous joints (4). Stiff joints and fatigue may
there is active resorption by large and increased numbers develop slowly and subtly.
of osteoclasts containing multiple nuclei, followed by Symptoms vary, depending on degree of involvement
deposition of bone by numerous osteoblasts which most and which bones are affected. The skull may enlarge,
often results in a weakened disorganized bony structure resulting in frontal bossing and a larger hat size. Hearing
that is interspersed with areas of fibrosis. Although loss may be due to petrous ridge Pagets disease inva-
localized to isolated areas of the skeleton, there may be sion of the cochlea. There may be headaches, dizziness,
widespread bony distribution. and bulging scalp veins.
The bones most commonly affected are the pelvis, Vertebrae may enlarge, weaken, and fracture, result-
femur, skull, tibia, vertebrae, clavicle, and humerus. ing in a loss in body height and a stooped forward (or
Pagets disease of bone is present in approximately simian) posturing. Involved vertebrae may compress
1% of the US population over the age of 40 (1). Preva- nerves from the spinal cord, resulting in pain, dysesthe-
lence increases with age with almost a 2:1 ratio of men sias, weakness, or even lower extremity paraparesis or
to women. Pagets disease is more common in Europe, paraplegia. Long bones become bowed, resulting in
particularly the United Kingdom, excluding Scandina- reduced function, abnormal gait, and contractures. The
via, and their immigrant descendants of Australia, New involved bone has a tendency to fracture.
Zealand, and the United States. It is rare in Africa and There is an association with high output cardiac
Asia. failure. Sarcomatous degeneration of pagetic lesions
The etiology of Pagets disease is unknown. It is more occurs in fewer than 1% of patients. Hypercalcemia can
common among relatives of those with Pagets disease, occur with/without hyperparathyroidism. The prognosis
and genetic studies have demonstrated an association is most often good, particularly if treated. The unfortu-
to mutation variants of the Sequestrosome 1 gene on nate few who develop pagetic sarcomas have a poor
the fifth chromosome (2). There is additional evidence prognosis.
suggesting a virus trigger (from the paramyxovirus
family) (3). There is man-to-man transmission.
DIAGNOSIS
SYMPTOMS Pagets disease is often discovered when x-rays or
laboratory tests are performed for other reasons. The
Although Pagets disease is usually asymptomatic, bone diagnosis is uncommonly suspected on the basis of
pain, bony enlargement, or bony deformity may occur. symptoms and physical examination. Confirmation of
Bone pain may be deep, aching, occasionally severe, the diagnosis is usually from the characteristic findings
573
574 ROY D. ALTMAN
on x-ray. In most patients there will be an increase in normalized. Alendronate is well tolerated with esopha-
the serum alkaline phosphatase. A bone-specific serum geal and gastric ulceration as the major adverse effect.
alkaline phosphatase can sometimes be of value. The Disodium etidronate (Didronel Procter & Gamble)
extent of bony involvement can be determined from a was the first of the bisphosphonates to be used in Pagets
pertechnitate radionuclide bone scan. Bone biopsy is disease (7). The duration of response correlates inversely
only needed when there is concern for malignancy. with the pretreatment level of serum alkaline phospha-
Other markers of active bone turnover (such as urinary tase. The response to repeat therapy with disodium eti-
markers of bone turnover) are elevated, but are uncom- dronate is variable and there is increasing resistance
monly of value in the care of patients with Pagets to repeated retreatments. Non-union fractures tend
disease. to calcify their callus following disodium etidronate
therapy. The dose of disodium etidronate is 5 mg/kg per
day or 400 mg daily for a 40-kg (88 lb) to 80-kg (176 lb)
THERAPY patient. Adverse reactions to disodium etidronate
include abdominal cramps, diarrhea, hyperphosphate-
The development of potent and generally safe suppres- mia, increasing bone pain, and a possible increase in
sive agents for therapy of Pagets disease has prompted fractures. Hyperphosphatemia appears to be due to a
a more aggressive change in therapeutic philosophy. direct renal effect of disodium etidronate. Esophagitis
Suppressive therapy for Pagets disease of bone now is uncommon.
appears warranted for anyone with evidence of active Pamidronate (APD, Aredia Novartis Pharmaceuti-
Pagets disease, including a serum alkaline phosphat- cals) is 100 times more potent than disodium etidronate
ase twice the upper limits of the normal range in an in its effect on osteoclasts. Pamidronate produces rapid
asymptomatic patient. Suppressive therapies are not and dramatic biochemical responses in Pagets disease
expected to correct existing hearing loss, deformity, or (8). Pamidronate should be administered as 60 to 90 mg
osteoarthritis. intravenous infusions with normal saline or dextrose/
Heel lifts may tend to normalize gait when one lower water. A variety of regimens have been used effectively,
extremity develops bowing. Bed rest should be avoided, including daily infusions for 3 to 5 days, once weekly for
if possible, to prevent hypercalcemia and immobiliza- 3 to 5 weeks, once with re-evaluation monthly, etc. Pro-
tion osteoporosis. Surgery is often helpful in removing gressive resistance often occurs with re-treatments.
pressure from compressed nerves or to replace a sec- Adverse reactions to pamidronate include transient
ondary osteoarthritic joint. fever (usually <39.2C), transient lymphopenia, mild
Analgesics or nonsteroidal anti-inflammatory drugs and transient nausea, and uveitis.
may reduce bone pain. Supplemental dietary calcium Risedronate (Actonel Procter & Gamble/sanofi-
and vitamin D should be considered. aventis) is a potent tertiary nitrogen containing bisphos-
Bisphosphonates are particularly effective and can phonate administered orally as 30 mg/day for 2 months
be useful before surgery to reduce bleeding from the (9). Prolonged remissions have been reported. There
involved bone during surgery; they are also given to are reports of esophagitis and other nonspecific gastro-
treat pain caused by Pagets disease, to prevent or slow intestinal complaints.
the progression of weakness or paralysis in people who Tiludronate (Skelid Sanofi Winthrop Industrie) is
are not surgical candidates, prevent secondary arthritis, a nitrogen-containing bisphosphonate administered
progressive hearing loss, or advancing deformity. Oral orally as 400 mg/day for 3 months (10). The major
bisphosphonates should be ingested with a large glass adverse event is esophagitis.
of water (68 oz) upon rising in the morning. The patient Zoledronate (Zometa Novartis Pharmaceuticals)
should remain upright and not eat for at least 30 minutes. is a potent bisphosphonate administrated as a 4-mg
Other agents such as parenteral calcitonin and plicamy- intravenous 15-minute infusion. Responses are longer
cin are still occasionally of value. than risedronate (11). Renal failure, fever, flulike syn-
Adverse effects that are common to the bisphospho- drome, and bone pain have been reported.
nates include esophagitis and bone pain. The intrave- Synthetic salmon calcitonin (Miacalcin) is adminis-
nous bisphosphonates may cause fevers and a flulike tered as 100 (MRC) units or 0.5 mL of salmon calci-
syndrome. Mandibular osteonecrosis has been re- tonin subcutaneously or intramuscularly daily for the
ported with all bisphosphonates, but is particularly first month (12). The dose can be decreased or the inter-
uncommon, and is most common with high-dose intra- val between doses increased depending on the response
venous bisphosphonates (5). to therapy. Primary and secondary resistance to calcito-
Alendronate (Fosamax, Merck) is a potent nitrogen- nin can occur. Most patients will have chemical exacer-
containing bisphosphonate administered orally as bation within 6 months of calcitonin discontinuation.
40 mg/day for 6 months (6). Alendronate can be admin- Salmon calcitonin is supplied as 400 units per 2-mL
istered for 3 months if the alkaline phosphatase has vial and should be refrigerated. Adverse reactions
C H A P T E R 3 4 P A G E T S D I S E A S E O F B O N E 5 75
include gastrointestinal, vascular, and local reactions at 4. Altman RD. Musculoskeletal manifestations of Pagets
the injection site. Most occur within several minutes of disease of bone. Arthritis Rheum 1980;23:11211127.
injection and last about 1 hour. 5. Woo S-B, Hellstein JW, Kalmar JR. Systematic review:
Plicamycin (Mithramycin) is used only in severely bisphosphonates and osteonecrosis of the jaw. Ann Intern
Med 2006;144:753761.
affected patients because of multiple associated adverse
6. Walsh JP, Ward LC, Stewart GO, et al. A randomized
effects.
clinical trial comparing oral alendronate and intravenous
Despite the fact that Pagets disease is uncommon, pamidronate for the treatment of Pagets disease of bone.
interest into its pathogenesis and therapy continue. Bone 2004;34:747754.
Much understanding about bone metabolism and bone 7. Altman RD, Johnston CC, Khairi MRA, Wellman H,
disease in general has been generated by research into Serafini AN, Sankey RR. Influence of disodium etidronate
Pagets disease. With our present state of knowledge, it on clinical and laboratory manifestations of Pagets disease
is most often rewarding to care for patients with Pagets of bone (osteitis deformans). N Engl J Med 1973;289:1379
disease of bonefor both the physician and patient. 1384.
8. Vasireddy S. Talwalkar A, Miller H, Mehan R, Swinson
DR. Patterns of pain in Pagets disease of bone and their
REFERENCES outcomes on treatment with pamidronate. Clin Rheuma-
tol 2003;22:376380.
1. Altman RD, Bloch DA, Hochberg MC, Murphy WA. 9. Crandall C. Risedronate: a clinical review. Arch Intern
Prevalence of pelvic Pagets disease of bone in the United Med 2001;161:353360.
States. J Bone Miner Res 2000;15:461465. 10. Morales-Piga A. Tiludronate. A new treatment for an old
2. Michou L, Collet C, Laplanche JL, Orcel P, Cornelis F. ailment: Pagets disease of bone. Expert Opin Pharmaco-
Genetics of Pagets disease of bone. Joint Bone Spine ther 1999;1:157170.
2006;73:243248. 11. Reid IR, Miller P, Lyles K, et al. Comparison of a single
3. Kurihara N, Zhou H, Reddy SV, et al. Expression of infusion of zoledronic acid with risedronate for Pagets
measles virus nucleocapsid protein in Osteoclasts induces disease. N Engl J Med 2005;353:898908.
Pagets disease-like bone lesions in mice. J Bone Miner 12. Martin TJ. Treatment of Pagets disease with calcitonins.
Res 2006;21:446455. Aust N Z J Med 1979;9:3643.
34
CHAPTER 35
Osteoporosis
A. Epidemiology and Clinical
Assessment
KENNETH G. SAAG, MD, MSC
More than 1.5 million osteoporosis-related fractures Two types of scores are used to quantify bone
occur each year in the United States. mineral density (BMD): The T score is the number of
Osteoporotic fractures most often involve the femoral standard deviations the patients BMD measurement
neck, the vertebral bodies, or the wrist. Ninety is above or below the young-normal mean BMD. The
percent (90%) of all hip and spinal fractures are Z score is the number of standard deviations the
related to osteoporosis. measurement is above or below the age-matched
Among individuals now 50 years old, the lifetime risk mean BMD.
of any fracture in the hip, spine, or distal forearm is The World Health Organization (WHO) defines
about 40% in Caucasian women and 13% in osteoporosis as a T score 2.5.
Caucasian men.
Epidemiology of Osteoporosis The public health consequences of fractures depend not

only upon fracture incidence, but also on population
and Fractures size. Fractures are a major international public health
concern. Despite the fact that hip fractures are less
Over 10 million people have osteoporosis, 34 million common among Asians than Caucasians, 33% of all
have low bone mineral density (BMD), and over 1.5 osteoporotic fractures occur in Asia. Moreover, the
million osteoporosis-related fractures occur each year number of fractures is rising rapidly in Asia and in many
in the United States alone (1). The 2002 year direct parts of the developing world. The economic costs of
medical costs for osteoporotic fractures exceeded $18 osteoporotic fractures include expenses for surgery and
billion in the United States (2). hospitalization, rehabilitation, long-term care, medica-
tions, and loss of productivity.
Incidence, Prevalence, and Clinical

Hip Fractures
Consequences of Common
In 1999, the estimated number of hip fractures among
Osteoporotic Fractures North American women was 340,000 (7). By 2050, this
Osteoporotic fractures most often involve the femoral figure is expected to increase to >500,000 (8). Among
neck, the vertebral bodies, or the wrist. Ninety percent women between the ages of 65 and 69, the incidence of
(90%) of all hip and spinal fractures are related to hip fractures is approximately 2 per 1000 patient-years.
osteoporosis. Fractures of the humerus, ribs, pelvis, In the 80 to 84 year old age group, however, the inci-
ankle, and clavicle also have been attributed to osteo- dence increases 13-fold, to 26 per 1000 patient-years (9).
porosis in 50% to 70% of cases. Compared to non-nursing home residents, nursing
The lifetime risk of any fracture in the hip, spine, or home residents have a fourfold increased risk of hip
distal forearm is about 40% in Caucasian women 50 fracture (10). Of the 300,000 annual hospitalizations
years of age and 13% in Caucasian men of similar age resulting from hip fractures, up to 20% of patients die
(3). The estimated lifetime risk for fracture at various within 1 year of the fracture, often due to comorbidities.
sites for men and women is shown in Table 35A-1 (36). In addition to the increased mortality within 1 year,
576
C H A P T E R 3 5 O S T E O P O R O S I S 5 77
TABLE 35A-1. LIFETIME RISK OF FRACTURE.

VERTEBRAL
POPULATION HIP FRACTURE (%) DISTAL FOREARM (%) FRACTURE CLINICAL (%) RADIOGRAPHIC (%)
White women 1417 (36) 1416 (36) 16 (3, 6) 35 (4)
White men 56 (35) 23 (35) 5 (3, 6) Unknown
Black women 6 (5) Unknown Unknown Unknown
Black men 3 (5) Unknown Unknown Unknown
20% require nursing home care and 50% of survivors rotic fracture of the hip, vertebral column, or wrist,
never fully recover. The economic costs of hip fracture bone mineral density (BMD) criteria can be used to
are similar to the costs of a stroke (11). diagnose osteoporosis. Two types of scores are used to
quantify bone mineral density. First, the T score is the
Vertebral Fractures number of standard deviations the patients BMD mea-
surement is above or below the young-normal mean
The incidence of vertebral fractures, low before age 50, BMD. Second, the Z score is the number of standard
rises almost exponentially thereafter. The most frequent deviations the measurement is above or below the
areas of fracture are the thoracolumbar juncture (T12 age-matched mean BMD. The T and Z scores were
and L1) and the mid-thoracic spine. Vertebral fractures developed because of variation in BMD measurement
are a harbinger of further osteoporosis problems: technology among different manufacturers.
approximately half of all individuals who sustain verte- The World Health Organization (WHO) defines
bral fractures later suffer other fractures. The loss of osteoporosis as a T score 2.5. Severe osteoporosis is
height from vertebral fractures can lead not only to defined as a T score 2.5 plus the presence of at least
reductions in lung function, but also to depression asso- one fracture. Osteopenia is a BMD between 1 and 2.5
ciated with undesirable changes in physical appearance. standard deviations below the mean value of peak bone
Beyond the acute morbidity of vertebral fractures mass. Normal bone density is a BMD less than 1 stan-
often 6 to 8 weeks of pain that may be intensethe dard deviation below the mean value of peak bone
mortality associated with vertebral fractures is also mass.
greater than for that of the general population. These WHO criteria are based upon epidemiological
data relating fracture incidence to BMD in Caucasian
Wrist Fractures women. The applicability of these BMD cutoff values
to other ethnic and gender groups is not certain. For
Among American women, the incidence of wrist frac- premenopausal women and men younger than age 50,
tures increases rapidly at the time of menopause and a Z scorewhich compares BMD to age- and sex-based
plateaus after age 60. This plateau effect relates to a reference standardsmay be more appropriate than a
pattern of falling common among older individuals: the T score. Nevertheless, T scores are the standard by
elderly are more likely to land on a hipthereby suf- which fracture risk is predicted and disease status clas-
fering a more serious fracturethan on an outstretched sified by the WHO. BMD criteria do not differentiate
hand. Women with radial fractures are more likely to among the causes of low BMD (e.g., hyperthyroidism
be thinner and have reduced triceps strength compared vs. glucocorticoid-induced osteoporosis) with regard to
to women who do not fracture. their relative fracture risks.
Using BMD criteria alone, one third of Caucasian
Bone Mineral Density Criteria for women aged 60 to 70 have osteoporosis. By the age of 35
80, more than two thirds of these women are osteopo-
Osteoporosis Diagnosis rotic (12). Based on the femoral neck bone density in
Osteoporosis is diagnosed most definitively on the basis the third National Health and Nutrition Examination
of an insufficiency fracture. Such injuries, often synony- Survey (NHANES), an estimated 18% of Caucasian
mously termed fragility or nontraumatic fractures, occur women have osteoporosis; approximately half have
with falls from standing heights or even lower levels osteopenia (13). Using the T score cutoffs applied to
(e.g., following slipping out of a chair) or as a result of women, between 1% and 4% of Caucasian men have
other low impact trauma. In the absence of an osteopo- osteoporosis and up to 33% have osteopenia (13).
578 KENNETH G. SAAG
Clinical Assessment
of Osteoporosis
The clinical evaluation of osteoporosis is dedicated to
identifying lifestyle risk factors for fracture (also see
Chapter 35B), pertinent physical findings, and second-
ary causes of metabolic bone disease. Beyond bone
mass measurement, typically by BMD, a medical evalu-
ation for a patient with osteoporosis should include a
comprehensive history and physical examination. The
goal of the evaluation is twofold: (1) to determine con-
sequences and complications of osteoporosis (i.e., pain
and disability) and (2) to identify any coexisting con-
ditions that could contribute to the progression or
complications of osteoporosis (e.g., dietary calcium
deficiency, glucocorticoid use, risk factors for low 25-
hydroxy vitamin D levels, and others).
History FIGURE 35A-1
A careful evaluation of a person with or at risk for Dowagers hump. Marked thoracic kyphosis in an osteoporotic
osteoporosis includes questions about family history of patient secondary to multiple thoracic vertebral fractures as
evidenced on this lateral radiograph.
metabolic bone disease, changes in height and weight,
the quantity and frequency of weight-bearing exercise,
level of sun exposure, previous fractures, reproductive
history (particularly for evidence of hypogonadism),
endocrine disorders, dietary factors (including lifetime buffalo hump, easy skin bruisability, and striae suggest
and current calcium consumption, vitamin D, sodium, Cushings syndrome. Blue sclerae could indicate osteo-
and caffeine), tobacco smoking, alcohol intake, exer- genesis imperfecta. The number of missing teeth has
cise, renal or hepatic failure, and past and current medi- been correlated with losses in BMD. A joint assessment
cations and supplements. In addition, factors that may suggest rheumatological causes of low BMD. A
increase the risk of falls, such as neuromuscular disease, testicular exam can help identify hypogonadism. The
gait instability, and unsafe living conditions, should also neurological examination highlights muscular weakness
be discussed. Although a history of bone pain is poten- or neurological compromise that could predispose to
tially useful if present, osteoporosis is not painful until falls. Observation of the patients gait is a critical part
the time of fracture (if then). Approximately two thirds of the examination.
of vertebral fractures, for example, are not diagnosed
at the time they occur. Skeletal Imaging for Osteoporosis
Conventional Radiography
Physical Examination Plain radiographs are inaccurate for the assessment of
Accurate height measurement using an instrument BMD. Bone loss must exceed 30% to 40% before it is
known as a stadiometer is a vital part of the osteoporo- visible by x-ray. Assessment of the trabecular pattern
sis physical examination (14). Comparison of a patients of the femoral neck (the Singh index) has been shown
current height and maximum height obtained in young to correlate with osteoporosis. Other radiographic mea-
adulthood (e.g., through reference to the patients driv- surements, such as hip axis length, also correlate with
ers license) is helpful in identifying height loss. The loss fracture risk. Vertebral fractures have different patterns
of 2 inches (5 cm) in height is a fairly sensitive indicator and can be graded semiquantitiatively on the basis of
of vertebral compression. The spine should be exam- endplate deformities, anterior wedging, and crush frac-
ined for alignment and for spinal or paraspinal tender- tures (15).
ness. If kyphosis is present (see Figure 35A-1), the
possibility of pulmonary compromise should be consid-
ered and the patient examined for a decrease in the
Dual-Energy X-Ray Absorptiometry
distance between the bottom of the ribs and the top of Dual-energy x-ray absorptiometry (DXA) is the most
the iliac crest measured (the iliocostal distance). A widely used bone mass measurement technique. DXA
affords a fast, reliable, accurate measurement of BMD area in the wrist, has a lower predictive value and mea-
that involves low radiation exposure. DXA is currently surements at that site are less reproducible than those
the gold standard for both patient care and clinical in the hip and spine. The clinical value of measurements
investigation in osteoporosis (16). of BMD at Wards triangle is very limited. Whenever
Bone mineral density measurements help stratify possible, decisions regarding the therapy of osteoporo-
fracture risk, guide therapy choices, and monitor sis should be made on the basis of BMD measurements
response to therapy. Although bone quality and rate from central sites.
of bone turnover correlate independently with bone The ability to detect significant serial changes in
strength, BMD measured by DXA is the strongest DXA depends on the rate of change in BMD at a par-
known predictor of hip and spinal fractures. For each ticular site. A 2.77% change is required between two
decline of approximately 1 standard deviation of BMD, successive DXA studies to achieve a statistically signifi-
there is a 1.3- to 3.0-fold increase in the risk of fracture. cant difference with 95% confidence. This change value
Although fracture risk at any site can be assessed accu- is multiplied by the precision error (coefficient of varia-
rately by DXA, BMD at the femoral neck is a better tion) of the measuring device to determine the amount
predictor of hip fracture than BMD at the spine, radius, of BMD change that is needed to indicate a significant
or calcaneus. With respect to response to anti-osteopo- improvement or worsening in BMD. For example, if the
rosis therapy, increases in BMD with pharmacological device has a 2% precision error, a change in BMD of
therapy account for a major component of the reduction about 5.6% is needed to be confident that this is not due
in fracture risk. to chance or precision error. Controversy exists about
Dual-energy x-ray absorptiometry, a two-dimen- the merit of serial DXA to monitor the response to
sional measure of BMD, does not measure true volu- anti-osteoporotic therapies.
metric density but rather areal density. BMD is reported Osteoporosis occurs nonhomogenously throughout
as an absolute value in g/cm2; as a comparison to age-, the body, dependent on age and underlying cause of
race-, and sex-matched reference range (the Z score); bone loss. Thus, discordance across measurement sites
and as a comparison to mean bone mass of young adult as high as 15% is not unusual, particularly in the elderly.
normal individuals [the T score or young adult Z score; Due to the high prevalence of spinal facet and posterior
Figure 35A-2(A,B)]. A change of 1 standard deviation element spinal osteoarthritis among adults over 65,
in either the T or Z score correlates to a change of measurement of spinal DXA in the posterioranterior
approximately 0.06 g/cm2, corresponding to a change in projection may yield a falsely elevated assessment of
BMD of approximately 10%. DXAs also produce a BMD. In older adults, measurement of the hip or lateral
density-based image useful in interpreting scan quality spine imaging may circumvent this problem. Artifacts
and identifying obviously compressed vertebrae and (i.e., calcium pills in the gut, metal objects on clothing,
various artifacts. Some newer DXA devices also gen- objects in pockets), positioning errors (imaging of the
erate a higher resolution lateral spine image that can wrong vertebra, hip malrotation), and anatomical defor-
identify vertebral fractures. mities or changes (severe scoliosis, calcified aorta, ver-
Most major DXA manufacturers use the National tebral crush fractures) can limit DXA precision and
Health and Nutrition Examination Service III (NHANES accuracy (16).
III) database to determine normal age- and sex-matched
BMD parameters, particularly at the hip. DXA results Quantitative Computed Tomography
vary between and within different machines, precluding
comparison of results across devices without the use of
and Ultrasound
conversion equations. Quantitative computed tomography (QCT) is similar to
Dual-energy x-ray absorptiometry is used to measure DXA in its ability to quantify the degree of bone loss
bone mass at both central and peripheral sites. The and assess fracture risk accurately. In contrast to DXA,
central DXA sitesthe hip and spineare the optimal QCT gives a true volumetric measurement of BMD and
imaging locations for two reasons. First, measurements accurately discriminates trabecular bone from cortical
at these sites are associated with superior precision. bone. QCT may overestimate the extent of bone loss
Second, the quantity of trabecular bone at these sites with age and glucocorticoid use because bone marrow 35
correlates well with osteoporosis burden and fracture fat increases in these two clinical settings. In addition to
risk. Measurement at multiple sites increases the sensi- a slightly higher radiation exposure (although less than
tivity for osteoporosis. For the spine, DXA reports mea- on a routine CT examination), reliance on an imaging
surements of individual vertebrae as well as total BMD device that is heavily utilized for other clinical applica-
of the L1 to L4 vertebrae. At the hip, BMD measure- tions and the higher cost of QCT have limited its wide-
ments of the femoral neck, trochanter, and total hip spread adoption.
provide full assessment of the bones contribution to Quantitative ultrasound is a complementary way to
fracture risk at that site. In contrast, Wards triangle, an measure bone mass and perhaps other properties of
580 KENNETH G. SAAG
DXA Results Summary:

Region Area BMC BMD T- Z-
(cm2) (g) (g/cm2) Score Score
L1 L1 13.91 10.86 0.781 1.3 0.4
L2 15.15 13.94 0.920 1.0 0.9
L3 16.98 16.54 0.974 1.0 1.0
L4 17.53 16.46 0.939 1.6 0.4
L2 Total 63.58 57.80 0.909 1.3 0.7
Total BMD CV 1.0%, ACF = 1.019, BCF = 1.055, TH = 8.785

WHO Classification: Osteopenia
L3 Fracture Risk: Increased
L1L4
1.6
L4
1.4
1.2
1.0
BMD 0.8
Image not for diagnostic use

0.6
k = 1.129, d0 = 44.3 0.4
116 145
0.2
60 65 70
Age
Source: Hologic
Scan Date Age BMD T- BMD Change
(g/cm2) Score vs Baseline vs Previous
05/19/2004 67 0.909 1.3 10.1%* 2.5%
05/28/2003 66 0.887 1.5 7.4%* 0.4%
05/22/2002 65 0.891 1.4 7.9%* 1.7%
03/07/2001 64 0.876 1.6 6.1%* 6.1%
10/01/1997 60 0.825 2.0
Total BMD CV 1.0%

A * Denotes significant change at the 95% confidence level.
FIGURE 35A-2
(A) Dual x-ray absorptiometry (DXA) report of lumbar spine. DXA of a lumbar spine showing
imaging windows for vertebrae L1 to L4. Estimated vertebral areas, bone mineral content (BMC),
and bone mineral density (BMD) are shown (top right). BMD is plotted against a lumbar spine
reference database showing the patients current value as well as previous readings indicated by
crosses (see middle right). The dark bar of the graph (middle right) indicates 2 standard devia-
tions above normal and the lighter bar indicates 2 standard deviations below normal for age. T
scores indicate that the patient was initially classified as osteopenic but T scores have increased
into the normal range following antiresorptive therapy. A 10.1% increase in BMD was noted at
the lumbar spine.
bone. Compared with DXA or QCT, this method has is relatively insensitive for osteoporosis diagnosis. Thus,
desirable attributes of lower instrument cost, portabil- even borderline abnormalities should prompt the per-
ity, and absence of ionizing radiation. Ultrasound studies formance of a central DXA.
are usually performed of the calcaneus, although the
tibia, patella, distal radius, and proximal phalanges can Indications for Bone Mass
also be examined. There are no universally accepted
criteria for an ultrasonic diagnosis of osteoporosis and
Measurement
it is not possible to predict BMD by ultrasound mea- Bone mass testing is indicated only when the results
surements. Compared with DXA and QCT, ultrasound will influence a treatment decision. Persons are more

Region Area BMC BMD T- Z-
(cm2) (g) (g/cm2) Score Score
Neck 5.22 3.27 0.626 2.0 0.4
Troch 12.52 10.13 0.809 1.1 2.2
Inter 16.30 16.99 1.042 0.4 0.7
Total 34.05 30.40 0.893 0.4 0.9
Wards 1.11 0.46 0.419 2.7 0.3
Total BMD CV 1.0%, ACF = 1.019, BCF = 1.055, TH = 5.865

WHO Classification: Normal
Fracture Risk: Not Increased
Total
1.6
1.4
1.2
Image not for diagnostic use 1.0
BMD
k = 1.141, d0 = 51.4
106 105 0.8
0.6
0.4
0.2
60 65 70
Age
Reference curve and scores matched to White Female
Source: NHANES
Source: NHANES
Scan Date Age BMD T- BMD Change
(g/cm2) Score vs Baseline vs Previous
05/19/2004 67 0.893 0.4 9.6%* 1.4%
05/28/2003 66 0.905 0.3 11.1%* 5.6%*
05/22/2002 65 0.857 0.7 5.2%* 0.0%
03/07/2001 64 0.856 0.7 5.1%* 5.1%*
10/01/1997 60 0.815 1.0
Total BMD CV 1.0%

B * Denotes significant change at the 95% confidence level.
FIGURE 35A-2
(B) DXA report of hip. Similar parameters as in (A) are shown for the left hip. There has been a
significant increase in BMD at the hip, as was seen in the spine. The asterisk denotes a signifi-
cant increase or decline between two values as determined by the precision error of the DXA
machine. A 9.6% increase in BMD was noted at the total hip.
likely to initiate osteoporosis therapy if they know sidering therapy for osteoporosis; and women who
their BMD is below normal. The US Preventive have been on hormone replacement therapy for pro- 35
Services Task Force has recommended that routine longed periods (18).
screening begin at age 60 for women at increased risk
for osteoporotic fractures (17). The International
Society for Clinical Densitometry has recommended
Measurement of Bone Turnover
bone density testing for all women aged 65 and over; Biochemical markers of bone turnover are cell-based
all men aged 70 and older; anyone with a fragility molecules that can be quantified in the urine or blood.
fracture; anyone with a medical condition or taking Although bone formation and resorption are usually
medication associated with osteoporosis; anyone con- coupled, assays on biochemical markers of bone
582 KENNETH G. SAAG
turnover permit the evaluation of net imbalances. Table TABLE 35A-3. EVALUATIONS OF SECONDARY
35A-2 lists bone markers that can be classified as indices CAUSES OF LOW BONE MASS.
of bone formation or resorption.
Typical laboratory workup
25-hydroxy vitamin D
Serum chemistry including calcium, creatinine, albumin,
Bone Formation Markers phosphorous, and total protein
The markers of bone formation reflect new bone syn- Complete blood count with differential
Liver function studies to include total alkaline phosphatase
thesis by osteoblasts or the postrelease metabolism of
Urinary calcium and creatinine (spot calcium/creatinine ratio or
procollagen (Table 35A-2). Bone-specific alkaline phos- on 24-hour urine collection)
phatase and osteocalcin increase in the face of osteo-
blastic activity. Collagen precursor proteins, particularly Additional workup to be considered as clinically indicated
Bone turnover markers (bone-specific alkaline phosphatase,
the serum carboxyterminal and aminoterminal peptides
osteocalcin, and/or urinary collagen cross-links)
of type I procollagen, can be measured as indicators of Serum intact parathyroid hormone (iPTH)
collagen formation. Thyroid-stimulating hormone (TSH)
Erythrocyte sedimentation rate (ESR)
Evaluation for gonadal insufficiency
Bone Resorption Markers Evaluation for hypercortisolism
Acid-base evaluation
Resorptive markers reflect the activity of osteoclasts Serum and urine immunoelectrophoresis
and collagen degradation (Table 35A-2). Pyridinium Consider tetracycline double-labeled bone biopsy
cross-links include pyridinoline and deoxypyridinoline.
These fragments, released into the circulation, ulti-
mately undergo renal excretion. Of the two cross-links,
deoxypyridinoline is more specific for bone collagen
breakdown.
Bone biomarkers provide an assessment of dynamic
Additional Laboratory Evaluation
aspects of skeletal metabolism as opposed to the more The laboratory assessment seeks possible secondary
static assessment by DXA. Bone markers are useful to causes of low BMD. Table 35A-3 lists laboratory tests
categorize an individual as having fast or slow bone that may be appropriate in certain clinical scenarios.
turnover. Fracture risk is related to faster bone turn- Many of these tests will lead to a large number of false-
over. A reduction in bone turnover with antiresorption positive results, however, if their pretest probability is
therapy diminishes the risk of fracture independent low. Consequently, these tests should be ordered if the
of changes in BMD. Bone markers may also be help- patients historical, physical examination, and other
ful in the monitoring of adherence to antiresorptive laboratory results suggest that additional evaluation will
therapies. enhance the evaluation.
One laboratory assessment currently receiving much
attention is vitamin D. Measurement of the 25-OH
vitamin D level is appropriate in person with osteopo-
TABLE 35A-2. BIOCHEMICAL MARKERS OF BONE rosis. Levels less than 32 ng/dL (80 nmol/mL) may merit
TURNOVER. supplementation.
FORMATION RESORPTION
Serum tests REFERENCES

Bone-specific alkaline Aminoterminal telopeptide
phosphatase of type I collagen 1. National Osteoporosis Foundation. Fast facts on osteo-
Osteocalcin Carboxyterminal telopeptide
porosis. Available at: http://www.nof.org/osteoporosis/
Procollagen I carboxyterminal of type I collagen
propeptide
diseasefacts.htm. Accessed July 2, 2007.
Procollagen I aminoterminal 2. National Osteoporosis Foundation. Physicians guide to
propeptide prevention and treatment of osteoporosis. Belle Mead,
NJ: Excerpta Medica; 1998.
Urine tests 3. Melton III LJ, Chrischilles EA. How many women have
Amino-terminal telopeptide osteoporosis? J Bone Miner Res 1992;7:10051010.
of type I collagen (NTX) 4. Chrischilles EA, et al. A model of lifetime osteoporosis
Carboxy-terminal telopeptide
impact. Arch Intern Med 1991;151: 20262032.
of type I collage (CTX)
Pyridinoline and
5. Cummings SR, Black DM, Rubin SM. Lifetime risks of
deoxypyridinoline hip, Colles, or vertebral fracture and coronary heart
cross-links disease among white postmenopausal women. Arch Intern
Med 1989;149:24452448.
6. National Osteoporosis Foundation. Osteoporosis: review 12. Ross PD. Osteoporosis: frequency, consequences, and
of the evidence for prevention, diagnosis, and treatment risk factors. Arch Intern Med 1996;156:13991411.
and cost-effectiveness analysis. Status report. Osteoporos 13. Looker AC, et al. Prevalence of low femoral bone density
Int 1998;8(Suppl 4):S1S88. in older US adults from NHANES III. J Bone Miner Res
7. Popovic JR. 1999 National Hospital Discharge Survey: 1997;12:17611768.
annual summary with detailed diagnosis and procedure 14. Green AD, et al. Does this woman have osteoporosis?
data. Vital Health Stat 2001;13:iv, 1206. JAMA 2004;292:28902900.
8. Cooper C, Campion G, Melton LJ III. Hip fractures in the 15. Genant HK, et al. Vertebral fracture assessment using a
elderly: a world-wide projection. Osteoporos Int 1992;2: semiquantitative technique. J Bone Miner Res 1993;8:
285289. 11371148.
9. Farmer ME, et al. Race and sex differences in hip fracture 16. Watts NB. Fundamentals and pitfalls of bone densitome-
incidence. Am J Public Health 1984;74:13741830. try using dual-energy X-ray absorptiometry (DXA).
10. Sugarman JR, et al. Hip fracture incidence in nursing Osteoporos Int 2004;15:847854.
home residents and community-dwelling older people, 17. Nelson HD, et al. Osteoporosis and fractures in post-
Washington State, 19931995. J Am Geriatr Soc 2002;50: menopausal women using estrogen. Arch Intern Med
16381643. 2002;162:22782284.
11. Johnell O. The socioeconomic burden of fractures: today 18. International Society for Clinical Densitometry (ISCD).
and in the 21st century. Am J Med 1997;103:20S25S, Official positions of the ISCD. J Clin Densitom 2002;
discussion 25S26S. 5(Suppl).
35
CHAPTER 35
Osteoporosis
B. Pathology and Pathophysiology
PHILIP SAMBROOK, MD, FRACP
The pathophysiology of osteoporosis includes many balance, muscle weakness, cognitive impairment, and
genetic, hormonal, nutritional, and environmental psychotropic medication.
influences. Some risk factors for this condition are Bone is continually undergoing a process of renewal
well defined. called remodeling. In the normal adult skeleton, new
Although genetic factors contribute strongly to bone laid down by osteoblasts exactly matches
determining peak bone mass, hormonal, nutritional, osteoclastic bone resorption; that is, bone formation
and environmental influences during intrauterine life, and bone resorption are closely coupled.
childhood, and adolescence modulate the genetically The principal cell types within bone are the
determined pattern of skeletal growth. osteoclasts, osteoblasts, and osteocytes. Osteoclasts
The bone mass of an individual in later life is a are responsible for resorption of bone; osteoblasts
consequence of the peak bone mass accrued in utero are responsible directly for bone formation; osteo-
and during childhood and puberty, as well as the cytes, derived from osteoblasts, appear to play a role
subsequent rate of bone loss. in response to mechanical loading.
The high rate of hip fracture in older people is not Key regulators of osteoclastic bone resorption include
only due to their lower bone strength but also their RANK ligand and its two known receptors, RANK and
increased risk of falling. Established risk factors for osteoprotegerin (OPG). RANK and OPG have
falls and, hence, hip fracture include impaired opposing effects on bone resorption.
The pathophysiological basis of osteoporosis is multi- Types of Bone

factorial and includes the genetic determination of peak
bone mass, subtle alterations in bone remodeling due The bone mass of an individual in later life is a conse-
to changes in systemic and local hormones, and envi- quence of the peak bone mass accrued in utero and
ronmental influences. It is useful to consider these pro- during childhood and puberty, as well as the subsequent
cesses at multiple biological levels as well as in terms of rate of bone loss. During development and growth,
known risk factors. Any consideration of the pathogen- bone is produced by two main processesintramem-
esis of osteoporosis requires an understanding of normal branous ossification, as occurs in skull bones; and endo-
bone structure and function. chondral ossification involving the growth plate, as
occurs in limb bones. Modeling is the process that results
in the achievement of bones characteristic shape and
overall structure.
Bone Structure and Function Bone has a strongly hierarchical nature, from the
molecular level up to the whole bone architecture.
Bones are an extremely dense form of connective tissue Above the level of the collagen fibril and its associated
made up principally of the fibrous protein collagen, mineral, bone exists in two usually distinct forms, woven
impregnated with a mineral phase of calcium phosphate bone and lamellar bone. Woven bone is laid down
crystals as well as other components such as water. quickly, most characteristically in the fetus but also in
Although they are one of the hardest structures in the the callus that is produced during fracture repair. The
body, bones maintain a degree of elasticity due to their collagen in woven bone is variable. Lamellar bone is
structure and material properties. laid down much more slowly and more precisely, with
584
Subperiosteal outer FIGURE 35B-1

Concentric circumferential lamellae
lamellae of osteon The Haversian system. Lamellar bone
(Haversian system) Periosteum comprises overlapping cylindrical units
termed Haversian systems (osteons), each
consisting of a central Haversian canal
Interstitial lamellae surrounded by concentric lamellae. The
Haversian canals communicate directly with
the medullary cavity. (From Sambrook,
Concentric Schrieber, Taylor, Ellis, eds. The musculo-
lamellae of osteor
skeletal system. Philadelphia: Churchill
(Haversian system)
Livingstone; 2001.)
Capillaries in
Haversian canal
Capillaries in
Volkmanns canal
the collagen fibrils and their associated mineral arranged Cellular Basis of Bone Remodeling
in sheets (lamellae). Lamellar bone exists in irregularly
spaced, overlapping, cylindrical units termed Haversian Bone is continually undergoing renewal called remodel-
systems (Figure 35B-1). Each Haversian system consists ing (Figure 35B-2). In the normal adult skeleton, new
of a central Haversian canal surrounded by concentric bone laid down by osteoblasts exactly matches osteo-
lamellae of bony tissue. The Haversian system is the clastic bone resorption; that is, bone formation and
result of the process of remodeling, discussed below. bone resorption are closely coupled. Although the skel-
Remodeling differs from modeling, mentioned above, eton contains less trabecular bone than cortical bone,
in which the gross shape of bone is altered by changes trabecular bone turns over between 3 to 10 times more
on periosteal or endosteal surfaces. rapidly than cortical bone and is therefore more sensi-
The principal cell types within bone are the osteo- tive to changes in bone resorption and formation. More-
clasts, osteoblasts, and osteocytes. Osteoclasts, the cells over, the rate of remodeling differs across anatomical
responsible for resorption of bone, are derived from sites according to physical loading, proximity to a syno-
hematopoietic stem cells. Osteoblasts, derived from vial joint, or the presence of hemopoietic rather than
local mesenchymal cells, are the pivotal bone cell, fatty tissue in adjacent marrow.
responsible directly for bone formation. Osteoblasts Bone remodeling follows an ordered sequence,
also regulate osteoclastic bone resorption, through referred to as the basic multicellular unit of bone turn-
paracrine factors. Osteocytes appear to derive from over or bone remodeling unit (BMU). In this cycle, bone
osteoblasts that are buried during the process of resorption is initiated by the recruitment of osteoclasts,
remodeling that connects osteoblasts with each other which act on matrix exposed by proteinases derived
via canaliculi and appears to play a role in response to from bone lining cells. A resorptive pit (called a How-
mechanical loading. ships lacuna) is created by the osteoclasts (Figure 35B-
At the next higher order of structure, there is the 2). This resorptive phase is then followed by a bone
mechanically important distinction between (a) compact formation phase in which osteoblasts fill the lacuna with
or cortical bone and (b) trabecular or cancellous bone. osteoid (unmineralized bone matrix). This cycle of
Cortical bone is found principally in the shafts (diaphy- coupling of bone formation and resorption is vital to
ses) of long bones. Cortical bone is solid with the only the maintenance of skeletal integrity. Uncoupling of the
spaces in it being for osteocytes, blood vessels, and remodeling cycle, so that either bone resorption or for-
erosion cavities. Trabecular bone is found principally at mation in excess of the other leads to net bone change
the ends of long bones, in vertebral bodies, and in flat (gain or loss).
bones. It has large spaces and is comprised of a mesh- Key regulators of osteoclastic bone resorption include 35
work of intercommunicating trabeculae. The skeleton RANK ligand (a member of the tumor necrosis factor
is comprised of approximately 80% cortical bone, ligand family) and its two known receptors, RANK and
largely in peripheral bones, and 20% trabecular bone, osteoprotegerin (OPG) (1). RANK and OPG have op-
mainly in the axial skeleton. These amounts vary accord- posing effects on bone resorption. Osteoblasts express
ing to site and need for mechanical support. Although RANK ligand (RANKL) constitutively on their cell
trabecular bone accounts for the minority of total skel- surfaces. RANKL interacts with its cognate receptor,
etal tissue, it is the site of greater bone turnover due to RANK, promoting osteoclast differentiation. Inter-
its greater surface area. action of RANKL with RANK on mature osteoclasts
586 PHILIP SAMBROOK
FIGURE 35B-2
The bone remodeling cycle. The process

of bone remodeling starts when the lining
cells reveal the bone surface upon
activation. Osteoclast precursors arrive at
the site and become active osteoclasts as
they start to dig out a resorption pit.
When the osteoclasts have finished the
process of resorption, osteoblasts are
attracted to the site. These osteoblasts lay
down the organic matrix (mainly collagen
type I), which is subsequently mineralized.
At the end of this process old bone has
been replaced by new bone. Bone
resorption and formation are coupled in
this process.
results in their activation and prolonged survival (Figure frequency). Estrogen deficiency following the meno-
35B-3). OPG, present in the bone microenvironment, is pause results in a remodeling imbalance with a substan-
secreted primarily by osteoblasts and stromal cells. OPG tial increase in bone turnover. Remodeling nearly
blocks the interaction of RANKL with RANK and thus doubles in the first year after menopause. This imbal-
acts as a physiological regulator of bone turnover. ance leads to a progressive loss of trabecular bone in
At the cellular level, bone loss occurs as a result of part due to increased osteoclastogenesis. Enhanced for-
an imbalance between the activity of osteoclasts and mation of functional osteoclasts appears to be the result
osteoblasts. If the processes of resorption and formation of increased elaboration of osteoclastogenic proinflam-
are not matched, there is a remodeling imbalance; this matory cytokines such as interleukin 1 (IL-1) and tumor
imbalance may be magnified by an increase in the rate necrosis factor, which are regulated in a negative fashion
of initiation of new bone remodeling cycles (activation by estrogen (2,3).
FIGURE 35B-3
OPG
Osteoclasts are formed from macrophage,
monocytic precursor cells (CFU-M).
RANKL
Osteoclasts express RANK, and RANKL CFU-M
RANK
enhances each of these steps. RANKL in Growth Factors
bone is mainly produced in osteoblasts Hormones
and stromal cells and RANKL then Cytokines Pre-Fusion
activates each of these steps. Osteoprote- Osteoclast
gerin (OPG) is a decoy receptor antagonist
KL
RAN
that blocks this interaction between
RANKL and RANK and therefore, the Multinucleated
formation, activation, and survival of Osteoclast
osteoclasts leading to enhanced apopto-
sis. CFU, colony forming units. Osteoblast Activated
Osteoclast
BONE
Pathophysiology A number of feedback loops operate to control the

level of serum calcium, PTH, and 1,25-dihydroxy vitamin
Osteoporotic fractures result from a combination of D. Low serum calcium levels stimulate 1,25-dihydroxy
decreased bone strength and an increased incidence of vitamin D synthesis directly through stimulation of PTH
falls with aging. Bone loss occurs as a consequence release (and synthesis). The physiological response to
of estrogen deficiency in the postmenopausal women, increasing levels of PTH and 1,25-dihydroxy vitamin D
as well as through estrogen-independent, age-related is a gradual rise in serum calcium level. A second set of
mechanisms (such as secondary hyperparathyroidism feedback loops maintain serum calcium within a narrow
and reduced mechanical loading). Menopausal status is physiological range. Disturbances in these control
probably the most important risk factor of all and post- mechanisms or over/underproduction of PTH, 1,25-
menopausal bone loss is the single most important cause dihydroxy vitamin D, calcitonin occurs in various clini-
of osteoporosis. The rate of loss is greatest soon after cal states, including osteoporosis.
the menopause. The earlier the menopause the greater
the risk. Age-related bone loss starts from 30 to 50 years Mechanical Properties of Bone
of age in both men and women. Loss from different bone
sites occurs at different ages and at different rates. The stiffness and strength of bone are dependent on
Although bone mineral density predicts bone two factors: its material properties and its three-
strength, many other skeletal characteristics also dimensional architecture. In simple biomechanical
contribute to bone strength. These include bone macro- terms, a bone will fracture if the load applied exceeds
architecture (shape and geometry), bone microarchi- its strength. Bone strength is affected by changes in
tecture (both trabecular and cortical), the degree of architecture, microdamage accumulation, mineral
mineralization and microdamage accumulation, and the change, and bone turnover.
rate of bone turnover, which can affect bones structural By engineering theory, the elastic modulus, also
and material properties. These other measures are often known as Youngs modulus, is the ratio of stress (load)
referred to as bone quality. Changes in the rate of bone to strain (deformation) or the slope of the curve, the
remodeling can also influence these material and struc- material stiffness. Toughness (the ability to absorb
tural properties of bone. energy in impact without breaking) is the area under the
curve. Increases in postyield strain leads to tougher
Calcium Homeostasis and bone. As the mineral content increases, the stiffness
(Youngs modulus of elasticity) also increases but the
Hormonal Control area under the stress/strain curve, which is equivalent to
In addition to its role as a support structure, the skele- toughness, decreases. Thus, bone cannot have a mineral
tons other primary function is calcium homeostasis. content that makes it both very stiff and very tough (4).
More than 99.9% of the total body calcium resides in In most forms of osteoporosis, the loss of bone is not
the skeleton. The maintenance of normal serum calcium distributed evenly throughout the skeleton (Figure 35B-
depends on the interplay of intestinal calcium absorp- 4). For reasons that are not clear, some of the struts of
tion, renal excretion, and skeletal mobilization or uptake
of calcium. Although serum calcium represents less
than 1% of total body supply, normal serum calcium
levels are extremely important for normal cellular func-
tion. Serum calcium regulates and is regulated by three
major hormones; parathyroid hormone (PTH), 1,25-
dihydroxy vitamin D, and calcitonin. PTH and 1,25-
dihydroxy vitamin D are the major regulators of calcium
and bone homeostasis. PTH acts on the kidney to
increase calcium reabsorption, phosphate excretion,
and 1,25-dihydroxy vitamin D production. It also acts
on bone to increase bone resorption. 1,25-Dihydroxy 35
vitamin D is a potent stimulator of bone resorption and
an even more potent stimulator of intestinal calcium
(and phosphate) absorption. It is also necessary for
bone mineralization. Intestinal calcium absorption is
probably the most important calcium homeostatic FIGURE 35B-4
pathway. Although calcitonin can directly inhibit osteo- Architecture of vertebral body in elderly subject. Note loss of
clastic bone resorption, it plays a relatively minor role trabecular structure with aging. (Courtesy of L. Mosekilde, Aarhus
in calcium homeostasis in normal adults. University Hospital, Denmark.)
588 PHILIP SAMBROOK
trabecular bone are resorbed completely, resulting in a TABLE 35B-1. RISK FACTORS FOR OSTEOPOROSIS.
loss of connectivity between adjacent bone plates. This
Established risk factors
contributes markedly to decreased bone strength and
Low bone mass/density
increased fracture risk. Because the remodeling surface/ Advanced age
volume ratio of trabecular bone is high, bone loss tends Female gender
to affect this type of bone, such as that in the spine and Ethnicity (white or Asian)
hip, to a greater extent. Family history
High falls risk
Changes in microarchitecture also appear to be
History of low trauma fracture
important. Compared with normal individuals, the cor- Calcium intake <400 mg/day
tical bone of patients with hip fractures is characterized Low body weight
by microarchitecture showing increased porosity and Smoking
decreased thickness.
Osteoporosis associated with endocrine causes
Cushings syndrome/corticosteroid therapy
Hyperthyroidism and thyroxine replacement therapy
Risk Factors Hypogonadism (see Table 35B-2)
Anorexia nervosa/exercise-induced amenorrhea
Hyperparathyroidism
A number of risk factors for osteoporosis have been
Pregnancy
identified (Table 35B-1). These may be considered in GNRH agonist/antagonists
relation to their underlying pathophysiological effects. Type 1 diabetes
Osteoporosis associated with altered activity

Genetic Influences Rheumatoid arthritis
Immobilization/weightlessness
Fracture risk has a direct relationship to bone mineral Chronic airways obstruction
density (BMD). BMD at any age is the result of the Cerebovascular accident
peak bone mass achieved and subsequent bone loss Ankylosing spondylitis
(postmenopausal and age-related). Although genetic Osteoporosis associated with environmental factors
factors contribute strongly to determining peak bone Alcoholism
mass, recent studies have demonstrated that environ- Celiac disease
mental influences during intrauterine life, childhood, Gastrectomy
Drugs (see Table 35B-3)
and adolescence modulate the genetically determined Post-transplantation bone loss
pattern of skeletal growth. Mastocytosis
There is a strong genetic contribution to skeletal size
and composition. Comparisons of identical and non- Osteoporosis associated with specific genetic conditions
Osteogenesis imperfecta
identical twins have led to estimates that more than Menkes syndrome
50% of peak bone mass is determined by genetic factors EhlersDanlos syndrome
(5). A family history of a relative sustaining a fracture Homocystinuria
after age 50 should be viewed as suspicious. Genetic Marfans syndrome
factors that regulate skeletal development and function Osteoporosispseudoglioma syndrome
including the CBFA1 gene and the RANK/RANKL
system.
Genetic factors underlie racial differences in osteo-
porosis prevalence. Hip fractures more commonly occur 5q3335, 6p1112, and 11q1213 that show definite or
in thin, frail individuals rather than those who are over- probable linkage to BMD.
weight. Low body weight is a risk factor for hip fracture. Polymorphisms of the vitamin D receptor have been
On average, African Americans have greater BMD associated with bone mass in several studies. This asso-
than whites of the same age, and African Americans ciation may be modified by dietary calcium and vitamin
sustain fewer fractures. People of Asian origin have D intake. Another important functional polymorphism
lower bone densities and higher fracture rates than affecting the transcription factor Sp1 has been identified
whites. In the more common forms of osteoporosis, in the collagen type I alpha 1 gene. This polymorphism
genetic factors play an important role in regulating skel- predicts osteoporotic fractures independently of BMD,
etal size and geometry, bone mass, ultrasound proper- probably through its influence on collagen gene regula-
ties of bone, and bone turnover. These phenotypes tion and bone quality (6). More rarely, osteoporosis or
appear to be determined by the combined effects of high BMD can occur as the result of mutations in
multiple genes, environmental influences, and gene a single gene. For example, inactivating mutations
environment interactions. Genomewide linkage studies in the lipoprotein receptorrelated protein 5 gene cause
have identified loci on chromosomes 1p36, 1q21, 2p21, the osteoporosispseudoglioma syndrome, a condition
associated with low BMD. In contrast, a high bone mass vidual lacunae in mineralized bone, respond to mechan-
syndrome is caused by activating mutations of the same ical deformation and loading. Early biochemical
gene. responses to mechanical loading may include induction
of prostaglandin synthesis, increased nitric oxide and
insulinlike growth factor preproduction, changes in
Nutritional Factors amino acid transporters, and eventually increases in
Calcium restriction in animals results in low bone mass. new bone formation. Bone is responsive to physical
In humans, calcium deficiency in childhood leads to strain. It has been hypothesized that there exists a
rickets. Although one might anticipate that low calcium mechanostat that senses and responds to loading.
intake would be associated with osteoporosis, therefore, Immobilization following major injury, illness, or
the relationship between calcium intake and osteopo- space flight, for example, is associated with rapid
rosis remains controversial. Calcium balance studies bone loss. If sustained, as in patients with paraplegia
suggest that premenopausal women require calcium or hemiplegia, fractures can occur. Increased bone
intakes in excess of 800 mg per day to avoid net bone resorption is associated with acute immobilization.
loss. Postmenopausal women may require as much as Positive effects of mechanical loading on bone mass
1500 mg per day. can be seen in athletes. The increase in bone density
Dietary calcium intake during growth may play a role is usually site-specific and localized to the loaded
in the development and maintenance of peak BMD. limb. Physical inactivity correlates with low BMD
Various environmental and lifestyle factors, particularly and fractures in epidemiological studies. Although
physical activity, also modulate this effect. Calcium exercise programs may produce only limited changes
supplementation in growing children produces small in BMD, even small changes have been shown to
increases in BMD, but these do not appear to be main- reduce fractures.
tained and may represent increased mineralization of
existing osteons rather than sustained increases in BMD.
In many trials involving patients with osteoporosis,
Hypogonadism
calcium supplementation has resulted in only modest Other than menopausal bone loss, any condition associ-
suppression of bone turnover and small gains (if any) in ated with hypogonadism may result in osteoporosis
bone mass. (Table 35B-2). Disorders resulting in oligo-amenorrhea
Calcium is not the only component of diet that may are a major cause of bone loss in the younger age groups.
affect bone. Vitamin D is vital for optimal absorption Common causes are anorexia nervosa and primary
of calcium from the diet and mineralization. In many ovarian failure associated with diseases such as Turners
countries, vitamin D is added to food. Adequate skin syndrome and chemotherapy. Secondary ovarian
exposure to ultraviolet light is also necessary for the failure due to pituitary disorders and functional hypo-
maintenance of normal vitamin D levels. gonadism caused by long-acting GnRH agonists (e.g.,
There is little evidence that micronutrients, such as for endometriosis therapy) may also be associated with
magnesium, zinc, copper, and boron have major effects osteoporosis.
on bone health. Some diets, particularly those rich in
soy protein, provide significant sources of estrogens.
Sodium intake may have important effects on bone
and calcium metabolism. Because sodium loading TABLE 35B-2. COMMON CAUSES OF
results in increased renal calcium excretion, lowering HYPOGONADAL OSTEOPOROSIS.
dietary sodium intake may diminish age-related bone In women
loss. Excessive protein and caffeine intakes are associ- Bilateral oophorectomy
ated with bone loss. The effects of sodium, dietary Chemotherapy
protein, and caffeine intake on bone health are proba- Aromatase inhibitors
Anorexia nervosa
bly relatively minor compared with other environmen-
Exercise-induced amenorrhea
tal influences. Alcohol is another dietary component
that may be quite important, with adverse effects in In men 35
excess but perhaps beneficial effects at moderate levels Klinefelters syndrome
Orchidectomy
of intake.
Kallmans syndrome
In men and women

Physical Activity Hemochromatosis
Gonadotrophin-releasing hormone analogues
Mechanical forces exert strong influences on bone
Gonadal dysgenesis
shape and modeling. At the cellular level, it is thought Pituitary disease
that the osteocytes, which lie embedded within indi-
590 PHILIP SAMBROOK
Drugs and Osteoporosis now recognized to be associated with bone loss and
fractures (10).
Many drugs lead to reduced BMD and therefore In contrast, some drugs may increase bone mass and
increase the risk of fracture (Table 35B-3). In rheumatic reduce fractures. Thiazide diuretics decrease urinary
diseases, glucocorticoids (GC) are among the most calcium excretion and have been associated with
important. Their effects are dose- and duration-depen- increased BMD and reduced hip fracture rates. A
dent (7). GCs affect bone through multiple pathways, variety of epidemiological studies have suggested that
influencing both bone formation and resorption, but the statin users have lower rates of hip fracture than non-
most important effects appear to be a direct inhibitory users, but large effects on bone mass and turnover have
effect on bone formation. For the most part, the not been demonstrated in prospective clinical trials.
decreased bone formation is due to direct effects on
cells of the osteoblastic lineage. Enhanced osteoblast
and osteocyte apoptosis has also been implicated as an Bone Turnover
important mechanism of glucocorticoid osteoporosis. High rates of bone turnover predict fractures indepen-
GCs have been shown to reduce the birth rate of osteo- dently of other factors such as BMD. Responses to
blasts and osteoclasts, to cause earlier death of osteo- treatment may be greater in those with high turnover.
blasts, and to reduce osteocyte viability. Changes in sex The rate of bone remodeling can be assessed by serum
steroid production have indirect effects that also lead to measurements of osteocalcin and specific alkaline phos-
decreased bone formation. GCs increase the expression phatase (markers of bone formation) or carboxytermi-
of RANKL and decrease OPG expression in osteo- nal telopeptide of type I collagen (a collagen breakdown
blasts, leading to postponement of osteoclast apoptosis. product used as a marker of bone resorption). Urinary
Another effect of GCs is to decrease intestinal absorp- pyridinolines can also be used for the assessment of
tion of calcium. In some patients, secondary hyperpara- bone resorption.
thyroidism may also increase bone turnover and expand
the remodeling space, but this appears to be a tempo-
rary phenomenon. With long-term GC use, bone turn- Risk Factors for Falls
over is actually reduced. The high rate of hip fracture in older people is not only
Anticonvulsant drugs are also now recognized to due to their lower bone strength and but also their
result in altered bone mass and an increased risk of increased risk of falling. Established risk factors for
osteoporosis (8), as are oral anticoagulants (9). Because falls and, hence, hip fracture include impaired balance,
deficiency of estrogen and testosterone both contribute muscle weakness, cognitive impairment, and psycho-
to bone loss, drugs that reduce sex hormone levels cause tropic medication.
bone loss. Androgen deprivation therapy with agonists
of gonadotropin-releasing hormone is now frequently
used in the treatment of recurrent and metastatic pros- REFERENCES
tate cancer because it induces medical castration, ren-
dering patients hypogonadal. This is becoming an 1. Boyle WJ, Scott Simonet W, Lacey DL. Osteoclast dif-
important iatrogenic cause of osteoporosis. Similarly, ferentiation and activation. Nature 2003;423:337342.
aromatase inhibitors (used to treat breast cancer) are 2. Cenci S, Weitzmann MN, Roggia C, et al. Estrogen defi-
ciency induces bone loss by enhancing T-cell production
of TNF-alpha. J Clin Invest 2000;106:12291237.
3. Pfeilschifter J, Koditz R, Pfohl M, Schatz H. Changes
in proinflammatory cytokine activity after menopause.
TABLE 35B-3. DRUGS ASSOCIATED WITH
OSTEOPOROSIS. Endocr Rev 2002;23:90119.
4. Currey JD. The mechanical properties of bone. In: Currey
Corticosteroids JD, ed. Bones: structure and mechanics. 2nd ed. Prince-
ton, NJ: Princeton University Press; 2002:54122.
Cyclosporine
5. Naganathan V, MacGregor A, Snieder H, Nguyen T,
Thyroxine Spector T, Sambrook PN. Gender differences in the
genetic factors responsible for variation in bone density
Heparin and ultrasound. J Bone Miner Res 2002;17:725733.
Anticonvulsants 6. Mann V, Hobson EE, Li B, et al. A COL1A1 Sp1 binding
site polymorphism predisposes to osteoporotic fracture by
Gonadotrophin-releasing hormone agonists affecting bone density and quality. J Clin Invest 2001;107:
899907.
Aromatse inhibitors
7. Van Staa TP, Leufkens HGM, Abenhaim L, Zhang B,
Cytotoxic drugs Cooper C. Use of oral glucocorticoids and risk of frac-
tures. J Bone Miner Res 2000;15:9931000.
8. Petty S, Paton LM, OBrien TJ, et al. Effect of antiepilep- taking warfarin: results from the national registry of Atrial
tic medication on bone mineral measures. Neurology Fibrillation 2. Arch Intern Med 2006;166:241246.
2005;65:13581365. 10. Eastell R, Hannon R. Long term effects of aromatase
9. Gage BF, Birman-Deych E, Radford, MJ, Nilasena, DS, inhibitors on bone. J Steroid Biochem Molec Biol 2005;
Binder EF. Risk of osteoporotic fracture in elderly patients 95:151154.
35
CHAPTER 35
Osteoporosis
C. Treatment of Postmenopausal
Osteoporosis
NELSON B. WATTS, MD
The main goal of osteoporosis treatment is the anabolic agents. The only anabolic drug available
prevention of fractures. currently is teriparatide (parathyroid hormone).
Increases in bone density through the use of Bisphosphonates work through two broad
medications explain only a small proportion of the mechanisms: They reduce the ability of individual
observed reduction in fracture risk. This suggests osteoclasts to resorb bone and they accelerate
that agents that have some additional effects on osteoclast apoptosis (programmed cell death).
bone quality to account for the reduction in fracture Calcitonin reduces bone resorption by binding to
risk. specific osteoclast receptors.
Important considerations in bone health include Selective estrogen-receptor modulators produce
adequate intake of calcium and vitamin D, regular different expression of estrogen-regulated genes in
weight-bearing exercise, and avoidance of cigarette different tissues, activating some and inhibiting
smoking and other negative factors. others. The net effect of this is a reduction in bone
Pharmacologic intervention is indicated for women resorption and possibly a reduction in the risk of
who have T scores of 2.5 and below and for breast cancer.
women with risk factors whose T scores are 1.5 or Teraparatide stimulates bone formation, producing
below. gains in spine bone mineral density two to three
Medications employed to treat osteoporosis include times greater than those observed with antiresorptive
the bisphosphonates, calcitonin, selective estrogen- drugs.
receptor modulators (SERMs), and parathyroid Bisphosphonates remain the first-line therapy for most
hormone. patients, but teraparatide may be preferred for higher
Pharmacologic medications for the treatment of risk patients and for those failing to achieve a desired
osteoporosis are classified as either antiresorptive or response to treatment with antiresorptive drugs.
Osteoporosis is a silent condition characterized by is also important but is usually the job of the orthope-
reduced bone mass and microarchitectural changes dist. Management of complications of osteoporosis
leading to increased bone fragility and susceptibility to (physical disability, psychosocial issues) may fall to
fracture. In other words, osteoporosis is a condition of the primary care physician or osteoporosis medical
reduced bone quality and quantity that predisposes to specialist.
fractures under conditions of daily living. A number of pharmacological agents are approved
The diagnosis of osteoporosis is made either from for treatment of osteoporosis. All increase bone mineral
the results of bone density testing or because of the density (BMD) and reduce the risk of fractures.
occurrence of a fragility fracture. The main goal of However, recent studies show that the increases in bone
treatment of osteoporosis is prevention of fractures. density explain only a small proportion of the observed
For patients who have low bone mass but have not reduction in fracture risk. This suggests that agents must
yet had fractures, the goal is prevention of the first have some additional effects on bone quality to
fracture. For the patient who already has had one or account for the reduction in fracture risk. However, it
more fractures, intervention is urgently needed to is not clear exactly what aspect of bone quality is
prevent subsequent fractures. Treatment of fractures improved or how to measure the change.
592
Lifestyle Issues TABLE 35C-2. ELEMENTS OF A FALL RISK-

REDUCTION PROGRAM.
A healthful lifestyle is appropriate for everyone, whether Use proper body mechanics and avoid pushing, pulling, bending,
they have osteoporosis or not. Important aspects for and lifting
bone health include adequate intake of calcium and
Hearing and visual impairment corrected as much as possible
vitamin D, an active lifestyle including regular weight-
bearing exercise, and avoidance of cigarette smoking Flooring and carpet in good condition without uneven surfaces
and other negative factors (Table 35C-1).
No throw rugs
The recommended intake of calcium for men and
women over age 50 is 1200 mg daily. The typical post- Lighting bright and without glare
menopausal woman gets between 500 and 600 mg of Night lights present throughout the house
calcium daily from dietary sources, and a supplement of
500 to 700 mg of calcium daily is needed. Calcium car- Telephones readily available
bonate is the least expensive supplement. For most effi- Electric cords short and not in walkways
cient absorption, calcium carbonate should be taken in
divided doses (no more than 500 mg per dose) and with Clutter does not obstruct walkways
food. Calcium citrate is more expensive but may cause Pets do not lie near feet or bedside
fewer gastrointestinal problems.
Vitamin D is essential for the absorption and assimi- Railings in tub, shower, and toilet areas
lation of calcium. Vitamin D also has direct effects on Nonslip surfaces on floors of tub and shower
bone remodeling and either direct or indirect effects on
muscle strength and balance. Vitamin D is produced in Water drainage in bathroom adequate to prevent slippery floors
skin by ultraviolet light and some foods are fortified Bedside table for items that might clutter floor
with vitamin D. Nevertheless, vitamin D deficiency is
Kitchen cleaning and cooking supplies within easy reach
quite common, being present in over half of women
receiving therapy for osteoporosis (1). Supplementation Stairs have railings on both sides, nonskid surfaces
with 1000 to 2000 IU of vitamin D per day is often neces-
No items stored on steps
sary to assure adequate serum levels of 25-hydroxy
vitamin D (3060 ng/mL). (Standard supplemental mul- All entry ways maintained in good condition
tivitamins contain 400 IU of vitamin D; some calcium
Shoes fit well
supplements also contain 100 or 200 IU of vitamin D.)
Vitamin D supplementation has been shown to reduce Be trained and use a cane if gait is unsteady
Above all, dont hurry!
TABLE 35C-1. LIFESTYLE ISSUES IMPORTANT FOR

PREVENTION AND TREATMENT OF OSTEOPOROSIS.
Calcium: recommended intake is 1200 mg daily for adults over
age 50 the risk of falls and may have other extraskeletal bene-
Most women need a calcium supplement of 500 to 700 mg fits as well.
daily Calcium and vitamin D may slow bone loss in recently
Calcium carbonate is inexpensive and effective menopausal women but do not prevent it. In older
Calcium citrate is often better tolerated for patients who have
women with established osteoporosis, however, calcium
digestive distress
and vitamin D prevent bone loss and reduce the risk of
Vitamin D: the official recommended intake is 400 to 800 IU both spinal and nonspinal fractures.
daily; higher doses (10002000 IU daily) are often required Weight-bearing exercise, such as walking or low-
Standard multivitamins contain 400 IU vitamin D
impact aerobics, is advisable. Patients should try to walk
Additional vitamin D (total 800 IU daily) is advisable for
persons over age 70 and can be achieved by taking calcium for 40 minutes or more, four times a week, if possible.
and vitamin D in combination in addition to a multivitamin Carrying light weights (1 or 2 lbs) when walking is desir- 35
or supplements of vitamin D able. Resistance exercises may be helpful.
Because most osteoporotic fractures involve some
Exercise
Weight-bearing exercise, if possible; recommend walking at element of trauma or falling, patients should be coun-
least 40 minutes a session, at least 4 sessions a week seled to reduce their risk of falling and to avoid activi-
Spinal strengthening exercises are also advisable ties that produce undesirable forces on the skeleton
(e.g., high-impact activities, pushing, pulling, bending,
Avoid cigarette smoking and other possible negative factors
such as high intake of caffeine, protein, phosphorus, etc. and lifting). Table 35C-2 lists some elements of pro-
grams designed to reduce fall risks.
594 NELSON B. WATTS
Possible consequences of fracture include acute and ment of osteoporosis is reduction of fracture risk, which
chronic pain, changes in appearance (height loss, kypho- can only be shown in large studies, and then only in
sis or dowagers hump), depression, dependency, and treatment populations. Evidence for fracture risk reduc-
deconditioning. These problems need to be identified tion for approved agents is shown in Table 35C-3. All
and treated. If the patient has pain, it is important have been shown to reduce the risk of vertebral frac-
for both the provider and the patient to understand tures but not all have demonstrated effectiveness for hip
that osteoporosis is not the cause of her pain and that and nonvertebral fractures.
treating the underlying osteoporosis is not likely to
relieve it.
Bisphosphonates
Bisphosphonates share a common chemical structure
Pharmacologic Agents (two phosphonic acids joined to a carbon) that causes
them to bind avidly to hydroxyapatite crystals on the
A number of pharmacologic agents reduce the risk of surfaces of bone. They are resistant to metabolic degra-
osteoporotic fractures in women who have already had dation, and work through two broad mechanisms. First,
a fracture (prevalent fractures), in women who have low bisphosphonates reduce the ability of individual osteo-
BMD (T score 2.5 and below), or both. Drugs have clasts to resorb bone. Second, they accelerate osteoclast
also been shown to prevent bone loss in women who apoptosis (programmed cell death). Three bisphospho-
have recently begun menopause. Agents approved by nates (alendronate, ibandronate, and risedronate) are
the US Food and Drug Administration (FDA) for treat- approved for prevention and treatment of postmeno-
ment of osteoporosis are shown in Table 35C-3. They pausal osteoporosis. Bisphosphonates are remarkably
can be classified based on mechanism as antiresorptive free from systemic toxicity.
(or anticatabolic) or anabolic. All but teriparatide, an Alendronate (Fosamax) was the first bisphosphonate
anabolic drug, work by reducing bone resorption. approved by the FDA (1995) for prevention and treat-
Prevention and treatment studies are performed ment of osteoporosis. In phase III trials involving almost
in very different groups of subjects. Prevention studies 1000 women in their late 60s who had established osteo-
are done in healthy women who are recently meno- porosis, alendronate 10 mg daily was shown to increase
pausal. A typical prevention study involves women in spinal bone density by almost 10% after 3 years, and,
their early or mid-50s, 3 to 5 years postmenopause, to a lesser degree, to increase BMD at other sites as
usually with normal or borderline low BMD. In con- well (2).
trast, treatment studies are done in older women who In the Vertebral Fracture Arm of the Fracture Inter-
have low bone mass, often after they have already had vention Trial (FIT), involving over 2000 older women
one or more fractures and are therefore at high risk for with low femoral neck BMD and prevalent vertebral
additional fractures. A typical treatment study involves fractures, alendronate reduced the frequency of verte-
women in their late 60s or early 70s, with low BMD at bral, hip, and wrist fractures by about 50% (3).
the spine or hip (usually both), often with one or more Alendronate is available in 5-mg, 10-mg, 35-mg,
prevalent vertebral compression fractures. Change in 40-mg, and 70-mg tablets and in unit-dose liquid of
BMD is an endpoint in both prevention and treatment 70 mg. It is also available in a 70-mg tablet containing
studies. However, the most important benefit of treat- 2800 IU of vitamin D intended for weekly dosing. Alen-
TABLE 35C-3. FDA-APPROVED PHARMACOLOGIC AGENTS FOR TREATMENT OF

POSTMENOPAUSAL OSTEOPOROSIS (IN ALPHABETICAL ORDER) AND EVIDENCE FOR
FRACTURE RISK REDUCTION.
VERTEBRAL NONVERTEBRAL
AGENT FRACTURE FRACTURE HIP FRACTURE
Bisphosphonates
Alendronate (Fosamax) Yes Yes Yes
Ibandronate (Boniva) Yes No No
Risedronate (Actonel) Yes Yes Yes
Calcitonin (Miacalcin, Fortical) Yes No No
Raloxifene (Evista) Yes No No
Teriparatide (Forteo) Yes Yes No

dronate is approved for prevention of bone loss Although they are not approved by the FDA for use in
(5 mg daily or 35 mg weekly) and treatment of osteo- osteoporosis, they are sometimes used off label.
porosis (10 mg daily or 70 mg weekly). Alendronate is Etidronate (Didronel) has been shown to increase
also approved for treatment of glucocorticoid-induced BMD in two prospective, randomized, controlled trials
osteoporosis (5 mg daily for men and estrogen-replete of women with postmenopausal osteoporosis. When
women, 10 mg daily for estrogen-deficient women). used to treat osteoporosis, it is given in an intermittent
Risedronate (Actonel) was approved by the FDA in cyclical regimen (400 mg etidronate daily for 14 days
2000. Its effectiveness for vertebral fracture reduction every third month). As with all bisphosphonates, etidro-
was shown in two pivotal studies of over 3600 women nate must be taken on an empty stomach to be effective,
with low BMD and prevalent vertebral fractures (2,4). but it may be taken between meals, at bedtime, or
The primary endpoint in these trials was new radio- during the night.
graphic vertebral fractures, which were reduced by Pamidronate (Aredia), another bisphosphonate, is
41% and 49% in these two studies. The reduction in the not approved by the FDA for use in osteoporosis. It is
rate of new vertebral fractures was significant after only given by intravenous infusion. A typical regimen is an
1 year of treatment. Nonvertebral fractures, a second- initial dose of pamidronate 90 mg, infused over about
ary endpoint in these studies, were reduced by 33% to 60 minutes, with subsequent doses of 30 mg every third
39%, (p = 0.02) (4). Risedronate therapy significantly month. Intravenous pamidronate is useful for patients
increased BMD at the spine and to a lesser degree at who cannot tolerate oral bisphosphonates.
the hip. Zoledronic acid (Zometa) is approved for treatment
In the largest trial of osteoporosis to date, involving of skeletal complications of malignancy and currently is
almost 9500 women, risedronate produced a significant in late phase III trials for osteoporosis. A phase II study
reduction in hip fractures in postmenopausal women suggested that a yearly dose of 4 mg intravenously pro-
who had low bone mass (5). A subset of elderly women duced changes in bone mineral density and bone turn-
who were enrolled in the trial because they had clinical over markers similar to other bisphosphonates (7).
risk factors for fractures (but not necessarily low bone
mass) did not show a benefit. Bisphosphonate Dosing, Tolerability
Risedronate has been shown to prevent bone loss in
recently menopausal women. Risedronate was well tol-
and Adverse Effects
erated in clinical trials of almost 16,000 subjects; in Bisphosphonates are poorly absorbed when taken by
aggregate, the adverse events rate has been no different mouth. To assure absorption, they must be taken first
from that of placebo. thing in the morning, on an empty stomach, with nothing
Risedronate is available in 5-mg and 35-mg tablets else but water for at least 30 minutes (in the case of
and in a packet containing 35-mg tablets with additional monthly oral ibandronate, the wait should be at least 60
tablets of calcium carbonate, to be taken separately. minutes). Because nitrogen-containing bisphosphonates
Risedronate is approved for the prevention and treat- can be irritating to the esophagus, bisphosphonates
ment of postmenopausal osteoporosis, as well as for the should be taken with a large glass of water (to wash the
prevention and treatment of glucocorticoid-induced tablet down), and the patient should not lie down until
osteoporosis. The dose of risedronate is 5 mg daily or after eating (to avoid reflux). Oral bisphosphonates
35 mg weekly for all of these indications. should not be given to patients who have active upper
Ibandronate (Boniva) 2.5 mg daily by mouth and an gastrointestinal disease, and should be stopped in
intermittent regimen (20 mg orally every other day for patients who develop upper gastrointestinal complaints
12 doses repeated every 3 months) was shown to reduce or who are unable to be upright after taking it.
new vertebral fractures in a study of almost 3000 women The most common side effect of oral bisphospho-
with preexisting vertebral fractures (6). Ibandronate, nates is esophageal irritation (heartburn, indigestion,
approved for prevention and treatment of postmeno- pain on swallowing). This was seen in perhaps 10% of
pausal osteoporosis, can be given orally (2.5 mg daily or patients taking daily oral alendronate, but is much less
150 mg monthly) or intravenously (3 mg over 1530 common with weekly or monthly dosing. Alendronate
seconds every 3 months). Ibandronate has not been liquid may be tolerable for patients who have side 35
shown to have an effect on hip fractures. Although effects from tablets. Class labeling indicates that mus-
there was no effect on nonvertebral fractures overall, culoskeletal complaints occur in a small number of
a post hoc analysis of the pivotal trial data showed a patients and may or may not resolve when treatment is
significant reduction with daily oral therapy (but not stopped; the mechanism for this is unclear. Intravenous
an intermittent regimen) in nonvertebral fractures in administration of bisphosphonates is often accompa-
women with femoral neck T scores of 3.0 or below. nied by an acute-phase response (fever and myalgias);
Etidronate, pamidronate, and zoledronic acid are if this occurs, it is likely only with the first dose. Osteo-
other bisphosphonates available in the United States. necrosis of the jaw has been described, mainly in cancer
596 NELSON B. WATTS
patients receiving high doses of intravenous pamidro- for prevention of bone loss but not for treatment of
nate or zoledronic acid, but also in a small number of osteoporosis. Estrogen and combination hormone
patients receiving oral bisphosphonates for treatment of therapy were shown to reduce vertebral, nonvertebral,
osteoporosis; the mechanism for this is not clear. and hip fractures in the Womens Health Initiative, but
hormone therapy is not recommended for the treatment
of osteoporosis because of an unfavorable balance of
How Long to Treat with Bisphosphonates
risks and benefits (9). The main indication for estrogen
Bisphosphonates have a long residence time in bone. In or postmenopausal hormone therapy is for relief of
theory, a reservoir of drug could accumulate to a point menopausal symptoms, when it should be used in the
that treatment could be stopped with some residual lowest dose necessary and for the shortest period of
antifracture benefit. Long-term data with alendronate time.
and risedronate suggest that treatment for up to 10
years is safe but that after 3 to 5 years of treatment, a Raloxifene
drug holiday of a year or two might be offered without
major sacrifice of antifracture efficacy. Raloxifene (Evista) is a selective estrogen-receptor
modulator (SERM). After binding to estrogen recep-
tors, SERMs produce different expression of estrogen-
Calcitonin regulated genes in different tissues, activating some and
Calcitonin is a peptide hormone secreted by specialized inhibiting others. Raloxifene (60 mg daily) is approved
cells in the thyroid gland. Salmon calcitonin is used for by the FDA for prevention of bone loss in recently
treatment of osteoporosis because it is more potent and menopausal women and for treatment of established
has a longer duration of action than human calcitonin. osteoporosis. For treatment of postmenopausal osteo-
Calcitonin acts directly to reduce bone resorption by porosis, raloxifene was evaluated in the Multiple Out-
binding to specific receptors of the osteoclast. comes of Raloxifene Evaluation (MORE) Study, which
Available since 1984 for subcutaneous injection involved over 7700 women (10). The risk of new verte-
(currently marketed as Calcimar, Miacalcin, Fortical), bral fractures was reduced by 30% to 50%. No effect of
salmon calcitonin (50100 IU daily) results in slight gains raloxifene on hip fractures or nonvertebral fractures
in spinal BMDsomewhat less than the gains induced was shown.
by other agents. Because of the perception of limited and Raloxifene is generally well tolerated, but is associ-
perhaps only transient effectiveness, the inconvenience ated with an increase in leg cramps and hot flashes.
and discomfort of injections, relatively high cost, and There is a small (3/1000 patient-years) but significant
limited tolerance (approximately 20% of patients given increased risk of venous thrombosis with raloxifene,
subcutaneous salmon calcitonin develop nausea or flush- similar to what is seen with estrogen. Raloxifene pro-
ing), subcutaneous calcitonin was not widely used. duces some favorable changes in lipids [decreases in
Nasal calcitonin (Miacalcin) was introduced in 1995. low-density lipoprotein (LDL) cholesterol, neutral for
Another brand, Fortical, was approved by the FDA in high-density lipoprotein (HDL) cholesterol and triglyc-
2005. The nasal form is much better tolerated than the erides], but appears to be neutral for cardiovascular
subcutaneous form. The recommended dose of nasal disease. Of interest, in the osteoporosis trials, raloxifene
calcitonin is 200 IU (one spray) daily. It is approved for was associated with a reduced incidence of breast cancer.
treatment of postmenopausal osteoporosis but not for Several large trials appear to confirm this effect, but as
prevention or for use in glucocorticoid-induced osteo- of this writing, raloxifene is not indicated for prevention
porosis. A 5-year study of nasal calcitonin in over 1000 of breast cancer.
women with preexisting vertebral fractures showed only
a modest effect on spinal bone mass, but a 33% reduc- Teriparatide (134 Recombinant
tion in the incidence of new vertebral fractures (8). No
effect of calcitonin on nonvertebral or hip fracture was
Human Parathyroid Hormone)
shown in this study. Although continuous exposure to parathyroid hormone
Nasal calcitonin is extremely well tolerated. There or its active fragments leads to increased osteoclastic
are no concerns about long-term safety. Calcitonin may bone resorption, teriparatide (rhPTH 134; Forteo)
have an analgesic effect and is sometimes prescribed for given by daily subcutaneous injection acts an anabolic
patients who have acute painful vertebral fractures. agent. It stimulates bone formation, producing gains
in spine BMD two to three times greater than those
observed with antiresorptive drugs. Vertebral and non-
Estrogen vertebral fractures were reduced 55% to 65% over 18
Estrogen (several oral and transdermal preparations) to 20 months of teriparatide therapy in the pivotal Frac-
alone or in combination with a progestin is approved ture Prevention Trial (11). Treatment with teriparatide
should be limited to 2 years because lack of both safety SERMs, including arzoxifene and bazedoxifene, are
and efficacy data with longer duration. It is much more being studied.
expensive than other agents ($20 per day). The dose Denosumab (AMG-162) is a monoclonal antibody
is 20 mcg SQ daily. Side effects include nausea, dizzi- that is an analog of osteoprotegerin, a naturally occur-
ness, and leg cramps. Hypercalcemia may occur but is ring decoy receptor for RANK ligand (RANKL).
infrequent. Rats given high doses of teriparatide over RANKL is required for osteoclast differentiation. By
most of their life span develop osteosarcomas. Thus, diverting RANKL, there are fewer osteoclasts and
Forteo contains a black box warning that the medica- therefore an antiresorptive effect. In a phase II trial,
tion is not to be used in patients at increased risk of denosumab was shown to increase bone density in the
malignant bone tumors (children, patients with prior spine, hip, and forearm at least as well as alendronate
radiation therapy, Pagets disease, or unexplained and to decrease bone turnover to a similar degree as
increase of serum alkaline phosphatase). Teriparatide alendronate (17). The dose of denosumab going forward
is generally reserved for patients at very high risk of in phase III trials is 60 mg given by subcutaneous injec-
fracture or patients who seem to be failing other tion every month. The drug seemed well tolerated in
therapies. this relatively small trial.
Combination Therapy Summary and Conclusions

Combining two antiresorptive agents (e.g., a bisphos-
phonate combined with estrogen or raloxifene) pro- Adequate calcium, vitamin D, and weight-bearing exer-
duces additional gains in bone mineral density; however, cise are important for everyone and fundamental to any
no studies have shown if combination therapy reduces program of bone loss prevention or osteoporosis treat-
the risk of fracture more than treatment with a single ment. Effective pharmacologic agents are available for
agent. Combining parathyroid hormone or teriparatide reducing the risk of fracture. Pharmacologic interven-
with an antiresorptive agent appears to lessen the BMD tion is indicated for women who have T scores of 2.5
response to teriparatide (12). However, cyclic 134 and below and for women with risk factors whose T
parathyroid hormone therapy (3 months on and 3 scores are 1.5 or below. Alendronate and risedronate
months off) produced similar gains in BMD to daily have the best evidence for reduction of a variety of
therapy in patients receiving alendronate (13). When types of fracture and are well tolerated. Teriparatide
therapy with parathyroid hormone is stopped, BMD has different mechanism of action and may be preferred
begins to decline, but following parathyroid hormone for higher risk patients and for those failing to achieve
or teriparatide treatment with a bisphosphonate appears a desired response to treatment with antiresorptive
to produce additional gains (14). drugs.
In the Future REFERENCES

184 Parathyroid hormone has been shown to reduce
new vertebral fractures in a large clinical trial. No effect 1. Holick MF, Siris ES, Binkley N, et al. Prevalence of
vitamin D inadequacy among postmenopausal North
on nonvertebral or hip fractures was demonstrated. In
American women receiving osteoporosis therapy. J Clin
the dose of 100 mcg SQ daily, hypercalcemia appeared Endocrinol Metab 2005;90:32153224.
to be more frequent than with teriparatide. In March 2. Reginster J-Y, Minne HW, Sorensen OH, et al. Ran-
2006, the sponsor received an approvable letter from domized trial of the effects of risedronate on vertebral
the FDA, with concerns regarding hypercalcemia and fractures in women with established postmenopausal
some issues with the delivery device needing further osteoporosis. Osteoporos Int 2000;11:8391.
discussion or data. 3. Black DM, Cummings SR, Karpf DB, et al. Randomised
Strontium ranelate is available in other countries but trial of effect of alendronate on risk of fracture in women
not in the United States. Strontium has both antiresorp- with existing vertebral fractures. Lancet 1996;348:1535
tive and anabolic actions. In a dose of 2 g orally b.i.d. it 1541. 35
has been shown to reduce the risk of vertebral and 4. Harris ST, Watts NB, Genant HK, et al. Effects of rise-
dronate treatment on vertebral and nonvertebral frac-
nonvertebral fractures (15,16). A post hoc analysis sug-
tures in women with postmenopausal osteoporosisa
gests an effect on hip fractures. randomized controlled trial. JAMA 1999;282:13441352.
Although more data on extraskeletal effects of ral- 5. McClung MR, Geusens P, Miller PD, et al. Effect of rise-
oxifene are being collected, clinical trials with newer dronate on the risk of hip fracture in elderly women. N
SERMs, such as droloxifene and idoxifene, have been Engl J Med 2001;344:333340.
discontinued because of adverse endometrial effects. 6. Chesnut CH III, Skag A, Christiansen C, et al. Effects of
Laxofoxifene was rejected by the FDA in 2005. Other oral ibandronate administered daily or intermittently on
598 NELSON B. WATTS
fracture risk in postmenopausal osteoporosis. J Bone 12. Black DM, Greenspan SL, Ensrud KE, et al. The effects
Miner Res 2004;19:12411249. of parathyroid hormone and alendronate alone or in com-
7. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zole- bination in postmenopausal osteoporosis. N Engl J Med
dronic acid in postmenopausal women with low bone 2003;349:12071215.
mineral density. N Engl J Med 2002;346:653661. 13. Cosman F, Nieves J, Zion M, Woelfert L, Luckey M,
8. Chesnut CH III, Silverman S, Andriano K, et al. A ran- Lindsay R. Daily and cyclic parathyroid hormone in
domized trial of nasal spray salmon calcitonin in post- women receiving alendronate. N Engl J Med 2005;353:
menopausal women with established osteoporosis: the 566575.
Prevent Recurrence of Osteoporotic Fractures study. Am 14. Black DM, Bilezikian JP, Ensrud KE, et al. One year of
J Med 2000;102:267276. alendronate after one year of parathyroid hormone (184)
9. Writing Group for the Womens Health Initiative Inves- for osteoporosis. N Engl J Med 2005;353:555565.
tigators. Risks and benefits of estrogen plus progestin in 15. Meunier PJ, Roux C, Seeman E, et al. The effects of
healthy postmenopausal women. JAMA 2002;288:321 strontium ranelate on the risk of vertebral fracture in
333. women with postmenopausal osteoporosis. N Engl J Med
10. Ettinger B, Black DM, Mitlak BH, et al. Reduction 2004;350:459468.
of vertebral fracture risk in postmenopausal women 16. Reginster J-Y, Seeman E, De Vernejoul M-C, et al. Stron-
with osteoporosis treated with raloxifeneresults from tium ranelate reduces the risk of nonvertebral fractures
a 3-year randomized clinical trial. JAMA 1999;282:637 in postmenopausal women with osteoporosis: treatment
645. of Peripheral Osteoporosis (TROPOS) Study. J Clin
11. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of Endocrinol Metab 2005;90:28162822.
parathyroid hormone (134) on fractures and bone 17. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab
mineral density in postmenopausal women with osteopo- in postmenopausal women with low bone mineral density.
rosis. N Engl J Med 2001;344:14341441. N Engl J Med 2006;354:821831.
CHAPTER 36
Rehabilitation of Patients with

Rheumatic Diseases
THOMAS D. BEARDMORE, MD, FACP, FACR
In the care of disabled individuals, the current system underlying rheumatic disease but the individual as
of health care delivery and education largely focuses a whole functioning person. Central to this health
on a disease-centered medical model that fails to promotion is involvement of patient responsibility for
consider the role of society and the interaction of his or her health and well being, including physical,
the disabled individual in that society over a psychological, social, and societal aspects.
lifespan. Multidisciplinary efforts are important to effective
A more holistic approach to the care of disabled rehabilitation of patients disabled by rheumatic
individuals considers the impact of environmental disease. Critical members of the multidisciplinary
factors on the patient and provides a biopsychosocial team are the rheumatologist, orthopedist, physical
orientation rather than a purely medical one. and occupational therapists, rehabilitation nurse,
Holistic health approaches promote optimal function psychologist, social worker, and vocational
of the disabled person by considering not only the rehabilitation specialist.
Rehabilitation of patients with rheumatic diseases ity as an integrated model that uses neutral terminol-
addresses activity limitation and mobility as primary ogy, includes environmental factors, and provides a
factors. It utilizes all healing disciplines and technolo- biopsychosocial model of orientation rather than a
gies with an emphasis on preservation and restoration purely medical model.
of function. Medical, surgical, psychological, and physi- In the ICF classification, a health condition (disease
cal treatments are utilized, with the rheumatologist as or disorder) may influence body functions (physiologic
leader and coordinator of the interdisciplinary team. and/or psychologic) or structures (anatomic parts), an
This program can provide functional success even if activity that an individual does (e.g., walking), and the
control of the disease process is suboptimal. individuals participation in his or her life and environ-
ment (e.g., job, sports, recreation). The health condi-
tion, body functions, activities, and participation all
CLASSIFICATION OF interrelate and are influenced by personal (e.g., age,
coping style) and environmental (e.g., architecture,
FUNCTIONING, DISABILITY, social attitudes) factors. Functioning and disability are
AND HEALTH multidimensional. Functioning can be considered the
positive abilities which encompass and result from a
The World Health Organization (WHO) in 2001 pub- bodily structure or function, activities, and participa-
lished the International Classification of Functioning, tion. Disability would be the negative aspect of function
Disability, and Health (ICF) (1). This was an attempt or restriction of activity and limitation of participation.
to understand and categorize the experiences of people Activity occurs at the individual level and participation
living with chronic illness. Much of current health care at the societal level. Hence, a disease (health condition)
delivery and education continues to follow the medical may result in impairment of a body function that has
model and to attribute disability to a disease-related impact on activity and participation, and the latter may
deficit that prevents normal function. This model, interrelate. Activity is functioning at the level of the
however, fails to consider the role of society and the person and may be limited in nature, duration, and
interaction of the disabled individual in that society quality. Participation is involvement in life situations
over a lifespan. The ICF approaches health and disabil- in relation to impairments, activities, health conditions,
599
600 THOMAS D. BEARDMORE
TABLE 36-1. RHEUMATIC DISEASES: EXAMPLES OF DISABILITIES.

HEALTH CONDITION BODY FUNCTION IMPAIRMENT ACTIVITY RESTRICTION PARTICIPATION IMPAIRMENT
Rheumatoid arthritis Knee pain, small flexion Unable to walk long distances Unable to participate in recreation
contracture (e.g., golf, walking)
DLE, face and scalp Hair loss and skin depigmentation None Social activity restrictions (social
phobia, shyness)
Scleroderma Raynauds phenomenon None Unable to participate in winter sports
Polymyositis Proximal muscle weakness Limited on stairs Unable to enter house, public
buildings, curbs
SLE Photosensitivity None Unable to participate in outdoor

activities
Ankylosing spondylitis Back pain and stiffness Limited ability to lift and bend Unable to do medium and heavy jobs,
limited in recreation (e.g., bowling)
ABBREVIATIONS: DLE, discoid lupus erythematosis; SLE, systemic lupus erythematosis.
and contextual factors, and may be restricted in nature, the appropriate consultations as problems arise, assures
duration, and quality. Examples of rheumatic disease that there is communication between team members,
disablements are illustrated in Table 36-1. In the ICF and that realistic achievable goals are selected.
model, medical treatment would be directed toward the Rehabilitation should start with the first doctor
health condition and its influence on bodily function. visit and extend throughout the course of the disease.
Rehabilitation therapies would address limitation of During early disease, the physician can address most
activity and participation. Public education, legislation, functional problems with attention to the medical
and universal architecture design would improve limited regimen. Rehabilitation can occur in a physicians office
participation by the disabled community. and by selected referral to the needed discipline: mobil-
ity problems can be referred to physical therapy for
outpatient treatment; activities of daily living problems
REHABILITATION TEAM can be referred to occupational therapy; and psycho-
AND SETTING logical problems can be referred to the psychologist, as
examples. With more advanced disease, short duration
A holistic health approach is indicated to promote inpatient rehabilitation should be considered, where
optimal function. This approach deals not just with the more intense treatment can be provided. Daily observa-
remission or absence of the underlying rheumatic tion of the patient will permit fine adjustments of
disease, but promotes consideration of the individual as medical and therapy programs.
a whole functioning person. Central to this health pro- In the United States, diagnostic related groups
motion is involvement of patient responsibility for his (DRGs) govern the current medical care system and
or her health and well being, including physical, psycho- reimbursement for inpatient stays. This has been
logical, social, and societal aspects. designed to reduce the total cost of health care in the
A health team, with multidisciplinary expertise, can United States and has been successful in doing so. For
help achieve optimal outcomes. In the hospital, this acute illnesses both inpatient stays and health care
team may consist of rheumatology as team leader, along costs have been reduced. Inpatient rehabilitation is not
with occupational therapy, physical therapy, psychol- defined by the DRG system but has also responded
ogy, social work, rehabilitation nursing, and orthopedic to the trend of reduced inpatient days. Currently, inpa-
surgery. Integral to this rehabilitation team is the patient tient care is reserved for patients who have the most
who must accept responsibilities for selection of realis- advanced rheumatic disease with the most functional
tic goals and their implementation. In early disease and impairment.
in the outpatient setting, it may be unnecessary to have The requirements for inpatient hospitalization are
all disciplines assist in the rehabilitation process. In dictated by Medicare rules. Currently, Medicare requires
advanced complicated disease, where there are disease that patients with rheumatic disease have reductions in
elements, problems with mobility, impaired activities of activities of daily living and mobility that have not
daily living, depression, job loss, and insurance loss, the responded to outpatient treatment. The illness must
expertise of a team is required. The team leader selects be sufficiently severe to require daily monitoring by
C H A P T E R 3 6 R E H A B I L I T A T I O N O F P A T I E N T S W I T H R H E U M A T I C D I S E A S E S 60 1
physicians and health professionals. Eighteen hours of PATIENT ASSESSMENT

multidisciplinary inpatient treatment from two major
rehabilitative disciplines (physical therapy, occupational In addition to the usual rheumatologic history and phys-
therapy, and speech therapy) must be provided weekly. ical, an assessment of the patients function is needed.
Social work and psychological rehabilitation can be This is obtained most effectively by indirect questions;
given during the hospitalization and may contribute 3 for example: How does your arthritis affect your life?
hours of adjunct therapy to the required 18 hours of and Describe to me what you do on a usual day. This
treatment. will give the patient an opportunity to relate functional
A transitional inpatient care unit or skilled nursing impact of the rheumatic disease on activities that are
facility can be used for patients who have significant important to him or her. From this information, mutu-
functional problems and do not need 3 hours of daily ally agreed upon goals formulated by the patient and
treatments but require at least one modality for 1 hour health care team can be made. All team members should
daily. This should be considered for patients who have obtain discipline-specific history. Inquiries should be
less disability and require skilled nursing as well as func- made about activities of daily living, including personal
tional training (e.g., postoperative total joint arthro- grooming and toileting, eating, transfers and ambula-
plasty strengthening and gait training). The goal for tion, vocational activities including homemaking, and
both inpatient and outpatient programs is maintenance hobbies and other avocational activities. Activities of
of the rehabilitative program by the patient in their daily living are usually described as independent, super-
environment. vised, assisted, or unable. Dressing is further subdivided
Clinical trials have shown that there is a beneficial into ability to do upper body and lower body dressing.
response to multidisciplinary team care when compared The occupational therapist should record specific
to regular outpatient care. For active rheumatoid arthri- hand and upper extremity function, including ability
tis, improvement from inpatient rehabilitation was with power grip, power and precision pinch, pill hand-
maintained for up to 2 years (2). The greatest changes ling, and cylindrical grasp. Physical therapy activities
were seen at 2 weeks after discharge when there was should be recorded, stressing trunk and lower extremity
statistical improvement in the Ritchie articular index, functions and mobility activities, such as being able to
number of swollen joints, disease activity by visual ana- prone, side lie, roll from side to side, to go from supine
logue scale (VAS), pain by VAS, and physician global to sitting and from sitting to standing, to ambulate, and
assessment. At 4 weeks, 7 of 39 patients who had ability to climb stairs. Ambulation can be divided into
received inpatient rehabilitation had achieved Ameri- household and community, with and without aids or
can College of Rheumatology ACR20 status or better wheelchair assistance.
compared to none receiving outpatient treatment. At 1 Because the rheumatic diseases affect primarily the
year, improved disease activity by VAS was still signifi- musculoskeletal system with resultant problems related
cantly greater for the inpatient group and ACR20 or to mobility, muscular strength, and joint range of
better was 46% in the inpatient group compared to 23% motion, the physical examination is likewise function-
in the outpatient group. Recent reports have shown that ally oriented. Manual muscle testing is a common way
outpatient multidisciplinary treatment is as effective of measuring strength (Table 36-2). This is graded from
as inpatient care. Patients treated as outpatients had 0 to 5, no motor activity to normal strength. It is impor-
significant improvement over time of functional status,
quality of life, health utility, and disease activity (3).
Additionally coordination of this care by a clinical nurse
specialist was equally effective at a reduced overall cost. TABLE 36-2. GRADES OF MUSCLE STRENGTH:
The importance of multidisciplinary care is established. MANUAL MUSCLE TESTING.
Additional work is needed before it can be recom-
GRADE DESCRIPTION
mended that all patients will do well with outpatient
care. At this time the setting is to be determined by the 5 (normal) Full ROM against gravity, strong resistance
skilled rheumatologist and not by economics alone. It
4 (good) Full ROM against gravity, some but not full
is likely that inpatient care is best for those with the resistance
greatest disability.
In addition to rheumatoid arthritis, multidisciplinary 3 (fair) Full ROM against gravity, no resistance
rehabilitation treatment is efficacious in ankylosing 2 (poor) Full ROM, gravity eliminated
spondylitis (4). Considering the inflammatory nature
and multi-articular nature of many other rheumatic dis- 1 (trace) Slight contracture, no ROM 36
eases, it is reasonable to think that rehabilitative medical 0 (zero) No muscle activity demonstrable
therapies would be beneficial and should be available
to all patients. ABBREVIATION: ROM, range of motion.
tant to remember that normal strength has great vari- PHYSICAL MODALITIES
ability and is dependent upon sex, size, and training
status, and normal individuals with normal strength can Heat and Cold
lose considerable motor function before it is detectable
by an examiner. Range of motion is measured by a Of the physical modalities that are commonly prescribed
goniometer and deviations from normal are noted. Par- for musculoskeletal illnesses, heat and cold have the
ticular attention should be given to alignment, noting largest body of literature to support their use. Heat and
flexion contractures, instabilities, and deformities. cold have been used for centuries in musculoskeletal
There are multiple ways of recording longitudinal impairments, especially in acute injuries. There is no
function. The most commonly used in the rheumato- evidence that harm is done when these modalities are
logic community is the ACR Functional Classification, applied properly, and the potential improvement in
groups I to IV (see Appendix I). This classification is pain, muscular spasm, and ability to participate in an
useful for broad grouping of individuals and measures active exercise program all have positive benefits for
normal function to incapacitation (where assistance in patient outcome. Their low cost and ease of use permit
ambulation and activities of daily living is needed). The their use in the outpatient clinic, private office, and
ACR classification has broad usage and is time-tested home. Most trials in musculoskeletal disorders report
but insensitive to small functional changes. Other useful beneficial effects including reduced pain and muscle
functional assessment tools are the Arthritis Impact spasms, increased circulation, and improved range of
Measurement Scale, the Stanford Health Assessment motion (5). Temperature change occurs in the skin,
Questionnaire, and the Functional Impact Measure. deeper tissues, and on occasion, joint cavities. In addi-
Each of these scales relies upon self-administered tion to beneficial effects in clinical conditions, there is
reports or professional observation of functional activi- experimental evidence for diminished pain response to
ties. They can be used in large studies to measure func- both heat and cold in experimental animal models with
tional change and have utility in both large groups and induced joint inflammation. Heat or cold treatment did
individuals in an office or hospital practice. The ICF (1) not change joint inflammation, but secondary pain
provides a framework for research into the disabling response and behavior were improved (6).
processes and has proposed comprehensive core sets A systematic review of the medical literature for
that can be applied to clinical settings by defining what clinical benefit from heat and cold treatment showed
to measure. Those that apply to rheumatology include little controlled data with accepted quality criteria of
core sets for rheumatoid arthritis, osteoarthritis, and randomization and double-blinding; however, of those
osteoporosis. These core sets are currently being studies that did meet these criteria, heat and cold had
validated. no effect on the objective measures of disease activity,
including inflammation (7). All patients reported that
they preferred heat or cold therapy to no treatment but
PAIN CONTROL there was no preference for either modality. Because
there are no harmful effects from heat or cold, it should
Pain is a frequent chief complaint and a cause of inactiv- be prescribed as a home treatment as needed for pain
ity and loss of function for patients with rheumatic relief.
disease. Patient cooperation and success with rehabili- Heat therapy is usually given as a superficial applica-
tative treatments cannot be achieved if patients have tion to the skin of hot packs, electrical pads, water baths,
pain. Disease control through standard medical regi- paraffin wax, or thermal packs. The use of water baths
mens is sometimes the most efficient way of controlling or whirlpool can be combined with active or passive
pain and, hence, improving activities. Supplemental use motion to improve joint range. Thermal packs contain
of intra-articular glucocorticoids in resistant joints can a chemical agent which upon activation produces heat
control inflammation and pain, prevent flexion contrac- by an exothermic reaction. They have no advantages
tures, and improve range of motion and function. The over electrical heating pads or moist heat and have the
use of topically applied medications (e.g., capsaicin and disadvantage of one-time usage and increased cost. Heat
salicylic acid cream) is also to be considered, particu- therapy is contraindicated when there is loss of normal
larly as an adjunct to physical therapy and occupational sensation and diminished or faulty blood supply.
therapy treatments. Oral analgesics, including low-dose With thermal therapy, deeper heating of tissues can
nonsteroidal anti-inflammatory drugs (NSAIDS) and be achieved by the use of therapeutic ultrasound. There
narcotics, are useful adjuncts to physical therapeutic are no controlled trials to indicate its utility in the rheu-
programs when given 20 to 30 minutes before the matic diseases. It has the disadvantage that it cannot be
onset of the exercise program. They can be used on an performed in the usual office setting but must be in a
occasional basis to permit normal exercise or work specialists office with the associated inconvenience and
periods. increased cost.
Cold reduces pain, muscular spasm, and circulation, lished literature for spa therapy showed many flaws in
causing vasospasm and associated decrease in tissue the designs of the treatments with lack of standardized
metabolism, inflammation, and edema. It is standard treatments, infrequent comparison groups, inconsistent
treatment for immediate care after musculoskeletal intention-to-treat groups, and little evidence of outcome
injury because of these effects. Cold is applied locally measures such as quality-of-life measurements. The
for up to 30 minutes and produces a cooling of the skin conclusion was that spa therapy could not be supported
and subcutaneous tissues. Deep cooling does occur and as a recommended treatment in spite of consistently
is dependant on application time and soft tissue depth. positive findings in the trials and acceptance by patients
Cold is typically prescribed as ice packs, reusable gel (10). Positive effects from spa therapy may be influ-
packs, chemical packs, or by ice massage directly over enced by environmental changes such as freedom from
the painful area. Chemical packs produce cold by an work and household duties, mental and physical relax-
endothermic reaction, but they have little utility except ation, and pleasant spa scenery that are unrelated to
on an infrequent basis because of their expense and the water therapy.
one-time use. Cooling sprays, such as ethyl chloride, are
used commonly in rheumatology in a spray and stretch
technique especially for painful syndromes of the neck
Rest
and back. The skin is superficially cooled by the spray, Rest prescription may be local or systemic. It reduces
resulting in relief of pain and muscular spasm. Active acute inflammation and pain, and promotes normal
or passive stretching can then be achieved. joint position. Local rest is achieved by use of splints or
braces, systemic rest by bed rest. Short periods of rest
as part of a comprehensive program will permit patients
Electrical Stimulation to participate in exercise programs and work activities.
Transcutaneous electrical nerve stimulation (TENS) Prolonged rest is to be avoided because both local and
may be used for outpatient treatment of pain. A low systemic rest are associated with significant muscle loss.
voltage electrical stimulus is delivered to the skin either Only a few weeks of local immobilization can reduce
intermittently or continuously by activation of a battery- muscle mass by 21% (11). About one third of patients
operated device worn about the waist. The patient can with rheumatoid arthritis will show improvement with
activate and control intensity as needed. It is adminis- bed rest that is similar to that seen with activity (12).
tered for non-inflammatory conditions, particularly There is increasing evidence that prolonged bed rest as
chronic pain from osteoarthritis of the back, knee pain, a primary treatment for medical conditions is not helpful
chronic shoulder pain, or pain in other major joints of the and should not be prescribed routinely. This includes its
body. TENS is usually given to patients who are resistant use in rheumatic disease rehabilitation. Some medical
to heat, cold, stretching, exercise, and other modalities. conditions, including acute back pain and postoperative
A careful review of trials comparing TENS to placebo in hip surgical patients, may worsen with bed rest (13).
knee osteoarthritis demonstrated superiority for TENS
in pain relief and improvement of knee stiffness (8).
Despite the lack of controlled trials showing efficacy in
Exercise Therapy
other conditions, TENS has high patient acceptance and Exercise therapy must take into consideration the under-
will likely continue to be commonly prescribed. lying disease activity, including degree of inflammation,
joint stability, muscle atrophy, and anticipated short- and
long-term functional goals. Prescribed exercise may be
Hydrotherapy active or passive, assisted, resistive, or aerobic.
Hydrotherapy combines exercise therapy and warm Passive exercises may be administered by a physical
water emersion. It may be given on an intermittent therapist in which stretch and gentle range of motion
basis as an outpatient or on a sustained basis in the exercises are given with a goal of maintaining range and
form of spa therapy, one of the oldest treatments for reducing contractures. They are used for conditions
rheumatic disease. The aim is to decrease pain, relieve associated with severe pain and weakness such as acute
suffering, and promote a feeling of wellness. There are inflammation, acute myositis, and in the postoperative
few controlled trials of this treatment. However, there period. Active exercise may be assisted in painful and
is some indication that, when administered on a regular weak conditions in which the person is unable to com-
basis as an outpatient, patients who received hydro- plete full range of motion. Isometric exercise, in which
therapy had greater benefit than those who were treated there is active muscle contracture without muscle short-
by seated emersion in water, land exercises, or relax- ening or joint motion, will maintain muscle strength and 36
ation therapy (9). This improvement was both physical is prescribed as initial therapy for those unable to toler-
and emotional as reflected by the AIMS-2 question- ate range of motion due to pain, for example, post-
naire. A more extensive systematic review of the pub- operative joint arthroplasty.
Most patients with rheumatic disease will benefit modified to accommodate these problems with forearm
from a resistive and aerobic exercise program. Resistive troughs, custom hand grips, and Velcro straps. These
exercises should be tailored to the individual, the area are fitted with the elbow at 90 flexion to avoid wrist
of weakness, and the underlying disorder with a goal and hand stress.
of increased strength and endurance. Aerobic and Crutches are prescribed for more severe problems
resistive exercises are beneficial for osteoathritis (OA). and provide increased support when used bilaterally.
Walking and resistive exercise administered for 1 hour They should be adjusted so that no pressure occurs on
three times a week in patients with osteoarthritis of the the axillae. Instruction needs to be given about proper
knee is associated with less pain, less disability, and weight bearing on the upper extremities with the wrist
greater flexion strength (14). Similar but lesser effects and elbow in extension. With crutch use, patients may
are seen with OA of the hip. Results include mild-to- use minimal or no weight bearing on a painful or weak
moderate improvement in pain, disability outcome leg. They will be most useful in the postoperative period
measures, and greater benefit on patients global assess- and for acute injuries and illnesses. Platform crutches
ment (15). Exercise therapy improves aerobic capacity should be prescribed for patients with significant hand
and motor strength for patients with rheumatoid arthri- and wrist arthritis and discomfort with conventional
tis without worsening pain or disease activity (16). In crutches.
ankylosing spondylitis, recreational exercise of at least Walkers provide a wider support base than do
30 minutes daily improved pain and stiffness (17). When canes or crutches for those who need greater ambula-
prescribed with back exercises 5 days a week, health tory stability. They must be lightweight so they can be
status improved as measured by the Health Assessment picked up and advanced. Wheels, brakes, and seats
Questionnaire Disability Index (HAQ-DI). The great- can be attached for patient comfort and safety. They
est benefit was seen in those with early disease. In are useful in the postoperative period, and for the
patients with systemic lupus erythematosis, aerobic elderly, frail, and those who need maximum support for
exercises and strengthening did not worsen disease balance.
activity and were associated with decreased fatigue and Wheelchairs should be prescribed when community
improvement in functional status, strength, and cardio- ambulation is impaired. Patients who are limited to
vascular fitness (18). household ambulation will have increased indepen-
dence with a wheelchair for community activities. A
manual wheelchair is advised for people with normal
AMBULATORY AIDS upper extremity function and strength and endurance
sufficient to propel the chair. Manual wheelchairs, which
Canes, crutches, and walkers are prescribed to improve are propelled by family, can be prescribed for the post-
gait, including weakness, pain, and instability of lower operative period and for the frail and elderly who do
extremity joints. The most useful canes are those made not wish to travel alone. Electric wheelchairs and carts
of wood or aluminum. They should be inexpensive and should be prescribed for those with poor upper extrem-
lightweight, easily adjusted for height, have a comfort- ity function.
able grip and wide rubber tip to firmly grip smooth floor
surfaces. Cane length should be fitted so that the elbow
is flexed 30. With the use of a single cane or crutch at UPPER EXTREMITY AIDS
least 25% of normal weight bearing can be shifted
from a weak or painful joint to the opposite limb. With There are a large variety of commercially available
bilateral support, up to 100% of weight bearing can be assistive devices to improve activities of daily living for
unloaded from a painful lower extremity to the upper impaired upper extremity function. Pinch and grasp can
extremities. Some patients will carry a cane and not use be improved by having build-up handles on tools, cook-
it for support. They use it only as a signal to others that ware, and eating utensils. Power equipment such as
they have ambulatory problems and should be given a electric knives and tools can substitute for decreased
greater courtesy when met. power grip and poor upper extremity strength. Reach-
Patients should be instructed on the proper use of ers can be used to retrieve objects from the floor and
an ambulatory aid. Single support is carried contralat- shelves. Sock cones and long handle shoehorns will
eral to the painful leg. It is advanced and used to bear facilitate donning and doffing socks and shoes. Dressing
weight during stance on the opposite leg. Multiple tips sticks can assist those with impaired shoulder mobility.
(e.g., a quad cane) will provide increased security for Long-handled brushes, combs, and sponges can improve
those with impaired proprioception or balance pro- upper extremity grooming and perineal care.
blems. For patients such as those with rheumatoid Dressing can be facilitated by attention to detail of
arthritis who cannot bear weight on the wrist or have clothing. Problems with pinch can improve by using
significant hand deformities, ambulatory aids can be button hooks, zippers with tabs, and Velcro closures for
clothing and shoeware. Elastic closures for trousers and made device is indicated for severe deformities in which
V necks for pullover sweaters and blouses will also immobilization is needed for pain relief and improved
facilitate dressing. stability.
Home safety and accessibility can be assessed via Orthoses that immobilizes the wrist are of value in
home visits by a physical and occupational therapist. carpal tunnel syndrome. The wrist is immobilized in a
Those who have mobility impairments can be aided by neutral position with 20 to 30 of extension of the hand
installation of half steps, ramps, and handrails in entry- at the wrist. Ring splints are useful for flexible swan
ways. Doorways should be wide to permit walker or neck deformities of the digits and can improve pinch
wheelchair access. Furniture placement and room size strength by putting the proximal interphalangeal (PIP)
should be sufficient for easy mobility with walking aids joint in a slightly flexed and more functional position
and wheelchairs. Scatter rugs and loose electrical cords for precision pinch. They are not effective for fixed
should be removed. For those with knee and hip prob- deformities and there are no studies to support pro-
lems including limited mobility and strength, the addi- longed use of ring splints for deformity prevention.
tion of 4-inch-thick, high density foam cushions or Ring splints may be made of silver to enhance cosmesis
blocks under the chair legs can increase chair height and and wearing compliance.
improve ability to rise from the seated posture. Raised The carpometacarpal (CMC) immobilization splint
toilet seats will facilitate transfer on and off of the toilet. (thumb post splint) is quite effective for degenerative
Within the bathroom, rubber mats should be placed on CMC joint disease and can be used when patients have
tub and shower surfaces to facilitate traction and prevent flare-ups and pain at the base of the thumb. Coupled
falls. Grab bars and tub and shower benches should with this, activity that increase forces across the CMC
be utilized if patients have problems with balance and joints, such as power pinch, should be reduced. One
are at risk of falling. Handheld shower nozzles can facil- common way of avoiding this is to increase the size of
itate bathing. pens and pencils by using a rubber or foam grip and
reminding the patient that light touch with writing
instruments will prevent pain.
Orthotic Devices Casting with plaster or lightweight fiberglass can be
Splints and braces are useful for improving stability and used for immobilization as a trial to see if pain is
reducing pain and inflammation. Because effective improved before more expensive orthoses are made
orthoses restrict motion, short-term use is recommended (e.g., ankle or foot braces) and prior to surgical arthro-
to preserve muscle strength. Splints for the upper desis. If cast immobilization results in pain relief, then
extremity are commonly used and they have general a rigid orthosis or arthrodesis will be associated with
patient and physician acceptance (Table 36-3). Although improved pain and function.
pain and inflammation are reduced, there are no studies
to indicate that deformities are prevented. Wrist ortho-
ses may decrease hand function in the short term as LOWER EXTREMITY ORTHOSES
measured by grip strength and finger and hand dexterity
(19). These potential adverse effects are not an issue for The simplest orthoses for restricting range of motion and
patients because most will continue to wear the splints decreasing pain would be the use of elastic bandages,
when given an option to discontinue them. Consultation elastic or neoprene sleeves, and taping. For degenerative
with an orthotist or occupational therapist for a custom- arthritis of the knee, many patients will have improve-
TABLE 36-3. COMMON UPPER EXTREMITY ORTHOSES.

DISORDER DEFORMITY PROBLEM SOLUTION
RA Flexible swan neck deformity None; clicking; cosmetic Ring splints (stabilizes PIP in flexion)
of fingers appearance
Carpal tunnel syndrome None Night pain, dysesthesias Wrist splint, 2030 extension
OA of first CMC None CMC pain with pinch Thumb post splint, thumb spica
RA None Pain; inflammation of wrist, MCPs, Hand-resting splint (resting posture

and PIPs from wrist to DIPs) 36
Mallet finger Flexion of DIP None Rigid DIP splint, 20 hyperextension
ABBREVIATIONS: CMC, carpometacarpal; DIP, distal interphalangeal; OA, osteoarthritis; PIP, proximal interphalangeal; RA, rheumatoid arthritis.
ment with use of an elastic or neoprene sleeve to reduce ses and special shoeware (21). These trials found no
range of motion. Patella taping has been shown to evidence of harm from orthoses and shoeware.
improve knee pain and function for people with patello-
femoral joint arthritis and abnormal tracking. Taping the
knee to promote normal patella tracking reduced knee VOCATIONAL REHABILITATION
pain by 25% compared to a control group (20). For AND DISABILITY
people who have marked weakness and deformities,
consultation with an orthotist or an orthopedic surgeon Musculoskeletal diseases are the leading cause of dis-
skilled in biomechanics is useful for more extensive ability and absence from work in the United States (22).
bracing. Disadvantages to more extensive bracing are Rheumatoid arthritis is associated with a high disability
high cost and a low rate of wearing compliance. rate and more than one third of working persons with
rheumatoid arthritis are no longer able to work after 5
years (23). For systemic lupus erythematosus, after 3
Shoeware years, 40% of persons are no longer working (24). One
Foot pain and deformities are common in rheumatoid of the goals of rehabilitation is to maintain employabil-
and degenerative arthritis. They can be easily handled ity. Achievement of this goal may require job modifica-
by attention to shoeware (Table 36-4). The most impor- tion, job retraining, and vocational rehabilitation.
tant thing about shoeware is that the upper should be Among patients with arthritis and musculoskeletal dis-
soft and the toebox should be deep and wide enough to orders, reported response rates for return to employ-
accommodate deformities. This will prevent rubbing, ment after vocational rehabilitation vary from no
blisters, and skin breakdown. response to 71% (25,26). The main impediment to suc-
Many patients with rheumatoid arthritis will have cessful vocational rehabilitation is disability insurance
pain on the soles of the feet, particularly at the meta- payments. Among patients with rheumatoid arthritis,
tarsal areas where deformities of cock-up toes and high pain level, older age, and lower education are also
prominent metatarsal heads with anterior displacement barriers for re-employment. For patients with systemic
of the fat pad is common. Because of these deformities, lupus erythematosus, low educational level, receiving
metatarsalgia, callosities, and breakdown can occur. Medicaid, no medical insurance, physically demanding
This can be avoided by the use of inserts, metatarsal jobs, poverty, and greater disease activity were all pre-
pads placed proximal to the metatarsal heads on the dictors of early work disability. Race, sex, cumulative
inner sole of the shoe, or external metatarsal bars placed organ damage, and disease duration were not significant
proximal to the metatarsal heads. Commercially avail- predictors of work disability (24).
able inserts of high density polypropylene may be The Social Security Administration administers the
satisfactory for metatarsalgia and painful bony promi- uniform disability program throughout the United
nences. For persistent symptoms, referral to an orthotist States. There are two programs for which patients are
for a custom-made polypropylene insert or a molded eligible, Social Security Disability Insurance (SSDI) and
insert is indicated. The use of sandals and custom made Social Security Insurance (SSI). For SSDI, patients must
shoeware from molded impressions may permit patients meet the requirements of being disabled and having
to ambulate pain-free. Randomized control trials paid into the Social Security system for the required
support decreased pain with walking and stair climbing, amount of time, usually 40 quarters. For SSI eligibility,
and more minutes of pain-free walking with foot ortho- patients must be disabled and have reduced income, but
TABLE 36-4. SHOEWARE SPECIFICS.

DISEASE DEFORMITY PROBLEM SOLUTION(S)
RA/OA Hallux valgus with bunion formation Pain, inflammation Wide, soft, deep toebox; stretch medial leather
RA Cock-up toes Pain, redness, ulcers on dorsum Deep toebox; soft leather upper; stretch
of toes upper; donut pads; sandals
RA Valgus hindfoot Hindfoot pain Medial wedge; lace-up canvas ankle support;
anklehind foot orthosis
RA MTP subluxation with callosities Metatarsalgia Metatarsal bar; metatarsal pad; sole inserts
OA Hallux rigidus First MTP pain Metatarsal bar; rigid sole; rocker bottom sole
ABBREVIATIONS: MTP, metatarsal phalangeal; OA, osteoarthritis; RA, rheumatoid arthritis.

there is no work requirement. Under the Social Security heat treatment in an animal model of acute arthritis. Arch
system, disability is defined by law and essentially means Phys Med Rehab 1999;80:313317.
an inability to do any type of work regardless of previous 7. Robinson VA, Brosseau L, Casimiro L, et al. Thermo-
job or experience. The definition is inability to engage therapy for treating rheumatoid arthritis (Cochrane
Review). Cochrane Database Syst Rev 2006:1.
in any substantial gainful activity by reason of a medi-
8. Osiri M, Welch V, Brosseau, L, et al. Transcutaneous
cally determinable physical or mental impairment(s)
electrical nerve stimulation for knee osteoarthritis.
which can be expected to result in death or which has Cochrane Database Syst Rev 2000:CD002823.
lasted or can be expected to last for a continuous period 9. Hall J, Skevington SM, Maddison PJ, Chapman K. A
of not less than 12 months (27). randomized trial of hydrotherapy in rheumatoid arthritis.
Once the decision to apply for disability is made, it Arthritis Care Res 1996;9:206215.
is important that longitudinal evidence-based informa- 10. Verhagen AP, Bierma-Zeinstra SMA, Cardosa JR, de Bie
tion is provided to the Social Security office that dem- RA, Boers M, de Vet HC. Balneotherapy for rheumatoid
onstrates the impact of the illness on function and ability arthritis. Cochrane Database Syst Rev 2003:CD000518.
to work. To apply for disability under the Social Secu- 11. Veldhuizen JW, Verstappen FT, Vroemen JP, Kuipers H,
rity system, patients must complete an application at the Greep JM. Functional and morphological adaptations fol-
lowing four weeks of knee immobilization. Int J Sports
local district office. The application is then reviewed to
Med 1993;14:283287.
see whether the patient is eligible for disability. If they
12. Alexander GJ, Hortas C, Bacon PA. Bed rest, activity and
meet the requirements of disability, payment will be the inflammation of rheumatoid arthritis. Br J Rheumatol
granted. If they do not, then additional medical infor- 1983;22:134140.
mation will be requested from the patient and the physi- 13. Allen C, Glasziou P, Del Mar C. Bed rest: a potentially
cian. If needed, a consultative examination by a medical harmful treatment needing more careful evaluation.
or psychological expert will be requested and paid for Lancet 1999;354:12291233.
by the Social Security Administration. If disability is not 14. Ettinger WH Jr, Burns R, Messier SP, et al. A randomized
allowed, then appeal by the patient is permitted and a trial comparing aerobic exercise and resistive exercise
court hearing before an administrative law judge is held. with a health education program in older adults with knee
At that meeting, patients are queried about how the osteoarthritis. The Fitness Arthritis and Seniors Trial.
JAMA 1997;277:2531.
rheumatic disease affects their life and ability to work.
15. Van Baar ME, Assendelft WJJ, Dekker J, Oostendorp
Patients can present additional medical information and
RAB, Bijlsma JWJ. Effectiveness of exercise therapy in
have witnesses and a lawyer as their advocate to inter- patients with osteoarthritis of the hip or knee: a systematic
pret the legal aspects of disability. When disability is review of randomized clinical trials. Arthritis Rheum
granted, law determines payment made. In addition to 1999;42:13611369.
the monthly payment, patients on SSI are eligible for 16. Van den Ende CH, Vliet Vlieland TP, Munneke M, Hayes
Medicaid immediately and those on SSDI are eligible JM. Dynamic exercise therapy in rheumatoid arthritis: a
for Medicare after 2 years. systematic review. Br J Rheumatol 1998;37:677687.
17. Uhrin Z, Kuzis S, Ward MM. Exercise and changes in
health status in patients with ankylosing spondylitis. Arch
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pilot study on the effects of exercise in patients with sys-
1. World Health Organization (WHO). International classi- temic lupus erythematosus. Arthritis Care Res 2000;13:
fication of functioning, disability and health: ICF. Geneva: 262269.
WHO; 2001. 19. Egan M, Brosseau L, Farmer M, et al. Splints/orthoses in
2. Vliet Vlieland TP, Breedveld FC, Hazes JM. The two- the treatment of rheumatoid arthritis. Cochrane Database
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for active rheumatoid arthritis. Br J Rheumatol 1997;36: medially: a new treatment for osteoarthritis of the knee
8285. joint? BMJ 1994;308:753755.
3. Vliet Vlieland TP. Multidisciplinary team care and out- 21. Farrow SJ, Kingsley GH, Scott DL. Interventions for food
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5. Oosterveld FG, Rasker JJ. Treating arthritis with locally 23. Yelin E, Meenan R, Nevitt M, Epstein W. Work disability
in rheumatoid arthritis: effects of disease, social, and work
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applied heat or cold. Semin Arthritis Rheum 1994;24:
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Reduction of pain-related behaviors with either cold or for early work disability in systemic erythematosus: results
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CHAPTER 37
Psychosocial Factors in Arthritis

ALEX ZAUTRA, PHD
DENISE KRUSZEWSKI, MS
Psychosocial factors are essential to a patients Interventions that improve self-efficacy improve pain
vulnerability to the most important symptoms of and psychological functioning.
rheumatic diseases, including pain and fatigue. Social factors also affect impact of diseases, with
Positive and negative emotions influence adaptation social resources and the ability to utilize them being
to rheumatic diseases with depression predictive of a strong determinant of well-being among rheumatic
adverse outcomes. disease patients.
Cognitive factors, including a sense of control over
illness, are of great importance to daily well-being.
Psychosocial factors play an important role in the etiol- symptoms in rheumatoid arthritis (RA) patients directly
ogy and course of rheumatic diseases. In this chapter, following major stressful events, but increased symp-
we introduce concepts that may aid the reader in under- toms in weeks when small stressful events had occurred
standing the relationship. Psychosocial challenges and (1). One explanation for this finding is that major stress-
physiological mechanisms involved in rheumatic disease ful events may set into motion a physiological stress
manifestations may be best understood within the con- response in which some aspects of immune functioning
ceptual framework of stress and the individual response are suppressed. In contrast, minor stressful events may
to stress. It has become increasingly evident that psy- enhance other aspects of immune functioning. Specifi-
chosocial factors are essential to understanding who is cally, elevations in the immune-stimulating hormones
most affected by illness and other stressors, as well as prolactin and estradiol have been shown to mediate the
when they are most vulnerable. We end the chapter with association between interpersonal conflict and disease
a discussion of resilience, as it important to acknowl- flares in RA patients (2). Thus, stressful events may
edge the capacities of individuals to cope successfully induce higher levels of immune-related hormones,
with their illness. which results in increased disease activity.
Traumatic events, including both childhood mal-
treatment and adverse events later in life, have also
STRESS been linked with increased disease severity in rheumatic
disease patients. For example, one study showed that a
Stressors can be conceptualized as initiating events that higher fibromyalgia tender point count during a physi-
may be acute or chronic, small, or major and traumatic cal examination was associated with reports of child-
events, that occur from childhood through adulthood. hood maltreatment (3). Additionally, adult traumatic
According to the model initially proposed by Hans events can also impact disease severity. In a study of
Seyle, illness can be considered a stressor. Stress fibromyalgia patients, post-traumatic stress disorder
responses can be conceptualized as reactions to these (PTSD) symptoms were linked with increased pain
initiating events that may be measured both physiologi- severity (4). Traumatic stressors induce psychological
cally and psychologically. These stress responses vary symptoms of PTSD, which in turn are linked with
between individuals, and may comprise the mechanisms increased pain severity. Additionally, disruption in
underlying the link between stressors and arthritis. hypothalamicpituitaryadrenal (HPA) functioning has
The nature of a stress event may impact disease been suggested as the physiological link between trau-
course and severity in rheumatic disease patients. For matic events and disease severity. In fact both hypo- and
example, one study demonstrated a reduction in disease hypercortisol reactivity has been associated with
609
610 ALEX ZAUTRA AND DENISE KRUSZEWSKI
traumatic experiences (5) and dysregulation of cortisol extroversion. Neuroticism has been shown to increase
secretion has been linked with increased vulnerability vulnerability to stress and is linked to both pain and
to disease (6). Lower levels of cortisol may fail to check mood in RA patients, which suggests that this personal-
proinflammatory processes that are often elevated ity trait may impact both symptoms (12). On the other
during stress, resulting in joint swelling and tenderness hand, the personality dimension of extroversion may set
for RA patients and greater fatigue for those with fibro- the stage for positive emotional experience, even during
myalgia. These examples underscore the complexities stressful times.
involved in charting an association between events and Thus far, the discussion has focused on differences in
disease severity, particularly when that relationship is affective experience between individuals. However,
mediated by both physiological and psychological stress affective experience may also vary within the individual,
responses. However, while stressors and stress responses from day to day and even hour to hour, potentially ele-
may be factors in the experience of chronic pain, psy- vating risks for illness exacerbation during those times
chosocial factors also play a role in this experience. In when affective disturbance is greatest. These differ-
fact, individual differences in coping responses likely ences are important, addressing not who is most affected
play a prominent role in determining how health-related by stress, but when the person is most vulnerable. Fur-
outcomes are modified by stress. Coping factors may be thermore, when thinking about how individual affective
characterized as primarily affective, cognitive, or social, experience varies over time, it is important to examine
and we address each component below. positive as well as negative emotions because both con-
tribute to the quality of life and adaptive capacities of
rheumatic patients and do so in different ways.
Increased negative affect has been linked with
PSYCHOLOGICAL FACTORS increased pain, and also has been associated with greater
sensitization to pain (13). Negative affect has also been
Affective Components linked to stress directly (14). This suggests that negative
Researchers have characterized emotions as fluctuating affect may be both a part of the experience of pain itself
mood states and also as stable personality traits. Both as well as a response to stress in pain patients. Con-
positive and negative emotions have been shown to versely, positive affect may actually decrease vulnerabil-
influence adaptation among patients with rheumatic ity to stress in rheumatic patients. In fact, higher levels
disease. One of the most frequently researched affective of positive affect may be particularly important during
disorders in rheumatic disease patients is depression. stress and pain episodes. Thus, indirectly, higher levels
Hudson and colleagues (7) have proposed that rheu- of positive affect may prevent the pain sensitization
matic conditions such as fibromyalgia can be classified associated with rheumatic diseases.
among a spectrum of disorders that share affective dis- As yet, little attention has been directed to other
turbances, such as depression, fatigue, and allodynia. In affective components that may be linked to chronic
fact, depressive symptoms can be considered part of the pain. Further inquiry into high and low activation states
experience of chronic pain, rather than as a cause of the of both positive and negative affect may be fruitful.
disorder. Neuroimaging studies have identified differen- For example, anger, a high-activation negative affective
tial locations for the processing of the affective and state, may have different associations with stress and
sensory components of the pain experience (8). Studies pain than fatigue, a low-activation negative affective
have consistently demonstrated associations between state. This may also be the case for excitement, a high-
depression and pain severity in rheumatic disease activation positive affective state, versus calm, a low-
patients. RA patients exhibiting more depressive symp- activation positive affective state. Different emotional
toms reported higher average pain across weeks, states then may lead to the construction of different
increased pain during stressful weeks, and more affec- types of psychosocial interventions designed to promote
tive disturbance in response to pain episodes (9). Depres- one or another feeling state.
sion and stress were associated with inflammatory
markers in RA patients, suggesting that these factors
also increase disease activity (10). Therefore, depression
Cognitive Components
appears to be key a vulnerability factor for increased It is helpful to distinguish between affective and cogni-
pain and inflammation in patients with rheumatic dis- tive components of stress response, even though this
eases during times of stress. This vulnerability appears distinction is somewhat arbitrary. A useful way of con-
to extend beyond current depression, as recent studies ceptualizing cognitive stress responses is as dimensions
have shown that RA patients with a history of depres- of coping, in particular, an individuals sense of control
sion suffer from more episodes of daily pain (11). or lack thereof. Among these cognitive processes are
Other stable personality traits that are infused with self-efficacy, personal mastery, and pain catastrophiz-
affect have also been studied, such as neuroticism and ing. While not considered coping, attentional deploy-
C H A P T E R 3 7 P S Y C H O S O C I A L F A C T O R S I N A R T H R I T I S 61 1
ment is also a fundamental cognitive process that has memory (21). These deficits have also been demon-
implications for the experience of pain in rheumatic strated in individuals who have experienced trauma,
disease patients. particularly childhood maltreatment (22). Additionally, 37
The daily experience of rheumatic pain patients is just as pain may result in part from impaired attentional
fraught with uncertainty about when and how pain deployment, pain itself may serve to disrupt other atten-
symptoms may occur. This uncertainty renders the indi- tional processes (23).
viduals sense of control of great importance to both Although cognitive factors are usually studied pri-
daily well-being as well as the response to stress. Self- marily as modifiable processes that influence adaptation
efficacy is a key component that characterizes an indi- to chronic pain, it is important to acknowledge that
viduals control beliefs with respect to their illness. This there are also cognitive factors that exhibit moderate
concept has its origins in the work of Bandura, who levels of stability over time. Investigators have exam-
defined self-efficacy as a persons confidence in their ined factors such as internal locus of control, optimism,
ability to execute and accomplish a given task (15). The pessimism, and memory, to name a few. More research
development of the Arthritis Self-Efficacy Scale by is needed at this point on both stable as well as more
Lorig and colleagues has helped researchers to quantify malleable cognitive contributions.
this set of beliefs with respect to pain, function, and
other arthritis symptoms. High scores on this scale have
been linked with higher pain thresholds and tolerance SOCIAL FACTORS
for laboratory pain in arthritis patients (16). Interven-
tions aimed at increasing self-efficacy in rheumatic Social stressors are among the most challenging types
disease patients have led to improvements in pain and of stressors. While this is true for even for those without
psychological functioning (17). Thus, not only is self- illness, the consequences of social stress and associated
efficacy a vital component of well-being in rheumatic responses may be particularly salient for individuals
patients, evidence suggests that individuals may be with rheumatic conditions. Richer formulations take
taught to improve and enhance their cognitive beliefs into account different attachment styles as well as rami-
in this arena. Additionally, these beliefs translate into fications of lasting positive social interactions.
behaviors that define the daily experience of individu- Social pain is an emerging concept that focuses on
als. For example, a study of fibromyalgia patients the interplay between social relationships and physical
showed that self-efficacy was related to decreases in pain. Social pain is an emotional response to perceived
pain behaviors, including grimacing and vocalizations of exclusion from desired social relationships or perceived
distress (18). devaluation by significant members of an individuals
On the negative side, pain catastrophizing is charac- social network (24). Just as physical pain is adaptive
terized by beliefs in limited self-efficacy and control, because it signals a threat to well-being, social pain is
particularly with regard to the experience of pain. These adaptive because it motivates social connectedness.
beliefs have been associated with increased pain sever- Neuroimaging studies have shown that the emotional
ity, increased levels of pain behaviors, higher pain- component of physical pain and the experience of social
related disability, and greater health care utilization in exclusion activate the same areas in the anterior cin-
patients with a variety of rheumatic disorders (19). Neu- gulate cortex (ACC) (25). This has particular ramifica-
roimaging studies have further illuminated these find- tions for chronic pain patients, who may be subject to
ings by demonstrating links between pain catastrophizing social exclusion due to conflict with others, including
and activation in key areas of the brain associated with medical professionals, who do not understand their pain
anticipation of pain, emotional aspects of pain, atten- experience (24). This lack of understanding sometimes
tion to pain, and motor control (20). Pain catastrophiz- leads to feelings of stigmatization in rheumatic disease
ing has also been characterized by a heightened focus patients, which further adversely impacts both their
on pain, which points to the importance of attentional disease severity and their social relations. Opportunities
processes for chronic pain patients. for social connectedness begin in the initial years of life,
Heightened attention to pain is related to the basic during interactions with family and other caregivers. It
cognitive process of attentional deployment. Atten- is widely believed that early attachment relationships
tional deployment is defined as the capacity to selec- with caregivers impact the development of self-regula-
tively focus on, or more importantly in some cases, tion processes as well as interpersonal relationships. In
deflect attention away from stimuli. Deficits in this particular, theories of emotion socialization postulate
capacity have implications for rheumatic patients, that children learn to modulate their own emotions
including increased pain symptoms (19). Indeed, rheu- based on the response of their caregivers to their emo-
matic disease patients have demonstrated decreased tions (26). Therefore, stable attachment relationships
attentional functioning, including deficits in overall provide the template for effective management of emo-
attentional deployment, selective attention, and working tions. Conversely, unstable caregiving relationships lay
612 ALEX ZAUTRA AND DENISE KRUSZEWSKI
the groundwork for ineffective emotion regulation as psychosocial model of health and illness to rheumatic
well as difficulties forming enduring social relations. It conditions.
is important to note that the type of difficulties an indi-
vidual develops in these arenas may vary according to
the type, severity, and chronicity of the maltreatment.
Interestingly, studies have also demonstrated that many,
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complex than it may seem. Relationships often have 5. Cicchetti D, Rogosch FA. Diverse patterns of neuroendo-
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helpful, it is not enough. Instead, the characteristics of Abuse-related posttraumatic stress disorder and altera-
these resources and the ability to utilize these resources, tions of the hypothalamic-pituitary-adrenal axis in women
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318.
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7. Hudson JI, Mangweth B, Pope HG, et al. (2003). Family
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RESILIENCE 8. Rainville P, Duncan GH, Price DD, Carrier B, Bushnell
MC. Pain affect encoded in human anterior cingulate but
The framework of resilience provides a means of not somatosensory cortex. Science 1977;277:968971.
approaching the vulnerabilities and the resources of 9. Zautra AJ, Smith B. Depression and reactivity to stress
rheumatic disease patients in their adaptation to their in older women with rheumatoid arthritis and osteoarthri-
illness and other stressors. Resilience is characterized tis. Psychosom Med 2001;63:687696.
by the presence of psychological, social, and economic 10. Zautra AJ, Yocum DC, Villanueva I, et al. (2003). Immune
resources and the individuals ability to access and activation and depression in women with rheumatoid
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utilize these resources. Resilience connotes both the
11. Conner T, Tennen H, Zautra AJ, Affleck G, Armeli S,
ability to protect against the detrimental impact of stress Fifield J. Coping with chronic arthritis pain in daily life:
as well as to recover from stressful events. Most impor- within-person analyses reveal hidden vulnerability for the
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how children survive the most difficult childhoods, and the pain-mood relation in rheumatoid arthritis:
describes resilience as ordinary magic, involving insights from a prospective daily study. J Consult Clin
readily accessible human adaptational systems rather Psychol 1992;60:119126.
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true for rheumatic patients as well, many of whom adapt Scand J Psychol 2002;43:131137.
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source of resilience for women in chronic pain. J Counsel
ter difficulty, behavioral interventions may be most suc-
Clin Psychol 2005;73:212220.
cessful when assisting individuals in accessing resources 15. Keefe FJ, Smith SJ, Buffington ALH, Gibson J, Studts JL,
that they already have rather than focusing on deficits Caldwell DS. Recent advances and future directions in
in psychosocial functioning. the biopsychosocial assessment and treatment of arthritis.
Empirical studies continue to provide strong support J Consult Clin Psychol 2002;70:640655.
for research on psychosocial factors and stress to 16. Keefe FJ, Affleck G, Lefebvre JC, Starr K, Caldwell DS,
advance our understanding of the relevance of a bio- Tennen H. Coping strategies and coping efficacy in rheu-
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24. MacDonald G, Leary MR. Why does social exclusion
37
ing that health education for self-management in patients
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reducing health care costs. Arthritis Rheum 1993;36:439 Psychol Bull 2005;131:202223.
446. 25. Eisenberger NI, Lieberman MD, Williams KD. Does
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271291. opment. Am Psychol 2001;56:227238.
CHAPTER 38
Self-Management Strategies*
TERESA J. BRADY, PHD
Self-management activities, such as participation in Evidence suggests that very few people with arthritis
education programs and physical activity, are central participate in self-management education.
to the nonpharmacological management of arthritis
Self-management education, physical activity, and
weight loss have all demonstrated health benefits for
people with arthritis.
Self-management activities, such as participation in KEY SELF-MANAGEMENT

education programs and physical activity, are central
to the nonpharmacological management outlined in STRATEGIES
American College of Rheumatology guidelines for
arthritis management. Anything a person does to try to Self-Management EducationBuild
manage their arthritis could be considered self-manage- Arthritis Control Skills
ment, but the Institute of Medicine (IOM) definition of
The patient-oriented public health message build your
self-management focuses on essential tasks. The IOM
arthritis control skills highlights the importance of self-
defines self-management as the tasks that the individ-
management education. Not all patient education is
uals must undertake to live well with one or more
designed to foster self-management. Much of the tradi-
chronic conditions (1). While individuals with arthritis
tional patient education emphasizes providing informa-
try a variety of strategies to live well with their disease,
tion about the disease and its treatment, using verbal
scientific evidence supports only a limited number of
instruction supplemented by handouts and pamphlets.
key self-management activities. This chapter reviews
Self-management education is designed to build patients
the evidence base for the three self-management strate-
confidence and skills to manage their arthritis on a day-
gies with the broadest applicability: participating in
to-day basis; it is less didactic and uses interactive
self-management education, maintaining regular, mod-
methods to help patients develop the necessary skills.
erate intensity physical activity, and controlling weight.
A meta-analysis of arthritis education trials demon-
These three strategies also form the core public health
strated that education interventions that included
messages for disability prevention promoted by the
behavioral techniques produced significantly greater
Centers for Disease Control and Preventions arthritis
improvements in pain, function, and tender joint counts
program (see Table 38-1 for a summary of these strate-
than did information dissemination interventions (2).
gies). A fourth strategy, seeking early diagnosis and
Similarly, handouts or booklets may be useful adjuncts,
appropriate medical treatment if rheumatoid arthritis
but do not constitute self-management education on
is suspected, is of more targeted applicability, and will
their own. Several studies have demonstrated short-
not be addressed here. This chapter will conclude with
term (36 month) knowledge change, but no change in
recommendations for improving the effectiveness of
health status (1).
clinician counseling through the use of a brief behav-
Evidence-based self-management education can be
ioral counseling model to assist patients in practicing
provided individually or in small groups. The most prac-
self-management.
tical and economical way to provide self-management
education is through referral to education programs
such as the Arthritis Self-Management Program
*The findings and conclusions in this book chapter are those (ASMP), also known as the Arthritis Foundation Self
of the author and do not necessarily represent the views of Help Program, or the Chronic Disease Self Manage-
the Centers for Disease Control and Prevention. ment Program (CDSMP). Both ASHP and CDSMP are
614
C H A P T E R 3 8 S E L F - M A N A G E M E N T S T R A T E G I E S 6 15
TABLE 38-1. ARTHRITIS SELF-MANAGEMENT STRATEGIES/KEY PUBLIC HEALTH MESSAGES FOR DISABILITY
PREVENTION.
STRATEGY/MESSAGE RATIONALE RESOURCES
Self-management education/Build your Research documents increases in self-efficacy Arthritis Self Management Program (also
arthritis control skills and health behaviors (exercise, relaxation, known as the Arthritis Foundation Self
cognitive symptom management) improved Help Program) http://www.arthritis.
health outcomes (pain, disability, depression, org/events/ 38
helplessness), and reductions in health care Chronic Disease Self Management
costs (physician visits) (1) Program http://patienteducation.
stanford.edu
Physical activity/Be active Research demonstrates clinically meaningful Arthritis Foundation Exercise Program
improvements in function, flexibility, muscle http://www.arthritis.org/events/
strength and endurance, cardiovascular Arthritis Foundation Aquatic Program
fitness, and psychological status (6) http://www.arthritis.org/events/
EnhanceFitness http://projectenhance.org
Weight control/Control your weight Modest weight loss (1015 pounds) can Analysis of weight loss programs
alleviate symptoms and delay progression available at http://www.consumer.
of knee OA (13) gov/weightloss
6- to 7-week small group education programs led by Goeppinger concluded that CDSMP may be advanta-
trained lay and professional leaders following a struc- geous for patients with multiple comorbidities.
tured protocol. Both programs, developed by Lorig and Several forms of individually delivered self-manage-
colleagues, were designed to enhance participants con- ment education have been developed and evaluated,
fidence in their ability to manage their chronic disease, but are not in widespread use. Several computer-tai-
and to teach management skills such as problem solving, lored mailed education programs have shown signifi-
action planning, decision making, and communicating cant benefits in health status and reductions in physician
with health care professionals (1). visits. Weekly educational mailings supplemented by
The arthritis-specific program, ASMP, has been dis- telephone support have also demonstrated positive
seminated by the Arthritis Foundation since 1981 and changes in health status. Lorig and colleagues are now
is called the Arthritis Foundation Self Help Program. testing an Internet-based version of the ASMP and
Lorig and colleagues have demonstrated a 43% reduc- CDSMP (1).
tion in pain and a 19% reduction in physician visits at Meta-analytic reviews of arthritis self-management
4-year follow-up after participation in the ASMP. The education studies have consistently found small but sig-
generic chronic disease program, which was evaluated nificant short-term benefits from these types of pro-
among a mix of participants with arthritis, diabetes, grams. For example, a recent Cochrane Collaboration
heart disease, and lung disease, produced significant review of education in rheumatoid arthritis (RA) found
improvements in health distress and health care utiliza- that behavioral interventions such as ASMP produced
tion (physician and emergency-room visits) at 2-year small-to-moderate effect sizes that equated to 10% to
follow-up. Lorig and colleagues have also developed 12% improvements in patients global health assess-
Spanish-language versions of ASMP and CDSMP, ment, depression, and disability. In the same analyses,
which have similar benefits (1). information-only interventions, such as verbal instruc-
Comparisons of the relative efficacy of ASMP and tion or informational brochures, and social support/
CDSMP among people with arthritis have produced counseling interventions showed no significant benefits
equivocal results. A study by Lorig and colleagues (1).
found more beneficial effects from ASMP at 4-month Although self-management education studies have
follow-up but this difference was largely gone at 12 demonstrated significant benefits in health status and
months (3). In a similar study, Goeppinger and col- cost savings, the majority of people with arthritis have
leagues found significantly greater decreases in pain and not received self-management education. Only 11% of
disability at 4-month follow-up from CDSMP among the adults with arthritis responding to a 2003 national
their largely African-American participants (4). Both survey reported that they had attended an educational
investigators concluded that both CDSMP and ASMP course or class that taught them how to manage prob-
are beneficial for people with arthritis; Lorig concluded lems related to arthritis (5). Clinicians can foster partici-
that the disease-specific ASMP may be preferred while pation by making specific referrals to self-management
616 TERESA J. BRADY
education programs such as ASMP and CDSMP. The pursued physical activity among the general public, and
self-management support section below will discuss people with arthritis can easily tailor walking to their
strategies clinicians can use to facilitate patient partici- abilities and current conditioning level by altering their
pation in self-management education programs. distance or speed. The Arthritis Foundation publishes
a commercially available book, Walk with Ease, which
helps people with arthritis start a walking program.
Physical ActivityBe Active The Arthritis Foundation has developed two com-
Physical activity is a core self-management activity for munity programs that provide safe physical activity
people with arthritis, and be active is a core public options for people with arthritis: the land exercise
health message for both the general population and program called the Arthritis Foundation Exercise
people with arthritis. Although early treatment recom- Program and a water exercise program called the Arthri-
mendations cautioned patients with arthritis not to be tis Foundation Aquatic Program. Both programs are
active, a burgeoning body of research supports both small group exercise programs that meet two to three
professionally directed therapeutic exercise and self- times per week for flexibility and light endurance exer-
directed moderate physical activity. As summarized by cise. Although the current evaluation data are based on
Westby and Minor, there is consistent evidence that small, uncontrolled studies, preliminary results of both
people with arthritis can safely participate in moderate programs suggest both physical and psychological
physical activity, such as walking, stationary bicycling, benefits (8).
aerobic dance, aquatic exercise, and circuit training, Nonarthritis-specific physical activity programs
without aggravation of their disease. This kind of regular may also help people with arthritis. For example, the
moderate exercise can produce clinically meaningful EnhanceFitness program, developed by the University
improvements in function, flexibility, muscle strength of Washington, uses flexibility, strengthening, endur-
and endurance, cardiovascular fitness, and psychologi- ance, and balance exercises to increase health outcomes
cal status (6). among seniors, 60% of whom are assumed to have
In 2002 the American College of Rheumatology arthritis. EnhanceFitness has demonstrated significant
(ACR) convened a conference that developed recom- improvements in most SF-36 health assessment sub-
mendations for physical activity for people with osteo- scales, including a 35% improvement in physical
arthritis (OA) and RA; both sets of recommendations function (9).
included aerobic activity (30 minutes at least 3 days per Despite the small number of people with arthritis
week for OA; 3060 minutes 23 days per week for RA) who are meeting arthritis-specific activity recommenda-
and lower extremity strengthening programs (6). These tions, 55% of adults with arthritis reported in 2003 that
recommendations are slightly modified from the Ameri- a doctor or health professional suggested increasing
can College of Sports Medicine recommendations for physical activity to help joint symptoms (5). Although
general health based on the absence of any data on studies on the results of physician counseling on physi-
physical activity programs for people with arthritis more cal activity are equivocal, a review by the US Preventive
frequent than three times per week. Services Task Force concluded that multicomponent
In addition to the clear benefits physical activity can interventions that combined provider advice with
produce for people with arthritis, inactivity can increase behavioral interventions such as patient goal setting,
disabling factors such as fatigue, low endurance, loss written prescriptions, and mailed or telephone follow-
of strength and flexibility, and depression frequently up appeared most promising (10). The American
attributed to arthritis. Inactivity also increases risks for College of Preventive Medicine statement on physical
comorbid conditions such as cardiovascular disease, activity counseling also recommended use of the five
diabetes, and osteoporosis among people with arthritis. As model described below (11). Linking physician
However, 43% of people with self-reported arthritis say counseling interventions with community-based physi-
they get no leisure time physical activity, and only 32% cal activity programs may also enhance the effective-
are meeting the arthritis-specific recommendation of 30 ness of physician counseling (10).
minutes of moderate physical activity at least three
times per week (7). Weight ControlControl
Research has demonstrated benefits of both group
and home exercise programs (6). Arthritis-appropriate
Your Weight
exercise programs are available through local agencies Weight loss is well recognized as a primary prevention
such as Young Mens Christian Association facilities strategy for knee OA. Felson and colleagues found that
(YMCAs), health or fitness clubs, senior or community women who lost an average of 11 pounds decreased
centers, and parks and recreation departments. Some of their risk of knee OA by 50% (12). Obesity is also con-
these programs are disseminated and cosponsored by sistently associated with progression of OA. In a review
the Arthritis Foundation. Walking is the most widely of the relationship between weight and OA, Felson and
Chaisson concluded that a modest amount of weight tant role in providing self-management support, defined
loss (1015 pounds) is likely to alleviate symptoms and by the IOM as the systematic provision of education
delay disease progression in patients with knee OA and supportive interventions by health care staff to
(13). More recently, Messier and colleagues demon- increase patients skill and confidence in managing their
strated that each pound of weight lost resulted in a health problems (1). Routine clinical practice does not
fourfold reduction in loading forces on the knee per afford the luxury of extended time to provide sophisti-
step taken (14). cated behavioral interventions, but simple behavioral
The Arthritis, Diet, and Activity Promotion Trial counseling techniques can enhance the effectiveness of 38
(ADAPT) demonstrated that a combined diet and exer- provider counseling or physician advice. The five As
cise intervention was effective in improving self-reported model, originally developed to guide smoking cessa-
pain and function, and physical performance measures tion, has been applied to self-management strategies
in moderately overweight to obese adults with knee such as physical activity and weight loss counseling and
OA. Participants in the combination arm of the trial lost can be a useful organizing framework to guide self-
more weight (5.7% of body weight) and achieved greater management support (1820).
health improvements (24% improvement in function,
30% decrease in knee pain) than the exercise-alone or
diet-alone participants (15). The Five As Model
The ADAPT study used structured diet and exercise The five As model is a pragmatic sequence of steps to
programs, but some commercial and mutual-support guide the development of realistic plans for self-man-
diet programs may also be effective. Although not spe- agement. Each of the five As outlines a specific task the
cific to arthritis, community-based programs such as clinician needs to accomplish regardless of which self-
Weight Watchers combine diet modification with physi- management activity is being promoted. The five As,
cal activity and have a reasonable track record for as described by Glasgow and others, are summarized
weight loss. In a large, multisite, controlled trial, Weight below (19).
Watchers produced a mean weight loss of approximately
5%. In a systematic review of commercial weight loss
programs, Tsai and Wadden concluded that although Assess
the evidence base is suboptimal, the health conse-
Assess current behaviors and beliefs, such as current
quences of the obesity epidemic necessitate attention to
physical activity level, participation in self-management
weight issues and referrals to commercial and self-help
education programs, or perceived importance of weight
programs such as Weight Watchers, TOPS, and Over-
loss. When helping patients develop an action plan for
eaters Anonymous (16).
the proposed self-management activity it is also impor-
However, the majority of overweight or obese
tant to assess their confidence in their ability to attend
patients with arthritis do not receive professional advice
class, be physically active, or lose weight, and their
to lose weight. In a 2003 survey, only 37% of the over-
intention to do so.
weight and obese respondents with arthritis reported
that a physician or health professional suggested losing
weight to help their joint symptoms (5). Mehrotra and Advise
colleagues found that receiving professional advice was
the strongest predictor of weight loss attempts; obese Offer clear, specific, personalized advice such as the
patients who received professional advice to lose weight need to lose weight or be more physically active, the
were three times more likely to attempt to lose weight benefits of increasing activity or attending an education
than those who did not (17). The five As brief counsel- class, and the risk of not making the recommended
ing model described below has been applied to weight change.
loss counseling and the Partnership for Healthy Weight
Management website provides information clinicians
can use to evaluate weight loss programs (http://www.
Agree
consumer.gov/weightloss; 18). Using collaborative goal setting, negotiate a mutually
agreeable, specific, and achievable action plan for
change. Realistic self-management action plans need to
PROVIDING SELF-MANAGEMENT focus on patients own goals, talking into account their
SUPPORT IN CLINICAL PRACTICE values, priorities, and confidence in their ability to
change. A clinician may see weight loss as the most
Self-management activities need to be, by their very important goal, but the person with arthritis may see
nature, carried out by arthritis patients themselves. increasing physical activity as a more feasible first step.
However, physicians and other clinicians play an impor- Written action plans facilitate success.
618 TERESA J. BRADY
Assist REFERENCES
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weight loss have all demonstrated health benefits
12. Felson DT, Lawrence RC, Dieppe PA, et al. Osteoarthri-
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ACR guidelines for arthritis management and the Intern Med 2000;133:635646.
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gests that very few people with arthritis attend self- Rheumatol 1997;11:671681.
management education programs. Even though the 14. Messier SP, Gutekunst DJ, Davis C, et al. Weight loss
majority of people with arthritis are not sufficiently reduces knee-joint load in overweight and obese older
physically active, more than half of them report re- adults with osteoarthritis. Arthritis Rheum 2005;52:2026
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dietary weight loss in overweight and obese older adults
are overweight or obese (5), just over a third of
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38
CHAPTER 39
Pain Management
JOHN B. WINFIELD, MD
Patients suffering with chronic diffuse pain who lack factors that can convert what should be a self-
objective clinical and laboratory findings (e.g., limited acute pain condition into a chronic pain
fibromyalgia) frequently are dismissed as not having syndrome.
real pain, which only perpetuates their illness. If the clinician suspects fibromyalgia, validation of the
There are four principal categories of pain: nocicep- patients pain is important.
tive pain, neuropathic pain, chronic pain of complex Pharmacologic agents that may be useful in the
etiology, and psychogenic pain. management of individual pain syndromes include
Pain assessment should include attention to possible nonsteroidal anti-inflammatory drugs, opioids, muscle
psychological and sociocultural factors that could be relaxants, antidepressants, antiepileptic medications,
contributing to the pain experience. and topical agents.
Diagnostic waffling, the ordering of frightening Physical therapy, cognitivebehavioral therapy,
tests, excessive use of physical therapy modalities, aerobic exercise, and complementary and alternative
activity limitation after minor trauma, and medicine approaches may all be useful in the
overly liberal work release are among the important management of pain in selected patients.
All too often in office-based practice, treatment of pain In addition to strictly sensory discriminative elements
is secondary to diagnosis and treatment of the disease of nociception and afferent input from somatic reflexes,
state. This is unfortunate because pain, especially there are major contributions from pathways and
chronic pain, is among the most disabling and costly regions of the brain concerned with emotional, motiva-
medical problems in Western countries (1). Patients suf- tional, and cognitive aspects of pain. These factors influ-
fering with chronic diffuse pain who lack objective clini- ence the subjective unpleasantness and distress
cal and laboratory findings (e.g., fibromyalgia) frequently associated with pain. The two principal effectors of the
are dismissed as not having real pain, which only stress response, the hypothalamicpituitaryadrenocor-
perpetuates their illness. Presence of pain should be tical axis and the sympathetic nervous system, are also
specifically sought and evaluated in all patients and, if activated. The stress response may become maladaptive
present, relief of pain should be a primary focus of the in chronic pain syndromes such as fibromyalgia. Nega-
physicians efforts. Indeed, pain should be addressed as tive emotions (depression and anxiety), other negative
a disease entity, not as a sensory entity (2). psychological factors (loss of control, unpredictability in
ones environment), and certain cognitive aspects (neg-
ative beliefs and attributions, catastrophizing) all can
NATURE OF PAIN function as stressors with actions in these systems.
A useful definition adopted by the International Asso-

ciation for the Study of Pain (IASP) defines pain as an
Pain Categories
unpleasant sensory and emotional experience associ- There are four principal categories of pain: nociceptive
ated with actual or potential tissue damage, or described pain, neuropathic pain, chronic pain of complex etiol-
in terms of such damage (3). Neurophysiologically, ogy, and psychogenic pain. Nociceptive pain is due to
pain is a complex sensationperception interaction stimulation of peripheral pain receptors on thinly
involving the simultaneous processing of nociceptive myelinated A delta and/or unmyelinated (C) afferents
input from the spinal cord. This input activates a central during inflammation or injury of tissues. The pain expe-
network that records the pain experience in multiple rienced generally matches the noxious stimulus.
regions of the brain (Figure 39-1). However, both peripheral sensitization (reduction in
620
C H A P T E R 3 9 P A I N M A N A G E M E N T 62 1
What is Pain? Parallel Processing (persistence after the stimulus has ended, spreading or
worsening in crescendo fashion with repeated touch-
ing). Central sensitization and ectopic firing of periph-
Emotional/Motivational
eral neurons, either spontaneously or through mechanical
forces developed during movement, contribute to this
Spinal inputs
Autonomic peculiar type of pain. Management may require special
pharmacologic approaches, as discussed below.
Chronic pain of complex etiology occurs in fibromy-
Discriminative algia and a large number of substantially overlapping
regional pain syndromes, such as migraine headache,
temporomandibular disorders, irritable bowel syn-
Motor/reflex
drome, and atypical chest pain. In practice, the diagnos- 39
tic label applied to illness in a given patient often
FIGURE 39-1 depends on which medical specialist evaluates the
patient first, for example, a rheumatologist might diag-
Pain signals from peripheral sites of tissue injury or inflamma- nose fibromyalgia, whereas a gastroenterologist would
tion are transmitted simultaneously to multiple areas of the
brain through parallel processing. The pain experience derives
diagnose irritable bowel syndrome. Previously termed
from the combined input of these multiple brain areas. For functional pain syndromes on the basis of absent struc-
example, a cognitive brain area gives meaning to the pain, tural pathology, these illnesses share very close relation-
which could be trivial (indigestion after eating a pizza) or very ships in terms of etiology and pathophysiology. Recent
frightening (same epigastic pain input from the periphery, but advances in the understanding of the psychophysiologic/
unprovoked in a person recently diagnosed with stomach
cancer). The latter pain experience would be much more
neurophysiologic dysregulation in such illnesses is
distressing. Similarly, if a person is depressed, contributions from impelling a unifying reclassification as central sensitivity
affective/motivational areas of the brain make the pain more syndromes (4).
distressing. (Courtesy of Alan R. Light, PhD.) Collectively, central sensitivity syndromes constitute
huge personal and societal burdens, but all too fre-
quently such illnesses are not approached effectively by
the threshold of nociceptor endings) and central sensi- traditional medicine. In fibromyalgia, the prototype of
tization [amplification of pain in the central nervous this category, pain radiates diffusely from the axial skel-
system (CNS)] can occur in normal nociceptive pain. eton over large areas of the body, involving muscles
These peripheral and central inputs may result in allo- predominately. The patient describes the symptoms
dynia (an alteration in pain perception such that nor- as exhausting, miserable, or unbearable. Altered
mally nonpainful stimuli, such as gentle touching, are central nociceptive processing results in a decrease in
perceived as painful) and hyperalgesia (increased pain the pain perception threshold and in the threshold for
response to a previously painful stimulus). In addition pain tolerance. The hallmarks of fibromyalgiachronic
to systemic inflammatory or degenerative rheumatic widespread pain, fatigue, and multiple somatic symp-
diseases, nociceptive pain occurs as regional musculo- tomshave both psychological and biological bases
skeletal pain in tenosynovitis, compressive neuropa- that derive, at least in part, from chronic stress and dis-
thies, nerve entrapment syndromes, bursitis, and various tress. Female gender, genes (5), adverse experiences
localized forms of arthritis. Usually self-limited with during childhood, psychological vulnerability to stress,
conventional treatment strategies, regional musculo- and a stressful, often frightening environment and
skeletal pain may become chronic and disabling. culture are important antecedents. Thus, fibromyalgia
Both peripheral and central nervous system pro- and related syndromes should be viewed from a bio-
cesses also play a role in neuropathic pain, which may psychosocial perspective (6). A useful guideline for the
follow injuries and diseases that directly affect the management of fibromyalgia syndrome pain in adults
nervous system. There are three common types: periph- and children has been published recently (7).
eral neuropathic pain (e.g., postherpetic neuralgia, More purely psychogenic pain is seen in somatoform
painful diabetic neuropathy, vasculitic neuropathy, and somatization disorders and hysteria.
radiculopathic pain due to injury to spinal nerve roots);
central neuropathic pain (e.g., central poststroke pain,
spinal cord injury pain); and cancer-associated neuro-
pathic pain. Complex regional pain syndrome (reflex
MANAGEMENT OF PAIN
sympathetic dystrophy; RSD) is another neuropathic
pain syndrome. Neuropathic pain may be paroxysmal,
General Approach
perceived as electric shocklike discomfort or burning. The first element in management of pain is accurate
Neuropathic pain may be associated with hyperpathia assessment and diagnosis of the cause of the pain.
622 JOHN B. WINFIELD
Assessment should include attention to possible psy- iors such as guarding, rubbing, grimacing, and sighing
chological and sociocultural factors that could be con- vary inversely with patients self-efficacy for control of
tributing to the pain experience. In addition, the chronic pain. A simple self-report form that incorpo-
physician should be aware that fibromyalgia frequently rates validated scales for physical and psychological
coexists with inflammatory disorders, such as rheuma- health status [the modified Health Assessment Ques-
toid arthritis (RA) and systemic lupus erythematosus tionnaire (HAQ)], visual analog scales for pain, fatigue,
(SLE). Diagnostic waffling, the ordering of frighten- patient global self-assessment, a checklist of current
ing tests, excessive use of physical therapy modalities symptoms, and scales for helplessness and cognitive
and activity limitation after minor trauma, and overly performance can be completed in just a few minutes
liberal work release are among the important factors (9). Easily adaptable to a busy practice, such informa-
that can convert what should be a self-limited acute pain tion is invaluable for the psychosocial assessment of
condition into a chronic pain syndrome. If one suspects pain and in monitoring response to therapy. Marital
fibromyalgia, validation of the patients pain is impor- adjustment, perceived levels of social support, and
tant. Comments such as its all in your mind serve current stressors in the patients life are important
only to perpetuate illness. To the patient, the pain is topics for evaluation. The simple inquiry how was
real. On the other hand, it is important to be aware of your childhood? often reveals adverse childhood
confounders to recovery, such as pending litigation or experiences, such as abuse, that have increased the
compensation claims. patients vulnerability to chronic pain (10). In multidis-
For acute nociceptive pain (< 30 days duration), ciplinary settings, information obtained from the Min-
pharmacological interventions should follow a stepwise nesota Multiphasic Personality Inventory (MMPI), the
approach using non-opioid and opioid analgesics either Social Support Questionnaire (SSQ), the Sickness
singly or in combination, as indicated by pain intensity. Impact Profile (SIP), and the Multidimensional Pain
Depending on the specific musculoskeletal disorder, ini- Inventory (MPI) is useful for more comprehensive
tially conservative combinations of corticosteroid injec- assessments. Subgroups of patients with chronic pain
tions, activity modification, splints, counterforce bracing, can be identified in this way that can predict response
local heat or cold, and in some cases, surgical proce- to interdisciplinary therapeutic interventions (11).
dures may be indicated for pain relief and/or to preserve
function. Education about the nature of the underlying
problem, limitations, and prognosis should err on the Pharmacological Management
side of optimism. Whenever possible, rapid return to of Pain
full activity and work is best.
If there is a significant nociceptive pain element, A useful stepwise approach for pharmacological inter-
chronic pain (>6 months duration) may be managed ventions based on nociceptive pain intensity [e.g., in
pharmacologically with analgesics using the same step- osteoarthritis (OA)] is illustrated in Figure 39-2. Low-
wise approach outlined for acute pain. Especially impor- dose opioids for patients with OA who fail acetamino-
tant is a multifaceted treatment plan that incorporates phen + nonsteriodal anti-inflammatory drugs (NSAIDs)
various adjuvant medicines, exercise, and psychological or a cyclooxygenase-2 (COX-2) inhibitor are effective
and behavioral approaches to reduce distress and when used as part of a multimodal approach to pain
promote self-efficacy and self-management. For many control, and also may have fewer potentially life-threat-
regional chronic pain syndromes, referral to an experi- ening complications (12). Reasonable guidelines for use
enced specialist who advocates holistic, nonsurgical of opioids in more severe musculoskeletal pain are the
approaches is recommended. exclusion of patients with histories of substance abuse,
concomitant attention to psychological and social per-
petuators of pain, use of an opioid treatment contract,
Assessment of Pain a one physician/one dispensing pharmacy rule, and
Assessment of pain in the physicians office should be close monitoring. Drug-seeking behavior (pseudoaddic-
based on a biopsychosocial perspective, that is, in addition) may indicate that pain is not being controlled
tion to identification of biological variables that con- adequately.
tribute to pain, the recognition that psychological and
sociocultural factors potentially amplify or perpetuate
Opioid Analgesic Drugs
the pain experience (see Ref. 8 for a full discussion).
Pain intensity should be measured with either a verbal Opioids bind to mu, kappa, or delta opioid receptors
or numerical rating scale or a visual analog scale. In (predominately mu for analgesic effects) in regions of
fibromyalgia, the author finds it useful to determine the brain involved in integrating pain and to pre- and
pain detection threshold (normal = 4 kg/cm2) at several postsynaptic terminals of peripheral sensory fibers,
tender point sites by pressure algometry. Pain behav- where they inhibit release of substance P and other
Severe frequent re-evaluation for efficacy and side effects

SR-Oxycodone, SR-Morphine, during initiation, titration, dose changes, and mainte-
Morphine, Hydromorphone, Step 3 nance therapy.
Transdermal Fentanyl
Pain Intensity
Muscle Relaxants
Codeine, Oxycodone Centrally acting skeletal muscle relaxants, for example,
Propoxyphene, Tramadol
Step 2
carisprodol (Soma), cyclobenzaprine (Flexeril), metax-
olone (Skelaxin), methocarbamol (Robaxin, Robaxi-
Topical Capsaicin sol), tizanidine (Zanaflex), and baclofen (Lioresal,
NSAIDs/COX-2 Inhibitors Step 1 Kemstro) to list a few, have modest benefit as adjunc-
Acetominophen tive therapy for nociceptive pain associated with muscle
Mild
strains. Used intermittently, or as a single bedtime dose 39
FIGURE 39-2 (e.g., 10 mg cyclobenzaprine), they have limited effec-
tiveness in fibromyalgia and other chronic pain syn-
Stepwise approach to pharmacologic management of pain.
dromes, as well. Sedation and other CNS side effects
occur frequently. Abuse may occur, particularly with
carisprodol, and abrupt cessation may be associated
mediators. Tramadol also inhibits reuptake of norepi-
with withdrawal symptoms.
nephrine and serotonin. Table 39-1 lists opioids com-
monly in use. The side effects of opioids include
Antidepressants
constipation, nausea and vomiting, sedation, cognitive
impairment, miosis, myoclonus, urinary retention, and Tricyclic antidepressants (TCAs) clearly are effective
respiratory depression. Older persons are more sensi- in neuropathic pain and may be of modest short-term
tive to opioids with respect to both efficacy for pain benefit in diffuse and regional chronic pain syndromes,
relief and vulnerability to side effects; starting doses but side effects (dry mouth, drowsiness, and weight
should be reduced 25% to 50%. In the great majority gain) limit patient acceptance. Selective serotonin
of patients with well-defined chronic rheumatic disease reuptake inhibitors (SSRIs), for example, fluoxetine
pain, opioids are effective, safe, and well tolerated. (Prozac, 1040 mg daily) or citalopram (Celexa, 20
Several weeks or months are required to titrate opioid 40 mg daily) have been shown to have limited efficacy
therapy in the outpatient setting. During opioid tapers, in randomized, controlled trials in fibromyalgia; the
which require 2 to 3 weeks, clonidine (0.20.4 mg/day) combination of a TCA with an SSRI in this disorder
is helpful in controlling withdrawal symptoms. Monitor- typically produces greater improvement in pain, sleep,
ing of patients taking analgesic medications requires and overall well-being than either drug used alone.
TABLE 39-1. OPIOID ANALGESIC DRUGS.

ORAL
DRUGS EQUIVALENT STARTING DOSE COMMENT
Short-acting
Morphine sulfate (Roxanol) 30 mg 1530 mg every 4 hours For all, start low and titrate; begin bowel program
early; most of these opioids are available in
combination with acetaminophen or aspirin (do
not exceed maximum dose). For all, short-acting
opioid often is needed for breakthrough pain.
Codeine (Fiornal) 120 mg 3060 mg every 46 hours
Hydrocodone (Lortab) 30 mg 510 mg every 34 hours
Oxycodone (Percodan) 2030 mg 510 mg every 34 hours
Hydromorphone (Dilaudid) 7.5 mg 1.5 mg every 34 hours
Propoxyphene (Darvon) 100 mg 100 mg every 4 hours
Tramadol (Ultram) 120 mg 50100 mg every 6 hours
Methadone (Dolophine) 1560 mg every 8 hours
Long-acting
SR-Morphine (MS Contin) 30 mg 510 mg every 34 hours
SR-Oxycodone (Oxycontin) 2030 mg 1020 mg every 12 hours
Transdermal fentanyl (Duragesic) Not available See package insert
Dual-action (serotonin/noradrenaline) reuptake inhibi- Pharmacologic Management

tors (SNRIs) such as venlafaxine (Effexor, 150225 mg
daily or duloxetine (Cymbalta, 3060 mg daily) (13) are
of Fibromyalgia
superior to SSRIs for pain control and improve many Low-dose amitriptyline at bedtime, perhaps in combi-
symptoms in fibromyalgia irrespective of comorbid nation with cyclobenzaprine (Flexeril), is a well-
depression. When concomitant depression is present in established therapy for fibromyalgia and related
a chronic pain syndrome, it is essential that depression chronic pain syndromes. SNRIs in combination with
be treated aggressively. SSRIs and SNRIs must be gabapentin (Neurontin) or pregabalin (Lyrica) are very
tapered gradually upon discontinuation. Following the useful in patients with severe allodynia and hyperalge-
institution of therapy, patients should be observed for sia. Corticosteroids and NSAIDs are of no benefit in
worsening of depression and the emergence of suicidal fibromyalgia pain per se, but are useful treatments for
thoughts. coexisting inflammatory processes (pain generators).
Opioids should be avoided if at all possible for fibromy-
algia pain. However, certain patients with extreme pain
Antiepileptic Drugs
unresponsive to other agents will require opioids to
Carbamazepine (Tegretol) and a series of other new improve quality of life and maintain function. If used,
antiepileptic drugs have become first-line agents for opioids should be combined with multidisciplinary
neuropathic pain (14). Gabapentin (Neurontin, 900 approaches, psychotherapeutic interventions, and the
1800 mg daily in three divided doses), a 3-alkylated cautions mentioned above.
gamma-amino butyric acid (GABA) analog originally Pharmacological and nonpharmacological treat-
introduced as an anticonvulsant and more recently ment of poor sleep is crucial for improving overall
released pregabalin (Lyrica, 150425 mg daily in divided sense of well-being. Sleep disturbances should be
doses) (15) are useful in chronic pain states, including managed aggressively, beginning with instruction in
fibromyalgia, related syndromes, and various types of the elements of good sleep hygiene, such as avoidance
neuropathic pain. These agents may ameliorate associ- of daytime naps and caffeine. Most patients require
ated depressed mood and anxiety, as well. The dose of medication, and many nonbenzodiazepine hypnotics,
these agents should be escalated slowly over weeks; for example, zolpidem (Ambien), zaleplon (Sonata,
discontinuance of these agents should likewise be done 1-hour half-life, useful with mid-sleep awakenings),
gradually. or eszopiclone (Lunesta) are now available in addition
to traditional hypnotics. Oxybate (Xyrem) also is
very promising. A formal sleep assessment may be
Topical Agents
required for patients who do not respond to the above
Obtained from red chili peppers, topical capsaicin measures.
binds to vanilloid receptors on peripheral terminals of Fatigue, often a dominant complaint in fibromyalgia,
nociceptive neurons, thereby inhibiting activation of generally improves with effective treatment of pain,
the pain pathway by noxious stimuli. Essentially free depression, and sleep disturbances in combination with
of toxicity other than mild burning at the site of appli- a graded aerobic exercise program. Modafinil (Provigil,
cation, capsaicin is useful as adjunctive therapy in 100200 mg q.a.m.) is beneficial in patients for whom
diffuse and regional musculoskeletal pain syndromes, overwhelming fatigue is a persistent complaint, and may
joint pain in arthritis, and in neuropathic pain disor- be useful as a bridge therapy during the early phase of
ders. Up to three 5% lidocaine patches (Lidoderm) an aerobic exercise program.
may be applied to localized painful areas for 12 to 18
hours in a 24-hour period with good efficacy and
safety.
Psychological and
Other Pharmacological Agents Behavioral Approaches
Anxiolytics, for example, clonazepam (Klonopin), The importance of strategies in this area has been
lorazepam (Ativan), temazepam (Restoril), alprazolam emphasized recently (8,16). Depression, anxiety, stress,
(Xanax), and buspirone (Buspar) have antinociceptive sleep disturbance, pain beliefs and coping strategies,
effects in chronic pain and are often used in combina- and self-efficacy all are central to the pain experience
tion with antidepressants and antiepileptic drugs. Prami- in many patients, and frequently determine the outcome
pexole (Mirapex, dopamine 3 receptor agonist) has of chronic pain. Unless psychosocial and behavioral
been shown to improve pain scores, fatigue, and func- variables are recognized and approached, strictly phar-
tion in patients requiring opioids for pain control. macological interventions to reduce nociceptive pain
from inflammation or the diffuse pain in fibromyalgia Heat and Cold

and related syndromes are of limited benefit. Estab-
lished behavioral treatments in RA and OA that Heat (hot packs, paraffin, hydrotherapy in its many
improve ratings of pain or pain behavior are the Arthri- forms) is of proven benefit in nociceptive pain, espe-
tis Self-Management Program (17) and cognitive cially when combined with exercise (range of motion,
behavioral therapy (cognitivebehavioral therapy stretching, strengthening). Diffuse and regional pain is
includes components for education, training in relax- improved by such strategies as sauna, hot baths and
ation and coping skills, rehearsals of the skills learned, showers, and hot mud. While not superior to superficial
and relapse prevention). Self-care education and tele- heat, cold (cold packs, immersion, or vapocoolant
phone counseling are probably efficacious in OA, but sprays) may provide more immediate analgesic benefit,
have not been studied in RA. The role of cognitive particularly when applied soon after an injury.
behavioral therapy for the diffuse pain of fibromyalgia 39
and related regional pain syndromes remains to be
Massage, Trigger Point Injections,
clarified.
Acupuncture, and Transcutaneous
Electrical Nerve Stimulation
Physical Therapy/ Gentle massage is well received by patients with diffuse
Physical Modalities pain syndromes, but as a totally passive modality it fails
to promote self-efficacy for control of pain. Injection of
The objectives here are to diminish pain, improve func- trigger points is of short-term benefit only and should
tion, minimize disability, and promote self-efficacy. generally be avoided. Neurophysiologic effects of acu-
Although certain strategies and modalities are clearly puncture and electroacupuncture include release of
beneficial, this area needs properly designed trials to opioids and other mediators in the nervous system.
establish efficacy. Several randomized, controlled trials have shown acu-
puncture to improve subjective pain and to raise pain
thresholds, but its long-term benefit in chronic pain syn-
Exercise dromes remains unclear. An advantage of transcutane-
ous electrical nerve stimulation (TENS) for localized
In addition to positive effects on underlying pathologi- musculoskeletal pain is that the patient can apply this
cal processes in bones, joints, and muscles, exercise is modality at home.
essential to the treatment of fibromyalgia and related
chronic pain syndromes. The benefits of exercise, in
addition to gains in cardiovascular fitness, muscle tone, Complementary and Alternative
and strength, include improvements in both subjective
and objective measures of pain and in the overall sense
Medicine
of well-being. Many patients with chronic pain perceive The immense popularity of complementary and alterna-
their muscles to be weak and easily fatigued, and bear tive medicine (CAM) today contrasts with the current
the negative belief (fear) that activity will exacerbate paucity of data regarding the biochemical nature and
their condition. Consequently, exercise is avoided and mechanism of action of most alternative remedies and
their muscles become deconditioned. Normal activities the lack of rigorous studies addressing efficacy, safety,
become challenging. Excessive activity on a good day and cost-effectiveness of these strategies. Many physi-
induces a major flare of pain and fatigue, possibly due, cians lack knowledge in this area and may be overtly
in part, to the peripheral and central effects of proin- hostile toward CAM. Consequently, patients are reluc-
flammatory cytokines (tumor necrosis factor, interleu- tant to inform their physicians about CAM they are
kins 1 and 6) released in response to exercise-damaged using for self-management. This can be dangerous
myofibers. Ideally, exercise should be low-impact because of unsuspected drug interactions. Patients with
(walking, water aerobics, stationary bicycle, rather than chronic pain and fatigue, for example, fibromyalgia, are
running), beginning very gently and progressing gradu- the largest users of CAM, often because of frustration
ally to endurance and strength training. Encouragement with the inefficacy of traditional medicine and lack of
and positive reinforcement can reduce the virtually uni- empathy and understanding on the part of many physi-
versal problem of poor compliance. Obesity, poor cians. Until neuroscience, behavioral science, and health
posture, and overloading activities at work and home care systems advance to such a point that effective bio-
also contribute to muscle pain and fatigue and should psychosocial treatment strategies are applied in most
be addressed. Daily stretching exercises after hot patients with chronic pain, CAM approaches will
showers are very helpful. continue to proliferate. In the meantime, a practical
approach is to inquire about CAM usage, refrain from in combination with celecoxib (Celebrex) is useful. The
expression of negative opinions if a particular CAM use of opioids for moderate or severe pain is appropri-
treatment is relatively inexpensive and appears to be ate, but dosing should follow the start low, go slow
safe, and to encourage whatever works in the context maxim. The health care provider must be aware of eco-
of the power of the placebo effect and the promotion nomic barriers that some elderly patients confront in
of self-efficacy for control of pain. obtaining medications. Nonpharmacologic treatment of
pain in older persons should be an integral part of care
plans.
Pain in Children
Except for children less than 1 year of age, the approach Procedure-Based Pain Management
to the management of pain in children is similar to that
Injection of local anesthetics, epidural techniques, and
in adults. Issues meriting particular attention include
radiofrequency ablation procedures all have a place in
the young childs inability to report pain and fear (e.g.,
certain cases, but not infrequently are used inappropri-
of doctors and needles), age-related pharmacological
ately in anesthesia pain clinics. Furthermore, risk
factors, and psychosocial variables that differ from
benefit and long-term efficacy of such approaches in
those in adults (e.g., school absenteeism). Although
chronic diffuse pain have not been fully established.
clinically significant pain often is not fully recognized
and treated, recurrent complaints of pain all over the
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CHAPTER 40
Therapeutic Injections of Joints

and Soft Tissues
JUAN J. CANOSO, MD, FACP, MACR
Successful needle placement for joint and soft tissue Joint or soft tissue injections with corticosteroids
aspiration and injection requires clear understanding may be beneficial for short- and long-term
of anatomy. treatment.
Aspiration of joint and soft tissue fluids may be
important for diagnosis and treatment.
Therapeutic injections used in rheumatology include Efficacy. Table 40-1 lists conditions in which cortico-
the articular, tenosynovial, and soft tissue injection of steroid infiltrations have been used. A long-term
corticosteroids esters and the articular injection of hyal- favorable response can be predicted in some. In others
uronate and radioactive colloids. While the latter is con- a steroid infiltration is a short-lived palliative. Finally,
troversial, corticosteroids and hyaluronate injections some conditions are refractory to this form of therapy.
are in widespread use and will be discussed here. Therapeutic trials based on US-guided injections
should help define the real utility of corticosteroid
infiltrations wherever controversy remains.
CORTICOSTEROID INJECTIONS Steroid preparations. The more soluble steroid esters,
such as methylprednisolone acetate, triamcinolone
Certain experience-derived criteria should guide these acetonide, and betametasone phosphate, have a
injections: (1) a prompt local improvement is desired; weaker local action. On the other hand, triamcino-
(2) evidence of efficacy is available; (3) alternative lone hexacetonide, a barely soluble agent, has the
treatment methods have been discussed with the patient; greatest potency (29) and should be reserved for
(4) local damage inflicted by the injected steroid is deep structures such as the elbow, the shoulder, and
judged unlikely; (5) possible untoward reactions have the knee. Proximal interphalangeal (PIP) and meta-
been informed; (6) treatment of the underlying condi- carpophalangeal (MCP) joints, subcutaneous bursae,
tion, such as rheumatoid arthritis (RA), has been opti- tendon sheaths, and the carpal tunnel are best injected
mized; (7) the physician is familiar with the relevant with one of the weaker esters to discourage tissue
anatomy; (8) the injected structure can be temporarily atrophy.
rested; and (9) a follow-up contact has been arranged. Steroid dose. Optimal doses for each site and accord-
Structures amenable to corticosteroid injection ing to diagnoses are not well established. Table 40-1
include diarthrodial joints, synovial tendon sheaths, show the doses I use expressed as methylpredniso-
superficial and deep bursae, and a variety of connective lone acetate.
tissue structures. Fibromyalgia tender points should Should a prefilled syringe or a multidose corticoste-
only be injected when an additional pathology respon- roid vial be used? A recent survey on the rate of
sive to steroids is believed to be contributing to the pain. infection following local corticosteroid injections
Intracavitary injections are accurate when synovial fluid showed that prefilled syringes had a lesser rate of
is withdrawn, when the needle can be moved radially iatrogenic infections (1/162,000) than corticosteroids
within the cavity, and, retrospectively, if some room air not packaged in a sterile syringe (1/21,000) (30).
left in place is shown to lie within the joint on follow-up Needle length. The majority of infiltrations can be
x-ray film. Ultrasound (US) needle guidance, when done with a 13-mm, 27-gauge needle (such as in insulin
available, improves accuracy and should lead to optimal syringes; Figures 40-140-5). This is true for stenos-
results (1). ing digital and thumb tenosynovitis, de Quervains
628
C H A P T E R 4 0 T H E R A P E U T I C I N J E C T I O N S O F J O I N T S A N D S O F T T I S S U E S 6 29
TABLE 40-1. EFFICACY OF CORTICOSTEROID INJECTIONS.

STEROID
CONDITION HELPFUL DOSEa REFERENCE
Trigger finger Yes 1015 mg 2
Trigger thumb Yes 10 mg 3
De Quervains tenosynovitis Yes 1015 mg 4
MCP and PIP joints Yes 1015 mg 5
Mucoid cysts Probably 5 mg 6
First carpometacarpal OA No 1015 mgb 7
Carpal tunnel syndrome Yes 3040 mg 8
Olecranon bursitis, nonseptic Yes 2030 mg 9
Tennis elbow Short term 1015 mg 10 40

Golfers elbow Yes 10 mg 11
Subacromial impingement Probably 40 mg 12
Frozen shoulder Yes 80 mg 13
Supraclavicular nerve block Short term 40 mg 14
Acromioclavicular (AC) syndrome Probably 1015 mg 15
Cervical pain No 16
Sciatica No 17
Facet joints No 18
Sacroiliac joints Short term 19
Hip osteoarthritis Short term 20
Knee osteoarthritis Short term 4080 mg 21
Knee RA Short term 80 mg 22
Anserine syndrome Yes 40 mg 23
Retrocalcaneal bursa Probably 1015 mg 24
Plantar fascia Yes 20 mg 25
Posterior tibialis tenosynovitis May encourage rupture
Achilles tendinitis May encourage rupture
Mortons neuroma Probably 20 mg 26
Isolated second MTP synovitis Probably 1015 mg
Rheumatoid nodules Yes 1520 mg 27
Myofascial trigger points Yes Lidocaine 28
Fibromyalgia tender points? Not shown Lidocaine
ABBREVIATIONS: MCP, metacarpophalangeal; MTP, metatarsophalangeal; OA, osteoarthritis; PIP, proximal interphalangeal; RA, rheumatoid arthritis.
a
Doses used by the author in methylprednisolone acetate; one half the dose if triamcinolone hexacetonide is used.
b
When clearly inflamed.
630 JUAN J. CANOSO
FIGURE 40-1 FIGURE 40-3
Trigger finger injection. In the second finger, needle entry is just de Quervains tenosinovitis injection. The needle is aimed at the
distal to the proximal palmar crease. distended tendon sheath.
disease, carpal tunnel syndrome, tennis elbow, and bursa, the straight steroid should be used. If a larger
wrist and elbow (radiocapitular) injections. Shoulder tissue volume needs to be infiltrated, such as in the
and knee injections require a 35- or 38-mm, 21-gauge trochanteric syndrome, adding a local anesthetic is
needle. In obese people, a trochanteric injection may advantageous.
call for the use of a spinal needle. Prepping the skin. Alcohol or an iodopovidone solu-
To dilute or not to dilute. I am often asked: Do you tion may be used for antisepsis. Both are effective
mix the steroid with a local anesthetic? If one wants against bacteria, fungi, and viruses. Alcohol (70%
to limit the spread of the injection, such as in a trigger 92%) acts by 1 minute and iodopovidone 10% by 2
finger or thumb, tennis elbow, and retrocalcaneal minutes. I rub the skin three times and wait for the
appropriate time. The last word on skin prepping has
not been said (31).
Gloves. Postinjection infection occurs irrespective of
the use of sterile gloves (30). I believe the use of
FIGURE 40-4
FIGURE 40-2
Carpal tunnel syndrome injection. Note the needle entry 1.5 cm
Trigger thumb injection. The needle is aimed at the thumb proximal to the distal wrist crease and ulnar to palmaris longus
sesamoids. tendon.
gloves is desirable, at the very least in the operators TABLE 40-2. LOCAL AND SYSTEMIC REACTIONS TO
nondominant hand, to avoid inadvertent contamina- THE INJECTED MATERIAL.
tion by leaking fluid when the syringe used to drain
Facial flushing and palpitations
the joint is replaced by the one containing the steroid
(32). Skin atrophy
Local anesthesia. Some clinicians spare the use of Fat atrophy
local anesthesia because they rely on a quick, almost
painless, effective thrust which brings the needle into Hypopigmentation
the desired place. I use lidocaine 2% without epi- Postinjection flare
nephrine because my entries are often inaccurate and
need to be retried. Infection
Should a synovial effusion be drained prior to the Tendon rupture
injection? In patients with RA, removal of a knee
effusion prior to injecting the steroid improves Corticosteroid arthropathy
outcome (33). Osteonecrosis
To avoid sudden disconnection of the needle while
injecting a thick steroid suspension. Hold the needle Hyperglycemia 40
between index and thumb (of the nondominant hand) Pituitary inhibition
while you depress the plunger with the other hands
thumb. Anaphylaxis
Is it possible to inject an anticoagulated patient?
There is evidence that anticoagulated patients with
an international normalized ratio (INR) in the thera-
peutic range can have the joints and soft tissues safely How many injections are allowed in a given struc-
injected (34). Firm pressure should be exerted at the ture? Three times total (not per year) appears to me
site for several minutes. Beware of carpal tunnel to be the right answer. Realities of life dictate many
injections in this setting because a bleed, however exceptions to this rule.
small, could be disastrous. Complications (Table 40-2). A frequent untoward
Hemostasis in hand and wrist injections. In hand and reaction is facial flushing with palpitations. This reac-
wrist injections, including carpal tunnel injections, tion seldom lasts more than 4 hours. In diabetics,
raising the extremity straight up prevents venous depending on the steroid dose (consider, e.g., a dia-
bleed. betic patient with three trigger fingers plus a bilateral
Should the injected structure be rested? In knee carpal tunnel syndrome) a transient elevation of
synovitis, resting the joint for 24 hours following the serum glucose should be expected. Skin hypopig-
steroid injection leads to a better outcome (35). mentation at the injection site occurs frequently in
dark skinned individuals after injecting a superficial
structure, such as in de Quervain tenosynovitis.
INTRA-ARTICULAR
HYALURONATES
(VISCOSUPPLEMENTATION)
Intra-articular hyaluronates are often used for the treat-
ment of pain in osteoarthritic joints (36). The beneficial
effect of viscosupplementation has a delayed action but
it lasts longer than intra-articular corticosteroids (37).
Two types of agents are available. One is Hylan G-F 20,
a high-molecular-weight preparation (MW 6,000,000).
There are also lower molecular weight hyaluronan
preparations in the range of MW 800,000 to 2,000,000.
Viscosupplementation was initially used in the knee.
FIGURE 40-5 However, other joints such as the shoulder, the hip, and
Tennis elbow injection. Needle entry is 2 to 3 mm distal to the the ankle have all been treated with benefit. The usual
lateral epicondyle. treatment course includes three weekly intra-articular
632 JUAN J. CANOSO
injections. Several untoward reactions may occur. 12. Akgun K, Birtane M, Akarirmak U. Is local subacromial
Postinjection pain, with or without a joint effusion, is corticosteroid injection beneficial in subacromial impinge-
common. Another complication is a pseudoseptic ment syndrome? Clin Rheum 2004;23:496500.
synovitis. This worrisome reaction requires hospital 13. Carette S, Moffet H, Tardif J, et al. Intraarticular cortico-
steroids, supervised physiotherapy, or a combination of
admission and parenteral antibiotics pending culture
the two in the treatment of adhesive capsulitis of the
results. A granulomatous reaction has also been
shoulder: a placebo-controlled trial. Arthritis Rheum
reported. Finally, allergic reactions may occur in patients 2003;48:829838.
with avian protein allergy. Indications of viscosupple- 14. Vecchio PC, Adebajo AO, Hazleman BL. Suprascapular
mentation include (a) patients who cannot take anti- nerve block for persistent rotator cuff lesions. J Rheuma-
inflammatory medications and whose pain is unrelieved tol 1993;20:453455.
by analgesics and (b) patients with advanced osteoar- 15. Jacob AK. Sallay PI. Therapeutic efficacy of corticoste-
thritis who refuse or are not candidates for surgery. roid injections in the acromioclavicular joint. Biomed Sci
Viscosupplementation is expensive. However, a recent Instrum 1997;34:380385.
cost analysis has shown superiority of viscosupplemen- 16. Carette S, Fehlings MG. Clinical practice. Cervical radicu-
tation over appropriate care without viscosupplementa- lopathy. N Engl J Med 2005;353:392399.
17. Carette S, Leclaire R, Marcoux S, et al. Epidural cortico-
tion (38).
steroid injections for sciatica due to herniated nucleus
pulposus. N Engl J Med 1997;336:16341640.
18. Carette S, Marcoux S, Truchon R, et al. A controlled trial
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tion versus sonographic-guided injection of local cortico- 2005;21:446455.
steroids in patients with painful shoulder. J Rheumatol 20. Kullenberg B, Runesson R, Tuvhag R, et al. Intraarticular
2004;31:308314. corticosteroid injection: pain relief in osteoarthritis of the
2. Murphy D, Failla JM, Koniuch MP. Steroid versus placebo hip? J Rheumatol 2004;31:22652268.
injection for trigger finger. J Hand Surg [Am] 1995;20: 21. Godwin M, Dawes M. Intra-articular steroid injections for
628631. painful knees. Systematic review with meta-analysis. Can
3. Maneerit J, Sriworakun C, Budhraja N, et al. Trigger Fam Physician 2004;50:241248.
thumb: results of a prospective randomised study of per- 22. Weitoft T, Larsson A, Saxne T, et al. Changes of cartilage
cutaneous release with steroid injection versus steroid and bone markers after intra-articular glucocorticoid
injection alone. J Hand Surg [Br] 2003;28:586589. treatment with and without postinjection rest in patients
4. Zingas C, Failla JM, Van Holsbeeck M. Injection accuracy with rheumatoid arthritis. Ann Rheum Dis 2005;64:1750
and clinical relief of de Quervains tendinitis. J Hand Surg 1753.
[Am] 1998;23:8996. 23. Calvo-Aln J, Rua-Figueroa I, Erausquin C. Treatment
5. McCarty DJ, Marman JG, Grassanovich JL, et al. Treat- of anserine bursitis. Local corticosteroid injection vs. a
ment of rheumatoid joint inflammation with intrasynovial NSAID. A prospective study. Rev Esp Reumatol 1993;
triamcinolone hexacetonide. J Rheumatol 1995;22:1631 20:1315.
1635. 24. Canoso JJ, Wohlgethan JR, Newberg AH, et al. Aspira-
6. Rizzo M, Beckenbaugh RD. Treatment of mucous cysts tion of the retrocalcaneal bursa. Ann Rheum Dis 1984;
of the fingers: review of 134 cases with minimum 2-year 43:308312.
follow-up evaluation. J Hand Surg [Am] 2003;28:519 25. Genc H, Saracoglu M, Nacir B, et al. Long-term ultraso-
524. nographic follow-up of plantar fasciitis patients treated
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tis. Ann Rheum Dis 2004;63:12601263. Rev 2004:CD003118.
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9. Smith DL, McAfee JH, Lucas LM, et al. Treatment of 28. Kamanli A, Kaya A, Ardicoglu O, et al. Comparison of
nonseptic olecranon bursitis. A controlled, blinded pro- lidocaine injection, botulinum toxin injection, and dry
spective trial. Arch Intern Med 1989;149:25272530. needling to trigger points in myofascial pain syndrome.
10. Smidt N, Lewis M, Hay EM, et al. A comparison of two Rheumatol Int 2005;25:604611.
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11. Stahl S, Kaufman T. The efficacy of an injection of ste- acetonide and triamcinolone acetonide in treatment of
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41:736739. Osteoarthr Cartil 2002;10:518527. 40
CHAPTER 41
Nonsteroidal Anti-Inflammatory
Drugs
LESLIE J. CROFFORD, MD
Nonsteriodal anti-inflammatory drugs (NSAIDs) relieve The most important NSAID toxicities include gastro-
inflammation and pain by inhibiting the production intestinal ulceration, asthma and allergic reactions,
of prostaglandins. and effects on the kidneys, liver, and cardiovascular
Prostaglandin (PG) biosynthesis occurs via a three- system.
enzyme cascade. Current NSAIDs inhibit the enzyme Safe use of NSAIDs requires consideration of indi-
cyclooxygenase (COX), accounting for their efficacy vidual comorbidities to choose the best agent,
and toxicity. appropriate monitoring for toxicity, and use of
Pharmacologic properties of the different NSAIDs, appropriate gastroprotective agents.
including specificity for COX-1 or -2 and drug half-life,
influence the toxicity profile.
Pain (dolor), swelling (tumor), erythema (rubor), and NSAIDs. In recent years, important progress has been
warmth (calor), the cardinal features of inflammation, made towards understanding the action of NSAIDs by
are present in most patients with rheumatic diseases. clarifying the biology of PG production. This advance
Therapeutic strategies to reduce inflammation have been came with the discovery of COX-2, the isoform whose
used for centuries, beginning with botanical treatments expression is increased during inflammation. Specific
in both Western and Eastern medical traditions (1). The inhibition of COX-2 blocks production of high levels of
first isolated plant constituent to be tested as an anti- PGs at sites of inflammation while preserving PG pro-
inflammatory drug was salicylic acid from willow bark, duction mediated by COX-1 in certain other tissues.
which was chemically altered to acetyl salicylic acid to Nonspecific NSAIDs, which inhibit both COX-1 and
improve its pharmacologic properties. Acetyl salicylic COX-2, have some differences when compared with
acid became aspirin in 1899, one of the first drugs to be COX-2specific NSAIDs with regard to their adverse-
widely marketed, and aspirin remains one of the most event profiles. Comparative studies, however, find equal
widely used drugs today. Other drugs that share the anti- efficacy demonstrating that COX-2derived PGs are
inflammatory, analgesic, and antipyretic properties of responsible for the inflammation and pain of arthritis.
aspirin are termed nonsteroidal anti-inflammatory drugs Other important differences between these NSAIDs
(NSAIDs), and are a chemically diverse group of com- are related to their chemical class and pharmacologic
pounds (Table 41-1). It was established in 1971 that properties other than the specificity for COX isoforms.
salicylates and other NSAIDs act by blocking the synthe- All these factors are involved in the relative efficacy and
sis of prostaglandins (PGs), products of the metabolism safety of NSAIDs for patients with rheumatic diseases.
of the membrane-associated fatty acid arachidonic acid. It should be emphasized that advances in the under-
This finding demonstrated conclusively that PGs play an standing of PG biology may lead to other targets that
important role in mediating symptoms and signs of would further advance anti-inflammatory therapy.
inflammation. However, PGs play a role in normal physi-
ology as well as in disease. As a consequence, all NSAIDs
possess predictable therapeutic and adverse effects that PROSTAGLANDIN BIOLOGY
must be understood in order to use these drugs safely.
Prostaglandins are synthesized by the action of at The diversity of PG functions is achieved by cell- and
least three biosynthetic enzymes, one of which, cyclo- tissue-specific generation of different stable PGs,
oxygenase (COX), is the target of all currently available multiple PG receptors linked to different intracellular
634
C H A P T E R 4 1 N O N S T E R O I D A L A N T I - I N F L A M M A T O R Y D R U G S 6 35
TABLE 41-1. NONSTERIODAL ANTI-INFLAMMATORY DRUGS AND SALICYLATES.

CHEMICAL CLASS GENERIC NAME BRAND NAME(S)
Carboxylic acids: salicylic acids and esters Aspirin Anacin,a Ascriptin,a Bayer,a Bufferin,a Easprin, Ecotrin,a
Diflunisal Empirin,a Midol,a others
Dolobid
Carboxylic acids: phenyl acetic acid Diclofenac potassium Cataflam

Diclofenac sodium Voltaren, Voltaren XR
Diclofenac sodium + misoprostol Arthrotec
Carboxylic acids: carbo- and heterocyclic Etodolac Lodine, Lodine XL

acids Indomethacin Indocin, Indocin SR
Ketorolac Toradol
Sulindac Clinoril
Tolmetin sodium Tolectin
Proprionic acids Flurbiprofen Ansaid

Ketoprofen Odudis, Oruvail, Actron,a Orudis KTa
Oxaprozin Daypro
Naproxen Naprosyn, Naprelan
Naproxen sodium Anaprox, Alevea
Ibuprofen Motrin, Dolgesic, Advil,a Motrin IB,a Excedrin IB,
Genpril,a Nuprin,a others
41
Fenamic acids Meclofenamate sodium Meclomen
Enolic acids Piroxicam Feldene

Meloxicam Mobic
Nonacidic Nabumetone Relafen
Sulfonamide Celecoxib Celebrex
Nonacetylated salicylates Choline salicylate Arthrotec

Magnesium salicylate Bayer Select,a Doans Pillsa
Choline magnesium trisalicylate Trilisate, tricosal
Salsalate Amigesic, Disalcid, others
Sodium salicylate
a
Available over-the-counter.
Not intended to be an exhaustive list.
signaling pathways, and PG production pathways involv- there are important differences in a small number of
ing enzymes that are induced to dramatically increase amino acids that lead to important biologic differences.
local PG production. Biosynthesis of PGs involves a For example, COX-2 is more easily primed by intra-
three-step sequence including (i) hydrolysis of the 20 cellular hydroperoxides and is active at lower concen-
carbon-containing polyunsaturated fatty acid, arachi- trations of arachidonic acid. In addition, amino acid
donic acid, from cell membranes; (ii) oxygenation to the changes in the hydrophobic core of the enzymes lead to
endoperoxide PGH2 by COX; and (iii) conversion to differences in shape of the COX active site that has
the biologically active end products via specific PG syn- been exploited to develop drugs that specifically inhibit
thases (Figure 41-1). The first step in PG synthesis is COX-2 (2).
mediated by a phospholipase A2 (PLA2). Although the The most striking difference between the COX iso-
synthesis of PGs is regulated acutely by activation of forms, however, is at the level of expression and regula-
phospholipases and release of arachidonate, the net tion of mRNA and protein levels. These differences
level of prostanoid production is determined by the lead directly to the differing biological roles of COX-1
level of COX expression (2). and COX-2. COX-1 is expressed in most tissues and
Cyclooxygenase-1 and COX-2 are homodimers that levels do not vary greatly. COX-1derived PGs mediate
insert into one half of the lipid bilayer of the nuclear important physiologic processes in many tissues and
envelope and endoplasmic reticulum. They are bifunc- COX-1 is available to increase PG production acutely
tional enzymes that catalyze both cyclooxygenation and when an abrupt increase in levels of arachidonic acid
peroxidation reactions. Although structurally similar, occurs following cell stimulation. However, COX-1
636 LESLIE J. CROFFORD
Cell Membrane Phospholipids number of cytokines, including interleukin 1 (IL-1) and

tumor necrosis factor alpha (TNF-alpha), and other
Phospholipase A2 mediators associated with inflammation (3). COX-2
expression is inhibited by glucocorticoids, accounting
COOH for some of their anti-inflammatory properties (see
Chapter 42).
Arachidonic Acid The product of the COX enzymes, PGH2, is an unsta-
ble intermediate that is rapidly converted to one of
Cyclooxygenase-1 several possible prostanoids by terminal synthases. In
Cyclooxygenase-2 general, this process is cell-specific with differentiated
COOH cells producing only one or two PGs in abundance (2).
O The most important stable prostanoids include PGD2,
O PGE2, PGF2, prostacyclin (PGI2), and thromboxane A2
OOH
(TXA2). All have different biological roles that are
PGG2 important to the understanding of NSAID efficacy and
safety.
COOH
O PGE2 is thought to be the most important mediator
O of inflammation (4). There are several forms of PGE
OH synthase enzymes, including the microsomal PGE syn-
PGH2 thase-1 (mPGES-1) which, like COX-2, is highly induced
TXS PGIS during inflammation. mPGES-1 expression is increased
by proinflammatory cytokines and inhibited by gluco-
cPGES PGDS corticoids. mPGES-1 acts in concert with COX-2 to
mPGES-1
TXA2 mPGES-2 PGI2
generate locally high levels of PGE2 during inflamma-
TXS tion. There are four receptors for PGE2 (EP receptors)
PGF2 PGE2 PGD2 with different signaling pathways. Molecular evolution
studies demonstrate several receptor clusters, all con-
TP FP EP1 DP1 IP taining receptors for PGE2 (5). The earliest divergence
EP2 DP2 is between clusters associated with either an increase of
EP3 cAMP (EP2, EP4, IPprostacyclin receptor, and DP
EP4
PGD2 receptor) or decrease of cAMP (one isoform of
FIGURE 41-1 EP3, TPthromboxane receptor). The ancestral EP1
receptor diverged from the EP3 receptors and functions
Prostaglandin biosynthetic pathway. The first step in prostaglan-
din (PG) biosynthesis is the release of arachidonic acid from cell
to increase intracellular Ca2+ along with the FP (PGF2)
membrane phospholipids by phospholipase A2. Cyclooxygenase and TP receptors.
(COX)-1 and COX-2 then adds two molecules of oxygen followed There is considerable interest in potential nuclear
by a hydroperoxidase reaction to create first PGG2 and then actions of PGs. This may occur by interaction with
PGH2. PGH2 is an unstable intermediate rapidly converted to nuclear receptors or by interaction with intracellular
stable PGs by the respective PG synthases in a cell- and tissue-
specific manner. PGE2 has three different synthase enzymes, one
proteins. In biological fluids, PGD2 is slowly dehydrated
of which (mPGES-1) is inducible by proinflammatory signals to yield the cyclopentanone PGs, PGJ2 (6). PGJ2 and
similar to COX-2. Stable PGs act in an autocrine or paracrine other cyclopentanone PGs contain a highly reactive
manner on cell surface receptors. alpha beta-unsaturated ketone moiety that allows aduct
formation with other proteins. It is thought that the
cyclopentanone PGs play a role in the resolution of
does not contribute substantially to the large increases inflammation by acting as ligands for peroxisome pro-
in PG production that occur during inflammation. COX- liferator-activated receptors (PPARs). It has also been
1 is the only isoform expressed in mature platelets and suggested that covalent modification of certain tran-
is the dominant isoform in normal gastric mucosa (3). scription factors may lead to modulation of immune and
Cyclooxygenase-2 expression is restricted to a few inflammatory responses (7).
tissues, notably the kidney and brain, under basal condi-
tions. COX-2 also plays an important role in normal
reproductive, cardiovascular, and skeletal physiology. MECHANISM OF ACTION
Most important for rheumatic diseases is the fact that
COX-2 expression is highly induced and accounts for The most important mechanism of NSAID action is to
the large increase in PG levels produced locally during inhibit production of PGs by competing with arachi-
inflammation. COX-2 expression is increased by a donic acid for binding in the COX catalytic site. NSAIDs
have little effect on peroxidase activity (2). It should be nesses, can lead to an increase in free drug and an
noted here that acetaminophen, while not classified as increased risk for toxicity. Due to increased vascular
an NSAID, inhibits COX activity in vitro. It is thought permeability in local sites of inflammation, the high
that acetaminophen acts by inhibiting the peroxidase degree of protein binding may result in delivery of
activity of the COX enzymes. Failure of acetaminophen higher levels of NSAIDs.
to act as an anti-inflammatory agent may be related to Nonsteriodal anti-inflammatory drugs with a longer
its lack of effect under conditions of high hydroperoxide half-life take a longer time to reach steady state con-
tone such as is found in inflammatory sites (8). NSAIDs centrations. This can have consequences for the time to
may exhibit different kinetic modes of inhibition in- reach full therapeutic effect. The clearance of NSAIDs
cluding (i) rapid, reversible binding (e.g., ibuprofen); is usually by hepatic metabolism with production of
(ii) rapid, lower affinity reversible binding followed inactive metabolites that are excreted in the bile and
by time-dependent, higher affinity, slowly reversible urine. Most NSAIDs are metabolized through the
binding (e.g., naproxen, celecoxib); or (iii) rapid, revers- microsomal cytochrome P450-containing mixed-func-
ible binding followed by covalent modification (e.g., tion oxidase system. Drugs metabolized through this
aspirin) (2). From a clinical perspective, it is important pathway are expected to have drug interactions. Fur-
to characterize NSAIDs according to specificity for thermore, there is genetic variation in enzyme activity
inhibition of COX-1 or COX-2 (9). All NSAIDs cur- such that some groups may metabolize drugs more
rently in clinical use that inhibit COX-1 also inhibit slowly. The pharmacokinetics of some NSAIDs can
COX-2 at therapeutic concentrations. However, at low be affected by liver disease, renal disease, or old age
doses (81 mg) aspirin acts as a specific inhibitor of COX- (11).
1. The specificity for COX-2 is based on the structural Salicylates are acetylated (e.g., aspirin) or nonacety- 41
difference between the hydrophobic channels resulting lated (e.g., sodium salicylate, choline salicylate, choline
in an NSAID binding site about 20% larger than COX- magnesium trisalicylate, salicysalicylic acid). Aspirin
1 and including a side pocket. and salicylates are readily absorbed in the acidic or
Very high doses of NSAIDs have been shown to neutralized stomach and intestine. The formulation of
have COX-independent activities on cellular processes these agents affects the absorption properties, but not
that could contribute to some of their actions. The prac- bioavailability. Buffered aspirin tablets contain antacids
tical importance of these mechanisms is unknown. that increase the pH of the microenvironment, while
Sodium salicylate and aspirin were shown to inhibit enteric coating slows absorption. The bioavailability of
activation of the transcription factor NF-B, leading rectal aspirin suppositories increases with retention
some to suggest that this could be an important anti- time. Aspirin is rapidly deacetylated to salicylate either
inflammatory mechanism. Similar to some PGs, certain spontaneously or enzymatically. Albumin is the domi-
NSAIDs bind to and activate members of the PPAR nant protein to which salicylates bind, and in conditions
family and other intracellular receptors. Another where albumin concentrations are low, including active
potential mechanism is induction of endogenous anti- RA, the pharmacologic and toxic effects of an incre-
inflammatory mechanisms. It was shown that the anti- ment in dose are more pronounced. Salicylate is metab-
inflammatory effect of salicylate can be inhibited by an olized principally by the liver and excreted primarily by
adenosine A2 receptor antagonist in a murine model of the kidney. The serum levels of salicylate bear only a
inflammation, suggesting that salicylate may stimulate modest relationship to the dose ingested and a small
adenosine release. Specific COX-2 inhibitors may have increment in dose may lead to a profound increment in
unique structural features that promote COX-indepen- serum level.
dent apoptosis of some cancer cells and angiogenesis
(10).
THERAPEUTIC ACTIONS
CLINICAL PHARMACOLOGY Nonsteriodal anti-inflammatory drugs have antipyretic,
analgesic, and anti-inflammatory properties. The major-
The chemical class and pharmacologic properties of ity of evidence suggests that most of these properties
various salicylates and other NSAIDs is listed in Table are mediated by inhibition of COX-2 (3). Fever occurs
41-1. Most NSAIDs are weak organic acids completely in response to inflammation and induction of cytokines
absorbed from the gastrointestinal (GI) tract. Once that function as endogenous pyrogens. PGs have long
absorbed, NSAIDs are highly (> 95%) bound to plasma been known to mediate the fever response. COX-2
proteins, and the amount of free drug is relatively small. expression is induced in the brain vasculature with
However, clinically significant reductions in albumin, temporal correlation to the development of fever. In
such as occur in patients with active rheumatoid arthri- the absence of COX-2, fever fails to develop. PGs pro-
tis (RA), the elderly, and those with other chronic ill- duced locally at the site of inflammation sensitize
peripheral nociceptors. PGs also prolong proinflamma- diovascular disease events in patients without a prior
tory actions of bradykinin, histamine, nitric oxide, and history of cardiovascular disease is controversial.
other pain mediators. Recent studies have also demon- However, recent recommendations from the US Pre-
strated a role for PGs in central sensitization at the ventive Services Task Force suggest that those patients
spinal level, resulting in hyperalgesia (increased pain with an increased (3%5%) risk for coronary heart
to a normally painful stimulus) and allodynia (pain to disease events over 5 years may receive greater benefit
a normally innocuous stimulus). There is constitutive than harm from aspirin chemoprophylaxis (13). There
expression of COX-2 in the dorsal horn of the spinal is no data to suggest that NSAIDs other than aspirin are
cord that is increased during inflammation, and inhibi- effective agents for prophylaxis of cardiovascular throm-
tion of COX-2, but not COX-1, reduces spinal PG pro- botic events, therefore NSAIDs are commonly used in
duction (12). combination with low-dose aspirin. Care should be
Nonsteriodal anti-inflammatory drugs are used in taken to illicit the history of aspirin use and to consider
virtually all rheumatic diseases associated with pain drug interactions. There is recent data to suggest that
and inflammation. Their efficacy is best studied in some NSAIDs may reduce the ability of aspirin to exert
osteoarthritis (OA), RA, gout, and acute pain. The its antithrombotic effect (14,15).
question of whether an individual NSAID provides
improved efficacy for a particular indication has been
difficult to discern in randomized, controlled trials. ADVERSE EFFECTS
However, historical preference for some agents in
some conditions (e.g., indomethacin for gout or anky- Nonsteriodal anti-inflammatory drugs produce toxic
losing spondylitis) continues, and a mechanistic basis effects in many organ systems (Table 41-2). Most of
for this preference may yet be identified. The utility of these adverse effects are related to inhibition of PGs
NSAIDs is limited chiefly by their adverse-effect profile mediating important physiologic functions. Because the
and, in general, NSAIDs should be used for the short- therapeutic and adverse effects are related to the same
est time possible and at the lowest dose that controls mechanism of action, the therapeutic window for these
symptoms. medications is relatively narrow. Of course, there are
Aspirin is indicated for secondary prevention of car- adverse effects related to specific drugs and unrelated
diovascular disease. The use of aspirin to prevent car- to inhibition of PGs.
TABLE 41-2. ADVERSE EFFECTS OF NONSPECIFIC AND COX-2SPECIFIC NONSTERIODAL ANTI-INFLAMMATORY DRUGS.
ORGAN SYSTEM NONSPECIFIC NSAIDS DIFFERENCES WITH COX-2SPECIFIC NSAIDs
Gastrointestinal Dyspepsia Decreased UGI ulceration

Gastroduodenal ulceration Decreased bleeding
Bleeding (all levels)
Colitis
Renal Hypertension
Edema
Acute renal failure
Interstitial nephritis
Papillary necrosis
Hepatic Elevated transaminases

Rare severe hepatic reactions
Asthma Exacerbation of AERD No cross-reactivity in AERD
Allergic reactions Hypersensitivity reactions Celecoxib contraindicated in patients with sulfonamide allergies
Cardiovascular Platelet dysfunction Arterial thrombosis in high-risk patients with high-dose, long-acting, highly
specific inhibitors (rofecoxib)
Central nervous system Dizziness

Somnolence
Cognitive dysfunction
Aseptic meningitis
ABBREVIATIONS: AERD, aspirin-exacerbated respiratory disease; NSAIDs, nonsteriodal anti-inflammatory drugs; UGI, upper gastrointestinal tract.
Gastrointestinal the GI tract under basal conditions and increases mark-

edly if colonic inflammation is present. COX-2 inhibition
Injury to the upper gastrointestinal tract in the form of or genetic deficiency markedly exacerbates experimen-
ulcers and their complications are the most important tal colitis, suggesting that COX-2derived PGs may be a
toxicity associated with aspirin and nonspecific NSAIDs. protective mechanism for mucosal defense (20).
Millions of individuals regularly use aspirin and NSAIDs, Mucosal damage associated with inhibiting PG syn-
magnifying the overall importance of NSAID gastroen- thesis is associated with a decrease in epithelial mucus,
teropathy from a public health standpoint. It was the secretion of bicarbonate, mucosal blood flow, epithelial
expectation of reduced gastroduodenal injury that drove proliferation, and mucosal resistance to injury. Impaired
development of specific COX-2 inhibitors. The risk mucosal resistance permits injury by endogenous factors
profile for gastric injury is reduced for those agents with (e.g., acid, pepsin, and bile salts) and exogenous factors
the lowest potential for COX-1 inhibition. (e.g., NSAIDs), thereby amplifying bleeding risk by
Prospective data derived from Arthritis, Rheuma- causing new mucosal lesions. Topical mucosal injury is
tism, and Aging Medical Information System (ARAMIS) initiated by the acidic properties of aspirin and many
showed that 13 of every 1000 patients with RA that take other NSAIDs. In addition, topical injury may occur as
nonspecific NSAIDs for 1 year have a serious gastroin- a result of indirect mechanisms, mediated through the
testinal complication (16). Although the rate of NSAID- biliary excretion and subsequent duodenogastric reflux
related serious gastrointestinal complications has of active NSAID metabolites (e.g., sulindac). Inhibition
decreased, in part due to use of protective strategies and of prostaglandins, however, is the principal mechanism
COX-2specific NSAIDs, no protective strategy has underlying development of gastroduodenal ulceration.
eliminated the risk of NSAID use. Unfortunately, This is most graphically illustrated by the fact that 41
despite a number of strategies available for risk reduc- enteric coating and parenteral or rectal administration
tion, there is a high level of failure to adequately protect fails to reduce ulcer risk. In addition, platelet dysfunc-
patients using NSAIDs. The mortality rate among tion can increase the risk of bleeding associated with
patients who are hospitalized for NSAID-induced upper damaged gastrointestinal mucosa (17).
gastrointestinal bleeding is 5% to 10%. Bleeding is by In the normal gastroduodenal mucosa and in plate-
far the most common ulcer complication, but obstruc- lets, COX-1 is the isoform responsible for PG produc-
tion and perforation may also occur (17). tion. However, inhibition of COX-2 may contribute to
Epidemiological studies have shown that the use of risk in situations where damage is present. During injury
nonspecific NSAIDs increases the risk of ulcer compli- of the GI tract, as in other tissues, COX-2 is induced.
cations by a factor of 4 compared with nonusers, and PGs derived from COX-2 would normally exert sup-
even low-dose aspirin (325 mg) doubles the risk of pressive effects on inflammatory cells, notably neutro-
bleeding ulcers (18). The absolute risk of serious GI phils, that contribute to damage. These findings are
complications (bleeding, perforation, or obstruction) in perhaps relevant to the high risk of recurrence (~ 25%)
a patient with no other risk factors is about 0.5% per in patients with previous ulcers even when protective
year and the risk in RA patients is about 2% to 4% per strategies are used (21).
year (16). Not all patients are at similar risk for NSAID-related
In addition to injury of the gastroduodenal mucosa, GI bleeding. Factors consistently associated with
NSAID use is associated with symptoms of dyspepsia increased risk for developing NSAID-associated gastro-
and damage to other regions of the gastrointestinal tract. duodenal ulcers are shown in Table 41-3 (17). These
At least 10% to 20% of patients taking NSAIDs experi- risk factors can be identified in prospective clinical trials
ence dyspepsia (17). Symptoms or the lack thereof are of gastroprotective strategies and risk reduction is
not good predictors of NSAID-related GI complications higher in those at greatest risk (22). The only way to
because only a minority of patients with serious GI completely prevent NSAID-associated GI injury is not
events report antecedent dyspepsia (16). Other adverse to use them; however, using the lowest effective dose of
GI events include pill esophagitis, small bowel ulcer- an NSAID for the shortest time required may reduce
ation, small bowel strictures, colonic strictures, divertic- risk. There are several other strategies available to
ular disease, and exacerbation of inflammatory bowel reduce the risks of upper GI complications due to
disease (17). Patients admitted to the hospital with large aspirin and NSAID use (Table 41-3).
or small bowel perforations or bleeding are twice as Several large randomized, controlled clinical trails
likely to be taking NSAIDs. In an autopsy series of over have been performed to evaluated the occurrence of
700 patients, 8% of patients taking NSAIDs or low-dose clinical significant ulcers and ulcer complications in
aspirin compared with 0.6% of those not taking NSAIDs patients treated with specific COX-2 inhibitors com-
revealed small intestinal ulceration, while 24% of NSAID pared to nonspecific NSAIDs (2325). Data from these
users had gastroduodenal ulcers (19). COX-2 expression randomized controlled trials and other studies suggest
is higher in the colon than in more proximal portions of that drugs that are more specific towards the COX-2
TABLE 41-3. NONSTERIODAL ANTI-INFLAMMATORY effects of NSAIDs on renal function include fluid and
DRUGINDUCED UPPER GASTROINTESTINAL ULCERS. electrolyte disturbances, acute deterioration of renal
function, interstitial nephritis, and papillary necrosis.
Established risk factors
Advanced age (linear increase in risk, substantial risk after The most common effects are hypertension and edema
age 65) associated with altered solute homeostasis. Acute renal
History of complicated or uncomplicated ulcer failure is more likely in those patients with decreased
Concomitant use of anticoagulants effective circulating volume and, in particular, those
Concomitant use of glucocorticoids
with congestive heart failure, cirrhosis, and renal insuf-
Serious systemic disorder
Higher dose or multiple NSAIDs (including low-dose aspirin) ficiency (Table 41-4). An increased risk for worsening
chronic renal failure is seen in patients with preexisting
Possible risk factors renal disease who regularly use aspirin (28).
Cigarette smoking
Both COX-1 and COX-2 are constitutively expressed
Alcohol consumption
Concomitant infection with Helicobacter pylori in the kidney; however, their distribution is somewhat
different (28). Both COX-1 and COX-2 are expressed
Protective strategies in the renal vasculature and glomerulus. COX-2 is
Proton pump inhibitor
Misoprostol (200 mcg four times daily)
expressed in the macula densa and is critical for basal
Specific COX-2 inhibitor (unless concomitant aspirin) and upregulated secretion of renin. In the medulla,
COX-1 is expressed primarily in the medullary collect-
ABBREVIATION: NSAIDs, nonsteriodal anti-inflammatory drugs. ing ducts and COX-2 in the interstitial cells. In knock-
out mice and mice treated with specific inhibitors,
COX-1 and COX-2 exert opposite effects on systemic
isoform are associated with a lower risk of adverse GI blood pressure and renal function (29). COX-2 inhibi-
events, reducing the risk of ulcers and ulcer complica- tors reduce renal medullary blood flow, decrease urine
tions by about 50%. However, use of concomitant flow, and enhance the pressor effect of angiotensin II.
aspirin may reduce the benefit and there is little data In contrast, the pressor effect of angiotensin II is blunted
that use of COX-2 inhibitors is superior to other gastro- by COX-1 inhibition.
protective strategies (24). Studies of renal physiology demonstrate that specific
Another strategy proven effective is replacement of COX-2 inhibitors have similar effects on renal function
PGs with misoprostol, a stable analogue of PGE1. Miso- as nonspecific inhibitors. In patients with moderate-to-
prostol at a dose of 200 cg four times daily was shown severe renal insufficiency or other risk factors for acute
to reduce serious gastrointestinal complications by 40% renal failure, both nonspecific and COX-2specific
[odds ratio (OR) 0.598; 95% confidence interval (CI), NSAIDs should be avoided or used with great caution
0.360.98] in RA patients taking nonspecific NSAIDs. (28).
Misoprostol is often poorly tolerated at high doses with
the most important side effect being diarrhea. There are
endoscopic studies that suggest proton pump inhibitors
Hepatic
(PPIs) may be effective in healing of gastroduodenal Borderline elevations of one or more liver tests may
ulcers and reducing recurrence of gastroduodenal ulcers occur in up to 15% of patients taking NSAIDs, and
in patients taking NSAIDs. An epidemiologic study also notable elevations of alanine aminotransferase (ALT)
suggested a 40% risk reduction for NSAID-associated or asparte aminotransferase (AST; approximately three
GI bleeding associated with use of antisecretory agents. or more times the upper limit of normal) have been
In patients continuing to use aspirin or NSAIDs after
ulcers due to Helicobacter pylori, the PPI omeprazole
was superior to the eradication of H. pylori in prevent- TABLE 41-4. RISK FACTORS FOR RENAL TOXICITY.
ing recurrent bleeding in patients on NSAIDs (26). In
High risk
patients taking NSAIDs and with a recent history of
Volume depletion (e.g., dehydration, hemodynamically
ulcer bleeding, the risk of recurrent ulcer bleeding was significant bleed, septic shock)
similar in patients receiving celecoxib (4.9%; 95% CI, Severe congestive heart failure
3.16.7) and diclofenac plus omeprazole (6.4%; 95% CI, Hepatic cirrhosis
4.38.4). There is no data that use of H2-blockers or
Low-to-moderate risk
antacids prevents serious GI complications (27). Intrinsic renal disease (e.g., diabetic or hypertensive
nephropathy, nephritic syndrome)
Induction of anesthesia
Renal
Possible risk
Renal PGs are important for salt and water homeostasis Advanced age
and maintaining renal blood flow. Potential adverse
reported in approximately 1% of patients in clinical highly specific, long-acting COX-2specific NSAID,

trials with NSAIDs. These laboratory abnormalities rofecoxib. Beyond the clearly increased risk of rofe-
may progress, may remain unchanged, or may be tran- coxib, it remains controversial as to the magnitude of
sient with continuing therapy. Rare cases of severe overall risk for nonspecific and COX-2specific NSAIDs;
hepatic reactions, including jaundice and fatal fulmi- however, the overall risk is likely to be low (33).
nant hepatitis, liver necrosis, and hepatic failure (some An increased risk of heart failure can be seen in
with fatal outcome) have been reported with NSAIDs. patients taking NSAIDs, particularly in elderly patients
Those NSAIDs that appear most likely to be associ- with preexisting cardiorenal disease. This is likely
ated with hepatic adverse events are diclofenac and related chiefly to renal effects of these agents, but it is
sulindac. Transaminase elevations, which can occur important to recognize this relationship and discontinue
with most NSAIDs, are particularly common with NSAIDs in patients with congestive heart failure. There
diclofenac. Sulindac is the drug most often associated is some evidence that celecoxib may be safer than other
with cholestasis. In children with viral illnesses, hepa- NSAIDs in this group of patients (34).
tocellular failure and fatty degeneration (Reyes syn-
drome) is associated with aspirin ingestion (30). After
initiating treatment with an NSAID, patients should be
Other Adverse Effects
evaluated within 8 to 12 weeks for changes in liver Due to antiplatelet effects, nonselective NSAIDs
function tests. increase risk of bleeding, particularly in patients on
systemic anticoagulation. Non-aspirin salicylates and
COX-2specific NSAIDs are preferred in this situation.
Asthma and Allergic Reactions Other hematologic effects are uncommon, but neutro- 41
Up to 10% to 20% of the general asthmatic population penia can be seen, particularly with indomethacin
has hypersensitivity to aspirin and nonspecific NSAIDs, and phenylbutazone which are no longer available for
leading to severe exacerbation of asthma and naso- human use.
ocular reactions. Formerly termed aspirin-sensitive Neurologic side effects include aseptic meningitis,
asthma, these patients are now characterized as having particularly with ibuprofen and other proprionic acid
aspirin-exacerbated respiratory disease (AERD) because derivatives and seen most commonly in patients with
they have chronic upper and lower respiratory mucosal systemic lupus erythematosus (SLE) for unknown
inflammation, sinusitis, nasal polyposis, and asthma reasons. Psychosis and cognitive dysfunction is most
independent of their hypersensitivity reactions. A common in elderly patients.
number of studies have now been reported that demon- Effects on reproductive function include the possibil-
strate the safety of the specific COX-2 inhibitors in ity of increased infertility because COX-2derived PGs
patients with AERD. Although these studies were per- are required for ovulation and implantation. Although
formed as challenge tests rather than long-term placebo- this is likely uncommon, discontinuing NSAIDs in
controlled trials, they are convincing (31). women with infertility problems seems reasonable.
Aspirin and all NSAIDs can cause hypersensitivity NSAIDs result in premature closure of the ductus arte-
reactions, including skin rash (including toxic epidermal riosis and they should not be used during the third tri-
necrolysis and StevensJohnson syndrome), urticaria/ mester of pregnancy.
angioedema, cutaneous vascultis, and anaphylactoid or
anaphylactic reaction. Celecoxib contains a sulfonamide
group and should not be given to patients that report DRUG INTERACTIONS
allergy to sulfa-containing drugs (31).
Because NSAIDs are metabolized by hepatic micro-
somal cytochrome P450-containing mixed-function
Cardiovascular oxidase system, drug interactions are expected. When
Consideration of the cardiovascular effects of COX starting NSAIDs for chronic use, evaluation of potential
inhibition accompanied the development and wide- drug interactions is essential.
spread use of specific COX-2 inhibitors. The role of PGs
in normal cardiovascular physiology and during cardio- Salicylate and Nonsteriodal Anti-
vascular injury is quite complex, making delineation of
NSAID effects problematic. It is known that vascular
Inflammatory Drug Interactions
PGI2 production is mediated predominantly by COX-2 Salicylates and NSAIDs compete with one another for
(32). PGI2 is functionally antagonistic to TXA2 in the protein binding sites and there may be metabolic inter-
vasculature, inhibiting platelet activation and acting as actions as well. This competition can result in either
an important mediation of vasodilation. An increased increased (e.g., with indomethacin) or decreased (e.g.,
risk for cardiovascular events caused withdrawal of a with ibuprofen, naproxen) NSAID concentrations. It
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CHAPTER 42
Glucocorticoids
FRANK BUTTGEREIT, MD
GERD-RDIGER BURMESTER, MD
Glucocorticoids (GCs) have powerful anti-inflamma- proteins, releasing proteins from intracellular
tory and immunomodulatory effects and are useful protein complexes that include GC receptors,
for treating many rheumatic diseases. and changing the properties of biological
Glucocorticoids work by inhibiting leukocyte access membranes.
to inflamed tissues, interfering with the function of Initial GC dosage should be determined by the type
cells involved in the inflammatory process, and and severity of the disease manifestation under
suppressing the production of humoral factors such treatment.
as cytokines and prostaglandins involved in immune Because of significant toxicity associated with
inflammatory processes. long-term GC use, doses of <7.5 mg daily are recom-
Glucocorticoids accomplish their effects by several mended only if required to control symptoms.
mechanisms, including altering synthesis of
Glucocorticoids (GCs) have been in use for more than lone, methylprednisolone, and dexamethasone. How-
50 years. They are powerful and cost-effective drugs ever, for daily practice we can summarize their clinical
with strong anti-inflammatory and immunomodulatory actions as follows:
effects that are used to treat rheumatic and other dis-
eases. Their therapeutic use has increased continuously Inhibit leukocyte traffic and access of leukocytes to
in recent years (1,2). Furthermore, our understanding the site of inflammation
of the action of glucocorticoids has advanced in recent Interfere with functions of leukocytes, fibroblasts,
years, especially with regard to mechanisms of action, and endothelial cells
clinical usage, side-effect potential, and the develop- Suppress the production and actions of humoral
ment of new glucocorticoid drugs (25). GCs are the factors involved in the inflammatory process
subject of this chapter as the terms corticosteroids or
corticoids do not precisely designate these compounds. Virtually all primary and secondary immune cells are
The adrenal cortex indeed synthesizes glucocorticoids, more or less affected. The most important effects on the
but also mineralocorticoids and androgens. The term different cell types are listed in Table 42-1.
steroids, although often used (e.g., in steroid-induced
osteoporosis), is similarly incorrect because it simply
describes chemical compounds characterized by a
Molecular Mechanisms
common multiple-ring structure which include choles- Four different mechanisms have been identified to date.
terol and sex hormones. The interested reader can find more details in recent
reviews (2,3). Cytosolic GC receptor (cGCR)-mediated
genomic effects refers to the classical mechanism by
which GCs up- or downregulate the synthesis of specific
MECHANISMS OF ACTION regulatory proteins. The GC molecules bind to the
cGCR alpha. The activated GC/cGCR complex in turn
Cellular Effects on Immune Cells binds to specific DNA-binding sites called glucocorti-
Glucocorticoids mediate important anti-inflammatory coid responsive elements. In some cases, this results in
and immunomodulatory effects when used therapeuti- upregulated synthesis of certain proteins. This process,
cally. There are many specific effects of the commonly called transactivation, affects between 10 and 100 genes
used GC drugs, which include prednisone, predniso- per cell that are regulated in this way (6). There are also
644
C H A P T E R 4 2 G L U C O C O R T I C O I D S 64 5
TABLE 42-1. IMPORTANT EFFECTS OF effects within a few minutes, far more rapidly than
GLUCOCORTICOIDS ON PRIMARY AND SECONDARY genomic effects (9).
IMMUNE CELLS. Glucocorticoids also mediate rapid and therapeutic
Monocytes/macrophages relevant effects via membrane-bound GCR (mGCR)
number of circulating cells ( myelopoiesis, release) termed mGCR-mediated nongenomic effects (2).
expression of MHC class II molecules and Fc receptors mGCRs have been recently identified on human PBMC
synthesis of proinflammatory cytokines (e.g., IL-2, IL-6, TNF- from healthy controls. A strong positive correlation
alpha) and prostaglandins
between the frequency of mGCR-positive monocytes
T cells and various parameters of disease activity was found in
number of circulating cells (redistribution effects) patients with rheumatoid arthritis (RA). One of the
production and action of IL-2 (most important) suggested functions of mGCR is to mediate cell lysis by
Granulocytes inducing apoptosis. Therefore, it is currently assumed
number of eosinophil and basophil granulocytes that mGCR mediates a negative feedback regulation as
number of circulating neutrophils follows: Immunostimulation (or high disease activity)
Endothelial cells
induces mGCR expression on immune cells, such as
vessel permeability monocytes. This in turn leads to a significantly higher
expression of adhesion molecules percentage of cells undergoing GC-induced apoptosis,
production of IL-1 and prostaglandins which ameloriates the activity of the immune system.
Fibroblasts
This mechanism remains speculative and further experi-
proliferation ments are needed to confirm the functional activity of
production of fibronectin and prostaglandins mGCR (2).
Finally, GCs at high concentrations are able to inter-
SOURCE: From Buttgereit F, Saag K, Cutolo M, et al. Scand J Rheum calate into cellular membranes, such as plasma and
2005;34:1421, by permission of Scandinavian Journal of Rheumatology
(www.tandf.no/rheumatology) and Taylor & Francis. mitochondrial membrane, and change their properties.
ABBREVIATIONS: IL, interleukin; MHC, major histocompatibility complex; This is the basis for nonspecific nongenomic effects,
TNF, tumor necrosis factor. possibly mediated by changes in the cation transport 42
through the plasma membrane and in the proton leak
of the mitochondria. These physicochemical interac-
tions with biological membranes are very likely to be
negative glucocorticoid responsive elements, but inhibi- the key to the very rapid immunosuppressive and anti-
tory effects are typically mediated instead by negative inflammatory effects of high dose GCs. Very high GC
interference of the GC/cGCR complex with transcrip- concentrations are achieved by intra-articular GC injec-
tion factors such as NF-B and activator protein 1 (AP- tions or intravenous GC pulse therapy.
1). Via this latter mechanism, GCs downregulate the
synthesis of proinflammatory cytokines, such as inter-
leukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis
THERAPEUTIC USE
factor alpha (TNF-alpha). Many genes are regulated via
Most of the desired clinical effects of GC treatment in
this mode of action, which is termed transrepression.
rheumatic patients are mediated by transrepression.
Altogether, it is estimated that GCs influence the tran-
These include the reduction of clinical signs and symp-
scription of approximately 1% of the entire genome
toms of inflammation and the retardation of the radio-
(7).
logical progression in rheumatoid arthritis.
With respect to the regulation of genomic GC actions,
it must be mentioned that an alternative splice variant
of the cGCR alpha exists, the cGCR beta isoform. This
Inhibition of Inflammation
isoform does not bind ligand and may inhibit classic An inflammatory process (e.g., arthritis, myositis) is
cGCR alphamediated transactivation of target genes usually characterized by upregulated synthesis of inflam-
(2,8). matory mediators, such as prostaglandin E2 (PGE2) and
Recently, it became evident that GCs also mediate cytokines. Among the most important clinical effects of
effects via so called cGCR-mediated nongenomic effects. GCs are reduced synthesis of enymes involved in the
Croxtall and colleagues have suggested that following biosynthesis of PGE2 (see Chapter 41) and proinflam-
GC binding the GC/cGCR complex mediates not only matory cytokines, such as IL-1 and TNF-alpha. This is
classical genomic actions, but ligand binding also initi- accomplished by transrepression that finally leads,
ates a rapid release of proteins (chaperones and co- usually within hours or a few days depending on the
chaperones such as Src) from the multiprotein complex dosage applied, to the well-known and striking relief
that includes the cGCR. These (co-)chaperones are from signs and symptoms of inflammation, including
considered to be responsible for producing measurable pain.
646 FRANK BUTTGEREIT AND GERD-RDIGER BURMESTER
Retardation of Radiographic reduce the synthesis of these proinflammatory cytokines

via transrepression may contribute to their effects on
Progression radiological progression in RA.
The ability of GC to retard radiological progression in
RA was first demonstrated by Kirwan (10). In 1997,
Boers and colleagues published a multicenter, double-
Glucocorticoid Use in Daily Practice
blind, randomized trial (COBRA), in which patients The basis for the use of different GC dosages in differ-
with early RA were randomized to either step-down ent clinical conditions is essentially empirical, as the
therapy with two disease-modifying antirheumatic drugs evidence to support preferences in specific clinical
(DMARDs; sulfasalazine and methotrexate) and pred- settings is remarkably scarce (5). It is clear, however,
nisolone (start 60 mg/day, tapered in 6 weekly steps to that the GC dosages used are proportionately higher
7.5 mg/day and stopped at 28 weeks), or sulfasalazine in patients with increased clinical activity and with
alone. In the combined drug strategy group, a statisti- increased severity of the disease under treatment. The
cally significant and clinically relevant effect in retard- rationale for this (mostly successful) clinical decision is
ing joint damage was shown compared with the effect the following: (i) Higher dosages increase cGCR satura-
of sulfasalazine alone (11). In an extension of this study, tion in a dose-dependent manner which intensifies the
long-term (45 years) beneficial benefits were also therapeutically relevant, genomic GC actions discussed
shown regarding radiological damage following the above; (ii) it is assumed that with increasing dosages the
combination strategy (12). These data were later sup- nongenomic actions of GCs increasingly come into play
ported by other studies, with some of them very recently (2).
published (1315). Over the last few decades, clinicians in their daily
Proinflammatory cytokines such as IL-1 and TNF- practice had already created landmark GC doses that
alpha are key players in the process of joint damage in were still cloudy in their definition but clearly grouped
RA. They stimulate osteoblasts and T cells to produce around 7.5, 30, and 100 mg prednisolone equivalent per
RANKL which bind to RANK on osteoclast precursor day. As a result of a consensus conference, in 2002 rec-
cells and on mature osteoblasts. This finally leads to ommendations on standardized nomenclature for GC
more activated osteoclasts, which are responsible for doses and GC treatment regimens were published
bone resorption/erosions in RA. The ability of GCs to (Table 42-2) (5).
TABLE 42-2. STANDARDIZED NOMENCLATURE FOR GLUCOCORTICOID DOSES AND GLUCOCORTICOID TREATMENT
REGIMENS.
GENOMIC ACTIONS
CLINICAL (RECEPTOR NONGENOMIC
TERMINOLOGY DOSAGEa APPLICATION SATURATION) ACTIONS ADVERSE EFFECTS
Low dose 7.5 Maintenance therapy + (<50%) ? Relatively few

for many rheumatic
diseases
Medium dose >7.5 to 30 Initially given in + + (>50% to (+) Dose-dependent and

primary chronic <100%) considerable if treatment is
rheumatic diseases given for longer periods
High dose >30 to 100 Initially given in + + (+) (almost 100%) + Cannot be administered for
subacute rheumatic long-term therapy because
diseases of severe side effects
Very high dose >100 Initially given in acute + + + ([almost] 100%) ++ Cannot be administered for
and/or potentially long-term therapy because
life-threatening of dramatic side effects
exacerbations of
rheumatic diseases
Pulse therapy 250 for one or Particularly severe + + + (100%) +++ High proportion of cases with
a few days and/or potentially a relatively low incidence
life-threatening of side effects
forms of rheumatic
diseases
a
Dosage is given in milligrams of prednisone equivalent per day.
Data from references 2 and 5.
TABLE 42-3. SUGGESTED MECHANISMS MEDIATING and dose-dependent, but there is no consensus about a
GLUCOCORTICOID RESISTANCE IN RHEUMATIC safe dose. Although some studies suggest that doses of
DISEASES (SELECTION). 7.5 mg of prednisone a day or less are relatively safe, a
Reduced number of GCR and/or reduced affinity of the ligand longitudinal study observed an average loss of 9.5%
from spinal trabecular bone over 20 weeks in patients
Polymorphic changes and/or overexpression of chaperones/co- exposed to 7.5 mg of prednisolone per day. It should be
chaperones
noted, however, that in cases of inflammatory diseases,
Increased expression of inflammatory transcription factors such as RA, osteoporosis is multifactorial. Beside the
use of GCs, there are other factors that promote the
Changes in the phosphorylation status of the GCR
development of osteoporosis, including decreased phys-
Overexpression of GCR beta ical activity, duration of disease, and disease activity
(1,17). In parallel, disease-independent risk factors
Multidrug resistance gene MDR1
such as age, gender, genetic predisposition, nutritional
Alteration in the expression of membrane bound GCRs (mGCRs) factors, endocrine changes, or body weight must be
considered (1). Nonetheless, osteoporosis is probably
SOURCE: From Buttgereit F, Saag K, Cutolo M, et al. Scand J Rheum the most common adverse effect of chronic low-dose
2005;34:1421, by permission of Scandinavian Journal of Rheumatology
(www.tandf.no/rheumatology) and Taylor & Francis. GC therapy. Strategies for the prevention and treat-
ABBREVIATIONS: GCR, glucocorticoid receptor. ment of GC-induced osteoporosis are well established
(see Chapter 35).
In patients treated with low doses of GCs, osteone-
Glucocorticoid Resistance crosis is uncommon. For GCs at higher dosages it is still
a matter of debate to what extent GCs and/or the under-
Glucocorticoid resistance in RA is not well defined. lying disease, respectively, contribute to the pathogen-
However, in routine daily practice the loss of symptom- esis of osteonecrosis. Although quite often suspected,
atic relief over time is considered to be a sign of GC myopathy is currently believed to be exceedingly rare
resistance (6). By this definition, over 30% of patients with GC doses of <7.5 mg prednisolone equivalent 42
with RA become resistant after 3 to 6 months. The daily.
current knowledge of the molecular basis for GC resis-
tance in the rheumatic diseases is summarized in Table
42-3. It should be noted that GC resistance in the sense Endocrine and Metabolic
defined above is different from a specific disease entity, Adverse Effects
called familial/sporadic GC resistance, a rare condition
In patients without preexisting abnormalities of glucose
defined as generalized, partial target-tissue resistance to
tolerance, GC dose-dependently cause increased fast-
GCs. In this disease, several different hereditary muta-
ing glucose levels and a more pronounced increase of
tions in the GCR gene have been identified which
postprandial values. Patients with risk factors for the
impair normal signal transduction (6).
development of diabetes mellitus, including family
history, increased age, obesity, and previous gestational
ADVERSE EFFECTS diabetes mellitus, are at increased risk of developing
new-onset hyperglycemia during GC treatment. This
Apart from their desired clinical actions, GCs unfortu- is usually rapidly reversible when GCs are stopped,
nately also have pleiotropic effects causing a number of but some patients will go on to develop persistent
adverse reactions which limit their clinical use, espe- diabetes.
cially at higher dosages and for longer time periods One of the most notable effects of chronic endoge-
(Table 42-2). A critical and pragmatic overview of sci- nous and exogenous GC excess is the redistribution of
entific evidence on the adverse effects of GCs given at body fat and the increase of body weight. Centripetal fat
lower dosages (10 mg/day prednisolone equivalent) accumulation with sparing of the extremities is a char-
in RA has been recently published (16). As one key acteristic feature of patients exposed to long-term
message, safety data from recent randomized, con- therapy with GCs.
trolled clinical trials of low-dose glucocorticoid treat-
ment in RA suggest that adverse effects associated with Cardiovascular Adverse Effects
these lower GC dosages are modest, and are often not
statistically different from those of placebo. Glucocorticoids induce dyslipidemia, whereas their role
in atherosclerosis is controversial. Higher dosages of
GCs are considered to contribute to the development
Musculoskeletal Adverse Effects of cardiovascular disease, but evidence is currently
Glucocorticoids are the most common cause of second- lacking to show that low-dose GCs significantly increase
ary osteoporosis. The incidence of osteoporosis is time- the incidence of cardiovascular disease in RA. Because
synthetic GCs have little mineralocorticoid effects, their Therefore, physicians should anticipate the risk of infec-
potential to induce hypernatraemia, hypokalaemia, and tions with both usual and unusual organisms, realizing
sodium and water retention is low at low doses. None- that GCs may blunt the classic clinical features and
theless, induction of hypertension is seen in about 20% delay the diagnosis.
of patients exposed to exogenous GC. The mechanisms
involved have not been fully elucidated, but it is sug- Psychological and Behavioral
gested that GC-induced hypertension is dose-related
and is less likely with medium or low-dose treatment.
Disturbances
Incidences of arrhythmia and sudden death are rare and It has become consensus in the literature that the overall
mostly limited to patients receiving high-dose pulse incidence of GC-induced psychosis is 5% to 6%.
GC. However, most cases are associated with high doses of
GCs and an influence of the underlying disease, such as
Dermatological Adverse Effects systemic lupus erythematosus (SLE), is often difficult to
rule out. GC treatment has been associated with a variety
Clinically relevant adverse effects on the skin include of minor mood disturbances such as depressed or elated
iatrogenic Cushings syndrome, catabolic effects (cuta- mood, irritability or emotional lability, anxiety and
neous atrophy, purpura, striae, easy bruisability, and insomnia, and memory and cognition impairments. The
impaired wound healing), steroid acne, and hair effects. exact incidence of such symptoms in rheumatic patients
Cushingoid appearance, purpura, and easy bruisability exposed to common doses of GCs is not known, but
is seen in over 5% of the patients exposed to 5 mg doses of < 20 to 25 mg prednisone equivalent per day are
prednisone equivalent for 1 year. associated with few or no significant disturbances.
Ophthalmological Adverse Effects NEW GLUCOCORTICOID

Long-term use of systemic GCs may induce formation RECEPTOR LIGANDS
of posterior subcapsular cataract attributed to GCs. In
a group of patients with RA treated with 5 to 15 mg/day IN THE PIPELINE
prednisone for a mean of 6 years, 15% were found to
have cataracts, compared with 4.5% of matched RA Over the last five decades, strategies such as intra-artic-
controls not using prednisone. Systemic GCs also ular injections or optimized dosing regimens have been
increase the risk of glaucoma. In the general population, developed to improve the benefit/risk ratio (4). A new
18% to 36% of those exposed to GCs had an increase approach is the targeted delivery of conventional gluco-
in intraocular pressure. The incidence of this adverse corticoids using liposomes. Liposomes are small vesicles
effect tends to be higher in families, suggesting a genetic approximately 100 nm in size, which are used as a carrier
basis. Patients with preexisting glaucoma are especially system for GC drugs. These liposomes have been
sensitive and will have this condition aggravated upon reported to accumulate selectively at the site of inflam-
exposure to GCs. mation (18). Consequently, very high local concentra-
tions of GCs are achieved, as, for example, in the
inflamed joint. It has been recently shown in mice that
Gastrointestinal Adverse Effects liposomal prednisolone phosphate is able to produce a
The overall estimated relative risk for gastrointestinal strong and sustained resolution of joint inflammation
ulcer disease among current GCs users has been reported (18). Other current approaches to optimize the therapy
to be 2.0. However, the increased risk was almost com- with conventional GC drugs are formulations to change
pletely due to cotreatment with nonsteroidal anti- the timing of glucocorticoid delivery (timed-release
inflammatory drugs (NSAIDs; see Chapter 41). The tablet formulation). Also, the investigation of glycyr-
relative risk for patients comedicated with NSAIDs was rhetinic acid as a potential drug needs to be mentioned
4.4, but for those receiving GCs alone there was no sig- here. This substance inhibits 11-beta-hydroxysteroid
nificantly increased risk (1.1). dehydrogenase and increases the levels and thus the
action of endogenous glucocorticoids.
It seems, however, that efforts with conventional GC
Infectious Adverse Effects drugs have almost reached their limits (4). Further
The use of GCs is associated with increased susceptibil- improvement will require qualitatively new drugs, which
ity to various viral, bacterial, fungal, and parasitic infec- are currently under development. The intensive research
tions. In a meta-analysis of 71 trials involving over 2000 to develop innovative novel GC receptor ligands with a
patients with different diseases and different dosages of clearly improved therapeutic ratio has yielded at least
GCs, a relative risk of infection was found to be 2.0. two promising developments to date. The first develop-
ment concerns the so-called nitrosteroids. These agents 6. Adcock IM, Lane SJ. Mechanisms of steroid action
are structurally characterized by an aliphatic or aro- and resistance in inflammation. Corticosteroid-insensitive
matic molecule which links a conventional GC drug asthma: molecular mechanisms. J Endocrinol 2003;178:
with nitric oxide (NO). Drugs such as NO-prednisolone 347355.
7. Goulding NJ, Flower RJ. Glucocorticoid biology a
or NO-hydrocortisone slowly release NO which syner-
molecular maze and clinical challenge. In: Goulding NJ,
gistically enhances anti-inflammatory effects and induces
Flower RJ, eds. Milestones in drug therapy: glucocorti-
less osteoporosis than prednisolone in animal models coids. Basel: Birkhuser Verlag; 2001:5.
(19). The second group of new agents are the selective 8. Buttgereit F, Saag K, Cutolo M, da Silva JAP, Bijlsma
glucocorticoid receptor agonists (SEGRAs) or disso- JWJ. The molecular basis for the effectiveness, toxicity,
ciating glucocorticoids. As a background, it has become and resistance to glucocorticoids: focus on the treatment
evident over the last few years that many adverse effects of rheumatoid arthritis. Scand J Rheum 2005;34:1421.
of GCs are predominantly caused by the transactivation 9. Croxtall JD, Choudhury Q, Flower RJ. Glucocorticoids
mechanism (e.g., diabetes, glaucoma), whereas anti- act within minutes to inhibit recruitment of signalling
inflammatory effects are mediated mostly by transre- factors to activated EGF receptors through a receptor-
pression mechanisms (e.g., inhibition of the synthesis of dependent, transcription-independent mechanism. Br J
Pharmacol 2000;130:289298.
proinflammatory cytokines and prostaglandin biosyn-
10. Kirwan JR. The effect of glucocorticoids on joint destruc-
thetic enzymes) (2,20,21). SEGRAs induce predomi-
tion in rheumatoid arthritis. The Arthritis and Rheuma-
nantly the desired transrepression effects while having tism Council Low-Dose Glucocorticoid Study Group. N
reduced undesirable transactivation activity as com- Engl J Med 1995;333:142146.
pared with conventional GC drugs (22,23). A recent 11. Boers M, Verhoeven AC, Markusse HM, et al. Ran-
report showed a drug of this class to have effective anti- domised comparison of combined step-down predniso-
inflammatory actions but to be accompanied by reduced lone, methotrexate and sulfasalazine with sulfasalazine
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In summary, results of research over the past few 12. Landewe RB, Boers M, Verhoeven AC, et al. COBRA
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arthritis: long-term structural benefits of a brief interven-
the most effective anti-inflammatory agents available.
tion. Arthritis Rheum 2002;46:347356.
In particular, novel findings on mechanisms of action
13. Van Everdingen AA, Jacobs JW, Siewertsz Van Reesema
and new information on dose/effect relationships have DR, Bijlsma JW. Low-dose prednisone therapy for
stimulated intensive research activity with the aim of patients with early active rheumatoid arthritis: clinical
bringing increased knowledge from scientific research efficacy, disease-modifying properties, and side effects: a
into clinical use as quickly as possible. There are prom- randomized, double-blind, placebo-controlled clinical
ising approaches aimed at developing new GC receptor trial. Ann Intern Med 2002;136:112.
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being of patients with rheumatic diseases. dose prednisolone in early rheumatoid arthritis retards
radiographic progression over two years: a multicenter,
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CHAPTER 43
Operative Treatment of Arthritis

JOSEPH A. BUCKWALTER, MS, MD
W. TIMOTHY BALLARD, MD
Surgical treatments of arthritis and musculoskeletal Total joint replacements are now possible for most
diseases may be used to prevent progression, relieve of the major joints affected and damaged by
pain, and/or improve joint function. arthritis.
The success of surgical interventions is dependent on
careful considerations of pre-, intra-, and postopera-
tive aspects of the surgery.
Pain not relieved by other treatments is the most PREOPERATIVE EVALUATION

common indication for operative treatment of arthritis.
Loss of joint function is a less common indication for With the exception of people in whom arthritic disor-
surgical treatment because function restoration is ders have caused or may cause spinal instability and
usually less predictable than pain relief. Operative treat- neurologic damage, operative treatment is elective.
ments include joint debridement, synovectomy, osteot- Patients should have an extensive preoperative evalua-
omy, soft tissue arthroplasty, resection arthroplasty, tion and should understand the full range of therapeutic
fusion, and joint replacement. In addition, people with options. The physician needs a thorough understanding
rheumatoid arthritis (RA) may benefit from tenosyno- of the degree of pain and functional limitation and an
vectomy and repair or reconstruction of ruptured understanding of the patients social and occupational
tendons. needs and expectations. Before planning surgery, pa-
Although operative treatments can produce excel- tients should understand the potential benefits and
lent results, they also expose patients to serious risks. risks. In general, the patients most likely to notice sig-
Potential operative and perioperative complications nificant lasting benefit from operative treatment are
include extensive blood loss, cardiac arrhythmia and those with joint pain unrelieved by nonsurgical treat-
arrest, nerve and blood vessel injury, infection, venous ment. Patient age, overall health status, and capacity to
thrombosis, and pulmonary embolism. Late postopera- adhere to postoperative rehabilitation and precautions
tive complications include delayed infection and loos- also help determine the outcome.
ening and wear of implants. Even in the absence of Even in people with obvious joint disease, pain, and
complications, the results of surgical procedures such loss of function, failure to carefully evaluate the cause
as joint debridements, synovectomies, and osteotomies of the symptoms can lead to disappointing results.
may deteriorate with time. For these reasons, the Common diagnostic dilemmas include differentiating
potential risks and expected short-term and long-term hip joint pain from lumbar radicular pain and shoulder
outcomes of operative treatment must be carefully joint pain from cervical radicular pain. Rheumatoid
considered for each patient. Nonetheless, individuals arthritis and other types of inflammatory arthritis may
who fail to gain satisfactory results from nonsurgical cause such severe joint deformity that detecting neuro-
therapy or who have progressive disease should be logic involvement becomes difficult. Patients may
evaluated by a surgeon before they develop deformity, develop joint sepsis that is not readily apparent because
joint instability, contractures, or advanced muscle of the inflammatory nature of their underlying disease
atrophy. Delaying surgery until these problems develop and the use of medications that suppress the inflamma-
can compromise the results and increase the risk of tory response to infection. A careful history, physical
complications. examination, and plain radiographs are sufficient to
651
652 JOSEPH A. BUCKWALTER AND W. TIMOTHY BALLARD
define the cause of symptoms for most, but in some function. To reduce the risks of operative and post-
cases, joint aspiration, electrodiagnostic studies, and operative complications, including excessive bleeding
additional imaging studies are needed to clarify the and compromised healing, doses of nonsteroidal anti-
cause of pain and loss of function. inflammatory drugs (NSAIDs) and corticosteroids
Before considering surgical intervention, patients should be decreased before surgery when possible. Pre-
should first be treated with nonoperative interventions operative evaluation and instruction by physical and
including medications, ambulatory aides, activity modi- occupational therapists facilitate rehabilitation for some
fication, physical therapy, and orthoses. Braces may patients. In selected patients, delaying surgery will make
control instability and decrease pain in the spine, knee, it possible to achieve optimal management of cardiovas-
ankle, wrist, or thumb. A cane may be considered for cular or other systemic disorders, allow them to improve
patients with lower extremity arthritis. In addition to their nutritional status and muscle strength, or reduce
reducing the body weight load to the joints of the lower their weight.
extremity, a cane reduces the hip abductor forces
required to keep the pelvis level during gait, thereby
reducing hip joint reactive forces by up to 20% in the DISEASE-RELATED FACTORS
contralateral hip.
Weight reduction for obese patients can decrease Options and indications for surgical treatment vary con-
symptoms and increase the probability of successful siderably among the arthritic diseases. Thus, the physi-
operative treatment. There is some evidence of an cian must consider the unique features of each disease
increased incidence of infection in obese patients fol- in making decisions or advising patients concerning
lowing total joint arthroplasty (1), as well as increased operative treatment.
intraoperative blood loss (2). It is not clear whether or
not obesity increases the risk of implant loosening, but
this may be because heavier patients are less active. For
Osteoarthritis
some overweight patients, the pain and loss of mobility A number of surgical procedures have the intent of
caused by arthritis makes it more difficult to reduce decreasing symptoms for people with OA while pre-
their weight or avoid gaining weight. In these individu- serving or restoring a cartilaginous articular surface.
als, surgeons may recommend proceeding with opera- These include arthroscopic joint debridement, resec-
tive treatment despite the increased risks associated tion or perforation of subchondral bone to stimulate
with obesity. formation of cartilaginous tissue, and use of grafts to
The importance of a thorough preoperative history replace degenerated articular cartilage. By removing
and physical examination, as well as careful periopera- loose fragments of cartilage, bone, and meniscus (and,
tive medical management, cannot be overemphasized. in some instances, osteophytes), joint debridement may
Many patients who could benefit from surgical treat- improve joint mechanical function and may decrease
ment, especially people with osteoarthritis (OA), are pain. Penetration of subchondral bone in regions of
elderly and may have decreased cardiac, pulmonary, advanced cartilage degeneration stimulates formation
renal, or peripheral vascular function. These conditions of cartilaginous repair tissue, but because it lacks the
require evaluation and, in some cases, treatment before properties of normal articular cartilage, this tissue fre-
surgery. Carious teeth, pharyngitis, cystitis, and other quently degenerates. Replacing localized regions of
potential sources of infection should be treated prior to degenerated cartilage with osteochondral, perichon-
surgery. Men with symptoms of prostatic hypertrophy dral, periosteal, and chondrocyte grafts has produced
need a urologic evaluation before surgery and women promising short-term results in small series of patients.
should be evaluated for asymptomatic urinary tract Overall, current procedures performed with the intent
infections. Preoperative laboratory evaluation should of preserving or restoring a cartilaginous articular
include a measure of hemoglobin and hematocrit, uri- surface and decreasing symptoms are not likely to be
nalysis, and other diagnostic tests as indicated by the beneficial in people with advanced joint degeneration,
individuals medical history. but they may be helpful in selected people with less
severe disease.
Osteotomies correct malalignment and shift loads
PREPARATION FOR OPERATIVE from severely degenerated regions of the articular
TREATMENT surface to regions that have remaining articular carti-
lage. In selected patients with OA, osteotomies of the
All patients should receive instruction concerning the hip and knee decrease pain, but in general the results
planned procedure, the risks and common complica- are less predictable than joint replacement. For these
tions, the type and extent of postoperative rehabilita- reasons, surgeons most commonly recommend osteoto-
tion, and expectations for postoperative pain relief and mies for young active people who have a stable joint
C H A P T E R 4 3 O P E R A T I V E T R E A T M E N T O F A R T H R I T I S 65 3
with a functional range of motion, good muscle func- ments cannot be expected to provide a lifetime of
tion, and some remaining articular cartilage. normal function for young active patients.
Joint fusion (i.e., arthrodesis) can relieve pain and
restore skeletal stability and alignment in people with
advanced OA. Because this procedure eliminates joint
motion, it has limited application. Furthermore, fusion People with RA require careful evaluation to prevent
of one joint increases the loading and motion of other operative and perioperative neurologic injury, establish
joints, perhaps accelerating degeneration. For example, the sequence and timing of joints to be treated surgi-
fusion of the hip increases the probability of developing cally, and reduce the risks of infection and other
degenerative disease in the lumbar spine and ipsilateral complications.
knee joints. Currently, surgeons most commonly per- People with RA commonly have cervical spine
form fusions for treating degeneration of cervical and involvement that can lead to spinal instability and
lumbar spine, hand interphalangeal, first metatarsopha- increased risk of neurologic deficits. Neurologic changes
langeal, wrist, and ankle joints. may be difficult to recognize due to limited joint motion
For selected joints, resection of degenerated articular and associated disuse muscle atrophy. To evaluate the
surfaces and replacement with implants fabricated from risk of neurologic injury, people with RA should have
polyethylene, metal, or other synthetic materials can active flexion and extension lateral cervical radiographs
relieve pain and allow the patient to maintain joint within 1 year before surgery. In a retrospective review
mobility (Figure 43-1). Over the past several decades, of 113 patients with RA who underwent total hip or
replacing the hip and knee have proven to be effective knee arthroplasty, Collins and colleagues (3) reported
methods of relieving pain and maintaining or improving significant atlantoaxial subluxation, atlantoaxial impac-
function. Recent advances have led to better methods tion, and/or subaxial subluxation in 69 patients (61%).
and implants for replacement of the hip, knee, shoulder, Thirty-five of these 69 patients (50%) had no clinical
and elbow. Unfortunately, joint replacements have limi- signs or symptoms of instability at the time of admission
tations, primarily because the new surface lacks the for joint replacement arthroplasty. Instability of greater
mechanical properties and durability of articular carti- than 7 to 10 mm at the atlantoaxial joint or greater than
lage and because the prostheses must be fixed to the 4 mm at subaxial levels on flexion and extension lateral
patients bones. None of the currently available syn- radiographs generally requires stabilization prior to
thetic materials duplicates the ability of articular carti- other elective surgery. Patients with lesser degrees of
lage to provide a painless, low friction gliding surface atlantoaxial and subaxial involvement should be evalu- 43
and to distribute loads across the synovial joint, nor can ated by the anesthesiologist preoperatively and consid-
current implants achieve the stability and durability of eration given to an awake intubation.
the bond between articular cartilage and bone. Thus, Patients with multiple joint involvement require
wear of implants limits their life span, and loosening can careful planning and timing of various joint procedures
lead to failure. For these reasons, current joint replace- to allow optimal rehabilitation. Patients undergoing
FIGURE 43-1
(A) Anteroposterior radiograph of the pelvis of a 61-year-old female showing a normal left hip
and severe osteoarthritis of the right hip. Note that the x-rays are turned as though the patient
was facing the reader. (B) The same patient after an uncemented total hip arthroplasty.
(C) Photograph of an uncemented total hip arthroplasty like that used in this patient.
A, B C
lower extremity surgery may require surgical stabiliza- plasties. Eight patients on methotrexate had a total of
tion of the upper extremity first to allow crutch ambula- eight wound complications (8.7%) versus five patients
tion and use of the upper extremities to assist with with a total of six wound complications in the non-
transfers, rising from a chair, and stair climbing. For methotrexate group (5.5%, p = 0.366). In a randomized,
example, a person with severe wrist involvement as well nonblinded prospective study of 64 patients with RA on
as hip involvement may benefit from wrist arthrodesis methotrexate therapy, Sany and coworkers (7) reported
prior to total hip arthroplasty. The patient with multiple no infections and no difference in wound healing
lower extremity joint involvement may benefit from between patients whose therapy was discontinued 7
treating joints either sequentially or simultaneously, days before an orthopedic procedure and those whose
depending on the joints involved and the severity of the therapy was continued perioperatively.
disease. The patient with severe disease and contrac- Tumor necrosis factor (TNF) inhibitors are an excit-
tures of both knees, for example, may benefit from ing class of agents which are relatively new to the treat-
having both knees replaced at the same time. In that ment of inflammatory arthritis. Tumor necrosis factor
situation, if only one knee is replaced, a flexion contrac- alpha (TNF-alpha) is one of the cytokines which stimu-
ture in the untreated knee will cause the patient to keep lates cartilage matrix degradation via metalloprotein-
the operatively treated knee flexed when standing and ases. Whereas these medications have offered decreased
thereby compromise rehabilitation following surgery. pain and increased function to many patients with
Foot and ankle disease are generally addressed prior to inflammatory arthritis, they are also now known to be
hip and knee arthroplasty to provide the patient a stable associated with an increased incidence of various infec-
lower extremity on which to stand and rehabilitate the tions. Strict guidelines for their perioperative utiliza-
hip and knee. tion have not been established. Nonetheless, it is
Long-term use of corticosteroids increases the com- currently not advisable to treat patients in the periop-
plexity of surgical treatment of people with RA. In erative period with TNF inhibitors, particularly when
general, these patients will require stress dose ste- an implant such as a total joint replacement is being
roids perioperatively due to inhibition of their adrenal placed.
function. Long-term corticosteroid use combined with
the effects of the disease can cause connective tissue
changes that make the skin and superficial blood vessels
Juvenile Inflammatory Arthritis
friable. Extreme caution must be used in physically Joint replacement arthroplasty in children with juvenile
handling such a patient. For example, in severely inflammatory arthritis (JIA) is reserved for patients
affected patients, mild pressure can cause a hematoma who are debilitated by pain and/or decreased function,
or skin ulceration and adhesive tape can tear the skin. and is generally delayed until patients are skeletally
In addition, chronic low-dose corticosteroid use in mature. Joint replacement is also delayed because the
patients with RA has been correlated with an increased life expectancy of the young patient is greater than that
incidence of fracture, infection, and gastrointestinal of current prostheses. Moreover, each subsequent revi-
hemorrhage or ulcer. People with RA treated with sion surgery necessarily involves greater periprosthetic
total joint arthroplasties demonstrated a higher inci- bone loss and less predictable long-term results. People
dence of infection than patients with OA treated with with JIA are often candidates for tendon lengthening to
total joint arthroplasties (1). Patients with RA fre- correct contractures, and prophylactic procedures, such
quently have more than one joint arthroplasty, and as synovectomy, to alleviate symptoms and possibly
infection of one arthroplasty is associated with an delay articular destruction.
increased incidence of subsequent infection of another Patients with JIA present important anesthetic risks.
replaced joint (4). Although they do not develop cervical spine involve-
Many people with RA are treated with NSAIDs and/ ment and accompanying neurologic deficits as com-
or methotrexate preoperatively. A review of 165 patients monly as adults with RA, these problems do occur in
undergoing total hip arthroplasty found a higher inci- association with JIA. Therefore, people with JIA
dence of gastrointestinal bleeding and/or hypotension require preoperative screening radiographs as described
in patients receiving NSAIDs at the time of hospital for patients with RA. Unilateral collapse of the lateral
admission (5). Several studies have demonstrated that mass of the atlas, with or without axis involvement,
there is no increase in wound or other postoperative may result in a fixed rotational head tilt deformity that
complications in patients who continue methotrexate makes it difficult to establish an airway for general
therapy perioperatively. Perhala and colleagues (6) anesthesia. Micrognathia associated with temporoman-
compared 60 patients with RA who underwent a total dibular joint involvement can also make endotracheal
of 92 joint arthroplasties without interruption of metho- intubation difficult. Restricted motion of the axial and
trexate therapy to a group of 61 patients not receiving appendicular skeleton can make regional anesthesia
methotrexate who underwent a total of 110 joint arthro- difficult as well.
Osteonecrosis atrophy. Various regimens have been tried to prevent

postoperative soft tissue ossification, but radiation
Treatment of osteonecrosis remains controversial, par- therapy delivered locally appears to be the most effec-
tially because the natural history of the disorder remains tive means of preventing heterotopic bone formation
unknown. Nonsteroidal anti-inflammatory agents and after surgery. Fractionated and single low-dose radia-
decreased joint loading are commonly employed for tion therapy to the hip and abductor musculature have
temporary symptomatic relief, though neither has been been effective when begun early in the postoperative
shown to affect the long-term results. Electromagnetic period.
stimulation has also been employed on an experimental
basis. Most surgical treatments of osteonecrosis have
been developed for treatment of the hip. Core decom- Psoriatic Arthritis
pression (i.e., drilling a channel from the lateral surface The perioperative concerns with NSAIDs and metho-
of the femur into the necrotic region of the femoral trexate discussed with RA apply to psoriatic arthritis
head), with or without bone grafting, has been advo- as well. A unique perioperative risk in people with pso-
cated for patients who have femoral osteonecrosis riatic arthritis is the development of a flare of psoriasis
without collapse or acetabular changes. In most series, at the operative site due to the physiologic and/or psy-
these procedures have decreased pain in a high percent- chological stress of surgery. Also known as isomorphic
age of the patients. This treatment is generally consid- or Koebners phenomenon, this process may pre-
ered ineffective in people whose femoral head shows dispose the patient to a generalized flare of psoriasis
any signs of collapse; however, for these patients, various as well. People with psoriatic arthritis may have an
other surgical options exist. These options include increased incidence of postoperative infections. Menon
femoral osteotomies, designed to place an intact segment and Wroblewski (8) reported superficial wound infec-
of the femoral head in a weight-bearing position, and tion in 9.1% and deep wound infections in 5.5% of
hip arthrodesis. Replacement of the femoral head or their 38 patients with psoriasis treated with total hip
total hip have met with excellent results in this popula- arthroplasty.
tion, but prosthesis durability is a concern, particularly
in young patients.
Hemophilic Arthropathy
Despite the risk of excessive bleeding, operative treat-
Ankylosing Spondylitis ment can produce good results in people with hemo- 43
Joint replacements decrease pain and improve function philic arthropathy. Synovectomy is commonly performed
for people with advanced joint disease due to ankylos- in the knee and elbow, and gives improved range of
ing spondylitis (AS). Osteotomies that correct spinal motion and decreased pain to the majority of patients.
deformities can also be of benefit for some. Spinal in- Total knee and total hip replacements can improve
volvement can lead to extensive ligamentous calcifica- function and relieve pain in hemophilic patients with
tion and heterotopic ossification that make regional advanced joint degeneration (9).
anesthesia difficult, if not impossible. Patients with pro- Hemophilic arthropathy may be particularly difficult
longed disease also develop severe kyphotic deformities to manage perioperatively. Factor replacement has
of the cervical, thoracic, and lumbar spine that impede important risks and must be carefully monitored. A
endotracheal intubation. Restricted chest excursion thrombotic event may be precipitated by repeated
may further complicate intraoperative and postopera- factor infusions, and resultant disseminated intravascu-
tive care. Patients with AS tend to bleed more during lar coagulation after elective surgery has been reported.
and after surgery than similar, otherwise healthy indi- The subgroup of patients with high levels of factor anti-
viduals. The explanation for this bleeding tendency body are generally contraindicated for major elective
appears to be that compared with normal tissues, the surgery.
ossified soft tissues are less capable of contracting to Whether or not people with well-controlled hemo-
assist in hemostasis. There does not appear to be an philia without acquired immunodeficiency syndrome
associated defect in blood coagulation or platelet (AIDS) are at increased risk for nontransfusion-related
function. infection is unclear. Septic arthritis has been reported
People with AS, diffuse idiopathic skeletal hyperos- as a rare complication of hemophilia, but one that must
tosis, or post-traumatic osteoarthrosis are at increased be promptly diagnosed and definitively treated. Human
risk for postoperative heterotopic ossification. Although immunodeficiency virus (HIV)-1infected hemophilia
patients with AS have excellent pain relief after total patients who have not developed AIDS do not appear
hip arthroplasty, gains in total range of motion are often to have an increased incidence of infection after surgery
limited due to periarticular heterotopic ossification, as when compared with patients who are seronegative for
well as longstanding soft tissue contractures and muscle HIV-l.
Pigmented Villonodular Synovitis eases. Recent long-term follow-up studies show that
total hip replacements will provide excellent function
Pigmented villonodular synovitis most commonly infor more than 20 years in appropriately selected patients
volves the knee and has been reported in patients (11). Initially, surgeons limited hip replacement to
ranging in age from the second to the ninth decade. It patients between the ages of 60 and 75 years, but over
also occurs in the ankle and shoulder, as well as in other the last decade studies have shown that younger and
joints where it may be more difficult to detect. Arthros- more elderly patients also can benefit from this proce-
copy may allow for early diagnosis. Synovectomy, by dure. Although most patients who have a hip replace-
arthrotomy or arthroscopy, usually provides symptom- ment increase their level of physical function, patients
atic relief, and may be curative in patients with the with limited expectation for improved function also can
localized form of the disease. The diffuse form of the benefit from the procedure.
disease responds less favorably to synovectomy, with The risk of postoperative venous thrombosis and
recurrences in more than one third of patients. Radia- infection in people treated who have undergone hip
tion does not appear to decrease the recurrence rate, replacements has significantly decreased in the past two
and may lead to local soft tissue complications. decades. Early series of hip replacements reported a
high rate of failure due to infection, but modern aseptic
Synovial Chondromatosis techniques and prophylactic antibiotics have reduced
Synovial chondromatosis is a rare condition that results the incidence of infection to less than 1 % (12). Loosen-
in the formation of cartilaginous fragments that may lie ing remains the predominant cause of long-term failure
in synovial joint cavities, the synovium, or, in some of hip replacements, but recent research has clarified
instances, in the periarticular soft tissues. The condition the causes of this problem. Particulate debris, the major-
causes pain, catching, and locking of the joint as well as ity of which appears to be generated from wear of poly-
loss of joint motion and possible degeneration of the ethylene surfaces, stimulates osteoclastic bone lysis at
articular surfaces. the bonecement interface in prostheses fixed with
Removal of intra-articular loose bodies and, in some poly(methyl methacrylate) and at the prosthesisbone
instances, synovectomy can relieve symptoms and interface in uncemented implants. The osteolysis can
improve motion in patients who have not developed lead to loosening of the prostheses, bone loss, and bone
degenerative joint disease. However, the cartilage frag- fractures (Figure 43-2). Improvements in cement tech-
ments reaccumulate in many joints. In patients with
degenerative joint disease, joint replacement combined
with synovectomy can cure the disease.
SITES OF SURGICAL
INTERVENTION
The operative treatments that provide the best results
vary not only among the different types of arthritis, but
also among anatomic sites. Thus, the most appropriate
procedure should be chosen based on the joint involved,
the type of arthritis, the patients age, and other social
and medical factors.
Hip
The most commonly employed operative treatments for
arthritis of the hip are cemented [i.e., anchored with FIGURE 43-2
poly(methyl methacrylate) cement] and uncemented
Radiograph showing a left hip replacement with bone resorption
total hip anhroplasty. More than 120,000 hip prostheses around the femoral bone cement, loosening of the prosthesis,
are implanted in the United States each year (Figure and a fracture through the proximal femur. This 67-year-old
43-1) (10). Osteotomies and fusions are performed less man had a hip replacement 14 years ago. He was not evaluated
frequently than hip replacements, but can produce good for the last 7 years. Despite the development of severe peripros-
results in certain patients. thetic osteolysis, he did not notice any problems with his hip
until he tripped on an electrical cord and sustained the fracture.
Nearly 40 years of clinical studies now document the Earlier detection of the asymptomatic osteolysis followed by
success of total hip replacement for the treatment of surgical revision would have prevented the fracture and
disabling pain and impairment due to chronic hip dis- extensive loss of bone.
niques have decreased the incidence of aseptic femoral Minimally invasive surgery (MIS) is a term com-
loosening from as high as 40% to less than 5% 10 years monly used with respect to conventional total knee and
after the procedure for many groups of patients. Even total hip arthroplasty. MIS is a qualitative term more
in a group of patients who were younger than 50 years than one specifically defined by an objective measure,
at the time of cemented hip arthroplasty, only 8% had such as the length of the incision. Most orthopedic sur-
evidence of femoral component loosening 16 to 20 years geons would agree that the length of the skin incision is
after the procedure (13). In contrast, cemented acetabu- in fact the least important factor in minimally invasive
lar components continue to have a high rate of loosen- surgery. Improved instrumentation and modification of
ing despite improved cement techniques. Preliminary surgical approaches in these instances now allow pres-
reviews of the results with uncemented acetabular com- ervation of deep tissues to a greater extent. To this end,
ponents [Figure 43-1(B)] suggest that they may have decreased blood loss, increased function, and quicker
better results. The global trend in total hip arthroplasty recovery can be expected.
has been toward uncemented femoral components as Resection arthroplasty, originally described for treat-
well. Through a variety of methods, porous coatings are ment of tuberculous arthritis of the hip and osteomyeli-
applied to a portion or all of the intramedullary stem. tis, is seldom employed as a primary procedure today.
Bone ingrowth into the pores allows stable intraosseous It remains an option for people with recalcitrant infec-
fixation without the need for cement. Changes in femoral tion involving a total hip arthroplasty and for low-
component geometry and porous coating have led to demand patients who are not candidates for more
improved tolerance such that the survivorship of the extensive reconstruction. After resection arthroplasty,
components can be reasonably expected to exceed 20 the proximal femur is allowed to articulate with the
years in the majority of patients. In September 1994, a acetabulum or the ilium. Surprisingly, the majority of
National Institute of Health Consensus Development otherwise healthy patients are pain-free and ambula-
Conference Panel convened to evaluate the available tory, but generally require one or two crutches and a
scientific information concerning total hip replacement, substantial heel lift to walk. Today, resection arthro-
and concluded that total hip replacement is a highly plasty is generally reserved for salvage of a failed hip
successful method of treating pain and disability and arthroplasty that is not amenable to revision.
that the vast majority of the patients have an excellent
prognosis for long-term improvement in symptoms and
function (10). The panel noted that implant loosening
Knee
remains a problem and recommended regular follow- A variety of operative procedures have been described 43
up to detect impending failure early and allow treat- for treatment of arthritis of the knee, including arthros-
ment before significant bone loss or fracture occur copy, osteotomy, and replacement arthroplasty. The
(Figure 43-2). indications for these procedures differ significantly.
Despite its great success, total hip arthroplasty has Arthroscopy has advanced the diagnosis and treat-
important limitations, particularly for young patients ment of many forms of knee arthritis. It is particularly
who are likely to outlive the prosthesis. Alternatives to useful for people whose symptoms may be attributed to
arthroplasty include osteotomy, arthrodesis, and resec- a specific mechanical etiology, such as a meniscus tear
tion arthroplasty. Femoral and pelvic osteotomy have or loose body (Figure 43-3). Arthroscopic synovectomy
been shown to be effective in relieving pain in young can decrease pain and swelling for patients with hemo-
patients with acetabular dysplasia and minimal or no philia, pigmented villonodular synovitis, synovial chon-
radiographic degenerative change. Whether or not they dromatosis, and early RA without significant cartilage
alter the natural history of hip dysplasia is unclear. erosion. Whether or not it alters the long-term course
Results are less favorable in adults older than 40 years of these diseases is unclear. Arthroscopic debridement
and in patients with significant degenerative change. or chondroplasty for degenerative knee arthritis, except
Arthrodesis of the hip offers young patients with hip in cases of degenerative meniscal tears or intra-articular
arthritis a dependable, durable, pain-free hip. Once loose bodies, does not appear to affect the natural
fusion is obtained, the patient may return to vigorous history of the disease. It may, however, provide short-
activity without the limitations imposed on arthroplasty term relief of symptoms for some patients.
patients. However, some patients find the prospect of a Osteotomy about the knee is intended to redirect the
stiff hip unacceptable. At long-term follow-up, patients weight-bearing axis away from a degenerative portion
complain of some difficulty sitting in a chair and using of the tibiofemoral joint, and may also stimulate devel-
public transportation, but otherwise perform activities opment of fibrocartilage in the unloaded degenerative
of daily living very well with excellent pain relief. compartment. The majority of knee osteotomies are
Patients who develop associated lumbosacral pain later valgus osteotomies of the proximal tibia, performed to
in life may be considered for conversion of the arthro- redirect weight-bearing forces from a degenerative
desis to a total hip arthroplasty. medial tibiofemoral articulation through a better-
A B
FIGURE 43-3
(A) Arthroscopic view of the medial knee compartment of a 35-year-old male showing a
displaced medial meniscal tear. The fragment is between the medial femoral condyle and the
medial tibial plateau. (B) The same medial compartment after removal of the meniscal fragment.
preserved lateral compartment. Femoral osteotomies postosteotomy, with 60% to 70% good results at 10 to
are preferred for valgus and excessive varus deformities 15 years follow-up (14). It is difficult to compare these
of the knee. Osteotomies generally are chosen over results with those of total knee arthroplasty, where the
total knee arthroplasties for young, heavy, active patients are generally older and less active.
patients, and should be reserved for patients with non- Total knee arthroplasty, similar to total hip arthro-
inflammatory disease. Appropriate candidates have plasty, may be performed with cement or bone ingrowth
<50 of flexion contracture, >90 of flexion, and isolated as the means of fixation (Figure 43-4). Several large
medial or lateral tibiofemoral arthritis without signifi- series reveal that tibial and femoral results are excellent
cant patellofemoral involvement. Good results have regardless of the type of fixation, with 97% survivorship
been reported in 80% to 90% of patients for 6 to 9 years of prostheses at 10- and 12-year analyses (15). Despite
FIGURE 43-4
(A) Anteroposterior radiograph of both knees in a 74-year-old patient with severe osteoarthritis.
(B) Acute postoperative radiograph showing bilateral cemented posterior stabilized total knee
arthroplasties. Note the staples from surgical repair of the skin.
A B
excellent results with cement fixation, some surgeons reserved for non-inflammatory arthritides, but it may
reserve cemented tibial and femoral components for also provide relief of pain and decreased frequency of
patients older than 50 or 60, or patients with poor bone intra-articular bleeding in patients with hemophilic
stock, based on the assumption that uncemented com- arthropathy.
ponents will last longer for young patients and preserve Arthrodeses of the foot and ankle offer pain relief
their bone stock. Patellar problems are the leading and stability to people with severe arthritis. Fusions of
cause of failure after total knee arthroplasty. Unlike these joints are well tolerated, even by children, despite
tibial and femoral results, results of uncemented patel- some restriction of stressful activities such as hilI climb-
lar components, which require a metal backing for bone ing and running. Although the vast majority of patients
ingrowth, are substantially inferior to results of cemented with ankle and/or peritalar arthrodeses obtain excellent
all-polyethylene patellar components, and have thus relief of pain and increased function, initial nonunion
fallen out of favor in recent years. of the arthrodesis occurs in 5% to 30% of cases. Infec-
Unicompartmental arthroplasty is a type of knee tion and delayed wound healing have been reported in
arthroplasty wherein the femoral condyle and adjacent 25% to 40% of patients with RA who undergo tibiotalar
proximal tibial plateau in either the medial or lateral arthrodesis, yet the majority have an excellent long-
compartment is replaced while the opposite side is left term result.
with native cartilage. Although these devices have Unlike total replacement arthroplasty of the hip and
been available for several decades, there has been a knee, ankle replacement arthroplasties have not pro-
resurgence of interest in their utilization due to the fact duced predictable results. By 5 to 10 years after surgery,
that they require removal of less bone and allow pres- 60% to 90% of these prostheses have failed. Most sur-
ervation of more of the native joint. In addition, they geons now limit the use of this procedure to treatment
may offer appropriately selected patients less blood of inflammatory arthritis in minimally active elderly
loss and quicker recovery than total knee arthroplasty. patients who have multiple joint involvement.
However, these devices are not recommended for
patients with substantial deformity or tricompartmen-
tal osteoarthritis.
Hand and Wrist
Knee arthrodesis is an option for patients with recal- The distal interphalangeal joints and thumb carpometa-
citrant infection or failed total knee arthroplasty that carpal joints are the most commonly involved joints
cannot be revised effectively. Despite loss of knee in OA of the hand, while proximal interphalangeal,
motion, a functional lower extremity that permits pain- metacarpophalangeal, carpometacarpal, radiocarpal, 43
less weight bearing can be expected using current tech- and distal radioulnar joints are more commonly involved
niques. Resection arthroplasty has also been used for in inflammatory arthropathy. Surgeons use a variety
patients with failed total knee arthroplasty. of joint and soft tissue procedures to treat these
disorders.
When evaluating the wrist and hand in people with
Foot and Ankle RA, it is imperative to obtain a history of the patients
Surgical options for arthritis of the foot and ankle functional abilities, carefully noting any recent changes.
include cheilectomy (resection of an osteophyte), Inability to actively flex or extend interphalangeal and/
arthroscopic debridement, osteotomy, arthrodesis, and or metacarpophalangeal joints with preservation of
replacement arthroplasty. passive motion usually signals a ruptured tendon. Flexor
Osteophytes may develop at the periphery of a joint and extensor tendons in patients with rheumatoid
and cause symptoms related to impingement during disease are more susceptible to rupture than normal
normal walking. These are not uncommon on the tendons. Underlying ultrastructural changes associated
dorsum of the first metatarsophalangeal joint and the with the inflammatory process weaken the tendons, and
anterior aspect of the tibiotalar joint. Although it does abnormal bony prominences, particularly at the distal
not cure the underlying disease, cheilectomy often pro- radioulnar joint, abrade the weakened tendons, making
vides relief of mechanical symptoms and associated them prone to rupture. Tenosynovectomy not only pro-
pain. Loose bodies may also be a source of mechanical vides decreased pain with increased range of motion
symptoms and are amenable to arthroscopic removal. and grip strength, but also appears to protect the
Supramalleolar tibial osteotomy allows realignment tendons, particularly when combined with resection of
of the weight-bearing axis through the tibiotalar joint. abnormal bony prominences. Acute tendon ruptures
This can help to preserve the joint in various congenital should be evaluated early by a surgeon for consider-
and post-traumatic degenerative conditions of the ankle. ation of reconstruction prior to the development of
Low tibial osteotomy has been shown to be particularly fibrosis and contractures. In the rheumatoid hand, the
effective in long-term relief of symptoms with inter- metacarpophalangeal joints of the fingers are generally
mediate-stage primary OA. Osteotomy is generally reconstructed with silicone implants that function as
flexible spacers. Ulnar drift of the digits with resultant of the radius is minimal after this procedure, and elbow
ulnar subluxation of the extensor tendons may be at instability is seldom a concern if the medial collateral
least partially corrected by surgical centralization of the ligament complex is intact. Patients generally have good
extensor tendons and transfer of the intrinsic hand intermediate-term relief of pain with increased range of
muscle insertions from one digit to the adjacent digit on motion. In one series, 84% of people with RA reported
the ulnar side. good pain relief 6 months after the procedure (16).
Arthrodesis is commonly employed in the interpha- Synovectomy may be performed alone or in conjunc-
langeal joints, carpus, and wrist for end-stage joint tion with other procedures, such as radial head resec-
degeneration due to most arthritic disorders. Interpha- tion. Patients with hemophilia likewise have decreased
langeal joints are best managed with arthrodesis in a pain and swelling following synovectomy, as well as a
partially flexed position. Solid fusion can be reliably decreased incidence of hemarthrosis. Arthroscopy has
obtained in more than 95% of cases using various tech- been used effectively to perform synovectomies as well
niques. Arthrodesis may also be performed at the radio- as remove loose bodies and osteophytes from arthritic
carpal joint or selectively at diseased intercarpal joints. elbows.
Although some reduction in wrist motion and grip Elbow joint replacement arthroplasty, while newer
strength are commonly noted with limited intercarpal than hip and knee arthroplasty, has developed rapidly.
arthrodeses, long-term pain relief and stability are The rate of loosening in young active patients with post-
excellent. traumatic arthropathy approaches 50% at 5- to 8-year
Surgeons rarely recommend arthrodesis of arthritic follow-up. However, intermediate-term results in low-
thumb carpometacarpal joints, because motion of these demand patients with inflammatory disease are prom-
joints is particularly important for overall hand func- ising, with survival of the components and good or
tion. The degenerative thumb carpometacarpal joint is excellent results reported in more than 90% of RA
amenable to interposition arthroplasty (resection of patients at 3- to 8-year follow-up (17). Motion was
the joint surfaces and interposition of soft tissue, reportedly improved to a functional range and pain
usually a portion of the abductor pollicis longus or relief was substantial for >90% of these patients.
flexor carpi radialis tendons), which yields excellent
pain relief and increased grip strength. Experience
with arthroplasty of the wrist is limited, partially due
Shoulder
to the predictable results obtained with wrist fusion. The high degree of compensatory movement in the
Intermediate-term results have been mixed. Silicone scapulothoracic articulation, as well as elsewhere
spacer implants yielded a high incidence of failure with throughout the upper extremity, may be responsible for
poor pain relief in approximately 50% of patients an the relatively low incidence of patients requiring opera-
average of 5 to 6 years after the procedure. Wrist tive treatment of arthritic glenohumeral joints. None-
arthroplasty designs have yielded improved clinical theless, some patients will be debilitated by an arthritic
outcome, but component failure remains a problem. In shoulder, fail nonoperative treatment, and present for
selected patients with degenerative disease of the consideration of surgical intervention.
radiocarpal joint, resection of the proximal row of Shoulder arthrodesis yields excellent pain relief and
carpal bones (i.e., proximal row carpectomy) can provides a stable upper extremity with long-term dura-
reduce pain. bility for young patients with severe glenohumeral
arthritis. Fusion is reliably obtained in the majority of
patients with relatively few complications. Despite rigid
Elbow fusion of the glenohumeral joint, abduction of 50 and
Routine activities of daily living require a wide range of flexion of 40 in the shoulder girdle is possible via scapu-
elbow flexion and extension as well as pronation and lothoracic motion.
supination. Although elbow fusion can be reliably Total shoulder arthroplasty has recently become
obtained with internal fixation, this results in substantial increasingly used for the treatment of severe glenohu-
impairment because shoulder and wrist motion cannot meral arthritis (Figure 43-5). The majority are per-
adequately compensate for loss of elbow motion. For- formed for RA of the glenohumeral joint. Pain relief
tunately, radial head excision, synovectomy, arthros- and improved general functions of daily living are
copy, and arthroplasty are alternatives that have yielded reported in the majority of patients; the most common
good results. long-term complication reported is glenoid component
Arthritis involving primarily the radiohumeral artic- loosening (18). To this end, recent efforts have explored
ulation is not uncommon with rheumatoid and post- the use of hemiarthroplasty, which is the replacement
traumatic joint disease. Radial head resection offers of the humeral head without resurfacing the glenoid.
increased range of motion and decreased pain in appro- This method has proven effective in selected patients
priately selected patients. Resultant proximal migration including those with cuff tear arthropathychronic,
A B
FIGURE 43-5
(A) Radiograph of an 80-year-old male with severe glenohumeral arthritis of the left shoulder.
(B) Same patient after a shoulder arthroplasty.
massive rotator cuff tears with secondary superior delayed. Some authors have recommended that patients
migration of the humeral head and resultant erosive with atlantoaxial subluxation and a posterior atlanto-
changes of the glenohumeral joint and inferior surface odontoid interval of 14 mm or less, patients who have 43
of the acromion. atlantoaxial subluxation and at least 5 mm of basilar
invagination, and patients who have subaxial sublux-
ation and a sagittal spinal canal diameter of 14 mm or
Cervical Spine less, even in the absence of neurologic findings, undergo
The clinical problems caused by arthritis of the cervical posterior surgical fusion at the involved levels. Pain is
spine are pain, compromised neurologic function, and relieved in the majority of patients, but neurologic
mechanical instability that causes or has the potential improvement is variable and closely related to preoper-
to cause pain and neurologic deficits. Spinal fusions can ative radiographic instability and neurologic status.
decrease pain, restore stability, and, in some instances, Radiographic evidence of OA in the cervical spine
prevent development of neurologic deficits. Surgical occurs in about 50% of people older than 50 years and
decompression of the spinal cord and nerve roots can 75% of people older than 65. In contrast to people with
relieve pain and improve neurologic function in selected RA, these patients rarely have instability. However,
patients. they may develop pain and neurologic signs as a result
Generally accepted indications for surgical interven- of degenerative stenosis. Posterior decompression may
tion in people with RA with cervical spine involve- be accomplished via laminectomy or laminaplasty.
ment are pain refractory to nonoperative modalities, Laminectomy, or removal of part or all of one or more
neurologic deterioration, and radiographic evidence of cervical laminae, allows excellent visualization and
impending spinal cord compression. Whereas the ante- decompression at the expense of potentially destabiliz-
rior atlantodental interval has been traditionally used to ing the spine with resultant kyphosis. Laminaplasty may
determine the degree of atlantoaxial instability, the pos- be performed by one of many techniques, but in general
terior atlantodental interval has been shown to be an involves cutting through the laminae completely on one
important predictor of the potential for postoperative side at the involved levels of the spine and cutting 80%
neurologic improvement (19). The available evidence of the way through the contralateral laminae at those
also suggests that patients who undergo cervical arthro- same levels. The cervical spinal canal may then be
desis earlier in the course of their disease have more opened on the hinge of the partially cut laminae. This
satisfactory results than those in whom arthrodesis is allows excellent multilevel decompression at the expense
of decreased cervical motion. The choice between these heparins were associated with a risk of postoperative
two procedures remains controversial. bleeding.
Patients undergoing major joint reconstruction com-
monly require perioperative blood transfusion. Concern
PERIOPERATIVE MANAGEMENT regarding the associated risks of blood-borne disease,
anaphylaxis, and transfusion reaction has given rise to
The goals of perioperative management include resto- improved techniques for postoperative blood manage-
ration of motion and function, relief of pain, and pre- ment. For many years, preoperative autologous dona-
vention of complications. To obtain optimal surgical tion has provided a relatively safe, albeit expensive and
results, joint replacement patients must participate in a time-consuming, alternative to allogeneic transfusion.
physical therapy regimen directed at improving range More recent advances have seen the advent of periop-
of motion and restoring function. Physical therapy typi- erative blood salvage and erythropoietin analogs.
cally starts within 24 hours after a joint replacement and Blood-salvage devices that reinfuse blood from the
is generally continued for 6 or more weeks through a operative site are an effective means of reducing allo-
combination of inpatient rehabilitation, home health geneic transfusion after arthroplasty (21). Erythropoie-
care, and outpatient services. Newer rehabilitation pro- tin analogs may further reduce the risk by stimulating
tocols have led to a dramatic increase in the number of the patients marrow to increase erythrocyte production
patients who are discharged from the hospital after 48 prior to elective surgery.
to 72 hours and follow-up with outpatient physical
therapy services. In general, inpatient rehabilitation is
now reserved for the postoperative care of patients with
POSTOPERATIVE
slow progress or multiple comorbid factors. Whereas COMPLICATIONS
continuous passive motion (CPM) machines were previ-
ously routinely used in the early phases of rehabilita- The majority of serious postoperative complications,
tion, they are now infrequently used except with including infection, nerve and blood vessel injury, pul-
extenuating circumstances. monary embolus, and joint dislocation, occur within the
Narcotic analgesics are generally required in the first postoperative weeks; however, complications may
acute postoperative period, and are tapered off during occur at any time after surgery. Arthroplasty patients in
the ensuing weeks. Patient-controlled analgesia (PCA) particular must be monitored indefinitely for subtle
pumps provide effective and efficient delivery of nar- radiographic evidence of periprosthetic osteolysis, which,
cotics through a combination of basal infusion rate and when treated early, may halt progression to massive
intermittent dosing, which the patient dictates as needed bone loss and catastrophic failure (see Figure 43-2) (10).
by pressing a button. The maximum dose per hour is The vast majority of failures among lower extremity total
preset by the physician. As an alternative, spinal and joint prostheses occur after the first decade postopera-
epidural infusions have become increasingly popular tively, and most patients remain asymptomatic until sub-
for total hip and knee arthroplasty patients. Each not stantial bone loss, subsidence, and even fracture have
only may be used for surgical anesthesia, but also can occurred. It is therefore imperative that routine follow-
provide postoperative analgesia. An indwelling epidu- up, including careful standardized clinical and compara-
ral catheter can be left in place for 2 to 3 days postop- tive radiographic evaluation, be obtained on a regular
eratively and titrated to provide pain relief while sparing basis throughout the patients life.
motor control for ambulation and other exercises. As In addition, patients must be carefully monitored for
an added benefit, the vasodilation associated with epi- early signs of infection. Early detection of infection in
dural anesthesia may further decrease the risk of a prosthetic joint may make it possible to save the
thromboembolus. implants. However, successful treatment of chronic
Thromboembolic disease is a potential complication joint infections without removal of the implants occurs
after any spine or lower extremity procedure. This com- rarely. Patients with multiple joint arthroplasties who
plication is particularly common among unprophylaxed develop sepsis in one prosthetic joint should be treated
hip arthroplasty patients. In the absence of prophylaxis, aggressively and observed closely because they have a
the incidence of deep venous thrombosis has been substantial risk of developing a metachronous infection
reported as high as 74% and the incidence of symptom- in another artificial joint.
atic pulmonary embolism as high as 3.4% (20). A recent The relationship between bacteremias caused by
meta-analysis of thromboembolic prophylactic agents diagnostic and surgical procedures and subsequent
has shown a significantly lower risk of deep venous infection of a total joint arthroplasty remain uncertain.
thrombosis and symptomatic pulmonary embolism with However, several reports suggest that bacteremias asso-
warfarin, pneumatic compression, and low-molecular- ciated with dental procedures can seed total joint
weight heparins (20). Of these, warfarin was thought to arthroplasties. For this reason, 2 g of penicillin 1 hour
be the safest and most effective. Low-molecular-weight prior to dental manipulation and 1 g 6 hours after the
first dose have been recommended for patients with 6. Perhala RS, Wilke WS, Clough JD, Segal AM. Local
total joint arthroplasties (22). One gram of erythromy- infections complications following large joint replacement
cin 1 hour prior to dental manipulation and 500 mg 6 in rheumatoid arthritis patients treated with methotrexate
hours after the first dose may be utilized for penicillin- versus those not treated with methotrexate. Arthritis
Rheum 1991:34:146152.
sensitive patients. Oral antibiotic prophylaxis appropri-
7. Sany J, Anaya JM, Canovas F, et al. Influence of metho-
ate for the regional flora has also been recommended
trexate on the frequency of postoperative infectious
prior to and following urologic, gastrointestinal, and complications in patients with rheumatoid arthritis.
other bacteremia-evoking manipulations. J Rheumatol 1993:20:11291132.
8. Menon TJ, Wroblewski BM. Charnley low-friction arthro-
plasty in patients with psoriasis. Clin Orthop 1983;300:
NEW OPERATIVE TREATMENTS 127128.
9. Kelly SS, Lachiewicz PE, Gilbert MS, Bolander ME,
Replacements of the hip and knee predictably relieve Jankiewicz JJ. Hip arthroplasty in hemophilic arthropa-
pain and provide stability and motion for large numbers thy. J Bone Joint Surg Am 1995;67:828834.
of patients. Unfortunately, wear and loosening can cause 10. Total Hip Replacement. NIH Consensus Statement 1994;
failure of these implants. Other current operative treat- 12:131. Available at: http://consensus.nih.gov/1994/
ments also relieve or reduce pain for many patients with 1994HipReplacement098html.htm.
arthritis: however, they are generally less successful in 11. Callagham JJ, Albright JC, Goetz DD, Olejniczak JP,
restoring joint function. Joint fusions and even joint Johnston RG. Charnley total hip arthroplasty. Minimum
twenty-five-year follow-up. J Bone Joint Surg Am 2000;
replacements place important limits on function and
82:487497.
other current treatments do not reliably arrest or reverse 12. Fitzgerald RH. Total hip arthroplasty sepsis. Prevention
joint degeneration. Thus, there is a clear need for new and diagnosis. Orthop Clin North Am 1992;23:259264.
therapeutic approaches. New articular bearing surfaces, 13. Sullivan PM, MacKenzie JR, Callaghan JJ, Johnston RG.
including highly polished metallic alloys, highly cross- Total hip arthroplasty with cement in patients who are less
linked polyethylene, and ceramic surfaces are under than fifty years old. J Bone Joint Surg Am 1994;76:863
investigation. Improved results of wrist and ankle joint 869.
replacement may be possible with new implant designs. 14. Insall IN, Joseph DM, Msika G. High tibial osteotomy for
Although they have not yet been shown to be effec- varus gonarthrosis. A long-term follow-up study. J Bone
tive in arthritic joints, operative approaches intended to Joint Surg Am 1984;66:10401048.
preserve or restore cartilaginous articular surfaces that 15. Rand JA, Ilstrup DM. Survivorship analysis of total knee
arthroplasty. Cumulative rates of survival of 9200 total 43
include surgical debridement of degenerated tissue and
knee arthroplasties. J Bone Joint Surg Am 1991;73:397
correction of mechanical abnormalities combined with 409.
implantation of artificial matrices, growth factors, and 16. Summers GD, Talor AR, Webley M. Elbow synovectomy
transplanted chondrocytes or mesenchymal stem cells and excision of the radial head in rheumatoid arthritis: a
have the potential to restore a joint surface. short term palliative procedure. J Rheumatol 1988;15:
566569.
17. Kraay MJ, Figgie MP, Inglis AE, Wolfe SW, Ranawat CS.
REFERENCES Primary semiconstrained total elbow arthroplasty. Sur-
vival analysis of l13 consecutive cases. J Bone Joint Surg
1. Wymenga AB, Horn JRY, Theeuwes A, Muyfiens HL, Br 1994;76:636640.
Siootl TJ. Perioperative factors associated with septic 18. Brostrom LA, Wallensten R, Olsson E, Anderson D. The
arthritis after arthroplasty. Prospective multicenter study Kessel prosthesis in total shoulder arthroplasty. A five-
of 362 knee and 2,651 hip operations. Acta Orthop Scand year experience. Clin Orthop 1992;277:155160.
1992;63:665671. 19. Boden SD, Dodge LD, Bohlman HH, Rechtine GR.
2. Lehman DE, Capello WN, Feinberg JR. Total hip arthro- Rheumatoid arthritis of the cervical spine. J Bone Joint
plasty without cement in obese patients. J Bone Joint Surg Surg Am 1993;75:12821297.
Am 1994;76:854862. 20. Freedman KB, Brookenthal KR, Fitzgerald RH, Williams
3. Collins DN, Barnes CL, FitzRandolph RL. Cervical spine S, Lonner JH. A meta-analysis of thromboembolic pro-
instability in rheumatoid patients having total hip or knee phylaxis following elective total hip arthroplasty. J Bone
arthroplasty. Clin Orthop 1991;272:127135. Joint Surg Am 2000;82:929938.
4. Murray RP, Bourne MH, Fitzgerald RH. Metachronous 21. Grosvenor D, Goyal V, Goodman S. Efficacy of postop-
infections in patients who have had more than one total erative blood salvage following total hip arthroplasty in
joint arthroplasty. J Bone Joint Surg Am 1991;73;1469 patients with and without deposited autologous units. J
1474. Bone Joint Surg Am 2000;82:951954.
5. Connelly CS, Panush RS. Should nonsteroidal anti- 22. Nelson JP, Fitzgerald RH, Jaspers MT, Little JW. Prophy-
inflammatory drugs be stopped before elective surgery? lactic antimicrobial coverage in arthroplasty patients. J
Arch lntern Med 1991;151:19631966. Bone Joint Surg Am 1990;72:12.
CHAPTER 44
Complementary and Alternative

Therapies
ERIN L. ARNOLD, MD
WILLIAM J. ARNOLD, MD
Complementary and alternative therapies are popular Scientific basis and clinical trails of most therapies is
and widely used among patients with rheumatic and limited or lacking.
musculoskeletal diseases.
Marketing and word of mouth, ready availability, and
interest in natural treatments contribute to their
popularity.
More and more people are employing complementary As the medical community awaits more rigorous assess-
and alternative medicine (CAM) to treat their illnesses. ment of CAM therapies, physicians should be moti-
A survey of English-speaking patients found that 42.1% vated by existing evidence (13) to ask patients about
used at least 1 of 16 specific CAM therapies during a their use of CAM therapies.
12-month period (1). In this study population, visits to
CAM practitioners exceeded total visits to primary care
physicians, and more than 50% of the patients had a MEDITATION, BIOFEEDBACK,
musculoskeletal disease (arthritis, back, or neck pain). AND STRESS REDUCTION
Total out-of-pocket expenditures for CAM treatments
were estimated to be $27 billion, similar to out-of-pocket Meditation, biofeedback, and stress reduction are used
expenditures for all US physician services. The study widely for the treatment of pain, depression, and anxiety.
found that patients were most likely to use CAM thera- These therapeutic modalities are especially popular
pies in conjunction with, rather than in place of, con- with people who have fibromyalgia.
ventional therapies. Meditation teaches the patient to develop concentra-
Most rheumatic conditions are characterized by tion, calmness, and insight as a way of treating symp-
chronic pain, an unpredictable disease course, and often toms (4). A prospective, observational, case-control
without satisfactory response to therapy. As a conse- study found that people with fibromyalgia were more
quence, patients with rheumatic diseases, in particular likely than control patients in a rheumatology practice
osteoarthritis (OA) and fibromyalgia, often seek out (p < 0.01) to use CAM (5). People with fibromyalgia
CAM therapies in addition to the conventional treat- perceived spiritual practices (meditation, relaxation,
ment their doctors recommend (2). self-help groups, prayer) as more beneficial than over-
Patients are often reluctant to discuss CAM thera- the-counter products, use of other health care practitio-
pies with their physicians. To protect patients from ners, and dietary modifications. In an uncontrolled
dangerous drug interactions and treatment modalities study of 225 patients with chronic pain enrolled in a
known to be harmful, use of CAM therapies must be meditation program, 60% showed continued improve-
elicited as a part of the comprehensive history and phys- ment of pain at 4 years follow-up (4).
ical examination (3). Between 38.5% and 55% of Biofeedback, with the assistance of electronic moni-
patients do not disclose use of CAM therapies to their tors, teaches people how to use their mind to affect
physicians (1,2) simply because their physicians fail to body functions (e.g., circulation and pain sensation). In
ask. The fear of physician disapproval of CAM thera- people with RA, biofeedback has been shown to
pies accounts for only 15% of patient nondisclosure (2). decrease clinic visits, hospitalization days, and medical
664
C H A P T E R 4 4 C O M P L E M E N T A R Y A N D A L T E R N A T I V E T H E R A P I E S 6 65
costs (6). In a review of 23 people with Raynauds phe- study, patients with carpal tunnel syndrome experienced
nomenon using biofeedback therapy, Yocum and col- a statistically significant improvement in grip strength
leagues (7) found that at 18 months, patients continued and pain reduction with a yoga program based on upper
to be able to raise baseline finger temperatures and that body postures; flexibility exercises; correct alignment of
the greatest temperature increase was observed in hands, wrists, arms, and shoulders; stretching; and in-
patients with connective tissue disorders, including creased awareness of optimal joint position (12).
lupus and scleroderma.
Relaxation techniques focus on the reduction of stress
by using such tactics as breathing exercises to help ACUPUNCTURE
provide relief. In a randomized, controlled trial of people
with RA, relaxation techniques were shown to signifi- Based on the belief that there are patterns of energy
cantly reduce pain, disease activity, and anxiety (8). flow (Qi) that are essential for health, acupuncture is a
procedure that treats illness by correcting Qi imbal-
ances. Solid, sterile metal needles are used to penetrate
PRAYER AND SPIRITUALITY the skin and manually or electrically stimulate known
flow patterns. Acupuncture frequently is used to treat
A majority of Americans believe in the healing power pain and is considered a useful therapy for such condi-
of prayer. Seven percent of patients surveyed by Eisen- tions as OA, Raynauds phenomenon, fibromyalgia,
berg and colleagues (1) reported using some form of and low back pain (13). A meta-analysis of randomized,
spiritual healing in conjunction with conventional thera- controlled trials of acupuncture for the treatment of
pies, and 35% reported using prayer to address health- back pain found that acupuncture was superior to other
related problems. Patients with chronic illnesses seek control interventions (14). A randomized, controlled
treatment that includes attention to the mind and spirit trial of acupuncture in people with OA of the knee
as well as the body. found statistically significant reductions of pain in
A number of studies have shown an association patients treated with acupuncture (15). Chronic low
between spiritual involvement and positive health out- back pain was effectively relieved by acupuncture in a
comes. Distant healing is considered to be a conscious, meta-analysis of randomized, controlled trials (16).
dedicated act directed at benefiting another persons
physical or emotional well-being at a distance. It includes
prayer, therapeutic touch, Reiki, and LeShane healing. MASSAGE
A systematic review of randomized trials of distant
healing found that 13 of 23 studies (57%) that met inclu- Massage is one of the CAM interventions used most
sion criteria yielded statistically significant, positive frequently and is, in general, risk-free. Various massage
treatment effects of distant healing (9). Nine of the 23 techniques can be used (Table 44-1), and patients need
studies showed no effect and one showed a negative 44
effect, making it difficult to draw definitive conclusions
about efficacy, but also difficult to simply dismiss the TABLE 44-1. MASSAGE AND BODYWORK.
power of distant healing.
Western massage
Swedish massage: full-body stroking and kneading of the
EXERCISE superficial muscle layers, using oil or lotion
Deep tissue massage: strong pressure on deep muscles or tissue
layers
Strengthening, stretching, general conditioning exer- Trigger point therapy: deep finger pressure on trigger points
cises, and yoga have been shown to provide symptom- Myofascial release: steady pressure to stretch fascia
atic relief for various forms of arthritis.. In older adults
Oriental bodywork and massage
a regular exercise program was shown to result in a 32% Acupressure (i.e., Shiatsu): finger and hand pressure used at
reduction in functional decline (10). The lack of regular acupuncture points
exercise almost doubled the odds of functional decline Structural integration bodywork
[adjusted odds ratio (OR) 1.5; 95% confidence interval Chiropractic adjustment: short-level, high velocity thrust directed
specifically at a manipulable lesion
(CI), 1.52.]. In a randomized, controlled trial, people
Osteopathic manipulation: thrust, muscle energy, counterstrain,
with OA of the knee who were enrolled in a program of articulation, and myofascial release directed at a specific lesion
physical therapy combined with supervised and unsu- Rolfing: release of muscles and tissue layers from surrounding
pervised exercise were found to have clinically and sta- fascia using deep pressure and fascia release techniques
tistically significant improvement (11). The benefits Reflexology: stimulation of massage points in the feet, hands,
and ears that correspond to organs and body parts
attained in the treatment group continued to be appar-
Crainiosacral therapy: gentle manipulation of the skull bones to
ent at 1 year, with fewer patients requiring knee surgery balance the fluids in the craniosacral system
than did patients in the control group. In a separate
666 ERIN L. ARNOLD AND WILLIAM J. ARNOLD
to be encouraged to discuss their medical conditions side effects, most clinicians have accepted or even
with the massage therapist. With this information, ther- encourage their use in people with OA of the knee.
apists can devise a plan for massage that will achieve Evidence from studies in an animal model of inflam-
the desired outcome and avoid negative experiences. matory arthritis suggests a protective effect of polyphe-
For example, people at risk for fracture because of nols contained in green tea (Camelia senensis) (19). The
known osteoporosis or chronic corticosteroid use should equivalent of three to four daily cups of green tea pre-
avoid deep pressure. In a randomized, placebo-con- vented or ameliorated the development of arthritis.
trolled trial comparing Swedish massage, transcutane- Methylsulfonyl methane (MSM) has been shown to
ous electrical nerve stimulation (TENS), and sham reduce WOMAC pain scores and improve functional
TENS therapy in people with fibromyalgia, patients in scores in patients with knee pain and osteoarthritis
the massage group showed decreases in insomnia, pain, when compared to placebo (20).
fatigue, anxiety, and depression as well as decreased In symptomatic patients with systemic lupus erythe-
cortisol production (17). matosus (SLE), omega 3 fish oil supplements signifi-
cantly reduced disease activity (measured with SLAM-R)
compared to placebo (21).
Vitamins C and D have been hypothesized to
HERBS, SUPPLEMENTS, benefit patients with OA. Low levels of vitamin D
AND VITAMINS have been found in people with OA of the hip and
knee (22). Hypovitaminosis D is an established risk
Herbal remedies are the fastest-growing form of CAM factor for fractures in patients with OA. Low serum
therapy in the United States. Viewed as natural, and 25-hydroxy vitamin D [25(OH)D] levels, have been
therefore safe, herbs actually are potent medications. found to correlate with low bone mineral density
Potential benefits of herbal therapy must be balanced (BMD) and the presence of primary knee OA (23).
against the possible harmful side effects from interac- Greater intake of vitamin D has been found to be asso-
tions with other prescription medications or the pres- ciated with a lower risk of developing RA [relative
ence of illicit constituents or contaminants. Because risk (RR) 0.66; 95% CI, 0.421.01; p = 0.06) in older
most herbs used to relieve pain affect eicosanoid metab- women (5569 years old) (24). Patients with higher
olism, the side effects may be similar to those of levels of vitamin C intake appear to have a lower inci-
nonsteroidal anti-inflammatory drugs (NSAIDs). Many dence of OA. Theoretically, antioxidant supplements
commonly used herbs and supplements affect the clot- could help to prevent the progression of OA of the knee
ting system and preoperative assessments must include (25).
questions concerning herbal intake.
Neither herbal nor supplement preparations undergo
strict production inspection or quality control under the DIET AND ARTHRITIS
1994 Dietary Supplement Health Education Act. Con-
taminants such as lead and arsenic as well as NSAIDs Except for prevention and treatment of gout, there is
and steroids have been found in herbal preparations. no definitive scientific evidence that what an individual
Supplement preparations may or may not contain speci- eats can cause or cure arthritis. However, an increasing
fied amounts or even any of the advertised supplement. amount of literature suggests that a change in diet may
Besides presenting a patient safety issue, this variability relieve some symptoms and even impact the progres-
also makes any studies of these supplements difficult to sion of disease. For example, oleocanthal, a component
interpret. of extra virgin olive oil can cause a dose-dependent
The best-studied nutritional supplements to date inhibition of both cyclooxygenase (COX)-1 and COX-
have been glucosamine sulfate and chondroitin sulfate. 2, therefore inhibiting inflammation (26) and, in some
The GlucosamineChondroitin Arthritis Intervention studies, reduce the risk of developing RA (27). Unfor-
Trial (GAIT) measured the effects of glucosamine tunately one would have to consume about a half liter
alone, chondroitin alone, a glucosaminechondroitin of oil to obtain the effects of two ibuprofen tablets. The
combination, and celecoxib alone against placebo in lack of consistency among findings limits the ability to
1583 people with either mild or moderate-to-severe make specific dietary recommendations for the preven-
pain from knee osteoarthritis (18). In moderate-to- tion or treatment of arthritis. However, encouraging
severe pain, 79% who took the glucosaminechondroi- patients to modify their diets may result in beneficial
tin combination reported pain relief compared to 54% weight loss as well as an overall improvement in health.
in people who took placebo. Patients with mild pain A weight loss of as little as 5 kg may reduce the inci-
responded similarly to the glucosaminechondroitin dence of OA of the knees by 50% in women, particu-
combination and placebo (63% and 62%, respectively). larly women who are more than 10% over their ideal
Because neither of these supplements have significant body weight (28).
C H A P T E R 4 4 C O M P L E M E N T A R Y A N D A L T E R N A T I V E T H E R A P I E S 6 67
Red meat and certain vegetable oils (corn, sunflower, AVAILABLE RESOURCES
and safflower) contain omega 6 fatty acids, which are
synthesized into arachidonic acid, the building blocks Internet sites to help physicians assist their patients in
for prostaglandins and leukotrienes. Eliminating or making educated decisions about the use of CAM ther-
reducing the amount of omega 6 while substituting apies can be found in Table 44-2 and Appendix IV.
omega 3 oils may help reduce pain and inflammation.
Omega 3 fatty acids are eicosapentaenoic acid (EPA)
and docosahexaenoic acid (DHA), fatty acids that TABLE 44-2. RESOURCES AVAILABLE ON THE
compete with omega 6 fatty acids to form arachidonic INTERNET.
acid. In fact, diets high in omega 3 fatty acids appear to
Alternative medicine
have a protective effect against rheumatoid arthritis Altmednet.com: http://www.altmednet.com (many CAM links)
onset (27). Good sources for omega 3 fatty acids are Arthritis Foundation: http://www.arthritis.org
fresh cold-water fish, sardines in their own oil, flaxseed, Cochrane Collaboration: http://www.cochrane.org/index.htm
green soybeans and tofu, and canola and olive oils. (systematic review)
National Center for Complementary and Alternative Medicine:
Patients also can take food supplements to get more
http://nccam.nih.gov (affiliated with NIH, conducts and
omega 3 fatty acids. supports research as well as providing information about
CAM)
Healing systems
Ayruvedic medicine: http://ayurvedahc.com
MISCELLANEOUS THERAPIES Chinese medicine: http://acupuncture.com
Naturopathic medicine: The American Association of
Wearing copper bracelets is believed to ease arthritis Naturopathic Physicians http://www.naturopathic.org
pain. In a placebo-controlled trial, Walker and Keats Homeopathic medicine: National Center for Homeopathy:
http://www.homeopathic.org
demonstrated that a significant number of patients
Chiropractic medicine: American Chiropractic Association:
assigned to wear copper bracelets experienced arthritis http://www.amerchiro.org
pain relief, compared with little relief reported by indi- Osteopathic medicine: American Osteopathic Association:
viduals assigned to wear bracelets that were painted to http://www.aoa-net.org
look like copper (29). These investigators also reported
Meditation, biofeedback, stress reduction
that the copper bracelets were lighter at the end of the The MindBody Medical Institute:
study period and suggested that copper was absorbed http://www.mindbody.harvard.edu (information and referrals)
by the skin. While the concept of absorbing copper Insight Meditation Society:
through the skin is controversial, it is worthwhile to http://www.dharma.org (information and links)
recommend that patients who are interested in trying Prayer and spirituality
this alternative therapy buy a bracelet that has not been National Institute for Healthcare Research: http://www.nihr.org
treated to prevent tarnishing. 44
Yoga
Static magnet therapy, as opposed to pulsed electro- The American Yoga Association:
magnetic therapy (the use of pulsed electric current in http://www.americanyogaassociation.org/
combination with a permanent magnet, a medically
accepted therapy) is believed to relieve pain by increas- Massage
The National Certification Board for Therapeutic Massage and
ing circulation, suppressing inflammation, affecting C- Bodywork: http://www.ncbtmb.com (referral list)
fibers, and changing the polarization of cells. Two The American Massage Therapy Association:
scientific trials (30,31) have suggested that static mag- http://www.amtamassage.org (information about massage as
netic therapy may relieve arthritis symptoms. However, well as locator service for therapists)
the short follow-up periods and the small sample sizes Herbs, supplements, vitamins
limit the results applicability and emphasize the need US Food and Drug Administration: http://www.fda.gov (access to
for more studies. MEDWATCH as well as warnings on herbal products)
Bee stings or injections are believed by some to American Botanical Council: http://www.herbs.org (factual
reduce arthritis symptoms. Applied at painful areas or information about herbs)
HerbMed: http://www.amfoundation.org/ (herbal database)
trigger points, the known anti-inflammatory chemicals NIH Office of Dietary Supplements:
in bee venom are thought to relieve inflammation. http://dietary-supplements.info.nih.gov
Animal studies have shown that bee venom reduces American Dietetic Association: http://www.eatright.org (referrals
inflammation (32) and prevents rats from getting an to registered dietitians)
induced form of arthritis (33). However, no human American Herbalists Guild: http://www.americanherbalistsguild.
com (referrals to herbal practitioners)
studies have been done, and it is felt that the risk of an
anaphylactic reaction outweighs the unproven benefit ABBREVIATIONS: CMA, complementary and alternative medicine; NIH, National
of symptom relief. Institutes of Health.
668 ERIN L. ARNOLD AND WILLIAM J. ARNOLD
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sulfate, and the two in combination for painful knee
osteoarthritis. N Engl J Med 2006;354:858860.
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JAMA 1998;280:15691575. tion from green tea. Proc Natl Acad Sci U S A 1999;
2. Rao JK, MiboIiak K, Kroenke K, Bradley J, Tierney WM, 96:45244529.
Weinberger M. Use of complementary therapies for 20. Kim L, Axelrod L, Howard P, et al. Efficacy of methyl-
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5. Pioro-Boisset M, Esdaile JM, Fitzcharles MA. Alternative 22. McAlindon TE. Influence of vitamin D status on the inci-
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6. Young LD, Bradley LA, Tllmer RA. Decreases in health 23. Bischoff-Ferrari HA, Zhang Y, Kiel DP, Felson DT. Posi-
care resource utilization in patients with rheumatoid tive association between serum 25-hydroxyvitamin D
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Biofeedback Self Regul 1995;259268. 2005;53:821826.
7. Yocum DE, Hodes R, Sundstrom WK, Cleeland CS. Use 24. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell
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and phenomenon. Rheumatology 1985;12:9093. intake is inversely associated with rheumatoid arthritis:
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lowup. Arthritis Rheum 1987;30:11051114. oxidant micronutrients protect against the development
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Intern Med 2000;132:903910. 26. Beauchamp GK, Keast RSJ, Morel D, et al. Ibuprofen-
10. Dunlop DD, Selmanik P, Song J, et al. Risk factors for like activity in extra-virgin olive oil. Nature 2005;437:
functional decline in older adults with arthritis. Arthritis 4546.
Rheum 2005;52:12741282. 27. Pattison DJ, Harrison RA, Symmons DPM. The role of
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and exercise in osteoarthritis of the knee. Ann Intern Med 28. Felson DT. Weight loss reduces the risk for symptomatic
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R, Schumacher HR. Yoga-based intervention of carpal 29. Walker WK, Keats DM. An investigation of the therapeu-
tunnel syndrome: a randomized trial. JAMA 1998;280: tic value of the copper bracelet - dermal assimilation of
16011603. copper in arthritic/rheumatoid conditions. Agents Actions
13. NIH Consensus Development Panel on Acupuncture. 1976;6:454459.
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Hochberg M. Effectiveness of acupuncture as adjunctive betic peripheral neuropathy: a novel intervention. Am J
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Meta-analysis: acupuncture for low back pain. Ann Intern 33. Eiseman JL, Von Bredow J, Alvar AP. Effect of
Med 2005;142:651663. honeybee (Apis mellifera) venom on the course of
17. Sunshine WI, Field TM, Quintino O, et al. Fibromyalgia adjuvant-induced arthritis and depression of drug meta-
benefits from massage therapy and transcutaneous electri- bolism in the rat. Biochem Pharmacol 1982;31:1139
cal stimulation. J Pain Rheumatol 1996;2:1822. 1146.
APPENDIX I
Criteria for the Classification and

Diagnosis of the Rheumatic
Diseases
The criteria presented in the following section have The proposed criteria are empiric and not intended
been developed with several different purposes in mind. to include or exclude a particular diagnosis in any indi-
For a given disorder, one may have criteria for (1) clas- vidual patient. They are valuable in offering a standard
sification of groups of patients (e.g., for population to permit comparison of groups of patients from differ-
surveys, selection of patients for therapeutic trials, or ent centers that take part in various clinical investiga-
analysis of results on interinstitutional patient compari- tions, including therapeutic trials.
sons); (2) diagnosis of individual patients; and (3) esti- The ideal criterion is absolutely sensitive (i.e., all
mations of disease frequency, severity, and outcome. patients with the disorder show this physical finding or
The original intention was to propose criteria as the positive laboratory test) and absolutely specific
guidelines for classification of disease syndromes for the (i.e., the positive finding or test is never present in any
purpose of assuring correctness of diagnosis in patients other disease). Unfortunately, few such criteria or sets
taking part in clinical investigation rather than for indi- of criteria exist. Usually, the greater the sensitivity of a
vidual patient diagnosis. However, the proposed criteria finding, the lower its specificity, and vice versa. When
have in fact been used as guidelines for patient diagno- criteria are established attempts are made to select rea-
sis as well as for research classification. One must be sonable combinations of sensitivity and specificity.
cautious in such application because the various criteria An updated listing of additional criteria sets for rheu-
are derived from the use of analytic techniques that matic and musculoskeletal disorders is available on the
allow the minimum number of variables to achieve the American College of Rheumatology website (http://
best group discrimination, rather than to attempt to www.rheumatology.org/publications/classification/
arrive at a diagnosis in an individual patient. index.asp?aud=mem).
CRITERIA FOR THE CLASSIFICATION Of FIBROMYALGIAa

1. History of widespread pain
Definition. Pain is considered widespread when all of the following are present: pain in the left side of the body, pain in the right side
of the body, pain above the waist, and pain below the waist. In addition, axial skeletal pain (cervical spine or anterior chest or
thoracic spine or low back) must be present. In this definition, shoulder and buttock pain is considered as pain for each involved
side. Low back pain is considered lower segment pain.
2. Pain in 11 of 18 tender point sites on digital palpation.b

Definition. Pain, on digital palpation, must be present in at least 11 of the following 18 tender point sites:
Occiput: bilateral, at the suboccipital muscle insertions.
Low cervical: bilateral, at the anterior aspects of the intertransverse spaces at C5C7.
Trapezius: bilateral, at the midpoint of the upper border.
Supraspinatus: bilateral, at origins, above the scapula spine near the medial border.
Second rib: bilateral, at the second costochondral junctions, just lateral to the junctions on upper surfaces.
Lateral epicondyle: bilateral, 2 cm distal to the epicondyles.
Gluteal: bilateral, in upper outer quadrants of buttocks in anterior fold of muscle.
Greater trochanter: bilateral, posterior to the trochanteric prominence.
Knee: bilateral, at the medial fat pad proximal to the joint line.
SOURCE: Adapted from Wolfe F, Smythe HA, Yunus MS, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report
of the multicenter criteria committee. Arthritis Rheum 1990;33:100172, with permission of the American College of Rheumatology.
a
For classification purposes, patients will be said to have fibromyalgia if both criteria are satisfied. Widespread pain must have been present at least 3 months.
The presence of a second clinical disorder does not exclude the diagnosis of fibromyalgia.
b
Digital palpation should be performed with an approximate force of 4 kg. For a tender point to be considered positive the subject must state that the palpa-
tion was painful. Tender is not to be considered painful.
669
670 APPENDIX I
CRITERIA FOR THE CLASSIFICATION OF RHEUMATOID ARTHRITISa

1. Morning stiffness Morning stiffness in and around the joints, lasting at least 1 hour before maximal
improvement
2. Arthritis of three or more joint areas At least three joint areas simultaneously have had soft tissue swelling or fluid (not bony
overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP,
MCP, wrist, elbow, knee, ankle, and MTP joints
3. Arthritis of hand joints At least one area swollen (as defined above) in a wrist, MCP, or PIP joint
4. Symmetric arthritis Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body
(bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry)
5. Rheumatoid nodules Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxta-articular
regions, observed by a physician
6. Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any method for which
the result has been positive in 5% of normal control subjects
7. Radiographic changes Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist
radiographs, which must include erosions or unequivocal bony decalcification localized in
or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify)
SOURCE: Reprinted from Arnett FC, Edworthy SM, Bloch DA. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheuma-
toid arthritis. Arthritis Rheum 1988;31:315324, with permission of the American College of Rheumatology.
ABBREVIATIONS: MCP, metacarpophalangeal; MTP, metatarsophalangeal; PIP, proxomal interphalangeal.
a
For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least four of these seven criteria. Criteria 1 through
4 must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid
arthritis is not to be made.
CLASSIFICATION OF PROGRESSION OF RHEUMATOID ARTHRITIS

Stage I, Early
*1. No destructive changes on roentgenographic examination
2. Radiographic evidence of osteoporosis may be present
Stage II, Moderate

*1. Radiographic evidence of osteoporosis, with or without slight subchondral bone destruction; slight cartilage destruction may be
present
*2. No joint deformities, although limitation of joint mobility may be present
3. Adjacent muscle atrophy
4. Extra-articular soft tissue lesions, such as nodules and tenosynovitis may be present
Stage III, Severe

*1. Radiographic evidence of cartilage and bone destruction, in addition to osteoporosis
*2. Joint deformity, such as subluxation, ulnar deviation, or hyperextension, without fibrous or bony ankylosis
3. Extensive muscle atrophy
4. Extra-articular soft tissue lesions, such as nodules and tenosynovitis may be present
Stage IV, Terminal

*1. Fibrous or bony ankylosis
2. Criteria of stage III
SOURCE: Reprinted from Steinbrocker O, Traeger CH. Batterman RC. Therapeutic criteria in rheumatoid arthritis. JAMA 1949;140:659662, with permission.
* The criteria prefaced by an asterisk are those that must be present to permit classification of a patient in any particular stage or grade.
C R I T E R I A F O R T H E C L A S S I F I C A T I O N A N D D I A G N O S I S 67 1
CRITERIA FOR CLINICAL REMISSION IN RHEUMATOID ARTHRITISa

Five or more of the following requirements must be fulfilled for at least 2 consecutive months:
1. Duration of morning stiffness not exceeding 15 minutes
2. No fatigue
3. No joint pain (by history)
4. No joint tenderness or pain on motion
5. No soft tissue swelling in joints or tendon sheaths
6. Erythrocyte sedimentation rate (Westergren method) less than 30 mm/hour for a female or 20 mm/hour for a male
SOURCE: Reprinted from Pinals RS, Masi AT, Larsen RA. et al. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981;24:1308
1315, with permission of the American College of Rheumatology.
a
These criteria are intended to describe either spontaneous remission or a state of drug-induced disease suppression, which simulates spontaneous remission.
No alternative explanation may be invoked to account for the failure to meet a particular requirement. For instance, in the presence of knee pain, which might
be related to degenerative arthritis, a point for no joint pain may not be awarded. Exclusions: Clinical manifestations of active vasculitis, pericarditis, pleuritis
or myositis, and unexplained recent weight loss or fever attributable to rheumatoid arthritis will prohibit a designation of complete clinical remission.
CRITERIA FOR CLASSIFICATION OF FUNCTIONAL STATUS IN RHEUMATOID ARTHRITISa

Class I Completely able to perform usual activities of daily living (self-care, vocational, and avocational)
Class II Able to perform usual self-care and vocational activities, but limited in avocational activities
Class III Able to perform usual self-care activities, but limited in vocational and avocational activities
Class IV Limited in ability to perform usual self-care, vocational, and avocational activities
SOURCE: Reprinted from Hochberg MC, Chang RW, Dwosh I. et al. The American College of Rheumatology 1991 revised criteria for the classification of global
functional status in rheumatoid arthritis. Arthritis Rheum 1992;35;498502, with permission of the American College of Rheumatology.
a
Usual self-care activities include dressing, feeding, bathing, grooming, and toileting. Avocational (recreational and/or leisure) and vocational (work, school,
homemaking) activities are patient-desired and age- and sex-specific.
AMERICAN COLLEGE OF RHEUMATOLOGY PRELIMINARY DEFINITION OF IMPROVEMENT IN RHEUMATOID ARTHRITIS

(ACR20)
Required { 20% improvement in tender joint count

20% improvement in swollen joint count
+
20% improvement in three of the following five:
Patient pain assessment
Patient global assessment
APPENDIX I
Physician global assessment
Patient self-assessed disability
Acute-phase reactant (ESR or CRP)
DISEASE ACTIVITY MEASURE METHOD OF ASSESSMENT
1. Tender joint count ACR tender joint count, an assessment of 28 or more joints. The joint count should be
done by scoring several different aspects of tenderness, as assessed by pressure and
joint manipulation on physical examination. The information on various types of
tenderness should then be collapsed into a single tender-versus-nontender dichotomy.
2. Swollen joint count ACR swollen joint count, an assessment of 28 or more joints. Joints are classified as
either swollen or not swollen.
3. Patients assessment of pain A horizontal visual analog scale (usually 10 cm) or Likert scale assessment of the patients
current level of pain.
4. Patients global assessment of disease The patients overall assessment of how the arthritis is doing. One acceptable method for
activity determining this is the question from the AIMS instrument: Considering all the ways
your arthritis affects you, mark X on the scale for how well you are doing. An
anchored, horizontal, visual analog scale (usually 10 cm) should be provided. A Likert
scale response is also acceptable.
(continued)
672 APPENDIX I
AMERICAN COLLEGE OF RHEUMATOLOGY PRELIMINARY DEFINITION OF IMPROVEMENT IN RHEUMATOID ARTHRITIS

(ACR20) (continued)
DISEASE ACTIVITY MEASURE METHOD OF ASSESSMENT
5. Physicians global assessment of disease A horizontal visual analog scale (usually 10 cm) or Likert scale measure of the physicians
activity assessment of the patients current disease activity.
6. Patients assessment of physical Any patient self-assessment instrument which has been validated, has reliability, has
function been proven in RA trials to be sensitive to change, and which measures physical
function in RA patients is acceptable. Instruments which have been demonstrated to be
sensitive in RA trials include the AIMS, the HAQ, the Quality (or Index) of Well Being,
the MHIQ, and the MACTAR.
7. Acute-phase reactant value A Westergren ESR or a CRP level.
SOURCE: Reprinted from Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid
arthritis. Arthritis Rheum 1995;38:727735, with permission of the American College of Rheumatology.
ABBREVIATIONS: ACR, American College of Rheumatology; AIMS, Arthritis Impact Measurement Scales; CRP, C-reactive protein; ESR, erythrocyte sedimentation
rate; HAQ, Health Assessment Questionnaire; MACTAR, McMaster Toronto Arthritis Patient Preference Disability Questionnaire; MHIQ, McMaster Health Index
Questionnaire; RA, rheumatoid arthritis.
CRITERIA FOR THE CLASSIFICATION OF SPONDYLOARTHROPATHYa

Inflammatory spinal pain or
Synovitis
Asymmetric or
Predominantly in the lower limbs and one or more of the following
Positive family history
Psoriasis
Inflammatory bowel disease
Urethritis, cervicitis, or acute diarrhea within 1 month before arthritis
Buttock pain alternating between right and left gluteal areas
Enthesopathy
Sacroiliitis
VARIABLE DEFINITION
Inflammatory spinal pain History or present symptoms of spinal pain in back, dorsal, or cervical region, with at least four of the
following: (a) onset before age 45, (b) insidious onset, (c) improved by exercise, (d) associated with
morning stiffness, (e) at least 3 months duration
Synovitis Past or present asymmetric arthritis or arthritis predominantly in the lower limbs
Family history Presence in first-degree or second-degree relatives of any of the following: (a) ankylosing spondylitis,
(b) psoriasis, (c) acute uveitis, (d) reactive arthritis, (e) inflammatory bowel disease
Psoriasis Past or present psoriasis diagnosed by a physician
Inflammatory bowel disease Past or present Crohns disease or ulcerative colitis diagnosed by a physician and confirmed by
radiographic examination or endoscopy
Alternating buttock pain Past or present pain alternating between the right and left gluteal regions
Enthesopathy Past or present spontaneous pain or tenderness at examination of the site of the insertion of the
Achilles tendon or plantar fascia
Acute diarrhea Episode of diarrhea occurring within 1 month before arthritis

CRITERIA FOR THE CLASSIFICATION OF SPONDYLOARTHROPATHYa (continued)
VARIABLE DEFINITION
Urethritis Nongonococcal urethritis or cervicitis occurring within 1 month before arthritis
Sacroiliitis Bilateral grade 24 or unilateral grade 34, according to the following radiographic grading system:
0 = normal, 1 = possible, 2 = minimal, 3 = moderate, and 4 = ankylosis
SOURCE: Reprinted from Dougados M, Van Der linden S, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification
of spondylarthropathy. Arthritis Rheum 1991;34:12181227, with permission of the American College of Rheumatology.
a
This classification method yields a sensitivity of 78.4% and a specificity of 89.6%. When radiographic evidence of sacroiliitis was included, the sensitivity
improved to 87.0% with a minor decrease in specificity to 86.7%. Definition of the variables used in classification criteria follow.
CRITERIA FOR THE DIAGNOSIS OF RHEUMATIC FEVERa

MAJOR SUPPORTING EVIDENCE OF PRECEDING
MANIFESTATIONS MINOR MANIFESTATIONS STREPTOCOCCAL INFECTION
Carditis Clinical findings Positive throat culture or rapid streptococcal antigen test
Polyarthritis Arthralgia Elevated or rising streptococcal antibody titer
Chorea Fever
Erythema marginatum Laboratory findings
Subcutaneous nodules Elevated acute phase reactants

Erythrocyte sedimentation rate
C-reactive protein
Prolonged PR interval
SOURCE: Reprinted from Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular
Disease in the Young, American Heart Association: guidelines for the diagnosis of rheumatic fever: Jones criteria, updated 1992. JAMA 1992;268:20692073,
with permission.
a
If supported by evidence of preceding group A streptococcal infection, the presence of two major manifestations, or of one major and two minor manifesta-
tions indicates a high probability of acute rheumatic fever.
CRITERIA FOR THE CLASSIFICATION AND REPORTING OF OSTEOARTHRITIS OF THE HAND, HIP, AND KNEE
CLASSIFICATION CRITERIA FOR OSTEOARTHRITIS OF THE HAND, TRADITIONAL FORMATa
Hand pain, aching, or stiffness and
Three or four of the following features:

Hard tissue enlargement of 2 or more of 10 selected joints
Hard tissue enlargement of 2 or more DIP joints
APPENDIX I
Fewer than three swollen MCP joints
Deformity of at least 1 of 10 selected joints
SOURCE: Reprinted from Altman R, Alarcon G, Appelrouth D, et al. The American College of Rheumatology criteria for the classification and reporting of osteo-
arthritis of the hand. Arthritis Rheum 1990;33:16011610, with permission of the American College of Rheumatology.
ABBREVIATION: MCP, metacarpophalangeal.
a
The 10 selected joints are the second and third distal interphalangeal (DIP), the second and third proximal interphalangeal (PIP), and the first carpometacarpal
(CMC) joints of both hands. This classification method yields a sensitivity of 94% and a specificity of 87%.
CLASSIFICATION CRITERIA FOR OSTEOARTHRITIS OF THE HIP, TRADITIONAL FORMATa
Hip pain
and
At least two of the following three features:

ESR 20 mm/hour
Radiographic femoral or acetabular osteophytes
Radiographic joint space narrowing (superior, axial, and/or medial)
SOURCE: Reprinted from Altman R, Alarcon G, Appelrouth D, et al. The American College of Rheumatology criteria for the classification and reporting of osteo-
arthritis of the hip. Arthritis Rheum 1991;34:505514, with permission of the American College of Rheumatology.
ABBREVIATION: ESR, erythrocyte sedimentation rate (Westergren).
a
This classification method yields a sensitivity of 89% and a specificity of 91%.
(continued)
674 APPENDIX I
CRITERIA FOR THE CLASSIFICATION AND REPORTING OF OSTEOARTHRITIS OF THE HAND, HIP, AND KNEE (continued)
CRITERIA FOR CLASSIFICATION OF OSTEOARTHRITIS (OA) OF THE KNEE
Clinical and laboratory

Knee pain plus at least five of nine:
Age >50 years
Stiffness <30 minutes
Crepitus
Bony tenderness
Bony enlargement
No palpable warmth
ESR <40 mm/hour
RF <1 : 40
SF OA
92% sensitive
75% specific
Clinical and radiographic

Knee pain plus at least one of three:
Age >50 years
Crepitus
+
Osteophytes
91% sensitive
86% specific
Clinicala
Knee pain plus at least three of six:
Age >50 years
Crepitus
Bony tenderness
Bony enlargement
No palpable warmth
95% sensitive
69% specific
SOURCE: Reprinted from Altman R, Asch E, Bloch G, et al. Development of criteria for the classification and reporting of osteoarthritis: classification of osteo-
arthritis of the knee. Arthritis Rheum 1986;29:10391049, with permission of the American College of Rheumatology.
ABBREVIATIONS: ESR, erythrocyte sedimentation rate (Westergren); RF, rheumatoid factor; SF OA, synovial fluid signs of OA (clear, viscous, or white blood cell
count <2000/mm3).
a
Alternative for the clinical category would be four of six, which is 84% sensitive and 89% specific.
CRITERIA FOR THE CLASSIFICATION OF ACUTE GOUTY ARTHRITIS

A. The presence of characteristic urate crystals in the joint fluid, or
B. A tophus proved to contain urate crystals by chemical means or polarized light microscopy or the presence of 6 of the following 12
clinical, laboratory, and x-ray phenomena listed below:
1. More than one attack of acute arthritis

2. Maximal inflammation developed within 1 day
3. Attack of monarticular arthritis
4. Joint redness observed
5. First metatarsophalangeal joint painful or swollen
6. Unilateral attack involving first metatarsophalangeal joint
7. Unilateral attack involving tarsal joint
8. Suspected tophus
9. Hyperuricemia
10. Asymmetric swelling within a joint (radiograph)
11. Subcortical cysts without erosions (radiograph)
12. Negative culture of joint fluid for microorganisms during attack of joint inflammation
SOURCE: Adapted from Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum
1977;20:895900, with permission of the American College of Rheumatology.
CRITERIA FOR THE CLASSIFICATION OF SYSTEMIC LUPUS ERYTHEMATOSUSa

1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may
occur in older lesions
3. Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician
5. Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or
effusion
6. Serositis (a) Pleuritis-convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion
OR (b) Pericarditis-documented by ECG or rub or evidence of pericardial effusion
7. Renal disorder (a) Persistent proteinuria greater than 0.5 g per day or greater than 3+ if quantitation not performed OR (b)
Cellular castsmay be red cell, hemoglobin, granular, tubular, or mixed
8. Neurologic disorder (a) Seizuresin the absence of offending drugs or known metabolic derangements; e.g., uremia,
ketoacidosis, or electrolyte imbalance OR (b) Psychosisin the absence of offending drugs or known
metabolic derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance
9. Hematologic disorder (a) Hemolytic anemia with reticulocytosis OR (b) Leukopenia, less than 4000/mm3 total on two or more
occasions OR (c) Lymphopenia, less than 1500/mm3 on two or more occasions OR (d) Thrombocytope-
nia, less than l00,000/mm3 in the absence of offending drugs
10. Immunologic disorderb (a) Anti-DNA: antibody to native DNA in abnormal titer OR (b) Anti-SM: presence of antibody to SM nuclear
antigen OR (c) Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of
IgG or IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard
method, or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and
confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test
11. Antinuclear antibody An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in
time and in the absence of drugs known to be associated with drug-induced lupus syndrome
SOURCE: Adapted from Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus (SLE). Arthritis Rheum
SOURCE: Adapted from Hochberg ME. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus
[letter]. Arthritis Rheum 1997;40:1725, with permission of the American College of Rheumatology.
a
This classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person must have SLE if any 4 or more of the 11 criteria
are present, serially or simultaneously, during any interval of observation.
b
The modifications to criterion number 10 were made in 1997.
APPENDIX I
CRITERIA FOR THE CLASSIFICATION OF SYSTEMIC SCLEROSIS (SCLERODERMA)a
A. Major criterion
Proximal scleroderma: Symmetric thickening, tightening, and induration of the skin of the fingers and the skin proximal to the
metacarpophalangeal or metatarsophalangeal joints. The changes may affect the entire extremity, face, neck, and trunk (thorax and
abdomen).
B. Minor criteria
1. Sclerodactyly: Above-indicated skin changes limited to the fingers
2. Digital pitting scars or loss of substance from the finger pad: Depressed areas at tips of fingers or loss of digital pad tissue as a result of
ischemia
3. Bibasilar pulmonary fibrosis: Bilateral reticular pattern of linear or lineonodular densities most pronounced in basilar portions of the
lungs on standard chest roentgenogram; may assume appearance of diffuse mottling or honeycomb lung. These changes should
not be attributable to primary lung disease.
SOURCE: Adapted from Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Pre-
liminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581590, with permission of the American College of
Rheumatology.
a
For the purposes of classifying patients in clinical trials, population surveys, and other studies, a person shall be said to have systemic sclerosis (scleroderma)
if the one major or two or more minor criteria are present. Localized forms of scleroderma, eosinophilic fasciitis, and the various forms of pseudoscleroderma
are excluded from these criteria.
676 APPENDIX I
CRITERIA FOR THE DIAGNOSIS OF POLYMYOSITIS AND DERMATOMYOSITISa

1. Symmetrical weakness Weakness of limb-girdle muscles and anterior neck flexors, progressing over weeks to months, with
or without dysphagia or respiratory muscle involvement
2. Muscle biopsy evidence Evidence of necrosis of type I and n fibers, phagocytosis, regeneration with basophilia, large vesicular
sarcolemmal nuclei and prominent nucleoli, atrophy in a perifascicular distribution, variation in
fiber size, and an inflammatory exudate, often perivascular
3. Elevation of muscle enzymes Elevation in serum of skeletal muscle enzymes, particularly creatine phosphokinase and often
aldolase, serum glutamate oxaloacetate, and pyruvate transaminases, and lactate dehydrogenase
4. Electromyographic evidence Electromyographic triad of short, small, polyphasic motor units, fibrillations, positive sharp waves,
and insertional irritability, and bizarre, high-frequency repetitive discharges
5. Dermatologic features A lilac discoloration of the eyelids (heliotrope) with periorbital edema, a scaly, erythematous
dermatitis over the dorsum of the hands (especially the metacarpophalangeal and proximal
interphalangeal joints, Gottrons sign), and involvement of the knees, elbows, and medial malleoli,
as well as the face, neck, and upper torso
Data from Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344347, with permission.
a
Confidence limits can be defined as follows: For a definite diagnosis of dermatomyositis, three of four criteria plus the rash must be present. For a definite
diagnosis of polymyositis, four criteria must be present without the rash. For a probable diagnosis of dermatomyositis, two criteria plus the rash must be
present. For a probable diagnosis of polymyositis, three criteria must be present without the rash. For a possible diagnosis of dermatomyositis, one criterion
plus the rash must be present. For a possible diagnosis of polymyositis, two criteria must be present without the rash.
The following findings exclude a diagnosis of dermatomyositis or polymyositis.
Evidence of central or peripheral neurologic disease, including motor-neuron disorders with fasciculations or long-tract signs, sensory changes, decreased
nerve conduction times, and fiber-type atrophy and grouping on muscle biopsy.
Muscle weakness with a slowly progressive, unremitting course and a positive family history or calf enlargement to suggest a muscular dystrophy.
Biopsy evidence of granulomatous myositis such as with sarcoidosis.
Infections, including trichinosis, schistosomiasis, trypanosomiasis, staphylococcosis, and toxoplasmosis.
Recent use of various drugs and toxins, such as clofibrate and alcohol.
Rhabdomyolysis as manifested by gross myoglobinuria related to strenuous exercise, infections, crush injuries, occlusions of major limb arteries, prolonged
coma or convulsions, high-voltage accidents, heat stroke, the malignant-hyperpyrexia syndrome, and envenomation by certain sea snakes.
Metabolic disorders such as McArdles syndrome.
Endocrinopathies such as thyrotoxicosis, myxedema, hyperparathyroidism, hypoparathyroidism, diabetes mellitus, or Cushings syndrome.
Myasthenia gravis with response to cholinergics, sensitivity to d-tubocurarine, and decremental response to repetitive nerve stimulation.
CRITERIA FOR THE CLASSIFICATION OF SJGRENS SYNDROMEa

1. Ocular symptoms
Definition. A positive response to at least one of the following three questions:
(a) Have you had daily, persistent, troublesome dry eyes for more than 3 months?
(b) Do you have a recurrent sensation of sand or gravel in the eyes?
(c) Do you use tear substitutes more than three times a day?
2. Oral symptoms
Definition. A positive response to at least one of the following three questions:
(a) Have you had a daily feeling of dry mouth for more than 3 months?
(b) Have you had recurrent or persistently swollen salivary glands as an adult?
(c) Do you frequently drink liquids to aid in swallowing dry foods?
3. Ocular signs
Definition. Objective evidence of ocular involvement, determined on the basis of a positive result on at least one of the following two
tests:
(a) Schirmer-I test (5 mm in 5 minutes)
(b) Rose bengal score ( 4, according to the van Bijsterveld scoring system)
4. Histopathologic features
Definition. Focus score 1 on minor salivary gland biopsy (focus defined as an agglomeration of at least 50 mononuclear cells; focus
score defined as the number of foci per 4 mm2 of glandular tissue)
CRITERIA FOR THE CLASSIFICATION OF SJGRENS SYNDROMEa (continued)

5. Salivary gland involvement
Definition. Objective evidence of salivary gland involvement, determined on the basis of a positive result on at least one of the
following three tests:
(a) Salivary scintigraphy
(b) Parotid sialography
(c) Unstimulated salivary flow ( 1.5 mL in 15 minutes)
6. Autoantibodies
Definition. Presence of at least one of the following serum autoantibodies:
(a) Antibodies to Ro/SS-A or La/SS-B antigens
(b) Antinuclear antibodies
(c) Rheumatoid factor
Exclusion criteria: preexisting lymphoma, acquired immunodeficiency syndrome, sarcoidosis, or graft-versus-host disease
SOURCE: Reprinted from Vitali C, Bombardieri S, Moutsopoulos HM, et al. Preliminary criteria for the classification of Sjgrens syndrome. Arthritis Rheum
a
For primary Sjgrens syndrome, the presence of three of six items showed a very high sensitivity (99.1%), but insufficient specificity (57.8%). Thus, this com-
bination could be accepted as the basis for a diagnosis of probable primary Sjgrens syndrome. However, the presence of four of six items (accepting as
serologic parameters only positive antiRo/SS-A and antiLa/SS-B antibodies) had a good sensitivity (93.5%) and specificity (94.0%), and therefore may be
used to establish a definitive diagnosis of primary Sjgrens syndrome.
CRITERIA FOR THE CLASSIFICATION OF POLYARTERITIS NODOSAa

1. Weight loss 4 kg Loss of 4 kg or more of body weight since illness began, not due to dieting or other factors
2. Livedo reticularis Mottled reticular pattern over the skin of portions of the extremities or torso
3. Testicular pain or tenderness Pain or tenderness of the testicles, not due to infection, trauma, or other causes
4. Myalgias, weakness, or leg Diffuse myalgias (excluding shoulder and hip girdle) or weakness of muscles or tenderness of leg
tenderness muscles
5. Mononeuropathy or Development of mononeuropathy, multiple mononeuropathies, or polyneuropathy

polyneuropathy
6. Diastolic BP >90 mm Hg Development of hypertension with the diastolic BP higher than 90 mm Hg
7. Elevated BUN or creatinine Elevation of BUN >40 mg/dL or creatinine >1.5 mg/dL, not due to dehydration or obstruction
APPENDIX I
8. Hepatitis B virus Presence of hepatitis B surface antigen or antibody in serum
9. Arteriographic abnormality Arteriogram showing aneurysms or occlusions of the visceral arteries, not due to arteriosclerosis,
fibromuscular dysplasia, or other non-inflammatory causes
10. Biopsy of small or Histologic changes showing the presence of granulocytes or artery containing
medium-sized polymorphonuclear leukocytes and mononuclear leukocytes in the artery wall
SOURCE: Reprinted from Lightfoot RW Jr, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis
nodosa. Arthritis Rheum 1990;33:10881093, with permission of the American College of Rheumatology.
ABBREVIATIONS: BP, blood pressure; BUN, blood urea nitrogen.
a
For classification purposes, a patient shall be said to have polyarteritis nodosa if at least 3 of these 10 criteria are present. The presence of any three or
more criteria yields a sensitivity of 82.2% and a specificity of 86.6%.
678 APPENDIX I
CRITERIA FOR THE CLASSIFICATION OF HENOCHSCHONLEIN PURPURAa

1. Palpable purpura Slightly raised palpable hemorrhagic skin lesions, not related to thrombocytopenia
2. Age at disease onset Patient 20 years or younger at onset of first symptoms
3. Bowel angina Diffuse abdominal pain, worse after meals, or the diagnosis of bowel ischemia, usually including
bloody diarrhea
4. Wall granulocytes on biopsy Histologic changes showing granulocytes in the walls of arterioles or venules
SOURCE: Reprinted from Mills JA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of HenochSchonlein
purpura. Arthritis Rheum 1990;33:11141121, with permission of the American College of Rheumatology.
a
For purposes of classification, a patient shall be said to have HenochSchonlein purpura if at least two of these four criteria are present. The presence of
any two or more criteria yields a sensitivity of 87.1% and a specificity of 87.7%.
CRITERIA FOR THE CLASSIFICATION OF CHURGSTRAUSS SYNDROMEa

1. Asthma History of wheezing or diffuse high-pitched rales on expiration
2. Eosinophilia Eosinophilia >10% on white blood cell differential count
3. Mononeuropathy or polyneuropathy Development of mononeuropathy, multiple mononeuropathies, or polyneuropathy (i.e.,

glove/stocking distribution) attributable to a systemic vasculitis
4. Pulmonary infiltrates, nonfixed Migratory or transitory pulmonary infiltrates on radiographs (not including fixed infiltrates),
attributable to a systemic vasculitis
5. Paranasal sinus abnormality History of acute or chronic paranasal sinus pain or tenderness or radiographic opacification
of the paranasal sinuses
6. Extravascular eosinophils Biopsy including artery, arteriole, or venule, showing accumulations of eosinophils in
extravascular areas
SOURCE: Adapted from Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of ChurgStrauss syndrome
(allergic granulomatosis and angiitis). Arthritis Rheum 1990;33:10941100, with permission of the American College of Rheumatology.
a
For classification purposes, a patient shall be said to have ChurgStrauss syndrome if at least four of these six criteria are positive. The presence of any four
or more of the six criteria yields a sensitivity of 85% and a specificity of 99.7%.
CRITERIA FOR THE CLASSIFICATION OF WEGENERS GRANULOMATOSISa

1. Nasal or oral inflammation Development of painful or painless oral ulcers or purulent or bloody nasal discharge
2. Abnormal chest radiograph Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities
3. Urinary sediment Microhematuria (> 5 red blood cells per high power field) or red cell casts in urine sediment
4. Granulomatous inflammation Histologic changes showing granulomatous inflammation within the wall of an artery or in
on biopsy the perivascular or extravascular area (artery or arteriole)
SOURCE: Reprinted from Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegeners granulo-
matosis. Arthritis Rheum 1990;33:11011107, with permission of the American College of Rheumatology.
a
For purposes of classification, a patient shall be said to have Wegeners granulomatosis if at least two of these four criteria are present. The presence of any
two or more criteria yields a sensitivity of 88.2% and a specificity of 92.0%.
CRITERIA FOR THE CLASSIFICATION OF GIANT CELL ARTERITISa

1. Age at disease onset 50 years Development of symptoms or findings beginning at age 50 or older
2. New headache New onset of or new type of localized pain in the head
3. Temporal artery abnormality Temporal artery tenderness to palpation or decreased pulsation, unrelated to
arteriosclerosis of cervical arteries
4. Elevated erythrocyte sedimentation rate Erythrocyte sedimentation rate 50 mm/hour by the Westergren method
5. Abnormal artery biopsy Biopsy specimen with artery showing vasculitis characterized by a predominance of
mononuclear cell infiltration or granulomatous inflammation, usually with
multinucleated giant cells
SOURCE: Reprinted from Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis.
Arthritis Rheum 1990;33:11221128, with permission of the American College of Rheumatology.
a
For purposes of classification, a patient shall be said to have giant cell (temporal) arteritis if at least three of these five criteria are present. The presence of
any three or more criteria yields a sensitivity of 93.5% and a specificity of 91.2%.
CRITERIA FOR THE CLASSIFICATION OF TAKAYASU ARTERITISa

1. Age at disease onset 40 years Development of symptoms or findings related to Takayasu arteritis at age 40 years
2. Claudication of extremities Development and worsening of fatigue and discomfort in muscles of one or more extremity
while in use, especially the upper extremities
3. Decreased brachial artery pulse Decreased pulsation of one or both brachial arteries
4. BP difference >10 mm Hg Difference of >10 mm Hg in systolic blood pressure between arms
5. Bruit over subclavian arteries or aorta Bruit audible on auscultation over one or both subclavian arteries or abdominal aorta
6. Arteriogram abnormality Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large
arteries in the proximal upper or lower extremities, not due to arteriosclerosis,
fibromuscular dysplasia, or similar causes; changes usually focal or segmental
SOURCE: Reprinted from Arend WP, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis.
Arthritis Rheum 1990;33:11291132, with permission of the American College of Rheumatology.
ABBREVIATIONS: BP, blood pressure (systolic; difference between arms).
a
For purposes of classification, a patient shall be said to have Takayasu arteritis if at least three of these six criteria are present. The presence of any three
APPENDIX I
or more criteria yields a sensitivity of 90.5% and a specificity of 97.8%.
CRITERIA FOR THE CLASSIFICATION OF HYPERSENSITIVITY VASCULITIS.a

1. Age at disease onset >16 years Development of symptoms after age 16
2. Medication at disease onset Medication was taken at the onset of symptoms that may have been a precipitating factor
3. Palpable purpura Slightly elevated purpuric rash over one or more areas of the skin; does not blanch with
pressure and is not related to thrombocytopenia
4. Maculopapular rash Flat and raised lesions of various sizes over one or more areas of the skin
5. Biopsy including arteriole and venule Histologic changes showing granulocytes in a perivascular or extravascular location
SOURCE: Reprinted from Calabrese LH, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of hypersensitivity
vasculitis. Arthritis Rheum 1990;33:11081113, with permission of the American College of Rheumatology.
a
For purposes of classification, a patient shall be said to have hypersensitivity vasculitis if at least three of these five criteria are present. The presence of any
three or more criteria yields a sensitivity of 71.0% and a specificity of 83.9%.
DIAGNOSTIC GUIDELINES FOR KAWASAKI SYNDROME.a
1. Fever lasting >5 days:
Plus four of the following criteria:
2. Polymorphous rash
3. Bilateral conjunctival injection
4. One or more of the following mucous membrane changes:

Diffuse injection of oral and pharyngeal mucosa
Erythema or fissuring of the lips
Strawberry tongue
5. Acute, nonpurulent cervical lymphadenopathy (one lymph node must be >1.5 cm)
6. One or more of the following extremity changes:

Erythema of palms and/or soles
Indurative edema of hands and/or feet
Membranous desquamation of the fingertips
SOURCE: Reprinted from Kawasaki T, Kosaki T, Okawa S, et al. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan.
Pediatrics 1974;54:271276, with permission.
a
Other illnesses with similar clinical signs must be excluded.
CRITERIA FOR THE DIAGNOSIS OF BEHETS DISEASE.a

1. Recurrent oral ulceration Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient, which
recurred at least three times in one 12-month period
Plus two of
2. Recurrent genital ulceration Aphthous ulceration or scarring, observed by physician or patient
3. Eye lesions Anterior uveitis, posterior uveitis, or cells in vitreous on slit lamp examination; or retinal vasculitis
observed by ophthalmologist
4. Skin lesions Erythema nodosum observed by physician or patient, pseudofolliculitis, or papulopustular lesions; or
acneiform nodules observed by physician in postadolescent patients not on corticosteroid treatment
5. Positive pathergy test Read by physician at 2448 hours
SOURCE: Reprinted from International Study Group for Behets Disease. Criteria for diagnosis of Behets disease. Lancet 1990;335:10781080, with permission.
a
Findings applicable only in the absence of other clinical explanations. The presence of recurrent oral ulceration and any two of the remaining criteria yields
a sensitivity of 91% and a specificity of 96%.
PRELIMINARY CLASSIFICATION CRITERIA FOR ANTIPHOSPHOLIPID SYNDROME.a

Vascular thrombosis
(a) One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ and
(b) Thrombosis confirmed by imaging or Doppler studies or histopathology, with the exception of superficial venous thrombosis and
(c) For histopathologic confirmation, thrombosis present without significant evidence of inflammation in the vessel wall.
Pregnancy morbidity
(a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal
morphology documented by ultrasound or by direct examination of the fetus or
(b) One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe
pre-eclampsia or severe placental insufficiency or
(c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or
hormonal abnormalities and paternal and maternal chromosomal causes excluded.
Laboratory criteria
(a) Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer on two or more occasions at least
6 weeks apart, measured by standard enzyme-linked immunosorbent assay for beta2 glycoprotein ldependent anticardiolipin
antibodies or
(b) Lupus anticoagulant present in plasma on two or more occasions at least 6 weeks apart, detected according to the guidelines of
the International Society on Thrombosis and Hemostasis.
SOURCE: Adapted from Wilson WA, Gharavi AE. Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospho-
lipid syndrome. Report of an International Workshop. Arthritis Rheum 1999;42:13091311 with permission of the American College of Rheumatology.
a
Definite APS is considered to be present if at least one of the clinical and one of the laboratory criteria are met.
WORLD HEALTH ORGANIZATION CRITERIA FOR THE DIAGNOSIS OF OSTEOPENIA AND OSTEOPOROSIS.
Normal BMC or BMD not more than 1 standard deviation below peak adult bone mass T score >1
Osteopenia BMC or BMD that lies between 1 and 2.5 standard deviations below peak adult bone mass T score between 1
and 2.5
Osteoporosis BMC or BMD value more than 2.5 standard deviations below peak adult bone mass T score 2.5
Severe Osteoporosis BMC or BMD value more than 2.5 standard deviations below peak adult bone mass and the presence of one or
more fragility fractures T score 2.5 plus fragility fracture
SOURCE: Adapted from Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO study group. World
Health Organ Techn Rep Ser 1994;843:1129.
a
World Health Organization criteria for the diagnosis of osteoporosis based on bone mineral content (BMC) or bone mineral density (BMD) measurements.
These criteria can be applied to either the central or peripheral skeletal measurement sites.
CRITERIA FOR THE DIAGNOSIS OF JUVENILE RHEUMATOID ARTHRITIS (JRA).

I. General
The JRA Criteria Subcommittee in 1982 reviewed the 1977 Criteria (1) and recommended that juvenile rheumatoid arthritis be the
name for the principal form of chronic arthritic disease in children and that this general class should be classified into three onset
subtypes: systemic, polyarticular, and pauciarticular. The onset subtypes may be further subclassified into subsets as indicated below.
The following classification enumerates the requirements for the diagnosis of JRA and the three clinical onset subtypes and lists
subsets of each subtype that may be useful in further classification.
II. General criteria for the diagnosis of juvenile rheumatoid arthritis

A. Persistent arthritis of at least 6 weeks duration in one or more joints
B. Exclusion of other causes of arthritis (see list of exclusions)
III. JRA onset subtypes

The onset subtype is determined by manifestations during the first 6 months of disease and remains the principal classification,
although manifestations more closely resembling another subtype may appear later.
A. Systemic onset JRA: This subtype is defined as JRA with persistent intermittent fever (daily intermittent temperatures to 103F or
more) with or without rheumatoid rash or other organ involvement. Typical fever and rash will be considered probable systemic
onset JRA if not associated with arthritis. Before a definite diagnosis can be made, arthritis, as defined, must be present.
B. Pauciarticular onset JRA: This subtype is defined as JRA with arthritis in four or fewer joints during the first 6 months of disease.
Patients with systemic onset JRA are excluded from this onset subtype.
C. Polyarticular JRA: This subtype is defined as JRA with arthritis in five or more joints during the first 6 months of disease. Patients
with systemic JRA onset are excluded from this subtype.
D. The onset subtypes may include the following subsets:
1. Systemic onset
a. Polyarthritis
b. Oligoarthritis
APPENDIX I
2. Oligoarthritis (pauciarticular onset)
a. Antinuclear antibody (ANA)positive chronic uveitis
b. Rheumatoid factor (RF) positive
c. Seronegative, B27 positive
d. Not otherwise classified
3. Polyarthritis
a. RF positivity
b. Not otherwise classified
IV. Exclusions
A. Other rheumatic diseases
1. Rheumatic fever
2. Systemic lupus erythematosus
3. Ankylosing spondylitis
4. Polymyositis or dermatomyositis
5. Vasculitic syndromes
6. Scleroderma
7. Psoriatic arthritis
8. Reiters syndrome
9. Sjgrens syndrome
10. Mixed connective tissue disease
11. Behets syndrome
(continued)
682 APPENDIX I
CRITERIA FOR THE DIAGNOSIS OF JUVENILE RHEUMATOID ARTHRITIS (JRA). (continued)

IV. Exclusions
B. Infectious arthritis
C. Inflammatory bowel disease
D. Neoplastic diseases including leukemia
E. Nonrheumatic conditions of bones and joints
F. Hematologic diseases
G. Psychogenic arthralgia
H. Miscellaneous
1. Sarcoidosis
2. Hypertrophic osteoarthropathy
3. Villonodular synovitis
4. Chronic active hepatitis
5. Familial Mediterranean fever
V. Other proposed terminology

Juvenile chronic arthritis (JCA) and juvenile arthritis (JA) are new diagnostic terms currently in use in some places for the arthritides
of childhood. The diagnoses of JCA and JA are not equivalent to each other, nor to the older diagnosis of juvenile rheumatoid
arthritis or Stills disease. Hence reports of studies of JCA or JA cannot be directly compared with one another nor to reports of JRA
or Stills disease. Juvenile chronic arthritis is described in more detail in a report of the European Conference on the Rheumatic
Diseases of Children (2) and juvenile arthritis in the report of the Ross Conference (3).
1. JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Current proposed revisions of
the JRA criteria. Arthritis Rheum 1977;20(Suppl):195199.
2. Ansell BW. Chronic arthritis in childhood. Ann Rheum Dis 1978;37:107120.
3. Fink CW. Keynote address: Arthritis in childhood. Report of the 80th Ross Conference in Pediatric Research. Columbus, OH: Ross Laboratories; 1979:12.
APPENDIX II
Guidelines for the Management

of Rheumatic Diseases
Practice guidelines represent a recent and important practice and serve a valuable educational function for
development in rheumatology. Guidelines, which are students of the rheumatic diseases. Moreover, because
developed by a panel of experts, address a broad range in very few instances have guidelines been tested in
of clinical issues from the approach to diagnosis of mus- clinical settings, they present an opportunity to study
culoskeletal signs and symptoms to patient manage- whether they result in efficiencies or improvements in
ment. Guidelines provide a framework for clinical diagnosis and patient management.
INITIAL EVALUATION OF THE ADULT PATIENT WITH ACUTE MUSCULOSKELETAL SYMPTOMS.

FEATURE DIFFERENTIAL DIAGNOSIS
History of significant trauma Soft tissue injury, internal derangement, or fracture
Hot, swollen joint Infection, systemic rheumatic disease, gout, pseudogout
Constitutional signs and symptoms Infection, sepsis, systemic rheumatic disease

(e.g., fever, weight loss, malaise)
Weakness
Focal Focal nerve lesion (compartment syndrome, entrapment neuropathy, mononeuritis multiplex,
motor neuron disease, radiculopathya)
Diffuse Myositis, metabolic myopathy, paraneoplastic syndrome, degenerative neuromuscular
disorder, toxin, myelopathy,a transverse myelitis
Neurogenic pain (burning, numbness,

paresthesia)
Asymmetric Radiculopathy,a reflex sympathetic dystrophy, entrapment neuropathy
Symmetric Myelopathy,a peripheral neuropathy
Claudication pain pattern Peripheral vascular disease, giant cell arteritis (jaw pain), lumbar spinal stenosis
SOURCE: Reprinted from American College of Rheumatology Ad Hoc Committee on Clinical Guidelines: guidelines for the initial evaluation of the adult patient
with acute musculoskeletal symptoms. Arthritis Rheum 1996;39:18, with permission of the American College of Rheumatology.
a
Radiculopathy and myelopathy may be due to infectious, neoplastic, or mechanical processes.
RECOMMENDED MONITORING STRATEGIES FOR DRUG TREATMENT OF RHEUMATOID ARTHRITIS.a

TOXICITIES MONITORING
REQUIRING BASELINE SYSTEM
DRUGS MONITORINGb EVALUATION REVIEW/EXAMINATION LABORATORY
Salicylates, nonsteroidal Gastrointestinal CBC, creatinine, AST, Dark/black stool, CBC yearly, LFTs, creatinine
anti-inflammatory drugs ulceration and ALT dyspepsia, nausea or testing may be requiredc
bleeding vomiting, abdominal
pain, edema,
shortness of breath
Hydroxychloroquine Macular damage None unless patient is Visual changes,

over age 40 or has funduscopic and
previous eye visual fields every
disease 612 months
(continued)
683
684 APPENDIX II
RECOMMENDED MONITORING STRATEGIES FOR DRUG TREATMENT OF RHEUMATOID ARTHRITIS.a (continued)

REQUIRING BASELINE SYSTEM
DRUGS MONITORINGb EVALUATION REVIEW/EXAMINATION LABORATORY
Sulfasalazine Myelosuppression CBC, and AST or ALT Symptoms of CBC every 24 weeks for
in patients at risk, myelosuppression,d first 3 months, then every
G6PD photosensitivity, rash 3 months
Methotrexate Myelosuppression, CBC, chest Symptoms of CBC, platelet count, AST,

hepatic fibrosis, radiography within myelosuppression,d albumin, creatinine every
cirrhosis, pulmonary past year, hepatitis shortness of breath, 48 weeks
infiltrates or fibrosis B and C serology in nausea/vomiting,
high-risk patients, lymph node swelling
AST or ALT,
albumin, alkaline
phosphatase, and
creatinine
Gold, intramuscular Myelosuppression, CBC, platelet count, Symptoms of CBC, platelet count, urine
proteinuria creatinine, urine myelosuppression,d dipstick every 12 weeks
dipstick for protein edema, rash, oral for first 20 weeks, then at
ulcers, diarrhea the time of each (or every
other} injection
Gold, oral Myelosuppression, CBC, platelet count, Symptoms of CBC platelet count, urine
proteinuria urine dipstick for myelosuppression,d dipstick for protein every
protein edema, rash, 412 weeks
diarrhea
D-penicillamine Myelosuppression, CBC, platelet count, Symptoms of CBC, urine dipstick for
proteinuria creatinine, urine myelosuppressiond, protein every 2 weeks
dipstick for protein edema, rash until dosage stable, then
every 13 months
Azathioprine Myelosuppression, CBC, platelet count, Symptoms of CBC and platelet count every
hepatotoxicity, creatinine, AST or myelosuppressiond 12 weeks with changes
lymphoproliferative ALT in dosage, and every 13
disorders months thereafter
Corticosteroids (oral Hypertension, BP, chemistry panel, BP at each visit, Urinalysis for glucose yearly
10 mg of prednisone or hyperglycemia bone densitometry polyuria, polydipsia,
equivalent) in high-risk patients edema, shortness of
breath, visual
changes, weight
gain
Agents for refractory RA or severe extra-articular complications
Cyclophosphamide Myelosuppression, CBC, platelet count, Symptoms of CBC and platelet count every
myeloproliferative urinalysis, myelosuppression,d 12 weeks with changes
disorders, creatinine, AST or hematuria in dosage, and every 13
malignancy, ALT months thereafter,
hemorrhagic cystitis urinalysis and urine
cytology every 612
months after cessation
Chlorambucil Myelosuppression, CBC, urinalysis, Symptoms of CBC and platelet count every
myeloproliferative creatinine, AST or myelosuppressiond 12 weeks with changes
disorders, ALT in dosage, and every 13
malignancy months thereafter
Cyclosporin A Renal insufficiency, CBC, creatinine, uric Edema, BP every 2 Creatinine every 2 weeks
anemia, acid, LFTs, BP weeks until dosage until dose is stable, then
hypertension stable, then monthly monthly; periodic CBC,
potassium, and LFTs
G U I D E L I N E S F O R T H E M A N A G E M E N T O F R H E U M A T I C D I S E A S E S 6 85
ANTIRHEUMATIC DRUG THERAPY IN PREGNANCY AND LACTATION, AND EFFECTS ON FERTILITY.

FDA USE-IN- MAJOR
PREGNANCY CROSSES MATERNAL FETAL
DRUG RATINGa PLACENTA TOXICITIES TOXICITIES LACTATION FERTILITY
Aspirin C; D in third Yes Anemia, Premature Use cautiously; No data

trimester peripartum closure of excreted at low
hemorrhage, ductus, concentration;
prolonged pulmonary doses >1 tablet
labor hypertension, (325 mg) result in
ICH high concentration
in infant plasma
NSAIDs B; D in third Yes As for aspirin As for aspirin Compatible No data

trimester according to AAP
Corticosteroids
Prednisone B Dexamethasone Exacerbation IUGR 5% to 20% of
and beta- of diabetes maternal dose
methasone and excreted in breast
hyperten- milk; compatible,
sion, PROM but wait 4 hours if
dose >20 mg
Dexamethasone C As above
Hydroxychloroquine C Yes: fetal Few Few Contraindicated No data

concentration (slow elimination
50% of rate, potential for
maternal accumulation)
Gold C Yes No data 1 report of cleft Excreted into breast No data

palate and milk (20% of
severe CNS maternal dose);
abnormalities rash, hepatitis,
and hematologic
abnormalities
reported, but AAP
considers it
compatible
D-penicillamine D Yes No data Cutis laxa No data No data

connective
tissue
abnormalities
APPENDIX II
Sulfasalazine B; D if near Yes No data No increase in Excreted into breast Females: no
term congenital milk (40% to 60% effect; males:
malformation, maternal dose); significant
kernicterus if bloody diarrhea in oligospermia
administered 1 infant; AAP (2 months to
near term recommends return to
caution normal)
Azathioprine D Yes No data IUGR (rate up to No data; hypotheti- Not studied; can
40%) and cal risk of interfere with
prematurity, immunosuppres- effectiveness of
transient sion outweighs IUD
immunosup- benefit
pression in
neonate,
possible effect
on germlines
of offspring
(continued)
686 APPENDIX II
ANTIRHEUMATIC DRUG THERAPY IN PREGNANCY AND LACTATION, AND EFFECTS ON FERTILITY. (continued)
FDA USE-IN- MAJOR
PREGNANCY CROSSES MATERNAL FETAL
DRUG RATINGa PLACENTA TOXICITIES TOXICITIES LACTATION FERTILITY
Chlorambucil D Teratogenic No data Renal Contraindicated No data

effects angiogenesis
potentiated
by caffeine
Methotrexate X No data Spontaneous Fetal Contraindicated; Females:

abortion abnormalities small amounts Infrequent
(including excreted with long-term
cleft palate potential to effect; males:
and accumulate in reversible
hydrocephalus) fetal tissues oligospermia
Cyclophosphamide D Yes: 25% of No data Severe abnor- Contraindicated; has Females: age
maternal malities; case caused bone >25 years,
level report: male marrow concurrent
twin devel- depression radiation, and
oped prolonged
papillary exposure
cancer at increase risk of
11 years and infertility;
neuroblas- males: dose-
toma at dependent
14 years oligospermia
and azoosper-
mia regardless
of age or
exposure
Cyclosporin A C Yes No data IUGR and Contraindicated due No data

prematurity; to potential for
1 case report: immunosuppression
hypoplasia of
right leg; not
an animal
teratogen and
unlikely to be
a human one
SOURCE: Reprinted from American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for monitoring drug therapy in rheumatoid
arthritis. Arthritis Rheum 1996;39:723731, with permission of the American College of Rheumatology.
ABBREVIATIONS: AAP, American Academy of Pediatrics; CNS, central nervous system; ICH, intracranial hemorrhage; IUD, intrauterine device; IUGR, intrauterine
growth retardation; PROM, premature rupture of membranes.
a
Food and Drug Administration (FDA) use-in-pregnancy ratings are as follows: A, controlled studies show no risk. Adequate, well-controlled studies in pregnant
women have failed to demonstrate risk to the fetus. B, No evidence of risk in humans. Either animal findings show risk but human findings do not, or, if no
adequate human studies have been performed, animal findings are negative. C, Risk cannot be ruled out. Human studies are lacking and results of animal
studies are either positive for fetal risk or lacking as well. However, potential benefits may justify the potential risk. D, Positive evidence of risk. Investigational
or post-marketing data show risk to the fetus. Nevertheless, potential benefits may outweigh the potential risk. X, Contraindicated in pregnancy. Studies in
animals or humans, or investigational or postmarketing reports, have shown fetal risk which clearly outweighs any possible benefit to the patient.
MONITORING DRUG THERAPY IN SYSTEMIC LUPUS ERYTHEMATOSUS.

REQUIRING
DRUG MONITORING Baseline evaluation System review Laboratory
Salicylates, NSAIDs Gastrointestinal bleeding, CBC, creatinine, Dark/black stool, CBC yearly, creatinine yearly
hepatic toxicity, renal urinalysis, AST, ALT dyspepsia, nausea/
toxicity, hypertension vomiting, abdominal
pain, shortness of
breath, edema
Glucocorticoids Hypertension, hyperglyce- BP, bone densitometry, Polyuria, polydipsia, Urinary dipstick for glucose
mia, hyperlipidemia, glucose, potassium, edema, shortness of every 36 months, total
hypokalemia, osteopo- cholesterol, triglycer- breath, BP at each cholesterol yearly, bone
rosis, avascular necrosis, ides (HDL, LDL) visit, visual changes, densitometry yearly to
cataract, weight gain, bone pain assess osteoporosis
infections, fluid
retention
Hydroxychloroquine Macular damage None unless patient is Visual changes Fundoscopic and visual fields
over 40 years of age every 612 months
or has previous eye
disease
Azathioprine Myelosuppression, CBC, platelet count, Symptoms of CBC and platelet count every
hepatotoxicity, lympho- creatinine, AST or myelosuppression 12 weeks with changes in
proliferative disorders ALT dose (every 13 months
thereafter), AST yearly, Pap
test at regular intervals
Cyclophosphamide Myelosuppression, CBC and differential Symptoms of myelo- CBC and urinalysis monthly,
myeloproliferative and platelet count, suppression, urine cytology and Pap test
disorders, malignancy, urinalysis hematuria, infertility yearly for life
immunosuppression,
hemorrhagic cystitis,
secondary infertility
Methotrexate Myelosuppression, hepatic CBC, chest radiograph Symptoms of myelo- CBC and platelet count, AST
fibrosis, cirrhosis, within past year, suppression, or ALT, and albumin every
pulmonary infiltrates, hepatitis B and C shortness of breath, 48 weeks, serum
fibrosis serology in high-risk nausea/vomiting, creatinine, urinalysis
patients, AST, oral ulcer
albumin, bilirubin,
creatinine
APPENDIX II
SOURCE: Reproduced from Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis Rheum 1999;42:17851796, with
permission of the American College of Rheumatology.
ABBREVIATIONS: ALT, alanine transaminase; AST, aspartate transaminase; BP, blood pressure; CBC, complete blood cell count; HDL, high-density lipoprotein;
LDL, low-density lipoprotein; Pap, Papanicolaou.
688 APPENDIX II
GUIDELINES FOR CLINICAL USE OF THE ANTINUCLEAR ANTIBODY TEST: CONDITIONS ASSOCIATED WITH POSITIVE IF-
ANA TEST RESULTS.a
DISEASE FREQUENCY OF POSITIVE ANA RESULT (%)
Diseases for which an ANA test is very useful for diagnosis

SLE 95100
Systemic sclerosis (scleroderma) 6080
Diseases for which an ANA test is somewhat useful for diagnosis

Sjgrens syndrome 4070
Idiopathic inflammatory myositis (dermatomyositis or polymyositis) 3080
Diseases for which an ANA test is useful for monitoring or prognosis

Juvenile chronic oligoarticular arthritis with uveitis 2050
Raynauds phenomenon 2060
Conditions in which a positive ANA test result is an intrinsic part of the diagnostic criteria
Drug-induced SLE 100
Autoimmune hepatic disease 100
MCTD 100
Diseases for which an ANA test is not useful in diagnosis

Rheumatoid arthritis 3050
Multiple sclerosis 25
Idiopathic thrombocytopenic purpura 1030
Thyroid disease 3050
Discoid lupus 525
Infectious diseases Varies widely
Malignancies Varies widely
Patients with silicone breast implants 1525
Fibromyalgia 1525
Relatives of patients with autoimmune diseases (SLE or scleroderma) 525
Normal personsa
1 : 40 2030
1 : 80 1012
1 : 160 5
1 : 320 3
ABBREVIATIONS: ANA, antinuclear antibody; IF, immunofluorescent; MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosus.
a
Values are titers. Prevalence of positive ANA test result varies with titer. Female sex and increasing age tend to be more commonly associated with positive
ANA.
FLOW CHART FOR CLINICAL ANTINUCLEAR ANTIBODY TESTING.
Clinician suspects LE or other rheu-

matic condition in table
ANA testing is
YES NO not indicated
Perform ANA test
Test positive Test negative
How should a positive No further autoantibody testing is indicated.

result be interpreted? Follow patient clinically, and consider repeat
testing if indicated clinically.
Does the patient have one of the
conditions listed in table?
Further testing for other autoantibodies is driven by specific clinical findings/impressions
Is further testing indicated?
Clinician SLE has been

Sjogrens has been Clinician suspects Clinician suspects Clinician suspects
Clinician sus-
suspects LE diagnosed diagnosed polymyositis or scleroderma or mixed connective
pects drug-
but the dermatomyositis or has established this tissue disease
induced LE
diagnosis has established this diagnosis
needs to be diagnosis
confirmed
Information
regarding Consider Consider Consider No further Consider
Consider prognosis is testing for testing for testing for testing is testing for
testing for desired anti-Ro/SSA anti-Jo-1 anti-Scl-70 indicated anti-RNP
anti-dsDNA and anti-La/
and anti-Sm SSB
Consider
anti-dsDNA Consider testing for
testing anti-Ro/SSA
Correlate with clinical findings
SOURCE: Reprinted from Kavanaugh A, Tomar R, Reveille J, et al. Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies
APPENDIX II
to nuclear antigens. Arch Pathol Lab Med 2000;124:7181, with permission of the College of American Pathologists.
ABBREVIATIONS: LE, lupus erythematosus; RNP, ribonucleoprotein.
690 APPENDIX II
RECOMMENDATIONS FOR THE MEDICAL RECOMMENDATIONS FOR THE PREVENTION AND

MANAGEMENT OF OSTEOARTHRITIS OF THE HIP AND TREATMENT OF GLUCOCORTICOID-INDUCED
KNEE. OSTEOPOROSIS.
Nonpharmacologic therapy for patients with osteoarthritis Patient beginning therapy with glucocortocoid (prednisone
Patient education equivalents of 5 mg/day) with plans for treatment
Self-management programs (e.g., Arthritis Foundation Self- duration of 3 months
Management Program) Modify lifestyle risk factors for osteoporosis
Personalized social support through telephone contact Smoking cessation or avoidance
Weight loss (if overweight) Reduction of alcohol consumption if excessive
Aerobic exercise programs Instruct in weight-bearing physical exercise
Physical therapy Initiate calcium supplementation
Range-of-motion exercises Initiate supplementation with vitamin D (plain or activated form)
Muscle-strengthening exercises Prescribe bisphosphonate (use with caution in premenopausal
Assistive devices for ambulation women)
Patellar taping
Appropriate footwear Patient receiving long-term glucocorticoid therapy
Lateral-wedged insoles (for genu varum) (prednisone equivalent of 5 mg/day)
Bracing Modify lifestyle risk factors for osteoporosis
Occupational therapy Smoking cessation or avoidance
Joint protection and energy conservation Reduction of alcohol consumption if excessive
Assistive devices for activities of daily living Instruct in weight-bearing physical exercise
Initiate calcium supplementation
Pharmacologic therapy for patients with osteoarthritisa Initiate supplementation with vitamin D (plain or activated form)
ORAL Prescribe treatment to replace gonadal sex hormones if deficient
Acetaminophen or otherwise clinically indicated
COX-2specific inhibitor Measure bone mineral density (BMD) at lumbar spine and/or hip
Nonselective NSAID plus misoprostol or a proton pump If BMD is not normal (i.e., T score below 1), then
inhibitorb Prescribe bisphosphonate (use with caution in premenopausal
Nonacetylated salicylate women)
Other pure analgesics Consider calcitonin as second-line agent if patient has
Tramadol contraindication to or does not tolerate bisphosphonate
Opioids therapy
INTRA-ARTICULAR If BMD is normal, follow-up and repeat BMD measurement
Glucocorticoids either annually or biannually.
Hyaluronan
Topical SOURCE: Reprinted from American College of Rheumatology Ad Hoc
Capsaicin Committee on Glucocorticoid-Induced Osteoporosis. Recommendations
Methylsalicylate for the prevention and treatment of glucocorticoid-induced osteoporosis.
2001 update. Arthritis Rheum 2001;44:14961503, with permission of the
SOURCE: Reprinted from American College of Rheumatology Subcommittee American College of Rheumatology.
on Osteoarthritis Guidelines. Recommendations for the medical manage-
ment of osteoarthritis of the hip and knee. Arthritis Rheum 2000;43:1905
1915, with permission of the American College of Rheumatology.
ABBREVIATIONS: COX-2, cyclooxygenase-2; NSAID, nonsteroidal anti-inflam-
matory drug.
a
The choice of agent(s) should be individualized for each patient.
b
Misoprostol and proton pump inhibitors are recommended in patients who
are at increased risk for upper gastrointestinal adverse events.
APPENDIX III
Supplement and Vitamin

and Mineral Guide
SUPPLEMENTS ASU (Avocado Soybean Unsaponifiables)
Originally published in Arthritis Today, September Origin: A natural vegetable extract made from avocado
October 2006, reprinted by permission of the Arthritis and soybean oils.
Foundation. Dosage: Softgel; take 300 mg daily.
Claims: Slows the progression of osteoarthritis (OA).
Supplements by Condition Black Currant Oil (Ribes nigrum; see GLA)

or Symptom
Origin: Black currant seed oil is obtained from seeds of
Cartilage Degeneration: ASU, Chondroitin, Glucos- the black currant. Black currant seed oil contains
amine, SAM-e 15% to 20% gamma-linolenic acid (GLA). Do not
Decreased Mobility: Chondroitin, DMSO, Flax, GLA, confuse with black currant berry.
Glucosamine, Indian frankincense, MSM, SAM-e Dosage: Liquid and capsules; typical dosage ranges
Depression: St. Johns wort, SAM-e from 360 mg to 3000 mg daily.
Inflammation: Bromelain, Cats claw, Chondroitin,
Devils claw, DMSO, Fish oil, Flax, Ginger; GLA, Caution: Black currant oil may increase immune
MSM, SAM-e, Stinging nettle, Thunder god vine, response in elderly.
Turmeric
Pain: Bromelain, Chondroitin, Devils claw, DMSO, Borage Oil (Borago officinalis; see GLA)
Ginger, GLA, Glucosamine, Indian frankincense,
MSM, SAM-e, Stinging nettle, Thunder god vine, Origin: Oil from the seeds of the borage plant. Borage
Turmeric seed oil contains about 20% to 26% GLA.
Sleep Difficulties: Melatonin, Valerian Dosage: Liquid and capsules; take 1300 mg (oil) daily.
Ankylosing spondylitis: DHEA, Melatonin
Fibromyalgia: SAM-e, St. Johns wort, Valerian Boswellia
Gout: Devils claw, Stinging nettle
Lupus: DHEA, Fish oil, Flax, Thunder god vine See Indian Frankincense
Osteoarthritis (OA): ASU, Bromelain, Cats claw,
Chondroitin, Devils claw, DMSO, Ginger; Bromelain (Pineapple, Ananas comosus)
Glucosamine, Indian frankincense, MSM, SAM-e,
Stinging nettle, Turmeric Origin: Group of enzymes found in pineapple that break
Psoriasis: Fish oil down protein.
Raynauds phenomenon: Evening primrose, Flax, Dosage: Capsules and tablets; take 500 to 2000 mg three
Ginger, Ginkgo, GLA times a day between meals.
Rheumatoid arthritis (RA): Black currant oil (or seed), Claims: Decreases pain and swelling of rheumatoid
Borage oil (or seed), Bromelain, DMSO, Evening arthritis (RA) and OA, and increases mobility.
primrose, Fish oil, Flax oil (or seed), Ginger, GLA,
Indian frankincense/boswellia, Thunder god vine, Caution: Bromelain can cause stomach upset and diar-
Turmeric rhea and should be avoided if the patient is allergic
Scleroderma: DMSO to pineapples. It can also increase the effect of blood-
Sjgrens Syndrome: GLA thinning medicine.
691
692 APPENDIX III
Cats Claw (Uncaria tomentosa) Claims: Relieves pain and inflammation. May help
lower uric acid levels in people with gout. Acts as a
Origin: Dried root bark of a woody vine that grows in digestive aid and appetite stimulant.
the Amazon rain forests in Peru and other South
American countries. Caution: Devils claw should not be taken in patients
Dosage: Capsules, tablets, liquid, and tea bags; 250 who are pregnant, have gallstones or ulcers, or are
to 1000 mg daily. Buy only products that contain taking an antacid or blood thinners. It can affect
Uncaria tomentosa. Another plant (Acacia heart rate and may interfere with cardiac, blood-
greggi), which also has the name cats claw, is thinning, and diabetes medications. It may also cause
highly toxic. diarrhea.
Claims: Believed to have anti-inflammatory properties;
may stimulate immune system. DHEA (Dehydroepiandrosterone)
Caution: Cats claw can cause headache, dizziness, and Origin: An androgen steroid hormone naturally pro-
vomiting, and can lower blood pressure, should be duced in the body by the adrenal glands. Do not
avoided with anti-hypertensive medications or blood confuse 7-Keto DHEA with DHEA.
thinners. Dosage: Capsule and tablets available both as prescrip-
tion (200 mg) and nonprescription (10, 15, or 25 mg)
Chondroitin Sulfate products; typically 200 mg for lupus. Effects of long-
term use are unknown.
Origin: Chondroitin is a component of human connec- Claims: Helps control lupus flares; increases the blood
tive tissues found in cartilage and bone. In supple- level of DHEA.
ments, chondroitin sulfate usually comes from bovine
trachea or pork byproducts. Caution: DHEA side effects include stomach upset,
Dosage: Capsules, tablets, and powder; 800 to 1200 mg abdominal pain, and high blood pressure, as well as
daily in two to four divided doses. Often combined acne. It also decreases levels of good cholesterol (high-
with glucosamine. Allow up to 1 month to notice density lipoprotein, or HDL) and may cause facial hair
effect. growth, voice deepening, and changes in menstrual
Claims: Reduces pain and inflammation, improves joint pattern. DHEA can also increase insulin resistance for
function and slows progression of OA. people with diabetes, and exacerbate liver disease. Use
is contraindicated in men with prostate cancer and
Caution: Some chondroitin tablets may contain high women with uterine fibroids.
levels of manganese, which may be problematic with
long-term use. Because chondroitin is made from DMSO (Dimethyl Sulfoxide; see MSM)
bovine products, there is the remote possibility of con-
tamination associated with mad cow disease. Chon- Origin: A colorless, sulfur-containing organic byprod-
droitin taken with blood-thinning medications or uct of wood pulp processing.
NSAIDs may increase the risk of bleeding. In patients Dosage: Cream, gel; topically, 25% DMSO solution;
who are allergic to sulfonamides, start with a low dose take internally, only if prescribed by a physician.
of chondroitin sulfate and watch for any side effects. Claims: Relieves pain and inflammation, improves joint
Other side effects include diarrhea, constipation, and mobility in OA, RA, juvenile rheumatoid arthritis
abdominal pain. (JRA), and scleroderma, and manages amyloidosis.
Increases blood flow to skin.
Curcumin Studies: Controlled studies as a topical application for
DMSO and OA have yielded conflicting results. Few
See Turmeric human studies.
Devils Claw (Also known as Devils Claw Root, Caution: Side effects of DMSO taken internally include
Grapple Plant or Wood Spider; Harpagophytum headache, dizziness, drowsiness, nausea, vomiting,
procumbens) diarrhea, constipation, and anorexia. Topical DMSO
also can cause skin irritation and dermatitis. Avoid
Origin: A traditional herb used in South Africa. in patients with diabetes, asthma, or liver, kidney, or
heart conditions. Never take industrial-grade DMSO.
Dosage: Capsules, tincture, powder, and liquid; take 750 Wash off any lotions or skin products before applying
to 1000 mg three times a day. DMSO.
S U P P L E M E N T A N D V I T A M I N A N D M I N E R A L G U I D E 69 3
Evening Primrose (Also known as Evening Primrose flour; 30 g (1 ounce) daily. Capsules, available in
Oil or Primrose; Oenothera biennis and other Oeno- 1000 mg to 1300 mg, no typical dosage. Oil, 1 to 3
thera species; see GLA) tablespoons daily.
Claims: Eases symptoms of RA, lupus, and Raynauds
Origin: The seeds of a native American wildflower, phenomenon. Lubricates joints and lessens stiffness
containing 7% to 10% gamma-linolenic acid and joint pain. Lowers total cholesterol and reduces
(GLA). risk of heart disease and some types of cancer.
Dosage: Capsules, oil, and softgel; generally five 500-mg Improves hot flashes and dry skin.
capsules per day. For RA, 540 mg daily to 2.8 g daily
in divided doses. Evening primrose oil may take up Caution: Fiber in flaxseed can impair absorption of
to 6 months to work. some medications, and as flaxseed acts as a blood
thinner, should be avoided in patients taking blood thin-
Fish Oil ners, aspirin, or other NSAIDs. Flaxseed should be
avoided in hormone-sensitive breast or uterine cancer,
Origin: Oil from cold-water fish such as mackerel, and used with caution with the use of hypercholesterol-
salmon, herring, tuna, halibut, and cod. emia and cholesterol-lowering drugs.
Dosage: Fish, capsules, or chewable tablets. For general
health, two 3-ounce servings of fish a week are rec-
Ginger (Zingiber officinale)
ommended. However, its difficult to get a thera-
peutic dose of fish oil from food alone. To treat
Origin: The dried or fresh root of the ginger plant.
arthritis-related conditions, use fish oil capsules with
Dosage: Powder, extract, tincture, capsules, and oils; up
at least 30% EPA/DHA, the active ingredients. For
to 2 g in three divided doses per day or up to 4 cups
lupus and psoriasis, 2 g EPA/DHA three times a day.
of tea daily.
For Raynauds phenomenon, 1 g four times a day.
Claims: Decreases joint pain and reduces inflammation
For RA, up to 2.6 g fish oil (1 .6 g EPA) twice a
in people with OA and RA. Increases circulation in
day.
people with Raynauds phenomenon.
Claims: Reduces inflammation and morning stiffness.
Studies: A recent study showed that ginger extract
Treats RA, lupus, psoriasis, depression, and
inhibited inflammatory molecules, including TNF-
Raynauds phenomenon. Important for brain func-
alpha and cyclooxygenase-2 (COX-2). A 2005
tion and may inhibit RA development.
study reinforced the anti-inflammatory effects of
Studies: An analysis of nine studies of people with RA
ginger. Another 2005 study showed ginger killed
taking omega 3 showed a reduction in the number of
Helicobacter pylori, a bacterium that causes stomach
tender joints but no reduction in joint damage. In six
ulcers.
studies, people with RA were able to reduce their
dosages of NSAIDs or corticosteroids. A 2005 study
Caution: Ginger can interfere with medications for
of people with RA showed enhanced positive effects
blood thinning and should be avoided in the presence
when fish oil supplements were used in combination
APPENDIX III
of gallstones.
with olive oil.
Caution: Women who are pregnant or hoping to con- Ginkgo (Ginkgo biloba)
ceive should avoid shark, swordfish, king mackerel, and
tilefish, and should eat no more than 8 ounces of alba- Origin: Leaf of the ginkgo biloba tree, native to East
core tuna each month, due to potentially dangerous Asia.
levels of mercury. Fish oil supplements at normal doses Dosage: Liquid, tablet, softgel, capsule, and extract;
are safe. Look for brands that follow good manufactur- typically 120 mg to 240 mg extract daily. Choose sup-
ing practices and contain fish oils without mercury. plements standardized to 5% to 7% terpene lactones
and 24% flavonol glycosides, the active ingredients
Flaxseed (Flax, Raxseed Oil, Linseed Oil; Linum in ginkgo.
usitatissimum) Claims: Increases blood flow and circulation in
Raynauds phenomenon and claudication.
Origin: Seed of the flax plant, containing omega 3 and
omega 6 fatty acids and lignans (beneficial plant com- Caution: Ginkgos side effects include stomach upset,
pounds, similar to fiber). dizziness, or headaches. Avoid ginkgo with blood-
Dosage: Whole seeds, ground meal or flour, capsules, thinning medication like aspirin, epilepsy, diabetes, or
or oil. Whole seeds must be ground into meal or prior to surgery.
694 APPENDIX III
GLA (Gamma-Linolenic Acid) Indian Frankincense (Frankincense, Boswellia,

Boswellin, Salai Guggal; Boswellia serrata)
Origin: A type of omega 6 fatty acid found in evening
primose oil, black currant oil, and borage oil. Origin: Gum resin from the bark of the Boswellia tree
Dosage: Capsules or oil; 2 g to 3 g daily. found in India.
Claims: Lessens joint pain, stiffness, and swelling associ- Dosage: Capsule or pill; typically 300 mg to 400 mg three
ated with RA. Eases symptoms of Raynauds phe- times per day. Look for products with 60% boswellic
nomenon and Sjgrens syndromes. acids, the active ingredient.
Studies: One of the most promising studies was a Claims: Reduces inflammation and treats RA, OA,
placebo-controlled trial of 56 patients with active and bursitis symptoms. Indian frankincense may
RA who received 2.8 g GLA for 6 months. Partici- treat symptoms of ulcerative colitis and Crohns
pants showed significant improvements related to disease.
joint pain, stiffness, and grip strength. GLA doses Studies: In a 2004 study, Indian frankincense was tested
at this level were found to be safe and effective for as a treatment for knee OA. Researchers recruited
RA. A 2005 study showed that people with Sjgrens 30 people with knee OA and gave half the group a
syndrome who took GLA and linolenic acid had daily supplement containing 333 mg of Indian frank-
significant improvement in eye discomfort and tear incense; others got placebo. People who took Indian
production. frankincense reported less knee pain, better mobil-
ity, and an ability to walk longer distances than those
Glucosamine (Glucosamine sulfate, glucosamine taking placebo.
hydrochloride, N-acetyl glucosamine)
Melatonin
Origin: Major component of joint cartilage. Supple-
Origin: A hormone produced by the pineal gland, which
ments are derived from the shells of shellfish such as
is located at the base of the brain.
shrimp, lobster, and crab.
Dosage: Capsules or tablets; 1 mg to 5 mg at bedtime for
Dosage: Capsules, tablets, liquid, or powder (to be
insomnia, for no longer than 2 weeks.
mixed into a drink); 1500 mg per day for all forms.
Claims: Aids sleep and treats jet lag.
Often combined with chondroitin. May take 1 month
Studies: A systematic review of studies shows no evi-
to notice effect.
dence that melatonin effectively treats sleep disor-
Claims: Slows deterioration of cartilage, relieves OA
ders or is useful for altered sleep patterns, such as
pain, and improves joint mobility.
from shift work or jet lag. However; there is evidence
Studies: The NIH Glucosamine/Chondroitin Arthritis
that it is safe with short-term use. Another review
Intervention Trail (GAIT) concluded that glucos-
of studies showed that melatonin reduced the onset
amine may be beneficial. The study of 1583 people
of sleep by 4 minutes and increased the duration of
with knee OA showed that the supplements were
sleep by nearly 13 minutes; another showed that
more effective when combined, but that they did
people taking melatonin slept almost 30 minutes
not work significantly better than placebo or the
longer than people taking placebo.
NSAID celecoxib in people with mild pain. However;
a subgroup of people in the study who had moder-
Caution: Certain medications interact with melatonin,
ate-to-severe pain did show significant benefit, even
including NSAIDs, beta-blockers, antidepressants,
more than with the NSAID. Half of the study
diuretics, and vitamin B12 supplements. Melatonin
participants will continue to be evaluated for 18
should be avoided in patients with autoimmune disease,
months to see if glucosamine and chondroitin can
depression, kidney disease, epilepsy, heart disease, or
slow or stop the progression of knee OA. A 2005
leukemia.
Cochrane review of glucosamine analyzed the out-
comes of 20 studies comprising 2570 patients. Glu-
MSM (Methylsulfonyfmethane)
cosamine was found to be safe, but not superior to
placebo in reducing pain and stiffness and improv-
Origin: Organic sulfur compound found naturally in
ing function.
fruits, vegetables, grains, animals, and humans.
Dosage: Tablets, liquid, capsule, or powder, topical and
Caution: Glucosamine may cause mild stomach upset, oral. Typically 1000 mg to 3000 mg daily with meals.
nausea, heartburn, diarrhea, and constipation, as well Claims: Reduces pain and inflammation.
as increased blood glucose, cholesterol, triglyceride, Studies: A 2006 pilot study of 50 men and women with
and blood pressure. Glucosamine should be avoided in knee OA showed that 6000 mg of MSM improved
individuals allergic to shellfish. symptoms of pain and physical function without
major side effects. No large, well-controlled human prescription antidepressants. St. Johns wort can cause
studies have been performed. insomnia, restlessness, anxiety, irritability, stomach
upset, fatigue, dry mouth, dizziness, or increased sensi-
Caution: MSM may cause stomach upset or diarrhea and tivity to sunlight. It should be avoided in patients with
should be avoided in patients taking blood thinners. Alzheimers disease, human immunodeficiency (HIV)
infection, depression, schizophrenia, infertility, or
SAM-e (S-adenosyl-L-methionine) bipolar disorder. It may also reduce effectiveness of oral
contraceptives.
Origin: A naturally occurring chemical in the body.
Dosage: Tablets; 600 mg to 1200 mg daily for OA; Stinging Nettle (Urtica dioica)
1600 mg daily for depression. Because of possible
interactions, SAM-e should not be taken without Origin: The leaves and stem of the stinging nettle plant,
doctors supervision. a stalk-like plant found in the United States, Canada,
Claims: Treats pain, stiffness, and joint swelling; and Europe.
improves mobility; rebuilds cartilage and eases symp- Dosage: Tea, capsule, tablet, tincture, extract, or whole
toms of OA, fibromyalgia, bursitis, tendinitis, chronic leaf; capsules, up to 1300 mg daily; tea, 1 cup, three
low back pain, and depression. times a day; tincture, 1 mL to 4 mL three times a day;
Studies: Over the last two decades, multiple clinical nettle leaf applied directly to the skin.
trials involving thousands of people have shown Claims: Reduces inflammation, aches, and pains of OA.
SAM-e to improve joint health and treat OA. It has Studies: A German study shows that hox alpha, a new
been found to be equal to NSAIDs in clinical studies. extract of stinging nettle leaf, contains an anti-
Most of this research has been done in Europe, where inflammatory substance that suppressed several cyto-
SAM-e is sold as a drug. A double-blind study of 61 kines in inflammatory joint diseases. In a Turkish
adults with knee OA done in the United States shows study, stinging nettle extract showed antimicrobial
that SAM-e had a slower onset of action but was as effects against nine microorganisms, as well as anti-
effective as celecoxib in reducing pain and improving ulcer and analgesic activity. Stinging nettle root extract
joint function. A 2002 analysis of 14 SAM-e studies combined with sabal fruit extract was shown to be
showed it is effective for reducing pain and improv- superior to placebo for treating prostate hyperplasia
ing mobility in people with OA. (a precancerous condition), and was well tolerated.
Caution: High doses of SAM-e can cause flatulence, Caution: Nettle may interfere with blood thinners, dia-
vomiting, diarrhea, headache, and nausea. SAM-e may betes, and heart medications, and lower blood pressure.
interact with antidepressive medications and should be
avoided in patients with bipolar disorder or who are Thunder God Vine (Tripterygium wilfordii)
taking monoamine oxidase inhibitors (MAOIs). It may
also worsen Parkinsons disease. Origin: Root of a vinelike plant from Asia.
Dosage: Extract; 30 mg daily.
APPENDIX III
St. Johns Wort (Hypericum perforatum) Claims: Reduces pain and inflammation and treats
symptoms of RA, lupus, and other autoimmune
Origin: The yellow flower, leaves, and stem of the St. diseases.
Johns wort plant is native to Europe and grows wild Studies: A 2006 review of randomized clinical trials
in the United States. shows that thunder god vine improved symptoms of
Dosage: Extract in the form of powder (dried), liquid RA but serious side effects occurred.
(10 to 60 drops one to four times per day) or tablet,
capsules, and tea; extract, typically 900 mg daily. Caution: This root can cause stomach upset, skin reac-
Claims: Acts as an antidepressant drug and reduces tions, temporary infertility in men, and amenorrhea in
inflammation and pain. women. It should not be used in patients taking immu-
Studies: No scientific evidence shows that St. Johns nosuppressive drugs or prednisone.
wort is effective for reducing inflammation. A
Cochrane review of studies on St. Johns wort for Tumeric (Curcuma longa, Curcuma domestica)
depression showed that current evidence is inconsis-
tent. A study also found that the herb is not effective Origin: A yellow-colored powder ground from the roots
for social anxiety disorder. of the lilylike turmeric plant. It is a common ingredi-
ent in curry powder. The turmeric plant grows in
Caution: Although St. Johns wort taken alone is con- India and Indonesia and is related to the ginger
sidered safe, it is potentially dangerous if taken with family.
696 APPENDIX III
Dosage: Capsules or spice. Capsule, typically 400 mg to Vitamin A

600 mg three times per day; or 0.5 g to 1 g of pow-
dered root up to 3 g per day. Other names: Beta-carotene, retinal, retinol, and reti-
Claims: Reduces pain, inflammation, and stiffness noic acid. Vitamin A palmitate and vitamin A acetate
related to RA and OA; treats bursitis. Known as a are retinol forms. Retinoids collectively refers to
cleansing agent, tumeric often is used as a digestive different forms of vitamin A.
aid in India. Why: Maintains the immune system; protects eyesight;
Studies: Several recent studies show that curcumin or keeps skin and tissues of the mouth, stomach,
turmeric has anti-inflammatory properties and modi- intestine, and respiratory system healthy; acts as an
fies immune system responses. A 2006 study showed antioxidant.
turmeric was more effective at preventing joint How much: RDA = 3000 IU for men; 2333 IU for
inflammation than reducing joint inflammation. women.
Too much: UL = 10,000 IU from retinol.
Caution: High doses of turmeric can act as a blood
thinner and cause stomach upset. It should be avoided High levels are associated with bone fractures, liver
in patients with gallstones or who are taking blood- abnormalities, and birth defects. Other signs: head-
thinning medications. aches; dry, itchy skin; hair loss; bone and joint pain; and
vomiting and appetite loss.
Valerian (Valeriana officianalis)
Too little: Rare; symptoms include night blindness and
Origin: The dried root of the perennial herb valerian. weakened immune system.
Dosage: Capsules, tablets, tincture, softgel, or tea; Foods: Beta-carotene: apricots, cantaloupe, carrots,
300 mg to 500 mg of valerian extract daily (maximum dark leafy greens, and sweet potato. Retinol: cheese,
dose is 15 g of root per day). For insomnia and muscle liver, eggs, and fortified milk.
soreness, take 1 teaspoon of liquid extract diluted in Supplements: Supplements often contain vitamin A.
water or a 400-mg to 450-mg capsule, tablet, or softgel Interactions: Cholestyramine (Questran), colestipol,
30 to 45 minutes before bedtime or as needed. For a and mineral oil can reduce vitamin A absorption,
milder effect, drink a cup of valerian tea before bed. while oral contraceptives can increase levels. Supple-
Avoid powdered valerian root. ments combined with isotretinoin (Accutane) can
Claims: Treats insomnia and eases pain; has antispas- increase drugs toxicity.
modic and sedative effects. Research note: Researchers found that high levels of
Studies: A randomized, placebo-controlled trial of 184 vitamin A from retinol (not beta-carotene) signifi-
adults showed two tablets per night for 28 nights cantly increased bone fractures among men, con-
produced significant improvements in sleep and firming research showing that high levels of vitamin
quality of life. A from retinol raised the risk of hip fractures in
women.
Caution: Valerian may cause headache, excitability,
uneasiness, and insomnia. Patients should be advised to Vitamin D
limit driving or operating machinery while taking it.
Patients should avoid or limit alcohol, barbiturates, Other names: Cholecalciferol, calciferol, ergocalciferol,
tranquilizers, or other sedative-type drugs or herbs. dihydroxy vitamin D-2 or D-3.
Valerian should not be used longer than 1 month, or in Why: Builds and maintains strong teeth and bones;
patients with liver disease. protects against osteoporosis; aids in calcium
absorption; helps utilize phosphorus. Both calcium
VITAMIN AND MINERAL GUIDE and phosphorus are important for bone
mineralization.
Originally published in Arthritis Today, September How much: RDA = 200 IU for adults through age
October 2005, reprinted by permission of the Arthritis 50; 400 IU from 51 to 70 years of age; 600 IU over
Foundation. age 70.
Too much: UL = 2000 IU: nausea, vomiting, poor appe-
tite, constipation, weakness, and weight loss; increases
Fat-Soluble Vitamins blood levels of calcium, causing confusion, heart
Getting sufficient doses of vitamins is important, but rhythm abnormalities, or calcinosis and deposits of
make sure diet and supplements dont exceed recom- calcium in soft tissues.
mendations. Excesses of these vitamins are stored, Too little: A high risk of osteoporosis. Low levels lead
rather than excreted. to muscle weakness.
Foods: Fortified milk and breakfast cereals are good Too little: Too little vitamin K increases blood clotting
sources of vitamin D; small amounts also are in egg time and can cause bruises beneath skin and bleeding
yolks, butter, salmon, tuna, and sardines. gums.
Supplements: Because vitamin D needs increase with Foods: Leafy greens.
age, many experts recommend as much as 800 IU for Supplements: Multivitamins often contain amounts
seniors. Just 10 to 15 minutes of sun exposure two to lower than the RDA because vitamin K may have a
three times a week (without sunscreen) is sufficient blood-clotting effect.
to meet daily requirements. Interactions: Antibiotics can decrease vitamin K pro-
Interactions: Corticosteroids, such as prednisone, duction. Excess vitamin K intake may decrease effec-
antacids that contain magnesium, cholestyramine tiveness of blood-thinning drugs.
(Questran), and mineral oil can interfere with vitamin Research note: A study of more than 72,000 women
D absorption. found a link between low dietary vitamin K intake
Research note: In a study of 221 people with knee and an increased risk of hip fracture. Women who
osteoarthritis (OA), those who increased their daily ate iceberg or romaine lettuce one or more times
vitamin D intake gained muscle strength and daily were 45% less likely to break a hip than those
improved physical function. who ate lettuce once a week or less.
Vitamin E
Water-Soluble Vitamins
Other names: Alpha-tocopherol, gamma-tocopherol, During digestion, these vitamins are absorbed into the
tocopherol acetate, and tocopherol succinate. blood and transported around the body. The body uses
Why: Acts as a scavenger, cleaning up free radicals; also them quickly, however, and excretesrather than
aids in the formation of red blood cells, reproduction, storeswhat it doesnt need.
and growth.
How much: RDA = 15 mg for adults. Vitamin B1
Too much: UL = 1000 mg daily. May cause increased
bleeding time. Other names: Thiamine and thiamin.
Too little: Associated with fat malabsorption diseases Why: Converts glucose to energy; essential for normal
like Crohns disease. functioning of the heart, brain, nervous system, and
Foods: Peanut butter, almonds, sunflower seeds, marga- muscles.
rine, wheat germ, corn oil, soybean oil, and turnip How much: RDA = 1.2 mg for men; 1.1 mg for women.
greens. Too much: No known symptoms, but an allergic reac-
Supplements: Supplements should include mixed tion may result in flushing, itching, or swelling.
tocopherols, natural vitamin E, generally labeled Too little: Deficiency is associated with abnormal carbo-
D. The synthetic form D,L is only half as hydrate metabolism. Prolonged deficiency can affect
active. the nervous and cardiovascular systems.
Interactions: Blood-thinning medications, aspirin, Foods: All plant and animal foods contain thiamine,
APPENDIX III
NSAIDs, and drugs for schizophrenia or especially whole wheat, brown rice, fish, and lentils.
chemotherapy. Enriched pasta, bread, cereals, and rice.
Research note: A 2004 review of 19 clinical studies Supplements: Multivitamins generally provide 100% or
sparked a debate about the safety of vitamin E sup- more of the daily requirements.
plementation. However; a closer look showed most Interactions: Research links long-term use of the diuretic
of the people who experienced negative effects were furosemid (Lasix) to vitamin B1 deficiency. Regular
elderly and had chronic illnesses. A study of 136 use of antacids also may interfere with thiamines
people with knee OA found that supplemental absorption.
vitamin E didnt have any beneficial effect.
Vitamin B2
Vitamin K
Other names: Riboflavin.
Other names: Phylloquinone (K-1), menaquinone Why: Promotes healthy development; helps produce
(K-2), menadione (K-3) and dihydophylloquinone. skin and red blood cells; helps convert glucose to
Why: Aids blood clotting and activates osteocalcin, a energy.
protein that builds and strengthens bones. How much: RDA = 1.3 mg daily for men; 1.1 mg daily
How much: RDA for vitamin K = 90 mcg for women; for women.
120 mcg for men. Too much: UL not determined. High doses are believed
Too much: No UL set. harmless, but may turn urine orange or yellow.
698 APPENDIX III
Too little: Absorption is decreased in people with hyper- Suboptimal levels are linked to high levels of homo-
thyroidism. Symptoms can include dry, cracked skin cysteine, which can increase the risk of stroke and
and sensitivity to light. heart disease.
Foods: Organ meats, eggs, milk; fortified cereals and Foods: Beans, meat, poultry, and fish.
grains. Riboflavin is easily destroyed by light. Supplements: Found in multivitamins, B complex, and
Supplements: Generally contained in B complex or vitamin B6 supplements.
multivitamins, which provide 100% or more of the Interaction: Too much vitamin B6 can decrease the
DV for riboflavin. effects of drugs for epilepsy and Parkinsons disease.
Interactions: None known. Vitamin B6 should be taken along with drugs for
Research note: A diet rich in vitamin B2 may help ward tuberculosis.
off or slow the progression of cataracts and may help Research note: A study showed that low blood levels
prevent migraine headaches. of vitamin B6 decreased as the activity, severity,
and pain of RA increased. Researchers suggest
Vitamin B3 that inflammation may decrease the level of vitamin
B6.
Other names: Niacin, nicotinic acid, and nicotinamide.
Why: Helps with producing energy from food (sugars Vitamin B12
and fats); keeps skin, nerves, and digestive system
healthy. Other names: Cobalamin, cyanocobalamin, and
How much: RDA = 16 mg for men; 14 mg for women. methylcobalamin.
Too much: UL = 35 mg, though some doctors prescribe Why: Helps make red blood cells, nerve cells, and
higher doses as a treatment to reduce cholesterol and genetic material; converts folate to its active form.
triglyceride levels. Flushing of the face, neck, and How much: RDA = 2.4 mcg.
ears; itching, nausea, and headache; can aggravate Too much: UL not determined; negative side effects
gout. More serious effects include insomnia, palpita- may include rash.
tions, and liver damage. Too little: Because vitamin B12 converts folate to its
Too little: Rare; symptoms include dermatitis, diarrhea, active form, too little B12 can lead to a folate defi-
and dementia. ciency, resulting in pernicious anemia causing
Foods: Chicken, tuna, turkey, fish, beef, beans, yeast, fatigue, weakness, nausea, loss of appetite, and
peanut butter, and salmon. weight loss.
Supplements: Typically in B complex and multivitamins, Foods: Found only in foods of animal origin: organ
which generally provide 100% or more of the daily meats, egg yolks, yams, and salmon. Fortified foods
requirements. such as cereal, pasta, and bread may contain syn-
Interactions: Taking niacin and diabetes medications thetic versions.
may interfere with blood glucose control. Some cho- Supplements: Recommended for strict vegetarians,
lesterol medications can reduce niacin absorption. those whove had gastric surgery, or those who have
Pregnant women should avoid taking more than the a malabsorption disease. Because vitamin B12 absorp-
RDA. Take with food. tion declines with age, it is recommended that people
Research note: Studies link diets rich in vitamin B3 with older than 50 get most of their B12 from fortified
a decreased risk of Alzheimers disease. foods and supplements. Most multivitamins and
B complex supplements contain 100% or more of
Vitamin B6 the daily requirements.
Interaction: Antacids, drugs for indigestion and reflux
Other names: Pyridoxine, pyridoxal, pyridoxamine, and disease, cholesterol-lowering medication, and the
pyridoxine hydrochloride diabetes medication metformin can decrease the
Why: Needed in more than 100 chemical reactions in absorption levels or production of B12.
the body and for forming amino acids, red blood Research note: Maintaining a healthy level of vitamins
cells, and antibodies; important for nerve and brain B12, B6, and folic acid may protect bones by keeping
function and energy production. blood levels of the amino acid homocysteine from
How much: RDA = 1.3 mg for all adults up to age 50; elevating. High homocysteine levels affect the heart
over age 50, 1.7 mg for men, 1.5 mg for women. and the skeleton.
Too much: UL = 100 mg. Long-term high doses of B6
can lead to nerve damage, resulting in pain and Vitamin C
numbness of the extremities.
Too little: Rare; symptoms include skin inflammation, Other names: Ascorbic acid, L-ascorbic acid, and calcium
sore tongue, depression, confusion, and convulsions. ascorbate.
Why: Builds and maintains collagen and connective Supplements: Multivitamins and B complex vitamin
tissue; enhances iron and folic acid absorption; acts supplements generally provide 100% of the RDA.
as an antioxidant; aids wound healing. Interactions: Antacids, alcohol, antibiotics, aspirin, car-
How much: RDA = 90 mg daily for men; 75 mg for bamazepine (Tegretol), some cholesterol-lowering
women; smokers and people with arthritis should drugs, indomethacin (Indocin), oral contraceptives,
aim for an additional 35 mg daily. methotrexate, and sulfasalazine (Azulfidine) can
Too much: UL of vitamin C is 2000 mg daily. Can lead decrease absorption levels or production of folic
to diarrhea, nausea, and risk of kidney stones. acid.
Too little: Weight loss; fatigue; inflamed or bleeding Research note: Methotrexate hinders absorption of
gums; slower healing times; repeated infections and folate. Patients taking methotrexate can safely use
colds. folate supplements. In a double-blind, placebo-con-
Foods: Peppers, orange juice, pineapple and other citrus trolled trial of more than 400 people with RA, folate
fruits, strawberries, papaya, broccoli, Brussels supplements helped curb the side effects of metho-
sprouts, cabbage, cauliflower, kale, and kiwi. Cooking trexate, including liver inflammation with no loss of
destroys vitamin C activity. efficacy. A double-blind study published in the
Supplements: Daily intake of 200 to 500 mg is frequently Journal of the American Medical Association reports
recommended for all adults because many experts stroke patients who took folate and vitamin B12 had
think the RDA for vitamin C is too low. Some studies a lower risk of hip fracture compared to those taking
suggest nearly 1000 mg are needed to maintain plasma placebo.
levels at high concentrations. Natural and synthetic
vitamin C react the same in the body. Additional
ingredients, such as rose hips or bioflavonoids, have
not been shown to improve benefit.
Minerals
Interactions: Regular use of nonsteroidal anti-inflamma- Minerals are found naturally in the soil and become part
tory drugs (NSAIDs), aspirin, antibiotics, nicotine, of the fruits, vegetables, and other plant foods you eat.
oral contraceptives, or corticosteroids increases the Minerals requirements are fulfilled in persons who eat
need for vitamin C. plenty of fruits, vegetable greens, and grains.
Research note: In a recent study of vitamin C consump- The mineral chart does not contain listings for boron,
tion and arthritis, people whose diets contained the iodine, manganese, molybdenum, or potassium because
least amount of the vitamin were three times more people need such small amounts of these minerals, and
likely to be diagnosed with arthritis than those who the amount in foods usually meet the needs.
ate the most fruits and vegetables rich in vitamin C.
Calcium
Folate
Other names: Calcium carbonate, calcium lactate,
Other names: Folic acid and folacin. calcium citrate, calcium gluconate, and calcium citrate
Why: Promotes healthy cell growth and reproduction, malate.
APPENDIX III
formation of DNA; regulates homocysteine levels. Why: Builds and maintains strong teeth and bones;
How much: RDA = 400 mcg for adults; 600 mcg for regulates muscle contractions; transmits nerve
pregnant women. At least half of this intake (200 mcg) impulses and monitors cell permeability. Calcium
should come from the folic acid found in fortified needs phosphorus and vitamin D present to be
foods and supplements. effective.
Too much: UL = 1000 mcg daily, or 1 mg. Doses higher How much: AI = 1000 mg daily for adults under age 50;
than 1500 mcg (1.5 mg) may cause minor discomfort 1200 mg daily for adults older than 50. Some experts
such as nausea, appetite loss, and gas, and can mask recommend as much as 1500 mg daily for adults with
a vitamin B12 deficiency, resulting in nerve and brain inflammatory conditions and postmenopausal women
damage. Folic acid may be prescribed at levels higher not taking hormone-replacement therapy.
than the UL for people taking methotrexate. Too much: UL = 2500 mg. Too much causes bloating,
Too little: Increases the toxic effects of methotrexate, constipation, impaired kidney function, and kidney
can increase homocysteine level. Low levels in preg- stones.
nant women increase the risk of neural tube defects Too little: Contributes to bone loss, tooth loss, muscle
in their babies. Increased risk for certain cancers, cramps, and hypertension.
depression, heart disease, and Alzheimers disease. Foods: Milk, yogurt, cheese, ice cream, canned sardines
Foods: Spinach, kale, collards, turnip greens, broccoli, and canned salmon (with bones), broccoli, kale,
garbanzo beans, lentils, peas, pinto beans, oranges, turnip greens and bok choy, plus calcium-fortified
liver, and fortified breads, cereals, and juices. orange juice, cereal, and soy products.
700 APPENDIX III
Supplements: Inflammatory arthritis accelerates bone Too little: Rare; anemia and osteoporosis.
loss, so getting the optimal intake daily is critical. Foods: Organ meats, seafood, cashews, semisweet choc-
Supplement with 500-mg doses one or more times olate, peanut butter, lentils, and mushrooms.
a day with meals but avoid taking after eating foods Supplements: Not necessary or recommended; a
containing oxalic or phytic acid, such as spinach, multivitamin, typically provides the RDA.
parsley, beans, and whole cereals. Calcium may inter- Interactions: High levels of zinc, iron, and possibly
fere with absorption of iron, magnesium, and zinc, so vitamin C can block copper absorption.
take it separate from a multivitamin. Avoid supple- Research note: Although copper does have anti-
ments containing coral calcium, bone meal, oyster inflammatory properties, there currently is no
shell, or dolomite; they may be contaminated with research to support dietary copper or supplementa-
lead. tion as a treatment for arthritis.
Interactions: Calcium may decrease absorption or effec-
tiveness of some bone drugs, antibiotics, and calcium
Fluoride
channel blockers. Aluminum-containing antacids,
anticonvulsants, corticosteroids, diuretics and laxa-
Why: Necessary for strong bones and teeth (especially
tives may reduce calcium levels.
tooth enamel).
Research note: A review of five studies shows the com-
How much: AI = 4 mg for men; 3 mg for women.
bination of calcium and vitamin D supplements sig-
Too much: UL = 10 mg daily: mottled and brown
nificantly prevented bone loss in people taking
teeth.
corticosteroids. In another study of 65 people with
Too little: Tooth decay.
RA, those who took calcium (1000 mg) and vitamin
Foods: Fluoridated water, tea, and canned salmon and
D (500 IU) supplements not only reversed steroid-
sardines (with bones).
induced bone loss but also gained bone mass.
Supplements: By prescription only for infants and chil-
dren without access to fluoridated water.
Chromium
Interactions: Calcium supplements and calcium- and
aluminum-containing antacids.
Why: Helps body use insulin, protein, fat, and
Research note: Doesnt prevent osteoporosis. Safety
carbohydrates.
concerns related to joint pain and stress fractures
How much: AI = 35 mcg for men age 14 to 50; 30 mcg
from taking extremely high doses.
for men over age 50; 25 mcg for women age 14 to 50;
20 mcg for women over age 50.
Too much: No known symptoms. Iron
Too little: Impaired glucose utilization.
Food: Black pepper, brewers yeast, brown sugar, mush- Other names: Ferrous fumarate, ferrous gluconate, and
rooms, whole grains, and wheat germ. ferrous sulfate.
Supplements: Not necessary or recommended. Why: Necessary for production of hemoglobin.
Research note: There is no conclusive evidence that How much: RDA = 8 mg daily for men; 18 mg daily for
chromium supplements can prevent or treat diabetes, women until menopause; 8 mg daily for women after
but research continues. Using chromium and beta- menopause.
blockers modestly increases levels of high-density Too much: UL = 45 mg per day: nausea, vomiting, diar-
lipoprotein (HDL) levels. Chromium may add to rhea or constipation, and dark-colored stools. Iron
effects of diabetes medications. Antacids, corticoste- builds up in body tissues and vital organs, leading to
roids, H2-blockers, and proton pump inhibitors may cirrhosis, diabetes, heart disease, and arthritis (par-
decrease chromium levels. ticularly in the knuckles). High levels also lower zinc
absorption.
Copper Too little: The most common form of nutritional defi-
ciency, mostly affecting young children, female teen-
Other names: Cupric oxide, copper gluconate, copper agers, and women of childbearing years. Symptoms
sulfate, and copper citrate. of mild deficiency include tiredness, shortness of
Why: Helps build red blood cells, transport iron, and breath, decreased mental performance, poor appe-
make connective tissue; keeps immune system, tite, unstable body temperature, and decreased
nerves, and blood vessels healthy; and removes free immunity.
radicals. Foods: Heme iron comes from beef, lamb, chicken,
How much: RDA = 900 mcg daily for adults. turkey, veal liver, ham, bologna or tuna, and is well
Too much: UL = 10,000 mcg: nausea, vomiting, diar- absorbed by the body. Non-heme iron comes from
rhea, abdominal pain, headache, or death. plant sources and fortified grains, such as raisins,
peas, lentils, figs, oatmeal, and grits, and is not as well Research note: There is no scientific evidence showing
absorbed. that phosphorus, namely in soft drinks, contributes
Supplements: Men and postmenopausal women should to bone loss. However, drinking soft drinks in lieu of
take multivitamins or other supplements with little milk may contribute to osteopenia or osteoporosis.
or no iron.
Interactions: Calcium. High doses of vitamin C, meat, Selenium
fish, poultry, citric acid, and cream of tartar enhance
absorption of iron from plant sources. Coffee, tea, Other names: Sodium selenite (inorganic, supplement
wine, tofu, legumes, grains, and rice inhibit absorp- form) and selenomethionine (organic form found in
tion of iron from plant sources. food).
Why: Works with vitamins C and E as an antioxidant;
Magnesium essential for proper function of immune system and
thyroid gland.
Other names: Magnesium chloride, gluconate, oxide, How much: RDA = 55 mcg daily.
citrate (supplement forms); magnesium hydroxide Too much: UL = 400 mcg daily. Too much may cause
(antacid) and magnesium sulfate (Epsom salt). hair and nail loss, fatigue, and mild nerve damage.
Why: Needed for more than 300 biochemical reactions Too little: Rare; impaired immunity and heart damage.
in the body. Maintains muscle and nerve function, Foods: Brazil nuts, walnuts, wheat germ, organ meats,
keeps heart rhythm regular, strengthens teeth and shrimp, crab, tuna, turkey, and garlic.
bones. Supplements: Not recommended beyond a multivitamin
How much: RDA = 420 mg for men older than 31; unless under a doctors supervision.
320 mg for women older than 31. Research note: Supplementation of 200 mcg daily may
Too much: UL = 350 mg, supplements only; no upper lower the risk of prostate cancer in men, but further
limit via diet. Too much causes diarrhea, confusion, studies must be done before scientists make any re-
muscle weakness, nausea, irregular heartbeat, and commendations. Although people with RA tend to
low blood pressure. have low selenium levels, there is no evidence that
Too little: Symptoms include loss of appetite, nausea, selenium supplements are beneficial.
vomiting, fatigue, and weakness.
Foods: Kelp, wheat germ, soy beans, almonds, cashews, Sodium
sunflower seeds, beans, potatoes, peanut butter, and
hard (high mineral) water. Other names: Sodium chloride (table salt), sodium
Supplements: Diet usually adequate, but supplementing citrate, monosodium glutamate (MSG), sodium
is OK. nitrate, sodium bicarbonate (baking soda),
Interactions: May reduce effects or absorption of some sodium phosphate (baking powder), and sodium
diuretics, bone drugs, antibiotics, and iron. Chemo- saccharin.
therapy may decrease magnesium level. Fiber may Why: Regulates body fluids and blood pressure and
increase absorption. helps nerve impulse function and muscle
APPENDIX III
contraction.
Phosphorus How much: AI = 1.5 g for adults 19 to 50; 1.3 g for
adults 51 to 70. DV is 2.4 g (2 g sodium = 1 teaspoon
Why: Strengthens teeth and bones; also involved in table salt). Average daily intake in the United States
energy production. is 5 g.
How much: RDA = 700 mg. Too much: No UL determined; excess may cause high
Too much: UL = 4000 mg daily before age 70; 3000 mg blood pressure, stomach cancer, kidney stones, and
daily after age 70. Too much may cause diarrhea and osteoporosis.
upset stomach. Chronic overdose may cause kidney Too little: Less than 0.5 g daily leads to headache, nausea,
damage. dizziness, fatigue, muscle cramps, and fainting.
Too little: Rare; symptoms could include weak bones Foods: Salt (75% percent of our salt intake comes
and muscles, fatigue, loss of appetite, bone pain, and from sodium added to seasonings or processed
increased susceptibility to infection. foods).
Foods: Milk, yogurt, cheese, eggs, whole wheat bread, Supplements: Not necessary or recommended.
soft drinks, turkey, salmon, halibut, peanuts, almonds, Interactions: Diuretics, NSAIDs, opiates, and tricyclic
and lentils. antidepressants. People taking corticosteroids should
Supplements: Not necessary or recommended. stay below 3 g daily.
Interactions: Aluminum-containing antacids, potassium Research note: One study found women who consumed
supplements, and potassium-sparing diuretics. a high salt diet (9 g daily) lost 33% more calcium and
702 APPENDIX III
23% more of a bone protein than those on a low salt Too little: Mild deficiency impairs immunity, leading to
diet (2 g/day). poor wound healing and infection.
Foods: Oysters, mussels, lobster, beef, pork, lamb,
Zinc chicken, turkey, milk, cheese, yogurt, maple syrup,
peanuts, peanut butter, beans, and lentils.
Other names: Zinc gluconate and zinc acetate. Supplements: Multivitamins with no more than 100%
Why: Involved in wound healing, cell reproduction, DV recommended.
tissue growth, sexual maturation, and taste and smell; Interactions: Antibiotics may bind with zinc, decreasing
also associated with more than 100 enzymatic reac- both drug and nutrient absorption. Take multivita-
tions in the body. mins and antibiotics separately. Calcium can decrease
How much: RDA = 11 mg daily for men; 8 mg daily for absorption of zinc supplements.
women. Research note: Zinc may protect against age-related
Too much: UL = 40 mg daily: immune suppression macular degeneration.
(same as deficiency), diarrhea, abdominal cramps
and vomiting, and copper deficiency.
INDEX
A outcome, 457 localized, 539540

Abatacept, 139140 pathogenesis, 455 myeloma-associated, 534
in PsA, 189 radiographic findings in, 455456 pathogenesis, 534
Abciximab, 449 treatment, 457458 precursors, 536
ACD. See Amplitude color Doppler acute disease, 457458 proteins, 536
ACE. See Angiotensin-converting chronic disease, 457458 secondary, 534
enzyme Advanced glycation endproduct (AGE), treatment, 537
Achilles tendon 539 Amyopathic dermatomyositis, 363
rupture, 82 Aerobic exercise, for fibromyalgia, 92 ANA. See Antinuclear antibodies
tendinitis, 8182 AFQUIP. See Arthritis Foundation Anakinra, 139
Achondroplasioas, 561 Quality Indicators Project Analgesic drugs, opioid, 622623
aCL. See Anticardiolipin AGE. See Advanced glycation Anaplasma phagocytophilum, 287
Acne fulminans, 501 endproduct ANCA. See Antineutrophil cytoplasmic
ACR. See American College of Alanine aminotransferase (ALT), 375 antibody
Rheumatology Alcohol, gout and, 252253 Anesthesia, in arthrocentesis, 2223
ACR20, 139 Alefacept, in PsA, 189 Angiitis, primary, 439441
Acrocyanosis, 430 Alendronate, 574, 594 clinical manifestations of, 439440
Acrodermatitis chronica atrophicans, Alkaptonuria, 525527 Angiofibroblastic tendinosis, 73
285 clinical features, 525526 Angiogenesis, 129
Acromegaly, 482483 laboratory features, 526527 Angiography, 28, 3940
rheumatological manifestations of, radiographic features, 526 Angioimmunoblastic T-cell lymphoma-
482 Allergic reactions, 641 associated arthritis, 476
ACTD. See Autoimmune connective Allopurinol, 260 Angiopathy, benign, 441
tissue disease Alopecia, 307 Angiotensin-converting enzyme (ACE),
ACTH. See Adrenocorticotropic Alprazolam, 624 352
hormone ALPS. See Autoimmune Ankle
Acupuncture, 625, 665 lymphoproliferative syndrome examination of, 1314
Acute febrile neutrophilic dermatosis, ALT. See Alanine aminotransferase palpation, 14
492 Alzheimers disease, 534 Ankylosing spondylitis
Adalimumab AMA. See American Medical anti-TNF agents and, 213214
ankylosing spondylitis and, 213 Association arthritogenic peptides, 202203
in PsA, 188 Amblyomma americanum, 284 biologic agents, 212213
Addisons disease, 483 American College of Rheumatology adalimumab, 213
Adenosine monophosphate, 387 (ACR), 88, 136 etanercept, 212
Adherence, in JIA American Medical Association infliximab, 213
assessment of, 166 (AMA), 4 bone formation in, 207
factors impacting, 166 Amplitude color Doppler (ACD), 38 classification criteria for, 198,
improving, 166 Amyloid arthropathy, 476 672673
Adhesive capsulitis, 72 Amyloid fibrillogenesis, 534 clinical assessment of, 209210
Adiposity, in gout, 253254 Amyloidosis, 56, 533541 clinical features of, 194
Adrenocorticotropic hormone (ACTH), clinical features, 535540 cytokine expression in, 207
in gout treatment, 259 AA, 537538 diagnosing, 197198
Adult Stills disease, 455458 AL, 535537 disease activity, 209210
clinical findings in, 455456 ATTR, 538539 epidemiology of, 193
clinical manifestations, 456 A2M, 539 etiology of, 193193
diagnosis, 456457 localized, 539540 exercise and, 210
criteria for, 457 diagnosis, 540541 gut microbes in, 204
differential diagnosis of, 457 histopathology, 541 histopathology in, 206207
disease course, 457 imaging, 540 HLA-B27 and, 201203
laboratory findings in, 455456 epidemiology, 535 aberrant cell surface heavy chains,
laboratory tests in, 456 hematologic abnormalities in, 536 203
703
704 INDEX
Ankylosing spondylitis (cont.) Antimalarials, in SLE, 330331 in SLE, 341

arthritogenic peptides, 202203 In RA XXX thrombosis, 341
as disease factor, 203 Antineutrophil cytoplasmic antibody Apatite, 267
endoplasmic reticulum stress, 203 (ANCA), 1719, 410 clinical features, 268269
enhanced bacterial survival, 203 assay, 423 acute arthritis, 269
protein misfolding in, 203 This entire section needs to be calcific periarthritis, 269
imaging in, 196197 moved to a separate heading calcinosis, 269
MHC genes in, 205 titled Vasculitis large joint destructive arthritis,
MTX treatment, 212 antigens, 422 268269
non-MHC genes in, 206 in blood, 420 Milwaukee shoulder syndrome,
pathogenesis, 200207 in bronchi, 419 268269
pathology, 200207 classification criteria, 417 ARAMIS. See Arthritis, Rheumatism,
patient education in, 210 clinical features of, 418420 and Aging Medical Information
pharmacologic modalities, 211212 clinical testing for, 422 System
glucocorticoids, 211 clinical utility of, 422 Arterial wall, immune response in,
muscle relaxants, 211 course, 425 399400
NSAIDs, 211 definitions of, 417 Arteritis, giant cell, 398404
pamidronate, 211212 differential diagnosis, 423, 424 Arthritis. See also specific types
SSZ, 212 epidemiology, 417 diagnosis of, 2
thalidomide, 211212 in eyes, 419 public health accomplishments, 34
tricyclic antidepressants, 211 in GI tract, 420 public health initiative for, 12
physical therapy for, 210 in heart, 420 Arthritis Foundation Quality Indicators
Move all of the headings below to in kidneys, 419420 Project (AFQUIP), 4
Clinical features of above in nervous system, 420 Arthritis, Rheumatism, and Aging
cardiovascular involvement, 196 nonmedical interventions, Medical Information System
enthesitis, 194 424425 (ARAMIS), 639
eye lesions, 195 pathology, 421 Arthritis Self-Management Program
IBD, 195196 pathophysiology, 423 (ASMP), 237, 614615
neurologic involvement, 196 prognosis, 425 Arthrocentesis, 2123
pulmonary involvement, 196 in skin, 420 indications for, 2122
renal consequences, 196 in trachea, 419 local anesthesia in, 2223
sacroiliitis, 194195 treatment, 424 sterile procedures, 22
skin involvement, 196 in upper respiratory tract, techniques, 22
synovitis, 195 418419 Arthrochalasia type EDS, 552553
uveitis, 195 cytoplasmic, 17 Arthrography, 28, 3839
surgical intervention, 214 perinuclear, 17 Arthus, Maurice, 427 Need to double
treatment guidelines, 213214 testing, 422 check this one no clue what
operative, 655 Antinuclear antibodies (ANA), 17, 52, this means.
Anserine bursitis, 80 89, 345 ASCT. See Autologous stem-cell
Anterior chest wall, disorders of, immunopathogenesis of, 321322 transplantation
8485 patterns, 17 ASMP. See Arthritis Self-Management
Anterior interosseous nerve syndrome, in RA, 119 Program
7576 in SLE, 321 Aspartate aminotransferase (AST), 375
Anteroposterior (AP) radiography, 29 specificity of, 324 Aspiration
standing, 32 testing, 688 anatomic approach to, 23t
Anti-Beta 2 glycoprotein, 340 Antiphospholipid antibody syndrome, image-guided, 40
Anticardiolipin (aCL), 340 316 Aspirin, 637, 638
ANTI-CCP. See Anti-cyclic citrullinated classification criteria, 340 AST. See Aspartate aminotransferase
peptide antibodies classification of, 680 Asthma, 641
Anticoagulants, NSAID interactions clinical features of, 339340 Autoantibodies, 18
with, 642 epidemiology of, 339 B cell, 126
Anti-cyclic citrullinated peptide laboratory features, 340 in idiopathic inflammatory
antibodies (ANTI-CCP), 1617, pathogenesis, 340341 myopathies, 366367, 377, 378
126 pathology, 340 in polymyositis, 378
Antidepressants, 623624. See also primary, 339 in RA, 125127
Selective serotonin reuptake secondary, 339 in Sjogrens syndrome, 390391
inhibitors; Tricyclic treatment, 341 in SLE, 312313
antidepressants asymptomatic, 341 in systemic sclerosis, 345
Antigen presentation, 9899 catastrophic, 341 Autoimmune exocrinopathy, 390
Antihypertensives, NSAID interactions experimental, 341 Autoimmune lymphoproliferative
with, 642 pregnancy loss, 341 syndrome (ALPS), 102
I N D E X 7 05
Autoimmunity, 106 Bioenergetics, skeletal muscle, 384 Bursitis

B cell, 126 Biofeedback, 664665 anserine, 80
in RA, 125127 Bisphosphonates, 574 cubital, 74
T cell, 126127 in osteoporosis treatment, iliopsoas, 7879
Autologous stem-cell transplantation 594595 ischial, 79
(ASCT) duration of, 596 olecranon, 73
in JIA treatment, 158 tolerability of, 595596 prepatellar, 80
in systemic sclerosis treatment, 361 Black currant oil, 691 retrocalcaneal, 82
Avocado Soybean Unsaponifiables Blastomyces dermatitidis, 294 septic, 275276
(ASU), 691 Blastomycosis, 294 subcutaneous, 82
Axial arthritis, 221 B lymphocytes, 98, 104106, 125 trochanteric, 78
Azathioprine, in SLE treatment, 331 activation, 104105 Buspirone, 624
autoantibodies, 126
B autoimmunity, 126 C
Babinskis sign, 66 depletion, 335 Calcific periarthritis, 269
Bacillus Calmette-Guerin, 292293 development, 104 Calcifying panniculitis, 496
Back pain, 5866 differentiation, 104105 Calcinosis, 269
disorders affecting, 59 inhibition of, 335 in systemic sclerosis, 347
fever and weight loss and, 60 specific tolerogen, 335 Calcitonin, in osteoporosis treatment,
initial evaluation of, 5860 BMD. See Bone mineral density 596
mechanical, 61 BMP. See Bone morphogenetic Calcium, 699700
recumbency, 60 proteins homeostasis, 587
stiffness and, 60 Bone and joint dysplasias, 559564 Calcium oxalate crystals, 26
Back strain, 61 Bone calcium phosphate crystals, 56 Calcium pyrophosphate dehydrate
Bakers cysts, 7980 Bone densitometry, 28, 39 deposition disease (CPPD), 35,
BAL. See Bronchoalveolar lavage Bone destruction, 130 49, 56, 259, 263267
BASDAI. See Bath Ankylosing Bone dysplasias, 559564 clinical features, 265266
Spondylitis Index Bone formation lanthanic, 266 _ ????
Basic calcium phosphates (BCP), 267 in ankylosing spondylitis, 207 pseudogout, 265
clinical features, 268269 markers, 582 pseudo-neuropathic arthropathy,
acute arthritis, 269 Bone mineral density (BMD), in 266
calcific periarthritis, 269 osteoporosis, 577 pseudo-OA, 265
calcinosis, 269 Bone morphogenetic proteins (BMP), pseudo-RA, 265266
large joint destructive arthritis, 181, 207 conditions associated with, 264
268269 Bone remodeling diagnostic criteria, 266
Milwaukee shoulder syndrome, cellular basis of, 585586 pathogenesis of, 264265
268269 in PsA, 180181 crystal deposition, 265
osteoarthritis, 268 Bone resorption markers, 582 radiographic features, 266267
crystal identification, 267268 Bone structure, 584586 treatment, 267
Bath Ankylosing Spondylitis Index Bone turnover CAM. See Complementary and
(BASDAI), 209 biochemical markers of, 582 alternative medicine
BBK32, 285 No clue what this means in osteoporosis, 580581, 590 Cancer
?? formation markers in, 582 musculoskeletal symptoms and,
BCP. See Basic calcium phosphates resorption markers in, 582 474477
Behavioral Risk Factor Surveillance Bone types, 584585 rheumatic diseases and, 474
System (BRFSS), 3 Bony abnormalities, 3536 Candidiasis, 392
INDEX
Behets disease, 56, 435439 BOOP. See Bronchiolitis obliterans Capsaicin, 624
brainstem involvement in, 437 organizing pneumonia Capsulitis, adhesive, 72
classification of, 680 Borage oil, 691 Carbamazepine, 624
clinical manifestations, 436438 Borrelia burgdorferi, 44, 52, 282283 Carcinomatous polyarthritis, 477
diagnosis, 438 Boswellia, 691 Cardiovascular system
disease activity, 438439 Brachialgia, 65 ANCA and, 420
international study group criteria for, Brachial plexopathy, 72 in ankylosing spondylitis, 196
436 Brachyolmia, 563 glucocorticoids and, 647
management of, 439 BRFSS. See Behavioral Risk Factor in idiopathic inflammatory
pathogenesis, 439 Surveillance System myopathies, 365, 366
ulcers in, 436 Bromelain, 691 NSAIDs, 641
Benign angiopathy, 441 Bronchiolitis obliterans organizing in SLE, 310311
Bicipital tendon pneumonia (BOOP), 118, 370 in systemic sclerosis, 348
rupture of, 7172 Bronchoalveolar lavage (BAL), 377 Carnitine palmitoyltransferases (CPT),
tendinitis, 7172 Bunionette, 83 386
706 INDEX
Carpal tunnel syndrome, 630 CINCA. See Chronic infantile in SLE treatment, 328330
Carpometacarpal (CMC) joint, 49, 75 neurological cutaneous in RA XXXX
Cartilage arthropathy Costimulatory interactions, 101,
destruction, 130 CK. See Creatine kinase 335336
enzymes in degradation of, 231 Clobetasol, 330 Costochondritis, 84
MRI of, 35 Clonazepam, 624 COX-2. See Cyclooxygenase-2
in OA, 229230 Clubbed finger, 505 CPM. See Continuous passive motion
Cartilaginous loose bodies, 545 CMC joint. See Carpometacarpal joint CPPD. See Calcium pyrophosphate
Caspar criteria, 172 Coccidioides immitis, 294 dehydrate deposition disease
Cats claw, 692 Coccidioidomycosis, 294 CPT. See Carnitine
Cauda equina compression, 58 Coccydynia, 79 palmitoyltransferases
CCP. See Cyclic citrullinated peptide Codfish vertebrae, 554 CRASP gene, 285
CDC. See Centers for Disease Control Cogans syndrome, 441442 C-reactive protein (CRP), 16, 52
CDSMP. See Chronic Disease Self localized corneal edema in, 441 Creatine kinase (CK), 375, 385
Management Program Cognitive behavioral therapy, for CRP. See C-reactive protein
Cell migration, 129 fibromyalgia, 92 CRPS. See Complex regional pain
Centers for Disease Control (CDC), 3 Colchicine, 44 syndrome
Cerebrospinal fluid (CSF), 90, 437 in gout treatment, 259 Cryoglobulinemic vasculitis, 429431
Cervical disc herniation, 65 Cold clinical presentation, 430
Cervical spine in pain management, 625 definition, 429
mechanical disorders of, 6466 in rehabilitation, 602604 diagnosis, 430431
operative treatment, 661662 Common variable immunodeficiency prognosis, 431
radiograph of, 197 (CVID), 105, 517 therapy, 431
Cervical spondylosis, 65 Complement, 19, 98 Cryoglobulins, 19
CHAQ. See Childhood Health in SLE, 312313 Cryopyrinopathies, 465466
Assessment Questionnaire Complementary and alternative clinical findings, 466
Charcots joints, 227 medicine (CAM), 625626, laboratory findings, 466
CHB. See Congenital heart block 664667 treatment, 466
Cheiralgia paresthetica, 76 miscellaneous, 667 Cryptococcosis, 294295
Childhood Health Assessment resources on, 667 Cryptococcus neoformans, 294
Questionnaire (CHAQ), 160 Complex regional pain syndrome Crystal disease, 486
Children, septic arthritis in, 275 (CRPS), 509511 Crystalline arthritis, 54
Chlamydia, 218 clinical features of, 509510 Crystals
Cholesterol crystals, 26 epidemiology of, 509 deposition, 265
Chondrocalcinosis, 267 in hands, 510 oxalate, 269
in hand, 35 laboratory features in, 510511 pathogenic, 269
Chondrocytes, activation by catabolic mechanisms of, 511 in synovial fluid analysis, 2526
pathways, 233 pathophysiology of, 511 urate, 255256
Chondrodysplasias, 559561 treatment, 511512 CSF. See Cerebrospinal fluid
classification, 559 Computed tomography (CT), 28, 3233 CT. See Computed tomography
achondroplasias, 561 of hip, 33 Cubital bursitis, 74
diagnosis, 559560 of osteonecrosis, 567 Curcumin, 692
features of, 560 of tarsal coalition, 33 Cushings syndrome, 483
management of, 564 Congenital heart block (CHB), 315 Cutaneous extravascular necrotizing
pathogenesis, 559 Continuous passive motion (CPM), 662 granulomas, 502
punctata, 563 Conventional radiography, 2829 Cutaneous leukocytoclastic angiitis,
rhizomelic, 563 Copper, 700 428
Chondroitin sulfate, 237, 692 Core decompression, 570 CVID. See Common variable
Chondromalacia patellae, 81 Corticosteroids, 23 immunodeficiency
Chondromatosis, synovial, 545 in idiopathic inflammatory myopathy Cyclic citrullinated peptide (CCP), 133
Chondrosarcomas, synovial, 547 treatment, 379 Cyclooxygenase-2 (COX-2), 134, 238,
Christmas disease, 470, 471 injections 256, 634636
Chromium, 700 complications, 631 Cyclophosphamide
Chronic Disease Self Management diluting, 630 in SLE treatment, 332333
Program (CDSMP), 614615 dose in, 628 in systemic sclerosis treatment, 361
Chronic infantile neurological cutaneous efficacy, 628, 629 Cyclosporine, 138, 157
arthropathy (CINCA), 151, 460 gloves, 630631 PsA treatment with, 187188
Chronic pain of complex etiology, 621 needle length in, 628629 in SLE treatment, 332
Churg-Strauss syndrome, 416425, 420 preparations, 628, 630 Cysts
classification criteria for, 417 reactions to, 631 Bakers, 7980
classification of, 678 in JIA treatment, 155156 popliteal, 7980
I N D E X 7 07
Cytokines Disc herniation EMG. See Electromyography

in ankylosing spondylitis, 207 cervical, 65 Endocrine factors, 165
blockade, 336 diagnosing, 36 Endoplasmic reticulum (ER), stress, 203
fibroblast, 127129 lumbar, 6162 Enteropathic arthritis, 55
in idiopathic inflammatory Disease-modifying antirheumatic drugs Enteropathic spondyloarthritis, 220221
myopathies, 373 (DMARDs), 134, 135137, 287 axial, 221
macrophage, 127129 in JIA treatment, 157 diagnostic studies on, 221
networks, 127, 128 DISH. See Diffuse idiopathic skeletal genetics, 221
in OA, 231233 hyperostosis peripheral, 220
cartilage repair, 232233 Disodium etidronate, 574 treatment, 221
lipid mediators, 231 Distal biceps insertion, rupture of, 74 Enthesitis
matrix degradation products, 232 Distal interphalangeal (DIP) joints, 49 in ankylosing spondylitis, 194
mechanical stress, 232 in RA, 115 juvenile idiopathic arthritis and,
reactive oxygen species, 231232 Distal renal tubular acidosis (dRTA), 146147, 152
oligoarthritis and inflammatory, 150 393 in PsA, 174
in PsA, 180 DMARDs. See Disease-modifying Environmental factors, in PsA, 179180
T cell-derived, 127 antirheumatic drugs Enzyme-linked immunofluorescent
Cytophagic histiocytic panniculitis, 496 Dowagers hump, 578 assay (ELISA), 16, 19, 118
Drug-induced lupus, 55 Eosinophilic fasciitis, 350
D Drug-related lupus, 316317 clinical features, 468
Dactylitis, 9, 14, 146 Drugs, osteoporosis and, 590 laboratory features, 468
in PsA, 173 Dry mouth symptoms, differential Eosinophilic synovitis, 468
Dapsone, in SLE treatment, 331 diagnosis, 392 Epicondylitis
DC. See Dendritic cells Dual-energy x-ray absorptiometry lateral, 73
Deep venous thrombosis (DVT), 438 (DXA), 3, 39 medial, 7374
Dehydroepiandrosterone, 692 in osteoporosis, 578579, 581 Epidemiology, of fibromyalgia, 88
Deletion/insertion polymorphisms Dupuytrens contracture, 78 Epididymitis, 438
(DIPs), 110 DVT. See Deep venous thrombosis Epstein-Barr virus (EBV), 53, 124, 390
Dendritic cells (DC), 97, 202 DXA. See Dual-energy x-ray Erythema elevatum diutinum, 442
Deposition diseases, 523531 absorptiometry Erythema migrans, 283
Depot corticosteroid-induced iatrogenic Erythema nodosum, 495
inflammation, 269 E Erythrocyte sedimentation rate, 1516,
De Quervains tenosynovitis, 10, 75, 630 EBV. See Epstein-Barr virus 52
Dermatologic disorders, 492503 Echinococcus granulosus, 295 Estrogen, in osteoporosis treatment, 596
Dermatomyositis, 9, 55, 368 Echocardiogram, in Kawasaki disease, Etanercept
amyopathic, 363 447 ankylosing spondylitis, 212
diagnosis of, 676 ECM. See Extracellular matrix PsA, 188
humoral and endothelial mechanisms EDS. See Ehlers-Danlos syndrome RA, XXXX
in, 372373 Education, self-management, 614615 Juvenile Polyarthritis, XXXX
juvenile, 363 Efalizumab, in PsA, 189 Ethnic differences, 111
Dermatosparaxis type, 553 Efferocytosis, 323 Etidronate, 595
Desert rheumatism, 294 Ehlers-Danlos syndrome (EDS), Evening primrose, 693
Desmopressin, 472 551553 Examination
Devils claw, 692 arthrochalasia type, 552553 ankle, 1314
Diabetes mellitus, 479480 classical type, 551 elbow, 10
neuropathic arthropathy in, 489490 dermatosparaxis type, 553 forefoot, 14
INDEX
rheumatologic manifestations of, 480 hypermobility type, 551 hand, 910
Diastrophic dysplasia, 562 kyphoscoliosis type, 552 hindfoot, 1314
Diet, 666667 types of, 552 hip, 1112
Diffuse idiopathic skeletal hyperostosis vascular type, 551552 in JIA, 163
(DISH), 227, 480 Elbow knee, 1213
Digital radiography, 29 disorders of, 7374 midfoot, 14
Digital tip pitting scars, 346 examination of, 10 monarticular joint disease, 43
Dimethyl sulfoxide, 692 operative treatment, 660 in OA, 225
DIP joints. See Distal interphalangeal Electrical stimulation, in rehabilitation, polyarthritis, 5152
joints 603 principles, 78
DIPs. See Deletion/insertion Electromyography (EMG), 62 in RA, 116118
polymorphisms in idiopathic inflammatory shoulder, 1011
Disability, 599600 myopathies, 365, 375 SI joint, 12
examples of, 600 ELISA. See Enzyme-linked spine, 12
prevention, 615 immunofluorescent assay wrist, 910
708 INDEX
Exercise therapy, 603604, 665 Fish oil, 692 GERD. See Gastroesophageal reflux
Extracellular matrix (ECM), damage, Flaxseed, 693 disease
130 Fluoride, 700 Giant cell arteritis (GCA), 398404
Eyes Folate, 699 classification of, 679
ANCA and, 419 Forefoot, examination of, 14 clinical features of, 401403
in ankylosing spondylitis, 195 Foreign body reactions, monarthritis cranial, 401402
glucocorticoids and, 648 and, 45 fever, 402
JIA and, 166 Fractures large vessel, 403
sarcoidosis and, 515516 hip, 576577 spectrum of, 402
in Sjogrens syndrome, 391 risk for, 577 diagnosis of, 403404
treatment of, 395 vertebral, 577 imaging studies, 403404
in SLE, 312 wrist, 577 laboratory testing, 403
Frozen shoulder, 72 epidemiology, 398399
F Functional losses, 7 histomorphology of, 399
Fabrys disease, 529530 Functioning, 599600 pathogenesis, 399400, 400402
clinical features, 529 artery in, 400401
treatment, 529530 G immune response in, 399400
Familial cold autoinflammatory GAIT. See Glucosamine-Chondroitin schematic diagram of, 400
syndrome (FCAS), 460 Arthritis Intervention Trial systemic inflammatory response,
Familial Mediterranean fever, 54, 96, Gait, Arms, Leg, Spine (GALS) 401
460463 system, 8 prognosis, 404
clinical features of, 462463 GALS system. See Gait, Arms, Leg, risk factors for, 401
laboratory features of, 462463 Spine system treatment, 404
treatment, 463 Gamma-linolenic acid (GLA), 694 vasculitic lesions, 399
Farbers disease, 530 Ganglion, 7475 Giant cell tumor, 547548
Fat-soluble vitamins, 696 Gastric antral venous ectasia Giardia lamblia, 295
Fertility, 685686 (GAVE), 362 Ginger, 693
Fever, GCA manifesting as, 402 Gastroesophageal reflux disease Gingko, 693
Fibrinoid necrosis, 413 (GERD), 347 GLA. See Gamma-linolenic acid
Fibroblastlike synoviocytes, 129130 Gastrointestinal (GI) tract Glenohumeral joint, motion, 11
Fibroblasts, cytokines, 127129 ANCA and, 420 Glucocorticoids, 483, 644649
Fibrodysplasia ossificans progressiva, glucocorticoids and, 648 adverse effects of, 647648
555 in idiopathic inflammatory cardiovascular, 647648
Fibromyalgia, 8, 87 myopathies, 365, 366 dermatological, 648
classification criteria of, 88 inflammation, 147 endocrine, 647
clinical features of, 88 microbes in, 204 gastrointestinal, 648
etiology and pathogenesis of, 9091 NSAIDs and, 639640 infectious, 648
environmental influences, 90 in SLE, 312 musculoskeletal, 647
genetic influences, 90 in systemic sclerosis, 347 ophthalmological, 648
hypothalamic-pituitary and Gauchers disease, 528529 psychological, 648
autonomic dysfunction, 90 clinical features, 528 in ankylosing spondylitis treatment,
psychological and behavioral laboratory features, 528529 211
factors, 91 radiographic features, 528 crystals, 26
sensory processing, 90 treatment, 529 mechanisms of action, 644645
evaluation and treatment for, 91 GCA. See Giant cell arteritis on immune cells, 644, 645
pharmacologic management of, Generalized pustular psoriasis, 500 molecular, 644645
624 Genetics osteoporosis induced by, 690
treatment, 9193 determining components, 111112 in PsA management, 187
aerobic exercise for, 92 disease cause and, 108109 receptor ligands, 648649
cognitive behavioral therapy, 92 enteropathic spondyloarthritis, standardized nomenclature on, 646
complementary therapies, 93 221 therapeutic use, 645647
diagnosis label, 91 in idiopathic inflammatory in daily practice, 646
education, 9192 myopathies, 370371 inflammation inhibition, 645
pharmacologic therapies, 92 ?? in JIA, 150 radiographic progression and,
Curious why page numbers for in osteoporosis, 588589 646
Pharmacologic Management in PsA, 179 resistance, 647
of above are different? in RA, 123 Glucosamine, 237, 694
Fibrosing diseases, 496499 in sarcoidosis, 514 Glucosamine-Chondroitin Arthritis
dermatological conditions in SLE, 323324 Intervention Trial (GAIT), 666
associated with, 497498 in systemic sclerosis, 352 Glycogenoses, muscle, 381385
Fibrosis, systemic sclerosis, 357358 terminology, 109 Gonococcal (GC) joint disease, 275
I N D E X 7 09
Gout, 477 Granuloma annulare, 501502 Heparin, 25

acute intermittent, 242243 on dorsal hands, 502 Hepatitis B, 53
clinical associations, 246247 subcutaneous, 502 viral arthritis, 279280
hyperlipidemia, 247 Growth, in JIA, 163166 Hepatitis C, 55, 120, 390
hypertension, 247 Growth hormone (GH), JIA therapy, 165 autoimmune conditions associated
obesity, 247 Gut-associated lymphoid tissue with, 279
renal disease, 246247 (GALT), 95 serologic abnormalities in, 279
diagnosis, 247248 GVHD. See Graft versus host disease viral arthritis and, 278279
early-onset, 244245 Herbs, 666
epidemiology, 250251 H Heritable disorders of connective tissue,
in hands, 242 Hallux valgus, 83 549557
laboratory features of, 247248 Hammer toe, 83 Ehlers-Danlos syndrome, 551
management of, 258262 Hand fibrodysplasia ossificans progressiva,
ACTH, 259 chondrocalcinosis in, 35 555
asymptomatic, 261 CRPS in, 510 ??? What is this ? homocystinuria, 550551
colchicine, 259 disorders, 7478 joint instability syndromes, 553
glucocorticosteroids, 259 examination, 910 Marfan syndrome, 549550
NSAID, 258259 global function of, 9 mucopolysaccharidoses, 555557
pharmacologic antihyperuricemic gout in, 242 osteogenesis imperfecta syndromes,
treatments, 259260 neutrophilic dermatosis of, 494 553555
prophylactic, 259 operative treatment, 659660 pseudoxanthoma elasticum, 555
uric acid lowering, 259260 Haplotypes, 110 stickler syndrome, 551
MRI of, 244 Haversian system, 585 HGPRT. See Hypoxanthine-guanine
in MTP joints, 243 hCMV. See Human cytomegalovirus phosphoribosyltransferase
normouricemic, 245246 HCQ. See Hydroxychloroquine Hidradenitis suppurativa, 500
in organ transplantation patients, 245, HDCT. See Heritable disorders of Highly active antiretroviral therapy
261 connective tissue (HAART), 280
pathogenesis of, 251254 Health Plan Employer Data and Hindfoot, examination of, 1314
adiposity, 253254 Information Set (HEDIS), 3, 4 Hip
alcohol and, 252253 Healthy People 2010, 4 CT scan of, 33
dietary influences, 252 Heat disorders, 7879
insulin resistance, 253254 in pain management, 625 examination of, 1112
urate metabolism, 251252 in rehabilitation, 602604 fractures, 576577
urate production pathways, 252 Heat shock protein (HSP), 439 in operative treatment, 656657
urate solubility, 251 HEDIS. See Health Plan Employer radiograph, 656
pathology of, 255 Data and Information Set Histoplasma capsulatum, 295
provocative factors of acute attacks, HELLP syndrome, 339 Histoplasmosis, 295
246 Hemangiomas, synovial, 547 History, 67
pseudo, 265 ?? Not sure what this Hemarthrosis, 25 family, 7
means ? At first I assumed it monarthritis and, 45 functional losses, 7
referred to pseudogout which Hematologic disorders, nonmalignant, in idiopathic inflammatory
makes sense but then note that 470474 myopathies, 367
there is a listing for that but with Hemochromatosis, 56, 523525 inflammation and weakness in, 7
different page numbers ?? clinical features, 523524 location and symmetry in, 6
radiographic features of, 247 laboratory features of, 524525 in OA, 225
refractory, 261262 radiographic features of, 524 onset and chronology in, 67
INDEX
in sickle cell disease, 473474 treatment of, 525 in polyarthritis, 4750
stages of, 241244 Hemoglobinopathy-associated distribution of, 4950
advanced, 243244 musculoskeletal manifestations, extra-articular symptoms, 50
asymptomatic hyperuricemia, 472474 family, 50
241242 Hemophilia, 57, 470472 pain characteristics, 49
unusual presentations of, 244246 operative treatment, 655 pattern of, 4849
in women, 245 radiographs in, 472 time course of, 48
Gouty arthritis, 54 ?? Not sure what treatment, 471472 questions in, 6
this refers to ? There is a whole Henoch-Schnlein purpura, 431432 systemic features, 7
section on Gout which is where classification of, 678 HIV. See Human immunodeficiency
this belongs but page numbers clinical presentation, 431 virus
dont seem to jive. definition, 431 HLA. See Human leukocyte antigens
classification of, 674 diagnosis, 431432 HOA. See Hypertrophic
Graft versus host disease (GVHD), prognosis, 432 osteoarthropathy
499 therapy, 432 Homocystinuria, 550551
710 INDEX
Hormonal therapy, in SLE treatment, pathogenesis of, 251254 genetic factors, 370371
333 adiposity, 253254 mechanisms, 371
HPA. See Hypothalamic-pituitary- alcohol and, 252253 MHC in, 373374
adrenal insulin resistance, 253254 pathology, 368370
Human cytomegalovirus (hCMV), 352 urate metabolism, 251252 prognosis, 367
Human immunodeficiency virus (HIV), urate production pathways, 252 treatment of, 378380
50, 53, 390 urate solubility, 251 extramuscular manifestations of,
viral arthritis, 280 pharmacologic treatments, 260261 380
Human leukocyte antigens (HLA), 98, urate-lowering agents and, 254 general measures, 378379
112, 120, 154 Hypochondroplasia, 561 pharmacologic, 379
B27, 218 Hypocomplementemic urticarial IFN. See Interferon
in ankylosing spondylitis, 201203 vasculitis syndrome, 432433 IL-1. See Interleukin 1
crystallized, 204 clinical presentation, 432433 IL-6. See Interleukin 6
evolutionary pathway of, 205 definition, 432 Iliopsoas bursitis, 7879
host immune responses and, 219 diagnosis, 433 Imaging, 2840. See also specific
host-pathogen interactions, 219 prognosis, 433 techniques
subtypes, 204205 therapy, 433 in amyloidosis, 540541
shared epitope hypothesis and, 123 Hypogonadism, osteoporosis and, 589 decisions, 40
Hyaluronan, 24 Hypoparathyroidism, 482 in GCA, 403404
Hyaluronates, intra-articular, 631632 Hypopyon, 437 HOA, 506
Hydrotherapy, 603 Hypothalamic-pituitary-adrenal (HPA), in osteoporosis, 578579
Hydroxyapatite, 26 609 Immune cells, 95
Hydroxychloroquine (HCQ), 135, 138 Hypothyroidism, 481 glucocorticoids and, 644, 645
Hyperbaric oxygen, 569 Hypoxanthine-guanine innate, 9798
Hypercholesterolemia, 486 phosphoribosyltransferase in SLE, 324325
HyperIgE syndrome (HIES), 102 (HGPRT), 245 Immune complex-mediated vasculitis,
Hyperimmunoglobulinemia D with 427433
period fever syndrome (HIDS), I clinical syndromes, 428433
460, 463464 Ibandronate, 595 cryoglobulinemic vasculitis,
clinical findings, 463464 IBD. See Inflammatory bowel disease 429431
laboratory findings, 463464 ICAM-1. See Intercellular adhesion hypersensitivity vasculitis,
Hyperlipidemia molecule 1 428429
classification of, 485 Idiopathic inflammatory myopathies hypocomplementemic urticarial
in gout, 247 assessment of, 375378 vasculitis syndrome, 432433
Hyperlipoproteinemia, 54, 485 tools, 375378 pathophysiology, 427428
management, 486 clinical features of, 363365 Immune system, 9496
Hyperparathyroidism, 481482 constitutional, 363364 Immunoablation
Hypersensitivity vasculitis, 428429 GI tract, 365 with stem cell transplantation, in SLE
classification of, 679 heart, 365 treatment, 334
clinical presentation, 428429 joints, 364 without stem cell transplantation, in
definition, 428 lungs, 364365 SLE treatment, 334
diagnosis, 429 malignancy, 365 Immunoglobulins, 104106
prognosis, 429 myositis, 365 gene rearrangement, 104106
purpura in, 428 skeletal muscle, 364 Immunological diseases, 94106
therapy, 429 skin, 364 Immunopathogenesis, of ANAs,
Hypertension, in gout, 247 immunopathology, 368370 321322
Hyperthyroidism, 481 investigations, 365367 Impingement test, 71
Hypertrophic osteoarthropathy electromyography, 365, 376 Inclusion body myositis, cytotoxic
(HOA), 57 heart, 366 mechanisms in, 372
classification of, 505 intestine, 366 Indian frankincense, 694
clinical features, 505506 lung, 366 Infections
diagnosis, 507 muscle biopsy, 365366, 376 identifying bone, 36
imaging, 506 radiography, 376 monarthritis, 4445
laboratory features, 506 serum autoantibodies, 366367, Infectious arthritis, 54, 56
pathogenesis, 504 377, 378 Inflammation, 7
theoretical, 506 serum muscle enzymes, 365 depot corticosteroid-induced
pathology, 504 skin, 366, 376 iatrogenic, 269
radiographs in, 507 natural history, 367 GI, 147
treatment, 507 pathogenesis, 370374 glucocorticoids and, 645
Hyperuricemia chemokines in, 373 in monarthritis, 43
asymptomatic, 241242 cytokines in, 373 ocular, 437
management, 261 environmental factors, 371372 pathogenesis of, 264265
I N D E X 7 11
in systemic sclerosis, 353 classification criteria for, 143 coronary and peripheral aneurysms,
urate crystal-induced, 255256 clinical features, 142144 445
Inflammatory bowel disease (IBD), 50 enthesitis, 146147, 152 cutaneous manifestations of, 446
in ankylosing spondylitis, 195196 epidemiology, 142 diagnosis of
nonarticular complications of, 221 examination, 163 principle criteria for, 445
Infliximab eye disease and, 166 revised guidelines, 447
ankylosing spondylitis and, 213 growth in, 163166 echocardiogram criteria, 447
in PsA, 188 general, 164 epidemiology, 447
in RA, XXX local, 164 etiology, 447448
Injections, image-guided, 40 nutrition, 165 pathogenesis, 448
Innate immunity, 9698 osteopenia, 164 peripheral aneurysms in, 445
cells, 9798 osteoporosis, 164 recommended therapy, 447
Insulinlike growth factor 1, 165 thyroid disease, 165 strawberry tongue in, 446
Insulin resistance, in gout, 253254 meta-analysis of, 148 treatment, 448449
Intercellular adhesion molecule 1 ocular involvement in, 147148 Kidneys
(ICAM-1), 355, 373 oligoarthritis, 145146, 149150 ANCA and, 419420
Interferon (IFN), 400 cause of, 150 in ankylosing spondylitis, 196
Interleukin 1 (IL-1), 128129 genetic predisposition, 150 in gout, 246247
receptor antagonist protein, 129 inflammatory cytokines, 150 NSAIDs and, 640
Interleukin 6 (IL-6), 129, 165 joint damage, 150 in SLE, 308310
Intermittent hydrarthrosis, 467468 laboratory findings, 149 in systemic sclerosis, 348349
clinical features, 467468 synovium in, 149 transplantation, 309
laboratory features, 467468 treatment, 158 Killer immunoglobulinlike receptors
Interphalangeal (IP) joints uveitis, 149150 (KIR), 179
swelling of, 116 outcomes, 160161 Klebsiella aeruginosa, 194
ultrasound of, 38 pain in, 168 Klebsiella pneumoniae, 218
Intersection syndrome, 75 polyarthritis, treatment, 158 Knee
Intravenous immunoglobulin (IVIg) polyarthritis RF negative, 145 arthroscopic view of, 658
in idiopathic inflammatory myopathy polyarthritis RF positive, 145 disorders, 7981
treatment, 379 polyarticular, 151152 examination of, 1213
in JIA treatment, 158 psoriatic, 146, 152 OA treatment, 236
in SLE treatment, 334 treatment, 159 operative treatment, 657659
Iron, 700701 psychosocial and educational issues, palpation, 13
Ischial bursitis, 79 167168 radiographs, 658
IVIg. See Intravenous immunoglobulin systemic arthritis, treatment, 158 Kniest dysplasia, 562
Ixodes scapularis, 282 systemic category, 145, 150151 Kyphoscoliosis, 552
laboratory findings in, 150151
J pathogenesis, 151 L
Jansen metaphyseal chondrodysplasias, treatment Labial salivary gland, 393
562563 anti-IL-6 receptor antibody, 158 Laboratory evaluation, 1519
JIA. See Juvenile idiopathic arthritis biologic-modifying medications, in alkaptonuria, 526527
Joint destruction, in RA, 129130 157158 CRPS, 510511 ??? What is this ??
Joint dysplasias, 559564 corticosteroid, 155156 in Gauchers disease, 528529
Joint instability syndromes, 553 DMARDs, 157 in GCA, 403
c-Jun N-terminal kinases (JNKs), 232 enthesitis-related, 159 in gout, 247248
Juvenile Arthritis Damage Index future research, 161 of hemochromatosis, 524525
INDEX
(JADI), 161 IL-1 receptor antagonists, 158 HOA, 506
humoral and endothelial mechanisms IVIg, 158 in monarticular joint disease, 44
in, 372373 leflunomide, 157 in multicentric reticulohistiocytosis,
Juvenile Arthritis Functional Assessment MTX, 156157 531
Report (JAFAR), 160 NSAIDs, 155 in ochronosis, 526527
Juvenile Arthritis Self-Report Index physical therapy in, 159 polyarthritis, 52
(JASI), 160 rationale, 154 in RA, 118119
Juvenile dermatomyositis (JDM), 363, SSZ, 157 in septic arthritis, 272273
375 uveitis, 159 in systemic juvenile idiopathic
Juvenile idiopathic arthritis (JIA), 56, undifferentiated, 147 arthritis, 150151
142149 Juvenile osteochondroses, 563564 in Wilsons disease, 527
adherence and, 166167 Lactate dehydrogenase (LDH), 375
assessment of, 167 K Lactation, 685686
factors impacting, 166 Kawasakis disease, 444449 Lateral epicondylitis, 73
improving, 167 classification of, 680 Lateral stenosis, 63
category characteristics, 144 clinical features of, 444445 LDH. See Lactate dehydrogenase
712 INDEX
LE. See Lupus erythematosus treatment, 287288 muscle glycogenoses, 381385

Leflunomide, 137138 recommended, 288 myoadenylate deaminase
in JIA treatment, 157 Western blot interpretation, 286 deficiency, 387
PsA treatment with, 188 Lymphoma, 476 secondary, 387
in SLE treatment, 333 Lyzosomal granule enzymes, 18 Metacarpophalangeal (MCP) joints, 9,
Leprosy, 293 49, 76, 77
Leukemia, 54 M in RA, 115
Leukemic arthritis, 475476 Macrophage activation syndrome subluxation of, 116
Lichen planus, 502, 503 (MAS), 448 ulcers, 345
Lichen sclerosus, 496 Macrophages, cytokines, 127129 ultrasound of, 38
Lidocaine, 22, 624 Magnesium, 701 Metaphyseal chondrodysplasias, 562
Lifestyle issues, in osteoporosis, Magnetic resonance imaging (MRI), 28, Jansen, 562563
593594 3336, 63 McKusick, 563
Linkage disequilibrium (LD), 110 in bone infection identification, 36 Schmid, 563
Lipid, 26 in bony abnormality detection, 3536 Metastatic carcinomatous arthritis, 475
metabolism disorders, 385386 of cartilage, 35 Metatarsalgia, 83
Lipochrome histiocytosis, 530 in disc herniation diagnosis, 36 Metatarsophalangeal (MTP) joints, 14,
Lipodermatosclerosis, 495496, 496 of gout, 244 49
Lipoma, intra-articular, 546 in idiopathic inflammatory gouty arthritis in, 243
Lipopolysaccharide (LPS), 96 myopathies, 366 in RA, 115
Livedoid vasculopathy, 501 muscle abnormalities and, 36 Metatropic dysplasia, 563
Liver, in SLE, 312 in muscular neoplasm evaluation, 36 Methotrexate (MTX), 135, 137, 140, 379
Localized bone pain, 60 of osteonecrosis, 567 in ankylosing spondylitis treatment,
Long thoracic nerve paralysis, 72 in osteonecrosis diagnosis, 36 212
Lorazepam, 624 in PVNS, 544 in JIA treatment, 156157
LPS. See Lipopolysaccharide Major histocompatibility complex NSAID interactions with, 642
Lumbar disc herniation, 6162 (MHC), 9899, 112113, 194 In PsA treatment, 187
Lumbar spine in ankylosing spondylitis, 205 in RA treatment, XXXX
radiograph of, 197 class I, 99 in SLE treatment, 331332
stenosis, 63 class II, 99 in systemic sclerosis treatment, 362
Lumbosacral spine, mechanical disease associations with, 113 Methylsulfonylmethane (MSM), 666,
disorders of, 6164 in idiopathic inflammatory 694695
Lumbosacral spondylosis, 6263 myopathies, 373374 MHC. See Major histocompatibility
Lungs MALT. See Mucosa-associated complex
ANCA and, 418419 lymphoid tissue Microaneurysms, 411
in ankylosing spondylitis, 196 MAPK. See Mitogen-activated protein Microscopic polyangiitis, 416425
in idiopathic inflammatory kinases alveolar hemorrhage in, 419
myopathies, 364365, 366 Marfans disease, 354 Midfoot, examination of, 14
sarcoidosis and, 515, 518, 519 Marfan syndrome, 549550 Migration inhibitory factor (MIF), 151
in SLE, 311312 MAS. See Macrophage activation Milwaukee shoulder syndrome, 268269
in systemic sclerosis, 347348 syndrome Minerals, 699702
Lupus anticoagulant (LA), 340 Massage, 625, 665666 Minimally invasive surgery (MIS), 657
Lupus erythematosus (LE), 25 Matrix metalloproteinases (MMPs), Minor allele frequency (MAF), 109
classification of, 309 178 Mitogen-activated protein kinases
Lupus nephritis McArdles disease, 381 (MAPK), 129130
active, 320 McKusick metaphyseal Mixed connective tissue disease, 55
immune deposits in, 320 chondrodysplasias, 563 MMF. See Mycophenolate mofetil
WHO classification of, 308 Medial epicondylitis, 7374 MMPs. See Matrix metalloproteinases
Lupus panniculitis, 495 Medial plica syndrome, 80 Molecular mimicry, 124
Lyme disease, 56, 282289 Medical model, public health model reactive arthritis and, 219220
clinical manifestations of, 283285 and, 2 Monarthritis, 120
early disseminated infection, 284 Meditation, 664665 crystal-induced, 45
early localized, 283284 Melatonin, 694 diagnosis of, 4243
late disease, 284285 Meniscus tears, 35 foreign body reactions, 45
diagnosis, 286287 Meralgia paresthetica, 79 hemarthrosis and, 45
epidemiology, 282283 Metabolic myopathies, 381387 infection in, 4445
erythema migrans in, 283 primary, 381387 inflammatory causes of, 43
pathogenesis, 285286 key features of, 382383 initial treatment, 44
in pregnancy, 287 lipid metabolism disorders, laboratory tests in, 44
prevention, 288289 385386 non-inflammatory causes of, 43
prognosis, 287288 mitochondrial, 386387 osteoarthritis and, 45
I N D E X 7 13
osteonecrosis, 45 Myeloma, multiple, 476 Neuropathic pain, 621

physical examination, 43 Myelopathy, 6566 Neuropathy, suprascapular neuropathy,
specific types of, 4445 Myeloperoxidase (MPO), 18 72
synovial fluid analysis, 4344 Myoadenylate deaminase deficiency, Neutrophilic dermatoses, 492495
systemic rheumatic diseases, 45 387 associations with, 493
trauma and, 45 Myopathy. See also Idiopathic of dorsal hands, 494
Monocyte chemoattractant protein inflammatory myopathies; rheumatoid, 494
(MCP), 314 Metabolic myopathies Neutrophils, 256
Mononeuritis multiplex, 412 in scleroderma, 349 NK cells. See Natural killer cells
Monosodium urate crystals, 26 Myositis Nociceptive pain, 620621
Morning stiffness, 60 in idiopathic inflammatory NOMID. See Neonatal-onset
Mortality, in PsA, 175 myopathies, 365, 375, 377378 multisystem inflammatory disease
Mortons neuroma, 8384 sarcoidosis and, 517 Nonspecific interstitial pneumonitis
MSM. See Methylsulfonyl methane in scleroderma, 349 (NSIP), 370
MTP joints. See Metatarsophalangeal in hyperlipoproteinemia management,
joints N 486
Mucin clots, 24 Nail pitting, 146 Nonsteroidal anti-inflammatory drugs
Muckle Wells syndrome (MWS), 151, National Arthritis Act, 3 (NSAIDs), 44, 61, 63, 65, 71, 76,
460 National Arthritis Action Plan 154, 634642
Mucopolysaccharidoses, 555557 (NAAP), 3 adverse effects of, 638639
Mucosa-associated lymphoid tissue National Committee on Quality allergic reactions, 641
(MALT), 95 Assurance (NCQA), 3 asthma, 641
Multicentric reticulohistiocytosis, 55 National Health Interview Survey cardiovascular, 641
clinical features, 530531 (NHIS), 4 gastrointestinal, 639640
fingers in, 530 Natural killer (NK) cells, 125, 179 hepatic, 640641
laboratory features, 531 NCQA. See National Committee on renal, 640
synovium in, 530 Quality Assurance in ankylosing spondylitis treatment,
treatment, 531 Neck pain, 5866 211
Multifocal sterile recurrent fever and weight loss and, 60 clinical pharmacology, 637
osteomyelitis, 492 initial evaluation of, 5860 drug interactions, 641642
Multiple epiphyseal dysplasia (MED), mechanical, 64 anticoagulants, 642
562 recumbency, 60 antihypertensives, 642
Multiple myeloma, 476 stiffness and, 60 MTX, 642
Muscle biopsy, in idiopathic Neck strain, 65 salicylates, 641642
inflammatory myopathies, Neisseria gonorrhoeae, 44, 45, 120 in gout treatment, 258259
365366, 375 Neonatal lupus, 315 in JIA treatment, 155
Muscle glycogenoses, 381385 Neonatal-onset multisystem list of, 636
Muscle relaxants, 211 inflammatory disease (NOMID), mechanism of action, 636637
in pain management, 623 96, 460 in OA treatment, 238239
Muscle strength testing, 601 Neoplasms, joint, 534548 prostaglandin biology, 634636
Musculoskeletal system primary, 543547 in PsA, 186187
bioenergetics, 384 secondary, 547548 in RA treatment, 654
cancer and, 474477 Neoplasms, musculoskeletal, evaluating, in reactive arthritis treatment, 220
evaluation of, 683 36 in SLE treatment, 328
glucocorticoids and, 647 Nephelometry, 19 therapeutic actions, 637638
in idiopathic inflammatory Nephrogenic fibrosing dermopathy, Nonsyphilitic interstitial keratitis, 441
INDEX
myopathies, 364 499 Nonvascularized bone grafting, 570
sarcoidosis and, 516517 Nephrogenic systemic fibrosis (NSF), NSAIDs. See Nonsteroidal
in SLE, 307312 349 anti-inflammatory drugs
in systemic sclerosis, 349 Neuroma, Mortons, 8384 Nutritional factors, osteoporosis and,
MWS. See Muckle Wells syndrome Neuropathic arthropathy, 227, 488491 589
Mycobacterial infections, 56, 290293 clinical features, 489490
Mycobacterium avium, 293 diagnosis of, 490 O
Mycobacterium bovis, 292293 epidemiology of, 488 OA. See Osteoarthritis
Mycobacterium kansasii, 293 of foot, 489, 490 Obesity, in gout, 247
Mycobacterium leprae, 293 management of, 491 Occlusive vasculopathy, 320
Mycobacterium marinum, 293 pathology of, 488489 Ochronosis, 56, 525527
Mycobacterium tuberculosis, 26, 290291 pathophysiology of, 489 clinical features, 525526
Mycophenolate mofetil (MMF) prevention of, 491 laboratory features, 526527
in SLE treatment, 333 pseudo, 266 radiographic features, 526
in systemic sclerosis treatment, 362 synovial fluid in, 490 Olecranon bursitis, 73
714 INDEX
Oligoarthritis differential diagnosis, 227 pathology, 567

acute inflammatory, 54 erosive inflammatory, 56 PET scans of, 567
chronic inflammatory, axial fungal, 291 radiographic staging, 567568
involvement and, 5556 initiation of, 233 risk factors, 565567
juvenile idiopathic, 145146, 149150 hypothetical model of, 234 in sickle cell disease, 473
cause of, 150 joints in, 230 treatment
genetic predisposition, 150 phase 1, 230 algorithm, 570571
inflammatory cytokines in, 150 phase 2, 230 nonoperative, 569
joint damage, 150 phase 3, 230 operative, 569570, 655
laboratory findings in, 149 localized, 56 prognosis, 570571
synovium in, 149 menopausal, 226227 resurfacing arthroplasty, 570
treatment, 158 monarthritis and, 45 total joint replacement, 570
uveitis, 149150 mycobacterial, 291 Osteopenia
management of, 486 operative treatment, 652653 hip fractures, 576577
Omenn syndrome, 100 outcomes, 227228 incidence of, 576577
Onycholysis, 146 pathogenesis, 230231 JIA and, 164
Operative treatment, 651663 enzymes involved in, 231 prevalence, 576577
disease-related factors, 652656 pathology, 229230 Osteoporosis, 3, 483, 592
ankylosing spondylitis, 655 normal to aging cartilage in, additional laboratory evaluation, 582
hemophilic arthropathy, 655656 229230 bone structure and function in,
juvenile RA, 654 primary generalized nodal, 56 584586
osteoarthritis, 652653 prognosis, 227228 remodeling in, 585576
osteonecrosis, 655 pseudo, 265 types of bone, 584585
psoriatic arthritis, 655 radiographic findings in, 29, 226 calcium homeostasis in, 587
PVNS, 656 rapidly progressing, 227 classification of, 681
RA, 653654 risk factors for, 225 clinical assessment of, 578582
synovial chondromatosis, 656 treatment, 690 bone mass measurement in,
new, 663 knee, 236 580581
perioperative, 662 localized pharmacologic, 239 bone turnover measurement,
postoperative, 662663 narcotic analgesic medication, 238 581582
preoperative evaluation, 651652 non-narcotic analgesic medication, history, 578
preparation for, 652 238 physical examination, 578
sites of intervention, 656662 nonpharmacologic, 235237 skeletal imaging for, 578579
ankle, 659 NSAIDs, 238239 DXA in, 578579, 581
cervical spine, 661662 surgery, 239 epidemiology of, 576577
elbow, 660 systemic pharmacologic, 237239 bone mineral density criteria in, 577
foot, 659 Osteoblasts, 585 glucocorticoid-induced, 690
hand, 659660 Osteocalcin, 165 JIA and, 164
hip, 656657 Osteochondroses, juvenile, 563564 lifestyle issues and, 593594
shoulder, 660661 Osteoclasts, 585, 586 pathophysiology of, 587588
wrist, 659660 Osteocytes, 585 mechanical properties of bone,
OPG. See Osteoprotegerin Osteogenesis imperfecta syndromes, 587588
Opioid analgesics, 622623 553555 pharmacologic treatment, 594597
Organ transplantation, gout and, 245, natural history, 553555 bisphosphonates, 594595
261 type I, 553 calcitonin, 596
Orthotic devices, 605 type II, 553 combination therapy, 597
Osteoarthritis (OA), 6, 56 type III, 553 estrogen, 596
classification of, 673674 type IV, 553 future of, 597
clinical features of, 224228 Osteolysis, 349 raloxifene, 596
disease patterns, 226227 Osteomyelitis teriparatide, 596597
epidemiology, 224 multifocal sterile recurrent, 492 postmenopausal, 594
history, 225 radionuclide imaging of, 37 QCT in, 579580
investigations, 225226 in sickle cell disease, 473 radiography in, 578579
physical examination, 225 Osteonecrosis, 483, 565571 risk factors, 588590
course, 227228 clinical presentation, 567 bone turnover, 590
cytokines in CT of, 567 drugs and, 590
cartilage repair, 232233 direct causes of, 566 falls, 590
lipid mediators, 231 indirect causes of, 566567 genetic influences, 588589
matrix degradation products, 232 monarthritis and, 45 hypogonadism, 589
mechanical stress, 232 MRI diagnosis of, 36, 567 nutritional factors, 589
reactive oxygen species, 231232 pathogenesis, 565567 physical activity, 589
I N D E X 7 15
Osteoprotegerin (OPG), 130 Palpation idiopathic intermittent, 466468

Osteotomy, 570, 657 ankle, 14 palindromic rheumatism, 466467
Otorhinolaryngeal relapsing knee, 13 Perioperative management, 662
polychondritis, 451 sternoclavicular joint, 11 Peripheral aneurysms, in Kawasakis
Oxalate crystals, 269 of wrist, 9 disease, 445
Oxalosis, 26 Pamidronate, 574, 595 Peripheral arthritis, 220
in ankylosing spondylitis treatment, Peripheral tolerance, 102
P 211 Peroneal nerve palsy, 81
Pagets disease of bone, 573575 PAN. See Polyarteritis nodosa Peroneal tendon
diagnosis, 573574 Pancreatic disease-associated dislocation, 8283
symptoms, 573 arthropathy, 57 tendonitis, 8283
therapy, 574575 Panniculitides, 495496 Pes cavus, 83
alendronate, 574 calcifying, 496 Pes planus, 83
bisphosphonate, 574 cytophagic histiocytic, 496 PET. See Positron emission
disodium etidronate, 574 PAPA syndrome, 500 tomography
pamidronate, 574 Paracoccidioides brasiliensis, 295 Phalens test, 76
plicamycin, 574 PA radiography. See Posterior-anterior Pharmacologic therapy, for
risedronate, 574 radiography fibromyalgia, 92
synthetic salmon calcitonin, 574 Paraneoplastic rheumatic syndromes, Phosphatidylinositol-3-kinase (PI-3K),
tiludronate, 574 476477 232
zoledronate, 574 Parasites, 295 Phosphorus, 701
Pain, 611. See also Back pain; Parathyroid disease, 481482 Physical activity, 616
Complex regional pain rheumatological manifestations of, 482 osteoporosis and, 589
syndrome; Neck pain; Parvovirus B19, 277278 Physical therapy
Regional rheumatic pain PAS. See Periodic acid-Schiff for ankylosing spondylitis, 210
syndromes Patellar tendon in JIA, 159
assessment, 622 rupture of, 81 in pain management, 625
back, 5866 tendinitis, 81 exercise in, 625
categories of, 620621 Patellofemoral pain syndrome, 81 heat and cold in, 625
in children, 626 Pathergy, 437 PI-3K. See
chronic, of complex origin, 621 Pathogen-associated molecular patterns Phosphatidylinositol-3-kinase
control in rehabilitation, 602 (PAMPs), 96 Pigmented villonodular synovitis
diffuse, 88 Patient-controlled analgesia (PCA), 662 (PVNS), 543545
in JIA, 168 Patient evaluation, 614 MRI in, 544
localized bone, 60 ANAs in, 17 operative treatment, 656
management, 620626 arthrocentesis, 2123 Pineapple, 691
antidepressants, 623624 complement in, 19 PIP joints. See Proximal interphalangeal
antiepileptic drugs, 624 CRP in, 16 joints
fibromyalgia, 624 cryoglobulins in, 19 Piriformis syndrome, 79
general approach to, 621622 erythrocyte sedimentation rate in, Plantar fasciitis, 82
muscle relaxants and, 623 1516 Plasmapheresis, in SLE treatment, 334
opioid analgesics, 622623 examination, 714 Platelet-derived growth factor (PDGF),
pharmacologic, 622624 history, 67 355
physical therapy, 625 imaging, 2840 Plexopathy, brachial, 72
procedure-based, 626 RF in, 16 Plicamycin, 574
psychological and behavioral Pattern recognition receptors (PRRs), 96 PMNs. See Polymorphonuclear
INDEX
approaches to, 624625 PDGF. See Platelet-derived growth leukocytes
topical agents, 624 factor Pneumocystis jirovecii, 331
nature of, 620621 Pellegrini-Stieda syndrome, 8081 Polyarteritis nodosa (PAN), 410414
neck, 5866 Pentoxifylline, 449 classification of, 677
neuropathic, 621 Peptidylarginine deiminases, 119 clinical features, 411412
nociceptive, 620621 Periodic acid-Schiff (PAS), 27 cutaneous ulcerations in, 412
in older persons, 626 Periodic syndromes diagnosis, 412413
in polyarthritis, 49 hereditary, 460466 biopsy, 413
psychogenic, 621 clinical features, 462463 classification, 413
visceral, 60 cryopyrinopathies, 465466 features of, 411
Palindromic rheumatism, 114, familial Mediterranean fever, imaging, 413
466467 460463 laboratory, 413
clinical findings, 466467 hyperimmunoglobulinemia D with pathology of, 412
laboratory findings, 466467 period fever syndrome, 463464 prognosis of, 414
treatment, 467 laboratory features, 462463 treatment of, 414
716 INDEX
Polyarticular joint disease Pregnancy outcome measures in, 186

acute inflammatory, 5354 in antiphospholipid syndrome, 341 pathogenesis, 179183
carcinomatous, 54, 477 drug therapy in, 685686 cytokine pathways in, 180
chronic inflammatory, 5455 Lyme disease in, 287 dysregulated bone remodeling in,
classification of, 47 SLE in, 314315 180181
inflammatory, 48 Preoperative evaluation, 651652 environmental factors, 179180
non-inflammatory, 49 Prepatellar bursitis, 80 of extra-articular, 182183
demographics in, 50 Prevention, 23 genetic basis of, 179
diagnostic approach to, 4753 Primary angiitis of central nervous pathology of, 178
history, 4750 system (PACNS), 439441 patterns of, 173
laboratory studies, 52 cerebral angiogram in, 440 QOL in, 175
physical examination in, 5152 clinical manifestations of, 439440 skin disease in, 174
radiographic studies, 5253 diagnosis of, 440 spondyloarthritis, 172173
differential diagnosis, 53 management and outcome, 440441 SSZ and, 187
diseases causing, 5357 Probenecid, 261 Psychogenic pain, 621
distribution of, 4950 Proliferative glomerulonephritis, 430 Psychological factors
extra-articular symptoms, 50 Proliferator-activated receptor-gamma affective components, 610
juvenile idiopathic, 145 receptor (PPAR), 256 cognitive components, 610611
treatment, 158 Pronator teres syndrome, 75 in fibromyalgia, 91
non-inflammatory, 56 Prostaglandin biology, 634636 glucocorticoids and, 648
pain in, 49 biosynthetic pathway, 635 Psychosocial factors, 609612
systemic involvement in, 50, 51 Protein tyrosine kinases (PTKs), 100 PTKs. See Protein tyrosine kinases
Polymorphonuclear leukocytes (PMNs), Proximal interphalangeal (PIP) joints, 9, PTSD. See Post-traumatic stress disorder
25, 285 49, 77 Public health
Polymyalgia rheumatica, 54, 398, in RA, 115 history of, 1
404406 PsA. See Psoriatic arthritis rationale for arthritis initiative, 12
clinical features, 405406 Pseudoachondroplasia, 562 medical model and, 2
epidemiology of, 405 Pseudogout, 54 prevention and, 23
pathogenesis of, 405 Pseudo-rheumatism, 90 Pulmonary arterial hypertension
prognosis, 406 Pseudoxanthoma elasticum, 555 (PAH), 348, 359360
treatment, 406 Psoriasis vascular therapy for, 360361
Polymyositis, 55, 363 generalized pustular, 500 Purpura
cytotoxic mechanisms in, 372 management of, 186 Henoch-Schnlein, 431432
diagnosis of, 676 NSAIDs in, 186187 in hypersensitivity vasculitis, 428
serum autoantibodies in, 378 Psoriatic arthritis (PsA), 6, 55 Pustular conditions, 500501
Poncets disease, 292 abatacept, 189 PVNS. See Pigmented villonodular
Popliteal cysts, 7980 adalimumab, 188189 synovitis
Popliteal tendinitis, 80 alefacept, 189 Pyoderma gangrenosum (PG), 493494,
Population structure, 111 articular manifestations of, 173174 494
Positron emission tomography (PET), dactylitis, 173174 atypical, 494
of osteonecrosis, 567 enthesitis, 174 Pyrin, 106
Postchemotherapy rheumatism, 477 tenosynovitis, 174
Posterior-anterior (PA) radiography, 29 assessment of, 185186 Q
standing, 32 clinical features of, 171173 QCT. See Quantitative computed
Posterior interosseous nerve syndrome, peripheral arthritis in, 172 tomography
76 course of, 175 QOL. See Quality of life
Posterior tibialis tendon rupture, 82 cyclosporine, 187188 Quadriceps tendon, rupture of, 81
Posterior tibial tendinitis, 82 diagnosing, 174175 Quality of life (QOL)
Postoperative treatment, 662663 DMARDs in, 187188 in JIA treatment, 161
Poststreptococcal reactive arthritis efalizumab, 189 in PsA, 175
(PSRA), 300301 epidemiology of, 170171 Quantitative computed tomography
clinical findings in, 301 classification criteria, 171 (QCT), 39
diagnostic criteria, 301 prevalence of, 170171 in osteoporosis, 579580
treatment, 301 etanercept in, 188
Post-traumatic stress disorder (PTSD), extra-articular features of, 174 R
609 infliximab in, 188 RA. See Rheumatoid arthritis
Potts disease, 291 juvenile idiopathic, 146, 152 Radial nerve palsy, 76
PPAR. See Proliferator-activated management, 186189 Radicular symptoms, 62
receptor-gamma receptor glucocorticoids in, 187 Radiography
PR3. See Serine protease-3 mortality in, 175 in alkaptonuria, 526
Pramipexole, 624 MTX and, 187 AP, 29, 32
Prayer, 665 operative treatment, 655 conventional, 2829
I N D E X 7 17
in CPPD, 266267 patient assessment in, 601602 prognosis, 300

digital, 29 physical modalities in, 602604 special tests for, 299
in Gauchers disease, 528 electrical stimulation, 603 treatment, 299300
glucocorticoids and, 646 exercise therapy, 603 Rheumatic sequelae, 479483
in gout, 247 heat and cold, 602604 diabetes mellitus, 479480
in hemophilia, 472 hydrotherapy, 603 thyroid disease, 480481
hip, 656 rest, 603 Rheumatoid arthritis (RA), 6, 52, 55, 89
in HOA, 507 setting, 600601 ANA in, 119
in idiopathic inflammatory team, 600601 assessment of, 133134
myopathies, 376 upper extremity aids, 604605 disease activity indices, 134
knee, 658 orthotic devices, 605 laboratory studies, 133134
of lateral cervical spine, 197 vocational, 606607 autoimmunity and autoantibodies in,
of lateral lumbar spine, 197 Relapsing polychondritis, 56 125127
in monarticular joint disease, 44 cardiovascular, 452 cell count in, 24
in OA, 29, 226 clinical manifestations of, 452 classification, 670
in ochronosis, 526 diagnosis of, 453 classification of, 115
of osteonecrosis, 567568 features of, 453 clinical remission in, 671
in osteoporosis, 578 management, 453 comorbidities, 140
PA, 29, 32 musculoskeletal, 452453 differential diagnosis of, 120121
polyarthritis, 5253 ocular, 452 DIP joints in, 115
in RA, 119120, 134 otorhinolaryngeal, 451 epidemiology and risk factors of,
in sarcoidosis, 518 respiratory, 451452 122124
shoulder, 661 Relapsing seronegative synovitis with bacteria as, 124
in synovial chondromatosis, 546 pitting edema (RS3PE), 5354 sex as, 123124
in Wilsons disease, 527 Relative risk (RR), 111 tobacco as, 124
Radionuclide imaging, 28 Renal dialysis, in SLE treatment, 334 viruses as, 124
of osteomyelitis, 37 Renal system. See Kidneys functional status in, 671
Raloxifene, in osteoporosis treatment, Replication, 112 genetic factors, 123
596 Resilience, 612 improvement in, 671672
Range of motion, 68 Resolution joint destruction in, 129130
shoulder, 11 high contrast, 28 juvenile, 654
Raynauds phenomenon, 361 high spatial, 28 classification of, 681682
in systemic sclerosis, 344345 Respiratory relapsing polychondritis, laboratory findings in, 118119
Reactive arthritis, 54, 217220 451452 macrophage and fibroblast cytokines
clinical features of, 218 Rest, 603 in, 127129
epidemiology of, 217218 Resurfacing arthroplasty, 570 MTP joints in, 115
HLA-B27 and Retrocalcaneal bursitis, 82 nongenetic factors, 123124
host immune responses RF. See Rheumatoid factor operative treatment, 653654
interactions, 219 Rheumatic diseases, 5354, 54 organ systems involved in, 117
host-pathogen interactions, 219 cancer and, 474 patient history in, 114116
molecular mimicry and, 219220 rehabilitation in patients with, physical examination in, 116118
pathogenesis of, 218219 599607 extra-articular, 117118
poststreptococcal, 300301 ambulatory aids, 604 joint examination, 116117
diagnostic criteria, 301 classifications in, 599600 PIP joints in, 115
treatment, 301 lower extremity orthoses, 605606 progression of, 670
therapy for, 220 pain control in, 602 pseudo, 265266
INDEX
NSAIDs, 220 patient assessment in, 601602 radiological findings in, 119120, 134
Reflex sympathetic dystrophy, 509 physical modalities in, 602604 synovial fluid in, 125
Regional rheumatic pain syndromes, setting, 600601 synovial pathology, 124125
6885 team, 600601 synovium in, 125
causative factors, 6869 upper extremity aids, 604605 treatment, 134137, 683684
management of, 69 vocational, 606607 abatacept, 139140
drug therapy, 69 Rheumatic fever, 53, 673 biologics for, 137
guidelines for, 69 clinical findings, 297298 DMARD, 135137
intralesional injections, 69 diagnostic criteria, 297 HCQ, 138
physical therapy, 69 major clinical criteria, 297298 NSAID, 654
Rehabilitation, 599607 minor clinical criteria, 298 rituximab, 139140
ambulatory aids, 604 diagnostic tests, 298, 673 SSZ, 138
classifications in, 599600 differential diagnosis, 299 Rheumatoid factor (RF), 16, 126
lower extremity orthoses, 605606 epidemiology of, 297 IgM, 119
shoeware, 606 modified Jones criteria for, 298 Rheumatoid neutrophilic dermatoses,
pain control in, 602 pathogenesis, 299 494
718 INDEX
Rhizomelic chondrodysplasia punctata, treatment, 520521 Severe combined immunodeficiency

563 clinical course, 520 (SCID), 100, 130
Risedronate, 574, 595 prognosis, 520 Sex, as RA risk factor, 123124
Risk factors steroid-sparing agents, 520521 Shared epitope hypothesis, 123
fractures, 577 therapy, 520 Shoeware, 606
of GCA, 401403 Sarcoma, synovial, 547 Short tau inversion recovery (STIR),
osteonecrosis, 565567 Schober test, 12 197
osteoporosis, 588590 SCID. See Severe combined Shoulder
genetic influences, 588589 immunodeficiency arthrogram of, 38
hypogonadism, 589 Scintigraphic techniques, 3637 disorders of, 7073
nutritional factors, 589 imaging agents, 3637 examination of, 1011
physical activity, 589 SCLE. See Subacute cutaneous lupus frozen, 72
of RA, 122124 erythematosus operative treatment, 660661
bacteria as, 124 Scleredema, 350 passive range of motion, 11
genetic, 123 Scleroderma, 9, 17 radiography, 661
nongenetic, 123124 dermatological conditions associated SI. See Sacroiliac
sex as, 123124 with, 497498 Sickle cell disease, 57, 472474
tobacco as, 124 disorders like, 349350 gout in, 473474
for renal toxicity, 640 forms of, 344 osteomyelitis in, 473
Rituximab, 105, 139140 limited, 343 osteonecrosis in, 473
Rotator cuff linear, 499 vertebra in, 473
tear, 71 localized, 343, 496 Single nucleotide polymorphisms
tendinitis, 7071 myopathy in, 349 (SNPs), 109, 352
RS3PE. See Relapsing seronegative myositis in, 349 Sjogrens syndrome, 389396
synovitis with pitting edema renal crisis, 348349, 361 classification of, 676677
Rubella, 278 Scleromyxedema, 350, 496 clinical features of, 391394
Sclerosing, 496499 extraglandular, 393394
S Scoliosis, 64 laboratory features of, 394
SAA. See Serum amyloid A Screening musculoskeletal exams, 8 ocular, 391
Sacroiliac (SI), examination of, 12 Scurvy, 501 oral salivary, 391392
Sacroiliitis, in ankylosing spondylitis, Selective serotonin reuptake inhibitors diagnosis of, 394395
194195 (SSRIs), 361, 623 classification criteria, 394395
Salicylates, NSAID drug interactions, Selenium, 734 epidemiology of, 389390
641642 Self-management strategies, 614618 etiology of, 390
Salivary glands education, 614615 immunopathology of, 390391
bilateral enlargement, 393 five As model, 617618 autoantibodies, 390391
eosinophilic infiltration of, 421 advise, 617 cellular, 390
hypofunction, 391 agree, 617 histopathology of, 390
Salmonella typhimurium, 218 arrange follow-up, 618 prognosis, 396
SAM-e, 695 assess, 617 treatment, 395396
SAPHO syndrome, 500 assist, 618 extraglandular, 396
Sarcoid arthritis, 54 support, 617618 ocular, 395
Sarcoidosis, 56 Septic arthritis, 271276 oral, 395396
abdominal, 517 in children, 275 Skin
acute, 515 clinical features, 272 ANCA and, 420
chronic cutaneous, 515 laboratory findings, 272273 biopsy in idiopathic inflammatory
clinical features, 514517 microbiology, 272 myopathies, 375
epidemiology, 514 outcome, 274 glucocorticoids and, 648
familial associations, 514 pathogenesis, 271 in idiopathic inflammatory
genetic associations, 514 prevention, 274 myopathies, 364, 366
laboratory features, 518 pseudo, 272 in PsA, 174
musculoskeletal, 516517 risk factors, 271 SLE. See Systemic lupus erythematosus
bone, 517 therapy, 273274 SLEDAI. See Systemic Lupus
joint, 516517 antibiotic, 273 Erythematosus Disease Activity
myositis, 517 Septic bursitis, 275276 Index
ocular, 515516 Serine protease-3 (PR3), 18 SLICC. See Systemic Lupus
osseous, 517 Serum amyloid A (SAA), 537 Erythematosus International
pathogenesis, 519520 Serum muscle enzymes, in idiopathic Cooperating Clinics
pathology, 518 inflammatory myopathies, 365, SNPs. See Single nucleotide
pulmonary, 515, 518, 519 375376 polymorphisms
radiographic features of, 518 Serum sickness, 428 Social factors, 611612
I N D E X 7 19
Sodium, 701702 Synovial chondromatosis, 545546 nervous system in, 310

Soluble endothelial protein C receptor operative treatment, 656 novel therapies, 334336
(sEPCR), 314 radiograph of, 546 cytokine blockade, 336
Somatic hypermutation, 105 treatment of, 546 targets for, 335
Speeds test, 72 Synovial fluid ocular system in, 312
Spinal tuberculosis, 291 analysis, 2326 organ systems in, 305307
Spine, examination of, 12 blood in, 25 mucocutaneous, 305307
Spirituality, 665 cell count, 2425 pleura in, 311312
Spondyloarthropathy. See Ankylosing crystals in, 2526 in pregnancy, 314315
spondylitis diagnosis by class, 24 renal system in, 308310
Spondyloepiphyseal dysplasias, 561562 gross examination, 24 therapy, 328334, 687
congenita, 561562 in monarticular joint disease, 4344 antimalarial, 330331
late-onset, 562 classes of, 23 azathioprine, 331
Spondylolisthesis, 64 detection of, 13 B cell depletion, 335
Sporotrichosis, 294 in neuropathic arthropathy, 490 B cell-specific tolerogen, 335
SSRIs. See Selective serotonin reuptake in RA, 125 B cell survival inhibition, 335
inhibitors Synovitis, 7 corticosteroids, 328330
SSZ. See Sulfasalazine in ankylosing spondylitis, 195 costimulatory interaction inhibition,
Staphylococcus aureus, 44 eosinophilic, 468 335336
Statistical power, 111112 inflammatory, 349 cyclophosphamide in, 332333
Stem cell transplantation, in SLE Synovium cyclosporine in, 332
treatment, 334 in juvenile idiopathic oligoarthritis, dapsone, 331
Sterile procedures, in arthrocentesis, 23 149 hormonal, 333
Sternoclavicular joint, 8485 in multicentric reticulohistiocytosis, immunoablation, 334
palpation of, 11 530 IVIg, 334
Sternocostoclavicular hyperostosis, 84 normal, 125 leflunomide, 333
Stickler dysplasia, 562 in RA, 125 MMF, 333
Stickler syndrome, 551 Synthetic salmon calcitonin, 574 MTX, 331332
Stiffness, 7 Systemic diseases, 54 novel, 334336
back pain and, 60 back and neck pain and, 60 NSAID, 328
morning, 60 Systemic lupus erythematosus (SLE), 9, plasmapheresis, 334
neck pain and, 60 43, 53, 55, 89, 109, 303317 renal dialysis, 334
Stills disease, 53 ANAs in, 321 thalidomide, 333334
Stinging nettle, 695 antiphospholipid antibody syndrome topical agents in, 330
STIR. See Short tau inversion recovery in, 316, 341 triggering events, 325
St. Johns wort, 695 cardiovascular system in, 310311 Systemic Lupus Erythematosus Disease
Storage diseases, 523531 cell count in, 24 Activity Index (SLEDAI), 315
Streptococcal reactive arthritis, 53 classification of, 675 Systemic Lupus Erythematosus
Stress, 609610 course of, 305 International Cooperating Clinics
reduction, 664665 cutaneous manifestations of, 306 (SLICC), 307
Stress-activated protein kinases diagnosis criteria, 304 Systemic rheumatic diseases, 55
(SAPKs), 232 disease susceptibility, 322323 monarthritis and, 45
Strongyloides stercoralis, 295 drug-related, 316317 Systemic sclerosis, 55
Subacute cutaneous lupus drug toxicity in, 329 animal models of, 354
erythematosus (SCLE), 306 epidemiology of, 319 assessment of, 359360
Sulfasalazine (SSZ), 135, 138 fatigue in, 327 autoantibodies in, 345
INDEX
in ankylosing spondylitis treatment, general management, 327328 calcinosis in, 347
212 genetics of, 323324 cardiac involvement in, 348
in JIA treatment, 157 GI tract, 312 cellular autoimmunity in, 356357
PsA treatment with, 187 immune cell disturbances in, 324325 classification of, 675
Superficial radial neuropathy, 76 immunopathology of, 319320 diffuse cutaneous disease, 343, 345
Supplements, 666, 691696 infections in, 327328 environmental factors, 352353
Suprascapular neuropathy, 72 laboratory features in, 312314 epidemiology, 351352
Surgery complement in, 312313 fibroblast activation in, 356
ankylosing spondylitis, 239 hallmark autoantibodies in, fibrosis in, 357358
OA, 239 312313 genetic factors, 352
Swan neck deformity, 307 hematologic abnormalities in, 312 in GI tract, 347
Sweets syndrome, 492 liver in, 312 humoral autoimmunity in, 356357
histopathological findings in, 493 lungs in, 311312 inflammation in, 353
Synovial biopsy, 2627 musculoskeletal system in, 307312 key clinical features of, 346
in monarthritis, 44 neonatal, 315 limited cutaneous disease, 343, 345
720 INDEX
Systemic sclerosis (cont.) Therapeutic injections, 628632 Trigger finger, 7778

musculoskeletal disease in, 349 corticosteroid, 628631 injections, 630
pathogenesis, 354 complications, 631 Trigger point injections, 625
pathology, 353354 diluting, 630 Trochanteric bursitis, 78
pulmonary disease in, 347348 dose in, 628 Trophermyma whippleii, 56
renal disease in, 348349 efficacy of, 628, 629 Tuberculosis, spinal, 291
schematic representation of, 355 gloves, 630631 Tuberculous arthritis, 291292
skin manifestations of, 346347 needle length in, 628629 Tumeric, 695696
TGF in, 357 preparations in, 628, 630 Tumor necrosis factor (TNF), 128, 135,
treatment of, 360362 reactions to, 631 448, 449, 460, 654
antifibrotic, 362 Thoracic outlet syndrome, 7273 alpha, 232, 256
anti-inflammatory, 361362 Thrombosis, in antiphospholipid ankylosing spondylitis treatment and,
vascular, 360361 syndrome, 341 213214
vasculopathy in, 343346, 354355 Thromboxane A2 (TXA2), 635 antagonists, 138139
Thunder god vine, 695 in PsA, 188189
T Thyroid disease, 480481 TXA2. See Thromboxane A2
Takayasus arteritis (TA), 398, in JIA, 165
406408 Tietzes syndrome, 84 U
classification of, 679 TIMP. See Tissue inhibitors of UIP. See Usual interstitial pneumonitis
clinical features of, 407 metalloproteinases Ulnar deviation, 116
spectrum, 407 Tinels sign, 76 Ulnar nerve entrapment, 74
diagnosis of, 408 Tissue inhibitors of metalloproteinases at wrist, 77
epidemiology, 406 (TIMP), 130 Ultrasound, 28, 3738
pathogenesis, 406407 TLR. See Toll-like receptors of IP joints, 38
prognosis, 408 T lymphocytes, 98, 99104, 125 of MCP joints, 38
treatment, 408 autoimmunity, 126127 Urates
Tarsal coalition, CT scan of, 33 CD8+, 103104 crystal-induced inflammation, 255256
Tarsal tunnel syndrome, 84 derived cytokines, 127 lowering agents, 254
T-cell receptors (TCR), 98, 99100 development, 101102 metabolism, 251252
signal transduction, 100101 differentiation, 102 production pathways, 252, 253
TCR. See T-cell receptors receptors, 202 renal transport of, 254255
Telangiectasia, in systemic sclerosis, regulatory, 102 solubility of, 251
346 subsets, 127 Urticarial vasculitis, 432
Temazepam, 624 TNF. See Tumor necrosis factor Usual interstitial pneumonitis (UIP),
Tendinitis, 68 TNF receptor-associated periodic 370, 421
bicipital tendinitis, 7172 syndrome (TRAPS), 460, Uveitis, 149150
patellar, 81 464465 in ankylosing spondylitis, 195
popliteal, 80 clinical features, 464465 treatment, 159
posterior tibial, 82 laboratory features, 464465
rotator cuff, 7071 treatment, 465 V
triceps, 74 Tobacco, as RA risk factor, 124 Valerian, 696
Tendinopathy, 74 Toll-like receptors (TLR), 96, 324, 399 Valley fever, 294
Tendinosis, 68 Topical agents, 624 Variants, relationships between, 110
angiofibroblastic, 73 Total joint replacement, 275, 570 Vascular cell adhesion molecule
Tendonitis, peroneal tendon, 8283 Toxoplasma gondii, 295 (VCAM-1), 373
Tenosynovitis Transcutaneous electrical nerve Vascular endothelial growth factor
De Quervains, 75 stimulation (TENS), 625 (VEGF), 181, 355356, 401, 504
in PsA, 174 Transforming growth factor (TGF), 181 Vascularized bone grafting, 570
volar flexor, 7778 in systemic sclerosis, 357 Vasculitic lesions, 399
of wrist, 75 Transient ischemic attacks (TIAs), 440 Vasculitis, 307
TENS. See Transcutaneous electrical Transrepression, 645 Vasculopathy, in systemic sclerosis, 343,
nerve stimulation Transthyretin (TTR), 535, 538 354355
Teriparatide, in osteoporosis treatm TRAPS. See TNF receptor-associated VCAM-1. See Vascular cell adhesion
ent, 596597 periodic syndrome molecule
TGF. See Transforming growth Trauma, monarthritis and, 45 VEGF. See Vascular endothelial growth
factor Treponema pallidum, 45 factor
Thalassemia, 474 Triceps Vertebral bodies, 587
Thalidomide tendinitis, 74 Vertebral fractures, 577
in ankylosing spondylitis treatment, tendon rupture, 74 Viral arthritis, 53, 277281
211212 Trichomonas vaginalis, 295 chronic, 277
in SLE treatment, 333334 Tricyclic antidepressants, 211, 623 common, 278
I N D E X 7 21
hepatitis B, 279280 Weber-Christian disease, 495 examination, 910

hepatitis C, 278279 Wegeners granulomatosis, 416425 fractures, 577
HIV, 280 classification criteria for, 417 operative treatment, 659660
latent, 277 classification of, 678 palpation of, 9
parvovirus B19, 277278 multifocal cavitary nodules in, 419 tenosynovitis, 75
rubella, 278 saddle-nose deformity in, 418 ulnar nerve entrapment at, 77
self-limited, 277 Weight control, 616617
Virchow, Rudolph, 533 Westergren method, 1516 X
Viscosupplementation, 631632 Western blot, in Lyme disease Xanthomas, 484485
Vitamin A, 696 confirmation, 286 osseous, 485
Vitamin B, 697698 Whiplash, 66 tuberous, 485
Vitamin C, 237, 666, 698699 Whipples disease, 56 Xiphodynia, 84
Vitamin D, 237, 593, 666, 696697 WHO. See World Health Organization Xiphoid cartilage syndrome, 84
Vitamin E, 697 Wilsons disease, 527528 X-linked agammaglobulinemia,
Vitamin K, 697 clinical features, 527 105
Vitamin supplements, 666 laboratory evaluation, 527528
Volar flexor tenosynovitis, 7778 radiographic features, 527 Y
treatment, 528 Yergasons sign, 72
W World Health Organization (WHO),
Waldenstroms macroglobulinemia, lupus nephritis classification, 308 Z
476 Wrist Zinc, 702
Water-soluble vitamins, 697699 disorders, 7478 Zoledronate, 574
Weakness, 7 dorsum of, 10 Zoledronic acid, 595
INDEX

Primer On The Rheumatic Diseases 13th

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Primer on the

Library of Congress Control Number: 2007925709

ISBN: 978-0-387-35664-8 e-ISBN: 978-0-68566-3

Printed on acid-free paper

Springer Science+Business Media, LLC. 2008

New chapters on Clinical Immunology and Applied Genetics designed to

A tripling of the text devoted to psoriatic arthritis, an acknowledgement of the

Foreword by Michael E. Weinblatt . . . . . . . . . . . . . . . . . . . . . . . . . . . v

1. Public Health and Arthritis: A Growing Imperative . . . . . . . . 1

2. Evaluation of the Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

A. History and Physical Examination . . . . . . . . . . . . . . . . . . . 6

C. Arthrocentesis, Synovial Fluid Analysis,

D. Imaging of Rheumatologic Diseases . . . . . . . . . . . . . . . . . . 28

3. Musculoskeletal Signs and Symptoms . . . . . . . . . . . . . . . . . . . 42

A. Monarticular Joint Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 42

B. Polyarticular Joint Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 47

C. Neck and Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

D. Regional Rheumatic Pain Syndromes . . . . . . . . . . . . . . . . 68

E. The Fibromyalgia Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 87

4. Molecular and Cellular Basis of Immunity

5. Genetics and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

6. Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

A. Clinical and Laboratory Manifestations . . . . . . . . . . . . . 114

B. Epidemiology, Pathology, and Pathogenesis . . . . . . . . . . 122

C. Treatment and Assessment . . . . . . . . . . . . . . . . . . . . . . . . 133

7. Juvenile Idiopathic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

A. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

B. Pathology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . 149

C. Treatment and Assessment . . . . . . . . . . . . . . . . . . . . . . . . 154

D. Special Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

8. Psoriatic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

A. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

B. Pathology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 178

C. Treatment and Assessment . . . . . . . . . . . . . . . . . . . . . . . . 185

9. Ankylosing Spondylitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

A. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

B. Pathology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . 200

C. Treatment and Assessment . . . . . . . . . . . . . . . . . . . . . . . . 209

10. Reactive and Enteropathic Arthritis . . . . . . . . . . . . . . . . . . . . 217

11. Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

A. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

B. Pathology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . 229

12. Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

A. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

B. Epidemiology, Pathology, and

13. Calcium Pyrophosphate Dihydrate,

14. Infectious Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

A. Septic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

B. Viral Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

C. Lyme Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

D. Mycobacterial, Fungal, and Parasitic

E. Rheumatic Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

15. Systemic Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . 303

A. Clinical and Laboratory Features . . . . . . . . . . . . . . . . . . . 303

B. Epidemiology, Pathology, and

C. Treatment and Assessment . . . . . . . . . . . . . . . . . . . . . . . . 327

16. Antiphospholipid Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 339

17. Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

A. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343