Photodermatology (PDFDrive)

Photodermatology
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BASIC AND CLINICAL DERMATOLOGY
Series Editors
AlAn R. ShAlitA, M.D.
Distinguished Teaching Professor and Chairman
Department of Dermatology
SUNY Downstate Medical Center
Brooklyn, New York
DAviD A. noRRiS, M.D.

Director of Research
Professor of Dermatology
The University of Colorado
Health Sciences Center
Denver, Colorado
1. Cutaneous Investigation in Health and Disease: Noninvasive Methods and

Instrumentation, edited by Jean-Luc Lévêque
2. Irritant Contact Dermatitis, edited by Edward M. Jackson and Ronald Goldner
3. Fundamentals of Dermatology: A Study Guide, Franklin S. Glickman and Alan R. Shalita
4. Aging Skin: Properties and Functional Changes, edited by Jean-Luc Lévêque and Pierre G.
Agache
5. Retinoids: Progress in Research and Clinical Applications, edited by Maria A. Livrea and
Lester Packer
6. Clinical Photomedicine, edited by Henry W. Lim and Nicholas A. Soter
7. Cutaneous Antifungal Agents: Selected Compounds in Clinical Practice and
Development, edited by John W. Rippon and Robert A. Fromtling
8. Oxidative Stress in Dermatology, edited by Jürgen Fuchs and Lester Packer
9. Connective Tissue Diseases of the Skin, edited by Charles M. Lapière and Thomas Krieg
10. Epidermal Growth Factors and Cytokines, edited by Thomas A. Luger and Thomas
Schwarz
11. Skin Changes and Diseases in Pregnancy, edited by Marwali Harahap and Robert C.
Wallach
12. Fungal Disease: Biology, Immunology, and Diagnosis, edited by Paul H. Jacobs and
Lexie Nall
13. Immunomodulatory and Cytotoxic Agents in Dermatology, edited by Charles J.
McDonald
14. Cutaneous Infection and Therapy, edited by Raza Aly, Karl R. Beutner, and Howard I.
Maibach
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15. Tissue Augmentation in Clinical Practice: Procedures and Techniques, edited by Arnold
William Klein
16. Psoriasis: Third Edition, Revised and Expanded, edited by Henry H. Roenigk, Jr., and
Howard I. Maibach
17. Surgical Techniques for Cutaneous Scar Revision, edited by Marwali Harahap
18. Drug Therapy in Dermatology, edited by Larry E. Millikan
19. Scarless Wound Healing, edited by Hari G. Garg and Michael T. Longaker
20. Cosmetic Surgery: An Interdisciplinary Approach, edited by Rhoda S. Narins
21. Topical Absorption of Dermatological Products, edited by Robert L. Bronaugh and
Howard I. Maibach
22. Glycolic Acid Peels, edited by Ronald Moy, Debra Luftman, and Lenore S. Kakita
23. Innovative Techniques in Skin Surgery, edited by Marwali Harahap
24. Safe Liposuction and Fat Transfer, edited by Rhoda S. Narins
25. Pyschocutaneous Medicine, edited by John Y. M. Koo and Chai Sue Lee
26. Skin, Hair, and Nails: Structure and Function, edited Bo Forslind and Magnus Lindberg
27. Itch: Basic Mechanisms and Therapy, edited Gil Yosipovitch, Malcolm W. Greaves, Alan B.
Fleischer, and Francis McGlone
28. Photoaging, edited by Darrell S. Rigel, Robert A. Weiss, Henry W. Lim, and Jeffrey S. Dover
29. Vitiligo: Problems and Solutions, edited by Torello Lotti and Jana Hercogova
30. Photodamaged Skin, edited by David J. Goldberg
31. Ambulatory Phlebectomy, Second Edition, edited by Mitchel P. Goldman, Mihael
Georgiev, and Stefano Ricci
32. Cutaneous Lymphomas, edited by Gunter Burg and Werner Kempf
33. Wound Healing, edited by Anna Falabella and Robert Kirsner
34. Phototherapy and Photochemotherapy for Skin Disease, Third Edition, Warwick L.
Morison
35. Advanced Techniques in Dermatologic Surgery, edited by Mitchel P. Goldman and
Robert A. Weiss
36. Tissue Augmentation in Clinical Practice, Second Edition, edited by Arnold W. Klein
37. Cellulite: Pathophysiology and Treatment, edited by Mitchel P. Goldman, Pier Antonio
Bacci, Gustavo Leibaschoff, Doris Hexsel, and Fabrizio Angelini
38. Photodermatology, edited by Henry W. Lim, Herbert Hönigsmann, and John L. M. Hawk
39. Retinoids and Carotenoids in Dermatology, Edited by Anders Vahlquist and Madeleine
Duvic
40. Acne and Its Therapy, Edited by Guy F. Webster; Anthony V. Rawlings
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Photodermatology
edited by
Henry W. Lim
Henry Ford Hospital
Detroit, Michigan, U.S.A.
Herbert Hönigsmann
Medical University of Vienna
Vienna, Austria
John L. M. Hawk
St. John’s Institute of Dermatology
London, U.K.
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Series Introduction
During the past 25 years there has been a vast explosion of new information relating to the art
and science of dermatology, as well as fundamental cutaneous biology. Furthermore, this
information is no longer of interest to only the small but growing specialty of dermatology.
Clinicians and scientists from a wide variety of disciplines have come to recognize both the
importance of skin in fundamental biological processes and the broad implications of under-
standing the pathogenesis of skin disease. As a result, there is now a multidisciplinary and
worldwide interest in the progress of dermatology.
With these factors in mind, we have undertaken this series of books specifically oriented
to dermatology. The scope of this series is purposely broad, with books ranging from pure basic
science to practical, applied clinical dermatology. Thus, while there is something for everyone,
all volumes in this series will ultimately prove to be valuable additions to the dermatologist’s
library.
The latest volume in the series (No. 38), by Lim, Hönigsmann, and Hawk, presents a com-
prehensive and current review of photomedicine by world renowned authorities. The role
of photobiology in medicine has received increased emphasis in the past decade as a result
of considerable new information regarding the molecular biological effects of ultraviolet
light, its effect on the immune system, its role in the promotion of skin cancer, and its
abuse by profiteers who market suntan parlors. It is, therefore, critically important that
dermatologists, physicians in general, biologists, and public health scientists remain current
in photomedicine. I believe that Dr. Lim and his coeditors have produced a timely and
critically important addition to our series, which is both timely and comprehensive.
Alan R. Shalita, MD
Distinguished Teaching Professor and Chairman
Department of Dermatology
SUNY Downstate Medical Center
Brooklyn, New York, U.S.A.
Preface
Within the past 30 years photomedicine has developed from empiricism into one of the most
exciting fields in biomedical research. Studies on the effects of visible and ultraviolet radiation
on skin have led to a fruitful collaboration between basic scientists and clinicians. The success-
ful use of the new ultraviolet techniques for the treatment of skin disease, along with a rapidly
increasing understanding of the pathogenesis of photodermatoses, thereby markedly improv-
ing their treatment, have been the driving force for the development of a new subspecialty of
photodermatology. This now encompasses the diagnosis and treatment of sunlight-induced
disorders; all aspects of phototherapy, including the use of such new modalities as photody-
namic therapy for skin tumors and other diseases; as well as photoprotection, which continues
to evolve with the development of new generations of ultraviolet filters. In the past decade,
therefore, very significant advances have occurred throughout this novel subspecialty, particu-
larly in photoimmunology, molecular biology, and genetics. In more detail, these include better
recognition and understanding of:
. Acute and chronic effects of ultraviolet radiation on the skin: in vitro studies, animal
models, photoaging, and epidemiology of skin cancers;
. Clinical manifestation of photodermatoses: actinic prurigo, pin-head papule form of poly-
morphous light eruption, novel genetic mutations in porphyrias, and so on;
. Pathophysiology and treatment of photodermatoses: polymorphous light eruption, actinic
prurigo, chronic actinic dermatitis, xeroderma pigmentatosum, photo-exacerbated derma-
toses, and so on;
. The science of photoprotection: new ultraviolet filters, photoprotection by clothing, photo-
protection by oral agents, and so on;
. Phototherapy: narrowband ultraviolet B, ultraviolet A1, visible light;
. Topical photodynamic therapy;
. Medical and cosmetic applications of laser and similar radiation sources; and
. New insight on the use of laser and radiation sources on people of color.
In planning for this book, our vision as editors was to create a book that is comprehensive
and up-to-date, yet is user-friendly to its intended readers who are busy, practicing dermatol-
ogists, photodermatologists, and trainees in dermatology. The editors are pleased that recog-
nized experts from many parts of the world willingly put in the effort and contributed most
informative chapters for this book.
The book consists of six sections. Section I is on history and basic principles, followed
by the effects of ultraviolet radiation on normal skin in Section II. Section III covers all the
photodermatoses, while Section IV and V discuss photoprotection and ultraviolet and visible
radiation therapy. Section VI is a practical description of testing methods used in photoderma-
tology and guidelines of setting up a phototherapy and laser center.
The three of us work in the United States, Europe, and the United Kingdom. We have
taken great care to make sure that materials covered in this book reflect an international
point of view. For example, international coverage is done on actinic prurigo (commonly
seen in Central and South America), photoprotection (different ultraviolet filters available in
different parts of the world), light sources and laser, and many other topics. It is our hope
that the readers will find that this book provides a good perspective on the worldwide scope
of photodermatology.
vi Preface
On a personal note, the three of us have been colleagues and friends for many years; all of
us have separately published books in photodermatology in the early and late 1990s. It has
been a real pleasure to combine our experience and to work on editing this book together.
We do hope that the readers will enjoy this book as much as we have enjoyed writing and
editing it.
Henry W. Lim, MD
Herbert Hönigsmann, MD
John L. M. Hawk, MD
Acknowledgments
Henry W. Lim would like to thank his parents, for providing him the opportunity to succeed,
and his wife Mamie, for her unending patience and support.
Hebert Hönigsmann would like to thank his wife Xandi, for tolerating the lack of care
and attention to the family during the preparation of this book.
John L. M. Hawk would like to thank his wife, Lorna, for her continuing tolerance and support,
as ever previously, throughout the preparation of this book.
The editors would like to thank Sandra Beberman and her team at Informa Healthcare for
working with us to produce this book.
Contents
Series Introduction Alan R. Shalita, MD iii

Preface v
Acknowledgments vii
Contributors xiii
Section I: History and Basic Principles

1. History of Human Photobiology 1
Rik Roelandts
2. Basic Principles of Photobiology 15

Brian L. Diffey and Irene E. Kochevar
3. Radiation Sources and Interaction with Skin 29

Harvey Lui and R. Rox Anderson
Section II: Effects of Ultraviolet Radiation on Normal Skin

4. The Molecular and Genetic Effects of Ultraviolet Radiation
Exposure on Skin Cells 41
Marjan Garmyn and Daniel B. Yarosh
5. Photoimmunology 55
Thomas Schwarz and Gary M. Halliday
6. The Acute Effects of Ultraviolet Radiation on the Skin 75

Lesley E. Rhodes and Henry W. Lim
7. The Chronic Effects of Ultraviolet Radiation on the Skin: Photoaging 91

Mina Yaar
8. The Chronic Effects of Ultraviolet Radiation on

the Skin: Photocarcinogenesis 107
Antony R. Young and Norbert M. Wikonkál
9. The Epidemiology of Skin Cancer 119

Luigi Naldi and Thomas Diepgen
Section III: Photodermatoses

Part A: Basic Principles
10. Evaluation of the Photosensitive Patient 139
Henry W. Lim and John L. M. Hawk
x Contents
Part B: Immunologically-Mediated Photodermatoses

11. Polymorphous Light Eruption, Hydroa Vacciniforme,
and Actinic Prurigo 149
Herbert Hönigsmann and Maria Teresa Hojyo-Tomoka
12. Chronic Actinic Dermatitis 169

John L. M. Hawk and Henry W. Lim
13. Solar Urticaria 185

Takeshi Horio and Erhard Hölzle
Part C: Drug and Chemical-Induced Photosensitivity

14. Drug and Chemical Photosensitivity: Exogenous 199
James Ferguson and Vincent A. DeLeo
15. Cutaneous Porphyrias 219

Gillian M. Murphy and Karl E. Anderson
Part D: DNA Repair-Deﬁcient Photodermatoses

16. Xeroderma Pigmentosum and Other DNA
Repair-Deficient Photodermatoses 239
Mark Berneburg and Kenneth H. Kraemer
Part E: Photoaggravated Dermatoses

17. Photoaggravated Dermatoses 251
Victoria P. Werth and Herbert Hönigsmann
Section IV: Photoprotection

18. Photoprotection 267
Henry W. Lim and Herbert Hönigsmann
19. Novel Developments in Photoprotection: Part I 279

Uli Osterwalder and Henry W. Lim
20. Novel Developments in Photoprotection: Part II 297

André Rougier, Sophie Seite, and Henry W. Lim
21. Public Education in Photoprotection 311

Cheryl Rosen and Mark Naylor
Section V: Ultraviolet and Visible Radiation Therapy

22. Phototherapy with UVB: Broadband and Narrowband 319
Michael Zanolli and Peter M. Farr
23. Ultraviolet-A1 and Visible Light Therapy 335

Jean Krutmann and Akimichi Morita
24. Psoralen Photochemotherapy 347

Warwick L. Morison and Herbert Hönigsmann
25. Extracorporeal Photochemotherapy (Photopheresis) 359

Robert Knobler and Peter W. Heald
Contents xi
26. Photodynamic Therapy 369

Sally H. Ibbotson and Rolf-Markus Szeimies
27. The Principles and Medical Applications of Lasers and Intense-Pulsed Light in
Dermatology 389
Iltefat Hamzavi and Harvey Lui
28. Lasers and Energy Sources for Skin Rejuvenation and Epilation 401
Robert A. Weiss and Michael Landthaler
29. Laser Treatment on Ethnic Skin 417

Henry Hin Lee Chan and Brooke Jackson
Section VI: Appendices

Appendix A. Phototesting 433
Peter M. Farr and Robert S. Dawe
Appendix B. Photopatch Testing 441

Percy Lehmann, Frank C. Victor, and David E. Cohen
Appendix C. Guidelines for Setting Up a Phototherapy Referral Center or an

Office-Based Phototherapy Unit 449
Michael Zanolli and Roy Palmer
Appendix D. Guidelines for Setting Up a Laser Center 457

Macrene R. Alexiades-Armenakas and Jeffrey S. Dover
Index 463
Contributors
Macrene R. Alexiades-Armenakas Department of Dermatology, Yale University School of

Medicine, New Haven, Connecticut, U.S.A.
Karl E. Anderson Department of Internal Medicine, Division of Gastroenterology and

Hepatology, University of Texas Medical Branch, Galveston, Texas, U.S.A.
R. Rox Anderson Wellman Center for Photomedicine and Department of Dermatology, Harvard
Medical School, and Massachusetts General Hospital, Boston, Massachusetts, U.S.A.
Mark Berneburg Department of Dermatology, Eberhard Karls University, Tuebingen, Germany
Henry Hin Lee Chan Division of Dermatology, Department of Medicine, University of

Hong Kong, and Department of Medicine and Therapeutics, Chinese University of
Hong Kong, Hong Kong, China
David E. Cohen Ronald O. Perelman Department of Dermatology, New York University

School of Medicine, New York, New York, U.S.A.
Robert S. Dawe Department of Dermatology, Ninewells Hospital and Medical School,

Dundee University, Dundee, Scotland, U.K.
Vincent A. DeLeo Columbia University, St. Luke’s– Roosevelt Hospital Center, New York,
New York, U.S.A.
Thomas Diepgen Department of Clinical Social Medicine, Occupational and Environmental

Dermatology, Heidelberg, Germany
Brian L. Diffey Department of Regional Medical Physics, Newcastle General Hospital,

Newcastle, England, U.K.
Jeffrey S. Dover Department of Dermatology, Yale University School of Medicine, New Haven,
Connecticut, and Dartmouth Medical School, Hanover, New Hampshire, U.S.A.
Peter M. Farr Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne,
England, U.K.
James Ferguson Photobiology Unit, Ninewells Hospital, Dundee, Scotland, U.K.
Marjan Garmyn Department of Dermatology, University of Leuven, Leuven, Belgium
Gary M. Halliday Dermatology Research Laboratories, Melanoma and Skin Cancer Research
Institute, University of Sydney, Sydney, Australia
Iltefat Hamzavi Department of Dermatology, Henry Ford Hospital, Detroit, and Hamzavi
Dermatology, Port Huron, Michigan, U.S.A.
John L. M. Hawk Photobiology Unit, St. John’s Institute of Dermatology, St. Thomas’ Hospital,
King’s College of London, London, England, U.K.
xiv Contributors
Peter W. Heald Department of Dermatology, West Haven VA Medical Center, Yale University
School of Medicine, New Haven, Connecticut, U.S.A.
Maria Teresa Hojyo-Tomoka Departamento de Dermatologia del Hospital General Dr. Manuel
Gea González, Tlalpan, Mexico City, Mexico
Erhard Hölzle Department of Dermatology and Allergology, Klinikum Oldenburg, Oldenburg,

Germany
Herbert Hönigsmann Department of Dermatology, Medical University of Vienna, Vienna, Austria
Takeshi Horio Department of Dermatology, Kansai Medical University, Osaka, Japan
Sally H. Ibbotson Department of Dermatology, Ninewells Hospital and Medical School,

University of Dundee, Dundee, Scotland, U.K.
Brooke Jackson Skin and Wellness Center of Chicago, Chicago, Illinois, U.S.A.
Robert Knobler Division of Special and Environmental Dermatology, Department of Dermatology,

Medical University of Vienna, Vienna, Austria, and Department of Dermatology, College of
Physicians and Surgeons, Columbia University, New York, New York, U.S.A.
Irene E. Kochevar Wellman Center for Photomedicine, Massachusetts General Hospital,

Harvard Medical School, Boston, Massachusetts, U.S.A.
Kenneth H. Kraemer Basic Research Laboratory, Center for Cancer Research, National Cancer
Institute, Bethesda, Maryland, U.S.A.
Jean Krutmann Department of Dermatology and Environmental Medicine, Institut für

Umweltmedizinische Forschung (IUF), Heinrich-Heine University, Düsseldorf, Germany
Michael Landthaler Department of Dermatology, University Clinic Regensburg, Regensburg,

Germany
Percy Lehmann Klinik für Dermatologie, Allergologie und Umweltmedizin, HELIOS-Klinikum

Wuppertal, Universitätsklinikum der Universität Witten-Herdecke, Wuppertal, Germany
Henry W. Lim Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, U.S.A.
Harvey Lui Department of Dermatology and Skin Science, Vancouver Coastal Health Research
Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Warwick L. Morison Department of Dermatology, Johns Hopkins University, Baltimore,

Maryland, U.S.A.
Akimichi Morita Department of Geriatric and Environmental Dermatology, Nagoya City

University Graduate School of Medical Sciences, Nagoya, Japan
Gillian M. Murphy Department of Dermatology, Beaumont Hospital, Dublin, Ireland
Luigi Naldi Centro Studi GISED, Ospedali Riuniti, Bergamo, Italy
Mark Naylor University of Oklahoma, Tulsa, Oklahoma, U.S.A.
Uli Osterwalder Ciba Specialty Chemicals, Basel, Switzerland
Roy Palmer Photobiology Unit, St. John’s Institute of Dermatology, St. Thomas’ Hospital,
London, England, U.K.
Rik Roelandts Photodermatology Unit, University Hospital, Leuven, Belgium

Contributors xv
Lesley E. Rhodes Department of Dermatological Sciences, Photobiology Unit, University of

Manchester, Salford Royal Foundation Hospital, Manchester, England, U.K.
Cheryl Rosen Division of Dermatology, Toronto Western Hospital, University of Toronto,

Toronto, Ontario, Canada
André Rougier La Roche-Posay Pharmaceutical Laboratories, Asnières, France
Thomas Schwarz Department of Dermatology, University of Kiel, Kiel, Germany
Sophie Seite La Roche-Posay Pharmaceutical Laboratories, Asnières, France
Rolf-Markus Szeimies Department of Dermatology, Regensburg University Hospital,

Regensburg, Germany
Frank C. Victor Ronald O. Perelman Department of Dermatology, New York University

School of Medicine, New York, New York, U.S.A.
Robert A. Weiss Department of Dermatology, Johns Hopkins University School of Medicine,

Baltimore, and Maryland Laser Skin & Vein Institute, Hunt Valley, Maryland, U.S.A.
Victoria P. Werth Department of Dermatology, University of Pennsylvania, and Philadelphia V.A.

Medical Center, Philadelphia, Pennsylvania, U.S.A.
Norbert M. Wikonkál Department of Dermatology, Semmelweis University, School of Medicine,

Budapest, Hungary
Mina Yaar Department of Dermatology, Boston University School of Medicine, Boston,

Massachusetts, U.S.A.
Daniel B. Yarosh Applied Genetics Incorporated Dermatics, Freeport, New York, U.S.A.
Antony R. Young Division of Genetics and Molecular Medicine, St. John’s Institute of
Dermatology, King’s College London, London, England, U.K.
Michael Zanolli Division of Dermatology, Vanderbilt University Medical Center, Vanderbilt

University, Nashville, Tennessee, U.S.A.
Section I: HISTORY AND BASIC PRINCIPLES
1 History of Human Photobiology

Rik Roelandts
Photodermatology Unit, University Hospital, Leuven, Belgium
B Study on visible light was first published by Newton in 1672, and study
on action spectrum of ultraviolet light was published by Hausser and
Vahle in 1922.
B Relationship between sunlight and skin aging was first published by

Unna in 1894, and relationship between sunlight and skin cancer was
published by Dubreuilh in 1907.
B First description of a photodermatosis (eczema solare) was in 1798 by

Wilan.
B First commercially available sunscreen (benzyl salicylate and benzyl

cinnamate) was in 1928 in the United States. The concept of SPF was
developed by Greiter in 1974, and adopted by the United States Food and
Drug Administration in 1978.
B Modern day phototherapy started with Goeckerman in 1925 and PUVA

with Parrish in 1974.
2 Roelandts
THE BEGINNING OF A SCIENTIFIC INTEREST

he endless chain of days and nights since life began must have been an important source
T of imagination during history. This may explain why the Egyptians saw the Sun God Re
sailing the heaven in a boat and why the Greeks saw Apollo driving a chariot through the
sky. The Aztecs even offered beating human hearts to the Sun God, to give him enough
strength to reappear the next day. In nearly every civilization, people have adored the sun.
It was not only a question of religion but also of necessity. The sun is the universal source
of light and heat, and without the sun it would be dark and cold forever. This has nothing
to do with science. However, from early humankind on, people realized that the sun is extre-
mely important for life and it was, therefore, a topic of major concern. Stimulating people’s inter-
est is the beginning of science. Apart from this, there is also human experience. In many
civilizations, people realized that the sun could have a beneficial effect on certain diseases and
this, of course, had a stimulating effect on people’s imagination. It can take a very long time
before imagination evolves into a critical and structured approach, and in many cases this is a
step-by-step process.
The beginning of a real scientific interest in the solar spectrum dates from the 17th
century. One of the most important steps forward was the discovery of the visible spectrum
of the sun by Isaac Newton in England. He published the results of his experiments in 1672,
whereby the visible spectrum of the sun was fractionated by a prism into the different colors
of the rainbow (1). When Newton projected green plus red light on a wall, no green or red
light appeared, but only yellow light. When he added blue light, no green, red, or blue light
appeared, but only white light. To make white light, Newton did not need all colors, but
only red, green, and blue—the three basic colors.
In 1800, William Herschel, again in England, did some experiments with a thermometer to
evaluate which colors of the visible solar spectrum had the highest temperature. He noted that the
thermometer registered a higher temperature above the red visible light and, thus, discovered the
infrared spectrum of the sun (2).
The discovery of ultraviolet rays came a year later and can be attributed to the German
Johann Wilhelm Ritter. This discovery was partly based on previous experiments, by Carl
Wilhelm Scheele in Sweden, which had already been published in 1777 (3). Scheele could
show that paper strips dipped in a silver chloride solution became black after exposure to
the sun, because of a reduction of the silver, and that silver chloride did not become black in
the dark. Later on, this became the principle of analogous photography. Scheele could also
show that this was more pronounced with blue light than with red light. Ritter, a young scien-
tist, was convinced that invisible rays not only existed beyond the red end of the visible spec-
trum, as Herschel had demonstrated, but he also believed a similar invisible spectrum must
exist below the visible blue end of the spectrum. He first started his experiments with a ther-
mometer as Herschel did. Because he could not find a further decrease in temperature below
the visible blue as compared to the blue, he changed to Scheele’s method of using paper strips
dipped in silver chloride. He started measuring below the visible blue, where Scheele had
ended, and noted that the paper strips became even darker when exposed to invisible wave-
lengths shorter than the visible blue light. He, thus, discovered in 1801 the ultraviolet spectrum
of the sun, which he called “infraviolet” (4,5). Ritter died, unhappy, at the age of 33, without
ever realizing the importance of his discovery (6).
It took many years before the importance of ultraviolet rays became clear. After Ritter’s
death it was still a common belief that sunburn was due to heat damage. This changed with the
experiments of Everard Home in England in 1820 (7). Home wondered why the skin of black
people living in a hot climate was better protected than white skin, although black was absorb-
ing more heat. Therefore he exposed one of his own hands to the sun and covered the other one
with a black cloth. He developed sunburn on the exposed hand although a thermometer regis-
tered a higher temperature on the hand under the black cloth (8). Information at that time was
not so easily available as it is nowadays, which is illustrated by the fact that Moriz Kaposi, as
late as 1891, still believed that solar-induced erythema, and also pigmentation, were due to the
heat of the sun (9). Another illustration is the fact that Niels Finsen in Denmark, as late as 1900,
repeated Home’s experiment, independently, unaware of the previous experiment.
History of Human Photobiology 3
Although the damaging effects of ultraviolet radiation became gradually better known, it
took a few more years before real action-spectrum studies were undertaken. During Word War
I, Karl Hausser was the chief radiation physicist for Siemens AG in Germany. While working
near the battlefields, he got pulmonary tuberculosis and was sent to Davos in Switzerland for
heliotherapy. He took long walks in the mountains and noted that sunburn occurred easier at
noontime than in the afternoon hours (10). As a result, he and Vahle made the first detailed
action-spectrum studies for erythema and pigmentation of human skin. They could show
that erythema and pigmentation depend upon the wavelengths of the ultraviolet radiation
and that the effect is mainly due to wavelengths shorter than 320 nm (11). In 1922, they pub-
lished the action spectra for the induction of erythema and pigmentation in human skin
using a monochromator and an artificial mercury lamp.
During the Second International Congress on Light in 1932 in Copenhagen, Denmark,
William Coblentz proposed to divide the ultraviolet spectrum of the sun into three spectral
regions: UVA (315 –400 nm), UVB (280 – 315 nm), and UVC (,280 nm) (9).
Measuring the intensity of solar irradiation was another problem. Many different systems
were available (12). Although cadmium cathodes were already used in Potsdam in Germany
and in Davos in Switzerland as early as 1910, the first integrating analog meter was developed
by Rentschler in the mid-1930s, using a zirconium photodiode (11). However, these photo-
diodes showed great individual variability and temperature sensitivity. In addition, good
amplifiers were not available at that time. In the mid-1950s, Robertson developed a UVB
detector with a stable cold cathode thyratron to amplify the weak detector output (11). This
detector was later redesigned and became the popular Robertson-Berger meter.
ERYTHEMA, PIGMENTATION, AND NATURAL PHOTOPROTECTION

The concept that sun exposure is responsible for sunburn is known since early humankind. In
1799, Johan Christoph Ebermaier in Germany noticed different degrees of sunburn depending
on the time of exposure, whereby paler skin types reacted more severely than darker skin types
(13). However, until the experiments of Home in 1820 and even much later, it was commonly
believed that the heat of the sun was responsible for sunburn. The first to show that solar-
induced erythema is really induced by ultraviolet rays was Jean Martin Charcot in France in
1858. He noticed severe sunburn and keratitis in two scientists working with electric arcs
(9,14). This is also the first medical publication about accidental UV exposure. In 1877,
Arthur Henry Downes and Thomas Porter Blunt in England could show that sunlight also
may have a bactericidal action (15).
For a long time, it was a common belief that the heat of the sun was also responsible for
tanning, induced by sun exposure. In 1808, the German Placidus Heinrich noticed that the light
and not the heat of the sun was responsible for tanning (16). In 1829, John Davy from Scotland
first described immediate pigment darkening (9). It was only in 1885 that Paul Unna of
Germany suggested that the violet end of the solar spectrum, and thus the ultraviolet radiation,
was responsible for the pigmentation of the skin (17). A few years later, in 1889, Erik Johan
Widmark proved experimentally in Sweden that sunburn and tanning were due to the ultra-
violet rays and had nothing to do with heat (9,18). As soon as this was generally accepted,
research started into the mechanism of pigmentation. In 1917, Bloch published his experiments
on the mechanism of melanin formation in human skin and discovered dopa-oxidase (19).
Around the same time, Riehl reported a particular form of hyperpigmentation on both
cheeks and on the lateral parts of the neck after chronic sun exposure (20).
In 1928, Jean Saidman of France, published an interesting textbook, Les rayons ultra-violets
en thérapeutique, in which he describes how the minimal erythema dose (MED) may vary
according to the individual pigmentation, the site of the body, and age. He also describes vari-
ations in the MED in the case of certain skin disorders and in the case of oral intake of certain
drugs (12). He even made a device with a timer and several diaphragms to determine the MED,
automatically.
That sun exposure could induce an increase in skin thickness was already reported in
1799 by Ebermaier in Germany (13). In 1900, Magnus Möller reported that sun exposure
could induce a double protection mechanism in the epidermis, an increase of the stratum
4 Roelandts
corneum thickness, and an increase in pigmentation (21). In 1931, Guido Miescher of

Switzerland noticed an increase in thickness of all layers of the epidermis after sun exposure,
thus reducing the intensity of the penetrating radiation (22).
SKIN AGING AND SKIN CANCER

Gradually, it became clear that sun exposure could not only induce short-term but also long-
term skin changes. In 1893, Robert Bowles of England had already suggested that
sunlight could be responsible for skin cancers: “If the sun’s rays will produce sunburn,
erythema, eczema solare, inflammation, and blistering, it is clearly capable of producing
deep and intractable ulcerations of a low and chronic nature” (23). One year later, in 1894,
Paul Unna in Germany discovered the relationship between sun exposure and skin aging,
by studying sailor’s skin (24). He also associated the severe degenerative changes on the
exposed areas of sailors’ skin with the development of skin cancer (11). Around the same
time, in France, Dubreuilh noticed that people working in the vineyards around Bordeaux
had more skin cancers than people living in the city (25). He was the first to establish a
clear-cut relationship in 1906 –1907 between skin cancer and solar exposure (26). Both con-
ditions were dose-dependent. Skin aging was, therefore, more pronounced in the neck of
people working outside, which resulted in the description of cutis rhomboidalis nuchae by
Jadassohn and Nikolsky in 1925 (27).
In 1928, George Findlay reported that daily irradiation of mice with ultraviolet light from a
mercury arc could induce skin cancer (28) and that the interval time was reduced if tar were used
before the ultraviolet exposure. The first action-spectrum studies of skin photocarcinogenesis were
published by Angel Roffo from Argentina in 1939 (29), where he showed that window glass can
prevent the induction of skin cancer by both mercury arc radiation and by natural sunlight.
Shortly afterward, Harold Blum, Kirkby-Smith, and Grady, in the United States, conducted a com-
prehensive series of experiments on photocarcinogenesis in mice and were able to obtain highly
reproducible ultraviolet-induced skin cancers (30). These experiments were the beginning of a
large number of experiments on animal photocarcinogenesis during the following decades.
PHOTODERMATOSES
Probably the first to describe a photodermatosis was Robert Willan in 1798. He called the
disease eczema solare (31). The same condition was again described in 1887 by Veiel. What
they called eczema solare was, most likely, what we currently consider as polymorphous or
polymorphic light eruption. The name polymorphous light eruption was first used by Rasch
in Copenhagen, in 1900 (8). The same condition had also been described as prurigo aestivalis,
by Jonathan Hutchinson in 1878 (32). In 1919, Haxthausen used the term polymorphous light
eruption as a collective name for eczema solare and prurigo aestivalis, because it was not pos-
sible to differentiate between the two conditions (33).
Hydroa vacciniforme was first described by Bazin in 1860 (8). Later on, this term became
more confusing because it was not only used to describe hydroa vacciniforme, as it is known
currently. Some authors used the same terminology to describe what is, presently, called con-
genital erythropoietic porphyria.
Moriz Kaposi was the first to describe xeroderma pigmentosum in 1870 (8), but he did not
make the relationship with solar exposure or light, which was only done many years later by
Paul Unna (24).
The symptoms of congenital erythropoietic porphyria have been described under differ-
ent names such as pemphigus leprosus by Schultz in 1874 (34), xeroderma pigmentosum by
Gagey in 1896 (35), hydroa vacciniforme by M’Call Anderson in 1898 (36), hereditary syphilis
by Vollmer in 1903 (37), hydroa aestivale by Ehrmann in 1905 (38) and Linser in 1906 (39), until
Günther described the condition, in 1911, as a porphyria (40). One of the first symptoms of this
disease is the dark coloration of the urine, which was already noticed in the first description by
Schultz in 1874 (34), whereas M’Call Anderson was the first to recognize in his description of
1898 that the disease was caused by light (36). That the lesions resulted from the sensitization of
the skin to light exposure by porphyrins, was first suggested by Ehrmann, in 1909 (41). The
name Günther’s disease, to describe congenital erythropoietic porphyria, dates from a later
period. Even in 1926, Rasch still proposed to call the disease M’Call Anderson’s disease (8).
The same year the same author published a case report of a patient with porphyrinuria
and blisters on the back of both hands (8). Rasch did not make use of the terminology por-
phyria cutanea tarda, till that time, but he clearly made the link with alcoholism. The name
porphyria cutanea tarda was first used in 1937 by Waldenström, who also extensively
studied acute intermittent porphyria (42). The other porphyrias were described later, even
after World War II.
While the previous photodermatoses have mainly been described for the first time in the
19th century, solar urticaria has been described at the beginning of the 20th century. Probably
the first report of the induction of urticaria by sunlight is the one reported by Merklen, in 1904
(43). He was the first to consider urticaria, caused by light, to be a distinct clinical entity. A year
later in 1905, Ward, for the first time, provoked urticaria by means of sun exposure under con-
trolled conditions (44). The name “solar urticaria” was suggested by Duke in 1923 (45), and in
1928, Wucherpfennig could quantify the urticarial response by phototesting with increasing
doses of different wavelengths (46). In 1942, Rajka reported the passive transfer to normal
volunteers by an intradermal injection of serum from a person with solar urticaria (47).
The history of topically or systemically-induced photosensibilization starts earlier.
The first reports of systemically-induced photosensibilization were mainly due to occasional
intake of plant extracts. Already, in the 16th century, skin reactions have been observed in
animals after eating buckwheat followed by sun exposure (48). Similar observations have
been made in the 18th century in Sicily and in Napels in Italy, where white sheep showed
severe skin reactions after eating Hypericum, while the black sheep did not (49).
Between 1908 and 1910 Hausmann discovered that hematoporphyrin can photosensitize
animal skin and that the responsible wavelengths are in the green visible light around 500 nm
(50). The first clinical proof that some substances can photosensitize human skin in combination
with sun exposure dates from 1912, when our colleague Meyer-Betz injected himself with hema-
toporphyrin and exposed himself to the sun (51). By doing this he could demonstrate that the
combination of a photosensitizing substance and sun exposure can induce a skin reaction that
each of these two components separately would not induce, which is the definition of a photo-
sensibilization. Another example of a systemic photosensibilization in human skin is the “eosin
disease,” which was seen in patients treated with oral eosin for epilepsy or for other reasons (50).
In 1939, Stephen Epstein could demonstrate in human volunteers, using sulfanilamide as
the photosensitizer, that two mechanisms are involved: a dose-dependent phototoxic reaction
and a nondose-dependent photoallergic reaction (52).
It was first reported in 1913 by Louis Lewin, that topically applied agents can photosen-
sitize in workers using coal tar pitch (53). In 1916, Emanuel Freund reported phototoxic reac-
tions to eau de cologne, which was the first description of a berloque dermatitis, and he
concluded that oil of bergamot was most probably the photosensitizing substance (54). The
first description of a phytophotodermatitis dates from 1920 by Moritz Oppenheim (55). Hans
Kuske could show that the photosensitizing substances in these plants were furocoumarins,
and that their action spectrum was mainly between 334 and 366 nm, which was the first deter-
mination of an action spectrum for the furocoumarins (56). The photopatch test was introduced
in 1941 by Burckhardt (57).
PHOTOPROTECTION
It has always been part of human nature to protect the skin against sunburn by avoiding sun
exposure or by wearing appropriate clothes. During history, many substances have probably
been tried out as photoprotectors. As far as we know, the first scientific reports date from
the end of the 19th century. In 1878, Veiel reported the use of tannin as a photoprotector, but
its use was limited because of its staining potential (58). In 1891, Friedrich Hammer of
Germany even published a monograph, probably the first large monograph on photobiology,
discussing photoprotection and experimenting with different topical agents, to prevent
sunburn (9,59).
6 Roelandts
When Hausser and Vahle, in 1922, reported that sunburn in human skin is caused by a
specific part of ultraviolet spectrum between 280 and 315 nm (60), one realized that the skin
could be protected by filtering out these specific wavelengths. This resulted in a growing inter-
est in sunscreen agents. The first commercially available sunscreen appeared on the market in
1928, in the United States, as an emulsion containing benzyl salicylate and benzyl cinnamate
(61). During the subsequent years, sunscreens were not widely available and were not used
on a large scale. In Germany the first commercial sunscreen became available in 1933 (62)
and in France, in 1936 (63). The German product was an ointment. The French one was an
oil preparation and became a great success, because it was launched the same year that paid
holidays were granted.
During World War II, there was a real need for good sun protection for soldiers engaged
in tropical warfare. One of the most practical and effective agents for sun protection turned out
to be Red veterinary petrolatum, and was used as standard equipment (64). After the war,
styles were changing in many countries and a number of filters were synthesized, tested,
and marketed. In many cases these were less effective oil preparations, apparently with the
sole purpose of promoting tanning. During the 1970s, holiday travel to sunny areas steadily
became more popular, resulting in an increasing demand for sunscreens with better and
broader protection. This became possible by incorporating UVB filters into milks and creams
instead of oils. In 1979, real UVA filters became available and a further advance was the intro-
duction of micronized inorganic powders such as titanium dioxide since 1989, and zinc oxide
since 1992 (65).
With the increasing use of sunscreens, there was also an increasing need to find a good
method to evaluate their protection. In the early years, the usual way was to determine the
absorption spectrum of the sunscreen. In 1934, Friedrich Ellinger in Berlin proposed to use a bio-
logical method by determining the MED in protected and unprotected skin, using both forearms
and a mercury lamp (66). He concluded that the method of choice was the way in which the MED
could be decreased. He was right, but the right irradiation source was not yet used. In 1956,
Rudolf Schulze in Germany proposed to test commercially available sunscreens by giving
them a protection factor (67). The idea was to divide the exposure time needed to induce erythema
with sunscreen by the exposure time needed without sunscreen. He used a series of Osram-Ultra-
Vitalux lamps to apply a series of increasing ultraviolet doses (40% increases), in both protected
and unprotected skin. The light source he used was more similar to the solar spectrum than the
light source used by Ellinger. The method was further improved in 1974 in Austria by Franz
Greiter, who developed the concept of the sun protection factor (SPF) (68). In 1978, this method
was adopted by the Food and Drug Administration (FDA), in the United States (69) and
became internationally accepted. At that time sunscreens were mainly used to prolong the
exposure time in order to tan, and at the same time to avoid sunburn.
THE BEGINNING OF A THERAPEUTIC INTEREST

Over the centuries, sunlight has been used in the treatment of many diseases in different
countries such as ancient Egypt, Greece, and Rome, but the records are mostly anecdotal. In
addition, many believed that the therapeutic effect was due to red light and the heat of the
sun, because there was no notion of ultraviolet rays.
Gradually, and especially in the second half of the 19th century, more and more people
became interested in heliotherapy. In 1855, Arnold Rikli from Switzerland opened a thermal
station in Veldes Slovenia for the provision of heliotherapy (70). In 1856, Florence Nightingale
in the United Kingdom protested against the orientation of the Royal Victoria Hospital in
Netley, near Southampton, observing that no sunlight could enter its wards (71). In 1877
Downes and Blunt showed that sunlight could kill anthrax bacilli and, thus, had a bactericidal
action (15). In 1890, Palm from Edinburgh suggested that the sun could play a therapeutic role
in rachitis (72).
At the end of the 19th century, many people started to realize that ultraviolet rays of the
sun were the most important wavelengths for its therapeutic effects. This resulted in the use of
filtered solar radiation and of artificial light sources. In 1893, Niels Finsen in Denmark
used filtered sunlight in the treatment of lupus vulgaris. At a time when no antibiotics or anti-
inflammatory agents were available, Finsen’s phototherapy was more than welcome. Because a
treatment session with filtered natural sunlight could take several hours, and because natural
sunlight was not always available in Denmark, Finsen became logically interested in more
powerful artificial irradiation sources. In 1894, Heinrich Lahmann in Germany was probably
the first to use an artificial light source in the treatment of skin diseases (70), although he
was not the first to construct such a lamp. The first to make a (mercury) lamp was, probably,
Way around 1856 to 1860 (12).
In April 1896, Finsen founded the “Lysinstitut” or Medical Light Institute (later Finsen
Institute), in Copenhagen, where he continued to use filtered natural sunlight; but from 1897
onward he also used a new carbon arc lamp in combination with quartz filters (73).
Around the same time, in 1898, Willibald Gebhardt published what is probably the first
book on phototherapy, Die Heilkraft des Lichtes (74). A major problem when using a carbon
arc lamp to irradiate human skin was the high temperature. Finsen et al. developed a water-
cooling system and an irradiation unit where four patients were irradiated at the same time.
This irradiation source became internationally known as the Finsen lamp. After Finsen in
1901 published his therapeutic results with lupus vulgaris, treated by concentrated UV
doses from a carbon arc lamp, he received the Nobel Prize for Medicine in 1903, the only
Nobel Prize ever to be awarded for dermatology (73). From this time on the Finsen lamp
was used in all major dermatology departments inside and also outside Europe in the treat-
ment of lupus vulgaris. Finsen also wrote the foreword in the first French textbook on photo-
therapy, Photothérapie et Photobiologie, written by Leredde and Pautrier and published in 1903
(75). In 1904, a smaller lamp was constructed by Finsen and Reyn, the Finsen-Reyn lamp,
which allowed therapist to irradiate one single patient and which was more convenient in
smaller treatment centers. All these lamps were used only for localized irradiations. In the
same year, 1904, the Schott Company in Jena, Germany, was able to construct an ultraviolet
tube (9), using the low-pressure mercury lamp developed by the American Peter Hewitt in
1902 (76), and using a new type of glass containing barium sulfate.
About the same time, the first experiments started with the use of photosensitizers and
visible light in the treatment of skin cancer that became the principle of photodynamic
therapy, nearly a century later. During the winter of 1897 and 1898, Oscar Raab, in Munich,
had already noticed that the death of the paramecia, which he was studying, not only
depended upon the concentration of the dye acridine but also on the intensity of the light
in the laboratory (77). In 1905, Albert Jesionek and Hermann von Tappeiner could cure
three out of five basal cell carcinomas they had treated with intralesional eosin and light
exposure (78).
A lot of research was done in the construction of new phototherapy equipment. In
1906, Hans Axmann in Germany constructed a horizontal treatment cabin equipped with
a series of low-pressure mercury tubes, allowing total body irradiations (9,79). Unfortunately,
the output of these lamps was not high enough to obtain a sufficient therapeutic effect in
lupus vulgaris and, therefore, could not compete with the Finsen-Reyn lamp. In 1906 also,
Richard Küch in Hanau, Germany, made the first quartz lamp. By using quartz instead of
lead glass, he was able to develop a high-pressure mercury lamp with a higher output
(80). In the beginning these lamps were only used to illuminate streets and warehouses,
where they gradually replaced the carbon arc lamps, which had a lower output and
higher running costs (9). Soon after, the high-pressure mercury lamp was also used for thera-
peutic purposes, because of the same reasons. In 1908, Carl Franz Nagelschmidt made a table
model of the high-pressure mercury lamp for total body irradiation, but this was nothing
more than a prototype. After Hugo Bach constructed his own quartz lamp in 1911, this
“Höhensonne” lamp was modified many times and was used for almost 50 years for total
body irradiations (9). When in 1912 Ernst Kromayer in Berlin made a quartz lamp with a
high UV output, and improved the lamp by using a water cooling system, it became possible
to treat different skin diseases (81,82). Kromayer commercialized his lamp in 1906, and it
became one of the most popular treatment lamps in dermatology for decades. It was not
only used in Europe but also in Asia and the United States, although it could only be
used for localized irradiations.
8 Roelandts
In 1919, the pediatrician Kurt Huldschinsky published his therapeutic results with high-
pressure mercury lamps in the treatment of rachitis (83). This again was a very interesting
indication for the use of phototherapy in medicine. Its success was greatly due to the use of
the new radiography technique as a way to control the evolution of the disease.
Lupus vulgaris was not the only indication for the use of phototherapy in dermatology.
William Henry Goeckerman, in the United States, started testing different photosensitizers in
the treatment of psoriasis in order to improve the therapeutic effect of the sun. In 1925, he
published his results using coal tar in combination with ultraviolet exposure from a high-
pressure mercury lamp (84). This treatment became very popular worldwide and was used
for decades to treat psoriasis. Later on, John Ingram in the United Kingdom combined this
treatment with dithranol (85).
In 1927, Erich Uhlmann could induce repigmentation in vitiligo patients combining
bergamot oil and exposure to natural sunlight or to a Kromayer lamp (86).
In 1947, a new type of lamp was born, the high-pressure xenon lamp. In contrast to the
high-pressure mercury lamp, this lamp had a continuous spectrum ranging from the ultra-
violet to the infrared spectrum, similar to the natural solar spectrum. Because this lamp was
more costly to use it did not become popular for therapeutic purposes but was only used for
research and phototesting.
In 1958, the use of blue light phototherapy (420 – 480 nm) was reported for the treatment
of newborns with jaundice, after a nurse noticed that the yellow pigmentation in jaundiced
babies faded away after sun exposure (87). Apart from its use in pediatrics to treat jaundice
in newborns, heliotherapy and phototherapy were done on an organized scale to treat tubercu-
losis, leg ulcers, and skin diseases.
HELIOTHERAPY FOR TUBERCULOSIS

In 1903, Rollier in Leysin, Switzerland, opened the first hospital to treat lung tuberculosis
and rachitis by sun exposure. In 1914, he published his therapeutic results in a book, La
Cure du Soleil, which unfortunately was published in French at the start of World War I
and therefore had no great effect outside Switzerland (88). When in 1923 his book was trans-
lated and published in English under the title Heliotherapy, the use of sun exposure in the
treatment of tuberculosis became increasingly popular (82). It was only when the first tuber-
culostatics became available, in 1946, that the use of sun exposure in the treatment of lung
tuberculosis and the use of phototherapy in the treatment of lupus vulgaris became part
of history.
HELIOTHERAPY AND PHOTOTHERAPY FOR LEG ULCERS

Another application of an organized use of sun exposure and phototherapy was in the treat-
ment of leg ulcers. The first to report a therapeutic effect of sun exposure in the treatment of
ulcers was Larrey, Napoleon’s private physician. He noted, during Napoleon’s campaign in
Egypt, in 1798 and 1799, that the soldiers’ traumatic ulcers healed more quickly after sun
exposure (89). In 1904, Bernhard in Switzerland described heliotherapy as a treatment for
skin ulcers (89,90). Later on, this was confirmed by other authors (91,92) whereafter the treat-
ment of wounds with sunlight gradually gained ground, especially in Switzerland, Germany,
and France. During World War I from 1914 to 1918, ulcers were treated by exposure to natural
sunlight or to quartz lamps in Germany, the United Kingdom, France, and Italy. During World
War II from 1940 to 1945, this “open-air treatment” with sunlight or with quartz lamps was
still being used. When the first antibiotics became available, however, interest in using
phototherapy for wound healing faded.
PHOTOTHERAPY FOR SKIN DISEASES

Heliotherapy with natural sunlight was mainly used in thermal stations to treat tuberculosis
and in wartime to treat leg ulcers. However, both indications became part of history. This
was not the case with the use of phototherapy in the treatment of skin disorders. During history
and up to the present, several skin disorders have been treated with heliotherapy or
phototherapy.
Before the end of the 19th century its use was more anecdotal. Probably the first report of
the use of sunlight in the treatment of skin disorders dates from about 1400 BC , when plant
extracts followed by sun exposure to treat vitiligo was used in India (93). The same treatment
was also used in ancient Egypt. The anecdotal use of heliotherapy during the centuries changed
at the end of the 19th century with Niels Finsen. He was the first to use sun exposure in a more
standardized way on a large scale for a specific indication, with a detailed account of its thera-
peutic results. He was also the first to switch from heliotherapy with natural sunlight to photo-
therapy with artificial lamps, making it more practical. The Nobel Prize he won in 1903 had a
booster effect on phototherapy. Probably a similar effect happened at the end of the last century
with the development of phototherapeutic UVA (PUVA) treatment or photochemotherapy.
Photochemotherapy has a long history (94). It started with the use of plant extracts
and sun exposure to treat vitiligo and resulted in the use of oral 8-methoxypsoralen
(8-MOP) and total body UVA-irradiation cabins to treat psoriasis. Many different steps
have been involved. The first step was the use of certain plant extracts to treat vitiligo
(95). The next step was the isolation of the active ingredients in these plants as 8-MOP
and 5-methoxypsoralen (5-MOP), in 1947, and the first trials with 8-MOP and sun exposure
in vitiligo patients (96 –99). Later, the action-spectrum studies were introduced (100,101).
These were followed by the topical use of 8-MOP in combination with UV irradiation to
treat psoriasis (102) and in 1967 by the oral use of 8-MOP to treat psoriasis (103). The
next step was the use of “blacklight” UVA tubes in combination with topical 8-MOP in
the treatment of vitiligo (104). One year later, in 1970, Mortazawi used the same type of
UVA tubes in a total body irradiation cabin, using topical 8-MOP to treat psoriasis
(105,106). The use of UVA tubes in a total body irradiation cabin was new. Although
the UVA output of these tubes was effective when the 8-MOP was used topically, it was
insufficient when administered orally. In 1974, Parrish et al. reported the use of a new
type of a high-intensity UVA tube in combination with oral 8-MOP in the treatment of psor-
iasis (107). This approach was more effective and was the real start of PUVA therapy, which
revolutionized dermatological treatment.
The history of UVB phototherapy is not as old as the history of photochemotherapy, and
was started at the end of the 19th century with the work of Niels Finsen on lupus vulgaris. In
1923, Alderson recommended the use of a mercury quartz lamp to treat psoriasis. In 1925,
Goeckerman associated tar with UV irradiations in the treatment of psoriasis, and this
remained for about half a century as the most popular form of phototherapy in dermatology
(84). The main drawback of this treatment was the low output of the lamps. In 1958,
Zimmerman in the United States described an irradiation cabin, using fluorescent UVB
tubes (108). Later, several other total body irradiation sources were described (109,110). After
a successful start of PUVA treatment, Wiskemann suggested, in 1978, using an irradiation
cabin with broadband UVB tubes (111). During the subsequent years, broadband UVB photo-
therapy became an alternative for PUVA treatment. Because broadband UVB phototherapy
was less efficient for psoriasis than PUVA therapy, it never achieved its popularity.
This changed in 1988 when narrowband UVB phototherapy was introduced in the treatment
of psoriasis by van Weelden et al. (112) and Green et al. (113). This was more efficient than
broadband UVB phototherapy.
In the meantime, other types of phototherapy have been developed such as extracorpo-
real photopheresis for cutaneous T-cell lymphoma (114), high-dose UVA1 phototherapy for
atopic dermatitis and localized scleroderma (115), and topical photodynamic therapy with
visible light for actinic keratoses and superficial basal cell carcinoma (116).
JOURNALS, SOCIETIES, AND MEETINGS

The first real journal dealing exclusively with photobiology and photodermatology was prob-
ably the Transactions from Finsen’s Medical Light Institute, which were published in Danish
10 Roelandts
and German. The journal appeared from 1900 until 1904, when Finsen died. In 1912, Hans
Meyer in Germany started the new journal Strahlentherapie, dealing not only with phototherapy
but also with radiotherapy. Because phototherapy became less important after World War II,
this journal is no longer a photobiological or photodermatological journal.
In 1927, the Deutsche Gesellschaft für Lichtforschung (German Society for Research on
Light) was founded (9). The first president was Hans Meyer, editor of the journal Strahlenther-
apie. One year later, in 1928, the first international society was founded by a group of French
colleagues, called Comité International de la Lumière, with Axel Reyn as the first president. Reyn
was Danish and a pupil of Finsen. The First International Congress on Light was held in 1929
in Paris, France, with Jean Saidman as its president. The second congress was in Copenhagen,
Denmark, in 1932 and the third one took place in Wiesbaden, Germany, in 1936. In 1937, the
decision was made to attribute a prize—the Finsen medal—during each congress to an out-
standing cutaneous photobiologist. The next congress was again held in Paris, France, in
1951. At that time, the name of the society became the Comité International de Photobiologie
and the name of the congress changed to the “International Congress on Photobiology” (9).
In 1962, Douglas McLaren started the first journal in English, named “Photochemistry
and Photobiology: An International Journal.” The American Society of Photobiology was
founded in 1972 (11) and the Japanese Society for Photomedicine and Photobiology in 1978.
In 1984, Christer Jansén from Finland and Göran Wennersten from Sweden started another
international journal in English, named “Photodermatology clinical and experimental,” the
name (and size) of which changed in 1990 to “Photodermatology, Photoimmunology & Photo-
medicine.” The Photomedicine Society in the United States was founded in 1991 and the Euro-
pean Society for Photodermatology in 1999.
In 2004, another journal was launched, named “Photodiagnosis and Photodynamic
Therapy.” Apart from these journals several other journals are available dealing only partly
with cutaneous photobiology and photomedicine, such as the “Journal of Photochemistry and
Photobiology. B: Biology,” which started in 1987 as part of the “Journal of Photochemistry.”
BUILDING ON THE PAST

The history of human photobiology is as old as humankind. During the centuries a lot of people
were involved. Some of them had the bright ideas and others had the merit of putting them into
practice. The result is a beautiful example of how science is built up stone by stone. In this
period, when we have the idea that we can realize everything, we often forget that we are
just building on the foundations laid out by others before us. History therefore is a good
lesson in modesty.
REFERENCES
1. Newton I. New theory about light and colours. Philosophical transactions 1672; I:3075– 3087.
2. Herschel W. Investigation of the powers of the prismatic colours to heat and illuminate objects.
Philos Trans R Soc Lond 1800; I:255 –283.
3. Scheele CW. Chemische Abhandlung von der Luft und dem Feuer. Upsala, Leipzig: Swederus,
Crusius, 1777.
4. Ritter JW. Physisch-chemische Abhandlungen in chronologischer Folge. Band II. Leipzig 1806;
81 – 107.
5. Ritter JW. Entdeckungen zur Elektrochemie, Bioelektrochemie und Photochemie. Ostwalds
Klassiker der exakten Wissenschaften. Band 271. Leipzig: Akademische Verlagsgesellschaft
Geest & Portig K.-G., 1986.
6. Roelandts R. Bicentenary of the discovery of the ultraviolet rays. Photochem Photoimmunol
Photomed 2002; 18:208.
7. Home E. On the black rete mucosum of the Negro, being a defense against the scorching effect of the
sun’s rays. Philos Trans R Soc London 1820; 111:1.
8. Rasch C. Some historical and clinical remarks on the effect of light on the skin and skin diseases. Proc
R Soc Med 1926; 20:11 – 20.
9. Lentner A. Geschichte der Lichttherapie. Aachen: Foto-Druck Mainz, 1992.
10. Hausser KW, Vahle W. Sonnenbrand und Sonnenbräunung. Wiss Veröff Siemens-Konzern 1927;
6:101.
11. Urbach F, Forbes PD, Davies RE, Berger D. Cutaneous photobiology: past, present, and future.
J Invest Dermatol 1976; 67:209– 224.
12. Saidman J. Les rayons ultra-violets en thérapeutique. Paris: Gaston Doin & Cie, 1928.
13. Ebermaier JC. Versuch einer Geschichte des Lichtes in Rücksicht seines Einflusses auf die gesamte
Natur, und auf den menschlichen Körper, ausser dem Gesichte, besonders. Osnabrück: Karl und
Comp, 1799.
14. Charcot P. Erythème produit par l’action de la lumière électrique. C R Soc Biol (Paris) 1858; 5:
63 – 65.
15. Downes AH, Blunt TP. Researches on the effect of light upon bacteria and other organisms. Proc R
Soc Lond 1877; 26:488– 500.
16. Heinrich P. Von der Natur und den Eigenschaften des Lichts. St. Petersburg: Veröffentl d kaiserli-
chen Akademie der Wissenschaften, 1808.
17. Unna PG. Uber das Pigment der menschlichen Haut nebst einem Vorschlag für wanderlustige
Kollegen. Med prakt Derm 1885; 4:277 – 294.
18. Widmark EJ. Ueber den Einfluss des Lichtes auf die Haut. Hygiea Festband 1889; 3:1– 23.
19. Bloch B. Das Problem der Pigmentbildung in der Haut. Arch f Derm u Syph 1917; 124:129– 208.
20. Riehl. Uber eine eigenartige Melanose. Wien klin Wochenschr 1917; 780.
21. Möller M. Der Einfluss des Lichtes auf die Haut in gesundem und krankhaften Haut. Stuttgart:
Nägele, 1900.
22. Miescher G. Die Schutzfunktionen der Haut gegenüber Lichtstrahlen. Strahlentherapie 1931; 39:
601 – 618.
23. Bowles RL. On the influence of solar rays on the skin. Br J Dermatol 1893; 237.
24. Unna PG. Die Histopathologie der Hautkrankheiten. Berlin: Hirschwald, 1894.
25. Dubreuilh W. Des hyperkeratoses circonscrites. Ann Derm Syph 1896; 7:1158 – 1204.
26. Dubreuilh W. Epithéliomatose d’origine solaire. Annales de Derm et Syph 1907; 387.
27. Jadassohn. Cutis rhomboidalis nuchä mit colloider Degeneration. Zentr f Haut u Geschlechtskrankh
1925; XVII :272.
28. Findlay GM. Ultraviolet light and skin cancer. Lancet 1928; 2:1070– 1073.
29. Roffo AH. Uber die physikalische Aetiologie der Krebskrankheit mit besonderer Betonung des
Zusammenhangs mit Sonnenbestrahlungen. Strahlentherapie 1939; 66:328– 350.
30. Blum HF, Kirkby-Smith S, Grady HG. Quantitative induction of tumors in mice with ultraviolet
radiation. J Natl Cancer Inst 1941; 2:259– 268.
31. Willan R. On cutaneous diseases. London: Johnson, 1808.
32. Hutchinson J. Lectures on clinical surgery. Vol 1. London: Churchill, 1878.
33. Brodthagen H. Polymorphous light eruption. In: Urbach F, ed. The Biological Effects of Ultraviolet
Radiation. New York: Pergamon Press 1969:479– 486.
34. Schultz JH. Ein Fall von Pemphigus leprosus, kompliciert durch Lepra visceralis. Inaug. Diss.
Greisswald, 1874.
35. Gagey. Cas d’hémoglobinurie au cours d’un xeroderma pigmentosum. Thèse de Paris, 1896.
36. M’Call Anderson T. Hydroa vacciniforme. Br J Dermatol 1898; 1.
37. Vollmer. Uber hereditäre Syphilis und Hämatoporphyrinuria. Archiv f Derm u Syph 1903; 1XV:221.
38. Ehrmann. Hydroa aestivale. Arch f Derm u Syph 1905; 1XXVII :163.
39. Linser. Hydroa aestivale und Hämatoporphyrinuria. Archiv f Derm u Syph 1906; 1XXIX :251.
40. Günther. Die Hämatoporphyrie. Dtsch Arch f klin Med 1911; 105:89– 146.
41. Ehrmann S. Weitere Untersuchungen über Lichtwirkung bei Hydroa aestivalis (Bazin), Summer-
eruption (nach Hutchinson). Arch f Derm u Syph 1909; 97:75 – 86.
42. Waldenström J. Studien über porphyrie. Acta Med Scand 1937; suppl. 82:133.
43. Merklen P. Urticaria. In: Besnier E, Brocq L, Jacquet L, eds. La Pratique Dermatologique: Trait de
Dermatologie Appliquée. Paris: Masson et Cie, 1904:728– 771.
44. Ward SB. Erythema and urticaria with a condition resembling angioneurotic edema caused by
exposure to sun’s rays. NY Med J 1905; 81:742– 743.
45. Duke WW. Urticaria caused by light. JAMA 1923; 80:1835– 1838.
46. Wucherpfennig V. Pathologische Lichtüberempfindlichkeit in qualitativer und quantitativer
Hinsicht, nebst Untersuchungen zur Pathogenese der Lichtquaddel. Arch Dermatol Syph (Berl.)
1928; 156:520– 544.
47. Rajka E. Passive transfer in light urticaria. J Allergy Clin Immunol 1942; 13:327– 345.
48. Merian L. Experimentelle Beiträge zur Buchweizenerkrankung (Fagopyrismus) der Tiere. Arch
Anat Physiol, Physiol Abt 1915; 161:188.
49. Barth J. Historische und aktuelle Aspekte der Fotosensibilisierung. Derm Mschr 1976; 162: 961 – 973.
50. Lipschitz W. Im Blut kreisende Substanzen als Grundlage für Lichtdermatosen. Strahlentherapie
1928; 29:9– 19.
51. Meyer-Betz F. Untersuchungen über die biologische (photodynamische) Wirkung des Hämatopor-
phyrins und anderer Derivate des Blut- und Gallenfarbstoffs. Dtsch Arch klin Med 1913;
112:476– 503.
12 Roelandts
52. Epstein S. Photoallergy and primary photosensitivity to sulfanilamide. J invest Derm 1939; 2:43– 51.
53. Lewin L. Uber die photodynamische Wirkungen von Inhaltsstoffen des Steinkohlenteerpechs am
Menschen. Münch Med Wochenschr 1913; 60:1529– 1530.
54. Freund E. Uber bisher noch nicht beschreibende künstliche Hautverfärbungen. Dermatol
Wochenschr 1916; 63:931.
55. Oppenheim M, Fessler A. Über eine streifenförmige bullöse Dermatitis (Freibad- und Wiesenderma-
titis). Derm Wschr 1928; 86:183– 187.
56. Kuske H. Perkutane Photosensibilisierung durch pflanzliche Wirkstoffe. Dermatologica 1940; 82:
274 – 338.
57. Burckhardt W. Untersuchungen über die Photoaktivität einiger Sulfanilamide. Dermatologica 1941;
83:63– 68.
58. Henschke U. Untersuchungen an Lichtschutzmitteln. Strahlentherapie 1940; 67:639– 668.
59. Hammer F. Uber den Einfluss des Lichtes auf die Haut. Stuttgart: F. Enke, 1891.
60. Hausser KW, Vahle W. Die Abhängigkeit des Lichterythems und der Pigmentbildung von der
Schwingungszahl (Wellenlänge) der erregenden Strahlung. Strahlentherapie 1922; 13:47– 71.
61. Jass HE. Cosmetic suntan products. Cutis 1979; 23:554 – 561.
62. Finkel P. Lichtschutzmittel. In: Umbach W, ed. Kosmetik. Stuttgart, New York: Georg Thieme Verlag,
1995:147– 163.
63. Rebut D. The sunscreen industry in Europe: past, present and future. In: Lowe NJ, Shaath NA, eds.
Sunscreens, Development, Evaluation, and Regulatory Aspects. New York: Marcel Dekker, Inc,
1990:161– 171.
64. MacEachern WN, Jillson OF. A practical sunscreen “Red Vet Pet.” Arch Dermatol 1946; 89:147 –150.
65. Roelandts R. Advances in sunscreen technology: choosing the sunscreen to suit. Current Opinion in
Dermatology 1995:173– 177.
66. Ellinger F. Zur Frage der Wertbestimmung von Lichtschutzmitteln. Arch exp Path u Pharmakologie
1934; 175:481– 488.
67. Schulze R. Einige Versuche und Bemerkungen zum Problem der handelsüblichen Lichtschutzmittel.
Parf u Kosmet 1956; 37:310– 315.
68. Greiter F. Sonnenschutzfaktor – Entstehung, Methodik. Parf u Kosmet 1974; 55:70 – 75.
69. Dept of Health, Education and Welfare, Food and Drug Administration. Sunscreen drug products
for over-the-counter human use. Federal Register, August 25 1978; 43:38206– 38269.
70. Barth J, Köhler U. Photodermatologie in Dresden-ein historischer Abriss. Festschrift anlässlich des
75. Geburtstages von Prof. Dr. h.c. H.-E. Kleine-Natrop (1917 – 1985). Dresden 1992.
71. From a special correspondent. Royal Victoria Hospital, Netley. Br Med J 1966; 5484:412– 413.
72. Palm TA. The geographical distribution and aetiology of rickets. The Practitioner October and
November 1890.
73. Roelandts R. A new light on Niels Finsen, a century after his nobel prize. Photodermatol Photoim-
munol Photomed 2005; 21:115 – 117.
74. Meffert H, Bahr T. Willibald Gebhardt (1861– 1921). Sein Leben und seine Verdienste um die
Photomedizin. Dermatol Monatsschr 1989; 175:699 –705.
75. Leredde, Pautrier. Photothérapie et Photobiologie. Paris: Naud, 1903.
76. Heusner HL. Zum zehnjährigen Jubiläum der medizinischen Quarzlampe. Strahlentherapie 1916;
7:628– 638.
77. Raab O. Untersuchungen über die Wirkung fluorezierende Stoffe. Z Biol 1899; 39:16.
78. Jesionek A, Tappeiner HV. Zur Behandlung der Hautcarcinome mit fluorescierenden Stoffen. Dtsch
Arch Klin Med 1905; 82:223– 227.
79. Axmann H. Weitere Erfahrungen über die Uviolbehandlung, sowie einen neuen Apparat zur
Bestrahlung des ganzen Körpers mittels ultravioletten Lichtes (Uviolbad). Dtsch Med Wochenschr
1906; 32:583– 584.
80. Küch R, Retschinsky T. Photometrische und spektralphotometrische Messungen am Quecksilberbo-
gen bei hohem Dampfdruck. Ann Physik 1906; 20:563– 583.
81. Kromayer E. Quecksilber-Wasserlampen zur Behandlung von Haut und Schleimhaut. Dtsch med
Wochenschr 1906; 32:377– 380.
82. Rollier A. Heliotherapy. Oxford: Oxford Medical Publications, 1923.
83. Huldschinsky K. Heilung von Rachitis durch künstliche Höhensonne. Dtsch med Wochenschr 1919;
45:712– 713.
84. Goeckerman WH. Treatment of psoriasis. Northwest Med 1925; 24:229– 231.
85. Ingram JT. The approach to psoriasis. Br Med J 1953; II:591– 594.
86. Uhlmann E. Pigmentbildung bei Vitiligo. Med Klin 1927; 23:279– 280.
87. Cremer RJ, Perryman PW, Richards DH. Influence of light on the hyperbilirubinaemia of infants.
Lancet 1958; I:1094– 1097.
88. Saleeby CW. Sunlight and Health. London: Nisbet & Co:1923– 1926.
89. Bernhard O. Light treatment in surgery. London: Edward Arnold & Co, 1926.
90. Bernhard O. Über offene Wundbehandlung durch Insolation und Eintrocknung. Münch med
Wochenschr 1904:Nr 1.
91. Haeberlin. Zur Behandlung granulierender Wunden. Münch med Wochenschr 1907:Nr 8.
92. Dosquet W. Offene Wundbehandlung und Freiluftbehandlung. Leipzig: Georg Thieme, 1916.
93. Fitzpatrick TB, Pathak MA. Historical aspects of methoxsalen and other furocoumarins. J Invest
Dermatol 1959; 31:229– 331.
94. Roelandts R. The history of photochemotherapy. Photodermatol Photoimmunol Photomed 1991;
8:184– 189.
95. Marquis L. Arabian contributors to Dermatology. Int J Dermatol 1985; 24:60 – 64.
96. Fahmy IR, Abu-Shady H. Ammi majus Linn: pharmacognostical study and isolation of a crystalline
constituent, ammoidin. Q J Pharmacol 1947; 20:281– 291.
97. Fahmy IR, Abu-Shady H, Schönberg A, et al. A crystalline principle from Ammi majus L. Nature
1947; 160:468– 469.
98. Fahmy IR, Abu-Shady H. Ammi majus Linn: the isolation and properties of ammoidin, ammidin
and majudin, and their effect in the treatment of leukoderma. Q J Pharmacol 1948; 21:499– 503.
99. El-Mofty AM. A preliminary clinical report on the treatment of leukoderma with Ammi majus Linn.
J Egypt Med Assoc 1948; 31:651– 665.
100. Buck HW, Magnus IA, Porter AD. The action spectrum of 8-methoxypsoralen for erythema in
human skin. Br J Dermatol 1960; 72:249– 255.
101. Pathak MA, Fellman JH. Activating and fluorescent wavelengths of furocoumarins: psoralens.
Nature 1960; 185:382– 383.
102. Allyn B. Studies on phototoxicity in man and laboratory animals. Paper presented at the Twenty-
First Annual Meeting of the American Academy of Dermatology. Chicago, December 1962.
103. Oddoze L, Témime P, Marchand JP, et al. L’association “meladinine” per os et rayons U.V. dans le
traitement du psoriasis. Bull Soc Fr Dermatol Syph 1967; 74:609– 610.
104. Fulton JE, Leyden J, Papa C. Treatment of vitiligo with topical methoxsalen and blacklite. Arch
Dermatol 1969; 100:224– 229.
105. Mortazawi SMA. Meladinine und UVA bei Vitiligo, Psoriasis, Parapsoriasis und Akne vulgaris.
Dermatol Monatsschr 1972; 158:908– 909.
106. Mortazawi SMA, Oberste-Lehn H. Lichtsensibilisatoren und ihre therapeutischen Fähigkeiten.
Z Haut-Geschl Kr 1973; 48:1– 9.
107. Parrish JA, Fitzpatrick TB, Tanenbaum L, et al. Photochemotherapy of psoriasis with oral methox-
salen and longwave ultraviolet light. N Engl J Med 1974; 291:1207– 1211.
108. Zimmerman MC. Ultraviolet light therapy. Arch Dermatol 1958; 78:646– 652.
109. Wiskemann A. Die neuere Entwicklung der Lichttherapie. Dermatol Wochenschr 1963; 147:377– 383.
110. Forck G. Ganzkörperbestrahlung mit UV-Licht. Aufbau einer neuartigen Anlage. Dermatol
Wochenschr 1964; 150:290– 294.
111. Wiskemann A. UVB-Phototherapie der Psoriasis mit einer fur die PUVA-Therapie entwickelten
Stehbox. Z Hautkr 1978; 53:633– 636.
112. van Weelden H, De La Faille HB, Young E, et al. A new development in UVB phototherapy of
psoriasis. Br J Dermatol 1988; 119:11 – 19.
113. Green C, Ferguson J, Lakshmipathi T, et al. 311 nm UVB phototherapy—an effective treatment for
psoriasis. Br J Dermatol 1988; 119:691– 696.
114. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal
photochemotherapy. Preliminary results. N Engl J Med 1987; 316:297– 303.
115. Krutmann J, Schopf E. High-dose-UVA1 phototherapy: a novel and highly effective approach for the
treatment of acute exacerbation of atopic dermatitis. Acta Derm Venereol Suppl (Stockh). 1992;
176:120– 122.
116. Kennedy JC, Pottier RH. Endogenous protoporphyrin IX, a clinically useful photosensitizer for
photodynamic therapy. J Photochem Photobiol B Biol 1992; 14:275– 292.
2 Basic Principles of Photobiology
Brian L. Diffey
Department of Regional Medical Physics, Newcastle General Hospital,
Newcastle, England, U.K.
Irene E. Kochevar
Wellman Center for Photomedicine, Massachusetts General Hospital,
Harvard Medical School, Boston, Massachusetts, U.S.A.
B Application of photobiology to dermatology relies on knowledge from

a wide range of areas, including climatology, optical physics,
photochemistry, cellular and molecular biology, and pathology.
B Ultraviolet, visible, and infrared radiations are all ranges of

optical radiation and are part of the electromagnetic spectrum.
B Ultraviolet radiation is divided into UVA, UVB, and UVC wavelength

ranges.
B The energy of a photon is inversely related to the wavelength of the

radiation.
B The exposure dose, rather than the rate of delivery of the radiation
(dose rate), is responsible for the photobiological response.
B Only photons that are absorbed by molecules in skin can initiate a

response.
B Each chromophore (light-absorbing molecule) in skin absorbs a unique

combination of wavelengths; this is termed the absorption spectrum.
B Photochemical reactions convert chromophores into new molecules

called photoproducts.
B Photoproducts stimulate processes in cells that lead to observed clinical

responses.
16 Diffey and Kochevar
INTRODUCTION
rom entering the skin to causing biological and clinical effects, optical radiation has to
F initiate a number of processes as shown in Figure 1. These pathways encompass a

variety of seemingly unconnected areas of knowledge ranging from climatology, optical
physics, photochemistry, cellular and molecular biology through to clinical medicine and
pathology (1).
The observable clinical effects that result from the interaction of optical radiation, especially
ultraviolet radiation (UVR), with the skin can be both beneficial and detrimental. The effects can
be either acute, which is of rapid onset and generally short duration, or chronic, which is of
gradual onset and long duration. Examples of acute effects include sunburn, tanning, and
vitamin D production, whereas photoaging and skin cancer are the results of chronic exposure
over many years. These effects are discussed in more detail elsewhere.
ULTRAVIOLET AND VISIBLE RADIATION

In 1666, Isaac Newton wrote: “. . . procured me a Triangular glass-Prisme, to try therewith the cele-
brated Phaenomena of Colours” and opened up a new era into the scientific investigation of
light (2). It was not until 1801 that Johann Ritter discovered the ultraviolet (UV) region of
the solar spectrum by showing that chemical action was caused by some form of energy in
the dark portion beyond the violet (3). In 1800, Sir William Herschel had demonstrated the
existence of radiation beyond the red end of the visible spectrum, a component now known
as infrared radiation (4).
These three components of the solar spectrum—UV, visible, and infrared—are referred to
collectively as optical radiation. But it is the UV rays, comprising about 5% of terrestrial
sunlight, which hold the greatest interest in photodermatology.
WAVELENGTH RANGES
Ultraviolet Radiation
UV radiation covers a small part of the electromagnetic spectrum. Other regions of this spec-
trum include radio waves, microwaves, infrared radiation (heat), visible light, X-rays, and
gamma radiation. The feature that characterizes the properties of any particular region of
the spectrum is the wavelength of the radiation. UV radiation spans the wavelength region
from 400 to 100 nm. Even in the UV portion of the spectrum the biological effects of the radi-
ation vary enormously with wavelength, and for this reason the UV spectrum is further sub-
divided into three regions. The notion to divide the UV spectrum into different spectral
regions was first put forward at the Copenhagen meeting of the Second International Congress
on Light held during August 1932 by Coblentz (5), using the transmission properties of three
Incident radiation
Skin optics
Radiation absorption
Photochemical reactions
Cellular changes
Clinical response
FIGURE 1 Pathways in skin photobiology.
Basic Principles of Photobiology 17
TABLE 1 Wavelength Ranges and Perception of Color

Color Wavelength range (nm)
Red 700– 610
Orange 610– 590
Yellow 590– 570
Green 570– 500
Blue 500– 440
Violet 440– 400
common glass filters. A barium-flint filter defined the UVA (315 – 400 nm); a barium-flint-pyrex
filter the UVB (280 – 315 nm); and a pyrex filter defined the UVC (wavelengths shorter than
280 nm). So, the basis of these divisions has its grounding in physics, and not biology. Although
these are the official designations of the Commission Internationale de l’Éclairage (CIE), other
authorities, especially in the biological and clinical sciences, use different definitions such as
UVA (320 – 400 nm), UVB (290 – 320 nm), and UVC (200 – 290 nm).
The division between UVB and UVC is chosen as 290 nm since UV radiation at shorter
wavelengths is unlikely to be present in terrestrial sunlight, except at high altitudes. The
choice of 320 nm as the division between UVB and UVA is perhaps more arbitrary. Although
radiation at wavelengths shorter than 320 nm is generally more photobiologically active than
longer wavelength UV, advances in molecular photobiology indicate that a subdivision at
330 – 340 nm may be more appropriate and for this reason the UVA region has, more recently,
been divided into UVA-1 (340 –400 nm) and UVA-2 (320 –340 nm).
Visible Radiation
Visible radiation, or light, is increasingly used in phototherapy as illustrated in section V of this
book. The visible spectrum is the portion of the optical radiation spectrum that is visible to the
human eye. A typical human eye will respond to wavelengths from 400 to 700 nm, although
some people may be able to perceive wavelengths from 380 to 780 nm. A light-adapted eye
typically has its maximum sensitivity at around 555 nm, in the green region of the optical spec-
trum. The wavelength ranges associated with the perception of different colors of visible light
are listed in Table 1.
It has been common practice in photomedicine to talk of ultraviolet light (UVL). This is
incorrect; the term “light” should be reserved for those wavelengths of radiation that reach
the retina and result in a sensation of vision. The correct term is UVR.
ENERGY AND WAVELENGTH

Electromagnetic radiation is so named due to the electric and magnetic properties of the wave.
These two properties propagate at right angles to one another in a sinusoidal manner at the
velocity of light, usually represented by the symbol c and equal to 3 108 ms21. The waves
obey the general form:
c ¼ nl
where n is the frequency of the radiation (in s21) and l is the wavelength of the radiation (in m),
that is the distance between successive troughs or peaks on the wave.
Although it is most often useful to think of electromagnetic radiation as a wave, the
radiation can also demonstrate particulate nature as well. By using a particle theory, electro-
magnetic radiation can be examined as if it were composed of small particles of energy
called quanta or photons. The energy (Q Joules) of each quanta or photon is expressed by
Planck’s law and is given by:
Q ¼ hn
where h is Planck’s constant (6.63 10234 Js). By combining the two equations it becomes clear
how the principles apply to one another.
Q ¼ hc=l
It can clearly be seen that the energy of each quanta of radiation is inversely proportional
to the wavelength; the longer the wavelength the smaller the energy content.
Planck’s law is applied if we need to know, for example, how many photons cause mild
erythema in whole body narrow-band UVB (TL01) phototherapy. These lamps emit an approxi-
mate monochromatic spectrum at a wavelength of 311 nm. The UV dose to result in mild
erythema from the lamps is typically 0.7 Jcm22, and the body surface area of a “standard”
adult male is 1.73 m2. Hence, the total energy incident over the body surface when mild
erythema results is:
0:7 Jcm2 17,300 cm2 ¼ 1:21 104 J
From Planck’s law we calculate that the energy of one photon having a wavelength of
311 nm is:
½6:63 1034 3 108 =½311 109 ¼ 6:4 1019 J
So the number of photons over the body surface is simply:
1:21 104 =6:4 1019 , which equals 2 1022 :
. Approximately 10% of radiation of wavelength 311 nm incident on the skin will be trans-
mitted to the dermis, so more than 1000 million, million, million photons reach the dermis
during a single session of narrow-band UVB phototherapy.
PRODUCTION OF OPTICAL RADIATION

Artificial sources of incoherent (i.e., nonlaser) optical radiation may be produced either by
heating a body to an incandescent temperature or by the excitation of a gas discharge. The
most common source of incandescent optical radiation is the sun, and although there are arti-
ficial incandescent sources such as the quartz halogen lamps, in general, they are not efficient
emitters of the UV component of optical radiation. For this reason, the most usual way to
produce UVR artificially is by the passage of an electric current through a gas, usually vapor-
ized mercury. Examples of lamps that emit incoherent UVR include low- and high-pressure
mercury arc lamps, fluorescent lamps, metal halide lamps, and xenon arc lamps. Further
details of optical radiation sources are given in Chapter 3.
Spectral Power Distribution

It is common practice to talk loosely of “UVA lamps” or “UVB lamps.” However, such a label
does not characterize adequately the UV sources since nearly all lamps (as well as the sun) used
in photobiology will emit both UVA and UVB, and sometimes even UVC, visible light, and
infrared radiation. The only correct way to specify the nature of the emitted radiation is by
reference to the spectral power distribution. This is a graph (or table) that indicates the radiated
power as a function of wavelength. An example of the spectrum of European summer daylight
is shown in Figure 2.
QUANTITIES AND UNITS

The two most common dosimetric terms found in photodermatology are irradiance and dose.
Irradiance refers to the intensity of radiation incident on a patient and is normally expressed in
units of milliwatts per square centimeter (mWcm22). Dose is the time integral of the irradiance
and is normally expressed in Joules per square centimeter (Jcm22). The term dose, commonly
FIGURE 2 The spectrum of European summer daylight. Source: Adapted from Ref. 35.
found in the dermatological literature, is rather loose and more strictly should be termed
radiant exposure or exposure dose.
The most frequent radiometric calculation is to determine the time for which a patient (or
other object), who is prescribed a certain dose (in Jcm22), should be exposed when the dosi-
meter indicates irradiance in mWcm22. The relationship between these three quantities
(time, dose, and irradiance) is simply:
1000 Prescribed dose (Jcm2 )
Exposure time (min) ¼
60 Measured irradiance (mWcm2 )
Although radiometric terminology is widely used in photobiology, the units chosen vary
throughout the literature. For example, exposure doses may be quoted in mJcm22 or kJm22.
Table 2 summarizes the equivalence of these units.
Standard Erythema Dose and Minimal Erythema Dose

The problem of dosimetry in photodermatology lies in the fact that the ability of UV radiation to
elicit erythema (and other clinical end-points) in human skin depends strongly on wavelength,
encompassing a range of four orders of magnitude between 250 and 400 nm (see section
“Action Spectra”) . Thus, a statement that a subject received an exposure dose of 1 Jcm22 of
UV radiation conveys nothing about the consequences of that exposure in terms of erythema.
If the radiation source were a UVA fluorescent lamp, no erythemal response would be seen
apart from in people exhibiting severe, abnormal pathological photosensitivity. The same
dose delivered from an unfiltered mercury arc lamp or fluorescent sunlamp would result in
marked erythema in most white-skinned individuals. Consequently, there is often a need to
express the exposure as an erythemal weighted quantity.
It has been common practice for many years to use the term minimal erythema dose
(MED) as a “measure” of erythemal radiation. This is absurd because the MED is not a standard
measure of anything but, on the contrary, encompasses the variable nature of individual
sensitivity to UV radiation.
TABLE 2 Equivalent Radiometric Quantities

To convert from To Multiply by
Jcm22 mJcm22 103
Jcm22 Jm22 104
Jm22 mJcm22 107
kJm22 Jcm22 107
kJm22 mJcm22 1010
TABLE 3 A Classification of Skin Phototypes Based on Susceptibility to Sunburn in Sunlight, Together with
Indicative Minimal Erythema Doses That Might be Expected Following UV Exposure on Unacclimatized Skin
UV exposure (in SED)
Skin Sunburn Tanning Classes of that results in a minimal
phototype susceptibility ability individuals erythema (i.e., 1 MED)
I Always burn No tan Melano-compromised 1 –3
II High Light tan
III Moderate Medium tan Melano-competent 3 –7
IV Low Dark tan
V Very low Natural brown skin Melano-protected 7 –.12
VI Extremely low Natural black skin
Abbreviations: SED, standard erythema dose; MED, minimal erythema dose.
The MED is generally determined by exposing adjacent areas of skin to increasing doses
of radiation (usually employing a geometrical series of dose increments) and recording the
lowest dose of radiation to achieve minimal erythema at a specified time, usually 24 hours,
after irradiation. The difficulty in judging a minimal erythema response accurately is reflected
by the varying definitions proposed for this value; these range from the dose required to initiate
a just perceptible erythema (6), to that dose which will just produce a uniform redness with
sharp borders (7). The former end-point has been shown to be more reproducible and less
prone to interobserver differences (8).
To avoid further confusing abuse of the term MED, it has been proposed (9) that this term
be reserved solely for observational studies in humans and other animals. The term standard
erythema dose (SED) should be used to refer to erythemal effective exposure doses from
natural and artificial sources of UV radiation; 1 SED is equivalent to an erythemal effective
exposure dose of 100 Jm22 (10).
A classification of skin phototypes based on susceptibility to sunburn in sunlight (11),
together with indicative MEDs (expressed in SEDs) that might be expected following exposure
on unacclimatized skin, is given in Table 3.
DOSE AND DOSE RATE EFFECTS

Experiments in which the photoresponse of a material is investigated as a function of irradiance
(or dose rate) are commonly called reciprocity law experiments. Bunsen and Roscoe (12) are
credited with conducting the first reciprocity law experiments. Reciprocity holds in photobiol-
ogy when the observable response depends only on the total administered dose and is indepen-
dent of the two factors that determine total dose, that is, irradiance and exposure time.
Since the reciprocity law depends only on total dose, its validation for a particular end-
point can have many experimental manifestations. Assuming that the reciprocity law is valid,
then each manifestation should be equivalent to the others as long as the integrated total dose is
the same. Thus, when the reciprocity law is obeyed, the same photobiological response is
observed when specimens receive the same integrated total dose regardless as to whether
the exposure is performed.
These exposure regimes, as shown in Figure 3, are adapted from a similar representation
given by Forbes et al. (13).
A summary of reciprocity experiments carried out in human and mouse skin are
reviewed by Martin et al. (14). In every case, reciprocity for erythema was shown to hold. Of
particular relevance to phototherapy, where exposure times will vary from a few minutes up
to half-an-hour or so depending on the power and spectral output of the lamps, Meanwell
and Diffey (15) showed that exposure to polychromatic radiation for time periods ranging
from 1 second to 1 hour induced degrees of delayed erythema ranging from minimal to
marked that depended only on dose and not dose rate. These findings both support and
extend those of previous studies in which the end point was confined to minimal erythema.
On the other hand, reciprocity has been shown not to hold in UV-induced carcinogenesis
where, in general, for a fixed dose of UV radiation the carcinogenic effectiveness increases as
the irradiance decreases or is fractionated (16– 18).
Irradiance
Irradiance
(A) (B)
Time Time
Irradiance
Irradiance
(C) (D)
Time Time
FIGURE 3 A selection of irradiance versus exposure time regimes for testing the law of reciprocity in which the
integrated areas (i.e., dose) for each exposure regime are identical. When the reciprocity law is obeyed, the
photoresponse for each of these exposure regimes is the same. (A) At a high irradiance for a short period of time.
(B) At a low irradiance for a long period of time. (C) By repeatedly switching a radiation source on-or-off and
controlling both the on-off frequency of the radiation and the length of time that the radiation remains in the on and
the off state. Experiments in which the radiation is turned on-and-off at an extremely high frequency are called flash
photolysis experiments, whereas experiments in which the radiation is turned on-and-off at a low frequency are
called intermittency experiments. (D) By ramping the irradiance to a high level, holding the irradiance for a specified
period of time, and then ramping it back down to a lower level or any variant of these stress regimes.
ABSORPTION OF UV AND VISIBLE RADIATION BY MOLECULES IN SKIN

UV and visible photons enter the skin where they may be absorbed by molecules in the epider-
mis and dermis or scattered by structures, such as collagen fiber bundles. The first process,
absorption, initiates acute and chronic responses in skin because the photon energy is trans-
ferred to molecules in cells, which then undergo chemical changes (Fig. 1). Only photons
that are absorbed can initiate biological and clinical responses. The second process, scattering,
influences the depth that photons of different wavelengths penetrate into the epidermis and
dermis. These effects are discussed under the topic of “Skin Optics” in chapter 3.
Absorption Spectra
Each type of molecule in skin, for example, an amino acid, a nucleotide, or a porphyrin, absorbs
a unique combination of wavelengths and is generally referred to as a chromophore. Some
chromophores absorb only UVB, some absorb both UVB and UVA, and others absorb through-
out the UV and visible wavebands. These differences in absorption characteristics between
biomolecules underlie the diverse effects produced when skin is exposed to different wave-
bands. In addition, information about the absorption spectra of chromophores is needed to
identify the wavelengths and radiation sources that are most appropriate for UV phototherapy
or photodynamic therapy (PDT). Thus, it is important to learn more about the relationship
between molecules and the wavelengths they absorb.
The structure of a molecule, that is, the arrangement of the atoms and the distribution of
electrons around this framework, strongly influence which wavelengths of UVor visible radiation
are absorbed. The chemical structure also determines the probability of absorption of photons at
each wavelength, that is, how much radiation is absorbed as a function of wavelength. A plot of the
probability of absorption of photons against the wavelength is called an absorption spectrum. The
wavelengths that are absorbed with the highest probability are called absorption maxima.
0.6
melanin
0.5
Absorption, uncorrected
protoporphyrin IX
0.4 7-DHC
0.3 protein
NADH
0.2 DNA
beta-carotene
0.1
(A) 0
300 320 340 360 380 400
Wavelength (nm)
1
beta-carotene
Absorption, uncorrected
0.8
FIGURE 4 Absorption spectra of chromophores

0.6 in skin. (A) Spectra of molecules in skin absorbing
in the UVB and UVA ranges. (B) Spectra of mol-
bilirubin ecules in skin absorbing in the visible range.
0.4
riboflavin Note that many molecules absorb in more than
melanin one wavelength range. The relative heights of
0.2 the absorption peaks in this figure do not
protoporphyrin IX indicate the relative amounts of radiation absor-
bed by these chromophores in skin. The actual
(B) 0 amount of radiation absorbed by each chromo-
400 450 500 550 600 650 700 phore is related to the amount of the present
Wavelength (nm) in skin.
Examples of absorption spectra for some of the chromophores in skin are shown in Figure 4.
The aromatic amino acids in proteins, in particular tryptophan and tyrosine, absorb UVB radi-
ation. The purine and pyrimidine bases in DNA and RNA are also important UVB-absorbing chro-
mophores for cutaneous responses. The 7-dehydrocholesterol (7-DHC) absorbs UVB and is one of
the few chromophores that initiate the beneficial effects of sunlight on skin. The absorption
maxima for these UVB-absorbing chromophores are actually in the UVC range and consequently
are not shown in Figure 4A. In fact, most chromophores absorb in more than one spectral range.
Some examples are NADH that has an absorption maximum at about 340 nm, but also absorbs
UVB radiation (Fig. 4A), b-carotene that has absorption maxima at about 465 and 490 nm in the
visible, but also absorbs in the UV range (Fig. 4B), and protoporphyrin IX that has an absorption
maximum at about 405 nm, but also absorbs UVA strongly (Fig. 4B). The NADH is shown as an
example of a UVA chromophore, but many others are also present in cells. Certain drugs
causing phototoxicity, such as tetracyclines and fluorinated quinolones, also absorb UVA
radiation. Other endogenous chromophores absorbing visible light include riboflavin, hemo-
globin, and bilirubin. The photosensitizing dyes used in PDT generally absorb at longer visible
wavelengths (.650 nm) (see chap. 25). Melanin is unique since it absorbs throughout the UVB,
UVA, and visible wavebands without an absorption maximum.
The spectra in Figure 4 are intended to show only the distribution of wavelengths
absorbed by various chromophores and not their relative absorption of UVR and visible
light in skin. The amount of radiation actually absorbed by these molecules in skin is
related to the amount of each chromophore present. For example, DNA absorbs much
more of the UVB radiation incident on skin than 7-DHC because it is present at a much
greater concentration than 7-DHC.
Excited States of Biomolecules

When a molecule absorbs the energy of a UV or visible photon, it becomes an “excited state,” a
higher energy state of the molecule. Originally, the molecule was in the so-called “ground
state,” where the electrons have a certain distribution around the framework of nuclei that
make up the structure of the molecule. The electron distribution, but not the nuclear frame-
work, changes when the molecule absorbs the photon energy. The principles of quantum mech-
anics allow only certain energy gaps between the ground state and the excited state.
Consequently, each molecule can only absorb photons with certain energies. Since the
photon energy is inversely related to the wavelength, each unique chromophore has a
unique absorption spectrum. A signature property of excited states is their brief lifetime.
Each excited state exists for only a very short period before returning to the ground state by
giving off light or heat or by undergoing chemical reactions.
The first excited state formed is called a singlet-excited state. It typically exists for only a
few nanoseconds (ns, 1029 s). Most singlet-excited states return to the ground state by emitting
the excess energy as fluorescence or releasing the energy as heat, a process called internal con-
version (Fig. 5). Fluorescence is used in diagnosis, for example, for the presence of porphyrins
in the urine of certain porphyria patients. Another example is the emission observed when
using a Wood’s lamp to examine skin pigmentation. The blue light observed is fluorescence
from components in the dermal collagen. The heat generated by the return of singlet-excited
states to the ground state is not usually apparent. The exception is when a laser with short,
intense pulses is used. In this case, many chromophores are excited to the singlet state at the
same time and give off their energy as heat when returning to the ground state almost simul-
taneously. This is the basis for the thermal effects produced during laser treatments as
discussed in chapter 26.
The singlet-excited state of a chromophore in skin can undergo photochemical reactions,
thereby initiating responses in cells as discussed subsequently (Fig. 5). Alternatively, the
singlet-excited state may convert into a triplet-excited state, which is more stable and exists
for a somewhat longer period, that is, a few microseconds (ms, 1026 s). Singlet- and triplet-
excited states differ by the “spins” of a pair of electrons. Spin is a quantum mechanical property
of electrons in molecules. If the spins of the pair of electrons are opposite, the molecule is a singlet
state. If the spins are the same, the molecule is a triplet state. Similar to the singlet-excited state,
the triplet-excited state can give off excess energy as optical radiation (phosphorescence), as heat
singlet
excited
state
triplet
excited
state
internal conversion
internal conversion
photochemistry
phosphorescence
fluorescence
absorption
photochemistry
ground
state
FIGURE 5 Energy levels and photoprocesses of a molecule (modified Jablonski diagram). The ground state molecule
absorbs the energy of a photon to form the excited singlet state (red arrow). The excited singlet state then either
releases the energy as light (fluorescence; blue) or as heat (internal conversion; purple), undergoes a chemical
reaction, or converts into a triplet excited state. The triplet excited state releases energy as light (phosphorescence;
orange) or heat (internal conversion; purple) or undergoes a chemical reaction (including energy transfer).
(internal conversion), or can undergo photochemical reactions, including energy transfer to

oxygen as described subsequently (Fig. 5).
Photochemical reactions of excited-state molecules are the processes of greatest interest in
photodermatology because the products formed initiate cellular changes that subsequently
lead to clinical responses (Fig. 1). However, some molecules that absorb in the UVR
and visible wavelength ranges very rarely undergo photochemical reactions. Hemoglobin
and b-carotene are two examples.
The efficiency of any of the processes of excited states is described in terms of a quantum
yield. The quantum yield is simply the ratio of the number of events, for example, number of
photons of fluorescence emitted, to the number of photons absorbed.
PHOTOCHEMICAL REACTIONS LEADING TO CELL RESPONSES

A photochemical reaction converts the chromophore into a new molecule with a different struc-
ture called a photoproduct. In some cases, the photochemical reaction only changes the
structure of the chromophore (unimolecular reaction) and in other cases an additional molecule
is changed (bimolecular reaction). An example of the former type is the photochemistry of
7-DHC. After absorbing a photon of UVB radiation, 7-DHC is transformed into previtamin
D3 by a rearrangement of some of the carbon – carbon bonds in its structure. Previtamin
D3 then undergoes another bond-switching rearrangement in the dark to form vitamin D3,
which is transported from the skin bound to vitamin D-binding protein (19). Further biochemi-
cal modifications produce the active forms of vitamin D. Thus, in contrast to other
UVR-induced clinical effects, the responses to 7-DHC photochemistry in the skin occurs at a
distant body sites.
DNA Photochemistry
Most photoproducts that initiate clinical responses arise from bimolecular reactions. A very
important example is the formation of photoproducts along the DNA strands after absorption
of UVB radiation in keratinocytes. These photoproducts are responsible for the mutations that
initiate skin cancer as well as being involved in UVB-induced immune suppression, tanning,
and sunburn. The excited-singlet states of purine and pyrimidine bases in DNA are extremely
short-lived (,0.1 ns). Even in this short time however, the excited singlet state of a pyrimidine
base (thymine or cytosine) can react with another pyrimidine base adjacent to it on a strand of
DNA. Covalent bonds are formed between two carbons on each of the pyrimidines and the
photoproduct is a cyclobutyl pyrimidine dimer (CPD). The CPD is stable and, unless accurately
repaired by specific repair enzymes, leads to a change in the sequence of DNA bases and, con-
sequently, a mutation. Another product, called a 6-4 photoproduct, is also formed between two
adjacent pyrimidine bases and is similarly mutagenic. Specific mutations that are signatures for
CPD and six to four photoproducts are found in most nonmelanoma skin cancers. The skin
responses to these DNA photoproducts are discussed in detail in section II.
Bimolecular photoreactions between a psoralen and pyrimidine nucleotides initiate the
phototoxic and phototherapeutic effects of psoralens. In this case, psoralen molecules that
are intercalated into double-stranded DNA absorb UVB and UVA radiation. The psoralen
excited state molecules react with thymine and cytosine to form cyclobutyl ring structures,
not unlike those in CPD. When the psoralen is positioned in the appropriate DNA sequences,
two cyclobutyl structures may form after two photons are absorbed resulting in a psoralen
crosslink between the two strands of DNA. Chapters 23 and 24 discuss the responses of skin
to the formation of psoralen photoproducts.
Photosensitization
In skin responses initiated by photosensitization reactions, the mechanism frequently involves
transfer of energy from the excited triplet state of the chromophore molecular oxygen that is
dissolved in the cell. The chromophore is referred to as a photosensitizer. The oxygen molecule
that has accepted the energy becomes an excited singlet state, “singlet oxygen.” Notice that the
ground state photosensitizer is regenerated after the energy transfer to oxygen.
1
! Photosensitizer þ
Photosensitizer þ O2 O2
Excited triplet state Ground state Singlet oxygen
Consequently, the same photosensitizer can recycle many times, typically .1000 times,
generating a singlet oxygen with each cycle. This cycle is at least partially responsible for the
high efficiency of photosensitization involving a singlet oxygen mechanism. Protoporphyrin
IX is the photosensitizer for the photosensitivity associated with EPP. When cells containing
protoporphyrin IX are exposed to blue light, singlet oxygen is produced that causes lipid per-
oxidation. A subsequent series of biochemical steps leads to the immediate smarting, erythema
and whealing produced by sunlight on skin of EPP patients (see chap. 15). Singlet oxygen is
also formed after PDT agents absorb longer wavelengths, for example, red light, and is believed
to initiate oxidation reactions that cause cytotoxicity to tumor cells (see chap. 25). In addition,
UVA-induced responses, such as apoptosis of lymphocytes in certain inflammatory skin dis-
eases, are believed to be initiated by formation of singlet oxygen, although the UVA-absorbing
chromophores have not been identified (20).
Singlet oxygen exists for less than 4 ms in cells, which limits the distance it can move to
less 200 nm (21). Consequently, it oxidizes nearby cellular molecules. For example, protopor-
phyrin IX, many PDT dyes and other photosensitizers localize at least partially in cell mem-
branes and oxidize unsaturated lipids in the membranes to form hydroperoxides. These
oxidized lipids react further in the dark, often in chain reactions, to amplify the oxidizing
effect initiated by singlet oxygen. Similarly, PDT dyes that localize in mitochondria photosen-
sitize damage to mitochondrial components and initiate apoptosis (22). Oxidation of guanine in
DNA forms specific oxidation products that are mutagenic. Certain amino acid side chains in
proteins (histidine, tyrosine, tryptophan, cysteine, and methionine) and other peptides, for
example, glutathione, are also highly susceptible to oxidation by singlet oxygen. Formation
of oxidation products in these molecules by photosensitization with UVA or visible radiation
generates oxidative stress in cells. Oxidative stress produces many responses by initiating
signal transduction pathways, leading to activation of transcription factors and enhanced
gene expression. For example, the oxidative stress induced by singlet oxygen after UVA
irradiation initiates a signaling pathway, leading to production of IL-1 and IL-6 and
subsequently to production of interstitial collagenase by dermal fibroblasts (23).
ACTION SPECTRA
The wavelength dependency of a given photobiological effect is demonstrated by its action
spectrum, which depends principally on the absorption spectrum of the chromophore and
1
Relative effectiveness
0.1
0.01
0.001
0.0001 FIGURE 6 The Commission Internationale de l’Éclairage

250 275 300 325 350 375 400 (CIE) (1987) reference action spectrum for erythema in
human skin (red), and the CIE (2000) action spectrum
Wavelength nm for photocarcinogenesis (blue).
the optical properties of the skin (24). Conventionally in dermatology, the reciprocal of the dose
required to produce a given end-point is plotted against wavelength to obtain an action spec-
trum. Action spectroscopy and studies with different broad-spectrum sources show that UVB
is much more effective than UVA for most endpoints studied in human skin. These include
erythema (25 –27), delayed pigmentation (28), DNA photodamage (29), urocanic acid photoi-
somerization (30), and nonmelanoma skin cancer (31,32). An example of two of these action
spectra is given in Figure 6.
In general, UVB is three to four orders of magnitude more effective per unit physical dose
(Jcm22) than UVA, but one exception is the action spectrum for immediate pigment darkening
(IPD) where UVA is more effective than UVB (33).
Knowing the action spectrum of a patient’s photosensitivity can be helpful in determin-
ing their management. This can be especially useful in drug-induced photosensitivity (34). In
addition, phototherapy will be most efficient when the emission of the lamp most closely
matches the action spectrum for the beneficial response.
REFERENCES
1. Magnus IA. Dermatological Photobiology. Oxford: Blackwell Scientific Publications, 1976:3.
2. Newton I. A new theory about light and colours. Phil Trans R Soc Lond 1672; 6:3075– 3087.
3. Ritter JW. Physisch-Chemische Abhandlungen, Vol. 2. Leipzig: 1801.
4. Herschel W. Experiments on the refrangibility of invisible rays of the sun. Phil Trans R Soc Lond 1800;
90:255– 326.
5. Coblentz WW. The Copenhagen meeting of the Second International Congress on Light. Science 1932;
76:412.
6. Epstein JH. Polymorphous light eruptions. Wavelength dependency and energy studies. Arch
Dermatol 1962; 85:82– 88.
7. Willis I, Kliginan AM. Aminobenzoic acid and its esters. Arch. Dermatol 1970; 102:405-417.
8. Quinn AG, Diffey BL, Craig PS, Farr PM. Definition of the minimal erythema dose used for diagnostic
phototesting. Br J Dermatol 1994; 131:56.
9. Diffey BL, Jansen CT, Urbach F, Wulf HC. The standard erythema dose: a new photobiological
concept. Photodermatol Photoimmunol Photomed 1997; 13:64– 66.
10. CIE Standard. Erythema reference action spectrum and standard erythema dose. CIE S 007/E-1998.
Vienna: Commission Internationale de l’Éclairage, 1998.
11. WHO World Health Organization. Artificial tanning sunbeds—risks and guidance. Geneva, 2003.
12. Bunsen RW, Roscoe HE. The laws of photochemical action. Phil Trans R Soc Lond 1859; 149:876– 926.
13. Forbes PD, Davies RE, Urbach F. Aging, environmental influences, and photocarcinogenesis. J Invest
Dermatol 1979; 73:131– 134.
14. Martin JW, Chin JW, Nguyen T. Reciprocity law experiments in polymeric photodegradation: a criti-
cal review. Prog Org Coat 2003; 47:292– 311.
15. Meanwell EF, Diffey BL. Reciprocity of ultraviolet erythema in human skin. Photodermatology 1989;
6:146-148.
16. Forbes PD, Blum HF, Davies RE. Photocarcinogenesis in hairless mice: dose – response and the
influence of dose – delivery. Photochem Photobiol 1981; 34:361– 365.
17. de Gruijl FR, van der Leun JC. Effect of chronic UV exposure on epidermal transmission in mice.
Photochem Photobiol 1982; 36:433– 438.
18. Kelfkens G, van Weelden H, de Gruijl FR, van der Leun JC. The influence of dose rate on ultraviolet
tumorigenesis. J Photoch Photobio B 1991; 10:41– 50.
19. Holick MF. Environmental factors that influence the cutaneous production of vitamin D. Am J Clin
Nutr 1995; 61 (suppl. 3):638– 645S.
20. Morita A, Werfel T, Stege H, et al. Evidence that singlet oxygen-induced human T helper cell apop-
tosis is the basic mechanism of ultraviolet-A radiation phototherapy. J Exp Med 1997; 186:1763 –1768.
21. Snyder JW, Skovsen E, Lambert JD, et al. Subcellular, time-resolved studies of singlet oxygen in single
cells. J Am Chem Soc 2005; 127:14,558 –14,559.
22. Xue LY, Chiu SM, Fiebig A, et al. Photodamage to multiple Bcl-xL isoforms by photodynamic therapy
with the phthalocyanine photosensitizer Pc 4. Oncogene 2003; 22:9197– 9204.
23. Wlaschek M, Wenk J, Brenneisen P, et al. Singlet oxygen is an early intermediate in cytokine-depen-
dent ultraviolet-A induction of interstitial collagense in human dermal fibroblasts in vitro. FEBS Lett
1997; 413:239– 242.
24. Young AR. Chromophores in human skin. Phys Med Biol 1997; 42:789– 802.
25. Anders A, Altheide H.-J, Knälmann M, Tronnier H. Action spectrum for erythema in humans
investigated with dye lasers. Photochem Photobiol 1995; 61:200– 205.
26. Diffey BL. Observed and predicted minimal erythema doses: a comparative study. Photochem
Photobiol 1994; 60:380– 381.
27. CIE Standard. Erythema reference action spectrum and standard erythema dose. CIE S 007/E-1998.
Vienna: Commission Internationale de l’Éclairage, 1998.
28. Parrish JA, Jaenicke KF, Anderson RR. Erythema and melanogenesis action spectra of normal human
skin. Photochem Photobiol 1982; 36:187– 191.
29. Young AR, Chadwick CA, Harrison GI, Nikaido O, Ramsden J, Potten CS. The similarity of
action spectra for thymine dimers in human epidermis and erythema suggests that DNA is the
chromophore for erythema. J Invest Dermatol 1998; 111:982– 988.
30. McLoone P, Simics E, Barton A, Norval M, Gibbs NK. An action spectrum for the production of
cis-urocanic acid in human skin in vivo. J Invest Dermatol 2005; 124:1071– 1074.
31. de Gruijl FR. Action spectrum for photocarcinogenesis. Recent Results Cancer Res 1995; 139:21– 30.
32. Commission Internationale de l’É clairage, Vienna. CIE 132/2; TC 6-32 report: action spectrum for
photocarcinogenesis (non-melanoma skin cancers) 2000.
33. Irwin C, Barnes A, Veres D, Kaidbey K. An ultraviolet radiation action spectrum for immediate
pigment darkening. Photochem Photobiol 1993; 57:504– 507.
34. Diffey BL, Farr PM. The action spectrum in drug induced photosensitivity. Photochem Photobiol
1988; 47:49– 54.
35. Ensminger PA. Life Under the Sun. Yale University Press, 2001.
3 Radiation Sources and Interaction
with Skin
Harvey Lui
Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute,
University of British Columbia, Vancouver, British Columbia, Canada
R. Rox Anderson
Wellman Center for Photomedicine and Department of Dermatology, Harvard Medical School,
and Massachusetts General Hospital, Boston, Massachusetts, U.S.A.
B Radiation refers to the transfer of energy as waves and particles, and

can be depicted on an electromagnetic spectrum.
B Quantum theory forms the basis for explaining why each photobiologic
event can be energized by only certain forms of light; this in turn, dictates
the need for many different types of radiation sources.
B Radiation sources encountered in dermatology include the sun and
medical devices that transform electrical power into specific forms of
light.
B Incandescent light is produced by heating tungsten filaments with
electricity.
B Fluorescent lamps produce radiation through low-pressure mercury
vapor lamps that are coated with fluorescing phosphors.
B Lasers generate intense, monochromatic, coherent light by amplifying
stimulated emission of radiation within specially configured optical
cavities.
B Light emitting diodes generate radiation by passing current through
semiconductor bilayers.
B The output spectrum of the radiation source should closely match the
absorption or action spectrum in order to have an efficient photobiologic
event.
30 Lui and Anderson
RADIATION AS A FORM OF ENERGY: THE ELECTROMAGNETIC SPECTRUM

adiation refers to the transfer of energy in the form of both electromagnetic oscillations
R and particles. According to wave theory, radiation is propagated through space as oscil-
lations that have frequency and wavelength. Radiation waves can be further character-
ized as being electromagnetic since they are composed of two orthogonal oscillatory waves
carrying electric and magnetic components. When electromagnetic radiation interacts with
matter, it exhibits particle-like behavior since its interactions with molecules are restricted to
discrete packets of energy called photons. The energy of a photon is directly proportional
to the frequency and inversely proportional to the wavelength of its simultaneous existence
as a wave.
Electromagnetic radiation exists on a continuum that can be depicted as a spectrum
(Fig. 1). While radiation can be characterized in terms of its physical properties (i.e., wave-
length, frequency, photon energy), it is more relevant to parse it according to its biologic
effects. Also keep in mind that even though radiation basically represents energy, by conven-
tion, the various forms of radiation are numerically distinguished and categorized according to
wavelength rather than by frequency or even photon energy. The ultraviolet (UV), visible, and
infrared (IR) regions of the electromagnetic spectrum are the most relevant for human photo-
biology, and the photon energy from these wavebands is sufficient to induce electronic and
vibrational energy transitions within molecules. Radiation sources that emit these wavebands
are therefore capable of driving covalent chemical reactions and/or producing heat. The indi-
vidual subdivisions of the electromagnetic spectrum are so named on the basis of their biologic
effects. The term “light” is sometimes restricted to electromagnetic radiation that is visible to the
human eye (i.e., 400 700 nm), but it is not uncommon for the entire region from UV through IR
to be referred to interchangeably as either light or radiation, as in this chapter. The UV region is
further subdivided into UVC, UVB, and UVA. The 290 mm cut off between UVC and UVB
defines the lower limit of UV light that reaches the earth’s surface, while the 320 nm boundary
between UVB and UVA separates terrestrial UV light that is either more (UVB) or less (UVA)
efficient at inducing cutaneous erythema.
Within molecules, energy transformations can occur only between discontinuous levels
known as quanta; these levels are, to some extent, like the individual steps of a staircase.
The interaction between matter and a photon is a phenomenon that is either all or none, and
absorption will occur only if a photon’s energy exactly matches the quantum difference or
step that corresponds to a specified molecular transition. The requirement that energy be trans-
ferred only through the absorption of specific photons is dictated by quantum mechanics, and
this principle explains why only certain wavelengths of light can induce any given photo-
biologic skin reaction, even though all light sources serve as sources of energy. Thus, in photo-
dermatology it is the quantum laws of physics that fundamentally drive the need for a wide
array of different radiation sources.
Increasing photon energy
Radio
X-Ray UVC UVB UVA Visible Infrared
waves
100 290 320 400 800 17,000
Increasing wavelength (nm)
FIGURE 1 The electromagnetic spectrum.

Radiation Sources and Interaction with Skin 31
RADIATION SOURCES
There is one natural radiation source, which sustains all life on our planet, and multiple
artificial devices that generate radiation to either mimic the output of the sun or isolate only
certain specific wavebands.
NATURAL LIGHT FROM THE SUN

Sunlight represents the ultimate source of life and energy on this planet, yet excessive exposure
to solar energy is clearly deleterious to biologic systems. For humans the correct balance of light
exposure necessary for health maintenance varies dramatically between individuals based on
skin phenotype, presence of pathologic photosensitivity, and genetic factors. For otherwise
normal and healthy individuals, sunlight is necessary for promoting a psychological sense of
well being as well as providing the energy for endogenous vitamin D synthesis. On the
other hand, excessive sunlight leads to photoaging, immunosuppression, and photocarcino-
genesis. For certain dermatologic patients, sunlight can represent either the key pathogen
that precipitates a dermatosis (e.g., solar urticaria) or the means by which a skin condition
can be ameliorated or treated (e.g., psoriasis). Furthermore, as exemplified by polymorphous
light eruption, sunlight can also, paradoxically, serve as the inciting factor and also a means
for relief (i.e., natural hardening with repeated sunlight exposure).
Solar radiation reaching the earth’s surface includes UV, visible, and IR radiation between
290 and 4000 nm (Fig. 2). Terrestrial sunlight fluctuates dramatically not only in terms of overall
intensity but also in its spectral composition by time of day, elevation, and latitude. These
effects on spectral irradiance predominantly affect the UV component of the solar spectrum.
The quality and quantity of solar radiation vary depending on geography and time. In
certain locations and climates sunlight is sufficiently uniform and predictable to be an inexpen-
sive and readily available radiation source that may be sufficient for diagnostic or therapeutic
use. Judicious and controlled exposure to outdoor sunlight may be helpful for confirming sus-
pected cases of clinical photosensitivity. For treatment, natural light dosimetry is empiric, since
providing light meters to patients is impractical. Nevertheless, with natural sunlight, exposure
guidelines can be individualized to some extent by considering a person’s light tolerance in
terms of his/her sunburn propensity and the rate at which photoadaptation occurs.
ARTIFICIAL RADIATION
Artificial light can be made to closely mimic the sun or to isolate only certain parts of the UV to
IR spectrum (Table 1). Solar simulators fall in the former category and are used primarily in
investigational settings for diagnostic evaluation of suspected photosensitivity or sunscreen
evaluation (1).
100
Relative irradiance
80
60
40
20
200 300 400 500 600 700 1000 3000 5000

Wavelength (nm)
FIGURE 2 Terrestrial solar light spectral irradiance.

32 Lui and Anderson
TABLE 1 Important Wavebands and Therapeutic Radiation Sources in Dermatologya

Radiation source
b
Waveband Arc (gas discharge) Fluorescent Laser IPL LED
UV UVB broadband X X
UVB narrowband X X
UVA X X
UVA-1 X X
Visible Blue X
Green X X
Yellow X X
Red X X X X
IR X X
a
Incandescent lamps are not included in this table since their use as therapeutic devices is relatively uncommon in
dermatology.
b
Metal halide lamps are the most common form of arc-type radiator now in use.
Abbreviations: IPL, intense pulsed light; LED, light emitting diode.
All devices that produce artificial radiation feature a means for generating light, then
modifying the light in terms of its spectral properties, and finally delivering the light to the
skin over a uniform exposure field. Virtually all medical light devices generate radiation by
converting electrical energy into photon energy. Optical filters or specific fluorophores are
used to shape the desired spectral output of the source, while mirrors, lenses, and fibers are
used to direct the light to the target. There are a multitude of radiation sources available
and the choice of device depends on the specific clinical application, photobiologic mechanism,
and region of the skin that needs to be exposed. Cost and practicality must also be factored in.
Light sources in dermatologic use include incandescent lamps, arc lamps, fluorescent lamps,
lasers, and intense pulsed light; with the latter three now being the most commonly used
devices for irradiating the skin.
Incandescent Lamps
When a metallic object is heated it will glow and release light energy by a process known as
incandescence. In an incandescent light bulb, electric current is passed through a thin tungsten
filament, which generates heat and light due to electrical resistance. The spectral output and
intensity of the light bulb is dependent on the temperature that the filament achieves, with a
more luminous and whiter beam being produced at higher temperatures. Incandescent
lamps are relatively inefficient visible light sources, since much of the electrical energy is
used to generate heat, which in turn leads to filament evaporation and eventual bulb burn
out. The potential for filament failure thus limits the operating temperature, intensity, and spec-
tral quality of incandescent lamps. The life of a tungsten bulb can be extended by sealing the
filament in a quartz envelope that contains a halogen, such as bromine or iodine. This
allows the filament to be electrically driven to a higher temperature where there is a spectral
shift towards more energetic photons in the UV range without reducing the bulb’s lifetime.
These so-called quartz halogen lamps can emit a significant amount of UV, in addition to
visible and IR light. The final desired spectral output of a quartz halogen lamp is achieved
with optical filters that allow only certain wavebands to pass. For example, quartz halogen
bulbs that are used for general illumination are fitted with a glass covering over the bulb in
order to block UV. In clinical dermatology incandescent lamps have been primarily used in situ-
ations where visible light is required including photodynamic therapy, photo-testing, and nonin-
vasive optical diagnosis, such as reflectance spectroscopy. For example, conventional slide
projector lamps provide a convenient and uniform beam of visible light that can be used in diag-
nostic phototesting (2).
Arc Lamps
An arc lamp discharges light when high voltage is applied across two electrodes that are sealed
in a transparent envelope containing a gas, such as mercury or xenon. The electric current will
excite electrons within the gas, which then emits light as the gas returns to its physical ground
state. The “arc” refers to the plasma between the electrodes from which light radiates. The
specific gas determines the spectral output of the lamp. These lamps are also referred to as
gas discharge lamps. The output spectrum of a gas discharge lamp can be further modulated
by varying the gas pressure within the glass envelope. At higher pressures the spectral emis-
sion peaks broaden and start to approach an output that is more continuous (or “spectrally
neutral”) throughout its output range.
Historically, the first effective artificial light sources were arc lamps. Finsen, the father of
modern photomedicine who received the 1903 Nobel prize in medicine, used carbon arc lamps
for treating lupus vulgaris (3). The carbon electrodes would be heated by the arc and actually
emit light by incandescence. Because these electrodes would burn out with use, this form of
“electric light,” eventually, gave way to mercury vapor lamps, which were equipped with
quartz envelopes in order to allow UV transmission.
In a mercury vapor lamp, mercury is first ionized and vaporized to a gas by electrically
igniting an arc. As the lamp heats up more mercury vapor builds up to sustain the arc. The
spectral output corresponds to mercury’s quantum transitions as the excited electrons in the
arc return to their ground state. At low operating pressures of mercury, the spectral emission
is predominantly at the UV end of the spectrum with sharp lines corresponding to mercury’s
characteristic quantum transitions, especially 254 nm. When mercury arc lamps are operated at
progressively higher pressures and temperatures, the output shifts towards UVB and UVA
with some broadening of the spectral maxima that are centered around the mercury lines at
297, 302, 313, 334, and 365 nm. Both low and high (“cold” and “hot” quartz) pressure
mercury vapor lamps were used in dermatology prior to the widespread adoption of fluor-
escent tube technology. Although hot quartz lamps have a limited field size, they can probably
be considered as the first practical form of targeted phototherapy. More recently a “short arc
maximum pressure” mercury lamp has been developed for clinical use. This is a relatively
compact light source and because the arc is small, its output can be coupled to a UV transmit-
ting fiber or light guide, which then directs light to a specific skin-target area. Due to the very
high pressure within a short arc mercury lamp, the UV output is spectrally more broad and
continuous than a hot quartz lamp.
If a metal halide is added to mercury in a high pressure gas discharge lamp, additional emis-
sions between the mercury spectral lines are filled such that the output becomes virtually continu-
ous throughout the UV spectrum. These lamps can be equipped with specific long pass optical
filters to restrict the output to UVB plus UVA, UVA (broad spectrum), or UVA-1 (4). Metal
halide lamps are more expensive and cumbersome to operate than fluorescent lamp-based photo-
therapy units, but the higher output with metal halide allows for shorter treatment times.
For simulating solar radiation, xenon is used in arc lamps because its output spectrum
provides the best match to that of terrestrial sunlight. Xenon discharge lamps are the same
type of light source used for projecting movies in cinemas. Recently, a xenon chloride-based
excimer device (excimer ¼ excited dimer) with very narrow-band incoherent emission
(308 + 2 nm) centered at the XeCl spectral line has been introduced for delivering targeted
UV phototherapy. The therapeutic effect of this device would be expected to be similar to
the XeCl excimer laser. Technical details as to how light is generated from XeCl in this “mono-
chromatic excimer light” device have not yet been published, although nominally, it also has
15% of its output as UVA (5).
Fluorescent Lamps
Fluorescent radiation represents the re-emission of photons following light absorption by a
chromophore. The photons that are emitted by the chromophore are usually of a lower
energy than the incident photons that were initially absorbed, and thus are of a longer wave-
length. In the context of fluorescence, chromophores are more specifically referred to as
“fluorophores.”
Fluorescent light is most commonly produced within sealed cylindrical glass tubes con-
taining mercury. The primary radiation that is initially produced within a fluorescent lamp is
analogous to that emitted by a low-pressure mercury lamp. When electric current is applied to
34 Lui and Anderson
the ends of a fluorescent tube, the mercury is vaporized and excited to a higher energy level.
Upon relaxation of the mercury to its ground state, radiation is released at emission peaks
characteristic for mercury. This primary output is then transformed by fluorescence to
higher wavelengths. The inside of the tubes is coated with special fluorophores called phos-
phors. The radiation that is generated from the primary mercury emissions is absorbed by
the phosphors that coat the fluorescent tube. These phosphors will, in turn, re-emit light at
longer wavelengths than the main mercury emission of 254 nm. The fluorescence properties
of the specific phosphor coating determine the final output of the fluorescent lamp.
In dermatology, fluorescent lamps are by far the most common source of therapeutic
UV light. Different phosphors are used to produce light that is predominantly UVB or UVA.
Fluorescent lamps for general illumination will have phosphors that generate visible light,
and for safety reasons, be constructed with glass to minimize UV transmission. The most
recent important advance in UVB fluorescent technology was the development of the
narrowband lamp, which has a prominent emission band centered at 311 nm (Phillips TL-01)
(6). The impetus for developing this lamp came from the classic psoriasis action spectrum
studies, showing that longer wavelength UVB was more effective while being less erythemo-
genic than shorter UVB wavelengths (7). A subdivision of the UVA spectrum has also been
demonstrated to have specific therapeutic advantages, and fluorescent lamps are now available
to provide UVA-1 light (340 – 400 nm). Fluorescent technology in dermatology is not limited
to UV phototherapy; “U-shaped” blue-light-emitting fluorescent lamps provide the energy
to activate protoporphyrin IX in topical aminolevulinic acid-based photodynamic therapy (8).
Other essential components of fluorescent lamps include electric ballasts, which stabilize
the lamp’s output and lifetime by regulating current flow within specific limits. Longitudinal
reflective mirrors are also configured to maximize the light reaching the skin. Fluorescent
lamps are available in a range of lengths and housings to treat smaller areas such as the
palms and soles, or the whole body at once.
Lasers
Laser is an acronym for “light amplification by the stimulated emission of radiation,” which
aptly defines this technology. Fundamental to understanding how lasers work is the concept
of stimulated emission. Excited molecules can emit radiation as they return to their lower
energy ground state. This process can occur in the absence of external factors in which case
the emission is said to be spontaneous. In contrast, stimulated emission occurs when an
excited molecule is struck by a photon whose energy exactly matches the quantal-energy tran-
sition between the excited and ground states for those molecules. In stimulated emission, the
incident and emitted photons are of identical wavelength, phase, and direction which gives rise
to the properties of monochromaticity, coherence, and collimation.
In a laser, light is amplified through a special optical configuration that is designed to dra-
matically increase the probability of stimulated emission. The essential components of a laser
include (i) a lasing medium within which stimulated emission occurs, (ii) a longitudinal optical
cavity (also known as an optical resonator) with mirrors at each end, one of which is only par-
tially reflecting, and (iii) an external energy source (Fig. 3). The lasing medium is contained
within the laser cavity and the external energy source serves to excite the molecules of the
medium. Energy is “pumped” into the lasing medium to create a population inversion in
which more molecules are present in an excited, rather than ground state. Spontaneous emis-
sion will generate photons that will, in turn, lead to the stimulated emission of additional radi-
ation within the population inversion; a photon cascade ensues, all the while generating
coherent monochromatic light. Amplification is further enhanced because the two mirrors
reflect photons back and forth within the lasing medium. Laser light is released from the laser
cavity through the partially reflecting mirror, which transmits some of the light generated
within the lasing medium to a laser delivery component, which then directs the light to the skin.
Laser radiation is spectrally very pure, because it is produced by stimulated radiation.
The spectral output of a laser is considered monochromatic and in practical terms is usually
specified by a single wavelength. The wavelength will be determined by the specific discrete
energy transitions of the lasing medium. The lasing medium can exist as a gas, liquid, or
Laser cavity Partially reflecting mirror
Lasing medium Laser

output
Reflecting mirror
Energy pump
FIGURE 3 Laser components and stimulated emission.
solid; lasers are named according to their lasing medium (i.e., ruby, carbon dioxide, excimer).
The laser-pumping source that provides the energy to generate and maintain the population
inversion within the lasing medium is most often a radiofrequency generator or an intense
light source such as a flashlamp.
Lasers produce light in either continuous or pulsed modes, and this is mostly determined
by the nature of the pumping source that is used. For example, flashlamps emit brief, intense
flashes of broadband incoherent light; lasers that are pumped by flashlamps will therefore
deliver pulsed radiation. By far, the most common use of lasers in dermatology is to generate
heat within the skin. Specific structures within the skin can be targeted for permanent photo-
thermal alteration by choosing the appropriate wavelength and pulse duration. This concept is
known as selective photothermolysis, and lasers are, arguably, the best light source available
for this technique because it is possible to match a laser with the required wavelength and
pulse duration. The laser wavelength used for a given application is chosen according to the
absorption characteristics and depth of the target chromophore, whereas the desired pulse dur-
ation is largely a function of the physical size of the target. Smaller targets require a correspond-
ingly shorter laser pulse in order to achieve selectivity. Targets such as melanosomes or tattoo
particles may require a sub-microsecond laser exposure. So-called Q-switched lasers provide
ultra high intensity and fast pulses, which last for less than 100 nanoseconds. The Q-switch
is an optical device that enhances the Q- or “quality” factor within the laser’s optical cavity
by allowing the population inversion to be maximally saturated before stimulated emission
is allowed to occur. In an optical cavity with a high Q factor, the laser will build to a very
intense level and be discharged very quickly as soon as the Q-switch is triggered.
There are now myriad lasers available for treating the skin, all within a complex matrix of
seemingly complicated parameters and competing medical claims. Lasers can be classified in a
number of ways according to the nature of the lasing medium (gas, liquid, or solid), wavelength,
or mode of operation (pulsed or continuous). Perhaps the most useful approach to organizing
lasers used in practice is to consider first the specific clinical applications (i.e., vascular, hair
removal, pigmented lesions, and resurfacing) and the corresponding photobiologic mechanisms.
This will determine the optimum treatment parameters required. The appropriate laser is then
considered from the menu of available devices. An exhaustive compilation of lasers and their
applications is beyond the scope of this chapter, but the general categories are outlined in Table 2.
Intense Pulsed Light

Intense pulsed light devices, also known as IPLs, are essentially filtered xenon flashlamps that
deliver intense light to the skin (9). The fundamental technology underlying an IPL is the same
as that of an electronic camera flash. Flashlamps are also found as components of many medical
lasers where they serve as the external power source for creating the population inversion
36 Lui and Anderson
TABLE 2 Classification of Common Cutaneous Laser Applications

Application Mechanism Chromophore Common lasers used
Vascular lesions Photocoagulation of blood vessels Hemoglobin Pulsed dye laser (585-600 nm)
Frequency doubled
Nd:YAG (532 nm)
Pigmented lesions and Photomechanical Melanin/Tattoo Q-switched Nd:YAG
tattoo removal disruption of ink particles (1064 and 532 nm)
melanosomes or tattoo Q-switched ruby (694 nm)
particles Q-switched alexandrite (755 nm)
Hair removal Photothermal destruction Melanin within Alexandrite (755 nm)
of hair follicles hair shafts Diode (800 nm)
Nd:YAG (1064 nm)
Ruby (694 nm)
Resurfacing Skin ablation and dermal Water Carbon dioxide (10,600 mm)
remodeling Erbium:YAG (2940 nm)
Psoriasis Photoimmunomodulation Unknown Excimer (308 nm)
Photocoagulation of Hemoglobin Pulsed dye laser (585–600 nm)
blood vessels
Vitiligo Photoimmodulation and Unknown Excimer (308 nm)
melanogenesis
PDT Photochemical generation of PDT photosensitizer Various
singlet oxygen
Abbreviations: PDT, photodynamic therapy; Nd:YAG, neodymium:yttrium-aluminum-garnet.
within the lasing medium. Unlike a laser, the spectral output of a flashlamp is polychromatic
and incoherent. Flashlamps and lasers are both capable of emitting very intense light over a
short time, which is essential for achieving selective photothermolysis. Because of this simi-
larity, the flashlamp has been developed and promoted as a means of simulating the biologic
and therapeutic effects of laser. This requires that the flashlamp’s spectral output need to be
modified by using appropriate optical filters.
In a flashlamp, a sealed transparent tube is filled with a mixture of gases, principally
xenon. The ends of the tubes are fitted with electrodes across which very high voltage is
applied. The voltage is delivered by a capacitor, which can be triggered to discharge its
energy over a short period of time. This results in ionization of the gas that is now more elec-
trically conductive. The pulse of current that then flows through the gas will excite electrons
with the xenon molecules. Return of these excited molecules to their resting state will generate
the broad-spectrum light characteristic of xenon. Xenon flashlamps produce very intense light
for short periods of time.
IPLs can, indeed, be used for many of the same applications that were originally devel-
oped for lasers (9). Their intense broadband output, particularly, in the IR range is of unknown
clinical importance, however. IPL is typically delivered to the skin via quartz crystals that are
held in direct contact with the skin.
Light Emitting Diodes

Light emitting diodes or LEDs are ubiquitous in modern life and are popular because of their
efficiency, low cost of operation, and compact size. LEDs generate light by passing current
through semiconductor diodes. Diodes are essentially semiconducting bilayers of aluminum-
gallium-arsenide (AlGaAs) that are doped with impurities. All diode bilayers consist of two
types of semiconductor materials, N- and P-type, that are bonded together. The N-type material
is doped in such a way that it contains an excess of electrons and, therefore, carries a net nega-
tive charge, while the P-type material is overall positively charged and, therefore, is said to
contain holes into which electrons can move. In a diode’s ground state, at the immediate junc-
tion between the N-type and P-type materials, some electrons from the N-type material will fill
the holes of the P-type material, thereby creating a zone that has no net charge, and across
which no electric current passes. If a sufficient voltage is applied across the diode by connecting
the N-side of the diode to the negative end of a circuit and the P-side to the positive end, the
nonconducting zone at the N-P junction will actually lessen to the point where electric current
can pass through the entire diode.
As the free electrons fill the holes in the diode, they move from a higher to a lower energy
state with the difference in energy being released as electromagnetic radiation. To create a
diode that functions primarily to produce light (i.e., a LED), the N- and P-materials are specifi-
cally chosen so that the energy difference corresponds to that of visible or IR photons as the free
electrons enter the holes. Thus the spectral output of an LED depends critically on the specific
N- and P-materials used to construct the diode.
Being small and compact, individual LEDs emit light within a relatively, narrow wave-
band and at low overall intensities. When configured in two-dimensional arrays a collection
of multiple LEDs will generate sufficient visible or IR light to drive some photobiologic reac-
tions. Unlike lasers, LED devices are not sufficiently powerful to photothermally target specific
structures via selective photothermolysis, but LEDs have been successfully used for driving
photochemical reactions in photodynamic therapy (10). The role of LEDs will likely expand
in dermatology as devices that emit in the UV range become practically available.
LED arrays have been advocated for use in so-called low intensity photobiologic reac-
tions, particularly photojuvenation (11). The exact clinical and scientific basis for these
claims has not yet been rigorously tested.
INTERACTIONS BETWEEN RADIATION SOURCES AND THE SKIN

In essence, exposing the skin to any radiation source is synonymous with applying energy to
the skin. In order for photon energy to have any biologic and therapeutic effect on the skin, two
essential processes must occur. First, the light must somehow reach the intended target struc-
ture within the skin and then, once there, the photon must be absorbed by a chromophore
within or near the target. Achieving the first step, propagating light through the skin, requires
an understanding of the optical properties of the skin, whereas the events that occur sub-
sequent to photon absorption is, generally, considered under the rubric of photobiology.
TISSUE OPTICS AND THE PROPAGATION OF LIGHT THROUGH THE SKIN

Until it interacts with the skin in some way, light that passes directly through any tissue com-
ponent is said to be transmitted. Most light does, eventually, interact directly with the skin in
one of three ways: reflection, scattering, or absorption. Reflection occurs at the skin surface
and can provide information about the topography of the skin. At any level in the skin,
the direction of light propagation can be physically altered through scattering.
Multiple scattering events can occur for any given photon and in any direction. The effect
of scattering is greatest in the dermis where collagen is the most important light scattering
material. The probability of scattering is wavelength dependent, and between the UV
through near IR regions, lower wavelength photons are scattered to a greater extent, denoting
that longer wavelength light penetrates more deeply in the skin. Only light that reaches the
target can be absorbed and, yet, the probability of absorption will depend on the absorption
spectrum of the chromophore in accordance with quantum theory. Once absorbed a photon
no longer exists and its energy is transferred to the chromophore which, in turn, is
promoted to an excited state. Subsequent release of the energy with return of the chromo-
phore to the ground state will drive photobiologic reactions and phenomena.
Clinical examination of the skin in dermatology fundamentally relies on complex
perceptual and cognitive processes by which the overall interplay of tissue-optical effects, as
manifested in the visual appearance of skin lesions, are used to render diagnoses. Clinical mor-
phology therefore exploits the effects that skin has on light. In contrast, phototherapeutics is
focused primarily on the effects of light on the skin.
PHOTOBIOLOGY AND THE SKIN

Photobiologic reactions can result in skin disease or be used to treat the skin. Specific clinical
details are described throughout this book. Although the range of light-dependent reactions
38 Lui and Anderson
is diverse, they must all be initiated by chromophore absorption of photons. Subsequent

relaxation of excited chromophores to the ground state releases the stored energy to
(i) drive chemical reactions, (ii) produce heat, or (iii) re-emit light. The vast majority of photo-
biologic reactions that occur in clinical dermatology are presumed to involve photochemical
processes. In some instances such as photodynamic therapy, PUVA, or drug-induced photo-
sensitivity the detailed photochemistry is very well characterized and understood, whereas
for idiopathic photodermatoses and UV phototherapy the exact photochemical links
between light absorption and the clinical effects or outcome are largely speculative. For
example, the putative chromophore and chemical reactions that underlie UVB phototherapy
have still not been resolved with any certainty.
In terms of pathologic photothermal effects, erythema ab igne is probably one of the few
examples where heat produced in the skin through photon absorption (i.e., infrared) leads to a
specific skin disorder. In dermatology, photothermal effects are more commonly encountered
on the therapeutic side when lasers or IPLs are used to irreversibly heat specific structures
in the skin through selective photothermolysis.
The re-emission of absorbed light by the skin is termed fluorescence and this is the third
possible path by which excited chromophores discharge their absorbed energy. Pathologically
or therapeutically, there are no clinical examples of skin diseases that result from or can be
treated by cutaneous fluorescence. The importance of fluorescence in the skin primarily lies
in its use for diagnosis. The Wood’s lamp emits longwave UVA near 365 nm. Cutaneous fluor-
ophores including collagen, elastin, and porphyrins will absorb the UVA, which is invisible and
then re-emit fluorescent light at a longer wavelength, where it is visible to the human eye.
Photoaging and photocarcinogenesis are the result of chronic light exposure, and demon-
strate that the skin has a finite capacity to repair damage resulting from repeated cycles of
pathologic photobiologic reactions.
CHARACTERIZING RADIATION SOURCES: SPECTRAL IRRADIANCE

It is absolutely critical to recognize that any given light source is important only in terms of the
quality and quantity of light that it delivers to the skin. Thus, when we refer to “fluorescent” or
“laser” light we are really referring only to the method by which the light was produced. A
photon is a photon—the skin does not truly care what particular light source a photon came
from, only that the photon that it receives is of the appropriate wavelength and that a sufficient
number of photons are delivered at an appropriate rate. A plethora of light sources are com-
mercially available to meet specific photobiologic (e.g., selective photothermolysis, photochem-
istry), clinical (e.g., localized vs. diffuse treatment areas), and practical (e.g., cost and efficiency)
needs. There is also a certain degree of redundancy amongst radiation sources since certain
specific spectral regions of interest can be produced by more than one type of radiation
source. For example, the 311 narrow band UVB lamp, the UV excimer laser, and the incoherent
monochromatic excimer light source all function as “narrow band” UVB sources.
The correct way to accurately characterize and compare light emitted from various radi-
ation sources is to determine their emission spectra. In an emission spectrum, the irradiance of
the source is measured and plotted as a function of wavelength. Figure 4 depicts the emission
spectrum of a narrowband TL-01 UVB lamp. This lamp was engineered to produce light maxi-
mally at 311 nm. It is also apparent from the emission spectrum that other UV wavebands,
including UVA, are emitted by this lamp (although not shown on the spectrum, some visible
light is also produced by this lamp). The same holds true for UVA and broadband UVB
lamps; they are not necessarily spectrally pure, and their nominal designation as being
“UVA” or “UVB” light sources only refers to the fact that their spectral emission and biologic
activity is predominantly that of a certain waveband. The emission spectrum of a light source is
rarely measured directly in the clinical setting, since spectroradiometers are expensive. Fortu-
nately for regular clinical use, commerical lamp manufactures maintain relatively consistent
standards for lamp operating characteristics such as spectral emission.
In the research setting, spectral irradiance is often a critical factor that is overlooked in
experiments involving light. Any photobiologic phenomenon can be attributed to a specific
1.0
Narrow band TL-01
Broad band TL-12
Relative spectral irradiance

0.1
0.01
0.001
250 300 350 400
Wavelength (nm)
FIGURE 4 Spectral irradiance for a narrow band Phillips TL-01, 311 nm UVB fluorescent lamp. Note that the relative
irradiance is shown on a logarithmic scale. Source: Adapted from Ref. 12.
waveband only if the spectral output of the light source used is reliably known. For example,
although a certain light source may be emitting UVA, the small traces of UVB that may also be
emitted may have a significant biologic effect since UVB can be more biologically active than
UVA by several orders of magnitude.
Only certain wavelengths of light are efficient for inducing or producing the desired bio-
logic or therapeutic effect and this relationship is best described through the action spectrum.
Analogous to an absorption spectrum, which depicts the efficiency by which photons are
absorbed by a chromophore according to wavelength, the action spectrum refers to the effi-
ciency of a given photobiologic reaction occurring as a function of wavelength. Action
spectra are usually plotted as the reciprocal photon numbers required for a photobiologic
effect on the ordinate and wavelength on the abscissa. Photobiologic reactions occur most effi-
ciently when there is a good match between the action spectrum and the spectral irradiance of
the light source that is driving the reaction. Where the action spectrum is known, it is ideal for
the spectral irradiance of the light source to match the action spectrum for maximal efficiency
and also to prevent potential unwanted side reactions.
LIGHT DOSIMETRY AND THE SKIN

Radiation is measured in units of total energy, joules (J) or energy flux or power, watts (W).
Since the skin surface is essentially two dimensional, it is customary to consider light that is
incident on the skin in terms of its energy or power density per unit area. These are referred
to as fluence or irradiance respectively, and in dermatology are generally measured in units
of J/cm2 or W/cm2. Irradiance and fluence are mathematically related as follows:
Fluence ¼ Irradiance Light exposure duration
In the clinic, the irradiance is measured with a radiometer. For a specified delivered radi-
ation dose, the duration of exposure can be calculated from the above formula. Each radiation
source requires its own specific radiometer, since the spectral sensitivity should match the
source’s spectral output.
Light dosimetry is largely determined empirically in clinical practice. In general it is
safest to start with subthreshold levels of light and then gradually increase the fluence with
40 Lui and Anderson
subsequent treatments. There is some degree of latitude in terms of the time duration over
which the light exposure can be delivered because of the Bunsen-Roscoe law of light dose reci-
procity. Basically, for any given delivered fluence there is a reciprocal relationship between the
duration of exposure and the irradiance of the source. For example, if the irradiance is reduced
by half, the same biologic or therapeutic effect will be achieved by doubling the exposure time.
One very important exception to the law of reciprocity is the use of lasers to selectively heat the
skin. Heat must be generated within a very narrow time frame otherwise selective photother-
molysis will not occur.
CONCLUSIONS
Available technologies that collectively cover the photobiologically active spectrum include
incandescent lamps, arc (gas discharge) lamps, fluorescent lamps, lasers, flashlamps, and
light-emitting diodes. Choosing the ideal light source for therapeutic or diagnostic purposes
is determined by the type of photobiologic reaction desired and by matching the action spec-
trum of the effect to the spectral irradiance of the light source. The area of skin that is to be
irradiated as well as the cost and practicality of the radiation source are also paramount
considerations.
REFERENCES
1. Food and Drug Administration. Sunscreen products for over-the-counter human use. Final mono-
graph FR. Federal Register 1999; 64(98):27666 – 27693.
2. Roelandts R. The diagnosis of photosensitivity. Arch Dermatol 2000; 136:1152– 1157.
3. Iversen Møller K, Kongshoj B, Philipsen PA, Thomsen VO, Wulf HC. How Finsen’s light cured lupus
vulgaris. Photodermatol Photoimmunol Photomed 2005; 21:118 – 124.
4. Mutzhas MF, Hölzle E, Hofmann C, Plewig G. A new apparatus with high radiation energy between
320 – 460 nm: physical description and dermatological applications. J Invest Dermatol 1981; 76:42– 47.
5. DEKA M.E.L.A., Excilite Operator’s Manual 2005, page II.2.
6. Van Weelden H, Baart de la Faille H, Young E, Van Der Leun JC. A new development in UVB
phototherapy of psoriasis. Br J Dermatol 1988; 119:11 – 19.
7. Parrish JA, Jaenicke KF. Action spectrum for phototherapy of psoriasis. J Invest Dermatol 1981;
76:359– 362.
8. Jeffes EW, McCullough JL, Weinstein GD, Kaplan R, Glazer SD, Taylor JR. Photodynamic therapy of
actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light. J Am
Acad Dermatol 2001; 45:96– 104.
9. Ross EV, Laser versus intense pulsed light: competing technologies in dermatology. Lasers Surg Med
2006; 38:261– 272.
10. Lui H, Hobbs L, Tope WD, et al. Photodynamic therapy of multiple nonmelanoma skin cancers with
verteporfin and red light-emitting diodes: two-year results evaluating tumor response and cosmetic
outcomes. Arch Dermatol 2004; 140:26– 32.
11. Weiss RA, McDaniel DH, Geronemus RG, et al. Clinical experience with light-emitting diode (LED)
photomodulation. Dermatol Surg 2005; 31:1199– 1205.
12. Das S, Lloyd JJ, Farr PM. Similar dose-response and peristence of erythema with broad-band and
narrow-band ultraviolet B lamps. J Invest Dermatol 2001; 117:1318– 1321.
Section II: EFFECTS OF ULTRAVIOLET RADIATION ON NORMAL SKIN
4 The Molecular and Genetic Effects

of Ultraviolet Radiation Exposure on
Skin Cells
Marjan Garmyn
Department of Dermatology, University of Leuven, Leuven, Belgium
Daniel B. Yarosh
Applied Genetics Incorporated Dermatics, Freeport, New York, U.S.A.
B Of the solar spectrum a small portion of UVB and more significant

portion of UVA penetrates human skin.
B The main cellular chromophores for UV are DNA, RNA, and reactive
oxygen species (ROS) generating chromophores.
B UVB mainly causes direct DNA damage, the common lesions being
cyclobutane pyrimidine dimers (CPDs), while ROS production becomes
more important with UVA.
B Ligand dependent or independent activation of cell surface receptors

triggers of signal transduction pathways leading to transcription
factor activation and modulation of gene expression.
B Cellular adaptive responses of skin against UV damage include growth

arrest, DNA repair, and when damage is beyond repair, apoptosis.
42 Garmyn and Yarosh
INTRODUCTION
ne of the greatest advances in photodermatology over the past decade is in the under-
O standing of the molecular events that follow ultraviolet (UV) irradiation of skin. These
studies have been able to trace the formation of skin cancer back to the initial absorption
of a UV photon by a base in the DNA as a critical step. A range of other molecules that absorb
UV are now connected to cellular responses. A vast network of intracellular signaling has been
revealed, which remains an intense area of study. Communication between UV-damaged cells
and both UV exposed and unexposed cells in the skin has been defined by their characteristic
cytokine and growth factor proteins, and now the profiles of their concerted induction, release,
and down-regulation are under investigation. The panorama of the molecular effects of UV
radiation (UVR) is reviewed here.
ULTRAVIOLET DAMAGE
Ultraviolet A and Ultraviolet B: Energy and Penetration
Solar Ultraviolet
UVR from the sun reaching the earth’s surface has wavelengths ranging from about 280 to
about 400 nm. For convenience, this spectrum is divided into UVB (280 –320 nm) and UVA
wavelengths (320 – 400 nm). This convenience should not obscure the fact that all UVR, given
in sufficient dose, can produce approximately the same biological effects in skin—whether it
is DNA damage, lipid oxidation, or skin cancer. The difference between them is that the effi-
ciency in producing one of these effects by photons at one wavelength is greater than that
by photons of another wavelength. The relationship between a range of wavelengths and the
efficiency for producing any biological endpoint is called an action spectrum. The shape and
peak of the action spectrum give important information about chromophore(s)—the
molecule(s) in skin that are responsible for absorbing the UVR and producing a biological
effect. The converse is also true: for UVR to have an effect on skin, it must be absorbed by a
molecule. Connecting molecules absorbing UVR to biological effects is a major goal of
modern photodermatology.
UVR that strikes the skin deposits its energy as it travels into the skin. The shorter the
wavelength, the more energetic the photons, and the more shallow in the skin the photons
are absorbed. Thus, most UVB is absorbed in the epidermis, but some does reach the
dermis. Conversely, longer wavelength UVA is partially absorbed in the epidermis, but a
higher fraction than UVB penetrates deeper into the skin and reaches the dermis. However,
because damaged epidermal cells release cytokines that communicate with dermal cells and
damaged immune-competent cells migrate from the epidermis, it is overly simplistic to
ascribe biological effects of UVB and UVA to higher or lower layers in skin simply on the
basis of how far on average the wavelengths penetrate.
DNA Effects
A biologically important chromophore in skin is the DNA in living cells. DNA absorbs all
wavelengths of UVR, but pure DNA has a peak of absorption at about 260 nm, and the
action spectrum for DNA damage shows a logarithmic decline in absorption as the
wavelengths grow longer. However, in order to reach DNA in skin, the UVR must travel to
layers beneath the outermost stratum corneum, which absorbs and diffuses particularly well
the shorter wavelengths of light. Therefore, the most efficient wavelengths of light for
causing DNA damage in living skin is around 313 nm—shorter wavelengths are absorbed
by stratum corneum and longer wavelengths are significantly less efficient in producing
damage.
The part of DNA that most efficiently absorbs UV is the 5-6 double bond of the
pyrimidine bases. When one of two adjacent pyrimidines absorbs a photon here, the most
common result is the instantaneous formation of a cyclobutane ring linking the two
pyrimidines at the 5 and 6 position—this is called a cyclobutane pyrimidine dimer (CPD).
Occasionally, a bond between the adjacent pyrimidines is formed through a 6-4 linkage,
which is called the pyrimidine– pyrimidone photoproduct. From experiments with cultured
Molecular and Genetic Effects of Ultraviolet Radiation Exposure 43
cells, it has been estimated that CPDs are 20 to 40 times more frequent than any other DNA
photoproduct after irradiation with simulated sunlight (1).
Aside from these direct effects of UVR, DNA damage can form by indirect effects,
particularly from oxidation. UVR absorbed by as yet poorly defined chromophores in skin
can generate oxygen radicals that react with DNA. The most vulnerable place in DNA is
oxidation of the 8 position of guanine, yielding 8-oxo-guanine (8oG). Another detectible
oxidized base is the thymine glycol. UVA, which produces relatively more oxidation damage
than photoproducts when compared with UVB, still produces three to six times more CPD
than 8oG in DNA (2). Single- or double-stranded breaks are uncommon events resulting
from UVR.
DNA is repaired by a complex of proteins and enzymes that organize together at the site
of damage (3). DNA that has sustained bulky lesions or lesions that distort its structure (such as
a CPD) is repaired by nucleotide excision repair (NER), in which approximately 29 bases are
replaced.
DNA that has modified bases (such as 8oG) is repaired by base excision repair, which
replaces only the damaged base and a few neighboring bases. In either case, the opposite unda-
maged strand of DNA is used as a template to resynthesize the DNA sequence. This type of
DNA repair occurs at anytime nearly anywhere in the genome [global genomic repair
(GGR)]. However, localized regions of transcribed DNA are repaired much faster by a group
of proteins performing transcription-coupled repair (TCR). They are attracted to the site by a
transcription fork that has stalled, and TCR accelerates repair of the transcribed strand. If a
lesion is not repaired by the time the DNA must be replicated, damage-specific polymerases
eta or zeta can insert bases to allow continued replication in a process called translesion syn-
thesis (4). If all these measures fail and too much DNA damage remains, the cell activates a
suicide pathway call apoptosis.
During the repair or replication of DNA damage, erroneous bases, additions, deletions, or
rearrangements are inserted at a frequency of approximately one in a million, or more fre-
quently if the cell relies on the very error-prone polymerase zeta for translesion synthesis.
Because of the large amount of unused DNA and the redundancy of the genetic code, these
mutations often make no difference. However, mutations introduced at certain sequence
locations in key genes, called oncogenes or tumor-suppressor genes, can contribute to the for-
mation of a cancer cell. The best-studied example is the p53 tumor-suppressor gene in squa-
mous cell carcinoma. This product of this gene, which has been called the “guardian of the
genome,” organizes many of the cells responses to UVR, including repair, cell division, and
apoptosis. Squamous cell carcinomas from sun-exposed skin frequently have mutations in
the p53 gene, and these mutations are characteristic of those induced by CPDs (5). Mutations
in key genes leading to both basal cell carcinoma and melanoma are also similar to these
signature mutations. This is among the strongest evidence directly linking UVR-induced
DNA damage to skin cancer.
Lipid Effects
The action spectrum for UV effects in skin does not correlate with the absorption spectrum of
lipids. However, UVR directly and indirectly damages the free lipids in the stratum corneum
and the lipid membranes of living cells by generating reactive oxygen species (ROS). Over the
course of a summer, the generation of ROS depletes the endogenous antioxidant system in
the stratum corneum (5). ROS oxidize lipids by directly oxidizing their double bonds or
by initiating a chain reaction of one oxidized lipid reacting with another. In living cells,
the damaged membranes are processed by nonenzymatic and enzymatic mechanisms. Kerati-
nocyte membranes damaged by singlet oxygen release ceramides by a nonenzymatic reaction,
and these signal activation of transcription factor activator protein-1 (AP-1), resulting in
expression of many stress response genes, for example, intercellular adhesion molecule-1
and vascular endothelial growth factor (5). Oxidized lipids in the membranes of keratinocytes
are cleaved by phospholipase A2 (PLA2) to form arachidonic acid, which is the substrate of
cyclo-oxygenase-1 and the inducible form-2 (COX-1 and COX-2) (5). These enzymes convert
arachidonic acid into prostaglandins, which mediate many inflammatory reactions in the skin
and elsewhere.
Protein Effects
Proteins in skin may also be oxidized by ROS generated from sunlight. However, since most
types of proteins occur in multiples and are constantly degraded and resynthesized, the
consequences may not be as severe. Enzymes from the family of methionine sulfoxide
reductases patrol the epidermis and keeps protein oxidation levels very low by degrading
oxidized proteins, even in chronically UV-exposed skin (5). UVR may also directly crosslink
proteins, particularly collagen and elastin in the dermis and even cause them to degrade.
However, the primary cause of degradation is probably not a direct effect of UVR, but rather
due to the production by fibroblasts of proteases that digest the surrounding collagen and
elastin (5).
Proteins that have been proposed as chromophores for many of the effects of UVR are cell
surface receptors. UVR causes these receptors to cluster even without binding ligands (5).
Receptor clustering is a well-known mechanism for transfer of extracellular signals into cellular
activation. For example, UVB-induced clustering of the CD95 receptors activates these death
receptors and leads to apoptosis, independently of nuclear DNA damage (5). UV has
also been proposed to inactivate protein tyrosine phosphatases, which results in their target
proteins remaining phosphorylated (5). The persistence of phosphorylated forms of key
signaling molecules may result in prolonged activation of damage response pathways, such
as metalloproteinase (MMP) production or immune suppression.
ULTRAVIOLET-INDUCED SIGNALING AND GENE REGULATION

Cytokines and Soluble Factors
UV exposure changes the cytokine profile within the epidermis. Keratinocytes are the main
source of these cytokines. Other epidermal cells, such as Langerhans cells (LHC) and melano-
cytes, together with infiltrating leukocytes are also active contributors to changed cytokine
profile after UV exposure. Keratinocytes are able to secrete a wide variety of pro-inflammatory
cytokines upon UV exposure, including interleukins IL-1a, IL-1b, IL-3, IL-6, IL-8, granulocytes
colony stimulating factor (G-CSF), macrophage-CSF (GM-CSF), interferon gamma, (INF-g),
platelet-derived growth factor (PDGF), transforming growth factor alpha (TGF-a), TGF-b,
and tumor necrosis factor alpha (TNF-a) (6 – 8).
The processes that regulate cytokine production by UV are complex. Nuclear factor
kappa B (NFkB) is an important transcription factor regulating cytokine gene expression by
UV, whereas the protein kinase p38 (a member of the MAPK family of protein kinases) is
known to mediate the expression of cytokine-encoding genes by events ranging from transcrip-
tional and translational control to mRNA stability (9). Both ROS-mediated and direct DNA
damage have been implicated in the production of the primary cytokine TNF-a (10,11).
These cytokines, induced by UV, can then act in a paracrine or autocrine way to stimulate
intracellular signaling and gene expression. Hence, cytokines like IL-1, TNF-a, and TGF-b can
bind to their respective receptors in the cell membrane and initiate signal transduction (12).
Nitric oxide (NO) is produced by keratinocytes after UVB irradiation (13), and keratino-
cytes express the enzyme required to synthesize NO. Increased expression of mRNA for indu-
cible NO synthetase has been detected in skin exposed to UV light (14). NO reacts with
superoxide to form peroxynitrite, which is a potent activator of various signaling pathways,
including the MAPK (15) and tyrosine kinase signaling cascades (16). Peroxynitrite can also
activate transcription factors including NFkB (17). NO is also involved in the inflammatory
response leading to vasodilation and erythema (13) and in the tanning response (18).
Urocanic acid (UCA) is a naturally occurring component of the superficial cornified
epidermis. It is synthesized as a trans-isomer, which contains an acyclic carbon – carbon
double bound and absorbs in the UVB range. Upon absorption of UVB light, trans-UCA iso-
merizes to cis-UCA, which can induce immune suppression (19). Although the mechanisms
by which UCA initiates biological activity are not known, there is evidence that absorption of
UV light by the chemical can generate ROS (20).
UV can also stimulate the release of lipid mediators such as the prostaglandin, PGE2,
platelet-activating factor, and sphingolipid ceramide (21). Released PGE2 and platelet-
activating factor can mediate their biological activities via highly specific membrane recep-
tor-initiated signaling (22,23). Inhibitors of PG synthesis, including indomethacin and
aspirin, have been shown to decrease (but not completely suppress) the erythemal response,
providing evidence for the involvement of PG in UV-induced erythema.
Cell Surface Receptor Activation

UVB-induced cytokines and growth factors can bind to their respective receptors and by this
activate downstream signal transduction pathways; however, UVB can also activate multiple
cell surface receptors in a ligand-independent way, including CD95/Fas (24), the TNF-alpha
receptor (TNF-aR), the interleukin-1 (IL-1) receptor, the epidermal growth factor (EGF)
receptor (25), the insulin receptor (26), the PDGF receptor (27), and the KGF receptor (28).
UVB induces clustering of these membrane receptors and subsequent activation of down-
stream signaling pathways (24,25). Aragane showed that UVB radiation induces CD95
clustering. Rosette and Karin showed that UVB induced TNF clustering and its associa-
tion with TNFR1-associated death domain. Tobin et al. (29) showed that UVB was able to
functionally activate the TNF-1 receptor by activating TNF receptor associated factor-2
(TRAF-2). How UVB leads to clustering and activation of the cell surface receptors remains
unclear. Physical perturbation of the plasma membrane (secondary to lipid peroxidation) or
conformational changes of the receptor, caused by energy absorption or oxidation, are possible
explanations.
Activation of the EGF receptor by UV light can not only be observed in human keratinocytes
in vitro but also in human skin in vivo (30).
Protein Kinase-Mediated Signal Transduction

Ligand-dependent or ligand-independent activation of cell surface receptors triggers off signal
transduction pathways that may result in the activation of transcription factors and ultimately
modulation of gene expression. This subsequent downstream signaling triggered off by
UV-induced receptor activation and leading to transcription factor activation is called the
“UV response.” Protein kinases, which activate their downstream targets via phosphorylation,
play an important role in signal transduction. Two important groups of protein kinases
are involved in the UV response: the MAPK family of protein kinases and a group directly
implicated in the genome integrity checkpoint, such as ATR, Chk2, and DNA-PK.
The MAPK family of protein kinases is known to respond to stress, such as membrane
damage and oxidative stress, and play an important role in the UV response. MAPK includes
the extracellular signal-regulated kinases (ERKs), the c-Jun NH2-terminal kinases (JNKs)
and the p38 MAPK. p38 MAPK has four isoforms (a, b, g, and d), JNK has three isoforms
(1/2/3), and ERK has two isoforms (1/2). All three groups of MAPKs are activated by dual
phosphorylation on threonine and tyrosine by one or more MAPK kinases (MAPKKs). These
MAPKKs are in turn phosphorylated and activated by MAPKK kinases (MAPKKK) (31).
JNKs and p38 kinases are activated by stress, including UVB. ERKs are typically activated
by growth factors, and UVB is only a weak activator of ERK in keratinocytes (32).
UVB also activates the phosphoinositide 3-kinase (PI3K) pathway in an ERK and p38
kinase-dependent mechanism (33). In human keratinocytes, activation of PI3K and its down-
stream target, the anti-apoptotic kinase, Akt, are also thought to be dependent on the activation
of EGF receptors (34). The mechanisms mediating MAPK activation by UV may occur
through binding of growth factors or cytokines to their receptors or may occur through
ligand-independent receptor activation, which may or may not involve UV-induced oxidative
stress. Recent studies indicate that MAP kinase activation, more specifically JNK and p38 sig-
naling, can also occur via growth factor and growth factor receptor independent mechanism,
via the ribotoxic stress response (35,36).
A second group of protein kinases (ATR, Chk2, DNA-PK,) is implicated in the genome
integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA
damage caused by genotoxic stress (37). ATR (ATM-Rad3-related kinase) is a primary DNA
sensor and essential for UV-induced phosphorylation of several G1/S checkpoint proteins.
ATR was also shown to bind UVB-damaged DNA, with a resulting increase in its kinase
activity towards p53 (38). Activated p53 in turn is known to orchestrate DNA damage response
pathways, including cell cycle arrest, DNA repair, and apoptosis, as discussed later.
Stalled DNA Replication and RNA Transcription

The UV-induced CPDs and pyrimidine (6-4) pyrimidone photoproducts cause distortions in
the DNA helix and halt RNA polymerase (RNAP) elongation along DNA, thus inhibiting
gene expression but also leading to recruitment of the NER complex (referred to as GGR),
which repair these helix distorting DNA photoproducts.
DNA lesions on the actively transcribed strands have been shown to arrest RNA-PII, and
thereby inhibit transcript cleavage. The active repression of transcription initiation occurs by
phosphorylation of RNA-PII. This stalled RNAP-II would, on the one hand, lead to fast recruit-
ment of the NER complex (referred to as TCR), but, on the other hand, interact with p53 result-
ing in stabilization and accumulation of the p53 protein.
TCR occurs fast, in a gene-dependent manner, and only repairs the template strand of
transcriptionally active DNA. GGR occurs slower, repairing also the nontemplate strand and
the nontranscribed areas. Cell survival depends more on TCR than GGR, but genomic integrity
is more influenced by GGR (39,40).
Transcription Factors (p53, AP-1, and NFKB)

Three transcription factors are strongly implicated in the UV response: p53, AP-1, and NFkB.
p53 is a tumor suppressor protein and is the most frequent target for mutations in human
cancer. p53 is mutated in approximately 50% of all cancers, and this frequency increases to
more than 90% in squamous cell carcinoma of the skin. The importance of wild-type p53 in
the regulation of the response to stress, and more specifically the UVB response, is ascribed pre-
dominantly to its ability to transactivate a plethora of genes with an active role in either cell
cycle arrest, global genomic DNA repair, or apoptosis. p53 becomes activated in response to
a myriad of stress types, which includes but is not limited to DNA damage (induced by
either UV, IR, or chemical agents). This activation is marked by two major events. First, the
half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53
in stressed cells. Secondly, a conformational change forces p53 to take on an active role as a
transcriptional regulator in these stressed cells. The critical event leading to p53 activation is
phosphorylation of its N-terminal domain, which contains a large number of phosphorylation
sites and can be considered as the primary target for kinases transducing stress signals. Both
the MAPK family of protein kinases and a group of kinases, directly implicated in the
genome integrity checkpoint such as ATR, are known to target the transcriptional activation
domain of p53 (39,41).
NFkB is a ubiquitously expressed transcription factor that belongs to the Re1 family and
regulates genes involved in inflammation, immunity, cell cycle progression, apoptosis, and
oncogenesis. The NFkB transcription factors are regulated through interaction with their
inhibitor IkB that sequesters them in the cytoplasm. NFkB can be activated by a wide range
of stimuli, including UV light. Most signals that activate NFkB stimulate directly or indirectly
the phosphorylation of IkB by IkB kinase (IKK), thereby increasing their susceptibility to
ubiquitin-dependent degradation (42), leading to the translocation of NFKB to the nucleus
and transcriptional activation of target. The mechanism of NFkB activation by UV radiation
does not exactly conform to this established pathway in that the ubiquitin dependence of
degradation of IkB occurs relatively late and does not depend on its phosphorylation on the
usual N-terminal serine residues nor on the activation of IKK (43).
Pathways responsible for NFkB activation by UVB in keratinocytes and skin are complex,
and over the years, several molecular mechanisms have been suggested. NFkB activation by
UVB can occur independent of DNA damage (44). Adachi (45) showed that in normal human
keratinocytes, UVB can activate NFkB, but the pathway does not involve IKK. It has also been
shown that NFkB can be activated by UVB via NADPH oxidase and COX, which activate ROS
(46). Additionally, UVB can cause a rapid association of TNF receptor 1 with its downstream
partner TRAF-2, which leads to NFkB activation in keratinocytes (29). It has also been
suggested that UV radiation causes the release of TNF-a in normal human keratinocytes,
which can activate NFkB (47). NFkB is an important transcription factor for cytokines and
can, in this way, regulate the pro-inflammatory and immunomodulatory effects of UVB.
NFkB has also been ascribed a role in regulating UVB-induced apoptosis; however, both
pro- and anti-apoptotic roles have been ascribed to NFkB (43,48).
AP-1 is not a single transcription factor, but instead a series of related dimeric complexes
of Fos and Jun family proteins. Changes in AP-1 activity due to changes in the expression of
AP-1 family members, post-translational modification, or both occur in response to a wide
variety of signals including UV light. Both the ERK and JNK pathways are important signaling
pathways leading to AP-1 activation; AP-1 activation by GF is at least partly regulated by ERK
pathway. The JNK pathway is an important signaling pathway leading to AP-1 activation upon
UV radiation (49). The transcription factor AP1 plays an important role in UVB-induced
photoaging, as it regulates several ECM proteins (e.g., matrix MMPs and type I procollagen)
(50) and UVB-induced skin tumor promotion (51). Both pro- and anti-apoptotic affects have
been attributed to UV-induced AP-1 activation as reviewed by Assefa et al. (43).
Transcriptional Responses to UV
DNA microarrays have allowed a large-scale analysis of transcriptional response of skin cells to
UV. Different factors may influence the transcriptional targets of UV, including wavelength,
dose, cell type, and the time of expression after irradiation. Hence, keratinocytes, melanocytes,
and fibroblasts have, in general, similar transcriptional targets involving DNA damage repair,
cell cycle arrest, and/or apoptotic machinery, whereas transcriptional responses of immunomodu-
latory factors seem overlapping but distinct. The dose applied also affects the transcriptional
response. Indeed, UV doses causing cell cycle arrest of apoptosis provoke transcriptionally
highly divergent responses. Downregulation of transcription is very prominent in apoptotic
cells. However, UV-induced repression of transcription is also specific, as the targets downregu-
lated by a low dose of UV are different from those downregulated by a high apoptotic dose (40).
Specifically, for p53-regulated genes, a low UVB dose resulting in survival induces genes involved
in cell cycle arrest and repair, such as p21 and p53R2, whereas the same genes are downregulated
after a high UVB dose (52). Genes also follow a specific time course; for example, genes involved in
cell cycle arrest are first upregulated, whereas genes involved in cytoskeleton are first downregu-
lated or unchanged, then upregulated later, reflecting the recovery of UVB-damaged cellular
activities (53).
A recent study by Enk et al. found that UVB-induced gene expression profile of human
epidermis in vivo is different from that of cultured keratinocytes. The expression profile in
intact epidermis was geared mainly towards repair, whereas cultured keratinocytes responded
predominantly by activating genes associated with cell cycle arrest and apoptosis, which may
reflect differences between mature differentiating keratinocytes in the suprabasal layers and
exponentially proliferating cells in culture (54).
CELLULAR RESPONSES
Cell Types in Skin (Keratinocytes, Fibroblasts, Melanocytes, and T-Cells)
The skin is composed of three layers: the epidermis, the dermis, and the subcutis. The epider-
mis is a stratified squamous epithelium and its prime function is to act as a skin barrier. This
skin barrier function is continuously challenged by environmental hazards, the most ubiqui-
tous of which is UV in sunlight. The three main cell populations in the epidermis are the
keratinocytes, the melanocytes, and the LHC. The basal layer of the epidermis consists of
keratinocytes that are either dividing or nondividing and is secured to the basement membrane
by hemidesmosome. During the upward migration of keratinocytes, from the proliferative
basal layer through the spinous and granular layer, keratinocytes undergo terminal differen-
tiation ultimately leading to anuclear corneocytes, continuously desquamating into the
environment.
The melanocytes make 5% to 10% of the basal cell population. These cells synthesize
melanin and transfer it via the dendritic processes to the neighboring melanocytes. The epider-
mis has an important immunological function. The LHC are involved in the cellular immunity.
They are dendritic bone marrow derived cells characterized by the Birbreck granules. They play
an important role in antigen presentation. The T-lymphocytes are believed to circulate through
normal skin where they are thought to mature to helper, delayed hypersensitivity, cytotoxic, and
suppressor Tcells. Keratinocytes are part of the innate immune system of the skin, since they can
produce themselves pro-inflammatory cytokines and express on their surface immune-reactive
molecules such as MHC class II antigens and intercellular adhesion molecules.
The dermis consists of an upper part, pars papillaris, which lies immediately below the
epidermis, and a deeper part, the pars reticularis. The dermis contains fibroblasts (which
synthesize collagen, elastin, and glycosaminoglycans), dermal dendrocytes, mast cells,
macrophages, and lymphocytes.
Cell Cycle Arrest

One of the cellular responses to UVB-induced damage is the induction of cell cycle arrest, both
in the G1 and G2 phases. These checkpoints allow DNA damage to be repaired before DNA
replication (G1/S checkpoint) or before chromosome segregation (G2/M checkpoint). The
cyclin-dependent kinase inhibitor p21/WAF1 is a direct target of p53 and an important
mediator of the G1 arrest (39). The involvement of cdk inhibitor p21 in a G1 arrest upon
UVB in keratinocytes has been demonstrated (55,56). p21 mediates cell cycle arrest by
binding to and inactivating Cyclin D/cdk4 and Cyclin D/cdk6, thereby inhibiting phosphoryl-
ation of the retinoblastoma protein, essential for G1-S transition. C/EBPa, a p53-regulated
UVB-inducible gene, has also a critical function in G1 checkpoint response (57).
Arrest in the G2 phase involves other p53-dependent factors, including 14-3-3 sigma (58)
and GADD45 (growth arrest and DNA damage inducible gene) (59). GADD45 promotes G2/M
arrest via nuclear export and kinase activity of Cdc2. Also p53-independent mechanisms (60)
are involved in UVB-induced growth arrest.
Apoptosis
Apoptosis is a conserved, energy-requiring and highly regulated form of cell death that ensures
the elimination of superfluous, infected, irreparably damaged, or transformed cells. Apoptosis
is induced by various stress conditions including genotoxic damage, such as UVB.
The apoptotic process itself is characterized by stereotypical morphological changes such
as cell shrinkage, membrane blebbing, chromatin condensation, and DNA fragmentation,
leading to a cell with a pycnotic nucleus, and ultimately the formation of apoptotic bodies.
Hence, when skin is irradiated with a sufficient high UVB dose, cells with pycnotic nucleus
and eosinophilic cytoplasm, a typical apoptotic morphology, also called “the sunburn cell”
(SBC), appear in the epidermis. At the biochemical level, the induction of apoptotic cell
death is accomplished by specialized cellular machinery where a family of cysteine proteases,
the caspases, play a central role. There are two main pathways leading to apoptotic cell death.
The intrinsic pathway is activated at the mitochondria. Death-inducing signals (including
DNA damage) promote BAX-dependent release of cytochrome C, which together with Apaf-
1 leads to formation of the apoptosome and procaspase 9 activation. In contrast, signaling
through the cell surface death receptor (e.g., CD95/Fas, TNF-alphaR) activates the extrinsic
pathway, which relies on initiator caspase-8 activation at the death-inducing signaling
complex. Both pathways converge into the activation of the effector caspases (caspases-3, -6,
and -7) that are directly responsible for the cleavage of cellular proteins resulting in the charac-
teristic morphology of apoptosis. Cleavage of Bid by caspase-8 allows crosstalk between both
pathways.
UV-induced cell death has been proposed to involve three processes contributing inde-
pendently to the activation of the intrinsic and the extrinsic apoptotic pathways. These three
processes are DNA damage, membrane receptor clustering, and formation of ROS (61).
Recent studies, however, indicate that irradiating keratinocytes with physiologically relevant
UVB doses induce apoptosis mainly through the intrinsic pathway (62).
Molecular determinants/signalling pathways regulating cell death in UVB-irradiated
keratinocytes are the p53 protein, p38, Fas/Fas-L, and the apoptosome (43). Molecular determi-
nants counteracting UVB-induced apoptosis are Bcl-2, surviving AKT, and NFkB (63). SBC’s
main function is to reduce the risk of malignant transformation, following the tenet “better
death than wrong.” Which death route in SBC is engaged depends on the keratinocyte’s
state, UVB dose, and on the balanced presence of survival and death factors in the keratinocyte
microenvironment. UVB-induced cell death in murine skin and cultured human keratinocytes,
for example, requires p53 in the differentiating population, whereas p53 or p53-regulated pro-
teins rather enhance DNA repair and not apoptosis in the basal layer, to maintain the prolifera-
tive potential of this cellular compartment (64). This assumption is reinforced by the
observation that p53 knockdown by siRNA in normal proliferating keratinocytes does not
prevent apoptosis but enhances cell sensitivity to UVB-induced cell death, whereas it delays
the onset of confluence-induced senescence (65).
Vitamin D Production
The cutaneous photosynthesis of vitamin D3 represents the main source of vitamin D in
humans. It is formed from 7-dehydrocholesterol (7-DHC of provitamin D3), which is present
in large amounts in the cell membranes of keratinocytes of the basal and spinous epidermal
layers. By the action of UVB light, the B ring of 7-DHC can be broken to form previtamin
D3. Previtamin D3 has a very low affinity for vitamin D binding protein (DBP), precluding
its entrance into the circulation. In the lipid bilayer of the membranes, the unstable previtamin
D3 is further isomerized to vitamin D3 by thermal energy. The conformational change due to
this isomerization can project vitamin D3 into the circulation, where it is caught by DBP and
transported to the liver and kidney for further metabolization to 1,25D3 (66). Epidermal kera-
tinocytes not only produce vitamin D3, but also express CYP27A1, CYP2R1, and CYP27B1,
enabling them to convert vitamin D3 via 25D3 to 1,25D3 (67,68).
Vitamin D is a well-known antioxidant in skin, with also an important role in calcium
metabolism. A growing body of evidence shows a reduction in different types of cancers
after intake of vitamin D supplements. Regarding this, UV irradiation might be part of
cancer therapy via elevation of vitamin D levels (69). In addition, results indicate that
vitamin D3 has photoprotective characteristics not related to its endogenous antioxidant
property (70). Consequently, addition of vitamin D3 to cell culture medium leads to heightened
viability, reduced CPD, and less SBC formation after UV irradiation. This protection appears to
be dependent on the dose and the duration of vitamin D exposure and is at least partially a con-
sequence of a vitamin D-induced growth arrest (70– 72).
Melanocyte Tanning Responses

Melanocytes are pigment-producing cells that are found in the basal layer of the epidermis
and disperse melanosomes, containing melanin, among the surrounding keratinocytes.
These melanosomes encapsulate two main classes of pigment found in human skin: eumelanin,
which is brown or black, and pheomelanin, which is reddish-brown. The relative amounts of
these two pigments and the size and density of the melanosomes largely determine the differ-
ences in skin color among humans. Skin color has an enormous effect on the risk of skin cancer
because this constitutive melanin absorbs and reflects a broad spectrum of UVR.
Some skin types respond to UVR by increasing pigment production, what we recognize
as a tanning response (73). The molecular signal-initiating tanning is not well understood, but it
has been suggested to be related to DNA damage or repair (74). Binding of a-melanocyte sti-
mulating hormone to melanocytes also stimulates increased melanin production by a pathway
that includes NO, cGMP, and protein kinase G (75). NO donors or compounds that stimulate
NO production also increase tanning (75).
Unfortunately, the tanning response does not contribute as much photoprotection as
is generally thought. The sun protection factor of a tan is in the range of only 2 to 3 (73).
This may be because the melanin produced in a tan is widely distributed throughout the epi-
dermis and is slowly sloughed off over a week or so as the tan fades. In contrast, constitutive
melanin is deposited as “caps” over the nuclei of keratinocytes, guaranteeing that the genetic
material is well protected.
Wound-Healing Response
It is not possible to get a full picture of the molecular responses to UVR by studying the effects
on individual cells or one cell type. Certainly, UVR directly induces responses in irradiated
cells. However, damaged cells also communicate with each other, as well as with undamaged
cells, by means of cytokines and growth factors. For example, UVR damages the DNA of
keratinocytes as well as other chromophores, which then activates transcription factors, such
as AP-1, AP-2, and NF-kappa B. These in turn increase the gene expression of many genes
including those for proteolytic enzymes that degrade collagen and elastin. Some of these
gene products are cytokines and growth factors that are released and travel to other cells
such as IL-10 and TNFa that alter the immune response of T-cells in the epidermis (whether
or not these cells have been irradiated) (76).
The emerging view is that photoaging is the result of repeated microscopic wound-
healing responses, which over time coalesce into “solar scars” (77). UVR signals directly to
fibroblasts, but also signals from damaged keratinocytes, causes the release of MMP-1,
which selectively degrade large collagen cables (78). As part of this response, MMP-2 and -9,
which are responsible for digesting small collagen fragments, are downregulated by UVR.
This results in the accumulation of collagen fragments, which severs the anchorage of fibro-
blasts and inhibits their ability to produce new collagen. Repeated rounds of this type of imper-
fect wound healing produces many of the microscopic hallmarks of photoaged skin.
CONCLUSIONS
A small fraction of the high-energy UVB (280 – 320 nm) and a significant portion of the UVA
(320 – 400 nm) reach the earth’s surface and penetrate the human skin. Most of the UVB wave-
lengths are absorbed in the epidermis, whereas UVA penetrates deeper into the skin and
reaches the dermis. These wavelengths cause damage to DNA, proteins, and lipids and modu-
late cell signaling and gene expression. The main cellular chromophores for UV are DNA, RNA,
and ROS generating chromophores. The nucleic acids of DNA contain strongly absorbing
chromophores for UVB, the most common result being the CPDs. Activation and synthesis
of many genes are associated with the formation of DNA photoproducts as they trigger
repair processes. UV light-induced damage to RNA has also been identified as a potential
mediator of signaling that can lead to changes in gene expression. UV produces also ROS
through interaction with endogenous photosensitizers. UVB can produce some amount of
ROS; however, UV-induced ROS production becomes more important with UVA. These ROS
can in turn damage proteins, membranes, and DNA and are important triggers for signaling
pathways modulating gene expression.
UV-induced release of cytokines and growth factors which bind to their respective recep-
tors are also important triggers of gene expression. UV can also directly activate these receptors
in ligand-independent way. Direct or indirect activation of these GF and cytokine
receptors subsequently may lead to MAPK signaling and activation of transcription factors,
such as AP-1 and NFkB, known as the UV response.
Cellular adaptive responses to UV damage include growth arrest, repair, and, when
damage is beyond repair, apoptosis. Hence, apoptosis can be considered as a fail-safe mechan-
ism to avoid replication of cells with damaged DNA. The tumor suppressor p53 plays an
important role in this response, which aims at safeguarding the genomic integrity of the cell.
The epidermis not only photosynthesizes vitamin D3 but is also able to convert it to 1,25
vitamin D3. Vitamin D3 has photoprotective characteristics related both to its endogenous anti-
oxidant property and to its capacity to induce growth arrest. UV-induced melanogenesis is
another important photoprotective response of the epidermis.
REFERENCES
1. Yoon J.-H, Lee C.-S, O’Connor TR, et al. The DNA damage spectrum produced by simulated sunlight.
J Mol Biol 2000; 299:681– 693.
2. Courdavault S, Baudouin C, Chreveron M, et al. Larger yield of cyclobutane dimers than 8-oxo-7,8-
dihydroguanine in the DNA of UVA-irradiated human skin cells. Mutat Res 2004; 556:135– 142.
3. Sancar A, Lindsey-Boltz L, Unsal-Kacmaz K, et al. Molecular mechanisms of mammalian DNA repair
and the DNA damage checkpoints. Ann Rev Biochem 2004; 73:39– 85.
4. Cleaver J. Common pathways for ultraviolet skin carcinogenesis in the repair and replication defec-
tive groups of xeroderma pigmentosum. J Dermatol Sci 2000; 23(1):1– 11.
5. Ziegler A, Jonason AS, Leffell DJ, et al. Sunburn and p53 in the onset of skin cancer. Nature 1994; 372:
773– 776.
6. Ansel J, Perry P, Brown J, et al. Cytokine modulation of keratinocyte cytokines. J Invest Dermatol
1990; 94:101S– 107S.
7. Luger TA, Schwarz T. Evidence for an epidermal cytokine network. J Invest Dermatol 1990;
95:100S– 104S.
8. Enk AH, Katz SI. Early molecular events in the induction phase of contact sensitivity. Proc Natl Acad
Sci USA 1992, 89:1398– 1402.
9. Hildesheim J, Fornace AJ Jr. Invited Mini Review: the dark side of light: the damaging effects of UV
rays and the protective efforts of MAP kinase signalling in the epidermis. DNA Repair 200; 3:567– 580.
10. Yarosh D, Both D, Kibital J, et al. Regulation of TNFa production and release in human and mouse
keratinocytes and mouse skin after UV-B irradiation. Photodermatol Photoimmunol Photomed
2000; 16:263– 270.
11. Pupe A, Degreef H, Garmyn M. Induction of tumor necrosis factor-alpha by UVB: a role for reactive
oxygen intermediates and eicosanoids. Photochem Photobiol. 2003; 78(1):68– 74.
12. Heck DE, Gerecke DR, Vetrano AM, et al. Solar ultraviolet radiation as a trigger of cell signal trans-
duction. Toxicol Appl Pharmacol 2004; 195:288– 297.
13. Deliconstantinos G, Villiotou V, Stavrides JC. Release by ultraviolet B (u.v.B) radiation of nitric oxide
(NO) from human keratinocytes: a potential role for nitric oxide in erythema production. Br J Phar-
macol 1995; 114:1257– 1265.
14. Kuhn A, Fehsel K, Lehmann P, et al. Aberrant timing in epidermal expression of inducible nitric
oxide synthase after UV irradiation in cutaneous Lupus erythematosus. J Invest Dermatol 1998;
111:149– 153.
15. Nabeyrat E, Jones GE, Fenwick PS, et al. Mitogen-activated protein kinases mediate peroxynitrite-
induced cell death in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2003;
284:L1112 – L1120.
16. Klotz LO, Schroeder P, Sies H. Peroxynitrite signalling: receptor tyrosine kinases and activation of
stress-responsive pathways. Free Radical Biol Med 2002; 33:737– 743.
17. Cooke CL, Davidge ST. Peroxynitrite increases ions through NFkB and decreases prostacyclin
synthase in endothelial cells. Am J Physiol 2002; 282:C395– C402.
18. Romero-Graillet C, Aberdam E, Clement M, et al. Nitric oxide produced by ultraviolet-irradiated
keratinocytes stimulates melanogenesis. J Clin Invest 1997; 99(4):635– 642.
19. De Fabo Ec, Noonan FP. Mechanism of immune suppression by ultraviolet irradiation in vivo.
I. Evidence for the existence of a unique photoreceptor in skin and its role in photo-immunology.
J Exp Med 1983; 158:84 –98.
20. Haralampus-Grynaviski N, Ransom C, Ye T, et al. Photogeneration and quenching of reactive oxygen
species by urocanic acid. J Am Chem Soc 2002; 124:3461– 3468.
21. Magnoni C, Euclidi E, Benassi L, et al. Ultraviolet B radiation induces activation of neutral and acidic
sphingomyelinases and ceramide generation in cultured normal human keratinocytes. Toxicol In
Vitro 2002; 16:349– 355.
22. Miller CC, Hale P, Pentland AP. Ultraviolet B injury increases prostaglandin synthesis through a
tyrosine kinase-dependent pathway. Evidence for UVB-induced epidermal growth factor receptor
activation. J Biol Chem 1994; 269:3529– 3533.
23. Barber LA, Spandau DF, Rathman SC, et al. Expression of the platelet-activating factor receptor
results in enhanced ultraviolet B radiation-induced apoptosis in a human epidermal cell line. J Biol
Chem 1998; 273:18891– 18897.
24. Aragane Y, Kulms D, Metze D, et al. Ultraviolet light induces apoptosis via direct activation of CD95
(Fas/APO-1) independently of its ligand CD95L. J Cell Biol 1998; 140:171– 182.
25. Rosette C and Karin M. Ultraviolet light and osmotic stress: activation of the JNK cascade through
multiple growth factor and cytokine receptors. Science 1996; 274:1194 – 1197.
26. Coffer PJ, Burgering BM, Peppelenbosch MP, et al. UV activation of receptor tyrosine kinase activity.
Oncogene 1995; 11:561– 569.
27. Gross S, Knebel A, Tenev T, et al. Inactivation of protein-tyrosine phosphatases as mechanism of
UV-induced signal transduction. J Biol Chem 1999; 10:26378– 26386.
28. Marchese C, Maresca V, Cardinali G, et al. UVB-induced activation and internalization of keratinocyte
growth factor receptor. Oncogene 2003; 22:2422– 2431.
29. Tobin D, Van Hogerlinden M, Toftgard R. UVB-induced association of tumor necrosis factor (TNF)
receptor 1/TNF receptor-associated factor-2 mediates activation of Rel proteins. Proc Natl Acad Sci
USA 1998; 95:565– 569.
30. Fisher GJ, Talwar HS, Lin J, et al. Retinoic acid inhibits induction of c-jun protein by ultraviolet radi-
ation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human
skin in vivo. J Clin Invest 1998; 101:1432– 1440.
31. Bode AM, Dong Z. Mitogen-activated protein kinase activation in UV-induced signal transduction.
Sci STKE 2003; 167:RE2.
32. Assefa Z, Garmyn M, Bouillon R, et al. Differential stimulation of ERK and JNK activities by
ultraviolet B irradiation and epidermal growth factor in human keratinocytes. J Invest Dermatol
1997; 108:886– 891.
33. Nomura M, Kaji A, Ma WY, et al. Mitogen- and stress-activated protein kinase 1 mediates activation
of Akt by ultraviolet B irradiation. J Biol Chem 2001; 276:25558– 25567.
34. Wang HQ, Quan T, He T, et al. EGF receptor-dependent, NF-kB independent activation of PI-3-kinase:
Akt pathway inhibits ultraviolet irradiation-induced caspases 3, 8, and 9 in human keratinocytes.
J Biol Chem 2003; 278:45737– 45745.
35. Laskin JD, Heck DE, Laskin DL. The ribotoxic stress response as a potential mechanism for MAP
kinase activation in xenobiotic toxicity. Toxicol Sci 2002; 69:289– 291.
36. Iordanov MS, Choi RJ, Ryabinina OP, et al. The UV (ribotoxic) stress response of human
keratinocytes involves the unexpected uncoupling of the Ras-extracellular signal-regulated kinase
signaling cascade from the activated epidermal growth factor receptor. Mol Cell Biol 2002;
22:5380– 5394.
37. Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature 2000;
408:433– 439.
38. Unsal-Kacmaz K, Makhov AM, Griffith JD, et al. Preferential binding of ATR protein to UV-damaged
DNA. Proc Natl Acad Sci USA 2002; 99:6673– 6678.
39. Decraene D, Agostinis P, Pupe A, et al. Acute response of human skin to solar radiation: regulation
and function of the p53 protein. J Photochem Photobiol B: Biol 2001; 63:78– 83.
40. Latonen L, Laiho M. Cellular UV damage responses—functions of tumor suppressor p53. Biochim
Biophys Acta 2005;1755:71 –89.
41. Decraene D, Smaers K, Gan D, et al. A synthetic superoxide dismutase/catalase mimetic (EUK-134
inhibits membrane-damage-induced activation of mitogen-activated protein kinase pathways and
reduces p53 accumulation in ultraviolet B-exposed primary human keratinocytes. J Invest Dermatol
2004; 122(2):484– 491.
42. Orlowski RZ, Baldwin AS Jr. NF-kappaB as a therapeutic target in cancer. Trends Mol Med 2002;
8:385– 389.
43. Assefa Z, Van Laethem A, Garmyn M, et al. Ultraviolet radiation-induced apoptosis in keratinocytes:
on the role of cytosolic factors, Biochim Biophys Acta 2005; 1755(2):90– 106.
44. Simon MM, Aragane Y, Schwarz A, Luger TA, Schwarz T. UVB light induces nuclear factor kappa B
(NF kappa B) activity independently from chromosomal DNA damage in cell-free cytosolic extracts.
45. Adachi M, Gazel A, Pintucci G, et al. Specificity in stress response: epidermal keratinocytes exhibit
specialized UV-responsive signal transduction pathways. DNA Cell Biol 2003; 22:665– 677.
46. Beak SM, Lee YS, Kim JA. NADPH oxidase and cyclooxygenase mediate the ultraviolet B-induced
generation of reactive oxygen species and activation of nuclear factor-kappaB in HaCaT human
keratinocytes. Biochimie 2004; 86:425– 429.
47. Köck A, Schwarz T, Kirnbauer R, et al. Human keratinocytes are a source for tumor necrosis factor
a. Evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp
Med 1990; 172:1609– 1614.
48. Claerhout S, Van Laethem A, Agostinis P. Pathways involved in sunburn cell formation: deregulation
in skin cancer. Photochem Photobiol Sci 2006; 5(2):199– 207.
49. Wisdom R. AP-1: one switch for many signals. Exp Cell Res 1999; 253:180– 185.
50. Rittie L, Fisher GJ. UV-light induced signal cascades and skin aging. Ageing Res Rev 2002;
1(4):705– 720.
51. Bowden GT. Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signalling. Nat
Rev Cancer 2004; 4:23– 35.
52. Decraene D, Smaers K, Maes D, Matsui M, Declercq L, Garmyn M. A low UVB dose, with the poten-
tial to trigger a protective p53-dependent gene program, increases the resilience of keratinocytes
against future UVB insults. J Invest Dermatol 2005; 125(5):xviii– xix.
53. Lee KM, Lee JG, Seo EYE, et al. Analysis of genes responding to ultraviolet B irradiation of HaCaT
keratinocytes using a cDNA microarray. Br J Dermatol 2005; 152:52– 59.
54. Enk AD, Jacob-Hirsch J, Gal H, et al. The UVB-induced gene expression profile of human epidermis
in vivo is different from that of cultured keratinocytes. Oncogene 1006:1 – 14.
55. Petrocelli T, Poon R, Drucker DJ, Slingerland JM, Rosen CF. UVB radiation induces p21Cip1/WAF1 and
mediates G1 and S phase checkpoints. Oncogene 1996; 12:1378– 1396.
56. Courtois SJ, Segaert S, Degreef H, Bouillon R, Garmyn M. Ultraviolet B suppresses vitamin D receptor
gene expression in keratinocytes. Biochem Biophys Res Commun 1998; 246:64 – 69.
57. Yoon K, Smart RC. C/EBPalpha is a DNA damage-inducible p53 regulated mediator of the G1
checkpoint in keratinocytes. Mol Cell Biol 2004; 24(24):10650– 10660.
58. Hermeking H, Lengauer C, Polyak K, et al. 14-3-3 sigma is a p53-regulated inhibitor of G2/M
progression. Mol Cell 1997; 1(1):3– 11.
59. Maeda T, Hanna AN, Sim AB, Chua PP, Chong T, Tron VA. GADD45 regulates G2/M arrest, DNA
repair, and cell death in keratinocytes following ultraviolet exposure. Soc Invest Dermatol 2002;
119(1):22– 26.
60. Pavey S, Russell T, Gabrielli B. G2 phase cell cycle arrest in human skin following UV irradiation.
Oncogene 2001; 20(43):6103– 6110.
61. Kulms D, Poppelman B, Yarosh D, et al. Nuclear and cell membrane effects contribute independently
to the induction of apoptosis in human cells exposed to UVB radiation. Proc Natl Acad Sci USA 1999;
96:7974– 7979.
62. Van Laethem A, Van Kelst S, Lippens, et al. Activation of p38 MAPK is required for Bax translocation
to mitochondria, cytochrome c release and apoptosis. FASEB J 2004; 18(15):1946– 1948.
63. Van Laethem A, Claerhout S, Garmyn M. The sunburn cell: regulation of death and survival of the
keratinocyte. Int J Biochem Cell Biol 2005; 37(8):1547– 1558.
64. Tron VA, Trotter MJ, Tang L, et al. p53-regulated apoptosis is differentiation dependent in ultraviolet
B-irradiated mouse keratinocytes. Am J Pathol 1998; 153(2):579– 585.
65. Chaturvedi V, Qin JZ, Stennet D, et al; Resistance to UVB induced apoptosis in human keratinocytes
during accelerated senescence in associated with functional inactivation of p53. J Cell Physiol 2004;
198:100– 109.
66. Holick MF. Evolution and function of vitamin D. Recent Results Cancer Research 2003; 164:3– 28.
67. Lehmann B, Tiebel O, Meurer M. Expression of vitamin D3 25-hydroxylase (CYP27) mRNA after
induction by vitamin D3 or UVB radiation in keratinocytes of human skin equivalents—a preliminary
study. Arch Dermatol Res 1999; 291:507– 510.
68. Vantieghem K, Kissmeyer AM, De Haes P, et al. UVB-induced production of 1,25-dihydroxyvitamin
D3 and vitamin D activity in human keratinocytes pretreated with a sterol Delta7-reductase inhibitor.
J Cell Biochem 2006; 98(1):81– 92.
69. Grant WB. Ecologic studies of solar UV-B radiation and cancer mortality rates. Recent Results Cancer
Res 2003; 164:371 – 377.
70. Lee J, Youn JI. The photoprotective effect of 1,25-dihydroxyvitamin D3 on ultraviolet light B-induced
damage in keratinocyte and its mechanism of action. J Dermatol Sci 1998; 18:11 – 18.
71. De Haes P, Garmyn M, Degreef H, et al. 1,25-Dihydroxyvitamin D3 inhibits ultraviolet B-induced
apoptosis, Jun kinase activation, and interleukin-6 production in primary human keratinocytes.
J Cell Biochem 2003; 89:663– 673.
72. De Haes P, Garmyn M, Verstuyf A, et al. 1,25-Dihydroxyvitamin D3 and analogues protect primary
human keratinocytes against UVB-induced DNA damage. J Photochem Photobiol B 2005; 78(2):
141– 148.
73. Young A, Sheehan J. UV-induced pigmentation in human skin. In: Giacomoni P, ed. Sun Protection in
Man. New York: Elsevier, 2001:357– 375.
74. Eller MS, Gilchrest BA. Tanning as part of the eukaryotic SOS response. Pigment Cell Res 2000; 8:
94– 97.
75. Brown D. Skin pigment enhancers. In: Giacomoni P, ed. Sun Protection in Man. New York: Elsevier,
2001: 637 – 675.
76. Barr R, Walker S, Tsang W, et al. Suppressed alloantigen presentation, increased TNFa, IL-1, IL-
rRa, IL-10 and modulation of TNF-R in UV-irradiated human skin. J Invest Dermatol 1999;
112:692– 698.
77. Fisher GJ, Datta SC, Talwar HS, et al. Molecular basis of sun-induced premature skin aging and
retinoid antagonism. Nature 1996; 379:335– 339.
78. Brennan M, Bhatti H, Nerusu KC, et al. Matrix metalloproteinase-1 is the major collagenolytic
enzyme responsible for collagen damage in UV-irradiated human skin. Photochem Photobiol 2003;
78:43– 48.
BIBLIOGRAPHY
1. An KP, Athar M, Tang X, et al. Cyclooxygenase-2 expression in murine and human nonmelanoma skin
cancers: implications for therapeutic approaches. Photochem Photobiol 2002; 76:73– 80.
2. Grether-Beck S, Timmer A, Felsner I, et al. Ultraviolet A-induced signalling involves a ceramide-
mediated autocrine loop leading to ceramide de novo synthesis. J Invest Dermatol 2005; 125:545– 553.
3. Hellemans L, Corstjens H, Neven A, et al. Antioxidant enzyme activity in human stratum
corneum shows seasonal variation with an age-dependent recovery. J Invest Dermatol 2003; 120:
434 – 439.
4. Ogawa F, Sander C, Hansel A, et al. The repair enzyme peptide methionine-S-sulfoxide reductase
is expressed in human epidermis and upregulated by UVA radiation. J Invest Dermatol 2006; 126:
1128 – 1134.
5 Photoimmunology
Thomas Schwarz
Department of Dermatology, University of Kiel, Kiel, Germany
Gary M. Halliday
Dermatology Research Laboratories, Melanoma and Skin Cancer Research Institute, University of Sydney,
Sydney, Australia
B Ultraviolet radiation suppresses the immune system in a specific rather

than a general fashion.
B Both UVB and UVA can affect the immune system though by different
mechanisms.
B UVB can suppress the immune system both in a local and systemic
fashion.
B UVB-induced immunosuppression is a complex process in which

alteration of antigen-presenting cells, release of immunosuppressive
cytokines, and induction of regulatory T-cells are involved.
B UV-induced immunosuppression certainly contributes to

photocarcinogenesis.
B A variety of therapeutic effects of UV radiation may be due to its

immunosuppressive effects.
56 Schwarz and Halliday
INTRODUCTION
ore than 25 years have passed since the discovery that ultraviolet (UV) radiation can
M affect the immune system. Since then, numerous studies in the field of photoimmunol-
ogy have tried to identify the biological impact of UV-induced immunosuppression. The
vast majority of photoimmunologic studies utilized UVB, although many studies have used
sources contaminated with UVC that does not reach the surface of the earth, and there is
also recent evidence that the long wave range (UVA, 320– 400 nm) can affect the immune
system. To better understand the biological impact of UV radiation on human health, great
efforts have been made to identify the molecular mechanisms underlying UV-induced
immunosuppression.
UV radiation is divided into three wavebands, UVC (200 – 290 nm), UVB (290 –320 nm),
and UVA (320 –400 nm). Longer wavelengths make up the visible light portion of sunlight.
UVC is absorbed by stratospheric ozone and the atmosphere and does not reach the surface
of the earth, as can be seen in Figure 1. However, many studies in photoimmunology have
used UV sources contaminated with UVC and these need to be treated with caution, as their
relevance to human biology or health is unclear. A small amount of UVB is present in terrestrial
sunlight, with about 20-fold greater levels of UVA. The intensity of different wavebands alone
does not indicate their biological effectiveness, as this is also dependent on absorption by
molecules in the skin (chromophores), and penetration of the skin. Shorter wavelength UVB
does not penetrate the skin as deeply as longer wavelength UVA (1); however, the shorter
wavelengths have greater energy per photon. These issues mean that the effects of different
wavebands on immunity can only be determined experimentally and are complex. The
immune system is an intricate organ with multiple levels of regulation at the molecular and
cellular levels. It also has components that work locally in the skin, and aspects that require
activation and regulation in secondary lymphoid organs, particularly skin draining lymph
nodes. Considering the nature of UV, the multiple potential chromophores in the skin and
the multifaceted cellular and molecular components of the immune system that are potential
targets for dysregulation by UV, it is not surprising that photoimmunology is an intricate
and incompletely understood topic.
THE SKIN’S IMMUNE SYSTEM

Immune responses can be divided into two arms, cellular and humoral, which are responsible
for immune recognition and destruction of the invading pathogen or skin cancer. They destroy
FIGURE 1 Sunlight measured in Sydney on November 18, 2004 at 3:15 PM on a cloudless afternoon at 1 nm intervals.
Photoimmunology 57
their target in different ways. Humoral immunity is due to B lymphocytes, which reside in sec-
ondary lymphoid organs where they secrete antibody, complex proteins that enter the blood
stream and from there find their target to cause its destruction by activation of a number of
mechanisms, including phagocytosis and the complement cascade. This contrasts with cellular
immunity, mediated by T lymphocytes. T cells, like B cells, become activated in secondary lym-
phoid organs, primarily skin draining lymph nodes, but unlike T cells they destroy their target
from close range, and therefore need to leave the secondary lymphoid organs and migrate to
the skin where they physically interact with their target, causing its destruction via a variety
of mechanisms. These include the activation of apoptosis by engaging with the Fas molecule
on their target cells (2); insertion of channels into the cell membrane of the target for secretion
of granzyme, which also initiates apoptosis of the target cell (3); or secretion of a variety of
cytokines such as lymphotoxin and interferon (IFN)-g that act at close range, destroying
their target.
Activation of both cellular and humoral immunity has grave consequences. It utilizes
large amounts of the body’s reserves of energy and protein and could destroy normal tissue.
Consequently, the activation of immunity has many checks and balances in the form of
T-helper cells required for activation of the effector T or B cells, and T regulatory or suppressor
lymphocytes that inhibit activation of the effector lymphocytes. Prior to first encounter with an
antigen, there are only a few lymphocytes in the body capable of recognizing any particular
antigen. During activation, these specific lymphocytes undergo massive levels of proliferation.
While many of these cells arising from clonal proliferation of the original few specific lympho-
cytes die after the target has been eliminated, many do not, and instead differentiate into
memory lymphocytes. Consequently, after resolution of the immune response there are
many more specific lymphocytes in the body than there were before initial encounter with
antigen. There is a major difference between these memory lymphocytes and naı̈ve lympho-
cytes that have not encountered antigen in addition to their vaster numbers; they are easier
to reactivate upon a subsequent encounter with the same antigen. Secondary or memory
immunity occurs faster than primary immunity due to the larger number of memory lympho-
cytes and their reduced reliance upon receiving activation signals. Nevertheless, as will be dis-
cussed subsequently, UV suppresses both the initial activation of naı̈ve lymphocytes and the
reactivation of memory lymphocytes. These cellular interactions, which coordinate immunity,
occur in the skin draining lymph nodes, and are dependent upon initiating signals from
antigen-presenting cells that migrate from the skin to these lymph nodes with antigen.
Before activation of immunity, the lymphocytes that cause the response reside in a different
part of the body to the target. The lymphocytes are in skin-draining lymph nodes, whereas
the target requiring destruction is in the skin. This problem is resolved by dendritic cells
(DCs) that reside in the epidermis, called Langerhans cells (LCs), or dermis, called dermal
DC (Fig. 2). These sample their environment, which may contain a target antigen to be
destroyed, and then transport this to the skin-draining lymph nodes where they interact
with the lymphocytes (4).
While many cell types, including B lymphocytes and macrophages, are involved in
antigen presentation or can reactivate memory lymphocytes, DC are the only type of
antigen-presenting cell capable of initiating activation of naı̈ve lymphocytes upon their first
encounter with antigen, and are therefore often referred to as professional antigen-presenting
cells (5). While skin-derived DC carry the antigen to draining lymph nodes, it is not clear
whether they are primarily responsible for presenting antigen to and activating lymphocytes,
as they pass the antigen to other DC that are resident in the lymph nodes and have not arrived
there from the skin (6,7). In addition to other types of antigen-presenting cells, such as B lym-
phocytes and macrophages within draining lymph nodes, there are many subtypes of DC
within lymph nodes that are likely to have specialized functions during induction of immunity
(8). Dermal DC arrive at the lymph node earlier than epidermally derived LC, at least under
some circumstances (9), raising the distinct possibility that, depending upon antigen concen-
tration and localization within the skin, different waves of DC at different times, which then
pass the antigen to other antigen-presenting cells, is likely to be required for optimal T-cell acti-
vation. Elegant studies have visualized the migration of LC through the basement membrane
separating the epidermis from dermis, and utilization of cytoplasmic processes to pull
FIGURE 2 Immunology of the skin. Infection of the epidermis with bacteria or virus results in production of factors,
such as LPS, that bind to toll-like receptors on Langerhans cells (LCs) inducing their migration from the epidermis.
Keratinocytes (K) stressed by the infection or other stimuli produce cytokines, including tumor necrosis factor and
interleukin-1b, that also induce LC migration from the epidermis. The LC and dermal dendritic cells take up antigen
(A) from the infectious agent or developing tumor, and migrate via dermal lymphatics to draining lymph nodes.
Here they pass the antigen to other antigen-presenting cells, such as lymph node resident dendritic cells and B
lymphocytes (B). These antigen-presenting cells activate antigen-specific T lymphocytes (T) resulting in clonal
expansion of these specific T cells into either long-lived memory T cells (Tm) or T effector lymphocytes (Te). The
effector T cells then migrate via the blood stream to the skin where they destroy the antigen-bearing target cells.
The UV interferes with this process resulting in immunosuppression. Abbreviations: IL-1b, interleukin-1b; LPS,
lipopolysaccharide; TNF, tumor necrosis factor.
themselves along collagen fibrils within the dermis during their migration from the epidermis
to draining lymph nodes (10). Additionally, LC need to disengage themselves from tight junc-
tions with keratinocytes via E-cadherin to enable them to leave the epidermis (11,12). This is
likely to explain why LC migration to draining lymph nodes takes longer than dermal DC
migration.
During DC migration from the skin to draining lymph nodes, they undergo functional
maturation whereby they become less able to take up and process antigen, but more capable
of presenting the antigen to T cells, resulting in their activation (13,14). These changes in LC
as they mature into a phenotype with greater ability to activate T lymphocytes include
increased expression of major histocompatibility complex (MHC) II molecules; costimulatory
molecules, such as CD86 and CD40; and increased production of T-cell activating cytokines,
such as interleukin (IL)-12 (15,16).
Many factors regulate this cascade of cellular events resulting in skin immunity, includ-
ing the production of certain molecules commonly produced by many infectious agents, release
of cytokines from keratinocytes, nerve fibers, and other mediators. Keratinocytes and mast cells
produce a wide range of cytokines and other soluble factors that regulate skin immunity,
including tumor necrosis factor (TNF) and IL-1b that enhance DC migration from the skin
(17,18), transforming growth factor b (TGFb) that inhibits DC migration from the skin (19),
IL-10 that inhibits skin immunity (20), and prostaglandins (PGs) such as PGE2 (21,22). All of
these factors regulate skin immunity at other levels in addition to DC migration or function,
such as T-cell function. Nerves in the skin produce factors, such as substance P and calcitonin
gene-related peptide (CGRP), that also influence skin immunity by regulating DC in addition
to blood flow and T-cell migration into the skin across endothelial cells lining blood vessels
(23,24). Pathogens produce a range of common molecules, such as lipopolysaccharide (LPS)
and single stranded RNA, that can be recognized by toll-like receptors on DC, initiating
their migration and maturation (25,26). Thus, recognition of factors, such as LPS, or altered pro-
duction of regulatory factors by pathogen-induced stress on keratinocytes, mast cells, or
nerves, can initiate skin immunity.
Photoimmunology 59
Considering the complexities of both the induction and mediation of skin immunity, the
multiple cell types, and regulatory factors involved, there are multiple levels at which UVB and
UVA radiation can influence this process, modulating the induction of primary or the reactiva-
tion of memory immunity. These include modulation of LC or dermal DC maturation, antigen
uptake, migration from the skin, interaction with lymph node antigen-presenting cells, acti-
vation of effector, regulatory or memory lymphocytes, migration of effector lymphocytes
into the skin, or the eventual function of effector lymphocytes. UV modulation of any of the
cellular or molecular events that regulate skin immunity will affect the final response.
UV RADIATION SUPPRESSES THE INDUCTION OF LOCAL OR SYSTEMIC

PRIMARY IMMUNITY AS WELL AS MEMORY, OR RECALL IMMUNITY
First evidence that UV radiation influences the immune system was the observation that UV
radiation inhibits the immunologic rejection of transplanted tumors. Skin tumors induced by
chronic UV exposure in mice are highly immunogenic since they are rejected when trans-
planted into naı̈ve syngeneic hosts (27). However, when the recipient mice were given immu-
nosuppressive drugs, the injected tumors were not rejected but grew, implying that the
rejection is immunologic in nature. Rejection was also prevented when the recipient
animals received an exposure to UVB radiation instead of immunosuppressive drugs. This
clearly indicated that UV radiation could act in a similar manner to immunosuppressive
drugs.
The same phenomenon can be observed for other immunologic in vivo models, the
induction of contact hypersensitivity (CHS) or delayed type hypersensitivity (DTH) responses,
induced by epicutaneous application of contact allergens or injection of antigens into the
dermis, respectively. The CHS and DTH differ from each other not only due to the site of
antigen exposure (epidermal or dermal), but also to the local antigen-presenting cell most
likely involved. For CHS the local antigen-presenting cell that first encounters the antigen
will be LC, whereas for DTH it will be the dermal DC. Exposure to UV causes a time-dependent
enhancement of the differences in local antigen-presenting cells between epidermis and dermis
as it induces the migration of IL-10 producing macrophages initially into the dermis and then
into the epidermis at later times (28,29). Furthermore, undefined factors produced by UV-
irradiated keratinocytes that suppress DTH but not CHS have been described (30), and
UV-induced IL-10 appears to be involved in the suppression of DTH but not CHS (31),
further highlighting the differences between these responses.
To fully develop their antigenic features, reactive, low molecular weight contact sensi-
tizers have to bind to proteins, and thus are called haptens. Trinitrochlorobenzene (TNCB) is
one such chemically reactive contact sensitizer. It conjugates the hapten trinitrophenyl (TNP)
directly to lysine groups on peptides already bound in the MHC-I and MHC-II grooves on
the surface of cells (32). T cells recognize the TNP group, and the peptide itself only affects
T cell recognition of the hapten via its ability to anchor the TNP group into the MHC
groove. Thus, TNP-specific T cells can react to TNP bound to different peptides, provided
that the peptides bind strongly to the MHC molecules (33– 35). It is probably for this reason
that an abnormally large number of T cells respond to contact sensitizers, so that the CHS
response is larger than normal immune responses. On the basis of up-regulation of T cell
activation markers CD11a (LFA-1) and CD44, as well as IFNg production, up to 15% of
lymph node cells have been shown to be hapten responsive (36). In sharp contrast to this,
DTH is usually to a protein or whole cells injected into the dermis. The antigen is taken up, pro-
cessed, and presented conventionally on MHC Class I and II molecules so that both the epitope
recognized by T cells and the MHC anchoring residues are unique to that particular antigen.
The hypersensitivity, therefore, is different to CHS as it is due to hyperimmunization activating
a large number of T cells or a large number of epitopes on the surface of whole cells or complex
proteins. It is difficult to know which is the better model for UV suppression of immunity to
skin tumors or skin infections. Skin tumors arise in the epidermis and therefore the location
of the antigen is modelled by CHS; however, the chemical nature of the protein antigen is
better modelled by a DTH.
FIGURE 3 Ultraviolet (UV) radiation

suppresses the induction of primary
immunity, as well as reactivation of memory,
or secondary immunity. The UV irradiation of
a naı̈ve individual who has not previously been
exposed to the specific antigen, followed by
antigen exposure at the UV-irradiated site
causes what is referred to as local UV-induced
immunosuppression (A). The UV irradiation of
a naı̈ve individual followed by antigen
exposure at a skin site distal to that which
was irradiated causes what is referred to as
systemic UV-induced immunosuppression (B).
The UV exposure of subjects previously
immunized, suppresses reactivation of
memory immunity in response to re-exposure
to the same antigen (C).
Nevertheless, UV suppresses both CHS and DTH, but probably by different mechanisms.
Local immunosuppression refers to the situation where the antigen is applied locally to the
same skin site as the UV radiation. Systemic immunosuppression is when antigen is applied
to a different skin site to that which was irradiated (Fig. 3). Additionally, UV can inhibit
both the activation of a primary immune response in an individual not previously exposed
to that antigen, and also the reactivation of memory immunity in an individual who has
been previously immunized to this specific antigen. Thus, UV can locally or systemically sup-
press the induction of primary, or reactivation of memory immunity. UV suppression of
memory immunity probably explains why UV radiation can be an effective therapy for
chronic autoimmune disorders, such as psoriasis.
For local induction of immunosuppression, painting of haptens on skin areas that have
been exposed to low doses of UV radiation does not induce CHS, whereas administration of
the same compound to the same skin site in an unirradiated animal induces a normal CHS
response (37). Inhibition of the induction of CHS by UV radiation is clearly associated with a
depletion in the number of LC at the site of exposure (37,38). The LCs are the primary
antigen-presenting cells in the epidermis, implying that UV radiation interferes with antigen
presentation. Local inhibition of recall immunity is also associated with UV-reducing LC
from human epidermis (39,40), although it is unclear whether reduced LC causes local suppres-
sion of memory immunity.
Higher UV doses also affect immune reactions induced at a distant, non-UV-exposed site.
Accordingly, CHS cannot be induced in mice that are exposed to high doses of UV radiation
even if the contact allergen is applied at an unirradiated site (41). Similarly, UV causes systemic
suppression of the reactivation of memory immunity in humans (42). This systemic immuno-
suppression is certainly mediated by different mechanisms than local immunosuppression.
Photoimmunology 61
The question how UV radiation can interfere with the induction of an immune response at a
distant non-UV-exposed skin area remained unanswered for quite a long time. Nowadays it
is clear that UV radiation stimulates keratinocytes to release immunosuppressive soluble
mediators, including IL-10, which enter the circulation and thereby can suppress the
immune system in a systemic fashion, as subsequently shown.
UVB, UVA, AND SOLAR-SIMULATED UV ARE ALL IMMUNOSUPPRESSIVE

IN BOTH HUMANS AND MICE
UVB and UVA, in addition to a spectrum containing both wavebands, designed to mimic the
UV portion of sunlight [solar-simulated UV (ssUV)], are immunosuppressive in humans
and animal models. UVA, UVB, and ssUV have been shown to be locally and systemically
immunosuppressive in humans (42– 45) and mice (46– 49).
While UVB is universally found by researchers to be immunosuppressive, this is not the
case for UVA, with reports that UVA can even protect the immune system from the suppressive
effects of UVB (50,51). Studies indicate that UVA immunosuppression is strongly regulated by
unknown genes, with not all mouse strains being suppressed under defined conditions (49,52).
Unlike UVB, which has a dose response showing increased levels of immunosuppression with
increasing dose, UVA, at least under some circumstances, has a bell-shaped dose – response
curve so that after the maximum immunosuppressive dose has been reached, higher doses
cause lower levels of immunosuppression until a dose is reached that is no longer suppressive
(49). This all occurs over dose ranges to which humans can be exposed during normal daily
outdoor activities. While this might appear to indicate that UVB is the more important wave-
band in sunlight for causing immunosuppression, ssUV-induced immunosuppression dose
responses have been reported to be identical to UVA. Removal of UVB from the irradiation
source has no discernable effect on ssUV-induced immunosuppression (48,52). Furthermore,
numerous studies using sunscreens to filter UVB from ssUV have shown the importance of
UVA within the sunlight spectrum for causing immunosuppression in humans and mice
(53 – 58).
A further complication in identification of the wavebands responsible for immuno-
suppression is the interactive effects between UVB and UVA and their different time courses
for causing immunosuppression. Recent studies in humans have shown that UVB suppresses
reactivation of memory immunity to antigen applied as early as 24 hours following exposure.
In contrast, 48 hours following UVA exposure is required for antigen to cause immunosuppres-
sion. However, by 72 hours following exposure, ssUV can cause immunosuppression at doses
lower than can be accounted for by either the UVB or UVA wavebands of the ssUV (59). Thus,
there are interactions between pathways activated by UVA and UVB, to make the combination
of these spectra in ssUV suppressive at lower doses than can be achieved by either UVA or UVB
alone (Fig. 4). However, this is dependent upon the time between irradiation and antigen
exposure.
Thus, even before delving into molecular or cellular mechanisms, UV has a complex sup-
pressive effect on the immune system. It is able to suppress not only the activation of primary
immunity at UV-irradiated and -unirradiated skin sites, but also the reactivation of memory
immunity. Additionally, both the UVB and UVA wavebands within sunlight are suppressive,
but they also interact to make sunlight more potent than either waveband alone. Only low
doses of sunlight are required to suppress immunity. Doses that can be achieved with
normal daily activities that are too low to cause sunburn can inhibit immunity. Considering
these issues, and the complexity of skin immunity, it is not surprising that the mechanism of
photoimmunosuppression is complex and incompletely understood.
UV RADIATION AFFECTS ANTIGEN PRESENTATION

Since LC are the major antigen-presenting cells in the epidermis (60), their depletion by UV
seems to be largely responsible for the inhibition of the induction of CHS following UV
exposure (37) and probably an important cause of UV suppression of the reactivation of
FIGURE 4 Solar-simulated UV (ssUV) is more immunosuppressive than the UVB and UVA wavebands, which make up
ssUV. Groups of 15 nickel allergic volunteers were given single exposures to ssUV, UVB or UVA, the UVA and UVB
doses were the relative amounts present in ssUV at each respective point. Nickel was applied 72 hrs after UV to
reactivate memory immunity. While UVB was significantly immunosuppressive only at the highest dose, tested
ssUV suppressed immunity at all doses and was greater than the additive effects of UVB and UVA. X axis shows the
doses given in mJ/cm2. Abbreviation: ssUV, solar-simulated UV. Source: Adapted from Ref. 59.
memory immunity (39). Depending on the UV dose applied the disappearance of LC may be
due to the emigration of LC out of the epidermis since LC harbouring UV-mediated DNA
damage can be detected in the draining lymph nodes (61). UV-induced LC migration from
the skin has been directly observed in sheep (62) and humans (63). Higher doses of UV may
also induce apoptotic death of LC (64). In addition, both UVB and UVA suppresses the
expression of MHC class II surface molecules and adenosinetriphosphatase (ATPase) activity
in LC and their ability to mature (38,65). Both markers, in particular MHC class II, are used
to identify LC in the epidermis. Furthermore, upon UV exposure LC are impaired in their
capacity to present antigens (66). Inhibition of the expression of the adhesion molecule
ICAM-1 by UV radiation may be responsible for impaired clustering between LC and T cells.
Accordingly, inhibition of antigen presentation by UV radiation was proven both in vitro
and in vivo. Injection of antigen-loaded LC or DC exposed to UV radiation does not result in
sensitization, whereas injection of antigen-pulsed unirradiated cells mounts an immune
response (67).
Other antigen-presenting cells, including human peripheral blood-derived DC and
splenic DC, when exposed to UV either in vitro or in vivo are also significantly impaired in
their ability to stimulate allogeneic T cells. The UV radiation suppresses the expression of the
costimulatory B7 surface molecules (CD80/86) that are expressed on antigen-presenting cells
and crucial for interaction with T cells. Accordingly, UV radiation down-regulates the
expression of CD80 and CD86 on human LC and on blood-derived DC (68,69). It was discov-
ered recently that UVB also induces reactive oxygen species that may also contribute to impair-
ment of the function of antigen-presenting cells by UV radiation (70). Reduced lipid
peroxidation by treatment with a-tocopherol inhibits UV from reducing the number of LC
from the epidermis (71). Nitric oxide (NO) is involved in UVA-induced loss of LC from the epider-
mis (72). Antigen presentation, however, may also be impaired indirectly by the photoproduct cis-
urocanic acid (UCA) and by immunosuppressive cytokines or neuropeptides (see subsequently).
The UV irradiation of human and murine skin causes infiltration by IL-10 producing
macrophages and other inflammatory cells into the dermis and epidermis that, along with
the reduction in DC, results in activation of immune suppression (28,73,74). Thus, UV radiation
results in marked changes in skin antigen-presenting cells (APC), with a reduced number of
damaged DC and infiltration by macrophages.
Photoimmunology 63
Despite the effect of UV radiation on DC and macrophages in the skin, UV does not
appear to alter the function or phenotype of DC in draining lymph nodes (75,76). UVB but
not UVA radiation, however, activates B lymphocytes in draining lymph nodes so that they
are larger and express higher levels of MHC Class II and B220 but not costimulatory molecules.
When conjugated to antigen and injected into host mice to present the antigen to the immune
system, these B cells induce immunosuppression via a mechanism that involves the inhibition
of lymph node DC. Because IL-10 has this same effect it appears likely that UVB induction of IL-
10 activates B lymphocytes in draining lymph nodes so that they inhibit DC activation of
immunity (76,77). Thus, in summary, UV disrupts antigen presentation by reducing the
number of DC and increasing the number of suppressive macrophages in the skin, and by acti-
vating B lymphocytes in draining lymph nodes so that they inhibit lymph node DC. It is likely
that after UV, defective DC migrate from the skin to lymph nodes and somehow pass antigen to
other antigen-presenting cells, such as B lymphocytes, and interact in a way that activates T-cell
mediated immunosuppression. The molecular mechanisms by which this occurs have not been
completely elucidated, but will be discussed subsequently.
UV RADIATION INDUCES IMMUNOLOGIC TOLERANCE

Painting of contact allergens onto UV-exposed skin does not result in the induction of CHS but
induces tolerance, since application of the same hapten several weeks later again does not
induce CHS (37). This indicates that the initial application of the hapten onto UV-exposed
skin induces long-term immunologic unresponsiveness. However, immune responses
against other unrelated haptens are not suppressed which excludes that the animals were gen-
erally immunosuppressed by the initial UV exposure. This also implies that the immunologic
unresponsiveness induced by UV radiation is hapten-specific, a phenomenon called hapten-
specific tolerance. Induction of UV-mediated tolerance is not only observed in local but also
systemic immunosuppression (78). The UV-induced tolerance appears to be mediated via
the generation of hapten-specific T suppressor cells, nowadays renamed regulatory T cells.
The UV-induced tolerance has been shown to occur in humans. In one investigation,
which purposefully used a dose of UV too low to induce immunosuppression in all individ-
uals, about 45% of UV immunosuppressed humans were tolerant (79). Tolerance was
hapten-specific, since the individuals responded normally upon subsequent immunization
with other, nonrelated haptens (79). Other studies reported a higher proportion of subjects to
develop tolerance when the hapten was applied onto skin areas exposed to higher erythemo-
genic UV doses (80). It is unclear whether all humans can be rendered tolerant following
exposure to UV radiation. This may be dependent on spectrum, dose, and timing. There are
no sufficient studies to resolve this issue.
UV RADIATION INDUCES T CELLS WITH REGULATORY/SUPPRESSOR ACTIVITY

Hapten-specific tolerance induced by UV radiation appears to be mediated via the generation
of T cells with inhibitory/suppressive activity. Injection of splenocytes from mice tolerized by
the application of a hapten onto UV-exposed skin into naı̈ve syngeneic mice rendered the reci-
pients unresponsiveness to this particular antigen (81). Transfer of tolerance can be observed
both in the local (81) and in the systemic model (82). The UV-induced activation of regulatory
T cells has also been implicated in suppression of memory immunity (83). Although the transfer
of UV-mediated suppression was subsequently shown in a convincing fashion in a variety of
different immunological in vivo models, the postulated UV-induced suppressor T cells were
unable to be phenotypically characterized for many years, causing many to doubt the
concept of suppressor T cells in general immunology. Nowadays, the concept of active suppres-
sion is unanimously accepted in general immunology, but the term regulatory T cells is
preferred to the term suppressor T cells.
For the first time, Shreedar et al. (84) succeeded in isolating T cell clones from UV-exposed
mice, which were sensitized against fluoresceine isothiocyanate. Cloned cells were CD4þ,
CD82, TCR-a/bþ, MHC restricted and specific for fluoresceine isothiocyanate. They produced
IL-10, but not IL-4 or IFN-g. These T cells blocked antigen-presenting cell functions and IL-12
production and, even more importantly, upon injection into naı̈ve recipients suppressed the
induction of CHS against fluoresceine isothiocyanate.
Because of the existence of different UV-mediated tolerance models (local, systemic,
induction, memory, high dose, and low dose), different regulatory T cells with unique pheno-
types appear to be involved in these systems. Currently, best characterized are the regulatory
T cells involved in the low dose suppression of CHS. Cells transferring suppression in this
model appear to belong to the CD4þCD25þ subtype (85); they express CTLA-4 (86), bind the
lectin dectin-2 (87), and in contrast to the classical CD4þCD25þ T cells, release high amounts
of IL-10 upon antigen-specific activation (86). These cells may represent a separate subtype
of regulatory T cells since they exhibit characteristics of naturally occurring regulatory T
cells, for example, expression of CD4 and CD25, but also of type 1 regulatory T (Tr1) cells,
for example, release of IL-10 (88).
Intravenous injection of T cells from UV-tolerized mice into naı̈ve but not sensitized reci-
pients was found to cause unresponsiveness to the respective hapten (89). This gave rise to the
speculation that regulatory T cells inhibit the induction but not the elicitation of CHS, and thus
are inferior to T effector cells. However, when regulatory T cells were injected into the area of
challenge of sensitized mice, the elicitation of CHS was suppressed in a hapten-specific
fashion (85). But when ears of oxazolone-sensitized mice were injected with dinitrofluoroben-
zene-specific regulatory T cells and painted with dinitrofluorobenzene before challenge with
oxazolone, CHS was suppressed. Therefore, once regulatory T cells are activated antigen-
specifically, they suppress in an antigen-independent fashion. This phenomenon is named
bystander suppression and has been initially described for type 1 regulatory T cells (Tr1).
The UV-induced regulatory T cells express the lymph node homing receptor L-selectin but
not the ligands for the skin homing receptors E- and P-selectin. Thus, UV-induced regulatory
T cells are able to inhibit T effector cells, but do not suppress the elicitation of CHS upon intra-
venous injection due to an inability to migrate into the skin. Because of the capacity of by-
stander suppression, speculations exist about the therapeutic potential of regulatory T cells,
which could be generated in response to antigens known to be present in the target organ
that are not necessarily the precise antigen that drives the pathogenic response (90).
However, these findings indicate that this strategy will be successful only if the regulatory
T cells can home to the target organ. The unique migratory behavior of regulatory T cells
might explain why in the vast majority of in vivo studies intravenous injection of regulatory
T cells prevents but does not cure various diseases.
IL-12 has been described by several groups to be able to prevent suppression of CHS by
UV and the development of regulatory T cells and even to break UV-induced tolerance by
unknown mechanisms (91– 93). Since the prevention of UV-induced DNA damage inhibits
UV-induced immunosuppression in humans and mice, DNA damage is regarded as a major
molecular trigger of UV-mediated immunosuppression (39,94 –96). DNA damage has been
implicated in UV suppression of the induction of primary as well as the reactivation of
memory immunity and therefore is an initiator of many manifestations of the effects of UV
on the immune system. The prevention of UV-induced immunosuppression by IL-12 may be
due to its recently described capacity to reduce DNA damage via induction of DNA repair
(97), since the preventative effect of IL-12 is not observed in DNA repair deficient mice (61).
The UV-induced DNA damage appears to be also an important trigger for the induction
of UV-induced regulatory T cells. This assumption is based on the observation that reduced
DNA damage in LC in the regional lymph nodes by IL-12 treatment prevents the development
of regulatory T cells (61). Again, in DNA repair deficient mice, IL-12 failed to prevent the
development of UV-induced regulatory T cells.
The UV-induced regulatory T cells also appear to play an important role in photocarcino-
genesis. Although their crucial role in supporting the development of UV-induced skin tumors
had been already described in the eighties (98), these cells have been characterized only
recently. They appear to belong to the natural killer T cell (NKT) lineage since they express
the T cell marker CD3 and also the NK marker DX5 (99). Transfer of these UV-induced
CD3þDX5þ cells, which produced high amounts of IL-4, into recipient mice suppressed
Photoimmunology 65
DTH responses and anti-tumoral immunity against highly immunogenic UV-induced skin
tumors in an antigen-specific manner.
UV RADIATION INDUCES THE RELEASE OF IMMUNOSUPPRESSIVE MEDIATORS

The UV radiation causes damage to genes, proteins, and lipids either directly or via reactive
oxygen or nitrogen species, disrupting antigen-presenting cells in the skin and lymph nodes,
eventually leading to activation of regulatory T cells that cause immunosuppression.
However, the molecular events downstream of UV that lead to these cellular alterations to
the immune system are only partially understood. The finding that mice, which are exposed
to higher doses of UV radiation, cannot be immunized even when the antigen is applied on
a skin area that was not UV exposed (41) clearly indicated that UV radiation suppresses the
immune system in a systemic fashion and that soluble mediators are likely to be involved.
As UVB and UVA are immunosuppressive but can interact to increase the level of suppression,
there are likely to be a number of different mediators with varying levels of importance,
depending upon the conditions. Keratinocytes have been recognized as a rich source of a
variety of soluble mediators, including immunostimulatory and pro-inflammatory cytokines.
Cytokine release by keratinocytes can be effectively induced by UV radiation (100). The UV
radiation, however, can also stimulate the secretion of immunosuppressive mediators since
intravenous injection into naive mice of supernatants obtained from UV-exposed keratinocytes
renders the recipients unresponsive to hapten sensitization (101). The UV-induced
keratinocyte-derived immunosuppressive mediators may get into the circulation and inhibit
immune reactions in the skin-draining lymph nodes, or at skin areas not directly exposed to
UV radiation, explaining the phenomenon of systemic immunosuppression.
A major soluble player involved in systemic UV-induced immunosuppression appears to
be IL-10. Keratinocyte-derived IL-10, released by UV radiation (102), abrogates the ability of LC
to present antigens to Th1 clones and even tolerizes them. Injection of IL-10 into the skin area of
hapten application prevents the induction of CHS and induces hapten-specific tolerance (103).
In turn, neutralization of IL-10 with an antibody in UV-irradiated mice prevents systemic
UV-induced suppression of the induction of DTH (104).
There are many other soluble mediators involved in UV-induced immunosuppression
besides IL-10. The TNF secreted in response to UV appears to be a major cause of LC migration
from the epidermis to draining lymph nodes where they have impaired function (105). It has
even been proposed that polymorphisms in the TNF gene regulate susceptibility to UVB-
induced immunosuppression (106). The neuropeptide calcitonin gene related peptide (CGRP)
is decreased following UV irradiation and a topical receptor antagonist reduces UV immunosup-
pression, showing that CGRP is also involved in UV immunosuppression, possibly by regulation
of LC (107). Another neuropeptide, a-melanocyte stimulating hormone, is secreted in response to
UV radiation, where it acts as an immunomodulator (108) and contributes to UV-induced immu-
nosuppression and tolerance, possibly by inducing the production of IL-10 and by effects on
antigen-presenting cells (23,109). Inhibition of UV-induced NO production has also been
shown to prevent UV-induced immunosuppression in rodents (107) and humans (110). The
NO inhibition appears to act at least in part by preventing UV-induced loss of LC from the
epidermis (72).
One pathway by which UV radiation causes systemic immunosuppression appears to
involve lipid peroxidation and release of the phospholipid mediator platelet-activating factor
(PAF), which activates cyclooxygenase-2 (COX-2) to produce prostaglandin E2 (PGE2) (111).
The UV-induced PGE2 then initiates a cytokine cascade of IL-4 and IL-10, leading to systemic
immunosuppression (112). IL-4-deficient mice are sensitive to UV-induced local but not systemic
immunosuppression, implying a role for IL-4 in systemic but not local immunosuppression
(113). Lack of IL-4 caused dysfunction in dermal mast cells, which therefore appear to be
involved further downstream of these events. Mast cell deficient mice are not susceptible to
UV-induced systemic immunosuppression and histamine appears to be the mast cells product
that then leads to immunosuppression (114,115). This suggests that a complex cascade of
events initiated by UV and involving PAF, PGE2, IL-4, and mast cell release of histamine
results in changes to antigen-presenting cells in draining lymph nodes, including activation of

suppressor B lymphocytes and activation of regulatory T cells, leading to systemic
immunosuppression.
UROCANIC ACID IS INVOLVED IN UV-INDUCED IMMUNOSUPPRESSION

UCA has been recognized as another chromophore in the epidermis to be involved in UV-
induced immunosuppression (116,117). UCA, a metabolic product of the essential amino
acid histidine, accumulates in the epidermis because keratinocytes lack the enzymes required
for its catabolization. There are two tautomeric forms of UCA, trans (E)- and cis (Z), and
UV converts trans- into cis-UCA. Removal of UCA by tape stripping the epidermis prevents
UV-induced suppression of the induction of CHS, suggesting that cis-UCA is involved in
photoimmunosuppression (116). Furthermore, injection of cis-UCA partially mimics the immu-
noinhibitory activity of UV radiation (118) and antibodies directed against cis-UCA restore
DTH but not CHS responses after UV exposure (119). Cis-UCA also inhibits the presentation
of tumor antigens by LC (120), which can be reversed by IL-12 (121). In addition, injection of
cis-UCA antibodies reduces the incidence of UV-induced skin tumors in a photocarcinogenesis
model, suggesting a role of cis-UCA in the generation of UV-induced skin cancer (121).
BIOLOGICAL RELEVANCE OF UV-INDUCED IMMUNOSUPPRESSION

UV-induced immunosuppression is a highly complex process in which several different path-
ways are involved (Fig. 5). The biological implications of UV-induced immunosuppression
may be several-fold. In a variety of experimental models it has been demonstrated that UV
FIGURE 5 Ultraviolet (UV) radiation causes a cascade of biological events that lead to immunosuppression. UV from
the sun causes DNA damage to Langerhans cells (LCs) and keratinocytes (K), causing the damaged LC to migrate to
draining lymph nodes with antigen (A). UV also causes trans to cis isomerisation of urocanic acid and lipid peroxidation.
These cause production of multiple immunoregulatory factors in the epidermis, including interleukin-10 (IL-10), tumor
necrosis factor, platelet-activating factor, and prostaglandin E2. These may act on the LC or at other levels. UV also
causes infiltration into the dermis of IL-10 secreting macrophages (M), release of histamine from mast cells, and
activation of B lymphocytes (B) into suppressor B cells in draining lymph nodes. In the lymph nodes, interactions
between the antigen-presenting cells, damaged LC, lymph node DC (DC) and suppressor B lymphocytes results in
the activation of regulatory T cells (Treg), which mediate immunosuppression. Abbreviations: PAF, platelet-
activating factor; PGE2, prostaglandin E2; TNF, tumor necrosis factor; UCA, urocanic acid.
Photoimmunology 67
radiation suppresses protective immune responses against viral, bacterial, and fungal infec-
tions (122). The most frequently used infectious agents to study these phenomena are herpes
simplex virus (HSV), listeria, leishmania, mycobacteria, and candida (123).
Exposure of mice previously immunized with HSV to UVB prior to epidermal chal-
lenge with HSV resulted in the development of severe lesions in 92% of mice. Only 59% of
unirradiated mice developed mild lesions (124). This was associated with reduced MHC
class II expression on antigen-presenting cells and therefore may have been due to UVB-
induced immunosuppression. The UVB prior to infection with Mycobacterium bovis bacillus
Calmette-Guerin (BCG) significantly delayed the development of DTH and increased the
number of bacteria in the spleen and lymph nodes (125). Thus, UVB inhibited the devel-
opment of immunity to BCG, enhancing infection. This inhibition of bacterial clearance
could be prevented with anti-IL-10 antibodies suggesting that UVB-induced immuno-
suppression was mediated via production of IL-10, which then prevented bacterial clear-
ance (126).
Other animal experiments indicating that UVB suppresses immunity to infectious agents,
inhibiting resistance to the infection, include the parasite Trichinella spiralis (127,128),
the murine malaria parasite Plasmodium chabaudi (129), the bacteria Listeria monocytogenes
(130), the Lyme spirochete Borrelia burgdorferi (131), and the extracellular Mycobacterium
ulcerans (132).
There is also evidence that UV exacerbates infections in humans, but it is not always clear
whether this is due to immunosuppression or some other effects of UV radiation. The HSV
causes a latent infection of local sensory ganglia in humans, which can be reactivated to
form skin lesions. Exposure of patients with HSV or herpes labialis to UV radiation results in
the development of skin lesions (133,134). A significantly higher frequency of herpes zoster
infection has been reported in the summer months in north-eastern Italy (135). In a cohort of
137 renal transplant patients, a high rate of HSV infections was found in spring, and high
rates of herpes zoster and fungal/yeast infections in summer, indicating an association of
these infections with short-term sunlight exposure. A higher risk of bacterial infections was
associated with a higher lifetime exposure (136). A transient reduction in antibody titre has
been observed in subjects who received their first Hepatitis B vaccination in summer compared
to winter (137). The immune response to antigens of Lepromin induces a granulomatus reac-
tion that limits or suppresses infection and is a measure of immunological activity. It has
been shown that UV irradiation significantly reduces the size of granulomatus reactions, and
suppresses the number of infiltrating lymphocytes in 29 healthy, lepromin-positive contacts
of leprosy patients immunized with Mycobacterium leprae (138). Thus, while the studies in
humans are limited, they support experiments in mice, indicating that UV immunosuppression
reduces immunity to a variety of infectious agents. However, based on daily clinical practice, it
is obvious that acute and severe exacerbations of infectious diseases, especially bacterial infec-
tions following solar exposure, are extremely rare in humans. It is possible that the effect of UV
immunosuppression on infections is subtle, or that chronic exposure is more important than
acute exposure.
However, the immune system not only protects from infectious agents, but also from
malignant cells. Transformed cells in particular in the early stage can be recognized as
“foreign” and attacked by the immune system (tumor immunology). This may apply in par-
ticular for both nonmelanoma skin cancer and malignant melanoma. Striking evidence exists
for a strong correlation between the risk of developing skin cancer and immunosuppression.
Individuals who are pharmacologically immunosuppressed, such as transplant patients,
exhibit a significantly increased risk of skin cancer (139). Patients with a positive history of
skin cancer are more sensitive than controls without a history of skin cancer to UVB-induced
suppression of CHS responses (79).
The negative impact of UV radiation on host defense against skin tumors has been con-
vincingly demonstrated in various experimental animal models. The UV-induced immunosup-
pression enables the outgrowth of transplanted epithelial skin cancers and melanomas in
mice (140 – 143). Specific T cells activated in UVB-irradiated mice by antigen exposure can trans-
fer suppression to normal recipients, inhibiting tumor immunity and therefore enabling
UV-induced skin tumors to grow (144).
Furthermore, restoration or even enhancement of an immune response by topical or sys-

temic application of immunomodulators, such as IFNs or imiquimod, is a successful thera-
peutic strategy for the treatment of skin cancer (145 –147). All this clearly supports the
notion that the immunosuppressive impact of UV radiation may be much more relevant for
carcinogenesis than for the exacerbation of infectious diseases.
CONCLUSION
Exposure to doses of UV radiation that are only 30 – 50% as high as what is required to cause
barely detectable sunburn suppress immunity in humans. Therefore, normal daily outdoor
activities during the spring and summer months are likely to cause some degree of immuno-
suppression in a large proportion of humans. Both the UVB and UVA wavebands contribute
to sunlight-induced immunosuppression, although an interaction between them makes sun-
light more suppressive than either waveband alone. It is therefore important to protect the
skin from both UVB and UVA. UV suppresses immunity to antigens applied to irradiated
skin and also to antigens applied to skin sites distal to the UV radiation indicating that systemic
factors can be released from irradiated skin, disrupting immunity at distant sites. The UV radi-
ation suppresses the activation of primary, and the reactivation of memory immunity. It can
suppress CHS responses initiated in the epidermis and DTH responses initiated in the
dermis. This is of clinical importance as it impedes immune rejection of skin cancers, and
also immune-mediated destruction of skin infections.
Owing to the multiple different experimental systems suppressed by UV and the
dependence on dose, timing, waveband and skin site, we currently do not have a comprehen-
sive understanding of how UV has this potent effect on the immune system. However, many
different molecular and cellular events have been implicated. The molecular mechanisms
responsible for disruption to cellular immunity are initiated by DNA damage, trans to cis
isomerization of UCA, and peroxidation of lipids. These alter the factors produced by
keratinocytes that regulate immunity, resulting in a cascade of factors with production
of PAF leading to PGE2, IL-4, IL-10, and histamine release from mast cells. While these
immunosuppressive factors could then directly effect T cell activation, migration into
skin sites, or their effector function, it appears more likely that they alter antigen-
presenting cells, leading to activation of suppressor lymphocytes, which then suppress skin
immunity.
UV radiation has profound effects on antigen-presenting cells. It damages LC so that they
migrate to lymph nodes with altered function, while causing IL-10 producing suppressor
macrophages to infiltrate the skin and activating B lymphocytes in draining lymph nodes so
that they have suppressor function. It is likely that interaction between these UV-altered
antigen-presenting cells results in the activation of suppressor T lymphocytes. There is good
evidence that these T suppressor cells are responsible for a large amount of the reduction in
immunity caused by UV.
It is both obvious and striking that UV radiation at rather low doses suppresses an
immune response. Thus, one may speculate that a certain degree of immunosuppression
may be beneficial. The skin is an organ which is constantly exposed to potential allergens,
in addition the skin is an organ which is prone to autoimmunity (148,149). Hence, it is tempt-
ing to speculate that a certain degree of constant immunosuppression by daily solar exposure
may prevent the induction of these immune responses. If this is the case it remains to be
clarified in the future. However, even if this turns out to be true, excessive and chronic
solar exposure will remain one of the major environmental threats for human health.
ACKNOWLEDGMENTS
This work was supported by grants of the German Research Association (DFG, SCHW1177/
1-1, SFB415/A16), Federal Ministry of Environmental Protection St.Sch_4491, the National
Health and Medical Research Council of Australia, Cure Cancer Australia, and the CERIES
Award 2004.
Photoimmunology 69
REFERENCES
1. Bruls WA, Slaper H, van der Leun JC, Berrens L. Transmission of human epidermis and stratum
corneum as a function of thickness in the ultraviolet and visible wavelengths. Photochem Photobiol
1984; 40:485– 494.
2. Satchell AC, Barnetson RS, Halliday GM. Increased Fas ligand expression by T cells and tumour
cells in the progression of actinic keratosis to squamous cell carcinoma. Brit J Dermatol 2004;
151:42 –49.
3. Sutton VR, Davis JE, Cancilla M, et al. Initiation of apoptosis by granzyme B requires direct cleavage
of Bid, but not direct granzyme B-mediated caspase activation. J Exp Med 2000; 192:1403– 1413.
4. Halliday GM. Skin immunity and melanoma development. In: Thompson JF, Morton DL, Kroon
BBR, eds. Textbook of Melanoma. London: Martin Dunitz, 2004:25– 42.
5. Steinman RM. Dendritic cells and the control of immunity: enhancing the efficiency of antigen
presentation. Mt Sinai J Med 2001; 68:160– 166.
6. Knight SC, Iqball S, Roberts MS, Macatonia S, Bedford PA. Transfer of antigen between dendritic
cells in the stimulation of primary T cell proliferation. Eur J Immunol 1998; 28:1636– 1644.
7. Carbone FR, Belz GT, Heath WR. Transfer of antigen between migrating and lymph node-resident
DCs in peripheral T-cell tolerance and immunity. Trends Immunol 2004; 25:655– 658.
8. Shortman K, Liu YJ. Mouse and human dendritic cell subtypes. Nat Rev Immunol 2002; 2:151– 161.
9. Kissenpfennig A, Henri S, Dubois B, et al. Dynamics and function of Langerhans cells in vivo:
dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans
cells. Immunity 2005; 22:643– 654.
10. Stoitzner P, Pfaller K, Strossel H, Romani N. A close-up view of migrating Langerhans cells in the
skin. J Invest Dermatol 2002; 118:117 – 125.
11. Tang A, Amagai M, Granger LG, Stanley JR, Udey MC. Adhesion of epidermal Langerhans cells to
keratinocytes mediated by E-cadherin. Nature 1993; 361:82 – 85.
12. Blauvelt A, Katz SI, Udey MC. Human Langerhans cells express E-cadherin. J Invest Dermatol 1995;
104:293– 296.
13. Streilein JW, Grammer SF, Yoshikawa T, Demidem A, Vermeer M. Functional dichotomy between
Langerhans cells that present antigen to naive and to memory/effector T lymphocytes. Immunol
Rev 1990; 117:159– 183.
14. Byrne SN, Halliday GM. Dendritic cells: making progress with tumour regression? Immunol Cell
Biol 2002; 80:520 – 530.
15. Hart DNJ. Dendritic cells—unique leukocyte populations which control the primary immune
response. Blood 1997; 90:3245– 3287.
16. Cumberbatch M, Gould SJ, Peters SW, Kimber I. MHC class-II expression by Langerhans cells and
lymph node dendritic cells—possible evidence for maturation of Langerhans cells following contact
sensitization. Immunology 1991; 74:414– 419.
17. Cumberbatch M, Kimber I. Dermal tumour necrosis factor-alpha induces dendritic cell migration to
draining lymph nodes, and possibly provides one stimulus for Langerhans’ cell migration. Immu-
nology 1992; 75:257– 263.
18. Cumberbatch M, Dearman RJ, Kimber I. Langerhans cells require signals from both tumour necrosis
factor-alpha and interleukin-1-beta for migration. Immunology 1997; 92:388 – 395.
19. Weber F, Byrne SN, Le S, et al. Transforming growth factor-beta(1) immobilises dendritic cells within
skin tumours and facilitates tumour escape from the immune system. Cancer Immunol Immun 2005;
54:898– 906.
20. Kondo S, Mckenzie RC, Sauder DN. Interleukin-10 inhibits the elicitation phase of allergic contact
hypersensitivity. J Invest Dermatol 1994; 103:811– 814.
21. Kanda N, Mitsui H, Watanabe S. Prostaglandin E-2 suppresses CCL27 production through EP2 and
EP3 receptors in human keratinocytes. J Allergy Clin Immunol 2004; 114:1403 –1409.
22. Luft T, Jefford M, Luetjens P, et al. Functionally distinct dendritic cell (DC) populations induced by
physiologic stimuli: prostaglandin E-2 regulates the migratory capacity of specific DC subsets. Blood
2002; 100:1362– 1372.
23. Luger TA, Bhardwaj RS, Grabbe S, Schwarz T. Regulation of the immune response by epidermal
cytokines and neurohormones. J Dermatol Sci 1996; 13:5– 10.
24. Asahina A, Hosoi J, Grabbe S, Granstein RD. Modulation of Langerhans cell function by epidermal
nerves. J Allergy Clin Immunol 1995; 96:1178 – 1182.
25. Blander JM, Medzhitov R. Toll-dependent selection of microbial antigens for presentation by dendri-
tic cells. Nature 2006; 440:808– 812.
26. Suzuki H, Wang BH, Shivji GM, et al. Imiquimod, a topical immune response modifier, induces
migration of Langerhans cells. J Invest Dermatol 2000; 114:135– 141.
27. Kripke ML. Immunologic unresponsiveness induced by UV radiation. Immunol Rev 1984; 80:
87– 102.
28. Meunier L, Batacsorgo Z, Cooper KD. In human dermis, ultraviolet radiation induces expansion of a
CD36(þ) CD11b(þ) CD1(2) macrophage subset by infiltration and proliferation—CD1(þ)
Langerhans-like dendritic antigen-presenting cells are concomitantly depleted. J Invest Dermatol
1995; 105:782– 788.
29. Kang KF, Gilliam AC, Chen GF, Tootell E, Cooper KD. In human skin, UVB initiates early induction
of Il-10 over Il-12 preferentially in the expanding dermal monocytic/macrophagic population. J
Invest Dermatol 1998; 111:31– 38.
30. Kim TY, Kripke ML, Ullrich SE. Immunosuppression by factors released from UV-irradiated epider-
mal cells: selective effects on the generation of contact and delayed hypersensitivity after exposure to
UVA or UVB radiation. J Invest Dermatol 1990; 94:26 – 32.
31. Rivas JM, Ullrich SE. The role of IL-4, IL-10, and TNF-alpha in the immune suppression induced by
ultraviolet radiation. J Leukocyte Biol 1994; 56:769 – 775.
32. Martin S, Lappin MB, Kohler J, et al. Peptide immunization indicates that CD8þ T cells are the
dominant effector cells in trinitrophenyl-specific contact hypersensitivity. J Invest Dermatol 2000;
115:260– 266.
33. Kohler J, Martin S, Pflugfelder U, Ruh H, Vollmer J, Weltzien HU. Cross-reactive trinitrophenylated
peptides as antigens for class II major histocompatibility complex-restricted T cells and inducers of
contact sensitivity in mice. Limited T cell receptor repertoire. Eur J Immunol 1995; 25:92– 101.
34. Martin S, von Bonin A, Fessler C, Pflugfelder U, Weltzien HU. Structural complexity of antigenic
determinants for class I MHC-restricted, hapten-specific T cells. Two qualitatively differing types
of H-2Kb-restricted TNP epitopes. J Immunol 1993; 151:678– 687.
35. Kohler J, Martin S, Pflugfelder U, Ruh H, Vollmer J, Weltzien HU. Cross-reactive trinitropheny-
lated peptides as antigens for class II major histocompatibility complex-restricted T cells and
inducers of contact sensitivity in mice—limited T cell receptor repertoire. Eur J Immunol 1995;
25:92– 101.
36. Xu H, Banerjee A, Dilulio NA, Fairchild RL. Development of effector CD8þ T cells in contact hyper-
sensitivity occurs independently of CD4þ T cells. J Immunol 1997; 158:4721– 4728.
37. Toews GB, Bergstresser PR, and Streilein JW. Epidermal Langerhans cell density determines
whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB. J
Immunol 1980; 124:445– 453.
38. Aberer W, Schuler G, Stingl G, Honigsmann H, Wolff K. Ultraviolet light depletes surface markers of
Langerhans cells. J Invest Dermatol 1981; 76:202– 210.
39. Kuchel JM, Barnetson RS, Halliday GM. Cyclobutane pyrimidine dimer formation is a molecular
trigger for solar-simulated ultraviolet radiation-induced suppression of memory immunity in
humans. Photoch Photobio Sci 2005; 4:577– 582.
40. Kuchel JM, Barnetson RSC, Zhuang L, Strickland FM, Pelley RP, Halliday GM. Tamarind inhibits
solar-simulated ultraviolet radiation-induced suppression of recall responses in humans. Lett
Drug Des Discov 2005; 2:165 – 171.
41. Noonan FP, De Fabo EC, Kripke ML. Suppression of contact hypersensitivity by ultraviolet radi-
ation: an experimental model. Springer Semin Immun 1981; 4:293– 304.
42. Moyal DD, Fourtanier AM. Broad-spectrum sunscreens provide better protection from the suppres-
sion of the elicitation phase of delayed-type hypersensitivity response in humans. J Invest
Dermatol 2001; 117:1186 – 1192.
43. Hersey P, Bradley M, Hasic E, Haran G, Edwards A, McCarthy WH. Immunological effects of solar-
ium exposure. Lancet 1983; 12(March):545– 548.
44. LeVee GJ, Oberhelman L, Anderson T, Koren H, Cooper KD. UVA II exposure of human skin results
in decreased immunization capacity, increased induction of tolerance and a unique pattern of epi-
dermal antigen-presenting cell alteration. Photochem Photobiol 1997; 65:622 –629.
45. Damian DL, Barnetson RS, Halliday GM. Low-dose UVA and UVB have different time courses for
suppression of contact hypersensitivity to a recall antigen in humans. J Invest Dermatol 1999;
112:939–944.
46. Bestak R, Halliday GM. Chronic low-dose UVA irradiation induces local suppression of contact
hypersensitivity, Langerhans cell depletion and suppressor cell activation in C3H/HeJ mice.
47. Halliday GM, Bestak R, Yuen KS, Cavanagh LL, Barnetson RS. UVA-induced immunosuppression.
Mutat Res—Fund Mol M 1998; 422:139– 145.
48. Nghiem DX, Kazimi N, Clydesdale G, Ananthaswamy HN, Kripke ML, Ullrich SE. Ultraviolet A
radiation suppresses an established immune response: Implications for sunscreen design. J Invest
Dermatol 2001; 117:1193 – 1199.
49. Byrne SN, Spinks N, Halliday GM. The induction of immunity to a protein antigen using an adju-
vant is significantly compromised by ultraviolet A radiation. J Photoch Photobio B 2006; 84:128– 134.
50. Reeve VE, Bosnic M, Boehm-Wilcox C, Nishimura N, Ley RD. Ultraviolet A radiation (320– 400 nm)
protects hairless mice from immunosuppression induced by ultraviolet B radiation (280 – 320 nm) or
cis-urocanic acid. Int Arch Allergy Immun 1998; 115:316– 322.
Photoimmunology 71
51. Reeve VE, Tyrrell RM. Heme oxygenase induction mediates the photoimmunoprotective activity of
UVA radiation in the mouse. P Natl Acad Sci USA 1999; 96:9317– 9321.
52. Byrne SN, Spinks N, Halliday GM. Ultraviolet A irradiation of C57BL/6 mice suppresses systemic
contact hypersensitivity or enhances secondary immunity depending on dose. J Invest Dermatol
2002; 119:858– 864.
53. Bestak R, Barnetson RSC, Nearn MR, Halliday GM. Sunscreen protection of contact hypersensitivity
responses from chronic solar-simulated ultraviolet irradiation correlates with the absorption spec-
trum of the sunscreen. J Invest Dermatol 1995; 105:345– 351.
54. Damian DL, Halliday GM, Barnetson RS. Broad-spectrum sunscreens provide greater protection
against ultraviolet-radiation-induced suppression of contact hypersensitivity to a recall antigen in
humans. J Invest Dermatol 1997; 109:146– 151.
55. Fourtanier A, Gueniche A, Compan D, Walker SL, Young AR. Improved protection against solar-
simulated radiation-induced immunosuppression by a sunscreen with enhanced ultraviolet A
protection. J Invest Dermatol 2000; 114:620– 627.
56. Kelly DA, Seed PT, Young AR, Walker SL. A commercial sunscreen’s protection against ultraviolet
radiation-induced immunosuppression is more than 50% lower than protection against sunburn in
57. Poon TSC, Barnetson RS, Halliday GM. Prevention of immunosuppression by sunscreens in humans
is unrelated to protection from erythema and dependent on protection from ultraviolet A in the face
of constant ultraviolet B protection. J Invest Dermatol 2003; 121:184– 190.
58. Wolf P, Hoffmann C, Quehenberger F, Grinschgl S, Kerl H. Immune protection factors of chemical
sunscreens measured in the local contact hypersensitivity model in humans. J Invest Dermatol
2003; 121:1080– 1087.
59. Poon TSC, Barnetson RSC, Halliday GM. Sunlight-induced immunosuppression in humans is
initially because of UVB, then UVA, followed by interactive effects. J Invest Dermatol 2005;
125:840– 846.
60. Stingl G, Tamaki K, Katz SI. Origin and function of epidermal Langerhans cells. Immunol Rev 1980;
53:149– 174.
61. Schwarz A, Maeda A, Kernebeck K, van Steeg H, Beissert S, Schwarz T. Prevention of UV radi-
ation-induced immunosuppression by IL-12 is dependent on DNA repair. J Exp Med 2005;
201:173– 179.
62. Dandie GW, Clydesdale GJ, Radcliff FJ, Muller HK. Migration of Langerhans cells and gamma
delta(þ) dendritic cells from UV-B-irradiated sheep skin. Immunol Cell Biol 2001; 79:41– 48.
63. Kolgen W, Both H, van Weelden H, et al. Epidermal Langerhans cell depletion after artificial ultra-
violet B irradiation of human skin in vivo: apoptosis versus migration. J Invest Dermatol 2002;
118:812– 817.
64. Rattis FM, Concha M, Dalbiezgauthier C, Courtellemont P, Peguetnavarro J. Effects of ultraviolet B
radiation on human Langerhans cells—functional alteration of CD86 upregulation and induction of
apoptotic cell death. J Invest Dermatol 1998; 111:373– 379.
65. Furio L, Berthier-Vergnes O, Ducarre B, Schmitt D, Peguet-Navarro J. UVA radiation impairs pheno-
typic and functional maturation of human dermal dendritic cells. J Invest Dermatol 2005; 125:1032–
1038.
66. Stingl LA, Sauder DN, Iijima M, Wolff K, Pehamberger H, Stingl G. Mechanism of UV-B-induced
impairment of the antigen-presenting capacity of murine epidermal cells. J Immunol 1983;
130:1586–1591.
67. Fox IJ, Sy MS, Benacerraf B, Greene MI. Impairment of antigen-presenting cell function by ultraviolet
radiation. II. Effect of in vitro ultraviolet irradiation on antigen-presenting cells. Transplantation
1981; 31:262– 265.
68. Young JW, Baggers J, Soergel SA. High-dose UV-B radiation alters human dendritic cell costimula-
tory activity but does not allow dendritic cells to tolerize T-lymphocytes to alloantigen in vitro.
Blood 1993; 81:2987– 2997.
69. Weiss JM, Renkl AC, Denfeld RW, et al. Low-dose UVB radiation perturbs the functional expression
of B7.1 and B7.2 co-stimulatory molecules on human Langerhans cells. Eur J Immunol 1995; 25:
2858– 2862.
70. Caceresdittmar G, Ariizumi K, Xu S, Tapia FJ, Bergstresser PR, Takashima A. Hydrogen peroxide
mediates UV-induced impairment of antigen presentation in a murine epidermal-derived dendritic
cell line. Photochem Photobiol 1995; 62:176– 183.
71. Yuen KS, Halliday GM. Alpha-tocopherol, an inhibitor of epidermal lipid peroxidation, prevents
ultraviolet radiation from suppressing the skin immune system. Photochem Photobiol 1997;
65:587– 592.
72. Yuen KS, Nearn MR, Halliday GM. Nitric oxide-mediated depletion of Langerhans cells from the
epidermis may be involved in UVA radiation-induced immunosuppression. Nitric Oxide 2002;
6:313– 318.
73. Kang KF, Hammerberg C, Meunier L, Cooper KD. CD11b(þ) macrophages that infiltrate human epi-
dermis after in vivo ultraviolet exposure potently produce IL-10 and represent the major secretory
source of epidermal IL-10 protein. J Immunol 1994; 153:5256– 5264.
74. Sluyter R, Halliday GM. Enhanced tumor growth in UV-irradiated skin is associated with an influx
of inflammatory cells into the epidermis. Carcinogenesis 2000; 21:1801– 1807.
75. Gorman S, Tan JWY, Thomas JA, et al. Primary defect in UVB-induced systemic immunomodulation
does not relate to immature or funtionally impaired APCs in regional lymph nodes. J Immunol 2005;
174:6677– 6685.
76. Byrne SN, Halliday GM. B cells activated in lymph nodes in response to ultraviolet irradiation or by
interleukin-10 inhibit dendritic cell induction of immunity. J Invest Dermatol 2005; 124:570– 578.
77. Byrne SN, Ahmed J, Halliday GM. Ultraviolet B but not A radiation activates suppressor B cells in
draining lymph nodes. Photochem Photobiol 2005; 81:1366 – 1370.
78. Kripke ML, Morison WL. Studies on the mechanism of systemic suppression of contact hypersensi-
tivity by ultraviolet B radiation. Photodermatol 1986; 3:4– 14.
79. Yoshikawa T, Rae V, Bruins-Slot W, Van den Berg JW, Taylor JR, Streilein JW. Susceptibility to effects
of UVB radiation on induction of contact hypersensitivity as a risk factor for skin cancer in humans.
J Invest Dermatol 1990; 95:530 – 536.
80. Cooper KD, Oberhelman L, Hamilton TA, et al. UV exposure reduces immunization rates and pro-
motes tolerance to epicutaneous antigens in humans—relationship to dose, CD1a-DRþ epidermal
macrophage induction, and Langerhans cell depletion. P Natl Acad Sci USA 1992; 89:8497– 8501.
81. Elmets CA, Bergstresser PR, Tigelaar RE, Wood PJ, Streilein JW. Analysis of the mechanism of unre-
sponsiveness produced by haptens painted on skin exposed to low dose ultraviolet radiation. J Exp
Med 1983; 158:781– 794.
82. Noonan FP, De Fabo EC, Kripke ML. Suppression of contact hypersensitivity by UV radiation and its
relationship to UV-induced suppression of tumor immunity. Photochem Photobiol 1981; 34:683– 689.
83. Nghiem DX, Kazimi N, Mitchell DL, et al. Mechanisms underlying the suppression of established
immune responses by ultraviolet radiation. J Invest Dermatol 2002; 119:600– 608.
84. Shreedhar VK, Pride MW, Sun Y, Kripke ML, Strickland FM. Origin and characteristics of ultra-
violet-B radiation-induced suppressor T lymphocytes. J Immunol 1998; 161:1327– 1335.
85. Schwarz A, Maeda A, Wild MK, et al. Ultraviolet radiation-induced regulatory T cells not only
inhibit the induction but can suppress the effector phase of contact hypersensitivity. J Immunol
2004; 172:1036– 1043.
86. Schwarz A, Beissert S, Grosse-Heitmeyer K, et al. Evidence for functional relevance of CTLA-4 in
ultraviolet-radiation-induced tolerance. J Immunol 2000; 165:1824– 1831.
87. Aragane Y, Maeda A, Schwarz A, Tezuka T, Ariizumi K, Schwarz T. Involvement of dectin-2 in ultra-
violet radiation-induced tolerance. J Immunol 2003; 171:3801– 3807.
88. Beissert S, Schwarz A, Schwarz T. Regulatory T cells. J Invest Dermatol 2006; 126:15 – 24.
89. Glass MJ, Streilein JW. UVB radiation and DNFB skin painting induce suppressor cells universally in
mice. J Invest Dermatol 1990; 94:273– 278.
90. Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001;
2: 816 – 822.
91. Schmitt DA, Owenschaub L, Ullrich SE. Effect of IL-12 on immune suppression and suppressor cell
induction by ultraviolet radiation. J Immunol 1995; 154:5114 – 5120.
92. Muller G, Saloga J, Germann T, Schuler G, Knop J, Enk AH. Il-12 as mediator and adjuvant for the
induction of contact sensitivity in vivo. J Immunol 1995; 155:4661– 4668.
93. Schwarz A, Grabbe S, Aragane Y, et al. Interleukin-12 prevents ultraviolet B-induced local immuno-
suppression and overcomes UVB-induced tolerance. J Invest Dermatol 1996; 106:1187 – 1191.
94. Kripke ML, Cox PA, Alas LG, Yarosh DB. Pyrimidine dimers in DNA initiate systemic immunosup-
pression in UV-irradiated mice. P Natl Acad Sci USA 1992; 89:7516– 7520.
95. Nishigori C, Yarosh DB, Ullrich SE, et al. Evidence that DNA damage triggers interleukin 10 cytokine
production in UV-irradiated murine keratinocytes. P Natl Acad Sci USA 1996; 93:10,354–10,359.
96. Stege H, Roza L, Vink AA, et al. Enzyme plus light therapy to repair DNA damage in ultraviolet-
B-irradiated human skin. P Natl Acad Sci USA 2000; 97:1790– 1795.
97. Schwarz A, Stander S, Berneburg M, et al. Interleukin-12 suppresses ultraviolet radiation-induced
apoptosis by inducing DNA repair. Nat Cell Biol 2002; 4:26 – 31.
98. Fisher MS, Kripke ML. Further studies on the tumor-specific suppressor cells induced by ultraviolet
radiation. J Immunol 1978; 121:1139 – 1144.
99. Moodycliffe AM, Nghiem D, Clydesdale G, Ullrich SE. Immune suppression and skin cancer
development: regulation by NKT cells. Nat Immunol 2000; 1:521– 525.
100. Schwarz T, Urbanski A, Luger TA. Ultraviolet light and epidermal cell derived cytokines. In:
Luger TA, Schwarz T, eds. Epidermal Growth Factors and Cytokines. New York: Marcel Dekker,
1994:303– 363.
101. Schwarz T, Urbanska A, Gschnait F, Luger TA. Inhibition of the induction of contact hypersensitivity
by a UV-mediated epidermal cytokine. J Invest Dermatol 1986; 87:289– 291.
Photoimmunology 73
102. Rivas JM, Ullrich SE. Systemic suppression of delayed-type hypersensitivity by supernatants from
UV-irradiated keratinocytes—an essential role for keratinocyte-derived IL-10. J Immunol 1992;
149:3865–3871.
103. Enk AH, Saloga J, Becker D, Mohamadzadeh M, Knop J. Induction of hapten-specific tolerance by
interleukin-10 in vivo. J Exp Med 1994; 179:1397– 1402.
104. Ullrich SE. Mechanism involved in the systemic suppression of antigen-presenting cell function by
UV irradiation—keratinocyte-derived IL-10 modulates antigen-presenting cell function of splenic
adherent cells. J Immunol 1994; 152:3410– 3416.
105. Moodycliffe AM, Kimber I, Norval M. Role of tumour necrosis factor-alpha in ultraviolet B light-
induced dendritic cell migration and suppression of contact hypersensitivity. Immunology 1994;
81:79– 84.
106. Niizeki H, Inoko H, Streilein JW. Polymorphisms in the TNF region confer susceptibility to UVB-
induced impairment of contact hypersensitivity induction in mice and humans. Methods 2002;
28:46– 54.
107. Gillardon F, Moll I, Michel S, Benrath J, Weihe E, Zimmermann M. Calcitonin gene-related peptide
and nitric oxide are involved in ultraviolet radiation-induced immunosuppression. Eur J Pharm—
Environ 1995; 293:395– 400.
108. Böhm M, Luger TA. Alpha-melanocyte-stimulating hormone. Its relevance for dermatology.
Hautarzt 2004; 55:436– 445.
109. Luger TA, Schwarz T, Kalden H, Scholzen T, Schwarz A, Brzoska T. Role of epidermal cell-derived
alpha-melanocyte stimulating hormone in ultraviolet light mediated local immunosuppression.
Ann NY Acad Sci 1999; 885:209– 216.
110. Kuchel JM, Barnetson RS, Halliday GM. Nitric oxide appears to be a mediator of solar-simulated
ultraviolet radiation-induced immunosuppression in humans. J Invest Dermatol 2003; 121:587– 593.
111. Walterscheid JP, Ullrich SE, Nghiem DX. Platelet-activating factor, a molecular sensor for cellular
damage, activates systemic immune suppression. J Exp Med 2002; 195:171– 179.
112. Shreedhar V, Giese T, Sung VW, Ullrich SE. A cytokine cascade including prostaglandin E-2, IL-4,
and IL-10 is responsible for UV-induced systemic immune suppression. J Immunol 1998;
160:3783– 3789.
113. Hart PH, Grimbaldeston MA, Jaksic A, et al. Ultraviolet B-induced suppression of immune responses
in interleukin-4-/-mice: Relationship to dermal mast cells. J Invest Dermatol 2000; 114:508–513.
114. Hart PH, Grimbaldeston MA, Finlay-Jones JJ. Mast cells in UV-B-induced immunosuppression.
J Photoch Photobio B 2000; 55:81– 87.
115. Reeve VE, Bosnic M, Boehmwilcox C, Cope RB. Pyridoxine supplementation protects mice from
suppression of contact hypersensitivity induced by 2-acetyl-4-tetrahydroxybutylimidazole (THI),
ultraviolet B radiation (280– 320 nm), or cis-urocanic acid. Am J Clin Nutr 1995; 61:571– 576.
116. De Fabo EC, Noonan FP. Mechanism of immune suppression by ultraviolet irradiation in vivo.
I. Evidence for the existence of a unique photoreceptor in skin and its role in photoimmunology.
J Exp Med 1983; 158:84– 98.
117. Norval M, Gibbs NK, Gilmour J. The role of urocanic acid in UV-induced immunosuppression—
recent advances (1992– 1994). Photochem Photobiol 1995; 62:209– 217.
118. Kondo S, Sauder DN, McKenzie RC, et al. The role of cis-urocanic acid in UVB-induced suppression
of contact hypersensitivity. Immunol Lett 1995; 48:181– 186.
119. Moodycliffe AM, Bucana CD, Kripke ML, Norval M, Ullrich SE. Differential effects of a monoclonal
antibody to cis-urocanic acid on the suppression of delayed and contact hypersensitivity following
ultraviolet irradiation. J Immunol 1996; 157:2891– 2899.
120. Beissert S, Mohammad T, Torri H, et al. Regulation of tumor antigen presentation by urocanic acid.
J Immunol 1997; 159:92– 96.
121. Beissert S, Ruhlemann D, Mohammad T, et al. IL-12 prevents the inhibitory effects of cis-urocanic
acid on tumor antigen presentation by Langerhans cells: implications for photocarcinogenesis.
J Immunol 2001; 167:6232– 6238.
122. Norval M. Effects of solar radiation on the human immune system. J Photoch Photobio B 2001;
63:28– 40.
123. Chapman RS, Cooper KD, Defabo EC, et al. Solar ultraviolet radiation and the risk of infectious
disease: Summary of a workshop. Photochem Photobiol 1995; 61:223– 247.
124. El-Ghorr AA, Norval M. The effect of UV-B irradiation on secondary epidermal infection of mice
with herpes simplex virus type 1. J Gen Virol 1996; 77:485– 491.
125. Jeevan A, Kripke ML. Effect of a single exposure to ultraviolet radiation on Mycobacterium bovis
Bacillus Calmette-Guerin infection in mice. J Immunol 1989; 143:2837– 2843.
126. Jeevan A, Ullrich SE, Degracia M, Shah R, Sun Y. Mechanism of UVB-induced suppression of the
immune response to Mycobacterium ovis Bacillus Calmette-Guerin—role of cytokines on
macrophage function. Photochem Photobiol 1996; 64:259– 266.
127. Goettsch W, Garssen J, Deijns A, De Gruijl FR, Van Loveren H. UV-B exposure impairs resistance to
infection by Trichinella spiralis. Environ Health Perspect 1994; 102:298– 301.
128. Goettsch W, Garssen J, De Gruijl FR, Van Loveren H. UVB-induced decreased resistance to Trichi-
nella spiralis in the rat is related to impaired cellular immunity. Photochem Photobiol 1996;
64:581– 585.
129. Yamamoto K, Ito R, Koura M, Kamiyama T. UV-B irradiation increases susceptibility of mice to
malarial infection. Infect Immun 2000; 68:2353– 2355.
130. Goettsch W, Garssen J, de Klerk A, et al. Effects of ultraviolet-B exposure on the resistance to Listeria
monocytogenes in the rat. Photochem Photobiol 1996; 63:672– 679.
131. Brown EL, Ullrich SE, Pride M, Kripke ML. The effect of UV irradiation on infection of mice with
Borrelia burgdorferi. Photochem Photobiol 2001; 73:537– 544.
132. Cope RB, Hartman JA, Morrow CK, Haschek WM, Small PL. Ultraviolet radiation enhances both the
nodular and ulcerative forms of Mycobacterium ulcerans infection in a Crl:IAF(HA)-hrBR hairless
guinea pig model of Buruli ulcer disease. Photodermatol Photo 2002; 18:271– 279.
133. Perna JJ, Mannix ML, Rooney JF, Notkins AL, Straus SE. Reactivation of latent herpes simplex virus
infection by ultraviolet light: a human model. J Am Acad Dermatol 1987; 17:473– 478.
134. Rooney JF, Bryson Y, Mannix ML, et al. Prevention of ultraviolet-light-induced Herpes Labialis by
sunscreen. Lancet 1991; 338:1419– 1422.
135. Gallerani M, Manfredini R. Seasonal variation in herpes zoster infection. Brit J Dermatol 2000;
142:588– 589.
136. Termorshuizen F, Hogewoning AA, Bavinck JNB, Goettsch WG, Fijter JW, Loveren H. Skin infections
in renal transplant recipients and the relation with solar ultraviolet radiation. Clin Transplant 2003;
17:522– 527.
137. Termorshuizen F, Garssen J, Norval M, et al. A review of studies on the effects of ultraviolet
irradiation on the resistance to infections: evidence from rodent infection models and verification
by experimental and observational humane studies. Int Immunopharmacol 2002; 2:263– 275.
138. Cestari TF, Kripke ML, Baptista PL, Bakos L, Bucana CD. Ultraviolet radiation decreases the gran-
ulomatous response to lepromin in humans. J Invest Dermatol 1995; 105:8 – 13.
139. Euvrard S, Kanitakis J, Pouteil-Noble C, Claudy A, Touraine JL. Skin cancers in organ transplant
recipients. Ann Transplant 1997; 2:28– 32.
140. Kripke ML. Antigenicity of murine skin tumors induced by ultraviolet light. J Natl Cancer I 1974;
53:1333– 1336.
141. Kripke ML, Fisher MS. Immunologic parameters of ultraviolet carcinogenesis. J Natl Cancer I 1976;
57:211 – 215.
142. Sluyter R, Halliday GM. Infiltration by inflammatory cells required for solar-simulated ultraviolet
radiation enhancement of skin tumor growth. Cancer Immunol Immun 2001; 50:151– 156.
143. Donawho CK, Kripke ML. Evidence that the local effect of ultraviolet radiation on the growth of
murine melanomas is immunologically mediated. Cancer Research 1991; 51:4176– 4181.
144. Ullrich SE, Kripke ML. Mechanisms in the suppression of tumor rejection produced in mice by
repeated UV Irradiation. J Immunol 1984; 133:2786– 2790.
145. Barnetson RSC, Satchell A, Zhuang L, Slade HB, Halliday GM. Imiquimod induced regression of
clinically diagnosed superficial basal cell carcinoma is associated with early infiltration by CD4 T
cells and dendritic cells. Clin Exp Dermatol 2004; 29:639– 643.
146. Ooi T, Barnetson RS, Zhuang L, et al. Imiquimod-induced regression of actinic keratosis is associated
with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial. Brit J Dermatol
2006; 154:72– 78.
147. Hersey P. Immunotherapy of melanoma: principles. In: Thompson JF, Morton DL, Kroon BBR, eds.
Textbook of Melanoma. London and New York: Martin Dunitz, 2004:559 –572.
148. Mehling A, Loser K, Varga G, et al. Overexpression of CD40 ligand in murine epidermis results in
chronic skin inflammation and systemic autoimmunity. J Exp Med 2001; 194:615– 628.
149. Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are
clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 1994;
179:1317– 1330.
6 The Acute Effects of Ultraviolet
Radiation on the Skin
Lesley E. Rhodes
Department of Dermatological Sciences, Photobiology Unit, University of Manchester,
Salford Royal Foundation Hospital, Manchester, England, U.K.
Henry W. Lim
Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, U.S.A.
B Exposure to UVB or UVA, can result in erythema with different time

course.
B Mediators of sunburn response include reactive oxygen species (ROS),

transcription factors, vasoactive mediators, proinflammatory cytokines,
and adhesion molecules.
B Pigment darkening and delayed tanning are predominantly the effect of

UVA; the latter is associated with melanogenesis.
B Mediators of melanogenesis include DNA repair fragments,

a-melanocyte stimulating hormone, nitric oxide, and histamine.
B Other acute effects of UV radiation include epidermal hyperplasis,

synthesis of vitamin D, photoimmunosuppression, exacerbation of
photodermatoses, and disturbance of skin barrier function.
76 Rhodes and Lim
INTRODUCTION
he acute effects of ultraviolet radiation (UVR) on the skin comprise a range of responses,
T many of which are harmful in the short term or after cumulative exposure in the longer
term, and others that are beneficial. The best-known short-term manifestations of UVR
exposure are sunburn, pigment darkening, tanning, vitamin D synthesis, immunosuppression,
and the photosensitivity disorders; and these types of manifestations form the focus of this
chapter.
Ultraviolet-A (UVA, 320– 400 nm) and -B (UVB, 290 –320 nm) reach the earth’s surface
and both can cause acute effects on human skin. Ninety-five percent of UVR reaching the
surface of the earth is UVA and the rest is UVB. The shorter wavelength UVB is more
potent in causing several acute effects of UVR, and the action spectrum for various acute
effects of UVR varies from UVB alone, to UVA alone, to a combination of both wavebands.
The effects are determined by the UVR absorption spectrum of the molecule(s) initiating the
specific effect; that is, the chromophore. The depth of UVR penetration in the skin also plays
a role; most UVB is absorbed in the epidermis with a small proportion reaching the upper
dermis (1,2), while UVA penetrates deeply into the dermis. UVB, nevertheless, produces a
range of dermal effects; these may be partly attributable to UVB-induced release of
mediators by epidermal cells, particularly keratinocytes (3), and partly due to direct
effects of UVB on upper dermal structures and cells, including endothelial cells (4), and
fibroblasts (5).
UVA is divided into UVA-1 (340 – 400 mm) and UVA-2 (320 –340 mm); this division is
made since the latter is more akin to UVB in its effects. However, the spectrum is a conti-
nuum with overlap of effects. UVR causes effects on a range of cellular structures; that is,
DNA, proteins, and lipids. Whereas UVB conveys direct effects through absorption by a
range of molecules, both UVB and UVA convey indirect effects through the generation of
reactive oxygen species (ROS), produced when UVR is absorbed by endogenous photosen-
sitizers in the presence of molecular oxygen. ROS mediate a range of UVR-induced effects
including induction of transcription factors, modulation of signal transduction pathways,
and downstream events.
THE SUNBURN RESPONSE

Nature of the Sunburn Response
Sunburn is an acute inflammatory response of the skin to the UVB radiation in sunlight (6).
UVA can also cause skin erythema, requiring approximately 1000-fold higher doses than
UVB. Thus, a higher risk of sunburn is seen when the UVB to UVA ratio is relatively high,
as occurs between 11 AM and 3 PM in the summer months in temperate climates, and at latitudes
approaching the Equator. In addition to being a UVB dose-dependent response, the risk of
sunburn depends on the skin phototype of the individual, with skin types 1 and 2 showing
the highest propensity to sunburn.
Time Course
As an acute inflammatory response, sunburn may manifest with features of heat, pain, swel-
ling, and erythema. Systemic upset can also occur in cases of severe generalized sunburn.
The most consistent clinical feature, however, is that of erythema. This first becomes visible
between three and six hours postexposure, peaks at 12 to 24 hours, and is maintained to 48
hours, followed by resolution (Fig. 1). With the use of noninvasive reflectance instruments
and laser Doppler flowimetry, it has been demonstrated that the vasodilatation, underlying
sunburn, commences much earlier than the clinically visible response— changes occurring
within 30 minutes of UV exposure (7). Such instrumentation has also revealed that the time
course of erythema is UVB dose dependent, with the minimal erythema dose (MED, the
sunburn threshold) of UVB producing an erythema that peaks earlier and resolves faster
than higher doses (8). In contrast to UVB, UVA causes an immediate postexposure erythema,
resolving gradually in 48 to 72 hours (Fig. 2).
The Acute Effects of Ultraviolet Radiation on the Skin 77
FIGURE 1 The time course of UVB-induced erythema, as determined by reflectance spectrophotometry, n ¼ 6, data
are mean + SEM. Abbreviation: MED, minimal erythemal dose. Source: Adapted from Ref. 111.
Histology
Although UVB is mainly absorbed within the epidermis, a proportion certainly reaches the
upper dermis (1,2), and dermal effects are also initiated indirectly via mediators released by
epidermal cells. Dermal endothelial cell swelling is an early feature, evident within
30 minutes of UV exposure, reaching a maximum by 24 hours and persisting for three days.
Langerhans cells show morphological changes, and depletion in cell numbers is seen within
a few hours. Neutrophils quickly accumulate in the dermis with a perivascular distribution
seen immediately to postirradiation, peak numbers occurring around 14 hours, and a
decline at 48 hours (9). A mononuclear infiltrate occurs later, reaching a plateau at around 14
to 21 hours and decreasing by 48 hours (9).
10
7,5 J.cm–2
9 11 J.cm–2
17 J.cm–2
8 25 J.cm–2
38 J.cm–2
7
Redness (Da*)
0
1h 2h 5h 24h 48h 72h
Time post-exposure (hour)
FIGURE 2 The time course of UVA-induced erythema, illustrating an immediate and sustained erythema.
Source: Adapted from Ref. 112.
78 Rhodes and Lim
In the epidermis, “sunburn cells” may be seen within 30 minutes of UVB exposure, with a
peak at 24 hours. These cells are damaged keratinocytes and show shrunken chromatin and
eosinophilic cytoplasm. They are apoptotic cells, representing a protective mechanism to elim-
inate DNA-damaged cells, and can occur in the absence of skin inflammation, but their number
increases as the sunburn response increases. Epidermal spongiosis is also evident at 24 hours
post irradiation. UVA induces less epidermal damage than UVB, sunburn cells not being
seen (10).
Mechanism
The sunburn response involves a concerted response of resident epidermal and dermal cells
and leukocytes, induced to migrate into the skin by UVR. Keratinocytes express a wide
range of cytokines and chemokines, following UVB exposure and are generally regarded as
the cells that most likely initiate the UVB-induced inflammatory response (Table 1) (3).
Dermal cells could be recruited to the response both via soluble mediators secreted by kerati-
nocytes and via the direct effects of UVR.
Initiating Events
The nature of the chromophore for the sunburn response is still uncertain. There is some evi-
dence to suggest that this may be DNA. Patients with the DNA-repair disorder xeroderma
pigmentosum show an abnormally amplified and prolonged sunburn response, which can
be reduced by topical application of the DNA repair enzyme endonuclease (11). Further, indir-
ect evidence is provided by the similarity of the action spectra for UVR-induced erythema and
thymidine dimer formation in human skin (12). UVR is known to damage many tissue com-
ponents, including membrane phospholipids, proteins, and nucleic acids; and these may
trigger a variety of proinflammatory molecular responses, which may appear in parallel as
well as in sequence. It is increasingly recognized, however, that many of the cellular effects
of UVR are due to alterations in signal transduction pathways leading to aberrant gene
expression. The mechanisms by which UVR triggers cell signal transduction are multifactorial,
and include the release of cytokines, growth factors, lipid mediators, and ROS (13).
Oxidative Stress
The contribution of oxidative stress to UVR-induced inflammation is poorly understood.
However, ROS, particularly superoxide anion, hydrogen peroxide, and hydroxyl radical, are
known to mediate induction of transcription factors, modulation of signal transduction path-
ways, and a range of downstream inflammatory events. Moreover, antioxidants are reported
to be effective in reducing the sunburn response in humans (14).
TABLE 1 Mediators of Sunburn Response

Reactive oxygen species
Transcription factors
NF-kB
AP-1
Vaso-active mediators
PGE2
Nitric oxide
Proinflammatory cytokines
TNF-a
IL-1
IL-6
IL-8
IL-12
Adhesion molecules
ICAM-1
E-selectin
Abbreviations: AP, activator protein; ICAM, intercellular adhesion molecule; IL, interleukin;
NF, nuclear factor; TNF, tumor necrosis factor.
Transcription Factors
UVR induces the activation of transcription factors, including NF-kB and AP-1, which control
the expression of a wide range of genes. The transcription factors may be induced through
UVR-induced ROS, growth factors, and cytokine signal transduction pathways. The activation
of NF-kB, in particular, leads to the formation of a wide range of inflammatory mediators
including cytokines, adhesion molecules, and inflammatory enzymes that include nitric
oxide synthase and cyclooxygenase (15).
Vasoactive Mediators
There is evidence that the erythema component of the sunburn response is mediated by the
vasoactive mediators prostaglandin (PG) E2 and nitric oxide, in combination (8). UVR activates
cell membrane phospholipase A2, releasing arachidonic acid that is then used to synthesize
mediators of the eicosanoid family. Prostanoids are elevated in suction blister fluid following
UVB, that is, the prostaglandins PGD2, PGI2, PGE2, and PGF2a, along with hydroxyeicosatetra-
noic acid (12-HETE) (16). It appears that PGE2 is the most potent with regards to erythema pro-
duction (17). Cyclooxygenase inhibitors applied by various routes reduce UVB-induced
erythema (16,18 – 20), and it has recently been found that PGE2 is more involved at higher
doses of UVB, whereas nitric oxide appears to play a greater role in the mediation of erythema
at lower doses around the MED (8). The latter inhibitor studies also provided evidence that
both these mediators are active throughout the first 48 hours of the sunburn response.
Increased expression of messenger RNA for inducible nitric oxide synthase (NOS)-2 has
been detected in skin, which is exposed to UVR (21), and nitric oxide has been directly detected
in the sunburn response by dermal microdialysis (8). In vitro studies have also shown
upregulation of the activity and expression of NOS1 and NOS3 by UVB (22,23). The vasoactive
mediator histamine is also reported to be elevated early in the course of UV-induced inflam-
mation (24), although the overall effects may be small since antihistamines reduce the
sunburn response minimally, if at all (25,26). Histamine and arachidonic acid metabolites are
also released following UVA exposure of the skin (27).
Proinflammatory Cytokines
UVR induces the release of several pro-inflammatory cytokines, including TNF-a (28,29),
Interleukin (IL)-1 (30), IL-6 (31), IL-8 (32,33), and IL-12 (34). These may play important roles
at various stages of UV-induced inflammation, including activation of transcription factors
(particularly by IL-1, TNF-a), induction of endothelial adhesion molecules, and the chemotaxis
of leukocytes from the vasculature into the dermis (particularly by IL-8, TNF-a). It has been
proposed from time-course studies of cytokine induction, following UVB radiation of
human skin, that TNF-a is the key early cytokine involved in UV-induced inflammation (35).
However, a later time course of expression has been found in an immunohistochemical
study (33). IL-1 activities have been detected in human skin in vivo within 30 minutes of
UVB exposure, with a biphasic time course, which may suggest the release of preformed IL-
1 and subsequent IL-1 synthesis (36). Both IL-1 and IL-6 have been found in the serum follow-
ing wide area UVB exposure, with IL-6 persisting longer than IL-1 and, probably, mediating the
systemic features of the sunburn response (37,38).
Adhesion Molecules
UVB radiation induces ICAM-1 expression on keratinocytes (39,40) and expression of
E-selectin and ICAM-1 on dermal endothelial cells (41,4). E-selectin and ICAM-1 induce
chemotaxis of neutrophils and lymphocytes, respectively, and it has been shown that in
human skin in vivo, the expression of E-selectin correlates with the dermal neutrophil count
(33). Similarly, UVA induces E-selectin and ICAM-1 on dermal endothelial cells (42). There is
evidence that the effects of UVA on adhesion molecule-expression are mediated by the gener-
ation of ROS (43). Once present in the skin, the leukocytic infiltrate, particularly the neutro-
phils, produce large amounts of ROS, which cause damage to the cells targeted by these
inflammatory cells.
80 Rhodes and Lim
PIGMENT DARKENING
UVR-induced skin pigmentation occurs in three distinct phases; that is, immediate pigment
darkening, persistent pigment darkening, and delayed tanning.
Immediate Pigment Darkening

Immediate pigment darkening (IPD) occurs as a response to low doses (1 – 5 J/cm2) of UVA; it
appears almost immediately after exposure and usually fades within 10 to 20 minutes (44).
Clinically, it manifests as grey-brown color. It is thought to result from oxidation and redistri-
bution of pre-existing melanin; no new melanin synthesis occurs.
Persistent Pigment Darkening

At higher UVA doses (.10 J/cm2), pigment darkening can persist for two hours to 24 hours;
this is termed persistent pigment darkening (PPD) (44). Clinically, it appears as brown color,
similar to IPD. It is also due to oxidation and redistribution of pre-existing melanin. Protection
against the development of PPD is the most commonly used surrogate worldwide for the
assessment of UVA protectiveness of sunscreen.
Delayed Tanning of the Skin

Nature of the Tanning Response
Tanning is a delayed effect of UVR. In contrast to IPD and PPD, delayed tanning is associated
with synthesis of new melanin. Both UVB and UVA are capable of inducing tanning, although
UVB is more efficient. A study on the action spectrum for melanogenesis in human skin in vivo
showed that peak melanogenesis occurs at about 290 nm, similar to the peak for erythema (6).
Because UVB is more erythemogenic than UVA, UVB-induced delayed tanning is always
preceded by erythema. In contrast, UVA can induce tanning without noticeable redness.
While both UVB and UVA can induce melanogenesis, UVB, additionally, induces epidermal
thickening. This is reflected by the observation that for visually identical tan, UVB-induced
tan resulted in a protection factor of 3 against UVB-induced erythema, while UVA-induced
tan only conferred a protection factor of 1.4 (45).
Tanning occurs as a response to UVR-induced damage of the skin and may serve to limit
the amount of subsequent damage caused by continued UVR exposure. Sun reactive skin types
3 and 4 and higher display a high ability to tan, whereas sun reactive skin types 1 and 2 show a
poor ability to tan. This clinical observation is supported by a study of solar-simulated,
radiation-induced tanning. Whereas tanning was associated with some protection against
DNA damage in skin types 3 and 4, no protection was seen in skin types one and two (2).
Time Course
Delayed tanning (melanogenesis) becomes visible at around 72 hours following UV exposure.
Melanin is formed and distributed within the basal layer of the epidermis. As cells move
upward through the layers of the epidermis, the melanin eventually reaches the outer layer
of the skin, that is, the stratum corneum, resulting in the tan fading as the surface layer is shed.
Mechanism and Mediators of Melanogenesis

It has been hypothesized that melanogenesis may be initiated by DNA excision repair (Table 2).
This is supported by in vitro studies showing an increase in melanin content in human mela-
nocytes following their exposure to thymidine dinucleotides, which mimic DNA excision frag-
ments (46). Delayed tanning is associated with increases in both the number of melanocytes
and melanocytic activity (47). The latter is characterized by increased tyrosinase activity,
elongation of dendrites, and increased transfer of melanosomes to keratinocytes.
TABLE 2 Mediators of Melanogenesis

DNA excision repair fragments Nitric oxide
a-Melanocyte stimulating hormone Histamine
Following UVR exposure, keratinocytes release a melanocortin, a-melanocyte stimulat-

ing hormone (a-MSH), which stimulates melanin production in melanocytes (48). UVR also
regulates the a-MSH receptors on melanocytes. The melanin is distributed in melanosomes
through the dendritic processes of the melanocytes where it absorbs and scatters UVR, thus
protecting other epidermal cells from damage. In particular, melanin forms “nuclear caps”
over the nuclei of basal keratinocytes. Hence, the epidermis is protected. However, the
amount of protection varies between individuals.
Two types of melanin are formed, eumelanin and phaeomelanin. Whereas eumelanin
provides additional protection by acting as a free-radical scavenger, phaeomelanin can increase
oxidative stress. Furthermore, not all melanocytes are responsive to a-MSH (49). In skin photo-
types 1 and 2, a lack of responsiveness to a-MSH is associated with melanocortin 1 receptor
(MC1R) variants, resulting in the production of little of the photoprotective eumelanin and
clinically showing a weak pigmentary response.
Mediators that have been implicated in melanogenesis include nitric oxide, which may
act in both an autocrine and paracrine manner to regulate pigmentation (50). Topical appli-
cation of the NOS inhibitor L-NAME (N-nitro-L-arginine methylester hydrochloride) to
guinea pig skin reduces the melanin content of melanocytes (51). Additionally, nitric oxide
has been reported to enhance the dendricity of melanocytes (52). In vivo studies in guinea
pig skin also support a role for histamine in UVR-induced melanogenesis (53). In vitro exper-
iments suggest that nitric oxide, along with histamine, may play a role in setting the eumela-
nin/phaeomelanin ratio in melanocytes (54). It is uncertain how nitric oxide exerts this
effect, although it may play a major role through the activation of tyrosinase (52).
EPIDERMAL HYPERPLASIA
Hyperproliferation of epidermal cells begins soon after UVB exposure and leads to epidermal
thickening, which is histologically evident within days and persists for some weeks, following
exposure. There is a several-fold increase in thickness, particularly affecting the stratum
corneum, and along with melanogenesis this conveys some protection against further UVR
damage. Dermal thickening may also occur.
VITAMIN D SYNTHESIS
The major and best understood beneficial effect of acute UVR on skin is the synthesis of vitamin
D3. The action spectrum for this lies in the UVB waveband (55).
Sources of Vitamin D
There are two forms of vitamin D, vitamin D3 and vitamin D2. Vitamin D3 is synthesized in the
epidermis, and is available through naturally occurring food sources. However, it is found
naturally in few foods, the main sources being oily fish (e.g., herring, salmon, sardines),
liver, and egg yolk; therefore, the amount obtained from dietary sources is generally low, typi-
cally around 10% of the body’s source. Vitamin D3 is available as a vitamin supplement.
Vitamin D2 is present in plants. It is the most widely used form in vitamin supplements, and
is in fortified milk, margarine, butter, and cereals.
Cutaneous Synthesis of Vitamin D

The initial step in vitamin D formation is the rapid conversion of 7-dehydrocholesterol to
previtamin D (cholecalciferol), by UVB. Previtamin D undergoes thermal isomerization to
vitamin D3, the isomer mixture reaching a pseudoequilibrium in sunlight that limits the
previtamin D that can be formed in a single UVB exposure, to 10% to 20% of the epidermal
7-dehydrocholesterol concentration. The vitamin D benefit of sunlight is reached long before
any risk of sunburn, and further sun exposure is of no benefit, only serving to increase UVR
hazards. Incidental sun exposure during normal daily activity along with balanced diet is
probably sufficient for most individuals to achieve adequate vitamin D levels. For those at
a high risk to develop vitamin D insufficiency, such as a elderly, home-bound individuals,
those with dark skin, and indoor workers, vitamin D3 supplement should be taken (56,57).
82 Rhodes and Lim
Metabolism of Vitamin D
Vitamin D derived from either cutaneous or dietary source is biologically inactive and under-
goes two hydroxylation steps. Firstly, it is metabolized in the liver to 25-hydroxy vitamin D
(25OHD), the main circulating storage form. Then it is converted under strict metabolic
control in the kidney to 1,25-dihydroxy vitamin D (1,25D), which promotes intestinal absorp-
tion of calcium and facilitates bone mineralization.
Vitamin D and Bone Health
It is well established that severe vitamin D deficiency leads to rickets and osteomalacia. Circu-
lating 25OHD levels above 5 ng/ml are sufficient to prevent these extreme health effects (58).
However, it has relatively recently been recognized that 25OHD values between 5 and
20 ng/mL are associated with secondary hyperparathyroidism, with consequent bone loss
and osteoporotic fractures (59 –61). Counter-intuitively, a study of over 36,000 women followed
for 7 years showed that daily supplements of vitamin D3 (400 IU) and calcium (1000 mg) did
not significantly reduce hip fractures (62). Elderly individuals and people with darker skin
appear particularly at risk of low serum 25OHD levels, due to low amounts of vitamin D
that may be achieved through both oral and cutaneous routes (63,64).
Vitamin D and Other Disorders
Circumstantial evidence is accumulating that inadequate vitamin D levels may have other
adverse health consequences, including the risk of a range of malignancies, hypertension
and diabetes mellitus (56,57,65,66). These are largely based on epidemiologic studies examin-
ing the relationship between the prevalence or mortality of a range of disorders and latitude
(67– 70). However, a 7-year study of over 36,000 women failed to show any protective effects
of vitamin D3 (400 IU/day) and calcium (1000 mg/day) supplements on the incidence of colo-
rectal cancer (71).
Although the concept is unproven, data from a variety of experimental approaches
provides support for the hypothesis that, via effects on vitamin D synthesis, UVR may convey
chemoprotective properties (72,73). Many tissues including colon, skin, breast, and prostate are
now known to synthesize 1,25D locally from precursor 25OHD. The antiproliferative effect of
1,25D in tumor cell lines provides a potential mechanism for its postulated anticarcinogenic
properties (73).
Vitamin D Controversies
Strategies to protect against skin cancer include avoidance of the midday sun and the use of
sunscreens and photoprotective clothings, both of which reduce the amount of UVB reaching
the skin (74,75) and thus may reduce cutaneous vitamin D synthesis. However, it is debatable
how completely the public follows these recommendations, including adequacy of sunscreen
application and use. At northern latitudes, there is insufficient ambient UVB to initiate
vitamin D synthesis in skin during the winter (55) and excess vitamin D formed in the
summer months is stored in fat for use throughout the winter months. However, stores may
be inadequate to maintain an optimal vitamin D status all year round, and strategies may be
needed to combat this. Whereas there is good evidence for the relationship between low
25OHD levels and bone health, other potential benefits of vitamin D are speculative, and the
subject of considerable international debate (57,56,76). Recent efforts have focused on defining
an optimal circulating 25OHD level. Many suggest that this is around 80 nmol/L (or 32 mgm/L)
(77,78), a level anticipated to be adequate for bone health plus giving a margin for other poten-
tial health benefits; this can be achieved with 800 to 1000 IU of daily vitamin D3, or 50,000 IU of
monthly vitamin D3 (79).
PHOTOIMMUNOSUPPRESSION
The Nature of Photoimmunosuppression in Human Skin
The induction of immunosuppression in human skin by UVR is a “normal” phenomenon
occurring in all individuals. This topic is discussed in greater detail in chapter 5. It is estab-
lished from several studies, that UVR exposure of human skin results in downregulation
of delayed hypersensitivity (DTH) responses, a measure of T cell function (80). It has been
demonstrated that UVR suppresses the contact hypersensitivity (CHS) responses to nickel in
nickel-sensitive individuals (81), and to DNCB (82). Further studies of CHS responses to
DNCB designated 40% of volunteers as UVB-susceptible (83). Furthermore, the same investi-
gators found that 92% of skin cancer patients fell into the UVB-susceptible category, thus
implying that UVB-induced suppression of CHS may be a risk factor for skin cancer. Studies
by Cooper et al. (84) illustrated, however, that a clear division into UVR-susceptible and
UVR-resistant individuals might be too simplistic.
Action Spectrum
It has previously been assumed that UVB is the waveband of importance when considering
immunosuppression. However, there has been increasing interest in the effects of UVA over
the last 10 years, and it is now clear that this waveband also has important immunosuppressive
properties. This is likely to be of clinical relevance when considering the high proportion of
UVA compared to UVB in sunlight (UVA 95%, UVB 5%); the augmentation of this difference
by the use of sunscreens, which are more effective at blocking UVB than UVA, and enable
the individual to stay longer in the sunlight without sunburn; and the growing popularity of
the use of commercial sunbeds.
Mechanisms of Photoimmunosuppression
UVR-induced immunosuppression appears as a complex phenomenon, including the interac-
tive processes mediated by resident keratinocytes and endothelial cells and infiltrating lym-
phocytes. These cells play important signalling roles, mediated by cell surface molecules and
soluble factors, which then influence the responses of skin immune cells. The following are
components of this response.
Antigen Presenting Cells

UVR modulates the number and function of epidermal Langerhans cells, a key antigen-
presenting cell. Following UVR exposure, Langerhans cells are observed to round up morpho-
logically into their migratory form, and to disappear from the epidermis. This could result
in diminished antigen presentation by these cells, that is, a reduction of their immunosurveil-
lance role. The phenomenon may be mediated through UVR induction of cytokines, particu-
larly TNF-a and IL-1b (85), and there is also evidence for the involvement of eicosanoids,
particularly PGE2 (86). Furthermore, UVR causes an influx of CD11þ macrophages with immu-
nosuppressive properties, which may largely be conveyed through their secretion of the immu-
nosuppressive cytokine, IL-10 (87).
Alteration of the Th1/Th2 Cytokine Profile

UVR alters the skin lymphocyte profile, such that there is a relative reduction in the secretion of
Th1 cytokines such as IL-12 and Gamma Interferon (IFN-g), which mediate the immune
responses of CHS and DTH, and a relative increase in Th2 cytokines, including IL-4 and
IL-10, which are immunosuppressive. IL-10 reduces T-lymphocyte responses by inhibiting
antigen presentation by antigen presenting cells. IL-10 is secreted by a range of cells including
T- and B-lymphocytes, monocytes, macrophages, and keratinocytes (88), and there is evidence
for its induction by both UVB and UVA (89).
Other Mediators of Immunosuppression

Several mediators other than Th2 cytokines mediate immunosuppression, many of which are
also active in conveying UVR-induced skin inflammation. This includes TNF-a, which plays a
role in the sunburn response, but also causes Langerhans cell migration away from the skin
(90). PGE2, a major mediator of sunburn erythema, is also a potent mediator of immunosup-
pression; as with TNF-a, there is evidence that it stimulates the migration of
Langerhans cells out of the epidermis. The neuropeptide, calcitonin gene related peptide
(CGRP), and nitric oxide are also implicated in UVR-induced immunosuppression (91).
In humans, topical application of a NOS inhibitor prevented both the suppression of recall
immunity to nickel, and the loss of epidermal Langerhans cells from the skin (92).
84 Rhodes and Lim
Candidate Chromophores: Urocanic Acid and DNA

The chromophore(s) of photoimmunosuppression are unknown, although both urocanic acid
and DNA have been speculated to play this role.
Urocanic Acid
Urocanic Acid (UCA) exists in two forms, the cis and the trans forms. It is normally found in its
trans form in the stratum corneum, and UVR causes its isomerization from the trans to the cis
form, which is associated with cutaneous immunosuppression. UCA has the capacity to reduce
Langerhans cell numbers (93) and to suppress contact hypersensitivity (CHS) in mice (94).
However, it remains uncertain what role UCA actually plays in skin in view of studies reveal-
ing an inconsistent effect on CHS (95) and the apparent lack of correlation between the action
spectra for CHS suppression and UCA photoisomerization (96).
DNA
DNA dimer formation has been associated with UVR-induced immunosuppression. The appli-
cation of the excision repair enzyme T4 endonuclease V (T4 N5), which increases dimer
removal, is associated with reversal of UVR-induced suppression of CHS and delayed hyper-
sensitivity (97).
Innate Immunity
UVR causes a dose-dependent inhibition of the activity of natural killer (NK) cells, which are
part of the innate immune system (98). In vivo studies in humans have confirmed that NK cell
function is reduced during a course of solarium tanning, (99) and in psoriasis patients during
a course of UVB therapy (100). Circulating NK cell numbers also fall following solarium
treatment but not during UVB therapy.
Oxidative Stress
It is likely that oxidative stress plays a larger role in UVA-induced immunosuppression than
UVB-induced immunosuppression. However, more work needs to be done to clarify the path-
ways of action of UVA (101). Antioxidant supplementation studies have demonstrated that
ROS are involved in UVR-induced immunosuppression in animals (102) and humans (103).
Sunscreens and Immune Protection

Sunscreens have been developed to protect against the sunburn response, rather than immu-
nosuppression, but attempts are in progress to develop a system for assessing the immune
protection factor of sunscreens, in addition to their erythema protection [sun protection
factor (SPF)] (101,104,105). Sunscreens combining a high SPF with high-UVA protection
appear most effective (106). Research continues with dietary and topical antioxidant agents,
in an attempt to improve the immunoprotection conveyed by traditional sunscreens (14,80,101).
OTHER ACUTE EFFECTS OF ULTRAVIOLET RADIATION

Photosensitivity Disorders
Unlike the other UVR effects described in this chapter, the photosensitivity disorders do not
represent a “normal” response of the skin to UVR. Rather, they involve abnormal responses
of the skin to low doses of UVA, and/or UVB, and/or visible light. The underlying etiology
shows wide diversity, including immune malfunction, biochemical disorders, and DNA
repair deficiency. It has been speculated that some of the immune mediated photosensitivity
disorders may result from a failure of “normal” photoimmunosuppression of skin, thus permit-
ting photoprovocation to occur (107). Photosensitivity conditions, which manifest with a range
of symptoms and/or signs following exposure to sunlight or artificial radiation sources, will be
discussed further in Section III of this book.
Disturbance of Skin Barrier Function

High-dose UVR causes alterations in epidermal barrier function, which become evident at
around 72 hours postexposure and manifest as increased transepidermal water loss. This
delayed barrier disruption appears to occur when lamellar body-deficient keratinocytes
arrive at the stratum granulosum/ stratum corneum interface (108), suggesting that failure
of secretion of lamellar body-derived lipids to the stratum corneum is at least partially
responsible for the reduced barrier function. T cell dependent epidermal hyperproliferation
(109) and reduced stratum corneum ceramide content (110) also correlate with the barrier
disturbance. Rapid recovery is seen.
ACKNOWLEDGMENT
With gratitude to Mrs. Vivien Robinson for her dedication in the preparation of this text.
REFERENCES
1. Everett MA, Yeargers E, Sayre RM, et al. Penetration of epidermis by ultraviolet rays. Photochem
Photobiol 1966; 5:533– 542.
2. Young AR, Potten CS, Chadwick CA, et al. Photoprotection and 5-MOP photochemoprotection from
UVR-induced DNA damage in humans: the role of skin type. J Invest Dermatol 1991; 97:942 –948.
3. Barker JNWN, Mitra RS, Griffiths CEM, et al. Keratinocytes as initiators of inflammation. Lancet,
1991; 337:211 – 214.
4. Rhodes LE, Joyce M, West DC, et al. Comparison of changes in endothelial adhesion molecule
expression following UVB irradiation of skin and a human dermal microvascular cell line
(HMEC-1). Photodermatol Photoimmunol Photomed 1996; 12:114 – 121.
5. Storey A, McArdle F, Friedmann PS, et al. Eicosapentaenoic acid and docosahexaenoic acid reduce
UVB- and TNF-a-induced IL-8 secretion in keratinocytes and UVB-induced IL-8 in fibroblasts.
J Invest Dermatol 2005; 124:248 –255.
6. Parrish JA, Jaenicke KF and Anderson RR. Erythema and melanogenesis action spectrum of normal
human skin. Photochem Photobiol 1982; 36:187– 191.
7. Diffey BL, Farr PM and Oakly AM. Quantitive studies on UVA-induced erythema in human skin.
Br J Dermatol 1987; 117:57– 66.
8. Rhodes LE, Belgi G, Parslew R, et al. Ultraviolet-B-induced erythema is mediated by nitric oxide and
prostaglandin E2 in combination. J Invest Dermatol 2001; 117:880– 885.
9. Hawk JLM, Murphy GM, Holden CA. The presence of neutrophils in human cutaneous ultraviolet-
B-induced inflammation. Br J Dermatol 1988; 118:27– 30.
10. Rosario R, Mark GJ, Parrish JA, et al. Histological changes produced in skin by equally erythemo-
genic doses of UV-A, UV-B, UV-C and UVA with psoralens. Br J Dermatol 1979; 120:767 –777.
11. Yarosh DB, Klein J, Kibetel J, et al. Enzyme therapy of xeroderma pigmentosum: safety and efficacy
testing of T4N5 liposome lotion containing a prokaryotic DNA repair enzyme. Photodermatol
Photoimmunol Photomed 1996; 12:122– 130.
12. Young AR. Chromophores in human skin. Phys Med Biol 1997; 42:789– 802.
13. Heck DE, Gerecke DR, Vetrano AM, et al. Solar ultraviolet radiation as a trigger of cell signal
transduction. Toxicol Appl Pharmacol 2004; 195:288 –297.
14. Swindells K, Rhodes LE. Influence of oral antioxidants on ultraviolet radiation-induced skin
damage in humans. Photodermatol Photoimmunol Photomed 2004; 20 (6):297– 304.
15. Terui T, Okuyama R, Tagami H. Molecular events occurring behind ultraviolet-induced skin inflam-
mation. Curr Opin Allergy Clin Immunol 2001; 1:461– 467.
16. Black AK, Greaves MW, Hensby CN, et al. The Effects of indomethacin on arachidonic acid and
prostaglandins E2 and F2 alpha levels in human skin 24 h after UVB and UVC irradiation. Br J
Clin Pharmacol 1978; 6:261– 266.
17. Crunkhorn P, Willis AL. Cutaneous reactions to intradermal prostaglandins. Br J Pharmacol 1971;
41:49– 56.
18. Greenberg RA, Eaglstein WH, Turnier H, et al. Orally given indomethacin and blood flow response
to UVL. Arch Dermatol 1975; 111:328– 330.
19. Snyder DS, Eaglstein WH. Topical indomethacin and sunburn. Br J Dermatol 1974; 90, 91 –93.
20. Farr PM, Diffey BL. A quantitative study of the effect of topical indomethacin on cutaneous
erythema induced by UVB and UVC radiation. Br J Dermatol 1986; 115, 453 – 466.
21. Kuhn A, Fehsel K, Lehmann P, et al. Aberrant timing in epidermal expression of inducible nitric
oxide synthase after UV irradiation in cutaneous lupus erythamatosus. J Invest Dermatol 1998;
111, 149 – 153.
86 Rhodes and Lim
22. Kang-Rotondo CH, Major S, Chiang TM, et al. Upregulation of nitric oxide synthase in cultured
human keratinocytes after ultraviolet B and bradykinin. Photodermatol Photoimmunol Photomed
1996; 12(2):57– 65.
23. Sasaki M, Yamaoka J, Miyachi Y. The effect of ultraviolet B irradiation on nitric oxide synthase
expression in murine keratinocytes. Exp Dermatol 2000; 9:417– 422.
24. Hruza LL, Pentland AP. Mechanisms of UV-induced inflammation. J Invest Dermatol 1993;
100:355– 415.
25. Farr PM, Diffey BL, Humphreys F. A quantitive study of the effect of terfenadine on cutaneous
erythema induced by UVB and UVC irradiation. J Invest Dermatol 1986; 87:771– 774.
26. Anderson PH, Abrams K, Maibach H. Ultraviolet B dose-dependant inflammation in humans: a
reflectance spectroscopic and laser Doppler flowmetric study using topical pharmacologic antagon-
ists on irradiated skin. Photodermatol Photoimmunol Photomed 1992; 9:17– 23.
27. Hawk JL, Black AK, Jaenicke KF, et al. Increased concentrations of arachidonic acid, prostaglandins
E2, D2, and 6-oxo-F1a, and histamine in human skin following UVA irradiation. J Invest Dermatol
1983; 80:496– 499.
28. Oxholm A, Oxholm P, Staberg B, et al. Immunohistological detection of interleukin 1-like molecules
and tumour necrosis factor in human epidermis before and after UVB-irradiation in vivo. Br J
Dermatol 1988; 118:369– 376.
29. Kock A, Schwartz T, Kirnbauer R, et al. Human keratinocytes are a source for tumour necrosis factor
alpha: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp
Med 1990; 172:1609– 1614.
30. Kupper TS, Chua AO, Flood P, et al. Interleukin 1 gene expression in cultured human keratinocytes
is augmented by ultraviolet irradiation. J Clin Invest 1987; 80:430– 436.
31. Oxholm A. Epidermal expression of interleukin-6 and tumour necrosis factor-alpha in normal and
immunoinflammatory skin states in humans. APMIS Suppl 1992; 24:1 – 32.
32. Kondo S, Kono T, Sauder DN, et al. IL-8 gene expression and production in human keratinocytes
and their modulation by UVB. J Invest Dermatol 1993; 101:690– 694.
33. Strickland I, Rhodes LE, Flanagan BF, et al. TNF-a and IL-8 are upregulated in the epidermis of
normal human skin after UVB-exposure, correlation with neutrophil accumulation and E-selectin
expression. J Invest Dermatol 1997; 108:763– 768.
34. Shen J, Bao S, Reeve VE. Modulation of IL-10, IL-12 and IFN-g in the epidermis of hairless mice by
UVA (320 – 400 nm) and UVB (280 – 320 nm) radiation. J Invest Dermatol 1999; 113:1059– 1064.
35. Barr RM, Walker SL, Tsang W, et al. Suppressed alloantigen presentation, increased TNF-a, IL-1,
IL-1Ra, IL-10 and modulation of TNF-R in UV-irradiated human skin. J Invest Dermatol 1999;
112:692– 698.
36. Murphy GM, Dowd PM, Hudspith BN, et al. Local increase in interleukin-1-like activity following
UVB irradiation of human skin in vivo. Photodermatol 1989; 6:268– 274.
37. Granstein RD, Sauder DN. Whole body exposure to ultraviolet radiation results in increased serum
interleukin-1 activity in humans. Lymphokine Res 1987; 6:193– 197.
38. Urbanski A, Schwarz T, Neuner P, et al. Ultraviolet light induces circulating interleukin-6 in
39. Norris DA, Lyons MB, Middleton MH, et al. Ultraviolet radiation can either suppress or induce
expression of intercellular adhesion molecule 1 (ICAM-1) on the surface of cultured human kerati-
nocytes. J Invest Dermatol 1990; 95:132– 138.
40. Krutmann J, Kock A, Schauer E, et al. Tumor necrosis factor beta and ultraviolet radiation are potent
regulators of human keratinocyte ICAM-1 expression. J Invest Dermatol 1990; 95:127– 131.
41. Norris P, Poston RN, Sian TD, et al. The expression of endothelial adhesion molecules (ICAM-1) and
vascular cell adhesion molecule-1 (VCAM-1) in experimental cutaneous inflammation: a compari-
son of ultraviolet B erythema and delayed hypersensitivity. J Invest Dermatol 1991; 96:763.
42. Heckmann M, Eberlein-Konig B, Wollenberg A, et al. Ultraviolet-A radiation induces adhesion mol-
ecule expression on human dermal microvascular endothelial cells. Br J Dermatol 1994; 131:311– 318.
43. Olaizola-Horn S, Christoph H, Budnik A, et al. Ultraviolet A1 radiation induced immunomodula-
tion is mediated via the generation of singlet oxygen. J Invest Dermatol 1994; 103:429.
44. Hönigsmann H. Erythema and pigmentation. Photodermatol Photoimmunol Photomed 2002; 18:
75 – 81.
45. Gange RW, Blackett AD, Matzinger EZ, et al. Comparative protection efficiency of UVA- and UVB-
induced tans against erythema and formation of endonuclease-sensitive sites in DNA by UVB in
human skin. J Invest Dermatol 1985; 85:362– 364.
46. Gilchrest BA, Zhai S, Eller MS, et al. Treatment of human melanocytes and S91 melanoma cells with
the DNA repair enzyme T4 endonuclease V enhances melanogenesis after ultraviolet irradiation.
47. Stierner U, Rosdahl I, Augustsson A, et al. UVB irradiation induces melanocyte increase in both
exposed and shielded human skin. J Invest Dermatol 1989; 92:561– 564.
48. Archambault M, Yaar M, Gilchrest BA. Keratinocytes and fibroblasts in a human skin equivalent
model enhance melanocyte survival and melanin synthesis after ultraviolet irradiation. J Invest
Dermatol 1995; 104:859– 867.
49. Hunt G, Todd C, Thody AJ. Unresponsiveness of human epidermal melanocytes to melanocyte-
stimulating hormone and its association with red hair. Mol Cell Endocrinol 1996; 116:131 –136.
50. Cals-Grierson MM, Ormerod AD. Nitric oxide function in the skin. Nitric Oxide 2004; 10:
179 – 193.
51. Horikoshi T, Nakahara M, Kaminaga H, et al. Involvement of nitric oxide in UVB-induced pigmen-
tation in guinea pig skin. Pigment Cell Res 2000; 13:358– 363.
52. Romero-Graillet C, Aberdam E, Biagoli N, et al. Ultraviolet B radiation acts through the nitric oxide
and cGMP signal transduction pathway to stimulate melanogenesis in human melanocytes. J Biol
Chem 1996; 271:28052– 28056.
53. Yoshida M, Hirotsu S, Nakahara M, et al. Histamine is involved in ultraviolet B-induced pigmenta-
tion of guinea pig skin. J Invest Dermatol 2002; 118:255– 260.
54. Lassalle MW, Igarashi S, Sasaki M, et al. Effects of melanogenesis-inducing nitric oxide and hista-
mine on the production of eumelanin and pheomelanin in cultured human melanocytes. Pigment
Cell Res 2003; 16:81– 84.
55. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin
D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in
human skin. J Clin Endocrinol Metab 1988; 67:373– 378.
56. Wolpowitz D, Gilchrest BA. The vitamin D questions: How much do you need and how should you
get it? J Am Acad Dermatol 2006; 54:301– 317.
57. Lim, HW, Gilchrest BA, Cooper KD, et al. Sunlight, tanning booths, and vitamin D. J Am Acad
Dermatol 2005; 52:868– 876.
58. Berry JL, Davies M, Mee AP. Vitamin D metabolism, rickets, and osteomalacia. Semin Musculoskelet
Radiol 2002; 6:173– 182.
59. Gomez-Alonso C, Naves-Diaz ML, Fernandez-Martin JL, et al. Vitamin D status and secondary
hyperparathyroidism: the importance of 25-hydroxyvitamin D cut off levels. Kidney Int 2003;
63:S44– S48.
60. LeBoff MS, Kohlmeier L, Hurwitz S, et al. Occult vitamin D deficiency in postmenopausal US
women with acute hip fracture. JAMA 1999; 281:1505– 1511.
61. Lukert BP, Higgins J, Stosopf M. Menopausal bone loss is partially regulated by dietary intake of
vitamin D. Calcif Tissue Int 1992; 51:173– 179.
62. Jackson RD, LaCroiz AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of
fractures. N Engl J Med 2006; 354(7):669– 683.
63. Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Positive association between 25-hydroxy vitamin D
levels and bone mineral density: a population-based study of younger and older adults. Am
J Med 2004; 116:634– 639.
64. Young AR, Walker SL. UV radiation, vitamin D and human health: an unfolding controversy intro-
duction. Photochem Photobiol 2005; 81(6):1243– 1245.
65. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and
osteoporosis. Am J Clin Nutr 2004; 79:362– 371.
66. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer
incidence and mortality in men. J Natl Cancer Inst 2006; 98:451– 459.
67. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int
J Epidemiol 1980; 9:227– 231.
68. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality. Evidence for a
protective effect of ultraviolet radiation. Cancer 1992; 70:2861– 2869.
69. Leftkowitz ES, Garland CF. Sunlight, vitamin D and ovarian cancer mortality rates in US women. Int
J Epidemiol 1994; 23:1133 – 1136.
70. Grant WB. An estimate of premature cancer mortality in the US due to inadequate doses of solar
ultraviolet-B radiation. Cancer 2002; 94:1867– 1875.
71. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and
the risk of colorectal cancer. N Engl J Med 2006; 354(7):684–696.
72. Moon SJ, Fryer AA, Strange RC. Ultraviolet radiation, vitamin D and risk of prostate cancer and
other diseases. Photochem Photobiol 2005; 81:1252– 1260.
73. Holick MF. A perspective on the beneficial effects of moderate exposure to sunlight: bone health,
cancer prevention, mental health and well being. In: Giacomoni PU, ed. Comprehensive Series in
Photosciences. Sun Protection in Man. Vol 3, Elsevier Science 2001:11 – 37.
74. IARC Handbooks of Cancer Prevention. Volume 5: Sunscreens. International Agency for Research
on Cancer. Lyon, World Health Organization, 2001.
75. Matsuoka L, Wortsman J, Hanifan N, et al. Chronic sunscreen use decreases circulating concen-
trations of 25-hydroxyvitamin D. Arch Dermatol 1988; 124:1802– 1804.
88 Rhodes and Lim
76. McKinlay A. Workshop round-up session. Rapporteur’s report. Prog Biophys Mol Biol 2006;
92:179– 184.
77. Heaney RP. Vitamin D: How much do we need, and how much is too much? Osteoporos Int 2000;
11:553– 555.
78. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications
for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 2005; 135:
317 – 322.
79. Lehmann B. The vitamin D3 pathway in human skin and its role for regulation of biological
processes. Photochem Photobiol 2005; 81(6):1246– 1251.
80. Duthie MS, Kimber I, Norval M. The effects of ultraviolet radiation on the human immune system.
Br J Dermatol 1999; 140:995– 1009.
81. Sjovall P, Christensen OB. Local and systemic effect of ultraviolet irradiation (UVB and UVA) on
human allergic contact dermatitis. Acta Dermato-venereologica (Stockh) 1986; 66:290– 294.
82. Friedmann PS, White SI, Parker S, et al. Antigenic stimulation during ultraviolet therapy in man
does not result in immunological tolerance. Clin Exp Immunol 1989; 76:68 –72.
83. Yoshikawa T, Rae V, Bruins-Slot W, et al. Susceptibility to effects of UVB radiation on induction of
contact hypersensitivity as a risk factor for skin cancer in humans. J Invest Dermatol 1990; 95:530–
536.
84. Cooper KD, Oberhelman L, Hamilton TA, et al. UV exposure reduces immunization rates and pro-
motes tolerance to epicutaneous antigens in humans: relationship to dose, CD1a—DR þ epidermal
macrophage induction, and Langerhans cell depletion. Proc Natl Acad Sci USA. 1992; 89:8497 –8504.
85. Cumberbatch M, Bushan M, Dearman RJ, et al. IL-1 beta-induced Langerhans cell migration and
TNF-a production in human skin: regulation by lactoferrin. Clin Exp Immunol 2003; 132:352– 359.
86. Gualde N, Harizi H. Prostanoids and their receptors that modulate dendritic cell-mediated immu-
nity. Immon Cell Biol 2004; 82:353 – 360.
87. Kang K, Hammerberg C, Meunier L, et al. CD11bþ macrophages that infiltrate human epidermis
after in vivo ultraviolet exposure potently produce IL-10 and represent the major secretory
source of epidermal IL-10 protein. J Immunol 1994; 153:5256– 5264.
88. DeVries JE. Immunosuppressive and anti-inflammatory properties of Interleukin 10. Ann Med 1995;
27:537– 541.
89. Grewe M, Gyufko K, Krutmann J. Interleukin-10 production by cultured human keratinocytes:
regulation by ultraviolet B and ultraviolet A1 radiation. J Invest Dermatol 1995; 104:3 – 6.
90. Cumberbatch M, Kimber I. Dermal tumour necrosis factor-alpha induces dendritic cell migration to
draining lymph nodes, and possibly provides one stimulus for Langerhans’ cell migration. Immu-
nology 1992; 75:257– 263.
91. Gillardon F, Moll I, Michel S, et al. Calcitonin gene-related peptide and nitric oxide are involved in
ultraviolet radiation-induced immunosuppression. Eur J Pharmacol 1995; 293:395– 400.
92. Kuchel JM, Barnetson RS, Halliday GM. Nitric oxide appears to be a mediator of solar-simulated
ultraviolet radiation-induced immunosuppression in humans. J Invest Dermatol 2003; 121:587– 593.
93. Moodycliffe AM, Kimber I, Norval M. The effect of ultraviolet B irradiation and urocanic acid
isomers on dendritic cell migration. Immunology 1992; 77:394– 399.
94. Ross JA, Howie SE, Norval M, et al. Systemic administration of urocanic acid generates suppression
of the delayed type hypersensitivity response to herpes simplex virus in a murine model of infec-
tion. Photodermatol 1988; 5:9 – 14.
95. El-Ghorr AA, Norval M. A monoclonal antibody to cis-urocanic acid prevents the ultraviolet-
induced changes in Langerhans cells and delayed hypersensitivity responses in mice, although
not preventing dendritic cell accumulation in lymph nodes draining the site of irradiation and
contact hypersensitivity responses. J Invest Dermatol 1995; 105:264– 268.
96. Reeve VE, Boehm-Wilcox C, Bosnic M, et al. Lack of correlation between suppression of contact
hypersensitivity by UV radiation and photoisomerization of epidermal urocanic acid in the hairless
mouse. Photochem Photobiol 1994; 60:268– 273.
97. Applegate LA, Ley RD, Alcalay J, et al. Identification of the molecular target for the suppression of
contact hypersensitivity by ultraviolet radiation. J Exp Med 1989; 170:1117 – 1131.
98. Schater B, Lederman MM, LeVine MJ, et al. Ultraviolet radiation inhibits human natural killer
activity and lymphocyte proliferation. J Immunol 1983; 130:2484– 2487.
99. Hersey P, Magrath H, Wilkinson F. Development of an in vitro system for the analysis of ultraviolet
radiation-induced suppression of natural killer cell activity. Photochem Photobiol 1993; 57:279– 284.
100. Gilmour JW, Vestey JP, George S, et al. Effect of phototherapy and urocanic acid isomers on natural
killer cell function. J Invest Dermatol 1993; 101:169– 174.
101. Halliday GM. Inflammation, gene mutation and photoimmunosuppression in response to UVR-
induced oxidative damage contribute to photocarcinogenesis. Mutation Res 2005; 571:107– 120.
102. Yuen KS, Halliday GM. Alpha-Tocopherol, an inhibitor of epidermal lipid peroxidation, prevents
ultraviolet radiation from suppressing the skin immune system. Photochem. Photobiol 1997;
65(3):587– 592.
103. Fuchs J, Packer L. Antioxidant protection from solar-simulated radiation-induced suppression of

contact hypersensitivity to the recall antigen nickel sulfate in human skin. Free Rad Biol Med
1999; 27:422– 477.
104. Rhodes LE, Callaghan TM. Beyond sun protection factor testing. Int J Cosmet Sci 2004; 26:207– 214.
105. Fourtanier A, Moyal D, Maccario J, et al. Measurement of sunscreen immune protection factors in
humans: a consensus paper. J Invest Dermatol 2005; 125(3):403– 409.
106. Poon TS, Barnetson RS, Halliday GM. Prevention of immunosuppression by sunscreens in humans
is unrelated to protection from erythema and dependent on protection from ultraviolet A in the face
of constant ultraviolet B protection. J Invest Dermatol 2003; 121:184– 190.
107. Van de Pas CB, Kelly DA, Seed PT, et al. Ultraviolet-radiation-induced erythema and suppression of
contact hypersensitivity responses in patients with polymorphic light eruption. J Invest Dermatol
2004; 122(2):295– 299.
108. Holleran WM, Uchida Y, Halkier-Sorensen L, et al. Structural and biochemical basis for the UVB-
induced alterations in epidermal barrier function. Photodermatol Photoimmunol Photomed 1997;
13:117 – 128.
109. Haratake A, Uchida Y, Schmuth M, et al. UVB-induced alterations in permeability barrier function:
roles for epidermal hyperproliferation and thymocyte-mediated response. J Invest Dermatol 1997;
108:769– 775.
110. Meguro S, Arai Y, Masukawa K, et al. Stratum corneum lipid abnormalities in UVB-irradiated skin.
111. Rhodes LE. Mechanisms of UVB-induced erythema. MD Thesis, University of Liverpool, Liverpool,
UK, 1995.
112. Moyal D, Fourtanier A. Acute and chronic effects of UV on skin: what are they and how to study
them? In: Rigel DS, Weiss RA, Lim HW, Dover JS, eds. Photoaging. New York: Marcel Dekker,
Inc., 2004:15– 32.
7 The Chronic Effects of Ultraviolet Radiation
on the Skin: Photoaging
Mina Yaar
Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, U.S.A.
B UVA, UVB, and infrared irradiation induce cutaneous photodamage.
B UV irradiation leads to DNA damage and also invokes membrane

signaling resulting in decreased collagen production and increased
degradation.
B Telomere signaling could be mediating DNA damage responses to UV

irradiation.
B Different ethnic groups display diverse photodamage responses.
B Several tools are currently available to assess skin aging and photoaging.
92 Yaar
INTRODUCTION
kin aging has been viewed as two distinct phenomena: intrinsic aging, changes attribu-
S table to the passage of time alone; and photoaging, the superposition of changes attribu-
table to chronic ultraviolet (UV) exposure on intrinsic aging. UV irradiation is harmful to
the skin invoking damage to DNA, proteins, and lipids and adversely affecting the skin struc-
ture and function. Intrinsically aged skin appears finely wrinkled, lax, dry, and rough; it dis-
plays a variety of benign neoplasms (1). Photoaged skin by definition is present in areas that
are habitually exposed to the sun. It prominently affects the face with its abundant vasculature
and other unique anatomic features, as well as the dorsal hands and forearms, upper chest, and
other areas more readily contrasted with less-exposed “control” areas. The rate and degree of
photoaging are determined by poorly understood genetic factors such as tanning ability and
DNA damage repair capacity. Generally, fair-skinned individuals are more severely affected;
however, individuals with darker skin phototypes are affected as well. Eventually, photodam-
age may lead to the development of skin cancer.
MECHANISMS OF PHOTOAGING
General Aspects
UV irradiation (wavelengths 100 –400 nm) comprises only 5% of the terrestrial solar irradiation.
It is arbitrarily divided into UVA (320 –400 nm), UVB (280 – 320 nm), and UVC (100 –280 nm)
[for review, see (2)]. The UVC portion of the spectrum is not present in terrestrial sunlight,
except at high altitudes, as it is absorbed by the atmospheric ozone layer. The predominant
component of solar UV irradiation is UVA, the intensity of which varies little with season or
during the day, and unlike UVB irradiation is not blocked by glass (3). Although the energy
per photon delivered by UVA irradiation is approximately 1000-fold weaker than that of
UVB, because of its longer wavelengths, UVA penetrates into the skin to reach deeper
dermal layers.
Most of UVA adverse effects in skin are assumed to be the result of oxidative
damage mediated through UVA absorption by cellular chromophores such as urocanic acid,
riboflavin, and melanin precursors that act as photosensitizers leading to the generation
of reactive oxygen species (ROS) and free radicals (4). Interestingly, advanced glycation
endproducts that accumulate with aging in long-lived proteins like those of the extra-
cellular matrix also act as UVA chromophores to become photosensitizers and affect
dermal fibroblasts. ROS also directly damage dermal matrix components inducing collagen
oxidation and degradation [for review, see (5)]. However, although it is evident that UV
irradiation plays a role in cutaneous photodamage, it is not clear what changes are the result
of UVA irradiation and what changes are induced by UVB irradiation (see subsequently
further discussion).
UVB irradiation primarily affects the epidermis. It is directly absorbed by cellular DNA,
leading to the formation of DNA lesions, mainly cyclobutane dimers and pyrimidine (6-4)
pyrimidone photoproducts (6). Despite comprehensive nuclear DNA damage repair
systems, DNA damage is rarely completely repaired. When cells sustain abundant DNA
damage, they undergo apoptosis [for review, see (1)], a process mediated largely by the
tumor suppressor p53 protein. p53 also participates in DNA damage repair and in transient
cell cycle arrest after DNA damage. However, those cells that have not undergone apoptosis
and in which the damage is not completely repaired risk developing mutations, eventually
become cancerous. This is particularly important in view of recent epidemiologic studies
showing that more than 90% of epidermal squamous cell carcinomas and more than 50% of
basal cell carcinomas display UV-induced mutations that inactivate p53 (7). Furthermore,
p53 mutations are present in the premalignant actinic keratoses, suggesting that p53 mutations
occur early, increasing the risk for malignant transformation of affected cells.
Apart from its direct effect on epidermal DNA, studies in the murine system show that
UVB irradiation affects both the cutaneous and systemic immune responses leading to defec-
tive antigen presentation and formation of suppressor T cells, allowing the propagation of
cancerous cells that would otherwise be rejected [for review, see (8)]. In this regard, it was
Chronic Effects of Ultraviolet Radiation: Photoaging 93
suggested that UVA, by inducing lipid peroxidation, stimulates the outward migration of
immune-responsive cells from the epidermis and thus further contributes to immunosuppres-
sion (8). Also, UVB irradiation induces the secretion of epidermal cytokines, and evidence
suggests that, of these cytokines, tumor necrosis factor-a and interleukin-10 play a major
role in UVB-induced immunosuppression.
In addition to UV irradiation, sunlight also transmits infrared (IR) irradiation (760 nm –
1 mm) [for review, see (9)]. Wavelengths of 760 to 1400 nm can penetrate the skin to reach
the subcutaneous tissue without inducing a significant increase in skin temperature. In con-
trast, wavelengths 1400 nm to 1 mm are primarily absorbed in the epidermis and considerably
increase the skin temperature (10). IR is particularly important in regions of high insulation,
and studies suggest that in addition to UV, IR contributes to cutaneous photoaging (discussed
subsequently).
UV-Induced Membrane Signaling

In addition to its well-known effects on DNA, UV irradiation directly activates cell surface
receptors, in part possibly through ROS generation, to induce intracellular signaling by activat-
ing the nuclear transcription complex AP-1, composed of the proteins c-Jun and c-Fos [for
review, see (11)] (Fig. 1). UV also activates NF-kB, a ubiquitous transcription factor composed
of Rel family members, which controls the expression of a large array of genes involved in
immune function and cell survival [for review, see (12)]. In intact human skin, even suberythe-
mogenic doses of UVB [0.1 minimal erythema dose (MED)] transcriptionally upregulate and
activate AP-1 (13). Increased AP-1 activity interferes with synthesis of the major dermal col-
lagens I and III by blocking the effect of transforming growth factor-b (TGF-b), a cytokine
that enhances collagen gene transcription (11,13). AP-1 also decreases the level of TGF-b recep-
tors, further inhibiting collagen transcription (14), and also antagonizes retinoid effects in skin,
leading to a functional retinoid deficiency and reducing collagen synthesis normally promoted
by retinoic acid bound to its nuclear receptors. Hence, in photodamaged skin, there is an
overall reduction in collagen synthesis (15).
Increased AP-1 activity also increases the levels and activity of several enzymes that
degrade extracellular matrix components, notably the matrix metalloproteinases (MMP)-1
(collagenase), MMP-3 (stromelysin-1), and MMP-9 (92-kd gelatinase) (11,16). Degradation of
matrix proteins is aggravated by NF-kB that increases the levels of MMP-1 and MMP-9 (13).
Finally, matrix degradation is further exacerbated by MMP-8 (collagenase) of neutrophil
FIGURE 1 Ultraviolet (UV) irradiation induces membrane signaling. UV irradiation directly activates cell surface
receptors, initiating intracellular signaling that eventually activates the nuclear transcription complex AP-1. AP-1
increases transcription of matrix metalloproteinases and decreases expression of the procollagen I and III genes
and transforming growth factor-b receptors, with a final consequence of reduced dermal matrix. Abbreviations:
MMPs, matrix metalloproteinases; TGFb, transforming growth factor b. Source: Adapted from Refs. 11, 81.
94 Yaar
origin, following neutrophil infiltration of UV-irradiated skin (17). Although there is also a con-
comitant upregulation of tissue inhibitors of metalloproteinases (TIMPs) that limit further
matrix degradation, TIMPs presumably are not completely effective in blocking cumulative
damage to dermal collagen (18).
UV-induced collagen degradation is generally incomplete, leading to accumulation of
partially degraded collagen fragments in the dermis, thus reducing the structural integrity
of the skin (11). In addition, the large collagen degradation products inhibit new collagen syn-
thesis (19), and thus, collagen degradation itself negatively regulates new collagen synthesis.
Interestingly, increased MMP levels and reduced collagen production have been documented
also in intrinsically aged skin (20), suggesting that similar mechanisms may contribute to
chronologic aging, perhaps again through the generation of ROS, as discussed above.
Mitochondrial Damage
Mitochondria are cellular organelles that produce energy (ATP) by consuming oxygen.
Although equipped with antioxidant defense systems, studies suggest that continuous gener-
ation of ROS damages mitochondrial DNA (mtDNA). To date, machinery to remove bulky
DNA lesions has not been identified in mitochondria, although they display capacity for
base excision repair and repair of oxidative damage. Still, mtDNA mutation frequency is
approximately 50-fold higher than that of nuclear DNA, and photodamaged skin has higher
mtDNA mutation frequency when compared with sun-protected skin, displaying large-scale
DNA deletions (21– 24) and resulting in decreased mitochondrial function, as a result of
faulty respiratory chain leading to further accumulation of ROS. Also, a correlation
was noted between decreased mitochondrial function and increased MMP-1 levels without
concomitant increases in MMP-1-specific TIMP (21), further exacerbating collagen degradation
(21– 24) and aggravating skin photoaging.
Telomeres
Telomere Shortening
The terminal portions of eukaryotic chromosomes are termed telomeres. In all mammals, they
are composed of repeats of the short DNA sequence TTAGGG (25) and in man are several thou-
sand bases in length. Telomeres appear to protect the chromosomes from degradation or fusion
(26). As well, because DNA polymerase, the enzyme that replicates chromosomes, cannot repli-
cate the final base pairs of each chromosome, chromosomes shorten after each round of DNA
replication (27), and the presence of telomeric repeats at the chromosome ends prevents loss of
critical-coding sequences (Fig. 2). Finally, by shortening with each round of cell division, telo-
meres serve as the biological clock, informing cells that they are young or old. Both epidermal
keratinocytes and dermal fibroblasts from older individuals have shorter telomeres than do
younger individuals (27,28), and telomeres of patients with disorders of premature aging,
such as Werner’s syndrome and progeria, are shorter than those of age-matched controls
(27,29). Germline cells as well as immortalized cell lines and almost all malignant cells
express the enzyme telomerase that adds bases to telomeres and thus maintains their length,
despite repeated cell divisions (30). In contrast, somatic cells generally lack this enzyme and
have a finite proliferative ability.
Telomeres and DNA Damage

A recent model proposes that telomere function is determined by more than just length. Telo-
mere ends appear to exist in a “capped” (hidden) or “uncapped” (exposed) form and, when
uncapped, cause DNA damage responses in the cell (Fig. 2) (25). It is known that telomeres
are normally present in a loop configuration (31) and that the loop is held in place by the
final 150 to 200 bases of the TTAGGG repeats on the 30 strand that forms a single-stranded over-
hang and insert into the proximal telomeric double helix (31). Further, when the loop is dis-
rupted experimentally, the overhang is digested and the cell mounts DNA damage responses,
including entry into senescence in some cell types (32,33). It was reported that oligonucleo-
tides homologous to the telomere overhang sequence (“T-oligos”) are taken up into the cell
nucleus and cause identical responses (34,35). These findings suggest that the physiological
FIGURE 2 Cellular responses induced by exposure of the telomere repeat sequence. Telomeres normally exist in a
loop configuration, held in place by the final 150 to 200 bases (TTAGGG repeats) on the 30 strand that form a
single-stranded overhang. When the loop is disrupted experimentally, for example, by interfering with the synthesis
of the protein that holds the loop together, the cell mounts DNA damage responses that, depending on the cell type,
include senescence or apoptosis. We speculate that the 30 telomere overhang may also be exposed when telomeres
become critically short, for example, after repeated cell divisions, or when telomeres are damaged as a result of UV
irradiation or other DNA damage. A sensor protein that invokes the DNA damage responses recognizes the exposed
overhang. We have shown that introducing oligonucleotides homologous to the telomere overhang sequence
(T-oligo) into cells invokes the same responses in the absence of telomere disruption and propose that a common
molecular pathway, involving the tumor suppressor protein p53, mediates the responses independent of the
initiating event. Source: From Ref. 81.
signal for cells to enter senescence following acute DNA damage or critical telomere shorten-
ing may be exposure of the TTAGGG overhang sequence, an event mimicked by T-oligos in
the absence of telomere disruption (Fig. 3). In all instances, the responses are mediated by the
same molecular pathways, centrally involving the tumor suppressor protein p53 (34,35).
It is well documented that many DNA damaging agents also produce aging-like changes.
Such agents include UV irradiation, ROS, cigarette smoke (presumably the carcinogen
benzo(a)pyrene), and many chemotherapeutic drugs, notably cisplatin (36). UV irradiation
causes pyrimidine dimers, most commonly between adjacent thymidines (37), ROS primarily
cause 8-oxo-guanine, and the other agents form adducts that alter DNA at guanine nucleotides
(38,39). In this context, it is interesting that one-third of the TTAGGG telomere overhang repeat
sequence is dithymidines (TT) and half is guanine (G) residues (35). The resultant concentration
of UVor chemical carcinogen damage in the telomere might therefore reasonably lead to disrup-
tion of the loop structure and exposure of the overhang, followed by DNA damage signaling.
Certainly, signaling through the p53 pathway is well documented after exposure to UV (40) or
other DNA-damaging agents (41), as well as during entry into senescence [for review, see (42)].
Repeated UV irradiation and/or prolonged exposure to ROS would thus be expected to
accelerate cellular senescence, as documented to occur during experimental loop disruption
(32) and/or as a consequence of compensatory cell divisions required to replace cells lost to
apoptosis. This model is supported by the findings that abnormally short telomeres are
found in cells after long exposure to oxidative stress or cisplatin (38,39).
96 Yaar
Chronologic Aging Photodamage
Repeated
Cell Divisions UVA UVB
Oxidative
Cellular
Metabolism
8-oxo-G
Telomere Thymine Dimers
…TTAGGG…
Signaling
SOS-like
Responses Coding DNA
Mutations
Senescence Cancer
FIGURE 3 Hypothetical common mechanism for intrinsic aging and photoaging. Repeated cell divisions shorten
telomeres. Exposure to ROS during aerobic cellular metabolism may also damage guanine residues in telomeres.
During the repair of such damage, the telomere loop would be temporarily disrupted. Both critical telomere
shortening and telomere loop disruption would invoke signaling leading to SOS-like responses, proliferative
senescence, or apoptosis, all of which interfere with carcinogenesis. Photodamage leads to thymine dimers (UVB)
and ROS (both UVA and UVB) that damage genomic DNA and give rise to mutations that may lead to cancer
development. However, these lesions also damage telomeres, disrupting the telomere loop. Consequent signaling
through the exposed TTAGGG sequence would lead to SOS-like responses, senescence, or apoptosis that would
interfere with carcinogenesis. Abbreviation: ROS, reactive oxygen species. Source: From Ref. 81.
A concept thus emerges that nature may employ the same molecular defenses against
DNA damage, with its inherent cancer risk, whether the damage is severe and acute or
subtle but cumulative over many rounds of cell division. Specifically, both extensive damage
to thymidine dinucleotides and to guanines within the TTAGGG tandem repeat sequence
and age-associated telomere shortening may lead to disruption of the telomere loop that in
turn activates p53 and other mediators of cell cycle arrest, apoptosis, and/or senescence.
Within this concept, the “genetic” or intrinsic component of aging that relies on progressive
telomere shortening during serial cell division and the “environmental” or “wear and tear”
component that in the skin results primarily from UV irradiation and oxidative cellular
metabolism similarly disrupt the telomere loop structure and activate a common final
pathway (Fig. 3). This concept explains the stereotyped predictable character of photoaged
skin and the substantial clinical overlap between intrinsically aged and photoaged skin.
The unique features of photoaged skin, including its predisposition to skin cancer, are
likely attributable to UV-induced mutations in key regulatory genes that accumulate
during the telomere-driven aging process.
ACTION SPECTRUM FOR PHOTOAGING

The action spectrum for human photoaging has not clearly been determined, and hence the
relative contribution of the various spectral bands within sunlight is unknown. There is no
truly appropriate animal model. In rodent skin, an elastosis-like condition can be produced
by prolonged intense irradiation with either a predominantly UVB or UVA source, but attempts
to determine the action spectrum for murine elastosis have yielded conflicting results (43,44).
Using UVA irradiation and the hairless mouse model, studies showed decreased activity of the
enzyme prolyl-hydroxylase that participates in post-translational modification of collagen (45).
In contrast to UVB, which renders collagen more susceptible to enzymatic degradation,

irradiation with UVA rendered dermal collagen more resistant to degradation, in part as a
result of increased cross-linking of the fibers.
As mentioned above, UVB photons are on average 1000 times more energetic than UVA
photons and are overwhelmingly responsible for sunburn, suntanning, and photocarcinogenesis
following sun exposure (46), although UVA also contributes to these endpoints (47,48). UVA
is suspected of playing a proportionately larger role in photoaging because of its minimally
10-fold greater abundance in terrestrial sunlight, far greater year-round and day-long
average irradiance, and greater average depth of penetration into the dermis compared with
UVB. Moreover, human skin exposed daily for only one month to suberythemogenic doses
of UVA alone demonstrates epidermal hyperplasia, stratum corneum thickening, Langerhans
cell depletion, and dermal inflammatory infiltrates with deposition of lysozyme on the elastic
fibers (49). These latter changes have been interpreted to suggest that frequent casual exposure
to sunlight containing principally UVA, for example, while wearing a UVB-absorbing sunsc-
reen, eventually may result in damage to dermal collagen and elastin in ways expected to
produce photoaging. Indeed, studies using reconstructed human skin in vitro containing
live fibroblasts in a dermal equivalent and differentiated epidermis showed that UVB primarily
affected epidermal cells, giving rise to cyclobutane – pyrimidine dimers and sunburn cells,
whereas UVA induced apoptosis of fibroblasts located in the upper dermal compartment as
well as secretion of MMPs (50,51).
Initially, histological changes in elderly sun-exposed skin were described by experienced
investigators as differing only in degree from those in elderly sun-protected skin at both the
light microscopic and electron microscopic levels. Many of the age-associated physiological
decrements, such as slowed wound healing and loss of immunoresponsiveness, also appear
to be accelerated in sun-exposed skin. Furthermore, cells cultured from chronically sun-
exposed skin sites differ from cells cultured from sun-protected sites of the same donors in
having shortened culture life spans, slower growth rates, lower saturation densities, and
altered responsiveness to retinoic acid (52), all changes also observed as a function of advanced
chronological donor age. Only in recent decades have qualitative differences in the dermal
fibrous proteins and microvasculature of paired sun-exposed and sun-protected sites been
documented. On a theoretical level, several of the mechanisms known to be involved in UV-
mediated cellular damage are also postulated to underlie chronological aging (53,54). These
include DNA injury and/or decreased DNA repair, oxidative damage, lysosomal disruption,
and altered collagen structure.
In addition to UV irradiation, IR aggravates UVA-induced dermal changes producing
severe elastosis in a guinea pig model. Even when delivered without UV, IR affects dermal
elastic fibers and increases the amount of dermal ground substance (10). In the hairless
mouse model, IR contributes to UV-induced thickening of the epidermis and dermis and
alone induces the expression of MMP-3 and the mouse equivalent of MMP-1 (9). Furthermore,
in human skin, the expression of tropoelastin, a major component of elastic fiber that associates
with microfibrils, is increased as a result of IR, and IR induces the expression of fibrillin-1, a
component of the microfibrils (55). In addition, the level of MMP-12, the enzyme that degrades
elastin, is increased (55). Thus, IR appears to contribute to UV-induced photoaging.
CLINICAL CHANGES
The features of actinically damaged skin are listed in Table 1. Photodamaged skin is character-
istically described as dry and sallow, displaying increases in both fine and deep wrinkling.
In addition, facial skin may display a pattern of papular elastosis with open comedones
(Favre– Racouchot disease) and telangiectasis [for review, see (56)]. Other changes include irre-
gular pigmentation manifesting as freckling, lentigines, and guttate hypomelanosis and a
variety of premalignant lesions, such as actinic keratoses (56). Functionally, photodamaged
skin displays decreased resilience and elasticity, increased fragility, and decreased capacity
for wound healing.
However, sun-induced cutaneous changes vary considerably among individuals,
undoubtedly reflecting inherent differences in vulnerability and repair capacity for the solar
98 Yaar
TABLE 1 Features of Actinically Damaged Skina

Clinical Abnormality Histologic Abnormality
Dryness (roughness) Increased compaction of stratum corneum, increased thickness of

granular cell layer, reduced epidermal thickness, reduced
epidermal mucin content
Actinic keratoses Nuclear atypia, loss of orderly, progressive keratinocyte maturation;
irregular epidermal hyperplasia and/or hypoplasia;
occasional dermal inflammation
Irregular pigmentation
Freckling Reduced or increased number of hypertrophic, strongly
dopa-positive melanocytes
Lentigines Elongation of epidermal rete ridges; increases in number and
melanization of melanocytes
Guttate hypomelanosis Reduced number of atypical melanocytes
Persistent hyperpigmentation Increased number of dopa-positive melanocytes and increased
melanin content per unit area and increased number
of dermal melanophages
Wrinkling
Fine surface lines None detected
Deep furrows Contraction of septae in the subcutaneous fat
Stellate pseudoscars Absence of epidermal pigmentation, altered fragmented
dermal collagen
Elastosis (fine nodularity and/or coarseness) Nodular aggregations of fibrous to amorphous material
in the papillary dermis
Inelasticity Elastotic dermis
Telangiectasia Ectatic vessels often with atrophic walls
Venous lakes Ectatic vessels often with atrophic walls
Purpura (easy bruising) Extravasated erythrocytes and increased perivascular inflammation
Comedones (maladie de Favre et Racouchot) Ectatic superficial portion of the pilosebaceous follicle
Sebaceous hyperplasia Concentric hyperplasia of sebaceous glands
a
Basal cell carcinoma and squamous cell carcinoma also occur in actinically damaged skin but, unlike the table entries, affect only a
small minority of individuals with photoaging.
Source: From Ref. 2.
insult but may also be the result of different culturally based behavior when outdoors. Even
among whites, the gross appearance of photodamaged skin of individuals with skin types I
and II differs from that of individuals with skin types III and IV, the former generally
showing atrophic skin changes with less wrinkles and at times focal depigmentation (gutate
hypomelanosis) and dysplastic changes such as actinic keratoses and epidermal malignancies
(Fig. 4A). In contrast, hypertrophic responses such as deep wrinkling, coarseness, leathery
appearance of the skin, and lentigines appear in individuals with skin types III and IV
(Fig. 4B). With time, exposed skin may remain persistently hyperpigmented (permanently
“tanned” or “bronzed”) even in the absence of further UV exposure. One study has noted
that white patients presenting with basal cell carcinomas are less wrinkled than peers
of similar complexion and degree of photodamage (57), suggesting that different factors
determine these two responses to chronic UV exposure.
Photoaging occurs not only in Caucasians but also in Asians, Hispanics, and African
Americans. The differences in clinical appearance of photoaged skin between Caucasians
and other ethnic groups is primarily due to differences in their UV defense systems. In the
latter three groups, melanin is the major form of protection, whereas in Caucasians, in addition
to melanin, stratum corneum thickening plays an important role. Indeed, the sun protection
factor (SPF) for black epidermis is 13.4 when compared with 3.4 for white epidermis (58).
Accordingly, black epidermis allows for approximately 6% of UVB to be transmitted into the
dermis when compared with almost 30% penetration into white dermis (58). Furthermore,
only 18% of UVA is transmitted into black dermis when compared with more than 55%
into white dermis (58). Interestingly, in black skin, most of the UV irradiation is filtered in
FIGURE 4 Photoaging. (A) An individual with skin type I displaying atrophic skin photodamage response with
relatively few wrinkles but with several actinic keratoses (arrows) and a site of previous basal cell carcinoma over
the lateral aspect of the nose. (B) An individual with skin type IV displaying hypertrophic skin photodamage
response with deep wrinkles and leather-like coarse skin.
the malpighiam layer when compared with the stratum corneum as a major area of filtration in
white skin [for review, see (59)].
The major clinical mark of photoaging in Asian people is pigmentary changes including
solar lentigines, flat seborrheic keratoses, and mottled pigmentation [for review, see (60)]. Also,
sun-induced melasma is common in Asians and is considered a clinical sign of photodamage in
this ethnic group. Nevertheless, moderate to severe wrinkling is also documented in Asians but
only in the sixth decade of life and only in individuals who spent more than five hours per day
in the sun (61).
There are no specific studies addressing photoaging in Hispanics. It appears that fair-
skinned Hispanics display clinical photoaging signs similar to darker skin Caucasians,
whereas Hispanics with darker skin phototypes are more similar to Asians and display fine
wrinkling and mottled pigmentation occurring late in the fourth through the sixth decade
(60). Published studies on photoaging of black skin have been conducted only in African-
Americans. Naturally, African-Americans with lighter complexions show signs of photoaging,
but usually not until the fifth or sixth decades of life (62) and these include fine wrinkling and
mottled pigmentation (60,62).
Wrinkling of photodamaged skin is exacerbated by cigarette smoking (63) and possibly
other environmental factors. The apparent influence of sex on the prevalence of certain photo-
aging features undoubtedly reflects different hair styles, patterns of dress, and nature of sun
exposure (occupational vs. recreational) between men and women over the past several gener-
ations. Other sex differences, such as epidermal thickness and sebaceous gland activity, and as
yet unrecognized effects of circulating sex hormones also may influence their development.
The characteristic distribution of different lesions is a complex function of relative sun exposure
for different body sites, anatomic distribution of the participating cutaneous structures (e.g.,
melanocytes and sebaceous glands), and other poorly understood factors.
100 Yaar
FIGURE 5 Histological appearance of photo-

damaged skin. Hematoxylin and eosin (H&E)
staining of photodamaged skin displaying bluish
masses of deranged elastic fibers characteristic
of solar elastosis. A thin subepidermal Grenz
zone (asterisk) is present. Source: Courtesy of
Jag Bhawan, M.D. From Ref. 8.
HISTOLOGICAL CHANGES
Photodamage affects both the epidermis and the dermis. In contrast to chronologically aged
skin, photodamaged epidermis is frequently acanthotic, although as discussed above, severe
atrophy also can be seen. The epidermis displays, in addition, loss of polarity and cellular
atypia. Also, there is a decrease in the number and function of Langerhans cells.
The dermis displays loss of mature collagen and the remaining collagen shows basophilic
degeneration [for review, see (5)]. Also, there is a reduction in the density of anchoring fibrils
affecting epidermal adhesion to the dermis (5). A major component of photodamaged dermis
is elastosis, a material characterized histologically by tangled masses of degraded elastic
fibers that further deteriorate to form an amorphous mass composed of disorganized tropo-
elastin and fibrillin (Fig. 5). Although fibrillin is abundant in the elastotic material deeper in
the dermis, in the upper portions of the dermis at the dermo-epidermal junction, fibrillin is
reduced (62). The amount of ground substance, largely composed of glycosaminoglycans
and proteoglycans, increases in photodamaged dermis (5). In contrast to aged sun-protected
skin that demonstrates hypocellularity, photodamaged skin frequently displays inflammatory
cells, including mast cells, histiocytes, and other mononuclear cells, giving rise to the term
heliodermatitis (literally, “cutaneous inflammation due to sun”). Fibroblasts are also more
numerous in photodamaged skin than in aged sun-protected skin and display an irregular stel-
late shape. Ultrastructurally, these cells contain active endoplasmic reticulum, consistent with
enhanced biosynthetic activity (2,5).
METHODS FOR MEASURING CUTANEOUS PHOTOAGING

In the clinical setting, it is important to develop a systematic approach of assessing and advis-
ing a patient regarding potential interventions that could improve the appearance of
photoaged skin. The correlation between clinical signs of actinically damaged skin to their
histological presentation is summarized in Table 1. The use of objective methods for assessing
the different parameters that affect skin photoaging could be beneficial for determining treat-
ment efficacy. The following paragraphs describe different methodologies currently
available to assess skin aging and photoaging.
Photonumeric Scales
In 1992, Griffiths et al. (64) proposed assessing several cutaneous aging parameters using a
photonumeric scale. They selected representative photographs of patients displaying different
grades of photodamage and assigned a progressive scale of nine grades to assess the different
parameters (0, none; 8, severe). Seven experienced dermatologists were asked to determine the
degree of photodamage of 25 patients by matching it to the photonumeric scale. In addition, the
dermatologists were asked to assess the degree of photodamage of 25 different patients as
determined by reading a written description of the different photodamage parameters. The
assessed parameters were fine wrinkling, coarse wrinkling, mottled pigmentation, and sallow-
ness. Using the photonumeric scale for assessment, the examiners agreed on the severity
(grade) of photodamage in 80% of the subjects. In contrast, when they used the descriptive
scale, they agreed only on 36% of the subjects. Furthermore, when the examiners assessed
the same patients a week later, they reached the same conclusions only when they used the
graded images, demonstrating that photonumeric scales based on representative images are
superior to written descriptions in assessing photodamage.
Photonumeric scales are easy to use and can be generated to assess different segments of
the face like the peri-orbital region. Because of the reproducibility of the assessment, photo-
numeric scales are also useful in assessing treatment outcome and can easily be used in the
outpatient office setting and when performing clinical studies.
Measuring Cutaneous Mechanical Properties

Different instruments were developed to assess the mechanical properties of the skin. To
investigate cutaneous limpness, a simple instrument called DensiScore was devised (65). The
device is attached to the patient’s skin and pressure is applied by pushing the two arms
of the instrument, compressing the skin horizontally, generating consistently the same level
of compression. Studies have shown that in young skin, horizontal compression results in
the generation of thin folds, whereas the number of folds and their width increase with
patient age. This instrument provides a simple straightforward technique for measuring
age-associated decrements of this mechanical property of the skin.
Different from the DensiScore, the Extensometer is an instrument composed of two
plates. Instead of compressing the skin, the device stretches it (66). A sensor records the
extent to which the skin can be pulled and its ability to stretch directly correlates with
cutaneous elasticity and suppleness.
A more sophisticated device that measures rotational deformation and recovery is the
Twistometer or Dermal Torque Meter (67). The instrument is equipped with a rotating head
that gently twists the skin. By applying a constant torque for a specific time interval, the inves-
tigator measures the degree of deformation imparted on the skin and the time required for the
deformation to return to its baseline condition. The measurements allow the investigator to cal-
culate cutaneous extensibility, viscosity, and recovery. Elasticity can then be calculated as the
ratio between recovery and extensibility.
Another instrument called Cutometer measures cutaneous elasticity by applying vacuum
to the skin pulling the skin vertically into the Cutometer probe (68). The resistance to the
deformation generated by the vacuum correlates with cutaneous elasticity.
Measuring Skin Surface Properties

One of the most noticeable changes that occur in photodamaged skin is loss of surface
smoothness and increased coarseness, often interpreted as dry skin. As it is difficult to
102 Yaar
objectively measure skin smoothness, different methodologies were developed to assess this
parameter.
Classically, to examine skin topography, investigators used silicone molds creating a
“negative” replica of the skin surface. This replica could be scanned into a computer or it
can be scanned by a laser beam that accurately measures 3D surfaces and converts them into
an image—a technique called laser profilometry (69). Naturally, these procedures are expensive
and time-consuming and cannot routinely be performed by the practicing dermatologist.
However, recently an instrument called Dermascore, a modified version of the dermato-
scope, was developed to assess skin topography (70). In addition to providing information on
surface morphology and pore size, by using polarized light and by rotating the instrument 908,
the dermatologist can assess cutaneous pigmentary and vascular homogeneity.
Measuring Skin Structure

Although it is convenient to evaluate photoage-associated changes in the structure of the skin
using skin biopsies, this method is invasive. Ultrasound echography is an alternative method to
skin biopsy for assessing cutaneous structure. Like all ultrasound-based techniques, the instru-
ment is attached to the skin and utilizes a transducer that emits ultrasonic sound waves. The
sound waves bounce off the skin like an echo; they are then picked up by the transducer
and converted into an electronic image of the skin (71,72). Using this methodology, the
investigator can measure skin thickness.
Magnetic resonance imagery (MRI), a technique widely used for various diagnostic pro-
cedures of other body parts, for a long time was not suitable for use on the skin because of
failure to obtain high spatial resolution. However, the recent development of a device that
can be attached to the standard MRI machine and that allows for a higher image resolution
now permits the use of this technology to assess skin structure (73). In particular, the device
is useful in obtaining a 3D structure of the hypodermis that can be used to evaluate changes
that take place in this cutaneous compartment.
Confocal microscopy is a noninvasive imaging methodology that allows for analysis of
different skin layers in vivo. By sensing light that is emitted from specific focal planes in the
skin, the confocal microscope permits the visualization of the skin layer by layer (74). Confocal
microscopic devices with spatial resolution of 1 mm enable the examiner to visualize separately
each layer of the epidermis. Ultrasound echography and MRI are more suitable to visualize the
dermis and hypodermis, respectively, whereas confocal micrsocopy is an excellent method to
visualize the stratum corneum, the epidermis, and the papillary dermis. Indeed, using this
technology on volar forearm skin of young (18 – 25 years) versus old (.65 years) individuals,
a layer by layer analysis of the epidermis and papillary dermis showed no age-associated
changes in the stratum corneum, an age-associated increase in the granular cell layer, an
increased thickness of the basal cell layer, and a significant decrease in the number of
dermal papillae (75).
Measuring Cutaneous Hydration

Barrier function of the skin is largely dependent on water and lipid content of the stratum
corneum. Stratum corneum hydration can be evaluated using a device called Corneometer
that measures the electrical properties of this cutaneous layer, specifically its capacitance
(76). The device has a probe that acts as a capacitor, an apparatus that accumulates electrical
charges. The ability of the probe to store the charges is proportional to the water content of
the stratum corneum. Stratum corneum hydration can also be measured using skin surface
hygrometer (77). The device has two electrodes and it measures conductance capacity by deter-
mining stratum corneum resistance to electrical current. Conductance is proportional to the
water content of the stratum corneum. Thus, both the corneometer and the skin surface
hygrometer provide straightforward, reliable, and easy methods for measuring water
content of the stratum corneum.
Another method that measures skin barrier examines the rate of trans-epidermal water
loss using a device called Evaporimeter, which is a hygrometer that measures the amount of
water vapor that is lost at a given time (78,79).
Measuring Sebum Production

Skin surface lipids and sebaceous gland activity can be measured using a device called
Lipometer or Sebumeter and Sebutape, a tape that absorbs sebum (80). The tape is an
opaque film that becomes transparent upon contact with cutaneous lipids. To measure
sebum production, the tape is applied to the skin surface for a specific length of time and
then it is inserted into the lipometer that registers the size and the number of the transparent
areas. From these measurements, sebum output can be calculated.
CONCLUSION
The rapid increase in older individuals in the population of developed countries has focused
the attention of dermatologists on issues associated with photoaging impacting the individ-
ual’s quality of life. Older individuals displaying photodamage, even when otherwise
healthy, direct their attention to their appearance and seek dermatologic advice with the
hope of reversing the damage. Dermatologists need to understand the mechanisms that con-
tribute to photoaging as well as the functional and structural changes displayed in photoaged
skin in order to better address prevention and treatment of photoaging.
REFERENCES
1. Gilchrest BA, Eller MS, Geller AC, Yaar M. The pathogenesis of melanoma induced by ultraviolet
radiation. N Engl J Med, 1999; 340:1341– 1348.
2. Yaar M, Gilchrest BA. Aging of the skin. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM,
Austen KF. eds. Dermatology in General Medicine. New York: McGraw-Hill, 2003.
3. Johnson JA, Fusaro RM. Broad-spectrum photoprotection: the roles of tinted auto windows,
sunscreens and browning agents in the diagnosis and treatment of photosensitivity. Dermatology
1992; 185:237– 241.
4. Gasparro FP. Sunscreens, skin photobiology, and skin cancer: the need for UVA protection and evalu-
ation of efficacy. Environ Health Perspect 2000; 108(suppl 1):71– 78.
5. Wlaschek M, Tantcheva-Poor I, Naderi L, et al. Solar UV irradiation and dermal photoaging.
J Photochem Photobiol B 2001; 63:41– 51.
6. Eller MS. Repair of DNA photodamage in human skin. In: Gilchrest BA, ed. Photodamage.
Cambridge: Blackwell, 1995: 26 – 50.
7. Brash DE, Ziegler A, Jonason AS, Simon JA, Kunala S, Leffell DJ. Sunlight and sunburn in human skin
cancer: p53, apoptosis, and tumor promotion. J Investig Dermatol Symp Proc 1996; 1:136– 142.
8. Granstein RD. Photoimmunology. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA,
Katz SI, eds. Fitzpatrick’s Dermatology in General Medicine. Vol. 1. New York: McGraw-Hill, 2003:
378– 386.
9. Kim HH, Lee MJ, Lee SR, et al. Augmentation of UV-induced skin wrinkling by infrared irradiation in
hairless mice. Mech Ageing Dev 2005; 126:1170– 1177.
10. Schieke SM, Schroeder P, Krutmann J. Cutaneous effects of infrared radiation: from clinical obser-
vations to molecular response mechanisms. Photodermatol Photoimmunol Photomed 2003;
19:228– 234.
11. Fisher GJ, Kang S, Varani J, et al. Mechanisms of photoaging and chronological skin aging. Arch
Dermatol 2002; 138:1462– 1470.
12. Ruland J, Mak TW. Transducing signals from antigen receptors to nuclear factor kappaB. Immunol
Rev 2003; 193:93– 100.
13. Fisher GJ, Datta SC, Talwar HS, et al. Molecular basis of sun-induced premature skin aging and
retinoid antagonism. Nature 1996; 379:335– 339.
14. Quan T, He T, Voorhees JJ, Fisher GJ. Ultraviolet irradiation blocks cellular responses to transforming
growth factor-beta by down-regulating its type-II receptor and inducing Smad7. J Biol Chem 2001;
276:26349–26356.
15. Fisher GJ, Datta S, Wang Z, et al. c-Jun-dependent inhibition of cutaneous procollagen trans-
cription following ultraviolet irradiation is reversed by all-trans retinoic acid. J Clin Invest 2000;
106:663– 670.
104 Yaar
16. Angel P, Szabowski A, Schorpp-Kistner M. Function and regulation of AP-1 subunits in skin physi-
ology and pathology. Oncogene 2001; 20:2413 – 2423.
17. Fisher GJ, Choi HC, Bata-Csorgo Z, et al. Ultraviolet irradiation increases matrix metalloproteinase-8
protein in human skin in vivo. J Invest Dermatol 2001; 117:219– 226.
18. Sudel KM, Venzke K, Knussmann-Hartig E, et al. Tight control of matrix metalloproteinase-1 activity
in human skin. Photochem Photobiol 2003; 78:355– 360.
19. Varani J, Spearman D, Perone P, et al. Inhibition of type I procollagen synthesis by damaged collagen
in photoaged skin and by collagenase-degraded collagen in vitro. Am J Pathol 2001; 158:931– 942.
20. Varani J, Warner RL, Gharaee-Kermani M, et al. Vitamin A antagonizes decreased cell growth and
elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in
naturally aged human skin. J Invest Dermatol 2000; 114:480 –486.
21. Berneburg M, Plettenberg H, Krutmann, J. Photoaging of human skin. Photodermatol Photoimmunol
Photomed 2000; 16:239 – 244.
22. Yang JH, Lee HC, Lin KJ, Wei YH. A specific 4977-bp deletion of mitochondrial DNA in human aging
skin. Arch Dermatol Res 1994; 286:386– 390.
23. Berneburg M, Gattermann N, Stege H, et al. Chronically ultraviolet-exposed human skin shows a
higher mutation frequency of mitochondrial DNA as compared to unexposed skin and the hemato-
poietic system. Photochem Photobiol 1997; 66:271– 275.
24. Birch-Machin MA, Tindall M, Turner R, Haldane F, Rees JL. Mitochondrial DNA deletions in human
skin reflect photo- rather than chronologic aging. J Invest Dermatol 1998; 110:149– 152.
25. Blackburn EH. Telomere states and cell fates. Nature 2000; 408:53– 56.
26. Cervantes RB, Lundblad V. Mechanisms of chromosome-end protection. Curr Opin Cell Biol 2002;
14:351– 356.
27. Allsopp RC, Vaziri H, Patterson C, et al. Telomere length predicts replicative capacity of human
fibroblasts. Proc Natl Acad Sci USA 1992; 89:10114 – 10118.
28. Nakamura K, Izumiyama-Shimomura N, Sawabe M, et al. Comparative analysis of telomere
lengths and erosion with age in human epidermis and lingual epithelium. J Invest Dermatol 2002;
119:1014– 1019.
29. Schulz VP, Zakian VA, Ogburn CE, et al. Accelerated loss of telomeric repeats may not explain
accelerated replicative decline of Werner syndrome cells. Hum Genet 1996; 97:750– 754.
30. Ahmed A, Tollefsbol T. Telomeres and telomerase: basic science implications for aging. J Am Geriatr
Soc 2001; 49:1105 – 1109.
31. Griffith JD, Comeau L, Rosenfield S, et al. Mammalian telomeres end in a large duplex loop. Cell 1999;
97:503– 514.
32. Karlseder J, Smogorzewska A, de Lange T. Senescence induced by altered telomere state, not telomere
loss. Science 2002; 295:2446– 2449.
33. Kruk PA, Rampino NJ, Bohr VA. DNA damage and repair in telomeres: relation to aging. Proc Natl
Acad Sci USA 1995; 92:258 – 262.
34. Li GZ, Eller MS, Firoozabadi R, Gilchrest BA. Evidence that exposure of the telomere 30 overhang
sequence induces senescence. Proc Natl Acad Sci USA 2003; 100:527– 531.
35. Eller MS, Puri N, Hadshiew IM, Venna SS, Gilchrest BA. Induction of apoptosis by telomere 30
overhang-specific DNA. Exp Cell Res 2002; 276:185– 193.
36. Wang X, Wong SC, Pan J, et al. Evidence of cisplatin-induced senescent-like growth arrest in
nasopharyngeal carcinoma cells. Cancer Res 1998; 58:5019– 5022.
37. Patrick MH. Studies on thymine-derived UV photoproducts in DNA—I. Formation and biological
role of pyrimidine adducts in DNA. Photochem Photobiol 1977; 25:357– 372.
38. Oikawa S, Kawanishi S. Site-specific DNA damage at GGG sequence by oxidative stress may
accelerate telomere shortening. FEBS Lett 1999; 453:365– 368.
39. Ishibashi T, Lippard SJ. Telomere loss in cells treated with cisplatin. Proc Natl Acad Sci USA 1998;
95:4219– 4223.
40. Zhan Q, Carrier F, Fornace AJ, Jr. Induction of cellular p53 activity by DNA-damaging agents and
growth arrest. Mol Cell Biol 1993; 13:4242– 4250.
41. Pei XH, Nakanishi Y, Takayama K, Bai F, Hara, N. Benzo[a]pyrene activates the human p53 gene
through induction of nuclear factor kappaB activity. J Biol Chem 1999; 274:35240– 35246.
42. Stein GH, Dulic V. Molecular mechanisms for the senescent cell cycle arrest. J Investig Dermatol Symp
Proc 1998; 3:14– 18.
43. Kligman LH, Sayre RM. An action spectrum for ultraviolet induced elastosis in hairless mice:
quantification of elastosis by image analysis. Photochem Photobiol 1991; 53:237– 242.
44. Wulf HC, Poulsen T, Davies RE, Urbach, F. Narrow-band UV radiation and induction of dermal
elastosis and skin cancer. Photodermatol 1989; 6:44 – 51.
45. Johnston KJ, Oikarinen AI, Lowe NJ, Clark JG, Uitto, J. Ultraviolet radiation-induced connective
tissue changes in the skin of hairless mice. J Invest Dermatol 1984; 82:587– 590.
46. Kochevar IE. Molecular and cellular effects of UV radiation relevant to chronic photodamage. In:
Gilchrest BA, ed. Photodamage. Cambridge, MA: Blackwell Science, 1995: 51.
47. Ying CY, Parrish JA, Pathak MA. Additive erythemogenic effects of middle-(280 – 320 nm) and
long-(320– 400 nm) wave ultraviolet light. J Invest Dermatol 1974; 63:273– 278.
48. Kligman LH. UVA enhances low dose UVB tumorigenesis. Photochem Photobiol 1988; 47:8s.
49. Lavker RM, Gerberick GF, Veres D, Irwin CJ, Kaidbey KH. Cumulative effects from repeated exposures
to suberythemal doses of UVB and UVA in human skin. J Am Acad Dermatol 1995; 32:53–62.
50. Bernerd F, Asselineau D. Successive alteration and recovery of epidermal differentiation and mor-
phogenesis after specific UVB-damages in skin reconstructed in vitro. Dev Biol 1997; 183:123– 138.
51. Bernerd F, Asselineau, D. UVA exposure of human skin reconstructed in vitro induces apoptosis of
dermal fibroblasts: subsequent connective tissue repair and implications in photoaging. Cell Death
Differ 1998; 5:792– 802.
52. Gilchrest BA. In vitro studies of aging human epidermis. In: Rothstein M, ed. Review of Biological
Research. Vol. 4. New York: Alan R. Liss, 1990: 281.
53. Lopez-Torres M, Shindo Y, Packer L. Effect of age on antioxidants and molecular markers of oxidative
damage in murine epidermis and dermis. J Invest Dermatol 1994; 102:476 –480.
54. Gilchrest BA, Bohr VA. Aging processes, DNA damage, and repair. FASEB J 1997; 11:322– 330.
55. Chen Z, Seo JY, Kim YK, et al. Heat modulation of tropoelastin, fibrillin-1, and matrix metalloprotei-
nase-12 in human skin in vivo. J Invest Dermatol 2005; 124:70 –78.
56. Yaar M, Gilchrest, BA. Skin aging: postulated mechanisms and consequent changes in structure and
function. In: Gilchrest BA, ed. Clinics in Geriatric Medicine. Vol. 17. Philadelphia: W.B. Saunders,
2001: 617 – 630.
57. Brooke RC, Newbold SA, Telfer NR, Griffiths CE. Discordance between facial wrinkling and the
presence of basal cell carcinoma. Arch Dermatol 2001; 137:751– 754.
58. Kaidbey KH, Agin PP, Sayre RM, Kligman AM. Photoprotection by melanin—a comparison of black
and Caucasian skin. J Am Acad Dermatol 1979; 1:249– 260.
59. Munavalli GS, Weiss RA, Halder RM. Photoaging and nonablative photorejuvenation in ethnic skin.
Dermatol Surg 2005; 31:1250 – 1260; discussion 1261.
60. Halder RM, Richards GM. Photoaging in patients of skin of color. In: Rigel DS, Weiss RA, Lim HW,
Dover JS, eds. Photoaging. New York: Marcell Dekker, Inc., 2004: 55 – 63.
61. Chung JH, Lee SH, Youn CS, et al. Cutaneous photodamage in Koreans: influence of sex, sun
exposure, smoking, and skin color. Arch Dermatol 2001; 137:1043– 1051.
62. Halder RM. The role of retinoids in the management of cutaneous conditions in blacks. J Am Acad
Dermatol 1998; 39:S98 – S103.
63. Smith JB, Fenske NA. Cutaneous manifestations and consequences of smoking. J Am Acad Dermatol
1996; 34:717– 732.
64. Griffiths CE, Wang TS, Hamilton TA, Voorhees JJ, Ellis CN. A photonumeric scale for the assessment
of cutaneous photodamage. Arch Dermatol 1992; 128:347– 351.
65. L’Oreal observing the skin: firm and supple. http://www.loreal.com/_en/_ww/loreal-skin-science/
vivre/ferme.aspx.
66. Quan MB, Edwards C, Marks R. Non-invasive in vivo techniques to differentiate photodamage and
ageing in human skin. Acta Derm Venereol 1997; 77:416– 419.
67. Boyce ST, Supp AP, Wickett RR, Hoath SB, Warden GD. Assessment with the dermal torque meter of
skin pliability after treatment of burns with cultured skin substitutes. J Burn Care Rehabil 2000;
21:55– 63.
68. Nishimori Y, Edwards C, Pearse A, Matsumoto K, Kawai M, Marks R. Degenerative alterations of
dermal collagen fiber bundles in photodamaged human skin and UV-irradiated hairless mouse
skin: possible effect on decreasing skin mechanical properties and appearance of wrinkles. J Invest
Dermatol 2001; 117:1458– 1463.
69. Leveque JL. Quantitative assessment of skin aging. In: Gilchrest BA, ed. Clinics in Geriatric Medicine.
Philadelphia: W.B. Saunders, 2001: 673 – 689.
70. Musnier C, Piquemal P, Beau P, Pittet JC. Visual evaluation in vivo of ‘complexion radiance’ using the
C.L.B.T. sensory methodology. Skin Res Technol 2004; 10:50– 56.
71. Sandby-Moller J, Thieden E, Philipsen PA, Schmidt G, Wulf HC. Dermal echogenicity: a biological
indicator of individual cumulative UVR exposure? Arch Dermatol Res 2004; 295:498– 504.
72. Sandby-Moller J, Wulf HC. Ultrasonographic subepidermal low-echogenic band, dependence of age
and body site. Skin Res Technol 2004; 10:57 – 63.
73. Liffers A, Vogt M, Ermert H. In vivo biomicroscopy of the skin with high resolution magnetic reson-
ance imaging and high frequency ultrasound. Biomed Tech (Berl), 2003; 48:130– 134.
74. Cullander C. Light microscopy of living tissue: the state and future of the art. J Investig Dermatol
Symp Proc 1998; 3:166 – 171.
75. Sauermann K, Clemann S, Jaspers S, et al. Age related changes of human skin investigated with
histometric measurements by confocal laser scanning microscopy in vivo. Skin Res Technol 2002;
8:52– 56.
106 Yaar
76. Alanen E, Nuutinen J, Nicklen K, Lahtinen T, Monkkonen J. Measurement of hydration in the stratum
corneum with the MoistureMeter and comparison with the Corneometer. Skin Res Technol 2004;
10:32– 37.
77. Mosely H, English JSC, Coghill GM, Mackie RM. Assessment and use of a new skin hygrometer.
Bioeng Skin 1985; 1:177– 192.
78. Wheldon AE, Monteith JL. Performance of a skin evaporimeter. Med Biol Eng Comput 1980;
18:201– 205.
79. Shah JH, Zhai H, Maibach HI. Comparative evaporimetry in man. Skin Res Technol 2005; 11:205– 208.
80. Pierard-Franchimont C, Pierard GE. Postmenopausal aging of the sebaceous follicle: a comparison
between women receiving hormone replacement therapy or not. Dermatology 2002; 204:17– 22.
81. Halachmi S, Yaar M, Gilchrest BA. Advances in skin aging/photoaging: theoretical and practical
implications. Ann Dermatol Venereol 2005; 132:362.
8 The Chronic Effects of Ultraviolet Radiation
on the Skin: Photocarcinogenesis
Antony R. Young
Division of Genetics and Molecular Medicine, St. John’s Institute of Dermatology, King’s College
London, London, England, U.K.
Norbert M. Wikonkál
Department of Dermatology, Semmelweis University, School of Medicine, Budapest, Hungary
B Skin cancers are among the most common types of cancer in humans, and
their incidence has been steadily increasing for several decades. These
cancers can be divided into three main types: malignant melanoma (MM),
basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). SCC and
BCC are often collectively referred to as nonmelanoma skin cancer.
B The clinical behavior of these three tumor types differs greatly. MM is one
of the most aggressive cancers seen in adults with early metastatic
capacity, such that the vast majority of skin cancer deaths results from
MM that normally account for less the 10% of all skin cancers. SCC can
also metastasize, but mainly only at advanced stages, whereas BCC
almost completely lacks the ability to metastasize.
B Epidemiology supports a relationship between solar radiation and skin
cancer, and a definitive role for ultraviolet radiation (UVR) was first
established in animals.
B In the “normal” population, the main risk factor for all types of skin
cancer is skin phototype, based on the Fitzpatrick classification.
B A direct role for UVR in SCC and BCC has been established in recent
years by the identification of UVR “signature mutations.” However, as
yet there is very little molecular evidence to confirm the relationship
between UVR and MM.
B Missense mutations are mostly manifest by impairing the function of the
translated protein. Tumor suppressor genes are particularly important
and perturbations of these genes greatly increase the likelihood of loss of
genetic surveillance with the consequent potential of favoring a clone of
cells that can progress into cancer. Probably, the most extensively studied
tumor suppressor gene is TP53, which translates into a protein that acts as
a transcription factor for a number of genes, including those that regulate
cell cycle, DNA synthesis, and programmed cell death (apoptosis).
B Skin cancer remains a major public health problem, and the best advice
for persons with susceptible skin types is to minimize solar exposure.
Many campaigns advocate the use of sunscreens that one might
reasonably expect to reduce skin cancer risk. Admittedly, the human
evidence for this is not very strong, except for actinic keratoses, and there
is no evidence that sunscreen use has any effect on MM.
108 Young and Wikonkál
INTRODUCTION: SKIN CANCER

kin cancers are among the most common types of cancer in countries where good regis-
S tration data exist, and their incidence has been steadily increasing for several decades.
These cancers, of epidermal origin, can be divided into three main types: malignant mel-
anoma (MM), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). SCC and BCC
are often collectively referred to as nonmelanoma skin cancer (NMSC). However, this historic
classification has little relevance to the pathogenesis of these tumors whose similarity is mostly
confined to their being derived from the keratinocyte. This also explains their lack of pigmen-
tation, although this is occasionally seen in BCC. In contrast, MM originates from epidermal
melanocytes that accounts for their usual dark pigmentation, although amelanotic MM do
occur. The clinical behavior of these three tumor types differs greatly. MM is one of the
most aggressive cancers seen in adults with early metastatic capacity, such that the vast
majority of skin cancer deaths result from MM that normally account for less than 10% of
all skin cancers. SCCs can also metastasize, but mainly at advanced stages only; whereas
BCC almost completely lack the ability to metastasize, leading some to argue that BCC should
not be termed a “cancer.” BCCs are generally tumors of the elderly, but dermatologists are
more likely to find BCC on a younger patient than SCC. A genodermatosis with autosomal domi-
nant inheritance, the Gorlin-Goltz syndrome is known to predispose to BCC at a very early age as
shown in Figure 1.
The Gorlin-Goltz syndrome has been shown to be the result of a mutation of the human ho-
mologue of the Drosophila “patched” gene, PTCH (1,2). Another member of the hedgehog signal
transduction pathway, sonic hedgehog (Shh) (Fig. 2), has also been shown to have a pronounced
effect on keratinocyte proliferation: overexpression of Shh in keratinocytes resulted in a BCC-like
phenotype after grafting on immunodeficient mice (3) (see Athar et al. (4) for recent review).
PHENOTYPIC AND SOLAR EXPOSURE RISK FACTORS FOR SKIN CANCER

In the “normal” population the main risk factor for all types of skin cancer is skin phototype,
based on the Fitzpatrick classification, as shown in Table 1. Thus, fair-skinned sun-sensitive
skin types I and II, who tan poorly if at all, are more susceptible than sun-tolerant skin types
III and IV who tan well. Skin types V (brown) and VI (black) with high levels of constitutive
pigmentation have the lowest incidence of skin cancer.
The risk for skin cancer, especially BCC and MM, is closely related to the number of
sunburn episodes in the person’s life, which is influenced by the skin color. Very light skin
FIGURE 1 Gorlin-Goltz syndrome. Left panel: Arrowheads indicate the keratotic pitting of the palms. Right panel:
A large number of basal cell cancers on the face of a female patient in her late 30s.
The Chronic Effects of Ultraviolet Radiation: Photocarcinogenesis 109
FIGURE 2 The sonic hedgehog (Shh) signal transduction

pathway. The receptor for Shh is the product of PTCH;
PTCH acts as a negative regulator of Shh, without which
PTCH represses the activation smoothened (SMO). This
inhibits the expression of various downstream target
genes, which include members of the TGF-b family, gli,
and PTCH itself. Abbreviations: PTCH; Drosophila
“patched” gene; Shh, sonic hedgehog; SMO,
smoothened.
color may increase skin cancer incidence up to 1100-fold compared to darkly pigmented indi-
viduals depending on the level of ultraviolet radiation (UVR) exposure (5). An important factor
is the melanin content of keratinocytes, as complete lack of melanin in cases of albinism predis-
poses to a higher rate of NMSC in both human and mouse (6,7). Human skin and hair color is
determined largely by one gene, the melanocortin 1 receptor (MC1R) gene (8). The human
MC1R gene encodes a 317 amino acid protein, a seven-pass transmembrane G protein
coupled receptor. This family has further members, such as MC2R, the receptor for ACTH
and MC4R, which play a crucial role in body-weight regulation. The cleavage of the proopio-
melanocortin (POMC) protein generates the melanocyte-stimulating hormone alpha (aMSH)
that serves as a ligand for the MC1R gene product. Its activation results in an increase in cellular
cAMP that leads to activation of protein kinase A, which then leads to increased transcription
of microphthalmia transcription factor (MITF). MITF directly regulates melanogenesis by acti-
vating the transcription in several genes that also include tyrosinase and tyrosinase-related
protein 1 and 2 (9). POMC is synthesized in the pituitary gland; but, in humans, keratinocytes
are a more important source of this peptide as they produce acetylated aMSH, a more powerful
agonist of the human MC1R. Thus, skin pigmentation is primarily regulated by locally pro-
duced aMSH that acts as paracrine and/or autocrine mediator of UVR-induced pigmentation
(10). Melanin is an organic polymer originated from the amino acid tyrosine with an oxidation
reaction by the tyrosinase enzyme. Two types of melanin are synthesized: (i) a cysteine-rich
red–yellow form known as pheomelanin, and (ii) a less-soluble black–brown form known as
eumelanin. MC1R activation results in primarily the synthesis of eumelanin (11).
TABLE 1 A Classification of Skin Phototypes Based on Susceptibility to Sunburn in Sunlight,

Tanning Ability, and Skin Cancer Risk, Together with Indicative Minimal Erythema Doses that Might
Be Expected Following UVR Exposure on Unacclimatized Skin
Skin
Skin Sunburn Tanning cancer No. SEDa for
phototype susceptibility ability risk 1 MED
I High None High 1 –3
II High Poor High
III Moderate Good Low 3 –7
IV Low Very good Low
V Very low Excellent Very low 7– .12
VI Very low Excellent Very low
a
A standard erythema dose (SED) is equivalent to an erythemally effective radiant exposure of 100 Jm22 (12). About
3 SEDs are required to produce just perceptible MEDs in the unacclimatized white skin of the most common northern
European skin types (13). See Chapter 2.
Abbreviations: MED, minimal erythema dose; SED, standard erythema dose.
Despite the extremely large differences between individuals’ skin color, light and dark
skin have similar numbers of melanocytes; the major difference lies in the size, number, and
pigment content of pigment-containing organelles, the melanosomes (14).
Melanin protects epidermal DNA by various mechanisms, and induced pigmentation
offers protection factors in the region of 3 (15). Protective melanin caps are often seen over
basal layer nuclei. Melanin also scavenges reactive oxygen species (ROS), although the two
major forms, pheomelanin and eumelanin, are not equally effective in this role (16).
In contrast to the above mentioned protective effects of melanin, it is also capable of
generating ROS upon UV irradiation (17 –19). It is now presumed that sunlight sensitivity of
individuals with pheomelanin, that is, the fair-skinned population, contributes to three-fold
greater DNA damage after UVB than eumelanin along with less efficient protection (19).
Solar exposure has long been presumed to play a role in the development of skin cancer,
and this has been supported by extensive clinical observation and epidemiological data. The
most direct association is for SCCs, which rarely appear before the age of 60 and are usually
seen in patients with habitual long-term solar exposure. Furthermore, these patients usually
have other signs of chronic photodamage such as photoaging with loss of skin elasticity, deep
wrinkles, and numerous solar lentigines. SCC is an occupational hazard for outdoor workers
such as farmers, but is also prevalent in avid golfers and boaters. SCC has a precancerous
lesion known as a solar or actinic keratosis (AK) that appears as a scaling reddish papule
or plaque that consists of aberrantly differentiating and proliferating cells. These precancers
may regress (20), but one in a thousand are thought to progress to carcinoma in situ and
then SCC (21). AKs are also biomarkers for SCC risk. Intermittent high-dose solar exposure
is thought to provoke BCC rather than regular moderate doses of UVR (22). Unlike SCCs,
BCCs never appear on mucus membranes and have no precursor/biomarker lesions.
Solar exposure is the major environmental risk factor for MM. A recent meta-analysis
has supported the conclusions of many individual case-control studies that intermittent
sun exposure is the most predictive environmental risk factor for melanoma [relative
risk (RR) ¼ 1.6, 95% confidence interval (CI) 1.3– 2.0] and that sunburn, especially in
childhood, is a significant risk factor (23). This analysis also suggested a highly significant
effect for sunburn at any age (RR ¼ 2.0, 95% CI 1.7 –2.4). There was no evidence for a
causal effect of chronic sun exposure on MM risk (RR ¼ 1.0, 95% CI 0.9 –1.0). Further
evidence for a role of sun exposure in MM comes from penetrance studies for the melanoma
susceptibility gene CDKN2A, in which there was evidence for an interaction between
susceptibility genes and latitude of residence, so that penetrance was highest in families
with germline CDKN2A mutations living in Australia when compared with those in
Europe (24).
Many case-control studies have established that phenotypic characteristics associated
with sun sensitivity are risk factors for MM and this has been confirmed in a recent
meta-analysis of 60 such studies (25). This showed that skin type I (vs. IV) was associated
with a RR of 2.1 for melanoma (95% CI 1.7 –2.6). A high density of freckles was associated
with a RR of 2.1 (95% CI 1.8– 2.5), eye color (Blue vs. Dark: RR ¼ 1.5, 95% CI 1.3 –1.7), and
hair color (Red vs. Dark: RR ¼ 3.6, 95% CI 2.6 – 5.4). Risk of melanoma is also greater in patients
with larger numbers of melanocytic nevi, whether banal or clinically atypical. A meta-analysis
of case-control studies by Gandini et al. (26) showed that the number of common nevi was con-
firmed as an important risk factor for MM with a substantially increased risk associated with
the presence of 101 to 120 nevi compared with ,15 (RR ¼ 6.9; 95% CI: 4.6, 10.3), as was the
number of atypical nevi (RR ¼ 6.4 95%; CI: 3.8, 10.3; for 5 vs. 0).
EVIDENCE FOR A ROLE OF UVR IN SKIN CANCER

Epidemiology supports a relationship between solar radiation and skin cancer, but terrestrial
sunlight contains visible and infrared as well as UVR. A definitive role for UVR was first
established in animals.
Detailed wavelength dependency (action spectrum) studies for SCC in mice have shown
that UVB (280 – 315 nm) is much more carcinogenic than UVA (315 –400 nm). The animal data
FIGURE 3 The CIE reference action spectrum for erythema

in human skin (12) (red) and the estimated CIE action
spectrum for human squamous cell carcinoma (27) (blue)
based on mouse studies. See Chapter 2.
have been used to generate a human action spectrum for SCC that is very similar to that for
human erythema as shown in Figure 3. This modeling implicates UVB as the main cause of
human SCC, and the recent development of mouse model for MM also indicates that UVB is
much more important than UVA (28). BCC animal models, such as Shh overexpressing (29)
and Ptch heterozygous mice (30) only incompletely reproduce this skin cancer. However, no
wavelength dependence studies have been done.
A direct role for UVR in SCC and BCC has been established in recent years by the identi-
fication of UVR “signature mutations” in these tumors as described subsequently. However, as
yet there is very little molecular evidence to confirm the relationship between UVR and MM.
DNA PHOTODAMAGE AND UVR SIGNATURE MUTATIONS

DNA is a major epidermal chromophore with absorption spectrum maximum in the nonterres-
trial UVC range, at 260 nm. However, there is also significant absorption in the UVB region and
to a much lesser extent in the UVA region. This absorption of UVR photon energy can result in
its dissipation by the rearrangement of electrons to form new bonds resulting in the structural
alteration of adjacent DNA pyrimidine bases into two major classes of DNA photolesions as
described further and shown in Figure 4. Thus, the target sites for UVR damage are determined
by the DNA-base sequence as well as the chemical structure of individual bases.
FIGURE 4 (A) Cyclobutane pyrimidine dimer. Two adjacent pyrimidine bases are linked by two new covalent bonds to
form a 4-C atom ring. (B) Pyrimidine-pyrimidone (6-4) photoproduct. A single new covalent bond is formed that distorts
the DNA helix.
Cyclobutane Pyrimidine Dimers

The most prevalent photoproduct is the cyclobutane pyrimidine dimer (CPD) that results from
a UVR photon’s energy splitting the C55 5C6 double bonds of each of the pyrimidine bases
[thymine (T) and cytosine (C)], after which their electrons form two new covalent bonds
between the bases that results in a 4-carbon cyclobutane ring. Simulated solar UVR readily
induces CPD in human epidermis in vivo with an action spectrum that is very close to that
for human erythema. Peak efficacy in vivo is at 300 nm rather than shorter wavelengths (31),
most probably because of screening by other skin chromophores such as stratum corneum-
bound urocanic acid, as well as DNA itself (32).
6-4 Photoproducts
The second major photoproduct is the pyrimidine-pyrimidone (6-4) [(6-4)PP] photoproduct. In
this case, the C555C6 double bond breaks and the surplus energy results in the rotation of one of
the pyrimidine rings, which offers its C4 to form a new bond with the C6 of the adjacent ring.
In this case, only one new bond is formed. This structure causes a more significant distortion in
the double helix than the cyclobutane ring.
Dipyrimidine lesions interfere with base pairing during DNA replication. The “A rule”
results in the correct pairing for T but not for C (33). Thus, C can be replaced by T (C ! T
mutation) and sometimes two adjacent C are changed to T (CC ! TT, known as a tandem
mutation). These changes are known as “UVR signature mutations” because they are almost
exclusively due to UVR (34– 36). Repair mechanisms are capable of monitoring and restoring
genetic integrity and may prevent mutation. In all systems studied, including human skin,
the repair of (6-4)PP is much faster than CPD, which probably explains why the CPD has
been demonstrated to be more important in skin cancer models. As discussed elsewhere, the
extremely high incidence of skin cancer in xeroderma pigmentosum (XP) patients, who
are deficient in DNA repair, demonstrates the crucial role of DNA repair mechanism in the pre-
vention of skin cancer. The enhancement of DNA repair, in particular of CPD, has been shown
to inhibit photocarcinogenesis in different animal models, and the application of a topical DNA
repair enzyme has been shown to reduce the incidence of AK in XP patients (37). Recently,
length mutations of mitochondrial DNA has also been proposed to play a role as deletions
and tandem duplications were found in tissues of AK, BCC, SCC, and sun-exposed normal
skin but not sun-protected skin (38).
UVR SIGNATURE MUTATIONS IN TUMOR SUPPRESSOR GENES

In general, the causes of cancer-inducing mutations are unknown. However, the specificity of
UVR-induced mutations enables the detection of the early molecular events in skin carcinogen-
esis. Missense mutations are mostly manifest by impairing the function of the translated
protein. The significance of a given mutation, in principle, is determined by the role of the
protein for which the mutated gene is coding. In functional terms, tumor suppressor genes
are particularly important, and perturbations of these genes greatly increase the likelihood
of loss of genetic surveillance with the consequent potential of favoring a clone of cells that
can progress into cancer. Probably, the most extensively studied tumor suppressor gene is
TP53, which translates into a 53-kDa molecular-weight protein that acts as a transcription
factor for a number of genes including those that regulate cell cycle, DNA synthesis, and pro-
grammed cell death (apoptosis) reviewed by Fisher (39). TP53 is mutated in about 50% of
human cancers and is considered a tumor suppressor gene, because its mutations inactivate
its ability to suppress tumor cell growth in culture (40). In addition, such mutations inactivate
its transcriptional activator function.
TP53 and Programmed Cell Death

In skin, UVB irradiation leads to the formation of “sunburn cells” (SBCs) that are apoptotic
keratinocytes (41). Apoptosis can also be induced by UVB in cultured human keratinocytes.
Mouse studies have shown that the TP53 tumor suppressor gene plays a role in SBC, but
apoptosis can also occur via a TP53 independent pathway, recently reviewed by Raj et al. (42).
The TP53 protein is thought to participate in a surveillance pathway that monitors the integrity
of the genome. In some cells, this appears to be a “guardian of the genome” route in which
DNA damage induces TP53 protein, leading to transient cell cycle arrest at a G1 checkpoint
(43). In other cases, however, the endpoint is TP53-dependent apoptotic death of the
damaged cell. This pathway has been termed “cellular proofreading” because it aborts the
aberrant cell rather than restoring its genome [for reviews see Sheehan and Young (44),
Harris and Levine (45)]. SBCs are evidently the end result of such a TP53-dependent DNA sur-
veillance mechanism, in which keratinocytes with unrepaired UVR lesions are killed by apop-
tosis. SBC formation thus appears to be one way that nature prevents skin cancer. Apoptosis
can also be induced by cell cycle abnormalities caused by a defective Rb gene or excessive
E2F-1 (46). This apoptosis pathway has a complex relation to TP53-dependent apoptosis and
the two act together as cellular proofreading of potentially precancerous cells.
TP53 in Squamous Cell Carcinoma

Induction of epidermal TP53 can be seen as early as 30 minutes after exposure to UVR (47). This
is a translational, rather than a transcriptional, event because no increase in its mRNA is
observed. The half-life of wild-type TP53 protein is short and its signal usually disappears
within a few hours of induction (48). However, mutated TP53 is relatively resistant to degra-
dation and this phenomenon can be used immunohistochemically to detect cells that are
likely to harbor mutated TP53 (49). This technique uses a mono- or polyclonal antibody to
detect epitopes of the TP53 protein, and the antigen-antibody binding is visualized as a
nuclear staining. The skin has a low background expression level of TP53 protein, which
means that a positive reaction is indicative of either: (i) expression in response to a very
recent challenge, in which case TP53 is likely to be wild-type; or (ii) the protein was not
degraded and is likely to be mutant. Some antibodies have been targeted against epitopes
that are most frequently mutated, which allows some selective detection of mutated TP53, as
shown in Figure 5. However, unlike sequencing, an immunohistochemical approach cannot
confidently distinguish between mutated TP53 protein and overexpressed wild-type protein.
Sections from BCC and SCC usually contain many cells that are positive for TP53
antibody (50 –52). Sequencing data from a large number of tumors show that TP53 is
mutated in more than 90% of SCCs (50,51,53 –55), the vast majority of which are UVR signa-
ture mutations. The most common is C ! T at dipyrimidine sites in about 70% of the cases.
Tandem CC ! TT mutations were also found with the frequency of 10%. Hence, two import-
ant pieces of the cancer-formation puzzle became apparent: (i) UVR is the most prominent
mutagen, and (ii) TP53 is the gene that undergoes mutations. The high frequency and nature
FIGURE 5 TP53-positive cells in murine

epidermal sheet detected by CM-5 antibody. The
darkly staining nuclei are the TP53 mutant cells.
of TP53 mutations in SCC strongly suggest that this modification is a significant contributor to
skin tumors. The SCC (and BCC) of XP patients contains high frequencies of UVR signature
mutations. One must note, however, that even though TP53 mutations are not exclusive to
skin cancer and such mutations are present in half of all human cancers, TP53 mutations in
internal cancers are more diverse with hardly any characteristic UVR signature mutations (56).
The assumption that UVR-induced TP53 mutations result in SCC leads one to assess TP53
status in AK that may progress to SCC, especially as the transition from severe sun damage to
AK, and from AK to in situ SCC have clear and seemingly sequential histological features with
increasing numbers of cell divisions, more apparent cellular atypia, and the appearance of the
horn cysts characteristic of SCC. Work in several laboratories shows a molecular similarity
between AK and to SCC with AK also containing anti-TP53 positive cells. Moreover, these
cells contain mutations with patterns similar to those of SCC (57). These observations further
support the view that TP53 mutations are an early event and play a critical role in the devel-
opment of skin cancer (58). Indeed, using the same anti-TP53 antibody approach, clones of
60 to 1000 positive cells have been identified in healthy human sun-exposed epidermis prior
to any micro- or macroscopic sign of skin cancer. These experiments also demonstrated
that sun-shielded skin harbors very few TP53-positive cells that appear singly or in very
small groups. Chronically sun-exposed skin, on the other hand, contains more patches of
TP53-positive-staining cells than sun-protected skin and these patches are also greater in
size. Sequencing TP53-positive cells from sun-exposed and sun-shielded sites revealed TP53
mutations in sun-exposed skin only. The presence of large numbers of TP53-positive clones
on sun-exposed skin strongly suggests that only a small percentage of these cells gives rise
to actual tumors. These clones are present in such a surprisingly large number that a compari-
son with the incidence of skin tumors leaves one to conclude that most of these clones disap-
pear. In fact, the frequency of apoptosis in AK is high, which supports the clinical observations
that these lesions often regress if further sun-exposure is prevented (20).
TP53-positive clones have also been shown in mouse skin exposed to UVB for 17 days,
which supports the theory that these clones arise as daughter cells of a single TP53-mutated
cell. However, these clones gradually disappear after the UVR exposure ceases (59). UVA, by
itself, in high doses, is also capable of inducing skin tumors, although its carcinogenesis
shows less of a dose-dependency than UVB (60). Psoralens in combination with UVA radi-
ation also give rise to mutations in the TP53 gene (61). Similarly to the human experiments,
groups of keratinocytes with mutated TP53 could be shown in murine epidermis (62). In a set
of experiments, wild-type C57BL/6 mice were shaved on the back and regularly irradiated
with a UVB source. At the end of the irradiation most of the dorsal skin was excised in
whole and the epidermis was peeled off in one sheet to stain for immunoreactive cells
with an anti-T53 antibody. At a time- and dose-dependent manner, the progression of
clones of TP53-positive cells could be shown in which process-continued UVB irradiation
was required for mutated cells to break in neighboring epidermal proliferation units, thus
allowing the growth of preclinical tumors.
TP53 in Basal Cell Carcinoma

Clinical differences between BCC and SCC may result from differences at the gene level.
Mutation analysis of TP53 in BCC showed that 60% of tumors contained TP53 gene mutations
(51). Some studies, based on the analysis of very small foci from the tumor tissue, have also
shown that all BCCs harbor TP53 mutations (63). It is important to consider the sample size
for mutation analysis. Current technology allows the extraction of DNA from a very small
cluster of cells (e.g., 50– 100 cells) (64) and the demonstration of genetic alteration after
several amplification steps in a thermocycler. However, this exquisite sensitivity can confound
data interpretation, and it is, therefore, desirable that mutation reports indicate the sample size
analyzed and the intensity of the mutated allele compared to its wild type, so that readers can
draw their own conclusions. BCCs have also been found to contain UVR signature mutations in
the human homologue of the PTCH gene (65), which suggests that this gene is important for
this type of tumor. Its function is less clear than that of TP53, but it is part of the hedgehog
signal transduction pathway that transmits extracellular growth and differentiation signals
to the nucleus. Interestingly, PTCH does not seem to play a role in SCC, leaving TP53 as the
only gene known to lead to SCC upon inactivation.
CONCLUSIONS
UVR has been established as a skin carcinogen by a combination of epidemiological, animal,
and molecular studies. The molecular evidence is very strong in the case of SCC and BCC,
whereas the vast majority of the evidence for MM is epidemiological. The phenotypic risk
factors for all types of skin cancer are well understood but we lack understanding of the
genetic basis of these factors. Skin cancer remains a major public health problem, and the
best advice one can give at the moment is for persons with susceptible skin types to minimize
solar exposure, as is done in many public health campaigns. Many such campaigns advocate
the use of sunscreens that one might reasonably expect to reduce skin cancer risk. However,
the human evidence for this is not very strong, except for AK (66), and there is no evidence
that sunscreen use has any effect on MM (67).
ACKNOWLEDGMENTS
We thank Professor Brian Diffey for his contributions to Table 1 and Figure 3.
REFERENCES
1. Gailani MR, Bale SJ, Leffell DJ, et al. Developmental defects in Gorlin syndrome related to a putative
tumor suppressor gene on chromosome 9. Cell 1992; 69:111 – 117.
2. Gailani MR, Stahle-Backdahl M, Leffell DJ, et al. The role of the human homologue of Drosophila
patched in sporadic basal cell carcinomas. Nat Genet 1996; 14(1):78– 81.
3. Fan H, Oro AE, Scott MP, et al. Induction of basal cell carcinoma features in transgenic human skin
expressing Sonic Hedgehog. Nat Med 1997; 3(7):788– 792.
4. Athar M, Tang X, Lee JL, et al. Hedgehog signalling in skin development and cancer. Exp Dermatol
2006; 15(9):667– 677.
5. Urbach F. The cumulative effects of ultraviolet radiation on the skin: photocarcinogenesis. In: Hawk J,
ed. Photodermatology. London: Arnold Publishers, 1999:89 – 111.
6. Perry PK, Silverberg NB. Cutaneous malignancy in albinism. Cutis 2001; 67(5):427– 430.
7. Kripke ML. Latency, histology, and antigenicity of tumors induced by ultraviolet light in three inbred
mouse strains. Cancer Res 1977; 37(5):1395– 1400.
8. Rees JL. Genetics of hair and skin color. Annu Rev Genet 2003; 37:67– 90.
9. Bertolotto C, Abbe P, Hemesath TJ, et al. Microphthalmia gene product as a signal transducer in
cAMP-induced differentiation of melanocytes. J Cell Biol 1998; 142(3):827– 835.
10. Tsatmali M, Ancans J, Yukitake J, et al. Skin POMC peptides: their actions at the human MC-1 receptor
and roles in the tanning response. Pigment Cell Res 2000; 13(suppl 8):125– 129.
11. Barsh GS. What controls variation in human skin color? PLoS Biol 2003; 1(1):E27.
12. CIE. Erythema reference action spectrum and standard erythema dose. Vienna: Commission Interna-
tionale de l’Éclairage; 1998. Report No.: CIE S ed 007/E.
13. Harrison GI, Young AR. Ultraviolet radiation-induced erythema in human skin. Methods 2002;
28(1):14– 19.
14. Szabo G, Gerald AB, Pathak MA, et al. Racial differences in the fate of melanosomes in human
epidermis. Nature 1969; 222(198):1081 – 1082.
15. Agar N, Young AR. Melanogenesis: a photoprotective response to DNA damage? Mutat Res 2005;
571(1– 2):121– 132.
16. Rees JL. The genetics of sun sensitivity in humans. Am J Hum Genet 2004; 75(5):739– 751.
17. Ortonne JP. Photoprotective properties of skin melanin. Br J Dermatol 2002; 146(suppl 61):7– 10.
18. Hill HZ, Li W, Xin P, Mitchell DL. Melanin: a two-edged sword? Pigment Cell Res 1997; 10(3):
158– 161.
19. Takeuchi S, Zhang W, Wakamatsu K, et al. Melanin acts as a potent UVB photosensitizer
to cause an atypical mode of cell death in murine skin. Proc Natl Acad Sci USA 2004;
101(42):15076– 15081.
20. Marks R, Foley P, Goodman G, et al. Spontaneous remission of solar keratoses: the case for conserva-
tive management. Br J Dermatol 1986; 115(6):649– 655.
21. Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol 1997; 36(4):650– 653.
22. Kricker A, Armstrong BK, English DR, et al. Does intermittent sun exposure cause basal cell carci-
noma? A case-control study in Western Australia. Int J Cancer 1995; 60(4):489– 494.
23. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun
exposure. Eur J Cancer 2005; 41(1):45– 60.
24. Bishop JA, Corrie PG, Evans J, et al. UK guidelines for the management of cutaneous melanoma. Br J
Plast Surg 2002; 55(1):46– 54.
25. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: III.
Family history, actinic damage and phenotypic factors. Eur J Cancer 2005; 41(14):2040– 2059.
26. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: I.
Common and atypical naevi. Eur J Cancer 2005; 41(1):28– 44.
27. CIE. Action spectrum for photocarcinogenesis (non-melanoma skin cancers). Vienna: Commission
Internationale de l’Éclairage; 2000. Report No.: CIE 132/2; TC 6-32 ed.
28. De Fabo EC, Noonan FP, Fears T, et al. Ultraviolet B but not ultraviolet A radiation initiates mela-
noma. Cancer Res 2004; 64(18):6372– 6376.
29. Xie J, Murone M, Luoh SM, et al. Activating smoothened mutations in sporadic basal-cell carcinoma.
Nature 1998; 391(6662):90– 92.
30. Aszterbaum M, Epstein J, Oro A, et al. Ultraviolet and ionizing radiation enhance the growth of
BCCs and trichoblastomas in patched heterozygous knockout mice. Nature Medicine 1999; 5(11):
1285 – 1291.
31. Young AR, Chadwick CA, Harrison GI, et al. The similarity of action spectra for thymine dimers
in human epidermis and erythema suggests that DNA is the chromophore for erythema. J Invest
Dermatol 1998; 111(6):982– 988.
32. Young AR. Chromophores in human skin. Phys Med Biol 1997; 42(5):789– 802.
33. Loeb LA, Preston BD. Mutagenesis by apurinic/apyrimidinic sites. Annu Rev Genet 1986; 20:201 –
230.
34. Miller JH. Mutagenic specificity of ultraviolet light. J Mol Biol 1985; 182:45– 68.
35. Brash DE, Seetharam S, Kraemer KH, et al. Photoproduct frequency is not the major determinant
of UV base substitution hot spots or cold spots in human cells. Proc Natl Acad Sci USA 1987; 84:
3782 – 3786.
36. Drobetsky EA, Grosovsky AJ, Glickman BW. The specificity of UV-induced mutations at an endoge-
nous locus in mammalian cells. Proc Natl Acad Sci USA 1987; 84:9103 – 9107.
37. Yarosh D, Klein J, O’Connor A, et al. Effect of topically applied T4 endonuclease V in liposomes on
skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study
Group. Lancet 2001; 357(9260):926 – 929.
38. Yang JH, Lee HC, Chung JG, et al. Mitochondrial DNA mutations in light-associated skin tumors.
Anticancer Res 2004; 24(3a):1753– 1758.
39. Fisher DE. Apoptosis in cancer therapy: crossing the threshold. Cell 1994; 78(4):539– 542.
40. Kemp CJ, Donehower LA, Bradley A, et al. Reduction of p53 gene dosage does not increase initiation
or promotion but enhances malignant progression of chemically induced skin tumors. Cell 1993;
74:813– 822.
41. Danno K, Horio T. Sunburn cell: factors involved in its formation. Photochem Photobiol 1987; 45:
683 – 690.
42. Raj D, Brash DE, Grossman D. Keratinocyte apoptosis in epidermal development and disease. J Invest
Dermatol 2006; 126(2):243– 257.
43. Lane DP. p53, guardian of the genome. Nature 1992; 358:15– 16.
44. Sheehan JM, Young AR. The sunburn cell revisited: an update on mechanistic aspects. Photochem
Photobiol Sci 2002; 1(6):365– 377.
45. Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogene 2005;
24(17):2899– 2908.
46. DeGregori J, Leone G, Miron A, et al. Distinct roles for E2F proteins in cell growth control and apop-
tosis. Proc Natl Acad Sci USA 1997; 94(14):7245– 7250.
47. Maltzman W, Czyzyk L. UV irradiation stimulates levels of p53 cellular tumor antigen in nontrans-
formed mouse cells. Mol Cell Biol 1984; 4(9):1689– 1694.
48. Ljungman M, Zhang F. Blockage of RNA polymerase as a possible trigger for u.v. light-induced apop-
tosis. Oncogene 1996; 13(4):823–831.
49. Hall PA, Lane DP. p53 in tumour pathology: can we trust immunohistochemistry?—Revisited:
[editorial] [see comments]. J Pathol 1994; 172(1):1 –4.
50. Brash DE, Rudolph JA, Simon JA, et al. A role for sunlight in skin cancer: UV-induced p53 mutations
in squamous cell carcinoma. Proc Natl Acad Sci USA 1991; 88:10124– 10128.
51. Ziegler A, Leffell DJ, Kunala S, et al. Mutation hotspots due to sunlight in the p53 gene of nonmela-
noma skin cancers. Proc Natl Acad Sci USA 1993; 90:4216– 4220.
52. Wikonkál NM, Berg RJ, van Haselen CW, et al. bcl-2 vs p53 protein expression and apoptotic rate in
human nonmelanoma skin cancers. Arch Dermatol 1997; 133(5):599– 602.
53. Campbell C, Quinn AG, Ro YS, et al. p53 mutations are common and early events that precede tumor
invasion in squamous cell neoplasia of the skin. J Invest Dermatol 1993; 100(6):746– 748.
54. Ren ZP, Hedrum A, Pontén F, et al. Human epidermal cancer and accompanying precursors have
identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non-
neoplastic keratinocytes. Oncogene 1996; 12(4):765– 773.
55. Jonason AS, Kunala S, Price GJ, et al. Frequent clones of p53-mutated keratinocytes in normal human
skin. Proc Natl Acad Sci USA 1996; 93(24):14025 – 14029.
56. Greenblatt MS, Bennett WP, Hollstein M, et al. Mutations in the p53 tumor suppressor gene: clues to
cancer etiology and molecular pathogenesis. Cancer Res 1994; 54(18):4855– 4878.
57. Ziegler A, Jonason AS, Leffell DJ, et al. Sunburn and p53 in onset of skin cancer. Nature 1994;
372(22):773– 776.
58. Wikonkál NM, Brash DE. Ultraviolet radiation induced signature mutations in photocarcinogenesis.
J Invest Dermatol Symp Proc 1999; 4(1):6– 10.
59. Berg RJ, van Kranen HJ, Rebel HG, et al. Early p53 alterations in mouse skin carcinogenesis by UVB
radiation: immunohistochemical detection of mutant p53 protein in clusters of preneoplastic epider-
mal cells. Proc Natl Acad Sci USA 1996; 93(1):274– 278.
60. de Laat A, van der Leun JC, de Gruijl FR. Carcinogenesis induced by UVA (365-nm) radiation:
the dose-time dependence of tumor formation in hairless mice. Carcinogenesis 1997; 18: 1013 – 1020.
61. Nataraj AJ, Black HS, Ananthaswamy HN. Signature p53 mutation at DNA cross-linking sites in
8-methoxypsoralen and ultraviolet A (PUVA)-induced murine skin cancers. Proc Natl Acad Sci
USA 1996; 93(15):7961– 7965.
62. Zhang W, Remenyik E, Zelterman D, et al. Escaping the stem cell compartment: sustained
UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units
without incurring additional mutations. Proc Natl Acad Sci USA 2001; 98(24):13948– 13953.
63. Pontén F, Berg C, Ahmadian A, et al. Molecular pathology in basal cell cancer with p53 as a genetic
marker. Oncogene 1997; 15(9):1059– 1067.
64. Pontén F, Williams C, Ling G, et al. Genomic analysis of single cells from human basal cell cancer
using laser-assisted capture microscopy. Mutat Res 1997; 382(1– 2):45– 55.
65. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila
patched in the nevoid basal cell carcinoma syndrome. Cell 1996; 85(6):841– 851.
66. IARC. Suncreens. Lyon: International Agency for Cancer Prevention; 2001.
67. Huncharek M, Kupelnick B. Use of topical sunscreens and the risk of malignant melanoma: a meta-
analysis of 9067 patients from 11 case-control studies. Am J Public Health 2002; 92(7):1173 – 1177.
9 The Epidemiology of Skin Cancer
Luigi Naldi
Centro Studi GISED, Ospedali Riuniti, Bergamo, Italy
Thomas Diepgen
Department of Clinical Social Medicine, Occupational and Environmental Dermatology,
Heidelberg, Germany
B Melanoma is the 19th most frequent tumor worldwide. Its incidence

varies over 100-fold around the world.
B The increase in melanoma incidence in recent decades is accompanied

by a much smaller increase in mortality and, after a steady increase,
mortality is now levelling off in many countries.
B Basal cell carcinoma is the most common cancer in white populations.

As compared to basal cell carcinoma, the incidence rates for squamous
cell carcinoma are four times lower in males, and six times lower in
females. The high incidence rates of these tumors are not paralleled by
increased mortality rates.
B The incidence of nonmelanoma skin cancer is remarkably high in organ

transplanted patients.
B Exposure to ultraviolet radiation appears as the major environmental

risk factor for nonmelanoma skin cancer and melanoma, and is the
most important avoidable cause.
120 Naldi and Diepgen
WHAT IS “SKIN CANCER”?

he term “skin cancer” is nonspecific. Different clinico-pathological entities with different
T etiologic factors, presentation, clinical course, and prognosis come under such a
heading. A distinction is usually made between “cutaneous melanoma” and “nonmela-
noma skin cancer.” The term “nonmelanoma skin cancer” includes a large number of different
disorders. Nonetheless, it is common practice to use it with reference to only two entities,
which, by far, are the most frequent ones, namely, basal cell carcinoma and squamous cell car-
cinoma, also collectively labeled as “keratinocyte carcinomas” or “epidermal skin cancer” (1).
Besides the aforementioned disorders, a large number of clinicopathological entities may be
listed as representing “skin cancer” (Table 1). Only a short mention will be made of the epide-
miology of clinicopathological entities other than cutaneous melanoma, basal cell carcinoma,
and squamous cell carcinoma.
EPIDEMIOLOGY: PURPOSES AND MEASURES

Epidemiology is mainly concerned with measuring disease frequency in a given population
and with the evaluation of variations with disease frequency in different populations and/or
according to the presence of specific factors, which may represent causal factors for the
disease (risk factors). In addition, epidemiology describes how a given disease progresses
once it has been developed and assesses those factors, which may affect the outcome of a
disease (prognostic factors). The final aim is to provide clues to prevent disease onset and to
TABLE 1 Classification of Skin Cancer

Example
Epidermal skin tumors Basal cell carcinoma
Squamous cell carcinoma
Paget’s disease
Keratoacantoma
Tumors of skin appendages
Hair-follicle tumors Pilary complex carcinoma
Sebaceous glands Sebaceous carcinoma
Apocrine gland tumors Apocrine carcinoma
Eccrine gland tumors Sweat-gland carcinoma
Microcystic adnexal carcinoma
Eccrine epithelioma
Mucinous eccrine epithelioma
Adenoid cystic carcinoma
Lymphoepithelioma-like carcinoma
Melanocytic tumors Melanoma
Malignant blue naevus
Langerhans cell tumors Histiocytosis X
Mast cell tumors Lymphadenopatic mastocytosis and eosinophilia
Subcutaneous tissue tumors Liposarcoma
Fibrohistiocytic tumors Dermatofibrosarcoma protuberans
Atypical fibroxanthoma
Malignant fibrous histiocytoma
Neoplasms of the vessel wall Angiosarcoma
Kaposi’s sarcoma
Smooth muscle tumors Superficial leiomyosarcoma
Neural and neuroendocrine tumors Granular cell tumor
Neuroendocrine and Merkel cell carcinoma
Cutaneous lymphoproliferative disease
T cell Mycosis fungoides
Sézary syndrome
Adult T-cell leukaemia/lymphoma
Primary cutaneous CD30þ lymphoproliferative disorders
B cell Primary cutaneous marginal zone B-cell lymphoma
Primary cutaneous diffuse large B-cell lymphoma, leg type
Precursor hematologic neoplasms
The Epidemiology of Skin Cancer 121
reduce morbidity and mortality associated with disease in humans. A number of measures are
usually adopted in epidemiological research. The most common are “incidence,” “prevalence,”
and the “relative risk” (2). Incidence is defined as the number of new cases of a disease occur-
ring in a population during a defined time interval. By population, it is meant not only natural
populations, that is, all the inhabitants of a given country or area, but also groups of people
identified by a common characteristic, for example, organ transplant patients. Person-time inci-
dence rate (or incidence density) is calculated for dynamic populations, that is, populations
that gain and lose members over time, such as all the natural populations. This is the
number of new cases that occur in a defined period divided by the sum of the different
times each individual was at risk of the disease (person-time). Alternatively, the average size
of the population during the period may be used, which is calculated as the estimated popu-
lation at the mid-period. In follow-up studies with no censoring, cumulative-incidence
measures may be used, which are calculated by dividing the number of new cases in a specified
period by the initial size of the cohort being followed. A special case of cumulative incidence is
the “lifetime incidence rate or risk,” which reflects the probability of a single individual of an
exposed group to develop a given disease at any time during life. When studying diseases like
cancer, which carry a relevant mortality, mortality rates can be used as a surrogate for inci-
dence. Mortality rates are easy to calculate from routinely collected data and are particularly
useful to assess the disease burden, and to compare it among different countries. The numer-
ator is the number of persons dying during the examined period of the disease of interest (as
resulting from death certificates) while the denominator is usually the mid-period population.
Prevalence is defined as the number of individuals with a certain disease in a population
at a specified time divided by the number of individuals in the population at that time. The
time interval considered may be short (point prevalence) or may extend over a longer
period (period prevalence). The “lifetime prevalence” refers to the total number of persons
known to have had the disease for at least part of their life. New cases enter the prevalence
pool and remain there until recovery or death. Prevalence measures are affected not only by
incidence but also by the duration of the disease, being roughly measured by the product of
the incidence and the average duration of the disease. To illustrate, a disease that is easily trans-
mitted but has a short duration may have a low prevalence and a high incidence.
Age and gender, among the others, may strongly influence the rate of a disease and
should be taken into account when comparing disease frequencies among different countries
or populations. Age- and sex-specific rates can be adopted. Alternatively, and more efficiently,
a set of techniques can be used to standardize the measures. Direct standardization involves,
using as weights the distribution of a specified standard population. Directly standardized
rates represent what the rate would have been in the study population if that population
had the same distribution in terms of age and sex (or other variables of interest) as the standard
population. Indirect methods involve calculation of standardized morbidity or mortality ratio,
that is, the ratio of the number of events observed in the study population to the number that
would be expected, if the study population had the same specific rates as the standard popu-
lation. In looking at trends of the incidence of a disease over time, at least three factors need to
be considered. These are the age at which the subject is diagnosed with the disease (age effect),
the calendar year of diagnosis (period effect), and the year of birth of the subject (cohort effect).
Age is usually considered when describing the incidence of cancer, therefore, the problem
remains in separating period and cohort effects. The effects of periods may reflect changes in
community activities such as education and screening programs, while cohort effects may be
the consequence of specific exposure early in life. Age-period-cohort models are used to
allow an analysis of incidence or mortality data, according to these different effects. A
number of methods can also be used to model the spatial distribution of disease incidence, ana-
lyzing spatial patterns such as clustering or dispersion as well as identifying the potential role
of environmental exposure.
A more refined analysis of the effect of candidate etiologic factors on the disease occurrence
is offered by analytical epidemiology methods, that is, cohort and case-control studies. A cohort
study involves following-up over time subjects with different levels of exposure to a candidate
etiologic factor comparing the incidence of diseases of interest in these subjects. A case-control
study involves comparing previous exposure to etiologic factors in a group of people diagnosed
with a disease of interest (cases) and in a group of people, otherwise comparable, without the
disease (controls). The measure adopted to express the link between the exposure and the
disease is the “relative risk.” This is the ratio of the incidence of a disease among the exposed
to the risk among the unexposed. Odds ratios, that is, the ratio of the odds in favor of getting
disease, if exposed to the odds in favor of getting the disease, if otherwise, can be calculated
from case-control studies as an estimate of the relative risk. The approximation works well for
rare disorders. Multivariate models can be used to simultaneously control the effects of variables
other than the one of interest, when calculating relative risks or odds ratios.
THE WORLD BURDEN OF SKIN CANCER

Skin cancer is by far the most common kind of cancer diagnosed in many western countries.
The chance of developing a skin cancer in British Columbia, Canada is approximately one in
seven, over a lifetime (3). This corresponds to, perhaps, one in three for a white population
in California (4), and even higher for a white population in Queensland, Australia (5). The
most common skin cancer is basal-cell carcinoma, followed by squamous carcinoma and mel-
anoma. The chance of developing a malignant melanoma during a lifetime, in North America,
is in the order of 1 in 100 (6). This is a startling increase over the figures of, for instance, 1935,
when the risk was 1 in 1500. Predictions of future incidence of skin cancer in the Netherlands
suggest that if the rates continue to increase and population growth and ageing remain una-
bated, a rise in annual demand for care of more than 5% could occur by the year 2015, a
heavy burden on the health system (7).
DESCRIPTIVE EPIDEMIOLOGY OF MELANOMA

The incidence of malignant melanoma varies over 100-fold around the world (Figs. 1 and 2).
According to data provided in Cancer Incidence in Five Continents, the lowest rates reported
around 1993 –1997 were 0.3 to 0.5 per 100,000 person-years, in parts of Asia, and in Asian and
black people in the United States, while the highest were up to 50 per 100,000 in Queensland,
Australia (8). Overall, melanoma is the 19th most frequent tumor worldwide (Fig. 3). Incidence
FIGURE 1 Melanoma of skin, males—ages-standardized incidence rate per 100,000. Source: From Ref. 126.
FIGURE 2 Melanoma of skin, females—ages-standardized incidence rate per 100,000. Source: From Ref. 126.
rates has risen significantly over the last 30 to 40 years, and continues to increase in the United
States, Canada, Australia, and Europe, being perceived as a major public health concern. A
number of campaigns to increase melanoma awareness have been developed in many areas
of the world. A sharp increase in melanoma incidence above preceding long-term trends has
FIGURE 3 World—ages-standardized incidence rate per 100,000 (all ages). Source: From Ref. 126.
been observed in Australia, with doubling in as little as two years, mainly linked to thin mel-
anoma (,1.5 mm thick), thicker melanoma not showing a levelling in incidence. Such an
increase was paralleled by a rise in excision of pigmentary lesions. It has been suggested
that the advancement of the time of diagnosis could not explain all of the increase and
increased diagnosis of a pre-existing, nonmetastasizing form of thin melanoma could also con-
tribute (9). In Switzerland, the increase in incidence of cutaneous melanoma over the period
1978 – 2002, was mainly due to lentigo maligna and superficial spreading melanoma, nodular
melanoma remaining stable (10). In contrast to populations of mainly European origin, there
has been no consistent upward trend over the full period from the early 1960s to the late
1980s in population of mainly non-European origin.
Geographic variations with incidence of cutaneous melanoma appears to reflect the
combined effect of constitutional characteristics and latitude. Epidemiological data from the
United States and Australia show that melanoma incidence in whites increases the closer to
the equator people live.
Variations by body site have been documented. It is of interest to consider not only fre-
quency but also density per unit of body surface area. While the greatest numbers of melano-
mas are found on the intermittently exposed areas of the back and legs, the greatest density is
on the more continuously exposed areas of the head and neck. Recent increases in incidence in
populations of European origin have been most pronounced on the trunk and other intermit-
tently exposed areas, particularly in men, while the incidence of melanoma of the face has
remained reasonably stable over time (11 – 15). The anatomical distribution in black people
and people of Asian origin is quite different with most melanomas occurring on the soles of
the feet (16,17).
Even if the increase in incidence in the last decades has been greater among women than
men, the overall incidence of melanoma tends to be higher in men compared to women. Age-
standardized incidence rates in more developed countries, according to Globocan data (2002),
were 1.8 per 100,000 in men and 1.2 in women. Melanoma is rare before age 15. Thereafter inci-
dence increases steadily and more or less linearly with age up to 45 to 49 years. From 50 to
55 years of age the curves for men and women diverge, climbing much more steeply in men
than women. The incidence rate of melanoma in those who had already had one is much
higher than in those who had never had one. At 20 years, the cumulative incidence of a
second melanoma approaches 5%. Interestingly, at variance with most epithelial cancers
whose incidence rises with a power of age, second melanoma presents a high constant inci-
dence curve compatible with the occurrence of a single mutational event in a population of sus-
ceptible individuals (18).
It is remarkable that the strong increase in melanoma incidence in many populations is
accompanied by a much smaller increase in mortality. Mortality from cutaneous malignant
melanoma has been increasing until the late 1980s in young and middle-aged populations
from most European countries, as well as from North America, Australia, and New Zealand
(19,20). A recent update of trends in skin cancer (mostly represented by malignant melanoma)
among young and middle-aged adults indicates that mortality from melanoma, after a steady
increase, is now levelling off in the European Community, following a similar tendency
observed in the United States (21,22), Australia (21,23), and New Zealand (15). In particular,
a decline in mortality can be observed among young adults from several European countries
(24). Trends in middle-aged adults are less favorable, with some countries still reporting an
increase, even if they started to level off in the mid-1990s, as well. The favorable mortality
trends in young people are of particular interest, since they suggest that a further decline in
mortality from melanoma in Europe is likely to occur over the next few years (25). Less favor-
able trends in middle-aged adults could be a consequence of comparatively heavier sun
exposure experienced at younger ages. Although some investigations reported less favorable
mortality trends for melanoma in men (12,21,26), characterized also by a worse prognosis
and survival in comparison with women (12,27), the analysis of mortality in different European
countries did not show meaningful differences in trends between men and women. Particularly
favorable trends have been observed in some northern European countries, characterized by a
high melanoma cancer incidence and mortality (28). Conversely, in countries from southern
Europe, such as France, Italy, and Spain, with lower skin cancer rates in the past, smaller
declines in mortality rates have been observed (21). This could be an effect of a higher aware-
ness in high-incidence countries, as a consequence of earlier preventive campaigns and inter-
vention programs launched (29,30). It is, however, possible that in the high-incidence countries
of northern Europe a peak has already been reached.
DESCRIPTIVE EPIDEMIOLOGY OF BASAL CELL CARCINOMA AND

SQUAMOUS CELL CARCINOMA
As already discussed, basal cell and squamous cell carcinoma are usually considered together
under the heading “nonmelanoma skin cancer” but they present rather different distribution
and etiologic factors. The two tumors share the difficulties of obtaining reliable incidence
data, and the limited contribution of mortality to understand their distribution and burden.
Incidence estimates for “cancer of the skin, other than melanoma,” based on registry data,
range from around 0.5 per 100,000 in Hispanics, Blacks, and Asian people to more than 100
per 100,000 in white people in Switzerland and Ireland (8). However, few cancer registries
provide reliable data on nonmelanoma skin cancer, and ad hoc studies need to be conducted
in a better way. To give an example, the cancer registry from Queensland, Australia, provides
estimates of 1.5 per 100,000, which are lower than the incidence for melanoma. A few ad hoc
studies have been performed providing specific incidence rates for basal cell and squamous
cell carcinoma. Based on these estimates, basal cell carcinoma appears as the most common
cancer in white people in the United States, Australia, and Europe.
A fundamental study to provide a reliable picture of the descriptive epidemiology of non-
melanoma skin cancer was the one conducted by Scotto et al. in several areas in the United
States, in two separate periods, that is, 1971 –1972 and 1977 –1978 (31). The locations varied
in latitude from 47.5 at Seattle to 30.0 at New Orleans. In the period 1977 –1978, indices of
solar radiation were obtained from Robertson-Berger meters placed at National Weather
Service stations, located at airports in metropolitan areas. Annual UVB estimates were
derived from data provided by the National Oceanic and Atmospheric Administration. In
the period 1977 –1978 the annual age-adjusted incidence rate for nonmelanoma skin cancer
among whites was 232.6 per 100,000 population, while the corresponding rate among blacks
being only 3.4. Hispanics also showed low incidence rates. On the average, the incidence
rates for basal cell carcinoma among whites were four times higher than squamous cell carci-
noma in males, and six times higher in females. However, as the UVB index increased, the
ratio of basal cell to squamous cell carcinomas decreased. On the whole, 10% of the cases had
skin cancer of multiple sites, usually diagnosed simultaneously, with the proportion of multiple
tumors being higher in southern areas. In a small proportion of all patients (2.5%), both basal
cell and squamous cell carcinomas were reported. Over 80% of all patients had at least one
skin cancer on the face, head, or neck. The risk for males was greater than for females, with a
two-fold excess risk apparent in many locations. However, women were at higher risk of
tumors of the lower extremities, presumably because of clothing habits and differential ultra-
violet-light exposure. The incidence rates for squamous cell carcinoma began to rise rapidly
around age forty, and showed a sharper increase with age than did basal cell carcinoma. In
addition, the male excess of squamous cell carcinoma was present throughout life in all
areas, while the sex disparity for basal cell carcinoma appeared at older ages. A model of the
relation between UVB intensity and nonmelanoma skin cancer was developed, the log of the
age-adjusted rates for each sex and each cell type being a linear function of UVB intensities.
In general, a 1% relative increase in UVB may result in a 2% increase in skin cancer incidence.
The increases in UVB exposure appeared to have a greater relative impact on the risk of squa-
mous cell than basal cell carcinoma. Although only four locations and six months were covered
in the survey period of 1971 – 1972, the results were consistent with the study conducted in the
period 1977 – 1978. After making adjustments for the month of diagnosis, there was a 15% to
20% increase in the age-adjusted rates for nonmelanoma skin cancer in the period 1977 – 1978
compared to the period 1971 – 1972. More recently, an overall increase in incidence among
people younger than 40 years was documented in Olmsted County, Minnesota, and notably,
a disproportionate increase in the incidence of basal cell carcinoma among young women (32).
Particular attention has been paid to the epidemiology of nonmelanoma skin cancer in
Australia, where the highest ever incidence rates have been documented. In a study among
2095 inhabitants of Queensland, Australia, the incidence rate of nonmelanoma skin cancer in
individuals aged 20 to 69 was 2389 per 100,000 person-years for males; 1908 per 100,000
person-years for females. The incidence of basal cell carcinoma was 4.5 times higher than
that of squamous cell carcinoma (33). The population with skin type 1 in Queensland is con-
sidered a unique group for studying induction of skin cancer by sunlight. Another important
study is the five-year longitudinal study (1982 –1986) performed in 2669 people over 40 years of
age, living in Maryborough, 180 kilometers north of Melbourne. The annual incidence rate for
basal cell carcinoma was estimated as 672 per 100,000, and for squamous cell carcinoma was
201 per 100,000. The ratio of the incidence of basal cell carcinoma to that of squamous cell car-
cinoma was 33. Age, sex, skin reaction to sunlight, and occupation were all significant factors in
the determination of the risk of developing nonmelanoma skin cancer (34). Recent data from
Australia suggest that, after a steady increase of incidence rates in recent decades, a stabiliz-
ation of incidence may have been reached in people younger than 60 years who were
exposed to skin cancer prevention programs in their youth (5). Similarly, in south-eastern
Arizona of the United States, where very high incidence rates compared to northern parts of
the United States have been reported, this high incidence is not increasing further and
especially the incidence of squamous cell carcinoma declined between 1985 and 1996 (35).
Downward trends of squamous cell carcinoma over the past decades are also observed from
Singapore, while the incidence of basal cell carcinoma increased on an average by 3% every
year over the years 1968 –1997 (36).
More sparse data are available from other countries and a number of studies are summar-
ized in Table 2 (37 – 51). Common features include the epidemic increase of incidence during
the last decades, the larger proportion of basal cell carcinoma as compared to squamous cell
carcinoma, a male excess, which is greater for squamous cell carcinoma than for basal cell
carcinoma, with a two-fold excess risk apparent in many locations, the preferential location
(on the average, 80% of lesions) on sun exposed areas, the rarity among blacks, Asian
people, and Hispanics. To give an example, in the period 1990 – 1992 the overall incidence
rate of nonmelanoma skin cancer in the African population of Harare, Zimbabwe, was
estimated as 4 per 100,000 (52). When phenotype is distributed uniformly, a UVB gradient
is also clearly evident, with skin cancer incidence rates being highest in geographic areas of
relatively higher UVB exposure.
One special population where the incidence of nonmelanoma skin cancer appears as
remarkably high worldwide is represented by organ transplanted patients (53), where the
increase is associated with immunosuppression and possibly human papilloma virus infection
(54). According to data from cohort studies, the cumulative incidence of nonmelanoma skin
cancer in transplanted patients increases from 10% after 10 years to 40% after 20 years of sur-
vival of the graft (53 – 58). Increased age at transplantation and male gender are established risk
factors. No clear-cut variations in risk, according to the transplanted organ or the immunosup-
pressive regimen adopted, have been documented. Post-transplant immunosuppression
appears to promote squamous cell carcinoma to a greater degree than basal cell carcinoma
with a reversal of the ratio between the two tumors observed in the general population. Inter-
estingly, such a reversal is seen much more dramatically in Northern European and Australian
transplant patients (55,56) than in Mediterranean transplant populations (57,58). It has been
repeatedly documented that once a person has developed a nonmelanoma skin cancer there
is a significantly increased risk of developing subsequent skin cancers at other sites. The risk
of a second basal cell carcinoma, after a first one is in the order of 40% after 20 years, and
the risk is greater at younger age (59). A first basal cell carcinoma or a first squamous cell car-
cinoma both are also associated with increased risk of another nonmelanoma skin cancer, mel-
anoma, non-Hodgkin lymphoma, and cancer of the salivary glands (60,61).
It is worth considering that the high incidence rates of basal cell and squamous cell carci-
nomas are not paralleled by increased mortality rates. On the contrary, mortality rates for “non-
melanoma skin cancer” are steadily decreasing in many geographic areas, for example,
Germany, Finland, and the United States (62 – 64). In Germany, the age-standardized mortality
rate for nonmelanoma skin cancer decreased from 0.56 per 100,000 in 1968 to 0.24 per 100,000 in
TABLE 2 Incidence Rates of Basal Cell Carcinoma and Squamous Cell Carcinoma in Selected Studies
Incidence rates 3 100,000 person-yearsa
Country Period
Basal cell carcinoma Squamous cell carcinoma
U.S.A. and Canada
U.S.A. 1971– 1972 202.1 (M); 115.8 (F) 65.5 (M); 21.8 (F)
1977– 1978 246.6 (M); 150.1 (F) 65.4 (M); 23.6 (F)
Minnesota (U.S.A.) 1984– 1992 180 (M); 105 (F) 48 (M); 16 (F)
Olmsted county, U.S.A. 1976– 2003 22.9– 26.7 (M); 13.4–31.6 (F) 1.3–4.2 (M); 0.6– 4.1 (F)
(40 yrs)
New Hampshire 1993– 1994 309.9 (M); 165.5 (F) 97.2 (M); 32.4 (F)
New Mexico 1998– 1999 930.3 (M); 485.5 (F) 356.2 (M); 150.4 (F)
Arizona 1996 935.9 (M); 497.1 (F) 270.6 (M); 112.1 (F)
Kauai, Hawaii 1983– 1997
Japanese 22 (M); 41 (F) 11 (M); 36 (F)
Filipinos 17 (M); 7 (F) 3 (M); 0 (F)
British Columbia (Canada) 1973– 1987 70.7– 120.4 (M); 61.5–92.2 (F) 16.6–31.2 (M); 9.4–16.9 (F)
Manitoba (Canada) 1960– 2000 30.7– 93.9 (M); 25.7–77.4 (F) 7.2– 26.1 (M); 2.8– 12.1 (F)
Australia
Australia 1985 735 (M); 593 (F) 209 (M); 122 (F)
1990 849 (M); 605 (F) 338 (M); 164 (F)
1995 955 (M); 629 (F) 419 (M); 228 (F)
2002 1541 (M); 1070 (F) 772 (M); 442 (F)
North Queensland 1997 2058 (M); 1195 (F) 1332 (M); 755 (F)
Europe
The Netherlands 1975– 1988 45.6 (M); 30.3 (F) 10.9 (M); 3.4 (F)
Norway 1982– 1996 42.8 (M); 38.7 (F) 6.4 (M); 3.2 (F)
Denmark 1988 30.4 (M); 23.7 (F) 6.7 (M); 2.5 (F)
Finland 1985 43.7 (M); 31.7 (F) 5.6 (M); 3.9 (F)
South Wales (U.K.) 1988 112.2 (M); 54.1 (F) 31.7 (M); 6.2 (F)
South Wales (U.K.) 1998 128 (M); 105 (F) 25 (M); 9 (F)
Schleswing-Holstein (Germany) 1998– 2001 80.8 (M); 63.3 (F) 18.2 (M); 8.5 (F)
Saarland (Germany) 1995– 1999 43.7 (M); 31.7 (F) 11.2 (M); 4.4 (F)
Trento (Italy) 1992– 1997 72.7 (M); 53.9 (F) 23.4 (M); 11.2 (F)
Vaud (Switzerland) 1976– 1985 51.6 (M); 38 (F) 16.1 (M); 7.7 (F)
Vaud (Switzerland) 1995– 1998 75.1 (M); 66.6 (F) 28.9 (M); 17.1 (F)
Slovakia 1993– 1995 38.0 (M); 29.2 (F) 6.7 (M); 3.8 (F)
Asia
Singapore, China 1993– 1997 6.4 (M); 5.8 (F) 3.2 (M); 1.8 (F)
Note : M, male; F, female.
a
Adjusted by age.
Source: Adapted from Refs. 3, 5, 7, 31, 32, 35 –51.
1999 among men, and from 0.42 to 0.11 among women. Age-cohort-period regression models of
the mortality data showed that the declining mortality was driven by both cohort and period
effect, the latter probably resulting from increased awareness of skin cancer (62). In Rhode
Island, U.S.A., in the period between 1988 and 2000, mortality rate from nonmelanoma skin
cancer was 0.91 per 100,000 person-years of which almost half (0.45) was due to genital carci-
noma. Skin cancers originating on the ear were responsible for more than a quarter of all deaths
caused by nongenital lesions. Many individuals had co-morbid psychiatric disorders or evi-
dence of unreasonable delay in seeking medical care for their lesions (64).
Some controversies exist about the recognition of actinic keratosis as precursor lesions
versus in situ squamous cell carcinoma (65,66). From an epidemiological point of view,
actinic keratosis should be better considered as separate from established and invasive squa-
mous cell carcinoma. Actinic keratoses are highly prevalent in the general population and
are usually manifested in multiple lesions. In the first Health and Nutrition Examination
Survey (HANES I) conducted in the United States, the overall point prevalence increased
from 15.9 per 1000 at age 45 to 54 to 65.1 per 1000 at age 65 to 74 (67). However, much
higher estimates has been obtained in other studies. In Nambour (Queensland, Australia),
44% of men and 37% of women between the age of 20 and 69 years had at least one actinic
keratosis of head, neck, hands, and arms (68). In a survey in South Wales, involving 1034 sub-
jects aged 60 years or older, the prevalence was 23% (69) while in another study in the Mersey
region in north-west England of people over 40 years of age the prevalence was 15.4% in men
and 5.9% in women (70). In the community of Freixo de Espada à Cinta in northeast Portugal,
actinic keratosis were identified in 9.6% of people (71). The fact that actinic keratoses are not
established tumors is supported by the high-turnover rate for actinic keratosis, which has
been documented in the Australian population, with a high rate of spontaneous regression
and the appearance of new lesions over time (72), and by the acceleration of regression of
actinic keratoses through regular use of sunscreens (73). In any case, the risk of progression
of actinic keratoses to invasive squamous cell carcinoma is remarkably low, being much
lower than 1 lesion in 1000 per year (74). These data, coupled with the lack of evidence, con-
cerning the benefit of treating individual actinic keratoses to prevent invasive skin cancer,
support a view of actinic keratosis as a risk marker prompting the adoption of sun protective
habits, and regular examinations, rather than a view of these lesions as representing early squa-
mous cell carcinoma that need individual lesion removal and consequent histologic
documentation.
LIMITED DATA ON LESS COMMON SKIN CANCERS

Sparse data exist on the epidemiology of skin tumors other than melanoma, squamous cell, and
basal cell carcinomas. Of interest, in this respect, were surveys conducted in Rochester,
Minnesota, the United States, and Kauai, Hawaii (40). Table 3 presents some data on rare
tumors (40,75).
ANALYTIC EPIDEMIOLOGY OF SKIN CANCER

Most of the discussion concerning environmental risk factors for skin cancer is centered around
the exposure to sun and ultraviolet radiation and its interaction with constitutional character-
istics. Light skin complexion (especially light skin and blond-red hair), freckling, and tendency
to burn, not tan, after sun exposure, are constitutional variables, which affect the risk of skin
cancer (76,77). People from Southern European ethnic origin are at a significantly lower risk
than those from English, Celtic, and Scandinavian origin. Those who migrate early in their
life from such regions to lower latitudes increase their exposure levels to sunlight and show
a higher risk of developing skin cancer (78).
In spite of some variations among the different studies available, mainly explained by the
latitude where the studies were conducted and the type of controls adopted, it can be stated
that the timing and character of sun exposure may affect differently for the risk of different
TABLE 3 Incidence Rates for Some Unusual and Rare Skin Cancers
Incidence
rates 3 100,000
Cancer Country (period) person-years
Dermatofibrosarcoma protuberans Minnesota (1973–1984) 0.45
Adenocarcinoma of sweat gland Minnesota (1973–1984) 0.27
Merkel cell carcinoma Minnesota (1973–1984) 0.16
SEER U.S.A. (2000) 0.34 (M); 0.17 (F)
Extramammary Paget’s disease Minnesota (1973–1984) 0.19
Liposarcoma Minnesota (1973–1984) 0.16
Cutaneous T cell lymphoma Minnesota (1973–1984) 0.9
Keratoacantoma Hawaii (1983– 1987)
White 104
Japanese 13
Filipinos 7
Hawaiians 6
Note: M, male; F, female.
Abbreviation: SEER, Surveillance Epidemiology and End Results Program.
Source: Adapted from Refs. 40, 75.
skin cancers. Both basal cell carcinoma and melanoma are most significantly linked to early
exposure to ultraviolet light. Intermittent sun exposure and sunburn history are more import-
ant than cumulative dose in predicting adult risk for these tumors (79 – 81). Basal cell carcinoma
and melanoma tumors appear to have a rapidly accelerating relative risk with relatively low
exposures, followed by a broad plateau. Among sensitive individuals, sun avoidance behavior
in adulthood may not markedly reduce risk for these tumors.
On the contrary, squamous carcinoma is associated with total lifetime sun exposure
(80,82,83). Overall, high occupational exposure is inversely associated with melanoma and
directly related to the risk of squamous cell carcinoma (79– 83). Late stage solar exposure
may play an important role in the development of squamous cell carcinoma, since sunlight
exposure just prior to diagnosis is associated with an increased risk of the tumor. Actinic ker-
atoses are well-established precursor lesions and recent sun exposure is connected to their
development (84). Actinic keratoses may spontaneously disappear in people who limit solar
exposure, and their progression to malignancy seems to require continued exposure to rela-
tively high doses of ultraviolet light.
Variations in risk profiles have been proposed for both basal cell carcinoma and melanoma
at different locations and with different clinicopathological variants. The frequency of superficial
basal cell carcinoma appears to be higher in females and seen in younger patients as compared
with nodular lesions. The latter occur mainly in the head/neck region while superficial lesions
occur mainly on the trunk. Chronic sun exposure may be an etiologic factor for nodular lesions
while intermittent sun exposure may play a role in superficial basal cell carcinoma (85,86). Simi-
larly, heterogeneity of risk by anatomical site, suggesting multiple causal pathways, have been pro-
posed for melanoma, with chronic sun exposure influencing the risk of melanoma of the head, and
neck and intermittent sun exposure associated with a nevus-prone phenotype influencing the risk
of melanoma elsewhere (87). However, limited data have been published on these issues.
The single greatest predictor of risk for developing melanoma is the total number of nevi
(88). Studies over the last decades have revealed a great deal about the way nevi develop and
the relationship between nevi and melanoma. Cross-sectional and cohort studies in school-
children are, particularly, informative since most nevi develop by the age of 20 (89 – 95). The
following aspects of the epidemiology of melanocytic nevi are well established:
1. Boys develop more nevi than girls;
2. While the number of nevi increases with age up to 18 to 20 years, nevus density (i.e.,
number per square meter of body surface area) reaches a plateau earlier in life, between
the age nine and 10 years, suggesting a genetic influence for such a variable;
3. Nevi are more common in children with lighter phenotype who burn and do not tan easily
in the sun, and with freckling. However, red-haired subjects have fewer nevi than other
children;
4. Higher counts are seen in children with a family history of skin cancer;
5. The number of nevi increases among children who live closer to the equator;
6. The number of nevi increases with increased history of sunburns.
It appears from these data that nevi are a complex exposure variable combining constitutional
and environmental effects. Reducing nevi in children may substantially lower melanoma rates
as they move into adulthood. Interestingly, red-haired children have a reduced count of nevi as
compared to other skin phenotypes, but a higher melanoma risk, suggesting different path-
ways to melanoma development.
Other risk factors considered for the development of skin cancers are listed in Table 4.
Smoking and other types of tobacco use are clearly associated with squamous cell carcinoma
of the lip. Squamous cell carcinoma at other sites of the skin has been positively related to ciga-
rette smoking in some studies (96,97), but negative results have also been reported (98). A two-
fold increase in risk has been calculated (99).
The relationship between squamous cell carcinoma and diet or serum levels of nutrients
has been investigated by a few studies. A high intake of n-3 fatty acids was associated with a
lower risk of squamous cell carcinoma in a case-control study (100). The incidence of squamous
cell carcinoma was not influenced by beta-carotene supplementation in a large-scale interven-
tional study (101).
TABLE 4 Summary of Risk Factors for Skin Cancer

Risk factor Melanoma Nonmelanoma skin cancer
Age Peak frequency in early More common with increasing age
adulthood, but age-related
incidence rises with
increasing age
Chemicals and exposures PUVA therapy probably Ionizing radiation increases risk.
increases risk The use of coal–tar products
and PUVA therapy increase risk.
Tobacco increases risk for
squamous cell carcinoma
Family history Occurrence of melanoma in a Family history is associated with
first- or second-degree increased risk for basal cell
relative confers increased carcinoma but not squamous
risk. Familial atypical mole cell carcinoma
melanoma syndrome confers
even higher risk
Gender Slight male predominance Substantially more common in
males
Geographic location Higher incidence in whites living Higher incidence in whites living
near the equator near the equator
Medical conditions Xeroderma pigmentosum, Chronic osteomyelitis sinus tracts,
immuno-suppression, other burn scars, chronic skin ulcers,
malignancies, and previous xeroderma pigmentosum,
nonmelanoma skin cancer all immuno-suppression, and
increase risk possibly human
papillomavirus infection all
increase risk
Nevi A large number of melanocytic Limited influence on risk
nevi, and giant pigmented
congenital nevi confer
increased risk. Melanocytic
nevi are markers for risk, not
precursor lesions
Occupation Higher incidence in indoor Higher incidence in outdoor
workers, as well as those with workers for squamous cell
higher education and income carcinoma
Previous history of skin cancer Previous melanoma is 36– 52% chance of a new skin
associated with increased risk cancer of any kind within five
years of index case
Race More common in whites More common in whites
Skin type/ethnicity Increased incidence in those Increased incidence in those with
with fair complexions; those fair complexions; those who
who burn easily, tan poorly burn easily, tan poorly and
and freckle; those who have freckle; those who have red,
red, blonde or light brown blonde or light brown hair; and
hair; and those of Celtic those of Celtic ancestry
ancestry
Sun exposure
Cumulative Probably does not influence risk Single greatest risk factor for
squamous cell carcinoma; 80%
of lifetime sun exposure is
obtained before 18 years of age
Episodic Intense, intermittent exposure Intense, intermittent exposure and
and blistering sunburns in blistering sunburns in
childhood and adolescence childhood and adolescence are
are associated with increased associated with increased risk
risk of basal cell carcinoma but not
squamous cell carcinoma
Abbreviation: PUVA, psoralen plus ultraviolet A.
Ionizing radiation has been shown to cause nonmelamoma skin cancer (102). For low-
level radiation, an increased risk has been documented in uranium miners and radiologists.
Also among survivors of the nuclear bomb there is an increased risk of basal cell carcinoma
(103). The risk of basal cell carcinoma is increased among persons exposed to occupational radi-
ation, and among patients receiving therapeutic ionizing radiation before the age of 40 (102).
There is a synergistic acceleration of the risk of skin cancer through cumulative DNA
damage by a combination of exposure to UVA radiation, environmental carcinogens, and ben-
z[a]pyrene (104). Exposure to arsenic, not only occupational but also environmental via drink-
ing water, has been associated with an increased risk of skin cancer, especially squamous cell
carcinoma (105).
Outdoor workers such as farmers, welders, watermen, police officers, physical education
teachers, pilots, and cabin attendants have an increased risk of skin cancer (106). There is scien-
tific and epidemiological evidence to recognize squamous cell carcinoma induced by occu-
pational UV-light exposure as an occupational disease, since a doubling of risk due to
occupational UV-radiation can be demonstrated (107).
Of particular interest, is the association of skin cancer with Psoralen plus Ultraviolet A
(PUVA) therapy and to a lesser extent ultraviolet B treatment. The best evidence on chronic tox-
icity of PUVA therapy comes from an ongoing study of more than 1300 people, who first
received PUVA treatment in 1975 (108). The study found a dose-dependent increased risk of
squamous cell carcinoma, basal cell carcinoma, and, possibly, malignant melanoma compared
with the risk in the general population (109). A systematic review (search date 1998) of eight
additional studies has confirmed the findings concerning nonmelanoma skin cancer (110).
After less than 15 years, about a quarter of people exposed to 300 or more treatments of
PUVA had at least one squamous cell carcinoma of the skin, with particularly high risk in
people with skin type 1 and 2. A combined analysis of two cohort studies of 944 people
treated with bath PUVA, excluded a three-fold excess risk of squamous cell carcinoma after
a mean follow up of 14.7 years, suggesting that bath PUVA is possibly safer than conventional
PUVA (111). One systematic review (search date 1996) estimated that the excess annual risk
of nonmelanoma skin cancer associated with ultraviolet B radiation was likely to be less
than 2% (112).
Limited data suggest that the use of tanning devices that emit ultraviolet radiation, such
as tanning lamps and tanning beds, may be associated with a two-fold increased risk of squa-
mous cell carcinoma, and a more limited increased risk of basal cell carcinoma, and, possibly,
melanoma (113,114). Negative results have also been published (115). Most exposures to ultra-
violet A tanning devices began after 1980; therefore, epidemiologic studies have difficulty in
revealing any increase in risk of melanoma and/or basal cell carcinoma because of the latent
period between exposure and occurrence of these tumors.
SKIN CANCER PREVENTION AND EDUCATION

Nonmelanoma skin cancer is seldom lethal, but if advanced can cause disfigurement and mor-
bidity. Although malignant melanoma represents only 9% of all skin cancers, it occurs rela-
tively early in life and causes more than 90% of overall skin cancer mortality.
In spite of the limitations in knowledge we have outlined earlier, exposure to ultraviolet
radiation appears as the major environmental risk factor for nonmelanoma skin cancer and
melanoma, and the most important avoidable cause. The aim of primary skin cancer preven-
tion is therefore to limit ultraviolet light exposure. Campaigns to prevent skin cancer have
incorporated numerous messages, including the need to avoid sunburn and, generally, to
reduce exposure to ultraviolet radiation, especially midday sun (between 11 AM and 3 PM ),
wearing protective clothing, seeking shade, and applying sunscreen (116). Additional public
health messages focus on prompt seeking medical attention when noticing suspicious or chan-
ging skin lesions. The detection of skin cancer at an early stage when it is most likely to be
cured, by simple outpatient excision, is classified as secondary prevention.
Skin cancer educational programs have been increasingly common in recent years
(117,118). However, there is no standardized procedure for these programs, which range
from broad community campaigns to those targeted at particular population subgroups (e.g.,
school children, outdoor workers, teachers, pharmacists). Community-wide educational cam-
paigns generally promote protection from sun exposure to reduce risk of skin cancer in later
life. It is difficult to evaluate directly the overall effectiveness of such campaigns, and
surveys on Australian population suggest that adequate, regular sun-protection measures
are used by only a small proportion of high-risk population (119).
Different forms of educational programs have been proposed, from standardized print
materials (e.g., pamphlets and posters) to more complex interventions (e.g., multimedia pro-
grams and written materials, combined with a supply of sunscreen samples). Even if some
experiences have suggested that awareness and attitudes may be changed by educational
efforts, there is little evidence that sun protection behavior has been significantly changed by
these interventions, or that any behavioral changes have been maintained in the longer term.
Changing human behavior is not easy, and the more complex the behavior, the more difficult
it is to change. The most effective behavioral interventions have been based on sound theoreti-
cal models for decision-making and cognitive development. A United States study identified
adolescents’ readiness to change their sun protection practices on the basis of the transtheore-
tical model of behavior change (120). The conceptual framework on which this model is based
has been applied to many health behaviors, including sun protection practices. The model pos-
tulates incremental stages from precontemplation of a behavior, to contemplation, preparation,
action, and maintenance. For sun protection practices amongst adolescents, it has been
reported that over half the surveyed adolescents were in precontemplative stage, 8% were in
contemplative stage, none were in preparation stage, 4.4% were in action stage, and over a
third identified themselves as being in the maintenance stage. These results have implications
for choice of effective skin cancer educational programs and may partly explain the variable
effectiveness of different educational programs. Halpern and Kopp found significant differ-
ences in skin cancer awareness and sun protection behaviors among Australia, United
States, and Europe (121). In Australia, where the incidence of skin cancer is high, more than
80% of respondents expressed concern over skin cancer. In comparison, Germany (30%) and
France (34%) demonstrated the lowest level of concerns about the risk of developing skin
cancer. This survey also demonstrated that the main source of information, through which
awareness was attained, was the media and not qualified healthcare representatives, and
support the importance of increased patient education by medical professionals in the
context of routine medical care.
The effectiveness of skin cancer educational programs depends on several factors, includ-
ing the perceived, likely outcome of behavior change and the magnitude of the value attached
to the outcome. Tangible immediate outcomes are more salient, and tend to have a greater
influence on behavior than theoretical long-term outcomes. Even if people are well informed
about skin cancer, they may not comply with prevention advice. Most health educators
agree that the greatest long-term benefits are expected to occur when targeting children. Child-
hood is an excellent time to form life-long prevention habits, and early preventive behaviors
may be less resistant to change than those acquired in adulthood. The best way to assess the
effectiveness of an educational campaign is by a randomized controlled trial (sometimes
with clusters), that compare either two or more alternative educational strategies, or one strat-
egy with no strategy at all (i.e., no specific educational intervention). Relevant outcomes are
influences on incidence/mortality of skin cancer. Behavior attitudes with reduction in sun
exposure and number of sunburns are a surrogate outcome measure. A recent systematic
review concluded that there was some evidence that approaches to increasing sun-protective
behaviors were effective when implemented in primary schools and in recreational settings,
but found insufficient evidence when implemented in other settings (117).
No sound data exist about the effectiveness of early diagnosis programs or screenings.
A significant proportion of patients with one skin cancer will develop a second cancer. Subjects
with atypical nevi and a family history of melanoma have a high chance of developing mela-
noma in their lifetime. Significantly, freckled individuals are at high risk for melanoma, as are
those with nevi numbering more than 50. All of these must be taken into account when recom-
mending appropriate follow-up examinations.
SUNSCREEN USE AND SKIN CANCER

The mainstay of sun protection is through avoidance of deliberate sun tanning, and use of
adequate protection measures such as wearing wide-brimmed hats, sunglasses and protective
clothing, and avoidance of peak hours for UV light. Sunscreens cannot be a substitute for other
protective means.
Broad-spectrum sunscreens can prevent sunburns, some aspects of photoaging, and
actinic keratoses (67). Some pre-existing actinic keratoses can regress as well. Squamous cell
carcinoma may also be prevented, since actinic keratoses are precursors of this condition. Evi-
dence does not suggest that sunscreens directly prevent basal cell carcinoma or melanoma
(122 –124). Concern has also been raised that they may directly or indirectly increase the risk
of malignancy, primarily, because of poor application and increased exposure to the sun.
The thickness of application has been shown to be less than half that is officially tested, and
key exposed sites are often missed completely (125).
REFERENCES
1. Weinstock MA. Controversies in the public health approach to keratinocyte carcinomas. Br J Derma-
tol 2006; 154(suppl):3 – 4.
2. Last A, Robert A, Spasoff RA, Harris SS. A Dictionary of Epidemiology. 4th ed. Oxford University
Press, New York, 2000.
3. Demers AA, Nugent Z, Mihalcioiu C, Wiseman MC, Kliewer EV. Trends of nonmelanoma skin
cancer from 1960 through 2000 in a Canadian population. J Am Acad Dermatol 2005; 53:320– 328.
4. Rigel DS, Friedman RJ, Kopf AW. Lifetime risk for development of skin cancer in the U.S. popu-
lation: current estimate is now 1 in 5. J Am Acad Dermatol 1996; 35:1012– 1013.
5. Staples MP, Elwood M, Burton RC, Williams JL, Marks R, Giles GG. Non-melanoma skin cancer in
Australia: the 2002 national survey and trends since 1985. Med J Aust 2006; 184:6– 10.
6. Merrill RM, Feuer EJ. Risk-adjusted cancer-incidence rates (United States). Cancer Cause Control
1996; 7:544– 552.
7. de Vries E, van de Poll-Franse LV, Louwman WJ, de Gruijl FR, Coebergh JW. Predictions of skin
cancer incidence in the Netherlands up to 2015. Br J Dermatol 2005; 152:481 –488.
8. Parkin DM, Whelan SL, Ferlay J, Storm H. Cancer Incidence in Five Continents. Volumes I to VIII.
IARC CancerBase No. 7, Lyon, 2005.
9. Burton RC, Armstrong BK. Recent incidence trends imply a nonmetastasizing form of invasive
melanoma. Melanoma Res 1994; 4:107 – 113.
10. Levi F, Te VC, Randimbison L, La Vecchia C. Trends in incidence of various morphologies of malig-
nant melanoma in Vaud and Neuchatel, Switzerland. Eur J Cancer 2004; 40:1630– 1633.
11. Osterlind A, Engholm G, Jensen OM. Trends in cutaneous malignant melanoma in Denmark
1943 – 1982 by anatomic site. APMIS 1988; 96:953– 963.
12. Thorn M, Bergstrom R, Adami HO, Ringborg U. Trends in the incidence of malignant melanoma in
Sweden, by anatomic site, 1960– 1984. Am J Epidemiol 1990; 132:1066– 1077.
13. Dennis LK, White E, Lee JA. Recent cohort trends in malignant melanoma by anatomic site in the
United States. Cancer Cause Control 1993; 4:93– 100.
14. Chen YT, Zheng T, Holford TR, Berwick M, Dubrow R. Malignant melanoma incidence in Connecti-
cut (United States): time trends and age-period-cohort modeling by anatomic site. Cancer Cause
Control 1994; 5:341– 350.
15. Bulliard JL, Cox B. Cutaneous malignant melanoma in New Zealand: trends by anatomical site,
1969 –1993. Int J Epidemiol 2000; 29:416– 423.
16. Cress RD, Holly EA. Incidence of cutaneous melanoma among non-Hispanic whites, Hispanics,
Asians, and blacks: an analysis of California cancer registry data, 1988 – 1993. Cancer Cause
Control 1997; 8:246– 252.
17. Stevens NG, Liff JM, Weiss NS. Plantar melanoma: is the incidence of melanoma of the sole of the
foot really higher in blacks than whites? Int J Cancer 1990; 45:691– 693.
18. Levi F, Randimbison L, Te VC, La Vecchia C. High constant incidence rates of second cutaneous
melanomas. Melanoma Res 2005; 15:73 – 75.
19. La Vecchia C, Lucchini F, Negri E, Boyle P, Levi F. Trends in cancer mortality in the Americas. Eur
J Cancer 1993; 29:431– 470.
20. Jemal A, Devesa SS, Fears TR, Hartge P. Cancer surveillance series: changing patterns of cutaneous
malignant melanoma mortality rates among whites in the United States. J Natl Cancer Inst 2000;
92:811 – 818.
21. Severi G, Giles GG, Robertson C, Boyle P, Autier P. Mortality from cutaneous melanoma: evidence
for contrasting trends between populations. Br J Cancer 2000; 82:1887– 1891.
22. Scotto J, Pitcher H, Lee JAH. Indication of future decreasing trends in skin melanoma mortality
among whites in the United States. Int J Cancer 1991; 49:490 –497.
23. Giles GG, Armstrong BK, Burton RC, Staples MP, Thursfield VJ. Has mortality from melanoma
stopped rising in Australia? Analysis of trends between 1931 and 1994. BMJ 1996; 312:1121 – 1125.
24. Bosetti C, La Vecchia C, Naldi L, Lucchini F, Negri E, Levi F. Mortality from cutaneous malignant
melanoma in Europe. Has the epidemic levelled off? Melanoma Res 2004; 14:301– 309.
25. La Vecchia C, Negri E, Levi F, Decarli A, Boyle P. Cancer mortality in Europe: effects of age, cohort of
birth and period of death. Eur J Cancer 1998; 34:118– 141.
26. Streetly A, Markowe H. Changing trends in the epidemiology of malignant melanoma: gender
differences and their implications for public health. Int J Epidemiol 1995; 24:897 – 907.
27. MacKie R, Aitchison TC, Hunter JAA, et al., for The Scottish Melanoma Group. Cutaneous malig-
nant melanoma, Scotland, 1979– 1989. Lancet 1992; 339:971 – 975.
28. de Vries E, Bray FI, Coebergh JW, Parkin DM. Changing epidemiology of malignant cutaneous
melanoma in Europe 1953 – 1997: rising trends in incidence and mortality but recent stabilizations
in western Europe and decreases in Scandinavia. Int J Cancer 2003; 107:119 – 126.
29. MacKie RM, Hole D, Hunter JA, et al. Cutaneous malignant melanoma in Scotland: incidence, sur-
vival, and mortality. The Scottish Melanoma Group, 1979 – 1994. BMJ 1997; 315:1117 –1121.
30. Melia J, Pendry L, Eiser JR, Harland C, Moss S. Evaluation of primary prevention initiatives for skin
cancer: a review from a UK perspective. Br J Dermatol 2000; 143:701– 708.
31. Scotto J, Fears TR, Fraumeni JF. Incidence of non-melanoma skin cancer in the United States. NIH
Pub. no. 83-2433. Bethesda, MD: U.S. Dept. of Health and Human Services, National Institutes of
Health, 1983.
32. Christenson LJ, Borrowman TA, Vachon CM, et al. Incidence of basal cell and squamous cell carci-
nomas in a population younger than 40 years. JAMA 2005; 294:681– 90.
33. Green A, Battistutta D. Incidence and determinants of skin cancer in a high-risk Australian popu-
lation. Int J Cancer 1990; 46:356– 361.
34. Marks R, Jolley D, Dorevitch AP, Selwood TS. The incidence of non-melanocytic skin cancers in an
Australian population: results of a five-year prospective study. Med J Aust 1989; 150:475– 478.
35. Harris RB, Griffith K, Moon TE. Trends in the incidence of nonmelanoma skin cancers in southeast-
ern Arizona, 1985– 1996. J Am Acad Dermatol 2001; 45:528 –536.
36. Koh D, Wang H, Lee J, Chia KS, Lee HP, Goh CL. Basal cell carcinoma, squamous cell carcinoma and
melanoma of the skin: analysis of the Singapore Cancer Registry data 1968 –1997. Br J Dermatol
2003; 148:1161 –1166.
37. Gray DT, Suman VJ, Su WP, Clay RP, Harmsen WS, Roenigk RK. Trends in the population-based
incidence of squamous cell carcinoma of the skin first diagnosed between 1984 and 1992. Arch
Dermatol 1997; 133:735– 740.
38. Karagas MR, Greenberg ER, Spencer SK, Stukel TA, Mott LA. Increase in incidence rates of basal cell
and squamous cell skin cancer in New Hampshire, USA. New Hampshire Skin Cancer Study
Group. Int J Cancer 1999; 81:555– 559.
39. Athas WF, Hunt WC, Key CR. Changes in nonmelanoma skin cancer incidence between 1977 – 1978
and 1998 – 1999 in Northcentral New Mexico. Cancer Epidemiol Biomarkers Prev 2003; 12:1105–
1108.
40. Chuang TY. Skin cancer II. Nonmelanoma skin cancer. In: Williams HC, Strachan DP, eds. The Chal-
lenge of Dermatoepidemiology. Boca Raton: CRC Press, 1997:209– 222.
41. Gallagher RP, Ma B, McLean DI, et al. Trends in basal cell carcinoma, squamous cell carcinoma, and
melanoma of the skin from 1973 through 1987. J Am Acad Dermatol 1990; 23:413– 421.
42. Buettner PG, Raasch BA. Incidence rates of skin cancer in Townsville, Australia. Int J Cancer 1998;
78:587– 593.
43. Magnus K. The Nordic profile of skin cancer incidence. A comparative epidemiological study of the
three main types of skin cancer. Int J Cancer 1991; 47:12– 19.
44. Roberts DL. Incidence of non-melanoma skin cancer in West Glamorgan, South Wales. Br J Dermatol
1990; 122:399– 403.
45. Holme SA, Malinovszky K, Roberts DL. Changing trends in non-melanoma skin cancer in South
Wales, 1988 – 98. Br J Dermatol 2000; 143:1224– 1229.
46. Katalinic A, Kunze U, Schafer T. Epidemiology of cutaneous melanoma and non-melanoma skin
cancer in Schleswig-Holstein, Germany: incidence, clinical subtypes, tumour stages and localization
(epidemiology of skin cancer). Br J Dermatol 2003; 149:1200– 1206.
47. Stang A, Stegmaier C, Jockel KH. Nonmelanoma skin cancer in the Federal State of Saarland,
Germany, 1995 – 1999. Br J Cancer 2003; 89:1205– 1208.
48. Boi S, Cristofolini M, Micciolo R, Polla E, Dalla Palma P. Epidemiology of skin tumors: data from the
cutaneous cancer registry in Trentino, Italy. Ann Epidemiol 2003; 13:436– 442.
49. Levi F, La Vecchia C, Te VC, Mezzanotte G. Descriptive epidemiology of skin cancer in the Swiss
Canton of Vaud. Int J Cancer 1988; 42:811 – 816.
50. Levi F, Te VC, Randimbison L, Erler G, La Vecchia C. Trends in skin cancer incidence in Vaud: an
update, 1976– 1998. Eur J Cancer Prev 2001; 10:371– 373.
51. Plesko I, Severi G, Obsitnikova A, Boyle P. Trends in the incidence of non-melanoma skin cancer in
Slovakia, 1978 – 1995. Neoplasma 2000; 47:137– 142.
52. Watts T, Siziya S, Chokunonga E. Cancer of the skin in Zimbabwe: an analysis based on the Cancer
Registry 1986 to 1992. Cent Afr J Med 1997; 43:181– 184.
53. Berg D, Otley CC. Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and man-
agement. 1. J Am Acad Dermatol 2002; 47:1 –17.
54. Bouwes Bavinck JN, Feltkamp M, Struijk L, ter Schegget J. Human papillomavirus infection and
skin cancer risk in organ transplant recipients. J Investig Dermatol Symp Proc 2001; 6:207– 211.
55. Lindelof B, Sigurgeirsson B, Gabel H, Stern RS. Incidence of skin cancer in 5356 patients following
organ transplantation. Br J Dermatol 2000; 143:513– 519.
56. Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in Australian heart transplant
recipients. J Am Acad Dermatol 1999; 40:27 – 34.
57. Naldi L, Fortina AB, Lovati S, et al. Risk of nonmelanoma skin cancer in Italian organ transplant reci-
pients. A registry-based study. Transplantation 2000; 70:1479– 1484.
58. Fuente MJ, Sabat M, Roca J, Lauzurica R, Fernandez-Figueras MT, Ferrandiz C. A prospective study
of the incidence of skin cancer and its risk factors in a Spanish Mediterranean population of kidney
transplant recipients. Br J Dermatol 2003; 149:1221– 1226.
59. Levi F, Randimbison L, Maspoli M, Te VC, La Vecchia C. High incidence of second basal cell skin
cancers. Eur J Cancer 2006; 42:656– 659.
60. Levi F, La Vecchia C, Te VC, Randimbison L, Erler G. Incidence of invasive cancers following basal
cell skin cancer. Am J Epidemiol 1997; 146:734– 739.
61. Levi F, Randimbison L, La Vecchia C, Erler G, Te VC. Incidence of invasive cancers following squa-
mous cell skin cancer. Int J Cancer 1997; 72:776 – 779.
62. Stang A, Jockel KH. Changing patterns of skin melanoma mortality in West Germany from 1968
through 1999. Eur J Cancer 2005; 41:45 – 60.
63. Hannuksela-Svahn A, Pukkala E, Karvonen J. Basal cell skin carcinoma and other nonmelanoma
skin cancers in Finland from 1956 through 1995. Arch Dermatol 1999; 135:781– 786.
64. Lewis KG, Weinstock MA. Nonmelanoma skin cancer mortality (1988 – 2000): the Rhode Island
follow-back study. Arch Dermatol 2004; 140:837– 842.
65. Lober BA, Lober CW, Accola J. Actinic keratosis is squamous cell carcinoma. J Am Acad Dermatol
2000; 43:881– 882.
66. Flaxman AB. Actinic keratoses- Malignant or not? J Am Acad Dermatol 2001; 45:466 – 467.
67. Johnson M.-LT, Roberts J. Skin conditions and related need for medical care among person 1 – 74
years. US Department of Health Education and Welfare, Hyattsville, 1978.
68. Frost CA, Green AC, Williams GM. The prevalence and determinants of solar keratoses at a subtro-
pical latitude (Queensland, Australia). Br J Dermatol 1998; 139:1033– 1039.
69. Harvey I, Frankel S, Marks R, Shalom D, Nolan-Farrell M. Non-melanoma skin cancer and solar ker-
atoses. I. Methods and descriptive results of the South Wales skin cancer study. Br J Cancer 1996;
74:1302– 1307.
70. Memon AA, Tomenson JA, Bothwell J, Friedmann PS. Prevalence of solar damage and actinic ker-
atosis in a Merseyside population. Br J Dermatol 2000; 142:1154 –1159.
71. Massa A, Alves R, Amado J, et al. Prevalence of cutaneous lesions in Freixo de Espada a Cinta. Acta
Med Port 2000; 13:247 –254.
72. Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a Queens-
land community. J Invest Dermatol 2000; 115:273– 277.
73. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J
Med 1993; 329:1193 – 1194.
74. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell
carcinoma. Lancet 1988; 1:795– 797.
75. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad
Dermatol 2003; 49:832– 841.
76. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: III.
Family history, actinic damage and phenotypic factors. Eur J Cancer 2005; 41:2040– 2059.
77. Zanetti R, Rosso S, Martinez C, et al. The multicentre south European study “Helios.” I: Skin charac-
teristics and sunburns in basal cell and squamous cell carcinomas of the skin. Br J Cancer 1996;
73(11):1440– 1446.
78. Whiteman DC, Green AC. Melanoma and sun exposure: where are we now? Int J Dermatol 1999;
38:481– 489.
79. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun
exposure. Eur J Cancer 2005; 41:28– 44.
80. Rosso S, Zanetti R, Martinez C, et al. The multicentre south European study “Helios.” II: Different
sun exposure patterns in the etiology of basal cell and squamous cell carcinomas of the skin. Br J
Cancer 1996; 73:1447– 1454.
81. Gallagher RP, Hill GB, Bajdik CD, et al. Sunlight exposure, pigmentary factors, and risk of nonme-
lanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol 1995; 131:157– 163.
82. Gallagher RP, Hill GB, Bajdik CD, et al. Sunlight exposure, pigmentation factors, and risk of nonme-
lanocytic skin cancer. II. Squamous cell carcinoma. Arch Dermatol 1995; 131:164– 169.
83. Vitasa BC, Taylor HR, Strickland PT, et al. Association of nonmelanoma skin cancer and actinic ker-
atosis with cumulative solar ultraviolet exposure in Maryland watermen. Cancer 1990; 65:2811 –
2817.
84. Harvey I, Frankel S, Marks R, Shalom D, Nolan-Farrell M. Non-melanoma skin cancer and
solar keratoses. II analytical results of the South Wales skin cancer study. Br J Cancer 1996;
74:1308– 1312.
85. Bastiaens MT, Hoefnagel JJ, Bruijn JA, Westendorp RG, Vermeer BJ, Bouwes Bavinck JN. Differences
in age, site distribution, and sex between nodular and superficial basal cell carcinoma indicate
different types of tumors. J Invest Dermatol 1998; 110:880– 884.
86. Lovatt TJ, Lear JT, Bastrilles J, et al. Associations between ultraviolet radiation, basal cell carcinoma
site and histology, host characteristics, and rate of development of further tumors. J Am Acad Der-
matol 2005; 52:468– 473.
87. Siskind V, Whiteman DC, Aitken JF, Martin NG, Green AC. An analysis of risk factors for cutaneous
melanoma by anatomical site (Australia). Cancer Cause Control 2005; 16:193– 199.
88. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma:
I. Common and atypical naevi. Eur J Cancer 2005; 41:28– 44.
89. English DR, Armstrong BK. Melanocytic nevi in children. I. Anatomic sites and demographic and
host factors. Am J Epidemiol 1994; 139:390– 401.
90. Kelly JW, Rivers JK, MacLennan R, Harrison S, Lewis AE, Tate BJ. Sunlight: a major factor associated
with the development of melanocytic nevi in Australian schoolchildren. J Am Acad Dermatol 1994;
30:40– 48.
91. Dennis LK, White E, Lee JA, Kristal A, McKnight B, Odland P. Constitutional factors and sun
exposure in relation to nevi: a population-based cross-sectional study. Am J Epidemiol 1996;
143:248– 256.
92. Dulon M, Weichenthal M, Blettner M, et al. Sun exposure and number of nevi in 5- to 6-year-old
European children. J Clin Epidemiol 2002; 55:1075– 1081.
93. Carli P, Naldi L, Lovati S, La Vecchia C; Oncology Cooperative Group of the Italian Group for Epi-
demiologic Research in Dermatology (GISED). The density of melanocytic nevi correlates with con-
stitutional variables and history of sunburns: a prevalence study among Italian schoolchildren. Int J
Cancer 2002; 101:375– 379.
94. MacLennan R, Kelly JW, Rivers JK, Harrison SL. The Eastern Australian Childhood Nevus Study:
site differences in density and size of melanocytic nevi in relation to latitude and phenotype. J
Am Acad Dermatol 2003; 48:367– 375.
95. Wiecker TS, Luther H, Buettner P, Bauer J, Garbe C. Moderate sun exposure and nevus counts in
parents are associated with development of melanocytic nevi in childhood: a risk factor study in
1,812 kindergarten children. Cancer 2003; 97:628– 638.
96. Doll R. Cancers weakly related to smoking. Br Med Bull 1996; 52:35– 49.
97. Moore S, Johnson N, Pierce A, Wilson D. The epidemiology of lip cancer: a review of global inci-
dence and aetiology. Oral Dis 1999; 5:185– 195.
98. Green A, Battistutta D, Hart V, Leslie D, Weedon D. Skin cancer in a subtropical Australian popu-
lation: incidence and lack of association with occupation. The Nambour Study Group. Am J Epide-
miol 1996; 144:1034– 1040.
99. De Hertog SA, Wensveen CA, Bastiaens MT, et al. Relation between smoking and skin cancer. J Clin
Oncol 2001; 19:231– 238.
100. Hakim IA, Harris RB, Ritenbaugh C. Fat intake and risk of squamous cell carcinoma of the skin. Nutr
Cancer 2000; 36:155– 162.
101. Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation
in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomized controlled trial.
Lancet 1999; 354:723– 729.
102. Lichter MD, Karagas MR, Mott LA, Spencer SK, Stukel TA, Greenberg ER. Therapeutic ionizing radi-
ation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire
Skin Cancer Study Group. Arch Dermatol 2000; 136:1007– 1011.
103. Ron E, Preston DL, Kishikawa M, et al. Skin tumor risk among atomic-bomb survivors in Japan.
Cancer Cause Control 1998; 9:393– 401.
104. Saladi R, Austin L, Gao D, et al. The combination of benzo[a]pyrene and ultraviolet A causes an
in vivo time-related accumulation of DNA damage in mouse skin. Photochem Photobiol 2003;
77:413– 419.
105. Yu RC, Hsu KH, Chen CJ, Froines JR. Arsenic methylation capacity and skin cancer. Cancer Epide-
miol Biomarkers Prev 2000; 9:1259– 1262.
106. Ramirez CC, Federman DG, Kirsner RS. Skin cancer as an occupational disease: the effect of ultra-
violet and other forms of radiation. Int J Dermatol 2005; 44:95– 100.
107. Diepgen TL, Drexler H. Skin cancer and occupational disease. Hautarzt 2004; 55:22– 27.
108. Stern RS, Laird N. The carcinogenic risk of treatments for severe psoriasis. Photochemotherapy
follow-up study. Cancer 1994; 73:2759– 2764.
109. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with meth-
oxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. N Engl J Med
1997; 336:1041– 1045.
110. Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UVA radi-
ation (PUVA). A meta-analysis. Arch Dermatol 1998; 134:1582– 1585.
111. Hannuksela-Svahn A, Sigurgeirsson B, Pukkala E, et al. Trioxsalen bath PUVA did not increase the
risk of squamous cell skin carcinoma and cutaneous malignant melanoma in a joint analysis of 944
Swedish and Finnish patients with psoriasis. Br J Dermatol 1999; 141:497– 501.
112. Pieternel CM, Pasker-de-Jong M, Wielink G, et al. Treatment with UVB for psoriasis and nonmela-
noma skin cancer. A systematic review of the literature. Arch Dermatol 1999; 135:834– 840.
113. Autier P, Dore JF, Lejeune F, et al. Cutaneous malignant melanoma and exposure to sunlamps or
sunbeds: an EORTC multicenter case-control study in Belgium, France and Germany. EORTC
Melanoma Cooperative Group. Int J Cancer 1994; 58:809– 813.
114. Karagas MR, Stannard VA, Mott LA, Slattery MJ, Spencer SK, Weinstock MA. Use of tanning devices
and risk of basal cell and squamous cell skin cancers. J Natl Cancer Inst 2002; 94:224– 246.
115. Bajdik CD, Gallagher RP, Astrakianakis G, Hill GB, Fincham S, McLean DI. Non-solar ultraviolet
radiation and the risk of basal and squamous cell skin cancer. Int J Cancer 1994; 58:809– 813.
116. Fry A, Verne J. Preventing skin cancer. BMJ 2003; 326:114 – 115.
117. Saraiya M, Glanz K, Briss PA, et al. Interventions to prevent skin cancer by reducing exposure to
untraviolet radiation: a systematic review. Am J Prev Med 2004; 27:422– 466.
118. Stoebner-Dalbarre A, Dafez C, Borrel E, Sancho-Garnier H, Guillot B, Group Epi-CES. Prevention of
skin cancer programs: analysis of the impact of randomised trials. Ann Dermatol Venereol 2005;
132:641– 647.
119. Livingston PM, White V, Hayman J, Dobbinson S. Sun exposure and sun protection behaviours
among Australian adolescents: trends over time. Prev Med 2003; 37:577– 584.
120. Prochaska JO. Strong and weak principles for progressing from precontemplation to action on the
basis of twelve problem behaviors. Health Psychol 1994; 13:47 – 51.
121. Halpern AC, Kopp LJ. Awareness, knowledge and attitudes to non-melanoma skin cancer and
actinic keratosis among the general public. Int J Dermatol 2005; 44:107– 111.
122. Vainio H, Miller AB, Bianchini F. An international evaluation of the cancer-preventive potential of
sunscreens. Int J Cancer 2000; 88:838– 842.
123. Bastuji-Garin S, Diepgen TL. Cutaneous malignant melanoma, sun exposure, and sunscreen use:
epidemiological evidence. Br J Dermatol 2002; 146(suppl. 61):24– 30.
124. Dennis LK, Beane Freeman LE, VanBeek MJ. Sunscreen use and the risk for melanoma: a quantitat-
ive review. Ann Intern Med 2003; 139:966– 978.
125. Johnson K, Davy L, Boyett T, Weathers L, Roetzheim RG. Sun protection practices for children:
knowledge, attitudes, and parent behaviors. Arch Pediatr Adolesc Med 2001; 155:891– 896.
126. http://www-dep.iarc.fr. (GLOBOCAN 2002 database).
Section III: PHOTODERMATOSES
PART A: BASIC PRINCIPLES
10 Evaluation of the Photosensitive Patient

Henry W. Lim
John L. M. Hawk
Photobiology Unit, St. John’s Institute of Dermatology, St. Thomas’ Hospital, King’s College of London,
B Systematic evaluation of photosensitive patients includes a thorough

history, physical examination, phototesting, and as needed, photopatch
testing and laboratory evaluation.
B Polymorphous light eruption, chronic actinic dermatitis, solar urticaria,

and photosensitivity secondary to systemic medications are the most
frequently encountered photodermatoses in photodermatology centers
around the world.
140 Lim and Hawk
INTRODUCTION
hotodermatoses can be classified into four categories: (i) immunologically mediated
P photodermatoses, (ii) drug- and chemical-induced photosensitivity, (iii) photodermatoses

associated with defective DNA nucleotide excision repair, and (iv) photoaggravated der-
matoses (Table 1). Systematic evaluation of patients with photosensitivity is an important step
in establishing the appropriate diagnosis. One of the earliest documented examples of such an
approach was reported by Wilkinson in 1961. He evaluated several patients with photo-distrib-
uted eruptions. By history, he noted that these patients were all working in the same factory,
and the eruption was exacerbated by exposure to sunlight. Patch testing with a germicidal
agent that the workers were exposed to, tetrachlorosalicylanilide, was positive in many
patients; the reaction was intensified by exposure to ultraviolet (UV) radiation. Biopsy speci-
mens from these patients showed changes consistent with photoallergic contact dermatitis.
Wilkinson (1) published these patients as examples of those with photosensitivity to
tetrachlorosalicylanilide.
Wilkinson’s approach exemplified the appropriate steps in evaluating the photosensitive
patient. This evaluation should include a thorough history-taking, complete cutaneous examin-
ation and, when appropriate, phototesting for the determination of the minimal erythema dose
(MED), photopatch testing and laboratory evaluation, such as skin biopsy, ANA panel, and/or
plasma porphyrin profile (Table 2). These steps will be discussed in detail in this chapter.
HISTORY
Thorough history-taking with special attention to the relationship between sun exposure and
the features of the skin eruption is an important step in the evaluation of photosensitivity.
This is outlined in Table 3, and discussed subsequently.
Age of Onset
The age of onset of photosensitivity frequently assists in the diagnosis (Table 4) (2). It should be
noted that the most common immunologically mediated photodermatosis, polymorphous light
eruption, and related disorders (juvenile spring eruption, actinic prurigo) tend to have their
onset in childhood and/or early adulthood. Photosensitivity associated with two of the
cutaneous porphyrias, congenital erythropoietic porphyria and erythropoietic protoporphyria,
TABLE 1 Classification of Photodermatoses

Immunologically mediated
Polymorphous light eruption
Juvenile spring eruption
Actinic prurigo
Hydroa vacciniforme
Chronic actinic dermatitis
Solar urticaria
Drug- and chemical-induced
Exogenous: phototoxicity and photoallergy
Endogenous: cutaneous porphyrias
Defective DNA repair
Xeroderma pigmentosum
Cockayne syndrome
UV-sensitive syndrome
Trichothiodystrophy
Bloom syndrome
Rothmund– Thomson syndrome
Kindler syndrome
Photoaggravated
Lupus erythematosus
Dermatomyositis
Others
Evaluation of the Photosensitive Patient 141
TABLE 2 Evaluation of the Photosensitive Patient

History
Physical examination
Phototesting for MED and abnormal morphological responses
Photopatch testing
Laboratory: skin biopsy, ANA panel, plasma porphyrin (and complete porphyrin profile if necessary)
Abbreviations: ANA, antinuclear antibodies; MED, minimal erythema dose.
have their onsets in infancy and early childhood, respectively. In contrast, chronic actinic der-
matitis, another immunologically mediated photodermatosis, and drug-induced photo-
sensitivity, most frequently manifest themselves in individuals older than 60 years; reflecting
the increased exposure to precipitating agents of sunlight and exacerbating airborne allergens
in this cohort of individuals.
Exposure to Photosensitizers
Possible exposure to known photosensitizers should be obtained in the history taking.
Questions should be asked not only about the intake of oral prescription medications, but
also over-the-counter oral agents, as well as topical agents. The more common photosensitizers
are listed in Table 5 (3). Examples of over-the-counter oral and topical photosensitizers include
nonsteroidal anti-inflammatory drugs, St. John’s wort, tar and tar-containing products, sun-
screen agents, and fragrances such as musk ambrette.
Seasonal Variation, Interval Before Onset, and Duration of the Eruption

An important part of the history is information about the relationship of sun exposure and
cutaneous eruption. For patients living in temperate climates, all photodermatoses are
almost always very severe in the sunny season, although actinic prurigo is very occasionally
worse in winter, or during spring and fall. While most photodermatoses tend to persist
during spring and summer, polymorphous light eruption (also known as polymorphic light
eruption) often has a rather unusual time course. It tends to manifest itself in greatest severity
in the early part of the sunny season and becomes less severe as the season progresses, a
phenomenon of the development presumed immunological tolerance, commonly referred to
as the “hardening” reaction.
The interval between sun exposure and the development of cutaneous lesions is also
characteristic for many of the photodermatoses. For example, in polymorphous light eruption,
patients typically notice development of the eruption after a few hours of exposure to the sun,
frequently by the evening of the day of the sun exposure, and rarely after a day or so of
continuing sun exposure. In contrast, lesions in solar urticaria generally appear within five
to ten minutes of sun exposure. In porphyria cutanea tarda (PCT), while the erosions and
blisters are on sun-exposed areas, patients may not notice the direct correlation between sun
exposure and the development of these lesions at all. Photo-provocation of lesions in patients
with lupus erythematosus may not appear for a few days after the exposure to sunlight.
TABLE 3 Evaluation of Photodermatoses: History

Age of onset
Exposure to oral or topical photosensitizers
Seasonal variation
Interval between sun exposure and skin eruption
Duration of lesions
Effect of window glass
Family history of photosensitivity
Systemic symptoms
History of connective tissue disease
142 Lim and Hawk
TABLE 4 Evaluation of Photodermatoses: Age of Onset

Infancy
Congenital erythropoietic porphyria (Günther disease)
Childhood
Juvenile spring eruption (a variant of polymorphous light eruption)
Actinic prurigo
Hydroa vacciniforme
Erythropoietic protoporphyria
Adulthood
Drug-induced photosensitivity
Solar urticaria
Lupus erythematosus
Porphyria cutanea tarda
Old age
Drug-induced photosensitivity
Dermatomyositis
The duration of the persistence of the lesions also gives a clue to the diagnosis. In the
absence of additional sun exposure, lesions in patients with polymorphous light eruption
tend to last for a few days. In contrast, those in solar urticaria resolve within one to two
hours, whereas those of chronica actinic dermatitis and PCT usually persist throughout the
sunny season.
TABLE 5 Common Phototoxic and Photoallergic Agents

Common phototoxic agents Common photoallergic agents
Antiarrhythmics Topical agents
Amiodarone Sunscreen agents
Quinidine Fragrances
Diuretics 6-Methylcoumarin
Furosemide Musk ambrette
Thiazides Sandalwood oil
Nonsteroidal anti-inflammatory drugs Antibacterial agents
Nabumetone Bithionol
Naproxen Chlorhexidine
Piroxicam Hexachlorophene
Phenothiazines Others
Chlorpromazine Chlorpromazine
Prochlorperazine Fenticlor
Psoralens Promethazine
5-Methoxypsoralen Systemic agents
8-Methoxypsoralen Antiarrhythmics
4,50 ,8-Trimethylpsoralen Quinidine
Quinolones Antifungal
Ciprofloxacin Griseofulvin
Lomefloxacin Antimalarial
Nalidixic acid Quinine
Sparfloxacin Antimicrobials
St. John’s wort Quinolone
Hypericin Sulfonamides
Tar Nonsteroidal anti-inflammatory drugs
Tetracyclines Ketoprofen
Demeclocycline Piroxicam
Doxycycline
Window Glass
Whether or not an eruption can be induced by window glass-filtered sunlight gives some infor-
mation on the action spectrum of the photodermatosis. However, it should be noted that while
window glass is known to filter out UVB, the long-standing belief that UVA regularly pene-
trates window glass well is no longer accurate. New developments in the glass industry in
the past ten years have resulted in a significant improvement of the UV-filtering property of
window glass. Currently, there are many types of glass used in buildings and in the automobile
industry that have excellent UVB and UVA2 (320 – 340 nm) filtering properties. Some would
even filter efficiently a good proportion of UVA1 (340 – 400 nm), allowing only UV wavelength
greater than 380 nm to penetrate the glass; this results in glass that would allow only ,1% of
wavelength below 380 nm to be transmitted (4). Obviously, unless the glass is opaque, visible
light always penetrates through the glass.
For safety reasons, windshields of cars are made of laminated glass, so that if the glass is
broken, fragments will adhere to a polyvinyl butyral interlayer rather than falling free, hence
reducing the likelihood of injury. Side and back windows of cars are made of nonlaminated
glass. Laminated glass is more efficient at filtering UVA than nonlaminated glass. Since the
occupants in cars are seated more closely to side windows than the windshield, there is a
significant risk that the side window-filtered sunlight will precipitate lesions in patients
with photodermatoses. These factors should be taken into account in obtaining the history in
relation to window glass-filtered sunlight.
Family History
Family history is another aspect that needs to be obtained during the history taking. This
is most relevant in evaluating patients who may have one of the cutaneous porphyrias
(chap. 15). The mode of inheritance of these porphyrias is shown in Table 6. In addition, a
study from the United Kingdom indicated that polymorphous light eruption and actinic
prurigo also appeared to have an important familial tendency (5).
Systemic Abnormalities
A history of acute abdominal pain, and peripheral neuropathy and paresis in a patient with
photosensitivity should lead one to consider the possibility of variegate porphyria or heredi-
tary coproporphyria. It should be noted that acute intermittent porphyria, which is also associ-
ated with abdominal and neurologic symptoms, is not associated with any cutaneous eruption.
A history of Raynaud’s phenomenon, cutaneous ulcerations, thrombosis, livedo reticularis,
and muscle weakness should raise the possibility of lupus erythematosus or dermatomyositis.
Photodermatoses associated with defective DNA nucleotide excision repair are rare.
These patients have multiple organ involvement; these disorders are covered in chapter 16.
PHYSICAL EXAMINATION
The second part of the evaluation is a complete physical examination of the skin, paying
special attention to sun-exposed and sun-protected areas. The eruption may not always be
present in intermittent conditions, such as polymorphous light eruption and solar urticaria;
however, in which case, a very careful history of the eruption as described earlier is of
particular importance in formulating the likely diagnosis. Virtually all photodermatoses when
TABLE 6 Mode of Inheritance of the Cutaneous Porphyrias

Porphyria Inheritance
Congenital erythropoietic porphyria (Günther disease) Autosomal recessive
Porphyria cutanea tarda (familial type) Autosomal dominant
Hereditary coproporphyria Autosomal dominant
Variegate porphyria Autosomal dominant
Erythropoietic protoporphyria 3 allele modela
a
N, normal; M, mutant; n, low output normal.
144 Lim and Hawk
present demonstrate the most severe eruptions on the sun-exposed areas of the skin, which
include the forehead, cheeks, V-region of neck, nape of neck, dorsum of the hands, and extensor
aspects of forearms. In addition, examination of exposed but relatively sun-protected areas of the
skin will also give important indication of the photosensitivity. These areas include nasolabial
folds, postauricular area, upper eyelids, peri-orbital area in patients who wear glasses, superior
aspects of the pinna, which may be covered by hair, especially in women, and area underneath
the chin. These areas tend to be spared in patients with photodermatosis. In contrast, they will
frequently be involved in patients with airborne allergic contact dermatitis.
While skin surfaces covered by clothing, such as the chest, back, and buttocks are gener-
ally spared; it should be noted that in markedly photosensitive patients, the eruption might
also occur to a lesser extent in these covered areas; especially if an area is covered by clothing,
which allows some penetration of UV radiation. The UV photoprotectivity of a garment is indi-
cated by its ultraviolet protection factor (UPF), which is an in vitro determination on the degree
of UV transmission through the fabric. However, many do not carry this label. A practical rule
of thumb is that while holding a fabric up to visible light, the more transparent the fabric, the
more UV is likely to penetrate.
The morphology of the skin eruption is also very important in determining the diagnosis
(Table 7). Urticaria is seen in association with pruritus in patients with solar urticaria.
The erythropoietic protoporphyria (EPP) is most commonly associated with no eruption, but
just severe pain within about half an hour of sun exposure. In some patients, an even, skin-
colored or pink edematous swelling with a sharp cut-off at clothing lines may be observed
within a couple of hours after sun exposure; very rarely vesicles or urticarial lesions may
occur. A papular eruption is commonly seen in patients with polymorphous light eruption,
and sometimes in the acute exacerbations of chronic actinic dermatitis. In polymorphous
light eruption, urticarial papules are the most common morphology for fair-skinned individ-
uals, whereas in dark-skinned individuals, pinpoint papules are the most frequently observed
lesions (6). Patients with polymorphous light eruption can also present with vesicular or very
rarely bullous eruption, especially in those who are acutely exposed to intense UV radiation as
most commonly seen during short vacations to resorts in tropical or subtropical climates (7).
Juvenile spring eruption, a variant of polymorphous light eruption occurring mostly in
young boys, usually presents with vesicles on the superior aspect of the pinna, and sometimes
also on the back of the hands.
Eczematous vesicular eruptions are possible in photoallergy, while phototoxicity presents
with acute inflammatory vesicles and bullae. Such vesicles and bullae are commonly seen
TABLE 7 Morphology of Lesions

Morphology Possible diagnosesa
Urticaria or urticarial Solar urticaria
Erythropoietic protoporphyria (rare)
Papule Polymorphous light eruption
Actinic prurigo
Chronic actinic dermatitis (acute eruption)
Vesicle Polymorphous light eruption
Juvenile spring eruption (ears)
Porphyria cutanea tarda
Phototoxicity
Photoallergy
Hydroa vacciniforme
Erosion, crust Porphyria cutanea tarda
Actinic prurigo (lips)
Hydroa vacciniforme
Variegate porphyria
Congenital erythropoietic porphyria
Hereditary coproporphyria
Eczema and/or lichenification Chronic actinic dermatitis
a
Listed in an approximate order of probability.
on dorsa of the hands of patients with PCT. It should be noted that these lesions reflect the skin
fragility that occurs in these patients; therefore, the patients may not directly relate the devel-
opment of lesions to sun exposure. Trauma frequently induces the development of this photo-
distributed eruption in PCT, resulting in erosions and crusting. Crusting of the lips, along with
conjunctivitis, is a common presentation in patients with actinic prurigo seen in Central and
South America. Marked lichenification of the sun-exposed skin from scratching is commonly
seen in patients with chronic actinic dermatitis, reflecting the chronic and pruritic nature of
the condition.
Patients with cutaneous porphyrias frequently have other characteristic lesions (chap. 15).
Patients with PCT have peri-orbital hypertrichosis and mottled dyspigmentation, and sclero-
dermoid changes in sun-exposed as well as in sun-protected areas. Patients with EPP may
develop acute ecchymoses of sun-exposed areas, usually the dorsa of the hands or extensor
forearms, along with chronic lesions of “cobble-stoning” of the knuckles of the hands, super-
ficial waxy linear or punctuate scars of the cheeks and nose, and radial scarring around the
lips. The exposed skin in these patients is often characteristically dry.
Heliotrope is frequently seen in patients with dermatomyositis, whereas periungal
telangiectasia is often observed in patients with lupus erythematosus or dermatomyositis.
PHOTOTESTING
Phototesting is an integral part of the evaluation of the photosensitive patient (see Appendix A
“Phototesting” for further information). Briefly, using a template, uninvolved skin of the
patient’s back or abdomen is exposed to different doses of UVB, UVA, and/or visible mono-
chromatic or broad-spectrum radiation. Evaluation immediately after the exposure is per-
formed to detect the development of solar urticaria. The patient is re-evaluated 24 hours
later for the development of erythema. The minimal erythema dose (MED) is defined as the
lowest dose of UVB, or UVA, that would produce just perceptible erythema, covering the
entire irradiated area. It should be noted that, while erythema can be produced by UVB and
UVA, positive response to visible light is most frequently the urticarial response of solar urti-
caria, although it may also rarely be the eczema of severe chronic actinic dermatitis. Appropri-
ately preformed, phototesting often but not always confirms the presence of photosensitivity,
though not necessarily the precise diagnosis, and helps to determine the action spectrum.
The induction of lesions by phototesting, which may require three to four consecutive days
of exposure to the same site, is known as photo-provocation testing. This latter test is often
helpful in confirming the diagnosis of polymorphous light eruption, or photosensitive form
of lupus erythematosus. In the former, lesions usually develop at third or fourth day of
exposure. In lupus erythematous, lesions may develop within one to two weeks after the com-
pletion of either phototesting or provocative phototesting.
Expected phototest results for some of the more common photodermatoses are shown in
Table 8.
PHOTOPATCH TESTING
Photopatch testing is performed in the evaluation of the photosensitive patient in whom photo-
allergic contact dermatitis is suspected. Such testing involves the application of duplicate sets
of photoallergens on uninvolved sites of the skin, usually on the upper back. Twenty-four
TABLE 8 Expected Results in Phototest and Photopatch Test

Disorder MED-A MED-B Visible light Photopatch test
Polymorphous light eruption Normal/ # Normal/ # Normal Negative
Chronic actinic dermatitis # # Normal/ # +
Solar urticaria Urticariaa Urticariaa Urticariaa Negative
Phototoxicity # Normal Normal Negative
Photoallergy # Normal Normal þ
a
Minutes after exposure; negative at 24 hours.
146 Lim and Hawk
TABLE 9 Interpretations of Results of Photopatch Test

Irradiated site Nonirradiated site Interpretation
þ — Photoallergic contact dermatitis
þþ þ Photoallergic contact dermatitis and allergic contact dermatitis
þ þ Allergic contact dermatitis
— — Normal
hours later, one set would be exposed to either 10 J/cm2 of UVA, or in patients with a markedly
decreased MED-A, to 50% of MED-A. Forty-eight hours after the initial application of the
photoallergens, the reactions on the irradiated and unirradiated sides are evaluated. Table 9
summarizes the interpretation of photopatch results (see Appendix B “Photopatch Testing”
for further information).
A summary of the photopatch test studies involving more than 100 patients is shown in
Table 10. At the completion of the evaluation, the percentage of patients with a diagnosis of
photoallergic contact dermatitis to a clinically relevant photoallergen ranged from 1.4% to
12%, with most series being in the 10% range (8 –15).
LABORATORY EVALUATION
The diagnosis of a photodermatosis relies on the history, physical examination, phototest
results, and if necessary, photopatch test results. Skin biopsy may be performed to help to
confirm diagnosis. This is helpful in the diagnosis of polymorphous light eruption and
chronic actinic dermatitis. Lymphoid follicles seen in biopsy specimens of the lip and conjunc-
tiva of patients with actinic prurigo seen in Central and South America are considered to be
diagnostic of that condition (16).
Descriptions of the skin biopsy results are discussed in Chapters 11 – 17 on the various
photodermatoses. Immunophenotypic markers studies and gene rearrangement analyses are
helpful in differentiating chronic actinic dermatitis from cutaneous T-cell lymphoma, which
may share similarities in their clinical manifestations.
In patients with polymorphous light eruption and photoaggravated dermatoses, assess-
ment of antinuclear antibody titers (ANA and ENA) is essential to exclude connective tissue
diseases. An excellent screening test for all types of cutaneous porphyrias is the determination
of plasma porphyrin level. Should the results be elevated, evaluation of the complete porphyrin
profile, which should include determination of erythrocyte porphyrin, 24-hour urinary
porphyrin, and stool porphyrin levels, is indicated.
STEPS IN THE EVALUATION OF THE PHOTOSENSITIVE PATIENT

These are summarized in Table 11. After obtaining the history and performing the physical
examination, the next step is to schedule phototesting, and if photocontact allergic dermatitis
TABLE 10 Summary of Studies on Photopatch Testing

% Diagnosed with
Number of photoallergic
Reference Location patients contact dermatitis
Thune et al. (8) Scandinavia 1993 11
Hölzle et al. (9) Germany, Austria, Switzerland 1129 7
DeLeo et al. (10) New York, U.S.A. 187 11
Fotiades et al. (11) New York, U.S.A. 138 12
Neumann et al. (12) Germany, Austria, Switzerland 1129 4
Neumann et al. (12) Germany, Austria, Switzerland 1261 8
Bell and Rhodes (13) Liverpool, U.K. 167 10
Darvay et al. (14) London, U.K. 2715 2.3
Crouch et al. (15) Melbourne, Australia 172 1.4
TABLE 11 Schedule of Phototesting and Photopatch Testing

Day Procedure
1 Phototesting: exposure to UVA, UVB, and visible light; immediate reading done (to detect solar urticaria)
Duplicate set of photoallergens applied
2 MED reading
One set of photoallergen sites exposure to UVA (the lower of 5– 10 J/cm2 or 50% MED-A)
3 Reading of the irradiated and unirradiated photopatch test sites
4 –5 Reading of the irradiated and unirradiated photopatch test sites
Abbreviation: MED, minimal erythema dose.
TABLE 12 Frequency of Photodermatoses Diagnosed at Photodermatology Centers

Detroit
New York Melbourne Athens Singapore Blacks Caucasians
City (n ¼ 203) (n ¼ 513) (n ¼ 310) (n ¼ 141) (n ¼ 135) (n ¼ 110)
Diagnosis (%) (%) (%) (%) (%) (%)
Polymorphous light eruption 26 23 65 28 67 46
Photoaggravated dermatoses — 23 — 26 — —
Chronic actinic dermatitis 17 7 10 15 11 7
Systemic drug photosensitivity 7 5 — 15 13 11
Solar urticaria 4 8 18 7 2 8
Source: Adapted from Refs. 11, 15, 17, 18, 19.
is suspected, photopatch testing. The exposure of skin to the appropriate radiation sources is
done on the first day, and the first reading should be done upon completion of the irradiation
to observe for solar urticaria. The patient then comes back on the second day, when the MED
reading is undertaken, and any reduction below expected range and any abnormal mor-
phology of the responses are noted.
If the patient is to receive photopatch testing, a duplicate set of photoallergens is placed
on symmetrical sites of the uninvolved skin on the patient’s back on the first day of phototest-
ing. On the second day, after the determination of MED-A, one set is exposed to UVA. If the
MED-A is normal (i.e., greater than 18 or 20 J/cm2), an exposure dose of 10 J/cm2 is most
commonly used, although some centers use the lower dose of 5 J/cm2. If the patient has a
low MED-A, 50% of the MED-A is used as the exposure dose. On the third day (i.e., 24
hours later), assessment of the responses at the irradiated and nonirradiated sites is done.
Readings at 48 and 72 hours are also performed in some centers.
CONCLUSION
A systematic approach to the evaluation of the photosensitive patient should lead to the appro-
priate diagnosis (Table 8). With the approach outlined in this chapter, a summary of the
frequency of photodermatoses reported from photodermatology centers in New York,
Melbourne, Athens, Singapore, and Detroit is given in Table 12 (11,15,17 – 19). Polymorphous
light eruption, chronic actinic dermatitis, solar urticaria, and photosensitivity secondary to sys-
temic medications are the most frequently encountered photodermatoses in these centers.
Photoaggravated dermatoses are also seen relatively frequently in Melbourne and Singapore,
reflecting their geographic locations.
REFERENCES
1. Wilkinson DS. Photodermatitis due to tetrachlorosalicylanilide. Br J Dermatol 1961; 73:213– 219.
2. Roelandts R. The diagnosis of photosensitivity. Arch Dermatol 2000; 136:1152 – 1157.
3. Lim HW, Hawk J. Photodermatoses. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed.
London: Mosby, 2007.
148 Lim and Hawk
4. Tuchinda C, Srivannaboon S, Lim HW. Photoprotection by window glass, automobile glass and
sunglasses. J Am Acad Dermatol 2006; 54:845 –854.
5. McGregor JM, Grabczynska S, Vaughan R, Hawk JL, Lewis CM. Genetic modeling of abnormal
photosensitivity in families with polymorphic light eruption and actinic prurigo. J Invest Dermatol
2000; 115:471– 476.
6. Kontos A, Cusack C, Chaffins M, Lim HW. Polymorphous light eruption in African-Americans:
pinpoint popular variant. Photodermatol Photoimmunol Photomed 2002; 18:303 – 306.
7. Elpern DJ, Morison WL, Hood AF. Papulovesicular light eruption. A defined subset of polymorphous
light eruption. Arch Dermatol 1985; 121:1286–1288.
8. Thune P, Jansen C, Wennersten G, Rystedt I, Brodthagen H, McFadden N. The Scandinavian multi-
center photopatch study 1980 –1985: final report. Photodermatol 1988; 5:261– 269.
9. Hölzle E, Neumann N, Hausen B, et al. Photopatch testing: the 5-year experience of the German,
Austrian, and Swiss Photopatch Test Group. J Am Acad Dermatol 1991; 25:59– 68.
10. DeLeo VA, Suarez SM, Maso MJ. Photoallergic contact dermatitis. Results of photopatch testing in
New York, 1985 to 1990. Arch Dermatol 1992; 128:1513– 1518.
11. Fotiades J, Soter NA, Lim HW. Results of evaluation of 203 patients for photosensitivity in a 7.3-year
period. J Am Acad Dermatol 1995; 33:597– 602.
12. Neumann NJ, Holzle E, Plewig G, et al. Photopatch testing: the 12-year experiences of the German,
Austrian, and Swiss photopatch test group. J Am Acad Dermatol 2000; 42(2 Pt 1):183 – 192.
13. Bell HK, Rhodes LE. Photopatch testing in photosensitive patients. Br J Dermatol 2000; 142:589– 590.
14. Darvay A, White IR, Rycroft RJ, Jones AB, Hawk JL, McFadden JP. Photoallergic contact dermatitis is
uncommon. Br J Dermatol 2001; 145:597– 601.
15. Crouch RB, Foley PA, Baker CS. Analysis of patients with suspected photosensitivity referred for
investigation to an Australian photodermatology clinic. J Am Acad Dermatol 2003; 48:714 –720.
16. Hojyo-Tomoka T, Vega-Memije E, Granados J. Actinic prurigo: an update. Int J Dermatol 1995;
34:380– 384.
17. Stratigos AJ, Antoniou C, Papathanakou E, et al. Spectrum of idiopathic photodermatosis in a
Mediterranean country. Int J Dermatol 2003; 42:449– 454.
18. Wong SN, Khoo LSW. Analysis of photodermatoses seen in a predominantly Asian population at a
photodermatology clinic in Singapore. Photodermatol Photoimmunol Photomed 2005; 21:40 – 44.
19. Kerr HA, Lim HW. A comparison of photosensitivity disorders in African Americans and
Caucasians. Presented at the Skin of Color Society meeting, New Orleans, USA. 2005.
PART B: IMMUNOLOGICALLY-MEDIATED PHOTODERMATOSES
11 Polymorphous Light Eruption, Hydroa

Vacciniforme, and Actinic Prurigo
Herbert Hönigsmann
Department of Dermatology, Medical University of Vienna, Vienna, Austria
Maria Teresa Hojyo-Tomoka

Departamento de Dermatologia del Hospital General Dr. Manuel Gea González, Tlalpan, Mexico City, Mexico
B Photodermatoses, though not life-threatening, can severely impair the

quality of life, particularly in outdoor workers and during leisure
activities.
B Polymorphous light eruption, hydroa vacciniforme, and actinic prurigo

belong to the group of so-called idiopathic photodermatoses. The term
denotes skin diseases that occur in otherwise healthy individuals from
exposure to natural or artificial light without the intervention of an
exogenous photosensitizer. The diseases included in this group have two
factors in common: first, they are precipitated by electromagnetic
radiation in the ultraviolet or visible range; secondly, their exact
pathomechanism remains to be elucidated, but is presumably
immunologic in nature.
B Polymorphous light eruption is the most common photodermatosis, with

a prevalence of as high as 10% to 20% in Western Europe and in the
U.S.A. It starts during the second and third decades of life.
B Hydroa vacciniforme is a very rare photodermatosis that starts in

childhood. Its name derives from pock-like scarring as the final state
after healing of sunlight-induced vesicles.
B Actinic prurigo is a common chronic photodermatosis mainly affecting

Mestizo populations of American countries, native American Indians,
and Inuit people. Some sporadic cases do occur in Europe and Asia.
There is a clear genetic predisposition with an association of specific
alleles of the major histocompatibility complex.
150 Hönigsmann and Hojyo-Tomoka
POLYMORPHOUS (OR POLYMORPHIC) LIGHT ERUPTION

olymorphous (or polymorphic) light eruption (PLE) is a common, recurrent, acquired
P sunlight-induced disorder of delayed onset. It is often incorrectly referred as to “sun

allergy” by the lay press. The PLE is characterized clinically by the occurrence within
hours to days of ultraviolet radiation (UVR) exposure of nonscarring, pruritic, erythematous
papules, papulovesicles, vesicles or plaques on sun-exposed skin areas, generally symmetri-
cally, which then resolve completely over several days to a week. It is commonly most
severe in the spring or early summer, often diminishing in severity as summer progresses,
before disappearing completely during the winter. Clinical manifestations may be manifold
with a number of different yet overlapping clinical subtypes. Within each patient the
single morphologic feature of the lesions mostly remains the same. The term “polymorphous”
designates the inter-individual variation in the clinical appearance of the disease. The minimal
erythema dose (MED) is usually normal.
Epidemiology
The PLE is the most common photosensitivity disease, and according to a survey of apparently
healthy individuals (1), it may be even more common than one would assume when consider-
ing only the number of patients who seek medical advice. The prevalence is however inversely
related to latitude: around 21% of Scandinavians appear to suffer from the condition (2) and
10% to 15% of those living in the Northern U.S. (1) and the U.K. (3), although only 5% of
Australians (3) and 1% Singaporeans (4) have the disease.
The disorder (1,2,5,6) usually starts during the second and third decades of life and affects
females twice to three times more often than males. It may also occur in all skin types and racial
groups, but appears more commonly to affect relatively fair-skinned individuals. A positive
family history is present in about one-sixth of patients (1).
Etiology and Pathogenesis

The condition has been considered for many years as a possible delayed-type hypersensitivity
(DTH) response to endogenous, cutaneous photo-induced antigen (7), because of the hours or
days delay between sun exposure and manifestation of PLE and the lesional histologic appear-
ance, but firm evidence has been lacking.
The UV irradiation may convert some precursors in the skin to those antigens that cause
the DTH reaction, resulting in the clinical appearance of the disease. The nature of the precur-
sors or antigens, however, remains obscure. More recently, timed biopsies following irradiation
with artificial light sources with doses below the MED have shown perivascular infiltrates of
mainly CD4þ T lymphocytes within a few hours and CD8þ cells within days; an increased
number of dermal and epidermal Langerhans cells (LC) and dermal macrophages has also
been noted, a pattern suggestive overall of DTH as seen in the allergic contact dermatitis
and tuberculin reactions (8). In addition, E-selectin, vascular cell adhesion molecule-1
(VCAM-1), and intercellular adhesion molecule-1 (ICAM-1), particularly a marked and charac-
teristic staining of the latter on keratinocytes above areas of dermal leukocyte infiltration, are
also expressed as in other DTH responses (9).
The UV-induced immunosuppression is a consistent finding in normal skin and it was
speculated that this process might protect the skin from UV-induced photoallergens. Thus, sus-
ceptibility of individuals to PLE could arise from a failure of normal UV-induced
immunosuppression.
Kölgen et al. (10) reported that the skin of PLE patients was less susceptible to
UVB-induced migration of CD1þ LC. Following a six MED dose of UVB, there was a signifi-
cant failure of LC to migrate from the epidermis of PLE compared with normal subjects. They
also found a significant reduction in UVB-induced infiltration by CD11bþ macrophage-like
cells in PLE compared with healthy skin, which was considered to represent an important
finding in view of the prominent role of these cells in secretion of the immunosuppressive cyto-
kine interleukin (IL)-10. It was therefore postulated that the pathologic defect underlying PLE
PLE, HV, and AP 151
might be a failure of normal photoimmunosuppression. Thus the balance of UV-induced sup-

pression and UV-induced provocation would be altered, allowing sunlight exposure to
provoke the PLE eruption (10). In a more recent study, Kölgen et al. assessed whether there
are abnormalities of UV-induced secretion of tumor necrosis factor (TNF) a and IL-1b, cyto-
kines known to be important in effecting LC migration. Secondly, they examined the effects
of UV on secretion of T helper cell type 2 (TH2) cytokines IL-4 and IL-10, which mediate
immunosuppression. They concluded that the reduced expression of TNF-a, IL-4, and IL-10
in the UVB – irradiated skin of patients with PLE appears largely attributable to a lack of neu-
trophils, and is indicative of reduced Langerhans cell migration and reduced TH2 skewing. An
impairment of these mechanisms underlying UV-B –induced immunosuppression may be
important in the pathogenesis of PLE (11).
Palmer and Friedmann (12) reported on functional studies examining DTH responses in
PLE and concluded that the induction of sensitization by 2,4-dinitrochlorobenzene (DNCB) is
suppressed less by UVR in patients with PLE than in healthy controls (12). Beyond this, van de
Pas et al. (13) recently showed a reduction in UV-induced suppression of the DTH response to
DNCB in PLE such that these patients are less easily sensitized to DNCB compared with
healthy subjects (13). Schornagel et al. (14) also suggested a role for neutrophils in the
pathogenesis of PLE by showing a relative reduction in UVB-induced neutrophilic infiltration.
It is conceivable that abnormalities in both neutrophil and mononuclear cell activity could be
involved in the pathogenesis of PLE.
However, the most recent findings on the effect of solar-simulated radiation on the elici-
tation phase of contact hypersensitivity revealed no significant difference between controls and
patients with PLE. These results contrasted with previous findings of the same group that had
indicated a resistance to UVR-induced suppression of sensitization to DNCB in PLE. This
difference may reflect the greater importance of Langerhans cells in the sensitization phase,
and is consistent with the hypothesis that PLE arises from impaired suppression of Langerhans
cell activation or migration (15).
The reason for the occurrence of PLE appears likely to be genetic with a substantial
environmental component, with 70% of the population perhaps having a tendency to the con-
dition, but not all expressing it because of poor penetrance (16,17). Examination of 119 mono-
zygotic twin pairs and 301 dizygotic twin pairs revealed an incidence of 21% among the
monozygotic twins and 18% in dizygotic twins (16). However, the culprit gene has not been
identified yet. This genetically-determined factor, which leads to the putative immune recog-
nition of an autologous cutaneous antigen, is generated by UVR in PLE but not normal subjects,
although the antigen is presumably expressed in all individuals. Inducing UV absorbers and
antigens in PLE have not been characterized; however, one suggestion for the latter has been
a form of heat-shock protein (18). A variety of such antigens within and between patients,
however, seems more likely. In addition, the induction of lesions by a UVA sunbed in the non-
tanning sacral pressure area (19) further suggests that the UV –chromophore interaction in at
least some patients may be oxygen-independent.
Induction of Polymorphous Light Eruption

Difficulty in the reliable laboratory induction of clinical lesions has long frustrated investigations
into the pathogenesis of PLE. Determination of the action spectrum of PLE by experimental
reproduction of skin lesions using artificial radiation sources has led to conflicting results. A
lack of response, often to adequate doses of artificially produced UV radiation, by patients
who react readily to just suberythemogenic doses of natural sunlight may be attributed to a
number of variables. These include the size of the UV irradiation site and its location, the
irradiation of small, normally unaffected areas perhaps not eliciting sufficient immunologic
stimulus to activate the response, but also to the UV spectrum, irradiation dose, dose rate, and
degree of cutaneous immunologic tolerance, which may be increased by any recent prior
exposure (20). There is also a lack of universally accepted, standardized phototest protocols.
The complex interrelationships between factors such as these have clearly contributed
significantly to the conflicting nature of reports concerning the most effective wavelengths
for PLE induction. In most series, UVA (320 – 400 nm) has been more reliably effective than
FIGURE 1 Polymorphous light eruption. Photoprovocation: small papulovesicles developing in the UVA-irradiated
area (left) after three exposures with one minimal erythema dose on consecutive days. The UVB-irradiated site
shows just erythema (right).
UVB (280 – 320 nm) (Fig. 1) (20 –22). Thus, in one of these studies (21), following exposures of
buttock skin to UVA or UVB daily for four to eight days, the action spectrum was in the UVA
range in 56%, UVB in 17%, and both UVA and UVB in 27%. In another study (22), the ratio was:
68% triggered by UVA, 8% by UVB, and 10% by both wavelengths (Fig. 2). This apparent diver-
sity in action spectrum for the induction of PLE is possibly the result of different UV-evoked
inducing antigens, and perhaps also of different cutaneous levels for these antigens. Contradic-
tory results regarding the action spectrum for PLE induction could also conceivably be
accounted for by the presence of inhibitory wavelengths in some patients.
Variation in the proportions of UVA and UVB present in terrestrial sunlight may also
explain certain clinical characteristics of PLE (23). Thus, the greater proportion of UVA to
UVB in temperate climates and during the spring and fall months might be expected to contrib-
ute to a higher incidence of PLE in temperate rather than tropical regions (3), with greater sus-
ceptibility to the condition in spring and occasionally fall, rather than summer in most patients.
FIGURE 2 Polymorphous light eruption (PLE). Photoprovocation: PLE

lesion induced after three exposures with one minimal erythema dose on
consecutive days on both the UVA- and UVB-irradiated area. More
pronounced with UVA.
PLE, HV, and AP 153
Moreover, the higher proportion of UVB to UVA in summer sunlight also very probably inhi-
bits PLE development through a predominantly UVB-induced cutaneous immunosuppressive
mechanism (13,24). Older generation sunscreens that are protective primarily against UVB
encouraged people to stay much longer in the sun, thereby receiving a much higher UVA
dose than without UVB protection, did not provide adequate protection against provocation
of PLE (23).
Clinical Features
Lesions generally develop symmetrically and affect only some sun-exposed areas of the skin,
often those normally covered in winter, such as the V-area of the chest (Fig. 3), the external
aspects of the arms and forearms, and lower anterior aspect of the neck. Occasionally, the
face can be involved.
The PLE occurs more often in temperate areas. The eruption typically begins each spring
or early summer, on sunny vacations, or after recreational sunbed use (25), often moderating
with continuing exposure. An attack may also be induced by outdoor activities in winter or
by exposure through window glass (26,27). The eruption develops after minutes to hours
(on vacation, sometimes days) of sun exposure and lasts for one to several days or occasionally
weeks, particularly with continuing exposure. The tendency to develop the condition,
however, often fades or ceases as summer or the vacation proceeds. A polymorphic light erup-
tion severity index (PLESI) has been proposed to produce a simple, valid and reproducible
method to assess the severity of the disease (28).
In the absence of further exposure, all the lesions gradually subside completely without
scarring over one to seven days, occasionally a week or two, or very rarely longer in severe
cases. In a given patient, the eruption tends always to affect the same skin sites, although its
distribution may gradually spread or recede overall.
Associated systemic symptoms are rare, but shivesing, headache, fever, nausea, and a
variety of other sensations are possible. The condition may be lifelong, but gradually improves
over years in many patients: Over seven years, 64 of 114 patients (57%) reported steadily dimin-
ishing sun sensitivity, including 12 (11%) who totally cleared (29).
The PLE has many morphologic variants. Lesions vary widely between patients, but are
generally pruritic, grouped, erythematous or skin-colored papules of varying size not infre-
quently coalescing into large, smooth or rough-surfaced plaques (Fig. 4). Vesicles, bullae,
and papulovesicles as well as confluent edematous swelling (particularly of the face) are
also possible, while rarely erythema or pruritus alone (PLE sine eruptione) may occur (30).
Insect bite-like and erythema multiform-like variants have also been described. In addition,
the helices of the ears, particularly in boys because they are relatively more exposed, may be
principally affected, often with vesicles, a form of PLE previously known as juvenile spring
eruption (Fig. 5) (31). Such subdivisions do not apparently relate to differences in disease
pathogenesis. The papular form, of either large or small separate or confluent lesions, and gen-
erally tending to be in clusters, is the most common, followed by the papulovesicular and
FIGURE 3 Polymorphous light eruption.

Photoprovocation: classical papulovesicular rash at
the V-area.
FIGURE 4 Polymorphous light ruption: close-

up of papular rash.
plaque variants; the others are rare. The eczematous form probably does not exist, representing
instead chronic actinic dermatitis, although PLE may on occasion become secondarily licheni-
fied or eczematized during resolution. Differing morphologies may also occur at different skin
sites in the same patient: diffuse facial erythema and swelling, for example, may accompany
typical papular lesions at other sites. A final morphologic variant, a small papular form gener-
ally sparing the face and occurring after several days’ exposure on vacations, has been desig-
nated as benign summer light eruption in Europe (32). Rarely, covered sites may be mildly
affected, due to radiation penetration through clothes.
Histopathology
The histologic features of PLE are quite characteristic but not diagnostic and vary with the
different clinical presentations (33,34). The epidermis shows edema, focal spongiosis, and
occasionally small vesicles. Acanthosis, spongiosis focal parakeratosis, and basal vacuolization
can be present. Sunburn cells are not a typical feature. There is a moderate-to-intense, super-
ficial and deep dermal perivascular infiltrate in all clinical types, the infiltrate consisting
FIGURE 5 Juvenile spring eruption in a 10-year-old boy.

PLE, HV, and AP 155
predominantly of T cells; while neutrophils and eosinophils are infrequent. Other common fea-
tures are upper dermal and perivascular edema and endothelial cell swelling. Direct immuno-
fluorescence is normal.
Diagnosis
The diagnosis of PLE is not difficult and is made largely on clinical grounds based on the
typical morphology of the eruption. Although the diagnosis is mainly clinical, provocative
phototesting may be valuable in winter, if no lesions are present, to confirm the diagnosis.
The best way to do this is by using repetitive irradiations on the V area of the neck or forearms
for one to four consecutive days. This can be done with high-intensity monochromatic UVA
and UVB sources or with a solar simulator (UVA plus UVB). The doses needed are not necess-
arily erythemal. Readings are made immediately and up to 72 hours after the last irradiation.
Abnormal cutaneous reactions can be provoked in more than 60% of patients. In most studies
more patients reacted to UVA than to UVB (20,21,35).
There are no diagnostic laboratory tests available for PLE. Laboratory examinations are
usually performed to exclude other dermatoses, such as erythropoietic protoporphyria and
photosensitive lupus erythematosus. Subacute cutaneous lupus erythematosus, which is gen-
erally not itchy as PLE, must be excluded in some patients by determining antinuclear, Ro
(SSA) and La (SSB) antibody titers. Persistent plaque-type PLE must also be differentiated
from Jessner-Kanof’s lymphocytic infiltration of the skin, while the photo-exacerbation of
dermatoses, such as atopic and seborrheic eczema, may occur in susceptible subjects with
the same time course as for PLE, but with differing and characteristic morphologies.
Treatment
The treatment of PLE has to be subdivided into therapy for the acute exacerbation and the pro-
phylactic therapy before expected sun exposure (Table 1) (36).
TABLE 1 Treatment Measures

Disease Treatment Reference
First-line therapy (acute flare) Topical/systemic corticosteroids (38)
First-line therapy (prevention) Moderation of sun exposure, high-factor broad-spectrum (36)
sunscreens, and avoidance of behavioral sunlight exposure
and/or artificial tanning devices in more severe cases
Second-line therapy (prevention) Narrowband UVB phototherapy or PUVA (21,41– 44)
Therapies of no or insufficiently Antimalarials, b-carotene, nicotinamide, v-3 polyunsaturated (45–51)
documented efficacy fatty acids, Escherichia coli-filtrate (Colibiogen) systemic
antioxidants, and systemic immunosuppressive therapy
Hydroa vacciniforme
First-line therapy (prevention) High-factor broad-spectrum sunscreens and avoidance of (58,59)
behavioral sunlight exposure and/or artificial tanning
devices
Second-line therapy (prevention) Narrowband UVB phototherapy or PUVA (58,60– 62)
Therapies of no or insufficiently Antimicrobials, antimalarials, and systemic
documented efficacy immunosuppressive therapy, including corticosteroids,
beta-carotene, and dietary fish oil
Actinic prurigo
First-line therapy (acute flare) Thalidomide (97,98)
First-line therapy (prevention) High-factor broad-spectrum sunscreens and avoidance of
behavioral sunlight exposure, protective hats and clothing,
and sunglasses
Second-line therapy (prevention) PUVA (reportedly not always successful)
Therapies of no or insufficient efficacy Antimalarials, b-carotene, and antihistamines
Abbreviation: PUVA, psoralen plus ultraviolet A.
The mild disease of many patients is satisfactorily controlled by the moderation of sun
exposure at times of high UV intensity, use of protective clothing, and the regular application
of broad-spectrum sunscreens with high protection factors, particularly against UVA. Combin-
ing a potent antioxidant with a broad-spectrum, highly UVA-protective sunscreen was
reported to be more effective in preventing PLE than sunscreen alone. However, this will
need further confirmation (37).
Patients with fully developed disease require topical corticosteroids, in some cases in
the form of wet dressings, for several days. More severe attacks may be treated effectively
with a short course of systemic (oral) corticosteroids (38). Since PLE will subside spontaneously
and is not a life-threatening condition, all possible risks of therapy should be carefully
considered.
Many patients will agree to undergo some sort of preventive measures. Prophylactic
treatment consists of several approaches: avoidance of sunlight during the summer, the use
of sunscreens with broadband filters, systemic treatment, and preventive phototherapy.
Severely affected subjects suffering frequent attacks of their disease throughout the
summer may require courses of prophylactic photo(chemo)therapy before the expected sun
exposure in the early spring. At first glance it appears somewhat bizarre to use light treatment
to prevent a condition that is caused by light, and the mechanisms by which UVB and psoralen-
photochemotherapy (PUVA) induce tolerance to sunlight are not completely understood. Pig-
mentation and thickening of the stratum corneum may be important factors for the protective
effect, and UVB, high-dose UVA, and PUVA are efficient triggers of both. Although these local
effects may provide some barrier against photosensitivity, they probably do not suffice to
explain the degree of protection induced in many patients. Thus other mechanisms may be
involved, since photodermatoses do occur in dark-skinned subjects (39). The ability of UV radi-
ation to affect the skin immune system was first recognized in the early 1970s in numerous
studies. It is therefore now generally accepted that UVA, UVB, and PUVA therapy exert a
variety of immunomodulatory effects on human skin and that this is of critical importance
for the therapeutic efficacy of phototherapy. Janssens et al. (40) showed that UVB hardening
significantly normalizes UV-induced cell migratory responses of Langerhans cells and neutro-
phils in patients with PLE.
The PUVA is a very effective preventive (hardening) treatment. In approximately 70% of
patients with this condition, a three- to four-week course of PUVA suffices to suppress the
disease upon subsequent exposure to sunlight. The initial exposure and dose increments
should be performed according to the guidelines outlined for psoriasis. The PUVA induces pig-
mentation rapidly and intensively at relatively low (suberythemogenic) UVA doses that
usually remain well below the threshold doses for eliciting the PLE. About 10% of the patients
develop typical lesions during the initial phase of PUVA. Interruption of treatment or reduction
in the UVA dose is rarely required in such cases. Usually, brief symptomatic treatment with
topical corticosteroids suffices (21,41,42). Treatment is given three times weekly over a
period of four weeks in the early spring. The PUVA therapy protects only temporarily, and reg-
ularly repeated sun exposures are subsequently required to maintain protection. However, a
considerable number of patients remain protected for two to three months, even after pigmen-
tation has faded.
The use of narrowband 312 nm UVB phototherapy (TL-01 bulb) has become increasingly
popular, being simpler to administer, possibly safer than, and apparently of comparable effi-
cacy to PUVA (43,44). Also, exposure of prophylactic UVB may sometimes trigger the eruption,
particularly in severely affected subjects, necessitating concurrent systemic corticosteroid
therapy on occasion, which is usually effective.
Patients who only develop their disorder during infrequent vacations also generally
respond well to oral corticosteroids prescribed for them in advance (38).
Other therapies are of uncertain efficacy. Such remedies include antimalarials, which
have long been advocated (45), b-carotene (46), and nicotinamide (47). Likewise, probably
only moderately effective are v-3 polyunsaturated fatty acids (36). The efficacy of an Escherichia
coli-filtrate (Colibiogen) awaits further confirmation (48). Also, systemic antioxidants did not
reduce the severity of the disease (49). The use of immunosuppressants is certainly restricted
to some rare, severe disabling cases (50,51).
PLE, HV, and AP 157
HYDROA VACCINIFORME
Hydroa vacciniforme (HV) is a very rare photodermatosis of unknown etiology that principally
starts in childhood, frequently resolving by adolescence or young adulthood. It is characterized
by recurrent crops of papulovesicles or vesicles most commonly on the face and the dorsa of the
hands, but other sun-exposed areas of the skin may also be involved. The vesicles resolve with
pocklike scarring. The disease was first described by Bazin (52) in 1862, and it is possible that
before the clear definition of erythropoietic protoporphyria by Magnus et al. (53), some cases
may have been protoporphyria rather than hydroa because of the similarity of symptoms.
Some recent reports of an association with Epstein –Barr virus (EBV) infection are interesting
(54 – 56), but not all of the described cases are typical, associated with lymphoma (57) and
may well be a different entity; but this is up to further investigations.
Epidemiology
Although it occurs in early childhood and may resolve spontaneously at puberty, some patients
may suffer from life-long photosensitivity. There appears to be a male predominance for the
severe manifestations, whereas milder forms (hydroa aestivale) are more common in females
(58,59). Familial incidence is exceptional. In a recent study the estimated prevalence of HV
was at least 0.34 cases per 100,000 with an approximately equal sex ratio. Males had a later
onset and longer duration of disease than females (58).

The pathogenesis of HV is unknown. No chromophores have been identified as yet. The UVB
MED reaction is normal in the majority of the patient reported, but reduced UVA MED values
have been found in some patients (58). Blood, urine, and stool porphyrins are negative and all
other laboratory parameters including immunological tests are within normal limits. The
course, distribution of lesions and histopathology with a perivascular lymphocytic infiltrate
are somewhat reminiscent of PLE. However, the clinical features are quite different. Although
the cause of the condition is unknown, its dermal, perivascular lymphocytic infiltrate suggests
it may possibly be a scarring variant of PLE and thus conceivably also a delayed type hyper-
sensitivity reaction. The action spectrum lies in the UVA region, and repetitive irradiation
with broad spectrum UVA has been shown to elicit typical skin lesions that are clinically
and histologically identical to those produced by natural sunlight and that heal with scarring
(58 – 61).
Clinical Features
The HV usually presents in childhood with sometimes spontaneous improvement during
adolescence. Erythema with a burning or itching sensation and sometimes associated swelling
begins within hours of sufficient sun exposure in light-exposed skin areas, particularly on the
face and the hands, followed by the appearance of symmetrically scattered tender papules
within up to 24 hours; these generally later becoming vesicular, umbilicated, and occasionally
confluent and hemorrhagic. Within a few weeks, crusting followed by detachment of the
lesions leaves permanent, depressed, hypopigmented scars. Vesicles and bullae as well as
the scars resemble the lesions of vaccinia (Fig. 6). Occasional systemic features include head-
ache, malaise, and fever (59). The HV usually occurs only during the summer months, and
sometimes but not always improves or resolves in adolescence (58,59). Parents generally
seek specialist advice as their children are unable to tolerate sunshine (play outdoors or
travel abroad) and because the eruption can result in considerable scarring, both causing sig-
nificant morbidity.
Histopathology
Distinctive histologic changes include initial intraepidermal vesicle formation with later focal
epidermal keratinocyte necrosis and spongiosis in association with dermal perivascular
FIGURE 6 Hydroa vacciniforme: acute hemorrhagic

lesions, crusting, and pock-like scarring on the face.
neutrophil leukocyte and lymphocyte infiltration. Vasculitic features have also been reported
(59). Immunofluorescence findings are nonspecific.
Diagnosis
The differential diagnosis includes several photosensitivity states. However, the typical history
and the clinical features are relatively characteristic. Of particular importance is the exclusion
of erythropoietic protoporphyria, which may have similar morphology. An evaluation of eryth-
rocyte protoporphyrin levels, red cell photohemolysis, and stool analysis will exclude
protoporphyria.
Photoprovocation testing induces typical blisters (Fig. 7). There is now strong evidence
that UVA radiation is the causal factor (58 – 62). In addition to reduced MED values to UVA,
repetitive broad-spectrum UVA has been shown to reproduce lesions that are clinically and
histologically identical to those produced by natural sunlight and that heal with scarring.
Serology for antinuclear antibody and extractable nuclear antigens (anti-Ro, La, and Sm),
will exclude bullous lupus erythematosus, which quite commonly can be ruled out by its
clinical symptoms. Screening for EBV is only indicated if lymphoma is suspected. However,
atypical HV in patients with latent EBV infection could be reproduced by repeated UVA
irradiations (63). Rare cases have been associated with metabolic disorders, such as Hartnup
disease, so aminoaciduria should be ruled out (64).
FIGURE 7 Hydroa vacciniforme. Photoprovocation: UVA irradiation (three times 30 J/cm2 on three consecutive
days). (Left) blistering after 24 hours; (middle) confluent hemorrhagic blisters after 48 hours; and (right) crusting
and scar formation after two weeks.
PLE, HV, and AP 159
Treatment
The HV is almost always refractory to any treatment, but restriction of sun exposure, appro-
priate clothing, and regular use of broad-spectrum sunscreens with an effective UVA filter
can help in mild-to-moderate disease (Table 1). Windows in the car and home could be
covered with certain films, which filter UV wavelengths less than 380 nm.
In patients with more severe disease, however, courses of narrow-band UVB photo-
therapy or PUVA administered as for PLE may occasionally help. Both phototherapy regimens
usually consist of thrice weekly treatments for an average of three to four weeks. It is important
to administer these therapies carefully in order not to provoke disease exacerbations (58,60 – 62).
Antimicrobial therapy has also been tried, as have antimalarials (59,62) and systemic immuno-
suppressive therapy, including intermittent oral corticosteroids; although occasionally helpful,
none of these appear to be reliably effective. b-carotene used in several studies, however, was
mostly shown to be ineffective (60,62).
Anecdotally, dietary fish oil induced mild to good improvement in some patients (65). For
severe and refractory HV unresponsive to other therapies, immunosuppressive agents,
including azathioprine and cyclosporin (66), may be effective, but thalidomide does not
seem to be (66). However, the use of immunosuppressive drugs for an admittedly unpleasant
but otherwise benign disease should be considered carefully.
The rare nature of this condition means that there are no large or randomized trials.
Evidence for treatment is based on case series or single reports.
ACTINIC PRURIGO
Actinic prurigo (AP) is a chronic photodermatosis of unknown etiology, frequent in Latin
American mestizos (Caucasians and indigenous offspring) and in Amerindians living at
high altitudes. A possible pathogenetic mechanism could consist of a delayed hypersensitivity
reaction to UV-induced autoantigens in subjects with genetic susceptibility. The AP has been
originally classified as a variant of PLE (67,68); however, there is now sufficient clinical, histo-
logic, epidemiological, and immunogenetic data that confirm that AP and PLE are two different
diseases (69).
The AP has been described under various names: solar dermatitis in 1954 (70), Guatema-
lan cutaneous syndrome in 1960 (71), solar prurigo in 1961 (72), light sensitive eruption in
American Indians in 1961 (73), familial AP in 1968 (74), PLE (prurigo type) in 1975 (68,75),
and hereditary PLE of American Indians in 1975 (76). The term that is used nowadays by
most authors is “actinic prurigo,” originally coined by Londoño in 1968 (74).
Epidemiology
The AP is a common chronic photodermatosis mainly affecting Mestizo populations of Amer-
ican countries (referring to people with mixed Indian and European ancestry), such as in
Mexico, Central America, and most of South America. In the United States (77,78) and
Canada (79,80), AP has been described in native American Indians and Inuit people, and
some sporadic cases in Europe (81) and Asia (82).
The AP begins in the first decade of life usually around the age of four to five, affecting
females more than males (ratio 2:1), and people living in regions located at altitudes higher
than 1000 meters above sea level; although cases have been reported at lower altitudes. It
runs a chronic course with partial or no remissions in patients living in tropical countries
with intense sunlight the whole year round. In Canada, the United States, and England, the
patient’s condition flares during spring and summer and improves during the winter.

In 1984, Moncada et al. (83) suggested an abnormal immune response in AP patients showing
an increase of T lymphocytes in peripheral blood as well as a predominance of dermal T helper
cells and Ia antigen-marked cells in the dermal infiltrate. Arrese et al. (84) re-examined the
histologic characteristics of AP lesions and determined the possible role of various cell popu-
lations and mediators that participate in the pathogenesis. Immunohistochemical analysis of
the dense inflammatory infiltrate showed a predominance of T helper cells clustered in the
center of the lymphoid follicles and scattered in the diffuse inflammatory infiltrate. Keratino-
cytes showed abundant immunoreactivity for both calprotectin and TNF-a. Focal IgG and
IgM deposits in the papillary dermis as well as IgMþ cells in the dense lymphocytic infiltrate
and follicular center have also been demonstrated. The IL-2 was expressed in most inflamma-
tory cells in the dermal infiltrate. It was concluded that in subjects genetically predisposed to
AP, UV light might trigger excessive TNF-a production by keratinocytes whose sustained
release in turn exerts its proinflammatory activity and deleterious epidermal effects.
Estrada et al. (85) described the effect of thalidomide on TNF-a serum levels, on IL-4, and
on IFNg-producing lymphocytes of AP patients. They showed that AP has indeed an immuno-
logic component, as the clinical efficacy of thalidomide is exerted not only by inhibition of TNF-
a synthesis but also by modulating of IFNg-producing CD3þ cells, and these cells could be
used as clinical markers for recovery.
Gomez et al. (86) compared cellular and humoral immunity by in vitro proliferation
studies, ELISA, and immunofluorescence in AP patients and healthy controls. They found
autoimmune reactivity in AP patients and postulated that AP patients may have one or
more skin antigens that stimulate an autoimmune response.
For the prevalence of AP in Mestizo populations in American countries, it has been long
suspected that AP patients may have a genetic predisposition that determines a particular
inflammatory response to UV light. In several studies, a possible association of the expression
of AP and specific alleles of the major histocompatibility complex (MHC) genes were investi-
gated. In Saskatchewan, Canada, AP patients from the Cree Indian group had a high associ-
ation with HLA-A24 and HLA-Cw4 (87), whereas in Colombia in the Chimila Indians, a
high frequency of HLA-Cw4 was reported (88). In British and Irish patients, HLA-DR4
(DRB1 0407) was found to be significantly increasing in patients with AP as compared with
patients with PLE (89,90). A recent study in the indigenous Chibcha family group from Colom-
bia also revealed a high frequency of DRB1 0407 (91).
Mexican AP patients have shown a significantly increased frequency of HLA-A28 and
HLA-B39 and HLA-DR4 (DRB1 0407) (92). In the Inuit people of Canada, an association
with HLA-DR4 (DRB114) was found (93). Menagè et al. (81) suggested that the HLA type
may have a causal role in patients with AP by determining the response to a particular
peptide antigen, probably induced by UV radiation, to initiate the cutaneous response.
Induction of Actinic Prurigo

The AP lesions can be experimentally induced by repeated exposures to MEDs of UVA,
with daily radiations of 2.5 J/cm2 for ten days in 90% of the patients, and with UVB doses of
3 to 5 mJ cm/day for 15 days in 100% of the cases. It was shown that these patients react to
broad-spectrum radiation (UVA and UVB), but their UVB and UVA MED is usually normal (94).
Clinical Features
The AP is characterized by symmetric involvement of sun-exposed areas of the skin, such as
the face (eyebrows, malar regions, nose, and lips) (Fig. 8), neck, V-area of the chest, the external
regions of the arms and forearms, as well as the dorsum of the hands. Lips and the conjunctiva
are commonly affected (95).
The primary lesions are erythematous papules and excoriations, and crusts and licheni-
fied plaques due to chronic scratching. Pruritus is always present and usually very intense. One
important clinical feature that differentiates AP from PLE is the absence of vesicles as primary
lesions in AP, although they can be seen as secondary lesions if eczema, impetigo, or contact
dermatitis develops.
The lips are affected in 84% of the patients and show cheilitis with edema, crusts, fissures,
ulcerations, and hyperpigmentation, whereas in mild cases only dry lips and scaling may be
seen (Fig. 9).
PLE, HV, and AP 161
FIGURE 8 Actinic prurigo: involvement of the sun-exposed area of the

face with lips affected.
Conjunctivae are affected in 45% of the patients in whom it manifests at the beginning
with conjunctivitis, photophobia, watery eyes, and pruritus; after some years patients
develop pigmentation and finally pseudopterygium, which in severe cases may even impair
vision (Fig. 10) (96).
Histopathology
Histopathologic changes in AP have been considered nonspecific; however, it does have dis-
tinct microscopic findings. On the basis of data obtained from a large number of biopsies, an
accurate diagnosis can be made and also allows to separate AP from other photodermatosis
(97). Skin biopsies show hyperkeratosis, regular acanthosis, thickening of basal lamina, and
a dense mainly lymphocytic perivascular infiltrate in the superficial dermis. The presence of
lymphoid follicles can be observed in areas of ulceration, which supports the protective role
of the stratum corneum and can explain why lymphoid follicles are more frequently found
in mucosal lesions.
FIGURE 9 Actinic prurigo: severe lip invol-

vement.
FIGURE 10 Actinic prurigo: chronic lesions

of conjunctiva with pseudopteryrium.
Lip biopsies show hyperkeratosis with parakeratosis, regular acanthosis, spongiosis, and
vacuolization of the basal cell layer, with areas of ulcerations in 50% of the biopsies. In the
lamina propria, stromal edema, dilated capillaries are present and a dense lymphocytic infil-
trate forming follicles with a prominent germinal center is found in up to 80% of the biopsies.
Abundant eosinophils and mast cells are present, and in some cases the infiltrate tends to have
a band-like distribution (Fig. 11).
Conjunctival biopsies exhibit areas of epithelial hyperplasia alternating with areas of
atrophy. In 60% of the biopsies, marked vacuolization of basal cells and melanophages in the
lamina propria are present, which are responsible for the brown discoloration observed clini-
cally. The most constant findings are a dense lymphocytic infiltrate with follicular pattern in
88% of the biopsies.
Guevara et al. (98) in an immunohistochemical study reported an inflammatory infiltrate
present in the skin, lips, and conjunctiva of AP patients, and they showed that T- and
FIGURE 11 Actinic prurigo: histopathology of a

lip lesion showing a dense lymphocytic infiltrate
with follicular centers (10).
PLE, HV, and AP 163
B-lymphocytes are present in all of the biopsies. The B cells are in the center, and T cells are in
the periphery of the lymphoid follicles.
Diagnosis
The diagnosis of AP is based on clinical and histopathological grounds. Lesions on the lips and
conjunctiva are specific, and the skin offers an adequate histopathologic correlation. The exper-
imental reproduction of AP lesions is possible with UVB and UVA.
The differential diagnoses of AP frequently include the following.
B Atopic dermatitis with photosensitivity, where the key findings are a familial incidence, an
early infancy onset, the presence of xerosis, the sparing of the tip of the nose, and good
response to topical corticosteroids and emollients.
B Chronic actinic dermatitis, which is quite rare, starts much later in life, and affects
predominantly elderly men, with the UVB and UVA MED dramatically reduced.
Histology reveals a dense lymphocytic infiltrate, which may sometimes resemble
lymphoma.
B PLE is seen more frequently in Caucasian patients with no association to any particular
HLA antigen. Vesicles and papulovesicles are the major part of the clinical picture and it
does not affect lips or conjunctivas. Histologically it does not show follicle formation.
Treatment
Out of numerous treatment modalities that have been tried, only thalidomide has proved to be
effective in most patients (Table 1). The excellent response is so constant that it can be used as a
diagnostic marker of the disease (99,100). The initial daily dose is usually 100 mg, which is
tapered as the patient shows clinical improvement. After several months of treatment, most
patients can stop the drug and are maintained with sun-protective measures only. A few
patients require maintenance doses of thalidomide as low as 25 mg weekly. Skin and lip
lesions respond rapidly (within 1 –2 months) but the conjunctival lesions tend to persist,
although the symptoms disappear. Women of childbearing age must use adequate contracep-
tive measures with a very close follow-up because of the known teratogenicity. Thalidomide is
usually very well tolerated, with somnolence as the most common side effect; peripheral
neuropathy has not been a problem in most patient series.
Treatment modalities that are either ineffective or less effective than thalidomide are anti-
malarials, b-carotene, antihistamines, PUVA, and topical or systemic corticosteroids (which may
be useful to treat lesions with secondary eczematization). Obviously, an essential part of AP treat-
ment is adequate sun protection. Sunscreens, protective hats and clothing, sunglasses, and sun
avoidance measures are usually enough for patients once they are clear of lesions and thalido-
mide is stopped. The problem is that AP affects more frequently people of lower economic
status who work outdoors most of the time and in whom sun protection is almost always
sub-optimal.
REFERENCES
1. Morison WL, Stern RS. Polymorphous light eruption: a common reaction uncommonly recognized.
Acta Derm Venereol (Stockh) 1982; 62(3):237– 240.
2. Ros AM, Wennersten G. Current aspects of polymorphous light eruption in Sweden. Photodermato-
logy 1986; 3(5):298– 302.
3. Pao C, Norris PG, Corbett M, Hawk JL. Polymorphic light eruption: prevalence in Australia and
England. Br J Dermatol 1994; 130(1):62– 64.
4. Khoo SW, Tay YK, Tham SN. Photodermatoses in a Singapore skin referral center. Clin Exp Derma-
tol 1996; 21(4):263– 268.
5. Norris PG, Hawk JLM. The idiopathic photodermatoses: polymorphic light eruption, actinic
prurigo and hydroa vacciniforme. In: Hawk JLM, ed. Photodermatology. London: Arnold,
1999:178– 190.
6. Jansen CT. The natural history of polymorphous light eruptions. Arch Dermatol 1979; 115(2):
165 – 169.
7. Epstein S. Studies in abnormal human sensitivity to light. IV. Photoallergic concept of prurigo
aestivalis. J Invest Dermatol 1942; 5:289– 298.
8. Norris PG, Morris J, McGibbon DM, et al. Polymorphic light eruption: an immunopathological
study of evolving lesions. Br J Dermatol 1989; 120(2):173– 183.
9. Norris PG, Barker JNWN, Allen M, et al. Adhesion molecule expression in polymorphic light erup-
tion. J Invest Dermatol 1992; 99(4):504– 508.
10. Kölgen W, Van Weelden H, Den Hengst S, et al. CD11bþ cells and ultraviolet-B-resistant CD1aþ
cells in skin of patients with polymorphous light eruption. J Invest Dermatol 1999; 113(1):4– 10.
11. Kölgen W, van Meurs M, Jongsma M, et al. Differential expression of cytokines in UV-B-exposed
skin of patients with polymorphous light eruption: correlation with Langerhans cell migration
and immunosuppression. Arch Dermatol 2004; 140(3):295– 302.
12. Palmer RA, Friedmann PS. Ultraviolet radiation causes less immunosuppression in patients with
polymorphic light eruption than in controls. J Invest Dermatol 2004; 122(2):291– 294.
13. van de Pas CB, Kelly DA, Seed PT, et al. Ultraviolet-radiation-induced erythema and suppression of
2004; 122(2):295– 299.
14. Schornagel IJ, Sigurdsson V, Nijhuis EHJ, et al. Decreased neutrophil skin infiltration after UVB
exposure in patients with polymorphous light eruption. Invest Dermatol 2004; 123(1):202– 206.
15. Palmer RA, Hawk JL, Young AR, et al. The effect of solar-simulated radiation on the elicitation phase
of contact hypersensitivity does not differ between controls and patients with polymorphic light
eruption. J Invest Dermatol 2005; 124(6):1308– 1312.
16. Millard TP, Bataille V, Snieder H, et al. The heritability of polymorphic light eruption. J Invest
Dermatol 2000; 115(3):467– 470.
17. McGregor JM, Grabczynska S, Vaughan RW, et al. Genetic modeling of abnormal photosensitivity
in families with polymorphic light eruption and actinic prurigo. J Invest Dermatol 2000;
115(3):471– 476.
18. McFadden JP, Norris PG, Cerio R, et al. Heat shock protein 65 immunoreactivity in experimentally
induced polymorphic light eruption. Acta Derm Venereol 1994; 74(4):283– 285.
19. Tegner E, Bradin AM. Polymorphous light eruption in hypopigmented pressure areas with a UVA
sunbed. Acta Derm Venereol 1986; 66(5):446– 448.
20. Hölzle E, Plewig G, Hofmann C, et al. Polymorphous light eruption: experimental reproduction of
skin lesions. J Am Acad Dermatol 1982; 7(1):111 –125.
21. Ortel B, Tanew A, Wolff K, et al. Polymorphous light eruption: action spectrum and photoprotection.
J Am Acad Dermatol 1986; 14(5 Pt 1):748– 753.
22. Van Praag MC, Boom BW, Vermeer BJ. Diagnosis and treatment of polymorphous light eruption. Int
J Dermatol 1994; 33(4):233– 239.
23. Farr PM, Diffey BL. Adverse effects of sunscreens in photosensitive patients. Lancet 1989;
1(8635):429– 431.
24. Baadsgaard O, Cooper KD, Lisby S, et al. Dose response and time course for induction of T6-DRþ;
human epidermal antigen-presenting cells by in vivo ultraviolet A, B, and C irradiation. J Am Acad
Dermatol 1987; 17(5 Pt 1):792– 800.
25. Rivers JK, Norris PG, Murphy GM, et al. UVA sunbeds: tanning, photoprotection, acute adverse
effects and immunological changes. Br J Dermatol 1989; 120(6):767– 777.
26. Piletta PA, Salomon D, Beani JC, et al. A pilot with an itchy rash. Lancet 1996; 348(9035):1142.
27. Hampton PJ, Farr PM, Diffey BL, et al. Implication for photosensitive patients of ultraviolet A
exposure in vehicles. Br J Dermatol 2004; 151(4):873– 876.
28. Palmer RA, van de Pas CB, Campalani E, et al. A simple method to assess severity of polymorphic
light eruption. Br J Dermatol 2004; 151(3):645– 652.
29. Jansen CT, Karvonen J. Polymorphous light eruption. A seven-year follow-up evaluation of 114
patients. Arch Dermatol 1984; 120(7):862– 865.
30. Dover JS, Hawk JLM. Polymorphic light eruption sine eruptione. Br J Dermatol 1988; 118(1):73– 76.
31. Hawk J. Juvenile spring eruption is a variant of polymorphic light eruption. NZ Med J 1996;
109(1031):389.
32. Thomas P, Amblard P. Lucite estivale benigne. In: Thomas P, Amblard P, eds. Photodermatologie et
Photothérapie, Paris: Masson, 1988:49– 51.
33. Hawk JLM, Smith NP, Black MM. The photosensitivity disorders. In: Elder DE, Elenitsas R,
Jaworsky C, Johnson B Jr, eds. Lever’s Histopathology of the Skin. Philadelphia: Lippincott-
Raven, 1997:305– 310.
34. Hölzle E, Plewig G, von Kries R, et al. Polymorphous light eruption. J Invest Dermatol 1987;
88(suppl. 3):32s– 38s.
35. van de Pas CB, Hawk JL, Young AR, et al. An optimal method for experimental provocation of
polymorphic light eruption. Arch Dermatol 2004; 140(3):286– 292.
36. Ling TC, Gibbs NK, Rhodes LE. Treatment of polymorphic light eruption. Photodermatol Photo-
immunol Photomed 2003; 19(5):217– 227.
PLE, HV, and AP 165
37. Hadshiew I, Stab F, Untiedt S, et al. Effects of topically applied antioxidants in experimentally
provoked polymorphous light eruption. Dermatology 1997; 195(4):362– 368.
38. Patel DC, Bellaney GJ, Seed PT, et al. Efficacy of short-course oral prednisolone in polymorphic light
eruption: a randomized controlled trial. Br J Dermatol 2000; 143(4):828– 831.
39. Kontos AP, Cusack CA, Chaffins M, et al. Polymorphous light eruption in African Americans:
pinpoint papular variant. Photodermatol Photoimmunol Photomed 2002; 18(6):303– 306.
40. Janssens AS, Pavel S, Out-Luiting JJ, et al. Normalized ultraviolet (UV) induction of Langerhans cell
depletion and neutrophil infiltrates after artificial UVB hardening of patients with polymorphic
light eruption. Br J Dermatol 2005; 152(6):1268– 1274.
41. Hönigsmann H. Polymorphous light eruption. In: Lim HW, Soter NA, eds. Clinical Photomedicine.
New York: Marcel Dekker, 1993:167– 179.
42. Murphy GM, Logan RA, Lovell CR, et al. Prophylactic PUVA and UVB therapy in polymorphic light
eruption—a controlled trial. Br J Dermatol 1987; 116(4):531– 538.
43. Bilsland D, George SA, Gibbs NK, et al. A comparison of narrow band phototherapy (TL-01) and
photochemotherapy (PUVA) in the management of polymorphic light eruption. Br J Dermatol
1993; 129(6):708– 712.
44. Man I, Dawe S, Ferguson J. Artificial hardening for polymorphic light eruption: practical points
from ten years’ experience. Photodermatol Photoimmunol Photomed 1999; 15(3 – 4):96– 99.
45. Murphy GM, Hawk JLM, Magnus IA. Hydroxychloroquine in polymorphic light eruption: a
controlled trial with drug and visual sensitivity monitoring. Br J Dermatol 1987; 116(3):379– 386.
46. Corbett MF, Hawk JL, Herxheimer A, et al. Controlled therapeutic trials in polymorphic light
eruption. Br J Dermatol 1982; 107(5):571– 581.
47. Ortel B, Wechdorn D, Tanew A, et al. Effect of nicotinamide on the phototest reaction in polymor-
phous light eruption. Br J Dermatol 1988; 118(5):669– 673.
48. Przybilla B, Heppeler M, Ruzicka T. Preventive effect of an E. coli-filtrate (Colibiogen) in polymor-
phous light eruption. Br J Dermatol 1989; 121(2):229– 233.
49. Eberlein-Konig B, Fesq H, Abeck D, et al. Systemic vitamin C and vitamin E do not prevent photo-
provocation test reactions in polymorphous light eruption. Photodermatol Photoimmunol Photo-
med 2000; 16(2):50– 52.
50. Norris PG, Hawk JLM. Successful treatment of severe polymorphic light eruption with azathiopr-
ine. Arch Dermatol 1989; 125(10):1377.
51. Shipley DR, Hewitt JB. Polymorphic light eruption treated with cyclosporin. Br J Dermatol 2001;
144(2):446– 447.
52. Bazin E: Leçons théorétiques et cliniques sur les affections génériques de la peau. Vol. 1. Paris:
Delebrage, 1862:132.
53. Magnus IA, Jarret A, Prankerd TAJ, et al. Erythropoietic protoporphyria: a new porphyria syndrome
with solar urticaria due to protoporphyrinaemia. Lancet 1961; 26(2):448– 451.
54. Cho KH, Kim CW, Heo DS, et al. Epstein-Barr virus-associated peripheral T-cell lymphoma in adults
with hydroa vacciniforme-like lesions. Clin Exp Dermatol 2001; 26(3):242–247.
55. Ohtsuka T, Okita H, Otuska S, et al. Hydroa vacciniforme with latent Epstein-Barr virus infection.
Br J Dermatol 2001; 145(3):509– 510.
56. Cho KH, Lee SH, Kim CW, et al. Epstein-Barr virus-associated lymphoproliferative lesions present-
ing as a hydroa vacciniforme-like eruption: an analysis of six cases. Br J Dermatol 2004; 151(2):
372 – 380.
57. Steger GG, Dittrich C, Hönigsmann H, et al. Permanent cure of hydroa vacciniforme after treatment
of Hodgkin’s disease with C-MOPP/AS VD regimen. Br J Dermatol 1988; 119(5):684– 685.
58. Gupta G, Man I, Kemmett D. Hydroa vacciniforme: a clinical and follow-up study of 17 cases. J Am
Acad Dermatol 2000; 42(2 Pt 1):208– 213.
59. Sonnex TS, Hawk JLM. Hydroa vacciniforme: a review of ten cases. Br J Dermatol 1988; 118(1):
101 – 108.
60. Jaschke E, Hönigsmann H. Hydroa vacciniforme-Aktionsspektrum, UV-Toleranz nach Photo-
chemotherapie. Hautarzt 1981; 32(7):350– 353.
61. Halasz CL, Leach EE, Walther RR, et al. Hydroa vacciniforme: induction of lesions with ultraviolet
A. J Am Acad Dermatol 1983; 8(2):171– 176.
62. Goldgeier MH, Nordlund JJ, Lucky AW, et al. Hydroa vacciniforme: diagnosis and therapy. Arch
Dermatol 1982; 118(8):588– 591.
63. Heo EP, Park SH, Kim TH. Artificial reproduction of atypical hydroa vacciniforme caused by latent
Epstein-Barr virus infection. Int J Dermatol 2003; 42(6):476– 479.
64. Ashurst PJ. Hydroa vacciniforme occurring in association with Hartnup disease. Br J Dermatol 1969;
81(7):486– 492.
65. Rhodes LE, White SI. Dietary fish oil as a photoprotective agent in hydroa vacciniforme. Br J Der-
matol 1998; 138(1):173– 178.
66. Blackwell V, McGregor JM, Hawk JLM. Hydroa vacciniforme presenting in an adult successfully
treated with cyclosporin A. Clin Exp Dermatol 1998; 23(2):73– 76.
67. Epstein JH. Polymorphous light eruption; phototest technique studies. Arch Dermatol 1962;
85(4):502– 504.
68. Epstein JH. Polymorphous light eruption. J Am Acad Dermatol 1980; 3(4):329– 343.
69. Addo HA, Frain-Bell W. Actinic prurigo—a specific photodermatosis? Photodermatol 1984;
1(3):119 – 128.
70. Escalona E. Dermatologı́a. Lo esencial para el estudiante. México: Impresiones Modernas, S.A.
1964:194.
71. Cordero CFA. Sı́ndrome cutáneo guatemalense en la dermatitis actı́nica. Med Cut ILA 1976;
4:393– 400.
72. López González G. Prúrigo solar. Arch Argent Dermatol 1961; 11(9):301– 318.
73. Everett MA, Crockett W, Lamb JH, et al. Light sensitive eruption in American Indians. Arch Derma-
tol 1961; 83(2):243– 246.
74. Londoño F, Mundi F, Giraldo F, et al. Familial actinic prurigo. Arch Argent Dermatol 1966;
16(4):290– 307.
75. Hojyo-Tomoka MT, Dominguez-Soto L. Clinical and epidemiological characteristics of polymor-
phous light eruption. Castellania 1975; 3:21– 23.
76. Birt AR, Davis RA. Hereditary polymorphic light eruption of American Indians. Int J Dermatol 1975;
14(2):105– 111.
77. Brandt R. Dermatological observations on the Navajo reservation. Arch Dermatol 1958;
71:681– 685.
78. Fusaro RM, Johnson JA. Hereditary polymorphic light eruption in American Indians. Photoprotec-
tion and prevention of streptococcal pyoderma and glomerulonephritis. J Am Med Assoc 1980;
244(13):1456– 1459.
79. Birt AR, Davis RA. Photodermatitis in North American Indians: familial actinic prurigo. Int J
Dermatol 1971; 10(2):107– 114.
80. Lane PR, Hogan DJ, Martel MJ, et al. Actinic prurigo: clinical features and prognosis. J Am Acad
Dermatol 1992; 26(5 Pt 1):683– 692.
81. Menagè HP, Vaughan RW, Baker CS, et al. HLA-DR4 may determine expression of actinic prurigo in
British patients. J Invest Dermatol 1996; 106(2):362– 364.
82. Wong NS, Khoo LS. Analysis of photodermatoses seen in a predominantly Asian population at a
photodermatology clinic in Singapore. Photodermatol Photoimmunol Photomed 2005;
21(1):40– 44.
83. Moncada B, Gonzalez-Amaro R, Baranda L, et al. Immunopathology of polymorphous light erup-
tion. T lymphocytes in blood and skin. J Am Acad Dermatol 1984; 10(6):970– 973.
84. Arrese JE, Dominguez-Soto L, Hojyo-Tomoka MT, et al. Effectors of inflammation in actinic prurigo.
J Am Acad Dermatol 2001; 44(6):957– 961.
85. Estrada I, Garibay-Escobar A, Núñez-Vazquez A, et al. Evidence that thalidomide modifies the
immune response of patients suffering from actinic prurigo. Int J Dermatol 2004; 43(12):893– 897.
86. Gomez A, Umaña A, Trespalacios AA. Immune responses to isolated human skin antigens in actinic
prurigo. Med Sci Monit 2006; 12(3):BR106– BR113.
87. Sheridan DP, Lane PR, Irvine J, et al. HLA typing in actinic prurigo. J Am Acad Dermatol 1990;
22(6 Pt 1):1019– 1023.
88. Bernal JE, Duran MM, Ordoñez CO, et al. Actinic prurigo among the Chimila Indians: HLA studies.
J Am Acad Dermatol 1990; 22(6 Pt 1):1049– 1051.
89. Grabczynska SA, McGregor JM, Kondeatis E, et al. Actinic prurigo and polymorphic light eruption:
common pathogenesis and the importance of HLA-DR4/DRB1 0407. Br J Dermatol 1999;
140(2):232– 236.
90. O’Reilly FM, Spencer S, Darke C, et al. HLA –DR4B1 0407 strong association with actinic prurigo in
Ireland. Br J Dermatol 1996; 135(suppl. 47):65.
91. Suarez A, Valbuena MC, Rey M, et al. Association of HLA subtype DRB1 0407 in Colombian
patients with actinic prurigo. Photodermatol Photoimmunol Photomed 2006; 22(2):55– 58.
92. Hojyo-Tomoka T, Grados J, Vargas-Alarcon G, et al. Further evidence of the role of HLA-DR4 in the
genetic susceptibility to actinic prurigo. J Am Acad Dermatol 1997; 36(6 Pt 1):935– 937.
93. Wiseman MC, Orr PH, McDonald SM, et al. Actinic prurigo: clinical features and HLA associations
in a Canadian Inuit population. J Am Acad Dermatol 2001; 44(6):952– 956.
94. Hojyo-Tomoka MT. Pruebas fotobiológicas en prurigo actı́nico. Dermatol Hojyo-Tomoka MT 1993;
37(suppl. 1):328.
95. Hojyo-Tomoka MT, Vega-Memije ME, Cortes-Franco R, et al. Diagnosis and treatment of actinic
prurigo. Dermatol Ther 2003; 16(1):40 –44.
96. Hojyo-Tomoka T, Vega-Memije E, Granados J, et al. Actinic prurigo: an update. Int J Dermatol 1995;
44(6):380– 384.
97. Vega ME. Caracterı́sticas histopatológicas del prurigo actı́nico. Dermatol Rev Mex 1993; 37(suppl.
1):295– 297.
PLE, HV, and AP 167
98. Guevara E, Hojyo-Tomoka MT, Vega-Memije ME. Cortes-Franco R, Domı́nguez-Soto L. Estudio

immunohistoquı́mico para demostrar la presencia de linfocitos T y B en el infiltrado inflamatorio
de las biopsias de piel, labio y conjuntiva de pacientes con prurigo actı́nico. Dermatol Rev Mex
1997; 41:223– 226.
99. Londoño F. Thalidomide in the treatment of actinic prúrigo. Int J Dermatol 1973; 12(5):326– 328.
100. Vega E, Hojyo-Tomoka MT, Dominguez-Soto L. Tratamiento del prurigo actı́nico con talidomida:
estudio de 30 pacientes. Dermatol Rev Mex 1993; 37(suppl 1):342– 343.
12 Chronic Actinic Dermatitis
John L. M. Hawk
Photobiology Unit, St. John’s Institute of Dermatology, St. Thomas’ Hospital, King’s College of London,
Henry W. Lim
B CAD is a form of eczema induced by ultraviolet and rarely also visible

radiation.
B The inducing action spectrum frequently resembles that for sunburn

in shape, although acting at lower doses and leading to eczema, but
suggesting a similar or associated absorbing molecule may be
responsible through a different mechanism.
B CAD has exactly the features of allergic contact dermatitis but seems
to be a response instead to a photo-altered absorbing molecule as
mentioned above rather than to an exogenous substance.
B Older people with outdoor interests, particularly gardening, are most

affected, often following prior eczema, particularly atopic in younger
people, later more frequently airborne contact or probably seborrheic,
whereas HIV disease may also rarely be a predisposing factor.
B CAD affects exposed areas, initially patchily, later confluently, sometimes

with marked lichenification or a pseudolymphomatous appearance
previously known as actinic reticuloid, with rare late progression to
erythroderma.
B The condition is harmless of itself but extremely persistent and distressing

before not infrequent gradual resolution over decades, although in
exceptionally rare instances it may perhaps represent a form of cutaneous
lymphoma.
B The treatment of CAD requires restriction of exposure to the inducing

ultraviolet and rarely visible wavelengths and to any contact allergens,
wearing of ultraviolet-protective clothing, regular application of high
protection factor, broad-spectrum sunscreens, topical eczema therapy
with emollients, steroids, and if necessary calcineurin inhibitors, or in
severe cases with immunosuppressive oral agents or
rarely phototherapy.
170 Hawk and Lim
INTRODUCTION
hronic actinic dermatitis (CAD), as originally proposed by Hawk and Magnus in 1979 (1),
C is a clinical entity embracing different presentations of the same condition, previously

known separately and somewhat confusingly as actinic reticuloid (AR) (2), photosensi-
tive eczema (3), and photosensitivity dermatitis (PD) (4), but now all shown to be variants
of CAD. It was also noted as essentially synonymous with the PD/AR syndrome as used in
a slightly less embracing way by Frain-Bell et al. (4), and the originally described form, per-
sistent light reaction (reactivity) (PLR) (5), not understood at that stage. All the previous
terms, although briefly mentioned for interest and historical reasons below, and except
perhaps for the occasional use of AR to refer to the severest variant of CAD, should now
be discarded for clarity.
PLR as first described by Wilkinson in 1962 (5) was a persisting eczema of light-
exposed sites following an apparently completed episode of topical photoallergic contact der-
matitis, thereafter remaining despite avoidance of the original allergen and irrespective of
whether the currently affected sites had been previously exposed to allergen. The wave-
lengths responsible for the eruption were reported to be not only in the UVA (315 –
400 nm) waveband, generally responsible for photoallergenic responses, but also in the
UVB (280 – 315 nm), thereby fulfilling the requirements later defined for CAD. PLR was
first noted to occur following photoallergic contact sensitization to halogenated phenols (tet-
rachlorsalicylanilide and tribromosalicylanilide) (5), then antibacterial agents present in
soaps, to antiseptics and toiletries such as bithionol (6), and later to the fragrance musk
ambrette (7), a synthetic agent once used widely in aftershave preparations. Other occasion-
ally implicated products have been quinoxaline-N-dioxide in animal foodstuffs (8), zinc pyr-
ithione (9), and certain bleaching agents (10), but such substances have largely been
withdrawn and PLR as originally described, although apparently an original precursor of
CAD, now appears vanishingly rare.
AR was first reported in 1969 by Ive et al. (2), its major clinical characteristic being infil-
trated erythematous, or reticuloid, plaques of the exposed skin of elderly men, arising on a
background of eczematous, erythematous, or normal skin. A clinical resemblance to the fea-
tures of severe photoallergic contact dermatitis was noted, but photopatch tests were generally
negative and the eruption was inducible by UVB, UVA, and sometimes also visible irradiation,
as later described for CAD. The histogical features were often noted closely to resemble those of
cutaneous T-cell lymphoma (CTCL). AR is still occasionally observed as the most severe
variant of CAD but with a much reduced frequency, almost certainly because of earlier recog-
nition, diagnosis, and treatment.
Photosensitive eczema, described by Ramsay and Kobza-Black in 1973 (3), was a much
milder, purely eczematous photo-eruption, also of exposed sites, without detectable photoal-
lergy. A resemblance to AR was noted but the disease action spectrum was essentially just in
the UVB region.
PD, reported shortly after by Frain-Bell et al. in 1974 (4), was also an exposed site eczema
but now with an action spectrum often extending beyond the UVB into the UVA.
Hawk and Magnus in 1979 (1) then demonstrated a significant overlap between the
features of photosensitive eczema, AR, and by implication PD, describing patients with
the clinical and histological changes of eczema and the photobiological abnormalities of
AR, and vice versa. They had also noted transitions between these disease states (11) and,
therefore, unified all the variants of what appeared to be the same condition within the
term CAD. Transition from PLR to AR was also later observed, as well as overlaps
between PLR and CAD (12). In 1990, it was therefore proposed that PLR should also be
included within the term CAD (13,14), thus at once simplifying the disease terminology
and relegating PLR, AR, photosensitive eczema, and PD to terms of predominantly historical
interest. Finally, the introduction of unifying diagnostic criteria has led to a better under-
standing of CAD and facilitated its recognition (13,15,16). Thus CAD is an eczema of
exposed skin generally induced by UVB, sometimes also UVA, and rarely visible light as
well, although sensitivity to other combinations of the above spectra have occasionally
been noted.
Chronic Actinic Dermatitis 171
PATHOGENESIS
The pathogenesis of CAD remains incompletely understood, although many aspects of it have
been elucidated, and the clinical and histological appearances of the disease and its immuno-
histochemical abnormalities are all similar in nature to those of delayed type hypersensitivity
(DTH) responses and, in particular, allergic contact dermatitis. This is further supported by the
known responsiveness of the condition to immunosuppressive agents such as cyclosporine and
azathioprine. It is therefore likely that CAD is of similar nature, but by inference a reaction
against cutaneous photo-induced endogenous antigen rather than an external contact agent.
Thus, the often pseudolymphomatous clinical and histological appearances of severe
forms of CAD, and the dermal infiltrate containing a predominance of CD8þ T cells (17), are
exactly the same as those previously reported in persistent allergic contact dermatitis against
phosphorus sesquisulphide (18).
Also, a variety of other studies characterizing the CAD dermal infiltrate have also shown
it to contain predominantly T cells, which are always present in DTH reactions, both in fully
evolved (19– 22) and new lesions (23,24), together also characteristically with Langerhans
cells, interdigitating reticulum cells, and monocyte-macrophages, particularly CD36þ
(OKM5þ), factor XIIIaþ, CD11bþ, CD11cþ, and CD14þ cells (23,24). Leukocyte epidermo-
tropism is also observed, whereas keratinocytes express major histocompatibility class II anti-
gens in induced lesions (23,24).
Further, a predominance of CD4þ cells has been noted in some studies (20,23), equal
ratios in others (20,21), and a predominance of CD8þ in others again (22,24), the last particu-
larly in lesions with more florid histological changes (17), and most workers agree that CD4þ
cells similarly predominate over CD8þ in the early stages of known DTH reactions (25,26),
with CD8þ cells becoming more numerous later (24). In addition, the pattern and time
course of the infiltrating cells in evoked lesions of the disease in one study (23), particularly
of epidermal and dermal activated T cells, epidermal Langerhans cells, and monocyte-macro-
phages, all peaking around 24 to 48 hours, again resembled the changes of DTH (25), and
clearly differed from those induced by UVB irradiation of normal skin in which T- and Langer-
hans cell epidermotropism is not observed (27).
Analysis of circulating blood lymphocyte CD4þ to CD8þ ratios in CAD is normal in
some patients (17,28) and reduced in others (17,21,24), particularly in florid CAD (29), correlat-
ing with simultaneous changes in the cutaneous infiltrate (17).
Specific changes in the kinetics and pattern of cell surface adhesion molecule expression
have also been reported in DTH, and in five patients with CAD, timed biopsies after several
minimal lesion-inducing doses of solar-simulated radiation (less than a minimal sunburning
dose in normal subjects) demonstrated the upregulated expression of perivascular ICAM-1,
VCAM-1, and E-selectin, dermal interstitial ICAM-1 and VCAM-1, and basal and focal epider-
mal keratinocyte ICAM-1, from within a few hours up to several days (30). These changes
again resemble those occurring in DTH reactions (31,32), further suggesting CAD is a
similar process, and differ from normal reactions to UVB irradiation, in which E-selectin
expression is less prolonged and keratinocyte ICAM-1 and VCAM-1 are not expressed, and
to combined UVB and UVA irradiation, in which keratinocyte ICAM-1 expression in vitro
is delayed by 48 hours (31,33).
Cytokine production by keratinocytes also plays an important role in the initiation and
maintenance of the allergic contact dermatitis reaction. Studies on this in the pathogenesis of
CAD lesions are limited, but one immunohistochemical time course study of induced lesions
supports a pro-inflammatory role for interleukin-1a, regulated by its receptor and receptor
antagonist (34), as also seen in delayed immunological reactions.
These presumed DTH changes might therefore be a response against putative antigen
created either through direct ultraviolet skin molecular absorption and distortion, or
through endogenously photosensitized secondary oxidative damage within the skin, sugges-
tions supported by the fact that albumin for example may become antigenic in vitro through
photo-oxidation of its component histidine (35). In addition, CAD often occurs in association
with pre-existing widespread, often airborne, contact dermatitis to an exogenous sensitizer
or photosensitizer (36), especially that reported from England and Scotland, or perhaps
172 Hawk and Lim
occasionally drug-induced photosensitivity (13,37), such reactions arguably enhancing

cutaneous immune function during light exposure to a sufficient degree to enable presumed
endogenous photo-antigen recognition. Instead or as well, chronic photo-damage may concei-
vably impair ultraviolet-induced cutaneous immunosuppression such that normal endogen-
ous ultraviolet-induced skin photo-antigen is more easily recognized, as seemingly occurs
genetically in polymorphic light eruption (38), particularly in that elderly outdoor workers
or enthusiasts are most often affected in CAD (36). Further, their photo-aged skin may concei-
vably lead to slower presumed antigen removal, as well as easier associated contact allergen
penetration, such that immune antigen recognition is further facilitated. Finally, CAD may
also occasionally develop in patients with long-standing endogenous eczema, very possibly
a reaction of equally predisposing nature to allergic contact dermatitis, although CAD may
also apparently arise in previously normal skin. As the disorder then gradually progresses
(39), so too do the characteristic irradiation abnormalities of CAD develop.
There is no evidence for a genetic susceptibility to CAD, no positive family history or sig-
nificant HLA association (personal communication, H. du P. Menagé) having been noted in
patients with the disease, suggesting that it is therefore acquired. This may perhaps occur
through continuing solar and ambient allergen exposure as suggested above, particularly as
the condition develops readily in those with outdoor occupations or hobbies, whereas a
report of onset after accidental UVC exposure again suggests that excessive ultraviolet exposure
may be contributory (40). Thus, environmental rather than genetic factors appear to explain why
patients develop CAD, and perhaps also the male and elderly predominance of the disorder.
Determination of the action spectrum for the induction of CAD might also help establish
the nature of the presumptive antigen. In fact, this action spectrum is often of the same shape as
that for sunburn (41), but in the case of CAD, the eruption is eczematous, and much lower
irradiation doses are generally needed to induce the response. Therefore, the ultraviolet-
absorbing molecule in at least some CAD is likely to be a similar or associated molecule to
that leading to sunburn, but now acting as an antigen, namely DNA (42), RNA, or the like.
It seems likely to be a different molecule altogether in rarer instances, some patients seeming
sensitive to just UVA (43), and possibly even more rarely to just 600 nm visible light (44). On
the other hand, preliminary studies with the autologous mixed epidermal cell leukocyte
culture reaction failed to detect antigen in lesional CAD dermal and epidermal skin (45),
although this may have been the result of experimental difficulties in ensuring adequate
antigen preservation within patient skin. Definitive evidence of an antigen-driven process as
the basis for CAD is therefore still awaited.
Thus in summary, CAD is very likely an allergic contact dermatitis-like response against
ultraviolet radiation-damaged DNA or a similar or associated molecule, at least in some
instances, perhaps because of airborne contact dermatitis-enhanced immune reactivity, or
else photo-damaged immunosuppressive activity, in often long-standing sunlight- and air-
borne allergen-exposed subjects.
CLINICAL ASPECTS (TABLE 1)

CAD is relatively uncommon, its incidence in Scotland for example being only around one in
6000 (46). Males are much more often affected, but women probably increasingly so, now
TABLE 1 Predisposing or Associated Features in Chronic Actinic Dermatitis

Male sex
Older age
Outdoor life style
Human immunodeficiency virus infection (probable, rare)
Chronic endogenous eczema, particularly atopic (early-onset disease), seborrheic, rarely palmar or plantar
Allergic contact dermatitis, often airborne
Topical photoallergic contact dermatitis (previously, then known as persistent light reactivity; probably no longer occurs)
Systemic drug photosensitivity (uncertain, rare)
representing between 10% (46) and 22% (47) of those with the disease. Older subjects are most
at risk, the mean CAD patient age being 65 years (47), although younger people, particularly
with atopic eczema (48), may occasionally be affected. White Caucasians are predominant,
although Japanese (12,47), other Asians (49), Afro-Caribbeans (47), and African Americans
(50) are not exempt. In fact, in the United States, CAD is commonly seen among individuals
with dark skin (13). The disease appears to be more common in temperate climates, although
it does represent 15% of patients with photodermatoses in a referral center in Singapore (49).
Familial incidence is not reported. Outdoor workers and leisure enthusiasts, particularly gar-
deners, most commonly develop CAD, although it has also been reported in patients treated
over long periods with potentially photosensitizing medications such as thiazide diuretics
(37); nevertheless, since such medicines are most commonly used in the elderly, it is not absol-
utely certain that they may induce the disorder. CAD has finally been noted to occur on
occasion in subjects with human immunodeficiency virus (HIV) infection (51,52).
Allergic contact dermatitis to ubiquitous, frequently airborne, allergens often accompa-
nies CAD (46) and may precede its onset (39,53). Positive responses to at least one of these aller-
gens are found in about 75% of patients and to two or more in 65% (47). Compositae plant
extracts, and to a lesser extent fragrance compounds and colophony are most often incrimi-
nated, with metals, rubber, epoxy resins, phosphorus sesquisulphide, medicaments, preserva-
tives, and vehicle bases being occasional offenders (36,47,53– 57). Rarely, contact dermatitis to
sunscreens also supervenes during the course of the disease (13,56). Photoallergic contact der-
matitis is also possible but rare, although the disorder as originally reported regularly evolved
from photocontact dermatitis, then being known as PLR; this progression has now essentially
ceased presumably with the gradual removal of potential photocontact allergens from the
environment.
Finally, a moderate number of CAD patients progress to the disorder following suffering
other eczemas, particularly atopic, and probably also seborrheic, palmar, or plantar (2,3,44).
Thus, only around 10% of those with CAD have had no previous contact, photocontact, or
endogenous eczema (47).
CAD is generally more severe in spring and summer (Fig. 1), although its dependence on
ultraviolet exposure is not always obvious to patient or physician. Thus, the eruption may not
deteriorate for hours to days after irradiation, and it may also continue into winter, albeit
usually in milder form. It may also become disguised further by progression toward erythro-
derma or the simultaneous presence of contact dermatitis. Nevertheless, many patients do
recognize an exacerbation of their condition by sun exposure, especially early in the disease,
increased itching, and worsening of the eruption occurring within minutes to hours of
exposure.
FIGURE 1 Chronic actinic dermatitis showing eczema of exposed facial skin worse in summer (right) than in
winter (left). Source: Courtesy of H. du P. Menagé.
174 Hawk and Lim
FIGURE 2 Chronic actinic dermatitis of exposed areas of face with clear cut-off on forehead where turban
normally worn.
There is normally subacute or chronic, extremely pruritic eczema of predominantly sun-

exposed sites, particularly face, back and sides of neck, upper chest, scalp, and backs of hands,
characteristically with clear cut-off at lines of clothing (Figs. 2 –4). In addition, the upper
eyelids, submental area, areas behind the earlobes, skin creases and folds, and finger webs
are often spared, more obviously when the eruption is confluent elsewhere (Fig. 5). In severely
affected patients, generalization of the eruption to covered sites is possible (Fig. 6) and erythro-
derma may rarely develop. Lichenification is common in chronic disease, whereas in the most
severely affected patients, probably following persistent failures of diagnosis or adequate treat-
ment, shiny, infiltrated papules, and plaques mimicking those of cutaneous lymphoma may
develop (2) (Fig. 7); palmar and occasionally plantar eczema may also supervene. Areas of
hyper- or hypopigmentation too may occur in severe CAD, the latter tending to mimic vitiligo
and probably occurring through melanocytic destruction by the disease process (58). Eyebrow
and scalp hair may also be stubbly or lost from constant rubbing or scratching.
CAD patients in the past have on occasion committed suicide, probably because of the
previously intractable nature of the condition (2), but this no longer seems to occur, almost
FIGURE 3 Chronic actinic dermatitis of backs of hands with cut-off at shirt cuffs at wrists.
FIGURE 4 Chronic actinic dermatitis of back of neck with cut-off at shirt collar.
certainly because of better diagnosis and treatment. However, some patients may still be
severely despondent.
Once established, CAD tends to persist over many years before not infrequent gradual
resolution. It has been estimated that the probability of resolution by 10 years from diagnosis
is 1 in 5; poorer prognosis is associated with severe abnormal UVB photosensitivity, and the
identification of contact allergens in two or more patch test series (59). Malignant lymphoma-
tous transformation has also been claimed on a number of occasions (60– 63), arguably follow-
ing chronic antigenic stimulation in long-standing, untreated disease (64), but it seems just as
likely that these rarities are coincidental occurrences or diagnostic confusions rather than
causal associations. Thus, a comparison of the incidence of lymphoma in CAD patients with
that obtained from sex-matched national morbidity data did not indicate any increased risk
(65), nor a study of the natural history of CAD over decades (59,66), nor again a flow cytometric
study showing no evidence of DNA aneuploidy in the cutaneous infiltrate of CAD patients
(67), nor finally T-cell receptor and immunoglobulin gene rearrangement studies demonstrat-
ing a lack of lymphoid clonality in the disorder (29). Thus, if present at all, the risk of lympho-
matous transformation in CAD must be at most exceptionally rare. On the other hand,
FIGURE 5 Chronic actinic dermatitis with sparing of finger-web skin.

176 Hawk and Lim
FIGURE 6 Chronic actinic dermatitis with sub-erythrodermic spread

on to trunk.
importantly, very occasional malignant lymphomas may just perhaps be markedly light-
sensitive of themselves (68).
HISTOPATHOLOGY
The histopathology of CAD (69) demonstrates epidermal spongiosis and acanthosis, on
occasion with hyperplasia, along usually with a deep dermal, predominantly perivascular,
often dense, mononuclear cell infiltrate, and not infrequently large, hyperchromatic, convo-
luted nuclei and mitotic figures. Macrophages, eosinophils, and plasma cells may also occur,
whereas in extreme situations, the disorder may be impossible to differentiate from CTCL.
FIGURE 7 Chronic actinic dermatitis showing shiny

pseudolymphomatous plaques of face in severe actinic
reticuloid variant.
Immunophenotypic marker studies are then helpful, which usually show the predominance of
CD8þ cells in CAD, and CD4þ cells in CTCL (17,70).
PHOTOTESTING
This is always abnormal in moderate to severe CAD, confirming the disorder, but in early, mild
disease as is now fairly often seen because of better recognition, abnormal phototest results are
not always observed. When the responses are abnormal, reduced ultraviolet doses are gener-
ally required to produce erythema at 24 hours, though sometimes earlier or later, and such reac-
tions are morphologically different from those of sunburn, representing instead papular or
eczematous lesions characteristic of the disease itself (4). They may also be pruritic and are
usually to the UVB wavelengths, often also the UVA, and rarely visible light as well, but
occasional abnormalities have been reported to just the UVA (4,43,50,71), and also very
rarely to just 600 nm visible light (44,50,71). These latter cases, although not fulfilling the orig-
inally proposed diagnostic criteria (1), appear to be rare examples of otherwise typical CAD,
presumably resulting from initial radiation absorption by other than usual chromophores.
With the solar simulator or other broad spectrum sources, reduced minimal erythema
doses are also often seen, except again perhaps in early, mild disease, whereas an appearance
approximating eczema or else just a confluent raised erythematous plaque may regularly occur
over the whole irradiation site. These areas may again be pruritic.
If oral or topical steroids are needed to clear any eruption at the test site before exposure,
testing should not take place until several days after their cessation, or the oral steroid dose has
been minimal for at least a few days; otherwise, false negative results will very likely occur (72).
DIAGNOSIS (TABLE 2)
CAD is initially suggested by the patient’s history and clinical appearance, assisted where
necessary by the histological features of eczema, sometimes pseudolymphomatous in severe
cases (Fig. 7). Abnormal phototest results following broad-band or monochromatic irradiation
of unaffected skin are in all cases the preferred final method of disease confirmation. Such
results were previously considered essential (1), but in early, very mild disease they may not
always be present, and diagnosis based on compelling clinical and if necessary histological
features seems acceptable in these occasional instances.
Patch and photopatch testing should be undertaken in all patients and frequently reveals
positive results to ubiquitous airborne, topical or rarely other allergens. These may have pre-
disposed to onset of the CAD, but in any case, they contribute to the clinical picture and
their avoidance is essential to optimal treatment of the patient.
In relatively rare instances where CAD is suspected but the skin sites for phototesting or
patch and photopatch testing are significantly eczematised, clearance of the eruption in a
darkened room over days to a week or two is necessary prior to testing to avoid false negative
TABLE 2 Diagnosis of Chronic Actinic Dermatitis

Clinical features Eczematous eruption of exposed areas, sometimes with
pseudolymphomatous features in severe cases
Histology of lesional skin Chronic eczema, sometimes with pseudolymphomatous features in severe
cases, rarely indistinguishable from cutaneous T-cell lymphoma
Phototest responses Irradiation monochromator: reduced 24-hr MED, papular responses to UVB
representing disease itself, usually also to UVA, rarely visible light as well;
occasionally to UVA alone; very rarely to long wavelength visible light
alone; may not be any clear abnormality in very early disease
Broad-band sources, preferably solar simulator: reduced 24-hr MED;
induction of eczema possible, sometimes smooth confluent plaque
Patch and photopatch tests Abnormalities frequently detected, often to widespread airborne allergens,
less frequently topical medications
Blood, urine, and faecal porphyrins Normal concentrations
Circulating lupus titres Normal
Abbreviations: MED, minimal erythema dose; UVA, ultraviolet A; UVB, ultraviolet B.
178 Hawk and Lim
results. If the disorder fails to settle, this makes the diagnosis of CAD unlikely. Also, as stated
above, to avoid false negative results if oral or topical steroids are used, testing should not take
place until several days after they have been stopped, or the oral steroid dose has been minimal
for at least a few days (72).
Circulating lupus titres, and if there is doubt, blood, urine, and stool porphyrins should
also be estimated but are always normal in CAD.
DIFFERENTIAL DIAGNOSIS (TABLE 3)

Contact dermatitis, especially to airborne allergens, and photocontact dermatitis may closely
resemble CAD, but can usually be largely distinguished by the clinical history and examin-
ation, or more definitively in the presence of positive patch or photopatch tests, by their
normal monochromatic irradiation tests, except at any sites of contact with the causative
agent. Clinically, contact dermatitis is not confined to the sun-exposed areas, whereas airborne
contact dermatitis usually affects exposed but also relatively photo-protected areas such as the
postauricular areas, upper eyelids, and nasolabial folds. It should be remembered, however,
that both contact, especially airborne, and photocontact dermatitis may occur in association
with CAD as additional diagnoses.
Photoaggravated atopic or seborrheic eczema may also resemble CAD but can generally
be distinguished clinically, whereas in more difficult cases, the cutaneous irradiation tests are
generally essentially normal in the light-exacerbated conditions. Again, both eczemas may
occur in association with CAD.
Erythrodermic CAD may be distinguished from other erythrodermas by its abnormal
irradiation tests, after prior clearance of the eruption in darkened conditions over days to a
week or two, essential to avoid false negative responses.
Systemic drug-induced photosensitivity may rarely suggest CAD in demonstrating an
erythema but generally not eczema of the light-exposed areas, and is usually associated with
either normal cutaneous irradiation tests or abnormalities only in the UVA range. In addition,
withdrawal of the drug normally results in steady resolution of the clinical and any phototest
abnormalities, generally rapidly but at most within a few months (73).
CTCL, including its Sézary form, may occasionally on examination and histologically be
indistinguishable from severe widespread CAD, whereas CAD patients with erythroderma
may demonstrate up to about 20% circulating Sézary cells (74). Analysis of phenotypic
markers, T-cell receptor gene rearrangement studies, and lymphocyte morphometry are all
helpful in distinguishing it from CAD (67,75). Further, clinical photosensitivity in CTCL is
TABLE 3 Differential Diagnosis of Chronic Actinic Dermatitis

Disease Distinguishing features
Allergic or photoallergic contact Normal cutaneous irradiation tests in absence of antigen, and abnormalities
dermatitis generally in UVA alone; eruption generally localized only to sites of
(photo)allergen contact
Systemic drug-induced photosensitivity Normal cutaneous irradiation tests, or abnormalities usually just in UVA
alone. Resolution of clinical and phototest abnormalities within months of
drug withdrawal; eruption usually sunburn-like, urticarial, just painful
without rash or fragile skin with bullae, not eczematous
Photoaggravated atopic eczema Usually normal cutaneous irradiation tests; other features of atopic eczema
Photoaggravated seborrheic eczema Usually normal cutaneous irradiation tests; other features of seborrheic
eczema
Erythroderma of non-CAD etiology Normal cutaneous irradiation tests undertaken after erythroderma is settled
Cutaneous T-cell lymphoma Normal cutaneous irradiation tests or usually only minor abnormalities,
predominantly in UVA
Predominance of CD4þ circulating lymphocytes (CD8þ in severe CAD)
Predominance of CD4þ lymphocytes in dermis (CD8þ in CAD)
T-cell receptor gene rearrangement studies positive
Abbreviations: CAD, chronic actinic dermatitis; UVA, ultraviolet A.
normally at most minimal, as are any phototest abnormalities, principally to the UVA wave-
lengths (76), and thus out of keeping with the clinical disease severity. On the other hand, a
recent report suggests that CTCL may very rarely be severely clinically photosensitive with
markedly positive phototests, and thus essentially indistinguishable from CAD, except
through T-cell receptor gene rearrangement studies (67), and these are always needed for
definitive differentiation of the disorders in any case of diagnostic doubt. Finally, there is gen-
erally a CD8þ circulating lymphocyte predominance in CAD, particularly when severe (29),
and a CD4þ preponderance in CTCL (77).
MANAGEMENT (TABLE 4)
CAD may often but not always be disabling and difficult to treat, imposing marked restrictions
on a patient’s lifestyle. Reduced exposure to solar ultraviolet radiation is the first line of man-
agement, time outdoors needing to be kept to a minimum whenever solar ultraviolet irradiance
is high, namely in the middle of the day in summer or all year round at low latitudes. The UVA
wavelengths, however, almost always at least partly responsible for inducing CAD, are more
difficult to avoid, being present moderately throughout the whole day and year, and severely
affected patients may need to stay indoors all day. Clothing offering high ultraviolet protection
should also be worn, generally close-weave loose-fitting clothing opaque when held up to the
light, although this may not always be so (78,79); clothing offering measured ultraviolet protec-
tion factors (UPFs) should probably be preferred when available, with high UPFs of 30 to 50
being most suitable. A broad-spectrum sunscreen offering high protection of around 50 or so
with similar maximal UVA protection should also be liberally applied to exposed skin every
hour or so during the day. Organic (i.e., chemical) and micronized inorganic (i.e., physical)
filters now often provide such protection and are preferable to the older reflectant preparations
for efficacy and cosmetic acceptability. Ultraviolet screening film applied to the windows of
home or car may also be helpful, whereas fluorescent lamps for room lighting may affect sen-
sitive patients, although tungsten bulbs, computer screens, and televisions are safe (80).
Exposure to contact allergens, particularly airborne, should also be carefully avoided,
whereas any apparent disease worsening may possibly be attributable to new contact or photo-
contact sensitization, particularly to a sunscreen (56).
All CAD needs regular treatment as for other eczemas, with emollients and usually
potent topical steroids to all affected sites; for occasional severe flares, intermittent oral
steroid courses may be necessary and helpful.
Difficult CAD, if moderate, or even occasionally severe, may sometimes settle with the
topical calcineurin inhibitors, tacrolimus (81– 83), or pimecrolimus (84), although responsive-
ness is unpredictable and they may cause annoying irritation. However, they should be tried
if the prior measures are ineffective before the use of more aggressive treatment.
TABLE 4 Management of Chronic Actinic Dermatitis

In all patients Avoidance of exposure to inducing UV wavelengths through avoidance of solar exposure when
UV intensity high, use of UV-protective clothing, regular application of non-irritant, broad-
spectrum sunscreening agents, avoidance of associated contact or photocontact allergens,
regular use of emollients, intermittent use of topical corticosteroids.
For acute flares Nursing in light-protected hospital cubicles or indoors with drawn blinds. Short-term oral
corticosteroid therapy.
In resistant cases Topical calcineurin inhibitors may occasionally be helpful.
Oral cyclosporine 3.5– 5 mg/kg/day, oral azathioprine 1–2.5 mg/kg/day, oral thioguanine
0.5–2 mg/kg/day, oral mycophenolate mofetil 15– 40 mg/kg/day, in decreasing order of
likely efficacy; careful supervision for varying possible side effects essential with each.
Therapy should be discontinued if possible in winter.
Very low-dose oral PUVA daily (with usually high-dose initial oral corticosteroid cover), gradually
reducing in frequency as resolution sets in over months; low-dose three to four-weekly
maintenance therapy likely to be necessary.
Abbreviation: PUVA, psoralen and UVA photochemotherapy.
180 Hawk and Lim
For intractable disease, either psoralen photochemotherapy (PUVA) or oral immuno-

suppressive agents may be required and are often helpful. Very low-dose PUVA is generally
gradually effective over months although often poorly tolerated in the early stages, even
under high-dose systemic steroid cover, whereas long-term maintenance therapy, possibly
just of light-exposed sites, is generally required (85,86), often only every three to four weeks.
The mode of action of PUVA is very likely through gradual cutaneous immunosuppression.
The oral immunosuppressive agent, cyclosporine, in doses of 3.5 to 5.0 mg/kg is usually
helpful within weeks if tolerated (87), as to a lesser degree is azathioprine 1.0 to 2.5 mg/kg over
several months (88). Mycophenolate mofetil 15 to 40 mg/kg may also be of benefit, but perhaps
less reliably again. Finally, thioguanine 0.5 to 2.0 mg/kg in the experience of one of the authors
(Hawk) may also help if the other drugs are not tolerated or ineffective, although care is needed
to avoid the early sudden or later gradual onset of lymphopenia. If adverse effects occur with
any of the drugs, often the case in elderly patients, two or more used in low doses may some-
times be helpful while minimizing the individual drug drawbacks.
REFERENCES
1. Hawk JLM, Magnus IA. Chronic actinic dermatitis—an idiopathic photosensitivity syndrome includ-
ing actinic reticuloid and photosensitive eczema. Br J Dermatol 1979; 101(suppl 17):24.
2. Ive FA, Magnus IA, Warin RP, et al. ‘Actinic reticuloid’: a chronic dermatosis associated with severe
photosensitivity and the histological resemblance to lymphoma. Br J Dermatol 1969; 81:469– 485.
3. Ramsay CA, Kobza-Black A. Photosensitive eczema. Trans St John’s Hosp Dermatol Soc 1973;
59:152– 158.
4. Frain-Bell W, Lakshmipathi T, Rogers J, et al. The syndrome of chronic photosensitivity dermatitis
and actinic reticuloid. Br J Dermatol 1974; 91:617– 634.
5. Wilkinson DS. Patch test reactions to certain halogenated salicylanilides. Br J Dermatol 1962;
74:302– 306.
6. Jillson OF, Baughman RD. Contact photodermatitis from bithionol. Arch Dermatol 1963; 88:409– 418.
7. Wojnarowska FT, Calnan CD, Hawk JLM. A study of patients with photocontact allergy to musk
ambrette. Br J Dermatol 1982; 107(suppl 22):22.
8. Zaynoun S, Johnson BE, Frain-Bell W. The investigation of quindoxin photosensitivity. Contact Der-
matitis 1976; 2:343– 352.
9. Yates VM, Finn OA. Contact allergic sensitivity to zinc pyrithione followed by the photosensitivity
dermatitis and actinic reticuloid syndrome. Contact Dermatitis 1980; 6:349– 350.
10. Burckhardt W. Photoallergic eczema due to blankophores (optic brightening agents). Hautarzt 1957;
8:486.
11. Hawk JLM, Magnus IA. Resolution of actinic reticuloid with transition to photosensitive eczema.
J Roy Soc Med 1978; 71:608.
12. Horio T. Actinic reticuloid via persistent light reactivity from photoallergic contact dermatitis. Arch
Dermatol 1982; 118:339– 342.
13. Lim HW, Buchness MR, Ashinoff R, et al. Chronic actinic dermatitis: study of the spectrum of chronic
photosensitivity in 12 patients. Arch Dermatol 1990; 126:317– 323.
14. Norris PG, Hawk JL. Chronic actinic dermatitis: a unifying concept. Arch Dermatol 1990;
126:376– 378.
15. Milde P, Hölzle E, Neumann N, et al. Chronic actinic dermatitis. Concept and case examples.
Hautarzt 1991; 2:617 – 622.
16. Roelandts R. Chronic actinic dermatitis. J Am Acad Dermatol 1993; 28:240 –249.
17. Norris PG, Morris J, Smith NP, et al. Chronic actinic dermatitis: an immunohistologic and photobio-
logic study. J Am Acad Dermatol 1989; 21:966– 971.
18. Orbaneja JG, Diez LI, Lozano JLS, Salazar LC. Lymphomatoid contact dermatitis. A syndrome
produced by epicutaneous hypersensitivity with clinical features and a histopathologic picture
similar to that of mycosis fungoides. Contact Dermatitis 1976; 2:139– 143.
19. Braathen LR, Førre Ø, Natvig JB. An anti-human T-lymphocyte antiserum: in situ identification of
T-cells in the skin of delayed type hypersensitivity reactions, chronic photosensitivity dermatitis,
and mycosis fungoides. Clin Immunol Immunopathol 1979; 13:211 – 219.
20. Ralfkiaer E, Lange Wantzin G, Stein H, et al. Photosensitive dermatitis with actinic reticuloid
syndrome: an immunohistological study of the cutaneous infiltrate. Brit J Dermatol 1986; 114:47– 56.
21. Takigawa M, Tokura Y, Shirahama S, et al. Actinic reticuloid: an immunohistochemical study. Arch
Dermatol 1987; 123:296– 297.
22. Toonstra H, van der Putte SCJ, Van Wichen DF, et al. Actinic reticuloid: immunohistochemical
analysis of the cutaneous infiltrate in 13 patients. Br J Dermatol 1989; 120:779.
23. Menagé H du P, Sattar N, Hawk JLM, et al. Immunophenotyping of the inflammatory cell infiltrate
during the evolution of induced lesions of chronic actinic dermatitis. J Invest Dermatol 1993;
100:482.
24. Fujita M, Miyachi Y, Horio T, et al. Immunohistochemical comparison of actinic reticuloid with
contact dermatitis. J Dermatol Sci 1990; 1:289 – 296.
25. Poulter LW, Seymour GJ, Duke O, et al. Immunohistological analysis of delayed type hypersensitivity
in man. Cellular Immunol 1982; 74:358– 369.
26. Gawkrodger DJ, McVittie E, Carr MM, et al. Phenotypic characterisation of the early cellular
responses in allergic and irritant contact dermatitis. Clin Exp Immunol. 1986; 66:590– 598.
27. Vandervleuten CJM, Kroot EJA, Dejong EMJ, et al. The immunohistochemical effects of a single chal-
lenge with an intermediate dose of ultraviolet B on normal human skin. Arch Dermatol Res 1996;
288:510– 516.
28. Kofoed ML, Munch-Petersen B, Larsen JK, et al. Non-replicative DNA synthesis detected in periph-
eral lymphocytes from a patient with actinic reticuloid. Photodermatol 1986; 3:158– 163.
29. Menagé H du P, Whittaker SJ, Ng YI, et al. Analysis of T-cell receptor genes in chronic actinic derma-
titis: no evidence of clonality. J Invest Dermatol 1992; 98:456.
30. Menagé H du P, Sattar N, Haskard DO, et al. A study of the kinetics and pattern of adhesion molecule
expression in induced lesions of chronic actinic dermatitis. Br J Dermatol 1996; 134:262– 268.
31. Norris DA, Bradley-Lyons, M, Middleton M, et al. Ultraviolet radiation can either suppress or induce
expression of intercellular adhesion molecule-1 on the surface of cultured human keratinocytes.
32. Griffiths CEM, Barker JNWN, Kunkel S, et al. Modulation of leucocyte adhesion molecules, a T-cell
chemotactin (IL-8), and a regulatory cytokine (TNF-a) in allergic contact dermatitis (rhus dermatitis).
Br J Dermatol 1991; 124:519.
33. Norris PG, Poston RN, Thomas DS, et al. The expression of endothelial leukocyte adhesion molecule-
1 (ELAM-1), intercellular adhesion molecule-1 (VCAM-1) in experimental cutaneous inflammation: a
comparison of ultraviolet B erythema and delayed type hypersensitivity. J Invest Dermatol 1991;
96:763– 770.
34. Menagé H du P, Kristensen M, Chu CQ, et al. Upregulation of interleukin 1, its receptor and interleu-
kin 1 receptor antagonist levels in induced lesions of chronic actinic dermatitis. Br J Dermatol 1992;
127:429.
35. Kochevar IE, Harber LC. Photo-reactions of 3,3’,4’,5’-tetrachlorsalicylanilide with proteins. J Invest
Dermatol 1977; 68:151 –156.
36. Addo HA, Ferguson J, Johnson BE, Frain-Bell W. The relationship between exposure to fragrance
materials and persistent light reaction in the photosensitivity dermatitis with actinic reticuloid syn-
drome. Br J Dermatol 1982; 107:261– 274.
37. Robinson HN, Morison WL, Hood AF. Thiazide diuretic therapy and chronic photosensitivity. Arch
Dermatol 1985; 121:522– 524.
38. van de Pas CB, Kelly DA, Seed PT, et al. Ultraviolet-radiation-induced erythema and suppression of
2004; 122:295– 299.
39. Murphy GM, White IR, Hawk JLM. Allergic airborne contact dermatitis to Compositae with photo-
sensitivity: chronic actinic dermatitis in evolution. Photodermatol Photoimmunol Photomed 1990;
7:38– 39.
40. Roelandts R, Huys I. Broad-band and persistent photosensitivity following accidental ultraviolet C
overexposure. Photodermatol Photoimmunol Photomed 1993; 9:144– 146.
41. Menagé H du P, Harrison GI, Potten CS, et al. The action spectrum for induction of chronic
actinic dermatitis is similar to that for sunburn inflammation. Photochem Photobiol 1995;
62:976– 979.
42. Freeman SE, Hacham H, Gange RW, et al. Wavelength dependence of pyrimidine dimer formation in
DNA of human skin irradiated in situ with ultraviolet light. Proc Natl Acad Sci USA 1989; 86:5605–
5609.
43. Patel DC, McGregor JM, Ross JS, Hawk JLM. UVA associated eczematous photosensitivity and mul-
tiple contact allergies: a further form of chronic actinic dermatitis? Br J Dermatol 1998; 139(suppl
51):27.
44. Yones SS, Palmer RA, Hextall JM, Hawk JL. Exacerbation of presumed chronic actinic dermatitis by
cockpit visible light in an airline pilot with atopic eczema. Photodermatol Photoimmunol Photomed
2005; 21:152– 153.
45. Sepulveda-Merrill C, Menagé H du P, Hawk JLM, et al. Functional studies of antigen presentation in
induced lesions of chronic actinic dermatitis. J Invest Dermatol 1994; 102:603.
46. Ferguson J. Photosensitivity dermatitis and actinic reticuloid syndrome (chronic actinic dermatitis).
Semin Dermatol 1990; 9:47– 54.
47. Menagé H du P, Ross J, Hawk JLM, et al. Contact and photocontact sensitisation in chronic actinic
dermatitis: sesquiterpene lactone mix is an important allergen. Br J Dermatol 1995; 132:543– 547.
182 Hawk and Lim
48. Kurumaji Y, Kondo S, Fukuro S, et al. Chronic actinic dermatitis in a young patient with atopic der-
matitis. J Am Acad Dermatol 1994; 31:667– 669.
49. Wong SN, Khoo LSW. Analysis of photodermatoses seen in a predominantly Asian population at a
photodermatology clinic in Singapore. Photodermatol Photoimmunol Photomed 2005; 21:40 – 44.
50. Lim HW, Morison WL, Kamide R, et al. Chronic actinic dermatitis: an analysis of 51 patients evalu-
ated in the United States and Japan. Arch Dermatol 1994; 130:1284– 1289.
51. Pappert A, Grossman M, DeLeo V. Photosensitivity as the presenting illness in four patients with
human immunodeficiency viral infection. Arch Dermatol Res 1994; 130:618– 623.
52. Meola T, Sanchez M, Lim HW, Buchness MR, Soter NA. Chronic actinic dermatitis associated with
human immunodeficiency virus infection. Br J Dermatol 1997; 137:431– 436.
53. Sharma VK, Sethuraman G, Bhat R. Evolution of clinical pattern of parthenium dermatitis: a study of
74 cases. Contact Dermatitis 2005; 53:84 – 88.
54. Addo HA, Sharma SC, Ferguson J, et al. A study of Compositae plant extract reactions in photosen-
sitivity dermatitis. Photodermatol 1985; 2:68– 79.
55. Frain-Bell W, Hetherington A, Johnson BE. Contact allergic sensitivity to chrysanthemum and the
photosensitivity dermatitis and actinic reticuloid syndrome. Br J Dermatol 1979; 101:491 –501.
56. Green C, Catterall M, Hawk JLM. Chronic actinic dermatitis and sunscreen allergy. Clin Exp Derma-
tol 1991; 16:70 – 71.
57. Thune P. Allergy to lichens with photosensitivity. Contact Dermatitis. 1977; 3:213– 214.
58. von den Driesch P, Fartasch M, Hornstein OP. Chronic actinic dermatitis with vitiligo-like depigmen-
tation. Clin Exp Dermatol 1992; 17:38– 43.
59. Dawe RS, Crombie IK, Ferguson J. The natural history of chronic actinic dermatitis. Arch Dermatol
2000; 136:1215– 1220.
60. Ashinoff R, Buchness MR, Lim HW. Lymphoma in a black patient with actinic reticuloid treated with
PUVA: possible etiologic considerations. J Am Acad Dermatol 1989; 21:1134– 1137.
61. Jensen NE, Sneddon IB. Actinic reticuloid with lymphoma. Br J Dermatol 1970; 82:287– 291.
62. Meynadier J, Peyron JI, Barneon G, et al. Hodgkin’s disease complicating actinic reticulosis. Ann
Dermatol Venereol 1984; 111:999.
63. Thomsen K. The development of Hodgkin’s disease in a patient with actinic reticuloid. Clin Exp
Dermatol 1977; 2:109– 113.
64. Tan RS, Butterworth CM, McLaughlin H, et al. Mycosis fungoides—a disease of antigen persistence.
Brit J Dermatol 1974; 91:607– 616.
65. Bilsland D, Crombie IK, Ferguson J. Is the photosensitivity dermatitis/actinic reticuloid syndrome
associated with cutaneous lymphoma? Br J Dermatol 1993; 129(suppl 42):42.
66. Sigurdsson V, Toonstra J, Hezemans-Boer M, et al. Erythroderma. A clinical and follow-up study of
102 patients, with a special emphasis on survival. J Am Acad Dermatol 1996; 35:53 – 57.
67. Norris PG, Newton JA, Camplejohn RS, et al. A flow cytometric study of actinic reticuloid. Clin Exp
Dermatol 1989; 14:128– 131.
68. Morris SD, Hawk JLM, Russell-Jones R, Whittaker SJ. Severe photosensitivity in four patients with
erythrodermic cutaneous T-cell lymphoma. Br J Dermatol 2002; 147(suppl 62):36– 37.
69. Hawk JLM, Calonje E. The photosensitivity disorders. In: Elder DE, Elenitsas R, Johnson Jr BL,
Murphy GF, eds. Lever’s Histopathology of the Skin. 9th ed. Philadelphia, Pennsylvania: Lippincott
Williams and Wilkins, 2005:345– 353.
70. Heller P, Wieczorek R, Waldo E, et al. Chronic actinic dermatitis: An immunohistochemical study of
its T cell antigenic profile with comparison to cutaneous T cell lymphoma. Am J Dermatopath 1994;
16:510– 516.
71. Healy F, Rogers S. Photosensitivity dermatitis/actinic reticuloid syndrome in an Irish population: a
review and some unusual features. Acta Dermatovenereol (Stockh). 1995; 75:72– 74.
72. Lowe JG, Ferguson J. A double blind control study to assess the effect of pre-treatment with a potent
topical steroid on the phototest response of photosensitivity dermatitis and actinic reticuloid syn-
drome (PD/AR). Scot Med J 1989; 34:509.
73. Bilsland D, Ferguson J. Management of chronic photosensitive eczema. Arch Dermatol 1991;
127:1065– 1066.
74. Neild VS, Hawk JLM, Eady RAJ, et al. Actinic reticuloid with Sézary cells. Clin Exp Dermatol 1982;
7:143– 148.
75. Preesman AH, Schrooyen SJ, Toonstra J, et al. The diagnostic value of morphometry in blood lympho-
cytes in erythrodermic actinic reticuloid. Arch Dermatol 1995; 131:1298– 1303.
76. Volden G, Thune PO. Light sensitivity in mycosis fungoides. Br J Dermatol 1977; 97:279 – 284.
77. Chu AC, Robinson D, Hawk JLM, et al. Immunologic differentiation of the Sézary syndrome due to
cutaneous T-cell lymphoma and chronic actinic dermatitis. J Invest Dermatol 1986; 98:134 – 137.
78. Davis S, Capjack L, Kerr N, et al. Clothing as protection from ultraviolet radiation: which fabric is
most effective? Int J Dermatol 1997; 36:374– 379.
79. Gambichler T, Rotterdam S, Altmeyer P, Hoffmann K. Protection against ultraviolet radiation by com-
mercial summer clothing: need for standardised testing and labelling. BMC Dermatol 2001; 1:6.
80. Moseley H, Johnston S, Susskind W. Is viewing television harmful to actinic reticuloid patients?
Photodermatol 1989; 6:191– 193.
81. Uetsu N, Okamoto H, Fujii K, et al. Treatment of chronic actinic dermatitis with tacrolimus ointment.
J Am Acad Dermatol 2002; 47:881 –884.
82. Evans AV, Palmer RA, Hawk JLM. Erythrodermic chronic actinic dermatitis responding only topical
tacrolimus. Photodermatol Photoimmunol Photomed 2004; 20:59 – 61.
83. Grone D, Kunz M, Zimmermann R, Gross G. Successful treatment of nodular actinic reticuloid with
tacrolimus ointment. Dermatology 2006; 212:377– 380.
84. Larangeira de Almeida H Jr. Successful treatment of chronic actinic dermatitis with topical pimecro-
limus. Int J Dermatol 2005; 44:343– 344.
85. Hindson C, Spiro J, Downey A. PUVA therapy of chronic actinic dermatitis. Br J Dermatol 1984;
113:157– 160.
86. Hindson C, Downey A, Sinclair S, et al. PUVA therapy of chronic actinic dermatitis: a 5 year follow-
up. Br J Dermatol 1990; 123:273.
87. Norris PG, Camp RDR, Hawk JLM. Actinic reticuloid: response to cyclosporin. J Am Acad Dermatol
1989; 21:307– 309.
88. Murphy GM, Maurice PM, Norris PG, et al. Azathioprine in the treatment of chronic actinic derma-
titis: a double-blind controlled trial with monitoring of exposure to ultraviolet radiation. Br J Derma-
tol 1989; 121:639– 646.
13 Solar Urticaria
Takeshi Horio
Department of Dermatology, Kansai Medical University, Osaka, Japan
Erhard Hölzle
Department of Dermatology and Allergology, Klinikum Oldenburg, Oldenburg, Germany
B Solar urticaria is an uncommon type of physical urticaria; the action

spectrum ranges from UVB to visible light. It is most probably a type I
allergic reaction to an as yet to be defined photoallergen.
B Spectrum of electromagnetic radiation that could inhibit, or augment,

the development of solar urticaria is present in many patients.
B Exogenous agents such as tar and pitch, benoxaprofen, repirinast,

and chlorpromazine have been reported to cause solar urticaria in rare
instances.
B Association with PMLE, chronic actinic dermatitis, atopy, and elevated

IgE has been reported in some studies.
B The course is chronic; 15% to 50% of patients are clear of disease within
five years of the onset.
B Management includes photoprotection, oral antihistamines,

desensitization with UVA or psoralen and UVA, cyclosporine,
plasmapheresis, and photopheresis.
186 Horio and Hölzle
rticaria is an extremely common disease that appears in 15% to 20% of the general popu-
U lation at some time in their lives (1). Among them, however, solar urticaria is a relatively
rare type of physical urticaria. As Magnus (2) stated, the practicing clinician might expect
to have an opportunity to see three or four patients in a professional lifetime. The present
authors have seen about 100 patients with solar urticaria so far during the past 30 years.
Careful and detailed examinations may reveal more cases than expected. The diagnosis of
solar urticaria can be easily made from its characteristic features, although the causative
factors, similar to other types of urticaria, are rarely found. Patients themselves usually recog-
nize sunlight as a provocative agent. Wheal reaction can be easily reproduced in most patients
with physical urticaria including solar urticaria. In this chapter, solar urticaria will be discussed
focussing mainly on the pathomechanism of the disease.
DEMOGRAPHY
Patients with solar urticaria have been reported throughout the world without specific racial
and geographic limitations. Forty-two Japanese and 31 German patients were extensively eval-
uated from 1973 to 2002 in our photodermatology sections. Table 1 shows the sex and age
distribution at the onset of the disease. Thirty-nine (63%) of the subjects were female and 23
(37%) were male. Consistent with our findings, a slight preponderance in women has also
been described in the literature. The onset is most common (43%) during the third decade in
this series. All but two patients were less than 60 years old at the onset of solar urticaria.
The earliest and the latest ages of onset were 13 and 73 years, respectively. In contrast, in 4
of 27 (15%) patients of Frain-Bell’s cohort, the disease developed before the age of 10 years
(3). To the best of our knowledge, there have been no familial or hereditary cases reported.
CLINICAL MANIFESTATIONS
Solar urticaria develops at the site of exposure to sunlight usually within a few minutes. Very
rarely, it may appear a few hours after irradiation. Solar urticaria begins as an itching or
burning sensation along with erythema and wheal. When the exposure time is short, the
wheal may be minimal or absent, and only erythema of short duration develops. Within a
few hours, the urticaria disappears completely without any residual skin changes, similar to
other types of urticaria. When large areas of the body are exposed to sunlight for a long
period of time, systemic symptoms can occur, such as dizziness, sleepiness, wheezing,
dyspnea, and syncope. Seven of 61 patients in our series had experienced dyspnea and
syncope following exposure of larger areas of the skin.
Regularly sun-exposed skin, such as the face, dorsal aspects of the hands, and extensor
aspects of the forearms, are often less sensitive than are covered body areas due to a hardening
phenomenon. In summer, solar urticaria may develop on covered parts of the body as a result
of small amounts of UV radiation or visble light penetrating thin clothing. In visible light
sensitive patients, artificial room light can produce urticaria.
TABLE 1 Disease Onset of 61 Japanese and German Patients with Solar Urticaria
Age of onset Number of cases Male Female
0– 9 0 0 0
10– 19 9 2 7
20– 29 23 11 12
30– 39 11 6 5
40– 49 6 2 4
50– 59 10 2 8
60– 69 1 0 1
70– 79 1 0 1
80 and above 0 0 0
Total 61 23 38
Solar Urticaria 187
In Europe, an uncommon variant of solar urticaria was described in which whealing

occurred in a patchy pattern strictly localized to the same circumscribed skin areas (4,5).
In these patients, wheals were reproducible in their pattern and location by eliciting radiation;
the action spectra ranged 320 to 700 nm, 320 to 585 nm, and 400 to 560 nm, respectively.
Intradermal injections of the patient’s plasma following in vitro irradiation induced wheals
only in the affected skin sites. For this subset of solar urticaria, the term “fixed solar urticaria”
has been proposed. It is hypothesized that differences in the mast cell population of afflicted
and nonafflicted skin sites account for the peculiar distribution pattern of lesions, since
even the in vitro photo-activated serum or plasma of the patients containing the putative
photoallergen failed to induce whealing in nonafflicted skin. Mast cells in affected skin
sites contained numerous lipid bodies within the cytoplasm and were conspicuously
devoid of association to fibrocytes as revealed by electron microscopical studies.
The fixed variant of solar urticaria seems to be associated with only a moderate degree of
photosensitivity. The patients are usually able to manage their disease by themselves.
Graduated exposures to natural sunlight induce hardening. Systemic symptoms are absent,
probably due to the relatively small skin areas involved and the consequently small amount
of mediators released. Thus, the patients are not dependent on medical assistance and this
variant may be largely under-reported.
PHOTO-PROVOCATION AND ACTION SPECTRUM TESTS

When the patients visit dermatologists, skin changes of solar urticaria are not always
observed. Therefore, to make an accurate diagnosis, urticaria reaction should be provocated
by exposure to UV and visible light; however, whole body exposures must be avoided,
since sycope may be an unwanted consequence. It is also important to determine the
action spectrum for protection and treatment of solar urticaria. For experimental induction
and action spectrum studies, we usually use a conventional slide projector for visible light
source, fluorescent black light for UVA, and sunlamp as UVB source (Fig. 1). However, it
should be kept in mind that the black light and sunlamp also emit a small amount of UVB
and UVA, respectively.
Although the clinical features of solar urticaria are almost identical in all patients, the
eliciting wavelengths (action spectra) are different among cases, ranging from UVB to visible
light. This suggests that chromophores or photosensitizers responsible for solar urticaria are
not uniform in all patients. We determined the action spectrum in 42 Japanese and in 31
German patients (Table 2). Among the Japanese group, 24 patients (57%) were sensitive only
to visible light, which was the most common action spectrum in our series. Further studies
using cut-off glass filters showed that the activating waveband occurs most often in a 400 to
500 nm region.
FIGURE 1 Urticaria following exposure to visible

light. Note lesion also developed in area covered
with one layer of clothing during the
phototesting (e.g., antecubital fossa). Source:
Courtesy of Henry W. Lim, MD.
TABLE 2 Action Spectrum of Solar Urticaria

Action spectrum Number of cases Male Female
In 42 Japanese patients
Visible light 24 12 12
UVA–visible 3 1 2
UVA 4 1 3
UVB 4 0 4
UVB–UVA 3 1 2
UVB–UVA– visible 4 2 2
Total 42 17 25
In 31 German patients
Visible light 6 — 6
UVA–visible 7 4 3
UVA 6 3 3
UVB — — —
UVB–UVA 8 2 6
UVB–UVA– visible 4 3 1
Total 31 12 19
In contrast, patients in Germany and other European countries have been reported to be
activated most frequently by UV radiation. Table 2 shows the German data also. Six patients
(19%) react to visible light only, all others to various parts of the UV spectrum with a prepon-
derance for the UVA part. The majority (77%) of patients in Scotland reported by Frain-Bell
reacted to a wide spectrum from UVB to visible light, and only 5 of 26 (19%) patients responded
to visible light alone (3). In contrast, only 4 of the 42 patients seen in Japan, and 4 of the
31 patients seen in Germany, reacted across the spectrum from UVB to visible light. (Table 2)
In a series of 25 cases reported from Belgium, five patients (20%) responded only to visible
light (6). Although no specific explanation is available, there may be some geographical or eth-
nical differences in action spectrum of solar urticaria.
A wheal usually develops within 5 to 10 minutes after termination of the irradiation.
However, in rare instances, urticaria may only appear hours after irradiation (7). The
delayed onset of solar urticaria after light exposure may be due to the influence of an inhibition
spectrum, which will be discussed later.
The activating wavelengths have been reported to vary from time to time with repeated
phototesting in a few patients (8– 10). The threshold dose to induce urticaria often varies
depending on the time of the photo-provocation test and the test site. This most likely is due
to the state of tolerance induced by repetitive irradiations.
INHIBITION SPECTRUM
An inhibition spectrum was first demonstrated in solar urticaria over 20 years ago (11). In
this case, wheal formation induced by visible light was inhibited by immediate post-
irradiation with longer wavelengths (.530 nm) than the action spectrum (400 –500 nm).
This phenomenon is not uncommon, and thereafter, similar cases have been further reported
by other investigators. We have found the inhibition spectrum in 13 of 42 patients so far
(Table 3). Wavelengths of inhibition spectrum were longer than those of action spectrum
in all but one case (Patient 10). Inhibition spectra shorter than the activating one have been
also reported by other authors (12). In 8 of 13 patients in our series, wheal formation
was inhibited only when the skin was exposed to action spectrum and then to inhibition spec-
trum (postexposure). In four patients, exposures before and after exposure (pre- and postex-
posure) to the action spectrum showed inhibitory effect. In one patient, only pre-exposure
was effective.
In some patients, only monochromotic radiation but not broadband spectrum can
induce urticaria. In such instances, the broadband spectrum may include an inhibition
spectrum. This could also be the explanation for urticaria reaction that appears with a long
latent time after irradiation.
Solar Urticaria 189
TABLE 3 Inhibition Spectrum in Solar Urticaria

Action Inhibition
Patient spectrum (nm) spectrum (nm) Pre or posta
1 400– 500 .550 Post
2 400– 500 .550 Post
3 380– 500 .500 Post
4 320– 420 .550–600 Pre- and post
5 400– 500 500– 600 Post
6 400– 500 .550 Post
7 400– 490 .550 Pre- and post
8 400– 490 500– 520 Post
9 300– 400 .400 Pre and post
10 400– 430 320– 400 Pre-
11 300– 320 .320 Pre- and post
12 300– 380 400– 500 Post
13 320– 480 .500 Post
a
Pre- or post-inhibition spectrum exerted its effect when irradiation was performed before or after
exposure to the action spectrum, respectively.
The mechanism of inhibition has not been elucidated. In our examinations, the
inhibition spectrum did not suppress the wheal formation induced by an intradermal injec-
tion of compound 48/80 or polymyxin B sulfate, mast cell degranulators (13). Therefore, it
is unlikely that the inhibition spectrum suppresses mast cell degranulation or inactivation
of released chemical mediators. An effect on vascular responses to chemical mediators
is not likely also, since a wheal formation by histamine injection was not affected by exposure
to the inhibition spectrum. In one patient, we observed that the photoallergen, which will
be discussed later, produced by action spectrum was apparently inactivated by a subsequent
exposure to the inhibition spectrum (13). Leenutaphong et al. (12) also described the similar
reaction. However, it is difficult to evaluate the test, because the results were not always
reproducible even in the same patient or were negative in other patients.
AUGMENTATION SPECTRUM
During the examination for an inhibition spectrum, we found that wavelengths apart from
the action spectrum could enhance the wheal development, but by itself were ineffective
(14). The action spectrum in this patient was defined in the 320 to 420 nm range using a
monochromator. An exposure to longer wavelengths at 450 or 500 nm increased the reaction
to 320 to 420 nm before but not after the irradiation with the action spectrum. Therefore,
irradiation at 450 to 500 nm showed an augmentative rather than an additive effect with
320 to 420 nm light. If additive, the post-irradiation exposure should have the same effect
as the pre-irradiation exposure. This theory was further supported by the observation that
a monochromatic light of 450 nm showed a stronger enhancing effect than that of 360 nm,
the peak of the action spectrum at the same irradiation dose. An augmentation spectrum
was recognized only in 4 of 14 cases examined (29%). Interestingly, in one of these, longer
wavelengths than the action spectrum showed both augmentative and inhibitory effects
when exposed before and after the irradiation with the activating waveband (15). Danno
and Mori (16) also reported two cases with augmentation spectrum. In their patients,
however, only postirradiation but not preirradiation with the augmentation spectrum
enhanced urticaria reactions.
In some patients with solar urticaria, a large amount of light dose is needed to
induce an urticaria reaction from artificial light sources, whereas the urticaria can be easily
produced by the natural sunlight. In such cases, the augmentation spectrum may play an
important role in the development of clinical manifestations. The mechanism of the augmen-
tation phenomenon has not been clarified. Various wavelengths simultaneously may
exert complicated activating, inhibiting, and augmentating effects on wheal formation in
solar urticaria.
PASSIVE TRANSFER
At the present time, the transfer of patients’ sera to normal subjects is not ethical, because this
test may transfer not only allergic reactions but also viral diseases. Until the 1970s, however,
many important information for understanding immunological reactions had been obtained
from passive transfer tests.
In 1942, Rajka (17) first demonstrated that solar urticaria could be passively transferred to
normal subjects by means of an intradermal injection of serum from a patient and subsequent
light exposure of injected skin (17). The passive transfer test in solar urticaria is a modification
of the Prausnitz– Küstner technique classically used in immediate hypersensitivity reactions.
Therefore, a positive result suggests that a specific IgE antibody to the urticaria development
may exist in the patient’s serum. In the passive transfer of this type, an incubation period of
at least a few hours is needed between the injection of the patient’s serum and antigen chal-
lenge. During this period, IgE antibody seems to adhere to the surface of mast cells. The orig-
inal work by Rajka (17) showed that the incubation time was also necessary for the positive
passive transfer reaction in solar urticaria. Kojima et al. (18) found that positive results were
obtainable from the passive transfer test at two to six hours after the injection of serum,
whereas the results were negative when the injection sites were irradiated at 30 minutes.
These observations indicate that the positive reaction could not be due to a phototoxic sub-
stance in the patient’s serum. An intradermal injection of a phototoxic substance can
produce a wheal even if light exposure is administered immediately after the injection (19,20).
Rajka tried reverse passive transfer, by first exposing the skin of normal subjects and
subsequently injecting the patient’s serum to the irradiated skin; he obtained a negative
result. In contrast, Epstein (21) reported reverse passive transfer with a positive result as
well as passive transfer test. He assumed that the antigen of the urticaria reaction might be a
normal photoproduct made in human skin by UVB radiation. However, the mechanism of
a positive reverse passive transfer cannot be explained by IgE-mediated hypersensitivity, in
which the antibody must be injected in the recipients at least a few hours before the antigen
challenge. An explanation of this phenomenon could be the hypothesis of a type II solar urti-
caria in which the presumable precursor of the photoallergen as well as the photoallergen
generated by irradiation occurs in both patients and normal subjects (22). In contrast, in type
I solar urticaria, the precursor is apparently an abnormal endogenous substance present
only in the patient.
PHOTOALLERGEN
The responsible photosensitizer has not been clearly identified in solar urticaria. Most patients
develop an urticaria reaction at the site of injection of autologous serum, which has been
previously irradiated in vitro with the action spectrum (Fig. 2) (23 – 26). This indicates that
the wheal-forming factor is a substance that is produced by electromagnetic radiation energy
in the patient’s serum. The irradiated patient’s serum does not produce the urticaria reaction
in normal subjects. Therefore, the photoresponse is specific to the patients with solar urticaria;
in other words, it may not be a phototoxic reaction. This is supported by positive passive trans-
fer test, as described above. The results of serum examination are summarized in Table 4. In the
Japanese study population, such a photoallergen was detected in 26 of 33 patients (79%) with
any type of action spectrum (Table 5); similar data with 16 positive results in 26 patients (62%)
were obtained from the German patients (Table 5).
After sunlight exposure, some patients developed easily or strongly a wheal at the skin
which had received a bruise or puncture by injection needle. This might be due to the extrava-
sation of serum into the skin by the physical trauma. This localized whealing is similar to but
not identical with that in fixed solar urticaria reported by Reinauer et al. (4). Using ultrafiltra-
tion technique, we indicated that a serum factor with molecular weight more than 100 kDa
might be transformed to the photoallergen after irradiation, in a patient sensitive to 400 to
500 nm radiation (24). In another patient, whose action spectrum ranged from UVA to
480 nm, the molecular weight was more than 300 kDa (15). However, Kojima et al. (18) reported
that the molecular weight of the wheal-forming serum factor produced by light exposure was
Solar Urticaria 191
FIGURE 2 In vitro-irradiated autologous serum produced a

wheal on a patient’s skin.
25 to 45 kDa in three patients and 300 to 1000 kDa in one patient after gel filtration. Substances
investigated in the serum differ between these two studies, in that chromophores were ana-
lyzed by us but photoproducts by Kojima et al. These examinations of molecular weight
suggest that the photoallergens are not simple chemical substances with low molecular
weight, although they vary among patients possibly depending upon the action spectra. The
photoallergen can keep its wheal-forming ability after freezing and thawing.
Taking these results together, solar urticaria may be an immediate type of photoallergic
reaction mediated by an IgE antibody to photoproducts of endogenous serum factors.
DRUG-INDUCED SOLAR URTICARIA

Solar urticaria may be an autoimmune disease, which is induced by endogenous factors. Very
rarely, however, a solar urticaria-like phototoxic reaction can be induced by exogenous chemi-
cal substances, including tar and pitch (27), benoxaprofen (28), and repirinast (29). Chlorpro-
mazine (CPZ) is also a phototoxic drug, but has been proved to be able to induce solar
urticaria by immediate type of photoallergic reaction (30). In this case, the usual passive trans-
fer study with the patient’s serum and UVA was negative, but a modified technique produced a
positive result. A wheal appeared immediately after UVA exposure at the site that had been
injected with the patient’s serum and subsequently with CPZ 24 hours later (Table 6). This is
not a phototoxic reaction, because the injection of CPZ and subsequent exposure to UVA at
TABLE 4 Serum Examination in Solar Urticaria

Recipient Injected serum Response
Patient Nonirradiated patient’s serum (2)
In vitro-irradiated patient’s serum (þ)
Nonirradiated normal serum (þ) or (2)!(2)
In vitro-irradiated normal serum (2)!(þ) or (2)
Normal control Nonirradiated normal serum (2)
In vitro-irradiated normal serum (2)
Non irradiated patient’s serum (2)
In vitro-irradiated patient’s serum (2)
In vivo-irradiated patient’s serum (passive transfer test) (þ)
TABLE 5 Serum Photoallergen in Patients with Solar Urticaria

Action spectrum Number tested (þ) (2)
Japanese
Visible light 18 15 3
UVA– visible 3 3 0
UVA 2 1 1
UVB 4 3 1
UVB– UVA 3 3 0
UVB– UVA–visible 3 1 2
Total 33 26 7
German
Visible light 5 3 2
UVA– visible 6 5 1
UVA 6 5 1
UVB — — —
UVB– UVA 6 2 4
UVB– UVA–visible 3 1 2
Total 26 16 10
the same dose did not produce any reaction, but the presence of the patient’s serum (antibody)
was essential for the positive result.
CHEMICAL MEDIATORS
Some investigators have found elevated histamine levels in venous blood draining the skin in
which urticaria had been induced (31,32), whereas others were unable to detect histamine and
kinins in dermal perfusates (33). We measured plasma histamine levels by radioimmunoassay
in a severe case of solar urticaria (15). The histamine level greatly increased after an exposure to
visible light on a limited area of the forearm and reached more than 100 times the preexposure
level in five minutes.
HISTOPATHOLOGY
Histopathological findings of solar urticaria are essentially identical to those of nonphotosen-
sitive urticaria. There is edema in the upper and mid-dermis resulting in separation of the
connective tissue. A minimal to moderate perivascular infiltrate, consisting of neutrophils,
mononuclear cells, and sometimes a few eosinophils, is found. Norris et al. (34) observed his-
tological alterations in urticaria lesions at five minutes to 24 hours after provocation by action
spectrum radiation at various doses, ranging from 2 to 32 minimal whealing doses (MWDs).
They found a significant increase in neutrophil and eosinophil numbers in the upper dermis
at five minutes and two hours, but not at 24 hours, in a dose-dependent manner.
The number of mononuclear cells did not change after an exposure to two MWDs at any
time interval; however, after exposure to 32 MWDs, the number of mononuclear cells increased
noticeably at 24 hours. Eosinophil degranulation associated with deposition of eosinophil
major basic protein has been reported in solar urticaria (35). Armstrong et al. (36) observed his-
tological findings of leukocytoclastic vasculitis, including dense infiltration of neutrophils,
TABLE 6 Passive Transfer of Immediate Drug Photoallergy

Serum Drug UVA Wheal
Patient (þ) (þ) (þ)
Patient (þ) (2) (2)
Patient (2) (þ) (2)
— (þ) (þ) (2)
Normal (þ) (þ) (2)
Solar Urticaria 193
nuclear dusts, and endothelial cell swelling, in a patient with unusual solar urticaria that
appeared a few hours after exposure and persisted for days.
Sequential ultrastructural analysis demonstrated margination and activation of platelets,
formation of interendothelial clefts, and alteration of nerve fibers as primary events in solar
urticaria, preceding mast cell degranulation. Mediators other than histamine are most probably
involved in the early stage of solar urticaria. Once the wheal is formed, mast cell degranulation
is evident by dissolution of granular matrix, fusion of perigranular membranes including
labyrinth formation and opening to the extracellular space. This is followed by extravasation
of eosinophils, erythrocytes, and neutrophils. Nerve fibers, which initially demonstrate
partial swelling, then show edema of endoneurium (37).
COEXISTING DISEASES
Solar urticaria usually occurs in otherwise healthy persons, but rarely is associated with other
photosensitivity diseases. In a study of 87 patients with solar urticaria from Scotland, 23% had
polymorphous light eruption (PMLE) and 3% had chronic actinic dermatitis (38). Two patients in
our series had coexisting PMLE. Magnus et al. (39) reported a patient with erythropoietic proto-
porphyria associated with features of solar urticaria. The patient developed a wheal immediately
after the sunlight exposure, whereas edematous erythema with burning sensation, blisters, and
scars, which are the typical manifestations of erythropoietic protoporphyria, were delayed. No
additional case has been reported, and the authors have not seen such a patient. It is our opinion
that this patient had erythropoietic protoporphyria with urticarial symptoms rather than solar urti-
caria sensu strictu. More recently, a patient with coexisting porphyria cutanea tarda and solar urti-
caria was reported (40). Although porphyrin is a phototoxic substance that is activated by visible
light, solar urticaria is not observed in the vast majority of patients with porphyrias. Frain-Bell
recorded two patients with solar urticaria that occurred in association with lymphocytoma (3).
There are sporadic case reports of solar urticaria associated with other physical urticarias including
cold urticaria (41), dermographism (14,41), heat urticaria (42), and pressure urticaria (43).
In our series, patients with solar urticaria lacked atopic dermatitis, and their total IgE
levels were normal. Frain-Bell also found both personal and family history of atopy only in
a minority of patients and stated that solar urticaria was not associated with an atopic back-
ground (3). In contrast, 12 of 25 (48%) Belgian patients in Ryckaert and Roelandts’ (6) survey
had a personal history of atopy such as asthma, hay fever, or atopic dermatitis. A study of
57 patients from Italy reported the occurance of atopic dermatitis in 21% of the patients,
asthma or rhinitis in 26%, and elevated serum immunoglobulin in 33% (42).
CLINICAL COURSE
The clinical course of solar urticaria is usually chronic and rather unpredictable. In the Japanese
patients followed by one of the authors, the disease had lasted for 5 to 10 years before consul-
tation in 7 of 42 patients and more than 10 years in five patients. Similarly, many of the patients
studied by Ryckaert and Roelandts (6) had the disease for 4 to 11 years before consultation.
Follow-up study has not been done in our series. In the Frain-Bell’s cohort, only 2 of 30
patients cleared completely (5). Five of 13 patients followed by Harber et al. (44) in the USA under-
went spontaneous remission after an average of 4.5 years following the onset of the disease. Nearly
half of the 57 patients reported from Italy were free of disease within five years of the onset of
disease (42). On the basis of a study of 87 patients, the group in Scotland estimated that the prob-
ability of disease resolution is 15%, 24%, and 46% in 5, 10, and 15 years, respectively (38).
TREATMENT
Multiple modalities need to be used since specific therapy is not available for solar urticaria
(Table 7). For the treatment of urticaria, the prevention of its development is required, since
the wheal, once appeared, spontaneously subsides in a short time.
Broadband sunscreening agents that contain both UVA and UVB filters are somewhat
helpful for UV-sensitive patients, but have little effect for patients who react to visible light.
TABLE 7 Therapeutic Ladder in Solar Urticaria

Photoprotection
Broad-spectrum sunscreen
Clothing
Wide-brimmed hat
Oral antihistamines
Desensitization/hardening
UVA
PUVA
Cyclosporine (3 –5 mg/kg/day)
Plasmapheresis
Extracorporeal photochemotherapy (photopheresis)
In these cases, self-tanning agents containing dihydroxyacetone may be of some help. Photo-
protection by the use of clothing, wide-brimmed hat, and gloves is an important measure to
prevent wheal development.
Oral histamine H1 receptor antagonists have a beneficial effect to some degree in redu-
cing the whealing and itching in patients with solar urticaria. Terfenadine, at doses higher
than the conventional dose (up to 360 mg per day), has been reported to be effective (45,46).
We observed that oral administration of terfenadine, 60 mg three times per day for three
days, partially suppressed the histamine release in plasma after light exposure of a patient’s
skin (15). However, high-dose terfenadine must be used with caution because of the risk of
life-threatening cardiac arrhythmias.
Other forms of antihistamines have also been widely used and reported to be at least
partially effective (38,42). The new generation of histamine H1 receptor blocking agents,
such as desloratadine and levocetiricine, are well tolerated and can be given in higher doses.
Even if they are not sufficient to control solar urticaria by themselves, they are very helpful
agents for combination therapy, For example, with broad-spectrum sunscreens, if the patient’s
action spectrum is in the UV region.
It is well known that the so-called “desensitization” or “hardening” can often occur in
patients with solar urticaria. Skin constantly exposed to the sunlight and an area in which urti-
caria has recently been produced are tolerant to subsequent irradiation. Broadband UVA is the
most commonly used radiation source in inducing hardening in patients with solar urticaria in
patients whose action spectra include UVA (46,47). After determination of the MWD to UVA,
50% to 70% of MWD is delivered to localized area of the body, such as the sun-exposed areas
only, or 25% of the body surface at each exposure. Single or multiple exposures with gradually
increasing UVA doses (25– 30% increase per exposure) can be done daily. However, caution
must be taken in not exposing too large an area and not to increase the dose too rapidly to
avoid systemic side effects that may include sycope.
The mechanism by which tolerance is induced is not clear, but may be partially due to the
exhaustion of chemical mediators by repeated exposures (24). In a series of experiments,
Leenutaphong et al. (48) showed that elevation of the mast cell degranulation threshold as
proposed by Keahey et al. (49) due to direct exposure of mast cells to UV irradiaton is probably
not the main underlying mechanism of tolerance. It is likely that the binding sites of IgE on
mast cells remain occupied by the photoallergen during the state of tolerance and IgE-mediated
histamine release from mast cells is blocked until new IgE is generated.
Photochemotherapy with psoralen and UVA (PUVA) has also been used with beneficial
effect (50,51). The tolerance induced by PUVA therapy lasts longer than that obtained by photo-
therapy. PUVA therapy is effective not only in UVA-sensitive patients, but also in those in
whom the action spectrum does not include UVA range. Therefore, the mode of action of
PUVA appears to be different from that of the tolerance induced by action spectrum radiation.
The mechanism of PUVA-induced hardening has not been clarified. Photoprotection by
PUVA-induced pigmentation and thickening of the stratum corneum may play a role. PUVA
therapy has been used for the treatment of nonphotosensitive mast cell-mediated conditions,
such as urticaria pigmentosa (52) and chronic urticaria (53), although the therapeutic effect
on the latter is debatable (54). Therefore, it is possible that PUVA has direct effect on mast
Solar Urticaria 195
cells in patients with solar urticaria. This is supported by our observation that PUVA-inhibited
mast cell degranulation and histamine release in animal models (55,56).
Cylosporine, at 4.5 mg/kg/day, has been successfully used to control solar urticaria in a
patient; however, the effect is transient as the condition recurred one to two weeks after the
discontinuation of the treatment (57).
Elimination of causative agent is very difficult in solar urticaria, because the photosensi-
tizer is of endogenous origin in the majority of cases. Plasmapheresis has been used with a
beneficial effect for the treatment of patients with solar urticaria in whom a photoallergen
can be detected in the serum or plasma (58,59). Also, plasmapheresis followed by PUVA
therapy has been proposed in order to prevent the formation of a new photoallergen after
plasmapheresis (60). More recently, extracorporeal photochemotherapy (photopheresis) has
been reported to be successful in one patient (61).
It should be emphasized that the use of a single treatment modality is not usually suffi-
cient to obtain a complete prevention. Combination therapy is necessary depending upon the
clinical response of the patients.
CONCLUSION
In the past, solar urticaria was often considered an idiopathic photodermatosis. However, more
information about pathomechanisms are now available in solar urticaria; it is most probably
a type I allergic reaction to an as yet to be defined photoallergen. Identification of this
photoallergen is the most important issue remaining to be resolved in the future.
REFERENCES
1. Humphreys F, Hunter JAA. The characteristics of urticaria in 390 patients. Br J Dermatol 1998;
138:635– 638.
2. Magnus IA. Solar urticaria. In: Magnus IA, ed. Dermatological Photobiology. Oxford: Blackwell
Scientific Publications, 1976:202– 210.
3. Frain-Bell W. Solar urticaria. In: Frain-Bell W, ed. Cutaneous Photobiology. Oxford: Oxford University
Press, 1985:51– 55.
4. Reinauer S, Leenutaphong V, Hölzle E. Fixed solar urticaria. J Am Acad Dermatol 1993; 29:161– 165.
5. Schwarze HP, Marguery MC, Journe F, Loche E, Bazex J. Fixed solar urticaria to visible light success-
fully treated with fexofenadine. Photodermatol Photoimmunol Photomed 2001; 17:39– 41.
6. Ryckaert S, Roelandts R. Solar urticaria—a report of 25 cases and difficulties in phototesting. Arch
Dermatol 1998; 134:71 –74.
7. Monfrecola G, Nappa P, Pini D. Solar urticaria with delayed onset; a case report. Photodermatol
8. Ravits M, Armstrong RB, Harber LC. Solar urticaria; clinical features and wavelength dependence.
Arch Dermatol 1982; 118:228– 231.
9. Murphy GM, Hawk JLM. Broadening of action spectrum in a patient with solar urticaria. Clin Exp
Dermatol 1987; 12:455 –456.
10. Ng JCH, Foley PA, Crouch RH, Baker CS. Changes of photosensitivity and action spectrum with time
in solar urticaria. Photodermatol Photoimmunol Photomed 2002; 18:191– 195.
11. Hasei K, Ichihashi M. Solar urticaria; detection of action and inhibition spectra. Arch Dermatol 1982;
118:346– 350.
12. Leenutaphong V, von Kries R, Hölzle E, Plewig G. Solar urticaria induced by visible light and inhib-
ited by UVA. Photodermatol 1988; 5:170– 174.
13. Horio T, Yoshioka A, Okamoto H. Production and inhibition of solar urticaria by visible light
exposure. J Am Acad Dermatol 1984; 11:1094– 1099.
14. Horio T, Fujigaki K. Augmentation spectrum in solar urticaria. J Am Acad Dermatol 1988;
18:1189 – 1193.
15. Miyauchi H, Horio T. Detection of action, inhibition and augmentation spectra in solar urticaria.
Dermatology 1995; 191:286– 291.
16. Danno K, Mori N. Solar urticaria: report of two cases with augmentation spectrum. Photodermatol
17. Rajka E. Passive transfer in light urticaria. Clin Immunol 1942; 13:327– 345.
18. Kojima M, Horiko T, Nakamura Y, Aoki T. Solar urticaria; the relationship of photoallergen and action
spectrum. Arch Dermatol 1986; 122:550– 555.
19. Kligman AM, Breit R. The identification of phototoxic drugs by human assay. J Invest Dermatol 1968;
51:90– 99.
20. Kaidbey KH, Kligman AM. Identification of systemic phototoxic drugs by human intradermal assay.
21. Epstein S. Urticaria photogenica. Ann Allergy 1949; 7:443– 457.
22. Leenutaphong, V., Hölzle, E., Plewig, G. Pathomechanism and classification of solar urticaria: a new
concept. J Am Acad Dermatol 1989; 21:237– 240.
23. Horio T, Minami K. Solar urticaria: photoallergen in a patient’s serum. Arch Dermatol 1977;
113:157– 160.
24. Horio T. Photoallergic urticaria induced by visible light: additional cases and further studies. Arch
Dermatol 1978; 114:1761– 1764.
25. Horio T. Solar urticaria—sun, skin and serum. Photodermatol 1987; 4:115 – 117.
26. Uetsu N, Miyauchi-Hashimoto H, Okamoto H, Horio T. The clinical and photobiological character-
istics of solar urticaria in 40 patients. Br J Dermatol 2000; 142:32– 38.
27. Crow KD, Alexander E, Buck WHL, Johnson BE, Magnus IA, Porter AD. Photosensitivity due to
pitch. Br J Dermatol 1961; 73:220– 232.
28. DeLeo VA, Hanson S, Scheide S. Benoxaprofen photosensitization of phospholipase activation in
mammalian cells in culture. Toxicol Lett 1986; 32:215– 220.
29. Kurumaji Y, Shono M. Drug-induced solar urticaria due to repirinast. Dermatology 1994;
188:117 – 121.
30. Horio T. Chlorpromazine photoallergy: coexistence of immediate and delayed type. Arch Dermatol
1975; 111:1469 –1471.
31. Hawk JLM, Eady RAJ, Challoner AVJ, Kobza-Black A, Keahey TM, Greaves MW. Elevated
blood histamine levels and mast cell degranulation in solar urticaria. Br J Clin Pharmacol 1980;
9:183– 186.
32. Soter NA, Wasserman SI, Pathak MA, Parish JA, Austen KF. Solar urticaria: release of mast cell
mediators in to the circulation after experimental challenge. J Invest Dermatol 1979; 72:282.
33. Sams WM Jr, Epstein JH, Winkelmann RK. Solar urticaria: investigation of pathogenetic mechanisms.
Arch Dermatol 1969; 99:390– 397.
34. Norris PG, Murphy GM, Hawk JLM, Winkelmann RK. A histological study of the evolution of solar
urticaria. Arch Dermatol 1988; 124:80– 83.
35. Leiferman KM, Norris PG, Murphy GM, Hawk JLM, Winkelmann RK. Evidence for eosinophil degra-
nulation with deposition of granule major basic protein in solar urticaria. J Am Acad Dermatol 1989;
21:75– 80.
36. Armstrong RB, Horan DB, Silver DN. Leukocytoclastic vasculitis in urticaria induced by ultraviolet
irradiation. Arch Dermatol 1985; 121:1145 – 1148.
37. Behrendt, H., Lehmann, P., Leenutaphong, V., Hölzle, E., Plewig, G. Sequential ultrastructural
analysis of solar urticaria: inflammatory cells, blood vessels, and nerve fibers. J Invest Dermatol
1989; 92:400a.
38. Beattie, PE, Dawe RS, Ibbotson SH, Ferguson J. Characteristics and prognosis of idiopathic solar
urticaria: a cohort of 87 cases. Arch Dermatol 2003; 139(9):1149 – 1154.
39. Magnus IA, Jarrett A, Prankerd TAJ, Rimington C. Erythropoietic protoporphyria: a new porphyria
syndrome with solar urticaria due to protoporphyrinaemia. Lancet 1961; 2:448– 451.
40. Dawe RS, Clark C, Ferguson J. Porphyria cutanea tarda presenting as solar urticaria. Br J Dermatol
1999; 141:590– 591.
41. Rantanen T, Suhonen R. Solar urticaria. A case with increased skin mast cells and good therapeutic
response to an antihistamine. Acta Derm Venereol (Stockh) 1980; 60:363– 365.
42. Monfrecola G, Masturzo E, Riccardo AM, Balato F, Ayala F, Di Costanzo MP. Solar urticaria: a report
on 57 cases. Am J Contact Dermat 2000; 11(2):89– 94.
43. Hölzle E. The idiopathic photodermatoses: solar urticaria. In: Hawk JLM, ed. Photodermatology.
London: Arnold, 1999:113 – 125.
44. Harber LC, Bickers DR. Solar urticaria. In: Harber LC, Bickers DR, eds. Photosensitivity Diseases. 2nd
ed. Toronto: B. C. Decker, 1989:209– 218.
45. Diffey BL, Farr PM. Treatment of solar urticaria with terfenadine. Photodermatol 1988; 5:25– 29.
46. Dawe RS, Ferguson J. Prolonged benefit following ultraviolet A phototherapy for solar urticaria. Br J
Dermatol 1997; 137(1):144– 148.
47. Beissert S, Stander H, Schwarz T. UVA rush hardening for the treatment of solar urticaria. J Am Acad
Dermatol 2000; 42(6):1030– 1032.
48. Leenutaphong V, Hölzle E, Plewig G. Solar urticaria: study on mechanisms of tolerance Br J Dermatol
1990; 122:601– 606.
49. Keahey TM, Lavker RM, Kaidbey KH, Atkins PC, Zweiman B. Studies on the mechanism of clinical
tolerance in solar urticaria.Br J Dermatol 1984; 110:327– 338.
50. Hölzle E, Hofmann C, Plewig G. PUVA-treatment for solar urticaria and persistent light reaction.
Arch Dermatol Res 1980; 269:87– 91.
Solar Urticaria 197
51. Parrish JA, Jaenicke KF, Morison WL, Momtaz K, Shea C. Solar urticaria: treatment with PUVA and
mediator inhibitors. Br J Dermatol 1982; 106:575– 580.
52. Christophers E, Hönigsmann H, Wolff K, Lagner A. PUVA treatment of urticaria pigmentosa. Br J
Dermatol 1978; 98:701 –702. Dermatology 1997; 195(1):35– 39.
53. Midelfart K, Moseng D, Kavli G, Stenvold SE, Volden G. A case of chronic urticaria and vitiligo,
associated with thyroiditis, treated with PUVA. Dermatologica 1983; 167:39 –41.
54. Olafsson JH, Larkö O, Roupe G, Granerus G, Bengtsson U. Treatment of chronic urticaria with PUVA
or UVA plus placebo: a double-blind study. Arch Dermatol Res 1986; 278:228– 231.
55. Danno K, Toda K, Horio T. The effect of 8-methoxypsoralen plus long-wave ultraviolet (PUVA) radi-
ation on mast cells: PUVA suppresses degranulation of mouse skin mast cells induced by compound
48/80 or concanavalin A. J Invest Dermatol 1985; 85:110 – 114.
56. Toda K, Danno K, Tachibana T, Horio T. Effect of 8-methoxypsoralen plus long-wave ultraviolet
(PUVA) radiation on mast cells. II. In vitro PUVA inhibits degranulation of rat peritoneal mast cells
induced by compound 48/80. J Invest Dermatol 1986; 87:113 – 116.
57. Edstrom DW, Ros AM. Cyclosporin A therapy for severe solar urticaria. Photodermatol Photoimmu-
nol Photomed 1997; 13(1 – 2):61– 63.
58. Duschet P, Leyen P, Schwarz T, Hocker P, Greiter J, Gschnait F. Solar urticaria: treatment by plasma-
pheresis. J Am Acad Dermatol 1986; 15:712– 713.
59. Leenutaphong V, Hölzle E, Plewig G, Grabensee B, Kutkuhn B. Plasmapheresis in solar urticaria.
Photodermatol 1987; 4:308– 309.
60. Hudson-Peacock MJ, Farr PM, Diffey BL, Goodship TH. Combined treatment of solar urticaria with
plasmapheresis and PUVA. Br J Dermatol 1993; 128:440 –442.
61. Mang R, Stege H, Budde MA, Ruzicka T, Krutmann J. Successful treatment of solar urticaria by
extracorporeal photochemotherapy (photopheresis)—a case report. Photodermatol Photoimmunol
Photomed 2002; 18(4):196– 198.
PART C: DRUG AND CHEMICAL-INDUCED PHOTOSENSITIVITY
14 Drug and Chemical Photosensitivity:

Exogenous
James Ferguson
Photobiology Unit, Ninewells Hospital, Dundee, Scotland, U.K.
Vincent A. DeLeo
Columbia University, St Luke’s– Roosevelt Hospital Center, New York, New York, U.S.A.
B The diagnosis of drug or chemical-induced photosensitization offers the

opportunity of cure through removal of the chromophore.
B Topical agents produce photosensitization by a range of toxic and allergic

mechanisms.
B The commonest recent photoallergens are sunscreens and topical non-

steroidal anti-inflammatory agents.
B Systemic photoactive drugs most commonly produce phototoxicity; five

distinguishable clinical patterns are seen.
B Drug phototoxicity can mimic chronic actinic dermatitis.
B Susceptibility to photosensitivity can persist for several months after

cessation of a photoactive drug.
200 Ferguson and DeLeo
INTRODUCTION
hen presented with an abnormally photosensitive patient, an important diagnostic
W group to be considered is that due to photosensitizing drugs and chemicals. The

correct diagnosis offers the possibility of prevention by simply avoiding the agent. To
miss that opportunity may result in a patient being considered as undiagnosed or worse, mis-
diagnosed, perhaps leaving the clinic with an incorrect label of an endogenous photodermato-
sis such as chronic actinic dermatitis (CAD). Systemic agents, either ingested or parenterally
administered, are usually therapeutic chemicals with photosensitivity as an adverse effect (1).
The photosensitization reaction is a process in which normally ineffective ultraviolet
(UV) and visible radiation interacts with a chromophore (a radiation-absorbing substance)
producing an abnormal reaction, usually in the skin. The radiation element, which is frequently
but not exclusively UVA (315 –400 nm) dependent can extend to shorter or longer wavelengths.
The clinical impact for the patient relates not only to the degree of sensitization, but also to the
wavelength involved. A mild sensitivity to UVA is quite different in its consequences on the
quality of life of a patient when compared with profound sensitivity to visible wavelengths,
where severe reactions may occur in extreme latitudes, even in the winter season.
A range of mechanisms exist to explain how a therapeutic drug enhances the photosen-
sitivity of cellular skin components. It does appear that phototoxicity, a nonimmunological
event due to combination of a drug or metabolite, with light of appropriate wavelength, is
the most commonly encountered mechanism. Other significant, less common, routes exist,
which includes drug-induced photosensitive lichen planus and lupus erythematous, pellagra,
photoallergy, and erythema multiforme. Although the latter mechanisms are uncommon, they
should be remembered. Photosensitization, whether immune-based or not, can be reduced to
the simple concept of absorption of radiant energy by a chromophore within the skin.
Excitation of the electronic state from ground level with transfer of the radiant energy into a
biologically active free radical species will induce cellular damage resulting in either direct
toxicity, that is, phototoxicity, or via the immune system or other mechanisms.
Topical photosensitizers, that is, those in contact with the skin, are often nontherapeutic
agents. A wide variety of plant materials and other chemicals, including sunscreens,
and topical drugs are recognized to be responsible (2). This chapter will consider topical and
systemic agents separately.
PHOTOSENSITIVITY INDUCED BY TOPICAL AGENTS

Many chemicals from the environment gain access to the skin from the topical route either
intentionally or inadvertently. Some of these have the ability to absorb radiation from the
sun or artificial sources. Usually, this radiation is in the UV and visible ranges and such
agents can act as chromophores and become potential photosensitizers. In all such reactions,
both chemicals and radiation are necessary for the photochemistry necessary to produce
biological changes and disease.
The mechanism of the response can be either irritant (toxic) or allergic. The topical chemi-
cal photosensitivities are therefore classified into two clinical entities: photoirritant (phototoxic)
contact dermatitis (PICD) or photoallergic contact dermatitis (PACD).
The mechanism of action (allergic vs. toxic) is fairly easy to discern on the basis of clinical
history and morphology in the case of topically applied chemicals (Table 1). The reaction occurs
on first exposure to the chemical agent and light in PICD, whereas a sensitization delay is
necessary for PACD.
Photopatch testing will confirm the diagnosis of the chemical-inducing PACD only in
sensitized individuals and negative responses in the population in general. In contrast, photopatch
testing of phototoxic agents in PICD is nondiscriminating since all or at least the vast majority of the
population will develop positive reactions to photopatch testing of such chemicals.
The timing of the response in the clinical history of the eruption and in testing is delayed
in PACD, as it is in allergic contact dermatitis. In PICD, the timing of the response varies
depending on the chemical involved. Tars routinely induce an immediate response referred
to as “tar smarts,” which usually occurs while the patient is being exposed to radiation,
Drug and Chemical Photosensitivity 201
TABLE 1 Differences between Photoallergic and Phototoxic Contact Dermatitis

Feature Photoallergic Phototoxic
Incidence Low High
Occurrence on first exposure No Yes
Onset after ultraviolet exposure 24– 48 hr Minutes to days
Dose dependence
Chemical Not crucial Important
Radiation Not crucial Important
Clinical morphological appearance Eczematous Erythematous and bullous,
hyperpigmentation
Histology Spongiotic dermatitis Necrotic keratinocytes
whereas the reaction to psoralens, whether from natural or synthetic material, is delayed
producing a response in skin 48 to 72 hours after exposure to light.
On clinical and histological examination, PACD presents as an eczematous response,
whereas PICD appears clinically as erythema, edema, and bullous lesions and histologically
as a toxic response with necrosis of keratinocytes.
The dose of both chemicals and radiation necessary to induce the response is more critical
to the production of PICD when compared with PACD, but such factors may also play a role in
PACD (3 – 6).
PICD is a clinical diagnosis made by a history of skin exposure to the photoirritant and a
photodistributed eruption of the type described above. Photopatch testing in such patients is con-
traindicated, since a positive response might be severe and since, as stated above, such a positive
response would be expected to occur in the general population and would not aid in the diagnosis.
The mechanism of action of PICD is dependent on the structure of the photosensitizing
chemical. Certain agents like tar absorb radiation and transfer that energy to membranes of
skin cells inducing cell damage. Furocoumarins like psoralens absorb radiation after intercalat-
ing into DNA and induce nuclear damage.
Although the mechanism of production has been extensively studied for a number of
photoallergens, the process is still poorly defined. The pathophysiological mechanisms
involved in production of the skin lesions, however, routinely reveal that the immunological
process involved in this reaction is analogous to the process occurring in plain allergic
contact dermatitis to a nonphotosensitized antigen.
The “action spectrum,” that is, the wavelengths of the radiation inducing photocontact
dermatitis, either toxic or allergic, falls almost always in the UVA-longwave (320 –400 nm)
and the visible ranges (400 – 800 nm) (5). This is of importance for a number of reasons. UVA
and visible radiation penetrates most window glass so that patients have been reported to
develop reactions to light coming through the windows of their cars and while sitting next
to windows at home or at work. Rarely, particularly sensitive patients may react to artificial
light from indoor lighting sources. Sunscreens that do not offer longwave protection offer
little benefit in preventing photochemical sensitivity, and most importantly, a UVA light
source is necessary for the performance of photopatch testing.
Photoirritant Contact Dermatitis

The incidence of PICD in the general population is unknown. Review of large studies of
patients being evaluated for photosensitivity reveals a fairly low incidence of this diagnosis
(7). This may be because the diagnosis is made clinically, since phototesting and photopatch
testing are not done in these patients. For this reason, patients with PICD would not
undergo testing and not appear in statistics. It is probably at least as common as PACD in
the general population.
The agents that induce the response are listed in Table 2. The two general patterns in the
history of individuals with PICD relate to either recreational or occupational exposure. As one
might expect from the agents listed in Table 2, most individuals who experience occupationally
related PICD are workers in outdoor occupations, but this is not always the case.
TABLE 2 Agents Commonly Inducing Photoirritant Contact Dermatitis

Tar-related products
Therapeutic agents–tars
Pitch
Acridine
Coal tar
Anthracene
Creosote
Dyes
Methylene blue
Eosin
Disperse blue 35
Amino-benzoic acid derivative
Amyl-ortho-dimethylaminobenzoic acid
Furocoumarins
Therapeutic 8-methoxypsoralen (Oxsoralen)
4,5,8-trimethylpsoralen (Trisoralen)
5-methoxypsoralen (Bergapten)
Fragrance materialsa
Plantsb
Rutaceace Lime, lemon, bergamot, burning bush, bitter orange,
Umbelliferae gas plant, common rue
Carrots, cow parsley, wild chervil, fennel, dill, parsnip,
cow parsnip, celery
Moraceae Fig
Cruciferae Mustard
Ranunculaceae Buttercup
a
Berloque dermatitis.
b
Phytophotodermatitis (not all-inclusive).
All individuals with a photodistributed eruption should be suspected of having PICD.

This necessitates a careful history for exposure to photosensitizers at home, in the work
place, and in the recreational setting.
The diagnosis is suggested by the classic morphology, erythema and edema, with bullae
in severe cases. Frequently, the lesions of PICD heal with pigmentation, especially when due to
furocoumarin sensitizers. In fact, patients may present with only hyperpigmentation without a
history of preceding inflammation. However, other clinical morphologies including psoriasi-
form dermatitis and even hypopigmentation after inflammation can occur.
Tar Products
Tar and related products produce a very distinctive photosensitive reaction known as “tar or
pitch smarts” (8,9). The patients experience burning and stinging almost immediately on
exposure to the sun. This can occur with very short exposure times. Roofers with exposure
to pitch and coal tar are most susceptible and direct skin contact is not necessary, since aeroso-
lized contact is sufficient to produce the reaction. Associated ophthalmological involvement
may occur (10). The sensitizers in coal tar include acridine, anthracene, benzopyrene, and fluor-
anthene (11).
Reactions to creosote in roof paper and creosote-soaked wood products including saw
dust and boxes have also been reported in a large number of workers (12,13).
Although not routinely reported, the other situation where “tar smarts” can occur is in
the therapeutic setting. Since tar-based products such as creams, soaks, and shampoos are
routinely used to treat skin disease, patients treated with these agents should be reminded
that sun exposure can cause skin lesions.
Furocoumarins
Furocoumarins are photosynthesizing chemicals that occur in nature in wild and cultivated
plants. Such agents have been synthesized for many uses including fragrances and as
therapeutic agents. The most common agents used therapeutically, 8-methoxypsoralen and
5-methoxypsoralen, are also the ones most commonly present in plants that are potent
photosensitizers.
Classically, these reactions have been divided into those produced by synthesized agents
usually used as fragrances and called “berloque,” the French word for pendant, dermatitis and
those in which the photosensitizer is contacted inadvertently from plants, called
“phytophotodermatitis.”
When an individual develops PICD to a fragrance product, it usually appears as a hyper-
pigmented macule at the site of application—usually on the neck—and so the term berloque or
pendant dermatitis (4). These reactions are relatively rare since most fragrance agents contain-
ing photosensitizers have been removed from products used in the United States and Western
Europe. Many consumers, however, do continue to use containers of perfumes and colognes
for many years or even decades.
Phytophotodermatitis is much more common. Although there have been reports of plants
other than those containing furocoumarins causing phytophotodermatitis, they are exceed-
ingly rare. For example, Cneoridium dumosum, a native bush, has been reported to cause
photosensitivity in field worker-students in the chaparral vegetation zone in California and
Mexico (14).
Unlike the reaction to tar-related products, the reaction to furocoumarins is delayed,
occurring one to many days after the plant and light exposure. Healing is frequently
accompanied with hyperpigmentation but in severe reactions hypopigmentation can occur.
The lime is the plant most often reported to induce phytophotodermatitis in our experi-
ence. Exposure to limes usually occurs in the recreational setting in sunny climates. Individuals
usually report making and drinking cocktails which entail squeezing lime juice into their
drinks. This process allows the furocoumarins from the exocarp, the outer green part of the
lime skin, to be absorbed into the skin of the fingers. From the fingers, it can be transferred
to other skin sites. Only short exposure to UVA radiation, just minutes of sun exposure, are
needed to elicit a response. Since the response is delayed, individuals rarely recognize the
association of exposure and skin lesions (Fig. 1).
The most common plant causing phytophotodermatitis in the workplace is celery.
Initially, it was believed that a fungal parasite, pink-rot, infecting the celery was responsible
for the reaction. It is now accepted that the infection induces increased productions of
FIGURE 1 Hyperpigmented photo-irritant dermatitis

(“berloque dermatitis”). This woman used a Brazilian oil
bath that contained plant-derived furocoumarins.
furocoumarins in the celery and therefore leads to the reaction (15,16). Reactions have been
reported in cannery workers, grocery store cashiers, baggers, produce clerks, and chefs (17).
In addition to limes, other citrus also contain furocoumarins but not as high a concentration
as the lime. However, handling of various citrus in great quantities may lead to phytophotoder-
matitis in bartenders. The lime still appears to be the most common cause of phytophotoder-
matitis in the nonoccupational setting (5).
Farmers and other outdoor workers as well as professional and recreational gardeners
and others with outdoor recreational exposure to plants are at risk for developing phytopho-
todermatitis from exposure to the other plants listed in Table 3. Many such reactions will
present with linear lesions as for poison ivy contact dermatitis.
Other Agents
Amyl ortho-dimethylaminobenzoic acid induced an immediate photosensitivity response
followed by a second delayed erythema in workers formulating UV-cured inks (18) and simi-
larly Disperse Blue Dye 35 produced a transient erythema and burning in workers on sun
exposure (19).
Photoallergic Contact Dermatitis

The incidence of PACD in the general population is unknown but such reactions have become
rarer in the last 25 years. The available incidence data are based on positive photopatch test
results in groups of patients with presumed photosensitivity who were referred to tertiary
care facilities for diagnostic photopatch testing. The rates of positive reactions and the diagno-
sis of PACD in groups ranged from 6% in a Canadian study to 25% in England in studies
published in the 1970s (3). The Scandinavian Multicenter Photopatch Study (1988) reported
274 positive photopatch test results and 369 positive plain patch test responses in 1993 patients
with a diagnosis of PACD in 11% of patients tested in the early 1980s (7,20). In the United States,
in two studies done more recently, 11% and 20% of patients tested were reported to have PACD
(21,22). Similarly, the North American Contact Dermatitis Group found approximately 20% of
250 patients tested in the 1990s to be diagnosed as having PACD after photopatch testing
(DeLeo, personal communication). Unlike PICD, the only way to confirm a diagnosis of
PACD is with photopatch testing. The technique is outlined in other sections and briefly
reviewed here.
CAD is discussed in more detail in other sections. It should be remembered in the
context of PACD that some patients with PACD may progress to persistent light reactions
now classified as a type of CAD and continue to react to sun exposure even after removable
of the antigen. These patients can be defined by phototesting with lowered minimal erythema
doses (MEDs) in the UVB and/or UVA ranges and sometimes with sensibility in the visible
light area. In the past, this reaction was more common than today. The most common
agents were antibacterials, which are only rarely used today and primarily in the occupational
setting and fragrances, especially musk ambrette, which is no longer used in colognes. It
should be remembered that some patients with PACD, for example, to sunscreens, may
react to light alone for a short period of time after removal of the antigen, probably
because of antigen persistence in the skin. These patients, once called transient light reactors,
will have normal MEDs on phototesting and as such will be distinguishable from those
with CAD.
Photopatch Testing Techniques

Photopatch testing is patch testing with the addition of radiation to induce formation of the
photoantigen. Application of antigens and scoring criteria are the same as those described
for plain patch testing (5). The only additional equipment that is necessary is an appropriate
light source and light opaque shielding for the period after removal of the Finn chambers
before readings.
With very few exceptions, the radiation responsible for formation of the photoantigen
and clinical PACD falls within the UVA spectrum (320 –400 nm). The light source utilized
should produce UVA radiation in a continuous spectrum (fairly uniform radiation from 320
TABLE 3
North American contact
dermatitis group European taskforce for photopatch testing Henry Ford Health System
Sunscreens
1—Octinoxate Octyl methoxycinnamate (2-ethylhexyl-p- Homosalate
methoxycinnamate, Parsol MCX, Eusolex
2292)
2—Sulisobenzone (BZP-4) Benzophenone-3 (2-hydroxy-4-methoxy 3-(4-methylbenzyliden) camphor
benzophenone, oxybenzone, Eusolex 4360) (Eusolex 6300)
10—Oxybenzone (BZP-3) Octyl dimethyl PABA (2-ethylhexyl-p-dimethyl- Menthyl anthranilate
aminobenzoate, Escalol 507, Eusolex 6007)
12—Para-aminobenzoic acid PABA (4-aminobenzoic acid) Octyl dimethyl p-aminobenzoic acid
(PABA)
13—Octisalate Butyl methoxydibenzoylmethane (Parsol 1789, Octyl methoxycinnamate
Eusolex 9020)
15—Menthylanthranilate 4-Methylbenzylidene camphor (Eusolex 6300, Benzophenone 3 (BZP-3)
Mexoryl SD)
19—2-Hydroxy-methoxy Benzophenone-4 (2-hydroxy-4-methoxy- PABA
methyl benzophenone benzophenone-5-sulfonic acid, Uvenyl MS-40)
21—Octyl dimethyl PABA Isoamyl p-methoxycinnamate (Neoheliopan, Parsol 1789
E1000)
23—Homosalate Phenylbenzimidazole sulphonic acid (2-phenyl-5- Benzophenone 4 (BZP-4)
benzimidazolsulphonic
acid, Eusolex 232)
24—Butyl
methoxydibenzoylmethane
22—Phenylbenzimidazole
Antimicrobials
4—Dichlorophene Bithionol (thiobisdichlorophenol)
5—Triclosan Chlorhexidine diacetate
6—Hexachlorophene Dichlorophen
7—Chlorhexidine diacetate Fenticlor (thiobisdichlorophenol)
11—Fenticlor (thiobis- Hexachlorophene
chlorophenol)
14—Tribromosalicylanilide Tribromosalicylanilide
20—Bithionol (thiobis- (triclocarban)
dichlorophenol)
Triclosan
Fragrances
8—Sandalwood oil Musk ambrette
9—Musk ambrette 6-methylcoumarin
Sandalwood oil
Medicaments
18—Ketoprofen Naproxen
Ibuprofen
Diclofenac
Ketoprofen
Plants
16—Sesquiterpene lactone Achillea millefolium (Yarrow)
mix
17—Lichen acid mix Alantolactone
Alpha-methylene-gammabutyrolactone
Arnica montana (mountain tobacco)
Chamomilla Romana
Chrysanthemum
cinerariaefolium
Diallyldisulfide
Lichen acid mix
Sesquiterpene lactone mix
Tanacetum vulgate (tansy)
Taraxacum officinale (dandelion)
Abbreviations: BZP-4, benzophenone-4; PABA, P-aminobenzoic acid.
to 400 nm) of sufficient irradiance and field size to allow irradiation of 20 to 25 antigen sites
with a dose of 5 to 10 J/cm2 within a reasonable time (about 30 minutes).
The dose of radiation used in photopatch testing has varied between 1 and 10 J/cm2 in
most studies. Theoretically, the largest dose not only induces erythema in skin but would be
most likely to yield production of the photoallergy and a positive test response. Since the
MED in the UVA range is between 20 and 60 J/cm2, any dose that can be conveniently delivered
below this level can be used, and 10 J/cm2 has been selected more or less arbitrarily to fulfill
these two criteria.
The photoallergens chosen for testing are determined by the usage patterns of photoaller-
gens in a given population. Table 3 lists the photoallergen series of the North American Contact
Dermatitis Group (DeLeo, personal communication), the Henry Ford Hospital System (23), and
the Photopatch Testing Taskforce of European Academy of Dermatology and Venereology (24).
The protocol for photopatch testing usually includes phototesting with UVA and UVB radi-
ation alone to determine a baseline photopatch dose in the UVA range and to rule out other
sensitivities in both the UVA and UVB ranges. Patches are applied in two sets, one to be irra-
diated and one left “dark” so as to differentiate between photocontact dermatitis and regular
allergic contact dermatitis.
A positive response in the irradiated site and a negative in the covered site are diagnostic
of photoallergy (Fig. 2). Equal positive responses in both irradiated and covered sites are diag-
nostic of plain contact allergy. When both sites are positive, but when the result in the irradiated
patch is significantly more positive than in the covered site, this is considered by researchers
either as simple allergic contact dermatitis or as allergic contact dermatitis with photocontact
dermatitis.
Occasionally, irradiation appears to inhibit a positive patch test reaction—the nonirra-
diated site will be reactive, whereas the irradiated site will be negative. The pathophysiology
of such an occurrence is not understood: neither are its clinical ramifications. Such a response, if
clinically relevant, may be significant.
As with plain patch testing, false-positive and false-negative results can occur in photo-
patch testing. The former is particularly common with drugs such as ketoprofen, prometha-
zine, and chlorpromazine (CPZ).
FIGURE 2 Positive photopatch test to musk ambrette

and UVA.
Some antigens produce an immediate photoirritant response. Erythema is noted at

the completion of the irradiation period. Rarely this is clinically relevant and may usually be
disregarded unless the clinical history suggests an immediate reactivity.
In addition to the photoallergens in the tray, patients can be tested to their own products,
particularly to sunscreens and fragrance-containing cosmetics. Industrial cleansers and the
like, as well as personal-care cleansers, which may be the source for antibacterial agents,
must be diluted appropriately.
Photosensitizing Agents
Sunscreens
Since the 1970s, people in the United States, Europe, and Australia have begun to increase their
usage of sunscreens, as they were educated to the dangers of sun exposure. This is particularly
true of outdoor workers and those seeking outdoor recreational activities. This has led to an
increased exposure to active ingredients in these products. Therefore, it is not surprising that
such agents induce contact allergy, and since such ingredients by definition absorb UV radi-
ation, it is not surprising that they also induce PACD (Fig. 3). The incidence of these reactions
in the sunscreen-using population is unknown, but it is probably very low. Sunscreen com-
ponents were the most common group of agents producing relevant photopatch test
reactions in many areas of the world (22) photopatch test series, but were less frequent than
antimicrobials and fragrances in the Mayo Clinic and Scandinavian studies (7,20,21).
The most common agents to induce this response are the benzophenones (oxybenzone and
sulisobenzone), octyl-dimethyl P-aminobenzoic acid (PABA), and the dibenzoylmethanes.
Antibacterial agents
Tetrachlorosalicylanilide and tetrabromosalicylanilide the most potent of the photosensitizers
caused an epidemic of PACD in many areas of the world. The former caused an outbreak in
factory workers in Great Britain in 1960 (25,26). These agents were responsible for producing
a large number of cases of debilitating CAD. Although these agents are no longer used in
consumer cleaners, that is, bar soaps and shampoos, in the United States, they may still be
used in industrial cleansers.
Triclosan (Irgasan DP 300) is a widely used antibacterial agent in bar soaps and deodor-
ants. Most deodorant-type bar soaps marketed in the United States today contain this agent.
It appears to be a very low level photosensitizer, and few cases have been reported despite
its widespread usage patterns.
FIGURE 3 Eczematous photoallergic contact

dermatitis to sunscreens in a patient
photoallergic to oxybenzone.
Dichlorophene (G-4) is widely used in this country and in Europe in shampoos, dentifrices,
antiperspirants, and “athlete’s foot” powder. Dichlorophene is also used in the treatment of
fabrics. It is a rarely reported photosensitizer.
Bithionol is a chlorinated phenol used in the 1960s in the United States and more exten-
sively in Japan. It caused an epidemic of PACD in Japan, where it was present in bar soaps.
It is banned in that country and is no longer used in bar soaps in the United States. It may
still be used in industrial cleaners and agricultural and veterinary products marketed in the
United States.
Fenticlor is a chlorinated phenol used as an antibacterial and antiseborrheic agent in hair-
care products made primarily in Canada, the British Isles, and Australia. It was never used
extensively in the United States. It appears to be a moderately potent photoallergen. It may
produce false-positive responses in photopatch testing. Such responses have features of true
photoallergy—they appear eczematous and occur in a delayed fashion with an increase in
severity of response at second reading.
Hexachlorophene was a widely used antibacterial in over-the-counter skin cleansers in the
United States. Reports of neurotoxicity resulted in a change of status to prescription only by the
Food and Drug Administration (FDA). pHisohex is still used in the United States, but with much
lower frequency. It is rarely reported photoallergen.
Chlorhexidine is used as an antibacterial in hospital cleansers for both skin and mucosa. It
is also used as a dental rinse. It is a rare photoallergen.
Fragrances
A number of fragrance ingredients have been associated with PACD. The three most common
include musk ambrette, 6-methylcoumarin, and sandalwood oil.
Musk ambrette is a synthetic fragrance fixative used primarily in men’s cosmetics because
of its potent floral odor. Related chemicals extracted from the scent glands of animals and some
plants have been used for years as fixatives and enhancers in perfumes. In the 1970s and 1980s,
huge quantities were used in the United States in various cosmetics, primarily men’s after-
shave lotions and colognes. Concentrations of musk ambrette as high as 15% were used in
such products. In the late 1970s, reports of photoallergy began to appear in the literature. By
the 1980s, this agent was the most frequently reported cause of PACD. Many of the men
sensitized to musk ambrette developed persistent reactions now called CAD.
The International Fragrance Association has recommended that musk ambrette not be
utilized in products that will have contact with skin. In other products, a concentration of
4% is recommended.
6-Methycoumarin is a synthetic fragrance that caused an epidemic of PACD when it was
used in a sun-tanning lotion in the late 1970s. The reactions were particularly severe, requiring
hospitalization in many cases. The morphology of many of the reactions suggested phototoxi-
city, but photoallergy was probably the underlying mechanism. The agent was removed from
sun-related lotions and it is no longer recommended for use as a fragrance component. An
early problem with the identification of this agent as etiologic occurred because of its apparent
instability as a photoallergen once applied to skin. In routine photopatch testing, antigens are
applied to skin 24 to 28 hours before UVA exposure. Such testing yielded negative results.
When the antigen was applied shortly (30– 60 minutes) before exposure, positive reactions
were found in sensitized individuals. Testing with this agent is therefore done differently
from the other routinely tested photoallergen.
Sandalwood oil is a “woodsy” smelling fragrance ingredient. It is a rarely reported
photosensitizer.
Therapeutic agents
A number of systemic drugs that produce photosensitivity have been reported to cause PACD
when contacted topically. Theoretically, this might occur with many such agents. The two most
frequently reported are the phenothiazines, chlorpromazine hydrochloride (Thorazine) and
promethazine (Phenergan). The PACD reported for the former has been found in health-care
workers who have frequent skin contact with the agents.
The newest groups of photoallergens are topical nonsteroidal anti-inflammatory agents

(NSAIDs). Since their entry into the marketplace in Europe, they have been widely used and
are now the most common cause of PACD in some areas of Europe. Ketoprofen is the most
common of these, and allergy to this agent is reported to cause cross-reactivity to benzophe-
nones. These agents are not available for use in the United States (27,28).
Other agents
Quindoxin is a growth-promoting agent used in animal foodstuffs. It has been reported to
cause PACD in farm workers handling the feed (29,30). It is no longer used.
Olaquindox similarly utilized in animal feed caused an outbreak of PACD in pig
farmers (31).
Folpet and captan used by farmers and groundskeepers have been recently reported to
induce PACD (32).
Air-Borne Contact Dermatitis

Photosensitivity can be mimicked by contact dermatitis in skin exposed to allergens, which can
be aerosolized. In addition, some individuals with air-borne contact dermatitis have gone on to
develop an idiopathic photosensitivity, CAD (discussed earlier). The major allergens in
this group include occupationally acquired agents like chromates (33,34) and plants of the
Compositae (35,36) and Lichen (37) families. An extensive review of this area as relates to
the Compositae experience has revealed that this is not truly a PACD, but conversion to photo-
sensitivity from contact dermatitis by an unknown mechanism. For this reason, as seen in
Table 3, plant allergens are routinely tested in the photoallergen tray.
SYSTEMIC DRUG-INDUCED PHOTOSENSITIVITY

The incidence of phototoxicity due to systemic medication varies greatly from drug to drug and
even within subjects taking a particular agent. It usually relates to drug dosage, the local inten-
sity of the relevant wavelengths, and individual factors such as skin type and drug handling.
This latter factor is as yet poorly understood, although it is to be anticipated that the current
interest in pharmacogenomics will explain why some individuals experience idiosyncratic
phototoxicity, whereas the majority taking that drug escape without problems.
Within a tertiary referral photobiology unit, the number of drug-induced photosensitive
patients seen makes up a small proportion of the total workload (38). Although it might
be inferred that systemic drug photosensitivity is a minor problem, it is highly likely
that many are misinterpreted as sunburn and go unnoticed, whereas others are diagnosed
by the family doctor or by patients themselves through reading the drug information leaflets.
In countries with postmarketing surveillance, drug-induced photosensitivity is commonly
reported, at least when a drug is new. Later, as the novelty reduces, further reports
are often thought unnecessary. Publications using such data exist (2) and include lengthy
lists of suspected drugs; there is no substitute for pre-registration data of knowledge
regarding the photosensitizing potential of a molecule prior to the licensing and marketing of
a particular drug.
Photosensitivity Testing of New Therapeutic Molecules Prior to Marketing

The pharmaceutical industry provides ever-increasing numbers of new molecules. While thank-
fully the days of discovering severe phototoxicity after regulatory authority approval and mar-
keting are now rare, we cannot yet predict idiosyncratic phototoxicity and rarer mechanisms
such as photoallergy, drug-induced lupus erythematosus (LE) or pellagra. Such cases only
usually emerge with post-marketing surveillance. The move towards standardized pre-launch
testing by the major regulatory authorities in North America, Europe, and Asia follows a simple
pathway. A new molecule is required to have an absorption spectrum conducted. If it absorbs in
the UVB/A or visible region and is known to be distributed to skin or the eye, standard in vitro
testing with a fibroblast 3T3 model follows. If phototoxicity is detected, human volunteer testing
may be recommended (40).
TABLE 4 Fluoroquinolone Phototoxicity Index Table

Phototoxicity index
Absent phototoxicity ,1.4
Mild 1.3– 3.0
Moderate .3.0– 6.0
Severe .6.0
One early test system which involved “volunteers” being given a drug or placebo
followed by a sunshine-soaked boat trip with erythema scoring thereafter did reveal
some important information. Today, the system has evolved into a randomized controlled
trial of healthy volunteers who have predrug phototesting using a relative monochromatic
and solar simulated sources. Phototesting is repeated on drug/placebo/positive control
with Good Laboratory and Good Clinical Practice standards of investigation. A within-
individual phototoxic index (PI) or sensitization factor is produced. On code breakage,
this index provides a clear indication of the degree of phototoxicity over a range of wave-
lengths. The morphology of the reaction and importantly the duration of susceptibility
postdrug cessation enable an overall picture of the molecule’s phototoxic potential and its
impact on later clinical usage. The PI can be graded into mild, moderate, or severe
(Table 4). A high PI may for some drugs end their development, particularly when nonphotoac-
tive alternatives exist, a situation particularly seen within the fluoroquinolone (FQ) family.
Many phototoxic drugs that have been marketed for years have never been studied in
such detail. Usually, they have postmarketing adverse reporting data, but limited other
information, which historically were appropriate but now are out-of-date with standards that
have improved considerably.
Drug Photosensitivity: Clinical Presentation

The wide spectrum of systemic therapies known to have a photosensitizing potential will be
considered individually (Table 5).
In general, a particular family of photosensitizers produces a similar clinical type of
presentation with a pattern of evolution that can be quite different from one family structure
to another, for example, psoralens and FQs. When faced with a patient suspected of drug-
induced photosensitivity, history taking and examination are equally important. Knowledge
as to whether the eruption has been induced by light through thin clothing or window glass
and how much light has been required often gives an indication of the responsible wavelength
and severity. Examination for photosensitive site involvement such as forehead, cheeks,
chin, rim of ears, back of hands, with a clothing cut-off, and the sparing of shadow sites
such as beneath chin, behind ears, and within the hair, as well as under spectacle frames
and watch strap, are often helpful in pinning down a photosensitive element. Having made
a diagnosis of photosensitivity, a careful drug history and an idea of the mechanism involved
will allow the correct diagnosis to emerge.
Phototoxicity, which will theoretically arise in any subject with sufficient exposure to
light and chemical, has a number of presentations (Table 6). Although often thought of as
an exaggerated sunburn, in fact an array of clinical features specific to each drug family is
evident. Within each phototoxic drug family, although differences in wavelength dependency
and morphology can be detected, these are the exceptions rather than the rule. In general, the
susceptibility does vary with photo skin type (41) and drug dosage. However, idiosyncratic
phototoxic skin reactions do occur with some photoactive drugs such as thiazides and
quinine where only a minority of those prescribed will eventually develop photosensitivity.
Often these patients describe it occurring after a number of years of drug taking rather
than in weeks. In a similar fashion, many phototoxic drugs when administered do show a
surprising variation and degree of photosensitivity independent of skin type. As pharmaco-
logical drug handling does vary between subjects, it is not surprising that there are
patients with more or less sensitivity with any group taking a particular phototoxic drug at
a specific dosage.
TABLE 5 Photosensitizing Drugs

Antibiotics
Fluoroquinolones
Nalidixic acid
Tetracyclines
Sulphonamides
Antifungals
Griseofulvin
Diuretics and cardiovascular agents
Thiazides
Furosemide
Amiodarone
Quinidine
Non-steroidal anti-inflammatory drugs
Naproxen
Tiaprofenic acid
Piroxicam
Azapropazone
Calcium channel antagonists
Nifedipine
Psoralens
8-methoxypsoralen
5-methoxypsoralen
Psychoactive drugs
Phenothiazines (chlorpromazine, thioridazine)
Protriptyline
Retinoids
Isotretinoin
Etretinate
Photodynamic therapy agents
Foscan
Photofrin
Persistent Light Reactor

If an initial photoallergic episode is followed by a state of continuing photosensitivity, despite
avoidance of the original photoallergen, the term “persistent light reactor” has been used. In
fact, the evidence for this type of event is slight. Until more data emerges to support the
concept, it seems sensible to use the term with caution, particularly as such a diagnosis may
have considerable consequences if exposure was occupational. It does seem likely that some
of those labeled as persistent light reactors do have CAD, a condition associated with multiple
contact allergies and eczematous phototest reactions.
Wavelength dependency and duration of susceptibility after drug cessation
Phototoxic drugs do vary in the wavelength responsible for the clinical problem. Almost all
involve the UVA spectrum (315 – 400 nm) with extension occasionally into the UVB or visible
TABLE 6 Major Patterns of Cutaneous Phototoxicity

Skin reactions Photosensitizers
Prickling or burning during exposure; immediate erythema; Photofrin, amiodarone, chlorpromazine
edema or urticaria with higher doses; sometimes delayed
erythema or hyperpigmentation
Exaggerated sunburn Fluoroquinolone antibiotics, chlorpromazine, amiodarone,
thiazide diuretics, quinine, demethylchlortetracycline,
and other tetracyclines
Late-onset erythema, blisters with slightly higher doses, Psoralens
hyperpigmentation only with low doses
Increased skin fragility with blisters from trauma Nalidixic acid, frusemide, tetracycline, naproxen,
(pseudoporphyria) amiodarone, fluoro-quinolone antibiotics
Photoexposed site telangiectasia Calcium channel antagonists
range. The degree of sensitization and the wavelength dependency are both key to predicting
the environmental conditions causing the problems. Some agents, particularly the porphyrin-
related systemic drugs used for photodynamic therapy for internal malignancy do have
maximal activity in the visible region (400 –700 nm). As would be expected, these latter patients
would have a quite different susceptibility pattern in relation to light transmitted through
cloud or clothing, or even artificial lighting conditions.
Drug-Induced Pseudoporphyria
This phenomenon, which is well recognized yet is uncommon, appears to have a porphyria
cutanea tarda/variegate-like porphyric features in the presence of normal or near-normal
values. Skin fragility/blistering of sunlight-exposed skin sites of face and hands are associated
with the ingestion of a number of known phototoxic drugs including NSAID (42,43), tetra-
cyclines, amiodarone, nalidixic acid, and voriconazole (44).
Duration of Susceptibility Following Drug Cessation

Although it would be expected that the duration of susceptibility to phototoxicity will relate to
the elimination half-life of a drug, and this is often the case, considerable variation exists with
some drugs, such as quinine and thiazide-induced photosensitivity lasting for up to nine
months, yet the drugs themselves are usually eliminated rapidly, that is, within hours. Some
pharmacological explanation will emerge, possibly related to an abnormal metabolite with a
much longer half-life or perhaps tissue binding which only slowly resolves. In others where
the duration of susceptibility is lengthy, such as is seen with amiodarone or photofrin, it
does directly relate to the persistence of the photoactive molecule within the skin and circula-
tion. Two of the most commonly encountered photoactive agents, psoralens and FQs, are
rapidly eliminated from the vasculature and tissues. Within 24 to 48 hours of stopping these
drugs, any increased susceptibility to photosensitive reactions has been lost.
Commonly Encountered Phototoxic Drugs

To a large extent, the responsible systemic agents encountered in the clinical setting relates to
prescribing practice which varies from country to country and even between clinicians. In those
latitudes furthest away from the equator, winter sunlight has little UVA and for many months
of the year none of the UVB wavelengths. This results in increased susceptibility in spring
when the UV environment does change significantly often occurring at a time when photo
adaptation has been lost. In contrast, patients prescribed photoactive drugs who live near
the equator, often have a greater UV-induced photoprotection due to high levels of the
shorter pigmentogenic and epidermal thickening wavelengths. These can reduce the severity
of reactions due to a natural “hardening” process. The phototoxic patients seen by clinicians
do vary greatly. Secondary care specialists tend only to see the diagnostic problems. Drug
photosensitivity as a diagnosis is well recognized by family doctors who are likely to see
and recognize the majority of such problems without the need to refer on to photodermatology
units.
Individual Drug Groups

Diuretics
Two subgroups are reported, the sulphonamide-based thiazide molecules and the loop diuretic
furosemide. Members of the thiazide group appear capable of an idiosyncratic problem with
phototoxicity, a lichen planus-like reaction (45) and a drug-induced lupus erythematosus reac-
tion (Fig. 4) (46) being evident. The commonest of these by far appears to be the phototoxic der-
matitis type of response (Fig. 5), which only occurs in a few patients taking a thiazide, often
appearing sometimes years after starting to take the drug. This can have a presentation
similar to CAD. The solution is to stop the agent and use a nonphotoactive substitute. Bume-
tanide, a loop diuretic, appears to have a lower phototoxic potential than thiazide and can be
considered as an alternative (47).
When one considers how commonly frusemide is used, it is surprisingly rare to see a
pseudoporphyric reaction with bullae and skin fragility (48).
FIGURE 4 Drug-induced lupus erythematosus. Note the distribution over the dorsum of hand and proximal
phalanges.
The Fluoroquinolones
This large group of antibiotics shows an interesting range of phototoxicity (49). Photoallergy,
if it does occur, must be extremely rare. The chemical progenitor of the group nalidixic acid
is itself a recognized photosensitive molecule. Introduction of fluorine at position 6 of the
quinolone ring structure produced the first generation of FQs. Early molecules that were
developed and marketed did show a phototoxic potential of a fairly marked type
with erythema and blistering of the photoexposed sites only occurring in subjects who
had taken a high-dose drug and been exposed to a significant amount of what seemed to
be particular UVA wavelengths.
FIGURE 5 Thiazide-induced phototoxicity. Note the cut-

off at the side of neck and similarity in penetration to
chronic actinic dermatitis.
Lomefloxacin was first approved in 1992 in the United States. Following postmarketing
surveillance, a large number of photosensitivity reports followed. Phototoxicity studies later
showed it to have a PI of 3 to 6. Since then, the FQ group has been the most thoroughly
studied family of molecules prior to licensing. A wide range of degree of phototoxicity has
been observed from the nonphototoxic, even photoprotective moxifloxacin, to the extremely
phototoxic molecule, clinafloxacin, which has PI values in some individuals as high as 90.
The creation of extensive in vitro and human in vivo phototoxic data has allowed a comparison
of the two methods. This has revealed FQ in vitro fibroblast study work to correlate with the in
vivo monochromator phototest findings, the only family of drugs to date that has shown this
correlation. The in vivo studies have revealed a predominantly UVA phenomenon with some
molecules demonstrating an extension into the visible range. This latter finding raised the
concern of ocular phototoxicity. Some FQs with encouraging broad-spectrum bactericidal
activity have had their development terminated due to adverse effects including marked
phototoxicity. Some FQs capable of severe phototoxicity have shown a marked pigmentary
response of skin photoexposed sites that can last for two years.
Amiodarone
This drug, which is often used to control cardiac arrhythmias resistant to more conventional
drug therapy, has a known phototoxic potential. The photosensitivity reaction is dose-related
and is caused by UVA and visible wavelengths. It has two erythemal components, an immedi-
ate prickling burning erythema coupled to a 24-hour delayed erythema response. The problem
is common, affecting 40% to 60% of those taking the drug (50,51). Elimination half-life is long
(.200 days) so that those affected, if they come off the drug, will continue to have problems
for many months. A complication seen in a number of patients is a golden or slate-gray
pigmentation due to a lipofuscin-like pigment that contains the amiodarone metabolite,
desethylamiodarone. In many patients, drug cessation is not a possibility, so broad-spectrum
photoprotection/behavioural avoidance of the wavelengths and wearing dark clothing are
advised. Occasionally, narrowband UVB phototherapy can help probably through a epidermal
thickening and pigmentation effect (artificial hardening) (52). The persistence of pigmentation
and photosensitivity can be protracted for years (53), although most generally clear over a
two-year period.
Phenothiazine
CPZ which continues to be used, although less commonly than in the past, was first described
in the 1950s as a photosensitizer. It is similar to amiodarone in that it produces a UV-induced
abnormal burning immediate erythema of exposed sites (Fig. 6), which has a second erythema
peak at approximately 24 hours. As a classical phototoxic drug, it is often used as an in vitro
positive control. It has a dose-related effect that does cause severe pigmentation of both
golden and slate-gray types. Both of these are reversible on drug cessation, although can
FIGURE 6 Chlorpromazine phototoxic

blistering of photoexposed forearm.
take many months. Unlike amiodarone, CPZ phototoxicity quickly resolves following drug
cessation.
It is interesting that CPZ is extensively metabolized with metabolites that are phototoxic.
Variability in the breakdown/accumulation of these metabolites may explain the different
degree of susceptibility to phototoxicity. CPZ has been reported capable of photoallergy.
This may occur following exposure to crushed CPZ tablet dust, a problem no longer seen
since the advent of CPZ syrup.
Quinine
Most commonly prescribed for night cramps, this agent occasionally produces an idiosyncratic
photodistributed leukomelanoderma. Phototesting of these patients reveals sensitivity within
the UVB/A region (54) with resolution of susceptibility lasting many months after taking the
drug. A similar problem has been described with hydroxychloroquine (55); again it appears
idiosyncratic. Laboratory studies suggest that the phototoxic mechanism is complex, raising
the possibility of interindividual pharmacokinetic factors. Treatment alternatives for painful
night cramps do exist. In those for whom that does not provide relief, drug dosage reduction
is worth considering.
Tetracyclines
This family of anti-inflammatory antibiotics has a number of members that are photoactive.
Originally, dimethylchlortetracycline (DMCT) was well recognized for phototoxicity, which
follows a sunburn pattern. DMCT is now rarely used. Minocycline seems only rarely associated
with sunburn-like phototoxicity, much more commonly reported is doxycycline, particularly
when taken at the higher dose of 200 mg/day or above (56,57). Occasionally, photo-onycholysis
is seen (58), although the majority shows the sunburn-like picture, rarely is pseudoporphyria
reported.
Calcium channel antagonists

An unusual form of photosensitivity has been reported with nifedipine (59). Telangiectasia of
photoexposed sites with sparing at clothing and watchstrap cut-off is seen when looked for.
Some patients do describe an erythematous phototoxicity. Both appear reversible.
Photodynamic therapy reactions

Two intravenous photosensitizers used therapeutically to induce phototoxic damage of
systemic tumors, include Photofrinw (porfimer sodium) and Foscanw (temoporfin). Both are
associated with persistent phototoxicity, which is visible wavelength – dependent and poten-
tially severe. Following intravenous injection, patients who have been administered Photofrin
are encouraged to avoid bright sunlight and even incandescent light for four to six weeks. Some
patients may develop severe phototoxicity within the infusion arm beyond this period
suggesting that the drug persists at a higher concentration at that site much longer than else-
where in the body. Work is underway to produce agents more rapidly eliminated, although
such an agent, Verteporfin, has been associated with severe skin photosensitization (60).
A wide range of therapeutic agents is associated with photosensitive skin reactions. For-
tunately, the majority of these therapies can be substituted by nonphotoactive alternatives. Pre-
dictable phototoxicity seen with the common drugs is rarely a diagnostic problem for
clinicians. Much more of an issue are the idiosyncratic reactions as seen in the rarer forms of
phototoxicity and other mechanisms.
REFERENCES
1. Ferguson J. Drug and chemical photosensitivity. In: Hawk JLM, ed. Photodermatology. New York:
Oxford University Press, 1999:155– 169.
2. Selvaag E. Clinical drug photosensitivity. A retrospective analysis of reports to the Norwegian
Adverse Drug Reactions Committee from the years 1970 – 1994. Photodermatol Photoimmunol Photo-
med 1997; 13(1 – 2):21– 23.
3. Cronin E. Contact Dermatitis. London: Churchill Livingstone, 1980.
4. DeLeo VA, Harber LC. Contact photodermatitis. In: Fisher AA, ed. Contact Dermatitis, 3rd ed.
Philadelphia: Lea & Febiger, 1986.
5. Marks JG Jr, DeLeo VA. Contact and Occupational Dermatology. 2nd ed. St. Louis: Mosby-Yearbook,
1992.
6. Emmett EA. Phototoxicity and photosensitivity reactions. In: Adams RM, ed. Occupational Skin
Disease. 2nd ed. Philadelphia: WB Saunders, 1990.
7. Thune P, Jansen C, Wennersten G, et al. The Scandinavian multicenter photopatch study: 1980 to 1985-
final report. Photodermatology 1988; 5:261– 269.
8. Crow KD, Alexander E. Buck WHL, Johnson BE, Magnus IA, Porter AD. Photosensitivity due to
pitch. Br J Dermatol 1961; 73:220– 232.
9. Emmett EA. Cutaneous and ocular hazards of roofers. Occup Med 1986; 1:307– 322.
10. Emmett EA, Stetzer W, Taphorn B. Phototoxic keratoconjunctivitis from coal-tar pitch volatiles.
Science 1977; 198:841– 842.
11. Kochevar IE, Armstrong RB, Einbinder J, Walther RR, Harber LC. Coal tar phototoxicity: active com-
pounds and action spectra. Photochem Photobiol 1982; 38(1):65– 69.
12. Jonas AD. Creosote burns. J Ind Hyg Toxicol 1943; 25:418– 420.
13. Heyl T, Mellett WA. Creosote dermatitis in an ammunition depot. S Afr Med J 1982; 62:66– 67.
14. Tunget CL, Turchen SG, Manoguerra AS, et al. Sunlight and the plant: a toxic combination: severe
phytophotodermatitis from Cneoridium dumosum. Cutis 1994; 54(6):400– 402.
15. Klaber R. Phytophotodermatitis. Br J Dermatol 1942; 54:193– 211.
16. Birmingham DJ, Key MM, Tubich GE, Perone VB. Phototoxic bullae among celery harvesters. Arch
Dermatol 1961; 83:73– 87.
17. Morbidity and Mortality Weekly Report. Phytophotodermatitis among grocery workers. JAMA 1985;
253:753.
18. Emmett EA, Taphorn BR, Kominsky JR. Phototoxicity occurring during the manufacture of ultraviolet
cured ink. Arch Dermatol 1977; 113:770– 775.
19. Gardiner JS, Dickson A, Macleod TM, Frain-Bell W. The investigation of photocontact dermatitis in a
dye manufacturing process. Br J Dermatol 1972; 86:264.
20. Thune P. Contact and photocontact allergy to sunscreens. Photodermatology 1984; 1:5 –9.
21. Menz MB, Sigfrid AM, Connolly SM. Photopatch testing: a six-year experience. J Am Acad Dermatol
1988; 18:1044– 1047.
22. DeLeo VA, Suarez SM, Maso MJ. Photoallergic contact dermatitis: results of photopatch testing in
New York—1985 to 1990. Arch Dermatol. 1992; 128:1513– 1518.
23. Yashar SS, Lim HW. Classification and evaluation of photodermatoses. Dermatol Therapy 2003;
16:1– 7.
24. Bruynzeel DP, Ferguson J, Anderson K, et al. Photopatch testing: a consensus methodology for
Europe. J Eur Acad Dermatol Venereol 2004; 18:679– 682.
25. Wilkinson DS. Photodermatitis due to tetrachlorosalicylanilide. Br J Dermatol 1961; 73:213– 219.
26. Calnan CD, Harman RRM, Wells GC. Photodermatitis from soaps. Br Med J 1961; 2:1266.
27. Matthieu L, Meuleman L, Van Hecke E, et al. Contact and photocontact allergy to ketoprofen. The
Belgium experience. Contact Dermatitis 2004; 50:238– 241.
28. Neumann NJ, Hölzle E, Plewig G, et al. Photopatch testing: the 12-year experience of the German,
Austrian, and Swiss photopatch test group. J Am Acad Dermatol 2000; 42:183– 192.
29. Frain-Bell W, Gardiner J. Photocontact dermatitis due to quindoxin. Contact Dermatitis 1976;
1:256– 257.
30. Scott KW, Dawson TAJ. Photocontact dermatitis arising from the presence of quindoxin in annual
feeding stuffs. Br J Dermatol 1974; 90:543– 546.
31. Schauder S, Schroder W, Geier J. Olaquindox-induced airborne photoallergic contact dermatitis
followed by transient or persistent light reactions in 15 pig breeders. Contact Dermatitis 1996;
35(6):344– 354.
32. Mark KA, Brancaccio RR, Soter NA, Cohen DE. Allergic and photoallergic contact dermatitis to plant
and pesticide allergens. Arch Dermatol 1999; 135:67– 70.
33. Feuerman EJ. Chromates as the cause of contact dermatitis in housewives. Dermatologica 1971;
143:292– 297.
34. Tronnier H. Zur Lichtempfindlichkeit von Ekzematikern (unter besonderer Berücksichtigung des
Chromatekzems). Arch Klin Exp Derm 1970; 237:494– 506.
35. Burry JM, Kuchel R, Reid JG, Kirk J. Australian bush dermatitis: compositae dermatitis in South
Australia. Med J Aust 1973; 1:110 – 116.
36. Epstein S. Role of dermal sensitivity in ragweed contact dermatitis. Arch Dermatol 1960; 82:48– 55.
37. Thune PO, Solberg YJ. Photosensitivity and allergy to aromatic lichen acids, compositae oleoresins
and other plant substances. Contact Dermatitis 1980; 6:81 – 87.
38. Ferguson J. Photosensitivity due to drugs. Photoderm Photoimmunol Photomed 2002; 18:262– 269.
39. EMEA: http://www.emea.eu.int/pdfs/human/swp/039801en.pdf; FDA: http://www.fda.gov.cder/
guidance/3640fnl.pdf.
40. Jacobs A, Brown PC, Conrad C, et al. CDER photosafety guidance for industry. Toxicol Pathol 2004;
32(suppl 2):17– 18.
41. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol
1988; 124:869– 871.
42. LaDuca JR, Bouman PH, Gaspari AA. Nonsteroidal anti-inflammatory drug-induced pseudopor-
phyria: a case series. J Cutan Med Surg 2002; 6(4):320– 326.
43. Maerker JM, Harm A, Foeldvari I, et al. Naproxen-induced pseudoporphyria. Hautarzt 2001;
52(11):1026– 1029.
44. Sharp MT, Horn, TD. Pseudoporphyria induced by voriconazole. J Am Acad Dermatol 2005;
53(2):341– 345.
45. Johnston GA. Thiazide-induced lichenoid photosensitivity. Clin Exp Dermatol 2002; 27(8):670– 672.
46. Reed BR, Huff J, Jones SK, et al. Subacute cutaneous lupus erythematosus associated with hydro-
chlorothiazide therapy. Ann Intern Med 1985; 103:49– 51.
47. Lowe G, Walker EM, Johnson BE, et al. Thiazide-induced photosensitivity, the use of bumetanide as
alternative therapy: in vitro and in vivo studies. Br J Dermatol 1989; 121(suppl):58.
48. Burry JN, Lawrence JR. Phototoxic blisters from high frusemide dosage. Br J Dermatol 1976;
94:495– 499.
49. Ferguson J. Phototoxicity due to fluoroquinolones. In: Hooper DC, Rubinstein E, eds. Quinolone Anti-
microbial Agents. 3rd ed. Washington, D.C.: ASM Press, 2003:449– 458.
50. Chalmers RTG, Muston HL, Srinivas V, et al. High incidence of amiodarone-induced photosensitivity
in North-West England. Br J Dermatol 1982; 285:341.
51. Rappersberger K, Hönigsmann H, Ortel B, et al. Photosensitivity and hyperpigmentation in amiodar-
one-treated patients: incidence, time course, and recovery. J Invest Dermatol 1989; 93(2):201– 209.
52. Collins P, Ferguson J. Narrow-band (TL-01) phototherapy: an effective preventative treatment for the
photodermatoses. Br J Dermatol 1995; 132:956– 963.
53. Yones SS, O’Donoghue NB, Palmer RA, et al. Persistent severe amiodarone-induced photosensitivity.
Clin Exp Dermatol 2005; 30(5):500– 502.
54. Ferguson J, Addo HA, Johnson BE, et al. Quinine induced photosensitivity: clinical and experimental
studies. Br J Dermatol 1987; 117(5):631– 640.
55. Metayer I, Balguerie X, Courville P, et al. Photodermatosis induced by hydroxychloroquine: 4 cases.
Ann Dermatol Venereol 2001; 128(6 – 7):729– 731.
56. Layton AM, Cunliffe J. Photosensitive eruptions to doxycycline—a dose related phenomenon. Br J
Dermatol 1992; 127(suppl 30):31.
57. VA Cooperative No. 475 Group. Benefits and harms of doxycycline treatment for Gulf War veterans’
illnesses: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2004; 141(2):85– 94.
58. Carroll LA, Laumann AE. Doxycycline-induced photo-onycholysis. J. Drugs Dermatol 2003;
2(6):662– 663.
59. Collins P, Ferguson J. Photodistributed nifedipine-induced facial telangiectasia. Br J Dermatol 1993;
129(5):630–633.
60. Asensio Sanchez VM, Carral Azor A, Garcia Pascual A. Verteporfin and photosensitivity in diabetic.
Arch Soc Esp Oftalmol 2003; 78 (5):227– 229.
15 Cutaneous Porphyrias
Gillian M. Murphy
Department of Dermatology, Beaumont Hospital, Dublin, Ireland
Karl E. Anderson
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Texas Medical
Branch, Galveston, Texas, U.S.A.
B The porphyrias are each caused by specific enzyme deficiencies in heme

biosynthesis.
B Patterns of elevated porphyrins and porphyrin precursors in urine stool
and blood enable delineation of each porphyria type.
B Porphyria cutanea tarda is commonest in adults, treatment induces

remission.
B Symptoms of erythropoietic protoporphyria usually stars in childhood.
B Bone marrow transplantation may induce cure in congenital

erythropoietic porphyria.
B Diagnosis of acute porphyria is essential as avoidance of trigger factors

for acute attacks may be lifesaving (an updated list of safe drugs is
available at www.porphyria-europe.com/); treatment of acute attacks
may be lifesaving.
B Genetic counseling should be provided with inherited porphyrias.

220 Murphy and Anderson
INTRODUCTION
he porphyrias are uncommon disorders due to deficiencies of enzymes in the metabolic
T pathway for synthesizing heme (Fig. 1). These enzyme deficiencies can lead to accumu-
lation of pathway intermediates and either skin photosensitivity (caused by porphyrins
in the cutaneous porphyrias) or neurological attacks (associated with increases in porphyrin
precursors in the acute porphyrias). Intermediates accumulate first in either the bone
marrow, where erythrocyte precursors actively synthesize heme for hemoglobin, or in liver,
which produces large amounts of cytochrome P450 enzymes. On this basis, porphyrias are
classified as either erythropoietic or hepatic (Table 1). Heme is also produced in other tissues
for a variety of essential hemoproteins such as respiratory cytochromes, catalase and
myoglobin.
The cutaneous manifestations of the porphyrias described in this chapter occur in both of
the erythropoietic porphyrias and in three of the five hepatic porphyrias. When porphyrins
absorb light at the Soret band region (400 – 410 nm), they enter an excited energy state
and then release energy as fluorescence and by the formation of singlet oxygen and other
FIGURE 1 The heme biosynthetic pathway. Enzymes catalyzing each step are indicated in italics, the products are in
bold, and the diseases resulting from deficiencies in activity of each enzyme are underlined. Mutations of the erythroid
form of d-aminolevulinic acid synthase, encoded by a gene on the X-chromosome, are found in many cases of
sideroblastic anemia. Deficiency of the ubiquitous enzyme, encoded by a gene on chromosome 3, has not been
described. Induction of the ubiquitous enzyme, which is rate limiting in liver, and its feedback repression by the
endproduct heme, play key roles in determining severity of the acute hepatic porphyrias.
Cutaneous Porphyrias 221
TABLE 1 Classification of the Porphyrias

Acute porphyrias Cutaneous porphyrias
Hepatic porphyrias ALAD porphyria Porphyria cutanea tarda
Acute intermittent porphyria
Hereditary coproporphyria
Variegate porphyria
Erythropoietic porphyrias Congenital erythropoietic porphyria
Erythropoietic protoporphyria
Abbreviation: ALAD, d-aminolevulinic acid dehydratase.
oxygen species that can produce tissue damage. Neurological manifestations are important to
recognize because they occur in two types of cutaneous porphyria, and are described briefly.
Porphyrins are tetrapyrroles, whereby four pyrroles form a large macrocycle. Heme
(iron protoporphyrin) and other metalloporphyrins are formed by inserting a metal atom into
the porphyrin macrocycle. Some porphyrins, including uroporphyrin, coproporphyrin and
protoporphyrin have many conjugated double bonds, are reddish in color and can absorb
visible light leading to generation of excited states. Most of the reduced porphyrin intermediates
in the pathway (e.g., uroporphyrinogen, coproporphyrinogen) and heme are colorless,
nonfluorescent and nonphotosensitizing.
The type of cellular damage depends on the solubility and tissue distribution of porphyr-
ins. Two main patterns of skin damage are seen in the porphyrias. Excess amounts of water
soluble uro- and coproporphyrins, which contain eight and four carboxyl groups, respectively,
leads to chronic blistering of sun exposed skin, as seen in most of the cutaneous porphyrias.
The quite different skin manifestations in erythropoietic protoporphyria (EPP), which consist
of immediate burning sensation in the skin, sometimes followed by swelling, redness,
purpura and erosions, are due to accumulation of protoporphyrin, which has only two
carboxyl side chains, and is water-insoluble and lipophilic.
Patterns of individual porphyrins in plasma, erythrocytes, urine and stool and porphyrin
precursors in urine help explain the clinical features of the porphyrias and allow the diagnosis
of each to be made by biochemical methods (Tables 2, 3). Porphyrin abnormalities occur without
TABLE 2 Heme Pathway Intermediates and Their Derivatives that Accumulate and are Excreted in the Various
Porphyrias
Porphyria Erythrocytes Plasma porphyrins Urine Feces
a
ADP Zn protoporphyrin NS ALA, coproporphyrin III Coproporphyrin III
AIP NS NS ALA, PBG, Uroporphyrin NS
CEP Uroporphyrin I, Marked increase Uroporphyrin I, Coproporphyrin I
coproporphyrin I, (peak 620 nm)b coproporphyrin I
Zn protoporphyrin
PCT NS Increased (peak 620 nm) Uroporphyrin, Isocoproporphyrinc
heptacarboxyl porphyrin
HEP Zn protoporphyrin Marked increase Uroporphyrin, Isocoproporphyrinc
(peak 620 nm) heptacarboxyl porphyrin
HCP NS ALA, PBG, coproporphyrin III Coproporphyrin III
VP NS Increased (peak 626 nm) ALA, PBG, coproporphyrin III Coproporphyrin III,
protoporphyrin
EPP Free protoporphyrin Increased (peak 635 nm) NS Protoporphyrin
Substantial increases that are diagnostically important are shown. With the exception of protoporphyrin, all porphyrins listed represent
auto-oxidized derivatives of the corresponding porphyrinogens (reduced porphyrins) that are the actual pathway intermediates.
a
Normal or not substantially increased.
b
Fluorescence emission maximum of diluted plasma at neutral pH, which differentiates variegate porphyria and erythropoietic
protoporphyria from other cutaneous porphyrias.
c
Isocoproporphyrin is usually not the predominant fraction of fecal porphyrins in porphyria cutanea tarda and hepatoerythropoietic
porphyria, but the increased amount is part of a complex pattern that is distinctive.
Abbreviations: ADP, d-Aminolevulinic acid dehydratase porphyria; AIP, acute intermittent porphyria; ALA, d-aminolevulinic acid; CEP,
congenital erythropoietic porphyria; EPP, erythropoietic protoporphyria; HEP, hepatoerythropoietic porphyria; HCP, hereditary
coproporphyria; PBG, porphobilinogen; PCT, porphyria cutanea tarda; VP, variegate porphyria.
TABLE 3 Diagnostic Evaluations for Cutaneous Porphyrias

Potential types of First-line tests (for Second-line testsa (for
Clinical features porphyria screening) confirmation)
Blistering lesions PCT, VP, HCP, CEP, Plasma totalb,c or Plasma fluorescence scanb,d
HEP
Urinary total porphyrinsb Fractionation of porphyrins if
totals elevated
Fecal and erythrocyte total
porphyrins
Urinary d-aminolevulinic acid and
porphobilinogene
Nonblistering EPP Erythrocyte porphyrinsb or
photosensitivity
Plasma total porphyrinsc
Particularly when clinical features suggest the more common porphyrias, it is useful and most cost-effective to rely on a few first-line
tests for screening.
a
In addition to all screening tests listed.
b
Screening tests that are sensitive for the uses shown.
c
Screening tests that are specific for the uses shown.
d
In some laboratories, plasma fluorescence scanning is used for screening, instead of measuring total plasma porphyrins.
e
Elevation of these porphyrin precursors (especially porphobilinogen) is specific evidence for the acute porphyrias, of which two
(hereditary coproporphyria and variegate porphyria) can cause blistering skin lesions.
Total urinary, fecal, and erythrocyte porphyrins are elevated nonspecifically in many medical conditions; determining patterns of the
individual porphyrins (for example by HPLC separation) provide more specific information, but adds expense and is seldom necessary
for screening.
Abbreviations: CEP, congenital erythropoietic porphyria; EPP, Erythropoietic protoporphyria; HCP, hereditary coproporphyria; HEP,
hepatoerythropoietic porphyria; PCT, porphyria cutanea tarda; VP, variegate porphyria.
photosensitivity or neurological symptoms in many other conditions, such as sideroblastic and

hemolytic anemias, iron deficiency, renal failure, hepatobiliary disease, and gastrointestinal
hemorrhage. Rarely, as in some cases of sideroblastic anemia, there are associated photosensi-
tivity features (1). A few conditions, such as lead poisoning and hereditary tyrosinemia type 1,
are associated with increases in porphyrin precursors as well as porphyrins, particularly in
erythrocytes, and urine.
Tests for porphyria should be carried out by a quality assured laboratory as missed diag-
noses may be a consequence of false negative tests. False positive results and inconsequential
abnormalities are also problematic. Measurement of plasma porphyrins or spectrofluorimetric
scanning of diluted plasma at neutral pH will detect active cutaneous porphyrias and are
useful for screening (2). Ethylene diamine tetra acetic acid (EDTA) plasma samples are more
stable than serum samples. Cholestasis and some drugs can interfere with plasma fluorimetric
assessment. Gene carriers with latent disease in family studies may be identified by measuring
enzyme activity. However, DNA analysis is more reliable and becoming more widely used.
HISTORY OF THE PORPHYRIAS

The first documented reference to porphyria was in 1841 by Scherer. Acute porphyria was first
described in Holland by Stokvis in 1889. In 1911, Günther described what we now term conge-
nital erythropoietic porphyria (CEP). In 1912, Meyer-Betz injected himself with haematopor-
phyrin and became acutely photosensitive, thereby demonstrated that porphyrins can cause
acute photosensitivity (3).
Acute intermittent porphyria was characterized by Waldenström in 1937, and variegate
porphyria was recognized in South Africa in the 1940s and 1950s. In the 1950s, a massive out-
break of porphyria cutanea tarda (PCT) occurred in eastern Turkey (4), where an impoverished
population consumed wheat that had been intended for planting and had been treated with the
fungicide hexachlorobenzene. EPP, now known to be the third most common porphyria, was
not clearly described until 1961.
In the 1970s and thereafter, specific enzyme deficiencies were recognized in the seven
major types of porphyria, and subsequently the genes encoding these enzymes were cloned
and sequenced. Multiple mutations have been identified in all porphyrias except the sporadic
TABLE 4 Defective Enzymes in Porphyrias

Porphyria Defective enzyme Chromosomal location
ALA dehydratase porphyria (ADP) ALA dehydratase (ALAD) 9q34
Acute intermittent porphyria (AIP) Porphobilinogen deaminase (PBGD) 11q23.3
Congenital erythropoietic porphyria (CEP) Uroporphyrinogen III synthase (UROS) 10q25.3 ! q26.3
Porphyria cutanea tarda (PCT) Uroporphyrinogen decarboxylase (UROD) 1p34
Hepatoerythropoietic porphyria (HEP)
Hereditary coproporphyria (HCP) Coproporphyrinogen oxidase (CPO) 3q12.1
Variegate porphyria Protoporphyrinogen oxidase (PPO) 1q22 ! q23
Erythropoietic protoporphyria (EPP) Ferrochelatase (FECH) 18q22
form of PCT (Fig. 1, Table 1). In addition, rare homozygous cases of the autosomal dominant
porphyrias, and more complex cases with dual enzyme defects have been described.
PORPHYRIAS CAUSING BLISTERING SKIN LESIONS

Five types of porphyria can present with identical blistering skin lesions, but are readily differ-
entiated by biochemical testing (Tables 1 – 3). Defective enzymes associated with these porphyr-
ias have been identified (Fig. 1, Table 4). In three, namely PCT, variegate porphyria (VP) and
hereditary coproporphyria (HCP) symptoms usually begin in adult life. HCP and VP can
also cause acute neurological symptoms. Cutaneous manifestations of CEP and hepatoerythro-
poietic porphyria (HEP) are usually much more severe and mutilating and begin in early child-
hood. However, cases of CEP and HEP with less severe symptoms, sometimes beginning in
adulthood, are also well documented.
PORPHYRIA CUTANEA TARDA

This is the most common and readily treated human porphyria. PCT is due to an acquired
deficiency of Uroporphyrinogen decarboxylase (UROD) in the liver, although an inherited
deficiency of this enzyme and other genetic factors sometimes contribute. This is an iron-
related disease, which develops only with a normal or increased amount of hepatic iron.
Clinical Manifestations
Fluid-filled vesicles develop most commonly on the backs of the hands (Fig. 2), and also on
the forearms, face, ears, neck, legs, and feet. These commonly rupture, leading to chronic,
crusted lesions, and denuded areas that heal slowly and may become infected. The
sun-exposed skin is also friable, and bullae or denudation of skin may result from minor
trauma. Milia may precede or follow vesicle formation. Facial hypertrichosis and hyperpig-
mentation are particularly troubling in women (Fig. 3). Affected areas of skin sometimes
become severely thickened, scarred and calcified. These findings have been termed pseudo-
scleroderma. Identical skin lesions can occur in VP and much less commonly in HCP. Skin find-
ings in CEP and HEP resemble PCT but are usually much more severe and mutilating. Mild
or moderate erythrocytosis is common in PCT, and is not well explained. Chronic lung
disease from smoking may contribute.
A number of factors contribute to the development of PCT. These include alcohol use,
smoking, estrogens, viral infections—particularly hepatitis C and less commonly HIV, and
genetic factors such as mutations in the hemochromatosis gene (HFE) and inherited uropor-
phyrinogen decarboxylase (UROD) deficiency (5). Onset of symptoms at an earlier age may
be noted in patients with genetic predisposing factors, such as an inherited partial deficiency
of UROD or the C282Y/C282Y HFE genotype (6). Hepatitis C is especially prevalent among
PCT patients in southern Europe and North America but in itself insufficient to cause PCT
(7). Since the large outbreak of PCT in Turkey after hexachlorobenzene ingestion, individual
cases and small outbreaks have been reported after exposure to other halogenated cyclic aro-
matic hydrocarbons, including di- and trichlorophenols and 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD, dioxin) (8).
FIGURE 2 Blistering, erosions and scarring of

the hand in porphyria cutanea tarda. Source:
Courtesy of Herbert Hönigsmann, MD, Vienna,
Austria.
Nonspecific liver abnormalities, such increased transaminases and gamma-glutamyltran-

speptidase, are common. The long term risk for hepatocellular carcinoma is increased.
PCT may occur with other conditions predisposing to iron overload (9), and with diabetes
mellitus. PCT occurs more commonly than expected in patients with cutaneous and systemic
lupus erythematosus, precipitated by antimalarial therapy such as chloroquine which is por-
phyrogenic. Other immunological disorders such as scleroderma, and hematological malig-
nancy are other recognized association (10). PCT that develop in patients with end-stage
renal disease is usually more severe, sometimes with severe mutilation. In these patients,
lack of urinary porphyrin excretion leads to much higher concentrations of porphyrins in
plasma and the excess porphyrins are poorly dialyzable (11,12).
PATHOLOGY
Skin histopathology in PCT includes subepidermal blistering and deposition of periodic acid –
Schiff-positive material around blood vessels and fine fibrillar material at the dermoepithelial
FIGURE 3 Hyperpigmentation and hypertrichosis in

a woman with porphyria cutanea tarda. Source:
Courtesy of Herbert Hönigsmann, MD, Vienna,
Austria.
junction. Immunoglobulin G, other immunoglobulins, and complement are also deposited

around dermal blood vessels and at the dermoepithelial junction. These histologic changes
are found in other cutaneous porphyrias and are not diagnostic.
Liver tissue shows red fluorescence on exposure to long-wave ultraviolet light, reflecting
accumulation of massive amounts of porphyrins. Microscopic, needle-like inclusions are fluor-
escent and birefringent; these are located in lysosomes. Paracrystalline inclusions are seen in
mitochondria. Nonspecific liver histopathology includes necrosis, inflammation, increased
iron, and increased fat.

Hepatic UROD activity is ,20% of normal in PCT; however, UROD protein level in the liver is
normal. Iron does not directly inhibit UROD, but plays an essential porphyrinogenic role prob-
ably by promoting formation of reactive oxygen species that oxidize uroporphyrinogen to
uroporphyrin and to a yet uncharacterized UROD inhibitor.
UROD is a dimeric enzyme that catalyzes the sequential, clockwise removal of the four
carboxyl groups from the acetic acid side chains of uroporphyrinogen III (an octacarboxyl
porphyrinogen) to form the four methyl groups of coproporphyrinogen III (a tetracarboxyl por-
phyrinogen). Substantial deficiency of this enzyme results in accumulation of uroporphyrino-
gen (isomers I and III), the intermediate substrates hepta-, hexa-, and pentacarboxyl
porphyrinogens, and isocoproporphyrinogen. The latter is formed from pentacarboxyl por-
phyrinogen by coproporphyrinogen oxidase—a minor pathway that becomes accentuated
when hepatic UROD is deficient. These excess porphyrinogens (reduced porphyrins)
undergo nonenzymatic oxidation to the corresponding porphyrins (uro-, hepta-, hexa-, and
pentacarboxyl porphyrins, and isocoproporphyrins). The excess porphyrins circulate from
the liver to the skin, where sunlight exposure generates reactive oxygen species, activates
the complement system, and produces lysosomal damage (13)
Susceptibility Factors in Human Porphyria Cutanea Tarda

The following factors can contribute to the development of all types of PCT, including the
familial form (14).
1. Iron and HFE mutations. Serum ferritin levels are usually in the upper part of the normal
range. Prevalence of the C282Y mutation of the HFE gene, which is the major cause of
hemochromatosis in Caucasians, is increased in PCT, and 10% of patients may be
C282Y homozygotes, and tend to have more substantial increases in ferritin (15). In
southern Europe, where the C282Y is less prevalent, the H63D mutation is more commonly
associated (16). Murine models with disruption of one UROD allele [UROD(þ/2)] and
either one or two disrupted HFE alleles [HFE(þ/2) or HFE(2/2)] provide insight into
the roles of these mutations (17).
2. UROD mutations. Most patients (80%) have no mutations of the UROD gene, and are said
to have type 1 (sporadic) PCT. These patients have normal UROD activity in nonhepatic
tissues such as erythrocytes and unaffected relatives. However, 20% of PCT patients,
who are said to have familial (type 2) PCT, are heterozygous for mutations that reduce
UROD activity and immunoreactivity to 50% of normal in all tissues (including erythro-
cytes). This partial deficiency of UROD is inherited as an autosomal dominant trait.
Because penetrance is low, many patients with type 2 PCT have no family history of the
disease. Many different mutations of the UROD gene have been identified in type 2 PCT
(18). Type 3 PCT, which has not been clearly distinguished from type 1, describes the
rare occurrence of PCT in more than one family member, but with normal erythrocyte
UROD activity and no demonstrable UROD mutations.
3. Hepatitis C. The prevalence of hepatitis C in PCT ranges from 50% to 75% in many countries
(14,19). How hepatitis C contributes to the development of PCT is poorly understood.
4. HIV. PCT is less commonly associated with HIV infection (20). The mechanism is unknown,
but presumably is due to injury to hepatic tissue.
5. Alcohol. PCT has long been associated with excess alcohol use. Proposed mechanisms
include generation of active oxygen species that contribute to oxidative damage,
mitochondrial injury, depletion of reduced glutathione and other antioxidant defenses,

increased production of endotoxin, activation of Kupffer cells, and increased iron
absorption.
6. Smoking and cytochrome P450 enzymes. Smoking is less extensively studied as a risk factor
but is commonly associated with alcohol use in PCT (5,14). Smoking may contribute by
increasing oxidative stress and inducing hepatic cytochrome P450 enzymes. The latter
are thought to be important in oxidizing uroporphyrinogen to uroporphyrin, and generat-
ing a UROD inhibitor.
7. Antioxidants. Plasma ascorbate levels were reported to be substantially reduced in the
majority of patients with PCT (21). Low levels of serum carotenoids further suggest
that oxidant stress is important in PCT. Ascorbic acid deficiency can clearly contribute to
uroporphyria in laboratory models.
8. Estrogens. These are commonly associated with PCT, especially in women (5,14).
Laboratory Evaluation and Diagnosis

Plasma and urinary porphyrins are substantially increased in clinically manifest PCT, and a
predominance of uroporphyrin and heptacarboxyl porphyrin is considered diagnostic
(Table 2). Measurement of total plasma porphyrins is perhaps most useful for screening,
because urinary porphyrins are more subject to nonspecific increases especially in patients
with liver dysfunction. A normal value excludes all porphyrias that produce blistering skin
lesions. When increased, it is useful to determine the plasma fluorescence emission
maximum at neutral pH, because a maximum near 620 nm is characteristic of PCT (as well
as CEP and HCP) and, most importantly, excludes VP, which has a fluorescence maximum
at or near 626 nm (22). Urinary d-aminolevulinic acid (ALA) may be increased slightly in
PCT, and PBG is normal.
After a diagnosis of PCT is established, the familial (type 2) form is distinguished from
sporadic (type 1) PCT by finding decreased erythrocyte UROD activity, or more reliably by
finding a disease-related UROD mutation.
Pseudoporphyria (also known as pseudo-PCT) is a poorly understood condition that
presents with lesions that closely resemble PCT. Plasma porphyrins are not significantly
increased in this condition, and there is no evidence that it is a disorder of porphyrin metab-
olism. Potentially photosensitizing drugs such as nonsteroidal antiinflammatory agents are
sometimes implicated.
Treatment
Pseudoporphyria, VP, HCP, and even mild cases of CEP can produce similar cutaneous lesions
but are unresponsive to treatment that is effective in PCT. Therefore, it is important to accu-
rately establish the diagnosis biochemically. Liver imaging and a serum a-fetoprotein determi-
nation are advisable to exclude complicating hepatocellular carcinoma and to serve as a
baseline for follow-up.
Patients should be evaluated for susceptibility factors including alcohol use, smoking,
HCV and HIV infections, estrogen use, and HFE mutations (5,14), and should cease exposures
to exogenous agents that have contributed. Although drugs that are associated with exacerbations
of acute porphyrias are seldom reported to contribute to PCT, they should be avoided initially as a
precaution. Familial and sporadic forms of PCT are treated in the same manner.
Phlebotomy and low-dose chloroquine (or hydroxychloroquine) are alternative therapies
that if completed correctly almost always achieve a full remission. Prospective comparative
treatment trials are lacking. Phlebotomy reduces body iron stores and liver iron content, and
is considered the standard treatment at most centers. About 450 ml of blood can be removed
at one-two-week intervals until the serum ferritin is below 15 ng/mL, after which plasma
porphyrin levels become normal. Hemoglobin or hematocrit levels should be followed to
prevent symptomatic anemia. Continued phlebotomies are generally not needed, even if ferri-
tin levels later return to normal. Porphyrin levels can be followed and treatment restarted if
porphyrin levels begin to rise.
A low-dose regimen of chloroquine or hydroxychloroquine is most appropriate when

phlebotomy is contraindicated or poorly tolerated. These 4-aminoquinoline antimalarial
drugs concentrate in liver lysosomes and mitochondria, and may form complexes with and
mobilize porphyrins, or possibly hepatic iron. A low-dose regimen (chloroquine 125 mg or
hydroxychloroquine 100 mg—one half of a normal tablet—twice weekly until plasma or
urine porphyrins are normalized) achieves a remission over several months with few
side effects. Standard doses are likely to cause fever, malaise, nausea and transient acute hepa-
titis; therefore, they should be avoided. Low-dose chloroquine was reportedly not effective
in patients homozygous for the C282Y mutation of the HFE gene (22). Infusions of desferriox-
amine, an iron chelator, may be an alternative treatment approach when phlebotomy or
antimalarials are contraindicated.
In general, treatment of hepatitis C should be delayed until after PCT is in remission. PCT
is usually the more symptomatic of these conditions; its treatment has a higher response rate
and is completed more quickly. Treatment of hepatitis C may be more effective after iron
reduction. PCT sometimes presents during interferon-ribavirin treatment of hepatitis C,
when treatment of PCT may be precluded by complications such as anemia.
Treatment of PCT is more difficult when associated with end-stage renal disease. Low
volume phlebotomy (100 – 200 mL per treatment), combined with erythropoietin, are usually
effective (23).
HEPATOERYTHROPOIETIC PORPHYRIA
This very rare disorder, in which excess porphyrins originate mostly from the liver, is the
homozygous form of familial (type 2) PCT (24). In most cases, the clinical manifestations
resemble CEP (see later discussion) rather the PCT. Blistering skin lesions, hypertrichosis, scar-
ring, and red urine usually begin in infancy or childhood, and sclerodermoid skin changes are
sometimes prominent (Fig. 4). Unusually mild cases have been described (25).
FIGURE 4 Sclerotic skin in a patient with

hepatoerythropoietic porphyria. Source: Courtesy of
Herbert Hönigsmann, MD, Vienna, Austria.

Affected individuals are either homozygous or compound heterozygotes for UROD mutations.
A variety of UROD mutations have been identified (24,25).
Laboratory Evaluation, Diagnosis and Treatment

HEP is recognized biochemically by predominant accumulation and excretion of uropor-
phyrin, heptacarboxyl porphyrin and isocoproporphyrins, hence resembling the profile
of PCT. However, in contrast to PCT, increased erythrocyte zinc protoporphyrin is substan-
tially increased. At least one genotype may be associated with predominant excretion of
pentacarboxyl porphyrin (25).
Avoiding sunlight is important, as in CEP. Oral charcoal was helpful in a severe case
associated with dyserythropoiesis. Phlebotomy has shown little or no benefit. Retrovirus-
mediated gene transfer can correct porphyria in cell lines from patients with this disease,
which suggests that gene therapy may be applicable in the future (26).
VARIEGATE PORPHYRIA AND HEREDITARY COPROPORPHYRIA

d-Aminolevulinic acid dehydratase porphyria (ADP), acute intermittent porphyria (AIP), VP,
and HCP are four types of hepatic porphyria that can present with acute neurological
attacks (Table 1). Of note, only VP and HCP can present with blisters identical to those seen
in PCT. AIP is most common of the four porphyrias, and ADP the least. AIP, HCP, and
VP are autosomal dominant, whereas ADP autosomal recessive. All are heterogeneous at the
molecular level.
VP is especially common among Caucasians of Dutch descent in South Africa, and
almost all cases share the same protoporphyrinogen oxidase (PPO) mutation (R59W) (27).
A founder effect also accounts for the very high prevalence of AIP in northern Sweden
where almost all cases have the same porphobilinogen deaminase (PBGD) mutation
(W198X). Very rare cases of homozygous AIP, HCP, and VP are manifested by severe neuro-
logical impairment early in life but not acute attacks (28). Homozygous cases of HCP and VP
also have severe photosensitivity.
Neurological Manifestations
Symptoms of AIP are more common in women. The few documented cases of ADP have been
mostly males. South African patients with VP have been reported recently to have milder and
less frequent attacks than do patients with AIP, and these occur equally in males and females.
Acute porphyric attacks may occur any time after puberty and are often precipitated by certain
drugs, steroid hormones or dietary indiscretions. Abdominal pain is the most common
symptom, and is usually severe, steady, and poorly localized. Other characteristic but nonspe-
cific findings include tachycardia, hypertension, nausea, vomiting, constipation, bladder dys-
function and pain in the limbs, chest, head, and neck. Mental symptoms may include insomnia,
agitation and hallucinations. Fever, abdominal tenderness and leukocytosis are usually not
prominent.
Peripheral neuropathy occurs with some attacks and is a potentially life-threatening
complication. Porphyric neuropathy is primarily motoric, but is often accompanied by
paresthesia, dysesthesia, and loss of sensation. Muscle weakness usually affects the more
proximal muscles of the upper extremities initially and may progress to quadraparesis and
bulbar paralysis. This neuropathy begins with axonal degeneration rather than demyeliniza-
tion. Cranial nerves may be affected. In addition to mental changes, central nervous system
involvement may include seizures and the syndrome of inappropriate ADH secretion
(SIADH).
Attacks may resolve within hours or days if the disease is recognized and treatment insti-
tuted early. Advanced motor neuropathy is usually associated with delayed diagnosis, but
with treatment may improve over a period of several years. Chronic pain and depression
have developed in some patients. AIP, HCP, and VP are commonly associated with mild
FIGURE 5 Erosions and hyperpigmentation in

variegate porphyria. Source: Courtesy of Herbert
Hönigsmann, MD, Vienna, Austria.
abnormalities in liver function, and the risks of cirrhosis and especially hepatocellular carci-
noma (not associated with increases in serum a-fetoprotein) are increased (29). Additional
long term risks include chronic hypertension and impaired renal function, which sometimes
requires renal transplantation (30).
Cutaneous Manifestations
Blisters identical to those occurring in PCT occur commonly in VP (Fig. 5), much less com-
monly in HCP, and never in ADP and AIP. In HCP, hepatitis and other superimposed liver
diseases may increase porphyrin retention and photosensitivity (31). Oral contraceptives
may precipitate cutaneous manifestations of VP.

As shown in Figure 1, ADP, AIP, HCP, and VP are due to deficiencies of the second, third, sixth
and seventh enzymes of the heme biosynthetic pathway. ALAD is a zinc-containing, cytosolic
enzyme consisting of eight identical subunits.
Coproporphyrinogen oxidase (CPO) is localized in the mitochondrial intermembrane
space, is a dimer with a single active site, requires molecular oxygen, and is specific for the
coproporphyrinogen III (not I) (32). Harderoporphyrinogen, a tricarboxyl porphyrinogen, is
an intermediate in the two-step decarboxylation. Decarboxylation occurs first and more
rapidly at the two position, and most of the harderoporphyrinogen formed is not released
before being further decarboxylated at the four position to produce protoporphyrinogen
IX(106). However, some CPO mutations associated with a variant form of HCP termed hard-
eroporphyria impair substrate binding, and harderoporphyrinogen is prematurely released
and excreted in excess amounts as harderoporphyrin (33).
PPO is a homodimer found in the inner mitochondrial membrane. It catalyzes the oxi-
dation of protoporphyrinogen IX to protoporphyrin IX. Accumulation of protoporphyrinogen
in VP may lead to inhibition of PBGD, which would account for increases in PBG, and
formation of porphyrin – peptide conjugates, which may be present in plasma.
Multiple mutations have been found in each of these disorders. Certain drugs (e.g., bar-
biturates, phenytoin, metoclopramide, rifampin, and progesterone) increase the synthesis of
heme and cytochrome P450 enzymes in the liver, which is associated with induction of
ALAS1, the initial and most rate-limiting enzyme of the pathway in the liver. This causes
the genetically deficient enzyme downstream form ALAS1 to become rate limiting. Restric-
tion of calories and carbohydrate may favor induction of ALAS1 in liver via the peroxisome
proliferator-activated receptor g coactivator 1a (PGC-1a).
Formation of neurotoxic intermediates (perhaps ALA), and impaired formation of

hemoproteins have been proposed as explanations for the neurologic symptoms.
Laboratory Findings and Diagnosis

A substantial increase in urinary PBG is a very specific indication that a patient has either AIP,
HCP or VP (34). Increased PBG is usually accompanied by a less pronounced increase in ALA.
Urinary coproporphyrin III are substantially increased in ADP, HCP, VP, and sometimes in AIP.
ALA and PBG are generally increased for some time after (and probably before) an attack and
increase further during the attack. Levels of these porphyrin precursors decrease more rapidly
with recovery in HCP and VP than in AIP. Urinary porphyrins can remain elevated in HCP and
VP after ALA and PBG return to normal.
Plasma porphyrins are normal or only slightly increased in ADP, AIP and most cases of
HCP. In HCP patients with skin lesions plasma porphyrins are presumably substantially
increased. Plasma porphyrins are commonly increased in VP. Fluorescence emission spectrum
of plasma porphyrins at neutral pH is characteristic and can rapidly and reliably distinguish
VP from other types of porphyria (Table 2). The emission peak is at or near 626 nm in VP,
620 nm in PCT, CEP, HCP, and (sometimes) AIP, and 634 nm in EPP (22). This fluorometric
method is more effective than examination of fecal porphyrins for detecting asymptomatic
VP (35).
Fecal porphyrins are normal or slightly increased in AIP, but substantially increased in HCP
and VP. Fecal porphyrins consist almost entirely of coproporphyrin III in HCP, while approxi-
mately equal amounts of coproporphyrin III and protoporphyrin is the usual finding in VP.
The ratio of fecal coproporphyrin III to coproporphyrin I is especially sensitive for detecting
latent HCP heterozygotes (especially adults) (35). An increase in fecal “pseudo-pentacarboxyl
porphyrin,” a dicarboxyl porphyrin derived from protoporphyrin, is sometimes noted in
VP. Increases in porphyrin precursors and porphyrins may be more severe in homozygous
AIP, HCP, and VP, and are accompanied by substantial increases in erythrocyte zinc
protoporphyrin.
Treatment and Prevention

Precipitating factors should be identified and removed whenever possible. Acute attacks often
require hospitalization and treatment with narcotic analgesics, a phenothiazine for nausea and
intravenous fluids for dehydration and electrolyte imbalances. Specific therapies, which act by
repressing ALAS1, are carbohydrate loading and hemin (hematin or heme arginate). Early
treatment with intravenous hemin is the most effective, and promptly reduces levels of ALA
and PBG to normal and leads to more rapid recovery. Carbohydrate loading (usually intrave-
nous glucose) can be used for mild attacks with mild pain and no paresis or hyponatremia.
Cimetidine has been recommended for human acute porphyrias, but the mechanism is
unclear and controlled observations are lacking. Treatment of seizures is problematic, since
most anticonvulsants can exacerbate acute porphyrias. Liver transplantation was effective
in a single case of severe AIP, but is still experimental. Long term control of hypertension
may help prevent chronic renal impairment. Liver imaging is recommended yearly for early
detection of hepatocellular carcinoma.
Symptoms can often be prevented by avoiding inciting factors. A list of safe and harmful
drugs that is updated periodically is available from the European Porphyria Initiative (37).
Pregnancy is usually well tolerated. Worsening symptoms during pregnancy are sometimes
due to harmful drugs, such as metoclopramide, or reduced caloric intake due to hyperemesis
gravidarum.
Consultation with a dietitian may be needed to address dietary indiscretions. GnRH ana-
logues are used for preventing repeated attacks that are confined to the luteal phase of the men-
strual cycle (37). Weekly or biweekly infusions of hemin are sometimes effective for preventing
noncyclic attacks. The intravenous hemin product usually given in Europe is heme arginate,
which is less thrombogenic than hematin (38).
No specific treatment is available for the chronic, blistering skin lesions, other than
protection from sunlight.
TABLE 5 Congenital Erythropoietic Protoporphyria: Clinical Features

Cutaneous features Other features and complications
Phototoxic burning on light exposure Red urine (pink staining of nappy)
Blistering and scarring of light exposed sites Brown-red teeth
Hypo and hyper-pigmentation Scleromalacia, with perforation in severe cases
Hypertrichosis and scarring alopecia Bone resorption
Deformities of hands, feet and face
Hemolytic anemia
Splenomegaly (+ hypersplenism)
Thrombocytopenia
CONGENITAL ERYTHROPOIETIC PORPHYRIA

CEP, also termed Günther disease, is a very rare autosomal recessive disease due to a deficiency
of UROS. Mathias Petry, one of the original cases described by Günther, had severe skin lesions
and mutilation and died at age 34.
Clinical features of CEP are summarized in Table 5. In most cases, reddish urine or pink stain-
ing of diapers by urine or meconium is observed shortly after birth. However, CEP can be
recognized a cause of fetal loss, or intrauterine hemolytic anemia and nonimmune hydrops
fetalis. Severe photosensitivity is usually noted soon after birth and may be worsened by photo-
therapy for hyperbilirubinemia (39). Skin friability, hypertrichosis, scarring, thickening, and
areas of hypo- and hyperpigmentation and scarring alopecia are common, and usually much
more severe than in PCT. In addition, phototoxic burning and blistering can lead to mutilation
of light-exposed parts (Fig. 6), and even resorption of acral regions and the nose. Scleral and
corneal damage (i.e., scleromalacia perforans) may occur. The teeth are characteristically red
brown in color due to porphyrin deposition—an appearance termed erythrodontia—and
FIGURE 6 Scarring and stained teeth in congenital

erythropoietic porphyria (Günthers disease).
fluoresce red with exposure to long-wave ultraviolet ligh (Fig. 6). Porphyrins are also deposited
in bone. Expansion of the hyperplastic bone marrow contributes to bone demineralization;
anemia is frequent, often hemolytic. Milder variants have been described with onset in adult
life, often associated with thrombocytopenia or myelodysplasia (40,41).

Many different mutations of the uroporphyrinogen III synthase (UROS) gene have been
described. Studies correlating genotype and phenotype suggest a link between mutation
type and disease severity (42). For example, a common mutation, C73R, is associated with
less than 1% of normal enzyme activity; it has a severe phenotype (severe and mutilating
photosensitivity, nonimmune hydrops fetalis, and/or transfusion dependency). Prenatal diag-
nosis is now possible. Late onset-CEP should prompt a search for underlying bone marrow
malignancy (40,41).
UROS catalyzes inversion one of the terminal pyrrole rings (ring D) of hydroxymethylbi-
lane (HMB), followed by rapid cyclization to form uroporphyrinogen III (Fig. 1). When the
enzyme is deficient, HMB accumulates in bone marrow erythroid cells and cyclizes nonenzy-
matically and less rapidly, to form uroporphyrinogen I. The excess amounts of uroporphyrino-
gen I are metabolized by UROD to coproporphyrinogen I; the latter is not a substrate for CPO
and therefore is not further metabolized. Both uroporphryinogen I and coproporphyrinogen
I are autooxidized to the corresponding porphyrins, which are then found in circulating
erythrocytes, plasma, urine and feces, and are photosensitizing.
Although UROS is markedly deficient in CEP, activity is sufficient to produce enough
uroporphyrinogen III for heme formation. Heme production is actually increased in the
bone marrow to compensate for ineffective erythropoiesis and hemolytic anemia. Intravascular
hemolysis and increased splenic uptake of circulating erythrocytes may occur because the cells
are damaged from the excess porphyrins or perhaps from a phototoxic mechanism.

CEP may is readily diagnosed by examination of porphyrins in urine, erythrocytes,
plasma, and stool. Immediate fluorescence is evident on illumination of urine with a
Wood’s lamp, and is confirmed by marked increases in urinary porphyrins. Stable fluor-
escence of erythrocytes is evident on blood smears by fluorescence microscopy. A Wood’s
light is also useful to demonstrate fluorescence of the teeth, and in bone and other tissues
post mortem.
Erythrocytes usually contain large amounts of uroporphyrin I, and to a lesser extent,
excessive amounts of coproporphyrin I (Table 2). However, zinc protoporphyrin predominates
in some cases, as in other autosomal recessive porphyrias. Urinary porphyrin excretion is
markedly increased, consisting mostly of uroporphyrin I and coproporphyrin I. Plasma
porphyrins are also markedly increased with a pattern similar to urine. Fecal porphyrins are
markedly increased, with a predominance of coproporphyrin I.
Treatment
The severity of the disease determines how much light restriction should be advocated. Man-
agement of severely affected individuals with CEP means absolute avoidance of solar radiation
of 360 to 500 nm for skin and eyes; scleromalacia perforans is an avoidable ocular complication.
Other therapeutic measures are summarized in Table 6. Reduction of light exposure by wearing
clothing, particularly hats, and gloves, greatly reduces damage to skin. Sunglasses excluding
UV and visible light in the blue region should be worn to avoid conjunctival damage and
scleromalacia perforans. Window glass and standard sunblocks are ineffective against visible
light. Opaque sunblocks are effective but not usually acceptable other than in young children.
Avoidance of outdoor activities is recommended and career guidance should advocate an
indoor occupation.
TABLE 6 Approaches to Treatment of Congenital Erythropoietic Porphyria

Mechanism Treatment Current status
Reduce light exposure Avoid sunlight, clothing, Essential
sunblocks.
Increase excretion of Oral superactivated charcoal Sometimes effective
porphyrins
Reduce hemolysis Splenectomy Sometimes effective; may be
temporary
Reduce bone marrow High level transfusion; may be Temporary effect; may be complicated
production of porphyrins combined with hydroxyurea by iron overload, or viral infections
Bone marrow transplantation Effective; requires suitable donor
Bone marrow or stem cell transplantation is the most effective current treatment, and has
resulted in marked reduction in porphyrin levels and photosensitivity (43,44). Gene therapy is
being studied in laboratory models including cells from CEP patients (45).
ERYTHROPOIETIC PROTOPORPHYRIA
EPP is due to impairment in the final step in the heme biosynthetic pathway, which is catalyzed
by the enzyme ferrochelatase (FECH). This is an autosomal dominant condition in most
affected families, with considerable variation in penetrance
EPP is the third most common porphyria and the commonest childhood porphyria, with symp-
toms usually evident by age two years (46). Table 7 summarizes the clinical features in EPP
(Fig. 7). Suspicion of EPP should be raised by the history of screaming or skin pain in a
child on going outdoors. Neurological symptoms are absent, except in some patients with
severe hepatic complications.
Protoporphyrin-containing gall stones may develop at an early age. Mild abnormalities of
liver function may be detected in about 10% (3), and liver failure affects about 5%. Protopor-
phyric liver disease may be chronic, but can progress rapidly and be fatal. Recently, a
variant form of EPP has been described in which FECH is not deficient and features of iron
deficiency are prominent, implying that a genetic defect impairing iron availability for the
final step in haem biosynthesis can cause EPP (47). Studies comparing hematological findings
in these patients and those with known FECH mutations are needed.
Pathology
Histological evaluation shows thickening of the basement membrane of the dermal vascula-
ture with an onion skin appearance due to repeated injury and repair. Complement activation
also appears to be part of the injury associated with EPP as is histamine release from
mast cells.
TABLE 7 Erythropoietic Protoporphyria: Cutaneous Features and Complications

Cutaneous features Complications
Pain or burning in sunlight Anemia
Erythema Gallstones
Swelling Liver failure
Purpura
Sores on light exposed areas, mainly face
Scarring (shallow, circular, or linear)
Waxy thickening
FIGURE 7 Typical scars on nose and cheeks with waxy

thickening of facial skin in erythropoietic protoporphyria.
Source: Courtesy of Herbert Hönigsmann, MD, Vienna,
Austria.

FECH is found in the mitochondrial inner membrane where it catalyzes the final step in heme
synthesis, which is the insertion of ferrous iron (Fe2þ) into protoporphyrin IX (Fig. 1). This
enzyme is specific for the reduced form of iron, but can utilize other metals such as Zn2þ
and Co2þ. The enzyme has a rate-limiting role in erythroid cells in the bone marrow,
which helps to explain protoporphyrin accumulation being almost entirely in erythroid
cells in EPP.
It is well recognized that EPP is not always inherited as a dominant disease and that clini-
cal expression does not occur in all affected family members. To date over 70 different FECH
mutations have been identified in EPP patients (48). EPP is explained in most families by the
combined presence of a disabling FECH mutation and a common, intronic polymorphism
(IVS3-48T/C) affecting the other FECH allele, which leads to an aberrantly spliced mRNA
that is degraded by a nonsense-mediated decay mechanism, such that the level of FECH
mRNA is decreased (49). In rare families without this polymorphism, EPP is associated with
inheritance of two FECH mutations and autosomal recessive inheritance. Therefore, it is
now established that EPP is an autosomal dominant disease at the molecular level in most
families, but that inheritance of two alleles associated with reduced FECH activity is required
for sufficient erythroid accumulation of protoporphyrin to cause symptoms.
Protoporphyric liver disease is believed to result from delivery of excess protoporphyrin
to the liver. Null mutations, result in a truncated protein, when heteroallelic with the IVS3-48T/
C polymorphism, have been associated with risk for EPP-related liver disease. For example,
amongst 89 patients with a null allele mutation, 18 developed liver disease, whereas all 19
patients with 16 missense mutations, which retain some enzyme activity, did not (50).
Similar to late-onset CEP, late-onset EPP can occur in patients who develop myelodyspla-
sia or myeloproliferative disorders. It is thought to be due to an acquired somatic mutation of
one FECH allele in bone marrow (51).

The diagnosis of EPP rests on finding substantially increased amounts protoporphyrin in
erythrocytes, with free protoporphyrin rather than zinc protoporphyrin accounting for the
increase (Table 3). Transient fluorescence of red cells by fluorescence microscopy reflects
this increase. Formation of zinc protoporphyrin is apparently depends on normal FECH

activity. In the variant form of EPP in which FECH activity is normal, erythrocytes contain
increased amounts of both free and zinc protoporphyrin. Erythrocyte zinc protoporphyrin
is also increased in many other conditions affecting erythrocytes, such as some homozygous
porphyrias, iron deficiency, lead poisoning, anemia of chronic disease and hemolytic
conditions (52).
A characteristic fluorescence peak (635 nm) is seen in plasma (diluted at neutral pH).
The urine does not contain excess porphyrins. Stool protoporphyrin is variably increased.
Protoporphyrin levels and sensitivity to sunlight generally are stable for many years in
the absence of liver disease, and precipitating factors that are important in the hepatic porphyr-
ias seldom contribute. Assays for FECH require cells containing mitochondria. DNA studies
are increasingly important, and will usually identify a disabling FECH mutation and the
IVS3-48T/C polymorphism.
Early diagnosis of liver complications is important, and is evidenced by abnormal liver
function tests, progressively increasing protoporphyrin levels in plasma and erythrocytes,
decreases in fecal protoporphyrin and increased photosensitivity (53). If liver function is pro-
gressively abnormal, liver biopsy may be indicated, and reveals marked deposition of proto-
porphyrin in hepatocytes and bile canniculi, fluorescent inclusions, periportal fibrosis, and
other features of cholestasis. Gallstones composed predominantly of protoporphyrin may
cause cholecystitis or biliary obstruction.
Treatment
Similar to CEP, photoprotection is essential. Other specific therapeutic options are summarized
in Table 8.
Patient follow up is advocated and erythrocyte and plasma porphyrin levels and liver
function tests can be repeated at 6 to 12 month intervals. DNA studies are recommended,
and the results facilitate genetic counseling. If patients need surgery, theatre personnel must
be warned about the potential hazards of exposure of internal organs to prolonged visible
light; severe burns to internal surfaces and wound dehiscence have been reported (54).
Theatre lights should be filtered to reduce radiation of 380 to 420 nm.
Cholestyramine and activated charcoal should be considered in the management of
hepatic complications of EPP. Other options include ursodeoxycholic acid, red blood cell
transfusions, exchange transfusion, plasma exchange, and intravenous hemin to suppress
TABLE 8 Approaches to Treatment of Erythropoietic Protoporphyria

Mechanism Treatment Current status
Reduce light exposure or b-Carotene Possible efficacy
quench reactive oxygen
species
Cysteine Possible efficacy
N-acetylcysteine Not effective
Narrowband UVB therapy Protection factor of 8 is useful
Reduce tissue wheal and flare Antihistamines Marginal efficacy
reaction
Interrupt enterohepatic Cholestyramine Reserve for incipient liver
circulation and increase disease
excretion of protoporphyrin
Reduce hemolysis or correct Splenectomy; transfusion Sometimes effective; may be
anemia temporary
Correct liver failure Liver transplantation Liver disease likely to recur
Reduce bone marrow Bone marrow transplantation Requires suitable donor
production of
protoporphyrin
Note: Indicated in patients with liver failure or liver transplantation.
erythroid and hepatic protoporphyrin production. Liver transplantation may be necessary

with more advanced disease (55). Acute neuropathy may occur with the very high porphyrin
levels encountered with liver failure (56). Intermediate survival rates (up to five years follow
up) after liver transplantation show survival rates comparable to the general transplant popu-
lation. However, recurrent disease in the graft is likely. Bone marrow transplantation pro-
duced a remission of EPP in a patient with acute myelogenous leukemia (57).
Sequential bone marrow transplantation was recently successful in preventing recurrence
of protoporphyric liver disease (58), and it is likely that this option will be considered
more often in the future. Studies mice suggest a potential future role for gene therapy in
human protoporphyria (59).
ACKNOWLEDGMENTS
Preparation of this chapter was supported in part by grants from the US Food and Drug
Administration Office of Orphan Product Development (FD-R-001459), the American Por-
phyria Foundation, and the National Center for Research Resources, National Institutes of
Health (MO1 RR-00073).
REFERENCES
1. Lim H, Cooper D, Sassa S, Dosik H, Buchness MR, Soter N. Photosensitivity abnormal porphyrin
profile and sideroblastic anemia. J Am Acad Dermatol 1992; 27 (2part 2):287– 292.
2. Gibbs NK, Traynor N, Ferguson J. Biochemical diagnosis of the cutaneous porphyrias: five years
experience of plasma spectro-fluorimetry. Br J Dermatol 1995; 133:18s
3. Murphy GM. Porphyria. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. London: Mosby.
2003:679– 689.
4. Schmid R. Cutaneous porphyria in turkey. N Eng J Med 1960; 263:397– 839
5. Egger NG, Goeger DE, Payne DA, Miskovsky EP, Weinman SA, Anderson KE. Porphyria cutanea
tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrino-
gen decarboxylase deficiency. Dig Dis Sci 2002; 47(2):419– 426.
6. Brady JJ, Jackson HA, Roberts AG, et al. Co-inheritance of mutations in the uroporphyrinogen
decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda.
J Invest Dermatol 2000; 115(5):868– 874.
7. O’Reilly FM, Darby C, Fogarty J, et al. Porphyrin metabolism in hepatitis C infection. Photodermatol
Photoimmunol Photomed 1996; 12(1):31– 33.
8. McConnell R, Anderson K, Russell W, et al. Angiosarcoma, porphyria cutanea tarda, and probable
chloracne in a worker exposed to waste oil contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Br J Ind Med 1993; 50:699– 703
9. O’Reilly FM, Darby C, Fogarty J, et al. Screening of patients with iron overload to identify hemochro-
matosis and porphyria cutanea tarda. Arch Dermatol 1997; 133(9):1098– 1101.
10. McKenna DB, Browne M, O’Donnell R, Murphy GM. Porphyria cutanea tarda and hematologic
malignancy—a report of 4 cases. Photodermatol Photoimmunol Photomed 1997; 13(4):143– 146.
11. Gibson GE, McGinnity E, McGrath P, et al. Cutaneous abnormalities and metabolic disturbance of
porphyrins in patients on maintenance haemodialysis. Clin Exp Dermatol 1997; 22(3):124– 127.
12. Anderson KE, Goeger DE, Carson RW, Lee S-MK, Stead RB. Erythropoietin for the treatment of por-
phyria cutanea tarda in a patient on long-term hemodialysis. N Engl J Med 1990; 322:315– 317.
13. Lim HW. Pathophysiology of cutaneous lesions in porphyria. Sem Hematol 1989; 26:114 – 119.
14. Elder GH. Porphyria cutanea tarda and related disorders. In: Kadish KM, Smith K, Guilard R, eds.
Porphyrin Handbook, Part II. Vol 14. San Diego: Academic Press, 2003:67– 92. chapter 88.
15. Roberts AG, Whatley SD, Nicklin S, et al. The frequency of hemochromatosis-associated alleles is
increased in British patients with sporadic porphyria cutanea tarda. Hepatology 1997; 25(1):159– 161.
16. Dereure O, Aguilar-Martinez P, Bessis D, et al. HFE mutations and transferrin receptor polymorph-
ism analysis in porphyria cutanea tarda: a prospective study of 36 cases from southern France.
Br J Dermatol 2001; 144(3):533– 539.
17. Philips JD, Jackson LK, Bunting M, et al. A mouse model of familial porphyria cutanea tarda. Proc
Natl Acad Sci USA 2001; 98(1):259– 264.
18. Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme biosynthesis: X-linked sideroblastic
anemias and the porphyries. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, eds.
The Metabolic and Molecular Basis of Inherited Disease. 8th ed. Vol II. New York: McGraw-Hill,
2001:2991– 3062, chapter 124.
19. Bulaj ZJ, Phillips JD, Ajioka RS, et al. Hemochromatosis genes and other factors contributing to the
pathogenesis of porphyria cutanea tarda. Blood 2000; 95(5):1565– 1571.
20. Wissel PS, Sordillo P, Anderson KE, Sassa S, Savillo RL, Kappas A. Porphyria cutanea tarda associated
with the acquired immune deficiency syndrome. Am J Hematology 1987; 25:107– 113.
21. Sinclair PR, Gorman G, Shedlofsky SI, et al. Ascorbic acid deficiency in porphyria cutanea tarda. J Lab
Clin Med 1997; 130:197– 201.
22. Poh-Fitzpatrick MB. A plasma porphyrin fluorescence marker for variegate porphyria. Arch Derma-
tol 1980; 116:543– 547.
23. Shieh S, Cohen JL, Lim HW. Management of porphyria cutanea tarda in the setting of chronic renal
failure: a case report and review. J Am Acad Dermatol 2000; 42(4):645– 652.
24. Moran-Jimenez MJ, Ged C, Romana M, et al. Uroporphyrinogen decarboxylase: complete human
gene sequence and molecular study of three families with hepatoerythropoietic porphyria. Am J
Hum Genet 1996; 58(4):712– 721.
25. Armstrong DK, Sharpe PC, Chambers CR, Whatley SD, Roberts AG, Elder GH. Hepatoerythropoietic
porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual
porphyrin excretion pattern. Br J Dermatol 2004; 151(4):920– 923.
26. Fontanellas A, Mazurier F, Moreau-Gaudry F, Belloc F, Ged C, de Verneuil H. Correction of uropor-
phyrinogen decarboxylase deficiency (hepatoerythropoietic porphyria) in Epstein-Barr virus-
transformed B- cell lines by retrovirus-mediated gene transfer: fluorescence-based selection of
transduced cells. Blood 1999; 94(2):465– 474.
27. Meissner P, Hift RJ, Corrigall A. Variegate porphyria In: Kadish KM, Smith K, Guilard R, eds.
Porphyrin Handbook, Part II. Vol 14. San Diego: Academic Press, 2003:93 – 120, chapter 89.
28. Solis C, Martinez-Bermejo A, Naidich TP, et al. Acute intermittent porphyria: studies of the severe
homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias.
Arch Neurol 2004; 61(11):1764– 1770.
29. Andant C, Puy H, Bogard C, et al. Hepatocellular carcinoma in patients with acute hepatic porphyria:
frequency of occurrence and related factors. J Hepatol 2000; 32(6):933–939.
30. Andersson C, Wikberg A, Stegmayr B, Lithner F. Renal symptomatology in patients with acute inter-
mittent porphyria. A population-based study. J Intern Med 2000; 248(4):319– 325.
31. Barone GW, Gurley BJ, Anderson KE, Ketel BL, Abul-Ezz SR. The tolerability of newer immunosup-
pressive medications in a patient with acute intermittent porphyria. J Clin Pharmacol 2000; 41:
113 – 115.
32. Cacheux V, Martasek P, Fougerousse F, et al. Localization of the human coproporphyrinogen oxidase
gene to chromosome band 3q12. Hum Genet 1994; 94:557– 559.
33. Nordmann Y, Grandchamp B, De Verneuil H, Phung L, Cartigny B, Fontaine G. Harderoporphyria: a
variant hereditary coproporphyria. J Clin Invest 1983; 72:1139 – 1149.
34. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment
of the acute porphyrias. Ann Intern Med 2005; 142(6):439– 450.
35. Hift RJ, Davidson BP, van der Hooft C, Meissner DM, Meissner PN. Plasma fluorescence scanning
and fecal porphyrin analysis for the diagnosis of variegate porphyria: precise determination of
sensitivity and specificity with detection of protoporphyrinogen oxidase mutations as a reference
standard. Clin Chem 2004; 50(5):915– 923.
36. (www.porphyria-europe.com/)
37. Anderson KE, Spitz IM, Bardin CW, Kappas A. A GnRH analogue prevents cyclical attacks of
porphyria. Arch Int Med 1990; 150:1469– 1474.
38. Timonen K, Mustajoki P, Tenhunen R, Lauharanta J. Effects of haem arginate on variegate porphyria.
Br J Dermatol 1990; 123:381– 387.
39. Murphy GM, Hawk JLM, Nicholson DC, et al. Congenital erythropoietic porphyria (Gunther’s
disease). Clin Exp Dermatology 1987; 12:61– 65.
40. Murphy A, Gibson G, Elder GH, Otridge BA, Murphy GM. Adult-onset congenital erythropoietic
porphyria (Gunther’s disease) presenting with thrombocytopenia. J Roy Soc Med 1995; 88:357– 358.
41. Kontos AP, Ozog D, Bichakjian C, Lim HW. Congenital erythropoietic porphyria associated
with myelodysplasia presenting in a 72-year-old man: report of a case and review of the literature.
Br J Dermatol 2003; 148(1):160– 164.
42. Xu W, Warner CA, Desnick RJ. Congenital erythropoietic porphyria: Identification and expression of
10 mutations in the uroporphyrinogen III synthase gene. J Clin Invest 1995; 95:905 –912.
43. Harada FA, Shwayder TA, Desnick RJ, Lim HW. Treatment of severe congenital erythropoietic
porphyria by Bone marrow transplantation. J Am Acad Dermatol 2001; 45:279– 282.
44. Dupuis-Girod S, Akkari V, Ged C, et al. Successful match-unrelated donor bone marrow transplan-
tation for congenital erythropoietic porphyria (Gunther disease). Eur J Pediatr 2005; 164(2):
104– 107. 2004, Nov 20.
45. Mazurier F, Geronimi F, Lamrissi-Garcia I, et al. Correction of deficient cd34(þ) cells from peripheral
blood after mobilization in a patient with congenital erythropoietic porphyria. Mol Ther 2001;
3(3):411 – 417.
46. Cox TM. Protoporphyria. In: Kadish KM, Smith K, Guilard R, eds. Porphyrin Handbook, Part II. vol
14. San Diego: Academic Press, 2003:121– 149, chapter 90.
47. Wilson JHP, Edixhoven-Bosdijk A, Koole-Lesuis R, Kroos MJ, de Rooij FWM. A new variant or ery-
thropoietic protoporphyria with normal ferrochelatase activity (abstract). Physiol Res 2003; 52:29S.
48. Stenson PD, Ball EV, Mort M, et al. Human Gene Mutation Database (HGMD): 2003 update. Hum
Mutat 2003; 21(6):577– 581.
49. Gouya L, Martin-Schmitt C, Robreau AM, et al. Contribution of a common single-nucleotide poly-
morphism to the genetic predisposition for erythropoietic protoporphyria. Am J Hum Genet 2006;
78(1):2– 14. 2005 Nov 15.
50. Minder EI, Gouya L, Schneider-Yin X, Deybach JC. A genotype-phenotype correlation between null-
allele mutations in the ferrochelatase gene and liver complication in patients with erythropoietic pro-
toporphyria. Cell Mol Biol (Noisy-le-grand) 2002; 48(1):91 –96.
51. Goodwin RG, Kell WJ, Laidler P, et al. Photosensitivity and acute liver injury in myeloproliferative
disorder secondary to late-onset protoporphyria caused by deletion of a ferrochelatase gene inhema-
topoietic cells. Blood 2006; 107(1):60– 62.
52. Hastka J, Lasserre JJ, Schwarzbeck A, Strauch M, Hehlmann R. Zinc protoporphyrin in anemia of
chronic disorders. Blood 1993; 81:1200– 1204.
53. Leone N, Marzano A, Cerutti E, et al. Liver transplantation for erythropoietic protoporphyria: report
of a case with medium term follow-up. Digestive & Liver Disease 2000; 32:799– 802.
54. Meerman L, Verwer R, Slooff MJ, et al Perioperative measures during liver transplantation for ery-
thropoietic protoporphyria. Transplantation 1994; 57:155– 158.
55. McGuire BM, Bonkovsky HL, Carithers RL, et al. Liver transplantation for erythropoietic protopor-
phyria liver disease. Liver Transpl 2005; 11(12):1590– 1596.
56. Muley SA, Midani HA, Rank JM, Carithers R, Parry GJ. Neuropathy in erythropoietic protoporphyr-
ias. Neurology 1998; 51(1):262– 265.
57. Poh-Fitzpatrick MB, Wang X, Anderson KE, Bloomer JE, Bolwell B, Lichtin AE. Erythropoietic proto-
porphyria: altered phenotype after bone marrow transplantation for myelogenous leukemia in a
patient heteroallelic for ferrochelatase gene mutations. J Amer Acad Dermatol 2002; 46:861 – 866.
58. Rand EB, Bunin N, Cochran W, Ruchelli E, Olthoff KM, Bloomer J. Sequential liver and bone marrow
transplantation for treatment of erythropoietic protoporphyria. Pediatrics 2006 (Epub ahead of print).
59. Richard E, Robert E, Cario-Andre M, et al. Hematopoietic stem cell gene therapy of murine protopor-
phyria by methylguanine-DNA-methyltransferase-mediated in vivo drug selection. Gene Ther 2004;
11(22):1638– 1647.
PART D: DNA REPAIR-DEFICIENT PHOTODERMATOSES
16 Xeroderma Pigmentosum and Other DNA

Repair-Deficient Photodermatoses
Mark Berneburg
Department of Dermatology, Eberhard Karls University, Tuebingen, Germany
Kenneth H. Kraemer
Basic Research Laboratory, Center for Cancer Research, National Cancer Institute,
Bethesda, Maryland, U.S.A.
B Xeroderma pigmentosum (XP), Cockayne Syndrome (CS), and

trichothiodystrophy (TTD): Rare autosomal recessive genodermatoses.
B XP: Photosensitivity, neuro-ophthalmological symptoms and a 1000-fold

increased skin cancer risk.
B CS: Photosensitivity, growth and mental retardation, neuro-

ophthalmological symptoms and progeria.
B TTD: Photosensitivity, growth and mental retardation, ichthyosis, and

sulfur deficient hair.
B Heterogeneity and overlaps exist between XP, CS, and TTD.
B The diagnosis of these diseases is based on their clinical symptoms and is

confirmed by cellular assays.
B Rigorous photoprotection is paramount in the care of DNA-repair

deficient photodermatoses.
240 Berneburg and Kraemer
INTRODUCTION
eroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD)
X are genodermatoses, characterized by deficiencies in DNA repair, basal transcription, or

translesion synthesis. They have defective nucleotide excision repair (NER), a mechanism
responsible for the repair of bulky forms of DNA damage such as sunlight induced DNA
photoproducts, DNA cross-links, and alkylation damage. With an estimated prevalence on
the order of one in a million in Western countries, these diseases are very rare. Consideration
of the typical symptoms usually permits making the correct clinical diagnosis. Patients sus-
pected of having one of these diseases can be referred to a center that specializes in their diag-
nosis and care. In recent years the underlying mechanisms as well as many of the genes
involved have been identified. The understanding of mechanisms such as DNA repair, basal
transcription, and translesion synthesis has helped to form a mechanistic explanation of symp-
toms of XP, TTD, and CS. These advances provide important insights into major physiological
processes such as aging and carcinogenesis. NER, the central defect in most of these diseases,
will be described in more detail.
NUCLEOTIDE EXCISION REPAIR

Patients suffering from XP, TTD, and CS are defective in the process of NER. This highly con-
served mechanism repairs a multitude of DNA lesions (1– 3). The repair of damage induced by
UV-radiation is one of its central functions. The most prevalent lesions induced by UV are
cyclobutane pyrimidine dimers (CPD). The 6-4 photoproducts (6-4PP) are less frequent but
far more helix-distorting. This distortion of the DNA helix permits easier recognition of the
6-4PP by repair enzymes and is probably why 6-4PP are removed from the genome at a
much faster rate than CPD.
Removal of DNA damage by NER can be carried out by two pathways, which differ
mainly in damage recognition. Damage present in actively transcribed genes stalls the tran-
scribing RNA polymerase at the site of the damage. This damage-polymerase complex leads
to recruitment of the repair machinery that removes the damage and allows transcription to
continue. The exact sequence, in particular the means of repair machinery recruitment of
this so-called transcription coupled repair (TCR), is not entirely clear (4, 5). The regulation of
the shift between transcription and repair is also not clear. However, it is known that a
protein complex of 10 components of the basal transcription factor TFIIH are involved in
DNA repair as well as in basal transcription, and the association of further proteins allows
this core complex to carry out either of these two functions (6,7). Repair of DNA damage
encountered by stalled RNA polymerase is very rapid. Within eight hours, TCR removes
about 50% of CPD from actively transcribed genes. Cells from patients with mutations in
most XP genes [except XPC and DDB2 (XPE)] have defects in TCR along with defects in
global genome repair (GGR) as described below. Cells from CS patients are defective in TCR
and have normal GGR.
GGR is a second form of repair that is carried out throughout the whole genome. GGR is
slower than TCR. In this subpathway DDB2 recognizes the damage attracting a heterodimer of
the XP-C protein and the human HR23B along with centrin 2. Cells from XP patients with
defects in DDB2 (XPE) or XP-C are defective in GGR but not in TCR (8).
Following damage recognition, both processes converge (9). The XP-A/RPA protein
complex binds to the damaged region and recruits the helicases XP-B and XP-D, which open
the DNA helix. The XP-F and XP-G endonucleases incise the damaged strand of DNA on
both sides of the lesion leaving a gap of about 21 to 29 nucleotides in length. This gap is
filled in by DNA polymerases.
In addition to repair of UV damage, the NER system repairs bulky DNA damage such as
that caused by carcinogens in cigarette smoke, by alkylating agents, and by DNA cross-linking
agents. They have functions in the repair of oxidative DNA damage, basal transcription (10 –
12), as well as transcriptional regulation of genes in cellular metabolism (13,14). Furthermore,
NER proteins are also involved in immunological processes (15 – 20). It appears likely that more
Xeroderma Pigmentosum and Other DNA Repair-Deﬁcient Photodermatoses 241
processes will be identified employing components of NER. With this as background, the
diseases XP, TTD, and CS will be described in further detail.
XERODERMA PIGMENTOSUM
Clinical Symptoms
XP is a rare autosomal recessive genetic disease with an estimated prevalence of 1 : 106 in the
United States and Europe and 1 : 105 in Japan. XP is characterized by an approximately 1000-
fold increased risk to develop skin cancer (1,21). The first symptoms of XP often manifest in
early childhood (Table 1). Some infants or small children with XP experience severe acute
sunburn reactions after a short exposure of the skin to sunlight. This reaction can persist for
several weeks. However, approximately half of the XP patients do not have this acute sun
sensitivity. They tan and freckle without burning. Many of these patients are in XP complementa-
tion group C. Freckling of the face of a child less than two years old is unusual in normal children
and is an indication that the diagnosis of XP should be considered. With continued sun exposure
freckling of sun-exposed skin continues to develop into the typical appearance of poikiloderma
with hypo- and hyperpigmentation, atrophy, and telangiectasias. These pigmentary changes in
addition to dry (xerotic) skin are reflected in the name of the disease (Fig. 1).
All XP patients are highly susceptible to development of sunlight-induced cancers of the
skin and eyes. The median age of onset of skin cancers in XP patients is less than 10 years. This
is a 50-year reduction in age of onset of first skin cancer as compared to the U.S. general popu-
lation and is an indication of the importance of DNA repair in protection against skin cancer.
In some XP patients who do not have acute sun sensitivity, the early pigmentary changes
might not be recognized, and the presence of skin cancers may be the first indication that the
child has XP. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) occur most fre-
quently. The frequency of BCC, SCC, and malignant melanoma is elevated about 1000-fold.
XP patients also have an increased frequency of internal cancers including central nervous
TABLE 1 Clinical Features of DNA Repair Deficient Photodermatoses Xeroderma Pigmentosum,

Cockayne Syndrome, and Trichothiodystrophy
Symptoms XP CS TTD
Skin photosensitivity þþ þþ þþ
Skin pigmentary changesa þþ – –
Skin telangiectasia þ – –
Ichthyosis – – þ
Skin cancer þþ – –
Fragile hair with cysteine – – þþ
deficiency
Ocular changesb þ (anterior eye) þ (cataracts, retinal þ (congenital catatacts,
degeneration) nystagmus)
Hearing loss—progressive þ or – þ –
sensorineural deafness
Mental retardation þ (early loss of cerebral þþ (early loss of þþ
function) cerebellar function)
Neuropathologyc – or þ (neuronal þ (dysmyelination) þ (dysmyelination)
degeneration)
Growth retardation – or þ þþ þþ
Infections – þ þ
Premature aging þ þþ þ
symptoms
a
Pigmentary changes include poikiloderma with hypo- and hyperpigmentation.
b
Ocular changes include conjunctival and corneal alterations in xeroderma pigmentosum (XP) and pigmentary retinal degeneration
and cataracts in Cockayne syndrome (CS).
c
Neurological changes in XP include microcephaly and are usually progressive and comprise reduction of deep tendon reflexes,
peripheral neuropathy and loss of intellectual function. CS patients often have microcephaly, lack of myelination, and may have
calcification of basal ganglia as well as other parts of the brain.
Abbreviations: 2, absent; þ, present; þþ, markedly abnormal; CS, Cockayne syndrome; TTD, trichothiodystrophy; XP, xeroderma
pigmentosum.
FIGURE 1 Clinical features of DNA repair deficiency syndromes. (A) Xeroderma pigmentosum (XP): Poikiloderma
with hypo- and hyperpigmentation, telangiectasia, and scars after multiple excisions of cancers in a 29-year-old
male patient with XP complementation group C. This patient developed the first skin symptoms at one year of age,
the first skin tumor (squamous cell carcinoma) at the age of five and metastasis of a malignant melanoma at the
age of 25. His whole facial skin was transplanted from the thigh region at the age of 18. (B) and (C) XP/Cockayne
syndrome (CS) complex: Patient XP20BE with features of XP and CS and a defect in the XPG (ERCC5). (B) Age 18
months showing interspersed areas of XP-like increased and decreased pigmentation on his cheek. (C) Age six
years showing typical CS cachexia, deep-set eyes, loss of subcutaneous tissue and XP-like pigmentation of his face
and arm. Source: From Ref. 50. (D) – (H) Trichothiodystrophy (TTD): (D) and (E) Three-year old girl (TTD352BE)
with short, brittle hair which is sparse and broken off at different lengths. She rarely has haircuts except to trim
uneven areas. She is not sun sensitive. (F) Tiger tail appearance of hair with polarizing microscopy. (G) Irregular,
undulating hair shaft with light microscopy [original magnifications (F) and (G), 10]. (H) Marked ichthyosis in a
five-year old male patient. Source: From Ref. 43.
system tumors (astrocytoma of brain or spinal cord, Schwanoma of the facial nerve) and lung
cancers in patients who smoke.
All tissues that are exposed to sunlight may show abnormalities in XP patients. In
addition to the skin, the eye and even the tip of the tongue can be involved. The eyes can
have various inflammatory lesions such as conjunctival injection and pinguecula, sunlight
induced keratitis, and corneal clouding. Many patients have dry eyes. The lids can develop
symblepharon, ectropion or, in extreme cases, loss of lids. The lids and conjunctiva can
develop BCC and SCC. The lips often show cheilitis. The tip of the tongue can show similar
changes of telangiectasias, atrophy, and even SCC. In some parts of North Africa, XP is more
common and children with tumors of the tip of the tongue should be considered as having
XP until proven otherwise.
Early diagnosis before the development of skin tumors should be the goal. Interdisciplin-
ary care in conjunction with dermatologists, ophthalmologists, and pediatricians is necessary.
Approximately 20% of XP patients show progressive neurological degeneration. The ear-
liest signs of neurological involvement are often absence of deep tendon reflexes and high
frequency sensorineural hearing loss. There is a tendency for the XP patients with neurological
abnormalities to have a history of acute sun sensitivity in early life. The rate of progression of
the neurological disease is variable. Patients develop loss of coordination, loss of ability to
walk, intellectual deterioration, and difficulty swallowing. They eventually may develop quad-
raparesis. Magnetic resonance imaging of the brain shows enlarged ventricles due to loss of cer-
ebral graymatter. The brain pathology shows primary neuronal degeneration without
calcification.
Differential Diagnosis
XP has to be distinguished from the other DNA repair deficient photodermatoses such as CS
and TTD (Table 1). Other diseases with increased photosensitivity in childhood, such as
hydroa vacciniforme or erythropoietic porphyria (EP) have to be excluded (22). EP shows
photosensitivity and poikiloderma followed by mutilations along with red fluorescence of
teeth, erythrocytes, and urine. Unlike XP, patients suffering from EP describe pain during
sun-exposure. Mutilations of EP patients do not come from tumors, but occur from phototoxic
reactions of protoporphyrin IX generating apoptosis induced by reactive oxygen species. EP
patients do not have an increased skin cancer risk.
Increased frequency of skin tumors may also point toward basal cell nevus syndrome
(BCNS) (Goltz-Gorlin syndrome) caused by mutations in the patched (PTCH ) gene (23,24).
Clinically, BCNS can readily be distinguished from XP by the lack of poikiloderma and the pre-
sence of jaw cysts, palmar pits, abnormalities of the ribs and vertebrae, and calcification of the
falx. BCNS patients do not have a high frequency of SCC or melanomas. Unlike XP patients,
BCNS patients are hypersensitive to therapeutic X rays for treatment of skin or internal
cancers and can develop hundreds of BCC in the field of X-ray treatment.
Epidermodysplasia verruciformis can also show poikiloderma and is characterized by
multiple Bowenoid tumors originating from verrucae vulgaris containing human papilloma
virus.
The rare diagnosis of dyschromatosis universalis hereditaria is particularly described to
occur almost exclusively in Japanese patients and represents the most important differential
diagnosis to the relatively frequent cases of XP-A. Patients with this disease suffer from dys-
chromia of the whole skin, with hyperpigmentation paralleled by mild xerosis cutis. In contrast
to XP, UV-radiation is well tolerated, and an increased skin cancer risk does not exist.
Patients with Carney syndrome or leopard syndrome have multiple pigmented lesions
without sun sensitivity. Unlike XP, the pigmentation of each lesion is more uniform and
there is no hypopigmentation or telangiectasia.
Laboratory Diagnosis
The clinical diagnosis XP can be obtained by measuring post-UV cell survival and DNA repair
capacity in cellular assays. For these assays, fibroblasts from the patient are generated from a
skin biopsy and grown in the laboratory. For the survival, assay cells are placed in plates and
exposed to increasing doses of UVC-radiation. Cell growth is assessed for several days. The
growth of most cells after UV-exposure is greatly reduced compared to normal cells. XP
variant cells have normal post-UV survival but are sensitized to post-UV cell killing by
addition of caffeine. Another assay is unscheduled DNA synthesis (UDS), which is reduced
in most XP patients with the exception of XP-variants (8). During the repair reaction necessary
to restore the genomic integrity of the cell, radioactively labelled tritium is supplied in the
medium. Radioactive incorporation into DNA, as assessed by autoradiography or scintillation
counting, is directly proportional to the repair capacity, since in the last step of the repair reac-
tion DNA polymerase incorporates nucleotides to fill the gap of excised damage-containing
DNA. This repair reaction is reduced in fibroblasts derived from patients suffering from XP
as compared to fibroblasts from normal donors. Specialized laboratories offer prenatal diagno-
sis for families with XP patients.
DNA Repair Genes

Complementation analysis revealed the presence of seven XP-subtypes (XP A to G), deficient in
NER as well as a variant form with a deficiency in DNA polymerase eta (3,25). The genes defec-
tive in these complementation groups are cloned and designated according to the respective
causative genes. The relationship between the defective genes and the clinical phenotypes is
very complex (Fig. 2). Clinical symptoms in the different complementation groups are hetero-
geneous. XP group A is characterized by a defect in both TCR and GGR. This complementation
group is most frequent in Japan. Most Japanese patients have the same splice site mutation due
to a founder-effect. They have a particularly severe course with rapid neurological degener-
ation and reduced life expectancy. Remarkably, other patients with different mutations in the
XPA gene may have minimal neurological abnormalities. XP complementation group B is extre-
mely rare, with only six families described in the literature. Surprisingly, four families have the
XP/CS complex, one has XP with mild neurological disease, and one has TTD. In Europe and
northern Africa, XP-C represents the most frequent subgroup. Without sun protection, the
clinical course of XP-C may be severe with multiple SCC, BCC, malignant melanoma, and
internal tumors. These patients usually do not have acute sun sensitivity and do not have
neurological abnormalities. As in other complementation groups, the high grade of consangui-
nity in affected families plays an important role. Patients with defects in the XPD gene have
marked phenotypic heterogeneity. They may have only the skin disease of XP; XP with
XP-type neurological disease, the XP/CS complex; TTD, combined TTD/XP; or cerebro-
ocular-facial-skeletal syndrome. The phenotype appears to depend on the specific mutation
in this gene that plays a role in NER and transcription. Patients with defects in the XPG
gene may have only the skin disease of XP or may have XP/CS complex. XP-E and XP
variant patients have skin disease without neurological abnormalities. XP-F patients may
have mild disease or late onset of severe neurological degeneration.
Care and Management of Patients

Central to the care and management of patients is the strict avoidance of any exposure to UV-
radiation. This does not categorically exclude outdoor activities. This would only deprive the
already impaired young patients even more of possible spare time activities and endanger
social development. Nevertheless, the skin has to be protected from UV by long sleeved
FIGURE 2 Relationship of clinical disorders to molecular defects in DNA repair diseases. Eight different clinical
phenotypes are represented by red rectangular boxes. Twelve genes involved in DNA repair are indicated by gray
ovals. The name of the complementation group is listed above the official name of the gene (in parentheses). The
overlap of the ovals with the rectangles indicates that mutations in the indicated gene have been associated with the
indicated phenotype. The diagram indicates that one clinical phenotype can be associated with defects in more than
one gene and conversely, different defects in one gene may be associated with several different clinical phenotypes.
Abbreviations: CS, Cockayne syndrome; TTD, trichothiodystrophy; XP, xeroderma pigmentosum. Source: From Ref. 51.
clothing covering the extremities to the wrists and heels. Since sports manufacturers included
fashionable clothes designed with UV-protective textiles, it has become easier for patients to
purchase practical and protective clothing. The head and facial area should be protected by
hats, providing shade for nose and ears. Facial skin can additionally be protected by a visor
mounted on the rim of a hat that holds a UV-protective screen, which allows good vision
but complete filtration of UV-radiation. UV-protective films filtering at least 90% of the UV-
spectrum should also cover all windows behind which XP patients live. This includes the
house, kindergarten, school, work, as well as the cars in which the patients are transported.
These films exist in formulations that do not stain or reduce the incoming visible light, thus
allowing the presence in a room of light that does not visibly differ from nonprotected rooms.
In addition to these technical measures, sun-blocking lotions with highest possible UVB
and UVA filters should be applied to the skin.
Effective chemoprevention of skin cancer by use of oral retinoids in XP patients has been
demonstrated in a controlled study (26), however, there was considerable toxicity with the high
doses used. Subsequent studies showed that some patients may respond to much lower doses.
Local injections of interferon were shown to be effective in treating multiple melanoma in-situ
lesions in one XP patient (27).
Experimental use of DNA repair proteins from algae or bacteria applied in topical formu-
lations containing liposomes have recently been reported. This has been shown for two differ-
ent repair proteins. Photolyase is an enzyme derived from the algae ancystis nidulans. This
protein repairs some forms of UV-induced genomic DNA damage after activation by visible
or UVA-radiation. Photolyase encapsulated in liposomes have been reported to exert immuno-
protective effects (28). This enzyme is currently available in pharmacies in Germany, but has
not been approved for use in the United States.
The second enzyme is a DNA glycosylase/AP lyase or T4 endonuclease V (T4endoV) that
also repairs some forms of UV-induced genomic DNA damage (29). A randomized double-
blind, placebo-controlled, international multicenter trial reported that application of
T4endoV to the skin of patients with XP significantly reduced the incidence of actinic keratoses
and BCC (30,31). As with photolyase, in this study T4endoV was encapsulated in liposomes
and topically applied to the skin. The advantage of this enzyme is its activity without UV-
radiation, since XP patients should not be exposed to UV-radiation at all. This enzyme has
not yet been approved for use by the U.S. Food and Drug Administration.
The treatment of skin cancers utilizes the same methods as in people who do not have XP.
However, the increased frequency of multiple primary neoplasms often necessitates multiple
excisions. These may lead to extensive scarring and removal of large amounts of skin particu-
larly in the face. Thus, methods to adequately remove cancers while sparing tissue are pre-
ferred. Biopsy followed by surgical excision or dessication and curettage is usually the first
method of treatment. In vital areas such as near the eye or nose or with recurrent neoplasms
of the face involving nerves, micrographic controlled surgery of tumors is often used. Standard
cryotherapy is an effective and simple method of removal. XP patients with difficult to treat
skin cancers or with internal cancers such as spinal cord or brain astrocytomas have been suc-
cessfully treated with X-ray therapy. Surprisingly, in contrast to UV, the skin reaction to X-ray
therapy in XP patients is usually normal (32).
In the past, before early diagnosis was possible, patients with XP had a markedly reduced
life expectancy. They often died in early childhood by multiple tumors of the skin and eyes.
With early detection, strict sun protection, and aggressive removal of early skin cancers, XP
patients live much longer than in the past. However, the course of patients with progressive
neurological degeneration does not appear to be altered by sun protection. Since XP is a reces-
sive disorder, unless the patient marries a close relative, their children are usually genetically
heterozygous and clinically indistinguishable from normal individuals.
COCKAYNE SYNDROME
Like XP, CS is an autosomal recessive genetic disease albeit with far lower prevalence (2,5,33).
XP patients with neurological disease and CS patients share many of the same clinical features
including marked skin sun sensitivity, microcephaly, progressive sensorineural hearing loss,
short stature, and progressive neurological degeneration (34). Their cells are also hypersensi-
tive to killing by UV-radiation and have defective DNA repair.
CS patients show a large variation with respect to severity of symptoms (Table 1). Charac-
teristic features include typical bird-like face, with beaked nose and deep-set eyes, loss of sub-
cutaneous fat, and prematurely aged appearance, which is why CS is considered to be a
progeroid syndrome (Fig. 1). Further clinical symptoms include gait abnormalities, dental
caries, and often cold hands and feet with blue discoloration. Particularly the combination of
growth and mental retardation with photosensitivity should lead to the clinical differential
diagnosis of CS or TTD. Neurological features of CS include dysmyelinisation of the white
matter of the brain as opposed to primary neurodegeneration in XP, as well as calcification
of basal ganglia, and other areas of the brain. Ocular changes seen in CS patients are cataracts
and pigmentary retinal degeneration with neurological and ocular changes generally occurring
later in the course of the disease. Clinical forms of CS can be divided into mild, moderate, and
severe with reduction of life expectancy increasing from mild to severe.
There are two complementation groups in CS: CS-A and CS-B, but in addition to this,
mutations in XP genes from complementation groups XP-B, XP-D, and XP-G can also lead
to a combination of clinical symptoms of XP and CS (The XP/CS complex) (35,36). Cells
from patients with CS are defective in transcription coupled DNA repair, although the exact
function of CS-A and CS-B proteins has not been elucidated so far. Recent reports indicate
that the CS-B protein may not only be involved in the repair of UV-induced DNA damage,
but that it may also be involved in the repair of oxidative damage (10,11,37). In contrast to
XP for which the DNA repair defect is presumed to be predominant, for CS as well as TTD
an additionally subtle defect in basal transcription of genes has been hypothesized, which
could be a possible reason why XP is characterized by an increased skin cancer risk but not
CS or TTD (38). However, experimental data in support of this hypothesis only exists for
TTD thus far.
As with XP, the clinical diagnosis is secured on the cellular level. For this, fibroblasts from
patients are measured for their ability to recover from inhibition of RNA synthesis following
UV-radiation. Although in normal cells the RNA synthesis has recovered within 24 hours,
this is not the case in CS. For families with CS patients, prenatal diagnosis is available in
specialized centers.
The care and management of patients with CS is difficult. Due to its photosensitivity,
strict UV avoidance is indicated along with sun protection employing high protection factors
in the UVA- and UVB-range.
TRICHOTHTIODYSTROPHY
TTD was termed by Price in 1980 (39,40) and like XP and CS, TTD is an autosomal recessive
disease. The clinical features of TTD show great variation in form, expression, and severity.
The large variety of clinical features was recently summarized by Itin et al. (41). Increased
photosensitivity and DNA repair defect may be present, but there are also cases where they
are absent. Clinical symptoms of TTD include a collodion membrane at birth and marked
skin sun sensitivity (Table 1). Their hair is brittle with thin hair shafts that break upon
minimal trauma. Stress factors such as fever and infections can lead to effluvium represented
by episodes of hair loss followed by re-growth (41). Further clinical features of TTD are growth-
and mental retardation, as well as ichthyosis (Fig. 1). Nail changes are features of TTD, and
patients show a large variety of different neuro-ectodermal abnormalities affecting the hair,
skin, nails, nerve system, and the eyes. The presence of brittle hair in combination with
growth- and mental retardation under the third percentile possibly in combination with photo-
sensitivity should lead to further diagnostic steps securing the diagnosis of TTD.
Most important diagnostic criterion are hair changes, caused by reduction of high
sulphur matrix proteins and reduced cysteine content of the hairshaft matrix also underlying
the fragility of the hair (18,42). As a hallmark of TTD, polarized light microscopy of TTD hair
regularly reveals a pattern of light and dark areas of the hair leading to a typical “tiger tail”
appearance in all hairs (43). Measurement of amino acid content of the hair by chromatography
showing reduced content of cysteine-rich matrix proteins can be used to secure the diagnosis.
There are three different complementation groups of TTD. The majority of cases reveal
mutations in the XPD gene and, in this complementation group, the site at which the nucleo-
tide is mutated determines the phenotype of the disease (42,44,45). However, two patients
have been reported that show the combination of TTD and XP features (46). The second
group shows mutations in the XPB gene and has been described in only one kindred.
Mutations in a newly discovered small protein component of the TFIIH complex, TTD-A,
have been found to cause TTD in a few families. (47,48). A gene of unknown function on
chromosome 7 (TTDN1) has been reported to be defective in some families with nonphotosen-
sitive TTD (49).
In contrast to XP, patients with TTD are not characterized by an increased risk of skin
cancer, although the causative mutations reside in the same gene. It has previously been
demonstrated that, in addition to a repair defect, cells from XP patients also show alterations
in immunosurveillance, whereas TTD cells do not exhibit this defect (15 –18). This could
help to explain the difference in skin cancer risk between the two syndromes. In addition to
this, it is currently believed that the phenotype of TTD is also caused by subtle defects in
basal transcription, which would make both CS and TTD transcription deficiency syndromes
(38). Patients with TTD exhibit lower levels of ß-hemoglobin than normal individuals (13).
This directly results in measurable decreases of simple clinical parameters. The mean corpus-
cular haemoglobin (MCH) as well as the mean cellular volume (MCV) of TTD-erythrocytes is
significantly reduced. This finding not only supports the hypothesis that basal transcription is
impaired but it also facilitates the diagnosis of TTD. Upon clinical suspicion of TTD, MCH, and
MCV can be assessed in any clinical setting before more specialized tests are initiated.
As with CS, care and management of TTD patients is difficult. It is restricted to stringent
photoprotective measures as described above in the case of photosensitivity and supportive
measures to reduce handicaps by neuro-ectodermal symptoms. Scaling induced by ichthyosis
can be improved by application of urea-containing lotions.
CONCLUSION
XP, CS, and TTD represent important model diseases for the pathogenesis of skin cancers as
well as mechanisms underlying the process of aging. Therefore, by understanding underlying
mechanisms it may not only be possible in the future to help these patients, but to also develop
strategies that are also relevant to aging and carcinogenesis in the normal population.
On the clinical level, early diagnosis of DNA repair deficient photodermatoses is essential
in order to allow early protective and supportive measures, which do help improve the quality
of life and possibly also life expectancy.
REFERENCES
1. Berneburg M, Lehmann AR. Xeroderma pigmentosum and related disorders: defects in DNA repair
and transcription. Adv Genet 2001; 43:71– 102.
2. de Laat WL, Jaspers NG, Hoeijmakers JH. Molecular mechanism of nucleotide excision repair. Genes
Dev 1999; 13:768 – 785.
3. Lehmann AR. Dual functions of DNA repair genes: molecular, cellular, and clinical implications.
Bioessays 1998; 20:146– 155.
4. van Hoffen A, Natarajan AT, Mayne LV, van Zeeland AA, Mullenders LH, Venema J. Deficient repair
of the transcribed strand of active genes in Cockayne’s syndrome cells. Nucleic Acids Res 1993;
21:5890– 5895.
5. van Gool A, van der Horst E, Citterio E, Hoeijmakers JH. Cockayne syndrome: defective repair of
transcription? EMBO J 1997; 16:4155– 4162.
6. Schaeffer L, Moncollin V, Roy R, et al. The ERCC2/DNA repair protein is associated with the class II
BTF2/TFIIH transcription factor. EMBO J 1994; 13:2388– 2392.
7. Chang RD, Kornberg RD. Electron crystal structure of the transcription factor and DNA repair. Cell
2000; 102:609– 613.
8. Lehmann AR. Nucleotide excision repair and the link with transcription. Trends Biochem Sci 1995;
20:402– 405.
9. Wood RD. DNA damage recognition during nucleotide excision repair in mammalian. Biochimie
1999; 81:39– 44.
10. Cooper T, Nouspikel SG, Clarkson SA, Leadon SA. Defective transcription-coupled repair of oxi-
dative base damage. Science 1997; 275:990– 993.
11. Le Page F, Kwoh A, Avrutskaya A, et al. Transcription-coupled repair of 8-oxoguanine: requirement
for XPG, TFIIH and CSB. Cell 2000; 101:159– 171.
12. Schaeffer L, Roy R, Humbert S, et al. DNA repair helicase: a component of BTF2 (TFIIH) basic tran-
scription factor. Science 1993; 260:58– 63.
13. Viprakasit V, Gibbons RJ, Broughton BC, et al. Mutations in the general transcription factor TFIIH
result in TTD. Hum Mol Genet 2001; 10:2797– 2802.
14. Keriel A, Stary A, Sarasin A, Rochette-Egly C, Egly JM. XPD mutations prevent TFIIH-dependent
transactivation by nuclear receptors. Cell 2002; 109:125– 135.
15. Norris PG, Limb GA, Hamblin AS, Hawk JL. Impairment of natural-killer-cell activity in xeroderma
pigmentosum. N Engl J Med 1988; 319:1668– 1669.
16. Norris PG, Limb GA, Hamblin AS, et al. Immune function, mutant frequency, and cancer risk in the
DNA repair deficiency syndrome xeroderma pigmentosum. J Invest Dermatol 1990; 94:94– 100.
17. Ahrens C, Grewe M, Berneburg M, et al. Photocarcinogenesis and inhibition of intercellular adhesion
molecule 1 expression in cells of DNA-repair-defective individuals. Proc Natl Acad Sci USA 1997;
94:6837– 6841.
18. Berneburg M, Clingen PH, Harcourt SA, et al. The cancer-free phenotype in trichothiodystrophy is
unrelated to its repair defect. Cancer Res 2000; 60:431– 438.
19. Vink AA, Shreedhar V, Roza L, Krutmann J, Kripke ML. Cellular target of UVB-induced DNA
damage resulting in local suppression of contact hypersensitivity. J Photochem Photobiol B 1998;
44:107– 111.
20. Shwarz A, Stander S, Berneburg M, et al. Interleukin-12 suppresses ultraviolet radiation-induced
apoptosis by inducing DNA repair. Nat Cell Biol 2002; 4:26 – 31.
21. Kraemer KH, Levy DD, Parris CN, et al. Xeroderma pigmentosum and related disorders: examining
the linkage. J Invest Dermatol 1994; 103:96– 101.
22. Fritsch C, Bolsen K, Ruzicka T, Goerz G. Congenital erythropoietic porphyria. J Am Acad Dermatol
1997; 36:594– 610.
23. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila
patched in the nevoid basal. Cell 85:841– 851.
24. Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell
nevus. Science 1996; 272:1668– 1671.
25. Lehmann AR. The xeroderma pigmentosum group D (XPD) gene: one gene, two functions. Genes
Dev 2001; 15:15– 23.
26. Kraemer KH, Di Giovanna JJ, Moshell AN, Tarone RE, Peck GL. Prevention of skin cancer with oral
13-cis retinoic acid in xeroderma pigmentosum. N Engl J Med 1988; 318:1633– 1637.
27. Turner M, Moshell A, Corbett D, et al. Clearing of melanoma-in-situ with intralesional interferon in a
patient with xeroderma pigmentosum. Arch Dermatol 1994; 130:1491– 1494.
28. Stege H, Roza L, Vink AA, et al. Enzyme plus Light therapy to repair immunosuppressive effects on
human skin damaged by ultraviolet B-radiation. Proc Natl Acad Sci 2000; 97:1790– 1795.
29. Kraemer KH, Di Giovanna J. Topical enzyme therapy for skin diseases? J Am Acad Dermatol 2002;
46:463– 466.
30. Yarosh D, Alas LG, Yee V, et al. Pyrimidine dimer removal enhanced by DNA repair liposomes
reduces the incidence of UV skin cancer in mice. Cancer Res 1992; 52:4227– 4231.
31. Yarosh D, Klein J, O’Connor A, Hawk J, Rafal E, Wolf P. Effect of topically applied T4 endonuclease V
in liposomes on skin cancer. Lancet 2001; 357:926– 929.
32. Di Giovanna JJ, Patronas N, Katz D, Abangan D, Kraemer KH. Spinal cord astrocytoma in a patient
with xeroderma pigmentosum: 9-year survival with radiation and isotretinoin therapy. J Cut Med
Surg 1998; 2:153– 158.
33. van Gool AJ, Citterio E, Rademakers S, et al. The Cockayne syndrome B protein, involved in tran-
scription-coupled DNA repair. EMBO J 1997; 16:5955– 5965.
34. Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma
pigmentosum: DNA repair disorders with overlaps and paradoxes. Neurology 2000; 55:1442– 1449.
35. Berneburg M, Lowe JE, Nardo T, et al. UV damage causes uncontrolled DNA breakage in cells from
patients with combined features of XP-D and Cockayne syndrome. EMBO J 2000; 19:1157– 1166.
36. Stefanini M, Fawcett H, Botta E, Nardo T, Lehmann AR. Genetic analysis of twenty-two patients with
Cockayne syndrome. Hum Genet 1996; 97:418– 423.
37. Nouspikel P, Lalle P, Leadon SA, Cooper PK, Clarkson SG. A common mutational pattern in Cock-
ayne syndrome patients from xeroderma pigmentosum. Proc Natl Acad Sci USA 1997; 94:3116 –3121.
38. Friedberg EC. Cockayne syndrome—a primary defect in DNA repair, transcription or both Bioessays
1996; 18:731– 738.
39. Price VH, Odom RB, Ward WH, Jones FT. Trichothiodystrophy: sulfur-deficient brittle hair as a
marker for a neuroectodermal symptom complex. Arch Dermatol 1980; 116:1375– 1384.
40. Poissonnier M, Blanc A, Bat P. Genetic counseling in a case of neuro-ectodermosis: Vera Price Syn-
drome. J Genet Hum 1988; 36:361– 365.
41. Itin PH, Sarasin A, Pittelkow M. Trichothiodystrophy: update on the sulfur-deficient brittle hair. J Am
Acad Dermatol 2001; 44:891– 920.
42. Botta E, Nardo T, Broughton BC, Marinoni S, Lehmann AR, Stefanini M. Analysis of mutations in the
XPD gene in Italian patients with Cockayne Syndrome. Am J Hum Genet 1998; 63:1036– 1048.
43. Liang C, Kraemer KH, Morris, A, et al. Characterization of tiger tail banding and hair shaft abnorm-
alities in trichothiodystrophy. J Am Acad Dermatol 2005; 52:224 – 234.
44. Taylor EM, Broughton BC, Botta E. Xeroderma pigmentosum and trichothiodystrophy are associated
with different mutations in the XPD (ERCC2) repair/transcription gene. Proc Natl Acad Sci USA 1997;
94:8658– 8663.
45. Mariani E, Facchini A, Honorati AM, et al. Immune defects in families and patients with xeroderma
pigmentosum and trichothiodystrophy. Clin Exp Immunol 1992; 88:376– 382.
46. Broughton BC, Berneburg M, Fawcett H, et al. Two individuals with features of both xeroderma pig-
mentosum and trichothiodystrophy. Hum Mol Genet 2001; 10:2539– 2547.
47. Vermeulen W, Bergmann E, Auriol J, et al. Sublimiting concentration of TFIIH transcription/DNA
repair factor causes TTD-A. Nat Genet 2000; 26:307– 313.
48. Giglia-Mari G, Coin F, Ranish JA, et al. A new, tenth subunit of TFIIH is responsible for the DNA
repair syndrome trichothiodystrophy group A. Nat Genet 2004; 36:714 – 719.
49. Nakabayashi K, Amann D, Ren Y, et al. Identification of C7orf11 (TTDN1) gene mutations and genetic
heterogeneity in non-photosensitive trichothiodystrophy. Am J Hum Genet 2005; 76:510– 516.
50. Moriwaki S-I, Stefanini M, Lehmann AR, et al. DNA repair and ultraviolet mutagenesis in cells from a
new patient with xeroderma pigmentosum group G and Cockayne syndrome resemble xeroderma
pigmentosum cells. J Invest Dermatol 1996; 107:647– 653.
51. Kraemer KH. From proteomics to disease. Nat Genet 2004; 36:677– 678.
PART E: PHOTOAGGRAVATED DERMATOSES
17 Photoaggravated Dermatoses
Victoria P. Werth
Department of Dermatology, University of Pennsylvania, and Philadelphia V.A. Medical Center,
Philadelphia, Pennsylvania, U.S.A.
B Atopic dermatitis can occasionally be exacerbated by ultraviolet

radiation.
B Sunlight-induced erythema multiforme may actually reflect the fact

that herpes may precipitate erythema multiforme.
B Antimalarials frequently can treat cutaneous lupus erythematosus

and skin manifestations of dermatomyositis.
B Pellagra improves with a balanced, high-protein diet.
B There is a need for organized trials with the autoimmune blistering

and connective tissue diseases.
252 Werth and Hönigsmann
PHOTOAGGRAVATED DERMATOSES
hotoaggravated dermatoses (or photoexacerbated skin diseases) represent a very heter-
P ogeneous group of conditions that share only one common feature: they can be induced
or exacerbated by exposure to sunlight or to artificial therapeutic or cosmetic ultraviolet
(UV) radiation (Table 1). It is important to recognize that these diseases are not true photoder-
matoses since they commonly develop without exposure to radiation. They are of diverse or
unknown etiology and photoexacerbation occurs only in some, but not in all, of the affected
subjects. In many instances, the role of light is clearly defined. In others, documentation of
photosensitivity is poor and UV radiation may be one of several nonspecific factors that
induce aggravation. In this chapter, a selection of common and important photoexacerbated
diseases is discussed. Treatment is restriction of light exposure, use of high protection sunsc-
reens, and appropriate treatment of the underlying disorder.
Acne
Acne aestivalis, first described by Hjorth et al. (1), is characterized by pruritic, 1 to 3 mm, pink or
pale, dome-shaped papules occurring after sun exposure, usually on the face, neck, or trunk.
Nieboer (2) further reported two such patients, describing the disorder as actinic superficial
folliculitis, a predominantly follicular, pustular rash occurring several hours after sun exposure,
but nonpruritic and affecting only the upper trunk and arms. Bacteriological, immunohisto-
pathological, and photo-experimental investigations failed to reveal a cause for this sunlight-
induced dermatosis. Verbov (3) described three additional patients with overlapping features
of both acne aestivalis and actinic superficial folliculitis and proposed the unifying term
actinic folliculitis. It was characterized by a pustular eruption appearing over the face, and some-
times the arms and upper chest, 4 to 24 hours after exposure to sunlight. The condition appears
indeed to be a form of UV-exacerbated acne, for which high-protection-factor sunscreens, stan-
dard acne treatments, including topical retinoic acid, and topical and systemic antibiotics have
not generally been helpful, although oral isotretinoin has been shown to be effective (4,5).
Darier’s Disease
Several cases of photoaggravated Darier’s disease have been reported (6). Baba and Yaoita (7)
carried out provocation studies on the lesions of keratosis follicularis with UV radiation. Non-
erythema-producing doses of UVB elicited the lesions in uninvolved skin sites in a 34-year-old
man with this disease. The elicited lesions were compatible with those of keratosis follicularis
both clinically and histopathologically. Similar irradiation with UVA produced no visible
changes in the test area. Otley et al. performed an unblinded, controlled trial using UVB,
UVA, or combination UVB/UVA phototherapy in patients with Darier’s disease and reported
that UVB irradiation was indeed capable of inducing lesions of Darier’s disease, whereas UVA
radiation alone and heat associated with phototherapy had no effect on the disease (8). We
ourselves found massive worsening in two patients experimentally treated with psoralen and
ultraviolet A (PUVA) (Fig. 1). Photoprotection by sunscreens and topical ascorbic acid may be
helpful (8).
TABLE 1 Photoexacerbated Dermatoses

Acne Atopic dermatitis
Darier’s disease Psoriasis
Transient acantholytic dermatosis Lichen planus actinicus
Disseminated superficial actinic porokeratosis Lupus erythematosus
Pellagra Dermatomyositis
Herpes simplex Bullous pemphigoid
Erythema multiforme Pemphigus
Photoaggravated Dermatoses 253
FIGURE 1 Darier’s disease. (A) Before PUVA and (B) after PUVA.
Transient Acantholytic Dermatosis

Grover’s disease is a nonimmune acantholytic dermatosis. The etiology and pathogenesis of
Grover’s disease is unknown. Factors that can trigger the disease include sweat, fever, heat,
and sunlight. Some reports have hypothesized causation by poral occlusion of damaged
eccrine intra-epidermal ducts, with spillage of sweat contents and focal acantholysis (9).
Acantholysis is often not associated with the eccrine duct outflow tract. Different studies
have shown the primary damage in the proteins of the desmosomal attachment plaque, such
as desmoplakins I and II and plakoglobin (10,11).
It was first described by Grover in 1970 (12). The male-to-female ratio is at least 3:1 (13).
Most reports are in older Caucasians, but there have been small numbers of cases reported from
Japan and Korea (14). In some cases, it has been reported in association with other systemic
diseases, such as both solid and hematological malignancies, human immunodeficiency
virus infections, chronic renal failure, and hemodialysis (13,15,16). Grover reported statistically
significant associations between transient acantholytic disease and asteatotic eczema, allergic
contact dermatitis, atopic dermatitis, and irritation from adhesive tape (17). This suggests
that nonspecific irritation can induce lesions.
Grover’s disease is characterized by pruritic papules and vesicles, mainly distributed on
the trunk. Some lesion can appear follicular, and plaques and bullous lesions have been noted.
The lesions are typically located on the trunk and, to a lesser extent, the proximal extremities.
Involvement of the face, scalp, and oral mucosa can occur, but palms and soles are typically
spared (13). Localized variants have been reported and are more common in younger
females (18). The disease lasts less than three months in most patients, but occasionally con-
tinues for two or three years, particularly in older patients. Seasonal recurrences can occur (19).
A history of initiation or exacerbation of lesions by sunlight has frequently been noted.
Other reports have found exacerbation from tanning salon exposure and UVB (13).
Treatment includes topical and oral glucocorticoids and antibiotics. Oral and bath PUVA,
as well as UVA1 phototherapy, have been successfully used (20 –22). It is difficult to evaluate
therapies because of the transient nature of this process.
Pellagra
Pellagra is a nutritional disorder due to nicotinic acid deficiency and is common in third-world
countries with high malnutrition rates, where millet or maize is the principal nutrient in the
diet (23). It can be seen in undernourished elderly people, chronic alcoholics, psychiatric and
diabetic patients, or in individuals with gastrointestinal malabsorption or carcinoid tumors
(24,25). Deficiency of niacin can occur with fever, thyrotoxicosis, and food faddism. Certain
drugs such as isoniazid, pyrazinamide, ethionamide, 6-mercaptopurine, azathioprine,
5-fluorouracil, phenytoin, phenobarbital, sodium valproate, and chloramphenicol can cause
this vitamin deficiency (26). Pellagra is a bilateral and symmetrical dermatosis affecting
sun-exposed areas.
Clinical findings in pellagra include dermatitis, diarrhea, and dementia. The skin find-
ings include intense red, scaly, and hyperpigmented plaques on sun-exposed areas, as well
FIGURE 2 Pellagra. Photodistribution of lesions on (A) anterior chest; (B) posterior neck
as areas of heat, friction, or pressure (Fig. 2). The lesions can be edematous, with occasional
vesicules or desquamation, and can have a burning sensation. Typical locations include invol-
vement around the neck (Casal’s necklace), which can extend towards the sternum, and follicu-
lar hyperkeratotic plugs can be present in a seborrheic distribution (Fig. 2A). Flexural areas can
be macerated. Angular cheilitis, glossitis with papillary atrophy, a beefy tender tongue, and
esophagitis are seen. The skin in long-standing lesions is thickened and hyperpigmented.
Treatment consists of a balanced, high-protein diet. Nicotinamide can be given 50 to
100 mg tid along with a vitamin B complex. Sunscreen and moisturizers are indicated.
Herpes Simplex and Other Viral Rashes

It is common knowledge that many patients experience herpes simplex eruptions after sun
exposure, particularly while sun bathing, mountain hiking, or skiing in higher altitudes. The
mechanism for viral activation by sunlight is unknown, but it may be possibly related to the
fact that UVB radiation induces modulation of antigen presentation of herpes simplex virus
(HSV) by Langerhans cells (27).
Several other nonspecific stimuli such as fever, hormonal changes (menses), or heat can
trigger herpes lesions. Reports on sunlight-induced erythema multiforme (EM) may actually
reflect the fact that herpes may precipitate EM (Fig. 3A). Relapsing gluteal herpes simplex is
common in patients treated with narrowband UVB or PUVA. In a study from Japan with
4295 patients, sun-induced HSV-1 flare-up was reported by 10.4% of the total study population.
However, this increased to 19.7% among patients diagnosed in July and August, to 28% among
patients younger than 30 years diagnosed in July and August, and to 40% among patients
younger than 30 years diagnosed in July and August with a recurrent infection (28). Also
vaccinia, lymphogranuloma venereum, and varicella have all been recognized as having a
photosensitivity component (29). In particular, varicella localizes in sun-exposed areas
(30,31). Viral rashes occurring in sun-exposed areas are quite commonly misdiagnosed as
drug eruptions or photodermatoses.
Erythema Multiforme
Photodistribution, that is, increased density or confluence of the lesions on skin exposed to
light, is a common phenomenon of EM (32). However, cases of EM triggered by exposure
to the sun are rare and have been reported as “photosensitive EM.” Almost all patients had
an otherwise normal tolerance to sunlight and eruptions developed only if HSV infection
(32– 34) or ingestion of drugs, such as carbanilides, phenylbutazone, aflaqualone, and antima-
larials (35– 37) had preceded the sun exposure (Fig. 3A and B).
FIGURE 3 Erythema multiforme. (A) Herpes simplex-induced and (B) drug-induced.
The pathogenesis of photosensitive EM is unknown and could be a hypersensitivity reac-

tion to a hypothetical photoproduct produced by UV radiation. In some cases, lesions could be
provoked by phototesting with UVA and UVB below the normal limits for minimal erythemal
doses (38).
In conclusion, photosensitive EM is very rare and may be secondary to HSV infection and
drug intake as well as apparently idiopathic (38). Its differentiation from EM-like polymor-
phous light eruption may be very difficult and further studies are needed in order to assess
diagnostic differential criteria, if any.
Atopic Dermatitis
A minority of patients with atopic eczema report mild to moderate, nonspecific exacerbation of
their disease with marked pruritus and eczema in sun-exposed areas. Some may be sensitive to
UV radiation on phototesting, but normal responses are the rule, thus allowing distinction from
chronic actinic dermatitis. Frain-Bell and Scatchard (39) described patients with atopic derma-
titis whose condition deteriorated during the summer by developing erythematous papules
confined to light-exposed areas (Fig. 4). Phototests with UVA, UVB, and visible light did not
reproduce such lesions. However, the majority of patients with atopic dermatitis will benefit
from both sunlight and artificial UV irradiation. Thus, “photoaggravation” may sometimes
be due to heat or humidity rather than a specific effect of sunlight.
FIGURE 4 Atopic dermatitis. Photodistribution of

lesions on neck, anterior chest.
FIGURE 5 Photosensitive psoriasis. Back of patient

showing clear involvement in photoexposed areas.
Psoriasis
Patients with psoriasis usually benefit from sunlight and UV phototherapy. However, some
patients experience exacerbation of their disease after sun bathing, particularly, after sunburn
(40– 42) (Fig. 5). The exact incidence of this photosensitive form of psoriasis is not known
and varies in the literature from 5.5% to 24%. In a questionnaire study encompassing 2000
patients in Sweden, the prevalence of photosensitivity was 5.5% (42). Forty-three percent of
the light-sensitive patients had a history of polymorphous light eruption with secondary
exacerbation of psoriasis lesions. Comparison between the photosensitive and the nonphoto-
sensitive patients showed a statistically significant increase in type I skin, psoriasis affecting
hands, heredity for photosensitivity, and advanced age in the photosensitive group. The inves-
tigators proposed that many patients developed polymorphous light eruption and secondarily
psoriasis as a Koebner phenomenon (42). Interestingly, despite photosensitivity, in our experi-
ence and in that of others such patients can be successfully treated with photochemotherapy
(43). In summary, photosensitivity is well recognized but poorly defined in psoriasis. Many
patients probably have polymorphous light eruption, other light sensitivity (44,45), or fair
skin to explain the subsequent development of psoriatic lesions as a Koebner phenomenon.
Lichen Planus Actinicus

Actinic lichen planus (LP) is a rare variant of LP that affects mainly Middle Eastern children
and teenagers (46,47). The lesions occur on sun-exposed skin, usually the face, and have
three clinical types: annular, dyschromic, and hyperpigmented (Fig. 6). The dyschromic type
presents as discrete and confluent whitish papules and the pigmented types consists of hyper-
melanotic patches. Lesions can occur on sun-protected skin and buccal mucosa (48,49), but not
the nails (50). Lesions are not pruritic and are not induced by trauma (50).
Sunlight is a major precipitating cause, with lesions occurring in the spring and summer,
with residual hyperpigmentation in the winter. The minimal erythema dose (MED) was
performed in one case, and was normal (51).
Treatment includes topical or intralesional steroids, antimalarials, and sunscreen (52).
Lupus Erythematosus
There are clearly both environmental and genetic factors in the pathogenesis of cutaneous
lupus erythematosus (CLE) (53 –55). Sunlight exposure, the anti-Ro antibody, HLA type, and
polymorphisms in complement molecules, and tumor necrosis factor-alpha (TNF-a) have all
been correlated with the presence of the subacute CLE (SCLE) subset (56– 60). The pathogenesis
of CLE is complex, with a role for UV light-induced apoptosis, potential delayed clearance of
FIGURE 6 Lichen planus actinicus.
apoptotic debris, antigen presentation with documented interferon (IFN)-alpha producing

plasmacytoid dendritic cells in the skin, subsequent T-cell and autoantibody responses, and
a complex pro-inflammatory cascade that includes induction of chemokines, cytokines, and
adhesion molecules that bring CD4þ T-cells into the skin (61).
Lupus Erythematosus-Specific Skin Lesions

Skin manifestations of LE include chronic CLE, subacute CLE, and acute CLE (62). Since sys-
temic evaluation and treatment are often indicated, it is important to confirm the clinical suspi-
cion of CLE with a skin biopsy. Chronic CLE includes a number of entities that can be found as
skin disease alone or in association with systemic lupus erythematosus (SLE). In one study,
10% of SLE patients had discoid LE (DLE) as their first manifestation of LE, and thus patients,
in addition to a baseline assessment for SLE activity, also need to be followed to assure that sig-
nificant SLE does not develop (63).
Chronic Cutaneous Lupus Erythematosus

DLE can occur as a localized process, commonly above the neck in photoexposed areas. Lesions
of DLE can be erythematous, raised, indurated papules, or plaques. The lesions may have
adherent, keratotic scale, with or without a carpet tack sign, follicular plugging, and telangiec-
tasias. Atrophic scarring as well as dyspigmentation may occur in older lesions, and involve-
ment of the scalp frequently results in permanent scarring alopecia. Hypertrophic LE, seen in
2% of CLE, shows a keratotic thicker plaque than is typical of DLE. There is no particular differ-
ent prognostic or therapeutic significance to this diagnosis beyond that of DLE. Lupus profun-
dus includes firm, deep subcutaneous nodules that atrophy over time. There may be overlying
skin surface changes typical of DLE. Another subcategory of chronic CLE is tumid or papulo-
mucinous LE. This is a particularly photosensitive variant of chronic CLE that is not typically
associated with the presence of lupus serologies or SLE (64).
Subacute Cutaneous Lupus Erythematosus

SCLE was first described as a distinct subset in 1979 (65). It can present as papulosquamous,
psoriasiform plaques and annular-polycyclic plaques, with either form seen in about 50% of
these patients, and some patients have features of both presentations. Some patients with
SCLE also have vesiculobullous lesions, often located at the periphery of annular SCLE
lesions. There are also some patients who develop EM or toxic epidermal necrolysis
(TEN)-like skin lesions in association with their SCLE lesions (66). Patients with SCLE are
photosensitive, with lesions commonly located on the extensor arms, shoulders, V of the
neck, back, and less commonly the face (Fig. 7A and B). SCLE lesions typically heal without
FIGURE 7 Subacute cutaneous lupus erythematosus: (A) face and (B) back.
scarring, but may have postinflammatory hypopigmentation and telangiectasias. About 50% of
patients meet criteria for SLE, and patients with SCLE frequently have high titers of anti-SSA
and anti-SSB antibodies in their serum (60). SCLE, a disease seen primarily in Caucasian
females, is associated with the ancestral haplotype HLA-B8, DR3, and an increased disease
association with the 2308A TNF-a promoter polymorphism has been found (54,57,67).
These patients have a lower incidence of renal or central nervous system disease, and the
more typical systemic symptoms that can be seen in up to 50% include arthritis/arthralgias,
fever/malaise, and myalgias. Drug-induced SCLE is frequent, and the list of implicated medi-
cations is growing (68,69).
Acute Cutaneous Lupus Erythematosus

Acute CLE can clinically present as the typical malar erythema, but other manifestations include
widespread morbilliform or exanthematous eruption in a photodistribution, sparing the
knuckles, and bullous or TEN-like acute CLE skin lesions. The lack of targeting of the metacarpal
phalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints can
help distinguish LE from dermatomyositis (DM). The malar erythema can be either patch or
plaque-like, and there is a tendency to spare the nalolabial folds, as opposed to DM, which
can sometimes be in the differential diagnosis. Unusual presentations seen in acute CLE skin
lesions also include involvement of the lips and periorbital edema. The bullous LE subset seen
in acute CLE is a subepidermal blistering process. The criteria normally utilized for making
the diagnosis include the diagnosis of SLE based on the American Rheumatologic Association
(ARA) criteria, vesicles and bullae arising on, but not limited to, sun-exposed skin, routine
histopathological findings consistent with dermatitis herpetiformis, and a direct immunofluores-
cence revealing IgG and/or IgM and often IgA and C3 at the dermal–epidermal junction (70,71).
Sera from such patients often contain autoantibodies that react with the epidermolysis bullosa
acquisita antigen, type VII collagen (70). However, some patients do have immunoreactants to
the epidermal side of 1 M NaCl split skin as well as other autoantibodies in their sera (71,72).
Skin lesions found to be associated with a worse prognosis include photosensitivity, alope-
cia, oral ulcers, and Raynaud’s phenomenon (73). Photosensitivity is a clinical observation that is
not specific to CLE. If a biopsy is obtained from sun-induced skin lesions, and if the photosensi-
tivity is due to the presence of LE, then the biopsy would show a lupus-specific skin lesion.
Phototesting in Cutaneous Lupus Erythematosus

UV light is a well-established trigger of CLE (74– 78), and SCLE is one of the more photosen-
sitive skin lesions in CLE (79). Skin lesions often occur in a photodistributed pattern and are
more common in summer (65,80). Photoprovocation studies employing artificial sources
of UVA (320 – 400 nm), UVB (290 –320 nm), and visible light show a large variability in the
reported results, with the percentages of SCLE patients showing photoprovocation ranging
from 50% to 100% in response to UV radiation (81– 88). The variation can be partially explained
by differences in light sources and filters, UV doses and dosing schedules, size of the testing
area, and site of testing (85). In one study, phototesting showed induction of CLE lesions in
63% of patients with SCLE, in 72% of tumid LE cases, in 60% of SLE cases, and in 45% of
CCLE cases (14). Of those with UV-induced lesions, 53% were induced by a combination of
UVB and UVA, 34% by UVA alone, and 42% by UVB alone (81).
There is no significant difference between the MED of CLE patients and control popu-
lations (81,85,88).
Therapy of Cutaneous Lupus Erythematosus

Treatment of CLE includes sun avoidance, sunblocking garments, and sunscreens. There is
evidence that sunscreens containing Mexoryl are more effective at inhibiting broad-spectrum
UVA and UVB phototesting-induced CLE lesions than non-Mexoryl containing sunscreen
(89). Topical glucocorticoids and topical calcineurin inhibitors (pimecrolimus and tacrolimus)
are helpful for limited disease or as adjunctive to systemic therapy. Antimalarials (Tables 2 and
3), immunosuppressives, thalidomide, dapsone, retinoids, and clofazamine can be helpful for
more extensive or scarring disease (90). Glucocorticoids are occasionally used for short-term
treatment if a patient has rapidly progressing scarring lesions or extensive involvement.
Low-dose UVA1 (5 J/cm2) has been reported to be beneficial (80). Recently, a validated index
to measure CLE activity and damage has been developed (91). This will hopefully facilitate
trials of therapies for CLE, and there is clearly a need for organized therapeutic trials (92).
Dermatomyositis
There are increased apoptotic cells in lesional DM skin (93). Exposure of normal keratinocytes
in vivo and in vitro to UVB induces DNA damage and apoptosis (94,95), but it is unclear
whether there is an increased susceptibility to UV or whether in fact there are cytotoxic
effects from CD4þ T-cells in the skin or from keratinocyte or T-cell derived inflammatory cyto-
kines. Adhesion molecules and chemokines are upregulated by UV light, which can bring
inflammatory cells into the skin. There are clearly genetic risk factors for DM, and Caucasian
females are at a much-increased risk of having cutaneous findings of DM (96).
TABLE 2 Treatment of Cutaneous Lupus Erythematosus

Sun and heat avoidance
Avoid or stop potentially triggering drugs, especially in SCLE
Sunscreens
UVB SPF-30 or greater
Avobenzone (Parsolw 1789)
Inorganic sunscreens (TiO2 and ZnO)
Sunscreens containing Mexorylw SX and Mexorylw XL
Sunscreens containing Tinosorbw S and Tinosorbw M
Topical and intralesional steroids
Topical calcineurin inhibitors (pimecrolimus and tacrolimus)
Antimalarials
Hydroxychloroquine (,6.5 mg/kg/day)
Combination hydroxychloroquine and quinacrine (100 mg/day)
Combination chloroquine (,3.5 mg/kg/day) and quinacrine
Dapsone (start at 50 mg/day and titrate up to 150 mg/day as tolerated)
Retinoids (1 mg/kg/day), usually for rapid control but not long-term therapy
Thalidomide (100 mg/day until responds, then gradually decrease to as little as 25 mg every
three days)
Methotrexate, CellCept, and azathioprine
Corticosteroids (for acute skin disease only)
Abbreviations: SCLE, subacute cutaneous lupus erythematosus; SPF, sun protection factor.
TABLE 3 Approach to Use of Antimalarials

Begin plaquenil (usually 300– 400 mg/day, depending on weight)
Wait 6– 8 wk for effect
If lupus still active, add quinacrine 100 mg/day
Taper quinacrine as tolerated after disease controlled
If still not controlled, switch from plaquenil to chloroquine
Try to stop antimalarials in winter
In Europe, the prevalence of DM increases with decreasing geographical latitude (97).

One study found the relative prevalence of DM correlated with surface UV irradiance and
there was a strong correlation to the amount of anti-Mi-2 autoantibodies (98).
The distribution of skin lesions in DM suggests that photoinduction is important (99,100).
Common skin changes include an erythematous, often violaceous eruption on the face, particu-
larly in the periorbital area (heliotrope pattern), sun-exposed areas of the face, anterior chest,
upper back and shoulders, posterior neck, scalp, and over the joints on the hands, elbows,
knees, and malleolus (Fig. 8). Skin biopsy show perivascular inflammation consisting of
CD4þ T-cells and B-cells, as well as vasculopathy. DM patients can have autoantibodies
directed against conformational epitopes on cytoplasmic and nuclear components (101).
These include autoantibodies that bind to and inhibit the function of aminoacyl-transfer
RNA synthetases (anti-synthetases), seen in both DM and polymyositis, and those that react
with Mi-2, a 240 kDa SNF2-superfamily helicase associated with the nucleosome remodeling
and deacetylase complex, seen only in DM.
DM can be associated with an underlying malignancy, and the increased risk of malig-
nancy is present for at least five years after initial diagnosis (102). Patients should obtain base-
line and regular screening for malignancy during that time (103). Frequently associated
malignancies include lung, ovarian, pancreatic, stomach, colorectal, and non-Hodgkins lym-
phoma (104). There are patients who have amyopathic or hypomyopathic forms of DM
(105,106). Patients should always be screened with pulmonary function tests (PFTs) for
occult interstitial lung disease, in addition to the usual screening for underlying malignancy.
If PFTs are abnormal, then chest X ray and high-resolution CAT scan should be obtained.
Studies have detected sunlight-induced exacerbation of cutaneous DM (107,108). One
study suggested that the MED to UVB radiation was decreased in DM (108).
Therapy must be directed at the manifestation of DM present. Patients with muscle and
skin disease must be treated with steroids and, for resistant disease, adjunctive immunosup-
pressive therapies. Patients with interstitial lung disease frequently require cyclophosphamide.
Cutaneous findings of DM can be treated with antimalarials, either hydroxychloroquine or
chloroquine, and if that is not effective, then quinacrine is added, as described in the lupus
erythematosus section (109,110). Resistant patients can benefit from additional treatment
FIGURE 8 Dermatomyositis.
with azathioprine, mycophenolate mofetil, or methotrexate (111). There have been recent case
reports and small case series reporting the efficacy of Rituximab in some patients (112).
Bullous Pemphigoid
One study suggested that activation of transcription of the bullous pemphigoid (BP) antigen
gene seen after UV radiation is a potential mechanism of exacerbation of BP by UV (113).
The exact mechanism of UV induction is unknown.
BP is a nonscarring bullous disease that presents with tense blisters, often in a flexural
distribution. It can be generalized or localized, and blister formation may preceed or be
accompanied by an urticarial or eczematous eruption.
It has been noted for years that BP can be induced or exacerbated with UV irradiation
(114,115). There are reports of exacerbations by UVB, UVA, and PUVA (116,117).
The therapy of BP includes glucocorticoids. Some reports suggest that mild disease can be
treated with topical steroids, topical tacrolimus, tetracycline and niacinamide, dapsone, or sul-
fapyridine (118,119). Severe disease usually requires systemic glucocorticoids, usually at a dose
of 0.75 mg/kg/day, although individual patients may respond to lower doses. One large study
found topical steroids worked and minimized side effects in moderate to severe disease (118).
Some patients require adjunctive therapy with immunosuppressives such as azathioprine,
methotrexate, mycophenolate mofetil, or in very unresponsive disease cyclophosphamide.
Very resistant patients may benefit from plasmapheresis in combination with glucocorticoids
and immunosuppressives or from intravenous immunoglobulin (120).
Pemphigus
The etiology of the photoexacerbation of pemphigus is unclear. There appears to be enhanced
binding of pemphigus autoantibodies to keratinocyte membrane after in vivo UV light
exposure, suggesting that UV exposure of the epidermis may uncover increased Dsg1 and
Dsg3 epitopes, which then become available to pathogenic autoantibodies. There is also
increased acantholysis of keratinocytes noted with UV (121 –123). In addition, adhesion
signals transmitted by binding of pemphigus antibodies may be modulated by additional as
yet undefined factors enhanced by UV irradiation (124). Pro-inflammatory cytokines such as
IL-1, IL-8, TNFa, and granulocyte macrophage colony stimulating factor are increased in
skin after UV radiation and could play a role in recruitment of inflammatory cells to skin
and in acantholysis (125 – 128).
Clinically, lesions can present with erosions or flaccid blisters (Fig. 9). One epidemiologi-
cal study linked sunlight and air temperature to disease activity in pemphigus vulgaris (129). It
has been noted for years that pemphigus erythematosus, pemphigus foliaceus, and pemphigus
vulgaris can be induced with UV, including UVB and PUVA irradiation (121,124,130 – 135). In
one patient, irradiation with two MEDs of UVB induced pemphigus lesions at 24 hours (132).
FIGURE 9 Pemphigus vulgaris.

Treatment of pemphigus vulgaris normally includes a combination of glucocorticoids

and an immunosuppressive, such as azathioprine, methotrexate, or mycophenolate mofetil.
Severe unresponsive disease or patients who may not tolerate glucocorticoids sometimes
require adjunctive therapy with intravenous immunoglobulin, plasmapheresis, or more
potent immunosuppressives like cyclophosphamide or chlorambucil. For more mild disease
or patients who are steroid-dependent, tetracycline or dapsone may provide additional
benefit (136,137). Rituximab, TNFa inhibitors, and photopheresis have been anecdotally
reported to be of benefit. There is a need for validated activity indices, standardized definitions,
and multicenter trials to systematically evaluate therapies in pemphigus.
REFERENCES
1. Hjorth N, Sjolin KE, Sylvest B, et al. Acne aestivalis—mallorca acne. Acta Derm Venereol 1972;
52:61– 63.
2. Nieboer C. Actinic superficial folliculitis; a new entity? Br J Dermatol 1985; 112:603– 606.
3. Verbov J. Actinic folliculitis. Br J Dermatol 1985; 113:630– 631.
4. Norris PG, Hawk JL. Actinic folliculitis—response to isotretinoin. Clin Exp Dermatol 1989;
14:69– 71.
5. Veysey EC, George S. Actinic folliculitis. Clin Exp Dermatol 2005; 30:659– 661.
6. Kimoto M, Akiyama M, Matsuo I. Darier’s disease restricted to sun-exposed areas. Clin Exp
Dermatol 2004; 29:37– 39.
7. Baba T, Yaoita H. UV radiation and keratosis follicularis. Arch Dermatol 1984; 120:1484– 1487.
8. Heo EP, Park SH, Yoon TJ, et al. Induction of Darier’s disease by repeated irradiation by ultraviolet
B; protection by sunscreen and topical ascorbic acid. J Dermatol 2002; 29:455– 458.
9. Antley CM, Carrington PR, Mrak RE, et al. Grover’s disease (transient acantholytic dermatosis):
relationship of acantholysis to acrosynringia. J Cutan Pathol 1998; 25:545 –549.
10. Hashimoto K, Moiin A, Chang MW, et al. Sudoriferous acrosyringeal acantholytic disease: a subset
of Grover’s disease. J Cutan Pathol 1996; 23:151 –164.
11. Hashimoto K, Fujiwara K, Harada M, et al. Junctional proteins of keratinocytes in Grover’s disease,
Hailey – Hailey’s disease, and Darier’s disease. J Dermatol 1995; 22:159– 170.
12. Grover RW. Transient acantholytic dermatosis. Arch Dermatol 1970; 101:426– 434.
13. Davis MD, Dinneen AM, Landa N, et al. Grover’s disease: clinicopathologic review of 72 cases.
Mayo Clin Proc 1999; 74:229– 234.
14. Kato N, Furuya K. Two cases of transient acantholytic dermatosis—with the analysis of 20 cases
reported in Japan. Nippon Hifuka Gakkai Zasshi 1991; 101:453– 460.
15. Rockley PF, Bergfeld WF, Tomecki KJ, et al. Myelodysplastic syndrome and transient acantholytic
dermatosis. Cleve Clin J Med 1990; 57:575– 577.
16. Casanova JM, Pujol RM, Taberner R, et al. Grover’s disease in patients with chronic renal failure
receiving hemodialysis: clinicopathologic review of 4 cases. J Am Acad Dermatol 1999;
41:1029– 1033.
17. Parsons JM. Transient acantholytic dermatosis (Grover’s disease): a global perspective. J Am Acad
Dermatol 1996; 35:653– 666.
18. Gudi VS, Edwards S, White MI. Localized transient acantholytic dermatosis in a patient with left
hemiparesis. Acta Derm Venereol 2004; 84:232.
19. Chalet M, Grover R, Ackerman AB. Transient acantholytic dermatosis: a reevaluation. Arch Derma-
tol 1977; 113:431– 435.
20. Paul BS, Arndt KA. Response to transient acantholytic dermatosis to photochemotherapy. Arch
Dermatol 1984; 120:121– 122.
21. Lüftl M, Degitz K, Plewig G, et al. Bath psoralen-UV-A therapy for persistent Grover disease. Arch
Dermatol 1999; 135:606– 607.
22. Breuckmann F, Appelhans C, Altmeyer P. Medium-dose ultraviolet A1 phototherapy in transient
acantholytic dermatosis. J Am Acad Dermatol 2005; 52:169– 170.
23. Malfait P, Moren A, Dillon JC, et al. An outbreak of pellagra related to changes in dietary niacin
among Mozambican refugees in Malawi. Int J Epidemiol 1993; 22:504– 511.
24. Stratigos JD, Katsambas A. Pellagra: a still existing disease? Br J Dermatol 1977; 96:99– 106.
25. Lu JY, Yu CL, Wu MZ. Pellagra in an immunocompetent patient with cytomegalovirus colitis. Am J
Gastroenterol 2001; 96:932– 934.
26. Gillman MA, Sandy KR. Nicotinic acid deficiency induced by sodium valproate. S Afr Med J 1984;
65:986.
27. van der Molen RG, Out-Luiting C, Claas FH, et al. Ultraviolet-B radiation induces modulation of antigen
presentation of herpes simplex virus by human epidermal cells. Hum Immunol 2001; 62:589–597.
28. Ichihashi M, Nagai H, Matsunaga K. Sunlight is an important causative factor of recurrent herpes
simplex. Cutis 2004; 74:14– 18.
29. Pace BF, Owens DW. Photosensitivity eruption following smallpox vaccination. Cutis 1969;
5: 850 – 853.
30. Castrow FF, Wolf JE Jr. Photolocalized varicella. Arch Dermatol 1973; 107:628.
31. Gilchrest B, Baden HP. Photodistribution of viral exanthems. Pediatrics 1974; 54:136– 138.
32. Huff C, Weston WL. The photodistribution of erythema multiforme. Arch Dermatol 1980; 116:477.
33. Galosi A, Plewig G, Hölzle E, et al. Light-induced postherpetic erythema exsudativum multiforme
[German]. Hautarzt 1986; 37:494– 498.
34. Wolf P, Soyer HP, Fink-Puches R, et al. Recurrent post-herpetic erythema multiforme mimicking
polymorphic light and juvenile spring eruption: report of two cases in young boys. Br J Dermatol
1994; 131:364– 367.
35. Shiohara T, Chiba M, Tanaka Y, et al. Drug-induced, photosensitive, erythema multiforme-like
eruption: possible role for cell adhesion molecules in a flare induced by Rhus dermatitis. J Am
Acad Dermatol 1990; 22:647– 650.
36. Ortel B, Sivayathorn A, Hönigsmann H. An unusual combination of phototoxicity and Stevens –
Johnson syndrome due to antimalarial therapy. Dermatologica 1989; 178:39– 42.
37. Leroy D, Le Maitre M, Deschamps P. Photosensitive erythema multiforme apparently induced by
phenylbutazone. Photodermatology 1985; 2:176– 177.
38. Calzavara Pinton PG, Venturini M, Capezzera R, et al. Photosensitive erythema multiforme and
erythema multiforme-like polymorphous light eruption. Photodermatol Photoimmunol Photomed
2003; 19:157– 159.
39. Frain-Bell W, Scatchard M. The association of photosensitivity and atopy in the child. Br J Dermatol
1971; 85:105– 110.
40. Farber EM, Bright RD, Nall ML. Psoriasis. A questionnaire survey of 2,144 patients. Arch Dermatol
1968; 98:248– 259.
41. Doyle JA. Photosensitive psoriasis. Australas J Dermatol 1984; 25:54– 58.
42. Ros AM. Photosensitive psoriasis. Sem Dermatol 1992; 11:267– 268.
43. Ros AM, Eklund G. Photosensitive psoriasis. An epidemiologic study. J Am Acad Dermatol 1987;
17:752– 758.
44. Zalla MJ, Muller SA. The coexistence of psoriasis with lupus erythematosus and other photosensi-
tive disorders. Acta Derm Venereol Supplementum 1996; 195:1– 15.
45. Sahoo B, Kumar B. The coexistence of photosensitive psoriasis with chronic actinic dermatitis. Der-
matology 2002; 204:77– 79.
46. Denguezli M, Nouira R, Jomaa B. Actinic lichen planus: an anatomical study of 10 Tunisian cases.
Ann Dermatol Venereol 1994; 121:543– 546.
47. Salman SM, Kibbi AG, Zaynoun S. Actinic lichen planus: clinicopathologic study of 16 patients.
J Am Acad Dermatol 1989; 20:226– 231.
48. Dostrovsky A, Sagher F. Lichen planus in subtropical countries. Arch Dermatol Syphilol 1949;
59:308– 328.
49. Dilaimy M. Lichen planus subtropicus. Arch Dermatol 1976; 112:1251– 1253.
50. Isaacson D, Turner ML, Elgart ML. Summertime actinic lichenoid eruption (lichen planus actinicus).
51. Skowron F, Grezard P, Merle P, et al. Erythematosus actinic lich planus: a new clinical form associated
with oral erosive lichen planus and chronic active hepatits B. Br J Dermatol 2002; 147:1032–1034.
52. Zanca A. Lichen planus actinicus. Int J Dermatol 1978; 17:506 – 508.
53. Millard TP, Kondeatis E, Cox A, et al. A candidate gene analysis of three related photosensitivity
disorders: cutaneous lupus erythematosus, polymorphic light eruption and actinic prurigo. Br J
Dermatol 2001; 145:229– 236.
54. Werth VP, Zhang W, Dortzbach K, et al. Association of a promoter polymorphism of TNFalpha with
subacute cutaneous lupus erythematosus and distinct photoregulation of transcription. J Invest
Dermatol 2000; 115:726– 730.
55. Werth VP, Bashir M, Zhang W. Photosensitivity in rheumatic diseases. J Investig Dermatol Symp
Proc 2004; 9:54– 63.
56. Racila DM, Sontheimer CJ, Sheffield A, et al. Homozygous single nucleotide polymorphism of the
complement C1QA gene is associated with decreased levels of C1q in patients with subacute
cutaneous lupus erythematosus. Lupus 2003; 12:124– 132.
57. Sontheimer RD, Maddison PJ, Reichlin M, et al. Serologic and HLA associations in subacute
cutaneous lupus erythematosus, a clinical subset of lupus erythematosus. Ann Intern Med 1982;
97:664– 671.
58. Lacour JP. Lupus and sun. Revue de Medecine Interne 1996; 17:196 – 199.
59. Watson RM, Talwar P, Alexander E, et al. Subacute cutaneous lupus erythematosus-immunogenetic
associations. J Autoimmun 1991, 4, 73 – 85.
60. Lee LA, Roberts CM, Frank MB, et al. The autoantibody response to Ro/SSA in cutaneous lupus
erythematosus. Arch Dermatol 1994, 130, 1262 – 1268.
61. Meller S, Winterberg F, et al. Ultraviolet radiation-induced injury, chemokines, and leukocyte
recruitment: an amplification cycle triggering cutaneous lupus erythematosus. Arthritis Rheum
2005, 52, 1504– 1516.
62. Sontheimer RD. The lexicon of cutaneous lupus erythematosus-A review and personal perspective
on the nomenclature and classification of the cutaneous manifestations of lupus erythematosus.
Lupus 1997, 6, 84 – 95.
63. Yell JA, Mbuagbaw J, Burge SM. Cutaneous manifestations of systemic lupus erythematosus . Br J
Dermatol 1996, 135, 355 – 362.
64. Kuhn A, Sonntag M, Richter-Hintz D, et al. Phototesting in lupus erythematosus tumidus-review of
60 patients. Photochem Photobiol 2001, 73, 532 – 536.
65. Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus: a cutaneous
marker for a distinct lupus erythematosus subset. Arch Dermatol 1979; 115:1409– 1415.
66. Perera GK, Black MM, McGibbon DH. Bullous subacute cutaneous lupus erythematosus. Clin Exp
Dermatol 2004; 29:265– 267.
67. Provost TT, Watson R. Anti-Ro(SS-A) HLA-DR3-positive women: the interrelationship between
some ANA negative, SS, SCLE, and NLE mothers and SS/LE overlap female patients. J Invest
Dermatol 1993; 100:14S– 20S.
68. Reed BR, Huff JC, Jones SK, et al. Subacute cutaneous lupus erythematosus associated with hydro-
chlorothiazide therapy. Ann Intern Med 1985; 103:49– 51.
69. Shapiro M, Sosis AC, Junkins-Hopkins JM, et al. Lupus eyrthematosus induced by medications,
ultraviolet radiation, and other exogenous agents: a review, with special focus on the development
of subacute cutaneous lupus erythematosus in a genetically predisposed individual. Int J Dermatol
2004; 43:87 –94.
70. Gammon WR, Briggaman RA. Bullous SLE: a phenotypically distinctive but immunologically
heterogeneous bullous disorder. J Invest Dermatol 1993; 100:28S– 34S.
71. Yell JA, Allen J, Wojnarowska F, et al. Bullous systemic lupus erythematosus: revised criteria for
diagnosis. Br J Dermatol 1995; 132:921– 928.
72. Chan LS, Lapiere JC, Chen M, et al. Bullous systemic lupus erythematosus with autoantibodies
recognizing multiple skin basement membrane components, bullous pemphigoid antigen 1,
laminin-5, laminin-6, and type VII collagen. Arch Dermatol 1999; 135:569– 573.
73. Parodi A, Massone C, Cacciapuoti M, et al. Measuring the activity of the disease in patients with
cutaneous lupus erythematosus. Br J Dermatol 2000; 142:457 –460.
74. Cripps DJ, Rankin J. Action spectra of lupus erythematosus and experimental imunofluorescence.
Arch Dermatol 1973; 107:563– 567.
75. Epstein JH, Tuffanelli D, Dubois EL. Light sensitivity and lupus erythematosus. Arch Dermatol
1965; 91:483– 485.
76. Wysenbeek AJ, Block DA, Fries JF. Prevalence and expression of photosensitivity in systemic lupus
erythematosus. Ann Rheum Dis 1989; 48:461– 463.
77. Haga HJ, Brun JG, Rekvig OP, et al. Seasonal variations in activity of systemic lupus erythematosus
in a subarctic region. Lupus 1999; 8:269– 273.
78. Amit M, Molad Y, Kiss S, et al. Seasonal variations in manifestations and activity of systemic lupus
erythematosus. Br J Rheumatol 1997; 36:449– 452.
79. Lee LA, Farris AD. Photosensitivity diseases: cutaneous lupus erythematosus. J Investig Dermatol
Symp Proc 1999; 4:73– 78.
80. Parodi A, Caproni M, Cardinali C, et al. Clinical, histological and immunopathological features of 58
patients with subacute cutaneous lupus erythematosus. A review by the Italian group of immuno-
dermatology. Dermatology 2000; 200:6 –10.
81. Lehmann P, Hölzle E, Kind P, et al. Experimental reproduction of skin lesions in lupus erythemato-
sus by UVA and UVB radiation. J Am Acad Dermatol 1990; 22:181– 187.
82. Wolska H, Blaszczyk M, Jablonska S. Phototests in patients with various forms of lupus erythema-
tosus. Int J Dermatol 1989; 28:98– 103.
83. van Weelden H, Velthuis PJ, Baart de la Faille H. Light-induced skin lesions in lupus erythematosus:
photobiological studies. Arch Dermatol Res 1989; 281:470– 474.
84. Walchner M, Messer G, Kind P. Phototesting and photoprotection in LE. Lupus 1997; 6:
167 – 174.
85. Sanders CJ, van Weelden H, Kazzaz GA, et al. Photosensitivity in patients with lupus erythemato-
sus: a clinical and photobiological study of 100 patients using a prolonged phototest protocol. Br J
Dermatol 2003; 149:131– 137.
86. Hasan T, Nyberg F, Stephansson E, et al. Photosensitivity in lupus erythematosus, UV photoprovo-
cation results compared with history of photosensitivity and clinical findings. Br J Dermatol 1997;
136:699– 705.
87. Leenutaphong V, Boonchai W. Phototesting in oriental patients with lupus erythematosus. Photo-
dermatol Photoimmunol Photomed 1999; 15:7 –12.
88. Kuhn A, Sonntag M, Richter-Hintz D, et al. Phototesting in lupus erythematosus: a 15-year experi-
ence. J Am Acad Dermatol 2001; 45:86– 95.
89. Stege H, Budde MA, Grether-Beck S, et al. Evaluation of the capacity of sunscreens to photoprotect
lupus erythematosus patients by employing the photoprovocation test. Photodermatol Photoimmu-
nol Photomed 2000; 16:256– 259.
90. Callen JP. Update on the management of cutaneous lupus erythematosus. Br J Dermatol 2004;
151:731– 736.
91. Albrecht J, Taylor L, Berlin JA, et al. The CLASI (cutaneous LE disease area and severity index): an
outcome instrument for cutaneous lupus erythematosus. J Invest Dermatol 2005; 125:889– 894.
92. Heath M, Raugi GJ. Evidence-based evaluation of immunomodulatory therapy for the cutaneous
manifestations of lupus. Adv Dermatol 2004; 20:257– 291.
93. Pablos JL, Santiago B, Galindo M, et al. Keratinocyte apoptosis and p53 expression in cutaneous
lupus and dermatomyositis. J Pathol 1999; 188:63 –68.
94. Coates PJ, Save V, Ansari B, et al. Demonstration of DNA damage/repair in individual cells using in
situ end labelling: association of p53 with sites of DNA damage. J Pathol 1995; 176:19-26.
95. Schwarz A, Bhardwaj R, Aragane Y, et al. Ultraviolet-B-induced apoptosis of keratinocytes: evidence
for partial involvement of tumor necrosis factor-alpha in the formation of sunburn cells. J Invest
Dermatol 1995; 104:922– 927.
96. Werth VP, Callen JP, Ang G, et al. Associations of tumor necrosis factor-a (TNFa) and HLA poly-
morphisms with adult dermatomyositis: implications for a unique pathogenesis. J Invest Dermatol
2002; 119:617– 620.
97. Hengstman GD, van Venrooij WJ, Vencovsky J, et al. The relative prevalence of dermatomyositis and
polymyositis in Europe exhibits a latitudinal gradient. Ann Rheum Dis 2000; 59:141– 142.
98. Okada S, Weatherhead E, Targoff IN, et al. Global surface ultraviolet radiation intensity may modu-
late the clinical and immunologic expression of autoimmune muscle disease. Arthritis Rheum 2003;
48:2285– 2293.
99. Sontheimer RD. Photoimmunology of lupus erythematosus and dermatomyositis: a speculative
review. Photochem Photobiol 1996; 63:583– 594.
100. Cheong WK, Hughes GR, Norris PG, et al. Cutaneous photosensitivity in dermatomoyositis. Br J
Dermatol 1994; 131:205– 208.
101. Miller FW. Myositis-specific autoantibodies: touchstones for understanding the inflammatory
myopathies. JAMA 1993; 270:1846– 1849.
102. Sigurgeirsson B, Lindelof B, Edhag O, et al. Risk of malignancy in patients with dermatomyositis or
polymyositis. N Engl J Med 1992; 326:363– 367.
103. Callen JP. When and how should the patient with dermatomyositis or amyopathic dermatomyositis
be assessed for possible cancer? Arch Dermatol 2002; 138:969– 971.
104. Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and
polymyositis: a population-based study. Lancet 2001; 357:96– 100.
105. Euwer R, Sontheimer R. Amyopathic dermatomyositis (dermatomyositis sine myositis).
Presentation of six new cases and review of the literature. J Am Acad Dermatol 1991; 24:959– 966.
106. Sontheimer RD. Would a new name hasten the acceptance of amyopathic dermatomyositis
(dermatomyositis sine myositis) as a distinctive subset within the idiopathic inflammatory derma-
tomyopathies spectrum of clinical illness? J Am Acad Dermatol 2002; 46:626– 636.
107. Everett MA, Curtis AC. Dermatomyositis: a review of 19 cases in adolescents and children. Arch Int
Med 1957; 100:70– 76.
108. Dourmishev L, Meffert H, Piazena H. Dermatomyositis: comparative studies of cutaneous photo-
sensitivity in lupus erythematosus and normal subjects. Photodermatol Photoimmunol Photomed
2004; 20:230– 234.
109. Sontheimer RD. The management of dermatomyositis:current treatment options. Exp Opin
Pharmacother 2004; 5:1083– 1099.
110. Ang GC, Werth VP. Combination antimalarials in the treatment of cutaneous dermatomyositis: a
retrospective study. Arch Dermatol 2005; 141:855– 859.
111. Edge JC, Outland JD, Dempsey JR, et al. Mycophenolate mofetil as an effective corticosteroid-sparing
therapy for recalcitrant dermatomyositis. Arch Dermatol 2006; 142:65– 69.
112. Levine TD. Rituximab in the treatment of dermatomyositis: an open-label pilot study. Arthritis
Rheum 2005; 52:601– 607.
113. Kayashima K, Koji T, Nozawa M, et al. Activation of bullous pemphigoid antigen gene in mouse ear
epidermis by ultraviolet radiation. Cell Biochem Funct 1998; 16:107– 116.
114. Person JR, Rogers III RS. Bullous pemphigoid and psoriasis; does subclinical bullous pemphigoid
exist? Br J Dermatol 1976; 95:535– 540.
115. Thomsen K, Schmidt H. PUVA-induced bullous pemphigoid. Br J Dermatol 1976; 95:568– 569.
116. Perl S, Rappersberger K, Fodinger D, et al. Bullous pemphigoid induced by PUVA therapy. Dermatol
1996; 193:245– 247.
117. Pfau A, Hohenleutner U, Hohenleutner S, et al. UV-A-provoked localized bullous pemphigoid. Acta
Derm Venereol 1994; 74:314– 316.
118. Joly P, Roujeau JC, Benichou J, et al. A comparison of oral and topical corticosteroids in patients with
bullous pemphigoid. N Engl J Med 2002; 346:321 –327.
119. Wojnarowska F, Kirtschig G, Highet A, et al. Guidelines for the management of bullous pemphigoid.
Br J Dermatol 2002; 147:214– 221.
120. Kirtschig G, Khumalo NP. Management of bullous pemphigoid. Recommendations for immunomo-
dulatory treatments. Am J Clin Dermatol 2004; 5:319 – 326.
121. Cram DL, Fukuyama K. Immunohistochemistry of ultraviolet-induced pemphigus and pemphigoid
lesions. Arch Dermatol 1972; 106:819– 824.
122. Gschnait F, Pehamberger H, Holubar K. Pemphigus acantholysis in tissue culture: studies on photo-
induction. Acta Derm Venereol 1978; 58:237– 239.
123. Reis VM, Toledo RP, Lopez A, et al. UVB-induced acantholysis in endemic pemphigus foliaceus
(fogo selvagem) and pemphigus vulgaris. J Am Acad Dermatol 2000; 42:571– 576.
124. Kano Y, Shimosegawa M, Mizukawa Y, et al. Pemphigus foliaceus induced by exposure to sunlight.
Dermatol 2000; 201:132– 138.
125. Oxholm A, Oxholm P, Staberg B, et al. Immunohistological detection of interleukin 1-like molecules
and tumor necrosis factor in human epidermis. Br J Dermatol 1988; 118:369– 377.
126. Felician C, Toto P, Amerio P, et al. In vivo and in vitro expression of interleukin-1alpha and tumor
necrosis factor-alpha are involved in acantholysis. J Invest Dermatol 2000; 114:71– 77.
127. Werth VP, Zhang W. Wavelength-specific synergy between ultraviolet radiation and interleukin-1
alpha in the regulation of matrix-related genes: mechanistic role for tumor necrosis factor-alpha.
128. Köck A, Schwarz T, Kirnbauer R, et al. Human keratinocytes are a source for tumor necrosis factor
alpha: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp
Med 1990; 172:1609– 1614.
129. Kyriakis KP, Vareltzidis AG, Tosca AD. Environmental factors influencing the biologic behavior of
patterns of pemphigus vulgaris: epidemiologic approach. Int J Dermatol 1995; 34:181– 185.
130. Cram DL, Winkelmann RK. Ultraviolet-induced acantholysis in pemphigus. Arch Dermatol 1965;
92:7– 13.
131. Jacobs SE. Pemphigus erythematosus and ultraviolet light. Arch Dermatol 1965; 91:139– 141.
132. Muramatsu T, Iida T, Ko T, et al. Pemphigus vulgaris exacerbated by exposure to sunlight.
J Dermatol 1996; 23:559– 563.
133. Fryer EJ, Lebwohl M. Pemphigus vulgaris after initiation of psoralen and UVA therapy for psoriasis.
134. Aghassi D, Dover JS. Pemphigus foliaceus induced by psoralen-UV-A. Arch Dermatol 1998;
134:1300– 1301.
135. Deschamps P, Pedailles S, Michel M, et al. Photo-induction of lesions in a patient with pemphigus
erythematosus. Photodermatology 1984; 1:38 – 41.
136. Bystryn JC, Rudolph JL. Pemphigus. Lancet 2005; 366:61– 73.
137. Werth VP, Fivenson D, Pandya A, et al. Multicenter randomized placebo-controlled clinical trial of
dapsone as a glucocorticoid-sparing agent in maintenance phase pemphigus vulgaris. J Invest
Dermatol 2005 [abstr]; 125:1088.
Section IV: PHOTOPROTECTION
18 Photoprotection
Henry W. Lim
B There are several new photostable broad-spectrum UV filters that are

available in many parts of the world except in the United States.
B Sun protection factor is a reflection of UVB protection of sunscreen;

harmonization of UVA protection is ongoing.
B Photoprotectiveness of garment is rated by ultraviolet protection factor

(UPF); UPF is becoming more widely used.
B Developments in the glass industry have resulted in the availability of

glass that has significant UV filtering properties up to 380 nm.
B Several non-UV filter, topical and systemic photoprotective agents have

been identified; larger studies are needed for most.
B These developments are of great benefit to our patients in reducing the

acute and chronic effects of sun exposure.
268 Lim and Hönigsmann
INTRODUCTION
cute and chronic exposures to sunlight are known to produce a range of deleterious effects
A including edema, sunburn, photoaging, photoimmunosuppression, and photocarcino-

genesis. As such, the use of photoprotective measures has long been advocated by the der-
matologic and general medical communities. Photoprotection includes the avoidance of
sunlight during the peak UVB hours (10 AM to 4 PM ), the use of sunscreen on exposed areas,
wearing of a hat, protective clothing, and sunglasses.
In Asian cultures, especially among women, fair and unblemished skin is highly valued.
Therefore, in Asian countries, many of which are in the tropical or subtropical area, photopro-
tection is used to minimize tanning and dispigmentation.
ASSESSMENT OF PHOTOPROTECTION
Sun Protection Factor
The concept of sun protection factor (SPF) was developed by Franz Greiter in 1962, and adopted
by the U.S. Food and Drug Administration (FDA) in 1978 (1,2). Currently, this is a universally
accepted method to measure the protectiveness of sunscreen. SPF is the ratio of the minimal
erythema dose (MED) of sunscreen-protected skin over the MED of the sunscreen-unprotected
skin. For this assessment, solar-simulated radiation light source is used and sunscreen is applied
at a concentration of 2 mg/cm2. Because the end point of this assessment is cutaneous erythema,
SPF is a reflection predominately of the biologic effect of UVB. SPF is not designed to measure the
protectiveness of against UVA; in fact, it is known that the SPF of a product does not correlate
with its UVA protectiveness. Furthermore, at the tested concentration of 2 mg/cm2, it requires
approximately one ounce (30 mL) of sunscreen to cover the entire body surface. It is now
known that in actual use, most consumers do not use sunscreen at this concentration. In fact,
the overall median application concentration has been found to be only 0.5 mg/cm2. This
results in significantly lower “in use” of SPF as compared to the labeled SPF (3,4).
The U.S. FDA requires that for any sunscreen to be labeled as “water resistant” and “very
water resistant,” the product would have to maintain its labeled SPF following 2 20 minutes
of water emersion, and 4 20 minutes water emersion, respectively (5).
UVA Protection Factor

Currently, there is no worldwide standard that has been accepted by all countries (see Chap.
19). For example, in vitro methods are use in Australia, the United Kingdom, and Germany,
and an in vivo method is used in Japan and several Asian countries. At the time of this
writing, the U.S. FDA has not recommended any UVA protection assessment method to be
used for sunscreens marketed in the United States.
In February 2005, the regulatory body governing the establishment of German industrial
standards (Deutsche Industrienorm, DIN) introduced the new DIN Method 67502, entitled
“Characterization of UVA protection of dermal sun care products by measuring the transmit-
tance with regards to the sun protection factor,” also known as the UVA balance method. The
DIN will probably be adopted by the European Commission as the standard (6 –8).
The objective of this new method is to balance the level of UVA protection provided by a
sunscreen with the level of UVB protection it provides, therefore addressing some of the limit-
ations of other standards. For example, according to the Australian standard, the level of UVA
protection may remain constant regardless of the level of UVB protection provided. In other
words, an SPF 4 sun care product could provide the same level of UVA protection as SPF 15
and SPF 30 products, and still in compliance with that standard.
The first step in the assessement of the UVA balance is the calculation of in vitro SPF,
taking into account the erythemal action spectrum. This value is then adjusted to the corre-
sponding SPF that is stated on the label. Based on this result, an in vitro UVA/persistent pig-
mentation darkening (PPD) protection factor can be calculated. The UVA balance represents
the ratio of the in vitro UVA/PPD protection factor (UVA) and the in vivo UVB protection,
reflected as the labeled SPF value (7,8). In the DIN Method 67502, no limits for UVA/UVB
balance are given (6).
Photoprotection 269
Immune Protection Factor

It is known that SPF, with erythema as its end point, is a poor predictor of immunosuppression
(9). As such, the concept of immune protection factor (IPF) has been developed (10). The prin-
ciple of IPF is to assess the ability of sunscreen to prevent the immunosuppression induced by
solar-simulated radiation. However, there are a variety of methods used, all are quite laborious
and time consuming to perform. It is likely that it will be many years before the IPF is used as
part of the labeling of commercial products.
Ultraviolet Protection Factor

This is a standard that was first developed in Australia in 1996 (11). It is now widely used in
Australia, the European Union, and the United States. Ultraviolet protection factor (UPF) is
an in vitro measurement of relative amount of UV that penetrates a fabric, resulting in
cutaneous erythema; the latter is derived from the erythemal action spectrum (12). The import-
ance of using the erythemal action spectrum data is that a fabric that allows a greater portion of
UVB to be transmitted will receive a UPF value that is lower than a fabric that allows less UVB
to penetrate, even though both fabrics may transmit the same amount of radiation.
TOPICAL UV FILTERS
Regulations
In the United States, sunscreens are regulated as over-the-counter medications by the FDA (5).
In order for a new UV filter to be included in the monograph, a New Drug Application (NDA)
needs to be made, a process that may take years. Similar regulations are also in place in
Australia and Japan. In 2002, the FDA instituted a second application process, the Time and
Extend Application (TEA) (13). The TEA process indicates that if a sunscreen has been
marketed and sold for a minimum of five years in a foreign country, data generated in that
country can be used for the application.
In the European Union, South America, Asia, and Africa, sunscreens are regulated as
cosmetics resulting in a simpler and more expeditious approval process.
UV FILTERS APPROVED IN THE UNITED STATES

The list of UV filters included in the latest version (1999) of FDA sunscreen monograph is
shown in Table 1.
New UV Filters
Through the TEA process, there are currently three UVB filters and two broad-spectrum UV
filters that are undergoing the approval by the U.S. FDA. These filters are isoamyl p-methoxy-
cinnamate [U.S. adopted name (USAN): amiloxate], 4-methylbenzylidene camphor (USAN:
enzacamene), ethylhexyl triazone (USAN: octyl triazone), methylene-bis-benzotriazolyl
tetramethylbutyl-phenol (Tinosorbw M; USAN: bisoctrizole), and bis-ethylhexyloxyphenol
methoxyphenyl triazine (Tinosorbw S; USAN: bemotrizinol). In addition, a UVA filter,
terephthalidene dicamphor sulfonic acid (Mexorylw SX; USAN: ecamsule) was approved by
the US FDA through the NDA in July, 2006 (14,15).
UV filters that are available in the European countries are listed in Table 2.
Sunscreen Use in Children

Regular use of sunscreen with an average SPF of 7.5 for the first 18 years of life could reduce
the lifetime incidence of nonmelanoma skin cancer by 78% (16). It should be emphasized,
however, that UV exposure occurs throughout life, with men over 40 years of age
receiving the most exposure (17,18). Therefore, sunscreen should be used by children as well
as adults.
TABLE 1 UV Filters Listed in the U.S. Food and Drug Administration Sunscreen Monograph
lmax (nm); or
absorption
USAN a INCI name range Comment
Organic absorbers: UVB filters
PABA derivatives
Aminobenzoic acid PABA 283 Stains clothing
(PABA) Not widely used
Padimate O Ethylhexyl dimethyl PABA 311 Most commonly used PABA
derivative
Photolabile
Cinnamates
Octinoxate Ethylhexyl methoxycinnamate 311 Most widely used UVB filter
Photolabile
Cinoxate Cinoxate 289
Salicylates
Octisalate Ethylhexyl salicylate 307 Weak UVB absorbers
Homosalate Homosalate 306 Improves photostabiltiy of
other filters
Trolamine salicylate TEA salicylate 260– 355 Weak UVB absorbers
Good substantivity—used in
water-resistant sunscreens
and hair-care products
Others
Octocrylene Octocrylene 303 Photostable
Improves photostability of
photolabile filters
Ensulizole Phenylbenzimidazole sulfonic acid 310 Water-soluble
Enhances SPF of the final
product
Organic absorbers: UVA filters
Benzophenones
Oxybenzone Benzophenone-3 288,325 Most commonly used UVA
filter
Most common cause of
photoallergic contact
dermatitis to UV filters
Photolabile
Sulisobenzone Benzophenone-4 366
Dioxybenzone Benzophenone-8 352
Others
Avobenzone Butyl methoxydibenzoylmethane 360 Photolabile
Enhances the
photodegradation of
octinoxate
Meradimate Menthyl anthranilate 340 A weak UVA filter
Inorganic Absorbers
Titanium dioxide Titanium dioxide See belowb No report of sentitization
reaction
b
Zinc oxide Zinc oxide See below Photostable; used to enhance
photostability of the
final product
Micronized zinc oxide has
better UVA1 protection
compared to micorfine
titanium dioxide
(Continued )
Photoprotection 271
TABLE 1 UV Filters Listed in the U.S. Food and Drug Administration Sunscreen Monograph (Continued)
lmax (nm); or
absorption
USAN a INCI name range Comment
Micronized zinc oxide has
lower refractive index
compared to micorfine
titanium dioxide, hence
appears less white
Commonly coated with
dimethicone or silica to
maintain their effectiveness
as sunscreen
a
USAN, United States Adopted Name; this is the name used by the FDA in the listing.
b
lmax ranges from visible to UVA to UVB range, depending on the particle size. As the pigment is micronized (10 – 50 nm in diameter),
lmax shifts towards UVB.
Abbreviations: INCI, International nomenclature of cosmetic ingredients; PABA, para-Aminobenzoic acid; SPF, sun protection factor;
TEA, the time and extend application.
Source: From Refs. 4, 5.
Because of the concern about percutaneous absorption of sunscreens, the 1999 FDA
sunscreen monograph recommends that the use of sunscreens in children under the age of
six months should be decided by their physicians (5). For this group of patients, it would be
prudent to use other means of photoprotection; and sunscreens could be used on an infrequent
basis on the exposed areas.
Photostability of UV Filters
All UV filters, especially avobenzone, octinoxate, and padimante O, are photolabile (Table 3) (19).
In the past few years, however, many sunscreen manufactures have been able to combine
TABLE 2 UV Filters Available in Europe

para-Aminobenzoic acid (PABA)a
Benzophenone-3 (oxybenzone)a
Benzophenone-4 (sulisobenzone)a
Benzylidene camphor
Benzylidene camphor sulfonic acid
bis-Ethylhexyloxyphenol methoxyphenol triazine (bemotrizinol; TinosorbwS)
Bisymidazylate
Butyl methoxydibenzoylmethane (avobenzone; Parsolw 1789)a
Camphor benzalkonium methosulfate
Diethylamino hydroxybenzoyl hexyl benzoate
Diethylhexyl butamido triazone
Dimethicodiethylbenzal malonate
Drometrizole trisiloxane (silatriazole; MexorylwXL)
Ethoxylated ethyl 4-aminobenzoic acid (PEG-25 PABA)
Ethylhexyl methoxycinnamate (octinoxate; octyl methoxycinnamate)a
Ethylhexyl dimethyl PABA (padimate O; octyl dimethyl PABA)a
Ethylhexyl salicylate (octisalate; octyl salicylate)a
Homosalate (homomenthyl salicylate)a
Isoamyl p-methoxycinnamate (amiloxate)
4-Methylbenzylidene camphor (enzacamene)
Methylene bis- benzotriazolyl tetramethylbutylphenol (bisoctrizole; TinosorbwM)
Octocrylenea
Octyl triazone
Phenylbenzimidazole sulfonic acid (ensulizole)a
Polyacrylamidomethyl benzylidene camphor
Terephthalylidene dicamphor sulphonic acid (ecamsule; MexorylwSX)
Titanium dioxidea
Zinc oxidea
a
Approved in the United States.
TABLE 3 Photostability of UV Filters

Filters/agent frequently added to enhance photostability of the
Photolabile filters (USAN/INCI/trade name) final product (USAN/INCI/trade name)
UVB filters UVB filters
Octinoxate (ethylhexyl methoxycinnamate) Enzacamene (4-methylbenzylidene camphor)a
Padimate O (ethylhexyl dimethyl PABA) Homosalate (homosalate)
Octisalate (ethylhexyl salicylate)
Octocrylene (octocrylene)
UVA filters UVA filter
Avobenzone (butyl methoxydibenzoylmethane; Oxybenzone (benzophenone-3)
Parsolw 1789)
Broad-spectrum UVB–UVA filter
bis-Ethylhexyloxyphenol methoxyphenol triazine (bemotrizinol;
Tinosorbw S)
Methylene-bis-benzotriazolyl tetramethylbutylphenol
(biscotrizole; Tinosorbw M)
Titanium dioxide (microfine)
Zinc oxide (micronized)
Not a UV filter
Diethylhexyl 2,6-naphthalate
a
Undergoing U.S. Food and Drug Administration Time and Extend Application approval process.
Abbreviations: INCI, International nomenclature of cosmetic ingredients; PABA, para-aminobenzoic acid; USAN, United States adopted
name.
these photolabile filters with other filters, which resulted in final products that are
photostable. Agents that are frequently used to increase the photostability are listed in Table 3
(4,20).
Photostable filters have also been developed. Four are available in many parts of the
world: methylene-bis-benzotriazolyl tetramethylbutyl-phenol (bisoctrizole; Tinosorbw M),
bis-ethylhexyloxyphenol methoxyphenyl triazine (bemotrizinol; Tinosorbw S), terephthalidene
dicamphor sulfonic acid (ecamsule; Mexorylw SX), and drometrizole trisiloxane (silatriazole;
Mexorylw XL). As of 2006, all except silatriazole are undergoing the approval processes in
the United States, and ecamsule has now been approved.
Sunscreen Use and Vitamin D

This topic has been extensively reviewed (21,22). The action spectrum for synthesis of vitamin
D3 in the epidermis is in the UVB range; such synthesis occurs at suberythemogenic doses of
UVB. Therefore, for many individuals, incidental sun exposure, along with balanced diet, is
sufficient to maintain sufficient vitamin D level. However, for individuals with a higher risk
of vitamin D insufficiency, such as elderly individuals who are home bound and dark-
skinned individuals who work mostly indoors, oral vitamin D3 supplementation is
recommended. Because the action spectrum for vitamin D photosynthesis and cutaneous
photocarcinogenesis cannot be separated, and because the public health message should be
delivered in a simple, clear, and understandable fashion, it is prudent not to advise the
general public to use sun exposure as a means of achieving sufficient vitamin D level.
CLOTHING
UV protectiveness of clothing is assessed by the UPF. This is an in vitro measurement combin-
ing the UV transmission data with two weighing factors, solar spectral irradiance and
erythema effectiveness at each UV wavelength. The latter accounts for the fact that UPF is a
better reflection of the protectiveness of fabrics against UVB than UVA (23).
Although UPF value could be measured for all swatches of fabrics, different guidelines
are used in different parts of the world to have a lable-UPF for a given garment. These
include the Australian Standard AS/NZS 4399; the standard commonly used in the United
States, ASTM D6603-00; British Standard EN 13758-1:2002; and European Standard EN
13758-2 (11,24– 26). The variations among these standards include the requirement for the
Photoprotection 273
TABLE 4 UV-Protection Classification of

Garments
Label Label-UPF
Good protection 15– 24
Very good protection 25– 39
Excellent protection 40– 50þ
Abbreviation: UPF, ultraviolet protection factor.
TABLE 5 Factors Affecting Sun-Protectiveness of Garments

Style of garment
Number of layers
Fabric thickness
Type of fibers (polyester . wool . silk . nylon . cotton, rayon)
Laundering
Wetness
Optical whitening agents
UV absorbers
Stretching
body parts that the garment is to cover, and the ways that the fabric must be prepared for
testing (number of launderings, hours of in vitro UV exposure), and the minimum UPF
value that is required to be classified as sun-protective clothing. For example, both AS/NZS
4399 and ASTM D6603-00 require a lable-UPF value of 15 or above, whereas EN 13758-2
requires UPF of greater than 40 for a garment to be labeled as sun-protective. ASTM D-6603
requires that fabrics be subjected to 40 launderings and many hours of UV exposure prior to
testing. UV-protection classification of garment is shown in Table 4.
As recently reviewed, there are several factors that affect the sun protectiveness of
clothing (Table 5) (12). The style of the garment dictates the body parts that would be
covered. Double layer fabrics, such as frequently used on the shoulder area, would provide
better protection compared to single layer. Thickness of the fabric also correlates with sun
protectiveness. The type of fibers used in fabrics contributes to the UPF (27). Polyester is
the best UV absorber, followed by wool, silk, and nylon. Cotton and rayon, which are cellulose
fibers, have the poorest UV absorption. Laundering garments made from cotton, rayon, or
linen will result in an increase in their UPF because of shrinkage, causing a decrease in the
fabric porosity. UPF is decreased when the garment is wet as more UV would be able to be
transmitted. Optical whitening agents are widely incorporated in many laundry detergents
in the United States and Europe. These agents absorbed UV radiation at 360 nm and
convert it to visible light wavelength of 430 nm; the emission of visible light from the fabric
makes the fabric look “brighter.” Therefore, optical brightening agents would result in
decreased UV transmission through the fabric. In addition, UV absorbers can be added to
the fabrics during the manufacturing process, resulting in an increase in the UPF. UV absor-
bers are also available in some laundry detergents, rise-cycle fabric softeners, or as a dedicated
laundry additive (11). Stretching of the fabric would decrease the UPF by increasing the por-
osity of the fabric.
GLASS
This topic has been recently reviewed (28). Glass is high quality silica sand mixed with other
materials such as salt cake, limestone, dolomite, feldspar, soda ash, and cullet (cullet is
broken glass) (29). As shown in Table 6, with recent developments, there are many types of
glass that have very good UV protection (up to 380 nm). It should be noted that most types
of glass have UV transmission at wavelengths beyond 380 nm; it is because, although technol-
ogies are available to develop coatings that could absorb up to 400 nm without significantly
TABLE 6 Type of Glass

Type Tvis TUV Comment
Clear glass .90% .72%
Tinted/heat-absorbing 62% 40% Absorbs 40–50% of solar energy.
glass
Reflective glass 19% 17% Mirror-like appearance.
Used in commercial buildings.
Low-emissivity glass 71% 20% Reduces loss of generated heat, and minimizes solar
heat gain.
Used in residential and commercial buildings.
Laminated glass 79% ,1% Two pieces of glass are bound to a plastic interlayer to
prevent fragments from falling free if broken.
Reduces sound transmission.
Used for car windshield, and in airports, museums,
and large public spaces.
UV-blocking coated glass 80% ,1% UV coating blocks .98% of UV (up to 380 nm)
Spectrally selective and UV- 69% ,1% Reduces heat loss/gain
blocking insulating glass Blocks .99% of UV (up to 380 nm)
Abbreviations: TUV, transmission in the UV range (assessed from 300 –380 nm); Tvis, transmission in the visible light range (assessed
from 400 – 780 nm).
Source: From Ref. 28; Adapted from Guardian Industries Corp. (Auburn Hills, Michigan, U.S.A.).
affecting the transmission of visible light, presently, application of such technologies would
increase the production cost that would prohibit the economic viability of such a product.
All windshields of cars are made of laminated glass, which allows ,1% of UV (300 –
380 nm) to pass through. However, side and rear windows are usually made from nonlami-
nated glass; therefore, a higher level of UVA can pass through those windows (28). It has
been demonstrated that when the arm is placed near a nonlaminated clear car window for
30 minutes, an exposure of 5 J/cm2 of UVA could be achieved, which is sufficient to induce
cutaneous eruption in patients with severe photosensitivity (30). If a laminated gray window
glass were used instead, at least 50 hours of UV exposure would be required to induce
lesions in these patients. After-market tinting of side and rear car windows has become
popular; in the United States, after-market tinting must comply with the federally-mandated
visible light transmittance of at least 70% for automobile windshields, except for the top 4
inches (31). Although the minimum allowable transmittance levels for side and rear
windows are determined by each state in the United States, most states do not allow tinting
with less than 35% visible light transmittance.
OTHERS
Sunless Tanning Agents
Preparations containing dihydroxy acetone (DHA) are now widely used as artificial tanning
agents. DHA was first recognized as a skin-coloring agent in the 1920s. DHA reacts with
basic amino acids in keratinized stratum cormeum to form yellow brown pigments called
melanoidins (32). Because the pigments bind covalently to stratum cormeum, the color does
not wash off easily until the stratum cormeum is shed-off in three to seven days. DHA is
considered to be safe and is approved by the FDA as a cosmetic agent. Because melanoidins
absorb primarily in the visible and UVA range, topical application of DHA results in SPF of
only 1.6 to 2.3 (33). Sunless tanning products use DHA in concentrations ranging from 1% to
15%; most drug store products are in the 3% to 5% range (34).
Bronzers are water-soluble dyes, commonly prepared as moistures or powders that can
be applied to the skin. They do easily wash off and, therefore, can only function as a cover up.
Antioxidants
Because UV radiation induces oxidative stress on the skin, antioxidants have been widely used
as a photoprotective measure. Topical antioxidants are poor UV absorbers; therefore, they are
Photoprotection 275
commonly used in combination with UV filters in sunscreen products. Antioxidants can be

administered orally or topically. Combination of high doses of oral antioxidants, L-ascorbic
acid (vitamin C, 3 gm/day), and alpha tocopherol (vitamin E, 2 gm/day) for 50 days resulted
in an increase in the MED to solar-simulated radiation; no increase was noted for patients
treated with either of the antioxidants alone (4,35). However, in healthy individuals, six
months of daily oral supplementation with 400 IU of vitamin E did not result in any protection
to UV-induced skin damage (36). Another antioxidant, beta-carotene (120 – 180 mg/day), is
known to diminish the photosensitivity in erythropoietic protoporphyria (37). In mice,
topical tocopherol (vitamin E) or topical L-ascorbic acid (vitamin C) could suppress the induc-
tion of UV-induced inflammation, prevent photoimmunosuppression, and decrease UV-
induced photocarcinogenesis (38,39).
Another potent antioxidant that has been widely studied is ( – )-epigallocatechin-3-
gallate, a polyphenol in green tea (40,41). Topical application of green tea extracts have been
reported to decrease inflammation, carcinogenesis, and immunosuppression. It has been esti-
mated that the above effect can be achieved with 10 caps of green tea a day, a relatively large
amount of ingestion. Over-the-counter capsules containing green tea extracts are now avail-
able. Topically, green tea polyphenols do not function as effective UVB filter, as they have an
absorption maximum at 273 nm (42).
DNA Excision Repair Enzyme and Photolyase

T4 endonuclease V is a DNA excision repair enzyme that repair cyclobutane pyrimidine dimers
formed following predominantly UVB exposure. Topical application of T4N5 liposomes for one
year in patients with xeroderma pigmentosum resulted in decreased formation of new actinic
kertoses and basil cell carcinomas, as compared to the controlled group (43). Investigations are
ongoing on the effect of this novel preparation as chemoprevention of skin cancers in otherwise
healthy individual.
Photolyase, which specifically converts cyclobutane dimers into their original DNA
structure after exposure to photoreactivating light, might also offer additional protection as
sunscreen component to reverse harm caused by sun (44). There exist only limited data on
its action in humans, and more research is needed to see if photolyase works with all
degrees of sunburn and whether it can reduce risk of skin cancer.
Polypodium Leucotomos
Polypodium leucotomos is an extract from a fern plant grown in Central America. Oral and
topical forms of this compound have been shown to be photoprotective against UVB and
PUVA-induced phototoxicity, to increase immediate pigment-darkening dose, MED, minimal
phototoxic dose, and minimal melanogenic dose. It has antioxidant and anti-inflammatory
property. Because P. leucotomos has SPF of only 3 to 8, it is thought that the above biologic prop-
erties are independent from its property as a UV filter (45). Although studies have been done in
human subjects, a larger study is needed. It is available in the United States and in many parts
of the world as an over-the-counter vitamin supplement.
Miscellaneous Agents
Other agents that have been reported to have photoprotective properties are listed in Table 7 (4).
CONCLUSION
In the past 20 years, significant advances have been achieved in the area of photoprotection.
There are several new photostable broad-spectrum UV filters that are available. Understanding
and labeling of photoprotectiveness of clothing have improved very significantly. Develop-
ments in the glass industry have resulted in the availability of glass that has significant UV
filtering properties up to 380 nm. In addition, several other topical and systemic photo-
protective agents have been identified, all functioning by mechanism(s) that is separate from
TABLE 7 Other Agents with Photoprotective Property

Agent Source Comment
N-Acetylcysteine Synthetic Increase of glutathione level
(endogenous antioxidant)
Butyrated hydroxytoluene Preservatives, additives Synthetic antioxidant
Cadmium chloride Synthetic Induction of metallothionein
Caffeic acid and ferulic acid Plants and vegetables Antioxidant and radial scavenging
Calcitriol (1,25-dihydroxyvitamin D3) Kidneys Induction of metallothionein
(scavenger of free radicals)
Celecoxib Synthetic Cyclooxygenase 2 inhibitor
Cistus Mediteranian shrubs Free radical scavenging
2-Furildioxime (FDO) Synthetic Iron chelator
Isoflavone metabolites Protection against UV-induced
Genistein Soybean inflammation and
Equol Red clover immunosuppression
Isoflavones Plants Antioxidants
Melatonin Synthetic Antioxidant
Plant oligosaccharides Prevention of UVB-induced systemic
Xyloglucans Tamarind seeds immunosuppression
Aloe poly/oligosaccharide Aloe barbadensis
Omega-3 polyunsaturated fatty acid Fish oil Decrease of sunburn cell formation,
anti-inflammation
Zinc Antioxidant
Source: Modified from Ref. 4.
filtration of the UV radiation. Taken together, these developments are of great benefit to our
patients in reducing the acute and chronic effects of sun exposure.
REFERENCES
1. Editorial. Von der Fettcreme zur Sonnenpflege. Parfümerie und Kosmetik 1999; 11/12:16– 18.
2. Department of Health, Education and Welfare, Food and Drug Administration. Sunscreen drug pro-
ducts for over-the-counter human use. Federal Register 1978; 43:38206– 38269.
3. Azurdia RM, Pagliaro JA, Diffey BL, Rhodes LE. Sunscreen application by photosensitive patients is
inadequate for protection. Br J Dermatol 1999; 140:255– 258.
4. Kullavanijaya P, Lim HW. Photoprotection. J Am Acad Dermatol 2005; 52:937– 958.
5. Department of Health and Human Services, Food and Drug Administration. Sunscreen drug pro-
ducts for over-the-counter human use; final monograph. Federal Register 1999; 64:27666– 27693.
6. Characterization of UVA protection of dermal suncare products by measuring the transmittance with
regard to the sun protection factor. DIN 67502, Deutsches Institut für Normung e.V., Berlin February
2005.
7. Gers-Barlag H, Wendel V, Klette E, Wolber R, Wittern KP. UVA balance—The accurate and skin
relevant assessment of the UVA protection of sunscreens. 7th Joint ASCC NZCSS Australasian
Conference Auckland, New Zealand, 2004.
8. Dippe R, Klette E, Mann T, Wittern K-P, Gers-Barlag H. Comparison of four different in vitro
test methods to assess the UVA protection performance of sunscreen products. SÖFW-J 2005;
131:1– 6.
9. Kelly DA, Young AR, McGregor JM, Seed PT, Potten CS, Walker SL. Sensitivity to sunburn is associ-
ated with susceptibility to ultraviolet radiation-induced suppression of cutaneous cell-mediated
immunity. J Exp Med 2000; 191:561– 566.
humans: a consensus paper. J Invest Dermatol 2005; 125:403– 409.
11. Standards Association of Australia. Standard AS/NZS 4399: sun protective clothing: evaluation and
classification. Homebush, Australia: Australian/New Zealand Standards, 1996. http://www.saiglo
bal.com (accessed May 22, 2006).
12. Hatch KL, Osterwalder U. Garments as solar ultraviolet radiation screening materials. Dermatol Clin
2006; 24(1):85– 100.
13. Department of Health and Human Services, Food and Drug Administration. Additional criteria and
procedures for classifying over-the-counter drugs as generally recognized as safe and effective and
not misbranded. Federal Register 2002; 67:3060– 3076.
Photoprotection 277
14. Department of Health And Human Services, Food and Drug Administration. Over-the-counter drug
products; safety and efficacy review; additional sunscreen ingredients, [Docket No. 2005 N – 0446],
Federal Register 2005; 70(232):Notices 72449.
15. Tuchinda C, Lim HW, Osterwalder U, Rougier A. Novel emerging sunscreen technologies. Dermatol
Clinics 2006; 24:105– 117.
16. Stern RS, Weinstein MC, Baker RS. Risk reduction for nonmelanoma skin cancer with childhood
sunscreen use. Arch Dermatol 1986; 122:537– 545.
17. Godar DE, Wengraitis SP, Shreffler J, Sliney DH. UV doses of Americans. Photochem Photobiol 2001;
73:621– 629.
18. Godar DE, Urbach F, Gasparro FP, van der Leun JC. UV doses of young adults. Photochem Photobiol
2003; 77:452– 457.
19. Maier H, Schauberger G, Brunnhofer H, Hönigsmann H. Change of ultraviolet absorbance of sun-
screens by exposure to solar-stimulated radiation. J Invest Dermatol 2001; 117:256– 263.
20. Chatelain E, Gabard B. Photostabilization of butyl methoxydibenzoylmethane (Avobenzone) and
ethylhexyl methoxycinnamate by bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), a
new UV broadband filter. Photochem Photobiol 2001; 74:401– 406.
21. Lim, HW, Gilchrest BA, Cooper KD, et al. Sunlight, tanning booths, and vitamin D. J Am Acad
Dermatol 2005; 52:868 –876.
22. Wolpowitz D, Gilchrest BA. The vitamin D questions: how much do you need and how should you
get it? J Am Acad Dermatol 2006; 54:301– 317.
23. Georgouras KE, Stanford DG, Pailthorpe MT. Sun protective clothing in Australia and the Australian/
New Zealand standard: an overview. Australas J Dermatol 1997; 38(suppl 1):S79– S82.
24. American Society for Testing and Materials (ASTM International). Standard D 6603-00, Standard
guide for labeling of UV-protective textiles. In: Bailey SJ, Baldwin NC, McElrone EK, et al., eds.
ASTM standards. Vol. 7:03. 2004:1187– 1191. Available from: http://www.astm.org (accessed May
22, 2006).
25. British Standards Institute. BS EN 13758-1:2002. Textiles. Solar UV protective properties. Method of
test for apparel fabrics. Available from: http://www.bsonline.bsi-global.com (accessed May 22, 2006).
26. European Committee for Standardization. Standard EN 13758-2: textiles—solar UV-protective prop-
erties. Part 2: classification and marking of apparel. Available from: http://www.cenorm.be (accessed
May 22, 2006).
27. Crews PC, Kachman S, Beyer AG. Influences on UVR transmission of undyed woven fabrics. Textile
Chemist Colorist 1999; 31:17– 26.
28. Tuchinda C, Srivannaboon S, Lim HW. Photoprotection by window glass, automobile glass and sun-
glasses. J Am Acad Dermatol 2006; 54:845– 854.
29. National Glass Association. General information on glass. Available from: http://www.glass.org/
indres/info.htm (accessed May 21, 2006).
30. Hampton PJ, Farr PM, Diffey BL, Lloyd JJ. Implication for photosensitive patients of ultraviolet A
exposure in vehicles. Br J Dermatol 2004; 151:873– 876.
31. LaMotte J, Ridder W III, Yeung K, De Land P. Effect of aftermarket automobile window tinting films
on driver vision. Hum Factors 2000; 42:327– 336.
32. Fu JM, Dusza SW, Halpern AC. Sunless tanning. J Am Acad Dermatol 2004; 50:706 – 713.
33. Faurschou A, Janjua NR, Wulf HC. Sun protection effect of dihydroxyacetone. Arch Dermatol 2004;
140(7):886–887.
34. Wikipedia: Dihydroxyacetone. Available from: http://en.wikipedia.org/wiki/Dihydroxyacetone
(accessed May 3, 2006).
35. Fuchs J, Kern H. Modulation of UV-light-induced skin inflammation by D-alpha-tocopherol and
L-ascorbic acid: a clinical study using solar simulated radiation. Free Radic Biol Med 1998;
25:1006– 1012.
36. Werninghaus K, Meydani M, Bhawan J, Margolis R, Blumberg JB, Gilchrest BA. Evaluation of the
photoprotective effect of oral vitamin E supplementation. Arch Dermatol 1994; 130:1257– 1261.
37. Mathews-Roth MM. Carotenoid functions in photoprotection and cancer prevention. J Environ
Pathol Toxicol Oncol 1990; 10:181– 192.
38. Krol ES, Kramer-Stickland KA, Liebler DC. Photoprotective actions of topically applied vitamin
E. Drug Metab Rev 2000; 32:413 – 420.
39. Darr D, Dunston S, Faust H, Pinnell S. Effectiveness of antioxidants (vitamin C and E) with and
without sunscreens as topical photoprotectants. Acta Derm Venereol 1996; 76:264– 268.
40. Katiyar SK, Challa A, McCormick TS, Cooper KD, Mukhtar H. Prevention of UVB-induced immuno-
suppression in mice by the green tea polyphenol (-)-epigallocatechin-3-gallate may be associated with
alterations in IL-10 and IL-12 production. Carcinogenesis 1999; 20:2117 – 2124.
41. Katiyar SK, Elmets CA. Green tea polyphenolic antioxidants and skin photoprotection (Review). Int J
Oncol 2001; 18:1307– 1313.
42. Elmets CA, Singh D, Tubesing K, Matsui M, Katiyar S, Mukhtar H. Cutaneous photoprotection from
ultraviolet injury by green tea polyphenols. J Am Acad Dermatol 2001; 44:425 – 432.
43. Yarosh D, Klein J, O’Connor A, et al. Effect of topically applied T4 endonucleaseV in liposomes on
skin cancer in xeroderma pigmentosum: a randomised study. Lancet 2002; 357:926– 929.
44. Decome L, De Meo M, Geffard A, Doucet O, Dumenil G, Botta A. Evaluation of photolyase (Photo-
some) repair activity in human keratinocytes after a single dose of ultraviolet B irradiation using
the comet assay. J Photochem Photobiol B 2005; 79:101 –108.
45. Middelkamp-Hup MA, Pathak MA, Parrado C, et al. Oral Polypodium leucotomos extract decreases
ultraviolet-induced damage of human skin. J Am Acad Dermatol 2004; 51:910– 918.
19 Novel Developments in Photoprotection:
Part I
Uli Osterwalder
Ciba Specialty Chemicals, Basel, Switzerland
Henry W. Lim
B Clothing is the ideal sunscreen, except when it is not suitable (e.g., face,
hands, and at the beach).
B Sunscreen’s major function is historically the prevention of erythema;

there is now an international method to determine the sun protection
factor.
B Uniform protection over the whole UVB- and UVA-range is the ultimate
goal in photoprotection.
B Progress in topical and systemic products for radical scavenging and

DNA repair may become an important supplement to the
photoprotection strategy.
B Sunscreens become better and better in UVA protection. Various new

broad-spectrum and UVA protection actives are now available.
B Standards for UV protection raise the level of photoprotection.
B Various standards to assess UVA protection are already established in

certain countries or are under discussion; international harmonization
attempts are ongoing.
280 Osterwalder and Lim
MODALITIES OF PHOTOPROTECTION
Preventing UV Radiation from Reaching the Skin
unscreens were originally developed to protect the skin from sunburn, which is caused
S predominantly by UVB. The need for UVA protection began to be recognized about 15
to 20 years ago. In 1991, a UVA conference was held in San Antonio, Texas. Brian Diffey
then said:
We do not yet know the importance of UVA with regard to photoaging. . .and. . .skin cancer. . . . It
would seem prudent, therefore, to encourage the development of sunscreens which absorb more
or less uniformly throughout the UV spectrum.
Diffey (1)
While UVA has long been known to induce pigment darkening and tanning, the understanding
of the other biologic effects of UVA was just emerging in 1991; these effects are now well-recog-
nized. These include oxidative damage to the DNA and cell membrane, photoaging, photoim-
munosuppression, and phtotocarcinogenesis (see Chaps 5– 8). Ninety-five percent of the UV
radiation reaching the surface of the earth is UVA, which is a long wave UV that penetrates
well into the mid-dermis. There is relatively little fluctuation of UVA throughout the day
and in different seasons of the year (2). Therefore, it is now recognized that it is equally import-
ant to develop UV filters to protect against the deleterious effects of UVB, as well as those of
UVA (3).
UV Protection by Topical Sunscreens

Topically applied sunscreens are widely used and come in various forms, as creams, lotions,
sprays, sticks, gels, mousse, etc. Whereas their benefit in preventing sunburn, actinic keratoses
and squamous cell carcinomas is undisputed, their role in prevention of other forms of skin
cancer is still controversial (4,5). It has been suggested by some authors (6) that sunscreens
with higher sun protection factor (SPF) may encourage people to stay for a longer time in
the sun, and thus lead to an increased exposure of UVA radiation, which would cause more
harmful effects for the skin. It should be emphasized that sunscreens should not be
considered and used as the only means of photoprotection, but should be regarded as a part
of a sensible photoprotection strategy, which includes sun avoidance during the peak UVB
hours (10 AM to 4 PM ), wearing photoprotective clothings, wide-brimmed hat, and sunglasses.
In this chapter, some of the new developments in photoprotection will be reviewed.
UV Protection by Clothings
Using clothing to protect one’s skin from damaging ultraviolet radiation while out-of-doors is not
a new concept or practice. What is relatively new is the interest in (i) developing methods to quan-
tify sun protection performance of fabrics, (ii) understanding how to engineer sun protection
performance into fabrics, (iii) establishing procedures for labeling garments with sun
protection information, and (iv) providing understandable guidelines to individuals about how
to select garments (those labeled and not labeled for sun protection performance) for wearing
out-of-doors on summer days. Hatch and Osterwalder (7) have recently reviewed the subject.
The focus in this chapter is to compare and contrast the use of fabric and topical sunsc-
reens for sun protection effectiveness. Textiles may be regarded as the ideal sunscreen when
compared with topical products and their ability to prevent sunburn. Over the last decade,
the UV transmission of textiles has been quantified and standardized in Australia, Europe,
and the United States. UV protection afforded by textile is rated using ultraviolet protection
factor (UPF), which is an in vitro measurement that assesses the relative amount of UV that
penetrates a fabric. Although the UPF is heavily influenced by UVB, in contrast to the issue
of UVA transmission with sunscreens, all fabrics do attenuate radiation in the UVA and the
visible range (7,8).
However, the common belief that clothings protect the skin reliably from sunburn and
other sun-induced damages is not generally correct. Any textile transmits a certain amount
of UV radiation. Fabric UPFs values can certainly be as high as, or higher than, that of
Novel Developments in Photoprotection: Part I 281
TABLE 1 Comparison of Garments and Sunscreens as Photoprotective Measure

Comparison factor Sunscreens Garments
Cost US $1 per one full body application Use of “regular” garments does not have an
additional cost unless dedicated UV
absorber is purchased and applied
Labeled UV protective clothing is costly
Replacement frequency Need to be purchased regularly Garments keep their protective property over
years (depends on wear)
UV protection testing method Sunscreen SPF testing is complex and Fabrics are easier to test because UPF is an in
costly because it is an in vivo test vitro test
Long-lasting/photostability Reapplication every two hours Garments keep their protective property over
Some UV filters are photolabile the whole day
Area of protection Can easily be applied on regularly sun- Not practical to cover face and dorsum of
exposed areas (e.g., face, neck, hands with garments
dorsum of hands, etc.)
Even and sufficient application Require an even application to avoid All garment covered areas benefit from
having areas of inadequate photoprotection
protection
People tend to under-use sunscreens
so the protection stated on the
product may not be realized
Timing of application Should be applied 20 to 30 minutes Could be put on at the last minute
prior to sun-exposure
Some “instant” protection is available
now
Water proofness-staying Even “very water resistant” UPF values may decrease (or increase in
power on the skin sunscreens can be rubbed off or some cases) when the fabric is wet, but it is
washed off never washed off
Abbreviations: SPF, sun protection factor; UPF, ultraviolet protection factor.
topical sunscreens. For example, cotton T-shirts have UPF of five to nine, cotton, linen, and
rayon have UPF of ,15, whereas denim has UPF of 1700 (7). The major disadvantage of
using garments as sun-screening materials is probably that most garments do not come
labeled with an UPF value. In general, the amount of light transmitted through the fabric
when it is held to a visible light source would give a rough estimation of the UPF values; there-
fore, consumers can make reasonable judgments about relative sun protection performance of a
fabric. In the past few years, laundry additive that increased the UPF values by up to four-folds
have become available (9). Application of broad-spectrum sunscreens along with garment is
part of the proper photoprotection strategy. Each option has its advantages and disadvantages
as outlined in Table 1.
Radical Scavenging in the Skin

Even the best sunscreen or sunproof clothing still let pass some UV radiation. Since UVR
induces reactive oxygen species (ROS) in the skin, radical scavenging by antioxidants is part
of a good photoprotection strategy. Antioxidants can be administered systemically or topically.
Oral ingestion of vitamins E and C, carotenoids, and polyphenols, for example, from green tea,
is commonly done (10). A recent study evaluated the effects of topical application of 47 different
substances (drugs, plant extracts, plant ingredients, and polysaccharides) on UV radiation-
induced lipid peroxidation (11). Amantadine, bufexamac, tryptophan, melatonin, propranolol,
and hyaluronic acid were found to have antioxidative property, whereas pro-oxidative effects
were shown with ascorbic acid. Buckwheat extract, extracts of St. John’s Wort, melissa, and
sage significantly reduced the level of radiation-induced lipid peroxidation. The authors
concluded that the administration of antioxidants in cosmetic formulations or sunscreens
might be helpful for the protection of the human skin against UV-induced damage. In vivo
experiments with antioxidants should follow to allow in vitro– in vivo correlation and clinical
interpretation of the data.
Helping the Repair of DNA and Cell Damage

Besides topical UV protection and radical scavenging, there is a third part of photoprotection
strategy that becomes increasingly more important. DNA is constantly damaged and repaired
by repair enzymes. The small protein T4 endonuclease V recognizes the major form of DNA
damage produced by UVB, which is the cyclobutane pyrimidine (CPD) (12). In a randomized
clinical study of the effects of liposomal T4 endonuclease V in patients with xeroderma pigmen-
tosum, the rate of formation of actinic keratoses and basal cell carcinoma was reduced by 68%
and 30%, respectively, compared to the control group (13). In another example, people with a
polymorphism in the DNA repair gene 8-oxo-guanine glycosylase (OGG1) have an increased
risk of skin cancer. Yarosh et al. (14) found that the cells with this variant polymorphism
have an increased sensitivity of about 20% to a broad range of cytotoxic agents. The DNA def-
icits caused by immunosuppressive drugs or the OGG1 polymorphism can be overcome by the
delivery of DNA repair enzymes in liposomes. The data suggest that deficits in DNA repair,
even if they are not as severe as in the case of XP, may contribute to increased rates of
cancer, and that topical therapy with DNA repair enzymes may be a promising avenue for
after-sun protection.
IMPROVEMENTS IN TOPICAL SUNSCREENS—NEW DEVELOPMENTS

AROUND CONVENTIONAL UV ABSORBERS
Stabilization
Photolabile UVA filter, butyl methoxydibenzoylmethane (BMBM; avobenzone; Parsolw 1789)
can be stabilized by combining it with other UV filters, such as octocrylene, 4-methylbenzyli-
dene camphor (MBC), or bis-ethylhexyloxyphenol methoxyphenyl triazine (BEMT) (15),
or with an agent which is not a UV filter, diethylhexyl 2,6-naphthalate (DEHN, Corapan TQ)
(16). The presence of other UV filters reduce the number of photons absorbed by
avobenzone and facilitate the transfer of absorbed energy from avobenzone to the other
UV filters, hence minimizing the photodegradation of avobenzone. Energy transfer from avo-
benzone to DEHN is probably the mechanism responsible for the photostabilizing effect of
the latter.
Encapsulation
The efficacy and safety aspect of UV absorbers has also been addressed by reducing skin
penetration via encapsulation
TM
of UV absorbers within a silica shell of 1 mm in diameter [e.g.,
Eusolexw UV Pearls containing octinoxate (ethylhexyl methoxycinnamate)] (17). With this
technique, the organic filter is entrapped in the capsule, decreasing the probability of allergic,
photoallergic, or irritant contact dermatitis. Furthermore, it would prevent the incompatibility
among sunscreen ingredients. The drawback of this technology is that it is rather expensive,
and thus only a few sunscreen manufacturers have incorporated it so far.
Micronization
The microfine inorganic pigments TiO2 and ZnO have been improved considerably to allow the
easier incorporation into formulations and to become cosmetically better accepted, but some
limitations still remain (18). Micronization to primary particle sizes of ,20 nm results in less
scattering of visible light, hence minimizing the whitening effect. However, as the particle
size is decreased, the peak of the absorption spectrum shifts to the shorter wavelength, decreas-
ing the absorption in the UVA range. Microfine ZnO has a more uniform but weaker absorption
at the 290 to 380 nm than microfine TiO2.
Upon exposure of TiO2 and ZnO to UV, photocatalytic process takes place, resulting in the
generation of ROS. To minimize the photocatalysis, inorganic filters are frequently coated with
aluminum oxide. In order to optimize formulating properties, a coating of dimethicone or
silica may be added. A new development is the coating of TiO2 with ,1% of manganese
(19) (Optisolw, Oxonica Healthcare, Oxfordshire, U.K.). There are two effects of the
coating: The production of radicals resulting from the electron elevation to the conduction
band is suppressed, and the extinction spectrum is changed towards higher extinction in the
UVA-range, resulting in better absorption in the UVA range. First products containing Optisolw
are available since 2006.
Formulation Improvement—Boosting Agents

A method to boost the efficacy of current filter systems is the incorporation of nonabsorbing
particles that refract UV radiation, thus leading to a longer pathway that the UV would have
to travel through the sunscreen film before reaching the epidermis (20). One such product
is SunSpheresw (Rohm and Hass, Philadelphia, Pennsylvania, U.S.A.), a styrene/acrylates
copolymer, which is a non-UV absorbing material. Products containing SunSpheresw are
available in the U.S. market (Nivea Vital, Dove, Yves Saint Laurent, etc.). Film-forming
agents may lead to better spreading of the product on the skin, resulting in a final product
that is more efficient for a given amount of UV filter.
NEW SUNSCREEN ACTIVES FOR SUNSCREENS

Strategy for Photostable Broad-Spectrum
Sunscreen manufacturers have four basic requirements on sunscreen actives, which all must be
fulfilled by the existing and new ingredients before they can be incorporated in a final product.
B Efficacy
B Safety
B Registration
B Patent freedom
In this chapter, the focus will be to demonstrate how the efficacy of new sunscreen actives is
achieved. A more comprehensive view on this topic has been published (21).
Efficacy
Besides an efficient UV absorption, photostability and solubility as described earlier, there are
other important parameters regarding efficacy that need to be considered. The UV absorber
substance must be compatible with all other ingredients in a formulation; there should be no
discoloration of skin and hair, no staining of textiles, and no odor. For water resistant claim,
the UV absorber should be insoluble in water. And last but not least, the cost of UV filter,
hence the final product, should be affordable to the general consumers.
Safety
Sunscreen actives should have no adverse effect on humans and environment. Although direct
comparison with a new pharmaceutical drug is not appropriate, the development of a new
sunscreen active for global use is highly demanding. The toxicological studies required for a
global registration are listed in Table 2 (22).
Registration
In order to exploit the full economic potential of a UV filter, UV absorber manufacturers aim for
global registration. In the European Union, South America, Asia, and Africa, where sunscreens
are regulated as cosmetics, approval is possible within one to two years of filing. In Australia,
Japan and, the United States, where sunscreens are regulated as over-the-counter medications,
the approval process normally takes longer. In the U.S., until 2002, approval of all new UV
filters need to go through the New Drug Application (NDA) process, with clinical studies to
be done in the U.S. At the time of this writing, a UVA filter, terephthalidene dicamphor sulfonic
acid (TDSA; ecamsule; Mexorylw SX), is undergoing the United States Food and Drug
Administration (FDA) approval through this process.
In 2002, the U.S. FDA initiated an additional approval process, the Time and Extend
Application (TEA) (23). The TEA process indicates that after a minimum of five years of
foreign marketing experience in the same country, a new sunscreen active can be submitted
TABLE 2 Typical International Safety Dossier

of a New Sunscreen
Acute oral and dermal toxicity
Dermal, ocular irritation, and skin sensitization
Photo-irritation and photo-sensitization
Subchronic oral and topical toxicity
Chronic toxicity
Fertility, early embryonic development
Embryofetal toxicity and peri-/postnatal toxicity
In vitro and in vivo percutaneous absorption
Topical and oral pharmacokinetic and metabolism
In vitro and in vivo genetic toxicity
Carcinogenicity
Photo-carcinogenicity
Safety and efficacy in man
for application for registration with the FDA. If the FDA deems the UV filter is acceptable to be
considered for inclusion in the Sunscreen Monograph, efficacy and safety data then have to be
submitted. As of 2006, three UVB filters and two broad-spectrum UV filters that are widely
used outside the U.S. have received the status of “eligibility to enter the Sunscreen Monograph”
through the TEA process (24). These are listed subsequently:
UVB filters
B Isoamyl p-methoxycinnamate (IMC). US adopted name (USAN): amiloxate.

B 4-Methylbenzylidene camphor (MBC). USAN: enzacamene.
B Ethylhexyl triazone (EHT). USAN: octyl triazone.
Broad-spectrum UV filters
B Methylene-bis-benzotriazolyl tetramethylbutyl-phenol (MBBT; Tinosorbw M). USAN:

bisoctrizole.
B Bis-ethylhexyloxyphenol methyoxyphenyl triazene (BEMT) (Tinosorbw S). USAN:
bemotrizinol.
Patent Freedom
Patenting of sunscreen actives and their applications deserve special attention (21). Some UV
filters are patented for the exclusive use of certain sunscreen companies. As a consequence,
the UV filter manufacturers/suppliers have to make sure that as soon as the identity of a
new ingredient becomes known, “all” measures have to be taken, for example, publication
of combinations of that novel ingredient with other sunscreen actives and other important com-
pounds, such as emollients, emulsifiers, or thickeners. Patent freedom means the free use of
sunscreen actives by any sunscreen manufacturer, that is, any infringement of any third
party patent rights must be avoided.
Chemistry/Actives
Over the last 5 to 10 years, a number of photostable UV filters that cover UVA or both the UVB
and UVA range have been developed and approved in the European Union (25) (Fig. 1). In
2006, three of these new ingredients, Mexorylw SX, Tinosorbw M, and Tinosorbw S, are at
various stages of approval process by the U.S. FDA.
B Approved in 1993, TDSA (ecamsule; Mexorylw SX) was the first photostable UVA filter. It is
water-soluble, that is, will be in the water phase of an emulsion system and can thus act
synergistically together with filters in the oil-phase. The TDSA is also used together with
stabilized avobenzone and UVB filters to give equal coverage of UVB and UVA.
1200 ®
TDSA TDSA (Ecamsule; Mexoryl SX). 1993
DTS UVA, photostable, soluble in aqueous
MBBT
1000 BEMT phase (Exclusive to L’Oreal sunscreens)
DPDT
DHHB ®
DTS (Silatriazole; Mexoryl XL). 1998
800 Broad-spectrum, photostable, soluble in oil-
phase (Exclusive to L’Oreal sunscreens)
E(1,1)
®
600 MBBT (Bisoctrizole, Tinosorb M). 2000
Broad-spectrum, photostable, microfine
particles dispersed in aqueous phase
400
®
BEMT (Bemotrizinol, Tinosorb S). 2000
Broad-spectrum, photostable, soluble in oil-
200 phase
®
DPDT (no USAN, Neoheliopan AP). 2000
0
290 310 330 350 370 390 UVA, photostable, soluble in aqueous
phase
Wavelength in nm
®
DHHB (no USAN, Uvinul A plus) 2005
UVA, photostable, soluble in oil-phase
FIGURE 1 Possibilities of covering the UVA range with new UV filters available in Europe. Abbreviations: BEMT, bis-
ethylhexyloxyphenol methoxyphenyl triazine; DTS, drometrizole trisiloxane; DPDT, disodium phenyl dibenzimidazole
tetrasulfonate; DNHB, diethylamino hydroxybenzoyl hexylbenzoate; MBBT, methylene-bis-benzotriazolyl
tetramethylbutyl-phenol; TDSA, terephthalidene dicamphor sulfonic acid; USAN, United States Adopted Name.
B Approved in 1998, drometrizole trisiloxane (DTS; silatriazole; Mexorylw XL) was the first
photostable broad-spectrum filter. Siloxane groups were added to the benzotriazole chro-
mophore for better water resistance.
B Approved in 2000, MBBT (bisoctrizole; Tinosorbw M) is a photostable broad-spectrum UV
filter with strong absorption both in UVB and UVA. Its unique feature is that it comes as
microfine organic particles. Hence, it is not only absorbing UV radiation, but also scattering
and reflecting it. The microfine organic particles are dispersed in the water phase, leading to
a synergistic effect together with oil-soluble filters.
B Approved in 2000, disodium phenyl dibenzimidazole tetrasulfonate (DPDT; Neo
Heliopanw AP) is a new water-soluble UVA filter. Similarly to TDSA and MBBT, it
should show synergistic effects together with filters in the oil phase.
B Approved in 2000, BEMT (bemotrizinol; Tinosorbw S) is a photostable broad-spectrum filter
that is oil-soluble. Similar to other photostable UV filters that have strong absorbance in
UVA and UVB range, number and amount of other UV filters can be reduced in a given
product that contains bemotrizinol.
Approved in 2005, diethylamino hydroxylbenzoyl hexyl benzoate (DHHB; Uvinulw A Plus) is a

replacement of avobenzone as an oil-soluble UVA filter. Unlike avobenzone, DHHB is
photostable.
Designing Oil-Soluble Broad-Spectrum UV Filter

Chemistry for Photostability in Broad-Spectrum/UVA Protection
The UV absorbers are widely used to protect polymers (e.g., plastics, fibers, and coatings)
against photo-degradation. Numerous investigations have demonstrated that photostability
is of key importance to the filters in order to provide long-term protection of polymer
substrates (e.g., no degradation after several years of Florida outdoor testing). In general,
UV absorbers with an intramolecular hydrogen bond exhibit very efficient radiation-free
energy transformation processes, resulting in inherent photostability. For polymer appli-
cations, the following UV stabilizer technologies have been subsequently developed, and
listed in the order of year of introduction:
B Methyl salicylates (1960) ! o-hydroxybenzophenones (1965 – 1970) ! 2-(2-hydroxyaryl)-

benzotriazoles (1975 – 1990) ! 2-(2-hydroxyaryl)-1,3,5-triazines (since 1995).
FIGURE 2 The general structure of hydroxyphenyltriazines. A model for the conversion of absorbed UV-energy to
heat by extremely fast photo-tautomerism (about 10212 sec).
Presently, hydroxyphenyltriazines (HPTs; Fig. 2) represent the most advanced class of UV

absorbers for the photoprotection of all kind of polymer substrates (26 – 28). Owing to their mol-
ecular structure, HPTs exhibit a UV absorption spectrum with two distinctive peaks (29). This is
due to the presence of two electronic transitions with strong dipole moments, both of which are
polarized perpendicular to each other (shown in Fig. 3). In order to obtain broad-spectrum
absorbance, OH and OR substituents at the three phenyl groups have to be introduced and
positioned as follows (Fig. 3): Two ortho-OH groups are required for efficient energy dissipa-
tion via intramolecular hydrogen bridges. In order to obtain strong absorption in the UVA, the
para-positions of the two respective phenyl moieties should be substituted by OR, resulting in
a bis-resorcinyl triazine chromophor (R¼alkyl). The remaining phenyl group attached to the
triazine is leading to UVB absorption. It can be demonstrated that maximal “full spectrum”
performance is achieved with OR located in the para-position.
Without solubilizing substituents, HPTs are nearly insoluble in cosmetic oils. They exhibit
the typical properties of pigments (e.g., high melting points). In order to increase solubility in
oil phases, the structure of this UV filter has to be modified accordingly. The introduction of
two 2-ethyl-hexyl groups (Fig. 3) results in the formation of BEMT, a new oil-soluble UV
filter with true broad-spectrum performance.
In general, the photostability of a UV filter depends on how well the molecule is able to
release the absorbed energy to the environment in form of heat. BEMT contains two intramo-
lecular hydrogen bonds (O-H-N), which lead to an excited state intramolecular proton transfer
(photo-tautomerism) after photoexcitation (Fig. 2). This results in rapid radiationless
900
600
para position OCH3
E(1,1)
ortho position UVB

UVB
HO N N OH
300 N
O O
UVA
UV A
FIGURE 3 Molecular structure and UV-
0 absorption spectrum of bemotrizinol, measured
290 320 340 370 400 in EtOH, normalized extinction (1 cm, 1%)
E(1,1) max ¼ 820 (342 nm). Arrows indicate
Wavelength / nm the directions of the UVA and UVB transitions.
TABLE 3 New class of UV Filter Vs. Conventional Categories

Physical form
Chemistry Soluble Insoluble
Organic Traditional UV filters, for example Bisoctrizole (Tinosorb M)
octinoxate, oxybenzone, and
avobenzone
Inorganic NA Traditional microfine UV filters
Titanium dioxide, Zinc oxide
Abbreviation: NA, not available.
conversion that ensures that the UV radiation, efficiently absorbed by the filter, is almost quan-
titatively transformed into harmless vibrational energy (i.e., heat). The entire photo-tautomeric
cycle only lasts about 10212 seconds, leaving no time for undesirable side reactions (e.g., for-
mation of triplet states and generation of singlet oxygen or radicals). This mechanism, which
has been elucidated only recently (30), explains well why BEMT is photostable (.95% recovery
of parent BEMT is observed analytically after exposure to 50 minimal erythema dose (MED) of
solar simulated UV). Figure 2 illustrates the role of the intramolecular hydrogen bridge in the
quantitative conversion of UV radiation to vibrational energy (31).
A New Class of Sunscreen Actives—Microfine Organic Particles

A new class of UV absorber has been developed by Ciba Specialty Chemicals (Basel, Switzer-
land). For the first time, organic UV absorbers come as microfine particles, thus combining the
typical properties of organic filters (strong absorbance) with those of particulate UV filters
(scattering and reflection) (32). The organic molecules used have an inherent extraordinary
photostability. The result is a highly efficient sunscreen due to its triple action: UV absorption,
light scattering, and light reflection. The new class is combining the best features of both con-
ventional classes of UV filters. The properties of this new class of UV filter are compared with
those of conventional filters in Table 3.
MBBT (bisoctrizole; Tinosorbw M) is the first representative of this new class of UV absor-
ber (Figs. 4 and 5). It is an aqueous dispersion containing 50% of colorless organic microfine
particles with a size below 200 nm. The small particles are stabilized in their size by a
surfactant.
Safety of the New UV Absorbers

All new UV absorbers underwent the scrutiny of the European approval process, hence they can
all be considered safe. In case some safety concerns should occur, the European Commission asks
the Scientific Committee of Cosmetic Products (SCCP) to re-evaluate the safety data. Thus, it is
possible that a certain filter can be delisted. In the United States, the FDA first asks the TEA
500
400
300
E(1,1)
N OH OH N
N N
200 N N
100
0
290 320 340 370 400
FIGURE 4 Bisoctrizole, the first microfine organic
Wavelength / nm particle UV filter.
FIGURE 5 Particle size distri-

bution of bisoctrizole.
process for the five-year marketing experience abroad, that is, the clinical evidence that a UV filter
does not show any adverse effects. The next step is the submission of the safety package contain-
ing additional preclinical long-term dermal cancer and photo-cocarcinogenicity studies; safety
data are evaluated prior to approval (33,34).
The 500 Dalton Rule

In the development of UV absorbers over the last decades, besides the new developments, such
as encapsulation, polymers, and microfine pigments, there was also a general development of
the new sunscreen actives towards higher molecular weight filters. The “500 Dalton rule,”
known from the development of transdermal drugs, can be seen as a common denominator.
The 500 Dalton rule for the skin penetration of chemical compounds and drugs states that
when topical dermatological therapy or percutaneous systemic therapy is the objective, the
development of new innovative compounds should be restricted to molecular weights of
under 500 Dalton (35). Conversely, one may postulate a 500 Dalton rule for the development
of sunscreen actives, which says that the development of new innovative compounds should
be restricted to molecular weight of over 500 Dalton, when UV filtering on, rather than in,
the skin is the objective. As shown in Figure 6, the development over the past 50 years is
clearly heading in that direction. However, it should be noted that the 500 Dalton rule is
neither a necessity nor a sufficient condition for the safety of a new sunscreen active.
COLIPA #, UV Filter (USAN)

1000 S1 PABA
Molecular weight in (Da)
S13 Octisalate
S28 Octinoxate
750
S38 Oxybenzone
S60 Enzacamene
500 Dalton S69 Octyltriazone
500
S71 Ecamsule
S73 Drometrizole
250 S74 "Polysilicone-15"
S78 "Dibutamidotriazone"
S79 Bisoctrizole
0 S80 "Dibenzimidazole"
S1 S13 S28 S38 S60 S66 S69 S71 S73 S74 S78 S79 S80 S81 S83
S81 Bemotrizinol
COLIPA order number S83 "Aminobenzophenone"
“ “ no USAN name
FIGURE 6 The 500 Dalton rule. A trend towards molecular weight of more than 500 Daltons in the development of oil-
soluble UV filters in the last 50 years. Abbreviations: COLIPA, European Cosmetic, Toiletry, and Perfumery Association;
USAN, United States Adopted Name.
EMERGING SUNSCREEN ASSESSMENT METHODS AND STANDARDS

Sunscreen assessment methods and standards assure transparency among products, and thus
also lead to better photoprotection. Over the last decades the average SPF of sunscreens has
steadily increased. While there have been significant awareness and concerns on the import-
ance of UVA protection by sunscreens, there has not been a worldwide consensus on the
methods of assessment of UVA protection. The United Kingdom is a good example that the
introduction of a UVA standard (the Boots Star Rating in 1992 as a measure of the UVA/
UVB ratio) leads to significantly better UVA protection (36).
Understanding Sun Protection Factor

Historically, the sole purpose of sunscreens was to prevent sunburn. The SPF is the ratio
between the minimal dose that produces perceptible erythema on the skin (i.e., MED) in the
presence or absence of 2 mg/cm2 of sunscreen, using solar-simulated radiation as a light
source (37). However, the actual protection provided by a sunscreen is a dynamic process;
therefore, it is also important to choose a representation of the sunscreen beyond the static
view commonly seen.
The exposure time is the most important influence factor for any effect of UV radiation.
This is best illustrated in Figure 7, inspired by the Australian Standard document (38). For indi-
viduals with skin phototype 1 to 2, one MED is reached within about 10 minutes without sun-
screen (i.e., SPF 1). With SPF 15 and SPF 30 sunscreens, the time to reach one MED is prolonged
accordingly to 150 and 300 min. However, in a proper photoprotection strategy, sunscreen is
not used to reach one MED. In contrast, sunscreen should be used to stay well below one
MED. The example in Figure 7 shows that a two-hour exposure of a person with skin photo-
type 1 leads to 80%, 40%, or 20% of a MED if a sunscreen of SPF 15, 30, or 60 (labeled 50þ)
is applied, respectively. It should be noted that the example shown in Figure 7 is based on
the assumption that the UV filters are photostable, and the sunscreens are applied at a concen-
tration of 2 mg/cm2 (the worldwide standard used in SPF testing). Many of the currently used
UV filters do degrade following UV exposure (39). In actual use, consumers apply on average
0.5 mg/cm2 of sunscreens (40). Some exposed sites are frequently missed, and with regular or
outdoor activities, sunscreens are rubbed off, or washed off with water and sweat exposure.
Furthermore, sunscreens with the same SPF frequently have different UVA protection factor;
therefore, a high SPF sunscreen may not necessarily provide good UVA protection (3). It is
for these reasons that sunscreens should be used as one of the measures to minimize the
acute and chronic effects of UV exposure in daily and recreational outdoor activities; they
should not be advocated to encourage unnecessary sun exposure.
FIGURE 7 Dynamics of the UV dose

reaching the skin through sunscreens
over time. The example shows the minimal
erythema dose received by skin phototype
1 or 2 with the assumption that the sun-
screen is photostable, and sunscreens are
applied at a concentration of 2 mg/cm2.
Abbreviations: MED, minimal erythema
dose; SPF, sun protection factor.
TABLE 4 Selected Methods for the Assessment of UVA Protection by Sunscreens that
are Currently in Discussion
Type of method Reference
In vivo UVA-PF via erythema (44)
PPD (Japanese Standard) (45,46)
Others
In vitro Australian Standard (47)
Critical wavelength (49)
UVA/UVB ratio, Boots star rating (49,50)
UVA-balance (51,52)
Harmonized in vitro UVA method (53)
(PPD, COLIPA)
Others
In silico Computer simulation based on spectral data (54– 57)
of UV filters and sunscreen film model
UVA Standards for Sunscreens

UVA and broad-spectrum claims are very common in modern sun protection products. The
introduction of the SPF began in the 1950s (41). It took several decades to gain global acceptance
and public understanding of this concept. A consensus on the method for UVA assessment
would also be highly desirable since this would provide the same criterion for all companies
and eventually result in better product quality and increased understanding by consumers
and the general public. To date, health authorities and regulatory agencies worldwide still
have not yet come to an agreement on a generally acceptable UVA assessment method (2).
There are several in vivo and in vitro methods available, and there is also the possibility to
assess the performance of a sunscreen by computer simulation, that is, in silico (Table 4).
In Vivo Determination of UVA Protection

A first attempt to determine the “right” degree of UVA protection came from the United States
by Urbach around 1990 (42,43). The SPF was seen as the only measure for UV damage. Accord-
ing to that reasoning, a UVA-protection factor (UVA-PF) of 20% of the SPF is always sufficient to
avoid any erythema from UVA radiation. The ratio of damage (erythema) from the UVB and
UVA components in sunlight over a day is 80% from UVB and 20% from UVA. Of the 20%
due to UVA (320 – 400 nm), 62% of the damage risk has been ascribed to the shorter UVA2
wavelengths (320 – 340 nm). The UVA-PF is determined similarly to the SPF by causing
erythema, but by applying UVA radiation instead of solar-simulated UVR, first described by
Cole (44).
The sunscreen manufacturer, L’Oreal, developed another in vivo method to assess UVA
protection (45). The persistent pigment darkening (PPD) method is based on the ability of
sunscreen to protect against the development of PPD, which is the result of a chemical reaction
of melanin following within hours of exposure to UVA radiation. The PPD method, with its
classification of PAþ, PA þ þ, PAþþþ, became the Japanese Standard in 1995 (46), and is
widely used in many countries in Asia. In France, there is an initiative to combine SPF and
UVA-PF (assessed by pigment darkening method) to a broad-spectrum pass/fail criterion
SPF/UVA-PF , 3.
In Vitro Determination of UVA Protection

In 1993, the Australian/New Zealand Standard was established (47). This standard sets an
absolute transmittance limit of 10% in the UV range of 320 to 360 nm for any product to
make “broad spectrum” claim. “Broad spectrum” product must have a SPF of not less
than four. An analysis of the data of about 50 sunscreen samples revealed that fulfilling the
Australian Standard corresponds to the a UVA-PF (PPD) of 4+1 (48).
Diffey was the first to describe two relative in vitro methods based on simple transmit-
tance measurement on a UV/VIS transparent substrate. The two methods are referred to as
the UVA/UVB ratio and the critical wavelength (49).
The sunscreen manufacturer and retailer Boots in the United Kingdom developed and
enforced the Boots Star Rating System based on Diffey’s ratio of the mean absorbance in the
UVA over the mean absorbance in the UVB (49). In 2005, the original four-star rating
system was revised to include a fifth-star, defined by a UVA/UVB ratio .0.91 (50). Today,
this rating comes closest to uniform UV protection, but does not take into account
photostability.
Only recently the UVA-balance has been developed (51). In 2005, it became an official
German industry standard DIN 67502 (52). In this method, an in vitro UVA-PF, analogous to
PPD, is determined from spectral transmittance data. The in vitro SPF is calculated, and the
whole spectral curve is adjusted to the in vivo SPF by a correction factor. This new curve is
then used to calculate the in vitro UVA-PF value. This method takes into account the photo-
stability of the UV filters at least partially by considering the SPF.
All other in vitro methods have a common limitation in not taking into account the photo-
stability of UVA absorbers. With photolabile UV filters (e.g., unstabilized avobenzone), these
methods can lead to an overestimation of the UVA protection capability.
A comparison of the in vitro methods discussed earlier regarding their ability to discrimi-
nate sunscreens providing different degrees of UVA protection revealed the following ranking
of the methods (48).
1. UVA-balance (UVA/UVB ratio that partially takes into account photostability).

2. UVA/UVB ratio (UVA protection proportional to UVB protection, different levels/star
rating).
3. Australian UVA Standard (absolute limit leads to relatively low UVA protection at high
SPF).
4. Critical wavelength (370 nm limit provides only relatively low UVA protection).
The latest attempt to address this issue is discussed in a task force of the European Cosmetic,
Toiletry, and Perfumery Association (COLIPA) (53). It is anticipated that in 2006, an improved
UVA-balance with an irradiation step prior to the transmittance measurement should become
the official recommendation. The UVA-PF value determined by the UVA balance (52) is used
to determine a preirradiation dose. The actual UVA-PF is then determined from the spectral
data of the preirradiated sample using the same (SPF) correction factor as before.
Australia and Japan have established their own official standards, whereas the Euro-
pean Union and the United States have not. There is a good probability that we will see a
consolidation of all this efforts and worldwide harmonization in the near future. In 2006,
the European Union issued a recommendation “on the efficacy of sunscreen products and
the claims made relating thereto,” stating that the UVA-PF should be at least 1/3 of the
SPF (54).
In Silico Determination of UVA Protection

Only recently yet another approach to determine the performance of a sunscreen, referred to
as in silico (Table 4), has become precise enough to be considered seriously. The SPF as well
as any UVA parameter can be calculated from the extinction spectrum of the UV filters in
the sunscreen and an assumption about the nonhomogenous sunscreen film that is
formed on the skin (55,56). The in vitro SPF is determined by calculating the transmittance
spectrum of the sunscreen and taking into account the nonuniform sunscreen film together
with the known solar spectrum. The latest more sophisticated version also takes into
account the photoinstability of certain UV filter combinations (e.g., avobenzone with octi-
noxate) as well as the distribution of the UV filters between oil and water phase that
may lead to a synergistic effect (57,58). Figure 8 shows the progress in UVA protection on
sample calculations of four SPF 30 sunscreens: (i) a “UVB sunscreen,” (ii) a sunscreen ful-
filling Australian Standard, (iii) a sunscreen fulfilling the German UVA-balance (33%
threshold), and (iv) a sunscreen that achieves five-star rating in the United Kingdom.
Note that all four sunscreens provide exactly the same protection against erythema, since
they are all SPF 30.
FIGURE 8 Progress in UVA protection. Sample calculations of four SPF 30 sunscreens with different degrees of UVA
protection: (A) a “UVB sunscreen,” (B) a sunscreen fulfilling Australian Standard, (C) a sunscreen fulfilling the German
UVA-balance (33% threshold), and (D) a sunscreen that achieves 5-star rating. Abbreviations: PPD, persistent pigment
darkening; SPF, sun protection factor.
Sample Calculation
In silico results A B C D
SPF 31 31 31 31
UVA-PF (PPD) 6 7 14 26
UVA PF/SPF 0.19 0.23 0.45 (,1/3) 0.84 (.1/3)
AUS STD FAIL PASS PASS PASS
Critical wavelength (nm) 369 373 379 381
UVA/UVB ratio 0.45 0.46 0.66 0.90
UVA balance (DIN 67502) 11 14 34 99
CONCLUSION
In addition to sun avoidance and sunproof clothing, topical sunscreens remain an important
part of any photoprotection strategy. Topical and systemic products that act as antioxidants
or help the repair of the skin become valuable supplements in photoprotection. Stimulated
by the new requirements towards better UV protection, seven new UV absorbers have been
developed and approved in Europe over the last few years. These new filters give the formu-
lators new possibilities to cover the whole UV range from 290 to 400 nm, and also to use less
filter due to the boosting effect of the new UVA and broad-spectrum filters. However, only
three of them, ecamsule, bisoctrizole, and bemotrizinol are currently under review by the
FDA for approval in the U.S. The full potential of the new sunscreen actives can only be
exploited when proper standards for the assessment of UVA protection are being established.
After the introduction of such standards in Australia, Japan, United Kingdom, and Germany,
UVA protection increased significantly in these countries. European harmonization is under
way; eventually, the assessment of UVA protection should be harmonized globally.
REFERENCES
1. Diffey BL. The need for sunscreens with broad spectrum protection. In: Urbach F. ed. Biological
Responses to Ultraviolet A Radiation. A Symposium on UVA Radiation. San Antonio, TX, June
1991. Overland Park, KS: Valdenmar Publication Co., 1992:321– 328.
2. Lim HW, Naylor M, Hönigsmann H, et al. American Academy of Dermatology Consensus Confer-
ence on UVA protection of sunscreens: summary and recommendations. J Am Acad Dermatol
2001; 44:505– 508.
humans: a consensus paper. J Invest Dermatol 2005; 125:403– 409.
4. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J
Med 1993; 329:1147 – 1151.
5. Green A, Williams G, Neale R, et al. Daily sunscreen application and beta-carotene supplementation
in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial.
Lancet 1999; 354:723– 729.
6. Autier P, Doré JF, Négrier S, et al. Sunscreen use and duration of sun exposure: a double-blind,
randomized trial, J Natl Cancer Inst 1999; 91:1304.
7. Hatch KL, Osterwalder U. Garments as ultraviolet radiation screening materials. Dermatol Clin 2006;
24:85– 100.
8. Hoffmann K, Laperre J, Avermaete A, Altmeyer P, Gambichler T. Defined UV protection by apparel
textiles. Arch Dermatol 2001; 137:1089– 1094.
9. Wang SQ, Kopf AW, Marx J, Bogdan A, Polsky D, Bart RS. Reduction of ultraviolet transmission
through cotton T-shirt fabrics with low ultraviolet protection by various laundering methods and
dyeing: clinical implications. J Am Acad Dermatol 2001; 44:767– 774.
10. Stahl W, Mukhtar H, Afaq F, Sies H. Vitamins and polyphenols in systemic photoprotection. In: Gilchrest
BA, Krutmann J, eds. Skin Aging. Berlin, Heidelberg, Germany: Springer-Verlag, 2006:113–120.
11. Trommer H, Neubert RH. Screening for new antioxidative compounds for topical administration
using skin lipid model systems. J Pharm Pharm Sci 2005; 15;8(3):494 – 506.
12. Krutmann J, Yarosh Daniel. Modern photoprotection of human skin. In: Gilchrest BA, Krutmann J,
eds. Skin Aging. Berlin, Heidelberg, Germany: Springer-Verlag, 2006:103– 112.
13. Yaros D, Klien J, O’Connor A, Hawk J, Rafal E, Wolf P. Effect of topically applied T4 endonuclease
V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Lancet 2001;
357:926– 929.
14. Yarosh DB, Canning MT, Teicher D, Brown DA. After sun reversal of DNA damage: enhancing skin
repair. Mutat Res 2005; 571(1 – 2):57– 64. Epub 2005 Jan 26.
15. Chatelain E, Gabard B. Photostabilization of butyl methoxydibenzoylmethane (avobenzone) and
ethylhexyl methoxycinnamate by bis-ethylhexyloxyphenol methoxyphenyl triazine (Tinosorb S), a
new UV broadband filter. J Photochem Photobiol 2001; 74:401– 406.
16. Bonda C, Steinberg DC. A new photostabilizer for full spectrum sunscreens. Cosmet Toiletries 2000;
115(6): 37 – 45.
17. Patent MERCK AG WO 00/09652, 2000, Silica-Mikrocapsules filled with functional molecules.
18. Schlossmann D, Shao Y. Inorganic ultraviolet filters. In: Shaath N, ed. Sunscreens: Regulations and
Commercial Development. Cosmetic Science and Technology Series. 3rd edn. Vol. 28. Chap. 14.
Boca Raton, FL: Taylor & Francis Group, 2005.
19. Wakefield G, Lipscomb S, Holland E, Knowland J. The effects of manganese doping on UVA absorp-
tion and free radical generation of micronised titanium dioxide and its consequences for the
photostability of UVA absorbing organic sunscreen components. Photochem Photobiol Sci 2004;
3(7):648– 652. Epub 2004 May 21.
20. Mufti J, Cernasov D, Macchio R. New Technologies in Topical Delivery Systems, HAPPI, March 2002
21. Herzog B, D Hueglin, Osterwalder U. New sunscreen actives. Chapter 16 In: Shaath N, ed. Sunsc-
reens: Regulations and Commercial Development. Cosmetic Science and Technology Series. 3rd
edn. Vol. 28. Chap. 16. Boca Raton, FL: Taylor & Francis Group, 2005.
22. Nohynek G, Schaefer H. Benefit and risk of organic ultraviolet filters. Regul Toxicol Pharm 2001;
33:1– 15.
23. Food and Drug Administration, Additional Criteria and Procedures for, Classifying Over-the-
Counter Drugs as, Generally Recognized as Safe and, Effective and Not Misbranded, 21 CFR Part
330, [Docket No. 96 N – 0277], RIN 0910– AA01, Federal Register/Vol. 67, No. 15/Wednesday,
January 23, 2002/Rules and Regulations, 3060-3076.
24. Food and Drug Administration Over-the-Counter Drug Products; Safety and Efficacy Review;
Additional Sunscreen Ingredients, [Docket No. 2005 N – 0446], Federal Register/Vol. 70, No. 232/
Monday, December 5, 2005/Notices 72449.
25. Tuchinda C, Lim HW, Osterwalder U, Rougier A. Novel emerging sunscreen technologies. Dermatol
Clinics 2006; 24:105– 117.
26. Rabek JF. Photostabilization of Polymers, Principles and Applications. London: Elsevier Applied
Science Publishers, 1990.
27. Gugumus F. In: Gächter R, Müller H, eds. Kunststoff-Additive. Munich, Germany: C. Hanser Verlag,
1989.
28. Waiblinger F, Fluegge AP, Keck J, Stein M, Kramer HEA, Leppard D. Irradiation-dependent equili-
brium between open and closed form of UV absorbers of the 2-(2-Hydroxyphenyl)-1,3,5-triazine
type. Res Chem Intermed 2001; 27:5 – 20.
29. Hueglin D, Herzog B, Mongiat S. Hydroxyphenyltriazines: a new generation of cosmetic UV filters
with superior photoprotection. Oral presentation at 22nd IFSCC, Edinburgh, 23– 26 September 2002.
30. Keck J, Roessler M, Schroeder C, et al. Ultraviolet absorbers of the 2-(2-hydroxyaryl)-1,3,5-triazine
class and their methoxy derivatives: fluorescence spectroscopy and X-ray structure analysis. J Phys
Chem B 1998; 102(36):6975– 6985.
31. Otterstedt J-EA. Photostability and molecular structure. J Chem Phys 1973; 58(12):5716– 5725.
32. Osterwalder U, Luther H, Herzog B. UV-A Protection with a new class of UV Absorber, 47. SEPAWA
Kongress, Proceedings 2000; 153 – 164.
33. Learn DB, Sambuco CP, Forbes PD, Hoberman AM, Plautz JR, Osterwalder U. Twelve-month topical
study to determine the influence of bisoctrizole (Tinosorbw M-active) on photocarcinogenesis in hair-
less mice. Biannual meeting, European Society of Photobiology, 3 – 8 September 2005.
34. Learn DB, Sambuco CP, Forbes PD, Hoberman AM, Plautz JR, Osterwalder U. Twelve-month topical
study to determine the influence of bemotrizinol (Tinosorbw S) on photocarcinogenesis in hairless
mice. Biannual meeting, European Society of Photobiology, 3 – 8 September 2005.
35. Bos JD, Meinardi MM: The 500 Dalton rule for the skin penetration of chemical compounds and
drugs. Exp Dermatol 2000; 9(3):165– 169.
36. Brown MW. UVA Protection, Sunscreen Conference. London: 2001, 11 – 12 June.
37. United States Food and Drug Administration, HHS. Sunscreen drug products for over-the-counter
human use; final monograph. Final rule. Fed Regist 1999; 64(98):27, 666-27, 693.
38. Australian/New Zealand StandardTM , Sunscreen products—Evaluation and classification, Origi-
nated in Australia as AS 2604—1983, Previous edition AS/NZS 2604:1997, Fifth edition 1998.
39. Maier H, Schauberger G, Brunnhofer K, Honigsmann H. Change of ultraviolet absorbance of
sunscreens by exposure to solar-simulated radiation. J Invest Dermatol 2001; 117:256– 262.
40. Kullavanijaya P, Lim HW. Photoprotection. J Am Acad Dermatol 2005; 52:937– 958.
41. Schulze R. Einige Versuche und Bemerkungen zum Problem der handelsüblichen Lichtschutzmittel,
Parfum und Kosmet 1956; 37:310.
42. Urbach F. Ultraviolet A transmission by modern sunscreens: is there a real risk? Photodermatol
Photoimmunol Photomed 1992 – 1993; 9(6):237– 241.
43. Agin PP, Cole CA, Corbet C, et al. Balancing UV-A and UV-B protection in sunscreen products: pro-
portionality, quantitative measurement of efficacy, and clear communication to consumers. In: Shaath
N, ed. Sunscreens: Regulations and Commercial Development. Cosmetic Science and Technology
Series. 3rd edn. Vol. 28. Chap. 40. Boca Raton, FL: Taylor & Francis Group, 2005.
44. Cole C. Multicenter evaluation of sunscreen UVA protectiveness with the protection Factor A test
method. J Am Acad Dermatol 1994; 30:729– 736.
45. Chardon A, Moyal D, Horseau C. Persistent pigment-darkening response as a method for evaluation
of ultraviolet A protection assays. In: Lowe NJ, Shaath, NA, Pathak MA, eds. Sunscreens: Devolop-
ment, Evaluation, and Regulatory Aspects. 2nd ed. New York: Marcel Dekker Inc., 1997:559– 582.
46. JCIA Measurement Standard for UVA Protection Efficacy. Japan Cosmetic Industry Association—
JCIA, 9-14, Toranomon 2-Chome, Minato-Ku Tokyo, 1995:105.
47. Australian/New Zealand Standard, AS/NZS 2604: 1993.
48. Osterwalder U, Baschong W, Herzog B. Broad Spectrum UV protection and its assessment. Australian
Society of Cosmetic Chemists, 39th Annual Conference, Brisbane, Queensland, 17 – 20 March 2005.
49. Diffey BL. A method for broad spectrum classification of sunscreens. Int J Cosm Sci 1994; 16:47– 52.
50. The Revised Guidelines to the Practical Measurement of UVA : UVB Ratios According to The Boots
Star Rating System, The Boots CO PLC, 2004.
51. Gers-Barlag H, Wendel V, Klette E, Wolber R, Wittern KP. UVA Balance The Accurate and Skin
Relevant Assessment of the UVA Protection of Sunscreens, 7th Joint ASCC NZCSS Australasian
Conference Auckland, New Zealand, 2004.
52. Characterization of UVA protection of dermal suncare products by measuring the transmittance
with regard to the sun protection factor, DIN 67502, Deutsches Institut für Normung e.V., Berlin,
February 2005.
53. Gers-Barlag H. Harmonized in vitro UVA Method, Sunscreen Conference “2010—A Sun Odysee,”
London, 8/9 June 2005.
54. Commission Recommendation on Efficacy of Sunscreen Products and the Claims Made Relating
Thereto. Official J Eur Union 2006; 49:39– 43.
55. Herzog B, Mendrok C, Mongiat S, Mueller S, Osterwalder U. The Sunscreen simulator: a formulator’s
tool to predict SPF and UVA parameters. SÖFW J 2003; 129(7):25– 36.
56. Ferrero L, Pissavini M, Marguerie S, Zastrow L. Efficiency of a continuous height distribution model
of sunscreen film geometry to predict a realistic sun protection factor. J Cosmet Sci 2003; 54:463– 481.
57. Herzog B, Müller S, Neuenschwander A, Deshayes C, Acker S, Osterwalder U. Improved Simulation
of Sun Protection Factors and UVA-Parameters—A Useful Tool for the Development of Sunscreen
Formulations, accepted as oral presentation at 24th IFSCC Congress, Osaka, Japan, 16 – 19
October 2006.
58. Ciba Specialty Chemicals, Cibaw Sunscreen Simulator, www.cibasc.com/sunscreensimulator.
20 Novel Developments in Photoprotection: Part II
André Rougier and Sophie Seite
La Roche-Posay Pharmaceutical Laboratories, Asnières, France
Henry W. Lim
B SPF is a reflection of UVB protection.
B No consensus has been reached on the standardized way to assess

UVA protection factor (UVA-PF).
298 Rougier et al.
INTRODUCTION
n vitro and in vivo studies provide a body of evidence that adequate protection of the skin
I against ultraviolet (UV)-induced damages requires photostable broad-spectrum sunscreens

with a proper level of UVA protection. The need is not restricted to products for sunbathers
for whom the main concern is acute effects of UVB. The increased use of UVA sources over the
last decade in the treatment of dermatoses and in artificial tanning has resulted in the increased
focus on the cutaneous damage likely to be caused by UVA radiation.
Solar radiation reaching the surface of the earth, and thereby the surface of our skin, con-
tains infrared, visible, and UV radiation (UVR). Of major interest to dermatologists is the UVR
segment of the radiation, as it is almost exclusively the cause of skin disorders arising from sun
exposure. The UVR component of sunlight reaching the surface of the earth is composed of
radiation with wavelengths of 280 to 400 nm and accounts for 10% of the total energy
emitted by the sun.
There are three types of UVR, based on their wavelength: (i) UVA (320 – 400 nm), (ii) UVB
(290 – 320 nm), and (iii) UVC (200 – 290 nm). Shorter wavelengths of radiation are more ener-
getic and potentially more destructive than longer wavelengths. Fortunately, UVC, the shortest
wavelength in the UV spectrum, is completely absorbed by the gases in the atmosphere. There-
fore, UVR reaching the skin consists only of UVB and UVA (Fig. 1).
UVB is the next shortest wavelength. It reaches the earth in relatively small amounts
(about 5%), but is very efficient in producing biological response. UVA is lower in energy
than UVB; nevertheless, UVA is 20 times more abundant than UVB. UVA can be further
subdivided into UVA1 (400 – 340 nm) and UVA2 (340 – 320 nm) (Fig. 2).
The extent of an individual’s exposure to UVR varies widely depending on a
multiplicity of factors, such as weather, hour of the day, season, pollution, humidity, tempera-
ture, and also geographic factors, such as altitude and latitude. These can be summarized as
follows.
1. In temperate climate, the quantity of UV reaching the skin first depends on seasons: UVB
exposure is much greater in summer than in winter.
2. There is greater exposure for both UVA and UVB with decreasing latitude.
3. The quantity of UVR increases by 4% every 1000 feet above sea level. Indeed, as the atmos-
pheric layer traveled by the UVR is thinner, the filtration effect is reduced.
4. The time of the day also plays an important part: UVB is strongest between 10 AM and 4 PM ,
especially around mid-day, whereas UVA follows the variation of visible light.
5. Finally, several environmental factors contribute to influence UV exposure. UV can be
modified according to the nature of terrain, which induces different reflection of the
FIGURE 1 Penetration of ultraviolet into the skin.

Novel Developments in Photoprotection: Part II 299
FIGURE 2 Electromagnetic radiation at the surface of the earth.
radiation. UVB is almost entirely filtered by clouds, whereas UVA is not. Glass filters UVB
and UVA2, but not the longer wavelength UVA1 (1).
UVB are far more sensitive to the above factors than UVA. Consequently, there is more
consistent exposure of the skin to UVA throughout the day when compared with UVB (2,3).
As wavelength increases, there is a corresponding percentage increase in the depth of pen-
etration of UVR (Fig. 1). UVB penetrates the epidermis and is almost fully absorbed in
upper dermis, whereas one-quarter of the UVA reaches as far as the mid-dermis.
UVA EFFECTS
The visible damaging effects of UVA only appear after years of exposure. Thus, it has been
demonstrated that UVA plays a major role in premature aging of the skin. In addition, it is
now well established that UVA has a significant role in DNA damage, photoimmunosuppres-
sion, and induction of various photodermatoses. UVA is by far the most common action spec-
trum for drug-induced photosensitivity. In the past few years, significant advances on UVA
protection has been achieved due to the development of potent UVA filters and the use of
novel combination of filters (4).
EVALUATION OF SUN-PROTECTION FACTORS AND

UVA-PROTECTION FACTOR
The classical approach to assess the protective efficacy of a sunscreen product is the worldwide
harmonized method of the determination of sun protection factor (SPF), which is based on
the evaluation of solar-simulated radiation (SSR)-induced erythema, that is, predominantly
UVB-induced sunburn reaction. SPF is the ratio of UVR dose producing minimal erythema
dose in sunscreen-protected versus unprotected skin area, using the product at a concentration
of 2 mg/cm2 (5). It is a reflection of predominantly the biological effect of UVB; SPF is not an
assessment of UVA protection. Despite the availability of several reliable methods, no consen-
sus has been reached in the United States and in the European Union on the method(s) to be
used for assessment of UVA protection (6). At present, persistent pigment darkening (PPD)
method, which evaluates the stable portion of pigment darkening of the skin following UVA
irradiation, is probably the most widely used one (6,7). This method has been approved by
the Japanese authorities as the official method to measure UVA protection (8).
In 2001, an in vitro UVA protection assessment method was published, which was
proposed as a candidate for the future harmonized UVA protection measurement (9). The
method combines the merits of in vitro as well as in vivo determinations by combining the
results of in vivo SPF with in vitro UV (290 –400 nm) transmission measurement.
300 Rougier et al.
SUNSCREEN FILTERS PHOTOSTABILITY

Photostability is the ability to resist the influence of UVR, visible light, and heat. Development
of photostable sunscreens is extremely important to preserve the UV-protective capacity and to
prevent the reactive intermediates of photo-unstable filter substances behaving as photo-
oxidants, when coming into direct contact with the skin.
The filter that was in a lower state (ground state) turns to higher energy state (excited
state) by absorbing the energy of an UV photon. From excited state, different relaxation
processes may occur.
1. The excited state molecule may simply return to its ground state while releasing the
absorbed energy to the environment as heat. Then the filter fully recovers its ability to
absorb UVR photon again and again. This filter is considered as photostable.
2. Structural transformation or degradation may take place whereby the filter loses, more or
less rapidly, its UV-absorbing capacity, and hence its protective potency. The filter is
considered to be photo-unstable.
3. The excited molecule can interact with other molecules in its micro-environment, such as
other ingredients contained in sunscreen product, ambient oxygen, or skin biomolecules
(proteins, lipids, etc.), and thus lead to the production of undesirable reactive species.
The filter is considered to be photoreactive.
Indeed, photostability is an essential requirement to protect against UVA-induced effects,

such as photoaging and genotoxicity (10,11); a photo-unstable formulation is not as protective
as the photostable one in the prevention of molecular events associated with photoaging and
genotoxicity (12 –14).
BROAD-SPECTRUM SUNSCREENS
The novel filters (4,15) of the broad-spectrum sunscreens used in the different studies presented
in this chapter are the following.
UVA Filters
Terephtalylidene Dicamphor Sulfonic Acid (ecamsule, Mexoryl Ò SX)
It is a strong short UVA photostable absorber, which absorbs UVR between 290 and 390 nm
with a peak at 345 nm (Fig. 3). Mexorylw SX was patented by L’Oréal in 1982 and approved
by the European Economic Community (EEC) in 1991.
Drometriazole Trisiloxane (silatriazole, Mexoryl Ò XL)

This was first introduced in the European Academy of Dermatology and Venereology meeting
in 1998. It is the first broad UV filter against UVA and UVB spectrum (Fig. 4). Mexorylw XL
1000
O
NaO3S
800 SO3Na
O
600
E(1,1)
400
200
0
290 310 330 350 370 390
Wavelength/nm
FIGURE 3 The structure and absorption spectrum of Mexorylw SX.

500
Si
400 N OH O
N Si
N
O
300
E(1,1)
Si
200
100
0
290 310 330 350 370 390
Wave length/nm
FIGURE 4 The structure and absorption spectrum of Mexoryl XL.
belongs to the photostable group of the hydroxybenzotriazole. Its structure composes of

two different chemical groups: hydroxyphenylbenzotriazol, which provides photostable UVA
and UVB absorption, and short siloxan chain, which provides liposolubility of the molecule.
Mexorylw XL has two absorption spectra in UVB and UVA range (290 – 320 nm, lmax 303 nm
and 320– 360 nm, lmax 344 nm). By combining the lipophilic Mexorylw XL with hydrophilic
Mexorylw SX, a high level of photoprotection can be achieved (9). Since 1999, the combination
of Mexorylw SX and Mexorylw XL has been used in the Anthélios product line of La Roche-Posay.
Butyl Methoxydibenzoylmethane (avobenzone, Parsolw1789)

Avobenzone is a broad UVA absorber; however, its drawback is photo-instability. The photo-
instability of avobenzone can be avoided by combining it with octocrylene or 4-methylbenzyli-
dene camphor (L’Oreal patents US5576354 and US5587150). The rationale for the photostabiliz-
ing property of this combination is that in the presence of either one of these filters, there would
be less photons directly affecting the avobenzone.
UVB Filters
Butyl Methoxydibenzoylmethane (Octocrylene, Uvinul 539R) and
4-Methylbenzylidene Camphor (Eusolex 6300)
These UVB filters prevent the photo-induced degradation of avobenzone, thus avoiding any
loss in the long-UVA absorbing properties of the final product.
BIOLOGICAL EFFECTS OF UVA, AND UVA PROTECTION BY SUNSCREENS

Protection of Cell Nucleus
The comet assay is a simple and visual technique for measuring DNA breakage. It has
been extensively used both to characterize genotoxins and to analyze DNA repair following
phototoxic effects of UV (16,17).
Following UV SSR, keratinocytes whose DNA is impaired (fragmented) show a “comet
shape.” Comets can be observed very early after irradiation without any sign of cell toxicity.
The amount of comets produced and the length of trail can be measured by image analysis
and recorded. These parameters reflect the size and number of DNA fragments and thus the
degree of photodamages.
When the same experiment is performed in the presence of Mexorylw SX in the culture
medium, comet induction is almost abrogated (18).
In contrast to UVB, UVA mainly impairs nuclear DNA by producing reactive oxygen
species (ROS), triggering genotoxic reaction. Moreover, the comet test is more easily detected
in melanocytes than in unpigmented cells; therefore, melanocytes are considered to be the
target cell for UV, especially UVA radiation (19). An in vitro study of two SPF 7 sunscreens
302 Rougier et al.
600
500 % of control
400
300
200
100
0
Control non UV exposed Anthelios XL Vehicle
exposed
alpha-MSH IL-10
FIGURE 5 Production of a-melanocyte-stimulating hormone and interleukin-10 in skin blisters fluids 24 hours
after ultraviolet irradiation. Abbreviations: a-MSH, a-melanocyte-stimulating hormone; UV, ultraviolet; IL-10,
interleukin-10.
with different UVA protection factor (UVA-PF) (7 vs. 3, assessed by PPD method) was per-
formed; the effect of these sunscreens on the UVA-induced genotoxicity in melocyte cell
culture was assessed by the comet assay. The results showed that only the broad-spectrum
sunscreen with an UVA-PF of 7 was able to prevent photo-oxidative damage (18).
It is known that increased p53 protein in nucleus of cells occurs following UV exposure.
Therefore, determination of p53 accumulation can be used as a marker for detection of UV-
induced cell damage and as an endpoint to evaluate sunscreen efficacy (20,21). In human
subjects, sunscreen with UVA-PF of 14 was more protective in preventing the accumulation
of p53 compared with sunscreen with low UVA-PF of 6, although both had the same SPF of 25.
Protection of the Immune System

It is well established that exposure to UVR can result in immunosuppression (22). Although the
precise chromophore for the photoimmunosuppression is not known, urocanic acid (UCA) has
been considered as a possible candidate. UCA is located in the epidermis and its peak of
absorption spectrum is at 277 nm. On absorption of photons, trans-UCA is isomerized to cis-
form, the latter has been implicated in UVR-induced immunosuppression and photocarcino-
genesis (3).
Photoproduction of cis-UCA in human skin exposed to UVB þ UVA radiation has been
used to compare the protection of sunscreens having the same SPF of 60 but different UVA-
PF (12 vs. 3) (23). Similar to the genotoxicity and p53 studies, product with higher UVA-PF
was more efficient in preventing cis-UCA production than sunscreen with lower UVA-PF.
A high SPF and a high UVA-PF sunscreen (SPF . 60, UVA-PF 28; Anthelios XL,
containing octocrylene, Mexorylw SX, Mexorylw XL, avobenzone, and TiO2) was found to
prevent the suppression of delayed type hypersensitivity response in human following six
days of sun exposure (24).
In a subsequent study, the protective effect of the same broad-spectrum sunscreen on the
UV-induced production of immunosuppressive mediators, interleukin-10 (IL-10), and a-mela-
nocyte-stimulating hormone (a-MSH) was investigated in suction blister fluids (25). The results
showed that IL-10 and a-MSH expressions were significantly upregulated in UV-irradiated
skin both at the protein and at the mRNA level. Pretreatment with the broad-spectrum sunsc-
reen resulted in decreased expression of both IL-10 and a-MSH (Fig. 5).
CLINICAL EFFECTS OF UVA AND PROTECTION BY SUNSCREENS

Protection Against Photosensitizations
Besides the direct actions of UVA radiation on the immune system, photosensitization reactions
also occur, which can be induced by skin contact with certain compounds. Photosensitization
by exogenous agents covers two large types of clinical scenarios, photoxicity and photoallergy.
These two types of reaction may be differentiated according to their etiology and their clinical
characteristics.
It should be noted that the vast majority of phototoxins and photoallergens have
their action spectra in the UVA range (26). The phototoxins include psoralens, porphyrins,
tars, antibiotics, (cyclins), and nonsteriodal anti-inflammatory substances. The photoallergens
include perfumes, UV filters, agents of vegetable origin, antibiotics, and nonsteriodal anti-
inflammatory substances. The most susceptible anatomical regions are, of course, those most
exposed to the sun: (i) the ears, (ii) nose, (iii) cheeks, (iv) upper chest, (v) nape of the neck,
(vi) lateral neck, (vii) extensor forearms, and (viii) dorsum of hands.
In a study in human subjects, a broad-spectrum sunscreen with SPF .60, UVA-PF 28
(Anthelios XL 50þ, containing octocrylene, Mexorylw SX, Mexorylw XL, avobenzone, and
TiO2) has been shown to be protective against UVA-induced phototoxicity in subjects taking
oral doxycycline or limecycline (27). In a study presented as a poster, the same broad-spectrum
sunscreen was reported to be protective against UV-induced erythema in patients using topical
chlorpromazine or topical benzoyl peroxide (28). Recently, the usage of Anthelios XL 50þ has
also been verified for targeted skin protection in patients treated during summer by Roaccuta-
new caps (Roche) for cystic acne or rosacea. This experiment clearly showed that the use of a
high SPF sunscreen with UVA-PF of 28, together with good co-operation of patients resulted
in trouble-free treatment by systemic retinoids even in summer (29).
Protection Against Photo-Induced Dermatoses

Polymorphous Light Eruption
Polymorphous light eruption (PLE) is one of the most frequent photodermatoses with an esti-
mated incidence of approximately 3% to 17%. Moreover, photoprovocation testing has revealed
that 75% of PLE patients are sensitive to either UVB þ UVA or to UVA alone (30). Photoprotec-
tion, including the use of broad-spectrum sunscreen, is an integral part of the management of
PLE (31).
Three different sunscreens with high SPFs, 35, 60, and 75, but different UVA-PFs of 3 to 28,
were compared for their ability to prevent the development of skin lesions in PLE patients (32).
The sunscreen with SPF 50þ and UVA-PF 28 (Anthelios XL 50þ: containing octocrylene,
Mexorylw SX, Mexorylw XL, avobenzone, and TiO2) protected the development of PLE in all
patients, whereas sunscreens with high SPFs of 35, 60, and 75; but low UVA-PF values of 3
to 5 protected only 23% to 45% of the patients. In addition, effective prevention of clinically
apparent skin lesions was associated with complete inhibition of UVA-induced expression of
ICAM-1 mRNA. Of interest, all three tested products had avobenzone as a UVA filter.
However, the one with the highest UVA-PF also had Mexorylw SX and Mexorylw XL, indicating
that the type of UV filters used is critical for the efficacy of a given sunscreen to provide photo-
protection. This observation further supports the concept that PLE represents an abnormal
response of human skin towards UV, including UVA radiation that results in an increased
expression of pro-inflammatory molecules such as ICAM-1.
Lupus Erythematosus
Lupus erythematosus (LE) is an autoimmune disease that is triggered and exacerbated by UVR. As
a consequence, photoprotection is one of the measures in the management of these patients (33).
Eleven patients with LE were repeatedly exposed to UVA; the ability of sunscreens with high
SPFs of 35 to 75 but different UVA-PF of 3 to 28 was studied. Similar to results observed in PLE, high
UVA-PF 28 sunscreen (Anthelios XL 50þ) prevented the development of lesions in all patients,
whereas those with lower UVA-PF only partially did so (34). High UVA-PF product also prevented
the increased expression of ICAM-1 associated with development of lesions (34).
Solar Urticaria
Solar urticaria (SU) is a rare photosensitive disorder. Within 5 to 10 minutes of sun exposure,
patients experience itching, erythema, and patchy or confluent whealing. Chronically exposed
skin (face and arms) is generally less susceptible to be involved than areas normally covered.
Action spectrum ranges from UVB to UVA and to visible range. Management of SU is challenging.
304 Rougier et al.
Anthelios L Vehicle
140
120
100
80
60 FIGURE 6 Solar urticaria protection factors
40 (SUPFs) in each triggering spectral band
[SUPF ¼ minimal urticarial dose with sunscreen
20
or vehicle/MUD unprotected]. Abbreviations:
0 SUPF, solar urticaria protection factor; MUD,
long UVA short UVA UVB minimal urticarial dose.
The protective effect of a high SPF and high UVA-PF product (SPF 60, UVA-PF 12;
Anthelios L containing Eusolex 6300, Mexorylw SX, avobenzone, and TiO2) was assessed in
SU patients (n ¼ 10) following 1000 W Xenon arc solar simulator exposure (35). The
minimal urticarial dose (MUD) on unprotected area was determined for each patient and
for each triggering spectral band (UVA1: 360 nm, UVA2: 335 nm, and UVB: 310 nm) by clini-
cal assessment of erythema and swelling in the early minutes following each UV exposure.
MUD on protected area was then measured for each triggering spectral band following appli-
cation (2 mg/cm2) of either the broad-spectrum sunscreen or its vehicle and SU protecting
factor (SUPF), which was determined by dividing the MUD value obtained with the sunsc-
reen or its vehicle by the MUD value obtained without any product. Results showed that
the SUPFs of the vehicle were 2.7, 2, and 3.3, respectively, in the long UVA, short UVA,
and UVB range, whereas these SUPFs were of 75, 56, and 133 on the broad-spectrum sunsc-
reen-treated areas (Fig. 6).
Therefore, these experiments confirmed that the different parts of the UV spectrum could
elicit SU. Moreover, it was found that most of the patients react to very low doses of UV,
particularly in the UVA domain, confirming the extreme skin sensitivity of this photodermato-
sis. The results also indicate that the use of broad-spectrum sunscreens with highly efficient UV
filters can be considered as an option in the management of patients with SU with action
spectra in the UV range. For those with visible light sensitivity, physical agents such as
opaque clothings are the only available external photoprotective measure at this time.
Melasma
Melasma or chloasma is a pigmentary disorder, which typically appears on the face and
occurs most frequently in women with a skin phototype III or higher (36). Clinically,
melasma is characterized by the appearance of hyperpigmentation that develops on the fore-
head, cheeks, and chin and is classified as medium, moderate, or severe. Melasma can
develop as a result of pregnancy or taking oral contraceptives, but it can also occur spon-
taneously. It can affect up to 50% to 70% of pregnant women, often motivating the request
for a therapeutic solution (37). It can be the result of a combination of several factors: (i)
genetic and ethnic (determining phototype), (ii) hormonal, and (iii) environmental (exposure
to UVB and UVA) (38). Treatment is difficult. Removing factors that trigger the condition,
such as exposure to the sun, tanning beds, or exogenous estrogen treatments constitutes
useful measures.
The effect of a high SPF and high UVA-PF sunscreen (SPF50þ, UVA-PF 28; Anthelios XL
containing octocrylene, Mexorylw SX, Mexorylw XL, avobenzone and TiO2) was assessed in the
course of a 12-month clinical trial carried out on 200 pregnant individuals (39). The results
showed that out of the 185 patients who completed the study, only five new cases of
melasma were observed, that is, an occurrence of 2.7%, which is much lower than the 53% pre-
viously observed in comparable conditions and same geographical area. It is also worth noting
that within six months, a clinical improvement was observed in 8 out of the 12 subjects who
were affected by a pre-existing melasma that had been observed at the time of their visit for
inclusion in the study.
Colorimetric measurements showed that, at the end of their pregnancy, the parturient’s skin
was significantly lightened (increase in parameter L in 38.4% of the cases) and significantly less
pigmented (reduction in parameter b in 50.3% of the cases), thus giving a significantly lighter
skin color [increase of individual tripology angle (ITA) in 68.6% of the cases] compared to their
visit at the beginning of the study. These observations demonstrate the benefits of external
broad-spectrum sunscreen in preventing and even improving this dermatosis.
Daily Photoprotection and Photoaging
The aging processes of the skin involve two clinically and biologically independent processes
that occur simultaneously: chronological aging (intrinsic aging), which affects the skin by
slow and irreversible tissue degradation, and photoaging (extrinsic aging), which
results from repeated exposure to UVRs. In areas exposed to sun, skin damages resulting
from photoaging are added to degenerations of tissues resulting from chronological aging.
Photoaging leads to marked cutaneous alterations, clinically characterized by wrinkles,
roughness, mottled dyspigmentation, telangectasia, and a variety of benign and malignant
neoplasms. Both UVB and UVA have been implicated in the pathophysiology of photoaging,
the former by its direct DNA-damaging effect and the latter through the generation of
ROS (40).
During UVA-induced oxidative process and free radicals production, part of the energy is
released in the form of photons, a process termed chemiluminescence. These photons can be
detected and amplified by a photomultiplier. This allows for the quantification of oxidative
stress and protection afforded by topically applied formulations. The oxidative stress
induced by a single suberythemal dose of UVA (320 – 400 nm, 1 J/cm2) has been assessed by
means of chemiluminescence; the effect of a day cream with photoprotection (SPF 15, UVA-
PF 12; Hydraphase XL, containing octocrylene, Mexorylw SX, Mexorylw XL, avobenzone)
was evaluated (41). The results showed that the day cream leads to a decrease of about 75%
and 40% of chemiluminescence when compared with untreated or placebo-treated skin.
These results suggest that the use of a cream with both UVB and UVA protection can possibly
prevent the deleterious effects of free radicals induced by daily exposure to suberythemal doses
of UV.
Induction of matrix metalloproteinases (MMPs) following UVR exposure is known to play
an important role in photoaging (40). A study was done to evaluate the effect of broad-spectrum
sunscreen in this process. Buttock skin of 10 healthy subjects was exposed to 100 J/cm2 UVA1
irradiation (340–400 nm). This dose was previously shown to induce MMP-1 expression.
Application of an SPF50þ, UVA-PF 28 product (Anthelios XL, containing octocrylene, Mexorylw
SX, Mexorylw XL, avobenzone, and TiO2) 20 minutes prior to exposure to 100 J/cm2
of UVA1 resulted in the suppression of UVA1-induced expression of ICAM1 and MMP-1
(Fig. 7) (42).
UVA is known to be involved in the development of pigmented skin lesions associated
with skin aging. The effect of a broad-spectrum sunscreen (SPF 15, UVA-PF 12; Hydraphase
XL, containing octocrylene, Mexorylw SX, Mexorylw XL, avobenzone) was evaluated in a
bilateral comparison study, using vehicle as a control. Twenty healthy women were
exposed on the neckline three times a week for three months to suberythemal doses
of UVA (20, 25, and 30 J/cm2, respectively, for the first, second, and third month).
Evaluation of skin pigmentation was performed monthly by visual examination and by
using a chromameter (Minolta CR 200). Clinically and following Wood’s lamp examination,
pigmentation was found to be more intense on the vehicle-treated side. Moreover, clinical
examination of actinic lentigines indicated that the pigmentation of these lesions was not
changed on the vehicle-treated side, whereas it was significantly decreased on the daily
cream-protected side (Fig. 8) (43). It thus appears that the use of a day cream containing
broad-spectrum filters in chronic UVA exposure conditions not only offers an efficient
protection on the induction of pigmentation, but also allows a lightening of pre-existing
pigmented lesions.
Broad-spectrum sunscreens containing Mexorylw with a high SPF and UVA-PF is protec-
tive against the deleterious effects of UV light radiation in vitro and in patients with photoder-
matoses, and in processes associated with photoaging.
306 Rougier et al.
5
Fold of increase
vs unirradiated
4
0
non irradiated UVA non protected UVA+Sunscreen
30
Fold of increase
25 vs unirradiated
20
15
10
FIGURE 7 Intercellular adhesion molecule 1
5 (ICAM-1) and matrix metalloproteinase-1 (MMP-
1) expression in skin biopsies following a single
0 UVA-1 irradiation (100 J/cm2) in broad-spectrum
non irradiated UVA non protected UVA+Sunscreen sunscreen protected and nonprotected areas.
daycream vehicle
score
2,5
1,5
FIGURE 8 Evolution of pigmented lesions

following chronic UVA irradiation on
0,5 nonprotected skin and skin protected by a
0 1 2 3 months daily cream with photoprotection.
CONCLUSION
The ideal sun-protection product should have good UVB and UVA filters, and the filters must
remain effective throughout the duration of long exposure time. Therefore, the ideal sunscreen
product should thus fulfill the following criteria:
1. well tolerated
2. cosmetically pleasant
3. nontoxic or allergenic, nonphototoxic, or photoallergenic
4. equally effective against UVA and UVB
5. photostable
6. water resistant
7. high SPF.
TABLE 1 EEC Rules for Sunscreen Products Labelling

Recommended Recommended
Measured sun minimum UVA minimum critical
protection factor protection factor wavelength
[measured in [measured in [measured
accordance with accordance with in accordance with
the principles principles principles
Labelled sun recommended in recommended in recommended in
Labeled category protection factor point 10 (a)] point 10 (b)] point 10 (c)]
Low protection 6 6 –9.9 1/3 of labelled sun 370 nm

protection factor
10 10–14.9
Medium protection 15 15–19.9
20 20–24.9
25 25–29.9
High production 30 30–49.9
50 50–59.9
Very high protection 50þ 60
In recent years, novel and highly efficient sunscreens that fulfill the above criteria have
been developed (4). Daily practice of sensible photoprotection, including the use of broad-
spectrum sunscreen, should help to prevent the acute and chronic side effects of sun exposure.
According to the very recent European Commission (EEC) guidelines (44), the minimum
degree of protection provided by sunscreen products should be as follows:
1. a UVB protection of SPF 6.

2. a UVA PF of 1/3 of the SPF, as obtained by the persistent pigment darkening method (PPD).
3. a critical wavelength of 370nm.
The new EEC rules for sunscreen labelling are presented in Table 1.
REFERENCES
1. Tuchinda C, Srivannaboon S, Lim HW. Photoprotection by window glass, automobile glass and
sunglasses. J Am Acad Dermatol 2006; 54:845– 854.
2. Godar DE. UV Doses Worldwide. Photochem Photobiol 2005; 81:736 –749.
3. Kullavanijaya P, Lim HW. Photoprotection. J Am Acad Dermatol 2005; 52(6):937– 958.
4. Tuchinda C, Lim HW, Osterwalder U, Rougier A. Novel emerging sunscreens technologies. Dermatol
Clin 2006; 24:105– 117.
5. Collaborative development of a sun protection factor test method: a proposed European standard. Int
J Cosm Sci 1996; 18:203– 218.
6. Lim HW, Naylor M, Hönigsmann H et al. American Academy of Dermatology Consensus Conference
on UVA Protection of Sunscreens: Summary and Recommendations. J Am Acad Dermatol 2001;
44:505– 508.
7. Moyal D, Chardon A, Kollias N. UVA protection efficacy of sunscreens can be determined by the persist-
ent pigment darkening (PPD) method (Part 2). Photodermatol Photoimmun Photomed 2000; 16:250–255.
8. Japan Cosmetic Industry Association (JCIA). Measurements standard for UVA protection efficacy.
Tokyo, Japan, 1996.
9. Wendel V, Klette E, Wittern KP, Gers-Barlag H. A new in vitro test method to assess the UVA protec-
tion performance of sun care products. SÖFW 2001; 127:12– 31.
10. Diffey BL, Stokes RP, Forestier S, Mazillier C, Richard A, Rougier A. Suncare product photostability: a
key parameter for more realistic in vitro efficacy evaluation. Part I: In vitro efficacy assessment.
In: Rougier A, Schaefer H, eds. Protection of the Skin Against Ultraviolet Radiations. Paris, France:
John Libbey Eurotext, 1998:137– 142.
11. Forestier S, Mazillier C, Richard A, Rougier A. Suncare product photostability: a key parameter for
more realistic in vitro efficacy evaluation. Part II: chromatographic analysis. In: Rougier A, Schaefer
H, eds. Protection of the Skin Against Ultraviolet Radiations. Paris, France: John Libbey Eurotext,
1998:143– 148.
12. Gaspar LR. Evaluation of the photostability of different UV filters combinations in a sunscreen. Int J
Pharm 2006; 307(2):123– 128.
308 Rougier et al.
13. Marrot L, Belaidi JP, Meunier JR. Comet assay combined with p53 detection as a sensitive approach
for DNA photoprotection assessment in vitro. Mutat Res 2005; 571(1– 2):175– 184.
14. Marrot L, Belaidi JP, Lejeune F, Meunier JR, Asselineau D, Bernerd. Photostability of sunscreen
products influences the efficiency of protection with regard to UV-induced genotoxic or photoageing-
related endpoints. Br J Dermatol 2004; 151(6):1234–1244.
15. Bouillon C. Recent advances in sun protection. J. Dermatol Sci 2000; 23(suppl 1):S57– S61.
16. Collins AR, Ai-guo M, Duthie SJ. The kinetics of repair of oxidative DNA damage (strand breaks and
oxidized pyrimidines) in human cells. Mutation Res 1995; 336:69– 77.
17. Alapetite C, Moustacchi E, Wachter T, Sage E. Use of alkaline comet assay to detect DNA repair
deficiencies in human fibroblasts exposed to UVC, UVB, UVA, and gama rays. Int J Radiat Biol
1996; 69:359– 369.
18. Fourtanier A, Bernerd F, Bouillon C. Protection of skin biological targets by different types of sunsc-
reens. Photoderm Photoimmunol Photomed 2006; 22:22– 32.
19. Marrot L, Belaidi JP, Meunier JR. The human melanocyte as a particular target for UVA radiation and
an endpoint for photoprotection assessment. Photochem Photobiol 1999; 69:686 –693.
20. Marrot L, Belaidi JP, Chaubo C, et al. An in vitro strategy to evaluate the phototoxicity of solar UV at the
molecular and cellular level: application to photoprotection assessment. Eur J Dermatol 1998; 8:403–412.
21. Marrot L, Belaidi JP, Meunier JR. Comet assay combined with p53 detection as a sensitive approach
for DNA protection assessment in vitro. Exp Dermatol 2002; 11 (suppl 1):33 – 36.
22. Schwarz T. Mechanism of UV induced immunosuppression. Keio J Med 2005; 54:163– 171.
23. Krien P, Moyal D, Rougier A. Influence of highprotective sunscreens on the photoisomerization of
urocanic acid in human skin. In: Rougier A, Schaefer H eds. Protection of the Skin Against Ultraviolet
Radiations. Paris, France: John Libbey Eurotext, 1998:183– 187.
24. Moyal D, Duteil C, Queille-Roussel C, Ortonne JP, Hourseau C, Rougier A. Prevention of solar
induced immunosuppression by highly protective broadspectrum sunscreen. Eur J Dermatol 2002;
12:XII– XIV.
25. Schiller M, Brzoska T, Böhm M. Solar-simulated ultraviolet radiation-induced upregulation of the
melanocortin-1 receptor, proopiomelanocortin, and / -melanocyte-stimulating hormone in human
epidermis in vivo. J Invest Dermatol 2004; 122:468– 476.
26. Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous
agents. J Am Acad Dermatol 1995; 33:551 – 576.
27. Duteil L, Queille-Roussel, Rougier A, Richard A, Ortonne JP. High protective effect of a broad-spec-
trum sunscreen against tetracycline phototoxicity. Eur J Dermatol 2002; 12:X– XI.
28. Duteil L, Quelle-Roussel C, Rougier A, Ortonne JP.High protective effect of UVA filter reinforced
sunscreens against phototoxicity of chlorpromazine and benzoyl peroxide. Poster AAD annual
meeting. 1998.
29. Zelenkova H, Stracenska J, Richard A, Rougier A. Protective effect of a broadspectrum UVA-UVB
sunscreen in the retinoid therapy during summer season. Poster EADV Annual Meeting, 2002.
30. Hawk J, Lim HW. Photodermatoses. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 1st ed.
London: Mosby, 2003:1365– 1384.
31. Hönigsmann H. Polymorphous light eruption. In: Lim HW, Soter NA, eds. Clinical Photomedicine.
New York: Marcel Dekker, 1993:167– 180.
32. Stege H, Budde M, Grether-Beck S, et al. Sunscreens with high SPF values are not equivalent in
protection from UVA induced polymorphous light eruption. Eur J Dermatol 2002; 12:IV – VI.
33. Costner MI, Sontheimer RD. Lupus erythematosus. In: Freedberg IM, Eisen AZ, Wolf K, Austen KF,
Goldsmith LA, Katz SI, eds. Fitzpatrick’s Dermatology in General Medicine. New York: McGraw-
Hill, 2003:1677– 1693.
34. Stege H, Budde MA, Grether-Beck S, Richard A, Rougier A, Krutmann J. Evaluation of the capacity of
sunscreens to photoprotect lupus erythematosus patients by employing the photoprovocation test.
Eur J Dermatol 2002; 12:VII – IX.
35. Peyron JL, Raison-Peyron N, Meynadier J, Moyal D, Rougier A, Hourseau C. Prevention of solar urti-
caria using a broadspectrum sunscreen and determination of solar urticaria protection factor (SUPF).
In: Rougier A, Schaefer H, eds:Protection of the Skin Against Ultraviolet Radiations. Paris, France:
John Libbey Eurotext, 1998:201 –205.
36. Halder RM, Nandedkar MA, Neal KW. Pigmentary disorders in ethnic skin. Dermatol Clin 2003;
21:617– 628.
37. Muzaffar F, Hussain J, Haroo H.S. Physiologic skin changes during pregnancy: a study of 140 cases.
Int J Dermatol 1998; 37(6):429– 431.
38. Perez ML. The stepwise approach to the treatment of melasma. Cutis 2005; 75(4):217– 222.
39. Lahkdar H, Zouhair K, Khadir K, Essari A, Richard A, Seite S and Rougier A. Evaluation of the effec-
tiveness of an external broad-spectrum sunscreen in the prevention of chloasma in pregnant women.
JEADV. In press.
40. Chung J, Cho S, Kang S. Why does the skin age? In: Rigel DS, Weiss RA, Lim, HW, Dover JS, eds.
Photoaging. New York: Marcel Dekker, Inc., 2004:1– 13.
41. Rougier A, Richard A. In vivo determination of the skin protection capacity of a day-cream by means
of ICL-S. Eur J Dermatol 2002; 12:XIX– XX.
42. Rougier A, Krutmann J. Unpublished data.
43. Duteil L, Queille-Roussel C, Rougier A, Richard A, Ortonne JP. Chronic UVA exposure: protective
effect on skin induced pigmentation by a daily use of a day care cream containing broad band sunsc-
reen. Eur J Dermatol 2002; 12:XVII– XVIII.
44. The Commission of the European Communities. Commission recommendation on the efficacy of
sunscreen products and the claims made. Official J Eur Union 2006; 265:3943.
21 Public Education in Photoprotection
Cheryl Rosen
Division of Dermatology, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
Mark Naylor
University of Oklahoma, Tulsa, Oklahoma, U.S.A.
B Public education about sun protection/skin cancer prevention is very

important.
B Improvement in knowledge in sun protection/skin cancer prevention

does not equal change in attitude or behavior.
B Programs should be ongoing, and include coordinated multilevel

approaches that use different strategies for different target populations
within the population as a whole.
B Programs need to be evaluated for their effectiveness, and adapted to

improve effectiveness if possible.
B Environmental change (e.g. increased provision of shade) and policy

change (e.g. at workplaces, day care centres, schools) at the community
level enable an individual to change their sun protection behavior.
312 Rosen and Naylor
INTRODUCTION
ecause of the etiologic relationship between sun exposure and skin cancer, a vast array of
B efforts have been made to increase the public’s awareness of the risks of sun exposure.
Programs have attempted to increase the public’s knowledge about the risks of sun
exposure, to modify attitudes toward tanning and prolonged sun exposure and to change
sun-protective behaviors. The behaviors that are generally recommended to decrease sun
exposure include limiting the time spent in the sun, particularly during times of peak ultra-
violet (UV) irradiance, use of protective clothing, use of sunglasses, and seeking shade when
outdoors. Use of sunscreens with both UVB and UVA coverage is also recommended.
A great deal of material has been developed and distributed to the public both on a small-
scale and on a large community-wide or country-wide basis. In 1998, an issue of Clinics in
Dermatology published reviews on prevention programs from many countries (1 – 11).
Different countries have established programs, often as collaborations between different
health-related organizations. Australia, with very high rates of skin cancer, has been a leader in
public education in photoprotection (12). The SunSmart program of the Cancer Council
Victoria, Australia, has been named the “World Health Organization Collaborating Center
for the Promotion of Sun Protection” (13).
The Centers for Disease Control and Prevention in the United States in conjunction with
the United States Department of Health and Human Services had developed a program called
Choose Your Cover, which was a five-year skin cancer prevention and education campaign.
This program was aimed at young people and focused on having fun outdoors while using
a variety of methods to protect the skin, including seeking shade, wearing clothing,
sunglasses and a hat, and using sunscreen. Although this campaign has concluded, the
material that was developed is available on the internet (14).
The evaluation of programs for effectiveness is very important. The Centers for Disease
Control and Prevention in the United States evaluated published studies to determine which
programs were supported by sufficient evidence to be recommended (15). It was determined
that the only programs that had sufficient evidence to recommend them were educational
and policy approaches in primary schools and in recreational or tourism sites. Studies done
in primary schools and recreational or tourism sites provided sufficient evidence of improving
the use of sun-protective clothing, including hats. Other behavioral endpoints were not found
to have been affected in reported studies (15).
However, because there is insufficient evidence to recommend a particular strategy does
not mean that the strategy has been proven to be ineffective (16). Many programs have not been
evaluated. Much research remains to be done on which programs are the most effective.
Programs which have been designed and implemented in one location can be adapted for
use by another area and the influence of the adapted programs on sun-protective behavior can
then be evaluated. Programs can evolve based on information learned during an evaluation
process.
A review paper examining primary prevention in Australia and in other countries (17)
focused on the prevalence of prevention activities and not on the outcomes of these activities.
The sun-protective behaviors of children, adolescents, and adults were studied. Although
sunscreen use is generally not recommended as the first method of protection, it was found
to be the most frequently used method in children. Hats and clothing were used much less fre-
quently. Not surprisingly, the sun-protective behavior of children was dependent on the advice
of parents. Sunscreen use was used most commonly by adolescents as well. Although adoles-
cents may have fairly good knowledge of the need for sun protection, their behavior may not
reflect this knowledge (18).
An educational program was presented to one group of students in Sweden, with another
group acting as the control (18). Although the knowledge of the risks of sun exposure increased
at a post-test three months after the intervention, attitudes toward sun protection and tanning
did not change. These authors utilized the transtheoretical model of behavior change that has
been applied in health promotion and disease prevention. It is postulated that people move
through five discrete stages, from (i) precontemplation to (ii) contemplation to (iii) preparation
to (iv) action, and (v) maintenance, when changing behavior (19). This model has also been
Public Education in Photoprotection 313
used in other sun-protection programs (20). Another model of behavior is termed the theory of
reasoned action [for review, see (21)]. Behaviors that are under volitional control are deter-
mined by intention, which is the result of the attitude toward the behavior and the subjective
perception of norms surrounding the behavior. The social-cognitive theories of attitude and
behavior change propose that people actively make decisions whose attitudes are based on
knowledge and beliefs about the benefits and negative aspects of the particular behavior
(12). Attempts to change behavior are affected by social and environmental factors. Health pro-
motion programs are often based on theoretical models of human behavior.
Positive attitudes toward tanning continue (22) and this remains a major difficulty in
changing sun-protective behavior . In Australia, attitudes towards tanning appeared to have
changed in the 1990s, with a preference for a light tan or no tan, when compared with a
deep tan (23). However, it later appeared that this changed attitude was becoming less
popular and that further ongoing public education would be required (23). The Canadian
National Survey on sun exposure and protective behaviors, conducted in 1996, revealed that
35% of adult Canadians surveyed wanted to get a tan (24). In a survey of American teenagers
published in 2002, 75.3% preferred tanned skin (25).
After surveying knowledge, attitudes, and behaviors of children, adolescents, and adults,
Stanton et al. (17) recommend the development of an ongoing “coordinated multilevel
approach to increase sun protection that uses a range of strategies.” Messages are required
within the overall strategy that specifically target particular groups, such as adolescents (17).
The Australian SunSmart program is an example of a comprehensive health promotion strat-
egy, which has developed over many years.
PROGRAMS
Melia et al. (26) evaluated primary prevention programs in the U.K., particularly those studies
investigating changes in behavior. Of note, the patterns of sun exposure and the lower inci-
dence and mortality of skin cancer in the U.K. may affect the design and messages of preven-
tion programs. Mass media programs may have increased knowledge of the risks of
overexposure to the sun, but positive attitudes to tanning persisted (26). A “Suncool”
program in schools which involved a booklet, a video, and other information handouts resulted
in an increase in knowledge at four months, but behavior in groups of children exposed to the
program did not differ from those who were not (26).
Schools
A number of programs have been developed for schools.
The Cancer Council Australia began a national program for schools in 1998. Schools that
implement the sun-protection policies become accredited SunSmart schools. Accredited
schools have written sun-protection policies, relating to educational curriculum, student and
staff behavior, and the school environment (27). Sun protection is to be taught to students of
all ages. Schools must work to increase the amount of shade available and to reschedule
outdoor activities to avoid peak UV exposure times. Students are required to wear wide-
brimmed hats or hats which cover the back of the neck. In 2001, the National Skin Cancer Steer-
ing Committee Secondary Schools Working Group on behalf of the Cancer Council Australia
published “UV risk reduction: a planning guide for secondary schools” (28). The CDC pub-
lished guidelines for school programs for skin cancer prevention (29). There are seven
guidelines put forward for schools to use.
B Guideline 1: Policy development to decrease UV exposure.

B Guideline 2: Environmental change. This guideline suggests physical and social environ-
mental conditions that support sun protection.
B Guideline 3: Education.
B Guideline 4: Family involvement.
B Guideline 5: Professional development for school administrators and teachers.
B Guideline 6: School health services.
B Guideline 7: Periodic evaluation of whether schools are implementing and continuing to

follow the guidelines.
These guidelines can be adapted to help establish sun-protection programs in a variety of

settings.
Recreation Areas
Outdoor recreation areas for children and adults appear to be natural targets for sun awareness
intervention. The supervisors of the facilities are able to provide educational material to
the people attending the centers. People working at the facilities, such as camp counselors,
lifeguards, and coaches can receive training sessions concerning sun-protection methods.
A number of programs have been carried out at swimming pools. A multicomponent
intervention to reduce children’s radiation (UVR) exposure during swimming classes was
designed (30). Forty-eight swimming classes (n ¼ 169 children, mean age ¼ 7) were randomly
assigned to either the intervention or the control condition. The six-week intervention included
a UVR reduction curriculum presented at poolside by aquatics instructors and home-based
activities for children and their parents. Apart from an increased use of hats, there was
no difference between the control swim classes and those that received the sun protection
intervention (30).
The Pool Cool program in Hawaii and Massachusetts was a randomized trial which con-
sisted of a six-week intervention effort involving lifeguards/swimming instructors at pools in
both states (31). The aquatic staff at the control group of swimming pools received instruction
on injury prevention, whereas those at the intervention group of pools received education
about sun protection, a curriculum to teach to their swimming students along with interactive
activities for the students and their parents. Sunscreen dispensers and signs with sun-
protection tips were provided and the staff received hats and sunscreen as incentives for
teaching the sun-protection lessons and for completing the surveys (31). The aquatic staff in
the interactive group had fewer sunburns and sun-protection policies improved significantly
compared to the control group, but overall sun-protection behaviors were no different at the
two groups of swimming pools. The post-test survey was at six to eight weeks. The children
enrolled in these swim classes were also studied, along with their parents (32). Statistically
significant increases were seen in the children’s use of sunscreen, shade-seeking behavior,
and “overall sun-protection habits” when compared with the control group. Parents of the
involved children were also noted to have an increase in their overall sun protection habits
(32). More recently, the Pool Cool program has continued to expand to more swimming
pools across the United States. Strategies to best result in implementation, maintenance, and
sustainability of the Pool Cool program are being studied (33).
Health Care Practitioners and Medical Students

The role of physicians, nurses, and medical students in skin cancer prevention has been
studied. In 1999, Guenther and Gooderham (34) developed a program about sun protection
for grade four children, to be delivered by medical students. This program is the culmination
of a week of dermatology teaching to the medical students. At the end of the week of
teaching, the medical students had increased their knowledge about skin cancer and
sun protection, and their intent to adopt sun-protective measures increased (34). One year
later, the medical students were surveyed and were found to have retained the knowledge
from the previous course and had had 50% fewer sunburns during the past summer (35).
However, the perception of the attractiveness of tanned skin persisted among the medical
students (35). The grade four children were interviewed before, immediately after, and one
month after the teaching session. An intention to increase sun-protection behaviors was
noted and knowledge about sun protection increased (36). When parents were involved in
the learning activities of their children, fewer children were reported to have sunburns over
the summer vacation (37).
Primary care physicians do not counsel their patients concerning skin cancer prevention
as frequently as they discuss other preventive measures (38). Skin cancer prevention education
and counseling was performed at 2.3% of visits to American primary care physicians (n ¼ 439)
when compared with review of breast self-examination at 13% of visits, diet at 25.3%, nutri-
tion at 5.7%, and tobacco at 17.9% of visits. One reason for this was thought to be a lack of
knowledge of the area. For this reason, a two-hour curriculum on skin cancer prevention, coun-
seling and screening was developed and provided to a group of physicians (39). Following this
course, physicians were surveyed and found to significantly increase how often they discussed
skin cancer prevention with their patients. This was confirmed by exit interviews with patients.
However, this study is limited by the small number of participating physicians (n ¼ 22) (39).
Workplace
Outdoor workers can be in the sun for prolonged periods of time. Complete avoidance of sun
exposure is not possible due to the nature of the occupation. Policies, education, and pro-
cedures at the workplace can lead to increased sun protection. Planning to allow maximum
use of available shade and use of sun-protection equipment such as protective clothing, hats
with broad brims, sunscreen, and sunglasses can decrease the exposure of outdoor workers
to the sun.
A randomized controlled trial investigated the effect of a week long intervention on the
knowledge, attitudes, and behaviors of outdoor electrical workers in Australia (40). Twelve
workplace sites were randomized to receive the intervention. The intervention consisted of
an education session (a 30-minute lecture about skin cancer in Australia, the increased risk
of developing skin cancer in outdoor workers, and methods of skin protection) and a skin
screening session. Although the knowledge level of the intervention group increased signifi-
cantly compared to the control group, and the use of sun-protective behaviors increased,
attitudes (including the perceived benefit of having a tan) toward sun exposure did not
change (40).
A program entitled Project SunWise was presented to the San Diego United States Postal
Service. This program offered free wide brim hats, free sunscreen, reminders to use sunscreen
and to wear hats as well as education on sun safety (41). Although baseline data reveal that
these outdoor workers do not protect themselves well against sun exposure, the results of
the intervention are not yet published (42).
An Israeli study examined a graded intensity program that led to an increase in sun pro-
tective behaviors over the 20-month study period (43). An education session stressed the risks
of skin cancer related to sun exposure and methods of sun protection. The complete and partial
intervention groups were given hats, sunscreens, and sunglasses. The complete intervention
group had the education session repeated one year after the first session. The minimal group
had only one education session eight months prior to the end of the study. At the end of the
study, the two groups with greater intervention had increased their use of sunscreen (increased
by 82% and 52%). There was also a decrease in the amount of sun-exposed skin in the group
with the greatest intervention (43). In a follow-up study, sun-protection behavior remained
higher in those employees who had received the education session (44). Regulations instituted
by the employer after the initial study was finished were more effective in those who had
received the education sessions (44).
A randomized trial was conducted to determine whether a sun-protection program (Go
SunSmart) could be effective at high altitude skin resorts (45). Twenty-six different skin resorts
were randomized to receive the program, which was comprehensive in its scope. Details of the
program components are noted within the published report. A 14% reduction in the number of
sunburns obtained while skiing or snowboarding during the winter of the study was found at
the resorts that received the Go SunSmart program.
Community-Wide Interventions
The SafeSun Project conducted in New Hampshire was a community-wide multicomponent
intervention, from 1995 until 1997, which measured children’s sun-protection behavior
at beaches as the outcome (46). Ten towns were randomized to receive the intervention.
Schools, day-care centers, doctors’ offices, and beaches were sites where sun-protective
programs occurred. Children were observed at the beach in the summer of 1995 and then again
in 1997. In the towns with the active intervention, the proportion of children using at least some
sun protection increased significantly. Increased protection was due primarily to an increase in
sunscreen use, while the use of shade and protective clothing remained low (46).
Another multicomponent, community-based study, The Falmouth Safe Skin Project, was
conducted in Falmouth, Massachusetts from 1994 to 1997 (47). This study involved an advisory
board from the community, with multiple target audiences including newborns and their
parents and children from infancy through elementary school. Parents at hospitals after
the birth of a baby, at childcare centers, at schools received information about sun protection.
Children at summer camps received instruction from their counselors. Sun-protection
materials were widely available. Local media was involved. Data were obtained by self-
report surveys by parents. Knowledge about sun protection was increased in the community.
The incidence of painful sunburns in children decreased. In children less than six years old,
18.6% had had a painful sunburn at baseline, whereas only 3.2% had a painful sunburn in
1997. The use of sunscreen increased but the use of protective clothing did not.
The Australian SunSmart program continues as an active advocate for sun protection in
Australia. The 20-year review of the program provides interesting insights into the successes
and difficulties of health promotion programs (12).
PUBLIC EDUCATION AND PHOTOPROTECTION

The risk of skin cancer is not uniformly the same in the population, as the risk factors for skin
cancer are known to be number of nevi, blue eyes, fair hair, inability to tan, a family history of
skin cancer, place of residence, and others outlined elsewhere in this book. The risk is lower for
people with darker skin, but is not nonexistent. In fact, the thickness of melanoma at the time of
diagnosis in blacks and Hispanic people in Florida is greater than that of white people (48).
Using the California Cancer Registry as a data source, a statistically significant 1.8% increase
per year in the incidence of invasive melanoma was found in Hispanic men between 1988
and 2001 (49). A similar but not significant increase was found in Hispanic women during
the same time period. Tumors that were greater than 1.5 mm at the time of diagnosis increased
by 11.6% per year in Hispanic men and 8.9% per year in Hispanic women (49). Melanoma is not
uncommon in Californian Hispanics, occurring at a comparable incidence to Hodgkin’s
disease. Skin cancer prevention campaigns can address the need for different messages for
different populations.
The message concerning sun protection can be delivered at several levels. An individual
can be reached by their physician, their school, and their workplace. Community-based pro-
gramming is received by the individual who decides whether it is a message that is important
to them.
Targeting messages to a specific audience may be required for further public education
programming. Research has shown that there are gender differences in the beliefs of young
American adults concerning sunscreen use (21). Teenagers have been a difficult group to
reach with the standard sun-protection messages (12).
Community-based intervention is not only public health messages delivered through the
mass media or by pamphlets distributed at various locations. Environmental change, enabling
people to more readily change their behavior, is extremely important. An example from Aus-
tralia is the removal of sales tax from sun-protection products (23). Governmental and nongo-
vernmental agencies interested in skin cancer prevention have worked toward changes in
policy. Municipalities may develop shade guidelines for new or existing buildings. Tree plant-
ing and maintenance can be made municipal or school board priorities. Policies to protect
outdoor workers can be put in place. By working with school boards, sun awareness and
skin cancer prevention can become part of the school science or health curriculum.
RECENT CONTROVERSY
Vitamin D, which is produced in the skin by exposure of a precursor molecule to UVB radi-
ation, has long been known to be involved in bone health and the prevention of rickets. The
role of vitamin D and/or UVR in the epidemiology of a variety of diseases is being examined.
For this reason, some are questioning the current sun protection messages (50). This is an issue
that must be followed carefully.
REFERENCES
1. Zaitz C, Campbell I, Santos OL. Sun education in Brazil. Clin Dermatol 1998; 16(4):533– 534.
2. Schulz EJ. Sun education in South Africa. Clin Dermatol 1998; 16(4): 531– 533.
3. Rivers JK. Sun education in Canada. Clin Dermatol 1998; 16(4):530–531.
4. Marks R. Sun education in Australia. Clin Dermatol 1998; 16(4):528– 530.
5. Kim ST. Sun education in Korea. Clin Dermatol 1998; 16(4):526– 527.
6. Katsambas AD, Katoulis AC, Varotsos C. Sun education in Greece. Clin Dermatol 1998; 16(4):
525– 526.
7. Graham-Brown RA. Sun education in the United Kingdom. Clin Dermatol 1998; 16(4):523– 525.
8. Goihman-Yahr M. Sun education in Venezuela. Clin Dermatol 1998; 16(4):522– 523.
9. George AO. Sun education in Africa: Nigeria and West African subregion. Clin Dermatol 1998;
16(4):520– 521.
10. Brenner S, Wohl Y, Landau M. Sun education in Israel. Clin Dermatol 1998; 16(4):518– 520.
11. Barnes L. Sun education in Ireland. Clin Dermatol 1998; 16(4):517– 518.
12. Montague M, Borland R, Sinclair C. Slip! Slop! Slap! and SunSmart 1980 – 2000: skin cancer control
and 20 years of population-based campaigning. Health Educ Behav 2001; 28(3):290– 305.
13. www.sunsmart.com.au, accessed August 2006.
14. www.cdc.gov/chooseyourcover/, accessed August 2006.
15. Saraiya M, Glanz K, Briss P, et al. Preventing skin cancer: findings of the task force on community
preventive services on reducing exposure to ultraviolet light. MMWR Recomm Rep 2003; 52(RR-15):
1– 12.
16. Glanz K, Halpern AC, Saraiya M. Behavioral and community interventions to prevent skin cancer:
what works? Arch Dermatol 2006; 142(3):356– 360.
17. Stanton WR, Janda M, Baade PD, et al. Primary prevention of skin cancer: a review of sun protection
in Australia and internationally. Health Promot Int 2004; 19(3):369 –378.
18. Kristjansson S, Helgason AR, Mansson-Brahme E, et al. ‘You and your skin’: a short-duration presen-
tation of skin cancer prevention for teenagers. Health Educ Res 2003; 18(1):88– 97.
19. Prochaska JO, Velicer WF. The transtheoretical model of health behavior change. Am J Health Promot
1997; 12(1):38– 48.
20. Weinstock MA, Rossi JS. The Rhode island Sun Smart Project: a scientific approach to skin cancer
prevention. Clin Dermatol 1998; 16(4):411– 413.
21. Abroms L, Jorgensen CM, Southwell BG, et al. Gender differences in young adults’ beliefs about
sunscreen use. Health Educ Behav 2003; 30(1):29– 43.
22. Alberg AJ, Herbst RM, Genkinger JM, et al. Knowledge attitudes and behaviors toward skin cancer in
Maryland youths. J Adolesc Health 2002; 31(4):372– 377.
23. Marks R. Two decades of the public health approach to skin cancer control in Australia: why, how and
where are we now? Australas J Dermatol 1999; 40(1):1– 5.
24. Shoveller JA, Lovato CY, Peters L, et al. Canadian national survey on sun exposure & protective
behaviours: adults at leisure. Cancer Prev Control 1998; 2(3):111 – 116.
25. Geller AC, Colditz G, Oliveria S, et al. Use of sunscreen, sunburning rates and tanning bed use among
more than 10,000 US children and adolescents. Pediatrics 2002; 109(6):1009– 1014.
26. Melia J, Pendry L, Eiser JR, et al. Evaluation of primary prevention initiatives for skin cancer: a review
from a UK perspective. Br J Dermatol 2000; 143(4):701– 708.
27. www.cancer.org.au, accessed August 2006.
28. National Skin Cancer Steering Committee S.S.W.G. UV Risk Reduction: A Planning Guide for Second-
ary School Communities. East Sydney: Cancer Council Australia, 2001.
29. Glanz K Saraiya M Wechsler H. Guidelines for school programs to prevent skin cancer. MMWR
Recomm Rep 2002; 51(RR-4):1 – 18.
30. Mayer JA, Slymen DJ, Eckhardt L, et al. Reducing ultraviolet radiation exposure in children. Prev
Med 1997; 26(4):516– 522.
31. Geller AC, Glanz K, Shigaki D, et al. Impact of skin cancer prevention on outdoor aquatics staff: the
Pool Cool program in Hawaii and Massachusetts. Prev Med 2001; 33(3):155– 161.
32. Glanz K, Geller AC, Shigaki D, et al. A randomized trial of skin cancer prevention in aquatics settings:
the Pool Cool program. Health Psychol 2002; 21(6):579– 587.
33. Glanz K, Steffen A, Elliott T, et al. Diffusion of an effective skin cancer prevention program: design,
theoretical foundations and first-year implementation. Health Psychol 2005; 24(5):477– 487.
34. Gooderham MJ, Guenther L. Impact of a sun awareness curriculum on medical students’ knowledge
attitudes and behaviour. J Cutan Med Surg 1999; 3(4):182– 187.
35. Liu KE, Barankin B, Howard J, et al. One-year follow-up on the impact of a sun awareness curriculum
on medical students’ knowledge, attitudes and behavior. J Cutan Med Surg 2001; 5(3):193– 200.
36. Gooderham MJ, Guenther L. Sun and the skin: evaluation of a sun awareness program for elementary
school students. J Cutan Med Surg 1999; 3(5):230– 235.
37. Barankin B, Liu K, Howard J, et al. Effects of a sun protection program targeting elementary school
children and their parents. J Cutan Med Surg 2001; 5(1):2– 7.
38. Oliveria SA, Christos PJ, Marghoob AA, et al. Skin cancer screening and prevention in the primary
care setting: national ambulatory medical care survey 1997. J Gen Intern Med 2002; 16(5):297– 301.
39. Mikkilineni R, Weinstock MA, Goldstein MG, et al. The impact of the basic skin cancer triage curri-
culum on provider’s skin cancer control practices. J Gen Intern Med 2001; 16(5):302– 307.
40. Girgis A, Sanson-Fisher RW, Watson A. A workplace intervention for increasing outdoor workers’ use
of solar protection. Am J Public Health 1994; 84(1):77– 81.
41. www.public health.sdsu.edu/communitymain/php.
42. Pichon LC, Mayer JA, Slymen DJ, et al. Ethnoracial differences among outdoor workers in key sun-
safety behaviors. Am J Prev Med 2005; 28(4):374– 378.
43. Azizi E, Flint P, Sadetzki S, et al. A graded work site intervention program to improve sun protection
and skin cancer awareness in outdoor workers in Israel. Cancer Causes Control 2000; 11(6):513– 521.
44. Shani E, Rachkovsky E, Bahar-Fuchs A, et al. The role of health education versus safety regulations in
generating skin cancer preventive behavior among outdoor workers in Israel: an exploratory photo-
survey. Health Promot Int 2000; 15:333 – 339.
45. Buller DB, Andersen PA, Walkosz BJ, et al. Randomized trial testing a worksite sun protection
program in an outdoor recreation industry. Health Educ Behav 2005; 32(4):514– 535.
46. Dietrich AJ, Olson AL, Sox CH, et al. Persistent increase in children’s sun protection in a randomized
controlled community trial. Prev Med 2000; 31(5):569– 574.
47. Miller DR, Geller AC, Wood MC, et al. The Falmouth Safe Skin Project: evaluation of a community
program to promote sun protection in youth. Health Educ Behav 1999; 26(3):369–384.
48. Hu S, Soza-Vento RM, Parker DF, et al. Comparison of stage at diagnosis of melanoma among
Hispanic, black and white patients in Miami-Dade County Florida. Arch Dermatol 2006; 142(6):
704 – 708.
49. Cockburn MG, Zadnick J, Deapen D. Developing epidemic of melanoma in the Hispanic population
of California. Cancer 2006; 106(5):1162 – 1168.
50. Lucas RM, Repacholi MH, McMichael AJ. Is the current public health message on UV exposure
correct? Bull World Health Organ 2006; 84(6):485– 491.
Section V: ULTRAVIOLET AND VISIBLE RADIATION THERAPY
22 Phototherapy with UVB: Broadband

and Narrowband
Michael Zanolli
Division of Dermatology, Vanderbilt University Medical Center, Vanderbilt University, Nashville,
Tennessee, U.S.A.
Peter M. Farr
Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, England, U.K.
B UVB continues to be a vital therapeutic option for treatment of skin

diseases.
B The most effective wavelength for treatment of psoriasis is within

the UVB range of ultraviolet light.
B The minimal erythema dose is important to determine for the most

effective and efficient use of UVB, especially with NBUVB.
B UVB effects can be enhanced with topical or systemic therapy when used
in combination treatment regimens.
B Diseases other than psoriasis can be effectively treated with UVB.

320 Zanolli and Farr
INTRODUCTION
he application of ultraviolet (UV) light B for the treatment of skin diseases illustrates the
T application of a natural process based on observation of its beneficial effect, followed by

further investigation and refinement of the delivery for practical use. The healing qualities
of terrestrial sunlight have been known for centuries. Sunlight has not only therapeutic effects
on inflammatory dermatosis such as psoriasis and eczematous dermatitis, especially the UVB
range of the UV light spectrum, but has essential functions which are adaptive for life on our
Earth.
This chapter is concerned with the application of UVB wavelengths and the medical
therapeutic effect on skin conditions and diseases. The discussion will include basic photo-
biology of the dosage and delivery of the various modalities incorporating UVB wavelengths,
and in what circumstances this therapeutic intervention may be most beneficial. It is the
opinion of the authors that the delivery of UVB radiation is not some obscure undefined
attempt at hopeful healing, but should be approached as delivery of a dose of radiation
containing a therapeutic window and based on current photobiologic principles and insight.
Previous decades have provided the basis for artificial sources of UVB to be used for
medical purposes, and we should continue its advancement by applying available technology
in conjunction with an enhanced insight into the photobiology of the skin and the cutaneous
immune system.
SOURCES OF UVB
Different Lamp Types
Sources used for whole body UVB phototherapy are now mainly fluorescent lamps, although
metal halide lamps may also be used for whole body use. Localized delivery of UVB wave-
lengths utilizes a xenon gas or a filamentous light source. Three broad types of fluorescent
lamp are available in addition to xenon gas sources of UV light:
1. Standard broadband (BB) UVB lamps (Fig. 1). These lamps, such as the TL-12 (Philips)
or FS40 (Westinghouse) are the archetypal BB lamps used for many years in phototherapy of
psoriasis. They have a broad spectral emission, with a significant component (5.5%) at
wavelengths less than 290 nm. With increased understanding of the wavelength-response
for clearance of psoriasis and subsequent clinical trials, it is clear that these lamps are not
the most efficient treatment sources currently available. Their usage is likely to be
limited, and with time may become obsolete, at least for treatment of skin disorders.
TL 12
1.0
0.8
Relative irradiance
0.6
0.4
0.2
0.0
250 260 270 280 290 300 310 320 330 340 350 360 370 380 390 400
Wavelength (nm)
FIGURE 1 The emission spectrum of a conventional broadband UVB fluorescent lamp (TL-12).
Phototherapy with UVB: Broadband and Narrowband 321
UV6
1.0
0.8
Relative irradiance
0.6
0.4
0.2
0.0
250 260 270 280 290 300 310 320 330 340 350 360 370 380 390 400
Wavelength (nm)
FIGURE 2 The emission spectrum of a selective broadband UVB fluorescent lamp (UV6).
2. Selective BBUVB lamps (Fig. 2) (1). These lamps, such as the UV6 (Sylvania) have been
available for many years. They also have a broad spectral emission, but with a significantly
smaller component (0.5%) at wavelengths less than 290 nm.
3. Narrowband (NB) UVB lamps (Fig. 3). The NBUVB lamp (TL-01, Philips) was introduced
in 1988, specifically to treat psoriasis (2). Unlike conventional fluorescent lamps, it has a
relatively narrow emission, with 87% at 311+2 nm and only 0.1% at wavelengths less
than 290 nm. The TL-01 lamp is now used widely in the United Kingdom, continental
Europe, and increasingly in the United States (3,4).
4. In addition to fluorescent lamps, which allow exposure of large areas of skin, a 308 nm
excimer laser has been used to treat individual plaques of psoriasis (5). Recently,
nonlaser 308 nm xenon chloride lamps have been developed (6). These can achieve high
irradiant values in the region of 50 mW/cm2 over a relatively wide area of 512 cm2.
Lamp Spectra
The lamp spectra is shown in the Figures 1– 3.
TL01
1.0
0.8
Relative irradiance
0.6
0.4
0.2
0.0
250 260 270 280 290 300 310 320 330 340 350 360 370 380 390 400
Wavelength (nm)
FIGURE 3 The emission spectrum of a narrowband UVB fluorescent lamp (TL-01).

UVB PHOTOTHERAPY—PSORIASIS
Action Spectrum for Clearance of Psoriasis
It is the potential for developing erythema in nonlesional skin, which limits the dose of UVB
that can be used for each treatment (7), lesional psoriasis being relatively resistant to develop-
ing erythema. The erythemal sensitivity of normal skin varies considerably within the UVB
waveband, and this needs to be taken into account when investigating the relative efficacy
of one wavelength for treating psoriasis compared with another. It is appropriate, therefore,
to compare response to different wavelengths (or lamps) using doses that are equivalent in
terms of the minimal erythema dose (MED).
Although it is often stated that wavelengths around 311 to 313 nm are the most effective at
clearing psoriasis, there is only limited evidence to support this assertion. In their early studies
of the UV wavelengths effective in clearing psoriasis, Fischer et al. (8) examined the efficacy of
discrete wavelengths from 254 to 405 nm. They demonstrated that radiation at 313 nm was
effective, particularly at higher doses. However, the investigators did not compare 313 nm
with other wavebands within the UVB region.
Parrish and Jaenicke (1) in their pioneering work on the action spectrum for clearance of
psoriasis studied the response to different wavelengths: 254, 280, 290, 296, 300, 304, and 313 nm.
They irradiated small areas of lesional skin on a daily basis, using various multiples of the
MED. No clearance of psoriasis was found with wavelengths of 290 nm or less at suberythemal
doses within the plaques of psoriasis. Clearance was achieved at wavelengths of between 296
and 313 nm without producing an observable erythema, with some suggestion of a better
response at 313 nm. However, only four patients were studied, and they were subsequently
found to have relatively treatment-resistant psoriasis.
It seems reasonable to conclude that wavelengths less than 290 nm, although highly
erythemogenic, are not effective at clearing psoriasis unless marked erythema is produced at
the treatment site, and that within the remainder of the UVB waveband (290 – 320 nm), there
is as yet insufficient evidence of differential efficacy (9). This information can be used to
predict the efficacy of different lamp types at treating psoriasis.
A conventional BBUVB lamp (such as the TL-12) emits 5.5% of its output at less than
290 nm, compared with around 0.5% for a selective UVB lamp (such as the UV6), and 0.1%
for a NB lamp (TL-01) (4). When the lamps’ spectra are weighted according to the erythema
action spectrum (10), the contribution to erythema from clinically ineffective radiation
,290 nm is 21.8% (TL-12), 6.9% (UV6), and 2.3% (TL-01).
A “phototherapy index,” based on the Parrish and Jaenicke (1) action spectrum, gives the
predicted efficacy of different lamp types at treating psoriasis (11). An index ,1 indicated
that doses greater than the MED would be required to clear psoriasis, whereas an index .1
indicated that clearance could be achieved with suberythemal doses. For minimal erythema
treatment doses, the calculated phototherapy indices were 0.6 (conventional BB), 1.3 (selective
BB) and 1.5 (NB) (11).
Minimal Erythema Dose

The MED is the designation for the production of pink erythema in response to delivery of UV
light. The utility of determining the MED is generally under-realized by those physicians who
treat patients having an inflammatory skin disease with any of the forms of UVB. Various
wavelengths of the UV light spectrum can produce erythema, and the wavelengths most
efficient at producing erythema are in the UVC range. UVA can also produce erythema if
given at high enough doses.
The determination of the MED from UVB wavelengths, whether BB or NB, has the most
therapeutic significance when incorporated into protocols that base dosing of UVB on the
MED. It is important to recognize that the skin does not have to turn pink or red to have a
therapeutic benefit from UVB phototherapy (12). It has been a longstanding observation,
however, that production of erythema within a plaque of psoriasis from any wavelength
may cause a clearing of the inflammatory skin disease (1). As a balance between the therapeutic
benefit and side effects of UV light, the best dose for whole body treatment should be below the
TABLE 1 Suggested Dosage for UVB Minimal Erythema Dose

Skin types I– III Skin types IV– VI
2
A. 20 mJ/cm 40 mJ/cm2
B. 30 mJ/cm2 50 mJ/cm2
C. 40 mJ/cm2 60 mJ/cm2
D. 50 mJ/cm2 70 mJ/cm2
E. 60 mJ/cm2 80 mJ/cm2
F. 80 mJ/cm2 100 mJ/cm2
burning threshold to reduce unwanted symptoms, but be aggressive enough to limit the
number of treatments and increase the efficacy.
The determination of a MED is dependent upon proper dosimetry of the phototherapy
device and wavelength used. The measurement of the dose must be matched to the wavelength
because if a photometer has optics designed for a broad spectrum of UVB, it will give an inac-
curate reading if applied to a set of lamps used to deliver NBUVB. The measurement of the
MED actually determines the dose – response to the UVB light delivered. The desired end
point is pink erythema with discernable edges. Table 1 provides the parameters for delivery
of graduated doses for BBUVB, whereas Table 2 provides the parameters for NBUVB doses.
The location of the body for testing of the MED should be the lateral hip or upper buttocks
areas. The MED will vary on different areas of the body if UVB hardening has occurred on
the forearm or sun-exposed areas, thus over-estimating the effects on more sun-protected
regions of the skin (13). The real benefit of having a known dose of BBUVB or NBUVB produ-
cing erythema is to more accurately estimate the dose with the least risk of a sunburn reaction.
This will allow the selection of a more accurate dose with the best therapeutic response for
delivery of whole body UVB or NBUVB, with fluorescent lamps and with localized delivery
of UVB to the affected skin.
Application of localized doses of UV to selected sites of involvement has been used more
frequently due to the availability of systems such as the excimer laser or high-fluence UVB
limited wavelength delivery. The MED is an essential part of the determination of dose since
the protocols developed thus far for targeted UVB treatment of inflammatory skin disease
depends upon using multiples of the MED to the site of active disease, most commonly
psoriasis (14). By utilizing the MED, the clinician has at least a defined parameter to proceed
with the treatment. Further refinement of the selection of the best dose for targeted therapy
of psoriasis will depend on more experience and dose –response prospective studies.
Currently, a multiple of four to six times the MED is used for the extremities and a multiple
of two to four times the MED is used for plaques of psoriasis on the trunk.
Treatment Regimens
Whole Body Treatment of Psoriasis (Table 3)
The application of UVB therapy is most often utilized for psoriasis. The treatment protocols for
other inflammatory skin diseases differ from psoriasis, and are addressed in a separate section
of this chapter. UVB has been a central part of treatment of psoriasis since the use of hot quartz
lamp in early Goeckerman and Ingram therapy (15,16). The hot quartz lamp has a discontinu-
ous emissions spectrum and high potential for sunburn reactions. Both treatment regimens
TABLE 2 Suggested Dosage for Narrowband-UVB Minimal Erythema Dose

Skin types I– III Skin types IV– VI
2
A. 200 mJ/cm 600 mJ/cm2
B. 400 mJ/cm2 800 mJ/cm2
C. 600 mJ/cm2 1000 mJ/cm2
D. 800 mJ/cm2 1200 mJ/cm2
E. 1000 mJ/cm2 1400 mJ/cm2
F. 1200 mJ/cm2 1600 mJ/cm2
TABLE 3 Whole Body Approach to UVB Treatment of Psoriasis

(Broadband and Narrowband)
General principles for UVB total body treatment for psoriasis
MED versus Fitzpatrick skin type to determine starting dose
Starting dose of 50–70% of MED
Frequency of 3 or 4 times/wk
Increase the dose by 10– 25% of the MED each treatment
Modification of the dose dependent upon clinical response
were very effective and produced long remissions when done properly and to the point of
clearing.
The main problems associated with the two previous therapies are the intensive special-
ized nursing time and the duration of the daily treatments. These are best delivered in a
Dermatology inpatient hospital service with seven day a week therapy. Very few centers are
able to deliver true Goeckerman or Ingram therapies, and they have been modified to be
more convenient and more conducive to outpatient therapy. Modification of the treatment
regimens occurred with the advancement of the delivery of UVB with fluorescent lamps and
moved to the outpatient setting or Day Care Center (17). Nonetheless, daily treatment is the
best approach, but the time off required from work and/or away from family, coupled with
the excessive expense of the treatment, led to a decline in its utilization. In the 1980s and
1990s, more and more emphasis was placed on office-based delivery of UV therapy including
photochemotherapy with psoralen and UVA light (PUVA).
The next step in advancement of UVB treatment of psoriasis has been the advent of a
reduced potential for erythema, which was the most frequent limiting side effect for completion
of a course of treatment. The use of lamps with emissions in an NB wavelength helped
maximize the therapeutic effects of UVB, although not containing a significant amount of
wavelengths less than 300 nm, which will cause a phototoxic effect on the skin due to direct
immediate injury. The uses of lamps or devices, which have either NB or limited wavelengths
within the UVB region, are the current UV treatment of choice for psoriasis in an office setting.
BBUVB can be used very effectively and is still very prevalent in the United States as the
treatment modality for physicians who have had the availability of UVB equipment prior to
the year 2000. Currently, however, the great majority of UVB treatment devices being sold
to Dermatologists are NBUVB, at least in North America (personal survey of UVB device
manufacturers in 2005).
There are actually very few accepted protocols for treatment of psoriasis, whether with
BBUVB or NBUVB. The one variable that can be utilized and at least gives an anchoring
data point is the MED. The most accurate and reliable protocols for delivery of UVB depend
on obtaining a MED prior to therapy. The initial dose of UVB light can then be determined.
Subsequent doses of UV light are most commonly calculated as an increase based on a percen-
tage of the initial MED. The alternative is to estimate a safe starting dose of UVB based on the
Fitzpatrick skin type (18).
An example of the use of the MED as a starting point with a conservative protocol is:
if a patient has a determination of an MED for NBUVB at 600 mj/cm2, the first dose may be
300 mj/cm2 or 50% of the MED. A common factor by which to increase the dose is 10% of
the MED. This simple calculation by the phototherapy technician would yield a second dose
of 300 þ 60 ¼ 360 mj/cm2. The third dose, if no redness occurs over a two-day time span,
would be 360 þ 60 ¼ 420 mj/cm2. Please note that due to the wider spectrum of the BBUVB
lamp and the dosimetry used to measure the flux of the lamp, the dosages for BBUVB are
dramatically different than for NBUVB.
The frequency of treatments is another variable parameter at different phototherapy
centers. In general, the frequency of the traditional BBUVB treatment is five times per week.
The advent of NBUVB has brought with it attempts to make this mode of therapy as accessible
as possible. Studies comparing treatment rates of five times per week versus three times per
week demonstrated a slight difference, but it was not statistically significant (19). This
information, coupled with the attempt to minimize travel and time away from work, have led
many centers to schedule NBUVB treatments three times per week. It should be noted that less
than three times per week usually does not bring about the induction of a sufficient initial
response or progressive clearing and the treatment series would be inadequate. In general,
the frequency of treatment using NBUVB is either three or four times per week (scheduled
Monday, Wednesday, Friday or Monday, Tuesday, Thursday, Friday).
A third major consideration of a regimen for treatment with either BBUVB or NBUVB is the
monitoring of the progress by the phototherapy technician and the physician. Progress should be
apparent from the first week onward. If the treatment’s aggressiveness is too modest, no
improvement will be appreciated and an increase in the dose increment should be implemented.
Conversely, modification of the advancement of the dose or even a reduction of the dose should
occur, if the patient displays redness or reports redness between treatments. If a patient is still red
48 hours following the previous treatment, whether from BBUVB or NBUVB, the treatment
should be postponed and the patient re-evaluated in 24 to 48 hours. The need for monitoring
of the patient and adjustment of the treatment schedules point toward the invaluable function
of the phototherapy technician and the benefits of having the phototherapy center within or
in close proximity to the general clinic or a location easily accessible by the clinician.
With any sort of longitudinal treatment regimens, such as treatments with UVB, a treat-
ment flow sheet is essential for documentation and determination of the next dose. Documents
such as consent forms, flow sheets, guidelines for treatment schedules, and dosage of either
BBUVB or NBUVB are available in a manual and can be modified by the attending physician,
depending on the individual response of each patient (18).
Localized UVB Treatment for Psoriasis (Table 4)

The use of NBUVB for total body treatment has been an advancement for outpatient photother-
apy for psoriasis. Application of existing technology in the form of the excimer laser at 308 nm
for the localized treatment of psoriasis was used and found to be beneficial (5,14). There are
major differences in the treatment with localized UVB to the areas of psoriasis as compared
to the whole body UVB treatment. The most important of which is the dosing schedule
being adapted for use and undergoing development over the past few years (20). The
overall approach is for high dose localized treatment limited to the areas of resistant psoriasis.
This treatment schedule is dependent upon obtaining the MED for the wavelength and
delivery system used. There are still clinical modifications necessary to have determination
of the best multiple of the MED for which area of the body, but the extremities tolerate four
to six times the MED within plaques of psoriasis with some crusting and blistering to be
expected. The benefit of just treating the resistant psoriasis is to spare the clinically uninvolved
skin the dose of the UV light and thus the potential for long-term UVB injury. Other more
recent devices have been developed for treatment of localized areas in addition to the laser
light, such as a xenon gas light source emitting light at 308 nm, but with asynchronous light
and a filamentous light source with a spectrum of UVB from 300 to 320 nm as the peak emis-
sion. The spot size for the laser delivery of UVB light isTMsmall at 1.8 cm2 as is the device
TM
with the
filamentous light source manufactured by Theralight . The hand held Excelite system has
variable sized ports up to 8 cm2, which has more utility in certain circumstances. Due to the
high doses used and the therapeutic effects on the psoriasis skin, the average treatment
course of localized UVB consists of 6 to 10 treatments. Prospective studies regarding the use
TABLE 4 Localized Approach to UVB Treatment of Psoriasis

General Principles for UVB Localized Treatment of Psoriasis
MED necessary
Multiples of the MED used for treatment
Fewer treatments needed
Local side effects expected
Frequency of once or twice a week
Modification of the dose dependent upon clinical response
of high dose localized UVB have reported fewer number of treatments and longer remission
times than with conventional total body NBUVB therapy (21).
Side Effects of UVB Therapy

Acute
The most obvious potential side effect of UVB phototherapy is the development of erythema or
“sunburn.” A degree of erythema is to be expected from time to time during a course of photo-
therapy, as treatment regimes frequently employ dose increments until erythema is achieved.
The dose –response curve for erythema is steep and appears identical for both BB and NBUVB
lamps (22); a risk of unpleasant burning is apparent at doses greater than the MED. The time-
course of erythema is also identical for NB and BB lamps, peaking at around 12 hours. There is
no published evidence to support the stated view that NB lamps have less burning potential
than other sources. Because of the time-course of UVB erythema, treatments are not normally
given more frequently than once daily.
A curious but infrequent side effect of NBUVB phototherapy of psoriasis is lesional blis-
tering. The blisters are painful, often multiple, and not necessarily associated with erythema.
It has been suggested that they may be due to excessive apoptosis induced by UVB within
the plaque of psoriasis (23). An in depth discussion of the acute effects of UV radiation on
the skin can be found in chapter 6 of this textbook.
Risk of Skin Malignancy With UVB Phototherapy

Although an increased risk of skin malignancy, particularly nonmelanoma skin cancer is pre-
dicted with UVB phototherapy, epidemiologic studies to date have failed to show any con-
sistent significant risk (24). This may be due partly to the small size of the study
populations and often relatively short follow-up. However, another factor may be that the
BBUVB lamps available at the time of these studies were of insufficient efficacy to be used
repeatedly as monotherapy for large numbers of patients and, therefore, cumulative UVB
doses have remained relatively small. With the development of more effective sources, par-
ticularly NBUVB lamps, phototherapy is increasingly being used as a first-line treatment
for patients with moderate psoriasis, and individual patients are likely, as was the case
with PUVA, to have repeated courses of treatment and accumulate high lifetime UVB
doses. A further point of concern is the possibility that NBUVB lamps may be more carcino-
genic than the BB lamps they have largely replaced. Young (25) summarized data from
murine studies (26– 28) as indicating that NBUVB may be two to three times more carcino-
genic per MED than BBUVB. It was suggested (25) that any increased cancer risk would
be negated by the increased efficacy of NBUVB. However, although clinical trials have
shown that NBUVB is more effective than BBUVB, the actual differences in response to treat-
ment are relatively small. Therefore, the relative risk of NBUVB phototherapy compared to
BB will remain uncertain until long-term follow-up studies become available, as was the
case with psoralen photochemotherapy (29). Presently available follow-up data (30,31) is of
too short duration to be definitive.
Another method of predicting risks of nonmelanoma skin cancer from UVB photother-
apy is to extrapolate from murine phototumorigenesis models. Diffey (32) has estimated
that eight annual whole body treatment courses, each of 25 exposures, would increase the
relative risk of skin cancer compared with a nontreated individual by a factor of 1.2. This
model presents an estimate of average risk that will clearly be modified by skin type
and other susceptibility factors, and makes an assumption that TL-01 radiation is no more
carcinogenic than sunlight for the same erythemal exposure. Nevertheless, in the absence of
epidemiologic data, this sort of modeling may allow explanation to patients of potential
risks of repeated courses of phototherapy.
Combination Therapy
Topical
The combination of topical therapies used in the treatment of psoriasis and UVB is so common,
it is considered routine. Insight must be utilized, however, because the chemical composition
of certain topical agents may either alter the effects of the dose of UVB on the skin, or the
chemicals in the topical agent may be altered. The most salient example of a common topical
chemical used in the treatment of psoriasis and alteration of the dose of UVB is salicylic
acid. It is common for a patient to use some sort of keratolytic agent to reduce scale thickness
overlying plaques of psoriasis. The use of a lotion or cream containing salicylic acid may be
unknown to the phototherapist or clinician, unless specifically inquired about. The problem
with concomitant use of salicylic acid and UVB is its significant photoabsorbant properties
in the UVB spectrum. Salicyclic acid has been used just for this property in some sunscreens.
Thus, the amount of UVB, whether BBUVB or NBUVB, actually reaching the epidermis
would be much lower than the delivered dose. The result would be an inadequate response
due to under treatment, or a variable response from one treatment to another depending
upon the presence of the topical lotion on any particular day. Unexpected phototoxic reactions
may occur in that instance. The problem can be avoided if the salicyclic acid is applied after the
delivery of UVB.
Topical therapy immediately preceding the delivery of UVB should be consistent, and
used to enhance the therapeutic effect by promoting better penetration of the UV radiation
into the skin or by the combination of a different therapeutic effect of the topical medications.
As part of the standard protocol for delivery of UVB light in a referral center or a practitioner’s
office, a petroleum-based topical agent should be used prior to treatment on the area of psor-
iasis. Simple mineral oil will suffice and does not have additives that may alter the desired
effects. The purpose for standard use of mineral oil is to help decrease the air-keratin interfaces
through which the light must travel prior to entering the stratum granulosum and then the
lower epidermis. This is especially important for treatment of psoriatic plaques having the
appearance of a white micaceous scale on their surface. Each time light passes from the air
and hits the surface of the keratin of a scale, a small portion of that light is reflected leaving
less energy to penetrate the skin. Saturating the top layer of the plaque of psoriasis with
mineral oil, or other petrolatum product, will reduce this reflectance and thereby increase
the percentage of delivered light that will actually reach the site of action.
Traditionally, the combination of UVB with tar and anthralin under occlusion has
been used with great success for treating psoriasis. The Goeckerman therapy uses crude
coal tar from 2% to 5%, and the Ingram method uses increasing concentrations of anthralin
paste over the plaques of psoriasis in combination with UVB. These two treatments have
been mentioned earlier in the chapter and require specialized facilities and using care to
execute (22).
The main categories of other topical psoriasis therapy can all be used in conjunction
with UVB phototherapy. They are: corticosteroids, topical calcipotriene, topical retinoids,
and topical calcineurin inhibitors. The basic principles of combining a topical agent with
UVB apply to all these classes of medication. If the mechanism of action of any of the topical
agents can help promote less scaling and a thinning of the plaque of psoriasis, the induction
and effect of the UVB will be enhanced.
Certain combinations of topical therapy with UVB are worth special comment. Calcipo-
triene can cause an alteration in the MED (33) and should not be used immediately prior to
UV therapy. However, the combination of calcipotriene twice a day with only two days of
UVB per week were equal to the treatment with UVB alone three days per week (34). Likewise,
the topical retinoid tazaratene, when used with UVB, was more effective in a shorter time
period and using a lower total dose than UVB treatment alone or UVB plus the vehicle of
the gel used for tazorotene (35). Recently, application of the topical anti-inflammatory calci-
neurin inhibitors for treatment of specialized locations, such as eyelids and body folds, has
become more prevalent. Small body surface areas (BSAs) and limited use in areas not routinely
exposed to UV light would be the most prudent course of utilization due to in vitro cell culture
inhibition of UV-induced DNA repair (36). Widespread and large BSA use of these agents in
combination with UVB needs further investigation.
Systemic
Patient selection is important when considering the combination of a systemic agent and the
various modalities of therapeutic UVB. Various systemic agents effective for psoriasis treat-
ment have appreciable immunosuppressive effects, which have to be considered when
adding another form of therapy with known direct effects on the skin’s immune mechanisms
and a potential increased risk of skin cancers. Of course, these effects and resultant changes in
the balance of the cytokine environment are some of the primary reasons for the effects when
treating a patient with psoriasis vulgaris. Specifically, patients who require suppression of
their immune regulation because of organ transplantation have a higher incidence of skin
cancer formation and UVB needs to be used with caution. Patients who have an increased
risk of developing skin cancer, such as long-term PUVA patients or individuals with a
history of multiple nonmelanoma skin malignancies, should not have the combination of
cyclosporine and UVB. Even if caution is warranted, there are systemic agents used in combi-
nation with UVB, which enhance the overall response and may help to reduce the overall total
dose and number of treatments necessary for adequate response.
The combination therapy with the most evidence of an enhanced therapeutic effect is
systemic retinoid plus UVB light (37 –39). To maximize the effectiveness of this combination
treatment, the systemic retinoid should be initiated two weeks prior to the start of UVB treat-
ment. This allows the retinoid to have effects on the psoriatic plaques, including a decrease in
the thickness and a decrease in surface scaling (40). This combination has comparable efficacy,
although demonstrating a reduction in the number of UVB treatments and total dose of
irradiation required when compared to UVB alone. The systemic retinoid may be added to a
treatment course already in progress, but a reduction or holding of the UVB dose should be
established for two weeks while the retinoid effect on the skin is realized. This caution is rec-
ommended to avoid unexpected phototoxic reactions after the addition of the retinoid. When
used in combination with UVB, the dose of the retinoid may be reduced as compared to a
monotherapy dose schedule (41).
UVB can be combined with other systemic agents, including the new generation of
protein and antibody immune modifiers. However, well-controlled long-term data for the
use of this particular combination are not yet available. In contrast, the success of using the
combination of methotrexate and UVB has been established (42). An uncommon potential
problem with the use of methotrexate and UVB is a severe reaction to a phototoxic side
effect in a patient who has had a previous sunburn or redness from UVB or sunlight. Cyclos-
porin is a very effective agent as a monotherapy and has been used to help decrease the activity
of psoriasis as a short-term agent followed by maintenance with UVB modalities (43).
Long-term use of this combination has a high theoretical risk of a marked increased incidence
of nonmelanoma skin cancer with UVB and a reported increased risk with PUVA (44).
Home UVB
The utilization of home delivery of UVB therapy, particularly NBUVB is increasing. Two
important parameters must be kept in mind when considering the option of home light
therapy. First, UVB home units are not designed for tanning. A home unit for treatment of psor-
iasis and other inflammatory skin diseases is a medical device only available by prescription.
There exists misconceptions by some physicians on the general nature of UV delivery systems,
and tanning parlor operators may at times misrepresent the efficacy of the UVA units they use
for tanning and make claims for treatment of skin diseases. A home UVB device should be used
as medical device for treatment of skin disease under the supervision of a Dermatologist.
Secondly, patient selection is vitally important for the best results and to decrease the
potential misuse of the home unit. Not every patient is a good candidate for home UVB
therapy just as not every patient should receive a TNF alpha inhibitor for treatment of psoriasis.
Characteristics most consistent with the proper use and prescription of home units for patients
with psoriasis are compliance, demonstrated efficacy to BBUVB or NBUVB previously, and no
relative contraindications for use of UVB whether in the office or home. Those patients selected
for home UVB therapy need to be able to follow the instructions given to them by the physician
and/or phototherapy technician. It is also preferable to require such patients to keep a log of the
treatments as is done in an office or treatment center.
Even though a thoughtful process should be undertaken when considering a patient
for home phototherapy, many patients prefer the convenience and time-saving aspects of a
home unit (45). With the advent of home unit utilization and the NBUVB wavelengths used
in the Tl-01 Lamp, a pilot study of a relatively small number of subjects had good results and
was compliant with the protocols (46). There is a need, however, to further explore the degree of
actual compliance and effectiveness of home NBUVB when not delivered by trained personnel
(47).
The notion that the use of commercial tanning parlors could be used for patients when
travel and time to the office or center is inconvenient or not possible has been entertained.
Tanning lamps with 99.3% of UVA output do not show any statistical benefit over a control
of commercial florescent lamps for home or office use (48). Even with the application of
tanning lamps with 4.7% of UVB, which has some therapeutic effect on psoriasis, the variability
and inconsistency of the delivery and monitoring of the output of lamps make the use of
tanning facilities substandard as a medical treatment (49).
Treatment regimens associated with home NBUVB therapy have not been standardized.
As a practical matter, the measurement of MED and treatment based on the MED is not feasible.
Therefore, assignment of a Fitzpatrick skin type and calculation of a starting dose based on the
irradiance of the unit (easily obtained from the manufacturer) is the usual approach to the
protocol. Maintenance of therapy is dependent upon the judgment of the clinician and can
be done during the winter months at once a week frequency. A vacation from treatment with
artificial sources of UVB is usually given during the summer months.
UVB PHOTOTHERAPY—OTHER DISORDERS

The application of UVB phototherapy for other skin diseases and conditions has been a natural
development and extension of the use of phototherapy for psoriasis. The observation of the
efficacy for selected diseases, and in some cases prospective clinical trials, has been the basis
for considering UVB phototherapy as an accepted practice and therapeutic option. The case
studies and isolated reports of the beneficial effects for a particular inflammatory skin disorder
or a T-cell proliferative diseases are many. The degree of prospective controlled trials regarding
diseases other than psoriasis are few compared to the list of diseases reported as responding to
UVB phototherapy. The advent of NBUVB over the past 10 years can serve as a model for
how reporting of studies and experiences lead to the induction of a therapy into the accepted
practice of dermatology. Hundreds of reports relating the application of NBUVB to other
dermatoses have been critically reviewed (50). Less than five percent of the reviewed articles
met the stringent criteria of a consistent adequate protocol with a sample size and control
group incorporated into the experience enabling interpretation of the reported results with a
high degree of confidence. Part of this dilemma is the frequency of the diseases being
treated with UVB does not provide a large sample size or an adequate cohorts of patients
able to participate in a prospective study. Thus, many of the reports on efficacy are of a
small sample size and accumulated over time rather than a coordinated clinical trial.
There is a definite list of skin disorders, which have both the common experience
and consistently favorable response coupled with reliable data to form a basis for treatment
with UVB therapy, whether BBUVB or NBUVB (Table 5). Other inflammatory disorders
certainly can have a favorable response to treatment with UVB, but the implementation of
a treatment plan depends upon the individual established protocols extrapolated from other
TABLE 5 List of UVB Responsive Dermatosis

Atopic Dermatitis
Vitiligo
CTCL
PMLE
Pruritus
Other
Lichen Planus
Granuloma Annulare
Acquired Perforating Disorders
Urticaria
Abbreviations: CTCL, cutaneous T cell lymphoma; PMLE, polymorphous light eruption.
diseases or from personal experience. In general, the application of UVB for disorders other than
psoriasis is based upon suberythemogenic doses of BB or NB UVB. Progression and frequency of
the treatment are based upon the clinical response and a physician’s previous experience for the
less frequently treated disorders. Short discussion regarding the application of UVB therapy to
diseases with the strongest foundation of evidence and experience follow.
Atopic Dermatitis (Atopic Eczema)

Use of UVB therapy for atopic dermatitis can be a very helpful addition to the treatment
approach (51). Phototherapy treatment is especially relevant to those children and adolescents
who have been maintained on topical corticosteroids with a high degree of BSA involvement.
One of the difficulties relevant to the treatment of atopic dermatitis with broad-spectrum UVB
lamps is the inclusion of more erythemogenic wavelengths below 300 nm. There is a variable
response to low wavelength UVB on the skin of atopic patients, which may result in uneven
erythema. The erythema and/or smarting reaction is a common concern and a limiting
factor for treatment with BBUVB. Open prospective studies (52,53) showed improvement of
eczema with NBUVB, and this was confirmed in a randomized trial comparing NBUVB,
BBUVA, and “placebo” visible light (54). The treatment protocol for atopic dermatitis treated
with NBUVB is usually twice a week, but up to three times a week can be done. Treatment
protocols adopted at various centers are generally based upon selection of the Fitzpatrick
skin type. Precautions and concerns are necessary to help modify the occurrence of other
acute side effects of UVB therapy, such as provocation of herpes simplex in an atopic
individual. Other forms of phototherapy, including UVA1, may also be used to treat eczema
effectively (see Chapter 23) (55).
Vitiligo
Vitiligo was the most frequently NBUVB treated disease, excluding psoriasis, reported in a
review of the experience of a major U.S. phototherapy referral center (56). Many types of photo-
therapy have been used to treat vitiligo, such as PUVA, topical PUVA, BBUVB, and NBUVB
(57). The application of UVB therapeutic modalities remain a mainstay of treatment due to
their simplicity and recently the additional availability of localized delivery systems to treat
the affected areas of depigmentation (58). The localized delivery systems have the advantage
of only treating diseased skin and also offers less potential for development of acute and
long-term side effects. A bilateral comparison trial showed a clear therapeutic benefit of
the use of standard delivery of NBUVB versus the control side (59,60). A critical review of
the reports for treatment of vitiligo with phototherapy options in comparison trials concluded
the efficacy, benefit/risk profile, and cost of NBUVB made it the primary choice for photo
(chemo)therapeutic options for the disease (50).
The approach to treatment with NBUVB for vitiligo is to treat the patient as if they had
type I Fitzpatrick response to UV. Therapy is usually two to three times weekly with initiation
of the dose at either 50% to 70% of the average NBUVB MED for type I skin, which is reported
as 400 mj/cm2 (61). The usual number of treatments as compared to atopic dermatitis is high
and the treatment course may last years as long as there is continued gradual improvement.
Cutaneous T Cell Lymphoma

Phototherapy of various modalities has been used to treat early stage cutaneous T cell lym-
phoma (CTCL) with good response. PUVA therapy has been used with high rates of clear-
ance for early stage CTCL (62). More recent investigations and experience helps define the
role of NBUVB for treatment of stage IA and IB CTCL specifically (63). Comparison trials
of the use of psoralen combined with UVB and NBUVB versus NBUVB alone have been
done to add insight into the patient selection and therapeutic response for early stage
CTCL (64).
The duration of remission is an important concern for any modality of treatment for
CTCL. The induction of a remission whether partial or complete can be obtained with photo-
therapy in stages IA, IB, and in IIA in the majority of the cases. The maintenance of response has
been associated with the use of PUVA as the best modality of phototherapy, but now there is
more experience with the use of NBUVB. Longer termed longitudinal studies are needed for
confidence in the maintenance of the response.
Polymorphous Light Eruption

UV light has been utilized to treat various forms of photosensitivity disorders, including poly-
morphous light eruption (PMLE) (65). The approach to treatment of PMLE with UVB has been
to gradually increase a suberythemogenic dose to induce a tolerance to UVB, prior to the spring
and summer seasons. This approach is termed hardening and helps permit normal amounts of
natural sunlight with less activation of the PMLE in affected individuals. A prospective
comparison trial of PUVA versus NBUVB in individuals with PMLE showed both to be
highly effective in preventing symptoms of the disease (66). The optimal approach to treatment
of PMLE with UVB requires the determination of an MED to start treatment at a tolerable dose
of UVB between 50% and 70% of the MED, followed by gradual increase of 10% of the MED or
as tolerated by the patient.
Pruritus
Pruritus can be induced as a sign of internal disease or as an associated symptom of an
inflammatory skin disease. Examples of pruritus as a symptom of a skin disease include
atopic dermatitis, contact dermatitis, lichen planus, psoriasis, among many others. The use
of UVB light in this type of circumstance is directed at treatment of the underlying dermatolo-
gic disease. Treatment of pruritus related as a symptom of chronic renal failure, polycythemia
vera, lymphoma, or other internal causes of pruritus has been accepted as an effective treat-
ment (67).
The application of BBUVB for treatment of pruritus associated with renal disease is
expected to provide significant relief from the symptom and has been recognized as more
effective than placebo over 25 years ago (68). Various protocols to treat pruritus associated
with the underlying disease both with using MED or estimating a skin type is available
(18,67). In either method used, it is apparent a suberythemogenic dose of UVB or NBUVB is
adequate for response at a frequency of twice a week.
Other
There are various other inflammatory disorders reported to be responsive to BBUVB or
NBUVB. These include lichen planus, granuloma annulare, acquired perforating disorders,
and urticaria. As more experience and clinical data is available regarding the expected
response and protocols which best treat each of the disorders, the clinician may apply the
same principles regarding suberythemogenic BB or NBUVB as with other nonpsoriasis dis-
eases. These disorders are included in the review of NBUVB treatment of skin disease
beyond psoriasis (50).
REFERENCES
1. Parrish JA, Jaenicke KF. Action spectrum for phototherapy of psoriasis. J Invest Dermatol 1981;
76(5):359– 362.
2. van Weelden H, De La Faille HB, Young E, van der Leun JC. A new development in UVB photo-
therapy of psoriasis. Br J Dermatol 1988; 119(1):11 – 19.
3. Zanolli M. Phototherapy treatment of psoriasis today. J Am Acad Dermatol 2003; 49(suppl 2):
S78 –S86.
4. Ibbotson SH, Bilsland D, Cox NH, et al. An update and guidance on narrowband ultraviolet B
phototherapy: a British Photodermatology Group Workshop Report. Br J Dermatol 2004;
151(2):283–297.
5. Bonis B, Kemeny L, Dobozy A, et al. 308 nm UVB excimer laser for psoriasis. Lancet 1997; 350:1522.
6. Aubin F, Vigan M, Puzenat E, et al. Evaluation of a novel 308-nm monochromatic excimer light deliv-
ery system in dermatology: a pilot study in different chronic localized dermatoses. Br J Dermatol
2005; 152(1):99– 103.
7. Speight EL, Farr PM. Erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA.
Br J Dermatol 1994; 131(5):667– 672.
8. Fischer T, Alsins J, Berne B. Ultraviolet-action spectrum and evaluation of ultraviolet lamps for
psoriasis healing. Int J Dermatol 1984; 23(10):633– 637.
9. Farr PM, Diffey BL. Action spectrum for healing of psoriasis. Photodermatol Photoimmunol Photo-
med 2006; 22(1):52.
10. McKinlay AF, Diffey BL. A reference action spectrum for ultraviolet induced erythema in human
skin. CIE J 1987; 6(1):17– 22.
11. Diffey BL, Farr PM. An appraisal of ultraviolet lamps used for the phototherapy of psoriasis. Br J
Dermatol 1987; 117(1):49– 56.
12. Hofer A, Fink-Puches R, Kerl H, Wolf P. Comparison of phototherapy with near vs. far erythemo-
genic doses of narrow band ultraviolet B in patients with psoriasis. Br J Dermatol 1998; 138:
96 – 100.
13. Olson RL, Sayre RM, Everett MA. Effects of anatomic location and time on ultraviolet erythema. Arch
Dermatol 1996; 93:211 – 215.
14. Asawanonda P, Anderson RR, Chang Y, Taylor CR. 308 nm excimer laser for the treatment of
psoriasis: a dose-response study. Arch Dermatol 2000; 136(5):619– 624.
15. Goeckerman WH. The treatment of psoriasis. Northwest Med 1925; 24:229– 231.
16. Ingram JT. The approach to psoriasis. Br Med J 1953; 2:591 – 594.
17. Mentor A, Cram DL. The Goeckerman regimen in two psoriasis day care centers. Arch Dermatol
1968; 98:178– 182.
18. Zanolli M, Feldman SR, eds. In: Phototherapy Treatment Protocols for Psoriasis and Other Photother-
apy Responsive Dermatosis. 2nd ed. London: Taylor and Francis Press, 2005.
19. Dawe RS, Wainright NJ, Cameron H, Ferguson J. Narrowband ultraviolet B phototherapy for
chronic plaque psoriasis: three times or five times weekly treatment? Br J Dermatol 1998;
138:833– 839.
20. Trehan M, Taylor CR. High dose 308 nm excimer laser for the treatment of psoriasis. J Am Acad
Dermatol 2002; 46:732– 737.
21. Feldman SR, Mellem BG, Housman TS, et al. Efficacy of the 308 nm excimer laser for treatment of
psoriasis: Results of a multicenter study. J Am Acad Dermatol 2002; 46:900– 906.
22. Das S, Lloyd JJ, Farr PM. Similar dose-response and persistence of erythema with broad-band and
narrow-band ultraviolet B lamps. J Invest Dermatol 2001; 117(5):1318– 1321.
23. Calzavara-Pinton PG, Zane C, Candiago E, et al. Blisters on psoriatic lesions treated with TL-01
lamps. Dermatology 2000; 200(2):115 – 119.
24. Lee E, Koo J, Berger T. UVB phototherapy and skin cancer risk: a review of the literature. Int J
Dermatol 2005; 44(5):355– 360.
25. Young A. Carcinogenicity of UVB phototherapy assessed. Lancet 1995; 345:1431– 1432.
26. Flindt-Hansen H, McFadden N, Eeg-Larsen T, et al. Effect of a new narrow-band UVB lamp on photo-
carcinogenesis in mice. Acta Derm Venereol 1991; 71(3):245– 248.
27. Wulf HC, Hansen AB, Bech-Thomsen N. Differences in narrow-band ultraviolet B and broad-
spectrum ultraviolet photocarcinogenesis in lightly pigmented hairless mice. Photodermatol Photo-
immunol Photomed 1994; 10(5):192– 197.
28. Gibbs NK, Traynor NJ, MacKie RM, et al. The phototumorigenic potential of broad-band (270–
350 nm) and narrow-band (311 – 313 nm) phototherapy sources cannot be predicted by their edema-
togenic potential in hairless mouse skin. J Invest Dermatol 1995; 104(3):359– 363.
29. Stern RS, Lange R. Non-melanoma skin cancer occurring in patients treated with PUVA five to ten
years after first treatment. J Invest Dermatol 1988; 91(2):120– 124.
30. Weischer M, Blum A, Eberhard F, et al. No evidence for increased skin cancer risk in psoriasis patients
treated with broadband or narrowband UVB phototherapy: a first retrospective study. Acta Derm
Venereol 2004; 84(5):370– 374.
31. Man I, Crombie IK, Dawe RS, et al. The photocarcinogenic risk of narrowband UVB (TL-01) photo-
therapy: early follow-up data. Br J Dermatol 2005; 152(4):755– 757.
32. Diffey BL. Factors affecting the choice of a ceiling on the number of exposures with TL01 ultraviolet B
phototherapy. Br J Dermatol 2003; 149(2):428– 430.
33. Lebwohl M, Quijije J, Gillard J, et al. Topical calcipotriol is degraded by ultraviolet light. J Invest
Dermatol 2003; 121(3):594– 595.
34. Ramsay CA, Schwartz BE, Lowson D, et al. Calcipotriene cream combined with twice weekly broad
band UVB phototherapy: a safe, effective and UVB sparing antipsoriatic combination therapy. The
Canadian Calcipotriol and UVB Study Group. Dermatology 2000; 200:17 – 24.
35. Koo J, Lowe N, Lew-Kaya D, et al. Tazarotene plus UVB in the treatment of psoriasis. J Am Acad
Dermatol 2000; 43:821– 828.
36. Yarosh DB, Pena AV, Nay SL, et al. Calcineurin inhibitors decrease DNA repair and apoptosis
in human keratinocytes following ultraviolet B irradiation. J Invest Dermatol 2005; 125(5):
1020 – 1025.
37. Fritsch PO, Höningsmann H, Jaschke E, et al. Augmentation of oral methoxsalen photochemotherapy
with an oral retinoic acid derivative. J Invest Dermatol 1978; 70:178– 182.
38. Iest J, Boer J. Combined treatment of psoriasis with acetretin and UVB phototherapy compared with
acetretin alone and UVB alone. Br J Dermatol 1989; 120:665– 670.
39. Green C, Lakshmipathi T, Johnson BE, Ferguson J. A comparison of the efficacy and relapse rates of
NBUVB (TL-01) monotherapy vs etretinate (re-TL-01) vs etretinate PUVA (re-PUVA) in the treatment
of psoriasis patients. Br J Dermatol 1992; 127:5– 9.
40. Lowe N, Prystowsky JH, Bourget T, et al. Acetretin plus UVB therapy for psoriasis: Comparisons with
placebo plus UVB and acetretin alone. J Am Acad Dermatol 1991; 24:591– 594.
41. Lebwohl M, Drake L, Menter A, et al. Consensus conference: acitretin in combination with UVB or
PUVA in the treatment of psoriasis. J Am Acad Dermatol 2001; 45(4):544– 553.
42. Paul BS, Monitaz K, Stern RS, et al. Combined methotrexate ultraviolet B therapy in the treatment of
psoriasis. Am Acad Dermatol 1982; 7:758 –762.
43. Koo J, Bandow G, Feldman SR. The art and practice of UVB phototherapy for the treatment of
psoriasis. In: Weinstein GD, Gottlieb AB, eds. Therapy of Moderate to Severe Psoriasis. New York:
Marcel Dekker Inc., 2003.
44. Oxholm A, Thomsen K, Menne T. Squamous cell carcinomas in relation to cyclosporine therapy of
non malignant skin disorders. Acta Derm Venereol (Stock) 1989; 69:89– 90.
45. Feldman SR, Clark A, Reboussin DM, Feischer AB. An assessment of potential problems of home
phototherapy treatment of psoriasis. Cutis 1996; 58(1):71– 73.
46. Cameron H, Yule S, Moseley H, et al. Taking treatment to the patient: development of a home TL-01
ultraviolet B phototherapy service. Br J Dermatol 2002; 147(5):957– 965.
47. Koek MB, Buskiens E, Bruijnzeel-Koomen CA, Sigurdsson V. Home ultraviolet B phototherapy for
psoriasis: discrepancy between literature, guidelines, general opinions and actual use. Results of a
literature review, a web search, and a questionnaire among dermatologists. Br J Dermatol 2006;
154(4):701–711.
48. Turner RJ, Walshaw D, Diffey BL, Farr PM. A controlled study of ultraviolet A sunbed treatment of
psoriasis. Br J Dermatol 2000; 143(5):919– 920.
49. Su J, Pearce DJ, Feldman SR. The role of commercial tanning beds and ultraviolet A light in the treat-
ment of psoriasis. J Dermatolog Treat 2005; 16(5 – 6):324– 326.
50. Gambichler T, Bruechkmann F, Altmeyer P, Kreuter A. NBUVB in skin conditions beyond psoriasis.
J Amer Acad Dermatol 2005; 52:660 – 670.
51. Jekler J, Larkö O. UVB phototherapy of atopic dermatitis. Br J Dermatol 1988; 119:697– 705.
52. George SA, Sisland DJ, Johnson BE, Ferguson J. Narrowband (TL-pq) UVB air conditioned photo-
therapy for chronic severe adult atopic dermatitis. Br J Dermatol 1993; 128:49– 56.
53. Hudson-Peacock MJ, Diffey BL, Farr PM. Narrow-band UVB phototherapy for severe atopic derma-
titis. Br J Dermatol 1996; 135(2):332.
54. Reynolds NJ, Franklin V, Gray JC, et al. Narrow-band ultraviolet B and broad-band ultraviolet
A phototherapy in adult atopic eczema: a randomised controlled trial. Lancet 2001; 357:
2012– 2016.
55. Krutmann J. Phototherapy for atopic dermatitis. Clin Exp Dermatol 2000; 25(7):552– 558.
56. Yashar SS, Gielczyk R, Scherschum L, Lim HW. Narrow band ultraviolet B treatment for
vitiligo, pruruitus, and inflammatory dematoses. Photdermatol Photimmunol Photomed 2003;
19:164– 168.
57. Njoo MD, Spuls PI, Bos JD, et al. Nonsurgical repigmentation therapies in vitligo: meta analysis of the
literature. Arch Dermatol 1998; 134:1532– 1540.
58. Asawanonda P, Charoenloap M, Korkij W. Treatment of localized vitiligo with targeted broadband
UVB pototherapy: a pilot study. Photodermatol Photoimmunol Photomed 2006; 22:133– 136.
59. Hamzavi I, Jain H, McLean D, et al. Parametric modeling of narrowband UV-B phototherapy
for vitiligo using a novel quantitative tool: the vitiligo area scoring index. Arch Dermatol 2004;
140:677– 683.
60. El-Mofty M, Mostafa W, Esmat S, et al. Narrow band ultraviolet B 311 nm in the treatment of vitiligo:
two right-left comparison studies. Photodermatol Photimmunol Photomed 2006; 22:6– 11.
61. Schershuon L, Kim JJ, Lin HW. Narrow Band ultraviolet B is a useful and well tolerated treatment for
vitiligo. J Amer Acad Dermatol 2001; 44:999 – 1003.
62. Herrmann JJ, Roenigk HH Jr, Honigsmann H. Ultraviolet radiation for treament of cutaneous T-cell
lymphoma. Hematology and Oncology Clinics of North America 1995; 9:1077– 1088.
63. Gathers RC, Scherschum L, Malick F, et al. Narrowband UVB phototherapy for early-stage mycosis
fungoides. J Am Acad Dermatol 2002; 47(2):191– 197.
64. El Mofty M, El-Arourty M, Salonas, M, et al. Narrow band UVB (311), psoralen UVB (311), and PUVA
therapy in the treatment of early stage mycosis fungoides: a right left comparative study.
Photodermatol Photoimmunol Photomed 2005; 21:281– 286.
65. Millard TP, Hhawk JL. Photosensitivity disorders: cause, effect, and management. Am J Clin
Dermatol 2002; 3:339 – 346.
66. Bisland D, George SA, Gibbs NK, et al. A comparison of narrow band phototherapy (TL-01) and
photochemotherapy (PUVA) in the management of polymorphic light eruption. Br J Dermatol
1993; 129:708– 712.
67. Rivard J, Lim HW. Ultraviolet phototherapy for pruritus. Dermatologic Therapy 2005; 18:344– 354.
68. Gilchrest BA, Rowe JW, Brown RS, et al. Ultraviolet phototherapy of uremic pruritus: long term
results and possible mechanism of action. Annual of Int Med 1979; 91:17– 21.
23 Ultraviolet-A1 and Visible Light Therapy
Jean Krutmann
Department of Dermatology and Environmental Medicine, Institut für Umweltmedizinische Forschung (IUF),
Heinrich-Heine University, Düsseldorf, Germany
Akimichi Morita
Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of
Medical Sciences, Nagoya, Japan
B UVA-1 phototherapy currently represents an investigational treatment

form that was originally elaborated and tested for its efficacy for atopic
dermatitis.
B The efficacy of UVA-1 in atopic dermatitis is confirmed by several

studies. Doses of 130 J/cm2 have been used, but more recently
medium- and low-dose regimens are being explored. UVA-1 has not yet
been compared directly with the standard phototherapies for atopic
dermatitis (narrowband UVB or Psoralen plus UVA).
B UVA-1 therapy appears promising in localized scleroderma, however,

controlled comparative studies needed. Its efficacy is probably based
on increased collagenase expression in treated skin.
B UVA-1 therapy was reported to be beneficial in several other dermatoses,

including systemic sclerosis, chronic sclerodermoid GvHD, urticaria
pigmentosa, and cutaneous T cell lymphoma. However, these indications
require confirmation in larger patient series.
B Studies indicate that UVA-1 may be also an effective treatment for

psoriasis in HIVþ patients but not in HIV2 patients and that UVA-1,
unlike UVB, does not activate HIV in human skin.
B Visible light therapy of atopic dermatitis showed some effect in one

study. However, these single center study results have not yet been
confirmed by other groups.
336 Krutmann and Morita
INTRODUCTION
n 1981, Mutzhas et al. (1) reported the development of an irradiation device, which almost
I exclusively emitted in the long-wave ultraviolet (UV) A range, that is, UVA-1 (340 – 400 nm).
The combination of a metal halide lamp with a novel filtering system offered, for the first
time, the unique possibility to expose human skin to high doses of UVA-1 radiation without
causing a sunburn reaction. Soon thereafter, UVA-1 irradiation devices proved to be useful
in photoprovocation testing for patients with UVA-sensitive photodermatoses, in particular
polymorphic light eruption. It took, however, more than a decade before the therapeutic poten-
tial of these novel irradiation devices was recognized and systematically exploited. In 1992,
Krutmann and Schöpf (2) reported that exposure to high doses of UVA-1 radiation was bene-
ficial for patients with severe acute atopic dermatitis. These observations prompted a continu-
ally growing interest in the therapeutic use of UVA-1 radiation. As a consequence, there is now
a substantial body of literature to suggest that for selected indications UVA-1 phototherapy is
superior to conventional phototherapeutic modalities (3). A major difference between UVA-1
and UVB or UVA/UVB radiation is given by the fact that with UVA-1 phototherapy it has
been possible to achieve therapeutic responses by penetrating deep into the dermis without
the usual side effects caused by less penetrating UVB and UVB-like wavelengths in the
UVA-2 region (4). In addition, UVA-1 radiation has some unique immunomodulatory features
indicating that, under appropriate circumstances, it might prove superior even when compared
with psoralen plus UVA (PUVA) therapy (5). UVA-1 phototherapy was used first to treat patients
with atopic dermatitis, but it has since been found to be efficacious in several other skin diseases,
such as localized and systemic scleroderma, in which other therapeutic options are limited. This
development has been fostered by studies, in which the photobiological and molecular basis of
UVA-1 phototherapy was analyzed. Currently, the indications for UVA-1 phototherapy fall into
four major categories: (i) T-cell-mediated skin diseases, (ii) mast cell-mediated skin diseases, (iii)
connective tissue diseases, and (iv) phototherapy in HIV positive patients (Table 1).
UVA-1 AND VISIBLE LIGHT THERAPY FOR T-CELL-MEDIATED SKIN DISEASES

In vitro studies have demonstrated that UVA-1 radiation is a potent inducer of apoptosis in
human T lymphocytes (6). At a molecular level, UVA-1 radiation-induced apoptosis differs
from apoptosis observed in UVB-irradiated or PUVA-treated cells because it is mediated
through a pathway that does not require protein synthesis. This so-called preprogrammed
cell death or early apoptosis appears to be highly specific for UVA-1 radiation and is mediated
through the generation of singlet oxygen. The in vivo relevance of these in vitro findings is
suggested by the observation that UVA-1 phototherapy of patients with atopic dermatitis
resulted in apoptosis of skin-infiltrating T-helper cells (7). The appearance of apoptotic
TABLE 1 Indications for UVA-1 Therapy

Indication Type of study Comment
Atopic dermatitis Several open studies, one multicenter trial Established indication
Urticaria pigmentosa Two open studies Promising results, “long-lasting effects”
controlled study lacking
Localized scleroderma Two open studies Very promising, “breakthrough”
controlled comparative studies needed
Systemic sclerosis One open study Very promising, “breakthrough”,
controlled comparative studies needed
CTCL Two open studies, one comparative study Promising multicenter trial ongoing
Psoriasis/HIV þ One open study Very promising, “therapy of choice”
larger studies required
Psoriasis/HIV– Case report Disappointing
Alopecia areata Unpublished study Not effective
Solar urticaria Several cases Not effective
Lichen planus Several cases Not effective
Abbreviation: CTCL, cutaneous T-cell lymphoma.
Ultraviolet-A1 and Visible Light Therapy 337
T cells was then followed by their depletion from lesional skin, a reduction in the in situ
expression of the pro-inflammatory T-cell-derived cytokine interferon-g, and clearing of
atopic eczema (8,9). Therefore, it is now generally believed that UVA-1 radiation-induced
T-helper cell apoptosis constitutes the basis of UVA-1 phototherapy in patients with atopic der-
matitis. As a clinical consequence, UVA-1 phototherapy has been extended to the treatment of
other T-cell-mediated skin diseases including cutaneous T-cell lymphoma (CTCL) (10).
UVA-1 and Visible Light for Atopic Dermatitis

The therapeutic efficacy of UVA-1 radiation in the management of patients with atopic derma-
titis was first evaluated in an open study in patients with acute, severe exacerbations (11). They
were exposed daily to 130 J/cm2 at an irradiation intensity of 70 mW/s for 15 consecutive days
(Fig. 1). Therapeutic effectiveness was assessed by a clinical scoring system as well as by moni-
toring serum levels of eosinophil cationic protein (12,13). The latter represents a laboratory
parameter that can be measured objectively and which has been shown to correlate well
with disease activity. In that study, UVA-1 phototherapy was found to be highly efficient in
promptly inducing clinical improvement. This was associated with a concomitant reduction
in elevated serum levels of eosinophil cationic protein. Patients treated with UVA-1 were
compared to subjects who had been treated with UVA/UVB phototherapy, which at that
time was considered the best phototherapy for atopic dermatitis available. Significant differ-
ences were observed in favor of UVA-1 phototherapy, indicating that UVA-1 phototherapy
was the phototherapy of choice for patients with severe atopic dermatitis.
During the subsequent years, there have been numerous reports confirming these
original observations (14– 16). It should be noted that in their pilot study, Krutmann et
al. (11) employed UVA-1 phototherapy as a monotherapy, thereby suggesting that it
might represent a therapeutic alternative to the gold standard in the treatment of
severe atopic dermatitis, glucocorticosteroids. Indeed, a direct comparison of UVA-1
phototherapy with a standardized topical glucocorticosteroid treatment revealed that for
the treatment of patients with severe, exacerbated atopic dermatitis UVA-1 phototherapy
was at least equivalent to topical glucocorticosteroids (17). To date, this study is also the
only one to provide a multicenter evaluation of the therapeutic efficacy of UVA-1
FIGURE 1 Patient with acute, severe atopic dermatitis before (A) and after (B) 15 exposures to 130 J/cm2 UVA-1.
phototherapy by studying a larger number of patients with severe atopic dermatitis

(n ¼ 53) in a controlled randomized fashion. Patients were treated with UVA-1
(10 130 J/cm2), UVA/UVB (minimal erythema dose-dependent), or topical fluocortolone.
After 10 treatments, patients in all three groups had improved, but improvement was sig-
nificantly greater in UVA-1 irradiated or fluocortolone-treated patients compared to UVA/
UVB phototherapy. Significant reductions in serum levels of eosinophil cationic protein
were only observed after glucocorticosteroid or UVA-1 therapy. The multicenter trial
thus confirmed the original observation that UVA-1 phototherapy was of great benefit
for patients with severe atopic dermatitis.
Local UVA-1 phototherapy appears to be an interesting option in the management of
patients with chronic vesicular dyshidrotic hand eczema. In an open pilot study, palms and
backs of hands of 12 patients with an acute exacerbation of their disease were exposed to 15
UVA-1 irradiations with a dose of 40 J/cm2 per day over a period of three weeks. After one
week, all but one patient reported a marked relief of itch. After the third week, significant clini-
cal improvement was noted in 10 out of 12 patients (18).
It has recently been shown that wavelengths within the visible range can be effectively
used to treat patients with atopic hand and foot eczema (19). This development was prompted
by the observation that UVA-1 phototherapy-induced apoptosis in house dust-mite specific
T-cells, which had been cloned from lesional skin of patients with atopic eczema, is mediated
through the generation of singlet oxygen. This reactive oxygen species, however, cannot only
be generated by wavelengths in the UV, but in particular in the near visible range (Soret
band, 405 nm). A UV-free partial body irradiation device with an emission maximum
between 400 and 450 nm has, therefore, been developed and found to induce prompt and
long-lasting improvement in patients with atopic hand and foot eczema (Fig. 2). In marked
contrast to UV radiation, which is a complete carcinogen, visible radiation does not increase
the risk for skin cancer, and UV-free phototherapy might, therefore, be well suited for the treat-
ment of children and young adults, who represent the vast majority of patients with atopic
dermatitis. Further studies are clearly required to confirm these preliminary results in
independent studies and to assess the efficacy of UV-free phototherapy for generalized
forms of atopic dermatitis.
There is currently a debate whether the therapeutic efficacy of UVA-1 for this indi-
cation is dose-dependent. Recent studies indicate that similar to a high-dose regimen with
FIGURE 2 Patient with atopic hand eczema before (A) and after (B) UV-free phototherapy.
130 J/cm2, a medium UVA-1 dosage schedule is superior to UVA/UVB (14). Also, thera-
peutic efficacy within the UVA-1 range seems to be dose-dependent, because irradiations
with 50 J/cm2 were superior to a low-dose regimen (20 J/cm2) (20). Very recently, a high-
dose protocol (130 J/cm2 was found to be superior to a medium-dose regimen (50 J/cm2),
which again was more efficient than a low-dose schedule (20 J/cm2). Thus, the use of low
doses of UVA-1 does not offer any advantage over conventional phototherapeutic modalities
such as UVA/UVB or 311 nm UVB and should, therefore, be discouraged. In contrast,
medium- and high-dose UVA-1 are clearly superior to conventional phototherapy, but for
achieving an optimal therapeutic response, a high-dose regimen with 130 J/cm2 seems to
be necessary.
UVA-1 for Cutaneous T-Cell Lymphoma

CTCL is a neoplasm of helper T-cells that initially manifests in the skin. The most common form
is mycosis fungoides. Helper T-cells in mycosis fungoides are located intra-epidermally and
below the epidermis as band-like dermal infiltrates. Topical treatment of patch and plaque
CTCL thus requires modalities capable of penetrating into the dermis. For stage IA and IB
CTCL, the treatment of choice is PUVA therapy, which, similar to UVA-1 radiation, induces
T-cell apoptosis (21). From a theoretical point of view, UVA-1 phototherapy is an alternative
to PUVA for this indication because UVA-1 radiation reaches deeper layers of the dermis at
higher intensities compared with PUVA and UVA-1 phototherapy avoids the unwanted side
effects resulting from the photosensitizer, 8-methoxypsoralen.
Plettenberg et al. (10) used UVA-1 phototherapy as a monotherapy in three patients with
histologically proven CTCL, stages IA and IB. For whole-body UVA-1 irradiations, patients
were exposed to 130 J/cm2 (n ¼ 2) or 60 J/cm2 (n ¼ 1) UVA-1 radiation daily (Fig. 2). In each
of the three patients, skin lesions began to resolve after only a few UVA-1 radiation exposures.
Complete clearance was observed between 16 and 20 exposures, regardless of whether the
high- or medium-dose regimen was used. These clinical data were corroborated by histological
evaluation. In all three patients, histological features of mycosis fungoides were present prior to
therapy, whereas after UVA-1 phototherapy, the epidermis looked almost normal and only a
few lymphocytic infiltrates were left in the dermis. In a second study, 10 patients with early
stages of CTCL were treated with daily doses of 100 J/cm2 UVA-1. In 10 out of 10 patients, com-
plete remissions were observed after a total of 20 to 25 exposures (22). In a recent comparative
study, CTCL patients were randomly assigned to either UVA-1 (n ¼ 10) or PUVA (n ¼ 10)
therapy (23). Again, UVA-1 phototherapy was found to be efficient in the treatment of early
stages of CTCL, and no significant differences in favor of PUVA therapy were observed.
The current mainstay for the treatment of stage IA-to IB-CTCL is PUVA therapy. From a
practical point of view, UVA-1 phototherapy has significant advantages over PUVA because
unwanted side effects resulting from the systemic application of the photosensitizer are com-
pletely avoided. Therefore, an international (Düsseldorf, Vienna, Brescia, Muenster, Nagoya,
and Heidelberg) multicenter trial has been initiated to compare the efficacy of UVA-1 and
PUVA therapy for early stages of CTCL in a controlled study. This trial will also provide infor-
mation about the duration of remission-free intervals that can be achieved with UVA-1 photo-
therapy. The UVA-1 dose being used in this study is in the medium rather than the high-dose
range and has been extrapolated from in vitro studies (24). In these experiments, neoplastic
T-cells were shown to be significantly more sensitive to UVA-1 radiation-induced apoptosis
when compared with normal T-cells. This is in line with the previous notion that exposure
to 60 J/cm2 UVA-1 was equally effective to a 130 J/cm2 UVA-1 regimen for patients with
CTCL. The optimal dose for treating CTCL patients might thus differ from the one to be
used for atopic dermatitis patients.
UVA-1 for Urticaria Pigmentosa

Induction of apoptosis in skin-infiltrating cells and their subsequent depletion from skin is
thought to represent the major mechanisms of action of UVA-1 phototherapy for yet another
indication, urticaria pigmentosa. In initial studies, skin sections from patients before and
after UVA-1 therapy were assessed for effects on mast cells by histochemical and immunohis-
tochemical techniques (25). It was found that UVA-1 phototherapy reduced the density of
dermal mast cells and that this decrease was closely linked to significant clinical improvement.
These studies indicated that changes in the number, and possibly function, of dermal mast cells
may contribute to the clinical effects of this treatment. It was, therefore, not surprising to learn
that UVA-1 therapy proved to be of benefit for patients suffering from cutaneous mastocytosis.
In a pilot study, four adult patients with severe generalized urticaria pigmentosa were treated
with a high-dose UVA-1 regimen, which was used as a monotherapy (26). UVA-1 phototherapy
was given once daily five times per week for two consecutive weeks. The initial dose was
60 J/cm2 UVA-1; subsequently, the daily dose was 130 J/cm2 UVA-1 per body half. In all
patients, UVA-1 therapy induced a prompt improvement of cutaneous symptoms, which
was reflected by a reduction of increased histamine in 24-hour urine to normal levels. In
addition to skin symptoms, two patients presented with systemic manifestations of urticaria
pigmentosa such as diarrhea and migraine. After 10 treatments, relief from systemic symptoms
was noted and elevated serum serotonin was reduced to normal in both patients. No relapse
occurred in any of the patients for more than two years after cessation of UVA-1 therapy.
This is in contrast to PUVA therapy for urticaria pigmentosa, which is characterized by recur-
rence after five to eight months. The long-lasting effectiveness of UVA-1 for urticaria pigmen-
tosa has recently been confirmed in a second study (27). In total, 15 patients with urticaria
pigmentosa were treated using a high-dose UVA-1 regimen. Of the patients, 14 of 15 showed
a prompt response to UVA-1 phototherapy and were free of cutaneous and/or systemic symp-
toms after cessation of phototherapy. A two-year follow-up of these patients revealed that eight
months after phototherapy, 100% of UVA-1- treated patients were still in full remission. Remis-
sion free intervals of one year were observed for 70% and of 18 months for 40% of these
patients.
Differences in the recurrence rate between UVA-1- and PUVA-treated urticaria pigmen-
tosa patients might be explained by the fact that UVA-1 therapy is associated with a reduction
in numbers of dermal mast cells, which has not been observed after PUVA therapy (28,29,15).
This hypothesis is supported by recent in vivo studies that demonstrate a significant decrease
in the number of dermal mast cells in UVA-1-, but not in PUVA-treated, patients. By employing
a double-staining technique, it could also be demonstrated that lesional skin of patients with
urticaria pigmentosa constitutively contained a low percentage of apoptotic mast cells and
that this percentage was significantly increased by UVA-1 phototherapy (27). In contrast,
PUVA therapy did not cause mast cell apoptosis. Taken together, these studies indicate that
UVA-1 phototherapy, by virtue of its capacity to induce apoptosis in skin-infiltrating mast
cells, is capable of depleting these cells from the skin of urticaria pigmentosa patients. As a con-
sequence, therapeutic responses to UVA-1 phototherapy are long-lasting and, therefore, UVA-1
phototherapy has the potential to replace PUVA as the therapy of choice for urticaria
pigmentosa patients.
UVA-1 for Connective Tissue Disease

Patients with localized scleroderma develop one or multiple, circumscribed, ivory-white, indu-
rated plaques, which may be up to 20 cm in diameter and are frequently surrounded by an
inflammatory halo known as the lilac ring (30). Although the disease has a self-limited
course, sclerosis of skin lesions may cause significant morbidity and discomfort. It is possible
that sclerotic skin lesions lead to muscle atrophy and thereby disfiguration of the trunk or face.
They may also extend over joints and cause flexion contractures with functional impairment.
Numerous modalities including penicillin, penicillamine, anti-malarial drugs, cyclosporin A,
interferon-g, and topical or systemic glucocorticosteroids have been employed; but in
general, there is no effective curative or symptomatic therapy for localized scleroderma.
In this regard, it is of particular interest that sclerosis of skin lesions appears to result from
an increased synthesis of type-I and type-III collagen (3,31,32). Evidence has been provided that
a major cause for this excessive collagen deposition is a malfunction of dermal fibroblasts, in
particular adecreased collagenase I expression (33). It is possible to increase synthesis of col-
lagenase I in cultured human dermal fibroblasts by in vitro exposure to UVA-1 radiation
FIGURE 3 Sclerotic plaques in the abdominal region of a patient with localized scleroderma before (A) and after (B)
UVA-1 phototherapy (30 130 J/cm2 UVA-1).
(34,35). In these studies, UVA-1 radiation-induced collagenase production was associated with
a dose-dependent upregulation of collagenase I mRNA expression, and maximal induction
was achieved in vitro by UVA-1 radiation doses, which are equivalent to those used in high-
dose UVA-1 phototherapy of atopic dermatitis or urticaria pigmentosa patients. It has, there-
fore, been hypothesized that UVA-1 radiation, by virtue of its capacity to increase collagenase
I expression, may have beneficial effects for patients with localized scleroderma (36,37). This
hypothesis has been tested in an open study, in which 10 patients with histologically proven
localized scleroderma were exposed 30 times to 130 J/cm2 of UVA-1 radiation (37) (Fig. 3). In
all patients, UVA-1 therapy softened sclerotic plaques, and complete clearance was observed
in 4 out of 10 patients. In addition, 20 MHz sonography revealed that UVA-1 therapy signifi-
cantly reduced thickness and increased elasticity of plaques (Fig. 4). These changes were not
due to spontaneous remission of skin lesions in these patients because they could only be
observed in UVA-1-irradiated, but not in unirradiated, control plaques of the same patients.
It has also been suggested that similar therapeutic effects can be achieved by exposing patients
with localized scleroderma to low doses (20 J/cm2) of UVA-1 radiation (38,39). Direct compari-
son of low- versus high-dose UVA-1 phototherapy, however, revealed that high-dose UVA-1
therapy was superior to low-dose UVA-1 therapy for all parameters assessed (clinical evalu-
ation, thickness of plaques, and cutaneous elastometry) (37). Patients were followed up for a
total of three months after cessation of therapy. Termination of UVA-1 therapy was not associ-
ated with a loss of the beneficial effects achieved in any of these patients. Accordingly, in six out
of seven patients, skin thickness values obtained at the end of the follow-up period were iden-
tical to those measured immediately after the last high-dose UVA-1 irradiation. In one patient, a
partial relapse of skin symptoms was observed, but skin thickness after the three-month
follow-up period was still significantly below values obtained before phototherapy was
started. In none of the patients, further improvement of skin symptoms was observed after
UVA-1 therapy was stopped.
FIGURE 4 Sonography (20 MHz) of a sclerotic plaque of a patient with localized scleroderma before (A) and after (B)
UVA-1 phototherapy (30 130 J/cm2 UVA-1).
The precise mechanism(s) by which UVA-1 therapy may act in localized scleroderma
are currently unknown. The rationale for employing a high-dose UVA-1 radiation regimen
for this indication was based on previous in vitro observations that UVA-1 irradiation
induced collagenase I expression in cultured human dermal fibroblasts in a dose-dependent
manner (34,36). This concept is strongly supported by recent studies, in which sequential
biopsies before and after high-dose UVA-1 therapy were obtained from sclerotic skin
lesions of patients with localized scleroderma. UVA-1 radiation-induced clinical improvement
and reduction of skin thickness were found to be associated with about a 20-fold upregulation
of collagenase I mRNA expression in irradiated sclerotic plaques (47). Taken together, these
studies strongly indicate that UVA-1 phototherapy is effective for localized scleroderma.
Effectiveness is UVA-1 dose-dependent and associated with induction of collagenase I
expression.
In addition to localized scleroderma, UVA-1 phototherapy has also been reported to be of
benefit for patients with systemic sclerosis. Morita et al. (40) exposed lesional skin on the fore-
arms of five patients with systemic sclerosis to single doses of 60 J/cm2 UVA-1. In all patients,
UVA-1 phototherapy treated skin lesions were markedly softened after 10 to 30 exposures.
Clinical improvement was associated with an increase in joint passive range of motion
values, skin temperature, and cutaneous elasticity.
Histological evaluation of skin specimens obtained, before and after therapy, revealed
loosening of collagen bundles and the appearance of small collagen fibers. A half-side compari-
son in one patient revealed that improvement of these parameters was only observed in UVA-
1-treated, but not in unirradiated control skin (40). This study further supports the concept that
UVA-1 phototherapy is a valuable treatment option for patients suffering from scleroderma.
The fact that, currently no other treatment options with proven efficacy for the management
of diseases associated with skin sclerosis are available, should further stimulate the interest
in UVA-1 phototherapy.
It should be noted that in addition to UVA-1 therapy, systemic as well as topical PUVA
therapy have been reported to be of benefit for patients with localized scleroderma and sys-
temic sclerosis (41,42). Future studies will therefore have to compare UVA-1 versus PUVA
therapy for both therapeutic efficacy and unwanted side effects. At least in the in vitro situation,
PUVA treatment, but not UVA-1 irradiation, induced terminal differentiation of cultured
human fibroblasts, indicating that PUVA therapy may be associated with a greater risk for
photoaging. In addition, clinical improvement in patients with systemic sclerosis required an
average of 50 PUVA treatments given over a period of four to five months (16). In contrast,
UVA-1 phototherapy required a total of 30 irradiations to achieve maximal therapeutic
effects (24). Since UVA-1, in contrast to PUVA therapy, was given on a daily basis, the total treat-
ment time was reduced to between 1 to 1.5 months, and UVA-1 phototherapy thus yielded
beneficial effects much faster than PUVA.
UVA-1 for HIV-Positive Patients

The safety of UVB or PUVA in the treatment of patients with skin disorders remains controver-
sial. On the one hand, clinical studies have not shown dramatic adverse effects on immune
status or plasma viral load. On the other hand, laboratory studies have clearly demonstrated
that UVB or PUVA can activate HIV in cultured cells and in vivo in transgenic animals. The
debate has been further stimulated by recent studies, in which HIV-1 (gag) expression was ana-
lyzed in a semiquantitative manner in human skin using a PCR-based assay. It was observed
that UVB administered in vivo in suberythemogenic doses can activate the virus in lesional
skin and nonlesional skin of seropositive patients with psoriasis or eosinophilic folliculitis. Pre-
vious in vitro studies have demonstrated that the only wavelength range within the UV that
does not activate the HIV promoter is UVA-1 (43). Since psoriasis is currently being regarded
as a T-cell-mediated skin disease and since UVA-1 phototherapy has proven to be highly effec-
tive for the treatment of T-cell-mediated inflammatory responses in human skin, it was obvious
to assess whether UVA-1 phototherapy can be used for the treatment of psoriasis in HIVþ indi-
viduals. In an open, uncontrolled trial, HIVþ patients (n ¼ 3) showed a beneficial response to
UVA-1 phototherapy, which was given on a daily base as a high-dose regimen (44) (Fig. 5).
FIGURE 5 HIV þ patient with psoriasis before (A) and after (B) UVA-1 phototherapy (20 130 J/cm2).
Prior to initiation of whole-body UVA-1 phototherapy, the safety of UVA-1 phototherapy in

HIVþ patients was assessed. For this purpose, paired lesional and nonlesional skin specimens
were obtained from all patients after a single exposure to UVB (150 mJ/cm2), UVA-1 (130 J/
cm2), or sham irradiation. By employing the quantitative PCR-based HIV assay, it was observed
that UVB-treated skin showed a 6- to 15-fold increase in HIV count compared to unirradiated
skin. By contrast, there were no differences in the HIV count of UVA-1 treated versus unirra-
diated skin. Moreover, complete clearance of psoriasis was observed in these patients
after 20 to 30 UVA-1 irradiations. Importantly, there were also no increments in the skin
viral counts of HIVþ patients with psoriasis after UVA-1 phototherapy (up to 41 total-body
UVA-1 radiation exposures). These studies indicate that (i) UVA-1 is an effective treatment
for psoriasis in HIVþ patients and (ii) that UVA-1, unlike UVB, does not activate HIV in
human skin. At least from the perspective of safety, UVA-1 phototherapy, therefore, seems to
represent the phototherapy of choice in HIVþ patients.
Miscellaneous Indications for UVA-1

In an open pilot study, 12 patients with an acute exacerbation of their chronic vesicular dyshi-
drotic hand eczema were subjected to a local UVA-1 phototherapy (18). Palms and backs of
hands were exposed to 15 UVA-1 irradiations with a dose of 40 J/cm2 per day over a period
of three weeks. After one week of treatment, all but one patient reported a marked relief of
itch. After the three-week treatment period, significant clinical improvement was noted in 10
out of 12 patients. This report is consistent with the observed therapeutic efficacy of UVA-1
phototherapy for atopic dermatitis and other T-cell-mediated skin diseases (45,7). Local
UVA-1 phototherapy may thus prove to be an effective therapeutic option in the management
of patients with chronic vesicular hand eczema.
A recent case report indicates that UVA-1 phototherapy is of benefit for patients with
keloids and hypertrophic scars (46). A 37-year-old man (skin type IV) with a 17-year history
of a stable chest keloid secondary to severe acne was treated 22 times with single exposures
of 130 J/cm2 UVA-1. Only two-thirds of the keloid were treated, whereas the remaining
served as the unirradiated control. Already, after three weeks, and even more so after six
weeks, of UVA-1 phototherapy, marked softening and flattening of the irradiated, but not
the unirradiated parts of the keloid were noted. Histological evaluation revealed the
reappearance of normal-looking collagen and elastic fibers in this keloid after phototherapy.
These very preliminary but exciting results indicate that UVA-1 phototherapy could be of
great help to patients with large scars such as burn scars for whom surgical remodeling or
intralesional corticosteroid injection can be difficult.
Combined UVA-1 radiation and acitretin therapy has been reported as a treatment option
in one patient with pityriasis rubra pilaris (47). From this case report, the relative contribution
of UVA-1 and acitretin to the therapeutic response remains unclear.
It has been suggested that daily low-dose UVA-1 irradiation is beneficial to patients with
lupus erythematosus. In support of this concept has been the publication of an open study of 10
patients with systemic lupus erythematosus who were treated with single doses of 6 J/cm2
UVA-1 for various durations (15 days – 8 months) (48). There was a decrease in clinical
indices of disease activity as well as in titers of anti-SSA or antinuclear antibodies. This
study has recently been confirmed in an 18-week, two-phase study (49). During the initial
six-week prospective, double blind, placebo-controlled phase, 26 female patients were
divided into two groups. Group A patients were exposed to 6 J/cm2 UVA-1 and group B
patients for an equal amount of time to visible light. Each group was subsequently crossed
over for three weeks. This was followed by a second phase of 12 weeks, in which patients
and physicians were unblinded and patients were treated with progressively decreasing
levels of UVA-1 radiation. In patients from group A, disease activity was significantly
decreased after three weeks of UVA-1 therapy but relapsed to baseline levels after three
weeks of visible light treatment. In contrast, group B patients showed no significant response
to the initial three weeks of visible light treatment or to the following three weeks of UVA-1
therapy. In both groups, however, significant improvement of clinical symptoms was detected
after six weeks of UVA-1 phototherapy, which was given under uncontrolled conditions in
phase two. These single center studies, however, have not yet been confirmed by other
groups. Also, treatment of a UV-sensitive autoimmune disease such as lupus erythematosus
with UVA-1 phototherapy may not be without risk, in particular, when UVA-1 is used at
higher doses for SCLE patients who might develop a systemic form due to phototherapy (50).
SIDE EFFECTS OF UVA-1 AND VISIBLE LIGHT THERAPY

UVA-1 phototherapy may not be performed in patients with UVA-sensitive photodermatoses
or photosensitive atopic dermatitis. It is necessary to exclude these diseases prior to initiation of
phototherapy. This can easily be accomplished by photoprovocation testing. Except for eczema
herpeticatum, no acute side effects have been observed in any patient treated with UVA-1. No
other side effects have been observed, although its potential carcinogenic risk is a concern.
Exposure of hairless albino Skh-hr1 mice to high doses of UVA-1 radiation has been shown
to induce squamous cell carcinoma (51). The actual contribution of UVA-1 radiation to the
development of malignant melanoma in humans is under debate and at this point cannot be
excluded (52). These theoretical concerns are mainly relevant for atopic dermatitis patients
who usually are at a younger age. Until more is known about UVA-1 phototherapy, its use
in patients with atopic dermatitis should be limited to periods of acute exacerbation, and
one treatment cycle should not exceed 10 to 15 exposures once or twice a year. As a general
rule, children should not be treated with UVA-1 phototherapy except for severe cases of scler-
oderma where other treatment options do not exist (13). For other indications such as CTCL,
urticaria pigmentosa, and connective tissue diseases, the benefits achieved by UVA-1 photo-
therapy probably outweigh its potential long-term risks.
No side effects have been reported with UV-free phototherapy, and in general, it can be
assumed that UV-free phototherapy, in contrast to UV phototherapy, does not cause skin cancer
and thus may be considered safe to be used in children, young adults, and in combination with
immunosuppressive drugs.
PERSPECTIVES
UVA-1 phototherapy has almost always been used as a monotherapy in order to unambigu-
ously prove its efficacy. Combination regimens integrating UVA-1 phototherapy are,
however, of obvious clinical interest and practical benefit because they should allow for the
maximization of therapeutic efficacy and safety at the same time. Combinations of interest
include the use of UVA-1 together with topical steroids or novel immunosuppressants for
atopic dermatitis or UVA-1 with systemic retinoids or interferon-a for CTCL.
Analysis of the mechanism of action of UVA-1 phototherapy has led to a rapid expansion
of its indication spectrum. It is anticipated that this development will continue within the near
future. In this regard, it has been of particular interest to learn that the generation of singlet
oxygen by UVA-1 radiation represents a central photobiological mechanism required for the
achievement of therapeutic effects (7). It is thus conceivable to assume that strategies directed
at the amplification of singlet-oxygen-mediated effects as well as the development of alterna-
tive modes for singlet oxygen generation in human skin such as UV-free phototherapy will
prove to be superior to UVA-1 phototherapy, as it is currently being employed. All these
efforts will eventually contribute to the further development of UVA-1 and visible light photo-
therapy as one of the driving forces of modern photomedicine.
REFERENCES
1. Mutzhas MF, Hölzle E, Hofmann C, et al. A new apparatus with high radiation energy between 320–
460 nm: physical description and dermatological applications.J Invest Dermatol 1981; 76:42– 47.
2. Krutmann J, Schöpf E. High-dose UVA1 therapy: a novel and highly effective approach for the treat-
ment of patients with acute exacerbation of atopic dermatitis. Acta Derm Venereol (Stockh) 1992;
176:120– 122.
3. LeRoy EC. Increased collagen synthesis by scleroderma skin fibroblasts in vitro. J Clin Invest 1979;
54:880– 889.
4. Jekler J, Larkö O. Combined UV-A– UV-B versus UVB phototherapy for atopic dermatitis. J Am Acad
Dermatol 1990; 22:49 – 53.
5. Krutmann J. Phototherapy for atopic dermatitis. Dermatol Ther 1996; 1:24 – 31.
6. Godar DE. UVA 1 radiation mediates singlet-oxygen and superoxide-anion production which trigger
two different final apoptotic pathways: the S and P site of mitochondria. J Invest Dermatol 1999;
112:3– 12.
7. Morita A, Werfel T, Stege H, et al. Evidence that singlet oxygen-induced human T helper cell apop-
tosis is the basic mechanism of ultraviolet-A radiation phototherapy. J Exp Med 1997; 186:1763– 1768.
8. Grewe M, Gyufko K, Schöpf E, et al. Lesional expression of interferon-g in atopic eczema. Lancet 1994;
343:25– 26.
9. Grewe M, Bruijnzeel-Koomen CAFM, Schöpf E, et al. A role for Th1 and Th2 cells in the immuno-
pathogenesis of atopic dermatitis. Immunol Today 1998; 19:359– 361.
10. Plettenberg H, Stege H, Megahed M, et al. Ultraviolet A1 (340– 400 nm) phototherapy for cutaneous
T-cell lymphoma. J Am Acad Dermatol 1999; 41:47 – 50.
11. Krutmann J, Czech W, Diepgen T, et al. High-dose UVA-1 therapy in the treatment of patients with
atopic dermatitis. J Am Acad Dermatol 1992; 26:225– 230.
12. Costa C, Rillet A, Nicolet M, Saurat JH. Scoring atopic dermatitis: the simpler the better. Acta Derm
Venereol (Stockh) 1989; 69:41– 47.
13. Czech W, Krutmann J, Schöpf E, et al. Serum eosinophil cationic protein is a sensitive measure for
disease activity in atopic dermatitis. Br J Dermatol 1992; 126:351– 355.
14. Kobyletzki G, Pieck C, Hoffmann K, et al. Medium-dose UVA1 cold-light phototherapy in the treat-
ment of severe atopic dermatitis. J Am Acad Dermatol 1999; 41:931– 937.
15. Kolde G, Frosch PJ, Czarnetzki BM. Response of cutaneous mast cells to PUVA in patients with urti-
caria pigmentosa: histophotometric, ultrastructural, and biochemical investigations. J Invest Derma-
tol 1984; 83:175– 178.
16. Meffert H, Sönnichsen N, Herzog M, et al. UVA-1 cold light therapy of severe atopic dermatitis. Der-
matol Monatsschr 1992; 78:291– 296.
17. Krutmann J, Diepgen T, Luger TA, et al. High-dose UVA1 therapy for atopic dermatitis: results of a
multicenter trial. J Am Acad Dermatol 1998; 38:589– 593.
18. Schmidt T, Abeck D, Boeck K, et al. UVA1 irradiation is effective in treatment of chronic vesicular dys-
hidrotic hand eczema. Acta Derm Venereol (Stockh) 1998; 78:318– 319.
19. Krutmann J, Medve-Koenigs K, Ruzicka, et al. UV-free phototherapy of atopic hand and foot eczema.
Photodermatol Photoimmunol Photomed 2005; 21:59– 61.
20. Kowalzick L, Kleinhenz A, Weichenthal M, et al. Low dose versus medium dose UVA-1 treatment in
severe atopic dermatitis. Acta Derm Venereol (Stockh) 1995; 75:43– 45.
21. Krutmann J. Therapeutic photomedicine: phototherapy. In: Freedberg IM, Eisen AZ, Wolff K, Austen
KF, Goldsmith LA, Katz SI, Fitzpatrick TB, eds. Fitzpatrick’s Dermatology in General Medicine. 5th
ed. New York: McGraw-Hill, 1999:2870– 2879.
22. Zane C, Leali C, Airo P, et al. High-dose UVA1 therapy of large plaques and nodular lesions of
cutaneous T-cell lymphoma. J Am Acad Dermatol 2001; 44:629– 633.
23. Plettenberg H, Stege H, Mang R, et al. A comparison of Ultraviolet A-1 and PUVA therapy for early
stages of cutaneous T-cell lymphoma. Photodermatol Photoimmunol Photomed 2001; 17:149– 155.
24. Yamauchi R, Morita A, Yasuda Y, et al. Different susceptibility of malignant versus nonmalignant
human T cells toward ultraviolet A-1 radiation-induced apoptosis. J Invest Dermatol 2004;
122(2):477– 483.
25. Grabbe J, Welker P, Humke S, et al. High-dose UVA1 therapy, but not UVA/UVB therapy, decreases
IgE binding cells in lesional skin of patients with atopic eczema. J Invest Dermatol 1996; 107:419 –423.
26. Stege H, Schöpf E, Ruzicka T, et al. High-dose-UVA1 for urticaria pigmentosa. Lancet 1996; 347:64.
27. Stege H, Budde M, Kürten V, et al. Induction of apoptosis in skin-infiltrating mast cells by high-dose
ultraviolet A-1 radiation phototherapy in patients with urticaria pigmentosa. J Invest Dermatol 1999;
112:561.
28. Christophers E, Hönigsmann H, Wolff K, et al. PUVA treatment of urticaria pigmentosa. Br J Dermatol
1978; 98:701– 702.
29. Granerus G, Roupa G, Swanbeck G. Decreased urinary histamine levels after successful PUVA treat-
ment of urticaria pigmentosa. J Invest Dermatol 1981; 76:1– 3.
30. Rosenwasser TA, Eisen AZ. Scleroderma. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen
KF, eds. Dermatology in General Medicine. 4th ed. New York: McGraw-Hill, 1993:2156– 2167.
31. Fleischmajer R. Localized and systemic scleroderma. In: Lapiere CM, Krieg T, eds. Connective Tissue
Diseases of the Skin. New York: Dekker, 1993:295– 313.
32. Rodnan GP, Lipinski I, Luksick J. Skin collagen content in progressive systemic sclerosis (sclero-
derma) and localized scleroderma. Arthritis Rheum 1979; 22:130 – 140.
33. Takeda K, Hahamochi A, Ueki H, et al. Decreased collagenase expression in cultured systemic scler-
osis fibroblasts. J Invest Dermatol 1994; 103:359– 363.
34. Petersen MJ, Nasen C, Craig S. Ultraviolet A irradiation stimulates collagenase production in cul-
tured human fibroblasts. J Invest Dermatol 1992; 99:440– 442.
35. Scharffetter K, Wlaschek M, Hogg A, et al. UVA irradiation induces collagenase in human dermal
fibroblasts in vitro and in vivo. Arch Dermatol Res 1991; 283:506– 511.
36. Kerscher M, Dirschka T, Volkenandt M. Treatment of localized scleroderma by UVA1 phototherapy.
Lancet 1995; 346:1166.
37. Stege H, Humke S, Berneburg M, et al. High-dose ultraviolet A1 radiation therapy of localized scler-
oderma. J Am Acad Dermatol 1996; 36:938– 943.
38. Gruss C, Strucker M, Kobyletzki G, et al. Low dose UVA1 phototherapy in disabling pansclerotic
morphea. Br J Dermatol 1997; 136:293 – 294.
39. Kerscher M, Volkenandt M, Gruss C, et al. Low-dose UVA1 phototherapy for treatment of localized
scleroderma. J Am Acad Dermatol 1998; 38:21– 26.
40. Morita A, Kobayashi K, Isomura I, et al. Ultraviolet A-1 (340– 400 nm) phototherapy for systemic
sclerosis. J Am Acad Dermatol 2000; 43:670 – 674.
41. Morita A, Sakakibara S, Sakakibara N, et al. Successful treatment of systemic sclerosis with topical
PUVA. J Rheumatol 1995; 22:2361– 2365.
42. Scharfetter-Kochanek K, Goldermann R, et al. PUVA therapy in disabling pansclerotic morphea of
children. Br J Dermatol 1995; 132:830– 831.
43. Zmudzka BZ, Olvey KM, Lee W, et al. Reassessment of the differential effects of ultraviolet and ioniz-
ing radiation on HIV promoter: the use of cell survival as the basis for comparisons. Photochem
Photobiol 1994; 59:643– 649.
44. Breur-McHam J, Simpson E, Dougherty I, et al. Activation of HIV in human skin by ultraviolet B
radiation and its inhibition by NF-kB blocking agents. Photochem Photobiol 2001; 74:805– 810.
45. Krutmann J. UVA1 induced immunomodulation. In: Krutmann J, Elmets CA, eds. Photoimmunology.
Oxford: Blackwell Science, 1995:246– 256.
46. Asawanonda P, Khoo LS, Fitzpatrick TB, et al. UV-A1 for keloid. Arch Dermatol 1999; 135:348– 349.
47. Herbst RA, Vogelbruich M, Ehnis A, et al. Combined ultraviolet A1 radiation and acitretin therapy as
a treatment option for pityriasis rubra pilaris. Br J Dermatol 2000; 142:574– 575.
48. McGrath H Jr. Ultraviolet-A1 irradiation decreases clinical disease activity and autoantibodies in
patients with systemic lupus erythematosus. Clin Exp Rheumatol 1994; 12:129– 135.
49. McGrath Jr H, Martinez-Osuna P, Lee FA. Ultraviolet A-1 (340 – 400 nm) irradiation in systemic lupus
erythematosus. Lupus 1996; 5:269– 274.
50. Soennichsen N, Meffert H, Kunzelmann V. UV-A-1 Therapie bei subakut-kutanem Lupus erythema-
todes. Hautarzt 1993; 44:723 – 725.
51. Sterenborg HJ, van der Leun JC. Tumorigenesis by a long wavelength UV-A source. Photochem
Photobiol 1990; 51:325– 330.
52. Setlow RB, Grist E, Thompson K, et al. Wavelengths effective in induction of malignant melanoma.
Proc Natl Acad Sci USA 1993; 90:6666– 6670.
24 Psoralen Photochemotherapy
Warwick L. Morison
Department of Dermatology, Johns Hopkins University, Baltimore, Maryland, U.S.A.
B The acronym PUVA refers to the combined use of photoactive psoralens

and UVA radiation.
B The most widely used form of PUVA therapy consists of oral admin-
istration of methoxsalen and exposure to UVA fluorescent bulbs.
B The goal of PUVA therapy is to clear skin disease, but the treatment has
two constraints: the risk of erythema from being too aggressive and the
risk of developing too much pigmentation from being too conservative.
B PUVA therapy is an effective treatment for many inflammatory and

neoplastic skin diseases.
B The commonest disease treated with PUVA therapy is psoriasis and it is

effective in .90% of patients with psoriasis vulgaris.
B Excessive exposure to PUVA therapy causes photoaging of the skin and

is associated with an increased risk of developing nonmelanoma skin
cancer and possibly melanoma.
B Topical PUVA therapy is an alternative approach to treatment and avoids

systemic exposure to psoralens.
348 Morison and Hönigsmann
INTRODUCTION
soralens are a group of phototoxic compounds that can interact with various components
P of cells and then absorb photons to produce photochemical reactions that alter the func-
tion of cellular constituents. The acronym PUVA refers to the combined use of psoralens
(P) and long-wave ultraviolet radiation (UVA). A combination of drug and radiation results in a
therapeutic effect after repeated controlled phototoxic reactions. Psoralens may be adminis-
tered orally or be applied topically to the skin; the initial discussion will be restricted to oral
PUVA therapy and topical therapy will be addressed later in the chapter.
PSORALENS
Background and History
Psoralens belong to the furocoumarin group of compounds and the parent compound, psora-
len, and many of its derivatives are naturally occurring compounds found in a large number of
plants. The medicinal properties of psoralens have been known for centuries and their use in
the treatment of vitiligo was recorded as long ago as 1550 BC (1). Three psoralens are used in
PUVA therapy (Fig. 1). Methoxsalen or 8-methoxypsoralen is obtained from the seeds of a plant
called Ammi majus and it is the most widely used psoralen and the only one available in the
United States. Bergapten or 5-methoxypsoralen and trioxsalen or 4,50 ,8-trimethylpsoralen are
available in Europe and elsewhere.
Pharmacology
Absorption
Psoralens are poorly soluble in water and this is a limiting factor in their absorption from the
gastrointestinal tract. There is a lot of interindividual variation in the absorption of the drug in
terms of both the amount absorbed and the rate of absorption (2). Peak blood levels vary a great
deal and timing also varies. Therefore, it is important to treat patients at a consistent time after
ingestion. There is also some intra-individual variation in the absorption of psoralens and this
is mainly due to what the patient has eaten and the time of day.
FIGURE 1 Psoralens used in therapy.

Psoralen Photochemotherapy 349
First-Pass Effect
Psoralens are subject to a significant but saturable first-pass effect in the liver (3). This means
that a proportion of any dose is metabolized by the liver after absorption and never reaches
the skin. However, since this effect can be saturated, as the dose is raised, the proportion of
active compound reaching the skin rises.
Concentration in Skin
The concentration level that is of importance is the level at the target site in the skin since it is
there that an interaction with UVA radiation will yield therapeutic benefit. Direct measurement
of the phototoxic response of skin is the only means available for assessing the cutaneous
content of psoralens.
Metabolism and Excretion

After oral administration, psoralens are distributed to all organs of the body, but in the absence
of photochemical binding, excretion is rapid. The compounds are metabolized in the liver
by cytochrome P-450 enzymes and drugs activating these enzymes accelerate metabolism of
psoralens (4).
Photobiology
Determinations of action spectra in vivo have shown that psoralen photosensitization occurs
with wavelengths .320 nm. Early studies in guinea pigs and humans indicated that the
action spectrum for delayed erythema with psoralens was between 340 and 380 nm and this
led to the use of UVA bulbs with a peak emission at those wavelengths; these are the bulbs
still used in therapy. More recent studies suggest that maximal photosensitization occurs at
the shorter wavelengths of 320 to 340 nm, but the precise action spectrum has not been
defined (5).
UVA RADIATION
Psoralens are mainly used in combination with broadband sources of UVA radiation. The most
commonly used source is fluorescent light bulbs, typically labeled PUVA lamps, having a
maximum emission at 352 nm and some emission in both UVB and visible light. Metal
halide lamps with suitable filters have also been used as a source of UVA radiation for activat-
ing psoralens. Their main advantage is a high irradiance so that treatment times are short.
Several sources of UVA radiation are not suitable for activating psoralens. The sun is a
very convenient source of UVA radiation but it is not a safe radiation source for use with psor-
alens because the therapeutic dose is close to the phototoxic dose. A high content of UVB in
sunlight might contribute to this problem. Black-light bulbs are also in general unsafe
because the emission spectrum is quite different from that of PUVA bulbs in most cases.
Tanning lamps are also unsuitable as a source of UVA radiation because they usually emit a
significant amount of UVB radiation and this will add to the unpredictability in psoralen
activation.
CUTANEOUS RESPONSES
Erythema
PUVA-induced erythema follows a different time course than that of UVB-induced erythema.
PUVA-induced erythema usually appears after 36 to 48 hours but in some patients may be
delayed until 72 hours. The peak of the erythema response is also delayed and may not be
reached until 96 to 120 hours after exposure and an erythema can persist for up to two or
even three weeks (6). Pruritus is a marked feature of PUVA-induced erythemas and often
occurs as a deep burning itch, feeling like insects crawling under the skin, and this can
persist for weeks or even months. This response is probably due to a direct phototoxic
injury of cutaneous nerves.
Pruritus
PUVA itch may occur as a symptom of phototoxicity in the absence of erythema and this typi-
cally begins on the outer aspect of the arms and thighs, the buttocks, and in women on the
breasts.
Pigmentation
PUVA produces pigmentation in all patients with functioning melanocytes. Pigmentation after
oral administration of psoralen and exposure to UVA radiation is usually darker and lasts
longer than the tan associated with a comparable UVB-induced erythema. Pigmentation fol-
lowing topical application of psoralens and exposure to UVA radiation can last for months. Pig-
mentation combined with hyperplasia of the epidermis and thickening of the stratum corneum
is effective in raising the threshold for erythema from subsequent exposure to UV radiation
with or without psoralens.
CELLULAR RESPONSES
Photoactive psoralens intercalate between the bases of DNA in the absence of radiation.
Absorption of photons by psoralens results in photochemical binding to a pyrimidine molecule
to give a monofunctional adduct. With some compounds, including methoxsalen, trimethylp-
soralen, and 5-methoxypsoralen, a second photon can be absorbed resulting in a cross-link to a
pyrimidine molecule on the sister strand of DNA. Such cross-links are also called bifunctional
adducts (7). Psoralens also react with RNA, protein, and cell membranes, but the importance of
these reactions is unknown.
TREATMENT
Psoralen Dosing
Both 5-methoxypsoralen and 8-methoxypsoralen are available as crystals in a capsule and as a
liquid in a soft gelatin capsule. The liquid formulation is preferred as it gives better and more
consistent absorption (8). The dose of 5-methoxypsoralen used is typically 1.2 mg/kg and that
of 8-methoxypsoralen is 0.4 to 0.6 mg/kg. The higher dose of 5-methoxypsoralen is necessary
to compensate for lower absorption (9). These compounds can be administered one or
two hours prior to exposure to UVA radiation but the time must be kept constant in any
given patient.
Determination of Sensitivity to PUVA Therapy

Two methods are used for determination of the initial dose of UVA radiation, skin typing, and
measurement of the minimal phototoxic dose (MPD). Phototesting to determine the MPD is a
superior approach in terms of requiring fewer treatments to clear disease but the total cumu-
lative dose and the frequency of erythema are higher with this technique (10).
Skin Typing
The patient is asked about their response to a 30-minute noontime exposure to sunlight at the
beginning of summer to determine skin types I through IV, whereas skin types V and VI are
decided on the basis of examination of the skin, skin type V being brown individuals and
skin type VI being black individuals. Suitable starting doses of UVA radiation and dose incre-
ments for a twice weekly or three times a week treatment schedule are given in Table 1.
Determination of the MPD

Dose ranges of UVA radiation for determining the MPD are given in Table 2. The phototest is
usually read at 72 hours and the starting dose of UVA radiation is 50% to 70% of the MPD and
the UVA radiation dose is increased weekly by 30% as tolerated (11).
TABLE 1 Dose of UVA Radiation Determined by Skin Types

UVA radiation dose (J/cm2)
Skin type Initial Increments
I 1.5 0.5
II 2.5 0.5
III 3.5 0.5–1.0
IV 4.5 1.0
V 5.5 1.0
VI 6.5 1.0–1.5
TABLE 2 Exposure Doses for MPD Test

With oral PUVA (J/cm2)
Skin types I –IV
UVA dose (8-MOP) 0.5 1 2 3 4 5
UVA dose (5-MOP) 1 2 4 6 8 10
With bath PUVA (J/cm2)
Skin types I and II
UVA dose (8-MOP) 0.25 0.5 1 1.5 2 2.5
Skin types III and IV
UVA dose (8-MOP) 0.5 1 2 3 4 5
Abbreviation: MPD, minimal phototoxic dose.
Treatment Schedules
Various treatment schedules have been used in PUVA therapy. A schedule using twice weekly
or three treatments a week appears to be equally efficacious. Treatments spaced at least 48
hours apart can determine whether erythema is developing from the previous treatment,
and the dose of UVA radiation is increased for each treatment provided no erythema is
present. A four times a week schedule is used in some centers with treatment on Monday,
Tuesday, Thursday, and Friday. The dose of UVA radiation is increased on Monday and Thurs-
day. For all schedules, if faint erythema is present, the dose of UVA radiation should be held
constant, but if widespread definite or tender erythema is present, treatment is stopped until
it has faded. Localized erythema, such as on the breasts or buttocks, can be managed by shield-
ing with clothing while treatment is continued.
MAINTENANCE THERAPY
One of the main advantages of PUVA therapy is that it is possible to maintain patients in a
relatively clear state using infrequent treatment, once their disease is controlled (12). The last
clearance dose of UVA radiation is held constant as the maintenance dose. There is no fixed
schedule of treatment for maintenance because individual responses are very variable and
the schedule outlined in Table 3 should only be used as a guide. If the patient has had four
months of monthly treatment without any significant recurrence, treatment can probably be
stopped. However, in our own left – right comparison study with psoriatics, short-term
PUVA maintenance treatment over two months did not increase the length of remission (13).
TABLE 3 Maintenance Schedule for PUVA Therapy

Four treatments at weekly intervals (Q.W)
Then four treatments every other week (Q.2W)
Then four treatments every third week (Q.3W)
Then four treatments at monthly intervals (Q.M)
TABLE 4 Protection During PUVA Therapy

During radiation
Eyes shielded by UVA-opaque goggles
Male genitalia covered with a jockstrap
Face protected
After ingestion of psoralen
Eyes protected by UVA-opaque glasses
Skin protected by clothing and sunscreens and avoidance of outdoor activities
Nontreatment days
Exposure to sunlight minimized
UV-blocking sunglasses worn
PRECAUTIONS
Attention must be focussed in two directions. First, psoralens enter all cells in the body and not
just those affected by the disease process. Second, there is a large amount of UVA radiation in
sunlight that can activate psoralens from the time of ingestion of the drug until it is excreted.
The eye is the most important consideration. Psoralens enter the eye and UVA radiation is
absorbed by the lens, so cataracts are a risk after repeated phototoxic insults. Clinical evalu-
ation of patients who neglected careful eye protection has shown no increase in lens opacities
(14). Obviously, there is no risk with topical or bath PUVA. Requirements for protection during
PUVA therapy are outlined in Table 4.
CONTRAINDICATIONS TO PUVA THERAPY

Table 5 lists the absolute and relative contraindications to therapy (15).
Short-Term Side Effects

The short-term problems with PUVA therapy are outlined in Table 6 (16). Most of these are
minor and can be easily overcome so that few patients cease treatment because of adverse
effects. Gastrointestinal disturbances, such as anorexia and nausea, and central nervous
system (CNS) disturbances, such as dizziness and insomnia, are the most common side
effects and are probably related to a high blood level of psoralen. Taking psoralen with food,
splitting the dose so that half is taken 90 minutes before treatment and the other half is
taken one hour before treatment or reducing the dose by 10 mg overcomes these problems
in most patients. With 5-MOP, these symptoms are much rarer. Symptomatic erythema is the
most troubling short-term problem of PUVA therapy and it occurs in around 10% of patients
during the clearance phase of treatment. There is no specific treatment for PUVA-induced
erythema and supportive measures such as cool baths, liberal use of moisturizing creams,
TABLE 5 Contraindications to PUVA Therapy

Absolute
Xeroderma pigmentosum
Albinism
Lactation
Lupus erythematosus with a history of photosensitivity or
a positive Ro antibody test
Relative
History or family history of melanoma
Past history of nonmelanoma skin cancer
Extensive solar damage
Uremia and severe hepatic failure
Pemphigus and pemphigoid
Immunosuppression
Pregnancy
Young age
TABLE 6 Short-Term Side Effects

Due to methoxsalen
Gastrointestinal effects
CNS symptoms
Bronchoconstriction
Drug fever
Exanthema
Phototoxicity
Erythema
Pruritus
Subacute phototoxicity
Photo-onycholysis
Koebner Phenomenon
Friction blisters
Phytophotodermatitis
Ankle edema
Nonphototoxic reactions
Cardiovascular stress
Hypertrichosis
Herpes simplex
Abbreviation: CNS, central nervous system.
aspirin, and antipruritics offer some relief. Unfortunately, some patients develop a new rash as
a side effect of treatment and the causes are listed in Table 7.
Long-Term Side Effects

Large prospective studies in the United States and Europe combined with smaller studies from
other areas have provided more than 25 years of follow-up data on the adverse effects of PUVA
therapy. Photoaging of the skin occurs with long-term treatment and is most marked with skin
types I and II, whereas little or no change is seen in skin types V and VI. Non-melanoma skin
cancer, mainly squamous cell carcinomas, has also been seen in patients receiving large doses
of treatment and again there is a strong correlation with skin type, with the lower skin types
being more susceptible (17 –19). A small increase in basal cell carcinomas has been observed
with lesions mainly occurring on the trunk (20). An increased incidence of melanoma began
to appear in one multicenter study 15 years after the start of treatment and the incidence
increased steadily in that study (21). This has not been observed in other studies but the dur-
ation and completeness of follow-up in those studies may be inadequate.
The potential ocular risk of PUVA therapy is cataracts and there are anecdotal reports of
several patients who developed cataracts following a course of PUVA therapy, but this has not
been revealed as a problem in a large prospective study (14).
DISEASES RESPONSIVE TO PUVA THERAPY

Psoriasis
Most forms of psoriasis are responsive to PUVA therapy with improvement after 6 to 10 treat-
ments and clearance occurring in 20 to 30 treatments in about 90% of patients (12,22,23). The
TABLE 7 Rashes Complicating Treatment

Lupus erythematosus
Transient acantholytic disease
Bullous pemphigoid
Guttate psoriasis
Sebborrheic dermatitis
Porokeratosis
Actinic lichen planus
most common indication for PUVA therapy is disabling psoriasis unresponsive to topical
therapy but there is no clear-cut definition of disability so it must be determined on a case-
by-case basis. In addition, generalized pustular psoriasis (24), palmoplantar pusulosis (25),
and erythrodermic psoriasis (26) have been reported to respond to PUVA therapy alone.
Combination therapy is often indicated in patients with severe inflammatory psoriasis,
erythrodermic, and generalized pustular psoriasis, in patients with thick plaques, or in those
with high skin types. Commonly used second agents are acitretin (27), methotrexate (28),
and broadband UVB (29). All these agents appear to improve the clearance rate and decrease
the duration of therapy.
Vitiligo
Vitiligo was the first indication for PUVA therapy, although it is less used now since narrow-
band UVB phototherapy has been demonstrated as an effective alternative for repigmentation
of this condition. Patients are treated as skin type I individuals with the aim of maintaining
minimal, light pink, phototoxicity in patches of vitiligo. It requires 100 to 200 exposures to
produce maximal repigmentation and about 70% of patients respond (30,31). Treatments are
given two or three times weekly. Combination therapy using topical corticosteroids or
topical calcipotriene may enhance the response to PUVA therapy (32).
Mycosis Fungoides
Mycosis fungoides in the most common of the cutaneous T-cell lymphomas, a group of
disorders that arise from malignant CD4þ helper T-cells and localize within the skin and
associated lymph nodes. The early phases of this disease, the so-called patch and plaque
phases, respond well to PUVA therapy with clearance rates of 70% to 90% (33). A high
relapse rate when short-term maintenance treatment alone is used may indicate a need for
long-term maintenance therapy in this condition; this approach has not been carefully evalu-
ated (34). According to the Swedish National Central Bureau of Statistics, it seems probable
that PUVA may be the main reason for a significant decrease in the death rate for mycosis
fungoides, which has dropped more than 50% since the introduction of PUVA (35). The
addition of systemic retinoids or combination with interferons may be beneficial but this
requires more controlled investigations (36,37).
Eczema
Most forms of eczema are responsive to PUVA therapy including atopic eczema (38) and hand
eczema (39). Clearance usually requires 30 to 50 treatments and maintenance is required for
several months.
Photodermatoses
Polymorphous light eruption is essentially prevented by PUVA therapy. A schedule of three
weekly exposures for three to four weeks is usually sufficient to prevent the rash and
regular sun exposure is required to keep up protection for the whole summer season (40).
Solar urticaria is also responsive to PUVA therapy with treatment of this condition requiring
careful dosimetry so as not to precipitate widespread urticaria (41). Chronic actinic dermatitis
can also be suppressed by PUVA therapy and this usually requires suppression with systemic
corticosteroids in the early phase of treatment (42).
Other Dermatoses
In addition to the diseases of the skin that have already been discussed, there are at least 30
other diseases reported to respond to PUVA therapy. Many of these conditions are rare, and
experience is limited to case reports but some have been studied in controlled or open trials
(Table 8).
TABLE 8 Other Dermatoses Responsive to PUVA Therapy

Alopecia areata (43,44)
Amyloidosis (45)
Darier’s disease (46)
Dermatitis herpetiformis (47)
Eosinophilic cellulitis (48)
Eosinophilic fasciitis (49)
Eosinophilic pustular folliculitis (50)
Erythema multiforme (51)
Flegel’s disease (52)
GVH disease (53,54)
Granuloma annulare (55,56)
Granuloma faciale (57)
Histiocytosis X (58)
Ichthyosis linearis circumflexa (59)
Keratosis lichenoides chronica (60)
Lichen planus (61,62)
Lymphomatoid papulosis (63)
Mastocytosis (64,65)
Necrobiosis lipoidica (66)
Papulerythroderma (67)
Pigmented purpuric dermatoses (68,69)
Pityriasis lichenoides (70)
Pruritus– polycythemia vera (71)
Sclerosing skin diseases
Morphea (72,73)
Systemic sclerosis (74)
Lichen sclerosis et atrophicus (75)
Scleredema (76,77)
Scleromyxedema (78,79)
Subacute prurigo (80)
Subcorneal pustular dermatosis (81)
Transient acantholytic dermatosis (82,83)
Vasculitis (84)
TOPICAL PUVA THERAPY

Direct application of psoralens to the skin combined with subsequent exposure to UVA radi-
ation is widely used as a treatment, particularly in Europe (85). The psoralen is usually
applied as a dilute solution in a bath or in a small container for local treatment of the hands
and feet, the so-called soak PUVA therapy. Methoxsalen is the preferred psoralen in most
centers because it gives a brief duration of photosensitivity, with all photosensitivity cleared
within four hours. Trimethylpsoralen has been used in Scandinavia but has the disadvantage
of causing prolonged photosensitivity that can last up to 48 hours.
Bath PUVA
The patient bathes in a dilute methoxsalen solution at 378C immersed up to the neck for 15
minutes, then dries, and is given immediate exposure to UVA radiation. Various concentrations
of methoxsalen have been used ranging from 0.5 up to 3 mg/L. The initial dose of UVA radi-
ation is usually determined by measuring the MPD, although skin typing has also been used
as a guide for treatment. Phototoxicity is the main adverse effect reported in studies and its fre-
quency depends on the aggressiveness of the treatment protocol. Gastrointestinal disturbances
and CNS symptoms are not seen with this form of PUVA therapy. Because of the very low
serum levels that occur with topical PUVA therapy, the potential risk of cataracts should be
nonexistent. There is no long-term safety data available for topical methoxsalen PUVA
therapy, but based on studies in Swedish and Finnish patients, bath PUVA with TMP (86)
and 8-MOP (87) appeared to have no relevant risk of carcinogenesis. Perhaps related to
lower cumulative UVA doses, these data on the long-term safety of bath PUVA are encouraging
but no premature conclusions should be drawn.
Other Forms of Therapy

Soak PUVA therapy uses a basin containing about 5 L of water and is useful for treating hand
and foot diseases. Methoxsalen in a cream or gel has been used for local treatments and the
kinetics of photosensitivity are similar to bath PUVA.
REFERENCES
1. Pathak MA, Fitzpatrick TB. The evolution of photochemotherapy with psoralens and UVA (PUVA):
2000 BC to 1992 AD. J Photochem Photobiol B: Biol 1992; 14:3– 22.
2. Herfst MJ, De Wolff FA. Intraindividual and interindividual variability in 8-methoxypsoralen kinetics
and effect in psoriatic patients. Clin Pharmacol Ther 1983; 34:117 – 125.
3. Brikl R, Schmid J, Koss FW. Pharmacokinetics and pharmacodynamics of psoralens after oral admin-
istration: considerations and conclusions. Natl Cancer Inst Monogr 1984; 66:63– 67.
4. Tantcheva-Poór I, Servera-Llaneras M, Scharffetter-Kochanek K, et al. Liver cytochrome P450
CYP1A2 is markedly inhibited by systemic but not by bath PUVA in dermatological patients. Br J
Dermatol 2001; 144:1127 – 1132.
5. Cripps DJ, Lowe NJ, Lerner AB. Action spectra of topical psoralens: a re-evaluation. Br J Dermatol
1982; 107:77– 82.
6. Ibbotson SH, Farr PM. The time-course of psoralen ultraviolet A (PUVA) erythema. J Invest Dermatol
1999; 113:346– 349.
7. Dall’Acqua F. Furocoumarin photochemistry and its main biological implications. In: Hönigsmann H,
Stingl G, eds. Current Problems in Dermatology. Vol. 15. Therapeutic Photomedicine. Basel: Karger,
1986:137– 163.
8. Hönigsmann H, Jaschke E, Nitsche V, et al. Serum levels of 8-methoxypsoralen in two different drug
preparations. Correlation with photosensitivity and UVA dose requirements for photochemotherapy.
9. Stolk LML, Westerhof W, Corman RH, et al. Serum and urine concentrations of 5-methoxypsoralen
after oral administration. Br J Dermatol 1981; 105:415– 420.
10. Collins P, Wainwright NJ, Amorim I, et al. 8-MOP PUVA for psoriasis: a comparison of a minimal
phototoxic dose-based regimen with a skin-type approach. Br J Dermatol 1996; 135:248– 254.
11. Wolff K, Gschnait F, Hönigsmann H, et al. Phototesting and dosimetry for photochemotherapy. Br J
Dermatol 1977; 96:1– 10.
12. Melski JW, Tanenbaum L, Fitzpatrick TB, et al. Oral methoxsalen photochemotherapy for the treat-
ment of psoriasis: a cooperative clinical trial. J Invest Dermatol 1977; 68:328– 335.
13. Tanew A, Radakovic-Fijans, Seeber A, et al. PUVA maintenance treatment for psoriasis. J Invest
Dermatol 2001; 117(3):816.
14. Stern RS, Parrish JA, Fitzpatrick TB. Ocular findings in patients treated with PUVA. J Invest Dermatol
1985; 85:269– 273.
15. American Academy of Dermatology Committee on Guidelines of Care. Guidelines of care for
psoriasis. J Am Acad Dermatol 1994; 31:643– 648.
16. Morison WL. Phototherapy and Phototherapy of Skin Disease. 3rd ed. Boca Raton, FL: Taylor &
Francis Group, 2005.
17. Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UV-A
radiation (PUVA). Arch Dermatol 1998; 134:1582– 1585.
18. Stern RS, Thibodeau LA, Kleinerman RA, et al. Risk of cutaneous carcinoma in patients treated with
oral methoxsalen photochemotherapy for psoriasis. N Eng J Med 1979; 300:809– 813.
19. Henseler T, Christophers E, Hönigsmann H, et al. Skin tumors in the European PUVA study. J Am
Acad Dermatol 1987; 16:108– 116.
20. Katz KA, Marcil I, Stern RS. Incidence and risk factors associated with a second squamous cell
carcinoma or basal cell carcinoma in psoralen þ ultraviolet A light-treated psoriasis patients.
21. Stern RS, Nichols KT, Vākevā LH. Malignant melanoma in patients treated for psoriasis with
methoxsalen (psoralen) and ultraviolet A radiation (PUVA). N Engl J Med 1997; 336:1041– 1045.
22. Parrish JA, Fitzpatrick TV, Tanenbaum L, et al. Photochemotherapy of psoriasis with oral methoxsa-
len and long wave ultraviolet light. N Engl J Med 1974; 291:1207– 1211.
23. Hönigsman H, Fitzpatrick TB, Pathak MA, et al. Oral photochemotherapy with psoralens and UVA
(PUVA): principles and practice. In: Fitzpatrick TB, Eisen AZ, Wolkk F, et al., eds. Dermatology in
General Medicine. 4th ed. New York: McGraw-Hill, 1993:1728– 1754.
24. Hönigsmann H, Gschnait F, Konrad K, et al. Photochemotherapy for pustular psoriasis
(von Zumbusch). Br J Dermatol 1977; 97:119 – 126.
25. Murray D, Corbett MF, Warin AP. A controlled trial of photochemotherapy for persistent palmoplan-
tar pustulosis. Br J Dermatol 1980; 102:659– 665.
26. Vukas A. Photochemotherapy in treatment of psoriatic variants. Dermatologica 1977; 155:355– 361.
27. Tanew A, Guggenbichler A, Hönigsmann H, et al. Photochemotherapy for severe psoriasis without or
in combination with acitretin: a randomized, double-blind comparison study. J Am Acad Dermatol
1991; 25:682– 684.
28. Morison WL, Momtaz K, Parrish JA, et al. Combined methotrexate-PUVA therapy in the treatment of
psoriasis. J Am Acad Dermatol 1982; 6(1):46– 51.
29. Momtaz-T K, Parrish JA. Combination of psoralens and ultraviolet A and ultraviolet B in the treat-
ment of psoriasis vulgaris: a bilateral comparison study. J Am Acad Dermatol 1984; 10:481– 486.
30. Pathak MA, Mosher DB, Parrish JA, et al. Relative effectiveness of three psoralens & sunlight in repig-
mentation of 365 vitiligo patients (abstract). J Invest Dermatol 1980; 74:252.
31. Grimes PE, Minus HR, Chakrabarti SG, et al. Determination of optimal topical photochemotherapy
for vitiligo. J Am Acad Dermatol 1982; 7:771– 778.
32. Ermis O, Alpsoy E, Cetin L, et al. Is the efficacy of psoralen plus ultraviolet A therapy for vitiligo
enhanced by concurrent topical calcipotriol? A placebo-controlled double-blind study. Br J Dermatol
2001; 145:472– 475.
33. Gilchrest BA, Parrish JA, Tanenbaum LT, et al. Oral methoxsalen photochemotherapy of mycosis
fungoides. Cancer 1976; 38:683– 689.
34. Hönigsmann H, Brenner W, Rauschmeier W, et al. Photochemotherapy for cutaneous T cell
lymphoma. J Am Acad Dermatol 1984; 10:238– 245.
35. Swanbeck G, Roupe G, Sandström MH. Indications of a considerable decrease in the death rate in
mycosis fungoides by PUVA treatment. Acta Derm Venereol 1994; 74:465– 466.
36. Mostow EN, Neckel SL, Oberhelman L, et al. Complete remissions in psoralen and UV-A (PUVA)-
refractory mycosis fungoides-type cutaneous T-cell lymphoma with combined interferon Alfa and
PUVA. Arch Dermatol 1993; 129:747– 752.
37. Stadler R, Otte HG, Luger T, et al. Prospective randomized multicenter clinical trial on the use of
interferon / 2a plus acitretin versus interferon / 2a plus PUVA in patients with cutaneous T-cell
lymphoma stages I and II. Blood 1998; 10:3578– 3581.
38. Morison WL, Parrish JA, Fitzpatrick TB. Oral psoralen photochemotherapy of atopic eczema. Br J
Dermatol 1978; 98:25 – 30.
39. Tegner E, Thelin I. PUVA treatment of chronic eczematous dermatitis of the palms and soles. Acta
Derm Venereol (Stockh) 1985; 65:451– 453.
40. Ortel B, Tanew A, Wolff K, et al. Polymorphous light eruption: action spectrum and photoprotection.
J Am Acad Dermatol 1986; 14:748 –753.
41. Parrish JA, Jaenicke KF, Morison WL, et al. Solar urticaria: treatment with PUVA and mediator inhibi-
tors. Br J Dermatol 1982; 106:575– 580.
42. Yokel BK, Hood AF, Morison WL. Management of chronic photosensitive eczema. Arch Dermatol
1990; 126:1283– 1285.
43. Claudy AL, Gagnaire D. Photochemotherapy for alopecia areata. Acta Dermatol Venereol (Stockh)
1979; 60:171– 172.
44. Healy E, Rogers S. PUVA treatment for alopecia areata—does it work? A retrospective review of 102
cases. Br J Dermatol 1993; 129:42– 44.
45. Jin AGT, Por A, Wee LKS, et al. Comparative study of phototherapy (UVB) vs. photochemotherapy
(PUVA) vs. topical steroids in the treatment of primary cutaneous lichen amyloidosis. Photodermatol
Phtoimmunol Photomed 2001; 17:42– 43.
46. Sönnichsen VN, Brenke A, Diezel W. Dyskeratosis follicularis vegetans (Morbus Darier) therapie mit
dem aromaitschen retinoid RO 10-9359 (Tigasonw) in kombination mit systemischer photo-
chemotherapie (ReUVA). Dermatol Monatsschr 1982; 168:520– 522.
47. Kalimo K, Lammintausta K, Viander M. PUVA treatment of dermatitis herpetiformis. Photodermatol
1986; 3:54– 55.
48. Diridl E, Hönigsmann H, Tanew A. Wells’ syndrome responsive to PUVA therapy. Br J Dermatol 1997;
137:479– 481.
49. Schiener R, Behrens-Williams SC, Gottlöber P, et al. Eosinophilic fasciitis treated with psoralen-
ultraviolet A bath photochemotherapy. Br J Dermatol 2000; 142:804 –807.
50. Buchness MR, Lim HW, Hatcher LA, et al. Eosinophilic pustular folliculitis in the acquired immuno-
deficiency syndrome. N Eng J Med 1988; 318:1183 – 1186.
51. Morison WL, Anhalt GJ. Therapy with oral psoralen plus UV-A for erythema multiforme. Arch
Dermatol 1997; 133:1465– 1466.
52. Cooper SM, George S. Flegel’s disease treated with psoralen ultraviolet A. Br J Dermatol 2000;
142:340– 342.
53. Vole-Platzer B, Hönigsmann H, Hinterberger W, et al. Photochemotherapy improves chronic
cutaneous graft-versus-host disease. J Am Acad Dermatol 1990; 23:220– 228.
54. Wolff D, Anders V, Corio R, et al. Oral PUVA and topical steroids for treatment of oral manifestations
of chronic graft-vs-host disease. Photodermatol Photoimmunol Photomed 2004; 20:184– 190.
55. Hindson TC, Spiro JG, Cochrane H. PUVA therapy of diffuse granuloma annulare. Clin Exp Dermatol
1988; 13:26– 27.
56. Kerker BJ, Huang CP, Morison WL. Photochemotherapy of generalized granuloma annulare. Arch
Dermatol 1990; 126:359– 361.
57. Hudson LD. Granuloma faciale: treatment with topical psoralen and UVA. J Am Acad Dermatol 1983;
8:559.
58. Iwatsuki K, Tsugiki M, Yoshizawa N, et al. The effect of phototherapies on cutaneous lesions of
histiocytosis X in the elderly. Cancer 1986; 57:1931– 1936.
59. Manabe M, Yoshiike T, Negi M. Successful therapy of ichthyosis linearis circumflexa with PUVA.
60. Lang PG. Keratosis lichenoides chronica. Arch Dermatol 1981; 117:105 –108.
61. Gonzalez E, Momtaz TK, Freedman S. Bilateral comparison of generalized lichen planus treated with
psoralens and ultraviolet A. J Am Acad Dermatol 1984; 10:958– 961.
62. Lundquist G, Forsgren H, Gajecki M, et al. Photochemotherapy of oral lichen planus. Oral Surg Oral
Med Oral Pathol Oral Radio Endod 1995; 79:554– 558.
63. Volkenandt M, Kerscher M, Sander C, et al. PUVA-bath photochemotherapy resulting in rapid
clearance of lymphomatoid papulosis in a child. Arch Dermatol 1995; 131:1094.
64. Briffa DV, Eady RAJ, James MP, et al. Photochemotherapy (PUVA) in the treatment of urticaria
pigmentosa. Br J Dermatol 1983; 109:67– 75.
65. Mackey S, Pride HB, Tyler WB. Diffuse cutaneous mastocytosis. Arch Dermatol 1996; 132:1429–1430.
66. Ling TC, Thomson KF, Goulden V, et al. PUVA therapy in necrobiosis lipoidica diabeticorum. J Am
Acad Dermatol 2002; 46:319– 320.
67. Mutluer S, Yerebakan O, Alpsoy E, et al. Treatment of papuloerythroderma of Ofuji with re-PUVA: a
case report and review of the therapy. J Eur Acad Dermatol Venereol 2004; 18:480– 483.
68. Krizsa J, Hunyadi J, Dobozy A. PUVA treatment of pigmented purpuric lichenoid dermatitis
(Gougerot-Blum). J Am Acad Dermatol 1992; 27:778– 780.
69. Ling TC, Goulden V, Goodfield MJD. PUVA therapy in lichen aureus. J Am Acad Dermatol 2001;
45:145– 146.
70. Boelen RE, Faber WR, Lambers JCCA, et al. Long-term follow-up of photochemotherapy in pityriasis
lichenoides. Acta Derm Venereol (Stockh) 1982; 62:442– 444.
71. Morison WL, Nesbitt JA. Oral psoralen photochemotherapy (PUVA) for pruritus associated with
polycythemia vera and myelofibrosis. Am J Heratol 1993; 42:409– 410.
72. Morison WL. Psoralen UVA therapy for linear and generalized morphea. J Am Acad Dermatol 1997;
37:657– 658.
73. Todd DJ, Askari A, Ektaish F. PUVA therapy for disabling pansclerotic morphoea of children. Br J
Dermatol 1998; 138:201– 202.
74. Hofer A, Soyer HP. Oral psoralen-UV-A for systemic scleroderma. Arch Dermatol 1999; 136:603 –604.
75. Reichrath J, Reinhold J, Tilgen W. Treatment of genito-anal lesions in inflammatory skin diseases
with PUVA cream photochemotherapy: an open pilot study in 12 patients. Dermatology 2002;
205(3):245– 248.
76. Grundmann-Kollman M, Ochsendorf F, Zollner TM, et al. Cream PUVA therapy for sclerodema
adultorum. Br J Dermatol 2000; 142:1058– 1059.
77. Hager CM, Sobhi HA, Hunzelmann N, et al. Bath-PUVA therapy in three patients with scleredema
adultorum. J Am Acad Dermatol 1998; 38:240– 242.
78. Adachi Y, Iba S, Horio T. Successful treatment of lichen myxoedematosus with PUVA photoche-
motherapy. Photodermatol Photoimmunol Photomed 2000; 16:229– 231.
79. Farr PM, Ive FA. PUVA treatment of scleromyxedema. Br J Dermatol 1984; 110:347– 350.
80. Clark AR, Pa C, Jorizzo JL, et al. Papular dermatitis (subacute prurigo “itchy red bump” disease):
pilot study of phototherapy. J Am Acad Dermatol 1998; 38:929– 933.
81. Todd DJ, Bingham EA, Walsh M, et al. Subcorneal pustular dermatosis and IgA paraproteinaemia:
response to both etretinate and PUVA. Br J Dermatol 1991; 125:387– 389.
82. Lüftl M, Degitz K, Plewig G, et al. Bath psoralen-UV-A therapy for persistent Grover disease.
Arch Dermatol 1999; 135:606– 607.
83. Paul BS, Arndt KA. Response of transient acantholytic dermatosis to photochemotherapy.
Arch Dermatol 1984; 120:121– 122.
84. Choi HJ, Hann SK. Livedo reticularis and livedoid vasculitis responding to PUVA therapy. J Am Acad
Dermatol 1999; 40:204– 207.
85. Halpern SM, Anstey AV, Dawe RS, et al. Guidelines for topical PUVA: a report of a workshop of the
British Photodermatology Group. Br J Dermatol 2000; 142:22– 31.
86. Hannuksela-Svahn A, Sigurgeirsson B, Pukkala E, et al. Trioxsalen bath PUVA did not increase the
risk of squamous cell skin carcinoma and cutaneous malignant melanoma in a joint analysis of 944
Swedish and Finnish patients with psoriasis. Br J Dermatol 1999; 141:497– 501.
87. Hannuksela-Svahn A, Pukkala E, Koulu L, et al. Cancer incidence among Finnish psoriasis patients
treated with 8-methoxypsoralen bath PUVA. J Am Acad Dermatol 1999; 40:694– 696.
25 Extracorporeal Photochemotherapy
(Photopheresis)
Robert Knobler
Division of Special and Environmental Dermatology, Department of Dermatology,
Medical University of Vienna, Vienna, Austria, and Department of Dermatology, College of Physicians and
Surgeons, Columbia University, New York, New York, U.S.A.
Peter W. Heald
Department of Dermatology, West Haven VA Medical Center, Yale University School of Medicine,
New Haven, Connecticut, U.S.A.
B Efficacy of treating CTCL with skin directed therapies such as PUVA lead
to the refinement of this therapeutic approach, where the target cells
responsible for the disease pathology are directly treated. In ECP,
extracorporeal PUVA therapy of the peripheral blood mononuclear cells
(lymphocyte enriched, red cell depleted buffy coat) is performed.
B Photopheresis is approved by the Food and Drug Administration for

the palliative treatment of refractory erythrodermic CTCL (Sézary’s
syndrome); however, the results in plaque and tumor stage disease are
not impressive. Photopheresis has engendered numerous therapeutic
trials with a wide range of other applications, particularly, acute and
chronic GVHD, which has become the second most common application,
and solid organ transplant rejection.
B Photopheresis for the treatment of systemic scleroderma and other

autoimmune diseases and bullous dermatoses, although reportedly
successful in several studies, is still under investigation. The efficacy
of this treatment for these diseases, except for systemic scleroderma, has
not been established by controlled clinical trials.
B Since its introduction, ECP has been shown to have only limited side
effects, most of which are associated with volume changes during
treatment, rarely anticoagulation toxicity such as bleeding or
hypersensitivity reactions (Table 2).
B Recent progress in the understanding of the mechanisms of action,

including possible induction of regulatory T-cells, may provide future
developments that can be tested in future clinical trials and new
indications within and outside dermatology.
360 Knobler and Heald
INTRODUCTION
any of the therapeutic effects of irradiating diseased skin arise from the unique suscep-
M tibility of the pathogenic leukocytes in the skin to ultraviolet therapy when compared to
normal resident cells. Hence, in the management of cutaneous T-cell lymphoma (CTCL),
Psoralen plus UVA (PUVA) has repeatedly demonstrated its efficacy (see chap. 24). Patients
with the mycosis fungoides type of CTCL have malignant lymphocytes infiltrating the epider-
mis and dermis. When those are the only lesions present, PUVA is an appropriate therapy. The
disease can progress by several mechanisms to spread beyond this epidermal-dermal unit.
When malignant lymphocytes accumulate in the blood and diffusely infiltrate the skin, patients
become erythrodermic (Fig 1). Thus, PUVA therapy of the peripheral blood became a concept
in the early 1980s. The major physical problem with irradiating circulating lymphocytes
is that they are surrounded with erythrocytes containing hemoglobin, providing multiple
interruptions to the delivery of UVA to the lymphocyte. Another obvious problem is that
not all lymphocytes can be exposed, most are in tissue, and even if they were in circulation,
the entire peripheral compartment cannot be removed. To effect a session of extracorporeal
photochemotherapy or photophoresis ECP, the peripheral blood would need to be pheresed,
returning removed erythrocytes to the patient. This creates a buffy coat, enriched for lymphocytes,
with a hematocrit of between 2% and 4%. This population of collected cells, some 10% of the cir-
culating pool, can be dosed with 8-methoxypsoralen (MOP) and perfused through a UVA emitting
light source. In the initial clinical trial, it was decided to perform consecutive days of therapy to
expose at least 20% of the circulating lymphocytes. The intervals between treatments would deter-
mine the size of the clinical trial, and intervals of four weeks were selected. As will be discussed in
the applications, efficacy and safety were noted and this two half-day-per-month schedule was
adopted. Since those initial developments, some of the patents on photopheresis have expired,
and there are now derivations developing that accentuate one or more aspects in the overall
process, to develop a wider range of phototherapy products than what was initially offered.
Photopheresis has engendered numerous therapeutic trials, a wide range of applications
(Table 1), immunologic insights, and concepts for future development that are presented in this
FIGURE 1 Erythrodermic cutaneous T-cell

lymphoma (A) with diffuse involvement of the
hands prior to photopheresis, and (B) in remission
(patient remained in complete remission for over
12 years).
Extracorporeal Photochemotherapy (Photopheresis) 361
chapter. The therapeutic applications are presented to portray the scope of the therapy. This is
followed by an attempt to project where this photoimmunotherapy will develop based on
current research.
APPLICATIONS OF PHOTOPHERESIS IN DISEASE

Cutaneous T-Cell Lymphoma
As mentioned, the current photopheresis regimens still reflect the schedules in the initial multi-
center clinical trial (1). In that initial study, the erythrodermic form of CTCL was noted to be
the variant most responsive to photopheresis. Based on the success of this schedule, most
CTCL patients undergo the two-day every four-week regimen.
The results of the initial clinical trials and follow-up studies showed that, as a monother-
apy, photopheresis (Fig. 2) can induce a remission in approximately one-fourth of the patients
treated (Figs. 1,3) (2). One-half of the patients with erythrodermic CTCL had a significant
partial response and the remaining one-fourth had no response or progressive disease. This
same proportion of responses was observed in the smaller series of CTCL (3 –5). From these
clinical experiences, several other common features were found. The response to photopheresis
is gradual; a periodic assessment of tumor burden measures should be conducted every four to
eight weeks with a time to response of typically 12 to 16 weeks into therapy. Peripheral blood
studies would include flow cytometry, following the lymphocyte population that expresses
CD4, but not CD7 (CD4þ/CD72). Along with a skin score, this is an objective parameter in
the management of erythrodermic CTCL patients (6). In the absence of this investigation,
one could also follow CD4:CD8 ratios as a measure of tumor burden in the peripheral blood
(7). Dose responsiveness of photopheresis has not been striking, but in one report, a patient
was treated using an every two-week regimen at the initiation of therapy. The CTCL patient
in that report had hyperleukocytic disease and after the leukemia improved, the patient was
put on a four-week cycle (8). Several other centers have since adopted this accelerated delivery
schedule at the initiation of therapy. After 12 to 16 weeks, a trend in the patient’s clinical
status should be evident. If there are signs of improvement, the therapy should be continued
to maximize the therapeutic response. Complete clearing may occur after six to eight
months of gradual improvement. Patients with incomplete responses at three to six months
are usually considered for adjunctive therapy.
Adjunctive therapy with photopheresis is as vast as the therapeutic armamentarium for this
disease in general. However, the major principle guiding the use of adjunctive therapy is that the
disease at this point is immunosuppressive in itself (7), so that therapies that avoid immuno-
suppression or even stimulate the immune system are preferred. There are agents used in
conjunction with photopheresis from all three categories of CTCL therapy: (i) skin-directed
FIGURE 2 A patient being treated with photopheresis.

The recumbent position or in bed (as illustrated) is
maintained for at least three hours. The device opened
to display the various components: A. Centrifuge,
B. Irradiation Chamber, C. Pheresed erythrocytes to be
returned, and D. Photoinactivated lymphocytes to be
reinfused.
FIGURE 3 Response of facial features of Sézary syndrome (A) before (with vegetating herpes simplex), and (B) after
photopheresis (pre-existing vitiligo became evident).
therapy, (ii) biologic response modifiers, and (iii) low-dose chemotherapy. In patients with sig-
nificant tumor burden, a reduction of that tumor burden with a skin-directed treatment can
work synergistically with photopheresis. Debulking of CTCL can reliably be performed with
radiotherapy (total skin electron beam therapy). In one series, patients treated with photopher-
esis and total skin electron beam had improved survival, when compared with similarly staged
patients at the same institution treated with total skin electron beam therapy alone (9). More
recently, however, the failing immunity in erythrodermic CTCL patients has become the
target of adjunctive therapy. This began with alfa-interferon (IFN-a).
In a review of a decade of using IFN-a with photopheresis, a greater response rate was
noted than with historic controls (10,11). Once the oral retinoid bexarotene was found to have
unique activity against CTCL, combinations of this with photopheresis have been reported.
The most intriguing results have now been reported with the combination of IFN-a, oral bexar-
otene, and photopheresis (12). This multimodality regimen is useful in that it can minimize
toxicity of the injected and oral agents by using low doses. Enough complete remissions have
been induced with this regimen to prompt discussion regarding the approach to managing
photopheresis patients (13). Typically, patients are started on monotherapy and if responding,
adjuncts are added to achieve a complete response. An alternative approach would be to com-
mence with the best chance of a response, with all the three therapies, and taper off if a complete
response has been achieved.
The failing immunity of advancing CTCL is the major reason why traditional high-dose
chemotherapy has been unsuccessful in treating CTCL, because it is too toxic. However, low-
dose chemotherapy has been employed with beneficial results. There are two oral agents that
TABLE 1 Indications for Photopheresis

Good evidence available
Erythrodermic CTCL Chronic graft-versus-host disease
Acute graft-versus-host disease Organ transplant rejection
Experimental and investigational
Scleroderma Nephrogenic fibrosing dermopathy
Bullous dermatoses Lichen planus
Crohn’s disease Multiple sclerosis
Abbreviation: CTCL, cutaneous T-cell lymphoma.
TABLE 2 Side Effects of Photopheresis

Volume loading with saline: exacerbation of congestive heart failure
Anticoagulation toxicity: bleeding, hypersensitivity
Venipuncture pain and prolonged recumbency
have theoretical and anecdotal benefits for photopheresis patients (14,15). Photochemotherapy
induces DNA damage and requires rescue from pathways that are inhibitable by methotrexate
and enzymes that are inhibited by etoposide. Each of these agents has an impact in the oral
low-dose therapy of CTCL. Oral corticosteroids can be palliative in CTCL patients, but their
immunosuppressive effects have been shown to negate the therapeutic effects of photopheresis
in an experimental model (16).
In summary, photopheresis can be used as monotherapy in patients with erythrodermic
CTCL, or as part of a multiagent regimen for CTCL patients with refractory disease or multiple
tumors. The goal of therapy should be to achieve palliation and, less frequently, remission.
After achieving the therapy goal, photopheresis is gradually tapered. The taper schedule
used in the majority of the initial study patients was to add a seven-day interval every three
cycles of therapy. Once patients achieved eight-week intervals, and their skin remained clear
for a period of six months, they were taken off therapy. Patients with an unacceptable response
or progressive disease while receiving photopheresis should have their next line of therapy
introduced before discontinuing treatment completely. Therapeutic effects of photopheresis
are sometimes not appreciated until they are unmasked by a disease flare with the cessation
of therapy.
Once photopheresis became an available modality for CTCL treatment, dermatologists
began exploring the therapeutic effects in other difficult to treat dermatoses. The majority of
these have been with autoimmune diseases. After therapeutic effects were noted and
defined, photopheresis was then utilized in the undeniably autoimmune disease of graft-
versus-host disease (GVHD) in allogeneic bone marrow and stem cell transplants. GVHD
has become the second most common application.
Graft-vs.-Host Disease
GVHD is a frequent complication of allogeneic bone marrow transplantation (BMT) and per-
ipheral blood stem cell transplantation. GVHD is mediated by donor T-cells, reactive against
the recipient’s major, and minor histocompatibility antigens. Photopheresis is capable of
eliciting an immunoregulatory response against such pathogenic T-cells in a mouse model
system (17). There has been a growing clinical experience in the use of photopheresis as treat-
ment of acute and chronic GVHD (18 –26).
The largest single center group of patients with chronic GVHD treated with photopher-
esis involved 15 patients (19). In this study, patients had extensive chronic GVHD, representing
a spectrum from lichenoid to sclerodermoid forms. They received photopheresis every two
weeks for the first three months, and monthly thereafter. Out of the 15 patients, 12 (80%)
obtained complete clearing of their cutaneous involvement. Of note, 11 of 11 patients with
oral mucosal involvement and 7 of 10 patients with liver involvement demonstrated complete
resolution of their extracutaneous involvement. Patients received photopheresis for 7 to 31
months, during which time corticosteroid therapy could be discontinued after a median of
80 days. In an independent study, 11 patients with chronic GVHD were treated with photopher-
esis twice monthly for four months, then once monthly thereafter. Although nearly all patients
initially demonstrated an improvement in skin and mucosal involvement by a blinded
observer scoring at the fourth month, the effects on visceral manifestations were less impress-
ive. For example, elevated liver enzymes improved in one of six patients but worsened in three
patients receiving photopheresis (20). In another report, four of five patients with chronic
GVHD (two of which had extensive cutaneous involvement) demonstrated improvement
with photopheresis, and three patients achieved complete remission. These complete respon-
ders were able to eventually discontinue all treatment modalities (20). Although these
reports and others are very encouraging, a large ongoing trial will more clearly delineate the
role of photopheresis in the treatment of chronic GVHD (21 –26).
Experience with photopheresis in the treatment of acute GVHD is equally promising,
but more limited than for chronic GVHD. As part of the study mentioned above, six patients
with histologic grade II to IV acute GVHD were treated with photopheresis twice monthly
(18). All were unresponsive to immunosuppressive therapy with combination of cyclosporine
and methylprednisolone. Overall, four of the six patients obtained complete resolution of
disease after only two to three months, at which time photopheresis was halted. Of note, pre-
dnisone was tapered off completely in the first two to four weeks of photopheresis, whereas
low-dose cyclosporine was continued as a maintenance modality. Prospective multicenter
studies under way should in the near future help delineate the significance of photopheresis
in the treatment of acute GVHD.
In a novel approach to using photopheresis in the management of GVHD, photopheresis
was reported to prevent the development of GVHD. The therapeutic regimen utilized the
combination of photopheresis, pentostatin, and radiotherapy in a series of 55 patients, where
only 9% developed greater than grade II GVHD (26).
Given the problems with the toxicity of the current standard of care therapy for GVHD
(i.e., various immunosuppressive medications) and the increasing incidence of GVHD as a
result of an expanding use of allogeneic BMT and peripheral blood stem cell transplantation,
photopheresis has grown in its use for GVHD. This is now the second largest group of patients
treated with photopheresis, behind CTCL.
Scleroderma
Scleroderma has been considered as a disorder of T-cells, a notion heavily reinforced by its
occurrence in the setting of allogeneic bone marrow or stem cell transplantation. The early
phase of scleroderma is characterized by an inflammatory infiltrate and edema within the
dermis. It is hypothesized that activated helper T-cells within the infiltrate help stimulate the
production of collagen synthesis and subsequent fibrosis. The degree to which fibrosis is
reversible in patients with scleroderma is unknown. One would anticipate that any successful
modality for scleroderma would demonstrate its greatest therapeutic effect in patients with
relatively recent disease onset. For that reason, the initial clinical trial of photopheresis for scler-
oderma focused on patients diagnosed within two years of starting therapy. The randomized,
parallel-group, single-blinded, multicenter clinical trial involved 79 patients and its goal was to
demonstrate safety and efficacy of photopheresis in the treatment of scleroderma (27). Patients
who had worsening of cutaneous involvement of at least 30% during the preceding six months
were randomized to receive photopheresis or oral D-penicillamine (maximum dose of 750 mg
daily) for six months. Exclusion criteria included significant renal disease (serum creatinine
.3 mg/dL) or pulmonary involvement (carbon monoxide diffusing capacity less than 50%
of normal). Clinical examiners, blinded to the treatment-type delivered, recorded a skin
score based on skin thickness, percentage surface area involved, oral aperture diameter, and
the capacity for hand closure. A significant improvement in skin score occurred in 68% (21
of 31) of patients receiving photopheresis and 32% (8 of 25) of patients on D-penicillamine,
whereas significant worsening was observed in 10% (three patients) receiving photopheresis
and 32% (eight patients) receiving D-penicillamine. The difference between the two groups
was statistically significant (P ¼ 0.02). Furthermore, adverse reactions in the photopheresis
study group were minimal, and all patients in the photopheresis group completed the study.
This is in contrast to the D-penicillamine group; 24% of these patients had to permanently
discontinue the treatment directly, because of adverse effects of this medication.
There were nine subjects in an open trial of scleroderma treated with photopheresis for 6
to 21 months. These patients demonstrated significant improvement in their skin, musculoske-
letal system, functional index, and symptoms including Raynaud’s phenomenon, dyspnea,
fatigue, dysphagia, and arthralgias (28). Again, patients in this study were relatively early in
their disease onset, with a history of scleroderma findings for only six months to four years.
However, there are two separate open trials of eight patients (29) and seven patients (30),
where subjects showed little response or worsening despite treatment with photopheresis.
Average disease duration in both trials was longer than in the randomized multicenter
trial discussed before. Furthermore, patients were not excluded on the basis of severe
internal organ involvement. In a recent randomized, double-blinded, placebo-controlled trial
with 64 patients, the efficacy of photopheresis on skin and joint involvement was also
reported (31).
A scleroderma variant, eosinophilic fasciitis, has been treated with photopheresis.
There have been reports of response in this autoimmune fibrotic disorder that can also
occur in the setting of GVHD. In a pilot study of eosinophilic fasciitis, two of three patients
showed softening of indurated skin as determined by a computerized measurement of skin
elasticity (32).
Autoimmune Bullous Diseases

Autoimmune bullous diseases (pemphigus vulgaris, pemphigus foliaceus, and epidermolysis
bullosa acquisita) represent disorders of humoral immunity with the elaboration of circulating
antibodies against distinctive structural proteins in the skin. In patients with pemphigus
vulgaris, production of autoantibodies against the desmoglein-3 protein component of kerati-
nocyte desmosomes leads to blister and erosion formation of cutaneous and mucosal surfaces.
Although the majority of patients are adequately controlled with the use of various immuno-
suppressive medications (i.e., high-dose corticosteroids, azathioprine, cyclosporin, or
cyclophosphamide), long-term treatment with these medications often results in significant
adverse effects. Thus, mortality remains around 5% to 15%, largely because of complications
from these drugs. Because photopheresis has a few adverse effects profile, it is a potential treat-
ment for pemphigus patients failing systemic drug therapy that is often immunosuppressing
and toxic.
The initial report of photopheresis efficacy involved four patients (ages 61 –78 years) with
extensive and refractory pemphigus vulgaris, despite large doses of immunosuppressive medi-
cations (33). Patients continued to receive prednisone alone or with azathioprine. All four
patients showed clinical improvement and a drop in antidesmosomal antibody titers,
despite tapering of immunosuppressive medications. After 36 to 48 months, three of the four
patients demonstrated a complete remission (no clinical evidence of active disease and
undetectable antidesmosomal antibody titers), which lasted an average 19.3 months (range
7 – 36 months). Relapses in the three patients responded to reinitiation of photopheresis after
three to four monthly cycles. Similar beneficial results of photopheresis for pemphigus vulgaris
have been reported in individual case reports. One involved a 31 year old man with a four-year
history of severe disease (34), and a woman, 37 years of age, with a five-year history of severe
pemphigus vulgaris (35). More recently, reported a beneficial effect of photopheresis in the
treatment of severe pemphigus foliaceus (36).
These case reports suggest that photopheresis may be a promising and relatively safe
treatment for the selective cases of pemphigus vulgaris. A randomized, controlled study
would be helpful to define its role.
Another notoriously difficult to treat bullous disease is epidermolysis bullosa acquisita
(EBA). In this disorder of antitype VII collagen antibodies, patients develop blisters and, in
addition, marked skin fragility. In an initial study of three adult patients with refractory
EBA, photopheresis treatment demonstrated objective improvements in blistering, whereas
two of three patients had significant subjective improvement in skin fragility (37). Certainly
further studies are necessary before photopheresis proves to be an effective treatment option
for aggressive forms of EBA.
Systemic Lupus Erythematosus

Disordered T-cell immunity has notoriously been associated with systemic lupus erythe-
matosus (SLE). Abnormal circulating B-cells and T-cells result in autoantibody production
against various nuclear and cytoplasmic antigens. The disease is usually controlled to
some degree with standard therapies, including antimalarials, corticosteroids, and other
immunosuppressive agents. A murine model of lupus has been modulated by infusions of
8-methoxypsoralen/UVA-light treated lymphocytes (38). This led to the concept of a clinical

trial in lupus patients. The initial investigators proceeded cautiously with concern that
photodamaged DNA would be infused into patients with anti-DNA antibodies.
The initial study of photopheresis in the treatment of SLE consisted of 10 patients who
met the American College of Rheumatology criteria for SLE (39). Study patients had their
disease adequately controlled with low-dose prednisone, chloroquine, azathioprine, or
cyclophosphamide; however, all patients had disease flares with multiple drug tapering
attempts. Strict inclusion criteria resulted in a study population with mild-to-moderate sys-
temic involvement. Patients were treated on two consecutive days every month for six
months, then every two months for another six months. In the eight patients who completed
the study, disease activity decreased as measured by the SLE Activity Index Scoring System
(40). The SIS score, based on a combination of clinical and laboratory findings, dropped
from a median seven (range 4 – 9) down to one (range 0 – 5). In all patients except one, the
dosages of corticosteroids and immunosuppressive medications were reduced during this
time. A marked resolution of cutaneous lesions was observed in six patients after four to six
months of photopheresis. Laboratory abnormalities showed no difference from baseline
values (39).
Oral Lichen Planus

The striking clinical similarities of lichen planus and GVHD continue into their respective
therapies. Photopheresis has been investigated in patients with lichen planus suffering from
one of the most symptomatic presentations: erosive oral lichen planus. In a study of seven
patients resistant to multiple medications, all patients demonstrated complete remission of
disease activity after a mean of 12 cycles (41).
PHOTOBIOLOGY OF PHOTOPHERESIS
Given the variety of immunomodulated diseases in dermatology, it would not be surprising to
see the repertoire of therapeutic applications increase over the next few years. Perhaps, these
clinical extensions will proceed from some of the parallel investigations being made in
ex-vivo studies of photoinactivated lymphocytes infusions. To date, no single mechanism is
consistent with the observations made, clinically or at the bench.
Investigators observed that CTCL patient’s peripheral lymphocytes that are isolated by
the photopheresis unit, after exposure to UVA in the presence of 8-MOP, undergo a pro-
grammed cellular death (apoptosis) (42,43). Thus, an alternative, nonimmunologic theory as
to the efficacy of photopheresis for CTCL is that repeated treatments eventually result in the
exposure of nearly all peripheral tumor cells to the induction of apoptosis. The explanation
may be limited by the asymptotic nature of such an exposure curve and by the fact that
many of the tumor cells are not in the peripheral circulation at any given time, although
they may repeatedly migrate in and out of the skin. Nonetheless, apoptotic malignant
T-cells may be actively phagocytized by antigen presenting cells (APC), which may facilitate
the presentation of relevant tumor antigens necessary to generate clone-specific, antitumor
immunity.
Photopheresis has been shown to induce large numbers of peripheral blood monocytes to
express markers of dermal dendritic cells (DC) (44). These cells have the capacity to actively
ingest 8-MOP/UVA-induced apoptotic T-cells, including malignant or autoreactive T-cells
that may be present in the circulation, which further stimulates DC activation and maturation.
Hence, photopheresis has been conjectured to result in the production and reinfusion of
putative T-cell-loaded APC capable of stimulating immunity against the pathogenic T-cells.
Importantly, especially in consideration of the mechanism of inhibition of autoreactivity, it is
also possible that under certain immune states, photopheresis may induce the production of
sufficient numbers of (e.g., immature) DC that may provide tolerogenic signals (45).
Recent experimental data suggest that infusion of autologous haptenated cells in which
apoptosis was induced by 8-MOP/UVA induces immunologic tolerance. The nature of this tol-
erance is primarily due to regulatory T-cells, because transfer in an animal model conferred
similar protection. The demonstration of the induction of regulatory T-cells may explain why,
in humans, ECP exerts a beneficial effect in a wide variety of diseases, which would be amen-
able to such activity. The generation of age-specific regulatory T-cells may explain why gener-
alized immunosuppression has not been noted with ECP (46).
The insight into the mechanism of photopheresis has provided several therapeutic devel-
opments that can be tested in future clinical trials. The conjecture that APC play a critical role in
photopheresis-induced activation of CD8þ T-cells leads to the conjectured use of cytokines
(e.g., GM-CSF) to activate APCs. Injections prior to a session of photopheresis would appear
to be the most timely, but post therapy may also be an important time of administration.
Not many dimensions of the photopheresis session can be manipulated (both the volume of
blood removed and the patient’s willingness to sit for long periods of time have limits);
however, the time that the lymphocytes are out of the body may also be increased in
an attempt to enhance efficacy (47). Future trials involving these and other adaptations of
photopheresis are anticipated.
REFERENCES
1. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal
photochemotherapy. Preliminary results. N Engl J Med 1987; 316(6):297– 303.
2. Heald P, Rook A, Perez M, et al. Treatment of erythrodermic cutaneous T-cell lymphoma with extra-
corporeal photochemotherapy. J Am Acad Dermatol 1992; 27(3):427– 433.
3. Zic J, Arzubiaga C, Salhany KE, et al. Extracorporeal photopheresis for the treatment of cutaneous
T-cell lymphoma. J Am Acad Dermatol 1992; 27(5):729– 736.
4. Armus S, Keyes B, Cahill C, et al. Photopheresis for the treatment of cutaneous T-cell lymphoma.
J Am Acad Dermatol 1990; 23(5):898– 902.
5. Bisaccia E, Gonzalez J, Palangio M, et al. Extracorporeal photochemotherapy alone or with adjuvant
therapy in the treatment of cutaneous T-cell lymphoma: A 9-year retrospective study at a single
institution. J Am Acad Dermatol 2000; 43(2):263– 271.
6. Stevens SR, Baron ED, Masten S, et al. Circulating CD4þ CD7 lymphocyte burden and rapidity of
response: predictors of outcome in the treatment of Sézary syndrome and erythrodermic mycosis
fungoides with extracorporeal photopheresis. Arch Dermatol 2002; 138(10):1347 – 1350.
7. Heald P, Yan SL, Latkowski J, Edelson R. Profound deficiency in normal circulating T-cells in erythro-
dermic cutaneous T-cell lymphoma. Arch Dermatol 1994; 130(2):198– 203.
8. Bowen GM, Steens SR, Dubin HV, et al. Diagnosis of Sézary syndrome in a patient with generalized
pruritus based on early molecular study and flow cytometry. J Am Acad Dermatol 1995; 33(4):678–680.
9. Wilson LD, Licata AL, Braverman IM, et al. Systemic chemotherapy and extracorporeal photoche-
motherapy and T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete
response to total skin electron beam therapy. Int J Rad Oncol 1995; 32(4):987– 995.
10. Rook A, Prystowsky M, Cassin M, et al. Combined therapy for Sézary syndrome with
extracorporeal photochemotherapy and low dose interferon alfa therapy. Arch Dermatol 1991;
127(10):1535– 1540.
11. Gottlieb SL, Wolfe JT, Fox F, et al. Treatment of cutaneous T-cell lymphoma with extracorporeal photo-
pheresis monotherapy and in combination with recombinant interferon alfa: a 10-year experience at a
single institution. J Am Acad Dermatol 1996; 35(6):946– 957.
12. Shapiro M, Rook AH, Lehrer MS, et al. Novel multimodality biologic response modifier therapy,
including bexarotene and long-wave ultraviolet A for a patient with refractory stage IVa. J Am
Acad Dermatol 2002; 47(6):956– 961.
13. Knobler R, Jantschitsch C. Extracorporeal photoimmunotherapy in cutaneous T-cell lymphoma.
Tranfus Apheresis Sci 2003; 28:81– 89.
14. Zackheim HS, Epstein EH. Low dose methotrexate for Sézary syndrome. J Am Acad Dermatol 1989;
21(4):757– 762.
15. Molin L, Thomsen K, Volden G, et al. Epipodophyllotoxin (VP-16-23) in mycosis fungoides: a report
for the Scandinavian mycosis fungoides group. Acta Derm Venereol 1979; 59(1):84– 90.
16. Perez MI, Edelson RL, LaRoche L, et al. Inhibition of anti-skin allograft immunity by infusions with
syngeneic photoinactivated effector lymphocytes. J Invest Dermatol 1989; 92(5):669– 674.
17. Girardi M, Heald P, Tigelaar RE. Specific suppression of lupus-like graft-versus-host disease using
extracorporeal photochemical attenuation of effector lymphocytes. J Invest Dermatol 1995;
104(2):177–182.
18. Greinix HT, Volc-Platzer B, Rabitsch W, et al. Successful use of extracorporeal photochemotherapy in
the treatment of severe acute and chronic graft-versus-host disease. Blood 1998; 92(9):3098– 3104.
19. Child FJ, Ratnavel R, Watkins P, et al. Extracorporeal photopheresis (ECP) in the treatment of chronic
graft-versus-host disease (GVHD). Bone Marrow Transplant 1999; 23(9):881– 887.
20. Besnier D, Chabannes D, Mahè B, et al. Treatment of graft-versus-host disease by extracorporeal

photochemotherapy. Transplantation 1997; 64(1):49– 54.
21. Owsianowski M, Gollnick H, Siegert W, et al. Successful treatment of chronic graft-versus-host
disease with extracorporeal photopheresis. Bone Marrow Transplant 1994; 14(5):845– 848.
22. Dall’Amico R, Rossetti F, Zulian F, et al. Photopheresis in paediatric patients with drug-resistant
chronic graft-versus-host disease. Br J Haematol 1997; 97(4):848– 854.
23. Rossetti F, Zulian F, Dall’Amico R, et al. Extracorporeal photochemotherapy as single therapy for
extensive, cutaneous, chronic graft-versus-host disease. Transplantation 1995; 59(1):49– 51.
24. Konstantinow A, Balda B-R, Starz H, et al. Chronic graft-versus-host disease: successful treatment
with extracorporeal photochemotherapy: a follow-up. Br J Dermatol 1996; 135(6):1003– 1017.
25. Richter H, Stege H, Ruzicka T, et al. Extracorporeal photopheresis in the treatment of acute
graft-versus-host disease. J Am Acad Dermatol 1997; 36(5 Pt 1):787– 789.
26. Miller KB, Roberts TF, Chan G, et al. A novel reduced intensity regimen for allogeneic hematopoietic
stem cell transplantation associated with a reduced incidence of graft-versus-host disease. Bone
Marrow Transplant 2004; 33(9):881– 999.
27. Rook AH, Freundlich B, Jegasothy BV, et al. Treatment of systemic sclerosis with extracorporeal
photochemotherapy. Results of a multicenter trial. Arch Dermatol 1992; 128(3):337– 346.
28. Di Spaltro FX, Cottrill C, Cahill C, et al. Extracorporeal photochemotherapy in progressive systemic
sclerosis. Int J Dermatol 1993; 32(6):417– 421.
29. Zachariae H, Bjerring P, Heickendorff L, et al. Photopheresis in systemic sclerosis: clinical and sero-
logical studies using markers of collagen metabolism. Acta Derm Venereol 1993; 73(5):356– 361.
30. Cribier B, Faradji T, Le Coz C, et al. Extracorporeal photochemotherapy in systemic sclerosis and
severe morphea. Dermatology 1995; 191(1):25– 31.
31. Knobler RM, French LE, Kim Y, et al. A randomized, double-blind, placebo-controlled trial of
photopheresis in systemic sclerosis. J Am Acad Dermatol 2006; 54(5):793– 796.
32. Romano C, Rubegni P, De Aloe G, et al. Extracorporeal photochemotherapy in the treatment of
eosinophilic fasciitis. J Eur Acad Dermatol Venereol 2003; 17(1):10– 13.
33. Rook AH, Jegasothy BV, Heald P, et al. Extracorporeal photochemotherapy for drug-resistant
pemphigus vulgaris. Ann Intern Med 1990; 112(4):303– 305.
34. Liang G, Nahass G, Kerdel FA. Pemphigus vulgaris treated with photopheresis. J Am Acad Dermatol
1992; 26(5 Pt 1):779– 780.
35. Gollnick HP, Owsianowski M, Taube KM, et al. Unresponsive severe generalized pemphigus vulgaris
successfully controlled by extracorporeal photopheresis. J Am Acad Dermatol 1993; 28(1):122– 124.
36. Azana JM, de Misa RF, Harto A, et al. Severe pemphigus foliaceus treated with extracorporeal photo-
chemotherapy. Arch Dermatol 1997; 133(3):287– 289.
37. Miller J, Stricklin GP, Fine JD, et al. Remission of severe epidermolysis bullosa acquisita induced by
extracorporeal photochemotherapy. Br J Dermatol 1995; 133(3):467– 471.
38. Berger CL, Perez M, Laroche L, et al. Inhibition of autoimmune disease in a murine model of systemic
lupus erythematosus induced by exposure to syngeneic photoinactivated lymphocytes. J Invest
Dermatol 1990; 94(1):52– 57.
39. Knobler RM, Graninger W, Lindmaier A, et al. Extracorporeal photochemotherapy for the treatment
of systemic lupus erythematosus. A pilot study. Arthritis Rheum 1992; 35(3):319– 324.
40. Brunner HI, Feldman BM, Bombardier C, et al. Sensitivity of the systemic lupus erythematosus
disease activity index, British isles lupus assessment group index, and Systemic Lupus Activity
Measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus.
Arthritis Rheum 1999; 42(7):1354– 1360.
41. Bécherel PA, Bussel A, Chosidow O, et al. Extracorporeal photochemotherapy for chronic erosive
lichen planus. Lancet 1998; 351(9105):805.
42. Yoo E, Rook A, Elenitsas R, et al. Apoptosis induction by ultraviolet light A and photochemotherapy
in cutaneous T-cell lymphoma: relevance to mechanism of therapeutic action. J Invest Dermatol 1996;
107(2):235– 242.
43. Miracco C, Rubegni P, DeAloe G, et al. Extracorporeal photochemotherapy induces apoptosis of infil-
trating lymphoid cells in patients with mycosis fungoides in early stages. A quantitative histological
study. Br J Dermatol 1997; 137(4):549– 557.
44. Berger CL, Xu AL, Hanlon D, et al. Induction of human tumor-loaded dendritic cells. Int J Cancer
2001; 91(4):438– 447.
45. Lamioni A, Parisi F, Isacchi G, et al. The immunological effects of extracorporeal photopheresis
unraveled: induction of tolerogenic dendritic cells in vitro and regulatory Tcells in vivo. Transplantation
2005; 79(7):846–850.
46. Maeda A, Schwarz A, Kernebeck K, et al. Intravenous infusion of syngeneic apoptotic cells by
photopheresis induces antigen-specific regulatory T cells. J Immunol 2005; 174(10):5968 –5976.
47. Girardi M, Schechner J, Glusac E, et al. Transimmunization and the evolution of extracorporeal
photochemotherapy. Transfus Apheresis Sci 2002; 26(3):181– 190.
26 Photodynamic Therapy
Sally H. Ibbotson
Department of Dermatology, Ninewells Hospital and Medical School,
University of Dundee, Dundee, Scotland, U.K.
Rolf-Markus Szeimies
Department of Dermatology, Regensburg University Hospital, Regensburg, Germany
B The efficacy of 5-aminolevulinic acid/methyl aminolevulinate PDT in the

treatment of nonmelanoma skin cancer, particularly actinic keratoses,
Bowen’s disease, and superficial basal cell carcinomas, has been
sufficiently documented and justifies that PDT is to be considered among
the standard therapeutic procedures for these diseases.
B The proven advantages of PDT include the simultaneous treatment of
multiple tumors, subclinical and large lesions, relatively short healing
times, good patient tolerance, and excellent cosmesis.
B The potential tumor control in immunocompromized patients (i.e.,
transplant recipients) is very promising.
B Cost-effectiveness analysis indicates that with relatively low costs for
permanent equipment, topical PDT is probably no more expensive
than conventional therapy when its lower side-effect profile is
considered.
B PDT may also find a place in the treatment of patients with inflammatory
dermatoses.
B Nevertheless, the limitations of PDT, including its topical variant, have to
be kept in mind. Crucial parameters are the depth of penetration of both
sensitizer and light into the skin. Moreover, for the treatment of skin
cancers with metastatic potential, patients need to be selected carefully,
and histologic diagnosis and determination of tumor thickness are a
prerequisite.
370 Ibbotson and Szeimies
INTRODUCTION AND HISTORICAL ASPECTS

he first attempt to use the amplifying effect of light in the presence of a chemical substance
T was undertaken by Oscar Raab, a medical student at the Department of Pharmacology at

the University of Munich, Germany. The Head of Department, Hermann von Tappeiner
was looking for new antimalarials and Raab’s task was to study the influence of acridine
orange and its derivatives on infusoria and other protozoa. Raab discovered that the cell-
killing effects of the drug were potentiated by the presence of light. In 1904, von Tappeiner
coined the term “photodynamic reaction.”
This new therapeutic approach was then applied to patients. Together with Albert Jesio-
nek, a young assistant professor at the Department of Dermatology, University of Munich, von
Tappeiner started the first experiments in man in February 1903. Their first paper of three was
published in 1903 and dealt with the photodynamic treatment of cancerous, syphilitic, and
tuberculous skin conditions.
In 1902, Georges Dreyer in Copenhagen examined the effect of light on bacteria.
Besides bacteria and animal skin, he also sensitized living human skin to demonstrate the
phototoxic effect.
In 1903, Dreyer started his first experiments in patients with lupus vulgaris by intra- and
subcutaneous injection of a sterile erythrosine solution and illumination after four to eight
hours. Within 24 hours, a severe phlegmonous reaction resulted which resolved leaving
prominent scar formation. The patients suffered from severe pain during irradiation and
Dreyer therefore, terminated his experiments.
In contrast, von Tappeiner and Jesionek reported on good results using topical appli-
cation of eosin or other dyes. In 1905, they extended their trial on patients with superficial
skin cancer and observed efficacy with repetitive photodynamic therapy (PDT) using topically
applied 0.1% to 5% eosin dye (Fig. 1) (1).
Today, it is known that PDT requires the simultaneous presence of a photosensitizer, light,
and oxygen inside the diseased tissue. The photosensitizer accumulates in the target cells and
absorbs light of a certain wavelength. The energy is transferred to oxygen and highly reactive
oxygen species, mainly singlet oxygen, are generated. Following an appropriate light dose, the
reactive oxygen species (ROS) directly lead to cell and tissue damage by inducing necrosis and
apoptosis or indirectly stimulate inflammatory cell mediators (Fig. 2).
In recent years, PDT has gained worldwide popularity as an experimental therapy for a
variety of human cancers. To date porphyrins, chlorine derivatives, or phthalocyanines have
been studied for primary or adjuvant cancer therapy (2). However, for dermatological
FIGURE 1 (Left): Seventy-year-old countrywoman with multiple skin cancers. The lesions were painted consecutively
with eosin dye plus intratumoral injection of eosin and were then exposed to sunlight or light from a carbon arc lamp for
six to eight hours a day. (Right): Reduction of tumors two months later.
Photodynamic Therapy 371
FIGURE 2 Upon illumination, a photosensitizer molecule transformed to the excited state is able to reach ground state
by either release of photons (fluorescence) or by induction of reactive oxygen species, mainly singlet oxygen (reaction
type-II). Depending on the subcellular localization of the photosensitizer, site-specific damage occurs, thus leading to
necrosis/apoptosis or modulation of cellular functions. Abbreviation: ROS, reactive oxygen species.
purposes, only hematoporphyrin derivatives (HPDs) such as porfimer sodium (Photofrinw),

benzoporphyrin derivative (Visudynew), or porphyrin-inducing precursors such as 5-aminole-
vulinic acid (ALA, Levulanw Kerastick) or methyl aminolevulinate (MAL, Metvixw/Metvixiaw)
are of practical use. As systemic photosensitizing drugs induce prolonged phototoxicity (3),
topical photosensitizers are preferred for use in dermatology. There is a growing interest in
the use of topical PDT not only for nonmelanoma skin cancer (NMSC), but also for other
skin tumors such as lymphoma as well as for non-oncological indications such as psoriasis,
localized scleroderma, acne, or skin rejuvenation (4 –6).
MECHANISM OF ACTION
During illumination, the photosensitizer absorbs light, a process followed by conversion to an
energetically higher status, the “singlet-status.” After a short half-life period (approximately
1029 seconds), the activated photosensitizer returns to the ground state after emission of fluor-
escence and/or internal conversion. Alternatively, the activated photosensitizer changes from
the singlet state into the more stable triplet state with a longer half-life period (1023 seconds) (a
process referred to as “intersystem crossing”). In the type-I photo-oxidative reaction, there is a
direct hydrogen- and electron transfer from the triplet state of the photosensitizer to a substrate.
This reaction results in the generation of radicals of the substrate. These radicals are able to
react directly with molecular oxygen and form peroxides, hydroxy-radicals, and superoxide
anions. This type-I reaction is strongly concentration-dependent. Direct damage to the cells
by this reaction can occur, especially when the photosensitizer is bound to easily oxidizable
molecules. In the type-II photo-oxidative reaction, electrons or energy are directly transferred
to molecular oxygen in the ground state (triplet) and singlet oxygen is formed. The highly reac-
tive state of singlet oxygen results in very effective oxidation of biological substrates. Both reac-
tion types can compete in parallel, as substrate and molecular oxygen compete for the
photosensitizer in the triplet state. What kind of reaction preferably happens depends on the
photosensitizer used, its subcellular localization, and the substrate, and oxygen supply
around the activated photosensitizer. Indirect experiments in vitro indicate that singlet
oxygen is the main mediator of PDT-induced biological effects (2,7).
Depending on the amount and localization in the target tissue, ROS, in particular singlet
oxygen, either modify cellular functions or induce cell death by necrosis or apoptosis (Fig. 2).
PHOTOSENSITIZERS FOR PHOTODYNAMIC THERAPY

Topically applied dyes such as eosin red or erythrosine were the first “photosensitizers” used to
treat conditions such as pityriasis versicolor, psoriasis, molluscum contagiosum, syphilis,
lupus vulgaris, or skin cancer (1). The tumor localizing effects of porphyrins have been studied
since 1908. The late 1970s witnessed a renaissance of PDT, as Thomas Dougherty used HPD for
the treatment of skin cancer (1,2). The main problem in the use of HPD is the prolonged skin
photosensitization that lasts for several weeks (8). Topical application of these drugs is not
possible since the rather large HPD molecules (tetrapyrrol rings) do not penetrate the skin.
Therefore, the introduction of porphyrin precursors such as ALA by Kennedy and
coworkers in 1990 or MAL was a significant milestone in the development of PDT in dermatol-
ogy. These small molecules easily penetrate the epidermis due to their low molecular weight
(2,7). Currently in Europe, MAL is approved under the name of Metvixw for the
treatment of basal cell carcinoma (BCC), actinic keratoses (AK) and Bowen’s disease (BD) in
combination with red light. In the United States, Metvixiaw was approved for treating AKs
in 2004, whereas 5-ALA hydrochloride (Levulanw Kerastick) was approved for photodynamic
treatment of AKs in combination with blue light in 1999 (3). The ALA-based photosensitizers
are not photoactive by themselves, but show a preferential intracellular accumulation inside
rapidly proliferating dysplastic and neoplastic cells (and to a lesser extent, normal skin).
These substances are then metabolized in the heme biosynthesis pathway to protoporphyrin
IX (PpIX), a potent photosensitizing porphyrin, in a milieu of depleted iron and ferrochelatase,
the rate limiting cofactor, and enzyme in the formation of heme (Fig. 3). If no surface illumina-
tion is given, the photoactive porphyrins are metabolized to the photodynamically inactive
heme within the next 24 to 48 hours (2,7).
Since proliferating, relatively iron-deficient tumor cells of epithelial origin are remarkably
sensitized by ALA or MAL, tissue damage is mostly restricted to the sensitized cells, thus
almost sparing the surrounding tissue, especially cells of mesenchymal origin like fibroblasts,
FIGURE 3 Upon topical application (1) of the small molecules aminolevulinic acid (ALA) or its methyl ester (methyl
aminolevulinate, MAL) on the targeted tissue, there is an enhanced penetration through abnormal stratum corneum
overlying epithelial skin tumors (2). Due to the need for heme proteins in rapidly proliferating cells, uptake of ALA
and MAL into altered keratinocytes is augmented. Since the rate-limiting step of heme biosynthesis is bypassed
then, fast synthesis of tetrapyrolic porphyrins occur (3), thus resulting in accumulation of protoporphyrin IX (PpIX),
the actual photosensitizer (4). The relative lack of ferric ions within tumor cells and the lower activity of the enzyme
ferrochelatase, further increases the amount of PpIX compared to the surrounding tissue thus leading to a high ratio
[up to 10 (8)]. Abbreviations: COPRO, coproporphyrinogen III; PBG, porphobilinogen; PROTO, protoporphyrinogen
IX; SCoA, succinyl coenzyme A; URO, uroporphyrinogen III.
resulting in excellent cosmesis (9). Aside from two case reports which were possibly coinci-
dental, there are no reports of carcinogenic potential of ALA/MAL-PDT (9). In fact, patients
with erythropoietic protoporphyria, who have a chronic excess of PpIX, are not at increased
risk of developing skin cancers. Moreover, a recent study showed that long-term topical appli-
cation of ALA and subsequent irradiation with blue light in a hairless mouse model did not
induce skin tumors (10). In a similar experimental setting, Stender et al. showed a delay of
photoinduced carcinogenesis in mice following repetitive treatments with ALA-PDT (11).
Although topically applicable photosensitizers are most commonly used in dermatology,
recent investigations have shown that the prolonged photosensitivity after systemic
application of photosensitizers can be alleviated by chemical modification. Meso-tetrahydrox-
yphenylchlorine or verteporfin have recently been studied with good success for BD and BCC
with significantly lower side effects than those reported for the first-generation photosensiti-
zers like HPD (12,13).
LIGHT SOURCES
Historically, PDT has been performed using laser sources, although these are expensive and
require a considerable amount of technical support. More recently, diode lasers, which are
compact, easy to use semiconductor devices, have facilitated the use of lasers for PDT and
these can be used in systemic PDT with endoscopic light delivery via fiber optic (14).
When using ALA or MAL, PpIX accumulates and can be activated by a range of
wavelengths in the Soret band. However, with respect to PDT treatment of skin, tissue
penetration in the blue light part of the spectrum is poor (1 –2 mm), whereas red light can
penetrate up to approximately 6 mm in depth (9,15). On this basis, although the efficiency of
blue light activation of PpIX is greater than that of red light, light delivery for PDT of skin is
a compromise and generally red light sources are chosen for their depth of penetration. ALA
with blue light irradiation is the approved form of PDT in the United States for the treatment
of AK (16).
For topical PDT, there is no evidence that laser irradiation is superior to the noncoherent
and much cheaper light sources. Broad spectrum, filtered sources have been successfully used
to treat superficial NMSC, dysplasia, and other nonmalignant skin diseases. Typically, filtered
xenon arc sources or tungsten filament quartz halogen sources have been used with emission
ranges between 600 and 700 nm. Other commercially available metal halide sources, such as
the Waldmann PDT 1200L, are also widely used and are convenient if requiring treatment of
large areas up to 20 cm in diameter. For the treatment of superficial NMSC, there is evidence
that laser and nonlaser light sources are of equivalent efficacy (17,18).
More recently, light emitting diode (LED) arrays have increasingly been used for PDT
(19). These have relatively narrow emission spectra with greater photosensitizer activation effi-
ciency and, therefore, lower dose requirements. These sources are much less expensive than
conventional sources and have facilitated the availability of PDT. Preliminary work indicates
that these LED sources may be more efficient than broader emission noncoherent sources,
although the validation of their use in terms of outcomes and patient tolerance of treatment
has yet to be substantiated (20). In general, irradiances of less than 150 mW/cm2 are used to
avoid hyperthermia, and indeed, the lower the irradiance, the less pain appears to occur
with treatment and outcomes may be improved (17,21).
The efficiency of different light sources for PDT can be considered in the concept of the
total effective fluence, which indicates that green light is more effective than red to a depth
of 2 mm, whereas red light provides more uniform radiation at greater tissue depth and is
more widely applicable for the treatment of lesions at or below 2 mm (22).
A wide variety of light sources, irradiances, and doses has been used in PDT (37 –
540 J/cm2), which makes comparison between studies difficult (Table 1). It is essential that
regular calibration of light sources is carried out by PDT clinic staff as a lack of uniformity
in irradiance may otherwise go undetected (19).
Fractionation of light delivery may improve the PDT effect by allowing tissue
reoxygenation, although the importance of this phenomenon in cutaneous PDT is not clear
TABLE 1 Examples of Commercial Light Sources Used for Topical Photodynamic Therapy
Peak/range of Skin surface
Type of source Trade name emission (nm) irradiance (mW/cm2)
Semiconductor Diomedw 630 120
diode laser
Metal halide Waldmann PDT 1200L 580–740 70– 90
Tungsten filament Curelightw 560–710 ,150
LED Aktilite 16w 632 + 19 full width Approximately 77
at half maximum
LED Aktilite 128w 632 + 19 full width Approximately 65
at half maximum
LED Omniluxw 633 + 15 Approximately 80
Xenon arc Phototherapeuticsw 630 + 15 ,130
Sodium Medeikonosw 590–670 100
(phosphor coated)
Abbreviations: LED, light emitting diode; PDT, photodynamic therapy.
(23). It is interesting that with the development of films for ALA delivery and the potential use
of LEDs, chemiluminescence and polymers for light delivery, ambulatory home delivery of
PDT may be feasible and this requires further study (24 –27).
PHOTODYNAMIC THERAPY AND ITS ADVERSE EFFECTS

Patients with histologically-confirmed BD, superficial BCC 2 mm in histological thickness,
and non-hyperkeratotic AK, particularly on face and scalp, are appropriately treated by
topical PDT. Nodular BCC may be treated by PDT if the lesion or patient is not suitable for
surgery. Nodular, morphoeic, or heavily pigmented BCCs should not routinely be treated by
PDT, and if treatment is performed, adequate surface curettage should be undertaken first.
Lesions on the lower legs and multiple lesions are particularly suited to PDT (9).
Assessment of the site and maximum diameter of the lesion is necessary and photo-
graphic documentation may be helpful. Application of petrolatum or debriding agents to the
lesion(s) for a few days prior to treatment may loosen surface crust or hyperkeratosis and, if
heavy crusting is present, surface preparation with either a spatula or curette without local
anesthetic is commonly practiced, although there is no evidence that this improves treatment
outcomes. The photosensitizer pro-drug, generally ALA, 20% w/v in an oil in water base
(Crawford’s Pharmaceuticals, U.K.; Photonamic, Germany, or alternative commercial or
in-house preparations) or MAL 160 mg/g (Galderma, France) is applied to the lesion under
occlusion with a 5 mm rim of surrounding normal tissue for three hours (MAL), four hours
(ALA for BD or AK), or six hours (ALA for BCC). A test area may be advisable if a large
field is to be treated. If the lesion is on a sunlight-exposed site, such as head and neck, an
additional light-opaque dressing is required to protect the treatment site prior to irradiation.
This can all be performed on an outpatient basis and the patient will then return for irradiation
later that day (28).
After the incubation period, ALA/MAL is removed and the lesion examined using
Wood’s light illumination or a fluorescence-imaging device to determine the sensitivity and
specificity of PpIX fluorescence. On the basis of naked eye and Wood’s light examination the
irradiation field is mapped out to include a 5 mm rim of clinically normal appearing tissue
and the maximum diameter of the field documented. Irradiation is performed with one of
several possible light sources, as discussed (Table 1). Generally, doses of 37 to 75 J/cm2 are
used with LED sources and 75 to 150 J/cm2 for noncoherent, broadband, or laser sources.
Lower doses have been used for nonmalignant disease (29).
The majority of patients will find irradiation during topical PDT uncomfortable and will
describe a burning, painful sensation, usually maximal in the first few minutes of treatment.
The mechanisms of PDT-induced pain and pain relief are poorly understood (9,30).
However, talking to patients to put them at ease, use of a cooling fan, xylocaine spray, and a
device such as the Cynosurew/Zimmer cold air blower, which delivers a jet of chilled air to the
skin surface may be helpful. At least 20% of patients will report topical PDT as being
significantly painful (17). Ametopw and EMLA are not significantly effective when compared
with placebo for PDT pain relief and injectable local anesthetic does not necessarily abolish dis-
comfort (30– 32). MAL may be less painful than ALA-PDT, although this has not been formally
studied in patients (33).
During irradiation, erythema, edema, urticaria, and exudation can occur (34). These
changes are maximal during and immediately after irradiation and usually subside within
24 to 48 hours of treatment, although inflammation and crusting will occur over one to two
weeks. Persistent erythema and hypo- or hyper-pigmentation may occur at the treatment
site for a few weeks after treatment, but usually resolve leaving no more than an extremely
faint scar and excellent cosmetic outcome (35). Infection, ulceration, and hair loss and
increase are also rarely reported. Generalized photosensitivity has not been reported as most
ALA/MAL-induced PpIX is cleared within 24 hours (36). PDT in vitro can induce DNA
damage and there are two reported cases of melanoma and squamous cell carcinoma arising
at sites of previous PDT treatments in humans (37,38). However, these cases may well have
been unrelated to PDT itself and there is no evidence of a significant risk of carcinogenicity
in humans (9).
There is evidence that two PDT treatments are more effective than one, although it is
unclear when the second treatment should be performed, and this may vary from one week
to 8 to 12 weeks (18,39 –41). Review after PDT by medical staff is advised and will generally
be performed three to six months after the last treatment, when treatment outcome and
remaining adverse events such as erythema, pigmentation, scarring, or milia will be recorded.
If persistent disease remains, treatment can be repeated and there is no evidence of cumulative
damage from PDT, although in our own center, if lesions do not clear within four treatments,
alternative therapeutic approaches are taken. There is evidence that late recurrences beyond
one to two years after PDT may occur and, therefore, long-term follow-up is theoretically
advised (18).
All aspects of the PDT procedure can be performed by fully trained nursing staff or tech-
nicians and this may be appropriate depending on local expertise and staff availability.
However, the assessment of lesion responses by medical staff is strongly advised, as it may
sometimes be difficult to distinguish whether persistent erythema is representative of residual
disease or merely the result of treatment.
DYPLASIA/NONMELANOMA SKIN CANCER

Regarding oncologic indications, AK, nodular or superficial BCC and BD are approved indi-
cations for MAL and ALA/MAL PDT is recommended by evidence-based guidelines in
Britain (9). However, for therapy of single lesions several efficient alternative treatments are
available, for example, cryotherapy or surgery, whereas for therapy of multiple lesions PDT
is among the first choice, in particular for AK of the scalp and face or in cases of basal cell
nevus syndrome (2). An international consensus for guidelines on the use of PDT for NMSC
has been established (42).
Actinic Keratoses
The efficacy of ALA-PDT has been observed so far in six open studies of 323 AK situated on the
face and scalp in Caucasian populations (Fig. 4). Clearance rates ranged from 71% to 100% after
a single treatment (9,43). For illumination purposes, either blue light (417 nm) or red (635 nm)
have been used (43,44).
In a European, multicenter, randomized prospective study, MAL-PDT was compared to
cryosurgery in the treatment of AK. A total of 193 patients (95%) with 699 lesions completed the
trial. Patients received either a single treatment with MAL-PDT (repeated after one week in 8%
of cases) or a double freeze-thaw course of liquid nitrogen cryosurgery. MAL was applied
for three hours after slight lesion preparation, followed by illumination with broad-spectrum
red light (75 J/cm2). A follow-up visit was performed three months after treatment. The efficacy
FIGURE 4 (Left): Male patient with multiple actinic keratoses on his face and scalp. Single treatment session with 5-
aminolevulinic acid-photodynamic therapy (PDT) (20% w/o cream, incubation for four hours, illumination with the
Waldmann PDT 1200L; 150 mW/cm2; 120 J/cm2). (Right): Clinical outcome after two months with significant
improvement, a second PDT-treatment was scheduled for the same day.
for MAL-PDT (single application) was 69% versus 75% for cryosurgery, the difference being of
no statistical significance. Thin lesions on the scalp had the highest response rates (80% and
82% for PDT and cryosurgery, respectively). Cosmetic outcome, as judged by the investigator,
was superior for MAL-PDT (96% vs. 81%) (40).
In accordance with this trial, another was conducted in Australia. Here MAL-PDT was
used as a dual cycle, with two treatment sessions, one week apart. PDT was compared to a
single course of cryosurgery or placebo in 204 patients. Lesion response was assessed after
three months. A significantly higher complete remission rate (91%) with MAL-PDT
was observed compared with 68% remission with cryosurgery and 30% with placebo. The
cosmetic result was rated excellent in 81% of MAL-PDT patients compared with 51% treated
with cryotherapy (41).
A multicenter, randomized, double blind, placebo-controlled study with two MAL-PDT
cycles was performed in 80 patients with AK in the United States. PDT treatment parameters
were similar to the aforementioned trials. Assessment after three months revealed a complete
lesion response rate of 89% for MAL-PDT versus 38% for placebo. An excellent or good
cosmetic outcome was reported in more than 90% of MAL-treated patients (45) MAL PDT
has also been shown to be effectice for AK in transplant recipients in a randomzied, double-
blind placebo controlled study (46).
Also for ALA-PDT in the treatment of AK a randomized, placebo-controlled, uneven-
parallel-group study was published recently. In 243 patients, clinical response, based on
lesion clearance, was assessed at weeks 8 and 12. Patients were randomized to receive either
vehicle or ALA (Levulanw Kerastick), followed within 14 to 18 hours by illumination with
visible blue light (BLU-Uw, DUSA, low pressure fluorescent lamps). Complete response rates
for ALA-PDT patients with 75% of the treated lesions clearing at weeks 8 and 12 were 77%
and 89%, respectively. In the placebo group, clearing rates were 18% and 13%. The 12-week
clearing rates included 30% of patients who received a second ALA-PDT course. Moderate
to severe discomfort during illumination was reported by at least 90% of patients; however,
only 3% of patients required discontinuation of therapy (44).
For the purpose of lowering the amount of side effects of ALA-PDT, shorter incubation
periods (one, two, and three hours), in conjunction with pretreatment with 40% urea in
order to enhance ALA penetration and the use of topical 3% lidocaine hydrochloride to
decrease discomfort were also evaluated. One and five months after therapy in 18 patients
with at least four non-hypertrophic AK, a reduction of lesions up to 90% in the target area
was observed. No difference was seen between the three incubation periods nor did pretreat-
ment with urea or lidocaine have an influence on the therapeutic outcome (6).
FIGURE 5 (Left): Bowen’s disease on the lower right cheek in this 72-year-old woman. Two cycles of methyl
aminolevulinate-photodynamic therapy (repetitive treatment after one week; three hours incubation; illumination with
the Aktilite light emitting diode; 37 J/cm2). (Right): Situation after two months. Complete clinical remission, slight
erythema, no scar formation.
Bowen’s Disease and Initial Squamous Cell Carcinoma

There have been several reports on the use of systemic PDT in BD (13), but these reports now
have been superseded by topical therapies with higher tolerability. Topical PDT using 20% ALA
has been extensively assessed in BD with more than 14 open and three randomized comparison
studies (9,46). Cure rates reported so far are the best for all epithelial cancers or precursors (up
to 100%). In a study by Salim et al., ALA-PDT was compared to topical 5-fluorouracil (5-FU). In
this bicenter, randomized, phase-III trial, 40 patients with one to three lesions of histologically
proven BD received either PDT or 5-FU. ALA 20% in an o/w-emulsion was applied four hours
prior to illumination with an incoherent red light source (Paterson lamp, Photo therapeutics,
U.K.; 50– 90 mW/cm2, 100 J/cm2). Treatment with 5-FU was once daily in week one and then
twice daily during weeks two to four. At first follow-up at week six, both ALA-PDT and 5-
FU application were repeated, if required. Twenty-nine of 33 lesions (88%) treated with PDT
showed complete response, versus 67% after 5-FU (22 of 33). After one-year of follow-up,
further recurrences reduced the complete clinical clearance rates to 82% and 42%, respectively
(47).
MAL-PDT has recently been studied in one of the largest existing studies in the treatment
of BD (Fig. 5). In a multicenter, comparative randomized controlled trial with a total of 225
patients carrying 275 lesions, MAL-PDT was compared to cryotherapy, topical 5-FU, and
placebo. At 12 months, the estimated sustained lesion complete response rate was 80% for
MAL-PDT, 67% for cryotherapy, and 69% for 5-FU. The cosmetic outcome was likewise
superior for MAL-PDT (94% vs. 66% cryotherapy vs. 76% 5-FU) (48).
Basal Cell Carcinoma

Numerous studies concerning ALA/MAL-PDT for BCC have been conducted in recent years
(3,7,49 –53). The weighted average complete clearance rates, after follow-up periods varying
between 3 and 36 months, were 87% in 12 studies treating 826 superficial BCCs and 53%
in 208 nodular BCCs (3,9). Available compiled data from other trials have shown an average
clearance of 87% for superficial BCCs and 71% for nodular BCCs (2).
In order to improve poor outcome after PDT of thicker BCC lesions, Thissen et al. treated
23 patients with 24 nodular BCCs once with ALA-PDT (incoherent red light; 100 mW/cm2,
120 J/cm2) three weeks after debulking of the BCCs. The former tumor areas were excised
three months later and histopathologically evaluated for residual tumor. Twenty-two (92%)
of the 24 nodular BCCs showed both clinical and histological complete response (50).
In a prospective phase-III trial comparing ALA-PDT with cryosurgery, Wang et al.
included 88 superficial and nodular BCCs. A 20 % ALA/water-in-oil cream was applied for
six hours under an occlusive dressing, followed by irradiation with a laser at 635 nm
(80 mW/cm2, 60 J/cm2). In the cryosurgery arm, lesions were treated with liquid nitrogen
in the open spray technique using two freeze-thaw cycles for 25 to 30 seconds each time.
After three months, punch biopsies were performed and revealed a recurrence rate of 25% in
the PDT group and 15% in the cryosurgery group. However, the clinical recurrence rates were
only 5% for ALA-PDT and 13% for cryosurgery. Besides better cosmetic outcome, healing time
was also shorter in the PDT treated group (53).
Solèr and colleagues studied the long-term effects of MAL-PDT in 59 patients with 350
BCCs. Nodular tumors were curetted before PDT and MAL (160 mg/g) was applied to all
tumors for 24 or 3 hours prior to irradiation with a broad-band halogen light source (50 –
200 J/cm2). Patients were followed for two to four years (mean 35 months). The overall cure
rate was 79%, cosmetic outcome was excellent or good in 98% of the completely responding
lesions (49).
In a recent open, uncontrolled, prospective, multicenter trial, both patients with super-
ficial and/or nodular BCC who were at risk of complications, poor cosmetic outcome, disfig-
urement, and/or recurrence using conventional therapy were studied. Ninety-four patients
were treated with a single cycle of MAL-PDT involving two treatment sessions one week
apart, and followed-up at three months, at which time nonresponders were retreated. The clini-
cal lesion remission rate after three months was 92% for superficial BCC and 87% for nodular
BCC. Histological cure rate at this time point was 85% in superficial BCC and 75% in nodular
BCC. At 24 months after treatment, the overall lesion recurrence rate was 18% (51).
In another European multicenter, open, randomized trial, MAL-PDT for nodular BCC
was compared with surgery. A total of 101 patients were included and received either PDT
twice, seven days apart (75 J/cm2 red light), or surgical excision. The primary end point of
this trial was the clinically assessed lesion clearance at three months after treatment, besides
cosmetic outcome. The cure rate after three months was similar with MAL-PDT or surgery
(91% vs. 98%), the 24 months recurrence rate was 10% with MAL and 2% with surgery. The
cosmetic result was rated good/excellent in 85% of the patients receiving PDT versus 33%
with surgery (52).
ALA-PDT can be used also for adjuvant therapy in combination with Mohs surgery,
as reported recently by Kuijpers et al. In four patients, who underwent Mohs micro-
graphic surgery for extensive BCC, first the central infiltrating tumor part was excised. After
re-epithelialization, ALA-PDT of the surrounding tumor rims (2– 5 cm) bearing remaining
superficial tumor parts, was performed. This led to a complete remission of the tumors with
excellent clinical and cosmetical results (follow-up period up to 27 months) (54).
However, even if clinical studies support the use of PDT as an effective treatment of BCC,
the relatively short follow-up of most of the studies to date have to be considered. Mandatory
indications for surgical treatment are different histological subtypes such as pigmented or
morphoeic BCCs or BCCs located in the area of the facial embryonic fusion clefts as well as
all BCCs thicker than 3 mm if no debulking procedure is performed prior to PDT.
NONMELANOMA SKIN CANCER INDICATIONS

Despite the increasing acceptance of topical PDT for superficial NMSC and dysplasia, its use in
other dermatological conditions has not been widely validated. Many benign skin conditions
show specificity of photosensitizer accumulation after ALA/MAL application and this
observation has led to the study of topical PDT in other non-NMSC conditions (Table 2) (4).
Recalcitrant Viral Warts and Viral Skin Diseases

After application of ALA to a pared viral wart, PpIX fluorescence can be demonstrated (55).
There is a clinical need for adjunctive treatments for recalcitrant viral warts, particularly
in immunosuppressed patients. However, much of the work with PDT has been done in
immunocompetent subjects.
Retrospective analysis of 62 patients showed that 58% of those who completed treatment
cleared with no recurrence up to 17 months follow-up, although pain was a significant adverse
effect. However, of the five-immunocompromized patients only one responded (56).
The same group compared PDTwith cryotherapy for recalcitrant warts (57). Randomization
in comparative treatment groups was performed: white light (22 mW/cm2) three times (W3) or
TABLE 2 Skin Conditions Other than Nonmelanoma Skin Cancer in Which Topical Photodynamic Therapy has
been Applied
Most studied Case reports/series
Acne Actinic cheilitis/oral leukoplakia Lichen sclerosus
Cutaneous T-cell lymphoma Alopecia areataa Lymphadenosis benigna cutis
Psoriasisb Bowenoid papulosis Melanomab
Warts Breast metastasesb Molluscum contagiosum
Chondrodermatitis nodularis helicis Nevus sebaceous
Condylomata acuminata Photoaging
Darier’s disease Porokeratosisb
Epidermodysplasia verruciformis Port wine stainb
Erythroplasia of Queyrat Sarcoidosis
Extramammary Paget’s Scleroderma
Goltz syndrome Sebaceous hyperplasia
Hailey–Hailey Superficial mycoses/antibacterial
Hidradenitis suppurativaa Vulval intraepithelial neoplasiaa
Hirsutism X-ray dermatitis
Keratoacanthoma
Leg ulcers
Leishmaniasis
Lichen planus
a
Contradictory evidence.
b
Poor response to photodynamic therapy.
once (W1) in 10 days; red light (17.5 mW/cm2) three times in 10 days (R3); blue light (22 mW/cm2)
three times in 10 days (B3) or cryotherapy with a double 10-second freeze/thaw cycle, repeated up
to four times over two months. The total light dose in the PDT-treated groups was 40 J/cm2. Re-
treatment was performed four to six weeks later for partial responders. Complete responders
were followed-up for 12 months, with no recurrence. Re-treatment was needed in 78% of the
W1 and W3, 40% of R3, and 22% of B3 groups. Significantly higher clearance rates occurred
after white light than red or blue light PDT or cryotherapy: 73% (W3), 71% (W1), 42% (R3), 28%
(B3), and 20% (cryotherapy), respectively. White-light PDT three times in 10 days was most effec-
tive, although pain was significant in the majority.
A definitive study in immunocompetent patients with hand and foot warts randomized
to receive either ALA-PDT or placebo-PDT was performed with weekly treatment for three
weeks, repeated one month later if warts persisted (55). Clearance of warts at week 18
follow-up was seen in 56% of actively treated and 43% of placebo-treated subjects. There
was also a significant decrease in wart area in the active treatment group compared with
placebo. The relatively low overall response rates and high placebo response rates probably
indicate the effect of regular paring and keratolysis and that patients had treatment-resistant
disease. Pain was significant and may be limiting, particularly in children. Others have con-
firmed the efficacy of ALA-PDT for viral warts (58).
To conclude, multiple treatments with ALA-PDT, combined with paring and keratolysis
are more effective than placebo or cryotherapy for recalcitrant viral warts, although optimal
treatment regimes need to be established in order to minimize pain. Immunosuppressed
patients may respond less well and this requires further study. There is potential for the use
of ALA-PDT in planar warts and others have shown that combined PDT and pulsed dye
laser may be effective, although this requires substantiation (59,60).
High response rates were seen in four of seven patients with condylomata acuminata,
using ALA (14 hours) and argon dye laser irradiation (630 nm, 75 or 150 mW/cm2, 100 J/
cm2) (61). Topical ALA-PDT was effective (95% clearance) and well tolerated with low recur-
rence rates (5%) in patients with urethral condylomata (n ¼ 164) and 66% clearance rates for
vulval and vaginal condylomata (n ¼ 16) have also been reported (62,63).
There may also be potential for the use of topical PDT for the treatment of epidermodys-
plasia verruciformis (64). PDT may also be effective for molluscum contagiosum in HIV
patients (n ¼ 6) (65,66). It is likely that direct virucidal action and cytotoxicity are important
determinants of the effects of PDT for viral diseases (60).
Acne Vulgaris, Diseases of the Sebaceous Gland, and Bacterial/Fungal Diseases

Visible light phototherapy for acne vulgaris has been investigated (67,68). Propionibacterium
acnes contain endogenous porphyrins and fluoresce (69). Indeed, P. acnes toxicity has been
shown in vitro on irradiation with blue light (70,71).
Improvement in inflammatory and comedonal acne occurs after visible light photo-
therapy, where combined red and blue light seems to be the most effective regime and it
is likely that anti-inflammatory, immunomodulatory, and endogenous PDT effects are
operative (72).
The use of PDT was examined in moderate trunkal acne in an open, randomized
controlled study (n ¼ 22, three hours ALA and visible light irradiation; 550– 700 nm; 150 J/
cm2) (73). Each subject received either one or four treatments with appropriate intra-subject
controls, and significant reduction in sebum, P. acnes fluorescence, and sebaceous gland size
occurred with clinical improvement for up to 20 weeks after four treatments. However, signifi-
cant side effects of pigmentation, folliculitis, and pain were seen.
Ten patients with mild to moderate trunkal acne were randomized to receive test sites of
either ALA-PDT, ALA alone, light alone, or untreated (three hours ALA, 635 nm diode laser,
25 mW/cm2, 15 J/cm2 weekly for three weeks). Reduction in inflammatory acne was seen
with ALA-PDT, but no change in sebum excretion or P. acnes counts. Significant phototoxicity
and pigmentation were seen, although permanent damage to sebaceous glands may be
avoided with this lower irradiation regime (74). More recently, the efficacy of MAL-PDT
(two treatments of three hours MAL; 37 J/cm2 Aktilite 128) for inflammatory lesions in moder-
ate to severe facial acne was shown in a randomized, controlled, investigator-blinded study
(n ¼ 21 MAL-PDT; n ¼ 15 control, no treatment) (75). However, severe pain and adverse
effects of erythema, pustular eruptions, and exfoliation occurred. In another blinded, prospec-
tive, randomized, placebo-controlled multicenter, MAL-PDT split-face study with 30 patients
with moderate to severe acne, patients received MAL- or placebo cream for three hours,
followed by illumination with red light. The treatment was repeated after two weeks. Inflam-
matory and non-inflammatory acne lesions were counted at baseline, 6 and 12 weeks later.
MAL-PDT resulted in a statistically significant greater reduction in inflammatory lesion
count than placebo at week 12 (median reduction 54% vs. 20%) However, MAL-PDT was
associated with more pain than placebo-PDT (76).
Topical PDT has also been applied to hidradenitis suppurativa, where 75% to 100%
clearance rates were reported in four subjects using a well-tolerated regime (77). This was
remarkable as short contact ALA and blue light with very limited tissue penetration were
used. In contrast, a study in four patients showed no sustained response of hidradenitis
suppurativa to topical PDT using red light (78). There are also reports of efficacy of topical
PDT for nevus sebaceous and sebaceous hyperplasia, which require further clarification.
The potential use of topical PDT for bacterial and fungal disease is of considerable inter-
est. ALA-PDT has been reported to be effective for inter-digital mycoses although associated
with rapid recurrence, and in vitro studies suggest possible efficacy of bioadhesive patch
ALA-PDT for Trichophyton interdigitale and Candida albicans (79,80).
Psoriasis
There are reports of PDT efficacy for psoriasis as far back as 1937 (81). Selective photosensitizer-
induced fluorescence in psoriatic plaque and photobleaching on irradiation occurs, although
uniform fluorescence is not seen (82). Peak fluorescence occurs approximately six hours after
ALA application to a psoriatic plaque (83).
An initial study in three patients showed topical PDT to be comparable in efficacy to
dithranol, although subsequent studies have not been encouraging (84). Improvement in
lesion severity was seen after topical PDT (n ¼ 14) (85). However, in 22 subjects treated with
ALA (four hours) and irradiation with a modified slide projector (400 – 650 nm, 25 mW/cm2,
up to 16 J/cm2) 10 of 36 sites within psoriatic plaques cleared but all relapsed within two
weeks (86). Multiple treatments [four hours ALA, slide projector irradiation (15 mW/cm2;
8 J/cm2) up to three times a week and a maximum of 12 treatments] resulted in clinical
improvement in 8 of 10 subjects but clearance in only 4 of 19 treated sites (87). PpIX
fluorescence varied within and between patients, there was variation in treatment response and
treatment was painful (87,88).
A randomized, within-patient observer-blinded study (n ¼ 29) using 1% ALA and 5 to
20 J/cm2 irradiation showed a 59% improvement with PDT, although a 25% improvement
was seen with keratolysis alone and, overall, responses and tolerance of treatment were poor
(89). In the second study, different ALA concentrations (0.1%, 1%, 5%) were used at a light
dose of 20 J/cm2. Treatment was conducted twice a week until complete clearance or for a
maximum of 12 irradiations. Again, clinical efficacy was disappointing with and unfavorable
adverse event profile (90). Certainly, ALA-PDT seems to be less effective than UVB photother-
apy for psoriasis and there is a concern about potential for koebnerisation (91). Thus, the role of
topical ALA-PDT with current regimes is questionable.
Cutaneous T-cell Lymphoma

Patients with limited patch or plaque stage cutaneous T-cell lymphoma (CTCL) whose disease
is resistant to conventional therapies present a particular therapeutic challenge. Selective
accumulation of PpIX in lymphocytes after ALA application and PDT-induced cytotoxicity
occurs in vitro (92 –96). In two patients with plaque stage CTCL, ALA-PDT was performed
on up to five occasions (four to six hours ALA, irradiation with a modified slide projector;
44 mW/cm2; 40 J/cm2) (97). Lesion-specific ALA-induced PpIX fluorescence was seen and
clinical and histological clearance achieved. Treatment was well tolerated and clearance main-
tained for 14 months in one patient, with recurrence in the other at eight months. In contrast, a
single PDT treatment in one patient showed clinical clearance but residual disease histologi-
cally (98). These studies support the need for multiple treatments in order to obtain histological
disease resolution (97,99 – 102).
In a study in two patients with four lesions of CTCL, a 50% response rate occurred with a
single treatment (four to six hours ALA, 630 nm laser irradiation, ,110 mW/cm2, 60 J/cm2)
and a fluorescence ratio of 5 : 1 for ALA-induced PpIX accumulation in tumor compared
with adjacent normal tissue was seen (103). It appears that tumor stage disease is not as respon-
sive, although clearance can be achieved with multiple treatments (100,101).
The optimal treatment parameters for topical PDT in CTCL are unclear, and ALA appli-
cations at 10 and 20% and up to 24 hours and irradiation doses of up to 380 J/cm2 have been
used (99,102). Higher intensity irradiation may spare the epidermis and specifically target
the dermal lymphocytic infiltrate, although this requires substantiation. PDT can also be
used in combination with other therapies such as radiotherapy and may be used as a debulking
procedure for more infiltrative disease (104,105). Treatment may also be of benefit for CTCL in
patients with HIV and other types of cutaneous lymphoma such as anaplastic lymphoma and
pagetoid reticulosis (105,106).
Encouraging Data for the Use of Topical Photodynamic Therapy

in Other Skin Diseases
Topical PDT can be effective for actinic cheilitis, oral leukoplakia, and verrucous hyperplasia,
with complete response rates in the majority of patients (n ¼ 3 – 12) (107 –110). The rationale
for use in these diseases is similar to that in AK. There have also been encouraging outcomes
for keratoacanthoma (n ¼ 4) treated by topical PDT (111). Topical PDT has been used for
erythroplasia of Queyrat (n ¼ 4) and was shown to be effective for limited stage disease and
MAL-PDT may also be effective (112,113). Extramammary Paget’s disease is difficult to
treat and often multiple treatment modalities are required with high recurrence rates
after surgery. However, PDT may be of benefit and can be combined with other therapies
(114 – 117). Interestingly, low dose multiple PDT treatments may be effective for chronic nonma-
lignant inflammatory diseases. For example, 100% response rates and prolonged remission
were achieved in cutaneous scleroderma.
Conditions that Require Additional Investigation

Subjective improvement of vulval lichen sclerosus was reported in two studies, although
without documented objective improvement. Topical PDT has also been used to treat
FIGURE 6 Fluorescence diagnosis of a superficial basal cell carcinoma at the mons pubis. (Upper left): Clinical image
after topical application of a 16% methyl aminolevulinate-cream for three hours. (Upper right): Sharp demarcation of
the lesion under excitation with CCD-Camera system (Dyaderm professional, Biocam, Germany) (b/w-fluorescence).
(Lower left): Real-time fusion image of both the upper left and upper right image (overlay technique). (Lower right):
False color-coded image of the original fluorescence image (upper right).
hirsutism, and interestingly, 50 to 100% response rates were achieved using 100 to 200 J/cm2
irradiations after ALA application. In a quite different condition, lesions of cutaneous leishma-
niasis have been reported to be effectively treated by either ALA- or MAL-PDT. Six patients
with Darier’s disease also responded with sustained responses to topical ALA-PDT.
However, for each of the above examples, perhaps besides leishmaniasis, these preliminary
observations require more robust study before PDT should definitively be considered.
Other conditions that require further substantiation but for which there are isolated
reports of topical PDT efficacy are lichen planus, Hailey – Hailey disease, cutaneous sarcoidosis,
chondrodermatitis nodularis helicis, Bowenoid papulosis, lymphadenosis benigna cutis, X-ray
dermatitis, and Goltz syndrome.
Contradictory Evidence Relating to the Use of Photodynamic Therapy

Single treatment topical ALA-PDT was shown to be ineffective for vulval intraepithelial
neoplasia. However, complete response rates of between 33 and 52% have been reported
with multiple treatments (n ¼ 9 –25) and PDT may be as effective as surgery or laser treatment
(118 – 120). Multi-focal high-grade disease, the presence of HPV, lack of cell-mediated immu-
nity, hyperpigmentation, and hyperkeratosis are all predictors of poor response to PDT
(118,121). Future use of bioadhesive patch delivery of ALA may also facilitate PDT at this
difficult body site (26).
There have also been contradictory reports of the use of topical PDT for alopecia areata
with an initial report in two patients showing regrowth of hair up to four months after
topical PDT using hematoporphyrin and UVA. More recently, ALA-PDT was shown to be
completely ineffective for alopecia areata even with multiple treatments (n ¼ 6) (122).
Poor Response to Photodynamic Therapy

Not all conditions investigated have responded to topical PDT. These include porokeratosis,
cutaneous breast metastases, malignant melanoma, and port wine stains.
In summary, topical PDT may be useful for the treatment of recalcitrant viral warts and
acne vulgaris, and early studies in CTCL are encouraging. The potential in psoriasis and other
diseases requires further investigation, and controlled, comparative studies are required in
larger numbers of patients. Furthermore, most of the studies performed to date have used
ALA and it will be of interest to determine whether ALA esters may be of benefit in some of
these conditions.
FLUORESCENCE DIAGNOSIS
The tissue selectivity of the porphyrin induction after topical application of ALA or MAL can
also be exploited for diagnostic purposes. The porphyrin-containing tissue can be illuminated
with blue light at the Soret band, thus inducing the emission of pink fluorescent light (Fig. 2),
which then enables the delineation of the tumor due to the high ratio of the porphyrin content
in the tumor versus the surrounding tissue (123,124).
This procedure is called fluorescence detection (FD), although misleadingly the term
“photodynamic diagnosis” is often used. FD can enable the dermatologist to perform either
a guided biopsy or a controlled and complete resection of the tumor, sparing unaffected
tissue. By combination of this procedure with a digital CCD camera system, together with
digital imaging, the contrast of the acquired fluorescence images can be enhanced significantly
(Fig. 6). This allows determination of a threshold, which can be utilized either for a directed
biopsy or for pre- and intra-operative planning when Mohs’ surgery is scheduled (125).
In addition, FD may be a helpful tool to demonstrate the efficacy of PDT. However, at
present the routine employment of such systems is still being assessed in prospective trials.
REFERENCES
1. Szeimies RM, Dräger J, Abels C, et al. History of photodynamic therapy in dermatology.
In: Calzavara-Pinton PG, Szeimies RM, Ortel B, eds. Photodynamic Therapy and Fluorescence
Diagnosis in Dermatology. Amsterdam: Elsevier, 2001:3– 16.
2. Zeitouni NC, Oseroff AR, Shieh S. Photodynamic therapy for nonmelanoma skin cancers.
Mol Immunol 2003; 39:1133– 1136.
3. Marmur ES, Schmults CD, Goldberg DJ. A review of laser and photodynamic therapy for the
treatment of nonmelanoma skin cancer. Dermatol Surg 2004; 30:264– 271.
4. Ibbotson SH. Topical 5-aminolaevulinic acid photodynamic therapy for the treatment of skin
conditions other than non-melanoma skin cancer. Br J Dermatol 2002; 146:178– 188.
5. Karrer S, Abels C, Landthaler M, et al. Topical photodynamic therapy for localized scleroderma.
Acta Derm Venereol 2000; 80:26– 27.
6. Touma D, Yaar M, Whitehead S, et al. Short incubation d-ALA photodynamic therapy for treatment
of actinic keratoses and facial photodamage. Arch Dermatol 2004; 140:33– 40.
7. Szeimies RM, Karrer S, Abels C, et al. Photodynamic therapy in dermatology. In: Krutmann J,
Hönigsmann H, Elmets CA, et al., eds. Dermatological Phototherapy and Photodiagnostic
Methods. Berlin: Springer, 2001:209– 247.
8. Schweitzer VG. Photofrin-mediated photodynamic therapy for treatment of aggressive head and
neck nonmelanomatous skin tumors in elderly patients. Laryngoscope 2001; 111:1091– 1098.
9. Morton CA, Brown SB, Collins S, et al. Guidelines for topical phototherapy therapy: report of a
workshop of the British Photodermatology Group. Br J Dermatol 2002; 146:552– 567.
10. Liu Y, Viau G, Bissonnette R. Multiple large-surface photodynamic therapy sessions with topical or
systemic aminolevulinic acid and blue light in UV-exposed hairless mice. J Cutan Med Surg 2004;
8:131– 139.
11. Stender IM, Bech-Thomsen N, Poulsen T, et al. Photodynamic therapy with topical delta-aminolevu-
linic acid delays UV photocarcinogenesis in hairless mice. Photochem Photobiol 1997; 66:493–496.
12. Baas P, Saarnak AE, Oppelaar H, et al. Photodynamic therapy with meso-tetrahydroxyphenyl-
chlorin for basal cell carcinoma: a phase I/II study. Br J Dermatol 2001; 145:75– 78.
13. Lui H, Hobbs L, Tope WD, et al. Photodynamic therapy of multiple nonmelanoma skin cancers with
verteporfin and red light-emitting diodes. Two-year results evaluating tumor response and cosmetic
outcomes. Arch Dermatol 2004; 140:41– 46.
14. Brancaleon L, Moseley H. Lasers and non-laser light sources for photodynamic therapy. Lasers Med
Sci 2002; 17:173– 186.
15. Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem Photobiol 1992;
55:145– 157.
16. Ormrod D, Jarvis B. Topical aminolevulinic acid HCl photodynamic therapy. Am J Clin Dermatol
2000; 1:133 –139.
17. Clark C, Bryden A, Dawe RS, et al. Topical 5-aminolaevulinc acid photodynamic therapy for
cutaneous lesions: outcome and comparison of light sources. Photodermatol Photoimmunol
Photomed 2003; 19:134– 141.
18. Moseley H, Ibbotson S, Woods J, et al. Clinical and research applications of photodynamic therapy in
dermatology: Experience of the Scottish PDT Centre. Lasers Surg Med 2006; 38:403– 416.
19. Moseley H. Light distribution and calibration of commercial PDT LED arrays. Photochem Photobiol
Sci 2005; 4:911 – 914.
20. Juzeniene A, Juzenas P, Ma LW, et al. Effectiveness of different light sources for 5-aminolevulinic
acid photodynamic therapy. Lasers Med Sci 2004; 19:139– 149.
21. Ericson MB, Sandberg C, Stenquist B, et al. Photodynamic therapy of actinic keratosis at varying
fluence rates: assessment of photobleaching, pain and primary clinical outcome. Br J Dermatol
2004; 151:1204– 1212.
22. Moseley H. Total effective fluence: a useful concept in photodynamic therapy. Lasers Med Sci 1996;
11:139– 143.
23. Robinson DJ, de Bruijn HS, Star WM, et al. Dose and timing of the first light fraction in two-fold
illumination schemes for topical ALA-mediated photodynamic therapy of hairless mouse skin.
24. Lieb S, Szeimies RM, Lee G. Self-adhesive thin films for topical delivery of 5-aminolevulinic acid.
Eur J Pharm Biopharm 2002; 53:99– 106.
25. Zelickson B, Counters J, Coles C, et al. Light patch: preliminary report of a novel form of blue light
delivery for the treatment of actinic keratosis. Dermatol Surg 2005; 31:375 – 378.
26. McCarron PA, Donnelly RF, Zawislak A, et al. Evaluation of a water-soluble bioadhesive patch for
photodynamic therapy of vulval lesions. Int J Pharm 2005; 293:11 – 23.
27. Moseley H, Allen JW, Ibbotson S, et al. Ambulatory photodynamic therapy: a new concept in
delivering photodynamic therapy. Br J Dermatol 2006; 154:747– 750.
28. Ibbotson SH. How to treat a superficial basal cell carcinoma with topical photodynamic therapy in
Dundee. Photodiagn Photodyn Ther 2006; 3:128 – 131.
29. Szeimies RM, Landthaler M, Karrer S. Non-oncologic indications for ALA-PDT. J Derm Treat 2002;
13(suppl 1):S13 – S18.
30. Grapengiesser S, Gudmundsson F, Larko O, et al. Pain caused by photodynamic therapy of skin
cancer. Clin Exp Dermatol 2002; 27:493– 497.
31. Holmes MV, Dawe RS, Ferguson J, et al. A randomized, double-blind, placebo-controlled study of
the efficacy of tetracaine gel (Ametopw) for pain relief during topical photodynamic therapy. Br J
Dermatol 2004; 150:337– 340.
32. Langan SM, Collins P. Randomized, double-blind, placebo-controlled prospective study of the effi-
cacy of topical anaesthesia with a eutetic mixture of lignocaine 2.5% and prilocaine 2.5% for topical
5-aminolaevulinic acid-photodynamic therapy for extensive scalp actinic keratoses. Br J Dermatol
2006; 154:146– 149.
33. Wiegell SR, Stender I-M, Na R, et al. Pain associated with photodynamic therapy using 5-aminole-
vulinic acid or 5-aminolevulinic acid methylester on tape-stripped normal skin. Arch Dermatol
2003; 139:1173 –1177.
34. Clark C, Dawe RS, Moseley H, et al. The characteristics of erythema induced by topical
5-aminolaevulinic acid photodynamic therapy. Photodermatol Photoimmunol Photomed 2004;
20:105– 107.
35. Monfrecola G, Procaccini EM, D’Onofrio D, et al. Hyperpigmentation induced by topical
5-aminolaevulinic acid plus visible light. J Photochem Photobiol B-Biol 2002; 68:147– 155.
36. Rhodes LE, Tsoukas MM, Anderson RR, et al. Iontophoretic delivery of ALA provides a quantitative
model for ALA pharmacokinetics and PpIX phototoxicity in human skin. J Invest Dermatol 1997;
108:87– 91.
37. Wolf P, Fink-Puches R, Reimann-Weber A, et al. Development of malignant melanoma after repeated
topical photodynamic therapy with 5-aminolevulinic acid at the exposed site. Dermatology 1997;
194:53– 54.
38. Varma S, Holt PJA, Anstey AV. Erythroplasia of Queyrat treated by topical aminolaevulinic acid
photodynamic therapy: a cautionary tale. Br J Dermatol 2000; 142:825– 826.
39. Haller JC, Cairnduff F, Slack G, et al. Routine double treatments of superficial basal cell carcinomas
using aminolaevulinic acid-based photodynamic therapy. Br J Dermatol 2000; 143:1270– 1274.
40. Szeimies RM, Karrer S, Radakovic-Fijan S, et al. Photodynamic therapy using topical methyl 5-
aminolevulinate compared with cryotherapy for actinic keratosis: a prospective, randomized
study. J Am Acad Dermatol 2002; 47:258– 262.
41. Freeman M, Vinciullo C, Francis D, et al. A comparison of photodynamic therapy using topical
methyl aminolevulinate (Metvixw) with single cycle cryotherapy in patients with actinic keratosis:
a prospective, randomized study. J Derm Treat 2003; 14:99 – 106.
42. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic
therapy (PDT) for non-melanoma skin cancer—an international consensus. J Am Acad Dermatol.
In press.
43. Sidoroff A. Actinic keratosis. In: Calzavara-Pinton PG, Szeimies RM, Ortel B, eds. Photodynamic
Therapy and Fluorescence Diagnosis in Dermatology. Amsterdam: Elsevier, 2001:199– 216.
44. Piacquadio DJ, Chen DM, Farber HF, et al. Photodynamic therapy with aminolevulinic acid topical
solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp:
investigator-blinded, phase 3, multicenter trials. Arch Dermatol 2004; 140:41– 46.
45. Pariser DM, Lowe NJ, Stewart DM, et al. Photodynamic therapy with topical methyl aminolevuli-
nate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol
2003; 48:227– 232.
46. Dragieva G, Hafner J, Dummer R, et al. Topical photodynamic therapy in the treatment of actinic
keratoses and Bowen’s disease in transplant recipients. Transplantation 2004; 77:115 – 121.
47. Salim A, Leman JA, McColl JH, et al. Randomized comparison of photodynamic therapy with
topical 5-fluorouracil in Bowen’s disease. Br J Dermatol 2003; 148:539– 543.
48. Morton CA, Horn M, Leman J, et al. Comparison of topical methyl aminolevulinate photodynamic
therapy with cryotherapy or fluorouracil for treatment of squamous cell carcinoma in situ. Arch
Dermatol 2006; 142:729– 735.
49. Solèr AM, Warloe T, Berner A, et al. A follow-up study of recurrence and cosmesis in completely
responding superficial and nodular basal cell carcinomas treated with methyl 5-aminolevulinate-
based photodynamic therapy alone and with prior curettage. Br J Dermatol 2001; 145: 467–471.
50. Thissen MR, Schroeter CA, Neumann HA. Photodynamic therapy with delta-aminolaevulinic acid for
nodular basal cell carcinomas using a prior debulking technique. Br J Dermatol 2000; 142:338–339.
51. Horn M, Wolf P, Wulf HC, et al. Topical methyl aminolaevulinate photodynamic therapy in patients
with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional
treatment. Br J Dermatol 2003; 149:1242– 1249.
52. Rhodes LE, de Rie M, Enstrom Y, et al. Photodynamic therapy using topical methyl aminolevulinate
vs surgery for nodular basal cell carcinoma: results of a multicenter randomized prospective trial.
Arch Dermatol 2004; 140:17– 23.
53. Wang I, Bendsoe N, Klinteberg CA, et al. Photodynamic therapy vs. cryosurgery of basal cell carci-
nomas: results of a phase III clinical trial. Br J Dermatol 2001; 144:832– 840.
54. Kuijpers DI, Smeets NW, Krekels GA, et al. Photodynamic therapy as adjuvant treatment of
extensive basal cell carcinoma treated with Mohs micrographic surgery. Dermatol Surg 2004;
30:794– 798.
55. Stender IM, Na R, Fogh H, et al. Photodynamic therapy with 5-aminolaevulinic acid or placebo for
recalcitrant foot and hand warts: randomised double-blind trial. Lancet 2000; 355:963– 966.
56. Stender IM, Wulf CH. Photodynamic therapy of recalcitrant warts with 5-aminolevulinic: a retro-
spective analysis. Acta Dermato-Venereol 1999; 79:400– 401.
57. Stender IM, Lock-Anderson J, Wulf HC. Recalcitrant hand and foot warts successfully treated with
photodynamic therapy with topical 5-aminolaevulinic acid: a pilot study. Clin Exp Dermatol 1999;
24:154– 159.
58. Schroeter CA, Pleuins J, van Nispen tot Pannerden C, et al. Photodynamic therapy: new treatment
for therapy-resistant plantar warts. Dermatol Surg 2005; 31:71– 75.
59. Mizuki D, Kaneko T, Hanada K. Successful treatment of topical photodynamic therapy using
5-aminolevulinic acid for plane warts. Br J Dermatol 2003; 149:1087– 1088.
60. Smucler R, Jatsova E. Comparative study of aminolevulinic acid photodynamic therapy plus pulsed
dye laser versus pulsed dye laser alone in treatment of viral warts. Photomed Laser Surg 2005;
23:202– 205.
61. Frank RG, Bos JD, Meulen FW, et al. Photodynamic therapy for condylomata acuminata with local
application of 5-aminolevulinic acid. Genitourin Med 1996; 72:70 – 71.
62. Fehr MK, Hornung R, Degen A, et al. Photodynamic therapy of vulvar and vaginal condyloma and
intraepithelial neoplasia using topically applied 5-aminolevulinic acid. Lasers Surg Med 2002;
30:273– 279.
63. Wang XL, Wang HW, Wang HS, et al. Topical 5-aminolaevulinic acid-photodynamic therapy for the
treatment of urethral condylomata acuminata. Br J Dermatol 2004; 151:880– 885.
64. Karrer S, Szeimies RM, Abels C, et al. Epidermodysplasia verruciformis treated using topical 5-ami-
nolaevulinic acid photodynamic therapy. Br J Dermatol 1999; 140:935– 938.
65. Moiin A. Photodynamic therapy for molluscum contagiosum infection in HIV-coinfected patients:
review of 6 patients. J Drugs Dermatol 2003; 2:637– 639.
66. Gold MH, Boring MM, Bridges TM, et al. The successful use of ALA-PDT in the treatment of recal-
citrant molluscum contagiosum. J Drugs Dermatol 2004; 3:187– 190.
67. Cunliffe WJ, Goulden V. Phototherapy and acne vulgaris. Br J Dermatol 2000; 142:855 –856.
68. Morton CA, Scholefield RD, Whitehurst C, et al. An open study to determine the efficacy of blue
light in the treatment of mild to moderate acne. J Dermatol Treat 2005; 16:219– 223.
69. Lee WLS, Shalita AR, Poh-Fitzpatrick MB. Comparative studies of porphyrin production in
Propionibacterium acnes and Propionibacterium granulosum. J Bacteriol 1978; 133:811 – 815.
70. Kjeldstad B, Johnsson A. An action spectrum for blue and near ultraviolet inactivation of Propioni-
bacterium acnes: with emphasis on a possible porphyrin photosensitization. Photochem Photobiol
1986; 43:67 –70.
71. Arakane K, Ryu A, Hayashi C, et al. Singlet oxygen (1 delta g) generation from coproporphyrin in
Propionibacterium acnes on irradiation. Biochem Biophys Res Commun 1996; 223:578– 582.
72. Papageorgiou P, Katsambas A, Chu A. Phototherapy with blue (415 nm) and red (660 nm) light in
the treatment of acne vulgaris. Br J Dermatol 2000; 142:973– 978.
73. Hongcharu W, Taylor CR, Chang Y, et al. Topical ALA-photodynamic therapy for the treatment of
acne vulgaris. J Invest Dermatol 2000; 115:183– 192.
74. Pollock B, Turner D, Stringer MR, et al. Topical aminolaevulinic acid-photodynamic therapy for the
treatment of acne vulgaris: a study of clinical efficacy and mechanism of action. Br J Dermatol 2004;
151:616– 622.
75. Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using methyl aminolaevulinate: a
blinded, randomized, controlled trial. Br J Dermatol 2006; 154:969– 976.
76. Hörfelt C, Funk J, Frohm-Nilsson M, et al. Topical methyl aminolaevulinate photodynamic therapy
for treatment of facial acne vulgaris: results of a randomized, controlled study. Br J Dermatol 2006;
155:608– 613.
77. Gold M, Bridges TM, Bradshaw VL, et al. ALA-PDT and blue light therapy for hidradenitis suppur-
ativa. J Drugs Dermatol 2004; 3(1 suppl):S32– S35.
78. Strauss RM, Pollock B, Stables GI, et al. Photodynamic therapy using aminolaevulinic acid does not
lead to clinical improvement in hidradenitis suppurativa. Br J Dermatol 2005; 152:803– 804.
79. Calzavara-Pinton PG, Venturini M, Capezzera R, et al. Photodynamic therapy of interdigital
mycoses of the feet with topical application of 5-aminolevulinic acid. Photodermatol Photoimmunol
Photomed 2004; 20:144– 147.
80. Donnelly RF, McCarron PA, Lightowler JM, et al. Bioadhesive patch-based delivery of
5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis. J Controlled
Release 2005; 103:381– 392.
81. Silver H. Psoriasis vulgaris treated with hematoporphyrin. Arch Dermatol Syphilol 1937;
36:1118 – 1119.
82. Boehncke WH, König K, Kaufmann R, et al. Photodynamic therapy in psoriasis: suppression of cyto-
kine production in vitro and recording of fluorescence modification during treatment in vivo. Arch
Dermatol Res 1994; 286:300– 303.
83. Fritsch C, Lehmann P, Stahl W, et al. Optimum porphyrin accumulation in epithelial skin tumours
and psoriatic lesions after topical application of delta-aminolaevulinic acid. Br J Cancer 1999;
79:1603– 1608.
84. Boehncke WH, Sterry W, Kaufmann R. Treatment of psoriasis by topical photodynamic therapy with
polychromatic light. Lancet 1994; 343:801.
85. Weinstein GD, McCullough JL, Jeffes EW, et al. Photodynamic therapy (PDT) of psoriasis with
topical delta aminolevulinic acid (ALA): a pilot dose-ranging study. Photodermatol Photoimmunol
Photomed 1994; 10:92.
86. Collins P, Robinson DJ, Stringer MR, et al. The variable response of plaque psoriasis after a single
treatment with topical 5-aminolaevulinic acid photodynamic therapy. Br J Dermatol 1997;
137:743– 749.
87. Robinson DJ, Collins P, Stringer MR, et al. Improved response of plaque psoriasis after multiple
treatments with topical 5-aminolaevulinic acid photodynamic therapy. Acta Derm Venereol 1999;
79:451– 455.
88. Stringer MR, Collins P, Robinson DJ, et al. The accumulation of protoporphyrin IX in plaque psor-
iasis after topical application of 5-aminolevulinic acid indicates a potential for superficial photody-
namic therapy. J Invest Dermatol 1996; 107:76 –81.
89. Radakovic-Fijan S, Blecha-Thathammer U, Schleyer V, et al. Topical aminolaevulinic acid-based
photodynamic therapy as a treatment option for psoriasis? Results of a randomized, observed-
blinded study. Br J Dermatol 2005; 152:279– 283.
90. Schleyer V, Radakovic-Fijan S, Karrer S, et al. Disappointing results and low tolerability of photo-
dynamic therapy with topical 5-aminolaevulinic acid in psoriasis. A randomized, double-blind
phase I/II study. J Eur Acad Dermatol 2006; 20:823– 828.
91. Beattie PE, Dawe RS, Ferguson J, et al. Lack of efficacy and tolerability of topical PDT for psoriasis in
comparison with narrowband UVB phototherapy. Clin Exp Dermatol 2004; 29:560 –562.
92. Malik Z, Ehrenberg B, Faraggi A. Inactivation of erythrocytic, lymphocytic and myelocytic
leukemic cells by photoexcitation of endogenous porphyrins. J Photochem Photobiol B Biol 1989;
4:195– 205.
93. Boehncke WH, König K, Rück A, et al. In vitro and in vivo effects of photodynamic therapy in
cutaneous T-cell lymphoma. Acta Dermato-Venereol 1994; 74:201– 205.
94. Rittenhouse-Diakun K, van Leengoed H, Morgan J, et al. The role of transferrin receptor (CD71) in
photodynamic therapy of activated and malignant lymphocytes using the heme precursor delta-
aminolevulinic acid (ALA). Photochem Photobiol 1995; 61:523 – 528.
95. Boehncke WH, Rück A, Naumann J, et al. Comparison of sensitivity towards photodynamic therapy
of cutaneous resident and infiltrating cell types in vitro. Lasers Surg Med 1996; 19:451– 457.
96. Grebenova D, Cajthamlova H, Bartosova J, et al. Selective destruction of leukaemic cells by
photo-activation of 5-aminolaevulinic acid-induced protoporphyrin IX. J Photochem Photobiol B
Biol 1998; 47:74– 81.
97. Wolf P, Fink-Puches R, Cerroni L, et al. Photodynamic therapy for mycosis fungoides after topical
photosensitisation with 5-aminolevulinic acid. J Am Acad Dermatol 1994; 31:678– 680.
98. Ammann R, Hunziker T. Photodynamic therapy for mycosis fungoides after topical photosensiti-
sation with 5-aminolevulinic acid. J Am Acad Dermatol 1995; 33:541.
99. Orenstein A, Halik J, Tamir J, et al. Photodynamic therapy of cutaneous lymphoma using
5-aminolevulinic acid topical application. Dermatologic Surg 2000; 26:765– 769.
100. Edstrom DW, Porwit A, Ros AM. Photodynamic therapy with topical 5-aminolevulinic acid for
mycosis fungoides: clinical and histological response. Acta Dermato-Venereol 2001; 81:184– 188.
101. Markham T, Sheahan K, Collins P. Topical 5-aminolaevulinic acid photodynamic therapy for
tumour-stage mycosis fungoides. Br J Dermatol 2001; 144:1262– 1263.
102. Leman JA, Dick DC, Morton CA. Topical 5-ALA photodynamic therapy for the treatment of
cutaneous T-cell lymphoma. Clin Exp Dermatol 2002; 27:516– 518.
103. Svanberg K, Andersson T, Killander D, et al. Photodynamic therapy of non-melanoma malignant
tumours of the skin using topical delta-aminolevulinic acid sensitisation and laser irradiation. Br
J Dermatol 1994; 130:743– 751.
104. Coors EA, von den Driesch P. Topical photodynamic therapy for patients with therapy-resistant
lesions of cutaneous T-cell lymphoma. J Am Acad Dermatol 2004; 50:363– 367.
105. Umegaki N, Moritsugu R, Katoh S, et al. Photodynamic therapy may be useful in debulking
cutaneous lymphoma prior to radiotherapy. Clin Exp Dermatol 2004: 29:42– 45.
106. Berroeta L, Lewis-Jones MS, Evans AT, et al. Woringer-Kolopp (localised pagetoid reticulosis)
treated with topical photodynamic therapy (PDT). Clin Exp Dermatol 2005; 31:1– 2.
107. Stender IM, Wulf HC. Photodynamic therapy with 5-aminolaevulinic acid in the treatment of actinic
cheilitis. Br J Dermatol 1996; 135:454– 456.
108. Hauschild A, Lischner S, Lange-Asschenfeldt B, et al. Treatment of actinic cheilitis using photo-
dynamic therapy with methylaminolevulinate: report of three cases. Dermatol Surg 2005;
31:1344– 1348.
109. Sieron A, Adamek M, Kawczyk-Krupka A, et al. Photodynamic therapy (PDT) using topically
applied delta-aminolevulinic acid (ALA) for the treatment of oral leukoplakia. J Oral Pathol Med
2003; 32:330– 336.
110. Chen HM, Chen CT, Yang H, et al. Successful treatment of oral verrucous hyperplasia with topical
5-aminolevulinic acid-mediated photodynamic therapy. Oral Oncol 2004; 40:630 – 637.
111. Calzavara-Pinton PG. Repetitive photodynamic therapy with topical delta-aminolaevulinic acid as
an appropriate approach to the routine treatment of superficial non-melanoma skin tumours.
Photochem Photobiol B Biol 1995; 29:53– 57.
112. Stables GI, Stringer MR, Robinson DJ, et al. Erythroplasia of Queyrat treated by topical aminolaevu-
linic acid photodynamic therapy. Br J Dermatol 1999; 140:514– 517.
113. Lee MR, Ryman W. Erythroplasia of Queyrat treated with topical methyl aminolevulinate photody-
namic therapy. Australas J Dermatol 2005; 46:196– 198.
114. Henta T, Itoh Y, Kobayashi M, et al. Photodynamic therapy for inoperable vulval Paget’s disease
using delta-aminolaevulinic acid: successful management of a large skin lesion. Br J Dermatol
1999; 141:347– 349.
115. Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget’s
disease. Br J Dermatol 2000; 142:59– 65.
116. Shieh S, Dee AS, Cheney RT, et al. Photodynamic therapy for the treatment of extramammary Paget’s
disease. Br J Dermatol 2002; 146:1000– 1005.
117. Madan V, Loncaster J, Allan D, et al. Extramammary Paget’s disease treated with topical and
systemic photodynamic therapy. Photodiagn Photodyn Ther 2005; 2:309– 311.
118. Martin Hirsch PL, Whitehurst C, Buckley CH, et al. Photodynamic treatment for lower genital tract
intraepithelial neoplasia. Lancet 1998; 351:1403.
119. Hillemanns P, Untch M, Dannecker C, et al. Photodynamic therapy of vulvar intraepithelial
neoplasia using 5-aminolevulinic acid. Int J Cancer 2000; 85:649– 653.
120. Fehr MK, Hornung R, Schwarz VA, et al. Photodynamic therapy of vulvar intraepithelial neoplasia
III using topically applied 5-aminolevlinic acid. Gynecol Oncol 2001; 80:62– 66.
121. Abel-Hady E-S, Martin-Hirsch P, Duggan-Keen M, et al. Immunological and viral factors associated
with the response of vulval intraepithelial neoplasia to photodynamic therapy. Cancer Res 2001;
61:192– 196.
122. Bissonnette R, Shapiro J, Zeng H, et al. Topical photodynamic with 5-aminolaevulinic acid does
not induce hair regrowth inpatients with extensive alopecia areata. Br J Dermatol 2000; 143:
1032 – 1035.
123. Ackermann G, Abels C, Bäumler W, et al. Simulations on the selectivity of 5-aminolevulinic
acid-induced fluorescence in vivo. J Photochem Photobiol B: Biol 1998; 47:121– 128.
124. Ericson MB, Sandberg C, Gudmundson F, et al. Fluorescence contrast and threshold limit: impli-
cations for photodynamic diagnosis of basal cell carcinoma. J Photochem Photobiol B: Biol 2003;
69:121– 127.
125. Bäumler W, Abels C, Szeimies RM. Fluorescence diagnosis and photodynamic therapy in
dermatology. Med Laser Appl 2003; 18:47– 56.
27 The Principles and Medical Applications of
Lasers and Intense-Pulsed Light in
Dermatology
Iltefat Hamzavi
Department of Dermatology, Henry Ford Hospital, Detroit, and Hamzavi Dermatology, Port Huron,
Michigan, U.S.A.
Harvey Lui
Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of
British Columbia, Vancouver, British Columbia, Canada
B In order to exert their effect, lasers and IPL must get photons of radiation
into the skin/chromophore and then an absorption event must happen.
B Tissue optics dictate how light gets to a particular structure and most
often thermal effects dictate the clinical result.
B There are different physical qualities of lasers and IPL, but both devices
can work for certain conditions.
B Q-switched lasers are best at removing tattoos with minimal scarring

but require many treatments and do not always clear tattoos.
B Laser hair removal can also be used for noncosmetic indications such
as dissecting cellultis.
B UV lasers and targeted phototherapy target diseased skin while

sparing uninvolved skin.
B Lasers and IPL with or without PDT may have a role in acne but it is
too early to say if they are better than medical therapy.
B Laser-activated PDT can be less painful for actinic keratosis than

noncoherent light activation but long-term efficacy has not been
defined yet.
390 Hamzavi and Lui
aser and light sources offer a potential benefit to many dermatology patients, but the rate
L of advance within the field can confuse even the experienced laser user without a proper
understanding of the principles, which lie behind their use. This chapter highlights some
of the most important advances in the medical use of lasers by relating how these advances
pertain to basic optical principles. Regardless of the device or dermatologic indication,
specific biophysical laws govern how all light affects the skin. This chapter will go on to
cover the medical uses of laser while deferring most of the cosmetic uses for photodamage
and ethnic skin to other chapter of this book. The distinction between cosmetic and
medical can be arbitrary and is often made by third party payers, but for the purposes of
this chapter noncarcinogenic UV-induced effects on the skin and hair removal are considered
cosmetic while other indications will fall within either the medical laser section or the ethnic
laser section.
The key to developing and refining any type of light-based therapy is understanding how
to efficiently and effectively deliver this energy to cutaneous structures in a highly targeted
fashion so as to limit collateral light-induced trauma or to modify certain immune-based
tissue responses. While the term “light” is sometimes restricted to electromagnetic radiation
that is visible to the human eye (i.e., 400– 700 nm), in this chapter, the entire region from ultra-
violet to infrared will be referred to as either light or radiation. Treating the skin with light can
be considered in two stages: (i) understanding how to selectively deliver photons to specific
structural targets in the skin, that is, tissue optics; and (ii) understanding the biological pro-
cesses that occur after a skin target absorbs light photons, that is, photobiological reactions.
The overwhelming majority of refinements to phototherapeutic devices such as lasers and
intense-pulsed light (IPL) exploit either one or both of these two aspects, and the advances
highlighted in the article will be discussed using this mechanistic perspective.
UNDERSTANDING TISSUE OPTICS AND PHOTOBIOLOGICAL REACTIONS

A detailed explanation of tissue optics and photobiological reactions is covered in the section on
radiation sources (chap. 3), but certain basic biophysical principles warrant a brief summary. The
interaction of radiation with tissue is governed by three basic processes that can occur when a
photon of light reaches the skin: reflection, scattering, and absorption (Fig. 1). Radiation that is
reflected from the skin and perceived by the human visual system provides the means for diag-
nosing skin disease, but reflected radiation does not itself result in any direct therapeutic
effect. In the absence of an absorption event (see below), the forward propagation of radiation
deeper within the skin is influenced by the degree to which its direction of travel has been scat-
tered by tissue structures. Tissue scattering of ultraviolet, visible, and near-infrared light is wave-
length-dependent, and in general longer wavelength radiation penetrates the skin more deeply
because longer wavelengths tend to scatter less in the skin. Thus, targets that are deeper in the
skin require the use of devices that can deliver longer wavelength radiation.
FIGURE 1 The various optical effects of photons

on the skin.
Lasers and Intense-Pulsed Light in Dermatology 391
Absorption is an important biophysical event that involves the transfer of energy from
radiation to tissue. The structure which absorbs energy is referred to as a chromophore.
Absorption is strictly defined as when a molecule, which makes up the chromophore,
absorbs electromagnetic energy with a characteristic efficiency given by the molecules extinc-
tion coefficient in a wavelength-dependent manner (1). Without photon absorption, energy will
not be taken up by the skin and no biological or therapeutic effect will occur. The absorption of
photons by specific molecules within the skin also influences light penetration, since
any photon that is absorbed is no longer capable of propagating through the skin, as that
particular photon no longer exists (2). Like scattering, absorption is wavelength-dependent,
but in a somewhat more complicated manner since it depends on the absorption profile or
“spectrum” of the chromophore. With the possible exception of the UVB wavelength
excimer laser, the specific chromophores for most light-based therapies are precisely known,
which include hemoglobin, melanin, water, exogenous dyes (i.e., tattoo pigment), and photo-
sensitizing drugs (i.e., psoralens and PDT photosensitizers). These chromophores absorb
light over a broad spectrum of wavelengths as shown in Figures 2A and B (3,4).
Absorption Spectrum
Oxy Hemoglobin Melanin
532nm YAG
Relative Absorption
694nm Ruby
1064nm YAG
(A)
400 500 600 700 800 900 1000 1100
Wavelength (nm)
2.5
2
Optical Density
1.5
Hemoglobin
Oxyhemoglobin
Water
1 Melanin
0.5
(B) 0
650 750 850 950 1050
Wavelength (nm)
FIGURE 2 (A,B) The absorption spectra of various chromophores in the skin.

392 Hamzavi and Lui
In summary, both scattering and absorption will determine the depth to which light will
penetrate the skin, but only absorption can lead to photobiological and phototherapeutic
effects. All phototherapeutic applications must, by definition be mediated by chromophores
present in the skin. Thus, in order for a given photon to have a clinical effect it must actually
reach the target structure within the skin and then be absorbed by a specific chromophore
within that target. Whether or not these events occur and the degree to which they occur is
dependent on the wavelength of light used, the structures of the skin which affect reflection/
scattering, and the concentration and location of chromophores.
Once the photon is absorbed by the chromophore, the source’s radiation energy is trans-
ferred to the skin to either (i) generate heat, or (ii) drive photochemical reactions. The former
scenario encompasses the mechanism behind the majority of lasers and IPLs in dermatology,
all of which, in essence involve the selective and irreversible alteration of tissue using heat (2).
In contrast, ultraviolet phototherapy using lasers or IPL and laser-assisted/IPL-assisted Photo-
dynamic therapy (PDT) do not primarily involve the use of light to generate heat, but rather rely
on photon absorption to energize photochemistry. In the case of ultraviolet therapy, it is now gen-
erally accepted that the therapeutically useful photochemical reactions culminate in cutaneous
immunosuppression although the exact sequence of reactions is less clear. In laser-/IPL-assisted
PDT, the first two photochemical reactions are very clearly defined. The energy of the excited
chromophore is first transferred to molecular oxygen to form singlet oxygen which then reacts
with a diverse range of biomolecules (2). The ever-expanding indications for PDT partly
mirrors the multiple ways by which singlet oxygen generated by light can affect the skin.
In clinical parlance, there is often an undue preoccupation with the technical specifica-
tions for a given light device rather than a well grounded understanding of the desired under-
lying photobiological and phototherapeutic endpoints. The reality is that for any clinical
indication a multiplicity of possible photonic devices are often available. This simply reflects
the fact that from the point of view of the tissue and its chromophores, the exact source of
the photons (e.g., laser vs. intense-pulsed light vs. light emitting diode vs. fluorescent lamp)
matters far less than whether the photons are of the appropriate wavelength and delivered
to the target in sufficient quantity to cause irreversible tissue changes to particular structures
without collateral damage to surrounding skin. As with any therapeutic modality, the ultimate
arbiters for the bewildering array of competing light-based therapies and devices are well-
designed and rigorously executed controlled clinical studies which must be evaluated with
photobiological principles in mind. Clinical trials information must be coupled to the operators
comfort level with regards to the devices ease of use for the particular indication for which the
patient seeks treatment.
USING LASERS AND INTENSE-PULSED LIGHT TO HEAT THE SKIN

Since most lasers in dermatology are used to precisely heat the skin, the advances for these
applications are related to increasing the selectivity of these devices by fine-tuning the wave-
length, spot size, and pulse duration (i.e., the time over which the laser energy is delivered)
(5,6), and simultaneously cooling the skin during light exposure. These variables are used to
selectively thermally damage particular structures in the skin. These modifications have
increased the safety and efficacy for photothermal lasers/IPL in dermatology, particularly
for targeting larger or deeper skin structures such as larger blood vessels, melanosomes,
porphyrins, and hair follicles. Another driving force in the evolution of lasers and IPL has
been the need to minimize “down-time” from postprocedure purpura to elaborate wound
care protocols. More information on the cosmetic uses of IPL and laser can be found in the
cosmetic laser chapter (chap. 29) within this book.
Intense-Pulsed Light
IPL sources are now very popular in medicine and have been heavily marketed to the public as
well as dermatologists, other physicians, and nonmedical practitioners. IPL devices are not
lasers, but like most cutaneous lasers, produce their desired effect by generating heat. The
core technology is relatively simple and involves the use of polychromatic broadband
flashlamps equipped with optical filters that allow preselected visible to infrared wavebands
(500 –1200 nm) to reach the skin (7). Since multiple wavelengths are delivered, several different
chromophores including hemoglobin, melanin, and perhaps, even water can be targeted with
the same light exposure. In practical terms, multiple IPL treatment sessions are often required,
and due to the complexity of selecting the appropriate wavelength cut-off filter, fluence, and
pulse duration there is a risk for developing side effects secondary to nonspecific thermal
damage. These side effects include crusting, pigmentary changes, hair loss, and paradoxical
increases in hair growth (8). Another potential area of concern with IPL relates in part to the
multiplicity of repeat treatments that are often advocated for both the initial treatment and
subsequent maintenance sessions. Lastly, the ergonomics of IPL make visualizing the skin
while firing a laser difficult when compared to laser technology (9). However, IPL is one of
the better treatment options to simultaneously treat pigment and telangiectasias. The versatility
and effective marketing of these devices is a driving force behind their popularity. In addition,
there is a much lower acquisition and maintenance cost along with their multiple uses which
have made them an often used technology (9).
CLINCIAL INDICATIONS
Getting the Red Out
The principle for treating vascular lesions such as port wine stains with yellow 577/585/595 nm
light was originally based on hemoglobin’s absorption spectrum, red to infrared light appears
to better target blood vessels that are situated more deeply (Fig. 3) (Table 1). In addition, vas-
cular laser pulse durations have been extended from the sub-microsecond to millisecond
domain for two reasons. A longer duration of exposure will heat a greater tissue volume,
which is necessary for larger caliber vessels. Second, longer pulses will conduct heat more
gradually within blood vessels resulting in a lesser tendency to immediate purpura which,
although temporary, patients find very disfiguring. The long-pulsed neodymium:YAG and
later-model pulsed-dye lasers both expand the range of blood vessels that can be treated by
incorporating these parameter changes. The longer penetration of the long-pulsed 1064 nm
neodymium:YAG laser facilitates its use for leg veins including blue veins up to 3 mm in
diameter. The depth of penetration of these wavelengths are enhanced using wider spot
sizes which increase forward scattering which minimizes superficial thermal injury (10,11).
Not unexpectedly, these lasers are often less effective for finer red telangiectasias presumably
due to a mismatch between the vessel’s thermal relaxation time and the laser’s pulsewidth.
The deeper penetration of the recently developed 595 nm, long pulse (up to 40 ms) dye
laser allows the operator to obtain clearance for some port wine stains that is equivalent to
the original 585 nm, 450 ms pulsed dye laser results with fewer side effects such as prolonged
purpura and crusting (12). IPL can also be used to treat erythema with a minimal amount
of purpura but requires more treatment and has the disadvantage of limiting the operators
visualization of vessels until after they are treated (9). A more detailed explanation of vascular
laser treatments can be found in the cosmetic laser chapter of this book (chap. 29).
FIGURE 3 A port wine stain treated with a pulsed-dye laser (left : before treatment; right : after eight treatments).
394 Hamzavi and Lui
TABLE 1 A Selected List of Lasers and Intense-Pulsed Light with Wavelength, Pulse Duration, and
Clinical Indications
Type of laser Wavelength (nm) Target Pulse duration/comments
Continuous wave
CO2 10,600 Water Less than 1.6–2.8 ms
which is the estimated
thermal relaxation
time of the skin
Ablative laser
Pulsed CO2 10,600 Water ,2 ms, but varies
Erbium 2940 Water Automatically adjusts
in most models
Fractional lasers
Microablative laser 1550,1540,1440 Water in dermis Creates microthermal
injury zones using light arrays
Pulsed lasers for
vascular, hair,
collagen, and
sebaceous glands
thermolysis; longer
pulse duration
and intermediate
peak power
Flashlamp-pumped 585 Blood vessel 450 ms
pulsed dye (30– 100 mm)
Long-pulsed dye 595 1.5– 40 ms Blood vessels (.1 mm)
KTP (potassium 532 1 –100 ms Blood vessels up to 1 mm
titanyl phosphate)
Nonablative Used for acne and photoaging
infrared lasers
Nd:YAG 1320 Water in Collagen Precools epidermis to
limit thermal effect to dermis
Diode 1450 Water in collagen Precools epidermis to
and sebaceous gland limit thermal effect to dermis
Glass Erbium 1540 Water in dermis 10– 100 ms
Pulsed lasers/light
sources for pigmented
lesions at very
high peak powers
and very short
pulse durations
Q-switched ruby 694 25 ns Melanin, black, blue, green tattoos
Q-switched alexandrite 755 50– 100 ns Melanin, black, blue, green tattoos
Q-switched Nd:YAG 1064 5-15 nsec Melanin, black tattoos
Q-switched Nd:YAG 532 (freq-doubled) 5 –15 ns Melanin, red, orange, yellow tattoos
IPL (not Q-switched) 590–1200 Variable (ms) Works on pigmented and vascular lesions
Hair-removal devices
694 ruby 694 3 –100 ms Most w/ cooling device
755 nm alexandrite 755 2 –40 ms Most w/ cooling device
800 nm diode lasers 800 5 –250 ms Most w/ cooling device
1064 nm long pulsed 1064 1 –350 ms Most w/ cooling device
IPL 590–1200 Variable (ms) Some w/ cooling device
Abbreviation: IPL, intense-pulsed light.
Getting the Melanin Out

Lasers and IPL can be used to selectively remove melanin in a variety of conditions with vari-
able success and safety. The selectivity can be obtained by appropriate selection of the wave-
length, pulse duration, spot size, and recognition of biological endpoints. There are a variety
of wavelengths in the visible range which are absorbed by melanin as indicated in Figures
2A and B, but the over-riding principle of this therapy is to target the melanin in the
pathological skin without destroying the normal skin. Selectivity is obtained by appropriate
selection of wavelength, pulsed duration, spot size, and cooling the targeted areas. Q-switched
lasers and IPL treatments are very helpful in pigmented lesions such as nevus of Ota, tattoo
removal, and lentigines. Nevus of Ota and tattoos are best treated with high-peak power
devices with very short pulse durations. Q-switched lasers are the best options for these con-
ditions but lead to some crusting post-treatment with the potential side effects of hypopigmen-
tation. In addition, they require multiple treatments. Q-switched lasers are effective devices but
they do suffer from an inadequate response in some patients along with postinflammatory
hyperpigmentation in Asians, in particular (9). IPL has the benefit of minimal crusting but
requires multiple treatments. The response of melasma to light treatment has been less than sat-
isfactory and this particular disorder of pigmentation must be approached differently. This is
covered in more detail in the cosmetic sections and the section on treatment of ethnic skin
diseases.
Tattoos
Lasers have been used to remove tattoos for more than 25 years. Initially, the CO2 laser in
continuous mode was used but resulted in significant irreversible textural changes and dyspig-
mentation. Other wavelengths that were specific to particular tattoo colors were added that
resulted in scarring as well. However, in the 1990s, lasers were designed based on experimental
data from the 1960s and 1980s, which suggested that shorter pulsed durations in the nano-
second domain of high-peak power could more specifically target smaller structures with
less collateral damage. Since that time, Q-switched lasers have become the preferred modality
of tattoo removal (5,13) (Fig. 4). These devices should be used by an experienced operator who
is aware of their limitations. These include the following key points: (i) the color of the tattoo
should match the wavelength used to ablate it (Table 1); (ii) larger spot sizes are preferred due
to the deeper depth of penetration; (iii) the laser should have a pulse duration in the nanose-
cond domain; and (iv) skin-colored tattoos should be treated with care, since they may
develop a paradoxical hyperpigmentation (14). Even if everything is optimal, laser tattoo
removal requires multiple treatments, cannot treat certain inks and may cause some hypopig-
mentation. However, the textural changes are much improved as compared with other types of
removal using heat or surgery (14). The skin-colored tattoos are best left alone, but if treatment
is desired then very careful pulsed CO2 laser can be performed with effective removal of the
tattoo (15).
Cooling the Skin to Protect the Epidermis and Superficial Dermis

Although the judicious selection of wavelength, spot size, pulse duration, and fluence allows
lasers and IPL sources to generate heat at specific targets within the skin, collateral heat
FIGURE 4 Tattoo removal with a 755 nm Q-switched laser (Left : before treatment; Right : after four treatments).
396 Hamzavi and Lui
damage can still be sustained by surrounding structures, particularly the epidermis which con-
tains melanin, a broad spectrum chromophore. Unwanted epidermal thermal damage becomes
even more problematic when treating darker skin types or when using higher fluences as may
be the case when treating deeper targets such as hair follicles. Cooling the skin surface during
laser exposures serves to protect the epidermis and superficial dermis from unintended
photothermal effects. Skin-cooling techniques include chilled probes held in contact with the
skin, timed cryogen sprays directed to the skin surface, and forced cold air fans directed
at the treatment site. All forms of cooling aim to prevent the superficial layers of the skin
from reaching the threshold temperature for thermal damage during laser exposure,
and they all differ in terms of reliability and the cost of consumables such as cyrogen. An
additional benefit of skin cooling beyond the reduction of superficial crusting and dyschromia
is intraoperative pain relief (16).
Treating Hair Disorders with Light

The use of lasers and IPL systems for hair removal has expanded tremendously over the
decade. This has mostly been used for cosmetic indications, which are covered in other chap-
ters of this work. In addition, Table 1 lists some of the laser hair-removal options presently
available. The benefits of this technology are expanding into medical arenas such as the treat-
ment of inflammatory scalp disorders such as pseudofolliculitis barbae, dissecting cellulites,
and scarring alopecias (Fig. 5). Since many of these conditions involve an immune response
to the hair, treatments that target the hair often improve the condition. Given the fact that
these diseases target people of color, the longer wavelength, long-pulsed lasers have added
new treatment options for these diseases. Treatment for pseudofollicultis has been documented
in a randomized clinical trials (17), whereas treatment for the other conditions has not. All
these conditions can often be quite disabling. There are reports of prolonged remissions of
these conditions with long-pulse Nd:YAG lasers (18).
Lasers for Warts

Lasers used for the treatment of Verrucae vulgaris is controversial. The treatment is often nonspe-
cific and can generate a plume of infectious smoke which must be evacuated by a filter (19).
However, the treatment can be effective for recalcitrant verruca that have not responded to the
traditional treatments (20). It is the author’s experience that the pulsed-dye laser can be an effec-
tive treatment for multiple verruca located on the hands, but several treatments are required and
the settings have to be adjusted to induce significant purpura of the affected lesions and sur-
rounding skin. The pulsed dye is less effective for Verruca plantaris. These may respond to the
CO2 laser, but scarring complications are not uncommon. However, the ability to simultaneously
FIGURE 5 An example of dissecting cellulitis treated with Nd:YAG laser (left : before treatment; right : after six
treatments).
destroy tissue while maintaining hemostasis can be very helpful and the CO2 can compare favor-
ably to other treatments for the treatment of recalcitrant verruca.
UV Lasers as Immunomodulators
Recent advances in ultraviolet phototherapy include a better mechanistic understanding of its
biological effects, more rational dosimetry approaches, and the deployment of several novel
UV sources. Although this book has a separate section on phototherapy, a quick review here
will explain the rationale behind laser and targeted phototherapy systems. The basic science
for UV phototherapy is characterized best for psoriasis where the induction of T-cell apoptosis
has been demonstrated for broad (21) and narrowband UVB (22). Narrowband UVB photother-
apy also seems to affect keratinocyte apoptosis as well (23). Multiple other cutaneous immuno-
logical reactions also occur with UV, but the T cell-depleting effects are likely pivotal for
clearing inflammatory dermatoses and cutaneous T cell lymphoma. These cytolytic effects on
activated immune cells may also explain why UV therapy can be considered a remittive
form of psoriasis treatment. The fundamental shift in concept of UV phototherapy as a
means of inducing localized cutaneous immunosuppression has provided a far more logical
rationale for its general efficacy in a broad range of dermatoses.
In conventional UV phototherapy, both diseased and normal skin are simultaneously
exposed to light. While the primary goal of treating inflammatory dermatoses such as psoriasis
is to clear skin lesions using light, our current approach to UV dosimetry is limited by the need
to avoid burning the unaffected skin. Very high-dose UV exposures—as high as several mul-
tiples of the baseline minimal erythema (UVB) (24) or phototoxic (PUVA) (25) dose—can
indeed clear psoriasis fairly efficiently, but using such fluences on a “whole body” basis at
the outset of therapy will cause severe burning of unaffected skin.
Novel UV Light Sources

Unlike selective photothermolysis with lasers, which is critically dependent on the rate and
number (i.e., irradiance and fluence, respectively) of photons delivered to the skin, the
effects of UV phototherapy are primarily determined by the total number of photons that
reach the skin which result in apoptosis and other immunosuppressive effects (23,26). Thus,
depending on the specific light source, psoriasis can be cleared with UV light exposures
ranging from several minutes (conventional fluorescent or incandescent lamps) to fractions
of a second (lasers and IPL). UV lasers and IPL sources aim to clear psoriasis more efficiently
than conventional broadband UVB in three ways. First, these sources emit relatively longer
wavelength UVB, or UVB, UVA, and visible light; second, they can be targeted to expose
only the affected areas while sparing normal skin thereby allowing much higher fluences to
be safely used; and finally, they operate at much higher irradiances so that exposure times
are much shorter than with fluorescent lamps. There are now at least three commercial
devices that can provide targeted phototherapy: the 308 nm excimer laser, broadband IPL,
and the broadband mercury lamp with dual UVB and UVA output. There are several published
controlled clinical studies to show that psoriasis responds to the excimer laser and other tar-
geted phototherapy systems (24,27,28). The disadvantages to targeted phototherapy are the
higher cost and the relatively time-consuming aspect of covering broad plaques on the body
with a series of relatively small spot size exposures. Parenthetically, non-UV lasers have
been successfully used for psoriasis (29), but these techniques have not been widely adapted
in dermatology, presumably because of practical limitations.
In addition to psoriasis, UV wavelength lasers have been shown to be effective in vitiligo
as well. They do appear to repigment skin faster than conventional UV light sources, but they
still have the issue of not being able to completely repigment most patient on most locations of
the skin (30).
Laser-/Intense-Pulsed Light-activated Photodynamic Therapy

Following its approval by the Food and Drug Administration (FDA) in 1999 for treating actinic
keratoses, PDT was initially slow to catch on in dermatology, and this was largely due to the
398 Hamzavi and Lui
low reimbursement for dermatologic PDT in the United States by third party payers. The
concept of PDT is a century old, and its dependence on oxygen-related photochemistry has
been well known for most of that time. In clinical practice, the treatment involves the admin-
istration of a photosensitizer followed by exposing the skin to light. The drug-activating
photons can come from lasers or noncoherent light sources. The photosensitizer, incubation
period, and wavelength used to activate the photosensitizer allow the nonthermal selective
destruction of neoplastic keratinocytes, sebaceous glands, and hair follicles to be fine-tuned.
Indications for PDT can include oncological uses and destruction of appendegeal structures.
The efficacy of topical PDT using 20% aminolevulinic acid (ALA) and a blue light has been
documented in the treatment of actinic keratosis (31). However, the procedure as approved by
the FDA is painful and requires two visits on separate days. A few studies where the incubation
period was reduced to a few hours and a pulsed-dye laser or IPL used to activate the photody-
namic reactions reduced the pain and overall patient treatment time (32). In addition, there are
reports of using lasers/IPL and ALA to treat photodamaged skin (33).
Lasers and Intense-Pulsed Light for Acne

Acne is a potential area of dermatology that lasers may impact. There are few studies com-
paring light-based devices to standard topical or oral medications, but there are several
split-faced no treatment/treatment-controlled studies showing a benefit (34,35). There have
been several reports suggesting that lasers may be helpful in the treatment of acne (34).
There also have been reports to the contrary stating that the lasers do not offer a treatment
benefit (36). Long pulsed-dye lasers may offer a benefit, but the optimal settings and the
desired biological endpoint have not been determined. There are reports that the 1450 nm
laser which targets water in the sebaceous gland is effective for up to 12 months (35).
There is also absorption of this wavelength by water in the epidermis, but the use of
cryogen cooling prevents the epidermis from suffering significant thermal damage while
the sebaceous gland is heated (37).
The use of PDT to ablate appendegeal structures is an area of active investigation. There
has been one case study on the use of topical 20% ALA to treat truncal acne with good results.
However, significant postinflammatory hyperpigmentation and pain were reported (38).
Recently, this technique has been modified by decreasing the incubation period and activating
the photosensitizer by a laser or IPL. This has been shown to be less painful and may induce a
clinical remission of moderate acne (39). However, the long-term ability of PDT to induce a
clinical remission of acne cannot be confirmed at this time. To date, no controlled trials have
been published.
CONCLUSION
It is no longer possible to practice dermatology without drawing on the healing power of lasers
and light. As compared to drugs, light therapy is in general vastly more versatile with an equal
or better safety profile. The range of indications for using light in dermatology cuts across all
areas including chronic inflammatory dermatoses, pigmentary disorders, cancer, infections,
and cosmetic applications. Physicians can remain current in their understanding of current
and evolving modalities by mastering the basic biophysical principles outlined in this
chapter. Once these concepts are understood all the advances in lasers and IPL can be kept
in perspective. Physicians can then apply the most appropriate technology to the care of
their patients while informing patients and themselves about the potential limitations and
pitfalls of over-marketed but inadequately proven strategies.
ACKNOWLEDGMENT
The authors gratefully acknowledge Michael Owen, BS, Graduate Student, Wayne State
University for formatting the images in this chapter.
REFERENCES
1. Stamatas GN, Zmudzka BZ, Kollias N, Beer JZ. Non-invasive measurements of skin pigmentation in
situ. Pigment Cell Res 2004; 17(6):618– 626.
2. Hamzavi I, Lui H. Using light in dermatology: an update on lasers, ultraviolet phototherapy, and
photodynamic therapy. Dermatol Clin 2005; 23(2):199– 207.
3. Dover JS, Arndt KA, Geronemus RG, Alora MB. Cutaneous and Aesthetic Laser Surgery. 2nd ed.
Stamford: Appleton and Lang, 2000.
4. Attas M, Hewko M, Payette J, Posthumus T, Sowa M, Mantsch H. Visualization of cutaneous hemo-
globin oxygenation and skin hydration using near-infrared spectroscopic imaging. Skin Res Technol
2001; 7(4):238– 245.
5. Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of
pulsed radiation. Science 1983; 220(4596):524 – 527.
6. Nouri K, Chen H, Saghari S, Ricotti CA, Jr. Comparing 18- versus 12-mm spot size in hair removal
using a gentlease 755-nm alexandrite laser. Dermatol Surg 2004; 30(4 Pt 1):494– 497.
7. Raulin C, Greve B, Grema H. IPL technology: a review. Lasers Surg Med 2003; 32(2):78– 87.
8. Moreno-Arias GA, Castelo-Branco C, Ferrando J. Side-effects after IPL photodepilation. Dermatol
Surg 2002; 28(12):1131 – 1134.
9. Ross EV. Laser versus intense pulsed light: competing technologies in dermatology. Lasers Surg Med
2006; 38(4):261– 272.
10. Sadick NS, Prieto VG, Shea CR, Nicholson J, McCaffrey T. Clinical and pathophysiologic correlates of
1064-nm Nd:Yag laser treatment of reticular veins and venulectasias. Arch Dermatol 2001;
137(5):613–617.
11. Omura NE, Dover JS, Arndt KA, Kauvar AN. Treatment of reticular leg veins with a 1064 nm long-
pulsed Nd:YAG laser. J Am Acad Dermatol 2003; 48(1):76– 81.
12. Greve B, Raulin C. Prospective study of port wine stain treatment with dye laser: comparison of two
wavelengths (585 nm vs. 595 nm) and two pulse durations (0.5 milliseconds vs. 20 milliseconds).
Lasers Surg Med 2004; 34(2):168– 173.
13. Goldman L, Wilson RG, Hornby P, Meyer RG. Radiation from a Q-switched ruby laser. Effect of repeated
impacts of power output of 10 megawatts on a tattoo of man. J Invest Dermatol 1965; 44:69– 71.
14. Bernstein EF. Laser treatment of tattoos. Clin Dermatol 2006; 24(1):43– 55.
15. Hamzavi I, Lui H. Surgical pearl: removing skin-colored cosmetic tattoos with carbon dioxide resur-
facing lasers. J Am Acad Dermatol 2002; 46(5):764–765.
16. Tunnell JW, Chang DW, Johnston C, et al. Effects of cryogen spray cooling and high radiant exposures on
selective vascular injury during laser irradiation of human skin. Arch Dermatol 2003; 139(6):743–750.
17. Ross EV, Cooke LM, Overstreet KA, Buttolph GD, Blair MA. Treatment of pseudofolliculitis barbae in
very dark skin with a long pulse Nd:YAG laser. J Natl Med Assoc 2002; 94(10):888– 893.
18. Krasner B, Hamzavi F, Murakawa G, Hamzavi I. Dissecting cellulitis treated with the long pulsed
Nd:YAG laser. Dermatol Surg 2006; 32(8):1039– 1044.
19. Garden JM, O’Banion MK, Bakus AD, Olson C. Viral disease transmitted by laser-generated plume
(aerosol). Arch Dermatol 2002; 138(10):1303 – 1307.
20. Kopera D. Verrucae vulgares: flashlamp-pumped pulsed dye laser treatment in 134 patients. Int J Der-
matol 2003; 42(11):905– 908.
21. Krueger JG, Wolfe JT, Nabeya RT, et al. Successful ultraviolet B treatment of psoriasis is accompanied
by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells. J Exp Med
1995; 182(6):2057– 2068.
22. Ozawa M, Ferenczi K, Kikuchi T, et al. 312-nanometer ultraviolet B light (narrow-band UVB) induces
apoptosis of T cells within psoriatic lesions. J Exp Med 1999; 189(4):711 – 718.
23. Aufiero BM, Talwar H, Young C, et al. Narrow-band UVB induces apoptosis in human keratinocytes.
J Photochem Photobiol B 2006; 82(2):132– 139.
24. Trehan M, Taylor CR. High-dose 308-nm excimer laser for the treatment of psoriasis. J Am Acad Der-
matol 2002; 46(5):732– 737.
25. Taylor CR, Kwangsukstith C, Wimberly J, Kollias N, Anderson RR. Turbo-PUVA: dihydroxyacetone-
enhanced photochemotherapy for psoriasis: a pilot study. Arch Dermatol 1999; 135(5):540–544.
26. Bianchi B, Campolmi P, Mavilia L, Danesi A, Rossi R, Cappugi P. Monochromatic excimer light
(308 nm): an immunohistochemical study of cutaneous T cells and apoptosis-related molecules in
psoriasis. J Eur Acad Dermatol Venereol 2003; 17(4):408– 413.
27. Dierickx C. Optimalization of treatment of psoriasis with B clear system(abstract). Lasers Surg Med
2003; 32(suppl 15):37.
28. Asawanonda P, Chingchai A, Torranin P. Targeted UV-B phototherapy for plaque-type psoriasis. Arch
Dermatol 2005; 141(12):1542– 1546.
29. Zelickson BD, Mehregan DA, Wendelschfer-Crabb G, et al. Clinical and histologic evaluation of psor-
iatic plaques treated with a flashlamp pulsed dye laser. J Am Acad Dermatol 1996; 35(1):64– 68.
30. Hong SB, Park HH, Lee MH. Short-term effects of 308-nm xenon-chloride excimer laser and narrow-
band ultraviolet B in the treatment of vitiligo: a comparative study. J Korean Med Sci 2005; 20(2):
273– 278.
400 Hamzavi and Lui
31. Jeffes EW, McCullough JL, Weinstein GD, Kaplan R, Glazer SD, Taylor JR. Photodynamic therapy of
actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light. J Am
Acad Dermatol 2001; 45(1):96– 104.
32. Alexiades-Armenakas MR, Geronemus RG. Laser-mediated photodynamic therapy of actinic kera-
toses. Arch Dermatol 2003; 139(10):1313– 1320.
33. Avram DK, Goldman MP. Effectiveness and safety of ALA-IPL in treating actinic keratoses and
photodamage. J Drugs Dermatol 2004; 3(suppl 1):S36– S39.
34. Seaton ED, Charakida A, Mouser PE, Grace I, Clement RM, Chu AC. Pulsed-dye laser treatment for
inflammatory acne vulgaris: randomised controlled trial. Lancet 2003; 362(9393):1347 – 1352.
35. Jih MH, Friedman PM, Goldberg LH, Robles M, Glaich AS, Kimyai-Asadi A. The 1450-nm diode laser
for facial inflammatory acne vulgaris: dose-response and 12-month follow-up study. J Am Acad Der-
matol 2006; 55(1):80– 87.
36. Orringer JS, Kang S, Hamilton T, et al. Treatment of acne vulgaris with a pulsed dye laser: a random-
ized controlled trial. JAMA 2004; 291(23):2834 – 2839.
37. Paithankar DY, Ross EV, Saleh BA, Blair MA, Graham BS. Acne treatment with a 1450 nm wavelength
laser and cryogen spray cooling. Lasers Surg Med 2002; 31(2):106– 114.
38. Hongcharu W, Taylor CR, Chang Y, Aghassi D, Suthamjariya K, Anderson RR. Topical ALA-
photodynamic therapy for the treatment of acne vulgaris. J Invest Dermatol 2000; 115(2):183– 192.
39. Goldman MP, Boyce SM. A single-center study of aminolevulinic acid and 417 nm photodynamic
therapy in the treatment of moderate to severe acne vulgaris. J Drugs Dermatol 2003; 2(4):393– 396.
28 Lasers and Energy Sources for Skin
Rejuvenation and Epilation
Robert A. Weiss
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, and
Maryland Laser Skin & Vein Institute, Hunt Valley, Maryland, U.S.A.
Michael Landthaler
Department of Dermatology, University Clinic Regensburg, Regensburg, Germany
B Type I photorejuvenation includes treatment of vascular and pigmentary

changes associated with photoaging, including lentigines,
telangiectasias, dull skin tone, diffuse redness, and rosacea.
B Type II photorejuvenation includes treatment of structural changes in
collagen and connective tissue, resulting in improvement in pore size,
elastosis, and rhytides.
B Visible light sources and lasers have more influence on type I
photorejuvenation treating telangiectatic and melanocytic components
of photoaging. These sources can be subdivided into coherent, single
wavelength, broadband (flash lamps) or narrowband, such as light
emitting diode.
B Infrared wavelengths with primarily water absorption are used to create
thermal dermal and collagen injury to effect type II photorejuvenation.
The most commonly employed devices are 1320 nm, 1450 nm, and
1540 nm lasers.
B Fractional or microthermal resurfacing refers to small, localized regions
of significant thermal injury (coagulation columns) surrounded by
circumscribed areas of untreated skin. As a result of direct micro-
columnar thermal coagulation of tissue, microrejuvenation techniques
stimulate direct replacement of photoaged dermal collagen, resulting in
improved skin texture and reduction of fine-to-moderate rhytids.
B Clinical tissue tightening following radiofrequency treatment is thought
to result from heat-induced immediate collagen contraction, subsequent
collagen remodeling, and neocollagenesis of the dermis and subcutis.
B Multiple lasers and intense pulse light can be used for epilation; most
patients will achieve 90% hair reduction. However, regrowth may occur
in 6 to 12 months.
402 Weiss and Landthaler
PHOTOREJUVENATION
INTRODUCTION
hotorejuvenation is the process whereby light or other energy sources are utilized to
P reverse the process of photo- or sun-induced aging or environmental damage to the

skin. Nonablative photorejuvenation accomplishes this without disturbance of the over-
lying epidermis. Nonablative typically refers to controlled wounding by thermal means indu-
cing photothermolysis of targeted structures. In addition, there is a relatively new modality of
nonwounding/nonthermal, termed photomodulation. The newest treatment for cosmetic
improvement is fractional resurfacing, which describes discrete micro-thermal zones of
injury, 100 to 250 m wide and 300 to 700 m deep with a zone of surrounding unaffected skin.
The goal of photorejuvenation with these devices is a reorganization in dermal structural
elements and an increase in dermal volume with minimal stimulation of epidermal turnover
or injury.
Dermal remodeling without epidermal injury evolved further from initial observations
with the use of the pulsed dye laser (PDL) for treatment of surface telangiectasia, but with a
secondary effect of skin textural smoothing (1). Subsequently, the development of the
1320 nm, 1450 nm, and 1540 nm infrared lasers with some form of epidermal protection
whether cryogen spray, contact cooling, or forced air cooling allowed deeper collagen remodel-
ing with targeted depths of 300 to 500 m for treatment of deeper scars and rhytids. Complete
cosmetic enhancement of the skin must also evolve to include reversal of some of the visible
changes that occur from photoaging, not entirely relating to structural changes. Reduction of
superficial dyspigmentation (both dermal and epidermal), reduction of dermal telangiectasias,
and the appearance of an overall smoother texture and tone became essential elements. As a
result, two types of photorejuvenation have been described (2). Type I deals with the elements
of vascular and pigmentary changes associated with photoaging, lentigines, telangiectasias,
dull skin tone, diffuse redness, and rosacea. Type II involves the structural changes in collagen
and connective tissue and can be associated with improvement in pore size, elastosis, and
rhytides. Type I and II skin rejuvenation represent photothermal nonablative therapies, as
traditionally described.
CLASSIFICATION AND USE OF LASERS/LIGHT SOURCES

FOR PHOTOREJUVENATION
Table 1 outlines the main classifications of laser, light, and other energy sources utilized for
cosmetic improvement of the skin. All such classifications are arbitrary, as many devices
are capable of delivering multiple wavelengths or energy forms. The first category is visible
light lasers or light sources, which have more absorption by hemoglobin and melanin. These
visible light sources and lasers have more influence on the telangiectatic and melanocytic
components of photoaging. These sources can be subdivided into coherent, single wavelength,
broadband (flash lamps) or narrowband, such as light emitting diode (LED). Intense pulsed
light (IPL) is a broadband light source with filters used to limit the lower end of the emitted
spectrum.
The next category is infrared with absorption predominantly by water. Infrared wave-
lengths with primarily water absorption are used to create thermal dermal and collagen
injury. The most commonly employed devices are 1320 nm, 1450 nm, and 1540 nm lasers,
although narrowband infrared LED devices and other filtered light sources and possibly ultra-
sound may be available in the future. A variant of this is fractional resurfacing. This method can
be thought of as microthermal, namely, small zones of thermal injury, tens to hundreds of
microns wide are placed into the dermis in a pixel-like fashion. The epidermis is not ablated
in these pinpoint thermal columns due to laser design and the use of rigorous skin cooling.
There are presently three devices; two use a 1550 nm wavelength and one uses a 1440 nm wave-
length to create small microthermal zones of thermal injury about 100 to 300 m in diameter. It is
speculated that this pixel-like microthermal dermal heating will result in skin contraction,
dermal collagen remodeling, and thickening and replacement of elastotic collagen. Hence, a
cosmetic improvement in the rhytid portion of photoaging.
Lasers and Energy Sources for Skin Rejuvenation and Epilation 403
TABLE 1 Classification of Lasers, Light, and Energy Sources

Visible laser light sources
Frequency doubled Nd:YAG, KTP (green 532 nm)
Pulsed dye (yellow 585– 595 nm)
Long pulse versus short PDL
Visible nonlaser light sources
Intense pulsed light—broadband filtered light of various origins
Visible infrared
LED—narrowband
UV, visible, infrared
Infrared lasers (target pigment, hemoglobin and water)
Q-switched and millisecond domain Nd:YAG 1064 nm
Infrared lasers (target water only)
1320 nm Nd:YAG laser
1450 nm diode laser
1540 nm erbium glass laser
Microablative infrared lasers (target water)
1440 nm microarray
1540 nm microarray
1550 nm scanned
Radio-frequency, microwave, and ultrasound
Abbreviations: KTP, potassium-titanyl-phosphate; LED, light emitting diode;
Nd:YAG, neodymium : yttrium-aluminum-garnet; PDL, pulsed dye laser.
When selecting an energy source for cosmetic improvement, it is critical to understand

the physics behind the wavelength or energy source and thoroughly understand the method
of delivery and histologic changes. Having knowledge of the output of a device, with under-
standing whether the target is hemoglobin, melanin or water (or all three) with spot size and
method of delivery, the physician may be better able to choose the correct system for the
correct application. For example, photorejuvenation of pigmented lesions would not be
possible with a unit emitting 1450 nm for which the target is water and not melanin. This
knowledge is also vital for the clinician to minimize possible adverse clinical events in
darker ethnic skin types. Visible light, more strongly absorbed by melanin, must therefore be
used with greater caution in darker skin. An algorithm for approaches to specific cosmetic
conditions is outlined in Table 2.
Visible Light Lasers

Frequency Doubled Nd:YAG, KTP (Green 532 nm)
This has been effectively used for the pigment and telangiectatic component of photoaging for
many years and has become an accepted modality for comprehensive photorejuvenation (3).
It can be enhanced by the simultaneous use of 1064 nm Nd:YAG laser. The use of this device
for many years was very technique-dependent, as the 532 nm light could only be delivered
via a relatively small spot size of 4 to 5 mm. The newest version of this device (Gemini, Laser-
scope, San Jose, California, U.S.A.) allows implementation of a 10 mm spot size of 532 nm green
so that a rapid technique to treat a cheek in one to three passes can be employed with repro-
ducible results. In a bilateral comparison of IPL versus large spot 532 nm, the large spot
532 nm was actually a little bit faster than the IPL and delivered slightly better results on pig-
mentation (4). This is predicted by the higher absorption of 532 nm by melanin over wave-
lengths cut off at 560 nm with the IPL device. It is now thought that the large spot size
532 nm is an additional to the armamentarium of cosmetic rejuvenation. It compares favorably
to some of the broadband devices that deliver energy in large spot sizes so that the entire face
can be treated quickly (Fig. 1).
Pulsed Dye (Yellow 585 –595 nm) (Pulsed Dye Laser)

The first nonablative wavelength cleared by the FDA for periocular wrinkling for both the 585
and 595 nm wavelengths, this laser has become popular for several components of photoaging
TABLE 2 Algorithm by Photoaging Problem for Nonablative Skin Photorejuvenation

Telangiectasias
IPL
PDL LP
Nd:YAG LP 532 nm
Diffuse redness (nonvisible telangiectasia)
IPL
LED photomodulation
Mottled pigmentation
IPL
Nd:YAG LP 532 nm
LED photomodulation
Mild rhytides
LED photomodulation
IPL
PDL
Nonablative infrared lasers
Microthermal infrared lasers
Moderate rhytides
Infrared
Microthermal infrared lasers
Deeper rhytids
Infrared wavelengths beyond main hemoglobin and melanin absorption
1320 nm, 1450 nm, and 1540 nm
Radiofrequency (more effective for skin tightening)
Radiofrequency plus additional energy source
Abbreviations: IPL, intense pulse light; LED, light emitting diode; LP, long pulse; PDL, pulsed dye laser.
with newer longer pulse durations. By avoiding the purpura of the original 0.45 msec pulse
durations, pulse durations from 6 to 40 msec and/or low fluences of 2 to 3 J/cm2 are being
utilized for the thermal remodeling effects on the dermis at lower energies. The utility of
this wavelength is that higher energies provide excellent reduction of telangiectasias (Fig. 2).
Light Sources
Intense Pulsed Light
One of the most controversial light-based technologies initially, IPL was first introduced as a
radically new concept with not being a coherent laser wavelength in 1994, and cleared by
the FDA in late 1995 as the PhotodermTM (Lumenis, Santa Clara, California, U.S.A.). IPL is a
noncoherent filtered flash lamp IPL source. It was initially launched and promoted as a
FIGURE 1 Photorejuvenation with the

Gemini (Laserscope, San Jose, CA) 10 mm
spot 532 nm laser. This 42-year-old patient
was treated with two passes of 10 mm spot
size, 532 nm green. At one month there is
textural improvement as well as reduction in
telangiectasias and pigmentation.
FIGURE 2 Use of extended pulsed dye laser for photorejuvenation. This 39-year-old patient was treated with the
extended pulsed dye laser (V-Star, Cynosure, Westford, Massachusetts, U.S.A.). The patient complained of flushing
episodes and facial telangiectasia (A). The patient was treated with stacked pulsing, three pulses per stack, of
595 nm, 10 mm spot, 7 J/cm2 and use of forced air cooling. This is the appearance at one month after one
treatment with a 75% reduction of telangiectasia (B). The patient’s facial flushing intensity and frequency was reduced.
radical improvement over existing methods for elimination of leg telangiectasias with
reduction in the risks of purpura common to PDLs of the time. It was quickly adapted to
facial vessels, which is presently the number one application of IPL. Present day IPL indications
have expanded to include nonablative facial rejuvenation, facial telangiectasias, pigmentation,
poikiloderma of Civatte, and treatment of scars (5).
In a study of IPL for poikiloderma, 135 patients randomly selected with typical changes of
poikiloderma of Civatte on the neck and/or upper chest were treated with one to five treat-
ments using IPL (6). Results indicated clearance of more than 75% of telangiectasias and
hyperpigmentation. The incidence of side effects was 5%, including pigment changes. In
many cases, improved skin texture was noted both by physician and patient. The authors
concluded that IPL was an effective mode of therapy for poikiloderma of Civatte. Cutoff
filters utilized in these treatments included primarily 550 to 570 nm. Median number of treat-
ments to achieve results was three. The significance of this study was to demonstrate that
cosmetic improvement with these devices was not confined to the face but could be used for
necks, chests, back, and so on.
Bitter (7) reported facial rejuvenation in 49 patients using similar parameters and cut-off
filters, with 550 to 570 nm cut-off filters and double pulsing of 2.4 to 4.7 pulses with varying inter-
pulse intervals. Subjects were treated with a series of four or more full-face treatments at three-
week intervals with fluences varying from 30 to 50 J/cm2. Subject evaluation and skin biopsies
were used to assess treatment results. The results reported were that all aspects of photodamage,
including telangiectasia, irregular pigmentation, wrinkling, skin coarseness, and pore size,
showed visible improvement in more than 90% of subjects with minimal downtime and no scar-
ring. Eighty-eight percent of subjects were satisfied with the overall results of their treatments.
Side effects of edema mild blistering and transient pigmentation changes were observed in a
small percentage of patients. Collagen synthesis was noted in the biopsy sample.
The longevity of improvement with light-based devices has always been questioned. A
recent study demonstrated that a five-year follow-up of 80 randomly selected patients with
skin types I–IV who were treated by IPL during 1996 and 1997 showed that at five years follow-
ing initial treatment, skin textural improvement was noted in 83% of the subjects (8). Photos and
patient self-assessment were also graded for telangiectasia severity and dyspigmentation. For
those patients practicing rigorous UV-blocking methods, telangiectasias were improved in 82%
of subjects, whereas pigmentation remained improved in 79% over the five year period (Fig. 3).
Photomodulation and Low Energy Light Emitting Diodes

The LEDs are narrowband emitters of a broad range of electromagnetic radiation ranging from
UV-visible to IR. The LEDs themselves are typically assembled on small chips or equipped with
FIGURE 3 Use of intense pulsed light (IPL) for photorejuvenation of the chest. The IPL is well suited for rejuvenation
of large surface areas due to the large crystal size, which often ranges to several cm2. This 52-year-old patient
presented with extensive photodamage of the face, chest, and neck. The images are before and after one treatment
at one month. The settings on the Quantum IPL (Lumenis, Santa Clara, California, U.S.A.) device were Program one
with a slight modification. The 560-nm filter with a setting of 2.4 msec, 10 msec delay, and 4 msec pulse shows a
dramatic reduction in pigmentation and improvement of surface texture.
tiny lenses and assembled into small lamps (typically up to 3 – 5 mm in diameter, but 10 mm
and larger lamps are available). These LEDs typically emit low intensity of light in the milliwatt
domain. However, the LEDs may be assembled into larger arrays or panels, and higher
energy intensities may also be generated, although the life of the LED is typically shortened.
The LEDs are extremely versatile and durable, exhibiting good resistance to temperature,
dirt, vibration, and other environmental insults with a typical lamp life of up to 100,000
hours. Also, they do not require expensive or dangerous high voltage power supplies or
complex optics, and thus alignment issues and maintenance tend to be very minimal. This
therapy is painless, and large LED panel arrays can be assembled so that the entire face may
be treated in a few minutes or less.
Typically, LEDs emit light in a +10 to 20 nm band around the dominant emitted wave-
length. We use 590 nm yellow most commonly in a 250 msec pulse duration. (GentlewavesTM ,
LightBioScience, Virginia Beach, Virginia, U.S.A.). The output of these LEDs is 90% 590 nm
light, far greater than a yellow LED in a laptop computer. For this scenario, packages of specifi-
cally pulsed photons are absorbed by the “antenna molecules” in mitochondria, thus activating
the electron transport system that amplifies the cell signals, eventually resulting in increased
production of the cell’s normal products. For fibroblasts in culture this translates into pro-
duction of extracellular matrix proteins, such as collagen and elastin, but without being
mediated via thermal injury. Laboratory in vitro testing suggests that a greater net increase
in total collagen may be created using nonthermal LED photomodulation than with thermal
injury techniques. Initial studies of over 90 patients treated with the GentlewavesTM LED
device showed up to 90% improvement in some aspect of cosmetic appearance of wrinkles
or skin tone or textural smoothness (9).
A multi-center clinical trial was also conducted on 90 photoaged females (10). One week
after the last treatment, the global improvement in appearance of skin in periorbital region was
62%. Upper lip improvement was 36%. Other observations in periorbital area included
reduction of 27% in skin roughness, 30% in elastosis, 14% in pore size, and 25% in redness.
Histopathology and immunohistopathology showed increase in several key extracellular
matrix proteins associated with clinical improvement in wrinkles. Data up to one-year post-
treatment in these same subjects indicate that improvement peaked at four to six months,
but that without further treatments of photomodulation, the results decline from 6 to 12
months. On the basis of this study, the FDA cleared the GentlewavesTM (LightBioScience,
Virginia Beach, Virginia, U.S.A.) LED photomodulation device for improvement of periocular
rhytids. The patients underwent a series of eight treatments over a four-week interval, and then
maintenance treatment was performed once a month. It was also found that the use of LED
FIGURE 4 GentlewavesTM light emitting diode photomodulation (LightBioScience, Virginia Beach, Virginia, U.S.A.)
for mild photoaging. A 38-year-old patient presents with mild photoaging changes, including mild periocular rhytids
and slight dyspigmentation (A). The after image was taken at four months following eight treatments given
over four weeks. Each treatment was delivered as 100 pulses of 250 msec each, at an extremely low fluence of
0.1 J/cm2 (B). Treatments are easily tolerated since no heat is involved. This device is cleared by the FDA for
improvement of periocular rhytids. This treatment regimen used alone is best for mild or early onset photoaging.
Strict sun protection measures must be enforced for patients to benefit from photomodulation.
photomodulation after other photorejuvenation procedures, such as IPL or fractional resurfa-

cing, improves results of textural smoothing and more rapidly reduces the thermal effects of
erythema and edema (Fig. 4) (11).
Infrared Lasers (Melanin, Hemoglobin, and Water Absorbing)

Short Pulse Q-switched Nd:YAG (1064 nm)
Although 1064 nm is typically used in the millisecond domain, it has been on the market for
over a decade as Q-switched laser for tattoos and pigmented lesions. Owing to the deep pen-
etration of 1064 nm and the safety with very small amounts of heat generated in the nano-
second pulse domain, the Q-switched nanosecond domain 1064 nm laser was actually one
of the first lasers used for nonablative skin rejuvenation. Used at a fluence of 5.5 J/cm2 at
around 40 nsec pulse duration, Q-switched 1064 nm was employed in an attempt to smooth
the skin of 11 patients (12). This initial group demonstrated pinpoint bleeding at this fluence,
thus making this more of an epidermal ablative treatment rather than a nonablative one.
Rhytid improvement was scored at about 25% by relatively nonobjective means, but fluences
utilized were low at 2.5 J/cm2 and so the goals of a nonablative were achieved.
Infrared Lasers (Water Absorbing Only)

1320 nm Nd:YAG
The 1320 nm wavelength is thought to accomplish collagen production by scattering thermal
energy throughout the laser-irradiated dermis after nonspecific absorption by dermal water.
Typical pulse durations are 30 to 50 msec with fluence ranging from 15 to 30 J/cm2. Once
slight thermal damage of collagen has been induced, the same mechanisms are triggered
for collagen regeneration as for other collagen damaging lasers. The 1320 nm wavelength
has an advantage in that inherent scatter allows penetration to at least 500 m with some
estimates of up to 2 mm into the dermis (13). Theoretically, this wavelength has the deepest
penetration into the dermis, since water absorption is the least of the available water-only
targeted infrared lasers. This penetration is unimpeded by absorption by hemoglobin or
melanin, which occurs at lower wavelengths. Deeper heating than 200 to 300 m may be detri-
mental to collagen synthesis as reported with the erbium glass laser (14). A study in a
mouse model has shown that 60 days after two treatments with 1320 nm laser, formation of
collagen type I and III was observed (15).
In the latest iteration of the 1320 nm delivery system (CoolTouch3, CoolTouch Corp.,
Roseville, California, U.S.A.), the epidermis is thermally protected from injury with a 20 to
30 msec cryogen spray delivered 10 msec pre-, mid pulse and 10 msec postlaser pulse.
Typical parameters are 16 to 19 J/cm2, fixed 50 msec pulse duration, 10 msec precooling, 5 to
10 msec mid-cooling, and 10 msec postcooling. The goal of this system, similar to other
nonablative systems, is improvement of rhytids without the creation of a visible epidermal
wound. In a study with 1320 nm without coordinated epidermal cooling, 10 patients received
laser treatments of their peri-ocular rhytids and postauricular skin (16). Postauricular skin
biopsies from before treatment and three months post-treatment showed a small post-treat-
ment increase in the amount of dermal collagen in three patients. Without epidermal
cooling, complications included hyperpigmentation in three patients and pitted scarring in
three patients. More recently, Nelson (17), using the dynamic cryogen cooling technique
before the laser pulse, showed that one or more passes of a 1320 nm Nd:YAG laser on photo-
aged skin led to improved facial rhytids at two months after treatment. Mild edema and
erythema appeared in the treated skin immediately after treatment, which disappeared
within hours.
A recent histologic study was reported on the preauricular cheek of 10 patients who
were biopsied following one to three laser passes of dynamically cooled millisecond
domain Nd:YAG 1320 nm laser (18). Biopsies were performed at one hour and at three
days following a single treatment. The number of passes was varied from one to three and
Tmax (peak temperature measured by integrated radiometer) during treatment was targeted
for 45 to 488C. At one hour post-treatment, epidermal spongiosis and edema of the basal
cell layer were present in all the specimens treated with three passes. At three days, the
three pass samples also showed micro-thrombosis, widened vessels, sclerosis of the vessel-
walls, and infiltration of neurophilic granulocytes. The clinical findings in our experience
with the 1320 nm wavelength are improvement in rhytids, more effectively on nondynamic
lines as well as significant improvement in acne scarring. This defines the meaning of “non-
ablative subsurface resurfacing,” which involves dermal heating over 1000 m into the dermis
(Fig. 5).
1450 nm Diode
This mid-infrared wavelength is thought to penetrate the skin to a maximum of 500 mm. It is
sold as a low power diode system with pulsed cryogen cooling delivered in small pulses
throughout the typical delivery cycle of 250 msec (Smoothbeam, Candela, Wayland,
FIGURE 5 CoolTouch 3 (CoolTouch Corp., Roseville, California, U.S.A.) 1320 nm collagen remodeling. A 44-year-old
patient presents with periocular rhytids and lower lid laxity (A). Three passes were performed for each treatment at a
fluence of 17 J/cm2 (B). Both the spot size and pulse duration are fixed at 10 mm and 50 msec, respectively.
The parameters of cooling utilized were 20 msec precooling to a final skin temperature of 458C after three passes.
Prior treatment for 30 minutes with a topical anesthetic, such as LMX (Ferndale Labs, Ferndale, Michigan, U.S.A.),
makes the treatment tolerable. Enhancement of results can be obtained with administration of botulinum toxin
immediately after the first treatment.
Massachusetts, U.S.A.). Relatively long times are required to achieve dermal heating, which
range up to 250 msec. Fluence typically ranges from 10 to 20 J/cm2. Preliminary results have
shown improvement in mean wrinkle score (19). Rhytid scores improved from a baseline
score of 2.3 to 1.8 at six months after treatment (P . 0.05). Patient acceptance of the treatment
was high, but most felt that there was little improvement of the treated rhytids. The device has
also recently received FDA clearance for the treatment of active acne, as sebaceous activity
seems to be diminished by this device. This device was found to be most useful for sebaceous
hyperplasia and acne scarring on the chin. It is also effective and FDA-cleared for active acne.
It shares this in common with the 1320 nm wavelength. Heating of sebaceous glands with
subsequent reduced activity is thought to be the mechanism.
1540 nm Erbium Glass

The 1540 nm erbium glass laser is delivered in 10 to 100 msec pulses with fluences ranging
from 20 to 30 J/cm2, although relatively long pulses comprised of pulselets are necessary to
effect dermal heating. The biggest problems for clinical treatment are the small spot size
(4 mm), very long pulse length (1 – 2 seconds for the entire pulse train envelope), and uncon-
trolled contact cooling. In one study, immediate post-treatment biopsies demonstrated
thermal damage in a 333 m thick band (mean range from 311 to 644 m deep in the dermis).
Dermal fibrosis was observed two months after treatment in a 272 m band (mean range from
148 to 420 m) (19). In earlier experiments with less sophisticated cooling, heat effects were
seen at up to 1.3 mm deep with some scarring-like effect, but this effect was considered a bit
too deep for optimal results with rhytids (13). The authors felt that the optimal depth for
thermal effects on rhytids was a 0.1 to 0.4 mm band of the dermis just below the epidermis.
A clinical study of 10 patients demonstrated some improvement in periocular rhytids, but
some changes in pigmentation; thus leading the authors to conclude that this wavelength
had the potential only to be used for collagen remodeling under the right conditions (20).
Microthermal, Fractional Resurfacing or Microrejuvenation (1440 –1550 nm)

As opposed to the relatively large spot sizes (4 – 10 mm) macropulses traditionally used with
the infrared lasers described earlier, these wavelengths have most recently been applied to
the concept of “microrejuvenation.” Cosmetic outcomes for dermal photoaging can be
improved by the creation of small, localized regions of significant thermal injury (coagulation
columns) surrounded by circumscribed areas of untreated skin (Fig. 6). These methods
produce significant tissue alterations that extend into the mid-dermis, a similar depth of
treatment as that associated with ablative methods. However, the effects are limited to a
small proportion of the tissue, surrounding each column with unaffected tissue, and thereby
allowing rapid healing. This approach appears to minimize much of the inflammatory
wound healing response and associated side effects of other ablative and nonablative
rejuvenation methods (21).
FIGURE 6 Micro-thermal zones of injury with

microablative resurfacing. Zones are seen as
darker zones of collagen with overlying
dermal-epidermal separation with H&E
staining (20).
As a result of direct micro-columnar thermal coagulation of tissue, microrejuvenation

techniques stimulate direct replacement of photoaged dermal collagen, resulting in improved
skin texture and reduction of fine-to-moderate rhytids. It can also be used for scar remodeling.
Most treatments have been performed one month apart for a total series of five treatments.
The immediate effects are urtication (hours) and erythema (100%), which can last for up
to several days (22). Other side effects include occasional patients with short-term bruising,
bleeding, edema, and crusting or bronzing (22).
FraxelTM (Reliant Technologies, Palo Alto, California, U.S.A.)

This 1550 nm device scans a linear array of “dots,” which are 100 m wide and 300 to 350 m
deep and at a density of 125 to 250 microthermal zones (MTZ) or dots/cm2. The biggest
downside of the scanning mode is the need for application of blue dye for optical scanning pur-
poses. The removal of the blue dye is difficult and may be visible as a blue hue on the patient’s
skin for up to three days. The treatment requires multiple passes, typically eight, to insure
uniformity of MTZ application, as the head of the device delivers a single row of microablative
points.
AffirmTM (Cynosure, Westford, Massachusetts, U.S.A.)

This device uses a microlens array to divide a 1440 nm beam into multiple diffractive
elements. The combined apex pulse (CAPTM ) array contains a laser-etched array of approxi-
mately 1000 diffractive elements in a 10-mm spot. These elements redistribute the laser’s
uniform energy into regions of high- and low-fluence treatment to tissue. Histologically,
the high-fluence CAP columns are limited to approximately 300-mm in depth, constraining
treatment to the zone of superficial photodamage. The treatment is performed by “stamping”
this 10-mm wide microarray with a 50% overlap. Only one to two passes are required.
Cooling is provided by a forced air system. Improvement is seen in wrinkles and scars
with three to five treatments spaced one month apart (Fig. 7).
Lux1540 Fractional 1540 nmTM (Palomar, Burlington, Massachusetts, U.S.A.)

This hand piece for the StarluxTM platform also delivers light in an array of high precision
microbeams. These microbeams create narrow, deep columns of tissue coagulation that pene-
trate well below the epidermis and into the dermis, while sparing the tissue surrounding
the columns from damage. A sapphire water-cooled hand piece protects the epidermis
from injury. Uniform microbeam delivery is more consistent and uniform than the scanned
approach. The 10-mm spot size head delivers fluences up to 100 mJ/mb and creates a
100 mb/cm2 array of columns for deep coagulation. The 15-mm spot size head delivers fluences
FIGURE 7 AffirmTM (Cynosure, Westford, Massachusetts, U.S.A.) resurfacing for superficial wrinkling. Note
improvement in periocular wrinkles after five treatments spaced one month apart.
up to 15 mJ/mb and creates a 320-mb/cm2 array of narrower columns for relatively more
shallow coagulation. This treatment is also performed by “stamping” this 10-mm wide
microarray with a 50% overlap. Only one to two passes are required. Similar erythema for
24 to 48 hours is seen.
Radio-Frequency
Primary effects of radio frequency (RF) energy on living tissue are considered to be thermal.
Clinical tissue tightening following radiofrequency treatment is thought to result from heat-
induced immediate collagen contraction, subsequent collagen remodeling, and neocollagenesis
of the dermis and subcutis.
The most frequently utilized device is a monopolar RF device in which the patient has a
grounding pad placed on the back or flank and RF energy is delivered through a inductive capaci-
tance membrane, which distributes RF evenly over a 1.5 cm2 area. Patients experience heat in the
region of each pulse. It is thought that the RF energy causes not only dermal heating, but heating
in the fibrous septae attaching the dermis to the fascial fascia below, thus causing contraction and
lifting of the skin. In a recent study, patients with facial and/or neck skin laxity were treated over
several years with a monopolar radiofrequency device (Thermacool, Thermage Corp., Haywood,
California, U.S.A.) (23). Treatment was delivered with one of three different tips as each became
available. Mild self-limited erythema and edema were the most common treatment responses.
Complications included one patient with a slight 1 cm2 depression, which resolved without inter-
vention at six weeks. Although depressions have been reported with the 1 cm2 standard tip, it is
believed that they were due to higher fluence, use of injectable anesthetics and/or IV sedation,
and the slower cycle tip.
Finzi et al. (24) reported 25 patients (skin types I to V) with mild-to-severe facial and neck
laxity receiving one treatment session with a multipass vector technique consisting of four to
five passes targeted over specific skin areas. Energy levels were kept low and ranged
from 62 to 91 J/cm2 per pulse. In the Finzi study all patients experienced some immediate
erythema and edema, which had completely resolved in most patients within 48 hours. No
severe side effects were seen, and specifically no scarring or dyspigmentation was noted.
Efficacy was high, as digital images revealed cosmetic improvement in facial and neck laxity
in 96% (Fig. 8).
CONCLUSIONS
Nonablative skin rejuvenation and cosmetic appearance improvement techniques produce
dermal remodeling without the obvious epidermal injury and the wound created with
earlier ablative approaches (16,18,25). The popularity of these new techniques lies signifi-
cantly in the lack of wound care and downtime as well as reduced costs. Experience with
attempts to control dermal thermal injury more subtly than the CO2 laser has led to the
belief that induction of collagen and ECM is possible with less injury. This has led to the
development of the infrared lasers with cryogen cooled epidermal protection and low
fluence PDLs. A new theory of photomodulation proposes that cosmetic improvements in
skin appearance, structure, and function may be achieved via a different nonthermal
pathway without the traditional activation of the wound healing mechanism. Total nonabla-
tive rejuvenation must encompass surface, deep dermal, or structural and subcutaneous tigh-
tening for skin laxity. Reversal of some of the visible changes that occur from photoaging are
not entirely relating to structural changes. These include reduction of superficial dyspigmen-
tation (both dermal and epidermal), reduction of dermal telangiectasias, and the appearance
of an overall smoother texture and tone. The visible wavelength lasers and IPL are especially
useful for these aspects of photoaging. Deep dermal photoaging can be treated with fractional
microthermal approaches. Tissue tightening requires the contraction of collagen-based fibrous
septae connection skin with subcutaneous tissue. Ongoing studies continue to delineate the role
of lasers, light, and other energy sources in the cosmetic improvement in the appearance of photo-
aged skin.
FIGURE 8 Monopolar radiofrequency (Thermacool, Thermage Corp., Haywood, California, U.S.A.) skin tightening.
Two months after one treatment of 438 pulses over the cheeks, jowls, and chin, visible lifting of the malar and
buccal fat pads is seen. (A, before; B, after) The mechanism is believed to be contraction of fibrous septae.
Tightening continues for six months following treatment.
PHOTOEPILATION
INTRODUCTION
The density of hair on scalp, face, and body and extremities on different individuals is highly
variable. There are three different types of increase in visible hair. In hypertrichosis, vellus
hair is transformed into dark and thick terminal hair. Wide variations exist depending on
the ethnic groups. Hypertrichosis can also be caused by medication, for example, by cyclos-
porin, interferons, minoxidil, and d-penicillamine. Hirsutism is defined as male pattern
hair growth under the influence of testosterone; typically, upper lip, cheeks, chin, breasts,
and the pubic triangle are involved. In virilism, hirsutism is accompanied by other signs of
masculinization.
Three phases of hair growth can be distinguished as: (i) growing phase (anagen);
(ii) transitional phase (catagen); and (iii) resting phase (telogen). The duration of hair cycles
and the percentage of hair in these three phases vary according to body areas (Table 3) (26).
For long-lasting epilation, destruction of the stem cell area of the hair bulb is necessary, that
is, the bulb region and the hair papilla (27). Since hair follicles are rather superficial in the
early anagen phase, that would be the ideal time for treatment.
Laser therapy may result in a synchronization of hair cycles and hair in the anagen phase
change to telogen phase. Regrowing hair in the early anagen phase is then more receptible to
laser therapy. Regrown hair is usually thinner compared to the original hair, a change that has
been termed miniaturization.
The absorption of light energy in hair requires melanin as absorber. Phaeomelanin in
blond and red hair has a different maximum of absorption compared to dark hair. Thus,
TABLE 3 Hair Cycle in Different Body Areas

Anagen Anagen Telogen Telogen Depth of hair
Localization (%) (duration) (%) (duration) follicle (mm)
Upper lip 65 16 wk 35 6 wk 1 –2.5
Chin 70 1 yr 30 10 wk 1 –2.5
Axilla 30 4 mo 70 3 mo 3.5–4.5
Bikini area 30 2 mo 70 3 mo 3.5–4.5
Arms 20 3 mo 80 4.5 mo 2.5–3.5
Legs 20 4 mo 80 6 mo 2.5–4.5
blond and red hair does not respond to laser therapy. Furthermore, physical parameters, such as
pulse duration, fluence, and spot size, are very important for efficacy. Longer wavelengths
(between 700 and 1000 nm) penetrate deeper into the dermis compared to shorter wavelengths,
and are less absorbed by melanin. A large spot size is important, since depth of penetration
increases with a larger spot size, and technically, the treatment is easier to perform. Theoreti-
cally, optimal pulse duration should be between the thermal relaxation time of hair follicles
(40 – 100 msec) and the epidermis (3– 10 msec); however, but in comparative studies, this
concept could no be proven (28).
PULSED RUBY LASER (694 nm)

Wimmershoff et al. (29) treated 74 patients with a follow-up of up to six months. After six
weeks, hair reduction of 50% to 75% could be seen, after six months this rate decreased to
less than 25%. Similar results were published by other groups (30).
ALEXANDRITE LASER (755 nm)

This wavelength is less absorbed by epidermal melanin; therefore, the risk of epidermal
damage is reduced. Protection of epidermis is increased by an additional cooling device. The
effectiveness of the alexandrite laser for epilation has been demonstrated in many studies.
In several studies, the influence of pulse duration was investigated; none showed any signifi-
cant influence. Nouri et al. (31) investigated the influence of spot sizes and found better
results with increasing spot size. Drosner et al. (32) investigated different fluences (5, 10, 15,
and 20 J/cm2) and did not find any statistically significant differences; the low fluences of 5
and 10 J/cm2 were nearly as effective with less pain and less side effects.
DIODE LASERS (800/810 nm)

This wavelength penetrates deeper into the dermis and is less absorbed in the epidermis. Long
pulse durations and high fluences require an epidermal cooling device. Sadick et al. (33) found
a hair reduction of 75% after three and six months; the best results were seen in patients with
skin type III. Better results with greater spot size has been reported.
PULSED ND:YAG LASER (1064 nm)

This wavelength, being the longest, has the highest penetration into the dermis and is less
absorbed in melanin. Therefore, this laser can also be used for epilation in patients with
dark skin. Since treatment is painful, cooling devices are necessary. The effectiveness of the
pulsed Nd:YAG laser has been proven in many studies (34– 36). Hair reduction of 30% to
60% after four to six treatments over several months has been reported. Best results were
obtained with larger spot sizes and longer pulse duration.
INTENSE PULSED LIGHT SOURCES (590 –1200 nm)

A cutoff filter at 600 nm and pulse duration of 15 to 20 msec are usually used for epilation
(Fig. 9). Hair reduction of 36% to over 80% was reported after several treatments (37). Up to
10% of the patients showed side effects, such as pain, erythema, and hyperpigmentation.
Comparative Studies
Bjerring et al. (38) compared IPL and ruby laser and found the IPL to be more effective.
Comparative studies between the pulsed diode laser and the alexandrite laser did not show
any significant differences between these two lasers (39,40) (Table 4).
Side Effects
Complications are mainly due to absorption of light energy by melanin in pigmented epi-
dermis, or caused by incorrect physical parameters. Immediately after laser or IPL therapy,
perifollicular erythema and edema may occur, and in some patients, with blistering and crust-
ing. Hypo- and hyper-pigmentations are usually transient. Reticular erythema resembling
livido reticularis has been observed in patients suffering from perniosis. Scarring is rare and
is mainly due to incorrect physical parameters.
Paradoxically, hair growth was observed in patients with dark skin and black hair follow-
ing alexandrite laser therapy (41). This could be explained by a synchronization of the hair
cycle by the stimulation of hair growth by light. Hair growth was also observed after IPL
therapy of women with hirsutism who had increased hair growth in untreated neighboring
areas (42).
Other reported side effects include leukotrichia, changes in melanocytic nevi located
in epilated areas, and the development of lichen planus and permanent scarring alopecia
following ruby laser epilation in a patient with mucosal lichen planus.
FIGURE 9 Hypertrichosis in a 65-year-old patient. Result of five intense pulsed light treatments.
TABLE 4 Comparative Studies

Type of Follow- Hair
laser Patients Parameters Treatments ups reduction Reference
IPL versus 31 600—950 nm, 48 10 mm, 3 6 mo 49.3% (38)
ruby 5– 40 msec, 18.4 J/cm2 versus 21.3%
694 nm, 5 mm, 0.9 msec, 19.5 J/cm2
Diode versus 20 800 nm, 9 mm, 12.5 msec, 3 6 mo No significant (39)
alexandrite 25– 40 0.9 J/cm2 difference
755 nm, 10 mm, 2 msec, 25 J/cm2
Diode versus 15 800–810 nm, 9 mm, 30–35 J/cm2 4 12 mo 84% (40)
Alexandrite 755 nm, 12 mm, 3 msec, 6– 40 J/cm2 versus 85%
Diode versus 15 800 nm, 9 mm, 30– 35 J/cm2 1 9 mo No significant (43)
Nd:YAG 1964 nm, 5 mm, 78–80 J/cm2 difference
Nd:YAG versus 75 1064 nm, 6– 8 mm, 25– 32 msec, 5.5 3 mo 42.5 % (44)
alexandrite 40– 55 J/cm2
versus diode 755 nm, 8–10 mm, 10– 20 msec, 5.2 65.6 %
15– 25 J/cm2
800 nm, 9 mm, 10– 30 msec, 2.6 46.8%
25– 40 J/cm2
CONCLUSION
For epilation, different lasers and IPLs can be used. Multiple treatments in four- to six-week
intervals for face, or two to three months for back, are necessary for achieving a significant
reduction of hair growth. Most patients will have 90% hair reduction; however, there will
always be some sparse and thinner diameter hair growth. As regrowth of hair can be observed
after 6 to 12 months, repeated treatments are necessary.
REFERENCES
1. Zelickson BD, Kilmer SL, Bernstein E, et al. Pulsed dye laser therapy for sun damaged skin. Lasers
Surg Med 1999; 25(3):229– 236.
2. Weiss RA, McDaniel DH, Geronemus RG. Review of nonablative photorejuvenation: reversal of the
aging effects of the sun and environmental damage using laser and light sources. Semin Cutan Med
Surg 2003; 22(2):93– 106.
3. Lee MW. Combination visible and infrared lasers for skin rejuvenation. Semin Cutan Med Surg 2002;
21(4):288– 300.
4. Butler EG, McClellan SD, Ross EV. Split treatment of photodamaged skin with KTP 532 nm laser
with 10 mm handpiece versus IPL: a cheek-to-cheek comparison. Lasers Surg Med 2006; 38(2):
124– 128.
5. Goldman MP, Weiss RA, Weiss MA. Intense pulsed light as a nonablative approach to photoaging.
Dermatol Surg 2005; 31(9 Pt 2):1179– 1187.
6. Weiss RA, Goldman MP, Weiss MA. Treatment of poikiloderma of Civatte with an intense pulsed
light source. Dermatol Surg 2000; 26(9):823– 827.
7. Bitter PH. Noninvasive rejuvenation of photodamaged skin using serial, full-face intense pulsed light
treatments. Dermatol Surg 2000; 26(9):835– 842.
8. Weiss RA, Weiss MA, Beasley KL. Rejuvenation of photoaged skin: 5 years results with intense pulsed
light of the face, neck, and chest. Dermatol Surg 2002; 28(12):1115 – 1119.
9. Weiss RA, Weiss MA, Geronemus RG, McDaniel DH. A novel non-thermal non-ablative full panel led
photomodulation device for reversal of photoaging: digital microscopic and clinical results in various
skin types. J Drugs Dermatol 2004; 3(6):605– 610.
10. Weiss RA, McDaniel DH, Geronemus R, Weiss MA. Clinical trial of a novel non-thermal LED array for
reversal of photoaging: clinical, histologic, and surface profilometric results. Lasers Surg Med 2005;
31:1099– 1205.
11. Weiss RA, Weiss MA, Beasley KL, Munavalli G. Our approach to non-ablative treatment of photo-
aging. Lasers Surg Med 2005; 37(1):2– 8.
12. Goldberg DJ, Whitworth J. Laser skin resurfacing with the Q-switched Nd:YAG laser. Dermatol Surg
1997; 23(10):903– 906.
13. Hardaway CA, Ross EV. Nonablative laser skin remodeling. Dermatol Clin 2002; 20(1):97– 111:ix.
14. Ross EV, Sajben FP, Hsia J, Barnette D, Miller CH, McKinlay JR. Nonablative skin remodeling: selec-
tive dermal heating with a mid- infrared laser and contact cooling combination. Lasers Surg Med
2000; 26(2):186– 195.
15. Dang YY, Ren QS, Liu HX, Ma JB, Zhang JS. Comparison of histologic, biochemical, and mechanical
properties of murine skin treated with the 1064-nm and 1320-nm Nd:YAG lasers. Exp Dermatol 2005;
14(12):876– 882.
16. Menaker GM, Wrone DA, Williams RM, Moy RL. Treatment of facial rhytids with a nonablative laser:
a clinical and histologic study. Dermatol Surg 1999; 25(6):440–444.
17. Nelson JS, Millner TD, Dave D, et al. Clinical study of non-ablative laser treatment of facial rhytides.
Lasers Surg Med 1998; 17(suppl. 9):150. Ref type: abstract.
18. Fatemi A, Weiss MA, Weiss RA. Short-term histologic effects of nonablative resurfacing: results with a
dynamically cooled millisecond-domain 1320 nm Nd:YAG Laser. Dermatol Surg 2002; 28(2):172– 176.
19. Hardaway CA, Ross EV, Barnette DJ, Paithankar DY. Non-ablative cutaneous remodeling with a 1.45
micron mid-infrared diode laser: phase I. J Cosmet Laser Ther 2002 Mar; 4(1):3– 8.
20. Levy JL, Besson R, Mordon S. Determination of optimal parameters for laser for nonablative remodel-
ing with a 1.54 microm Er:glass laser: a dose-response study. Dermatol Surg 2002; 28(5):405– 409.
21. Geronemus RG. Fractional photothermolysis: current and future applications. Lasers Surg Med 2006;
38(3):169– 176.
22. Fisher GH, Geronemus RG. Short-term side effects of fractional photothermolysis. Dermatol Surg
2005; 31(9 Pt 2):1245– 1249.
23. Burns AJ, Holden SG. Monopolar radiofrequency tissue tightening—how we do it in our practice.
Lasers Surg Med 2006; 38(6):575– 579.
24. Finzi E, Spangler A. Multipass vector (mpave) technique with nonablative radiofrequency to treat
facial and neck laxity. Dermatol Surg 2005; 31(8 Pt 1):916– 922.
25. Goldberg DJ. Nonablative resurfacing. Clin Plast Surg 2000; 27(2):287– 292, xi.
26. Gottschaller C, Hohenleutner U. Laser- und lichtepilation. In: Landthaler M, Hohenleutner U, eds.
Lasertherapie in der Dermatologie. 2nd edn. Heidelberg: Springer, 2006:179– 192.
27. Kolinko VG, Littler CM. Mathematical modeling for the prediction and optimization of laser hair
removal. Lasers Surg Med 2000; 26:164– 176.
28. Stangl S, Hertenberger B, Drosner M. Does pulse duration influence efficacy of photo-epilation? Med
Laser Appl 2005; 19:205– 211.
29. Wimmershoff MB, Scherer K, Lorenz S, Landthaler M, Hohenleutner U. Hair removal using a 5-msec
long-pulsed ruby laser. Dermatol Surg 2000; 26:205– 209.
30. Polderman MC, Pavel S, le Cessie S, Grevelink JM, van Leeuwen RL. Efficacy, tolerability, and safety
of a long-pulsed ruby laser system in the removal of unwanted hair. Dermatol Surg 2000; 26:240– 243.
31. Nouri K, Chen H, Saghari S, Ricotti CA. Comparing 18- versus 12-mm spot size in hair removal using
a GentleLase 755-nm Alexandrite laser. Dermatol Surg 2004; 30:494 –497.
32. Drosner M, Stangl S, Hertenberger B, Klimek H, Pettke-Rank C. Low dose epilation by alexandrite
laser: a dose response study. Med Laser Appl 2001; 16:293– 298.
33. Sadick NS, Prieto VG. The use of a new diode laser for hair removal. Dermatol Surg 2003; 29: 30– 34.
34. Lorenz S, Brunnberg S, Landthaler M, Hohenleutner U. Hair removal with the long-pulsed Nd:YAG
laser: a prospective study with one year follow-up. Lasers Surg Med 2002; 30:127 – 134.
35. Tanzi EL, Alster TS. Long-pulsed 1064-nm Nd:YAG laser-assisted hair removal in all skin Types. Der-
matol Surg 2004; 30: 13 – 17.
36. Raff K, Landthaler M, Hohenleutner U. Optimizing treatment parameters for hair removal using
long-pulsed Nd:YAG-lasers. Lasers Med Sci 2004; 18:219– 222.
37. El Bedewi AF. Hair removal with intense pulsed light. Lasers Med Sci 2004; 19:48– 51.
38. Bjerring P, Cramers M, Egekvist H, Christiansen K, Troilius A. Hair reduction using a new intense
pulsed light irradiator and a normal mode ruby laser. J Cutan Laser Ther 2000; 2:63– 71.
39. Handrick C, Alster T. Comparison of long-pulsed diode and long-pulsed alexandrite lasers for hair
removal: a long-term clinical and histologic study. Dermatol Surg 2001; 27:622– 626.
40. Eremia S, Li C, Newman N. Laser hair removal with alexandrite versus diode laser using four treat-
ment sessions: 1-year results. Dermatol Surg 2001; 27:925– 930.
41. Alajlan A, Shapiro J, Rivers JK, MacDonald N, Wiggin J, Harvey L. Paradoxical hypertrichosis after
laser epilation. J Am Acad Dermatol 2005; 53:85– 88.
42. Moreno-Arias G, Castelo-Branco C, Ferrando J. Paradoxical effect after IPL photoepilation. Dermatol
Surg 2002; 28:1013– 1016.
43. Chan HH, Ying S-Y, Ho W-S, Wong DSY, Lam L-K. An in vivo study comparing the efficacy and com-
plications of diode laser and long-pulsed Nd:YAG laser in hair removal in Chinese patients. Dermatol
Surg 2001; 27:950– 954.
44. Bouzari N, Tabatabai H, Abbasi Z, Firooz A, Dowlati Y. Laser hair removal: comparison of long-
pulsed Nd:YAG, long-pulsed alexandrite, and long-pulsed diode lasers. Dermatol Surg 2004;
30:498– 502.
29 Laser Treatment on Ethnic Skin
Henry Hin Lee Chan
Division of Dermatology, Department of Medicine, University of Hong Kong, and Department of
Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
Brooke Jackson
Skin and Wellness Center of Chicago, Chicago, Illinois, U.S.A.
B Cutaneous manifestations of photoaging in ethnic skin differ from those

in Caucasian skin, with more pigmentary changes and less wrinkling.
B Some conditions, such as nevus of Ota and dermatosis papulosa nigra,

are more common in ethnic skin.
B Ethnic skin, with its higher epidermal melanin context, is more likely to
develop adverse pigmentary reactions following laser surgery.
B Nonablative skin rejuvenation with low down time and minimal risk of
adverse effects is particularly popular among patients with ethnic skin.
B Fractional resurfacing can be used for the treatment of acne scarring and
melasma in ethnic skin.
B Effective skin cooling allows protection of the epidermis and enables

laser procedures such as laser-assisted hair removal and the treatment
of vascular lesions to be performed.
B Longer pulsed width further improves laser safety for laser-assisted hair
removal in ethnic skin.
418 Chan and Jackson
INTRODUCTION
utaneous laser surgery has been a mainstay of dermatologic therapy for more than a
C decade. Yet, the published literature has until recently focussed on the Caucasian
patient. Based on statistics from the 2000 U.S.A. census, it is evident that the face of the
patient who is seeking aesthetic services is changing to be more representative of the increasing
ethnic diversity of the United States population. Besides cosmetic procedures, conditions such
as nevus of Ota and dermatosis papulosa nigra are particularly common in ethnic skin. Fur-
thermore, ethnic skin, with its higher epidermal melanin context, is more likely to develop
adverse pigmentary reactions following laser surgery. As a result, it is imperative that the der-
matologic laser surgeon has not only an awareness of the unique needs of those with ethnic
skin, but is also well versed in the available laser technology to select an appropriate modality
for the treatment of the ethnic patient.
CUTANEOUS MANIFESTATIONS OF AGING ETHNIC SKIN

Ninety five percent of the visible signs of aging are caused by sun exposure, which begins in
infancy and continues throughout life (1). Other intrinsic factors such as gravity and external
factors (pollution) that are unrelated to sun exposure also contribute to the cutaneous aging
process. Crows feet, lipstick lines, and fine perioral and periorbital lines seen as early as the
20s in the Caucasian patient, tend not to occur in the patient with more darkly complexed
skin tones. Aging in patients with darker skin manifests not only ten to twenty years later
than age-matched Caucasian counterparts, but also occurs in the deeper muscular layers of
the face rather than within the skin. Other cutaneous manifestations of aging ethnic skin
include the development of benign cutaneous growths such as dermatosis papulosa nigra
and the development of solar lentigenes.
ETHNIC SKIN: SPECIAL PRECAUTIONS

When treating skin of any type, an understanding of laser tissue interaction and laser physics is
necessary (2 – 7). Hemoglobin, melanin, and water are the primary organic chromophores
within the skin, each with specific wavelengths of peak absorption on the electromagnetic spec-
trum (5). The broad absorption spectrum of melanin on the electromagnetic spectrum, and the
increased melanin content of ethnic skin create significant therapeutic challenges for cutaneous
laser surgeons when treating patients with ethnic skin (6). The highly melanized epidermis of
ethnic skin absorbs and/or interferes with the absorption of laser energy that is intended for
another target, such as pigment within the hair follicle, a blood vessel, or tattoo ink within
the dermis. The unique features of ethnic skin must be considered when selecting treatment
parameters.
PREOPERATIVE CONSIDERATIONS
In general, ethnic patients wish to preserve and enhance their unique features, not westernize
them. Their darker skin is prone to dyschromia and scarring, which are often why these
patients initially seek cosmetic consultation. However, corrective procedures each carry their
own risks of dyschromia and scarring, both of which should be discussed in detail
preoperatively.
Patients with darker skin tones are less likely to wear photoprotection on a daily basis
because such products are marketed toward the prevention of skin cancer, which many
darkly completed patients feel will not affect them. Although the majority of people with
darkly complected skin may never develop skin cancer, many are at increased risk of develop-
ing other systemic diseases, such as hypertension and diabetes, that require medications, which
are photosensitizing. All laser patients in our practice are advised to wear daily sun protection
throughout the course of treatment.
Laser Treatment on Ethnic Skin 419
MEDICAL HISTORY
A history of treatment with isotretinoin should be obtained before the initiation of any
surgical corrective procedure (8). Disorders such as sickle cell anemia, thalassemia, and
glucose 6-phosphate dehydrogenase (G6PD) deficiency are more prevalent in African,
American, Mediterranean, and Southeast Asian patients. A detailed medical history should
be taken in an effort to determine the personal or family history of these hereditary hemolytic
diseases that may affect postoperative healing. Given our mobile society, the physician
should also be aware of dermatologic conditions that are endemic to certain areas of the
world, such as cutaneous leishmaniasis. This parasitic infection is endemic in the Middle
East, Central and South America, and Africa, and often causes cutaneous scarring for which
patients may request cosmetic correction.
CULTURAL CONCERNS
The preprocedure consultation is an opportunity to not only identify and discuss therapeutic
options for the patient’s chief complaint, but also to understand whether the patient’s expec-
tations of the procedure, postoperative period, and outcome are realistic. To achieve a success-
ful procedural outcome, a surgeon’s understanding of cultural differences and preferences
among ethnic patients is equally as important as technical proficiency in the procedures to
be performed. Cultural preferences can be understood through open discussion with the
patient and knowledge of the way in which cultural variations affect communication. For
example, Asian cultures place great importance on physical beauty to the extent that there is
a belief that prospects for personal success in life are related to one’s physical traits. In
general, most Asian patients have great respect for authority, which may limit communication
with the physician by the patient assuming the physician will understand and do what the
patient desires (9). Questioning authority is considered to be disrespectful in some cultures.
The surgeon should encourage the patient to verbalize concerns and expectations. Addition-
ally, because of strong cultural beliefs in fate and destiny, Asian patients may often have associ-
ated feelings of guilt after undergoing procedures that may alter given physical characteristics,
as this act is perceived to be disrespectful to one’s parents (9). These feelings of guilt may lead
to postoperative withdrawal.
ABLATIVE AND NONABLATIVE SKIN REJUVENATION IN ETHNIC SKIN

The Use of a Laser/Light Source for the Treatment of Solar Lentigines, Seborrhoeic
Keratosis, and Dermatosis Papulosa Nigra in Ethnic Skin
For many years, Q-switched (QS) lasers have been used to treat lentigines, and although the
approach is mostly effective, postoperative postinflammatory hyperpigmentation (PIH)
occurs in 10% to 20% of darker-skinned patients. Several years ago, a study compared the effi-
cacy and complication rates in Chinese patients who were treated with QS 532 nm neodymium:
yttrium-aluminum-garnet (Nd:YAG) laser to those who were treated with long-pulsed 532 nm
Nd:YAG laser, and found that although the two groups had similar degrees of clearing,
treatment with the QS device was associated with a greater risk of PIH (10).
The study created controversy as the authors suggested that QS lasers were not
suitable for the removal of lentigines in Asians due to the photomechanical effect of these
systems that can lead to a greater risk of PIH. Since then, others looking at the use of
intense pulsed light (IPL) source and long-pulsed 532 nm Nd:YAG laser in the treatment of
lentigines in dark-skinned patients have confirmed the observation (11,12). A recent study
looking at the use of QS Alexandrite (QS Alex) laser versus IPL for the treatment of freckles
and lentigines in Chinese further confirmed the risk of PIH, when QS laser is used in ethnic
skin (13).
By choosing a pulse width (millisecond domain) that matches the thermal relaxation
time of the epidermis (10 msec), the risk of thermal injury to the dermis is minimized
(Fig. 1).
FIGURE 1 Lentigines under cross polarized light: (A) before treatment, (B) after second treatment with long-pulsed
532 nm neodymium: yttrium-aluminum-garnet laser with 2 mm spot size, 2 millisecond pulse duration, 12 J/cm2.
Most pigment laser/light source is also absorbed to a lesser degree by hemoglobin. There-
fore, besides the use of long pulsed rather than QS laser, another means of further reducing the
risk of PIH is to compress and empty the dermal vessels and, in doing so, reduce the risk of
dermal vascular damage (14). A recent study compared the efficacy and complications of QS
ruby laser to those of long-pulsed, 595 nm pulsed dye laser (PDL) with a compression
window attached for the removal of lentigines among Japanese patients. The results indicated
that the group treated with the compression technique was associated with a lower risk of PIH
than the group treated with QS laser, while the degree of efficacy was the same in both groups
(15). Table 1 shows the suggested laser parameters and clinical endpoint to be considered for
the removal of lentigines in ethnic skin.
TABLE 1 Laser/Intense Pulsed Light Source for the Treatment of Lentigines

Wavelength
Type of laser/IPL (nm) Pulse width Clinical endpoint Special consideration
QS 532 nm Nd:YAG, 532,694,755 Nanosecond Immediate whitening Use the smallest spot size and
ruby, alexandrite, lowest fluence to induce clinical
laser endpoint.
Useful for light color lentigines.
PIH rate: 5%– 50% (10,13,15)
Test area especially for solar
lentigo.
KTP/Nd:YAG laser 532 Millisecond Slate gray darkening Choose pulse width at 2 ms to
match the thermal relaxation
time of the epidermis, with
cooling window, pulse width
can be increased to 5– 10 ms.
Light color lentigines are not as
effective.
Alexandrite 755 Millisecond Slate gray
Intense pulsed light 560– 1200 nm Millisecond Erythema or darkening IPL with shorter pulsed width
of the lentigines depends (2.5 ms) tend to have a more
upon the type of IPL. apparent clinical endpoint.
A longer pulsed width
(10– 40 ms) allows greater
epidermal protection, but the
endpoint is more subtle and
can even be delayed.
Abbreviations: IPL, intense pulsed light; KTP, potassium-titanyl-phosphate; Nd:YAG, neodymium:yttrium-aluminum-garnet; PIH, post-
inflammatory hyperpigmentation; QS, Q-switching.
Another means of further reducing the risk of PIH is to use a laser/light source with a
shorter wavelength (350 –500 nm) and therefore confine the thermal injury to the epidermal
layer (14). Interestingly, a 351 nm XeF pulsed excimer laser, one of the first used, experimen-
tally, for the treatment of pigmented lesion when the concept of selective photothermolysis
was proposed, is one such example. With the use of this laser, dermal penetration is limited
(the damage is confined to 100 um within the epidermis). This lack of dermal penetr-
wavelength filter is being tested at this moment for the removal of lentigines in ethnic skin.
Due to the high epidermal melanin context of ethnic skin, adequate cooling is necessary to
avoid epidermal injury.
Seborrhoeic keratosis and dermatosis papulosa nigra are common cutaneous mani-
festations of photoaging of ethnic skin. While no treatment is needed, these manifestations
are often of cosmetic concern and are easily removed through a variety of means including
scissor excision, electrodessication, and laser ablation. When using either the CO2 or
erbium:YAG laser, one must be careful to use a spot size that does not exceed the
diameter of the lesion to minimize the risk of collateral thermal damage and PIH of the
surrounding skin.
ABLATIVE AND NON-ABLATIVE SKIN REJUVENATION

AND FRACTIONAL RESURFACING
Ablative skin rejuvenation is less commonly performed in ethnic skin for two reasons. First,
aging in ethnic skin tends to present with more pigmentary issues rather than wrinkle, further-
more laser resurfacing in ethnic skin is associated with more adverse effects such as IPL (16). As
a result, nonablative skin rejuvenation with a laser/light source is particularly popular for ethnic
skin due to the lower risk of complication and limited down time (17). Nonablative skin rejuve-
nation involves the use of a laser/light source together with a cooling device, and in doing so
improves the features of photoaging including lentigines, telangiectasia, pore size, skin
texture, wrinkles, and skin laxity with minimal down time. Green and yellow laser/light
sources target the epidermal pigment and papillary dermal vessels. Injury to the papillary
dermal vessels not only allows effective treatment of facial telangiectasia, but also leads to
the subsequent healing process and new collagen formation. Producing an effect on the micro-
vascular supply of the sebaceous gland can reduce sebum production and improve pore size
(17– 20). Near-infrared and infrared lasers/light sources together with skin cooling target the
water content in the dermis, and their photothermal effect, produced as a result of the laser-
tissue interaction, is to cause a rise in the dermal temperature (21– 24). The consequences are
collagen tightening, increased fibroblastic activity, and increased collagen production. Table 2
summarizes the use of different lasers for nonablative skin rejuvenation in ethnic skin.
For non-ablative skin rejuvenation, repeated monthly treatment intervals are necessary to
achieve the desired effect. More recently, combined modalities using different lasers and light
sources in the same treatment session have been advocated (17,18,20). To reduce the risk of
complications from such a combined approach, lower fluence is necessary.
Although the results of some studies support the use of non-ablative skin rejuvenation
for the treatment of acne scarring, ablative skin resurfacing can achieve a significantly superior
result and therefore remains the gold standard for the treatment of acne scarring in ethnic skin.
For laser resurfacing, patients are prescribed a systemic antiviral (Famciclovir 250 mg three
times daily) and a systemic antibiotic (cefuroxime 250 mg three times daily) 48 hours before
laser surgery and until complete re-epithelization. To further optimize the result, a punch
biopsy and subcision two weeks before surgery is recommended. A more aggressive approach
(three passes of carbon dioxide laser resurfacing, followed by one pass of Erbium YAG laser)
has become less popular due to the down time and potential complications that include pro-
longed erythema, pigmentary disturbance, and increased risk of scarring. More recently,
single pass laser resurfacing has been recommended by some investigators to reduce the mor-
bidity that is associated with this procedure (25). Postoperatively, a closed dressing is applied
for 48 hours, followed by an open dressing thereafter. Daily follow up is necessary to ensure
that wound infection does not occur.
TABLE 2 Laser for Nonablative Skin Rejuvenation

Type of laser Wavelength (nm) Pulse width Target Special consideration
KTP/Nd:YAG 532 Millisecond Vessel/pigment Better efficacy if used in combination with
long pulsed 1064 nm (18)
Pulsed dye laser 585/595 Millisecond Vessel/pigment Mainly vessel, development of compression
window allows pigment to be targeted (15)
Better efficacy if combine with 1450 nm diode
laser (20)
Nd:YAG 1064 Nanosecond Water/pigment Can be used with carbon dioxide
Nd:YAG 1064 Millisecond Water Better efficacy if used in combination with
long-pulsed 532 nm Nd:YAG (18)
Nd:YAG 1320 Millisecond Water More painful than other treatments, effective
for fine wrinkle and acne scarring
Diode 1450 Millisecond Water Postinflammatory hyperpigmentation is an
issue in ethnic skin and is thought to be due
to excessive cryogen injury
Erbium glass 1540 Millisecond Water Less painful than 1320 nm Nd:YAG and
1450 nm diode laser; the lack of clinical end
point is a disadvantage
Abbreviations: KTP, potassium-titanyl-phosphate; Nd:YAG, neodymium:yttrium-aluminum-garnet.
Fractional resurfacing is a new technology that involves the use of a laser to generate
microscopic spots of thermal injury that are surrounded by healthy skin tissue (26). By
taking into account the discrepancy between epidermal and dermal healing properties
(given the microscopic nature of the lesion, epidermal healing is completed within 24 hours,
whereas dermal collagen remodeling takes 4 –6 weeks), fractional resurfacing can lead to excel-
lent clinical outcomes with minimal adverse effects. There are two main variables in fractional
resurfacing: (i) energy expressed in minijoules, and (ii) density expressed as the microscopic
thermal injury zone per cm2 (MTZ). Fractional resurfacing is now approved by US Food and
Drug Administration for the treatment of wrinkles, melasma, and acne scarring (Fig. 2). Mul-
tiple devices can now perform fractional resurfacing. The initial device involves the use of a
scan to deliver laser injury when the device moves across the skin surface (scanning mode),
and the others involve the placement of the laser handpiece on the skin surface in a stamping
fashion (stamping mode). Some stamping devices are multiplatform. The advantages and dis-
advantages of these two different modes are summarized in Table 3.
For ethnic skin, fractional resurfacing can be particularly effective for the treatment of
acne scarring, and is the main indication for its use. PIH is the main potential complication.
Previous studies indicated that the risk of PIH is associated with the energy and density of
FIGURE 2 Parallel polarized light-acne scarring: (A) before treatment, (B) after 12th treatment with fractional
resurfacing 20 mJ, four passes of 125 microscopic thermal injury zone per cm2 per treatment.
TABLE 3 Advantages and Disadvantages of Fractional Device

Advantages Disadvantages
With scanning mode
Much published clinical data in peer Single platform
review journals
Robust and reliable Blue dye: reduce visibility
Even distribution of MTZ Need a separate cooling device
Faster treatment time
With stamping mode
Single platform with multipurposes No published peer review data. (?Efficacy is the same as the scanning device, which
particularly applies to those that are not 1540 nm in wavelength)
More space efficient Lack of multiplatform reliability; if the device breaks down, no treatment can be
performed
Cooling sapphire window Overlapping/under treatment
Less painful Longer treatment time
Abbreviation: MTZ, microscopic thermal injury zone per cm2.
the laser, with density being particularly important (27,28). In one study, 7% of acne scar
patients who were treated with 16 mJ, 1000 MTZ/cm2 were found to have PIH (27). Several
factors contribute to the development of PIH. Skin type and recent sun exposure are important.
The degree of inflammation and the extent of derma-epidermal junction disruption are also
important. To reduce the risk of PIH, several measures should be taken, including reducing
the density of each treatment but increasing the total number of treatment sessions (17). The
interval between treatment sessions can also be increased so that inflammation at the derma-
epidermal junction can completely subside. The use of cooling is also important to reduce
the risk of bulk tissue heating that occurs after repeat treatment at a short interval.
THE USE OF LASER FOR THE TREATMENT OF OTHER

MELANOCYTIC LESIONS
In ethnic skin, besides pigmentary conditions that are associated with photoaging, other
conditions are particularly prevalent, including melasma, Hori’s macules, and nevus of Ota.
Another important factor is the risk of malignant transformation. Melanoma is uncommon
in ethnic skin. As a result, it is common for laser to be used for the treatment of congenital
melanocytic lesions in ethnic skin.
EPIDERMAL LESIONS
Café au Lait Patch
The use of lasers in the treatment of café au lait patch has yielded variable results, and although
some early studies indicated complete removal without recurrence, such findings have not
always been repeated (29). A study using a Q-Switched ruby laser (QS ruby) and a frequency
double QS 532 nm, Neodymium:Yttrium-Aluminum-Garnet (QS 532 nm Nd:YAG) laser found
that the degree of clearance varied across lesions (30). Furthermore, categorization of the
patches into histological subtypes did not help to predict the clinical outcome. One possibility
is that QS lasers fail to remove the follicular melanocytic component of the café au lait patch.
Based on this hypothesis, long-pulsed pigmented lasers such as normal mode ruby have been
used for the removal of café au lait patch, and preliminary data has indicated a lower rate of
recurrence as compared with a QS ruby laser (40% as compared to 80%) (31) (Fig. 3).
Becker’s Nevus
A previous study using QS ruby laser indicated a postoperative increase in pigmentation after
four weeks (32). More recently, in a study that compared the use of Erbium YAG laser to that of
QS 1064 nm Nd:YAG laser, 22 patients were treated with either Erbium YAG laser or QS
FIGURE 3 Café au lait spot. (A) before treatment, (B) two months after treatment. One treatment with long-pulsed
Alexandrite 755 nm laser, 40 J/cm2, 10 mm spot size, 3 ms pulse duration.
1064 nm Nd:YAG and were followed up after two years (33). The group that was treated with
Erbium YAG laser achieved a significantly better result, with complete clearance in 54% of the
patients after a single treatment. For the group that was treated with QS 1064 nm Nd:YAG, mul-
tiple treatments were necessary, and only 1 out of 11 patients had significant clearing after three
treatment sessions. Long-pulsed pigmented laser has also been used to remove hair and reduce
pigmentation, but texture can still occur (34).
DERMAL AND MIXED LESION

Nevus of Ota and Hori’s Macules
QS ruby, QS Alex, and QS 1064 nm Nd:YAG have been used for the treatment of nevus of Ota
with excellent results and minimal risk of complications (16). QS ruby laser can achieve a good
to excellent degree of lightening after three or more treatment sessions. The side effects were
few, with transient hyperpigmentation after the first treatment being the most common (35).
A study that compared the use of QS Alex and QS 1064 nm Nd:YAG lasers found that most
patients better tolerated the former (36). However, QS 1064 nm Nd:YAG laser appeared to be
more effective than QS Alex in the lightening of nevus of Ota after three or more treatment
sessions (37). In term of complications, hypopigmentation was common, especially among
those who were treated with QS ruby and those who were treated with different lasers in
different treatment session (38,39). The original pigmentation could also recur in patients
after complete laser-induced clearing, which is an important issue, especially for pediatric
patients. The risk of recurrence is estimated to be between 0.6% and 1.2%. Nevertheless, treat-
ment is optimal at a younger age as there is a lower number of mean treatments and a lower
rate of complications (40).
Hori’s macules differ from nevus of Ota because they occur in adults, are bilateral rather
than unilateral, and have no mucosal involvement. Hori’s macules are thought to occur due to a
range of aetiological factors such as sex hormones, ultraviolet light exposure, and trauma,
which lead to a dropping off of the hair follicular melanocytes to the dermis. Frequently,
Hori’s macules coexist with other pigmentary conditions, such as melasma and lentigines.
QS ruby, QS Alex, and 1064 nm Nd:YAG lasers have been shown to be effective in the treatment
of this condition (41 – 43). However, previous studies indicated that Hori’s macules are more
resistant to treatment than nevus of Ota and require shorter treatment intervals and more treat-
ment sessions before the lesions gradually subside. Transit pigmentary disturbance is the main
adverse effect, with hyperpigmentation particularly common during the first few treatment
sessions. Recently, it was proposed to combine QS 532 nm Nd:YAG and QS 1064 nm
Nd:YAG to obtain a greater degree of improvement (44) (Fig. 4).
FIGURE 4 Hori’s macules under cross polarized light: (A) before treatment, and (B) after fourth treatment with QS
ruby 4.6, 5 J/cm2, 5 mm spot size.
Melasma
The results of previous studies have discouraged the use of laser in the treatment of melasma.
Over a decade ago, 510 nm PDL was found to be ineffective in the removal of melasma, and
could increase pigmentation (45). The same finding was observed when melasma was
treated with a QS ruby laser (46). Regardless of fluence (7.5 –15 J/cm2), there was no permanent
improvement and, in some cases, hyperpigmentation occurred. A more recent study indicated
that IPL could lead to the manifestation of previously subtle subclinical melasma (47). Wood’s
light examination before any IPL treatment of ethnic skin is now recommended.
The cause for such unwanted effects is unknown, but is probably related to the pathogen-
esis of melasma. It has been suggested that in epidermal and mixed type melasma, which is
characterized by epidermal hyperpigmentation, the pathogenesis involves an increased
number of melanocytes and increased activity of melanogenic enzymes overlying dermal
changes that are caused by solar radiation (48). This may explain the development of hyperpig-
mentation after the use of pigment laser for treatment. An increase in melanogenic enzyme
activity suggests that melanocytes are hyperactive. Sublethal laser damage to these melano-
cytes by pigment lasers can increase the production of melanin and result in hyperpigmenta-
tion. Hence, before any laser/IPL treatment, it is important to suppress the hyperactivity of
these abnormal melanocytes by the use of sunscreen and bleaching agents for at least six
weeks and preferably three months (49). The prolonged use of topical treatment is necessary
as it does require more than six weeks for the follicular melanocytes to be affected. Even
with the prolonged application of topical treatment, there is still a risk of hyperpigmentation.
A recent study in Taipei that compared 16 patients on topical treatment against 17 who received
topical and IPL treatment for melasma indicated 39.8% improvement in the treatment group as
compared to 11.6% in the control group (50). Despite, three months use of topical bleaching
agents before recruitment into the study, two patients in the treatment group developed
increases in pigmentation.
To prevent increases in pigmentation, low fluence is essential, and one should look for the
mildest clinical endpoint. Slight erythema should be used for IPL. Large spot size QS 1064 nm
Nd:YAG laser can also be used, and once again slight erythema is the appropriate clinical
endpoint. More recently, fractional resurfacing has been used for the removal of melasma. In
a small-scale study, 60% of the treated subjects were found to have a significant degree of
improvement, 30% had a mild degree of improvement, and 10% had an increase in pigmenta-
tion (51). Fractional resurfacing in this study involved the formation of melanocytic epidermal
necrotic debris that acted as a melanocytic shuttle and effectively removed epidermal pigmen-
tation. Other factors that may contribute to the effectiveness of fractional resurfacing in the
treatment of melasma include transit impairment of the epidermal barrier function, which
allows better absorption of the topical agents, and ablative removal of abnormal hyperactive
melanoctyes.
Congenital Melanocytic Nevi

The use of laser for the treatment of congenital melanocytic nevi is controversial. Advocates
have proposed that by reducing the melanocytic mass of the nevi, the risk of neoplastic
changes can be reduced. Opponents are skeptical because there have been cases in which
the use of laser delayed the diagnosis of melanoma or contributed to an incorrect diagnosis.
Furthermore, whether there are long-term complications, such as increased risk of neoplastic
changes, is not known.
Whereas the use of laser for the treatment of melanocytic nevi in Caucasians is controver-
sial, there are more justifications for doing so with dark-skinned patients (52). First, unlike in
the Caucasian population, melanoma is less common among darker-skinned patients;
genetic difference rather than a difference in skin type is likely to be the main reason.
Indeed, among patients with skin of color, melanoma tends to be acral in nature. Furthermore,
the only long-term follow up study looking at the use of laser for the treatment of congenital
melanocytic nevi was from Japan, and it indicated no histological evidence of malignant
changes eight years after normal ruby laser treatment for congenital nevi (53). As a result,
the use of laser for the removal of melanocytic nevi can be justified in ethnic skin, provided
that there is no family history of melanoma and the lesion is not acral in nature.
In terms of the treatment approach, various pigmented lasers have been used in the
removal of melanocytic nevi. A study looking at the use of QS Ruby laser found that an
average clearance of 76% could occur after an average of eight treatment sessions (54).
However, other studies showed that depending on the depth of the nests of melanocytes, recur-
rence could be a problem. Normal mode ruby laser (NMRL) can be used for the treatment of
melanocytic nevi based on the principle that with longer pulse durations, a greater degree of
clearance is achieved when nests of cells are destroyed (55). A combined approach with a
QS ruby laser followed immediately, or two weeks later, with an NMRL was used with the
intention of removing the superficial pigment first with the QS ruby laser, thereby enhancing
the penetration of the NMRL (56). A previous study found that although 52% of the nevi
showed a visible decrease in pigment, no lesion had complete histological clearance. Subtle
microscopic scarring of the underlying nevus cells was considered to be important in creating
the appearance of a significant reduction in pigmentation. More recently, another study
reported better clearance by first using an NMRL to remove the epidermis, immediately fol-
lowed by multiple passes of a QS ruby laser (57). The removal of the epidermis allows a
greater degree of penetration by the QS laser, of which multiple passes further improve the
clinical efficacy (Fig. 5).
LASER-ASSISTED HAIR REMOVAL IN ETHNIC SKIN

Laser-assisted hair removal techniques have been available since the mid 1990s. The first
generation of hair-removal lasers with short 2 to 5 ms pulse durations allowed for successful
FIGURE 5 Congenital melanocytic nevus. (A) before treatment; (B) after sixth treatment with long-pulsed 532 mm,
6.2 J/cm2, 2 mm spot size, followed immediately by Q-switching Alexandrite laser 7.5 J/cm2, 2 mm spot size.
FIGURE 6 Laser hair removal using long-pulsed alexandrite, pre- (Left ) and post- (Right ) treatment. Effective hair
removal in dark skin with some posttreatment dyschromia.
hair removal in those with fair skin and dark hair, but proved problematic in those with darker
skin, resulting in blistering, dyschromia, and scarring. For effective treatment, laser energy
must be transmitted unimpeded through the skin toward the intended target of melanin
within the hair shaft and follicle. Darker skin (Fitzpatrick III –VI), with its increased melanin
content, creates competition for the laser energy between the epidermal melanin and the tar-
geted melanin. The selective destruction of the melanin within the hair follicle, while
sparing epidermal melanin is possible through the process of thermokinetic selectivity,
which is a corollary of the theory of selective photothermolysis (58,59). Smaller structures (epi-
dermal melanocytes) dissipate heat more quickly than larger structures of the same chromo-
phore with a greater surface to volume ratio (hair follicle). The ability of these smaller
structures to dissipate heat more quickly acts as a protective mechanism. Newer generation
laser hair removal devices incorporate longer pulse durations and a variety of cooling
devices, thus allowing the safer treatment of dark skin.
Among all of the systems that are currently available for laser hair removal, long-pulsed
Alexandrite laser, long-pulsed 800 nm diode laser (800 – 810 nm, 9 – 12 mm spot size,
30 – 100 msec pulse duration), and long-pulsed Nd:YAG laser (1064 nm, 10– 100 msec pulse
duration, 5– 10 mm spot size) have fulfilled the above criteria, and may be particularly
applicable to ethnic skin.
Initial studies with the long-pulsed Alexandrite laser (60,61) demonstrated effective hair
removal in darker skin with pulse durations of 40 ms and fluences of 11 to 15 J/cm (Fig. 6)
Although successful hair removal was achieved, post treatment dyschromia was noted in
patients with very dark skin (skin type VI). Lengthening the pulsewidth to 200 ms (62) and
using the long-pulsed diode laser resulted in effective hair removal and no post treatment dys-
chromia (Fig. 7).
Another study investigated the efficacy and complications of long-pulsed diode and
long-pulsed Nd:YAG lasers in removing the hair of Chinese patients. The long-pulsed
Nd:YAG laser was associated with significantly greater pain immediately after surgery and
more protracted treatment time (63). Transient adverse effects were erythema and perifollicular
edema, and only one patient developed hypopigmentation, at week six, which resolved by
week 36. Such findings were further confirmed by Alster et al. (64), who examined twenty
dark-skinned patients who were treated with long-pulsed Nd:YAG laser, which was found
to be safe and effective.
A newer generation IPL sources with greater selectivity have also been shown to be effec-
tive in hair removal on ethnic skin. A recent study that looked at 28 Koreans who were treated
with four sessions of IPL indicated minimal adverse effects with a clearance rate of up to
80% (65).
Laser assisted hair removal is now a successful treatment for hypertrichosis and
pseudofolliculitis barbae. Despite the use of cooling devices, darker-skinned patients experi-
ence more pain with laser hair removal procedures (personal observation), are generally not
able to tolerate higher fluences (58), and should be treated with conservative parameters.
FIGURE 7 Pre- and post-treatment photos of two patients using super long-pulsed diode showing effective
hair removal, no post-treatment dyschromia and resolution of pseudofolliculitis barbae. Pretreatment (Left ),
post-treatment (Right ).
One must also be cautious while using cryogen cooling-devices in patients with darker skin
tones to avoid possible hypopigmentation that is a result of the damage caused by cryogen
to the melanocyte.
THE USE OF LASER FOR THE TREATMENT OF OTHER VASCULAR LESIONS

Beside facial telangiectasia, laser and IPL sources are also used for the treatment of port wine
stain and proliferative hemangioma. With greater epidermal melanin context, ethnic skin is at a
higher risk of adverse effects such as vesiculation and pigmentary changes after laser treat-
ments of vascular lesions. Furthermore, with the epidermal melanin acting as a competing
chromophore for hemoglobin, higher fluence or more treatment sessions are necessary to
produce the desirable clinical endpoint. Before the development of skin cooling technology,
studies indicated that the treatment of port wine stain in ethnic skin was associated with
greater risk of transient PIH and texture changes (66,67). Adequate skin cooling allows epider-
mal protection, and in doing so improves safety and efficacy. Several cooling methods, includ-
ing cold gel, air cooling, cryogen spray cooling (CSC), and contact cooling with a sapphire
window, can be used in conjunction with vascular laser.
There is limited data on the use of air cooling with PDL for the treatment of vascular
lesions in ethnic skin. Most of the published data is on CSC with pulsed dye laser (PDL-
CSC) for the treatment of port wine stain. In a retrospective study, Chang and Nelson (68)
found that PDL-CSC could enhance clinical efficacy, and a higher fluence could be used
without an increase in complications for the treatment of port wine stain in Asian patients.
Kelly et al. (69) demonstrated that PDL-CSC could be safely used at higher fluences in 20
port wine stain patients with skin types I – IV.
Another prospective study looking at 35 Chinese patients who were treated with PDL
alone compared with PDL-CSC indicated that PDL-CSC was more effective, better tolerated,
and had lower adverse effects than PDL alone (70) (Fig. 8). More recently, in a large-scale retro-
spective study, PDL-CSC was found to be effective for the treatment of a wide range of vascular
lesions in 239 Korean patients (71).
Multiple intermittent cryogen spurts and laser pulses have been proposed to provide
adequate epidermal protection, while permitting port wine stain photocoagulation for
darker-skinned patients using heat diffusion, light distribution, and thermal damage compu-
tational models. Further clinical study using these new developments is necessary for
darker-skinned patients with port wine stain (72).
FIGURE 8 Thirteen-year-old Chinese female with port wine stain (PWS) of the right forearm: (A) before laser therapy,
and (B) two months after fourth treatment with PDL alone and PDL-CSC using mean energy densities of 6.75 and
10.5 J/cm2, respectively. Abbreviations: PDL, pulsed dye laser; PDL-CSC, pulsed dye laser-cryogen spray cooling.
A retrospective study that examined the results of a glass cooling chamber equipped
variable pulse 532 nm Nd:YAG laser (VP 532) in the treatment of port wine stain in Chinese
patients found that the VP 532 laser was only partially effective. High fluence was necessary,
and even though contact cooling reduced the risk of epidermal damage, texture changes still
occurred (73).
IPL sources have also been shown to be effective in the treatment of PDL resistant port
wine stain. However, this method of treatment is only effective in experienced hands; compli-
cations can occur and the method should only be used as a second line therapy (74).
For proliferative hemangioma, the role of laser treatment is controversial. A previous
study that looked at the use of PDL without cooling did not indicate that it had a beneficial
effect (75). However, more recently, long PDL with cooling has been shown to be effective
in reducing the proliferative phase of hemangioma among Japanese patients (76). Further
study is necessary to confirm this finding.
CONCLUSION
When performing laser procedures in patients with ethnic skin, the challenge of effective treat-
ment lies in one’s ability to balance effective treatment with minimal risk to the patient. Unto-
ward effects can be minimized with the use of conservative treatment parameters and lower
energy settings for darker-skinned patients. Cutaneous laser surgery has been a mainstay of
dermatologic therapy for more than a decade, but until recently most published studies
excluded patients with ethnic skin. The changing demographics of the United States and the
development of laser technologies that protect epidermal melanin from damage mean that
with appropriate patient selection and proper physician training, laser surgery has become
increasingly safe for darker-skinned patients.
REFERENCES
1. Matory WE. Skin care. In: Matory WE, ed. Ethnic Considerations in Facial Aesthetic Surgery.
Philadelphia: Lippincott-Raven, 1998:100.
2. O’shea DC, Callen WR, Rhodes WT. Introduction to Lasers and Their Applications. Menlo Park, CA:
Addison-Wesley Publishing Co, 1978.
3. Stratigos AJ, Alora MB, Uroste S, et al. Cutaneous laser surgery. Curr Probl Dermatol 1998; 10:127– 174.
4. Anderson RR, parish JA. Optical properties of human skin. In: Regan JD, Parrish JA, eds. The Science
of Photomedicine. New York: Plenum Press, 1982:147– 194.
5. Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of
pulsed radiation. Science 1983; 220:524.
6. Anderson RR. Laser-Tissue Interaction. In: Goldman MP, Fitzpatrick RE, eds. Cutaneous Laser
Surgery the Art and Science of Selective Photothermolysis. St Louis: Mosby, 1994.
7. Arndt KA, Noe JM, Northam DBC. Laser therapy: basic concepts and nomenclature. J AmAcad
Dermatol 1981; 5:649– 654.
8. Jackson BA, Junkins-Hopkins J. Super long pulsed diode laser treatment for hair removal in dark
skin: clinical-pathologic correlation. 2001 oral presentation and abstract. L’Oreal Ethnic Hair and
Skin Symposium.
9. McCurdy JA. Facial surgery in the asian patient. In: Matory WE, ed. Ethnic Considerations in Facial
Aesthetic Surgery. Philadelphia: Lippincott-Raven, 1998:263– 284.
10. Chan HH, Fung WK, Ying SY, Kono T. An in vivo trial comparing the use of different types of 532 nm
Nd:YAG lasers in the treatment of facial lentigines in oriental patients. Dermatol Surg 2000; 26:743–749.
11. Rashid T, Hussain I, Haider M, Haroon TS. Laser therapy of freckles and lentigines with quasi-
continuous, frequency-doubled, Nd:YAG(532 nm) laser in Fitzpatrick skin type IV: A 24 month
follow up. J Cosmet Laser Ther 2002; 4:81– 85.
12. Negishi K, Tezuka Y, Kudshikata N,Wakamatsu S. Photorejuvenation for Asian skin by intense
pulsed light. Dermatol Surg 2001; 27:627– 632.
13. Wang CC, Sue YM, Yang CH, Chen CK. A comparison of Q-switched alexandrite laser and intense
pulsed light for the treatment of freckles and lentigines in Asian persons: a randomized, phys-
ician-blinded, split-face comparative trial. J Am Acad Dermatol 2006; 54:804 – 810.
14. Chan HH. Treatment of photoaging in asian skin. In: Rigel DS, Weiss RA, Lim HW, Dover JS, eds.
Photaging. New York: Marcel Dekker, Inc, 2003:343– 364. ISBN 0-8247-5450-6.
15. Kono T, Manstein D, Chan HH, Nozaki M, Anderson RR. Q-switched ruby vs. long-pulsed dye
laser delivered with compression for treatment of facial lentigines in Asians. Lasers Surg Med
2006; 38:94– 97.
16. Chan HH, Alam M, Kono T, Dover J. Clinical application of lasers in Asians. Dermatol Surg 2002;
28:556– 563.
17. Chan HH. Recent advances in the use of lasers, light sources, and radiofrequency in Asians. Lasers
Surg Med 2005; 37:179– 185.
18. Lee MW. Combination visible and infrared lasers for skin rejuvenation. Semin Cutan Med Surg 2002;
21:288– 300.
19. Hse TS, Zelickson B, Dover JS, et al. Multicenter study of the safety and efficacy of a 585 nm pulsed-
dye laser for the nonablative treatment of facial rhytides. Dermatol Surg 2005; 31:1– 9.
20. Trelles MA, Allones I, Levy JL, Calderhead RG, Moreno-Arias GA. Combined nonablative skin
rejuvenation with the 595- and 1450-nm lasers. Dermatol Surg 2004; 30:1292– 1298.
21. Chan HH, Lam LK, Wong DS, Kono T, Trend-Smith N. Use of 1320 nm Nd:YAG laser for wrinkle
reduction and the treatment of atrophic acne scarring. Lasers Surg Med 2004; 34:98– 103.
22. Tanzi EL, Williams CM, Alster TS. Treatment of facial rhytides with a nonablative 1,450 nm diode
laser: a controlled clinical and histologic study. Dermatol Surg 2003; 29:124– 128.
23. Goh CL, Chua SH, Ang P, Khoo L. Efficacy of smoothbeam 1,450 nm laser for treatment of acne scars
in Asian skin. Lasers Surg Med 2004; S16:S76.
24. Fournier N, Dahan S, Barneon G, et al. Nonablative remodeling: a 14-month clinical ultrasound
imaging and profilometric evaluation of a 1540 nm Er:Glass laser. Dermatol Surg 2002; 28:926– 931.
25. Alster T, Hirsch R. Single-pass CO2 laser skin resurfacing of light and dark skin: extended experience
with 52 patients. J Cosmet Laser Ther 2003; 5:39– 42.
26. Manstein D, Herron GS, Sink RK, Tanner H, Anderson RR. Fractional photothermolysis: a new
concept for cutaneous remodeling using microscopic patterns of thermal injury. Lasers Surg Med
2004; 34:426– 438.
27. Chan HH, Shek S, Yu CY, Yeung CK, Kono T, Mainstein D. Prevalence and risk factor of post-
inflammatory hyperpigmentation in Chinese patients treated with fractional resurfacing. Lasers
Surg Med 2006; S18:S77.
28. Kono T, Chan HH, Manstein D, Sesova IP, Nozaki M. Comparison study of the down time and
complications of fraxel laser skin rejuvenation. Lasers Surg Med 2006; S18:S20.
29. Alster TS. Complete elimination of large café au lait birthmarks by the 510 nm pulsed dye laser. Plast
Reconstr Surg 1995; 96:1660 –1664.
30. Grossman MC, Anderson RR, Farinelli W, Flotte TJ, Grevelink JM. Treatment of cafe au lait macules
with lasers. A clinicopathologic correlation. Arch Dermatol 1995; 131:1416– 1420.
31. Chan HH, Kono T. The use of lasers and intense pulsed light sources for the treatment pigmentary
lesions. Skin Ther Lett 2004; 9:5– 7.
32. Kopera D, Hohenleutner U, Landthaler M. Quality-switched ruby laser treatment of solar lentigines
and Becker’s nevus: a histopathological and immunohistochemical study. Dermatology 1997;
194:338– 343.
33. Trelles MA, Allones I, Moreno-Arias GA, Velez M. Becker’s naevus: a comparative study between
erbium: YAG and Q-switched neodymium:YAG; clinical and histopathological findings. Br J Derma-
tol 2005; 152:308– 313.
34. Nanni CA, Alster TS. Treatment of a Becker’s nevus using a 694 nm long-pulsed ruby laser. Dermatol
Surg 1998; 24:1032– 1034.
35. Watanabe S, Takahashi H. Treatment of nevus of ota with the Q-switched ruby laser. N Engl J Med
1994; 331:1745– 1750.
36. Chan HH, King WWK, Chan ESY, et al. An vivo trial comparing the patients’ tolerability of
Q-switched Alexandrite (QS Alex) and Q-switched Neodymium: Yttrium-Aluminum-Garnet
(QS Nd-YAG) lasers in the treatment of nevus of ota. Laser Surg Med 1999; 24:24– 28.
37. Chan HH, Ying SY, Ho WS, Kono T, King WW. An in vivo trial comparing the clinical efficacy and
complications of Q-switched Alexandrite (QS Alex) and Q-switched 1064 nm Neodymium:
Yttrium-Aluminum-Garnet (QS 1064 Nd-YAG) lasers in the treatment of nevus of ota. Dermatol
Surg 2000; 26:919– 922.
38. Chan HH, Leung RS, Ying SY, Lai CF, Kono T, Chua JK, Ho WS. A retrospective study looking at
the complications of Q-switched Alexandrite (QS Alex) and Q-switched Neodymium: Yttrium-
Aluminum-Garnet (QS Nd-YAG) lasers in the treatment of nevus of Ota. Dermatol Surg 2000;
26:1000– 1006.
39. Kono T, Nozaki M, Chan HH, Mikashima Y. A retrospective study looking at the long-term compli-
cation of Q-switched ruby laser in the treatment of nevus of Ota. Lasers Surg Med 2001; 29:156– 159.
40. Kono T, Chan HH, Ercocen AR, et al. Use of Q-switched ruby laser in the treatment of nevus of ota in
different age groups. Lasers Surg Med 2003; 32:391– 395.
41. Kunachak S, Leelaudomlipi P, Sirikulchayanonta V. Q-Switched ruby laser therapy of acquired bilat-
eral nevus of ota-like macules. Dermatol Surg 1999; 25:938– 941.
42. Lam AY, Wong DS, Lam LK, Ho WS, Chan HH. A retrospective study on the efficacy and compli-
cations of Q-switched. Alexandrite laser in the treatment of acquired bilateral nevus of ota-like
macules. Dermatol Surg 2001; 27:937– 941.
43. Polnikorn N, Tanrattanakorn S, Goldberg DJ. Treatment of Hori’s nevus with the Q-switched Nd:YAG
laser. Dermatol Surg 2000; 26:477– 480.
44. Ee HL, Goh CL, Khoo LS, et al. Treatment of acquired bilateral nevus of ota-like macules (Hori’s
nevus) with a combination of the 532 nm Q-Switched Nd:YAG laser followed by the 1,064 nm
Q-switched Nd:YAG is more effective: prospective study. Dermatol Surg 2006; 32:34 – 40.
45. Grekin RC, Shelton RM, Geisse JK, Frieden I. 510 nm pigmented lesion dye laser. Its characteristics
and clinical uses. J Dermatol Surg Oncol 1993; 19:380– 387.
46. Taylor CR, Anderson RR. Ineffective treatment of refractory melasma and postinflammatory hyper-
pigmentation by Q-switched ruby laser. J Dermatol Surg Oncol 1994; 20:592– 597.
47. Kang WH, Yoon KH, Lee ES, et al. Melasma: histopathological characteristics in 56 Korean patients.
Br J Dermatol 2002; 146:228– 237.
48. Negishi K, Kushikata N, Tezuka Y, Takeuchi K, Miyamoto E, Wakamatsu S. Study of the incidence
and nature of “very subtle epidermal melasma” in relation to intense pulsed light treatment.
2004;30:881– 886; discussion 886.
49. Chan HH. The use of laser and intense pulsed light source in the treatment of melasma. Cosmet
Dermatol 2007 (in press).
50. Wang CC, Hui CY, Sue YM, et al. Intense pulsed light for the treatment of refractory melasma in Asian
patients. Dermatol Surg 2004; 30:1196– 1200.
51. Rokhsar CK, Fitzpatrick RE. The treatment of melasma with fractional photothermolysis: a pilot
study. Dermatol Surg 2005; 31:1645– 1650.
52. Imayama S, Ueda S. Long- and short-term histological observations of congenital nevi treated with
the normal mode ruby laser. Arch Dermatol 1999; 135:1211 – 1218.
53. Chan HH. Laser treatment of nevomelanocytic nevi—can results from an Asian study be applicable to
the white population? Arch Dermatol 2002; 138:535.
54. Waldorf HA, Kauvar ANB, Geronemus RG. Treatment of small and medium congenital nevi with the
Q-switched ruby laser. Arch Dermatol 1996; 132:301– 304.
55. Vibhagool C, Randolph Byers H, Grevelink JM. Treatment of small nevomelanocytic nevi with a
Q-switched ruby laser. J Am Acad Dermatol 1997; 36:738– 741.
56. Duke D, Randolph Byers H, Sober AJ, Anderson RR, Grevelink JM. Treatment of benign and atypical
nevi with the normal mode ruby laser and the Q-switched ruby laser. Arch Dermatol 1999; 135:290–296.
57. Kono T, Nozaki M, Chan HH, Sasaki K, Kwon SC. Combined use of a normal mode ruby laser and a
Q-switched ruby laser in the treatment of congenital melanocytic nevi. Brit J Plast Surg 2001; 54:
640–642.
58. Fuchs M. Thermokinetic selectivity—a new highly effective method for permanent hair removal:
experience with the LPIR Alexandrite laser. Derm Prakt Dermatologie 1997; 5:1.
59. Anderson RR. Laser-Tissue interaction. In: Goldman MP, Fitzpatrick RE, eds. Cutaneous Laser
Surgery the Art and Science of Selective Photothermolysis. St Louis: Mosby, 1994.
60. Jackson BA, Junkins-Hopkins JM. Effect of Pulsewidth Variation on laser Hair removal in African-
American Skin. 1999 oral presentation ASDS meeting Miami, FL.
61. Jackson BA. Lasers in Ethnic skin. 1999 AAD Annual meeting focus session, New Orleans, LA.
62. Jackson BA, Junkins-Hopkins J. Super long pulsed diode laser treatment for hair removal in dark
skin: clinical-pathologic correlation. 2001 Oral presentation and abstract. L’Oreal Ethnic Hair and
Skin Symposium.
63. Chan HH, Ying SY, Ho WS, Wong DS, Lam LK. An in vivo study comparing the efficacy and compli-
cations of Diode laser and long-pulsed Neodymium: Yttrium-Aluminum-Garnet (Nd:YAG) laser in
hair removal among Chinese patients. Dermatol Surg 2001; 27:950– 954.
64. Alster TS, Bryan H, Williams CM. Long-pulsed Nd:YAG laser-assisted hair removal in pigmented
skin. Arch Dermatol 2001; 137:885 –889.
65. Lee JH, Huh CH, Yoon HJ, Cho KH, Chung JH. Photoepilation results of axillary hair in dark-skinned
patients by IPL: a comparison between different wavelength and pulse width. Dermatol Surg 2006;
32:234– 241.
66. Goh CL. Treatment response of port wine stains with the flashlamp-pulsed dye laser in the national
skin centre: a report of 36 patients. Ann Acad Med Singapore 1996; 25:536– 540.
67. Sommer S, Sheehan-Dare RA. Pulsed dye laser treatment of port-wine stains in pigmented skin. J Am
Acad Dermatol 2000; 42:667– 671.
68. Chang CJ, Nelson JS. Cryogen spray cooling and higher fluence pulsed dye laser treatment improve
port wine stain clearance while minimizing epidermal damage. Dermatol Surg 1999; 25:767– 772.
69. Kelly KM, Nanda VS, Nelson JS. Treatment of port-wine stain birthmarks using the 1.5-msec pulsed
dye laser at high fluences in conjunction with cryogen spray cooling. Dermatol Surg 2002; 28:309 –313.
70. Chiu CH, Chan HH, Ho WS, Yeung CK, Nelson JS. Prospective study of pulsed dye laser in con-
junction with cryogen spray cooling for treatment of port wine stains in Chinese patients. Dermatol
Surg 2003; 29:909– 915.
71. Woo SH, Ahn HH, Kim SN, Kye YC. Treatment of vascular skin lesions with the variable-pulse
595 nm pulsed dye laser. Dermatol Surg 2006; 32:41– 48.
72. Aguilar G, Diaz SH, Lavernia EJ, Nelson JS. Cryogen spray cooling efficiency: improvement of port
wine stain laser therapy through multiple-intermittent cryogen spurts and laser pulses. Lasers Surg
Med. 2002; 31:27– 35.
73. Chan HH, Chan E, Kono T, Ying SY, Ho WS. The use of variable pulse width frequency doubled
Nd:YAG 532 nm laser in the treatment of port-wine stain in Chinese patients. Dermatol Surg 2000;
26:657– 661.
74. Ho WS, Ying SY, Chan PC, Chan HH. Treatment of port-wine stains with intense pulsed light:
a prospective study. Dermatol Surg 2004; 30:887– 890.
75. Batta K, Goodyear HM, Moss C, et al. Randomised controlled study of early pulsed dye laser treatment
of uncomplicated childhood haemangiomas: results of a 1-year analysis. Lancet 2002; 360:521–527.
76. Kono T, Sakurai H, Groff WF, et al. Comparison study of a traditional pulsed dye laser versus a long-
pulsed dye laser in the treatment of early childhood hemangiomas. Lasers Surg Med 2006; 38:112 – 115.
Section VI: APPENDICES
Appendix Phototesting
A Peter M. Farr
Department of Dermatology, Royal Victoria Infirmary,
Newcastle upon Tyne, England, U.K.
Robert S. Dawe
Department of Dermatology, Ninewells Hospital and Medical
School, Dundee University, Dundee, Scotland, U.K.
INTRODUCTION
hototesting is exposure of the skin to ultraviolet (UV) or visible radiation followed by
P the observation, recording, and evaluation of irradiated skin responses at appropriate

times thereafter. In general, there are two broad phototesting categories.
1. Phototesting for therapeutic purposes. Here the minimal erythema or phototoxic dose
(MED or MPD) is measured to enable choice of an appropriate UV dose with which to
start a phototherapy or psoralen photochemotherapy (PUVA) course.
2. Phototesting for diagnostic purposes in patients with suspected photosensitivity. Here,
measurement of the MED is again undertaken, and in appropriate clinical situations,
provocation testing as well.
Phototesting can also be used to monitor changes in a condition, for example, phototest-
ing at intervals to determine whether or not chronic actinic dermatitis (CAD) has resolved, or
before and after antihistamine medication to help assess its efficacy in solar urticaria.
MEASURING THE MINIMAL ERYTHEMA DOSE PRIOR TO NARROWBAND

OR BROADBAND UVB PHOTOTHERAPY
Here, it is essential that the lamp type used for phototesting is the same as that to be used for the
treatment course. Closely apposed areas of skin are exposed to increasing UV doses, which
given the positively skewed distribution of MED values in the normal population
(see subsequently), should follow a geometric series. In general, increments of 40% (equivalent
to doubling alternate doses, for example, 2.5, 3.5, 5.0, 7.1, 10, 14, 20, 28, and so on), provide an
accurate enough indication of a patient’s erythemal sensitivity. The exact range of doses will be
determined by the predominant skin type of the population under test, with the aim in each
individual of achieving a range of responses from no erythema to just above the MED. The
skin site for testing may vary according to the method used, but the back is frequently
chosen because the trunk is usually the most sensitive site and the back is often practically
easier to test than the abdomen (1).
Two methods are available for achieving a series of doses on the skin.
1. A UV-opaque template with several apertures able to be covered or uncovered in turn is

applied to the skin and different doses achieved for each uncovered site by adjusting
the exposure time (Fig. 1). A special bank of fluorescent lamps may be used, or with appro-
priate body protection, the actual phototherapy unit to be employed for treatment. This
method has the advantage that the irradiation geometry will be similar to that used for
phototherapy, and dosimetry will be relatively simple. However, it is time-
consuming and requires multiple interventions by trained staff.
2. A template is applied to the skin with apertures containing variably perforated metal grills
that differentially attenuate the radiation (Fig. 2A) (2). A single exposure from a fluorescent
434 Appendix A
FIGURE 1 Measurement of the minimal erythema dose prior to a phototherapy course using a UV-opaque template
with apertures covered in turn to achieve a series of doses. The patient’s skin is protected, and a bank of fluorescent
UV lamps is used to expose the test sites. Source: Photographs courtesy of Dr. S.H. Ibbotson.
lamp mounted closely above the template then results in a graded series of doses. This
method has the advantage that testing can be performed rapidly—a dose series may be
obtained with a single exposure of typically five minutes—but the irradiation geometry
is unlike that to be used during the phototherapy and dosimetry can be problematic. An
instrument based on these principles containing a compact fluorescent lamp is commer-
cially available (Fig. 2B).
Whatever method is used, the exposed sites are observed at a specified time after
irradiation, usually 24 hours for convenience (although UVB erythema peaks before this) (3),
and the smallest dose to achieve “just perceptible erythema” is taken as the MED. It will be
apparent that the MED is not an exact measurement, as the actual value can lie anywhere
between the dose at which erythema is first observed and just above the dose below that in
the exposure series.
FIGURE 2 (A) A phototesting template with perforated metal grills to attenuate the radiation, allowing a series of
doses to be achieved with a single exposure. (B) A commercially available device for minimal erythema dose
measurement incorporating the attenuating template. Source: Figure 2A adapted from Ref. 2.
Appendix A 435
MEASURING THE MINIMAL PHOTOTOXIC DOSE PRIOR TO

PSORALEN PHOTOCHEMOTHERAPY
This is performed in a similar fashion to MED testing. The appropriate psoralen dose is
administered before irradiation by the appropriate route (oral or topical), and the test
irradiation undertaken with the same UV source (usually broad-band UVA), as to be used
for treatment. Peak PUVA erythema occurs later than after UVB or UVA alone, such that
PUVA readings are usually made at 72 or 96 hours. As with MED testing, MPD assessment
helps determine an appropriate UV starting dose, but also ensures before oral PUVA that suf-
ficient drug reaches the skin to cause a reaction, given that individual variations in bioavail-
ability, and drug and dietary interactions, may occur. If there is no response, repeat testing
may be undertaken after a higher oral psoralen dose.
MEASURING THE MINIMAL ERYTHEMA DOSE WHEN INVESTIGATING

PATIENTS WITH SUSPECTED PHOTOSENSITIVITY
Here, in addition to measuring the UVB MED, it is necessary also to measure the MED within
the UVA and, sometimes, visible wavebands. However, UVA fluorescent lamps are not of
sufficiently high irradiance to allow MED measurements except in severe photosensitivity,
such that an irradiation monochromator is generally used instead.
IRRADIATION MONOCHROMATOR
An irradiation monochromator is a versatile instrument allowing small areas of skin to be
exposed to specific wavelengths of radiation. It is particularly used to measure MEDs in
patients under investigation for suspected abnormal photosensitivity (Table 1). It is also
ideal for lesion induction in patients with solar urticaria, but not generally in other disorders,
particularly polymorphic light eruption (PLE), where a larger irradiation field is required.
An irradiation monochromator typically contains a xenon arc lamp UV source provid-
ing continuous emission from the UVC (100 – 280 nm) into the visible region. A diffraction
grating, less commonly a prism, then disperses this into its component wavelengths.
Finally, a selection of specific wavelengths is shone on to the patient’s skin, either by
direct contact with the instrument’s exit aperture, or more conveniently through a flexible
liquid-filled light guide (4).
Although the term monochromator implies that a single wavelength is delivered, the
spectral distribution of the emitted radiation is generally triangular in shape, with its width
(or bandwidth) being varied by adjusting the size of the slits through which it passes to and
from the diffraction grating. The bandwidth is typically quoted after the central wavelength,
for example: 350 nm (bandwidth 30 nm or +15 nm), and is conventionally defined as the
full width of the emission at half-maximum intensity (Fig. 3). The smaller the bandwidth,
the more accurately a specific observed effect may be attributed to a specific wavelength.
However, as the output irradiance, and thus the irradiation time to achieve a given dose,
is highly dependent on the bandwidth, a compromise is necessary depending on the
time available for testing and the specific wavelength(s) under investigation. For the UVB
wavelengths, to which the skin is highly erythemally sensitive, a narrow bandwidth may be
used, for example, 5 nm, whereas in the UVA region, where the skin is much less
erythemally-sensitive, a bandwidth of 30 nm may be required. With such a large bandwidth,
a filter is commonly used to cut off shorter wavelengths, which would otherwise contribute
to the erythemal response.
The MED is measured with a monochromator by exposing adjacent areas of skin to
incremental doses of radiation in turn, using a geometric dose series as described previously.
Dose increments of 40% are again generally accurate enough for diagnostic purposes.
Smaller dose increments (10% or 20%) might theoretically be used to improve precision, but
judging whether erythema is present or not under such circumstances is often difficult, and
variations in skin sensitivity, even over a defined area such as the back, also make this approach
436 Appendix A
FIGURE 3 The spectral emission of an irradiation monochromator set at central wavelengths (bandwidths) of 300 (5)
nm, 320 (10) nm, and 350 (30) nm. The bandwidth (full width of the emission at half-maximum intensity) is shown at
350 nm. Source: Spectra courtesy of Dr. J.J. Lloyd.
questionable. The results are examined at appropriate time intervals after exposure, and the
lowest dose to cause just perceptible erythema is recorded, along with any abnormal morpho-
logical responses. In solar urticaria (whether idiopathic, drug-induced or associated with
porphyria), wealing typically occurs within 30 minutes of irradiation. However, in
porphyria, a response of erythema alone may be seen, typically maximal at around seven
hours after irradiation. Additional observational time-points may be required for a few
conditions, such as some drug-induced photosensitivity, xeroderma pigmentosum (XP), and
psoralen-sensitized skin.
The selection of wavelengths used to investigate patients with suspected photosensitivity
has not yet been standardized between specialist centers (5). As normal ranges are highly
dependent upon wavelength, bandwidth, and other technical factors, they too will be specific
to a particular investigating center. In the normal population, MEDs have a positively skewed,
log-normal distribution (6,7), and it is therefore preferable to quote average MED values as the
TABLE 1 Summary of Photosensitivity Disorders and Phototesting Abnormalities

Diagnosis Results of MED testing Results of provocation testing
Polymorphic light eruption Usually normal. Around 15% of Positive papular response in
and actinic prurigo patients may have low MEDs around 80% of patients
Solar urticaria Normal if able to be tested Urticarial response
Chronic actinic dermatitis Abnormally low UVB and UVA MED responses often palpable with
MEDs with abnormal response to spongiotic eczematous change
visible light in some patients on biopsy
Drug-induced May be abnormal, particularly in
photosensitivity UVA waveband
XP May be abnormal, particularly in UVB.
In classical (not variant) XP,
maximal reaction may be
delayed until 72 hours
Abbreviations: MED, minimal erythema dose; XP, xeroderma pigmentosum.
Appendix A 437
TABLE 2 Wavebands and Normal Ranges Used for Routine Irradiation Monochromator Phototesting in
The Newcastle Photobiology Unit
Waveband Typical irradiance Normal range
(bandwidth) (nm) Filter (mW/cm2) for MED Dose range used
300 (5) None 5 14–80 mJ/cm2 2.5, 3.5, 5, 7.1, 10, 14,
20, 28, 40, and 56
320 (10) WG305 20 1– 4 J/cm2 0.5, 0.7, 1, 1.4, and 2
350 (30) WG320 180 14–80 J/cm2 2.5, 3.5, 5, 7.1, 10, 14, and 20
400 (30) WG320 190 .40 J/cm2 20 and 40
Note: The choice of wavebands and doses varies according to the suspected diagnosis. A typical MED investigation with the wavebands
shown will be completed within 30 minutes. The normal ranges are derived from unpublished data and previous publications.
Source: Adapted from Refs. 4, 7.
median, or geometric mean, rather than the arithmetic mean. Details of the routine testing
methodology used in the Newcastle photobiology unit, together with the relevant normal
ranges, are shown in Table 2 and Figure 3.
PROVOCATION TESTING
Provocation testing, used principally to confirm a diagnosis, involves the sometimes repeated
irradiation of skin to induce a response similar to that seen following sunlight exposure
(Table 1). The UV source and exposure protocol depend upon the suspected clinical diagnosis,
as described subsequently.
POLYMORPHIC LIGHT ERUPTION AND ACTINIC PRURIGO

An irradiation field of several square centimetres is required, not achievable with an irradiation
monochromator. Suitable UV sources include the following.
1. A solar simulator. This is a xenon arc lamp filtered to provide an emission spectrum similar
to that of natural sunlight.
2. A bank of fluorescent lamps. When configured as a cylindrical array, a high irradiance may
be achieved to allow provocation testing on the arm with either narrowband (NB)-UVB or
broadband UVA (8).
Provocation testing may be performed on any convenient body site, frequently the arm or
back. However, irradiation of recently sun-exposed or tanned skin may produce false negative
results. The doses used will be limited by the possibility of normal delayed erythema for
sources emitting significant UVB (such as the solar simulator and NB-UVB lamps), or by the
time available for testing with UVA fluorescent lamps. Repeated exposures are generally
given every 24 hours until a positive response is obtained, or the test is evaluated as negative.
Positive results may be obtained in around 81% to 90% of PLE patients (8,9), although such
a high success rate may perhaps be achievable only in patients with severe disease. Testing
with both NB-UVB and broadband UVA increases the chances of a successful outcome (8).
The percentage of patients testing positive increases from 18% after one exposure to 69%
after two exposures and 81% after three (8). Positive results generally consist of small erythe-
matous papules scattered throughout the irradiation field (Fig. 4), but other responses, such as
large edematous papules or vesicles, are also possible.
SOLAR URTICARIA
The action spectrum for solar urticaria may be narrow and confined to a specific waveband
within the UVB, UVA, or visible regions, or more commonly encompass a wide range of wave-
lengths. The monochromator is ideally suited for provocation testing in this condition, as only
438 Appendix A
FIGURE 4 Papular lesions induced on the forearm of a

patient with polymorphic light eruption after exposure
to NB-UVB.
small irradiation fields are needed but testing is required at several wavelengths, including
within the visible region. A typical investigation might entail a series of single exposures at
300, 320, and 350 nm, and then every 50 nm up to 500 nm (blue light) or 550 nm (green
light). At 300 and 320 nm, the doses used will be limited by the need to avoid excessive
delayed normal erythema, whereas at longer wavelengths, where such erythema is unlikely,
a maximum of about 20 J/cm2 may be appropriate. Irradiation sites should be observed for
10 to 15 minutes, by which time any weal and flare responses will generally be maximal
(Fig. 5). An approximate action spectrum can be deduced from this initial series of tests, and
a decision then made whether minimal urticarial dose testing is also needed. If so, this can
be undertaken by again using a geometric dose series and examining the skin 10 to 15
minutes later to determine the smallest dose needed just to induce wealing. Typically, at
doses slightly below the minimal urticarial dose, erythema alone is seen without weal or
flare, and this may be termed the minimal reaction dose. Finally, if patients are taking antihis-
tamines at the time of testing, any weal and flare responses may be inhibited, but erythema
localized to the irradiation field usually still occurs (10).
CHRONIC ACTINIC DERMATITIS

Phototesting with a monochromator is very appropriate in suspected CAD as it not only deter-
mines the presence and severity of any abnormal photosensitivity but also allows definition of
the responsible UV and visible wavebands. There are generally delayed responses, typically
both clinically and histologically eczematous, often following extremely low irradiation
doses at wavelengths nearly always including the UVB (Fig. 6). Where no monochromator is
available, however, the simpler and cheaper solar simulator (see above), with filters to allow
visible as well as UV testing, can instead provide sufficient information to make a probable
diagnosis of CAD. Also, in the absence of a solar simulator, MED testing with UVB and
UVA phototherapy units, with a slide projector as a visible light source, is an alternative
Appendix A 439
FIGURE 5 Investigating a patient with idiopathic solar urticaria. From the top of the back down, single exposures
were given at 300, 320, 350, 400, 450, 500, and 550 nm (bottom of back) to define the approximate action
spectrum (from 300 to 500 nm in this case). A series of reducing doses was then given at 300 nm and 350 nm in
an attempt to define the minimal urticarial dose.
approach. If such a slide projector is used, a few local normal subjects should be tested first
to determine suitable exposure times to avoid excessive skin heating, which may itself flare
eczema and lead to an incorrect CAD diagnosis. Finally, in resource-poor settings, the sun
can be used as a test irradiation source, both unfiltered and filtered with window glass, to
expose small areas of unaffected skin to the solar spectrum with and without UVB.
However, sunlight is unpredictably variable, making dose estimations difficult, while any
associated heat might again flare the rash, possibly leading to an incorrect diagnosis of CAD.
DRUG-INDUCED PHOTOSENSITIVITY
Drug-induced photosensitivity reaction patterns include sunburn-like phototoxicity, an UV-
induced dermatitis response, a porphyria cutanea tarda-like response, lichenoid reactions,
urticarial, and pigmentary abnormalities. For most forms of such photosensitivity, the
irradiation monochromator is again the most useful investigative tool. If abnormally
low delayed MEDs are seen, particularly in the UVA waveband (7), this supports drug
photosensitivity, but repeated testing is needed after the drug is stopped to confirm the
FIGURE 6 Minimal erythema dose testing at two wavelengths in a patient with chronic actinic dermatitis.
A palpable response has been obtained, which would show spongiotic eczema on biopsy.
440 Appendix A
diagnosis. However, patients must sometimes be off the drug (particularly quinine or bendro-
flumethiazide) for at least six months before the phototests return to normal.
OTHER DISORDERS
Similar provocation testing methods to those for PLE can induce the early lesions of hydroa
vacciniforme (11).
Abnormal phototest reactions may also be found in many patients with cutaneous por-
phyria. Typically, early urticarial reactions and low MEDs, usually lower at seven hours than
24, occur on visible light testing, such as at 400 and 430 nm. The porphyrias are definitively
diagnosed biochemically, but phototesting can sometimes help educate patients about the
role of daylight in inducing their rash, for instance, if marked urticarial responses occur in
erythropoietic protoporphyria, and can also help assess the responsiveness of the disorder to
therapies.
Finally, in some patients with lupus erythematosus (LE), repeated exposures to broad-
band UVA, UVB or both can induce abnormal reactions with histological changes in keeping
with LE (12).
REFERENCES
1. Waterston K, Naysmith L, Rees JL. Physiological variation in the erythemal response to ultraviolet
radiation and photoadaptation. J Invest Dermatol 2004; 123(5):958–964.
2. Gordon PM, Saunders PJ, Diffey BL, et al. Phototesting prior to narrowband (TL-01) ultraviolet B
phototherapy. Br J Dermatol 1998; 139(5):811 – 814.
3. Man I, Dawe RS, Ferguson J, et al. An intraindividual study of the characteristics of erythema induced
by bath and oral methoxsalen photochemotherapy and narrowband ultraviolet B. Photochem Photo-
biol 2003; 78(1):55 –60.
4. Diffey BL, Farr PM, Ive FA. The establishment and clinical value of a dermatological photobiology
service in a district general hospital. Br J Dermatol 1984; 110(2):187– 194.
5. Bilsland D, Diffey BL, Farr PM, et al. Diagnostic phototesting in the United Kingdom. Br J Dermatol
1992; 127(3):297– 299.
6. Mackenzie LA. The analysis of the ultraviolet radiation doses required to produce erythemal
responses in normal skin. Br J Dermatol 1983; 108(1):1– 9.
7. Diffey BL, Farr PM. The normal range in diagnostic phototesting. Br J Dermatol 1989; 120(4):
517 – 524.
8. Das S, Lloyd JJ, Walshaw D, et al. Provocation testing in polymorphic light eruption using fluorescent
ultraviolet (UV) A and UVB lamps. Br J Dermatol 2004; 151(5):1066–1070.
9. Hölzle E, Plewig G, Hofmann C, et al. Polymorphous light eruption. Experimental reproduction of
skin lesions. J Am Acad Dermatol 1982; 7(1)111 – 125.
10. Cox NH, Higgins EM, Farr PM. Terfenadine inhibits itch and wheal, but not abnormal erythema,
in physical urticarias. J Am Acad Dermatol 1989; 21:586– 587.
11. Sunohara A, Mizuno N, Sakai M, et al. Action spectrum for UV erythema and reproduction of the
skin lesions in hydroa vacciniforme. Photodermatol 1988; 5(3):139– 145.
12. Lehmann P, Hölzle E, Kind P, et al. Experimental reproduction of skin lesions in lupus erythematosus
by UVA and UVB radiation. J Am Acad Dermatol 1990; 22(2):181– 187.
Appendix Photopatch
Testing
B
Percy Lehmann
Klinik für Dermatologie, Allergologie und Umweltmedizin,
HELIOS-Klinikum Wuppertal, Universitätsklinikum der
Universität Witten-Herdecke, Wuppertal, Germany
Frank C. Victor and David E. Cohen

Ronald O. Perelman Department of Dermatology, New York
University School of Medicine, New York, New York, U.S.A.
INTRODUCTION
horough evaluation of any photosensitive patient can be difficult, there often being a
T legion of possible diagnoses. Where photoallergic contact dermatitis is suspected,

however, the photopatch test (PPT) is the most important diagnostic procedure, potentially
enabling correct diagnosis through identifying the responsible allergen or allergens. PPTs
should be performed in all patients with eczema of predominantly the sun-exposed skin, in
chronic actinic dermatitis, and as appropriate in other photosensitive disorders of uncertain
diagnosis.
Although the investigation of photopatch testing was first described as early as 1939 by
Epstein (1), the methodology used was not at all standardized until the early 1980s (2). Even
since then, however, it has continued to vary between dermatological centers and countries
with regard to every procedural aspect, namely the selection of test substances, their concen-
trations, the allergen vehicles, the time schedule for allergen application, the spectral distri-
bution of the irradiation sources, the irradiation doses, and the reading schedules for test
reactions (2).
In comprehensive multicenter studies in Scandinavia and later Germany, Austria, and
Switzerland (3–8) and in several other single center studies (9–12), however, continuing
efforts have been made to standardize PPT technique. The information gathered from
these has led to a greatly increased knowledge of the procedure, including, in particular, the vari-
ations and limitations in interpretation of its results. However, despite such efforts towards
standardization, PPT methodology still varies considerably between countries and centers.
WHO IN A CENTER SHOULD UNDERTAKE PHOTOPATCHTES?

For any given center, PPTs may be conducted by either dermatologists or nondermatologist
photobiologists. This itself has influenced PPT methodology, particularly with regard to how
and when allergens are irradiated. In 2001, a survey of 40 known PPT centers in Europe
yielded 34 replies, most (13) with separate photo-irradiation and contact allergy services. In
those with separate services, the patches were applied in the contact unit and the irradiations
performed by photobiology staff. Readings were also undertaken by the photobiology staff in
14 of these 21 centers, with contact staff performing them in seven. In the 13 centers with
combined units, the readings were always performed by the contact specialists.
TEST SUBSTANCES
A standard photoallergen tray should include all the local environmental agents known to be
photosensitizers. Such trays normally differ between centers, reflecting the geographic location
of the unit and the population being tested. Ideally, the tray should be regularly updated with
the addition of new potential photosensitizers within the population at risk and removal of
442 Appendix B
FIGURE 1 Photoallergic contact dermatitis.

Dermatitis affecting predominantly exposed sites.
older products no longer used. This information is best acquired from both published reports
incriminating new photoallergens and also large retrospective PPT studies, data from the latter
clearly demonstrating how photoallergens change in relevance over time. Thus, in a multicen-
ter study by Thune et al. (8), 1993 patients with a history and clinical features suggestive of
photosensitivity were photopatch tested between 1980 and 1985. Photoallergic contact derma-
titis was diagnosed in 10.9%, the fragrance, musk ambrette, being the most common photosen-
sitizer responsible for 20% of positive reactions, with para-aminobenzoic acid the second most
FIGURE 2 Photopatch test substances

applied in duplicate on the back.
Appendix B 443
FIGURE 3 Positive photopatch test reac-

tion (Right side) to ultraviolet filters. Nega-
tive test reaction at the unirradiated site
(Left).
common and responsible for 16%. Darvay et al. (13) also conducted a retrospective analysis of
2715 patients tested between 1983 and 1998, finding that of the 2.3% of patients with photoal-
lergic contact dermatitis, only 11% were sensitive to musk ambrette but 65% to ultraviolet (UV)
sunscreen filters, most commonly benzophenone-3. This decrease in musk ambrette prevalence
as a photosensitizer was the result of its removal from most world markets, whereas the UV
filter increase reflected their rapidly growing use.
In the United States, between 1985 and 1990, DeLeo et al. (11) photopatch tested 187
patients with photosensitivity. Eleven percent were diagnosed with photoallergic contact
dermatitis, most commonly from oxybenzone, with musk ambrette second. In another
United States study, Fotiades et al. (14) tested 138 patients between 1986 and 1993, diagnosing
photoallergic contact dermatitis in 12%. UV filters were again most commonly incriminated,
responsible for 57% of cases, with fragrances responsible for 18%. These studies clearly illus-
trate how photoallergen prevalence can change over just a few years, reflecting their frequency
of use in the population. The most common photosensitizers documented in retrospective PPT
studies conducted between 1980 and 2002 are listed in Table 1. Such fluxes in photosensitizer
prevalence reinforce the need for continuous re-evaluation of PPT allergen series.
Currently, organic sunscreens are the most common photoallergens in most populations
tested and should be included in all trays. In countries where topical nonsteroidal
TABLE 1 Most Common Photosensitizers in Retrospective Studies of Photopatch Testing (1980 –2002)
Number of Study
Location patients period % (1) Top allergens
Scandinavia (8) 1993 1980–1985 11 Musk ambrette, para-aminobenzoic acid, promethazine,
chlorpromazine
Minnesota (15) 70 1980–1985 20 Chlorpromazine, musk ambrette, promethazine
New York (11) 187 1985–1990 11 Sunscreen agents, antibacterials, fragrances
Austria, Germany, 1129 1985–1990 3.8 Tiaprofenic acid, fentichlor, carprofen,
Switzerland (7) 4-isopropyl-dibenzoylmethane
New York (14) 138 1986–1993 12 Sunscreens, fragrances, antimicrobials
Rotterdam (9) 44 1989–1994 9 Chlorpromazine, promethazine, musk ambrette
Austria, Germany, 1261 1991–1997 8.1 Fenticlor, carprofen, chlorpromazine,
Switzerland (7) 2-hydroxy-4-methoxybenzophenone
Australia (16) 81 1991–1999 39.5 Oxybenzone, benzophenone-4
France (17) 2067 1991–2001 41 Sesquiterpene lactone, ketoprofen, benzophenone,
dibenzoylmethane
India (18) 50 1994–1999 20 Musk ambrette, chlorpromazine, promethazine,
Balsam of Peru
Rotterdam (9) 55 1995–1999 27 Eusolex 8020, avobenzone, benzophenone-3
U.K., Europe (19) 1155 2000–2002 4 Oxybenzone
444 Appendix B
anti-inflammatory agents are routinely available, these agents should also be tested. It further
seems reasonable that historic photosensitizers such as tetrachlorosalicylanilide might still be
tested, as they may remain rare etiologic agents in chronic actinic dermatitis. A similar
phenomenon is now commonly recognized in this disorder with airborne agents such as
sesquiterpene lactone from Compositae plants (20), though this is more usually just a
contact allergen. In addition to the standard photoallergens, relevant other agents should
also be tested if there is an indication for this, such as, for example, chlorpromazine or in
farmers olaquindox. The inclusion of plant and pesticide allergens has also been recom-
mended (21). Thus, a modern photoallergen tray should integrate all photosensitizers relevant
to the population being tested, with additional trays for special cases as suggested by the
history. A comprehensive photoallergen series with recommended supplements is listed in
Table 2.
Ultraviolet Dose
Although our knowledge of wavelength dependency for photoallergen activation is incom-
plete, the UVA (315 –400 nm) radiation band is regularly used for photopatch testing, largely
because most photoallergens for which information is available do react to this waveband.
However, the irradiation doses used vary between centers, generally ranging between 5 and
15 J/cm2, with 5 J/cm2 being usual in Scandinavia, England, and Australia and 10 J/cm2 in
the United States. In patients with a known photosensitivity disorder such as chronic actinic
dermatitis, however, a lower dose is often necessary to avoid flaring the underlying disease,
some centers in fact performing minimal erythema dose (MED) testing beforehand and
using 50% of the MED-A as the test dose (22).
METHODOLOGY
Despite the efforts toward standardization, PPT methodology varies between institutions. In all
centers, however, duplicate sets of test materials should be applied in a similar array to both
sides of the patient’s back, starting 3 cm lateral to the vertebrae so as to avoid the paravertebral
groove. MED testing may also be performed if necessary at this time. At 24 or 48 hours after
application, one set of test agents should be uncovered, revealing the allergen-exposed sites
for irradiation by a reliably calibrated and metered broad-spectrum UVA source. The duplicate
allergen set on the contralateral back should remain fully covered and UV-protected through-
out. Initial and follow-up PPT readings are then performed at specified times afterwards as
discussed below. Details of PPT methodology as performed at the New York University Skin
and Cancer Unit are depicted in Table 3.
There has been little consideration of exactly when allergens should be irradiated after
their application, apart from in one retrospective review of 74 patients tested with three iden-
tical photoallergen sets, one irradiated at 24 hours, one at 48, and one nonirradiated as a control
(23). There were 49 positive results in 15 patients, 34 consistent with photoallergy. Thirteen of
these 34 were positive in both irradiated sets, five only in the set irradiated at 24 hours and 16
only in that at 48 hours. The authors therefore concluded that irradiation 48 hours after
application might be more sensitive, given the greater number of positive results only in that
set. Nevertheless, further studies are needed to confirm this, as well as to investigate the
bioavailability of allergens at various application and irradiation times.
INTERPRETATION
Times at which PPT readings should be performed as well as the interpretation of results also
vary between centers. A first reading should however be performed at either 24 or 48 hours
after irradiation, with a second generally at 72 or 96 hours. The European consensus group
has also agreed, in contrast with some previous recommendations in the literature (24), that
readings should be recorded according to the International Contact Dermatitis Research
Group scoring system (Table 4). Thus, they should include pre-irradiation, immediate post-
irradiation, and 48-hour post-irradiation assessments. Further readings are also recommended
Appendix B 445
TABLE 2 Comprehensive Photoallergen Series

1 Octinoxate
2 Sulisobenzone (BZP-4) 10%
3 Thiourea (thiocarbamide) 0.1%
4 Dichlorophene 1%
5 Triclosan 2%
6 Hexachlorophene 1%
7 Chlorhexidine diacetate 0.5%
8 Sandalwood oil 2%
9 Musk ambrette 1%
10 Oxybenzone (BZP-3) 10%
11 Fenticlor (thiobis-chlorophenol) 1%
12 Para-aminobenzoic acid 10%
13 Octisalate
14 Tribromosalicylanilide 1%
15 Menthylanthranilate 5%
16 Sesquiterpene lactone mix 0.1%
17 Lichen acid mix 0.3%
18 Ketoprofen 5%
19 2-Hydroxy-methoxy-methyl-benzophenone 10%
20 Bithionol (thiobis-dichlorophenol) 1%
21 Octyldimethyl para-aminobezoic acid 10%
22 Phenylbenzimidazole sulphonic acid 10%
23 Homosalate 5%
24 Butyl methoxydibenzoylmethane 5%
25 Octyl methoxycinnamate 10%
26 4-Methylbenzylidene camphor 10%
27 Isoamyl p-methoxycinnamate 10%
28 Naproxen 5% in petrolatum
29 Ibuprofen 5% in petrolatum
30 Diclofenac 1% in petrolatum
31 Ketoprofen 2.5% in petrolatum
32 Tetrachlorosalicylanilide
33 Bromosalicylchloranilide
34 Buclosamide
35 Chlorpromazine
36 Chamomilla romana
37 Diallyldisulfide
38 Arnica montana
39 Taraxacum officinale
40 Achillea millefolium
41 Propolis
42 Chrysanthemum cinerariaefolium
43 Sesquiterpene lactone mix
44 A-methylene-Y-butyrolactone
45 Tanacetum vulgara
46 Alantolactone
47 Lichen acid mix
48 Captan
49 Zineb
50 Captafol
51 Maneb
52 Folpet
53 Pyrethrum
54 Benomyl
55 Ziram
Note: North American Contact Dermatitis Group Photoallergen Series
(1– 24). New York University Skin and Cancer Unit Supplemental
Series (36– 55).
446 Appendix B
TABLE 3 Methodology of Photopatch Testing as Performed at New York University Skin and Cancer Unit
Day 1 Perform MED testing. Apply duplicate sets of photoallergens on left and right back
Day 2 Read MEDs. Irradiate one set of allergens with UVA (10 mJ/cm2 or 50% of MED-A,
whichever is less), covering the other with an opaque material
Day 3 Remove nonirradiated patches and perform first reading of reactions to both sets of photoallergens
(irradiated and nonirradiated sites)
Day 5 Perform second reading of reactions to both sets of photoallergens
TABLE 4 International Contact Dermatitis Research Group Scoring System

+ Doubtful reaction (faint erythema only)
þ Weak positive reaction (erythema, infiltration, possibly papules)
þþ Strong positive reaction (erythema, infiltration, papules, vesicles)
þþþ Extreme positive reaction (intense erythema, infiltration,
coalescing vesicles or bulla
IR Irritant reaction
NT Not tested
at 72 and 96 hours to detect reaction patterns such as crescendo, decrescendo, combined or

plateau, suggesting allergic, nonallergic, or combined mechanisms, respectively. This full
assessment of such variations can be particularly important and sometimes specific for a
photosensitizer (25), especially agents with phototoxic and photoallergic potential (26).
The interpretation of PPTs as used in most United States centers is outlined in Table 5. If
there is no reaction at either the irradiated or the nonirradiated sites, this is interpreted as an
absence of contact or photocontact allergy. If there is a positive reaction only at the irradiated
site, this is interpreted as just photocontact allergy. If there is an equally positive reaction at
both sites, this is considered as just contact allergy. Finally, if there are positive reactions at
both sites but more marked at the irradiated site, a diagnosis of combined contact and photo-
contact allergy is made. There is variation among centers in regard to this last interpretation;
however, both the United States Mayo Clinic and Scandinavian groups regard a positive
reaction at both sites as representative only of contact allergy, even if one reaction is more posi-
tive than the other. However, there has been no formal validation of this. Although it would
seem logical that a reaction of greater intensity at an irradiated site compared with a non-
irradiated one would establish combined contact and photocontact allergy, the converse
argument is also possible. Thus, concordance studies in the evaluation of patch test results
have shown that positive reactions are not always reproducible in intensity. Rietschel et al.
(27), for example, evaluated 48 patients with known positive response to epoxy resin, nickel,
and ethylenediamine by both the Finn Chamber and True Test methods, and found equal inten-
sities 67% of the time, but clear differences on 27% of occasions. It therefore seems that reactions
of different intensities to the same allergen in the same patient are possible through testing pro-
cedure limitations and perhaps also site-specific immunological variations. Repeat PPTs in any
given patient would clearly always be necessary to try and assess the true situation.
TABLE 5 Interpretation of Photopatch Tests

Reading
Diagnosis Irradiated site Nonirradiated site
No sensitivity 2 2
Photocontact allergy þ 2
Contact allergy þ þ
Photocontact allergy and þþ þ
contact allergya
a
The Mayo Clinic and Scandinavian groups do not recognize a diagnosis of combined photoallergy and
contact allergy. This outcome would be read as contact allergy only.
Appendix B 447
Nevertheless, it is essential that PPT interpretation guidelines should always remain consistent
within a given center.
RELEVANCE
Subsequent to the evaluation of PPT reactions, an interpretation of their relevance to the patient
is also essential. A system developed for the similar assessment of positive patch test reactions
(COADEX) (28) may also be used for PPTs as follows:
B Current relevance (the patient has had allergen exposure during the current episode of
dermatitis and improved when exposure ceased)
B Cross-reaction (the patient has had exposure to a cross-reacting allergen)
B Old or past relevance (the patient has had a past dermatitis from allergen exposure)
B Actively sensitized (the patient has presented with a late sensitization reaction from
allergen exposure during testing)
B Do not know (the patient has had allergen exposure but it is not clear if this is current or old)
B EXposed (the patient has a history of allergen exposure but no dermatitis or no history of
exposure but a definite positive allergic patch test).
[C, current; O, old; A, actively sensitized; D, do not know; EX, exposed (COADEX)].
CONCLUSION
Photopatch testing remains the gold standard for the detection of chemical substances respon-
sible for the onset and perpetuation of dermatitis on photo-exposed skin. It is also the only
established method potentially able to distinguish between contact and photocontact allergy.
Although some variability exists worldwide regarding the methodology of such testing,
these differences may be clinically minimized through a careful study of the at-risk population
and its allergen exposure and the consistent execution of established PPT protocols.
REFERENCES
1. Epstein S. Photoallergy and primary photosensitivity to sulphanilamide. J Invest Dermatol 1939;
2:43– 51.
2. Hölzle E, Plewig G, Hoffmann C, Braun-Falco O. Photpatchtesting: results of a survey on test
procedures and experimental findings. Z Hautkr 1985; 151:361 –365.
3. Hölzle E, Neumann J, Hausen B, et al. Photopatch testing: the 5-year experience of the German,
Austrian, and Swiss Photopatch Test Group. J Am Acad Dermatol 1991; 25:59– 68.
4. Jansen CT, Wennersten G, Rystedt I, Thune P, Brodthagen H. The Scandinavian standard photopatch
test procedure. Contact Dermatitis 1982; 8:155– 158.
5. Neumann NJ, Hölzle E, Plewig G, et al. Photopatch testing: the 12-year experience of the German,
Austrian, and Swiss photopatch test group. J Am Acad Dermatol 2000; 42:183 – 192.
6. Neumann NJ, Fritsch C, Lehmann P. Photodiagnostic test methods. 1: stepwise light exposure and the
photopatch test. Hautarzt 2000; 51:113 – 125.
7. Neumann NJ, Lehmann P. The photopatch test procedure of the German, Austrian and Swiss
photopatch test group. Photodermatol Photoimmunol Photomed 2003; 19:8– 10.
8. Thune P, Jansen C, Wennersten G, Rystedt I, Brodthagen H, McFadden N. The Scandinavian
multicenter photopatch study 1980– 1985: final report. Photodematol 1988; 6:261 – 269.
9. Bakkum RSLA, Heule F. Results of photopatch testing in Rotterdam during a 10-year period. Br J
Dermatol 2002; 146:275– 279.
10. Berne B, Ros AM. 7-years experience of photopatch testing with sunscreen allergens in Sweden.
Contact Dermatitis 1998; 38:61– 64.
11. DeLeo VA, Suarez SM, Maso MJ. Photoallergic contact dermatitis: results of photopatch testing in
New York; 1985 – 1990. Arch Dermatol 1992; 128:1513– 1518.
12. Schauder S, Ippen H. Contact and photocontact sensitivity to sunscreens: review of a 15-year
experience of the literature. Contact Dermatitis 1997; 37:221– 232.
13. Darvay A, White IR, Rycroft RJG, Jones AB, Hawk JLM, McFadden JP. Photoallergic contact derma-
titis is uncommon. Br J Dermatol 2001; 145(4):597– 601.
14. Fotiades J, Soter NA, Lim HW. Results of evaluation of 203 patients for photosensitivity in a 7.3-year
period. J Am Acad Dermatol 1995; 33:597– 602.
448 Appendix B
15. Menz J, Muller SA, Connolly SM. Photopatch testing: a six-year experience. J Am Acad Dermatol
1988; 18:1044– 1047.
16. Lee PA, Freeman S. Photosensitivity: the 9-year experience at a Sydney contact dermatitis clinic.
Australas J Dermatol 2002; 43:289– 292.
17. Leonard F, Adamski H, Bonnevalle A, et al. The prospective multicenter study on standard photo-
patch tests by the French Society of Photodermatology from 1991– 2001. Ann Dermatol Venereol
2005; 132(4):313– 320.
18. Kanchan PA, Shenoi SD, Balachandran C. Five years’ experience of photopatch testing in 50 patients.
Indian J Dermatol Venereol Leprol 2002; 68:86– 87.
19. Bryden AM, Ibbotson SH, Ferguson J. Photopatch testing: results of the U.K. multicentre photopatch
study. Br J Dermatol 2003; 149(suppl 64):3.
20. Lim HW, Cohen D, Soter NA. Chronic actinic dermatitis: results of patch and photopatch tests with
Compositae, fragrances, and pesticides. J Am Acad Dermatol 1998; 38:108 – 111.
21. Mark KA, Brancaccio RR, Soter NA, Cohen DE. Allergic contact and photoallergic contact dermatitis
to plant and pesticide allergens. Arch Dermatol 1999; 135(1):67– 70.
22. Przybilla B, Hölzle E, Enders F, Gollhausen R, Ring J. Photopatch testing with different ultraviolet A
sources can yield discrepant test results. Photodermatol Photoimmunol Photomed 1991; 8:57 – 61.
23. Batchelor RJ, Wilkinson SM. Photopatch testing—a restrospective review using the 1 day and 2 day
irradiation protocols. Contact Dermatitis 2006; 54:75– 78.
24. Bruynzeel DP, Ferguson J, Andersen K, et al. Photopatch testing: a consensus methodology for
Europe. J Eur Acad Dermatol Venereol 2004; 18:679– 682.
25. Neumann NJ, Hölzle E, Lehmann P, Benedikter S, Tapernoux B, Plewig G. Pattern analysis of
photopatch test reactions. Photodermatol Photoimmunol Photomed 1994; 10:65– 73.
26. Neumann NJ, Hölzle E, Lehmann P. Guidelines for phototoxic and photoallergic reactions. J Dtsch
Dermatol Ges 2004; 2:710 – 716.
27. Rietschel RL, Marks JG, Adams RM, et al. Preliminary studies of the TRUE Test patch test system in
the United States. J Am Acad Dermatol 1989; 21:841– 843.
28. Bourke J, Coulson I, English J. Guidelines for care of contact dermatitis. Br J Dermatol 2001; 145:
877 – 885.
Appendix Guidelines for Setting Up
a Phototherapy Referral
C Center or an Office-Based
Phototherapy Unit
Michael Zanolli
Division of Dermatology, Vanderbilt University Medical Center,
Vanderbilt University, Nashville, Tennessee, U.S.A.
Roy Palmer
Photobiology Unit, St. John’s Institute of Dermatology,
St. Thomas’ Hospital, London, England, U.K.
INTRODUCTION
hototherapy for psoriasis and other photoresponsive dermatoses remains an essential
P therapeutic tool for a dermatologist. Specialized facilities with the full range of irradiation
options serve as a major resource for the region or city they serve. In general, such a photo-
therapy referral center is located in a densely populated urban area to serve a large referring
physician and patient base, and should preferably also be the location for photodiagnostic pro-
cedures to help evaluate difficult photodermatoses. In a less-populated local community or
rural region, the needs and basic services clearly differ from those of such a major referral
center. Although a small office- or clinic-based phototherapy unit will be limited in equipment
and staffing, the majority of patients likely to undergo the treatment will have psoriasis and
need only simple whole-body UVB treatment as either broadband (BB) or narrowband (NB)
UVB. These patients are better served locally rather than needing to travel to a major center,
where specialized treatments such as bath psoralen plus ultraviolet A (PUVA) or UVA-1
therapy will also be available at a site designed to accommodate a high volume of patients.
Much is justifiably made of the sophisticated equipment and physical facilities necessary
for the high quality patient evaluations and treatment offered at such centers. The experience of
the authors however also recognizes the invaluable contributions of their staff, also a major
contribution in office-based units. The dermatologist can certainly evaluate and set forth an
appropriate course of action but unless there are trained personnel to execute and monitor
the treatments, the results will often not be optimal or even effective. Careful consideration
must therefore be given to dedicated staffing when planning a center and also when consider-
ing adding an ultraviolet (UV) unit in the office.
The guidelines set forth here concerning the two main type of treatment settings
mentioned above are intentionally concise and discuss only the essential points needed.
PHOTOTHERAPY REFERRAL CENTER (TABLE 1)

Space
Within the hospital, a phototherapy unit benefits greatly from being close to the dermatology
outpatient center, to ensure close cooperation between the two units. This phototherapy center
needs its own reception and waiting area, in addition to individual patient phototherapy rooms
or cubicles, a bath or shower facility, a storage area, and a patient lounge.
When determining the number of treatment rooms or cubicles required, it should be
remembered that a minimum patient treatment slot is about 15 minutes. Therefore, given
that a typical unit is open for about eight hours per day, and that some patients may wish
for or need twice weekly therapy (Tuesday and Thursday) and others three times weekly
450 Appendix C
TABLE 1 Requirements for a University Center

Treating Approximately 75 Patients Per Week with
Phototherapy
Space 80 m2
Equipment 1 UVA whole-body unit
1 Medium dose UVA-1 unit (optional)
1 NBUVB whole-body unit
1 BBUVB whole-body unit
1 combined NBUVB/UVA whole-body unit
1 Canopy unit
1 Bath
1 Hand-foot unit or localized delivery unit
1 Shower
Waiting room
Reception area
Storage room
Staff 2 Full-time nursing staff
1 Administrative staff (receptionist)
Abbreviations: BBUVB, broadband ultraviolet B; NBUVB, narrow-
band ultraviolet B.
(Monday, Wednesday, and Friday), the theoretical maximum number of patients able to be
treated each week in one room or cubicle is 64. In reality, however, taking account of logistical
factors, it will be less than this. Some phototherapy cabinets offer a choice of two types of
lamp giving increased flexibility, but each exposure then takes longer because of the decreased
irradiance from the smaller numbers of each lamp type. The special electrical supply required
needs to be installed in collaboration with a competent electrician and, in many cases, will be
of relatively high voltage such as, for example, 415 V. Dedicated air flow, both intake and
outlet, and cooling systems are essential within the treatment rooms or cubicles to maintain
a comfortable temperature and efficient functioning of the lamps, since major heat output is
a by-product of all irradiation units. This is an even more critical consideration if a UVA-1
unit is installed, whether for high or medium dose irradiation.
Most stand-up commercial irradiation cabinets measure approximately 1.4 1.4 m, and a
similarly sized adjoining area is required for the patient to undress. Curtains suspended from
the ceiling, or room walls and doors, are essential to provide patient privacy in the undressing
area. Hand and foot units on the other hand measure approximately 0.7 0.7 m and do not
necessarily require such a large adjoining area or any partitioning. Localized UVB delivery
is also now available from units on desktops or on carts, to enable transport from room to room.
The waiting area is important because it may often be where patients spend most of their
time: magazines, music, and educational posters should be made available as appropriate.
A floor of nondark color so as to conceal any psoriatic scale is preferable. A shower for patients
who perspire significantly during treatment and to wash off topical therapies is also essential.
Finally, storage areas are necessary for spare lamps, towels, gowns, pillowcases, emollients,
sunscreens, and cleaning supplies.
Staff
A receptionist, phototherapy technician, who may often be a nurse, and a lead nurse are the
core staffing. Either special training at courses designed for phototherapy technicians or a
set of procedures to be taught by the lead nurse is essential to achieve the level of care required
of a phototherapy center, especially since nursing school curricula do not provide adequate
course work for this.
Flexibility within the working week is another important point for consideration. In most
instances, phototherapy is optimally delivered two or three times weekly, and many patients
therefore prefer the convenience of attending slightly outside normal working hours, so a
center offering appointments between 8 am and 7 pm on at least two days a week is much
Appendix C 451
appreciated. It should also be remembered that many other patients prefer their treatments at
peak hours, such that multiple treatments will be needed simultaneously, and staffing arrange-
ments should take note of this. Further, it is not unusual for patients to arrive early or late, or to
have taken their psoralen medication at the wrong time, or to have additional requirements
such as requests for advice concerning topical therapies, and flexibility to cope with these vari-
ations is also essential. Procedure manuals should provide full guidelines concerning all these
matters.
Equipments
Stand-Up Whole-Body Units
For most patients affected by generalized eruptions, these are most appropriate. Such units
should always be open at the top to allow heat release and give patients a less claustrophobic
impression.
Hand and Foot Units

Hand and foot units are very useful, both for supplemental treatment to palms and soles for
patients having whole-body therapy, and also for the dedicated therapy of those only affected
on the hands and feet. Palms and soles respond very poorly to BB and usually also NBUVB
therapy, and PUVA units are therefore preferable for this therapy.
Canopy Units
These consist of flat or nearly flat panels of lamps for the treatment of localized areas. They
are also useful for minimal erythema dose (MED) and minimal phototoxic dose (MPD)
testing prior to whole-body phototherapy, provided that the lamps are the same as those in
the whole-body units and that the lamp calibrations are in close agreement. They are useful
too for UVA delivery during diagnostic photopatch testing and also for provocation testing
in abnormal photosensitivity.
Localized Delivery
The excimer laser is a self-contained unit not requiring a separate cooling supply, which may be
used to target localized psoriatic lesions. More recent compact BB and NBUVB delivery
systems are also available, and these may also be conveniently placed on a desktop or else
on a cart for easy transport from room to room.
Fluorescent Lamps
Broadband UVB
Two of the commonest of these are the Waldmann UV6 and Waldmann UV21 lamps, the latter
identical also to the Philips TL-12. The output of all is predominantly within the UVB range, but
the UV21 and TL-12 tubes emit a greater proportion of wavelengths below 290 nm, more
erythemogenic, and also ineffective against psoriasis (1), such that the UV6 is theoretically
preferable for BBUVB phototherapy.
Narrowband UVB (TL-01)

These Philips lamps have a very narrow emission spectrum, emitting predominantly within
the range of 311 to 312.
PUVA
There are several UVA lamps marketed for PUVA therapy, all with similar emission spectra and
all appropriate for such use.
Ultraviolet A-1
There is a major distinction between the equipment necessary to deliver high dose and medium
dose UVA-1 phototherapy. Only very specialist referral centers will wish to provide the major
weight bearing and demanding cooling requirements necessary for high dose systems.
However, medium dose units are similar in size and specification to routine PUVA units,
apart from their much longer treatment times and greater heat generation.
452 Appendix C
All the above lamps also emit at least some visible light, such that it is clear when they are
switched on. In addition, they should have Perspex screens or Teflon sleeves to protect patients
from falling against and breaking them, although still allowing adequate UV transmission.
They will also prevent injury if a lamp implodes, which is very rarely possible.
Procedures
Dosimetry
In the past, some centers have used treatment times as the only monitored variable. This
is extremely undesirable, however. A knowledge of the actual dose administered through accu-
rate dosimetry being essential for safe phototherapy. There are two options to achieve this:
1. Automatic dosimetry (radiometry). In this situation, the operator enters the dose to be admi-
nistered, and a built-in dosimeter measures the accumulating radiation during exposure
before terminating the session, when the desired dose has been achieved. This is
convenient, but for safety any such unit should sound an immediate alarm if the measured
irradiance suddenly decreases, suggesting that the patient’s body may suddenly have
blocked the detector. The detector should also be cleaned regularly to remove any dirt
obscuring it. Internal dosimeters require regular checks for accuracy, for example, every
six months, as described next.
2. Intermittent dosimetry (radiometry). In this case, the output of the unit is regularly
measured, for example, every four weeks. This measured output is then used to calculate
the exposure time required according to time ¼ dose/irradiance, such that for each treat-
ment the operator enters the time to be administered.
Calibration of dosimeters has been found to vary considerably between centers, NBUVB
output measurements varying by a factor of at least 2.7 between units in the United Kingdom
(2). A detailed description of dosimetry and calibration procedures is provided elsewhere (3),
but in brief, preferably under the supervision of a medical physicist or the cabinet manufac-
turer’s engineer, the irradiance within a stand-up unit may be checked accurately with a radio-
meter on a tripod (“indirect method”), or else by a member of staff in protective clothing
standing within the unit holding the dosimeter (“direct method”). This latter method produces
a reading more accurately representing “real-life” patient irradiance, and is typically 20% less,
depending on the cabinet design, than the former. If this variation is always taken into account
through the use of the appropriate “shielding factor” to correct up to the true dose, the indirect
method is acceptable. Shielding factors for some cabinets have been published (4), but should
be checked at least annually for each cabinet to allow for possible changes in the unit’s optical
properties. Dosimeters themselves also require validation, preferably annually, by a recognized
physics laboratory. Finally, within any center, all these procedures for dosimetry should be rig-
orously standardized.
Records should also be kept by each unit detailing the dates of lamp replacement,
numbers of hours of lamp use, and dosimeter calibration dates with the measured irradiances
at those times.
Because changes in lamp temperature during operation influence their output, manufac-
turers’ advice on lamp warming prior to the therapy should always be followed if a lamp has
been allowed to cool, and especially at the start of a working day.
Lamp Changes
By 12 hours of use, lamp outputs will have always reduced by approximately 10%, by 2000
hours by more than 50%, and by 3000 hours they will have ceased to function entirely. There
are two approaches to dealing with this:
1. Replacing all lamps at 1000 to 2000 hours. This has the disadvantages of being costly and
resulting in abrupt output changes requiring fresh calibration.
2. Waiting until approximately three or four lamps within a unit have ceased to operate and
replacing only those. If the unit dosimeter is not built in, it will have to be recalibrated at
Appendix C 453
this time. Treatment times will be longer with this approach but output changes with new
lamps will be less marked.
Therapy Guidelines
The administration of phototherapy requires many choices, examples including the following.
Will the center employ starting doses based on skin type, or MED and MPD testing? If the
former, will localized test doses be administered beforehand to exclude pathological photo-
sensitivity? If the latter, what anatomical site will be used to test the MED or MPD, and
what will be the timing of the MPD reading (72 or 96 hours)? What doses will be used to
assess the MED and MPD? For bath PUVA, what concentration of psoralen will be used in
the bath water? Will there be a maximum dose for therapy?
Unfortunately, for many such issues the evidence base is weak. However, some off-the--
shelf guidance is available, as in “Phototherapy Treatment Protocols” (5) and “Evidence-Based
Phototherapy Guidelines” (6).
Recording Treatments
Computerized methods for recording patient exposure data have been developed but are infre-
quently used, paper records still being usual. Whatever method is used, however, it is essential
to record the following at each patient visit: date of visit, patient side effects after last
session, increment in dose since previous visit, exposure dose at this visit, cumulative dose,
additional or reduced therapy to particular anatomical sites, and exposure time if an external
dosimeter is used.
In most major phototherapy centers, patient phototherapy records are kept separately
from the main hospital notes. It is therefore highly beneficial if the number of phototherapy ses-
sions, cumulative dose, side effects, and efficacy of therapy are made available to the dermatol-
ogist by the phototherapy unit for patient consultations.
Safety Guidelines
In most settings, local rules for UV installations apply. These details, for example, that eye
protection for staff and patients is mandatory, and that eyewear should be checked regularly
for UV transmission. For staff working close to cabinets, it is also important that the environ-
mental UV level be checked when open-topped cabinets are switched on; U.K. regulations
state that UVA exposure should not exceed 1 mW/cm2. This is facilitated if the ceiling is not
reflective, and high curtains surround the cabinets.
Forms
Arrangements should be made prior to therapy for patients to receive information about their
therapy in the form of a handout (describing, for example, the importance of using emollients,
correct posture in the cabinet, proper use of eye protection, and so on) and sign a consent form.
Arrangements to review the patient every 6 to 10 sessions should be made. For children,
phototherapy units may be very daunting, and time should be spent explaining to them
how the machine works and how it helps their skin. Regular audit of activity is also important
to ensure continuing effective and safe phototherapy.
Ancillary Equipment
In addition to the equipment above, many other miscellaneous items are essential, particularly
goggles, visors, glasses, pillowcases, gowns, sunscreens, stopwatches, and a hand-held
dosimeter to ensure there is no UV transmission through patients’ spectacles.
OFFICE-BASED PHOTOTHERAPY UNIT

Space
The estimate of one treatment every 15 minutes holds true for both office and hospital clinic-
based phototherapy units. The room used for the phototherapy does not have to be any
454 Appendix C
larger than a normal clinic examination room and should be an integral part of the design of the
clinic also accommodating patients, administrative staff, nurses, and dermatologists. Storage
space for eye protection, gowns, and other immediate necessities for treatment can be kept
in this same room.
The modifications to an existing examination room needed to transform it into a
phototherapy room are: special electrical requirements dependent on manufacturers’
regulations and local requirements, probable modifications to the air intake and outflow
systems to permit increased heat disposal, and privacy curtains for patient dressing and
undressing.
Staff
There should not be any need for added personnel in the office or hospital clinic while a new
phototherapy service is being initiated, just a slight adjustment to the normal clinic flow to
enable a nurse to act also as a phototherapy technician. However, as the number of photo-
therapy treatments moves above 15 treatments a day, the unit will come to need more space
and staffing.
Equipment
Whole-Body Unit
The single most useful phototherapy unit is an upright whole-body cabinet, whereas the most
useful and safest therapeutic waveband for the widest variety of problems seen in the private
office or hospital clinic is NBUVB. A question the clinician must also address is whether or not
there is a need for PUVA to treat cutaneous Tcell lymphoma (CTCL) in the clinic. If not, because
CTCL patients are referred to a major phototherapy center, an NBUVB unit will provide
treatment for most patients requiring UV therapy, although severe psoriatics may sometimes
do better with PUVA. In addition, there are also creditable reports of efficacy for stages 1A
and 1B CTCL with NBUVB.
Combination units offering both NBUVB and UVA lamps are an option for units wishing
to provide both NBUVB and PUVA. However, this approach will lengthen the time needed for
both treatments, since the numbers of lamps in the unit providing each will be smaller.
Another consideration is to make available a localized delivery system for UVB offering a
small spot size. These units are now more readily available and obviate the need for a laser
device. They might also be used for localized treatment of the hands and feet, so avoiding
the need for a separate hand and foot fluorescent unit.
Procedures
Dosimetry
Dosimetry is just as important for the single unit in the office as for a large treatment center.
Internal dosimetry is more convenient in most cases since patients will not be switching
cabinets during a treatment course, as often happens in a large center. Even so, periodic cali-
bration of the internal sensor should be undertaken as described above for major referral
centers to ensure accurate UV dose calculation, particularly as patients moving to another
city will need to take a correct dose record with them for future treatment.
Lamp Changes
This is the major expense of the unit after the initial cabinet purchase cost. Lamp life depends
on the number of hours of use. Two approaches for changing lamps have been previously
suggested for major referral centers. In an office or clinic with only one unit, however, it is
easier to change all the lamps at one time, either after 2000 hours of operation or once the
irradiance of a unit appreciably diminishes. This decreases the need for lamp storage and
also prevents uneven distribution of light within the cabinet.
Appendix C 455
Therapy Guidelines
Protocols are available for both MED-based treatments and treatment courses based on the
Fitzpatrick skin type of the individual. Attending nursing staffs need a set protocol to enable
them to advance patient therapy, without constant review by the attending physician. Measure-
ment of the MED is not a complicated procedure even in an office-based treatment setting, and
gives valuable information such as a basis for the treatment starting dose and also whether
there may be abnormal patient photosensitivity.
Defined protocols as stated above are available in at least two manuals, namely
“Phototherapy Treatment Protocols” (5), and “Evidence-Based Phototherapy Guidelines” (6).
Recording Treatments
It is essential that the following information be recorded each time a patient visits the unit: date
of visit, side effects after last session, increment in dose since previous visit, exposure dose at
this visit, cumulative dose, additional or reduced therapy to particular anatomical sites, and
exposure time if an external dosimeter is used. Examples of such daily treatment records
are again available in the referenced treatment protocol and treatment guidelines manuals
previously mentioned (5,6).
Safety Guidelines
In most settings, the development of specific local rules for UV installations is essential. These
will detail, for example, that eye protection for staff and patients is mandatory and that
eyewear must be checked regularly for efficacy of UV protection. Close to cabinets, it is import-
ant that the environmental UV level be checked when open-topped cabinets are switched on;
U.K. regulations, for example, state that UVA exposure should not exceed 1 mW/cm2. This is
easier to achieve if the ceiling is not reflective, and high curtains surround the cabinets.
Forms
Arrangements should be made prior to therapy for patients to sign a consent form, receive a
handout containing information about their therapy (describing, for example, the importance
of using emollients, correct posture in the cabinet, proper use of eye protection, and so on).
Arrangements for the attending physician to review the patient every 6 to 10 sessions
should also be made. For children, phototherapy units may be very daunting, and time
should therefore be spent explaining to them how the machine works and how it helps their
skin. Regular audit of activity is also important to ensure continuing effective and safe
phototherapy.
REFERENCES
1. Ibbotson SH, Bilsland D, Cox NH. An update and guidance on narrowband ultraviolet B phototherapy:
a British Photodermatology Group Workshop Report. Br J Dermatol 2004; 151(2):283–297.
2. Lloyd JJ. Variation in calibration of hand-held ultraviolet (UV) meters for psoralen plus UVA and
narrow-band UVB phototherapy. Br J Dermatol 2004; 150(6):1162—1166.
3. Taylor DK, Anstey AV, Coleman AJ, et al. Guidelines for dosimetry and calibration in ultraviolet
radiation therapy: a report of a British Photodermatology Group workshop. Br J Dermatol 2002;
146(5):755– 763.
4. Moseley H. Scottish UV dosimetry guidelines, “ScUViDo”. Photodermatol Photoimmunol Photomed
2001; 17(5):230– 233.
5. Zanolli MD, Feldman SR, eds. Phototherapy Treatment Protocols for Psoriasis and Other Phototherapy
Responsive Dermatoses. 2nd ed. London: Taylor and Francis, 2005.
6. Palmer RA, Garibaldinos T, Hawk JLM. Evidence-Based Phototherapy Guidelines. Available from:
Dr Roy Palmer, Photobiology Unit, Second Floor, St. John’s Institute of Dermatology, St. Thomas’
Hospital, London, U.K.
FURTHER READING
Coleman AJ. A Template of Local Rules for Operation of a Phototherapy Unit.
Available from: Dr AJ Coleman, UV Calibration Unit, Medical Physics Department,
St. Thomas’ Hospital, London, U.K.
456 Appendix C
Morison WL. Phototherapy and Photochemotherapy of Skin Disease. 3rd ed. Taylor and
Francis, 2005.
Taylor CR, Ortel B. Basic guidelines on the establishment of a UVB/PUVA treatment
centre. Appendix C. In: Hawk JLM, ed. Photodermatology. London: Arnold, 1999.
Appendix Guidelines for Setting Up
a Laser Center
D
Macrene R. Alexiades-Armenakas
Department of Dermatology, Yale University School of Medicine,
New Haven, Connecticut, U.S.A.
Jeffrey S. Dover
Department of Dermatology, Yale University School of Medicine,
New Haven, Connecticut, and Dartmouth Medical School, Hanover,
New Hampshire, U.S.A.
INTRODUCTION
n setting up a laser center, the major considerations include the selection of lasers for the
I practice and laser safety guidelines. The major categories of laser and light treatment,
including treatment of vascular and pigmented lesions, hair removal, tattoo removal,
wrinkle reduction, and skin rejuvenation, should ideally be offered in a comprehensive unit.
At least one device should be selected in each category and strict laser safety guidelines and
staff training should be implemented. Laser use standards must be maintained among laser
practices to ensure proper protection to office staff and patients.
LASER SELECTION
Tables 1 – 4 list the most commonly employed laser systems in each main category of treatment.
A thorough examination of each group should be considered along with the patient population
in one’s practice. For example, if one is commonly treating facial erythema and telangiectasia,
more than one laser from the vascular category might be selected. If one’s practice treats a
significant proportion of dark-skinned patients, lasers that are safest in this patient group
should be selected from each category. In most cases, at least one laser or other light source
should be selected from each category.
LASER SAFETY
The other crucial step in setting up a laser center is to implement guidelines for laser safety.
The American National Standards Institute (ANSI) is a private, nonprofit organization,
which provides voluntary standardization and assessment of laser practices. Its pertinent
standards regarding laser safety include ZI36.3-2005, the Safe Use of Lasers in Health Care
Facilities, Z136.1-2000, the Safe Use of Lasers, and Z136.5-2000, the Safe Use of Lasers in Edu-
cational Institutions (1– 3). Among these, ANSI ZI36.3 is the general standard for laser centers
to follow (1). The key points to these standards include the appointment of a laser safety officer
(LSO) and control measures for prevention of accidents or injury.
The LSO serves as the liaison between regulatory agencies and the center. The officer’s
responsibilities include monitoring and reporting hazards, enforcing compliance with
control measures, providing policies and procedures in writing, evaluating and approving
protective gear, implementing safety training and education, arranging maintenance and
service of laser equipment, supervising daily operations, and reviewing and updating standards,
regulations, and legal requirements. It is generally agreed that an individual be appointed as an
LSO and assume these important responsibilities at the outset of setting up the center (4).
The second main components to the ANSI standards are control measures to protect
patients and staff from both direct and nonbeam laser hazards (1,4). Such control measures
include engineering controls, which comprise the built-in safety features of the laser
458 Appendix D
TABLE 1 Vascular Lasers

Laser options Wavelengths (nm) Indications
Pulsed dye 585, 590, 595, Port-wine stains, rosacea, facial telangiectasia,
and 600 hemangiomas, cherry angiomas, spider leg telangiectasia,
keloids, striae, and verrucae
Variable pulsed green 532 Facial telangiectasia, rosacea, spider leg telangiectasia,
venous malformations, and cherry angiomas
Long-pulsed alexandrite 755 Spider leg telangiectasia and nodular port-wine stains
Diode 800–810 Spider leg venulectasia and telangiectasia, reticular blue veins
Long-pulsed Nd:YAG 1064 Spider leg venulectasia and telangiectasia, reticular blue veins,
facial telangiectasia, and nodular port-wine stains
Intense pulsed light 400–1200 Rosacea, facial telangiectasia, and spider leg telangiectasia
systems. These include the key lock, emission indicators, and aperture covers or shutters.
Administrative control measures include the LSO and their responsibilities, education and
training programs for all staff, and a system in place for reporting hazards. Procedural
control measures involve the steps taken prior to and during every laser operation, such as lim-
iting treatment room access to laser-trained personnel, preparation of a nonflammable operat-
ive site, placement of proper protective eyewear, plume evacuation, and assisting the physician
(5). Finally, protective equipment control measures encompass the provision of labeled protec-
tive eyewear, window barriers, room signage, fire extinguishers, facemasks, plume evacuators,
nonflammable drapes, and anodized instruments. These control measures serve to address
the hazards unique to laser operation.
The ANSI standards provide a credible basis for laser safety guidelines within a laser
center. The U.S. Occupational Safety and Health Administration (OSHA) cites the ANSI stan-
dards. The OSHA also has guidelines for laser safety and hazard assessment (STD 01-05-001
(1991) (6). In addition, once these laser safety standards have been put in place, accreditation con-
firming that the center is in conformity with such standards may be attained (7). The ANSI pro-
vides accreditation services, as does the Joint Commission for Accreditation of Healthcare
Organizations (JCAHO) and the Accreditation Association for Ambulatory Health Care
(AAAHC). While accreditation is costly and time-consuming, making it unrealistic for most
small laser centers, it is the highest standard towards which facilities may strive to achieve.
DOCUMENTATION
Consent Forms
In starting a laser practice, it is imperative to review all the potential complications of each type
of laser system and prepare written documentation for patient consent forms. The most
common complications are included in the consenting process. It is very helpful to have
a separate consent form for every group of lasers and light sources. Having a single general
consent to cover all laser, light-based and surgical procedures is not considered the highest
TABLE 2 Lasers for Pigmented Lesions and Tattoos

Wavelength
Laser type (nm) Target skin structure Tattoo color
Q-switched lasers
Q-switched Nd:YAG 532 Lentigines, ephelids, and CALM Yellow, orange, red, and purple
Q-switched ruby 694 Lentigines, nevi, and CALM Green, blue, and black
Q-switched alexandrite 755 Lentigines, nevi, and CALM Green, blue, and black
Q-switched Nd:YAG 1064 Nevi and CALM Blue and black
Long-pulsed lasers
Diode 800 Lentigines and Nevi NA
Nd:YAG (1064 nm) 1064 Nevi NA
Intense pulsed light 500 –1200 Lentigines NA
Abbreviations: CALM, caf́e au lait macule; NA, not applicable; Nd:YAG, neodymium : yttrium-aluminum-garnet.
Appendix D 459
TABLE 3 Lasers for Hair Removal

Laser type Wavelength (nm) Skin type
Long-pulsed lasers
Alexandrite 755 I –III
Diode 800 I –VI
Nd:YAG 1064 I –VI
Intense pulsed light 510– 1200 I –III
standard of care. However, one consent form can be created to cover a group of laser
procedures. An example of a general laser consent form is shown in Figure 1.
Operative Report
The type of laser used, wavelength, fluence, spot size, pulse duration, and areas treated need to
be documented in reproducible fashion. Many laser centers employ standard forms for the
physician, an example of which is shown in Figure 2.
Postoperative Instructions
The postoperative period following laser treatment contains unique sequelae, which require
their own instruction sheet. Considerations during post-laser recovery include the avoidance
of sun exposure, possibility of blistering, crusting or dyspigmentation, and specific wound
care. An example of a postlaser instruction sheet is shown in Figure 3.
PRACTICAL CONSIDERATIONS FOR THE PHYSICIAN

When first starting laser surgery, it is imperative to be very familiar with the parameters of each
laser system and the potential complications. It is often helpful for the beginner to attach para-
meter guidelines to each laser, which can be used as a reference during treatment. Beginner
TABLE 4 Lasers for Wrinkle Reduction and Skin Rejuvenation

Laser Advantages Disadvantages
Nonablative
Vascular lasers Excellent safety, no recovery time, Minimal efficacy,
(LP 532 nm, PDL and improvement in telangiectasia multiple treatments necessary
585 nm and 595 nm)
Near-infrared lasers Excellent safety, no recovery time, Modest efficacy, painful,
(1320 nm, 1450 nm, higher efficacy for rhytides, multiple treatments necessary
and 1540 nm) and acne scars
Intense pulsed light Moderate safety, no recovery time, Minimum-to-modest efficacy,
and improvement in telangiectasia multiple treatments necessary
and pigment
Radiofrequency Excellent safety, no recovery time, Moderate efficacy,
and efficacy for laxity multiple treatments necessary
Fractional
1320 nm Er:Glass Higher efficacy than nonablative for Two- to three-day recovery time,
rhytides, some recovery time multiple treatments necessary but
fewer than nonablative with higher efficacy
1.5 U Er:Glass Higher efficacy than nonablative for Two- to three-day recovery time,
rhytides, some recovery time multiple treatments necessary but fewer
than nonablative with higher efficacy
Ablative
Carbon dioxide Excellent efficacy for Two-week recovery time, higher risk profile
10,600 nm rhytides and photodamage
Erbium 2940 nm Excellent efficacy for Two-week recovery time or less
rhytides and photodamage depending on extent of treatment,
higher risk profile
Abbreviations: LP, long-pulsed; PDL, pulsed dye laser.
460 Appendix D
I hereby authorize Dr. _____________________________ and his/her associates/assistants to perform upon the named patient or me the
following surgical/medical/laser procedure(s), invasive test(s), and/or treatment(s) for my condition which has been explained to me:
Procedure(s)/Test(s)/Treatment(s): _________________________________________________
Diagnosis/Condition(s): _________________________________________________
1. Nature, Purpose, Risks and Benefits of Procedure(s)/Test(s)/Treatment(s)

The nature and purpose of the procedure(s), test(s), and/or treatment(s) have been explained to me. The expected benefits and possible
complications or risks have also been explained. I understand that there is no guarantee of a specific result or cure, and that discomforts,
risks and complications may arise. The possible alternatives to proposed treatment, including no treatment, have been explained to me.
I have been given the opportunity to ask questions and all of my questions have been answered fully and to my satisfaction.
2. Possibility of Additional Unplanned Procedure(s)/Test(s)/Treatment(s)
I understand that during the course of the procedure/test/treatment, unforeseen conditions may require that different and/or additional
procedures/tests/treatments be performed. I therefore consent to the above-named physician and assistants to perform such additional
procedures/tests/treatments, as they consider necessary.
3. Risks and Complications
. I understand that surgical procedures, incisions, and laser procedures may result in scars, hyperpigmentation (darkening of skin),
hypopigmentation (lightening of skin), or localized hair loss in hair-bearing areas that are treated. I confirm that the areas to be
treated have been delineated in advance of the procedure with my approval. I understand that scars, hyperpigmentation, and
hypopigmentation may be amenable to additional procedures or treatments in the future in order for them to be improved.
. I understand that laser procedures may result in a burn. I have informed my physician of any recent tanning or prior history of laser
procedures.
. I understand that other common side effects or complications from surgical procedures/tests/and/or treatments include bleeding
and infection. I understand that the risk of bleeding either during or after the procedure is increased when taking certain medications
or supplements, and I have informed my doctor as to which medications and supplements I am taking. The risk of infection is
increased in individuals with certain medical problems, and I have informed my doctor as to my medical conditions.
. I understand that uncommonly allergic reactions may occur, which may manifest as a red bump at the site of injection, incision,
procedure, test or treatment; theoretically, an extreme, severe form of allergy may result in anaphylaxis, which manifests as
itching, skin swellings, difficulty breathing, and exceedingly rarely, even death. I have informed my physician of any allergies
that I am known to have.
. Other risks include blood clot formation in a superficial (thrombophlebitis) or deep (deep venous thrombosis) vessel; bruising,
swelling or tenderness at the treated areas; or delayed wound healing, which may require additional procedures/tests/treatments.
Such risks are increased in smokers, and if I am a smoker, understand that I should discontinue smoking for at least two weeks
following the procedure, test, or treatment.
. Unusual risks include superficial nerve damage at the treated sites, which may result in prolonged pain, disturbed sensation, or
impaired movement at the treated areas.
4. Laser Hair Removal Information
I understand that laser hair removal results in most cases in gradual thinning of hairs, with the potential for long-term hair loss. I
understand that in some cases the hair may regrow completely, and that multiple treatments are necessary. A rare complication is the
darkening of hairs in treated areas; I understand that should this occur, further treatments with laser are advised.
5. Laser Tattoo Removal and Cosmetic Tattoo Information
I understand that tattoos that are red, flesh-toned, white, or brown in color may permanently darken following laser treatment. I have
informed my doctor of any cosmetic tattoos I may have. I understand that tattoo removal requires multiple treatments, that removal
may result in lightening or discoloration of the skin, and that complete removal may not be achieved.
6. Post-Treatment Instructions
I understand the post-operative instructions given to me.
7. Contraindications
I hereby confirm that I am not pregnant or breastfeeding, nor have I taken isotretinoin (Accutane or Roaccutane) in the past year, nor gold
therapy. I understand that I should inform my physician of any medical conditions, allergies, medications, smoking history, or recent sun
exposure.
8. Photography
I also agree to having photographs taken. These photographs will be used for educational purposes and may be used for publication.
9. Consent
I have read the above information regarding the procedure(s)/test(s)/treatment(s), pre- and post-treatment information and instructions,
risks and complications, and contraindications. I have asked my physician any questions I may have and am satisfied by the answers
to these questions. I accept the risks and potential complications resulting from the procedure(s)/test(s)/treatment(s), deny any
contraindications in my medical history, and give hereby give my informed consent to the procedure(s)/test(s)/treatment(s).
—————————————————————————————————————————————————————————————
Patient/Healthcare Agent/Next-of-Kin Signature Printed Name Date
—————————————————————————————————————————————————————————————
Relationship Interpreter
—————————————————————————————————————————————————————————————
Witness
Physician/Practitioner Certification
I hereby certify that the nature, purpose, benefits, risks, and alternatives to (including no treatment and associated risks), the surgical
procedure(s)/test(s)/procedure(s), and/or treatments(s) have been explained to the patient And any and all questions answered in full.
I believe that the patient/health care agent/guardian/next-of-kin fully understands what has been explained.
—————————————————————————————————————————————————————————————
Physician Signature Date
Consent form from M. R. Alexiades-Armenakas, M.D., P.C.
FIGURE 1 Informed consent form for laser treatment. Source: From Macrene R. Alexiades-Armenakas.
Appendix D 461
Patient Name:
Date:
Treatment #:
Photos: Pre _________ Post _________
Operative Time:
Diagnosis: _________
Anatomic Location: _________
Procedure: _________
The patient was fully informed of the planned procedure, the alternative treatment options, limitations, expected
results, risks and complications, both short and long-term. A full disclosure was given. Written informed consent
was obtained.
Response to previous treatment was _________
The patient was brought to the procedure room and the area to be treated, was prepared and draped in the usual
fashion.
Anesthesia: No ______ Yes ______ Type: Topical ______ Intralesional 1% lidocaine ______
Photosensitizer (5-aminolevulinic acid) applied: No ______ Yes ______ Duration time: ______
Laser therapy was performed using all standard safety precautions. The patient tolerated the procedure well.
Wound care was discussed and appropriate dressings were applied. The patient left the procedure room in
good condition and was informed concerning postoperative care, both verbally and in writing.
_______________ MD _______________ Assistant
Laser Fluence Spot Size Pulse Duration Pulses Endpoint Sites
Adapted from: 8. Continuous Wave and Quasi-continuous Wave Lasers, Appendix C. Operative Record, In: Dover,
J.S., Arndt, K.A., Geronemus R.G., Alora, M.B.T., eds. Illustrated Cutaneous and Aesthetic Laser Surgery, 2nd
Edition., Appleton & Lange, Stamford CT, 2000:184.
FIGURE 2 Operative record. Source: From Ref. 8.
Immediately following laser treatment:

. The treated areas may be red and swollen for hours and, uncommonly, for days.
. Cool compresses are helpful if applied for a ten-minute period per hour for the first several hours.
. For swelling of the face, sleep on your back with your head elevated on pillows. This can be continued over
the first few nights.
. Blistering and/or crusting may occur. If so, apply Aquaphor healing ointment twice daily, and healing
generally occurs in 7– 14 days. If this was not explained to you as an expected event, please call the
physician.
In the days and weeks following laser treatment:
. Makeup and sunscreen may be worn except over blisters and crusts.
. Avoid excessive sun exposure. If you must go out during midday hours, wear a hat and apply a
hypoallergenic sunscreen of SPF 30 or greater except to blisters and crusts.
. Avoid swimming in chlorinated water such as swimming pools for 7– 14 days. Ocean or seawater
swimming is just acceptable, but also best avoided.
. Do not manipulate the treated areas or undergo any additional procedures for at least 4 weeks following
your laser treatment.
Follow-up and ongoing treatments:
. You will be instructed as to the appropriate follow-up interval following your laser treatment. This
typically ranges from 3 to 6 weeks, depending upon the laser treatment performed.
. Most laser applications, with some exceptions, require a series of ongoing treatments spaced at defined
intervals apart. This is necessary to safely and effectively treat the skin condition at hand. It is important
to keep your follow-up appointments in order to be properly evaluated and to achieve the best possible
results.
Post-laser Instruction Sheet from M. R. Alexiades-Armenakas, M.D., P.C.
FIGURE 3 Postlaser instruction sheet. Source: From Macrene R. Alexiades-Armenakas.

462 Appendix D
laser specialists should start with the lowest settings on the laser initially, until adequate experi-
ence is obtained. Laser test spots may be recommended if the patient is dark-skinned.
SCHEDULING PATIENTS
Patient scheduling in a laser center is complicated and requires that the secretarial, technical,
and medical staff all be fully aware of the steps involved in each type of treatment. For
example, procedures requiring topical anesthetics require an initial application appointment
followed by the treatment. In a center with multiple physicians sharing the same lasers, it
is important that the patients not be scheduled for the same laser in the same time slot.
Space must also be allocated for the numbing and recovery of patients.
CONCLUSIONS
In summary, setting up a laser center requires a careful selection of lasers by the physician,
the implementation of strict and comprehensive laser safety guidelines, careful medical
documentation, and the specialized training of office staff. Once these elements are in place,
the physician will be able to offer the patients state-of-the-art treatments for a wide variety
of dermatologic conditions.
REFERENCES
1. American National Standards Institute (ANSI): Z136.3-2005: Safe Use of Lasers in Health Care Facilities,
2005, The Institute.
2. American National Standards Institute (ANSI): Z136.1-2000, Safe Use of Lasers, 2000, The Institute.
3. American National Standards Institute (ANSI): Z136.5-2000, Safe Use of Lasers in Educational
Institutions, 2000, The Institute.
4. Smalley PJ, Goldman MP. Laser safety: regulations, standards, and guidelines for practice. In: Goldman
MP, Fitzpatrick RE, eds. Cutaneous Laser Surgery: The Art and Science of Selective Photothermolysis.
2nd edn. St. Louis, Missouri: Mosby, 1999:459– 472.
5. Nori S Greene MA, Schrager HM, Falanga V. Infectious occupational exposures in dermatology—
review of risks and prevention measures I. For all dermatologists. J Am Acad Dermatol 2005;
53(6):1010– 1019.
6. U.S. Department of Labor Occupational Safety and Health Administration, Guidelines for Laser Safety
and Hazard Assessment, STD 01-05-001 [PUB 8-1.7], 1991, August 5.
7. Sterling JB, Hanke CW. Office accreditation in dermatology. Semin Cutan Med Surg 2005; 24(3):128– 132.
8. Continuous wave and quasi-continuous wave lasers, Appendix C. Operative record. In: Dover JS,
Arndt KA, Geronemus RG, Alora MBT, eds. Illustrated Cutaneous and Aesthetic Laser Surgery.
2nd edn. Stamford CT: Appleton & Lange, 2000:184.
Index
AAADP. See Aminolevulinic acid dehydratase Antioxidants, 274– 275

porphyria PCT, 226
Ablative skin rejuvenation AP. See Actinic prurigo
ethnic skin, 419– 421 Apoptosis, 48–49
Absorption spectra, 25 TP53, 112–113
Acid dehydratase porphyria (ADP) Arc lamps, 32– 33
cutaneous manifestations, 229 Artificial radiation, 31–37
etiology, 229 Atopic dermatitis, 255
laboratory findings and diagnosis, 230 Autoimmune bullous disease
neurological manifestations, 228– 229 photopheresis, 365
Acne, 252 Axmann, Hans, 7
intense pulsed light, 398
Acne vulgaris Basal cell carcinoma (BCC), 108
photodynamic therapy, 380 descriptive epidemiology, 125– 128
Actinic keratoses incidence rates, 127
photodynamic therapy, 375– 376 photodynamic therapy, 377
Actinic keratosis, 127 BCC. See Basal cell carcinoma
Actinic prurigo (AP), 149–163,437 Becker’s nevus
clinical features, 160 ethnic skin
diagnosis, 163 lasers, 423
epidemiology, 159 Berloque dermatitis, 203
etiology and pathogenesis, 159–160 Biomolecules
histopathology, 161–163 excited states, 23–24
induction, 160 Bithionol, 205
treatment, 163 inducing PACD, 208
Action spectrum, 25–26 Blum, Harold, 4
photoaging, 96– 97 Bowen’s disease
photoimmunosuppression, 82 photodynamic therapy, 377
Activated charcoal Bowls, Robert, 4
erythropoietic protoporphyria, 235–236 Broadband, 319– 334
Acute cutaneous lupus erythematosus, 258 Broad-spectrum sunscreens, 300– 301
Acute intermittent porphyria (AIP), 222–223, 228–230 Bullous pemphigoid, 261
cutaneous manifestations, 229 Butyl methoxydibenzoylmethane, 205, 301
etiology, 229
laboratory findings and diagnosis, 230 CAD. See Chronic actinic dermatitis
neurological manifestations, 228– 229 Café au lait patch
treatment and prevention, 230 ethnic skin
Adenocarcinoma lasers, 423
sweat gland Calcium channel antagonists, 215
incidence rates, 128 Candidate chromophores
ADP. See Acid dehydratase porphyria photoimmunosuppression, 84
Age Captan, 209
ethnic skin Cell cycle arrest, 48
cutaneous manifestations, 419–421 Cell responses
skin cancer, 130 photochemical reactions, 23– 24
AIP. See Acute intermittent porphyria Cell surface receptor activation, 45
Airborne contact dermatitis, 209 Cellular immunity, 56–59
Alcohol Characterizing, 38– 39
PCT, 225–226 Charcoal
Aminolevulinic acid dehydratase porphyria activated
(AAADP), 228– 230 erythropoietic protoporphyria, 235
Amiodarone, 214 Charcot, Jean Martin, 3
Antigen presenting cells Chlorhexidine diacetate, 205, 208
photoimmunosuppression, 82–84 Chloroquine
Antimalarials, 260 PCT, 226
464 Index
Chlorpromazine hydrochloride (Thorazine), 208– 209 Dermatofibrosarcoma protuberans

phototoxicity, 215 incidence rates, 128
Cholestyramine Dermatomyositis, 259– 261
erythropoietic protoporphyria, 235 Dermatosis
Chronic actinic dermatitis (CAD), 169– 183, 438 –439 photoaggravated, 251–266
See also Dermatitis photo-induced
clinical aspects, 172 –176 protection against, 303–305
diagnosis, 177– 178 transient acantholytic, 253–254
differential diagnosis, 178–179 Dermatosis papulosa nigra
histopathology, 176 laser, 419–421
management, 179– 180 Dichlorophen, 205
pathogenesis, 171– 172 inducing PACD, 207
phototesting, 177 Diet. See Vitamin D
CIE. See Commission Internationale de l’Eclairage skin cancer, 131
CLE. See Cutaneous lupus erythematosus Defective enzymes
Coblentz, William, 3 cutaneous porphyrias, 223
Cockayne syndrome, 245– 246 Diode
clinical symptoms, 241 1450nm, 408 –409
Commission Internationale de Diuretics, 212
l’Eclairage (CIE), 25 DNA
Congenital erythropoietic porphyria (CWP), 231– 233 excision repair enzyme and photolyase, 275
Congenital melanocytic nevi photochemistry, 24
ethnic skin photoimmunosuppression, 82
lasers, 426 DNA repair
Congenital nevi photoprotection, 282
giant pigmented Documentation
skin cancer, 130 laser center, 458–459
Consent forms Dose, 18
laser center, 458, 460 dose rate effects, 20
Contact dermatitis. See also Photoallergic contact Drometriazole trisiloxane, 300– 301
dermatitis (PACD) Drug-induced lupus erythematosus, 209
airborne, 209 Drug-induced photosensitivity, 439– 440
photoirritant, 201–204 systemic, 209–215
CPD. See Cyclobutyl pyrimidine dimer (CPD) Drug-induced pseudoporphyria, 212
Cutaneous lupus erythematosus (CLE), 258 Drug photosensitivity, 210
Cutaneous photoaging. See also Photoaging DTH. See Delayed type hypersensitivity
cutaneous hydration, 102– 103
measuring, 100 Ebermaier, Johan Christoph, 2
photonumeric scales, 101 Eczema
properties, 101 PUVA, 354
sebum production, 103 solare, 4
skin structure, 102 Education. See also Public education
skin surface properties, 101 skin cancer, 131–132
Cutaneous phototoxicity, 198 Electromagnetic spectrum, 30
Cutaneous porphyrias, 221– 238 Ellinger, Friedrich, 6
diagnosis, 222 EM. See Erythema multiforme
defective enzymes, 223 Emerging sunscreens
mode of inheritance, 143 assessment methods and standards, 289– 292
Cutaneous T cell lymphoma Energy
incidence rates, 128 molecule, 23
photodynamic therapy, 381 wavelength, 17–18
photopheresis, 360– 363 Epidermal hyperplasia, 81–82
CWP. See Congenital erythropoietic porphyria Epstein, Stephen, 5
Cyclobutyl pyrimidine dimer (CPD), 24, 112 Equivalent radiometric quantities, 19
Cytochrome P450 enzyme Erbium glass, 394
PCT, 226 Erythema, 3– 4
Cytokines, 44– 45 Erythema multiforme (EM), 254–255
Erythropoietic protoporphyria, 233– 236
Darier’s disease, 252 activated charcoal, 235
Delayed type hypersensitivity (DTH), 59– 61 cholestyramine, 235
Dendritic cells, 57– 58 Estrogen
Dermatitis. See also Chronic actinic PCT, 223– 224
dermatitis (CAD) Ethnic skin
atopic, 255 ablative and nonablative skin rejuvenation, 419–423
berloque, 203 aging
contact cutaneous manifestations, 418– 419
airborne, 209 Becker’s nevus
hyperpigmented photoirritant, 203 lasers, 423– 424
Index 465
[Ethnic skin] Heliotherapy

café au lait patch leg ulcers, 8
lasers, 423 Hemangioma
congenital melanocytic nevi proliferative
lasers, 426–428 ethnic skin, 428
cultural concerns, 419 Heme biosynthetic pathway, 220
facial telangiectasia intermediates, 221
lasers, 428 HEP. See Hepatoerythropoietic porphyria
Hori’s macules Hepatitis C
lasers, 423 PCT, 225
lasers, 417–432 Hepatoerythropoietic porphyria (HEP), 223, 227–228
dermal and mixed lesions, 424–426 diagnosis, 228
epidermal lesions, 423– 424 etiology, 228
hair removal, 426– 428 laboratory evaluation, 228
medical history, 419 pathogenesis, 228
melasma treatment, 228
lasers, 423 Hereditary coproporphyria (HCP), 223, 228–230
port wine stain cutaneous manifestations, 229
lasers, 423 etiology, 229
preoperative considerations, 418 laboratory findings and diagnosis, 230
proliferative hemangioma Hereditary syphilis, 4
lasers, 428 Herpes simplex, 254
special precautions, 418 Herschel, William, 2
Extracorporeal photochemotherapy Hexachlorophene, 205, 208
(photopheresis), 359– 368 High-pressure mercury lamp, 8
Extramammary Paget’s disease High-pressure xenon lamp, 8
incidence rates, 128 Höhensonne lamp, 8
Home, Everard, 2
Facial telangiectasia Homosalate, 205
ethnic skin Hori’s macules
lasers, 428 ethnic skin
Fenticlor, 205 lasers, 423, 424
inducing PACD, 208 Huldschinsky, Kurt, 8
Fibroblasts, 47 Humoral immunity, 56–57
Filtered solar radiation, 6 Hutchinson, Jonathan, 4
Findlay, George, 4 Hydroa vacciniforme (HV), 4, 149– 167, 157– 159
Finsen, Niels, 2, 6, 8 clinical features, 160–161
Finsen lamp, 7 diagnosis, 163
Finsen-Reyn lamp, 7 epidemiology, 157
500 Dalton rule, 288 etiology and pathogenesis, 157
Fluorescence diagnosis, 383 histopathology, 157–158
Fluorescent lamps, 33 treatment, 159
phototherapy referral center, 451– 452 Hydroxychloroquine
Fluoroquinolones, 213– 214 PCT, 226
phototoxicity index table, 210 2-Hydroxy-methoxy methyl benzophenone, 205
Folpet, 209 Hyperpigmented photoirritant dermatitis, 203
Foscan (temoporfin), 215
Fractional resurfacing, 421– 423
Immediate pigment darkening (IPD), 80
Fragrances, 208
Immune system
Fraxel
photorejuvenation, 410 protection factor, 269, 302
Immunity
Frequency doubled Nd:YAG, KTP, 403
humoral, 56–57
Furocoumarins
systemic
PICD, 202–204
UV suppression, 60
Giant pigmented congenital nevi Immunomodulators
skin cancer, 130 intense pulsed light, 397
Goeckerman, William Henry, 8 Incandescent lamps, 32
Gorlin-Goltz syndrome, 108 Infrared lasers
Graft-vs-host disease photorejuvenation, 406 –407
photopheresis, 363– 364 Ingram, John, 8
Greiter, Franz, 6 Innate immunity
Grover’s disease, 253 photoimmunosuppression, 84
Günther disease, 231– 233 Instruction sheet
laser center, 461
Hammer, Friedrich, 5 Intense pulsed light, 35, 389– 400
Hausser, Karl, 2 acne, 398
HCP. See Hereditary coproporphyria clinical indications, 394
Heinrich, Placidus, 3 cooling skin, 395 –396
466 Index
[Intense pulsed light] Leucotomos

getting melanin out, 394 polypodium, 275
getting red out, 393 Lichen acid mix, 205
hair disorders, 396 Lichen planus actinicus, 256
heating skin, 392– 393 Light
immunomodulators, 397 dosimetry
melanin, 394 skin, 39– 40
novel UV light sources, 397 emitting diodes (LED), 36– 37
photodynamic therapy, 397 eruption. See Polymorphous light eruption
photorejuvenation, 404–406 lasers
tattoos, 395 natural, 31
warts, 396 propagation
Ionizing radiation through skin, 37– 38
skin cancer, 131 sources
IPD. See Immediate pigment darkening photorejuvenation, 402–403
Iron mutations visible
PCT, 225 photorejuvenation, 402
Irradiance, 18 Liposarcoma
vs. exposure time, 21 incidence rates, 128
spectral, 38–39 Local or systemic primary immunity
Irradiation monochromator, 435– 437 UV suppression, 59–61
Lomefloxacin, 214
Kaposi, Moriz, 4 Lupus erythematosus, 256 –257, 303
Keratinocytes, 47– 48 drug-induced, 213
Keratoacantoma subacute cutaneous, 258
incidence rates, 128 systemic
Ketoprofen, 205 photopheresis, 366
Kromayer lamp, 8 Lupus vulgaris
Kuske, Hans, 5 phototherapy, 8
Lux1540 fractional 1540nm
Lamp changes photorejuvenation, 410–411
phototherapy referral center, 452–453 radiofrequency, 411
Lamps
Finsen, 6 Malignant melanoma, 108
Finsen-Reyn, 7 McLaren, Douglas, 10
fluorescent, 33–34 MED. See Minimal erythema dose
phototherapy referral center, 449–450 Medical Light Institute, 7
high-pressure mercury, 8 Melanin
high-pressure xenon, 8 intense pulsed light, 392
Höhensonne, 7 Melanocytes, 47
incandescent, 32 tanning responses, 49
Kromayer, 7 Melanocytic nevi
mercury skin cancer, 130
rachitis, 8 Melanogenesis
phototherapy referral center, 449–450 mechanism, 80
Laser(s), 34–35, 389– 400 mediators, 80
applications, 36 Melanoma
heating skin, 392– 393 descriptive epidemiology, 122– 125
pigmented lesions, 458 malignant, 108
seborrheic keratosis, 419– 421 Melasma, 304– 305
skin epilation, 401–416 ethnic skin
skin rejuvenation, 401–416, 459 lasers, 423, 425–426
solar lentigines, 419– 420 Memory or recall immunity
tattoos, 458 UV suppression, 59–61
Laser center Menthylanthranilate, 205
consent forms, 458, 460 Mercury lamps
documentation, 458– 459 rachitis, 6
instruction sheet, 461 Merkel cell carcinoma
laser selection, 457–458 incidence rates, 128
operative report, 459, 461 6-Methycoumarin, 208
patient scheduling, 462 Microfine organic particles, 287
physicians, 459–460 Microthermal, fractional resurfacing or
postoperative instructions, 459 microrejuvenation
setting up, 457 photorejuvenation, 402–403
LED. See Light emitting diodes Miescher, Guido, 4
Leg ulcers Minimal erythema dose (MED), 3, 6, 19
heliotherapy, 8 measuring prior to narrowband or broadband
phototherapy, 8 UVB phototherapy, 433– 434
Index 467
[Minimal erythema dose (MED)] Photoaging, 92– 106, 305 See also Cutaneous
measuring with suspected photosensitivity, 435 photoaging
Minimal phototoxic dose action spectrum, 96
measuring prior to psoralen photoche clinical changes, 97– 99
motherapy, 435 histological changes, 100
Mitochondrial damage mechanisms, 92–96
photoaging, 94 mitochondrial damage, 94
Moller, Magnus, 3 telomeres, 94
8-MOP. See Oral 8-methoxypsoralen telomeres DNA damage, 94– 96
Musk ambrette, 205, 206, 208 telomeres shortening, 94
Mycosis fungoides UV-induced membrane signaling, 93– 94
PUVA, 353 Photoallergen
solar urticaria, 190– 191
Nagelschmidt, Carl Franz, 7 Photoallergic agents, 142
Narrow band, 319–334 Photoallergic contact dermatitis (PACD), 200,
Natural light, 31 204–207, 442. See also Contact dermatitis
Natural photoprotection, 3– 4 photopatch testing techniques, 204
Nd:YAG photosensitizing agents, 207 –209
1320nm, 407 Photobiological reaction, 390– 392
Nevus of Ota Photobiology
ethnic skin history, 1–14
lasers, 423, 424– 425 photopheresis, 366– 367
New therapeutic molecules principles, 15– 28
photosensitivity testing, 209 skin, 37
Newton, Isaac, 16 Photocarcinogenesis, 107– 118
Nightingale, Florence, 6 Photochemical reactions
Nonmelanoma skin cancer (NMSCs), 108 cell responses, 24– 25
Nonsteroidal anti-inflammatory agents (NSAIDs), 209 Photochemotherapy, 9
extracorporeal, 359– 368
Octinoxate, 205 psoralen, 347–358
Octisalate, 205 Photodermatology
Octyl dimethyl PABA, 205 dosimetric terms, 18
Office-based phototherapy unit, 449– 456 Photodermatoses
phototherapy referral center classification, 140
dosimetry, 454 evaluation, 141, 142
Olaquindox, 209 history, 141
Operative report PUVA, 354
laser center, 459, 462 Photodynamic therapy, 369– 388
Oppenheim, Moritz, 5 acne vulgaris, 380
Optical radiation, 18 actinic keratoses, 375–376
Oral lichen planus adverse effects, 374– 375
photopheresis, 366 basal cell carcinoma, 377– 378
Oral 8-methoxypsoralen (8-MOP), 9 Bowen’s disease, 377
Oxidative stress cutaneous T-cell lymphoma, 381
photoimmunosuppression, 84 dysplasia, 359– 361
Oxybenzone, 205 intense pulsed light, 397
light sources, 373–374
PACD. See Photoallergic contact dermatitis mechanism of action, 371
Paget’s disease nonmelanoma skin cancer, 375
extramammary nonmelanoma skin cancer indications, 378–383
incidence rates, 128 photosensitizers, 371
Papulosa nigra poor response, 383
laser, 419– 421 psoriasis, 380
Para-aminobenzoic acid, 205 reactions, 215
Patient scheduling recalcitrant viral warts, 378–379
laser center, 462 Photofrin (porfimer sodium), 215
Pellagra, 253– 254 Photoimmunology, 55–74
Pemphigoid, 261 Photoimmunosuppression, 82–84
Pemphigus leprous, 4 action spectrum, 83
Persistent light reactor, 211 antigen presenting cells, 83
Persistent pigment darkening (PPD), 80 candidate chromophores, 84
Phenergan, 208 innate immunity, 84
Phenothiazines, 208, 214–215 mechanisms, 83–84
Phenylbenzimidazole, 205 mediators, 83
PHisoHex, 208 oxidative stress, 84
Phlebotomy Th1/Th2 cytokines, 83
PCT, 228 Photo-induced dermatoses
Photoaggravated dermatoses, 251– 266 protection against, 303– 304
468 Index
Photoirritant contact dermatitis (PICD), 200– 204 [Photosensitivity]

furocoumarins, 202 –203 testing
Photopatch testing, 5, 441– 448 new therapeutic molecules, 209
indication, 444 Photosensitization, 24
interpretation, 444–447 protection against, 302–303
methodology, 444 Photosensitizers, 7
PACD, 204 exposure, 140– 141
photosensitive patient, 145 PACD, 207–209
positive, 443 photodynamic therapy, 371
relevance, 447 Photosensitizing drugs, 211
test substances, 441– 444 Phototesting, 433– 440
ultraviolet dose, 444 photosensitive patient, 145
Photopheresis, 359– 368 Phototherapeutic UVA, 9
autoimmune bullous disease, 365 Phototherapy, 319– 334
cutaneous T-cell lymphoma, 361– 363 leg ulcers, 8
graft-vs-host disease, 363– 364 lupus vulgaris, 8
oral lichen planus, 366 skin diseases, 8 –9
photobiology, 366–367 Phototherapy referral center, 449–456
scleroderma, 364–365 ancillary equipment, 453
systemic lupus erythematosus, 365 broadband UVB, 451
Photoproducts, 112 canopy units, 451
Photoprotection, 267– 278 dosimetry, 452
assessment, 268–269 equipment, 451
daily, 305 fluorescent lamps, 451 –452
DNA repair, 282 forms, 453
natural, 3 –4 hand and foot units, 451
novel developments, 279 –310 lamp changes, 452– 453
UVA effects, 299 localized delivery, 451
public education, 3113– 318, 313– 317, 316 narrowband UVB, 451
community-wide interventions, 315 office-based phototherapy unit
health care practitioners and medical students, dosimetry, 454
314– 315 equipment, 454
programs, 313– 316 forms, 455
recreation areas, 314 lamp changes, 454
schools, 313– 314 procedures, 454 –455
workplace, 315 recording treatments, 455
Photorejuvenation safety guidelines, 455
affirm, 410 space, 453– 454
fraxel, 410 staff, 454
infrared lasers, 407– 409 therapy guidelines, 455
intense pulsed light, 404 –405 whole-body unit, 454
lasers/lights sources classification, 402– 403 procedures, 452– 453
light sources, 404–407 PUVA, 451
low energy light emitting diodes, 405–407 recording treatments, 453
Lux1540 fractional 1540nm, 410– 411 safety guidelines, 453
microthermal, fractional resurfacing or space, 449– 450
microrejuvenation, 409–410 staff, 450– 451
visible light lasers, 403 standup whole body units, 451
Photosensitive patients therapy guidelines, 453
age of onset, 140 ultraviolet A-1, 451–452
eruption duration, 141–142 Phototherapy unit
evaluation, 139– 148, 141, 146 office-based, 449–456
family history, 143 Phototoxic agents, 142
history, 140–141 Phototoxic drugs, 211– 212
laboratory evaluation, 146 Phototoxicity
lesion morphology, 144 cutaneous, 211
photopatch testing, 145 thiazide-induced, 213
phototesting, 145 Phototoxicity index table
physical examination, 143 –144 fluoroquinolones, 210
seasonal variation, 141– 142 Physical examination
systemic abnormalities, 143 photosensitive patient, 143–145
window glass, 143 Physicians
Photosensitivity laser center, 459–460
chemical, 199–218 PICD. See Photoirritant contact dermatitis
disorders, 84 Pigmentation, 3 –4
drug-induced, 200– 218, 209– 210, 439 –440 Pigment darkening, 80–81
induced by topical agents, 200–201 Pigmented lesions
systemic drug-induced, 209–215 lasers, 458
Index 469
Polymorphous light eruption (PLE), 149– 167, [Psoralen plus ultraviolet A (PUVA)]
303, 437 phototherapy referral center, 449
diagnosis, 155 psoriasis, 353
epidemiology, 150 skin cancer, 131
etiology, 150–151 topical therapy, 355– 356
histopathology, 154–155 vitiligo, 354
induction, 151– 152 Psoriasis, 8, 256
pathogenesis, 150–151 photodynamic therapy, 381
treatment, 155– 156 PUVA, 353– 354
Polypodium leucotomos, 275 Public education. See also Education
Porfimer sodium, 215 photoprotection, 311 –318
Porphyria cutanea tarda, 223 –224 recreation arenas, 314
blistering, 224 schools, 313–314
hyperpigmentation, 224 workplace, 315
hypertrichosis, 224 Pulsed dye laser, 403– 404
Porphyrias. See also Acid dehydratase porphyria Pulsed light. See Intense pulsed light
(ADP); Acute intermittent porphyria PUVA. See Psoralen plus ultraviolet A
(AIP); Cutaneous porphyrias;
Hepatoerythropoietic porphyria (HEP); Quindoxin, 209
Hereditary coproporphyria (HCP); Quinine, 215
Variegate porphyria (VP)
aminolevulinic acid dehydratase, 228–230 Raab, Oscar, 7
causing blistering skin lesions, 223 Rachitis
classification, 221 mercury lamps, 8
congenital erythropoietic, 231– 233 Radiation. See also Ultraviolet radiation
history, 222 –223 (UVR)
Port wine stain artificial, 31–33
ethnic skin energy form, 30
lasers, 428 ionizing
Postoperative instructions skin cancer, 131
laser center, 459 optical, 18
PPD. See Persistent pigment darkening visible, 16
Programmed cell death, 48– 49 Radiation sources, 29–40, 31, 38
TP53, 112–113 skin, 37
Proliferative hemangioma therapeutic, 32
ethnic skin wavebands, 32
lasers, 428 Radiometric calculation, 19
Promethazine (Phenergan), 208 Recalcitrant viral warts
Protection factor photodynamic therapy, 379– 380
immune system, 269, 302 Recall immunity
sun, 268, 289 UV suppression, 59– 61
evaluation, 299 Red veterinary petrolatum, 6
Protein kinase-mediated signal Rikli, Arnold, 6
transduction, 45–46 Ritter, Johann Wilhelm, 2
Protoporphyria Roffo, Angel, 4
erythropoietic, 227–228
cholestyramine, 235 Safety
Provocation testing, 437 sunscreens, 283 –284
Pseudoporphyria Safety guidelines
drug-induced, 212 phototherapy referral center, 453
Pseudoscleroderma, 223 Saidman, Jean, 3
Psoralen, 348–349 Sandalwood oil, 205, 208
cellular responses, 350 SCC. See Squamous cell carcinoma
cutaneous responses, 349 Scheele, Wilhelm, 2
maintenance therapy, 351 Schulze, Rudolf, 6
pharmacology, 348– 349 SCLE. See Subacute cutaneous lupus
photobiology, 349 erythematosus
precautions, 352 Scleroderma
PUVA photopheresis, 364– 365
contraindications, 352 –353 Seborrheic keratosis
treatment, 350– 351 lasers, 419–421
UVA radiation, 349 Short pulse Q-switched Nd:YAG, 407
Psoralen photochemotherapy, 347–358 Singlet excited state, 23
Psoralen plus ultraviolet A (PUVA), 9 Skin
bath, 355 delayed tanning, 80–81
eczema, 354 radical scavenging, 281
mycosis fungoides, 354 Skin barrier
photodermatoses, 354 disturbances, 85
470 Index
Skin cancer, 108 Sunburn response, 76–79

age, 130 adhesion molecules, 79
analytic epidemiology, 128– 131 histology, 77
classification, 120 initiating events, 78
defined, 121 mechanism, 78
diet, 129 mediators, 78
epidemiology, 119–138 oxidative stress, 78
gender, 130 proinflammatory cytokines, 79
melanocytic nevi, 130 time course, 76
phenotypic and solar exposure risk factors, 108–110 transcription factors, 79
prevention and education, 131–132 vasoactive mediators, 79
PUVA, 131 Sunless tanning agents, 274
risk factors, 130 Sunlight
smoking, 129 measurement, 56
sunscreens, 133 Sun protection factor, 268, 289
tanning devices, 131 evaluation, 299
UVR, 110 Sunscreen filters photostability, 300
world burden, 122 Sunscreens. See also Topical sunscreens
Skin diseases broad-spectrum, 300– 301
phototherapy, 8– 9 chemistry/actives, 284
Skin epilation children, 269
lasers, 401–416 efficacy, 283
Skin immune system, 56– 59 emerging
Skin phototypes classification, 20, 109 assessment methods and standards, 289 –292
Skin rejuvenation immune protection, 84
ablative, 421–423 inducing PACD, 207– 208
ablative and nonablative new actives, 283–285
ethnic skin, 419 –421 patent freedom, 284
lasers, 401–416, 459 registration, 283
Smoking safety, 283
PCT, 226 skin cancer, 133
skin cancer, 131 UVA standards, 290
Societies, 9 UV protection, 281
Solar lentigines vitamin D, 272
laser, 419–421 Sweat gland
Solar radiation adenocarcinoma
filtered, 6 incidence rates, 128
Solar ultraviolet Syphilis
energy and penetration, 42 hereditary, 4
immunosuppression, 61 Systemic drug-induced photosensitivity, 209–215
Solar urticaria, 185 –198, 303, 437– 438 Systemic immunity
augmentation spectrum, 189 UV suppression, 60
chemical mediators, 192 Systemic lupus erythematosus
clinical course, 193 photopheresis, 365
clinical manifestations, 186 Systemic primary immunity
coexisting disease, 193 UV suppression, 59–61
demography, 186
drug-induced, 191 Tanning agents
histopathology, 192–193 sunless, 274
inhibition spectrum, 188– 189 Tanning devices
passive transfer, 190 skin cancer, 131
photoallergen, 190– 191 Tanning response, 80–81
photo-provocation and action spectrum tests, melanocytes, 49
187– 188 time course, 80
treatment, 193 –195 Tar products
Soluble factors, 44– 45 PICD, 200– 201
Space Tattoos
phototherapy referral center, 449–450 intense pulsed light, 394
Spectral irradiance, 38– 39, 39 lasers, 458
Squamous cell carcinoma (SCC), 108 T cell lymphoma
descriptive epidemiology, 125– 128 cutaneous
incidence rates, 127 incidence rates, 128
Stalled DNA replication and RNA transcription, photodynamic therapy, 381
46–47 photopheresis, 361–363
Standard erythema dose, 19 T-cells, 47
Subacute cutaneous lupus erythematosus Telangiectasia
(SCLE), 257 facial
Sulisobenzone, 205 ethnic skin, 428
Index 471
Telomeres [Ultraviolet A (UVA)]

DNA damage biological effects, 301
photoaging, 94– 96 in silico determination, 291
photoaging, 94 sunscreen effects, 302– 303
shortening in vivo determination, 290
photoaging, 94 and visible light therapy, 335– 346
Temoporfin, 215 Ultraviolet A1, 335– 343
Terephtalylidene dicamphor sulfonic acid, 300 visible light therapy
Tetrabromosalicylanilide atopic dermatitis, 337–339
inducing PACD, 207 connective tissue disease, 340– 342
Tetracyclines, 215 cutaneous T-cell lymphoma, 339
Thiazide-induced phototoxicity, 212 HIV-positive patients, 342– 343
Thorazine, 208 side effects, 342
phototoxicity, 215 T-cell mediated skin disease, 336– 337
Th1/Th2 cytokines urticaria pigmentosa, 339
photoimmunosuppression, 84 Ultraviolet B (UVB), 319–334
Tissue optics, 37, 390–392 damage, 42–43
Topical sunscreens. See also Sunscreens filters, 301
boosting agents, 283 immunosuppression, 61
formulation improvement, 283 induced erythema
improvements, 282–283 time course, 76
micronization, 282 lamp spectra, 321
UV protection, 280 lamp types, 320–321
Topical UV filters, 269 phototherapy, 9
TP53 action spectrum, 322
basal cell carcinoma, 114–115 atopic dermatitis, 330
programmed cell death, 112 combination therapy, 326– 328
squamous cell carcinoma, 113–114 cutaneous T cell lymphoma, 330
Transient acantholytic dermatosis, 253 home therapy, 328–329
Tribromosalicylanilide, 205 localized treatment, 325–326
Trichothiodystrophy, 246– 247 minimal erythema dose, 322– 323
clinical symptoms, 241 polymorphous light eruption, 331
Triclosan, 205 pruritus, 331
inducing PACD, 207 psoriasis, 322–329
Tuberculosis side effects, 326
heliotherapy, 8 treatment regimens, 323– 326
vitiligo, 330
UCA. See Urocanic acid whole body treatment, 323– 326
Uhlmann, Erich, 8 sources, 320– 321
Ulcers Ultraviolet damage, 42– 43
leg Ultraviolet-induced signaling and gene regulation,
heliotherapy, 8 44–47
phototherapy, 8 Ultraviolet radiation (UVR), 16. See also Radiation
Ultraviolet (UV) acute effects, 75–90
absorbers antigen presentation, 61–63
safety, 287– 288 cellular responses, 47– 50
absorption chronic effects, 91– 118
skin molecules, 21 DNA effects, 42
filters immunologic tolerance, 63
Europe, 271 immunosuppressive mediators, 65–66
new, 269 lipid effects, 43
photostability, 271 molecular and genetic effects, 41– 54
topical, 269 protein effects, 44
USA approved, 269– 271 signature mutations
induced erythema DNA photodamage, 111
time course, 76 tumor suppressor genes, 112– 115
induced immunosuppression T cells, 63–65
biological relevance, 66– 68 Urocanic acid (UCA)
protection factor, 268, 269 photoimmunosuppression, 84
radiation UV-induced immunosuppression, 66
preventing from reaching skin, 280–281 Uroporphyrinogen decarboxylase (UROD), 223, 225
transcriptional responses, 47 mutations
Ultraviolet A (UVA) PCT, 225– 226
biological effects, 301 Urticaria. See Solar urticaria
damage, 42 UV. See Ultraviolet
filters, 300–301 UVA. See Ultraviolet A
immunosuppression, 61 UVB. See Ultraviolet B
protection UVR. See Ultraviolet radiation
472 Index
Variegate porphyria (VP), 223, Vitiligo

228– 231 PUVA, 354
cutaneous manifestations, 229 VP. See Variegate porphyria
etiology, 229
laboratory findings and diagnosis, 230 Warts
neurological manifestations, 228–229 intense pulsed light, 396
Viral warts Wavelength
recalcitrant color, 17
photodynamic therapy, 379–380 ranges
Visible light lasers UVR, 16
photorejuvenation, 403–404 Willan, Robert, 4
Visible radiation, 16 Wound-healing response, 50
skin molecules, 21 Wrinkle reduction
UVR, 17 lasers, 459
Vitamin D, 316
bone health, 82 Xeroderma pigmentosum (XP), 4, 239– 250
controversies, 82 care and management, 244–245
cutaneous synthesis, 81 clinical symptoms, 241–245
metabolism, 82 differential diagnosis, 243
production, 49, 81 DNA repair genes, 244
sources, 81 laboratory diagnosis, 243
sunscreens, 272 nucleotide excision repair, 240 –241

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Photodermatology

DK7496_C000a.indd 1 12/14/06 1:27:45 PM

DAviD A. noRRiS, M.D.

1. Cutaneous Investigation in Health and Disease: Noninvasive Methods and

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No claim to original U.S. Government works

International Standard Book Number‑10: 0‑8493‑7496‑0 (Hardcover)

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Series Introduction Alan R. Shalita, MD iii

Section I: History and Basic Principles

2. Basic Principles of Photobiology 15

3. Radiation Sources and Interaction with Skin 29

Section II: Effects of Ultraviolet Radiation on Normal Skin

6. The Acute Effects of Ultraviolet Radiation on the Skin 75

7. The Chronic Effects of Ultraviolet Radiation on the Skin: Photoaging 91

8. The Chronic Effects of Ultraviolet Radiation on

9. The Epidemiology of Skin Cancer 119

Section III: Photodermatoses

Part B: Immunologically-Mediated Photodermatoses

12. Chronic Actinic Dermatitis 169

13. Solar Urticaria 185

Part C: Drug and Chemical-Induced Photosensitivity

15. Cutaneous Porphyrias 219

Part D: DNA Repair-Deﬁcient Photodermatoses

Part E: Photoaggravated Dermatoses

Section IV: Photoprotection

19. Novel Developments in Photoprotection: Part I 279

20. Novel Developments in Photoprotection: Part II 297

21. Public Education in Photoprotection 311

Section V: Ultraviolet and Visible Radiation Therapy

23. Ultraviolet-A1 and Visible Light Therapy 335

24. Psoralen Photochemotherapy 347

25. Extracorporeal Photochemotherapy (Photopheresis) 359

26. Photodynamic Therapy 369

29. Laser Treatment on Ethnic Skin 417

Section VI: Appendices

Appendix B. Photopatch Testing 441

Appendix C. Guidelines for Setting Up a Phototherapy Referral Center or an

Appendix D. Guidelines for Setting Up a Laser Center 457

Macrene R. Alexiades-Armenakas Department of Dermatology, Yale University School of

Karl E. Anderson Department of Internal Medicine, Division of Gastroenterology and

Mark Berneburg Department of Dermatology, Eberhard Karls University, Tuebingen, Germany

Henry Hin Lee Chan Division of Dermatology, Department of Medicine, University of

David E. Cohen Ronald O. Perelman Department of Dermatology, New York University

Robert S. Dawe Department of Dermatology, Ninewells Hospital and Medical School,

Thomas Diepgen Department of Clinical Social Medicine, Occupational and Environmental

Brian L. Diffey Department of Regional Medical Physics, Newcastle General Hospital,

James Ferguson Photobiology Unit, Ninewells Hospital, Dundee, Scotland, U.K.

Marjan Garmyn Department of Dermatology, University of Leuven, Leuven, Belgium

Erhard Hölzle Department of Dermatology and Allergology, Klinikum Oldenburg, Oldenburg,

Herbert Hönigsmann Department of Dermatology, Medical University of Vienna, Vienna, Austria

Takeshi Horio Department of Dermatology, Kansai Medical University, Osaka, Japan

Sally H. Ibbotson Department of Dermatology, Ninewells Hospital and Medical School,

Robert Knobler Division of Special and Environmental Dermatology, Department of Dermatology,

Irene E. Kochevar Wellman Center for Photomedicine, Massachusetts General Hospital,

Jean Krutmann Department of Dermatology and Environmental Medicine, Institut für

Michael Landthaler Department of Dermatology, University Clinic Regensburg, Regensburg,