Rheumatoid Arthritis

Article Last Updated: May 24, 2006

AUTHOR AND EDITOR INFORMATION

Section 1 of 10
Authors and Editors
Introduction
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Miscellaneous
References
Author: Howard R Smith, MD, Adjunct Professor of Medicine, Case Western
Reserve University, Chief of Rheumatology, Director of the Pain Management
Center, Department of Internal Medicine, Division of Rheumatology, Huron
Hospital, Cleveland Clinic Health Systems
Howard R Smith is a member of the following medical societies: American
Association of Immunologists, American College of Rheumatology, American
Federation for Medical Research, and American Medical Association
Editors: Kristine M Lohr, MD, Associate Chief, Program Director, Professor,
Department of Internal Medicine, Division of Rheumatology, University of
Tennessee School of Medicine; Francisco Talavera, PharmD, PhD, Senior
Pharmacy Editor, eMedicine; Elliot Goldberg, MD, Dean of the Western
Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple
University School of Medicine; Alex J Mechaber, MD, FACP, Assistant Dean for
Medical Curriculum, Associate Professor of Medicine, Division of General Internal
Medicine, University of Miami Miller School of Medicine; Herbert S Diamond, MD,
Professor of Medicine, Temple University School of Medicine; Chairman Emeritus,
Department of Internal Medicine, Western Pennsylvania Hospital
Author and Editor Disclosure
Synonyms and related keywords: RA, systemic inflammatory disease,
rheumatoid factor, RF, cyclooxygenase, COX-1, COX-2, nonsteroidal antiinflammatory drugs, NSAIDs, disease-modifying antirheumatic drugs, diseasemodifying anti-rheumatic drugs, DMARDs, joint destruction, uncontrolled
inflammation, cartilage destruction, bone destruction, morning stiffness, rheumatoid

nodules

INTRODUCTION
Background
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown
cause that primarily affects the peripheral joints in a symmetric pattern.
Constitutional symptoms, including fatigue, malaise, and morning stiffness, are
common. Extra-articular involvement of organs such as the skin, heart, lungs, and
eyes can be significant. RA causes joint destruction and thus often leads to
considerable morbidity and mortality. The treatment of RA is rapidly advancing with
the recent addition of new and innovative therapies.

Pathophysiology
RA has an unknown cause. Although an infectious etiology has been speculated
(eg, Mycoplasma organisms, Epstein-Barr virus, parvovirus, rubella), no organism
has been proven responsible. RA is associated with a number of autoimmune
responses, but whether autoimmunity is a secondary or primary event is still
unknown.
RA has a significant genetic component, and the so-called shared epitope of the
HLA-DR4/DR1 cluster is present in up to 90% of patients with RA, although it is
also present in more than 40% of controls. Synovial cell hyperplasia and
endothelial cell activation are early events in the pathologic process that
progresses to uncontrolled inflammation and consequent cartilage and bone
destruction. Genetic factors and immune system abnormalities contribute to
disease propagation.
Major cellular roles are played by CD4 T cells, mononuclear phagocytes,
fibroblasts, osteoclasts, and neutrophils, while B lymphocytes produce
autoantibodies (ie, rheumatoid factors [RFs]). Abnormal production of numerous
cytokines, chemokines, and other inflammatory mediators (eg, tumor necrosis
factor alpha [TNF-alpha, interleukin (IL)1, IL-6, transforming growth factor beta,
IL-8, fibroblast growth factor, platelet-derived growth factor) have been
demonstrated in patients with RA. Ultimately, inflammation and exuberant
proliferation of synovium (ie, pannus) leads to destruction of various tissues such
as cartilage, bone, tendons, ligaments, and blood vessels. Although the articular
structures are the primary sites, other tissues are also affected.

Frequency

International
The worldwide incidence of RA is approximately 3 cases per 10,000 population,
and the prevalence rate is approximately 1%. RA affects all populations, although a
few groups have much higher prevalence rates (eg, 5-6% in some Native American
groups) and some have lower rates (eg, black persons from the Caribbean region).
First-degree relatives of patients with RA have an increased frequency of disease
(approximately 2-3%). Disease concordance in monozygotic twins is approximately
15-20%, suggesting that nongenetic factors play an important role. Because
worldwide frequency is relatively constant, a ubiquitous infectious agent has been
postulated to play an etiologic role.

Mortality/Morbidity
RA does not usually follow a benign course. It is associated with significant
morbidity, disability, and mortality.

Daily living activities are impaired in most patients. Spontaneous clinical

remission is uncommon (approximately 5-10%). After 5 years of disease,
approximately 33% of patients will not be working; after 10 years,
approximately half will have substantial functional disability. Poor prognostic
factors include persistent synovitis, early erosive disease, extra-articular
findings (including subcutaneous rheumatoid nodules), positive serum RF
findings, family history of RA, male sex, and advanced age.
Life expectancy for patients with RA is shortened by 5-10 years, although
those who respond to therapy may have lower mortality rates. Increased
mortality rates are associated with poor functional status, age, male sex,
socioeconomic factors (eg, level of education), positive RF findings, extraarticular disease, elevated acute phase response (erythrocyte sedimentation
rate [ESR], C-reactive protein [CRP]), and increased clinical severity (eg,
more involved joints). Mortality is increased by causes such as infections,
cardiovascular disease, renal disease, GI bleeding, and lymphoproliferative
disorders; these events may be directly due to the disease and its
complications (eg, vasculitis, amyloidosis) or to therapy-induced adverse
effects.

Race
RA affects all populations, although a few groups have much higher prevalence
rates (eg, 5-6% in some Native American groups) and some have lower rates (eg,
black persons from the Caribbean region).

Sex
Females are 2-3 times more likely to develop RA than males.

Age
The frequency of RA increases with age and peaks in persons aged 35-50 years.
Nevertheless, the disease is observed in both elderly persons and children.

Juvenile inflammatory arthritis (JIA) has been classified as polyarticular

(multiple joints), pauciarticular (<5 joints), and systemic. Systemic JIA is
often associated with fever, rash, and organ involvement; it is also called
Still disease.
Children with polyarticular RF-positive arthritis generally have a clinical
course similar to those with adult RA.

CLINICALHistory

The American College of Rheumatology developed the following criteria for the
classification of RA.
1. Morning stiffness: This occurs in and around the joints and lasts at least 1
hour before maximal improvement.
2. Arthritis of 3 or more joint areas: At least 3 joint areas simultaneously have
soft tissue swelling or fluid (not bony overgrowth) observed by a physician.
The 14 possible areas are right or left proximal interphalangeal (PIP),
metacarpophalangeal (MCP), wrist, elbow, knee, ankle, and
metatarsophalangeal (MTP) joints.
3. Arthritis of hand joints of at least one area swollen in a wrist, MCP, or PIP
joint
4. Symmetric arthritis with simultaneous involvement of the same joint areas
on both sides of the body: Bilateral involvement of PIPs, MCPs, and MTPs
is acceptable without absolute symmetry.
5. Rheumatoid nodules: Subcutaneous nodules are present over bony
prominences or extensor surfaces or in juxta-articular regions.
6. Serum RF: Abnormal amounts of serum RF are demonstrated by any
method for which the result has been positive in fewer than 5% of healthy
control subjects.
7. Radiographic changes typical of RA on posteroanterior hand and wrist
radiographs, which must include erosions or unequivocal bony
decalcification localized in or most marked adjacent to the involved joints:
Osteoarthritic changes alone do not qualify.
A patient can be classified as having RA if 4 of 7 criteria are present. Criteria 1-4
must be present for at least 6 weeks, and a physician must observe criteria 2-5.
These criteria are intended as a guideline for classification of patients, often for
research purposes. They do not absolutely confirm or exclude a diagnosis of RA in
a particular patient, especially in those with early arthritis.

Patients often present with constitutional complaints including malaise, fever,

fatigue, weight loss, and myalgias. They may report difficulty performing activities
of daily living (eg, dressing, standing, walking, personal hygiene, using their
hands).
Most patients with the disease have an insidious onset. It may begin with systemic
features, such as fever, malaise, arthralgias, and weakness, before the
appearance of overt joint inflammation and swelling. A small percentage of patients
(approximately 10%) have an abrupt onset with the acute development of synovitis
and extra-articular manifestations. Spontaneous remission is uncommon,
especially after the first 3-6 months.

Physical
Joint involvement is the characteristic feature of patients with RA. In general, the
small joints of the hands and feet are affected in a relatively symmetric distribution.
Those most commonly affected joints, in decreasing frequency, are the MCP, wrist,
PIP, knee, MTP, shoulder, ankle, cervical spine, hip, elbow, and
temporomandibular. Joints show inflammation with swelling, tenderness, warmth,
and decreased range of motion. Atrophy of the interosseous muscles of the hands
is a typical early finding. Joint and tendon destruction may lead to deformities such
as ulnar deviation, boutonnire and swan-neck deformities, hammer toes, and
occasionally joint ankylosis.
Other commonly observed musculoskeletal manifestations are tenosynovitis and
associated tendon rupture (due to tendon and ligament involvement, most
commonly involving the fourth and fifth digital extensor tendons at the wrist),
periarticular osteoporosis due to localized inflammation and generalized
osteoporosis due to systemic chronic inflammation, immobilization-related changes
or corticosteroid therapy, and carpal tunnel syndrome. Most patients have muscle
atrophy from disuse, which is often secondary to joint inflammation.

Effect of RA on organs and organ systems

Skin: Subcutaneous nodules (rheumatoid nodules) occur in many

patients with RA whose RF value is abnormal. They are often present
over pressure points (eg, olecranon). Vasculitic lesions of the skin
may manifest as palpable purpura or skin ulceration.
Cardiac: The incidence of cardiovascular morbidity and mortality is
increased in patients with RA. Nontraditional risk factors appear to
play an important role. Myocardial infarction, myocardial dysfunction,
and asymptomatic pericardial effusions are common; symptomatic
pericarditis and constrictive pericarditis are rare. Myocarditis,
coronary vasculitis, valvular disease, and conduction defects are
occasionally observed.

Pulmonary: RA involvement of the lungs may take several forms,

including pleural effusions, interstitial fibrosis, nodules (Caplan
syndrome), and bronchiolitis obliterans-organizing pneumonia.
o GI: Intestinal involvement, as with kidney involvement, is often
secondary to associated processes such as medication effects,
inflammation, and other diseases. The liver is often affected in
patients with Felty syndrome (ie, RA, splenomegaly, and
neutropenia).
o Renal: The kidneys commonly are not affected directly by RA.
Secondary involvement is common, including that due to medications
(eg, nonsteroidal anti-inflammatory drugs [NSAIDs], gold,
cyclosporin), inflammation (eg, amyloidosis), and associated
diseases (eg, Sjgren syndrome with renal tubular abnormalities).
o Vascular: Vasculitic lesions can occur in any organ but are most
commonly found in the skin. Lesions may present as palpable
purpura, skin ulcers, or digital infarcts.
o Hematologic: Most active patients have an anemia of chronic
disease. Several hematologic parameters parallel disease activity,
including normochromic-normocytic anemia, thrombocytosis, and
eosinophilia, although the latter is uncommon. Leukopenia is a
finding in patients with Felty syndrome.
o Neurologic: Entrapment of nerves is common, such as with the
median nerve in carpal tunnel syndrome. Vasculitic lesions,
mononeuritis multiplex, and cervical myelopathy may cause serious
neurological consequences.
o Ocular: Keratoconjunctivitis sicca is common in RA and is often the
initial manifestation of secondary Sjgren syndrome. The eye may
also have episcleritis, uveitis, and nodular scleritis that may lead to
scleromalacia.
The American College of Rheumatology developed criteria to aid in
determining the progression, remission, and functional status of patients
with RA.
Progression of RA (clinical and radiological staging)
o

Stage 1 (early RA)

o

No destructive changes observed upon roentgenographic

examination
Radiographic evidence of osteoporosis possible
Stage II (moderate progression)
o

Radiographic evidence of periarticular osteoporosis with or

without slight subchondral bone destruction
Slight cartilage destruction possible
Joint mobility possibly limited; no joint deformities observed
Adjacent muscle atrophy

Extra-articular soft tissue lesions (eg, nodules, tenosynovitis)

possible
Stage III (severe progression)

Radiographic evidence of cartilage and bone destruction in

addition to periarticular osteoporosis
Joint deformity (eg, subluxation, ulnar deviation,
hyperextension) without fibrous or bony ankylosis
Extensive muscle atrophy
Extra-articular soft tissue lesions (eg, nodules, tenosynovitis)
possible
Stage IV (terminal progression)
o

Fibrous or bony ankylosis

Criteria of stage III
Remission of RA - Five or more of the following conditions present for at
least 2 consecutive months

o
o
o
o
o
o

Duration of morning stiffness not exceeding 15 minutes

No fatigue
No joint pain
No joint tenderness or pain with motion
No soft tissue swelling in joints or tendon sheaths
ESR of less than 30 mm/h for a female or less than 20 mm/h for a
male
Functional status of patients with RA

o
o
o
o

Class I - Completely able to perform usual activities of daily living

Class II - Able to perform usual self-care and vocational activities but
limited in avocational activities
Class III - Able to perform usual self-care activities but limited in
vocational and avocational activities
Class IV - Limited in ability to perform usual self-care, vocational, and
avocational activities

Causes
The cause(s) of RA is unknown. Genetic, environmental, hormonal, immunologic,
and infectious factors may play significant roles. Socioeconomic, psychological,
and lifestyle factors may influence disease outcome.

Genetic

Approximately 60% of US patients with RA carry the so-called shared

epitope of the HLA-DR4 cluster, which constitutes one of the peptide
binding sites of certain HLA-DR molecules associated with RA (eg,

HLA-DR beta *0401, 0404, or 0405); in addition, HLA-DR1 (HLA-DR

beta *0101) also carries this shared epitope and confers risk,
particularly in certain southern European areas.
o Other HLA-DR4 molecules (eg, HLA-DR beta *0402) do not share the
same epitope and do not confer risk. Genes other than those of the
major histocompatibility complex are also involved, and results from
sequencing genes of RA families suggest the presence of several
susceptibility genes and several resistance genes.
Environmental

For many decades, numerous infectious agents have been

suggested to induce RA. Among these are Mycoplasma organisms,
Epstein-Barr and rubella viruses, and others.
This supposition is further supported indirectly by the following:
o

Occasional reports of flulike disorders preceding the start of

arthritis
The inducibility of arthritis in experimental animals with
different bacteria or bacterial products (eg, streptococcal cell
walls)
The presence of bacterial products including bacterial RNA in
patients' joints
The activity of several agents that have antimicrobial effects as
disease-modifying drugs (eg, gold salts, antimalarials,
minocycline)

Hormonal

Sex hormones may play a role, as evidenced by the disproportionate

number of females with RA, its amelioration during pregnancy, its
recurrence in the early postpartum period, and its reduced incidence
in women using oral contraceptives.
o Hyperprolactinemia may be a risk factor for RA.
Immunologic

All of the major immunologic elements play fundamental roles in the

initiation, propagation, and maintenance of the autoimmune process
of RA. The exact orchestration of the cellular and cytokine events that
lead to pathologic consequences, such as synovial proliferation and
subsequent joint destruction, is complex. It involves T and B
lymphocytes, antigen-presenting cells (eg, B cells, macrophages,
dendritic cells), and numerous cytokines. Aberrant production and
regulation of both pro- and anti-inflammatory cytokines and cytokine
pathways are found in RA.
T cells are assumed to play a pivotal role in the initiation of RA, and
the key player in this respect is assumed to be the Th1 CD4 cells. (T
helper 1 cells produce IL-2 and interferon gamma.)

These cells may subsequently activate macrophages and other cell

populations, including synovial fibroblasts. The latter 2 populations
are the main producers of the proinflammatory cytokines TNF-alpha
and IL-1 that appear to be the major driving forces of inflammation.
B cells are important in the pathologic process because they may
serve as antigen-presenting cells and activated T cells, produce
numerous autoantibodies (eg, RF, to citrullinated proteins), and
secrete cytokines. Elimination of populations of B cells with
monoclonal antibodies (eg, rituximab) offers another effective
therapeutic option.
Experimental models suggest that synovial macrophages and
fibroblasts may become autonomous and thus lose responsiveness
to T-cell activities in the course of the disease.
The hyperactive and hyperplastic synovial membrane is ultimately
transformed into pannus tissue and invades cartilage and bone, the
latter being degraded by activated osteoclasts.
The major difference between RA and other forms of inflammatory
arthritis, such as psoriatic arthritis, does not lie in their cytokine
patterns but rather in the highly destructive potential of the RA
synovial membrane and in the local and systemic autoimmunity.
Whether these 2 events are linked is unclear; however, the
autoimmune response conceivably leads to the formation of immune
complexes activating the inflammatory process to a much higher
degree than is otherwise the case. This theory is supported by the
much worse prognosis of RA among patients positive for RF.
In patients with RA, autoantibodies are not only directed against
immunoglobulin G (IgG), ie, RFs, but also against a variety of other
antigens such as nuclear antigens (RA 33, EBNA), citrullinated
proteins (anti-CCP antibodies), collagen, and glucose-6-phosphate
isomerase.

DIFFERENTIALS
Section 4 of 10
Authors and Editors
Introduction
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Miscellaneous
References

Amyloidosis, Overview
Calcium Pyrophosphate Deposition Disease
Cryoglobulinemia
Fibromyalgia
Hepatitis B
Hypothyroidism
Inflammatory Bowel Disease
Lyme Disease
Mediterranean Fever, Familial
Multicentric Reticulohistiocytosis
Myelodysplastic Syndrome
Osteoarthritis
Paraneoplastic Syndromes
Polychondritis
Polymyalgia Rheumatica
Psoriatic Arthritis
Sarcoidosis
Sjogren Syndrome
Systemic Lupus Erythematosus
Whipple Disease

Other Problems to be Considered

Infectious arthritis - Bacteria (eg, Lyme disease, fungi, mycobacteria),

viruses (eg, hepatitis B, rubella, parvovirus, human T-cell leukemia virus 1)
Autoimmune connective tissue diseases (eg, systemic lupus erythematosus,
progressive systemic sclerosis, mixed connective tissue disease, Sjgren
syndrome, vasculitis, cryoglobulinemias)
Other rheumatic diseases (eg, polyarticular gout, seronegative
spondyloarthropathy [eg, ankylosing spondylitis, reactive arthritis])
Subacute bacterial endocarditis
Hemoglobinopathies
Angioimmunoblastic lymphadenopathy

WORKUP
Section 5 of 10
Authors and Editors
Introduction
Clinical
Differentials
Workup
Treatment

Medication
Follow-up
Miscellaneous
References

Lab Studies

No pathognomonic test is available to help confirm the diagnosis of RA;

instead, the diagnosis is made using clinical, laboratory, and imaging
features.
Markers of inflammation, such as ESR and CRP, are associated with
disease activity; additionally, the CRP value over time correlates with
radiographic progression.
Hematologic parameters include a CBC count and synovial fluid analysis.

Complete blood cell count

o

Anemia of chronic disease is common and correlates with

disease activity; it improves with successful therapy.
Hypochromic anemia suggests blood loss, commonly from the
GI tract (associated with NSAIDs).
Anemia may also be related to disease-modifying
antirheumatic drug (DMARD) therapy.
Thrombocytosis is common and is also associated with
disease activity.
Thrombocytopenia may be a rare adverse event of therapy
and may occur in patients with Felty syndrome.
Leukocytosis may occur but is usually mild.
Leukopenia may be a consequence of therapy or a component
of Felty syndrome, which may then respond to DMARD
therapy.
Synovial fluid analysis
o

An inflammatory synovial fluid (WBC count >2000/L) is

present with counts generally from 5,000-50,000/L.
Usually, neutrophil predominance (60-80%) is observed in the
synovial fluid (in contrast with mononuclear cell predominance
in the synovium).
Note that because of a transport defect, the glucose levels of
pleural, pericardial, and synovial fluids from patients with RA
are often low compared to serum glucose levels.
Immunologic parameters include RF, antinuclear antibodies, and, possibly,
other newer antibodies (anti-RA33, anti-CCP).

Rheumatoid factor
o

RF is present in approximately 60-80% of patients with RA

over the course of their disease but is present in fewer than
40% of patients with early RA.
RF values fluctuate somewhat with disease activity, although
high-titered RF generally remains present even in patients with
drug-induced remissions.
Antinuclear antibodies: These are present in approximately 40% of
patients with RA, but test results for antibodies to most nuclear
antibody subsets are negative.
Newer antibodies (eg, anti-RA33, anti-CCP): Recent studies of antiCCP antibodies suggest a sensitivity and specificity equal to or better
than those of RF, with an increased frequency of positive results in
early RA. The presence of both anti-CCP antibodies and RF is highly
specific for RA. Additionally, anti-CCP antibodies, as do RF, indicate a
worse prognosis.

Imaging Studies

Radiographs: Note that erosions may be present in the feet, even in the
absence of pain and in the absence of erosions in the hands.

Extremities - Hands, wrists, knees, feet, elbows, shoulders, hips,

cervical spine
o Others when indicated
MRI: This modality is primarily used in patients with abnormalities of the
cervical spine; early recognition of erosions based on MRI images has been
sufficiently validated.
Sonography: This allows recognition of effusions in joints that are not easily
accessible (eg, hip joints, shoulder joints in obese patients) and cysts (Baker
cysts). High-resolution ultrasound images may allow visualization of tendon
sheaths, changes and degree of vascularization of the synovial membrane,
and even erosions; however, this needs further validation. Sonography may
be used as an office-based procedure.
Bone scanning: Findings may help to distinguish inflammatory from
noninflammatory changes in patients with minimal swelling.
Densitometry: Findings are useful for helping diagnose changes in bone
mineral density indicative of osteoporosis.

Other Tests

HLA-DR4 (shared epitope) may constitute a helpful marker in early

undifferentiated arthritis.

Procedures

Joint aspiration, diagnostic arthroscopy (histology), and biopsies (eg, skin,

nerve, fat, rectum, kidney) may be considered if vasculitis or amyloidosis is
suggested.

Histologic Findings
The lymphoplasmacytic infiltration of the synovium with neovascularization seen in
RA is similar to that seen in other conditions characterized by inflammatory
synovitis. Early rheumatoid nodules are characterized by small vessel vasculitis
and later by granulomatous inflammation.

TREATMENT
Section 6 of 10
Authors and Editors
Introduction
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Miscellaneous
References

Medical Care
Optimal care of patients with RA requires an integrated approach of pharmacologic
and nonpharmacologic therapies.

Nonpharmacologic

o
o
o

Education is important in helping patients to understand their disease

and to learn how to cope with its consequences.
Physiotherapy and physical therapy are initiated to help improve and
sustain range of motion, increase muscle strength, and reduce pain.
Occupational therapy is initiated (1) to help patients to use joints and
tendons efficiently without stressing these structures, (2) to help

patients decrease tension on the joints through the use of specially

designed splints, and (3) to help patients to cope with daily life
through the use of adaptations to the patients' environment and the
use of different aids.
o Orthopedic measures include reconstructive and replacement-type
surgical measures.
Pharmacologic

o
o

o
o

The most important measure to successfully treat RA is the use of

DMARDs. DMARDs can retard or prevent disease progression and,
thus, joint destruction and subsequent loss of function.
Successful DMARD therapy may eliminate the need for other antiinflammatory or analgesic medications.
Until the full action of DMARDs takes effect, anti-inflammatory or
analgesic medications may be required as bridging therapy to reduce
pain and swelling.
DMARDs can be classified into xenobiotic and biologic agents.
Xenobiotic agents
o

The xenobiotic DMARDs, ie, gold salts (eg, aurothiomalate,

auranofin, others), D-penicillamine, chloroquine and
hydroxychloroquine, sulfasalazine (SSZ), methotrexate (MTX),
azathioprine, and cyclosporin A, have been widely used to
treat RA; some have been used for decades.
MTX and SSZ are the most active compounds in terms of
frequency of remissions and time to onset of action and
provide the best risk-benefit ratios. MTX alone or in
combination with other agents has become the standard of
care for moderate-to-severe RA.
Interest in the use of minocycline has recently been increasing
because of its capacity to act as a DMARD.
Leflunomide is the most recent addition to the xenobiotics and
has an activity similar to that of SSZ and MTX.
SSZ is dosed up to 2-4 g/d, while MTX is administered up to
25 mg once a week (PO, IV, IM, or SC). Both SSZ and MTX
are started at low dosages and are increased to full dosages
within approximately 4-6 weeks. Monitoring of CBC counts and
liver enzymes is important because of the drugs' hematologic
and hepatic toxicities. Approximately 1% of patients develop
agranulocytosis to SSZ or pneumonitis to MTX. Leflunomide is
usually initiated with a loading dose of 100 mg/d for 3 days
and is then continued at 20 mg/d. CBC counts and liver
enzymes also must be monitored. Most of these drugs have
been shown to improve signs and symptoms (as well as
quality of life) and to significantly retard radiographic
progression of RA.

Combination therapy appears to be helpful in patients whose

RA insufficiently or completely fails to respond to monotherapy
with a DMARD. Several compounds have been successfully
combined without unexpected added risks; these usually
include MTX as one of the drugs, ie, MTX plus cyclosporine A,
MTX plus SSZ plus an antimalarial, MTX plus leflunomide, or
MTX plus biologics. In general, the same precautions are
needed as with the single compounds, although liver and bone
marrow toxicity may be increased if compounds affecting
these organs are combined.
The most important and most common adverse events relate
to liver and bone marrow toxicity (MTX, SSZ, leflunomide,
azathioprine, gold compounds, D-penicillamine), renal toxicity
(cyclosporine A, parenteral gold salts, D-penicillamine),
pneumonitis (MTX), allergic skin reactions (gold compounds,
SSZ), autoimmunity (D-penicillamine, SSZ, minocycline) and
infections (azathioprine, cyclosporine A). Antimalarials may
cause ocular toxicity. Nevertheless, these drugs, when used
with appropriate clinical and laboratory control monitoring, are
usually tolerated well. Adverse events typically become more
rare after the first 2-3 months. Most adverse events are
reversible with cessation of the drugs or with reduction of the
doses.
In clinical trials, 30-70% of patients using DMARDs, either
alone or in combination therapy, achieve partial responses
according to the American College of Rheumatology's disease
activity score. Predicting which patients will not respond is
impossible. In clinical practice, attempting to reduce disease
activity as much as possible by (1) increasing the dose of
medication (eg, MTX), (2) switching to other DMARDs in those
who do not respond or in those with responses regarded as
insufficient, or (3) initiating combination therapy is important.
Because patients may require 2-3 months to achieve a full
response to DMARDs, decisions regarding changes in
medication are often delayed until that time.
Biologic agents

The recognition of TNF-alpha and IL-1 as central

proinflammatory cytokines has led to the development of
agents that block these cytokines or their effects. The TNF
blockers include etanercept, infliximab, and adalimumab.
Etanercept, a bivalent p75TNF receptor linked to the Fc
portion of human IgG, is administered at 25 mg SC twice
weekly or 50 mg SC weekly, with or without concomitant MTX.
Infliximab, a chimeric monoclonal antibody against TNF-alpha,
is administered at doses of 3 mg/kg IV at weeks 0, 2, and 6

and then every 4-8 weeks, usually with MTX. Adalimumab, a

recombinant human IgG1 monoclonal antibody specific for
human TNF monoclonal antibody, is administered 40 mg SC
every 2 weeks.
These agents are expensive. Consensus statements do not
recommend their use until at least one xenobiotic DMARD,
usually MTX, has been administered without sufficient
success. In clinical trials, up to 70% of patients achieve
significant responses, but remissions are not usually observed.
These agents bind TNF and thus prevent its interaction with its
receptors; infliximab binds to cells that express membrane
TNF, while etanercept binds lymphotoxin (formerly termed
TNF-beta) in addition to soluble TNF-alpha. Failure to respond
to one TNF blocker does not preclude response to another. As
with xenobiotics, the decision to continue or stop biologic
agents can often be made within 3 months after initiation of
therapy.
Adverse effects associated with the biologic agents include the
generation of antibodies against these compounds,
emergence of antinuclear antibodies, occasional drug-induced
lupuslike syndromes, and infections (including tuberculosis).
Rarely, demyelinating disorders and bone marrow suppression
may occur. Acute and chronic infections, demyelinating
disorders, and recent malignancies are contraindications for
TNF blockers. Thoroughly searching for latent tuberculosis
using chest x-ray films and/or purified protein derivative (PPD)
testing is recommended before starting these agents.
Another biologic is anakinra (IL-1 receptor antagonist [IL-1ra]).
IL-1ra occupies the IL-1 receptor without triggering it and
prevents receptor binding of IL-1. It is given at a dose of 100
mg/d SC. In clinical trials, a significant response was observed
in approximately 40% of patients with RA.
Abatacept is a selective costimulation modulator that inhibits
T-cell activation by binding to CD80 and CED86, thereby
blocking CD28 interaction. CD28 interaction provides a signal
needed for full T-cell activation that is implicated in RA
pathogenesis. It is dosed according to body weight (vida infra);
after initial infusion, repeat on week 2 and week 4, then every
4 weeks following.
In addition to improving signs and symptoms and quality of life,
all biologics significantly retard radiographic progression of
joint erosions.
Glucocorticoids
o

Glucocorticoids are potent anti-inflammatory drugs and are

commonly used in patients with RA to bridge the time until
DMARDs are effective.
Doses of up to 10 mg of prednisone per day are typically used,
but some patients may require higher doses.
Timely dose reductions and cessation are important because
of the adverse effects associated with long-term steroid use.
Nonsteroidal anti-inflammatory drugs

NSAIDs interfere with prostaglandin synthesis through

inhibition of the enzyme cyclooxygenase (COX), thus reducing
swelling and pain. However, they do not retard joint destruction
and, therefore, when used alone, are not sufficient to treat RA.
Similar to glucocorticoids, they can be reduced in dose or
discontinued with successful DMARD therapy.
Several dozen NSAIDs are available and can be classified into
different groups of compounds. Commonly used NSAIDs
include ibuprofen, naproxen, ketoprofen, piroxicam, and
diclofenac.
In the early 1990s, 2 isoforms of COX were discovered, ie,
COX-1 and COX-2. Traditional NSAIDs inhibit both COX-1 and
COX-2.
The coxibs (COX-2 inhibitors), a new group of compounds,
have recently been developed. These compounds have a
significant preference for COX-2 over COX-1. COX-1 has a
protective role, particularly in the stomach, while COX-2 is
strongly up-regulated during inflammation.
Coxibs, with their selectivity for COX-2, have been shown to
be clinically efficacious and are accompanied by significantly
reduced GI toxicity, the major adverse event related to the use
of nonselective COX inhibitors (ie, NSAIDs). Other adverse
effects, such as water retention, hypertension, and abnormal
transaminase levels, are observed with both nonselective and
COX-2selective drugs. Whether and to what degree
nonaspirin NSAIDs, coxibs, or both have cardiovascular
toxicity has not been definitively settled.
Analgesics
o

Acetaminophen/paracetamol, tramadol, codeine, opiates, and

a variety of other analgesic medications can also be employed
to reduce pain.
These agents do not affect swelling or joint destruction.
Experimental therapies
o

Despite significant advances over the past decades, RA

continues to be an incurable disease. The disease remains

active in many patients whose conditions partially or

completely fail to respond to DMARDs. Therefore, a vigorous
search is underway for new therapeutic agents.
Although not truly experimental because it has been approved
for use in RA, an immunoadsorbent column (Prosorba) is used
on occasion to treat patients with resistant disease. Weekly
exchanges are given for 12 weeks.
New TNF blockers are in clinical trials and include CDP 870, a
Fab fragment of a humanized monoclonal antibody; and a
pegylated version of the p55 TNF receptor.
Biologics capable of blocking IL-6 or interfering with Tcell/nonT-cell interactions may also be promising.
Xenobiotics directed at molecules involved in transduction of
TNF or IL-1mediated signals could prove helpful.
Inhibition of matrix metalloproteinases, although initially
unsuccessful, could prove to be efficacious, as could agents
that inhibit activation of osteoclasts.
Apheresis procedures are being investigated.
High-dose immunosuppression combined with autologous
stem cell transplantation has been used in study protocols for
patients whose conditions are resistant to other therapies.
Early therapy
o

Many studies have revealed that early treatment of RA (ie,

within 3-12 mo of onset) with DMARDs can not only more
efficiently retard disease progression than later treatment, but
also may induce more remissions. Thus, early therapy with
DMARDs has become the standard of care.
Importantly, note that patients with early forms of arthritis
should be evaluated by, and if necessary, referred to
physicians who are experienced in the diagnosis and
treatment of this disease.

Surgical Care
Cervical spine involvement usually affects C1-C2 and may potentially cause
serious neurological consequences. Patients who are to undergo intubation or
procedures that may involve manipulation of the neck should have careful
evaluation of the cervical spine.
Patients with RA often need multiple operations over time (eg, synovectomy,
tendon corrections, joint replacements).

Consultations

Orthopedists

Physical and rehabilitative medicine specialists