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Howard R Smith, MD, Adjunct Professor of Medicine, Case Western Reserve University; Chief of Rheumatology, Director of The Herbert Bell
Pain Management Center, Director of Research, Cleveland Clinic, Huron Hospital
Updated: Sep 22, 2010
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. With the recent addition of new and innovative
therapies, the treatment of RA is rapidly advancing.
Pathophysiology
RA has no known 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 numerous autoimmune responses, but whether autoimmunity is a secondary or
primary event is still unknown.
RA has a significant genetic component, and the 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.
CD4 T cells, mononuclear phagocytes, fibroblasts, osteoclasts, and neutrophils play major cellular
roles in the pathophysiology of RA, 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) has been
demonstrated in patients with RA. Ultimately, inflammation and exuberant proliferation of synovium
(ie, pannus) leads to destruction of various tissues, including cartilage, bone, tendons, ligaments,
and blood vessels. Although the articular structures are the primary sites involved by RA, other
tissues are also affected.
Frequency
International
Worldwide, the annual incidence of RA is approximately 3 cases per 10,000 population, and the
prevalence rate is approximately 1%. RA affects all populations, although the disease is much
more prevalent in some groups (eg, 5-6% in some Native American groups) and much less
prevalent in others (eg, black persons from the Caribbean region). First-degree relatives of
individuals with RA are at an increased risk (2- to 3-fold) of the disease. Disease concordance in
monozygotic twins is approximately 15-20%, suggesting that nongenetic factors play an important
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role. Because the worldwide frequency of RA 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 individuals with RA. Spontaneous clinical remission
is uncommon (approximately 5-10%). After 5 years of disease, approximately 33% of patients
are unable to work; after 10 years, approximately half 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 in patients with RA is shortened by 5-10 years, although the mortality rate
may be lower in those who respond to therapy. Increased mortality rates are associated with
poor functional status, age, male sex, socioeconomic factors (eg, level of education), positive
RF findings, extra-articular disease, elevated acute-phase response (erythrocyte
sedimentation rate [ESR], C-reactive protein [CRP]), and increased clinical severity (eg, more
involved joints). Factors that increase the mortality risk include 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.
A meta-analysis by Meune et al (2009) suggests that, despite data suggesting that the
course of RA may have become milder over the past decades, the risk of cardiovascular
death in patients with RA continues to be 60% higher than in the general population. In
studies including 91,916 patients with RA, the overall pooled standardized mortality ratio
(SMR) was 1.6 (95% confidence interval, 1.5-1.8; I(2) = 93%; P (het) <0.0001).
Meta-regression analyses revealed neither any trend in SMR over time (P = 0.784) nor any
relation with disease duration at the time of inclusion (P = 0.513). Meune et al conclude that
reducing cardiovascular mortality should remain a major issue in RA management.[1 ]
Race
RA affects all ethnic groups, although the disease is much more prevalent in some groups (eg,
5-6% in some Native American groups) and much less prevalent in others (eg, black persons from
the Caribbean region).
Sex
RA is 2-3 times more common in females than in 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.
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to adult RA.
For additional information on juvenile rheumatoid arthritis, see the article Juvenile
Rheumatoid Arthritis in eMedicine’s Pediatrics: General Medicine volume.
Clinical
History
The American College of Rheumatology developed the following criteria for the classification of
rheumatoid arthritis (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
include the right and left proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist,
elbow, knee, ankle, and metatarsophalangeal (MTP) joints.
3. Arthritis of hand joints: At least one area in a wrist, MCP, or PIP joint is swollen.
4. Symmetric arthritis (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.
The presence of 4 criteria supports the diagnosis of RA. 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 with RA often present with constitutional symptoms, 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 RA 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 with RA (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 RA. In general, the small joints of the hands and
feet are affected in a relatively symmetric distribution. The most commonly affected joints, in
decreasing frequency, include the MCP, wrist, PIP, knee, MTP, shoulder, ankle, cervical spine,
hip, elbow, and temporomandibular joints. 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,
boutonnière and swan-neck deformities, hammer toes, and, occasionally, joint ankylosis.
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The American College of Rheumatology has developed criteria to aid in determining the
progression, remission, and functional status of patients with RA.
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Causes
The cause 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 a 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.
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
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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:
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.
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-inflammatory 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. Macrophages and synovial fibroblasts are the main
producers of the proinflammatory cytokines TNF-alpha and IL-1.
B cells are important in the pathologic process and may serve as antigen-presenting
cells. B cells also 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. While rituximab may be used
as a sole agent, it is often used in combination with MTX. Rituximab has been shown to
be effective in reducing the signs and symptoms in adult patients with moderately to
severely active RA who have had an inadequate response to one or more
TNF-antagonist therapies.[2,3,4 ]
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
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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 two events are linked is unclear; however, the
autoimmune response conceivably leads to the formation of immune complexes that
activate the inflammatory process to a much higher degree than normal. This theory is
supported by the much worse prognosis of RA among patients with positive RF results.
In patients with RA, autoantibodies are directed not only against immunoglobulin G
(IgG), ie, RFs, but also against various other antigens, such as nuclear antigens (RA
33, EBNA), citrullinated proteins (anti-CCP antibodies), collagen, and glucose-
6-phosphate isomerase.
Differential Diagnoses
Amyloidosis, Overview Myelodysplastic Syndrome
Calcium Pyrophosphate Deposition Disease Osteoarthritis
Cryoglobulinemia Paraneoplastic Syndromes
Fibromyalgia Polychondritis
Hepatitis B Polymyalgia Rheumatica
Hypothyroidism Psoriatic Arthritis
Inflammatory Bowel Disease Sarcoidosis
Lyme Disease Sjogren Syndrome
Mediterranean Fever, Familial Systemic Lupus Erythematosus
Multicentric Reticulohistiocytosis 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, Sjögren syndrome, vasculitis,
cryoglobulinemias)
Other rheumatic diseases (eg, polyarticular gout, seronegative spondyloarthropathy [eg,
ankylosing spondylitis, reactive arthritis])
Subacute bacterial endocarditis
Hemoglobinopathies
Angioimmunoblastic lymphadenopathy
Workup
Laboratory Studies
No pathognomonic test is available to help confirm the diagnosis of rheumatoid arthritis (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;
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additionally, the CRP value over time correlates with radiographic progression.
Hematologic parameters include a CBC count and synovial fluid analysis.
Complete blood cell count
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
Inflammatory synovial fluid (WBC count >2000/µL) is present with WBC counts
generally from 5,000-50,000/µL.
Usually, neutrophil predominance (60-80%) is observed in the synovial fluid (in
contrast with mononuclear cell predominance in the synovium).
Because of a transport defect, the glucose levels of pleural, pericardial, and
synovial fluids in patients with RA are often low compared to serum glucose
levels.
Imaging Studies
Radiography: 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
Others when indicated
MRI: This modality is used primarily in patients with abnormalities of the cervical spine; early
recognition of erosions based on MRI images has been sufficiently validated.
Ultrasonography: This allows recognition of effusions in joints that are not easily accessible
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(eg, hip joints, shoulder joints in obese patients) and cysts (Baker cysts). High-resolution
sonograms may allow visualization of tendon sheaths, changes and degree of
vascularization of the synovial membrane, and even erosions; however, this needs further
validation. Ultrasonography 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
Medical Care
The optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach of
pharmacologic and nonpharmacologic therapies.
Nonpharmacologic
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, to increase muscle strength, and to reduce pain.
Occupational therapy is initiated (1) to help patients to use joints and tendons
efficiently without stressing these structures, (2) to help decrease tension on the joints
with specially designed splints, and (3) to cope with daily life through adaptations to
the patients' environment and the use of different aids.
Orthopedic measures include reconstructive and replacement-type surgical measures.
Pharmacologic
The American College of Rheumatology is developing RA recommendations and
algorithms for the use of nonbiological and biological DMARDs for patients with RA.
DMARDs represent the most important measure in the successful treatment of RA.
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 anti-inflammatory or
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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 biological agents.
Xenobiotic agents include the following:
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.
Minocycline may act as a DMARD through its action as a matrix metalloproteinase
inhibitor.
Leflunomide is the most recent addition to the xenobiotics and has an activity that
is 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 lower 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.
Visser et al (2009) conducted a systematic review to assess the evidence for the
optimal treatment of RA with MTX. The study sought to establish the optimal
dosage and route of administration of MTX. In the review of 1748 articles
identified in the literature, 38 met inclusion criteria. The analysis concluded that
an initial MTX dose of 15 mg/week orally with escalation of 5 mg/month to achieve
target doses of 25-30 mg/week or maximum tolerable doses was the optimal,
evidence-based dosing strategy. Starting at higher initial doses or too rapid of
escalation is limited by toxicity. Conversion from oral to subcutaneous
administration of MTX is suggested for patients who have an inadequate
response to oral therapy.[5 ]
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 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. Wolfe and
Marmor studied nearly 4,000 patients with RA or SLE who had used the
antimalarial hydroxychloroquine and concluded that the risk of
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hydroxychloroquine toxicity was relatively low but increased (>1%) after 7 years of
therapy.[6 ]Nevertheless, these drugs, when used with appropriate clinical and
laboratory control monitoring, are usually well tolerated. Adverse events typically
become rarer after the first 2-3 months. Most adverse events are reversible with
drug cessation or with dose reduction.
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. Currently, predicting which patients will
not respond is not possible. 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.
Biological agents include the following:
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 p 75–TNF 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.[7 ]
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 biological agents can often be made
within 3 months after initiation of therapy.
Adverse effects associated with the biological 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 radiography and/or purified protein derivative
(PPD) testing is recommended before these agents are started.
Another biological agent 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 CD86, thereby blocking their interaction with CD28. 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.
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Surgical Care
Cervical spine involvement usually affects C1-C2 and may potentially cause serious neurologic
consequences. Patients who are to undergo intubation or procedures that may involve
manipulation of the neck should undergo 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
Medication
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Optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach of
pharmacologic and nonpharmacologic therapies.
Leflunomide (Arava)
First new DMARD approved in more than 10 years. Blocks autoimmune antibodies and reduces
inflammation. Inhibits dihydroorotate dehydrogenase, an enzyme in the de novo pyrimidine
synthesis pathway. Studies indicate that it reduces symptoms, possibly better than MTX, and may
even slow progression of RA. Use with caution in renal insufficiency
Dosing
Adult
Pediatric
Not established
Interactions
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
Precautions
Serious adverse reactions include hepatotoxicity and immunosuppression; other reactions include
nausea, diarrhea, abdominal pain, rash, bronchitis, headache, hypertension, dizziness, and
alopecia; caution if impaired liver or renal function or if immunodeficient; leflunomide is a prodrug
and active metabolite has a very long plasma half-life (approximately 15 d); with serious toxicity,
can be cleared more quickly using cholestyramine 8 mg tid
Dosing
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Adult
Pediatric
Not established
Interactions
Oral aminoglycosides may decrease absorption and blood levels of concurrent oral MTX; charcoal
lowers levels; coadministration with etretinate may increase hepatotoxicity; folic acid or its
derivatives contained in some vitamins may decrease response; probenecid, NSAIDs, salicylates,
procarbazine, and sulfonamides, including TMP-SMZ, can increase plasma levels; may decrease
phenytoin plasma levels; may increase plasma levels of thiopurines
Contraindications
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Monitor CBC counts monthly and liver and renal function every 1-3 mo during therapy (monitor
more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg,
renal insufficiency, dehydration); has toxic effects on hematologic, GI, and pulmonary systems;
discontinue if significant drop in blood counts occurs; fatal reactions reported when administered
concurrently with NSAIDs or in setting of significantly impaired renal function; folic acid
supplementation (1 mg/d) may decrease adverse GI effects
Acts locally to decrease inflammatory response and systemically inhibits prostaglandin synthesis.
Dosing
Adult
Initial: 1 g PO tid/qid
Maintenance: 2 g/d PO in divided doses
Pediatric
Interactions
Decreases effects of iron, digoxin, and folic acid; conversely, increases effect of oral
anticoagulants, oral hypoglycemic agents, and MTX
Contraindications
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Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in patients with renal or hepatic impairment, blood dyscrasias, or urinary obstruction;
adverse effects include anorexia, nausea/vomiting, diarrhea (enteric-coated tabs may reduce
adverse GI effects), photosensitivity, headache, dizziness, urticaria/pruritus, hemolytic anemia,
interstitial nephritis, acute nephropathy, hematuria, cirrhosis, jaundice, and hepatic necrosis (rare)
Hydroxychloroquine (Plaquenil)
Dosing
Adult
Pediatric
Not established
Interactions
Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption
Contraindications
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus
Precautions
Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for
long-term use in children; visual symptoms or muscular weakness may occur; perform periodic
(q6mo) ophthalmologic examinations; test periodically for muscle weakness
Biologicals
Various biologic agents are used to rheumatic actions on joints and may include TNF–alpha
inhibition and targeted monoclonal antibodies.
Data accumulated from 3 Swedish registries analyzed the cancer risk in 6,366 patients with RA
taking TNF blockers. Data were compared with 61,160 patients with RA who were biologics-naive,
5,989 patients starting methotrexate, 1,838 patients starting DMARD combination therapy, and the
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general Swedish population. Results showed that, among patients taking TNF blockers (25,693
person-years of follow-up in 6,366 patients over 6 y), 240 developed first-time cancer, yielding a
relative risk (RR) of 1.00 (confidence interval, 95%; 0.86-1.15) compared with the biologics-naive
cohort. Similar RRs were shown with the other cohorts. The authors did not observe an increased
risk for cancer with TNF blockers in this study.[15 ]
Tsuzaka et al found that the baseline ADAMTS5 (a disintegrin and metalloproteinase with
thrombospondin motifs 5) mRNA level may be used as a biomarker for prediction of the response
to infliximab in patients with rheumatoid arthritis. ADAMTS5 is said to play a significant role in
cartilage deterioration. Low baseline ADAMST5 levels were significantly lower in the good
responder group compared with those in the nonresponder and moderate responder groups.[17 ]
According to a study by Caporali et al, anti-TNF-alpha therapy is safe and hepatitis B reactivation
did not occur in carriers of antibodies to hepatitis B core antigen (anti-HBc) who were affected by
chronic inflammatory arthropathies.[18 ]
Rituximab (Rituxan)
Chimeric IgG1-kappa monoclonal antibody directed against the CD20 antigen found on the
surface of normal and malignant B lymphocytes. The Fab domain of rituximab binds to CD20
antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell
lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC)
and antibody-dependent cell-mediated cytotoxicity (ADCC). Rituximab in combination with
methotrexate is indicated to reduce signs and symptoms in adult patients with moderately to
severely active RA who have had an inadequate response to one or more TNF antagonist
therapies.
Dosing
Adult
Pediatric
Not established
Interactions
No formal drug interaction studies performed with rituximab; renal toxicity reported with drug in
combination with cisplatin in clinical trials (in clinical trials involving patients with RA, concomitant
administration of methotrexate or cyclophosphamide did not alter pharmacokinetics of rituximab)
Contraindications
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Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus
Precautions
Safety and efficacy of re-treatment not established in controlled trials; not recommended in
patients with RA and no prior inadequate response to one or more TNF antagonists; has caused
severe infusion reactions (in some cases, reactions were fatal); hepatitis B virus (HBV) reactivation
with fulminant hepatitis, hepatic failure, and death has been reported in some patients with
hematologic malignancies treated with rituximab; hypersensitivity reactions (non–IgE-mediated
reactions reported); mucocutaneous reactions, some with fatal outcome, have been reported in
patients treated with rituximab; vaccination with live-virus vaccines not recommended
Infliximab (Remicade)
Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its binding
to TNF-alpha receptor. Reduces infiltration of inflammatory cells and TNF-alpha production in
inflamed areas. Used with MTX in patients who have inadequate response to MTX monotherapy.
Dosing
Adult
3 mg/kg IV at weeks 0, 2, and 6; then q4-8wk, usually with MTX; some patients require higher
doses (4-5 mg/kg)
Pediatric
Not established
Interactions
None reported
Contraindications
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus
Precautions
TNF-alpha modulates cellular immune responses; anti–TNF therapies, such as infliximab, may
adversely affect normal immune responses and allow development of superinfections; may
increase risk of reactivation of TB in patients with certain granulomatous infections; PPD-positive
patients require TB prophylaxis; may cause anti-DNA antibodies and drug-induced lupus; caution
in congestive heart failure
Etanercept (Enbrel)
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Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surface
receptors, which, in turn, decreases inflammatory and immune responses.
Dosing
Adult
Pediatric
Administer as in adults
Interactions
None reported
Contraindications
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in impaired renal function and asthma; discontinue administration if serious infection
develops; adverse effects may include injection-site pain, localized erythema, rash, URI
symptomology, GI upset, nausea, vomiting, rhinitis, cough, and drug-induced lupus; caution in
congestive heart failure
Adalimumab (Humira)
Recombinant human IgG1 monoclonal antibody specific for human TNF. Indicated to reduce
inflammation and inhibit progression of structural damage in moderate-to-severe rheumatoid
arthritis. Reserved for those who experience inadequate response to one or more DMARDs. It can
be used alone or in combination with MTX or other DMARDs. Binds specifically to TNF-alpha and
blocks interaction with p55 and p75 cell-surface TNF receptors.
Dosing
Adult
40 mg SC q2wk; may increase to 40 mg SC qwk in some patients not taking concomitant MTX
Pediatric
Not established
Interactions
May interfere with immune response to live virus vaccine (MMR) and reduce efficacy; MTX
decreases clearance (available data do not support adjusting dose of either HUMIRA or MTX)
Contraindications
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tuberculosis
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Causes immunosuppression; may reactivate tuberculosis infection; increases risk for lymphoma
development; associated with CNS demyelination (rare); discontinue if serious infection develops;
autoantibody development may occur, causing lupuslike syndrome; caution in congestive heart
failure
Golimumab (Simponi)
Dosing
Adult
Pediatric
Interactions
Higher incidence of serious infections may occur when coadministered with abatacept, anakinra,
or rituximab (do not administer concurrently); may decrease humoral response to live-virus
vaccines (eg, MMR)
Contraindications
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Similar to other TNF-alpha inhibitors, may cause reactivation of tuberculosis or hepatitis B; test
patients for latent tuberculosis before initiating treatment; serious infections (eg, bacterial sepsis,
severe invasive fungal infections, opportunistic infections) may occur; do not initiate if infection
exists, and discontinue if serious infection or sepsis develops; lymphoma incidence increased over
general population; may exacerbate existing demyelinating disease or cause new onset of
demyelinating disease; may worsen heart failure or may cause new onset of heart failure; common
adverse effects include upper respiratory tract infection, sore throat, and nasal congestion
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reducing swelling and pain. However, they do not retard joint destruction and alone are not
sufficient to treat RA. As with glucocorticoids, dose can be reduced or drug discontinued with
successful DMARD therapy.
Coxibs and NSAIDs have been given a "black box" warning by the US Food and Drug
Administration regarding their potential for increased serious cardiovascular thrombotic events.
NSAIDs may increase the risk of serious cardiovascular thrombotic events, MI, and stroke, which
can be fatal. NSAIDs also increase the risk of serious adverse GI effects, including stomach or
intestinal bleeding, ulceration, and perforation, which can be fatal. Elderly patients are at greater
risk for serious GI events.
Several dozen NSAIDs are available, which can be classified into different groups of compounds.
Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac.
Selective COX-2 inhibitors may be considered for patients at risk for GI bleeding. Combination
products that include an NSAID and a proton pump inhibitor are also an option.
Indicated for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by
decreasing prostaglandin synthesis.
Dosing
Adult
Pediatric
Interactions
Administration with aspirin increases risk of inducing serious NSAID-related adverse effects;
probenecid may increase concentrations and, possibly, toxicity; may decrease effect of
hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and
thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of
bleeding); may increase risk of MTX toxicity; phenytoin levels may be increased when
administered concurrently
Contraindications
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in congestive heart failure, hypertension, and decreased renal and hepatic function;
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Celecoxib (Celebrex)
Primarily inhibits COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and
inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic
concentrations, COX-1 isoenzyme is not inhibited, thus GI toxicity may be decreased. Seek lowest
dose for each patient.
Dosing
Adult
Pediatric
Not established
Interactions
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
May cause fluid retention and peripheral edema; caution in compromised cardiac function,
hypertension, and conditions predisposing to fluid retention; caution in severe heart failure and
hyponatremia because may deteriorate circulatory hemodynamics; NSAIDs may mask usual signs
of infection; caution in the presence of existing controlled infections; evaluate therapy when
symptoms or lab results suggest liver dysfunction
For relief of mild to moderate pain and inflammation. Small dosages are initially indicated in small
and elderly patients and in those with renal or liver disease. Doses of more than 75 mg do not
increase therapeutic effects. Administer high doses with caution and closely observe patient for
response.
Dosing
Adult
Pediatric
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Interactions
Coadministration with aspirin increases risk of inducing serious NSAID-related side effects;
probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of
hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and
thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of
bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when
administered concurrently
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in congestive heart failure, hypertension, and decreased renal and hepatic function;
caution in coagulation abnormalities or during anticoagulant therapy
Naproxen (Naprosyn)
For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity
of cyclo-oxygenase, which is responsible for prostaglandin synthesis.
NSAIDs decrease intraglomerular pressure and decrease proteinuria.
Dosing
Adult
Pediatric
Interactions
Coadministration with aspirin increases risk of inducing serious NSAID-related side effects;
probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of
hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and
thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of
bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when
administered concurrently
Contraindications
Precautions
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Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary
necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk
acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during
therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation
and may require discontinuation of drug
Naproxen component is indicated for relief of signs and symptoms of osteoarthritis, rheumatoid
arthritis, and ankylosing spondylitis. Naproxen is an NSAID that inhibits inflammatory reactions
and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin
synthesis.
Esomeprazole component is indicated to decrease risk of gastric ulcers in patients at risk of
developing NSAID-associated gastric ulcers. Esomeprazole is the S-isomer of omeprazole, a
proton pump inhibitor. Inhibits gastric acid secretion by inhibiting H+/K+-ATPase enzyme system at
secretory surface of gastric parietal cells.
Dosing
Adult
Pediatric
Interactions
Concomitant use of NSAIDs may reduce antihypertensive effect of ACE inhibitors, diuretics, and
beta-blockers; NSAIDs increase lithium plasma levels; concomitant use with methotrexate may
increase methotrexate toxicity; concomitant use with warfarin may result in increased risk of
bleeding complications (monitor INR and prothrombin time); esomeprazole inhibits gastric acid
secretion and may interfere with absorption of drugs for which gastric pH is an important
determinant of bioavailability (eg, ketoconazole, iron salts, digoxin, atazanavir, nelfinavir);
esomeprazole inhibits CYP2C19 and therefore may alter serum levels/activity of CYP2C19
substrates; esomeprazole is extensively metabolized by CYP2C19 and CYP3A4
Contraindications
Documented hypersensitivity; NSAIDs are contraindicated for perioperative pain in the setting of
coronary artery bypass graft surgery (increased risk of MI and stroke); NSAIDs are contraindicated
during late pregnancy (risk of premature closure of ductus arteriosus)
Precautions
Pregnancy
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C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
May cause anaphylactoid reaction; not recommended with severe hepatic impairment or moderate-
to-severe renal impairment; common adverse effects (>5%) include erosive gastritis, dyspepsia,
gastritis, diarrhea, gastric ulcer, upper abdominal pain, and nausea
NSAIDs carry black box warning regarding GI hemorrhage and serious thrombotic sequelae
Piroxicam (Feldene)
Dosing
Adult
10-20 mg/d PO qd
Pediatric
Interactions
Coadministration with aspirin increases risk of inducing serious NSAID-related side effects;
probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of
hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and
thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of
bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when
administered concurrently
Contraindications
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary
necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease
or compromised renal perfusion; reversible leukopenia may occur (discontinue if there is persistent
leukopenia, granulocytopenia, or thrombocytopenia)
Diclofenac (Voltaren)
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Dosing
Adult
25 mg PO bid/tid
If well tolerated, increase by 25 or 50 mg at weekly intervals until satisfactory response is obtained
or total daily dose of 150-200 mg PO is reached
Higher doses generally do not increase effectiveness
Pediatric
Interactions
Coadministration with aspirin increases risk of inducing serious NSAID-related side effects;
probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of
hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and
thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of
bleeding) may increase risk of methotrexate toxicity; phenytoin levels may be increased when
administered concurrently
Contraindications
Documented hypersensitivity; do not administer into CNS or give to patients with peptic ulcer
disease, recent GI bleeding or perforation, renal insufficiency, and those at high risk of bleeding
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary
necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease
or compromised renal perfusion; low white blood cell counts occur rarely, and usually return to
normal in ongoing therapy; discontinuation of therapy may be necessary if there is persistent
leukopenia, granulocytopenia, or thrombocytopenia
Analgesics
Acetaminophen/paracetamol, tramadol, codeine, opiates, and various other analgesic medications
can be used to reduce pain. These agents do not affect swelling or joint destruction.
Used for analgesia in patients with documented hypersensitivity to aspirin or NSAIDs, with upper
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Dosing
Adult
Pediatric
<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d
>12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h
Interactions
Contraindications
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Hepatotoxicity possible in persons with chronic alcoholism following various dose levels; severe or
recurrent pain or high or continued fever may indicate serious illness; contained in many OTC
products, and combined use with these products may result in cumulative doses exceeding
recommended maximum dose
Tramadol (Ultram)
Inhibits ascending pain pathways, altering perception of and response to pain. Also inhibits
reuptake of norepinephrine and serotonin.
Dosing
Adult
Pediatric
Not established
Interactions
Contraindications
Precautions
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Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus
Precautions
Can cause dizziness, nausea, constipation, sweating, or pruritus; additive sedation with alcohol
and TCAs; abrupt discontinuation can precipitate opioid withdrawal symptoms; adjust dose in liver
disease, myxedema, hypothyroidism, or hypoadrenalism; pregnancy and breastfeeding; seizure;
development of tolerance or dependency with extended use
Immunomodulators
These agents interfere with cytokine actions responsible for inflammation.
Anakinra (Kineret)
Competitively and selectively inhibits IL-1 binding to type I receptor (IL-1RI). IL-1 is found in excess
in patients with RA and is produced in response to inflammatory stimuli. By blocking IL-1 binding,
inflammation and pain associated with RA are inhibited. Indicated for RA in patients in whom one
or more DMARDs have failed. Should be administered at approximately the same time every day.
Dosing
Adult
100 mg/d SC
Pediatric
Not established
Interactions
None reported; higher rate of serious infections and neutropenia possible when coadministered
with TNF blocking agents (eg, etanercept, infliximab); may decrease response to live virus
vaccines
Contraindications
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Serious infections may occur (discontinue treatment if serious infection develops); neutropenia
may occur (especially if administered concomitantly with TNF blocking agents); most common
adverse effect is local reaction at site of injection; caution in breastfeeding
Abatacept (Orencia)
Selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86,
thereby blocking CD28 interaction. CD28 interaction provides a signal needed for full T-cell
activation that is implicated in RA pathogenesis. Indicated for reducing signs and symptoms of RA,
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slowing progression of structural damage, and improving physical function in adults with
moderate-to-severe RA who have inadequate response to DMARDs, methotrexate, or TNF
antagonists. May be used as monotherapy or with DMARDs (other than TNF antagonists, because
of increased risk of serious infections [4.4% vs 0.8%]). Not recommended for concomitant use with
anakinra (insufficient experience).
Dosing
Adult
Dose according to body weight; after initial administration, repeat at 2 and 4 wk after first infusion,
then q4wk; infuse over 30 min
<60 kg: 500 mg IV
60-100 kg: 750 mg IV
>100 kg: 1 g IV
Pediatric
Not established
Interactions
In clinical trials, coadministration with TNF antagonists resulted in increased risk of serious
infections; do not administer concurrently with live virus vaccines (eg, MMR) or within 3 mo of
discontinuation
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus
Precautions
Discontinue if serious infection occurs; patients with COPD developed adverse effects more
frequently, including COPD exacerbations, cough, rhonchi, and dyspnea; serious adverse
reactions include serious infections (3% vs 1.9% placebo); malignancy frequency was similar to
that of placebo (1.3% vs 1.1% placebo), with the exception of lung cancer (0.2% vs 0% placebo);
common adverse effects include headache, upper respiratory tract infection, nasopharyngitis, and
nausea
Tocilizumab (Actemra)
Interleukin 6 (IL-6) receptor inhibitor. IL-6 inhibition results in a decreased C-reactive protein level
to within reference range, decreased values in other pharmacodynamic parameters (eg,
rheumatoid factor, erythrocyte sedimentation rate, amyloid A), and increased hemoglobin value.
Indicated for moderate-to-severe active RA in adults who have had an inadequate response to 1 or
more TNF-antagonist therapies. May be used alone or in combination with methotrexate or other
disease-modifying antirheumatic drugs.
Dosing
Adult
4 mg/kg IV q4wk initially; may increase to 8 mg/kg q4wk based on clinical response; not to exceed
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800 mg/dose q4wk; administer IV infusion over 1 h (do not administer as bolus or push)
Pediatric
Not established
Interactions
Not studied with TNF antagonists; do not give live vaccines concurrently; inhibition of IL-6
signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels
than those prior to therapy, leading to increased metabolism of drugs that are CYP450 substrates;
affects multiple CYP450 enzymes, and resultant enzyme restoration may increase metabolism and
decrease effectiveness of certain drugs (eg, oral contraceptives, lovastatin, simvastatin,
atorvastatin, warfarin, cyclosporine, theophylline, omeprazole); effect may last for several weeks
after stopping therapy
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus
Precautions
Boxed warning
Serious infections can occur; if serious infection develops, discontinue until infection is controlled;
monitor for tuberculosis before and throughout therapy
Precautions
Anaphylaxis or serious hypersensitivity has been reported; common adverse effects (ie, >5%)
include upper respiratory tract infections, nasopharyngitis, headache, hypertension, and increased
ALT level; do not use in the presence of any active infection (including localized); caution in GI
perforation; monitor neutrophil, platelet, lipid, and liver function test values
Recommended not to initiate if absolute neutrophil count <2000/mm3, platelet count
<100,000/mm3, or AST/ALT value >1.5 times the upper limit of normal
Glucocorticoids
These agents are potent anti-inflammatory drugs commonly used in patients with RA to bridge the
time until DMARDs are effective. Doses of up to 10 mg/d of prednisone are typically used, but
some patients may require higher doses. Adverse events associated with long-term steroid use
make dose reductions and cessation important in due course.
Dosing
Adult
10-60 mg/d PO or divided bid/qid; generally, maintenance dose should be <10 mg/d; alternatively,
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Pediatric
Not established
Interactions
Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause
digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase
metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia
with coadministration of diuretics
Contraindications
Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective
tissue infections, and fungal or tubercular skin infections; GI ulceration
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Dosing
Adult
100 mg IV or equivalent
Pediatric
Not established
Interactions
Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens
may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease
levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when administered
concurrently with diuretics; grapefruit juice increases prednisolone concentrations;
methylprednisolone and cyclosporine mutually inhibit one another, resulting in increased plasma
levels of each drug
Contraindications
Precautions
Pregnancy
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C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus
Precautions
Follow-up
Deterrence/Prevention
The older traditional DMARDs, injectable gold salts and penicillamine, rarely induce
sustained remission and are usually discontinued within 2 years. Because better agents are
available, they are rarely used.
DMARDs, such as MTX and SSZ, have greater long-term effectiveness but still rarely induce
true remission.
Optimal control may require combination therapy. Recent studies have shown that MTX
combined with other DMARDs is more effective and has acceptable toxicity compared with
monotherapy. Although the combination is not commonly used, cyclosporine with MTX
results in greater clinical improvement than MTX alone. Triple therapy with MTX, SSZ, and
hydroxychloroquine may provide substantially greater clinical improvement than MTX alone
or SSZ plus hydroxychloroquine.[19 ]In combination with infliximab, MTX provides a superior
response to monotherapy.[20 ]In combination with etanercept, MTX provides a higher rate of
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meaningful clinical response. Toxicities of these drug combinations are rarely more
significant than those occurring with any of the individual agents used alone.
The goal of contemporary management of RA should be complete remission or no evidence
of disease activity.
Achieving this goal likely requires ongoing drug therapy, probably using a combination
of MTX with some other DMARD, although some patients may still respond
satisfactorily to monotherapy.
More long-term studies are needed to evaluate potential important adverse effects
associated with combination therapy before definite recommendations can be made.
Complications
RA itself is not fatal, but complications of the disease may shorten survival by years in some
individuals. In general, RA is progressive and cannot be cured; in some, the disease
gradually becomes less aggressive and symptoms may even improve. However, if bone and
ligament destruction and any deformities have occurred, the effects are permanent.
Joint disability and pain with daily life are common. Affected joints can become deformed,
and the performance of even ordinary tasks may be very difficult or impossible. According to
one survey, 70% of patients with RA believe the disease prevents them from living a fully
productive life. In 2000, a study in England found that approximately one third of individuals
stop working within 5 years of the onset of disease.
RA is a systemic disease that can affect other parts of the body in addition to joints. These
effects include the following:
Peripheral neuropathy: This condition affects nerves, most often those in the hands
and feet. It can result in tingling, numbness, or burning.
Anemia
Scleritis: This is an inflammation of the blood vessels in the eye that can result in
corneal damage, scleromalacia, and, in severe cases of nodular scleritis, perforation.
Infections: Patients with RA have a higher risk for infections. The immunosuppressive
drugs required for treatment further increase that risk.
GI problems: Although patients with RA may experience stomach and intestinal
distress, lower rates of stomach and colorectal cancers have been reported among
patients with RA.
Osteoporosis: Osteoporosis is more common than average in postmenopausal women
with RA. The hip is particularly affected. The risk for osteoporosis also appears to be
higher than average in men with RA who are older than 60 years.
Lung disease: One small study found a very high prevalence of lung disease
(pulmonary inflammation and fibrosis) in patients newly diagnosed with RA. However,
the association between a history of smoking and a higher risk for RA may at least
partially account for this finding. Cigarette smoking, in any case, may increase the
severity of the disease.
Heart disease: RA can affect the blood vessels and independently increases the risk for
coronary ischemic heart disease.
Sjögren syndrome: Keratoconjunctivitis sicca is a common complication of RA. Oral
sicca and salivary gland enlargement are less common.
Felty syndrome: This condition is characterized by the combination of splenomegaly,
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Prognosis
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Patient Education
Patient education and counseling are well worth the time invested because they help to reduce
pain, disability, and frequency of physician visits. They represent the most cost-effective
intervention for RA.
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For excellent patient education resources, visit eMedicine's Arthritis Center and Muscle
Disorders Center. Also, see eMedicine's patient education articles Rheumatoid Arthritis,
Juvenile Rheumatoid Arthritis, Understanding Rheumatoid Arthritis Medications, Chronic
Fatigue Syndrome, and Chronic Pain.
Miscellaneous
Medicolegal Pitfalls
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Keywords
rheumatoid arthritis, RA, systemic inflammatory disease, rheumatoid factor, RF, cyclooxygenase,
COX-1, COX-2, nonsteroidal anti-inflammatory drugs, NSAIDs, disease-modifying antirheumatic
drugs, disease-modifying anti-rheumatic drugs, DMARDs, joint destruction, uncontrolled
inflammation, cartilage destruction, bone destruction, morning stiffness, rheumatoid nodules
Howard R Smith, MD, Adjunct Professor of Medicine, Case Western Reserve University; Chief of
Rheumatology, Director of The Herbert Bell Pain Management Center, Director of Research,
Cleveland Clinic, Huron Hospital
Howard R Smith, MD is a member of the following medical societies: American College of
Rheumatology and Ohio State Medical Association
Disclosure: Pfizer Honoraria Speaking and teaching; Roche Consulting fee Consulting
Medical Editor
Kristine M Lohr, MD, MS, Professor, Department of Internal Medicine, Center for the
Advancement of Women's Health and Division of Rheumatology, Director, Rheumatology Training
Program, University of Kentucky College of Medicine
Kristine M Lohr, MD, MS is a member of the following medical societies: American College of
Physicians, American College of Rheumatology, and American Medical Women's Association
Disclosure: Nothing to disclose.
Pharmacy Editor
Managing Editor
Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department
of Medicine, Temple University School of Medicine
Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American
College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.
CME Editor
Alex J Mechaber, MD, FACP, Senior Associate Dean for Undergraduate Medical Education,
Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha,
American College of Physicians-American Society of Internal Medicine, and Society of General
Internal Medicine
Disclosure: Nothing to disclose.
Chief Editor
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Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman
Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha,
American College of Physicians, American College of Rheumatology, American Medical
Association, and Phi Beta Kappa
Disclosure: ACP PEER Honoraria Independent contractor; Stock ownership in multiple
Pharmaceutical companies Ownership interest Other
Further Reading
Additional resources on rheumatoid arthritis are available at Medscape's Rheumatoid Arthritis Resource Center.
Clinical trials
RESTART C0168Z05 Rheumatoid Arthritis Study
A Study to Evaluate the RNA Signature of Rheumatoid Arthritis From Synovium and Whole Blood
Evaluation of EULAR-RAID Score in Rheumatoid Arthritis Patients (Rainbow)
PPAR-Gamma Agonists, Rheumatoid Arthritis and Cardiovascular Disease (RA PPAR)
Rheumatoid Arthritis (RA) Moderate to Low Disease Activity Study (CERTAIN)
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