Online Medical Reference

Rheumatoid Arthritis

William S. Wilke

Published: August 2010

Definition

Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis. Although most readily recognized by its articular manifestations, RA can affect any organ system. The presentation and disease course are distinct for any individual patient, making diagnosis and management a thoughtful, complex, and dynamic process. The diagnostic criteria for RA (Box 1)1 may be used to classify disease in patients in the appropriate clinical setting, but in early disease the criteria may be less helpful in establishing the diagnosis. Whether disease expression is confined to mild articular manifestations or manifests as severe, multisystem disease, our current understanding demands that patients receive early and aggressive therapy. Achieving prompt control of local and systemic inflammatory processes minimizes damage of articular structures, preserves function, and reduces early mortality.

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Prevalence

RA affects about 1% of the world's population2 when defined by either the presence of serum rheumatoid factor (RF) or erosive changes on radiographs in a patient with a compatible clinical presentation. Its incidence is two to three times greater in women, and this disparity is most pronounced in patients younger than 50 years.3 The incidence of RA continues to increase with age until about the seventh decade of life.4

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Pathophysiology

The cause of RA is unknown. The combination of genetic susceptibility with an as-yet-unidentified inciting event (or events) leads to disease expression. The concordance of RA in identical twins is reported as 15% to 30%, suggesting that nongenetic factors have a predominant impact on disease expression.2,5 However, the association of HLA-DR with RA is well established. There is an increased relative risk of RA of about 4 to 5 in patients with this allele.6 Whether shared alleles contribute to disease severity is controversial. More data are needed to establish the precise role of genetic factors.

Infectious agents have long been suspected as potential triggers of RA. Although investigations have failed to identify any one organism in synovial tissue or fluid, polymerase chain reaction techniques have detected bacterial nucleotide sequences in synovial tissues in RA patients. Viral pathogens are also under study, with the Epstein-Barr virus (EBV) targeted for several reasons. RA patients have been found to have higher levels of virus-infected B cells and higher levels of EBV antibody titers than the general population. In addition, the ability of the virus to activate B cells to produce RF has generated interest in this virus as a potential trigger.7 Other viruses of interest include parvovirus B19 and the retroviruses, but conclusive data definitely identifying any viral pathogen as a causative agent are lacking. In fact, bacterial and viral antigenic particles may be carried to sites of inflammation by gut-associated macrophages.8

Rheumatoid factor, an immunoglobulin (Ig)M antiglobulin against the Fc portion of human IgG, is detected in about 70% of patients with RA. Evidence suggests its participation in disease pathogenesis. The presence of RF in RA is associated with extra-articular manifestations of disease, and its absence is generally associated with milder disease. Its proposed mechanisms include enhanced presentation of immune-complexed antigens, cross-linkage and stabilization of low-avidity IgG antibodies, and cryoprecipitation.4 RF is not specific for RA, despite its name, and it may be found in other conditions including bacterial infection, lymphoproliferative disorders, liver disease, and other autoimmune disorders.

Although inciting factors have yet to be identified, the presence and activity of a number of proinflammatory chemokines and cytokines have established roles in disease pathogenesis. The activation and infiltration of T cells and macrophages in the synovium result in production of interleukin-1, -2, -6, -8, -10, -17; tumor necrosis factor-α (TNF-α); platelet-derived growth factor; insulin-like growth factor; and transforming growth factor β.9 These effector molecules are implicated in synovial tissue inflammation and proliferation, cartilage and bone destruction, and systemic effects. B cells also infiltrate the synovium and differentiate into plasma cells, producing polyclonal immunoglobulin and RF. In addition, synovial fibroblasts are activated, releasing collagenases and activating metalloproteinase gene expression, which leads to destruction of matrix tissues. The net result of these activities is pannus formation with articular cartilage invasion, periarticular erosions and osteoporosis, and joint swelling with destruction of periarticular structures. Cigarette smoking increases the risk of developing RA and negatively influences disease course.10,11

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Box 1: Criteria for the Classification of Rheumatoid Arthritis
For classification purposes, a patient has rheumatoid arthritis if he or she has satisfied at least four of these seven criteria. Criteria 1 through 4 must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid arthritis is not to be made.
Morning stiffness
  • Morning stiffness in and around the joints
  • Lasting at least 1 hour before maximal improvement
Arthritis of three or more joint areas
  • At least three joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician
  • The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints.
Arthritis of hand joints
  • At least one area swollen (as defined in 2) in a wrist or in an MCP or PIP joint
Symmetrical arthritis
  • Simultaneous involvement of the same joint areas (as defined in 2) on both sides of the body
  • Bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry
Rheumatoid nodules
  • Subcutaneous nodules over bony prominences, or extensor surfaces, or in juxta-articular regions, observed by a physician
Serum rheumatoid factor
  • Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects
Radiographic changes
  • Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in, or most marked adjacent to, the involved joints
  • Osteoarthritis changes alone do not qualify

MCP, metacarpophalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal.
Adapted with permission from Kirkham BW, Lassere MN, Edmonds JP, et al: Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum 2006;54:1122-1131.


Clinical Manifestations

Generally, signs and symptoms of RA begin insidiously and are additive over weeks to months. They commonly include fatigue, malaise, generalized stiffness, and generalized arthralgias or myalgias. Synovitis usually develops gradually, often involving the hands, wrists, knees, or feet, often symmetrically. However, in 10% to 15% of patients, the onset of disease is explosive, with polyarthritis, fever, lymphadenopathy, and splenomegaly developing over days to weeks.2,8 It is imperative in patients with the latter manifestation to consider other common causes of acute polyarthritis, such as parvovirus infection.

Evidence of articular disease in RA can appear as swelling, tenderness, warmth, and painful motion. The outward appearance of the joints does not necessarily correlate with the amount of active synovitis or pain expressed by the patient. Patients often complain of morning stiffness, a characteristic of inflammatory arthritis. Stiffness, known as gelling, can also manifest after brief periods of inactivity. The joints most often involved in RA include the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints, wrists, elbows, shoulders, knees, ankles, and subtalar and metatarsophalangeal (MTP) joints. The cervical spine is the only characteristic axial location, and atlantoaxial subluxation is a known complication. Inadequately treated articular inflammation progresses to weakening or destruction of supportive structures, including the associated joint ligaments, tendons, cartilage, and bone. In addition, the pain associated with ongoing synovitis often leads to decreased motion at the affected joints. This, in addition to the ongoing pathologic tissue changes, results in loss of range of motion or, at its most extreme, soft-tissue contractures, fibrosis, and bony ankylosis.

One of the most common extra-articular manifestations of RA is the formation of rheumatoid nodules. This is usually associated with the presence of RF, and it occurs most often in patients with high titers of RF. Rheumatoid nodules develop in 20% to 35% of patients, most often on extensor surfaces and often in response to repetitive trauma.2 However, they can develop at any location and have rarely been identified within the pleura or meninges. Rheumatoid nodules are identified definitively by biopsy, which reveals an outer zone of granulation tissue, a mid-zone of palisading macrophages, and a central zone of necrotic material.9

Vasculitis can also occur as an extra-articular manifestation of RA. This most often manifests as leukocytoclastic vasculitis, which may be an isolated skin finding. With involvement of medium-sized vessels, which is less common, any organ system may be involved, and the disorder may be organ or life threatening. Patients should be carefully assessed for other possible causes (such as infection) before vasculitis is attributed solely to RA. Rheumatoid vasculitis has been associated with a variety of predisposing factors including male sex, high RF titers, erosive joint disease, other extra-articular disease, and glucocorticoid (GC) therapy.2

Ocular manifestations of RA are diverse and range from mild, asymptomatic findings to aggressive, vision-threatening disease. RA is often associated with secondary Sjögren's syndrome (keratoconjunctivitis sicca), which can manifest with eye dryness, foreign-body sensation in the eye, or photophobia. Both scleritis and episcleritis are associated with RA. Scleritis may be associated with severe corneal inflammation, leading to a corneal melt, or with scleromalacia perforans. Chronic inflammation, resulting in perturbation of the intraocular anatomy, can lead to glaucoma. Corticosteroid therapy can be an important factor in cataract formation.

The most common manifestation of pulmonary disease in RA is interstitial lung disease (ILD). The manifestation of RA-associated ILD often parallels that of idiopathic pulmonary fibrosis, often with similar imaging and histopathologic findings. Patients with severe RA or those who smoke are more likely to develop RA-associated ILD. Bronchiolitis obliterans organizing pneumonia has also been described in association with RA. Patients can present with cough, fever, dyspnea, and fatigue. This is a nonspecific entity that could also result from an unrelated process, such as infection. Biopsy is required to exclude other underlying causes. Nodular lung disease in RA can occur in both the pleura and lung parenchyma, with solitary or multiple lesions that can coalesce or cavitate. Diagnosis of RA-associated nodular lung disease requires biopsy. The histopathologic appearance of the lesion is that of a rheumatoid nodule. Evidence of pleural inflammation in RA patients is often noted at autopsy, but it is usually subclinical in life.12 Effusions are often exudative and characteristically have a low glucose concentration. It is important to remember that effusions associated with infectious processes often share these characteristics, mandating cultures to exclude infection.

Rheumatoid pericarditis, as with rheumatoid pleuritis, is often diagnosed at autopsy. Pericardial disease is seen most often in RF-positive patients and is more common in patients with nodular disease.13 Although pericardial tamponade and constrictive pericarditis are very rare, this can result in hemodynamic compromise that requires intervention. Myocarditis can occur in RA, either in the form of nodular granulomatous disease or as diffuse interstitial inflammation. Nodular disease in the conduction system can cause atrioventricular block. Granulomatous disease of the heart valves can lead to valvular insufficiency. Coronary arteritis in RA is rare and can result in myocardial infarction, but most events from ischemic coronary disease in RA patients are caused by atherosclerosis. Patients with RA have an increased atherosclerotic burden (as demonstrated by increased carotid intima-medial thickness and plaque scores) and increased risk of cardiovascular events compared with age- and sex-matched controls.14,15 Although the exact mechanisms of increased atherogenesis in RA are not understood, RA activity has been associated with increased arterial stiffness and endothelial dysfunction that correlate with cardiovascular risk.16,17

Renal disease associated with RA is rare. Manifestations include renal vasculitis, glomerulonephritis and, in patients with sustained inflammation, secondary renal amyloidosis.13 The most common hematologic manifestation of RA is a mild normocytic hypochromic anemia, which occurs in most patients, representing the anemia of chronic disease. Felty's syndrome is characterized by neutropenia, often with associated anemia and thrombocytosis, with splenomegaly and occasionally with leg ulcers. This closely resembles the large granular lymphocyte (LGL) syndrome in RA. Although it is likely that these disorders are related and represent different points on a spectrum of hematologic disease in RA, it is important to differentiate the two, because LGL may be associated with transformation to leukemia. In addition, patients with RA have a risk of lymphoma (both Hodgkin's and non-Hodgkin's) and leukemia two to three times greater than that of the general population.13

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Diagnosis

There is no unique test or feature that is pathognomonic for RA. Rather, the diagnosis is made by recognizing a pattern of signs and symptoms. The classification criteria listed in Box 1 are helpful in classifying patients for the purpose of clinical research studies, but they might not clearly establish the diagnosis in any individual patient.

A history consistent with the diagnosis of RA includes prolonged morning stiffness that may be improved by activity, polyarthralgias or polyarthritis (or both), joint gelling, and fatigue. Examination findings that suggest RA include symmetrical polyarthritis and rheumatoid nodules. Serologic and imaging studies may be helpful in excluding mimics of RA and confirming the diagnosis when pretest probability is high. Arthrocentesis is not diagnostic but is useful in excluding infection. Radiographic changes include periarticular osteopenia, joint space loss, and erosions. Although most serologic studies are not sensitive or specific for RA in general, the use of antibodies to cyclic citrullinated peptides (anti-CCP antibodies) has been demonstrated18 to be more than 90% specific for RA. In patients with an atypical presentation or when another diagnosis is equally likely (e.g., hepatitis C), anti-CCP antibodies may be useful in confirming a diagnosis of RA.

Differential Diagnosis

The list of RA mimics is extensive. RA can resemble any disorder causing acute or chronic polyarthritis. A thorough history and examination are often helpful in the differential diagnosis in the individual patient.

Infectious arthropathies are an important consideration in the setting of fever and polyarthritis. Infections often result in a transiently positive RF, so this is not helpful in differentiation. If bacterial arthritis is suspected, joint aspiration and synovial fluid cultures and blood cultures are often helpful in establishing the diagnosis. One exception is gonococcal arthritis, in which synovial cultures are often negative. Lyme disease is also associated with negative synovial fluid cultures, and it should be considered when a patient has been in an endemic region where tick exposure was likely. Viral infections, both acute and chronic, can result in a polyarthritis that is clinically indistinguishable from RA. Acute viral infections, such as parvovirus B19 infection, often distinguish themselves by a history of exposure, an accompanying rash, and their self-limited course. Even when disease is well established, it is essential to exclude chronic hepatitis infection or human immunodeficiency virus, especially when considering instituting immunosuppressive therapy.

Other connective-tissue diseases can manifest similarly to RA. Patients with systemic lupus erythematosus (SLE) can have a similar distribution of joint involvement but rarely have erosive disease. Jaccoud's arthropathy often leads to deformities that are similar in appearance to those in RA, but these changes result not from joint destruction but from tendon and ligament laxity. These deformities, unlike those in RA, are readily reducible on examination. In most cases, the other clinical manifestations of SLE and serologic findings are helpful in establishing the diagnosis. Psoriatic arthritis, when present without rash, may be difficult to distinguish from RA. Involvement of the sacroiliac joints or the distal interphalangeal joints of the hands can provide a clue to diagnosis. Fortunately, their treatment regimens have significant overlap, so even when differentiation is not possible, instituting effective and appropriate treatment is not hampered.

The other seronegative spondyloarthropathies (reactive arthritis, ankylosing spondylitis, inflammatory bowel disease–associated arthropathy) can also closely resemble RA. Asymmetrical joint involvement, the absence of small-joint disease, sausage-like appearance of digits, and involvement of the lumbosacral spine all favor the seronegative arthropathies. Polymyositis and dermatomyositis can manifest with arthralgias, arthritis, and joint stiffness, similar to RA. Muscle weakness and antibodies associated with these disorders most often readily distinguish these disorders from RA.

Polyarticular crystal arthropathies can also mimic RA. Radiographs might also show joint erosions, but in calcium pyrophosphate dihydrate deposition disease, chondrocalcinosis is often apparent. Synovial fluid analysis is diagnostic of crystal arthropathy.

Polymyalgia rheumatica and giant cell arteritis can manifest with symmetrical polyarthritis. In these patients, a detailed history can help identify the characteristics of these disorders (e.g., a new, unrelenting headache, predominant shoulder and hip girdle involvement). In cases where history does not make the distinction, careful observation of the evolution of the disease over time is key, because the clinical courses and potential serious complications associated with these disorders are quite different.

Systemic vasculitis can manifest with polyarthritis, and, in the case of Wegener's granulomatosis, it can also be RF positive. A thorough history and examination with directed serologic and imaging evaluation aid in differentiating these disorders.

Fibromyalgia (FMS) can manifest with diffuse symmetrical arthralgias and stiffness at rest, but the absence of synovitis, the lack of pain on motion, and normal laboratory and imaging studies confirm the diagnosis of FMS. It is important to remember that FMS is present in 10% to 15% of patients with rheumatic diseases such as SLE and RA; hence, its diagnosis does not exclude other concomitant disease.19,20

Sarcoidosis can manifest with polysynovitis and is not infrequently RF-positive, but it has other distinguishing characteristics that often help to differentiate it from RA. In Löfgren's syndrome, the acute onset of polyarthritis is accompanied by erythema nodosum and hilar adenopathy. Chronic sarcoid arthropathy may clinically closely mimic RA, and on radiographs it can show bony destruction similar to that in RA. Tissue biopsy may be necessary in these instances if no other manifestations of sarcoidosis are present to establish the diagnosis.

Osteoarthritis is best differentiated from RA by a careful history and examination. The absence of systemic inflammatory signs and symptoms, onset in later life, and the pattern of joint involvement are often enough to distinguish the two disorders. Erosive osteoarthritis can have an inflammatory appearance on examination, but it tends to involve the PIP joints primarily, is not associated with proliferative synovitis, is not RF positive, and has a distinct radiographic appearance.

Malignant diseases are uncommon RA mimics. Local bone or joint involvement from cancer usually manifests as monoarticular arthritis. However, lymphoproliferative or myeloproliferative disorders can occur with polyarthralgias or polyarthritis. In addition, paraneoplastic syndromes can manifest with polyarticular symptoms designated as hypertrophic osteoarthropathy. Digital clubbing, bone pain on palpation or percussion, and periosteal reaction on radiography help to establish this diagnosis.

Imaging

Characteristic radiographic findings of RA include periarticular osteopenia, joint space loss, and marginal joint erosions. These changes are often not seen in early disease; only 15% to 30% of patients have erosions visible on radiographs during the first year of the disease.21 Because erosions most often appear first on the hands, wrists, or feet, these are the areas that should be initially imaged when the diagnosis is suspected.

Magnetic resonance imaging (MRI) is useful in detecting RA before radiographic changes can be detected. MRI is more sensitive in detecting erosions, and it is capable of identifying bone marrow edema and synovial hypertrophy.22 Both of these findings predict the development of erosive disease.

Ultrasonography is used infrequently in establishing a diagnosis of RA, and it is more sensitive in detecting synovial and tendon inflammation than clinical examination alone.23,24 Ultrasonography might also be useful in guided joint aspiration and injection.

Monitoring Disease Activity

It cannot be overemphasized that the timely institution of therapy in RA has a significant impact on preserving joint structure and function and has implications for the patient's long-term overall health and function. If control of disease is achieved early (e.g., within the first several months), the rate of radiographic progression and joint destruction is minimized. Although the best outcomes are obtained with early aggressive control of disease, it is never too late to intervene if ongoing inflammation is present.

Disease activity and response to therapy are best followed clinically by the use of scaled measurements that are assessed at each visit. A number of instruments have been validated for use in RA. The ACR preliminary definition of improvement in rheumatoid arthritis (ACR 20, 50, and 70, with the numbers referring to percentage of improvement) is commonly used in assessment for clinical trials and includes serologic and physical assessments (Box 2).25

Box 2: American College of Rheumatology Preliminary Definition of Improvement in Rheumatoid Arthritis (ACR 20)
Required
  • ≥20% improvement in tender joint count
  • ≥20% improvement in swollen joint count
In addition to >20% improvement in three of the following five categories:
  • Patient pain assessment
  • Patient global assessment
  • Physician global assessment
  • Patient self-assessed disability
  • Acute-phase reactant (erythrocyte sedimentation rate or C-reactive protein)

Adapted from Felson DT, Anderson JJ, Boers M, et al: American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727-735.


However, the dichotomous ACR criteria are less sensitive for overall changes than are continuous measures such as the Disease Activity Score or the Simple Disease Activity Index. For this reason, these continuous scales are recommended for monitoring disease activity and response to therapy. The Stanford Health Assessment Questionnaire is another often-used tool that provides much useful information regarding the ability of the patient to carry out the activities of daily living and is a practical means of tracking the efficacy of therapy. The common coexistence of depression in chronic disease and its impact on emotional and physical health should not be overlooked.

Failure to treat depression in patients with RA significantly affects their well-being no matter how well their disease is controlled. The Beck Depression Index is a useful questionnaire to screen for clinical depression in patients with RA and other chronic diseases.

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Treatment

The mainstays of therapy in RA are the disease-modifying antirheumatic drugs (DMARDs). These medications prevent or reduce joint destruction, maintain or improve function, and, in some cases, improve other aspects of the patient's general health.

Glucocorticoids

Glucocorticoids (GCs) are used to suppress inflammation and preserve joint structure and thus may be considered DMARDs. They are often used at disease onset or with disease flares as a temporary aid in obtaining disease control. Because of their long-term side effects, it is desirable to obtain disease control without chronic use of GCs whenever possible and to use the lowest doses necessary. In a long-acting form, they are also useful for intra-articular injection when only one or two joints are active. GCs in high doses are an essential part of treating organ-threatening disease in RA, such as in rheumatoid vasculitis. They are also useful in maintaining disease control during pregnancy when most other DMARDs are contraindicated.

Methotrexate

Methotrexate (MTX) should be considered first-line therapy for the treatment of RA. MTX is a folic acid antagonist, but its precise mechanism of action in RA treatment is unknown. MTX acts within weeks to diminish disease activity. It has also been shown to decrease radiographic progression of disease.26 MTX can be used in combination with other DMARDs to achieve and maintain disease remission.

Although initially the potential hepatotoxicity of MTX caused concern, long-term follow-up of patients on chronic MTX therapy has alleviated many of these worries. Serious irreversible liver damage is rare in patients who do not have hepatitis and who consume minimal amounts of alcohol and have regular laboratory monitoring. Generally, liver enzymes are measured after 1 month of therapy, and are repeated at 8- to 12-week intervals after a stable dose is established.

MTX can result in a hypersensitivity-type reaction, MTX-associated pneumonitis, that can manifest with nonspecific symptoms such as fever, fatigue, cough, or dyspnea. When this diagnosis is suggested, MTX should be discontinued immediately. This manifestation can be indistinguishable from infection, and appropriate investigations and treatment for both should be initiated immediately. Biopsy may be necessary to establish the diagnosis.

Because the half-life of MTX primarily depends on renal function, patients with chronic renal insufficiency should not be treated with this agent. To minimize alopecia, mouth ulcers, nausea, and hepatic toxicity, folic acid (1-2 mg/day) should be given to all MTX-treated patients.

Hydroxychloroquine, Sulfasalazine, and Leflunomide

Hydroxychloroquine and sulfasalazine are DMARDs that provide mild anti-inflammatory activity in most patients. They are used as single agents (only in patients with very mild, nonerosive disease) or in combination. They are both well tolerated and have few side effects. Their major application in RA is as a supplement to MTX or other DMARD therapy. Leflunomide, a pyrimidine synthesis inhibitor, is also used as add-on therapy with MTX or other agents. Leflunomide can cause liver enzyme elevation and requires regular liver enzyme monitoring.27

Two important combination strategies have been tested and reported. Triple therapy combining sulfasalazine, hydroxychloroquine, and MTX is more effective than monotherapy and not more toxic.28 The BeSt trial demonstrated that initial treatment with MTX combined with an anti–tumor necrosis factor (anti-TNF) agent was the safest and most effective therapy when compared with three less-aggressive strategies.29

Anti–Tumor Necrosis Factor Agents

The anti-TNF agents are highly effective DMARDs. Etanercept, infliximab, and adalimumab are all in use as second-line therapy for RA. They are most often added to MTX or other ongoing therapy. A bonus effect of the anti-TNF agents in RA is their impact on vascular function. Endothelium-dependent vasodilation, a marker of endothelial function, is improved by anti-TNF therapy, suggesting a potential protective effect on vascular function.30 Further studies are needed to determine the impact of anti-TNF agents on the accelerated atherogenesis associated with RA. Infliximab should be administered with MTX to prevent the development of neutralizing antibodies that can render infliximab less effective.

Before therapy with an anti-TNF agent is initiated, patients should be screened by skin test and chest radiograph for the presence of tuberculosis. TNF has an important role in the formation of granulomas; this was recognized when reactivation tuberculosis emerged as a complication of anti-TNF therapy.

The anti-TNF agents also have other significant immunosuppressive effects. Infections in patients being treated with these agents can progress more rapidly and follow a more fulminant course. Signs and symptoms of any significant infectious process (e.g., anything requiring antibiotic, antiviral, or antifungal therapy) mandate the temporary discontinuation of any of these agents until the infection is resolved.

The role of these agents in the development of hematologic malignancies is unclear. Although the development of lymphomas during therapy with these agents has been documented, as previously discussed, these occur de novo at higher rates in patients with RA.13 No further malignancy evaluation outside of routine health screening is advised for patients on anti-TNF therapies. The development of a malignancy, however, is an indication to discontinue anti-TNF therapy.

The significance of the induction of antinuclear and other autoantibodies by anti-TNF agents is unclear because most patients with this phenomenon do not phenotypically express autoimmune syndromes associated with these antibodies.31

The relation of anti-TNF therapy to congestive heart failure is unclear. Studies of anti-TNF therapy for the treatment of heart failure were discontinued because of lack of efficacy, and a few studies have associated high doses of infliximab with exacerbation of congestive heart failure in patients with preexisting cardiovascular disease.32,33 However, this finding is controversial. A study by Wolfe and Michaud34 found that patients with RA, when compared with patients with OA, have an increased incidence of heart failure at baseline. However, patients with RA in this study who were treated with an anti-TNF agent had a decreased incidence of heart failure. The standard of care is avoidance of anti-TNF therapy in decompensated heart failure.

A rare but potentially devastating adverse effect of anti-TNF therapies is demyelinating disease. New-onset multiple sclerosis, optic neuritis, and transverse myelitis have been reported with anti-TNF therapy.35-37

Other DMARDs

Two new biologic agents have been approved for the treatment of RA. The first is abatacept, a fully humanized fusion protein that binds to CD80/86 on the lymphocyte, thereby preventing interaction with CD on the macrophage. This interaction prevents T cell activation. The second, rituximab, is a chimeric IgG1 monoclonal antibody, which depletes circulating B lymphocytes. Both are demonstrated to be safe and effective when combined with MTX and to provide a significant response in patients who had previously failed anti-TNF therapy.38,39 They appear to be equally safe when compared with anti-TNF therapy with similar infusion reactions. Abatacept should not be given to patients with chronic obstructive pulmonary disease because of a small but significant increase of pulmonary infection encountered in early trials.

Several other agents are used as second- and third-line therapies in RA. There is evidence that minocycline, cyclosporine, mycophenolate mofetil, and azathioprine have some efficacy in patients with RA. Fewer data exist for their use than for the other DMARDs. Since the advent of anti-TNF agents, these agents are used less often.

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics should be used as symptomatic therapy only in combination with DMARD therapy in RA. These agents do not have any significant positive impact on disease progression or function. They should never be the primary or sole therapy in patients with RA. Therapy with these drugs can result in gastritis, peptic ulcer disease, hypertension, edema, or renal insufficiency. Selective cyclooxygenase-2 inhibitors, such as celecoxib and rofecoxib, confer a lower risk of gastrointestinal erosions and ulcerations, but they are otherwise as toxic as their predecessors. The concern with these newer agents, as for the older NSAIDs, is that there may be an increased risk of cardiovascular events for patients taking these medications. Indeed, one of these agents, rofecoxib (Vioxx), was withdrawn from the market because of evidence documenting such side effects. Whether these findings are specific to rofecoxib or represent a class effect remains to be determined. They should be used with extreme caution or not at all in people with renal or cardiovascular disease.

Preservation of bone integrity in RA is an important component of therapy. Osteopenia and osteoporosis are common comorbid conditions of RA, which can be accelerated by episodic or chronic GC therapy. Patients with RA who are receiving GCs should have regular bone density measurements, independent of age.

Physical and occupational therapy are important in maintaining joint mobility and function. Goals of therapy include restoring and preserving function, decreasing pain, improving strength and endurance, and enhancing cardiovascular fitness. Therapy also provides patient education regarding the use of assistive devices, joint protection, and rest.

Surgical intervention is indicated in RA when medical therapy fails to adequately preserve joint function or achieve acceptable pain control. Preoperative evaluation of the patient with RA is key in reducing surgery-related morbidity and mortality. Patients should be evaluated with flexion and extension radiographs for cervical spine instability. Cervical spine instability with significant subluxation places the patient at risk for impingement of the spinal cord with routine procedures such as endotracheal intubation. Patients with cervical spine instability should undergo neurosurgical evaluation before any surgical intervention. Hoarseness or pain with phonation should alert the clinician to possible cricoarytenoid joint involvement, which can complicate intubation. The increased prevalence of atherosclerotic cardiovascular disease in patients with RA warrants cardiac clearance before surgery. Active joint or systemic infection is a contraindication to elective surgical intervention.

Perioperative DMARD therapy remains a topic of debate. Studies have demonstrated conflicting data; both increased and decreased incidence of infectious complications have been reported when MTX is continued perioperatively. However, it is clear that postoperative flares increase when MTX therapy is withheld for 1 month.40 A dialogue with the surgical team is often helpful in assessing perioperative infection risk to determine how best to minimize complications while decreasing the risk of disease flare. As a compromise, we recommend withholding MTX for one dose before and after surgery. Anti-TNF agents are generally discontinued for several weeks before and after surgery, even for limited procedures.

GC therapy should not be abruptly discontinued under any circumstances. Patients should be receiving the minimum required dose of steroids preoperatively to lessen adverse effects on wound healing. There is no general consensus on stress-dose steroids (administered as 50 to 100 mg intravenous hydrocortisone every 8 hours on the day of surgery). When this therapy is used, the steroid dose should be quickly tapered over several days to the preoperative dose.

NSAIDs are usually withheld 1 to 2 weeks before any surgical procedure because of their effect on platelet function.

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Special Considerations

There should be little delay in initiating DMARD therapy, including combinations, in patients with RA after the diagnosis is established. The goal of complete suppression of disease activity as determined by clinical and serologic assessments should be continuously pursued, as allowed by potential and experienced adverse medication effects.

Patients with inactive RA can suffer progressive degenerative joint structural damage as a consequence of prior inflammatory disease, leading to significant pain and disability. DMARD therapy should not be initiated or modified based on these changes if no active inflammation is ongoing. Treatment should address pain control and improvement of function by other medical or surgical means, as appropriate.

In patients with monoarticular arthritis or flare of just one joint, even in established RA, it is critical to assess for posttraumatic, crystal-induced, and septic arthritis by joint aspiration with synovial fluid examination and cultures.

In the setting of acute infection, most DMARDs (except for GC and hydroxychloroquine) should be discontinued until treatment has been completed and the infectious process has resolved.

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Summary

  • The clinical diagnosis of RA is made by the history and physical examination and depends on the insidious onset of symmetrical pain and swelling in mostly small peripheral joints.
  • Rheumatoid factor is not necessary to confirm the diagnosis, but when present it is associated with more-severe joint disease and extra-articular manifestations.
  • MRI can be used to facilitate diagnosis in occult or early cases because it is more sensitive for synovitis and changes in bone than radiographic studies.
  • Prompt treatment with disease-modifying agents to normalize C-reactive protein and minimize the swollen joint count represents the standard of care.
  • Measures of disease activity, such as the Disease Activity Index, and measures of outcome, such as the Health Assessment Questionnaire, should be recorded at every outpatient visit.

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References

  1. Arnett FC, Edworthy SM, Bloch DA, et al: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988, 31: 315-324.
  2. Firestein GS. Etiology and pathogenesis of rheumatoid arthritis. In: Ruddy S, Harris E, Sledge C (eds): Kelly's Textbook of Rheumatology. 6th ed. Philadelphia: WB Saunders, 2001, 921-966.
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