DEFINITION

Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis. Although most readily recognized by its articular manifestations, RA may 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 (Table 1)¹ may be used to classify disease in patients in the appropriate clinical setting, but in early disease 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.

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, with this disparity most pronounced in patients under the age of 50.³ The incidence of RA continues to increase with age until about the seventh decade of life.⁴

The etiology 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-DR4 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

RF, an IgM antiglobulin against the Fc portion of human IgG, is detected in about 70% of patients with RA.4 There is evidence implying 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, and -10; tumor necrosis factor (TNF)-alpha; platelet-derived growth factor; insulin-like growth factor; and transforming growth factor-beta.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. Finally, cigarette smoking increases the risk of developing RA, and negatively influences disease course.^10,11

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, frequently involving the hands, wrists, knees, or feet, often symmetrically. However, in 10% to 15% of patients, the onset of disease may be explosive, with polyarthritis, fever, lymphadenopathy, and splenomegaly developing over days to weeks.^2,8 It is imperative in patients with the latter presentation to consider other common causes of acute polyarthritis, such as parvovirus infection.

Evidence of articular disease in RA may 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 frequently complain of morning stiffness, a characteristic of inflammatory arthritis. Stiffness, known as "gelling," may 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, subtalar, and metatarsophalangeal (MTP) joints. The cervical spine is the only characteristic axial location, with atlantoaxial subluxation 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 frequently 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 occurs most often in patients with high titers of RF. Rheumatoid nodules may develop in 20% to 35% of patients, most often on extensor surfaces, and often in response to repetitive trauma.² However, they may 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 midzone of palisading macrophages, and a central zone of necrotic material.⁹

Vasculitis may also manifest as an extra-articular manifestation of RA. This most often presents as leukocytoclastic vasculitis, which may occur as an isolated skin finding. With less-common medium-sized vessel involvement, 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 the following predisposing factors: 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 frequently associated with secondary Sjögren's syndrome (keratoconjunctivitis sicca), which may present 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, may 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 presentation of RA-associated ILD often parallels that of idiopathic pulmonary fibrosis, frequently 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 may present with cough, fever, dyspnea, and fatigue. This is a nonspecific entity that may also result from an unrelated process, such as infection. Biopsy is required to exclude other underlying causes. Nodular lung disease in RA may occur in both the pleura and lung parenchyma, with solitary or multiple lesions that may 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 frequently noted at autopsy, but it is usually subclinical.¹² Effusions are frequently 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 frequent in patients with nodular disease.¹³ Although rare, pericardial tamponade or constrictive pericarditis may result in hemodynamic compromise that requires intervention. Myocarditis may occur in RA, either in the form of nodular granulomatous disease or as diffuse interstitial inflammation. Nodular disease in the conduction system may cause atrioventricular block. Granulomatous disease of the heart valves may lead to valvular insufficiency. Coronary arteritis in RA is rare and may result in myocardial infarction, but most events from ischemic coronary disease in RA patients are caused by atherosclerosis. Patients with RA have both an increased atherosclerotic burden (as demonstrated by increased carotid intima-media thickness and plaque scores) and increased risk of cardiovascular events compared with age- and gender-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, 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

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 Table 1 are helpful in classifying patients for the purpose of clinical research studies, but may 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 and/or polyarthritis, joint gelling, and fatigue. Examination findings that are suggestive of RA include symmetric 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 recently been demonstrated¹⁸ to have specificity for RA of more than 90%. In patients with an atypical presentation or when another diagnosis is equally likely (eg, 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 narrowing the differential diagnosis in the individual patient.

Infectious arthropathies are an important consideration in the setting of fever and polyarthritis. Infections frequently 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 should be considered when a patient has been in an endemic region where tick exposure was likely. Viral infections, both acute and chronic, may result in a polyarthritis 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 may manifest similarly to RA. Patients with systemic lupus erythematosus (SLE) may 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 may 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. Asymmetric joint involvement, the absence of small-joint disease, sausaging of digits, and the involvement of the lumbosacral spine all favor the seronegative arthropathies. Polymyositis and dermatomyositis may 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 may also mimic RA. Radiographs may 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 may present with symmetric polyarthritis. In these cases, a detailed history may be helpful in identifying the characteristics of these disorders (eg, a new, unrelenting headache, predominant shoulder and hip girdle involvement), but in cases where this does not make the distinction, careful observation of the evolution of the disease over time is key, since the clinical courses and potential serious complications associated with these disorders are very different.

Systemic vasculitis may present with polyarthritis, and, in the case of Wegener's granulomatosis, may also be RF-positive. Again, a thorough history and examination with directed serologic and imaging evaluation will aid in differentiating these disorders. Fibromyalgia (FMS) may present with diffuse symmetric 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 may present 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 may show bony destruction similar to that in RA. Tissue biopsy may be necessary in these cases 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 may 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 by cancer usually presents as monoarticular arthritis. However, lymphoproliferative or myeloproliferative disorders may present with polyarthralgias or polyarthritis. In addition, paraneoplastic syndromes may 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; as few as 15% to 30% of patients may have erosions visible on radiographs during the first year of the disease.²¹ Since erosions most often appear first in the hands, wrists, or feet, these are the areas that should be initially imaged when the diagnosis is suspected.

MRI is useful in detecting RA before radiographic changes can be detected. MRI is not only more sensitive in detecting erosions, but in addition is capable of identifying bone marrow edema and synovial hypertrophy.²² Both these findings predict the development of erosive disease.

Ultrasonography is used infrequently in establishing a diagnosis of RA, and is more sensitive in the detection of synovial and tendon inflammation than clinical examination alone.^23,24 Ultrasonography may 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 the preservation of joint structure and function, and has implications for the long-term overall health and functional status of the patient. If control of disease is achieved early (eg, within the first several months), the rate of radiographic progression and joint destruction is minimized. Although the best outcomes are obtained with early aggressive disease control, 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 (Table 2).²⁵ 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 frequent 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 will significantly affect 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.

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 (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 (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 without hepatitis 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 may present with nonspecific symptoms such as fever, fatigue, cough, or dyspnea. When this diagnosis is suggested, MTX should be immediately discontinued. This manifestation can be indistinguishable from infection, and appropriate investigations and treatment for both should immediately be initiated. Biopsy may be necessary to establish the diagnosis. Because the half-life of MTX is primarily dependent 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 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, with few side effects. Their major application in RA currently 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 may cause liver enzyme elevation and requires regular liver enzyme monitoring.²⁷

The anti-TNF agents are highly effective DMARDs. Etanercept, infliximab, and adalimumab are all currently in use as second-line therapy for RA. Again, 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.²⁸ 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 may 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 may progress more rapidly and follow a more fulminant course. Signs and symptoms of any significant infectious process (eg, 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, since most patients with this phenomenon do not phenotypically express autoimmune syndromes associated with these antibodies.²⁹ 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.^30,31 However, this finding is controversial. A recent study by Wolfe et al³² 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. Currently, 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.^33-35

Several other agents are used as second- and third-line therapy 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 frequently. There is data demonstrating efficacy of rituximab, an anti-CD20 monoclonal antibody, in patients with persisting disease activity on methotrexate therapy. Further studies are needed to determine its appropriate place in the treatment algorhythm of RA.³⁶

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 may result in gastritis and/or 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 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 recently 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 comorbidities of RA, which can be accelerated by episodic or chronic GC therapy. Patients with RA receiving GCs should have regular bone density measurements, independent of age.

Physical and occupational therapy is 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 may 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.³⁷ A dialogue with the surgical team is often helpful in assessing perioperative infection risk in order to determine how best to minimize complications while decreasing the risk of disease flare. As a compromise, we recommend withholding MTX for one dose pre- and postoperatively. Anti-TNF agents are generally discontinued for several weeks pre- and postoperatively, 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 50-100 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 back down to the preoperative dose. NSAIDs are usually withheld 1 to 2 weeks before any surgical procedure because of their effect on platelet function.

• There should be little delay in initiating DMARD therapy in patients with RA after the diagnosis is established. The goal of complete suppression of disease activity as determined by clinical and serologic assessment should be continuously pursued, as allowed by potential and experienced adverse medication effects.
• Patients with inactive RA may 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 post-traumatic, 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.

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: Kelly's Textbook of Rheumatology; Ruddy S, Harris E, Sledge C; 6th ed., W. B. Saunders, Philadelphia, PA, 2001:921-966.
3. Linos A, Worthington JW, O'Fallon WM, Kurland LT. The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence, and mortality. Am J Epidemiol. 1980;111:87-98.
4. Silman AJ, Hockberg MC. Epidemiology of the rheumatic diseases. Oxford, UK: Oxford University Press, 1993.
5. Silman AJ, MacGregor AJ, Thomson W, et al. Twin concordance rates for rheumatoid arthritis; results from a nationwide study. Br J Rheumatol. 1993;32:903-907.
6. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978; 298:869-871.
7. Depper JM, Zvaifler NJ. Epstein-Barr virus. Its relationship to the pathogenesis of rheumatoid arthritis. Arthritis Rheum. 1981;24:755-761.
8. Brandtzaeg P. Review article: Homing of mucosal intestinal immune cells-a possible connection between intestinal and articular inflammation. Aliment Pharmacol Ther. 1997;11(suppl 3):24-39.
9. Goronzy JJ, Weyand CM. Rheumatoid arthritis: epidemiology, pathology, and pathogenesis. In: Klippel JH, Crofford LJ, Stone JH, Weyand CM, eds. Primer on the Rheum.
10. Stolt P, Bengtsson C, Nordmark B, et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis. 2003;62:835-41.
11. Saag KG, Cerhan JR, Kolluri S, Ohashi K, Hunninghake GW, Schwartz DA. Cigarette smoking and rheumatoid arthritis severity. Ann Rheum Dis. 1997;56:463-469.
12. Lipsky P. Rheumatoid arthritis. In: Harrison's Principles of Internal Medicine, Braunwald E, Fauci A, Isslebacher K, Kasper D, Hauser S, Longo D; 14th ed., McGraw-Hill, 1998:1880-1888.
13. Harris ED. Clinical features of rheumatoid arthritis. In: Kelly's Textbook of Rheumatology, Ruddy S, Harris E, Sledge C; 6th ed., W. B. Saunders, Philadelphia, PA, 2001:967-1000.
14. Gonzalez-Juanatey C, Llorca J, Testa A, Revuelta J, Garcia-Porrua C, Gonzalez-Gay MA. Increased prevalence of severe subclinical atherosclerotic findings in long-term treated rheumatoid arthritis patients without clinically evident atherosclerotic disease. Medicine. 2003;82:407-413.
15. Meyer O. Atherosclerosis and connective tissue diseases. Joint Bone Spine. 2001;68:564-575.
16. Klocke R, Cockeroft JR, Taylor GJ, Hall IR, Blake DR. Arterial stiffness and central blood pressure, as determined by pulse wave analysis, in rheumatoid arthritis. Ann Rheum Dis. 2003;62:414-418.
17. Vaudo G, Marchesi S, Gerli R, et al. Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity. Ann Rheum Dis. 2004;63:31-35.
18. Saraux A, Berthelot JM, Devauchelle V, et al. Value of antibodies to citrulline-containing peptides for diagnosing early rheumatoid arthritis. J Rheumatol. 2003;30:2535-2539.
19. Taylor J, Skan J, Erb N, et al. Lupus patients with fatigue-is there a link with fibromyalgia syndrome? Rheumatology. 2000;39:620-623.
20. Wolfe F, Michaud K. Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic disadvantage characterize ra patients with fibromyalgia. J Rheumatol. 2004;31:695-700.
21. Dixey J, Solymossy Y, Young A, Early RA Study. Is it possible to predict radiological damage in early rheumatoid arthritis (RA)? A report on the occurrence, progression, and prognostic factors of radiological erosions over the first 3 years in 866 patients from the Early RA Study (ERAS). J Rheumatol Suppl. 2004;69:48-54.
22. Hoving JL, Buchbinder R, Hall S, et al. A comparison of magnetic resonance imaging, sonography, and radiography of the hand in patients with early rheumatoid arthritis. J Rheumatol. 2004;31:663-675.
23. Koski JM. Ultrasound detection of plantar bursitis of the forefoot in patients with early rheumatoid arthritis. J Rheumatol. 1998;25:229-230.
24. Kane D, Balint PV, Sturrock RD. Ultrasonography is superior to clinical examination in the detection and localization of knee joint effusion in rheumatoid arthritis. J Rheumatol. 2003;30:966-971.
25. 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.
26. Rich E, Moreland LW, Alarcon GS. Paucity of radiographic progression in rheumatoid arthritis treated with methotrexate as the first disease modifying antirheumatic drug. J Rheumatol. 1999;26:259-261.
27. Weinblatt ME, Dixon JA, Falchuk KR. Serious liver disease in a patient receiving methotrexate and leflunomide. Arthritis Rheum. 2000; 43: 2609-11.
28. Hurlimann D, Forster A, Noll G, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation. 2002;106:2184-2187.
29. Louis M, Rauch J, Armstrong M, Fitzcharles MA. Induction of autoantibodies during prolonged treatment with infliximab. J Rheumatol. 2003;30:2557-2562.
30. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107:3133-3140.
31. Kwon HJ, Cote TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med. 2003;138:807-811.
32. Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. Am J Med. 2004;116:305-311.
33. Sicotte NL, Voskuhl RR. Onset of multiple sclerosis associated with anti-TNF therapy. Neurology. 2001;27:1885-1888.
34. Strong BY, Erny BC, Herzenberg H, Razzeca KJ. Retrobulbar optic neuritis associated with infliximab in a patient with Crohn disease. Ann Intern Med. 2004;140:W34.
35. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44:2862-2869.
36. Edwards JCW, Szczepanski L, Szechinski J, et al. Efficacy of B-cell targeted therapy with rituximab in patient with rheumatoid arthritis. NEJM. 2004;350:2572-81.
37. Kremer JM, Rynes RI, Bartholomew LE. Severe flare of rheumatoid arthritis after discontinuation of long-term methotrexate therapy. Double-blind study. Am J Med. 1987;82:781-786.

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