Rheumatoid arthritis

Targeted interventions can minimize joint destruction

Eleanor Anderson Williams, MD; Kenneth H. Fye, MD, FACP, FACR

VOL 114 / NO 5 / NOVEMBER 2003 / POSTGRADUATE MEDICINE

CME learning objectives

• To identify the major articular manifestations of rheumatoid arthritis
• To recognize the major extra-articular manifestations of rheumatoid arthritis
• To formulate a basic therapeutic regimen for rheumatoid arthritis

The authors disclose no financial interests in this article and no unlabeled uses of any product mentioned.

This is the second of three articles on rheumatic disease.

Preview: Rheumatoid arthritis can cause joint erosion and deformity, pain, stiffness, and decreased function and range of motion. Early diagnosis is crucial to prevent permanent joint damage. In this article, Drs Williams and Fye discuss articular and extra-articular manifestations of rheumatoid arthritis as well as the evolving treatment approaches to this complex disease. Williams EA, Fye KH. Rheumatoid arthritis: targeted interventions can minimize joint destruction. Postgrad Med 2003;114(5):19-28

Rheumatoid arthritis is a chronic systemic disease with articular and extra-articular manifestations. Its clinical hallmark is a symmetrical inflammatory polyarthritis affecting small proximal diarthrodial joints. The abnormal laboratory finding characteristic of rheumatoid arthritis is a positive rheumatoid factor (RF) (circulating autoantibodies against the Fc portion of immunoglobulin G [IgG]). Patients with high titers of RF are more likely to have rheumatoid nodules, the typical histologic lesions of rheumatoid arthritis, as well as extra-articular manifestations of disease that may affect organ systems throughout the body, including the skin, eyes, lungs, heart, and blood vessels.

Rheumatoid arthritis is a common disorder, affecting people of all ethnic groups worldwide. An estimated 1% to 3% of people in the United States have rheumatoid arthritis. The incidence of the disease typically peaks during the fourth and fifth decades of life. As with most other autoimmune disorders, it is more common in women than men, with a female-male ratio of 3:1. The causes of rheumatoid arthritis are unknown, but there is a genetic predisposition in that various HLA-DR4 genotypes are associated with an increased incidence and severity of disease in different populations (1). Although most cases of rheumatoid arthritis are sporadic, the concordance rates in monozygotic twins range from 15% to 30%.

Diagnosis rests on typical clinical, laboratory, and radiographic manifestations of disease, many of which are included in the American College of Rheumatology's 1987 revised criteria for the classification of rheumatoid arthritis (table 1). Effective therapies for rheumatoid arthritis are now available. Because significant joint destruction can occur within 2 years of the onset of disease, it is important to diagnose rheumatoid arthritis and initiate therapy as soon as possible. The modern paradigm of therapy stresses early, aggressive treatment with multiple drugs (2,3). The goal of therapy is to maximize control of the disorder within 2 years of diagnosis in order to prevent irreversible damage (4).

Other arthritic conditions, such as systemic lupus erythematosus, postparvovirus B19 arthropathy, cryoglobulinemia, or even hepatitis B or C virus infection, can also present with a symmetrical inflammatory polyarthritis involving small proximal joints, reminiscent of rheumatoid arthritis. In addition, no single clinical feature or laboratory test clinches the diagnosis. RF is found in 80% of patients with rheumatoid arthritis, but it can be seen in a variety of other arthritides, including bacterial endocarditis, types II and III mixed cryoglobulinemia, Sjögren's syndrome, systemic lupus erythematosus, and postviral arthropathies. Nevertheless, RF remains an important laboratory feature of rheumatoid arthritis, since serum RF titers have been shown to correlate with both disease severity and the likelihood of extra-articular manifestations of disease (5).

Articular manifestations

The hands are affected in virtually all patients with rheumatoid arthritis. The wrists, metacarpophalangeal joints, and proximal interphalangeal joints are most commonly involved. The distal interphalangeal and first carpometacarpal joints, which are commonly affected in osteoarthritis, are usually spared in rheumatoid arthritis. Classic complications involving the hands include:

1. Swan-neck deformities (hyperextension of the proximal interphalangeal joints and hyperflexion of the distal interphalangeal joints due to contractures of the intrinsic muscles of the hand)

2. Boutonnière deformities (hyperflexion of the proximal interphalangeal joints and hyperextension of the distal interphalangeal joints due to laxity of the extensor mechanism and periarticular supporting structures of the proximal interphalangeal joints)

3. Ulnar deviation of the metacarpophalangeal joints

4. Subluxation of the wrists and metacarpophalangeal joints

5. Tendon ruptures, particularly of the fourth and fifth extensor tendons of the fingers

Although rheumatoid arthritis typically affects small joints, any diarthrodial joint can be involved. It is not uncommon to see involvement of the shoulders, elbows, hips, knees, and ankles. Deformities result from erosions of cartilage and bone and digestion of periarticular supporting structures. Valgus deformities are typical in long-standing knee or ankle inflammation. Hip arthritis may lead to loss of joint space, subchondral cyst formation, collapse of the femoral head, and protrusio acetabuli. Involvement of the feet is very common in rheumatoid arthritis. Pes planus, hammer-toe deformities, bunion formation, and collapse of the midfoot are complications of severe foot and ankle disease.

Extra-articular manifestations

Extra-articular manifestations (table 2) may precede the onset of articular symptoms. Predictors for the development of extra-articular manifestations include severe joint disease, a positive antinuclear antibody assay, IgA (but not IgG or IgM) RF, rheumatoid nodules, and certain HLA-DR haplotypes (5).

Cutaneous manifestations
The cutaneous feature most characteristic of rheumatoid arthritis is the rheumatoid nodule. The initial pathologic process in nodule formation is unknown but is thought to be related to small-vessel inflammation. The mature lesion is defined by an area of central necrosis surrounded by palisading histiocytes and a cuff of cellular connective tissue and chronic inflammatory cells. The typical rheumatoid nodule may be a few millimeters to a few centimeters in diameter and is usually found over bony prominences, the Achilles tendon, the metacarpophalangeal joints, or areas that have sustained trauma or chronic pressure. Nodules are associated with a positive RF titer and severe erosive arthritis. They can occur throughout the body and are responsible for many of the extra-articular manifestations of rheumatoid arthritis.

Livedo reticularis is a blotchy, erythematous to purplish discoloration of the skin due to the presence of an obliterative cutaneous capillaropathy. This lesion is sometimes associated with the antiphospholipid-antibody syndrome, a hypercoagulable state linked to antiphospholipid antibodies and characterized by recurrent vascular thrombosis and second trimester miscarriages.

Rheumatoid arthritis is one of the causes of pyoderma gangrenosum, a necrotizing, ulcerative, noninfectious neutrophilic dermatosis. Sweet's syndrome, a neutrophilic dermatosis usually associated with myeloproliferative disorders, viral infections, and drug reactions, also occurs in rheumatoid arthritis (6). Other complications include erythema nodosum, lobular panniculitis, atrophy of digital skin, palmar erythema, diffuse thinning (rice paper skin), and skin fragility.

Ocular manifestations
Keratoconjunctivitis sicca is the most common ocular problem associated with rheumatoid arthritis and occurs in those patients who have associated Sjögren's syndrome. Episcleritis, a relatively asymptomatic inflammatory process that requires no specific therapy, is the most common ophthalmologic problem in patients without Sjögren's syndrome. Scleritis, an inflammation of the sclera that is sometimes associated with nodule formation, can cause pain, photophobia and, if untreated, decreased vision. Severe anterior scleronodular disease may lead to thinning of the sclera with devastating protrusion of the choroid and vitreous.

Rarely, cryoglobulins (complexes of RF and polyclonal IgG that precipitate at temperatures lower than 37°C [98.6°F]) precipitate in the perilimbic circulation, leading to ulcers that can perforate the cornea with extrusion of the aqueous.

Respiratory manifestations
The most common respiratory manifestation of rheumatoid arthritis is pleuritis. Asymptomatic pleural disease can occur in up to 40% of patients with seropositive rheumatoid arthritis. The pleural effusions of rheumatoid arthritis typically have high protein levels and low glucose levels, but the white blood cell count is less than 5,000/microliter. Rheumatoid nodules can sometimes be seen on pleural biopsy. Interstitial lung disease is more frequent in males than in females. Manifestations of interstitial lung disease include rheumatoid nodulosis, diffuse interstitial pneumonitis with or without pulmonary fibrosis, bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia, bronchiectasis, and pulmonary hypertension.

Patients with rheumatoid arthritis are more susceptible to small-airways disease and emphysema, even in the absence of immunosuppressive therapy. In addition, many of the drugs used to treat rheumatoid arthritis, such as methotrexate, gold, penicillamine, and cyclophosphamide, can cause interstitial lung disease. Also, use of tumor necrosis factor (TNF) antagonists may lead to reactivation of tuberculosis and increased susceptibility to fungal infections.

Chest radiographs are too insensitive to be of value in the assessment of early or subtle interstitial lung disease. Pulmonary function testing, high-resolution computed tomography, bronchoalveolar lavage, or echocardiography is required to evaluate rheumatoid arthritis patients with pulmonary complaints. Cricoarytenoid arthritis can result in vocal cord dysfunction with manifestations ranging from hoarseness to upper airway obstruction with inspiratory stridor (7).

Hematologic manifestations
The majority of patients with rheumatoid arthritis have a normochromic-normocytic anemia of chronic disease. However, some patients may also be deficient in iron, folic acid, or vitamin B₁₂. Felty's syndrome occurs most commonly in patients in whom seropositive nodules develop. It is characterized by the triad of chronic and often quiescent rheumatoid arthritis, neutropenia, and splenomegaly, sometimes with lymphadenopathy, thrombocytopenia, and leg ulcers. Large granular lymphocytes can be seen in the peripheral blood and bone marrow in a subset of patients with rheumatoid arthritis.

Active rheumatoid disease is generally associated with an elevated erythrocyte sedimentation rate (a nonspecific indicator of inflammation). However, a number of investigators believe that C-reactive protein is a better measure of disease activity than the routine erythrocyte sedimentation rate. Other laboratory abnormalities include thrombocytosis (a reflection of acute and chronic inflammation), polyclonal or monoclonal hypergammaglobulinemia, and a positive antinuclear antibody assay. In patients with Sjögren's syndrome, results positive for anti-SS-A or anti-SS-B antibodies may also be found. Patients with rheumatoid arthritis and concomitant autoimmune thyroiditis have antithyroglobulin or antithyroperoxidase antibodies.

The risk of lymphoma in patients with rheumatoid arthritis is independent of immunosuppressive therapy and is two to three times that of the general population. There is no association between rheumatoid arthritis and nonlymphoid malignancies (8).

Renal manifestations
Renal disease is rare in patients with rheumatoid arthritis. When it does occur, it is often related to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), cryoglobulinemia, or vasculitis. Renal manifestations include glomerulonephritis, azotemia, interstitial nephritis, and papillary necrosis. Patients with secondary renal amyloidosis due to long-standing chronic inflammation may have proteinuria (9).

Vascular manifestations
Small-vessel vasculitis, manifested by periungual and digital infarctions, may occur in up to 30% of patients who are seropositive for rheumatoid arthritis. Ten percent of seropositive patients manifest cutaneous arteriolitis with malleolar ulcers. Occasionally, a necrotizing arteritis indistinguishable from polyarteritis nodosa may be observed. Male patients with high titers of RF, erosive disease, and extra-articular manifestations are more commonly affected. Treatment is similar to that of polyarteritis nodosa (5).

Neurologic manifestations
The thoracic and lumbar sections of the spine are generally spared in rheumatoid arthritis. However, the cervical region, particularly the atlantoaxial joint, is often affected. Cervical involvement may develop in 30% of patients with rheumatoid arthritis over the course of their disease. Because arthritis of the atlantoaxial joint can lead to laxity of the transverse ligament, patients with cervical involvement are at risk for significant cervical cord compression. New onset of neck pain, weakness, or gait disturbance signals the need for appropriate radiographs of the cervical spine. Patients who develop shocklike dysesthesias down the spine or over the shoulders and into the arms (Lhermitte's sign) should undergo cervical fusion immediately to prevent catastrophic compressive myelopathy (10).

Peripheral nerves, such as the median nerve that passes through the carpal tunnel, the ulnar nerve in Guyon's canal, or the posterior tibial nerve in the tarsal tunnel, are susceptible to compression due to local synovial inflammation. Involvement can be confirmed by nerve conduction studies. Mononeuritis multiplex may develop and is usually due to necrotizing rheumatoid vasculitis. Biopsy of the sural nerve sometimes reveals the underlying vasculitic process. Small-vessel vasculitis can cause a "stocking-glove" polyneuropathy.

Cardiac manifestations
Cardiac involvement occurs in the majority of patients with seropositive rheumatoid arthritis. The most common manifestation is pericarditis. Although it is usually asymptomatic, rheumatoid pericarditis can be associated with pericardial effusion and the development of acute or chronic pericarditis with tamponade. The restrictive pericarditis of rheumatoid arthritis responds poorly to medical therapy and generally requires pericardiectomy.

Rheumatoid nodules may affect the pericardium, myocardium, and endocardium. Nodulosis of the heart valves can lead to valvular insufficiency severe enough to require valve replacement. The aortic, mitral, and tricuspid valves can be affected. Myocardial nodulosis and nonnodular myocarditis, with or without myocardial fibrosis, have been associated with conduction defects and congestive heart failure. Rarely, rheumatoid vasculitis affecting the coronary arteries leads to angina or myocardial infarction (5).

Treatment

Advances in therapy have dramatically altered the long-term outlook for patients with rheumatoid arthritis. It is now clear that early diagnosis and subsequent treatment with combination drug regimens can minimize or even prevent the pain, joint destruction, and extra-articular complications associated with rheumatoid disease. Rheumatoid arthritis is treated with a comprehensive program of pharmacologic agents to decrease inflammation (table 3), physical therapy to maintain function, and surgery to prevent or correct deformities, should they occur despite aggressive medical therapy.

NSAIDs
NSAIDs inhibit prostaglandin production by blocking the ability of cyclooxygenase (COX) to divert arachidonic acid, a component of cell membrane, into the endoperoxide pathways. To the extent that prostaglandins can mediate inflammation, NSAIDs, by blocking prostaglandin production, help decrease the inflammation associated with rheumatoid arthritis. The isoenzyme COX-1 produces prostaglandins in tissues, where they subserve homeostatic functions. In contrast, the isoenzyme COX-2 produces prostaglandins largely in areas of inflammation. The newer, selective COX-2 inhibitors do not inhibit COX-1 and, therefore, produce fewer side effects than are experienced with the older, nonselective agents that inhibit both COX-1 and COX-2. The expense of the selective COX-2 inhibitors limits their use. However, NSAIDs alone do not usually provide sufficient relief of symptoms or signs of rheumatoid arthritis.

Corticosteroids
Oral corticosteroids have been a mainstay of rheumatoid arthritis therapy for more than four decades. Corticosteroids provide rapid symptomatic relief of inflammation through inhibition of the inflammatory cascade. They can be used to treat acute flares of disease and to help maintain control of chronic arthritis. Corticosteroids are even associated with a modest decrease in radiographic progression of disease (11). However, prolonged use may result in a variety of adverse effects, including cataracts, mood alteration, hypertension, hyperglycemia and insulin resistance, impaired wound healing, myopathies, osteonecrosis, osteoporosis with or without fractures, and a predisposition to infections.

Corticosteroid injections are useful in alleviating pain and swelling associated with localized arthritis or soft-tissue inflammation. Fluorinated compounds should not be used for soft-tissue or superficial injections, since they can result in skin or fat atrophy. Corticosteroid preparations are typically injected with lidocaine hydrochloride to decrease the pain of inflammation.

Disease-modifying antirheumatic drugs
Multiple drug therapies with two or even three disease-modifying antirheumatic drugs (DMARDs) are more effective and better tolerated than regimens including only a single agent. Methotrexate, a dihydrofolate reductase inhibitor that suppresses purine production, is now the cornerstone of anti-inflammatory therapy. Regular use of folic acid along with methotrexate reduces the incidence of methotrexate-induced oral ulcers without decreasing drug efficacy. Bone marrow suppression and hepatotoxicity are uncommon at the doses used in the treatment of rheumatoid arthritis, but routine monitoring of bone marrow and liver function should be performed in patients undergoing long-term methotrexate therapy. Hydroxychloroquine sulfate, sulfasalazine, and minocycline are DMARDs with unclear modes of action that are often used in combination with methotrexate (12,13). Leflunomide, a pyrimidine antagonist, can be used in patients who do not respond to or who cannot tolerate methotrexate. Patients taking leflunomide should be carefully monitored for bone marrow suppression and hepatotoxicity. Azathioprine, cyclosporine, mycophenolate mofetil, parenteral and oral gold, and penicillamine have been used to treat rheumatoid arthritis with varying degrees of success and varying toxicities.

Mediators of inflammation and joint damage include several cytokines, such as interleukin-1 and TNF-alpha. Development of biologic agents that target these important cytokines has led to treatments that appear to slow or prevent clinical and radiographic progression of disease (14).

Three TNF-alpha antagonists are available for the treatment of rheumatoid arthritis. Etanercept is a recombinant TNF-alpha receptor (p75) Fc fusion protein that binds soluble TNF-alpha, thereby rendering TNF-alpha unavailable to bind cell surface TNF-alpha receptors. Subcutaneous injection is administered twice weekly. Etanercept may be used in combination with methotrexate or other DMARDs. Injection site reactions and mild upper respiratory infections are common side effects (15).

Infliximab, a chimeric human-murine monoclonal antibody that inhibits TNF-alpha, is used with methotrexate and is initially administered intravenously at weeks 0, 2, and 6. Maintenance doses are then given every 8 weeks. Mild infusion reactions include headache and nausea; severe reactions include chest pain, dyspnea, hypotension, and urticaria or other evidence of an immediate hypersensitivity reaction (16). Adalimumab, a fully humanized monoclonal antibody, is the newest TNF-alpha antagonist approved for the treatment of rheumatoid arthritis and is administered subcutaneously every 2 weeks (17). While no formal routine laboratory tests are recommended, cases of bone marrow suppression and elevation of serum transaminase levels have been reported. The presence of New York Heart Association class III or IV congestive heart failure or active infection is a relative contraindication to the use of all TNF-alpha antagonists.

Long-term use of anti-TNF-alpha agents can lead to the development of autoantibodies. Anti-idiotype antibodies may develop against the Fab portion of monoclonal antibodies. Development of human anti-chimeric autoantibodies in patients taking infliximab is inversely related to the dose, and human anti-chimeric autoantibody formation is less likely in patients taking high doses. Concurrent methotrexate use decreases the formation of autoantibodies. Autoantibodies to etanercept also occur, but their clinical importance is unclear. Antinuclear antibodies and, less commonly, anti-double-stranded DNA antibodies have been noted with anti-TNF-alpha therapy, but clinical lupus is rare. Demyelinating diseases such as multiple sclerosis may also occur (18).

These agents predispose patients to the development of a variety of infections, including staphylococcal sepsis, atypical bacterial and fungal infections, and the reemergence of tuberculosis (14). Baseline purified protein derivative (tuberculin) testing and chest radiographs are recommended.

Anakinra, an interleukin-1 receptor antagonist, is administered daily as a subcutaneous injection. It should not be used in combination with TNF-alpha antagonists because of the possibility of marked immunosuppression with increased rates of infection. The most common adverse effect of anakinra is local injection site reactions (19).

Nonpharmacologic modalities
Physical therapy is an important modality that provides pain relief and can preserve joint function. A variety of exercises are used to increase muscle strength and improve range of motion and function without worsening disease activity. Aerobic activities such as walking, swimming, and stationary bicycling are beneficial. Other modalities include the application of heat or cold, ultrasound, and iontophoresis.

Surgical intervention is indicated for patients who do not respond to pharmacologic and nonpharmacologic medical modalities and may include soft-tissue repairs, arthroscopy, arthrodesis, and total joint arthroplasty. Goals of surgical intervention are pain relief and restoration of function and mobility.

Arthroscopic visualization of articular and cartilaginous surfaces facilitates identification of ligamentous tears and loose bodies and allows for direct synovial biopsy, lavage, debridement, synovectomy, or soft tissue repair. Arthrodesis can provide long-term pain relief and stability, although the resultant loss of range of motion can be debilitating. Total joint arthroplasty is indicated for patients who have intractable joint pain or severe impairment in function that has failed to respond to conservative medical therapies. Total joint replacement may be performed on shoulders, elbows, hands, hips, knees, and ankles.

Immunosuppressive medications such as TNF-alpha antagonists and methotrexate should be withheld during the perioperative period, to minimize the risk of infections. Appropriate and judicious use of perioperative stress doses of corticosteroids is warranted in patients receiving long-term treatment with corticosteroids. Evaluation of the cervical spine for evidence of atlantoaxial subluxation should be done before surgery, because cervical involvement is not always symptomatic (5).

Future treatment approaches
There is still no perfect laboratory test for diagnosis of rheumatoid arthritis. However, a new anticyclic citrullinated peptide antibody assay recently approved by the US Food and Drug Administration appears promising. This assay reportedly has a specificity of 99%, a sensitivity of about 80%, and a high positive predictive value. The sensitivity and specificity of this new assay are better than those of the assays for RF now available. Although the assay will probably not supplant the current method of testing for RF, it may prove to be particularly useful in diagnosis of early or RF-negative rheumatoid arthritis (20).

Newer therapeutic agents under investigation include protein kinase inhibitors, upstream inhibitors of both interleukin-6 and TNF-alpha production. Several studies involving p38 kinase inhibition have been performed in murine models of arthritis, and human trials are under way. Blockade of other important cytokines, such as interleukin-10, and blockade of costimulatory molecules or their ligands, such as the CD40/CD40L interaction or the CTLA-4Ig/B-7 interaction, are also under investigation. Rituximab, a monoclonal antibody that targets CD20 on the surface of B cells, is another promising therapeutic agent.

Conclusion

A chronic systemic disease, rheumatoid arthritis has both articular and extra-articular manifestations. Its identification and diagnosis rest on clinical, laboratory, and radiographic evidence. Although the cause of this common disorder is unknown, better understanding of the basic pathophysiologic mechanisms involved in rheumatoid arthritis has improved our ability to target key mediators of the disease process. Today's treatment strategies include nonpharmacologic techniques and drug interventions--some with potentially serious side effects--and involve monitoring for signs of both adverse effects and therapeutic response. A comprehensive approach to rheumatoid arthritis therapy can help slow joint injury and alleviate pain, thus improving function and comfort. Future approaches will include new assays for disease identification and tracking and increasingly targeted drug intervention.

References

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Dr Williams was a fellow in rheumatology, University of California, San Francisco, when she coauthored this article. Dr Fye is clinical professor of medicine, division of rheumatology, University of California, San Francisco. Correspondence: Kenneth H. Fye, MD, FACP, FACR, Division of Rheumatology, University of California, San Francisco, 400 Parnassus Ave, Box 0326, San Francisco, CA 94143.

Symposium Index

• INTRODUCTION TO THE SYMPOSIUM. By Kenneth E. Sack, MD
• OSTEOARTHRITIS: What therapies for this disease of many causes? By Kerstin Morehead, MD, Kenneth E. Sack, MD
• RHEUMATOID ARTHRITIS: Targeted interventions can minimize joint destruction. By Eleanor Anderson Williams, MD, Kenneth H. Fye, MD, FACP, FACR
• SYSTEMIC LUPUS ERYTHEMATOSUS: How to manage, when to refer. By Maria Dall'Era, MD, John C. Davis, MD, MPH

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