Rheumatoid Arthritis

A chronic syndrome of symmetric inflammation of the peripheral joints, resulting in progressive destruction of articular and periarticular structures.

Prevalence of rheumatoid arthritis increases up to age 80. Rheumatoid arthritis is an important cause of disability in elderly persons.

The cause is unknown. Intense inflammation of the synovium of the diarthrodial joints is characteristic. Synovial tissue becomes hyperplastic and infiltrated with lymphocytes and plasma cells. Various inflammatory mediators, including cytokines, prostaglandins, and immunoglobulins, are present in the synovial fluid.

Symptoms and Signs

In many elderly patients, the disease process began during middle age. Some patients have secondary joint deformities and degenerative changes even though the inflammation is inactive. When rheumatoid arthritis develops de novo in an elderly person, the onset may be insidious or acute. In most patients, the arthritis is accompanied by mild or moderate constitutional symptoms (eg, malaise, anorexia). Fever and night sweats occasionally are reported. Rheumatoid arthritis occurs primarily in the joints of the hands (eg, wrists, proximal interphalangeal, and metacarpophalangeal) and feet (eg, metatarsophalangeal and interphalangeal) and in the larger joints (eg, elbows, shoulders, knees). Patients report pain, swelling, and stiffness in these areas, especially in the mornings. Eventually, rheumatoid arthritis becomes a symmetric, additive disease of the joints.

Diagnosis

The diagnosis is based on clinical judgment and requires that the patient exhibit symmetric inflammatory arthritis involving the appropriate joints and prolonged morning stiffness lasting >= 1 hour (see Table 52-1). The physical examination detects soft tissue swelling, warmth, and tenderness in these areas and, sometimes, nodules along extensor surfaces of the upper extremities and around joints. Other diseases (eg, polymyalgia rheumatica, systemic lupus erythematosus, the arthritis of malignancy) must be excluded.

Patients with rheumatoid arthritis may have normochromic-normocytic anemia, mild leukocytosis, or thrombocytosis. The ESR is elevated in about 80% of cases, and rheumatoid factor is present in about 50%; however, these findings are not specific for rheumatoid arthritis. High titers of rheumatoid factor (>= 1:320) are highly specific; in contrast, low titers are found in patients with other diseases and in up to 25% of elderly patients without evidence of any disease.

Initially, x-rays of involved joints usually show only soft tissue swelling. Characteristic late features include periarticular osteoporosis, joint space narrowing, and marginal erosions.

Prognosis and Treatment

In general, the long-term prognosis is poor. Many patients become progressively disabled despite appropriate treatment, and higher rates of serious infections and cardiovascular disease increase mortality. Nevertheless, many patients respond to treatment.

Nonpharmacologic treatment: Physical and occupational therapy, exercise, use of assistive devices, and possibly physical modalities for pain relief (eg, locally applied heat or cold) are essential. Rest should be encouraged when symptoms are severe. However, prolonged bed rest in elderly patients exacerbates age-related loss of aerobic capacity and muscle strength and may lead to irreversible immobility; elderly patients can easily cross the threshold at which functional ability is so severely compromised that it cannot be restored.

Nonsteroidal anti-inflammatory drugs: Therapy should include a nonsteroidal anti-inflammatory drug (NSAID) to relieve pain and swelling. Regular use of a full-dose NSAID is often required. The therapeutic effects of NSAIDs are due to the inhibition of cyclooxygenase (COX), which is required for the synthesis of prostaglandins. Two COX isoforms exist: COX-1 is expressed in most tissues, including gastric mucosa, and COX-2 is induced in inflammatory cells and synovium during inflammation. COX-2 is also found in the kidney but not in platelets.

Most NSAIDs inhibit both COX-1 and COX-2, but newer selective COX-2 inhibitors (also called coxibs) affect only the COX-2 isoform and therefore cause fewer gastric ulcers and do not inhibit platelets. With nonspecific NSAIDs, gastrointestinal toxicity occurs up to four times more frequently among persons > 65 than among younger persons. Thus, a COX-2 inhibitor can be considered instead of older NSAIDs because gastrointestinal toxicity and platelet inhibition are less likely. However, one of the COX-2 inhibitors, rofecoxib (withdrawn from market), appears to increase the risk of cardiovascular events after long-term use. The risk of cardiovascular events with other COX-2 inhibitors is undergoing evaluation. Because one study has shown a 2.5-fold increase in cardiovascular events with celecoxib, FDA recommendations, pending further evidence, are to limit use of any coxib to patients who are at a high risk of GI bleeding, have a history of intolerance to nonselective NSAIDs, or are not doing well on nonselective NSAIDs. Use of coxibs for long periods or in patients with cardiovascular risk factors should be approached cautiously.

Corticosteroids: Low-dose prednisone (eg, 5 to 10 mg/day) may help reduce pain and disability. However, corticosteroids are difficult to discontinue, and their long-term adverse effects (eg, osteoporosis, cataracts, poor wound healing, hyperglycemia, hypertension, hyperlipidemia, reactivation of tuberculosis, increased risk of infection) must be balanced against their therapeutic benefits. Intra-articular injections of corticosteroid esters may temporarily help control local synovitis in one or two particularly painful joints.

Disease-modifying antirheumatic drugs: These drugs slow the disease process, improve function, and reduce mortality. They should be used early in the course of rheumatoid arthritis to prevent joint destruction and disability. These drugs even improve survival. No evidence suggests that elderly patients respond less well to these drugs than do younger patients or that toxicity is different. Therefore, therapy with these drugs should not be withheld because of the patient's age; however, therapy should be managed by a rheumatologist.

Usually, methotrexate is the first choice. The initial oral dosage is usually 7.5 mg/week, which may be increased up to 20 mg/week. Patients receiving methotrexate should be closely monitored for hepatic toxicity, interstitial pneumonitis, bone marrow suppression, and gastrointestinal ulceration and bleeding. Aspirin may increase the toxicity of methotrexate by slowing its excretion rate. Folic acid supplementation (5 mg/week) helps prevent toxicity. Methotrexate is contraindicated in patients with renal insufficiency.

Hydroxychloroquine 6.5 mg/kg/day or 400 mg/day po can be used. Rarely, severe and sometimes irreversible adverse effects, particularly vision loss, occur. Vision should be checked by an ophthalmologist before treatment.

Sulfasalazine 3 to 4 g/day po is an effective disease-modifying antirheumatic drug. The major adverse effects are nausea, vomiting, and upper gastric distress. Patients should be monitored periodically with the use of CBCs and liver function tests.

Combination therapy using methotrexate, hydroxychloroquine, and sulfasalazine has been shown to be more effective than monotherapy. However, high cost and toxicity may limit this approach to therapy.

The biologic response modifier etanercept (10 to 25 mg sc biweekly) is a soluble tumor necrosis factor receptor that blocks the action of the proinflammatory cytokine tumor necrosis factor. The most common adverse effect is a reaction at the injection site. Long-term adverse effects (> 2 years) are unknown. Another biologic response modifier, leflunomide, is given in a loading dose of 100 mg/day po on days 1 to 3, followed by 20 mg/day, to inhibit de novo pyrimidine synthesis. The most common serious adverse effect is hepatic toxicity.

Gold compounds and penicillamine are older drugs that are used less frequently but can be considered for patients who cannot tolerate other drugs. Gold sodium thiomalate and gold thioglucose (aurothioglucose) are injectable (eg, intramuscularly); a test dose of 10 mg for the 1st week is followed by a 25-mg dose 1 week later. All subsequent IM doses of 25 to 50 mg are given weekly until a cumulative dose of 1 g is achieved and a therapeutic response or toxicity occurs. If a therapeutic response occurs, maintenance doses of 25 to 50 mg are continued weekly, then every 2 weeks, then every 3 weeks, then monthly. Monthly therapy should be continued indefinitely to prevent a recurrence. Auranofin, an oral gold compound, may be less effective than the injectable forms; the usual dosage is 3 mg bid or 6 mg/day for 6 months. If no therapeutic response occurs, the dosage may be increased to 3 mg tid.

The most common adverse effects of gold therapy are pruritus, dermatitis, stomatitis, proteinuria, and pancytopenia. Pruritus often precedes diffuse dermatitis, which may cause exfoliation, and stomatitis. When pruritus or even minor dermatitis develops, gold therapy should be discontinued. If the dermatitis resolves, the drug may be restarted at a lower dose. Proteinuria, leukopenia, or thrombocytopenia requires permanent discontinuation of gold therapy. Oral gold therapy causes less mucocutaneous and renal toxicity but more diarrhea and gastrointestinal reactions.

Penicillamine is started at 125 to 250 mg/day po, which is increased at 2- to 3-month intervals by 125- to 250-mg increments to a total of 750 mg/day. Penicillamine should be taken between meals because food decreases absorption. Adverse effects include dermatitis, proteinuria, dysgeusia, and thrombocytopenia; more severe adverse effects (eg, pemphigus, myasthenia gravis, a lupus-like syndrome, severe bone marrow suppression) have also been reported. Patients taking penicillamine must be monitored closely.

Azathioprine, cyclophosphamide, and cyclosporine can be used to treat refractory rheumatoid arthritis. For very advanced cases, a new treatment option consists of apheresis using a staphylococcus protein A immunoadsorption column.