CORTICOSTEROIDS.

Because of its side effects, long-term corticosteroid therapy should be reserved for patients with unresponsive and aggressive joint disease whose ability to function is threatened. When necessary, the smallest possible dose should be used, i.e., prednisone, 5 to 10 mg every other day or daily. Higher doses are necessary for patients with neuropathy, vasculitis, pleuritis, pericarditis, scleritis, and related conditions. Local steroid injections can sometimes be helpful in relieving persistent effusions and are the treatment of choice for Baker's cyst of the knee.

DISEASE-MODIFYING THERAPIES.

The more slowly acting drugs include antimalarials, methotrexate, gold, penicillamine, sulfasalazine, and minocycline. Antimalarials are usually given as hydroxychloroquine (Plaquenil), 200 mg once or twice daily. This drug, or chloroquine, may cause retinal lesions and loss of vision; therefore, the patient should be examined by an ophthalmologist at least twice a year.

Currently, the most widely used and effective form of long-term therapy for RA appears to be methotrexate. An oral dosage of 7.5 to 15 mg one time per week is usually efficacious, and a therapeutic response can be anticipated in several weeks. Side effects include hepatotoxicity and possibly cirrhosis, bone marrow suppression, oral ulcers, and a potential life-threatening pneumonitis. Methotrexate may also cause a leukocytoclastic vasculitis and may promote the formation of rheumatoid nodules, including systemic nodulosis. Concomitant treatment with folic acid, 1 mg/day, reduces toxicity from methotrexate without impairing efficacy. Sulfonamides must be avoided because of potentiation of hematologic side effects.

Leflunomide (Arava), a pyrimidine antagonist that selectively inhibits activated T lymphocytes, has been recently introduced for long-term treatment of RA. The drug given with an oral loading dose of 100 mg for each of 3 days, followed by 20 mg daily thereafter, has shown considerable efficacy and little toxicity, although liver function tests require regular monitoring.

Sulfasalazine given in a dose of 2 to 3 g daily may be effective in some patients. Headache and gastrointestinal upset are the most common side effects. Another antibiotic, minocycline in a dosage of 100 mg twice daily, has also recently been found to be effective in RA. The most common side effect is gastrointestinal upset.

Gold salts, especially weekly intramuscular injections, produce remission in many cases. An oral gold salt, auranofin, appears to be therapeutically effective and to have less toxicity than do intramuscular injections. A dose of 3 mg two to three times per day is recommended. A therapeutic effect should not be expected before 4 to 6 months. Common side effects include pruritic skin rashes and painful mouth ulcers. Severe manifestations include bone marrow suppression, usually leukopenia or thrombocytopenia, renal damage with proteinuria, and rarely a nephrotic syndrome. Therefore, frequent urinalysis and blood counts must be performed, especially during the early phases of treatment.

Penicillamine is also effective in inducing improvements and sometimes even remissions. Like gold, however, its effects are slow in coming, and it may affect both the bone marrow and the kidneys, so careful monitoring for toxicity is required. In addition, it may induce other autoimmune diseases such as myasthenia gravis, Goodpasture's syndrome, or lupus erythematosus.

Immunosuppressive agents such as azathroprine, cyclophosphamide, chlorambucil, and cyclosporine have been used to treat especially severe, unremitting RA. A soluble recombinant TNF-alpha receptor, etanercept (Embrel), has recently been introduced for patients with severe RA who have failed other disease-modifying agents. Short-term clinical trials have shown it to be quickly, highly effective in a majority of patients. Toxicity appears to be low short-term, but concerns about potential oncogenesis or infectious complications from TNF-alpha blockade with time remain to be determined. Other disadvantages include high cost and need for bi-weekly subcutaneous injections.

Combinations of certain long-lasting agents are increasingly being advocated for severe RA and may prove beneficial in some patients. The likelihood of serious side effects is significantly increased, however, and close consultation with a rheumatologist is strongly recommended.