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History of combination therapy of rheumatoid arthritis.

Faced with continued active rheumatoid arthritis (RA) despite conventional treatments, clinicians have added and combined whatever drugs were available to them, attempting to increase the benefits and minimize the adverse effects of treatment. First, combined antimalarial and gold salts therapy was favorably compared with antimalarial therapy in a large series of patients reported in 1963, but was cautioned against in 1966 because of concern about increasing toxicity. This concern discouraged subsequent publication of clinical experiences with combination therapies until 1982, when major benefits were reported in 17 patients treated with cyclophosphamide, azathioprine, and hydroxychloroquine. This report opened the door to numerous abstracts and publications during the 1980s, describing anecdotal series and poorly controlled clinical trials with various combinations of disease modifying antirheumatic drugs (DMARD), mostly with favorable results. During the past 5 or 6 years, a few, large, well controlled, randomized, double blind clinical trials with a balanced design have been published, but conclusive evidence of benefit from combinations of DMARD was lacking. Recent abstracts have suggested that triple therapy with methotrexate (MTX), hydroxychloroquine, and sulfasalazine produces additive benefits, and that the addition of cyclosporine, in patients who are poorly controlled by MTX, is more effective than continuing MTX alone. Only a few of the many possible permutations and combinations of drugs and doses have been evaluated, and confirmatory studies have not been done. Combination therapy of RA is only now starting to evolve, with most major milestones yet to be achieved.