Rheumatoid arthritis is a progressive inflammatory disease historically treated according to a “pyramid” or sequential strategy, beginning with a nonsteroidal anti-inflammatory drug. Traditionally, early use of disease-modifying antirheumatic drugs (DMARDs) has been avoided until patients show signs of joint damage. However, this strategy has proved ineffective over several years. Patients experienced poor long-term outcomes, including severe functional declines, radiographic progression of disease, work disability and premature mortality. The current approach to management emphasizes aggressive control of inflammation to prevent long-term damage. Pincus and associates review early treatment strategies, including use of single or combination DMARDs, designed to control inflammation as much as possible to prevent or slow the joint damage associated with rheumatoid arthritis.

Two issues appear to be sources of confusion with regard to long-term outcomes of treatment. First, some patients who meet diagnostic criteria for rheumatoid arthritis have a self-limited process with spontaneous remission. Thus, in the absence of signs of progression, some patients are diagnosed with, and subsequently treated for, other conditions. Second, measures of inflammatory activity such as joint swelling or erythrocyte sedimentation rate are often used to assess inflammatory activity. However, these indices are less useful end points for evaluation than severe long-term outcomes such as work disability or joint deformity and radiographic changes, in which the latter two are irreversible. During a period in which inflammatory markers may be stable or even improved, radiographic progression and functional decline can occur.

Traditional DMARDs such as injectable gold salts and penicillamine rarely induce sustained remission and are usually discontinued within two years. Newer DMARDs such as methotrexate, hydroxychloroquine and sulfasalazine have greater long-term effectiveness but still rarely result in true remission. Optimal control may require combination therapy. Recent studies have shown that methotrexate combined with other DMARDs is more effective and has acceptable toxicity when compared with use of a single agent. In combination with cyclosporine, methotrexate resulted in greater clinical improvement than methotrexate alone. Triple therapy with methotrexate, sulfasalazine and hydroxychloroquine provided substantially greater clinical improvement than methotrexate alone or sulfasalazine plus hydroxychloroquine. In combination with infliximab, methotrexate provided a superior response to monotherapy. In combination with etanercept, methotrexate provided a higher rate of meaningful clinical response. Toxicities of these drug combinations were rarely more than those occurring with any of the individual agents used alone.

The authors conclude that the goal of contemporary management of rheumatoid arthritis should be complete remission or “no evidence of disease.” Achieving this goal likely requires ongoing drug therapy, probably using a combination of methotrexate with some other DMARD, although some patients may still respond satisfactorily to monotherapy. More long-term studies are needed to evaluate potential severe long-term outcomes associated with combination therapy before definite recommendations can be made.