Emerging Treatments for Rheumatoid Arthritis : August 01 , 2005

Early treatment with disease-modifying anti-rheumatic drugs (DMARDs)--alone or in combination-can prevent joint damage and minimize disability. Until recently, the DMARDs used predominantly in patients with rheumatoid arthritis had been methotrexate, sulfasalazine, and hydoxychloroquine. Older DMARDs such as gold, d-penicillamine, and azathioprine have fallen out of favor because of their longterm toxicities or modest benefit. Six newer DMARDs--leflunomide, etanercept, infliximab, adalimumab, rituximab, and anakinra--have greatly expanded the current treatment options. Disease progression in patients with rheumatoid arthritis (RA) frequently leads to joint destruction, physical dysfunction, and reduced quality of life--sometimes culminating in work disability and even premature death. Patients with RA are usually treated with disease-modifying anti-rheumatic drugs (DMARDs) to control arthritis activity. These diverse agents exhibit a broad range of anti-rheumatic properties that reduce joint inflammation and slow the progression of radiologically assessed joint damage. However, the clinical efficacy of individual DMARDs varies--as does patient response. DMARD therapy, although effective, usually results in partial improvement but not complete remission. Residual disease activity is the rule rather than the exception, which explains the progressive course suffered by most patients with RA. Because joint damage often occurs more rapidly early in the course of the disease, it is best prevented by early intensive DMARD therapy. The extent to which DMARD therapy will improve long-term outcomes of RA is not known. However, the short-term effectiveness observed with newer RA therapies provides hope that long-term improvement is an attainable goal. In this article, we discuss the rationale for early, intensive treatment. In addition, we provide an overview of the major comorbidities associated with RA, and we review current DMARD therapies and their side effects. DISEASE BURDEN OF RA Uncontrolled RA leads to poor outcomes, which include joint damage, increased costs of medical care, disability, need for joint replacement surgery, and increased mortality. (Table 1). The clinical and laboratory parameters of disease that correlate with these outcomes include persistent joint inflammation, presence of serum rheumatoid factor (RF), elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level, and reduced functional status. Intervention with DMARDs has been shown to improve these clinical and laboratory disease measures, reduce structural damage and physical disability, lower direct medical and nonmedical costs, and enhance quality of life. Whether DMARD therapy improves other important outcomes of RA, such as hospitalization rates and mortality, is not known. Structural damage. Erosive changes occur in 50% to 70% of patients within 2 years of disease onset.1 Although patterns vary, damage generally accrues more rapidly during the first 5 to 10 years of disease onset. Therefore, patients with early disease or patients with active RA are at high risk for further joint destruction. It is becomng easier to predict the future development of joint damage in patients with RA. Risk factors for subsequent joint damage and more rapid disease progression include elevated serum RF levels, multiple erosions on x-ray films, metatarsophalangeal (MTP) involvement, more than 3 affected joints, and active disease for more than 3 months. Elevated ESR and the presence of disease-related HLA-DRB1 alleles are variable risk factors for subsequent joint damage.1-3 Thus, we can generally identify patients who have a greater likelihood of a poor prognosis. What is difficult, however, is predicting individual responses to DMARD therapy. Disability. Functional disability often occurs early in RA and usually increases if disease control is inadequate. In early disease, high functional disability scores derived from self-administered health assessment questionnaires are the strongest predictors of future disability.4