Preventing joint damage as the best measure of biologic drug therapy

Joint damage occurs progressively in patients with rheumatoid arthritis (RA), leading to functional decline and disability. The proinflammatory cytokines interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are thought to play a key role in promoting cartilage and bone erosion in the rheumatoid joint. In randomized clinical trials, inhibitors of these cytokines significantly slowed the rate of progressive joint damage as assessed by radiographic techniques. The IL-1 receptor antagonist anakinra significantly reduced erosions, joint space narrowing, and total joint damage when a modified Sharp score was used to evaluate serial hand radiographs. The maximum benefit of anakinra on joint space narrowing was achieved within the first 24 weeks and was maintained during continued treatment, whereas the slowing of erosions by anakinra increased with continued treatment beyond 24 weeks. In terms of TNF-alpha inhibition, infliximab significantly reduced joint damage in patients with long-standing RA, when used in combination with methotrexate (MTX), whereas etanercept significantly reduced erosions relative to MTX in patients with early stage disease. Comparisons among the cytokine inhibitors are made problematic by differences in the designs, patient populations, and outcome measures of these trials. Nevertheless, these studies demonstrate that IL-1 or TNF-alpha inhibition effectively suppresses the pathophysiological mechanisms associated with cartilage degradation and bone erosion, resulting in a slowing of further radiographic progression.