The prospect of treating rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist

The prospect of introducing a potent novel therapy that specifically targets a pivotal mediator of disease offers new hope to patients with rheumatoid arthritis (RA). There is convincing evidence that interleukin-l (IL-1) plays a critical role in the pathogenesis of RA. In RA, the inadequate production of IL-1 receptor antagonist (IL-1Ra), the natural inhibitor of IL-1. results in increased IL-l-mediated pathophysiological activity. Unregulated IL-l-mediated effects produce enhanced tissue inflammation and progressive degradation of cartilage and bone matrix. Recombinant IL-1Ra treatment in experimental models of arthritis results in profound suppression of synovial inflammation and joint damage. Recombinant human IL-1Ra (rhu-IL-1 Ra) has been evaluated in RA in several randomised clinical trials and was shown to significantly reduce both the clinical manifestations of arthritis and the rate of progressive joint damage. Firstly, in a 6-month placebo-controlled study, 43% of the patients who received the highest dose of rhu-IL-1Ra (150 mg/day) demonstrated a 20% improvement (American College of Rheumatology clinical criteria) compared to 27% of the patients who received placebo. In addition. the patients who received rhu-IL-1Ra demonstrated 46% less joint damage (Larsen scores). Secondly, in a 6-month extension of the placebo-controlled study, the treated patients maintained their clinical improvement and there was further significant reduction in the rate of progressive joint damage. The patients who had originally received placebo demonstrated both clinical and radiological responses that were similar to those observed in the treated patients during the initial phase of the study. Finally, in a combination study with methotrexate (MTX), 42% of patients who received MTX and the optimal dose of rhu-IL-1Ra (1.0 mg/kg/day) demonstrated an ACR 20% clinical response, compared to 23% of those receiving MTX and placebo, rhu-IL-1Ra was well tolerated in all studies and adverse events were uncommon. The most frequently reported adverse event causing withdrawal of treatment was an injection site reaction, occurring in approximately 5% of patients. In conclusion, targeted IL-1 inhibition significantly reduced both the clinical manifestations and the rate of progressive joint damage in patients with RA. These observations suggest that rhu-IL-1Ra has a potential role as a novel therapeutic modality in the future management of RA.