The safety and efficacy of interleukin-1 receptor antagonist in the treatment of rheumatoid arthritis

Background: Interleukin (IL)-1 has been associated with joint inflammation and damage in rheumatoid arthritis (RA). Endogenous IL-1 receptor antagonis t (IL-1Ra) may inhibit IL-1-mediated effects by binding to the IL-1 recepto rs. Objectives: These studies were conducted to determine the efficacy and safe ty of human recombinant IL-1 receptor antagonist (IL-1ra) in blunting the e ffects of IL-1 in patients with RA. Methods: Three randomized clinical trials have been completed. First, in a 24-week, double-blind, placebo-conrtrolled study of 472 patients with sever e RA, patients were randomly placed into 4 groups: placebo or IL-1ra at 30, 75, or 150 mg/d. In a second study, 309 patients from the placebo-controll ed trial enrolled in a 24-week extension study. Patients who had been recei ving placebo were randomized into 1 of the 3 treatment groups. Those receiv ing treatment continued to receive their previous dosages. Finally, in a se cond double-blind, placebo-controlled study, 419 patients with RA receiving methotrexate at 12.5 to 25 mg/wk for at least 6 months were randomly place d into 1 of 6 groups: placebo or IL-1ra at 0.04, 0.1, 0.4, 1.0, or 2.0 mg/k g/d. Results: In the first study, the primary therapeutic endpoint-an American C ollege of Rheumatology 20% response (ACR20)-was reached by 27% of the place bo group, compared with 43% of the IL-1ra 150-mg/d group. Individual clinic al responses, as well as the arrest of joint damage, were also superior in treated patients. In the second trial, 52% of the randomized patients achie ved an ACR20. This was maximal (71%) in those receiving the highest treatme nt dosage. Of patients continuing with the same dosage, 49% maintained an A CR20 at 48 weeks. Radiologic evaluation showed that the reduced rate of car tilage degradation observed in treated patients during the first 24 weeks w as maintained, and the rate of joint erosion was slowed even more significa ntly in the second phase of the study. In the third study, significantly mo re patients receiving IL-1ra at 1.0 (46%, P = .001) or 2.0 (38%, P = .007) mg/kg/d achieved an ACR20 at week 12 than those receiving placebo (19%). Si milar responses were noted at week 24. IL-1ra was generally well tolerated, with injection site reaction the most frequent adverse event. No serious a dverse events attributable to IL-1ra treatment were observed. Conclusions: These studies suggest an important role for IL-1ra as a novel therapeutic agent in the treatment of RA. Semin Arthritis Rheum 30:17-20 (S uppl 2). Copyright (C) 2001 by W.B. Saunders Company.