IL-1Ra was initially tested in a trial in 25 patients with rheumatoid arthritis. In the group receiving a single subcutaneous dose of 6 mg/kg, there was a fall in the mean number of tender joints (P < .05) (25). In patients receiving 4 mg/kg per day for 7 days, there was a reduction in the number of tender joints from 24 to 10, the erythrocyte sedimentation rate fell from 48 to 31, and C-reactive protein decreased from 2.9 to 1.9 |g/mL. In this group, the mean plasma concentration of IL-1Ra was 660 ± 240 ng/mL.
In an expanded double-blind trial, IL-1Ra was given to 175 patients (26). Patients were enrolled into the study with active disease and taking non-steroidal anti-inflammatory drugs and/or up to 10 mg/day of prednisone. There was an initial phase of 3 weeks of either 20, 70, or 200 mg one, three, or seven times per week. Thereafter, patients received the same dose once weekly for 4 weeks. Placebo was given to patients once weekly for the entire 7-week study period. To maintain the blindness of the study, patients received daily injections of either IL-1Ra or placebo on the days IL-1Ra was not administered.
Four measurements of efficacy were used: number of swollen joints, number of painful joints, patient and physician assessment of disease severity. A reduction of 50% or greater in these scores from baseline was considered significant in the analysis. After 3 weeks, a statistically significant reduction in the total number of parameters was observed with the optimal improvement in patients receiving 70 mg per day. Daily dosing appeared more effective than weekly dosing when assessed by the number of swollen joints, the investigator and patient assessments of disease activity, pain score, and C-reactive protein levels.
A large double-blind, placebo-controlled multicenter trial of IL-1Ra in 472 patients with rheumatoid arthritis (RA) has been reported (27). The study comprised patients who had discontinued the use of disease-modifying agents such as gold and methotrexate 6 weeks prior to entry. Patients had active and severe RA (disease duration 8 years) and were recruited into a 24-week course of therapy into placebo or one of three IL-1Ra groups. Patients had stable disease of 2 or more years' duration and were controlled on nonsteroidal anti-inflammatory agents. Some were taking less than 10 mg of prednisone daily. There were three doses of IL-1Ra administered subcutaneously: 30, 75, and 150 mg/day for 24 weeks. At entry, age, sex, disease duration, and percentage of patients with rheumatoid factor and joint bone erosions were similar in each of the groups. After 24 weeks, 43% of the patients receiving 150 mg/day of IL-1Ra met the American College of Rheumatology criteria for response (the primary efficacy measure), 44% met the Paulus criteria, and statistically significant (P = .048) improvements were seen in the number of swollen joints, number of tender joints, investigator's assessment of disease activity, patient's assessment of disease activity, pain score on a visual analog scale, duration of morning stiffness, and Health Assessment score. In addition, there was a dose-dependent reduction in the C-reactive protein level and erythrocyte sedimentation rate.
Importantly, the rate of radiological progression in the patients receiving IL-1Ra was significantly less than in the placebo group at 24 weeks, as evidenced by the Larsen score and the erosive joint count. The reduction in new bone erosions was assessed by two radiologists who were blinded to the patient treatment as well as blinded to the chronology of the x-ray films. This finding suggests that IL-1Ra blocks the osteoclast-activating factor property of IL-1, as has been reported in myeloma cell cultures (28). This study confirmed both the efficacy and the safety of IL-1Ra in a large cohort of patients with active and severe rheumatoid arthritis.
The only side effect was the local skin rash which was observed primarily during the first 2 weeks of therapy. After 24 weeks, there were no statistically significant increases in infection in the IL-1Ra arm compared to placebo. When the trial was extended another 24 weeks, there was also no statistically significant increases in infection. Some patients have now been treated with IL-1Ra for over 3 years and there are no reports of increased infection or cancer. Another trial of IL-1Ra in patients with rheumatoid arthritis is being carried out in patients randomized to receive treatment with methotrexate or different doses of IL-1Ra plus methotrexate treatment.
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