Therapeutic benefit of blocking interleukin‐6 activity with an anti–interleukin‐6 receptor monoclonal antibody in rheumatoid arthritis: A randomized, double‐blind, placebo‐controlled, dose‐escalation trial

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Abstract
Objective To investigate the safety and efficacy of MRA, a recombinant human anti–interleukin‐6 (anti–IL‐6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL‐6, in patients with established rheumatoid arthritis (RA). Methods A randomized, double‐blind, placebo‐controlled, dose‐escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment. Results Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1‐ and 1‐mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C‐reactive protein values fell significantly in the 5‐ and 10‐mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1‐, 1‐, 5‐, and 10‐mg/kg MRA cohorts, respectively) required corticosteroid or disease‐modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1‐, 1‐, and 10‐mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug. Conclusion This is the first randomized controlled trial showing that inhibition of IL‐6 significantly improved the signs and symptoms of RA and normalized the acute‐phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.