Rheumatoid Arthritis: Hazleman B

Choy EH, Isenberg DA, Garrood T, Farrow S, Ioannou Y, Bird H, Cheung N, Williams B, Hazleman B, Price R, Yoshizaki K, Nishimoto N, Kishimoto T, Panayi GS. · Guy's, King's, and St. Thomas' School of Medicine, King's College, London, UK. · Arthritis Rheum. · Pubmed #12483717 links to  free full text

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.

Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, Patel J, Sopwith M, Isenberg DA. · Academic Department of Rheumatology, GKT School of Medicine, King's College London, King's College Hospital, London, UK. · Rheumatology (Oxford). · Pubmed #12364632 links to  free full text

Abstract: OBJECTIVE: Biological products that neutralize tumour necrosis factor alpha (TNF-alpha) are beneficial in rheumatoid arthritis (RA). We studied the effects of CDP870, a novel anti-TNF-alpha antibody fragment modified to obtain a prolonged plasma half-life ( approximately 14 days). METHODS: Thirty-six patients were randomized in a double-blind, ascending-dose group study to a single intravenous infusion of placebo (n = 12) or 1, 5 or 20 mg/kg CDP870 (each n = 8). The patients were predominantly female (30/36), had a mean age of 56 yr and a mean duration of RA of 13 years. They had received a mean of five DMARDs or experimental therapies (with 1 month washout before the study started) and had active disease. Continuation of NSAIDs and up to 7.5 mg prednisolone daily was allowed. Following the blinded dosing period, 32 patients received a single open-label infusion of either 5 or 20 mg/kg CDP870. RESULTS: In the blinded dosing period, 6/12 placebo patients withdrew from the study (for deteriorating RA < or =4 weeks after dosing). Two of 24 CDP870-treated patients withdrew, both in the 1 mg/kg group (for deteriorating RA or lost to follow up >4 weeks after dosing). The proportion of patients with ACR20 improvement for the per-protocol population with the last observation carried forward was 16.7, 50, 87.5 and 62.5% after 0, 1, 5 and 20 mg/kg CDP870 respectively (combined treatment effect, P = 0.012, primary analysis) at 4 weeks and 16.7, 25, 75 and 75% (P = 0.032) at 8 weeks. The proportion of patients with ACR50 improvement for the per-protocol population with the last observation carried forward was 0, 12.5, 12.5 and 50% after 0, 1, 5 and 20 mg/kg CDP870 respectively (combined treatment effect, P = 0.079) at 4 weeks and 0, 12.5, 12.5 and 50% (P = 0.079) at 8 weeks. Following the open-label dose of CDP870, similar beneficial effects were achieved. CONCLUSION: CDP870 is effective, was very well tolerated in this small study, and has an extended duration of action following one or more intravenous doses.