Infliximab and Methotrexate in the Treatment of Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Dosage Regimens

Background: Because of its long-term effectiveness in clinical practice, methotrexate (MTX) is currently the preferred disease-modifying antirheumatic drug (DMARD) for patients with active rheumatoid arthritis (RA). However, many patients do not experience remission and continue to have signs and symptoms of active disease while receiving a maximally tolerated dose. Objectives: The aims of this meta-analysis were to estimate the efficacy and tolerability of the various dosage schemes of infliximab versus MTX for the treatment of active RA, to eliminate size-related uncertainty of effects, and to identify subgroups of patients who benefit most from infliximab + MTX therapy. Methods: Using the MEDLINE online database (inception through November 2006) and the Cochrane Database of Systematic Reviews (Issue 4, 2006), we identified English-language articles on randomized controlled clinical trials. Studies investigating infliximab + MTX regimens versus a control group receiving MTX alone to assess efficacy in active RA, using the American College of Rheumatology (ACR) criteria for 20% improvement (ACR20), 50% improvement (ACR50), and 70% improvement (ACR70), were considered eligible for the meta-analysis. Pooled odds ratios (ORs) and 95% CIs were calculated to compare the relative risks and benefits of adding infliximab to MTX. Results: From a total of 78 initially identified studies, 42 were considered potentially eligible for this review and 1.2 were considered eligible for the meta-analysis. Overall, 4899 patients were randomized to either infliximab + MTX (391.9 patients) or MTX alone (980 patients). Mean patient age ranged from 44.6 to 56 years in the MTX-only arms and from 45.8 to 56 years in the infliximab + MTX arms. The proportion of female patients ranged from 66.6% to 100% in the MTX arms and from 68% to 100% in the infliximab arms. Infliximab 3 mg/kg + MTX was more effective than MTX alone (OR = 3.52 [2.14-5.79] for reaching ACR20; 2.87 [2.28-3.61] for ACR50; and 2.42 [1.87-3.13] for ACR70). Infliximab 10 mg/kg + MTX was also more effective than MTX alone (OR = 5.06 [3.88-6.59] for reaching ACR20; 5.72 [4.05-8.08] for ACR50; and 7.32 [2.28-23.50] for ACR70). Infliximab 10-mg/kg regimens appeared to be more effective than infliximab 3-mg/kg regimens (P = NS, P = 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), without being associated with an increased risk for adverse events. Infliximab 10 mg/kg appeared to be more effective in trials of longer duration ( >= 54 weeks) compared with those of shorter duration (P = 0.03, P = 0.02, and P = 0.01 for reaching ACR20, ACR50, and ACR70, respectively) and in those that enrolled patients with severe disease activity (P = 0.05, P = 0.05, and P = NS for reaching ACR20, ACR50, and ACR70, respectively). Steroid coadministration (P < 0.001, P < 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), previous DMARD exposure (P < 0.001, P < 0.001, and P = 0.04 for reaching ACR20, ACR50, and ACR70, respectively), and MTX naivete (P = NS, P < 0.001, and P = 0.013 forreaching ACR20, ACR50, and ACR70, respectively) correlated with higher infliximab efficacy Conclusions: Based on this meta-analysis, higher dose infliximab (10 mg/kg) in combination with MTX appeared to be more effective than the standard 3 mg/kg dose, particularly for patients with severe disease activity. The benefits of high-close treatment appeared to accrue over time, and patients who received higher doses of infliximab did not experience a higher incidence of severe adverse events. The addition of oral low-dose steroids significantly enhanced infliximab efficacy. (Clin Ther. 2008;30:1939-1955) (C) 2008 Excerpta Medica Inc.