Infliximab and methotrexate in the treatment of rheumatoid arthritis: A systematic review and meta-analysis of dosage regimens

• Published in: Clinical therapeutics Vol. 30; no. 11; pp. 1939 - 1955
• Main Authors: Zintzaras, Elias, PhD, Dahabreh, Issa J., MD, Giannouli, Stavroula, MD, Voulgarelis, Michael, MD, Moutsopoulos, Haralampos M., MD
• Format: Journal Article
• Language: English
• Published: Bridgewater, NJ EM Inc USA 01.11.2008; Elsevier; Elsevier Limited
• Subjects: Administration, Oral; Adult; Age Factors; Alcoholism; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - therapeutic use; Antirheumatic Agents - administration & dosage; Antirheumatic Agents - adverse effects; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - drug therapy; Biological and medical sciences; Clinical trials; Cytokines; Disease; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Drug Therapy, Combination; efficacy; Female; Genomes; Humans; Inflammatory joint diseases; Infliximab; Internal Medicine; Male; Medical Education; Medical sciences; Meta-analysis; methotrexate; Methotrexate - administration & dosage; Methotrexate - adverse effects; Methotrexate - therapeutic use; Middle Aged; Monoclonal antibodies; Pharmacology. Drug treatments; Randomized Controlled Trials as Topic; Rheumatoid arthritis; Rheumatology; Systematic review; Time Factors; TNF inhibitors; tolerability; Treatment Outcome; Tumor necrosis factor-TNF; meta-analysis; methotrexate; rheumatoid arthritis; infliximab; efficacy; tolerability; Antineoplastic agent; Toxicity; Diseases of the osteoarticular system; Autoimmune disease; Systematic review; Inflammatory joint disease; Monoclonal antibody; Review; Posology; Metaanalysis; Antifolate; Infliximab; Anticytokine; Methotrexate; Tumor necrosis factor α; Immunopathology; Treatment efficiency; Cytokine; Anti-Tumor Necrosis Factor-alpha; Immunomodulator; Chronic; Treatment; Antimetabolic; Rheumatoid arthritis; Immunosuppressive agent
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2008.11.007

Abstract 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 (RRA). 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, usinng the American College of Rheumatology (A criteria for 20% improvement (AA, 50% improvement (ACR50), and 70% improvement (AA, were considered eligible for the meta-aanalysis. 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 12 were considered eligible for the meta-analysis. Overall, 4899 patients were randomized to either infliximab + MTX (3919 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/kkg + MTX was moreeffective than MTX alone (OR = 3.52 [2.14-5.79] for reaching ACR20; 2.87 [2.228-3.61] for ACR50; and 2.42 [1.87-3.13] for ACR70). Infliximab 10 mg/kkg + 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-mm/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 for reaching ACR20, ACR50, and ACR70, respectively) correlated with higher infliximab efficacy. Conclusions: Based on this meta-aanalysis, 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-dose 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.