Most Appropriate Conventional Disease‐Modifying Antirheumatic Drug to Combine With Different Advanced Therapies in Rheumatoid Arthritis: A Systematic Literature Review With Meta‐Analysis

Objective In rheumatoid arthritis, the association between advanced therapies (including biologic disease‐modifying antirheumatic drugs [DMARDs] and targeted synthetic DMARDs) and methotrexate (MTX) is recommended by international societies. When MTX cannot be used, other conventional synthetic DMARDs (csDMARDs) may be proposed. We aimed to compare the safety and efficacy of MTX and non‐MTX csDMARDs in combination with advanced therapies. Methods We systematically searched the literature for studies comparing the effectiveness, retention rate, and safety of MTX versus non‐MTX csDMARDs (leflunomide or others) in combination with tumor necrosis factor inhibitors (TNFi), abatacept, rituximab, tocilizumab, and JAK inhibitors. Meta‐analysis was performed with RevMan, using an inverse variance approach with fixed or random‐effects models. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were estimated. Results The literature search revealed 3,842 articles; 41 studies were included for the systematic literature review and 21 for the meta‐analysis: 13 with TNFi, 3 with abatacept, and 5 with rituximab. For TNFi, the European Alliance of Associations for Rheumatology (EULAR) response at 6 months was lower for patients receiving non‐MTX csDMARDs than for those using MTX (RR 0.93 [95% CI 0.87, 1.0], P = 0.04; n = 3,843; I 2 = 28%), with a lower retention rate at 12 months. For abatacept, effectiveness and safety were similar between the 2 groups. For rituximab, a good EULAR response was higher with leflunomide than MTX (RR 1.38 [95% CI 1.13, 1.68], P = 0.001; n = 2,078; I 2 = 0%), with similar adverse event rates. Meta‐analysis for tocilizumab or JAK inhibitors could not be performed. Conclusion The different csDMARDs seem safe and efficient to combine with advanced therapies in RA patients. Although MTX seems slightly superior to other csDMARDs in combination with TNFi, leflunomide might be superior to MTX in combination with rituximab.