Comparative disproportionality signals for methotrexate monotherapy versus methotrexate combined with hydroxychloroquine, leflunomide, or sulfasalazine in rheumatoid arthritis: newly highlighted signals evaluated using drug information safety profiles

Methotrexate (MTX) is the anchor conventional synthetic disease-modifying antirheumatic drug (csDMARD) in rheumatoid arthritis. Postmarketing safety patterns may differ between MTX monotherapy and MTX-based dual-csDMARD combinations. This study aimed to compare disproportionality signals for MTX alone versus MTX combined with hydroxychloroquine, leflunomide, or sulfasalazine and comparison with drug information safety profiles. A retrospective disproportionality study was conducted using a spontaneous reporting database across 2016Q1 to 2025Q2. Groups were MTX only (MTX as primary suspect) and MTX + hydroxychloroquine, leflunomide, or sulfasalazine (two drug reports with one primary suspect and one secondary suspect). Reporting odds ratios (RORs) were estimated at system organ class (SOC) and preferred term (PT) levels. Significant PTs were checked against drug information safety profiles. Time-to-onset (TTO) was summarized. A total of 148,315 reports were eligible. SOC signals were modest for MTX only, and highest for infections and infestations (ROR = 1.77) and blood and lymphatic disorders (ROR = 1.77). Combination cohorts showed strong musculoskeletal signals (ROR 8.13 to 9.64) and investigations (ROR = 3.25 to 3.72). Selected PT RORs included mucosal inflammation = 12.47, bone marrow failure = 12.83, and B-cell lymphoma = 13.94 in MTX only. Chondropathy reached 19.16 in MTX + leflunomide. Lip blister reached 17.02 and compartment syndrome 17.56 in MTX + sulfasalazine. Early TTO was seen for vomiting (median 22 days; 67% within 30 days) and mucosal inflammation (median 14 days; 58% within 30 days) in MTX only. Drug ineffective was delayed across groups, up to 1422 days in MTX + hydroxychloroquine. Strict exposure signal detection identified regimen-specific SOC, PT, and TTO patterns. Several significant PTs were not captured in drug information profiles and warrant follow-up.