Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a Multicentric, Registry-based, Cohort Study (Biobadabrasil).

Objective To evaluate the safety of the methotrexate (MTX)-leflunomide (LEF) combination in rheumatoid arthritis (RA), comparing it with other therapeutic schemes involving conventional synthetic (cs-) and biologic (b-) disease modifying anti-rheumatic drugs (DMARDs) or JAK inhibitors (JAKi). Methods RA patients starting the first treatment course with a csDMARD (without previous use of biologic or JAKi) or first bDMARD/JAKi were followed-up in a registry-based, multicentric cohort study in Brazil (BiobadaBrasil). The primary outcome was the incidence of serious adverse events (SAEs); secondary outcomes included serious infections. Multivariate Cox proportional hazards models and propensity score matched analysis (PSMA) were used for statistical comparisons. Results In total, 1671 patients (5349 patient-years [PY]) were enrolled; 452 patients (1537 PY) received MTX plus LEF. The overall incidence of SAEs was 5.6/100 PY. The hazard of SAEs for MTX plus LEF was not higher than for MTX or LEF (adjusted hazard ratio: 1.00, 95% CI, 0.76 to 1.31, P=0.984). The MTX-LEF combo presented a lower hazard of SAEs (0.56, 0.36 to 0.88, P=0.011) and infectious SAEs (0.48, 0.25 to 0.94, P=0.031) than bDMARDs/JAKi with MTX or LEF. MTX plus LEF presented lower hazard of SAEs than MTX plus SSZ (0.33, 0.16 to 0.65, P=0.002). Analysis using PSMA confirmed the results obtained with traditional multivariate Cox analysis. Conclusion In our study, MTX plus LEF presented a relatively good overall safety profile in comparison to MTX plus SSZ and schemes involving advanced therapies in RA.