Comparative safety of biologic and targeted synthetic disease-modifying anti-rheumatic drugs for cardiovascular outcomes in rheumatoid arthritis

Objectives To assess the comparative safety of tumor necrosis factor inhibitor (TNFi), non-TNFi, and Janus kinase inhibitor (JAKi) biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARD) in patients with rheumatoid arthritis (RA) for the risk of major adverse cardiovascular events (MACE) using US administrative claims data. Methods We performed a cohort study using MerativeTM Marketscan® Research Databases (2012–2021) of individuals aged 18–64 years with RA initiating b/tsDMARD treatment. We used Cox proportional hazard models to estimate hazard ratios (HR) and 95% CI for developing MACE within 2 years of b/tsDMARD initiation, adjusting for potential confounders. Results We included a total of 34 375 treatment exposures: 71% TNFi, 10% JAKi, 8% abatacept, 5% rituximab, and 5% IL-6i. Most individuals were female (77–84%) with a median (interquartile range) of 50 (42, 56) years. Rituximab had the highest incidence rate of MACE (196/10 000 person-years; 95% CI 126, 291), followed by IL-6i (111/10 000 person-years; 95% CI 57, 193). Multivariable analyses showed non-statistically significantly higher MACE risk with rituximab (HR 1.5; 95% CI 0.9, 2.4) and IL-6i (HR 1.3; 95% CI 0.7, 2.4) exposures but no increased risk with JAKi relative to TNFi use. Conclusion In this large nationwide study, rituximab and IL-6i users had numerically higher, but not statistically significant, MACE risk. Our data support the safety of b/tsDMARD use for RA treatment. This study was limited by short follow-up time and confounding by indication; further studies that can overcome these limitations are needed.