Comparative safety of biologic and targeted-synthetic DMARDs in patients with rheumatoid arthritis: a multi-database real-world cohort study

Background: Real-world evidence on the comparative safety of biologic (b) and targeted synthetic (ts) disease modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) is essential for improving the care of patients with rheumatoid arthritis. There is little evidence on safety of b/ts-DMARDs related to malignancy, heart failure (HF), and venous thromboembolism (VTE) given the rising number of newly available treatments for RA.

Objectives: To examine comparative safety of b/ts DMARDs in RA patients regarding safety endpoints of malignancy, HF, and VTE.

Methods: We conducted a multi-database observational cohort study using 3 US insurance claims data: Medicare (2009-2019), MarketScan IBM (2009-2020), and Optum (2009-2022). Study population was adult patients with RA who initiated one of abatacept (common reference drug), tumor necrosis factor inhibitors (TNFi), rituximab, interleukin-6 inhibitors (IL-6i), or janus kinase inhibitors JAKi). Patients with prior outcome events or other indications of b/ts DMARDs were excluded. Outcomes were any malignancies except non-melanoma skin cancer, hospitalized HF, and hospitalized VTE. The follow-up time started 1 day after the index date until the earliest of: outcome, treatment switch or discontinuation, disenrollment, death, or end of data. For malignancy, the follow-up started from 91 days after the index date to account for delayed onset. Inverse probability of treatment weighting approach was applied for confounding adjustment. Database-specific effect estimates were reported as hazard ratios (HR) with 95% confidence intervals (CI) estimated from Cox-proportional hazard model, comparing each of study drug group vs. abatacept, then combined using random-effects meta-analysis.

Results: We identified a total of 26908 abatacept, 11176 IL-6i, 115437 TNFi, 14045 JAKi, and 12097 rituximab initiators. Combined weighted HR (95% CI) of malignancy was 0.73 (0.60, 0.88) for IL-6i, 0.85 (0.60, 1.19) for JAKi, 1.30 (1.14, 1.49) for rituximab, and 0.93 (0.85, 1.02) for TNFi, compared to abatacept. The corresponding estimates for HF was 1.00 (0.69, 1.46), 1.24 (0.62, 2.51), 1.52 (1.04, 2.22), and 1.54 (1.22, 1.94), respectively. The corresponding estimates for VTE was 0.92 (0.62, 1.35), 1.17 (0.73, 1.86), 1.43 (1.50, 1.95), and 1.16 (0.93, 1.46), respectively.

Conclusions: We observed increased risks of malignancies, HF, and VTE among rituximab initiators; increased risk of HF among TNFi initiators; and lower risk of malignancies among IL-6i initiators, compared to abatacept initiators. These findings should be interpreted cautiously given the potential role of residual confounding.