Detectable safety gestalt of rheumatoid arthritis treatments from pivotal clinical drug trials

OBJECTIVE: To provide a meta-level comparison of standardized safety profiles ("gestalt") of currently licensed biologic and targeted synthetic disease-modifying anti-rheumatic drugs (bDMARDs and tsDMARDs) in rheumatoid arthritis (RA) from pivotal clinical trials. METHODS: We systematically searched EMBASE, Medline and the Cochrane Library for randomized controlled RA drug approval trials of bDMARDs and tsDMARDs. The Medical Dictionary for Regulatory Activities (MedDRA) hierarchy system was applied to account for the heterogeneous safety reporting across trials, and random-effects meta-analyses of adverse events (AE) were performed at lower MedDRA levels as well as for major system organ classes. Serious adverse events (SAE) and AE of special interest (AESI) were studied descriptively. Forest plots and radar charts were used for visualization, to generate distinct safety profiles, referred to as "safety gestalt", for each compound. RESULTS: Sixty-four randomized, placebo-controlled drug approval trials were considered, of which 25 studied tumour necrosis factor alpha inhibitors, 10 studied interleukin 6 receptor inhibitors, 5 studied rituximab, 7 studied abatacept, and 18 studied Janus kinase inhibitors. Meta-level comparisons of the total number of AE and SAE showed comparable overall safety and tolerability, while a more granular insight into distinct organ classes and AESI disentailed differences between compounds and drug classes. CONCLUSION: Standardized safety reporting and profiling of bDMARDs and tsDMARDs from pivotal clinical drug trials provides an overview of safety outcomes of commonly used RA therapies, supports safety-oriented treatment selection in individual patients, and provides essential context for safety evaluation of novel therapies during periods before long-term safety data become available.