Safety of Janus kinase inhibitors in rheumatoid arthritis: a disproportionality analysis using FAERS database from 2012 to 2022.

Introduction/objective: Janus kinase (JAK) inhibitors have expanded treatment options for rheumatoid arthritis (RA), particularly for patients unresponsive to traditional disease-modifying antirheumatic drugs (DMARDs). However, safety concerns necessitate a thorough post-market evaluation. This study is aimed at comparing the safety profiles of tofacitinib, baricitinib, and upadacitinib using adverse event (AE) reports from the FDA Adverse Event Reporting System (FAERS).

Methods: A retrospective disproportionality analysis was performed using the FAERS data from 2012 to 2022. The AE reports were categorized into cardiovascular, cancer, respiratory, gastrointestinal, musculoskeletal, and arthralgia-related events. Proportional reporting ratio (PRR) and reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated to identify significant safety signals.

Results: Of 273,657 AE reports, tofacitinib had the most (227,144), with increased musculoskeletal-related events (ROR = 1.53, 95% CI 1.49-1.57) and a reduced cancer risk (ROR = 0.44, 95% CI 0.41-0.47). Baricitinib (9305 reports) showed the highest risk of cardiovascular events (ROR = 1.63, 95% CI 1.50-1.78) and cancer (ROR = 2.17, 95% CI 1.83-2.58). Upadacitinib (37,208 reports) had elevated risks for respiratory events (ROR = 2.04, 95% CI 1.88-2.21) and cancer (ROR = 2.24, 95% CI 2.05-2.43).

Conclusion: The distinct safety profiles of these JAK inhibitors suggest that baricitinib poses higher cardiovascular and cancer risks, whereas upadacitinib increases the risk of respiratory and gastrointestinal events. Tofacitinib may be safer for patients with a history of cancer but requires monitoring for musculoskeletal AEs. Personalized risk assessments are critical for safe use of JAK inhibitors. Key Points • This study provides a comprehensive post-market safety assessment of three JAK inhibitors-tofacitinib, baricitinib, and upadacitinib-using the FAERS data from 2012 to 2022. • Distinct safety profiles were identified, with baricitinib showing a higher risk of cardiovascular events and cancer, while upadacitinib posed an increased risk of respiratory and gastrointestinal events. • Tofacitinib demonstrated a lower cancer risk than other JAK inhibitors but was associated with more musculoskeletal-related adverse events. • These findings emphasize the importance of personalized risk assessment and vigilant monitoring when prescribing JAK inhibitors for rheumatoid arthritis.