Gastrointestinal Perforations Associated With JAK Inhibitors: A Disproportionality Analysis of the FDA Adverse Event Reporting System

Background: Gastrointestinal perforations have been reported in a small number of rheumatoid arthritis (RA) patients treated with Janus kinase (JAK) inhibitors in clinical trials. However, large-scale postmarketing data repositories are needed to further investigate this potentially rare but serious adverse event. Methods: A retrospective, pharmacovigilance study of the FDA adverse event reporting system (July 2014 to September 2023) assessing the reporting of gastrointestinal perforations following JAK inhibitors compared to biological disease-modifying antirheumatic drugs (bDMARDs) in RA patients. The adjusted reporting odds ratio (adj.ROR) was calculated using a multivariable logistic regression model. Results: Of 399,983 RA patients included in the study, 76,446 were treated with JAK inhibitors (tofacitinib, n = 52,365; upadacitinib, n = 21,856; baricitinib, n = 2225) and 323,537 were treated with bDMARDs (TNF inhibitors, rituximab, and abatacept). Overall, 230 cases of gastrointestinal perforation following JAK inhibitors were identified, with a median time of 9 (IQR: 4–22) months from treatment initiation. Compared with bDMARDs, JAK inhibitors were associated with a higher-than-expected reporting of gastrointestinal perforations (adj.ROR = 1.98[1.69−2.31]). Increased reporting of gastrointestinal perforations was observed among recipients of JAK inhibitors or bDMARDs who used steroids or non-steroidal anti-inflammatory drugs concurrently (adj.ROR = 2.82 [2.41–3.31]). Perforations of both the upper and lower gastrointestinal tract were significantly over-reported (n = 51, adj.ROR = 1.55 [1.12–2.14], n = 143, adj.ROR = 1.78 [1.46–2.17], respectively). Furthermore, the safety signal was significant across all JAK inhibitors: tofacitinib (n = 125, adj.ROR = 1.52 [1.25–1.85]), upadacitinib (n = 84, adj.ROR = 2.73 [2.17–3.44]), and baricitinib (n = 21, adj.ROR = 5.38 [3.46–8.37]). Conclusion: In this global pharmacovigilance study, all JAK inhibitors were associated with increased reporting of gastrointestinal perforations compared with bDMARDs in RA patients. Until more data on IBD patients emerge, careful surveillance and increased clinicians' awareness should also be advocated for this population.