Journal Article

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

Sharif, Kassem, Ben‐Horin, Shomron, Raschi, Emanuel, Lahat, Adi, Ben‐Zvi, Ilan, Druyan, Amit, Goldman, Adam

2025

Overview

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.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Adult / Adverse Drug Reaction Reporting Systems - statistics & numerical data / adverse events / Aged / Antirheumatic Agents - adverse effects / anti‐JAK / Arthritis, Rheumatoid - drug therapy / autoimmune diseases / Azetidines - adverse effects / baricitinib / Clinical trials / complications / Diverticulitis / Drugs / FDA approval / Female / Heterocyclic Compounds, 3-Ring - adverse effects / Humans / Inflammatory Bowel Disease / Intestinal Perforation - chemically induced / Intestinal Perforation - epidemiology / JAKi / Janus Kinase Inhibitors - adverse effects / Kinases / Male / Marketing / Medical personnel / Middle Aged / Original / Pharmacovigilance / Piperidines - adverse effects / Professionals / Purines - adverse effects / Pyrazoles - adverse effects / Pyrimidines - adverse effects / Retrospective Studies / rheumatoid arthritis / Steroids / Sulfonamides - adverse effects / Surveillance / TNF inhibitors / tofacitinib / Ulcers / United States - epidemiology / United States Food and Drug Administration - statistics & numerical data / upadacitinib