Risk of Incident Immune-Mediated Inflammatory Diseases with Second Tumor Necrosis Factor Inhibitor Versus Alternative Biologic Therapy in Patients with Inflammatory Bowel Disease and First TNFi Exposure: A Real-World Cohort Study

Introduction Immune-mediated inflammatory diseases (IMIDs) can develop during tumor-necrosis-factor inhibitor (TNFi) therapy for inflammatory bowel disease (IBD). The impact of exposure to a second TNFi compared to alternative biologic therapy on the risk of IMIDs is unknown. Methods Using the US Collaborative Network (2014–2023), we identified adults with Crohn’s disease (CD) or ulcerative colitis (UC) with previous exposure to a TNFi who were either switched to a second TNFi or ustekinumab/vedolizumab. Patients with any pre-existing IMID prior to switching to a second biologic were excluded. The primary outcome was the risk of IMID in the TNFi cohort compared to ustekinumab/vedolizumab cohort (reference treatment cohort) within 5 years. A 1:1 propensity score matching (PSM) was performed. Cox proportional hazard model was used to identify risk factors for new onset IMID in the TNFi cohort. Results Among 14,360 patients, 5962 (41.5%) received a second TNFi (mean age 34.4 ± 16.7, 49.6% female, 73.9% White, 80% CD) and 8398 (58.5%) were switched to ustekinumab or vedolizumab (mean age 39.7 ± 17 years, 51.3% female, 75.3% White, 77.3% CD). After PSM, the second TNFi cohort had a higher risk of IMID compared to the reference treatment cohort (10.8% vs 6.9%, adjusted hazard ratio [aHR] 1.57, 95% CI 1.37–1.79). The increased risk was seen in both UC (aHR 1.90, 95% CI 1.53–2.37) and CD (aHR 1.43, 95% CI 1.22–1.67). Sensitivity analysis after excluding psoriasis, rheumatoid arthritis and ankylosing spondylitis also showed an increased risk of IMID in the TNFi cohort (aHR 1.67, 95% CI 1.37–2.05). Sub-group analysis based on age and sex also showed an increased risk of IMID in the TNFi cohort. Within the TNFi cohort, age ≥ 40 years, primary sclerosing cholangitis and methotrexate use predicted IMID, whereas male sex and concomitant azathioprine were protective. Discussion In this large real-world IBD cohort with exposure to a TNFi, second TNFi use was associated with a higher risk of de-novo IMIDs compared to ustekinumab or vedolizumab.