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. 2025 Dec 9.
doi: 10.1007/s10620-025-09598-4. Online ahead of print.

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

Aakash Desai  1   2 , Gursimran S Kochhar  3   4 , Himsikhar Khataniar  5 , Jana G Hashash  6 , Francis A Farraye  6
Affiliations

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

Aakash Desai et al. Dig Dis Sci. .

Abstract

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.

Keywords: Crohn’s disease; Immune-mediated inflammatory diseases; Tumor necrosis factor inhibitors; Ulcerative colitis; Ustekinumab; Vedolizumab.

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Conflict of interest statement

Declarations. Conflict of interest: AD and HK: None exist GSK: Speaker: Eli Lilly Pharma. Advisory Board: GIE Medical, Eli Lilly Pharma, Consultant: Pentax endoscopy, Olympus endoscopy, Boston Scientific endoscopy, Takeda Pharmaceuticals. Stock Options: Digbi Health JGH: Advisory Board BMS. FAF: Consulting Fee: Astellas, Avalo Therapeutics, Bausch, Biocon, Braintree Labs, GI Reviewers, GSK, IBD Educational Group, Iterative Health, Janssen, Metaphore Biotechnologies, Pharmacosmos, Pfizer, Sandoz Immunology. DSMB: Eli Lilly, MoonLake.

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