Comparative risk of Clostridioides difficile infection in patients with Crohn’s disease receiving ustekinumab versus anti-TNF therapy: a retrospective cohort study

Background: Antitumor necrosis factor (anti-TNF) agents are associated with an increased risk of Clostridioides difficile ( C. difficile ) infection (CDI). The risk associated with Ustekinumab (UST) in real-world clinical practice remains poorly defined. Objectives: To compare the incidence densities (IDs) and risks of CDI and C. difficile nucleic acid positivity ( C. difficile positivity) between patients with Crohn’s disease (CD) initiating UST and those initiating anti-TNF therapy. Design: Single-center retrospective cohort study. Methods: In a retrospective cohort study, we included 627 CD patients with a negative baseline C. difficile nucleic acid test who initiated UST or anti-TNF therapy between November 2020 and October 2024. IDs and incidence density ratios (IDRs) were calculated. Hazard ratios (HRs) for CDI and C. difficile positivity were estimated using marginal structural models based on Cox regression. Results: The cohort included 277 patients (381 person-years, PY) treated with UST and 350 patients (454 PY) treated with anti-TNF agents. CDI developed in 4 of 277 UST-treated participants (1.05/100 PY) and 9 of 350 anti-TNF-treated participants (1.98/100 PY), corresponding to an IDR of 0. 53 (95% confidence interval (CI): 0.14–1.99, p = 0.347). C. difficile positivity was recorded in 12 of 277 participants, compared with 25 of 350 participants, corresponding to IDs of 3.15 and 5.50/100 PY, respectively (IDR = 0.57, 95% CI: 0.27–1.19, p = 0.137). After adjustment, no significant differences were observed in the risk of CDI (HR = 0.51, 95% CI: 0.16–1.17, p = 0.274) or C. difficile positivity (HR = 0.59, 95% CI: 0.29–1.21, p = 0.151). An exploratory sensitivity analysis in biologic-naïve patients yielded an adjusted HR of 0.27 (95% CI: 0.05–1.30), which did not reach statistical significance ( p = 0.102). Conclusion: In this real-world cohort, treatment with UST was not associated with a significantly higher risk of CDI or C. difficile positivity compared to anti-TNF therapy. The consistent direction of point estimates, suggesting a potential risk reduction especially in biologic-naïve patients, remains exploratory and warrants further investigation in larger studies.