Acid-Suppressive Therapy Choice and Risk of Treatment Escalation in Inflammatory Bowel Disease: A Real-World Comparative Retrospective Study to Inform Personalized Treatment

Background/Objectives: Proton pump inhibitors (PPIs) are known to alter gut microbiota composition; however, their association with disease courses and outcomes in patients with inflammatory bowel disease (IBD) remains uncertain. Our aims were to evaluate the association between PPI use and treatment escalation, Clostridioides difficile infection, and healthcare utilization in IBD. Methods: We conducted a retrospective cohort study on the TriNetX platform. IBD patients with PPIs or histamine-2 receptor antagonists (H2RAs) were matched one-to-one using propensity scores. Outcomes included initiation of corticosteroids, biologic therapy, Clostridioides difficile (C. difficile) infection, and healthcare utilization. Outcomes were assessed during the 0–12-month and 3–12-month follow-up windows. Associations were estimated using odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals. Results: After matching, 12,808 patients were included in each group. During 0–12 months of follow-up, PPI use was associated with higher odds of systemic corticosteroid exposure (OR 1.56, 1.35–1.79), biologic therapy initiation (OR 1.99, 1.72–2.29), C difficile infection (OR 1.42, 1.18–1.70), and healthcare utilization (OR 1.18, 1.03–1.36) compared with H2RA use. Time-to-event analyses showed persistent associations with systemic corticosteroid exposure (HR 1.50, 1.31–1.72) and biologic therapy initiation (HR 1.91, 1.66–2.19), with attenuation of associations for infection and healthcare utilization in 3–12-month lag-time analyses. Similar patterns were observed in ulcerative colitis and Crohn’s disease subgroups. Conclusions: PPI was associated with higher risks of treatment escalation and C. difficile compared with H2RA in IBD. These findings highlight the importance of individualized selection and periodic reassessment of acid suppression therapy as part of personalized management strategies in IBD.