Ustekinumab and JAK inhibitors outperform vedolizumab as second-line therapy in anti-TNF-experienced patients with ulcerative colitis

Background and aims: With the advent of agents targeting distinct inflammatory pathways, therapeutic sequencing after anti-TNF-α failure in ulcerative colitis (UC) represents a major challenge. We compared the real-world effectiveness and safety of vedolizumab, ustekinumab, and Janus kinase inhibitors (JAKi) in anti-TNF-α-exposed patients. Methods: In this retrospective, multicenter European study, adults with UC initiating second-line vedolizumab, ustekinumab, or a JAKi after anti-TNF-α were evaluated. Baseline confounding was addressed by applying energy balancing weights (EBWs). Effectiveness outcomes included probability of steroid-free clinical remission (SFCR) and biochemical SFCR at 12 months, analyzed using EBW-weighted Royston-Parmar survival models to derive adjusted time-averaged hazard ratios (aHRs). Adverse event (AE) rates were compared using EBW-weighted Poisson regression. Results: A total of 596 patients were included (301 vedolizumab, 149 ustekinumab, 146 JAKi); 54.7% were male, with a mean age of 43.9 ± 15.5 years. Clinical activity, endoscopic scores, and biomarker levels were broadly comparable across treatment groups. Infliximab was the most common prior anti-TNFα (74.8%), and secondary failure the predominant discontinuation reason (47.3%). Compared to vedolizumab, both ustekinumab and JAKi showed significantly higher probability of SFCR (aHR 1.54; 95% CI: 1.09-2.07 and aHR 1.66; 1.07-2.53, respectively) and biochemical SFCR (aHR 2.26; 1.48-3.28 and 3.37; 2.01-5.36, respectively) at 12 months, with no differences between them. JAKi recipients experienced an approximately fourfold higher incidence of AEs, compared to both vedolizumab and ustekinumab, with no differences between ustekinumab and vedolizumab. Conclusion: Ustekinumab and JAKi were more effective than vedolizumab in inducing steroid-free and biochemical remission following anti-TNFα failure. Safety concerns with JAKi warrant careful patient selection in clinical practice.