Ustekinumab and Janus Kinase Inhibitors Outperform Vedolizumab as Second-Line Therapy in Anti-Tumor Necrosis Factor-Experienced Patients With Ulcerative Colitis

BACKGROUND & AIMS: With the advent of agents targeting distinct inflammatory pathways, therapeutic sequencing after anti-tumor necrosis factor alpha (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 (JAKis) 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-TNF-α (74.8%), and secondary failure was the predominant discontinuation reason (47.3%). Compared with vedolizumab, both ustekinumab and JAKi showed significantly higher probability of SFCR (aHR, 1.54; 95% confidence interval [CI], 1.09-2.07; and aHR, 1.66; 95% CI, 1.07-2.53, respectively) and biochemical SFCR (aHR, 2.26; 95% CI, 1.48-3.28 and 3.37; 95% CI, 2.01-5.36, respectively) at 12 months, with no differences between them. JAKi recipients experienced an approximately 4-fold higher incidence of AEs, compared with both vedolizumab and ustekinumab, with no differences between ustekinumab and vedolizumab. CONCLUSIONS: Ustekinumab and JAKi were more effective than vedolizumab in inducing steroid-free and biochemical remission following anti-TNF-α failure. Safety concerns with JAKi warrant careful patient selection in clinical practice. CLINICALTRIALS: gov, Number: NCT06691061.