Differential Efficacy of Advanced Therapies in Inducing Remission in Ulcerative Colitis Based on Prior Exposure to TNF Antagonists.

Background And Aims: We sought to ascertain how prior exposure to tumor necrosis factor (TNF) antagonists impacts treatment response with various classes of advanced therapies in patients with ulcerative colitis (UC), through a systematic review and meta-analysis.

Methods: Through a systematic review of multiple databases through June 30, 2024, we identified 17 randomized controlled trials in 8871 adults with moderate-severe UC who were treated with different advanced therapies vs placebo, and reported efficacy in induction of clinical remission, stratified by prior exposure to TNF antagonists. We calculated the ratio of odds ratio of achieving remission with active drug vs placebo, in TNF antagonist-naïve vs TNF antagonist-exposed patients. We grouped advanced therapies based on primary mechanism of action: lymphocyte trafficking inhibitors (anti-integrins and sphingosine-1 phosphate [S1P] receptor modulators), anti-interleukins (interleukin-12/23 antagonist and selective interleukin-23 antagonists) and Janus kinase inhibitors.

Results: Lymphocyte trafficking inhibitors were more efficacious in TNF antagonist-naïve vs exposed patients (5 trials; odds ratio [OR], 1.88; 95% confidence interval [CI], 1.02-3.49), whereas JAK inhibitors were less efficacious in TNF antagonist-naïve vs exposed patients (6 trials; ratio of OR, 0.47; 95% CI, 0.22-1.01). No significant difference was observed in efficacy of selective interleukin-23 antagonists vs placebo in TNF antagonist-naïve vs exposed patients (6 trials; ratio of OR, 1.07; 95% CI, 0.64-1.80). There was minimal heterogeneity across analyses.

Conclusion: There is significant heterogeneity of treatment efficacy with different advanced therapies in inducing remission in patients with UC based on prior exposure to TNF antagonists, with plausible potentiation of JAK inhibitors and attenuation of lymphocyte trafficking inhibitors. Future studies on the mechanistic basis for these observations are warranted.