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 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 RCTs 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 IL-23 antagonists) and Janus kinase inhibitors.

Results: Lymphocyte trafficking inhibitors were more efficacious in TNF antagonist-naïve vs. exposed patients (five trials; ratio of OR,1.88 [95% CI, 1.02-3.49]), whereas JAK inhibitors were less efficacious in TNF antagonist-naïve vs. exposed patients (six trials; ratio of OR,0.47 [0.22-1.01]). No significant difference was observed in efficacy of selective IL-23 antagonists vs. placebo in TNF antagonist-naïve vs. exposed patients (six trials; ratio of OR,1.07 [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.