Comparative Efficacy of Advanced Therapies for Achieving Endoscopic Outcomes in Crohn’s Disease: A Systematic Review and Network Meta-Analysis

Background & Aims We conducted a network meta-analysis to compare the efficacy of advanced therapies for achieving endoscopic outcomes in patients with moderate to severely active CD. Methods MEDLINE, Embase, and Cochrane CENTRAL databases were searched from inception to Aug 2, 2023 to identify phase-II and III randomized controlled trials (RCTs) in adults (≥18 years) with moderate-to-severe CD treated with tumor necrosis factor (TNF) antagonists, etrolizumab, vedolizumab, anti-interleukin (IL)-12/23p40, anti-IL23p19 or Janus kinase-1 (JAK1) inhibitors, compared with placebo/active comparator, for induction and/or maintenance of remission and reported endoscopic outcomes. Primary outcome was endoscopic response after induction therapy, and endoscopic remission after maintenance therapy. We performed a random-effects network meta-analysis using a frequentist approach, and estimated relative risk (RRs), 95% CI values and p-score for ranking agents. We used GRADE to ascertain certainty of evidence. Results A total of twenty RCTs (19 placebo-controlled and one head-to-head trial; 5592 patients) were included out of which 12 RCTs reported endoscopic outcomes for the induction phase, five reported for the maintenance phase and three reported for both induction and maintenance phases. JAK1 inhibitors (RR 3∙49 [95% CI, 1∙48-8∙26]) and anti-IL23p19 (RR 2∙30 [1∙02-5∙18]) agents were more efficacious than etrolizumab (moderate certainty of evidence), and JAK1 inhibitors (RR 2∙34 [1∙14-4∙80]) were more efficacious than anti-IL12/23p40 agents for inducing endoscopic response (moderate certainty of evidence). JAK1 inhibitors and anti-IL-23p19 ranked highest for induction of endoscopic response. There was paucity of RCTs of TNF antagonists reporting endoscopic outcomes with induction therapy. On network meta-analysis of six RCTs, all agents except vedolizumab (RR 1.89 [95% CI: 0.61-5.92]) were effective in maintaining endoscopic remission compared with placebo. TNF antagonists, IL12/23p40 and JAK1 inhibitors were ranked highest. Conclusions On network meta-analysis, JAK1 inhibitors and anti-IL23p19 agents may be the most effective amongst non-TNF-targeting advanced therapies for inducing endoscopic response. Future head-to-head trials will further inform positioning of different therapies for the management of CD.