Abstract Background Perianal Crohn’s disease (pCD) is a debilitating complication of CD. Although several advanced medical therapies (biologics and oral small molecules) for luminal CD have been approved, their efficacy for pCD has not been comprehensively reviewed. We evaluated the most recent evidence for the efficacy of advanced therapies in patients with pCD through an updated systematic review and meta-analysis. Methods A comprehensive literature search was conducted in MEDLINE, Embase, and Cochrane CENTRAL up to October 2, 2025. Placebo-controlled randomized controlled trials (RCTs) evaluating treatment efficacy in pCD were included. Outcomes of interest were fistula response and fistula remission as defined by primary studies during the induction and maintenance trials. Pooled relative risks (RRs) were calculated using a random-effects model. Results Fourteen studies met the inclusion criteria. Evaluated therapies included TNF antagonists, anti-integrins, interleukin (IL)-12/23 and IL-23p19 antagonists, and JAK inhibitors. Only four RCTs directly randomized patients with pCD to active advanced therapy versus placebo; the remaining were post hoc analyses of RCTs, which carried a moderate to serious risk of bias. In pooled analyses of induction trials (4–28 weeks), advanced therapies were associated with significantly higher rates of fistula response (n = 8; RR 1.65, 95% CI 1.22–2.22) (Figure) and fistula remission (n = 8; RR 1.91, 95% CI 1.37–2.67) compared with placebo. When analyzed by individual agent, infliximab (one RCT) and upadacitinib (one post hoc analysis) demonstrated significant benefit for both fistula response and remission, ustekinumab (one RCT and one post hoc analysis) significantly increased rates of fistula remission only. Study designs varied among maintenance trials. In pooled analyses of maintenance trials (22–52 weeks), advanced therapies were associated with significantly higher rates of fistula response (n = 6; RR 1.54, 95% CI 1.21–1.97) and remission (n = 6; RR 2.08, 95% CI 1.49–2.90) compared with placebo. Among individual agents, infliximab showed significantly greater fistula response and remission compared with placebo in an RCT, while adalimumab was significantly associated with higher fistula remission rates based on a post hoc analysis. Conclusion Despite the growing availability of advanced therapies for CD, few dedicated trials have specifically evaluated their efficacy in pCD. Findings from our meta-analysis indicate that infliximab is effective for pCD, while limited evidence suggests potential benefit with adalimumab, ustekinumab and upadacitinib. Well-designed RCTs investigating newer advanced therapies are needed to better guide targeted treatment strategies for this patient population. Conflict of interest: Dr. Yuan, Yuhong: No conflict of interest Vuyyuru, Sudheer: has received consulting fee from Alimentiv Inc. Hanzel, Jurij: Speaker’s fees from Abbvie, Eli Lilly, Janssen, and Takeda, and consulting fees from Alimentiv Inc and Janssen. Hupé, Marianne: has received advisory board fees and speaker’s fees from Takeda, Celltrion Healthcare, Amgen, Abbvie, Pfizer, Johson & Johnson, Lilly Sedano, Rocio: has received consulting fees from AbbVie, Alimentiv, Pendopharm and Takeda. Shehab, Mohammad: has received speaker/advisory board fees from AbbVie, Hikma, Ferring, Janssen, Acino, Pfizer, Sandoz, and Takeda Nardone, Olga Maria: Advisory board fees from Eli Lilly, Nestlè, Janssen Speaker fees from AbbVie, Janssen, Eli Lilly, Ferring, Alfa Sigma, Recordati, Noòs, and Pfizer Jairath, Vipul: Consulting Fees: Abbvie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, BMS, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Janssen, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma.
Yuan et al. (Thu,) studied this question.