Abstract Background Treatment efficacy may vary by disease location in Crohn’s disease (CD). We assessed the maintenance efficacy of biological and small molecule therapies in moderate-to-severe luminal CD, stratified by disease location. Methods A systematic review and Bayesian network meta-analysis (NMA) of randomized controlled trials (RCTs) in adults (≥ 18 years) with CD (CDAI 220-450) were conducted per PRISMA, Cochrane, and NICE-DSU guidelines (PubMed/Embase to 12/08-2025). Outcomes included clinical and endoscopic remission and response at week 52, stratified by Montreal location (L1 ileal, L2 colonic, L3 ileocolonic), and randomization design. Results Twenty RCTs were included evaluating adalimumab (ADA), infliximab (IFX), vedolizumab (VDZ), ustekinumab(UST), mirikizumab (MIRI), risankizumab (RZB), guselkumab (GUS) and upadacitinib (UPA). In re-randomization trials, IFX ranked highest in L1 (SUCRA 93.7) compared to VDZ (RR 2.83 95% CI 1.10–10.53), RZB (3.35 1.09–14.49), and UPA 15 mg (7.68 1.81–51.40). In L2, UPA 30 mg (SUCRA 94.5) showed greatest efficacy compared toVDZ (2.39 1.06–5.61), RZB (3.23 1.53–7.55), and IFX (3.35 1.58–7.34). In L3, UPA 30 mg (3.40 1.79–7.27; SUCRA 90.2) and ADA (3.20 1.52–7.75; SUCRA 84.6) ranked highest, while IFX (2.23 1.51–3.54) and VDZ (1.57 1.25–2.03) also proved beneficial. GUS 100/200 mg outperformed placebo across all locations in treat-through trials. In pairwise meta-analysis, only GUS (treat-through) significantly improved clinical remission rates vs. placebo in L1. In L2, IFX, UPA15 mg/30 mg, RZB, MIRI, and UST were superior to placebo. In L3, ADA, IFX, VDZ, RZB, MIRI, and UPA but not UST were significantly more effective compared to placebo. In network meta-regression, UPA 15 mg was 12.3 × (95% CI 3.15–47.8) more effective in maintaining clinical remissionat week 52 in L2 and 8.08 × (2.04–32.0) higher in L3 vs. L1; for UPA 30 mg, 4.60 × (1.68–12.6) and 3.45 × (1.23–9.64), respectively. VDZ showed similar patterns (Figure 1), whereas IFX efficacy ratios were lower (0.52 0.16–1.65; 0.84 0.26–2.75). UST, RZB, GUS and MIRI showed no significant location effect in terms of clinical remission (Figure 1). Conclusion A location-dependent efficacy gradient was observed with reduced responsiveness in isolated ileal disease and greater efficacy in colonic and ileocolonic involvement, and superiority of specific drug classes in ileal and colonic disease location, emphasizing the importance of considering CD location in treatment algorithms and personalized CD management. Conflict of interest: Ms. Dalsgarð, Sóley Poulsen: No conflict of interest Kalinga Bandara Pkb, Kavini: No conflict of interest Seidelin, Jakob Benedict: has received research grants from Takeda, Janssen, the Danish Research Council, and the Capital Region Denmark, and is national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim. Wium Bjerrum, Jacob Tveiten: reports personal fees from Johnson and Johnson, Tillotts, and Pfizer. Attauabi, Mohamed: Research grants from Novo Nordisk Fonden and Lundbeck Foundation. Personal fees from Eli Lilly, Celltrion, and Lundcbeck foundation, outside the submitted work.
Dalsgarð et al. (Thu,) studied this question.