Abstract Background Real-world evidence comparing ustekinumab (UST), vedolizumab (VDZ) and anti–tumor necrosis factor (anti-TNF) agents as first-line biological treatment for luminal Crohn’s disease (CD) remains limited. Methods Biologic-naïve patients with luminal Crohn’s disease initiating ustekinumab (UST), vedolizumab (VDZ), or anti-TNF therapy (infliximab/adalimumab) at two tertiary centers (2015–2025) were retrospectively included. The primary outcome was 48–52-week clinical response, defined by clinician assessment and/or ≥3-point Harvey-Bradshaw index (HBI) decrease. Secondary outcomes were 12–16-week clinical response; steroid-free clinical remission at 12–16 and 48–52 weeks; biomarker response (C-reactive protein and fecal calprotectin), defined as 50% reduction from baseline; and treatment persistence. Between-group differences were adjusted for sex, age at treatment initiation, disease duration, Montreal classification, perianal disease, and baseline HBI using multivariable logistic regression. Treatment persistence was compared using Kaplan–Meier analysis. Results Among 442 patients, 85/442 (19.2%) received UST, 158/442 (35.7%) VDZ, and 199/442 (45.1%) an anti-TNF agent. At 12–16 weeks, clinical response was achieved in 50/71 patients (70.4%) with UST, similar to 113/170 patients (66.5%) with anti-TNF (OR 1.25; 95% CI 0.63–2.48; p = 0.517) but higher than 76/138 patients (55.1%) with VDZ (UST vs VDZ: OR 2.11; 95% CI 1.08–4.09; p = 0.028; anti-TNF vs VDZ: OR 1.81; 95% CI 1.06–3.03; p = 0.027). Biomarker response was achieved in 44/55 patients (80%) with UST and 52/81 patients (64.2%) with anti-TNF (OR 2.21; 95% CI 0.86-5.68; p = 0.101), both significantly higher than 42/88 patients (47.7%) with VDZ (UST vs VDZ: OR 5.76; 95% CI 2.38–13.95; p 0.001; anti-TNF vs VDZ: OR 3.57; 95% CI 1.58–7.69; p = 0.001). At 48–52 weeks, clinical response was achieved in 48/69 patients (69.6%) with UST, similar to 118/167 patients (70.7%) with anti-TNF (OR 1.56; 95% CI 0.75–3.26; p = 0.236) and 83/136 patients (61.0%) with VDZ (OR 1.82; 95% CI 0.91–3.67; p = 0.092). Biomarker response was achieved in 45/58 patients (77.6%) with UST and 80/113 patients (70.8%) with anti-TNF (OR 1.95; 95% CI 0.82–4.63; p = 0.13), both significantly higher than 52/106 patients (49.1%) with VDZ (UST vs VDZ: OR 4.25; 95% CI 1.91–9.49; p 0.001; anti-TNF vs VDZ: OR 3.125; 95% CI 1.63–5.88; p = 0.001). Treatment persitence was higher with UST and anti-TNF than with VDZ (UST vs VDZ p = 0.015; anti-TNF vs VDZ p = 0.042; UST vs anti-TNF p = 0.459; overall log-rank p = 0.051). Conclusion In biologic-naïve Crohn’s disease, ustekinumab and anti-TNF agents show comparable effectiveness as first-line therapy, whereas vedolizumab has a slower onset of clinical and biomarker response. Conflict of interest: Dr. Shani, Uria: No conflict of interest Yaakobi, Hadas: Leibovitzh, Haim: No conflict of interest Maharshak, Nitsan: Grant support from Janssen, Abbott, Abbvie, Pfizer, BMS, Nestle, Helmsley Charitable Trust Personal fees/ advisory board- from Abbvie, Magentiq eye, Lilly, Pfizer, Janssen, BMS, Nestle, Teva, Baemek Advanced Technologies Abitbol, Chaya Mushka: No conflict of interest Ungar, Bella: Bella Ungar has recieved lecture fees / consultation fees fro Ely Lilly, Abbvie, Takeda, Padagis Ben-Horin, Shomron: Grant: Abbvie, Takeda, Janssen, Celltrion, Pfizer, Medtronic, Galmed, OutSense Personal Fees: Advisory board and/or consulting and/or Speaker fees from Abbvie, Takeda, Janssen, Celltrion, Pfizer, GSK, Ferring, Novartis, Roche, Gilead, NeoPharm, EviNature, Galmed, Medial Earlysign, BMS, Pfizer, Falk, Medtronic and Eli Lilly. Options/stocks in Predicta Med, Evinature, Galmed, Alma Therpeautics. Kopylov, Uri: Grant: Takeda, Janssen,Abbvie, Medtronic, Ely Lilly Other: Takeda, Janssen, ,Ely Lilly, Roche, Celtrion, Abbvie, Medtronic, CTS, Pfizer, BMS- speaker and advisory fees
Shani et al. (Thu,) studied this question.