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Importance With the availability of multiple classes of advanced therapies for the treatment of Crohn disease (CD), understanding the comparative safety of different therapies can inform treatment positioning. Objective To compare the risk of serious infections, venous thromboembolism (VTE), and major adverse cardiovascular events (MACE) with different advanced therapies in patients with CD. Design, Setting, and Participants This retrospective comparative effectiveness research study was conducted between January 1, 2016, and December 31, 2022, with a mean (SD) follow-up of 26.9 (2.4) months until July 1, 2024. Using an administrative claims database (OptumLabs Data Warehouse), commercially insured patients with CD, who initiated treatment with tumor necrosis factor-α (TNF) antagonists, anti-integrin agents (vedolizumab), interleukin (IL)-12/23p40 antagonists (ustekinumab), IL-23p19 antagonists (primarily risankizumab), or Janus kinase inhibitors (upadacitinib) between 2016 and 2022 and had follow-up for at least 1 year before and after treatment initiation, were included. Exposure TNF antagonists vs anti-integrin agents (vedolizumab) vs IL-12/23p40 antagonists (ustekinumab) vs IL-23p19 antagonists (risankizumab) vs Janus kinase inhibitors (upadacitinib). Main Outcomes and Measures The risk of serious infections, VTE, and MACE was compared with various advanced therapies through multinomial propensity score-based inverse probability treatment weighting, with propensity scores estimated through generalized boosted models, accounting for disease characteristics, health care utilization, comorbidities, and prior and concomitant medications, and through competing risk of mortality. Cause-specific hazard ratios (HRs) and 95% CIs for multiple treatment comparisons were calculated. Results This study included 12 245 patients with CD (mean [SD] age, 46.5 [17.5] years; 6642 females [54.2%]), who were treated with TNF antagonists (n = 5274), vedolizumab (n = 2716), ustekinumab (n = 3544), risankizumab (n = 559), or upadacitinib (n = 152). Serious infection incidence rates ranged from 5.46 (95% CI, 4.86-6.07) to 9.02 (95% CI, 6.38-11.89) per 100 person-years across therapies. After adjusting for confounding variables, there were no statistically significant differences in the risk of serious infections across different agents, including between risankizumab and ustekinumab (HR, 1.14 [95% CI, 0.78-1.67]), risankizumab and TNF antagonists (HR, 1.00 [95% CI, 0.68-1.47]), or ustekinumab and TNF antagonists (HR, 0.88 [95% CI, 0.74-1.04]). The incidence of VTE (incidence rate, 0.90 [95% CI, 0.71-1.10] to 2.33 [95% CI, 1.06-3.82] per 100 person-years) and MACE (0.68 [95% CI, 0.51-0.85] to 1.49 [95% CI, 0.43-2.76] per 100 person-years) was low, without any significant differences across agents. Conclusions and Relevance In this comparative effectiveness research study of patients with CD, no significant differences in the risks of serious infections, VTE, or MACE across various advanced therapies were found. These findings support clinical decision-making on choice of advanced therapies for most individual patients with CD to be driven primarily by comparative treatment effectiveness rather than driven by concerns of serious adverse events.

Abstract Background There is an unmet need for ulcerative colitis (UC) treatments that show improved effectiveness while maintaining safety profiles comparable with existing advanced therapies. Dual targeted therapy (DTT) has been proposed as a strategy to combine benefits of different advanced therapies to improve outcomes. The ExiGem study (NCT06095128) aims to assess the efficacy and safety of combined therapy with vedolizumab (VDZ) and tofacitinib (TOF) in adults with UC. We report results for the induction phase from the first 24 patients. Methods ExiGem is an ongoing phase 4, single-arm, multicentre study including adults with moderately to severely active UC (complete Mayo [cMayo] score of 6–12 with a rectal bleeding subscore ≥ 1 and centrally read endoscopic subscore ≥ 2). Eligible patients have previously had an inadequate response, loss of response, or intolerance to 1 or 2 anti-tumour necrosis factor α treatments. Patients receive induction therapy with intravenous (IV) VDZ 300 mg at weeks 0, 2, and 6 plus twice-daily oral TOF 10 mg for 8 weeks and then VDZ 300 mg IV monotherapy as maintenance from week 14. The primary endpoint is the proportion of patients in clinical remission by cMayo score at week 8. Secondary endpoints include clinical response and clinical remission by modified Mayo (mMayo) score at week 8. Changes in faecal calprotectin (FCP) levels and endoscopic improvement were evaluated. Efficacy data were analysed using non-responder imputation. For the final analysis a pre-specified Bayesian approach will be used. The safety profile of DTT was evaluated. Results Patient baseline characteristics are shown in Table 1. At week 8, 12/24 patients (50%) and 14/24 patients (58%) had clinical remission assessed by cMayo and mMayo scores, respectively; these rates were higher than pre-specified benchmark rates (Figure 1). Clinical response was observed in 21/24 patients (88%). At week 8, 14/24 patients (58%) showed endoscopic improvement, and 12/21 patients (57%) had normalization of FCP levels (< 250 µg/g). Treatment-emergent adverse events (TEAEs) were experienced by 10 patients (42%), and 1 serious TEAE was reported (suspected viral infection). One severe adverse event (AE; cough) and 2 moderate AEs (herpes zoster, drug intolerance) were considered related to TOF. No moderate or severe AEs were considered related to VDZ. One patient withdrew from the study before week 8 owing to intolerance to TOF. Conclusion Initial data suggest that induction with a combination of VDZ and TOF can produce improved rates of response and remission in patients with UC with a comparable safety profile to existing advanced monotherapies. Further data, including outcomes of VDZ maintenance as monotherapy, are pending. Conflict of interest: Prof. Dr. Yarur, Andres: Andres Yarur has served as an advisory board member for Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Roche/Genentech, and Takeda. This study was funded by Takeda Pharmaceuticals U.S.A., Inc. Medical writing support was provided by Adam Errington PhD of PharmaGenesis Cardiff, Cardiff, UK, and funded by Takeda Pharmaceuticals U.S.A., Inc. Barnes, Edward: Personal Fees: Consultant for Takeda, Pfizer, Roche, Merck, Abbvie, Eli Lilly. Bristol Myers Squibb, Celltrion, Johnson and Johnson. Deepak, Parakkal: Parakkal Deepak has received research support under a sponsored research agreement unrelated to the data in the abstract from AbbVie, Johnson and Johnson, Sanofi, Merck, Teva, Direct Biologics, Tr1x, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Roche Genentech, Eli Lilly, AstraZeneca, Spyre and Agomab, has received consulting fees from Johnson and Johnson, Abbvie, Merck, Sobi, Celltrion, Fresenius Kabi, Asahi Kasei Pharma, Sandoz and CorEvitas, LLC and has served on the board of the Srategic Alliance for Intercultural Advocacy in GI. Ha, Christina: Christina Ha has served as an advisory board member for AbbVie, Bausch Health, Johnson & Johnson, Lilly, Merck, Takeda, and Sanofi has received educational programming support from AbbVie, Celltrion, Johnson & Johnson, Lilly, Pfizer, and Takeda and has received consulting fees from AbbVie. Hudesman, David: Consultant: Abbvie, Abivax, BMS, Biocon, Eli Lilly, Fresenius Kabi, Pfizer, Prometheus, CorEvitas, Takeda, Johnson and Johnson, Sanofi Research Support: Johnson and Johnson, 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. Lukin, Dana: Dana Lukin has served as a consultant/advisory board member for AbbVie, AltruBio, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Palatin, Pfizer, Prime, PSI, Takeda, and Vedanta has received grants from Boehringer Ingelheim and Johnson & Johnson and serves as a speaker for AbbVie and Johnson & Johnson. Rubin, David T.: Grant support: Takeda Pharmaceuticals. Consultant: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Mirador, Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx. Schreiber, Stefan Wolfgang: Stefan Schreiber has received consulting fees from AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Eli Lilly, Ferring, Fresenius, Galapagos, Genentech, Gilead, GlaxoSmithKline, I-MAB Biopharma, Janssen, Merck, Novartis/Sandoz, Pfizer, Protagonist, Takeda, and Ventyx Biosciences. Gower, Megan: Megan Gower is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Jones, Stephen: Stephen Jones is an independent medical consultant who provides services for Takeda Pharmaceuticals U.S.A., Inc. Robinson, Ian: Ian Robinson is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Sanchirico, Marie: Marie Sanchirico is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc. Yajnik, Vijay: Vijay Yajnik is an employee and hold stock/stock options at Takeda Pharmaceuticals U.S.A., Inc.

Abstract Background Colonic strictures in Crohn’s disease (CD) present a complex and relatively underexplored clinical issue. Imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and intestinal ultrasound (IUS), have established criteria for evaluating small bowel CD strictures. However, radiologic definitions of benign colonic strictures and their diagnostic accuracy are not well-developed. Endoscopic definitions of colonic strictures are the most well-described. We conducted a systematic review to summarize definitions, diagnosis, and identification of inflammation and fibrosis of colonic strictures on endoscopy, CT, MR, and IUS. Methods A systematic review following PRISMA guidelines, from inception to October 6, 2024, was conducted using MEDLINE, Scopus, CINAHL, and CENTRAL databases to identify literature on diagnostic imaging of patients with colonic CD strictures. Only studies with comparison to endoscopy or imaging to a full-thickness histologic gold standard to differentiate fibrosis from inflammation were included. Two stage screening was completed in duplicate, and risk of bias was assessed using QUADAS-2. Results 46 studies were eligible for inclusion of 4623 abstracts screened. Definitions of colonic strictures on CT, MR, and IUS were highly variable with combinations of bowel wall thickness, luminal narrowing, and pre-stenotic dilation. Endoscopic definitions of colonic strictures were the most consistently reported as lack of passage of a colonoscope through a narrowed lumen. Diagnostic imaging definitions used various combinations of increased bowel wall thickness, luminal narrowing, and pre-stenotic dilation with no clear cutoffs. Few studies directly compared imaging features with histologic or endoscopic gold standards, limiting evaluation of diagnostic accuracy. Meta-analyses were not conducted due to methodological heterogeneity of grading fibrosis across studies. In addition, statistical heterogeneity of sensitivity, specificity, and accuracy of colonic stricture diagnoses was limited by pooling with small bowel strictures in the studies. Conclusion This systematic review highlighted the absence of standardized definitions for diagnosing colonic Crohn’s disease strictures, particularly on diagnostic imaging, and the limited data distinguishing inflammatory from fibrotic components. Bowel wall thickening, luminal narrowing, and pre-stenotic dilation are key features of small bowel strictures, but their relevance to the colon requires further assessment. Establishing standardized definitions for colonic strictures that incorporate both endoscopic and imaging modalities is essential to advancing the field. Conflict of interest: Dr. Lu, Cathy: Advisory board - Abbvie, Johnson and Johnson, Takeda, Ferring, Merck, Celltrion, Lilly, Pfizer, Pendopharm, Agomab. Research Funding - Abbvie, Helmsley Charitable Trust, Alberta Innovates Dhaliwal, Ravdip: No conflict of interest Kellar, Amelia: No conflict of interest Rowan, Catherine: No conflict of interest St-Pierre, Joelle: Consultant for Pfizer, Abbvie, Eli Lilly and Pendopharm, and speaker for Takeda. Ernest-Suárez, Kenneth: Consulting/Advisory Board fees: Abbvie, AstraZeneca, Johnson & Johnson, Pfizer, Ferring, Sandoz, SatisfAI, Takeda O’Brien, Maureen: No conflict of interest Rosentreter, Ryan: No conflict of interest Gulhati, Vishrut: No conflict of interest Baker, Mark: No conflict of interest Bettenworth, Dominik: DB is on the advisory board or consultant for AbbVie, Amgen, Arena, Atheneum, BNG Service GmbH, Bristol Myers Squibb, CED-Service GmbH, Celltrion, Doctorflix, DGVS, Diaplan, Else Kröner-Fresenius Foundation, Falk Foundation, Galapagos, Guidepoint, Impulze, Ferring, Janssen Cilag, Lilly, Medical Tribune, MedTriX, MSD, Mylan, Onkowissen, Pharmacosmos, Pfizer, Roche, Sandoz, Takeda, Tetrameros, Thieme, Tillotts Pharma, UCB Biopiharma, Viatris and Vifor Pharma. Bruining, David: Advisory board fees from Janssen Bari, Dane: Grant from Helmsley Charitable Trust speaker honorarium from Siemens Healthineers support for attending meetings or travel from Siemens Healthineers member of the Olympus advisory board co-chair Society of Abdominal Radiology (SAR) Inflammatory Bowel Disease Disease Focused Panel (IBD DFP) and SAR Photon-Counting Detector CT Emerging Technology Commission and chair of the Society for Advanced Body Imaging Scientific Committee. Dillman, Jonathan: Grants from Philips Healthcare, GE HealthCare, Motilent, Perspectum, Guerbet, and Bracco. El Ouali, Sara: Speaker and/or consulting fees from Takeda, Eli Lilly, Janssen, Abbvie. Fletcher, John: Grant supports from Siemens Healthineers Gordon, Ilyssa: Grants to institution from Morphic Therapeutics, Alimentiv, Pliant Therapeutics, and UCB patent pending with Case Western Reserve University on radiomics signatures 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. Feagan, Brian Gordon: Consulting Fees: AbbVie, Abivax, Adaxion, Adiso, AgomAB Therapeutics, Akros, Alira Health, Ally Bridge Group, Apini Therapeutics, Argenx, Attovia Tx, Avoro Capital Advisors, Belmore Law, Biora Therapeutics, Blackbird Laboratories, Boehringer-Ingelheim, BMS, Boxer Capital, Celgene/BMS, Clarivate, Connect Biopharm, EcoR1, Eli Lilly, Ensho Therapeutics, Equillium, Evida, Enveda, Evommune Inc. Faes Farma, First Wave, Forbion, Galapagos, Genentech/Roche, General Atlantic, Genesis Therapeutics, Gerson Lehrman Group, Gilead, Guidepoint, Imhotex, ImiDomics, Immunic Therapeutics, Janssen, Japan Tobacco Inc., LifeMine Therapeutics, Mage Biologics, Merck, Mirador Therapeutics, Mobius Care, Monte Rosa Tx, Morphic Therapeutics, Nimbus Therapeutics, Novartis, Nxera, OncoC3, Palisade Bio, Pendopharm, Pfizer,Q32 Bio, REDX, Roche, Sanofi, Sobi, Sorriso, Spyre Therapeutics, Sun Pharma, Surrozen Inc., Synedgen, Takeda, Tegus Inc., Teva, Tillotts, Trex Bio, TR1X Inc. TVM Lifesciences, Ventyx Biosciences, Versant Ventures, Vida Ventures, Ysios Capital, Zagbio Stock Shareholder: Connect Biopharm, EnGene, Evida, SRT, Imidomics, Enveda Rieder, Florian: Personal Fees: Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, Astra Zeneca, Boehringer-Ingelheim, Celgene/BMS, Celltrion, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Jannsen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Palisade, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, 89Bio

Abstract Background Icotrokinra is the first targeted oral peptide that selectively blocks the IL-23 receptor (IL-23R) and precisely inhibits the IL-23 pathway. In ANTHEM-UC—a Phase 2b, randomised, double-blind, placebo (PBO)-controlled, dose-ranging study in adults with moderately to severely active ulcerative colitis (UC)—all doses of icotrokinra achieved the primary endpoint of clinical response and delivered clinically meaningful improvements across key secondary endpoints at Week (W)12,1 which were maintained or improved at W28.2 Here we report the impact of icotrokinra on systemic and tissue biomarkers of inflammatory burden in UC. Methods Participants were randomised (1:1:1:1) to receive once-daily icotrokinra 100 mg, 200 mg, 400 mg, or PBO. Clinical inflammatory biomarkers, C-reactive protein (CRP) and faecal calprotectin (FCP), along with serum IL-23 pathway biomarkers (IL-22, IL-17A, and IL-17F) were used to determine the impact of icotrokinra on systemic inflammation. Gene expression changes in colonic biopsies were used to confirm tissue IL-23 pathway engagement and dampening of tissue inflammation with icotrokinra. Results At the W12 primary timepoint, all doses of icotrokinra attenuated levels of serum CRP and FCP (Figure 1). All doses of icotrokinra, but not PBO, markedly reduced serum levels of IL-22, IL-17A, and IL-17F at W12 relative to baseline. Greater reductions in these serum biomarkers of IL-23 pathway activation were observed with the 200 mg and 400 mg doses relative to the 100 mg dose (Figure 1, nominal p < 0.05). All doses of icotrokinra, but not PBO, markedly reduced expression of gene sets associated with the IL-23–driven inflammation in tissue at W12 relative to baseline (Figure 2, nominal p < 0.0001). With icotrokinra treatment, the tissue transcriptome more closely resembled that of healthy individuals, with decreased expression of gene sets associated with UC-relevant inflammatory cell types and increased expression of genes characteristic of healthy epithelial cells. Importantly, dampening of systemic and tissue inflammation with icotrokinra was sustained at W28 (Figures 1 & 2). Conclusion We show for the first time that blocking the IL-23R can inhibit IL-23-mediated inflammatory signaling in UC patients. Icotrokinra treatment induced a sustained (W28) reduction in systemic and tissue biomarkers of inflammatory burden in UC. Furthermore, icotrokinra induced transcriptional changes that are consistent with dampening of IL-23–driven inflammation and normalization of the tissue transcriptome. While all once-daily doses of icotrokinra attenuated systemic and tissue inflammation, greater reduction of systemic inflammatory burden was observed with the 200 mg and 400 mg doses of icotrokinra. References: 1. Abreu MT, et al. United European Gastroenterol J. 2025 10;13(suppl 8):172-3. 2. Jairath V, et al. Am J Gastroenterol. 2025 120;10(suppl 2):S312. Conflict of interest: Louis, Edouard: Education and Research Grants for my department: Abbvie, Takeda, Janssen, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Janssen, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Jairath, Vipul: Consulting fees from AbbVie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, Bristol Myers Squibb, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Johnson & Johnson, 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. Siegmund, Britta: Consultant for AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Galapagos, Johnson & Johnson, Materia Prima, MSD, Pfizer, Takeda, Wedbush Securities speaker for AbbVie, AlfaSigma, Bristol Myers Squibb, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MD Education, MSD, Pfizer, Tr1xBio grant from Pfizer. Kannan, Arun K: Employee and shareholder of Johnson & Johnson Zeeman, Martha: Employee and shareholder of Johnson & Johnson Hart, Amy: Employee and shareholder of Johnson & Johnson Strawn, David: Employee and shareholder of Johnson & Johnson Venkat, Swati: Employee and shareholder of Johnson & Johnson Tomsho, Lynn: Employee and shareholder of Johnson & Johnson Mcrae, Bradford: Employee and shareholder of Johnson & Johnson Ruane, Darren: Employee and shareholder of Johnson & Johnson Surace, Lindsey: Employee and shareholder of Johnson & Johnson Erondu, Ngozi: Employee and shareholder of Johnson & Johnson Zhan, Joyce: Employee and shareholder of Johnson & Johnson Chen, Minhu: I have received speaker honoraria from Takeda China, Xian Janssen, and AbbVie China, as well as research funding from Takeda (China). Chachu, Karen: Advisory board for Johnson & Johnson consultant for OptumRx Matsuoka, Katsuyoshi: Grant: Abbvie Inc., Mochida Pharmaceutical Co., Ltd., ZERIA Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., JIMRO Co., Ltd. Personal Fees: Mitsubishi Tanabe Pharma, Janssen Pharmaceutical K.K., Abbvie Inc., EA Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., ZERIA Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Kyorin Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Gilead Sciences, Celltrion Healthcare, Bristol-Myers Squibb Limdi, Jimmy: Speaker/consultancy fees from AbbVie, Abivax, Arena, BioHit, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MSD, Pfizer, Takeda research support from Galapagos, Takeda Rydzewska, Grazyna: Speaker and consultant fees from AbbVie, AlfaSigma, AstraZeneca, Bayer, Biocodex, Bristol Myers Squibb, Ferring, Johnson & Johnson, Lilly, PRO.MED.Pl, Recordati, Sanprobi, SOBI, Takeda travel/accommodation meeting expenses from AbbVie, Ferring, Takeda Abreu, Maria Teresa: Grant/Research Support: Janssen, Prometheus Bioscience, Takeda Consultant: Janssen, Prometheus Bioscience, Takeda Gilead, Eli Lilly, AbbVie Inc., Bristol Myers, Imedex, Loftus Jr, Edward V: Consultant/advisory board member for AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Genentech, Gilead Sciences, Johnson & Johnson, Pfizer, Takeda, UCB.

Abstract Background & Aims Central reading of endoscopy and histopathology is the current standard for disease activity assessment in inflammatory bowel disease (IBD) clinical trials but is limited by interreader and intrareader variability, operational delays, and cost. Artificial intelligence (AI) and machine learning (ML) offer the potential to improve accuracy, efficiency, and reproducibility. The International Organization for the Study of IBD (IOIBD) developed consensus statements on AI/ML use for endoscopic and histologic endpoint assessment in IBD trials. Methods As part of the IOIBD endpoints cluster initiative, a narrative, evidence-informed review with literature searches of Medline and Embase (January 2018-February 2025) identified studies applying AI/ML to endoscopy or histology in IBD. Relevant evidence informed 36 survey statements formulated by a steering committee. Seventy-two IOIBD members were invited to vote online; consensus required ≥80% agreement (score: 7-10 on a 10-point scale). Results Forty-five members completed the survey. Consensus was reached for 28 statements related to endoscopy, pathology, and trial design. Experts agreed that AI-based central reading could improve diagnostic accuracy, expedite processes, reduce costs, and enhance reproducibility. Combining human and AI assessments was favored over AI replacement. The key limitations identified included insufficient validation, generalizability concerns, and dependence on human-annotated training datasets. Conclusions This IOIBD consensus supports the integration of AI/ML into central reading for IBD clinical trials to improve objectivity, efficiency, and consistency, while maintaining human oversight. Further research should address validation, regulatory frameworks, and multimodal integration to enable broader adoption in both trials and clinical practice.

INTRODUCTION: We conducted a retrospective cohort study comparing the safety of advanced therapies in patients with ulcerative colitis (UC). METHODS: Using an administrative claims database (OptumLabs Data Warehouse), we identified patients with UC who initiated treatment with tumor necrosis factor-α (TNF) antagonists, anti-integrin agents, anti-interleukin, Janus kinase inhibitors (JAK), or sphingosine-1 phosphate receptor modulators between 2016 and 2022 and had followed up for at least 1 year before and after treatment initiation. We compared the risk of serious infections, venous thromboembolism, and major adverse cardiovascular events through multinomial propensity score-based inverse probability weighting, with propensity scores estimated through generalized boosted models that accounted for disease characteristics, healthcare utilization, comorbidities, and previous and concomitant medications, and the competing risk of mortality. We calculated cause-specific hazard ratios (HR) and 95% confidence intervals for multiple treatment comparisons. RESULTS: We included 9,430 patients with UC treated with TNF antagonists (n = 4,111), anti-integrins (n = 3,165), anti-ILs (n = 1,342), JAK inhibitors (n = 701), or sphingosine-1 phosphate receptor modulators (n = 111), followed over median 27 months. After adjusting for confounding variables, anti-ILs were associated with a lower risk of serious infections compared with TNF antagonists (HR, 0.66 [95% confidence interval, 0.51–0.87]) and anti-integrins (HR, 0.75 [0.57–0.98]). JAK inhibitors were associated with a lower risk of serious infections compared with TNF antagonists (HR, 0.66 [0.46–0.94]). The incidence of venous thromboembolism (incidence rate, 1.4–2.0 per 100 py) and major adverse cardiovascular event (0.5–1.0 per 100 py) was very low, without any significant differences across agents. DISCUSSION: In a real-world cohort of patients with UC, anti-ILs and JAK inhibitors were associated with a lower risk of serious infections and may offer net benefit, especially in patients with previous TNF antagonist exposure.

ABSTRACT Background Advanced therapies increase the risk of shingles in inflammatory bowel diseases (IBD). Aim To compare the risk of shingles with different advanced therapies in patients with IBD. Methods We identified patients with IBD who initiated treatment with tumour necrosis factor (TNF) antagonists, anti‐integrins, anti‐interleukins, Janus kinase (JAK) inhibitors, or sphingosine‐1 phosphate receptor (S1PR) modulators between 2016 and 2022 and had follow‐up for at least 1 year before and after treatment initiation. We estimated the incidence rate (IR per 100 person‐year [PY]) of shingles (overall and complicated) and compared the risk with different advanced therapies through multinomial propensity score‐based inverse probability of treatment weighting (IPTW), with propensity scores estimated through generalised boosted models, accounting for disease characteristics, healthcare utilisation, comorbidities and prior and concomitant medications. Weighted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for multiple treatment comparisons. Results We included 21,675 patients followed over 27 months. IRs per 100 PY of shingles and complicated shingles were: TNF antagonists 1.0/0.3, anti‐integrin agents 1.4/0.4, anti‐interleukins 1.2/0.5, JAK inhibitors 3.3/0.9 and S1PR modulators 2.0/1.0. After adjusting for confounding variables, JAK inhibitors were associated with higher risks of shingles than TNF antagonists (HR 2.19; 1.28–3.75), anti‐integrins (HR 1.87; 1.12–3.14) and anti‐interleukins (HR 1.70; 0.98–2.96). Conclusions JAK inhibitors were associated with 1.7–2.2‐fold higher risk of shingles than other advanced therapies.

Abstract Background and Aims Intestinal ultrasound (IUS) is increasingly used to monitor treatment efficacy in inflammatory bowel disease (IBD) trials. However, standardized definitions for response, remission, and optimal assessment timing remain undefined. An international expert consensus meeting was held to establish IUS endpoints for clinical trials. Methods A panel of 35 international gastroenterologists and radiologists participated in a modified Delphi process, reviewing the literature and developing consensus statements. Agreement was defined as at least 75% consensus. Results Consensus was reached on 150 statements across four domains: general IBD (30 statements), luminal Crohn’s disease (CD) (43), perianal CD (51), and ulcerative colitis (UC) (26). For luminal CD and UC, ultrasound response was defined by: (1) a ≥25% reduction in bowel wall thickness (BWT) from baseline, or (2) multifactorial improvement, combining BWT reduction with ≥1 grade decrease in color Doppler signal (CDS) or another IUS parameter. Assessments were set at weeks 4-8 for the colon and week 12 for the terminal ileum. Ultrasound remission in luminal CD was defined as: (1) BWT normalization (≤3 mm) or (2) normalization of multiple parameters, including BWT, CDS, and all other IUS parameters. Similar remission criteria were proposed for UC, but the sigmoid BWT normal range (3-4 mm) remained uncertain. The bowel ultrasound score (BUSS) for CD and the Milan ultrasound criteria (MUC) for UC were supported as standardized scoring systems for trials. Conclusion This consensus provides standardized IUS definitions to enhance consistency in IBD trials, supporting the integration of IUS in future research.