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Saeed Shakibfar,1 Kristine H Allin,2 Tine Jess,2 Maria Antonietta Barbieri,1,3 Vera Battini,1,4 Eva Simoncic,1 Julien Kirchgesner,5 Trond Ulven,1,* Maurizio Sessa1,* 1Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark; 2Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark; 3Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 4Pharmacovigilance & Clinical Research, International Centre for Pesticides and Health Risk Prevention, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Università Degli Studi Di Milano, Milan, Italy; 5Department of Gastroenterology, INSERM, Institut Pierre Louis d’Epidémiologie Et de Santé Publique, AP-HP, Hôpital Saint-Antoine, Sorbonne Université, Paris, France*These authors contributed equally to this workCorrespondence: Saeed Shakibfar, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark, Email saeed.shakibfar@sund.ku.dkAim: Drug repurposing, utilizing electronic healthcare records (EHRs), offers a promising alternative by repurposing existing drugs for new therapeutic indications, especially for patients lacking effective therapies. Intestinal fibrosis, a severe complication of Crohn’s disease (CD), poses significant challenges, increasing morbidity and mortality without available pharmacological treatments. This article focuses on identifying medications associated with an elevated or reduced risk of fibrosis in CD patients through a population-wide real-world data and artificial intelligence (AI) approach.Methods: Patients aged 65 or older with a diagnosis of CD from 1996 to 2019 in the Danish EHRs were followed for up to 24 years. The primary outcome was the need of specific surgical procedures, namely proctocolectomy with ileostomy and ileocecal resection as proxies of intestinal fibrosis. The study explored drugs linked to an increased or reduced risk of the study outcome through machine-learning driven survival analysis.Results: Among the 9179 CD patients, 1029 (11.2%) underwent surgery, primarily men (58.5%), with a mean age of 76 years, 10 drugs were linked to an elevated risk of surgery for proctocolectomy with ileostomy and ileocecal resection. In contrast, 10 drugs were associated with a reduced risk of undergoing surgery for these conditions.Conclusion: This study focuses on repurposing existing drugs to prevent surgery related to intestinal fibrosis in CD patients, using Danish EHRs and advanced statistical methods. The findings offer valuable insights into potential treatments for this condition, addressing a critical unmet medical need. Further research and clinical trials are warranted to validate the effectiveness of these repurposed drugs in preventing surgery related to intestinal fibrosis in CD patients.Keywords: Crohn’s disease, drug repurposing, inflammatory bowel disease, intestinal fibrosis, machine-learning, real-world data

Background and Aims: Breast cancer is the most common malignancy observed in patients with inflammatory bowel diseases (IBD). The aim of our study was to evaluate incident cancer rate (recurrence or new-onset cancer) in a cohort of IBD patients with a history of breast cancer according to the subsequent IBD treatment provided., Methods: A multicenter retrospective study included consecutive IBD patients with prior breast cancer. The inclusion date corresponded to the diagnosis of index malignancy. Follow-up lasted from cancer diagnosis until the occurrence of incident cancer., Results: Among 207 patients included (median disease duration: 13 years [IQR 6 - 21]), first line treatment (median interval of 28 months [IQR 7 - 64]) was a conventional immunosuppressant in 19.3 % of patients, anti-TNF in 19.8 %, vedolizumab in 7.2 % and ustekinumab in 1.9 %. After a median follow-up of 71 months [IQR, 34 - 148], 42 (20%) incident cancers were observed (34 breast cancer recurrences). Adjusted incidence rates per 1000 person-years were 10.2 (95%CI 6.0- 16.4) for the untreated arm and 28.9 (95%CI 11.6-59.6) for exposed patients (p= 0.0519). There was no significant difference between treated patients and controls regarding incident-cancer free survival rates (p=0.4796). In multivariable analysis, factors associated with incident cancer were stage T4d (p=0.036), triple negative tumor (p=0.016) and follow-up of less than 71 months (p=0.005)., Conclusion: We did not find a statistically significant increase in incident breast cancer related to IBD treatment beyond the already known poor prognostic factors of breast cancer., (Copyright © 2024. Published by Elsevier Inc.)

Background: Early complicated Crohn's disease (CD) may require ileal resection as first-line treatment., Aim: To evaluate the long-term outcomes of patients who underwent early ileal resection., Methods: We conducted a retrospective study in two inflammatory bowel diseases (IBD) referral centres, including patients with ileocaecal resection and segmental ileal resection within 5 years of CD diagnosis. Early resection was defined as within 6 months of diagnosis, intermediate resection between 6 months and 2 years, and late resection between 2 and 5 years. The primary outcome was the cumulative risk of a second ileal surgery. Secondary outcomes included the use of postoperative treatments and morphological recurrence after initial surgery (Rutgeerts score ≥i2, or recurrence on imaging)., Results: Among 393 patients who underwent ileal resection within 5 years of diagnosis, 130, 128 and 135, respectively, had early, intermediate and late resection. The cumulative risk of second surgery at 10 years was not significantly different in the early resection group (25.0% [95% CI 17.4-35.2]), than the intermediate (16.8% [95% CI 10.5-26.2]; p = 0.17) or late resection group (22.7% [95% CI 15.1-33.3]; p = 0.83). The early resection group required fewer postoperative treatments than the late resection group with median survivals without treatments of 3.7 and 0.9 years, respectively (p = 0.002). Patients who had early resection had significantly less morphological recurrence than the late resection group (p = 0.02)., Conclusion: Early ileal resection in CD is not associated with a higher risk of a second resection. It may be associated with reduced use of medical treatments and fewer morphological recurrences., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: While recruitment rates in inflammatory bowel disease (IBD) trials are continuously decreasing, the underlying reasons are likely multifactorial but remain poorly defined. Screen failure (SF) proportions and causes have not been extensively explored in IBD., Aim: We assessed SF proportions and underlying SF reasons in IBD phase 2 and 3 clinical trials., Methods: We analyzed SF-related data from 17 randomized controlled phase 2 or 3 IBD trials. Twelve trials were in ulcerative colitis (UC) and 5 trials were in Crohn's disease (CD) operated by a single contract research organization, IQVIA. Differences between patient groups were tested for significance by Mann-Whitney and Fisher's tests when appropriate., Results: We analyzed a total of 11 161 patients with UC and 5752 patients with CD. The mean SF proportion was 0.43 per trial in UC. The primary reason for SFs in UC was not meeting the overall (modified) Mayo score inclusion threshold and/or the endoscopic subscore of at least 2 (33.8% of all SF). In CD clinical trials, the mean SF proportion was at 0.53. The primary cause for SFs was not meeting the CDAI eligibility criteria (23.1% of all SFs). SF proportions were significantly higher in CD versus UC trials (P = .027). Clostridium difficile or any other intestinal infection and not meeting tuberculosis screening criteria were other major reasons for SFs both in UC and CD., Conclusion: High SF proportion in IBD clinical trials, particularly for CD studies, pose obstacles to patient recruitment. While underlying causes are diverse, arbitrarily defined clinical and/or endoscopic eligibility criteria remain the major limiting factors., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Aims: Small-bowel (SB) capsule endoscopy (CE) is a first-line procedure for exploring the SB. Endoscopic GI PlacemenT (EGIPT) of SB CE is sometimes necessary. Although experience with EGIPT is considerable in pediatric populations, we aimed to describe the safety, efficacy, and outcomes of EGIPT of SB CE in adult patients., Methods: The international CApsule endoscopy REsearch (iCARE) group set up a retrospective multicenter study. Patients over age 18 years who underwent EGIPT of SB CE before May 2022 were included. Data were collected from medical records and capsule recordings. The primary endpoint was the technical success rate of the EGIPT procedures., Results: Of 39,565 patients from 29 centers, 630 (1.6%) were included (mean age, 62.5 years; 55.9% women). The technical success of EGIPT was achieved in 610 procedures (96.8%). Anesthesia (moderate to deep sedation or general anesthesia) and centers with intermediate or high procedure loads were independent factors of technical success. Severe adverse events occurred in 3 patients (.5%). When technically successful, EGIPT was associated with a high SB CE completion rate (84.4%) and with a substantial diagnostic yield (61.1%). The completion rate was significantly higher when the capsule was delivered in the SB compared with when it was delivered in the stomach., Conclusions: EGIPT of SB CE is highly feasible and safe, with a high completion rate and diagnostic yield. When indicated, it should be performed with patients under anesthesia, and the capsule should be delivered in the duodenum rather than the stomach for better SB examination outcomes., Competing Interests: Disclosure The following authors disclosed financial relationships: S. Ouazana: Speaker for Medtronic. P. Baltes: Speaker for Medtronic; research support from AnX Robotics. E. Toth: Consultant for AnX Robotics, Jinshan, Medtronic, and Norgine; speaker for Jinshan, Medtronic, and Tillotts Pharma; research support from AnX Robotics, Jinshan, and Norgine. H. Beaumont: Speaker for Medtronic. C. Spada: Advisor for AnX Robotics and Medtronic; speaker for AnX Robotics, Boston Scientific, and Olympus; research support from Pentax. A. Mussetto: Consultant for Boston Europe and Olympus Italia. R. Sidhu: Consultant for AnXRobotics. D. McNamara: Speaker for Medtronic and Takeda. B. González-Suárez: Research support from Medtronic; speaker for Norgine and Olympus. C. Carretero: Advisor for Medtronic. E. Despott: Research support from Fujifilm, Aquilant Endoscopy, Pentax Medical, Olympus, Boston Scientific, GI Supply, Cook Medical, Diagmed Healthcare, Norgine, Takeda, Abbvie, Cantel Medical, Ardmore Medical, Apollo Endosurgery, Erbe, APR Medical, AnX Robotics, and Medtronic; consultant for Fujifilm, Norgine, and Ambu; speaker for Fujifilm, Aquilant Endoscopy, Olympus, Boston Scientific, GI Supply, Ambu, and Aquilant Endoscopy. E. Rondonotti: Speaker and consultant for Fujifilm; consultant for Medtronic. J. Kirchgesner: Consultant for Janssen, Celltrion, Roche, Pfizer, and Gilead; speaker for Janssen and Lilly. X. Dray: Speaker for Alfasigma, Bouchara Recordati, Fujifilm, Medtronic, Norgine, and Sandoz; co-founder of and shareholder in Augmented Endoscopy; consultant for Norgine and Provepharma. All other authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Pragmatic studies designed to test interventions in everyday clinical settings can successfully complement the evidence from registration and explanatory clinical trials. The European consensus project PRACTICE-IBD was developed to identify essential criteria and address key methodological issues needed to design valid, comparative, pragmatic studies in inflammatory bowel diseases [BDs]., Methods: Statements were issued by a panel of 11 European experts in IBD management and trial methodology, on four main topics: [I] study design; [II] eligibility, recruitment and organisation, flexibility; [III] outcomes; [IV] analysis. The consensus process followed a modified Delphi approach, involving two rounds of assessment and rating of the level of agreement [1 to 9; cut-off ≥7 for approval] with the statements by 18 additional European experts in IBD., Results: At the first voting round, 25 out of the 26 statements reached a mean score ≥7. Following the discussion that preceded the second round of voting, it was decided to eliminate two statements and to split one into two. At the second voting round, 25 final statements were approved: seven for study design; six for eligibility, recruitment and organisation, flexibility; eight for outcomes; and four for analysis., Conclusions: Pragmatic, randomised, clinical trials can address important questions in IBD clinical practice, and may provide complementary, high-level evidence, as long as they follow a methodologically rigorous approach. These 25 statements intend to offer practical guidance in the design of high-quality, pragmatic, clinical trials that can aid decision making in choosing a management strategy for IBDs., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background & Aims: Colonoscopic surveillance is recommended in patients with colonic inflammatory bowel disease (IBD) given their increased risk of colorectal cancer (CRC). We aimed to develop and validate a dynamic prediction model for the occurrence of advanced colorectal neoplasia (aCRN, including high-grade dysplasia and CRC) in IBD., Methods: We pooled data from 6 existing cohort studies from Canada, The Netherlands, the United Kingdom, and the United States. Patients with IBD and an indication for CRC surveillance were included if they underwent at least 1 follow-up procedure. Exclusion criteria included prior aCRN, prior colectomy, or an unclear indication for surveillance. Predictor variables were selected based on the literature. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modeling. Model performance was assessed with Harrell's concordance-statistic (discrimination) and by calibration curves. Generalizability across surveillance cohorts was evaluated by internal-external cross-validation., Results: The surveillance cohorts comprised 3731 patients, enrolled and followed-up in the time period from 1973 to 2021, with a median follow-up period of 5.7 years (26,336 patient-years of follow-up evaluation); 146 individuals were diagnosed with aCRN. The model contained 8 predictors, with a cross-validation median concordance statistic of 0.74 and 0.75 for a 5- and 10-year prediction window, respectively. Calibration plots showed good calibration. Internal-external cross-validation results showed medium discrimination and reasonable to good calibration., Conclusions: The new prediction model showed good discrimination and calibration, however, generalizability results varied. Future research should focus on formal external validation and relate predicted aCRN risks to surveillance intervals before clinical application., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)