Screen Failures and Causes in Inflammatory Bowel Disease Randomized Controlled Trials: A Study of 16 913 Screened Patients.

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.

Analyzing data from 17 IBD clinical trials with over 16 000 screened patients, we found a screen failure (SF) proportion of 44% for UC and 51% for CD. The primary cause of SF was inadequate clinical and/or endoscopic activity scores.

Early ileal resection in Crohn's disease is not associated with severe long-term outcomes: The ERIC study.

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.

Long-term Outcome of Risankizumab in Crohn's Disease: a Real-world GETAID Study.

BACKGROUND & AIMS: The aim of this study was to assess the long-term effectiveness and safety of risankizumab maintenance treatment in a large real-world cohort of patients with Crohn's Disease (CD). METHODS: From May 2021 to August 2023, all consecutive patients with CD treated with risankizumab in 25 GETAID centers have been retrospectively included. The primary endpoint was steroid-free clinical remission (Harvey Bradshaw Index [HBI] <5) at 52 weeks. RESULTS: Of the 174 patients included, 99%, 93%, and 96% had been previously exposed to anti-TNF, vedolizumab, and ustekinumab, respectively. All patients had received ≥3 biologics, and 108 (62%) had previous intestinal resection. Median follow-up was 13.7 months (interquartile range, 10.0-18.1 months). The rates of steroid-free clinical remission and clinical remission at week 26 were 47% (72/152) and 52% (79/152), and 46% (58/125), and 48% (60/125) at week 52, respectively. Risankizumab persistence rates were 94%, 89%, and 79% at weeks 12, 26, and 52, respectively. At the end of follow-up, 45 (45/174; 26%) patients had discontinued risankizumab (loss of response, 42%; primary failure, 37%; intolerance, 13%). Thirty-six patients (36/174; 20.9%) were hospitalized, and 22 (22/174; 12.6%) required intestinal resection. Fifty-one patients (29%) had an adverse event, including 26 (15%) serious adverse events (CD flare, n = 17). One death (myocardial infarction) and one cancer (papillary thyroid carcinoma) were observed. CONCLUSION: This is the first real-life study to report long-term outcomes in patients with refractory CD treated with risankizumab. One-half of the patients achieved steroid-free clinical remission after 1 year, and the safety profile was consistent with the literature.

Dynamic Prediction of Advanced Colorectal Neoplasia in Inflammatory Bowel Disease.

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.

Pragmatic Trial Design to Compare Real-world Effectiveness of Different Treatments for Inflammatory Bowel Diseases: The PRACTICE-IBD European Consensus.

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.

Drug Repurposing in Crohn's Disease Using Danish Real-World Data.

Aim: 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.

A methodological review of the high-dimensional propensity score in comparative-effectiveness and safety-of-interventions research finds incomplete reporting relative to algorithm development and robustness.

OBJECTIVES: The use of secondary databases has become popular for evaluating the effectiveness and safety of interventions in real-life settings. However, the absence of important confounders in these databases is challenging. To address this issue, the high-dimensional propensity score (hdPS) algorithm was developed in 2009. This algorithm uses proxy variables for mitigating confounding by combining information available across several healthcare dimensions. This study assessed the methodology and reporting of the hdPS in comparative effectiveness and safety research. STUDY DESIGN AND SETTING: In this methodological review, we searched PubMed and Google Scholar from July 2009 to May 2022 for studies that used the hdPS for evaluating the effectiveness or safety of healthcare interventions. Two reviewers independently extracted study characteristics and assessed how the hdPS was applied and reported. Risk of bias was evaluated with the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool. RESULTS: In total, 136 studies met the inclusion criteria; the median publication year was 2018 (Q1-Q3 2016-2020). The studies included 192 datasets, mostly North American databases (n = 132, 69%). The hdPS was used in primary analysis in 120 studies (88%). Dimensions were defined in 101 studies (74%), with a median of 5 (Q1-Q3 4-6) dimensions included. A median of 500 (Q1-Q3 200-500) empirically identified covariates were selected. Regarding hdPS reporting, only 11 studies (8%) reported all recommended items. Most studies (n = 81, 60%) had a moderate overall risk of bias. CONCLUSION: There is room for improvement in the reporting of hdPS studies, especially regarding the transparency of methodological choices that underpin the construction of the hdPS.

Endoscopic GI placement of capsule endoscopy to investigate the small bowel: a multicenter European retrospective series of 630 procedures in adult patients.

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.

Tumor Necrosis Factor Inhibitors in Inflammatory Bowel Disease and Risk of Immune Mediated Inflammatory Diseases.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors (anti-TNF) are effective therapies for several immune-mediated inflammatory diseases (IMIDs). However, case reports have identified the paradoxical occurrence of IMIDs in patients treated with anti-TNF. We studied the risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa after the initiation of anti-TNF therapy for inflammatory bowel disease (IBD). METHODS: We conducted 2 nationwide cohort studies comprising all patients with IBD in Denmark (2005-2018) and France (2008-2018). We obtained individual-level information on exposure to anti-TNF, diagnoses of IMIDs including rheumatoid arthritis, psoriasis, and hidradenitis suppurativa, and potential confounders from healthcare registers in the respective countries. We used Cox models to estimate hazard ratios (HRs) for the association between anti-TNF exposure and IMIDs and then pooled the estimates from the 2 cohorts. To test the robustness of our results, we performed an active comparator analysis of anti-TNF monotherapy vs azathioprine monotherapy. RESULTS: The Danish and French cohorts comprised 18,258 and 88,786 subjects with IBD, respectively, contributing a total of 516,055 person-years of follow-up. Anti-TNF was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa in both the Danish (HR, 1.66; 95% confidence interval [CI], 1.34-2.07) and the French cohort (HR, 1.78; 95% CI, 1.63-1.94), with a pooled HR of 1.76 (95% CI, 1.63-1.91). Anti-TNF was also associated with an increased risk of the outcomes when compared with azathioprine (pooled HR, 2.94; 95% CI, 2.33-3.70). CONCLUSIONS: In 2 nationwide cohorts of IBD patients, anti-TNF therapy was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa.

Tofacitinib for Patients with Anti-TNF Refractory Ulcerative Proctitis: A Multicentre Cohort Study from the GETAID.

BACKGROUND: Although ulcerative proctitis [UP] can dramatically impair quality of life, treatment efficacy has been poorly investigated in UP as it was historically excluded from phase 2/3 randomised controlled trials in ulcerative colitis. Our aim was to assess the effectiveness and safety of tofacitinib for the treatment of UP. METHODS: We conducted a retrospective, multicentre study in 17 GETAID centres, including consecutive patients with UP treated with tofacitinib. The primary endpoint was steroid-free remission between Week 8 and Week 14, defined as a partial Mayo score of 2 [and no individual subscore above 1]. Secondary outcomes included clinical response and steroid-free remission after induction and at 1 year. RESULTS: All the 35 enrolled patients previously received anti-tumour necrosis factor [TNF] therapy and 88.6% were exposed to at least two lines of biologics. At baseline, the median partial Mayo score was 7 (intequartile range [IQR] [5.5-7]). After induction [W8-W14], 42.9% and 60.0% of patients achieved steroid-free remission and clinical response, respectively. At 1 year, the steroid-free clinical remission and clinical response rates were 39.4% and 45.5%, respectively, and 51.2% [17/33] were still receiving tofacitinib treatment. Survival without tofacitinib withdrawal was estimated at 50.4% (95% confidence interval [CI] [35.5-71.6]) at 1 year. Only a lower partial Mayo at baseline was independently associated with remission at induction (0dds ratio [OR] = 0.56 for an increase of 1, (95% CI [0.33-0.95], p = 0.03). Five [14.3%] adverse events were reported, with one leading to treatment withdrawal [septic shock secondary to cholecystitis]. CONCLUSION: Tofacitinib may offer a therapeutic option for patients with refractory UP.

Focal loss of mural stratification as a radiological predictor for small bowel adenocarcinoma in Crohn's disease.

AIM: Patients with Crohn's disease (CD) are at higher risk of small bowel adenocarcinoma (SBA). We aimed to identify radiological predictors of SBA in CD. METHODS: We conducted a retrospective case-control study at two tertiary inflammatory bowel disease centers and identified CD patients diagnosed with SBA between 2003 and 2019. Patients were matched with up to four controls. Pre-operative imaging (magnetic resonance imaging (MRI) or computed tomography (CT)) were reviewed by three gastrointestinal radiologists. RESULTS: Nineteen patients with CD-associated SBA with a mean age of 54.9 and 32 matched controls were included. Mean length of small bowel involvement was 216 (± 188) mm in the SBA group versus 156 (± 167) mm in the control group (p = 0.76). Only 11.8 % of cases had a diagnosis of SBA made preoperatively. In univariate analysis, focal loss of mural stratification (odds ratio [OR], 11; 95%CI, 2.43-49.5, p = 0.002), and wall thickening (OR, 1.32; 95%CI, 1.05-1.66, p = 0.02) were significantly associated with SBA. After adjustment, focal loss of mural stratification was the only independent risk factor (OR, 11; 95 % CI, 2.43-49.5, p = 0.002). CONCLUSIONS: Focal loss of mural stratification was identified as a predictor of CD-associated SBA, which should be described in imaging reports and further validated.

Review article: Updated management of acute severe ulcerative colitis: From steroids to novel medical strategies.

Acute severe ulcerative colitis (ASUC) occurs in up to 25% of patients with ulcerative colitis (UC). Therapeutic approaches have evolved during the past years with the increasing bio exposure of admitted patients and the extension of the number of approved drugs for UC. In this review, we aimed to summarize the latest evidence in short-term and long-term medical strategies for ASUC. In addition to general principles such as venous thromboembolism prophylaxis, screening for triggering and worsening factors and close monitoring, first-line therapy for ASUC remains intravenous corticosteroids. In naive patients, the optimum maintenance strategy for steroid-responding patients does not necessarily include biologics. Second-line therapy includes infliximab or calcineurin inhibitors (CNIs) with similar short- and long-term colectomy rates. Despite its pathophysiological relevance, there is insufficient evidence to promote intensified induction with infliximab. Prior treatment exposure is a cornerstone for guiding therapeutic choice of short- and long-term therapies in the context of ASUC: in anti-TNF exposed patients, CNIs may be favored as a bridge therapy to vedolizumab or ustekinumab. Third-line salvage therapy could be a therapeutic option in selected patients referred to expert centers. Additionally, evidence is accumulating regarding the use of tofacitinib in ASUC.