Virginia Solitano

Background: Drug-induced enterocolitis (DIC) consists of a heterogeneous group of gastrointestinal inflammatory disorders with clinical, endoscopic, and histological features that often overlap with inflammatory bowel disease (IBD). Given the increasing recognition of immune checkpoint inhibitor (ICI)-induced enterocolitis and the lack of standardized management algorithms, the European Crohn’s and Colitis Organisation (ECCO) convened a multidisciplinary panel to review DIC, with a particular focus on ICI-induced disease. Methods: Gastroenterologists, histopathologists, and oncologists systematically reviewed the literature using Medline, PubMed, EMBASE, and Scopus. Evidence was synthesized into ECCO Current Practice Positions addressing diagnostic principles, histopathological patterns, therapeutic strategies, and ICI-specific considerations. Statements were refined and approved through structured consensus. Results: Twenty-three practice positions were agreed upon. DIC may present with diverse histological patterns, including IBD-like/chronic enterocolitis, acute enterocolitis, microscopic colitis, ischemic-type injury, and mixed features, none of which are pathognomonic. Close clinicopathological collaboration is therefore essential. In suspected ICI-induced enterocolitis, assessment should include Common Terminology Criteria for Adverse Events-based grading, stool testing for pathogens, fecal calprotectin, endoscopy with biopsies, and imaging when indicated. Corticosteroids remain first-line therapy, while mild or microscopic disease may respond to budesonide or beclomethasone. Corticosteroid-refractory or corticosteroid-dependent disease should prompt early escalation to infliximab or vedolizumab. Surgery is reserved for refractory or complicated cases. Rechallenge with ICIs may be considered following multidisciplinary evaluation. Conclusion: DIC represents a diagnostically complex spectrum of disorders that require integrated multidisciplinary evaluation. These ECCO Current Practice Positions provide a practical framework for diagnostic work-up and treatment, particularly for ICI-induced enterocolitis.

Background: Criteria to define difficult‐to‐treat (DTT) inflammatory bowel disease (IBD) have recently been proposed, yet the inclusion and participation of patients with DTT‐IBD in randomized controlled trials (RCTs) are heterogeneous and poorly defined. Aims: To explore inclusion and representation of patients with DTT‐IBD in RCTs. Methods: We reviewed RCTs of advanced therapies (ATs) in ulcerative colitis (UC) and Crohn's disease (CD). DTT‐IBD was defined as active disease despite exposure to ATs with ≥ 2 different mechanisms of action. Secondary analyses assessed eligibility and participation of patients exposed to ≥ 1 or ≥ 2 ATs irrespective of mechanism of action, and in CD only, active disease after ≥ 2 intestinal resections and fistulizing disease. Results: We included 179 RCTs, 93 in UC and 86 in CD, comprising 54,258 patients. In UC, 72% (67/93) of studies included patients with prior exposure to ATs and 16.1% (15/93) included participants exposed to agents with ≥ 2 mechanisms of action (DTT); among the 10 trials reporting patient‐level data, DTT‐UC accounted for 16.2% (814/5019). In CD, 73.3% (63/86) of RCTs included patients with prior exposure to ATs, and 10.5% (9/86) reported patients with DTT‐CD due to exposure to multiple classes of ATs. Patients with multifailure DTT‐CD accounted for 22.4% (773/3455) of the reported study populations. Subgroup‐specific efficacy outcomes for DTT‐IBD were not reported, except for one small trial that enrolled only DTT‐UC. Conclusions: Few RCTs of advanced medications include patients with DTT‐IBD. In most trials, participants with DTT‐IBD represent a minority of the study population, and subgroup‐specific data are lacking.

Background: Crohn’s disease (CD) is characterized by transmural inflammation, and achieving transmural healing (TH), may lead to improved long-term outcomes. However, evidence supporting this hypothesis is limited. Methods: Adult patients diagnosed with CD who underwent ileocolonoscopy and cross-sectional imaging within 6 months were included. Long-term outcomes of CD-related surgery and hospitalization in patients with TH, endoscopic healing (EH) alone, radiologic healing (RH) alone, and no healing (NH) were assessed. We used Cox proportional hazards models and modified Poisson regression. Results: Among 180 included patients, 26.7% achieved TH, 21.1% achieved EH, 12.8% achieved RH, and 39.4% were classified as NH. At baseline, 54.4% were on biologics which increased to 81.7% at last follow-up (76-78 months across groups). Cumulative probabilities of surgery were lowest in patients with TH (0%, 2.3%, 7.0% at 1, 3, and 5 years) and highest in patients with NH (13%, 20.5%, and 26.9%, respectively) (P = .03). On Cox proportional hazard regression analysis, TH was associated with a significantly reduced risk of CD-related surgery (hazard ratio, 0.01; 95% confidence interval, 0.00-0.35; P = .009) compared with NH. The probabilities of surgery were lower for patients with RH compared with EH (10% vs 13.2%, 10% vs 18.4%, and 21.2% vs 26.9% at 1, 3, and 5 years) but were not statistically significant (P = .41). Probabilities of CD-related hospitalization were lowest with TH (4.3%, 8.8%, and 13.6% at 1, 3 and 5 years) but were not statistically different than other healing categories (P = .67). Conclusions: TH was associated with superior long-term outcomes compared with EH or RH alone. Future studies should focus on standardizing its definition and evaluate treat-to-target strategies.

Introduction: Despite regulatory mandates for advanced therapy (AT) washout periods of up to 5 drug half-lives before enrolling patients in inflammatory bowel disease (IBD) trials, the evidence base for these requirements is largely empirical, and whether shorter intervals independently increase the risk of serious infections in real-world practice remains unknown. Methods: Using the OptumLabs Data Warehouse, we identified adult patients with IBD who initiated a new AT (tumor necrosis factor antagonists, vedolizumab, interleukin (IL)-12/23 or IL-23 antagonists, or Janus kinase inhibitors) between 2018 and 2023 using a class-specific new-user design. We examined whether exposure to AT within the preceding 12 months (vs no exposure to AT within that window) and timing of discontinuation (≤1 month, 1-<3 months, or 3-12 months) were associated with risk of serious infections using multivariable Cox proportional hazards regression. Results: Among 21 564 AT initiators (47 ± 18 years; 52% female; 57% Crohn’s disease), 7490 (34.7%) had AT exposure within the preceding 12 months. Over a mean follow-up of 1.6 ± 0.9 y, 1955 (9.1%) experienced a serious infection. Prior AT exposure was associated with higher infection risk (hazard ratio [HR]: 1.19, 95% confidence interval [CI]: 1.07-1.33), consistent in inverse probability of treatment-weighted analyses (HR, 1.20 [1.06-1.37]). Among patients with prior exposure, timing of discontinuation was not associated with infection risk (HR, 1.17 [0.95-1.43] for ≤1 month vs 3-12 months; HR, 1.01 [0.83-1.22] for 1-<3 months), with no dose–response relationship on continuous modeling. Discussion: AT exposure within the preceding 12 months is associated with modestly higher risk of serious infection after initiating a new AT in IBD, but timing of discontinuation does not independently influence this risk.

Despite progress in understanding placebo effects in clinical trials of inflammatory bowel disease (IBD), there is a limited understanding of how socioeconomic factors of recruiting countries impact placebo rates. We investigated the association of socioeconomic factors across recruitment sites on placebo rates in IBD randomized controlled trials. We examined the association of clinical and endoscopic remission and response to the weighted Gross National Index (GNI) per capita, Human Development Index (HDI), and out-of-pocket health expenditures as a percentage of current health expenditures (OOP_CHE) of identified trials using mixed effects linear regression. Across 76 trials (Crohn's disease [CD]: n = 32; ulcerative colitis [UC]: n = 44), placebo response rates over time were largely stable, with a small increase across time in clinical remission for CD trials (β = 0.4% per increase in study year, 95% CI: 0.3%-0.84%, P = .04) and a small decrease across time in endoscopic response for UC trials (β = -1.39% per increase in study year, 95% CI: -1.79, -0.99, P < .001). Clinical response was most susceptible to changes in socioeconomic factors in IBD trials (β = -2.96% per 10 000 USD increase in study GNI, 95% CI: -4.98, -0.95%, P = .004; P < .05 for HDI and OOP_CHE). Across both conditions, decreases in clinical response were associated with increases in HDI and OOP_CHE (CD HDI: β = -1.15% per 0.01 increase in study HDI, 95% CI: -2.24, -0.06%, P = .04; UC HDI: β = -0.66% per 0.01 increase in study HDI, 95% CI: -1.19, -0.12%, P = .02). We found that placebo clinical response was most susceptible to influences of site-level socioeconomic wellbeing. These findings highlight that estimation of placebo rates in trial planning should account for geographic location of recruiting sites.

Background/Aims: Patients with Crohn’s disease (CD) are at an increased risk of urolithiasis, particularly after ileocolic (IC) resection. This study aimed to investigate the prevalence of hyperoxaluria, hypocitraturia, and hypomagnesuria in CD patients with and without IC resection, compared to healthy controls. Methods: This cross-sectional study included three groups: CD patients who had undergone IC resection (group 1), CD patients with IC involvement but without active inflammation and without resection (group 2), and healthy controls (group 3). Each participant collected a 24-hour urine sample for analysis of oxalate, citrate, and magnesium excretion. Results: A total of 107 participants were enrolled (34 in group 1, 42 in group 2, and 31 in group 3). The prevalence of hyperoxaluria was 26.5% in group 1, 35.7% in group 2, and 29.0% in group 3, with no significant differences between groups (p = 0.664). Hypocitraturia was more common in CD groups: 35.3% in group 1, 31.0% in group 2, compared to 9.7% in controls, with a significant difference from controls (p = 0.034). A significant difference in hypomagnesuria was found in group 1 compared to groups 2 and 3 (p = 0.001). Conclusion: While hyperoxaluria prevalence was similar across groups, hypocitraturia and hypomagnesuria were more frequent in CD patients, particularly those with IC resection. Monitoring these biomarkers may help identify at-risk individuals and guide prevention of urolithiasis in CD.

Background: Immune-mediated extraintestinal manifestations (IM-EIMs) are common in paediatric inflammatory bowel disease (pIBD). This systematic review and meta-analysis aimed to summarise the incidence and prevalence of IM-EIMs in pIBD. Methods: MEDLINE, EMBASE, CENTRAL and clinicaltrials.gov were searched up to May 6, 2024, for studies that included pIBD (2-17 years) patients diagnosed with IM-EIMs. Primary outcomes included the incidence and prevalence of IM-EIMs among pIBD. Meta-analysis included pooled proportions of prevalence with DerSimonian-Laird random-effects analysis. Results: The pooled proportion of IM-EIMs among pIBD overall was 10% (95% CI, 8-12%; I2=97.2%) among 65 studies (35,343 patients). The pooled proportion of IM-EIMs was 10% (95% CI, 7-13%; I2=94.8%) among 37 Crohn’s disease (CD) studies (7657 patients), compared to 11% (95% CI, 7-15%; I2=93.3%) among 39 ulcerative colitis (UC) studies (4698 patients). Enthesitis was the highest reported individual IM-EIM (23%, 95% CI, 4-50%; I2=94.7%) in pIBD. Arthritis was the second highest reported individual IM-EIM (8%, 95% CI, 6-10%; I2=96%) in pIBD, followed by primary sclerosing cholangitis (PSC) in UC (5%, 95% CI, 4-7%; I2=81%). Uveitis, pyoderma gangrenosum, autoimmune hepatitis and PSC in CD were the lowest reported IM-EIMs at 1% or less. The largest difference in proportions between IBD phenotypes was PSC, which was 4% higher in UC than CD. Conclusions: While musculoskeletal manifestations are common, fewer than 5% of pIBD patients experience ophthalmological, dermatological, and liver IM-EIMs. The small number of studies resulted in significant methodological and statistical heterogeneity. Multicentre collaborative efforts are needed to systematically describe the epidemiology of IM-EIMs in pIBD.

Immunometabolism exerts a bimodal action at the interface of extracellular immune response and intracellular metabolism, putting it at the center of many immune-mediated inflammatory disorders (IMIDs). Research has shown that immunometabolic pathways may act as a dual checkpoint for the inflammatory cycle to return the system to homeostasis by inactivating inflammatory pathways and shifting metabolism in favor of regulatory phenotypes. In addition, immunometabolic targets may act in non-immune cells such as epithelial and mesenchymal cells. Therefore, the therapeutic approach to targeting the uniquely robust mechanisms of immunometabolism may ameliorate aspects of IMIDs that remained to be addressed. Several emerging targets, including mitochondrial regulators (eg NLRX1), membrane-bound receptors (eg PLXDC2), and hormonal peptides (eg GLP-1), illustrate the diverse ways immunometabolism can be leveraged therapeutically. Preclinical models of inflammatory bowel disease (IBD) and other IMIDs have highlighted the bimodal immunoregulatory roles of these pathways. Preliminary clinical data support the potential utility of immunometabolic modulation, particularly in combination with existing therapies, to overcome the current therapeutic ceiling in clinical efficacy. Continued research is needed to validate the efficacy, safety, and mechanistic precision of immunometabolic agents across the spectrum of IMIDs.

Most specialist organizations have integrated a young society committee within their structure to support younger members and those still in training. These committees are ideally placed to suit the educational and developmental needs of members, while ensuring sustainability of the organization. This viewpoint explores the evolution, impact, and strategic integration of the Young European Crohn's and Colitis Organization (Y‐ECCO) within ECCO to train and develop future leaders in inflammatory bowel diseases (IBDs). Using comparative insights from other young societies including: EMEUNET in rheumatology, yEFIS in immunology, ESMO young oncologists committee in oncology, and the Young Talent Group within United European Gastroenterology, we highlight best practice examples and underscore the importance of inclusivity and multidisciplinary collaboration in developing and training the IBD expert clinicians and scientists of the future.

Background: Bowel urgency (BU) is reported by over 80% of patients with ulcerative colitis (UC) and 60% of those with Crohn's disease (CD). However, the impact of advanced therapies on BU has not been consistently evaluated. Objectives: To assess the effect of advanced therapies on BU improvement in patients with UC and CD. Methods: This retrospective cohort study included all consecutive patients with confirmed UC or CD who started an advanced therapy with available data regarding BU before and after induction therapy between 2023 and 2024 at two tertiary centers. BU was assessed using the numeric‐rating‐scale urgency score (NRS‐us), with BU defined as NRS‐us ≥ 3. The primary endpoint was BU improvement (NRS‐us ≤ 3 or reduction of at least two points) after the induction phase. Multivariate logistic regression analysis identified factors associated with BU improvement. Results: A total of 159 patients were included (56% male; 65% UC; median age: 36 years (Interquartile range [IQR] 27–25)). TNFα inhibitors were the most frequently used agents (49.6%). At baseline, the median NRS‐us was 7. After induction, 50.9% of patients achieved BU improvement, with a mean reduction of 2.3 ± 2.9 points. BU improvement was significantly associated with clinical remission (false‐discovery‐rate [FDR] = 0.009 in CD and FDR = 0.010 in UC), normalization of fecal calprotectin (FDR = 0.001), CRP (FDR = 0.008), and bowel wall thickness on intestinal ultrasound (FDR = 0.001). No significant differences were observed between therapeutic classes. Conclusion: BU improved in approximately half of IBD patients following induction with advanced therapies. Its improvement correlated with clinical, biochemical, and ultrasound remission, supporting the incorporation of BU assessment into routine clinical monitoring.