BACKGROUND AND AIMS:Extraintestinal manifestations (EIMs) and immune-mediated inflammatory diseases (IMIDs) are common in inflammatory bowel diseases (IBD) and contribute substantially to morbidity. The aim was to evaluate the real-world effectiveness of JAK inhibitors on EIMs/IMIDs. METHODS:This multicenter retrospective study included adults with ulcerative colitis (UC) or Crohn's disease (CD) and one or more EIM/IMID initiating a JAK inhibitor (tofacitinib, upadacitinib, or filgotinib). Baseline was defined as treatment initiation; EIM/IMID and IBD activity were assessed at fixed timepoints using physician global assessment. Response rates are reported as observed, with patients discontinuing for worsening of the manifestation counted as non-responders. Logistic and Cox regression analyses identified factors associated with response and treatment discontinuation. RESULTS:A total of 246 patients were included; 67% had two or more prior advanced therapies. Peripheral spondyloarthritis (SpA) (48%) and axial SpA (43%) were the most prevalent EIMs/IMIDs. Peripheral SpA response rates were 82% post-induction and 74% at month 12; axial SpA response rates were 71% and 59%, respectively. Psoriasis response was observed in 65% post-induction and in 50% at month 12, and hidradenitis suppurativa response in 91% and 78%, respectively. Steroid-free clinical IBD remission was 58% at month 12, and was independently associated with peripheral SpA response (adjusted odds ratio [aOR] 4.2, 95% CI 1.2-14.7). Treatment was discontinued in 31%; factors associated with discontinuation were filgotinib use (adjusted hazard ratio [aHR] 3.0, 95% CI 1.4-6.2) and co-existing axial and peripheral SpA (aHR 2.8, 95% CI 1.5-5.1). CONCLUSIONS:JAK inhibitors were associated with favorable physician-assessed outcomes for EIMs/IMIDs in treatment-experienced IBD patients. Co-existing axial and peripheral SpA was associated with treatment discontinuation, suggesting a more complex phenotype.
BACKGROUND AND AIMS:Intestinal fibrosis involves extracellular matrix stiffening. Piezo1, a mechanosensitive ion channel highly expressed in intestinal epithelial cells (IECs), may sense this change. We investigated whether IEC Piezo1 drives fibrosis and explored the underlying mechanobiological mechanism. METHODS:Dextran sulfate sodium (DSS)-induced fibrosis models, inflammatory bowel disease (IBD) patient samples, and IEC-specific Piezo1 knockout (Piezo1ΔIEC) mice were used. RNA-sequencing, Seahorse assays, and stiffness-gradient hydrogels (1-10 kPa) were applied to assess Piezo1 function, oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS), epithelial-mesenchymal transition (EMT) of IECs, and the anti-fibrosis effect of vitamin C. RESULTS:Piezo1 expression was significantly upregulated in IECs from fibrotic regions of both DSS model mice and IBD patients. IEC Piezo1 deficiency alleviated DSS-induced intestinal fibrosis without substantially altering chronic inflammation or fibroblast activation/proliferation. Piezo1 deficiency suppressed the partial EMT phenotype in IECs, as evidenced by preserved E-cadherin and Claudin-1 expression. RNA-sequencing and functional assays revealed enhanced OXPHOS activity in Piezo1-deficient IECs. In vitro, matrix stiffness of 4 kPa (mimicking fibrotic tissue) activated Piezo1, increased intracellular Ca2+ and ROS accumulation, and induced EMT. Knockout of Piezo1 or treatment with vitamin C prevented these stiffness-induced changes. Oral administration of high-dose vitamin C in vivo reduced intestinal fibrosis and suppressed IEC EMT. CONCLUSIONS:Piezo1 plays a critical role in the sensing of pathological extracellular matrix stiffness in intestinal fibrosis, driving an ROS-EMT axis that promotes disease progression. Targeting Piezo1 or its downstream ROS pathway, for instance with vitamin C, represents a potential therapeutic strategy for intestinal fibrosis.
BACKGROUND:Endoscopic assessment in ulcerative colitis (UC) is critical for clinical decision-making but limited by interobserver variability. AI-powered systems may improve consistency, but dataset heterogeneity has hindered clinical translation. We developed and evaluated a deep learning framework for standardized Mayo Endoscopic Score (MES) prediction across adult and pediatric populations from diverse regions. PATIENTS AND METHODS:Using three multi-institutional datasets, we trained and validated convolutional neural network models to predict MES. The primary dataset (LIMUC; 564 adults, 11 276 images, Turkey) supported model development, with external validation on TMC (308 adults, 7978 images, China) and the Emory Pediatric dataset (EPC; 80 children, 113 images, USA). Two models were developed: UC-Re for binary remission classification (MES 0-1 vs 2-3) and UC-MES for four-class grading (MES 0-3). Imaging artifacts were corrected using inpainting, and Fourier-Spatial Image Harmonization (FSIH) mitigated inter-institutional domain shifts. Performance was evaluated using area under the operating characteristic curve (AUC), F1-score, and quadratic weighted kappa (QWK). RESULTS:UC-Re achieved AUCs of 0.98, 0.95, and 0.98 across LIMUC, TMC, and EPC, with F1-scores of 0.92, 0.87, and 0.93, respectively. UC-MES demonstrated strong ordinal consistency (QWK = 0.81-0.85), comparable to inter-expert agreement (QWK = 0.88). Most misclassifications occurred between adjacent MES categories, reflecting human-like patterns. CONCLUSIONS:This novel AI-based framework predicts MES across geographically diverse adult and pediatric UC datasets. Its strong performance, including comparability to expert gastroenterologists in EPC, supports its potential as a decision-support tool for standardized endoscopic monitoring. However, prospective multicenter validation is warranted prior to routine clinical implementation.
BACKGROUND AND AIMS:Monoclonal antibodies against tumor necrosis factor (anti-TNF) are effective agents in the treatment of moderate-to-severe ulcerative colitis (UC). It is unclear whether such treatment can safely be discontinued without relapse. This study aimed to identify biomarkers to predict which patients can successfully stop anti-TNF treatment, and to increase our understanding of the pathogenesis of relapse after withdrawal and flare on continued therapy. METHODS:We analyzed longitudinal bulk RNA-sequencing data derived from rectal mucosal biopsies from 163 patients in the BIOSTOP study collected at baseline, after 2 years (end of study), and at flares or relapse points. RESULTS:In this cohort, pre-withdrawal transcriptomic profiles did not distinguish patients who later relapsed from those who remained in long-term remission. Longitudinal analysis of patients who relapsed or flared were both characterized by inflammatory gene expression profiles (eg, CXCL9, CXCL10, OSMR, SELE) and changes in cell-type composition typical for active UC (eg, monocytes/macrophages and THY1+ FAP+ PDPN+ activated fibroblasts). Both groups showed enrichment of T-cell-associated transcriptional signatures, including CD8 T-cell-related genes and IL-17-associated pathways. Additionally, both patient groups showed increased expression of targets of alternative therapeutic agents, suggesting potential treatment options for specific patient subgroups. CONCLUSIONS:Our findings provide insights into the inflammatory mechanisms driving relapse after anti-TNF withdrawal and flare on continued treatment. The dataset offers a valuable resource for future research to improve personalized treatment strategies in UC.
BACKGROUND:5-Aminosalicylic acid (5-ASA) remains the first-line therapy for mild-to-moderate ulcerative colitis (UC). Modern treatment goals extend beyond symptom control to include steroid-free remission, endoscopic healing, and biomarker normalization. Real-world evidence on 5-ASA's ability to achieve these targets is limited. This study assessed remission levels and associated factors in Belgian UC patients in clinical remission on 5-ASA. METHODS:This cross-sectional, multicenter, phase 4 study included UC patients in clinical remission (PRO-2 ≤ 1, no rectal bleeding) treated with 5-ASA for ≥6 months. Patients receiving corticosteroids, immunomodulators, or advanced therapies were excluded. Outcomes were complete clinical remission (PRO-2 = 0, no urgency), endoscopic remission (MES ≤ 1, UCEIS ≤ 1), complete endoscopic remission (MES = 0), histological remission (Geboes 0-1), biological remission (fecal calprotectin <150 µg/g), and deep remission (clinical, endoscopic, and histological). Adherence was assessed using MARS-5. RESULTS:In total, 198 patients were enrolled (median age 50 years; 41% female). Treatment was oral 5-ASA only (n = 134, 68%), rectal only (n = 19, 9%), or combination (n = 45, 23%). Biological remission was observed in 78%, endoscopic remission in 87%, complete endoscopic remission in 70%, and histological remission in 80%. Deep remission occurred in 24%, limited by persistent urgency (63%). Adherence was high (median MARS-5: 24). Oral 5-ASA only was significantly associated with endoscopic remission (P < .001). CONCLUSION:In this real-world Belgian cohort, patients in clinical remission on 5-ASA achieved high rates of objective remission, while deep remission was low because of persistent urgency. These findings confirm 5-ASA's continued relevance in mild-to-moderate UC and highlight the importance of addressing residual symptoms despite mucosal healing.
BACKGROUND:The expanding use of biologic and small-molecule therapies for ulcerative colitis (UC) has raised concerns regarding perioperative safety. We conducted a network meta-analysis to compare short-term postoperative complications associated with preoperative exposure to these agents in patients undergoing colorectal surgery. METHODS:We systematically searched PubMed, Web of Science, and the Cochrane Library through September 15, 2025, for cohort studies of adults with UC who were exposed to biologic or small-molecule therapy within 12 weeks prior to surgery. Interventions included biologic therapy, small-molecule therapy, and no biologic or small-molecule therapy (control). The primary outcome was overall postoperative complications at 30 and 90 days. Venous thromboembolism (VTE) was assessed as a key secondary outcome. Random-effects network meta-analysis was performed using risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS:Sixteen retrospective cohort studies involving 3235 patients were included. At 30 days, ustekinumab and tofacitinib were associated with lower overall postoperative complication rates than control (RR: 0.29; 95% CI: 0.09-0.96; and RR: 0.66; 95% CI: 0.46-0.96, respectively). Anti-tumor necrosis factor (TNF) therapy was associated with higher complication rates compared with vedolizumab, ustekinumab, and tofacitinib at 30 days (RR: 1.27; 95% CI: 1.00-1.63; RR: 3.67; 95% CI: 1.12-12.03; and RR: 1.61; 95% CI: 1.14-2.27, respectively). At 90 days, anti-TNF therapy was associated with higher complication rates than control (RR 1.20, 95% CI 1.03-1.40), although the 90-day analysis was based on limited data. VTE rates were similar across treatments at both time points. CONCLUSION:Preoperative ustekinumab and tofacitinib were associated with fewer 30-day postoperative complications than control or anti-TNF therapy, while vedolizumab was associated with fewer complications than anti-TNF therapy. At 90 days, anti-TNF therapy was associated with higher complication rates compared with control. These findings, particularly at 90 days based on limited data, should be interpreted with caution and require confirmation in well-designed prospective studies with rigorous adjustment for confounding factors.
BACKGROUND:Mucosal healing (MH) is associated with improved long-term outcomes in Crohn's disease (CD), but longitudinal pan-enteric data are limited. METHODS:This prospective observational study enrolled adults with CD initiating first-line biologic who were assessed at weeks 0, 14, 26, 52, 78, and 104 using fecal calprotectin (FCP), intestinal ultrasound (IUS), and pan-enteric video capsule endoscopy (VCE). The primary outcome was biologic discontinuation for any reason within 104 weeks. Secondary outcomes included MH (Lewis score < 135 and Eliakim score = 0) and flare-driven biologic discontinuation. Analyses used generalized estimating equations (GEE), Kaplan-Meier, and Cox models. RESULTS:Among 59 patients (median age-30 [23-43] years, male-52.5%, inflammatory phenotype-79.7%), 35 received anti-TNF, 21 vedolizumab, and 3 ustekinumab. Overall, 29 (49.2%) patients discontinued biologics after 39 (28-52) weeks, including 21 (35.6%) flare-driven discontinuations. With non-responder imputation, pan-enteric MH increased from 3.4% to 16.9%, 18.6%, and 32.2% at weeks 14, 52, and 104 (P < .001), consistent on observed-data GEE. Week-14 log-transformed FCP was most strongly associated with week-52 MH (area under the curve 0.804, 95% CI, 0.685-0.923, P = .002, optimal cutoff 172 mcg/g; lagged GEE odds ratio [OR] 0.59, 0.39-0.89, P = .012), whereas same-visit transmural remission (bowel wall thickness ≤ 3mm) showed the strongest association with MH (OR 4.97, 1.91-12.91, P = .001). Week-14 Lewis score ≥ 350 (Hazard ratio [HR] 3.18, 95% CI, 1.16-8.73, P = .025) and perianal disease (HR 3.93, 95% CI, 1.45-10.62, P = .007) were independently associated with flare-driven discontinuation. CONCLUSION:Pan-enteric MH accrues incrementally beyond year 1. Integrated FCP, IUS, and VCE assessments may optimize individualized biologic decisions in CD.
BACKGROUND AND AIMS:The role of residual mesentery after ileocolic resection in Crohn's disease (CD) remains controversial. We conducted a multicenter retrospective study to evaluate the association between postoperative residual ileocolic artery length (RIAL), a surrogate marker of residual mesenteric burden, and endoscopic recurrence (ER) in CD. METHODS:This multicenter retrospective study involved patients with CD who underwent ileocolic resection between January 2019 and December 2024. RIAL was measured using postoperative contrast-enhanced computed tomography. The primary outcome was ER at the first endoscopic assessment. Least absolute shrinkage and selection operator (LASSO) logistic regression was used to identify predictors of ER and to construct a nomogram. Kaplan-Meier and Cox regression analyses were applied to evaluate ER outcome within 36 months after surgery. RESULTS:Among 270 patients, 90 (33.3%) developed ER at the first postoperative endoscopy. LASSO logistic regression and the derived nomogram identified that a longer RIAL was associated with an increased risk of ER. ROC curve analysis identified 32.8 mm as the optimal cutoff of RIAL for predicting ER. Kaplan-Meier curve showed that patients with a RIAL < 32.8 mm had significantly longer ER-free survival (log-rank P < .001). Cox analysis identified an RIAL < 32.8 mm and the postoperative use of biologics were independent protective factors for ER-free survival. CONCLUSIONS:Postoperative ER risk was positively correlated with RIAL in CD. Though these correlative data reveal at a statistical association between ileocolic pedicle division and reduced ER risk, our observational analysis does not prove a causal protective effect of pedicle resection.
BACKGROUND AND AIM:Methotrexate has demonstrated efficacy in Crohn's disease (CD) as monotherapy and is increasingly used in combination therapy. We investigated for the first time the use of methotrexate in a very large cohort of patients with inflammatory bowel disease (IBD) in a real-world setting. METHODS:This was an observational, retrospective, multicenter study including consecutive adult IBD patients treated with methotrexate in monotherapy or combination therapy between January 2015 and December 2022 in 15 French centers. RESULTS:Among the 1115 patients included, 77% had CD and 34.5% had at least one extra-intestinal manifestation (EIM). Regarding prior treatments, 44.0% of patients had been exposed to azathioprine and 75.1% to anti-tumor necrosis factor agents. The primary indication for methotrexate was IBD (81.5%), followed by EIM (rheumatological [11.9%] or dermatological [3.9%]). Methotrexate was prescribed in combination therapy in 90.6% of cases. The most frequent induction and maintenance dose was 15 mg/week (47.5% and 51.1% respectively). The persistence rate of methotrexate was 27.7 months in CD and 22.4 months in ulcerative colitis (UC). For CD, factors associated with persistence were female gender (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.05-1.51) and the presence of EIM (HR 0.71; 95% CI 0.58-0.86), and for UC, the presence of EIM (HR 0.63; 95% CI 0.42-0.94). Among the 344 (31.7%) patients who experienced an adverse event related to methotrexate, nine experienced a serious adverse event. CONCLUSION:The French multicenter MICI-METHO study is the first to provide a comprehensive overview of the real-world use, persistence, and safety of methotrexate in patients with IBD.
BACKGROUND AND AIMS:Postoperative recurrence of Crohn's disease (CD) is common and may occur without symptoms. Ileocolonoscopy is the reference standard for detecting endoscopic recurrence, but its invasiveness limits repeated use. Intestinal ultrasound (IUS) is a non-invasive monitoring tool, although diagnostic criteria and ultrasound modalities vary across studies. We conducted a systematic review and diagnostic test accuracy meta-analysis to evaluate the performance of IUS for detecting postoperative recurrence. METHODS:PubMed/MEDLINE, EMBASE, Scopus, and the Cochrane Library were searched from inception to April 2025. Eligible studies evaluated IUS for postoperative recurrence in CD using ileocolonoscopy as the reference standard. Data were extracted to reconstruct independent 2 × 2 diagnostic tables. The primary synthesis used hierarchical bivariate binomial random-effects models to jointly estimate summary sensitivity and specificity. Heterogeneity was explored through subgroup analyses by ultrasound modality, Doppler use, contrast route, bowel wall thickness threshold, diagnostic definition, data collection period, and recurrence severity. RESULTS:Twelve studies were included in the systematic review and narrative synthesis; 11 provided reconstructable independent 2 × 2 data and were included in the bivariate meta-analysis. IUS showed high summary sensitivity of 87.6% (95% CI, 81.0%-92.1%; P < .001) and good summary specificity of 80.2% (95% CI, 60.6%-91.5%; P < .001). The false negative rate was 12.4% (95% CI, 7.9%-19.0%), the false positive rate was 19.8% (95% CI, 8.5%-39.4%), positive likelihood ratio was 4.436 (95% CI, 2.070-9.505), negative likelihood ratio was 0.154 (95% CI, 0.101-0.236), and diagnostic odds ratio was 28.8 (95% CI, 11.0-75.4). Diagnostic performance was generally consistent across studies, although differences in ultrasound protocols and bowel wall thickness thresholds, most commonly ≥3 or ≥5 mm, appeared to contribute to between-study variability. CONCLUSIONS:IUS shows high sensitivity and good specificity for postoperative recurrence surveillance in CD. Its interpretation should remain linked to ultrasound protocol, threshold, recurrence definition, and clinical context.
BACKGROUND & AIMS:Endoscopic assessment of disease activity in pediatric ulcerative colitis (UC) is invasive and burdensome. Intestinal ultrasound (IUS) represents a promising noninvasive alternative, but comparative data on IUS-based activity indices in children remain limited. This study evaluated the accuracy of 3 IUS activity indices, the Milan Ultrasound Criteria (MUC), the Ulcerative Colitis-Intestinal Ultrasound (UC-IUS) index, and the Civitelli index, for detecting moderate-to-severe endoscopic activity in pediatric UC and explored the added value of fecal calprotectin (FC) and the Pediatric Ulcerative Colitis Activity Index (PUCAI). METHODS:In this prospective bicentric study, 75 pediatric patients with UC underwent IUS within 7 days of colonoscopy. Moderate-to-severe endoscopic activity was defined as Mayo Endoscopic Subscore (MES) ≥ 2. Diagnostic accuracy was assessed using receiver operating characteristic analysis. RESULTS:Moderate-to-severe endoscopic activity was present in 73.3% of patients. All IUS indices significantly discriminated moderate-to-severe from no-to-mild disease (P < .001), with comparable performance (AUC 0.80 [0.68-0.92] for MUC, 0.79 [0.66-0.93] for UC-IUS, and 0.76 [0.62-0.90] for Civitelli). Bowel wall thickness (BWT) alone showed similar accuracy (AUC 0.80 [0.68-0.91]). Models combining IUS indices with FC or PUCAI yielded higher AUC (0.83 and 0.87, respectively), although differences were not statistically significant. Accuracy was highest in severe disease (MES = 3). CONCLUSIONS:MUC, UC-IUS, and Civitelli demonstrated comparable accuracy for detecting moderate-to-severe endoscopic activity in pediatric UC. BWT alone performed similarly to composite indices. Combining IUS with FC or PUCAI may provide modest additional diagnostic value, supporting a multimodal, noninvasive approach for disease monitoring and treat-to-target strategies.
BACKGROUND & AIMS:Inflammatory bowel disease (IBD) is associated with increased mortality, but whether death rates and causes of death have changed across the biologic era is unclear. We aimed to assess all-cause and cause-specific mortality in Crohn's disease (CD) and ulcerative colitis (UC) across therapeutic eras. METHODS:We conducted a retrospective, population-based matched cohort study (1984-2019). IBD cases were matched 1:10 to unaffected controls by age, sex, and geography. Follow-up was stratified into a pre-biologic era (1984-2000) and biologic era (2001-2019). All-cause mortality was assessed using Cox models and cause-specific mortality using competing-risk methods. RESULTS:We identified 13 306 patients with IBD (5955 CD; 7351 UC) and 133 060 matched controls. During follow-up, 2156 patients with IBD (16.2%) and 19 095 controls (14.4%) died. CD was associated with higher all-cause mortality than controls (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.19-1.37). UC mortality did not differ from controls (HR 1.03, 95% CI 0.97-1.10). In era-stratified analyses, mortality was comparable in the pre-biologic era (IBD HR 1.04, 95% CI 0.93-1.15). In the biologic era, excess mortality was observed in CD (HR 1.34, 95% CI 1.24-1.45) but not in UC (HR 1.05, 95% CI 0.98-1.12). Compared with controls, CD had higher mortality from colorectal cancer (HR 2.28), renal disease (HR 2.79), non-Hodgkin lymphoma (HR 1.89), and sepsis (HR 2.12), while UC had higher mortality from colorectal cancer (HR 1.56) and cholangiocarcinoma (HR 3.21). CONCLUSIONS:All-cause mortality was modestly higher in CD, while UC mortality was similar to matched controls. The CD mortality gap appeared most evident with longer follow-up.
This is the second of two articles presenting the European Crohn's and Colitis Organisation [ECCO] evidence‑based consensus guidelines on the management of adult patients with ulcerative colitis [UC]. The first article covers the medical management of UC, including acute severe colitis. The present article addresses the surgical management of medically refractory UC, including the general surgical approach and perioperative optimisation, surgical strategies and techniques, and recommended levels of centre expertise and surgical specialisation. Together, these two articles aim to inform shared decision‑making and to guide clinicians and healthcare professionals involved in the care of patients with UC, drawing on the best available evidence.
BACKGROUND:Extra-intestinal manifestations of inflammatory bowel disease (IBD) are well-recognized, but the long-term risk of developing interstitial lung disease (ILD) in IBD and its impact on mortality remain poorly understood. We aimed to assess the risk of ILD in patients with IBD and the subsequent effect on survival. METHODS:This nationwide cohort study (1978-2022) utilized the Danish National Patient Registry, including 53 591 patients with IBD and 267 955 age- and sex-matched controls. Adjusted hazard ratios (aHRs) were estimated using Cox regression, adjusted for age, sex, education, and Charlson Comorbidity Index (CCI). Cumulative incidence was assessed via the Aalen-Johansen estimator. Mortality in patients with comorbid IBD-ILD was analyzed using Cox regression and Kaplan-Meier curves. RESULTS:The 45-year cumulative incidence of ILD was 2.1% for IBD versus 0.9% for controls (P < .001), and aHR was 2.1 (95% CI, 1.8-2.4). Furthermore, the aHR was 3.0 (95% CI, 2.2-4.1) in patients with frequent IBD-related hospitalizations compared to matched controls. The 5-year mortality in concomitant IBD and ILD was 29.3% (95% CI, 23.3-35.3) compared to 11.9% (95% CI, 9.8-14.0) for matched patients with only IBD. Male sex and higher CCI were independent risk factors for both ILD and mortality (all P < .001). CONCLUSION:IBD is associated with a two-fold increase in ILD risk. Risk factors may include old age, longstanding disease, male sex, and comorbidity. Comorbid IBD-ILD increases mortality substantially compared to only IBD, highlighting the need for clinical awareness and early detection to improve outcomes.
BACKGROUND:Perianal fistulas remain a major complication in Crohn's disease, profoundly impacting quality of life. Although often therapy refractory, strong heterogeneity exists between patients, both in clinical behavior and therapy response. In this study, we aimed to identify biological factors involved in the clinical behavior of perianal fistulas, allowing better stratification. METHODS:Forty-nine patients were included (Crohn's n = 36, cryptoglandular n = 13). Gene expression was analyzed in internal fistula openings and tracts by RNA sequencing. Data were verified using spatial transcriptomics and functionally in human adult organoid cultures. A gene-module score for keratinization activity was calculated and correlated to the Crohn's TOpClass classification as well as to long-term fistula outcomes. RESULTS:Perianal fistulas were associated with the development of stratified squamous epithelium, expressing specific keratins (KRT5, KRT7, and KRT13). In human organoid models, exposing intestinal mucosa to a pro-inflammatory cytokine mixture partially induced similar changes, supporting rectal mucosal redifferentiation in response to perianal wounding. A gene-module score based on the keratinization-associated markers showed a decreasing gradient from cryptoglandular to mild Crohn-related to severe Crohn-related fistula (0.448 vs. -0.125 vs. -0.448, P = .018). Interestingly, the score was also predictive of long-term outcomes: Patients with low keratinization often showed progressive disease (14/20 patients), whereas this was not seen in the high keratinization group (0/16, P < .001). CONCLUSION:We identify an epithelial redifferentiation process characterized by a keratinization-associated gene module as part of the healing process in perianal fistula. The extent of the keratinization not only distinguished Crohn-related from cryptoglandular fistulas but also aligned with disease severity and healing potential.
BACKGROUND AND OBJECTIVE:Perianal fistulas, either of cryptoglandular origin (CgF) or associated with Crohn's disease (CDF), have limited treatment options and pose a tremendous burden for affected patients. We recently showed that the epithelial-mesenchymal transition (EMT) contributes to CDF pathogenesis, but detailed mechanisms need further evaluation. Here, we performed multiomics analysis to gain further molecular insights into fistula pathogenesis. DESIGN:Rectal biopsies, swabs, fistula curettage, and serum samples were derived from patients with either CDF (n = 23) or CgF (n = 17) and analyzed by bulk RNA sequencing, metagenomics, untargeted metabolomics, or multiplex-ELISA, where appropriate. RESULTS:Transcriptomics revealed striking differences in gene expression between rectal mucosa and fistula tract samples. However, the transcriptomes of CDF and CgF were comparable, and genes involved in EMT, inflammation and tumor necrosis factor signaling were prominent in both fistula types. A set of 18 genes was found to be differentially expressed in CDF and CgF and might allow discrimination. The overall microbiome composition within fistula tracts did not differ between CDF and CgF patients, but there was a significant difference in rectal microbiome compositions. On a species level, we detected an enrichment of disease-specific, pathogenic species in the fistula tracts. Of note, Bacteroides ssp., Fusobacterium animalis, and Staphylococcus aureus prevailed within CDF. CONCLUSION:Our data demonstrate only minor differences in the transcriptome and the microbiome between CDF and CgF, but clear differences when compared to rectal mucosa biopsies. Thus, our data suggest that the molecular makeup underlying the pathophysiology of fistulas might be comparable between CDF and CgF.
Immune suppression with advanced biologics or small-molecule therapies is the recommended treatment for Crohn’s Disease (CD). However, biologics do not cure CD, and a significant portion of patients experience flares of disease despite treatment, for reasons that are still largely elusive. We aimed to identify dietary and gut signals during Crohn’s disease (CD) remission that differ from the healthy state to highlight targets that may improve disease control and clearance. We analyzed diet, ileal transcriptomics, microbiomics, and metabolomics across patients with CD in remission, patients with active CD, and non-IBD controls as the reference for healthy signals. 191 subjects were included; 77 CD patients in remission in stable clinical remission for at least three months, with the majority (81%) receiving biologic therapy (Fig. 1A). Non-IBD controls (n = 77) were used as a reference for normal signals. We also compared these groups to data from 37 active, mostly treatment-naïve CD patients at diagnosis, before any IBD-related therapies or dietary guidance. Ileal transcriptomics revealed a significant decrease in genes and pathways associated with adaptive T-cells and innate granulocytes during remission, which was notably deeper than the levels seen in control subjects, impairing host mucosal immune response (Fig. 1B-E). Despite this observed mucosal ileal immune suppression, patients in remission showed an increase in the expression of epithelial antimicrobial pathways and related genes, including DUOX2, along with a rise in genes associated with goblet cells and mucin glycosylation. These signals during remission coincided with a persistent pathogenic gut microbial composition, metabolic alterations, and less healthy dietary habits (Fig. 2), which were characterized by a higher intake of ultra-processed foods and lower consumption of fiber, folate, vitamin C, and vegetables. Greater exposure to ultra-processed foods was significantly associated with more dysbiotic gut signals and negatively correlated with genes enriched for mucin glycosylation, which is essential for maintaining gut barrier homeostasis. Perturbations in dietary, ileal, microbial, and metabolic signatures persist during CD remission despite advanced, effective immune treatments. These findings likely underline the remitting-relapsing nature of CD and suggest that interventions targeting diet, epithelial health, microbial, and metabolic functions may promote deeper, longer-lasting remission states. Conflict of interest: Braun, Tzipi: No conflict of interest Levhar, Nina: No conflict of interest Efroni, Gilat: No conflict of interest Hadar, Rotem: No conflict of interest Jessula Levy, David: No conflict of interest Talan Asher, Adi: No conflict of interest Ungar, Bella: No conflict of interest Picard, Orit: No conflict of interest Yablecovitch, Doron: No conflict of interest 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 Eliakim, Rami: No conflict of interest 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. Amir, Amnon: No conflict of interest Prof. Haberman Ziv, Yael: Grant: ECCO, CCF, ISF, I-Core, Helmsley, ERC, NIH.
The LIR!C trial demonstrated that laparoscopic ileocaecal resection (ICR) is an effective alternative to infliximab therapy (IFX) in patients with uncomplicated ileocaecal Crohn’s disease (CD) failing conventional treatment, with comparable quality-of-life outcomes. [1,2] We aimed to assess the 10-year outcomes of the LIR!C trial, focusing on the long-term therapy-free and clinical remission rates of both interventions. This cohort study included patients from the LIR!C trial, a multicentre randomised controlled trial comparing ICR to IFX treatment in patients with ileal CD. Long-term data were retrospectively collected between February 3 and July 17, 2025, including initiation or switch of CD-related treatments and (re-)resections. Follow-up ranged from trial enrolment to the latest visit with the gastroenterologist or surgeon. Outcomes of interest were (i) therapy-free remission rates, defined as clinical remission without the initiation of CD-related therapy in the ICR group and discontinuation of IFX in the IFX group, and compared between groups using bootstrapping; and (ii) clinical remission rates, defined as the absence of changes in CD-related therapy or the need for additional resection in both groups, and compared between groups using Cox regression. Flexible parametric survival modelling was used to investigate potential age-dependent effect modification of ICR vs IFX for 10-year clinical remission rates. Sufficient follow-up data were available from 66/69 ICR patients and 63/65 IFX patients. The median follow-up time was 11 years (IQR 9–14). The 10-year therapy-free remission rate was 35·8% (95% CI 25·6–50·1) in the ICR group, compared to 13·2% (6.1–23.1) in the IFX group (difference, 22·6% [95% CI 7.8–36.8]; p = 0·004). Although overall 10-year clinical remission rates were similar in the ICR and IFX groups (36·5% vs 28·4%; hazard ratio, 0.79 [95% CI 0.52 to 1.20]; p = 0·27), interaction analyses showed an age-dependent effect of ICR on clinical remission rates (pinteraction sss= 0·020) and a significant treatment benefit with ICR for younger patients. The estimated 10-year clinical remission rates for a 20-year-old patient were 54% with ICR vs 24% with IFX (difference, 30% [7 to 53]), compared to 38% vs 28% for a 30-year-old patient (difference, 10% [–6 to 26]). This study shows superior 10-year therapy-free remission rates with ICR and a greater benefit in terms of sustained clinical remission in younger patients. These findings support early ICR as an attractive treatment option for ileal CD in the early disease course. References: 1.Ponsioen, C.Y., et al., Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: a randomised controlled, open-label, multicentre trial. Lancet Gastroenterol Hepatol, 2017. 2(11): p. 785-792. 2.Stevens, T.W., et al., Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: retrospective long-term follow-up of the LIR!C trial. Lancet Gastroenterol Hepatol, 2020. 5(10): p. 900-907. Conflict of interest: Haanappel, Anouck: No conflict of interest Oldenburg, Lotte: none Ali, Mahsoem: No conflict of interest Bosman, Carolijn: No conflict of interest Buskens, Christianne J.: Grant: C. Buskens has received an unrestricted grant from Boehringer Ingelheim and Roche Personal Fees: C. Buskens has received consultancy fees and/or speaker’s honoraria from Tillotts, Takeda, MSD and Janssen Ponsioen, Cyriel: No conflict of interest D’Haens, Geert: Grant: Pfizer, BMS, Johnson and Johnson, Abbvie, Alimentiv BV, Eli Lilly, Takeda, Prometheus Laboratories Personal Fees: Abbvie, Abivax, Agomab, Alimentiv, Anaptys Bio, AstraZeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Galapagos, Glaxo Smith Kline, Dr Falk Pharma, Pfizer, Johnson and Johnson, Merck, Mirador, Polpharma, Procise Diagnostics, Prometheus Biosciences, Sorriso Pharma, Spyre, Takeda, Ventyx Bemelman, Willem: Other: Speakersfees from Applied 4.9% shares Semiflex bv
