Strictures In Crohn's Disease Research Articles

Radiomics to Detect Inflammation and Fibrosis on Magnetic Resonance Enterography in Stricturing Crohn's Disease.

Non-invasive cross-sectional imaging via magnetic resonance enterography (MRE) offers excellent accuracy for the diagnosis of stricturing complications in Crohn's disease (CD) but is limited in determining the degrees of fibrosis and inflammation within a stricture. We developed and validated a radiomics-based machine-learning model for separately characterizing the degree of histopathologic inflammation and fibrosis in CD strictures and compared it to centrally read visual radiologist scoring of MRE. This single center, cross-sectional study, included 51 CD patients (n=34 for discovery; n=17 for validation) with terminal ileal strictures confirmed on diagnostic MRE within 15 weeks of resection. Histopathological specimens were scored for inflammation and fibrosis and spatially linked with corresponding pre-surgical MRE sequences. Annotated stricture regions on MRE were scored visually by radiologists as well as underwent 3D radiomics-based machine learning analysis; both evaluated against histopathology. Two distinct sets of radiomic features capturing textural heterogeneity within strictures were linked with each of severe inflammation or severe fibrosis across both discovery (area under the curve (AUC)=0.69, 0.83) and validation (AUCs=0.67,0.78) cohorts. Radiologist visual scoring had an AUC=0.67 for identifying severe inflammation and AUC=0.35 for severe fibrosis. Use of combined radiomics and radiologist scoring robustly augmented identification of severe inflammation (AUC=0.79) and modestly improved assessment of severe fibrosis (AUC=0.79 for severe fibrosis) over individual approaches. Radiomic features of CD strictures on MRE can accurately identify severe histopathologic inflammation and severe histopathologic fibrosis, as well as augment performance of radiologist visual scoring in stricture characterization.

Contemporary Imaging Assessment of Strictures and Fibrosis in Crohn Disease, With Focus on Quantitative Biomarkers: From the AJR Special Series on Imaging of Fibrosis.

Patients with Crohn disease commonly have bowel strictures develop, which exhibit varying degrees of inflammation and fibrosis. Differentiation of the distinct inflammatory and fibrotic components of strictures is key for the optimization of therapeutic management and for the development of antifibrotic drugs. Cross-sectional imaging techniques, including ultrasound, CT, and MRI, allow evaluation of the full thickness of the bowel wall as well as extramural complications and associated mesenteric abnormalities. Although promising data have been reported for a range of novel imaging biomarkers for detection of fibrosis and quantification of the degree of fibrosis, these biomarkers lack sufficient validation and standardization for clinical use. Additional methods, including PET with emerging radiotracers, artificial intelligence, and radiomics, are also under investigation for stricture characterization. In this review, we highlight the clinical relevance of identifying fibrosis in Crohn disease, review the histopathologic aspects of strictures in Crohn disease, summarize the morphologic imaging findings of strictures, and explore contemporary developments in the use of cross-sectional imaging techniques for detecting and characterizing intestinal strictures, with attention given to emerging quantitative biomarkers.

P1125 Incidence and Neoplastic Risk Associated with Colonic Stricture in Pediatric-Onset Crohn's Disease: A Population-based Study

Abstract Background The identification of colonic stricture in patients with Crohn's disease (CD) often leads to surgery due to concerns about associated neoplasia. Nevertheless, information regarding the neoplastic risk associated to colonic stricture is still limited. The objective of this study was to assess both the incidence of colonic stricture in pediatric-onset CD and the associated neoplastic risk at the population-based level. Methods All patients diagnosed with CD before age 17 between 1988 and 2011, and included in a population-based registry, were followed until 2013. Colonic stricture was defined as a narrowing of the digestive lumen observed on endoscopic or radiological examination. Excluded were stricture in the ileocaecal valve, anal canal, or low rectum. Univariate risk factors for colonic stricture were explored using Cox proportional hazards models with time-dependent variables, and a multivariable Cox model analysis was performed. Results A total of 1,007 patients diagnosed with CD between 1988 and 2011 were included. Median age at diagnosis was 14.5 years [IQR: 12.0-16.1]. Throughout the follow-up period (median follow-up, 8.8 years [4.6-14.2]), patients were predominantly exposed to 5-aminosalicylates (88.1%), immunosuppressants (70.6%), and biologics (47.9%). Colonic stricture was diagnosed in 52 patients, including 11 at CD diagnosis. The cumulative incidence of colonic stricture in CD was 2.9% [1.8%-4.0%] at 5 years. The overall incidence rate of colonic stricture in CD was 5.4 cases/1000 person-years, 95% CI [4.1-7.1]. In multivariable analysis, an increased risk of colonic stricture was observed during periods of active disease (HR = 2.62, [1.40-4.89], p<0.01). Conversely, the absence of colonic involvement at diagnosis (HR = 0.18, [0.04, 0.80], p<0.05) or treatment with aminosalicylates (HR = 0.39, [0.19-0.79], p<0.05) was associated with a lower risk of colonic stricture. After a median follow-up of 6.4 [2.4-12.7] years, colonic stricture surgical resection was performed in 29 patients (55.8%). Colon adenocarcinoma was detected in one patient (1.9%) within 6 months after the diagnosis of colonic stricture. Conclusion In this population-based study of pediatric-onset Crohn's disease, 52 patients (5%) experienced colonic stricture, with a 2.9% incidence rate observed after 5 years of follow-up. Additionally, one patient (2%) presented with an associated adenocarcinoma.

P771 Comparing obstructive symptoms and dietary restrictions with Crohn's disease stricture severity

Abstract Background Stricturing Crohn’s Disease (CD) is characterized by bowel narrowing often leading to obstruction. Obstructive symptoms (OS) have been evaluated in patients with CD strictures using OS scores (STRIDENT). Clinical observations suggest that OS are generally associated with end-stage strictures requiring dietary restrictions and surgery. Evaluating the prevalence of symptoms in strictures is important as regulatory agencies require symptom response to therapies in trials. Intestinal ultrasound (IUS) accurately assesses CD strictures. IUS criteria for ileal strictures includes: 1) bowel wall thickness (BWT) > 3mm, 2) luminal narrowing, and 3) pre-stenotic dilation (PSD) > 2.5 cm. It remains unclear whether stricture severity is correlated with OS (nausea, vomiting, bloating, abdominal pain). We aim to assess if OS and dietary restrictions occur more often in those with more severe strictures (pre-stenotic dilation size). Methods In this pilot study, prospective ileal CD patients with inflammatory (non-stricture) phenotype versus definitive or probable strictures were surveyed. OS for the past 2 months were queried in patients with definitive (BWT >3mm, luminal narrowing < 1cm, PSD ≥ 2.5cm), and probable strictures (definitive with PSD < 2.5cm) as identified on IUS. OS queried included nausea, vomiting, bloating, abdominal pain, and dietary restrictions. Chi-squared tests for categorical symptoms and one-way ANOVA (Kruskal Wallis) was used to compare symptom prevalence within the non-stricture or stricture category. Results 39 patients were recruited with a median diagnosis age of 23.5 years (range 24-69) with 12 non-stricture phenotype (30.8%), 13 definitive (33.3%), and 14 probable stricture (35.9%). Patients with definitive strictures (35.3%) have significantly more nausea than those without strictures (11.8%) (p = 0.01), and no difference with probable strictures. Nausea with probable strictures (41.2%) was not significantly different from non-stricture patients (11.7%) (p = 0.07). In those with definitive versus non strictures, bloating (53.6 % vs 61.5 %, p = 0.69), post prandial pain (57.6 % vs 25.0 %, p = 0.14), and vomiting (10.0% vs. 20.0%, p = 0.47) were not significantly different. No difference was found in obstructive pain (F=2.27, p=0.12) among all groups. Dietary restrictions occurred in 40% (5/12) without strictures, 43.8% (7/12) with probable strictures, and 69.2% (9/13) with definitive strictures. Conclusion Nausea was the sole indicator distinguishing definitive from probable strictures. Pain, vomiting, and bloating did not differentiate those with severe from probable strictures, possibly due to dietary restrictions. More recruitment will refine these findings and enable comparison with specific IUS parameters.

P750 Endoscopic balloon dilation associated with biological therapy in Crohn's Disease strictures: a single center experience

Abstract Background Symptomatic luminal stricture in Crohn’s Disease (CD) occurs in up to 20% of patients at the diagnosis and in more than 50% during their lifetime. A considerable percentage of patients often require further surgery for post-operative CD recurrence, with a consequent increased burden of short bowel syndrome. In this scenario, combining biological therapy with endoscopic balloon dilation (EBD) could potentially reduce this risk. Our study aimed to evaluate the efficacy of EBD combined with biologic therapy in symptomatic gastrointestinal strictures in CD patients. Methods We conducted a retrospective study including consecutive CD patients who underwent EBD for low gastrointestinal strictures from December 2015 until November 2022 at our tertiary IBD Center. Subsequent subocclusive/occlusive episodes, the need for steroids, and surgery due to CD stenosis were evaluated during a follow-up period of 6 and 12 months. Results A total of 52 patients treated with EBD with an overall number of 55 strictures were included. The mean age was 46,8 (18-77) years. The median of disease duration was 9 (0-42) years. Among the total of 55 studied strictures: 14 (25%) in patients with active smoking, 21 (38%) with increased CRP values at the time of dilation, 43 (78%) had evidence of moderate or severe endoscopic disease activity with ulcerative lesions at stricture site. Anastomotic strictures accounted for 26 (47%) of all 55 strictures. The remaining 29 (53%) were de novo stricture: 8 (15%) ileal, 11 (20%) at ileocecal valve, 4 (7%) colonic, and 6 (11%) anal . Forty-two patients (76%) were under biologic therapy at the time of EBD and 2 (4%) started after EBD. EBD technical success was reported in 60% of the procedures, and no adverse events were recorded. After 6 months from EBD, at univariate analysis, increased CRP at the time of dilation resulted in a risk factor for the need for steroids (OR 14,63, IC 2,690 to 71,50; p-value = 0,0006, Table 2). Concomitant biological therapy, active smoke, and the presence of ulcerative lesions did not show a significant correlation with considered outcomes. After 12 months from EBD, concomitant biological therapy resulted in being a protective factor for surgery (OR 0,06; IC 0,005 to 0,502; p-value=0,0047), while subocclusive and occlusive events were less frequent in anastomotic strictures than ileal stenosis (OR 0,07; IC 0,005 to 0,651; p-value=0,0152). Conclusion In patients with CD undergoing EBD for intestinal CD stricture, concomitant biological therapy reduces the risk of surgery for CD stenosis recurrence. Further prospective and controlled studies are underway to confirm these observations.

P099 Neutrophil extracellular traps enhance profibrotic activity of intestinal fibroblasts in Crohn's disease through TLR2/NF-kB pathway

Abstract Background Neutrophil extracellular traps (NETs) consist of DNA filaments and cytoplasmic protein granules, extruded by neutrophils after PAD4-dependent activation. NETs release occurs early during inflammation in various immune-related diseases, further aggravating tissue injury and contributing to fibrosis. Our aim was to investigate the potential profibrotic effect of NETs in Crohn’s disease (CD). Methods NETs and activated fibroblasts were labelled by multiplex immunofluorescence staining on unaffected, inflamed and fibrotic ileum derived from patients with stricturing CD undergoing ileocaecal resection. Intestinal fibroblasts isolated from unaffected CD ileum were co-cultured with NETs for 24 hours to analyse their transcriptome and quantify collagen released with SIRCOL®. Fibroblast migratory activity was investigated with a scratch test. Immunofluorescence intensity of collagen and fibroblast activation protein (FAP) was quantified using the Operetta® Analysis System. Transfection of fibroblasts with NF-kB-luciferase reporter plasmid was performed to evaluate the TLR2/NF-kB pathway, and a specific TLR2 inhibitor (TL2-C29) tested. Finally, mice with selective deletion of PAD4 in neutrophils (PAD4fl/flMRP8Cre+) were subjected to chronic Dextran Sulphate Sodium (DSS) colitis to assess the role of PAD4-mediated NETosis in intestinal fibrosis development. Results We found spatial tissue distribution of clusters of NETs adjacent to FAP+ fibroblasts in ileal ulcerations in patients with active CD. Transcriptomics demonstrated upregulation of various profibrotic processes in fibroblasts stimulated with NETs, including TGFβ-receptor signalling pathway, positive regulation of collagen metabolic process, and TLR-signalling pathways. This correlated with increased proliferation rate (p<0.0001), slower wound healing capability (p<0.0001) and higher collagen release in the medium (p<0.01) in the NET-treated group, as well as higher expression of collagens and FAP. Among TLR genes, TLR2 was found upregulated after stimulation with NETs (p=0.02). Transfection data showed significant upregulation (p<0.05) of NF-kB in the NETs-treated group, whereas its expression and soluble collagen release decreased with the addition of the TLR2 antagonist TL2-C29. In line, a significantly lower amount of collagen deposition was observed in the colon of PAD4fl/flMRP8Cre+ mice subjected to chronic DSS colitis, as well as modulation of MMP2/TIMP2 balance and reduced fibroblast activation. Conclusion NETs may represent an early trigger of intestinal fibroblast activation via the TLR2/NF-kB axis. As NETs are early players during inflammation, blocking PAD4 may reduce inflammation and thus fibrogenesis in CD.

P243 Multi-modality intestinal ultrasound is accurate and reproducible to distinguish inflammatory from chronic fibrotic strictures in Crohn’s disease – results from the STRICTURE study

Abstract Background In 30%-50% of patients with Crohn’s disease (CD) stenotic complications occur1. There is currently no imaging modality to identify stricture composition, which would allow early targeted (anti-inflammatory vs surgical) treatment. Intestinal ultrasound (IUS) and advanced modalities (contrast-enhanced ultrasound (CEUS) and shear-wave elastography (SWE)) have the potential for transmural disease evaluation. The STRICTURE study investigated whether (advanced) IUS techniques could distinguish between inflammatory- (IP) and non-inflammatory phenotypes (non-IP) of stricturing CD. Methods In this prospective, cross-sectional study consecutive patients with small bowel CD undergoing surgery were included. Patients were eligible if they had a non-passable stricture during endoscopy in the small bowel and/or a stricture at cross-sectional imaging (IUS or MRE)2. Prior to surgery, IUS, CEUS and SWE were performed. Two blinded sonographers scored the cine-loops for IUS and CEUS. After surgery, histological slides were retrieved and location matched with IUS. Two blinded pathologists scored for inflammation, adipocytes and fibrosis. Subsequently the predominant phenotype was determined as: [1] inflammatory (IP; Nancy score 4 with no marked fibrosis/adipocytes), [2] fibrotic (FP; structural changes due to marked fibrosis/adipocytes3) or [3] mixed phenotype (MP; inflammatory and fibrotic aspects but no predominant phenotype). FP and MP were both classified as non-IP. Results A total of 36 patients (age: 42±18 years) with a mean BWT of 6.7±1.7 mm were included. Median time between IUS and surgery was 14 [3-50] days. A total of 7 patients had an IP, 18 a FP and 11 a MP. For the conventional IUS parameters, loss of wall layer stratification (WLS) was more frequently found in IP strictures(OR: 7.87 [1.24-50.00], p=0.029). For CEUS, most parameters were significantly higher in IP versus non-IP (Table 1) and at multi-variable logistic regression Wash-in area under the curve remained the only accurate parameter to distinguish IP from non-IP (OR:1.55 [1.03-2.34], p=0.035) [Figure 1]. SWE inversely correlated with CEUS (Table 1, Figure 1) but did not differentiate between IP and non-IP (33.30 kPa vs 43.49 kPa, p=0.48). The agreement for BWT and loss of WLS was good (ICC: 0.77, p<0.001) and moderate (κ: 0.56, p<0.001), respectively. For CEUS, the most accurate parameters had good to excellent agreement [Table 1]. Conclusion Loss of WLS and CEUS are accurate to distinguish an IP from a non-IP stricture in CD and CEUS inversely correlates with SWE. In addition to accuracy, reproducibility was high and multi-modality IUS could be of additional value in this specific population to select patients most suitable for anti-inflammatory treatment. Table 1 Figure 1

Stricture dilation via balloon-assisted endoscopy in Crohn's disease: approach and intraprocedural outcomes with the single-balloon and double-balloon systems.

Despite recent emerging literature involving the utility of endoscopic balloon dilation (EBD) of strictures via balloon-assisted endoscopy (BAE), specifically regarding the management of Crohn's disease (CD), the optimal clinical approach with balloon systems has been largely neglected in academic literature. This study assesses the intra-procedural success and safety of EBD via BAE for small bowel CD strictures while detailing our clinical approach and technique. Secondarily, we compare the single-balloon endoscope (SBE) and double-balloon endoscope (DBE) systems for EBD-related outcomes. Retrospective consecutive patient cohort analysis. We retrospectively assessed a consecutive small bowel CD patient cohort undergoing BAE at the University of Alberta Hospital endoscopy unit from 2013 to 2020. The primary endpoint discerned the safety and immediate success rate of EBD during endoscopy, and comparisons of the dilation parameters and efficacy of SBE versus DBE were assessed as secondary outcomes. During the study period, 87 patients (44 male) with a mean age of 56 ± 14.7 years underwent 179 endoscopic procedures (92 DBE and 87 SBE). Of 358 strictures encountered, 320 (89.4%) were successfully dilated and traversed. The mean maximum dilation diameter was 15.76 ± 2.10 mm. There were no perforations or major adverse events. EBD via BAE is a safe procedure in small bowel CD with a high intraprocedural success rate. Overall, SBE had a higher success rate in traversing strictures before and after dilation using our technique. This analysis is limited by the retrospective nature of our study and must be balanced against the inherent benefits of the DBE system.

Imaging of Strictures in Crohn's Disease.

Crohn's disease (CD) is a chronic inflammation of the digestive tract, and it frequently affects young patients. It can involve any intestinal segment, even though it frequently affects the distal ileum. Up to 80% of patients with CD present with inflammatory behavior, and 5% to 28% develop stricturing disease. Based on the predominant mechanism causing them, strictures can be categorized as inflammatory, fibrotic, or mixed. Determining the relative amounts of inflammation and fibrosis in a stricture can influence treatment decisions. Imaging is an extremely useful tool in patients with small bowel stricturing CD to confirm the diagnosis and to evaluate disease characteristics, usually using CT or MRI. The aim of this paper is to describe how imaging can evaluate a patient with small bowel CD stricture.

Re-intervention rates and symptom-free survival at 1year after endoscopic versus surgical management of strictures in Crohn's disease: A propensity matched analysis of a prospective inflammatory bowel disease cohort.

Resection for Crohn's disease (CD) related strictures is definitive but carries risk of morbidity, recurrence, and short bowel syndrome. On the contrary, the durability of endotherapy (ET) for CD-related strictures is questionable. Prospective comparative studies are limited. We aimed to prospectively compare the outcomes of ET in CD strictures with a case-matched surgical therapy (ST) cohort. Patients undergoing ET or resection for primary CD strictures (symptomatic, non-traversable, <5cm length, n≤3) between January 2021 and March 2022 in a high-volume tertiary center were compared with regard to recurrent symptoms, escalation of therapy, re-intervention, and re-operation based on propensity matched analysis. Fifty-nine patients [49% ET, 57.6% male, median (years): 34 (15-74)] had ≥12months of follow up. Before propensity matching, cumulative re-intervention rate was significantly higher with ET [34.5% (10/29) vs 3.3% (1/30) ST, P=0.002]. Recurrent symptoms (34.5% vs 26.7%, P=0.42), escalation of medical therapy (27.5% vs 23.3%, P=0.64), and re-operation (7.4% vs 3.1%, P=0.55) were comparable. In propensity matched analysis adjusted for demographics, disease, and stricture characteristics [n=42, 21 each, 62% male, median (years): 32 (15-60)], cumulative probability of re-intervention rates was higher in ET (28.6% vs 4.8%, P=0.042). The cumulative probability of recurrent symptoms (ET: 33.3% vs surgery 33.3%, P=0.93), therapy escalation (ET: 23.8% vs surgery 28.6%, P=0.75), and re-operation (ET: 9.5% vs surgery 4.8%, P=0.57) was similar. ET for CD strictures require higher re-interventions compared with resection although re-operation could be avoided in the majority with comparable symptom free survival at 1year.

Analysis of the risk of future gastrointestinal surgery in Crohn's disease with stricture.

Stricture in patients with Crohn's disease (CD) carries a high risk of CD-related surgery in the course of the disease. The aim of this study was to assess the rate of occurrence of CD-related surgery and to determine baseline risk factors predicting subsequent surgery in this patient group. Patients registered with stricturing CD were included. All baseline and follow-up data were collected retrospectively. Patients attended the clinic for follow-up at week 14 to assess their response to infliximab (IFX). CD-related surgery was the observational endpoint. Univariate and multivariate Cox regression analyses were used. A total of 123 patients with stricturing CD were included in this study. The cumulative risk of CD-related surgery for years 1-5 after diagnosis was 18.0%, 26.7%, 32.6%, 40.7%, and 46.4%, respectively. Prior gastrointestinal (GI) surgery, low body mass index (BMI), and high platelet count might be risk factors for future CD-related surgery. With 97 participants treated by IFX, prior GI surgery and primary non-response (PNR) to IFX correlated with future CD-related surgery. Prior GI surgery, BMI, and platelet counts were related to future CD-related surgery. Patients who were PNR to IFX had a higher risk of CD-related surgery in the future.

Stricturing Crohn's disease: what is the role of endoscopic stenting? A systematic review.

Endoscopic stenting for stricturing Crohn's disease (CD) is an emerging treatment that achieves more persistent dilatation of the stricture over time than endoscopic balloon dilatation (EBD). We aimed to explore the efficacy and safety of stenting for the treatment of CD strictures. A systematic electronic literature search was performed (PROSPERO; no. CRD42022308033). The primary outcomes were technical success, efficacy, complication rate, and the need for further interventions due to reobstruction. The outcomes of partially covered self-expanding metal stents (PCSEMS) with scheduled retrieval after seven days were also analyzed. Eleven eligible studies were included in the review. Overall, 173 patients with CD were included in this study. Mean percentage of technical success was 95% (range, 80%-100%), short-term efficacy was 100% in all studies, and long-term efficacy was 56% (range, 25%-90%). In patients with a scheduled PCSEMS retrieval, the long-term efficacy was 76% (range, 59%-90%), the mean complication rate was 35% (range, 15%-57%), and the major complication rate was 11% (range, 0%-29%). Endoscopic stenting with scheduled PCSEMS retrieval may be considered a feasible second-line treatment for short CD strictures to postpone surgery. However, larger head-to-head prospective studies are needed to understand the role of stenting as an alternative or additional treatment to EBD in CD.

Serial Changes in Intestinal Stenotic Stiffness in Patients with Crohn's Disease Treated with Biologics: A Pilot Study Using Ultrasound Shear Wave Elastography.

Intestinal strictures represent an important serious complication of Crohn's disease. Shear wave elastography is a promising noninvasive ultrasound technique for assessing tissue stiffness. This study aimed to evaluate stiffness in the areas of intestinal stricture in patients with Crohn's disease using shear wave elastography and the changes in stiffness after biologics. We enrolled 21 Crohn's disease patients having intestinal stricture. The patients consisted of 3 groups, which were the infliximab naïve (n = 6) group, the ustekinumab naïve (n = 8), and the bio-switch from infliximab to ustekinumab (n = 7) group. Bowell wall thickness was examined by ultrasound sonography, and the stiffness of Crohn's disease stricture lesions was evaluated using Shear wave speed before and 1 year after anti-tumor necrosis factor-alpha antibody infliximab, anti-interleukin 12/23 antibody ustekinumab, and bio-switch from infliximab to ustekinumab. Bowell wall thickness was significantly improved after infliximab, ustekinumab, and the bio-switch. However, shear wave speed indices only in the ustekinumab group significantly decreased after treatment (P = .028), but not in the other group. Shear wave elastography might be a useful method to evaluate stiffness in the areas of intestinal stricture in patients with Crohn's disease treated with biologics. However, a prospective randomized study evaluating the development of obstruction after biological treatment is needed to validate the study findings.

Stricturing Crohn’s Disease Single-Cell RNA Sequencing Reveals Fibroblast Heterogeneity and Intercellular Interactions

Fibroblasts play a key role in stricture formation in Crohn's disease (CD) but understanding its pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full-thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single-cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation. We performed scRNAseq of 13 fresh full-thickness CD resections containing noninvolved, inflamed nonstrictured, and strictured segments as well as 7 normal non-CD bowel segments. Each segment was separated into mucosa/submucosa or muscularis propria and analyzed separately for a total of 99 tissue samples and 409,001 cells. We validated cadherin-11 (CDH11) as a potential therapeutic target by using whole tissues, isolated intestinal cells, NanoString nCounter, next-generation sequencing, proteomics, and animal models. Our integrated dataset revealed fibroblast heterogeneity in strictured CD with the majority of stricture-selective changes detected in the mucosa/submucosa, but not the muscle layer. Cell-cell interaction modeling revealed CXCL14+ as well as MMP/WNT5A+ fibroblasts displaying a central signaling role in CD strictures. CDH11, a fibroblast cell-cell adhesion molecule, was broadly expressed and up-regulated, and its profibrotic function was validated using NanoString nCounter, RNA sequencing, tissue target expression, invitro gain- and loss-of-function experiments, proteomics, and knock-out and antibody-mediated CDH11 blockade in experimental colitis. A full-thickness bowel scRNAseq atlas revealed previously unrecognized fibroblast heterogeneity and interactions in CD strictures and CDH11 was validated as a potential therapeutic target. These results provide a new resource for a better understanding of CD stricture formation and open potential therapeutic developments. This work has been posted as a preprint on Biorxiv under doi: 10.1101/2023.04.03.534781.

Clinical outcome is distinct between radiological stricture and endoscopic stricture in ileal Crohn's disease.

Differences in clinical adverse outcomes (CAO) based on different intestinal stricturing definitions in Crohn's disease (CD) are poorly documented. This study aims to compare CAO between radiological strictures (RS) and endoscopic strictures (ES) in ileal CD and explore the significance of upstream dilatation in RS. This retrospective double-center study included 199 patients (derivation cohort, n = 157; validation cohort, n = 42) with bowel strictures who simultaneously underwent endoscopic and radiologic examinations. RS was defined as a luminal narrowing with wall thickening relative to the normal gut on cross-sectional imaging (group 1 (G1)), which further divided into G1a (without upstream dilatation) and G1b (with upstream dilatation). ES was defined as an endoscopic non-passable stricture (group 2 (G2)). Strictures met the definitions of RS (with or without upstream dilatation) and ES were categorized as group 3 (G3). CAO referred to stricture-related surgery or penetrating disease. In the derivation cohort, G1b (93.3%) had the highest CAO occurrence rate, followed by G3 (32.6%), G1a (3.2%), and G2 (0%) (p < 0.0001); the same order was found in the validation cohort. The CAO-free survival time was significantly different among the four groups (p < 0.0001). Upstream dilatation (hazard ratio, 1.126) was a risk factor for predicting CAO in RS. Furthermore, when upstream dilatation was added to diagnose RS, 17.6% of high-risk strictures were neglected. CAO differs significantly between RS and ES, and clinicians should pay more attention to strictures in G1b and G3. Upstream dilatation has an important impact on the clinical outcome of RS but may not be an essential factor for RS diagnosis. This study explored the definition of intestinal stricture with the greatest significance for the clinical diagnosis and prognosis of patients with CD, and consequently provided effective auxiliary information for clinicians to formulate strategies for the treatment of CD intestinal strictures. • The retrospective double-center study showed that clinical adverse outcome is different between radiological strictures and endoscopic strictures in CD. • Upstream dilatation has an important impact on the clinical outcome of radiological strictures but may not be an essential factor for diagnosis of radiological strictures. • Radiological stricture with upstream dilatation and simultaneous radiological and endoscopic stricture were at increased risk for clinical adverse outcomes; thus, closer monitoring should be considered.

MRI texture analysis of T2-weighted images is preferred over magnetization transfer imaging for readily longitudinal quantification of gut fibrosis.

To investigate the value of magnetization transfer (MT) MRI and texture analysis (TA) of T2-weighted MR images (T2WI) in the assessment of intestinal fibrosis in a mouse model. Chronic colitis was induced in mice by cyclic administration of dextran sodium sulphate (DSS) resulting in chronic inflammation and progressive bowel fibrosis. Mice underwent 7-T MR imaging at various time points. Bowel wall MT ratio (MTR) and textural features (skewness, kurtosis, entropy), extracted by a filtration histogram technique, were correlated with histopathology. Performance of both techniques were validated using antifibrotic therapy. Finally, a retrospective study was conducted in five patients with Crohn's disease (CD) who underwent bowel surgery. MTR and texture entropy correlated with histopathological fibrosis (r = .85 and .81, respectively). Entropy was superior to MTR for monitoring bowel fibrosis in the presence of coexisting inflammation(linear regressionR2 = .93 versusR2 = .01). Furthermore, texture entropy was able to assess antifibrotic therapy response (placebo mice versus treated mice at endpoint scan;Δmean = 0.128,p < .0001). An increase in entropy was indicative of fibrosis accumulation in human CD strictures (inflammation: 1.29; mixed strictures: 1.4 and 1.48; fibrosis: 1.73 and 1.9). MT imaging and TA of T2WI can both noninvasively detect established intestinal fibrosis in a mouse model. However, TA is especially useful for the longitudinal quantification of fibrosis in mixed inflammatory-fibrotic tissue, as well as for antifibrotic treatment response evaluation. This accessible post-processing technique merits further validation as the benefits for clinical practice as well as antifibrotic trial design would be numerous. • Magnetization transfer MRI and texture analysis of T2-weighted MR images can detect established bowel fibrosis in an animal model of gut fibrosis. • Texture entropy is able to identify and monitor bowel fibrosis progression in an inflammatory context and can assess the response to antifibrotic treatment. • A proof-of-concept study in five patients with Crohn's disease suggests that texture entropy can detect and grade fibrosis in human intestinal strictures.

A107 VISCERAL ADIPOSE TISSUE VOLUME DIFFERENTIATES BETWEEN FIBROSTENOTIC AND INFLAMMATORY CROHN’S DISEASE

Abstract Background Creeping fat, a form of visceral adipose tissue (VAT) that wraps the intestinal wall, influences the formation of Crohn’s disease (CD) strictures. The degree of fat wrapping from intestinal stricture resections is correlated with the extent of chronic inflammation, fibrosis, stricture formation, and response to biologic therapy. VAT and subcutaneous adipose tissue (SAT) ratios from CTE (computed tomography) scans are elevated in CD strictures. However, the definition of strictures in these studies has been poorly defined and not included current well-recognized criteria: 1) bowel wall thickness (BWT), 2) narrowed luminal diameter, and 3) pre-stenotic dilation. (PSD). Purpose The objective of this pilot study was to assess the relationship of 2D and 3D VAT:SAT ratios with CT stricture parameters in patients with terminal ileal (TI) CD strictures. Method 2D VAT:SAT ratios from CT’s of CD patients with TI strictures defined as increased BWT, narrowed luminal diameter (&amp;lt; 50% relative to normal adjacent distended loop), and PSD greater than the stricture diameter were retrospectively obtained from a database and chart review. CT’s from fibrostenotic CD patients were sex and BMI matched to patients with only TI inflammatory behaviour. Patient demographics, medication, smoking, and surgical history were also obtained. Analyses were adjusted for age, sex, and BMI covariates. Unpaired t-tests and multi-variable logistic regression analyses were conducted. Result(s) Twenty-eight patients with stricturing CD had a significantly greater mean VAT:SAT volume ratio than 29 non-stricturing CD (41.5 cm3 vs 34.2 cm3, p=0.03). Thirty-six percent (10/28) of CD stricture patients had prior ileocolic resection with a mean disease duration of 13.5 years (range 0-48). The median ileal BWT (7.0 mm, range 4.0-13.0 mm) for the stricturing group was significantly greater than those with inflammatory behaviour (BWT 2.0 mm, p&amp;lt;0.0001). The median luminal diameter and PSD for the stricture group was 2.0 mm (range 0 - 14.0 mm), and 3.0 cm (range 1.0 - 7.3 cm), respectively. Image Conclusion(s) Fibrostenotic TI CD patients have increased VAT:SAT ratios in comparison to those with only inflammatory behaviour. These pilot VAT:SAT results provide an initial foundation for further studies to assess its predictive role in responsiveness of medical or surgical therapies in stricturing CD. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

A225 QUANTIFICATION OF BONE DENSITY AND DIETARY RISK FACTORS FOR BONE FRAGILITY IN INFLAMMATORY BOWEL DISEASE

Abstract Background Nutrition and bone fracture risk are intimately related in inflammatory bowel disease (IBD). Crohn’s disease (CD) patients are at increased risk of low bone mineral density (BMD) and fractures. This may be due to chronic inflammation, corticosteroid exposure, inadequate consumption of nutrients and minerals such as calcium (ie. lactose intolerance), food aversion, bowel symptoms, and/or possible altered absorption. Fibrostenotic CD is characterized by debilitating strictures where patients are known to alter food intake to avoid obstructive symptoms. However, relationships between food intake patterns and BMD have not been well delineated according to CD phenotypes. Purpose Our study evaluated 1) BMD as measured by dual X-ray absorptiometry (DXA), and 2) energy intake, dietary components and/or micronutrients in CD patients with strictures versus inflammatory (non-stricture) behaviour. Method In this prospective pilot study, patients &amp;gt; 55 years old with ileal CD strictures or inflammatory behavior were recruited from the University of Calgary IBD clinic. All patients completed hip and spine DXA scans and two dietary assessment questionnaires: 1) The Automated Self-Administered 24-hour Dietary Assessment Tool (ASA24) and 2) the Diet History Questionnaire III (DHQ III). Additional data collected included past fracture history, medication (glucocorticoid exposure), smoking, and surgical history. Standard of care laboratory investigations obtained included C-reactive protein, parathyroid hormone, calcium, albumin, and 25-hydroxyvitamin D. Patients with celiac disease, cirrhosis, heart failure, kidney disease, short gut, estrogen use, and dysphagia were excluded. Independent samples t-test and multi-variable regression analyses was conducted. Result(s) Seventeen patients had stricturing and twelve had non-stricturing CD (demographics Table 1). The mean BMD for non-stricturing CD patients was not significantly different from those with a stricturing CD phenotype (p =0.140). Non-stricture patients consumed significantly more dairy, calcium, and phosphate. For all CD patients, there was a positive correlation with BMD and intake of fat (p=0.03), carbohydrates (p=0.01), fiber (p=0.01), and alcohol (p=0.01). There was no statistically significant difference in corticosteroid exposure or smoking status. 74.7% (11/17) patients with stricturing CD had past bowel resection compared to only one patient with non-stricturing CD. Image Conclusion(s) In this pilot study, there was no difference in BMD between CD patients with and without small bowel strictures despite inflammatory behaviour patients having less surgical resections and consuming more calcium rich foods known to improve BMD. Further studies may delineate the dietary differences among CD phenotypes and provide information for interventions for nutrient supplementation, and a greater understanding of their relationships with BMD. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Koopmans Memorial Research Fund Disclosure of Interest None Declared

Approach to Endoscopic Balloon Dilatation in Pediatric Stricturing Crohn Disease: A Position Paper of the Endoscopy Special Interest Group of ESPGHAN.

Crohn disease (CD) is often complicated by bowel strictures that can lead to obstructive symptoms, resistant inflammation, and penetrating complications. Endoscopic balloon dilatation of CD strictures has emerged as a safe and effective technique for relieving these strictures, which may obviate the need for surgical intervention in the short and medium term. This technique appears to be underutilized in pediatric CD. This position paper of the Endoscopy Special Interest Group of European Society for Pediatric Gastroenterology, Hepatology and Nutrition describes the potential applications, appropriate evaluation, practical technique, and management of complications of this important procedure. The aim being to better integrate this therapeutic strategy in pediatric CD management.

DOP85 Crohn's Disease Strictures Respond to Drug Treatment and Treat-to-Target Intense Combination Therapy is More Effective than Standard Anti-TNF Therapy. Two year results of the STRIDENT Randomised Controlled Trial.

Abstract Background The randomised STRIDENT (Stricture Definition and Treatment) trial showed that Crohn’s disease symptomatic strictures are responsive to anti-TNF therapy with most patients clinically improved after 12 months treatment with adalimumab +/- thiopurine. Treat to target intensification resulted in greater stricture morphology improvement. We present here 2 year (from study entry) follow up to assess response durability and risk of surgery. Methods Patients with symptomatic Crohn’s disease strictures and associated inflammation (elevated faecal calprotectin and CRP) were assessed with imaging (intestinal ultrasound and MRI) and ileo-colonoscopy. The Obstructive Symptom Score (OSS) was used for clinical assessment. Patients were randomised 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) followed by 40mg fortnightly plus thiopurine, with adalimumab dose increase at 4 and/or 8 months if evidence of ongoing inflammation, versus standard dose adalimumab monotherapy. The primary endpoint was improved OSS at 12 months. Patient interview was conducted at 24 months, assessing drug treatment, symptoms, need for endoscopic therapy, hospitalisation and surgery. Results In the initial 12 months study 52 patients were randomised to the intensive and 25 to the standard treatment arm. 64/77 (83%) patients recorded an outcome at 12 months (13/77 (17%) withdrawn: 8 surgery, 5 other) 74/77 (96.1%) patients were followed up at a mean of 25.3 (IQR 24.4-26.3) months. Of these, 59 (79.7%) remained on adalimumab, 10 (13.5%) had switched to another biologic and 5 (6.7%) had ceased biologic therapy. For patients who were on adalimumab at 12 months the risk of surgery by 24 months was 15%. Of patients on adalimumab 40mg fortnightly at 12 months, 12/48 (25%) had been dose escalated by 24 months. Endoscopic balloon dilatation, hospitalisation or surgery was required in 6 (8.1%), 14 (18.9%) and 13 (17.5%) respectively; rates were not different between the standard and intensive treatment groups (P = 0.982). Median time to intestinal resection was 12.2 (IQR 6.9-18.6) months. Clinical responders at 12 months, compared to non-responders, had a reduced likelihood of surgery at 24 months (9% vs 42%, P=0.003). Conclusion Clinical response to adalimumab for structuring Crohn’s disease is durable in a majority of patients, with most patients remaining on adalimumab and avoiding surgery at two years. Rates of surgery were not different between the standard and intensive therapy arms. Clinical response to adalimumab at 12 months is an important predictor of future surgical risk.