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Background and Aims: Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures., Methods: We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal)., Results: Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties., Conclusions: There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn's disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion., Design: Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures., Results: In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials., Conclusion: Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development., Competing Interests: Competing interests: IOG receives grant support from UCB, Celgene, Morphic and Pliant Therapeutics. DB is on the advisory board or consultant for Amgen, AbbVie, Celltrion, Dr Falk Foundation, Ferring, MSD, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts Pharma and Vifor. GdH reports fees to his institution (KULeuven) for his participation as a central pathology reviewer in clinical trials sponsored by GlaxoSmithKline, Shire Pharmaceuticals, Teva Pharma, Galapagos, Genentech, Novartis Pharma, Fast Forward Pharmaceuticals, Takeda and Janssen R&D. MR reports Merck, speaker panel; Bayer, pathologist on a clinical trial; Chief Scientific Officer of Beyond Celiac, a non-profit patient support organisation, outside of the submitted work. NH is a consultant for AbbVie, BMS, Celgene and Lilly USA. PB reports personal fees from MSD, personal fees from Roche and personal fees from AstraZeneca, outside the submitted work. RiKP has received consulting fees from Genentech, Eli Lilly, Allergan, AbbVie and Alimentiv. RF is a central reader for Alimentiv (formerly Robarts Clinical Trials) and received speaker’s fees in 2020 from Takeda. CEP, LG, LMS and TN are employees of Alimentiv. WJS reports research grants from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, Theravance Biopharma; consulting fees from AbbVie, Abivax, Admirx, Alfasigma, Alimentiv (formerly Robarts Clinical Trials), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Meyers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, Zealand Pharma; and stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences, Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Biosciences. Spouse: Iveric Bio—consultant, stock options; Progenity—stock; Oppilan Pharma—consultant, stock options; Prometheus Biosciences—employee, stock, stock options; Ventyx Biosciences—stock, stock options; Vimalan Biosciences—stock, stock options. VJ receives salary support from the John and Susan McDonald Endowed IBD Chair at Western University, London, Ontario, Canada; has received has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genetech, Pendopharm, Pfizer, Fresenius Kabi, Bristol Myers Squibb, Roche, Ferring, Sandoz, Merck, Takeda, Janssen, Alimentiv (formerly Robarts Clinical Trials), Topivert, Celltrion, Mylan, Gilead; speaker’s fees from Takeda, Janssen, Shire, Ferring, AbbVie, Pfizer. MB receives no direct support. Cleveland Clinic receives support for him from Siemens Healthineers in the form of salary, software and hardware for the investigation of reduced exposure in CT Enterography, as well as from The Leona and Harry Helmsley Charitable Trust and from Pfizer grants through the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium in the form of salary. DHB is a consultant for and receives research support from Medtronics, and receives research support from Takeda. JGF receives research funding support from grants from Siemens Healthineers, Helmsley Charitable Trust through the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium, Takeda Pharmaceuticals and National Institutes of Health (R01 EB017095, U24 EB28936, R01 DK120559). Funds from all grants are paid to Mayo Clinic. He is a consultant for Takeda Pharmaceuticals, Medtronic, Janssen, Pfizer, GlaxoSmithKline and Boheringer-Ingelheim, with fees paid to institution. BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix and Wyeth Pharmaceuticals; consulting fees from Millennium Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, AstraZeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging, Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma and Sigmoid Pharma; and speakers bureaux fees from UCB, AbbVie and J&J/Janssen. FR is on the advisory board or consultant for Agomab, Allergan, AbbVie, Boehringer-Ingelheim, Celgene/BMS, CDISC, Cowen, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Index Pharma, Janssen, Koutif, Mestag, Metacrine, Morphic, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Surrozen, Takeda, Techlab, Theravance, Thetis, UCB. AB, CR, JI, ReKP, LMS, MAV, RF, RO and RM report no conflicts of interest., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Evidence for endoscopic balloon dilation of small intestinal strictures in Crohn's disease (CD) using balloon-assisted enteroscopy is scarce., Aim: To evaluate endoscopic balloon dilation for the treatment of small intestinal CD strictures using balloon-assisted enteroscopy., Methods: Citations in Embase, MEDLINE, and Cochrane were systematically reviewed. In a meta-analysis of 18 studies with 463 patients and 1189 endoscopic balloon dilations, technical success was defined as the ability to dilate a stricture. Individual data were also obtained on 218 patients to identify outcome-relevant risk factors., Results: In the pooled per-study analysis, technical success rate of endoscopic balloon dilation was 94.9%, resulting in short-term clinical efficacy in 82.3% of patients. Major complications occurred in 5.3% of patients. During follow-up, 48.3% of patients reported symptom recurrence, 38.8% were re-dilated and 27.4% proceeded to surgery. On the per-patient-based multivariable analysis, that patients with disease activity in the small intestine had lower short-term clinical efficacy (odds ratio 0.32; 95% confidence interval 0.14-0.73, P = 0.007). Patients with concomitant active disease in the small and/or large intestine had an increased risk to proceed toward surgery (hazard ratio 1.85; 95% confidence interval 1.09-3.13, P = 0.02 and hazard ratio 1.77; 95% confidence interval 1.34-2.34, P < 0.001)., Conclusions: Balloon-assisted enteroscopy for dilatation of CD-associated small intestinal strictures has high short-term technical and clinical efficacy and low complication rates. However, up to two-thirds of patients need re-dilation or surgery., (© 2020 John Wiley & Sons Ltd.)

Patients with Crohn's disease commonly develop ileal and less commonly colonic strictures, containing various degrees of inflammation and fibrosis. While predominantly inflammatory strictures may benefit from a medical anti-inflammatory treatment, predominantly fibrotic strictures currently require endoscopic balloon dilation or surgery. Therefore, differentiation of the main components of a stricturing lesion is key for defining the therapeutic management. The role of endoscopy to diagnose the nature of strictures is limited by the superficial inspection of the intestinal mucosa, the lack of depth of mucosal biopsies and by the risk of sampling error due to a heterogeneous distribution of inflammation and fibrosis within a stricturing lesion. These limitations may be in part overcome by cross-sectional imaging techniques such as ultrasound, CT and MRI, allowing for a full thickness evaluation of the bowel wall and associated abnormalities. This systematic literature review provides a comprehensive summary of currently used radiologic definitions of strictures. It discusses, by assessing only manuscripts with histopathology as a gold standard, the accuracy for diagnosis of the respective modalities as well as their capability to characterise strictures in terms of inflammation and fibrosis. Definitions for strictures on cross-sectional imaging are heterogeneous; however, accuracy for stricture diagnosis is very high. Although conventional cross-sectional imaging techniques have been reported to distinguish inflammation from fibrosis and grade their severity, they are not sufficiently accurate for use in routine clinical practice. Finally, we present recent consensus recommendations and highlight experimental techniques that may overcome the limitations of current technologies., Competing Interests: Competing interests: DB is on the advisory board or consultant for AbbVie, Dr Falk Foundation, Ferring, MSD, Pharmacosmos, Roche, Takeda, Tillotts Pharma and Vifor. MB receives support from Siemens Healthineers in the form of salary support, hardware and software for investigating the effect of lower exposure CT in detecting active Crohn’s disease. CEP is an employee of Robarts Clinical Trials. JP has received consultancy fees from AbbVie, Arena, Boehringer Ingelheim, Galapagos, Genentech, Janssen, MSD, Novartis, Pfizer, Robarts, Second Genome, Takeda, Theravance, TiGenix and Topivert. JR is on the advisory board or consultant for Robarts Clinical Trials, Takeda and TiGenix and received research grant from AbbVie and Genentech. JGF receives grants to his institution from Siemens Healthineers and Medtronic. VJ receives salary support from the John and Susan McDonald Endowed IBD Chair at Western University, London, Ontario, Canada; consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genentech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert and Celltrion; speaker fees from Takeda, Janssen, Shire, Ferring, AbbVie and Pfizer. BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma, AbbVie, Novartis Pharmaceuticals, Centocor, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix and Wyeth Pharmaceuticals; consulting fees from Millennium Pharmaceuticals, Merck, Centocor, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, AstraZeneca, Serono, Genentech, Tillotts Pharma, Unity Pharmaceuticals, Albireo Pharma, Given Imaging, Salix Pharmaceuticals, Novonordisk, GSK, ActoGenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma and Sigmoid Pharma; and speaker’s bureau fees from UCB, AbbVie and J&J/Janssen. FR is on the advisory board or consultant for AbbVie, Allergan, Celgene, Gossamer, Receptos, Thetis, UCB, Samsung, Pliant, Boehringer Ingelheim, Metacrine, Takeda, Allergan, Helmsley, RedX and Roche. RM has no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti-fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD., Aim: To standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Chron's disease., Methods: An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting., Results: Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre-stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post-prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24-48 weeks is considered the appropriate endpoint in pharmacological trials., Conclusions: Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design., (© 2018 John Wiley & Sons Ltd.)

This ECCO topical review of the European Crohn's and Colitis Organisation [ECCO] focused on prediction, diagnosis, and management of fibrostenosing Crohn's disease [CD]. The objective was to achieve evidence-supported, expert consensus that provides guidance for clinical practice., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Crohn's disease (CD) is a chronic remittent idiopathic disease. Although the early phase of the disease is commonly characterized by inflammation-driven symptoms, such as diarrhea, the frequency of fibrostenotic complications in patients with CD increases over the long-term course of the disease. This review presents the current diagnostic options for assessing CD-associated strictures. In addition to the endoscopic evaluation of CD strictures, this review summarizes the currently available imaging modalities, including ultrasound and cross-sectional imaging techniques. In addition to stricture detection, differentiating between the primarily inflammatory strictures and the predominantly fibrotic ones is essential for selecting the appropriate treatment strategy (anti-inflammatory medical treatment vs endoscopical or surgical approaches). Therefore, recent imaging advances, such as contrast-enhanced ultrasound and ultrasound elastography, contribute to the development of non-invasive non-radiating imaging of CD-associated strictures. Finally, novel magnetic resonance imaging techniques, such as diffusion-weighted, motility and magnetization transfer imaging, as well as (18)F-FDG PET/CT, molecular imaging approaches and biomarkers, are critically reviewed with regard to their potential role in assessing stricturing CD.

Intestinal fibrosis is a common feature of Crohn's disease and may appear as a stricture, stenosis, or intestinal obstruction. Fibrostenosing Crohn's disease leads to a significantly impaired quality of life in affected patients and constitutes a challenging treatment situation. In the absence of specific medical antifibrotic treatment options, endoscopic or surgical therapy approaches with their potential harmful side effects are frequently used. However, our understanding of mechanisms of fibrogenesis in general and specifically intestinal fibrosis has emerged. Progression of fibrosis in the liver, lung, or skin can be halted or even reversed, and possible treatment targets have been identified. In face of this observation and given the fact that fibrotic alterations in various organs of the human body share distinct core characteristics, this article aims to address whether reversibility of intestinal fibrosis may be conceivable and to highlight promising research avenues and therapies.