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.
- crohn's disease
Data availability statement
Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
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Contributors Development of the study concept and design: IOG, RKP, DB, BGF, FR. Study supervision: IOG, VJ, RKP, BGF, FR. Systematic review of the literature: DB, AB, FR. Survey respondents: IOG, AS, CR, GDH, MER, MAV, NH, PB, RKP, RKP, RO, RF, FR. Data collection and analysis: LG. Drafting of the manuscript: IOG, DB, LMS, RM, JL, CEP, TN. Funding: FR, BGF, DB, JGF, MB, VJ. All authors performed critical revision of the manuscript for intellectual content and approved the final draft.
Funding All authors approved the final version of the manuscript. This work was supported by grants from the National Institutes of Health (K08DK110415, P30DK097948 and R01DK123233) to FR and the Helmsley Charitable Trust through the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium to FR, BGF and JGF. WJS is supported in part by the NIDDK-funded San Diego Digestive Diseases Research Center (P30 DK120515).
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.
Provenance and peer review Not commissioned; externally peer reviewed.
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