[en] BACKGROUND: Mucosal healing (MH) is an established treatment goal in inflammatory bowel disease (IBD). However, various definitions of MH exist. We aimed to identify how MH is defined in randomized controlled trials (RCTs) in ulcerative colitis (UC) and Crohn's disease (CD). METHODS: We searched MEDLINE, EMBASE, and the Cochrane library from inception to December 2023 for phase 2 and 3 RCTs of advanced therapies in IBD. RESULTS: One hundred forty-four studies were included, 72 in UC and 72 in CD, published between 1997 and 2023. In UC, 64% (46/72) RCTs reported MH as an endpoint. 12 definitions of MH were found, from endoscopic assessment alone (35/46; 76%) to the more recent combination of histology and endoscopy (10/46; 22%). 96% (44/46) of studies used the Mayo Endoscopic Subscore. In CD, reporting of MH lagged behind UC, with only 12% (9/72) of trials specifically defining MH as an endpoint, 7 as "absence of ulceration," 2 as Simplified Endoscopic Score for CD score ≤2 or 0. Histological assessment was performed in 3 RCTs of CD. Centralized reading of endoscopy was used in 48% (35/72) of RCTs of UC and 22% (16/72) of CD. Only 1 RCT included transmural healing as an endpoint. CONCLUSIONS: A standard definition of MH in IBD is lacking. Definitions have evolved particularly in UC, which now includes the addition of histological evaluation. Transmural healing holds promise as a future target in CD. We support a greater standardization of definitions as we expect endpoints to become increasingly stringent and multimodal with computers automating the assessment.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Parigi, Tommaso Lorenzo; Division of Immunology, Transplantation and Infectious Disease, Università Vita-Salute San Raffaele, Milan, Italy. ; Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy.
Solitano, Virginia; Division of Immunology, Transplantation and Infectious Disease, Università Vita-Salute San Raffaele, Milan, Italy. ; Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada.
Armuzzi, Alessandro; IBD Center, IRCCS Humanitas Research Hospital, Milan, Italy. ; Department of Biomedical Sciences, Humanitas University, Milan, Italy.
Barreiro de Acosta, Manuel ; Gastroenterology Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago, Spain.
Begun, Jake; Faculty of Medicine, Mater Research Institute University of Queensland, Brisbane, Queensland, Australia.
Ben-Horin, Shomron ; Sheba Medical Center, Tel Aviv, Israel.
Biedermann, Luc; Department of Gastroenterology & Hepatology, University Hospital Zurich, Zurich, Switzerland.
Colombel, Jean-Frederic; The Henry Janowitz Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Dignass, Axel; Department of Medicine and Agaplesion Markus Hospital, Goethe University, Frankfurt am Main, Germany.
Fumery, Mathurin; Gastroenterology Department, Centre Hospitalier Universitaire d'Amiens, and PeriTox, Université de Picardie Jules Verne, Amiens, France.
Ghosh, Subrata; University College Cork, Cork, Ireland.
Kobayashi, Taku ; Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
Louis, Edouard ; Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie
Magro, Fernando ; Hospital de Sao Joao, Porto, Portugal.
Panaccione, Remo; Inflammatory Bowel Disease Unit, University of Calgary, Calgary, Alberta, Canada.
Rausch, Astrid; Hospital Britanico de Buenos Aires, Buenos Aires, Argentina.
Reinisch, Walter; Division Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Selinger, Christian ; Leeds Gastroenterology Institute, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Jairath, Vipul ; Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada. ; Alimentiv Inc, London, Ontario, Canada.
Danese, Silvio; Division of Immunology, Transplantation and Infectious Disease, Università Vita-Salute San Raffaele, Milan, Italy. ; Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy.
Peyrin-Biroulet, Laurent ; Department of Gastroenterology, INFINY Institute, FHU-CURE, Nancy University Hospital, and INSERM, Nutrition-Genetics and Environmental Risk Exposure, University of Lorraine, Vandœuvre-lès-Nancy, France.
Cellier C, Sahmoud T, Froguel E, Adenis A, Belaiche J, Bretagne JF, et al. Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn’s disease. A prospective multicentre study of 121 cases. The Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives. Gut. 1994;35(2):231–235. https://doi.org/10.1136/gut.35.2.231
Peyrin-Biroulet L, Sandborn W, Sands BE, Reinisch W, Bemelman W, Bryant RV, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324–1338. https://doi.org/10.1038/ajg.2015.233
Ma C, Hanzel J, Panaccione R, Sandborn WJ, D’Haens GR, Ahuja V, et al. CORE-IBD: a multidisciplinary international consensus initiative to develop a core outcome set for randomized controlled trials in inflammatory bowel disease. Gastroenterology. 2022;163(4):950–964. https://doi.org/10.1053/j.gastro.2022.06.068
Ordás I, Rimola J, Rodríguez S, Paredes JM, Martínez-Pérez MJ, Blanc E, et al. Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn’s disease. Gastroenterology. 2014;146(2):374–382.e1. https://doi.org/10.1053/j.gastro.2013.10.055
Allocca M, Fiorino G, Bonovas S, Furfaro F, Gilardi D, Argollo M, et al. Accuracy of humanitas ultrasound criteria in assessing disease activity and severity in ulcerative colitis: a prospective study. J Crohn’s Colitis. 2018;12(12):1385–1391. https://doi.org/10.1093/ecco-jcc/jjy107
Allocca M, Fiorino G, Bonifacio C, Furfaro F, Gilardi D, Argollo M, et al. Comparative accuracy of bowel ultrasound versus magnetic resonance enterography in combination with colonoscopy in assessing Crohn’s disease and guiding clinical decision-making. J Crohn’s Colitis. 2018;12(11):1280–1287. https://doi.org/10.1093/ecco-jcc/jjy093
Turner D, Ricciuto A, Lewis A, D’Amico F, Dhaliwal J, Griffiths AM, et al. STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the international organization for the study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology. 2021;160(5):1570–1583. https://doi.org/10.1053/j.gastro.2020.12.031
Sedano R, Hogan M, Nguyen TM, Chang J, Zou GY, Macdonald JK, et al. Systematic review and meta-analysis: clinical, endoscopic, histological and safety placebo rates in induction and maintenance trials of ulcerative colitis. J Crohns Colitis. 2022;16(2):224–243. https://doi.org/10.1093/ecco-jcc/jjab135
Almradi A, Sedano R, Hogan M, Zou GY, MacDonald JK, Parker CE, et al. Clinical, endoscopic, and safety placebo rates in induction and maintenance trials of Crohn’s disease: meta-analysis of randomised controlled trials. J Crohns Colitis. 2022;16(5):717–736. https://doi.org/10.1093/ecco-jcc/jjab194
Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353(23):2462–2476. https://doi.org/10.1056/nejmoa050516
Sandborn WJ, Bhandari BR, Randall C, Younes ZH, Romanczyk T, Xin Y, et al. Andecaliximab [Anti-matrix metalloproteinase-9] induction therapy for ulcerative colitis: a randomised, double-blind, placebo-controlled, phase 2/3 study in patients with moderate to severe disease. J Crohns Colitis. 2018;12(9):1021–1029. https://doi.org/10.1093/ecco-jcc/jjy049
Radeke HH, Stein J, Van Assche G, Rogler G, Lakatos PL, Muellershausen F, et al. A multicentre, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of the S1P receptor agonist KRP203 in patients with moderately active refractory ulcerative colitis. Inflamm Intest Dis. 2020;5(4):180–190. https://doi.org/10.1159/000509393
Reinisch W, Gottlieb K, Colombel JF, Danese S, Panaccione R, Panes J, et al. Comparison of the EMA and FDA guidelines on ulcerative colitis drug development. Clin Gastroenterol Hepatol. 2019;17(9):1673–1679.e1. https://doi.org/10.1016/j.cgh.2018.10.032
U Colitis: Clinical trial endpoints guidance for Industry. 2016;
Vermeire S, Sands BE, Tilg H, Tulassay Z, Kempinski R, Danese S, et al. ABX464 (obefazimod) for moderate-to-severe, active ulcerative colitis: a phase 2b, double-blind, randomised, placebo-controlled induction trial and 48 week, open-label extension. Lancet Gastroenterol & Hepatol. 2022;7(11):1024–1035. https://doi.org/10.1016/s2468-1253(22)00233-3
Danese S, Vermeire S, Zhou W, Pangan AL, Siffledeen J, Greenbloom S, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022;399(10341):2113–2128. https://doi.org/10.1016/s0140-6736(22)00581-5
Feagan BG, Sands BE, Sandborn WJ, Germinaro M, Vetter M, Shao J, et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol. 2023;8(4):307–320. https://doi.org/10.1016/s2468-1253(22)00427-7
Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946–1960. https://doi.org/10.1056/nejmoa1602773
Sandborn WJ, Feagan BG, Wolf DC, D’Haens G, Vermeire S, Hanauer SB, et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016;374(18):1754–1762. https://doi.org/10.1056/nejmoa1513248
Sandborn WJ, Feagan BG, D’Haens G, Wolf DC, Jovanovic I, Hanauer SB, et al. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385(14):1280–1291. https://doi.org/10.1056/nejmoa2033617
Vermeire S, Danese S, Sandborn WJ, Schreiber S, Hanauer S, D’Haens G, et al. Efficacy and safety of the anti-mucosal addressin cell adhesion molecule-1 antibody ontamalimab in patients with moderate-to-severe ulcerative colitis or Crohn’s disease. J Crohns Colitis. 2023:jjad199.
Vermeire S, Sandborn WJ, Danese S, Hébuterne X, Salzberg BA, Klopocka M, et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10090):135–144. https://doi.org/10.1016/s0140-6736(17)30930-3
Rutgeerts P, Diamond RH, Bala M, Olson A, Lichtenstein GR, Bao W, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc. 2006;63(3):433–442. https://doi.org/10.1016/j.gie.2005.08.011
Feagan BG, Sandborn WJ, D’Haens G, Panés J, Kaser A, Ferrante M, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2017;389(10080):1699–1709. https://doi.org/10.1016/s0140-6736(17)30570-6
Ferrante M, Colombel J, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, et al. Validation of endoscopic activity scores in patients with Crohn’s disease based on a post hoc analysis of data from SONIC. Gastroenterology. 2013;145(5):978–986.e5. https://doi.org/10.1053/j.gastro.2013.08.010
Research C for DE. Crohn’s disease: developing drugs for treatment [internet]. FDA; 2022. [cited 2024 Mar 13]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/crohns-disease-developing-drugs-treatment
Vermeire S, D’Haens G, Baert F, Danese S, Kobayashi T, Loftus EV, et al. Efficacy and safety of subcutaneous vedolizumab in patients with moderately to severely active Crohn’s disease: results from the VISIBLE 2 randomised trial. J Crohns Colitis. 2022;16(1):27–38. https://doi.org/10.1093/ecco-jcc/jjab133
Sandborn WJ, Feagan BG, Loftus EV, Peyrin-Biroulet L, Van Assche G, D’Haens G, et al. Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn’s disease. Gastroenterology. 2020;158(8):2123–2138.e8. https://doi.org/10.1053/j.gastro.2020.01.047
Sands BE, Feagan BG, Sandborn WJ, Schreiber S, Peyrin-Biroulet L, Frédéric Colombel J, et al. Mongersen (GED-0301) for active Crohn’s disease: results of a phase 3 study. Am J Gastroenterol. 2020;115(5):738–745. https://doi.org/10.14309/ajg.0000000000000493
Rutgeerts P, Van Assche G, Sandborn WJ, Wolf DC, Geboes K, Colombel JF, et al. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology. 2012;142(5):1102–1111.e2. https://doi.org/10.1053/j.gastro.2012.01.035
Allez M, Sands BE, Feagan BG, D’Haens G, De Hertogh G, Randall CW, et al. A phase 2b, randomised, double-blind, placebo-controlled, parallel-arm, multicenter study evaluating the safety and efficacy of tesnatilimab in patients with moderately to severely active Crohn’s disease. J Crohn’s Colitis. 2023;17(8):1235–1251. https://doi.org/10.1093/ecco-jcc/jjad047
D’haens G, Van Deventer S, Van Hogezand R, Chalmers D, Kothe C, Baert F, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology. 1999;116(5):1029–1034. https://doi.org/10.1016/s0016-5085(99)70005-3
Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, et al. Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med. 2004;351(20):2069–2079. https://doi.org/10.1056/nejmoa033402
Guideline on the development of new medicinal products for the treatment of Ulcerative Colitis.
Feagan BG, Sandborn WJ, D’Haens G, Pola S, McDonald JWD, Rutgeerts P, et al. The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis. Gastroenterology. 2013;145(1):149–157.e2. https://doi.org/10.1053/j.gastro.2013.03.025
Yoshimura N, Watanabe M, Motoya S, Tominaga K, Matsuoka K, Iwakiri R, et al. Safety and efficacy of AJM300, an oral antagonist of α4 integrin, in induction therapy for patients with active ulcerative colitis. Gastroenterology. 2015;149(7):1775–1783.e2. https://doi.org/10.1053/j.gastro.2015.08.044
Reinisch W, Pradhan V, Ahmad S, Zhang Z, Gale JD. Alternative endoscopy reading paradigms determine score reliability and effect size in ulcerative colitis. J Crohn’s Colitis. 2024;18(1):82–90. https://doi.org/10.1093/ecco-jcc/jjad134
D’Haens GR, Lee S, Taylor SA, Serone A, Rimola J, Colombel JF, et al. Filgotinib for the treatment of small bowel Crohn’s disease: the DIVERGENCE 1 trial. Gastroenterology. 2023;165(1):289–292.e3. https://doi.org/10.1053/j.gastro.2023.03.234
Ungaro RC, Yzet C, Bossuyt P, Baert FJ, Vanasek T, D’Haens GR, et al. Deep remission at 1 Year prevents progression of early Crohn’s disease. Gastroenterology. 2020;159(1):139–147. https://doi.org/10.1053/j.gastro.2020.03.039
Yzet C, Diouf M, Le Mouel JP, Brazier F, Turpin J, Loreau J, et al. Complete endoscopic healing associated with better outcomes than partial endoscopic healing in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2020;18(10):2256–2261. https://doi.org/10.1016/j.cgh.2019.11.025
FDA. Ulcerative colitis: developing drugs for treatment. Guid Industry [Internet]. 2022. https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
Gupta A, Yu A, Peyrin-Biroulet L, Ananthakrishnan AN. Treat to target: the role of histologic healing in inflammatory bowel diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2021;19(9):1800–1813.e4. https://doi.org/10.1016/j.cgh.2020.09.046
Neurath MF, Vieth M. Different levels of healing in inflammatory bowel diseases: mucosal, histological, transmural, barrier and complete healing. Gut. 2023;72(11):2164–2183. https://doi.org/10.1136/gutjnl-2023-329964
Magro F, Sabino J, Rosini F, Tripathi M, Borralho P, Baldin P, et al. ECCO position on harmonisation of Crohn’s disease mucosal histopathology. J Crohns Colitis. 2022;16(6):876–883. https://doi.org/10.1093/ecco-jcc/jjac006
Rimola J, Colombel JF, Bressler B, Adsul S, Siegelman J, Cole PE, et al. Magnetic resonance enterography assessment of transmural healing with vedolizumab in moderate to severe Crohn’s disease: feasibility in the VERSIFY phase 3 clinical trial. Clin Exp Gastroenterol. 2024;17:9–23. https://doi.org/10.2147/ceg.s429039
Kucharzik T, Wilkens R, D’Agostino MA, Maconi G, Le Bars M, Lahaye M, et al. Early ultrasound response and progressive transmural remission after treatment with ustekinumab in Crohn’s disease. Clin Gastroenterol Hepatol. 2023;21(1):153–163.e12. https://doi.org/10.1016/j.cgh.2022.05.055
D’Amico F, Magro F, Siegmund B, Kobayashi T, Kotze PG, Solitano V, et al. Disease clearance as a new outcome in ulcerative colitis: a systematic review and expert consensus. Inflamm Bowel Dis. 2023:izad159.
Iacucci M, Smith SCL, Bazarova A, Shivaji UN, Bhandari P, Cannatelli R, et al. An international multicenter real-life prospective study of electronic chromoendoscopy score PICaSSO in ulcerative colitis. Gastroenterology. 2021;160(5):1558–1569.e8. https://doi.org/10.1053/j.gastro.2020.12.024
Nardone OM, Bazarova A, Bhandari P, Cannatelli R, Daperno M, Ferraz J, et al. PICaSSO virtual electronic chromendoscopy accurately reflects combined endoscopic and histological assessment for prediction of clinical outcomes in ulcerative colitis. United Eur Gastroenterol J. 2022;10(2):147–159. https://doi.org/10.1002/ueg2.12185
Rath T, Atreya R, Bodenschatz J, Uter W, Geppert CE, Vitali F, et al. Intestinal barrier healing is superior to endoscopic and histologic remission for predicting major adverse outcomes in inflammatory bowel disease: the prospective ERIca trial. Gastroenterology. 2022;164(2):241–255. [cited 2022 Dec 27]. https://doi.org/10.1053/j.gastro.2022.10.014
Takenaka K, Fujii T, Kawamoto A, Suzuki K, Shimizu H, Maeyashiki C, et al. Deep neural network for video colonoscopy of ulcerative colitis: a cross-sectional study. Lancet Gastroenterol Hepatol. 2021;29(21):S2468.
Iacucci M, Cannatelli R, Parigi TL, Nardone OM, Tontini GE, Labarile N, et al. A virtual chromoendoscopy artificial intelligence system to detect endoscopic and histologic activity/remission and predict clinical outcomes in ulcerative colitis. Endoscopy. 2023;55(4):332–341. https://doi.org/10.1055/a-1960-3645
Iacucci M, Parigi TL, Del Amor R, Meseguer P, Mandelli G, Bozzola A, et al. Artificial intelligence enabled histological prediction of remission or activity and clinical outcomes in ulcerative colitis. Gastroenterology. 2023;164(7):1180–1188.e2. https://doi.org/10.1053/j.gastro.2023.02.031
Stidham RW, Cai L, Cheng S, Rajaei F, Hiatt T, Wittrup E, et al. Using computer vision to improve endoscopic disease quantification in therapeutic clinical trials of ulcerative colitis. Gastroenterology. 2023;166(1):155–167.e2. [cited 2023 Oct 14]. https://doi.org/10.1053/j.gastro.2023.09.049
Nardone OM, Iacucci M, Villanacci V, Peyrin-Biroulet L, Ghosh S, Danese S, et al. Real-world uptake of standard indices in the reporting of endoscopy and histology of ulcerative colitis: results of a global survey. United Eur Gastroenterol J. 2023;11(6):514–519. in press. https://doi.org/10.1002/ueg2.12423
Argmann C, Hou R, Ungaro RC, Irizar H, Al-Taie Z, Huang R, et al. Biopsy and blood-based molecular biomarker of inflammation in IBD. Gut. 2023;72(7):1271–1287. https://doi.org/10.1136/gutjnl-2021-326451
Alsoud D, Ho J, Verstockt B. The serum-based endoscopic healing index can monitor therapeutic response in Crohn’s disease. J Crohn’s Colitis. 2023;17(10):1703–1704. https://doi.org/10.1093/ecco-jcc/jjad077
Li X, Liang D, Meng J, Zhou J, Chen Z, Huang S, et al. Development and validation of a novel computed-tomography enterography radiomic approach for characterization of intestinal fibrosis in Crohn’s disease. Gastroenterology. 2021;160(7):2303–2316.e11. https://doi.org/10.1053/j.gastro.2021.02.027
Carter D, Albshesh A, Shimon C, Segal B, Yershov A, Kopylov U, et al. Automatized detection of Crohn’s disease in intestinal ultrasound using convolutional neural network. Inflamm Bowel Dis. 2023;29(12):1901–1906. https://doi.org/10.1093/ibd/izad014
