An Expert Consensus to Standardise Definitions, Diagnosis and Treatment Targets for Anti–fibrotic Stricture Therapies in Crohn's Disease

F. Rieder; D. Bettenworth; C. Ma; C. E. Parker; L. A. Williamson; S. A. Nelson; G. van Assche; A. Di Sabatino; Y. Bouhnik; R. W. Stidham; A. Dignass; G. Rogler; S. A. Taylor; J. Stoker; J. Rimola; M. E. Baker; J. G. Fletcher; J. Panes; W. J. Sandborn; B. G. Feagan; V. Jairath


Aliment Pharmacol Ther. 2018;48(3):347-357. 

In This Article

Abstract and Introduction


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.


The lifetime risk of stricture is approximately 50% among patients with Crohn's disease (CD).[1] In addition to causing abdominal pain, distension, bloating and vomiting, evidence suggests that stricturing CD may precede the development of internal penetrating disease with fistula formation.[2,3]

Whilst there has been an unprecedented expansion in CD drug development over the last decade, novel and established treatments are primarily directed towards reducing inflammation.[4,5] Anti–inflammatories may be effective in patients with small bowel strictures;[6] however, they do not specifically target or reverse fibrosis. Most often, stricturing CD is treated with surgical resection.[7] Unfortunately, post–operative disease recurrence and re–stricturing are common.[8] Effective drug therapy to prevent and treat CD–associated strictures is therefore a substantial unmet medical need.

Multiple anti–fibrotic compounds are currently under evaluation for the treatment of liver, skin, kidney, heart and lung disease,[9] with 2 agents approved for use in patients with lung fibrosis (pirfenidone and nintedanib).[10,11] In contrast, there have been no trials of anti–fibrotics in inflammatory bowel diseases (IBD). This lack of progress is potentially attributable to several factors, including heterogeneous disease definitions, diagnostic methods, clinical trial eligibility criteria and endpoints, and treatment targets.[12]

We assembled a global, multidisciplinary panel of experts (the CrOhN's disease anti–fibrotic STRICTure Therapies [CONSTRICT] group) and conducted a three–round consensus process using modified RAND/University of California Los Angeles (UCLA) appropriateness methodology[13,14] with the aim of standardising assessment of CD strictures and treatment targets. Additionally, we developed a conceptual framework for the conduct of early–phase clinical trials of anti–fibrotic agents.