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

Disclosures

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

In This Article

Discussion

Management of small bowel strictures associated with CD is a challenging clinical problem.[1] Accordingly, there is an urgent need to develop targeted anti–fibrotic therapies. Drug development has been hampered by the lack of well–defined diagnostic modalities, eligibility criteria and endpoints.[12] Furthermore, disagreement surrounding stricture definition, clinical symptoms and what constitutes improvement has led to heterogeneous studies and clinical practices.[1,18,32–34]

Despite the availability of several indices to measure intestinal stenosis and corresponding symptoms,[6,18,35,36] descriptors are not consistently applied (particularly within the context of treatment response), and none of these instruments are fully validated. There is also lack of clarity on preparation and recording of cross–sectional imaging procedures.

The CONSTRICT consensus is an initial step towards establishing valid stricture definitions, diagnostic modalities, eligibility criteria and endpoints for use in CD trials and clinical care. We compiled a comprehensive list of items based on a systematic literature review and expert opinion to assess appropriateness using modified RAND/UCLA methodology. This approach combines the best available evidence with personal clinical experience of international experts and is widely accepted.

Based on the appropriateness rating results, The CONSTRICT group devised detailed recommendations for defining small bowel strictures in CD, including specific radiologic and endoscopic features indicative of stricture, and what constitutes therapeutic improvement. Key definitions are summarised in Table 1. Naïve and anastomotic strictures were discussed separately, which revealed differences in the appropriateness criteria for bowel wall thickness. This is possibly explained by post–surgical changes and the potential for chronically dilated bowel that may fail to normalise following resection. Although clinically relevant strictures without pre–stenotic dilation exist, the panelists found the inclusion of pre–stenotic dilation as a definition criterion for a stricture important due to its high specificity. This would provide a homogenous patient population, increasing the chances to see a meaningful difference with anti–fibrotic treatment. The panelists considered none of the existing cross–sectional imaging techniques appropriate to confidently quantify the fibrotic component of a small bowel stricture, which reflected the opinion of the group that existing technologies for quantification of fibrosis have not been validated.

In addition to having clinical applicability, the current initiative addresses the heterogeneity that prevents direct comparisons across stricturing CD trials.[1,18,32–34] Fully validated scoring instruments are particularly needed. While there is no validated patient–reported outcome (PRO) available, the successful launch of a novel anti–fibrotic drug will likely require PRO development. Patients with symptomatic strictures might be included in proof of concept studies with evaluation by imaging, endoscopy or biomarkers whereas registration studies will likely require studies conducted in symptomatic patients with co–primary endpoints of improvement in a PRO and reduction in imaging–based outcomes of fibrosis.

To develop fully validated clinical trial endpoints, novel scoring indices must undergo responsiveness testing. However, this presents a challenge since there are no approved anti–fibrotic therapies for stricturing CD. In Figure 1, we propose a framework for proof of concept clinical trials in an ideal scenario where the study population exclusively consists of patients with terminal ileal CD. In this population, strictures consist of a mix of inflammation and fibrosis.[19] While recruitment of such a homogenic population may be a challenge, this design would enhance trial rigor and allow for inclusion of endoscopy as an endpoint. Moreover, by targeting mucosal healing and using stratified randomisation to ensure groups receiving placebo and anti–fibrotic therapy are balanced with respect to receipt of balloon dilation, it may be possible to measure reduction in fibrosis despite the lack of noninvasive techniques to separate inflammation from fibrosis. While the panel chose 24 weeks as the optimal desired primary endpoint in clinical trials, incorporation of an additional later timepoint (52 weeks) may help to understand the kinetics of imaging features in early–phase trials.

Our study has limitations. Given that research in stricturing CD is limited, and no randomised controlled trials are available, most of our recommendations are based on observational data that are vulnerable to bias. For example, assessment of endpoint appropriateness was entirely subjective, given that no validated PROs or clinical instruments currently exist. A specific limitation of this work is the lack of patient representation on the panel. The initial process of evaluating the validity of the symptom items was initiated to identify items that might be considered in future PRO development. The list is not meant to be used in totality for a clinical trial endpoint. Ultimately, any PRO item must be patient–derived; however, the procedure we completed is a recommended exercise as a prelude to PRO development, an extensive and iterative process that may require several years.

The strength of our study lies in the inclusion of internationally recognised IBD radiologists and clinical experts and adoption of rigorous methodology to minimise bias. The individual items are not meant to be read in isolation (eg, individual diagnostic modalities to detect a stricture), and while some items were rated highly (eg, MRE), they may not perform with perfect accuracy. Additionally, it may be advantageous to combine items, for instance cross–sectional imaging and symptoms, given the relevance of the latter in clinical practice.

In conclusion, we performed an international consensus process using modified RAND/UCLA appropriateness methodology to standardise CD stricture definitions, inclusion criteria and endpoints for use in routine clinical practice. Based on the items considered appropriate, we constructed a prototypic clinical trial design to be shared with the scientific community as a starting point for future investigations. Initiatives are underway to determine reliability of radiologic items identified in the current study and to create a PRO tool specifically for ileal CD–associated strictures. The ultimate goal is the development of a fully validated set of criteria for use in clinical practice and in drug development.

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