Disease activity indices in coeliac disease: systematic review and recommendations for clinical trials

Abstract

ObjectiveAlthough several pharmacological agents have emerged as potential adjunctive therapies to a gluten-free diet for coeliac disease, there is currently no widely accepted measure of disease activity used in clinical trials. We conducted a systematic review of coeliac disease activity indices to evaluate their operating properties and potential as outcome measures in registration trials.DesignMEDLINE, EMBASE and the Cochrane central library were searched from 1966 to 2015 for eligible studies in adult and/or paediatric patients with coeliac disease that included coeliac disease activity markers in their outcome measures. The operating characteristics of histological indices, patient-reported outcomes (PROs) and endoscopic indices were evaluated for content and construct validity, reliability, responsiveness and feasibility using guidelines proposed by the US Food and Drug Administration (FDA).ResultsOf 19 123 citations, 286 studies were eligible, including 24 randomised-controlled trials. Three of five PROs identified met most key evaluative criteria but only the Celiac Disease Symptom Diary (CDSD) and the Celiac Disease Patient-Reported Outcome (CeD PRO) have been approved by the FDA. All histological and endoscopic scores identified lacked content validity. Quantitative morphometric histological analysis had better reliability and responsiveness compared with qualitative scales. Endoscopic indices were infrequently used, and only one index demonstrated responsiveness to effective therapy.ConclusionsCurrent best evidence suggests that the CDSD and the CeD PRO are appropriate for use in the definition of primary end points in coeliac disease registration trials. Morphometric histology should be included as a key secondary or co-primary end point. Further work is needed to optimise end point configuration to inform efficient drug development.

Elevated serum interleukin‐2 after gluten correlates with symptoms and is a potential diagnostic biomarker for coeliac disease

“…The poor correlation of histology and serology with symptoms has highlighted the need for suitable tests to monitor relevant clinical responses to gluten in trials of novel therapies intended for coeliac disease patients on gluten‐free diet . Symptoms measured by patient‐reported outcome instruments are increasingly used as efficacy endpoints in clinical trials .…”

“…Coeliac disease is caused by ingestion of dietary gluten and activation of gluten‐specific CD4 + T cells; chronic gluten exposure results in characteristic histological abnormalities in the duodenal mucosa and production of autoantibodies specific for transglutaminase . Symptoms caused by gluten in coeliac disease are generally considered nonspecific, and delayed for days or weeks after gluten is reintroduced into the diet . Thus, acute provocation testing has not played a role in the diagnosis of coeliac disease …”

Latiglutenase Improves Symptoms in Seropositive Celiac Disease Patients While on a Gluten-Free Diet

“…If a given symptom was present on a given day, follow-up questions were asked to establish its severity on that occasion. Further detail is given elsewhere [12,13]. Briefly, for all symptoms except constipation, each patient’s daily severity score was normalized from 0 to 10 where 0 represents no symptom.…”

Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten‐free diet

“…Quantitative histology provides accurate assessment of duodenal mucosal injury in coeliac disease by using highly reproducible measurements of villous height, crypt depth and intraepithelial lymphocyte density in well‐oriented distal duodenal biopsies . With implementation of rigorous standard operating procedures, quantitative duodenal histology outperforms conventional qualitative histology using grouped classifications such as Marsh score, and is emerging as a preferred measure of efficacy in therapeutics trials for coeliac disease . Perhaps surprisingly, quantitative histology has not yet, to our knowledge, been used to evaluate disease activity/duodenal injury in patients with coeliac disease who appear clinically ‘well controlled’ and are in serological remission.…”