Outcome measures in coeliac disease trials: the Tampere recommendations

Abstract

ObjectiveA gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures.DesignBased on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed.ResultsWe comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease.ConclusionCareful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry.

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

“…To our knowledge, patient‐reported outcome symptom severity scores have not previously been correlated with cytokine elevations or any other contemporaneous disease‐relevant biomarker in coeliac disease or any other condition. As such, interleukin‐2 elevation triggered by standardised gluten challenge appears to be the first biomarker identified in coeliac disease that correlates with symptoms …”

“…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 .…”

“…Here, we show that standardised oral gluten challenge, combined with cytokine assessment and patient‐reported outcomes adapted for hourly rating (as described for the first time in this study), is well suited to monitoring the effects of gluten in coeliac disease patients. To date, clinical trials have not utilised one‐off gluten challenge . The validity of the coeliac patient‐reported outcome instrument as a measure of symptoms caused by gluten‐mediated immune activation was strongly supported by showing significant increases in gastrointestinal symptoms after gluten challenge, and by finding that symptom severity correlated with elevations of serum interleukin‐2, a cytokine derived from antigen‐activated T cells .…”

“…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 …”

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.…”