Alimentary Pharmacology & Therapeutics | 2021
Editorial: testing novel interventions for coeliac disease—which outcomes matter?
Abstract
The only proven therapy for coeliac disease is lifelong adherence to a strict glutenfree diet, an extremely challenging regimen for many patients. For some, the burden of a glutenfree diet can impact quality of life, including mood, and patients with coeliac disease often have ongoing symptoms and persistent mucosal damage that can be slow to recover. There is a need for novel interventions as an adjunct or alternative to the existing standard of care. Newnham et al conducted a pilot doubleblind, placebocontrolled randomised trial to evaluate whether budesonide dissolved in water concurrent with a glutenfree diet could hasten small bowel healing and improve gastrointestinal symptoms in patients with newly diagnosed coeliac disease.1 Patients with coeliac disease of less than 4 weeks duration were randomised to 9 mg of budesonide dissolved in water daily for 8 weeks (followed by a 2week taper), versus placebo. Symptoms were assessed at multiple timepoints and duodenal histology was assessed at weeks 8 and 52. The primary outcome was mucosal response (Marsh 0 or 1) at 8 weeks. The study found that there was no statistically significant difference between the groups regarding the outcome (37% in the treatment group vs 28% in the placebo group, P = 0.73). Symptom improvement was not significantly associated with budesonide use. Strengths of the study include its prospective, randomised design and histologic assessment via both the Marsh score (a more clinically oriented classification) as well as quantitative morphology using the villus height to crypt depth ratio, a more reproducible and finely calibrated measurement.2 Assessment of bone density in participants as a safety consideration is another strength. The main limitation is the small sample size, raising the possibility of type 2 error; in fact, a 9% absolute difference in the primary outcome was seen, favouring treatment. Although a small pilot, this study likely grappled with big decisions— decisions many researchers conducting coeliac disease trials must face when deciding on a study endpoint. Which outcomes matter? How quickly the patient will heal? How they will feel? Or both? When considering the primary endpoint, Newnham et al chose the proportion of patients who reached a predefined level of histologic improvement by study end. Although mucosal healing has been linked with longterm relevant outcomes, including risk of lymphoma and fracture,3,4 this is a surrogate outcome, and may not correlate with important short and intermediateterm outcomes that matter to patients. As such, Newnham et al also evaluated symptoms including anxiety, depression and fatigue as secondary outcomes. Ultimately, an effective behavioural or nondietary therapy should improve outcomes on both scales. The prevalence of persistent or recurrent symptoms in coeliac disease is considerable, and a medication or behavioural therapy should address this unmet need.5 But given concerns regarding longterm morbidity in coeliac disease, histology can offer an indirect look at that difficulttomeasure outcome. Treating coeliac disease is both a longterm proposition and a daytoday challenge; by incorporating both symptoms and histology, we can evaluate therapies on multiple fronts.