Abstract and Introduction
Abstract
Background: Coeliac disease (CeD) is an immune-mediated small bowel enteropathy resulting from dietary gluten exposure. Presently, the only effective treatment is adoption of a gluten-free diet (GFD), although strict adherence is challenging to maintain, and inadvertent gluten exposures are inevitable for most patients. Hence, there is substantial interest in drug development in CeD and multiple novel therapies are under investigation.
Aims: To review existing and upcoming clinical trial programmes for pharmacologic agents for CeD.
Methods: A narrative review was performed, informed by a search of MEDLINE, Embase, the Cochrane CENTRAL Library and clinicaltrials.gov.
Results: We summarise the pathophysiology of CeD and the specific steps that are potentially amenable to pharmacologic treatment. We evaluate the evidence supporting existing and future drug targets, including trials of peptidases, gluten sequestrants, tight junction regulators, anti-transglutaminase 2 therapies, immune tolerizing agents, advanced biologics and small molecules, and microbiome-targeted strategies. We highlight unique considerations for conducting CeD trials, including identifying appropriate study populations, assessing results in the context of a gluten challenge, and interpreting CeD-specific clinical and histologic outcomes. Understanding these factors is crucial for accurately appraising the evidence. Finally, we outline what the future of CeD therapy may hold with the introduction of pharmacotherapies.
Conclusions: There is a need for pharmacologic options for CeD, either used adjunctively with a GFD for accidental or intentional gluten exposures or for refractory disease. Multiple promising agents are in development, and these trials are likely to lead to approvals for the first generation of pharmacologic agents for CeD within the next 5 years.
Introduction
Coeliac disease (CeD) is an autoimmune small bowel enteropathy triggered by dietary gluten ingestion in a genetically susceptible host.[1] It is one of the most common, chronic, food-related conditions, affecting ~1% of the population, with rising global incidence and prevalence rates.[2,3] Symptoms typically include chronic diarrhoea, abdominal pain/bloating and weight loss, although silent presentations and extraintestinal manifestations are common.[4] The diagnosis of CeD involves detection of CeD-specific autoantibodies (anti-tissue transglutaminase [TG2]), anti-endomysial antibody [EMA] or anti-deamidated gliadin peptide). Histologic confirmation of small bowel enteropathy remains the gold standard.[5] Approximately 0.31%–0.38% of patients with CeD have refractory CeD (RCD), characterised by persistent malabsorption and villous atrophy despite strict gluten avoidance.[6–8] The true prevalence of RCD has been challenging to ascertain, although it is thought to be a rare condition, as many patients with symptomatically non-responsive CeD (often in the context of inadvertent persistent gluten exposure) or those with slow histologic healing may be misdiagnosed with RCD.[9] However, accurate diagnosis of RCD is important prognostically as patients with type II RCD are at higher risk for developing enteropathy associated lymphoma.[10,11] Compared to the general population, patients with CeD are at increased risk for cardiovascular-related, cancer-related and all-cause mortality.[12]
Currently, the only recommended treatment for CeD is strict adherence to a gluten-free diet (GFD). However, adherence rates vary significantly and are dependent on socioeconomic, disease-related and patient-related factors.[13,14] Inadvertent gluten exposure is inevitable for most patients because of occasional dietary transgressions and potential contamination. Given the near-ubiquity of gluten, strictly adhering to a GFD may result in both nutritional deficits (eg, inadequate fibre, iron, folate and zinc intake) and other nutritional imbalances including overconsumption of dietary fat and foods with high glycaemic index.[15,16] Maintaining a GFD can also exacerbate social isolation, anxiety and disordered eating habits.[17]
These limitations highlight the need for safe and effective pharmacologic therapies for the treatment of CeD. In this review, we summarise the pathogenesis of CeD and describe potential therapeutic targets and the associated therapies currently in development while highlighting the unique challenges of drug development in CeD. Finally, we postulate how medical treatments may change the future for patients with CeD and their role in management paradigms beyond 2021.