Persistent symptoms and enteropathy in coeliac disease: clinical considerations and therapeutic opportunities

Coeliac disease is an immune-mediated enteropathy triggered by gluten ingestion. While a strict gluten-free diet remains the basis of treatment, a sizeable proportion of patients continue to experience symptoms or histological abnormalities despite adherence. This clinical entity of non-responsive coeliac disease imposes diagnostic and therapeutic challenges. Inadvertent gluten intake is a leading cause and can be difficult to detect, but measuring gluten immunogenic peptides in the urine or stool can provide objective evidence of exposure. Persistent symptoms or enteropathy can also originate from coexisting gastrointestinal disorders or the rare complication of refractory coeliac disease, which requires specialized treatment. Several novel therapies, including intestinal gluten neutralization, intestinal permeability modulation, HLA-gluten or cytokine blockade, transglutaminase inhibition and induction of gluten tolerance have reached Phase 1b/2 clinical trials. While coeliac drug development still faces several hurdles, these advances offer hope for more personalized, effective management beyond the gluten-free diet.