Coeliac disease (CD) is a chronic life-long immune-mediated enteropathy triggered by gluten ingestion in genetically susceptible individuals [1]. The prevalence of CD varies substantially by region and country, with the global point prevalence approximately 1.4 %, based on serological tests, and 0.7 %, based on histology [2]. Globally, prevalence rates have been rising due to improved diagnostic methods and an actual increase in cases [3]. The disease is characterized by a wide range of clinical manifestations, including gastrointestinal symptoms (such as diarrhoea, bloating and weight loss) and extraintestinal symptoms (such as anaemia, osteoporosis and neurological problems) [1]. Diagnosis of CD relies on a combination of serologic markers (antibodies against tissue transglutaminase, endomysium or deamidated gliadin) and characteristic histological features in small bowel biopsies, including villous atrophy and crypt hyperplasia [4].

The cornerstone of CD management is a strict lifelong gluten-free diet (GFD), which usually leads to symptom relief and histological recovery. However, adherence to a GFD poses significant challenges for patients, including social, psychological and financial burdens [5,6]. Moreover, even with strict adherence, some patients continue to have histological abnormalities or persistent symptoms [7]. These observations have led to a renewed focus on understanding the variability in response to a GFD and the need for novel therapeutic strategies beyond dietary gluten exclusion.

The aim of this article is to provide a comprehensive overview of current therapeutic options beyond dietary gluten restriction for patients with CD. The search strategy focused on identifying recent findings related to mucosal healing, persistent enteropathy, persistent symptoms and emerging therapies beyond the GFD, using PubMed, Embase, the Cochrane Library and clinical trials.gov using combinations of the following keywords and MeSH terms: “celiac disease”, “coeliac disease”, “persistent enteropathy”, “persistent symptoms”, “non-responsive celiac disease”, “mucosal healing”, “gluten-free diet”, “novel therapy”, “immune therapy” and “clinical trial”. The search was limited to articles published between January 2005 and June 2025, with additional relevant references identified from citation lists of retrieved papers.

Overall, patients with CD can be divided in 3 major groups based on presence of symptoms and histological alterations after following the GFD (Fig. 1) [8].