Management Strategy for Non‐Responsive and Refractory Celiac Disease in Adults

Background and Objectives: A significant proportion of adults with celiac disease (CeD), estimated at 10-30%, experience non-responsive celiac disease (NRCD), characterized by persistent symptoms and/or incomplete mucosal healing despite a gluten-free diet (GFD). A smaller subset progresses to refractory CeD (RCD), a severe condition defined by ongoing villous atrophy with negative serology after 12-24 months on a GFD. The management of NRCD and RCD remains challenging due to heterogeneous presentations and a lack of standardized guidelines. This review aims to synthesize current evidence on the diagnostic and therapeutic strategies for NRCD and RCD in adults and to provide a comprehensive, stepwise management algorithm. Methods: A systematic search was conducted in PubMed, Embase, Cochrane Library, Web of Science, and Scopus for peer-reviewed studies and conference abstracts on adults with NRCD or RCD. Included studies involved patients ≥18 years with persistent symptoms or histological abnormalities despite a GFD and described pharmacological, dietary, or immunological interventions. Data extraction and risk-of-bias assessment were performed, followed by a narrative synthesis. Key Results: The most common cause of NRCD is ongoing gluten exposure, necessitating a thorough dietary assessment, often aided by the detection of gluten immunogenic peptides (GIPs). For true RCD, a systematic diagnostic workup in a specialist referral center is essential, incorporating clinical evaluation, duodenal biopsy with immunophenotyping and T-cell clonality analysis, and cross-sectional imaging to distinguish RCD-I from RCD-II and exclude EATL. Treatment strategies differ significantly: RCD-I often responds to open-capsule budesonide and immunomodulators, while RCD-II requires more aggressive therapies and carries a poorer prognosis. Conclusions: This review provides a comprehensive evidence-based overview of the diagnosis and management of NRCD and RCD. It highlights the critical importance of a structured diagnostic approach to identify treatable causes of NRCD and to accurately subtype RCD, thereby guiding appropriate therapy. The findings underscore significant gaps in the current evidence base, particularly for treating RCD-II, and aim to inform future research and the development of standardized clinical guidelines.