Complicated and refractory celiac disease: a model of antigen-independent immune escape and lymphoproliferation

Celiac disease (CeD) is an immune-mediated enteropathy triggered by dietary gluten and treated with a gluten-free diet. However, a subset of patients develops refractory or complicated forms characterized by persistent immune activation and increased risk of malignant transformation. These conditions challenge the traditional view of CeD as a fully reversible, antigen-driven disorder.

This narrative review reframes refractory and complicated CeD as a biological continuum driven by sustained immune dysregulation and partial independence from the antigenic trigger. Literature was identified through PubMed and Embase searches (January 2000-March 2026), focusing on clinical, translational, and molecular studies relevant to refractory and complicated CeD. Current definitions and the clinical spectrum are discussed, spanning refractory CeD types 1 and 2 (RCeD1 and RCeD2), ulcerative jejunoileitis, intestinal lymphomas, and small bowel adenocarcinoma. Immunological mechanisms, including aberrant intraepithelial lymphocyte populations, clonal T-cell expansions, and cytokine-driven survival pathways, especially IL-15 signaling, are discussed. Evidence linking chronic inflammation, immune escape, and lymphoproliferation is reviewed.

Current diagnostic and therapeutic strategies remain inadequate to identify early immune escape and pre-malignant evolution. A shift toward biologically driven risk stratification and integration of molecular diagnostics is essential to enable early identification and targeted intervention in high-risk patients.