IgG4-related gastrointestinal disease

Abstract IgG4-related disease (IgG4-RD) is a chronic, immune-mediated, systemic fibroinflammatory disorder characterized by a dense IgG4-positive lymphoplasmacytic infiltrate, storiform fibrosis and, in many organs, obliterative phlebitis1,2. Although the pancreas is its hallmark site as type 1 autoimmune pancreatitis, the disease may also involve the biliary tract, liver, gastrointestinal tract, mesentery and several extra-digestive organs2,4,5. Clinical heterogeneity and overlap with malignancies, infections and other autoimmune diseases make early recognition challenging2,8. Diagnosis relies on the integration of clinical, serological, radiological and histopathological findings. Elevated serum IgG4 may support suspicion, but it lacks specificity and can be normal in a relevant proportion of patients5,8,26. Recent advances in immunopathogenesis have highlighted the role of clonal cytotoxic CD4+ T cells and circulating plasmablasts as key drivers of inflammatory activity and fibrosis2,10,27. In pancreatic disease, the HISORt criteria remain particularly useful in clinical practice, whereas the 2019 ACR/EULAR classification criteria have helped standardize patient inclusion in research settings3,13,15. Glucocorticoids remain the first-line therapy for remission induction, with high response rates13,. Rituximab has become established in refractory or relapsing disease and in selected high-risk patients, although uncertainty remains regarding the optimal maintenance strategy24,25,30. In this evolving therapeutic landscape, inebilizumab has emerged as one of the most relevant recent advances after positive phase 3 results, reinforcing the role of B-cell–targeted therapy in IgG4-RD. This review summarizes current evidence on epidemiology, pathogenesis, diagnosis, gastrointestinal manifestations, treatment and prognosis of IgG4-RD, with special emphasis on its relevance in Digestive Diseases.