Is a Functional Cure Possible in Autoimmune Diseases? Evidence from Trigger Eradication, Transplantation, and Cellular Therapies

Abstract

Introduction: Traditionally considered incurable, autoimmune diseases (AIDs) may—in specific circumstances—achieve sustained remission or even a “functional cure,” defined as durable clinical and laboratory remission without immunosuppression. This review evaluates evidence across five therapeutic axes: infectious trigger eradication, immune reset via autologous hematopoietic stem cell transplantation (HSCT), cellular therapies (CAR-T, extracorporeal photopheresis), environmental/nutritional strategies, and paraneoplastic syndromes. Methods: Systematic review according to PRISMA guidelines in PubMed/MEDLINE, Embase, Scopus, Web of Science, and Cochrane (up to September 2025). Eligible studies included trials, meta-analyses, cohorts, case series, and reports describing sustained or drug-free remission. Definitions applied were clinical remission, complete remission, sustained remission ≥ 12 months, drug-free remission, and functional cure (complete, off-therapy remission with stable biomarkers and no new organ damage). Results: Strong evidence supports Helicobacter pylori eradication in immune thrombocytopenic purpura, with signals in dermatoses and urticaria. In systemic sclerosis, HSCT outperformed cyclophosphamide in randomized trials, improving survival and reducing prolonged immunosuppression; lupus series reported extended drug-free remissions. Anti-CD19 CAR-T therapies induced deep remission in B-cell-mediated AIDs, normalizing autoantibodies over 12–24 months. Photopheresis showed safety but heterogeneous efficacy. Environmental interventions (vitamin D, plant-based diet, microbiota modulation) suggested benefit, though with limited evidence for cure. In paraneoplastic syndromes, tumor control often coincided with autoimmune remission. Conclusions: Functional cure in AIDs appears achievable in selected cases through trigger removal, immune reset, or profound immune depletion. Advancing this paradigm requires standardized definitions, predictive biomarkers, and long-term controlled trials to integrate these strategies into routine care.