Abstract
BACKGROUND: Heterozygous germline mutations in cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications.
A number of therapeutic options are currently used with variable effectiveness. BJECTIVE: To characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic work-up and therapy at an organ-specific level.
METHODS: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 CTLA4 mutation carriers. Patients were followed between 2014 and 2020 for a total of 2,624 months from diagnosis.
Clinical manifestations were grouped based on organ-specific involvement. Medication use and response were recorded and evaluated.
RESULTS: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity especially in case of cytopenias and lymphocytic organ-infiltration of the gut, lungs and central nervous system.
Immunoglobulin replacement was effective in infection prevention. Only four (25%) of 16 patients with cytopenia who were splenectomized had a sustained clinical response.
Cure was achieved with stem cell transplantation in 13 (72%) of 18 patients. As a result of the above, organ-specific treatment pathways were developed.
CONCLUSION: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
CLINICAL IMPACT: The benefits and risks of symptomatic and curative therapies need to be considered when deciding on the best treatment for patients with CTLA-4 insufficiency.