Therapeutic options for CTLA-4 insufficiency.
Adolescent
Adult
Agammaglobulinemia
/ etiology
Aged
Autoimmune Diseases
/ etiology
CTLA-4 Antigen
/ deficiency
Child
Child, Preschool
Female
Genetic Association Studies
Germ-Line Mutation
Hematopoietic Stem Cell Transplantation
Humans
Immunologic Deficiency Syndromes
/ complications
Infant
Lung Diseases, Interstitial
/ etiology
Male
Middle Aged
Transplantation, Homologous
Young Adult
CTLA-4
HSCT
LRBA
abatacept
common variable immunodeficiency
diagnosis
primary immunodeficiency
rituximab
sirolimus
treatment
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
19
11
2020
revised:
23
03
2021
accepted:
23
04
2021
pubmed:
11
6
2021
medline:
4
3
2022
entrez:
10
6
2021
Statut:
ppublish
Résumé
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 being used with variable effectiveness. Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level. Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated. Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed. 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.
Sections du résumé
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 being used with variable effectiveness.
OBJECTIVE
Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup 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 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of 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 cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, 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.
Identifiants
pubmed: 34111452
pii: S0091-6749(21)00891-5
doi: 10.1016/j.jaci.2021.04.039
pii:
doi:
Substances chimiques
CTLA-4 Antigen
0
CTLA4 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
736-746Subventions
Organisme : NCI NIH HHS
ID : K08 CA219473
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021. Published by Elsevier Inc.