TY - JOUR

T1 - Therapeutic options for CTLA-4 insufficiency

AU - Egg, David

AU - Rump, Ina Caroline

AU - Mitsuiki, Noriko

AU - Rojas-Restrepo, Jessica

AU - Maccari, Maria Elena

AU - Schwab, Charlotte

AU - Gabrysch, Annemarie

AU - Warnatz, Klaus

AU - Goldacker, Sigune

AU - Patiño, Virginia

AU - Wolff, Daniel

AU - Okada, Satoshi

AU - Hayakawa, Seiichi

AU - Shikama, Yoshiaki

AU - Kanda, Kenji

AU - Imai, Kohsuke

AU - Sotomatsu, Manabu

AU - Kuwashima, Makoto

AU - Kamiya, Takahiro

AU - Morio, Tomohiro

AU - Matsumoto, Kazuaki

AU - Mori, Takeshi

AU - Yoshimoto, Yuri

AU - Dybedal, Ingunn

AU - Kanariou, Maria

AU - Kucuk, Zeynep Yesim

AU - Chapdelaine, Hugo

AU - Petruzelkova, Lenka

AU - Lorenz, Hanns Martin

AU - Sullivan, Kathleen E.

AU - Heimall, Jennifer

AU - Moutschen, Michel

AU - Litzman, Jiri

AU - Recher, Mike

AU - Albert, Michael H.

AU - Hauck, Fabian

AU - Seneviratne, Suranjith

AU - Pachlopnik Schmid, Jana

AU - Kolios, Antonios

AU - Unglik, Gary

AU - Klemann, Christian

AU - Snapper, Scott

AU - Giulino-Roth, Lisa

AU - Svaton, Michael

AU - Platt, Craig D.

AU - Hambleton, Sophie

AU - Neth, Olaf

AU - Gosse, Geraldine

AU - Reinsch, Steffen

AU - Holzinger, Dirk

AU - Kim, Yae Jean

AU - Bakhtiar, Shahrzad

AU - Atschekzei, Faranaz

AU - Schmidt, Reinhold

AU - Sogkas, Georgios

AU - Chandrakasan, Shanmuganathan

AU - Rae, William

AU - Derfalvi, Beata

AU - Marquart, Hanne Vibeke

AU - Ozen, Ahmet

AU - Kiykim, Ayca

AU - Karakoc-Aydiner, Elif

AU - Králíčková, Pavlína

AU - de Bree, Godelieve

AU - Kiritsi, Dimitra

AU - Seidel, Markus G.

AU - Kobbe, Robin

AU - Dantzer, Jennifer

AU - Alsina, Laia

AU - Armangue, Thais

AU - Lougaris, Vassilios

AU - Agyeman, Philipp

AU - Nyström, Sofia

AU - Buchbinder, David

AU - Arkwright, Peter D.

AU - Grimbacher, Bodo

N1 - Publisher Copyright: © 2021

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - abatacept

KW - common variable immunodeficiency

KW - CTLA-4

KW - diagnosis

KW - HSCT

KW - LRBA

KW - primary immunodeficiency

KW - rituximab

KW - sirolimus

KW - treatment

U2 - 10.1016/j.jaci.2021.04.039

DO - 10.1016/j.jaci.2021.04.039

M3 - Journal article

C2 - 34111452

AN - SCOPUS:85109673099

VL - 149

SP - 736

EP - 746

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 2

ER -