Therapeutic options for CTLA-4 insufficiency

David Egg; Ina Caroline Rump; Noriko Mitsuiki; Jessica Rojas-Restrepo; Maria Elena Maccari; Charlotte Schwab; Annemarie Gabrysch; Klaus Warnatz; Sigune Goldacker; Virginia Patiño; Daniel Wolff; Satoshi Okada; Seiichi Hayakawa; Yoshiaki Shikama; Kenji Kanda; Kohsuke Imai; Manabu Sotomatsu; Makoto Kuwashima; Takahiro Kamiya; Tomohiro Morio; Kazuaki Matsumoto; Takeshi Mori; Yuri Yoshimoto; Ingunn Dybedal; Maria Kanariou; Zeynep Yesim Kucuk; Hugo Chapdelaine; Lenka Petruzelkova; Hanns Martin Lorenz; Kathleen E. Sullivan; Jennifer Heimall; Michel Moutschen; Jiri Litzman; Mike Recher; Michael H. Albert; Fabian Hauck; Suranjith Seneviratne; Jana Pachlopnik Schmid; Antonios Kolios; Gary Unglik; Christian Klemann; Scott Snapper; Lisa Giulino-Roth; Michael Svaton; Craig D. Platt; Sophie Hambleton; Olaf Neth; Geraldine Gosse; Steffen Reinsch; Dirk Holzinger; Yae Jean Kim; Shahrzad Bakhtiar; Faranaz Atschekzei; Reinhold Schmidt; Georgios Sogkas; Shanmuganathan Chandrakasan; William Rae; Beata Derfalvi; Hanne Vibeke Marquart; Ahmet Ozen; Ayca Kiykim; Elif Karakoc-Aydiner; Pavlína Králíčková; Godelieve de Bree; Dimitra Kiritsi; Markus G. Seidel; Robin Kobbe; Jennifer Dantzer; Laia Alsina; Thais Armangue; Vassilios Lougaris; Philipp Agyeman; Sofia Nyström; David Buchbinder; Peter D. Arkwright; Bodo Grimbacher

doi:10.1016/j.jaci.2021.04.039

Therapeutic options for CTLA-4 insufficiency

David Egg, Ina Caroline Rump, Noriko Mitsuiki, Jessica Rojas-Restrepo, Maria Elena Maccari, Charlotte Schwab, Annemarie Gabrysch, Klaus Warnatz, Sigune Goldacker, Virginia Patiño, Daniel Wolff, Satoshi Okada, Seiichi Hayakawa, Yoshiaki Shikama, Kenji Kanda, Kohsuke Imai, Manabu Sotomatsu, Makoto Kuwashima, Takahiro Kamiya, Tomohiro MorioKazuaki Matsumoto, Takeshi Mori, Yuri Yoshimoto, Ingunn Dybedal, Maria Kanariou, Zeynep Yesim Kucuk, Hugo Chapdelaine, Lenka Petruzelkova, Hanns Martin Lorenz, Kathleen E. Sullivan, Jennifer Heimall, Michel Moutschen, Jiri Litzman, Mike Recher, Michael H. Albert, Fabian Hauck, Suranjith Seneviratne, Jana Pachlopnik Schmid, Antonios Kolios, Gary Unglik, Christian Klemann, Scott Snapper, Lisa Giulino-Roth, Michael Svaton, Craig D. Platt, Sophie Hambleton, Olaf Neth, Geraldine Gosse, Steffen Reinsch, Dirk Holzinger, Yae Jean Kim, Shahrzad Bakhtiar, Faranaz Atschekzei, Reinhold Schmidt, Georgios Sogkas, Shanmuganathan Chandrakasan, William Rae, Beata Derfalvi, Hanne Vibeke Marquart, Ahmet Ozen, Ayca Kiykim, Elif Karakoc-Aydiner, Pavlína Králíčková, Godelieve de Bree, Dimitra Kiritsi, Markus G. Seidel, Robin Kobbe, Jennifer Dantzer, Laia Alsina, Thais Armangue, Vassilios Lougaris, Philipp Agyeman, Sofia Nyström, David Buchbinder, Peter D. Arkwright, Bodo Grimbacher

School of Medicine

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English (US)
Pages (from-to)	736-746
Number of pages	11
Journal	Journal of Allergy and Clinical Immunology
Volume	149
Issue number	2
DOIs	https://doi.org/10.1016/j.jaci.2021.04.039
State	Published - Feb 2022

Keywords

CTLA-4
HSCT
LRBA
abatacept
common variable immunodeficiency
diagnosis
primary immunodeficiency
rituximab
sirolimus
treatment

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.jaci.2021.04.039

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Egg, D., Rump, I. C., Mitsuiki, N., Rojas-Restrepo, J., Maccari, M. E., Schwab, C., Gabrysch, A., Warnatz, K., Goldacker, S., Patiño, V., Wolff, D., Okada, S., Hayakawa, S., Shikama, Y., Kanda, K., Imai, K., Sotomatsu, M., Kuwashima, M., Kamiya, T., ... Grimbacher, B. (2022). Therapeutic options for CTLA-4 insufficiency. Journal of Allergy and Clinical Immunology, 149(2), 736-746. https://doi.org/10.1016/j.jaci.2021.04.039

Egg, D, Rump, IC, Mitsuiki, N, Rojas-Restrepo, J, Maccari, ME, Schwab, C, Gabrysch, A, Warnatz, K, Goldacker, S, Patiño, V, Wolff, D, Okada, S, Hayakawa, S, Shikama, Y, Kanda, K, Imai, K, Sotomatsu, M, Kuwashima, M, Kamiya, T, Morio, T, Matsumoto, K, Mori, T, Yoshimoto, Y, Dybedal, I, Kanariou, M, Kucuk, ZY, Chapdelaine, H, Petruzelkova, L, Lorenz, HM, Sullivan, KE, Heimall, J, Moutschen, M, Litzman, J, Recher, M, Albert, MH, Hauck, F, Seneviratne, S, Pachlopnik Schmid, J, Kolios, A, Unglik, G, Klemann, C, Snapper, S, Giulino-Roth, L, Svaton, M, Platt, CD, Hambleton, S, Neth, O, Gosse, G, Reinsch, S, Holzinger, D, Kim, YJ, Bakhtiar, S, Atschekzei, F, Schmidt, R, Sogkas, G, Chandrakasan, S, Rae, W, Derfalvi, B, Marquart, HV, Ozen, A, Kiykim, A, Karakoc-Aydiner, E, Králíčková, P, de Bree, G, Kiritsi, D, Seidel, MG, Kobbe, R, Dantzer, J, Alsina, L, Armangue, T, Lougaris, V, Agyeman, P, Nyström, S, Buchbinder, D, Arkwright, PD & Grimbacher, B 2022, 'Therapeutic options for CTLA-4 insufficiency', Journal of Allergy and Clinical Immunology, vol. 149, no. 2, pp. 736-746. https://doi.org/10.1016/j.jaci.2021.04.039

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title = "Therapeutic options for CTLA-4 insufficiency",

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 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.",

keywords = "CTLA-4, HSCT, LRBA, abatacept, common variable immunodeficiency, diagnosis, primary immunodeficiency, rituximab, sirolimus, treatment",

author = "David Egg and Rump, {Ina Caroline} and Noriko Mitsuiki and Jessica Rojas-Restrepo and Maccari, {Maria Elena} and Charlotte Schwab and Annemarie Gabrysch and Klaus Warnatz and Sigune Goldacker and Virginia Pati{\~n}o and Daniel Wolff and Satoshi Okada and Seiichi Hayakawa and Yoshiaki Shikama and Kenji Kanda and Kohsuke Imai and Manabu Sotomatsu and Makoto Kuwashima and Takahiro Kamiya and Tomohiro Morio and Kazuaki Matsumoto and Takeshi Mori and Yuri Yoshimoto and Ingunn Dybedal and Maria Kanariou and Kucuk, {Zeynep Yesim} and Hugo Chapdelaine and Lenka Petruzelkova and Lorenz, {Hanns Martin} and Sullivan, {Kathleen E.} and Jennifer Heimall and Michel Moutschen and Jiri Litzman and Mike Recher and Albert, {Michael H.} and Fabian Hauck and Suranjith Seneviratne and {Pachlopnik Schmid}, Jana and Antonios Kolios and Gary Unglik and Christian Klemann and Scott Snapper and Lisa Giulino-Roth and Michael Svaton and Platt, {Craig D.} and Sophie Hambleton and Olaf Neth and Geraldine Gosse and Steffen Reinsch and Dirk Holzinger and Kim, {Yae Jean} and Shahrzad Bakhtiar and Faranaz Atschekzei and Reinhold Schmidt and Georgios Sogkas and Shanmuganathan Chandrakasan and William Rae and Beata Derfalvi and Marquart, {Hanne Vibeke} and Ahmet Ozen and Ayca Kiykim and Elif Karakoc-Aydiner and Pavl{\'i}na Kr{\'a}l{\'i}{\v c}kov{\'a} and {de Bree}, Godelieve and Dimitra Kiritsi and Seidel, {Markus G.} and Robin Kobbe and Jennifer Dantzer and Laia Alsina and Thais Armangue and Vassilios Lougaris and Philipp Agyeman and Sofia Nystr{\"o}m and David Buchbinder and Arkwright, {Peter D.} and Bodo Grimbacher",

note = "Publisher Copyright: {\textcopyright} 2021",

year = "2022",

month = feb,

doi = "10.1016/j.jaci.2021.04.039",

language = "English (US)",

volume = "149",

pages = "736--746",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

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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

PY - 2022/2

Y1 - 2022/2

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 - CTLA-4

KW - HSCT

KW - LRBA

KW - abatacept

KW - common variable immunodeficiency

KW - diagnosis

KW - primary immunodeficiency

KW - rituximab

KW - sirolimus

KW - treatment

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UR - http://www.scopus.com/inward/citedby.url?scp=85109673099&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2021.04.039

DO - 10.1016/j.jaci.2021.04.039

M3 - Article

C2 - 34111452

AN - SCOPUS:85109673099

SN - 0091-6749

VL - 149

SP - 736

EP - 746

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 2

ER -

Therapeutic options for CTLA-4 insufficiency

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