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Therapeutic options for CTLA-4 insufficiency

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 cur...

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Main Authors: Egg, David (Author) , Lorenz, Hanns-Martin (Author) , Rump, Ina Caroline (Author) , Mitsuiki, Noriko (Author) , Rojas-Restrepo, Jessica (Author) , Maccari, Maria-Elena (Author) , Schwab, Charlotte (Author) , Gabrysch, Annemarie (Author) , Warnatz, Klaus (Author) , Goldacker, Sigune (Author) , Patiño, Virginia (Author) , Wolff, Daniel (Author) , Okada, Satoshi (Author) , Hayakawa, Seiichi (Author) , Shikama, Yoshiaki (Author) , Kanda, Kenji (Author) , Imai, Kohsuke (Author) , Sotomatsu, Manabu (Author) , Kuwashima, Makoto (Author) , Kamiya, Takahiro (Author) , Morio, Tomohiro (Author) , Matsumoto, Kazuaki (Author) , Mori, Takeshi (Author) , Yoshimoto, Yuri (Author) , Dybedal, Ingunn (Author) , Kanariou, Maria (Author) , Kucuk, Zeynep Yesim (Author) , Chapdelaine, Hugo (Author) , Petruzelkova, Lenka (Author) , Sullivan, Kathleen E. (Author) , Heimall, Jennifer (Author) , Moutschen, Michel (Author) , Litzman, Jiri (Author) , Recher, Mike (Author) , Albert, Michael H. (Author) , Hauck, Fabian (Author) , Seneviratne, Suranjith (Author) , Pachlopnik Schmid, Jana (Author) , Kolios, Antonios (Author) , Unglik, Gary (Author) , Klemann, Christian (Author) , Snapper, Scott (Author) , Giulino-Roth, Lisa (Author) , Svaton, Michael (Author) , Platt, Craig D. (Author) , Hambleton, Sophie (Author) , Neth, Olaf (Author) , Gosse, Geraldine (Author) , Reinsch, Steffen (Author) , Holzinger, Dirk (Author) , Kim, Yae-Jean (Author) , Bakhtiar, Shahrzad (Author) , Atschekzei, Faranaz (Author) , Schmidt, Reinhold (Author) , Sogkas, Georgios (Author) , Chandrakasan, Shanmuganathan (Author) , Rae, William (Author) , Derfalvi, Beata (Author) , Marquart, Hanne Vibeke (Author) , Ozen, Ahmet (Author) , Kiykim, Ayca (Author) , Karakoc-Aydiner, Elif (Author) , Králíčková, Pavlína (Author) , de Bree, Godelieve (Author) , Kiritsi, Dimitra (Author) , Seidel, Markus G. (Author) , Kobbe, Robin (Author) , Dantzer, Jennifer (Author) , Alsina, Laia (Author) , Armangue, Thais (Author) , Lougaris, Vassilios (Author) , Agyeman, Philipp (Author) , Nyström, Sofia (Author) , Buchbinder, David (Author) , Arkwright, Peter D. (Author) , Grimbacher, Bodo (Author)
Format: Article (Journal)
Language:English
Published: 2022
In: The journal of allergy and clinical immunology
Year: 2022, Volume: 149, Issue: 2, Pages: 736-746
ISSN:1097-6825
DOI:10.1016/j.jaci.2021.04.039
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.jaci.2021.04.039
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0091674921008915
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Author Notes: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, and Bodo Grimbacher

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520 |a 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. 
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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, and Bodo Grimbacher"]},"id":{"eki":["1796349739"],"doi":["10.1016/j.jaci.2021.04.039"]},"recId":"1796349739"} 
SRT |a EGGDAVIDLOTHERAPEUTI2022 

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