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Egg D, Rump IC, Mitsuiki N, et al. Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol. 2021;doi: 10.1016/j.jaci.2021.04.039.
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., Morio, T., Matsumoto, K., Mori, T., Yoshimoto, Y., Dybedal, I., Kanariou, M., Kucuk, Z. Y., Chapdelaine, H., Petruzelkova, L., Lorenz, H. M., Sullivan, K. E., Heimall, J., Moutschen, M., Litzman, J., Recher, M., Albert, M. H., Hauck, F., Seneviratne, S., Pachlopnik Schmid, J., Kolios, A., Unglik, G., Klemann, C., Snapper, S., Giulino-Roth, L., Svaton, M., Platt, C. D., Hambleton, S., Neth, O., Gosse, G., Reinsch, S., Holzinger, D., Kim, Y. J., Bakhtiar, S., Atschekzei, F., Schmidt, R., Sogkas, G., Chandrakasan, S., Rae, W., Derfalvi, B., Marquart, H. V., Ozen, A., Kiykim, A., Karakoc-Aydiner, E., Králíčková, P., de Bree, G., Kiritsi, D., Seidel, M. G., Kobbe, R., Dantzer, J., Alsina, L., Armangue, T., Lougaris, V., Agyeman, P., Nyström, S., Buchbinder, D., Arkwright, P. D., & Grimbacher, B. (2021). Therapeutic options for CTLA-4 insufficiency. The Journal of allergy and clinical immunology, . https://doi.org/10.1016/j.jaci.2021.04.039
Egg, David, et al. "Therapeutic options for CTLA-4 insufficiency." The Journal of allergy and clinical immunology vol. (2021). doi: 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. Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol. 2021 Jun 07; doi: 10.1016/j.jaci.2021.04.039. Epub 2021 Jun 07. PMID: 34111452.
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J Allergy Clin Immunol. 2021 Jun 07; doi: 10.1016/j.jaci.2021.04.039. Epub 2021 Jun 07.

Therapeutic options for CTLA-4 insufficiency.

The Journal of allergy and clinical immunology

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

Affiliations

  1. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.
  2. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany; Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.
  3. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany; Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.
  4. Immunology Team, American Insurance, Montevideo, Uruguay.
  5. Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
  6. Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
  7. Division of Infection, Immunology and Infection, Kanagawa Children's Medical Center, Yokohama, Japan.
  8. Department of Pediatrics, Hikone Municipal Hospital, Shiga, Japan.
  9. Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
  10. Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan.
  11. Department of Pediatrics, Kiryu Kosei General Hospital, Kiry?, Japan.
  12. Department of Lifetime Clinical Immunology, Tokyo Medical and Dental University, Tokyo, Japan.
  13. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
  14. Department of Hematology and Oncology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.
  15. Department of Pediatrics, Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan.
  16. Department of Hematology, Oslo University Hospital, Oslo, Norway.
  17. Department of Immunology and Histocompatibility, Center for Primary Immunodeficiencies-Paediatric Immunology, Aghia Sophia Children's Hospital, Athens, Greece.
  18. Division of Bone Marrow Transplantation and Immune Deficiency, Children's Hospital Medical Center, Cincinnati, Ohio.
  19. Division of Clinical Immunology, Montreal Clinical Research Institute, Montreal, Quebec, Canada.
  20. Department of Paediatrics, Motol University Hospital, Second Medical Faculty in Prague, Charles University, Prague, Czech Republic.
  21. Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
  22. The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania.
  23. Department of Infectious Diseases and General Internal Medicine, University Hospital of Liège.
  24. Department of Clinical Immunology and Allergology, Medical Faculty, Masaryk University, Brno, Czech Republic; Department of Clinical Immunology and Allergology, St. Anne's University Hospital, Brno, Czech Republic.
  25. Immunodeficiency Clinic, Medical Outpatient Unit and Immunodeficiency Lab, Department Biomedicine, University Hospital, Basel, Switzerland.
  26. Department of Pediatrics, Dr von Hauner Children's Hospital, University Hospital, Ludwig Maximilians Universität München, Munich, Germany.
  27. Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, United Kingdom.
  28. Division of Immunology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
  29. Department of Immunology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
  30. Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Melbourne, Australia.
  31. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
  32. Department of Pediatrics, Division of Pediatric Hematology/Oncology, Weill Cornell Medicine, New York, NY.
  33. Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
  34. Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
  35. Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, and Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom.
  36. Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Virgen del Rocío/Instituto de Biomedicina de Sevilla, Sevilla, RECLIP, Spain.
  37. Montreal Clinical Research Institute, Université de Montréal, Montreal, Quebec, Canada.
  38. Jena University Hospital, Pediatric Gastroenterology, Jena, Germany.
  39. Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany.
  40. Division of Infectious Diseases and Immunodeficiency, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  41. Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany.
  42. Department for Clinical Rheumatology and Immunology, Hannover Medical School, Hannover, Germany.
  43. Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga.
  44. Department of Immunology, University Hospital Southampton NHSFT, Southampton, United Kingdom; Southampton National Institute for Health Research Clinical Research Facility, University Hospital Southampton NHSFT, Southampton, United Kingdom.
  45. Division of Immunology, IWK Health Centre and Dalhousie University, Department of Pediatrics, Halifax, Nova Scotia, Canada.
  46. Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
  47. Marmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkey.
  48. Institute of Clinical Immunology and Allergy, University Hospital Hradec Kralove, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic.
  49. Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
  50. Department of Dermatology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.
  51. Research Unit for Pediatric Hematology and Immunology, Division of Pediatric Hemato-Oncology, Department of Pediatric and Adolescent Medicine, Medical University Graz, Graz, Austria.
  52. Division of Infectious Diseases, First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  53. Division of Pediatric Allergy and Immunology, and Rheumatology, Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, Md.
  54. Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona; Clinical Immunology Unit Hospital Sant Joan de Déu-Hospital Clínic Barcelona, Universitat de Barcelona, Barcelona, Spain.
  55. Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
  56. Pediatric Neuroimmunology Unit, Neurology Department, Sant Joan de Déu Children's Hospital, University of Barcelona, Barcelona, Spain.
  57. Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, ASST-Spedali Civili of Brescia, Brescia, Italy.
  58. Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
  59. Department of Clinical Immunology and Transfusion Medicine, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
  60. Division of Pediatric Hematology, Children's Hospital of Orange County, Orange, Calif.
  61. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany; Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany; Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, United Kingdom; Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom; German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany; Centre for Integrative Biological Signaling Studies, Albert Ludwig University of Freiburg, Freiburg, Germany; RESIST-Cluster of Excellence 2155 to Hannover Medical School, Satellite Center Freiburg, Freiburg, Germany. Electronic address: [email protected].

PMID: 34111452 DOI: 10.1016/j.jaci.2021.04.039

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.

Copyright © 2021. Published by Elsevier Inc.

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

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