Therapeutic options for CTLA-4 insufficiency - 03/02/22
Doi : 10.1016/j.jaci.2021.04.039
David Egg a, Ina Caroline Rump, MD a, Noriko Mitsuiki, MD, PhD a, Jessica Rojas-Restrepo a, Maria-Elena Maccari, MD a, b, Charlotte Schwab, MD a, Annemarie Gabrysch, MD a, Klaus Warnatz, MD a, c, Sigune Goldacker, MD a, c, Virginia Patiño, MD d, Daniel Wolff, MD e, Satoshi Okada, MD, PhD f, Seiichi Hayakawa, MD f, Yoshiaki Shikama, MD g, Kenji Kanda, MD h, Kohsuke Imai, MD, PhD i, Manabu Sotomatsu, MD j, Makoto Kuwashima, MD k, Takahiro Kamiya, MD, PhD l, Tomohiro Morio, MD, PhD m, Kazuaki Matsumoto, MD m, Takeshi Mori, MD, PhD n, Yuri Yoshimoto, MD o, Ingunn Dybedal, MD, PhD p, Maria Kanariou, MD q, Zeynep Yesim Kucuk, MD r, Hugo Chapdelaine, MD s, Lenka Petruzelkova, MD, PhD t, Hanns-Martin Lorenz, MD u, Kathleen E. Sullivan, MD, PhD v, Jennifer Heimall, MD v, Michel Moutschen, MD, PhD w, Jiri Litzman, MD x, y, Mike Recher, MD z, Michael H. Albert, MD aa, Fabian Hauck, MD, PhD aa, Suranjith Seneviratne, MD, PhD bb, Jana Pachlopnik Schmid, MD, PhD cc, Antonios Kolios, MD dd, Gary Unglik, MBBS ee, Christian Klemann, MD a, b, Scott Snapper, MD, PhD ff, Lisa Giulino-Roth, MD gg, Michael Svaton, MD hh, Craig D. Platt, MD, PhD ii, Sophie Hambleton, FRCPCH, DPhil jj, Olaf Neth, MD, PhD kk, Geraldine Gosse, MSc ll, Steffen Reinsch, MD mm, Dirk Holzinger, MD nn, Yae-Jean Kim, MD, PhD oo, Shahrzad Bakhtiar, MD pp, Faranaz Atschekzei, MD, PhD qq, Reinhold Schmidt, MD qq, Georgios Sogkas, MD, PhD qq, Shanmuganathan Chandrakasan, MD rr, William Rae, MD ss, tt, Beata Derfalvi, MD, PhD uu, Hanne Vibeke Marquart, MD, PhD vv, Ahmet Ozen, MD ww, Ayca Kiykim, MD ww, Elif Karakoc-Aydiner, MD ww, Pavlína Králíčková, MD, PhD xx, Godelieve de Bree, MD, PhD yy, Dimitra Kiritsi, MD zz, Markus G. Seidel, MD aaa, Robin Kobbe, MD bbb, Jennifer Dantzer, MD, MHS ccc, Laia Alsina, MD, PhD ddd, Thais Armangue, MD, PhD eee, Vassilios Lougaris, MD fff, Philipp Agyeman, MD ggg, Sofia Nyström, MD, PhD hhh, David Buchbinder, MD iii, Peter D. Arkwright, MD, PhD jjj, Bodo Grimbacher, MD a, c, bb, kkk, lll, mmm, nnn, ⁎ 
a Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
b Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
c Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
d Immunology Team, American Insurance, Montevideo, Uruguay
e Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
f Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
g Division of Infection, Immunology and Infection, Kanagawa Children's Medical Center, Yokohama, Japan
h Department of Pediatrics, Hikone Municipal Hospital, Shiga, Japan
i Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan
j Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan
k Department of Pediatrics, Kiryu Kosei General Hospital, Kiryū, Japan
l Department of Lifetime Clinical Immunology, Tokyo Medical and Dental University, Tokyo, Japan
m Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
n Department of Hematology and Oncology, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan
o Department of Pediatrics, Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan
p Department of Hematology, Oslo University Hospital, Oslo, Norway
q Department of Immunology and Histocompatibility, Center for Primary Immunodeficiencies-Paediatric Immunology, Aghia Sophia Children's Hospital, Athens, Greece
r Division of Bone Marrow Transplantation and Immune Deficiency, Children’s Hospital Medical Center, Cincinnati, Ohio
s Division of Clinical Immunology, Montreal Clinical Research Institute, Montreal, Quebec, Canada
t Department of Paediatrics, Motol University Hospital, Second Medical Faculty in Prague, Charles University, Prague, Czech Republic
u Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
v The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania
w Department of Infectious Diseases and General Internal Medicine, University Hospital of Liège
x Department of Clinical Immunology and Allergology, Medical Faculty, Masaryk University, Brno, Czech Republic
y Department of Clinical Immunology and Allergology, St. Anne's University Hospital, Brno, Czech Republic
z Immunodeficiency Clinic, Medical Outpatient Unit and Immunodeficiency Lab, Department Biomedicine, University Hospital, Basel, Switzerland
aa Department of Pediatrics, Dr von Hauner Children's Hospital, University Hospital, Ludwig Maximilians Universität München, Munich, Germany
bb Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, United Kingdom
cc Division of Immunology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
dd Department of Immunology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
ee Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Melbourne, Australia
ff Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass
gg Department of Pediatrics, Division of Pediatric Hematology/Oncology, Weill Cornell Medicine, New York, NY
hh Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
ii Division of Immunology, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass
jj 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
kk Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Virgen del Rocío/Instituto de Biomedicina de Sevilla, Sevilla, RECLIP, Spain
ll Montreal Clinical Research Institute, Université de Montréal, Montreal, Quebec, Canada
mm Jena University Hospital, Pediatric Gastroenterology, Jena, Germany
nn Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany
oo Division of Infectious Diseases and Immunodeficiency, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
pp Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany
qq Department for Clinical Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
rr Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
ss Department of Immunology, University Hospital Southampton NHSFT, Southampton, United Kingdom
tt Southampton National Institute for Health Research Clinical Research Facility, University Hospital Southampton NHSFT, Southampton, United Kingdom
uu Division of Immunology, IWK Health Centre and Dalhousie University, Department of Pediatrics, Halifax, Nova Scotia, Canada
vv Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
ww Marmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkey
xx Institute of Clinical Immunology and Allergy, University Hospital Hradec Kralove, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
yy Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
zz Department of Dermatology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
aaa Research Unit for Pediatric Hematology and Immunology, Division of Pediatric Hemato-Oncology, Department of Pediatric and Adolescent Medicine, Medical University Graz, Graz, Austria
bbb Division of Infectious Diseases, First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
ccc Division of Pediatric Allergy and Immunology, and Rheumatology, Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, Md
ddd 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
eee Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
fff Pediatric Neuroimmunology Unit, Neurology Department, Sant Joan de Déu Children’s Hospital, University of Barcelona, Barcelona, Spain
ggg 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
hhh Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
iii Department of Clinical Immunology and Transfusion Medicine, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
jjj Division of Pediatric Hematology, Children's Hospital of Orange County, Orange, Calif
kkk Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom
lll German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany
mmm Centre for Integrative Biological Signaling Studies, Albert Ludwig University of Freiburg, Freiburg, Germany
nnn RESIST–Cluster of Excellence 2155 to Hannover Medical School, Satellite Center Freiburg, Freiburg, Germany
∗Corresponding author: Bodo Grimbacher, MD, Center for Chronic Immunodeficiency, Universitätsklinikum Freiburg, Breisacher Straße 115, 79106 Freiburg, Germany.Center for Chronic ImmunodeficiencyUniversitätsklinikum FreiburgBreisacher Straße 115Freiburg79106Germany
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.
Le texte complet de cet article est disponible en PDF.Key words : CTLA-4, common variable immunodeficiency, primary immunodeficiency, diagnosis, treatment, abatacept, sirolimus, LRBA, rituximab, HSCT
Abbreviations used : AIHA, CNS, CSF, CVID, CTLA-4, DEF6, GFP, GLILD, HSCT, ICOS, IEI, IPEX, IgRT, ITP, IVIG, LRBA, MOG, MRI, PRCA, TPO-RA, Treg
Plan
| Supported by the Deutsche Forschungsgemeinschaft (grant SFB1160/2_B5), under Germany's Excellence Strategy (CIBSS–EXC-2189 [project identifier 390939984] and RESIST–EXC 2155 [project identifier 39087428] [to B.D.]); the E-Rare Program of the European Union, managed by the Deutsche Forschungsgemeinschaft (grant code GR1617/14-1/iPAD [to B.D.]); the Netzwerke Seltener Erkrankungen of the German Ministry of Education and Research (grant code GAIN 01GM1910A [to B.D.]); the Ministry of Health of the Czech Republic (grant code NV19-05-00332 [to M.S.]); the Torrons Vicens Foundation (grant code PFNR0144 [to L.A. and T.A.]); the Else Kröner-Fresenius-Stiftung (EKFS, 2017_A110 [to F.H.]), and the German Federal Ministry of Education and Research (BMBF, 01GM1910C [to F.H.]); and the Cancer Research Center Funding Program (CRC, C3Z) of the University of Zurich, Zurich, Switzerland (to J.P.S.). |
|
| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
© 2021
Publié par Elsevier Masson SAS.
Vol 149 - N° 2
P. 736-746 - février 2022 Retour au numéro
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