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1. Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

Author

David Egg, Charlotte Schwab, Annemarie Gabrysch, Peter D. Arkwright, Edmund Cheesman, Lisa Giulino-Roth, Olaf Neth, Scott Snapper, Satoshi Okada, Michel Moutschen, Philippe Delvenne, Ann-Christin Pecher, Daniel Wolff, Yae-Jean Kim, Suranjith Seneviratne, Kyoung-Mee Kim, Ji-Man Kang, Samar Ojaimi, Catriona McLean, Klaus Warnatz, Maximilian Seidl, and Bodo Grimbacher

Subjects
CTLA4, combined immunodeficiency, primary immunodeficiency, malignancy, cancer predisposition, EBV, Immunologic diseases. Allergy, RC581-607
Abstract

Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown.Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled.Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated.Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers.

Published
2018
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2. Vedolizumab as a successful treatment of CTLA-4-associated autoimmune enterocolitis

Author

Raphael Jeker, Rebecca Higgins, Thomas Daikeler, Olivier Bignucolo, Anne-Valérie Burgener, Annemarie Gabrysch, Benedikt J. Meyer, Annaïse Jauch, Christoph Hess, Jan-Olaf Gebbers, Matthias Mehling, Alexander A. Navarini, Fabian Baldin, Bodo Grimbacher, Charlotte Schwab, Anne Kistner, Petr Hruz, Fabian Meienberg, Ingmar Heijnen, Barbara-Christina Padberg Sgier, Florian Marquardsen, David M. Sansom, Lukas T. Jeker, Marc B. Bigler, Olle Kämpe, Mike Recher, Christoph Berger, Natalie Frede, and Tie Zheng Hou

Subjects
0301 basic medicine, Enterocolitis, biology, business.industry, Immunology, Vedolizumab, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, CTLA-4, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Monoclonal, medicine, biology.protein, Immunology and Allergy, Missense mutation, Antibody, medicine.symptom, business, medicine.drug
Published
2017
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3. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects

Author

Scott B. Snapper, Alla Bulashevska, Kjetil Taskén, Michael H. Albert, Virginia Patiño, Fabian Hauck, Stephan Ehl, Peter Olbrich, Charlotte Schwab, Craig D. Platt, Mike Recher, Hanns-Martin Lorenz, Janet Chou, Veronika Kanderova, Veronika Reiser, Tim Niehues, Akihiro Hoshino, Zdenek Sumnik, Tomáš Freiberger, Ulrich Salzer, Olaf Neth, Masatoshi Takagi, Gregor Dückers, Charlotte Cunningham-Rundles, Elizabeth M. McDermott, Raif S. Geha, Talal A. Chatila, Su Bunn, Monika Kurzai, Lisa Giulino-Roth, Gary Unglik, Jamanda A. Haddock, David M. Sansom, Bodo Grimbacher, Natalie Frede, Klaus Warnatz, Laia Alsina, Eva Fronkova, Olivier Elemento, Ansgar Schulz, Annette Schmitt-Graeff, Christina Price, Anna Sediva, Masao Kobayashi, Andre Franke, Florian Emmerich, Jana Pachlopnik Schmid, Satoshi Okada, Richard S. Blumberg, Alan M. Leichtner, Hugo Chapdelaine, Antonios G.A. Kolios, Desirée Schubert, Annemarie Gabrysch, Hirokazu Kanegane, Suranjith L. Seneviratne, Zeynep Yesim Kucuk, Ferran Casals, Alessandro Plebani, Lenka Petruzelkova, Andrew J. Cant, Thomas Giese, Carsten Speckmann, José Manuel Lucena, Seiichi Hayakawa, Jiri Litzman, Angela Deyà-Martínez, Mary Slatter, Maria Kanariou, Kathleen E. Sullivan, Christian Klemann, Maximilian Seidl, Daniel Wolff, Sebastian Zeissig, Vassilios Lougaris, Ingunn Dybedal, Kohsuke Imai, Sophie Hambleton, Frank L. van de Veerdonk, Peter D. Arkwright, and Michel Moutschen

Subjects
Male, 0301 basic medicine, medicine.medical_treatment, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], medicine.disease_cause, abatacept, Hypogammaglobulinemia, Immunology and Allergy, CTLA-4 Antigen, Child, hematopoietic stem cell transplantation, Aged, 80 and over, autoimmunity, common variable immunodeficiency, Cytotoxic T-lymphocyte antigen 4, hypogammaglobulinemia, immune dysregulation, primary immunodeficiency, sirolimus, Immunology, Immunosuppression, Middle Aged, Penetrance, 3. Good health, Phenotype, Female, Adult, Adolescent, chemical and pharmacologic phenomena, Young Adult, 03 medical and health sciences, Germline mutation, medicine, Humans, Aged, business.industry, Common variable immunodeficiency, Immunologic Deficiency Syndromes, Immune dysregulation, medicine.disease, 030104 developmental biology, CTLA-4, Mutation, Primary immunodeficiency, business
Abstract

Item does not contain fulltext BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

Published
2018

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