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J Allergy Clin Immunol. 2018 Mar;141(3):1036-1049.e5. doi: 10.1016/j.jaci.2017.10.041. Epub 2017 Dec 11.

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study.

Author information

1
San Raffaele Telethon Institute for Gene Therapy, Pediatric Immunohematology and Bone Marrow Transplantation Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
2
Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
3
Paediatric Immunology, Haematology and Rheumatology Department, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes-Université Sorbonne Paris Cité, Institut Imagine, Paris, France.
4
Pediatric Immunology, "Anna Meyer" Children's Hospital, Florence, Italy.
5
Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
6
Institute of Cellular Medicine, Newcastle University and Children's Bone Marrow Transplant Unit, Great North Children's Hospital, Newcastle Upon Tyne, United Kingdom.
7
Pediatrics, Boston Children's Hospital, Boston, Mass.
8
Department of Immunology, Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
9
Department of Immunology and Gene Therapy, Great Ormond Street Hospital, London, United Kingdom.
10
Department of Stem Cell Transplantation, Great Ormond Street Hospital, London, United Kingdom.
11
San Raffaele Telethon Institute for Gene Therapy, Pediatric Immunohematology and Bone Marrow Transplantation Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
12
Division of Clinical Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
13
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
14
Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo and Hospital Albert Einstein, São Paulo, Brazil.
15
Stem Cell Transplantation Unit, Instituto da Criança, Faculdade de Medicina da Universidade de São Paulo and Hospital Albert Einstein, São Paulo, Brazil.
16
Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey.
17
Department of Pediatrics, University Medical Center, Ulm, Germany.
18
Pediatric Onco-Hematology and Bone Marrow Transplant (BMT) Unit, Children's Hospital, Spedali Civili, Brescia, Italy.
19
Department of Hematology-Oncology: Bone Marrow Transplant (BMT) Unit, "Anna Meyer" Children's Hospital, Florence, Italy.
20
Gastroenterology Unit, University of Florence, Department of "NEUROFARBA": Section of Child's Health, "Anna Meyer" Children's Hospital, Florence, Italy.
21
Department of Pediatrics, Section of Immunology Allergy Rheumatology, Baylor College of Medicine Texas Children's Hospital, Houston, Tex.
22
Department of Pediatric Hematology and Oncology, Baylor College of Medicine Texas Children's Hospital, Houston, Tex.
23
Pediatric Gastroenterology unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes-Université Sorbonne Paris Cité, Paris, France.
24
Hematology Unit, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
25
Institut national de la santé et de la recherche médicale (INSERM) UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmune Disease, Paris, France.
26
Biotherapy Department, Necker-Enfants Malades University Hospital, Paris Descartes -Université Sorbonne Paris Cité, Institut Imagine, Paris, France.
27
Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
28
Department of Pediatric Hematology-Oncology, University of Pavia, Istituto di Ricovero e Cura a Carattere Scientifico, Bambino Gesù Children's Hospital, Rome, Italy.
29
Pediatric Hematology-Oncology, Dr. von Hauner Children's hospital, Ludwig-Maximilians Universität, Munich, Germany.
30
Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.
31
Paediatric Haematology and Oncology, Hospital Universitario Vall D'Hebron, Barcelona, Spain.
32
Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
33
St. Anna Children's Hospital, Medical University Vienna, Vienna, Austria.
34
Pediatrics, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.
35
Hematopoietic Stem Cell Transplantation Unit, Pediatric Department, Children's University Hospital Niño Jesús, Madrid, Spain.
36
Division of Blood and Marrow Transplantation and Cellular Therapies, Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pa.
37
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
38
Pediatric Stem Cell Transplantation Unit, Medicalpark Hospital Goztepe and Antalya Hospitals, Antalya, Turkey.
39
Pediatric Allergy, Immunology and Rheumatology, Columbia Medical Center, New York, NY.
40
Pediatric Hematology, Oncology and Stem Cell Transplantation, Columbia Medical Center, New York, NY.
41
Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia Medical Center, New York, NY.
42
Pediatric Endocrinology, National Children's Hospital, San Jose, Israel.
43
Division of Immunology and Rheumatology, Department of Paediatric Infectious Diseases, University of Turin, Regina Margherita Children's Hospital, Turin, Italy.
44
Department of Paediatric Infectious Diseases, Rheumatology and Immunodeficiency, Instituto de Biomedicina de Sevilla/CSIC/Universidad de Sevilla, Seville, Spain.
45
Department of Pediatric Hematology, Instituto de Biomedicina de Sevilla/CSIC/Universidad de Sevilla, Seville, Spain.
46
Department of Paediatirc Gastroenterology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla/Unite Mixte de Recherche (UMR) or Mixed Unit of Research Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla, Seville, Spain.
47
Pediatric Immunology Clinic, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
48
Pediatric Ambulatory Care Unit, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
49
Department of Pediatrics, Helios Children's Hospital, Krefeld, Germany.
50
Department of Pediatrics, Center for Primary Immunodeficiencies, Ghent University Hospital, Ghent, Belgium.
51
Division of Pediatric Allergy, Immunology and Rheumatology, University of California-Los Angeles School of Medicine, Los Angeles, Calif.
52
Pediatric Immunology, Infections and Stem Cell Transplantation (SCT), Leiden University Medical Center, Leiden, The Netherlands.
53
Department of Pediatric Hematology, Oncology and Bone Marrow Transplant (BMT) Unit, Wroclaw Medical University, Wroclaw, Poland.
54
Department of Pediatrics, Saint Justine Hospital, University of Montreal, Montreal, Quebec, Canada.
55
Division of Pediatric Hematology-Oncology, Research Unit Pediatric Hematology and Immunology, Medical University Graz, Graz, Austria.
56
Pediatrics, Boston Children's Hospital, Boston, Mass; Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Mass.
57
Pediatric Allergy, Immunology and Bone Marrow Transplant, University of California-San Francisco Benioff Children's Hospital, San Francisco, Calif.
58
Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
59
Pediatrics, University of Alabama, Birmingham, Ala.
60
Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif. Electronic address: roasb@stanford.edu.

Abstract

BACKGROUND:

Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.

OBJECTIVE:

This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.

METHODS:

Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.

RESULTS:

We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.

CONCLUSIONS:

Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

KEYWORDS:

FOXP3; IPEX; Treg cells; enteropathy; genetic autoimmunity; hematopoietic stem cell transplantation; immunosuppression; neonatal diabetes; primary immune deficiency; rapamycin

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