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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:141

Article

Barzaghi, Federica¹  Hernandez, Laura Cristina Amaya²  Neven, Benedicte³  Ricci, Silvia⁷  Kucuk, Zeynep Yesim¹⁰  Bleesing, Jack J.¹⁰  Nademi, Zohreh^11,12  Slatter, Mary Anne^11,12  Ulloa, Erlinda Rose¹³  Shcherbina, Anna¹⁴  Roppelt, Anna¹⁴  Worth, Austen¹⁵  Silva, Juliana¹⁶  Aiuti, Alessandro^1,17  Murguia-Favela, Luis¹⁸  Speckmann, Carsten^19,20  Carneiro-Sampaio, Magda²¹  Fernandes, Juliana Folloni²²  Baris, Safa²³  Ozen, Ahmet²³  Karakoc-Aydiner, Elif²³  Kiykim, Ayca²³  Schulz, Ansgar²⁴  Steinmann, Sandra²⁴  Notarangelo, Lucia Dora²⁵  Gambineri, Eleonora⁸  Lionetti, Paolo⁹  Shearer, William Thomas²⁶  Forbes, Lisa R.²⁶  Martinez, Caridad²⁷  Moshous, Despina³  Blanche, Stephane³  Fisher, Alain³  Ruemmele, Frank M.⁴  Tissandier, Come⁴  Ouachee-Chardin, Marie⁶  Rieux-Laucat, Frederic²⁸  Cavazzana, Marina⁵  Qasim, Waseem²⁹  Lucarelli, Barbarella³⁰  Albert, Michael H.³¹  Kobayashi, Ichiro³²  Alonso, Laura³³  De Heredia, Cristina Diaz³³  Kanegane, Hirokazu³⁴  Lawitschka, Anita³⁵  Seo, Jong Jin^36,37  Gonzalez-Vicent, Marta³⁸  Diaz, Miguel Angel³⁸  Goyal, Rakesh Kumar³⁹  Sauer, Martin G.⁴⁰  Yesilipek, Akif^41,42  Kim, Minsoo⁴³  Yilmaz-Demirdag, Yesim⁴³  Bhatia, Monica⁴⁴  Khlevner, Julie⁴⁵  Padilla, Erick J. Richmond⁴⁶  Martino, Silvana⁴⁷  Montin, Davide⁴⁷  Neth, Olaf⁴⁸  Molinos-Quintana, Agueda⁴⁹  Valverde-Fernandez, Justo⁵⁰  Broides, Arnon⁵¹  Pinsk, Vered⁵²  Ballauf, Antje⁵³  Haerynck, Filomeen⁵⁴  Bordon, Victoria⁵⁴  Dhooge, Catharina⁵⁴  Garcia-Lloret, Maria Laura⁵⁵  Bredius, Robbert G.⁵⁶  Kalwak, Krzysztof⁵⁷  Haddad, Elie⁵⁸  Seidel, Markus Gerhard⁵⁹  Duckers, Gregor⁵³  Pai, Sung-Yun^13,60  Dvorak, Christopher C.⁶¹  Ehl, Stephan²⁰  Locatelli, Franco³⁰  Goldman, Frederick⁶²  Gennery, Andrew Richard^11,12  Cowan, Mort J.⁶¹  Roncarolo, Maria-Grazia²  Bacchetta, Rosa² 

[1] Ist Ricovero & Cura Carattere Sci San Raffaele Sc, Pediat Immunohematol & Bone Marrow Transplant Uni, San Raffaele Telethon Inst Gene Therapy, Milan, Italy

[2] Stanford Univ, Sch Med, Dept Pediat, Div Stem Cell Transplantat & Regenerat Med, Stanford, CA 94305 USA

[3] Paris Descartes Univ, Necker Enfants Malades Univ Hosp, Sorbonne Paris Cite, Paediat Immunol Haematol & Rheumatol Dept, Paris, France

[4] Paris Descartes Univ, Necker Enfants Malades Univ Hosp, Sorbonne Paris Cite, Pediat Gastroenterol Unit, Paris, France

[5] Paris Descartes Univ, Necker Enfants Malades Univ Hosp, Sorbonne Paris Cite, Biotherapy Dept, Paris, France

[6] Robert Debre Hosp, AP HP, Hematol Unit, Paris, France

[7] Univ Florence, Dept NEUROFARBA, Anna Meyer Childrens Hosp, Sect Childs Hlth,Pediat Immunol, Florence, Italy

[8] Univ Florence, Dept NEUROFARBA, Anna Meyer Childrens Hosp,Sect Childs Hlth, Dept Hematol Oncol,Bone Marrow Transplant BMT Uni, Florence, Italy

[9] Univ Florence, Dept NEUROFARBA, Anna Meyer Childrens Hosp,Sect Childs Hlth, Gastroenterol Unit,Sect Childs Hlth, Florence, Italy

[10] Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA

[11] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England

[12] Great North Childrens Hosp, Childrens Bone Marrow Transplant Unit, Newcastle Upon Tyne, Tyne & Wear, England

[13] Boston Childrens Hosp, Pediat, Boston, MA USA

[14] Res & Clin Ctr Pediat Hematol Oncol & Immunol, Dept Immunol, Moscow, Russia

[15] Great Ormond St Hosp Sick Children, Dept Immunol & Gene Therapy, London, England

[16] Great Ormond St Hosp Sick Children, Dept Stem Cell Transplantat, London, England

[17] Univ Vita Salute San Raffaele, Milan, Italy

[18] Hosp Sick Children, Dept Pediat, Div Clin Immunol & Allergy, Toronto, ON, Canada

[19] Univ Freiburg, Fac Med, Dept Pediat & Adolescent Med, Freiburg, Germany

[20] Univ Freiburg, Fac Med, Ctr Chron Immunodeficiency Med Ctr, Freiburg, Germany

[21] Univ Sao Paulo, Fac Med, Dept Pediat, Inst Crianca, Sao Paulo, Brazil

[22] Univ Sao Paulo, Fac Med, Stem Cell Transplantat Unit, Inst Crianca, Sao Paulo, Brazil

[23] Marmara Univ, Pediat Allergy & Immunol, Istanbul, Turkey

[24] Univ Med Ctr, Dept Pediat, Ulm, Germany

[25] Spedali Civil Brescia, Childrens Hosp, Pediat Oncohematol & Bone Marrow Transplant BMT, Brescia, Italy

[26] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Sect Immunol Allergy Rheumatol, Houston, TX 77030 USA

[27] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat Hematol & Oncol, Houston, TX 77030 USA

[28] INSERM, UMR 1163, Lab Immunogenet Pediat Autoimmune Dis, Paris, France

[29] UCL, Great Ormond St Inst Child Hlth, London, England

[30] Univ Pavia, Ist Ricovero & Cura Carattere Sci, Bambino Gesu Childrens Hosp, Dept Pediat Hematol Oncol, Rome, Italy

[31] Ludwig Maximilians Univ Munchen, Dr von Hauner Childrens Hosp, Pediat Hematol Oncol, Munich, Germany

[32] KKR Sapporo Med Ctr, Ctr Pediat Allergy & Rheumatol, Sapporo, Hokkaido, Japan

[33] Hosp Univ Vall DHebron, Paediat Haematol & Oncol, Barcelona, Spain

[34] Tokyo Med & Dent Univ, Pediat & Dev Biol, Tokyo, Japan

[35] Med Univ Vienna, St Anna Childrens Hosp, Vienna, Austria

[36] Univ Ulsan, Coll Med, Pediat, Seoul, South Korea

[37] Asan Med Ctr, Seoul, South Korea

[38] Childrens Univ Hosp Nino Jesus, Dept Pediat, Hematopoiet Stem Cell Transplantat Unit, Madrid, Spain

[39] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Dept Pediat,Div Blood & Marrow Transplantat & Cel, Pittsburgh, PA 15260 USA

[40] Hannover Med Sch, Dept Pediat Hematol & Oncol, Hannover, Germany

[41] Medicalpk Hosp Goztepe, Pediat Stem Cell Transplantat Unit, Antalya, Turkey

[42] Antalya Hosp, Antalya, Turkey

[43] Columbia Med Ctr, Pediat Allergy Immunol & Rheumatol, New York, NY USA

[44] Columbia Med Ctr, Pediat Hematol Oncol & Stem Cell Transplantat, New York, NY USA

[45] Columbia Med Ctr, Pediat Gastroenterol Hepatol & Nutr, New York, NY USA

[46] Natl Childrens Hosp, Pediat Endocrinol, San Jose, CA USA

[47] Univ Turin, Regina Margherita Childrens Hosp, Dept Paediat Infect Dis, Div Rheumatol & Immunol, Turin, Italy

[48] Univ Seville, CSIC, Mixed Unit Res,Dept Paediat Infect Dis Rheumatol, UMR,Hosp Univ Virgen del Rocio,Inst Biomed Sevill, Seville, Spain

[49] Univ Seville, CSIC, Mixed Unit Res,Dept Pediat Hematol, UMR,Hosp Univ Virgen del Rocio,Inst Biomed Sevill, Seville, Spain

[50] Univ Seville, CSIC, Mixed Unit Res,Dept Paediatirc Gastroenterol, UMR,Hosp Univ Virgen del Rocio,Inst Biomed Sevill, Seville, Spain

[51] Ben Gurion Univ Negev, Fac Hlth Sci, Soroka Univ, Med Ctr,Pediat Immunol Clin, Beer Sheva, Israel

[52] Ben Gurion Univ Negev, Fac Hlth Sci, Soroka Univ, Pediat Ambulatory Care Unit,Med Ctr, Beer Sheva, Israel

[53] Helios Childrens Hosp, Dept Pediat, Krefeld, Germany

[54] Ghent Univ Hosp, Ctr Primary Immunodeficiencies, Dept Pediat, Ghent, Belgium

[55] Univ Calif Los Angeles, Sch Med, Div Pediat Allergy Immunol & Rheumatol, Los Angeles, CA 90024 USA

[56] Leiden Univ, Med Ctr, Pediat Immunol Infect & Stem Cell Transplantat SC, Leiden, Netherlands

[57] Wroclaw Med Univ, Dept Pediat Hematol, Oncol & Bone Marrow Transplant BMT Unit, Wroclaw, Poland

[58] Univ Montreal, St Justine Hosp, Dept Pediat, Montreal, PQ, Canada

[59] Med Univ Graz, Res Unit Pediat Hematol & Immunol, Div Pediat Hematol Oncol, Graz, Austria

[60] Dana Farber Canc Inst, Pediat Oncol, Boston, MA 02115 USA

[61] Univ Calif San Francisco, Pediat Allergy Immunol & Bone Marrow Transplant, Benioff Childrens Hosp, San Francisco, CA 94143 USA

[62] Univ Alabama Birmingham, Pediat, Birmingham, AL USA

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

DOI  :  10.1016/j.jaci.2017.10.041

来源: Elsevier

【 摘 要 】

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 5 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.

【 授权许可】

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