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Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients With Rag Deficiency Publisher Pubmed



Farmer JR1 ; Foldvari Z2 ; Ujhazi B3 ; De Ravin SS4 ; Chen K5 ; Bleesing JJH6 ; Schuetz C7 ; Alherz W8, 9 ; Abraham RS10, 11 ; Joshi AY12 ; Costacarvalho BT13 ; Buchbinder D14 ; Booth C15 ; Reiff A16 Show All Authors
Authors
  1. Farmer JR1
  2. Foldvari Z2
  3. Ujhazi B3
  4. De Ravin SS4
  5. Chen K5
  6. Bleesing JJH6
  7. Schuetz C7
  8. Alherz W8, 9
  9. Abraham RS10, 11
  10. Joshi AY12
  11. Costacarvalho BT13
  12. Buchbinder D14
  13. Booth C15
  14. Reiff A16
  15. Ferguson PJ17
  16. Aghamohammadi A18
  17. Abolhassani H18
  18. Puck JM19
  19. Adeli M20
  20. Cancrini C21, 22
  21. Palma P23
  22. Bertaina A24
  23. Locatelli F24, 25
  24. Di Matteo G21, 22
  25. Geha RS26
  26. Kanariou MG27
  27. Lycopoulou L28
  28. Tzanoudaki M27
  29. Sleasman JW29
  30. Parikh S30
  31. Pinero G29
  32. Fischer BM29
  33. Dbaibo G31
  34. Unal E32
  35. Patiroglu T32, 33
  36. Karakukcu M32
  37. Alsaad KK34
  38. Dilley MA35
  39. Pai SY36, 37, 38
  40. Dutmer CM39
  41. Gelfand EW40
  42. Geier CB41
  43. Eibl MM41, 42
  44. Wolf HM41, 43
  45. Henderson LA44
  46. Hazen MM44
  47. Bonfim C45
  48. Wolskakusnierz B46
  49. Butte MJ47
  50. Hernandez JD48
  51. Nicholas SK49
  52. Stepensky P50
  53. Chandrakasan S51
  54. Miano M52
  55. Westermannclark E53
  56. Goda V54
  57. Krivan G54
  58. Holland SM55
  59. Fadugba O56
  60. Henrickson SE57, 58
  61. Ozen A59
  62. Karakocaydiner E59
  63. Baris S59
  64. Kiykim A60
  65. Bredius R61
  66. Hoeger B62, 63
  67. Boztug K62, 63, 64, 65
  68. Pashchenko O66
  69. Neven B67, 68, 69
  70. Moshous D67, 68, 70
  71. De Villartay JP70
  72. Bousfiha AA71, 72
  73. Hill HR73
  74. Notarangelo LD52
  75. Walter JE3, 74
Show Affiliations
Authors Affiliations
  1. 1. Massachusetts General Hospital, Harvard Medical School, Boston, Mass, United States
  2. 2. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway
  3. 3. University of South Florida and Johns Hopkins All Children's Hospital, Saint Petersburg, Fla, United States
  4. 4. Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, Md, United States
  5. 5. Division of Allergy and Immunology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, United States
  6. 6. Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
  7. 7. Department of Pediatrics, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany
  8. 8. Faculty of Medicine, Pediatrics Department, Kuwait University, Kuwait City, Kuwait
  9. 9. Allergy and Clinical Immunology Unit, Pediatrics Department, Alsabah Hospital, Kuwait City, Kuwait
  10. 10. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, United States
  11. 11. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn, United States
  12. 12. Division of Pediatric Allergy/Immunology, Mayo Clinic Children's Center Rochester, Rochester, Minn, United States
  13. 13. Department of Pediatrics, UNIFESP-EPM, Sao Paulo, Brazil
  14. 14. Pediatrics/Hematology, CHOC Children's Hospital - UC Irvine, Irvine, Calif, United States
  15. 15. Department of Paediatric Immunology, Great Ormond Street Hospital, London, United Kingdom
  16. 16. Division of Rheumatology, Children's Hospital Los Angeles, Keck School of Medicine, USC, Los Angeles, Calif, United States
  17. 17. Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, United States
  18. 18. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  19. 19. Department of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, Calif, United States
  20. 20. Sidra Medicine, Weill Cornell Medicine, and Hamad Medical Corporation, Doha, Qatar
  21. 21. Academic Department of Pediatrics (DPUO), Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesu, Rome, Italy
  22. 22. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
  23. 23. Academic Department of Pediatrics (DPUO), Research Unit in Congenital and Perinatal Infection, Children's Hospital Bambino Gesu, Rome, Italy
  24. 24. Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Bambino Gesu, Rome, Italy
  25. 25. Department of Pediatrics, Sapienza, University of Rome, Rome, Italy
  26. 26. Immunology Division, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass, United States
  27. 27. Department of Immunology - Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies - Paediatric Immunology, �Aghia Sophia� Children's Hospital, Athens, Greece
  28. 28. 1st Department of Pediatrics, University of Athens, Aghia Sofia Children's Hospital, Athens, Greece
  29. 29. Division of Allergy, Immunology and Pulmonary Medicine, Duke University School of Medicine, Durham, NC, United States
  30. 30. Division of Pediatric Blood and Marrow Transplantation, Duke University School of Medicine, Durham, NC, United States
  31. 31. Department of Pediatrics and Adolescent Medicine, Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon
  32. 32. Division of Pediatric Hematology and Oncology & HCST Unit, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
  33. 33. Division of Pediatric Immunology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
  34. 34. Salmanyia Medical Complex, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Manama, Bahrain
  35. 35. Department of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass, United States
  36. 36. Division of Hematology-Oncology, Boston Children's Hospital, Boston, Mass, United States
  37. 37. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Mass, United States
  38. 38. Harvard Medical School, Boston, Mass, United States
  39. 39. Division of Allergy & Immunology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colo, United States
  40. 40. Department of Pediatrics, National Jewish Health, Denver, Colo, United States
  41. 41. Immunology Outpatient Clinic, Vienna, Austria
  42. 42. Biomedizinische Forschungs GmbH, Vienna, Austria
  43. 43. Sigmund Freud Private University-Medical School, Vienna, Austria
  44. 44. Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass, United States
  45. 45. Hospital Infantil Pequeno Principe, Curitiba, Brazil
  46. 46. Immunology Department, Children's Memorial Health Institute, Warsaw, Poland
  47. 47. Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics and Jeffrey Modell Diagnostic and Research Center, University of California, Los Angeles, Los Angeles, Calif, United States
  48. 48. Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, Calif, United States
  49. 49. Section of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States
  50. 50. Department of Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Jerusalem, Israel
  51. 51. Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga, United States
  52. 52. Haematology Unit, Department of Pediatric Haematology-Oncology, IRCCS Istituto Giannina Gaslini, Genova, Italy
  53. 53. Department of Internal Medicine, Division of Allergy/Immunology, University of South Florida Morsani College of Medicine, Tampa, Fla, United States
  54. 54. Department for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest- National Institute of Hematology and Infectious Diseases, Budapest, Hungary
  55. 55. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Md, United States
  56. 56. Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa, United States
  57. 57. Allergy Immunology Division, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pa, United States
  58. 58. Institute for Immunology, the University of Pennsylvania, Philadelphia, Pa, United States
  59. 59. Marmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkey
  60. 60. Ministry of Health, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey
  61. 61. Department of Pediatrics, Section Pediatric Immunology, Infections and Stem Cell Transplantation, Leiden University Medical Center, Leiden, Netherlands
  62. 62. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
  63. 63. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
  64. 64. St Anna Kinderspital and Children's Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna, Austria
  65. 65. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
  66. 66. Department of Immunology, Pirogov Russian National Research Medical University, Russian Clinical Children's Hospital, Moscow, Russian Federation
  67. 67. Paris Descartes Sorbonne Paris Cite University, Imagine Institute, Paris, France
  68. 68. Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hopitaux de Paris, Paris, France
  69. 69. Laboratory “Immunogenetics of Pediatric Autoimmune Diseases�, INSERM UMR1163, Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris, France
  70. 70. Laboratory “Genome Dynamics in The Immune System�, INSERM UMR1163, Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris, France
  71. 71. Laboratoire d'Immunologie Clinique, d'Inflammation et d'Allergie LICIA, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
  72. 72. Clinical Immunology Unit, Casablanca Children's Hospital, Ibn Rochd Medical School, Hassan II University, Casablanca, Morocco, Morocco
  73. 73. Division of Clinical Immunology, Departments of Pathology, Pediatrics and Medicine, University of Utah, Salt Lake City, UT, United States
  74. 74. Division of Allergy and Immunology, Massachusetts General Hospital for Children, Boston, Mass, United States

Source: Journal of Allergy and Clinical Immunology: In Practice Published:2019


Abstract

Background: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. Objective: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. Methods: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. Results: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. Conclusions: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management. © 2019 The Authors