Journal article
Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency
The journal of allergy and clinical immunology in practice (Cambridge, MA), Vol.7(6), pp.1970-1985.e4
07/2019
DOI: 10.1016/j.jaip.2019.02.038
PMCID: PMC6612449
PMID: 30877075
Abstract
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.
Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency.
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.
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.
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.
Details
- Title: Subtitle
- Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency
- Creators
- Jocelyn R Farmer - Massachusetts General Hospital, Harvard Medical School, Boston, MassZsofia Foldvari - Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, NorwayBoglarka Ujhazi - University of South Florida and Johns Hopkins All Children's Hospital, Saint Petersburg, FlaSuk See De Ravin - Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, MdKarin Chen - Division of Allergy and Immunology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UtahJack J.H Bleesing - Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioCatharina Schuetz - Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, GermanyWaleed Al-Herz - Faculty of Medicine, Pediatrics Department, Kuwait University, Kuwait City, KuwaitRoshini S Abraham - Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OhioAvni Y Joshi - Division of Pediatric Allergy/Immunology, Mayo Clinic Children's Center Rochester, Rochester, MinnBeatriz T Costa-Carvalho - Department of Pediatrics, UNIFESP-EPM, São Paulo, BrazilDavid Buchbinder - Pediatrics/Hematology, CHOC Children's Hospital - UC Irvine, Irvine, CalifClaire Booth - Department of Paediatric Immunology, Great Ormond Street Hospital, London, United KingdomAndreas Reiff - Division of Rheumatology, Children's Hospital Los Angeles, Keck School of Medicine, USC, Los Angeles, CalifPolly J Ferguson - Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IowaAsghar Aghamohammadi - Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, IranHassan Abolhassani - Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, IranJennifer M Puck - Department of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, CalifMehdi Adeli - Sidra Medicine, Weill Cornell Medicine, and Hamad Medical Corporation, Doha, QatarCaterina Cancrini - Academic Department of Pediatrics (DPUO), Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, ItalyPaolo Palma - Academic Department of Pediatrics (DPUO), Research Unit in Congenital and Perinatal Infection, Children's Hospital Bambino Gesù, Rome, ItalyAlice Bertaina - Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Bambino Gesù, Rome, ItalyFranco Locatelli - Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Bambino Gesù, Rome, ItalyGigliola Di Matteo - Academic Department of Pediatrics (DPUO), Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, ItalyRaif S Geha - Immunology Division, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MassMaria G Kanariou - Department of Immunology - Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies - Paediatric Immunology, ”Aghia Sophia” Children's Hospital, Athens, GreeceLilia Lycopoulou - 1st Department of Pediatrics, University of Athens, Aghia Sofia Children's Hospital, Athens, GreeceMarianna Tzanoudaki - Department of Immunology - Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies - Paediatric Immunology, ”Aghia Sophia” Children's Hospital, Athens, GreeceJohn W Sleasman - Division of Allergy, Immunology and Pulmonary Medicine, Duke University School of Medicine, Durham, NCSuhag Parikh - Division of Pediatric Blood and Marrow Transplantation, Duke University School of Medicine, Durham, NCGloria Pinero - Division of Allergy, Immunology and Pulmonary Medicine, Duke University School of Medicine, Durham, NCBernard M Fischer - Division of Allergy, Immunology and Pulmonary Medicine, Duke University School of Medicine, Durham, NCGhassan Dbaibo - Department of Pediatrics and Adolescent Medicine, Center for Infectious Diseases Research, American University of Beirut, Beirut, LebanonEkrem Unal - Division of Pediatric Hematology and Oncology & HCST Unit, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, TurkeyTurkan Patiroglu - Division of Pediatric Hematology and Oncology & HCST Unit, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, TurkeyMusa Karakukcu - Division of Pediatric Hematology and Oncology & HCST Unit, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, TurkeyKhulood Khalifa Al-Saad - Salmanyia Medical Complex, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Manama, BahrainMeredith A Dilley - Department of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MassSung-Yun Pai - Division of Hematology-Oncology, Boston Children's Hospital, Boston, MassCullen M Dutmer - Division of Allergy & Immunology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, ColoErwin W Gelfand - Department of Pediatrics, National Jewish Health, Denver, ColoChristoph B Geier - Immunology Outpatient Clinic, Vienna, AustriaMartha M Eibl - Immunology Outpatient Clinic, Vienna, AustriaHermann M Wolf - Immunology Outpatient Clinic, Vienna, AustriaLauren A Henderson - Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MassMelissa M Hazen - Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MassCarmem Bonfim - Hospital Infantil Pequeno Principe, Curitiba, BrazilBeata Wolska-Kuśnierz - Immunology Department, Children's Memorial Health Institute, Warsaw, PolandManish J Butte - Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics and Jeffrey Modell Diagnostic and Research Center, University of California, Los Angeles, Los Angeles, CalifJoseph D Hernandez - Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, CalifSarah K Nicholas - Section of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, TexasPolina Stepensky - Department of Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Jerusalem, IsraelShanmuganathan Chandrakasan - Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GaMaurizio Miano - Haematology Unit, Department of Pediatric Haematology-Oncology, IRCCS Istituto Giannina Gaslini, Genova, ItalyEmma Westermann-Clark - Department of Internal Medicine, Division of Allergy/Immunology, University of South Florida Morsani College of Medicine, Tampa, FlaVera Goda - Department for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest- National Institute of Hematology and Infectious Diseases, Budapest, HungaryGergely Kriván - Department for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest- National Institute of Hematology and Infectious Diseases, Budapest, HungarySteven M Holland - Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MdOlajumoke Fadugba - Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PaSarah E Henrickson - Allergy Immunology Division, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PaAhmet Ozen - Marmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, TurkeyElif Karakoc-Aydiner - Marmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, TurkeySafa Baris - Marmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, TurkeyAyca Kiykim - Ministry of Health, Marmara University Pendik Training and Research Hospital, Istanbul, TurkeyRobbert Bredius - Department of Pediatrics, Section Pediatric Immunology, Infections and Stem Cell Transplantation, Leiden University Medical Center, Leiden, the NetherlandsBirgit Hoeger - Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, AustriaKaan Boztug - Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, AustriaOlga Pashchenko - Department of Immunology, Pirogov Russian National Research Medical University, Russian Clinical Children's Hospital, Moscow, RussiaBenedicte Neven - Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, FranceDespina Moshous - Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, FranceJean-Pierre de Villartay - Laboratory “Genome Dynamics in The Immune System”, INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, FranceAhmed Aziz Bousfiha - Laboratoire d'Immunologie Clinique, d'Inflammation et d'Allergie LICIA, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, MoroccoHarry R Hill - Division of Clinical Immunology, Departments of Pathology, Pediatrics and Medicine, University of Utah, Salt Lake City, UtahLuigi D Notarangelo - Haematology Unit, Department of Pediatric Haematology-Oncology, IRCCS Istituto Giannina Gaslini, Genova, ItalyJolan E Walter - University of South Florida and Johns Hopkins All Children's Hospital, Saint Petersburg, Fla
- Resource Type
- Journal article
- Publication Details
- The journal of allergy and clinical immunology in practice (Cambridge, MA), Vol.7(6), pp.1970-1985.e4
- DOI
- 10.1016/j.jaip.2019.02.038
- PMID
- 30877075
- PMCID
- PMC6612449
- NLM abbreviation
- J Allergy Clin Immunol Pract
- ISSN
- 2213-2198
- eISSN
- 2213-2201
- Publisher
- Elsevier Inc
- Grant note
- T32-HL116275; 5K08AI103035; R01AI100887-05; R01AR059703; 5K12HD043245 / National Institutes of Health (https://doi.org/10.13039/100000002) Clinical Immunology Society Division of Intramural Research, National Institute of Allergy and Infectious Diseases (https://doi.org/10.13039/100006492) AAAAI Foundation University of South Florida (https://doi.org/10.13039/100008900) Robert A. Good Endowment
- Language
- English
- Date published
- 07/2019
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Rheumatology, Allergy, and Immunology
- Record Identifier
- 9984070355402771
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