@article{3105891,
    title = "Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency",
    author = "Farmer, J.R. and Foldvari, Z. and Ujhazi, B. and De Ravin, S.S. and Chen, K. and Bleesing, J.J.H. and Schuetz, C. and Al-Herz, W. and Abraham, R.S. and Joshi, A.Y. and Costa-Carvalho, B.T. and Buchbinder, D. and Booth, C. and Reiff, A. and Ferguson, P.J. and Aghamohammadi, A. and Abolhassani, H. and Puck, J.M. and Adeli, M. and Cancrini, C. and Palma, P. and Bertaina, A. and Locatelli, F. and Di Matteo, G. and Geha, R.S. and Kanariou, M.G. and Lycopoulou, L. and Tzanoudaki, M. and Sleasman, J.W. and Parikh, S. and Pinero, G. and Fischer, B.M. and Dbaibo, G. and Unal, E. and Patiroglu, T. and Karakukcu, M. and Al-Saad, K.K. and Dilley, M.A. and Pai, S.-Y. and Dutmer, C.M. and Gelfand, E.W. and Geier, C.B. and Eibl, M.M. and Wolf, H.M. and Henderson, L.A. and Hazen, M.M. and Bonfim, C. and Wolska-Kuśnierz, B. and Butte, M.J. and Hernandez, J.D. and Nicholas, S.K. and Stepensky, P. and Chandrakasan, S. and Miano, M. and Westermann-Clark, E. and Goda, V. and Kriván, G. and Holland, S.M. and Fadugba, O. and Henrickson, S.E. and Ozen, A. and Karakoc-Aydiner, E. and Baris, S. and Kiykim, A. and Bredius, R. and Hoeger, B. and Boztug, K. and Pashchenko, O. and Neven, B. and Moshous, D. and de Villartay, J.-P. and Bousfiha, A.A. and Hill, H.R. and Notarangelo, L.D. and Walter, J.E.",
    journal = "The Journal of Allergy and Clinical Immunology: In Practice",
    year = "2019",
    volume = "7",
    number = "6",
    pages = "1970-1985.e4",
    publisher = "American Academy of Allergy, Asthma and Immunology",
    issn = "2213-2198",
    doi = "10.1016/j.jaip.2019.02.038",
    keywords = "immunoglobulin;  rituximab;  steroid;  homeodomain protein;  immunosuppressive agent;  RAG-1 protein, Article;  autoimmunity;  clinical feature;  cytopenia;  dermatitis;  granuloma;  hematopoietic stem cell transplantation;  hemolytic anemia;  human;  idiopathic thrombocytopenic purpura;  immune dysregulation;  immunopathology;  inflammation;  neutropenia;  patient risk;  recombination activating gene deficiency;  risk factor;  treatment outcome;  vaccination;  adolescent;  adult;  autoimmunity;  case report;  child;  female;  immune deficiency;  immunology;  infant;  inflammation;  male;  middle aged;  preschool child;  young adult, Adolescent;  Adult;  Autoimmunity;  Child;  Child, Preschool;  Female;  Hematopoietic Stem Cell Transplantation;  Homeodomain Proteins;  Humans;  Immunologic Deficiency Syndromes;  Immunosuppressive Agents;  Infant;  Inflammation;  Male;  Middle Aged;  Treatment Outcome;  Young Adult",
    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"
}