TY - JOUR
T1 - Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency
AU - Farmer, Jocelyn R.
AU - Foldvari, Zsofia
AU - Ujhazi, Boglarka
AU - De Ravin, Suk See
AU - Chen, K.
AU - Bleesing, Jack J.H.
AU - Schuetz, Catharina
AU - Al-Herz, Waleed
AU - Abraham, Roshini S.
AU - Joshi, Avni Y.
AU - Costa-Carvalho, Beatriz T.
AU - Buchbinder, D.
AU - Booth, Claire
AU - Reiff, Andreas
AU - Ferguson, Polly J.
AU - Aghamohammadi, Asghar
AU - Abolhassani, Hassan
AU - Puck, Jennifer M.
AU - Adeli, M.
AU - Cancrini, Caterina
AU - Palma, P.
AU - Bertaina, A.
AU - Locatelli, Franco
AU - Di Matteo, Gigliola
AU - Geha, Raif S.
AU - Kanariou, Maria G.
AU - Lycopoulou, L.
AU - Tzanoudaki, Marianna
AU - Sleasman, John W.
AU - Parikh, S.
AU - Pinero, Gloria
AU - Fischer, Bernard M.
AU - Dbaibo, Ghassan
AU - Unal, E.
AU - Patiroglu, Turkan
AU - Karakukcu, Musa
AU - Al-Saad, Khulood Khalifa
AU - Dilley, Meredith A.
AU - Pai, Sung-Yun
AU - Dutmer, Cullen M.
AU - Gelfand, Erwin W.
AU - Geier, Christoph B.
AU - Eibl, Martha M.
AU - Wolf, Hermann M.
AU - Henderson, Lauren A.
AU - Hazen, Melissa M.
AU - Bonfim, Carmem
AU - Wolska-Kuśnierz, B.
AU - Butte, Manish J.
AU - Hernandez, Joseph D.
AU - Nicholas, Sarah K.
AU - Stepensky, Polina
AU - Chandrakasan, Shanmuganathan
AU - Miano, Maurizio
AU - Westermann-Clark, Emma
AU - Goda, Vera
AU - Kriván, Gergely
AU - Holland, Steven M.
AU - Fadugba, Olajumoke
AU - Henrickson, Sarah E.
AU - Ozen, A.
AU - Karakoc-Aydiner, Elif
AU - Baris, Safa
AU - Kiykim, Ayca
AU - Bredius, Robbert
AU - Hoeger, Birgit
AU - Boztug, Kaan
AU - Pashchenko, Olga
AU - Neven, Benedicte
AU - Moshous, Despina
AU - De Villartay, Jean-Pierre
AU - Bousfiha, Ahmed Aziz
AU - Hill, Harry R.
AU - Notarangelo, Luigi D.
AU - Walter, Jolan E.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Autoimmune cytopenias
KW - Hematopoietic stem cell transplantation (HSCT)
KW - Immune dysregulation
KW - Recombination activating gene (RAG)
KW - Severe combined immunodeficiency (SCID)
KW - Autoimmune cytopenias
KW - Hematopoietic stem cell transplantation (HSCT)
KW - Immune dysregulation
KW - Recombination activating gene (RAG)
KW - Severe combined immunodeficiency (SCID)
UR - http://hdl.handle.net/10807/228277
U2 - 10.1016/j.jaip.2019.02.038
DO - 10.1016/j.jaip.2019.02.038
M3 - Article
SN - 2213-2198
VL - 7
SP - 1970-1985.e4
JO - JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE
JF - JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE
ER -
