Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency

Jocelyn R. Farmer; Zsofia Foldvari; Boglarka Ujhazi; Suk See De Ravin; K. Chen; Jack J.H. Bleesing; Catharina Schuetz; Waleed Al-Herz; Roshini S. Abraham; Avni Y. Joshi; Beatriz T. Costa-Carvalho; D. Buchbinder; Claire Booth; Andreas Reiff; Polly J. Ferguson; Asghar Aghamohammadi; Hassan Abolhassani; Jennifer M. Puck; M. Adeli; Caterina Cancrini; P. Palma; A. Bertaina; Franco Locatelli; Gigliola Di Matteo; Raif S. Geha; Maria G. Kanariou; L. Lycopoulou; Marianna Tzanoudaki; John W. Sleasman; S. Parikh; Gloria Pinero; Bernard M. Fischer; Ghassan Dbaibo; E. Unal; Turkan Patiroglu; Musa Karakukcu; Khulood Khalifa Al-Saad; Meredith A. Dilley; Sung-Yun Pai; Cullen M. Dutmer; Erwin W. Gelfand; Christoph B. Geier; Martha M. Eibl; Hermann M. Wolf; Lauren A. Henderson; Melissa M. Hazen; Carmem Bonfim; B. Wolska-Kuśnierz; Manish J. Butte; Joseph D. Hernandez; Sarah K. Nicholas; Polina Stepensky; Shanmuganathan Chandrakasan; Maurizio Miano; Emma Westermann-Clark; Vera Goda; Gergely Kriván; Steven M. Holland; Olajumoke Fadugba; Sarah E. Henrickson; A. Ozen; Elif Karakoc-Aydiner; Safa Baris; Ayca Kiykim; Robbert Bredius; Birgit Hoeger; Kaan Boztug; Olga Pashchenko; Benedicte Neven; Despina Moshous; Jean-Pierre De Villartay; Ahmed Aziz Bousfiha; Harry R. Hill; Luigi D. Notarangelo; Jolan E. Walter

doi:10.1016/j.jaip.2019.02.038

Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency

Jocelyn R. Farmer
, Zsofia Foldvari
, Boglarka Ujhazi
, Suk See De Ravin
, K. Chen
, Jack J.H. Bleesing
, Catharina Schuetz
, Waleed Al-Herz
, Roshini S. Abraham
, Avni Y. Joshi
, Beatriz T. Costa-Carvalho
, D. Buchbinder
, Claire Booth
, Andreas Reiff
, Polly J. Ferguson
, Asghar Aghamohammadi
, Hassan Abolhassani
, Jennifer M. Puck
, M. Adeli
, Caterina Cancrini

P. Palma, A. Bertaina, Franco Locatelli, Gigliola Di Matteo, Raif S. Geha, Maria G. Kanariou, L. Lycopoulou, Marianna Tzanoudaki, John W. Sleasman, S. Parikh, Gloria Pinero, Bernard M. Fischer, Ghassan Dbaibo, E. Unal, Turkan Patiroglu, Musa Karakukcu, Khulood Khalifa Al-Saad, Meredith A. Dilley, Sung-Yun Pai, Cullen M. Dutmer, Erwin W. Gelfand, Christoph B. Geier, Martha M. Eibl, Hermann M. Wolf, Lauren A. Henderson, Melissa M. Hazen, Carmem Bonfim, B. Wolska-Kuśnierz, Manish J. Butte, Joseph D. Hernandez, Sarah K. Nicholas, Polina Stepensky, Shanmuganathan Chandrakasan, Maurizio Miano, Emma Westermann-Clark, Vera Goda, Gergely Kriván, Steven M. Holland, Olajumoke Fadugba, Sarah E. Henrickson, A. Ozen, Elif Karakoc-Aydiner, Safa Baris, Ayca Kiykim, Robbert Bredius, Birgit Hoeger, Kaan Boztug, Olga Pashchenko, Benedicte Neven, Despina Moshous, Jean-Pierre De Villartay, Ahmed Aziz Bousfiha, Harry R. Hill, Luigi D. Notarangelo, Jolan E. Walter

Department of Molecular Biology
University of Oslo
University of South Florida
National Institutes of Health
University of Utah
Cincinnati Children's Hospital Medical Center
Technische Universität Dresden
Kuwait University
Center for Microbial Pathogenesis
Mayo Clinic Rochester, MN
Universidade Federal de São Paulo
University of California at Irvine
Great Ormond Street Hospital for Children
University of Southern California
University of Iowa
Tehran University of Medical Sciences
University of California at San Francisco
Hamad Medical Corporation
IRCCS Ospedale pediatrico Bambino Gesù - Roma
Boston Children's Hospital
Aghia Sophia Children's Hospital
National and Kapodistrian University of Athens
Duke University
American University of Beirut
Erciyes University
Ministry of Health, Kingdom of Bahrain
University of Colorado Anschutz Medical Campus
National Jewish Health
Immunology Outpatient Clinic
Hospital Pequeno Príncipe
Children's Memorial Health Institute
University of California at Los Angeles
Stanford University
Texas Children's Hospital Houston
Hadassah University Medical Centre
Emory University
IRCCS Istituto Giannina Gaslini - Genova
South-Pest Central Hospital National Institute of Hematology and Infectious Diseases
University of Pennsylvania
The Children's Hospital of Philadelphia
Marmara University
Leiden University
Ludwig Boltzmann Institute
Pirogov Russian National Research Medical University
and health
l'Institut des Maladies Génétiques Imagine
University of Hassan II Casablanca

Research output: Contribution to journal › Article

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.

Original language	English
Pages (from-to)	1970-1985.e4
Journal	JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE
Volume	7
DOIs	https://doi.org/10.1016/j.jaip.2019.02.038
Publication status	Published - 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Autoimmune cytopenias
Hematopoietic stem cell transplantation (HSCT)
Immune dysregulation
Recombination activating gene (RAG)
Severe combined immunodeficiency (SCID)

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10.1016/j.jaip.2019.02.038

Cite this

Farmer, J. R., Foldvari, Z., Ujhazi, B., De Ravin, S. S., Chen, K., Bleesing, J. J. H., Schuetz, C., Al-Herz, W., Abraham, R. S., Joshi, A. Y., Costa-Carvalho, B. T., Buchbinder, D., Booth, C., Reiff, A., Ferguson, P. J., Aghamohammadi, A., Abolhassani, H., Puck, J. M., Adeli, M., ... Walter, J. E. (2019). Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE, 7, 1970-1985.e4. https://doi.org/10.1016/j.jaip.2019.02.038

@article{511ad17f3ed8447ea2f0232385f220a8,

title = "Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency",

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.",

keywords = "Autoimmune cytopenias, Hematopoietic stem cell transplantation (HSCT), Immune dysregulation, Recombination activating gene (RAG), Severe combined immunodeficiency (SCID), Autoimmune cytopenias, Hematopoietic stem cell transplantation (HSCT), Immune dysregulation, Recombination activating gene (RAG), Severe combined immunodeficiency (SCID)",

author = "Farmer, \{Jocelyn R.\} and Zsofia Foldvari and Boglarka Ujhazi and \{De Ravin\}, \{Suk See\} and K. Chen and Bleesing, \{Jack J.H.\} and Catharina Schuetz and Waleed Al-Herz and Abraham, \{Roshini S.\} and Joshi, \{Avni Y.\} and Costa-Carvalho, \{Beatriz T.\} and D. Buchbinder and Claire Booth and Andreas Reiff and Ferguson, \{Polly J.\} and Asghar Aghamohammadi and Hassan Abolhassani and Puck, \{Jennifer M.\} and M. Adeli and Caterina Cancrini and P. Palma and A. Bertaina and Franco Locatelli and \{Di Matteo\}, Gigliola and Geha, \{Raif S.\} and Kanariou, \{Maria G.\} and L. Lycopoulou and Marianna Tzanoudaki and Sleasman, \{John W.\} and S. Parikh and Gloria Pinero and Fischer, \{Bernard M.\} and Ghassan Dbaibo and E. Unal and Turkan Patiroglu and Musa Karakukcu and Al-Saad, \{Khulood Khalifa\} and Dilley, \{Meredith A.\} and Sung-Yun Pai and Dutmer, \{Cullen M.\} and Gelfand, \{Erwin W.\} and Geier, \{Christoph B.\} and Eibl, \{Martha M.\} and Wolf, \{Hermann M.\} and Henderson, \{Lauren A.\} and Hazen, \{Melissa M.\} and Carmem Bonfim and B. Wolska-Ku{\'s}nierz and Butte, \{Manish J.\} and Hernandez, \{Joseph D.\} and Nicholas, \{Sarah K.\} and Polina Stepensky and Shanmuganathan Chandrakasan and Maurizio Miano and Emma Westermann-Clark and Vera Goda and Gergely Kriv{\'a}n and Holland, \{Steven M.\} and Olajumoke Fadugba and Henrickson, \{Sarah E.\} and A. Ozen and Elif Karakoc-Aydiner and Safa Baris and Ayca Kiykim and Robbert Bredius and Birgit Hoeger and Kaan Boztug and Olga Pashchenko and Benedicte Neven and Despina Moshous and \{De Villartay\}, Jean-Pierre and Bousfiha, \{Ahmed Aziz\} and Hill, \{Harry R.\} and Notarangelo, \{Luigi D.\} and Walter, \{Jolan E.\}",

year = "2019",

doi = "10.1016/j.jaip.2019.02.038",

language = "English",

volume = "7",

pages = "1970--1985.e4",

journal = "JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE",

issn = "2213-2198",

publisher = "Amsterdam [u.a.] : Elsevier",

}

Farmer, JR, Foldvari, Z, Ujhazi, B, De Ravin, SS, Chen, K, Bleesing, JJH, Schuetz, C, Al-Herz, W, Abraham, RS, Joshi, AY, Costa-Carvalho, BT, Buchbinder, D, Booth, C, Reiff, A, Ferguson, PJ, Aghamohammadi, A, Abolhassani, H, Puck, JM, Adeli, M, Cancrini, C, Palma, P, Bertaina, A, Locatelli, F, Di Matteo, G, Geha, RS, Kanariou, MG, Lycopoulou, L, Tzanoudaki, M, Sleasman, JW, Parikh, S, Pinero, G, Fischer, BM, Dbaibo, G, Unal, E, Patiroglu, T, Karakukcu, M, Al-Saad, KK, Dilley, MA, Pai, S-Y, Dutmer, CM, Gelfand, EW, Geier, CB, Eibl, MM, Wolf, HM, Henderson, LA, Hazen, MM, Bonfim, C, Wolska-Kuśnierz, B, Butte, MJ, Hernandez, JD, Nicholas, SK, Stepensky, P, Chandrakasan, S, Miano, M, Westermann-Clark, E, Goda, V, Kriván, G, Holland, SM, Fadugba, O, Henrickson, SE, Ozen, A, Karakoc-Aydiner, E, Baris, S, Kiykim, A, Bredius, R, Hoeger, B, Boztug, K, Pashchenko, O, Neven, B, Moshous, D, De Villartay, J-P, Bousfiha, AA, Hill, HR, Notarangelo, LD & Walter, JE 2019, 'Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE, vol. 7, pp. 1970-1985.e4. https://doi.org/10.1016/j.jaip.2019.02.038

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 -

Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency

Abstract

UN SDGs

Keywords

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