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

Jocelyn R Farmer, Zsofia Foldvari, Boglarka Ujhazi, Suk See De Ravin, Karin Chen, Jack J H Bleesing, Catharina Schuetz, Waleed Al-Herz, Roshini S Abraham, Avni Y Joshi, Beatriz T Costa-Carvalho, David Buchbinder, Claire Booth, Andreas Reiff, Polly J Ferguson, Asghar Aghamohammadi, Hassan Abolhassani, Jennifer M Puck, Mehdi Adeli, Caterina CancriniPaolo Palma, Alice Bertaina, Franco Locatelli, Gigliola Di Matteo, Raif S Geha, Maria G Kanariou, Lilia Lycopoulou, Marianna Tzanoudaki, John W Sleasman, Suhag Parikh, Gloria Pinero, Bernard M Fischer, Ghassan Dbaibo, Ekrem 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, Beata 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, Ahmet 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

Research output: Contribution to journalArticle

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 languageEnglish
JournalJournal of Allergy and Clinical Immunology: In Practice
DOIs
Publication statusE-pub ahead of print - Mar 12 2019

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Autoimmunity
Genetic Recombination
Idiopathic Thrombocytopenic Purpura
Genes
Neutropenia
Delayed Diagnosis
Hematopoietic Stem Cell Transplantation
Intravenous Immunoglobulins
Cell Transplantation
Therapeutics
Immunosuppressive Agents
Granuloma
Vaccination
Steroids
Databases
Pathology
Skin
Infection
Evans Syndrome

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

In: Journal of Allergy and Clinical Immunology: In Practice, 12.03.2019.

Research output: Contribution to journalArticle

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, Villartay, J-PD, 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. https://doi.org/10.1016/j.jaip.2019.02.038
Farmer, Jocelyn R ; Foldvari, Zsofia ; Ujhazi, Boglarka ; De Ravin, Suk See ; Chen, Karin ; Bleesing, Jack J H ; Schuetz, Catharina ; Al-Herz, Waleed ; Abraham, Roshini S ; Joshi, Avni Y ; Costa-Carvalho, Beatriz T ; Buchbinder, David ; Booth, Claire ; Reiff, Andreas ; Ferguson, Polly J ; Aghamohammadi, Asghar ; Abolhassani, Hassan ; Puck, Jennifer M ; Adeli, Mehdi ; Cancrini, Caterina ; Palma, Paolo ; Bertaina, Alice ; Locatelli, Franco ; Di Matteo, Gigliola ; Geha, Raif S ; Kanariou, Maria G ; Lycopoulou, Lilia ; Tzanoudaki, Marianna ; Sleasman, John W ; Parikh, Suhag ; Pinero, Gloria ; Fischer, Bernard M ; Dbaibo, Ghassan ; Unal, Ekrem ; Patiroglu, Turkan ; Karakukcu, Musa ; Al-Saad, Khulood Khalifa ; Dilley, Meredith A ; Pai, Sung-Yun ; Dutmer, Cullen M ; Gelfand, Erwin W ; Geier, Christoph B ; Eibl, Martha M ; Wolf, Hermann M ; Henderson, Lauren A ; Hazen, Melissa M ; Bonfim, Carmem ; Wolska-Kuśnierz, Beata ; Butte, Manish J ; Hernandez, Joseph D ; Nicholas, Sarah K ; Stepensky, Polina ; Chandrakasan, Shanmuganathan ; Miano, Maurizio ; Westermann-Clark, Emma ; Goda, Vera ; Kriván, Gergely ; Holland, Steven M ; Fadugba, Olajumoke ; Henrickson, Sarah E ; Ozen, Ahmet ; Karakoc-Aydiner, Elif ; Baris, Safa ; Kiykim, Ayca ; Bredius, Robbert ; Hoeger, Birgit ; Boztug, Kaan ; Pashchenko, Olga ; Neven, Benedicte ; Moshous, Despina ; Villartay, Jean-Pierre de ; Bousfiha, Ahmed Aziz ; Hill, Harry R ; Notarangelo, Luigi D ; Walter, Jolan E. / Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency. In: Journal of Allergy and Clinical Immunology: In Practice. 2019.
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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.",
author = "Farmer, {Jocelyn R} and Zsofia Foldvari and Boglarka Ujhazi and {De Ravin}, {Suk See} and Karin 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 David Buchbinder and Claire Booth and Andreas Reiff and Ferguson, {Polly J} and Asghar Aghamohammadi and Hassan Abolhassani and Puck, {Jennifer M} and Mehdi Adeli and Caterina Cancrini and Paolo Palma and Alice Bertaina and Franco Locatelli and {Di Matteo}, Gigliola and Geha, {Raif S} and Kanariou, {Maria G} and Lilia Lycopoulou and Marianna Tzanoudaki and Sleasman, {John W} and Suhag Parikh and Gloria Pinero and Fischer, {Bernard M} and Ghassan Dbaibo and Ekrem 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 Beata Wolska-Kuśnierz 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 Ahmet 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 Villartay, {Jean-Pierre de} and Bousfiha, {Ahmed Aziz} and Hill, {Harry R} and Notarangelo, {Luigi D} and Walter, {Jolan E}",
note = "Copyright {\circledC} 2019 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = "3",
day = "12",
doi = "10.1016/j.jaip.2019.02.038",
language = "English",
journal = "Journal of Allergy and Clinical Immunology: In Practice",
issn = "2213-2198",
publisher = "American Academy of Allergy, Asthma and Immunology",

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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, Karin

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, David

AU - Booth, Claire

AU - Reiff, Andreas

AU - Ferguson, Polly J

AU - Aghamohammadi, Asghar

AU - Abolhassani, Hassan

AU - Puck, Jennifer M

AU - Adeli, Mehdi

AU - Cancrini, Caterina

AU - Palma, Paolo

AU - Bertaina, Alice

AU - Locatelli, Franco

AU - Di Matteo, Gigliola

AU - Geha, Raif S

AU - Kanariou, Maria G

AU - Lycopoulou, Lilia

AU - Tzanoudaki, Marianna

AU - Sleasman, John W

AU - Parikh, Suhag

AU - Pinero, Gloria

AU - Fischer, Bernard M

AU - Dbaibo, Ghassan

AU - Unal, Ekrem

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, Beata

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, Ahmet

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 - Villartay, Jean-Pierre de

AU - Bousfiha, Ahmed Aziz

AU - Hill, Harry R

AU - Notarangelo, Luigi D

AU - Walter, Jolan E

N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2019/3/12

Y1 - 2019/3/12

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.

U2 - 10.1016/j.jaip.2019.02.038

DO - 10.1016/j.jaip.2019.02.038

M3 - Article

C2 - 30877075

JO - Journal of Allergy and Clinical Immunology: In Practice

JF - Journal of Allergy and Clinical Immunology: In Practice

SN - 2213-2198

ER -