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 journalArticlepeer-review


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
Publication statusE-pub ahead of print - Mar 12 2019


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