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Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features
  1. Daniella Muallem Schwartz1,
  2. Moses M Kitakule1,
  3. Brian LP Dizon2,
  4. Cristhian Gutierrez-Huerta3,
  5. Sarah A Blackstone1,
  6. Aarohan M Burma1,
  7. Aran Son1,
  8. Natalie Deuitch4,
  9. Sofia Rosenzweig4,
  10. Hirsh Komarow1,
  11. Deborah L Stone4,
  12. Anne Jones4,
  13. Michele Nehrebecky4,
  14. Patrycja Hoffmann4,
  15. Tina Romeo4,
  16. Adriana Almeida de Jesus5,
  17. Sara Alehashemi5,
  18. Megha Garg6,
  19. Sofia Torreggiani5,
  20. Gina A Montealegre Sanchez5,
  21. Katelin Honer5,
  22. Gema Souto Adeva5,
  23. Karyl S Barron7,
  24. Ivona Aksentijevich4,
  25. Amanda K Ombrello4,
  26. Raphaela Goldbach-Mansky5,
  27. Daniel L Kastner4,
  28. Joshua D Milner8,
  29. Pamela Frischmeyer-Guerrerio1
  1. 1Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
  2. 2NIAMS, National Institutes of Health, Bethesda, Maryland, USA
  3. 3NHLBI, National Institutes of Health, Bethesda, Maryland, USA
  4. 4Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA
  5. 5Translational Autoinflammatory Diseases Section, LCIM, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
  6. 6Rheumatology, Rochester Regional Health System, Rochester, New York, USA
  7. 7NIAID, National Institutes of Health, Bethesda, Maryland, USA
  8. 8Division of Pediatric Allergy, Immunology and Rheumatology, Columbia University, New York, New York, USA
  1. Correspondence to Dr Daniella Muallem Schwartz, NIAID, National Institutes of Health, Bethesda, Maryland, USA; Daniella.Schwartz{at}


Background Monogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown.

Objectives We investigated allergic, immunological and clinical phenotypes in FMF (familial Mediterranean fever), CAPS (cryopyrin-associated periodic syndrome), TRAPS (tumour necrosis factor receptor-associated periodic syndrome), HIDS (hyper-IgD syndrome), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), CANDLE (chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature) and SAVI (STING-associated vasculopathy of infancy).

Methods In this cross-sectional study, clinical data were assessed in 425 patients with AID using questionnaires and chart reviews. Comparator data were obtained from public databases. Peripheral blood mononuclear cells obtained from 55 patients were stimulated and CD4+ cytokine production assessed.

Results Clinical laboratory features of Type 2 immunity were elevated in CAPS but reduced in most AID, particularly DADA2. Physician-diagnosed allergic diseases were prevalent in multiple AID, including CAPS and DADA2. T helper 2 (Th2) cells were expanded in CAPS, TRAPS and HIDS; Th9 cells were expanded in HA20.

Conclusions CAPS is characterised by an enhanced Type 2 signature, whereas FMF and CANDLE are associated with reduced Type 2 responses. DADA2 is associated with reduced Type 2 responses but a high rate of physician-diagnosed allergy. Therefore, NLRP3-driven autoinflammation may promote Type 2 immunity, whereas AID like DADA2 may manifest clinical phenotypes that masquerade as allergic disorders. Further investigations are needed to determine the contribution of autoinflammation to allergic clinical and immunological phenotypes, to improve the treatment of patients with AID.

  • cryopyrin-associated periodic syndromes
  • familial mediterranean fever
  • epidemiology
  • T-lymphocyte subsets
  • inflammation

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  • JDM and PF-G are joint senior authors.

  • Handling editor Josef S Smolen

  • Contributors DMS, JDM, PFG, MMK, HK: study design; DMS, MMK, BLPD, ND, DLS, AJ, MN, PH, TR, AAdJ, SA, MG, SR, ST, GAMS, KH, GSA, IA, AKO, KB: patient recruitment, clinical evaluations, genetic testing and sample collection; DMS, MMK, BLPD, CGH, SAB, AMB, AS: data collection and statistical analysis; DMS, JDM, PFG: writing; DMS, JDM, PFG, DLK, RGM: supervision.

  • Funding This study was funded through the National Institutes of Health (NIAID, NHGRI).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Studies were performed on IRB-approved protocols 94-HG-0105, 17-I-0016 or 10-I-1048.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. De-identified participant data (clinical diagnoses and laboratories) and flow cut-metric data are either included in the manuscript or available upon request to the corresponding author, Daniella Schwatz;

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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