Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

Deficiency of the IL-1 Receptor Antagonist (DIRA)

  • Megha Garg
  • Adriana A. de JesusEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-9209-2_125-1



DIRA, deficiency of the IL-1 receptor antagonist, is a monogenic autosomal recessive autoinflammatory disease that presents with systemic inflammation, pustulosis, sterile osteomyelitis, and osteolytic lesions and is caused by loss-of-function mutations in IL1RN, the gene that encodes the IL-1 receptor antagonist (IL-1Ra) (MIM#612852).

Introduction and Background

At a time when whole exome sequencing was not yet available, the diagnosis of sporadic diseases required a candidate gene approach. DIRA was in fact discovered in two patients who had complete responses to empirically administered IL-1 blocking treatments with recombinant IL-1 receptor antagonist, anakinra, which strongly suggested an IL-1-mediated disease, and resulted in a candidate screen of genes in the IL-1/inflammasome pathway that eventually led to finding “the needle in the haystack” (Reddy et al. 2009; Aksentijevich...

This is a preview of subscription content, log in to check access.


  1. Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426–37.CrossRefGoogle Scholar
  2. Altiok E, Aksoy F, Perk Y, Taylan F, Kim PW, Ilikkan B, et al. A novel mutation in the interleukin-1 receptor antagonist associated with intrauterine disease onset. Clin Immunol. 2012;145(1):77–81.Google Scholar
  3. Garg M, de Jesus AA, Chapelle D, Dancey P, Herzog R, Rivas-Chacon R, et al. Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist. JCI Insight. 2017;2(16):e94838.  https://doi.org/10.1172/jci.insight.94838
  4. Infevers: an online database for autoinflammatory mutations. Copyright. Available at http://fmf.igh.cnrs.fr/ISSAID/infevers/. Accessed 12 Mar 2019. [Internet].
  5. Ivker RA, Grin-Jorgensen CM, Vega VK, Hoss DM, Grant-Kels JM. Infantile generalized pustular psoriasis associated with lytic lesions of the bone. Pediatr Dermatol. 1993;10(3):277–82.CrossRefGoogle Scholar
  6. Jesus AA, Osman M, Silva CA, Kim PW, Pham TH, Gadina M, et al. A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: description of two unrelated cases from Brazil. Arthritis Rheum. 2011;63(12):4007–17.CrossRefGoogle Scholar
  7. Kuemmerle-Deschner JB, Hoertnagel K, Schlipf S, Hansmann S, Hospach T, Tsiflikas I, et al. Expanding the Phenotype: New Variant in the IL1RN-Gene Associated with Late Onset and Atypical Presentation of Dira [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10).Google Scholar
  8. Leung VC, Lee KE. Infantile cortical hyperostosis with intramedullary lesions. J Pediatr Orthop. 1985;5(3):354–7.CrossRefGoogle Scholar
  9. Mendonca LO, Malle L, Donovan FX, Chandrasekharappa SC, Montealegre Sanchez GA, Garg M, et al. Deficiency of Interleukin-1 receptor antagonist (DIRA): report of the first Indian patient and a novel deletion affecting IL1RN. J Clin Immunol. 2017;37(5):445–51.CrossRefGoogle Scholar
  10. Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M, Broeckel U, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009;360(23):2438–44.CrossRefGoogle Scholar
  11. Schnellbacher C, Ciocca G, Menendez R, Aksentijevich I, Golbach-Mansky R, Duarte A, et al. Deficiency of interleukin-1 receptor antagonist responsive to anakinra. Pediatr Dermatol. 2013;30(6):758–760.Google Scholar
  12. Stenerson M, Dufendach K, Aksentijevich I, Brady J, Austin J, Reed AM. The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist. Arthritis Rheum. 2011;63(12):4018–22.CrossRefGoogle Scholar
  13. Stern SM, Ferguson PJ. Autoinflammatory bone diseases. Rheum Dis Clin N Am. 2013;39(4):735–49.CrossRefGoogle Scholar
  14. Ulusoy E, Karaca NE, El-Shanti H, Kilicoglu E, Aksu G, Kutukculer N. Interleukin-1 receptor antagonist deficiency with a novel mutation; late onset and successful treatment with canakinumab: a case report. J Med Case Rep. 2015;9:145.CrossRefGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  1. 1.Translational Autoinflammatory Diseases Section (TADS), National Institute of Allergy and Infectious Diseases (NIAID)National Institutes of Health (NIH)BethesdaUSA

Section editors and affiliations

  • Raphaela Goldbach-Mansky
    • 1
  1. 1.NIAID, Translational Autoinflammatory Disease StudiesNational Institutes of Health Clinical CenterBethesdaUSA