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An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist

Aksentijevich, Ivona; Masters, Seth L.; Ferguson, Polly J.; Dancey, Paul; Frenkel, Joost; van Royen-Kerkhoff, Annet; Laxer, Ron; Tedgård, Ulf LU ; Cowen, Edward W. and Pham, Tuyet-Hang, et al. (2009) In New England Journal of Medicine 360(23). p.2426-2437
Abstract
BACKGROUND Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS We identified homozygous mutations of IL1RN in nine... (More)
BACKGROUND Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1 beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.) (Less)
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New England Journal of Medicine
volume
360
issue
23
pages
2426 - 2437
publisher
Massachusetts Medical Society
external identifiers
  • wos:000266590500008
  • scopus:66649121678
ISSN
0028-4793
language
English
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yes
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98c4619d-cca4-47fa-8975-388208289e23 (old id 1424767)
date added to LUP
2009-07-02 17:01:06
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2017-12-17 03:21:55
@article{98c4619d-cca4-47fa-8975-388208289e23,
  abstract     = {BACKGROUND Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1 beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)},
  author       = {Aksentijevich, Ivona and Masters, Seth L. and Ferguson, Polly J. and Dancey, Paul and Frenkel, Joost and van Royen-Kerkhoff, Annet and Laxer, Ron and Tedgård, Ulf and Cowen, Edward W. and Pham, Tuyet-Hang and Booty, Matthew and Estes, Jacob D. and Sandler, Netanya G. and Plass, Nicole and Stone, Deborah L. and Turner, Maria L. and Hill, Suvimol and Butman, John A. and Schneider, Rayfel and Babyn, Paul and El-Shanti, Hatem I. and Pope, Elena and Barron, Karyl and Bing, Xinyu and Laurence, Arian and Lee, Chyi-Chia R. and Chapelle, Dawn and Clarke, Gillian I. and Ohson, Kamal and Nicholson, Marc and Gadina, Massimo and Yang, Barbara and Korman, Benjamin D. and Gregersen, Peter K. and van Hagen, P. Martin and Hak, A. Elisabeth and Huizing, Marjan and Rahman, Proton and Douek, Daniel C. and Remmers, Elaine F. and Kastner, Daniel L. and Goldbach-Mansky, Raphaela},
  issn         = {0028-4793},
  language     = {eng},
  number       = {23},
  pages        = {2426--2437},
  publisher    = {Massachusetts Medical Society},
  series       = {New England Journal of Medicine},
  title        = {An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist},
  volume       = {360},
  year         = {2009},
}