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

作者：Aksentijevich Ivona; Masters Seth L; Ferguson Polly J; Dancey Paul; Frenkel Joost; van Royen Kerkhoff Annet; Laxer Ron; Tedgard Ulf; Cowen Edward W; Pham Tuyet Hang; Booty Matthew; Estes Jacob D; Sandler Netanya G; Plass Nicole; Stone Deborah L; Turner Maria L; Hill Suvimol; Butman John A; Schneider Rayfel; Babyn Paul; El Shanti Hatem I; Pope Elena; Barron Karyl; Bing Xinyu; Laurence Arian; Lee Chyi Chia R; Chapelle Dawn; Clarke Gillian I; Ohson Kamal

来源：New England Journal of Medicine, 2009, 360(23): 2426-2437.

DOI：10.1056/NEJMoa0807865

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.)

• 出版日期2009-6-4