An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist

Ivona Aksentijevich, Seth L. Masters, Polly J. Ferguson, Paul Dancey, Joost Frenkel, Annet Van Royen-Kerkhoff, Ron Laxer, Ulf Tedgård, Edward W. Cowen, Tuyet Hang Pham, Matthew Booty, Jacob D. Estes, Netanya G. Sandler, Nicole Plass, Deborah L. Stone, Maria L. Turner, Suvimol Hill, John A. Butman, Rayfel Schneider, Paul BabynHatem I. El-Shanti, Elena Pope, Karyl Barron, Xinyu Bing, Arian Laurence, Chyi Chia R Lee, Dawn Chapelle, Gillian I. Clarke, Kamal Ohson, Marc Nicholson, Massimo Gadina, Barbara Yang, Benjamin D. Korman, Peter K. Gregersen, P. Van Martin Hagen, A. Elisabeth Hak, Marjan Huizing, Proton Rahman, Daniel C. Douek, Elaine F. Remmers, Daniel L. Kastner, Raphaela Goldbach-Mansky

Research output: Contribution to journalArticle

575 Citations (Scopus)

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-1β 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.).

Original languageEnglish
Pages (from-to)2426-2437
Number of pages12
JournalNew England Journal of Medicine
Volume360
Issue number23
DOIs
Publication statusPublished - 4 Jun 2009

Fingerprint

Mutation
Interleukin-1
Interleukin-1 Receptors
Interleukin 1 Receptor Antagonist Protein
Periostitis
Inflammation
Lebanon
Newfoundland and Labrador
Bone and Bones
Puerto Rico
Skin
Osteomyelitis
Deficiency of interleukin-1 receptor antagonist
Netherlands
Autoantibodies
Canada
Proteins
Cytokines
T-Lymphocytes
Infection

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Aksentijevich, I., Masters, S. L., Ferguson, P. J., Dancey, P., Frenkel, J., Van Royen-Kerkhoff, A., ... Goldbach-Mansky, R. (2009). An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. New England Journal of Medicine, 360(23), 2426-2437. https://doi.org/10.1056/NEJMoa0807865

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; 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; Nicholson, Marc; Gadina, Massimo; Yang, Barbara; Korman, Benjamin D.; Gregersen, Peter K.; Van Martin Hagen, P.; Hak, A. Elisabeth; Huizing, Marjan; Rahman, Proton; Douek, Daniel C.; Remmers, Elaine F.; Kastner, Daniel L.; Goldbach-Mansky, Raphaela.

In: New England Journal of Medicine, Vol. 360, No. 23, 04.06.2009, p. 2426-2437.

Research output: Contribution to journalArticle

Aksentijevich, I, Masters, SL, Ferguson, PJ, Dancey, P, Frenkel, J, Van Royen-Kerkhoff, A, Laxer, R, Tedgård, U, Cowen, EW, Pham, TH, Booty, M, Estes, JD, Sandler, NG, Plass, N, Stone, DL, Turner, ML, Hill, S, Butman, JA, Schneider, R, Babyn, P, El-Shanti, HI, Pope, E, Barron, K, Bing, X, Laurence, A, Lee, CCR, Chapelle, D, Clarke, GI, Ohson, K, Nicholson, M, Gadina, M, Yang, B, Korman, BD, Gregersen, PK, Van Martin Hagen, P, Hak, AE, Huizing, M, Rahman, P, Douek, DC, Remmers, EF, Kastner, DL & Goldbach-Mansky, R 2009, 'An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist', New England Journal of Medicine, vol. 360, no. 23, pp. 2426-2437. https://doi.org/10.1056/NEJMoa0807865
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. New England Journal of Medicine. 2009 Jun 4;360(23):2426-2437. https://doi.org/10.1056/NEJMoa0807865
Aksentijevich, Ivona ; Masters, Seth L. ; Ferguson, Polly J. ; Dancey, Paul ; Frenkel, Joost ; Van Royen-Kerkhoff, Annet ; Laxer, Ron ; Tedgård, 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 ; Nicholson, Marc ; Gadina, Massimo ; Yang, Barbara ; Korman, Benjamin D. ; Gregersen, Peter K. ; Van Martin Hagen, P. ; Hak, A. Elisabeth ; Huizing, Marjan ; Rahman, Proton ; Douek, Daniel C. ; Remmers, Elaine F. ; Kastner, Daniel L. ; Goldbach-Mansky, Raphaela. / An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. In: New England Journal of Medicine. 2009 ; Vol. 360, No. 23. pp. 2426-2437.
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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-1β 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.).",
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T1 - An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist

AU - Aksentijevich, Ivona

AU - Masters, Seth L.

AU - Ferguson, Polly J.

AU - Dancey, Paul

AU - Frenkel, Joost

AU - Van Royen-Kerkhoff, Annet

AU - Laxer, Ron

AU - Tedgård, Ulf

AU - Cowen, Edward W.

AU - Pham, Tuyet Hang

AU - Booty, Matthew

AU - Estes, Jacob D.

AU - Sandler, Netanya G.

AU - Plass, Nicole

AU - Stone, Deborah L.

AU - Turner, Maria L.

AU - Hill, Suvimol

AU - Butman, John A.

AU - Schneider, Rayfel

AU - Babyn, Paul

AU - El-Shanti, Hatem I.

AU - Pope, Elena

AU - Barron, Karyl

AU - Bing, Xinyu

AU - Laurence, Arian

AU - Lee, Chyi Chia R

AU - Chapelle, Dawn

AU - Clarke, Gillian I.

AU - Ohson, Kamal

AU - Nicholson, Marc

AU - Gadina, Massimo

AU - Yang, Barbara

AU - Korman, Benjamin D.

AU - Gregersen, Peter K.

AU - Van Martin Hagen, P.

AU - Hak, A. Elisabeth

AU - Huizing, Marjan

AU - Rahman, Proton

AU - Douek, Daniel C.

AU - Remmers, Elaine F.

AU - Kastner, Daniel L.

AU - Goldbach-Mansky, Raphaela

PY - 2009/6/4

Y1 - 2009/6/4

N2 - 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-1β 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.).

AB - 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-1β 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.).

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