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

@article{citeulike:4762190, 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-1beta 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.) Copyright 2009 Massachusetts Medical Society.}, author = {Aksentijevich, Ivona and Masters, Seth L L. and Ferguson, Polly J J. and Dancey, Paul and Frenkel, Joost and van Royen-Kerkhoff, Annet and Laxer, Ron and Tedg\r{a}rd, Ulf and Cowen, Edward W W. and Pham, Tuyet-Hang H. and Booty, Matthew and Estes, Jacob D D. and Sandler, Netanya G G. and Plass, Nicole and Stone, Deborah L L. and Turner, Maria L L. and Hill, Suvimol and Butman, John A A. and Schneider, Rayfel and Babyn, Paul and El-Shanti, Hatem I I. and Pope, Elena and Barron, Karyl and Bing, Xinyu and Laurence, Arian and Lee, Chyi-Chia R C. and Chapelle, Dawn and Clarke, Gillian I I. and Ohson, Kamal and Nicholson, Marc and Gadina, Massimo and Yang, Barbara and Korman, Benjamin D D. and Gregersen, Peter K K. and van Hagen, P Martin M. and Hak, A Elisabeth E. and Huizing, Marjan and Rahman, Proton and Douek, Daniel C C. and Remmers, Elaine F F. and Kastner, Daniel L L. and Goldbach-Mansky, Raphaela}, citeulike-article-id = {4762190}, citeulike-linkout-0 = {http://dx.doi.org/10.1056/NEJMoa0807865}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19494218}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19494218}, day = {4}, doi = {10.1056/NEJMoa0807865}, issn = {1533-4406}, journal = {The New England journal of medicine}, keywords = {rheum}, month = {June}, number = {23}, pages = {2426--2437}, posted-at = {2009-06-06 18:26:07}, priority = {2}, title = {An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist.}, url = {http://dx.doi.org/10.1056/NEJMoa0807865}, volume = {360}, year = {2009} }

TY - JOUR ID - citeulike:4762190 L3 - citeulike-article-id:4762190 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-1beta 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.) Copyright 2009 Massachusetts Medical Society. IS - 23 JF - The New England journal of medicine SN - 1533-4406 EP - 2437 TI - An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist. VL - 360 SP - 2426 KW - rheum 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 Hagen, P Martin 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 - 2009/06/04/ UR - http://dx.doi.org/10.1056/NEJMoa0807865 ER -