{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T16:33:03Z","timestamp":1793291583342,"version":"4.5.0"},"reference-count":15,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2017,10,17]],"date-time":"2017-10-17T00:00:00Z","timestamp":1508198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001388","name":"Wenner-Gren Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001388","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Cryopyrin\u2010associated periodic syndromes (<jats:styled-content style=\"fixed-case\">CAPS<\/jats:styled-content>) result from gain\u2010of\u2010function mutations in the <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> gene, which causes excessive release of interleukin\u20101\u03b2 (<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2) and systemic inflammation. While pathogenetic <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variant phenotypes are well\u2010characterized, low\u2010penetrance <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in\u00a0vitro biologic phenotype, and the effect of anti\u2013<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101 treatment in patients with low\u2010penetrance <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A multicenter study of consecutive symptomatic patients with low\u2010penetrance <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variant. Clinical presentation and <jats:styled-content style=\"fixed-case\">CAPS<\/jats:styled-content> markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010\u03baB release, cell death, and <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 release, were performed. Treatment effects of <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101 were determined. Comparisons between low\u2010penetrance and pathogenetic <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variants were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> low\u2010penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variants. Patients with low\u2010penetrance <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low\u2010penetrance <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variants as compared to wild\u2010type and pathogenetic <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variants. All treated patients responded to <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101 inhibition, with complete response documented in 50% of patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Patients with low\u2010penetrance <jats:italic><jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>3<\/jats:italic> variants display a distinct clinical phenotype and an intermediate biologic phenotype, including <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 and non\u2013<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2\u2013mediated inflammatory pathway activation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40208","type":"journal-article","created":{"date-parts":[[2017,7,10]],"date-time":"2017-07-10T15:22:37Z","timestamp":1499700157000},"page":"2233-2240","source":"Crossref","is-referenced-by-count":84,"title":["Brief Report: Clinical and Molecular Phenotypes of Low\u2010Penetrance Variants of <i><scp>NLRP<\/scp>3<\/i>: Diagnostic and Therapeutic Challenges"],"prefix":"10.1002","volume":"69","author":[{"given":"J. B.","family":"Kuemmerle\u2010Deschner","sequence":"first","affiliation":[{"name":"University Hospital Tuebingen Tuebingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Verma","sequence":"additional","affiliation":[{"name":"Rady Children's Hospital and University of California at San Diego San Diego California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Endres","sequence":"additional","affiliation":[{"name":"University Hospital Tuebingen Tuebingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Broderick","sequence":"additional","affiliation":[{"name":"Rady Children's Hospital and University of California at San Diego San Diego California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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