{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:56:10Z","timestamp":1790488570073,"version":"4.1.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2011,12,6]],"date-time":"2011-12-06T00:00:00Z","timestamp":1323129600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2011,12,6]],"date-time":"2011-12-06T00:00:00Z","timestamp":1323129600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The <jats:italic>NLRP3\/CIAS1<\/jats:italic> E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>A total of 42 patients and family members were screened for the presence of the <jats:italic>NLRP3<\/jats:italic> mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys\/E311K encoded by exon 3 of the <jats:italic>NLRP3<\/jats:italic> gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-\u03b1, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusion<\/jats:title>\n                        <jats:p>The <jats:italic>NLRP3<\/jats:italic> E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/ar3526","type":"journal-article","created":{"date-parts":[[2011,12,6]],"date-time":"2011-12-06T19:24:00Z","timestamp":1323199440000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["NLRP3 E311K mutation in a large family with Muckle-Wells syndrome - description of a heterogeneous phenotype and response to treatment"],"prefix":"10.1186","volume":"13","author":[{"given":"Jasmin B","family":"Kuemmerle-Deschner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Lohse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina","family":"Koetter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guenther E","family":"Dannecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Reess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Ummenhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolay","family":"Tzaribachev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Bialkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne M","family":"Benseler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,12,6]]},"reference":[{"key":"3292_CR1","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1086\/302589","volume":"65","author":"L Cuisset","year":"1999","unstructured":"Cuisset L, Drenth JP, Berthelot JM, Meyrier A, Vaudour G, Watts RA, Scott DG, Nicholls A, Pavek S, Vasseur C, Beckmann JS, Delpech M, Grateau G: Genetic linkage of the Muckle-Wells syndrome to chromosome 1q44. Am J Hum Genet. 1999, 65: 1054-1059. 10.1086\/302589.","journal-title":"Am J Hum Genet"},{"key":"3292_CR2","doi-asserted-by":"publisher","first-page":"2361","DOI":"10.1056\/NEJMoa070265","volume":"356","author":"HJ Lachmann","year":"2007","unstructured":"Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, Hawkins PN: Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007, 356: 2361-2371. 10.1056\/NEJMoa070265.","journal-title":"N Engl J Med"},{"key":"3292_CR3","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1097\/01.bor.0000198006.65697.5b","volume":"18","author":"J Samuels","year":"2006","unstructured":"Samuels J, Ozen S: Familial Mediterranean fever and the other autoinflammatory syndromes: evaluation of the patient with recurrent fever. Curr Opin Rheumatol. 2006, 18: 108-117. 10.1097\/01.bor.0000198006.65697.5b.","journal-title":"Curr Opin Rheumatol"},{"key":"3292_CR4","doi-asserted-by":"publisher","first-page":"109","DOI":"10.2165\/00129785-200404020-00005","volume":"4","author":"I Touitou","year":"2004","unstructured":"Touitou I, Notarnicola C, Grandemange S: Identifying mutations in autoinflammatory diseases: towards novel genetic tests and therapies?. Am J Pharmacogenomics. 2004, 4: 109-118. 10.2165\/00129785-200404020-00005.","journal-title":"Am J Pharmacogenomics"},{"key":"3292_CR5","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1093\/nar\/gkg031","volume":"31","author":"C Sarrauste de Menthiere","year":"2003","unstructured":"Sarrauste de Menthiere C, Terriere S, Pugnere D, Ruiz M, Demaille J, Touitou I: INFEVERS: the Registry for FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res. 2003, 31: 282-285. 10.1093\/nar\/gkg031.","journal-title":"Nucleic Acids Res"},{"key":"3292_CR6","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1086\/340786","volume":"70","author":"C Dod\u00e9","year":"2002","unstructured":"Dod\u00e9 C, Le D\u00fb N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, Meyrier A, Watts RA, Scott DG, Nicholls A, Granel B, Frances C, Garcier F, Edery P, Boulinguez S, Domergues JP, Delpech M, Grateau G: New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet. 2002, 70: 1498-1506. 10.1086\/340786.","journal-title":"Am J Hum Genet"},{"key":"3292_CR7","doi-asserted-by":"publisher","first-page":"3340","DOI":"10.1002\/art.10688","volume":"46","author":"I Aksentijevich","year":"2002","unstructured":"Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P, Rosenberg HF, Austin F, Remmers EF, Balow JE, Rosenzweig S, Komarow H, Shoham NG, Wood G, Jones J, Mangra N, Carrero H, Adams BS, Moore TL, Schikler K, Hoffman H, Lovell DJ, Lipnick R, Barron K, O'Shea JJ, Kastner DL, Goldbach-Mansky R: De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002, 46: 3340-3348. 10.1002\/art.10688.","journal-title":"Arthritis Rheum"},{"key":"3292_CR8","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1086\/341357","volume":"71","author":"J Feldmann","year":"2002","unstructured":"Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, Teillac-Hamel D, Fischer A, de Saint Basile G: Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002, 71: 198-203. 10.1086\/341357.","journal-title":"Am J Hum Genet"},{"key":"3292_CR9","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1056\/NEJMoa055137","volume":"355","author":"R Goldbach-Mansky","year":"2006","unstructured":"Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak SR, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O'Neil K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, et al: Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006, 355: 581-592. 10.1056\/NEJMoa055137.","journal-title":"N Engl J Med"},{"key":"3292_CR10","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1517\/14712590902875518","volume":"9","author":"HM Hoffman","year":"2009","unstructured":"Hoffman HM: Rilonacept for the treatment of cryopyrin-associated periodic syndromes (CAPS). Expert Opin Biol Ther. 2009, 9: 519-531. 10.1517\/14712590902875518.","journal-title":"Expert Opin Biol Ther"},{"key":"3292_CR11","doi-asserted-by":"publisher","first-page":"2416","DOI":"10.1056\/NEJMoa0810787","volume":"360","author":"HJ Lachmann","year":"2009","unstructured":"Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, Gitton X, Widmer A, Patel N, Hawkins PN: Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009, 360: 2416-2425. 10.1056\/NEJMoa0810787.","journal-title":"N Engl J Med"},{"key":"3292_CR12","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1002\/art.30149","volume":"63","author":"JB Kuemmerle-Deschner","year":"2011","unstructured":"Kuemmerle-Deschner JB, Tyrrell PN, Koetter I, Wittkowski H, Bialkowski A, Tzaribachev N, Lohse P, Koitchev A, Deuter C, Foell D, Benseler SM: Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome. Arthritis Rheum. 2011, 63: 840-9. 10.1002\/art.30149.","journal-title":"Arthritis Rheum"},{"key":"3292_CR13","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1002\/art.21807","volume":"54","author":"T Mirault","year":"2006","unstructured":"Mirault T, Launay D, Cuisset L, Hachulla E, Lambert M, Queyrel V, Quemeneur T, Morell-Dubois S, Hatron PY: Recovery from deafness in a patient with Muckle-Wells syndrome treated with anakinra. Arthritis Rheum. 2006, 54: 1697-1700. 10.1002\/art.21807.","journal-title":"Arthritis Rheum"},{"key":"3292_CR14","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1002\/art.25057","volume":"62","author":"B Neven","year":"2010","unstructured":"Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, Pinto G, Pagnier A, Bodemer C, Bodaghi B, Tardieu M, Prieur AM, Quartier P: Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease\/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 2010, 62: 258-267.","journal-title":"Arthritis Rheum"},{"key":"3292_CR15","doi-asserted-by":"publisher","first-page":"3783","DOI":"10.1002\/art.27696","volume":"62","author":"JB K\u00fcmmerle-Deschner","year":"2010","unstructured":"K\u00fcmmerle-Deschner JB, Tyrrell PN, Reess F, K\u00f6tter I, Lohse P, Girschick H, Huemer C, Horneff G, Haas JP, Koitschev A, Deuter C, Benseler SM: Risk factors for severe Muckle-Wells syndrome. Arthritis Rheum. 2010, 62: 3783-3791. 10.1002\/art.27696.","journal-title":"Arthritis Rheum"},{"key":"3292_CR16","doi-asserted-by":"publisher","first-page":"1779","DOI":"10.1016\/S0140-6736(04)17401-1","volume":"364","author":"HM Hoffman","year":"2004","unstructured":"Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, Anderson JP, Wanderer AA, Firestein GS: Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004, 364: 1779-1785. 10.1016\/S0140-6736(04)17401-1.","journal-title":"Lancet"},{"key":"3292_CR17","doi-asserted-by":"crossref","unstructured":"Murphy G, Daly M, O'Sullivan M, Stack J, Rowczenio D, Lachmann H, Shanahan F, Harney S, Hawkins P, Molloy M: An unusual phenotype in Muckle-Wells syndrome associated with NLRP3 E311K. Rheumatology (Oxford). 50: 419-420.","DOI":"10.1093\/rheumatology\/keq280"},{"key":"3292_CR18","first-page":"531","volume":"22","author":"JB Kuemmerle-Deschner","year":"2004","unstructured":"Kuemmerle-Deschner JB, Koetter I, Dannecker GE, Bialkowski A, Tzaribachev N, Koch S, Lohse P: New CIAS1 E311K mutation and cytokine profile in a family of 3 generations with the clinical picture of Muckle-Wells Syndrome. Clin Exp Rheumatol. 2004, 22: 531-","journal-title":"Clin Exp Rheumatol"},{"key":"3292_CR19","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1136\/ard.2010.138420","volume":"70","author":"L Cuisset","year":"2011","unstructured":"Cuisset L, Jeru I, Dumont B, Fabre A, Cochet E, Le Bozec J, Delpech M, Amselem S, Touitou I: Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis. 2011, 70: 495-499. 10.1136\/ard.2010.138420.","journal-title":"Ann Rheum Dis"},{"key":"3292_CR20","first-page":"235","volume":"31","author":"TJ Muckle","year":"1962","unstructured":"Muckle TJ, Wells M: Urticaria, deafness, and amyloidosis: A new heredo-familial syndrome. Q J Med. 1962, 31: 235-248.","journal-title":"Q J Med"},{"key":"3292_CR21","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1002\/art.20033","volume":"50","author":"PN Hawkins","year":"2004","unstructured":"Hawkins PN, Lachmann HJ, Aganna E, McDermott MF: Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum. 2004, 50: 607-612. 10.1002\/art.20033.","journal-title":"Arthritis Rheum"},{"key":"3292_CR22","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1002\/art.22491","volume":"56","author":"I Aksentijevich","year":"2007","unstructured":"Aksentijevich I, D Putnam C, Remmers EF, Mueller JL, Le J, Kolodner RD, Moak Z, Chuang M, Austin F, Goldbach-Mansky R, Hoffman HM, Kastner DL: The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007, 56: 1273-1285. 10.1002\/art.22491.","journal-title":"Arthritis Rheum"},{"key":"3292_CR23","doi-asserted-by":"publisher","first-page":"2445","DOI":"10.1002\/art.10509","volume":"46","author":"E Aganna","year":"2002","unstructured":"Aganna E, Martinon F, Hawkins PN, Ross JB, Swan DC, Booth DR, Lachmann HJ, Bybee A, Gaudet R, Woo P, Feighery C, Cotter FE, Thome M, Hitman GA, Tschopp J, McDermott MF: Association of mutations in the NALP3\/CIAS1\/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 2002, 46: 2445-2452. 10.1002\/art.10509.","journal-title":"Arthritis Rheum"},{"key":"3292_CR24","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1111\/j.1600-0609.2004.00270.x","volume":"73","author":"G P\u00f6rksen","year":"2004","unstructured":"P\u00f6rksen G, Lohse P, R\u00f6sen-Wolff A, Heyden S, F\u00f6rster T, Wendisch J, Heubner G, Bernuth H, Sallmann S, Gahr M, Roesler J: Periodic fever, mild arthralgias, and reversible moderate and severe organ inflammation associated with the V198M mutation in the CIAS1 gene in three German patients--expanding phenotype of CIAS1 related autoinflammatory syndrome. Eur J Haematol. 2004, 73: 123-127. 10.1111\/j.1600-0609.2004.00270.x.","journal-title":"Eur J Haematol"},{"key":"3292_CR25","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1002\/art.20032","volume":"50","author":"HM Hoffman","year":"2004","unstructured":"Hoffman HM, Patel DD: Genomic-based therapy: targeting interleukin-1 for autoinflammatory diseases. Arthritis Rheum. 2004, 50: 345-349. 10.1002\/art.20032.","journal-title":"Arthritis Rheum"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar3526.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/ar3526\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar3526.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T10:25:14Z","timestamp":1728383114000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/ar3526"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,12,6]]},"references-count":25,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2011,12]]}},"alternative-id":["3292"],"URL":"https:\/\/doi.org\/10.1186\/ar3526","relation":{},"ISSN":["1478-6354"],"issn-type":[{"value":"1478-6354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,12,6]]},"assertion":[{"value":"3 April 2011","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2011","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 December 2011","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 December 2011","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"R196"}}