{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:03:12Z","timestamp":1790960592307,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016580","name":"Kennedy Trust for Rheumatology Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016580","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["779295"],"award-info":[{"award-number":["779295"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Adult\u2010onset Still disease (AOSD) is a systemic autoinflammatory disorder (AID) of unknown etiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large cohort with AOSD to investigate the underlying pathology and identify novel targets for potential treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated AOSD cases (n = 60) for rare germline and somatic variants using whole exome sequencing with virtual gene panels. Transcriptome profiles were investigated by bulk RNA sequencing whole blood. Cytokine profiling was performed on an extended patient cohort (n = 106) alongside measurements of <jats:italic>NLRP3<\/jats:italic> inflammasome activation using a custom assay and type I interferon (IFN) score using a novel method.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed higher than expected frequencies of rare germline variants associated with monogenic AIDs in AOSD cases (AOSD 38.4% vs healthy controls [HCs] 20.4%) and earlier onset of putative somatic variants associated with clonal hematopoiesis of indeterminate potential. Transcriptome profiling revealed a positive correlation between Still Activity Score and gene expression associated with the innate immune system. ASC\/<jats:italic>NLRP3<\/jats:italic> specks levels and type I IFN scores were significantly elevated in AOSD cases compared with HCs (<jats:italic>P<\/jats:italic> = 0.0001 and 0.0015, respectively), in addition to several cytokines: interleukin (IL)\u20106 (<jats:italic>P<\/jats:italic> &lt; 0.0001), IL\u201010 (<jats:italic>P<\/jats:italic> &lt; 0.0075), IL\u201012p70 (<jats:italic>P<\/jats:italic> = 0.0005), IL\u201018 (<jats:italic>P<\/jats:italic> &lt; 0.0001), IL\u201023 (<jats:italic>P<\/jats:italic> &lt; 0.0001), IFN\u2010\u03b12 (<jats:italic>P<\/jats:italic> = 0.0009), and IFN\u03b3 (<jats:italic>P<\/jats:italic> = 0.0002).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study shows considerable genetic complexity within AOSD and demonstrates the potential utility of the ASC\/<jats:italic>NLRP3<\/jats:italic> specks assay for disease stratification and targeted treatment. The enriched genetic variants identified may not by themselves be sufficient to cause disease, but may contribute to a polygenic model for AOSD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.43054","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T03:40:41Z","timestamp":1730691641000},"page":"582-595","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Characterization of Genetic Landscape and Novel Inflammatory Biomarkers in Patients With Adult\u2010Onset Still's Disease"],"prefix":"10.1002","volume":"77","author":[{"given":"Joanne","family":"Topping","sequence":"first","affiliation":[{"name":"University of Leeds  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Chang","sequence":"additional","affiliation":[{"name":"University of Leeds  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Nadat","sequence":"additional","affiliation":[{"name":"St James's University Hospital  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Poulter","sequence":"additional","affiliation":[{"name":"University of Leeds  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Ibbotson","sequence":"additional","affiliation":[{"name":"University of Leeds  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Lara\u2010Reyna","sequence":"additional","affiliation":[{"name":"University of Leeds  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2371-1844","authenticated-orcid":false,"given":"Christopher M.","family":"Watson","sequence":"additional","affiliation":[{"name":"St James's University Hospital  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clive","family":"Carter","sequence":"additional","affiliation":[{"name":"St James's University Hospital  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3810-5524","authenticated-orcid":false,"given":"Linda P.","family":"Pournara","sequence":"additional","affiliation":[{"name":"University of Leeds  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Zernicke","sequence":"additional","affiliation":[{"name":"Charit\u00e9 Universit\u00e4tsmedizin Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7750-4280","authenticated-orcid":false,"given":"Rebecca L.","family":"Ross","sequence":"additional","affiliation":[{"name":"University of Leeds and National Institute for Health and Care Research Leeds Biomedical Centre, Chapel Allerton Hospital  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Cargo","sequence":"additional","affiliation":[{"name":"St James's University Hospital  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Lyons","sequence":"additional","affiliation":[{"name":"University of Cambridge  Cambridge United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth G. C.","family":"Smith","sequence":"additional","affiliation":[{"name":"University of Cambridge  Cambridge United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8528-2283","authenticated-orcid":false,"given":"Francesco","family":"Del Galdo","sequence":"additional","affiliation":[{"name":"University of Leeds and National Institute for Health and Care Research Leeds Biomedical Centre, Chapel Allerton Hospital  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2569-2029","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Rech","sequence":"additional","affiliation":[{"name":"Friedrich\u2010Alexander University Erlangen\u2010N\u00fcrnberg and Universit\u00e4tsklinikum Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Fautrel","sequence":"additional","affiliation":[{"name":"Sorbonne University, AP\u2010HP, 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