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Although complement can drive inflammation, its involvement in SD remains to be defined. Thus, we aimed to assess complement activation in SD.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Complement was assessed using transcriptomic, proteomic, and in vitro approaches. RNA sequencing of monocytes was performed in healthy donors (n\u00a0=\u00a015), those with nonsystemic juvenile idiopathic arthritis (JIA; n\u00a0=\u00a08), patients with SD at onset (n\u00a0=\u00a019) and remission (n\u00a0=\u00a018), and those with macrophage activation syndrome (n\u00a0=\u00a02). Whole\u2010blood NanoString analysis of complement and interferon (IFN)\u2010related gene expression was conducted in patients with SD (active n\u00a0=\u00a041, inactive n\u00a0=\u00a033) and JIA (n > 600). Complement products and inflammatory mediators were measured by Luminex and enzyme\u2010linked immunosorbent assay. Functional complement activity was evaluated in SD (active n\u00a0=\u00a030, inactive n\u00a0=\u00a067) and JIA sera (n\u00a0=\u00a012). In vitro assays examined monocytic C1q induction and complement\u2010mediated CD8\n +<\/jats:sup>\n T cell activation.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Transcriptomic analysis of monocytes from patients with SD at onset revealed enrichment of the complement cascade compared with patients in remission (adjusted\n P<\/jats:italic>\n \u00a0=\u00a03.7\u2009\u00d7\u200910\n \u221236<\/jats:sup>\n ), ranking among the top 10 up\u2010regulated pathways. Classical complement genes (\n C1QB<\/jats:italic>\n \/\n C1QC<\/jats:italic>\n ) were markedly up\u2010regulated in onset SD compared with patients with remission SD and JIA. Patients with active SD showed increased C1q, C3a, C5a, and terminal complement complex protein levels, with enhanced functional classical complement activity. Whole\u2010blood\n C1QB<\/jats:italic>\n \/\n C1QC<\/jats:italic>\n expression correlated with IFN\u2010related markers, including interleukin\u201018, CXCL9, and CXCL10. Recombinant IFN\u2010\u03b3 induced monocytic C1q, whereas C1q enhanced IFN\u2010\u03b3 production by CD8\n +<\/jats:sup>\n T cells, supporting a feed\u2010forward loop.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n SD is characterized by complement activation with marked up\u2010regulation of C1q, which is closely linked to IFN\u2010\u03b3\/type II signaling.<\/jats:p>\n \n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.70307","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:56:08Z","timestamp":1787658968000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Complement Activation Linked to Type\n II<\/scp>\n Interferon Signaling in Still Disease"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4807-8568","authenticated-orcid":false,"given":"Freya M. C. H.","family":"Huijsmans","sequence":"first","affiliation":[{"name":"Division of Pediatrics, Department of Pediatric Rheumatology and Immunology Wilhelmina Children's Hospital, University Medical Center Utrecht Utrecht the Netherlands"},{"name":"Center for Translational Immunology University Medical Center Utrecht, Utrecht University Utrecht the Netherlands"},{"name":"Faculty of Medicine Utrecht University Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7716-368X","authenticated-orcid":false,"given":"Tabea","family":"Thalheim","sequence":"additional","affiliation":[{"name":"Department of Pediatric Rheumatology & Immunology University Children's Hospital Muenster Muenster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2361-8156","authenticated-orcid":false,"given":"Alejandra","family":"Bodel\u00f3n","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology University Medical Center Utrecht, Utrecht University Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3922-7224","authenticated-orcid":false,"given":"Greta","family":"Rogani","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Department of Pediatric Rheumatology and Immunology Wilhelmina Children's Hospital, University Medical Center Utrecht Utrecht the Netherlands"},{"name":"Center for Translational Immunology University Medical Center Utrecht, Utrecht University Utrecht the Netherlands"},{"name":"Faculty of Medicine Utrecht University Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyanne J. 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