{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T17:55:33Z","timestamp":1793987733931,"version":"4.8.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify biomarkers and endotypes predictive of treatment response, monitor disease activity, and explore pathways associated with the clinical efficacy of leflunomide and hydroxychloroquine combination therapy (LEF\/HCQ) in patients with primary Sj\u00f6gren\u2019s disease (SjD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Serum proteome (Olink Immuno-oncology panel, analyzing 92 proteins) of 29 patients with SjD of the RepurpSS-I study and 8 healthy controls was analyzed at baseline and after 24 weeks of LEF\/HCQ. Proteomic changes were correlated to standard and novel clinical endpoints. Transcriptome data of blood mononuclear cells and monocytes were used to assess type I and II IFN scores.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At baseline, 29 proteins were differentially expressed between SjD and HC. LEF\/HCQ significantly downregulated 22 out of 27 over-expressed proteins, which was not observed in the placebo-arm. Fourteen baseline proteins and the changes of four of these proteins, CXCL10, CXCL11, TNF, and soluble CD70 concentrations, were correlated with clinical response (|r| 0.40\u20130.62, p&amp;lt;0.05). Principal Component Analysis revealed an IFN-\u03b3-associated set of coherent proteins. At baseline, using only two proteins, CXCL10 and CXCL11 effectively distinguished patients from healthy controls and responders from non-responders (all p&amp;lt;0.05). Finally, in addition to changes in type I IFN signatures, type II IFN signatures were observed in monocytes that were associated with changes in disease activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data support a significant role for a type II IFN-associated immune response in SjD pathogenesis, which is targeted by LEF\/HCQ. Proteins associated with type II IFN-driven immune responses hold potential to monitor disease activity and predict treatment response.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1566377","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T05:31:20Z","timestamp":1760679080000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Proteins linked to type II interferon response in Sj\u00f6gren\u2019s disease: novel indicators for disease monitoring and predicting treatment response to leflunomide and hydroxychloroquine combination therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Wing-Yi","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen L.","family":"Leavis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofie L. 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