{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T08:34:22Z","timestamp":1790238862863,"version":"4.1.0"},"reference-count":28,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T00:00:00Z","timestamp":1690934400000},"content-version":"unspecified","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["446002502"],"award-info":[{"award-number":["446002502"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["806975"],"award-info":[{"award-number":["806975"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006315","name":"ReumaNederland","doi-asserted-by":"publisher","award":["Translational round 2, projectnummer: 446002502"],"award-info":[{"award-number":["Translational round 2, projectnummer: 446002502"]}],"id":[{"id":"10.13039\/501100006315","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100013322","name":"EFPIA","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013322","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2023,5,24]]},"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To assess to what extent leflunomide (LEF) and hydroxychloroquine (HCQ) therapy in patients with primary Sj\u00f6gren\u2019s syndrome (RepurpSS-I) targets type I IFN-associated responses and to study the potential of several interferon associated RNA-based and protein-based biomarkers to predict and monitor treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In 21 patients treated with LEF\/HCQ and 8 patients treated with placebo, blood was drawn at baseline, 8, 16 and 24 weeks. IFN-signatures based on RNA expression of five IFN-associated genes were quantified in circulating mononuclear cells and in whole blood. MxA protein levels were measured in whole blood, and protein levels of CXCL10 and Galectin-9 were quantified in serum. Differences between responders and non-responders were assessed and receiver operating characteristic analysis was used to determine the capacity of baseline expression and early changes (after 8 weeks of treatment) in biomarkers to predict treatment response at the clinical endpoint.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>IFN-signatures in peripheral blood mononuclear cell and whole blood decreased after 24 weeks of LEF\/HCQ treatment, however, changes in IFN signatures only poorly correlated with changes in disease activity. In contrast to baseline IFN signatures, baseline protein concentrations of galectin-9 and decreases in circulating MxA and Galectin-9 were robustly associated with clinical response. Early changes in serum Galectin-9 best predicted clinical response at 24 weeks (area under the curve 0.90).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>LEF\/HCQ combination therapy targets type-I IFN-associated proteins that are associated with strongly decreased B cell hyperactivity and disease activity. IFN-associated Galectin-9 is a promising biomarker for treatment prediction and monitoring in pSS patients treated with LEF\/HCQ.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/rmdopen-2023-002979","type":"journal-article","created":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T13:55:38Z","timestamp":1690984538000},"page":"e002979","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Leflunomide\/hydroxychloroquine combination therapy targets type I IFN-associated proteins in patients with Sj\u00f6gren\u2019s syndrome that show potential to predict and monitor clinical response"],"prefix":"10.1136","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2522-3609","authenticated-orcid":false,"given":"Safae","family":"Hamkour","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eefje HM","family":"van der Heijden","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4954-5151","authenticated-orcid":false,"given":"Ana P","family":"Lopes","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofie L M","family":"Blokland","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelis P J","family":"Bekker","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia G","family":"Van Helden-Meeuwsen","sequence":"additional","affiliation":[{"name":"Immunology, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjan A","family":"Versnel","sequence":"additional","affiliation":[{"name":"Immunology, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aike A","family":"Kruize","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Utrecht University, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy RDJ","family":"Radstake","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen L","family":"Leavis","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9505-3468","authenticated-orcid":false,"given":"Maarten R","family":"Hillen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel AG","family":"van Roon","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,8,2]]},"reference":[{"key":"2025090313315928000_9.3.e002979.1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.rdc.2016.03.006","article-title":"Salivary gland pathology in Sj\u00f6gren's syndrome","volume":"42","author":"Campos","year":"2016","journal-title":"Rheum Dis Clin North Am"},{"key":"2025090313315928000_9.3.e002979.2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201381"},{"key":"2025090313315928000_9.3.e002979.3","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2019.02096","article-title":"Plasmacytoid DCS from patients with Sj\u00f6gren\u2019s syndrome are transcriptionally primed for enhanced pro-inflammatory cytokine production","volume":"10","author":"Hillen","year":"2019","journal-title":"Front Immunol"},{"key":"2025090313315928000_9.3.e002979.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.02.012"},{"key":"2025090313315928000_9.3.e002979.5","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0183946","article-title":"Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype","volume":"12","author":"Berggren","year":"2017","journal-title":"PLOS ONE"},{"key":"2025090313315928000_9.3.e002979.6","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2018.31"},{"key":"2025090313315928000_9.3.e002979.7","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1002\/art.39962","article-title":"Anifrolumab, an anti-interferon-\u0391 receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus","volume":"69","author":"Furie","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"2025090313315928000_9.3.e002979.8","doi-asserted-by":"crossref","first-page":"e260","DOI":"10.1016\/S2665-9913(20)30057-6","article-title":"Leflunomide\u2013hydroxychloroquine combination therapy in patients with primary Sj\u00f6gren\u2019s syndrome (Repurpss-I): a placebo-controlled, double-blinded, randomised clinical trial","volume":"2","author":"van der Heijden","year":"2020","journal-title":"Lancet Rheumatology"},{"key":"2025090313315928000_9.3.e002979.9","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-199602270-00020"},{"key":"2025090313315928000_9.3.e002979.10","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1517\/14740338.2011.566555","article-title":"Hydroxychloroquine in systemic lupus erythematosus and rheumatoid arthritis and its safety in pregnancy","volume":"10","author":"Abarientos","year":"2011","journal-title":"Expert Opin Drug Saf"},{"key":"2025090313315928000_9.3.e002979.11","doi-asserted-by":"publisher","DOI":"10.1136\/ard.61.6.554"},{"key":"2025090313315928000_9.3.e002979.12","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-206008"},{"key":"2025090313315928000_9.3.e002979.13","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202552"},{"key":"2025090313315928000_9.3.e002979.14","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.4049\/jimmunol.150.5.1715","article-title":"Control of IFN-inducible MxA gene expression in human cells","volume":"150","author":"Ronni","year":"1993","journal-title":"J Immunol"},{"key":"2025090313315928000_9.3.e002979.15","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1136\/annrheumdis-2018-213497","article-title":"Galectin-9 is an easy to measure biomarker for the interferon signature in systemic lupus erythematosus and antiphospholipid syndrome","volume":"77","author":"van den Hoogen","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"2025090313315928000_9.3.e002979.16","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2018-000772","article-title":"Salivary gland secretome: a novel tool towards molecular stratification of patients with primary Sj\u00f6gren\u2019s syndrome and non-autoimmune sicca","volume":"5","author":"Blokland","year":"2019","journal-title":"RMD Open"},{"key":"2025090313315928000_9.3.e002979.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2015.07.002"},{"key":"2025090313315928000_9.3.e002979.18","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/rheumatology\/kez242","article-title":"Hydroxychloroquine treatment downregulates systemic interferon activation in primary Sj\u00f6gren\u2019s syndrome in the Joquer randomized trial","volume":"59","author":"Bodewes","year":"2020","journal-title":"Rheumatology"},{"key":"2025090313315928000_9.3.e002979.19","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1080\/1744666X.2019.1624527","article-title":"Additive immunosuppressive effect of leflunomide and hydroxychloroquine supports rationale for combination therapy for Sj\u00f6gren\u2019s syndrome","volume":"15","author":"van der Heijden","year":"2019","journal-title":"Expert Rev Clin Immunol"},{"key":"2025090313315928000_9.3.e002979.20","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-201026"},{"key":"2025090313315928000_9.3.e002979.21","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.060905"},{"key":"2025090313315928000_9.3.e002979.22","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2004.031781"},{"key":"2025090313315928000_9.3.e002979.23","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1002\/art.40881","article-title":"Galectin\u20109 and CXCL10 as biomarkers for disease activity in juvenile dermatomyositis: a longitudinal cohort study and multicohort validation","volume":"71","author":"Wienke","year":"2019","journal-title":"Arthritis Rheumatol"},{"key":"2025090313315928000_9.3.e002979.24","doi-asserted-by":"crossref","DOI":"10.1136\/annrheumdis-2018-214651","article-title":"Galectin-9 reflects the interferon signature and correlates with disease activity in systemic autoimmune diseases. response to: \u2018biomarkers: to be or not to be\u2019 by Yavuz and R\u00f6nnblom","volume":"79","author":"van den Hoogen","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"2025090313315928000_9.3.e002979.25","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s12264-020-00608-1","article-title":"CXCL10\/CXCR3 signaling in the DRG exacerbates neuropathic pain in mice","volume":"37","author":"Kong","year":"2021","journal-title":"Neurosci Bull"},{"key":"2025090313315928000_9.3.e002979.26","first-page":"1026","article-title":"Effect of Chemokines CXCL9 and CXCL10 on bone erosion in patients with rheumatoid arthritis","volume":"53","author":"Zhong","year":"2021","journal-title":"Beijing Da Xue Xue Bao Yi Xue Ban"},{"key":"2025090313315928000_9.3.e002979.27","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1007\/s10096-018-3265-z","article-title":"Interferon-\u0393 and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome","volume":"37","author":"Raijmakers","year":"2018","journal-title":"Eur J Clin Microbiol Infect Dis"},{"key":"2025090313315928000_9.3.e002979.28","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201343335"}],"container-title":["RMD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rmdopen-2023-002979","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T20:32:11Z","timestamp":1756931531000},"score":1,"resource":{"primary":{"URL":"https:\/\/rmdopen.bmj.com\/lookup\/doi\/10.1136\/rmdopen-2023-002979"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8]]},"references-count":28,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,8,2]]},"published-print":{"date-parts":[[2023,8]]}},"alternative-id":["10.1136\/rmdopen-2023-002979"],"URL":"https:\/\/doi.org\/10.1136\/rmdopen-2023-002979","relation":{},"ISSN":["2056-5933"],"issn-type":[{"value":"2056-5933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8]]}}}