{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T04:46:42Z","timestamp":1791780402893,"version":"4.3.4"},"reference-count":46,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["6591924"],"award-info":[{"award-number":["6591924"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp;amp; Rheumatology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to characterize whole blood transcriptomic profiles in adults with active Sj\u00f6gren's disease (SjD) treated with anti\u2010CD20 or B lymphocyte stimulator\/BAFF inhibition, identify markers of clinical response, and define inflammatory pathways linked to nonresponse.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Whole blood RNA sequencing was performed at baseline and Week 24 in participants (n\u00a0=\u00a043) from a phase 2 GSK trial (NCT02631538) evaluating rituximab (RTX), belimumab (BEL), and sequential BEL\u2010RTX versus placebo. Differential expression (DESeq2; fold change &gt;1.5; unadjusted\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.01) was integrated with pathway enrichment and ligand\u2013receptor analyses (Metascape, gene set enrichment analysis, curated interaction databases). Clinical response was defined using EULAR Sj\u00f6gren's Syndrome Disease Activity Index (ESSDAI) and Sj\u00f6gren's Tool for Assessing Response (STAR); responder groups were compared using descriptive statistics, correlations, and logistic regression with receiver operating characteristic\u2013based evaluation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Sequential BEL\u2010RTX induced the largest transcriptional shift from baseline to Week 24. Baseline differential expression identified distinct ligand\u2013receptor predictors for each response definition. ESSDAI nonresponse was associated with higher baseline transforming growth factor \u03b2\u20102 (TGF\u03b2\u20102), C4A, and CD8A expression, and lower complement component 4 BP alpha (C4BPA) expression, defining complement\u2010regulated, cytotoxic, and stromal\u2010remodeling pathways (area under the curve [AUC] 0.89). In contrast, STAR nonresponders showed higher baseline expression of SPP1, TLR4, IL1R1, IL18R1, IL1RAP, TREM1, and FCGR2A, forming an IL\u20101\/IL\u201018\/Fc\u03b3R\u2010centered myeloid module (AUC 0.80). No ligand\u2013receptor genes overlapped between ESSDAI and STAR. ESSDAI genes clustered nonresponders distinctly, whereas STAR genes showed weak separation with no cluster concordance between the two response definitions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The distinct ESSDAI and STAR ligand\u2013receptor signatures indicate different systemic biologic drivers of nonresponse to B cell therapies in SjD. Their complete nonoverlap suggests entrenched B cell\u2013independent inflammatory circuits, highlighting complement regulation, TGF\u03b2\u20102\u2013mediated remodeling, IL\u20101\/IL\u201018 signaling, and Fc\u03b3R activation as rational treatment pathways beyond B cell\u2013targeted therapies.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art70354-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  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