Treatment‐driven peripheral blood transcriptomic remodelling and baseline predictors of ESSDAI and STAR response to B‐cell therapy in Sjögren's disease

Objective To characterise whole‐blood transcriptomic profiles in adults with active Sjögren's disease (SjD) treated with anti‐CD20 or BlyS/BAFF inhibition, identify markers of clinical response, and define inflammatory pathways linked to non‐response. Methods Whole‐blood RNA sequencing was performed at baseline and week‐24 in participants (n=43) from a phase II GSK trial (NCT02631538) evaluating rituximab (RTX), belimumab (BEL), and sequential BEL–RTX versus placebo. Differential expression (DESeq2; fold change >1.5; unadjusted P<0.01) was integrated with pathway enrichment and ligand–receptor analyses (Metascape, GSEA, curated interaction databases). Clinical response was defined using ESSDAI and STAR; responder groups were compared using descriptive statistics, correlations, and logistic regression with ROC‐based evaluation. Results Sequential BEL–RTX induced the largest transcriptional shift from baseline to week‐24. Baseline differential expression identified distinct ligand–receptor predictors for each response definition. ESSDAI non‐response was associated with higher baseline TGFB2, C4A, CD8A, and lower C4BPA, defining complement‐regulated, cytotoxic and stromal‐remodelling pathways (AUC 0.89). In contrast, STAR non‐responders showed higher baseline expression of SPP1, TLR4, IL1R1, IL18R1, IL1RAP, TREM1, and FCGR2A, forming an IL‐1/IL‐18/FcγR‐centred myeloid module (AUC 0.80). No ligand–receptor genes overlapped between ESSDAI and STAR. ESSDAI genes clustered non‐responders distinctly, whereas STAR genes showed weak separation with no cluster concordance between the two response definitions. Conclusion The distinct ESSDAI and STAR ligand–receptor signatures indicate different systemic biological drivers of non‐response to B‐cell therapies in SjD. Their complete non‐overlap suggests entrenched B‐cell‐independent inflammatory circuits, highlighting complement regulation, TGFB2‐mediated remodelling, IL‐1/IL‐18 signalling and FcγR activation as rational treatment pathways beyond B‐cell‐targeted therapies. image