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.