Whole-blood RNA sequencing at baseline and week-24 was used to characterise transcriptomic changes and identify predictors of clinical response in 43 adults with active Sjögren's disease (SjD) treated with rituximab (RTX), belimumab (BEL), sequential BEL-RTX, or placebo in a phase II GSK trial (NCT02631538).
Sequential BEL-RTX produced the largest transcriptional shift; baseline gene signatures distinguished ESSDAI non-responders (TGFB2, C4A, CD8A↑; C4BPA↓; AUC 0.89) from STAR non-responders (SPP1, TLR4, IL1R1, IL18R1, IL1RAP, TREM1, FCGR2A↑; AUC 0.80), with zero gene overlap between the two response definitions.
Small sample size (n=43) limits statistical power and generalisability; unadjusted p-values were used for differential expression, raising risk of false positives; this is a secondary transcriptomic analysis of a phase II trial not powered for biomarker discovery.
ESSDAI and STAR capture biologically distinct non-response states to B-cell therapies in SjD, so choice of outcome measure matters when evaluating treatment failure. Persistent IL-1/IL-18, complement, and FcγR-driven pathways in non-responders point to targets that may warrant investigation beyond anti-CD20 and BLyS/BAFF inhibition.
