Background/Purpose: Sjögren disease (SD) is characterised by B-cell hyperactivity associated with increased levels of B-lymphocyte stimulator (BlyS), but there are no effective biologic treatments for patients with SD.  Rituximab (anti CD20) and belimumab (anti-BlyS), which can act synergistically, were tested in a 68-week, phase II, double-blind study (GSK study 201842; NCT02631538) in adults with active SD randomised to one of four arms:  placebo (PBO), s.c. belimumab (BEL), i.v. rituximab (RTX), or sequential therapy with BEL and RTX (1).

The impact of BEL and RTX alone or in combination on the whole blood transcriptomic profile of adults with active SD and differentially expressed gene (DEG) profiles in responders versus non-responders defined based on ≥5 points improvement in ESSDAI at week (W)24 (primary endpoint of the GSK trial) were investigated (1).

Methods: RNA-sequencing was performed on whole blood from 43 SD patients at two timepoints, baseline and W24. Patients were assigned to treatment groups (PBO, n=6; BEL, n=12; RTX, n=13;  BEL/RTX, n=12) and DEG analysis (log2fold change >1.5, adjusted p-value < 0.05) was performed between matched samples at baseline vs W24 followed by pathway enrichment analysis. Patient groups were stratified into responder and non-responder groups.

Results: Patients treated with BEL/RTX demonstrating the greatest number of DEGs between baseline and W24 (n=417 down, n=52 up-regulated) compared with RTX only (n=300 down, n=16 up), BEL only (n=146 down, n=41 up) and PBO (n=41 down and n=64 up) groups. Only DEGs detected in the combination therapy arm could stratify patients between baseline and W24 timepoints by principal component analysis. ‘Immunoglobulin production‘, ‘B-cell activation‘ and ‘IL4 production‘ were the most significantly enriched downregulated pathways within this group. Notably, 152 genes were uniquely downregulated by the combination therapy alone, associated with ‘lymphocyte activation and signalling‘, while 60 genes were shared across all treatment groups. Pathways enriched within DEGs from the PBO group (including ‘regulation of kinase activity‘, ‘epigenetic regulation of gene expression‘) did not overlap with enriched pathways from the treatment arms.

When patients were stratified for clinical response/non-response to treatment, the combination therapy induced the greatest number of DEGs between baseline and W24 (n=347/n=128) compared to RTX (n=185/n=180) and BEL (n=52/n=3) monotherapy, in responders/non-responders, respectively. DEGs, in responders/non-responders to all therapies, were enriched in pathways associated with ‘B-cell receptor signalling‘, ‘immunoglobulin production‘ and ‘B cell activation‘.  However, in patients responding to RTX alone and/or combination therapy, DEGs were enriched in ‘cell junction‘, ‘morphogenesis‘, ‘actin filament assembly‘ and ‘regulation of leukocyte activation‘ pathways suggesting unique molecular pathways associated with treatment response.  

Conclusion: B cell targeted treatments alone and in combination impact the peripheral blood transcriptome in adults with SD. The differential effect of treatment on responders vs. non-responders, highlights the role of B cells in SD disease pathogenesis.  

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-impact-of-b-cell-targeted-monotherapy-and-combination-regimen-on-the-peripheral-blood-transcriptome-of-adults-with-active-sjogren-disease/