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Updated: Sep 26, 2026
Isolating Human Peripheral Blood Mononuclear Cells and CD4+ T cells from Sézary Syndrome Patients for Transcriptomic Profiling
Published on: October 14, 2021
Treatment-Driven Peripheral Blood Transcriptomic Remodeling and Baseline Predictors of ESSDAI and STAR Response to B
Aimen Ibrahim1, Junjie Peng1, Eileen Tian1
1Centre for Ageing, Rheumatology and Regenerative Medicine, Division of Medicine, University College London, London, United Kingdom.
Objective:
This study aimed to characterize whole blood transcriptomic profiles in adults with active Sjögren's disease (SjD) treated with anti-CD20 or B lymphocyte stimulator/BAFF inhibition, identify markers of clinical response, and define inflammatory pathways linked to nonresponse.
Methods:
Whole blood RNA sequencing was performed at baseline and Week 24 in participants (n = 43) from a phase 2 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, gene set enrichment analysis, curated interaction databases). Clinical response was defined using EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and Sjögren's Tool for Assessing Response (STAR); responder groups were compared using descriptive statistics, correlations, and logistic regression with receiver operating characteristic-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 nonresponse was associated with higher baseline transforming growth factor β-2 (TGFβ-2), C4A, and CD8A expression, and lower complement component 4 BP alpha (C4BPA) expression, defining complement-regulated, cytotoxic, and stromal-remodeling 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-1/IL-18/FcγR-centered myeloid module (AUC 0.80). No ligand-receptor 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.
Conclusion:
The distinct ESSDAI and STAR ligand-receptor signatures indicate different systemic biologic drivers of nonresponse to B cell therapies in SjD. Their complete nonoverlap suggests entrenched B cell-independent inflammatory circuits, highlighting complement regulation, TGFβ-2-mediated remodeling, IL-1/IL-18 signaling, and FcγR activation as rational treatment pathways beyond B cell-targeted therapies.
