Blood transcriptomic signatures and disease progression were analyzed across three predefined Sjögren's Disease (SjD) patient clusters — B-cell active with low symptoms (BALS), high systemic activity (HSA), and low systemic activity with high symptoms (LSAHS) — using the ASSESS cohort (n=351). An evolutive BALS subgroup (BALS_Evol) was defined by need for new immunosuppressants and/or lymphoma occurrence.
BALS and HSA both showed strong type I/II interferon (IFN)-stimulated gene upregulation vs. LSAHS. BALS_Evol had the highest IFN activity, enriched for IFNα/γ, TNFα, IL-6, complement, and mTORC1 pathways. HSA, compared to BALS, showed attenuated IFN/KRAS activity but upregulated MYC, mTOR, and oxidative phosphorylation — suggesting a shift toward proliferative and metabolic pathways.
Observational transcriptomic design limits causal inference. The evolutive BALS subgroup definition (new immunosuppressants or lymphoma) may introduce heterogeneity. Findings are from a single cohort (ASSESS/GSE140161) without external validation.
Clinicians should be aware that SjD is molecularly heterogeneous — patients in the BALS cluster, especially those progressing (BALS_Evol), show a hyperinflammatory IFN-driven state that may warrant closer monitoring for immunosuppressant escalation and lymphoma risk. The distinct proliferative pathway signature in HSA raises the possibility that targeted therapies (e.g., mTOR inhibitors) may need to differ by patient cluster.
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