Distinct Molecular Pathways Supporting Sjögren Disease Clusters and Disease Progression.

OBJECTIVE

Sjögren disease (SjD) is a heterogeneous autoimmune disease. We aimed to investigate blood transcriptomic signatures and disease progression among three recently defined clusters of patients with SjD: (1) B cell active disease with low symptom burden (BALS), (2) high systemic activity (HSA), and (3) low systemic activity with high symptom burden (LSAHS).

METHODS

We analyzed transcriptomic data from the ASSESS cohort (GSE140161; n = 351). Patients were classified into the three clusters previously described. Within BALS, an evolutive subgroup was defined based on need for new immunosuppressants and/or occurrence of lymphoma (BALS subgroup of patients with progressive/evolving disease [BALS_Evol]). Differential expression analysis and Gene Set Enrichment Analysis were performed to evaluate subgroup-specific signatures and biologic pathways.

RESULTS

Both BALS and HSA displayed robust types I/II interferon (IFN)-stimulated gene up-regulation compared to LSAHS. BALS exhibited stronger IFN activity and inflammatory signaling than HSA, particularly in the evolutive subgroup (BALS_Evol). This subgroup showed enrichment of IFNα/γ, tumor necrosis factor α, interleukin-6, complement activation, and mechanistic target of rapamycin (mTOR) complex 1 pathways, indicating a hyperinflammatory and dysregulated immune state linked to disease progression. In contrast, compared with BALS, the HSA cluster displayed attenuated IFN and KRAS pathway activity, coupled with activation of MYC, mTOR, and oxidative phosphorylation, suggesting a molecular shift toward proliferation and metabolism that may promote systemic disease evolution.

CONCLUSION

IFN signaling is a hallmark of both HSA and BALS clusters. In BALS, it may drive early disease progression, which can be replaced later by proliferative pathways leading to an HSA. These findings pave the way for new hypotheses regarding the mechanisms driving disease progression in SjD.