Distinct Molecular Pathways Supporting Sjögren Disease Clusters and Disease Progression

Sacha E Silva-Saffar; Yann Nguyen; Raphaèle Seror; Jacques-Eric Gottenberg; Anna Niarakis; Xavier Mariette; Gaetane Nocturne

doi:10.1002/art.70251

Distinct Molecular Pathways Supporting Sjögren Disease Clusters and Disease Progression

Arthritis Rheumatol. 2026 Jun 11. doi: 10.1002/art.70251. Online ahead of print.

Authors

Sacha E Silva-Saffar^{1

2

3}, Yann Nguyen^{4

5}, Raphaèle Seror^{2

3}, Jacques-Eric Gottenberg⁶, Anna Niarakis^{7

8}, Xavier Mariette^{2

3}, Gaetane Nocturne^{2

3}

Affiliations

¹ GenHotel - European Research Laboratory for Rheumatoid Arthritis, Université Évry Paris-Saclay, Evry-Courcourconnes, France.
² Paris-Saclay University, Inserm, Commissariat à l'Energie Atomique, Immune diseases, microbiology and innovative therapies (IDMIT/UMRS1184), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France.
³ Department of Immuno-Rheumatology, Hôpital Bicêtre, Université Paris-Saclay, Assistance Publique - Hôpitaux de Paris, Paris, France.
⁴ Centre for Research in Epidemiology and Statistics, Université Paris Cité and Université Sorbonne Paris Nord, Inserm, Institut national de recherche pour l'agriculture, l'alimentation et l'environnement, Paris, France.
⁵ Department of Internal Medicine, Hôpital Beaujon, Université Paris Cité, Assistance Publique - Hôpitaux de Paris, Clichy, France.
⁶ Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
⁷ Molecular, Cellular and Developmental Biology Unit, Centre de Biologie Integrative, University of Toulouse, Paris Saclay University, Centre national de la recherche scientifique, Toulouse, France.
⁸ Lifeware Group, Inria Saclay-île de France, Palaiseau, France.

PMID: 42272274
DOI: 10.1002/art.70251

Abstract

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.

Abstract

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