Distinct pathophysiological pathways support stratification of Sjögren's disease based on symptoms, clinical, and routine biological data.

Objective: Recently, three distinct phenotypes of Sjögren's disease (SjD) patients have been described, based on cluster analysis: B-cell active with low symptoms (BALS), high systemic activity (HSA), and low systemic activity with high symptoms (LSAHS). We aimed to assess whether these clusters were associated with distinct biomarkers and the prognostic value of IFN signature.

Methods: The ASSESS cohort is a 20-year prospective cohort of SjD patients. The following biomarkers were compared: IFN-α2, IFN-γ, CXCL10, CXCL13, BAFF, IL7, FLT3, CCL19, and TNFRII. IFN signature was assessed using transcriptomic analysis. We then compared systemic and symptomatic evolution, and the risk of new immunosuppressant prescription and of lymphoma, according to the IFN signature across the three clusters.

Results: 395 patients (94% female, median age 53 [43-63] years) were included. Higher levels of CXCL-13, IL7, and TNF-RII levels were found in the BALS and HSA clusters compared to the LSAHS cluster. A high IFN signature was mainly found in the BALS cluster (57%, vs. 48%, and 38% in the HSA and LSAHS clusters, respectively). This IFN signature was mainly driven by type I IFN, with higher levels of IFN- α2. In the BALS cluster, a high IFN signature was associated with a higher risk of new immunosuppressant treatment (HR 9.38; 95% CI 1.22-72.16). All lymphoma occurred in patients with high IFN signature.

Conclusion: The three SjD clusters displayed distinct expression of IFN signature, and markers of T- and B-cell activation, confirming distinct pathophysiological mechanisms. High IFN signature could predict systemic evolution in the BALS cluster.