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

in Arthritis & rheumatology (Hoboken, N.J.) by Yann Nguyen, Maxime Beydon, Jacques-Eric Gottenberg, Jacques Morel, Aleth Perdriger, Emmanuelle Dernis, Divi Cornec, Valérie Devauchelle-Pensec, Damien Sène, Philippe Dieudé, Marion Couderc, Anne-Laure Fauchais, Claire Larroche, Olivier Vittecoq, Carine Salliot, Eric Hachulla, Véronique Le Guern, Xavier Mariette, Raphaèle Seror, Gaëtane Nocturne

TLDR

  • The study found that Sjögren's disease patients can be classified into three distinct clusters based on biomarkers and IFN signature, with the BALS cluster showing a higher risk of new immunosuppressant treatment and lymphoma.

Abstract

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. 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. 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. 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.

Overview

  • The study aimed to investigate whether three distinct phenotypes of Sjögren's disease (SjD) patients, identified through cluster analysis, were associated with distinct biomarkers and the prognostic value of IFN signature.
  • The study analyzed a 20-year prospective cohort of SjD patients, comparing biomarkers such as IFN-α2, IFN-γ, and cytokines, and assessing IFN signature through transcriptomic analysis.
  • The primary objective was to examine whether the IFN signature was associated with systemic and symptomatic evolution, and the risk of new immunosuppressant prescription and lymphoma, across the three clusters.

Comparative Analysis & Findings

  • Higher levels of CXCL-13, IL7, and TNF-RII 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%), with type I IFN being the main driver, and 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 cases occurred in patients with high IFN signature.

Implications and Future Directions

  • The study highlights the importance of IFN signature as a predictive biomarker for systemic evolution in the BALS cluster, and potentially for lymphoma development.
  • Further research is needed to confirm these findings and explore the potential of IFN signature as a tool for patient stratification and personalized treatment strategies.
  • Future studies could investigate the underlying mechanisms driving the distinct pathophysiological mechanisms in each cluster, and explore the role of IFN signature in other autoimmune diseases.
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