Abstract
There is currently no approved treatment for primary Sjögren’s syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren’s syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials.
Highlights
There is currently no approved treatment for primary Sjögren’s syndrome, a disease that primarily affects adult women
We report on the integrated molecular profiling of 304 Primary Sjögren’s syndrome (pSS) patients compared to 330 matched healthy volunteers (HV) performed using high-throughput multi-omics data collected within the PRECISESADS IMI JU project
Cluster 1 (C1) patients present a high prevalence of single nucleotide polymorphisms (SNPs), Cluster 3 (C3) patients an involvement of B cell component more prominent than in the other clusters and especially an increased frequency of B cells in the blood while Cluster 4 (C4) patients have an inflammatory signature driven by monocytes and neutrophils, together with an aberrant methylation status
Summary
There is currently no approved treatment for primary Sjögren’s syndrome, a disease that primarily affects adult women. 11 Klinik für Immunologie und Rheumatologie, Medical University Hannover, Primary Sjögren’s syndrome (pSS) is a chronic, disabling, complex systemic autoimmune disease that mostly affects adult women and still lacks a specific therapy. Limited knowledge of existing pSS disease variants arguably represents the greatest obstacle to improve patients’ diagnosis and identify patients’ subsets in view of early stratification and personalized treatment[4] It was recently shown in the PRECISESADS IMI JU project that systemic autoimmune diseases exhibit a diverse spectrum and a complex nuanced or overlapping molecular phenotype with four clusters identified, representing ‘inflammatory’, ‘lymphoid’, ‘interferon’ and ‘healthy-like’ patterns each including all diagnoses and defined by genetic, clinical, serological and cellular features[5]. Decision trees coming from this patient classification have an immediate application to re-evaluate response to treatments in clinical trials
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