Unique Sjögren’s syndrome patient subsets defined by molecular features

Abstract

Objective To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes. Methods pSS patients met American–European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200. Results Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell–attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters. Conclusion Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.

Predicted Disease-Specific Immune Infiltration Patterns Decode the Potential Mechanisms of Long Non-Coding RNAs in Primary Sjogren’s Syndrome

“…Interestingly, our study found a strong correlation between CTA-250D10.23 and CXCL13. Serum CXCL13 is a biomarker of salivary gland local pathology (37) and local increased of CXCL13 also serves as one of features of the pSS patient subset (38). As an echo to these lines of evidence, CXCL13 was identified as the most robustly up-regulated gene in pSS (Supplemental Figure 1).…”

A new molecular classification to drive precision treatment strategies in primary Sjögren’s syndrome

“…Thereby, pSS patients could be stratified in interferon negative, Type I or Type I + II positive subgroups with higher prevalence of anti-SSA and anti-SSB among those with IFN activation without relation with systemic activity. Another group 42 performed a clustering analysis of blood gene expression microarray which classified the 47 pSS patients in three clusters characterized by IFN and inflammation with no discriminant clinical features Moreover, four subgroups of patients with similar patients’ clinical characteristics were identified based on absolute cell counts per μL of blood 23 . Lastly, a stratification based on patient clinical phenotypes characterized a posteriori at the molecular level was proposed 43 .…”

Applications of Protein Microarrays in Biomarker Discovery for Autoimmune Diseases

“…Both studies confirmed that protein microarrays are capable of higher sensitivity than ELISA. In recent years, similar multiplex approaches were developed to screen specific autoantibody biomarkers for various AIDs, such as rheumatoid diseases ( 71 , 72 ), type 1 diabetes ( 73 ), lupus nephritis ( 74 ), multiple sclerosis ( 75 , 76 ), systemic sclerosis ( 46 ), SLE ( 37 , 77 , 78 ), juvenile dermatomyositis ( 67 ), and Sjogren's syndrome ( 79 ). Importantly, most of these studies included dozens to several hundreds of autoantigens.…”

“…Importantly, most of these studies included dozens to several hundreds of autoantigens. In addition, a multiplexed, bead-based system was developed that is also suitable for array construction and detection for this application ( 79 ). However, only a few of the most well-studied autoantigens were used to construct this detection system for screening autoantibodies in patients' sera.…”