Genome-wide stratification of patients into molecularly similar groups is rapidly becoming a key component of genetic-based precision medicine. Stratification using a patient's gene expression fingerprint found in end target tissues such as skin is highly reproducible and can break down and quantify the heterogeneity in SSc. Although significant insights have been gained by analysis of individual datasets probing gene expression in end target tissues (skin, lung and PBMCs), integrative analysis of gene expression and proteomic data across multiple SSc cohorts and mulitiple SSc tissues provides additional power, inherent replication and the ability to identify deregulated processes common to each affected organ. We analyzed ten independent genome-wide gene expression datasets from multiple SSc tissues that allow for a systematic reanalysis of the SSc transcriptome and, in particular, allow us to identify the conserved molecular drivers of the intrinsic gene expression subsets (inflammatory, fibroproliferative, limited and normal-like) that are found in multiple end-target tissues including skin, esophagus and lung. These data show the intrinsic gene expression subsets are conserved across different tissues in SSc and may represent fundamental mechanisms underlying the pathogenesis of the disease. We find that different pathways are deregulated in each of these subsets, suggesting each subset will respond differently to therapy. We also performed analysis of the autoantibody targets in SSc using immunopreciptiation of protein lysates with patient autoantibodies followed by mass spectrometric analysis of the recovered antigens, which suggests a model in which a combination of chronic and acute cellular stresses results in aberrant cell death, leading to autoantibody generation directed against intracellular macromolecular structures. Analysis of skin biopsies from SSc patients in multiple, independent clinical trials provides support for our hypothesis that patient gene expression subset will be a major determinant of those individuals most likely to respond to a particular therapeutic intervention.
Disclosure of Interest None declared