PT - JOURNAL ARTICLE AU - Kristina Elizabeth Neergaard Clark AU - Corrado Campochiaro AU - Eszter Csomor AU - Adam Taylor AU - Katherine Nevin AU - Nicholas Galwey AU - Mary A Morse AU - Jennifer Singh AU - Yee Voan Teo AU - Voon H Ong AU - Emma Derrett-Smith AU - Nicolas Wisniacki AU - Shaun M Flint AU - Christopher P Denton TI - Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis AID - 10.1136/annrheumdis-2021-220402 DP - 2021 Dec 01 TA - Annals of the Rheumatic Diseases PG - 1584--1593 VI - 80 IP - 12 4099 - http://ard.bmj.com/content/80/12/1584.short 4100 - http://ard.bmj.com/content/80/12/1584.full SO - Ann Rheum Dis2021 Dec 01; 80 AB - Objectives Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin-based and organ-based complications. Understanding molecular differences between patients will benefit clinical practice and research and give insight into pathogenesis of the disease. We aimed to improve understanding of the molecular differences between key diffuse cutaneous SSc subgroups as defined by their SSc-specific autoantibodiesMethods We have used high-dimensional transcriptional and proteomic analysis of blood and the skin in a well-characterised cohort of SSc (n=52) and healthy controls (n=16) to understand the molecular basis of clinical diversity in SSc and explore differences between the hallmark antinuclear autoantibody (ANA) reactivities.Results Our data define a molecular spectrum of SSc based on skin gene expression and serum protein analysis, reflecting recognised clinical subgroups. Moreover, we show that antitopoisomerase-1 antibodies and anti-RNA polymerase III antibodies specificities associate with remarkably different longitudinal change in serum protein markers of fibrosis and divergent gene expression profiles. Overlapping and distinct disease processes are defined using individual patient pathway analysis.Conclusions Our findings provide insight into clinical diversity and imply pathogenetic differences between ANA-based subgroups. This supports stratification of SSc cases by ANA antibody subtype in clinical trials and may explain different outcomes across ANA subgroups in trials targeting specific pathogenic mechanisms.Data are available upon reasonable request. All data, code and materials used in the analysis are available to any researcher for purposes of reproducing or extending the analysis upon request to the corresponding author.