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Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis.

Clark, KEN; Campochiaro, C; Csomor, E; Taylor, A; Nevin, K; Galwey, N; Morse, MA; ... Denton, CP; + view all (2021) Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis. Annals of the Rheumatic Diseases 10.1136/annrheumdis-2021-220402. (In press). Green open access

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Abstract

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 autoantibodies METHODS: 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.

Type: Article
Title: Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1136/annrheumdis-2021-220402
Publisher version: http://dx.doi.org/10.1136/annrheumdis-2021-220402
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Autoantibodies, systemic sclerosis, therapeutics
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10131480
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