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.
- systemic sclerosis
Data availability statement
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.
Statistics from Altmetric.com
Handling editor Josef S Smolen
Contributors All authors contributed significantly to the study design and manuscript and reviewed and edited the final manuscript. Individual contribution as set out below. Conceptualisation: CPD and NW. Methodology: ED-S, NW, CPD, JS and YVT. Investigation: KENC, CC, JS and YVT. Data analysis: KENC, AT, NG and YVT. Supervision: KENC, CC and CPD. Writing—original draft: KENC and CPD. Writing—review and editing: KENC, CC, EC, AT, KN, NG, MAM, JS, YVT, VO, ED-S, NW, SMF and CPD.
Funding This work was funded by a research grant to UCL from GlaxoSmithKline and Medical Research Council UK grant MR/T001631/1 (fellowship to KENC).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.