{
  "abstract": "Introduction S100A4 is one of a family of damage-associated molecular peptide proteins causing downstream intracellular and extracellular fibrotic effects. Pre-clinical animal and functional studies have shown that S100A4 is implicated in skin and lung fibrosis in systemic sclerosis (SSc).Previous work [Denton et al, 2023] demonstrated that recombinant S100A4 protein promotes a fibrotic phenotype in normal fibroblasts whilst anti-S100A4 neutralising monoclonal antibody (AX-202) attenuated the profibrotic phenotype of SSc fibroblasts (SScF). Integrated analysis determined a set of 475 genes (the ‘’S100A4 signature’’) that are differentially expressed between normal (NDF) and SScF, induced in NDF by recombinant S100A4, and significantly attenuated in SScF by AX-202.Material and Methods Gene set enrichment analysis interrogated the S100A4 signature gene expression in whole skin in 68 well characterised SSc patients or healthy controls prospectively from a large tertiary centre over the course of 24 months (BIOPSY cohort). These included early diffuse cutaneous (dc)SSc (n=21), limited cutaneous (lc)SSc (n=15) and established dcSSc (n=14) with 16 matched healthy controls. Bulk RNA sequencing assessed genome-wide gene expression of whole skin samples to obtain normalised gene expression values for each sample.Results Of the 475 S100A4 signature genes, 460 genes were also identified in the BIOPSY cohort. 191 of the 460 genes showed statistically significant expression (p value <0.01) across all subsets of SSc compared to healthy controls. Principal component analysis shows the variability of expression of the top 50 differentially expressed genes with the tightest expression profile in the healthy control samples. The early diffuse subset scatter more widely and overlap with the established subset suggesting transitional heterogeneity.Supervised hierarchical clustering by samples and genes (figure 1) revealed distinct genetic signatures as illustrated by the dendrograms. Expression values of each gene are calculated using normalised z scores to highlight relative over and under expression of the gene in each sample.The relative expression by fold change of each of the top 20 differentially expressed genes by subset (early diffuse, all SSc and established diffuse SSc) compared to healthy controls is shown in the bar plot (figure 2).Conclusions Our findings confirm differential activation of S100A4 regulated genes across the spectrum of SSc subsets that is not present in healthy skin.Since S100A4 is a potential molecular marker and target in different SSc subgroups our findings may inform future clinical study design to help understand differential treatment response.Abstract P.006 Figure 1–2",
  "authors": [
    {
      "affiliations": [
        "University College London, London, United Kingdom",
        "Royal Free London NHS Foundation Trust, London, United Kingdom"
      ],
      "name": "Medha Kanitkar"
    },
    {
      "affiliations": [
        "University College London, London, United Kingdom",
        "Royal Free London NHS Foundation Trust, London, United Kingdom"
      ],
      "name": "Philip Yee"
    },
    {
      "affiliations": [
        "University College London, London, United Kingdom",
        "Royal Free London NHS Foundation Trust, London, United Kingdom"
      ],
      "name": "Stefano Rodolfi"
    },
    {
      "affiliations": [
        "University College London, London, United Kingdom"
      ],
      "name": "Kristina Clark"
    },
    {
      "affiliations": [
        "University College London, London, United Kingdom",
        "Royal Free London NHS Foundation Trust, London, United Kingdom"
      ],
      "name": "Voon Ong"
    },
    {
      "affiliations": [
        "University College London, London, United Kingdom",
        "Royal Free London NHS Foundation Trust, London, United Kingdom"
      ],
      "name": "Christopher Denton"
    }
  ],
  "title": "P.006 S100A4 regulated genes are differentially activated in systemic sclerosis skin across limited and diffuse cutaneous subsets",
  "uid": "d4278ad9-fad4-5041-8436-b78e5c3de1bb"
}