{
  "abstract": "Introduction Regression of skin fibrosis is a feature of the natural history of diffuse cutaneous systemic sclerosis (SSc). This study aims to establish a molecular fingerprint characterizing regression of skin fibrosis in SSc patients, to better leverage these mechanisms for improved treatment strategies.Material and Methods All patients fulfilled the 2013 ACR/EULAR classification criteria for SSc. Regressors were defined by a 5-point decrease in the modified Rodnan Skin Score (mRSS), and progressors by a 5-point increase at annual follow-up. Serum proteomics using the Olink High Throughput Explore panel (5,400 proteins) was performed on 43 SSc patients (25 regressors, 18 stable/progressors=non-regressors). Differentially abundant proteins (DAPs) were identified using the limma package. For single-cell RNA sequencing (scRNA-seq), peripheral blood mononuclear cells (PBMCs) were isolated from 10 SSc patients (N=5; regressors&progressors). Single-cell libraries were prepared and raw reads aligned to the human genome using Cellranger 7.0. Transcriptomic data were analyzed with Seurat (v5.1.0), and differential gene expression analysis (DGEA) was performed using the MAST package, followed by Gene Set Enrichment Analysis (GSEA).Results Olink® proteomics analysis identified 124 DAPs between skin regressors and non-regressors. Pathway enrichment analysis (PEA) on the DAPs identified cellular extravasation and angiogenesis among the top enriched downregulated processes in regressors. Seventy-three percent of the DAPs in these processes were functionally linked to monocyte extravasation. Additional, activin receptor activity-related proteins were also downregulated in the regressors, indicating a further suppression in cellular extravasation in the regressors. PBMC scRNA-seq revealed five distinct clusters of monocytes (Mo1-Mo5). Compositional analysis revealed a significant increase in Mo1 CD14+ antigen presenting monocytes in the regressors. A gene module score was calculated using the ‘Positive Regulation of Extravasation’ gene set to identify extravasation-primed monocyte subpopulations. This was increased in the Mo1 and Mo2 CD14+ subpopulations. The Mo1 subpopulation demonstrated a suppression in genes relating to cell adhesion and motility in the regressors. PEA demonstrated a downregulation in the interferon gamma (IFN-γ), interferon alpha (IFN-α), TNF-α and general inflammatory response in the regressors. Similarly, the GSEA for the Mo2 subpopulation showed a suppression cell migration and motility in the regressors. PEA demonstrated a downregulation in the IFN-γ, IFN-α, and TNF-α signalling in the regressors. IFN-γ is linked to a decrease in vascular permeability, further supporting altered extravasation profile between patient groups.Conclusions Our multi-omics approach points to a reduction in monocyte extravasation to the tissue linked to the regression of skin fibrosis in SSc.",
  "authors": [
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Astrid Hofman"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Pietro Bearzi"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Cosimo Bruni"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Lumeng Li"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Laura Much"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Kristina Buerki"
    },
    {
      "affiliations": [
        "Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway"
      ],
      "name": "Anna-Maria Hoffmann-Vold"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Mike Oliver Becker"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Elena Pachera"
    },
    {
      "affiliations": [
        "Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"
      ],
      "name": "Oliver Distler"
    }
  ],
  "title": "OC.22 Multi-omic analysis identifies a monocyte-vascular signature linked to skin fibrosis regression in systemic sclerosis",
  "uid": "653fadb4-c84b-55d2-8fc9-802afdd37f36"
}