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Large-scale analysis of longitudinal skin gene expression in systemic sclerosis reveals relationships of immune cell and fibroblast activity with skin thickness and a trend towards normalisation over time
  1. Brian Skaug1,
  2. Marka A Lyons1,
  3. William R Swindell2,
  4. Gloria A Salazar1,
  5. Minghua Wu1,
  6. Tuan M Tran3,
  7. Julio Charles1,
  8. Connor P Vershel1,
  9. Maureen D Mayes1,
  10. Shervin Assassi1
  1. 1Division of Rheumatology, University of Texas Health Science Center Houston, McGovern Medical School, Houston, Texas, USA
  2. 2Department of Internal Medicine, The Jewish Hospital, Cincinnati, Ohio, USA
  3. 3Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  1. Correspondence to Dr Brian Skaug, Division of Rheumatology, University of Texas Health Science Center Houston, McGovern Medical School, Houston, TX 77030, USA; brian.a.skaug{at}uth.tmc.edu; Dr Shervin Assassi, Division of Rheumatology, University of Texas Health Science Center Houston, McGovern Medical School, Houston, TX 77030, USA; shervin.assassi{at}uth.tmc.edu

Abstract

Objectives Determine relationships between skin gene expression and systemic sclerosis (SSc) clinical disease features, and changes in skin gene expression over time.

Methods A total of 339 forearm skin biopsies were obtained from 113 SSc patients and 44 matched healthy controls. 105 SSc patients had a second biopsy, and 76 had a third biopsy. Global gene expression profiling was performed, and differentially expressed genes and cell type-specific signatures in SSc were evaluated for relationships to modified Rodnan Skin Score (mRSS) and other clinical variables. Changes in skin gene expression over time were analysed by mixed effects models and principal component analysis. Immunohistochemical staining was performed to validate conclusions.

Results Gene expression dysregulation was greater in SSc patients with affected skin than in those with unaffected skin. Immune cell and fibroblast signatures positively correlated with mRSS. High baseline immune cell and fibroblast signatures predicted higher mRSS over time, but were not independently predictive of longitudinal mRSS after adjustment for baseline mRSS. In early diffuse cutaneous SSc, immune cell and fibroblast signatures declined over time, and overall skin gene expression trended towards normalisation. On immunohistochemical staining, most early diffuse cutaneous SSc patients with high baseline T cell and macrophage numbers had declines in these numbers at follow-up.

Conclusions Skin thickness in SSc is related to dysregulated immune cell and fibroblast gene expression. Skin gene expression changes over time in early diffuse SSc, with a tendency towards normalisation. These observations are relevant for understanding SSc pathogenesis and could inform treatment strategies and clinical trial design.

  • scleroderma
  • systemic
  • fibroblasts
  • autoimmune diseases

Data availability statement

Data are available in a public, open access repository. Gene expression, demographic and clinical data were uploaded to NCBI’s Gene Expression Omnibus (GEO), accession number GSE181549. The data can be accessed using the token: mdqtwqkqldwtjml.

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Data availability statement

Data are available in a public, open access repository. Gene expression, demographic and clinical data were uploaded to NCBI’s Gene Expression Omnibus (GEO), accession number GSE181549. The data can be accessed using the token: mdqtwqkqldwtjml.

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Footnotes

  • Handling editor Josef S Smolen

  • Twitter @ShervinAssassi

  • BS and MAL contributed equally.

  • Contributors SA, BS, MAL, MDM and GS designed the study. All authors were involved in analysis and interpretation of the data. All authors were involved in manuscript preparation and approved the final version of the manuscript. SA was responsible for the overall content as guarantor and accepts full responsiblity for the conduct of the study, had access to the data, and controlled the decision to publish.

  • Funding BS was supported by a grant from the Arthritis National Research Foundation (ANRF). SA and MW are supported by a grant from the NIH NIAMS (R56AR078211). SA is supported by grants from the NIH NIAMS (R01AR073284 and R61AR078078) and DoD (W81XWH-16-1-0296).

  • Competing interests MDM reports support from Mitsubishi-Tanabe, Boehringer Ingelheim, EICOS and Corbus to her institution outside the submitted work, and fees from Medtelligence, Actelion Pharma, Mitsubishi-Tanabe, Boehringer Ingelheim and EICOS to her outside the submitted work. SA reports grant support from Momenta, Boehringer Ingelheim, Janssen, and the Scleroderma Research Foundation to his institution outside the submitted work; consulting fees from Boehringer Ingelheim, Novartis, Corbus, CSL Behring, Abbvie, AstraZeneca to him outside the submitted work; honorarium from Boehringer Ingelheim for lectures and payment from the American College of Rheumatology to him outside the submitted work. BS, MAL, WRS, GS, MW, TMT, JC and CPV have no relevant competing interests to declare.

  • 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.

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