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Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile
  1. Brian Skaug1,
  2. Dinesh Khanna2,
  3. William R Swindell3,4,
  4. Monique E Hinchcliff5,
  5. Tracy M Frech6,
  6. Virginia D Steen7,
  7. Faye N Hant8,
  8. Jessica K Gordon9,
  9. Ami A Shah10,
  10. Lisha Zhu11,
  11. W Jim Zheng11,
  12. Jeffrey L Browning12,
  13. Alexander M S Barron12,
  14. Minghua Wu1,
  15. Sudha Visvanathan13,
  16. Patrick Baum14,
  17. Jennifer M Franks15,16,
  18. Michael L Whitfield15,16,
  19. Victoria K Shanmugam17,
  20. Robyn T Domsic18,
  21. Flavia V Castelino19,
  22. Elana J Bernstein20,
  23. Nancy Wareing1,
  24. Marka A Lyons1,
  25. Jun Ying1,
  26. Julio Charles1,
  27. Maureen D Mayes1,
  28. Shervin Assassi1
  1. 1 Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA
  2. 2 Scleroderma Program, Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
  3. 3 Ohio University Heritage College of Osteopathic Medicine, Athens, Ohio, USA
  4. 4 Department of Internal Medicine, The Jewish Hospital, Cincinnati, Ohio, USA
  5. 5 Department of Medicine, Section of Allergy, Rheumatology, and Immunology, Yale University, New Haven, Connecticut, USA
  6. 6 Division of Rheumatology, Department of Internal Medicine, University of Utah and Salt Lake Regional Veterans Affairs Medical Center, Salt Lake City, Utah, USA
  7. 7 Division of Rheumatology, Department of Medicine, MedStar Georgetown University Hospital, Washington, DC, USA
  8. 8 Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
  9. 9 Department of Rheumatology, Hospital for Special Surgery, New York City, New York, USA
  10. 10 Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  11. 11 School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas, USA
  12. 12 Department of Microbiology, Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts, USA
  13. 13 Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA
  14. 14 Boehringer Ingelheim International GmbH, Biberach, Germany
  15. 15 Department of Biomedical Data Science, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USA
  16. 16 Department of Molecular and Systems Biology, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire, USA
  17. 17 Division of Rheumatology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
  18. 18 Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  19. 19 Division of Rheumatology, Massachusetts General Hospital, Boston, Massachusetts, USA
  20. 20 Division of Rheumatology, Vagelos College of Physicians and Surgeons, New York City, New York, USA
  1. Correspondence to Dr Brian Skaug, Department of Internal Medicine, Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; brian.a.skaug{at}uth.tmc.edu

Abstract

Objectives Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.

Methods Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.

Results SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.

Conclusions Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

  • systemic Sclerosis
  • inflammation
  • autoimmunity
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Footnotes

  • Handling editor Josef S Smolen

  • Twitter @ShervinAssassi

  • Contributors SA, BS, DK, SV and TF designed the study. BS, DK, MEH, TF, VS, FH, JG, AAS, JB, AMSB, MW, SV, PB, NW, JC and SA were involved in acquisition of data. 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.

  • Funding BS is supported by a grant from the Arthritis National Research Foundation. DK is supported by a Scleroderma Foundation SCORE grant and NIH/NIAMS K24 AR 063120. The PRESS Data Coordinating Center at University of Michigan was supported by NIH/NIAMS K24 AR063120 to DK. SA is supported by a Scleroderma Foundation SCORE grant, a DoD grant W81XWH-61-1-0296 and by NIH/NIAMS R01AR073284. MW is supported by a grant from the Scleroderma Foundation. This work was partly supported by the UT Houston Bioinformatics and High Performance Computing Service Center and CPRIT grant RP170668 (WJZ). WJZ is supported by NIH 1UL1 TR003167-01. JMF and MLW are supported by the Scleroderma Research Foundation, Dr Ralph and Marian Falk Medical Research Trust Catalyst and Transformational Award and NIH/NIAMS P50 AR060780-01. JMF is supported by NIH 5T32LM012204-03. EJB is supported by NIH/NIAMS K23 AR075112.

  • Competing interests DK reports consultancy fees from Acceleron, Actelion, Bayer, Blade Therapeutics, BMS, Galapagos, Genentech/Roche, GSK, Mitsubishi Tanabi, Sanofi-A ventis/Genzyme, and UCB Pharma, and reports grants from Bayer, BMS, and Genentech/Roche outside the submitted work, and reports ownership interest in Eicos Sciences, Inc. WRS reports consulting fees from UT Health Science Center at Houston. JKG reports grants from Corbus Pharmaceuticals, Cumberland Pharmaceuticals and Eicos Pharmaceuticals outside the submitted work. AAS reports support from Sanofi outside the submitted work. MLW reports grants and personal fees from Celdara Medical, LLC and personal fees from Abbvie, Acceleron, BMS, Corbus Pharmaceuticals and Boehringer Ingelheim outside the submitted work. JLB reports grants from Hoffman La Roche and the Scleroderma Foundation outside the submitted work. SB and PB are employees of Boehringer Ingelheim. FVC reports personal fees from Boehringer Ingelheim outside the submitted work. EJB reports a grant from Pfizer and support from Bohringer Ingelheim, Corbus Pharmaceuticals and Eicos outside the submitted work. MDM reports personal fees from Medtelligence, Actelion Pharma, Astellas, Mitsubishi-Tanabe, and Boehringer Ingelheim and grants from Bayer, Reata, Sanofi, Corbus, Eicos and Boehringer Ingelheim outside the submitted work. SA reports personal fees from Boehringer Ingelheim and grants from Boehringer Ingelheim, Bayer and Momenta outside the submitted work.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement RNA sequencing data are available at NCBI's Gene Expression Omnibus, accession GSE130955.

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