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Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis
  1. Christopher P Denton1,
  2. Voon H Ong1,
  3. Shiwen Xu1,
  4. Haiyin Chen-Harris2,
  5. Zora Modrusan2,
  6. Robert Lafyatis3,
  7. Dinesh Khanna4,
  8. Angelika Jahreis2,
  9. Jeffrey Siegel2,
  10. Thierry Sornasse2
  1. 1 Division of Medicine, Royal Free Campus, University College London, London, UK
  2. 2 Genentech, South San Francisco, California, USA
  3. 3 University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
  4. 4 University of Michigan Scleroderma Program, Ann Arbor, Michigan, USA
  1. Correspondence to Professor Christopher P Denton, University College London Division of Medicine, Royal Free Campus, London, NW3 2PF, UK; c.denton{at}ucl.ac.uk

Abstract

Objectives Skin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFβ) and interleukin-6 (IL-6) are key candidate mediators in SSc. Our aim was to elucidate the specific effect of IL-6 pathway blockade on the biology of SSc fibroblasts in vivo by using samples from a unique clinical experiment—the faSScinate study—in which patients with SSc were treated for 24 weeks with tocilizumab (TCZ), an IL-6 receptor-α inhibitor.

Methods We analysed the molecular, functional and genomic characteristics of explant fibroblasts cultured from matched skin biopsy samples collected at baseline and at week 24 from 12 patients receiving placebo (n=6) or TCZ (n=6) and compared these with matched healthy control fibroblast strains.

Results The hallmark functional and molecular-activated phenotype was defined in SSc samples and was stable over 24 weeks in placebo-treated cases. RNA sequencing analysis robustly defined key dysregulated pathways likely to drive SSc fibroblast activation in vivo. Treatment with TCZ for 24 weeks profoundly altered the biological characteristics of explant dermal fibroblasts by normalising functional properties and reversing gene expression profiles dominated by TGFβ-regulated genes and molecular pathways.

Conclusions We demonstrated the exceptional value of using explant dermal fibroblast cultures from a well-designed trial in SSc to provide a molecular framework linking IL-6 to key profibrotic pathways. The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases.

Trial registration number NCT01532869; Post-results.

  • cytokines
  • fibroblasts
  • systemic sclerosis

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors All authors were involved in drafting the manuscript or revising it critically for important intellectual content, made substantial contributions to the conception or design of the study or the acquisition, analysis or interpretation of data, approved the final version of the manuscript to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved.

  • Funding This study was funded by F Hoffmann-La Roche. Writing and editorial assistance was provided by Maxwell Chang, BSc, and Sara Duggan, PhD, on behalf of F Hoffmann-La Roche Ltd. Additional funding from EULAR via the Orphan Diseases Programme is gratefully acknowledged.

  • Competing interests CPD reports personal fees from Roche/Genentech, Actelion, GlaxoSmithKline, Sanofi-Aventis, Inventiva and Boehringer-Ingelheim; grants and personal fees from Bayer; and grants from CSL Behring during the conduct of the study. VHO and SX have nothing to disclose. HC-H is an employee of Genentech. ZM, JS and TS are employees of and own stock in Genentech. RL reports personal fees from Biocon and Merck, grants from Elpidera and grants and personal fees from PRISM Biolab outside of the submitted work. DK reports personal fees from Actelion, Cytori, EMD Serono, Gilead, GlaxoSmithKline, Sanofi-Aventis, Corbus, ChemomAb, Eicos and UCB Pharma; grants from Bristol-Myers Squibb, the National Institutes of Health and Pfizer; grants and personal fees from Bayer, Roche/Genentech and Boehringer-Ingelheim during the conduct of the study; and personal fees from AstraZeneca outside the submitted work. AJ is an employee of Genentech, owns stock and stock options in Roche and has a patent issued for tocilizumab.

  • Patient consent Obtained.

  • Ethics approval The study protocol was approved by the institutional review boards or ethics committees before the study commenced. All subjects provided written consent. The study was conducted in accordance with the Declaration of Helsinki and with Good Clinical Practice. ‘Control’ skin biopsy samples were obtained with informed consent from healthy volunteers (London-Hampstead NRES Committee, MREC Reference 6398).

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

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