Abstract
BACKGROUND Systemic sclerosis (SSc) is an autoimmune, connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs.METHODS We randomized 15 participants with early diffuse cutaneous SSc to tofacitinib 5 mg twice a day or matching placebo in a phase I/II double-blind, placebo-controlled trial. The primary outcome measure was safety and tolerability at or before week 24. To understand the changes in gene expression associated with tofacitinib treatment in each skin cell population, we compared single-cell gene expression in punch skin biopsies obtained at baseline and 6 weeks following the initiation of treatment.RESULTS Tofacitinib was well tolerated; no participants experienced grade 3 or higher adverse events before or at week 24. Trends in efficacy outcome measures favored tofacitnib. Baseline gene expression in fibroblast and keratinocyte subpopulations indicated IFN-activated gene expression. Tofacitinib inhibited IFN-regulated gene expression in SFRP2/DPP4 fibroblasts (progenitors of myofibroblasts) and in MYOC/CCL19, representing adventitial fibroblasts (P < 0.05), as well as in the basal and keratinized layers of the epidermis. Gene expression in macrophages and DCs indicated inhibition of STAT3 by tofacitinib (P < 0.05). No clinically meaningful inhibition of T cells and endothelial cells in the skin tissue was observed.CONCLUSION These results indicate that mesenchymal and epithelial cells of a target organ in SSc, not the infiltrating lymphocytes, may be the primary focus for therapeutic effects of a Janus kinase inhibitor.TRIAL REGISTRATION ClinicalTrials.gov NCT03274076.FUNDING Pfizer, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01 AR070470, NIH/NIAMS K24 AR063120, Taubman Medical Research Institute and NIH P30 AR075043, and NIH/NIAMS K01 AR072129.
Authors
Dinesh Khanna, Cristina Padilla, Lam C. Tsoi, Vivek Nagaraja, Puja P. Khanna, Tracy Tabib, J. Michelle Kahlenberg, Amber Young, Suiyuan Huang, Johann E. Gudjonsson, David A. Fox, Robert Lafyatis
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
