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Abstract Number: 118

Pharmacological Inhibition of JAK/STAT Signaling By Tofacitinib Prevents Experimental Organ Fibrosis: Novel Therapy for Systemic Sclerosis

Swati Bhattacharyya1, Wenxia Wang2, Jun Wei3 and John Varga1, 1Northwestern University, Chicago, IL, 2Feinberg School of Medicine, Northwestern University, Chicago, IL, 3Northwestern University, chicago, IL

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: fibrosis, systemic sclerosis and tofacitinib

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Session Information

Date: Sunday, October 21, 2018

Title: Systemic Sclerosis and Related Disorders – Basic Science Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

Synchronous fibrosis in systemic sclerosis (SSc) leads to failure of the skin, lungs and other organs, and has no effective treatments. Myofibroblast activation underlies fibrosis in different organs, but the pathogenesis of fibrosis and the key extracellular cues driving the process remains poorly understood. Multiple intracellular pathways are triggered by cytokines and chemokines implicated in SSc. Of special interest is IL-6, which activates JAK/STAT signaling. A recent multi-ethnic GWAS identified strong associations of JAK-STAT variants with SSc. In order to illuminate the mechanisms linking these risk genes with disease pathogenesis, we investigated the IL6/JAK/STAT axis in SSc, and the effect of tofacitinib, a JAK/STAT inhibitor, in preclinical model of organ fibrosis.

Methods:

We measured JAK/STAT expression and activity in SSc skin biopsies by immunohistochemistry and by unbiased transcriptome profiling. We defined a tofacitinib gene signature, and measured its activity in SSc. The effects of tofacitinib treatment were determined in explanted fibroblasts, and in a preclinical model of multiple organ fibrosis.

Results:

We measured JAK/STAT expression and activity in SSc skin biopsies by immunohistochemistry and by unbiased transcriptome profiling. We defined a tofacitinib gene signature, and measured its activity in SSc. The effects of tofacitinib treatment were determined in explanted fibroblasts, and in a preclinical model of multiple organ fibrosis.

RESULTS:

Expression of both phospho-JAK2 and phospho-STAT3 was significantly elevated in SSc skin biopsies (n=19) compared to matched healthy controls (n=10) (p<0.0001). Moreover, activated JAK/STAT expression showed significant negative correlation with pulmonary function (r=-0.48, p<0.01). We next analyzed gene expression signatures in transcriptome datasets comprised of 84 SSc and 12 healthy control skin biopsies, that clustered SSc biopsies into four distinct subsets. We found a significant correlation of the IL6/JAK/STAT signature (63 genes) with the inflammatory intrinsic subset, accounting for 40% of all SSc biopsies. The strength of an experimentally-derived “tofacitinib gene signature” of 39 genes was significantly reduced (p<0.001) in the same SSc biopsies, and was negatively correlated with TNFα and IFNα pathway scores. In fibroblasts, tofacitinib effectively inhibited induction of inflammatory and fibrotic genes induced by IL-6. Notably, tofacitinib treatment resulted in dramatic attenuation of bleomycin-induced skin and lung fibrosis in mice.

Conclusion:

The JAK/STAT signaling pathway is markedly activated in a subset of SSc patients, and appears to contribute to disease progression. Blocking JAK/STAT activity with tofacitinib abrogates core fibrotic responses in fibroblasts, and prevents multiple organ fibrosis in mice. These results are the first to demonstrate that in SSc patients with genomic evidence of enhanced JAK/STAT pathway activity in target organs, tofacitinib treatment might be effective in slowing or reversing fibrosis.


Disclosure: S. Bhattacharyya, None; W. Wang, None; J. Wei, None; J. Varga, BSM, 2,Pfizer, Inc., 2,Boehringer, 5,Mitsubishi, 5,Corbus, 5,Scleroderma Foundation, 6.

To cite this abstract in AMA style:

Bhattacharyya S, Wang W, Wei J, Varga J. Pharmacological Inhibition of JAK/STAT Signaling By Tofacitinib Prevents Experimental Organ Fibrosis: Novel Therapy for Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/pharmacological-inhibition-of-jak-stat-signaling-by-tofacitinib-prevents-experimental-organ-fibrosis-novel-therapy-for-systemic-sclerosis/. Accessed .
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