ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2153

Nintedanib Ameliorates Fibrotic and Vascular Manifestations in Preclinical Models of Systemic Sclerosis

Jingang Huang1, Christian Beyer1, Yun Zhang1, Katrin Palumbo-Zerr2, Clara Dees1, Oliver Distler3, Georg A. Schett4, Stefan Lutz Wollin5 and Jorg HW. Distler1, 1Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 2Department of Internal Medicine 3 and Institute for Clinical Immunology, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 3Department of Rheumatology, Research of Systemic Autoimmune Diseases, University Hospital Zurich, Zurich, Switzerland, 4Institute for Clinical Immunology, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 5Boehringer-Ingelheim Pharma, Div. Research Germany, Bad Biberach, Germany

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords:

Session Information

Date: Monday, November 9, 2015

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics I

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose:

Nintedanib is a tyrosine kinase inhibitor that inhibits PDGF-, FGFR-, VEGFR-receptors and Src kinases. Nintedanib has recently been approved for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this study was to analyze the effects of nintedanib on fibrotic and vascular manifestations in preclinical models of systemic sclerosis (SSc) and to provide a scientific rationale for clinical trials in SSc.

Methods: The effects of nintedanib on migration, proliferation, myofibroblast differentiation and release of extracellular matrix were investigated by MTT- and scratch assays, stress fiber staining, qPCR and SirCol assays. The effects of nintedanib were evaluated in bleomycin-induced skin fibrosis, in murine sclerodermatous cGvHD, in Tsk-1 mice and in Fra2-tg mice. 

Results:

Nintedanib reduced the PDGF- and TGFbeta-induced proliferation and migration more effectively than selective inhibition of PDGF-, VEGF or FGF-receptors. Nintedanib dose-dependently inhibited PDGF- and TGFbeta-induced myofibroblast differentiation and collagen release. In SSc fibroblasts, nintedanib also reduced the endogenous activation and decreased the collagen release even in the absence of exogenous stimulation. Nintedanib exerted potent anti-fibrotic effects in bleomycin-induced skin fibrosis, in experimental cGvHD, in Tsk-1 and in Fra2-tg mice with dose-dependent amelioration of dermal and pulmonary fibrosis. Of note, treatment with nintedanib also inhibited vascular manifestations in Fra2-tg mice. Nintedanib reduced proliferation of vascular smooth muscle cells and prevented thickening of the vessel walls and luminal occlusion of pulmonary arteries. Of note, treatment with nintedanib also inhibited apoptosis of dermal microvascular endothelial cells and blunted the capillary rarefication in Fra2-tg mice. 

Conclusion:

Nintedanib exerts potent anti-fibrotic effects in several complementary mouse models of SSc, but also ameliorates the histological features of PAH and of microangiopathy in Fra2-tg mice. The potent effects of nintedanib on fibrosis and vascular manifestations might have direct implications for the upcoming phase III clinical trial with nintedanib in SSc.

Disclosure: J. Huang, None; C. Beyer, None; Y. Zhang, None; K. Palumbo-Zerr, None; C. Dees, None; O. Distler, None; G. A. Schett, None; S. L. Wollin, employee of Boehringer-Ingelheim, 3; J. H. Distler, Research collaboration with Boehringer-Ingelheim, 9.

To cite this abstract in AMA style:

Huang J, Beyer C, Zhang Y, Palumbo-Zerr K, Dees C, Distler O, Schett GA, Wollin SL, Distler JH. Nintedanib Ameliorates Fibrotic and Vascular Manifestations in Preclinical Models of Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/nintedanib-ameliorates-fibrotic-and-vascular-manifestations-in-preclinical-models-of-systemic-sclerosis/. Accessed .

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