Drs. Oliver Distler and Jörg H. W. Distler have received consulting fees, speaking fees, and/or honoraria from Encysive and Actelion (less than $10,000 each). They also have received support from Novartis for a clinical trial with imatinib in systemic sclerosis.
Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis
Version of Record online: 30 DEC 2008
Copyright © 2008 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 1, pages 219–224, January 2009
How to Cite
Akhmetshina, A., Venalis, P., Dees, C., Busch, N., Zwerina, J., Schett, G., Distler, O. and Distler, J. H. W. (2009), Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. Arthritis & Rheumatism, 60: 219–224. doi: 10.1002/art.24186
- Issue online: 30 DEC 2008
- Version of Record online: 30 DEC 2008
- Manuscript Accepted: 25 SEP 2008
- Manuscript Received: 30 JUN 2008
- University Erlangen–Nuremberg. Grant Number: ELAN grant 53410022
- Interdisciplinary Center of Clinical Research, Erlangen. Grant Number: A20
- Ernst Jung Foundation Career Support Award of Medicine
Imatinib is a small-molecule tyrosine kinase inhibitor capable of selective, dual inhibition of the transforming growth factor β and platelet-derived growth factor (PDGF) pathways. Imatinib has previously been shown to prevent the development of inflammation-driven experimental fibrosis when treatment was initiated before administration of the profibrotic stimulus. The aim of this study was to confirm the efficacy of imatinib in a murine model of systemic sclerosis (SSc) that is less driven by inflammation and to investigate whether imatinib is also effective for the treatment of established fibrosis.
The tight skin 1 (TSK-1) mouse model of SSc was used to evaluate the antifibrotic effects of imatinib in a genetic model of the later stages of SSc. In addition, the efficacy of imatinib for the treatment of preestablished fibrosis was analyzed in a modified model of bleomycin-induced dermal fibrosis in which the application of bleomycin was prolonged and the onset of treatment was late.
Treatment with imatinib reduced dermal and hypodermal thickening in TSK-1 mice and prevented the differentiation of resting fibroblasts into myofibroblasts. In the model of preestablished dermal fibrosis, imatinib not only stopped further progression of fibrosis but also induced regression of preexisting dermal fibrosis, with a reduction in dermal thickness below pretreatment levels.
These results indicate that combined inhibition of the tyrosine kinase c-Abl and PDGF receptor might be effective in the later, less inflammatory stages of SSc and for the treatment of established fibrosis. Thus, imatinib might be an interesting candidate for clinical trials in patients with longstanding disease and preexisting tissue fibrosis.