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Tyrosine Kinase Inhibitors in the Treatment of Systemic Sclerosis: From Animal Models to Clinical Trials

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Abstract

Efficient antifibrotic therapies are not available for patients with systemic sclerosis (SSc). This review summarizes the current preclinical and clinical evidence for imatinib and related tyrosine kinase inhibitors as potential antifibrotic therapies for SSc and other fibrotic diseases. In experimental models of SSc, imatinib, nilotinib, and dasatinib demonstrated strong antifibrotic effects. Imatinib not only prevented fibrosis in the bleomycin-induced model of dermal fibrosis and the tight skin mouse-1 model but also reduced established fibrosis in a modified bleomycin model. Open-label, proof-of-concept trials in SSc showed moderate effects on skin fibrosis, biological measures of skin fibrosis, and lung fibrosis compared with baseline measures. However, whether this reflects the natural course of the disease or is a result of treatment effects is unclear and needs to be analyzed in larger, multicenter, randomized, placebo-controlled trials. Toxicity is expected from cancer trials with frequent mild to moderate adverse events.

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Disclosure

Dr. Jörg Distler has served as a consultant for Actelion Pharmaceuticals, Pfizer, and GlaxoSmithKline; has received grant support from Novartis, Bayer Schering Pharma, Cell Gen Therapeutics, NicOx, Array BioPharma, Bristol-Myers Squibb, and Ergonex Pharma GmbH; and has received payment for development of educational presentations (including service on speakers’ bureaus) from Actelion Pharmaceuticals, Pfizer, GlaxoSmithKline, and Bayer Schering Pharma.

Dr. Oliver Distler has served as a consultant for Actelion Pharmaceuticals, Pfizer, FibroGen, Ergonex Pharma GmbH, Bristol-Myers Squibb, Sanofi-Aventis, and United BioSource Corp.; has received grant support from Pfizer and Ergonex Pharma GmbH; has received payment for development of educational presentations (including service on speakers’ bureaus) from Actelion Pharmaceuticals, Pfizer, and Medac; and has had travel/accommodations covered or reimbursed by UCB. Dr. Iwamoto reported no conflicts of interest relevant to this article.

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Authors and Affiliations

  1. Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Gloriastr. 25, 8091, Zürich, Switzerland

    Naoki Iwamoto & Oliver Distler

  2. Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany

    Jörg H. W. Distler

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  1. Naoki Iwamoto
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  2. Jörg H. W. Distler
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  3. Oliver Distler
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Correspondence to Oliver Distler.

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Iwamoto, N., Distler, J.H.W. & Distler, O. Tyrosine Kinase Inhibitors in the Treatment of Systemic Sclerosis: From Animal Models to Clinical Trials. Curr Rheumatol Rep 13, 21–27 (2011). https://doi.org/10.1007/s11926-010-0142-x

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