Novel Treatment Approaches to Fibrosis in Scleroderma
ABSTRACT The molecular mechanisms leading to tissue fibrosis were only poorly understood in the past, and even today the cause or trigger of systemic sclerosis is still unknown. Remarkable breakthrough findings have been obtained regarding the identification of key molecules, key cellular mechanisms, and key intracellular signaling cascades, which mediate the perpetuation of fibrosis rather than trigger it. These findings have true translational implications, because modifiers of these key mediators and key mechanisms are often in clinical use in other disease indications, such as cancer. This article summarizes the clinical and preclinical evidence of examples of these novel antifibrotic treatment approaches in systemic sclerosis, including stem cell transplantation, modifiers of transforming growth factor-beta1 signaling, intravenous immunoglobulins, tyrosine kinase inhibitors, and histone deacetylase inhibitors.
Article: Sklerodermie[Show abstract] [Hide abstract]
ABSTRACT: Scleroderma (synonyms: systemic sclerosis, systemic scleroderma) is a systemic disease which affects the skin as well as internal organs such as the lungs, gastrointestinal tract, kidneys, and the heart. Pathogenetically a distinction should be made between uncontrolled formation of extracellular matrix proteins (fibrosis) and vasculopathy. In addition to organ fibrosis, this leads to a clinical picture of vascular manifestations. These include fingertip ulcers, pulmonary arterial hypertension, and acute renal crisis. Localized forms of scleroderma, such as morphea, which do not involve organ complications, should be differentiated from systemic sclerosis. Due to its clinical heterogeneity and high rate of morbidity and mortality, systemic sclerosis poses an enormous diagnostic and therapeutic challenge in everyday clinical practice. This review article summarizes the current status of classification and epidemiology, pathogenesis, and the most important clinical manifestations such as interstitial fibrosis, pulmonary arterial hypertension, acute renal crisis, and peripheral vasculopathy and provides an overview of current and future treatment options.Der Internist 01/2010; 51(1):30-38. DOI:10.1007/s00108-009-2405-z · 0.31 Impact Factor
Article: SCLERODERMA.[Show abstract] [Hide abstract]
ABSTRACT: Scleroderma is a descriptive construct that defines a large family of diseases characterized clinically by thickening of the skin. Systemic sclerosis (SSc) is a complex disease affecting multiple organ systems and is the most representative and prevalent of this spectrum of disorders. Generalized subcutaneous morphea (GSM, morphea profunda) is a form of localized scleroderma that tends to spare the internal organs. We are presenting two cases illustrating the aforementioned clinical entities.Journal of the Indian Medical Association 06/1965; 44:484-6. DOI:10.1007/978-1-60761-296-4_18
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ABSTRACT: Imatinib is a small-molecule tyrosine kinase inhibitor capable of selective, dual inhibition of the transforming growth factor beta 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.Arthritis & Rheumatology 01/2009; 60(1):219-24. DOI:10.1002/art.24186 · 7.76 Impact Factor