RESUMEN

Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFRbeta and Abl with imatinib therapy. By gene expression profiling, an imatinib-responsive signature specific to dcSSc was identified (P < 10(-8)). The response of these patients and the findings of the analyses suggest that PDGFRbeta and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc.

Asunto(s)

Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Esclerodermia Difusa/tratamiento farmacológico , Benzamidas , Femenino , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Humanos , Mesilato de Imatinib , Persona de Mediana Edad , Proteínas Oncogénicas v-abl/genética , Proteínas Oncogénicas v-abl/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Esclerodermia Difusa/metabolismo , Esclerodermia Difusa/patología , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Adulto Joven