Juvenile dermatomyositis (JDMS) is one of the most serious of the childhood rheumatic diseases. Mortality is 3-39% with over 40% of patients demonstrating long term disability. Current first line therapy is high dose corticosteroids with the attendant significant drug related toxicity. Over 30% of JDMS patients fail to respond adequately to steroids and require additional immunosuppression, none of which have been tested in prospective, randomized, controlled trials. The unique occlusive vasculopathy in JDMS is critical in the pathogenesis, predictive of prognosis but poorly understood. Elevated levels of TNF alpha have been shown to be present in JDMS and are associated with a more severe and chronic course. HYPOTHESIS: The early introduction of etanercept or methotrexate will prove to be effective in the treatment of JDMS and in pretreatment muscle biopsies there will be abnormalities in quantitative vascular morphology and levels of angiogenic factors that will be significantly negatively correlated with physical strength and daily functional ability. METHODOLOGY: 75 children with definite JDMS will be enrolled in a 24 month prospective, randomized, multicentered trial comparing 3 treatments: oral prednisone (P), combination of oral prednisone and methotrexate (P/MTX), and combination of oral prednisone and etanercept (P/E). Primary response measures will be muscle strength and mean duration of steroid therapy. Secondary response variables are disability in daily function and height and weight growth velocity (steroid toxicity measures). The combination of PIE will be tested and compared to both P alone and the combination of P/MTX after 3, 6, 12, 18 and 24 months of treatment. In addition, the combination of P/MTX will be compared to P alone after 3, 6, 12, 18 and 24 months of treatment. In pretreatment muscle biopsies, proangiogenic factors (such as vascular endothelial cell growth factor and basic fibroblast growth factor), angiostatic factors (such as angiostatin and endostatin) and vascular morphology (vessel number, width, length and area) will be quantified and tested for ability to predict muscle strength and functional ability 3, 6, 12, 18 and 24 months SIGNIFICANCE. The long-term goal is to improve the treatment of this serious childhood onset rheumatic disease and to better understand the pathogenic mechanism for the development of the vasculopathy of JDMS. Identification of the specific mechanism of the vasculopathy may allow for the rational introduction of biologic treatments focused on vascular growth.
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