Systemic sclerosis: pathophysiology of a multifaceted disease

Systemic sclerosis is a rare disease characterized by vascular hyperreactivity and collagen deposition. Endothelial cell, fibroblast and lymphocyte abnormalities have been reported in systemic sclerosis. Fibroblast dysfunction is characterized by uncontrolled activation of the transforming growth factor-beta (TGF-beta) pathway and excess synthesis of both connective tissue growth factor (CTGF) and free radicals. These promote the accumulation of extracellular matrix. Endothelial cells produce excess quantities of endothelin 1 and inducible NO synthase. They also undergo early apoptosis. Oxidative stress appears to play a major role in disease progression. Increased levels of interleukin 4, a profibrotic cytokine, hove been detected in plasma and skin of systemic sclerosis patients. Autoantibodies are detectable in the serum of almost all systemic sclerosis patients. Some ore directed against well-identified ubiquitous nuclear proteins and hove no demonstrated pathogenic role. Other autoantibodies bind to endothelial cells or fibroblasts and may have a pathogenic role.