Introduction: The etiopathogenesis of systemic sclerosis-an integrated overview

Systemic sclerosis (SSc) is a heterogeneous chronic multisystem disease of unknown etiology. It has global distribution and, like other connective diseases, a strong female predominance. The onset of SSc shows age-dependence and modest familial clustering, but no compelling geographic or temporal clustering. Multiple genes are implicated in SSc susceptibility, and the genetic architecture, dominated by the HLA locus, shows considerable overlap with other autoimmune diseases. The variable disease course, its high burden of mortality and morbidity, and lack of effective therapies make SSc a top research priority in the field of rheumatic diseases. A bird’s-eye view of SSc suggests the following paradigm for disease pathogenesis, supported by current data in the chapters that follow: initial injury in an individual with a permissive genetic background triggers complex and sustained interactions among immune and vascular cells in a variety of tissues. Oxidative stress ensues, and a range of soluble and matrix-associated signals are generated that trigger and maintain mesenchymal cell activation and survival, leading to matrix accumulation and culminating in progressive multi-organ fibrosis.