Systemic sclerosis B. epidemiology, pathology, and pathogenesis

Systemic sclerosis (SSc) is a chronic, multisystem disease of unknown etiology characterized by autoimmunity and inflammation, functional and structural abnormalities in small blood vessels, and progressive fibrosis of the skin and visceral organs. Estimates of its incidence in the United States range from 9 to 19 cases per million per year. The only community-based survey of SSc yielded a prevalence of 286 cases per million population. SSc is more common in females, with women-to-men ratios of 3 to 5 : 1. African Americans have a higher incidence than whites, and disease onset occurs at an earlier age. Furthermore, African Americans are more likely to have the diffuse cutaneous form of the disease with interstitial lung involvement and worse prognosis. Some SSc patients (1.6%) have a first-degree relative with the disease [relative risk (RR) = 13], indicating an important genetic contribution to disease susceptibility. Among environmental factors, infectious agents (particularly viruses), exposure to environmental and occupational toxins, and drugs have been suspected of playing a role in the etiology of SSc. The distinguishing pathological hallmark of SSc is an obliterative vasculopathy of small arteries and arterioles, combined vascular and interstitial fibrosis in target organs. In patients with established SSc, these lesions occur in the absence of inflammation. In relatively early-stage disease, perivascular cellular infiltrates are detected in many organs prior to the appearance of fibrosis. The organs most prominently affected by obliterative vasculopathy are the heart, lungs, kidneys, and intestinal tract. Fibrosis is prominent in the skin, lungs, gastrointestinal tract, heart, tendon sheath, perifascicular tissue surrounding skeletal muscle, and in some endocrine organs, such as the thyroid gland. Multiple cell types and their products interact in the processes that underlie the diverse clinical manifestations of SSc. An integrated view of the pathogenesis of SSc must incorporate the development of vasculopathy, activation of the cellular and humoral immune responses, and progressive fibrosis of multiple organs. Autoimmunity, altered endothelial cell function, and vascular reactivity may be the earliest manifestations of SSc, leading to Raynaud's phenomenon years before other disease features are present. Complex interplay among these processes initiates, amplifies, and sustains aberrant tissue repair and fibrosis.