Systemic sclerosis: pathogenic mechanisms and their implications for treatment.

Abstract

Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by a triad of pathogenic mechanisms, including: a) microvascular hyperreactivity secondary to endothelial dysfunction, b) dysregulated immune activation of both innate and adaptive immunity, with the production of autoantibodies targeting nuclear antigens (e.g., anticentromere antibodies, anti-RNA polymerase III antibodies, and anti-topoisomerase I antibodies), and c) fibrosis of the skin and internal organs, such as the lungs, due to excessive extracellular matrix deposits produced by dysregulated myofibroblasts. Skin involvement plays a crucial role in the detrimental impact of SSc on quality of life. Skin fibrosis in SSc is characterized by the progressive accumulation of extracellular matrix components, including collagen, in the dermis, and is associated with adipocyte atrophy in the hypodermis. Visceral manifestations include fibrotic interstitial lung disease (ILD), myocardial involvement, pulmonary arterial hypertension, gastrointestinal manifestations, and scleroderma renal crisis. These manifestations are key determinants of prognosis and significant contributors to mortality in SSc. This review will explore the clinical features of SSc, the existing subtypes based on different classification approaches (such as skin-driven classifications, autoantibodies, or molecular subsets), epidemiology, identified etiologies, pathogenesis, current standards of care, and a selection of potential therapeutic perspectives. This review will emphasize SSc-related skin manifestations, including their pathogenesis and treatment, while also discussing other organ manifestations.