SYSTEMIC SCLEROSIS: PATHOGENESIS OF VASCULAR AND FIBROTIC PROCESSES

Abstract

Systemic sclerosis (SSc, scleroderma) is a chronic autoimmune connective tissue disease characterized by the triad of vasculopathy, immune dysregulation, and progressive fibrosis affecting the skin and internal organs. This narrative review synthesizes current evidence on the pathogenesis of the vascular and fibrotic processes underlying SSc, drawing on the 2013 ACR/EULAR classification criteria and the 2023 EULAR recommendations for the treatment of systemic sclerosis. Vascular injury is now recognized as the earliest event in SSc pathogenesis: endothelial cell damage from autoantibodies, ischemia-reperfusion injury, and oxidative stress leads to endothelial dysfunction, intimal proliferation, platelet activation, and progressive vascular remodeling, clinically manifesting as Raynaud phenomenon, digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. In parallel, dysregulated innate and adaptive immunity — including autoantibody production and a dominant Th2/Th17 cytokine profile driven by transforming growth factor-beta (TGF-β) and interleukin-6 (IL-6) — activates dermal and visceral fibroblasts, promoting their differentiation into myofibroblasts and excessive deposition of collagen and other extracellular matrix proteins, compounded by impaired matrix degradation. The 2023 EULAR recommendations introduced, for the first time, synthetic and biologic disease-modifying agents — including mycophenolate mofetil, nintedanib, rituximab, and tocilizumab — for key fibrotic manifestations, alongside first-line combination therapy for newly diagnosed pulmonary arterial hypertension, reflecting a therapeutic shift toward mechanism-targeted intervention across both vascular and fibrotic domains. A mechanism-based understanding of SSc pathogenesis, combined with early classification and individualized, organ-specific management, is central to limiting irreversible organ damage and improving long-term outcomes, including within the healthcare system of Uzbekistan.