Systemic Sclerosis (Scleroderma)

Systemic sclerosis (SSc/scleroderma) is a chronic autoimmune connective tissue disease characterized by three pathological processes: (1) Vasculopathy — endothelial cell injury and dysfunction → intimal proliferation and fibrosis → progressive vessel narrowing → tissue ischemia. Raynaud phenomenon (the earliest and most common manifestation) reflects this vasculopathy in digital arteries. (2) Immune dysregulation — T-cell and B-cell activation, production of disease-specific autoantibodies (anti-centromere, anti-Scl-70/topoisomerase I, anti-RNA polymerase III), and release of pro-fibrotic cytokines (TGF-beta, PDGF, IL-4, IL-13). (3) Fibrosis — excessive collagen deposition by activated myofibroblasts in skin, lungs, GI tract, heart, and kidneys. SSc is classified into two major subtypes: Limited cutaneous SSc (lcSSc, formerly CREST syndrome): skin thickening limited to distal extremities (fingers, hands, forearms, face) and associated with anti-centromere antibody; slower progression but risk of pulmonary arterial hypertension (PAH — develops in ~15%) and esophageal dysmotility. CREST = Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia. Diffuse cutaneous SSc (dcSSc): rapid, widespread skin thickening (trunk, proximal extremities) associated with anti-Scl-70 antibody; higher risk of scleroderma renal crisis (SRC — acute hypertensive emergency with microangiopathic hemolytic anemia, treated with ACE inhibitors)...