Localized scleroderma: Etiology, pathogenesis, clinical manifestations

Localized scleroderma (LS) is a chronic autoimmune disease of the connective tissue characterized by focal fibrosis of the skin and subcutaneous tissues. The urgency for in-depth study of the etiological factors and pathogenetic mechanisms of development of LS is determined by the need to identify new biomarkers of the disease that will enable the disease to be diagnosed and the pathological process to be predicted at an early stage. Investigating the role of genetic predisposition, environmental factors, and infectious agents in initiating the autoimmune response, as well as exploring molecular mechanisms of activation of fibrosis formation is of particular scientific interest. Current data indicate significant clinical polymorphism of LS, which creates essential diagnostic challenges and requires improvement of classification approaches. This article presents a review of the current literature on the etiology, pathogenesis, and clinical forms of localized scleroderma. It discusses the multifactorial nature of the disease, including genetic predisposition (polymorphisms located in HLA-DRB1*04:04, STAT4, and IRF5), exposure to infectious agents (Borrelia burgdorferi, herpes viruses), and the influence of exogenous factors (mechanical trauma, ionizing radiation, and chemicals). The pathogenetic section provides coverage of three key aspects of LS development: autoimmune inflammation with a predominant Th2 lymphocyte response and hyperproduction of IL-4, IL-6, and IL-13; vascular disorders manifested by endothelial cell apoptosis and microthrombosis; and activation of fibrogenesis through the TGF-β/Smad signalling pathway followed by excessive deposition of type I collagen. The clinical section presents a detailed classification of LS forms and description of their diagnostic criteria: plaque, linear (including “en coup de sabre” variant), bullous, deep, generalized, pansclerotic, and mixed LS. Lichen sclerosus et atrophicus (LS & A) remains a point of contention among dermatologists due to the ambiguity of its classification and pathogenesis. Results of the systematic literature review indicate the existence of three main concepts explaining the pathogenesis of LS: systemic autoimmune disease, localized scleroderma, or bullous dermatosis variant. In recent years, immunohistochemical and molecular genetic studies have been shown to reveal significant heterogeneity in LS, which requires a revision of existing classifications.

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