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Pathogenesis of systemic sclerosis (scleroderma)

Christopher P Denton, MD
Section Editor
John S Axford, DSc, MD, FRCP, FRCPCH
Deputy Editor
Monica Ramirez Curtis, MD, MPH


The pathogenesis of systemic sclerosis (SSc; scleroderma) is complex and remains incompletely understood. Immune activation, vascular damage, and excessive synthesis of extracellular matrix with deposition of increased amounts of structurally normal collagen are all known to be important in the development of this illness [1,2]. These mechanisms result from cell-cell, cell-cytokine, and cell-matrix interactions. The heterogeneity in the clinical features of patients with SSc is most likely a reflection of the variable contributions from each of these pathogenic factors.

Most hypotheses of the pathogenesis of SSc focus on the interplay between early immunological events and vascular changes, which result in the generation of a population of activated fibrogenic fibroblasts generally considered to be the effector cell in the disease (figure 1) [2-4]. There is no doubt that vascular and immunologic processes are central to the pathogenesis of scleroderma, although it is unclear what the initial events are and how different processes respectively trigger, amplify, and facilitate the development of the skin- and organ-based fibrosis with vasculopathy that is the hallmark of the disease.

Considering the clinical differences between scleroderma and other autoimmune rheumatic diseases and the relatively modest effects that have been observed in clinical trials of immunosuppressive agents (eg, cyclophosphamide), it is perhaps surprising that genetic and serologic approaches to understanding scleroderma pathogenesis have highlighted the importance of cellular and humoral immunity. Many of the genetic loci associated with scleroderma susceptibility in large-scale genetic analyses are also associated with systemic lupus and other autoimmune conditions [5]. Moreover, even when non-immune genes are associated in subphenotype analyses of genetic loci, these associations are often defined by hallmark scleroderma autoantibodies [6], again supporting the key role of the immune system in the development and clinical features of the disease.

The multiple factors felt to be involved in the pathogenesis of SSc are reviewed here. The possible causes of SSc, as well as the clinical manifestations, diagnosis, and treatment of this disorder, are discussed separately. (See "Risk factors for and possible causes of systemic sclerosis (scleroderma)" and "Overview of the clinical manifestations of systemic sclerosis (scleroderma) in adults" and "Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults" and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".)


Vascular and endothelial cell changes, primarily mediating vascular tone, appear to precede other features of systemic sclerosis (SSc).


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