What causes systemic sclerosis (SSc)?

From the Guidelines

The exact cause of systemic sclerosis (SSc) is unknown, but it is believed to be an autoimmune disorder triggered by a combination of genetic and environmental factors, as suggested by the most recent and highest quality study 1. Scleroderma likely develops due to:

• Genetic predisposition: Certain genes may make individuals more susceptible.
• Environmental triggers: Exposure to certain chemicals, viruses, or toxins may initiate the disease process in genetically susceptible individuals.
• Immune system dysfunction: The body's immune system mistakenly attacks healthy tissues, particularly those involved in collagen production.
• Vascular abnormalities: Blood vessel damage and dysfunction contribute to the disease progression.
• Excessive collagen production: Overproduction of collagen leads to the characteristic skin thickening and organ fibrosis. While these factors are believed to play a role, no single cause has been definitively identified, as noted in a recent review of the current management of SSc 1. The interplay between genetics, environment, and the immune system likely contributes to the development of scleroderma, and understanding these potential causes helps guide research into prevention and treatment strategies, but currently, there is no way to prevent scleroderma or pinpoint a specific cause in individual cases, as highlighted in a joint statement on early detection of interstitial lung disease in rheumatic diseases 1.

The disease is characterized by a triad of pathogenic factors, including vasculopathy, inflammation and autoimmunity, and fibrosis, as described in a recent systematic literature review 1. The extent and distribution of skin fibrosis determine the phenotype of SSc, which can be classified as diffuse cutaneous (dcSSc) or limited cutaneous (lcSSc), with dcSSc being associated with a higher risk of interstitial lung disease (ILD) and other organ-based manifestations, as reported in a study of 3656 patients with SSc from the EULAR Scleroderma Trials and Research (EUSTAR) cohort 1.

In terms of morbidity, mortality, and quality of life, SSc is a rare and heterogeneous systemic autoimmune disease that can have a significant impact on patients' lives, with ILD being the prevailing pulmonary manifestation and a leading cause of hospitalization, morbidity, and mortality, as noted in a recent review of the current management of SSc 1. Therefore, early detection and treatment of SSc and its organ-based manifestations, such as ILD, are crucial to improve patient outcomes and quality of life, as recommended by the European Scleroderma Trials and Research (EUSTAR) under the aegis of EULAR 1.

From the Research

Causes of Systemic Sclerosis (SSc)

The exact causes of systemic sclerosis (SSc) are not fully understood, but several factors are thought to contribute to its development. These include:

• Genetic predisposition: Individuals with a family history of SSc are more likely to develop the disease 2, 3, 4
• Autoimmune responses: SSc is characterized by the presence of autoantibodies and abnormal immune cell function, suggesting an autoimmune component to the disease 2, 3, 4
• Vascular damage: Vascular injury and dysfunction are key features of SSc, and may contribute to the development of fibrosis and other disease manifestations 2, 3, 5
• Extracellular matrix abnormalities: Alterations in the production and regulation of extracellular matrix components, such as collagen, may contribute to the development of fibrosis in SSc 2, 3, 5
• Oxidative stress: Reactive oxygen species (ROS) have been implicated in the pathogenesis of SSc, and may contribute to the development of fibrosis and vascular damage 6

Pathophysiology of SSc

The pathophysiology of SSc is complex and involves multiple cellular and molecular mechanisms. These include:

• Abnormal immunologic processes: Such as cytokine and chemokine dysregulation, abnormal T cell signaling, and B cell dysfunction 2
• Vascular damage: Including endothelial cell injury and dysfunction 2, 3, 5
• Fibrosis: Characterized by the excessive deposition of collagen and other extracellular matrix components 2, 3, 5
• Oxidative stress: Associated with the accumulation of ROS and disruption of antioxidant defenses 6