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Etiology

Systemic sclerosis (SSc) is a rare, complex, chronic autoimmune-mediated disorder that affects the microvasculature and connective tissue.^1,2 It is characterized by the widespread development of scar tissue (fibrosis) and abnormal blood vessels in the skin, joints, and multiple organ systems. Involved organs include the heart, lungs, kidneys, esophagus, and lower digestive tract.²

Unconfirmed Etiology

The exact cause of SSc has not been identified; however, it is understood that abnormal immune mechanisms and genetic factors contribute to the condition.^1,2

The clinical signs and symptoms of SSc develop as the consequence of 3 distinct processes, including¹:

Increased immune system production of autoantibodies resulting in cell-mediated autoimmunity;
Microvascular endothelial cell damage and fibroproliferative vasculopathy in small blood vessels; and
Production of excessive amounts of collagen in various organ systems throughout the body by overactivated fibroblasts.

Exactly how these processes involve and sustain one another is still under investigation.¹Researchers have proposed many explanations for the vascular and endothelial cell damage associated with SSc, including¹:

Autoantibody attacks against vascular endothelial cells;
Increase in nitric oxide-associated free radicals leading to widespread inflammation and tissue damage;
Ischemic-reperfusion injury;
Cytotoxic T cells;
Antibody-dependent cellular cytotoxicity; and
Infection (especially with human cytomegalovirus).

Scientists believe that vascular endothelial damage triggers a cascade effect in which many cells, including fibroblasts, macrophages, mast cells, and T lymphocytes, are stimulated. The activated cells release cytokines, enzymes, and other soluble substances that alter the extracellular matrix to increase collagen deposition in the tissues. The excess collagen then interferes with the normal structure and proper function of multiple organ systems.³

Read more about SSc pathophysiology

Researchers have discovered links between both the innate and adaptive immune systems and the development of fibrosis. The stimulation of immune cells, such as lymphocytes and monocytes, by an antigen triggers fibroblast growth, chemotaxis, and the excessive synthesis of collagenase and collagen. Levels of the following are increased in patients with SSc¹:

Various interleukins (IL-4, IL-6, IL-1, IL-13, IL-17, IL-5)
Growth factors, such as transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and connective tissue growth factor (CTGF)
Monocyte chemoattractant protein 1 (MCP-1)

These cytokines and chemokines are responsible for the signaling between immune cells and fibroblasts that may contribute to the development of fibrosis in SSc.¹

Read more about SSc histology

Potential Environmental Exposures

As with other autoimmune conditions, the exact trigger that causes the immune system to start producing autoantibodies is unknown. Studies suggest that abnormal responses in both the innate and adaptive immune systems contribute to the development of autoimmunity. The innate immune system mounts a general immune response to any antigen, while the adaptive immune system responds to specific antigens.¹

Most patients with SSc exhibit an interferon (IFN) signature indicative of innate immune system activation.¹ Immunohistochemical evaluation of perivascular and skin tissue from an individual with SSc also demonstrates an accumulation of activated CD4+ T cells, doubly positive (CD4+/CD8+) T cells, and monocytes expressing high levels of IL-4. These changes reflect activation of the adaptive immune system in SSc.¹

Researchers have identified the following environmental exposures that may activate the immune system^2,4:

Pesticides
Substances used in cosmetic procedures, such as silicone and paraffin
Silica
Epoxy resin
Contaminated rapeseed oil
Organic solvents, such as benzene, toluene, and xylene
Vibration injury
Drugs (eg, carbidopa, cocaine, penicillamine, pentazocine, paclitaxel, bleomycin, vitamin K)
Appetite suppressants (eg, phenylethylamine derivatives)
Aromatic/aliphatic hydrocarbons (eg, hexane, trichloroethylene, vinyl chloride)
Amino acid compound L-5-hydroxytryptophan

In addition to environmental toxins and exposures, infection with agents such as Epstein-Barr virus, cytomegalovirus, and Toxoplasma gondii has been implicated as a trigger of SSc.¹

Read more about SSc risk factors

Genetic Predisposition to SSc

Many researchers suggest that SSc develops in individuals with a genetic predisposition or susceptibility, especially those with specific HLA subtypes. In particular, certain HLA class I and HLA class II complexes have been associated with SSc.¹

Genes other than HLA whose variants correlate with an increased susceptibility to SSc include CD247, interferon regulatory factor 5 (IRF5), and signal transducer and activator of transcription 4 (STAT4).¹

Read more about SSc genetics

References

Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE. Pathogenesis of systemic sclerosis. Front Immunol. 2015;6:article 272. doi:10.3389/fimmu.2015.00272
Nevares AM. Systemic sclerosis (scleroderma). Merck Manual Professional Version. Reviewed October 2022. Accessed April 14, 2023.
Schwartz RA. Systemic sclerosis: pathophysiology. Medscape. Updated April 16, 2021. Accessed April 14, 2023.
Schwartz RA. Systemic sclerosis: etiology. Medscape. Updated April 16, 2021. Accessed April 14, 2023.

Reviewed by Harshi Dhingra, MD, on 4/18/2023.

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.

Systemic Sclerosis (SSc)