Rare but mighty: Systemic sclerosis

Systemic Sclerosis

Systemic sclerosis (SSc), also known as scleroderma, is a rheumatological disorder involving fibrosis of the connective tissue impacting 30-120 individuals per million. Although SSc is a rare disease, patients experience high morbidity and mortality due to fibrosis and vasculopathy that drive disease pathogenesis Fibrosis is excessive deposition of collagen at sites of inflammation. Normally, deposition of extracellular proteins, such as collagen, are critical in tissue repair and can be reversible. In contrast, fibrosis can become irreversible and therefore collagen deposits may not be cleared out. In other words, fibrosis is scarring of the tissue. Such excessive accumulation of extracellular matrix proteins can in turn inhibit normal organ function.

SSc can be categorized into 1) limited cutaneous systemic sclerosis, impacting distal extremities, or 2) diffuse cutaneous systemic sclerosis, impacting both distal and proximal extremities. In some patients, the skin is not impacted, but rather they may have significant complications involving internal organs, in which case SSc is categorized as SSc sine scleroderma. Some patients, for example, may experience gastrointestinal involvement, in which case damage to the gastrointestinal tract, whether due to fibrosis or immune-mediated damage, results in malnutrition and causing mortality.

Potential triggers of SSc are infections, either viral or bacterial, chemical/toxic exposure, and genetic predispositions.

Genetic predispositions: Estrogen plays a role in the promoting autoimmunity; similar to other autoimmune disorders, females are 3-4 times more susceptible to SSc than males. There are also familial risks, with a 1.6% risk of SSc in first-degree relatives of SSc patients. There are also epigenetic factors, which are changes in gene expression capacities, than may also contribute to SSc.

Infections: Human cytomegalovirus, human herpes virus 6, Epstein-Barr virus, parvovirus B19 are examples of viral infections implicated in SSc. Cellular damage induced by these infections can promote signals mediating fibrosis. Detection of molecular patterns from these infections can also induce immune signaling that induce production of pro-inflammatory cues that contribute to tissue injury promoting fibroblast function.

Clinical presentation:

·      Raynaud’s phenomenon

·      Digital ulcers

·      Autoreactive antibodies

·      Fibrosis of the skin

·      Vasculopathy

·      Calcinosis

·      Interstitial lung disease

·      Pulmonary arterial hypertension

Treatment of SSc:

Current treatments available to patients are aimed at controlling symptoms and preventing complications, but these do not attenuate collagen depositions. A common treatment is blood pressure medication. Most people with scleroderma experience Raynaud’s phenomenon, in which small blood vessels in the finger and toes constrict. Blood pressure medication aids in dilating blood vessels and improving blood flow, with calcium channel blockers being highly effective in reducing Raynaud’s phenomenon. Additionally, therapies suppressing the immune system are utilized to limit inflammation and tissue damage, and therefore reducing SSc progression. Current interest lies around identifying anti-fibrotic agents targeting collagen production or breakdown.

What should patients know?

While SSc is a rare disease with high morbidity and mortality, it can be manageable. It is important to know that the severity of the disease can vary greatly between patients. Not all patients experience skin disease and not all patients experience internal organ disease. Understanding that each case is different mean that treatment needs to be tailored to patient needs.

 References:

·      Wynn, T. A., & Ramalingam, T. R. (2012). Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nature medicine, 18(7), 1028–1040. https://doi.org/10.1038/nm.2807

·      Lescoat, A., Lecureur, V., Gudjonsson, J. E., & Khanna, D. (2025). Systemic sclerosis: pathogenic mechanisms and their implications for treatment. Seminars in immunopathology, 47(1), 39. https://doi.org/10.1007/s00281-025-01065-6

·      Jimenez, S. A., Mendoza, F. A., & Piera-Velazquez, S. (2025). A review of recent studies on the pathogenesis of Systemic Sclerosis: focus on fibrosis pathways. Frontiers in immunology, 16, 1551911. https://doi.org/10.3389/fimmu.2025.1551911

·      Son, H. H., & Moon, S. J. (2025). Pathogenesis of systemic sclerosis: an integrative review of recent advances. Journal of rheumatic diseases, 32(2), 89–104. https://doi.org/10.4078/jrd.2024.0129

·      https://www.mayoclinic.org/diseases-conditions/scleroderma/diagnosis-treatment/drc-20351957

·      https://www.hopkinsscleroderma.org/patients/scleroderma-treatment-options/

Assessed and Endorsed by the MedReport Medical Review Board