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Scleroderma

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Scleroderma

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A 37-year-old woman comes to the office because of fragile nails and fingertip ulcerations. She says that prior to the lesions her fingertips and toes would undergo strange color changes with associated numbness. However, she did not think that this was significant and she attributed it to the recent cold weather. She has a history of gastroesophageal reflux disease (GERD), hypertension, and asthma. She drinks alcohol occasionally but does not smoke. Her temperature is 37.5°C (99.5°F), pulse is 70/min, respirations are 14/min, and blood pressure is 130/79 mmHg. Physical examination reveals digital ulcerations and patched of lighter-colored skin. Cardiac and respiratory examinations are normal. Which of the following is a symptom that can be associated with her disease?



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Content Reviewers:

Rishi Desai, MD, MPH

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Scleroderma refers to systemic sclerosis, a rare autoimmune disorder in which normal tissue is replaced with thick, dense connective tissue. It affects the skin, blood vessels and internal organs. Now, there are two main types of scleroderma: limited cutaneous systemic scleroderma, better known as CREST syndrome; and diffuse cutaneous systemic scleroderma. The word scleroderma comes from the Greek words ‘sclero,’ meaning hard, and ‘derma,’ meaning skin, which points to the hard skin as its most visible feature.

So, normally, when there’s an infection in the body, macrophages will eat some of the invading organisms and break them down. In addition to destroying the pathogen, they also present a fragment of the pathogen, called an antigen, to naive T cells. When the naive T-cells bind to this presented antigen, they mature into T-helper cells, also called CD4+ T-cells, and they go on to help and recruit more immune cells. The T-helper cells release cytokines, which increase the activity of macrophages and attract nearby neutrophils. Macrophages also release cytokines, like TGF-β, that tell fibroblasts to repair damaged tissue after the infection by laying down collagen.

Scleroderma affects women three times more often than men. The exact pathology of scleroderma is not completely understood, but generally, it’s thought that some individuals have a genetic predisposition to scleroderma which is triggered by external triggers. Some known triggers include viral infection by cytomegalovirus and parvovirus B19; exposure to silica dust, organic solvents, and vinyl chloride; and drugs and medications like cocaine, bleomycin, and pentazocine.

It’s thought that there’s initially an injury to endothelial cells lining the small arteries. These cells then start expressing adhesion molecules that attach to T cells floating by. T cells attach and then migrate outside of the blood vessel into the surrounding tissue and start releasing cytokines like TGF-β which causes inflammation, and further damages small blood vessels. Cytokines also activate fibroblasts that produce and deposit collagen which builds up and forms a highly stable matrix that is responsible for the stiffness of the tissue. This buildup of excessive connective tissue is called fibrosis. Finally, blood vessel damage and fibrosis reduce blood flow to the tissue and cause ischemic tissue damage. 

There is another type of immune cell that plays a role in scleroderma, and that’s B cells. It is not known how they are activated or if they cause any damage, but activated B cells do produce antinuclear antibodies or ANA which bind to the content of the cell nucleus. Some ANA’s are highly specific to scleroderma and can help make the diagnosis. These include anti-Scl 70 which targets DNA topoisomerase I, anti-RNA polymerase III antibodies called ARA, and anti-centromere antibodies called ACA.