Scleroderma: Pathology review

Definitions & Key takeaways

Scleroderma, also known as systemic sclerosis, is a chronic systemic autoimmune disease characterized by progressive fibrosis of skin and internal organs such as the gastrointestinal tract, lungs, heart, and kidneys. The exact cause is unknown but is associated with autoimmune processes that lead to excessive collagen production in individuals with a genetic predisposition. Scleroderma can be either limited or diffuse, with symptoms varying according to the organs involved. Treatment options involve immunosuppressants and medications to relieve symptoms and slow the progression of the disease.

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Case Study0:00–1:12

While doing your rounds, you see Rosa, a 35-year-old woman who has complained of puffy hands and feet for the past 4 months.
On examination, the skin on the limbs and trunk is stiff and shiny, with decreased markings. Other important findings are sclerodactyly, Raynaud's phenomenon, and digital ulceration.
Pulmonary function tests were performed as well, and they showed a pattern suggestive of restrictive lung disease. Then you see Haruki, a 65-year old who says that he noticed skin changes recently, stating that the wrinkles on his face have disappeared.
He also said that his acid reflux got worse in the past 6 months. On examination, his hands show Raynaud's phenomenon and sclerodactyly.
The skin on his face and the arms below the elbow were tight, shiny, smooth, with no wrinkles. Pulmonary function tests are normal.
Blood tests were performed in both cases, showing increased serum levels of anti-Scl 70 and and-RNA polymerase III antibodies in Rosa, and increased anti-centromere antibodies in Haruki.
Now, both seem to have scleroderma. Scleroderma refers to systemic sclerosis, a rare autoimmune disorder in which normal tissue is replaced by thick, dense collagen.

Physiology1:12–3:57

It affects the skin, blood vessels and internal organs. Now, there are two main types of scleroderma, diffuse cutaneous systemic scleroderma; and limited cutaneous systemic scleroderma, which was formerly called CREST syndrome.
The condition’s pathology is not completely understood, but it’s believed that some individuals have a genetic predisposition to scleroderma which is triggered by external factors.
These triggers include: viral infection by cyto-megalo-virus and parvovirus B19; exposure to silica dust, organic solvents, vinyl chloride; and medication like cocaine, bleomycin, and pentazocine.
Okay, for pathology, scleroderma usually starts with an injury to the endothelial cells that line the interior surface of small blood vessels, causing non-inflammatory vasculitis.
These cells then start expressing adhesion molecules that T cells stick to. T cells then migrate outside of the blood vessels and into the surrounding tissue, where they start releasing cytokines, which attract other immune cells that further damage small blood vessels; and activate fibroblasts that produce and deposit collagen.
In time, collagen builds up and forms a highly stable matrix that is responsible for the stiffness of the tissue. This buildup of excess 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, B cells.
What’s causing them to activate is currently unknown, but we do know that activated B cells produce antinuclear antibodies, or ANA, that bind to the content of the nucleus that leaks out of damaged or dead cells.
Some ANA’s are both highly specific to Scleroderma so they are very high yield! These include anti-Scl 70 , which targets DNA topoisomerase I, anti-RNA polymerase III, and anti-centromere antibodies.
For symptoms of scleroderma, both types affect women three times more often than men, especially women over 50 years of age.
The two types can affect the same organs and cause similar symptoms, but the disease progression can differ. Let’s start with diffuse cutaneous systemic scleroderma, where symptoms are usually rapidly progressive and its associated with visceral involvement early in its evolution.

Diffuse Scleroderma3:57–7:28

Ok, so skin lesions start in the fingers and move up across the arm to the shoulders, neck, and face. At first, the affected skin is swollen and puffy.
Later when fibrosis develops, the skin becomes tight, stiff, shiny, smooth, but with no wrinkles, especially around the fingers and dorsum of the hands.
When it happens on the fingers it is called sclerodactyly, which can cause fingers to curl inward, so the hand becomes shaped like a claw.
On the face, the mouth can become narrow, which is called microstomia, and the nose becomes beaked. Sometimes, calcium can deposit in the skin and subcutaneous tissue through an unknown mechanism, and this is called calcinosis cutis.
Small vessel involvement can lead to Raynaud's phenomenon, where the distal parts of the fingers turn white when exposed to cold, due to vasospasm.
Then the color changes to blue and finally red as the blood vessels expand to get enough oxygen-rich blood to the fingers.
In time, because vasospasm can cause ischemia, individuals might develop digital ulcerations. Scleroderma can cause telangiectasias as well, also known as spider veins, which are small dilated blood vessels that can occur near the surface of the skin or mucous membranes.
Another common site of damage is the joints, where symptoms are typically non specific and can include joint pain, stiffness, and restricted joint mobility.
In the gastrointestinal tract, there can be esophageal dysmotility and incompetence of the lower esophageal sphincter due to atrophy and fibrous replacement of the esophageal muscularis.
This can result in gastroesophageal reflux disease, or GERD, which is when the content of the stomach flows up to the esophagus and damages it.
Due to stomach acid irritating the normal esophageal mucosa, Barrett's esophagus can develop, which is when the normal stratified squamous epithelium of the esophagus transforms into simple columnar epithelium with interspersed goblet cells, like the ones normally found in the small and large intestine.
This is high yield because it can lead to esophageal adenocarcinoma. Chronic damage and fibrosis to the esophagus can cause stricture formation.
The intestines can also be involved, which leads to malabsorption, and malabsorption to anemia due to iron deficiency. The next high yield fact to remember is that lungs are commonly involved.
Small blood vessels can be damaged and cause pulmonary arterial hypertension and pulmonary fibrosis, which can be seen as restricted inhalation and coughing.
Lung damage can lead to hypertrophy of the heart's right ventricle and heart failure. Finally, kidney involvement is very common where the small arteries in the kidneys undergo concentric hypertrophy, resulting in ischemia over time.
But sometimes severe and rapid damage can occur during a scleroderma renal crisis. This is where the damaged blood vessels trigger thrombosis, causing blockage in capillaries.
The end result is acute kidney injury and severe hypertension. Okay, in contrast, in limited cutaneous systemic scleroderma, or CREST syndrome, the progression is usually slower, so there’s no sign of internal organ involvement in its initial stages, and even in the later stages, the damage to organs tend to be less severe.

Limited Scleroderma7:28–8:27

However, remember that pulmonary hypertension is quite common. But thankfully, renal and intestinal involvement are pretty rare.
Remember that there are 5 key symptoms of CREST: calcinosis cutis, Raynaud's phenomenon, which is usually the first symptom; esophageal dysfunction, which is actually common in both types; sclerodactyly; and telangiectasia.
For the skin manifestations, a high yield concept is that in the limited type, it tends to be… well, “limited” to the face and the distal limbs, meaning below the elbow and knees, whereas in the diffuse type, it can affect the entire body.

Diagnosis8:27–9:43

Diagnosis of scleroderma is based on its symptoms, but antibody tests can help confirm the diagnosis. A high yield concept to remember is that diffuse scleroderma are associated with anti-Scl-70 and anti-RNA polymerase III antibodies.
The limited type is more commonly associated with anticentromere antibodies. Next, evaluating organ damage is also important.
Pulmonary function tests can be used to look for restrictive lung disease. It’s also important to look for signs of pulmonary artery hypertension.
This can be done by electrocardiography, which shows right ventricular hypertrophy and right axis deviation, and by chest x-ray, which can show right ventricular enlargement, a prominent central pulmonary artery, or peripheral hypervascularity.
If any of these tests are positive, right heart catheterization is required to confirm the diagnosis of pulmonary artery hypertension and to evaluate the severity.
And, of course, there are other tests like upper endoscopy for gastrointestinal symptoms, complete blood count to detect anemia due to malabsorption, which can be used to look for other organ involvement in scleroderma.

Treatment9:43–10:49

For treatment for this condition, immunosuppressants like glucocorticoids are used to slow down the disease. Other medication can be used to relieve symptoms: proton pump inhibitors for gastroesophageal reflux; calcium channel blockers for Raynaud's phenomenon; non-steroid anti-inflammatory medication for joint pain; ACE inhibitors for hypertension; and medication like oral anticoagulants like warfarin or vasodilators for pulmonary arterial hypertension.
Now, extra attention needs to be paid in those with scleroderma renal crisis since this is a really important complication.
A crisis is usually managed with strict blood pressure monitoring. A sudden increase in blood pressure indicates a scleroderma renal crisis and ACE inhibitors like captopril may be needed to control blood pressure.
Calcium-channel blockers like amlodipine, diuretics like furo-semide, and alpha-blockers such as doxa-zosin should be used as additional therapy if blood pressure control remains suboptimal.
All right, as a quick recap, scleroderma is a rare autoimmune disorder in which normal tissue is replaced with thick, dense connective tissue.

Review10:49–12:17

It affects the skin, blood vessels, and internal organs. There are two main types: diffuse cutaneous systemic scleroderma , which affects a larger area of the skin, progresses quicker, involves internal organs earlier with more severe symptoms; and limited cutaneous systemic scleroderma, formerly called CREST syndrome, which usually has only five of the main symptoms, affects a smaller area of the skin, progresses slower and involves internal organs much later.
The cause is not known, but a genetic predisposition is thought to be involved. It is more often found in women over 50 years old, and some of its symptoms include tight, stiff, shiny, and smooth skin with no wrinkles, sclerodactyly, microstomia, calcinosis cutis, Raynaud's phenomenon, telangiectasias, esophageal dysmotility, gastroesophageal reflux, pulmonary fibrosis, and scleroderma renal crisis.
It is diagnosed based on a suggestive clinical picture, antinuclear antibodies, and additional findings related to scleroderma complications.
The treatment includes immunosuppressants and other medications to relieve symptoms. Ok, now back to our cases.

Summary12:17–13:24

Rosa came in with the complaint that her hands and feet were puffy. An examination revealed the skin on her limbs and trunk to be stiff and shiny.
Other important findings are sclerodactyly, digital ulceration, and Raynaud's phenomenon. These symptoms all suggest scleroderma.
Since entire limbs are affected, this is more suggestive of the diffuse type because the limited type tends to affect only the distal limbs.
Pulmonary function tests showed a pattern suggestive of restrictive lung disease, which also makes us think that this is diffuse cutaneous systemic scleroderma.
This was confirmed when antibodies anti-Scl 70 and and-RNA polymerase III were found. Haruki also presents with the symptoms of scleroderma: Raynaud's phenomenon, esophageal dysfunction; sclerodactyly; and telangiectasia.
A clue that he might have limited cutaneous systemic scleroderma is that his skin lesions were limited to the face and distal limbs.
And because pulmonary function tests are normal and blood tests showed anti-centromere antibodies, we can confirm the diagnosis.
Scleroderma: Pathology Review: Video and Causes | Osmosis