What is Mixed Connective Tissue Disease (MCTD)?

Mixed connective tissue disease is a rare autoimmune disease involving symptoms of various overlapping syndromes such as lupus, arthritis, and myositis. This disease often occurs due to high levels of the anti-U1 ribonucleoprotein (RNP). Anti-U1 RNPs are antibodies produced by the immune system and mistakenly target proteins involved in DNA processing.¹

Mixed Connective Tissue Disease and High Blood Pressure

Mixed connective tissue disease can cause arterial hypertension (high blood pressure) in the lungs, which is known as pulmonary arterial hypertension (PAH). This occurs due to the overall dysregulation of the immune system and chronic inflammation.¹

In MCTD, the anti-U1 RNP antibodies and other immune cells often target the arteries in the lungs. This leads to inflammation of the walls of the arteries and signals to the immune system that there is damage in the body. The immune system then stimulates further cells to cause inflammation, which continues to damage the lining of the blood vessels in the lungs.^1,2

When damage occurs to the lining of the blood vessels, they lose their ability to regulate blood pressure. This is because the endothelium (cells lining the blood vessels) releases chemicals, which relax the blood vessels and dilate them (e.g. nitric oxide). However, this regulation of the blood vessels does not occur in MCTD, as stiff and narrow blood vessels make it harder for blood to flow from the right side of the heart. This means the heart must work harder to pump blood through the lungs, leading to high arterial blood pressure in the lungs - pulmonary arterial hypertension.^1,2

How is MCTD diagnosed?

Diagnostic methods used to confirm MCTD include testing for the presence of anti-U1 RNP antibodies, as high levels are a key marker for MCTD. Health professionals may also assess patients for any clinical features presented, such as puffy and swollen fingers (hand oedema), arthritis, and myositis. Medical professionals often consider a successful diagnosis to be combined with anti-U1 RNP antibody positivity, accompanied by at least two of the clinical features.³

Key diagnostic tools in MCTD evaluation include right heart catheterisation, echocardiography, and pulmonary function tests. These tools help investigate the activity and involvement of the heart and lungs, and how they are affected by MCTD. They help detect complications which arise from MCTD, such as pulmonary arterial hypertension or interstitial lung disease.³

Right heart catheterisation

Right heart catheterisation is a low-level invasive procedure, which specifically measures the blood pressure in the right side of the heart and in the pulmonary arteries. This is the primary diagnostic method to confirm pulmonary arterial hypertension in MCTD. It is used when echocardiograms detect elevated pulmonary pressure, symptoms such as shortness of breath and fatigue are present and when screening tools are inconclusive.

Right heart catheterisation is important as it confirms true PAH and distinguishes it from other complications and causes. It also allows for more accurate classification of pulmonary hypertension. It is crucial to perform right heart catheterisation before starting PAH treatment.⁴

Echocardiography

Echocardiography is a non-invasive procedure which measures heart structure and function. It uses an ultrasound to test the systolic blood pressure of the pulmonary artery in the heart, as this gives key information about the blood pressure incoming at the lungs and therefore shows signs of PAH.⁴

Pulmonary function tests

Pulmonary function tests measure the ability of the lungs to inhale and exhale air and how effectively they can donate oxygen to the blood. Key values that are often measured during these tests are the forced vital capacity (FVC) (which typically stays the same in PAH) and the diffusing capacity of carbon monoxide, which is typically reduced in pulmonary arterial hypertension before other symptoms are expressed. These lung function tests are crucial for detecting early signs of MCTD and PAH.⁵

Lung-specific treatments for PAH in MCTD

Endothelin receptor antagonists (ERAs)

Endothelin receptor antagonists (ERAs) are a class of drugs used to treat pulmonary arterial hypertension in patients with MCTD. ERAs block endothelin receptors. Endothelin receptors cause vasconstriction (narrowing of the blood vessels) and cell growth. ERAs block endothelin receptors in order to dilate the blood vessels in order to lower the pulmonary arterial blood pressure. Examples include: bosentan (which requires monitoring of the liver with use) and ambrisentan, a well-tolerated ERA.⁶

Overall, ERAs are an effective treatment which aims to lower pulmonary artery pressure, delay disease progression, improve exercise capacity, and even reduce hospitalisation. It is particularly efficient in relieving the inflammation and vascular dysfunction seen in MCTD. However, some key side effects to watch out for include liver toxicity, fluid retention, and anaemia which can induce inflammation.⁶

Phosphodiesterase-5 inhibitors (PDE-5 inhibitors)

Phosphodiesterase-5 inhibitors block the enzyme phosphodiesterase type 5. Phosphodiesterase 5 breaks down cyclic guanosine monophosphate (cGMP). cGMP is a chemical that helps to relax the muscle lining in our blood vessels to dilate them so that the blood pressure decreases. By inhibiting PDE-5, less cGMP is broken down, meaning that the pulmonary blood vessels will stay open and dilated for longer, lowering blood pressure and improving oxygen delivery to the blood.⁷

PDE-5 inhibitors are used to reduce the vascular stiffening in the lungs caused by MCTD, as well as to reduce symptoms such as shortness of breath and fatigue. Common PDE-5 inhibitors include sildenafil and tadalafil. However, side effects may include headache, flushing, nasal congestion due to widened blood vessels and hypotension if patients are using multiple vasodilators. Therefore, those taking PDE-5 inhibitors must be monitored (with echocardiography and right heart catheterisation) in order to look out for low blood pressure.⁷

Lung-supportive therapies for PAH in MCTD

There is a range of supportive lung therapies that can be used to help treat pulmonary arterial hypertension in MCTD and alleviate symptoms. Oxygen therapy is often used if the patient is suffering from low oxygen levels in the blood (hypoxemia) when at rest or sleeping. Oxygen therapy helps reduce the narrowing of the blood vessels in the lungs, so that oxygen can flow through and be delivered to organs to increase energy levels. However, this is not used in all patients.⁸

Blood thinners (anticoagulants) are used in selected patients if they have a high risk of thrombosis or have had thromboembolisms in the veins. Anticoagulants help to reduce the risk of blood clots that can interfere with blood circulation in the lungs.

Exercise is always encouraged in MCTD-related PAH to improve cardiovascular fitness and reduce symptoms such as fatigue and shortness of breath. These are typically used when the patient is stable on therapy and often involve activities such as walking, cycling, breathing exercises, and low-level resistance exercises.⁸

Summary

Mixed connective tissue disease is an autoimmune condition combining features of various diseases, such as lupus, scleroderma, and myositis.

A serious complication of MCTD is pulmonary arterial hypertension (PAH), which involves high blood pressure in the arteries of the lungs.

PAH occurs when the immune system causes inflammation and damage in the blood vessel lining within the lungs, narrowing and stiffening them. This makes it harder to transport blood through the lungs, damaging the right side of the heart (which is responsible for pulmonary blood flow).

Diagnostic tests include echocardiography, pulmonary function tests, and right heart catheterisation.

Treatments include lung-specific medications such as endothelin receptor antagonists and phosphodiesterase-5 inhibitors.

Supportive therapies are also available, including oxygen, diuretics, and exercise therapy. Early diagnosis and treatment are important in preventing worsening conditions and improving quality of life.

FAQs

What is MCTD-related PAH?

MCTD-related PAH is a type of high blood pressure that affects the arteries of the lungs. It is caused by the autoimmune disorder Mixed Connective Tissue Disease.

Why does MCTD cause PAH?

The immune system attacks the lung blood vessels, causing inflammation, narrowing and scarring, which increases the blood pressure in those vessels. This makes it harder for blood to flow efficiently and prevents oxygen from being transported to vital organs.

What are the main symptoms?

These typically occur during light physical activity and even at rest. Symptoms include: shortness of breath, tiredness, chest pain, leg swelling, dizziness, and fainting.

Is PAH in MCTD treatable?

Yes, there is no cure; however, there is a range of medications and supportive therapies that can improve symptoms and slow down disease progression. These include medicines such as endothelin receptor antagonists and phosphodiesterase-5 inhibitors.

Do lifestyle changes make a difference?

Yes, light exercise can improve cardiovascular health and relieve the symptoms that come with MCTD-related PAH. Lifestyle changes that are often recommended alongside treatment are: light exercise, oxygen therapy, cycling, and avoiding infections.