Introduction

Mixed connective tissue disease (MCTD) is a rare systemic autoimmune disease. It is a disease that emerges over several years, with symptoms arising in a gradual manner that can complicate correct diagnosis. It shares characteristics with at least two overlapping connective tissue diseases, such as rheumatoid arthritis, polymyositis, dermatomyositis, Lupus, and systemic sclerosis. Raynaud's phenomenon and the presence of anti-U1-ribonucleoprotein (RNP) antibodies are additional characteristics that define the illness.¹

Anti-U1 RNP antibody positivity: key biomarker

Inside our body, there exist antibodies referred to as U-numbered. These antibodies are essential for diagnosing MCTD. The U1 RNP antigen serves as the main antigen for diagnosing MCTD. Nonetheless, difficulties emerge due to their common occurrence in SLE cases, which may impact diagnostic accuracy and result in possible misdiagnosis.²

Importance of early recognition of heart involvement

People with MCTD often exhibit cardiac involvement, but it is typically not detectable in clinical settings. Since cardiac involvement is a leading cause of mortality, non-invasive cardiac assessments can be beneficial for screening for subclinical diseases and diagnosing and treating conditions early.³

Cardiovascular involvement

Immune-mediated inflammation of cardiac tissues and blood vessels

Cardiovascular diseases (CVDs) are the leading cause of death in the world and cause a significant economic burden on healthcare systems at a global scale. There is mounting evidence that inflammation and immune dysregulation are the root causes of many CVDs, including atherosclerosis, heart attacks, arrhythmias, and heart failure. The immune-mediated cellular responses are modulated by controlling the timing and rate of immune cell recruitment to the injured site.⁴

Endothelial impairment

Chronic inflammatory diseases are associated with increased CVD and atherosclerosis. Early-stage endothelial dysfunction can be screened using the flow-mediated dilatation (FMD) method.

Inflammation is a key factor throughout all phases of vascular lesion development, which are sustained and intensified by risk factors. Based on traditional risk factors, endothelial dysfunction, caused by chronic inflammation, can be seen as a sign of damage to arterial walls.⁵

Common cardiac manifestations in MCTD

Pericardial disease

Connective tissue diseases frequently lead to pericardial disorders, presenting as either acute or chronic pericarditis, with or without effusion. The pericardium is a double-layered wall that protects and facilitates the normal function of the heart. Nonetheless, pericardial involvement in connective tissue disorders is often not identified until post-mortem examination. Frequent connective tissue disorders that impact the pericardium consist of:⁶

• Rheumatoid arthritis
• Myositis (polymyositis and dermatomyositis)
• Mixed connective tissue disease (MCTD)
• Lupus
• Scleroderma (systemic sclerosis)

Pulmonary arterial hypertension (PAH)

Increased pulmonary arterial pressure and pulmonary vascular resistance are defining features of pulmonary arterial hypertension (PAH), potentially leading to right heart failure and mortality. Lupus, MCTD, and scleroderma account for about 90% of CTD-PAH cases, highlighting their importance in these disorders, and should be managed accordingly.⁸

Vascular and atherosclerotic risk factors

Raynaud’s phenomenon and digital ischaemia

The main causes of Raynaud's disease, also known as Raynaud's phenomenon, are emotional stress or sensitivity to cold temperatures, resulting in vasospasm. In healthy people, approximately 20% of females assigned at birth and 13% of males assigned at birth experience it. The colour changes that accompany Raynaud's disease progress from white to blue to red. These colour changes symbolise the initial ischaemia caused by vasospasm (white), the slow circulation that results in an increased amount of deoxygenated blood (blue), and the final state following vessel dilatation (red).

Digital ischaemia is a painful, deformity-causing condition which often results in tissue loss. Vasculopathies, vasculitis, embolic disease, trauma, or extrinsic vascular compression can all result in digital ischaemia.⁹

Thrombosis risk

Patients with Mixed Connective Tissue Disease (MCTD) are more likely to have venous and arterial thromboembolic events due to antiphospholipid antibodies and systemic inflammation. These can lead to complications like recurrent pregnancy loss, stroke, pulmonary embolism, or deep vein thrombosis (DVT). Early detection and long-term anticoagulation medications are important for prevention.

Diagnosis and management strategies

Diagnostic tools

Imaging, laboratory testing, and clinical evaluation help diagnose cardiac involvement in MCTD. An electrocardiogram (ECG) identifies pericarditis, conduction blocks, and arrhythmias. Echocardiography assesses heart structure and function. Cardiac MRI detects inflammation or fibrosis, while blood markers like troponin and BNP/NT-proBNP indicate heart failure or injury.⁹

Treatment approaches

Right heart catheterisation is used to confirm the diagnosis and gauge the severity of pulmonary hypertension, a dangerous complication that is initially detected by Doppler echocardiography. Classical beta-blockers consist of substances that selectively block β1-adrenergic receptors (like atenolol and metoprolol) or substances that block both β1- and β2-adrenergic receptors (like propranolol).⁹

Management strategies

The goal of management is to control cardiac complications and the autoimmune process. Immunosuppressants such as methotrexate, azathioprine, or mycophenolate aid in long-term control, while corticosteroids are used to treat active inflammation. In severe cases, biologics like rituximab may be used.

Summary

Mixed connective tissue disease (MCTD) is a rare autoimmune condition that develops gradually over time, making diagnosis challenging. It exhibits features of various connective tissue diseases, including rheumatoid arthritis, lupus, and systemic sclerosis, among others. Key characteristics of MCTD are Raynaud's phenomenon and the presence of anti-U1-ribonucleoprotein (RNP) antibodies, which are crucial for diagnosis but can lead to misdiagnosis due to their overlap with other conditions. Cardiac involvement is common in MCTD and is a major cause of mortality. Early recognition of heart issues through non-invasive assessments can help diagnose and treat these problems sooner. Cardiovascular diseases, often linked to immune inflammation, are the leading causes of death globally. Conditions like heart attacks and heart failure can arise from immune dysregulation, with chronic inflammation also linked to atherosclerosis and endothelial dysfunction. MCTD can lead to specific cardiac issues such as pericarditis, which may be missed until after death, and pulmonary arterial hypertension (PAH), which can cause serious complications like right heart failure.

Raynaud's phenomenon, characterised by colour changes in fingers due to cold or stress, can impact blood flow and lead to painful conditions known as digital ischemia. Patients with MCTD also face a higher risk of blood clots due to inflammation and antiphospholipid antibodies. Diagnosing cardiac issues involves imaging, lab tests, and clinical evaluations, including ECG, echocardiography, and cardiac MRI. Treatment focuses on managing cardiac problems and controlling the autoimmune process through immunosuppressants, corticosteroids for inflammation, and possibly biologics in severe cases. Early detection and proactive management are vital to prevent serious complications.