MCTD is considered rare, with an estimated prevalence of 3 to 4 cases per 100,000 people. It most commonly affects women, occurring at a rate 3 times higher in people born genetically female than male. Symptoms of MCTD generally begin to appear between the ages of 20 and 50, and it is rarely diagnosed in children.

The exact cause of MCTD is unknown, but it is believed to result from a combination of genetic predisposition and environmental triggers. Like other autoimmune diseases, MCTD involves a dysregulated immune response in which the body’s immune system mistakenly attacks its own tissues. The presence of anti-U1 RNP antibodies suggests a targeted autoimmune reaction involving nuclear components of cells.

Higher-than-normal levels of anti-U1 ribonucleoprotein (RNP) antibodies are an indication of MCTD. It is uncertain whether these antibodies are a symptom of the disease, causing disease progression, or attempting to prevent further inflammatory damage. It is most likely that these antibodies lead to MCTD disease progression and other complications such as pulmonary arterial hypertension (PAH) by participating in vasculopathy. This means that it prevents the flow of blood throughout the body by restricting blood vessels. 

Mixed connective tissue disorder has similar symptoms to other connective tissue disorders, and can flare up and worsen at different times. MCTD presents with a mix of symptoms commonly seen in other autoimmune diseases, which may develop gradually or in phases. Common manifestations include:

• Raynaud’s phenomenon: reduced blood flow in fingers, toes, ears, and nose, causing cold-induced color changes (white, blue, red) in fingers or toes, sensitivity, and numbness

• Swollen fingers or "sausage digits" (dactylitis) - can develop into sclerodactyly which is thin fingers with hardened skin and limited movement

• Reddish brown patches of skin on knuckles

• Arthritis and joint pain

• Muscle weakness due to inflammatory myopathy

• Esophageal dysmotility causing difficulty swallowing or acid reflux

• Skin changes resembling scleroderma, such as thickening or tightening

• Fatigue, fever, and malaise

• Pulmonary involvement: Including interstitial lung disease or pulmonary hypertension, which can be life-threatening

• Cardiac and kidney issues: Less common, but possible in more advanced or severe cases

Diagnosis is based on clinical features and results of blood tests for specific antibodies. The overlap of symptoms with other diseases often makes diagnosis challenging, particularly early in the disease course. The presence of anti-U1 RNP antibodies in high blood titers is a key diagnostic marker. Raynaud’s phenomenon characterized by puffy hands and fingers is also a key indicator of MCTD. 

• Blood tests:

  • High titers of anti-U1 RNP antibodies (essential for diagnosis)

  • Other autoantibodies (e.g., anti-Smith, anti-dsDNA) may be present at lower levels

  • Inflammatory markers (ESR = Erythrocyte Sedimentation Rate, CRP = C-reactive protein) may be elevated

  • Positive antinuclear antibody (ANA), often in a speckled pattern

• Muscle enzyme levels (e.g., creatine kinase) may be elevated with muscle involvement

• Pulmonary function tests and echocardiography to monitor lung and heart function

• Imaging: X-rays or MRIs of joints or muscles to assess inflammation

• Capillaroscopy: Examination of nailfold capillaries, often altered in connective tissue diseases

There is no cure for MCTD, but symptoms can often be managed effectively with medications and lifestyle changes:

• Corticosteroids (e.g., prednisone) are commonly used to control inflammation and immune activity

• Immunosuppressive drugs: Such as methotrexate, azathioprine, or mycophenolate mofetil to prevent antibodies from targeting the body’s own tissues

• Antimalarials: Such as hydroxychloroquine for joint and skin symptoms

• Calcium channel blockers for Raynaud’s phenomenon

• Pulmonary vasodilators for pulmonary hypertension

• Physical therapy to preserve muscle and joint function

The prognosis of MCTD varies depending on the severity and extent of organ involvement. Many patients experience a relatively mild course with long periods of stability, especially with appropriate treatment. However, complications such as pulmonary hypertension or interstitial lung disease can significantly worsen outcomes and may be life-threatening. Regular monitoring and a multidisciplinary approach are essential for early detection and management of complications. Some individuals may eventually develop features predominantly associated with one of the component diseases, altering their diagnosis and long-term outlook.

Follow-up regularly with a pulmonologist or lung specialist.

Lifestyle changes are important for living with MCTD, such as reducing stress, quit smoking, and keeping the skin warm has known benefits.

1. https://www.merckmanuals.com/en-ca/home/bone,-joint,-and-muscle-disorders/autoimmune-disorders-of-connective-tissue/mixed-connective-tissue-disease-mctd
2. https://www.arthritis.org/about-arthritis/types/mixed-connective-tissue-disease/
3. https://rarediseases.info.nih.gov/diseases/7051/mixed-connective-tissue-disease

4. NIH National Library of Medicine Article 

5. Cleveland Clinic: Vascular Disease

6. Mayo Clinic: Mixed connective tissue disease

7. Cleveland Clinic: MCTD

8. MedCentral