Mixed connective tissue disease (MCTD) is a relatively rare, autoimmune disease with overlapping features of other connective tissue diseases, as the name suggests.¹ Autoimmune diseases, like MCTD, occur when the immune system, which usually protects the body, mistakenly attacks its own tissues and organs. The primary target for the immune system in MCTD is the connective tissues, which can be thought of as the glue that holds bodies together.

Understanding connective tissues

Connective tissues are a diverse group of structural tissues in the human body that have many essential functions. These functions include providing support, protection, and connectivity for different organs and muscles.² Understanding these connective tissues and their roles is important in appreciating how they contribute to the function of the body and how they are adversely impacted in conditions like MCTD.

Here are some examples of connective tissues and their properties 

• Adipose tissue: Also known as fat tissue, adipose tissue is a type of connective tissue involved in energy storage. It is found underneath the skin and surrounding organs to offer insulation and cushioning. Adipose tissue helps to regulate body temperature and protects vital organs
• Collagen: Collagen is the most common connective tissue in the body. It forms strong yet flexible fibers that provide tissues and organs with strength. Collagen is a major component of tendons, which connect muscle to bones, and it’s found in the skin, providing elasticity and strength
• Cartilage: a flexible yet strong type of connective tissue that reduces friction between the joints. Cartilage provides protection to the bones, as well as acting as a shock absorber for pain-free movement. It can also be found in the nose and ears
• Fibrous tissues: Fibrous connective tissues are found in ligaments, which connect bone to bone. These tissues provide the joints and muscles with strength and stability
• Bone: Bones are dense and rigid, they support the body’s structure, protect vital organs, and act as storage for important minerals such as calcium
• Blood: Blood is a specialised connective tissue that transports oxygen and nutrients throughout the body. It plays a crucial role in responding to injuries and fighting off infections
• Lymph: Lymphatic tissue is another specialised connective tissue that forms a framework in the body. Lymphatic tissue supports healthy fluid levels in the body and provides support to the immune system ²

Read on to learn more about the symptoms, diagnosis and treatment of MCTD. An Introduction to Mixed Connective Tissue Disease

As mentioned above, MCTD is an autoimmune disease, where the immune system targets and destroys the body’s connective tissues. In MCTD, the immune system produces autoantibodies, which can be thought of as antibodies that have gone rogue, turning against the body’s own tissues and organs instead of protecting them from external threats. These autoantibodies attack the connective tissues, leading to tissue damage, inflammation, and a broad range of other symptoms. The specific autoantibodies responsible for tissue damage in MCTD are called anti-U1 RNP (ribonucleoprotein) antibodies.³  

MCTD can be described as an “overlap syndrome” because it combines signs and symptoms of many other autoimmune diseases that affect connective tissues, such as systemic lupus erythematosus (SLE), systemic sclerosis, and polymyositis.^[4] Symptoms amongst individuals with MCTD can widely vary, making it difficult to diagnose. The cause of MCTD is currently unknown, and no clear risk factors have yet been identified. However, it is thought to involve a combination of genetic and environmental factors. MCTD has been documented to be most common in women under the age of 50.⁴ 

Symptoms and complications of MCTD

Individuals with MCTD may experience a variety of symptoms associated with SLE, polymyositis and/or systemic sclerosis. MCTD can be especially hard to diagnose, as the symptoms vary widely between individuals, and can mimic other autoimmune conditions, appearing slowly over several years.⁵ 

Symptoms of MCTD include, but are not limited to:

• Joint pain and inflammation
• Skin discoloration and/or rashes
• Cold/numb fingers and/or toes (Raynaud’s phenomenon)
• Muscle weakness
• Difficulty swallowing solid food
• Heartburn

Complications of MCTD include, but are not limited to:

• Increased blood pressure in the lungs (pulmonary hypertension)
• Heart disease and failure
• Interstitial lung diseases
• Digestive tract damage
• Nerve damage
• Kidney damage ⁴

Diagnosis

Although MCTD can be difficult to diagnose at first, due to the variability in symptoms and the time in which they appear, it can be distinguished from other autoimmune conditions. Healthcare providers rely on a combination of clinical evaluation and laboratory tests to make an accurate diagnosis of MCTD. The diagnostic criteria required to correctly diagnose MCTD include the confirmation of a combination of clinical symptoms and the presence of anti-U1 RNP autoantibodies.⁶ 

• Medical history and physical examination – Diagnosis of MCTD will begin with a detailed medical history and a physical examination. During the medical history, the healthcare provider will ask about the patient's symptoms, how long they have been experiencing the symptoms, and family history of autoimmune diseases. Physical examinations of the patient aim to identify clinical signs of MCTD, such as joint pain and muscle weakness which are characteristic of MCTD.
• Blood tests – Blood tests are essential for diagnosing MCTD as they reveal the presence of anti-U1 RNP antibodies which are a marker for the condition. Blood tests can also assess inflammation levels by detecting the presence of inflammation markers, such as specific proteins that promote inflammation.
• Imaging Studies – Imaging studies can be particularly helpful in confirming the presence of clinical symptoms for MCTD. Chest X-rays can confirm pulmonary hypertension by identifying dilation of the pulmonary artery and enlargement of the heart (cardiomegaly). Joint X-rays can reveal swelling, erosion, and deformities in the joints. An echocardiogram, which is an ultrasound scan of the heart, can reveal enlargement of the left ventricle (left ventricular hypertrophy) and fluid build-up in the space surrounding the heart (pericarditis).^1,6

Treatment Options

As of now, there is no cure for MCTD. The goal of treatment is to manage the severity of the clinical symptoms and medication is prescribed according to the patient’s symptoms and symptom severity. Healthcare providers can also suggest avoiding behaviours that could exacerbate existing symptoms.

Here is a list of medications that may be used to control the symptoms of MCTD followed by example drugs:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) – Used for general pain management and inflammation associated with muscle weakness and joint stiffness
  • Ibuprofen
• Calcium channel blockers – Cause muscles in blood vessel walls to relax and dilate to allow blood to flow with decreased resistance, which decreases pulmonary hypertension
  • Nifedipine and amlodipine
• Corticosteroids – Used for the management of inflammation, joint pain, and joint stiffness
  • Prednisone
• Antimalarial drugs – Used to improve muscle and joint pain, treat skin rashes, and reduce pericarditis
  • Hydroxychloroquine
• Immunosuppressants – Used to suppress the immune system which reduces the production of autoantibodies¹
  • Methotrexate

Here are some other suggestions for symptomatic management of MCTD:

• Protecting hands and feet from cold – Wearing gloves and thick socks can keep the extremities warm and help to prevent Raynaud’s phenomenon
• Avoiding smoking – Smoking can cause blood vessels to become restricted which can worsen blood flow to the hands and feet⁵

Prognosis

The prognosis for individuals with MCTD can vary considerably, and depends on many factors such as:

• Early diagnosis and treatment – As with most diseases, early diagnosis and treatment can greatly improve the long-term prognosis of MCTD. Early intervention is key to help manage symptom severity, prevent complications, and improve the quality of life
• Organ involvement severity – MCTD can affect many different organs, such as the heart, lungs, skin, and kidneys. Prognosis depends on which organ is impacted and the degree of damage to the organ e.g., patients with kidney damage may have a worse prognosis than those with skin rashes
• Response to treatments– Individual responses to medication play an important role in prognosis. Some patients may achieve symptom control using medication, while others may have more persistent symptoms or may experience resistance to certain medications, in which case other treatments must be considered^{1, 7}

Summary

Mixed connective tissue disease, or MCTD, is a complex autoimmune condition with overlapping features from other connective tissue diseases. Understanding the importance of connective tissues, such as collagen, adipose tissue, cartilage, and blood, is vital for understanding the impact of MCTD on the body. Despite the variability of symptoms and the difficulty in diagnosis, MCTD is distinguishable from other autoimmune conditions through a combination of clinical evaluation, blood tests, and imaging scans.

Managing MCTD typically involves the use of medications to control symptoms and prevent disease progression. Medications include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressive drugs, and antimalarial drugs. Lifestyle modification techniques also play a role in enhancing the quality of life for those with MCTD.

The prognosis for individuals with MCTD is highly variable, influenced by factors such as early diagnosis, the severity of organ involvement, and treatment response. Early diagnosis and timely treatment are important for a better prognosis. The extent of organ damage and the response to medications also significantly affect the outcome. As there is currently no cure for MCTD, the management approach focuses on symptom control and improving the patient's quality of life.