Mixed Connective Tissue Disease

What is Mixed Connective Tissue Disease?

Mixed Connective Tissue Disease (MCTD) is a rare disease where the immune system mistakenly attacks its own tissues. It possesses traits from at least two different diseases that affect the tissues connecting organs, such as Systemic Lupus Erythematosus, Systemic Sclerosis, Polymyositis, Dermatomyositis, and Rheumatoid Arthritis. Also, this disease is identified by the presence of particular antibodies (anti-U1-ribonucleoprotein or RNP), and a condition known as Raynaud phenomenon which affects blood flow to the fingers and toes.

Despite being first identified in 1972, there’s still some debate over whether MCTD is its own separate disease or just an early stage of a specific connective tissue disease. Each patient’s case can vary significantly, and there is no set list of symptoms unique to MCTD.

Currently, there is no universally agreed-upon set of criteria to diagnose MCTD. However, most health professionals agree on some commonalities. The diagnosis usually includes the presence of high levels of anti-U1-RNP antibodies and signs of Raynaud phenomenon, along with any two of a list of potential symptoms that include joint inflammation, muscle inflammation, abnormal white blood cell counts, problems with the esophagus, pleuritis (inflammation of the lining of the lungs), pericarditis (inflammation of the lining around the heart), and a lung condition called interstitial lung disease.

In 2019, a Japanese panel suggested a revised set of standards for diagnosing MCTD. These standards included the same initial criteria, but they considered organ involvement and the manifestations of other diseases a patient might exhibit. Diagnosis under these standards also relies on a general symptom, an immune-related symptom, and either one significant organ-related symptom or features from two or more other diseases that overlap with MCTD. These criteria have a high rate of correct identification (90.6% sensitive, 98.4% specific), but they are yet to be widely adopted.

What Causes Mixed Connective Tissue Disease?

The exact cause of mixed connective tissue disease (MCTD) is unknown, but it’s thought that genes and interaction with the environment play a role. Certain alleles (differences in sequences of DNA within a gene), marked HLA-B*08 and DRB1*04:01, appear to increase the risk of developing MCTD. On the flip side, some alleles, such as DRB1*04:04, DRB1*13:01, and DRB1*13:02, seem to protect against the disease.

There isn’t a specific environmental risk factor that’s been identified for MCTD. However, it’s believed that if someone has a genetic susceptibility to MCTD, something in their environment may cause their immune system to become overly active. Some elements of the environment, like infections, medications, toxins, ultraviolet radiation, and certain chemicals (like vinyl chloride and silica), might be associated with MCTD.

One leading theory is that the start of the disease is triggered by “molecular mimicry.” Simply put, this is when proteins from outside the body have the same structure as proteins in the body, which may cause the body to mistakenly attack its own cells. For example, some research has found that about 91% of MCTD patient’s DNA contained a sequence similar to one found in HIV type-1. Moreover, 75% of MCTD patients were found to have antibodies to certain HIV proteins.

Risk Factors and Frequency for Mixed Connective Tissue Disease

MCTD, or mixed connective tissue disease, is relatively rare and its exact frequency is still unknown. Some studies have tried to estimate it, though. For example, a study in Minnesota found that MCTD affects about 1.9 adults out of every 100,000 each year. The average age of diagnosis was 48, and 84% of the patients were women. Another study in Norway reported slightly fewer annual cases, about 2.1 out of every million people, but also found it was more common in women and diagnosed on average at the age of 37.9.

A study in France with 330 patients over eight years showed similar findings: a large majority, or 88%, of patients were women and the median age was 35. It’s important to note that MCTD can occur in anyone, regardless of their race or ethnicity, and symptoms seem to be similar across different groups. However, some differences might be identified as more studies are conducted.

MCTD, or mixed connective tissue disease, is a relatively rare condition.
In a Minnesota study, there were 1.9 cases per 100,000 adults each year.
The same study found that the average age at diagnosis is 48, and 84% of those affected are women.
A study in Norway reported 2.1 cases per million people each year.
In this Norwegian study, the ratio of females to males was 3.3 to 1, and the average age at diagnosis was 37.9.
A French study showed that 88% of MCTD patients were women, and the median age was 35.
MCTD can affect people of all races and ethnicities.

Signs and Symptoms of Mixed Connective Tissue Disease

Mixed connective tissue disease (MCTD) is a medical condition with symptoms that can affect almost any part of the body. These symptoms can reflect other rheumatological diseases because MCTD overlaps with them. From the start, you might experience general symptoms such as joint pain, fatigue, muscle pain, and mild fever.

Common Symptoms Include:

Skin issues: The most common skin symptoms are Raynaud’s phenomenon and swollen fingers. Other symptoms may include nail capillary abnormalities, skin thickening, the build-up of calcium under the skin, small blood vessels becoming visible on the skin, hair loss, inflammation and destruction of blood vessels, and multiple types of rash.
Musculoskeletal problems: Some people may develop an inflammation of the joints similar to lupus or rheumatoid arthritis.
Muscle inflammation: This results in weakness in the muscles around your trunk, and you might also have high levels of certain proteins in your blood.
Cardiopulmonary complications: You may experience lung and heart issues. Common lung symptoms are shortness of breath and dry cough. Some people might also experience chest pain, blocked airway, and coughing up of blood. Heart-related problems may include inflammation of the heart lining, an excess of fluid around the heart, heart valve issues, certain types of fever, and irregular heart rhythms.
Gastrointestinal symptoms: You might experience issues with your esophagus which may include difficulties in swallowing, heartburn, acid reflux, and regurgitation of undigested food.

Less common symptoms include:

Renal problems: In some cases, the disease may affect the kidneys, with membranous nephropathy being the most common issue. This can lead to high blood pressure and progressive kidney disease.
Central nervous system: Some people might experience nervous system-related symptoms such as sharp nerve pain, headaches, peripheral neuropathy, meningitis, cerebral venous sinus thrombosis, and hearing loss.
Blood issues: Some may also have issues like anemia, low white blood cell count, and a low platelet count. Very rarely, some people develop idiopathic immune-mediated thrombocytopenia and hemolytic anemia.

Testing for Mixed Connective Tissue Disease

To assess mixed connective tissue disease (MCTD), a condition that features symptoms of multiple connective tissue diseases, doctors use a detailed medical history, a physical examination, and various diagnostic tests. This allows them to understand the diverse symptoms and the overlap with other connective tissue diseases.

Laboratory tests play a crucial role in this process, particularly in detecting the U1-RNP antibody, a molecule produced by the immune system, which could indicate MCTD. These tests can also help determine the severity of the disease, particularly its impact on various organs, and check for symptoms of other diseases with similar symptoms.

One common feature in MCTD patients is the presence of anti-nuclear antibodies at a high level, which are autoimmune antibodies that bind to contents of the cell nucleus. Another marker that could potentially indicate MCTD is an antibody called survival of motor neuron (SMN).

Other lab tests can help identify symptoms of conditions that often overlap with MCTD, such as systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. About 65% of MCTD patients have a positive rheumatoid factor test result, and 50% can have a positive anti-cyclic citrullinated peptide test result, both of which indicate potential autoimmune conditions. Some patients may also have increased muscle enzyme levels. MCTD patients may also have a full blood count demonstrating anemia and leukopenia (involved in about 75% of patients).

Imaging and other diagnostic studies may not always be necessary unless doctors suspect the disease has started to affect specific organs. If a patient is showing signs of lung or heart disease, heart and chest x-rays, and computed tomography scans might be used. Features often seen on these scans can include changes in lung tissue, fluids in the pleural space (the area between the two layers of tissue that line the lungs), and heart enlargement.

An echocardiogram, which is an ultrasound of the heart, may be used to monitor for right heart disease and pulmonary hypertension (high blood pressure in the lungs), or changes in heart function.

If the doctor thinks there may be damage to bones, joints, or muscles, X-rays or ultrasounds of the joints might be performed. In some cases, an MRI scan may be taken to give a more detailed image of the body’s soft tissues.

If symptoms include problems with the gastrointestinal tract, an esophagram (an X-ray examination of the throat), upper endoscopy (viewing the upper digestive tract with a flexible tube), or colonoscopy (inspection of the colon with a long, flexible tube) might be performed. If muscle disease or nerve disease is suspected, an electromyogram (a test for evaluating muscle electrical activity) and nerve conduction study could be used.

Treatment Options for Mixed Connective Tissue Disease

Mixed connective tissue disease (MCTD) refers to an uncommon health condition that, due to its rarity, doesn’t have standardized treatments since they can’t be subjected to common controlled research trials. The goal of therapy primarily focuses on controlling the symptoms, determined by the area of the body that’s affected and how the disease presents itself.

The disease’s most crucial complications occur in the heart and lungs, predominantly as a result of pulmonary hypertension (high blood pressure affecting the arteries in the lungs and the right side of the heart) and a non-specific pattern of interstitial lung disease (a group of disorders leading to scarring of lung tissues). The mentioned complications are the main causes of health deterioration and death in patients with MCTD. Lung disease treatment often involves combining treatment strategies employed for MCTD, scleroderma (another connective tissue disease), among others. The main medicines given to these patients include mycophenolate mofetil, cyclophosphamide, and rituximab, with mycophenolate mofetil being the first choice as it’s often as effective as the others, but with fewer side effects. A recent medical study suggested that both rituximab and cyclophosphamide are relatively equivalent in their effectiveness for lung-related issues, with rituximab causing fewer side effects overall.

Pulmonary hypertension is generally less treatable using steroids. Vasodilators – medicines that help widen the blood vessels – including prostaglandins, endothelin receptor antagonists and phosphodiesterase 5 inhibitors could be considered for treating this condition under the supervision of a pulmonary hypertension expert. Steroids and cyclophosphamide might also be suitable for these patients.

For patients dealing with Raynaud’s disease (where blood vessels spasm and restrict blood flow), symptomatic treatment strategies could involve lifestyle changes such as staying away from caffeine, smoking, cold temperature, and hand injuries. In addition to this, heart medicines such as nifedipine, which lowers blood pressure, can also be used as a treatment method. Other treatments include prostaglandins, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and nitroglycerin creams which help in blood vessel dilation.

Joint pain and arthritis symptoms often respond well to non-steroidal anti-inflammatory drugs (NSAIDs) and hydroxychloroquine. For the more stubborn cases of synovitis (inflammation of the synovial membrane), steroids, methotrexate, and other drugs designed to modify the progression of the disease can be considered.

For inflammation of the pleura (lung lining), pericardium (heart lining), muscles (myositis), and the protective membranes of the brain (meningitis), steroids are typically an effective treatment. In addition, medicines such as methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil are often used as alternative or second-line treatments. For resistant inflammation of the muscles, intravenous (through a vein) immunoglobulin (proteins that function as antibodies within the immune system) can be administered.

For patients dealing with acid reflux, proton pump inhibitors (PPI) or histamine blockers, and lifestyle changes such as quitting smoking, losing weight, and avoiding foods and drinks that trigger heartburn can be considered. Furthermore, for those who do not respond to PPI therapy, prokinetics and possibly surgery to create a barrier to reflux may be considered. For individuals with an esophageal motility disorder, they may require prokinetics. Those with malabsorption issues are advised to follow a lactose-free diet and replace long-chain fatty acids with medium-chain ones in their diet.

In cases of MCTD patients with autoimmune hemolytic anemia and thrombocytopenia (low platelet count in the blood that hampers clotting), the initial treatment often involves the use of steroids. In patients who don’t respond to steroid treatment, rituximab may be considered by the clinician.

Mixed Connective Tissue Disease (MCTD) has symptoms that are not easily identifiable and can affect various organs. This makes it easily mistaken for several other conditions, particularly other types of connective tissue diseases. Here’s a simplified rundown of what these other conditions might be:

Systemic Lupus Erythematosus: This autoimmune disease has a range of symptoms including arthritis, skin problems, inflammation around heart and lungs, kidney problems, and issues with blood cells. It is identified by the presence of specific antibodies in the blood.
Rheumatoid Arthritis: Mostly affects small joints in hands, wrists, ankles, and feet. Majority of patients have abnormal blood markers known as rheumatoid factor and anti-cyclic citrullinated peptide antibody.
Polymyositis: This disease causes muscle weakness, usually more in muscles close to the body than those further away. It shows signs of muscle inflammation through biochemical tests and imaging, and lacks any autoantibodies.
Dermatomyositis: Similar to polymyositis but also affects skin, lungs, digestive system, and joints. It is associated with specific antibodies related to muscle inflammation.
Scleroderma: This is a long-term disease that leads to abnormal blood flow, skin scarring, and damage to internal organs. It’s linked to an overactive immune response.

Recognizing and differentiating these conditions are crucial to correctly diagnosing MCTD.

What to expect with Mixed Connective Tissue Disease

MCTD, short for Mixed Connective Tissue Disease, typically has a good outlook, but this depends upon which organ is affected, how much inflammation there is, and how quickly the disease progresses. It’s reported that the mortality rate (the chance of death) ranges between 3.1% and 10%.

According to a study done in Hungary, out of 5 and 10 years after being diagnosed, 98% and 96% of people survived respectively. In a French study that followed 330 patients with MCTD for an average of 8 years, 45.2% of patients achieved remission (disease-free state), 7.6% developed high blood pressure in the lungs (pulmonary hypertension), and 27.9% developed a lung disease that causes scarring of the lung tissue (interstitial lung disease).

Pulmonary hypertension is the leading cause of death in people with MCTD. Other common causes include interstitial lung disease, infections, heart-related complications, and cancer. The presence of certain antibodies (immune system proteins that respond to threats), specifically immunoglobulin G anticardiolipin, may be associated with a more severe form of the disease.

The detection of a specific type of autoantibody, an antibody that mistakenly attacks one’s own body tissues, known as the anti-SMN complex can also indicate the likely outcome of the disease. Patients with MCTD with this autoantibody tended to have a poorer disease-related outcome compared to those without it, with complications mainly tied to pulmonary hypertension and interstitial lung disease. Having another type of autoantibody, the anti-Ro52, also suggested a worse prognosis, particularly in relation to the severity of interstitial lung disease.

During the course of the disease, patients may develop new autoantibodies, a process known as epitope spreading. This might lead to changes in symptoms. For instance, a lower rate of skin hardening and a higher percentage of interstitial lung disease was observed in patients who experienced epitope spreading. Moreover, some patients with MCTD may later develop other diseases affecting connective tissue, like systemic sclerosis, rheumatoid arthritis, Sjogren syndrome, and systemic lupus erythematosus. A study following MCTD patients over time found that approximately 25.6% went on to develop a specific connective tissue disease. Similarly, patients with other connective tissue diseases can eventually develop MCTD.

Possible Complications When Diagnosed with Mixed Connective Tissue Disease

Patients with Mixed Connective Tissue Disease (MCTD) may experience serious health complications. These can include high blood pressure in the lungs, a disease that affects the spaces around the lung’s air sacs, and infections. These health problems are common causes of death among people with MCTD. Patients may also have problems with their kidneys, heart, and digestive system making their condition more complex to manage. It’s important that these complications are identified quickly and monitored regularly. By doing this, it’s possible to improve the patient’s health outcomes and reduce the chances of severe health problems caused by MCTD.

Possible health risks include:

High blood pressure in the lungs
A disease that affects the spaces around the lung’s air sacs
Infections
Kidney problems
Heart issues
Digestive system difficulties

Preventing Mixed Connective Tissue Disease

Teaching patients about their disease and how to manage it can greatly improve their quality of life. If you’re dealing with a condition known as mixed connective tissue disease (MCTD), it’s important to understand how it can affect different organs in your body. Early recognition of any complications can be helpful to manage them effectively. Regular doctor’s appointments to oversee these complications and coordinate a management plan are crucial.

Self-care is also a significant aspect of managing MCTD, especially if you’re experiencing a symptom called Raynaud’s phenomenon. In this condition, your fingers and toes may feel cold or numb in response to cold temperatures or stress. It’s important that you keep your hands and feet warm, use warming methods such as hand warmers, and be alert for any complications like non-healing sores or ulcers on your fingertips or toes. This can help to prevent loss of these digits.

Remember, your active involvement in decisions regarding your treatment is vital. You have the right to know and understand all your therapeutic options to choose the best possible path for your case.

Frequently asked questions

MCTD, or mixed connective tissue disease, is a relatively rare condition.

Signs and symptoms of Mixed Connective Tissue Disease (MCTD) include: - General symptoms such as joint pain, fatigue, muscle pain, and mild fever. - Skin issues: Raynaud's phenomenon, swollen fingers, nail capillary abnormalities, skin thickening, build-up of calcium under the skin, visible small blood vessels on the skin, hair loss, inflammation and destruction of blood vessels, and multiple types of rash. - Musculoskeletal problems: Inflammation of the joints similar to lupus or rheumatoid arthritis. - Muscle inflammation: Weakness in the muscles around the trunk and high levels of certain proteins in the blood. - Cardiopulmonary complications: Lung symptoms like shortness of breath and dry cough, chest pain, blocked airway, coughing up of blood. Heart-related problems like inflammation of the heart lining, excess fluid around the heart, heart valve issues, certain types of fever, and irregular heart rhythms. - Gastrointestinal symptoms: Difficulties in swallowing, heartburn, acid reflux, and regurgitation of undigested food. - Less common symptoms: Renal problems like membranous nephropathy leading to high blood pressure and progressive kidney disease. Central nervous system symptoms like sharp nerve pain, headaches, peripheral neuropathy, meningitis, cerebral venous sinus thrombosis, and hearing loss. Blood issues like anemia, low white blood cell count, low platelet count, idiopathic immune-mediated thrombocytopenia, and hemolytic anemia.

The exact cause of Mixed Connective Tissue Disease (MCTD) is unknown, but it is believed that genes and interaction with the environment play a role. Certain alleles, such as HLA-B*08 and DRB1*04:01, increase the risk of developing MCTD, while others like DRB1*04:04, DRB1*13:01, and DRB1*13:02, seem to protect against the disease. Additionally, environmental factors such as infections, medications, toxins, ultraviolet radiation, and certain chemicals may be associated with MCTD. One theory is that the disease is triggered by "molecular mimicry," where proteins from outside the body have a similar structure to proteins in the body, leading to the body mistakenly attacking its own cells.

Systemic Lupus Erythematosus, Rheumatoid Arthritis, Polymyositis, Dermatomyositis, and Scleroderma.

The types of tests that are needed for Mixed Connective Tissue Disease (MCTD) include: 1. Laboratory tests: - U1-RNP antibody test to detect the presence of the U1-RNP antibody, which could indicate MCTD. - Anti-nuclear antibody test to check for the presence of autoimmune antibodies that bind to contents of the cell nucleus. - Survival of motor neuron (SMN) antibody test, which could potentially indicate MCTD. - Rheumatoid factor test to indicate potential autoimmune conditions. - Anti-cyclic citrullinated peptide test to indicate potential autoimmune conditions. - Muscle enzyme level test to check for increased levels. - Full blood count to check for anemia and leukopenia. 2. Imaging and diagnostic studies: - X-rays or ultrasounds of the joints to assess damage to bones, joints, or muscles. - MRI scan to provide a more detailed image of the body's soft tissues. - Heart and chest x-rays, computed tomography scans, and echocardiogram to assess lung and heart disease. 3. Gastrointestinal tests: - Esophagram, upper endoscopy, or colonoscopy to assess problems with the gastrointestinal tract. 4. Muscle and nerve tests: - Electromyogram and nerve conduction study to evaluate muscle electrical activity and nerve function. These tests help doctors diagnose MCTD, determine its severity, and check for symptoms of other diseases with similar symptoms.

Mixed Connective Tissue Disease (MCTD) is treated by primarily focusing on controlling the symptoms based on the affected area of the body and how the disease presents itself. Treatment strategies for MCTD often involve a combination of medications such as mycophenolate mofetil, cyclophosphamide, and rituximab. Mycophenolate mofetil is often the first choice due to its effectiveness with fewer side effects. For lung-related issues, both rituximab and cyclophosphamide are relatively equivalent in effectiveness, with rituximab causing fewer side effects. Pulmonary hypertension may be treated with vasodilators and steroids, while Raynaud's disease can be managed with lifestyle changes and medications such as nifedipine. Joint pain and arthritis symptoms respond well to non-steroidal anti-inflammatory drugs (NSAIDs) and hydroxychloroquine. Steroids are typically effective for inflammation of various body parts, and other medications like methotrexate and mycophenolate mofetil may be used as alternative treatments. Acid reflux can be managed with proton pump inhibitors (PPI), histamine blockers, lifestyle changes, and possibly surgery. Autoimmune hemolytic anemia and thrombocytopenia are initially treated with steroids, and rituximab may be considered if steroid treatment is ineffective.

The text does not mention the specific side effects of treating Mixed Connective Tissue Disease (MCTD). However, it does mention that mycophenolate mofetil is often the first choice of medication for MCTD due to its effectiveness and fewer side effects compared to other medications. It also states that rituximab causes fewer side effects overall for lung-related issues. It is important to consult with a healthcare professional for a comprehensive understanding of the potential side effects of MCTD treatment.

The prognosis for Mixed Connective Tissue Disease (MCTD) can vary depending on factors such as which organ is affected, the level of inflammation, and the rate of disease progression. However, studies have shown that the mortality rate ranges from 3.1% to 10%. Some specific outcomes and complications associated with MCTD include achieving remission (45.2% of patients), developing pulmonary hypertension (7.6% of patients), and developing interstitial lung disease (27.9% of patients). The presence of certain antibodies, such as immunoglobulin G anticardiolipin and anti-SMN complex, may be associated with a more severe form of the disease and poorer outcomes.

A rheumatologist.

Autoimmune Connective Tissue Disease Health