It can be a scary and confusing experience to be diagnosed with Mixed Connective Tissue Disease (MCTD) while combating fatigue and pain, and trying to make sense of shifting symptoms. MCTD can feel unpredictable, and one of the bigger, scarier questions you might have is: Will this get worse? However, you are not alone, and understanding what might lead to more severe complications can be a big first step in taking control over the disease. 

What is it?

What is mixed connective tissue disease (MCTD)? 

Mixed Connective Tissue Disease (MCTD) is a rare autoimmune disorder affecting the connective tissues in joints and muscles.¹ An autoimmune disorder occurs when your immune system abnormally identifies your body’s tissues as foreign bodies and attacks them. The result of it is a weakened bodily function, damaged tissues, chronic pain, and in some cases, severe complications.² 

As the name suggests, patients with MCTD can show overlapping symptoms with three other connective tissue diseases: Systemic lupus erythematosus (SLE), Scleroderma, and Polymyositis. In addition to these, the disease is also characterised with having high levels of anti-U1-ribonucleoprotein (RNP) antibodies and Raynaud’s phenomenon. In some instances, people can also show symptoms of dermatomyositis, rheumatoid artheritis and Sjögren’s syndrome.³  

Due to its overlapping symptoms and multisystem involvement, MCTD can lead to a range of serious health complications if not properly monitored. These complications vary in severity and can affect major organs, including the lungs, heart, and kidneys. 

Therefore, recognising early signs and predictors of severe outcomes is vital to improving patient prognosis and quality of life.

Importance of identifying predictors for severe complications 

The importance of identifying the predictors for severe complications is due to how they can impact the morbidity and mortality of MCTD. Early prediction and intervention can improve the quality significantly. 

In the upcoming sections of this article, we will be explaining the severe complications in MCTD and reviewing the key predictors of these complications in order to help you understand the scarier parts of the disease, and possibly help with early intervention. 

Severe complications in MCTD

The initial symptoms of MCTD are less specific to organs and may include pain in joints and muscles, fatigue, swollen and puffy fingers, reddish brown rashes on the knuckles, Raynaud’s Phenomenon (numbness and loss of colour in extremities such as fingers and toes due to reduced blood flow to the area).^3,4 However, when left untreated, patients with MCTD can develop severe complications that could be life-threatening. The most common severe complications are as follows: 

Pulmonary arterial hypertension (PAH)

PAH is a progressive disorder affecting the blood vessels in the lungs, specifically blood vessels carrying low-oxygenated blood called arteries. In PAH, the arteries in the lungs are damaged, blocked, or narrowed, reducing the blood flow. Due to the obstructed blood flow, the blood pressure increases in the lung arteries. Prolonged hypertension results in the heart working harder, and the extra effort could eventually lead the muscles to weaken and the heart to fail.⁵ 

Interstitial lung disease (ILD)

ILD is a general term that encompasses a variety of diseases that affect the lungs, mainly characterised by scarring of the lungs due to prolonged inflammation. These scar tissues in the lungs make it difficult to breathe and transfer the much-needed oxygen to the blood. People with MCTD might develop ILD due to increased inflammation, and it can get worse if left untreated. Hence, early intervention makes a big difference.⁶

Myocarditis and pericarditis

In MCTD heart is another organ that can be affected by the inflammation caused by the immune system. Myocarditis happens when the heart muscle itself gets inflamed, while pericarditis is the inflammation of the thin lining surrounding the heart. These can lead to chest pain, fatigue, and difficulty in breathing. If not caught early, the symptoms might develop and turn severe.⁷

Severe raynaud’s phenomenon and digital ulcers

Raynaud’s Phenomenon is very common in MCTD. In response to cold or stress, the extremities, such as fingers and toes, turn white, blue, or purple. This is due to restricted blood flow to the area. Albeit being scary and painful, normally, Raynaud’s Phenomenon is not as dangerous. However, in extreme cases, the lack of blood flow might lead to sores or ulcers. These ulcers are prone to getting infected, causing pain and discomfort.⁴

Clinical predictors

Before going into the more technical predictors of severe complications in MCTD, it might be helpful to get a better understanding of the prognosis of the disease. MCTD is a highly rare disease, with an occurrence rate of 1.9 per 100000 adults per year. Additionally, MCTD is an older onset disease, with a mean age of diagnosis of 48 years old. It predominantly affects people assigned female at birth (AFAB), with a 3.3 to 1 AFAB to AMAB (assigned male at birth) ratio.⁸

The typical clinical manifestation of MCTD is Raynaud’s Phenomenon and high blood pressure affecting the blood vessels in the lungs. Raynaud’s Phenomenon is the most common and an early symptom in MCTD, presenting in up to 93% of patients.⁹ Even though less common than Raynaud’s Phenomenon, lung and heart problems are still evident and occur in 73% of patients, mostly with later onset.¹⁰ Depending on the organs affected and the severity of the inflammation, the prognosis of MCTD can differ. High blood pressure in the lungs is the leading cause of death, with infections and heart complications following it. Several other factors are associated with worse disease progression, which could be a predictor of severe complications.⁸ We will be discussing these different predictors in the upcoming section.

Laboratory predictors

Since MCTD has a diverse range of symptoms and can have overlapping features with other autoimmune diseases, it is important to employ different types of testing methods. Through different methods of testing, different predictors of severe complications in MCTD can be determined. One of those methods is evaluating the bodily fluids - mainly blood- through several laboratory tests. In this section we will delve into different aspects that can be identified through blood tests. 

Presence of anti-U1 RNP antibodies

Among the many symptoms present, the disease is characterised by the presence of anti-U1-ribonucleoprotein (RNP) antibodies. These antibodies are due to a faulty immune response against the ribonucleoproteins found in all cells. The high levels of anti-U1 RNP antibodies in blood tests are a hallmark of the disease, and it is believed that they play a role in the complications and progression of the disease. According to a 2018 study, people with the highest levels of anti-U1-RNP showed Raynaud’s syndrome. This can give us a clue about how much the immune system is alarmed, helping in predicting the potential damage to blood vessels and organs.⁸ 

Inflammatory markers & blood cell abnormalities

Since inflammation of joints and muscles is common in MCTD, the high levels of inflammatory markers in the blood, such as ESR, CRP, and ferritin, can be a predictor of the severity of the disease progression. Few studies have also shown that seeing low amounts of white or red blood cells in the blood tests can be indicative of how bad the symptoms, like Raynaud’s Syndrome and arthritis, can be.^11,1

Radiological and functional predictors

While blood tests can be used as early predictors of severe complications, other methods can give functional analysis and help paint a more detailed picture of the disease progression. High-resolution CT (HRCT) is an imaging technique that employs X-rays in order to visualise lung structure. HRCT findings can reveal the condition of the lungs in MCTD patients, giving clues on ILD progression. Increased opacity in the lung tissue, abnormal lung structure, presence of thin dark lines are all findings that indicate inflammation and can be used to identify the severity of ILD, which affects the prognosis of MCTD.^12,13 

Echocardiography (using sound waves to visualise the heart and blood vessels), and right heart catheterisation (RHC), are two techniques to measure the blood pressure in the blood vessels of the lung. A blood pressure reading of ≥25 mmHg from these tests is categorised as having PAH, and this can be a crucial predictor for the severity of lung complications in MCTD.¹⁴ In addition, pulmonary function tests, like DLCO, where the lung’s effectiveness to transfer oxygen from air to blood is measured, can be an early indication of lung health and other lung disease to come.¹⁵

Genetic and environmental risk factors

Although the exact cause of MCTD is still unknown, several genetic and environmental factors have been identified that increase the risk of developing MCTD. HLA genes (information in our DNA that determines characteristics) play a central role in our immune systems. Different versions of these genes, called alleles, have been linked to developing MCTD. Specifically, HLA-B*08 and DRB1*04:01 have been identified as risk alleles for MCTD, increasing the chances of developing MCTD. 

While the case for environmental factors has been less clear-cut, exposure to ultraviolet radiation (UV), chemicals such as silica, and continued infections resulting in sustained inflammation have been associated with developing MCTD. In addition, smoking has been shown to play a role in exacerbating the severity of lung disease complications in MCTD.⁸

Treatment-related predictors

MCTD is a progressive disease - once left untreated, constant inflammation and destruction of the blood vessels lead to the development of lung, neurological, and renal complications, and they can get worse over time.¹ Hence, a delayed diagnosis and treatment can impact the disease progression immensely. Likewise, mistreatment or inadequate treatment can be crucial in developing severe complications. Traditionally, mild cases of MCTD are treated with corticosteroids (also called steroids), which are hormones that stifle the immune system, restraining it from attacking healthy cells. However, if major organs such as lungs and kidneys are affected, stronger immunosuppressants might be needed. Insufficient or faulty use of medication can lead to organ damage in the long run.³

Conclusion

Living with MCTD can be extremely overwhelming, especially when trying to understand the unpredictable symptoms. The uncertainty of the disease can progress, which can be scary. However,  understanding the symptoms before they further develop can help slow down the progression of the disease. Knowing the predictors of severe complications associated with MCTD, whether it be unusual blood test results, heart and lung problems, or treatment quality, gives you a head start in overcoming this disease.

Summary

Mixed Connective Tissue Disease (MCTD) is a rare autoimmune disease that can affect many organs and tissues in the body, such as blood vessels, lungs, heart, joints, skin, and muscles. While the symptoms can be mild, such as joint and muscle pain, fatigue, and Raynaud’s Phenomenon. In severe cases, such as lung disease, heart inflammation, painful ulcers, and high blood pressure can arise from complications and develop over time. This article explores the predictors of these complications, from laboratory predictors like antibody levels and inflammatory markers in the blood, to functional techniques like lung imaging findings and hypertension readings. By informing yourselves on what puts you at higher risk, you and your doctor can work together for early diagnosis, better treatment, and more positive disease progression.