Introduction 

Mixed Connective Tissue Disease (MCTD) is a rare, autoimmune disease that has combined symptoms of other connective tissue diseases such as lupus, scleroderma and polymyositis. Common signs and symptoms include puffy or swollen fingers, cold fingers and toes (due to reduced blood flow to extremities), muscle and joint pain, feeling unwell, fever and rash. 

In autoimmune disorders, your immune system (responsible for protecting your body) mistakenly attacks its own healthy cells. In connective tissue diseases, the immune system targets the cells that connect and support the body’s organs, tissues and overall structure. Some individuals with MCTD have a family history of connective tissue disease or other autoimmune conditions, although this has yet to be proved by research to pinpoint which genes are responsible. Because of its rarity, no clinical trials have been conducted to further investigate the disease. 

There is no known cure for MCTD. Treatment focuses on managing symptoms and complications of the condition.¹ It depends on how severe the disease is and what tissues have been affected.¹ Some drug-related treatment options include: 

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), such as ibuprofen for pain relief
• Corticosteroids to reduce inflammation, and suppress the immune system
• Immunosuppressants to control an overactive immune system
• Calcium channel blockers to help increase blood flow

Treatment using immune system suppressing medication 

What are immune system-suppressing medications? 

Immune system-suppressing medications are drugs designed to weaken part of the immune system when it's overactive in the body. It slows down the activity of the immune system and prevents it from fighting healthy cells. It is usually given for people with autoimmune conditions, organ transplants, severe inflammation and some cancers. 

There are different kinds of immune system-suppressing medications used in the treatment of MCTD: corticosteroids, immunosuppressants (steroid-sparing agents), biologics and JAK inhibitors.² Each works differently but has a similar function: to lower the immune system response.

Other non-immune-suppressing medications, such as calcium channel blockers and anticoagulants, are used to manage some of the symptoms of MCTD.³

Why suppress the immune system?

Usually, the immune system attacks dangerous foreign substances that enter the body, protecting it from infection and disease. However, in autoimmune diseases such as MCTD, the immune system targets its own body. This attack causes inflammation and damage to various tissues and organ systems such as joints, muscles, skin, the lungs, the heart and the kidneys.⁴ Suppressing the immune response reduces this destructive process. 

Immune suppression also controls the symptoms of MCTD, such as pain, fever, swelling in fingers and some organ-related symptoms such as pericarditis, pulmonary hypertension and renal issues (for example, proteinuria).¹ 

Moreover, if the immune system continues to attack the connective tissues in the body, it could lead to severe complications, such as infections, interstitial lung disease, cardiovascular issues, pulmonary hypertension and gastrointestinal problems.⁴

How does immune-suppressing medication work in MCTD? 

In order to understand how immunosuppressive medication works in MCTD, we must first look at how the immune system in MCTD functions. The faulty immune system produces autoantibodies – antibodies that attack the body’s own proteins. Usually, these proteins are hidden within the cell nuclei but get exposed when the cell dies (cell death). This triggers an immune response. Long-term activation of the immune system leads to chronic inflammation in the body. Immune-suppressing medication targets the cells (T cells and B cells) that are responsible for these attacks. Some medication inhibits the gene expression that leads to the production of T cell and B cell antibodies. This reduces the number of immune cells attacking the body’s tissues, thus reducing inflammation and organ damage. 

Common immune-suppressing medications used in MCTD

Corticosteroids 

This is generally the first line of treatment for MCTD. Corticosteroids are a type of immune system-suppressing medication or immunosuppressant. It is usually given to those with moderate to severe MCTD with a combination of other immunosuppressants. Its main responsibility is to control the gene expression responsible for inflammation and activates genes that have anti-inflammatory properties. One of its secondary functions is to control the number of white blood cells that enter an area of inflammation. If there are fewer immune cells at the site, there will be less swelling and damage. 

Corticosteroids are proven to help control inflammation in the body that leads to various symptoms such as skin rash, arthritis, aseptic meningitis, anaemia and more.¹ Some common corticosteroids for MCTD are prednisone and methylprednisolone. Prednisone is taken as an oral tablet and methylprednisolone is given intravenously (IV, through the vein) to treat severe levels of the disease. 

Risks and side effects 

As much as corticosteroids help in fighting inflammation, there are a few things to look out for when taking the medication. Possible side effects include weight gain, puffy face, gastrointestinal issues (food indigestion, stomach pain), problems with sleep, feeling restless, sweating and slight changes in mood. A risk with taking any immunosuppressant is being more prone to catching infections due to a weakened immune system. 

Immunosuppressants 

These are medications whose sole function is to suppress the immune system and reduce its ability to fight. It is prescribed when corticosteroids aren't enough or it needs to be tapered (slowly taken off). That is why it is called steroid-sparing agents (without the need of high doses of steroids). Some immunosuppressants control the genes responsible for immune function, even interfering with the DNA synthesis of rapidly dividing immune cells. They can be taken orally (as tablets), intravenously and subcutaneously (injected beneath the skin). 

Some commonly used immunosuppressants for MCTD are:

• Methotrexate, used for inflammatory conditions like rheumatoid arthritis
• Azathioprine, for severe symptoms like muscle inflammation, lupus and interstitial lung disease (ILD)
• Mycophenolate mofetil, used for ILD, lupus nephritis (a kidney disease caused by lupus and scleroderma-related symptoms like skin thickening)⁵
• Cyclophosphamide, can improve ILD, lupus nephritis, severe organ damage and other life threatening complications⁵ 

These drugs are also known as disease-modifying antirheumatic drugs (DMARDs), which treat the disease itself and not just a control on the symptoms. Not all immunosuppressants are DMARDs. Research has shown that using immunosuppressants can be effective in managing pulmonary arterial hypertension.⁶

Risks and side effects 

Possible side effects can include gastrointestinal problems, nausea, diarrhoea, loss of appetite, feeling tired, headaches, hair loss, bone marrow disorders, fever, seizures, sepsis, tachycardia (fast heart rate), skin reactions and weight loss. There is also a risk for infections and damage to some organs. 

Biologics 

Biologics are medications that are more advanced and target specific parts of the immune system. They block the specific cells that trigger an immune response. There are no oral medications for biologics and it is given by IV or injections. As protocol, blood tests and screening for infections such as HIV and tuberculosis are conducted before prescribing biologics. Common biologics used are rituximab, tocilizumab, and abatacept. These medications were initially proven to help with certain cancers and blood disorders, but they are now proven to help with arthritis and ILD in MCTD.⁷

Risks and side effects 

Live vaccinations must not be given before taking biologics. There will also be an increased risk for infections such as tuberculosis, gastrointestinal infections, sepsis and urinary tract infections.⁸ 

JAK Inhibitors 

Janus kinases (JAKs) inhibitors are synthetic medications that block pathways used by the immune system to produce inflammation. Some JAK inhibitors are used to treat various connective tissue diseases, and used for MCTD when steroids or conventional immunosuppressants do not work. Some examples of JAK inhibitors are tofacitinib, baricitinib, upadacitinib and peficitinib. These are taken as oral tablets. 

Research has shown that JAK inhibitors are useful in treating diseases like rheumatoid arthritis, lupus, dermatomyositis and polymyositis as they have anti-inflammatory effects on the skin, joints and muscles, which would prove helpful for MCTD as well.⁹ 

Risks and side effects 

The main risk would be an increased risk of infection, especially herpes zoster or shingles. 

Managing MCTD with Medications 

The importance of ongoing management in MCTD

It is crucial for individuals with MCTD to consult with their healthcare providers when it comes to taking any immunosuppressant drugs. These drugs are chosen based on the organ systems and specific tissues that are affected in MCTD. Each person with MCTD has a unique set of challenges and symptoms that are accounted for by the healthcare consultant when they prescribe medications. Therefore, treatment will depend on multiple factors such as patient characteristics (including their age and overall health) and disease characteristics like the severity of symptoms and which organs are affected. 

Moreover, once medication is prescribed, it is important to have consistent check-ups with the healthcare team for evaluation of any potential complications from the medication. 

Lifestyle changes 

It is essential to incorporate lifestyle changes when taking medications for MCTD. A study on lifestyle factors in connective tissue diseases found that diet plays a crucial role in predicting the risk of inflammation and conditions like lupus.¹⁰ Unprocessed and anti-inflammatory foods are key to supporting overall health and healing. Additionally, physical activity can help maintain muscle function.¹⁰ They found that poor sleep and high levels of stress are also associated with disease progression and unhealthy outcomes in connective tissue diseases. Moreover, smoking and alcohol consumption can lead to worse disease progression and health outcomes, unless those behaviours are changed. Therefore, medication combined with lifestyle changes tend to have the best outcomes for connective tissue diseases.¹⁰

Summary

In conclusion, immune system-suppressing medication is used to suppress an overactive immune system that attacks its own body in a condition like MCTD. It targets both genetic and non-genetic components and pathways responsible for inflammation and excess immune response in the body. From corticosteroids, which are the first line of treatment, to JAK inhibitors, these medications improve symptoms of MCTD, control progression of disease and support overall health. Tailoring these medications to each person’s needs, consistent monitoring by healthcare professionals and healthy lifestyle changes are all essential for long-term management of MCTD.