Undifferentiated Connective Tissue Disease

What is Undifferentiated Connective Tissue Disease?

Connective tissues are essential parts of our organs. They hold together different types of tissues, providing support and structure. Sometimes, the immune system can mistakenly attack these tissues, leading to what we refer to as a ‘connective tissue disease’. This can result in a variety of symptoms.

Connective tissue disease is a broad term covering many different types of diseases. Each one has specific criteria that doctors use to diagnose it. However, if a patient’s symptoms don’t match any known disease, doctors may diagnose them with ‘undifferentiated connective tissue disease’.

Undifferentiated connective tissue disease is a type of autoimmune disease – a condition in which the body’s immune system attacks its own healthy tissues. Yet, it doesn’t meet the criteria for any other known connective tissue diseases, like lupus, mixed connective tissue disease, Sjögren syndrome, systemic sclerosis, polymyositis, dermatomyositis, or rheumatoid arthritis. Despite this, undifferentiated connective tissue disease can be quite common in a medical setting.

An early stage of a major type of joint disease was first identified as undifferentiated connective tissue disease by a researcher named LeRoy back in 1980. He noted this in patients who didn’t meet the classification criteria for any other type of connective tissue diseases.

What Causes Undifferentiated Connective Tissue Disease?

Autoimmune diseases are complex and their causes aren’t fully understood. It’s generally accepted that both your genes and your environment can play a part in causing them. These diseases occur when your body’s immune system, the system responsible for fighting off illnesses, is overly active and mistakenly begins to attack your own body.

In autoimmune connective tissue diseases, your immune system incorrectly targets the connective tissues, which provide support for other body tissues and organs. Certain environmental factors, like exposure to chemicals in cigarette smoke, air pollution, and ultraviolet light, can trigger this response.

These diseases can have all sorts of symptoms and can develop either quickly or slowly. They might begin with very few signs and later show more clear signs of the disease.

Scientists have been trying to figure out what exactly causes these diseases and what triggers the flare-ups. They have found a connection between these diseases and a certain type of cell in the immune system, called T-regulatory cells. When the number of these cells is decreased, symptoms of the disease begin to appear. This suggests that these cells play an important role in preventing the development of autoimmune diseases. Moreover, a further decrease in the number of T-regulatory cells can worsen the condition, and cause undifferentiated connective tissue disease to develop into a differentiated connective tissue disease, which generally has a worse outcome.

Risk Factors and Frequency for Undifferentiated Connective Tissue Disease

Undifferentiated connective tissue disease is a condition that primarily affects females, particularly those between the ages of 32 and 44. Despite this, up to 90% of these cases don’t develop into a full-fledged connective tissue disease. Most of these patients remain stable over time, only experiencing mild symptoms and a single type of autoantibody.

Interestingly, due to different criteria for diagnosis, as many as half of all individuals diagnosed with a connective tissue disease may actually have undifferentiated connective tissue disease.

• In the United States, about 72% of people diagnosed with this disease are white.
• Approximately 78% of patients with the disease are females. This percentage goes up to 93-95% in Italy and 94% in Hungary.

Signs and Symptoms of Undifferentiated Connective Tissue Disease

Undifferentiated connective tissue disease (UCTD) was outlined in 1999 with a set of preliminary criteria used for its diagnosis. The unique aspect of these criteria is that they depend on no other major connective tissue disease being present.

Key criteria for UCTD diagnosis are:

• Signs similar to a specific connective tissue disease, but not meeting all requirements for that disease
• Positive test results for specific antibodies, confirmed twice
• At least three years with symptoms

Symptoms can mirror any other connective tissue disease, which means they can differ a great deal from patient to patient. Common symptoms experienced by most patients can include muscle and joint pain, skin complaints such as urticaria (hives), telangiectasias (small dilated blood vessels near the surface of the skin), or purpura (bruising), and the Raynaud’s phenomenon where some areas of your body like fingers and toes feel numb and cool in response to cold temperatures or stress. Some people may have dry mouth and eyes, or hair loss, and others may have a rash that worsens in sunlight.

UCTD usually follows a mild course and doesn’t cause severe damage to organs, specifically kidneys and the brain. Some patients may display other symptoms such as low white blood cell count, anemia, pleuritis (inflammation of the tissues that line the lungs and chest cavity), pericarditis (inflammation of the pericardium, the thin sac-like membrane surrounding your heart), low platelet count, strange sensations in the arms and legs, and a type of pneumonia known as interstitial pneumonia. Some patients initially experience fever, malaise, and fatigue.

This disease can present as either localized or diffuse physical findings, which are better demonstrated when grouped by organ system:

• Skin: Issues like sclerodactyly (thick and tight skin on fingers), calcinosis (calcium deposits under the skin), and erythema nodosum (red, painful lumps)
• Eyes: Conditions like iritis (inflammation in the eye’s iris), uveitis (inflammation inside the eye), and conjunctivitis (pink eye)
• Lungs: Symptoms such as rales (abnormal sounds heard through a stethoscope), pleural effusion (extra fluid around the lungs), and wheezing
• Heart: Conditions like cardiomegaly (enlarged heart), heart murmur, or irregular heartbeat
• Stomach and gut: Enlarged spleen or liver, stomach tenderness
• Genitals: rashes, abnormal discharge or ulcers
• Muscles: Proximal muscle weakness, tenderness, muscle shrinking and friction within a tendon

Testing for Undifferentiated Connective Tissue Disease

If your doctor suspects that you may have undifferentiated connective tissue disease, they will perform several lab tests. These are important for making a diagnosis. The most important tests are for antibodies called anti-Ro/SSA and anti-U1-RNP. Other tests include a complete blood count, C-reactive protein (a marker of inflammation), erythrocyte sedimentation rate (another inflammation marker), serum creatinine (a measure of kidney function), a urinalysis with microscope examination, rheumatoid factor (which can indicate rheumatoid arthritis), and antinuclear antibodies (which can indicate autoimmune disease).

In some cases, your doctor may order extra tests checking for other antibodies and various substances in your blood, such as complement components (proteins that help the immune system function), creatine kinase and aldolase (which can indicate muscle damage), anti-cyclic citrullinated peptide (another marker for rheumatoid arthritis), anti-La/SSB (which can indicate Sjögren’s syndrome), thyroid-stimulating hormone (to check your thyroid function), and vitamin D levels.

Depending on your symptoms, your doctor might also order imaging tests like a chest X-ray. This can help detect abnormal fluid in the lungs or heart, or changes in lung or heart size. Sometimes, a computed tomography (CT) scan of the chest is necessary, particularly for examining lung tissue more closely. Another imaging test, an ultrasound of your salivary glands, has been found to be a good test to distinguish between undifferentiated connective tissue disease and Sjögren’s syndrome.

Other tests that might be needed include lung function tests, if your doctor suspects you may have lung disease, and an electrocardiogram (a heart rhythm test), if you have symptoms affecting your heart. There’s also a test called a Schirmer test for people with dry eyes, but this test isn’t as reliable if you take certain types of medication.

Treatment Options for Undifferentiated Connective Tissue Disease

Undifferentiated connective tissue disease is typically a mild condition that can be mostly managed on an outpatient basis, meaning you don’t usually need to stay in the hospital for treatment. Several types of medications may be used. Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are commonly used to reduce inflammation. Calcium channel blockers can help relax the muscles in the blood vessels, while antimalarial drugs like hydroxychloroquine can be used to manage symptoms like severe skin rash.

In more severe cases where there’s significant damage or involvement of organs, medications that suppress the immune system may be necessary. Surgery is usually not used to treat this condition. Sometimes, simple measures like using sunblock and wearing protective clothing can benefit those with light sensitivity.

Regarding specific medications, NSAIDs like Naproxen can be helpful for pain relief. COX-2 selective medication such as celecoxib, a type of NSAID, could be a better choice for patients who are at risk of developing stomach ulcers and bleeding.

Systemic corticosteroids, drugs that reduce inflammation, are used when the disease flares up. An example would be Prednisone. They are often used in combination with other drugs.

If the symptoms of undifferentiated connective tissue disease are severe or not controlled with other medications, then drugs such as methotrexate or azathioprine may be used. These drugs control severe symptoms, and methotrexate in particular helps decrease the symptoms of inflammation associated with this disease.

Antimalarial drugs, typically used in cases of severe rash or light sensitivity, can prevent the development of the harmful agents causing inflammation. When used with NSAIDs, they can help control symptoms affecting the joints, mucous membranes, and general body constitution. Hydroxychloroquine is a common antimalarial drug that prevents the activation of inflammation-causing cells.

Calcium channel blockers such as Nifedipine and diltiazem, which relax the muscles in blood vessels, are also used commonly for this disease. They help manage Raynaud’s phenomenon, which is a condition that affects the blood supply to certain parts of the body, usually fingers and toes.

What else can Undifferentiated Connective Tissue Disease be?

Undifferentiated connective tissue disease is considered a diagnosis of exclusion. This means that the diagnosis is firmly established only after conducting an extensive investigation to rule out other similar diseases. Sometimes, the features of different connective tissue diseases can be same, which makes early identification necessary for the right treatment and monitoring. However, similar criteria between diseases can also make the diagnostic process more complicated for those who may have a connective tissue disease.

The following diseases are typically considered as part of this diagnostic process:

• Dermatomyositis
• Antiphospholipid syndrome
• Fibromyalgia
• Linear scleroderma and regional fibrosis
• Systemic lupus erythematosus (SLE)
• Overlap syndromes
• Mixed connective tissue disease (MCTD)
• Raynaud phenomenon
• Polymyositis
• Sjögren syndrome
• Systemic sclerosis
• Rheumatoid arthritis (RA)

What to expect with Undifferentiated Connective Tissue Disease

The outcome for patients with undifferentiated connective tissue disease largely depends on how far the disease has spread within their bodies. Despite this fact, up to 60% of cases will continue to remain undefined and others may eventually develop into a defined form of connective tissue disease.

Certain factors can help doctors predict if the disease might progress, such as reductions in certain types of blood cells found at diagnosis, changes in a specific test of the small blood vessels in the nails (known as the nail fold-capillaroscopy test), and high levels of certain proteins that the immune system creates to fight various diseases. All these factors may provide some hint as to how the disease will progress in the future.

It’s worth noting that 10 to 20% of patients diagnosed with undifferentiated connective tissue disease will not see their condition evolve into a defined disease. Instead, their symptoms may lessen or even go away completely. Generally, the chance of this disease progressing into a specific disease is highest within the first five years after onset, with the likelihood dropping over time. Those who do progress to a defined disease late in their journey often have a milder experience with the disease and are less likely to develop complications. Their survival rates appear similar to those seen in patients with systemic lupus erythematosus and rheumatoid arthritis — two other types of autoimmune disorders.

There’s also a need to provide patients with better clarity and understanding of the disease. As per a recent study in 2019, clear guidelines or recommendations concerning undifferentiated connective tissue disease haven’t been defined yet. Also, the uncertainty regarding the disease name often leaves patients feeling unsure about how to understand and manage their condition.

Possible Complications When Diagnosed with Undifferentiated Connective Tissue Disease

Undifferentiated connective tissue disease is a type of autoimmune disease, which can affect any connective tissue in the body. This means that it can cause a variety of different symptoms.

One of the main challenges with this disease is figuring out if it will progress into a more clearly defined connective tissue disease, and when this might happen. While this disease can stay stable for a long time and usually needs only minor treatment, it can still significantly impact a patient’s quality of life.

What complications occur depend on which system in the body is affected. For example, if the lungs are affected over a long period, it can lead to interstitial lung disease or even lung fibrosis. If the heart is damaged, it can become enlarged, leading to a condition called cardiomegaly. Up to 40% of patients can progress into a more clearly defined connective tissue disease.

Severe complications, like nerve or kidney damage, or even life-threatening conditions, can sometimes happen. Severe lung complications can also occur. Additionally, around 88% of patients with a certain type of lung disease called idiopathic nonspecific interstitial pneumonia can also meet the criteria for undifferentiated connective tissue disease.

In terms of the disease’s progression, it’s rare for it to evolve into a specific disease, like systemic lupus erythematosus, especially if the patient’s condition has been stable for over three years. Certain symptoms, like sensitivity to light, Raynaud’s phenomenon, and sicca symptoms, are associated with a lower likelihood of the disease becoming systemic lupus erythematosus.

Some patients may be diagnosed with a dormant form of lupus if they don’t meet the full criteria for systemic lupus erythematosus. Pregnant women with undifferentiated connective tissue disease need close monitoring, as the disease can worsen or progress during pregnancy. Most pregnant patients with this disease will continue to have it throughout the pregnancy, but around 25% will develop a more specific connective tissue disease by the end of the pregnancy. Furthermore, nearly half of these pregnancies result in premature birth.

Main Complications:

• Interstitial lung disease
• Lung fibrosis
• Cardiomegaly (heart enlargement)
• Progression to a defined connective tissue disease
• Nerve or kidney damage
• Life-threatening health conditions
• Pregnancy complications and premature birth

Preventing Undifferentiated Connective Tissue Disease

Identifying connective tissue disease early and being well-informed about it can help patients manage their condition in the best possible way.

Patients should be educated about the common causes and factors that might worsen their symptoms. This knowledge can help them handle their symptoms better.

It’s also important to teach patients about the symptoms that need immediate medical help. Being aware of this can help patients ease their discomfort, shorten the time they are sick, and stop any complications from happening.