Undifferentiated Connective Tissue Disease – In-Depth Overview

What is undifferentiated connective tissue disease?

The term "undifferentiated connective tissue disease" (UCTD) is used to describe a condition in people who have symptoms and lab test results which suggest a a systemic autoimmune disorder or connective tissue disease but which are not extensive or specific enough to meet usual criteria for a diagnosis of a defined connective tissue disease such as systemic lupus erythematosus (lupus), rheumatoid arthritis, systemic sclerosis (scleroderma), Sjogren’s syndrome, or myositis.

The term "undifferentiated connective tissue disease" was first used in the 1980s to identify people who were recognized as being in the early stages of, but who did not yet meet the standard criteria for, a defined connective tissue disease.1 At that time, it was noted that a substantial proportion of these patients either remained “undifferentiated” or experienced a disease remission and never developed a defined connective tissue disease. Other names used early on to describe some of these patients included "latent lupus" and "incomplete lupus erythematosus.”2 While many patients with UCTD have symptoms that are also seen in lupus, others have symptoms more characteristic of a different defined connective tissue disease, which is why we prefer to use the term “UCTD.” There is also more recent evidence to suggest that stable UCTD may in fact be a distinct disease process, as opposed to an early phase of a defined connective tissue disease.3,4

Although the word "undifferentiated" sounds vague, it describes a real problem and one that is quite common 5. In fact, as many as a quarter of all patients seen by rheumatologists have UCTD. It does not mean that a doctor does not know what to call the condition, it just means that some or all of the clinical features traditionally seen in defined connective tissue disease are not present.

UCTD is different from another group of vague-sounding disorders called “overlap syndromes,” and from “mixed connective tissue disease” (MCTD), which is a term used to describe a more specific pattern of overlapping symptoms. Rheumatologists and scientists do not all agree on a precise definition for overlap syndromes. In general, these two terms are used when patients have clear features of at least two defined connective tissue diseases, and thus may have more than one diagnosis at the same time.

What are the causes of undifferentiated connective tissue disease?

The actual pathogenesis, or cause, of UCTD, like that of many rheumatic diseases, is not well understood. UCTD is difficult to study because it affects people with so many different symptoms and blood markers. One theory is that some people have a genetic predisposition or risk of developing connective tissue disease and then experience an environmental trigger, such as an infection. This then leads the immune system to incorrectly target the body itself as if it is a “foreign invader” (as it is designed to target harmful bacteria in the context of infection). It is presumed that many of the same immunologic mechanisms that play a role in defined connective tissue diseases like lupus or rheumatoid arthritis may be involved. However, precisely which of these elements are involved in UCTD, and in what ways, remains unknown. We do know that, like other rheumatic diseases, UCTD is not contagious.

What are the symptoms of undifferentiated connective tissue disease?

The most common symptoms of UCTD are:

• Arthralgia – joint aches.
• Arthritis – joints that are tender, swollen, and warm.
• Raynaud’s phenomenon – extreme color changes in the hands and feet in response to cold.
• Xerophthalmia – dry eyes due to decreased tears.
• Xerostomia – dry mouth due to decreased saliva.
• Photosensitivity – development of rashes or other symptoms after being in the sun
• Pleuritis or pericarditis – inflammation of the lining surrounding the lungs or heart, respectively, which may cause pain in the chest especially with deep breathing.
• Rashes, usually on the face, which can worsen after being in the sun.
• Oral ulcers – sores inside the mouth.

The majority of people with UCTD do not develop major organ damage (such as problems with the kidneys, liver, heart, lungs, brain) or a life-threatening disease. The hallmark of UCTD is its mild course and low likelihood of progression to a more serious condition.6

What blood tests are associated with undifferentiated connective tissue disease?

Several blood tests may be ordered to help make a diagnosis, including those that measure levels of certain types of blood cells as well as tests for antibodies and other immunologic factors.

Hematologic

Laboratory tests in people with UCTD may show decreased levels of certain blood cells, including:

• White blood cells – cells that help fight infection (“leukopenia” is the term for low white blood cells).
• Red blood cells – cells that carry oxygen to tissues in the body (“anemia” is the term for low red blood cells).
• Platelets – component of blood that help with forming clots (“thrombocytopenia” is the term for low platelet levels).

These abnormalities are relatively common in UCTD but rarely severe enough to cause symptoms or require treatment.6

Immunologic

A broad range of immunologic abnormalities (markers in the blood that the immune system may not be functioning properly) can be seen in people with UCTD, including:

• Antinuclear antibodies (ANAs) – markers in the blood that may indicate your immune system is misidentifying parts of your body as harmful. The majority of people with UCTD have a positive ANA test. However, many people who do not have UCTD or a defined connective tissue disease have low levels of ANA in their blood. This is not always a sign of disease.
• Other antibodies that can also be associated with defined connective tissue disease: anti-double-stranded DNA (anti-dsDNA), anti-Ro/SSA, anti-La/SSB, anti-Smith (anti-SM), anti-RNP, rheumatoid factor (RF), anti-centromere, anti-Scl-70, or antiphospholipid antibodies.
• Nonspecific markers in the blood that indicate inflammation in the body: elevated erythrocyte sedimentation rate (also known as ESR or “sed rate”) or C-reactive protein (also known as CRP).
• Decreased level of complement (commonly referred to as C3 and C4) – proteins that help fight bacteria and other cells (“hypocomplementemia” is the term for low complement levels)

It is always wise for patients to discuss the meaning of laboratory test results with their doctors. A result that is flagged as “positive” or “abnormal” may or may not be of clinical concern, depending on the patient and the specific context.

How is undifferentiated connective tissue disease diagnosed?

UCTD is diagnosed by a doctor when a patient’s symptoms and blood test results fit the common patterns rheumatologists see in this disease. What the patient tells us, rather than any one specific test, is most important. If new symptoms develop, this diagnosis may be reconsidered.

Diagnosis versus classification

Diagnostic criteria are the list of problems that a doctor looks for to make a clinical diagnosis. Classification criteria are the list of problems scientists use to determine which patients with a given diagnosis are eligible for research studies; these tend to be stricter because studies may require a more homogeneous group of patients to answer a specific research question. It is possible to have a given diagnosis without meeting classification criteria for the disease.

There are no commonly accepted diagnostic or classification criteria for UCTD, as there are for other defined connective tissue diseases.7 A preliminary set of classification criteria has been proposed,2 some version of which is commonly used for UCTD research.

Preliminary classification criteria for UCTD

1. Signs and symptoms suggestive of a connective tissue disease, but not fulfilling the criteria for any of the defined connective tissue diseases, for at least three years.
2. The presence of antinuclear antibodies (ANAs) identified on two different occasions.

Differential diagnosis

Differential diagnosis is the process by which a doctor reviews all possible causes of a patient’s symptoms to determine which disease is the most likely cause. There are many different diseases that can cause symptoms similar to those of UCTD, but which might require different treatment, so it is very important to consider and rule out alternatives in order to make a diagnosis of UCTD. Doctors do this by conducting a thorough history, physical exam, and laboratory evaluation.

Other defined connective tissue diseases that may be considered in the differential diagnosis for UCTD include: lupus, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, and myositis (most commonly dermatomyositis or polymyositis).

(Find a specialist at HSS at HSS who treats undifferentiated connective tissue disease.

What is the treatment for undifferentiated connective tissue disease?

There are no treatments that are approved specifically for use in patients with UCTD. The medications that physicians commonly use for UCTD are those that are effective for treating defined connective tissue diseases. The specific choice of medication for a given patient with UCTD is based primarily on the symptoms that patient is experiencing. These might include:

1. Analgesics (pain relievers such as acetaminophen) and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen for joint and muscle aches or pains.
2. Topical corticosteroids (creams, lotions or gels that have anti-inflammatory action) for rashes.
3. Hydroxychloroquine (also known as Plaquenil) which modifies the immune system and may help with joint pain, rashes, oral ulcers, and other symptoms.

It is unknown whether a particular therapy might decrease the risk of disease flare or of evolution to a defined connective tissue disease. Some data suggest that treatment with hydroxychloroquine may decrease the risk or delay possible progression of UCTD to lupus, but this has not yet been confirmed in randomized controlled trials.8,9

For other symptoms that are not addressed by these medications, doctors may prescribe oral corticosteroids such as prednisone or methylprednisolone (usually at low doses for short periods of time). In very rare cases, higher doses of corticosteroids or other immunosuppressive medications (such as methotrexate, azathioprine, mycophenolate, leflunomide, sulfasalazine, or others) may be used.

What is the prognosis for someone with undifferentiated connective tissue disease?

A prognosis is a prediction about the likely course of a disease. Overall, patients with UCTD have an excellent prognosis.

Studies show that the majority of people with UCTD will not go on to develop a defined connective tissue disease. When this does occur, it is typically in the first five years after the onset of symptoms. Overall, the most common connective tissue disease that patients with UCTD develop is lupus. However, the nature of the symptoms may predict which defined connective tissue disease a given patient is more likely to develop. Some people with UCTD will experience complete remission of their symptoms. The rest continue to have stable disease, usually with mild symptoms.10-14

Researchers have been studying people with UCTD to identify ways to predict which patients are more likely to develop a defined connective tissue disease, who will experience remission, and who will have stable disease. So far, this question has not been answered. However, some studies have found that certain clinical and laboratory features may be associated with an increased risk of developing defined connective tissue disease, including having high levels of ANA or other antibodies in the blood, low blood cell counts, and having abnormalities of the small blood vessels in the nailbeds (which are called nailfold capillaries and can be evaluated by a rheumatologist using a special microscope, called a dermatoscope).11,13

Although patients with UCTD typically do not have major organ damage or severe symptoms that require long-term immunosuppressive medications, they often suffer from fatigue, depression, and anxiety which can lead to impaired quality of life.15,16 In a qualitative pilot study, we found that patients with UCTD experience challenges due to the disease itself, but also struggle with difficulty understanding the implications of the diagnosis and uncertainty about the future.17 As a result, we recognize the importance for patients to have access to a rheumatologist with expertise in this area as well as additional support services and educational resources.

Pregnancy considerations in UCTD

Like many systemic autoimmune and connective tissue diseases, UCTD commonly affects women of childbearing age. Many connective tissue diseases have remissions (periods of no symptoms) and flares (periods of increased symptoms that, in some cases, correspond with changes in blood tests), and pregnancy may impact this pattern. Some connective tissue diseases (most notably, lupus) are known to increase patients’ risks of certain pregnancy complications.

Early studies of pregnancy in patients with UCTD suggest that, while the vast majority of patients had successful pregnancies and delivered at term, up to 25% of patients may experience a flare of their disease during pregnancy or in the post-partum period. Symptoms are typically mild and manageable. In rare cases, disease flares during pregnancy can be more severe and lead to a diagnosis with defined connective tissue disease18,19

More recent studies have provided additional insight into potential risk factors for disease flare and complications of pregnancy in patients with UCTD. Having double-stranded-DNA antibodies (based on blood tests done at the beginning of pregnancy) may be associated with an increased risk of disease flare during,20 and having antiphospholipid antibodies may be associated with an increased risk of spontaneous pregnancy loss (miscarriage or stillbirth) in patients with UCTD.21 One study found that patients with UCTD were less likely to have premature delivery and preeclampsia (a common complication of pregnancy) than patients with highly active lupus, but the frequency of these complications was similar to that seen in patients with less active lupus.22

Taken together, current research suggests it may be important for your rheumatologist to check certain laboratory tests before you get pregnant, or early on in pregnancy, and to closely monitor your condition during and after pregnancy.

(Find a specialist at HSS who treats undifferentiated connective tissue disease.)

Updated: 3/1/2022

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References

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