- What is undifferentiated connective tissue disease?
- What are the causes of UCTD?
- What are the symptoms of UCTD?
- What blood tests are associated with UCTD?
- How is UCTD diagnosed?
- What is the treatment for UCTD?
- What is the prognosis for someone with UCTD?
- Pregnancy considerations in UCTD
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 laboratory test results that suggest:systemic autoimmune diseaseÖconnective tissuebut are not extensive or specific enough to meet the usual criteria for diagnosing a defined connective tissue disorder, such assystemic lupus erythematosus(Lupus),rheumatoide Arthritis, systemic sclerosis (scleroderma),Sjogren's Syndrome, ÖMyositis.
The term "undifferentiated connective tissue disease" was first used in the 1980s to identify individuals who were in the early stages of a defined connective tissue disease but did not yet meet standard criteria.1At that time it was found that a significant proportion of these patients remained "undifferentiated" or experienced remission of the disease and never developed definitive connective tissue disease. Other names used early on to describe some of these patients were "latent lupus" and "incomplete lupus erythematosus."2While many patients with UCTD have symptoms that are also seen in lupus, others have symptoms that are more characteristic of a connective tissue disease defined in another way, which is why we prefer to use the term "UCTD". There is also recent evidence that stable UCTD may actually be a disease process in its own right, as opposed to an early phase of defined connective tissue disease.3,4
Although the word "undifferentiated" sounds vague, it describes a real and fairly common problem.5. In fact, up to a quarter of all patients seen by rheumatologists have UCTD. That doesn't mean a doctor doesn't know what to call the condition, it just means that some or all of the clinical features traditionally seen in certain connective tissue disorders are absent.
UCTD is distinct from another group of vague-sounding disorders called "overlap syndromes," and from "mixed collagen disease" (MSCD), a term used to describe a more specific pattern of overlapping symptoms. Not all rheumatologists and scientists agree on an exact definition of overlap syndrome. In general, these two terms are used when patients have clear features of at least two defined connective tissue diseases and therefore 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, as with many rheumatic diseases, is not well understood. UCTD is difficult to study because it affects people with many different symptoms and blood markers. One theory is that some people have a genetic predisposition or are at risk of developing connective tissue disease and then experience an environmental trigger such as an infection. This causes the immune system to misguide the body itself as if it were a "foreign invader" (since it is designed to attack harmful bacteria associated with infection). It is hypothesized that many of the same immunological mechanisms may be involved that are involved in defined connective tissue diseases such as lupus or rheumatoid arthritis. However, exactly which of these elements are involved in UCTD and in what way is unknown. We know that UCTD, like other rheumatic diseases, is not contagious.
What are the symptoms of undifferentiated connective tissue disease?
The most common symptoms of UCTD are:
- Arthralgia: Pain in the joints.
- Arthritis: tender, swollen and hot joints.
- Raynaud's phenomenon: extreme color changes in hands and feet in response to cold.
- Xerophthalmia: dry eyes due to reduced tear fluid.
- Xerostomia: Dry mouth caused by decreased salivation.
- Photosensitivity: Development of a rash or other symptoms after exposure to the sun.
- Pleurisy or pericarditis: inflammation of the lining of the lungs or heart, which can cause chest pain, especially with deep breathing.
- Rashes, usually on the face, which may get worse after sun exposure.
- Mouth ulcers: sores in the mouth.
Most people with UCTD do not develop major organ damage (such as kidney, liver, heart, lung, brain problems) or life-threatening diseases. The hallmark of UCTD is its mild nature and little chance of progressing to a more serious condition.6
What blood tests are associated with undifferentiated connective tissue disease?
Various blood tests may be ordered to help make a diagnosis, including those that measure the levels of certain types of blood cells and tests for antibodies and other immune factors.
Laboratory tests in people with UCTD can show reduced levels of certain blood cells, including:
- White blood cells: Cells that help fight infection (“leukopenia” is the term for low white blood cell counts).
- Red blood cells: Cells that carry oxygen to the body's tissues ('anemia' is the term for low red blood cell counts).
- Platelets: A component of the blood that contributes to the formation of blood clots (“thrombocytopenia” is the term for low blood platelet counts).
These abnormalities are relatively common in UCTD but are rarely severe enough to cause symptoms or require treatment.6
A variety of immune abnormalities (markers in the blood that indicate the immune system may not be working properly) can be seen in people with UCTD, including:
- Antinuclear antibodies (ANA): Markers in the blood that may indicate that your immune system is misinterpreting parts of your body as harmful. Most people with UCTD have a positive ANA test. However, many people who do not have UCTD or a clear connective tissue disease have low levels of ANA in their blood. This is not always a sign of illness.
- Other antibodies that may also be associated with defined connective tissue diseases: anti-double-stranded DNA (anti-dsDNA), anti-Ro/SSA, anti-La/SSB, anti-Smith (anti-SM), anti-RNP, Rheumatoid factor (RF), anticentromere, anti-Scl-70 or antiphospholipid antibodies.
- Non-specific markers in the blood that indicate inflammation in the body: increasederythrocyte sedimentation rate(also known as ESR or “sed rate”) or C-reactive protein (also known as CRP).
- Decreased levels of complement (commonly known as C3 and C4): proteins that help fight bacteria and other cells ("hypocomplementemia" is the term for low complement levels)
It is always advisable for patients to discuss the meaning of laboratory test results with their doctor. A result labeled “positive” or “abnormal” may or may not be of clinical concern depending on the patient and the specific situation.
How is undifferentiated connective tissue disease diagnosed?
UCTD is diagnosed by a doctor when the patient's symptoms and blood test results match the usual patterns that rheumatologists see for the disease. More than a specific test, what the patient tells us is the most important thing. If new symptoms appear, this diagnosis can be reconsidered.
Diagnosis versus classification
Diagnostic criteria are the list of problems a doctor looks for in order to make a clinical diagnosis. Classification criteria are the list of problems scientists use to determine which patients with a particular diagnosis are eligible for research studies; these tend to be more rigorous, as studies may require a more homogeneous group of patients to answer a particular research question. It is possible to have a specific diagnosis without meeting the disease's classification criteria.
There are no universally accepted diagnostic or classification criteria for UCTD as for other defined connective tissue disorders.7A tentative set of grading criteria has been proposed,2Some versions of these are commonly used for UCTD research.
Preliminary classification criteria for UCTD
- Signs and symptoms suggestive of connective tissue disease but have not met criteria for any of the defined connective tissue disorders for at least three years.
- The presence of antinuclear antibodies (ANAs) identified on two separate occasions.
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 UCTD but may require different treatment, so considering and ruling out alternatives is very important to making a UCTD diagnosis. Doctors do this by taking a full medical history, physical exam, and laboratory evaluation.
Other defined connective tissue diseases that can be considered in the differential diagnosis of UCTD are: lupus, rheumatoid arthritis, scleroderma, Sjogren's syndrome and myositis (most commonlyDermatositiso Polymyositis).
(Find a specialistin HSS in HSS for the treatment of undifferentiated connective tissue diseases.
What is the treatment for undifferentiated connective tissue disease?
There are no treatments specifically approved for use in patients with UCTD. Medications commonly used by physicians for UCTD are those that are effective in treating defined connective tissue disorders. The specific choice of medication for a particular patient with UCTD is based primarily on the symptoms that the patient is experiencing. This can include:
- Pain relievers (painkillers such as acetaminophen) and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen for muscle and joint pain or discomfort.
- Topical corticosteroids (creams, lotions, or gels with anti-inflammatory effects) for skin rashes.
- Hydroxychloroquine (also known as Plaquenil), which modifies the immune system and may help with joint pain, rashes, mouth ulcers, and other symptoms.
It is not known whether any particular therapy might reduce the risk of disease worsening or progression to definitive connective tissue disease. Some data suggest that treatment with hydroxychloroquine may reduce the risk or delay the possible progression of UCTD to lupus, but this has yet to be confirmed in randomized controlled trials.8,9
For other symptoms not treated with these drugs, doctors may prescribe oral corticosteroids such as prednisone or methylprednisolone (usually in low doses for short periods of time). In very rare cases, higher doses of corticosteroids or other immunosuppressive drugs (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 of the likely course of a disease. In general, patients with UCTD have an excellent prognosis.
Studies show that most people with UCTD do not develop definitive connective tissue disease. When this occurs, it is usually within the first five years of symptoms onset. In general, lupus is the most common connective tissue disease that patients with UCTD develop. However, the nature of the symptoms can predict which particular connective tissue disorder a particular patient is most likely to develop. Some people with UCTD will experience complete remission of their symptoms. The remainder continue with stable disease, generally with mild symptoms.10-14
Researchers have studied people with UCTD to find ways to predict which patients are most likely to develop definitive connective tissue disease, which will go into remission, and which will develop 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 definitive connective tissue disease, including high blood levels of ANA or other antibodies, low blood cell counts, and abnormalities in the small blood vessels in the nail bed (known as nailfold capillaries). and can be examined 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 medication, they often experience fatigue, depression, and anxiety, which can result in reduced quality of life.15,16In a qualitative pilot study, we found that patients with UCTD face challenges because of the disease itself, but also struggle to understand the implications of the diagnosis and uncertainty about the future.17Because of this, we know how important it is for patients to have access to a rheumatologist with expertise in the field, 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 disorders have remissions (periods without symptoms) and exacerbations (periods with increased symptoms, sometimes accompanied by changes in blood counts), and pregnancy can change this pattern. Some connective tissue diseases (particularly lupus) are known to increase the risk of certain pregnancy complications in patients.
Early pregnancy studies in patients with UCTD suggest that although the vast majority of patients have had successful pregnancies and delivered at term, up to 25% of patients may experience a disease flare during or at the time of pregnancy. Symptoms are usually mild and manageable. In rare cases, flare-ups during pregnancy can be more severe and lead to the diagnosis of a definite connective tissue disorder.18,19
Recent studies have provided additional information on potential risk factors for disease worsening and pregnancy complications in patients with UCTD. The presence of double-stranded DNA antibodies (based on blood tests done early in pregnancy) may be associated with an increased risk of flare-ups during,20and the presence of antiphospholipid antibodies may be associated with an increased risk of spontaneous pregnancy loss (miscarriage or stillbirth) in patients with UCTD.21One study found that patients with UCTD were less likely to have preterm labor and preeclampsia (a common pregnancy complication) than those with highly active lupus, but the incidence of these complications was similar to those with less active lupus.22
In summary, current research suggests that it may be important for your rheumatologist to monitor certain laboratory tests before you become pregnant or early in your pregnancy, and to closely monitor your condition during and after pregnancy.
(Find an HSS specialistTreatment of undifferentiated connective tissue diseases).
Caroline H. Siegel, MD
Fellow in Rheumatology, Special Surgery Hospital
Dra. Jessica R. Berman
Resident, Special Surgery Hospital
Associate Professor of Medicine (Education), Weill Cornell Medical College
Medha Barbhaiya, MD, MPH
Senior Physician Assistant, Hospital for Special Surgery
Assistant Professor of Medicine, Weill Cornell Medical College
Pull. Lisa R. Sammaritano
Senior Physician, Hospital for Special Surgery
Professor of Clinical Medicine, Weill Cornell Medicine
- How to deal with the uncertainty of your lupus diagnosis
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Undifferentiated connective tissue disease (UCTD) is a systemic autoimmune disease. This means the body's natural immune system does not behave normally. Instead of serving to fight infections such as bacteria and viruses, the body's own immune system attacks itself.What is the prognosis for undifferentiated connective tissue disease? ›
Overall, patients with UCTD have an excellent prognosis. 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.What is undifferentiated connective tissue disease symptoms? ›
- Weight loss.
- Low-grade fevers.
- Joint pain.
- Joint swelling.
- Color changes of hands and feet with cold exposure (known as Raynaud's disease)
- Dryness of the eyes.
A patient with undifferentiated connective-tissue disease (UCTD) can be evaluated and treated primarily as an outpatient. Nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials (eg, hydroxychloroquine), and corticosteroids are the mainstay of therapy.Can undifferentiated connective tissue disease go into remission? ›
When Spanish researchers followed 98 UCTD patients for a number of years, they found that 62 percent of patients continued with a UCTD diagnosis, 24 percent went into remission, and 14 percent eventually got diagnosed with another connective disease. In Dr.How do you live with UCTD? ›
Most people with UCTDs live normal lives and need no treatment. Since it takes time for doctors to determine if your UCTD will turn into CTD, a healthy lifestyle is encouraged. Doctors may suggest getting flu or pneumonia vaccines to stay healthy. See your doctor regularly.How rare is undifferentiated connective tissue disease? ›
It can cause symptoms like joint pain and swelling, skin symptoms, and more. The exact prevalence of UCTD is unknown, but it's believed to be one of the more common conditions seen in rheumatology clinics. In fact, it may account for 10% to 20% of referrals to rheumatology specialists.Does UCTD qualify for disability? ›
Undifferentiated and Mixed Connective Tissue Disease (Section 14.06 of the SSA's Bluebook) – If you are diagnosed with undifferentiated and mixed connective tissue disease, you may be eligible for disability benefits if this disorder impacts more than one body part and result in at least two serious symptoms.