The term "undifferentiated connective tissue disease" (UCTD) is used to describe a condition in people who have symptoms and lab test results that indicate a systemic autoimmune disorder or connective tissue disease, but which do not meet enough such characteristics to indicate a diagnosis for a well-defined connective tissue disease such as rheumatoid arthritis, systemic lupus erythematosus (lupus) or scleroderma. Thus, they seem to have another, similar disorder that doctors call undifferentiated connective tissue disease.
Although the word "undifferentiated" sounds vague, it describes a real problem. It does not mean that a doctor does not know what to call the condition, it just means that all or most of the clinical features (problems) traditionally seen in lupus or another connective tissue disease aren't present but some of those features are present.
This undifferentiated category is distinctly separate from another group of vague-sounding disorders called overlap syndromes. People with overlap syndromes have the clear features of at least two or more CTDs, and thus may meet the diagnoses for several at the same time. (Rheumatologists and scientists do not all agree on a precise definition for "overlap syndrome." In general, this term refers to a condition in which a patient has symptoms of two or more recognized autoimmune diseases.)
In contrast, patients with UCTD do not have enough of the features of a definite CTD (systemic lupus, systemic sclerosis, or dermatomyositis/polymyositis) to be firmly classified with such a diagnosis. However, because they may have a few features from several known diseases, they are said to be "undifferentiated." (See Fig. 1)
The term "undifferentiated connective tissue disease" was first used in 1980s to identify people who were recognized as being in the early stages of a CTD but who did not yet meet the standard criteria for a well-defined CTD. At that time, it was noted that a substantial proportion of these patients either remained undifferentiated or experienced a disease remission and never evolved in to a more defined rheumatic disease. Other names used early on to describe some of these patients included "latent lupus" and "incomplete lupus erythematosus," which meant that some features suggestive of lupus were present, but not enough to confirm the diagnosis. As many as a quarter of all patients seen by rheumatologists have UCTD.
Many researchers have been studying people with UCTD to identify serologic profiles (markers in the blood) that may predict who will eventually develop a well-defined connective tissue disease. They are also looking for markers to help predict whether the disease may go away, remain unchanged or get worse. It is currently believed that less than 20% of patients with UCTD go on to develop a definite connective tissue disease. As many as one in three will experience a remission of their symptoms. The rest continue with generally mild disease in the undifferentiated form.
Pathogenesis refers to the origin and development of a disease. The actual cause of UCTD, like many rheumatic diseases, is not well understood. Indeed, there have been no rigorous attempts to define the basic science of UCTD. It is presumed that many of the same immunologic mechanisms that play a role in lupus and rheumatoid arthritis may be involved. One theory is that some people have a genetic predisposition that is subsequently triggered by an environmental factor, such as an infection, that is then improperly responded to by the immune system. This in turn causes the immune system to incorrectly react and target the tissues of one's body instead of foreign invaders (such as harmful bacteria). Precisely which of these elements may be involved in UCTD remains unknown. UCTD is very difficult to study because it includes a heterogeneous population – people with so many different symptoms and blood markers. UCTD is not contagious.
In the patient studies conducted so far, the most common symptoms of UCTD are:
Some people also develop:
Problems with the kidneys, liver, lungs or brain are almost unheard of in UCTD.
The overwhelming majority of people with UCTD do not develop major organ damage or a life-threatening disease. The hallmark of UCTD is its mild course and low likelihood of progression to a more serious state.
"Criteria" are the list of problems that a doctor looks for to make a diagnosis. There are no commonly accepted criteria yet for UCTD, as there are for many other rheumatic diseases. However, a preliminary set of criteria has recently been proposed (see "Mosca" in annotated bibliography below):
At the present time, UCTD is diagnosed clinically by a doctor when the symptoms, lab results and history fit the common patterns doctors see in relation to this disease. It is not based on meeting a checklist of required criteria alone. As doctors develop more specific criteria for UCTD, however, it will be easier to study the disease and learn about its causes and best treatments.
Some markers in your blood indicate possible abnormal function of your immune system. While most studies note that the majority of patients with UCTD have ANAs, a broad range of immunologic abnormalities can be seen in people with UCTD. These may include:
As noted above, several blood disorders – thrombocytopenia, leukopenia, and anemia – may also occur in patients with UCTD. They are rarely severe enough to require treatment alone.
Research has attempted to determine which, if any, of the laboratory test findings may predict the evolution of UCTD to lupus or other connective tissue diseases.
In a study of 148 patients who had detectable anti-Ro/SSA antibodies and a diagnosis of UCTD for at least one year, leukopenia was more frequent in those patients who ultimately developed a defined connective tissue disease. Anti-dsDNA antibodies were predictive of evolution to SLE (lupus). However, the majority of patients in this study who developed a connective tissue disease were eventually diagnosed as having primary Sjogren's syndrome (50%) – which is notable for dry eyes and dry mouth.
Another study found that anti-RNP antibodies were significantly correlated with Raynaud's phenomenon and arthritis. Anti-Ro/SSA antibodies also correlated with dry eyes and dry mouth. Most interestingly, 82% of those studied were found to have a simple autoantibody profile characterized by a single specificity. The serologic profile of these UCTD patients remained unchanged in follow-up.
Among those UCTD patients with features more suggestive of lupus (termed "incomplete lupus"), it has been noted in a group of 87 patients that elevated dsDNA and decreased C4 (one type of complement) were associated with subsequent development of lupus. Others have noted that the presence of homogeneous ANA (one of several "patterns" of ANA that are seen in the microscope) and presence of anti-Sm antibody predicted the development of lupus.
One physical finding which is thought to predict the evolution to a defined CTD is the presence of abnormalities in the capillaries (the tiniest blood vessels) in the folds of fingernails or toenails. One study followed 43 patients with UCTD; it found that 23% of those with abnormal capillaries progressed to definite scleroderma (also called systemic sclerosis). Similar studies have suggested that the rate of progression might be even higher. (A person who is worried about this can have a doctor can examine the nailfolds under a microscope.) However, nailfold capillary abnormalities have been seen in many other diseases, such as dermatomyositis, lupus, Sjogren's syndrome and psoriasis.
A study conducted more recently on 94 patients found that arthritis, Raynaud's phenomenon and the presence of photosensitivity were predictors for the development of CTD. Only 13 patients (13.8%) evolved into a defined connective tissue disease with 8.5% developing systemic lupus erythematosus, 4.2% Sjogren's syndrome and 1.1% rheumatoid arthritis. In follow-up, almost all patients had a favorable outcome regardless.
It is always wise for patients to discuss laboratory tests with their doctors, and to ask for explanations about what those tests mean. Patients may want to ask for copies of their test results to keep in a folder at home so they can see how the results change – or do not change – over time.
Many different diseases can cause symptoms similar to those of UCTD. Differential diagnosis is the process by which the physician determines which condition is causing the symptoms. This is important because diseases that may cause such symptoms are often treated in a very different manner from UCTD.
Other well-defined connective tissue diseases that need to be considered in the process of differential diagnosis include: rheumatoid arthritis, systemic lupus erythematosus (lupus), myositis, Sjogren's syndrome, and scleroderma. Diffuse body pain without other objective features, even in the presence of a positive ANA, is more strongly evidence of fibromyalgia than an autoimmune or connective tissue disease.
A thorough history, exam and laboratory evaluation to rule out these other rheumatic diseases is important. In this sense, the diagnosis of UCTD is one of exclusion. When the suspicion of an autoimmune disease is high in a patient because several features of one or more of these diseases is present, but signs and symptoms are insufficient to meet their criteria, UCTD is diagnosed. However, the threshold for reconsideration of a more definite CTD must be low if and when new symptoms present in such patients. As with most of the problems rheumatologists see, what the patient tells us, rather than any one specific test, is most important in making a diagnosis.
(Find a specialist at HSS who treats undifferentiated connective tissue disease.)
No formal study of various treatments in patients with UCTD has been conducted. Most therapies used are ones physicians have found to be effective in other connective tissue diseases. However, it is unknown to what degree a particular therapy improves the symptoms of UCTD or decreases the rate of flare or the likelihood of evolution to a more defined connective tissue disease.
Most therapies are symptomatic and include:
For symptoms that don't respond to these drugs, the physician may occasionally prescribe low dose corticosteroids in pill form (such as prednisone) for short periods of time. High doses of corticosteroids, other immunosuppressives (such as azathioprine, brand named Imuran) and cytotoxic agents (such as cyclophosphamide, brand named Cytoxan), are almost never used.
However, there is one interesting study of another immunosuppressive drug, methotrexate (Rheumatrex) that evaluated its use in lupus patients who did not have kidney disease and in 15 UCTD patients whose most common clinical findings were positive ANA, nonerosive polyarthritis, and Raynaud's phenomenon. Overall efficacy was noted in 53% of patients, including 6 out of 10 with arthritis; 60% had side effects, with 33% discontinuing the drug. It is possible that this drug may be useful for hard-to-treat joint and skin problems in some cases.
One study of 25 pregnancies in 20 patients with the diagnosis of UCTD for at least one year showed 22 pregnancies were successfully brought to term. Complications were observed in 6 out of 22 of the successful pregnancies, but these complications were mostly restricted to early deliveries and lower birth weights. Some systemic autoimmune diseases tend to have alternating remissions (periods of no symptoms) and flares (periods of increased disease activity). In this pregnancy study, flares of UCTD were seen in six patients, with symptoms including arthritis, fever, and skin rash. One patient developed systemic lupus erythematosus. The flare rate was higher than the incidence of flares in a control population of non-pregnant UCTD patients.
A study in 2011 assessing pregnancy outcomes in 55 UCTD patients showed that the mean duration of the successful pregnancies was 38.6 weeks. Miscarriage was rare, found in only three pregnancies (5.4%). In 16 patients (32%) their disease flared during pregnancy or in the six months after delivery. Of these, five went on to develop a well-defined CTD after the delivery.
These studies suggest that your condition should be closely monitored during and after pregnancy.
Thyroid disease, especially hypothyroidism (an underactive thyroid gland), is a common autoimmune condition which can be seen more frequently in patients with other autoimmune diseases, such as lupus and rheumatoid arthritis. One small study of 75 patients with UCTD showed that thyroid disease was present in 6%, suggesting that monitoring for the occurrence of thyroid disease by a doctor may be appropriate.
A prognosis is a forecast about the likely course of a disease. Patients with UCTD have an excellent prognosis. Almost all studies to date indicate a low likelihood of progression to any involvement of organs such as the kidney, lungs or brain. Less than 20% of patients go on to develop a well-defined connective tissue disease, but the data suggests that this becomes much less likely if the disease has been present unchanged for more than five years.
In a substantial proportion of patients, the disease is mild and no treatment is needed. Rarely, in some people, the symptoms can go away completely. The majority of patients can be treated symptomatically, and very few patients ever require the use of immunosuppressive medications.
If your primary care physician suspects that you may have UCTD – or if you are believed to have any other systemic autoimmune or connective tissue disease – you should be seen by a rheumatologist for evaluation and to confirm the diagnosis. Consultation with a rheumatologist is important to exclude the presence of any other definite connective tissue disease and get appropriate treatment to lessen the likelihood of progression.
Once your symptoms have stabilized with effective medical management, ongoing monitoring should be done at least twice a year by the rheumatologist. Checking kidney and liver function and blood counts several times a year is usually sufficient unless new symptoms develop. Any new symptoms should be promptly evaluated to rule out evolution to a well-defined connective tissue disease that merits more aggressive treatment.
(Find a specialist at HSS who treats undifferentiated connective tissue disease.)