Undifferentiated Connective Tissue Disease

The terminology Undifferentiated Connective Tissue Disease is used in describing conditions or disorders in people who present symptoms and are diagnosed with a systemic autoimmune disorder or connective tissue disease, but which do not meet enough criteria to be indicated as a well-defined connective tissue disease.

Simply put, an undifferentiated connective tissue disease is an autoimmune condition that is not well-defined but shows similar characteristics as any other connective tissue disease such as scleroderma, rheumatoid arthritis, and systemic lupus erythematosus.

An autoimmune disorder is a severe condition where the body begins to produce antibodies to attack its tissue. The word “Undifferentiated.” may sound very ambiguous, but it points to a severe illness.

The term is often used interchangeably with “mixed connective tissue disease,”; a syndrome of overlapping connective tissue diseases.

Mixed connective tissue disease was first introduced in 1973; more research led to the emergence of a new term and was first explored in 1980 by LeRoy.

At that time, physicians used the name for patients recognized as being in the early stages of a connective tissue disease but who did not yet meet the complete criteria for a well-defined connective tissue disease.

It was also observed at that time that the majority of these patients either remained undifferentiated or experienced.

a disease remission and never evolved into a more defined disease. In the early days of UCTD, other names were used to describe the condition in these patients, such as “latent lupus and “incomplete lupus erythematosus,” which meant that some symptoms suggestive of lupus were present, but not just enough to confirm the diagnosis.

Over time, much research has been conducted on persons suspected of undifferentiated connective tissue disease conditions to identify markers in the blood that may predict who will eventually develop a well-defined connective tissue disease.

Secondly, to indicate the disease’s progression, whether the disease may disappear, or remain unchanged, or even get worse. Less

than 20% of patients with undifferentiated connective tissue disease develop a definite connective tissue disease. As many as 1 in 3 may experience remission of symptoms, and others continue with generally mild disease in the undifferentiated form.

Classification of Undifferentiated Connective Tissue Disease

Undifferentiated connective tissue diseases (autoimmune connective tissue disease) according to conditions developed by ARC (America College of Rheumatology) and EULAR (European League Against Rheumatism), may be classified into:

  • Early Raynaud’s phenomenon
  • Early Inflammatory arthritis (that is not classified as rheumatoid arthritis)
  • Early Scleroderma
  • Some manifestations are the same as inflammatory myopathy, Sjogren’s Syndrome, Systemic lupus erythematosus, serositis, vasculitis, or interstitial lung disease, which do not meet diagnostic criteria for each of them.


The etiology of undifferentiated connective tissue disease has not yet been identified. But what is known is that it is a type of autoimmune disease, meaning to state that it is a condition where the immune system malfunctions and attacks the healthy tissues of a person.

However, like many other autoimmune conditions, its origin is unknown. Scientists suspect that there is both a genetic and an environmental trigger factor that interacts to cause the development of UCTD in an individual.

Risk Factors of Undifferentiated Connective Tissue Disease

“Undifferentiated connective tissue disease, just like many other autoimmune diseases, mostly affects young women who get diagnosed between age 15 and 35.” This was a statement by Terry Moore, MD, a rheumatologist and professor at the Dept. of Internal Medicine (DIM), division of rheumatology, Saint Louis University School of Medicine. And one is not confident as to why this is so. 

Aside from this observed pattern, there is no recorded risk factor for undifferentiated connective tissue disease, and there is an absence of any epidemiology study to date regarding the condition.

However, it is estimated that UCTD represents about 60% of connective tissue disease with undifferentiated onset.

Symptoms of UCTD

Signs and symptoms of undifferentiated connective tissue disease widely vary from patient to patient as the disease is by label “nonspecific.”

Typical; symptoms include constitutional complaints that are mostly common with connective tissue diseases, such as the general sense of feeling unwell, fatigue, and fever.

Other non-constitutional symptoms include:

  • Dry mouth and eyes
  • Hair loss
  • Inflammation of the joints
  • Joint pains
  • Oral ulcer
  • Raynaud’s phenomenon
  • Sun sensitive rash
  • Positive ANA (antinuclear antibodies) test

Clinical presentation in some persons diagnosed with UCTD may present:

Diagnosis of Undifferentiated Connective Tissue Disease

The first approach in the diagnosis of undifferentiated connective tissue disease is examining the medical history of the patient, and laboratory tests are then conducted to exclude the possibility of other rheumatic diseases.

Some significant laboratory indications of undifferentiated connective tissue disease include leukopenia, C-Reactive protein, antinuclear antibodies, anti-Ro/SSA antibodies, anti-DNA antibodies, erythrocyte sedimentation rate, and anti-RNP antibodies.

A deviation for the expected levels of these named indicators in the blood may suggest an undifferentiated connective tissue disease condition.

Rheumatologists may also order X-rays to observe joint damage, which serves as one of the hallmarks of both rheumatoid arthritis and UCTD, although this is not as common in UCTD as it is in CTD. CT scan can also be conducted to observe any organ or tissue damage.               

Treatment of Undifferentiated Connective Tissue Disease

Pharmacological treatment of undifferentiated connective tissue disease is typically directed at managing the symptoms, and these medical therapies are recommended based on rheumatic disease patterns.

Treatments primarily consist of some combinations of analgesic and NSAIDs (non-steroidal anti-inflammatory drugs) to minimize pain, and also medications such as corticosteroids are used for managing the affected areas on the skin and mucous tissue.

In some cases, hydroxychloroquine (Plaquenil), a disease-modifying anti-rheumatic drug, is employed. Also, in cases where improvement is insufficient, oral prednisone is administered in low doses for a short period of treatment time.

For hard-to-treat cases of undifferentiated connective tissue disease, methotrexate may be an option, primarily in patients exhibiting dermatitis and arthritis.

Other supportive therapies that may be recommended include avoiding the sun in photosensitivity, use of sunscreen, avoiding exposure to cold in those experiencing Raynard’s phenomenon, use of emollients for dry skin and rash.


Few experienced complications that can arise during a case of UCTD include:

  • Interstitial lung disease
  • Atherosclerosis
  • Nonspecific interstitial pneumonia

For preventive measures, there is not yet an established measure for the prevention of undifferentiated connective tissue disease.

Undifferentiated Connective Tissue Disease (UCTD) vs. Mixed Connective Tissue Disease (MCTD)

Both conditions may sound the same and may even sometimes be used interchangeably, but they are different. Patients with undifferentiated connective tissue diseases (UCTD) experience some symptoms of various connective disorders such as arthritis or muscle pain and positive ANA antibodies. Still, they do not meet the criteria to make an official diagnosis.

On the other hand, patients with mixed connective tissue diseases (MCTD) present overlapping symptoms of three various autoimmune rheumatic disorders: Scleroderma, lupus, and myositis. Patients of MCTD have features of all three conditions either at the same time or overtime.


Not minding the symptoms presented by undifferentiated connective tissue disease, a future disease outlook is surprisingly good. An undifferentiated connective tissue disease has a low risk of progression to a well-defined connective tissue disease. Some patients have experienced unchanged UCTD for more than five years. Most cases remain mild, and features are mostly treated without the need for heavy immunosuppressants.