Scleroderma and Mixed Connective Tissue Disease

By Coburn Hobar, M.D., Rheumatology Fellow, and Arnold Postlethwaite, M.D., Professor of Medicine and Director, Division of Connective Tissue Diseases, University of Tennessee Health Science Center, Memphis, Tennessee, and Department of Veterans Affairs Medical Center, Memphis, Tennessee (originally published in "Scleroderma Voice," 2003 #1)

Introduction
In the early phases, scleroderma can be difficult to diagnose because it can be confused with other rheumatic diseases including rheumatoid arthritis (RA), systemic lupus erythematosis (SLE), polymyositis (PM), and mixed connective tissue disease (MCTD).

In this article, we will review the features of scleroderma and MCTD and discuss how the diseases might be related.

Features of Scleroderma
Scleroderma, also known as systemic sclerosis (SSc), is a disease affecting connective tissue, the fibrous tissue that supports and unites various organs and tissues of the body.

There is a broad range of symptoms and varying degrees of severity from patient to patient.
Many physicians agree on classifying SSc into 4 subgroups:

  1. diffuse SSc (generalized scleroderma);
  2. limited SSc (formerly known as CREST syndrome);
  3. localized SSc (morphea); and
  4. SSc sine scleroderma (internal organs involved but not skin).

The average age at which symptoms begin is between 45 and 65 years, but SSc has been seen in all age groups from children on up. Overall it is three times more common in women than men.

The exact cause of scleroderma is not known. It is suspected that an unknown inciting event triggers injury, probably to cells lining the blood vessels (small arteries).

There are also changes in the body’s immune system that cause the immune cells to react to body components including the connective tissue.

A major consequence of these so-called “autoimmune reactions” is stimulation of fibroblasts (cells that make collagen and other connective tissue components).

The net result is excessive accumulation of collagen and other connective tissue components in parts of the body such as skin, lungs, and walls of the arteries.

Common autoantibodies in scleroderma are the “FANA,” “Scl 70,” and “anti-centromere.”
A FANA is present in almost all scleroderma patients, whereas Scl 70 is more commonly seen in diffuse SSc and anti-centromere in limited SSc.

The thickening or excessive deposition of connective tissue is responsible for the clinical manifestations of SSc. The term scleroderma itself is derived from the Greek skleros meaning “hard” and derma meaning “skin.”

Characteristic Symptoms of Scleroderma
As the name suggests, the vast majority of patients develop thickening and hardening of the skin. In the early phase, the skin swells and the affected areas look puffy. Later the swelling subsides and the skin tightens.

Other skin changes can include changes in pigmentation, calcium deposits under the skin, and small red spots called telangiectasias.

Ninety percent of patients also have Raynaud’s phenomenon, in which exposure to cold causes blood vessels in the fingers and toes to constrict. The result is that the hands and feet turn white and then blue as circulation decreases, then red once they are rewarmed and circulation improves.

Other features of systemic sclerosis include muscle pains, joint pain and swelling, and weakness.

Over 80% of patients have problems with the digestive tract, and any part of the digestive pathway can be affected.

Lung involvement, seen to some extent in most patients, can be severe. The most common symptom is shortness of breath and often dry cough. This is secondary to deposition of excessive connective tissue in the lungs (fibrosis) interfering with exchange of oxygen and carbon dioxide. High blood pressure in the blood vessels of the lungs, called pulmonary hypertension, is a serious complication that can lead to death. It is seen more commonly in limited SSc, whereas lung fibrosis is more common in diffuse SSc.

There can also be heart disease with an abnormal rhythm; inflammation, fluid, and thickening around the heart; and heart failure. Kidney disease can result in dangerously high blood pressure and failure of the kidneys to function properly.

Undifferentiated Connective Tissue Disease (UCTD)
Patients often start with vague symptoms such as Raynaud’s phenomenon, fatigue, and joint pains. At this point it is difficult to make a definite diagnosis; the term undifferentiated connective tissue disease (UCTD) may be used.

Over time these patients generally develop more features of a particular disease and a clearer diagnosis can be made.

Mixed Connective Tissue Disease
In some cases there may be symptoms of more than one disease present, such as Raynaud’s and swelling of the skin of the hands as in SSc, rash and joint disease like SLE, and muscle pain and inflammation like PM. In these cases the term MCTD is used.

These patients have an autoantibody called “anti-U1 RNP” detectable in their blood.

Is MCTD a Unique Illness or an Early Stage of Another Disease?
There is controversy about whether MCTD is a unique illness or whether it is actually an early stage of one of the above mentioned diseases. Some studies have found that patients who originally were diagnosed with MCTD often over time develop predominantly the features of one disease.

However, other studies have disputed this. Some researchers have suggested that since some symptoms respond well to treatment such as steroids, only those that do not respond well remain. The features that do not respond are often those consistent with scleroderma, and therefore after treatment with steroids the clinical picture may well resemble scleroderma. This is an area of ongoing debate among physicians and researchers who work with these illnesses.

In cases where there is evolution to a particular disease, there does appear to be some difference in course of disease in people who have the U1-RNP antibody versus those who do not.

It has been noted that even in patients who appear to evolve into systemic lupus erythematosis (SLE), they rarely develop the severe kidney and central nervous system (seizures, psychosis) features that can be seen with SLE. It has also been found that most of these patients have Raynaud’s phenomenon and that they are more likely to die of pulmonary hypertension, as in limited SSc.

Conclusion
Overall, SSc is a chronic disease that can cause significant disability in many patients and that can be difficult to diagnose in its early stages. It is related to other autoimmune diseases and in early phases may resemble RA, SLE, UCTD, or MCTD.

There is still much to be learned about SSc. Researchers continue to study its causes and potential treatments.

References

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