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)
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| Arnold
Postlethwaite, M.D. |
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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:
- diffuse SSc (generalized scleroderma);
- limited SSc (formerly known as CREST syndrome);
- localized SSc (morphea); and
- 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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in Rheumatic Disease Clinics of North America, 1990 May;
16(1): 185–98.
- Black, C.M. “Systemic sclerosis: management,”
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edition), London: Mosby; 1998: 7.11.1–7.11.10.
- Burdt, M.A., Hoffman, R.W., Deutscher, S.L., Wang, G.S.,
Johnson, J.C., and Sharp, G.C. “Long-term outcome
in mixed connective tissue disease longitudinal clinical
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