Pulmonary Arterial Hypertension in
Scleroderma: A New Treatment
By M. Kari Connolly, M.D., Associate Professor of Dermatology
and Medicine, University of California/San Francisco (originally
published in "Scleroderma Voice," 2002 #2)
Editor's note: This is a long article. You can skip
directly to the sections that interest you, by clicking on
these links:
Pulmonary arterial hypertension (PAH) is a serious, but potentially
treatable condition in patients with scleroderma (systemic
sclerosis). Because PAH occurs in scleroderma patients, it
is important to raise awareness of this potentially life-threatening
condition.
In this article, I will discuss PAH as a potential problem
for scleroderma patients, and introduce the echocardiogram
as a reasonable screening test for PAH.
I will also discuss diagnosis and treatment of PAH. In particular,
I would like to inform the scleroderma community about a new
FDA-approved treatment for symptomatic PAH. This new medication,
taken as a tablet, is called bosentan (Tracleer™).
Lung Involvement in Scleroderma
Scleroderma can cause serious complications in the lungs
in two major ways. The first and more common is interstitial
lung disease. The second is pulmonary arterial hypertension
(PAH).
Pulmonary arterial hypertension occurs when the blood vessels
that supply the lungs constrict, or tighten up. It is more
difficult for blood to get through to the lungs, and the heart
must pump harder to overcome the resistance.
As time passes, scarring (or fibrosis) of the vessels makes
them stiffer and thicker, and some may even become blocked.
The extra stress causes the heart to enlarge and become less
flexible. Less and less blood is able to flow out of the heart,
through the lungs, and into the body; and the symptoms of
PAH begin to show.
For these reasons, PAH is a very serious medical problem
with a poor prognosis.
Pulmonary Arterial Hypertension:
A Definition
Pulmonary arterial hypertension can occur all by itself,
without any apparent cause, in which case it is referred to
as primary pulmonary hypertension (PPH).
PAH can also occur associated with another disease, and in
that case is called secondary pulmonary hypertension. Scleroderma
is the most common cause of secondary PAH.
The precise number of patients with scleroderma who also
have PAH is not known. Estimates range from 10% to 60% of
scleroderma patients, depending on how PAH is measured and
defined.
Both the diffuse and the limited (the CREST syndrome) subsets
of scleroderma patient may develop PAH, but it is more common
in patients with limited scleroderma.
This situation is in contrast to interstitial lung disease,
in which the diffuse patient is affected more often. Some
patients may have both interstitial lung disease and PAH.
While interstitial lung disease often develops early in the
disease (within the first five years), PAH tends to occur
later, often in the second decade of disease.
What Causes PAH?
The exact cause of PAH is not known, nor is it possible to
predict who will get PAH.
Similar to the blood-vessel problems so common in scleroderma
patients, a dysfunction in the regulation of blood flow results
in vasoconstriction, or the narrowing of blood vessels. The
blood vessels become hypersensitive to stimuli that cause
them to constrict.
Although this vasoconstriction may be reversible in the earlier
stages, over time the blood vessel walls become thicker and
stiffer and it is more difficult for blood to flow through
them. The opening of the blood vessel (lumen) becomes narrowed
or even blocked off. The consequence of this poor blood flow
is tissue damage. There are many factors that may play a role
in this process. One possible factor in PAH is the elevation
of a substance in the body called endothelin, a potent vasoconstrictor
that has been shown to be elevated in the blood of scleroderma
patients and in lung tissue affected by sclerodema.
Symptoms of PAH
In the earliest stages of PAH the patient may not have any
symptoms. Just as with systemic hypertension, a patient cannot
feel when his/ her blood pressure is high, and often does
not discover high blood pressure until it is measured with
a blood pressure cuff.
The next symptom, which a patient generally recognizes, is
shortness of breath. This shortness of breath often occurs
with exercise, such as climbing up stairs or walking around
town, and the patient will notice that he/she has to breathe
harder than usual or feels winded and fatigued.
Often, going to higher elevations may precipitate an episode
of shortness of breath from an activity that ordinarily would
not have caused a problem.
In the more advanced stages of PAH, the patient experiences
shortness of breath at rest and is extremely limited in activities
of daily life. Other symptoms such as chest pain, dizziness,
and fainting may also occur.
Although these symptoms may indicate PAH, they are non-specific
and can occur in a number of settings. This is why it is important
to undergo appropriate testing to rule out possible other
causes for shortness of breath.
Importance of Screening for PAH
in Scleroderma Patients
In 1998 the World Health Organization (WHO) convened a World
Symposium on Primary Pulmonary Hypertension in Evian, France.
Experts from all over the world were brought together to discuss
all aspects of PAH.
Because of the high prevalence of PAH in scleroderma patients,
new guidelines recommended that scleroderma patients be screened
annually for PAH.
How to Diagnose PAH
As noted above, when a patient with scleroderma becomes short
of breath, it is important to investigate the cause.
At the WHO Evian meeting, it was recommended that an echocardiogram
be performed annually in scleroderma patients, with or without
symptoms of pulmonary hypertension.
In addition to suspecting PAH, other possible problems include
interstitial lung disease, pneumonia, blood clots to the lungs,
and heart failure.
To diagnose PAH related to scleroderma, a series of tests
is given to determine the specific cause of shortness of breath.
These tests may include pulmonary function tests, chest X-rays,
high-resolution CT scan, scans for blood clots, and bronchoscopy.
The best screening test for PAH is a doppler echocardiogram.
This study can determine the size of the chambers of the heart,
how well the heart valves are working, and can estimate the
pulmonary arterial pressures.
Additionally, once PAH is diagnosed, a test called a right-heart
catheterization can confirm a diagnosis.
How to Treat PAH
Therapies that relax and open up blood vessels (vasodilate)
are the mainstay treatment for PAH. In some patients, calciumchannel
blockers such as nifedifine or diltiazem can be effective.
Additional medications may be used such as water pills (diuretics),
blood thinners (anticoagulants) to prevent blood clots, and
drugs that block endothelin such as bosentan (Tracleer™).
Bosentan (Tracleer™) has recently been developed. It
is the first PDA-approved drug that blocks the endothelin
receptors. It has been shown to be effective in treating both
primary pulmonary hypertension and PAH due to scleroderma.
If PAH progresses and becomes very severe, treatment with
epoprostenol (Flolan™) can be started. Flolan™ is
effective, but requires a continuous intravenous infusion
into the heart from a pump.
Patients who do not respond to drug treatment may be candidates
for lung transplantation. More About Bosentan (Tracleer™)
Bosentan (Tracleer™) is the first oral medica tion recently
approved by the FDA to improve exercise ability and decrease
the rate of clinical worsening in PAH patients with significant
limitation of physical activity (WHO Class III and IV).
In clinical trials, bosentan has been shown to offer several
important benefits to patients with PAH. It can
- alleviate symptoms and improve the patient's ability to
perform normal daily activities;
- slow the worsening of a patient's physical condition and
symptoms;
- lower high blood pressure in the lungs; and
- enable the heart to pump blood more effectively.
In general, bosentan is well tolerated with relatively few
side effects.
Because abnormal liver function tests occurred in about 11%
of patients, it is very important to have liver function tests
before treatment starts, and each month thereafter.
In addition, bosentan (Tracleer™) may cause birth defects
if taken during pregnancy.
Therefore it is essential that patients on Tracleer™
are not pregnant and do not become pregnant.
How to Get Bosentan
Bosentan is a prescription drug, but is not available through
a regular pharmacy. To prescribe bosentan, a doctor simply
faxes the prescription to the "Tracleer Access Program."
The medication will then be mailed to the patient.
To receive the prescribing information, your doctor can visit
www.tracleer.com
or call 1-866-228-3546.
Other Uses for Bosentan
Because endothelin is strongly implicated in the pathogenesis
of PAH and several other manifestations of scleroderma (including
fibrosis and pro-inflammatory properties; see Abraham, D.J.
et al.), there may be additional applications for an endothelin
blocker like bosentan (Tracleer™) in scleroderma. Refractory
Raynaud's phenomenon with finger ulceration is one area under
investigation. A multi-center trial is currently underway
and results are expected in late 2002.
Conclusion
In summary, it is important to be aware of the complication
of pulmonary arterial hypertension (PAH) in patients with
scleroderma.
A physician should consider the possibility of PAH in any
patient who has exerciseinduced shortness of breath. The best
way to screen for this complication is with an echocardiogram.
There is a new FDA-approved drug called bosentan (Tracleer™)
that is effective in treating symptomatic PAH. It has advantages
over other treatments because it can be taken by mouth, and
is generally well tolerated. Additional studies are currently
being done to evaluate its effects in other aspects of scleroderma.
Visit the Scleroderma Foundation's Website for More Information
The Scleroderma Foundation has a Tracleer™ PDF file
on its website. Visit http://www.scleroderma.org/pdf/Tracleer_is_Here.pdf
for more information.
References
Abraham, D.J., Vancheeswaran, R., Dashwood, M.R., et al.
"Increased levels ofendothelin-1 and differential endothelin
type A and B receptor expression in scleroderma-associated
fibrotic lung disease." American Journal of Pathology,
151: 831-841 (1997).
Channick, R.N., Simonneau, G., Sitbon, 0., et al. "Effects
of the dual endothelin-receptor antagonist bosentan in patients
with pulmonary hypertension: a randomised placebo-controlled
study." Lancet, 358: 1119-1123(2001).
Kahaleh, M.B. "Endothelin, an endothelial dependent
vasoconstrictor in scleroderma. Enhanced production and profibrotic
action." Arthritis Rheum., 34: 978-83 (1991).
Medsger, T.A. "Systemic sclerosis (sclero derma): Clinical
aspects." In: Arthritis and Allied Conditions. W.J. Koopman,
ed., 14th edition. Lippincott Williams & Wilkins, Philadelphia,
PA, pp. 1590-1624 (2001).
Rubin, L.J. "Primary pulmonary
hypertension." New England Journal of Medicine, 336:
111-117(1997).
Disclosure: Dr. Connolly
is a paid consultant for Actelion. |
