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)

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.