Pulmonary Arterial Hypertension in Scleroderma
An explanation of the mechanisms behind PAH, diagnostic tests, and current and emerging therapies
by Ioana Preston, M.D.* (originally published in Scleroderma Voice, 2006 #1)
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Ioana Preston, M.D. is Assistant Professor of Medicine and Co-Director of the New England Center for Pulmonary Hypertension in the Pulmonary, Critical Care and Sleep Division of Tufts-New England Medical Center in Boston. |
Pulmonary arterial hypertension (PAH) comprises a spectrum of diseases characterized by elevated mean pulmonary artery pressure above 25 mm Hg at rest, or 30 mm Hg with exercise. PAH is a common complication of systemic sclerosis and adversely affects survival. PAH is more common in patients with the limited form of scleroderma, formerly called the CREST syndrome, whereas diffuse scleroderma is associated more often with pulmonary fibrosis. The prevalence of PAH in limited scleroderma has been reported to be 30 to 50%.
While most patients have mild PAH, some go on to develop progressive PAH that markedly limits their functional capacity and decreases their survival. Patients at increased risk for developing PAH are postmenopausal females and those with more severe Raynaud’s phenomena and digital ulcers.
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Pathophysiology
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| Fig 1. Schematic of pulmonary circulation. Right ventricle pumps venous blood, through the pulmonary artery, into the lungs, where the blood becomes oxygenated. Pulmonary veins carrying red blood filled with oxygen return into the left ventricle, which will pump the blood into the rest of the body. PAH thickens and constricts the small branches of the pulmonary artery, and consequently, the right ventricle workload increases. |
The main disturbance resides in constriction of pulmonary arteries and thickening of the pulmonary arterial wall. As a consequence, the right ventricle that pumps blood into the lungs works against an abnormally high resistance (Fig. 1). Initially, the right ventricle is able to compensate for the increased workload, but in time, it decompensates, and patients develop right heart failure.
The mechanism involves an imbalance between factors that promote dilatation of pulmonary vessels and those that promote vasoconstriction and proliferation of cells in the vascular wall.
Previous studies have shown that patients with pulmonary arterial hypertension are deficient in a vasodilator called prostacyclin. Conversely, there seems to be an abundance of a potent vasoconstrictor called endothelin-1. These important observations are further supported by the effective treatment with both prostacyclin replacement, and blockage of endothelin-1 with endothelin receptor antagonists in PAH patients.
Clinical Presentation
Typically, patients with PAH have no complaints at rest. The main symptom is shortness of breath with activity. Shortness of breath develops initially with exercise, such as climbing up a few flights of stairs.
Later, patients feel limited during activities of daily living, such as bathing or dressing, and ultimately, they feel short of breath even getting out of bed. In advanced cases, chest pain, lightheadedness, or loss of consciousness may occur with exertion and leg swelling may become prominent especially at the end of the day. Because of lack of specific symptoms and the fact that symptoms may appear late in the course of the disease, especially in patients whose activities are limited by arthritis, we recommend that patients with scleroderma have annual echocardiograms and pulmonary function tests.
When pulmonary arterial hypertension is suspected, a number of studies need to be performed. There are two diagnoses that need to be excluded in the setting of shortness of breath with activity in a patient with scleroderma: (1) pulmonary fibrosis, which can be assessed by pulmonary function tests and CT scan of the chest; and (2) pulmonary embolic disease (blood clots in the lungs), which can be assessed by a lung scan or a CT pulmonary angiogram.
(During a CT pulmonary angiogram, a dye is injected into the bloodstream. The chest is then imaged using Computerized Tomography. If a pulmonary embolism is present, this will show up as an area where there is no dye.) It is very important to differentiate between these two conditions, as the treatment for each one is completely different.
Echocardiography is a very useful noninvasive screening tool when testing for PAH. Echocardiography estimates pulmonary arterial pressure and assesses the right ventricular function. Although echocardiographic estimations of pulmonary artery pressure correlate well with measurements obtained during right heart catheterization, under and overestimation of PA pressures is common. Therefore, echocardiography is not the ultimate diagnostic test.
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| Fig 2. Schematic of right heart catheterization. This illustrates the placement of the cathether through the groin, but your physician may choose to insert in through the neck.
Copyright 2005, A.D.A.M., Inc. |
The definitive diagnosis of PAH is achieved by right heart catheterization (Fig. 2). This test provides important information about parameters of the lung and the right heart, called pulmonary hemodynamics. This test should be accompanied by an acute vasodilator trial and measurements at rest and during exercise should be recorded.
The parameters that can be achieved only during the right heart catheterization are:
- The accurate measurement pulmonary artery pressure and function of the heart (by determining the cardiac output)
- The strength of the heart; knowledge of the degree of impairment of the right heart (by measuring the right atrial pressure)
- The presence or absence of left heart stiffness (common in patients with scleroderma)
- The acute response to vasodilators, such as nitric oxide, epoprostenol, or adenosine
It is advisable to have the right heart catheterization performed at a pulmonary hypertension center that has the set up and medications required to performing this procedure. It is very important to perform this test before any therapy is initiated. The valuable information obtained during the right heart catheterization enables your physician not only to accurately stage the degree of pulmonary hypertension, but to better decide on the course of therapy.
Therapies for PAH Related to Scleroderma
Three pathways have been found to play a major role in PAH related to scleroderma:
Prostacyclins
Therapy with prostacyclins has been shown to improve functional status, pulmonary hemodynamics, and quality of life in PAH (idiopathic and related to scleroderma). Several long term trials suggest that the beneficial effects of prostacyclin replacement therapy are dramatic and appear to be sustained for years in many patients with PAH.
Currently, three prostacyclin analogues are approved by the United States Food and Drug Administration:
- Epoprostenol (Flolan), which is administered as continuous intravenous infusion.
- Treprostinil (Remodulin), administered either as intravenous infusion, or as continuous subcutaneous infusion (under the skin).
- Iloprost (Ventavis), which is administered via inhalational therapy.
The disadvantage is that the mode of administration is complex. The intravenous forms require a permanent intravenous catheter and the patient has to mix the medication once a day (Flolan) or every other day (Remodulin). The complex delivery system requires education of sterile technique, operation of the pump, and care of the catheter.
A strong support system, a “partner” is often strongly recommended to obviate problems if the subject is too ill or unable to prepare medication on a given day. There is a risk of catheter infections that in some cases may be fatal. The subcutaneous form of treprostinil is safe to administer and does not require mixing of the drug, but is associated with pain at the site of infusion. Iloprost permits the avoidance of a permanent catheter but because of its short duration of action, it must be inhaled six to 12 times per day.
In conclusion, prostacyclin analogues are very powerful and effective therapy, and even with their complex administration and potential side effects, they should be considered the first line of treatment in patients with either very advanced disease, or rapidly progressive PAH.
Endothelin Receptor Antagonists
Endothelins have been recently implicated in the pathophysiology of PAH. Endothelin-1 is a very potent constrictor on the pulmonary vessels and is abundant in different forms of PAH. Endothelin-1 exerts its actions via two receptors: the A receptor that mediates vasoconstriction; and the B receptor that mediates both vasoconstriction and vasodilation and also clears endothelin-1 from the blood.
Recent trials suggest that endothelin receptor antagonists hold promise as therapeutic agents for pulmonary arterial hypertension. Bosentan (Tracleer) is the first endothelin-1 receptor antagonist to be approved by the Food and Drug Administration. Bosentan blocks both receptor A and B (nonselective antagonist) and it was shown to improve symptoms, functional capacity, and hemodynamics in PAH (both idiopathic and scleroderma related).
In a recent long-term follow-up study on bosentan, PAH patients maintained their improvement in exercise capacity and functional status for as long as one year. Bosentan is administered twice daily.
There are several notable potential toxicities associated with bosentan. Liver toxicity has been described in 12% of patients and the Food and Drug Administration requires that liver function tests be performed at least once monthly.
Mild anemia (decreased red blood cell count) and fluid accumulation (worsening leg swelling) may also occur. It is also important to note that bosentan may decrease the effectiveness of hormonal contraceptives.
Because pregnancy is absolutely contraindicated in patients with PAH, we suggest that two methods of contraception be used (for example hormonal barrier and condom or diaphragm). In addition, due to possible teratogenic effects of bosentan (birth defects in offsprings), males with PAH should be counseled regarding this risk.
There is great debate whether preserving the function of endothelin receptor B has additional favorable effects on the pulmonary vasculature. There is a theoretical benefit in selectively blocking the receptor A only and achieving further vasodilation and maintenance of endothelin clearance through receptor B activity.
The newer generation of endothelin antagonist, sitaxsentan, is a highly selective receptor A blocker and is administered as a once a day pill. It has approximately 6500-fold selectivity for endothelin A receptors compared with B receptors. Sitaxsentan was shown to significantly improve functional capacity and hemodynamics in patients with idiopathic PAH, PAH related to connective tissue disease and PAH related to congenital heart defects. Sitaxsentan has been shown to maintain its therapeutic benefits for as long as one year.
The Food and Drug Administration is currently weighing the evidence on sitaxsentan as a therapy for PAH. Recent evidence also suggests that sitaxsentan may have a better safety profile on liver function than bosentan. Sitaxsentan seems to potentiate the effects of warfarin (coumadin), but this interaction can be managed by reducing the warfarin dose. The third endothelin receptor antagonist ambrisentan is currently being investigated in a phase III clinical trial.
Phospohdiesterase 5 (PDE-5) Inhibitors
The PDE-5 enzyme, abundant in lung vessels, metabolizes a chemical that plays a critical role in dilation of pulmonary vasculature. Sildenafil, initially approved to treat erectile dysfunction, has been shown to be an effective therapy in PAH, by producing pulmonary vasodilation. In a recent clinical trial, sildenafil improved both functional capacity and hemodynamics in patients with PAH (idiopathic, related to connective tissue disease, and congenital heart disease). Sildenafil (Revatio) was recently approved by the Food and Drug Administration for the treatment of PAH. The treatment consists of one pill three times a day.
Combination Therapy
Current available therapies are neither curative, nor do they normalize pulmonary pressures in the majority of cases, leaving patients with persisting pulmonary hypertension and functional impairment. Therefore, treatment of PAH by inhibiting multiple pathways concurrently may produce additive benefit, and/or may permit lowering the dosages and minimizing drug toxicity. At this time, there is very little information regarding any interaction between different agents. Currently, there are few clinical trials focused on investigating the potential benefit and safety profile of combination therapy.
In conclusion, an exciting development has been made with the introduction of therapies such as prostacyclins, endothelin receptor antagonists and PDE-5 inhibitors, which improve functional status, pulmonary pressures and quality of life in patients with PAH, including PAH related to scleroderma. Newer, more selective endothelin receptor antagonists also show promise as therapy. Although remarkable progress in understanding the pathogenesis and in therapy of PAH related to systemic sclerosis has been made, much more work is needed to alter the natural history and reverse the complications of systemic sclerosis.
*Ioana Preston, M.D. is Assistant Professor of Medicine and Co-Director of the New England Center for Pulmonary Hypertension in the Pulmonary, Critical Care and Sleep Division of Tufts-New England Medical Center in Boston. | 
