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)
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
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.
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.
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