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)
 |
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.
Editor's note: This is a long article. You can
skip directly to the sections that interest you, by
clicking on these links:
Pathophysiology
 |
| 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.
 |
| 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. |
