|
Clinical Presentation and Evaluation
Dyspnea is the most common presenting symptom of scleroderma-
associated pulmonary hypertension. The clinical evaluation
is similar to that of patients with primary pulmonary
hypertension. History and physical examination often reveal
findings of the underlying connective tissue disease (ie,
Raynaud’s, telangiectasias, rash, synovitis, interstitial
lung disease, etc). Decreased diffusing capacity of the
lung is the most common pulmonary function abnormality
and should prompt an evaluation for both pulmonary vascular
and interstitial lung disease.38 A diffusing capacity
of less than 40% of predicted for lung volume places the
patient in a poor prog-nostic category. Echocardiography
may be helpful in the evaluation of patients suspected
of having pulmonary hypertension as suggested by unexplained
dyspnea or an isolated reduction in diffusing capacity.
As previously discussed, patients with scleroderma should
be considered an “at risk” group for the development of
pul-monary hypertension, and echocardiography may reveal
right ventricular hypertrophy and dilatation even before
the onset of symptoms.39 Ultimately, as with primary
pulmonary hyperten-sion, right-heart catheterization is
needed to confirm the diagnosis, assess hemodynamic severity,
and exclude other possible contributing factors, such
as an occult congenital heart defect. While it is generally
thought that patients with scleroderma- associated pulmonary
hypertension are less likely to demonstrate a favorable
response to vasodilator therapy than patients with primary
pulmonary hypertension (in whom the response rate is approximately
20% to 25%), a hemodynamically monitored assessment of
vasoreactivity is still advocated by some experts.
Therapy
Several therapeutic options are available for the treatment
of scleroderma-associated pulmonary hypertension
(Table 2). Oral vasodilators (calcium channel
|
| Table
2—Potential Therapeutic Options |
|
|
Vasodilators |
| |
|
Calcium channel blockers |
| |
|
Angiotensin converting
enzyme inhibitors |
| |
|
Alpha-adrenergic blockers |
| |
|
Prostaglandin preparations |
| |
|
|
Intravenous epoprostenol |
| |
|
|
Subcutaneous treprostinil |
| |
|
|
Inhaled iloprost |
| |
|
|
Inhaled nitric oxide |
| |
|
|
Alpha-adrenergic blockers |
|
Phosphodiesterase
inhibitors |
|
Endothelin receptor
antagonists |
|
Serotonin antagonists |
|
Immunosuppressive
therapy |
| |
|
Corticosteroids |
| |
|
Cyclophosphamide |
| |
|
Bone
marrow transplantation |
|
Lung/Heart-lung transplantation |
|
antagonists, angiotensin converting enzyme inhibitors, and
alpha-adrenergic antagonists) have been used to treat pulmonary
hypertension in pa-tients with scleroderma. Although it
has been reported that calcium channel blockers have improved
survival in some patients with scleroderma-associated pulmonary
hypertension, 40-42 it is generally acknowledged that only
a small percentage of such patients respond favorably to
these agents. Angiotensin converting enzyme inhibitors and
an alpha-adren-ergic blocker (prazosin) have also been used
both acutely and over the long term in the treatment of
connective tissue disease-associated pulmonary hypertension.41,43
In a randomized, multicenter study of continuously intravenously
infused epoprostenol we reported short-term improvement
in patients with pulmonary hypertension due to scleroderma;44
111 patients with pulmonary hypertension and the scleroderma
spectrum of disease (70% limited disease, 13% diffuse
disease, 11% to 14% overlap syndrome, and 5% with features
of scleroderma) were randomized to receive con-tinuous
infusion of epoprostenol vs. conventional treatment for
12 weeks. Epoprostenol improved exercise capacity, cardiopul-monary
hemodynamics, New York Heart Association functional class,
Borg dyspnea index, and likely Raynaud’s. However, there
was no mortality benefit as had been seen in the same
treatment duration with primary pulmonary hypertension,45
possibly because of the multisystem nature of this disease.44
It is important to point out that the study was not powered
to detect a survival difference. Others have also found
both short and long-term improvement with epoprostenol.46,47
Long-term follow up of the patients in our study has suggested
that epoprostenol may improve survival compared with historical
controls. However, in general it appears as though survival/
prognosis is worse for patients with scleroderma-associated
pulmonary hypertension as compared with patients with
primary pulmonary hypertension and needs further investigation.
Treatment with epoprostenol in some patients has been
associated with reports of pulmonary edema possibly resulting
from pulmonary veno-occlusive disease or pulmonary capillary
hemangiomatosis.48 Although very rare, pulmonary veno-occlusive
disease may be more common in patients with connective
tissue disease.49
Increasing evidence has suggested the importance of endothelin-1
in the pathogenesis of pulmonary hypertension. In a multicenter,
randomized, double-blinded placebo controlled trial of
the endothelin receptor antagonist bosentan (Tracleer
® ) for the treatment of pulmonary arterial hyperten-sion,
213 patients with pulmonary hypertension, either pri-mary
or due to connective tissue disease (scleroderma and lupus),
were randomized to receive placebo or bosentan at 125
or 250 mg orally twice daily.35 After 16 weeks, distance
walked in six minutes, functional class, Borg dyspnea
index, and time to clinical worsening improved in patients
receiving either dose of bosentan. In contrast to the
improvement in patients with primary pulmonary hypertension,
bosentan prevented the deterioration in six-minute walk
compared with placebo. This suggested that patients with
scleroderma did less well overall. Nevertheless, relative
stability may represent a favorable outcome in a disease
with an otherwise very poor prognosis. Bosentan has been
associated with a dose-dependent increase in liver function
tests, and monthly follow-up of these tests is required
by the Food and Drug Administration. Other potential side
effects are thought to include mild anemia, fluid retention,
teratogenicity, and possibly testicular dysfunction and
male infertility. Even in light of these potential adverse
effects, the development of this oral therapy is thought
to represent a significant advance.
Various prostacyclin analogues and delivery systems have
been recently studied. Inhaled iloprost, a stable analogue
of epoprostenol, was studied in a large placebo-controlled
trial comparing inhaled iloprost with placebo in patients
with severe pulmonary hypertension. Iloprost improved
six-minute walk test results, functional status, and hemodynamics
after 12 weeks of treatment.50 The effect was greatest
in patients with primary pulmonary hypertension. Combination
with a phosphodiesterase inhibitor appears to increase
the effective-ness of inhaled iloprost in patients with
pulmonary hyperten-sion. 51 Treprostinil, a stable prostacyclin
analogue adminis-tered subcutaneously, was recently approved
for use in patients with pulmonary arterial hypertension
with efficacy at the highest doses of the drug.52 Beraprost
sodium, an orally bioactive prostacyclin analogue, improved
six-minute walk distance in patients with primary pulmonary
hypertension compared with patients with connective tissue
disease.53
Although nitric oxide has utility in acute pulmonary
vasodilator testing in patients with scleroderma, there
have not been any reports of its long-term use in the
treatment of scleroderma-associated pulmonary hypertension.
The selective serotonin receptor 2 antagonist ketanserin
acutely improved pulmonary artery pressure and cardiac
output in patients with scleroderma-associated pulmonary
hypertension 54 while sarpogrelate, another receptor 2
antagonist, administered orally for 12 months, decreased
mean pulmonary arterial pressure and increased right ventricular
ejection fraction.55 These reports suggest a role for
serotonin in the pathogenesis of scleroderma-associated
pulmonary arterial hypertension, although a randomized,
controlled trial has not been done.
Corticosteroids with and without cyclophosphamide,13
long-term plasma exchange,56 and autologous stem cell
transplantation 57 have been reported to improve or stabilize
pul-monary hypertension in patients with scleroderma.
However, these represent case reports or retrospective
case studies and no prospective study of immunosuppressive
therapy has been completed in patients with connective
tissue disease-related pulmonary hypertension. Use of
immunosuppressive therapy may be more successful in patients
with SLE than in those with scleroderma.
Surgical treatment, including atrial septostomy 58 and
lung or heart-lung transplantation may be considered for
patients with severe pulmonary arterial hypertension in
association with connective tissue disease. Survival in
patients with con-nective tissue disease-associated pulmonary
hypertension who undergo lung or heart-lung transplantation
is not different from that in patients with primary pulmonary
hypertension.59 Lung transplantation may also be of benefit
in patients with severe fibrotic lung disease. Appropriate
patient selection is important, though, and lung transplantation
may be relatively contraindicated in patients with significant
esophageal dys-motility or renal dysfunction.
|
