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Introduction
Pulmonary arterial hypertension is a life-threatening
complication of several connective tissue diseases, including
both dif-fuse and limited scleroderma (with a subgroup
of limited scle-roderma called the CREST syndrome), systemic
lupus erythe-matosus (SLE), mixed connective tissue disease
(MCTD), and less commonly, rheumatoid arthritis, and dermatomyositis/
polymyositis (Table 1). This review will discuss the incidence,
potential etiologies, clinical presentation, and treatment
options for patients with pulmonary hypertension and the
scleroderma spectrum of diseases.
Epidemiology
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| Table
1—Connective Tissue Diseases Associated with
Pulmonary Arterial Hypertension |
|
| Scleroderma |
|
Diffuse |
|
Limited |
|
CREST |
| Systemic lupus erythematosis |
| Mixed connective tissue
disease |
| Rheumatoid arthritis |
| Dermatomyositis/Polymyositis |
|
Pulmonary hypertension complicates several of the connective
tissue diseases (Table 1). Scleroderma is a progressive,
multi-system disease manifested by connective tissue and
vascular lesions in many organs, including lung, kidney,
and skin. Pulmonary manifestations include interstitial
fibrosis, pulmonary arterial hypertension, constriction
of the chest wall due to skin thickening, diaphragmatic
dysfunction, and chronic aspiration due to esophageal
dysmotility.1 Pulmonary complications are
the most frequent cause of death in patients with scleroderma,1
and pulmonary vascular disease has a particularly adverse
effect on prognosis.2
The incidence of pulmonary hypertension varies between
6% and 60% of patients with scleroderma. Up to 33% of
patients with diffuse scleroderma have pulmonary hyperten-sion,
both isolated and in association with interstitial lung
disease. 3-6 In patients with limited scleroderma, formerly
referred to as CREST (calcinosis cutis, Raynaud’s phenomenon,
esophageal dysmotility, sclerodactyly, and telangiectasias),
up to 60% of patients have pulmonary hypertension.4,
6-8 While not all patients have clinically significant
pulmonary hyperten-sion, two thirds of patients with scleroderma
will have patho-logic evidence of pulmonary vascular disease.7,
9 Stupi et al reported two-year survival in patients
with CREST without pulmonary hypertension to be greater
than 80% while patients with pulmonary hypertension had
a two-year survival of 40%.8 Sacks et al
reported two-year survival of patients with pul-monary
hypertension and either diffuse or limited scleroderma
to be approximately 50%.5 Koh et al reported
40% survival in patients with scleroderma and pulmonary
hypertension com-pared with higher survival in scleroderma
patients without organ failure or with other lung involvement
(i.e. interstitial lung disease) at two years.2
Pulmonary hypertension has been reported in 4% to 14%
of patients with systemic SLE with an overall mortality
rate of 25% to 50% at two years from diagnosis of pulmonary
hyper-tension. 10-13 Patients with MCTD have
features of several connective tissue diseases, including
SLE, scleroderma, rheumatoid arthritis, and polymyositis.
Most MCTD patients have either predominantly SLE or scleroderma
with a myositis overlap. The behavior of the disease therefore
follows either a predominantly SLE or a scleroderma pattern.
The incidence of pulmonary hypertension in patients with
MCTD is not cer-tain but one report found two thirds of
patients with MCTD had evidence of pulmonary hypertension
14 and pulmonary hypertension has been frequently
cited as a cause of death in patients with MCTD.15
The high incidence of pulmonary hypertension in MCTD is
probably a result of the predominant scleroderma pattern
of this disease in many patients with MCTD.
Rheumatoid arthritis affects 5% of the population over
age 65 and pulmonary complications include interstitial
pul-monary fibrosis, rheumatoid nodules, and pleural effusions.
The incidence of isolated pulmonary hypertension is not
known. In a recent report, 21% of patients with rheumatoid
arthritis without evidence of other pulmonary or cardiac
disease had mild pulmonary hypertension.16
The prognosis is not known. Other connective tissue diseases
including dermatomyositis/ polymyositis have been associated
with pulmonary arterial hypertension but the incidence
and prognosis are not known.17
Pathogenesis
The etiology of pulmonary hypertension in the scleroderma
spectrum of diseases remains obscure. There appears to
be direct involvement of the pulmonary circulation with
intimal proliferation and medial hypertrophy, similar
to that seen in primary pulmonary hypertension.6-9,
18 Some cases may also be related to severe pulmonary
parenchymal disease, such as interstitial disease with
hypoxemia. Additionally, diastolic dysfunction of the
right and left ventricles has been seen in patients with
scleroderma and may contribute to pulmonary hypertension.19
Autoimmune processes have been implicated in the patho-genesis
of pulmonary hypertension although the mechanism is not
known. Positive antinuclear antibodies are frequently
found in pulmonary hypertension patients without a diagnosis
of connective tissue disease and pulmonary hypertension
can occur before the onset of an identifiable connective
tissue disease. In patients with scleroderma, anticentromere
and antihi-stone antibodies have been associated with
vascular disease. Anticentromere antibodies are primarily
seen in the limited form of systemic sclerosis. Since
patients with the limited form of systemic sclerosis have
a higher incidence of pulmonary hypertension than do patients
with diffuse disease, it is not surprising that anticentromere
antibodies would be associated with a higher incidence
of pulmonary hypertension. Antifibrillarin antibodies
(anti-U3-RNP) are frequently found in patients with scleroderma
and are more common with dif-fuse scleroderma-associated
pulmonary hypertension.20 Anti-endothelial antibodies
(aECA) are present in 40% and 13% of patients with diffuse
scleroderma and CREST, respectively, and are associated
with a higher incidence of pulmonary hypertension and
digital infarcts.21 Antifibrillarin antibodies
and aECAs are also associated with pulmonary hypertension
in SLE.22 In patients with scleroderma and pulmonary
hyperten-sion, especially when accompanied by HLA-B35
antigen, anti-topoisomerase II-alpha antibodies are more
common, as are antibodies to fibrin-bound tissue type
plasminogen activator.23
Raynaud’s phenomenon, vasospasm of the arterioles in
the distal systemic circulation, is commonly reported
in patients with scleroderma. In one report, all patients
with pulmonary hypertension and CREST had Raynaud’s, while
68% without pulmonary hypertension had Raynaud’s.8 Raynaud’s
is also common in patients with SLE and MCTD and pulmonary
hypertension 11, 24 but only 10% to 14% of patients
with pri-mary pulmonary hypertension have Raynaud’s.25
This observa-tion has led to the “pulmonary Raynaud’s”
hypothesis that vasospasm contributes to the development
of pulmonary hypertension.26
Acute hypoxic pulmonary vasoconstriction may be more
pronounced in patients with pulmonary hypertension and
scleroderma than in patients with primary pulmonary hypertension.
27 However, another report found that pulmonary
vasospasm was not present in patients with Raynaud’s and
scleroderma without pulmonary hypertension.28 In
support of this hypothesis, patients with scleroderma
have defective endothelial-dependent vasodilation 15
and this may be related to decreased endothelial nitric
oxide synthase (eNOS).29 Although controversial,
decreased lung eNOS has been report-ed in severe primary
pulmonary hypertension.30 While the level of eNOS
in connective tissue disease is not known, decreased production
of lung nitric oxide has been found in patients with scleroderma
and pulmonary hypertension.31 Similarly, expression
of prostacyclin synthase in pulmonary endothelium may
be decreased in patients with severe connective tissue
disease-associated pulmonary hypertension.32
Endothelin-1 is increased in serum of patients with both
diffuse and limited scleroderma 33 and while endothelin
levels correlate with survival in patients with scleroderma,34
they are not higher in those with pulmonary hypertension.33
In contrast, higher serum endothelin levels are found
in patients with SLE-associated pulmonary hypertension
than in nonpul-monary hypertensive SLE patients.12
The role of endothelin-1 in pulmonary hypertension has
led to the use of endothelin antagonists in treatment
of patients with connective tissue disease-associated
pulmonary hypertension.35 Serotonin may also play
a role in the pathogenesis of pulmonary hypertension.
In patients with systemic sclerosis and Raynaud’s, platelet
serotonin concentrations are decreased and serum levels
are increased.36, 37
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