Rheumatology 2006 45(Supplement 4):iv22-iv25; doi:10.1093/rheumatology/kel314
© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Pulmonary arterial hypertension and rheumatic diseases—from diagnosis to treatment
O. Distler and
A. Pignone1
Department of Rheumatology, University Hospital Zurich, Switzerland and 1Department of Medicine, Section of Rheumatology, University of Florence, Italy.
Correspondence to: O. Distler, MD, Department of Rheumatology, University Hospital Zurich, Gloriastrasse 25, 8091 Zurich, Switzerland. E-mail: Oliver.Distler{at}usz.ch
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Abstract
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Survival rates in pulmonary arterial hypertension (PAH) associated
with rheumatic diseases, in particular connective tissue diseases
such as systemic sclerosis, are even lower than in idiopathic
PAH. These low survival rates highlight the need for early diagnosis
and treatment in these patients. Transthoracic Doppler-echocardiography
is most often used for diagnostic screening of patients at risk.
Other screening tests are serum pro-brain-natriuretic peptide
(pro-BNP) and diffusion capacity for carbon monoxide (DLCO),
which appear to be changed early in the course of the PAH associated
with connective tissue diseases. The diagnosis needs to be confirmed
by right heart catheterization, which is recommended in all
patients with suspected PAH. Besides the conventional background
therapy, a number of specific therapies have been evaluated
in randomized controlled trials in the recent years. These therapies
include prostacyclins and prostacyclin analogues, endothelin-receptor
antagonists and phosphodiesterase-5 inhibitors. Response to
treatment can be measured by exercise capacity (e.g. 6 min walk
distance) and pro-BNP, although certain aspects of validation
for these outcome measures are lacking in PAH associated with
connective tissue diseases.
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Introduction
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Pulmonary arterial hypertension (PAH) is haemodynamically defined
as a resting mean pulmonary arterial pressure
25 mmHg with a
normal pulmonary capillary wedge pressure of
15 mmHg on right
heart catheterization. According to the clinical classification
of Third World Symposium on PAH held in Venice in 2003, the
diagnosis of idiopathic PAH (IPAH) is made, when no other risk
factor can be identified [
1]. However, PAH can occur in a variety
of other conditions and circumstances including a number of
rheumatic diseases. In this regard, systemic sclerosis (SSc),
mixed connective tissue disease (MCTD), systemic lupus erythematodes
(SLE) and to a lesser extent rheumatoid arthritis, dermato/polymyositis
and primary Sjögren's syndrome are associated with PAH.
The reported prevalence for PAH in connective tissue diseases
shows a wide range depending on the criteria used for diagnosis,
on the methods used to confirm the diagnosis and on the patient
population used for the studies. In a recent study in community-based
rheumatology practices in the US, the prevalence of PAH was
13.3% in patients with SSc and MCTD as analysed by echocardiography
[
2]. This was confirmed in a British study that used haemodynamic
confirmation by right heart catheterization after a diagnostic
algorithm and that found a prevalence of 12% in SSc patients
[
3]. PAH appears to be less common in SLE, however, well-controlled
prospective trials are missing and retrospective studies reported
a prevalence of up to 14% as assessed by echocardiography [
4].
In rheumatoid arthritis, dermato/polymyositis and primary Sjögren's
syndrome, clinically significant PAH appear to be a rare manifestation.
PAH is a major cause of morbidity and mortality in connective
tissue diseases. While 3 yr survival rates after diagnosis in
IPAH are as low as 48%, these alarming numbers are even worse
in PAH associated with SSc. Median survival in untreated patients
is only 12 months, and the risk of death is nearly tripled [
5,
6]. This survival rate is in the range of some malignant diseases
and highlights the need for early diagnosis and treatment.
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The diagnostic approach
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The diagnosis of PAH in connective tissue diseases requires
the clinical awareness of symptoms associated with PAH, the
use of screening tools and the confirmation of the diagnosis
by independent diagnostic procedures. In addition, outcome measures
need to be defined to assess the response to treatment in these
patients.
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Clinical symptoms: be aware!
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As with PAH in general, clinical symptoms of PAH in connective
tissue diseases are unspecific. The cardinal sign is shortness
of breath on exertion, but patients often do not report this
symptom until asked specifically. Additional symptoms include
among others fatigue, weakness, angina, syncope and pre-syncope
and abdominal distension [
1]. However, these symptoms are late
manifestations of the disease and haemodynamic as well as morphological
changes in the pulmonary vasculature occur long before these
manifestations are detectable. The same accounts for physical
findings of PAH such as peripheral oedema, jugular vein distension,
accentuated pulmonary component of S2, hepatomegaly and ascites.
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Use of screening tools? Yes!
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The lack of early clinical and physical signs is the rationale
for the regular use of screening tools in patients with connective
tissue diseases. This regular, e.g. yearly, use of screening
tools is questioned by some authors, because approved medications
are currently not available for these early stages of PAH associated
with connective tissue diseases and thus an early detection
would have no consequences for therapy [
1]. However, based on
the pathogenesis of the disease and the experience from animal
models, early intervention is likely to prevent the progression
of the disease and respective therapeutic studies are currently
under way. We, therefore, recommend the use of screening tools
in connective tissue disease patients unless studies show that
early intervention does not improve the outcome of these patients.
Among the diagnostic procedures that can be used for screening, transthoracic Doppler-echocardiography (TTE) is the most widely used non-invasive screening test. TTE estimates the right ventricular systolic pressure (RVSP), which is equivalent to the pulmonary artery systolic pressure in the absence of pulmonary outflow obstruction, by measuring the systolic regurgitant tricuspid flow velocity [1]. Echocardiography is also important to address other causes of PAH, because it can recognize left heart valvular and myocardial diseases responsible for pulmonary venous hypertension. However, while TTE is an excellent screening tool for PAH, it has limitations: the RVSP increases with age and body mass index and is reported to be 28 ± 5 mmHg with a range of 15–57 mmHg [7]. Thus, assuming a diagnosis of PAH with a RSVP of 40 mmHg, a number of false positive diagnosis will be made [8]. Moreover, TTE tends to underestimate RVSP in patients with severe PAH and to overestimate RVSP in patients with normal pressures or less severe PAH [9]. Additional diagnostic screening tools might include biomarkers such as BNP and pro-BNP, which appear to be increased already in early disease stages and correlate well with haemodynamic measures and survival [10, 11]. ECG and chest radiography are less sensitive and specific for the detection of PAH. A decrease in the diffusion capacity for carbon monoxide (DLCO) without concomitant changes of restrictive parameters has been identified as one of the strongest risk factors for the later development of PAH in patients with SSc [6, 12].
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Confirmation of the diagnosis
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Right heart catheterization is the gold-standard to confirm
the diagnosis of PAH suspected on echocardiography and is recommended
in all patients with PAH [1, 9] before the initiation of specific
therapies. Right heart catheterization is also used to directly
measure the severity of haemodynamic changes and to test the
vasoreactivity of the pulmonary circulation by using short-acting
pulmonary vasodilators (see subsequently). Additional diagnostic
tests have to be performed to exclude other causes of PAH that
can occur in connective tissue diseases. This includes high-resolution
CT for interstitial lung disease and ventilation and perfusion
lung scan for chronic thrombembolic disease.
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Outcome measures for treatment responses
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Unfortunately, the measures of response to treatment for PAH
remain limited. Endpoints most often used for clinical trials
are exercise capacity measured by 6 min walk distance, pulmonary
haemodynamics, clinical events and peak VO
2 [
13]. However, some
of these measures are not applicable for routine clinical use.
For instance, right heart catheterization is an invasive diagnostic
test important for the confirmation of the diagnosis, but is
less adequate for repeated use to assess treatment responses.
Based on the Omeract filter of truth, discrimination and feasibility
for outcome measures, we currently recommend to measure 6 min
walk distance and pro-BNP at baseline and regularly after treatment
initiation [
14]. Although these outcome measures lack certain
aspects of validation in PAH associated with connective tissue
diseases, they are easy to perform in daily clinical practice
and are, therefore, feasible for the follow-up of such patients.
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Therapeutic challenges
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There is a general consensus about histopathological similarities
among various forms of PAH, including IPAH and PAH associated
with rheumatic diseases, leading to the assumption of shared
pathogenetic mechanisms and therapeutic approaches.
Concerning the therapeutic approach, it is possible to split basic and general measures from treatments focused on the supposed main pathogenetic pathways leading to a significant imbalance between thrombogenic, mitogenic, proinflammatory and vasoconstrictive factors on the one hand and anticoagulant, antimitotic and vasodilating mechanisms on the other hand.
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Basic and general therapies
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Appropriate active lifestyle might be encouraged in patients
affected with PAH, with particular caution for patients with
advanced stages at increased risk for life-threatening syncope.
Pulse steroid therapy has been suggested as an effective treatment in PAH associated with connective tissue diseases and overlap syndromes, leading to an improvement of haemodynamic parameters and New York Heart Association (NYHA) functional class [15]. However, although intermittent pulse therapy with cyclophosphamide demonstrated efficacy on mild and moderate PAH associated with SLE [16], no controlled data are available about the efficacy on PAH associated with other autoimmune rheumatic diseases. This is in particular true for SSc, where it may be contraindicated for the enhanced risk of renal crisis in patients with the diffuse disease subset.
Considering hypoxaemia as a pulmonary vasoconstrictor, supplemental oxygen should be used to maintain saturation up to 90%, obviously with a careful individual control.
Long-term anticoagulant therapy, associated with improved survival in IPAH [17], is still controversial for patients affected with PAH due to other causes, including autoimmune rheumatic diseases, because its efficacy has not been well-demonstrated by controlled trials and its relative risks and benefits should be evaluated on the individual basis.
Diuretic therapy, including aldosterone-antagonists, may produce effective clinical results by reducing the right ventricular preload.
Therapy with cardiac glycosides, although useful for refractory right ventricular failure and concomitant atrial arrhythmias, it is not considered a first therapeutic choice in PAH associated with rheumatic diseases.
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Therapies targeting pathogenetic pathways
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Long-term therapy with calcium-channel blockers (CCBs) has been
for many years the most widely used vasodilating therapy. Nowadays,
it is well-documented that this therapy is effective in IPAH
in <10% of patients [
18]. Patients responding to CCBs are
identified by performing an acute vasodilator challenge with
the use of short-acting agents, such as intravenous prostacyclin,
adenosine or inhaled nitric oxide, during right heart catheterization.
For this reason, all therapeutic guidelines indicate these invasive
diagnostic procedures as mandatory before starting therapy with
CCB agents that may also be complicated by systemic side effects.
In addition, in PAH secondary to connective tissue diseases,
the percentage of non-responders to CCBs is higher than in IPAH
[
19], thus reflecting a substantial non-efficacy of such therapy.
Agents with specific negative inotrope effects, such as verapamil, should be avoided. Angiotensin converting enzyme inhibitors demonstrated controversial results in PAH due to rheumatic diseases and their use is not included in the proposed therapeutic algorithm.
The recent advances in understanding the mechanisms leading to endothelial dysfunction in PAH allowed to identify three major pathogenetic pathways involving the following mediators: (a) prostacyclin, (b) endothelin-1, (c) nitric oxide (NO). Consequently, these mediators are modified by the new specific treatments.
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Prostacyclin therapy
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Prostacyclins are potent vasodilators. The introduction of continuous
intravenous prostaglandin I2 (PGI2) therapy (epoprostenol) in
the standardized treatment for PAH, either idiopathic or secondary
to other causes, improved exercise capacity, quality of life
and survival of these patients [
20,
21]. Unfortunately, because
of its short half-life, the continuous intravenous application
is the only efficient route for drug administration and may
generate several problems in terms of local and systemic side
effects. For these reasons, more stable prostacyclin analogues
have been developed that can be given by intravenous infusion
(iloprost, treprostinil), subcutaneous injection or inhalation
(treprostinil, iloprost). Many reports demonstrated their clinical
and haemodynamic efficacy [
22–25]. There is also an oral
prostacyclin analogue available (Beraprost) that has been shown
to improve functional capacity and haemodynamic parameters [
26].
An interesting clinical report suggested the clinical efficacy of prostaglandin E1 (PGE1) infusion utilizing lipid microspheres as drug carriers. Lipid microspheres accumulate at sites of inflammation and vascular lesions thereby enhancing drug action and reducing side effects [27].
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Endothelin-receptors antagonists
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Endothelin-1 is a pleitropic molecule with vasoconstrictive
effects that is increased in PAH. Bosentan was the first endothelin
receptors antagonist (with affinity for both ET-A and ET-B receptors)
approved in the EU and the USA for the treatment of IPAH and
PAH associated with collagen vascular diseases and WHO functional
class III (in the United States also WHO functional class IV).
Selective oral endothelin-A receptor antagonists, such as Sitaxsentan and Ambrisentan, have been already utilized in the treatment of IPAH as well as PAH associated with connective tissue diseases. Controlled clinical trials demonstrated improvement of exercise capacity and haemodynamic parameters [28, 29], thus confirming the great therapeutic potential of orally active endothelin receptor antagonists that opened a new era in the treatment of PAH.
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Nitric oxide pathway targeted therapy
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Since many forms of PAH are associated with a defect of endothelium-dependent
NO production, drugs interfering with the production of NO have
been proposed as potential therapies. Although short-term inhalation
of NO demonstrated pulmonary specific vasodilator effects in
humans [
30], its short half life and its potential systemic
side effects allow its therapeutic use only in the short-term
management of critically ill patients and not for a routinely
treatment of PAH. However, its use is accepted in the context
of diagnostic vasoreactivity testing. An alternative way is
to increase the endogenous NO production by the inhibition of
NO degradation. Specific phosphodiesterase-5 (PDE-5) inhibitors
block the degradation of cyclic guanosine monophosphate (cGMP),
which is the main cellular mediator of NO-induced pulmonary
vasodilation. In fact, the PDE-5 inhibitor sildenafil demonstrated
significant effects on exercise capacity as measured by 6 min
walk test and WHO functional class as well as an improvement
of haemodynamic parameters, without significant side effects
related to the treatment [
31]. Other specific PDE-5 inhibitors,
such as vardenafil and taladafil, differ in their kinetics of
pulmonary vasorelaxation (most rapid effect by vardenafil),
their selectivity for the pulmonary circulation (sildenafil
and tadalafil, but not vardenafil) and their impact on arterial
oxygenation (improvement with sildenafil only) [
32].
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Combination therapy
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An attractive therapeutic approach is the combination of drugs
with different mechanisms of action, with the objective to maximize
their clinical benefit. Indeed, many recent report demonstrated
the efficacy and good tolerability of combination therapy with
prostanoids, endothelin receptor antagonists and PDE5 inhibitors
in patients with severe PAH deteriorating under single-agent
therapy [
33–35]. This promising approach could be proposed
not only for unresponsive case to single therapy but also as
initial therapy.
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Future directions
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The growing knowledge about the pathogenetic mechanisms and
the bad long-term prognosis in the majority of patients with
PAH, in particular if associated with autoimmune systemic rheumatic
disease, well-explains the huge amount of new therapeutic approaches
present in the literature, either on humans or in experimental
models. Indeed, interesting reports have been published on the
potential use of selective serotonin-reuptake inhibitors [
36],
vasoactive intestinal peptide [
37], statins [
38], BNP [
39],
selective antagonist of the platelet-derived growth factor receptor
[
40], anti-tumour necrosis factor (TNF)-
therapy [
41], Rho-Kinase
inhibitors [
42], gene therapy [
43,
44], sex hormones [
45], selective
potassium channel opener [
46] and autologous haematopoietic
stem cell transplantation [
47]. Both basic and clinical researches
are essential to improve our impact on the disease, and the
possibility to achieve an early diagnosis and an effective therapy
remains a big challenge for researchers and clinicians.
O. Distler has received speaker's honoraria from Actelion Pharmaceuticals. The other author has declared no conflict of interest.
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Abstract
Introduction