Pulmonary arterial hypertension (PAH) in connective tissue diseases
Pneumology Service, Division of General Internal Medicine, Department of Internal Medicine, Medical University of Innsbruck, Austria.
Correspondence to: Ao. Univ.-Prof. Christian M. Kähler MD, Pneumology Service, Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail: C.M.Kaehler{at}uibk.ac.at
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Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of the small pulmonary vascular bed as a result of vascular proliferation and remodelling of the vessel wall leading to permanently increased pulmonary vascular resistance and elevated pulmonary artery pressures, which result in right heart failure and premature death. Pathologic processes behind the complex vascular changes associated with PAH include vasoconstrictor/vasodilator imbalance, thrombosis, misguided angiogenesis and inflammation. Besides idiopathic PAH, it can also occur in association with portal hypertension, HIV infection, congenital cardiac left-to-right shunts and connective tissue diseases (CTD). Unfortunately, despite recent major improvements in PAH treatment, no current therapy can yet cure this devastating condition. This review will briefly highlight epidemiology, pathogenesis, and diagnostic and treatment options known so far for PAH occurring in connection with CTD.
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Pulmonary arterial hypertension (PAH) is mainly characterized as a disease of the small arteries of the pulmonary vasculature leading to an increased mean pulmonary artery pressure (PAP) over 25 mmHg at rest and over 30 mmHg during exercise. The elevated pressures in the pulmonary circulation result in right heart dysfunction and failure. The diagnostic classification of PAH was recently redefined by the WHO Venice Conference (Table 1) [1]. The diagnosis of idiopathic PAH (IPAH) is made when no known risk factors have been identified [1]. Besides the idiopathic and the familial forms PAH can also occur in a variety of other conditions such as connective tissue diseases (CTD).
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In this respect, mainly patients suffering from systemic sclerosis (SSc), systemic lupus erythematosus (SLE), mixed connective tissue diseases (MCTD) and—to a lesser extent—rheumatoid arthritis, dermatomyositis and primary Sjoegren's syndrome may be affected [2].
Epidemiology
PAH is an orphan disease, and with all categories included, its prevalence has been estimated to be up to 15 cases per million. However, PAH has been increasingly recognized as a more common and severe complication of CTD. In a population-based approach, the prevalence of pulmonary hypertension (PH) was 2.6% in over 3500 investigated patients [3]. In the National Institute of Health (NIH) registry, among 236 cases of unexplained PH, about 8% was associated with CTD [4].
It is a well-recognized phenomenon in PAH associated with CTD that mainly women are affected. However, compared with IPAH, the patients are older, have a significantly lower cardiac output and there is a trend towards worse survival compared with IPAH patients: 1-, 2- and 3-yr survival rates were reported to be 45, 35 and 28%, respectively, with a median survival of only 1 yr following diagnosis (IPAH: 1- and 3-year survival, 68 and 48%, respectively, with a median survival of 2.8 yrs) [2, 5]. Unfortunately, the risk factors for PAH development in CTD are as yet unknown.
A recently finished registry study of PH in 722 patients with SSc in the UK showed a prevalence of about 12% [6]. In another series of 930 patients with SSc, the cumulative incidence was 13% [7] and in the French registry, which included haemodynamic confirmation of PAH, it was calculated to be 10% [8].
PAH is less commonly seen in SLE (0.5–14%, [9]), and is a rare clinical finding in dermatomyositis and rheumatoid arthritis [2].
As a limitation of the data given above, estimation of the real prevalence of PAH in CTD remains open for discussion due to the lack of a consistent epidemiological data. Available data are highly variable according to the definition and the method used for assessing PAP and the potential biases concerning the study populations investigated.
Pathophysiology
The pathophysiological mechanisms leading to PAH remain unknown. Histopathological changes in the various recognized forms of PAH have been shown to be qualitatively similar [10]. Even if many pathobiological mechanisms have been identified, exact initiation and perpetuation pathological processes are still not well understood. A commonly accepted pathophysiological model includes the imbalance between vasoconstrictive, thrombogenic, mitogenic and pro-inflammatory factors as opposed to anti-coagulant, anti-mitotic and vasodilating mechanisms resulting in endothelial dysfunction and vascular remodelling. Chronically impaired production of vasodilators such as nitric oxide and prostacyclin goes along with an over-expression of vasoconstrictors such as thromboxane A2 or endothelin-1 (ET-1) [11].
In CTD, PAH may occur in association with interstitial fibrosis, but also in isolation, i.e. in the absence of overt interstitial lung disease or chronic hypoxia. This might be a result of direct vascular involvement. Deregulated activity of mediators controlling vasomotor tone has been implicated, and levels of ET-1 are elevated in the circulation and in the lungs. By causing enhanced vasoconstriction, vascular endothelial cell proliferation, smooth muscle hypertrophy and irreversible vascular remodelling in the lungs, ET-1 appears to play a significant role in the pathogenesis of PAH in CTD.
Besides the hypothetically occurring pulmonary vasospasm, the so-called pulmonary Raynaud's phenomenon, it is further discussed whether anti-endothelial cell antibodies and other occurring immunological mechanisms could be associated with the development of PAH in CTD [2].
Diagnostic tools
Recently, the diagnostic approach has been defined more clearly according to the new clinical classification (Table 1, [1]) and with consensus reached on algorithms of various investigative tests and procedures [12]. (Differential) diagnosis of PAH includes clinical history and physical examination, ECG, chest radiography, transthoracic Doppler echocardiography, pulmonary function tests, arterial blood gas analyses, ventilation and perfusion lung scans, high-resolution and contrast-enhanced spiral CT of the lung (and/or pulmonary angiography), blood and immunology tests, abdominal ultrasound scan, exercise capacity assessment and haemodynamic evaluations.
Given the insidious symptoms of PAH (dyspnoea, fatigue, palpitations, angina or syncopes during exercise), a high degree of clinical suspicion is required in order to make the diagnosis. Together with a careful clinical evaluation, a chest radiograph and ECG, a 2D-echo Doppler examination is considered as the first-line diagnostic tool [12].
Results by Murata et al. [13] indicate that 2D-echo is useful in detecting subclinical PAH and estimating PAP in patients with CTD. Also, the detection of elevated levels of the brain natriuretic peptide (BNP) may be useful in identifying those patients with CTD at highest risk for developing cardiac involvement [14]. However, the gold standard in the diagnosis of PAH is still the right heart catheterization (mean PAP >25 mmHg and a pulmonary capillary wedge pressure <15 mmHg). It is recommended that after diagnosis of PAH at the latest, CTD patients should be referred to a specialized PAH clinic for further evaluation and the initiation of a specific therapy.
Treatment options
Treatment of PAH associated with CTD mirrors the diagnosis and treatment for PAH of any other aetiology (Table 1, 1st category, [1]). As prognosis of CTD patients with PAH, especially SSc, is substantially worse than that of patients with IPAH [5, 6], intensive efforts are underway to develop effective treatment options. However, treatment appears more complex as compared with other forms of PAH.
The risk-to-benefit ratio of oral anti-coagulation is not yet well-understood. Also, the rate of acute vasoreactivity and of a long-term favourable response to calcium channel blocker treatment is suggested to be lower when compared with IPAH [2]. Therapeutic agents like prostacyclins or drugs that modulate the synthesis of nitric oxide and additional agents targeting the ET-1 signalling system are under ongoing investigation.
Intravenous epoprostenol has been shown to be effective in a 3-month randomized trial of patients suffering from scleroderma spectrum. It has been shown that epoprostenol treatment can improve exercise capacity, symptoms and haemodynamics [15]. However, no improvement in survival was observed, and further retrospective analyses have shown that the effect of intravenous epoprostenol on survival of IPAH patients seems to be better when compared with its effects in SSc patients [16].
Prostacyclin application by another route, a continuous subcutaneous administration of treprostinil, was evaluated in a subset of 90 patients with PAH and CTD who were enrolled in a larger randomized controlled trial. After 3 months, an improvement in exercise capacity, symptoms and haemodynamics too was shown [17].
Also, the endothelin receptor antagonists bosentan and sitaxsentan have shown favourable results. The clinical efficacy of the dual ET-receptor antagonist bosentan was demonstrated in BREATHE-1: 213 PAH patients (either idiopathic or associated with CTD) were randomized to placebo or bosentan [18]. Compared with placebo, administration of bosentan improved exercise capacity, as measured by the 6-min walk test, WHO functional class and the Borg dyspnoea index, and significantly improved the overall time to clinical worsening [18]. In the subgroup of SSc patients included in this trial, bosentan just prevented deterioration and did not significantly improve exercise capacity. Interestingly, a recent post hoc analysis revealed that the survival rate has improved after first-line bosentan therapy also in this subset of patients: 82% after 1 yr, 66.6% after 2 yrs and 63.5% after 3 yrs [18, 19]. However, it has to be considered that 16% of the patients received epoprostenol as an add-on therapy and 14% epoprostenol after the discontinuation of bosentan [19].
Additionally, the selective ET-A receptor antagonist sitaxsentan has also shown favourable results in patients with PAH associated with CTD, in a recently performed trial [20].
An upcoming new treatment strategy in PAH is the inhibition of phosphodiesterase-5. In a randomized controlled study, sildenafil had improved the exercise capacity and haemodynamics also in a subgroup of patients with CTD [21].
Lung transplantation is the last option for patients with severe PAH. However, the presence of CTD with possible multi-organ involvement may represent a contraindication for lung transplantation in advanced cases not responsive to medical treatment. Thus, each patient needs to be considered individually for increased risks as a consequence of the presence of multisystem disease.
In conclusion, long-term survival has improved in CTD associated with PAH but is still worse compared with IPAH patients receiving a ‘specific PAH’ medication. Upcoming combination strategies might result in higher survival rates of patients with PAH and CTD. Further investigations have to be performed to understand the pathophysiology of PAH in CTD more clearly.
C.M.K. received speaker's honorarium for participation at Actelion Winter School 2006, and received research support from Actelion. D.C. has declared no conflicts of interest.
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References |
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TopAbstractIntroductionReferences |
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- Humbert M, Sitbon O, Simonneau G. (2004) Treatment of pulmonary arterial hypertension. N Engl J Med 351:1425–36.
[Free Full Text] - Galie N, Manes A, Farahani KV, et al. (2005) Pulmonary arterial hypertension associated to connective tissue diseases. Lupus 14:713–7.
[Abstract/Free Full Text] - Yoshida S and Katayama M. (2001) Pulmonary hypertension in patients with connective tissue diseases. Nippon Rinsho 59:1164–7.[Medline]
- Rich S, Dantzker DR, Ayres SM, et al. (1987) Primary pulmonary hypertension. A national prospective study. Ann Intern Med 107:216–23.[CrossRef][ISI][Medline]
- Humbert M and Simonneau G. (2005) Drug Insight: endothelin-receptor antagonists for pulmonary arterial hypertension in systemic rheumatic diseases. Nat Clin Pract 1:93–101.
- Mukerjee D, St George D, Coleiro B, et al. (2003) Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 62:1088–93.
[Abstract/Free Full Text] - MacGregor AJ, Canavan R, Knight C, et al. (2001) Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology 40:453–9.
[Abstract/Free Full Text] - Humbert M, Chaouat A, Bertocchi M, et al. (2004) ItinerAIR-HTAP: A French National Prospective Registry of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 169:A169.
- Haas C. (2004) Pulmonary hypertension associated with systemic lupus erythematosus. Bull Acad Natl Med 188:985–97.[ISI][Medline]
- Pietra GG, Capron F, Stewart S, et al. (2004) Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 43:25–32.
- Budhiraja R, Tuder RM, Hassoun PM. (2004) Endothelial dysfunction in pulmonary hypertension. Circulation 109:159–65.
[Free Full Text] - Barst RJ, McGoon M, Torbicki A, et al. (2004) Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 43:40–7.
- Murata I, Kihara H, Shinohara S, Ito K. (2006) Echocardiographic evaluation of pulmonary arterial hypertension in patients with progressive systemic sclerosis and related syndromes. Jpn Circ J 173:744–750.
- Leuchte HH, Baumgartner RA, El Nounou M, et al. (2006) Brain natriuretic peptide is a prognostic parameter in chronic lung disease. Am J Respir Crit Care Med.
- Badesch DB, Tapson VF, McGoon MD, et al. (2000) Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 132:425–34.
[Abstract/Free Full Text] - Humbert M, Sanchez O, Fartoukh M, et al. (1999) Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study. Eur Respir J 13:1351–6.[Abstract]
- Oudiz RJ, Schilz RJ, Barst RJ, et al. (2004) Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest 126:420–7.[CrossRef][ISI][Medline]
- Rubin LJ, Badesch DB, Barst RJ, et al. (2002) Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346:896–903.
[Abstract/Free Full Text] - Denton CP. (2005) Dual endothelin receptor antagonism in pulmonary arterial hypertension related to systemic sclerosis. Eur J Clin Invest 35:AI72.
- Barst RJ, Langleben D, Frost A, et al. (2004) Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 169:441–7.
[Abstract/Free Full Text] - Galie N, Ghofrani HA, Torbicki A, et al. (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148–57.
[Abstract/Free Full Text]
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