Pulmonary arterial hypertension (PAH) is a common and fatal complication of connective tissue diseases (CTDs). By expert consensus, PAH is diagnosed when at right heart catheterisation a mean pulmonary arterial pressure (PAP) >25mmHg at rest or >30mmHg during exercise is measured, together with a normal wedge pressure and a normal or reduced cardiac output.1 The exact pathophysiological process of PAH is yet to be determined, but is characterised by vascular remodelling within small-calibre pulmonary arteries resulting from endothelial injury, which in CTDs is probably caused by the systemic disease itself. The endothelial injury causes overproduction of mediators such as endothelin-1, angiotensin II and serotonin, leading to vasoconstriction and smooth-muscle cell proliferation, as well as decreased production of vasodilating mediators such as nitric oxide and prostacyclin.
Connective Tissue Diseases
CTDs, or collagen vascular diseases, consist of the scleroderma spectrum of diseases – namely systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) – and systemic lupus erythematosus (SLE), among others.
SSc is characterised by vascular lesions, induration and thickening of the skin and fibrotic changes in other organs, predominantly the muscles, joints, intestinal tract, heart, lungs and kidneys.2,3 Antinuclear antibodies (ANAs) are positive in 90% of patients with SSc, whereas disease-specific auto-antibodies such as anticentromere and antitopoisomerase antibodies are positive in approximately 50%. Mortality in SSc is high, the five-year mortality rate being at least 30%. Pulmonary complications such as pulmonary fibrosis and pulmonary hypertension are the leading causes of death in SSc.
It is still debated whether MCTD is a distinct entity or an overlap syndrome. It is often associated with Raynaud’s phenomenon, oedema of the hands, arthritis and anti-ribonuclear protein (anti-RNP) antibodies.4,5 MCTD is often regarded as part of the scleroderma spectrum of diseases.
SLE is characterised by chronic inflammation with remissions and relapses, predominantly affecting the skin, joints, kidneys, lungs, nervous system and membranes. ANAs are positive in virtually all patients with SLE. The prognosis of patients with SLE varies according to the clinical course; however, the five-year survival rate has increased tremendously over the last few decades and is currently above 90%.6 The major causes of death in the first few years of illness are active disease or infection due to immunosuppression, while late deaths are caused by the disease itself, treatment complications or malignancies.
The differential diagnosis of pulmonary hypertension in CTD consists of pulmonary hypertension caused by myocardial involvement, pulmonary veno-occlusive disorder, pulmonary hypertension due to interstitial lung disease, chronic thrombo-embolic pulmonary hypertension and PAH. The latter is the primary focus of this paper. All causes of pulmonary hypertension in CTD are summarised in Table 1, which provides the revised clinical classification of pulmonary hypertension.7
PAH has been studied widely in systemic sclerosis and the estimated prevalence of 12–15% is based on studies with right heart catheterisation.8 However, in both MCTD and SLE the prevalence is primary based on echocardiography, and is reported to be 20–30% in MCTD9,10 and 5–14% in SLE.11,12
The most common symptoms of pulmonary hypertension are breathlessness, fatigue and (near) syncope.13 Since these symptoms are non-specific, pulmonary hypertension is often overlooked or diagnosed only in its advanced stages. Patients are used to coping with the physical limitations arising from CTD, and patients with pulmonary hypertension as a complication of these diseases complain of shortness of breath at a later stage than the normal population would. Deaths that have previously been assigned to heart attacks may in fact have been caused by pulmonary hypertension.
Screening for Pulmonary Hypertension
Pulmonary hypertension usually occurs late in the course of CTD. Since the majority of these patients are seen at regular intervals by rheumatologists or internists, there is a unique opportunity to screen for pulmonary hypertension at an earlier stage; this would allow therapy to be started earlier, which could prevent the progression of pulmonary hypertension and premature death.
There are several reasons in favour of screening for PAH in CTD patients. First, the prognosis is worse for these patients than for those with idiopathic PAH.14 Second, effective treatments are available and early treatment could prevent, delay or at least alleviate the severe, irreversible and deadly forms of PAH.15 Third, patients with New York Heart Association (NYHA) functional class III – i.e. patients with a marked limitation of physical activities due to dyspnoea – already have significant right ventricular (RV) damage. Moreover, morphometric studies have shown that the intima proliferation correlates with the disease duration – in other words, structural changes take time to develop.15,16
Unfortunately, complaints and physical examination are of little use for screening and early diagnosis of PAH. The symptoms of PAH occur rather late in the course of the disease and are too unspecific to use as a screening tool. With physical examination, signs of right heart failure can be detected, as can an accentuated pulmonary component of the second heart sound; however, these signs are absent in early PAH.17 Chest radiography in PAH can demonstrate enlargement of the central pulmonary arteries (see Figure 1), and an electrocardiogram (ECG) can show right-axis deviation and RV hypertrophy.16 Pulmonary function testing can often detect a mild restriction, and Steen and co-workers found that an isolated decrease in diffusing capacity for carbon monoxide (DLco) predicts PAH in SSc, even 4.5 years before clinically evident PAH is diagnosed.18 However, a decrease in DLco can also be caused by smoking and interstitial lung disease.
The most widely used screening method is Doppler echocardiography estimation of the systolic and diastolic PAP by measuring the tricuspid regurgitation velocity and right atrial pressure. The sensitivity of echocardiography is approximately 75%, using a threshold of an estimated systolic PAP >35mmHg. However, echocardiography is flawed by both false-positive and false-negative results, as well as by overestimation of PAP, and may lead to unnecessary right heart catheterisations.19 The accuracy of echocardiography could be enhanced by the addition of other markers, such as the RV Tei index,19 tissue Doppler imaging20 or biomarkers such as N-terminal pro-hormone brain natriuretic peptide (NT-proBNP);21 however, the value of these markers is yet to be confirmed. In theory, evaluation during exercise – for example a cycle ergometer and echocardiography during exercise – could provide valuable information in early PAH patients, but the invasive nature of the first and practical issues to do with the latter are major obstacles to their use as screening tools.
In conclusion, the optimal screening tool to date is an annual echocardiography combined with a thorough history and, when feasible, pulmonary function testing.1 However, a clinical history of declining exercise capacity should be regarded as a potential sign of pulmonary hypertension regardless of the findings of pulmonary function testing and echocardiography,22 and should prompt a right heart catheterisation, the gold standard for the assessment of pulmonary hypertension. According to the guidelines, once the diagnosis of PAH is confirmed at right heart catheterisation, a vasoreactive study should be performed. In our experience, and also in that of others, vasoreactivity is absent in CTD patients and could be left out of the evaluation. For classification of a patient with pulmonary hypertension, a complete evaluation is indispensable; this is also the case in known CTD patients.
The complete evaluation consists of, among others, an echographic study of the abdomen with Doppler of the splenic vein, perfusion scintigraphy and HIV serology23 (see Figure 2). In cases in which no other cause is found for the pulmonary hypertension besides the CTD, the diagnosis of PAH associated with CTD can be established. In order to apply the appropriate treatment options, the next step is to determine the functional class of the patient according to the NYHA scale (see Table 2).
Treatment of Pulmonary Hypertension
Treatment of PAH consists of general therapeutic options and specific treatment. Oxygen therapy is indicated in patients with hypoxaemia. Anticoagulation therapy, which is used in patients with idiopathic PAH, is often contraindicated in CTD patients. In patients with SSc and MCTD, oesophageal dysmotility frequently leads to occult blood loss, and the regularly present angiodysplasias in the intestinal tract may cause life-threatening bleeding when combined with anticoagulation therapy. In cases of RV failure, diuretics and possibly digoxin should be applied.
Specific treatment of patients with PAH is targeted to produce vasodilatation and vascular growth inhibition; since acute vasoreactivity is absent in CTD patients, remodelling of the pulmonary vasculature is regarded as the mechanism of action in those patients. The treatment arsenal for PAH consists of the endothelin receptor antagonists, the prostacyclin analogues and phosphodiesterase-5 inhibition. Current treatment algorithms for PAH recommend first-line treatment with oral medication such as bosentan24 and sitaxsentan,25 both endothelin receptor antagonists, and sildenafil,26 a phosphodiesterase-5 inhibitor, for class III patients; and treprostinil27 and epoprostanol,28 both prostacyclin analogues, for class III and class IV patients. Up-to-date treatment is ‘goal-orientated’ – i.e. a 6-minute walking test (6MWT) distance >380m, a peak oxygen uptake >10.4ml/min/kg, a peak systolic blood pressure during exercise >120mmHg,29 NYHA functional class I and a decrease in plasma brain natriuretic peptide (BNP) levels.30 In order to achieve an optimal treatment result, all initiated treatments should be evaluated regularly – at least once every three months. This evaluation may consist of a careful history, 6MWT, plasma BNP levels, echocardiography, pulmonary function tests and right heart catheterisation.
In CTD patients, this evaluation must be individualised, since the majority of patients are impaired in condition and motility due to the CTD itself. Also, 6MWT results in CTD patients are in general lower than the score achieved by the general PAH population.
In all treatment studies in PAH the proportion of CTD patients is small and the observation time is short, in general between 12 and 18 weeks. Therefore, the results should be interpreted with care. Denton performed a subanalysis of CTD patients treated in the bosentan pivotal trial and found 64 evaluable patients, with a mean follow-up of 1.8 years. 6MWT distance improved by 14.7m and 25% of the patients improved in terms of NYHA class.31 Survival after two years was 73.4% compared with 13.6% in Kawut’s study, which was before endothelin receptor antagonists had become available.32
In the Sitaxsentan To Relieve Impaired Exercise (STRIDE-1) study only 24 CTD patients were included. In all patients treated with sitaxsentan, improvement of NYHA class was achieved in 13% and 6MWT distance improved by 24.9m.25 In the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) study, a subanalysis of 62 patients with CTD showed a 46m improvement of 6MWT distance; however, no decline in time to clinical worsening was determined.26 In the study by Barst et al. with epoprostanol, only patients with idiopathic PAH were included. Active treatment resulted in improved survival, improved quality of life and an increase of 44m in the 6MWT.28 In a subanalysis of the 90 CTD patients included in the two placebo-controlled studies of subcutaneous treprostinil, a 25m improvement in the 6MWT was reported, as well as improvement of symptoms of PAH and haemodynamics.33 Since the literature does not provide treatment guidelines in PAH associated with CTD, most information is gathered by observing daily practice.
Daily Clinical Care of Pulmonary Arterial Hypertension–Connective Tissue Disease Patients in Nijmegen
The pulmonary hypertension team in the Radboud University Nijmegen Medical Centre in The Netherlands consists of rheumatologists, chest physicians, cardiologists, radiologists, pathologists and nurses. Working in a tertiary referral hospital for SSc, our team specialises in PAH associated with CTD, which is diagnosed in almost 50% of our PAH patients.
After a thorough evaluation of each patient, as described above and shown in Figure 2, we initiate treatment with bosentan 125mg twice daily in NYHA class III patients, together with oxygen when applicable. Our experience with sitaxsentan is limited, since the registration and reimbursement of sitaxsentan in The Netherlands was completed only very recently, but it could be an alternative treatment option in CTD patients.
When evaluation of treatment after three months shows an improvement in terms of complaints and exercise capacity as measured by 6MWT and NYHA classification, together with a stabilisation or improvement of pulmonary function tests and echocardiography, the treatment is continued and evaluations are repeated every three months. When treatment goals are not achieved, or no longer achieved, add-on therapy with sildenafil 20mg thrice daily is applied. If this is not effective, add-on therapy with subcutaneous treprostinil is employed.
Dosage is built up over three days to the effective dose of 20ng/kg/min, with weekly evaluations using telephone interviews and a complete evaluation after eight weeks. In patients presenting with NYHA class IV, treatment is initiated with either subcutaneous treprostinil or intravenous epoprostanol. When applicable, these patients are registered as lung transplantation candidates. Patients who deteriorate to NYHA class IV and right heart failure are initiated on either intravenous epoprostanol or inhaled iloprost 100μg daily – divided into six doses – using an ultrasonic nebuliser, combined with continuous intravenous diuretics.
When patients are stabilised with this treatment, conversion to subcutaneous treprostinil is proposed, since this treatment is also feasible for patients with hand problems such as digital ulcers, sclerosis of the fingers and arthritis. Although in theory the application of a subcutaneous system in patients in whom the disease affects the skin could cause dosage problems or more severe side effects, such as pain at the infusion side, this treatment is found to be effective and well-tolerated in the vast majority of CTD patients at our centre.
To date, no data are available to support the use of immunosuppression in PAH associated with SSc. However, a few case reports and a retrospective study suggested that a minority of patients with PAH associated to SLE or MCTD could benefit from immunosuppression using cyclophosphamide intravenous pulse therapy and glucocorticosteroids.34 In our practice, immunosuppression is applied in patients when other signs of active CTD are present, and patients are always treated with specific PAH medication when their functional class is NYHA III or IV. An example of the treatment scheme is shown in the box below.
In summary, the treatment of patients with PAH associated to CTD can differ from the treatment of idiopathic PAH. In general, this complication is more aggressive and, despite the slow rise of more or less regular screening schemes, patients tend to present with more severe PAH and their life expectancy is worse. The specific treatments for PAH are found to be effective in CTD-related-PAH patients, although long-term results are lacking. With this in mind, as well the fact that doctors already know their at-risk population, screening schemes consisting of an annual echocardiography combined with a thorough history and pulmonary function testing, and easily accessible right heart catheterisation in cases of doubt, provide us with an unique opportunity to start timely treatment.