Treatment of Connective Tissue Disease-associated Pulmonary Arterial Hypertension - Where Do New Oral Therapies Fit In?

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Pulmonary arterial hypertension (PAH) is a devastating disease that without specific therapy is characterised by a progressive increase in pulmonary vascular resistance (PVR), leading to right ventricular failure and ultimately death. Among the conditions associated with PAH, connective tissue disease-associated PAH (CTD-PAH) is linked with the gravest prognosis (one-year survival of 50%) without appropriate therapy.1,2

Extraordinary advances in PAH treatment have been made in the last 10 years, benefiting not only patients with idiopathic PAH (IPAH), but also those with CTD-PAH.3,4 CTD-PAH is easily overlooked, as many of these patients will have breathlessness secondary to interstitial lung disease or myocardial involvement.5 Thus, PAH should be considered in all patients with CTD presenting with breathlessness in the absence of obvious other cardio-respiratory disease. This article will discuss the evidence base for current therapies and consider the potential role for combination therapy.

Most data in CTD-PAH have been acquired from subanalysis of larger studies.6–10 Although scleroderma is a relatively uncommon CTD, the high prevalence of PAH associated with scleroderma results in systemic sclerosis-associated PAH (SSc-PAH) being the most common form of CTD-PAH.11 Most available data concerning CTD-PAH are derived from the SSc-PAH population, and these data are used to inform our management of other forms of CTD-PAH. This may not be an entirely valid approach, as clinical experience shows us that lupus patients respond better to endothelin (ET-1) receptor antagonist (ERA) therapy than SSc-PAH patients, and both lupus and mixed CTD (MCTD) patients are more likely to respond to immunosuppressive therapies than patients with scleroderma.12 Importantly, with current treatments the one-year survival in SSc-PAH remains around 80%,3,4 while in mixed populations with significant numbers of lupus and MCTD patients one-year survival is closer to 90%.13,14

Supportive Therapies

There is no evidence supporting the use of calcium channel blockers (CCBs) in SSc-PAH. There have been no studies looking at anticoagulation, diuretics or oxygen therapies in CTD-PAH, although they are thought to be beneficial and are widely used. Acute vasodilator responses are rare in SSc-PAH,15 and in the few patients in whom these are observed there is no evidence to date that a sustained response occurs. Given the negative chronotropic impact of CCB therapy, these agents should be used only in exceptional circumstances – if at all – in SSc-PAH. Whether there is a greater role for them in other forms of CTD-PAH is uncertain.

Renin–Angiotensin System Modifiers

Given the histological similarities between the vascular changes in the lungs and kidneys of patients with scleroderma-associated pulmonary hypertension and renal crises, it has been suggested that angiotension-converting enzyme (ACE) inhibition may have a role in SSc-PAH. One small study (n=8) suggested that captopril may reduce pulmonary pressures in CTD-PAH.16 We have used candesartan in 15 SSc-PAH patients and were unable to show any decrease in disease progression after six months.17 Thus, at present there is no significant body of evidence suggesting a role for ACE-inhibitor therapy in this population.

Endothelin Receptor Antagonists

Imbalances in key endothelial cell-derived mediators – prostacyclin (PGI2), nitric oxide (NO) and, especially, ET-1 – are believed to be key pathogenic drivers in PAH.18 Plasma levels of ET-1 have been shown to correlate with disease severity in IPAH.19 ET-1 exerts its effects through ETA and ETB receptors on the vascular smooth muscle, causing vasoconstriction, cellular proliferation and vascular remodelling.20,21 In normal vessels these actions are primarily through ETA receptor activation, whereas ETB receptors mediate the release of vasodilators22 and the clearance of ET-1.23 However, it has been shown that in pathological conditions ETB receptors may undergo a change in function and become pro-fibrotic,24 so dual ET-1 antagonism could theoretically be pivotal for sustained clinical benefit.


The dual (ETA and ETB) ERA bosentan has been licensed since 2002. A subgroup analysis has been published of two randomised, controlled, double-blind clinical trials, Bosentan Therapy for Pulmonary Arterial Hypertension (BREATHE)-1 and 351.25 Sixty-six patients with CTD-PAH (SSc, 84%; systemic lupus erythematosus (SLE), 11%; overlap/MCTD, 5%) were randomised to either placebo or bosentan and studied over 12–16 weeks. A trend towards improved six-minute walk test (6MWD) scores (+19.5m, confidence interval (CI) –3 to 42) and reduced rate of clinical worsening was observed in the patients receiving bosentan. Sixty-four of these patients were followed up in the open-label extension trials (mean duration of follow-up 1.8 years). In marked contrast to previous published studies, one-year survival was 86%.

In a six-year longitudinal study4 of 92 patients with SSc-PAH, we compared survival of matched historical control patients with those receiving first-line oral bosentan. Kaplan-Meier (KM) estimates of survival in the bosentan group at one and two years were 81 and 71%, respectively, significantly higher than in the historical control group (68 and 47%, respectively; p<0.02).

The Internet-based program TRAX11 collated information about 1,421 patients with CTD-PAH who were treated with bosentan for an average of nine months (31% were treated for longer than one year). The frequency of elevation of aminotransferases was almost identical in the SSc-PAH population (9.4 versus 8.4%) and discontinuation rates were similar (30.2 versus 28.8%) compared with IPAH. In practice, this confirms that this agent is safe in the CTD subpopulation.

The Tracleer Use in PAH associated with Scleroderma and other connective Tissue diseases (TRUST) registry14 prospectively evaluated the long-term outcome in 53 CTD-PAH patients, showing that KM estimates for survival of bosentan-treated CTD-PAH patients (79% of whom had SSc-PAH) at 48 weeks was 92% (95% confidence interval (CI) 85–100). An improvement in some aspects of the short form (SF)-36 quality of life (QoL) questionnaire was observed, in particular in respect of health transition. Finally, in the Quality of LiVes Improved with BosenTan in Australian Open Label (VITAL) trial,26 a significant improvement in quality of life has been shown in 62 scleroderma patients treated with bosentan. Improvements (p=0.03–p<0.0001) in five of the nine domains were found comparing baseline with six-month SF36 QoL assessments. The most evident improvements were physical function and health transition. Thus, we have data on safety, survival and improved exercise tolerance and QoL for SSc-PAH and, to a lesser extent, in other forms of CTD-PAH in patients receiving bosentan.


The highly selective ETA receptor antagonist (6,500:1 selective for ETA versus ETB) sitaxsentan has been approved in Europe for use in PAH since August 2006. Selective ETA blockade is thought to maintain ET-1 clearance while preventing ETA-mediated vasoconstriction, smooth muscle proliferation and inflammation.22,27

Sitaxsentan inhibits the CYP2C9 hepatic enzyme system, reducing clearance of warfarin, and it is thus imperative that warfarin doses are modified when initiating sitaxsentan. A reduction of warfarin dosage by two-thirds and early international normalized ratio (INR) assessment is essential for safe use of this agent. Seibold et al.28 evaluated the impact of sitaxsentan in 110 CTD-PAH patients by combining the CTD subpopulations included in the three completed randomised, double-blind, placebo-controlled clinical trials Sitaxsentan To Relieve ImpaireD Exercise in Pulmonary Arterial Hypertension (STRIDE)-1, 2 and 4.

Patients were World Health Organization (WHO) class II to IV at baseline. Just over half had scleroderma (SSc, 57%; SLE, 23%; MCTD, 20%). The studies varied slightly in design as treatment doses varied from 50 to 300mg and study duration varied from 12 to 18 weeks.

An improvement in 6MWD was observed only in the 100mg group (21m+10.4). This becomes significanct when the placebo group is subtracted (37.7m; p=0.042). Interestingly, elevated liver enzymes were seen only in the placebo group (3.6%). These data suggest that sitaxentan 100mg is well tolerated and may be associated with an improvement in 6MWD in CTD-PAH. However, time to clinical worsening did not differ between treatment groups and placebo.

Highland et al.13 reported on the STRIDE-2X (a prospective, randomised, multicentre, open-label extension of STRIDE-29). This study compared sitaxentan 100mg once-daily with bosentan 125mg twice-daily in 175 PAH patients followed for one year. Although there was no difference between the treatment groups overall, in the 52 patients with CTD-PAH sitaxsentan appeared more effective.

Baseline CTD-PAH subsets were different. Eighty per cent of those receiving bosentan had SSc-PAH, while only 66% of those in the sitaxsentan group had SSc-PAH. Survival at one year was 96% for the sitaxentan group compared with 79% for the bosentan group, p=NS (95% CI 0.02–1.42). Time to clinical worsening appeared improved with sitaxentan compared with bosentan (hazard ratio 0.2, CI 0.05–0.72).

These results raise the possibility that selective ERA antagonism may be superior to dual ERA therapy in CTD-PAH. However, one must be cautious as this was an open-label extension of a subpopulation of a negative trial (the extension trial overall did not show any differences). Importantly, patients could progress to open-label sitaxsentan as part of the STRIDE-3 trial if they reached pre-defined criteria for clinical worsening. This may have induced some investigators to discontinue bosentan more readily than sitaxsentan.

Despite the limitations of the study, this is the first study to compare the effects of selective versus dual ERA therapy in CTD-PAH, and it is reasonable to conclude that sitaxentan is at least of equivalent efficacy to bosentan in this population.


Sildenafil inhibits phosphodiesterase type 5 (PDE5), an enzyme that metabolises cyclic guanosine monophosphate (cGMP), thereby augmenting cGMP-mediated pulmonary vasodilatation and inhibition of vascular smooth muscle proliferation. The Sildenafil Use in Pulmonary Arterial Hypertension (SUPER)10 study randomised 278 patients (IPAH, CTD-PAH or PAH associated with repaired congenital systemic pulmonary shunts) to placebo or sildenafil 20, 40 or 80mg three times daily.

A subgroup analysis29 of 84 CTD-PAH patients (SSc 45%, SLE 23%, others 32%) showed significant improvements in 6MWD after 12 weeks in the sildenafil group compared with placebo in the 20mg (42m, CI 20–64) and 40mg (36m, CI 14–58) groups, but not in the 80mg group. Trends towards improvement in WHO functional class were seen, particularly in the 40 and 80mg groups. Intriguingly, in contrast to the study group as a whole, the haemodynamic benefit was confined to the 20mg group. No subgroup analysis of survival at one year has been published, so although overall one-year survival was excellent, it is not possible to comment on whether sildenafil at any dose is associated with the one-year survival we now expect in this population (over 90% in a population comprising mainly non-SSc CTD-PAH). Thus, as regards sildenafil we have impressive short-term data in the 20mg subgroup, but no long-term data. Furthermore, the data are biased toward non-SSc CTD patients.


Prostanoids replace endogenous prostacyclin, production of which is decreased or absent in the pulmonary vessels of patients with PAH. The only randomised trial performed exclusively in CTD patients is the trial of epoprostanol published by Badesch et al.30 This study randomised 111 SSc-PAH patients to continuous ambulatory epoprostanol or conventional therapy. An impressive 46m gain in 6MWD at 12 weeks (placebo-subtracted change in 6MWD 108m, CI 55–180) was not matched by any improvement in prognosis. Subsequent registry populations3,4 tend to confirm the absence of prognostic benefit when populations in whom prostanoids were used are compared with Koh’s1 original survival curves.

Subcutaneous (s/c) infusion of treprostinil – another prostanoid – offers an alternative. The pivotal 12-week double-blind, multicentre trials7 of 470 PAH patients included a subset of 90 CTD-PAH patients. Patients received either treprostinil or placebo via continuous s/c infusion. The population consisted of SSc 45, SLE 25 and overlap/MCTD 20. At 12 weeks, there was a trend towards improvement in 6MWD (+24m+12, placebo-corrected 21m; p=NS) and significant haemodynamic benefit in the treprostinil group compared with placebo.32 This study suggests that s/c treprostinil is beneficial in CTD-PAH; however, again no long-term data have been published. There are little available data on inhaled prostanoids in CTD-PAH, only the general impression that this therapy is generally less successful in this subpopulation.

Combination Therapy

Multiple combination therapy trials are currently under way, and subanalysis of these trials will provide useful insights to the next steps in managing this difficult population. At present we have limited insights from a few registry populations.

Hoeper and colleagues have reported that a goal-orientated strategy improves survival and reduces the need for intravenous (IV) prostacyclin and lung transplantation in 123 patients with PAH, using combinations of oral and inhaled therapy.33 While the approach (incremental therapy addition to achieve or exceed a minimum required functional class and exercise performance) appeared to improve overall survival, the numbers with CTD-PAH (n=15) were too low to analyse independently. In another study, Mathai et al. added sildenafil to bosentan in patients who failed to improve WHO class and 6MWD. This approach significantly improved both parameters in IPAH patients, but failed to improve either parameter in SSc-PAH patients.34

Accepting that a poor evidence base exists at present, we use our knowledge that the prognosis associated with a mean pulmonary arterial pressure (mPAP) of >40mmHg in patients with SSc-PAH on therapy remains poor, and aim to achieve an mPAP of <40mmHg using stepped augmentation of therapy (ERA, PDE5 inhibitor then prostaglandins) in an attempt to reach this goal.

Early Intervention

Some investigators have questioned the benefit of screening for early forms of CTD-PAH (WHO functional class I and II) since current therapies have not been approved for use in these earlier groups. Theoretically, early therapeutic intervention should slow disease progression. From the NIH study,35 we know that patients with WHO class I and II dyspnoea have only a 50% five-year survival. Furthermore, we know that from onset of symptoms to diagnosis takes around 24 months. In CTD-PAH, given the more malignant nature of the condition, it is essential that patients are identified early, and thus treated as soon as they deteriorate to class III. In addition, the Endothelial Assessment of Risk from Lipids in Youth) EARLY trial36 will be presented later this year. In this study, patients with WHO class I and II PAH were treated over six months in a double-blind, placebo-controlled, randomised trial. A significant reduction in PVR and a significantly reduced tendency towards clinical worsening were observed in the bosentan-treated patients. Efforts will now be required to convince regulatory authorities to support earlier intervention in this population.


Oral therapies have revolutionised the management of CTD-PAH, and one-year survival approaching or exceeding 90% can now be expected depending on the type of patient treated. The outcome in this population is still poor compared with IPAH patients, and many questions need to be addressed. Is combination therapy effective and cost-effective? Which oral therapy should be used as first-line? Does early therapy alter the natural history of the condition or simply shift the survival curve to the right? How do we identify those patients with pulmonary fibrosis who have an associated pulmonary vasculopathy? Which patients should receive immunosuppressive therapy, and are there other therapeutic approaches such as tyrosine kinase inhibition that would be more effective? Will unravelling the pathobiology of CTD-PAH provide insights that help unravel the complex sequence of events that lead to this devastating condition in other patient populations and improve our ability to predict CTD-PAH in individuals? CTD-PAH remains a dynamic area of investigation and our knowledge will continue to grow rapidly over the coming decade.


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