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 review 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 connective tissue disease, 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: clinical experience shows us that lupus patients respond better to endothelin receptor antagonist (ERA) therapy than SScPAH patients, and both lupus and mixed connective tissue disease (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 (Calcium Channel Blockers, Anticoagulants, Diuretics and Oxygen
There have been no studies looking at anticoagulation, diuretics or oxygen therapies in CTD-PAH even though they are thought to be beneficial and are widely used. There is no evidence supporting the use of calcium channel blockers (CCBs) in SSc-PAH. Acute vasodilator responses are rare in SSc-PAH,¹⁵ and in the few patients in whom these are observed there is to date no evidence that a sustained response occurs. Given the negative chronotropic impact of CCB therapy, these agents should be used only in very 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 angiotensionconverting enzyme (ACE) inhibition might 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, endothelin (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 ET_A and ET_B receptors on the vascular smooth muscle, causing vasoconstriction, cellular proliferation and vascular remodelling.^20,21 In normal vessels these actions are primarily through ET_A receptor activation, whereas ET_B receptors mediate the release of vasodilators²² and the clearance of endothelin.²³ However, it has been shown that in pathological conditions ET_B receptors may undergo a change in function and become pro-fibrotic,24 so dual endothelin antagonism could theoretically be pivotal for sustained clinical benefit.