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Pulmonary arterial hypertension: are we doing enough to identify systemic sclerosis patients at high risk of this rare condition?

Pulmonary arterial hypertension (PAH) is a rapidly progressive disorder that is lethal if it remains undiagnosed and untreated. However, modern treatments represent a tremendous advance upon the therapies available just a few years ago and the prognosis for this life-threatening disease has changed. There is now good reason to ensure earlier diagnosis of PAH among systemic sclerosis (scleroderma) patients. PAH is defined as a mean pulmonary artery pressure (PAP) exceeding 25mmHg at rest or 30mmHg during exercise. If left untreated between 45 and 60% of patients with PAH will die within 2 yr of diagnosis [1]. However, when it occurs as a manifestation of scleroderma PAH is particularly severe and 1-yr survival following diagnosis is approximately 55% [2]. Since scleroderma patients with PAH deteriorate quickly and there is a risk of early death, speedy diagnosis, referral and treatment is vital [3]. Also, patients with PAH have a poor quality of life: they become unable to perform even routine daily tasks without severe shortness of breath, fatigue and fainting. Pulmonary disease has emerged as a major cause of death in scleroderma patients [4]. PAH is the most likely complication of scleroderma and can develop in around 15% of these patients [5], primarily due to pulmonary vascular abnormalities or secondary to interstitial lung disease. PAH is most common in the limited cutaneous subset of scleroderma patients, and it is important that this group of patients in particular are monitored for signs of the disease. This strategy offers the potential for much earlier detection of PAH in this high-risk population than is usually possible in sporadic PAH. Patients should be encouraged to report any change in their symptoms: the earliest symptom of PAH is typically breathlessness on exertion or reduced exercise capacity. Symptomatically this may lead to dyspnoea on exertion, commonly first noted when climbing stairs or hills, although later this can occur at rest. Other symptoms that occur at later stages are chest pain due to right ventricular angina and syncope or near syncope on exertion due to reduced cardiac reserve. Rheumatologists have an important role in early recognition of PAH as a complication of connective tissue diseases. Anyone with dyspnoea should be carefully evaluated. Pulmonary function tests and Doppler echocardiography, supplemented by an electrocardiogram, are the traditional methods for investigating possible PAH, but their results can be misleading in scleroderma patients and definitive diagnosis requires direct measurement of PAP by right-heart catheterization. Since around 15% of scleroderma patients may develop PAH and most cases of early PAH are likely to be asymptomatic, it is important to monitor them regularly for signs of this complication. The British Cardiac Society guidelines recommend that patients with limited cutaneous scleroderma, particularly those who are anticentromere antibody positive, should be screened by transthoracic echocardiography annually, even if they have no symptoms of PAH [6]. Screening for PAH is certainly worthwhile in these high-risk patients since it is the only way to identify PAH earlier and begin treatment early. Although PAH is incurable [6], it can now be contained for many years through use of new effective treatments for the condition. We now have a greater incentive to identify PAH patients and manage them through combined clinics, with rheumatologists working closely together with cardiologists, pulmonologists and pulmonary hypertension nurses. Since PAH is a complex disease with high morbidity and mortality, patient management should take advantage of the expertise provided by the specialist centres in the UK and Ireland. The advantages of this multidisciplinary team approach include more effective clinical decision-making, sharing of experience and knowledge between different specialists and nursing staff and better continuity of care. This approach also makes it easier to undertake research into this disease. Shared care identifies patients suitable for state-of-the art treatment—medical and surgical—and inclusion in clinical trials. Amultidisciplinary approach also allows prompt identification of patients failing medical therapy who require urgent consideration for transplantation. Before the introduction of the prostaglandins in the early 1980s the only hope for scleroderma patients with PAH was a heart–lung transplant, although this procedure was rarely performed in these patients since donor availability generally limited this option to younger patients with primary pulmonary hypertension or a small number of other isolated cardiopulmonary conditions. Patients were treated with calcium channel blockers and anticoagulants, oxygen was provided with the aim of reducing or reversing hypoxia-induced pulmonary vasodilation, and right-heart failure was treated conventionally. However, the development of longterm parenteral prostacyclin analogue infusions gave new hope for PAH patients. Iloprost, a stable prostacyclin analogue, is commonly used in the Europe and has the potential advantage of being an antifibrotic, as well as vasodilator agent. Continuous intravenous PG12 (epoprostenol; Flolan), is commonly used and is a treatment approved by the US Food and Drug Administration (the FDA) for both primary and secondary hypertension and pulmonary hypertension caused by scleroderma spectrum disorders. The difficulties with delivering intravenous prostacyclin chronically stimulated interest in devising stable analogues of the compound that can be administered using less complex delivery systems. A stable form of prostacyclin that can be delivered via inhalation, iloprost (Ventavis ), became available in the UK in 2004 to improve exercise capacity and symptoms in patients with primary pulmonary hypertension. Two further epoprostenol analogues have also been studied—treprostinol (Remodulin ), which is given subcutaneously, and beraprost, which is active orally. The first and only licensed oral treatment for PAH, approved in the UK in 2002, is bosentan (Tracleer ). Bosentan is a treatment for PAH in patients with WHOClass III symptoms and in children down to 3 yr of age. It is the first of a new class of orally active drugs known as endothelin receptor antagonists (ERA) [7]. Endothelin (ET-1) is a key mediator of disease processes in PAH [8, 9]. Levels of ET-1 are elevated in PAH [10] and can cause vasoconstriction, inflammation, fibrosis and vascular hypertrophy [11]. ET-1 binds to two receptor subtypes, ETA and ETB [12]. Bosentan is a dual ERA that fully and effectively blocks the