Scleroderma-Related PAH: The Need for Early Diagnosis and Treatment PDF Print E-mail
Saturday, 04 June 2011 01:06
Pulmonary arterial hypertension (PAH) associated with scleroderma (systemic sclerosis) is an aggressive disorder with a poor prognosis. Effective therapies are available for PAH but patients with scleroderma-associated PAH have a poorer response to these therapies compared with those with idiopathic PAH (IPAH). Nonetheless, improvement in outcomes has been obtained, but early diagnosis and early institution of PAH-specific therapy are of paramount importance. 

Estimates of the prevalence of scleroderma-associated PAH vary widely in the published literature depending on the definition of PAH used and the diagnostic tools used to identify PAH. Using echocardiography as a diagnostic tool, up to 60% of scleroderma patients have been reported to have PAH. However, using cardiac catheterization as a diagnostic tool to confirm the presence of PAH, a much lower prevalence rate in the range of 8%-12% has been reported.

Certain subsets of patients appear to have an increased susceptibility to develop PAH. Those with late-onset scleroderma, an isolated reduction in diffusing capacity for carbon monoxide (DLCO), a forced vital capacity (FVC)/DLCO ratio > 1.6, high serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), long-standing limited cutaneous scleroderma (formerly called CREST [calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia] syndrome), or anticentromere antibodies have been identified as having an increased risk of developing PAH.

Vigilance to the presence of these risk factors in scleroderma patients may help in the early detection of PAH.

The diagnosis of PAH in scleroderma patients is clinically challenging. Although the initial clinical presentation symptoms of exertional dyspnea, fatigue, and general weakness are the same as in IPAH, exertional dyspnea may go unnoticed in scleroderma patients because of their sedentary lifestyle. Musculoskeletal comorbidities are common in scleroderma patients and diminish patients' mobility. Thus, the inability to walk up a flight of stairs without gasping for breath, for example, could be misinterpreted as being due to musculoskeletal impairment rather than exertional dyspnea. Also, because of musculoskeletal abnormalities, the 6-minute walk test (6MWT) has limited utility as a diagnostic tool in scleroderma patients. Even scleroderma patients without cardiopulmonary disease have impaired performance on the 6MWT.

Scleroderma patients have other comorbidities as well, including interstitial lung disease (pulmonary fibrosis), left heart disease with diastolic dysfunction, and kidney disease. The signs and symptoms of these comorbidities overlap with those of PAH, confounding the diagnosis of PAH. Pulmonary fibrosis can lead to increased pulmonary pressure as a consequence of fibrosis of lung parenchyma. Diastolic dysfunction associated with left heart disease can also result in increased pulmonary pressure. Because the treatment approaches of interstitial lung disease, left heart disease, and PAH differ, differentiating between these clinical conditions is critical.

Perhaps as a consequence of the clinical challenges inherent in the diagnosis of PAH, scleroderma-associated PAH is typically identified in its late stages. Even in the modern era of improved diagnostic strategies, 75%-85% of patients have functional class III or IV limitations at diagnosis. Functional class at diagnosis is predictive of mortality in scleroderma-associated PAH, as in IPAH, with patients at functional class II having a better survival advantage than those at functional class III or IV. Early diagnosis and early intervention are therefore critical in PAH, especially in scleroderma patients, in whom PAH disease progression can be rapid.

To enable the early diagnosis of PAH, the American College of Cardiology Foundation/American Heart Association consensus statement recommends routine screening with a yearly echocardiography in all scleroderma patients. In patients with echocardiographic hemodynamic features suggestive of PAH (elevated tricuspid regurgitation jet, elevated right ventricular systolic pressure, right heart chamber enlargement, or pericardial effusion), a right heart catheterization is required to confirm the diagnosis. Yearly pulmonary functional tests are also highly useful for screening in scleroderma patients because a low DLCO at presentation (< 80% predicted at baseline) or a declining DLCO (annual reduction of > 10%‐15% of predicted) and an FVC/DLCO ratio of > 1.6, are predictive of PAH.

Available evidence indicates that screening allows the detection of PAH at an early stage in scleroderma patients. In a French nationwide study, scleroderma patients without severe pulmonary function abnormalities were subjected to Doppler echocardiography screening. Of those with suspected PAH (tricuspid regurgitation of > 3 ms-1, or 2.5-3.0 ms-1 with unexplained dyspnea), 55% were confirmed to have PAH by right heart catheterization; of those with confirmed PAH, 44% had functional class II limitations. The utility of screening and the discriminatory and predictive value of echocardiography, as well as NT-proBNP and ECG as screening tools, are currently being evaluated in the ongoing DETECT (early, simple, and reliable detection of PAH in systemic sclerosis) study, a prospective, observational, cohort study in scleroderma patients.

The treatment strategy for scleroderma-associated PAH is essentially the same as for IPAH. Patients with functional class II and early class III limitations are generally recommended to commence therapy with oral agents (endothelin receptor antagonists [bosentan and ambrisentan] or phosphodiesterase-5 inhibitors [tadalafil and sildenafil]). Parenteral agents (epoprostenol and treprostinil) are generally reserved for patients with functional class III limitations who do not improve on oral therapies and in those with class IV limitations. Calcium channel blocker therapy is rarely used in scleroderma patients because they are rarely vasoreactive. However, low-dose calcium channel blockers are sometimes used for the treatment of Raynaud phenomenon in scleroderma patients.

The efficacy of PAH therapies has not been specifically evaluated in scleroderma patients, except for epoprostenol, but pivotal trials have included scleroderma patients, and subgroup analyses have been performed to determine the specific effects of PAH therapies in scleroderma patients. To date, epoprostenol is the only PAH therapy that has been evaluated specifically in scleroderma patients. Continuous intravenous epoprostenol was shown to improve exercise capacity (6MW distance), hemodynamics, and PAH symptoms compared with conventional therapy in patients with scleroderma-associated PAH, although it had no effect on survival. Similarly, continuous subcutaneous treprostinil was found to improve exercise capacity, PAH symptoms, and hemodynamics compared with placebo in a subset of patients with connective tissue disease (CTD) (61% with scleroderma). With respect to the efficacy of oral agents, a meta-analysis of 10 randomized controlled trials of bosentan, sitaxsentan (not approved in the United States and withdrawn from the global market in January 2011), and sildenafil found no clinically relevant improvement in exercise capacity in patients with CTD (62% with scleroderma) after 12-18 weeks of treatment. In contrast, a subgroup analysis of pivotal studies and their open-label extensions of bosentan in patients with CTD-associated PAH (84% with scleroderma) showed a trend toward improvement in exercise capacity and improved 1-year and 2-year survival compared with historical cohorts. Further, a post hoc subgroup analysis of sildenafil in patients with CTD-associated PAH (45% with scleroderma and 23% with lupus) showed improvement in exercise capacity, hemodynamic measures, and functional class after 12 weeks of treatment. There are no reports of subgroup analysis of tadalafil in scleroderma-associated PAH. 

Given the relatively poor response of scleroderma patients to PAH-specific therapies and the poor prognosis of these patients, it is hoped that early identification and early initiation of PAH treatment would increase the chances of an improved outcome. 

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