Pulmonary arterial hypertension in systemic sclerosis: clinical manifestations, pathophysiology, evaluation, and management.

It is increasingly recognized that significant pulmonary arterial hypertension (PAH) develops in more than 15% of patients with systemic sclerosis (SSc). As this complication of SSc may occur even in the absence of overt interstitial lung disease (isolated PAH), it has been likened to primary PAH and is attributable to intrinsic vascular pathology that is the hallmark of SSc. Deregulated activity of mediators controlling vasomotor tone has been implicated, and levels of endothelin-1 (ET-1) are elevated in the circulation and in the lungs. By causing enhanced vasoconstriction, vascular endothelial cell proliferation, smooth muscle hypertrophy, and irreversible vascular remodeling in the lungs, ET-1 appears to play a significant role in the pathogenesis of SSc-associated PAH. Although patients with the limited cutaneous form of SSc are more likely to develop PAH than those with the diffuse form, the true prevalence of PAH in SSc, and the risk factors for its development, are not yet known. Because the prognosis of patients with SSc-associated PAH is substantially worse than that of patients without this complication, intensive efforts are underway to develop sensitive screening strategies and effective treatments. Serial evaluation of SSc patients with Doppler echocardiography appears to be prudent. Antibodies against the centromere or fibrillarin proteins may be useful in identifying those patients with SSc at highest risk for developing PAH. The US FDA has approved a number of novel treatments, including long-acting oral ET-1 receptor antagonists such as bosentan and short-acting parenteral prostacyclin analogs, such as epoprostenol, for PAH. In particular, bosentan appear to be well tolerated, and short-term therapy results in improved exercise tolerance, improved hemodynamics, and possibly improved survival in patients with advanced PAH. These agents may be used alone, or possibly in combination with prostacyclin analogs. Therapeutic agents that modulate the synthesis of nitric oxide, and additional agents targeting the ET-1 signaling system are under preclinical development. Although the large-scale clinical trials that resulted in obtaining FDA approval for these agents were generally carried out in patients with primary PAH, it appears that patients with SSc-associated PAH respond similarly. Therefore, it is reasonable to conclude that ET-1 receptor antagonists and parenteral prostacyclin analogs should be used in SSc patients with moderate to severe PAH. The efficacy of these agents for treating patients with PAH who also experience significant interstitial lung disease, as occurs in many SSc patients, remains unknown. Additional important unresolved issues relate to the long-term efficacy of ET-1 receptor antagonists, and their effects on survival and progression of PAH. Additionally, it is not yet clear if early intervention for SSc patients with mild PAH is beneficial.