Complex Pathophysiology of Pulmonary Hypertension Associated with Systemic Sclerosis: Potential Unfavorable Effects of Vasodilators

Abstract

achieved in total PAH population, sub-analysis within CTD-PAH patients showed failure to achieve short-term primary endpoints (2-4). In addition, current PH registries, such as REVEAL and ASPIRE, showed that patients with SSc-PAH had worse prognosis than those with other PH subgroups (5, 6). Recent meta-analysis on prognosis of patients with SSc-PAH reported that 1-, 2-, and 3-year survival rates were 82%, 67%, and 56%, respectively, even in modern treatment era (7). Furthermore, a recent striking report has demonstrated that survival in SSc-PAH had not improved at all after availability of oral pulmonary vasodilators, whereas survival in patients with idiopathic or heritable PAH had improved remarkably (8). Precipitating factors for poor prognosis of SSc-PAH still remain unclear, but at least two mechanisms can be speculated: poor responsiveness to pulmonary vasodilators and potential emergence of unfavorable effects by use of pulmonary vasodilators. The histology of pulmonary vasculature in patients with SSc-PAH is unique and is characterized by concentric intimal fibrosis with less prominent hypertrophy of vascular smooth muscle cells (9), which is a main target of pulmonary vasodilators. On the other hand, pathophysiological conditions of SSc-PAH are highly complex, since SSc affects not only pulmonary arteries, but also other organ systems, including lung interstitium, myocardium, gastrointestinal tract, and peripheral vasculature (10). Therefore, upon introduction of pulmonary vasodilators, it is necessary to consider their potential beneficial or harmful effects on the entire SSc lesions.

Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis

“…By contrast, in patients with an increased risk of left heart disease (low PVR and high PAWP) and/or restrictive lung disease (low TLC), the benefit of combination therapy was less pronounced. Therefore, in the ex-PAS population (an older subgroup of patients with more cardiovascular comorbidities),21 less benefit may be gained from combination therapy 22. Further research to determine the optimal treatment approach in addition to standard PAH therapies is required for this population.…”

Pulmonary hypertension in systemic sclerosis: different phenotypes

“…The prevalence of pulmonary arterial hypertension (PAH) is around 10% and, despite recent advances in the treatment armamentarium, PAH survival is still poor with a median survival time of 3 years [2]. Moreover, SSc-PAH patients are most often less responsive than patients with idiopathic PAH and have a worse prognosis, although they present with milder haemodynamic impairment [2][3][4][5]. However, recent studies have suggested that where aggressive therapy is used, a similar reduction in event rate is achievable in SSc and idiopathic PAH populations [6,7].…”

Elderly-onset calcinosis of hyperphosphataemic familial tumoural calcinosis/hyperostosis-hyperphosphataemia syndrome: the role of comorbid scleroderma

“…Calcinosis in scleroderma patients also comprises calcium hydroxyapatite and foamy macrophage clusters, similar histopathological characteristics to that found in HFTC/HHS calcinosis (9). However, there is no difference in serum calcium and phosphate levels between the two subgroups of scleroderma patients with and without symptomatic ectopic calcinosis (10). Furthermore, higher serum FGF23 levels correspond to increased ectopic calcinosis in female scleroderma patients (11).…”