Abstract
Systemic sclerosis is an auto-immune disease characterized by skin involvement that often affects multiple organ systems. Pulmonary hypertension is a common finding that can significantly impact prognosis. Molecular pathophysiological mechanisms underlying pulmonary hypertension in systemic sclerosis can be extremely heterogeneous, leading to distinct clinical phenotypes. In addition, different causes of pulmonary hypertension may overlap within the same patient. Since pulmonary hypertension treatment is very different for each phenotype, it is fundamental to perform an adequate diagnostic work-up to properly and promptly identify the prevalent mechanism underlying pulmonary hypertension in order to start the right therapies. When pulmonary hypertension is caused by a primary vasculopathy of the small pulmonary arteries, treatment with pulmonary vasodilators, often in an initial double-combination regimen, is indicated, aimed at reducing the mortality risk profile. In this review, we describe the different clinical phenotypes of pulmonary hypertension in the scleroderma population and discuss the utility of clinical tools to identify the presence of pulmonary vascular disease. Furthermore, we focus on systemic sclerosis-associated pulmonary arterial hypertension, highlighting the advances in the knowledge of right ventricular dysfunction in this setting and the latest updates in terms of treatment with pulmonary vasodilator drugs.
Highlights
Systemic sclerosis (SSc), known as scleroderma, is an immune-mediated disease of the connective tissue, mainly characterized by thickening and fibrosis of the skin and internal organs [1]
A pooled analysis conducted by Yang and colleagues in 2013, by examining 20 studies (17 on connective tissue disease associated pulmonary arterial hypertension (PAH) and three on idiopathic PAH) found that the prevalence of PAH in SSc patients was 35 per million population, while the prevalence of idiopathic PAH was 12 cases per million population, demonstrating that, beyond the rarity of both SSc and PAH, PAH is a “common comorbidity” in SSc patients [22]. Those data are based on the diagnosis of pulmonary hypertension (PH) by the measurement of mean pulmonary arterial pressure (mPAP) >25 mmHg, as the studies included were published before the sixth World Symposium on Pulmonary Hypertension held in 2018, so global prevalence could be higher, and the distribution of patients may vary slightly. It seems that the true impact of this new definition may be minimal in terms of an increase in the number of SSc patients diagnosed with PH, because of the unalerted thresholds of pulmonary vascular resistance (PVR) and pulmonary artery wedge pressure (PAWP) working as buffer zones against its overdiagnosis, as it was recently shown that, in the DETECT study cohort, only 36 (15% of total) patients out of 244 presented a borderline mPAP, of which only four (1.6% of total) were classified as SSc–PAH [23]
Concerning upfront combination therapy with ambrisentan and tadalafil, a prospective, multicenter, open-label trial on 24 treatment-naïve SSc–PAH patients showed an improvement in hemodynamics, right ventricle (RV) structure and function, and functional status [90], while another prospective, multicenter, open-label clinical trial on 24 SSc–PAH naïve patients highlighted a significant improvement in hemodynamics, clinical status and regional and global RV contractility [45]
Summary
Systemic sclerosis (SSc), known as scleroderma, is an immune-mediated disease of the connective tissue, mainly characterized by thickening and fibrosis of the skin and internal organs [1]. In the context of SSc, PH etiology can be extremely heterogeneous, developing as a complication of both heart or lung diseases, which are common comorbidities in scleroderma patients, or as a consequence of chronic thromboembolism. PAH in SSc is among the most frequent pulmonary vascular complication in SSc and its presence significantly worsens scleroderma patients’ prognosis [6]. Treatment of PAH consists of the administration of pulmonary vasodilator drugs, which target different molecular pathways involved in the balance of vasodilation and vasoconstriction mechanisms that regulate pulmonary vascular tone [3]. The aims of this review are to describe the different molecular and clinical phenotypes of PH that can affect the scleroderma population and to discuss the utility of clinical and instrumental tools to identify the presence of pulmonary vascular disease. We focused on SSc–PAH, highlighting the advances in the knowledge of right ventricular dysfunction in this setting and the latest updates in terms of treatment with pulmonary vasodilator drugs
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