Systemic Sclerosis-Related Pulmonary Arterial Hypertension: History
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Subjects: Cardiac & Cardiovascular Systems
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Afroditi Boutou

Systemic sclerosis (SSc)-related pulmonary arterial hypertension (SSc-PAH) is a leading cause of mortality in SSc. The extent of peripheral microvasculopathy assessed through nailfold capillaroscopy might correlate with the presence of PAH in SSc patients. 

  • pulmonary arterial hypertension
  • systemic sclerosis
  • nailfold capillaroscopy

1. Introduction

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by microvascular damage and extensive skin and visceral organ fibrosis. These mechanisms synergistically lead to severe internal organ impairment and, subsequently, to increased mortality [1]. Despite better understanding of its pathogenesis, SSc remains a devastating disease with a calculated pooled standardized mortality ratio of 3.5 [2], predominantly due to cardiopulmonary involvement [3]. Pulmonary arterial hypertension related to SSc (SSc-PAH) occurs in approximately 10–15% of SSc individuals and accounts for a significant proportion of early mortality in this population [4][5]. Prompt diagnosis of SSc-PAH and initiation of targeted therapy are of paramount importance [6][7][8], since timely intervention has been associated with improved survival [9].

Nailfold capillaroscopy is a non-invasive diagnostic tool in SSc, allowing clinicians to assess microvascular damage in early stages of the disease [10]. It is included in the latest classification criteria for SSc [11] as well as in the criteria for the very early diagnosis of SSc (VEDOSS) [12]. Recently, nailfold capillaroscopy has also emerged as a potential surrogate marker of SSc progression [13] as several studies have demonstrated that microvascular alterations might correlate with visceral organ involvement, particularly vascular complications such as PAH [13][14][15]. The concept that peripheral microcirculatory changes may be suggestive of a more systemic vascular disorder including pulmonary vasculature is gaining ground [16][17].

2. Nailfold Capillaroscopy in Systemic Sclerosis Patients with and without Pulmonary Arterial Hypertension

We demonstrated that capillary density was reduced in SSc-PAH patients and this effect was accentuated when RHC was utilized for PAH diagnosis. Accordingly, SSc-PAH individuals had more than thirty times higher likelihood of vascular deletion score greater than 1. Increased capillary loop width, severe scleroderma pattern, and nailfold capillaroscopy rating scale score greater than 1 were also associated with the existence of PAH. The results of our analysis indicate that despite overall microvascular injury in SSc patients, those with SSc-PAH present with more advanced changes in peripheral microcirculation.

Microvasculopathy represents a fundamental part of SSc pathogenesis, leading to several clinical manifestations such as Raynaud’s phenomenon and digital ulcers [18]. Multiple cohort studies have postulated that nailfold capillaroscopic abnormalities correlate with the severity of organ involvement including PAH [13][19][20][21]. Indeed, in a 3-year longitudinal study, progressive loss of capillaries, presence of angiogenesis, and late scleroderma pattern were identified as markers for the occurrence of PAH [20]. SSc-PAH has also been associated with higher scores for capillary loss and capillary disorganization [19]. Additionally, it has been reported that increasing echocardiographically derived systolic pulmonary arterial pressure correlates with the severity of scleroderma pattern [21]. Furthermore, a diagnostic accuracy meta-analysis assessing the value of NVC in the diagnosis of SSc-PAH demonstrated that lower capillary density and increased capillary loop width could potentially detect patients with SSc-PAH [22]. These findings are consistent with the results of our study, suggesting that a higher degree of peripheral nailfold microangiopathy is more common in SSc-PAH, supporting the hypothesis that peripheral microvascular changes may parallel with similar abnormalities in the pulmonary vascular tree.

Interestingly, changes in peripheral microcirculation have also been observed in other forms of pulmonary hypertension [23][24][25][26][27][28]. Hofstee et al. suggested that capillary density is significantly reduced in individuals with idiopathic PAH compared to healthy controls and inversely correlated with the severity of idiopathic PAH [23]. These findings have later been confirmed by other studies, which additionally reported a significant increase in capillary loop width in idiopathic PAH patients [24][25]. Similar patterns of capillaroscopic abnormalities have been reported in chronic thromboembolic pulmonary hypertension [25] and in connective tissue disease-related PAH beyond SSc [27]. For example, the incidence of scleroderma pattern as well as high vascular deletion score were established as independent predictors of PAH in systemic lupus erythematous patients [27]. Recently, a cross-sectional study showed that patients with Eisenmenger syndrome had a reduced capillary density, an increased loop width and more abnormal capillaries than age- and sex-matched healthy controls. NVC shape abnormalities in Eisenmenger syndrome were positively correlated with N-terminal-pro brain natriuretic peptide and negatively associated with estimated glomerular filtration rate [28]. The presence of reduced capillary density and increased capillary width across the whole spectrum of pre-capillary PAH might indicate that besides SSc-associated microangiopathy, PAH may serve as an additional contributing factor to the pronounced microvascular abnormalities observed in SSc-PAH compared to SSc-noPAH.

Early detection of SSc-PAH remained an unmet need for years. According to recent studies from European PAH registries, the percentage of SSc-PAH presenting with New York Heart Association (NYHA) functional class III or IV symptoms at the time of diagnosis reaches 75% [29][30], and remains approximately as high as 30 years ago [31]. Recently, significant progress has been marked with the development of risk assessment algorithms such as the DETECT and Australian Scleroderma Interest Group (ASIG) algorithm as well as the latest European Society of Cardiology (ESC)/European Respiration Society (ERS) guidelines [32][33][34]. Studies have demonstrated that the implementation of these algorithms annually in asymptomatic patients reduces or even eliminates missed PAH cases [35][36][37]. However, the high referral rate for RHC as well as the unclear cost-effectiveness of yearly screening in asymptomatic patients constitute major throwbacks, leading clinicians to poor adherence to PAH screening guidelines [34][38]. Since nailfold capillaroscopy seems to correlate with the presence of PAH, it could potentially navigate clinicians in PAH risk stratification and enhance the performance characteristics of current algorithms, whilst reducing the rate of needless RHCs.

3. Future Perspectives and Conclusions

The results of our analysis suggest that SSc-PAH individuals present with worsening stages of peripheral microangiopathy compared to SSc-noPAH patients, suggesting a more widespread microvasculopathy in these individuals. Future research should explore whether capillaroscopic characteristics are able to identify patients at high risk for developing PAH. Large, well-designed, multi-center, adequately powered RHC-based studies, encompassing sequential nailfold capillaroscopy for longitudinal evaluation of microcirculation, are needed to establish nailfold capillaroscopy as a reliable indicator of pulmonary vasculopathy and determine its performance as part of current screening algorithms in patients at higher risk for SSc-PAH. Such approaches require prespecified methodology for the evaluation of certain capillaroscopic parameters and the application of a homogeneous nailfold capillaroscopy scoring system in order to ensure the validity of measurements [39]. Toward this direction, new automated systems for the calculation of capillary density in NVC images have been introduced with promising results in terms of reliability and time consumption [40]. A potential validation of these findings would showcase the value of nailfold capillaroscopy, particularly NVC, due to the shorter training duration it requires and the better image quality it offers [39], as a useful adjunct for PAH screening and a helpful guide for clinical decision making.

This entry is adapted from the peer-reviewed paper 10.3390/jcm10071528

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