Pulmonary Arterial Hypertension In Systemic Sclerosis Research Articles

Aberrant long-chain fatty acid metabolism associated with evolving systemic sclerosis-associated pulmonary arterial hypertension.

We sought to investigate differential metabolism in patients with systemic sclerosis (SSc) who develop pulmonary arterial hypertension (PAH) versus those who do not, as a method of identifying potential disease biomarkers. In a nested case-control design, serum metabolites were assayed in SSc subjects who developed right heart catheterization-confirmed PAH (n = 22) while under surveillance in a longitudinal cohort from Johns Hopkins, then compared with metabolites assayed in matched SSc patients who did not develop PAH (n = 22). Serum samples were collected at "proximate" (within 12 months) and "distant" (within 1-5 yr) time points relative to PAH diagnosis. Metabolites were identified using liquid chromatography-mass spectroscopy (LC-MS). An LC-MS dataset from SSc subjects with either mildly elevated pulmonary pressures or overt PAH from the University of Michigan was compared. Differentially abundant metabolites were tested as predictors of PAH in two additional validation SSc cohorts. Long-chain fatty acid metabolism (LCFA) consistently differed in SSc-PAH versus SSc without PH. LCFA metabolites discriminated SSc-PAH patients with mildly elevated pressures in the Michigan cohort and predicted SSc-PAH up to 2 yr before clinical diagnosis in the Hopkins cohort. Acylcholines containing LCFA residues and linoleic acid metabolites were most important for discriminating SSc-PAH. Combinations of acylcholines and linoleic acid metabolites provided good discrimination of SSc-PAH across cohorts. Aberrant lipid metabolism is observed throughout the evolution of PAH in SSc. Lipidomic signatures of abnormal LCFA metabolism distinguish SSc-PAH patients from those without PH, including before clinical diagnosis and in mild disease.NEW & NOTEWORTHY Abnormal lipid metabolism is evident across time in the development of SSc-PAH, and dysregulated long-chain fatty acid metabolism predicts overt PAH.

Systemic sclerosis-associated pulmonary arterial hypertension is characterized by a distinct peripheral T helper cell profile.

Systemic sclerosis (SSc) is characterized by multiple clinical manifestations. Vasculopathy is a main disease hallmark and ranges in severity from an exacerbated Raynaud phenomenon to pulmonary arterial hypertension (PAH). The potential involvement of immune system in SSc associated vascular abnormalities is not clear. Here, we set out to study SSc-related immune parameters and determine whether and which peripheral T cell subsets associate with vascular severity in SSc patients. Peripheral blood and clinical data were collected from 30 SSc patients, 5 patients with idiopathic pulmonary arterial hypertension (IPAH) and 15 age and sex-matched healthy donors (HD). In this cross-sectional cohort SSc patients with PAH (n = 15) were matched for their age, sex and medication with SSc patients with no signs of PAH (n = 15). Lymphocyte subsets were quantified by multi-colour flow cytometry. SSc patients exhibited elevated percentages of T peripheral helper cells (Tph), CD4+GZMB+ T cells and decreased levels of Th1 cells compared with HD. Increased presence of both CD4+ and CD8+ exhausted-like (CD28-) T cells, characterized by raised cytokine and cytotoxic signature, was also observed in SSc compared with HD blood. Furthermore, IL-4 expressing CD4+CD8+ T cells were significantly increased in SSc peripheral blood. Interestingly, the presence of PAH in SSc was accompanied by a distinct T helper profile, characterized by raised percentages of Th17 and Tph cells. SSc patients with severe vasculopathy (presence of PAH) exhibited a distinct T cell profile, suggesting for a potential role of auto-immune inflammation in SSc vascular complications.

Use of exercise tests in screening for pulmonary arterial hypertension in systemic sclerosis: A systematic literature review

Background and objective: Patients with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH) have a poor prognosis, accounting for 30% of all SSc-related deaths. Guidelines recommend annual screening for PAH regardless of symptoms, as early treatment improves outcomes. Current protocols include combinations of clinical features, biomarkers, pulmonary function tests, and echocardiography. None include exercise testing, although early-stage PAH may only be evident during exercise. This systematic review assessed the performance of exercise tests in predicting the presence of PAH in patients with SSc, where PAH was confirmed through right heart catheterisation (RHC). Methods: Comprehensive literature searches were performed using MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trails, CINAHL, Scopus and Web of Science from inception to May 2023. Articles were screened for eligibility by two independent reviewers. Eligibility criteria included the use of a non-invasive exercise test to screen adult patients to detect PAH in a population without a previous diagnosis of PAH, with diagnosis confirmed by RHC. Results: Eight studies met the inclusion criteria, describing at least one of three different non-invasive exercise tests: cardiopulmonary exercise test, six-minute walk test and stress Doppler echocardiography. All studies found that exercise tests had some ability to predict the presence of PAH, with sensitivity between 50% and 100% and specificity from 73% to 91%. Conclusion: Exercise tests are infrequently used for screening for PAH in SSc but can predict the presence of PAH. More data are required to establish which tests are most effective.

Connective tissue disease‐associated pulmonary hypertension: A comprehensive review

AbstractConnective tissue diseases (CTDs) can be associated with various forms of pulmonary hypertension, including pulmonary arterial hypertension (PAH), pulmonary veno‐occlusive disease, pulmonary venous hypertension, interstitial lung disease‐associated pulmonary hypertension, chronic thromboembolic pulmonary hypertension, and sometimes a combination of several processes. The prevalence of PAH varies among the different CTDs, with systemic sclerosis (SSc) having the highest at 8%–12%. The most recent European Society of Cardiology/European Respiratory Society guidelines recommend routine annual screening for PAH in SSc and CTDs with SSc features. As CTDs can be associated with a myriad of presentations of pulmonary hypertension, a thorough evaluation to include a right heart catheterization to clearly delineate the hemodynamic profile is essential in developing an appropriate treatment plan. Treatment strategies will depend on the predominant phenotype of pulmonary vasculopathy. In general, management approach to CTD‐PAH mirrors that of idiopathic PAH. Despite this, outcomes of CTD‐PAH are inferior to those of idiopathic PAH, with those of SSc‐PAH being particularly poor. Reasons for this may include extrapulmonary manifestations of CTDs, including renal disease and gastrointestinal involvement, concurrent interstitial lung disease, and differences in the innate response of the right ventricle to increased pulmonary vascular resistance. Early referral for lung transplant evaluation of patients with CTD‐PAH, particularly SSc‐PAH, is recommended. It is hoped that in the near future, additional therapies may be added to the armamentarium of effective treatments for CTD‐PAH. Ultimately, a better understanding of the pathogenesis of CTD‐PAH will be required to develop targeted therapies for this morbid condition.

Pulmonary Hypertension in Scleroderma– Evaluation and Management

Pulmonary Arterial Hypertension (PAH) is a clinical syndrome consisting of physiologic/hemodynamic criteria that are a consequence of several etiologies. Systemic Sclerosis (SSc), one of the most common causes of PAH, is an autoimmune disorder of the connective tissue leading to fibrosis that involves the skin, gastrointestinal tract, lungs, heart, kidney etc. SSc has an annual prevalence of one to five cases for every 1000 individuals and nearly 15 percent of all cases develop PAH.At its core, Pulmonary hypertension (PH) in SSc is an obliterative vasculopathy in small to medium-sized pulmonary arterioles. A host of other local and systemic mechanisms operate in concert to gradually alter the hemodynamics resulting in elevated pulmonary vascular resistance and thus right ventricular afterload. A diagnosis of PAH in SSc is virtually a death sentence, with studies reporting a mortality rate of 50 per cent in the 3 years of diagnosis. Therefore, developing and implementing a robust screening and diagnosis protocol is crucial in the fight against this pervasive disease.This review aims to summarize the current literature of PAH in SSc, with a special focus on the screening and diagnosis protocols, newer treatment options and prognostic indicators for the same.

The evaluation of right ventricle dyssynchrony by speckle tracking echocardiography in systemic sclerosis patients.

Systemic sclerosis (SSc) is associated with right ventricle (RV) remodeling and dysfunction. The primary aim of this study was to evaluate RV dyssynchrony (RV-Dys) in SSc patients using two-dimensional speckle tracking echocardiography (2D-STE). Fifty-five SSc patients with functional class I-II and 45 healthy controls were consecutively included and underwent 2D-STE. RV-Dys was defined as the standard deviation of time to peak strain of mid and basal segments of RV free wall and interventricular septum. SSc group was further classified according to the presence of pulmonary arterial hypertension (PAH). Patients with tricuspid regurgitant velocity >2.8m/s with additional echocardiographic PAH signs were defined as SSc PAH (+). SSc patients had lower RV longitudinal strain (RV-LS) (-17.6 ± 4.6% vs. -20.8 ± 2.8%, p < 0.001) and greater RV-Dys (49.9 ± 25.4ms vs 24.3 ± 11.8ms, p=0.006) than controls despite no significant difference in conventional echocardiographic variables regarding RV function. Although SSc PAH(+) patients had lower RV-LS and higher RV-Dys than SSc PAH(-) patients, the differences were not statistically significant. The only independent predictor of RV-Dys was RV-LS (β:-0.324 [-3.89- -0.45]; p=0.014). SSc patients had not only reduced RV-LS but also impaired RV synchronicity even as conventional echocardiographic variables were preserved.

Pulmonary arterial hypertension: guidelines and unmet clinical needs.

The term pulmonary arterial hypertension (PAH) identifies a heterogeneous group of diseases characterized by a progressive increase in pulmonary arterial resistance (PVR), which causes a significant burden in terms of quality of life, right heart failure and premature death. The pathogenesis of PAH is not completely clear: the remodeling of the small pulmonary vessels is crucial, causing an increase in the resistance of the pulmonary circle. Its diagnosis is based on cardiac catheterization of the right heart. According to the present hemodynamic definition of pulmonary hypertension (PH) proposed by the Guidelines of the European Society of Cardiology/European Respiratory Society (ESC-ERS), the mean pulmonary arterial pressure (mPAP) values are ≥25 mmHg. In case of PAH, apart from an mPAP value ≥25 mmHg, patients must have a >3 Wood units increase in PVR and normal pressure values of the left heart. PH is a pathophysiological condition observed in more than 40 different diseases, while PAH is a primary disease of the pulmonary bloodstream potentially treatable with specific drugs. PAH is a severe complication of systemic sclerosis (SSc) affecting about 10% of the patients. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. In fact, despite awareness of the negative impact of SSc-PAH on quality of life and survival, as well as on the severity of lung function, at the moment standardized and shared guidelines and/or screening programs for the diagnosis and the subsequent early treatment of PAH in SSc are not available. The aim of the present paper is to highlight the lights and shadows of SSc-PAH, unraveling the unmet clinical needs on this topic with a proposal of clinical-diagnostic and therapeutic guidelines.

Identifying early pulmonary arterial hypertension biomarkers in systemic sclerosis: machine learning on proteomics from the DETECT cohort

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort.Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK).Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity/86.5% specificity).This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc.

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy.

The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized.

Atrial natriuretic peptide predicts disease progression and digital ulcers development in systemic sclerosis patients.

Systemic sclerosis (SSc) is an autoimmune disease characterized by micro/macrovascular damage due to the underlying fibrosis. Markers able to predict the progression of cardiovascular damage, including digital ulcers, in SSc are warranted. We aimed at characterizing the relevance of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide plasma levels in relation to cardiovascular damage and digital ulcers in a cohort of Italian SSc patients. Seventy patients were enrolled (64 women and six men; mean age 56.7 ± 14 years) with a disease duration of 11.1 ± 8.3 years. Clinical, instrumental (nailfold videocapillaroscopy, ECG, transthoracic echocardiography, pulmonary function test with diffusion lung CO), NT-proANP and N-terminal probrain natriuretic peptide plasma levels measurement were performed at baseline. The clinical follow-up lasted 24 months. The statistical approach used to achieve the study objectives included multivariate analysis, receiver operating characteristic curve, Kaplan-Meier and Cox regression analyses. Both NT-proNPs levels correlated with systolic pulmonary arterial pressure, but only the NT-proANP level correlated with right heart dimension. Both NT-proNPs levels were higher in patients experiencing events at follow-up but only the NT-proANP level significantly predicted the progression of cardiovascular damage, including development of pulmonary arterial hypertension (PAH). NT-proANP levels were higher in patients with digital ulcers and strongly predicted their development. Our results show that the NT-proANP plasma level significantly correlates with disease progression such as new onset of PAH, worsening of pulmonary hypertension and development of digital ulcers in a cohort of SSc Italian patients. If future studies will confirm our findings, the plasma NT-proANP level could be used in clinical practice as a novel sensitive marker for PAH and digital ulcers development in SSc.

P6478Resting and exercise pulmonary artery systolic pressure to rule out later development of pulmonary arterial hypertension in systemic sclerosis

Abstract Background Patients with systemic sclerosis (SSc) are at risk of developing pulmonary arterial hypertension (PAH), which is often diagnosed late when the benefits of vasoactive therapies are limited. The concept of exercise pulmonary hypertension as a possible transitional phase anticipating resting PAH has been assessed in several pathologies, but has not been endorsed by the latest European Guidelines, because not supported by sufficient data. Purpose To evaluate whether PASP values at rest and at peak exercise, estimated at echocardiography, could be predictors of further development of PAH. Methods Four hundred and twenty-nine SSc patients without a previous diagnosis of PAH, enrolled at 4 referral Centres, underwent standard exercise Doppler echocardiography with PASP estimation at rest and at peak stress. Patients were then followed-up to assess the development of PAH, as diagnosed by a complete diagnostic work-up including right heart catheterization. PAH was defined by pre-capillary pulmonary hypertension (mean pulmonary artery pressure ≥25 mmHg with pulmonary arterial wedge pressure ≤15 mmHg), without significant interstitial lung disease and/or left heart disease. Results During the median follow-up of 75 months (IQR 29–114), 16 patients developed PAH. A combined cut-off of ≥24 mmHg as resting PASP and ≥40 as peak PASP was identified as the best predictor of further development of PAH (see Figure). Both resting PASP and peak PASP were predictors of PAH at univariate analysis (resting PASP OR 1.13, 95% C.I. 1.07–1.19, p&lt;0.0001; peak PASP OR 1.13, 95% C.I. 1.07–1.18, p&lt;0.0001). At multivariate analysis, only peak PASP was independently associated to PAH development (OR 1.13, 95% C.I. 1.04–1.18, p&lt;0.001). Only one patient among those with resting PASP &lt;24 mmHg and peak PASP &lt;40 mmHg (34.7% of the total population) developed PAH during the follow-up (after 10 years from normal exercise Doppler echocardiography). Kaplan-Meier curves Conclusions Exercise increase in PASP is an independent predictor of later development of PAH in SSc. An increase in exercise PASP is frequent and is not necessarily associated with a later development of PAH, whereas the very high negative predictive value of a normal PASP both at rest and at peak exercise can be used in the clinical practice to confidently rule out about one third of patients. Acknowledgement/Funding Italian Ministry of Health (Ricerca Finalizzata 2011-2012)

Validating Alinity immuno- and clinical chemistry assays for routine use

The autoantibody profile, which varies between races, has rarely been reported in Chinese Han systemic sclerosis (SSc) patients. The present study aims to investigate the autoantibody profile of Chinese Han SSc patients using a commercial line immunoassay.The prevalence of autoantibodies to Ro-52, PDGFR, Ku, PM75, PM100, Th/To, NOR90, Fib, RP155, RP11, CENP-B, CENP-A and Scl-70 were analyzed in serum samples obtained from healthy controls (n = 30), SSc patients (n = 320) and non-SSc connective-tissue disease patients (n = 100) using an Euroline Systemic Sclerosis Profile kit.SSc patients had increased prevalence of anti-RP11 (P = 0.032), anti-CENPB (P < 0.001), anti-CENPA (P = 0.001) and anti-Scl-70 (P < 0.001), but had decreased prevalence of anti-Ro-52 (P = 0.004), when compared to non-SSc CTDs. Furthermore, SSc patients had increased prevalence of anti-Ro-52 (P = 0.003), anti-CENPB (P = 0.034), anti-CENPA (P = 0.034) and anti-Scl-70 (P < 0.001), when compared to HCs. In addition, SSc patients with interstitial lung disease (ILD) had increased prevalence of anti-Ro-52 (P = 0.046) and anti-Scl-70 (P = 0.035), but had decreased prevalence of anti-CENPB (P < 0.001) and anti-CENPA (P < 0.001). Moreover, SSc patients with pulmonary arterial hypertension (PAH) had increased prevalence of anti-Ro-52 (P = 0.013) and decreased prevalence of anti-Scl-70 (P = 0.001). Anti-Ro-52 and anti-Scl-70 had increased values for predicting ILD in SSc patients, while anti-Ro-52 had increased values for predicting PAH in SSc patients.A commercial line immunoassay was used to evaluate the diagnostic value of autoantibodies in Chinese Han SSc patients. The results clearly indicate that the immunoblot assay has good diagnostic utility for SSc. Anti-Ro-52, anti-RP11, anti-CENPB, anti-CENPA and anti-Scl-70 are useful for diagnosing SSc in the Chinese Han population. Anti-Ro-52, anti-CENPB, anti-CENPA and anti-Scl-70 have a potential value for diagnosing ILD in SSc patients. Furthermore, anti-Ro-52 and anti-Scl-70 may be used to diagnose PAH in SSc patients.

Harmonization protocols for Lp-PLA2 activity reagents: An initial attempt in China

The autoantibody profile, which varies between races, has rarely been reported in Chinese Han systemic sclerosis (SSc) patients. The present study aims to investigate the autoantibody profile of Chinese Han SSc patients using a commercial line immunoassay.The prevalence of autoantibodies to Ro-52, PDGFR, Ku, PM75, PM100, Th/To, NOR90, Fib, RP155, RP11, CENP-B, CENP-A and Scl-70 were analyzed in serum samples obtained from healthy controls (n = 30), SSc patients (n = 320) and non-SSc connective-tissue disease patients (n = 100) using an Euroline Systemic Sclerosis Profile kit.SSc patients had increased prevalence of anti-RP11 (P = 0.032), anti-CENPB (P < 0.001), anti-CENPA (P = 0.001) and anti-Scl-70 (P < 0.001), but had decreased prevalence of anti-Ro-52 (P = 0.004), when compared to non-SSc CTDs. Furthermore, SSc patients had increased prevalence of anti-Ro-52 (P = 0.003), anti-CENPB (P = 0.034), anti-CENPA (P = 0.034) and anti-Scl-70 (P < 0.001), when compared to HCs. In addition, SSc patients with interstitial lung disease (ILD) had increased prevalence of anti-Ro-52 (P = 0.046) and anti-Scl-70 (P = 0.035), but had decreased prevalence of anti-CENPB (P < 0.001) and anti-CENPA (P < 0.001). Moreover, SSc patients with pulmonary arterial hypertension (PAH) had increased prevalence of anti-Ro-52 (P = 0.013) and decreased prevalence of anti-Scl-70 (P = 0.001). Anti-Ro-52 and anti-Scl-70 had increased values for predicting ILD in SSc patients, while anti-Ro-52 had increased values for predicting PAH in SSc patients.A commercial line immunoassay was used to evaluate the diagnostic value of autoantibodies in Chinese Han SSc patients. The results clearly indicate that the immunoblot assay has good diagnostic utility for SSc. Anti-Ro-52, anti-RP11, anti-CENPB, anti-CENPA and anti-Scl-70 are useful for diagnosing SSc in the Chinese Han population. Anti-Ro-52, anti-CENPB, anti-CENPA and anti-Scl-70 have a potential value for diagnosing ILD in SSc patients. Furthermore, anti-Ro-52 and anti-Scl-70 may be used to diagnose PAH in SSc patients.

Microparticles in systemic sclerosis: Potential pro-inflammatory mediators and pulmonary hypertension biomarkers.

Endothelial microparticles (EMP) are submicron vesicles released from endothelial cells. We aimed to determine the utility of EMP as biomarkers of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) patients and the pathogenic role of microparticles (MP) in vascular inflammation. Levels of EMP (CD144+, CD31+, CD62E+ and CD143+) were compared between three groups (10 SSc patients with PAH, 10 SSc patients without pulmonary hypertension (no-PH) and 10 healthy age- and sex-matched controls). Human pulmonary artery endothelial cells (HPAEC) were exposed in vitro to MP obtained from SSc patients or healthy controls, and levels of cytokines and inflammatory adhesion molecules were compared. CD144+ EMP were significantly higher in the SSc-PAH group compared to either the SSc-no PH or healthy controls (diagnostic accuracy 80%, P = 0.02). Compared to controls, SSc patients had higher CD31+/CD62E+ ratios, indicating larger contributions of apoptosis to EMP release (P = 0.04). Patients with limited SSc had significantly higher levels of CD143+ EMP compared to those with diffuse subtype (P = 0.008). When HPAEC were exposed to MP from SSc patients, there was a significant increase in inflammatory cytokines and adhesion molecules. Interestingly, exposure to healthy control MP caused a reduction in inflammatory markers. EMP (particularly CD144+) are promising biomarkers of PAH in SSc but require further study. MP isolated from SSc patients induced an increase in endothelial cell inflammation and may be an important pathogenic factor in SSc.

Pulmonary arterial hypertension in Saudi patients with systemic sclerosis: Clinical and hemodynamic characteristics and mortality.

BACKGROUND:Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc). The objective of this study is to describe the clinical characteristics, mortality, and predictors of SSc-PAH in Saudi patients.METHODS:Retrospective chart review study of SSc patients who were followed for at least 1 year in three tertiary care centers in Saudi Arabia was conducted. Clinical information, echocardiographic findings, and right heart catheterization (RHC) results were collected. Descriptive statistics were used for demographic and disease characteristics.RESULTS:Fifty-seven patients with SSc were reviewed. PAH was confirmed by RHC in 40 patients (87.5%, females). Their mean age was 45.43 ± 13.48 years. The mean pulmonary artery pressure was 42.9 ± 12.7 mmHg, the pulmonary vascular resistance index was 19.4 ± 7.7 woods unit, and cardiac index was 2.43 ± 0.68 min/m2. The median time from symptoms to first assessment was 42.8 ± 115.62 months. Most patients (77.5%) presented with functional Class III or IV and more than half (22.55%) were on dual combination therapy. Ten patients (25%) SSc PAH died over a follow up period of 37 ± 7 months. Compared to SSc patients without PAH, SSc-PAH patients had shorter 6-min walk distance (6MWD) (296.1 ± 116.5 vs. 399.59 ± 40.60 m, P < 0.0001), higher pro-brain natriuretic peptide (1755.8 ± 2123.4 vs. 69.8 ± 44.3 pg/ml P = 0.004), and more frequent Raynaud's phenomenon (RP) (90% vs. 35%, P < 0.0001). Logistic regression showed RP (odds ratio [OR] =48.58, 95% confidence interval [CI]; 3.73–633.10) and 6MWD (OR 1.02: 95% CI; 1.01–1.03) were associated with the development of PAH.CONCLUSION:Our cohort of Saudi SSc-PAH patients has a younger disease onset and a lower mortality than what is described worldwide despite late presentation and requirement of combination therapy. The presence of RP and lower were associated with the development of SSc-PAH.

A normal diffusing capacity of the lungs for carbon monoxide is rare in incidental pulmonary arterial hypertension in systemic sclerosis: Data from the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma cohort.

Our purpose was to determine the frequency of normal diffusing capacity for carbon monoxide defined as ⩾70% predicted, in those diagnosed with pulmonary arterial hypertension in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma cohort. We compared those with normal diffusing capacity for carbon monoxide to those with reduced diffusing capacity for carbon monoxide <70% in order to better clarify the role of pulmonary function testing as a screening test for pulmonary arterial hypertension and to better understand this population. Entry criteria included a right heart catheterization with mean pulmonary artery pressure ⩾25 mm Hg and pulmonary capillary wedge pressure ⩽15 mm Hg. Demographics, echocardiogram variables, B-type natriuretic peptide levels, right heart catheterization findings, and survival were described for both groups. Of (n = 202), 11 (5.4%) had a diffusing capacity for carbon monoxide of ⩾70% versus 191 (94.6%) who had a diffusing capacity for carbon monoxide <70%. There were no identified statistical differences between the groups. Left atrium size was 4.1 cm in the normal diffusing capacity for carbon monoxide patients compared to 3.7 cm in the low diffusing capacity for carbon monoxide group but did not reach statistical significance. There were no statistically significant differences in survival. On repeat testing, seven patients subsequently developed a diffusing capacity for carbon monoxide <70%. Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma data suggest that it is very rare for a patient to develop pulmonary arterial hypertension with a preserved diffusing capacity for carbon monoxide. The data support the importance of obtaining diffusing capacity for carbon monoxide and that a patient with a normal diffusing capacity for carbon monoxide while suspected to have systemic sclerosis-pulmonary arterial hypertension should be considered critically. Diffusing capacity for carbon monoxide >70% was present in too few patients to find significant differences in B-type natriuretic peptide and atrium size. Future research should seek to confirm abnormal B-type natriuretic peptide, increased left atrium size, and other evidence of myocardial involvement on diffusing capacity for carbon monoxide.

Pros and Cons of Echocardiography in the Screening, Diagnosis and Follow-up of Patients with Systemic Sclerosis Pulmonary Arterial Hypertension – a Rheumatologist's Perspective

Purpose Our objective was to review the evidence regarding echocardiography in patients with systemic sclerosis (SSc) and possible pulmonary hypertension (PH). Methods The literature was reviewed. In addition, a survey was conducted of 315 rheumatologists/internists with a self-declared interest in SSc, to determine their preferred use of echocardiograms. Results The most relevant literature findings come from two studies, the DETECT study and one from the Australian Scleroderma Interest Group. In both these studies, it appears that the use of non-echocardiographic variables such as pulmonary function tests (PFTs) and values of serum N-terminal pro-brain natriuretic peptide (NT-proBNP), are adequate on their own in suggesting which patients are at high risk of PH. Echocardiograms added very little information and in fact may confuse the picture by appearing to be normal when in fact underlying PH is present. With regard to the survey, 157 physicians (49.8%) responded. Of those, 67% felt that an echocardiogram should be ordered on every patient with SSc every year. Ninety-five percent (95%) said the reason was to screen for the development of significant PH, 65% said the reason was to screen for the development of significant intrinsic cardiac disease and 38% said that the reason was to adhere to accepted international recommendations. Conclusions Despite popular belief and current recommendations, in the opinion of the author, echocardiograms are not necessary in every SSc patient every year. Cheaper tests such as PFTs and NT-proBNP are adequate in most cases to suggest when a right heart catheterization should be performed.

Exhaled nitric oxide in pulmonary arterial hypertension associated with systemic sclerosis.

The fractional exhaled concentration of nitric oxide (FENO) has been shown to be reduced in idiopathic pulmonary arterial hypertension (PAH) but has not been adequately studied in PAH associated with systemic sclerosis (SSc). We measured FENO at an expiratory flow rate of 50 mL/s in 21 treatment-naive patients with SSc-associated PAH (SSc-PAH), 94 subjects with SSc without pulmonary involvement, and 84 healthy volunteers. Measurements of FENO at additional flow rates of 100, 150, and 250 mL/s were obtained to derive the flow-independent nitric oxide exchange parameters of maximal airway flux (J'awNO) and steady-state alveolar concentration (CANO). FENO at 50 mL/s was similar (P = 0.22) in the SSc-PAH group (19 ± 12 parts per billion [ppb]) compared with the SSc group (17 ± 12 ppb) and healthy control group (21 ± 11 ppb). No change was observed after 4 months of targeted PAH therapy in 14 SSc-PAH group patients (P = 0.9). J'awNO was modestly reduced in SSc group subjects without lung disease (1.2 ± 0.5 nl/s) compared with healthy controls (1.64 ± 0.9; P < 0.05) but was similar to that in the SSc-PAH group. CANO was elevated in individuals with SSc-PAH (4.8 ± 2.6 ppb) compared with controls with SSc (3.3 ± 1.4 ppb) and healthy subjects (2.6 ± 1.5 ppb; P < 0.001 for both). However, after adjustment for the diffusing capacity of CO, there was no significant difference in CANO between individuals with SSc-PAH and controls with SSc. We conclude that FENO is not useful for the diagnosis of PAH in SSc. Increased alveolar nitric oxide in SSc-PAH likely represents impaired diffusion into pulmonary capillary blood.

The heart and pulmonary arterial hypertension in systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of the skin and visceral organs (gastrointestinal tract, heart, kidneys and lungs). Although the prevalence is low, SSc is a disease with high morbidity and mortality. Since pulmonary arterial hypertension (PAH) associated with SSc (SSc-PAH) and clinically evident cardiac involvement is associated with increased mortality, the cardiac complications and PAH in SSc are reviewed. Both diffuse cutaneous (DcSSc) and limited cutaneous (LcSSc) subgroups are at risk for cardiac involvement and SSc-PAH. Cardiac involvement can be divided in pericardial involvement, myocardial involvement and rhythm disturbances and mostly occurs asymptomatically. However, when symptomatic, it is associated with a poor prognosis. Screening for asymptomatic cardiac involvement should be considered in SSc in order to initiate treatment in an early stage. However, there are no randomized controlled trials on treatment options for cardiac involvement in SSc. SSc-PAH is a devastating complication of SSc, which can develop early in DcSSc and LcSSc. Screening for PAH should be performed since screening leads to earlier diagnosis and earlier treatment is associated with a better prognosis. Today, screening is performed by clinical judgement and echocardiography. Recently the DETECT algorithm, a 2-step screening algorithm is proposed in a SSc-subgroup at increased risk for PAH, but further validation is needed. Despite current treatment options with prostacyclins, endothelin-1 receptor antagonists and phosphodiesterase type-5 inhibitors, mortality remains high. Several promising new treatment options for PAH are evaluated in phase II and III clinical trials.

Survival in systemic sclerosis–pulmonary arterial hypertension by serum autoantibody status in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry

ObjectiveTo determine the association between serum autoantibodies and survival in patients with incident systemic sclerosis (SSc)–pulmonary arterial hypertension (PAH) enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry. MethodsPatients with definite PAH diagnosed by right heart catheterization within 6 months of registry enrollment were studied. Serum autoantibodies were assayed at each participating institution’s clinical laboratory. Mortality data were collected from electronic medical records and/or the Social Security Death Index. Kaplan−Meier survival estimates were reported for five autoantibody groups (anticentromere/AC, nucleolar ANA/NUC, anti-topoisomerase/Scl-70, overlapping or non-specific autoantibodies/other, and a combined group with similar survival consisting of RNA polymerase III, U1RNP, and autoantibody-negative patients). Cox proportional hazards models permitted examination of the association between autoantibody groups and overall survival, controlling for age, sex, race, and SSc disease duration. ResultsIn all, 162 subjects had PAH, and serum autoantibody and survival information; 60 (37%) had AC, 39 (24%) NUC, 11 (7%) Scl-70, 28 (17%) had other, 9 (6%) RNA pol, 8 (5%) U1RNP autoantibodies, and 7 (4%) had negative antibodies; 32 (20%) subjects died over a median follow-up time of 2.1 years (range: 0.01–6.8); 1- and 3-year survival estimates were, respectively, 94% and 78% for AC, 94% and 72% for NUC, 89% and 63% for Scl-70, 92% and 79% for the other group, and 100% and 93% for the combined group. Unadjusted and adjusted hazard ratios revealed no statistically significant association between risk of death and autoantibodies. ConclusionAnticentromere and NUC autoantibodies are prevalent in SSc-PAH patients. An association between serum autoantibodies and survival in patients with SSc-PAH was not identified in the PHAROS cohort.