SSc-PAH Patients Research Articles

E061 Attitudes and barriers to pulmonary arterial hypertension screening in systemic sclerosis patients: a survey of UK-based rheumatologists

Abstract Background/Aims Pulmonary arterial hypertension (PAH) affects approximately 10% of patients with SSc and is a major cause of morbidity and mortality. PAH is often asymptomatic, and therefore, proactive screening is crucial for early detection and improved survival, including through early treatment intervention. Although there are various proposed international guidelines for screening, there is currently no dedicated UK-based guidance. Our aim is to explore current UK screening practices for SSc-PAH patients, including identifying barriers and potential solutions. Methods A survey of 31 questions was developed and included six sections: clinician demographics, the importance of screening, screening practices, barriers to screening, treatment, and patient education. The survey was disseminated among rheumatologists working in the UK. Results Forty-four rheumatologists working in the UK participated in the study, and the majority completed all the questions. Around one-third (37.0%) worked in specialised SSc units (university or general hospitals [54.5% and 45.4%, respectively]). The majority recognised that SSc-PAH is a major cause of morbidity and mortality. Over half (60.0%) reported using the DETECT algorithm to screen for SSc-PAH, although other algorithms were also sometimes used. All of the respondents utilised transthoracic echocardiogram, and almost all (95.0%) performed pulmonary function tests for screening purposes. Various challenges and barriers were identified relating to SSc-PAH screening (Figure 1A), with the difficulty in interpreting results from other hospitals and extended wait times for diagnostic tests being the most reported (76.0% and 74.0%, respectively). Most respondents agreed that access to key investigations (87.0%), ongoing clinician education (82.0%), multidisciplinary meetings (79.5%) and a better understanding of proposed screening algorithms (79.5%) could be potential solutions (Figure 1B). Conclusion Rheumatologists recognise that SSc-PAH screening is crucial to improve outcomes including survival; however, variable practices exist. There are various barriers to SSc-PAH screening and we have identified a number of practical potential solutions. Disclosure M.P. Álvarez Hernández: None. Y. Allanore: Honoraria; Speaking fees from Janssen outside the submitted work. I. Andrade: Other; Honoraria (speaker) fees, scientific board member for EchoRight™and advisory board participant for ‘Pulmonary hypertension in the primary care setting’ for Janssen, outside the submitted work. M.H. Buch: Other; Speaker fees from Boehringer Ingelheim, outside the submitted work. G. Coghlan: Other; Consultancy and working groups fees from Janssen and MSD; honoraria from Inari and Janssen; grants from Janssen. F. Del Galdo: Other; Consulting fees and research support from Janssen, outside the submitted work. C. Denton: Honoraria; Consulting fees and research support from Janssen, outside the submitted work. D. Khanna: Honoraria; Consultant: Amgen, Abbvie, BI, AZ, Merck, Horizon, Prometheus, Janssen, GSK. Grants- Pfizer, BI, Horizon. D.G. Kiely: Honoraria; Participation in advisory boards, steering committees, speaker fees and support to attend educational meetings from Acceleron, Gossamer, GSK, Janssen, Ferrer, MSD and United Therapeutics. Other; grant funding from GSK and Janssen. His work is supported by a grant from the NIHR Biomedical research Centre Sheffield. J. Pauling: Honoraria; Consultancy work for AstraZeneca, Boehringer Ingelheim, IsomAb, Janssen, Permeatus and Sojournix; speaker honoraria and educational support from Janssen. S. Ramjug: Consultancies; Consulting fees from Janssen, outside the submitted work. M. Hughes: Other; Speaking fees from Actelion, Eli Lilly, Janssen and Pfizer, outside the submitted work; research funding from Janssen; member of a data and safety monitoring board for Certa Therapeutics.

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.

Peripheral microvascular function is linked to cardiac involvement on cardiovascular magnetic resonance in systemic sclerosis-related pulmonary arterial hypertension.

Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH). Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05). SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

Significant nailfold capillary loss and late capillaroscopic pattern are associated with pulmonary arterial hypertension in systemic sclerosis.

To evaluate differences in nailfold videocapillaroscopy (NVC) findings between SSc patients with and without a diagnosis of pulmonary arterial hypertension (PAH). One hundred and ten SSc patients were enrolled in this cross-sectional, case-control, multicentre study. Patients were divided into cases (SSc-PAH confirmed by right heart catheterization) and controls (SSc-nonPAH with low probability of PAH). NVC patterns (early, active and late) and morphological parameters (microvascular density, non-specific abnormalities, giant capillaries, micro-haemorrhages, avascular areas) were considered using a semiquantitative scoring system. SSc-PAH patients showed higher frequencies of late pattern (P < 0.01), non-specific abnormalities (P < 0.01), lower capillary density (P < 0.01), higher avascular areas (P < 0.01) and a higher mean NVC score (P < 0.01). Contrarily, the early/active pattern (P < 0.01) and a higher rate of micro-haemorrhages (P = 0.04) were more frequent in non-PAH patients. By a multivariate analysis, SSc-PAH patients, compared with non-PAH, had more non-specific abnormalities [27/55, 49.1% vs 10/55, 18.2%; adjusted odd ratio (OR) 16.89; 95% CI: 3.06, 93.16], a lower capillary density (grade 3, 20/55, 36.4% vs 5/55, 9.1%; adjusted OR 38.33; 95% CI: 2.34, 367.80) and avascular areas (18/55, 32.7% vs 10/55, 18.2%; adjusted OR 16.90; 95% CI: 2.64, 44.35). A correlation was found between the mean pulmonary arterial pressure and avascular areas (P < 0.01), capillary density (P < 0.01) and non-specific abnormalities (P < 0.01). A clinical model including the NVC variables may be able to predict a diagnosis of PAH. Our results indicate that the distinctive peripheral microcirculatory injury of SSc, i.e. capillary loss and morphological abnormalities, appear more severe and pronounced in patients with SSc-PAH.

Peripheral microvascular function is linked to cardiac involvement on CMR in systemic sclerosis-related pulmonary arterial hypertension patients

Abstract Background Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation and fibrosis, and carries one of the worst prognosis in patients who also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, SSc-PAH patients demonstrate disproportionately high morbidity and mortality, presumably due to cardiac involvement. Purpose To determine the pathophysiology of cardiac involvement in SSc, cardiovascular magnetic resonance (CMR) measures of perfusion, inflammation and fibrosis were compared between SSc-PAH and idiopathic PAH (IPAH) patients. In addition, the correlation between myocardial involvement on CMR and known markers of peripheral microvascular function was assessed. Methods Consecutive patients with SSc-PAH and IPAH of similar age and gender, consecutively underwent CMR imaging, and nailfold capillaroscopy (NC) with post-occlusive reactivity hyperaemia-test (PORH-test). CMR imaging included T2 mapping (inflammation), pre- and postcontrast T1 mapping to calculate the extracellular volume fraction (ECV, fibrosis), and adenosine-stress perfusion imaging to measure the relative myocardial upslope (microvascular perfusion), all measurements were performed on the left ventricle. These CMR markers were related to peripheral microvascular function by NC and PORH-test. Results Twenty SSc-PAH patients (71 [62–77] years, 14% male) and 5 IPAH patients (69 [47–77] years, 20% male) were included. SSc-PAH patients had higher ECV and T2 values than IPAH patients. NC showed lower average capillary density and reduced recruitment of capillaries after PORH in SSc-PAH patients, corresponding to impaired microvascular structure and function. Both higher ECV and T2 values correlated with lower average capillary density (r=−0.454 and −0.583, respectively, p&amp;lt;0.05 for both). Additionally, higher T2 values and lower relative myocardial upslope correlated with worse peripheral microvascular function measured by PORH-test (r=−0.471 and r=0.421, respectively, p&amp;lt;0.05 for both). Conclusion SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared to IPAH patients. These markers correlated well with worse peripheral microvascular function, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may have important therapeutic implications, for which future studies are warranted evaluating the role of anti-inflammatory/anti-fibrotic therapy. Funding Acknowledgement Type of funding sources: None.

Target organ expression and biomarker characterization of chemokine CCL21 in systemic sclerosis associated pulmonary arterial hypertension.

IntroductionSystemic sclerosis (SSc) is a heterogenous disorder that appears to result from interplay between vascular pathologies, tissue fibrosis and immune processes, with evidence for deregulation of chemokines, which normally control immune trafficking. We recently identified altered levels of chemokine CCL21 in SSc associated pulmonary arterial hypertension (PAH). Here, we aimed to define target organ expression and biomarker characteristics of CCL21.Materials and methodsTo investigate target organ expression of CCL21, we performed immunohistochemistry (IHC) on explanted lung tissues from SSc-PAH patients. We assessed serum levels of CCL21 by ELISA and Luminex in two well-characterized SSc cohorts from Oslo (OUH, n=552) and Zurich (n=93) University hospitals and in 168 healthy controls. For detection of anti-CCl21 antibodies, we performed protein array analysis applying serum samples from SSc patients (n=300) and healthy controls. To characterize circulating CCL21 in SSc, we applied immunoprecipitation (IP) with antibodies detecting both full length and tailless and a custom-made antibody detecting only the C-terminal of CCL21. IP products were analyzed by SDS-PAGE/western blot and Mass spectrometry (MS).ResultsBy IHC, we found that CCL21 was mainly expressed in the airway epithelial cells of SSc patients with PAH. In the analysis of serum levels of CCL21 we found weak correlation between Luminex and ELISA (r=0.515, p<0.001). Serum levels of anti-CCL21 antibodies were higher in SSc patients than in healthy controls (p<0.001), but only 5% of the SSc population were positive for anti-CCL21 antibodies in SSc, and we found no correlation between anti-CCl21 and serum levels of CCL21. By MS, we only identified peptides located within amino acid (aa) 23-102 of CCL21, indicating that CCL21 in SSc circulate as a truncated protein without the C-terminal tail.ConclusionThis study demonstrates expression of CCL21 in epithelial lung tissue from SSc patients with PAH, and indicate that CCL21 in SSc circulates as a truncated protein. We extend previous observations indicating biomarker potential of CCL21, but find that Luminex is not suitable as platform for biomarker analyses. Finally, in vivo generated anti-CCL21 antibodies exist in SSc, but do not appear to modify serum CCL21 levels in patients with SSc-PAH.

Soluble markers of B cell activation suggest a role of B cells in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension.

IntroductionSoluble markers of B cell activation are interesting diagnostic and prognostic tools in autoimmune diseases. Data in systemic sclerosis (SSc) are scarce and few studies focused on their association with disease characteristics.Methods1. Serum levels of 14 B cell biomarkers (β2-microglobulin, rheumatoid factor (RF), immunoglobulins (Ig) G, IgA, IgM, BAFF, APRIL, soluble (s)TACI, sBCMA sCD21, sCD23, sCD25, sCD27, CXCL13) were measured in SSc patients and healthy controls (HC). 2. Associations between these biomarkers and SSc characteristics were assessed. 3. The pathophysiological relevance of identified associations was explored by studying protein production in B cell culture supernatant.ResultsIn a discovery panel of 80 SSc patients encompassing the broad spectrum of disease manifestations, we observed a higher frequency of RF positivity, and increased levels of β2-microglobulin, IgG and CXCL13 compared with HC. We found significant associations between several biomarkers and SSc characteristics related to disease phenotype, activity and severity. Especially, serum IgG levels were associated with pulmonary hypertension (PH); β2-microglobulin with Nt-pro-BNP and DLCO; and BAFF with peak tricuspid regurgitation velocity (TRV). In a validation cohort of limited cutaneous SSc patients without extensive ILD, we observed lower serum IgG levels, and higher β2-microglobulin, sBCMA, sCD23 and sCD27 levels in patients with pulmonary arterial hypertension (PAH). BAFF levels strongly correlated with Nt-pro-BNP levels, FVC/DLCO ratio and peak TRV in SSc-PAH patients. Cultured SSc B cells showed increased production of various angiogenic factors (angiogenin, angiopoietin-1, VEGFR-1, PDGF-AA, MMP-8, TIMP-1, L-selectin) and decreased production of angiopoietin-2 compared to HC.ConclusionSoluble markers of B cell activation could be relevant tools to assess organ involvements, activity and severity in SSc. Their associations with PAH could plead for a role of B cell activation in the pathogenesis of pulmonary microangiopathy. B cells may contribute to SSc vasculopathy through production of angiogenic mediators.

Peripheral Microangiopathy Changes in Pulmonary Arterial Hypertension Related to Systemic Sclerosis: Data From a Multicenter Observational Study

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune-system alterations, fibrosis involving the skin and internal organs and diffuse microangiopathy. Pulmonary arterial hypertension (PAH) is a severe complication of SSc affecting about 10–15% of the patients and it is a leading cause of mortality. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. Nail fold videocapillaroscopy (NVC) studies have shown a more severe peripheral microvascular dysfunction in SSc patients with PAH suggesting that abnormalities in peripheral microcirculation may correlate with pulmonary microangiopathy. This is a cross-sectional study involving four tertiary University Rheumatology Units in the Center-North of Italy. Seventy patients, 35 adults with SSc and PAH confirmed by RHC (F/M 34/1; median age 65.2 ± 8.9 SD yrs), and 35 SSc patients without PAH were enrolled (F/M 3471; median age 63.3 ± 10.3 SD yrs). Clinical, laboratoristic and instrumental data were collected and NVC was performed in all patient. Specific NVC parameters were evaluated and a semi-quantitative rating scale was adopted to score these changes. Finally, patients were distributed into the suitable NVC pattern belonging to the scleroderma pattern. Our aim was to compare the peripheral microangiopathy changes in SSc patients with and without PAH, and to investigate the relationship between NVC findings and the main hemodynamic parameters of pulmonary vasculopathy. Patients with SSc-PAH+ showed a significant higher frequency of interstitial lung disease (ILD). No significant differences regarding clinical and laboratoristic parameters were observed. NVC abnormalities, avascular areas were more frequent in SSc patients with PAH, respect to those without (p = 0.03), and capillary density was significantly lower when considering grade 3 (p = 0.02). A higher NVC semiquantitative mean was found in SSc-PAH+ patients and a greater rate of the “late” pattern was detected in SSc-PAH+ subjects in respect to PAH- (57.1% vs. 25.7%) (p = 0.03). A significant correlations between pulmonary pressure values (sPAP by TTE and mPAP by RHC) and the capillary density (Spearman's rho 0.35, p = 0.04 for both). Our findings provide additional evidence to the literature data, confirming that a higher degree of peripheral nailfold microangiopathy is more common in SSc-PAH patients, and further strengthening the concept that NVC changes may run parallel with similar abnormalities inside pulmonary microcirculation.

MiRNAs in Systemic Sclerosis Patients with Pulmonary Arterial Hypertension: Markers and Effectors.

Background: Pulmonary arterial hypertension (PAH) is a major cause of death in systemic sclerosis (SSc). Early detection may improve patient outcomes. Methods: We searched for circulating miRNAs that would constitute biomarkers in SSc patients with PAH (SSc-PAH). We compared miRNA levels and laboratory parameters while evaluating miRNA levels in white blood cells (WBCs) and myofibroblasts. Results: Our study found: 1) miR-26 and miR-let-7d levels were significantly lower in SSc-PAH (n = 12) versus SSc without PAH (SSc-noPAH) patients (n = 25); 2) a positive correlation between miR-26 and miR-let-7d and complement-C3; 3) GO-annotations of genes that are miR-26/miR-let-7d targets and that are expressed in myofibroblast cells, suggesting that these miRNAs regulate the TGF-β-pathway; 4) reduced levels of both miRNAs accompanied fibroblast differentiation to myofibroblasts, while macitentan (endothelin receptor-antagonist) increased the levels. WBCs of SSc-noPAH and SSc-PAH patients contained equal amounts of miR-26/miR-let-7d. During the study, an echocardiograph that predicted PAH development, showed increased pulmonary artery pressure in three SSc-noPAH patients. At study initiation, those patients and an additional SSc-noPAH patient, who eventually developed PAH, had miR-let-7d/miR-26 levels similar to those of SSc-PAH patients. This implies that reduced miR-let-7d/miR-26 levels might be an early indication of PAH. Conclusions: miR-26 and miR-let-7d may be serological markers for SSc-PAH. The results of our study suggest their involvement in myofibroblast differentiation and complement pathway activation, both of which are active in PAH development.

Clinical phenotypes, hemodynamic characteristics and prognosis of Chinese patients with systemic sclerosis-associated precapillary pulmonary hypertension: a retrospective study.

Systemic sclerosis (SSc) is associated with interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). This study aimed to explore the prevalence, clinical features, hemodynamic characteristics and prognosis of different severity of ILD in a cohort of patients with SSc-associated precapillary pulmonary hypertension (SSc-PH) and investigate the differences between SSc-PAH and idiopathic pulmonary arterial hypertension (IPAH) patients. SSc-PH patients and IPAH patients, admitted to Shanghai Pulmonary Hospital (August 1, 2008-January 31, 2020) and diagnosed by right-sided heart catheterization (RHC) or echocardiography, were retrospectively included. SSc-PH patients had a baseline chest high-resolution computed tomography (HRCT), and PH classification was based on the extent of ILD. Clinical, pulmonary function, hemodynamic characteristics and survival data were extracted. The study included 45 SSc-PH patients (60% had coexisting ILD and 77.8% were SSc-Group 1 PH/SSc-PAH [without ILD or with mild ILD], 22.2% were SSc-Group 3 PH/SSc-PH with severe ILD) and 52 IPAH patients. SSc-PH with ILD had lower arterial oxygen partial pressure (PaO2) than those without ILD. Hemodynamic characteristics and survival rates were comparable between SSc-PAH with mild ILD and those without ILD. SSc-Group 3 PH had lower pulmonary vascular resistance (PVR) and more severe restrictive ventilatory dysfunction than SSc-Group 1 PH, but the survival rate was equally poor. SSc-PAH had a poorer prognosis than IPAH patients despite the better hemodynamic characteristics. ILD was common in SSc-PH patients. Careful phenotyping of PH in SSc-PH patients is very important as it is imperative to recognize its impact on clinical course, treatment and survival. • ILD was common in Chinese SSc-PH patients. • SSc-PH patients with ILD had lower PaO2 than those without ILD. • Hemodynamic characteristics and survival rates were similar in SSc-PAH patients with mild ILD and those without ILD. • Patients in SSc-Group 3 PH had lower pulmonary vascular resistance (PVR) and more severe restrictive ventilatory dysfunction than those in SSc-Group 1 PH, but the survival rate was equally poor. SSc-PAH patients had a poorer prognosis than IPAH patients despite their better hemodynamic characteristics.

Systemic sclerosis-associated pulmonary arterial hypertension in children.

Systemic sclerosis (SSc) is a rare disease in childhood and is characterized by a combination of vasculopathy, inflammation, autoimmunity, and fibrogenesis with individually varying expression pattern. Pulmonary arterial hypertension (PAH) is a serious complication of SSc and affects approximately 10% of SSc patients. SSc-PAH is complex and difficult to diagnose, as symptoms are non-specific and may be complicated by other SSc-associated diseases such as interstitial lung disease or left heart disease. SSc-PAH patients can deteriorate rapidly, and disease progression can occur even in patients with mild PAH symptoms at diagnosis. Therefore, interdisciplinary care of SSc patients is essential, and treating physicians must be aware of the association between SSc and PAH. In order to detect PAH early, children with SSc should be regularly screened for PAH by pediatric cardiologists. If PAH is detected, a systematic diagnostic approach by trained PH specialists including careful phenotyping of PAH is required. Relevant interstitial lung disease and left heart disease should be ruled out in the differential diagnosis of SSc-PAH before starting any targeted therapy. Due to the progressive character of SSc-PAH known from adult studies, it appears appropriate to initiate targeted PAH-therapy in juvenile SSc-PAH early. Adapted from adult treatment algorithms, combination therapy regimens (addressing at least two pathophysiological pathways) are increasingly used for pediatric PAH patients, and there is growing evidence to support this approach also in SSc-PAH patients.

Nailfold videocapillaroscopic changes in patients with pulmonary arterial hypertension associated with connective tissue diseases.

Pulmonary arterial hypertension (PAH) represents one of the most devastating complications in connective tissue diseases (CTDs). The aim of this study was to investigate the presence of peripheral microangiopathy in patients with PAH associated with CTDs (CTD-PAH) by exploring nailfold videocapillaroscopic (NVC) changes and identify possible associations of NVC characteristics with markers of disease severity. Α cross-sectional study was performed in 18 CTD-PAH patients [13 PAH due to systemic sclerosis (SSc-PAH) and 5 with other types of CTD-PAH], 14 patients with SSc without PAH (SSc-non-PAH) and 20 healthy controls. NVC quantitative and qualitative parameters were evaluated using Optilia Digital Capillaroscope. To ensure inter-observer repeatability, capillaroscopic images were reviewed by two independent investigators. When compared to healthy controls, patients with CTD-PAH (77.8% women, mean age 65.9years) presented reduced capillary density (6.5 ± 1.6 loops/mm vs. 9.7 ± 0.7 loops/mm, p < 0.001) and increased capillary loop width (23.3 ± 10.1μm vs. 11.2 ± 2.5μm, p < 0.001). SSc-PAH patients presented lower capillary density in comparison with other CTD-PAH patients and SSc-non-PAH subjects and abnormal and disorganized capillaries compared to controls. Patients with other CTD-PAH had also reduced capillary density and increased loop diameter compared to controls. A significant linear correlation was identified between capillary density and estimated glomerular filtration rate in the total CTD-PAH population (r = 0.63, p = 0.007). In SSc-PAH group, capillary loop diameter was positively correlated to cardiac index (r = 0.61, p = 0.02). Significant NVC microvascular changes were detected in patients with various types of CTD-PAH, suggesting an impaired peripheral microcirculation parallel to pulmonary vasculopathy.

Vascular endothelial injury assessed with functional techniques in systemic sclerosis patients with pulmonary arterial hypertension versus systemic sclerosis patients without pulmonary arterial hypertension: a systematic review and meta-analysis.

Microvascular dysfunction is one of the hallmarks of systemic sclerosis (SSc). The presence of pulmonary-arterial-hypertension (PAH) in SSc-patients is associated with poor prognosis. This is a systematic review and meta-analysis of studies assessing microvascular and endothelial injury with functional techniques in SSc-patients with PAH (SSc-PAH) compared to those without PAH (SSc-non-PAH) (PROSPERO: CRD42021236212). Literature search involved PubMed, the-Cochrane-Library, Web-of-Science, Scopus and manual search of article references. Studies assessing microvascular function by all available functional methods were considered eligible. Preclinical studies and studies using structural nailfold-videocapillaroscopy or biomarkers were excluded. Newcastle-Ottawa-Scale (NOS) was applied to evaluate the quality of retrieved studies. From a total of 602 retrieved articles, four studies (n = 159 participants) were included in meta-analysis; three studies were of high quality (NOS ≥ 7). In pooled analysis, a marginally significant impaired microvascular function was observed in SSc-PAH compared to SSc-non-PAH patients [SMD - 0.71, 95% CI (- 1.53, 0.12)], with significant between-study heterogeneity (I2 = 80%, p = 0.002). Among the studies examining endothelium-dependent and -independent vasodilation with LDF-iontophoresis, SSc-PAH subjects had significantly impaired endothelium-dependent-vasodilation [Ach-stimulated %change WMD - 216.79, 95% CI (- 337.87, - 95.71), I2 = 0%, p = 0.40], but no significant differences in endothelium-independent-vasodilation [SNP-stimulated %change WMD 90.84, 95% CI (- 82.52, 264.19), I2 = 44%, p = 0.18] compared with SSc-non-PAH subjects. In sensitivity analysis including only studies where SSc-PAH patients were diagnosed by right-heart-catheterization, a borderline difference between the two groups was noted [SMD - 1.09, 95% CI (- 2.30, 0.13), I2 = 82%, p = 0.004]. SSc-PAH patients showed marginally impaired microvascular function in the pooled analysis, as well as impaired endothelium-dependent-vasodilation in subgroup analysis compared with SSc-non-PAH patients. Vascular endothelial dysfunction could be involved in high cardiovascular risk of patients with SSc and PAH.

Candidate Genes Identified in Systemic Sclerosis-Related Pulmonary Arterial Hypertension Were Associated with Immunity, Inflammation, and Cytokines.

Background Pulmonary complications of systemic sclerosis (SSc), including pulmonary arterial hypertension (PAH), are the leading causes of patient death. However, the precise molecular mechanisms of its etiology are unclear. This study's objective was to identify the candidate genes involved in the progression of SSc-PAH and investigate the genes' function. Methods The gene expression profiles of GSE33463 were obtained from the Gene Expression Omnibus (GEO) database. A free-scale gene coexpression network was constructed using the weighted gene coexpression network analysis (WGCNA) to explore the association between gene sets and clinical features and identify candidate biomarkers. Then, gene ontology analysis was performed. A second dataset was used, GSE19617, to validate the hub genes. The verified hub genes' potential function was further explored using gene set enrichment analysis (GSEA). Results Through average link-level clustering, a total of seven modules were classified. A total of 938 hub genes were identified in the key module, and the key module's function mainly enriched was related to chemokine activities. Subsequently, four candidate genes, BTG3, CCR2, RAB10, and TMEM60, were filtered. The expression levels of these four hub genes were consistent in the GSE19617 and GSE33463 datasets. We plotted the ROC curve of the hub genes (all AUC > 0.70). Furthermore, the results of the GSEA for hub genes were correlated with complement and inflammatory responses. Conclusions The hub genes (BTG3, CCR2, RAB10, and TMEM60) performed well in distinguishing the SSc-PAH patients from controls, and some biological functions, related to immunity, inflammation, and cytokines, might pave the way for follow-up studies on the diagnosis and treatment of SSc-PAH.

CLINICAL CHARACTERISTICS, TREATMENT RESPONSE, AND SURVIVAL OF PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOSITIS AND PULMONARY ARTERIAL HYPERTENSION

CLINICAL CHARACTERISTICS, TREATMENT RESPONSE, AND SURVIVAL OF PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOSITIS AND PULMONARY ARTERIAL HYPERTENSION

Interleukin-32 in systemic sclerosis, a potential new biomarker for pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc), associated with a progressive elevation in pulmonary vascular resistance and subsequent right heart failure and death. Due to unspecific symptoms, the diagnosis of PAH is often delayed. On this basis, it is of great value to improve current diagnostic methods and develop new strategies for evaluating patients with suspected PAH. Interleukin-32 (IL-32) is a proinflammatory cytokine expressed in damaged vascular cells, and the present study aimed to assess if this cytokine could be a new biomarker of PAH during SSc.MethodsThe IL-32 expression was evaluated in the sera and skin samples of 18 SSc-PAH patients, 21 SSc patients without PAH, 15 patients with idiopathic PAH (iPAH) and 14 healthy controls (HCs), by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). Receiver-operating characteristic (ROC) curves were performed to evaluate the cut-off of IL-32 in identifying patients with PAH. Furthermore, in SSc patients, correlation analyses were performed between IL-32 sera levels and mean pulmonary artery pressure (mPAP) evaluated by right heart catheterization (RHC) and systolic pulmonary artery pressure (sPAP), obtained by echocardiography. Additionally, the number of skin IL-32+ cells was correlated with modified Rodnan skin score (mRSS).ResultsIn SSc-PAH patients, IL-32 sera levels were significantly higher when compared with SSc patients without PAH and patients affected by iPAH. The analysis of ROC curve showed that IL-32 sera levels above 11.12 pg/ml were able to predict patients with PAH (sensitivity = 90%, specificity = 100%). Furthermore, the IL-32 sera levels of patients with SSc correlated with both mPAP and sPAP. In the skin derived from SSc-PAH patients, the number of IL-32+ cells was significantly increased when compared with the skin derived from SSc patients without PAH, correlating with the mRSS.ConclusionOur study suggested that sera determination of IL-32 may be a promising approach to evaluate the presence of PAH in SSc patients and together with longitudinal future studies could help to increase the understanding how these biomarkers mirror the vascular changes and the inflammatory process during SSc.

The effects of oral treatment for systemic sclerosis related pulmonary arterial hypertension: A systematic review and meta-analysis

Objectives The usage of oral therapies, endothelin receptor antagonists (ERAs), phosphodiesterase type-5 (PDE-5) inhibitors and prostaglandin analogs has resulted in improved outcomes in patients with pulmonary arterial hypertension related to systemic sclerosis (SSc-PAH). However, the optimal therapeutics have not been determined. Methods A systematic searching in the databases of Medline (PubMed), Embase, the Cochrane Library (Central) and unpublished clinical trials (clinicaltrials.gov) was conducted to identify the clinical studies with oral treatment for SSc-PAH patients published before 1 June 2019. The data were extracted and the quality was assessed. The main outcomes are exercise capacity and hemodynamic parameters, which were synthesized and analyzed. Results In total, 27 clinical trials were enrolled for further analysis. It was demonstrated that bosentan treatment, the widely used drug for PAH, might improve the exercise capacity and pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in this clinical setting, although without significant difference. Meanwhile, the usage of prostaglandin analogs could improve the parameters mentioned above. Furthermore, combined therapy with ambrisentan and tadalafil significantly increased the treatment efficacy of key parameters in SSc-PAH patients compared with basic treatment. Conclusion This meta-analysis reveals that combination therapy might provide more benefits to exercise capacity and hemodynamic parameters in SSc-PAH patients. Still more RCTs are needed to provide more solid evidence.

Therapeutic Challenges And Advances In The Management Of Systemic Sclerosis-Related Pulmonary Arterial Hypertension (SSc-PAH).

Systemic sclerosis (SSc) is a rare autoimmune disorder with multi-organ involvement. SSc-associated pulmonary arterial hypertension (SSc-PAH) is one of the leading causes of morbidity and mortality in the SSc population. With advances in our understanding of pulmonary arterial hypertension (PAH) diagnosis and treatment, outcomes for all PAH patients have significantly improved. While SSc-PAH patients have also benefited from these advances, significant challenges remain. Diagnosis of PAH is a challenging endeavor in SSc patients who often have many co-existing pulmonary and cardiac comorbidities. Given the significantly elevated prevalence and lifetime risk of PAH in the SSc population, screening for SSc-PAH is a critically useful strategy. Treatment with pulmonary arterial (PA) vasodilators has resulted in a dramatic improvement in the survival and quality of life of PAH patients. While therapy with PA vasodilators is beneficial in SSc-PAH patients, therapy effects appear to be attenuated when compared to responses in patients with idiopathic PAH (IPAH). This review attempts to chronicle and summarize the advances in our understanding of the optimal screening strategies to identify PAH in patients with SSc. The article also reviews the advances in the therapeutic and risk stratification strategies for SSc-PAH patients.

The economic burden of systemic sclerosis related pulmonary arterial hypertension in Australia

BackgroundTo quantify the financial cost of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc).MethodsHealthcare use was captured through data linkage, wherein clinical data for SSc patients enrolled in the Australian Scleroderma Cohort Study were linked with hospital, emergency department (ED) and ambulatory care databases (MBS) for the period 2008–2015. PAH was diagnosed on right heart catheter according to international criteria. Determinants of healthcare cost were estimated using logistic regression.ResultsTotal median (25th–75th) healthcare cost per patient (including hospital, ED and MBS cost but excluding medication cost) for our cohort during 2008–2015 was AUD$37,685 (18,144-78,811) with an annual per patient healthcare cost of AUD$7506 (5273-10,654). Total healthcare cost was higher for SSc-PAH patients compared with those without PAH with a total cost per patient of AUD$70,034 (37,222-110,814) vs AUD$34,325 (16,093 – 69,957), p < 0.001 respectively with an annual excess healthcare cost per PAH patient of AUD$2463 (1973-1885), p < 0.001. The cost of SSc-PAH occurs early post PAH diagnosis with 89.4% utilizing a healthcare service within the first 12 months post PAH diagnosis with an associated cost per patient of AUD$4125 (0–15,666). PAH severity was the main significant determinant of increased healthcare cost (OR 2.5, p = 0.03) in our PAH cohort.ConclusionsDespite SSc-PAH being a low prevalence disease, it is associated with significant healthcare resource utilization and associated economic burden, predominantly driven by the severity of PAH.

Clinical case of delayed systemic sclerosis and pulmonary arterial hypertension diagnostics

Pulmonary hypertension is a frequent and severe complication of systemic sclerosis (SSc). SSc-PAH patients have a worse prognosis than patients with idiopathic PAH. We report a case of a patient with delayed SSc and PAH diagnostics. Limited SSc was established in a 61-year-woman with 20 years of Raynaud’s syndrome anamnesis. But diagnosis of SSc-PAH was determined in severe and late symptomatic stage with signs of right heart congestion, NYHA III FC and mPAP 48 mmHg. This emphasizes the need for clinicians to be aware of limited SSc and have a high index of PH suspicion in such patients.