Levels In Systemic Sclerosis Patients Research Articles

Left atrial volumetric-mechanical coupling index as a marker of subclinical primary heart involvement in systemic sclerosis

Abstract Background Primary heart involvement in systemic sclerosis (SSc) is a common yet often clinically silent marker of poor prognosis. Up to 80% of patients have histopathological evidence of heart involvement, highlighting the need for better screening and diagnostic methods. N-terminal pro-brain natriuretic peptide (NTproBNP), a well-established cardiac biomarker, is often increased in patients with SSc, but with a not fully understood mechanism. Meanwhile, left atrial volumetric-mechanical coupling index (LACI), a new echocardiographic parameter, has been shown to predict cardiovascular outcomes in heart failure patients and the general population, but it has not been studied in SSc. Purpose To identify new echocardiographic parameters, particularly related to left atrial volume and function, as markers of increased NTproBNP in SSc patients without overt heart involvement. Methods Consecutive SSc patients without overt heart disease referred for routine cardiac screening underwent 2D and 3D transthoracic echocardiography, including atrial and ventricular strain analysis. LACI was calculated by both 2D and 3D echocardiography as the ratio between the left atrial volume index and the tissue-Doppler-imaging septal a’ velocity. Patients with significant structural and functional changes suggestive of systolic or diastolic dysfunction or pulmonary hypertension, and those with impaired global left ventricular strain were excluded. Logistic regression, Pearson correlation coefficients, and area under the receiver-operating characteristic curve (AUC) are used to analyze the association and predictive power of LACI for elevated NTproBNP. Results A total of 36 SSc patients (55±10 years old; 34 (94%) women; mean disease duration 14±11 years) were included. Sixteen (44.4%) had diffuse cutaneous involvement (dcSSc). Seventeen (47%) patients had increased NTproBNP levels (i.e. >125 pg/mL). Among all tested variables, 3D LACI had the best correlation with NTproBNP values (r = 0.63, p<0.001). A 3D LACI of >2 associated with NTproBNP of >125 pg/mL (odds ratio 7.33 [95%CI 1.38-38.8]; p=0.01) and predicted these increased values with a sensitivity of 76.9% and a specificity of 81.2% (AUC 0.78). NTproBNP was also correlated with 2D LACI (r=0.55, p<0.001), peak left atrial longitudinal strain (r=-0.42, p=0.01), and left atrial contraction strain (r=0.48, p=0.005). Compared to patients with limited cutaneous involvement, those with dcSSc had higher NTproBNP values (250±139.6 vs 107.2±110.9 pg/mL, p=0.001), higher 3D LACI values (2.6±0.9 vs 1.9±0.5, p=0.02), with similar left atrial and ventricular strain parameters. Conclusion Left atrial volumetric-mechanical coupling index assessed by 3D echocardiography is significantly associated with and predictive of elevated NTproBNP levels in SSc patients without overt heart disease and may be a potentially useful non-invasive marker for screening for early subclinical heart involvement in SSc patients.

Vitamin D serum levels in patients with systemic sclerosis and very early systemic sclerosis (VEDOSS)

Introduction: Vitamin D may be capable of interfering with the pathophysiological pathways involved in systemic sclerosis, by virtue of its well-known immunomodulatory effects. In this study, we aimed at evaluating the differences and the correlations between vitamin D levels in systemic sclerosis patients versus patients with very early systemic sclerosis. Methods: One hundred twenty-six patients (80 definite systemic sclerosis and 46 very early systemic sclerosis) were included in this case control study. Anthropometric, clinical, biochemical, and instrumental data were recorded and correlated with serum vitamin D levels. Results: Briefly, systemic sclerosis patients and very early systemic sclerosis subjects significantly differed for telangectasias, scleredema, autoantibody profile, and videocapillaroscopic pattern. In addition, the mean vitamin D levels were significantly lower in systemic sclerosis patients when compared to those of very early systemic sclerosis subjects. When systemic sclerosis patients were divided into two groups, that is, those with ⩽20 ng/ml versus >20 ng/ml vitamin D serum levels, significantly higher serum vitamin D levels were observed in patients with a lesser skin and vascular involvement. With regard to very early systemic sclerosis subjects, who exhibited baseline satisfactory vitamin D levels, only the autoantibody profile was found to correlate with vitamin D serum levels. Conclusion: Vitamin D serum levels were found to be generally satisfactory in very early systemic sclerosis subjects, but they were reduced in systemic sclerosis patients. Advanced skin and microvascular involvement were found to predispose to hypovitaminosis D. Due to the well-documented immunomodulatory properties of vitamin D, studies are needed to determine whether vitamin D supplementation may prevent the subsequent evolution of very early systemic sclerosis into definite systemic sclerosis.

Troponin I levels in systemic sclerosis patients with myocardial involvement.

Troponin I has been suggested as a more specific diagnostic biomarker for myocardial involvement in systemic sclerosis than the frequently used troponin T. The aim of this study is to evaluate the additive value of troponin I to detect myocardial involvement in systemic sclerosis. To this end, we evaluated the association between troponin I levels and myocardial involvement in systemic sclerosis patients. A cross-sectional observational study was performed, including 20 healthy controls and four groups of each 20 systemic sclerosis patients from the Leiden Combined Care in Systemic Sclerosis cohort: (1) patients with myocardial involvement, (2) patients with myositis, (3) patients with elevated troponin T and creatine kinase levels but without organ involvement, and (4) patients without any signs of organ involvement. Troponin I levels were measured using enzyme-linked immunosorbent assay. Troponin I levels were compared between the different groups using the Mann-Whitney U and Kruskal-Wallis tests. The mean age of the 80 included patients was 56 years; 61% of the study population was female. Troponin I levels were not significantly different between patients with and without myocardial involvement (2.7 (0.5-15.3) vs 1.2 (0.1-6.6) ng/L; p = 0.117). Systemic sclerosis patients were more often positive for troponin I than healthy controls (70.0% vs 30.0%; p = 0.001). Elevated troponin I was not of additional value to diagnose myocardial involvement in systemic sclerosis patients.

Serum levels of AGGF1: Potential association with cutaneous and cardiopulmonary involvements in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, aberrant immune activation, and extensive tissue fibrosis of the skin and internal organs. Because of the complicated nature of its pathogenesis, the underlying mechanisms of SSc remain incompletely understood. Angiogenic factor with a G-patch domain and a Forkhead-associated domain 1 (AGGF1) is a critical factor in angiogenesis expressed on vascular endothelial cells, associated with inflammatory and fibrotic responses. To elucidate the possible implication of AGGF1 in SSc pathogenesis, we investigated the association between serum AGGF1 levels and clinical manifestations in SSc patients. We conducted a cross-sectional analysis of AGGF1 levels in sera from 60 SSc patients and 19 healthy controls with enzyme-linked immunosorbent assay. Serum AGGF1 levels in SSc patients were significantly higher than those in healthy individuals. In particular, diffuse cutaneous SSc patients with shorter disease duration had higher levels compared to those with longer disease duration and limited cutaneous SSc patients. Patients with higher serum AGGF1 levels had a higher incidence of digital ulcers, higher modified Rodnan Skin Scores (mRSS), elevated serum Krebs von den Lungen-6 (KL-6) levels, C-reactive protein levels, and right ventricular systolic pressures (RVSP) on the echocardiogram, whereas they had reduced percentage of vital capacity (%VC) and percentage of diffusing capacity of the lungs for carbon monoxide (%DLCO) in pulmonary functional tests. In line, serum AGGF1 levels were significantly correlated with mRSS, serum KL-6 and surfactant protein D levels, RVSP, and %DLCO. These results uncovered notable correlations between serum AGGF1 levels and key cutaneous and vascular involvements in SSc, suggesting potential roles of AGGF1 in SSc pathogenesis.

Association of serum Ly6/PLAUR domain-containing protein 1 levels with skin sclerosis in systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disease characterized by aberrant immune activation, vascular injury, and fibrosis of the skin and internal organs. Ly6/PLAUR domain-containing protein 1 (LYPD1) was reported to be secreted and to have various physiological functions such as anti-angiogenic effects. Here we investigated serum LYPD1 levels in SSc patients and the association of serum LYPD1 levels with clinical features of SSc. Serum samples were obtained from 75 SSc patients and 22 healthy individuals as controls. We measured serum LYPD1 levels using enzyme-linked immunosorbent assay kits. Then, the relationship between serum LYPD1 levels and clinical features of SSc was analyzed. Serum LYPD1 levels in diffuse cutaneous SSc (dcSSc) patients were significantly higher than those in the limited cutaneous SSc (lcSSc) patients (median [25–75th percentiles], 1693.43 [1086.61–1917.57] vs. 904.55 [714.356–1285.56] pg/mL), while there were no significant differences in the serum LYPD1 levels between lcSSc and healthy controls (904.55 [714.356–1285.56] vs. 750.71 pg/mL [544.00–912.14]). Further analysis revealed that serum LYPD1 levels in patients correlated with skin thickness scores and serum interleukin (IL)-6 levels, which were known to reflect the extent of skin thickening in SSc. Moreover, serum LYPD1 levels showed a decrease with improvement in skin thickness after treatment, along with a decrease in serum IL-6 levels. These results indicate that LYPD1 might be a potential marker for monitoring skin sclerosis and evaluating the efficacy of skin fibrosis treatment in SSc patients.

Accelerated calciprotein crystallization time (T50) is correlated with impaired lung diffusion capacity in systemic sclerosis.

Systemic sclerosis (SSc) is a complex auto-immune disease characterized by vascular damage, inflammation, fibrosis and calcinosis, where pulmonary involvement is the leading cause of mortality. Calciprotein particles (CPPs) are increasingly formed upon disbalance of the physiological mineral buffering system and induce pro-inflammatory effects. This exploratory study investigated whether functional indicators of the endogenous mineral buffering system are dysregulated in SSc and linked to disease activity. T50 (calciprotein crystallization test or serum calcification propensity) and hydrodynamic radius of secondary CPPs (CPP2) were determined in serum samples from 78 SSc patients and 44 controls without SSc, and were associated with disease activity markers of SSc. T50 was reduced and CPP2 radius was increased in SSc patients as compared to controls, indicating a deranged mineral buffering system. This was accompanied by slightly higher serum phosphate and PTH levels in SSc patients, while iFGF23 was not significantly modified. Longitudinally, all parameters remained unchanged over time in SSc patients, only iFGF23 increased. While the modified Rodnan skin score showed some inconsistent correlations with mineral buffering indicators, their association was not independent of other factors. However, lower T50 was significantly correlated to reduced lung diffusion capacity and this association remained significant in a multivariate linear regression model. This study provides indications for a disturbed mineral buffering system in SSc. Increased serum calcification propensity (lower T50) is correlated with impaired lung diffusion capacity, suggesting a possible role of deranged mineral buffering in disease progression. Further studies are required to confirm these observations in larger cohorts and to investigate a putative functional relevance.

Serum netrin-1 levels in systemic sclerosis patients with capillary abnormalities

BackgroundSystemic sclerosis (SSc) is a rare, potentially destructive systemic autoimmune disease characterized by organ fibrosis and vasculopathy. Netrin-1 is associated with angiogenesis, inflammation, and apoptosis. Aim of the workTo assess the level of serum netrin-1 in SSc patients with capillary abnormalities and to evaluate its relation to disease manifestations. Patients and methodsThis study investigated the relationship between netrin-1 and fibrosis in 56 SSc patientsand 58 matched control. The modified Rodnan skin score (mRss) was used to assess skin thickness. Serum netrin-1 level was quantitatively measured using an enzyme-linked immunosorbent assay. ResultsThe study included 56 patients; 53 females and 3 males (F:M 17.7:1) with a mean age of 48·1 ± 13·6 years and disease duration of 13.01 ± 8·7 years. They were 43 (76.7 %) diffuse and 13 (23.3 %) limited subtypes. The median mRss was 6.58 ± 2.2. Raynaud’s disease was present in 50 % and interstitial lung disease in 57.1 %. The median netrin-1 level was significantly higher in SSc patients (268·8 pg/mL; 82·8-1006·6 pg/mL) than in the controls (108·6 pg/mL;21·02-351·5 pg/mL, p < 0·0001). There was no significant difference in the serum netrin-1 levels in SSc patients with and without Raynaud’s disease (p = 0.55), interstitial lung disease (p = 0.18), anti-Scl70 positive antibodies (p = 0·78), and anti-centromere antibody (p = 0·493). Netrin-1 was significantly related to SSc (OR = 1·02, 95 %CI: 1·01 − 1·03, p < 0·0001). At a cut-off value 126·3 pg/mL, netrin-1 would diagnose SSc (sensitivity 60·3%, specificity 94·6%, 95 %CI: 0·83 − 0·95, p < 0·0001). ConclusionSSc patients had significantly high levels of serum netrin-1 with a potential role in the pathophysiology of the disease.

Maresin1 is a predictive marker of new digital ulcers in systemic sclerosis patients.

Digital ulcers (DUs) are one of the main causes of disability among systemic sclerosis (SSc) patients. The inflammation plays a crucial role in mediating the pathophysiological process underlying SSc. Objective of this study was to evaluate Maresin1 (MaR1) serum levels in SSc patients and in healthy controls (HC). Secondary aims were to evaluate the relationship between MaR and diseases variables and to assess the predictive role of MaR1 in the development of new digital ulcers (DUs) during 18weeks follow-up. MaR1 serum level was evaluated in 55 SSc patients and 24 HC. In SSc patients, clinical assessment was performed at baseline and after 18week follow-up by the same-blinded observer on serum MaR1 levels. MaR1 was significantly lower in SSc patients than in HC [367pg/ml (IQR 304-468.3pg/ml) vs 467.7pg/ml (IQR 422-522pg/ml), p<0.001]. During follow-up, six patients (10.9%) developed DUs. MaR1 was higher in SSc patients with new DUs than in patients without new DUs [518.2pg/ml (IQR 468.2-596.5pg/ml) vs 355pg/ml (IQR 299.8-444.7pg/ml), p<0.01]. Free survival from new DUs is significantly lower in SSc patients with increased MaR1 serum level than in SSc patient with normal MaR1 serum level. In multivariate analysis, serum level of MaR1>393.2pg/ml is a predictive marker for new DUs. In SSc patients, MaR1 is reduced compared to HC and it is a predictive marker of new DUs.

IL33 and sST2 serum level in systemic sclerosis microvascular involvement.

Endothelial dysfunction and microvascular damage are hallmarks of systemic sclerosis (SSc). Objective of this study was to evaluate IL33 and ST2 serum levels in SSc patients and healthy controls (HC). Secondary aim was to evaluate the IL33 axis in the SSc microvascular manifestation. IL33 and sST2 have been assessed in 46 SSc patients and 24 HC matched for sex and age. Main clinimetric indexes were assessed. Skin perfusion of hands was evaluated by Laser Speckle Contrast Analysis (LASCA) and echocolordoppler ultrasound of renal arteries was performed to evaluate subclinical renal involvement. SSc patients had higher serum level of IL33 and sST2 than HC. IL33 and sST2 were significantly higher in SSc patient with digital ulcers (DUs) compared to SSc patients without DUs. SSc patients with late nailfold videocapillaroscopy (NVC) pattern had higher serum levels of sST2 than SSc patients with active NVC pattern. SSc patients without proximal-distal gradient (PDG) at LASCA had significantly higher sST2 serum level compared to SSc patients with PDG. SSc patients with renal resistive index (RRI)≥0.70 had higher serum levels of sST2 than SSc patients with RRI<0.70. A positive linear correlation was shown between sST2 and RRI, between sST2 and intrarenal S/D and between sST2 and PI. Kaplan-Meier curves show a significantly reduced free survival from DUs in patients with increased sST2 (p=0.025). In multivariate analysis, sST2 is associated with the development of new DUs. IL33 and sST2 are increased in SSc patients and ST2 might be a marker of microvascular damage.

Peripheral blood IL-6 levels in systemic sclerosis patients: Correlation between IL-6 levels and clinical phenotypes.

Detect the expression of Interleukin-6 (IL-6) in the serum of patients with systemic sclerosis (SSc) and assess its association with clinical and laboratory features of the disease. The clinical data from 50 patients with SSc in the affiliated hospital of Xuzhou Medical University, China were retrospectively analyzed. The level of IL-6 in peripheral blood of systemic sclerosis patients was compared between the different clinical phenotypes groups. Spearman correlation test was used to analyze the correlation of the IL-6 with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), creatinine, and cystatin C. Interleukin-6 increased in the disease course ≥5 years, systemic sclerosis-Interstitial lung disease (SSc-ILD), pulmonary arterial hypertension (PAH), gastrointestinal involvement, and cardiac involvement group compared with the group with disease course <5 years, no SSc-ILD, PAH, gastrointestinal involvement, and no cardiac involvement group. The differences were statistically significant (p< 0.05). Correlation analysis showed that IL-6 in the group with disease course ≥5 years had a positive correlation with ESR (Rs=0.438, p=0.022) and CRP (Rs=0.825, P < 0.001), whereas it was negatively correlated with creatinine (Rs=-0.481, p=0.011). Nevertheless, when it came to disease course <5 years, the figures had no statistically significant difference. Serum IL-6 in patients with systemic sclerosis is related to different clinical phenotypes. IL-6 helps to diagnose various phases of diseases, monitor severities of diseases, and predict the prognosis of patients.

Transforming growth factor beta isoforms and TGF-βR1 and TGF-βR2 expression in systemic sclerosis patients.

Systemic sclerosis (SSc) is characterized by chronic inflammation and fibrosis, two processes associated with transforming growth factor β (TGF-β) functions. In the present study, we investigated the expression of TGF-β isoforms in serum and the skin distribution of TGF-β and two receptors (TGF-βR1 and TGF-βR2) and their relationship with some clinical, inflammatory, autoimmune (autoantibodies), and vascular (platelets) biomarkers in SSc patients. A total of 56 SSc patients and 120 control subjects (CS) were included. The serum levels of TGF-β isoforms were quantified by immunoassay with magnetic microspheres, and the skin biopsies were processed by immunohistochemistry. The soluble levels of the three active TGF-β isoforms were lower in SSc patients than in CS (p < 0.0001). However, sTGF-β1 and sTGF-β3 levels were positively correlated with C-reactive protein levels in SSc patients. Additionally, sTGF-β2 and sTGF-β3 levels were positively correlated with the number of platelets in SSc patients. In skin biopsies, TGF-β1, TGF-βR1, and TGF-βR2 expression levels were higher in SSc patients than CS. In conclusion, this is the first study showing a joint decrease of the 3 active TGF-β isoforms in SSc patients. However, TGF-β1, TGF-βR1, and TGF-βR2 are possibly increased in clinically involved skin. Therefore, it is likely that a distinct role is played by TGF-β at the local (skin lesions) and systemic levels in SSc patients.

Increased Complement Activation in Systemic Sclerosis Patients with Skin and Lung Fibrosis.

Introduction: The involvement of complement system in the phenotypic expression of systemic sclerosis (SSc) is a debated topic. We aimed to assay complement fractions in SSc patients and to correlate their levels with the clinical course of disease. Key points: 1. CH50 is increased in SSc patients compared to HC; 2. Serum C2 levels are increased in SSc patients compared to HC; 3. CH50 may represent a biomarker of skin and lung fibrosis severity in SSc patients. Method: Complement hemolysis 50% (CH50), C2, C3 and C4 levels have been assessed in 85 SSc patients and 47 healthy controls (HC). Results: SSc patients displayed a statistically significant higher value of CH50 [76.3 U/mL (IQR 65.8–89.4 U/mL) vs. 29.6 U/mL (IQR 24.7–34 U/mL); p < 0.0001] and of C2 [26.1 mg/L (IQR 24.1–32.1 mg/L) vs. 22.7 mg/L (IQR 20.6–24.4 mg/L); p < 0.0001] if compared to HC. Patients with diffuse cutaneous SSc (dcSSc) had higher levels of CH50 than patients with limited cutaneous SSc (lcSSc) [83.6 U/mL (IQR 72.3–102.7 U/mL) vs. 71.3 U/mL (IQR 63.7–83.6 U/mL); p = 0.003]. SSc patients with interstitial lung disease (ILD) had higher CH50 levels if compared to SSc patients without ILD [79.6 U/mL (IQR 68.3–97.4 U/mL) vs. 69.7 U/mL (54.6–85.7 U/mL); p = 0.042]. A positive linear correlation existed between CH50 and the modified Rodnan Skin Score (mRSS) (r = 0.285, p = 0.008) and disease severity scale (DSS) (r = 0.285, p = 0.005); a negative linear correlation was demonstrated between CH50 and the diffusing capacity of carbon monoxide (DLco) (r = −0.252, p = 0.012). In multiple linear regression analysis, only DSS was significant (p = 0.01, beta coefficient 2.446). Conclusions: Our results show an increment of CH50 and serum C2 levels in SSc patients in comparison to HC; we retain that CH50 may represent a biomarker of disease severity and of skin and lung fibrosis in these patients.

Regulatory B cell imbalance correlates with Tfh expansion in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease with fibrosis, microangiopathy and immune dysfunction. B cell abnormalities characterised by autoantibody production and polyclonal B cell activation play an important role in the pathogenesis of SSc. We previously identified an expansion of functional and activated circulating T follicular helper (cTfh) cells in SSc patients. The aim of this study was to analyse the frequency of regulatory B (Breg) cell subsets and the correlation with Tfh in SSc patients. Circulating Breg cells CD24hiCD38hi and CD27+CD24hi levels and cTfh cells CD4+CXCR5+PD1+ were determined by cytometry in 50 SSc patients and 32 healthy subjects. The frequency of Breg cells CD24hiCD38hi and CD24hiCD27+ was significantly reduced in patients with SSc as compared to controls (p=0.02 and p<0.001, respectively). In contrast, when examining the CD21low B cell subset, the frequency was significantly increased in SSc patients compared to healthy controls, (p<0.001). There was no difference in Breg cell levels in patients with diffuse SSc and limited SSc. However, CD24hiCD27+ Breg cell frequency was significantly decreased in SSc patients with pulmonary arterial hypertension (p=0.014), but not in patients with interstitial lung disease (p=0.058). Furthermore, we observed a negative correlation between cTfh and CD24hiCD27+ Breg cell levels in SSc patients but not in healthy controls (p=0.02). These results suggest that Breg cell subsets may participate in the regulation of cTfh and disease severity. Decreased CD24hiCD27+ Breg cell frequency may contribute to the development of SSc.

Combining multi-antigenic immunodot with indirect immunofluorescence on HEp-2 cells improves the diagnosis of systemic sclerosis

Systemic sclerosis (SSc) is associated, in nearly all patients, with autoantibodies (Ab). Accordingly, and in order to identify major (anti-CEN A/B and anti-Topo I) but also minor Abs, the usefulness of combining indirect immunofluorescence (IIF) on HEp-2 cells with an 11 multi-antigenic SSc immunodot was explored. 1689 samples tested at the request of clinicians, were evaluated retrospectively. The positivity rate was 28.8% and the diagnosis of SSc was supported for 232 samples. Two groups of Abs were considered: group 1, Abs (anti-CENP A/B, anti-Topo I) present at elevated levels in SSc patients; group 2, Abs for which the Ab specificity (odds ratio and/or positive predictive value) was improved by using IIF on HEp-2 cells (RNA-Polymerase III, fibrillarin, Th/T0, PM-Scl). Altogether, this study highlights the utility of combining IIF on HEp-2 cells with the SSc immunodot as the first line of an SSc Abs detection/SSc diagnostic strategy.

Serum levels of tissue factor pathway inhibitor: Potential association with Raynaud's phenomenon and telangiectasia in patients with systemic sclerosis.

Vasculopathy is a critical step of systemic sclerosis (SSc) development, bridging between autoimmune inflammation and tissue fibrosis. Impaired coagulation system is a part of SSc vasculopathy, but the role of tissue factor pathway inhibitor (TFPI), a critical regulator of the extrinsic coagulation pathway, remained unknown. Therefore, we evaluated the clinical correlation of serum TFPI levels in SSc patients. Serum TFPI levels were comparable between SSc and control participants, but SSc patients with Raynaud's phenomenon and telangiectasia had significantly lower serum TFPI levels than those without. Importantly, there was a significant positive correlation between serum TFPI levels and protein S activity. These results support the critical role of impaired coagulation system in SSc.

Serum TARC Levels in Patients with Systemic Sclerosis: Clinical Association with Interstitial Lung Disease.

Systemic sclerosis (SSc) is a multisystem fibrotic disorder with autoimmune background. Accumulating evidence has highlighted the importance of T helper (Th) 2 cells in the pathogenesis of SSc and its complications. Because thymus and activation-regulated chemokine (TARC) is a potent chemoattractant for Th2 cells, we measured serum TARC levels in SSc patients and analyzed their correlation with interstitial lung disease (ILD), a major complication of SSc. Serum TARC levels were significantly elevated in patients with SSc, especially in those with the diffuse subtype, compared with healthy controls. In particular, dcSSc patients with SSc-associated ILD (SSc-ILD) showed higher TARC levels than those without SSc-ILD. However, there was no significant correlation between serum TARC levels and pulmonary function in SSc patients. Serum TARC levels did not correlate with serum levels of interleukin-13, an important Th2 cytokine, either. Furthermore, in the longitudinal study, serum TARC levels did not predict the onset or progression of SSc-ILD in patients with SSc. These results were in contrast with those of KL-6 and surfactant protein D, which correlated well with the onset, severity, and progression of SSc-ILD. Overall, these results suggest that serum TARC levels are not suitable for monitoring the disease activity of SSc-ILD.

Serum Calponin 3 Levels in Patients with Systemic Sclerosis: Possible Association with Skin Sclerosis and Arthralgia.

Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis and vasculopathy in various organs with a background of inflammation initiated by autoimmune abnormalities. Calponin 3 plays a role in the cell motility and contractibility of fibroblasts during wound healing in the skin. We aimed to evaluate serum calponin 3 levels in SSc patients and their association with clinical manifestations of SSc. Serum samples were collected from 68 patients with SSc and 20 healthy controls. Serum calponin 3 levels were examined using enzyme-linked immunosorbent assay kits, and their association with clinical features of SSc was statistically analyzed. The upper limit of the 95% confidence interval of serum calponin 3 levels in healthy controls was utilized as the cut-off value when dividing SSc patients into the elevated and normal groups. Serum calponin 3 levels were significantly higher in SSc patients than in healthy controls (mean (95% confidence interval), 15.38 (14.66–16.11) vs. 13.56 (12.75–14.38) ng/mL, p < 0.05). The modified Rodnan total skin thickness score was significantly higher in the elevated serum calponin 3 level group than in the normal level group (median (25–75th percentiles), 10.0 (2.0–16.0) vs. 6.5 (3.25–8.75), p < 0.05). Moreover, SSc patients with increased serum calponin 3 levels also had a higher frequency of arthralgia (40% vs. 9%, p < 0.05). Elevated serum calponin 3 levels were associated with skin sclerosis and arthralgia in SSc patients. Serum calponin 3 levels might be a biomarker that reflects the severity of skin sclerosis and joint involvement in SSc.

Prognostic role of right ventricular and atrial mechanics in systemic sclerosis

Abstract Background Left ventricular diastolic dysfunction implies a worse prognosis in systemic sclerosis (SSc). Little is known, however, about the prognostic value of right ventricular (RV) and right atrial (RA) mechanics in this disease. Thus we aimed to investigate the long term prognostic value of the traditional and modern echocardiographic parameters of the RV and RA function as well as N-terminal pro B-type natriuretic peptide (NT-proBNP) levels in SSc patients. Patients and methods Seventy SSc patients (age: 57±12 years) were enrolled into the study. They underwent echocardiography in the years 2014–15. Parameters of the RV systolic function (tricuspid annular plane systolic excursion /TAPSE/, RV fractional area change /RVFAC/), inferior vena cava, collapsibility index, RV wall thickness were measured. Doppler data were collected: tricuspid E and A, peak velocity of tricuspid regurgitation (TR), tricuspid annular myocardial systolic (S), early- (e') and late- (a') diastolic velocities, tricuspid E/e' ratio. Maximal RA volume index as well as RA reservoir (εR), conduit (εCD) and contractile (εCT) strain were measured with the speckle tracking method. RA stiffness was calculated as ratio of E/e' to εR. Survival was assessed after 5 years. Since in some cases the cause of death was unknown, all-cause mortality was chosen as outcome. Results During the follow-up period of 4.7±0.9 years, 6 patients (8.6%) died. In univariate Cox regression analysis TAPSE, peak velocity of TR, tricuspid annular a' and S, tricuspid E/e' ratio, maximal RA volume index, RA stiffness and lnNT-proBNP were significantly associated with outcome. In multivariate Cox regression analysis RA stiffness was proved to be the only independent predictor of mortality (p=0.013). Using ROC analysis, RA stiffness ≥0.156 was the strongest predictor of the mortality (sensitivity=83.3%, specificity =89.1%, AUC=0.859). Conclusion Our results suggest that RA stiffness is an independent predictor of all-cause mortality in SSc. Larger prospective validation studies are required to prove our findings. ROC and Kaplan-Meier survival curve Funding Acknowledgement Type of funding source: None

The risk of circulating angiogenic T cells and subsets in patients with systemic sclerosis

To ascertain the number and percentage of angiogenic T (Tang) cell subsets by flow cytometry in systemic sclerosis (SSc), and their relation with specific clinical features.Thirty SSc patients and 15 healthy controls (HCs) were included. Luminex was performed to analyze the levels of interleukin (IL)-17A, vascular endothelial growth factor (VEGF), tumor necrosis factor-α, and vascular cell adhesion molecule (VCAM). The ratio of circulating CD3 + CD31 + CXCR4 + T (CD3 + Tang) cells and CD8+ CD31 + CXCR4 + T (CD8+ Tang) cells in SSc patients was enlarger than in HCs, while CD4 + CD31 + CXCR4 + T cells (CD4 + Tang) exhibited no difference between SSc patients and HCs. The number and percentage of Tang cells were higher in SSc patients with pulmonary artery hypertension (PAH) than in non-PAH SSc patients and HCs. The ratios of Tang cell subsets in nucleolar pattern-positive SSc patients were markedly raised as compared with their negative ones and HCs. Additionally, the percentage of circulating CD3 + Tang cells was positively associated with VEGF serum levels in SSc patients. Meanwhile, the rate of CD8+ tang cells might have been emphatically corresponded to VEGF and VCAM serum levels in SSc patients. These results imply that the increase in Tang cells in peripheral blood are associated with immunoregulatory disturbances in SSc patients.

Vitamin D and Cytokine Profiles in Patients With Systemic Sclerosis.

Hypovitaminosis D has been frequently described in systemic sclerosis (SSc). Cytokines are important mediators of tissue damage and clinical dysfunction in SSc and may be influenced by vitamin D levels. To evaluate the serum levels of vitamin D and its correlation with the clinical features and cytokine profiles in SSc patients. Case-control study, including 50 SSc patients and 35 healthy non matched controls. Serum levels of 25(OH) vitamin D were measured by chemiluminescence assay, and serum concentrations of interleukin 2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor, and interferon γ were determined by flow cytometry. Fourteen patients (28%) had diffuse cutaneous SSc, 94% were female, 80% European derived, with a mean age of 57.2 ± 12.8 years. The serum vitamin D levels in SSc patients were 23.9 ± 8.5 ng/mL and 30.2 ± 6.2 ng/mL in the control group (standardized mean difference -6.19; 95% confidence interval, -9.9 to -2.3; p = 0.002), despite the more frequent supplementation of vitamin D in SSc patients (p = 0.014). No significant associations were found among vitamin D concentrations and cytokine levels. Serum levels of IL-6 were significantly elevated in SSc patients (p = 0.024) and were positively correlated with the modified Rodnan skin score (rs = 0.291, p =0.041). Despite lower vitamin D levels in SSc patients, there was no clear association with any cytokine. Serum levels of IL-6 were significantly elevated and positively correlated with the extent of skin involvement in SSc patients.