Vasculopathy In Systemic Sclerosis Research Articles

Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: From Bedside to Bench and Back Again.

Systemic sclerosis (SSc) is a heterogeneous disease characterized by autoimmunity, vasculopathy, and fibrosis which affects the skin and internal organs. One key aspect of SSc vasculopathy is pulmonary arterial hypertension (SSc-PAH) which represents a leading cause of morbidity and mortality in patients with SSc. The pathogenesis of pulmonary hypertension is complex, with multiple vascular cell types, inflammation, and intracellular signaling pathways contributing to vascular pathology and remodeling. In this review, we focus on shared molecular features of pulmonary hypertension and those which make SSc-PAH a unique entity. We highlight advances in the understanding of the clinical and translational science pertinent to this disease. We first review clinical presentations and phenotypes, pathology, and novel biomarkers, and then highlight relevant animal models, key cellular and molecular pathways in pathogenesis, and explore emerging treatment strategies in SSc-PAH.

Association between systemic sclerosis and risk of cerebrovascular and cardiovascular disease: a meta-analysis

We aimed to evaluate the association between systemic sclerosis (SSc) and major cerebrovascular/cardiovascular risks through a systematic approach. Databases were systematically searched from their inception to October 10, 2023 for studies comparing cerebrovascular/cardiovascular event rates between patients with SSc and controls. The primary outcome was the stroke risk in patients with SSc. Secondary outcomes included risk of myocardial infarction (MI), cardiovascular disease (CVD), peripheral vascular disease (PVD), and venous thromboembolism (VTE). Seventeen studies with 6,642,297 participants were included. SSc was associated with a significantly increased risk of stroke (HR, 1.64; 95% confidence interval [CI], 1.35–2.01), CVD (HR, 2.12; 95% CI, 1.36–3.3), MI (HR, 2.15; 95% CI, 1.23–3.77), VTE (HR, 2.75; 95% CI, 1.77–4.28), and PVD (HR, 5.23; 95% CI, 4.25–6.45). Subgroup analysis revealed a significantly increased stroke risk in the non-Asian group (HR, 1.55; 95% CI, 1.26–1.9), while the Asian group displayed a higher but not statistically significant risk (HR, 1.86; 95% CI, 0.97–3.55). The study found that SSc is associated with a significantly increased risk of cerebrovascular/cardiovascular events. These findings highlight the importance of vasculopathy in SSc and suggest the need for enhanced clinical monitoring and preventive measures in this high-risk population.

Long non-coding RNA H19X as a regulator of mononuclear cell adhesion to the endothelium in systemic sclerosis.

To define the functional relevance of H19 X-linked co-expressed lncRNA (H19X) in endothelial cell (EC) activation as a key process in systemic sclerosis (SSc) vasculopathy. H19X expression in SSc skin biopsies was analyzed from single cell RNA sequencing (scRNA-seq) data. Differential expression and pathway enrichment analysis between cells expressing (H19Xpos) and non expressing H19X (H19Xneg) cells was performed. H19X function was investigated in human dermal microvascular EC (HDMECs) by silencing. H19X and EC adhesion molecules levels were analyzed by RT-qPCR and Western Blot after stimulation with proinflammatory cytokines. Cytoskeletal rearrangements were analyzed by fluorescent staining. Endothelial adhesion was evaluated by co-culture of HDMECs and fluorescent labelled peripheral blood mononuclear cells (PBMCs). Shedding VCAM1 was evaluated by ELISA on HDMEC supernatant. scRNA-seq showed significant upregulation of H19X in SSc compared with healthy EC. In HDMEC, H19X was consistently induced by type I and II interferons. H19X knockdown lead to a significant decrease of the mRNA of several adhesion molecules. Particularly, vascular cell adhesion protein 1 (VCAM1) was significantly reduced at protein and mRNA levels. Co-expression analysis of the scRNA-seq data confirmed a higher expression of VCAM1 in (H19Xpos) EC. EC were also strongly associated with the 'cell adhesion molecule' pathway. Moreover, VCAM1 downstream pathway displayed less activation following H19X knockdown. Contractility of HDMEC, PBMC adhesion to HDMEC and VCAM1 shedding were also reduced following H19X knockdown. lncRNA H19X may contribute to EC activation in SSc vasculopathy, acting as a regulator of expression of adhesion molecules in EC.

Practice pattern for the use of intravenous iloprost for the treatment of peripheral vasculopathy in systemic sclerosis: A case–control study from the Italian national multicenter “SPRING” (Systemic Sclerosis Progression InvestiGation) Registry

Background: Intravenous iloprost has been widely used for the treatment of systemic sclerosis peripheral vasculopathy. No agreement has been found on the regimen and the dosage of intravenous iloprost in different scleroderma subset conditions. This study aimed to evaluate the modalities of intravenous iloprost administration within a large cohort of systemic sclerosis patients from the SPRING Registry and to identify any associated clinical-demographic, instrumental or therapeutic data. Patients and Methods: Data of systemic sclerosis patients treated with intravenous iloprost for at least 1 year (case group) were retrospectively analyzed, including different timing and duration of intravenous iloprost session, and compared with those of untreated patients (control group). Results: Out of 1895 analyzed patients, 937 (49%) received intravenous iloprost treatment, while 958 (51%) were assigned to the control group. Among cases, about 70% were treated every 4 weeks, 24% with an interval of more than 4 weeks, and only 6% of less than 4 weeks. Most patients receiving the treatment every 4 weeks, or less, underwent infusion cycle for 1 day only, while if it was scheduled with an interval of more than 4 weeks, a total number of 5 consecutive days of infusions was the preferred regimen. The comparison between the two groups revealed that patients treated with intravenous iloprost had a higher frequency of DUs (p < 0.001), pitting scars (p < 0.001), diffuse cutaneous involvement (p < 0.001), interstitial lung disease (p < 0.002), as well as higher rates of anti-topoisomerase I, “ late” scleroderma pattern at nailfold videocapillaroscopy. These findings were confirmed by multivariate analysis. Conclusion: Our data provide a picture on the Italian use of intravenous iloprost among systemic sclerosis patients and showed that it was usually employed in patients with a more aggressive spectrum of the disease. The disparity of intravenous iloprost treatment strategies in the different centers suggests the need of a rational therapeutical approach based on the clinical characteristics of different patients’ subsets.

A journey to vasculopathy in systemic sclerosis: focus on haemostasis and thrombosis.

Systemic sclerosis is a multisystem connective tissue disease, characterized by endothelial autoimmune activation, along with tissue and vascular fibrosis leading to vasculopathy and to a progressive loss of angiogenesis. This condition further deranges the endothelial barrier favouring the opening of the endothelial junctions allowing the vascular leak in the surrounding tissues: this process may induce cell detachment which allows the contact between platelets and collagen present in the exposed subendothelial layer. Platelets first adhere to collagen via glycoprotein VI and then, immediately aggregate because of the release of von Willebrand factor which is a strong activator of platelet aggregation. Activated platelets exert their procoagulant activity, exposing on their membrane phospholipids and phosphatidylserine, enabling the adsorption of clotting factors ready to form thrombin which in turn drives the amplification of the coagulative cascade. An essential role in the activation of blood coagulation is the tissue factor (TF), which triggers blood coagulation. The TF is found abundantly in the subendothelial collagen and is also expressed by fibroblasts providing a haemostatic covering layer ready to activate coagulation when the endothelial injury occurs. The aim of this review is to focus the attention on the underlying mechanisms related to haemostasis and thrombosis pathophysiology which may have a relevant role in SSc as well as on a possible role of anticoagulation in this disease.

Dangui Huoxue Preparation (DHP) Ameliorates Skin Fibrosis, Inflammation, and Vasculopathy in the Bleomycin-Induced Murine Model of Systemic Sclerosis.

Systemic sclerosis (SSc) is an immune-mediated rheumatic disease that is characterized by fibrosis of the skin and internal organs and vasculopathy with poor prognosis. Dangui Huoxue Preparation (DHP) is a clinically effective traditional Chinese herbal formula for the treatment of SSc in the hospital. This study aims to investigate the therapeutic effects and underlying molecular mechanisms of DHP in the treatment of SSc. SSc mice models are induced by bleomycin (BLM). Tissues of DHP group, normal control group, and positive control drug Sanqi Tongshu Capsule (STC) group are collected for inflammation, fibrosis, and vasculopathy. Also, the human dermal fibroblasts (HDF) stimulated with TGF-β1 are analyzed for in vitro study. The expression levels of MCP-1, IFN-γ, IL-1β, IL-10, Fizz1, iNOS, and IL12p40, and the mRNA levels of Col1a1, Col1a2, Col3a1, and Col5a1 are significantly decreased in all DHP groups and STC group compare with those in the BLM group. The main drug of DHP inhibits the proliferation and migration of HDF, reduces Ctgf, Itgb3, Itgb5 expression, and also inhibits the Smad3 pathway. In conclusion, DHP can ameliorate SSc skin inflammation, fibrosis, and vasculopathy, possibly suppressing the TGF-β1/Smad3 signaling pathway through extracellular and intracellular mechanisms.

The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity.

Systemic sclerosis (SSc) is an autoimmune disease associated with increased mortality and poor morbidity, impairing the quality of life in patients. Whilst we know that SSc affects multiple organs via vasculopathy, inflammation, and fibrosis, its exact pathophysiology remains elusive. Microvascular injury and vasculopathy are the initial pathological features of the disease. Clinically, the vasculopathy in SSc is manifested as Raynaud's phenomenon (reversible vasospasm in reaction to the cold or emotional stress) and digital ulcers due to ischemic injury. There are several reports that medications for vasculopathy, such as bosentan and soluble guanylate cyclase (sGC) modulators, improve not only vasculopathy but also dermal fibrosis, suggesting that vasculopathy is important in SSc. Although vasculopathy is an important initial step of the pathogenesis for SSc, it is still unclear how vasculopathy is related to inflammation and fibrosis. In this review, we focused on the clinical evidence for vasculopathy, the major cellular players for the pathogenesis, including pericytes, adipocytes, endothelial cells (ECs), and myofibroblasts, and their signaling pathway to elucidate the relationship among vasculopathy, inflammation, and fibrosis in SSc.

Pathogenesis of vasculopathy in systemic sclerosis and its contribution to fibrosis.

In patients with systemic sclerosis (SSc), vascular manifestations precede skin and organ fibrosis. There is increasing evidence demonstrating a pathogenic link between early vascular injury and subsequent development of tissue fibrosis. Our knowledge of cellular and molecular mechanisms underlying a unique relationship between SSc-related vasculopathy and fibrosis has changed over the last few years. There is increasing evidence showing viral infection as a potential trigger elucidating vascular injury. Due to defective vascular repair machinery, this initial event results in endothelial cell activation and apoptosis as well as the recruitment of inflammatory/immune cells, leading to endothelial-to-mesenchymal transition. This sequential process induces destructive vasculopathy in capillaries, fibroproliferative vascular lesions in arteries, and excessive fibrosis in the surrounding tissue. A variety of molecular mechanisms and pathways involved in vascular remodeling linked to subsequent excessive fibrosis have been identified and serve as attractive therapeutic targets for SSc. Endothelial injury may play a central role in connecting three features that characterize SSc pathogenesis: vasculopathy, chronic inflammation, and fibrosis. Our understanding of the processes responsible for myofibroblast differentiation triggered by vascular injury will provide the rationale for novel targeted therapies for SSc.

Clinical and LASCA preliminary data on selexipag efficacy for the treatment of digital vasculopathy in systemic sclerosis.

Systemic sclerosis (SSc) is burdened by Raynaud's phenomenon (RP) and digital ulcers (DUs) and sometimes standard vasoactive therapies are ineffective or contraindicated. Selexipag is an oral selective IP prostacyclin receptor agonist approved for the treatment of SSc-related pulmonary arterial hypertension. We aimed to evaluate clinical and instrumental efficacy of selexipag in SSc digital vasculopathy. SSc patients with severe digital vasculopathy refractory or with contraindication to all other vasoactive therapies were administered selexipag, evaluating at baseline and after 3 months clinical outcomes regarding RP and DUs and digital perfusion assessed by laser speckle contrast analysis (LASCA). Selexipag was administered to 9 SSc patients (66.6% female, mean age 52.3 ±16.6 years). One of them had to stop the drug for adverse effects. After three months selexipag determined a significant reduction of RP daily episodes (p=0.012) and RP mean duration (p=0.044). DUs decreased from 10 to 4 without reaching the statistical significance. A significant improvement in the mean perfusion of the fingers (p=0.016) was observed at LASCA. Selexipag showed good potential for the treatment of SSc-digital vasculopathy. Our results are certainly preliminary but yet quite encouraging. New trials for the evaluation of selexipag efficacy in SSc-digital vasculopathy are needed.

Ultra-high frequency ultrasound for digital arteries: improving the characterization of vasculopathy in systemic sclerosis

ObjectivesTo provide a full characterization of proper palmar digital arteries (PPDA) in systemic sclerosis (SSc) with ultra-high frequency ultrasound (UHFUS), and to investigate possible relationships between digital macroangiopathy and microangiopathy. MethodsSSc patients without active digital ulcers and healthy controls (HC) were enrolled. Each subject underwent UHFUS 70 MHz evaluation of PPDA from II to V fingers bilaterally, searching for vessel occlusion and measuring the thickness of the three arterial layers and the systolic-diastolic excursion range. Microcirculation was investigated with capillaroscopy and laser speckle contrast analysis (LASCA). ResultsForty-six SSc patients (87% female, mean age 55.5 years) and 15 HC comparable for age and sex were enrolled. UHFUS in SSc revealed the occlusion of 124 (16.8%) PPDA, whereas in HC they were all patent. Considering a finger with at least one PPDA occluded as ultrasonographically pathological, 67.4% patients presented ≥1 pathological fingers. All three arterial layers were significantly thicker and excursion range significantly reduced in SSc than in HC (p<0.001 for all). Seventy-three percent of fingers previously affected by digital ulcers, were ultrasonographically pathological. Disease duration was directly correlated to the thickness of all three arterial layers. No significant correlations emerged between capillaroscopy or LASCA findings and UHFUS features. ConclusionUHFUS allows the characterization of vasculopathic involvement of PPDA in SSc, also showing subclinical vasculopathy. The lack of correlations between UHFUS and capillaroscopy or LASCA likely mirrors non-overlapping vasculopathic processes. UHFUS evaluation of PPDA emerges as complementary to microcirculation assessment for a more accurate and complete characterization of SSc vasculopathy.

Imaging techniques for assessment of vascular involvement in systemic sclerosis.

Vascular assessment in systemic sclerosis (SSc) is included in classification criteria for this disease, thus routinely used in the evaluation of patients in which this diagnosis is being considered. In this review, imaging techniques for assessment of vascular involvement in SSc hands and skin are discussed. Longitudinal use of imaging techniques has important implications for understanding the progressive vasculopathy and fibrotic transition in SSc. Nailfold and oral capillaroscopy as well as laser speckle contrast analysis are established techniques for vascular functional assessment, but longitudinal use is challenged by equipment costs and clinical time constraints. Ultrasound techniques are well described but require technical training. Advances in mobile infrared thermography and optical coherence tomography could potentially provide a point-of-care, quantitative outcome measure in clinical trials and practice. The equipment cost, technical training, data standardization, and invasiveness of vascular assessment techniques that quantify morphological (microangiopathy) and functional (blood flow reduction) are critical for implementation into SSc clinical trials and practice to understand progressive vasculopathy, such as wound development.

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.

Practical management of Raynaud's phenomenon - a primer for practicing physicians.

Raynaud's phenomenon (RP) is a common vasospastic condition that results in digital hypoperfusion in response to cold and/or emotional stress and is associated with significant pain and disability. The aim of our review is to provide a practical approach for clinicians to inform assessment and management of patients with RP. Autoantibodies and nailfold capillaroscopy are key investigations to stratify the risk of progression to systemic sclerosis (SSc) in patients RP, which was recently confirmed in the multicenter, very early diagnosis of systemic sclerosis (VEDOSS) project. Research has explored the complex lived-patient experience of RP including digital vasculopathy in SSc and has highlighted the need for outcome measure development to facilitate research in the field. Pharmacological treatment strategies vary significantly internationally and there is continued interest in developing surgical approaches. We provide a practical and up-to-date approach to inform the assessment and management of patients with RP including guidance on drug initiation and escalation. Calcium channel blockers are first-line treatment and can be initiated by primary care physicians. We also highlight second-line drug therapies used for refractory RP and the potential role for surgical intervention.

Downregulation of Vascular Hemeoxygenase-1 Leads to Vasculopathy in Systemic Sclerosis.

Systemic sclerosis (SSc) is a terminal disease characterized by vasculopathy, tissue fibrosis, and autoimmunity. Although the exact etiology of SSc remains unknown, endothelial dysfunction, oxidative stress, and calcium handling dysregulation have been associated with a large number of SSc-related complications such as neointima formation, vasculogenesis, pulmonary arterial hypertension, impaired angiogenesis, and cardiac arrhythmias. Hemeoxygenase-1 (HO-1) is an antioxidant enzyme involved in multiple biological actions in the cardiovascular system including vascular tone, angiogenesis, cellular proliferation, apoptosis, and oxidative stress. The aim of this work was to investigate the physiological role of HO-1 and its relevance in the cardiovascular complications occurring in SSc. We found that, in early phases of SSc, the expression of HO-1 in dermal fibroblast is lower compared to those isolated from healthy control individuals. This is particularly relevant as reduction of the HO-1/CO signaling pathway is associated with endothelial dysfunction and vasculopathy. We show evidence of the role of HO-1/carbon monoxide (CO) signaling pathway in calcium handling. Using an in vitro model of pulmonary arterial hypertension (PAH) we investigated the role of HO-1 in Ca2+ mobilization from intracellular stores. Our results indicate that HO-1 regulates calcium release from intracellular stores of human pulmonary arterial endothelial cells. We interrogated the activity of HO-1 in angiogenesis using an organotypic co-culture of fibroblast-endothelial cell. Inhibition of HO-1 significantly reduced the ability of endothelial cells to form tubules. We further investigated if this could be associated with cell motility or migration of endothelial cells into the extracellular matrix synthesized by fibroblasts. By mean of holographic imaging, we studied the morphological and functional features of endothelial cells in the presence of an HO-1 activator and selective inhibitors. Our results demonstrate that inhibition of HO-1 significantly reduces cell proliferation and cell motility (migration) of cultured endothelial cells, whilst activation of HO-1 does not modify either morphology, proliferation or motility. In addition, we investigated the actions of CO on the Kv7.1 (KCQN1) channel current, an important component of the cardiac action potential repolarization. Using electrophysiology (whole-cell patch-clamp in a recombinant system overexpressing the KCQN1 channel), we assessed the regulation of KCQN1 by CO. CORM-2, a CO donor, significantly reduced the Kv7.1 current, suggesting that HO-1/CO signaling may play a role in the modulation of the cardiac action potential via regulation of this ion channel. In summary, our results indicate a clear link between: 1) downregulation of HO-1/CO signaling; and 2) pathophysiological processes occurring in early phases of SSc, such as calcium homeostasis dysregulation, impaired angiogenesis and cardiac arrhythmias. A better understanding of the canonical actions (mainly due to the biological actions of CO), and non-canonical actions of HO-1, as well as the interaction of HO-1/CO signaling with other gasotransmitters in SSc will contribute to the development of novel therapeutic approaches.

Angiotensin-converting enzyme inhibitors prior to scleroderma renal crisis in systemic sclerosis: A systematic review and meta-analysis.

Angiotensin-converting enzyme inhibitors (ACEIs) are widely used in the treatment of scleroderma renal crisis (SRC), and their use prior to the onset of SRC in patients with systemic sclerosis (SSc) has received wide attention in recent years. We undertook an evidence-based approach to identify whether the use of ACEIs prior to the onset of SRC is beneficial for patients with SSc. We searched PubMed and Embase for any published studies produced between database inception and 22 October 2021. Articles obtained after using appropriate keywords were selected independently by two reviewers according to the established inclusion and exclusion criteria. Nine studies were included. Pooled results indicated that using ACEIs prior to SRC was associated with a higher incidence of SRC than no ACEIs prior to SRC (RR 2.05, 95% confidence interval 1.08-3.91, p=0.03). Compared with patients who did not use ACEIs prior to the onset of SRC, a higher proportion of patients with SRC who used ACEIs prior to its onset had a poorer prognosis (RR 1.46, 95% confidence interval 1.20-1.78, p<0.01). The difference in mortality between patients who used ACEIs prior to SRC onset and those who did not was not statistically significant (RR 1.12, 95% confidence interval 0.76-1.65, p=0.57). We recommend against using ACEIs prior to SRC in SSc patients. The use of ACEIs prior to SRC is associated with a higher incidence of SRC and poorer prognosis, especially in patients with progressive SSc or SSc-related renal vasculopathy (SSc-related hypertension and proteinuria).

Successful Endovascular Therapy for Total Occlusion of the Distal Radial and Ulnar Artery with Palmar Artery Lesion in a Patient with Critical Hand Ischemia Associated with Systemic Sclerosis

Vasculopathy of systemic sclerosis (SSc) is known to lead to severe limb ischemia and is often associated with macrovascular diseases. Revascularization of proximal macrovascular lesions that cause limb ischemia in patients with SSc has been recommended; however, it has rarely been reported for lesions below-the-elbow (BTE) involving the palmar artery. A 66-year-old female patient with SSc experienced critical hand ischemia (CHI) with gangrene of the left third finger that failed to respond to conventional pharmacological treatment. Angiography revealed total occlusion of the distal radial and ulnar arteries with a palmar artery lesion. Balloon angioplasty was performed for bilateral occlusive lesions around the wrist, which improved antegrade flow to the digital artery. Endovascular therapy may be a feasible option for BTE lesions involving palmar artery disease, presenting with CHI in SSc, when conventional conservative treatments fail.

Reduction of carotid baroreceptor sensitivity in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterised by diffuse vasculopathy and fibrosis of skin and visceral organs. Moreover, autonomic dysfunction is also suggested as an important step during the multifactorial SSc pathogenesis. Baroreceptors are responsible for maintaining blood pressure by means of autonomic system modulation. Considering that autonomic dysfunction and arteriosclerosis can both reduce baroreceptor sensitivity (BRS), in this cross-sectional study we investigated BRS in SSc patients. Twenty-one SSc patients (mean age 55±10 years, 18 females) and 147 age/sex-matched healthy controls were recruited for the study. BRS (ms/mmHg) was measured by a Finapres® Midi device (Finapres Medical Systems, Amsterdam, The Netherlands). Other parameters were measured: blood pressure, heart rate, heart rate variability triangular index (HRVI), intima-media thickness (IMT), carotid distensibility and pulse wave velocity (PWV). BRS was significantly lower in SSc patients compared to controls (6.3±3.3 vs. 10.7±6.8 ms/mmHg; p=0.004). IMT was comparable between SSc and controls, whereas carotid distensibility was lower in SSc (20.1±7.6 vs. 26.6±13.3 KPa-1·10-3; p=0.02) and PWV higher in SSc (8.4±1.3 vs. 7.1±1.1 m/sec; p=0.01). Furthermore, HRVI was lower in SSc (4.5±2.1 vs. 7.5±2.8; p<0.001). BRS impairment was independent from age and carotid distensibility in SSc patients, suggesting that BRS dysfunction could be only partially a consequence of SSc vasculopathy. BRS was reduced in SSc patients compared with healthy controls. This finding could represent a SSc-related alteration involving the autonomic system, besides being the mere consequence of sclerodermic vasculopathy.

Ultrasound evaluation of bowel vasculopathy in systemic sclerosis

BackgroundGastrointestinal (GI) manifestations are frequent in systemic sclerosis (SSc) with an impact on quality of life and morbidity. Bowel vasculopathy is a key pathogenetic factor responsible for GI involvement. ObjectivesTo compare abdominal ultrasound (US) and Color Doppler Ultrasonography (CDU) features of splanchnic vessels of SSc patients with healthy controls. MethodsThe charts of SSc patients who underwent an abdominal US and CDU study were retrospectively analyzed. For Superior Mesenteric Artery (SMA) and Inferior Mesenteric Artery (IMA) caliber, Peak Systolic Velocity (PSV), Reverse Velocity (RV), End-Diastolic Velocity (EDV), Mean Velocity (mV), Blood-flow, Resistive Index (RI) and Pulsatility Index (PI) were recorded. Results28 SSc patients and 28 controls were enrolled. In SSc, caliber of SMA was significantly smaller than in controls (5.75 ± 0.62 mm vs. 6.45 ± 0.60 mm, p < 0.0001 – p adj =0.0002). The flow study of SMA and IMA showed a significant reduction of RV (SMA: 7.25 ± 6.37 cm/s vs. 18.52 ± 6.16 cm/s, p < 0.0001 - p adj <0.0001; IMA: 2.69 ± 6.10 cm/s vs. 17.06 ± 5.75 cm/s, p < 0.0001 - p adj <0.0001) and PI (SMA: 3.33 ± 0.75 vs. 4.53 ± 1.03, p < 0.0001 - p adj =0.0002; IMA: 3.54 ± 0.95 vs. 6.08 ± 1.53, p < 0.0001 - p adj <0.0001) in SSc patients than controls. Conclusioninvolvement of splanchnic vessels in SSc may be non-invasively investigated with abdominal US and CDU. Morphological and functional changes of Doppler parameters observed in SMA and IMA clearly demonstrate that these vessels are affected by SSc vasculopathy.

Management of Endothelial Dysfunction in Systemic Sclerosis: Current and Developing Strategies.

Systemic Sclerosis (SSc) is an autoimmune disease marked by dysregulation of the immune system, tissue fibrosis and dysfunction of the vasculature. Vascular damage, remodeling and inadequate endothelial repair are hallmarks of the disease. Since early stages of SSc, damage and apoptosis of endothelial cells (ECs) can lead to perivascular inflammation, oxidative stress and tissue hypoxia, resulting in multiple clinical manifestations. Raynaud's phenomenon, edematous puffy hands, digital ulcers, pulmonary artery hypertension, erectile dysfunction, scleroderma renal crisis and heart involvement severely affect quality of life and survival. Understanding pathogenic aspects and biomarkers that reflect endothelial damage in SSc is essential to guide therapeutic interventions. Treatment approaches described for SSc-associated vasculopathy include pharmacological options to improve blood flow and tissue perfusion and, more recently, cellular therapy to enhance endothelial repair, promote angiogenesis and heal injuries. This mini-review examines the current knowledge on cellular and molecular aspects of SSc vasculopathy, as well as established and developing therapeutic approaches for improving the vascular compartment.

Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis

BackgroundWe have recently demonstrated that serum CCL20 levels positively correlate with mean pulmonary arterial pressure in patients with systemic sclerosis (SSc). Considering a proangiogenic effect of CCL20 on endothelial cells via CCR6, the CCL20/CCR6 axis may contribute to the development of SSc vasculopathy. Therefore, we explored this hypothesis using clinical samples, cultured cells, and murine SSc models.MethodsThe expression levels of CCL20 and CCR6 in the skin, mRNA levels of target genes, and the binding of transcription factor FLI1 to the target gene promoter were evaluated by immunostaining, quantitative reverse transcription PCR, and chromatin immunoprecipitation, respectively. Vascular permeability was evaluated by Evans blue dye injection in bleomycin-treated mice. Angiogenic activity of endothelial cells was assessed by in vitro angiogenesis assay.ResultsCCL20 expression was significantly elevated in dermal fibroblasts of patients with early diffuse cutaneous SSc, while CCR6 was significantly up-regulated in dermal small vessels of SSc patients irrespective of disease subtypes and disease duration. In human dermal microvascular endothelial cells, FLI1 siRNA induced the expression of CCR6, but not CCL20, and FLI1 bound to the CCR6 promoter. Importantly, vascular permeability, a representative SSc-like vascular feature of bleomycin-treated mice, was attenuated by Ccr6 siRNA treatment, and CCR6 siRNA suppressed the angiogenic activity of human dermal microvascular endothelial cells assayed by in vitro tube formation.ConclusionsThe increased expression of endothelial CCR6 due to FLI1 deficiency may contribute to the development of SSc vasculopathy.