Nailfold Videocapillaroscopy Research Articles

Vasoprotective Effects of Prolonged Therapy With Perindopril A in Patients with Hypertension Including Concomitant Type 2 Diabetes Mellitus

Objective Investigate the dynamics of morphological and functional markers of vascular remodeling in patients with arterial hypertension (AH), including those with concomitant type 2 diabetes mellitus (DM2), during 12-month administration of perindopril A.Material and Methods The study included patients with grade I-II AH, with and without DM2 (30 and 32 patients, respectively), who underwent outpatient correction of initially ineffective antihypertensive therapy and administration of perindopril A, 10 mg/day. Morphological and functional parameters of vascular remodeling were evaluated in all patients at baseline and at 12 months using photoplethysmography. Stiffness index (SI) and phase shift (PS) were measured in large vessels. Reflection index (RI) and occlusion index (OI) were measured in microvessels. Computed nailfold videocapillaroscopy was used to determine capillary density (CD) at rest (CDr), CD during venous occlusion test (CDvo), and CD during reactive hyperemia test (CDrh). Data are medians [interquartile range].Results After 12-month administration of perindopril A, the morphological and functional parameters of vascular remodeling in AH patients without DM2 significantly improved at all vascular levels. SI decreased to 9.25 [7.8; 10.93 ] m/s and PS increased to 7.4 [5.6; 9.05] ms. In microvasculature, a statistically significant reduction was observed in RI, 31 [27; 36.5]%, and an increase was observed in OI, which characterizes endothelium function, 1.75 [1.68; 1.9]. Capillary CDr significantly increased to 40.5 [34.93; 46] cap/mm2, as did CDvo and CDrh. At the same time, in the group of patients with AH and DM2, a significant improvement was observed for the large vessels. SI decreased to 9.8 [9.08; 10.58] m/s, and PS increased to 6.95 [5.13; 10.08]. The RI index, reflecting the structural condition of arterioles, significantly decreased to 34 [25.9; 45.53]%, and the OI index, characterizing endothelial function, did not change significantly, 1.4 [1.3; 1.6]. Capillary CDr significantly increased to 31.55 [27.68; 34.7 ] cap/mm2; however, CDvo and CDrh did not change significantly. Renal function improved in both groups.Conclusion Both groups demonstrated improvement of morphological parameters at all levels of the arterial bed. However, patients with AH and concomitant DM2 showed no improvement of the endothelial function of arterioles and capillaries compared to improvement in AH patients without DM2. This reflected the more severe endothelial dysfunction present in AH patients with DM2.

Phase angle could be a marker of microvascular damage in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by endothelial dysfunction with fibrosis of skin and internal organs. Integrity of the endothelial cell is important to its physiologic function such as production of angiogenetic factors. The aim of this study was to assess whether phase angle (PhA) is altered in patients with SSc and whether its values correlate with vascular endothelial growth factor (VEGF) and digital microvascular damage. Patients with SSc and matched healthy controls underwent VEGF determination and bioimpedentiometry (BIA) for PhA assessment. Clinical assessment, disease activity index (DAI), disease severity scale, and nailfold videocapillaroscopy (NCV) were performed in patients with SSc. Fifty-five patients (46 women) with a mean age of 53.2 ± 13.7 y were studied. The mean value of VEGF was significantly higher in patients with SSc than in the healthy controls (240.3 ± 149.5 versus 139 ± 87.5; P=0.035). The mean value of PhA was significantly lower in the patient grouop than in the healthy controls (4.51 ± 0.87 versus 5.22 ± 0.55; P < 0.0001). A significant positive correlation was found between VEGF and PhA (P=0.009, beta coefficient=1.48) in SSc patients. A negative correlation between VEGF and DAI (P=0.048, β coefficient=0.48) was found. PhA median value was significantly (P=0.006) lower in patients with late pattern SSc (4.2 [2.5-5.3]). PhA median value was significantly (P < 0,0001) lower in patients with digital ulcers (DUs; 4.2 [2.5-5.3]) than in those without DUs (3.80 [2.50-5] versus 4.75 [2.80-7.3]). These data were confirmed in both female and male patients. The evaluation of VEGF with PhA, NVC, and DUs could be useful to estimate cellular and microvascular damage in patients with SSc.

Peripheral Microangiopathy in Patients with Precapillary Pulmonary Hypertension: Correlation with Cardiac Function and Patients' Functional Capacity. Study Design and Rationale.

Pulmonary hypertension (PH) is a rare, heterogenous clinical entity characterised by a progressive remodelling of pulmonary arterioles, which leads to obstructive pulmonary arteriopathy, increased pulmonary vascular resistance, and eventually, right heart failure. Inflammation, endothelial dysfunction, and microvascular changes of the pulmonary vasculature constitute the hallmarks of pulmonary arterial hypertension (PAH), explaining much of the pathophysiology and clinical manifestations of the disease. Besides pulmonary vasculature, a systemic component of endothelial dysfunction and microcirculation may be involved in PAH, affecting different vascular beds. Nailfold videocapillaroscopy (NVC) is an established method for the assessment of the microvasculature with clinical implications in the diagnostic assessment of individuals with Raynaud syndrome and systemic sclerosis (SSc). Nowadays, growing amounts of evidence suggest that NVC changes in SSc are correlated with other vascular complications such as PAH, supporting a potential link between peripheral and internal organ vasculopathy. The purpose of the current prospective observational study is to explore: 1. the presence of peripheral microangiopathy in precapillary PH using NVC, 2. possible NVC differences among PH subgroups, 3. a potential relationship between NVC morphological abnormalities and clinical, functional, biochemical, echocardiographic and hemodynamic markers of cardiac dysfunction in precapillary PH.

Abnormal nailfold videocapillaroscopic findings in heart failure patients with preserved ejection fraction.

Microvascular dysfunction is one of the pathophysiological mechanisms in heart failure. Nailfold videocapillaroscopy is a noninvasive technique used to examine the microvasculature. In this study, we aimed to investigate the nailfold capillaroscopic abnormalities in heart failure patients with reduced and preserved ejection fraction and compare those with control group. Three groups of patients were recruited for the study: HFrEF group includes the patients with heart failure with reduced ejection fraction (HFrEF), HFpEF group, patients with heart failure with preserved ejection fraction (HFpEF) and control group, healthy asymptomatic individuals. Nailfold videocapillaroscopy was performed with a videodermatoscope and all nailfold images were evaluated for enlargement and hemorrhages. Abnormal videocapillaroscopic findings including enlargement and/or hemorrhages were present in 7 (24%) patients in HFrEF group, 19 (66%) patients in HFpEF group and 11 (37%) in control group. The number of patients with abnormal videocapillaroscopic findings were significantly greater in HFpEF group compared to HFrEF (p < 0.05) and control groups (p < 0.05). However, no significant difference was observed in videocapillaroscopic findings between HFrEF and control groups. Our study showed that microvascular abnormalities demonstrated by videodermatoscopic examination of nailfold capillaries are considerably more common in HFpEF patients compared to HFrEF and control groups.

Significance of the angiotensin I/angiotensin II/angiotensin-(1-7) axis in the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is a multisystemic disease with an extensive microvasculopathy. Previously, disturbances in plasma levels of angiotensin II (Ang II) and its antagonistic angiotensin-(1-7) (Ang-(1-7)) were found in patients with SSc. Their significance in a pathogenesis of SSc stays unclear due to discrepancies of earlier studies. To evaluate a significance of disturbances in production pathway of angiotensins in a development of SSc. There were enrolled 27 patients with established SSc, 23 subjects with very early SSc and 23 healthy controls. The diagnosis of SSc was established in patients who met EULAR/ACR 2013 classification criteria. Very early SSc described patients with Raynaud's phenomenon having SSc-specific antinuclear antibodies and SSc-like abnormalities in nailfold videocapillaroscopy. Patients were submitted to evaluation of internal organ involvement and blood sampling to assay plasma levels of angiotensin I, angiotensin II and angiotensin-(1-7) with ELISA technique. Plasma level of angiotensin-(1-7) was significantly reduced in both SSc group (median=47.2pg/mL; P<0.001) and ones with very early SSc (median=102.7pg/mL; P=0.002) when compared to healthy controls (median=176.1pg/mL). A tendency to higher than in control group (median=214pg/mL) plasma level of angiotensin I was seen in SSc group (median=392pg/mL; P=0.059). Differences in plasma level of angiotensin II were insignificant between all study groups. Those disturbances produced unfavourable angiotensin-(1-7)/angiotensin II (%) ratio in both groups of patients, which achieved statistical significance in subjects with established SSc (P<0.001). Production pathway of angiotensins showed a dependence on a subtype of SSc, immune profile and a presence of interstitial lung disease. Production of angiotensin-(1-7) was significantly reduced in both SSc patients and those ones with very early SSc, although a significant imbalance between angiotensin II and angiotensin-(1-7) occurred only in subjects with established disease.

Nailfold Capillaroscopy in Systemic Lupus Erythematosus (SLE): a Point-of-Care Tool That Parallels Disease Activity and Predicts Future Complications

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by vascular complications, endothelial cell injury with subsequent dysfunction. Nailfold video capillaroscopy (NVC) is a non-invasive and reliable point-of-care method that can be used to directly visualize microscopic digital capillaries and monitor patients. In this review, we will describe NVC’s role in assessing SLE disease activity and prognosticating risk for developing vascular complications. In SLE, qualitative NVC changes like the presence of microhemorrhages and enlarged capillaries correlate with disease activity. These abnormalities are also associated with specific autoantibody profiles (e.g., anti-phospholipid and anti-U1-RNP antibodies). Recent studies show NVC changes may increase risks of digital ulceration, pulmonary arterial hypertension, and accelerated cardiovascular disease. NVC may be used in personalized medicine as an adjunct in assessing SLE activity which may help prognosticate risk of serious complications, but more studies are needed to further delineate its role in specific SLE disease subtypes.

NEMO score in nailfold videocapillaroscopy is a good tool to assess both steady state levels and overtime changes of disease activity in patients with systemic sclerosis: a comparison with the proposed composite indices for this disease status entity

BackgroundIn previous studies, we demonstrated that the NEMO score, i.e. the cumulative number of microhaemorrhages (MHEs) and microthromboses (MTs), observed in nailfold videocapillaroscopy was a good indicator of the steady state level of disease activity (DA) in patients with systemic sclerosis (SSc) when the European Scleroderma Study Group (EScSG) index was considered the gold standard.Aim of the studyTo verify whether the NEMO score could be (i) a valid tool to assess DA, even when the modified European Scleroderma Trials and Research (EUSTAR) index was considered to be the comparator, and (ii) a sensitive method to capture the DA overtime changes.Patients and methodsThe NEMO score and the EScSG and EUSTAR indices were contemporarily assessed at baseline (T0) and after a follow-up of 4–56 months (T1) in 98 patients with SSc. The differences (Δ) between the T1 and T0 values of the NEMO score and the EScSG and EUSTAR indices were calculated and compared to each other.ResultsNEMO score values were very closely correlated with the corresponding values of the EScSG and EUSTAR indices both at T0 and T1 observations (p < 0.0001 in all cases with the exception of the correlation with EScSG values at T1 (p < 0.03)). The values of the two composite DA indices were also strictly related to each other in both T0 and T1 observations (p < 0.0001).Receiver operating characteristic (ROC) curve analysis showed the NEMO score had a good sensitivity and specificity in classifying patients with a predefined level of DA (scores ≥ 3.0 and ≥ 2.5 for the EScSG and EUSTAR indices, respectively, p < 0.0001 in both cases).Δ values of the NEMO score were significantly correlated with the corresponding values of both the EScSG and EUSTAR indices. Weighted Cohen’s k level of agreement between Δ values of the NEMO score and those of the EScSG and EUSTAR indices was moderate (0.55 and 0.59, respectively).ConclusionsNEMO score proves to be a feasible, non-invasive, and valid tool to assess steady state levels and changes over time of DA in patients with SSc. Thus, it can represent an alternative or complementary method to measure this disease status entity in this disorder.

Arterial stiffness correlates with progressive nailfold capillary microscopic changes in systemic sclerosis: results from a cross-sectional study

BackgroundWhile microangiopathy is well-documented in systemic sclerosis (SSc), a potential link between SSc and macrovascular disease is highly debated and remains to be established. The aim of the present study is to investigate the association between micro- and macrovascular involvement in the setting of SSc.MethodsConsecutive, consenting SSc patients were assessed by nailfold video-capillaroscopy (NVC) to evaluate the microcirculation. The number of capillaries per mm2 and the capillaroscopic skin ulcer risk index (CSURI) were measured, and findings were also classified into three scleroderma patterns (i.e., early, active, and late). Carotid intima-media thickness (IMT), aortic augmentation index corrected for a heart rate of 75 beats per minute (AIx-75), carotid-femoral pulse wave velocity (PWV), and central systolic and diastolic blood pressure were also determined to assess macrovascular function.ResultsA total of 37 patients were studied. A significant correlation was observed between AIx and the average number of capillaries per mm2 (r = − 0.34, p = 0.047) and between AIx and CSURI (r = 0.35, p = 0.044). Patients with the “early” scleroderma pattern had lower AIx values compared with “active” (20.5 ± 11.4 vs 34.1 ± 11.5%, p = 0.02) and “late” (20.5 ± 11.4 vs 33.4 ± 8.8%, p = 0.05) patterns. No other significant correlations were found between macrovascular biomarkers (PWV, carotid IMT, systolic and diastolic central blood pressure) and the capillaroscopic measurements.ConclusionsThese data suggest that arterial stiffness (as assessed by AIx-75) correlates with microvascular damage in patients with SSc.

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

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

Th1- and Th17-Related Cytokines in Venous and Arterial Blood of Sclerodermic Patients with and without Digital Ulcers.

The earliest clinical manifestation of SSc is usually Raynaud's phenomenon, a small-arteries vasospasm driven by vascular tone dysregulation and microcirculatory abnormalities, resulting in digital ulcers (DU) in up to 50% of patients. Many cytokines as well as growth factors have been shown to play a role in promoting vascular smooth muscle cell proliferation and fibroblast activation, leading to ischemic damage as well as skin fibrosis. We aim to investigate a possible difference in venous and arterial blood levels of many cytokines (Th1- and Th17-related), GM-CSF, and endothelin-1 (ET1) in patients with and without DU. In the same patients, the correlations between capillary damage, evaluated by nailfold videocapillaroscopy (NVC), extension of skin fibrosis, calculated by modified Rodnan skin score (mRSS), and cytokines, ET-1, and GM-CSF levels were also measured. Patients with DU showed venous levels of IL-1β (p=0.024), IL-6 (p=0.012), IL-22(p=0.006), and TGF-β (p=0.046) significantly higher compared to arterial levels and arterial levels of GM-CSF and TNF-alpha significantly higher compared to venous levels (p < 0.001). NVC abnormalities were correlated with arterial TNFa and venous IL22, IL23, and IL17 levels and negatively correlated with venous ET-1 levels, whereas mRSS showed a negative correlation with IL-21(ρ = −0.427, p=0.050). The increased Th17-cytokine levels in venous compared to arterial blood of patients with DU suggest local cytokine production on ulcer site. The higher TNFa and GM-CSF levels in arterial blood of DU patients support the attempt to mitigate the hypoxic damage, and the correlation between Th17-cytokines, mRSS, NVC, and ET1 agrees with the potent profibrotic stimulus at the onset of the disease, which decreases as the SSc progresses.

Lower urinary tract symptoms in systemic sclerosis: a detailed investigation.

Urinary tract involvement is a seldom-reported manifestation of SSc that could compromise patients' quality of life. This study compares lower urinary tract symptoms (LUTS) in SSc patients and in healthy subjects and their association with clinical and diagnostic parameters. LUTS were assessed through self-reported questionnaires in 42 SSc patients and 50 matched healthy subjects. Statistical analyses were performed to explore LUTS in the two populations and their association with SSc variables, including nailfold videocapillaroscopy patterns, SSc-related antibodies and DXA parameters. SSc patients showed significantly higher prevalence and severity of urinary incontinence (UI) and overactive bladder (OAB) than healthy controls (P < 0.005, P < 0.01). SSc was a strong predictor of LUTS, independent of demographic data, comorbidities and treatments (odds ratio 5.57, 95% CI 1.64-18.88). In SSc patients OAB positively correlated with sarcopenia (P < 0.001), and both OAB and UI significantly correlated with reduced BMD (P < 0.05, P = 0.001). UI positively correlated with Scl70 antibodies (P < 0.05) and ciclosporin treatment (P = 0.001) and negatively with RNA polymerase III antibodies (P < 0.05); OAB positively correlated with calcinosis (P < 0.005) and negatively with methotrexate treatment (P < 0.05). Nailfold videocapillaroscopy 'active' and 'late' patterns were predominant among SSc patients presenting urinary symptoms, although no statistical correlation was found. For the first time urinary tract involvement was found to be significantly higher in SSc patients than in healthy matched controls. In addition, sarcopenia, bone damage and calcinosis appeared significantly correlated with LUTS, suggesting a possible interplay.

Progression of nailfold capillaroscopic patterns and correlation with organ involvement in systemic sclerosis: a 12 year study.

The aim of this observational study was to investigate the evolution of scleroderma microangiopathy throughout different nailfold videocapillaroscopy (NVC) patterns ('early', 'active', 'late') as well as the prevalence of organ involvement in SSc patients during a 12-year follow-up. Thirty-four SSc patients showing at baseline (first capillaroscopic analysis) the 'early' NVC pattern of microangiopathy were enrolled and followed for 12 years (s.d. 2). Complete NVC analysis and clinical and serological findings were collected. Patients were in a standard therapeutic care setting. Statistical analysis was carried out by non-parametric tests. After a 12-year follow-up, the 'early' NVC pattern changed from baseline in 76% of the patients. The NVC pattern was found to be 'active' in 9 patients (26%), 'late' in 13 (38%) and characterized by non-specific capillary abnormalities in 4 (12%). In the subgroup whose microangiopathy progressed from the 'early' to the 'late' NVC pattern, the median time of progression from the 'early' to the 'active' pattern was significantly shorter (11 months) when compared with patients who progressed from the 'early' to the 'active' NVC pattern (55 months) (P = 0.002). The median time of progression between NVC patterns was significantly shorter in SSc patients showing either a nucleolar ANA pattern or Scl70 autoantibodies (P = 0.048). Organ involvement was progressively greater in SSc patients with 'early', 'active' and 'late' NVC patterns, respectively. This longitudinal study confirms over a 12-year follow-up the evolution of specific NVC patterns associated with the progressive severity of organ involvement in SSc patients in a standard clinical care setting.

Nailfold videocapillaroscopy alterations in dermatomyositis, antisynthetase syndrome, overlap myositis, and immune-mediated necrotizing myopathy.

The aim of our study was to investigate possible differences in nailfold videocapillaroscopy (NVC) features between patients with dermatomyositis (DM), overlap myositis (OM), antisynthetase syndrome (ASS), and immune-mediated necrotizing myopathy (IMNM). We performed a cross-sectional monocentric study. All patients with inflammatory myopathies (IMs) over a 6-month period were analyzed by NVC for giant and ramified capillaries, tortuosities, capillary density, disorganization, and scleroderma pattern. Clinical, biological, and pathological characteristics were retrospectively recorded. Patients were classified as having DM, OM, ASS, or IMNM for comparison. Patients were also compared with a group of patients with systemic sclerosis (SSc). NVC was analyzed in DM (n = 17), OM (n = 8), ASS (n = 12), and IMNM (n = 6). Vascular disorganization and avascular zones were observed only in DM (11.8%) and OM (62.5%). The percentage of patients with giant capillaries was higher in OM (n = 4/8) than in DM (n = 3/17) and absent in ASS and IMNM. Frequency of ramified capillaries, tortuosities, hemorrhages, or thrombosis was not different between subgroups. A scleroderma pattern was only observed in OM patients. In this limited series of patients, we observed that DM and OM NVC abnormalities are different from ASS and IMNM. We could not determine NVC specific patterns associated with myositis-specific antibody subtypes of DM because of the small number of patients.Key Points• Nailfold videocapillaroscopy abnormalities are different in subgroups of inflammatory myopathies.• Giant capillaries, disorganization, and major capillary loss are observed in overlap myositis and dermatomyositis but not in antisynthetase syndrome (ASS) or immune-mediated necrotizing myopathy.• Nailfold videocapillaroscopy abnormalities in overlap myositis (with the exclusion of ASS) are close to systemic sclerosis.

Nailfold Videocapillaroscopy in Systemic Sclerosis-related Pulmonary Arterial Hypertension: A Systematic Literature Review.

Pulmonary arterial hypertension (PAH) is one of the leading causes of death in systemic sclerosis (SSc). Current screening algorithms are hampered by low positive predictive values. Outcome measures that could add to performance characteristics would be welcome. We aim to evaluate the role of nailfold videocapillaroscopy (NVC) using standardized definitions, in SSc-related PAH (SSc-PAH). A systematic review to identify original research papers documenting an association between NVC and right heart catheterization-defined SSc-PAH was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Subsequently, NVC characteristics were subdivided into quantitative (capillary density, dimension, morphology, and hemorrhages), semiquantitative, and qualitative assessment (NVC pattern), according to the definitions of the European League Against Rheumatism Study Group on Microcirculation in Rheumatic Diseases. The systematic search identified 316 unique search results, of which 5 were included in the final qualitative analysis. The occurrence of incident SSc-PAH unequivocally associated in 2 longitudinal studies with progressive capillary loss (p = 0.04 and p = 0.033) and the progression to a severe (active/late) NVC pattern (p = 0.05/0.01 and HR = 5.12, 95% CI 1.23-21.27). In 3 cross-sectional studies, SSc-PAH was found to be unequivocally inversely associated with capillary density (p = 0.001 and p < 0.05) and associated with the presence of a severe NVC pattern (p = 0.03 and p < 0.05). This is the first systematic literature review investigating the role of NVC in SSc-PAH using standardized description, to our knowledge. Unequivocal associations were found between (incident) SSc-PAH and capillary density and NVC pattern. Integration of NVC into current screening algorithms to boost their performance may be a future step.

Distinctive association of peripheral immune cell phenotypes with capillaroscopic microvascular patterns in systemic sclerosis.

The pathological changes in SSc include immune system dysregulation and microvascular damage. However, the association of immune cell phenotype heterogeneity and microvascular abnormalities is unclear. The aim of this study is to elucidate this association in SSc. Peripheral blood mononuclear cells obtained from 150 SSc patients were used for comprehensive flow cytometric analysis based on the Human Immunology Project. Hierarchical cluster analysis was used to classify SSc patients into subgroups and their association with microvascular abnormalities, as assessed by nailfold videocapillaroscopy (i.e. 'early', 'active' and 'late' patterns), was analysed. The proportions of activated CD4+ T cells, T cells re-expressing CD45RA, activated Th1 and Th17 cells and IgD-CD27- B cells were higher in SSc patients than in healthy individuals. Hierarchical cluster analysis stratified SSc patients into three groups: patients with few immune abnormalities (fewer abnormalities group), patients with high proportions of activated T and Treg cells (Treg-dominant group) and patients with high proportions of Tfh and plasmablasts (Tfh-dominant group). Age and disease duration were comparable among the groups. On the other hand, microvascular abnormalities, especially the 'late' nailfold videocapillaroscopy pattern, correlated with internal organ involvement. Among the groups stratified according to immune cell phenotype, the progression to the 'late' nailfold videocapillaroscopy pattern was more frequent in the Tfh-dominant group. Our study confirmed the presence of immunophenotypic abnormalities in SSc. Immunological abnormalities were not uniform but rather limited to subpopulations, particularly the Tfh-dominant group, where they were highly associated with microvascular abnormalities and organ involvement.

Imbalanced serum levels of Ang1, Ang2 and VEGF in systemic sclerosis: Integrated effects on microvascular reactivity

Introduction and aimMicroangiopathy is a hallmark of systemic sclerosis (SSc). It is a progressive process from an early inflammatory and proangiogenic environment to insufficient microvascular repair with loss of microvessels. The exact underlying mechanisms remain ill-defined. Aim of the study was to investigate whether imbalanced angiopoietins/VEGF serum profile should be related in SSc to the altered microvascular reactivity characterized by aberrant angiogenesis and avascularity. Materials and methodsSerum levels of Angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2) and VEGF were measured by ELISA in 47 SSc patients and 27 healthy controls. Microvascular alterations were assessed by nailfold videocapillaroscopy (NVC). ResultsSerum concentrations of Ang1 were significantly lower [mean (S.D.): 21516.04 (11,441.035) pg/ml], and Ang2 significantly increased [25,89.55 (934.225) pg/ml] in SSc as compared with the control group [Ang1: 28,457.08 (10,431.905) pg/ml; Ang2: 1556.23 (481.255) pg/ml, p < 0.01, respectively], whereas VEGF did not differ significantly. The ratios of Ang1/Ang2 and Ang1/VEGF were significantly lower in SSc patients (8.346 ± 4.523 and 95.17 ± 75.0, respectively) than in healthy subjects (17.612 ± 6.731 p < 0.000001 and 183.11 ± 137.73; p = 0.004]. Formation of giant capillaries with vascular leakage and collapse was associated with significant increase in VEGF and concomitant Ang1 deficiency. Capillary loss was related to significant increase in VEGF with respect to those with preserved capillary number (395.12 ± 256.27 pg/mL vs. 254.80 ± 213.61 pg/mL) whereas elevated Ang2 levels induced more advanced capillary damage as indicated by the presence of the “Late” NVC pattern. ConclusionsWe found that serum levels of Ang1, Ang2 and VEGF are differentially expressed in SSc and altered Ang1/Ang2 profile might underlay the aberrant angiogenesis in SSc despite increase in VEGF. For the first time we identified that significant deficiency of Ang1 might be involved in early capillary enlargement, followed by collapse and lack of stable newly-formed vessels in VEGF-enriched environment, whereas Ang2 levels seem to increase later in disease progression and advanced microvascular damage (“Late” NVC pattern).

Detection of systemic sclerosis in patients with pulmonary hypertension

Introduction. The problem of early detection of pulmonary arterial hypertension (PAH) is closely related to the diagnosis of systemic sclerosis (SSc). It is especially important in patients with slight manifestations of the disease, making it diffcult to verify the diagnosis before the clinic of right ventricular heart failure, and low knowledge of the general practitioners of the available diagnostic opportunities.The aim of the work was to identify the earliest clinical signs of PAH associated with SSc for its early diagnosis.Material and methods. The study included 51 patients with limited SSc. The investigators evaluated the extent of skin lesion, levels of the level of N­terminal brain natriureticpropeptide (NT­proBNP) and uric acid, the fluorescent pattern and titer of antinuclear factor. All patients underwent an echocardiography, nailfold videocapillaroscopy, a comprehensive assessment of external respiratory functions. When there were symptoms of PAH, right heart catheterization was performed to confrm it.Results. PAH was detected in 19 of the 51 patients included in the study. Patients with PAH were signifcantly older than those without PAH: (60±8) and (54±7) years, respectively (p=0.02); there were also differences between these groups in the signs of right cardiac remodeling (p&lt;0.05), in the indices estimated in the six­minute walk test (p&lt;0.05), in the assessment of lung diffusing capacity (p&lt;0.001), in levels of NT­proBNP and uric acid (p&lt;0.001), in the density of the nailfold capillaries (p=0.009); in a semiquantitative assessment of nailfold capillary alterations (p=0.022). Among patients with PAH associated with SSc, seven patients were diagnosed with SSc for the frst time after referring to cardiologists and verifying the genesis of PAH, while other 12 patients were previously observed by rheumatologists. Differences in the duration of the period from the onset of symptoms to the diagnosis of SSc (p=0.043) were revealed between these groups.Conclusion. The study shows the probability of the presence of SSc in patients with suspected idiopathic PAH, that determines the necessity of additional immunological and instrumental examinations in such patients.

Organ dysfunction in cirrhosis: a mechanism involving the microcirculation.

Microcirculation is essential for adequate tissue perfusion and organ function. Microcirculatory changes may occur in cirrhosis, inducing loss of multiorgan function. The aim was to evaluate preliver transplantation and postliver transplantation aspects of multiorgan function, microcirculation, inflammatory, and endothelial biomarkers and survival in a controlled study including cirrhotic outpatients. We accessed functional capillary density (FCD) and red blood cell acceleration (RBCA) by nailfold videocapillaroscopy. Inflammatory and endothelial biomarkers [interleukin-6 (IL-6), soluble intercellular adhesion molecule-1, endothelin-1, and tumor necrosis factor-α] were analyzed. Cerebral and renal functions were assessed to represent organ dysfunction and regression analyses were carried out. Receiver operating characteristic curves were constructed and survival Kaplan-Meier analysis was carried out. Fifty-four patients and 18 controls were included. Inflammatory and endothelial markers increased in advanced disease. FCD was reduced and RBCA was progressively lower according to disease severity. RBCA correlated inversely with inflammatory and endothelial biomarkers, and directly with renal function. The presence of hepatic encephalopathy correlated inversely with RBCA and directly with IL-6 and endothelin-1. In multivariate analysis, RBCA was an independent factor for organ dysfunction. The area under the receiver operating chartacteristic curve for IL-6 for survival was 0.74 (0.59-0.89), P=0.05. Transplant-free survival was 97.5% for values under 5.78 ng/ml (IL-6 best cutoff) and 83.9% above 5.78 ng/ml, log-rank=0.018. Eleven patients underwent transplantation, with an overall improvement in microcirculatory function. Our results suggest a mechanism of organ damage in cirrhosis, where microcirculatory dysfunction could be correlated to inflammatory and endothelial biomarkers, and loss of multiorgan function. IL-6 seems to be an important survival marker of inflammation. Liver transplantation improved microcirculatory dysfunction, corroborating this hypothesis.

Characterization of microvascular disease in patients with sickle cell disease using nailfold capillaroscopy

Sickle cell disease (SCD) is a disorder characterized by repetitive vaso-occlusive crises causing microvascular obstruction, tissue ischemia and pain that may lead to chronic multi-organ ischemic sequelae. Nailfold videocapillaroscopy (NFC) is a non-invasive imaging technique used in clinical rheumatology to directly visualize capillaries located near the fingertip. To characterize NFC abnormalities in the setting of SCD, we performed NFC on 71 SCD patients and 70 age matched controls using a video capillaroscope on 8 digits. As compared to controls, mean capillary number was lower and the final capillary score (measure of capillary dropout inversely related to capillary density) was higher in the SCD group. The SCD group had a lower percentage of stereotype hairpin shapes and a higher percentage of crossing type capillaries. On multivariate linear analyses, both mean capillary number and final capillary score were independently associated with SCD after adjusting for age, body mass index, and gender. SCD was associated with more dilated capillaries but similar numbers of hemorrhages. In conclusion, SCD is associated with lower capillary density and more dilated capillaries on NFC. These changes appear unrelated to markers of disease severity including frequency of sickle crises, number of transfusions, and HbS levels. The relation between NFC and target organ involvement merits further study.

Microangiopathy in Naifold Videocapillaroscopy and Its Relations to sE- Selectin, Endothelin-1, and hsCRP as Putative Endothelium Dysfunction Markers among Adolescents with Raynaud's Phenomenon.

The aim of this study was to analyze the relationship between the qualitative abnormalities on nailfold videocapillaroscopy (NVC), and the concentrations of selected biomarkers (sE-selectin, endothelin-1, high-sensitivity c-reactive protein (hsCRP)) and lipid metabolism parameters in children and adolescents with Raynaud’s phenomenon (RP). Raynaud’s phenomenon, to assess whether nailfold capillary changes may reflect the degree of systemic blood vessel abnormalities. The study group included 66 patients (34 undifferentiated—uRP and 32 secondary—sRP) aged 6–19 years and the control group. In both groups, NVC was performed and the selected biomarkers were measured (sE-selectin, endothelin-1, hsCRP) and lipid profile. Endothelin-1, sE-selectin and hsCRP concentrations in patients from both RP groups were significantly higher; concentration of HDL fraction was significantly lower compared with the control group. The analysis of multiple linear regression demonstrated that megacapillaries most strongly determine the sE-selectin value (p = 0.04) and hsCRP (p = 0.03). Both the total cholesterol and low-density lipoprotein (LDL) fraction concentrations were determined by the presence of avascular areas (p = 0.02). In conclusion, specific pathologic NVC changes were associated with higher endothelial damage biomarkers concentration and adverse changes in the lipid profile.