Nailfold Videocapillaroscopy Pattern Research Articles

Gastric dysrhythmias in patients with early systemic sclerosis: a cross-sectional study.

Gastric involvement in patients with early systemic sclerosis (SSc) has not been previously investigated. We aim to evaluate the association of gastric dysrhythmias with gastrointestinal (GI) symptoms and nailfold video capillaroscopy (NVC). Cross-sectional study. Patients with early SSc, completed the UCLA GIT 2.0 questionnaire, performed an NVC, and a surface Electrogastrography (EGG). Descriptive statistics was used for demographic and clinical characteristics and Fisher and Kendall Tau tests were used for association analysis. 75 patients were screened, 30 patients were consecutively enrolled, 29 performed the EGG and 1 patient had a non-interpretable NVC. 29/30 were female with a mean age of 48.7 years (25-72). The mean disease duration from the first non-RP symptom was 22.6 +/-10.8 months and most of the patients had limited disease (76.6%). Total GIT 2.0 score symptoms were moderate-severe in 63% of the participants and 28/29 had an abnormal EGG. Bradygastria was the most common pattern present in 70% of the participants. NVC patterns: 17% early, 34% active, 28% scleroderma-like, 14% non-specific, and 2 patients had a normal NVC. There was no association between severe GI symptoms or NVC patterns and severely abnormal EGG, but the presence of bradygastria was associated with severe impairment in the social functioning area (p 0.018). Gastric dysmotility is common in early SSc and there is a lack of correlation between GI symptoms and NVC scleroderma patterns. EGG is a sensitive, cheap, and non-invasive exam, that may be an alternative to early diagnosis of GI involvement.

Microvascular status in juvenile Sjögren’s disease: the first nailfold videocapillaroscopy investigation

IntroductionJuvenile Sjögren’s disease (jSjD) is a rare autoimmune disease characterized by exocrine gland involvement and systemic manifestations, including small vessel vasculitis and Raynaud’s phenomenon (RP). We aimed to investigate the microvascular status in jSjD patients by nailfold videocapillaroscopy (NVC) and the potential correlations with clinical and serological features.MethodsClinical data from thirteen consecutive jSjD patients (11 females and 2 males), with a mean age of 16 ± 4 years, diagnosed before 16 years of age (mean age at diagnosis 12 ± 3) according to the 2016 American College of Rheumatology/EULAR criteria for adult SjD, were collected including age- and sex-matched healthy controls (HCs). Clinical, laboratory, and instrumental data were collected, together with NVC examination. Non-specific and specific NVC parameters were investigated, such as capillary density, capillary dilations, giant capillaries, microhaemorrhages and abnormal shapes. Associations between NVC findings and clinical/serological features were explored and analysed using parametrical and non-parametrical tests.ResultsCapillary density reduction correlated significantly with articular involvement (arthralgias) (p = 0.024). Microhaemorrhages correlated with lower C3 levels (p = 0.034). No specific NVC pattern for jSjD was identified, whereas abnormal capillary shapes were significantly higher in jSjD patients than HCs (p = 0.005). NVC abnormalities were not associated with SjD-specific instrumental tests (biopsy, imaging, Schirmer’s test). RP was present in 8% of jSjD patients.ConclusionsThe reduction of capillary density, as well as microhaemorrhages at NVC analysis, are significantly associated with some clinical aspects like articular involvement and serum biomarkers (C3 reduction). The NVC is suggested as safe and further analysis in jSjD patients.Key Points• Juvenile Sjögren’s disease (jSjD) exhibits a higher rate of abnormal shapes at nailfold videocapillaroscopy (NVC) compared to matched healthy controls.• Articular involvement in jSjD is significantly associated with a lower capillary number at NVC.• Microhaemorrhages on NVC are associated with lower C3 levels, prompting this finding as a putative novel negative biomarker/prognostic factor for jSjD.

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

To evaluate differences in nailfold videocapillaroscopy (NVC) findings between systemic sclerosis-SSc patients with and without a diagnosis of pulmonary arterial hypertension (PAH). 110 SSc patients were enrolled in this cross-sectional, case-control, multi-centre study. Patients were divided into cases (SSc-PAH confirmed by right hearth catheterization-RHC) and controls (SSc-nonPAH with low probability of PAH). NVC patterns (early, active, and late) and morphological parameters (microvascular density, non-specific abnormalities, giant capillaries, micro-haemorrhages, avascular areas) were considered using a semiquantitative scoring system. SSc-PAH patients showed higher frequencies of late pattern (p < 0.01), non-specific abnormalities (p < 0.01), lower capillary density (p < 0.01), higher avascular areas (p < 0.01), and a higher mean NVC score (p < 0.01). Contrarily, the early/active pattern (p < 0.01) and a higher rate of micro-haemorrhages (p = 0.04) were more frequent in non-PAH patients. By the multivariate analysis, SSc-PAH patients, compared to non-PAH, had more non-specific abnormalities (27/55, 49.1% vs 10/55, 18.2%, adjusted OR: 16.89, 95%CI: 3.06-93.16), a lower capillary density (grade 3, 20/55, 36.4% vs 5/55, 9.1%, adjusted OR: 38.33, 95%CI: 2.34-367.80), and avascular areas (18/55, 32.7% vs 10/55, 18.2%, adjusted OR: 16.90, 95%CI: 2.64-44.35). A correlation was found between the mean pulmonary arterial pressure-mPAP and avascular areas (p < 0.01), capillary density (p < 0.01), and non-specific abnormalities (p < 0.01). A clinical model including the NVC variables may be able to predict the diagnosis of PAH. Our results indicate that the distinctive peripheral microcirculatory injury of SSc, i.e capillary loss and morphological abnormalities, appear more severe and pronounced in patients with SSc-PAH.

Nailfold videocapillaroscopy patterns in systemic sclerosis: implications for cutaneous subsets, disease features and prognostic value for survival.

To assess the associations and prognostic value of scleroderma patterns by nailfold videocapillaroscopy (NVC) in patients with systemic sclerosis (SSc) and cutaneous subsets. At baseline, 1356 SSc patients from the RESCLE registry were compared according to the scleroderma pattern as Late pattern and non-Late pattern, which included Early and Active patterns. Patient characteristics, disease features, survival time and causes of death were analysed. Late pattern was identified in 540 (39.8%), and non-Late pattern in 816 (60.2%) patients (88% women; 987 lcSSc/251 dcSSc). Late pattern was associated to dcSSc (OR=1.96; p<0.001), interstitial lung disease (ILD) (OR=1.29; p=0.031), and scleroderma renal crisis (OR=3.46; p<0.001). Once the cutaneous subset was disregarded in an alternative analysis, both digital ulcers (DU) (OR=1.29; p<0.037) and anti-topoisomerase I antibodies (OR=1.39; p< 0.036) emerged associated with the Late pattern. By cutaneous subsets, associations with Late pattern were: (1) in dcSSc, acro-osteolysis (OR=2.13; p=0.022), and systolic pulmonary artery pressure >40 mmHg by Doppler echocardiogram (OR=2.24; p<0.001); and (2) in lcSSc, ILD (OR=1.38; p=0.028). Survival was reduced in dcSSc with Late pattern compared to non-Late pattern (p=0.049). Risk factors for SSc mortality in multivariate regression Cox analysis were age at diagnosis (HR=1.03; p<0.001), dcSSc (HR=2.48; p<0.001), DU (HR=1.38; p=0.046), ILD (HR=2.81; p<0.001), and pulmonary arterial hypertension (HR=1.99; p<0.001). SSc patients with Late pattern more frequently present dcSSc and develop more fibrotic and vascular manifestations. Advanced microangiopathy by NVC identifies dcSSc patients at risk of reduced survival due to SSc-related causes.

Serum kynurenic acid is lower in systemic sclerosis patients with microvascular damage of hands.

Endothelial dysfunction occurs early in systemic sclerosis (SSc), leading to tissue hypoxia, vasoconstriction and fibrosis. It has been demonstrated that endothelial cells (ECs) are able to produce kynurenic acid (KYNA) in response to vascular inflammation, due to its anti-inflammatory and anti-oxidants activity. In SSc patients, blood perfusion of hands, assessed by laser speckle contrast analysis (LASCA), correlated negatively with the extent of the nailfold microvascular damage, scored according to nailfold videocapillaroscopy (NVC) classification. Aim of this study was to evaluate the difference of serum KYNA in SSc patients with different stages of microvascular damage. Serum KYNA was assessed in 40 SSc patients at the enrolment. NVC was performed to evaluate capillaroscopic patterns (early, active and late). LASCA was performed to evaluate mean peripheral blood perfusion (PBP) of both hands and to evaluate the proximal-distal gradient (PDG). Median PDG was significantly lower in SSc patients with late NVC pattern compared to SSc patients with early and active NVC pattern [3.79pU (IQR -8.55-18.16) vs 23.55pU (IQR 14.92-43.80), p<0.01]. Serum KYNA was significantly lower in SSc patients with late NVC pattern compared to SSc patient with early and active NVC pattern [45.19ng/mL (IQR 42.70-54.74) vs 52.65ng/mL (IQR 49.99-60.29), p<0.05]. Moreover, SSc patients without PDG had significantly lower serum KYNA than in SSc patients with PDG [48.03ng/mL (IQR 43.87-53.68) vs 59.27ng/mL (IQR 49.15-71.00), p<0.05]. KYNA is lower in SSc patients with late NCV pattern and without PDG. KYNA may be associated with early endothelial dysfunction.

Clinical and Serological Characteristics of a Monocentric Cohort of Patients Affected by Interstitial Pneumonia with Autoimmune Features (IPAF).

Interstitial lung diseases (ILDs) are diseases characterised by excessive deposition of collagen matrices in the pulmonary interstitium. Some of them are considered idiopathic (idiopathic pulmonary fibrosis - IPF), others are related to known pathologies such as connective tissue diseases (CTDs-ILD). Patient affected by ILD and features referable to CTD, not satisfying CTD criteria, are called Interstitial pneumonia with autoimmune features (IPAF) patients. The aim of this report was to investigate clinical and serologic features of a monocentric cohort of patients with IPAF. Another objective was to describe the autoantibody profile, clinical features, High Resolution Computerised Tomography (HRCT) and Nailfold Video Capillaroscopy (NVC) patterns. 36 IPAF patients were consecutively enrolled. Clinical, serological, and morphological features were collected. 36 consecutive IPAF patients were enrolled from January 2021 to January 2022. Raynaud's phenomenon was the most frequent symptom identified. We also described other signs and symptoms not included in IPAF criteria. 36,1% of patients demonstrated a Usual Interstitial Pneumonia (UIP) pattern by HRCT. Pulmonary arterial pressure estimation (PAPs) resulted elevated (≥ 25 mmHg) in 6 patients. Antinuclear antibodies (ANA) ≥ 1/80 was the most frequent autoantibody, followed by anti-Ro, in patients with UIP pattern and Non-Specific Interstitial Pneumonia (NSIP) pattern at HRCT. NVC highlighted non-specific microangiopathy as the most common pattern especially in UIP patients. This paper may contribute to stimulate the interest in better characterisation of clinical, serologic, and instrumental features for IPAF patients by redefining IPAF classification criteria in order to treat them as best as possible.

Results of Nailfold Videocapillaroscopy in Patients with Pseudoexfoliative Glaucoma.

The studied group consisted of 39 Caucasian patients with XFG and 32 patients in a control group. The patients were classified into two subgroups: the hypertensive pseudoexfoliative glaucoma (hXFG) subgroup and the normotensive pseudoexfoliative glaucoma (nXFG) subgroup. The nailfold videocapillaroscopy (NVC) was performed on all participants. The results of each NVC were classified as having a normal or abnormal pattern. There was no statistical difference between the results of an abnormal NVC pattern in the study group vs. the control group (p = 0.8773). Microhemorrhages were shown in 30.0% of patients with nXFG vs. the control group (6.25%) (p = 0.0520). Microhemorrhages tended to be more frequent in the XFG group (p = 0.1221). A prevalent number of tortuous capillaries was observed in hXFG patients with advanced glaucomatous neuropathy. Dilatation in the capillaries and microbleedings were observed in the group of patients with lower IOP values. Tortuosity in the capillaries was significantly more frequent in PEXG patients (XFG vs. control: p = 0.0386). No relationships between the results of NVC and age, c/d, BCVA, time of treatment, and visual field defect were found. Specific features of NVC examination differentiate nXFG from hXFG patients. Some capillaroscopic features may correlate with the patient's clinical status of XFG.

Nailfold Videocapillaroscopy for Non-Invasive Assessment of Microcirculation and Prognostic Correlation with Endothelial Dysfunction, Cardiovascular Risk Factors, and Non-HLA Antibodies in Heart Transplant Recipients: A Pilot Study.

Early identification of allograft vasculopathy and the concomitant elimination of adverse risk factors is essential for improving the long-term prognosis of heart transplant (HTx) recipients with underlying cardiovascular disease (CVD). The major aim of this pilot study was to conduct a non-invasive imaging evaluation of the HTx patient microcirculation by employing nailfold video-capillaroscopy (NVC) in a well-characterized patient and control cohort, and to correlate these data with endothelial cell function, accompanied by studies of traditional cardiovascular risk factors and non-HLA antibodies in HTx recipients. Ten patients undergoing HTx (mean age of 38 ± 14 years) were recruited for the study and compared to a control group of 12 well-matched healthy volunteers (mean age 35 ± 5 years) with normal body mass index (BMI). Detailed medical records were collected from all individuals. NVC was performed using CapillaryScope 200 MEDL4N microscope. For functional readout and correlation analysis, endothelial cell network formation in conjunction with measurements of patient serum levels of vascular endothelial growth factor (VEGF) and non-HLA autoantibodies directed against the angiotensin II type-1-receptor (anti-AT1R-Ab), endothelin-1 type-A-receptor (anti-ETAR-Ab), protease-activated receptor-1 (anti-PAR-1-Ab), and VEGF-A (anti-VEGF-A-Ab) were studied. Our NVC analysis found that the average apical loop diameter of nailfold capillaries was significantly increased in HTx recipients (p = 0.001). In addition, HTx patients with more prominent changes in capillaroscopic patterns were characterized by the presence of traditional cardiovascular risk factors, and HTx patients had increased levels of anti-AT1R-ab, anti-ETAR-ab, and anti-VEGF-A-Ab (p = 0.017, p = 0.025, and p = 0.003, respectively). Capillary diameters most strongly correlated with elevated serum levels of troponin T and triglycerides (R = 0.69, p = 0.028 and R = 0.81, p = 0.004, respectively). In conclusion, we found that an abnormal NVC pattern in HTx patients is associated with traditional CVD risk factors and that NVC is a useful non-invasive tool to conveniently monitor changes in the microvasculature of HTx patients.

Peripheral Macrovascular Involvement in Systemic Sclerosis: A Cohort Study by Color and Spectral Doppler Ultrasonography.

Systemic sclerosis (SSc) is a disease characterized by diffuse sclerosis of skin and organs and small vessel vasculopathy. Despite it, large vessels can also be involved with ulnar artery vasculopathy, revealing as a more frequent feature of SSc. The aim of this paper is to assess the macrovascular involvement of SSc patients through an ultrasound (US) evaluation of radial and ulnar arteries. Radial and ulnar resistance indices (RIs) and peak systolic velocity (PV) (cm/s) together with clinical features of SSc patients were evaluated. Raynaud phenomenon (RP) and healthy control (HC) groups were used for comparison. Forty-three SSc patients were evaluated. Twelve patients (28%) had ulnar artery occlusions (UAOs). In nine cases (75%), UAOs were bilateral. A high UAO prevalence (42%) was found in SSc patients with late nailfold-video-capillaroscopy (NVC) pattern (p = 0.0264). Patients with UAOs had digital ulcers (DUs) in 10 cases (83.3%). Radial and ulnar PVs were lower in SSc and RP patients than the HC group. Radial and ulnar RIs were higher in SSc and RP patients than the HC group. A decision tree analysis led to the classification of 70% of SSc patients with an ulnar RI > 0.82 and ulnar PV > 2.8 cm/s. The most influential variables on UAO development were interstitial lung disease (ILD) (p = 0.002) and NVC pattern (p = 0.002). A positive correlation was shown between modified Rodnan skin score (mRSS) and ILD (p = 0.283; r = 0.033), mRSS and DU (r = 0.344; p = 0.012) and DU and ILD (r = 0.303; p = 0.024). Male sex was associated with increased UAO frequency (p = 0.042). UAO is a peculiar feature of severe SSc present in 28% of the cases, particularly associated with the presence of ILD and late NVC pattern. In 75% of the cases, UAOs are bilateral. DUs are very frequent in patients with UAOs (83%). The RI evaluated by US could be useful to distinguish SSc from HC patients. US could be a useful tool for assessing high-risk DU development in patients.

Specific Autoantibodies and Microvascular Damage Progression Assessed by Nailfold Videocapillaroscopy in Systemic Sclerosis: Are There Peculiar Associations? An Update

Specific autoantibodies and nailfold videocapillaroscopy (NVC) findings are serum and morphological diagnostic hallmarks of systemic sclerosis (SSc) as well as useful biomarkers which stratify the microvascular progression and prognosis of patients. The aim of our narrative review is to provide an update and overview of the link between SSc-related autoantibodies, used in clinical practice, and microvascular damage, evaluated by NVC, by exploring the interaction between these players in published studies. A narrative review was conducted by searching relevant keywords related to this field in Pubmed, Medline and EULAR/ACR conference abstracts with a focus on the findings published in the last 5 years. Our search yielded 13 clinical studies and 10 pre-clinical studies. Most of the clinical studies (8/13, 61.5%) reported a significant association between SSc-related autoantibodies and NVC patterns: more specifically anti-centromere autoantibodies (ACA) were associated more often with an "Early" NVC pattern, whereas anti-topoisomerase autoantibodies (ATA) more frequently showed an "Active" or "Late" NVC pattern. Five studies, instead, did not find a significant association between specific autoantibodies and NVC findings. Among the pre-clinical studies, SSc-related autoantibodies showed different mechanisms of damage towards both endothelial cells, fibroblasts and smooth muscle vascular cells. The clinical and laboratory evidence on SSc-related autoantibodies and microvascular damage shows that these players are interconnected. Further clinical and demographic factors (e.g., age, sex, disease duration, treatment and comorbidities) might play an additional role in the SSc-related microvascular injury whose progression appears to be complex and multifactorial.

Asymmetric dimethylarginine correlates with worsening peripheral microangiopathy in systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterized primarily by micro-angiopathy and endothelial dysfunction which stimulate a fibrotic process. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor and represents a novel biomarker for vascular dysfunction. Nailfold video capillaroscopy (NVC) represents a non-invasive and reliable technique for the evaluation of microvasculopathy in SSc. The aim of this study was to examine the possible association between ADMA and microvascular involvement in patients with SSc. This was a cross-sectional study including consecutive SSc patients attending the Scleroderma Outpatient Clinic. ADMA was measured in serum samples using a commercial enzyme immunoassay. Participants underwent NVC with qualitative and semi-quantitative assessment and all NVC parameters were measured in the distal row of each finger. The findings were classified in one of the three qualitative NVC patterns: early, active, and late. Eighty-one (92,6% women) SSc individuals with mean age 55.44±13.4years were included in this analysis. Within-groups comparisons revealed a trend between higher ADMA levels and progressive micro-vasculopathy (1,29 [2,1] vs 1,57 [1,95] vs 2,41 [3,87]; for early, active and late patterns respectively, p=0.039). Furthermore, ADMA concentration was significantly associated with the number of capillaries/mm (r=-0.235; p=0.035). Serum ADMA levels were significantly associated with advancing stages of microcirculatory abnormalities suggesting that ADMA may have a role in promoting microvascular endothelial dysfunction in SSc individuals.

Increased Circulating Soluble Junctional Adhesion Molecules in Systemic Sclerosis: Association with Peripheral Microvascular Impairment

Systemic sclerosis (SSc, scleroderma) is a severe disease characterized by peripheral microcirculation abnormalities manifesting with Raynaud's phenomenon, nailfold videocapillaroscopic (NVC) changes, and even ischemic digital ulcers (DUs) that are often refractory to treatments. In the wake of previously described associations between the circulating levels of soluble junctional adhesion molecules (sJAMs) and SSc clinical features, here, we measured sJAM-A and sJAM-C levels by enzyme-linked immunosorbent assay in serum samples from a large case series of 110 SSc patients and 85 healthy controls, focusing on their possible association with peripheral vascular clinical features and their potential as biomarkers that are either diagnostic or mirror SSc-related microvasculopathy severity. Our data demonstrated that serum sJAM-A and sJAM-C are significantly increased in patients with SSc vs. healthy controls, especially in those featuring early/active NVC patterns and the presence of ischemic DUs. Moreover, circulating sJAM-C levels showed good diagnostic accuracy in discriminating between patients and controls, as assessed by receiver operator characteristics curve analysis. Finally, logistic regression revealed that, when comparing sJAM-A to sJAM-C, the latter might be better suited as a biomarker for SSc-related DUs. Our promising findings provide the necessary groundwork for longitudinal follow-up analyses of SSc patients aiming to assess whether circulating sJAM-C levels might be predictive for the development of new DUs, as well as DU recurrence and/or refractoriness to targeted therapies.

Eye Sign is an Alternative for Evaluation of the Microcirculation in Patients with Systemic Sclerosis.

To investigate consistency between eye sign and nailfold video capillaroscopy (NVC) in systemic sclerosis (SSc) patients and to evaluate eye sign with various parameters of disease and potential pulmonary involvement. A total of 60 SSc patients and 20 healthy individuals were enrolled. 20 SSc patients were complicated with pulmonary arterial hypertension (PAH); 20 SSc patients with interstitial lung diseases (ILD); 20 SSc patients without pulmonary involvement. All subjects were assessed using the methods of NVC and eye sign. Skin involvement was evaluated by modified Rodnan skin score (mRSS) and disease activity according to Medsger's severity score (MSS). Clinical manifestations and the presence of autoantibodies were carefully recorded. Any correlations between were evaluated with the Spearman correlation coefficient test. According to the morphological changes revealed by NVC, 3 types of NVC patterns have been characterized (early pattern, active pattern, and late pattern). Eye sign showed distinguishing morphologic changes in three patterns of NVC and pulmonary involvements (PAH vs ILD) in SSc. A positive linear correlation was found between scores of eye sign and NVC in all patients with SSc (r = 0.629, P=0.001). A positive correlation of eye sign was found in all SSc patients with mRSS (r = 0.748, P=0.045) and MSS (r = 0.636, P=0.001). The study demonstrates that eye sign had a high consistency with NVC for the evaluation of the microcirculation in SSc patients and exhibited specific patterns in the early, active, and late phases of SSc. Eye sign can be used as a reliable method to classify and monitor SSc patients and replace the measurement of NVC.

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

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

Capillaroscopic analysis of the microvascular status in mixed versus undifferentiated connective tissue disease.

Raynaud phenomenon (RP), typically, precede the clinical onset of systemic manifestations in several connective tissue diseases (CTDs). These autoimmune disorders usually share a microvascular damage whose alterations can be detected by nailfold videocapillaroscopy (NVC). The aim of the study was to compare the NVC microvascular status in Mixed Connective Tissue Disease (MCTD) versus the Undifferentiated Connective Tissue Disease (UCTD), and to search correlations between NVC findings and specific autoantibodies in UCTD patients. Clinical data and NCV patterns were retrospectively obtained from the files of 46 MCTD patients, 47 stable UCTD patients and 51 individuals with primary RP (PRP) as controls collected in a central database (VideoCap®, DS Medica, Milan, Italy). ANA and ENA Abs were tested respectively by indirect immunofluorescence and enzyme-linked immunosorbent assay. "Scleroderma-like" (SSc-like) NVC pattern was significantly more frequent in MCTD than in UCTD patients (48% vs 11%, p<0.001). Giant capillaries, abnormal shapes (i.e. neoangiogenesis) and lower capillary density were predominantly detected among MCTD versus UCTD patients (48% vs 11%, 49% vs 13%, 52% vs 9%, respectively, p<0.001). The absolute number of capillaries was significantly lower in MCTD versus UCTD patients (mean 7±1.7 SD vs mean 9.2±1.3 SD, respectively, p<0.001). Fully normal NVC pattern and non-specific NVC alterations were respectively observed in 6% and 46% of MCTD and in 6% and 83% of UCTD. Moreover, PRP patients showed normal NVC pattern and non-specific capillary abnormalities in 23% and in 77%, respectively. No statistically significant correlations were observed between NVC patterns and ANA patterns/specific ENA-Abs among the UCTD patients. The significant presence of the SSc-like NVC pattern and reduced number of capillaries seem the most typical NVC findings in MCTD in comparison to UCTD patients, suggesting a reflection of more complex and severe disease in MCTD ones.

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.

Is There a Link Between Nailfold Videocapillaroscopy and Pulmonary Function Tests in Systemic Sclerosis Patients?: A 24-Month Follow-up Monocentric Study.

The aim of this study was to explore the associations between nailfold videocapillaroscopy (NVC) and pulmonary function tests (PFTs) in systemic sclerosis (SSc) patients. This was a longitudinal study with follow-up of unselected Brazilian SSc patients. Baseline clinical examination, serological workup, high-resolution chest tomography, and NVC were performed. Pulmonary function test was performed at baseline and after 24 months. Pulmonary function test worsening over time was defined as either a ΔFVC decline ≥10% or a ΔFVC decline ≥5% and <9%, combined with a ΔDLCO decline ≥15%, at 24 months. The NVC parameters were quantitatively (capillary density number, dimension, morphology, and hemorrhages) and qualitatively (NVC pattern) evaluated according to the consented standardized definitions of the EULAR Study Group on Microcirculation in Rheumatic Diseases. Seventy-nine patients were included. Fifty-nine were rated to have a scleroderma pattern (6 "early"/16 "active"/37 "late"). The mean FVC and DLCO were 76.8% and 67.2% at baseline and 73.8% and 64.3% at 24 months, respectively. After multivariate analysis, we found that a reduced baseline FVC was associated with reduced capillary density (odds ratio [OR], 11; 95% confidence interval [CI], 1.5-90.7; p = 0.03) and a reduced baseline DLCO associated with the late scleroderma pattern (OR, 6.75; 95% CI, 1.09-42; p = 0.03). No association between worsening of PFT over time and NVC was found. The association between NVC and PFTs might corroborate the link between microangiopathy and interstitial lung disease in patients with SSc. This finding might strengthen the idea of incorporating NVC as a tool to predict progressive interstitial lung disease in these patients in the future.

Nailfold Microvascular Imaging by Dynamic Optical Coherence Tomography in Systemic Sclerosis: A Case-Controlled Pilot Study

In systemic sclerosis, outcome measures of skin microvasculopathy are needed for both clinical trials and practice. The aim of this study was to determine whether dynamic-optical coherence tomography (D-OCT) is able to provide information on microvasculopathy compared with the current gold standard, nailfold videocapillaroscopy (NVC), in patients with systemic sclerosis. This case-controlled study included (i) 40 patients with systemic sclerosis, classified by NVC pattern in four age- and sex-matched groups (normal/nonspecific, early, active, late); (ii) a fifth group of 10 age- and sex-matched healthy controls. All participants underwent NVC and D-OCT. D-OCT images were compared with the corresponding NVC images. Reliability was assessed. D-OCT images visualized the corresponding NVC patterns. D-OCT microvascular flow density was different across the five NVC pattern groups (P= 0.0114) with a significant trend test (P= 0.0006). Microvascular flow density correlated with the NVC semiquantitative score (r=-0.7, P < 0.0001), number of abnormal shapes/mm (r= ‒0.3, P= 0.0264), and number of capillaries/mm (r= 0.6, P < 0.0001). Reliability was excellent (intraclass correlation coefficient > 0.9). In conclusion, in patients with systemic sclerosis, D-OCT provided qualitative and quantitative information on nailfold microvasculopathy, showing a correlation between microvascular flow density and NVC scores. The development of D-OCT as a standardized imaging technique could provide a quantitative outcome measure in clinical trials and practice.

Peripheral microcirculatory abnormalities are associated with cardiovascular risk in systemic sclerosis: a nailfold video capillaroscopy study.

Microvascular dysfunction is the key element in the pathogenesis of systemic sclerosis (SSc), whereas the contribution of large and medium size vessel abnormalities is yet to be established. The aim of the present study is to assess the association between micro- and macrovascular function by utilizing a broad spectrum of assessments of vascular performance. We included consecutive, consenting SSc patients who underwent nailfold video capillaroscopy (NVC) for microcirculation evaluation. Peripheral and central systolic and diastolic blood pressure, carotid intima-media thickness (cIMT), aortic augmentation index (AIx) corrected for a heart rate of 75 beats per minute (AIx-75), and carotid-femoral pulse wave velocity (PWV) were also performed to assess macrovascular function. Cardiovascular risk disease (CVD) algorithms were also calculated and included in the analysis. A total of 81 patients (6 males) were studied with mean age 55.44 ± 13.40years. Reduced capillary density was inversely correlated with arterial stiffness (Alx-75) and augmentation pressure (r = - 0.262, p = 0.018, and r = - 0.249, p = 0.025 respectively). Alx was significantly lower in the early compared to late pattern (28.24 ± 11.75 vs 35.63 ± 10.47, p = 0.036). A significant trend was found among NVC patterns with Alx-75 values being higher with the progression of microangiopathy towards the "late" group (26.36 ± 10.90 vs 30.81 ± 11.59 vs 35.21 ± 7.90, p = 0.027 for trend). Similarly, Framingham risk score and Atherosclerotic Cardiovascular Disease score were progressively higher across the worsening NVC patterns (4.10 ± 4.13 vs 2.99 ± 2.72 vs 6.36 ± 5.65, p = 0.023, and 6.99 ± 7.18 vs 5.63 ± 4.41 vs 12.09 ± 9.90, p = 0.019, respectively, for trends). Finally, QRISK3 (10-year cardiovascular disease risk) and ASCVD (Atherosclerotic Cardiovascular Disease) scores were inversely correlated with the number of capillaries (r = - 0.231, p = 0.048, and r = - 0.260, p = 0.038 respectively). These data suggest that CVD risk scores and macrovascular parameters are strongly correlated with microvasculopathy in patients with SSc. Key Points • Microangiopathy is the hallmark of SSc, but the relationship between subclinical atherosclerosis and small vessel disease remains unknown. • Arterial stiffening and CVD risk scores are positively associated with the degree of progression of peripheral microvasculopathy assessed with NVC. • The results of the study suggest an association between NVC abnormalities and higher CVD risk in SSc patients.

A candidate gene study reveals association between a variant of the SRp55 splicing factor gene and systemic sclerosis.

To examine the possible implication of the mRNA-binding protein serine/arginine protein 55 (SRp55, also known as SRSF6) rs2235611 single nucleotide polymorphism (SNP) in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotype. A total population of 872 white Italian individuals (414 SSc patients, 458 controls) was studied. SSc patients were assessed for limited and diffuse cutaneous subsets and the presence of autoantibodies, interstitial lung disease (ILD), and nailfold videocapillaroscopy (NVC) abnormalities. The SRp55 rs2235611 SNP was genotyped by TaqMan real-time PCR. SRp55 rs2235611 genotype distribution and allele frequency were similar in SSc and healthy controls, though a trend toward significance was observed for genotype distribution (p=0.07). The SRp55 rs2235611 AA genotype significantly influenced the predisposition to SSc (p= 0.03). The SRp55 rs2235611 A minor allele and AA genotype showed a significant risk association with susceptibility to SSc-related ILD (A allele: p=0.046; AA genotype: p=0.007). A significant association of the AA genotype with SSc late NVC pattern was also found (p=0.006). After Bonferroni correction for multiple comparisons, the risk association of the SRp55 rs2235611 AA genotype with SSc-related ILD and late NVC pattern remained significant (padj=0.049 and padj=0.042, respectively). The SRp55 rs2235611 AA genotype significantly influences the susceptibility to SSc, and specifically associates with the presence of SSc-related ILD and late NVC pattern. Further in-depth studies on the SRp55 gene locus will hopefully contribute to extend our knowledge of the genetic predisposition to major SSc-related manifestations such as pulmonary fibrosis and peripheral microvasculopathy.