Changes In Systemic Sclerosis Research Articles

Dermatoscopy of pigmentary changes in systemic sclerosis.

Dermatoscopy of pigmentary changes in systemic sclerosis.

Pigmentary Changes in Systemic Sclerosis are Associated with More Severe Cutaneous Sclerosis and Severity of Other Systems: A Cross-sectional Study from India.

Pigmentary changes of the skin in systemic sclerosis in the form of diffuse hyperpigmentation and salt-and-pepper pigmentation are well documented in the literature; however, its association with disease severity and extent of underlying internal organ involvement has not been well studied. To assess the correlation between morphology and extent of pigmentary changes with the degree of cutaneous sclerosis and frequency and degree of major organ involvement. This was a cross-sectional descriptive study conducted in a tertiary care teaching hospital from December 2014 to November 2016. Consecutive patients of systemic sclerosis attending the outpatient department were screened, and patients satisfying the diagnosis as per the American Rheumatism Association criteria were recruited. Skin sclerosis was quantified using modified Rodnan skin score (MRSS), whereas pigmentary changes were calculated in terms of percentage of body surface area involved by rule-of-nine method. Investigations were carried out depending on organ involvement and as per respective specialty consultations with focus on pulmonary, cardiac, and gastrointestinal systems. Of the 50 patients recruited, all had cutaneous involvement in the form of binding down of skin, followed by pigmentary changes. MRSS was significantly higher in patients with any pigmentary alteration (P = 0.03) compared to those without any pigmentary changes. There was a rising trend in between the MRSS severity and the proportion of patients with hyperpigmentation, and it was statistically significant (P = 0.04). Among systemic involvement, lung was involved in the form of interstitial lung disease in 94% patients (n = 47). However, skin pigmentation of any type was associated with lower high-resolution computed tomography scores (P = 0.02). This study shows that in systemic sclerosis patients presenting with pigmentary skin manifestations, cutaneous sclerosis is significantly higher.

Vision transformer assisting rheumatologists in screening for capillaroscopy changes in systemic sclerosis: an artificial intelligence model.

The first objective of this study was to implement and assess the performance and reliability of a vision transformer (ViT)-based deep-learning model, an 'off-the-shelf' artificial intelligence solution, for identifying distinct signs of microangiopathy in nailfold capilloroscopy (NFC) images of patients with SSc. The second objective was to compare the ViT's analysis performance with that of practising rheumatologists. NFC images of patients prospectively enrolled in our European Scleroderma Trials and Research group (EUSTAR) and Very Early Diagnosis of Systemic Sclerosis (VEDOSS) local registries were used. The primary outcome investigated was the ViT's classification performance for identifying disease-associated changes (enlarged capillaries, giant capillaries, capillary loss, microhaemorrhages) and the presence of the scleroderma pattern in these images using a cross-fold validation setting. The secondary outcome involved a comparison of the ViT's performance vs that of rheumatologists on a reliability set, consisting of a subset of 464 NFC images with majority vote-derived ground-truth labels. We analysed 17 126 NFC images derived from 234 EUSTAR and 55 VEDOSS patients. The ViT had good performance in identifying the various microangiopathic changes in capillaries by NFC [area under the curve (AUC) from 81.8% to 84.5%]. In the reliability set, the rheumatologists reached a higher average accuracy, as well as a better trade-off between sensitivity and specificity compared with the ViT. However, the annotators' performance was variable, and one out of four rheumatologists showed equal or lower classification measures compared with the ViT. The ViT is a modern, well-performing and readily available tool for assessing patterns of microangiopathy on NFC images, and it may assist rheumatologists in generating consistent and high-quality NFC reports; however, the final diagnosis of a scleroderma pattern in any individual case needs the judgement of an experienced observer.

Comment on: Combination of immunosuppressive therapy and nintedanib improves capillaroscopic changes in systemic sclerosis-interstitial lung disease: a case report.

Comment on: Combination of immunosuppressive therapy and nintedanib improves capillaroscopic changes in systemic sclerosis-interstitial lung disease: a case report.

Detection of microvascular changes in systemic sclerosis and other rheumatic diseases.

Morphological and functional analysis of the microcirculation are objective outcome measures that are recommended for use in the presence of clinical signs of altered peripheral blood flow (such as Raynaud phenomenon), which can occur in systemic sclerosis (SSc) and other autoimmune rheumatic diseases. Several advanced non-invasive tools are available for monitoring the microcirculation, including nailfold videocapillaroscopy, which is the best-studied and most commonly used method for distinguishing and quantifying microvascular morphological alterations in SSc. Nailfold videocapillaroscopy can also be used alongside laser Doppler techniques to assist in the early diagnosis and follow-up of patients with dermatomyositis or mixed connective tissue disease. Power Doppler ultrasonography, which has been used for many years to evaluate the vascularity of synovial tissue in rheumatoid arthritis, is another promising tool for the analysis of skin and nailbed capillary perfusion in other autoimmune rheumatic diseases. Other emerging methods include raster-scanning optoacoustic mesoscopy, which offers non-invasive high-resolution 3D visualization of capillaries and has been tested in psoriatic arthritis and SSc. The principle functions and operative characteristics of several non-invasive tools for analysing microvascular changes are outlined in this Review, and the clinical roles of validated or tested imaging methods are discussed for autoimmune rheumatic diseases.

Machine learning associated with respiratory oscillometry: a computer-aided diagnosis system for the detection of respiratory abnormalities in systemic sclerosis

IntroductionThe use of machine learning (ML) methods would improve the diagnosis of respiratory changes in systemic sclerosis (SSc). This paper evaluates the performance of several ML algorithms associated with the respiratory oscillometry analysis to aid in the diagnostic of respiratory changes in SSc. We also find out the best configuration for this task.MethodsOscillometric and spirometric exams were performed in 82 individuals, including controls (n = 30) and patients with systemic sclerosis with normal (n = 22) and abnormal (n = 30) spirometry. Multiple instance classifiers and different supervised machine learning techniques were investigated, including k-Nearest Neighbors (KNN), Random Forests (RF), AdaBoost with decision trees (ADAB), and Extreme Gradient Boosting (XGB).Results and discussionThe first experiment of this study showed that the best oscillometric parameter (BOP) was dynamic compliance, which provided moderate accuracy (AUC = 0.77) in the scenario control group versus patients with sclerosis and normal spirometry (CGvsPSNS). In the scenario control group versus patients with sclerosis and altered spirometry (CGvsPSAS), the BOP obtained high accuracy (AUC = 0.94). In the second experiment, the ML techniques were used. In CGvsPSNS, KNN achieved the best result (AUC = 0.90), significantly improving the accuracy in comparison with the BOP (p < 0.01), while in CGvsPSAS, RF obtained the best results (AUC = 0.97), also significantly improving the diagnostic accuracy (p < 0.05). In the third, fourth, fifth, and sixth experiments, different feature selection techniques allowed us to spot the best oscillometric parameters. They resulted in a small increase in diagnostic accuracy in CGvsPSNS (respectively, 0.87, 0.86, 0.82, and 0.84), while in the CGvsPSAS, the best classifier's performance remained the same (AUC = 0.97).ConclusionsOscillometric principles combined with machine learning algorithms provide a new method for diagnosing respiratory changes in patients with systemic sclerosis. The present study's findings provide evidence that this combination may help in the early diagnosis of respiratory changes in these patients.

Evaluation of brain changes in systemic sclerosis (SSc) patients using two different techniques of MRI: Is it really worthy?

BackgroundSystemic sclerosis (SSc) is a rare chronic multi-system autoimmune disease of unknown cause and a complex pathogenesis. The hallmark of the disease is microvascular vasculopathy which results in tissue ischemia with recurrent episodes of reperfusion. Diffusion-weighted (DW) Magnetic Resonance imaging (MRI) is an excellent tool for the detection of activity of any vascular or inflammatory lesions. ObjectivesDetect brain changes in systemic sclerosis patients with asymptomatic CNS manifestations using fluid attenuation inversion recovery (FLAIR) weighted sequence and diffusion-weighted (DW) sequence MRI. MethodsFifteen systemic sclerosis female patients aged 27–60 years old with disease duration of 1–20 years with no CNS clinical manifestations were included. A controlled group of 14 clinically normal persons, age and sex matched. Both groups were subjected to brain MR examination at 1.5T; a FLAIR weighted sequence and a DW sequence. SPSS (version 20) was used for statistical analysis. Results37 white matter hyperintense lesions (≤2 to ≥ 5mm in diameter) were detected in patient group using FLAIR weighted MRI while diffusion-weighted MRI failed to detect the same lesions. A non-significant relation (P=.259) between the presence of white matter hyperintense lesions and the severity of peripheral vascular affection of the disease was observed. ConclusionsAsymptomatic central nervous system vasculopathy is detected in systemic sclerosis using FLAIR MRI, while diffusion MRI failed to detect such lesions. These findings suggest a non-inflammatory form of central nervous system microvasculopathy in SSc patients.

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.

Radiologic hand and wrist changes in systemic sclerosis: Associations with the disease duration, skin score and capillaroscopy

Objectives Patients with systemic sclerosis (SSc) have some musculoskeletal manifestations. The radiologic manifestations can be articular or non-articular. There is inconsistency in the correlation between clinical manifestations and radiologic changes; there are few reports on the correlation between them and capillaroscopy. Material and Methods We evaluated 81 patients with SSc, using a cross- sectional single center study, referred to scleroderma clinic affiliated to Shiraz University of Medical Sciences, Iran. Skin score and capillaroscopy were performed and an expert radiologist did the radiologic evaluation of the posterior-anterior views of both hands and wrists. For data analysis, SPSS version 19 was used.Results The participants consisted of 73 women and eight men aged 42±2.6 years old. There were 60.5% limited scleroderma (lcSSc) and 39.5% diffuse scleroderma (dcSSc) patients. After 5 years, 91% of them had some radiologic changes mostly asymptomatic.The most common radiologic changes were non-articular (70.1%), including acro-osteolysis, subcutaneous and peri-articular calcinosis and avascular necrosis. Flexion deformities and DIP joint space narrowing were more seen in patients with dcSSc. Resorption of the distal ulna and avascular necrosis was observed more in lcSSc. There was a correlation between radiologic changes and duration, but not with the skin score. The most common capillaroscopic pattern in patients with radiologic change was late scleroderma pattern.Conclusions Radiologic changes which were mostly asymptomatic were common in patients with SSc. The changes were different in patients with dcSSc and lcSSc and there were associations with duration and capillaroscopic patterns, but not with the skin score.

Evaluation of brain changes in systemic sclerosis (SSc) patients using two different techniques of MRI: Is it really worthy?

Systemic sclerosis (SSc) is a rare chronic multi-system autoimmune disease of unknown cause and a complex pathogenesis. The hallmark of the disease is microvascular vasculopathy which results in tissue ischemia with recurrent episodes of reperfusion. Diffusion-weighted (DW) Magnetic Resonance imaging (MRI) is an excellent tool for the detection of activity of any vascular or inflammatory lesions. Detect brain changes in systemic sclerosis patients with asymptomatic CNS manifestations using fluid attenuation inversion recovery (FLAIR) weighted sequence and diffusion-weighted (DW) sequence MRI. Fifteen systemic sclerosis female patients aged 27-60 years old with disease duration of 1-20 years with no CNS clinical manifestations were included. A controlled group of 14 clinically normal persons, age and sex matched. Both groups were subjected to brain MR examination at 1.5T; a FLAIR weighted sequence and a DW sequence. SPSS (version 20) was used for statistical analysis. 37 white matter hyperintense lesions (≤2 to ≥ 5mm in diameter) were detected in patient group using FLAIR weighted MRI while diffusion-weighted MRI failed to detect the same lesions. A non-significant relation (P=.259) between the presence of white matter hyperintense lesions and the severity of peripheral vascular affection of the disease was observed. Asymptomatic central nervous system vasculopathy is detected in systemic sclerosis using FLAIR MRI, while diffusion MRI failed to detect such lesions. These findings suggest a non-inflammatory form of central nervous system microvasculopathy in SSc patients.

Nailfold capillaroscopy in systemic sclerosis - state of the art: The evolving knowledge about capillaroscopic abnormalities in systemic sclerosis.

Capillaroscopy is a unique method for morphological evaluation of the nailfold capillaries that plays a crucial role for early diagnosis of systemic sclerosis. The first description of the pathological capillaroscopic changes in systemic sclerosis was made by Brown and O'Leary in 1925. Several decades later they have been validated and accepted as a diagnostic criterion in the current 2013 EULAR/ACR classification criteria. This article summarizes the evolving knowledge about the use of nailfold capillaroscopy in systemic sclerosis. Initially, Maricq et al. suggested two major categories of capillaroscopic findings in systemic sclerosis - an 'active'and 'slow' capillaroscopic pattern. Their description and terminology suggested a correlation between capillaroscopic changes and disease activity and progression. In the later classification of Cutolo et al., three phases were defined, i.e. 'early', 'active' and 'late' that reflect the time-related evolution of the capillaroscopic changes suggesting their association with disease duration. Current knowledge about the microvascular changes in systemic sclerosis supports both associations with disease activity and disease duration. The general opinion about the association of capillaroscopic findings with clinical involvement and disease activity in systemic sclerosis is not uniform. This is supposedly because the phase changes of systemic sclerosis-related microangiopathy are almost a universal feature in scleroderma and are not specific for a certain type of an accompaning clinical manifestation. Thus, the speed of progression of microvascular alterations might be a decisive criterion, and in cases of rapid dynamics of capillaroscopic findings, it could be considered as an indicator of disease activity. Interestingly, vascular 'recovery' has been observed after treatment with immunosuppressive drugs, haematopoietic stem cell transplantation, and the endothelin receptor antagonist - bosentan. The evolving knowledge about nailfold capillaroscopy in systemic sclerosis will further spread its application from a mainly diagnostic tool to an established, reliable method for evaluation of disease activity, prognosis and therapeutic response.

Nailfold capillaroscopic changes in patients with idiopathic pulmonary arterial hypertension and systemic sclerosis-related pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) represents one of the main clinical expressions of the vascular changes in systemic sclerosis (SSc). Lung microvascular changes can play a role in the pathogenesis of idiopathic PAH (IPAH) also. The aim of this study is to investigate the presence of capillaroscopic abnormalities in patients with IPAH and to evaluate the differences in capillary nailfold changes between patients with IPAH and patients with SSc with and without PAH. Methods39 SSc patients (19 with PAH – SSc-PAH and 20 without – SSc-noPAH), 21 subjects with IPAH and 20 healthy subjects were recruited. PAH was diagnosed by right heart catheterization. Nailfold videocapillaroscopy was performed (NVC) in all recruited subjects; capillary quantitative parameters (loops length and width, capillary density, neoangiogenesis) were evaluated and a semiquantitative scoring was used (normal, minor or major abnormalities for healthy controls and IPAH subjects and specific patterns – early, active and late – for SSc subjects) to define microvascular alterations. ResultsThe presence of capillaroscopic abnormalities was detected in 38,1% subjects with IPAH; particularly, compared to healthy controls, capillary density was significantly lower (7,5±1,65loops/mm vs 9±1,37loops/mm p<0,05) and mean capillary width was significantly higher (21±13μm vs 17±3μm p<0,05). A more severe NVC pattern (active/late) was described. SSc-PAH patients compared to SSc-noPAH patients (73,2% vs 50% respectively, p<0,05), with a significantly lower capillary density (5,64±1,9loops/mm vs 6,5±1,3loops/mm p<0,05) and a significantly higher capillary width (55±7μm vs 35±8μm - p<0,05) and mean number of neoangiogenesis (N/mm) (1±0,33 vs 0,2±0,22 respectively p<0,05). ConclusionsThese data, beyond to confirm the role of microvascular damage in SSc-related PAH, support the hypothesis of systemic microvascular involvement in IPAH also, which can be detected by NVC, although further studies are needed to establish whether the changes in the systemic microcirculation are causal or consequential to PAH.

Anti-angiotensin II type 1 receptor autoantibodies (AT1R-AAs) in patients with systemic sclerosis: lack of association with disease manifestations.

Angiotensin II type 1 receptor autoantibodies (AT1R-AAs) are known to be associated with malignant hypertension, preeclampsia, and vascular rejection in kidney transplantation. They were also suspected to have pathogenetic role in vasculopathic changes in systemic sclerosis (SSc). Clinical data regarding AT1R-AAs in SSc are scarce. In this work, we will examine the relationship between serum levels of AT1R-AAs and disease manifestations. Serum samples from SSc patients and healthy controls were analyzed for AT1R-AAs by using a commercial ELISA kit. We examined the association of serum levels of AT1R-AA with disease duration, systolic pulmonary artery pressure (sPAP) measurements, and disease manifestations like cutaneous, lung and esophageal involvements, and the presence of digital ulcers in a cross-sectional manner. There was no statistically significant difference in levels of AT1R-AAs between SSc (n=93) patients and healthy controls (n=66) (p=0.23). Serum levels of AT1R-AAs were not correlated with disease duration, sPAP measurements, and showed no association with disease manifestations like lung involvement, esophageal involvement, digital ulcers, and cutaneous fibrosis. In our SSc cohort, AT1R-AA serum levels were not different from healthy subjects and higher levels were not associated with any disease manifestation neither.

Capillaroscopic findings and vascular biomarkers in systemic sclerosis: Association of low CD40L levels with late scleroderma pattern

ObjectiveTo determine the relationship between vascular biomarkers reflecting the vascular injury and neoangiogenesis with capillaroscopic changes in systemic sclerosis (SSc). MethodsNailfold video-capillaroscopy (NVC) was performed qualitatively (early, active and late scleroderma patterns) in 72 SSc patients (66 female) fulfilling ACR/EULAR (2013) criteria. Serum samples of patients were collected and analysed by flow cytometer with multiplex kits of sCD40L, tPA, MCP-1, sE-selectin, IL-8, IL-6, VEGF, sP-selectin, TGF-β1 and VCAM at the same time with NVC. ResultsCompared to healthy subjects; tPA (p=0.02), MCP-1 (p=0.001), sE-selectin (p=0.008) and TGF-β1 (p=0.001) levels were significantly higher, however sP-selectin (p=0.011) and IL-8 (p=0.001) levels were lower in SSc patients. SSc patients were defined according to NVC patterns as ‘early’ (n=10), ‘active’ (n=37) and ‘late’ (n=25). According to NVC patterns of SSc patients, only sCD40L levels were significantly lower in the ‘late’ group (p=0.039). The other markers were similar among NVC groups. ConclusionsNVC is a useful method for investigating the vascular pathogenesis and severity of SSc. Although the levels were similar to healthy controls in patients with early/active NVC patterns, there were lower sCD40L serum levels in patients with late NVC pattern. CD40L may have a role in the early/active phase of vascular involvement.

The Place of Nailfold Capillaroscopy Among Instrumental Methods for Assessment of Some Peripheral Ischaemic Syndromes in Rheumatology.

Micro- and macrovascular pathology is a frequent finding in a number of common rheumatic diseases. Secondary Raynaud's phenomenon (RP) is among the most common symptoms in systemic sclerosis and several other systemic autoimmune diseases including a broad differential diagnosis. It should be also differential from other peripheral vascular syndromes such as embolism, thrombosis, etc., some of which lead to clinical manifestation of the blue toe syndrome. The current review discusses the instrumental methods for vascular assessments. Nailfold capillaroscopy is the only method among the imaging techniques that can be used for morphological assessment of the nutritive capillaries in the nailfold area. Laser-Doppler flowmetry and laser-Doppler imaging are methods for functional assessment of microcirculation, while thermography and plethysmography reflect both blood flow in peripheral arteries and microcirculation. Doppler ultrasound and angiography visualize peripheral arteries. The choice of the appropriate instrumental method is guided by the clinical presentation. The main role of capillaroscopy is to provide differential diagnosis between primary and secondary RP. In rheumatology, capillaroscopic changes in systemic sclerosis have been recently defined as diagnostic. The appearance of abnormal capillaroscopic pattern inherits high positive predictive value for the development of a connective tissue disease that is higher than the predictive value of antinuclear antibodies. In cases of abrupt onset of peripheral ischaemia, clinical signs of critical ischaemia, unilateral or lower limb involvement, Doppler ultrasound and angiography are indicated. The most common causes for such clinical picture that may be referred to rheumatologic consultation are the antiphospholipid syndrome, mimickers of vasculitides such as atherosclerosis with cholesterol emboli, and neoplasms.

SP0045 The Prognostic Value of the Capillaroscopic Analysis

Structural capillary changes in systemic sclerosis (SSc) may be easily investigated and quantified by nailfold videocapillaroscopy (NVC), and in recent years there have been identified disease-specific progressive capillary abnormalities and...

SP0154 The Prognostic Value of the Capillaroscopic Analysis

Structural capillary changes in systemic sclerosis (SSc) may be easily investigated and quantified by nailfold videocapillaroscopy (NVC), and in recent years there have been identified disease-specific progressive capillary abnormalities and...

Up-regulation of CC chemokine ligand 20 and its receptor CCR6 in the lesional skin of early systemic sclerosis

Mononuclear cell (MNC) infiltrate is one of the earliest pathological changes in systemic sclerosis (SSc) skin. However, little is known about the recruitment of these cells into skin lesions. Recently, the role of chemokines has been suggested in the pathogenesis of SSc. Here we studied the expressions and distributions of CC chemokine CCL20 and its receptor CCR6 in early SSc skin lesions and the difference in CCL20 expressions and ability to recruite MNCs of normal dermal fibroblast (NDF) and scleroderma dermal fibroblast (SSDF). We found that the expressions of CCL20 and its receptor CCR6 were obviously up-regulated in SSc in contrast to normal human skin. mRNA levels were significantly expressed in SSc lesional skins vs normal skin tissues. SSDF displayed increased constitutive expressions of CCL20 mRNA and protein. In addition, Th1 cytokines (TNF-α and IL-1β) remarkably increased the expression of CCL20 in both NDF and SSDF in a dose- and time-dependent manner. Supernatants from SSDF showed stronger chemotactic activity to PBMCs than those from NDF. Thus our findings suggest that CCL20 released from cytokine-activated SSDF plays an important role in the induction of SSc by further recruiting more MNCs to the skin.

Transcription Factor Fos-Related Antigen-2 Induces Progressive Peripheral Vasculopathy in Mice Closely Resembling Human Systemic Sclerosis

Microvascular damage is one of the first pathological changes in systemic sclerosis. In this study, we investigated the role of Fos-related antigen-2 (Fra-2), a transcription factor of the activator protein-1 family, in the peripheral vasculopathy of systemic sclerosis and examined the underlying mechanisms. Expression of Fra-2 protein was significantly increased in skin biopsies of systemic sclerosis patients compared with healthy controls, especially in endothelial and vascular smooth muscle cells. Fra-2 transgenic mice developed a severe loss of small blood vessels in the skin that was paralleled by progressive skin fibrosis at 12 weeks of age. The reduction in capillary density was preceded by a significant increase in apoptosis in endothelial cells at week 9 as detected by immunohistochemistry. Similarly, suppression of Fra-2 by small interfering RNA prevented human microvascular endothelial cells from staurosporine-induced apoptosis and improved both the number of tubes and the cumulative tube lengths in the tube formation assay. In addition, cell migration in the scratch assay and vascular endothelial growth factor-dependent chemotaxis in a modified Boyden chamber assay were increased after transfection of human microvascular endothelial cells with Fra-2 small interfering RNA, whereas proliferation was not affected. Fra-2 is present in human systemic sclerosis and may contribute to the development of microvasculopathy by inducing endothelial cell apoptosis and by reducing endothelial cell migration and chemotaxis. Fra-2 transgenic mice are a promising preclinical model to study the mechanisms and therapeutic approaches of the peripheral vasculopathy in systemic sclerosis.

Collagen V and vascular injury promote lung architectural changes in systemic sclerosis

Systemic sclerosis (SSc) is a multisystem disorder characterized by inflammation, fibrosis and vascular damage. The aim of this study was to evaluate the interactions between basement membrane disruption, endothelial injury and collagen V deposition on the vascular wall, as well as their association with pulmonary function tests in patients with SSc. The endothelial apoptosis was assessed by TUNEL and electron microscopy, and quantified through the point-counting technique. To evaluate basement membrane integrity, laminin immunostaining and electron microscopy were used. Immunofluorescence and morphometric analysis were used to determine the amount of collagen V in the vascular walls in 23 open lung biopsies of patients with SSc without pulmonary hypertension. Normal lung tissue was obtained from five individuals who had died of traumatic injuries. The apoptosis index in SSc was higher in the endothelial cells (13.83 +/- 6.83) when compared with the control (2.51 +/- 2.06) group (P < 0.001) and confirmed by electron microscopy. We observed an important disruption of the basement membrane on the vascular wall shown by discontinuous laminin immunostaining and electron microscopy. An increase in collagen V on the vascular wall of the SSc group was observed (45.28 +/- 13.21), when compared with control group (22.90 +/- 4.13, P < 0.001), and this difference was statistically significant. An inverse correlation was found between vital capacity, forced vital capacity, forced expiratory volume in 1 s, vascular collagen V and endothelial apoptosis (P < 0.05). We conclude that the endothelial apoptosis and vascular collagen V interaction reinforce the vascular pathway in the SSc pathogenesis. Further studies are needed to determine whether this relationship is causal or consequential.