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1.
Int J Mol Sci ; 20(24)2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31817940

RESUMO

In systemic sclerosis (SSc), the possible involvement of lymphatic microcirculation and lymphangiogenesis has traditionally been overshadowed by the greater emphasis placed on dysfunctional blood vascular system and angiogenesis. In the present in vitro study, we explore for the first time whether the SSc microenvironment may interfere with lymphangiogenesis, a complex, multi-step process in which lymphatic microvascular endothelial cells (LMVECs) sprout, migrate, and proliferate to generate new lymphatic capillaries. Normal human adult dermal LMVECs from three donors were treated with serum from SSc patients (n = 8), serum from healthy individuals (n = 8), or recombinant human vascular endothelial growth factor (VEGF)-C as a positive control for lymphangiogenesis. Cell proliferation, Boyden chamber Matrigel chemoinvasion, wound healing capacity, and lymphatic capillary morphogenesis on Geltrex were assayed. VEGF-C serum levels were measured by enzyme-linked immunosorbent assay. Gene and protein expression levels of the lymphangiogenic orchestrators VEGF receptor-3 (VEGFR-3)/Flt-4 and neuropilin-2 (NRP-2) were determined by real-time PCR and Western blotting, respectively. Conditioning with SSc serum significantly inhibited LMVEC proliferation, Matrigel invasion, and wound healing capacity with respect to healthy serum. The ability of LMVECs to form lymphatic tubes on Geltrex was also severely compromised in the presence of SSc serum. VEGF-C levels were comparable in SSc and healthy sera. Treatment with SSc serum resulted in a significant downregulation of both VEGFR-3/Flt-4 and NRP-2 mRNA and protein levels. In SSc, the pathologic environment severely hampers every lymphangiogenesis step, likely through the reduction of pro-lymphangiogenic VEGFR-3/NRP-2 co-receptor signaling. The impairment of the lymphangiogenic process opens a new scenario underlying SSc vascular pathophysiology, which is worth investigating further.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31764972

RESUMO

OBJECTIVES: Cardiac rhythm disturbances constitute the most frequent cardiovascular cause of death in SSc. However, electrocardiographic findings are not a part of risk stratification in SSc. We aimed to translate 24 h Holter findings into a tangible risk prediction score using cardiovascular magnetic resonance. METHODS: The Scleroderma Arrhythmia Clinical Utility Study (SAnCtUS) was a prospective multicentre study including 150 consecutive SSc patients from eight European centres, assessed with 24 h Holter and cardiovascular magnetic resonance, including ventricular function, oedema (T2 ratio) and late gadolinium enhancement (%LGE). Laboratory/clinical parameters were included in multivariable corrections. A combined endpoint of sustained ventricular tachycardia requiring hospitalization and sudden cardiac death at a median (interquartile range) follow-up of 1 (1.0-1.4) year was generated. RESULTS: Only T2 ratio and %LGE were significant predictors of ventricular rhythm disturbances, but not of supraventricular rhythm disturbances, after multivariable correction and adjustment for multiple comparisons. Using decision-tree analysis, we created the SAnCtUS score, a four-category scoring system based on T2 ratio and %LGE, for identifying SSc patients at high risk of experiencing ventricular rhythm disturbance at baseline. Increasing SAnCtUS scores were associated with a greater disease and arrhythmic burden. All cases of non-sustained ventricular tachycardia (n = 7) occurred in patients with the highest SAnCtUS score (=4). Having a score of 4 conveyed a higher risk of reaching the combined endpoint in multivariable Cox regression compared with scores 1/2/3 [hazard ratio (95% CI): 3.86 (1.14, 13.04), P = 0.029] independently of left ventricular ejection fraction and baseline ventricular tachycardia occurrence. CONCLUSION: T2 ratio and %LGE had the greatest utility as independent predictors of rhythm disturbances in SSc patients.

3.
Clin Exp Rheumatol ; 37 Suppl 119(4): 3-14, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31587697

RESUMO

Systemic sclerosis (SSc) is a complex disorder characterised by the involvement of small arteries, microvessels and connective tissue, with deposition of fibrotic tissue and microvascular obliteration in the skin and internal organs. Due to the multifaceted nature of the disease, several articles are published in the medical literature every year, aimed at exploring different aspects of the pathogenesis, internal organ involvement and clinical aspects, and possible therapeutic approaches. In this article we have reviewed the literature on SSc of the past year, with the aim of identifying novel approaches that may help the treating physician in the clinical management of patients.


Assuntos
Microvasos/patologia , Escleroderma Sistêmico , Vasos Sanguíneos/patologia , Fibrose , Humanos , Escleroderma Sistêmico/fisiopatologia , Escleroderma Sistêmico/terapia , Pele
4.
Eur J Intern Med ; 70: 43-49, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31540806

RESUMO

BACKGROUND: Renal Resistive Index (RRI), reflects changes in both renal vascular and tubular-interstitial compartments and in systemic vascular compliance related to age and comorbidities. OBJECTIVES: a) To investigate determinants of RRI in SSc population, b) its association with SSc-related features and c) to test its prognostic impact on organ specific worsening or death. METHODS: 380 SSc patients ≥18 years were enrolled after giving informed consent. Baseline data on RRI, laboratory, instrumental and therapeutic features were retrospectively collected. Age-SSc adjusted cut-offs were created by dividing the population in age quartiles and considering RRI values >75th percentile as pathologic. Clinical follow-up was performed until last available visit or the development/worsening of specific internal organ involvement or death. RESULTS: RRI was independently predicted by age and systolic pulmonary arterial pressure on Echo. Therefore, we created Age-SSc adjusted pathologic RRI cut-offs, which were significantly associated with various disease related skin and lung fibrotic manifestations, as well as vasculopathic complications. After a mean follow-up of 3.6 ±â€¯2.6 years, RRI was one of the independent predictors (together with modified Rodnan skin score, interstitial lung disease, presence of dyspnoea and late nailfold-videocapillaroscopy pattern) for mortality, with 0.68 as best cut-off (sensitivity 88.5%, specificity 50.9%). CONCLUSION: If corroborated, Renal Resistive Index cut-offs might be used to evaluate renal and extrarenal involvement in SSc and could serve as predictors of mortality.

5.
J Rheumatol ; 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31474594

RESUMO

OBJECTIVE: Through a systemic literature research (SLR) and meta-analysis, to determine maternal and foetal outcomes in SSc pregnancies, to analyse the effect of pregnancy on disease activity and to explore predictors of foetal and maternal outcomes. METHODS: A SLR was performed for articles on SSc and pregnancy published between 1950 and 1st February 2018. Reviewers double extracted articles to obtain agreement on>95% of pre-defined critical outcomes. RESULTS: 461 publications were identified, 16 were included in the meta-analysis. The metanalysis showed that SSc pregnancies were at higher risk of miscarriages (OR 1.6,CI95% 1.22-2.22), foetuses with intrauterine growth retardation (IUGR) (OR 3.2,CI95% 2.21-4.53), preterm births (OR 2.4,CI95% 1.14-4.86) and newborns with low birth weight (OR 3.8,CI95% 2.16-6.56). SSc patients had 2.8 times higher chance of developing gestational hypertension (OR 2.8,CI95% 2.28-3.39) and 2.3 times higher chance of having Caesarean delivery compared to controls (OR 2.3,CI95% 1.37-3.8). The definitions of disease worsening/new visceral organ involvement were too inexact to have any confidence in the results although there were said to be worsening or new disease manifestations during pregnancy in 44/307(14.3%) cases and during the 6-months post-partum in 32/306(10.5%) cases. The data did not permit definition of predictors of disease progression and of maternal and foetal outcomes. CONCLUSION: SSc pregnancies have increased frequency of miscarriages, IUGR, pre-term deliveries and newborns with low birth weight compared to healthy controls. SSc women were more prone to develop gestational hypertension and to undergo Caesarean section. Disease manifestations seem to remain stable or improve in most patients.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31410485

RESUMO

OBJECTIVES: SSc is a chronic autoimmune disease characterized by inflammation of the skin and multiple internal organs. Articular involvement is one of the main features of SSc, and typical hallmarks of SpA have been found in SSc patients. The aim of the present study was to estimate the prevalence of entheseal and synovio-entheseal complex (SEC) alterations in a cohort of SSc patients. METHODS: One hundred SSc patients and 25 healthy subjects were included in this cross-sectional study. The enthesis sites of lateral epicondylar common extensor tendons (CET) and the enthesis of the Glasgow Ultrasound Enthesis Scoring System were evaluated. SEC involvement was evaluated only at CET enthesis. RESULTS: In SSc, the Glasgow Ultrasound Enthesis Scoring System score was significantly higher (median 4.0, interquartile range 2.0-7.0) than in controls (median 1.0, interquartile range 0.0-3.0) (P < 0.0001). CET enthesis of SSc patients showed more frequent US B-mode alterations than that of controls (χ2 = 11.47, P = 0.0007 for size; χ2 = 13.79, P = 0.0002 for cortical irregularity, χ2 = 5.24, P = 0.022 for calcification/enthesophytes). Power Doppler US signal at CET enthesis was significantly more frequent in SSc patients than in healthy controls (χ2 = 9.11, P = 0.0025), as was the concomitant SEC involvement (χ2 = 8.52, P = 0.0035). CONCLUSION: These data show that SSc patients frequently present US features of enthesopathy. Moreover, CET enthesopathy was correlated with SEC inflammation, suggesting that entheseal inflammation in SSc may share the same micro-anatomical targets as found in SpA.

7.
J Clin Med ; 8(8)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430950

RESUMO

Systemic sclerosis (SSc; scleroderma) is characterized by life-threatening progressive multiorgan fibrosis orchestrated by profibrotic myofibroblasts originating from different sources. Because recent data demonstrated that the majority of myofibroblasts in a murine scleroderma model arise from adipocytic progenitors through the adipocyte-myofibroblast transition process, we sought to determine whether the SSc microenvironment may affect the differentiation potential of adipose-derived stem cells (ADSC). Normal human ADSC from three donors were treated with serum from SSc patients (n = 6), serum from healthy individuals (n = 6), or recombinant human transforming growth factor-ß1 (TGFß1) as positive control of myofibroblastic phenotype induction. ADSC were subjected to in vitro adipogenic differentiation for up to 21 days in the presence of different stimuli followed by lipid content quantification. In selected experiments, adipocytic and mesenchymal/myofibroblast marker gene and protein expression levels were assessed by Real-Time PCR, immunoblotting and immunofluorescence after administration of different stimuli for 72 and 96 h, respectively. Cell contractile phenotype was assayed by collagen gel contraction assay. Likewise stimulation with TGFß1, SSc serum was able to significantly inhibit the adipocyte differentiation of ADSC as testified by a strong decrease in red-colored lipid droplets after 21 days of adipogenic induction. Treatment of ADSC either with SSc serum or TGFß1 resulted in the acquisition of a myofibroblast-like phenotype characterized by a reduced expression of the adipocytic markers perilipin and adiponectin, a significant upregulation of the mesenchymal/myofibroblast markers α-SMA+ stress fibers, S100A4 and type I collagen, and an ability to effectively contract collagen gels. In SSc, the pathologic environment may favor the differentiation of ADSC into profibrotic and contractile myofibroblast-like cells. These findings strengthen the notion that the generation of myofibroblasts from ADSC may be relevant in SSc pathophysiology potentially representing a new target for the prevention/treatment of multiorgan fibrosis.

8.
Ann Rheum Dis ; 78(11): 1576-1582, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31391176

RESUMO

OBJECTIVES: To investigate the influence of vasodilator drugs on the occurrence of features depending on myocardial ischaemia/fibrosis (ventricular arrhythmias, Q waves, cardiac blocks, pacemaker implantation, left ventricular ejection fraction (LVEF) <55%, and/or congestive heart failure and sudden cardiac death) in systemic sclerosis (SSc). METHODS: 601 patients with SSc were enrolled from 1 December 2012 to 30 November 2015 and had a second visit 0.5-4 years apart. 153 received no vasodilators; 448 received vasodilator therapy (ie, calcium channel blockers and/or ACE inhibitors or angiotensin II receptor blockers or combinations of them), 89 of them being also treated with either endothelin receptor antagonists or PDE5 inhibitors or prostanoids. Associations between the occurrence of myocardial disease manifestations and any demographic, disease and therapeutic aspect were investigated by Cox regression analysis. A Cox frailty survival model with centre of enrolment as random effect was performed. RESULTS: During 914 follow-up patient-years, 12 ventricular arrhythmias, 5 Q waves, 40 cardiac blocks, 6 pacemaker implantations and 19 reduced LVEF and/or congestive heart failure (CHF) occurred. In multivariate Cox regression analysis, vasodilator therapy was associated with a lower incidence of ventricular arrhythmias (p=0.03); low-dose acetylsalicylic acid (ASA) with a lower incidence of cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.02); active disease with a higher incidence of LVEF <55% and/or CHF and cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.05). CONCLUSIONS: The present study might suggest a preventative effect on the occurrence of distinct myocardial manifestations by vasodilator therapy and low-dose ASA.

9.
Medicine (Baltimore) ; 98(26): e16086, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261523

RESUMO

Pleuroparenchymal fibroelastosis (PPFE) is a rare new interstitial lung disease (ILD) characterized by the fibrotic thickening of the visceral pleura and subadjacent parenchymal areas of the upper lobes This study reveals that patients with ILD-SSc associated with chest HRCT evidence of PPFE require close and recurrent follow-up with periodic evaluation of lung function parameters, DLCO and chest HRCT. Rheumatologists should be aware of this new radiological finding which is accompanied by a negative prognosis, especially when associated with a progressive course. Patients with this radiological pattern need to be monitored with particular attention.


Assuntos
Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pleurais/complicações , Doenças Pleurais/diagnóstico por imagem , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico por imagem , Idoso , Feminino , Seguimentos , Humanos , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/terapia , Masculino , Doenças Pleurais/terapia , Prognóstico , Fibrose Pulmonar/complicações , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/terapia , Estudos Retrospectivos , Reumatologistas , Escleroderma Sistêmico/terapia
10.
Clin Exp Med ; 19(3): 357-366, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30989453

RESUMO

Vasculopathy is a crucial feature of systemic sclerosis (SSc), and Raynaud's phenomenon (RP) and digital ulcers (DU) have a deep impact on the quality of patients' life. The management of vascular disease can be challenging for the clinician because of the suboptimal tolerability of the treatments and lack of consensus on the best therapeutic approach. Intravenous iloprost, a synthetic analogue of prostacyclin, is broadly used for the treatment of RP and ischemic ulcers secondary to SSc. However, no standardized protocol on iloprost use is currently available and, consequently, the management of this treatment is largely based on the experience of each single center. The PROSIT project is an observational, multicenter study aiming to investigate the current treatments for SSc vasculopathy, the use of prostanoids, with special regard to iloprost, and the perception of the treatment from a patient's perspective. The study was conducted on a cohort of 346 patients from eight Italian centers and included a structured survey addressed to physicians, data collected from patient's medical records and two patient-administered questionnaires assessing the level of satisfaction, tolerability and perception of the efficacy of Iloprost. PROSIT data confirmed that in the contest of SSc iloprost represents the first-line choice for the management of severe RP and DU. Moreover, it is a well-tolerated treatment as reported by patients' experience. Although a standard protocol for the treatment of SSc-related vasculopathy is lacking, PROSIT study identified different therapeutic approaches largely supported by tertiary Italian centers. Further studies are needed in order to optimize the best treatment for SSc vascular diseases, in particular to improve the best iloprost schedule management.


Assuntos
Gerenciamento Clínico , Iloprosta/uso terapêutico , Doenças Vasculares Periféricas/tratamento farmacológico , Doenças Vasculares Periféricas/patologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Vasodilatadores/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Atenção Terciária , Resultado do Tratamento , Adulto Jovem
11.
Clin Exp Rheumatol ; 37 Suppl 119(4): 133-140, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31025932

RESUMO

Systemic sclerosis (SSc) is a connective tissue disorder characterised by immune dysregulation, endothelial cell dysfunction followed by defective vascular repair and neovascularization and progressive tissue fibrosis of the skin and internal organs, whose pathophysiology remains to be fully elucidated. Perturbed neuroendothelial control mechanisms comprising either endothelial cell or peripheral nerve fiber impairment are supposed to play an important role in the onset of Raynaud's phenomenon and development of microvascular abnormalities which are the earliest events and key features of SSc. Such pathogenic neuroendothelial mechanisms may trigger both the early endothelial cell damage and the subsequent loss of peripheral microvascular integrity characterised by the lack of compensatory angiogenesis. Of note, the vascular and nervous systems have several anatomical similarities that extend to molecular level, and the molecular mechanisms of nerve regulation are shared by the vascular system. In this context, increasing evidence demonstrated that endothelial cells express receptors for axon guidance molecules, including Ephrin family receptor tyrosine kinases, Neuropilins, Plexins, Robos, and UNC5B that are able to respond to their soluble neuroendothelial trophic ligands, such as Semaphorins and Slits, to guide the sprouting of endothelial tip cells. Here, we first provide a historical view of neuroendothelial control mechanism alterations in the pathogenesis of SSc, and then discuss the emerging role of a class of molecules sharing neurogenic and angiogenic properties, such as members of Semaphorin/Plexin/Neuropilin and Slit/Roundabout families, in SSc-related peripheral microvasculopathy.


Assuntos
Neovascularização Patológica , Doenças Vasculares Periféricas/fisiopatologia , Doença de Raynaud , Escleroderma Sistêmico , Células Endoteliais , Humanos , Sistema Nervoso , Escleroderma Sistêmico/fisiopatologia
13.
J Rheumatol ; 46(6): 603-608, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30442833

RESUMO

OBJECTIVE: To date, "healed/non-healed" and clinical judgment are the only available assessment tools for digital ulcers (DU) in patients with systemic sclerosis (SSc). The aim of our study is to examine a preliminary composite DU clinical assessment score (DUCAS) for SSc for face, content, and construct validity. METHODS: Patients with SSc presenting at least 1 finger DU were enrolled and assessed with the Health Assessment Questionnaire-Disability Index, Cochin scale, visual analog scale (VAS) for DU-related pain, patient global DU status, and global assessment as patient-reported outcomes (PRO), and physician VAS for DU status (phyGDU) as an SSc-DU expert physician/nurse measure. The DUCAS included 7 DU-related variables selected by a committee of SSc DU experts and weighted on a clinical basis. Face validity was examined by consensus and partial construct validity was tested through convergent correlation with other measures of hand function, using Spearman's correlations. A range of patients with SSc was examined. A linear regression model with backward stepwise analysis was used to determine the relationship of individual variables with the primary clinical parameter, phyGDU. RESULTS: Forty-four patients with SSc (9 males, mean age 55 ± 15 yrs, mean disease duration 9.9 ± 5.8 yrs) were enrolled in the study. Overall DUCAS showed significant positive correlations with all abovementioned PRO (r > 0.4, p < 0.01). When all scores and scales were modeled, only DUCAS significantly predicted phyGDU (r = 0.59, R2 = 0.354, Akaike information criterion = 385.4). CONCLUSION: Preliminarily, we suggest that the DUCAS may be a new clinical score for SSc-related DU, having face and content validity and convergent/divergent correlations (construct validity). These early data suggest that this score deserves further evaluation.

16.
Clin Exp Rheumatol ; 36 Suppl 113(4): 135-141, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30277859

RESUMO

OBJECTIVES: The aim of our study was to evaluate the effect of animal-assisted intervention (AAI), a complementary support to traditional therapies focused on the interaction between animals and human beings, in improving psychological trait, anxiety and pain in a cohort of systemic sclerosis (SSc) patients. METHODS: 42 SSc patients, undergoing iloprost intravenous infusion, were divided in three groups: 1) 14 patients submitted to 20 AAI sessions; 2) 14 patients engaged in alternative social activity (control group 1 - C1); and 3) 14 patients without any alternative activity (control group 2 - C2). All patients underwent Visual Analog Scale (VAS), the State-anxiety (STAI-S) and emotional faces at the beginning (s0) and at the end (s1) of each single session, while General Anxiety State-Trait Anxiety Inventory (STAI-T), Beck Depression Inventory (BDI), Social Interaction Anxiety Scale (SIAS), Eysenck Personality Questionnaire-Revised (EPQ-R), the Social Phobia Scale (SPS), the Toronto Alexythymia Scale (TAS-20), the Thought Control Questionnaire (TCQ) were administered at baseline (t0) and at the end of the project (t1). RESULTS: AAI group showed a significant decrease of the anxiety state level in respect to the two control groups (p<0.001). VAS scale resulted lower both in AAI (p < 0.001) and C1 group (p<0.01). Moreover, STAI-T and TAS scores were significantly reduced in AAI group (p<0.001). TCQ scale showed that patients treated with AAI, compared to control group C2, had greater capacity to avoid unpleasant and unwanted thoughts (p<0.05). In AAI group, the EPQ-R test revealed an enhancement of extroversion trait compared to both control groups (p<0.05). CONCLUSIONS: Our data show that AAI significantly reduces pain perception, anxiety, neuroticism and ameliorates patients' social interaction, therefore it may be a useful to allow a better compliance to traditional therapies.


Assuntos
Terapia Assistida por Animais , Ansiedade/terapia , Relações Interpessoais , Neuroticismo , Dor/prevenção & controle , Escleroderma Sistêmico/terapia , Idoso , Animais , Ansiedade/diagnóstico , Ansiedade/fisiopatologia , Ansiedade/psicologia , Terapia Combinada , Cães , Feminino , Humanos , Iloprosta/administração & dosagem , Infusões Intravenosas , Masculino , Saúde Mental , Pessoa de Meia-Idade , Dor/diagnóstico , Dor/fisiopatologia , Dor/psicologia , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/fisiopatologia , Escleroderma Sistêmico/psicologia , Resultado do Tratamento , Vasodilatadores/administração & dosagem
17.
Clin Exp Rheumatol ; 36 Suppl 113(4): 3-23, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30277868

RESUMO

Systemic sclerosis is a rare acquired systemic disease characterised by a complex pathogenesis and multi organ involvement. Every year the scientific world contributes to enrich the knowledge on the pathogenesis, clinical manifestations, diagnosis and treatment of this complex and severe disease. Herewith, we provide an overview of the most significant literature contributions published over the last year.


Assuntos
Escleroderma Sistêmico , Animais , Epigênese Genética , Predisposição Genética para Doença , Humanos , Fenótipo , Prognóstico , Fatores de Risco , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/terapia
18.
Front Immunol ; 9: 2045, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30245695

RESUMO

The early phase of systemic sclerosis (SSc) presents edema as one of the main features: this is clinically evident in the digital swelling (puffy fingers) as well as in the edematous skin infiltration of the early active diffuse subset. Other organs could be affected by this same disease process, such as the lung (with the appearance of ground glass opacities) and the heart (with edematous changes on cardiac magnetic resonance imaging). The genesis of tissue edema is tightly linked to pathological changes in the endothelium: various reports demonstrated the effect of transforming growth factor ß, vascular endothelial growth factor and hypoxia-reperfusion damage with reactive oxygen species generation in altering vascular permeability and extravasation, in particular in SSc. This condition has an alteration in the glycocalyx thickness, reducing the protection of the vessel wall and causing non-fibrotic interstitial edema, a marker of vascular leak. Moreover, changes in the junctional adhesion molecule family and other adhesion molecules, such as ICAM and VCAM, are associated with an increased myeloid cells' extravasation in the skin and increased myofibroblasts transformation with further vascular leak and cellular migration. This mini-review examines current knowledge on determinants of vascular leak in SSc, shedding light on the role of vascular protection. This could enhance further studies in the light of drug development for early treatment, suggesting that the control of vascular leakage should be considered in the same way that vasodilation and inflammation reduction, as potential therapeutic targets.


Assuntos
Permeabilidade Capilar , Endotélio Vascular/metabolismo , Escleroderma Sistêmico/etiologia , Escleroderma Sistêmico/metabolismo , Animais , Biomarcadores , Capilares/metabolismo , Suscetibilidade a Doenças , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Doenças Linfáticas/diagnóstico , Doenças Linfáticas/etiologia , Doenças Linfáticas/metabolismo , Doenças Linfáticas/fisiopatologia , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/fisiopatologia
19.
Ann Rheum Dis ; 77(11): 1665-1674, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30021803

RESUMO

OBJECTIVE: In systemic sclerosis (SSc), early microvascular injury is followed by impaired angiogenesis and peripheral capillary loss. Here, we investigated the possible contribution of the neurovascular guidance molecule Slit2 and its Roundabout (Robo) receptors to SSc-related endothelial cell dysfunction. METHODS: Circulating Slit2 levels were measured in patients with SSc and healthy controls. Slit2, Robo1 and Robo4 expression was investigated in SSc and healthy skin biopsies and explanted dermal microvascular endothelial cells (MVECs). Slit2/Robo4 function in MVEC angiogenesis was studied by cell viability, wound healing and capillary-like tube formation assays. RESULTS: Circulating Slit2 was significantly increased in either SSc or patients with a very early diagnosis of SSc (VEDOSS) compared with controls. Interestingly, serum Slit2 levels were raised in patients with VEDOSS with nailfold videocapillaroscopy (NVC) abnormalities, while they were similar in VEDOSS with normal NVC and controls. In SSc, Slit2 and Robo4 expression was upregulated in clinically affected skin and explanted MVECs in respect to controls. The angiogenic performance of healthy MVECs was significantly reduced after challenge with recombinant human Slit2 or SSc sera. These inhibitory effects were significantly attenuated when SSc sera were preincubated with an anti-Slit2 blocking antibody. In vitro angiogenesis was severely compromised in SSc-MVECs and could be significantly ameliorated by Slit2 neutralisation or ROBO4 gene silencing. Slit2/Robo4 axis interfered with angiogenesis through the inhibition of Src kinase phosphorylation. CONCLUSIONS: In SSc, increased circulating levels of Slit2 and activation of the Slit2/Robo4 antiangiogenic axis may contribute to peripheral microangiopathy since the very early phase of the disease.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Neovascularização Patológica/sangue , Proteínas do Tecido Nervoso/fisiologia , Receptores de Superfície Celular/fisiologia , Escleroderma Sistêmico/patologia , Adulto , Idoso , Sobrevivência Celular/fisiologia , Células Cultivadas , Células Endoteliais/fisiologia , Endotélio Vascular/patologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Proteínas do Tecido Nervoso/sangue , Receptores de Superfície Celular/sangue , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/fisiopatologia , Pele/irrigação sanguínea , Cicatrização/fisiologia
20.
J Scleroderma Relat Disord ; 3(2): 170-174, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29876526

RESUMO

Introduction: The reliability of clinician grading of systemic sclerosis-related digital ulcers has been reported to be poor to moderate at best, which has important implications for clinical trial design. The aim of this study was to examine the reliability of new proposed UK Scleroderma Study Group digital ulcer definitions among UK clinicians with an interest in systemic sclerosis. Methods: Raters graded (through a custom-built interface) 90 images (80 unique and 10 repeat) of a range of digital lesions collected from patients with systemic sclerosis. Lesions were graded on an ordinal scale of severity: 'no ulcer', 'healed ulcer' or 'digital ulcer'. Results: A total of 23 clinicians - 18 rheumatologists, 3 dermatologists, 1 hand surgeon and 1 specialist rheumatology nurse - completed the study. A total of 2070 (1840 unique + 230 repeat) image gradings were obtained. For intra-rater reliability, across all images, the overall weighted kappa coefficient was high (0.71) and was moderate (0.55) when averaged across individual raters. Overall inter-rater reliability was poor (0.15). Conclusion: Although our proposed digital ulcer definitions had high intra-rater reliability, the overall inter-rater reliability was poor. Our study highlights the challenges of digital ulcer assessment by clinicians with an interest in systemic sclerosis and provides a number of useful insights for future clinical trial design. Further research is warranted to improve the reliability of digital ulcer definition/rating as an outcome measure in clinical trials, including examining the role for objective measurement techniques, and the development of digital ulcer patient-reported outcome measures.

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