FRI0416 Characteristics and capillaroscopic findings of systemic sclerosis patients with severe peripheral vascular involvement receiving specific vasodilator treatment

Background:The low overall prevalence of systemic sclerosis (SSc) and the low proportion of male patients have resulted in a scarcity of studies assessing sex differences in SSc patients, and contradictory results.Objectives:To evaluated sex influence on disease characteristics at baseline and then to estimate the effects of sex on disease progression and survival.Methods:We performed a retrospective observational study using data extract from the EULAR scleroderma trials and research (EUSTAR) cohort 096. 173 patients were analysed (26 males).The severity of organ system involvement was defined as described previously (1).Results:Males were significantly older at symptom onset (p=0.007) and at first center visit (p=0.009). There were no differences regarding disease duration at first visit or the interval between the onset of Raynaud syndrome and other non-Raynaud manifestations (p=0.06). Male patients were significantly more likely to have ever smoked (p<0.001), males more often had severe or end-stage peripheral vascular involvement (p=0.01). Modified Rodnan skin score (mRSS) was significantly higher in males (p=0.004). We found no difference regarding musculoarticular involvement, except for digital contractures (p=0.001) and tendon friction rubs (p=0,044). Males more often had interstitial lung disease (ILD) (p=0.013) which was also more frequently severe or end-stage (p = 0.003). Cardiac involvement was more common in males: pulmonary hypertension (PAH) (p = 0.018), arrhytmias (p=0.012), left ventricle ejection fraction<45% (p=0.014). The frequency of scleroderma renal crisis (SRC) was higher in males (p=0.025). Gastrointestinal involvement did not differ between groups EScSG (European Scleroderma Study Group) disease activity scores were higher in males (p=0.001). The isolated presence of antitopoisomerase-1 or anticentromere antibodies did not differ between groups. Mortality rate was similar between sexes, although male sex is a independent predictor for the death associated with ILD, SRC, arrythmiasIn multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.56, (1.35 to 1.84); p<0.001), a higher frequency of severe vascular disease (OR: 1.38 (1.11 to 1.67); p<0.001), severe digital contractures (OR:1.92(1.68 to 2,42); p<0.001), interstitial lung disease OR: 1.22 (0.9 to 1.47); p<0.001), severe heart involvement (OR: 1.56 (1.22 to 2,1); p<0.001) and SRC (OR: 3.31 (1.87 to 5620); p<0.003). In the longitudinal analysis, after a mean follow-up of 7.2 (±2.6) years, male sex was predictive of new onset of scleroderma renal crisis (HR: 3.66 (1.82 to 4.86); p=0.006) and heart failure (HR: 1.9 (1.36 to 3.18); p=0.01).Conclusion:In essence, the disease prophyle in females is that of younger age of onset, longer disease duration at first center visit, less severe peripheral vascular involvement, the most frequent cause of death being PAH. In contrast, males are older at onset, present earlier in their disease, have dcSSc, more severe peripheral vascular disease, higher mRSS, more frequent and severe ILD, more frequent heart involvement, higher risk of PAH and SRC, the most common cause of death being ILD. These results raise the point of including sex in the management and the decision-making process.References:[1]Peoples C, Medsger TA Jr, Lucas M et al Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes.J Scleroderma Relat Disord. 2016;1(2):177–240Disclosure of Interests:Laura Groseanu Speakers bureau: novartis, eli-lilly, ucb, pfizer,sandoz, Andra Balanescu Consultant of: pfizer, Speakers bureau: Abbvie, Eli-Lilly, Novartis, Pfizer, Roche, Sandoz, UCB, Violeta Bojinca Speakers bureau: Eli-Lilly, Novartis, Pfizer, Daniela Opris-Belinski Speakers bureau: Abbvie, Eli-Lilly, Novartis, Pfizer, Roche, Ioana Saulescu Speakers bureau: Eli-Lilly, Pfizer, Diana Mazilu: None declared, Sanziana Daia-Iliescu Speakers bureau: sandoz, Andreea Borangiu: None declared, Florian Berghea Paid instructor for: abbvie, Speakers bureau: gideon richter, egis, novartis,ucb, cosmin-laurentiu constantinescu: None declared, CLAUDIA COBILINSCHI Speakers bureau: novartis, Maria Magdalena Negru: None declared, mihai abobului Speakers bureau: gideon richter, Ruxandra Ionescu Consultant of: Consulting fees from Abbvie, Eli-Lilly, Novartis, Pfizer, Roche, Sandoz, Speakers bureau: Consulting and speaker fees from Abbvie, Eli-Lilly, Novartis, Pfizer, Roche, Sandoz

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Anti-endothelial cell antibodies in systemic sclerosis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.102400 ◽

2010 ◽

Vol 69 (2) ◽

pp. 319-324 ◽

Cited By ~ 55

Author(s):

C Mihai ◽

J W C Tervaert

Keyword(s):

Systemic Sclerosis ◽

Endothelial Cell ◽

Autoimmune Diseases ◽

Detection Method ◽

Vascular Involvement ◽

Peripheral Vascular ◽

Serum Samples ◽

Systemic Autoimmune Diseases ◽

Clinical Associations ◽

Heterogeneous Class

Anti-endothelial cell antibodies (AECA) are a heterogeneous class of antibodies whose role in the pathogenesis of autoimmune diseases with vascular involvement has been extensively studied. Systemic sclerosis (SSc) is one of the systemic autoimmune diseases in which endothelial dysfunction is well defined and important in the development of the disease. AECA are present in the serum samples of many patients with SSc. Depending on the detection method and on patient selection, 22–86% of patients test positive for AECA. Among the demonstrated clinical associations, lung and peripheral vascular involvement are the most common. In this paper, the methods of detection, various molecular specificities and the possible pathogenic mechanisms of AECA in SSc are reviewed.

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Reassessing the Role of the Active TGF-β1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations

Disease Markers ◽

10.1155/2016/6064830 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 13

Author(s):

Andréa Tavares Dantas ◽

Sayonara Maria Calado Gonçalves ◽

Anderson Rodrigues de Almeida ◽

Rafaela Silva Guimarães Gonçalves ◽

Maria Clara Pinheiro Duarte Sampaio ◽

...

Keyword(s):

Systemic Sclerosis ◽

Clinical Manifestations ◽

Serum Levels ◽

Vascular Involvement ◽

Digital Ulcers ◽

Serum Samples ◽

Peripheral Blood Mononuclear ◽

Pbmc Culture ◽

Significant Difference ◽

Skin Biopsies

Objective. To determine active TGF-β1 (aTGF-β1) levels in serum, skin, and peripheral blood mononuclear cell (PBMC) culture supernatants and to understand their associations with clinical parameters in systemic sclerosis (SSc) patients.Methods. We evaluated serum samples from 56 SSc patients and 24 healthy controls (HC). In 20 SSc patients, we quantified spontaneous or anti-CD3/CD28 stimulated production of aTGF-β1 by PBMC. The aTGF-β1 levels were measured by ELISA. Skin biopsies were obtained from 13 SSc patients and six HC, and TGFB1 expression was analyzed by RT-PCR.Results. TGF-β1 serum levels were significantly higher in SSc patients than in HC (p< 0.0001). Patients with increased TGF-β1 serum levels were more likely to have diffuse subset (p= 0.02), digital ulcers (p= 0.02), lung fibrosis (p< 0.0001), positive antitopoisomerase I (p= 0.03), and higher modified Rodnan score (p= 0.046). Most of our culture supernatant samples had undetectable levels of TGF-β1. No significant difference in TGFB1 expression was observed in the SSc skin compared with HC skin.Conclusion. Raised active TGF-β1 serum levels and their association with clinical manifestations in scleroderma patients suggest that this cytokine could be a marker of fibrotic and vascular involvement in SSc.

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Characterization and clinical implications of peripheral arterial involvement in transthyretin cardiac amyloidosis cardiomyopathy

European Heart Journal ◽

10.1093/ehjci/ehaa946.3247 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

K Stamatelopoulos ◽

D Delialis ◽

D Bampatsias ◽

M.E Tselegkidi ◽

I Petropoulos ◽

...

Keyword(s):

Risk Factors ◽

Clinical Significance ◽

Vascular Involvement ◽

Control Group ◽

Peripheral Vascular ◽

Cvd Risk Factors ◽

Wave Reflections ◽

Cvd Risk ◽

Arterial Involvement ◽

Peripheral Arterial

Abstract Background The sporadic form of transthyretin amyloidosis cardiomyopathy (ATTR-CM) is underdiagnosed but its prevalence is increasing due to the aging population. Given the poor prognosis of ATTR-CM understanding the underlying pathophysiologic mechanisms of the disease is imperative in order to improve strategies for early diagnosis and risk stratification and to develop new effective therapeutic options. ATTR-CM is associated with hypotension and there is preliminary experimental evidence of vascular involvement but its presence and clinical significance remains unknown. Purpose To characterize peripheral arterial involvement and explore its clinical role in ATTR-CM. Methods We consecutively recruited 28 previously untreated patients with newly diagnosed ATTR-CM and 34 elderly controls >70 years old, without ATTR-CM or heart failure. In both groups, flow-mediated dilatation (FMD) and intima-media thickness (IMT) in the carotid arteries were measured by high-resolution ultrasonography as markers of peripheral vascular reactivity and of subclinical atherosclerosis, respectively. Carotid-femoral pulse wave velocity (PWV) was measured as a marker of arterial stiffness. Aortic blood pressure (BP) and augmentation index (AI) using applanation tonometry were measured as markers of arterial wave reflections, peripheral arterial resistance and central hemodynamics. Echocardiography was performed in all ATTR patients. All cardiovascular (CV) measurements were performed before administration of any ATTR-specific therapy. Results ATTR patients were older and had lower prevalence of hypertension and male gender (p<0.05 for all) than the control group. Aortic and peripheral BP (p=0.016–0.088) and AI (p=0.003) were lower in ATTR patients. IMT in the common (cc) and internal carotid (ic) as well as in the carotid bulb (cb) were significantly higher in ATTR patients (p=0.001–0.042). After multivariable adjustment for traditional CV disease (CVD) risk factors, the ATTR group was independently associated with AI and IMT in cc, cb and ic (p<0.05 for all). In a subgroup of subjects with similar age between groups (n=13 and n=33 and 74.5±2.9 vs. 75.6±3.6 years, for ATTR vs. controls, respectively) differences in AI and cbIMT remained significant. Interestingly, AI was strongly and inversely associated with interventricular wall thickness (IVwt) in ATTR patients (spearman rho=−0.651, p=0.001). After adjustment for traditional CVD risk factors this association remained significant. Conclusion ATTR-CM is associated with lower aortic wave reflections, which correlate with more advanced structural cardiac disease, as assessed by IVwt. Further, ATTR-CM patients present accelerated subclinical carotid atherosclerosis as compared to elderly control subjects. These findings suggest that in ATTR-CM there is disease-specific peripheral vascular involvement in parallel to cardiac involvement. The clinical significance of these findings merits further investigation. Funding Acknowledgement Type of funding source: None

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AB0608 CARDIAC VESSELS CALCIFICATION IN A COHORT OF SYSTEMIC SCLEROSIS PATIENTS: POSSIBLE ROLE IN VASCULOPATHY AND HEART ABNORMALITIES.

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5746 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1600.2-1600

Author(s):

S. Sciacca ◽

C. Rotondo ◽

A. Corrado ◽

L. Giardullo ◽

S. Stefania ◽

...

Keyword(s):

Uric Acid ◽

Systemic Sclerosis ◽

Disease Duration ◽

Vascular Complications ◽

Hypovitaminosis D ◽

Older Age ◽

Vascular Involvement ◽

Cvd Risk ◽

1 John ◽

The Impact

Background:Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Myocardial calcifications have been related with cardiovascular diseases (CVD) such as focal wall motion abnormalities and arrhythmias. The impact of vascular calcifications is under investigation in order to define the risk of cardiovascular events. The relationship between cardiac calcification and systemic sclerosis (SSc) has not been investigated.Objectives:The aim of the study is to evaluate the frequency of different patterns of cardiac calcification in SSc patients, and to correlate them to other CVD risk factors.Methods:We analyzed thoracic-CT scanners of 35 SSc patients (88% female, aged 47,8 ys ±12,9, disease duration 12,8 ys ±9) to determine the location and extension of vascular and cardiac calcification. All recruited patients fulfilled the 2013 ACR-EULAR classification criteria for SSc. No one patients had renal failure, cardiomyopathy, myocarditis, history of cardiac surgery or radiotherapy.Results:We found myocardial vessels calcifications (MCv) in 37% SSc patients, aortic wall calcifications (ACw)in 60% SSc patients, cardiac valve calcifications (VC) in 28% SSc patient and heart wall calcifications (HCw) in 20%.The SSc patients with almost one calcification had older age (65±9,8 ys vs 50±8,8 ys; p=0,0001) and higher values of circulating NTproBNP (336,9±351,9 vs 144,2±107,8; p=0,04) compared to those without.In particular, the SSc patients with MCv had and uric acid (5,3 ±1,5 vs 4,1 ±1,3; p=0,05), higher rate of PAH (25% vs 0%; p=0,037), arrhythmia (38,5% vs 9%; p=0,036) and higher prevalence of CENP-B antibodies(46% vs 4%; p=0,01) compared to patients without MCv.Patients with HCw had lower C reactive protein (0,16 ±0,10 vs 0,7±0,7; p=0,008) compared to those without HCw. No differences in the rate of heart and vascular complications of SSc were observed.The SSc patients with ACw had higher frequency of arrhythmia (33% vs 0%; p=0,016) and longer disease duration (15,5 y ±9,9 vs 8,8 ±5,8; p=0,03).The SSc patients with VC had higher rate of PAH (33%vs0%; p=0,003) and uric acid (6±0,5vs3,8±1,2 p=0,0001).Regression analysis excluded any association with gender, BMI, systemic arterial hypertension, steroid therapy, hypovitaminosis D or smoke habit. No cardiovascular event was recorded in one year of observation.Conclusion:All patterns of calcifications may be related mostly with the older age. Myocardial vessels calcifications have been found in a high percentage of SSc patients and in particular in those with PAH and positive for anti CENP-B. Furthermore, myocardial vessels calcifications could be associated to the higher occurrence of arrhythmia. More studied are needed to assess the importance of vascular calcification as a part of the vascular involvement in SSc.References:[1]John W. Nance Jr. MD. Myocardial calcifications: Pathophysiology, etiologies, differential diagnoses, and imaging findings. Journal of Cardiovascular Computed Tomography 9 (2015) 58 e 67.[2]Pagkopoulou E, Poutakidou M. Cardiovascular risk in systemic sclerosis: Micro- and Macro-vascular involvement. Indian J Rheumatol 2017;12, Suppl S1:211-7[3]Plastiras SC, Toumanidis ST. Systemic sclerosis: the heart of the matter. Hellenic J Cardiol. 2012;53(4):287–300.Disclosure of Interests:None declared

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Potential Biomarkers in Systemic Sclerosis: A Literature Review and Update

Journal of Clinical Medicine ◽

10.3390/jcm9113388 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3388

Author(s):

Akira Utsunomiya ◽

Noritaka Oyama ◽

Minoru Hasegawa

Keyword(s):

Systemic Sclerosis ◽

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Surfactant Protein ◽

Vascular Involvement ◽

Surfactant Protein D ◽

Plasma Cytokines ◽

Precise Diagnosis ◽

Pulmonary Arterial ◽

Chronic Autoimmune Disease

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by dysregulation of the immune system, vascular damage, and fibrosis of the skin and internal organs. Patients with SSc show a heterogeneous phenotype and a range of clinical courses. Therefore, biomarkers that are helpful for precise diagnosis, prediction of clinical course, and evaluation of the therapeutic responsiveness of disease are required in clinical practice. SSc-specific autoantibodies are currently used for diagnosis and prediction of clinical features, as other biomarkers have not yet been fully vetted. Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D), and CCL18 have been considered as serum biomarkers of SSc-related interstitial lung disease. Moreover, levels of circulating brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) can provide diagnostic information and indicate the severity of pulmonary arterial hypertension. Assessment of several serum/plasma cytokines, chemokines, growth factors, adhesion molecules, and other molecules may also reflect the activity or progression of fibrosis and vascular involvement in affected organs. Recently, microRNAs have also been implicated as possible circulating indicators of SSc. In this review, we focus on several potential SSc biomarkers and discuss their clinical utility.

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Fli1 Deficiency Induces CXCL6 Expression in Dermal Fibroblasts and Endothelial Cells, Contributing to the Development of Fibrosis and Vasculopathy in Systemic Sclerosis

The Journal of Rheumatology ◽

10.3899/jrheum.161092 ◽

2017 ◽

Vol 44 (8) ◽

pp. 1198-1205 ◽

Cited By ~ 13

Author(s):

Takashi Taniguchi ◽

Yoshihide Asano ◽

Kouki Nakamura ◽

Takashi Yamashita ◽

Ryosuke Saigusa ◽

...

Keyword(s):

Endothelial Cells ◽

Systemic Sclerosis ◽

Mrna Expression ◽

Target Genes ◽

Critical Role ◽

Dermal Fibroblasts ◽

Vascular Involvement ◽

Digital Ulcers ◽

Mrna Levels ◽

Predisposing Factor

Objective.CXCL6, a chemokine with proangiogenic property, is reported to be involved in vasculopathy associated with systemic sclerosis (SSc). We investigated the contribution of CXCL6 to SSc development by focusing on the association of friend leukemia virus integration 1 (Fli1) deficiency, a potential predisposing factor of SSc, with CXCL6 expression and clinical correlation of serum CXCL6 levels.Methods.mRNA levels of target genes and the binding of Fli1 to the CXCL6 promoter were evaluated by quantitative reverse transcription-PCR and chromatin immunoprecipitation, respectively. Serum CXCL6 levels were determined by ELISA.Results.FLI1 siRNA significantly enhanced CXCL6 mRNA expression in human dermal fibroblasts and human dermal microvascular endothelial cells, while Fli1 haploinsufficiency significantly suppressed CXCL6 mRNA expression in murine peritoneal macrophages stimulated with lipopolysaccharide. Supporting a critical role of Fli1 deficiency to induce SSc-like phenotypes, CXCL6 mRNA expression was higher in SSc dermal fibroblasts than in normal dermal fibroblasts. Importantly, Fli1 bound to the CXCL6 promoter in dermal fibroblasts, endothelial cells, and THP-1 cells. In patients with SSc, serum CXCL6 levels correlated positively with the severity of dermal and pulmonary fibrosis and were elevated in association with cardiac and pulmonary vascular involvement and cutaneous vascular symptoms, including Raynaud phenomenon, digital ulcers (DU)/pitting scars, and telangiectasia. Especially, serum CXCL6 levels were associated with DU/pitting scars and heart involvement by multiple regression analysis.Conclusion.CXCL6 expression is upregulated by Fli1 deficiency in fibroblasts and endothelial cells, potentially contributing to the development of fibrosis and vasculopathy in the skin, lung, and heart of SSc.

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