Lysyl oxidase—a possible role in systemic sclerosis–associated pulmonary hypertension: a multicentre study

Abstract Objective Lysyl oxidase (LOX) is an extracellular enzyme that cross-links collagen fibrils. LOX was found to be increased in serum of SSc patients and was suggested to be related to skin fibrosis, yet a vascular source of LOX has been demonstrated in idiopathic pulmonary arterial hypertension (iPAH). We aimed to validate elevated LOX serum levels in SSc and to study its correlation with clinical characteristics and investigate its main source at the tissue level. Methods A total of 86 established SSc patients were compared with 86 patients with very early diagnosis of systemic sclerosis (VEDOSS), 110 patients with primary RP (PRP) and 80 healthy controls. LOX serum levels were determined by ELISA. Five lung and 12 skin biopsies from SSc patients were stained for LOX and compared with controls. Results Serum levels of LOX in SSc were significantly higher than in VEDOSS, PRP and healthy controls (P < 0.001). LOX inversely correlated with the diffusing capacity of the lung for carbon monoxide diffusing capacity (DLCO) in diffuse SSc (r = −0.376, P = 0.02). Patients with moderate to severe estimated systolic PAH had higher LOX levels (P < 0.01). Lung biopsies demonstrated intense LOX staining in SSc patients with PAH that was predominantly located in the endothelium of the remodelled pulmonary vessels. Conclusion Serum LOX levels are increased in established SSc and inversely correlate with the DLCO. LOX is elevated in patients with moderate to severe PAH and is located in the proliferating endothelium in lung arterioles, suggesting a possible role for LOX in SSc-associated PAH.

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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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HLA-G Expression in the Skin of Patients with Systemic Sclerosis

The Journal of Rheumatology ◽

10.3899/jrheum.080552 ◽

2009 ◽

Vol 36 (6) ◽

pp. 1230-1234 ◽

Cited By ~ 24

Author(s):

ISABELA J. WASTOWSKI ◽

PERCIVAL D. SAMPAIO-BARROS ◽

ELIANE M.I. AMSTALDEN ◽

GUSTAVO MARTELLI PALOMINO ◽

JOÃO FRANCISCO MARQUES-NETO ◽

...

Keyword(s):

Systemic Sclerosis ◽

Control Sample ◽

Healthy Controls ◽

Skin Disorders ◽

Disease Prognosis ◽

Laboratory Variables ◽

Skin Biopsies ◽

Dermal Cells

Objective.To determine HLA-G expression in skin biopsies from patients with systemic sclerosis (SSc), and its association with epidemiological, clinical, and laboratory variables and survival.Methods.Paraffin-embedded skin biopsies obtained from 21 SSc patients (14 limited SSc, 7 diffuse SSc) and from 28 healthy controls were studied. HLA-G expression was evaluated by immunohistochemistry.Results.HLA-G molecules were detected in 57% of skin biopsies from patients with SSc (9 from limited SSc, 3 from diffuse SSc), whereas no control sample expressed HLA-G (p = 0.000004). In patients, HLA-G molecules were consistently observed within epidermal and some dermal cells. HLA-G expression was associated with a lower frequency of vascular cutaneous ulcers (p = 0.0004), telangiectasias (p = 0.008), and inflammatory polyarthralgia (p = 0.02). After a 15-year followup, SSc patients who exhibited HLA-G survived longer than patients who did not.Conclusion.HLA-G is expressed in skin biopsies from patients with SSc, and this is associated with a better disease prognosis. This suggests a modulatory role of HLA-G in SSc, as observed in other skin disorders.

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Female sexual dysfunction in systemic sclerosis: The role of endothelial growth factor and endostatin

Journal of Scleroderma and Related Disorders ◽

10.1177/2397198318776593 ◽

2018 ◽

Vol 4 (1) ◽

pp. 71-76 ◽

Cited By ~ 1

Author(s):

Antonietta Gigante ◽

Luca Navarini ◽

Domenico Margiotta ◽

Biagio Barbano ◽

Antonella Afeltra ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Blood Flow ◽

Systemic Sclerosis ◽

Growth Factor ◽

Sexual Dysfunction ◽

Resistive Index ◽

Serum Levels ◽

Vascular Endothelial ◽

Healthy Controls ◽

Endothelial Growth Factor

Introduction: Since female sexual dysfunction in systemic sclerosis women is multifactorial, we can assume that vascular damage may play a role in pathogenesis. The aim of the study was to evaluate the clitoral blood flow, by Echo color Doppler, and to correlate it whit serum levels of vascular endothelial growth factor and endostatin. Methods: A total of 15 systemic sclerosis women and 10 healthy controls matched for sex and age were enrolled in this study. Serum VEGF165 and endostatin levels were determined in systemic sclerosis patients by commercial enzyme-linked immunosorbent assay kit. Clitoral blood flow was measured by Doppler indices of clitoral artery: pulsatile index, resistive index, and systolic/diastolic ratio were measured. Sexual dysfunction was assessed by Female Sexual Function Index. Results: Vascular endothelial growth factor (pg/mL) and endostatin (ng/mL) median values were significantly higher in systemic sclerosis women than healthy controls. Resistive index and systolic/diastolic ratio median values were significantly higher in systemic sclerosis women than healthy controls. Negative correlation exists between serum levels of vascular endothelial growth factor and resistive index (r = −0.55, p < 0.05). Positive correlation was observed between serum levels of endostatin and resistive index (r = 0.70, p < 0.01) and systolic/diastolic ratio (r = 0.77, p < 0.01). Discussion: We can suppose that clitoral blood flow in systemic sclerosis women is reduced not only for macro- and microvascular damage but also for impaired angiogenesis.

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Serum Levels of Galectin-3: Possible Association with Fibrosis, Aberrant Angiogenesis, and Immune Activation in Patients with Systemic Sclerosis

The Journal of Rheumatology ◽

10.3899/jrheum.110755 ◽

2012 ◽

Vol 39 (3) ◽

pp. 539-544 ◽

Cited By ~ 26

Author(s):

TAKASHI TANIGUCHI ◽

YOSHIHIDE ASANO ◽

KANAME AKAMATA ◽

SHINJI NODA ◽

YURI MASUI ◽

...

Keyword(s):

Systemic Sclerosis ◽

Immune Activation ◽

Developmental Process ◽

Systolic Pressure ◽

Serum Levels ◽

Digital Ulcers ◽

Healthy Controls ◽

Ventricular Systolic Pressure ◽

Multifunctional Protein ◽

Galectin 3

Objective.Galectin-3 is a multifunctional protein implicated in a variety of biological processes including fibrosis, angiogenesis, and immune activation, all of which are associated with the development of systemic sclerosis (SSc). We investigated the clinical significance of serum galectin-3 levels in SSc.Methods.Serum galectin-3 levels were determined by a specific ELISA in 58 patients with SSc and 19 healthy controls.Results.Serum galectin-3 levels were significantly lower in patients with diffuse cutaneous SSc (dcSSc) than in controls (3.29 ± 3.27 ng/ml vs 4.91 ± 2.67 ng/ml, respectively; p < 0.05), while being comparable between limited cutaneous SSc (3.70 ± 2.39 ng/ml) and healthy controls. In dcSSc, serum galectin-3 levels significantly correlated with total skin score (r = 0.45, p < 0.05). Serum galectin-3 levels were significantly decreased in early dcSSc (disease duration < 1 year; 1.64 ± 1.74 ng/ml; p < 0.05), but not in mid-stage dcSSc (1 to 6 years; 3.22 ± 3.16 ng/ml) or late-stage dcSSc (> 6 years; 4.86 ± 4.10 ng/ml), compared with controls. Serum galectin-3 levels were higher in SSc patients with both digital ulcers (DU) and elevated right ventricular systolic pressure (RVSP) than in those without each symptom (DU: 5.44 ± 3.74 ng/ml vs 2.99 ± 2.36 ng/ml, p < 0.05; elevated RVSP: 4.44 ± 3.14 ng/ml vs 2.82 ± 2.64 ng/ml, p < 0.05).Conclusion.Galectin-3 may be related to the developmental process of skin sclerosis in dcSSc and of DU and pulmonary vascular involvements in total SSc.

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LIM and SH3 Protein 1 Stands for a Bio-Marker for Cholangiocarcinoma Detection

10.21203/rs.3.rs-51777/v1 ◽

2020 ◽

Author(s):

Ning Wang ◽

Yanni Li ◽

Yanfang Zheng ◽

Huoming Chen ◽

Xiaolong Wen ◽

...

Keyword(s):

Serum Level ◽

Roc Curve ◽

Serum Levels ◽

Diagnostic Value ◽

Tissue Level ◽

Healthy Controls ◽

Roc Curve Analysis ◽

Chi Square ◽

Chi Square Test ◽

Auc Value

Abstract Background: LIM and SH3 protein 1 (LASP-1) has been demonstrated to be overexpression in several types of cancers. The aim of this study was to verify the serum level of LASP-1 and investigate its diagnostic value in cholangiocarcinoma (CCA) patients.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of LASP-1 in CCA patients and healthy controls. The correlation of LASP-1 expression with clinicopathological characteristic of CCA patients was analyzed via Chi-square test. Receiver operating characteristic (ROC) curve was built to evaluate the diagnostic value of serum LASP-1 in CCA.Results: Serum levels of LASP-1 were upregulated in CCA compared with healthy controls (P<0.01). And the serum level and tissue level of LASP-1 mRNA exhibited significant correlation (R=0.454, P=0.000). Serum expression of LASP-1 was closely associated with lymph node metastasis (P=0.018) and TNM stage (P=0.021). ROC curve analysis revealed that serum LASP-1 was of great value in differentiating CCA patients from healthy individuals. The area under the ROC curve (AUC) value was 0.879 corresponding with a sensitivity of 81.9% and a specificity of 79.6%.Conclusions: Serum LASP-1 might be an useful diagnostic biomarker for CCA.

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Serum Endoglin Levels in Patients Suffering from Systemic Sclerosis and Elevated Systolic Pulmonary Arterial Pressure

International Journal of Rheumatology ◽

10.1155/2010/969383 ◽

2010 ◽

Vol 2010 ◽

pp. 1-6 ◽

Cited By ~ 9

Author(s):

Paola Ximena Coral-Alvarado ◽

Maria Fernanda Garces ◽

Jorge Eduardo Caminos ◽

Antonio Iglesias-Gamarra ◽

José Félix Restrepo ◽

...

Keyword(s):

Systemic Sclerosis ◽

Arterial Pressure ◽

Pulmonary Arterial Pressure ◽

Serum Levels ◽

Cross Sectional Study ◽

Healthy Controls ◽

Cross Sectional ◽

Systolic Pulmonary Arterial Pressure ◽

Healthy Control ◽

Pulmonary Arterial

Background. Pulmonary arterial hypertension (PAH) is the main cause of morbimortality in systemic sclerosis (SSc). Increased Eng expression has been demonstrated in SSc patients.Objective. Ascertaining serum levels of Eng in SSc patients with and without elevated systolic pulmonary arterial pressure (sPAP) and comparing them with that of healthy volunteers.Methods. A cross-sectional study was carried out. A commercial ELISA kit was used for measuring serum concentrations of Eng in 60 subjects: 40 patients with SSc with and without elevated sPAP, compared to 20 healthy control subjects. Elevated sPAP was detected by echocardiogram.Results. No association between positive Eng and elevated sPAP was found when compared to the SSc without elevated sPAP group (OR=2.85; 0.65–12.88 95% CI;P=.11); however, an association was found between positive Eng and elevated sPAP compared to healthy controls (OR=23.22; 2.46–1050.33 95% CI;P=.001), and weak association was found between the positive Eng with SSc without elevated sPAP group compared to healthy controls (OR=8.14, 0.8–393.74 95% CI;P=.046).Conclusion. Raised serum levels of Eng in SSc patients compared to healthy controls were found, suggesting a role for Eng in SSc vasculopathy and not just in elevated sPAP. However, prospective studies are needed to verify such observations.

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AB0406 ASSOCIATION OF ENDOTHELIN-1 WITH PULSE WAVE VELOCITY IN SYSTEMIC SCLEROSIS PATIENTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.304 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1231.2-1232

Author(s):

A. Alvarez de Cienfuegos ◽

L. Cantero-Nieto ◽

J. A. García-Gómez ◽

J. L. Callejas-Rubio ◽

J. Martin Ibanez ◽

...

Keyword(s):

Systemic Sclerosis ◽

Connective Tissue ◽

Arterial Stiffness ◽

Pulse Wave Velocity ◽

Wave Velocity ◽

Pulse Wave ◽

Serum Levels ◽

Healthy Controls ◽

Endothelin 1 ◽

Female Patients

Background:Systemic sclerosis (SSc) is a multisystemic disease featured by vascular and immunological disorders along with an excessive accumulation of the components of the connective tissue that cause cutaneous sclerosis and fibrosis of different organs. The occurrence of endothelial dysfunction together with fibrosis indicates that endothelial cell-derived factors, such as endothelin-1 (ET-1), may have an important role in the pathogenesis of SSc. The upregulation of ET-1 activates inflammatory cells and leads to nitric oxide synthase inhibition associated with arterial stiffness.Objectives:The purpose of this study was to evaluate ET-1 serum levels in women with systemic sclerosis (SSc) compared with healthy controls and to examine possible associations between ET-1 and markers of arterial stiffness.Methods:This cross-sectional study was performed in San Cecilio Hospital, Granada (Spain) from November 2017 to May 2019. Sixty-two women with SSc and 62 age and sex matched healthy controls were enrolled in this study. Pulse Wave Velocity (PWV) was measured non-invasively along the carotid–femoral arterial segment. Serum ET-1 was analysed using indirect enzyme-linked immunosorbent assay (ELISA).Results:A total of 62 female patients were included in our study, with a mean (SD) age of 53 ± 10 years. The majority were Caucasian (90.5%). The mean disease duration was 8.8 ± 6.9 years. Forty-four (70.9%) patients had a limited form of the disease and 18 (29.1%) had a diffuse form.There was a significant difference in ET-1 serum levels between SSc female patients and healthy controls (28.4 ± 10.6 vs. 21.1 ± 11.7 pg/ml, p = 0.001). Serum levels of ET-1 were positively associated with PWV (r = 0.26, p < 0.05), within the study group. In addition, in the linear regression model, higher ET-1 concentrations were associated with higher PWV [β = 0.03 95% CI (0.001, 0.060); p < 0.05].Conclusion:This study shows that ET-1 serum levels are associated with PWV in women with SSc. Therefore, drugs that block ET-1 may be effective in reducing large artery stiffness in women with SSc, and thus cardiovascular risk.References:[1]LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, bubsets and pathogenesis. J Rheumatol 1988; 15(2):202-205.[2]Shi-Wen X, Denton CP, Dashwood MR, Holmes AM, Bou-Gharios G, Pearson JD, et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol 2001; 116(3):417–425.[3]Heintz B, Dörr R, Gillessen T, Walkenhorst F, Krebs W, Hanrath P, et al. Do arterial endothelin 1 levels affect local arterial stiffness?. Am Heart J 1993; 126 (4): 987–989.[4]McEniery CM, Qasem A, Schmitt M, Avolio AP, Cockcroft JR, Wilkinson IB. Endothelin-1 regulates arterial pulse wave velocity in vivo. J Am Coll Cardiol 2003; 42 (11): 1975–1981.Disclosure of Interests:None declared

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Elevated IL-38 Serum Levels in Newly Diagnosed Multiple Sclerosis and Systemic Sclerosis Patients

Medical Principles and Practice ◽

10.1159/000510915 ◽

2020 ◽

pp. 1-8

Author(s):

Maryam Zarrabi ◽

Mohammadali Nazarinia ◽

Abbas Rahimi Jaberi ◽

Nasser Gholijani ◽

Zahra Amirghofran

Keyword(s):

Multiple Sclerosis ◽

Systemic Sclerosis ◽

Serum Levels ◽

Healthy Controls ◽

Newly Diagnosed ◽

Inflammatory Conditions ◽

Probable Role ◽

Previously Treated ◽

Inflammatory Profile

Objective: Interleukin (IL)-38 is a newly discovered member of the IL-1 cytokine family with a proposed anti-inflammatory profile. We studied the probable role of this cytokine in the pathogenesis of two autoimmune diseases: multiple sclerosis (MS) and systemic sclerosis (SSc). Subjects and Methods: A total of 87 MS patients and 86 SSc patients (40 new and recently untreated cases and 46 treated cases) were selected for this study. Eighty-seven and 80 age- and sex-matched healthy subjects were included as controls for MS and SSc, respectively. Clinical and paraclinical features of the patients were recorded at the time of sampling. Serum IL-38 was measured by ELISA. Results: Levels of serum IL-38 did not significantly differ between the total MS or SSc patients compared to controls. However, levels of IL-38 were significantly higher in newly diagnosed patients of MS (206.43 ± 38.97 pg/mL, p < 0.0001) than in those previously treated (158.04 ± 39.45 pg/mL). Similarly, new/recently untreated cases of SSc patients showed increased IL-38 levels (185.19 ± 36.27 pg/mL, p = 0.001) compared to treated patients (166.82 ± 33.08 pg/mL). IL-38 levels in newly diagnosed MS patients (p = 0.007) and new/recently untreated SSc patients (p = 0.032) were significantly higher than those in healthy controls. Conclusion: The higher serum levels of IL-38 in new or recently untreated cases of MS and SSc patients than in treated patients and healthy controls suggest the possible role of this cytokine in the development of these diseases or as part of a feedback loop to attenuate the inflammatory conditions in early stages of these diseases.

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Use of Serum Clara Cell 16-kDa (CC16) Levels as a Potential Indicator of Active Pulmonary Fibrosis in Systemic Sclerosis

The Journal of Rheumatology ◽

10.3899/jrheum.100591 ◽

2011 ◽

Vol 38 (5) ◽

pp. 877-884 ◽

Cited By ~ 32

Author(s):

MINORU HASEGAWA ◽

MANABU FUJIMOTO ◽

YASUHITO HAMAGUCHI ◽

TAKASHI MATSUSHITA ◽

KATSUMI INOUE ◽

...

Keyword(s):

Longitudinal Study ◽

Systemic Sclerosis ◽

Pulmonary Fibrosis ◽

Lupus Erythematosus ◽

Characteristic Curve ◽

Serum Levels ◽

Clara Cell ◽

Inactive Disease ◽

Surfactant Protein D ◽

Healthy Controls

Objective.To clarify the clinical significance of concentrations of serum Clara cell 16-kDa protein (CC16; previously denoted CC10) in the diagnosis and monitoring of pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc); and to compare CC16 levels with levels of the current most reliable serum markers for PF, such as Krebs von den Lungen-6 (KL-6) antigen and surfactant protein-D (SP-D).Methods.Serum levels of CC16, KL-6, and SP-D were determined by ELISA in 92 patients with SSc, 20 patients with systemic lupus erythematosus (SLE), and 20 healthy controls. In a retrospective longitudinal study, correlation of serum CC16 levels with the activity of PF was assessed in 16 SSc patients with PF.Results.Although CC16 levels were higher in patients with SSc than in SLE patients or healthy controls, the difference was not significant. Increased serum CC16 levels were associated with involvement of PF, especially active PF, as well as KL-6 and SP-D. Receiver operating characteristic curve analysis revealed that the utility of CC16 is slightly inferior to KL-6, but was comparable with that of SP-D for detecting PF in patients with SSc. In the longitudinal study, serum levels of CC16, KL-6, and SP-D were significantly decreased in the inactive disease phase compared to the active disease phase.Conclusion.CC16 levels can be used as a potential serum biomarker for PF in addition to KL-6 and SP-D in patients with SSc.

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Serum lysyl oxidase concentration increases in long-standing systemic sclerosis: Can lysyl oxidase change over time?

Archives of Rheumatology ◽

10.46497/archrheumatol.2022.8977 ◽

2021 ◽

Author(s):

Mohammad Hassan Jokar1† ◽

Simin Jafaripour2† ◽

Nafiseh Abdollahi1† ◽

Maryam Nazemipour ◽

Maliheh Moradzadeh ◽

...

Keyword(s):

Systemic Sclerosis ◽

Lysyl Oxidase ◽

Disease Onset ◽

Significant Negative Correlation ◽

Healthy Controls ◽

Recent Onset ◽

Modified Rodnan Skin Score ◽

The Relationship ◽

Circulating Levels ◽

Onset Group

Objectives: This study aims to investigate the association of serum lysyl oxidase (LOX) levels with systemic sclerosis (SSc), to examine the relationship between LOX and disease onset, and to evaluate the probable effects of hyperlipidemia on the circulating levels of LOX among patients with SSc. Patients and methods: Between May 2017 and November 2018, a total of 39 patients with SSc (2 males, 37 females; mean age: 46.6±12.3 years; range, 18 to 65 years) and 35 healthy controls (4 males, 31 females; mean age: 43.1±14.1 years; range, 18 to 65 years) were included. Serum LOX concentration was measured using the enzyme-linked immunoassay in triplicate. Results: We found higher levels of serum LOX in patients with SSc compared to healthy controls. There was a significant relationship between serum LOX levels and disease onset. Patients with long-standing disease demonstrated increased levels of LOX in the blood compared to the recent-onset group. Hyperlipidemia did not have a significant effect on circulating levels of LOX. There was a significant negative correlation between LOX levels and modified Rodnan Skin Score in the subgroup of patients with skin involvement only and in patients without gastrointestinal involvement. Conclusion: Our study findings show an increased level of LOX protein level in the blood of patients diagnosed with SSc. Hyperlipidemia seems not to affect the concentrations of LOX in the peripheral blood of patients with SSc.

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