The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019
RESEARCH ARTICLE

Serum Level of Endothelial Cell-Specific Molecule -1 (ESM -1) as a New Potential Biomarker for Rheumatoid Arthritis Disease Activity



Noha Abdelsalam1, Ashraf Hussein Mohamed2, *, Sameh Abdellatif 3, Eslam Eid2, Ehsan Mohamed Rizk4, Mohamed Anies Rizk5
1 Lecturer of Internal Medicine, Mansoura University, Mansoura, Egypt
2 Assistant professor of Internal Medicine, Mansoura University, Mansoura, Egypt
3 Assistant professor of Rheumatology and Rehabilitation, Al-Azhar University, Cairo, Egypt
4 Assistant professor of Clinical Pathology, Mansoura University, Mansoura, Egypt
5 Lecturer of Clinical Pathology, Mansoura University, Mansoura, Egypt

Abstract

Background:

Rheumatoid arthritis is a chronic inflammatory autoimmune disease characterized by destruction of the joint cartilage and bone. Endothelial dysfunction (ED) in RA may be related to disease activity. Our objective is to explore serum levels of endothelial cell-specific molecule-1 (ESM-1) as a biomarker for RA disease activity.

Methods:

A cross-sectional study was carried out and included 83 adult patients with RA, in addition to 20 healthy subjects (age and sex-matched) as a control group. Based on Disease Activity Score in 28 joints (DAS-28), the patient's group was subdivided into four subgroups(remission, mild, moderate and severe disease activity state). The demographic & clinical data, BMI, DAS-28 and Serological assessment [Erythrocyte Sedimentation Rate (ESR), CRP, Rheumatoid Factor (RF) and Anti-Citrullinated Peptide Antibody (ACPA)] were recorded. ESM-1was assayed for all participants.

Results:

Serum levels of ESM1 were significantly higher in the patient group than the control group (P < 0.0001). ESM-1 serum levels were significantly higher in patients with severe disease activity subgroup compared with patients with remission and mild disease activity subgroups (P < 0.0001). ESM-1 was positively and significantly correlated with DAS-28 score, The Health Assessment Questionnaire Disability Index (HAQ-DI) and modified Larsen score (P = 0.002, 0.0001 & 0.0001 respectively).

Conclusion:

ESM-1 could be a biomarker for RA disease activity.

Keywords: Biomarker, ESM-1, Disease activity, RA, RF, ESR.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 189
Last Page: 196
Publisher Id: TORJ-12-189
DOI: 10.2174/1874312901812010189

Article History:

Received Date: 19/8/2018
Revision Received Date: 15/10/2018
Acceptance Date: 2/11/2018
Electronic publication date: 30/11/2018
Collection year: 2018

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© 2018 Abdelsalam et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Internal Medicine, Mansoura University, Mansoura, Egypt, Tel: 00201150584474; E-mail: mashraf2011@yahoo.com




1. INTRODUCTION

Rheumatoid Arthritis (RA) is a chronic auto-inflammatory disease [1Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women The New Engl J Med 2000; 342(12): 836-43.]. Evaluation of Disease progression in RA is based on certain parameters including clinical disease activity indices (e.g. DAS -28), radiological, and specific serological biomarkers. The laboratory markers, specifically Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP), are not specific and are influenced by several other variables [2Mota DA. L.M.H., dos Santos Neto, L.L. & de Carvalho, J.F.: Auto antibodies and other serological markers in rheumatoid arthritis: predictors of disease activity? Clin Rheumatol 2009; 28: 1127.[http://dx.doi.org/10.1007/s10067-009-1223-y] [PMID: 19597699] ]. Endothelial cells play a vital part in the initiation of the inflammatory process [3Pober JS, Cotran RS. The role of endothelial cells in inflammation. Transplantation 1990; 50(4): 537-44.[http://dx.doi.org/10.1097/00007890-199010000-00001] [PMID: 2219269] ]. Endothelial Dysfunction (ED) in RA may be linked to the Functional defect of endothelial progenitor cells, which are included in vasculogenesis and vascular repair [4Pompilio G, Capogrossi MC, Pesce M, et al. Endothelial progenitor cells and cardiovascular homeostasis: clinical implications. Int J Cardiol 2009; 131(2): 156-67.[http://dx.doi.org/10.1016/j.ijcard.2008.08.033] [PMID: 18823669] ]. However, the exact pathophysiological mechanisms of ED in RA are still ill-defined [5Favero G, Paganelli C, Buffoli B, Rodella LF, Rezzani R. Endothelium and its alterations in cardiovascular diseases: Life style intervention BioMed Research International 2014; 2014]. Definitely, numerous markers of endothelial cell abnormalities are linked with the inflammatory progression seen in RA [6Spinelli FR, Di Franco M, Metere A, et al. Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis. Drug Dev Res 2014; 75: S67-9.]. Endothelial cell-specific molecule-1 (ESM-1) is a significant immunoregulator glycoprotein secreted by endothelial linings of the lungs and kidneys [7Bechard D, Gentina T, Delehedde M, et al. Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. J Biol Chem 2001; 276: 48341-9., 8Lassalle P, Molet S, Janin A, et al. ESM-1 is a novel human endothelial cell-specific molecule expressed in lung and regulated by cytokines. J Biol Chem 1996; 271: 20458-64.] and can be detected in healthy persons [9Bechard D, Meignin V, Scherpereel A, et al. Characterization of the secreted form of endothelial-cell-specific molecule 1 by specific monoclonal antibodies. J Vasc Res 2000; 37: 417-25.]. ESM-1 is used as a biomarker for endothelial cell dysfunction [10Mosevoll KA, Lindås R, Wendelbo O, Bruserud O, Reikvam H. Systemic levels of the endothelium-derived soluble adhesion molecules endocan and E-selectin in patients with suspected deep vein thrombosis. Springerplus 2014; 3: 571. [Internet].[http://dx.doi.org/10.1186/2193-1801-3-571] [PMID: 25332871] , 11Adekola H, Romero R, Chaemsaithong P, et al. 2014.] and has been identified as a key player in inflammatory conditions [12Sarrazin S, Adam E, Lyon M, et al. Endocan or endothelial cell specific molecule-1 (ESM-1): A potential novel endothelial cell marker and a new target for cancer therapy. Biochim Biophys Acta 2006; 1765(1): 25-37.[PMID: 16168566] -14Balta I, Balta S, Koryurek OM, et al. Serum endocan levels as a marker of disease activity in patients with Behçet disease. J Am Acad Dermatol 2014; 70(2): 291-6.[http://dx.doi.org/10.1016/j.jaad.2013.09.013] [PMID: 24176522] ]. Levels of ESM-1 were elevated in synovial tissue of RA patients causing angiogenesis and share in pannus formation [15Béchard D, Scherpereel A, Hammad H, et al. Human endothelial-cell specific molecule-1 binds directly to the integrin CD11a/CD18 (LFA-1) and blocks binding to intercellular adhesion molecule-1. J Immunol 2001; 167(6): 3099-106.[http://dx.doi.org/10.4049/jimmunol.167.6.3099] [PMID: 11544294] ]. Whether serum levels of ESM-1 are associated with endothelial dysfunction or disease activity in patients with RA, at this point, we were targeting to explore serum levels of ESM-1 as a new potential biomarker for RA disease activity.

2. METHODS

Our cross-sectional study was designed to include 83 adult patients with RA from OPC of rheumatology and immunology clinic, Mansoura University hospitals from June to Dec. 2016 (RA patients were identified who satisfied the 2010 ACR diagnostic criteria) [16Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010; 69(9): 1580-8.[http://dx.doi.org/10.1136/ard.2010.138461] [PMID: 20699241] ]. Exclusion criteria included the history of cancer, any history of cardiovascular disorders, hematological abnormality, any acute or other infection, a granulomatous chronic disease, Inflammatory Bowel Diseases (IBD), a metabolic disease, other autoimmune disorders, DM and anti-TNF usage (anti-TNF therapy). The study protocol had an approval from the Ethics Committee of the School of Medicine, Mansoura University (R1/16.10.06). The study cohort was divided into four subgroups according to DAS-28 score: 15 patients in remission (ACR/EULAR 2011 remission criteria [17Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423(6937): 356-61. View Article: Google Scholar: PubMed/NCBI.[http://dx.doi.org/10.1038/nature01661] [PMID: 12748655] ] (DAS-28 < 2.6), 15 patients with low disease activity (DAS28: 2.6 --3.2), 38 patients with moderate disease activity (DAS-28: 3.2--5.1) and 15 patients with high disease activity (DAS-28 > 5.1). In addition to 20 age and sex matched healthy subjects, were included as a control group. All demographic & clinical data, BMI, Disease Activity Score in 28 joints (DAS-28) and Serological assessment comprised Erythrocyte Sedimentation Rate (ESR), CRP, Rheumatoid Factor (RF) and Anti-Citrullinated Peptide Antibody (ACPA) were recorded. The Health Assessment Questionnaire Disability Index (HAQ-DI) was consisted of 20 questions regarding the limitations patients experience in performing daily physical activities [18Rau R, Herborn G. A modified version of Larsen’s scoring method to assess radiologic changes in rheumatoid arthritis. J Rheumatol 1995; 22(10): 1976-82.[PMID: 8992004] ] which were assisted for all patients in the same visit. Patients were asked how difficult it is to perform an activity on a scale of 0 (without any difficulty) to 3 (unable to do). Patients are also asked whether they need assistance or aids for the activity. X-ray scoring for disease activity using the modified version of the Larsen method [19Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum 1980; 23(2): 137-45. [PubMed].[http://dx.doi.org/10.1002/art.1780230202] [PMID: 7362664] ] was evaluated by rheumatologist and radiologist who assessed joint damage on plain films of the hand or wrist taken at the time of the study. This method analyses plain films of eight proximal interphalangeal joints, two interphalangeal thumb joints, 10 metacarpophalangeal joints, and both wrists. The degree of joint damage was rated as follows: grade 0, normal; grade 1, soft tissue swelling, joint space narrowing, and subchondral osteopenia; grade 2, bone erosion with destruction of < 25% of the joint space; grade 3, 26% to 50% joint space destruction; grade 4, 51% to 75% destruction; and grade 5, > 75% destruction of the joint space. The sum of all scores equaled 110 points.

Serum samples were collected from the patients and controls in order to assay ESM-1. RF IgM was measured by nephelometry, with a level of 20 IU/ml considered positive. ACPA was measured using an enzyme-linked immunosorbent assay with a level of 5U/ml considered positive. ESR and CRP (high sensitive) were measured immediately after blood collection.

2.1. Quantitative Determination of ESM-1 by ELISA Technique.

2.1.1. RF Positive Serum Samples Oreparation

To neutralize the effect of RF antibodies, HeteroBlock (omega Biologicals) reagent was added to the serum samples with positive RF antibody to block and neutralize it (blocking agent) according to manufacturer’s instructions.

Quantification of Human Endothelial Cell-Specific Molecule -1 levels in the sera of all studied subjects was performed by sandwich ELISA technique using a commercially available Enzyme-linked Immunosorbent Assay Kit for Human ESM1 (Cloud-Clone Corp., Wuhan, CHINA). The sera were collected and stored at -20°C to -80°C. All the reagents were brought and the samples were centrifuged again after thawing before the assay. It is recommended that all samples and standards should be assayed in duplicate. 100μL of Standard, Blank, or Sample per well were added. The blank wells were added with Reference Standard & Sample diluent. The plate were covered with sealer. The samples were then incubated for 90 minutes at 37°C. The liquids were then removed from each well, but the sample were not washed. Immediately, 100μL of Biotinylated Detection Ab working solutions were added to each well, then were covered with the Plate sealer. Gently, the plate were tapped to ensure thorough mixing, followed by incubation for 1 hour at 37°C. Each well was aspirated and washed, repeating the process three times. Washing was conducted by filling each well with Wash Buffer (approximately 350μL). After the last wash, remaining Wash Buffer was removed by aspirating or decanting. Add 100μL of HRP Conjugate working solution to each well. Cover with the Plate sealer, followed by incubation for 30 minutes at 37°C. The wash process was repeated for five times as conducted in step 3. 90μL of substrate solution were added to each well and covered with a new Plate sealer, followed by incubation for about 15 minutes at 37°C. The plate were protected from light. 50μL of Stop Solution were added to each well, which turned the color to yellow immediately. The order to add stop solution should be the same as the substrate solution. The Optical Density (OD value) of each well was determined at once, using a micro-plate reader set to 450 nm. Calculation of the results averaged the duplicate readings for each standard and samples, from which the average zero was subtracted from standard optical density. A standard curve was made by plotting the mean OD value for each standard on the y-axis against the concentration on the x-axis and a premium appropriate curve was drawn over the points on the graph. If the samples were diluted, the concentration calculated from the standard curve was multiplied by the dilution factor. The detection range of test was 15.6-1,000pg/ml with a minimum detectable level less than 6.2pg/ml. This assay has high sensitivity and excellent specificity for detection of ESM1.

2.1.2. Statistical Analysis

SPSS statistical software was used for all statistical analyses (IBM SPSS statistics version 21.0). Numerical data were expressed as mean value ± SD while categorical data presented as numbers and percentage. Variations among groups in clinical & serological data were linked by t-test for normally distributed values. Correlations between variables were estimated by the Pearson correlation. Correlations between categorical data were compared using chi-square analysis. P values < 0.05 were considered statistically significant.

3. RESULTS

Serum levels of ESM-1 were statistically and significantly higher in the patient group than the control group (2652.25±2803.40 vs. 546.74±181.64 pg/ml, P < 0.0001) Fig. (1). Mean level of RF, ACPA, ESR, and CRP were significantly higher in the patients group compared to the control group. As regard gender, age, and BMI, there were no significant difference between both groups Table 1.

Table 1
Demographic, clinical and serological data of the studied groups.


Fig. (1)
ESM-1 serum levels in the studied groups.


3.1. In the Patient’s Subgroups

In patients with severe disease activity subgroup, compared with patients on remission; serum levels of ESM-1, CRP, ESR, and RF were (P < 0.0001) Fig. (1) were significantly higher (P < 0.0001) Table 2. CRP and RF levels were significantly higher when compared with a patient with moderate disease activity (P < 0.0001 & 0.001 respectively). ESM-1, CRP and RF levels were significantly higher when compared with a patient with mild disease activity (P < 0.0001, < 0.0001 & 0.003 respectively). HAQ-DI and modified Larsen score were significantly higher when compared with other patients’ subgroups.

Table 2
Demographic, clinical and serological data of the RA subgroups.


In patients with moderate disease activity, compared with the patient with remission; ESM-1 was significantly higher (P = 0.040) and ESR, CRP, RF, HAQ-DI, and modified Larsen score were also significantly higher (P = 0.008, < 0.0001, 0.012, 0.0001 &0.0001respectively) but CRP, HAQ-DI, and modified Larsen score were significantly higher (P = 0.018, 0.0001 & 0.0001 respectively) when compared with patient with mild disease activity.

In patients with mild disease activity; serum levels of ESM-1, ESR, CRP, HAG-DI, and modified Larsen score were significantly higher (P = 0.004, 0.034, <0.0001, 0.0001 &0.0001respectively) compared with patients with remission. ACPA levels showed insignificant differences between subgroups.

3.2. Correlations (Pearson Correlation)

In our cohort, we found that ESM-1 was positively and significantly correlated with DAS-28 score, CRP, and ESR (P = 0.002, 0.035 & < 0.0001, respectively). Also, DAS-28 score was positively and significantly correlated with HAQ-DI and modified Larsen score (P < 0.0001) Table 3. We assessed the linear regression analysis curve estimation between ESM-1 as a dependent variable and DAS-28 which showed a significant correlation (r = .141- P < 0.0001) (Fig. 2).

Fig. (2)
Curve estimation for ESM-1 and DAS-28 by linear regression analysis.


Table 3
Pearson Correlation between ESM-1 and other clinical and serological data in RA patients.


4. DISCUSSION

RA is known by severe angiogenesis, which is required for its pathogenesis [20Weber AJ, De Bandt M. Angiogenesis: General mechanisms and implications for rheumatoid arthritis. Joint Bone Spine 2000; 67(5): 366-83.[PMID: 11143903] ]. Moreover, the pannus tissue in RA joints displays destructive behavior and attacks and erodes the adjacent cartilage and subchondral bones [17Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423(6937): 356-61. View Article: Google Scholar: PubMed/NCBI.[http://dx.doi.org/10.1038/nature01661] [PMID: 12748655] ]. ESM-1 serum levels increase in inflammatory disorders [21Sarrazin S, Lyon M, Deakin JA, et al. Characterization and binding activity of the chondroitin/dermatan sulfate chain from Endocan, a soluble endothelial proteoglycan. Glycobiology 2010; 20(11): 1380-8.[http://dx.doi.org/10.1093/glycob/cwq100] [PMID: 20581009] ]. Accordingly, we explored the possible link between RA disease activity and ESM-1. We found that ESM-1 serum levels were higher in patients with RA than the healthy control and is significantly higher in patients with severe disease activity compared with patients with lower disease activity (Table 2). Moreover, its levels were positively correlated with disease activity (DAS-28), HAQ-DI and modified Larsen score (Table 3). This result was partially in line with others who reported the same results in juvenile RA but with lower levels in active disease than those in remission which could be secondary to drug effect or more healthy endothelial in young age and also mostly the absence of vascular disorders, mainly atherosclerosis [22Yilmaz Y, Durmuş RB, Saraçoğlu B, Şahin S, et al. The assessment of serum endocan levels in children with juvenile idiopathic arthritis. Arch Rheumatol 2018; 3(x): i-vi.[http://dx.doi.org/10.5606/ArchRheumatol.2018.6528] [PMID: 30207559] ]. It is suggested that serum ESM-1 levels rise in synovial tissue of rheumatoid patients and arouse mainly by adiponectin. Furthermore, ESM-1 can induce angiogenesis, which can elucidate pannus formation [23Kim KS, Lee YA, Ji HI, et al. Increased expression of endocan in arthritic synovial tissues: Effects of adiponectin on the expression of endocan in fibroblast-like synoviocytes. Mol Med Rep 2015; 11(4): 2695-702.[http://dx.doi.org/10.3892/mmr.2014.3057] [PMID: 25483913] ] and was detected in affected inflamed joints and its level was correlated with inflammation magnitude [23Kim KS, Lee YA, Ji HI, et al. Increased expression of endocan in arthritic synovial tissues: Effects of adiponectin on the expression of endocan in fibroblast-like synoviocytes. Mol Med Rep 2015; 11(4): 2695-702.[http://dx.doi.org/10.3892/mmr.2014.3057] [PMID: 25483913] ]. We reported a positive correlation between ESM-1 and ESR and CRP indicated that ESM-1 is linked to the inflammatory state in RA but another study failed to report such correlation [22Yilmaz Y, Durmuş RB, Saraçoğlu B, Şahin S, et al. The assessment of serum endocan levels in children with juvenile idiopathic arthritis. Arch Rheumatol 2018; 3(x): i-vi.[http://dx.doi.org/10.5606/ArchRheumatol.2018.6528] [PMID: 30207559] ]. Others reported that ESM-1 was elevated and correlated with ESR and CRP in Behcet’s disease [14Balta I, Balta S, Koryurek OM, et al. Serum endocan levels as a marker of disease activity in patients with Behçet disease. J Am Acad Dermatol 2014; 70(2): 291-6.[http://dx.doi.org/10.1016/j.jaad.2013.09.013] [PMID: 24176522] ], SLE [24Icli A, Cure E, Cure MC, et al. Endocan levels and subclinical atherosclerosis in patients with systemic lupus erythematosus. Angiology 2016; 67(8): 749-55.[http://dx.doi.org/10.1177/0003319715616240] [PMID: 26614790] ], SS [25Bălănescu P, Lădaru A, Bălănescu E, Voiosu T, Băicuş C, Dan GA. Endocan, novel potential biomarker for systemic sclerosis: Results of a pilot study. J Clin Lab Anal 2016; 30(5): 368-73.[http://dx.doi.org/10.1002/jcla.21864] [PMID: 26331941] ] & IBD [13Voiosu T, Bălănescu P, Benguş A, et al. Serum endocan levels are increased in patients with inflammatory bowel disease. Clin Lab 2014; 60(3): 505-10.[PMID: 24697130] ]. The production of ESM-1 is controlled by pro-inflammatory factors like Tumor Necrosis Factor alpha (TNF-α) and also by pro-angiogenic agents, including VEGF and FGF-2 [26Maurage CA, Adam E, Minéo JF, et al. Endocan expression and localization in human glioblastomas. J Neuropathol Exp Neurol 2009; 68(6): 633-41. [View Article: Google Scholar: PubMed/NCBI].[http://dx.doi.org/10.1097/NEN.0b013e3181a52a7f] [PMID: 19458546] , 27Grigoriu BD, Depontieu F, Scherpereel A, et al. Endocan expression and relationship with survival in human non-small cell lung cancer. Clin Cancer Res 2006; 12(15): 4575-82. [View Article: Google Scholar: PubMed/NCBI].[http://dx.doi.org/10.1158/1078-0432.CCR-06-0185] [PMID: 16899604] ] which may explain the high cardiovascular risk in these patients than the others and ESM-1 can be considered as a marker for vascular endothelial dysfunction [28Balta S, Mikhailidis DP, Demirkol S, Ozturk C, et al. Endocan-a novel inflammatory indicator in newly diagnosed patients with hypertension: A pilot study. Angiology 2014; 65: 77-37.[http://dx.doi.org/10.1177/0003319713513492] ]. In patients subgroups, we found significantly high levels of ESR, CRP,RF, and ESM-1 in patients with severe disease activity compared with other subgroups with lower disease activity and remission indicating that ESM-1 may play a role in disease activity. As in our patients, we excluded patients with cardiovascular risk which are a main cause of elevated ESM-1. The association between RF levels and ESM-1 in our patients matched with many previous studies showing that the presence of RF antibodies were related to impaired endothelial function individually from cardiovascular risk factors, in RA patients [29Hjeltnes G, Hollan I, Førre Ø, Wiik A, Mikkelsen K, Agewall S. Anti-CCP and RF IgM: Predictors of impaired endothelial function in rheumatoid arthritis patients. Scand J Rheumatol 2011; 40(6): 422-7.[http://dx.doi.org/10.3109/03009742.2011.585350] [PMID: 22150462] ]. However, we detected no link between ESM-1 levels and body mass index while others reported a link between obesity (adipocytes) and ESM-1 mainly through adiponectin, an adipokine, which was implicated in the pathogenesis and progression of RA [23Kim KS, Lee YA, Ji HI, et al. Increased expression of endocan in arthritic synovial tissues: Effects of adiponectin on the expression of endocan in fibroblast-like synoviocytes. Mol Med Rep 2015; 11(4): 2695-702.[http://dx.doi.org/10.3892/mmr.2014.3057] [PMID: 25483913] ]. We moreover found a positive correlation between ESM-1 and HAQ-DI and modified Larsen score plus a linear correlation between ESM-1 levels and DAS-28 in the studied subgroups (Fig. 2), which supported the link between ESM-1 and RA disease activity and highlighted the possible future use of therapeutic anti- ESM-1 in treatment of RA and management of its activity. Finally, we can concluded that ESM-1could be a biomarker for RA disease activity.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The study was approved from the Ethics Committee of the School of Medicine, Mansoura University (R1/16.10.06).

HUMAN AND ANIMAL RIGHTS

No Animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.

CONSENT FOR PUBLICATION

All patients gave an informed consent when they were enrolled.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women The New Engl J Med 2000; 342(12): 836-43.
[2] Mota DA. L.M.H., dos Santos Neto, L.L. & de Carvalho, J.F.: Auto antibodies and other serological markers in rheumatoid arthritis: predictors of disease activity? Clin Rheumatol 2009; 28: 1127.[http://dx.doi.org/10.1007/s10067-009-1223-y] [PMID: 19597699]
[3] Pober JS, Cotran RS. The role of endothelial cells in inflammation. Transplantation 1990; 50(4): 537-44.[http://dx.doi.org/10.1097/00007890-199010000-00001] [PMID: 2219269]
[4] Pompilio G, Capogrossi MC, Pesce M, et al. Endothelial progenitor cells and cardiovascular homeostasis: clinical implications. Int J Cardiol 2009; 131(2): 156-67.[http://dx.doi.org/10.1016/j.ijcard.2008.08.033] [PMID: 18823669]
[5] Favero G, Paganelli C, Buffoli B, Rodella LF, Rezzani R. Endothelium and its alterations in cardiovascular diseases: Life style intervention BioMed Research International 2014; 2014
[6] Spinelli FR, Di Franco M, Metere A, et al. Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis. Drug Dev Res 2014; 75: S67-9.
[7] Bechard D, Gentina T, Delehedde M, et al. Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. J Biol Chem 2001; 276: 48341-9.
[8] Lassalle P, Molet S, Janin A, et al. ESM-1 is a novel human endothelial cell-specific molecule expressed in lung and regulated by cytokines. J Biol Chem 1996; 271: 20458-64.
[9] Bechard D, Meignin V, Scherpereel A, et al. Characterization of the secreted form of endothelial-cell-specific molecule 1 by specific monoclonal antibodies. J Vasc Res 2000; 37: 417-25.
[10] Mosevoll KA, Lindås R, Wendelbo O, Bruserud O, Reikvam H. Systemic levels of the endothelium-derived soluble adhesion molecules endocan and E-selectin in patients with suspected deep vein thrombosis. Springerplus 2014; 3: 571. [Internet].[http://dx.doi.org/10.1186/2193-1801-3-571] [PMID: 25332871]
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[15] Béchard D, Scherpereel A, Hammad H, et al. Human endothelial-cell specific molecule-1 binds directly to the integrin CD11a/CD18 (LFA-1) and blocks binding to intercellular adhesion molecule-1. J Immunol 2001; 167(6): 3099-106.[http://dx.doi.org/10.4049/jimmunol.167.6.3099] [PMID: 11544294]
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[18] Rau R, Herborn G. A modified version of Larsen’s scoring method to assess radiologic changes in rheumatoid arthritis. J Rheumatol 1995; 22(10): 1976-82.[PMID: 8992004]
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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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