The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 12, 2018
RESEARCH ARTICLE

Correlation Between Tumor Necrosis Factor-α Levels, Free Fatty Acid Levels, and Soluble Vascular Cell Adhesion Molecule-1 Levels in Rheumatoid Arthritis Patients



Fazria Nasriati1, Rudy Hidayat2, *, Budiman Budiman3, Ikhwan Rinaldi4
1 Department of Internal Medicine, Faculty of Medicine Universitas Indonesia -s Cipto Mangunkusumo General Hospital, Jalan Diponegoro 71, Jakarta 10310, Indonesia
2 Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo General Hospital, Jalan Diponegoro 71, Jakarta, Indonesia
3 Division of Endocrinology and Metabolic Diseases, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo General Hospital, Jalan Diponegoro 71, Jakarta, Indonesia
4 Clinical Epidemiology Unit, Department of Internal Medicine, Universitas Indonesia - Cipto Mangunkusumo General Hospital, Jalan Diponegoro 71, Jakarta, Indonesia

Abstract

Background:

The mortality of Rheumatoid Arthritis (RA) is quite high, which is largely due to cardiovascular complications caused by endothelial dysfunction. One of the important inflammatory mediators that contribute to RA joints arthritis of TNF-α, also proven to play a role in endothelial dysfunction and play a role in increasing intracellular lipolysis, thus increasing circulating FFA levels.

Objectives:

To determine the correlation between TNF-α levels with VCAM-1 levels, correlation of TNF-α levels with FFA levels, and correlation of FFA levels with VCAM-1 levels.

Methods:

Cross sectional and retrospective design studies of adult RA patients treated at Cipto Mangunkusumo Hospital (RSCM), without metabolic disturbances, acute infection, cardiovascular disorders, or other autoimmune diseases. The cross-sectional data was collected from October to November 2017, while retrospective samples were collected since August 2016. TNF-α, VCAM-1, and FFA levels were assessed by serum blood test by ELISA method. Correlation analysis is done by Pearson analysis when the data distribution is normal and with Spearman analysis when the data distribution is not normal.

Results:

A total of 35 subjects were enrolled in the study. Most (97.1%) were women with an average age of 45.29 years, median disease duration of 48 months, and most had moderate disease activity (65.7%). No significant correlation was found between TNF-α levels and VCAM-1 levels (p = 0.677; r = +0.073). as well betwen TNF-α levels and FFA levels (p = 0.227; r = -0.21). The correlation between FFA and VCAM-1 levels showed significant correlation with negative correlation and weak correlation (p = 0.036; r = -0.355).

Conclusions:

(1) There was no correlation between TNF-α levels and VCAM-1 levels in RA patients; (2) There was no correlation between TNF-α levels and FFA levels in RA patients; (3) There was a negative correlation between FFA levels and VCAM-1 levels in RA patients.

Keywords: Tumor Necrosis Factor-α, Free Fatty Acids, Vascular Cell Adhesion Molecule-1, Rheumatoid Arthritis, SLE, ELISA, SLE, FFA.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 86
Last Page: 93
Publisher Id: TORJ-12-86
DOI: 10.2174/1874312901812010086

Article History:

Received Date: 11/5/2018
Revision Received Date: 02/6/2018
Acceptance Date: 5/6/2018
Electronic publication date: 19/7/2018
Collection year: 2018

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© 2018 Nasriati 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 Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo General Hospital, Jalan Diponegoro 71, Jakarta, Indonesia; Tel: +628151887206; E-mail: rudy_hid@yahoo.co.id




1. INTRODUCTION

Rheumatoid Arthritis (RA) is one of the chronic autoimmune diseases with an estimated prevalence of 1 to 2 percent of the total population in the world [1Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J Manag Care 2012; 18(13)(Suppl.): S295-302.[PMID: 23327517] ]. The mortality of the disease is quite high, which is largely due to earlier cardiovascular complications [2Lévy L, Fautrel B, Barnetche T, Schaeverbeke T. Incidence and risk of fatal myocardial infarction and stroke events in rheumatoid arthritis patients. A systematic review of the literature. Clin Exp Rheumatol 2008; 26(4): 673-9.[PMID: 18799105] ] Cardiovascular risk is mainly due to the atherosclerosis process initiated by endothelial dysfunction and recorded 2 times greater in RA patients than in the general population [3Totoson P, Maguin-Gaté K, Nappey M, Wendling D, Demougeot C. Endothelial dysfunction in rheumatoid arthritis: Mechanistic insights and correlation with circulating markers of systemic inflammation. PLoS One 2016; 11(1): e0146744.[http://dx.doi.org/10.1371/journal.pone.0146744] [PMID: 26761790] , 4Cavagna L, Boffini N, Cagnotto G, Inverardi F, Grosso V, Caporali R. Atherosclerosis and rheumatoid arthritis: More than a simple association 2012; 1-8.]. Endothelial dysfunction itself is a process that involves various factors, such as genetic, traditional cardiovascular risk factors, and systemic inflammation [3Totoson P, Maguin-Gaté K, Nappey M, Wendling D, Demougeot C. Endothelial dysfunction in rheumatoid arthritis: Mechanistic insights and correlation with circulating markers of systemic inflammation. PLoS One 2016; 11(1): e0146744.[http://dx.doi.org/10.1371/journal.pone.0146744] [PMID: 26761790] ].

Del Rincon et al. in his prospective study of 236 RA patients over 8 years, reported that the cardiovascular risk in RA patients was 3.96 times compared to controls (95% CI 1.86-8.43). After being adjusted for traditional risk factors, this relative risk only decreased into 3.17 times compared to controls (RR 3.17 [95% CI 1.33-6.36]). The differences of RR obtained in this study showed that traditional risk factors are not the most important factor in cardiovascular events in RA patients, but other mechanisms may involved in the pathogenesis of RA disease itself, i.e. systemic inflammation [5del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001; 44(12): 2737-45.[http://dx.doi.org/10.1002/1529-0131(200112)44:12<2737::AID-ART460>3.0.CO;2-#] [PMID: 11762933] ].

Systemic inflammation that occurs in RA patients involves various pro inflammatory mediators, especially Tumor Necrosis Factor-α (TNF-α) [3Totoson P, Maguin-Gaté K, Nappey M, Wendling D, Demougeot C. Endothelial dysfunction in rheumatoid arthritis: Mechanistic insights and correlation with circulating markers of systemic inflammation. PLoS One 2016; 11(1): e0146744.[http://dx.doi.org/10.1371/journal.pone.0146744] [PMID: 26761790] ] The role of TNF-α against endothelial dysfunction is evidenced by an experimental study conducted by Goodwin et al. (2007) on endothelial aortic cell cultures, where TNF-α lowered nitric oxide (NO) production by endothelial cells [6Goodwin BL, Pendleton LC, Levy MM, Solomonson LP, Eichler DC. Tumor necrosis factor-α reduces argininosuccinate synthase expression and nitric oxide production in aortic endothelial cells. Am J Physiol Heart Circ Physiol 2007; 293(2): H1115-21.[http://dx.doi.org/10.1152/ajpheart.01100.2006] [PMID: 17496212] ]. The effects of TNF-α on endothelial dysfunction and cardiovascular events in RA patients were then demonstrated in a study by Rho et al. which found a significant association between TNF-α (OR = 1.49, 95% CI (1.16-1.90)) with coronary calcium levels [7Rho YH, Chung CP, Oeser A, et al. Inflammatory mediators and premature coronary atherosclerosis in rheumatoid arthritis. Arthritis Rheum 2009; 61(11): 1580-5.[http://dx.doi.org/10.1002/art.25009] [PMID: 19877084] ]. Meanwhile, the direct effect of TNF-α on endothelial dysfunction markers in RA patients was showed by Foster et al. (2009), where there was a strong correlation between TNF-α and VCAM (r = 0.322, P = 0.009) [8Foster W, Carruthers D, Lip GY, Blann AD. Inflammatory cytokines, endothelial markers and adhesion molecules in rheumatoid arthritis: Effect of intensive anti-inflammatory treatment. J Thromb Thrombolysis 2010; 29(4): 437-42.[http://dx.doi.org/10.1007/s11239-009-0370-y] [PMID: 19578810] ].

TNF-α is also one of the cytokines that have the ability to regulate various biological processes such as energy metabolism [9Cawthorn WP, Sethi JK. TNF-alpha and adipocyte biology. FEBS Lett 2008; 582(1): 117-31.[http://dx.doi.org/10.1016/j.febslet.2007.11.051] [PMID: 18037376] ]. Study of Kawakami et al. (1987) demonstrated the decreased of lipopolysaccharide activity and increased of intracellular lipolysis of rat adipocyte tissue after administration of recombinant TNF-α, thus increasing circulating FFA levels [10Kawakami M, Murase T, Ogawa H, et al. Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells. J Biochem 1987; 101(2): 331-8.[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a121917] [PMID: 3495531] ]. Zhang et al. in his experimental study concluded that TNF-α was shown to stimulate lipolysis in human healthy adipocyte tissue [11Zhang HH, Halbleib M, Ahmad F, Manganiello VC, Greenberg AS. Tumor necrosis factor-α stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 2002; 51(10): 2929-35.[http://dx.doi.org/10.2337/diabetes.51.10.2929] [PMID: 12351429] ]

The role of FFA to endothelial function in RA patients is not known, but in a study by Ormseth et al. (2013) on Systemic Lupus Erythematosus (SLE) patients, there was an association between FFA and endothelial activation markers i.e. E-selectin (r = 0.33, P = <0.001) and ICAM-1 (r = 0.35, P <0.001), but there is no correlation with sVCAM-1 [12Ormseth MJ, Swift L, Fazio S, et al. Free fatty acids are associated with metabolic syndrome and insulin resistance, but not inflammation in SLE patients. Lupus 2013; 22(1): 26-33.[http://dx.doi.org/10.1177/0961203312462756] [PMID: 23060481] ].

These theories then raise the question of whether the process of endothelial dysfunction and atherosclerosis in RA patients can occur through TNF-α stimulation mechanisms against lipolysis.

2. METHODS

This research was a cross sectional design research conducted at Rheumatology Clinic, Cipto Mangunkusumo Hospital from October 8th 2017 until November 15th 2017. The subjects involved are rheumatoid arthritis patients who seek treatment at Rheumatology Clinic, Department of Internal Medicine and met the inclusion criterias: 1. Patients who have been diagnosed rheumatoid arthritis according to ACR / EULAR 2010 criteria. 2. Age ≥ 18 years. 3. Willing to be included in research and sign the informed consent form as research subject.

Patients with acute infection, diabetes mellitus, hypertension, dyslipidemia or obesity, suffer from cardiovascular disorders, such as coronary heart disease, heart failure, arrhythmia, or other vascular problems, such as stroke; has a smoking habit or previous smoking history; suffer from other autoimmune diseases besides rheumatoid arthritis; suffer from osteoarthritis accompanied by genus effusion; were in exclusion of this study. Subjects who met the inclusion criteria were chosen consecutively as many as 35 people according to the large sample calculation using the reference correlation coefficient from Klimiuk et al. [13Klimiuk PA, Sierakowski S, Fiedorczyk M, Chwieӕko J. Serum Tumour Necrosis Factor alpha (TNF-a) concentration correlates with soluble adhesion molecules and Vascular Endothelial Growth Factor (VEGF) in rheumatoid arthritis. Przegl¹d Lekarski 2004; 61(2): 86-9.]. The subjects then underwent serum sampling for laboratory tests of TNF-α, FFA, and sVCAM-1 levels. TNF-α examination was performed using the Quantikine ELISA (Human TNF-α Immunoassay) kit from R & D Systems Incorporate Minneapolis, Minnesota, USA. VCAM-1 examination was performed using the ELISA Quanticine kit (Human sVCAM-1 / CD106 Immunoassay) from R & D Systems Incorporate Minneapolis, Minnesota, USA. While the FFA examination as performed using the kit Free Fatty Acid Quantification Colorimetric / Fluorometric from BioVision Incorporate Milpitas, California, USA.

The data was correlated using Pearson analysis, or alternatively Spearman analysis. [14Dahlan MS. Correlative hypothesis Statistics for medicine and health 2009; 155-74., 15Sastroasmoro S, Ismael S. Dasar-dasar metodologi penelitian klinis 4th ed. 4th ed.2011.].

The sudy had been approved by the committee of the Medical Research Ethics of the Faculty of Medicine, Universitas Indonesia.

3. RESULTS

3.1. Basic Characteristics

Most of the subjects of this study were women (97.1%) with an average age of 45.29 years. Most patients had moderate disease activity (65.7%). The full characteristics of the subject are shown in Table 1. Subject characteristics based on levels of inflammatory mediator and adhesion molecule are shown in Table 2.

Table 1
Demographic characteristic of the study.


Table 2
Subject characteristics based on levels of inflammatory mediator and adhesion molecule.


3.2. Correlation Between TNF-α Level and sVCAM-1 Level in Rheumatoid Arthritis

The result of bivariate test on the correlation between TNF-α and sVCAM-1 levels with Pearson correlation test showed that r = 0.073 (p = 0.677) (Fig. 1).

Fig. (1)
Scatter plot of correlation between TNF-α level and sVCAM-1 level in Rheumatoid Arthritis.


Based on these results, there appears to be no correlation between TNF-α levels and sVCAM-1 levels.

3.3. Correlation between FFA Level and sVCAM-1 Level in Rheumatoid Arthritis

The bivariate analysis test to assess the correlation between the FFA and sVCAM-1 variables was performed by Pearson test and shown in Fig. (2).

Fig. (2)
Scatter Plot of Correlation between FFA level and sVCAM-1 level in Rheumatoid Arthritis.


The correlation between the FFA and sVCAM-1 variables as illustrated in Fig. (2) shows a significant correlation with the direction of negative correlation and weak correlation strength.

3.4. Correlation Between TNF-α Level and FFA Level in Rheumatoid Arthritis

The bivariate analysis test to assess the correlation between the TNF-α and FFA variables was performed by Pearson test and shown in Fig. (3).

Fig. (3)
Scatter Plot of Correlation between TNF-α level and FFA level in Rheumatoid Arthritis.


Fig. (3) shows the correlation between and FFA with negative direction and weak correlation strength but these results show a non-significant relationship.

4. DISCUSSION

4.1. Characteristics of Subjects

The majority of the subjects in this study were women (97.1%), which shows the ratio of female and male of this study is 40:1. This result was clearly different from those mentioned in many literatures, where RA ratio in the population among female is compared to male of 3:1 [16van Vollenhoven RF. Sex differences in rheumatoid arthritis: More than meets the eye. BMC Med 2009; 7: 12.[http://dx.doi.org/10.1186/1741-7015-7-12] [PMID: 19331649] ].

The average age of this research was 45.29 years. This average corresponds to the existing literature, which states that RA peak incidence occurs between the fourth and fifth decades[17Tehlirian CV, Bathon JM. Rheumatoid arthritis: A clinical and laboratory manifestations.Primer on the Rheumatic Diseases 13th ed. 13th ed.2008; 114-21.]. The Foster et al. study showed a slightly different case, where the median age of the subject was 58.5 years [8Foster W, Carruthers D, Lip GY, Blann AD. Inflammatory cytokines, endothelial markers and adhesion molecules in rheumatoid arthritis: Effect of intensive anti-inflammatory treatment. J Thromb Thrombolysis 2010; 29(4): 437-42.[http://dx.doi.org/10.1007/s11239-009-0370-y] [PMID: 19578810] ].

All subjects in this study used MTX therapy, with or without steroids. The average dose of steroids used by the study population was 8 mg per day metilprednisolone. This therapy is in line with the EULAR recommendation that recommends MTX treatment as first-line therapy in RA[18Ghosh A, Gao L, Thakur A, Siu PM, Lai CWK. Role of free fatty acids in endothelial dysfunction. J Biomed Sci 2017; 24(1): 50.[http://dx.doi.org/10.1186/s12929-017-0357-5] [PMID: 28750629] ].

4.2. TNF-α Level, sVCAM-1 Level, and FFA Level in Rheumatoid Arthritis Patients

The mean of TNF-α level in this study was 6.95 (± 1.65 pg / ml). The Foster et al. study conducted a study assessing levels of inflammatory mediators in RA patients with metabolic risk factors and obtained TNF-α levels of 5.9 (0-47.5) pg / ml.

In addition to TNF-α levels, differences were also found in sVCAM-1 levels. The mean of sVCAM-1 concentration in this research was 609.96 (±171.70) pg / ml. In the Foster study, obtained sVCAM-1 levels in the RA patient group of 439 (196-553) pg / ml [8Foster W, Carruthers D, Lip GY, Blann AD. Inflammatory cytokines, endothelial markers and adhesion molecules in rheumatoid arthritis: Effect of intensive anti-inflammatory treatment. J Thromb Thrombolysis 2010; 29(4): 437-42.[http://dx.doi.org/10.1007/s11239-009-0370-y] [PMID: 19578810] ].

Other parameters assessed in the Foster study were the levels of the ESR, which obtained a median of 23 (8-50) mm/hour [8Foster W, Carruthers D, Lip GY, Blann AD. Inflammatory cytokines, endothelial markers and adhesion molecules in rheumatoid arthritis: Effect of intensive anti-inflammatory treatment. J Thromb Thrombolysis 2010; 29(4): 437-42.[http://dx.doi.org/10.1007/s11239-009-0370-y] [PMID: 19578810] ]. This result was much different from that obtained in this study that the median of 42 (10 - 130). mm/hour Based on the differences in these levels, our study showed a higher degree of inflammation and disease activity than Foster's study.

The degree of disease activity was likely to be the cause of higher levels of TNF-α and sVCAM-1 levels in this study than the Foster’s study. In addition, other factors that may also play a role was the treatment used by the subject of the research. In the Foster’s study the majority of subjects (87%) used anti-TNF-α therapy, while in this study all patients only used MTX without any biologic agents [13Klimiuk PA, Sierakowski S, Fiedorczyk M, Chwieӕko J. Serum Tumour Necrosis Factor alpha (TNF-a) concentration correlates with soluble adhesion molecules and Vascular Endothelial Growth Factor (VEGF) in rheumatoid arthritis. Przegl¹d Lekarski 2004; 61(2): 86-9.].

In addition to therapeutic factors, patient compliance rates in treatment as well as duration of treatment were also factors that can not be excluded. In this study, the duration of illness was shorter with median 48 (3-300) months, while Foster’s study showed a longer time of median of 10.7 years. This is related to the control of the disease which is thought to be better in the Foster’s research subject.

The FFA concentration in this study was obtained a mean of 0.051 (±0.027 pg / ml), where the mean was equivalent to 2 x 10-9 mmol / l (±9.59 x 10-11 mmol / l). In the Ormseth study, FFA levels were obtained with a median of 0.56 mmol / L (0.383-0.748 mmol / L) [12Ormseth MJ, Swift L, Fazio S, et al. Free fatty acids are associated with metabolic syndrome and insulin resistance, but not inflammation in SLE patients. Lupus 2013; 22(1): 26-33.[http://dx.doi.org/10.1177/0961203312462756] [PMID: 23060481] ].

Ormseth's study obtained an elevation of FFA serum in RA patients with metabolic syndrome (0.62 mmol / L [0.44-0.80]) compared with subjects without metabolic syndrome (0.54 mmol / L [0.37-0.69]) [12Ormseth MJ, Swift L, Fazio S, et al. Free fatty acids are associated with metabolic syndrome and insulin resistance, but not inflammation in SLE patients. Lupus 2013; 22(1): 26-33.[http://dx.doi.org/10.1177/0961203312462756] [PMID: 23060481] ]. This result showed the role of metabolic disturbance factors as one of the factors affecting serum FFA levels. This is also thought to be the cause of low levels of FFA in this study, where there was no metabolic disorders in the study subjects.

4.3. Correlation Between TNF-α Level and sVCAM-1 Level in Rheumatoid Arthritis

The result of Pearson correlation test between TNF-α and sVCAM-1 levels was found to be a non-significant correlation. These results differ from those obtained in the Foster et al. study, wherein the correlation between TNF-α levels and sVCAM-1 levels showed significant results [8Foster W, Carruthers D, Lip GY, Blann AD. Inflammatory cytokines, endothelial markers and adhesion molecules in rheumatoid arthritis: Effect of intensive anti-inflammatory treatment. J Thromb Thrombolysis 2010; 29(4): 437-42.[http://dx.doi.org/10.1007/s11239-009-0370-y] [PMID: 19578810] ].

In the Foster’s study there was no exclusion of traditional cardiovascular risk factors such as DM, hypertension, smoking, obesity and dyslipidemia. Diabetes mellitus as well as other metabolic disorders can increase FFA levels thus affecting inflammation and oxidative stress in endothelium [18Ghosh A, Gao L, Thakur A, Siu PM, Lai CWK. Role of free fatty acids in endothelial dysfunction. J Biomed Sci 2017; 24(1): 50.[http://dx.doi.org/10.1186/s12929-017-0357-5] [PMID: 28750629] ].

Among the types of FFA, Saturated Fatty Acid (SFA) has an important role in cardiovascular events (pro inflammation), while Unsaturated Fatty Acid (UFA) is more protective (anti-inflammatory) [18Ghosh A, Gao L, Thakur A, Siu PM, Lai CWK. Role of free fatty acids in endothelial dysfunction. J Biomed Sci 2017; 24(1): 50.[http://dx.doi.org/10.1186/s12929-017-0357-5] [PMID: 28750629] ]. Study by Platat et al. demonstrated that compared adults with overweight, normal-weight adults were shown to have higher UFA levels (p <0.001) and lower SFA (p <0.001) [19Klein-Platat C, Drai J, Oujaa M, Schlienger JL, Simon C. Plasma fatty acid composition is associated with the metabolic syndrome and low-grade inflammation in overweight adolescents. Am J Clin Nutr 2005; 82(6): 1178-84.[http://dx.doi.org/10.1093/ajcn/82.6.1178] [PMID: 16332649] ]. The controlled metabolic risk factor in this study was also thought to be related to a better lipid profile, in which the fraction UFA was more dominant in this research subject. The effect of UFA as anti-inflammatory occurs through the mechanism of inhibition of the NF-kB pathway, where TNF-α-stimulated sVCAM-1 expression is proven to occur through transcription and protein translation, involving multiple pathways, one of which is the NF-kB [20Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 2009; 1(6): a001651.[http://dx.doi.org/10.1101/cshperspect.a001651] [PMID: 20457564] , 21Luo SF, Fang RY, Hsieh HL, et al. Involvement of MAPKs and NF-kappaB in tumor necrosis factor α-induced vascular cell adhesion molecule 1 expression in human rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 2010; 62(1): 105-16.[http://dx.doi.org/10.1002/art.25060] [PMID: 20039412] ]. In addition, MTX is also thought to be another factor contributing to the inhibition of the NF-kB pathway, which, in an experimental study by Majumdar et al., it was proved that there were inhibition of NF-kB pathway after administration of MTX 10μΜ and incubation for 60-120 min [22Majumdar S, Aggarwal BB. Methotrexate suppresses NF-kappaB activation through inhibition of IkappaBalpha phosphorylation and degradation. J Immunol 2001; 167(5): 2911-20.[http://dx.doi.org/10.4049/jimmunol.167.5.2911] [PMID: 11509639] ].

4.4. Correlation Between FFA Level and sVCAM-1 Level in Rheumatoid Arthritis

There was a significant correlation with the direction of negative correlation and weak correlation strength between FFA and sVCAM-1. Negative correlation means the higher the FFA level, the lower the sVCAM-1 level.The negative correlation in this study was allegedly influenced by the anti-inflammatory effect possessed by FFA, precisely the UFA fraction. In the study of Carluccio et al. oleic acid, one type of UFA, was shown to decrease sVCAM-1 expression by more than 40% after incubation for 72 hours on HUVEC media. From this study, it was thought that the effect of inhibition on the expression of adhesion molecules by oleates occurs through the mechanism of inhibition of Nuclear factor-kappa B (NF-kB) pathway [23Carluccio MA, Massaro M, Bonfrate C, et al. Oleic acid inhibits endothelial activation : A direct vascular antiatherogenic mechanism of a nutritional component in the mediterranean diet. Arterioscler Thromb Vasc Biol 1999; 19(2): 220-8.[http://dx.doi.org/10.1161/01.ATV.19.2.220] [PMID: 9974401] ].

The above points show another effect possessed by FFA aside from being a pro inflammatory compound, vice versa, as anti-inflammatory. The dominantly anti-inflammatory FFA fraction that present in this study is thought to be one of the causes of the negative correlation found in this study.

4.5. Correlation Between TNF-α Level and FFA Level in Rheumatoid Arthritis

Pearson correlation test results in this study showed no correlation between levels of TNF-α and FFA. The results were similar to the one that obtained in the Ormseth et al. (2013) study, in which the study also found no correlation between TNF-α and FFA levels (r = -0.002, p = 0.98) [12Ormseth MJ, Swift L, Fazio S, et al. Free fatty acids are associated with metabolic syndrome and insulin resistance, but not inflammation in SLE patients. Lupus 2013; 22(1): 26-33.[http://dx.doi.org/10.1177/0961203312462756] [PMID: 23060481] ]. However, this was not compatible with the clinical evidence described earlier in this paper, which has shown the increased of intracellular lipolysis of mouse adipocyte tissue after the administration of recombinant TNF-α, thus increasing circulating FFA levels [10Kawakami M, Murase T, Ogawa H, et al. Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells. J Biochem 1987; 101(2): 331-8.[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a121917] [PMID: 3495531] ].

In Ormseth's study the results were thought to caused by chronic exposure to inflammatory cytokines that are likely to alter lypolytic activity, thereby impacting the effects of TNF-α stimulation on FFA and negative correlations between them. [12Ormseth MJ, Swift L, Fazio S, et al. Free fatty acids are associated with metabolic syndrome and insulin resistance, but not inflammation in SLE patients. Lupus 2013; 22(1): 26-33.[http://dx.doi.org/10.1177/0961203312462756] [PMID: 23060481] ]. In addition, another possible underlying reason for the absence of a correlation between TNF-α and FFA is the anti-inflammatory properties of the dominant FFA fraction in the subject, so that the FFA examination method could not be generalized and should be done separately according to the specific fractions to meet the desired effect.

4.6. Strengths and Limitations

The strenght of this study is one of the studies in Indonesia that assessed the correlation between TNF-α levels, FFA levels, and sVCAM-1 levels in rheumatoid arthritis patients by excluding risk factors for metabolic disorders. The main limitation of this research is the cross sectional design in this study which cannot explain the causal relationship between the variables assessed.

CONCLUSION

In conclusion, our study showed that there was a negative correlation between FFA levels and sVCAM-1 levels in RA patients. It may indicate another effect possessed by FFA that is protective against endothelial dysfunction. However, research is needed with better designs that can prove the cause-and-effect relationship. Besides, the examination of FFA should be done specificallyby means of a device capable of indicating specific types or fractions of FFA present in the sample, in order to demonstrate the specific effects posed by those fractions.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The study had been correlated approved by the committee of the medical Research Ethics of the Faculty of Medicine, Universitas Indonesia.

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

A written informed consent was taken from the patients when they were enrolled.

CONFLICT OF INTEREST

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

ACKNOWLEDGEMENTS

We thank all internal medicine residents and staffs at RS Cipto Mangunkusumo who fully supported this study. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.

REFERENCES

[1] Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J Manag Care 2012; 18(13)(Suppl.): S295-302.[PMID: 23327517]
[2] Lévy L, Fautrel B, Barnetche T, Schaeverbeke T. Incidence and risk of fatal myocardial infarction and stroke events in rheumatoid arthritis patients. A systematic review of the literature. Clin Exp Rheumatol 2008; 26(4): 673-9.[PMID: 18799105]
[3] Totoson P, Maguin-Gaté K, Nappey M, Wendling D, Demougeot C. Endothelial dysfunction in rheumatoid arthritis: Mechanistic insights and correlation with circulating markers of systemic inflammation. PLoS One 2016; 11(1): e0146744.[http://dx.doi.org/10.1371/journal.pone.0146744] [PMID: 26761790]
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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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