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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 106-112

Retinol-binding protein 4 as a biomarker of cardiometabolic risk in rheumatoid arthritis


1 Department of Internal Medicine, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
2 Department of Internal Medicine, Faculty of Medicine for Girls, Al-Azhar University, Cairo; Department of Clinical Pathology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
3 Department of Clinical Pathology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt

Date of Submission03-Jan-2020
Date of Decision16-Jan-2020
Date of Acceptance20-Jan-2020
Date of Web Publication29-Jun-2020

Correspondence Address:
MSc Radwa M Fath Allah
Al Zahraa University Hospital, Al-Azhar University
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_3_20

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  Abstract 


Background Retinol-binding protein 4 (RBP4) has been implicated in the pathogenesis of cardiovascular disease. Higher circulating RBP4 concentrations have been observed in patients with previous clinical arteriosclerosis. RBP4 concentrations are positively related to the early endothelial dysfunction measured using marker flow-mediated dilation in patients with rheumatoid arthritis (RA).
Aim This study was done to measure the serum RBP4 level in patients with RA and to assess its clinical relevance to cardiometabolic risk and carotid atherosclerosis in RA.
Patients and methods The current study enrolled 50 patients with RA, fulfilling the American College of Rheumatology criteria for the diagnosis of RA, who were divided into three groups: group Ia (severe disease activity), group Ib (moderate disease activity), and group Ic (mild disease activity), together with 40 apparently healthy participants as a control group (group II). Clinical symptoms, disease activity using disease activity score 28, BMI, and blood pressure were assessed. RBP4 levels were measured by enzyme-linked immunosorbent assay technique. Complete blood count; C-reactive protein; fasting blood glucose; lipid profile including total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides; fasting plasma insulin level; calculation of insulin resistance by homeostatic model assessment of insulin resistance; autoantibody profiles; ECG; and carotid artery ultrasound were done.
Results RBP4 levels were highly significantly increased in all patients with RA when compared with the control group (P<0.01). There was a statistically significant positive correlation between the level of RBP4 and BMI, carotid intima media thickness (CIMT) RT, CIMT LT, and mean CIMT (r=0.319, 0.292, 0.315, and 0.323 and P<0.05, 0.05, 0.05, and 0.05, respectively).
Conclusion Our data suggest that the level of RBP4 was increased in patients with RA compared with control, and increased level of RBP4 is associated with presence of atherosclerosis in patients with RA as demonstrated by CIMT. RBP4 could be used as a marker for early prediction of premature atherosclerosis in patients with RA.

Keywords: rheumatoid arthritis, retinol-binding protein 4, XXXX


How to cite this article:
Fath Allah RM, El-Refaei KE, Osman EE, Sabry S, Elbagoury IM. Retinol-binding protein 4 as a biomarker of cardiometabolic risk in rheumatoid arthritis. Sci J Al-Azhar Med Fac Girls 2020;4:106-12

How to cite this URL:
Fath Allah RM, El-Refaei KE, Osman EE, Sabry S, Elbagoury IM. Retinol-binding protein 4 as a biomarker of cardiometabolic risk in rheumatoid arthritis. Sci J Al-Azhar Med Fac Girls [serial online] 2020 [cited 2020 Jul 11];4:106-12. Available from: http://www.sjamf.eg.net/text.asp?2020/4/2/106/288273




  Introduction Top


Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder characterized by a persistent joint inflammation, leading to cartilage and bone damage, disability, and eventually, to systemic complications, including cardiovascular and pulmonary disorders [1]. Patients with RA have increased prevalence of premature atherosclerosis even after adjusting for traditional cardiovascular risk factors [2].

Retinol-binding protein 4 (RBP4) was discovered to be an adipokine in that it is produced by adipocytes, induces gluconeogenesis by stimulating phosphoenolpyruvate carboxykinase in the liver and impairs peripheral and hepatic insulin sensitivity [3]. RBP4 concentrations are associated with increased atherosclerosis and incident coronary event rates [4].


  Patients and methods Top


Study population

This is a cross-sectional case–control study conducted on 50 patients (group I) fulfilling the 2010 American College of Rheumatology criteria for diagnosis of RA [5], in addition to 40 age-matched and sex-matched healthy participants as a control group (group II). Informed consent was taken from all patients. Also approval of ethical committee of Faculty of Medicine for Girls Al-Azhar University was obtained. Patients were selected from inpatient and outpatient clinic of rheumatology (Al-Zahraa University Hospital). All patients gave their informed consent before their inclusion in the study. They were divided into three groups according to disease activity score 28 (DAS28) using [6]: group Ia comprised patients with severe disease activity, and included 12 patients who had a DAS more than 5.1. Group Ib comprised patients with moderate disease activity and included 27 patients who had a DAS more than 3.2 but less than or equal to 5.1. Group Ic comprised patients with mild disease activity and included 11 patients who had a DAS less than or equal to 3.2.

All patients underwent a medical interview through a preset questionnaire including the detailed demographic data, medical history, as well as clinical examination. We have excluded any patient with infection, history of cerebrovascular stroke or ischemic heart disease, diabetes at onset of RA, and other autoimmune rheumatological diseases.

Laboratory studies

Complete blood counts were done using Coulter Counter T890 (Coulter Counter, Harpenden, UK), 1-h erythrocyte sedimentation rate was measured using Westergren’s method, C-reactive protein was measured using enzyme immunoassay, as well as fasting blood glucose, liver enzymes including serum ALT and serum AST, and kidney function tests including blood urea and serum creatinine were done. Lipid profile was carried out on Dimension RxL Max analyzer (Siemens Healthcare GmbH - Henkestr. 127, 91052 Erlangen, Germany) by colorimetric techniques. Fasting plasma insulin level (6 h fasting) was measured using enzyme-linked immunosorbent assay (ELISA), and calculation of insulin resistance by homeostatic model assessment of insulin resistance (HOMA-IR) was done as follows: [fasting insulin (mU/l)]×[fasting glucose (mmol/l)]/22.5. The reference range was 5–35 μ/ml. Measurements of serum RBP4 was done by ELISA technique; the reference range was 12 700–48 600 ng/ml.

Immunological tests

Rheumatoid factor IgM (rheumatoid factor IgM) was measured using enzyme immunoassay; the normal reference range for rheumatoid factor is less than 15 IU/ml. Anti-citrullinated peptide antibody was measured using ELISA technique; the normal value was less than 20 EU/ml.

Imaging and other investigations

ECG was done, as well as carotid artery ultrasound by GE VIVID 7 apparatus (GE Ultrasound: Horten, Norway) with tissue Doppler imaging capability using the superficial probe (7 MHz), with normal carotid intima media thickness (CIMT) of less than or equal to 0.8 mm. Plain radiograph on both hands was done.

Statistical analysis

Data were analyzed using Statistical Program for Social Science (SPSS), version 18.0. Quantitative data were expressed as mean±SD. Qualitative data were expressed as frequency and percentage. Comparison of the mean±SD of groups was done using Student t test. Measurement of the mutual correspondence between two value was done using Pearson correlation coefficient (r) test. P value less than 0.05 is considered significant, P value less than 0.01 is considered as highly significant, and P value more than 0.05 is considered insignificant. Moreover, receiver operating characteristic curve was used to assess the best cutoff point with sensitivity, specificity, positive and negative predictive value, and area under curve.


  Results Top


This is a cross-sectional case–control study that enrolled 50 patients with RA diagnosed according to American College of Rheumatology criteria [5], who were divided into three groups: group Ia comprised patients with severe disease activity, group Ib comprised patients with moderate disease activity and comprised group Ic patients with mild disease activity, together with 40 apparently healthy individuals as a control group (group II).

The demographic, clinical characteristics, and laboratory data of the studied patients with RA are shown in

[Table 1],[Table 2],[Table 3],[Table 4], respectively. The DAS28, carotid duplex, and blood pressure finding in 50 patients with RA are shown in [Table 5],[Table 6],[Table 7], correspondingly, and [Figure 1].
Table 1 Demographic characteristics of 50 patients with rheumatoid arthritis

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Table 2 The main clinical manifestation of 50 patients with rheumatoid arthritis

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Table 3 Frequency of extra-articular manifestation in 50 patients with rheumatoid arthritis

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Table 4 Laboratory data among 50 patients with rheumatoid arthritis

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Table 5 Disease activity score 28 among studied patients with rheumatoid arthritis

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Table 6 Carotid duplex finding in 50 patients with rheumatoid arthritis

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Table 7 Blood pressure finding in 50 patients with rheumatoid arthritis

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Figure 1 Disease activity score 28 (DAS28) among studied patients with RA.

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Group Ia comprised patients with severe disease activity. This group included 12 patients with RA who had a DAS more than 5.1. All patients were females (100%), and their age ranged from 24 to 58 years, with mean±SD of 40.58±10.70, and the disease duration ranged from 1 to 20 years, with a mean of 10.33±5.97.

Group Ib comprised patients with moderate disease activity. This group included 27 patients with RA with moderate disease activity who DAS more than 3.2 but less than or equal to 5.1. There were 22 (81.5%) females and five (18.5%) males, and their age ranged from 28 to 61 years, with mean±SD of 49.56±8.25 years, and the disease duration ranged from 2 to 25 years, with mean±SD of 9.96±5.20 years.

Group Ic comprised patients with mild disease activity. This group included 11 patients with RA with mild disease activity who had a DAS less than or equal to 3.2. All were females (100%), and their age ranged from 32 to 58 years, with mean±SD of 42.54±7.99 years, and the disease duration ranged from 3 to 12 years, with mean of 7.64±3.23 years.

Group II included 40 healthy participants as a control group. There were 31 (77.5%) females and nine (22.5%) males, and their age ranged from 26 to 58 years, with mean age of 42.70±7.57 years.

The RBP4 in total patients with RA (group I) and in group Ia (severe disease activity), group Ib (moderate disease activity), and group Ic (mild disease activity) are shown in [Table 8] and [Table 9].
Table 8 Comparison between patients with rheumatoid arthritis and control group as regard retinol-binding protein 4

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Table 9 Comparison among groups Ia, Ib, and Ic regarding retinol-binding protein 4

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There was a highly significant increase of RBP4 in the total patients with RA when compared with control group (group II) (P<0.01) ([Table 8] and [Figure 2]). There was a highly significant increase in RBP4 in group Ic compared with groups Ia and Ib and also in group Ib compared with group Ia (P<0.01) ([Table 9]).
Figure 2 Comparison between patients with RA and control group regarding RBP4. RA, rheumatoid arthritis; RBP4, retinol-binding protein 4.

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In patients with RA, there was a statistically significant positive correlation between the level of RBP4 and BMI and CIMT (CIMT RT, CIMT LT, and mean CIMT) (r=0.319, 0.292, 0.315, and 0.323, and P<0.05, 0.05, 0.05, and 0.05, respectively) ([Table 10] and [Figure 3],[Figure 4],[Figure 5],[Figure 6]). There was a statistically significant negative correlation between RBP4 and systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, DAS, and erythrocyte sedimentation rate (r=−0.421, −0.344 −0.389, −0.385, and −0.325 and P< 0.01, 0.05, 0.01, 0.01, and 0.05, respectively) ([Table 10]).
Table 10 Correlation between retinol-binding protein 4 and demographic data and carotid intima media thickness in patients with rheumatoid arthritis

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Figure 3 Correlation between RBP4and BMI in 50 patients with RA (r=0.319, P<0.05). RA, rheumatoid arthritis; RBP4, retinol-binding protein 4.

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Figure 4 Correlation between RBP4 and RT CIMT in 50 patients with RA. CIMT, carotid intima media thickness; RA, rheumatoid arthritis; RBP4, retinol-binding protein 4.

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Figure 5 Correlation between RBP4 and LT CIMT in 50 patients with RA. CIMT, carotid intima media thickness; RA, rheumatoid arthritis; RBP4, retinol-binding protein 4.

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Figure 6 Correlation between RBP4 and mean CIMT in 50 patients with RA. CIMT, carotid intima media thickness; RA, rheumatoid arthritis; RBP4, retinol-binding protein 4.

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The cutoff point for retinol was more than or equal to 24.8 IU, with sensitivity of 76.00%, specificity of 90%, positive predictive value of 90.5, and negative predictive value of 75.00, as shown in [Table 11] and [Figure 7].
Table 11 Receiver operating characteristic curve to differentiate between 50 patients with rheumatoid arthritis and control group regarding retinol-binding protein 4

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Figure 7 Receiver operator characteristic curve (ROC) between patients with RA and control group as regard retinol. RA, rheumatoid arthritis.

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  Discussion Top


RA is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens [7].

Epidemiologic data suggest that patients with RA have increased prevalence of premature atherosclerosis even after adjusting for traditional cardiovascular risk factor [2]. There were two key aspects in the pathogenesis of cardiovascular disease in course of RA: the chronic inflammatory state and the apparent paradoxical alteration of lipid profile [2]. This accelerated atherosclerosis and increased risk of cardiovascular disease in patient with RA may be influenced at least in part by the presence of IR [8].

RBP4 was discovered to be an adipokine in that it is produced by adipocytes and induces gluconeogenesis by stimulating phosphoenolpyruvate carboxykinase in the liver and impairs peripheral and hepatic insulin sensitivity [4].

This study was done to measure the serum RBP4 level in patients with RA and to assess its clinical relevance to cardiometabolic risk and carotid atherosclerosis in RA.

The results of our study showed that there was a highly statistically significant increase in RBP4 in all patients with RA in comparison with the control group. This agreed with Dessein et al. [9], who studied 217 patients with RA and found increased RBP4 in all patients with RA. On the contrary, our results disagreed with Amaro et al. [8], who in a study conducted on 101 patients with RA found a significant decrease of RBP4 in the whole group of patients with RA.

RBP4 concentrations are positively related to oxidative stress markers and may have a role in the initiation of endothelial inflammation. Farjo et al. [10] indicated that RBP4 induces gene expression of factors that are implicated in the initiation of vascular inflammation. Li et al. [11] reported that RBP4 has a major role in plaque rupture by increasing vascular smooth muscle cell proliferation. RBP4 is also known as an independent determinant index of plaque severity [12].

Our study revealed a strong positive correlation between RBP4 and CIMT, both right and left, and means CIMT, and this was similar to Crouse et al. [13], who reported that RBP4 is positively related to carotid artery intima media thickness and considered as a marker of subclinical atherosclerosis. Moreover, these results are in agreement with Dessein et al. [9], who reported that RBP4 concentrations were independently associated with enhanced atherosclerosis in patients with RA with generalized or/and abdominal obesity, and Bobbert et al. [14], who reported that circulating RBP4 levels have been positively correlated with intima-media thickness.

In the present study, obesity was evident in 66% of patients with RA. This agreed with the previous studies which reported a positive association between obesity and the risk of RA development [15],[16]. In this study, we found a strong positive correlation between RBP4 and BMI, which is in agreement with Yang et al. [17], who indicated that RBP4 was adipokine and its concentrations are elevated in insulin resistance and was associated with obesity and type 2 diabetes. Several other studies observed high concentration of RBP4 in obesity as a chronic inflammatory state and its complication, including type 2 diabetes, metabolic syndrome, and cardiovascular disease [18],[19],[20].

In the present study, elevated blood pressure was evident in 28% of patients with RA. This agreed with Panoulas et al. [21], who found an increased prevalence of hypertension in patients with RA compared with the general population. Moreover, we found a negative correlation between RBP4 and systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure, and this was in agreement with Solini et al. [22], who found an inverse relation between RBP4 and flow-mediated vasodilatation.Our study revealed no significant correlation between RBP4 and lipid profile and HOMA-IR, which is in agreement with a study by Dessein et al. [9], who revealed that RBP4 concentrations are inversely related to metabolic risk. Moreover, this agreed with Amaro et al. [8], who reported no correlation between RBP4 and presence of IR in patient with RA. This was different from Wei et al. [23], who found a positive correlation between serum levels of RBP4 and HOMA-IR score in 403 patients with RA.

In the present study, there was a statistically significant negative correlation between RBP4 and DAS in patients with RA. Amaro et al. [8] found that RBP4 levels do not correlate with disease activity in patients with RA. On the contrary, our results disagreed with Wei et al. [23], who found a positive correlation between increased serum RBP4 and increased severity of RA. Additional studies are needed to confirm this observation.


  Conclusion Top


In conclusion, level of RBP4 is increased in patients with RA compared with control and increased level of RBP4 is associated with presence of atherosclerosis in patients with RA as proved by CIMT. RBP4 has a significant negative correlation with the disease activity as evaluated by DAS28. So RBP4 could be used as marker for early prediction of premature atherosclerosis in patients with RA. All patients with RA should be screened for presence of atherosclerosis for early prevention, and further studies are needed to assess role of RBP4 in atherosclerosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Lambadiari V, Kadoglou NP, Stasinos V, Maratou E, Antoniadis A, Kolokathis F et al. Serum levels of retinol-binding protein-4 are associated with the presence and severity of coronary artery disease. Cardiovasc Diabetol 2014; 13:121.  Back to cited text no. 20
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11]



 

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