Metabolic syndrome in rheumatoid arthritis patients: Relationship among its clinical components

Abstract Background Metabolic syndrome (MetS) prevalence in rheumatoid arthritis (RA) patients is known to vary considerably across the world. This study aimed to determine the prevalence of MetS in RA patients from western Mexico and to analyze the interrelation of the MetS components with the clinical variables of RA. Methods This case‐control study included 216 RA patients and 260 control subjects (CS). MetS prevalence was determined according to the NCEP/ATP III and the Latin American Consensus of the Latin American Diabetes Association (ALAD) criteria. Results MetS was observed in 30.6% RA patients and 33.3% of controls (p > 0.05) according to NCEP/ATP III and 28.7% in RA patients and 31.1% for controls using ALAD criteria. Total cholesterol, LDL‐C, and Castelli's I‐II indexes were lower in RA (p < 0.001) than in CS. The RA patients with MetS had more swollen joints than those without MetS (p = 0.018). In RA patients with MetS, DAS‐28 score correlated with smoking index (rho = 0.4601, p = 0.0004) and VLDL‐C (rho = 0.3108, p = 0.0056); similarly, rheumatoid factor (RF) correlated with age (rho = 0.2031, p = 0.0027), smoking index (rho = 0.3404, p < 0.0001), triglycerides (rho = 0.1958, p = 0.0039), and VLDL‐C (rho = 0.1761, p = 0.0162). Conclusions The MetS prevalence in RA patients from western Mexico is not higher than controls; however, in RA patients with MetS, some inflammatory markers are associated with MetS components; thus, the control of MetS in RA could be beneficial to regulate disease activity.


| INTRODUC TI ON
Rheumatoid arthritis (RA) is an autoimmune inflammatory rheumatic disease associated with high levels of inflammatory markers and chronic comorbidities such as cardiovascular disease (CVD). [1][2][3][4] It has been demonstrated that RA life expectancy is reduced compared to that of the general population. Currently, CVD is the leading cause of mortality in patients with RA, being approximately 50% of the total of RA-associated deaths. 1,3,5 The RA is also associated with insulin resistance, dyslipidemia, and altered adipokines profile, which are included as metabolic syndrome (MetS) components. 6 MetS is defined as a set of manifestations that are contemplated as cardiovascular risk factors (obesity, glucose intolerance, dyslipidemia, and hypertension), that along with systemic inflammation, contributes to CVD, [7][8][9] and the prevalence of MetS has been associated with disease activity in RA. 8,9 In several populations, the overall risk of developing MetS seems to be significantly higher among patients with RA than in healthy controls; however, this differs considerably, based upon the diagnostic criteria used and the population ancestry. 10 On the other hand, the relationship between RA and MetS showed a significantly negative correlation in other countries such as Korea. 11 In Latin American countries, including Mexico, [12][13][14] there have been few solid studies regarding this topic 10 ; therefore, more research is needed to understand the metabolic changes of MetS in RA and its critical role in the development of CVD in RA patients from different geographic regions.
The biochemical profiles in RA occasionally does not reflect what observed in the general population, for example, low total cholesterol levels in RA patients have been associated with an increased cardiovascular risk, as well as, a high body mass index (BMI) has a protective effect on the amount of joint destruction in small joints in early RA. [15][16][17] The RA association with MetS also differs between chronic and early RA, 3,9 and the role of different characteristics of the disease, such as disease duration, activity, and the frequency of treatments, is not well defined yet. [17][18][19][20] Identifying MetS components in RA patients could provide a crucial opportunity for a preventive intervention; however, the controversy is evident about which factors are the most important to drive RA-associated MetS. [18][19][20] This study aimed to assess the prevalence of MetS in RA patients from western Mexico and analyze the interrelation of the MetS components with the clinical variables of RA.

| Subjects
From February 2017 to May 2019, 216 RA patients and 270 control subjects (CS) were enrolled. The sample size was calculated with OPENEPI calculator 21 to detect an 80% statistical power with a confidence degree of 95% and an expected prevalence of MetS in RA patients of 17.5% reported in a previous study. 12 The Ethics Committee approved the protocol of the Hospital "Fray Antonio Alcalde" (HCG/CEI-0153/18); written informed consent was obtained from all individuals.
According to the ACR 1987 classification criteria, 22 RA patients were diagnosed by a rheumatologist. They were enrolled in the study when they came to their clinical control visit at the Department of Internal Medicine/Rheumatology of the OPD Hospital Civil de Guadalajara "Fray Antonio Alcalde" in the state of Jalisco, Mexico.
The rheumatologist conducted a medical record and 28 joints evaluation to estimate the clinical activity using the Disease Activity Score-28 (DAS-28). 23 The CS group included subjects without either known medical condition or treatment, with similar age, sex, and geographic regions as the RA group. They were randomly selected from the clinical laboratory of the OPD Hospital Civil de Guadalajara "Fray Antonio Alcalde" when they went for a regular health check-up. The evaluation of physical activity, food consumption, and smoking index (number of cigarettes smoked per day × years of tobacco use) was realized during a personal interview in both study groups. Subjects were excluded from the study if they suffered from congestive heart disease, renal disease, endocrinological abnormalities, or were under medications that altered blood pressure, glucose, or lipid metabolism.

| Anthropometric measurements
Anthropometric measurements were determined for all individuals with absolute reliability. Weight was measured with the subjects wearing lightweight clothes without shoes, and after an overnight fasting, using a standard scale (TANITA BC-568 INNERSCAN).
Height was measured and approximate to the nearest 0.1 cm using a Seca 213 mobile stadiometer, with the participant standing in a vertical plane with head in the Frankfort horizontal plane. Waist circumference was measured at the minimum circumference between the iliac crest and the lowest rib. Blood pressure was measured twice, while the patients were seating and resting for 5 min, using a digital sphygmomanometer. BMI was calculated as weight (kg) divided by height squared (m 2 ). Serum C-reactive protein (CRP) levels were determined by immunoturbidimetry (OSR6147). Castelli's Risk Index I was calculated as total serum cholesterol (mg/dl) divided by HDL-C (mg/dl), and Castelli's Risk II was calculated as LDL-C (mg/dl) divided by HDL-C (mg/dl).

| MetS definition
Subjects were diagnosed with MetS based on NCEP ATP III 24

and The
Latin American Consensus of the Latin American Diabetes Association (ALAD) 25 criteria. Demographic data were collected by questionnaire.

| Statistical analysis
Statistical analysis was performed using GraphPad Prism v6.0. The Shapiro-Wilk normality test was applied to verify the normal distribution of the data. As it is appropriate, parametric or non-parametric tests were used for the analysis. The nominal discontinuous variables were expressed as frequencies (number and percentages); the continuous variables with parametric distribution were expressed as means ± standard deviation (SD) and the non-parametric variables as medians and interquartile ranges. The chi-square (χ 2 ) test was used to compare proportions. Student's t test was applied for two groups parametric quantitative analysis, and the Mann-Whitney U test was used for non-parametric quantitative determinations. Spearman's correlation analysis was used to discover the strength of a link between two sets of data. A multivariate logistic regression model was used to examine the independence of the predictors of RA parameters and MetS. A probability (p) value of less than 0.05 (p < 0.05) was considered significant.

| Clinical and demographic characteristics
The demographic, clinical, and laboratory characteristics of RA patients and control subjects (CS) are described in Table 1

| Biochemical and paraclinical parameters of CS and RA patients
Glucose, lipid profile, and the Castelli's risk index-I (CRI-I) and (CRI-II) were determined in both study groups.

| Frequency of MetS in CS and RA patients
According to NCEP/ATP-III criteria, the overall frequency of MetS was 33.3% in CS and 30.6% in RA patients (p = 0.514, Table 3). This result did not suffer significant variations after adjusting for height and weight (p = 0.325). The waist circumference criterion was more

| Relationship of MetS parameters with RA characteristics
As it was expected, Table 4 shows that all lipid and paraclinical components of MetS were higher in RA patients with MetS (p < 0.05) than those without MetS. However, the inflammatory parameters (CRP, ESR, RF) and the activity of the disease (DAS-28 index) did not show significant differences between both groups (p > 0.05).
Multivariate logistic regression analysis did not show any variable with statistical significance (data not shown).
A Spearman correlation analysis was performed between the activity variables of RA (RF, CRP, ESR, and disease activity) and the parameters of MetS. Table 5   groups. Nevertheless, a potential weakness of this study could be the differences observed between weight, size, and meals per day between groups (p < 0.001), being RA patients lighter and less tall than controls, but not BMI changes were observed. RA patients also reported a lower number of meals per day, even though multivariate analysis models did not show any changes according to these variables (data not shown).

| D ISCUSS I ON
Considering the previous findings among the Mexican population, [12][13][14] we suggest that ethnicity could be a significant component of the differences between MetS prevalence in RA patients from Mexico and other countries. However, as nutritional habits are major risk factors for MetS, a more detailed and validated survey evaluation of food consumption is also further required to clear this hypothesis, including the amount of food, energy, and nutrients consumed, or patterns of food consumption and physical activity.
The differences regarding weight (p = 0.0001) and the number of meals eaten per day (p < 0.0001) between RA and CS could be due to a "rheumatoid cachexia" status in RA patients, which includes a loss of cell mass (skeletal muscle) and the increase in fat mass, resulting in an apparently stable body composition throughout life. 32 It has been studied that the development of depressive factors due to RA pathology's disabling effects 33 could be one of the likely causes answers to minor food intake throughout the day, and also to the low weight among RA patients.  41 Based on these findings, we suggest that MetS is not a subsequent RA pathophysiology event, but it could be a promoter of some of components that influence the disease activity or disability.
On the other hand, there was a positive correlation between disease activity (DAS-28 score) in RA patients with MetS with smoking index and VLDL-C levels. This finding could be explained by the effect of tobacco smoking on tissue protein citrullination, and also detonate of autoantibodies synthesis, which show to induce the disease progression and disease activity in patients with rheumatoid arthritis. [42][43][44] On the other hand, the association of DAS-28 and VLDL-C levels is not clear yet, but it has been reported that RA patients with high disease activity had alterations of the lipid profile. 38,45 Rheumatoid factor (RF) correlated with age and smoking index, which agrees with other reports [46][47][48] ; likewise, RF correlated with triglycerides, which could be explained by this autoantibody´s positive correlation with a high RA disease activity, 49 a status associated with lipids alteration.
Regarding the correlation of CRP with some MetS components such as weight, waist circumference, and BMI, it could be explained by the fact that because these factors are the primary determinant of chronic inflammation in subjects with the MetS and are strongly related with proinflammatory cytokines such as IL-6, which induces the synthesis of CRP. 50 Some limitations of this study are that most patients were being treated on a combined drug therapy, since some drugs like chloroquine could alter metabolism, lipid profile, and inflammation markers in RA. Also, patients with a low disease activity (DAS-28 ranges of 2.6-3.9) were overrepresented because most of the patients (75%) had DAS-28 < 3.9.
In conclusion, the present study's findings suggest that there is

ACK N OWLED G M ENTS
The authors thank all the contributors of this work.

CO N FLI C T O F I NTE R E S T
There is no conflict of interest in this work.

DATA AVA I L A B I L I T Y S TAT E M E N T
All the data related to this work are available at the corresponding author. The data used to support the findings of this study are included in the article.