Association between metabolic syndrome, BMI, and serum vitamin D concentrations in rheumatoid arthritis
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Rheumatoid arthritis (RA) is the most common autoimmune arthritis. The impact of chronic inflammation on atherosclerosis and insulin resistance has been observed in several autoimmune diseases. On the other hand, metabolic syndrome (MetS); a cluster of traditional risk factors for atherosclerosis and diabetes seems to be prevalent in RA patients. It is reasonable to think that protective factors against inflammation can protect patients against atherosclerosis and diabetes, too. Vitamin D (Vit D), a novel immunomodulator, is recently considered to play a protective role against cardiovascular diseases, insulin resistance, and obesity. This cross-sectional study was designed to evaluate the impact of serum Vit D on MetS and body mass index (BMI). One hundred twenty RA patients were enrolled. MetS was assessed according to Adult Treatment Panel III criteria. All patients with known confounders influencing Vit D serum levels were excluded. Serum value of 25-hydroxyvitamin D (25(OH)D) was measured using a commercial ELISA kit. Data were analyzed by SPSS software. A logistic regression analysis stated that prednisolone dosage [p = 0.028, β = 0.177, odds ratio (OR) = 1.194, confidence interval (CI, 1.09–1.32)], age [p = 0.002, β = 0.146, OR = 1.57, CI (1.05–1.27)] and Vit D serum levels [p = 0.049, β = −3.766, OR = 0.023, CI (0.001–0.978)] are all significant predictors of MetS occurrence in RA patients. It was shown that 25(OH)D is a protective factor against MetS. It was also shown that there is a negative correlation between BMI and 25(OH)D serum levels (P = 0.037, rs = −0.266). In summary, this study suggested that 25(OH)D plays a protective role against MetS in RA patients. However, this cross-sectional study did not permit a power calculation on the causal relationship between Vit D and metabolic syndrome. On the other hand, Vit D has a negative correlation with BMI in these patients.
KeywordsBMI Body mass index Metabolic syndrome Rheumatoid arthritis Vitamin D
Rheumatoid arthritis (RA) is the most common systemic autoimmune arthritis that affects 0.5–1 % of the population . RA is associated with increased morbidity and mortality [2, 3]. Emerging epidemiological evidence suggests that cardiovascular diseases (CVDs) account for about half of all deaths in this population.
Metabolic syndrome is a cluster of traditional risk factors that include hyperglycemia, hypertriglyceridemia, low level of high-density lipoprotein cholesterol (HDL-C), hypertension, and central obesity , which is considered as a strong predictor for diabetes and CVDs [5, 6].
Recent population-based, cross-sectional studies propose that vitamin D can contribute to an increased risk of cardiovascular diseases and metabolic syndrome (MetS) [7, 8, 9, 10]. Vitamin D (Vit D) concentrations are also suggested to be associated with obesity [11, 12]. However, in the setting of RA, the clinical consequences of vitamin D deficiency remain a matter of debate [13, 14, 15]. It is supposed that vitamin D deficiency is associated with autoimmune diseases [13, 14, 15]. However, the correlation among vitamin D, autoimmune diseases, and metabolic syndrome is not clearly understood. In particular, the association between Vit D deficiency and MetS among RA patients is not known.
In this study, we aimed to determine whether a low serum concentration of 25-hydroxyvitamin D (25(OH)D) is associated with MetS among RA patients or not. We assumed that a low serum 25(OH)D level is an independent risk factor for MetS in RA. Therefore, it was hypothesized that RA patients with lower serum concentrations of 25(OH)D would be more likely to develop MetS compared with patients with higher levels of Vit D. In other words, investigating the correlation between serum values of 25(OH)D and MetS and its components like hypertension, diabetes, and hyperlipidemia is the main goal of this study. Affirmation of this correlation would distinguish hypovitaminosis D as a potentially modifiable diabetes and cardiovascular risk factor among RA patients.
Materials and methods
One hundred and twenty RA patients including 106 (88.3 %) females and 14 (11.7 %) males with different stages of disease activity were enrolled in this cross-sectional study. The study was conducted in Mashhad city, Iran, which is located at 36.20° latitude and 59.35° east longitudes. All RA patients fulfilled the 1987 American College of Rheumatology revised criteria for RA. Every consecutive patient who did not have exclusion criteria of this study was recruited from clinical RA cohorts, local rheumatologists, and rheumatology clinics of two of our university hospitals between January 2009 and March 2010. The exclusion criteria were considered as follows: use of vitamin D injectable compounds or vitamin D pearls (more than physiologic doses) in the previous 6 months, anticonvulsive therapy and a prior history or clinical features of medical conditions including intestinal surgery, malignancies, parathyroid disorders, recent or chronic diarrhea, malabsorption, renal insufficiency, liver failure, and infections. All patients in this study were treated with daily doses of hydroxychloroquine 6 mg/kg and calcium–Vit D tablets including 1,000 mg calcium and 800 units of vitamin D (physiologic doses).
At baseline, volunteers' demographic, anthropometric, clinical, and laboratory data were collected for evaluation of MetS. MetS were defined by the presence of any three of the following five characteristics according to the National Cholesterol Education Program's Adult Treatment Panel III report: abdominal obesity based on waist circumference (>102 cm in men and >88 cm in women), triglycerides at least 150 mg/dl, high-density lipoprotein (HDL) below 40 mg/dl for men and 50 mg/dl for women, blood pressure at least 130/85 mmHg, and fasting glucose at least 110 mg/dl (or who are undertreatment for hyperlipidemia, hypertension, or diabetes) . Vitamin D deficiency is defined as a 25-hydroxyvitamin D serum level of less than 50 nmol per liter. Serum values of 25(OH)D of 51 to 75 nmol per liter is considered as vitamin D insufficiency . According to an epidemiologic study in our country which included Mashhad city (the city in which this study was conducted) another classification was defined: 25(OH)D serum values more than 35 nmol/L is considered sufficient Vit D, 25 < 25(OH)D ≤ 35 nmol/L and 25(OH)D ≤ 25 nmol/L were considered insufficiency and deficiency, respectively.
All participants gave an informed written consent prior to participation in this study, which was approved by the Ethic Committee of Mashhad University of Medical Sciences.
Anthropometric parameters including height, weight, waist circumference, and body mass index (BMI), as well as systolic and diastolic blood pressures were measured for all participants. Height (centimeters) was recorded in all subjects without shoes, and weight (kilograms) was measured for participants in light clothing using electronic weighing scales. Waist (at the level of the umbilicus) and hip (defined as the widest part of the body below the waist) measurements were also taken, and the WHR was computed. BMI was computed using weight in kilograms divided by the square of the height in meter. For measuring blood pressure, the participants remained seated for 15 min and at least two readings of blood pressure were taken.
Fasting blood sugar (FBS), lipid profile including total cholesterol, triglycerides, HDL-C, and low-density lipoprotein cholesterol (LDL-C) were determined for each participant after an overnight fasting. Erythrocyte sedimentation rate (ESR) was measured by Westergren method. After being allowed to clot, the blood was then centrifuged at 2,500 rpm for 15 min at room temperature to obtain serum. Hemolyzed samples were excluded from analysis. Serum was stored at −20 °C prior to analysis. Serum FBS and lipid profile were measured by enzymatic methods. Serum 25(OH)D was measured using a commercial ELISA kit (immunodiagnostic system, UK) in accordance with manufacturer's instruction.
Their assessment also included a structured interview, laboratory tests, review of medical records and smoking habits including cigarette and hookah, and personal or family history of ischemic heart disease.
The SPSS software (version 11.5, Chicago, IL, USA) was used for statistical analysis. Kolomogrov–Smirnov test was used to evaluate the normality of data. Values were expressed as mean±SD for normally distributed variables and median with interquartile range (IQR) for non-normally distributed data. Baseline demographics and clinical characteristics were compared between groups using independent samples t test, Mann–Whitney U test, chi-square, and/or Fisher's exact test, as appropriate. Bivariate correlations were assessed using Pearson's and Spearman's correlation coefficients for normally and non-normally distributed data respectively. Variables including Vit D or those of clinical interest in development of MetS were selected for logistic regression analysis of variance. Odds ratios with a 95 % confidence interval were calculated. A P value < 0.05 was considered significant. As Vit D serum values did not have statistically normal distribution, its logarithm was used for computing logistic regression analysis. Potential confounding variables including age, sex, season of Vit D measurement and medications such as methotrexate and prednisolone dosage were evaluated by forward conditional model.
One hundred twenty patients (106 women and 14 men) participated in this study. There was no significant difference between RA patients with and without MetS regarding gender and age. Thirteen patients had early RA (less than 6-month history of arthritis). The average age and BMI of our subjects were 45.5 years and 26.8 kg/m2, respectively.
The mean duration of the disease was 5.5 ± 5.2 years. The patients had a mean ESR of 20 (13–37) mm/h, CRP 20 (0–40) mg/L, and rheumatoid factor (RF) 20 (0–40) units/mL. Antibodies to cyclic citrullinated peptides were positive in 70 % and RF was positive in 79 % of sera of this population. Patients' drug history included prednisolone with an average dose of 5.5 ± 3.6 mg/day (108 patients), 6 mg/kg of hydroxychloroquine (all patients) and methotrexate with an average dose of 7.9 ± 5.7 mg per week (90 patients). Besides, 32 patients were being treated with sulfasalazine or azathioprine; six patients were under treatment with rituximab or infliximab in addition to mentioned drugs. All patients received supplementary calcium (1,000 mg/day) and vitamin D (800 U/day). Thirteen patients had early RA (duration of RA less than 6 month). Seven percent of our patients were smoker. The mean disease activity score (DAS28ESR) of patients was 4.45 ± 1.67.
Demographics of total patients, patients with and without MetS
Demographics and metabolic components
Patients (n = 120)
MetS (n = 54) 45.2 %
No MetS (n = 66) 54.8 %
P value (patents with MetS vs. patients without MetS)
Age (years), mean±SD
45.49 ± 14.21
53.25 ± 9
42.47 ± 14.8
P < 0.001
t = 3.6
Systolic BP (mmHg), median (IQR)
z = 3.7
Diastolic BP (mmHg), median (IQR)
z = 3.15
Weight (kg), median (IQR)
z = 2.5
Belt circumference (cm), median (IQR)
z = 4.76
BMI (kg/m2), mean±SD
26.57 ± 4.7
28.74 ± 4.6
25.7 ± 4.5
t = 2.99
FBS (mg/dL)a, median (IQR)
z = 2.6
Triglyceride (mg/dL)a, median (IQR)
z = 3.49
Cholesterol (mg/dL)a, mean±SD
216 ± 180
204.35 ± 178.5
248 ± 185
t = 1.02
LDL-C (mg/dL)a, mean±SD
115.6 ± 35
122.5 ± 42.8
113.2 ± 31.8
t = 1.05
HDL-C (mg/dL)a, mean±SD
47.13 ± 12.7
4,522 ± 9.5
47.9 ± 13.9
t = 0.93
The mean serum concentration of 25-hydroxyvitamin D was 57.15 ± 34.96 nmol/L. Forty six percent of patients had vitamin D deficiency (serum values less than 50 nmol/L) and 26 % had vitamin D insufficiency (serum values between 51 and 75 nmol/L).
Association between 25-hydroxyvitamin D levels and metabolic syndrome
In this study, up to 45.2 % of 120 participants met the definition of MetS. Among patients without MetS (54.8 % of patients), 67 % were vitamin D sufficient [25(OH) D ≥ 50 nmol/L].
Logistic regression analysis of predictors for MetS occurrence in RA patients
95 % Confidence interval
The Vit D effect on concomitance of MetS with RA was evaluated by logistic regression analysis of variance. Confounding factors including age, gender, season of sampling, and dosage of prednisolone and methotrexate were controlled by the forward conditional method. Statistical analysis showed that gender (p = 0.3), season of sampling (p = 0.46), and methotrexate dosage (p = 0.95) had no effect on this association. A logistic regression analysis revealed that prednisolone dosage, age of patients, and Vit D serum levels were all significant predictors of MetS occurrence in RA patients. It was shown that 25(OH)D is a protective factor against MetS (Table 2). In the presence of other variables, the statistical analysis showed that BMI has no direct influence on MetS. In addition, we found no association between MetS and prednisolone dosage (p = 0.16, t = −1.4).
Association between 25-hydroxyvitamin D levels and BMI
distribution of BMI in different 25(OH)D serum values of RA patients
Vitamin D (nmol/L)
12.5 < Vit D ≤ 25
25 < Vit D ≤ 35
Vit D > 35
33.06 ± 2.12
25.98 ± 3.28
25.9 ± 5.06
In this study, we found a high prevalence of Vit D insufficiency among RA patients. Although these patients received physiologic doses of Vit D, the conservative dress code in the country, nutritional Vit D deficiency, which is due to inaccessibility of Vit D-enriched food products in our country and sedentary life styles, which are caused by joint pain and morning stiffness are leading causes of Vit D insufficiency in our patients.
Vit D had a protective role against MetS. Likewise, we observed an inverse correlation between Vit D concentrations and BMI. Several studies suggest that low serum levels of Vit D may be common in RA [18, 19, 20]. Some other studies have observed a higher rate of MetS in RA patients [21, 22]. In a previous study on middle-aged individuals in our population, we did not find a significant difference between MetS among RA patients and age and sex match healthy controls. We found MetS to be more common in normal population (45.2 %) than in RA patients (30.8 %) .
Low Vit D status has been associated with an increased risk of MetS. Ford et al.  observed that individuals in the lowest quintile of 25(OH)D (<48.4 nmol/L) were twice as likely to contract MetS compared with those in the highest quintile (>96.4 nmol/L). Another recent cross-sectional analysis of 1,654 men and women reported a substantially lower odds ratio (OR) for MetS in the highest quintile of 25(OH)D (median 88.0 nmol/L; OR 0.15) compared with the lowest quintile (median 26.8 nmol/L; OR 0.46). The mechanisms by which low Vit D could be associated with MetS remain speculative . Several studies suggest that low 25(OH)D levels are associated with glucose intolerance and insulin resistance[25, 26]. For a long time, 1,25(OH)D has been known to be a positive regulator of insulin secretion by pancreatic β cells .
Numerous studies have observed that obesity is a negative predictor of vitamin D status [11, 28]. Data from the sixth Tromso study, which was a longitudinal analysis, showed an inverse association between serum 25(OH)D concentration and BMI in over 10,000 adults. Using data from the 1958 British birth cohort (n = 7,189), Hypponen and Power observed that 80 % of subjects (BMI > or = 30 kg/m2) had a 25(OH)D less than 75 nmol/L, compared with 68 % of the non-obese subjects.
To our knowledge, there is no report of an association between MetS and BMI with vitamin D concentrations in rheumatoid arthritis. The findings of our study are consistent with those of non-RA-affected individuals and suggest that; despite treatment with physiologic doses of Vit D, the inverse association between vitamin D and MetS is also persistent among RA patients. In our study, serum 25-hydroxyvitamin D levels were inversely correlated with BMI.
Inflammation has been long recognized as a hallmark of RA and plays a remarkable role in the development of type 2 diabetes mellitus and MetS. Several lines of evidence now suggest that atherosclerosis also has an important inflammatory component . Many of the cells comprising the inflammatory infiltrate in the joint lining are likewise found in atherosclerotic plaques .
Vitamin D has anti-inflammatory effects on RA patients, which may explain its protective role in type 2 diabetes mellitus and cardiovascular diseases . Vitamin D may lower the risk of metabolic syndrome in RA by reducing the heightened inflammation associated with the disease . Actions including suppression of vascular calcification, inhibition of vascular smooth muscle proliferation, modulation of inflammatory cytokines, and regulation of the renin–angiotensin system have all been described . In this study, we found a significant difference in hypertension and fasting blood sugar among patients with or without MetS, which is in agreement with previous findings in RA patients.
Strength and limitation
One of the criticisms of the epidemiological studies linking low Vit D levels with MetS is the fact that Vit D is fat soluble and these associations may be simply representative of the larger volume of distribution of this vitamin in overweight individuals who are also prone to diabetes and MetS by virtue of their adiposity. Hence, low Vit D levels may simply be as a result of adiposity without necessarily having a significant relation with MetS . In this study, MetS had higher prevalence in patients with higher BMI; howbeit, there was not a significant correlation between these two parameters. This may stem from the more important role of abdominal obesity, which is considered as waist circumference, in comparison to BMI in prediction of MetS. On the other hand, adiposity was not prevalent in our subjects (average BMI = 26.8 ± 4 kg/m2) that could partially eliminate this error. Besides, our patients were under treatment with hydroxychloroquine and supplementary physiologic doses of Vit D that are reported to increase Vit D serum levels. Thus, relative higher levels of vitamin D in our patients; as a consequence of these treatments, did not affect these correlations.
Our study had some limitations. Since we used a cross-sectional design, we could not establish whether the relationship between MetS and Vit D levels is causal. Besides, different unknown confounders may affect Vit D serum values in a point of time; therefore, in the next step a longitudinal study should be designed to establish the casualty of these findings. In addition, participants were from Mashhad, Iran, a homogeneous population, potentially limiting the generalizability of our results.
To summarize, we suggested that 25(OH)D plays a protective role against MetS in RA patients. We also found an inverse relationship between BMI and vitamin D concentration in these patients. However, this cross-sectional study did not permit a power calculation on the causal relationship between Vit D and metabolic syndrome. Future long-term clinical trials should examine whether vitamin D supplementation can reduce MetS burden in RA patients or not.
This article was extracted from the thesis prepared by Mrs. Ladan Ghoshayeshi to fulfill the requirements needed for earning the internal medicine specialty degree. The Research Council of the Mashhad University of Medical Sciences, Mashhad, Iran is appreciated for financially supporting this study, grant number . We are grateful to all patients for their kind participation.
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