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CLINICAL RESEARCH STUDY

Vitamin D, Metabolic Dyslipidemia, and MetabolicSyndrome in Rheumatoid ArthritisJoshua F. Baker, MD, MSCE,a Nehal N. Mehta, MD, MSCE,b,c Daniel G. Baker, MD,d Gary Toedter, PhD,e

Justine Shults, PhD,b Joan Marie Von Feldt, MD, MSEd,f Mary B. Leonard, MD, MSCEb,g

aDepartment of Medicine, Division of Rheumatology, bCenter for Clinical Epidemiology and Biostatistics, and cDepartment ofedicine, Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia; dClinical Immunology and eBiomarker,entocor Research and Development, Malvern, Pa; fDivision of Rheumatology, Veteran’s Affairs Medical Center, Philadelphia, Pa;

gChildren’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia.

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E-mail address

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ABSTRACT

PURPOSE: Vitamin D deficiency is a potential risk factor for cardiometabolic disease. We investigated theassociations between vitamin D and dyslipidemia and the metabolic syndrome in patients with rheumatoidarthritis, a group at high risk for cardiovascular disease.METHODS: Serum 25(OH)vitamin D and lipoprotein levels were measured at baseline in a random sample of499 participants, ages 18-85 years, enrolled in a randomized trial of golimumab (GOlimumab Before Employ-ing methotrexate as the First-line Option in the treatment of Rheumatoid arthritis of Early onset or GO-BEFORETrial). Participants had rheumatoid arthritis with active disease, and were naïve to methotrexate and biologictherapies. Multivariable linear regression was performed to assess associations between vitamin D levels andlipoprotein fractions. Multivariable logistic regression was performed to determine the odds of hyperlipidemiaand the metabolic syndrome in participants with vitamin D deficiency (�20 ng/mL).RESULTS: In multivariable linear regression, vitamin D levels (per 10 ng/mL) were associated inverselywith low-density lipoprotein (�: �0.029 [�0.049, �0.0091], P � .004) and triglyceride (�: �0.094�0.15, �0.039] P � .001) levels, adjusted for demographic, cardiovascular, and disease-specific vari-bles. Vitamin D and high-density lipoprotein levels were not associated in univariate or multivariatenalyses. Vitamin D deficiency was associated independently with an increased odds of hyperlipidemiaodds ratio 1.72; 95% confidence interval, 1.10-2.45; P � .014) and metabolic syndrome (odds ratio 3.45;

95% confidence interval, 1.75-6.80; P �.001) in adjusted models.CONCLUSIONS: In conclusion, vitamin D deficiency was associated with the metabolic syndrome anddyslipidemia in rheumatoid arthritis, suggesting a potential role in cardiovascular disease risk. Large-scale,prospective studies are needed to determine if vitamin D supplementation improves lipoprotein levels andreduces cardiovascular risk in rheumatoid arthritis.© 2012 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2012) 125,1036.e9-1036.e15

KEYWORDS: Lipoproteins; Metabolic syndrome; Rheumatoid arthritis; Triglycerides; Vitamin D

Funding: None.Conflict of Interest: None. Gary Toedter and Daniel Baker are em-

loyees of Janssen Biotech, Inc.Authorship: All authors had access to the data and a direct role in

riting the manuscript.Requests for reprints should be addressed to Joshua F. Baker, MD,

SCE, Division of Rheumatology, Department of Medicine, Hospital ofhe University of Pennsylvania, 8 Penn Tower Building, One Conventionenter Blvd., Philadelphia, PA 19104.

: bakerjo@uphs.upenn.edu

ront matter © 2012 Elsevier Inc. All rights reserved..1016/j.amjmed.2012.01.025

Recent studies have reported that vitamin D deficiency isassociated with an increased risk of cardiovascular diseasein the general population.1 Potential mechanisms includeup-regulation of the renin-angiotensin-aldosterone system,adverse effects on vascular endothelial and smooth musclefunction,2 and impaired glucose tolerance in vitamin D-de-ficient states.3 Vitamin D deficiency has been linked todyslipidemia and metabolic syndrome.4,5

Rheumatoid arthritis is associated with an increased

risk of dyslipidemia,6 metabolic syndrome,7 and cardio-

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1036.e10 The American Journal of Medicine, Vol 125, No 10, October 2012

vascular disease.8 Vitamin D deficiency also is commonn rheumatoid arthritis.9 How vitamin D deficiency mayelate to the cardiometabolic abnormalities often seen inhronic inflammatory diseases such as rheumatoid arthri-is is not known.

To our knowledge, the associ-tions between vitamin D defi-iency, dyslipidemia, and meta-olic syndrome have not beenxamined in systemic inflamma-ory diseases such as rheumatoidrthritis. The objective of thistudy was to examine the associa-ions among vitamin D levels,ow-density lipoprotein (LDL),riglyceride (TG), and high-den-ity lipoprotein (HDL) levels, andhe metabolic syndrome at base-ine in rheumatoid arthritis partici-ants in the randomized controlledrial of golimumab (GOlimumabefore Employing methotrexate as the First-line Option in

he treatment of Rheumatoid arthritis of Early onset orO-BEFORE Trial). Assessment of these associations willrovide greater insight into potentially modifiable risk fac-ors for metabolic syndrome and cardiovascular disease inhese high-risk patients.

METHODS

Study SettingGolimumab is a fully human monoclonal antibody to tumornecrosis factor alpha. This study is ancillary to the GO-BEFORE trial (Clintrials.gov identifier NCT00361335) thatincluded 637 rheumatoid arthritis patients. The study com-pared the efficacy of methotrexate or golimumab alone tocombination therapy with methotrexate and golimumab inmethotrexate and biologic therapy naïve subjects. The trialresults have been previously published.10

Subjects 18 years or older were recruited multinationallyfrom 90 centers. Inclusion criteria included meeting Amer-ican College of Rheumatology criteria for rheumatoid ar-thritis for at least 3 months and active disease defined by thepresence of at least 4 swollen and tender joints. Participantswere required to have at least 2 of the following: an elevatederythrocyte sedimentation rate or C-reactive protein; ero-sions on radiographs; an elevated cyclic citrullinated pep-tide antibody titer or rheumatoid factor; or morning stiffnessfor �30 minutes. Using a random-number generator, weselected 499 participants (80% sample) from the originaltrial and determined vitamin D levels at baseline, before theinitiation of therapy.

Vitamin D MeasurementVitamin D levels were measured on baseline samples stored at�70°C (Heartland Assays, Ames, IA). This laboratory uses a

CLINICAL SIGNIF

● Vitamin D deficigreater odds of pindependent of dverity, and cardamong subjects w

● Low vitamin D ledently associateprevalent metab

DiaSorin (DiaSorin Inc., Stillwater, Minn) 25(OH)vitamin D i

I125 radioimmunoassay method considered more sensitive andpecific than other radioimmunoassays without any significantositive or negative bias.11,12 The antibody has equal affinity

for both vitamin D2 and vitamin D3, and the assay has com-arable measurement characteristics to liquid chromatography,

tandem mass spectrometry, the goldstandard.11,13 Vitamin D deficiencywas defined as 25(OH) vitamin D�20 ng/mL based on the recent In-stitute of Medicine report.14,15

Wang et al16 have previously dem-onstrated that a cutoff of 15-20ng/mL best defines risk categoriesfor incident cardiovascular events inFramingham offspring.

It is accepted that 25(OH) vi-tamin D is the most appropriatemeasure of adequate vitamin Dstores,17 because 1,25(OH) vita-min D levels are often preservedin the case of deficiency. Fur-

hermore, recent literature suggests that 25(OH) vitaminis substrate for intracellular synthesis of 1,25 vitaminin monocytes, macrophages, and other immune cells

hat may be important in the development oftherosclerosis.18

Five possible geographic regions were assigned to par-ticipants based on the country of measurement (NorthAmerica, South America, Europe, Southeast Asia, and Aus-tralia). Season of vitamin D measurement was determinedusing the hemisphere of the country and the month ofmeasurement.

Outcome MeasuresAs part of the original trial, fasting whole blood sampleswere sent to Quintiles Central Laboratories (Quintiles, Dur-ham, NC) for laboratory studies including a standard clini-cal lipid profile (TG, total cholesterol, HDL, and calculatedLDL). This laboratory service is certified for standardiza-tion of lipid analyses by the Standardization Program of theCenter for Disease Control and Prevention and the NationalHeart, Lung and Blood Institute. Hyperlipidemia was de-fined as: 1) a TG level of �150 mg/dL; 2) an LDL of �160mg/dL; or 3) an HDL �50 mg/dL for women or �40 mg/dLfor men, as previously described.19,20 Participants that re-orted lipid-lowering therapy also were considered to haveyperlipidemia.

Metabolic syndrome was defined using the Internationaliabetes Federation definition and the Adult Treatmentanel III definition.21 Comparable results were obtainedsing both definitions; therefore, the International Diabetesederation criteria are presented throughout. Measures ofaist circumference were not available, thus metabolic syn-rome was considered present in an obese patient (bodyass index [BMI] �30) with any 2 of the following: an

levated TG level �150 mg/dL; an HDL level �40 mg/dL

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1036.e11Baker et al Vitamin D and Dyslipidemia in Rheumatoid Arthritis

mg/dL (or previous diagnosis of diabetes); or a previousdiagnosis of hypertension or treatment with medications forhypertension. We also evaluated metabolic syndrome as acategorical outcome in ordinal logistic regression using thecomponents of the syndrome. Because there were only 3subjects with all 5 components, the subjects with 4 or 5components were combined.

Potential confounders included estimated glomerular fil-tration rate (GFR) generated using the Modification of Dietin Renal Disease Study Equation.22 Nonlaboratory variablesevaluated included patient-reported regular aerobic exercise(yes/no), a history of smoking (ever/never), presence ofmetabolic syndrome, diabetes, and hypertension, and theuse of steroids at baseline. Disease activity was measuredusing the disease activity score 28 (DAS28), which incor-porated the erythrocyte sedimentation rate. Results from aHealth Assessment Questionnaire also were available.

Statistical AnalysisData were analyzed using Stata version 11 software (Stata-Corp LP, College Station, Tex). The association betweenvitamin D levels and continuous variables were assessedusing Spearman’s rank (for skewed correlations). Mean andmedian lipoprotein levels were tested for equality acrosscategorical variables using t-tests (or rank-sum tests fornonparametric data) and analysis of variance.

A primary goal of this study was to evaluate the associ-ations between vitamin D level (as a continuous and cate-gorical variable) and baseline lipoprotein and TG levelsusing multivariable linear and logistic regression analysis.In initial multivariable linear regression analysis, LDL, TG,HDL, and vitamin D levels were evaluated as continuousnatural log-transformed variables. Possible confoundingcardiovascular and disease-specific covariables were con-sidered in development of the model as described. Con-founding was considered present if the strength of associa-tion changed by more than 15% when the variable ofinterest was included in the model.23 Multivariable logisticegression models using categorical variables for the asso-iation between vitamin D deficiency (�20 ng/mL) and theresence of hyperlipidemia and presence of metabolic syn-rome were used to facilitate clinical interpretation of thetudy findings. Ordinal logistic regression also was used tovaluate the association of vitamin D deficiency and theumber of components of the metabolic syndrome (1, 2, 3,nd 4-5). Goodness of fit for regression models was evalu-ted using Hosmer-Lemeshow goodness-of-fit tests for lo-istic regression models and by graphing residuals andsing Wilk tests for linear regression models. The Brant testas used to test the proportional odds assumption in therdinal regression models.

RESULTS

Baseline Characteristics of ParticipantsSubject characteristics at enrollment are summarized in Ta-

le 1 in the entire sample and according to vitamin D p

eficiency category. Very few participants reported use ofitamin D supplements at baseline (2.2%). The medianitamin D level (interquartile range) among study partici-ants was 20.7 (14.5-28.2) ng/mL, with 48% of participantsefined as deficient (�20 ng/mL). Patients with vitamin Deficiency were older, had a higher BMI, and were moreikely to be female. Deficient patients also were significantlyore likely to have diabetes, hypertension, and metabolic

yndrome. Overall, 12.4% of participants met criteria for theiagnosis of metabolic syndrome and 49.4% were defined asaving hyperlipidemia. Thirty-one patients (6.2%) were onipid-lowering therapy.

Association of Vitamin D and LipoproteinsMedian LDL and TG levels varied significantly accordingto vitamin D level (P �.01) (Figure). Linear regressionanalyses demonstrated a significant inverse association be-tween vitamin D levels and LDL and TG levels (Table 2).These associations were unchanged after adjusting for age,sex, race, BMI, GFR, DAS28, season of measurement,geographic region, steroid use at baseline, diabetes, hyper-tension, and exercise. The associations remained significantand unchanged in magnitude after excluding patients onlipid-lowering therapy. In contrast, there were no significantassociations between vitamin D and HDL levels (data notshown) in any of the models.

The associations between vitamin D deficiency (�20ng/mL) and hyperlipidemia (defined as above) are presentedin Table 3. In multivariable analyses, vitamin D deficiencywas independently associated with greater odds of hyper-lipidemia (odds ratio [OR] 1.66; 1.11-2.47; P � .013), ad-usted for age, sex, race, BMI, GFR, DAS28, season ofeasurement, geographic region, steroid use, diabetes, hy-

ertension, and exercise. Similarly, each 10 ng/mL greateritamin D level was associated with a lower odds of hyper-ipidemia (OR 0.78; 0.63-0.96; P � .019). Exclusion of par-icipants reporting lipid-lowering therapy did not change theesults. In multivariable models, vitamin D deficiency wasssociated with a greater odds of an LDL level over 160g/dL (OR 2.35; 1.25-4.41; P � .008) and a greater odds ofTG level over 150 mg/dL (OR 2.32; 1.46-3.68; P �.001).itamin D deficiency was not associated with a higher oddsf low HDL.

Association of Vitamin D and MetabolicSyndromeTable 4 demonstrates an independent, dose-dependent in-crease in odds of the metabolic syndrome for each succes-sive quartile of vitamin D level after controlling for theabove factors (excluding BMI, diabetes, and hypertension).In separate analyses, a vitamin D level �20 ng/mL (OR3.45; 1.75-6.80; P �.001) and a vitamin D level �30 ng/mLOR 6.39; 1.47-27.7; P � .013) were both associated with anncreased odds of metabolic syndrome. Vitamin D defi-iency also was associated with a greater number of com-

onents of the metabolic syndrome in an ordinal regression

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1036.e12 The American Journal of Medicine, Vol 125, No 10, October 2012

model (OR 1.80; 1.28-2.53; P � .001). In multivariableanalysis, vitamin D deficiency was increasingly more likelyin patients with a greater number of components of themetabolic syndrome (P � .03). Predicted mean vitamin Dlevels were lower in subjects with a greater number ofcomponents of the metabolic syndrome after adjustment inmultivariable models (P � .02). Vitamin D deficiency wasnot significantly associated with significantly greater oddsof hyperglycemia or diabetes (OR 1.29; 0.80-2.07), nor witha history of hypertension (OR 1.23; 0.77-1.96).

DISCUSSIONThese data demonstrate that vitamin D deficiency was as-

Table 1 Baseline Participants Characteristics According to Vita

Baseline Variables All Participants V

n (%) 499 (100)ge (years) 49.5 � 12.4 4ace

Asian, n (%) 92 (18)White, n (%) 367 (74)Black, n (%) 6 (1)Other, n (%) 34 (7)

ex, male, n (%) 83 (17)MI (kg/m2) 27.2 � 6.0 2

GFR (mL/min/1.73m2) 89.3 � 21.5 8Winter measurement, n (%) 219 (45)Diabetes, n (%) 25 (5)Hypertension, n (%) 135 (27)Metabolic syndrome, n (%) 53 (11)Smoking, past/current, n (%) 169 (34)Regular exercise, n (%) 69 (14)Steroid use, n (%) 268 (54)Lipid-lowering therapy, n (%) 31 (6)Laboratory studies

Serum albumin (g/dL) 4.2 � 0.4Low-density lipoprotein 108 (88-130)Triglycerides 107 (82-151)High-density lipoprotein 57 (48-67)

Disease-specific measuresDAS28 Score ESR 6.30 (1.15) 6ESR (mm/h) 38 (28-60)CRP (mg/dL) 1.3 (0.5-3.4)HAQ score 1.56 (0.66) 1Evaluator assessment 6.2 (5.1-7.4)Pain on VAS 6.65 (5.1-8) 6Erosion score 4.5 (1.5-12.5)Joint space narrowing 1 (0-7)Van der Heidje-Sharpscore

6 (2-21.5)

CCP positive, n (%) 373 (75)Disease duration (years) 1.2 (0.5-4.2)

Continuous variables are presented as mean � (SD) or median (interqthe comparison between vitamin D deficiency categories.

BMI � body mass index; CCP � cyclic citrullinated peptide; CRP � C-rtation rate; GFR � glomerular filtration rate; HAQ � Health Assessment Q

sociated with higher LDL and TG levels and greater odds of

hyperlipidemia and the metabolic syndrome in participantswith rheumatoid arthritis from the golimumab (GO-BE-FORE) randomized controlled trial. These results expand onthis potential novel pathway involved in metabolic dyslip-idemia.24 These novel findings were independent of tradi-ional cardiovascular risk factors and measures of diseasectivity. Taken together, these observations suggest thatitamin D deficiency might contribute to the increased prev-lence of metabolic syndrome and cardiovascular diseasebserved in rheumatoid arthritis and possibly other inflam-atory diseases.

Vitamin D deficiency is common in the general popula-ion and in patients with rheumatoid arthritis.9,25 Vitamin D

Deficiency Status

D �20 ng/mL Vitamin D �20 ng/mL P Value

2) 240 (48) N/A11.8 51.5 � 12.6 �.001

�.057) 48 (20)5) 172 (72).4) 5 (2)) 15 (6)1) 29 (12) �.015.98 27.9 � 5.99 �.0120.7 90.8 � 22.2 .14) 108 (46) .7) 17 (7) �.053) 74 (31) .07) 37 (15) �.016) 77 (32) .46) 28 (12) .24) 128 (53) .9) 18 (8) .2

0.4 4.2 � 0.4 .84-126) 111 (94-137) �.0019-139) 116 (85-171) �.016-67) 58 (47-67) .5

.24) 6.37 (1.04) .25-62) 38 (29-60) .5.5-3.5) 1.45 (0.5-3.35) .4.68) 1.62 (0.63) �.05.1-7.6) 6.1 (5.1-7.3) .3.9-7.8) 6.7 (5.2-8.2) .07.5-12.5) 4.5 (2-12.5) .7-7.8) 1 (0-6.5) .8-21) 6 (2-21.75) .8

7) 172 (72) .2.5-4) 1.4 (0.55-4.55) .2

range). Categorical variables are presented as %. The P value represents

protein; DAS28 � disease activity score 28; ESR � erythrocyte sedimen-naire; VAS � visual analog scale.

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1036.e13Baker et al Vitamin D and Dyslipidemia in Rheumatoid Arthritis

ments, including abnormal lipoproteins, which also may befrequently seen in rheumatoid arthritis.6 Therefore, our find-ngs are highly relevant in helping to provide a potential linketween rheumatoid arthritis, dyslipidemia, and an in-reased risk of cardiovascular disease. Indeed, vitamin Das been associated with atherosclerosis at each stage of itsevelopment from subclinical plaque to the associated car-iovascular morbidity and mortality.26,27

The mechanism by which vitamin D deficiency is asso-ciated with increased prevalence of metabolic syndrome anddyslipidemia has not been elucidated. Prior studies demon-strated that vitamin D stimulated the expression of insulinreceptor,28 and low vitamin D levels were associated withbeta-cell dysfunction.29 Vitamin D deficiency was indepen-dently associated with insulin resistance and beta-cell func-tion in patients at risk for diabetes.30 Vitamin D receptorpolymorphisms also have been associated with insulin re-sistance.31 One study demonstrated that correction of vita-min D deficiency was associated with improvements inmetabolic syndrome, suggesting that vitamin D deficiencymay contribute to impaired insulin signaling.”32 In addition,the relationship between vitamin D deficiency and dyslipi-demia may be due, in part, to vitamin D effects on hepaticlipid metabolism.33 Vitamin D promotes intestinal calcium

Figure Box plots of low-density lipoprotein and triglyceride

levels by vitamin D quartile.

bsorption, and calcium may bind to fatty acids to formnsoluble complexes that inhibit lipid absorption. Thus, vi-amin D deficiency may lead to abnormal processing ofipids due to alterations in calcium availability.34

Alternatively, vitamin D is sequestered in body fat, andobesity may be associated with a decreased bioavailabilityof the hormone.35 Therefore, vitamin D may instead be a

Table 2 Multivariable Linear Regression Analysis Evaluatingthe Associations between Natural Log-transformed Vitamin DLevel and Natural Log-transformed LDL and TG Level

Lipoprotein Fraction � Coefficient 95% CI P Value

Model 1*LDL –0.084 –0.15 to –0.018 .013TG �0.31 �0.50 to –0.12 .002

Model 2†LDL �0.080 �0.15 to –0.014 .017TG �0.26 �0.44 to –0.073 .006

Model 3‡LDL �0.091 �0.16 to –0.023 .008TG �0.28 �0.47 to –0.098 .003

Model 4§LDL �0.093 �0.16 to –0.025 .008TG �0.28 �0.47 to –0.088 .004

CI � confidence interval; LDL � low-density lipoprotein;TG � triglycerides.

*Adjusted for age, sex, race.†Adjusted for age, sex, race, body mass index (BMI), diabetes,

hypertension, and smoking status.‡Adjusted for age, sex, race, BMI, diabetes, hypertension, smoking,

glomerular filtration rate (GFR), exercise, and C-reactive protein (CRP).§Adjusted for age, sex, race, BMI, GFR, exercise, smoking, diabetes,

hypertension, CRP, geographic region, disease activity (DAS28), steroiduse, and season of measurement.

Table 3 Multivariable Logistic Regression AnalysisEvaluating the Odds of Hyperlipidemia According to Vitamin DStatus

Variable Odds Ratio 95% CI P Value

Model 1*Vitamin D �20 ng/mL 1.63 1.14-2.35 .008

odel 2†Vitamin D �20 ng/mL 1.51 1.03-2.21 .033

odel 3‡Vitamin D �20 ng/mL 1.62 1.10-2.39 .015

odel 4§Vitamin D �20 ng/mL 1.64 1.10-2.45 .015

CI � confidence interval.*Adjusted for age, sex, race.†Adjusted for age, sex, race, body mass index (BMI), diabetes,

hypertension, and smoking status.‡Adjusted for age, sex, race, BMI, glomerular filtration rate (GFR),

exercise, smoking, diabetes, hypertension, and C-reactive protein (CRP).§Adjusted for age, sex, race, BMI, GFR, exercise, smoking, steroid use

at baseline, diabetes, hypertension, CRP, geographic region, disease

activity (DAS28), and season of measurement.

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1036.e14 The American Journal of Medicine, Vol 125, No 10, October 2012

marker of visceral fat content. Additionally, fatty liver dis-ease is associated with low vitamin D levels, suggesting thatgreater hepatic fat content might impair hepatic 25-hy-droxylation of vitamin D.33 Furthermore, vitamin D-bindingprotein, a member of the albumin gene family that trans-ports vitamin D to target tissues, along with 25(OH) vitaminD3 itself, has been identified in very low-density lipoproteinarticles.36 Thus, it is not known if measurement of vitamin

is affected by the presence of lipoprotein particles. Fur-her study is necessary to clarify the nature of this associa-ion in rheumatoid arthritis.

Strengths of this study include the large sample size,tandardized measures of disease characteristics, cardiovas-ular risk factors, confounding variables, and comprehen-ive assessment of lipoprotein and vitamin D levels. Therimary limitation of this study is the observational andross-sectional design, which may be subject to residualonfounding and prevents assessment of temporal associa-ions. Randomized clinical studies are essential to establishhese associations. An additional limitation is the lack ofata on dietary intake. Subjects with poor dietary habitsight be more likely to have both elevated lipoproteins and

ow vitamin D levels. However, the association was inde-endent of albumin, a measure of nutritional status. Thendings also were independent of geographic region; there-ore, they are not likely explained by regional variation inietary habits. A third limitation is that the study populationas predominantly female (congruent with the demograph-

cs of the disease), and there were too few men to stratify theesults by sex. Our study did not include measures of waistircumference, and the use of BMI as a surrogate measureay have resulted in misclassification of the number of

omponents of the metabolic syndrome. However, thetrength and consistency of the associations between vita-in D status, the presence of metabolic syndrome, and the

umber of components of the metabolic syndrome suggestshat the lack of waist circumference data was not an impor-ant limitation.

In conclusion, low 25(OH) vitamin D was associated withncreased odds of elevated LDL and TG as well as metabolicyndrome at baseline in subjects with rheumatoid arthritis

Table 4 Multivariable Logistic Regression Analysis for theOdds of the Presence of Metabolic Syndrome by Quartile ofVitamin D Level

Vitamin D Quartile* Odds Ratio 95% CI P Value

28.2 ng/mL 1 — —0.8-28.2 ng/mL 2.66 0.77-9.20 .124.5-20.7 ng/mL 5.40 1.67-17.45 .00514.5 ng/mL 7.59 2.37-24.30 .001

CI � confidence interval.*Adjusted for age, sex, race, glomerular filtration rate (GFR), region,

disease activity (DAS28), smoking, exercise, steroid use at baseline,C-reactive protein, and season of measurement.

ndependent of numerous potential confounders. These find-

ngs mandate further studies evaluating the effects of vitaminsupplementation in patients with rheumatoid arthritis, a

igh-risk group for cardiovascular disease.

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11. Binkley N, Krueger D, Cowgill CS, et al. Assay variation confoundsthe diagnosis of hypovitaminosis D: a call for standardization. J ClinEndocrinol Metab. 2004;89(7):3152-3157.

12. Hollis B. Quantitation of 25-hydroxyvitamin D and 1, 25-dihydroxyvi-tamin D by radioimmunoassay using radioiodinated tracers. MethodsEnzymol. 1997;282:174-186.

13. Hollis BW, Horst RL. The assessment of circulating 25(OH)D and1,25(OH)2D: where we are and where we are going. J Steroid BiochemMol Biol. 2007;103(3-5):473-476.

14. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietaryreference intakes for calcium and vitamin D from the Institute ofMedicine: what clinicians need to know. J Clin Endocrinol Metab.2011;96(1):53-58.

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