**4. Discussion**

In our cohort, the prevalence of MetS was 28.2% and had significant association with CVD. The few existing studies that have examined the relationship of RA with MetS primarily involved women, and indicated increased mortality from CVD among those satisfying criteria for MetS. Men with RA have more extra-articular disease and a greater overall mortality (Janghorbani et al., 1993; Jawaheer et al., 2006; Mikuls et al., 2011). In general, there is a disproportionate individual impact of MetS, CVD, and RA in men. Our findings provide data previously lacking regarding the frequency of MetS in older men with RA and its relationship with RA-specific factors and CVD co-morbidity.

In non-RA populations, MetS has been reported to increase the risk for CVD by two fold, and death by as much as 4 fold (Dekker et al., 2005; Lakka et al., 2002). In a Finnish cohort of men aged 42 to 60 years of age, MetS was found in only 14.3%, but with a 2.9 to 4.3 greater risk of death from coronary heart disease (Lakka et al., 2002). In a population-based cohort


**P values not statically significant for all variables** 

۩ **V**eteran **A**ffairs **R**hematoid **A**rthritis Registry

238 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

were nearly universal among those meeting criteria for MetS, with over 95% use. Logistic regression analysis revealed MetS to be associated with an approximately three-fold risk of CVD (OR=2.9; 95% CI 1.95-4.34), after adjusting for age, sex, DMARD / biologic use, and smoking status (Table 2). There was no increased CVD risk with individual components of

Anti-DM = Treatment for diabetes with insulin and/or oral hypoglycemic medications Anti-Lipid = Treatment for dyslipidemia with cholesterol lowering medications

In our cohort, the prevalence of MetS was 28.2% and had significant association with CVD. The few existing studies that have examined the relationship of RA with MetS primarily involved women, and indicated increased mortality from CVD among those satisfying criteria for MetS. Men with RA have more extra-articular disease and a greater overall mortality (Janghorbani et al., 1993; Jawaheer et al., 2006; Mikuls et al., 2011). In general, there is a disproportionate individual impact of MetS, CVD, and RA in men. Our findings provide data previously lacking regarding the frequency of MetS in older men with RA and its

In non-RA populations, MetS has been reported to increase the risk for CVD by two fold, and death by as much as 4 fold (Dekker et al., 2005; Lakka et al., 2002). In a Finnish cohort of men aged 42 to 60 years of age, MetS was found in only 14.3%, but with a 2.9 to 4.3 greater risk of death from coronary heart disease (Lakka et al., 2002). In a population-based cohort

Anti-HTN = Treatment for high blood pressure with medications Fig. 1. MetS Components Frequency in VARA cohort

relationship with RA-specific factors and CVD co-morbidity.

the metabolic syndrome.

MetS= Metabolic Syndrome BMI = Body Mass Index

**4. Discussion** 

 MetS = Metabolic Syndrome DMARDS=Disease-Modifying Anti-Rheumatic Drugs \*Biological Agents (mainly anti-tumor necrosis factor) †Disease Activity Score, 28 joints SD = Standard Deviation

Table 1. Demographics and Parameters of Disease Severity and Activity of Veterans Affairs Rheumatoid Arthritis Patients with and without the Metabolic Syndrome


DMARDS (Disease Modifying Anti-rheumatic drugs) \*Biologic Agents (mainly anti-tumor necrosis factor)

CI = Confidence Interval

Table 2. Multivariable Logistic Regression Model examining the association of Metabolic Syndrome with Cardiovascular Disease in VARA cohort

of 615 men aged 50 to 75 years, the prevalence of MetS varied from 17% - 32% when assessing the agreement in the various definitions of MetS (Dekker et al., 2005). When using NCEP-ATPIII criteria, the hazard ratio for fatal and non-fatal CVD in men with MetS was 1.91 (1.31–2.79), compared to 1.68 (1.11–2.55) in the 749 women.

A similar risk for CVD occurs for RA patients with MetS, but these results are obtained from cohorts consisting primarily of female patients (Dessein et al., 2002; Karvounaris et al., 2007).

Association of Cardiovascular Disease

**5. Acknowledgement** 

1988 Mar;31(3):315-24.

*2005 March* 

Baumgartner et al., 1999, Am J Epidemiol 147:755-763

**6. References** 

with the Metabolic Syndrome in a Predominantly Male Cohort with Rheumatoid Arthritis 241

The role of adipose tissue and BMI in inflammatory disease is evolving as is its impact on response to disease-modifying therapies (Klaasen et al., 2011; Ouchi et al., 2011). Yet the association of MetS with RA disease activity and severity is equivocal. One study has reported an increase of nine-fold in odds ratio correlation between MetS and disease activity, but not with severity (Karvounaris et al., 2007). A relationship between MetS and disease activity and severity was not found in our cohort, but the mean disease activity was low and the effect of DMARD therapies on MetS is unknown. Aware that statin use may be more frequent in the context of MetS and of its potential anti-inflammatory and immunomodulatory effects, we explored but were unable to find an association between

There are limitations to our study. The use of BMI in place of waist-to-hip circumference may have limited the sensitivity of our criteria. However, the use of BMI in lieu of waist-tohip circumference allows pragmatic application in clinical practice, and thereby easier identification of MetS. There is a reported positive correlation between BMI and CVD and increased CRP levels, and BMI is inversely related to functional status in inflammatory rheumatic diseases (Choi et al., 2002; Kremer & Reed, 2006). There was no difference in disease activity amongst the cohort, and the increased risk for CVD in RA patients with MetS was independent of disease activity. Whether a lower DAS score is found in RA patients with MetS, regardless of traditional or biologic DMARD, remains to be determined. Strengths of the study include that it is of a well-characterized group of males with RA, a group that to date has been vastly underrepresented in clinical research. Moreover, the patients treated at these sites have equal access to medical care and RA therapies, hence providing the unique opportunity to explore disease related outcomes in a uniform health system. Although premature atherosclerosis occurs in RA independent of traditional risk factors, our findings indicate that it is the composite entity of the metabolic syndrome rather than its individual components that pose the risk for CVD. Optimum control of all

statin use and disease activity in RA patients with and without MetS.

individual components is required to minimize cardiovascular morbidity.

Jeffrey Huang, Research Assistant, for manuscript preparation and literature review.

Alberti KG, Zimmet P, Shaw J, for the IDF Epidemiology Task Force Consensus Group. The metabolic syndrome--a new worldwide definition. *Lancet* 2005;366:1059-1062. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987

Balkau B, Sapinho D, Petrella A, et al. D.E.S.I.R. Study Group. Prescreening tools for

Bawa, S, Fowler L, Bradlow A. Comparison between DAS 28 4 Score & 3 Score- Would it

hip ratio. The D.E.S.I.R. Study*. Eur J Clin Nutr.* 2006 Mar;60(3):295-304.

revised criteria for the classification of rheumatoid arthritis. *Arthritis and Rheum,* 

diabetes and obesity-associated dyslipidaemia: comparing BMI, waist and waist

influence patient eligibility for, or evaluation of response to Anti-TNF alpha*? British Society for Rheumatology Annual Meeting, 19-22 April 2005. Supplement 1:i99.* 

Further, as in the non-RA study cohorts, the definitions and criteria of both MetS and CVD varied. In one study, MetS, as defined by WHO criteria, was a better predictor of coronary calcification than NCEP-ATPIII criteria (Pandya et al., 2006). Though coronary calcification detection by electron beam computer tomography is a more sensitive means of detecting atherosclerosis than clinical diagnoses, the association with MetS achieved an odds ratio of 2.02, (95% CI: 1.03-3.97, p=0.04.), less than the 2.91 (95% CI: 1.95-4.34, p<0.001) in our cohort. In that study (Pandya et al, 2006), almost 50% of the patients had longstanding disease (median = 20 years), were younger than our cohort (median 59 years), and were majority female. The almost three-fold risk for CVD in our cohort was independent of anti-rheumatic treatment, smoking, age or gender. There was, however, a trend to increased risk with increasing age and DMARD therapy alone, the latter perhaps related to channeling bias or confounding by indication.

Given the notable comorbidity in our study population, and the historically age-matched prevalence of MetS in 44% of the US NHANES III population aged 65 years, our prevalence of 28% was unexpected. The limited data from other disease cohorts involving U.S. veteran populations report higher frequencies on the order of 50% (Meyer et al., 2006; Pandya et al., 2006). However, our results are similar to another US RA cohort, 40% of whom were male. The prevalence of MetS was approximately 26% as defined by NCEP-ATPIII criteria, and was almost half that of controls (Rodriguez-Pla et al., 2007). In that study, the difference in prevalence between RA and controls could not be explained by differences in physical activity. In contrast, in 200 similarly aged but primarily female RA patients, MetS occurred in 44% of patients at a similar rate to the age- and sex- matched controls, but used ATPIII criteria (National Cholesterol Education Program, 2001). Of the 53 men in the study, approximately 30% with MetS had coronary disease (p=0.02). Not only do differences in MetS classifications make comparisons amongst cohorts difficult, but the disparate muscle loss with fat retention that occurs in RA patients, affects BMI assessments. Rheumatoid cachexia, which is present in most (two-thirds) RA patients, doesn't merely involve fat "retention"; there is exacerbated fat gain. When body composition is assessed (i.e. % body fat), up to 80% of RA patients satisfy BMI criteria for obesity i.e. ≥27% for males, and ≥38% for females (Baumgartner et al., 1999). This prevalence of obesity in RA is not reflected by BMI because of the concomitant loss of muscle. Thus, for individuals with the same BMI, an RA patient will have, on average, 4.3% higher % body fat than a healthy, age- and sexmatched subject. Therefore, in RA patients, a BMI greater than 28kg/m2 has been proposed to define obesity, and may therefore lead to higher, and more accurate, estimations of MetS in RA cohorts. (Stavropoulos-Kalinoglou et al., 2007).

Our modified definition of MetS based on NCEP-ATPIII criteria though highly specific, may have lacked sensitivity by excluding otherwise eligible patients with discordance between waist-to-hip ratio and BMI, or those who had not received pharmacological treatment for component diseases. We recognize therefore that our prevalence estimate may have trended towards the conservative and underestimated the true impact of MetS in this population; an important concern given the strong association between MetS and CVD. However, of note is the rigor with which VA patients are screened and treated for diabetes mellitus, hypertension and hyperlipidemia based on adherence to select process indicators (Steven, 2004). Therefore it is likely that our use of medication is a reasonable surrogate for the select comorbidities of MetS. Surprisingly, our study found no significant risk of any of the individual components of MetS, and may indicate that traditional risk factors do not impart the same risk for CVD in RA as in the general population.

The role of adipose tissue and BMI in inflammatory disease is evolving as is its impact on response to disease-modifying therapies (Klaasen et al., 2011; Ouchi et al., 2011). Yet the association of MetS with RA disease activity and severity is equivocal. One study has reported an increase of nine-fold in odds ratio correlation between MetS and disease activity, but not with severity (Karvounaris et al., 2007). A relationship between MetS and disease activity and severity was not found in our cohort, but the mean disease activity was low and the effect of DMARD therapies on MetS is unknown. Aware that statin use may be more frequent in the context of MetS and of its potential anti-inflammatory and immunomodulatory effects, we explored but were unable to find an association between statin use and disease activity in RA patients with and without MetS.

There are limitations to our study. The use of BMI in place of waist-to-hip circumference may have limited the sensitivity of our criteria. However, the use of BMI in lieu of waist-tohip circumference allows pragmatic application in clinical practice, and thereby easier identification of MetS. There is a reported positive correlation between BMI and CVD and increased CRP levels, and BMI is inversely related to functional status in inflammatory rheumatic diseases (Choi et al., 2002; Kremer & Reed, 2006). There was no difference in disease activity amongst the cohort, and the increased risk for CVD in RA patients with MetS was independent of disease activity. Whether a lower DAS score is found in RA patients with MetS, regardless of traditional or biologic DMARD, remains to be determined. Strengths of the study include that it is of a well-characterized group of males with RA, a group that to date has been vastly underrepresented in clinical research. Moreover, the patients treated at these sites have equal access to medical care and RA therapies, hence providing the unique opportunity to explore disease related outcomes in a uniform health system. Although premature atherosclerosis occurs in RA independent of traditional risk factors, our findings indicate that it is the composite entity of the metabolic syndrome rather than its individual components that pose the risk for CVD. Optimum control of all individual components is required to minimize cardiovascular morbidity.
