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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

Abdominal adiposity, especially visceral adiposity, is emerging as a recognized cardiometabolic risk factor. This study was undertaken to investigate how abdominal fat is distributed in rheumatoid arthritis (RA), and its RA-related determinants.

Methods

Men and women with RA were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis. Participants underwent anthropometric studies and quantification of visceral and subcutaneous fat areas (VFA and SFA) using abdominal computed tomography.

Results

A total of 131 RA patients were compared with 121 controls. Despite similar body mass index and waist circumference between the RA and control groups, the adjusted mean VFA was 45 cm2 higher (+51%) in male RA patients versus male controls (P = 0.005), but did not significantly differ by RA status in women. The adjusted mean SFA was 119 cm2 higher (+68%) in female RA patients versus female controls (P < 0.001), but did not significantly differ by RA status in men. Elevated VFA (≥75th percentile) was associated with a significantly higher adjusted probability of having an elevated fasting glucose level, hypertension, or meeting the composite definition of the metabolic syndrome in the RA group compared with controls. Within the RA group, rheumatoid factor seropositivity and higher cumulative prednisone exposure were significantly associated with a higher mean adjusted VFA. Higher C-reactive protein levels and lower Sharp/van der Heijde scores were significantly associated with both VFA and SFA.

Conclusion

The distribution of abdominal fat differs significantly by RA status. Higher VFA in men with RA, and the more potent association of VFA with cardiometabolic risk factors in men and women with RA, may contribute to cardiovascular risk in RA populations.

Body composition has recently emerged as an important determinant of health outcomes. More than a passive storage depot, adipose tissue is a dynamic and metabolically active organ with the ability to elaborate mediators with widespread effects on metabolism, immune function, and vascular homeostasis (1). In particular, adipose tissue deposited around the mesentery and omentum (visceral fat) is highly associated with insulin resistance and cardiovascular disease (CVD) (2–4). In contrast, subcutaneous adipose tissue (concentrated around the hips and buttocks) is less strongly associated with CVD, and may even exert a protective effect in women (5).

Rheumatoid arthritis (RA) is a highly inflammatory systemic autoimmune disorder affecting ∼1–2% of adults, frequently resulting in significant joint deformity and disability. Total body fat is increased, and skeletal muscle is decreased, in RA patients compared with matched controls, with both inflammatory and noninflammatory factors contributing to these differences (6, 7). Whether the increase in body fat is reflective of increased visceral fat, or fat in an adipose depot associated with less metabolic and CV risk (i.e., subcutaneous fat), is currently unknown, since there have been no reported studies involving quantification of visceral or subcutaneous fat in RA patients.

Abdominal computed tomography (CT) scanning at the L4–L5 interspace (level of the umbilicus) with quantification of visceral fat area (VFA) and subcutaneous fat area (SFA) of this single section is validated, reproducible, and has been the most frequently utilized representation of visceral and subcutaneous fat mass in epidemiologic investigations (8, 9). Cross-sectional abdominal fat area at this level is highly correlated with the total volume of visceral fat in the compartment (10).

In the present cross-sectional investigation, we sought to identify the association of RA disease status with CT measures of abdominal fat, adjusting for potentially confounding sociodemographic, lifestyle, and comorbidity characteristics. Further, we explored whether the magnitude of the association between abdominal fat measures and cardiometabolic risk factors differed between RA patients and controls. Finally, we sought to identify the RA disease–related characteristics with the strongest associations with abdominal fat measures. We hypothesized that abdominal fat would be quantitatively increased in RA patients relative to controls and that this excess abdominal fat load would contribute to cardiometabolic risk in RA.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Study participants.

RA patients.

The RA patients included in the present study were men and women participating in ESCAPE RA (Evaluation of Subclinical Cardiovascular disease And Predictors of Events in Rheumatoid Arthritis), a cohort study, described in detail previously (11), of the prevalence, progression, and risk factors for subclinical cardiovascular disease in RA. ESCAPE RA participants were recruited from among patients being followed up at the Johns Hopkins Arthritis Center and by referral from local rheumatologists. Among 351 consecutive patients screened, 188 (54%) were ineligible or declined participation, resulting in 163 RA patients enrolled through the Johns Hopkins Arthritis Center. The remaining 34 enrolled participants were referred from community rheumatologists. All 197 enrolled patients met the American College of Rheumatology (formerly, the American Rheumatism Association) 1987 classification criteria for RA (12), and all were between 45 and 84 years of age without prior prespecified cardiovascular events, peripheral arterial disease or peripheral arterial vascular procedures, implanted pacemaker or defibrillator devices, or atrial fibrillation. Participants weighing >300 pounds were excluded due to weight limitations of cardiovascular imaging equipment.

A two-thirds sample of the RA group (n = 131) underwent abdominal CT scanning for determination of abdominal fat and muscle areas. Sequential participants had abdominal CT scanning concurrent with cardiac CT scanning, until the two-thirds sample was met. The study was approved by the Institutional Review Board of the Johns Hopkins Hospital, with all participants providing written informed consent prior to enrollment. Enrollment began in October 2004 and concluded in May 2006.

Non-RA controls.

Non-RA controls were participants in the Multi-Ethnic Study of Atherosclerosis (MESA). A description of the MESA design and methods has been published previously (13). Briefly, recruitment for the MESA study was conducted through mailed letters of solicitation at most sites, and random-digit dialing at one site (the University of California, Los Angeles). Interested individuals were prescreened via telephone interview and enrolled through the MESA field center that had solicited their interest. MESA participants from 5 sites (Wake Forest University, Columbia University, the University of Minnesota, Northwestern University, and the University of California, Los Angeles) underwent abdominal CT scanning for evaluation of aortic calcification, at the second or third study visit. An unmatched convenience sample of these participants (n = 121), randomly selected except for the exclusion of those currently receiving medications commonly used as disease-modifying agents to treat RA, comprised the non-RA control group for the present analyses. Identifying RA patients based on RA medications has been shown to be a more reliable method for identification than self-report of the disease (14). CT scanning in this group occurred between April 2003 and August 2005. While VFA data were available on all 121 controls, complete SFA (and thus also total fat area [TFA]) measures were available on only 41 controls (16 women and 25 men), due to a reduced scanning field of view. Considering the number of RA patients and the distribution of SFA in the RA group, the smallest detectable significant difference in SFA was calculated to be 99 cm2 for women and 76 cm2 for men, assuming a 2-tailed α of 0.05 and 80% power.

Abdominal CT scanning and anthropometric outcomes.

For both the RA and control groups, the cross-sectional abdominal CT image from the level of the interspace between the fourth and fifth lumbar vertebrae was selected. A single trained reader (MA), who was blinded with regard to the clinical characteristics of the participants, quantified TFA, VFA, and SFA on all of the scans, using the National Institute on Aging Musculoskeletal Analysis Program, as previously described (15). RA participants underwent abdominal CT scanning on the same CT scanner used for Baltimore MESA procedures, which shared quality control and calibration procedures with the other MESA sites. Anthropometric measurements (of height, weight, body mass index [BMI], and waist and hip circumference) were performed similarly in RA patients and controls, as previously described (15).

Covariates.

With the exception of data acquisition specific to the RA disease state, all data were collected using the same questionnaires and procedures for both the RA and control participants. RA study personnel were trained and certified in MESA procedures. Questionnaires were administered by study personnel after anthropometric testing and phlebotomy, but just prior to CT scanning. Questionnaires were scanned into a database using commercial software (Teleform). Data checks for consistency were performed at the time of entering each record into the database and when the completed data set was compiled at the MESA coordinating center, for both the RA and control groups.

Sociodemographic and lifestyle covariates.

Age, sex, race/ethnicity, educational attainment, and current and past smoking were ascertained from patient self-report. Physical activity was assessed with the 7-Day Physical Activity Recall Questionnaire (16), with the weekly total of physical activity for intentional exercise activities (moderate or brisk walking for exercise, and moderate or vigorous individual or team sports and conditioning activities) calculated for each participant. Duration of television watching, a measure of sedentariness, was also assessed.

Comorbidities.

Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (17). Thyroid disease was classified based on the use of thyroid replacement therapy. Diabetes was defined as a fasting serum glucose level of >126 mg/dl or use of antidiabetic medication. Hypertension was defined as a blood pressure of >140/90 mm Hg or use of antihypertensive medication. The so-called “metabolic syndrome” was defined according to the National Cholesterol Education Program—Adult Treatment Panel III (ATP III) criteria (18).

RA disease characteristics.

Forty-four joints were examined for swelling, tenderness, deformity, and surgical replacement or fusion, by a single trained assessor. RA disease duration was recorded according to the date of diagnosis, ascertained by patient self-report. RA disease activity was calculated using the 28-joint Disease Activity Score with C-reactive protein (CRP) (19). Current and past use of glucocorticoids and biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs) was queried using detailed examiner-administered questionnaires. The correlation of prior self-reported glucocorticoid exposure compared against medical records in a subset of 20 participants was 0.92.

The 21-item Health Assessment Questionnaire (20) was used to assess disability related to common activities. Single-view anteroposterior radiographs of the hands and feet were obtained and scored using the Sharp/van der Heijde (SHS) method (21), by a single, trained radiologist who was blinded with regard to patient characteristics.

Laboratory covariates.

Fasting serum and plasma samples were collected on the day of body composition analysis and stored at −80°C. Assays for ESCAPE RA and MESA samples were performed at the same laboratory (Laboratory for Clinical Biochemistry Research, University of Vermont). High-sensitivity CRP and interleukin-6 (IL-6) were measured as previously described (22). Plasma lipids and glucose were measured by standard assays; low-density lipoprotein cholesterol was estimated in plasma specimens having a triglyceride value of >400 mg/dl, using the Friedewald equation. Rheumatoid factor (RF) was assessed by enzyme-linked immunosorbent assay (ELISA), with seropositivity defined as a level of ≥40 units. Anti–cyclic citrullinated peptide (anti-CCP) antibody was assessed by ELISA, with seropositivity defined as a level of ≥60 units.

Statistical analysis.

The distributions of all variables were examined. Means and standard deviations were calculated for all normally distributed continuous variables, while medians and interquartile ranges were calculated for continuous variables that were not normally distributed. For categorical variables, counts and percentages were calculated. Transformation of variables was used for highly skewed variables (e.g., VFA, SFA) to satisfy the requirements of regression modeling. Differences in means for normally distributed continuous variables were compared using t-tests, and differences in medians for non-normally distributed continuous variables were compared using the Kruskal-Wallis test. Differences in proportions were compared by chi-square goodness-of-fit test or Fisher's exact test, as appropriate.

The associations of RA status with abdominal adiposity measures were modeled using multivariable linear regression, first in unadjusted models in which RA status was the only covariate modeled. Because of important sex differences in the outcomes and in the associations with many of the potential confounders, analyses were conducted in sex-specific groups. Next, extended models, including RA status and covariates for potential confounders (age, ethnicity, education, exercise, hours of television watching, depression, current and former smoking, thyroid disease, and use of hormone replacement therapy), were fit. Menopausal status was not modeled, due to collinearity with age. The Shapiro-Wilk statistic was used to examine normality of the modeled outcome variables across the extent of independent variables in multivariable modeling. Variance inflation factors were calculated to ensure that variables with excessive collinearity were not modeled simultaneously. For each model, studentized residuals were calculated and plotted against predicted values to visually inspect equal variance assumptions.

Next, the associations of adiposity measures with cardiometabolic risk factors (i.e., the ATP III–defined metabolic syndrome and its components) were explored in the RA and control groups, using linear regression in simple models and with adjustment for the covariates listed above. Additional adjustment for the use of antihypertensive and lipid-lowering medication was performed. Heterogeneity by RA status was tested by analysis of covariance.

Finally, within the RA group, the associations of RA characteristics with the normally transformed abdominal adiposity measures were modeled using linear regression. Covariate selection, model fitting, and model checking were performed using the methods described above.

All statistical calculations were performed using Intercooled Stata 10 (StataCorp). In all tests, a 2-tailed α of 0.05 was set as the level of statistical significance.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

A total of 131 RA patients and 121 controls underwent abdominal adiposity assessment. While VFA data were available on all 121 controls, complete SFA (and thus also TFA) measurements were available on only 41 controls (16 women and 25 men), due to a reduced scanning field of view. There were no significant differences in sociodemographic characteristics, anthropometric features, or VFA measures between the controls with complete SFA measurement and the controls without complete SFA measurement (data not shown). Characteristics of the subjects in the RA and control groups are summarized in Table 1.

Table 1. Participant characteristics according to RA status*
CharacteristicRA patients (n = 131)Controls (n = 121)P
  • *

    Except where indicated otherwise, values are the median (interquartile range). RA = rheumatoid arthritis; CES-D = Center for Epidemiologic Studies Depression scale; BMI = body mass index; HDL = high-density lipoprotein; LDL = low-density lipoprotein; RF = rheumatoid factor; anti-CCP = anti–cyclic citrullinated peptide; DAS28-CRP = 28-joint Disease Activity Score using C-reactive protein; IL-6 = interleukin-6; HAQ DI = Health Assessment Questionnaire disability index; SHS = Sharp/van der Heijde; DMARDs = disease-modifying antirheumatic drugs.

Age, mean ± SD years61 ± 963 ± 90.017
Male, no. (%)51 (39)70 (58)0.003
White race, no. (%)113 (86)101 (84)0.54
Any college, no. (%)99 (76)96 (79)0.48
Exercise, minutes/day32 (0–83)31 (5–69)0.96
Television watching, hours/day2 (1–3)1.5 (0.6–3)0.048
CES-D score5 (2–12)4 (1–8)0.032
Hormone replacement (women), no. (%)9 (11)19 (37)<0.001
Ever smoking, no. (%)75 (57)69 (57)0.97
Current smoking, no. (%)12 (9)21 (17)0.054
Thyroid disease, no. (%)18 (14)16 (13)0.90
Weight loss drugs, no. (%)0 (0)0 (0)1.00
BMI, mean ± SD kg/m228.5 ± 5.527.4 ± 4.30.086
Waist circumference, mean ± SD cm95 ± 1597 ± 110.28
Waist-to-hip ratio, mean ± SD0.92 ± 0.100.93 ± 0.060.34
Diabetes, no. (%)10 (8)10 (8)0.85
Hypertension, no. (%)74 (57)49 (42)0.022
HDL, mean ± SD mg/dl54 ± 1951 ± 140.14
LDL, mean ± SD mg/dl114 ± 29107 ± 280.070
Triglycerides, mg/dl105 (74–155)101 (70–162)0.97
Metabolic syndrome, no. (%)47 (36)31 (27)0.12
RA duration, years9 (5–17)
RF or anti-CCP seropositivity, no. (%)103 (79)
Any shared epitope alleles, no. (%)92 (71)
DAS28-CRP3.6 (2.8–4.5)
Swollen joints, possible range 0–426 (3–10)
Tender joints, possible range 0–446 (2–12) 
CRP, mg/liter3.0 (1.1–7.8)
IL-6, pg/ml3.7 (1.8–8.2)
HAQ DI, possible range 0–30.63 (0.13–1.25)
Total SHS score47 (20–114)
Current prednisone, no. (%)49 (37)
Cumulative prednisone, gm2.8 (0–8.7)
Current nonbiologic DMARDs, no. (%)110 (84)
Current biologic DMARDs, no. (%)54 (41)

Comparison of abdominal adiposity measures by RA status.

Comparisons of measures of abdominal adipose areas in the RA group versus the control group, according to sex, are depicted in Figure 1. In women, the adjusted mean TFA was 118 cm2 higher among RA patients versus controls (Figure 1A), representing a 41% difference (P = 0.004). In men, the adjusted mean TFA was 45 cm2 among RA patients versus controls (Figure 1A), representing a 15% difference; however, this difference was not statistically significant. After adjustment, mean VFA did not differ in women by RA status (Figure 1B). In contrast, the adjusted mean VFA was 45 cm2 higher among men with RA versus male controls (Figure 1B), representing a 51% difference (P = 0.005). In women, the adjusted mean SFA was 119 cm2 higher among RA patients versus controls (Figure 1C), a 68% difference (P < 0.001). In contrast, the adjusted mean SFA was not significantly different in men with RA compared with male controls (Figure 1C).

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Figure 1. Crude and adjusted means and 95% confidence intervals for measures of A, total abdominal fat area, B, visceral fat area, and C, subcutaneous fat area, by rheumatoid arthritis (RA) status (patient with RA or control subject) and sex. Analyses were adjusted for age, ethnicity, education, exercise, hours of television watching, depression, current and former smoking, thyroid disease, and use of hormone replacement therapy (female subgroup only).

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Associations of abdominal adiposity measures with cardiometabolic risk factors by RA status.

In both the RA and the control groups, higher BMI, waist circumference, VFA, and SFA were each associated with a higher prevalence of the metabolic syndrome and individual components of the metabolic syndrome. These associations remained after adjustment for demographic characteristics, duration of exercise and sedentary activities, depression, thyroid disease, and use of antihypertensive and lipid-lowering medications (Table 2).

Table 2. Adjusted odds ratios for cardiometabolic risk factors per quartile increase in body composition measures in RA patients compared with controls*
Adjusted outcomeBMIWaist circumferenceVisceral fat areaSubcutaneous fat area
OR (95% CI)POR (95% CI)POR (95% CI)POR (95% CI)P
  • *

    Outcomes (cardiometabolic risk factors) were adjusted for age, ethnicity, education, exercise, sedentary activity, CES-D score, thyroid disease, use of antihypertensive medications, and use lipid-lowering medication (including statins). Odds ratios (ORs) indicate the increase in the odds of each cardiovascular risk factor for each quartile increase in the body composition measure of interest. 95% CI = 95% confidence interval (see Table 1 for other definitions).

  • For test of interaction by RA status.

Elevated fasting glucose        
 Total (RA + control)1.53 (1.12–2.08) 1.81 (1.30–2.52) 2.09 (1.47–2.97) 1.56 (1.05–2.32) 
 Control only1.37 (0.86–2.18) 2.14 (1.25–3.66) 1.67 (1.07–2.59) 1.06 (0.45–2.48) 
 RA only1.64 (1.10–2.43)0.561.66 (1.11–2.49)0.452.79 (1.63–4.79)0.131.67 (1.04–2.69)0.35
Elevated blood pressure        
 Total (RA + control)1.40 (0.89–2.20) 1.28 (0.77–2.12) 1.53 (0.92–2.53) 1.39 (0.76–2.54) 
 Control only1.10 (0.36–3.39) 0.96 (0.28–3.32) 1.01 (0.35–2.87) 1.64 (0.19–14.1) 
 RA only1.56 (0.88–2.75)0.591.65 (0.89–3.05)0.442.10 (1.01–4.35)0.261.19 (0.62–2.28)0.78
Low HDL        
 Total (RA + control)1.75 (1.32–2.31) 1.61 (1.21–2.15) 1.92 (1.41–2.63) 1.38 (0.97–1.95) 
 Control only1.88 (1.21–2.92) 1.94 (1.21–3.13) 2.26 (1.46–3.48) 1.32 (0.61–2.87) 
 RA only1.65 (1.16–2.35)0.651.47 (1.04–2.08)0.341.58 (1.03–2.43)0.231.37 (0.91–2.06)0.93
High triglycerides        
 Total (RA + control)1.39 (1.05–1.84) 1.65 (1.22–2.24) 1.80 (1.31–2.47) 0.95 (0.67–1.33) 
 Control only1.69 (1.09–2.61) 1.93 (1.20–3.11) 1.64 (1.11–2.43) 1.02 (0.46–2.26) 
 RA only1.22 (0.85–1.74)0.251.50 (1.03–2.18)0.392.12 (1.30–3.46)0.400.94 (0.63–1.41)0.77
Elevated waist circumference        
 Total (RA + control)13.0 (6.64–25.3) 2.06 (1.51–2.81) 3.51 (2.24–5.49) 
 Control only10.4 (4.6–23.5) 1.40 (0.95–2.06) 2.03 (0.80–5.19) 
 RA only17.9 (7.2–44.7)0.324.42 (2.58–7.55)<0.0016.72 (3.40–13.3)0.035
Metabolic syndrome        
 Total (RA + control)3.20 (2.17–4.72) 3.55 (2.36–5.34) 2.79 (1.91–4.07) 1.97 (1.31–2.96) 
 Control only2.95 (1.65–5.28) 3.78 (1.99–7.20) 1.78 (1.13–2.80) 1.23 (0.50–3.04) 
 RA only3.49 (2.12–5.75)0.653.64 (2.21–5.97)0.925.31 (2.82–9.99)0.0042.25 (1.38–3.70)0.24

The associations of VFA with the metabolic syndrome and some of its components were dissimilar between the RA and control groups (Figure 2). While RA patients and controls whose VFA was in the lower 3 quartiles demonstrated similar associations of VFA with the probability of having an elevated fasting glucose level, elevated blood pressure, or meeting the composite definition of the metabolic syndrome, RA patients whose VFA was in the 75th percentile or higher (≥167 cm2) had a significantly greater probability of having these outcomes, compared with the control group. Specifically, the adjusted probability of having an elevated fasting glucose level was 58% for RA patients in the highest quartile of VFA, compared with only 29% for controls in the same VFA quartile (P = 0.008) (Figure 2A). Similarly, the adjusted probability of having elevated blood pressure was 63% for RA patients in the highest quartile of VFA, compared with only 44% for controls in the same VFA quartile (P = 0.012) (Figure 2B), and the adjusted probability of meeting the composite definition of the metabolic syndrome was 74% for RA patients in the highest quartile of VFA, compared with only 37% for controls in the same VFA quartile (P = 0.004) (Figure 2D). In contrast, the adjusted probabilities of having a low level of high-density lipoprotein (HDL) (Figure 2C) or an elevated triglyceride level (data not shown) were not significantly different between the RA and control groups within each quartile of VFA.

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Figure 2. Adjusted probabilities and 95% confidence intervals for meeting the National Cholesterol Education Program—Adult Treatment Panel III metabolic syndrome definitions according to quartile of visceral fat area, by rheumatoid arthritis (RA) status (patient with RA or control subject). A, Elevated level of fasting glucose (>100 mg/dl). B, Elevated blood pressure (≥130/85 mm Hg). C, Low level of high-density lipoprotein cholesterol (HDL-c) (<50 mg/dl for men, <40 mg/dl for women). D, Fulfilling ≥3 of the 5 metabolic syndrome criteria. Analyses were adjusted for age, ethnicity, education, exercise, hours of television watching, depression, current and former smoking, thyroid disease, and use of antihypertensive, antidiabetic, and lipid-lowering medications.

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Association of RA characteristics with abdominal adiposity.

Visceral fat area.

The crude and adjusted associations between RA characteristics and VFA (square root transformed to normality, as required) are summarized in Table 3. After adjustment for sociodemographic characteristics, depression, exercise, television watching, smoking, and thyroid disease, RF seropositivity, log CRP level, and cumulative prednisone exposure were significantly associated with VFA, while higher log total SHS scores were inversely associated with VFA. These differences translated into an adjusted mean VFA that was 29 cm2 higher in RF-positive patients compared with RF-negative patients (118 cm2 versus 89 cm2 [33% higher]; P = 0.003), 38 cm2 lower in patients with SHS scores of ≥116 (the 75th percentile) compared with those with scores of ≤21 (the 25th percentile) (90 cm2 versus 128 cm2 [30% lower]; P = 0.008), and 32 cm2 higher in patients with a CRP level of ≥8.7 mg/liter (the 75th percentile) compared with those with a level of ≤1.1 mg/liter (the 25th percentile) (117 cm2 versus 85 cm2 [38% higher]; P = 0.015).

Table 3. Associations of RA characteristics with visceral and subcutaneous fat areas*
RA characteristicUnadjusted model 1Adjusted model 2Adjusted model 3Adjusted mean, cm2§
βPβPβPWithWithoutP
  • *

    The outcomes of visceral and subcutaneous fat areas were square root transformed to fulfill the normality requirements of linear regression. See Table 1 for definitions.

  • Change in the body composition outcome per unit increase in the indicated RA characteristic.

  • Model 2 represents a series of models in which each RA characteristic covariate is modeled individually (without including any other RA characteristics), adjusted for age, sex, ethnicity, education, CES-D, habitual exercise, television watching, current and former smoking, and thyroid disease. Model 3 includes all of the RA characteristics from model 2 with significance at the P < 0.20 level, adjusted for the model 2 covariates.

  • §

    For characteristics with significance at the P < 0.05 level in model 3, adjusted mean visceral and subcutaneous fat areas were back-transformed to absolute values. The models were adjusted for model 3 covariates. Groups are divided into those with and those without the characteristic of interest. For continuous variables, the groups compared were those in the ≥75th percentile for the characteristic (designated “with”) versus those in the ≤25th percentile (designated “without”).

Visceral fat area         
 RA duration, per year−0.0020.950.0170.51     
 RF seropositivity1.2870.0391.6590.0021.8130.003118890.003
 Anti-CCP seropositivity0.3320.600.9330.093−0.5100.41   
 Any shared epitope alleles0.0700.91−0.1450.80     
 DAS28-CRP−0.2270.400.3270.20     
 HAQ DI−0.5560.170.0710.87     
 Log total SHS−0.3780.098−0.4420.037−0.5670.004901280.008
 Log CRP0.3860.0860.3580.0700.5090.007117850.015
 Current prednisone−0.0340.960.2980.57     
 Cumulative prednisone >9 gm1.7120.0121.7840.0032.113<0.0011381000.010
 Current nonbiologic DMARDs1.1430.150.4510.53     
 Current biologic DMARDs0.0400.950.9830.0730.8060.12   
Subcutaneous fat area         
 RA duration, per year−0.0240.49−0.0130.68     
 RF seropositivity0.7460.341.0010.150.8790.28   
 Anti-CCP seropositivity1.3330.0941.4790.0350.6580.43   
 Any shared epitope alleles−0.6840.39−0.4220.55     
 DAS28-CRP0.6390.0550.3790.24     
 HAQ DI1.0880.0280.3840.47     
 Log total SHS−0.2630.36−0.3840.14−0.5580.0312402830.047
 Log CRP0.6810.0140.6740.0060.6790.0082891990.002
 Current prednisone−0.1770.81−0.4960.45     
 Cumulative prednisone >9 gm0.3280.70−0.2690.73     
 Current nonbiologic DMARDs0.8770.380.5180.57     
 Current biologic DMARDs1.2930.0780.1860.79     

For cumulative prednisone exposure, the association with VFA was not linear across exposure level. Only the group of patients in the highest quartile of cumulative exposure (≥9 gm) had significantly higher median VFA compared with those in the lowest exposure group (no prior prednisone exposure), i.e., 138 cm2 versus 100 cm2 (P = 0.010). The combined associations of RF and cumulative prednisone dose with VFA are shown in Figure 3. Among patients who were both RF positive and had a cumulative prednisone exposure of ≥9 gm, the adjusted mean VFA was 87 cm2 higher than that in patients with neither of these characteristics (P < 0.001), a more than doubling of VFA. The associations of RF and cumulative prednisone dose with VFA were merely additive (the P value for the interaction between RF and cumulative prednisone dose was 0.53 in the adjusted model).

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Figure 3. Adjusted mean visceral fat area and 95% confidence intervals, in rheumatoid arthritis patients divided into subgroups based on seropositivity for rheumatoid factor (RF) and cumulative prednisone exposure. Analyses were adjusted for age, ethnicity, education, exercise, hours of television watching, depression, current and former smoking, thyroid disease, C-reactive protein level, and total Sharp/van der Heijde score.

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Subcutaneous fat area.

The crude and adjusted associations of RA characteristics with SFA (square root transformed to normality, as required) are also summarized in Table 3. After adjustment for sociodemographic characteristics, depression, exercise, television watching, smoking, and thyroid disease, log CRP level was significantly associated with SFA, while log total SHS scores were inversely associated with SFA. These differences translated into an adjusted mean SFA that was 43 cm2 lower in patients with total SHS scores in the 75th percentile compared with those with SHS scores in the 25th percentile (18% lower; P = 0.047), and 90 cm2 higher in patients with CRP levels in the 75th percentile compared with those with CRP levels in the 25th percentile (31% higher; P = 0.002).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

The findings of this cross-sectional study demonstrate striking differences in the distribution of abdominal fat between RA patients and non-RA controls, even after adjustment for important potential confounders, despite the lack of significant differences in BMI or waist circumference. Higher levels of visceral fat were linked more strongly to some cardiometabolic risk factors in the RA group compared with controls. Among RA patients, a number of inflammatory and noninflammatory factors may contribute to these observed differences, including some factors that are modifiable within the context of RA disease management (e.g., limiting cumulative exposure to glucocorticoids).

This is, to our knowledge, the first reported study of abdominal adiposity measures in RA patients. Our findings linking higher VFA to RA in men and higher SFA to RA in women may have important potential implications regarding subsequent risk for CVD. For example, in the Framingham Heart Study (23), both SFA and VFA were associated with CV risk factors (systolic and diastolic blood pressure, total and HDL cholesterol, triglyceride, and fasting glucose levels); however, only visceral fat remained strongly associated with CV risk factors after accounting for other anthropometric variables. Visceral fat, in particular, has been associated with downstream CV outcomes, including aortic stiffness (24), coronary artery and abdominal aortic calcification (25), and CVD events (myocardial infarction and stroke) (26). Thus, increased visceral fat in RA may account for a portion of the increased risk of CVD observed in the RA population, with rates of CVD events and CVD mortality increased an average of 50% compared with non-RA controls (27).

The origins of increased VFA and SFA in RA patients are likely multifactorial. In the present study, we identified 2 RA disease factors associated with increased VFA in both men and women: RF seropositivity and cumulative prednisone exposure. The basis of the association of RF with VFA is not clear. Since there is no known biologic link between RF and adipose accumulation, the association may relate to RF as a disease severity marker. However, other markers of RA severity assessed in our study (e.g., anti-CCP antibodies, shared epitope alleles) were not associated with VFA. There is biologic plausibility behind the observed association between cumulative prednisone dose and VFA. A variety of changes in fat deposition have long been recognized to accompany endogenous and exogenous hypercortisolism (e.g., “moon facies,” “buffalo hump”); however, our study is the first to explore the effect of long-term low-dose glucocorticoid therapy on abdominal fat distribution in RA. Glucocorticoids have been shown to differentially affect glucose uptake and insulin receptor signaling in visceral, but not subcutaneous, fat adipocyte explants (28), processes that may serve to preferentially increase free fatty acid storage within the visceral adipocyte, and thus increase adipocyte size.

Many of the inflammatory cytokines that are chronically elevated in RA and are the hallmark of the disease (e.g., tumor necrosis factor α [TNFα], IL-6) have been shown to promote migration of mesenchymal precursors to adipose tissue depots (in a process deemed “adipotaxis”) (29), stimulate adipocyte differentiation, and reduce the sensitivity of adipocytes to signaling by insulin, leptin, and other adipocytokines. The potential end result of these processes is an increase in visceral fat. Adipocytes and resident adipose tissue macrophages are an additional source of inflammatory cytokines. Antagonism of TNFα was successful in reversing these processes in one study (29). However, we did not identify an association between measures of current disease activity and VFA, nor did treatment with biologic DMARDs (the majority of which were antagonists of TNFα) appear to be protective against elevated VFA. Similarly, no dynamic effects of TNF inhibition on body composition parameters were observed in a randomized clinical trial conducted in non-RA patients (30) or in the handful of small-scale studies of RA patients (31–33).

Our finding that increasing levels of visceral fat were negatively associated with articular damage seems counterintuitive, particularly since visceral fat accumulation is associated with higher levels of systemic inflammation. However, recent studies by us (15) and others (34) have suggested that alterations in levels of adiponectin may explain this apparent contradiction. Adiponectin, an adipocytokine, activates proinflammatory processes in inflamed rheumatoid synovium, potentially contributing to articular damage (35). However, adiponectin expression by adipocytes is suppressed as visceral fat increases. Therefore, higher abdominal adiposity may lead to lower adiponectin levels and thus less articular damage. In support of this, an association between increasing BMI and protection against articular damage in RA has been reported (36).

A salient finding of our study is the demonstration of markedly different patterns of abdominal obesity in RA patients in the absence of differences in simple measures often used to estimate body composition (i.e., BMI, waist circumference). How this can occur is likely related to two processes: 1) preferential accumulation of body fat into a specific adipose depot (i.e., the visceral compartment in men) and/or 2) equalization of the reduction in muscle by a compensatory increase in fat mass. While the present study is the first to explore adipose partitioning in RA, compensatory gain of fat as a feature of RA was suggested in studies by Roubenoff et al more than a decade ago (37). The result of such partitioning and compensation is that markedly abnormal body composition may go unrecognized in RA patients when anthropometric measures such as BMI are used to approximate fat mass.

There are some notable limitations to our study. The exclusion of patients weighing more than 300 pounds could have introduced selection bias, as RA patients whose weight exceeded this limit may have had proportionally more visceral and/or subcutaneous fat than the controls. However, inclusion of these individuals would likely have strengthened, not diminished, the magnitude of the associations detected. Several potential confounders not measured in the study, such as physical fitness, could have influenced the inferences about the association of RA status with body composition measures. Although self-reported physical activity was used to approximate this, this measure is subject to imprecision. Another limitation is that SFA data were not available on a substantial number of control subjects due to a reduced CT field of view. Although the controls with and those without SFA measurements were not substantially different in the characteristics evaluated, the loss of these subjects could have reduced precision and power in comparing the RA and control groups. However, differences in SFA in women were of sufficient magnitude to enable detection of significant differences. Finally, differences in mode of recruitment and participation between the RA and non-RA groups could account for some of the differences in adiposity measures observed; however, the effect of this bias would have had to have been large in order to account for the large between-group differences observed in VFA and SFA measures.

In summary, we have identified striking differences in the amount and distribution of abdominal adiposity in RA patients compared with controls. Both the increase in the amount of visceral adipose in men with RA, and the larger magnitude of the association between elevated levels of visceral adipose and cardiometabolic risk factors in both men and women with RA, may contribute to the recognized excess in cardiovascular risk in RA populations. Measures to reduce visceral fat (i.e., weight loss) may ameliorate cardiovascular risk to a greater extent in RA than in non-RA groups. However, identification of RA patients with increased abdominal adiposity may be challenging in the clinic, as anthropometric measures were not different between the RA group and the controls despite significantly increased adiposity in the RA group. Although our results indicate that there are some unmodifiable factors contributing to the observed increase in visceral fat (i.e., RF), modifiable factors (i.e., long-term exposure to glucocorticoids) appear to have a comparable impact.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Giles had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Giles, Post, Petri, Szklo, Bathon.

Acquisition of data. Giles, Allison, Tracy, Szklo, Bathon.

Analysis and interpretation of data. Giles, Blumenthal, Post, Gelber, Szklo, Bathon.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

We would like to thank the Johns Hopkins Bayview Medical Center General Clinical Research Center staff for providing support for the dual x-ray absorptiometry scanning used in this study, and the field center of the Baltimore MESA cohort and the MESA Coordinating Center at the University of Washington, Seattle. We are indebted to the ESCAPE RA staff (Marilyn Towns, Michelle Jones, Patricia Jones, Marissa Hildebrandt, and Shawn Franckowiak) for their dedication and hard work, and to the participants in the ESCAPE RA study who graciously agreed to take part in this research. Drs. Uzma Haque, Clifton Bingham, III, Carol Ziminski, Jill Ratain, Ira Fine, Joyce Kopicky-Burd, David McGinnis, Andrea Marx, Howard Hauptman, Achini Perera, Peter Holt, Alan Matsumoto, Megan Clowse, Gordon Lam and others generously recommended their patients for this study.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
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