These cross-sectional findings demonstrate that RA patients show striking differences in the distribution of abdominal fat, even after adjusting for important potential confounders, despite no significant differences in BMI or waist circumference when they are compared with non-affected individuals. Higher visceral fat was linked more strongly to some cardiometabolic risk factors in the RA group compared to non-RA controls. Within the RA group, a number of inflammatory and non-inflammatory factors may contribute to these observed differences, including factors that are modifiable within the context of RA disease management (e.g., limiting cumulative exposure to glucocorticoids).
This investigation, to our knowledge, is the first to report 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 for their subsequent risk for CV disease. For example, in the Framingham Heart Study (23
) both SFA and VFA were associated with CV risk factors (systolic and diastolic blood pressures, total and HDL cholesterol, triglycerides, and fasting glucose); 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 CVD outcomes, including aortic stiffness (24
), coronary artery and abdominal aortic calcification (25
), and CVD events (MI 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, in which rates of CVD events and CVD mortality are increased an average of 50% compared to non-RA controls (27
The origins of increased VFA and SFA in RA patients are likely multifactorial. In the present study, we identified two 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. As there is no known biologic link between RF and adipose accumulation, the association may relate to RF as a disease severity marker. However, in our study, other markers of RA severity (i.e. anti-CCP antibodies, shared epitope alleles, etc…) were not associated with VFA. There is biologic plausibility behind the observed association of cumulative prednisone with VFA. A variety of changes in fat deposition have long been recognized to accompany endogenous and exogenous hypercortisolism (e.g. “moon face”, “buffalo hump”); however, our data are the first to explore the effect of chronic, low dose glucocorticoid therapy on abdominal fat distribution in rheumatoid arthritis. 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 (i.e. TNF-α, 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 TNF-α was successful in reversing these processes several of these in vitro
and animal studies. However, we did not detect an association between measures of current disease activity and VFA, nor did treatment with biologic DMARDs (the majority of which were antagonists of TNF-α) 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 in RA patients (31
Our finding that increasing visceral fat was negatively associated with articular damage seems counter-intuitive, 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 the adipocytokine, adiponectin, may explain this apparent contradiction. Adiponectin activates pro-inflammatory processes in inflamed rheumatoid synovium, potentially contributing to articular damage (35
). However, adiponectin expression by adipocytes is suppressed as visceral fat increases. Thus, higher abdominal adiposity may lead to lower adiponectin levels and thus less articular damage. Supporting this, an association of increasing BMI with 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 from 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 lbs could have introduced selection bias, as the RA patients exceeding 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-report of physical activity was used to approximate this, this measure is subject to imprecision in measurement. Another limitation was that SFA was not available on a substantial number of control patients due to a reduced CT field-of-view. Although the controls with and without SFA measures were not substantially different in their characteristics, the loss of these patients could have reduced precision and power in comparing RA and control groups. However, differences in SFA in women were of sufficient magnitude to detect 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 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 to controls. Both the increase in the amount of visceral adipose in men with RA, and the larger magnitude of association for elevated levels of visceral adipose with 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 anthropometrics were not different between the RA group and controls, despite significantly increased adiposity in the RA group. Although these data point to unmodifiable factors as contributing to the observed increase in visceral fat (i.e. RF), modifiable factors (i.e. chronic exposure to glucocorticoids) appear to have a comparable impact.