BALTIMORE, Maryland—In women with rheumatoid arthritis (RA)—but not in men—high levels of body fat are associated with elevations of the inflammatory marker C-reactive protein (CRP). Relying on CRP levels as a surrogate marker for systemic inflammation may lead to incorrect estimations of RA disease activity in such patients, according to Jon T. Giles, MD, in research reported in Arthritis & Rheumatism.¹

“In summary, we demonstrated a strong association between body fat, in particular truncal fat, and the serum CRP concentration in women with RA. Neither the level of articular activity nor the use of biologic DMARDs modified the association. Men with RA did not exhibit the same association of body fat with the CRP level, suggesting that there is a fundamental sex-related difference in the interplay between body fat and CRP induction that warrants further investigation. These findings suggest that body fat may confound the commonly ascribed associations between RA disease-related factors and serum CRP concentration in certain patients, and body fat should be considered when using the level of CRP for diagnostic and therapeutic decision making in RA patients,” said Dr. Giles, assistant professor of medicine at Johns Hopkins University in Baltimore.

CRP levels are frequently used together with joint counts to estimate RA disease activity and are a component of the American College of Rheumatology core set of clinical response measures and of the Disease Activity Score in 28 joints. Serum CRP levels both increase in response to stimulation of hepatocytes by inflammatory cytokines and can then produce downstream pro-inflammatory effects such as activatin of complement and induction of tissue factor.

Inflamed synovium and circulating monocytes are sources of the cytokines that induce CRP production in RA patients, but so is body fat. Dr. Giles noted, “Adipose tissue is a potent source of inflammatory cytokines, including TNFα and IL-6, that induce hepatic production of CRP.”

This study included 196 men and women with RA who were participants in the Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis (ESCAPE-RA) cohort study. The trial is investigating the prevalence, progression, and risk factors for subclinical cardiovascular disease in RA. Subjects with cardiovascular events prior to enrollment were excluded, as were those who weighed >300 lbs and thus were too heavy for the cardiovascular imaging equipment.

The researchers conducted anthropometric assessment and total body dual-energy X-ray absorptiometry (DXA) to measure total and regional body fat and lean mass. Association between fat and lean mass, CRP, and interleukin-g (IL-6) levels were stratified by sex and adjusted for demographic, lifestyle, RA disease activity, treatment factors, and articular activity.

The analysis showed that

• All measures of adiposity were associated with CRP levels in women but not in men
• In women, truncal fat had the strongest association with CRP level, and each kilogram increase was associated with a 0.101-unit increase in CRP (P <.001)
• Articular activity did not change this association in women but decreased CRP levels in men
• Use of biologic agents did not affect the association between fat and CRP levels in women

“This translates into an expected difference in the CRP level, solely related to the effect of the difference in truncal fat, of 4.70 mg/L when we compared a women with 20 kg of truncal fat (the 75th percentile for women with RA in this cohort) with a woman with 10 kg of truncal fat (the 25th percentile in this cohort),” Dr. Giles said. “Similarly, when we compared the woman with the highest truncal fat mass in our cohort (34.5 kg) with the woman with the lowest truncal fat mass (2.4 kg), the expected difference in CRP level, solely related to the difference in truncal fat, was 31.32 mg/L (actual difference of 26.04 mg/L).”

Likewise, each unit increase in body mass index  was associated with a 0.084-unit increase in the log CRP in multivariate analysis.

Translating research into practice

Adipose tissue within the intra-abdominal cavity and surrounding the mesentery and omentum is the fat store that contributes the most to system inflammation, according to Dr. Giles. The researchers found that each 1-cm increase in waist circumference in women was associated with a 0.027-unit increase in the log CRP (P<0.001).

“These results suggest that body fat, in particular truncal fat, should be considered when interpreting the significance of elevated CRP level in women with RA, and imply that a fat-associated elevation in CRP may confound clinical diagnostic and therapeutic decision making in a variety of settings,” Dr. Giles warned.

“For example, when using serum CRP as a diagnostic tool, a fat-associated elevation in the CRP in a woman with noninflammatory musculoskeletal symptoms could prompt an inaccurate diagnosis of seronegative RA. In other settings, such as the use of serum CRP concentrations to guide therapeutic decision making, a fat-associated elevation in the CRP may be misinterpreted as a reflection of persistent synovitis.”

In the study truncal fat mass was quantified by total body DXA. In clinical practice, Dr. Giles suggested using waist circumference or BMI as a proxy for truncal fat to estimate what proportion of the markers of systemic inflammation are due to truncal fat.

Reference

1. Giles JT, Bartlett SJ, Ross Andersen, et al. Association of body fat with C-reactive protein in rheumatoid arthritis. Arthritis Rheum. 2008;58:2632-2641.