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Objective Rheumatoid arthritis (RA) is an inflammatory disease associated with premature atherosclerosis. We hypothesized that mediators of inflammation associated with atherosclerosis in other populations (interleukin-6 [IL-6], tumor necrosis factor α [TNFα], serum amyloid A [SAA], vascular endothelial growth factor, neutrophil count, IL-1α, E-selectin, intercellular adhesion molecule 1 [ICAM-1], myeloperoxidase [MPO], matrix metalloproteinase 9, and vascular cell adhesion molecule 1) would be increased and associated with the severity of coronary atherosclerosis in patients with RA. Methods Clinical variables, concentrations of inflammatory mediators, and coronary artery calcification were measured in 169 patients with RA and 92 control subjects. Differences in concentrations of inflammatory mediators were compared using median quantile regression. The relationship of inflammatory mediators with the severity of coronary calcification in RA and control subjects was examined using proportional odds logistic regression, allowing for interaction with disease status. Models were adjusted for traditional cardiovascular risk factors. Results Median serum concentrations of IL-6, SAA, ICAM-1, E-selectin, TNFα, and MPO and peripheral blood neutrophil count were higher in patients with RA than controls (all P < 0.05), independent of Framingham risk score and diabetes mellitus (DM). IL-6 (main effect odds ratio [OR] 1.72; 95% confidence interval [95% CI] 1.12, 2.66) and TNFα (main effect OR 1.49; 95% CI 1.16, 1.90) concentrations were significantly associated with higher amounts of coronary calcium, independent of Framingham risk score and DM, and such main effects significantly differed from controls (P = 0.001 and 0.03 for interaction, respectively). Conclusion TNFα and IL-6 are significantly associated with the severity of subclinical atherosclerosis, independent of Framingham risk score, in RA.

Objective Obesity protects against radiographic joint damage in rheumatoid arthritis (RA) through poorly defined mechanisms. Adipocytokines are produced in adipose tissue and modulate inflammatory responses and radiographic joint damage in animal models. The purpose of this study was to examine the hypothesis that adipocytokines modulate inflammation and radiographic joint damage in patients with RA. Methods We compared serum concentrations of leptin, resistin, adiponectin, and visfatin in 167 RA patients and 91 control subjects. The independent association between adipocytokines and body mass index (BMI), measures of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor α [TNFα]), and radiographic joint damage (Larsen score; n = 93 patients) was examined in RA patients by multivariable regression analysis first controlling for age, race, and sex, and then for obesity (BMI) and inflammation (TNFα, IL-6, and CRP). Results Concentrations of all adipocytokines were significantly higher in RA patients than in controls; for visfatin and adiponectin, this association remained significant after adjusting for BMI, inflammation, or both. Visfatin concentrations were associated with higher Larsen scores, and this association remained significant after adjustment for age, race, sex, disease duration, BMI, and inflammation (odds ratio [OR] 2.38 [95% confidence interval (95% CI) 1.32–4.29], P = 0.004). Leptin concentrations showed a positive association with the BMI (ρ = 0.58, P < 0.01) and showed a negative association with the Larsen score after adjustment for inflammation (OR 0.32 [95% CI 0.17–0.61], P < 0.001), but not after adjustment for BMI (OR 0.86 [95% CI 0.42–1.73], P = 0.67). Conclusion Concentrations of adipocytokines are increased in patients with RA and may modulate radiographic joint damage. Visfatin is associated with increased, and leptin with reduced, levels of radiographic joint damage.

Objective Increased concentrations of N-terminal pro–brain natriuretic peptide (NT-proBNP) are associated with cardiovascular morbidity and mortality, but little is known about their relationship to chronic inflammation. Patients with rheumatoid arthritis (RA) have chronic inflammation, increased arterial stiffness, and accelerated coronary atherosclerosis. This study was undertaken to test the hypothesis that NT-proBNP concentrations are elevated in patients with RA and are associated with coronary artery calcification and markers of inflammation. Methods In 159 patients with RA (90 with early RA and 69 with longstanding RA) without heart failure and 88 control subjects, serum concentrations of NT-proBNP, interleukin-6 (IL-6), and tumor necrosis factor α (TNFα) were measured and coronary calcification was assessed. Associations between NT-proBNP levels and the other parameters were investigated. Results NT-proBNP concentrations were elevated in patients with longstanding RA (median 142.8 pg/ml [interquartile range 54.8–270.5]) and those with early RA (median 58.1 pg/ml [interquartile range 19.4–157.6]) compared with controls (18.1 [3.2–46.0]) (P < 0.001). In patients with RA, NT-proBNP concentrations were associated with age (ρ = 0.35, P < 0.001), levels of IL-6 (ρ = 0.33, P < 0.001), TNFα (ρ = 0.23, P = 0.003), and C-reactive protein (CRP) (ρ = 0.21, P = 0.01), coronary calcium score (ρ = 0.30, P < 0.001), systolic blood pressure (ρ = 0.30, P < 0.001), and disease activity (ρ = 0.29, P < 0.001). After adjustment for age, race, and sex, the associations between NT-proBNP concentrations and disease activity, TNFα, IL-6, and CRP remained significant, but those with systolic blood pressure and coronary calcium score were attenuated. Conclusion NT-proBNP concentrations are increased in patients with RA without clinical heart failure and may indicate subclinical cardiovascular disease and a chronic inflammatory state.

In recent studies, we showed a marked increase in the prevalence of the metabolic syndrome, a constellation of cardiovascular risk factors that includes central obesity, dyslipidemia, hypertension, and disturbed glucose metabolism, in patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) (1,2). Insulin resistance is a key component of the World Health Organization–defined metabolic syndrome that is increased in patients with RA or SLE (3,4). Insulin resistance is an important contributor to the increased cardiovascular risk attributed to the metabolic syndrome (5,6), and therefore, it is important to understand its pathogenesis. There are several mechanisms that could contribute to altered insulin sensitivity that may be important in patients with RA or SLE, and they provide insights into the pathogenesis of insulin resistance associated with inflammation. These include obesity (7), the medications used to treat inflammatory diseases (8,9), and inflammatory mediators (3). Obesity is a highly prevalent and modifiable risk factor associated with insulin resistance and the metabolic syndrome (10). In addition, adipose tissue functions as an endocrine organ and produces several inflammatory mediators, thus contributing to a proinflammatory state and increased cardiovascular risk (10). Glucocorticoids modulate appetite, metabolism and energy partitioning, exacerbate obesity (11), and induce insulin resistance and redistribution of fat, features of the metabolic syndrome (12,13). Inflammation, acting through cytokines such as tumor necrosis factor α (TNFα), facilitates the development of insulin resistance (14). The concentrations of TNFα and other mediators are elevated in patients with inflammatory diseases, but their role in the mechanisms underlying insulin resistance associated with inflammation is unknown. Thus, we examined the hypothesis that decreased insulin sensitivity is differentially associated with mediators of inflammation by studying 2 chronic inflammatory diseases of different pathogenesis, SLE and RA.