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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.

Obesity induces a proinflammatory state and is a major cause of morbidity in the general population. However, little is known about the effects of obesity in patients with chronic inflammatory illnesses such as systemic lupus erythematosus (SLE).One hundred consecutive patients with SLE were studied to determine the relationship between body mass index (BMI) and functional capacity, measures of fatigue, quality of life, and the inflammation markers C-reactive protein (CRP), the erythrocyte sedimentation rate, and interleukin-6 (IL-6). The association between BMI and patient characteristics was determined, and multiple logistic regression models were used to adjust for age, sex, disease activity, and disease-related damage.Thirty-three patients had a normal BMI (25 kg/m(2)), 28 were overweight (25-29.9 kg/m(2)), and 39 were obese (or =30 kg/m(2)). Obese patients had worse functional capacity, more fatigue, and higher concentrations of inflammation markers. The mean +/- SD modified Health Assessment Questionnaire (M-HAQ) score was 0.6 +/- 0.4 in obese patients compared with 0.3 +/- 0.4 and 0.2 +/- 0.3 in overweight patients and those with a normal BMI, respectively (P = 0.001). The mean +/- SD concentrations of CRP in obese patients (10.0 +/- 8.6 mg/liter) were higher than those in patients who were overweight (4.7 +/- 5.4 mg/liter) or had a normal BMI (6.2 +/- 9.9 mg/liter) (P0.001). Similarly, concentrations of IL-6 were higher in obese patients (P = 0.003). After adjusting for age, sex, disease activity, and damage indices, the associations between BMI and CRP (P0.001), M-HAQ scores (P = 0.005), and IL-6 concentrations (P = 0.01) remained significant.Obesity is independently associated with impaired functional capacity and inflammation markers in patients with lupus. Thus, weight loss may improve functional capacity and decrease cardiovascular risk factors.

Objective To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA). Methods This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes. Results ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1–23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3–39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7–46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8–62.3%) (P ≤ 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation ≥40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41–59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose tacrolimus groups (31–33%). Discontinuation for creatinine elevation occurred in the 3 mg (3.1%) and 5 mg (10.9%) tacrolimus groups. Conclusion Tacrolimus improved disease activity in methotrexate-resistant or -intolerant patients with RA. A dose response was observed when efficacy and toxicity were assessed at different doses. The optimal dose of tacrolimus appears to be >1 mg but ≤3 mg daily.

To determine whether the clinical benefit and favorable safety profile previously noted with the combination of cyclosporine (CSA) and methotrexate (MTX) given for 24 weeks in patients with rheumatoid arthritis (RA) would be maintained for a further 24 weeks, and whether the addition of CSA in patients who had previously been randomized to receive placebo + MTX would result in clinical benefit.Eligible subjects from the initial study (weeks 0-24), in which the addition of placebo or CSA to MTX therapy was compared in patients with RA that was partially responsive to MTX, were enrolled. Patients who had received CSA + MTX continued this regimen for a further 24 weeks (weeks 24-48) (group 1; n = 48), and patients who had initially received placebo + MTX now received CSA + MTX for 24 weeks (weeks 24-48) (group 2; n = 44), in an open-label extension study. The primary outcome measures were the number of tender joints, number of swollen joints, physician and patient global assessments, pain, functional disability as measured by the modified Health Assessment Questionnaire, and erythrocyte sedimentation rate.Of the 92 patients enrolled, 80 (87%) completed the extension study. In patients in group 1, the clinically and statistically significant improvement in response outcomes previously noted at week 24, ranging from 25% to 50%, was maintained through week 48. In patients in group 2, the addition of CSA resulted in significant clinical improvement. By week 48, most outcome measures in group 2 patients were similar to those in group 1 patients. CSA treatment resulted in a small increase in serum creatinine levels, but only 1 patient was withdrawn from the study for this reason.The clinical improvement previously observed in patients treated with the CSA + MTX combination for 24 weeks was maintained for 24 subsequent weeks, without serious adverse effects, and was also observed in the patients whose treatment was switched from placebo + MTX to CSA + MTX.

Objective. Free radical-induced oxidative stress with consequent lipid peroxidation and resultant tissue damage has been suggested as a potential mechanism of the pathogenesis of scleroderma. However, because reliable measurement of lipid peroxidation in vivo is difficult, it has not been possible to adequately examine this hypothesis. We have previously described a series of bioactive prostaglandin F 2 -like compounds, termed F 2 -isoprostanes, produced in vivo in humans by the non-cyclooxygenase, free radical-catalyzed, peroxidation of arachidonic acid and have shown them to be a reliable measure of lipid peroxidation in vivo. In the present study, we determined whether scleroderma is associated with enhanced oxidative stress. Methods. As a measure of oxidative stress, we determined urinary concentrations of a tetranordicarboxylic acid metabolite of F 2 -isoprostanes (F 2 IP-M) by mass spectrometry in 8 patients with scleroderma (representing a wide spectrum of disease, including limited disease with refractory digital ulceration or pulmonary hypertension, and diffuse disease) and in 10 healthy control subjects. Results. F 2 IP-M concentrations were significantly higher in patients with scleroderma (mean ± SEM 3.41 ± 0.64 ng/mg of creatinine) than in healthy controls (1.22 ± 0.14 ng/mg of creatinine) (P = 0.002). These elevations occurred in patients with limited disease and in those with diffuse disease. Conclusion. The increased level of urinary F 2 IP-M supports the hypothesis that free radical-induced oxidative injury occurs in scleroderma and provides a biologic marker whose relationship to disease activity and disease therapy may be important. These findings may also provide a rationale for exploring whether antioxidant therapy may influence the natural course of the disease.