Visfatin is not associated with inflammation or metabolic syndrome in patients with severe rheumatoid arthritis undergoing anti-TNF-alpha therapy.

BACKGROUND AND OBJECTIVE: Visfatin is an insulin-mimetic adipokine. In non-rheumatoid arthritis (RA) patients circulating levels of visfatin are correlated with the amount of visceral fat. Recent studies have disclosed an implication of visfatin in inflammation. Chronic systemic inflammation is of major importance in the development of atherosclerosis in RA. In the present study we investigated whether inflammation, obesity or metabolic syndrome are potential determinants of circulating visfatin concentrations in a group of RA patients on periodical treatment with the TNF-alpha blocker infliximab due to severe disease. We also assessed whether the infusion of infliximab may alter circulating visfatin concentrations in patients with severe RA. METHODS: We investigated 33 non-diabetic patients with RA on periodical treatment with infliximab. Serum visfatin levels were determined immediately prior to and after infliximab infusion. RESULTS: There was no correlation between body mass index of RA patients and baseline serum level of visfatin. Also, no significant correlations between baseline visfatin levels and the age at the time of the study or at the onset of the disease, disease duration, ESR and CRP levels, DAS28, lipids, insulin sensitivity, resistin or the cumulative prednisone dose at the time of the study were found. Visfatin levels did not change upon infliximab infusion. CONCLUSIONS: In RA patients on TNF-alpha blocker treatment, circulating visfatin levels are unrelated to disease activity, adiposity or metabolic syndrome. The beneficial effect of anti-TNF-alpha therapy on cardiovascular mortality in RA does not seem to be mediated by changes in serum levels of visfatin.

Short-term effect of anti-TNF-alpha therapy on nitric oxide production in patients with severe rheumatoid arthritis.

OBJECTIVE: TNF-alpha increases expression of inducible nitric oxide synthase (iNOS) in macrophages and vascular endothelial cells. Under normal conditions, iNOS activity is very low. However, iNOS activity is stimulated during inflammation by cytokines such as TNF-alpha and the amount of NO produced by iNOS may be a 1,000-fold greater than that produced by endothelial NOS. Since functional iNOS gene polymorphisms have been associated with susceptibility to rheumatoid arthritis (RA), drugs blocking TNF-alpha might decrease production of cytotoxic concentrations of NO leading to beneficial effect on RA or its complications. In the present study we investigated whether the infusion of the anti-TNF-alpha-infliximab may yield a short-term effect altering circulating NO oxidation products in patients with severe RA. METHODS: We investigated 33 RA patients on periodical treatment with infliximab. Serum levels of nitrates, nitrites and NOx (nitrites+nitrates) were determined immediately prior to and after infliximab infusion. Correlation with clinical variables, laboratory markers of inflammation, metabolic syndrome features, adipokines and adhesion molecules was also assessed. RESULTS: Upon infliximab administration, serum NOx concentrations (microM) decreased significantly ([mean+/-SD: 15.0+/-8.8; median: 11.9; interquartile range: 9.2-18.5] before infliximab-time 0 (baseline) and [12.9+/-6.3; 10.9; 7.8-17.2] after infliximab infusion-time 120 minutes; p=0.03). It was also the case for nitrates (9.8+/- 8.3; 7.6; 5.5-10.2] before infliximab and [7.5+/-4.0; 6.6; 5.2-10.0] after infliximab infusion; p=0.008). There was a positive correlation between basal levels of nitrites and leptin concentration prior to infliximab administration. However, no significant correlations between NO oxidation products and clinical or other laboratory variables were found. CONCLUSIONS: Our results show, for the first time, a short-term effect of anti-TNF-alpha therapy on the levels of nitric oxide production.

Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis.

OBJECTIVE: The adipocytokine leptin regulates weight centrally and participates in the regulation of the immune and inflammatory responses. Chronic systemic inflammation is of major importance in the development of atherosclerosis in rheumatoid arthritis (RA). In the present study we investigated whether inflammation, obesity or both of these characteristics are potential determinants of circulating leptin concentrations in a group of RA patients on periodical treatment with the TNF-alpha-blocker-infliximab due to severe disease. We also assessed whether the infusion of infliximab may alter circulating leptin concentrations in patients with severe RA. METHODS: We investigated 33 patients with RA on periodical treatment with infliximab. Serum leptin levels were determined immediately prior to and after infliximab infusion. RESULTS: There was a positive correlation between body mass index of RA patients and baseline serum level of leptin (rho=0.665, p<0.001). Apart from a significant correlation with VCAM-1 (rho=0.349, p=0.04), no significant correlations between baseline leptin levels and the age at the time of the study or at the onset of the disease, disease duration, ESR and CRP levels, DAS28, lipids, insulin sensitivity, adhesion molecules, resistin, adiponectin, ghrelin or the cumulative prednisone dose at the time of the study were found. Leptin levels did not change upon infliximab infusion (p=0.48). CONCLUSION: In RA patients on TNF-alpha blocker treatment, circulating leptin levels are unrelated to disease activity but constitute a manifestation of adiposity. The beneficial effect of anti-TNF-alpha therapy on cardiovascular mortality in RA does not seem to be mediated by reduction in serum levels of leptin.

High-grade inflammation, circulating adiponectin concentrations and cardiovascular risk factors in severe rheumatoid arthritis.

OBJECTIVE: To assess whether obesity and systemic inflammation are potential determinants of circulating adiponectin concentrations and whether low adiponectin levels cluster with metabolic syndrome features that are previously documented cardiovascular risk factors in rheumatoid arthritis (RA). METHODS: We investigated 33 RA patients who were treated with the TNF-alpha antagonist infliximab, immediately prior to an infliximab infusion. Adiponectin levels were also determined immediately after administration of an infliximab dose. RESULTS: Adiponectin concentrations correlated with age (R=0.465, p=0.008) and were higher in women (mean [95% confidence interval]=21,595 [15,366 to 30,349] ng/ml) than in men (9,310 [5,653 to 15,335] ng/ml)(p=0.008). C-reactive protein (CRP) levels correlated with circulating adiponectin concentrations (partial (p) R=-0.370, p=0.04), independent of age and gender. By contrast, the body mass index (BMI) did not correlate with adiponectin levels (pR=-0.039, p=0.8). Adiponectin concentrations correlated with triglycerides/HDL cholesterol ratios (pR=-0.396, p=0.03), total cholesterol/HDL cholesterol ratios (pR=-0.444, p=0.01) and high fasting plasma glucose levels (pR=-0.366, p=0.04), independent of CRP levels and the BMI. Adiponectin levels did not change (p=0.3) upon infliximab administration. CONCLUSION: In this cohort, high-grade inflammation was independently and negatively correlated with circulating adiponectin concentrations whereas low adiponectin levels clustered with metabolic syndrome features that reportedly contribute to atherogenesis in RA. Circulating adiponectin may be involved in cardiovascular disease in RA. The impact of inflammation on circulating adiponectin concentrations is not likely to be TNF-alpha mediated in RA.

Anti-TNF-alpha therapy modulates resistin in patients with rheumatoid arthritis.

OBJECTIVE: Chronic systemic inflammation plays a pivotal role in the development of atherosclerosis in rheumatoid arthritis (RA). In the present study, we investigated whether anti-TNF-alpha antagonist-monoclonal antibody-infliximab administration alters circulating levels of resistin, a proinflammatory adipokine. We further assessed associations of circulating resistin concentrations with CRP and ESR levels, platelet counts and metabolic syndrome and demographic characteristics in RA patients on periodical treatment with infliximab. METHODS: We investigated 33 patients with RA on periodical treatment with infliximab. Serum resistin levels were determined immediately prior to and after infliximab infusion. RESULTS: Upon infliximab administration, mean (SD) serum resistin concentrations (ng/ml) decreased from 21.9 (9.9) to 17.4 (8.9) (p=0.005). Also, a significant association between the mean ESR (r=0.405; p=0.03) and CRP (r=0.571; p=0.0005) from disease diagnosis and ESR (r=0.486; p=0.004), CRP (r=0.599; p=0.0005) and platelet count (r=0.559; p=0.0007) at the time of the study and baseline resistin levels was found. CONCLUSION: The present study shows that anti-TNF-alpha therapy results in a rapid reduction of serum resistin levels in patients with RA. It also confirms a close association between laboratory markers of inflammation, particularly CRP and resistin levels. These observations support a potential role of resistin in the inflammatory cascade in RA.

Influence of anti-TNF-alpha infliximab therapy on adhesion molecules associated with atherogenesis in patients with rheumatoid arthritis.

OBJECTIVE: Chronic systemic inflammation plays a pivotal role in the development of atherosclerosis in rheumatoid arthritis (RA). Soluble (s) adhesion molecules were found significantly increased in RA patients with active disease. Since increased levels of some adhesion molecules were closely linked to the development of endothelial dysfunction and atherosclerosis and administration of anti-TNF-alpha-infliximab resulted in a rapid and dramatic improvement of endothelial function in long-term infliximab treated RA patients, we assessed whether infusion of the chimeric anti-TNF-alpha infliximab might also yield a rapid and favorable effect on serum levels of soluble adhesion molecules in RA patients periodically treated with this drug because of severe disease. METHODS: We recruited patients with RA refractory to conventional therapy seen over a period of 2 months at Hospital Xeral-Calde, Lugo, Spain, who were on periodical treatment with infliximab for at least 14 weeks. Blood samples for determination of sICAM-1, sICAM-3, sVCAM-1, sE-selectin, and sP-selectin levels by ELISA were taken immediately before and after infliximab infusion. RESULTS: Thirty-four RA patients (25 women; mean age: 55.4 years; mean DAS28: 4.27) fulfilled the inclusion criteria. Following infliximab infusion a reduction of the overall mean values of the five adhesion molecules was observed. However, when a Wilcoxon signed-rank test was used, only significant differences for sICAM-3 and sP-selectin were observed. In this regard, sICAM-3 and sP-selectin levels fell in 26 (77%) and 28 (82%) of the 34 patients. CONCLUSION: Our study confirms a rapid and beneficial effect of infliximab infusion on expression of some adhesion molecules in RA patients treated periodically with this anti-TNF-alpha monoclonal antibody because of severe disease.

Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis.

OBJECTIVE: Systemic inflammation, insulin resistance, and endothelial dysfunction have been implicated in the development of cardiovascular disease in rheumatoid arthritis (RA). Since insulin resistance can promote endothelial dysfunction and anti-TNF-alpha blockade yield a rapid improvement of endothelial function, we have sought to assess whether TNF-alpha blockade may also result in a reduction of insulin serum levels and improvement of insulin resistance in RA patients who require this therapy because of severe and refractory disease. METHODS: We recruited patients with RA seen over a period of 1 month at Hospital Xeral-Calde, Lugo, Spain, that were on treatment with anti-TNF-alpha monoclonal antibody-infliximab. Patients with diabetes mellitus or plasma glucose > 110 mg/dl were excluded. Fasting blood samples were taken for determination of plasma glucose and serum insulin levels immediately prior to and after infliximab infusion. RESULTS: Twenty-seven RA patients (21 women; mean age: 57.1 years; mean DAS28: 4.43) fulfilled the inclusion criteria. Dramatic reduction in the serum insulin levels and insulin/glucose index was observed following infliximab infusion. Also, a significant improvement of insulin resistance and insulin sensitivity was found. CONCLUSION: Our study confirms a rapid beneficial effect of infliximab on insulin resistance and insulin sensitivity in RA patients treated periodically with this drug. It may support the long-term use of drugs that act blocking TNF-alpha function to reduce the mechanisms implicated in the development of atherosclerosis in patients with RA.