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

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.

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.

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.

Our results show, for the first time, a short-term effect of anti-TNF-alpha therapy on the levels of nitric oxide production.