Reduction of NOS2 overexpression in rheumatoid arthritis patients treated with anti-tumor necrosis factor alpha monoclonal antibody (cA2)

Objective. Peripheral blood mononuclear cells (PBMC) from patients with rhe umatoid arthritis (RA) have increased expression of nitric oxide synthase t ype 2 (NOS2) protein and enhanced formation of nitric oxide (NO) that corre late with disease activity. NO may play a role in the inflammation of RA. T reatment of RA patients with a chimeric monoclonal antibody against tumor n ecrosis factor alpha (TNF alpha; cA2) results in clinical improvement in th e majority of patients. The present study was designed to determine if cA2 therapy decreases PBMC NOS2 protein expression and NOS enzyme activity in R A patients. Methods. RA patients receiving background oral methotrexate participated in a double-blind, placebo-controlled clinical trial in which they were rando mly assigned to receive a single infusion of either placebo or cA2 at 5, 10 , or 20 mg/kg, NOS2 protein and NOS enzyme activity were measured in PBMC a t baseline and 4 weeks following cA2 therapy. These results were compared w ith the degree of clinical change in disease activity, Results. At baseline, elevated levels of NOS2 protein and NOS enzyme activi ty were more frequently detected in PBMC from RA patients than in those fro m healthy controls. Treatment of the RA patients with cA2 significantly red uced NOS2 protein expression and NOS enzyme activity. Changes in NOS activi ty following treatment correlated significantly with changes in the number of tender joints. Conclusion. These results indicate that TNF alpha likely plays an important role in enhancing NOS2 expression in RA, and that the antiinflammatory eff ects of cA2 treatment may be mediated by a reduction of NO overproduction.