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The Effect of Methotrexate and Leflunomide on the Cytokine Profile and Nitric Oxide Metabolism in Rheumatoid Arthritis Patients

Dubikov AI, Medved EE and Belogolovykh LA

Objective: To reveal the role of individual cytokines and nitric oxide in pharmacological effects of methotrexate and leflunomide in rheumatoid arthritis (RA) patients. Materials and methods: Ninety four patients with confirmed seropositive RA aged 20-60 yrs were examined. The patients were separated into groups of early and late RA and of “erosive” and “non-erosive” RA. 63 patients received methotrexate, and 31, leflunomide. The levels of IL-1β, IL-6, IL-10, and TNF-α were determined in blood serum and synovial fluid using solid-phase enzyme immunoassay. The levels of NO2 and NO3 were determined in blood serum, synovial fluid, and urine by spectrophotometry. All analyses were performed both before and 6 months post therapy. Therapy effectiveness was estimated in the same period. Results: The levels of NO metabolites and cytokines except for IL-6 were increased in synovial fluid and urine of all patients compared to the control. The methotrexate therapy resulted in an increase in IL-1, TNF, and NO metabolites in the peripheral blood. As distinct from methotrexate, leflunomide strongly suppressed IL-6 production in blood serum. The therapy using either drug resulted in a manifold decrease in the levels of IL-1, TNF, and NO metabolites in synovial fluid. Conclusions: There were opposite changes of levels of cytokines and NO metabolites in RA patient’s blood and synovial fluid receiving methotrexate and leflunomide respectively.