RESEARCH: Leflunomide reduces nitric oxide production in patients with active rheumatoid arthritis.

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Immunopharmacol. 2005 Jun;5(6):1085-90. Epub 2004 Dec 15.

Leflunomide reduces nitric oxide production in patients with active

rheumatoid arthritis.

Reddy SV, Wanchu A, Khullar M, Govindrajan S, Bambery P.

Department of Internal Medicine, Postgraduate Institute of Medical

Education and Research, Chandigarh 160012, India.

OBJECTIVES: Leflunomide is an immunomodulatory agent that was

recently approved for the treatment of rheumatoid arthritis (RA). The

mechanism of action is not fully understood. Nitric oxide (NO) plays an

important role in the pathogenesis of RA. Leflunomide has been shown to

cause cell specific inhibition of inducible nitric oxide synthase

(iNOS) activation in animal models. We carried out this study to

determine if there was alteration in NO production in patients with RA.

METHODS: An 8-week open label study was carried out on patients with

adult onset active RA. We measured levels of nitrite and citrulline

spectrophotometrically as surrogate markers of NO production.

Within-patient serum levels of nitrite and citrulline were compared

with leflunomide therapy at three points of time (at 0, 4 and 8 weeks

of therapy). RESULTS: Thirty-three patients with active RA were

enrolled for this study. These patients were a subset of 63 individuals

who are studied for clinical efficacy of leflunomide. Three patients

were lost to follow-up. Median nitrite levels were 817.2 (nmol/ml) at

the start of therapy and this declined to 440.9 nmol/ml and 301.1

nmol/ml at 4 and 8 weeks of therapy. Median citrulline levels were

649.3 nmol/ml at the start of the study, which declined to 549.2

nmol/ml and 485.4 nmol/ml at 4 and 8 weeks, respectively. Statistically

significant decrease in median values for serum nitrite and citrulline

levels was documented after 4 weeks of leflunomide therapy (p<0.01),

which was sustained at 8 weeks (p<0.01), although there was no further

fall between 4 and 8 weeks (p>0.1). CONCLUSIONS: Leflunomide inhibits

nitric oxide production in patients with active RA. Inhibition of NO

synthesis may be one of the mechanisms responsible for the

immunomodulatory activity of leflunomide.

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