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Rheumatology 2000; 39: 533-536
© 2000 British Society for Rheumatology

Methotrexate as a preferential cyclooxygenase 2 inhibitor in whole blood of patients with rheumatoid arthritis

S. B. V. Mello, D. M. Barros1, A. S. F. Silva1, I. M. M. Laurindo2 and G. S. Novaes3

Rheumatology Division, Department of Internal Medicine, School of Medicine, University of Sao Paulo,
1 School of Medicine, University of Sao Paulo,
2 Rheumatology Division, Department of Internal Medicine, Clinical Hospital, School of Medicine, University of Sao Paulo and
3 Rheumatology Division, Department of Medicine, School of Medicine, Catholic University of São Paulo, Brazil

Objective. To investigate the regulation of whole-blood cyclooxygenase-1 and -2 (COX-2 and COX-1) activities by methotrexate (MTX) in rheumatoid arthritis (RA) patients.

Methods. Whole blood was withdrawn from nine healthy volunteers, 12 RA patients treated with MTX (RA/MTX) and six RA patients treated with chloroquine (RA/CQ). COX-1 activity was quantified as platelet thromboxane B2 production in unstimulated blood and COX-2 activity was measured as prostaglandin E2 (PGE2) production in whole blood stimulated with LPS. Thromboxane B2 and PGE2 were measured by radioimmunoassay. We studied the drug effect in vitro by direct incubation of MTX with blood obtained from normal donors. Ex vivo assays were performed with blood collected from RA/MTX and RA/CQ patients. The influence of serum factors on enzyme activities was analysed in blood collected from normal donors and incubated with RA/MTX, autologous or heterologous serum.

Results. In vitro assays showed no direct action of MTX on the activity of either enzyme. Assays performed with blood from RA/MTX patients showed preferential inhibition of COX-2 activity (PGE2 = 10.11 ± 2.42 ng/ml) when compared with blood of normal donors (PGE2 = 37.7 ± 4.36 ng/ml; P = 0.001). Inhibition of COX-2 activity was also observed when blood of normal donors was co-incubated with RA/MTX serum.

Conclusion. Our results clearly show that the anti-inflammatory action of low-dose MTX is partly mediated by a serum factor induced by MTX or a MTX metabolite that preferentially inhibits the activity of COX-2.

KEY WORDS: Methotrexate, Anti-inflammatory agents, Cyclooxygenases, Rheumatoid arthritis.

Correspondence to: S. B. V. Mello, Rheumatology Division, Department of Internal Medicine, School of Medicine, University of São Paulo, Av. Dr Arnaldo 455, Sala 3118, Sao Paulo, SP, Brazil CEP 01246-903.


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Home page
 Ann Rheum DisHome page
M CUTOLO, A SULLI, C PIZZORNI, B SERIOLO, and R H STRAUB
Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis
Ann Rheum Dis, August 1, 2001; 60(8): 729 - 735.
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