Suppressive effect of combination treatment of leflunomide and methotrexate on chemokine expression in patients with rheumatoid arthritis.

To study the immunosuppressive and anti-inflammatory effects of combined leflunomide and methotrexate (MTX) therapy on chemokine expression in patients with rheumatoid arthritis (RA), nine patients were enrolled for the combination therapy for 24 weeks. These patients have been on treatment with MTX 15 mg/week for not less than 3 months before entry to the study. A loading dose of l00 mg/day of leflunomide was given for 3 days, followed by 10 mg/day for the rest of the study period. Plasma concentrations of monocyte chemotactic protein-1 (MCP-1), thymus- and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) were assayed before and after combination treatment by ELISA. Gene expression of inflammatory cytokines and chemokines of peripheral blood mononuclear cells was analysed by cDNA expression array. Plasma MCP-1, TARC and MDC concentrations were significantly lower in patients after combination treatment [median (interquartile range) before versus after treatment: MCP-1 of 118.0 (64.0-515.2) versus 3.2 (0.0-22.8) pg/ml, P < 0.01; TARC of 126.1 (27.2-197.4) versus 0.0 (0.0-52.5) pg/ml, P < 0.05; MDC of 503.3 (446.2-600.9) versus 366.8 (337.4-393.4) pg/ml, P < 0.05]. Positive correlations among reductions in plasma chemokines and clinical outcome measures were also found. Expression of chemokine genes including MDC and TARC was suppressed after combination treatment [% suppression of 38.7 (54.3-13.0) and 53.7 (55.9-28.4), respectively]. Combination therapy with leflunomide and MTX exhibits anti-inflammatory activity in the suppression of chemokine expression and subsequent recruitment of inflammatory cells into the inflammatory sites in RA.