Divergent effect of cyclosporine on Th1/Th2 type cytokines in patients with severe, refractory rheumatoid arthritis

Objective, To investigate the effect of cyclosporine on cytokine production , especially on T helper 1 (Th1) and T helper 2 (Th2) type cytokines, in pa tients with rheumatoid arthritis (RA). Methods. A 16 week randomized, double blind, placebo controlled study of cy closporine (2.5 to 4 mg/kg/day) was conducted in 40 patients with severe, r efractory RA who had residual inflammation and disability despite partial r esponses to prior maximal tolerated dose of methotrexate (MTX; < 15 mg/week ) and low dose prednisone (< 10 mg/day). Clinical and laboratory variables, and circulating levels of interleukin 2 (IL-2), IL-4, IL-10, IL-12, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) measure d by ELISA were compared between patients (cyclosporine group) treated with cyclosporine plus MTX and those (placebo group) treated with placebo plus MTX at entry and at 16 weeks. Results. At 16 weeks, the cyclosporine group (n = 17), compared with the pl acebo group (n = 17), had greater decreases in tender joints, swollen joint s, patient global assessment, patient self-assessed disability, and C-react ive protein, as well as having more patients with > 20% improvement. Compar ison of circulating cytokines at entry and at 16 weeks showed significant d ecreases of IL-2. (median -61 vs 7 pg/ml; p = 0.004) ("+" denotes increase, "-" denotes decrease), IL-12 (median -313 vs -14 pg/ml; p = 0.002), TNF-al pha (median -55 vs 5 pg/ml; p < 0.001), and IFN-gamma (median -21 vs 5 pg/m l; p = 0.003), and a significant increase of IL-10 (median 55 vs -12 pg/ml; p < 0.001) in the cyclosporine group compared with the placebo group. The degree of IL-10 increases correlated strongly with the degree of IL-12 decr eases in the cyclosporine group (r = 0.572, p = 0.016). However, there was no change in circulating IL-4 between the 2 groups. Within the cyclosporine group, the improved patients (n = 10) compared to the non-improved patient s (n = 7) had a greater increase in circulating IL-10 (median 172.0 vs 85.2 %; p = 0.01). The rate of increase of IL-10 strongly correlated with the ra te of improvement of joint scores (r = 0.718, p = 0.001) after administrati on of cyclosporine. Conclusion. Our results suggest that the therapeutic effect of cyclosporine is achieved by correcting a Th1/Th2 imbalance (a shift of Th1 type to Th2 type), which may be involved in the pathogenesis of RA; and that circulatin g IL-IO is useful to assess the clinical improvements in patients with RA a fter administration of cyclosporine.