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

Abstract

Objective: To investigate the effect of cyclosporine on cytokine production, especially on T helper 1 (Th1) and T helper 2 (Th2) type cytokines, in patients with rheumatoid arthritis (RA).

Methods: A 16 week randomized, double blind, placebo controlled study of cyclosporine (2.5 to 4 mg/kg/day) was conducted in 40 patients with severe, refractory RA who had residual inflammation and disability despite partial responses 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) measured 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 placebo group (n = 17), had greater decreases in tender joints, swollen joints, patient global assessment, patient self-assessed disability, and C-reactive protein, as well as having more patients with > 20% improvement. Comparison of circulating cytokines at entry and at 16 weeks showed significant decreases 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-alpha (median -55 vs 5 pg/ml; p < 0.001), and IFN-gamma (median -21 vs 5 pg/ml; 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 decreases 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 patients (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 rate of improvement of joint scores (r = 0.718, p = 0.001) after administration 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 circulating IL-10 is useful to assess the clinical improvements in patients with RA after administration of cyclosporine.