Combined Treatment of Etanercept and MTX Reverses Th1/Th2, Th17/Treg Imbalance in Patients with Rheumatoid Arthritis

To explore the mechanism of Etanercept in the treatment of rheumatoid arthritis (RA), we investigated whether the Th1/Th2 and Th17/regulatory T cells (Treg) imbalance could be reversed by Etanercept and whether the reversal was related to the improvement of clinical indications. We conducted a 12-week study in 40 active RA patients, of whom 20 were given a stable weekly dose of methotrexate (MTX) alone and the other ten received a combined therapy of Etanercept and MTX. Ten healthy donors were chosen as controls. Frequencies of Th1, Th2, Th17, and Treg were quantified using flow cytometry, and related serum cytokines were detected by enzyme-linked immunosorbent assay. The composite 28-joint count Disease Activity Score, erythrocyte sedimentation rate, and C-reactive protein were assessed at each visit. Percentages of IFN-gamma(+)Th1 and IL-17(+)Th17 among CD4(+) T cells were significantly higher, while CD4(+)CD25(high)Foxp3(+) Treg were significantly lower in RA patients compared with those in healthy control. After 12 weeks of therapy of MTX single or combination of MTX and Etanercept, the circulating Th17/Treg ratio significantly decreased, while no significant difference was observed in Th1/Th2 ratio. In combined therapy group, the Th17/Treg ratio was positively correlated with the remittance of disease activity. IL-1 beta, TNF-alpha, IL-6, IL-17, and IL-23 were significantly decreased, while TGF-beta was significantly elevated. The Th17/Treg ratio was positively related to TGF-beta, but negatively correlated with IL-6. Etanercept in combination with MTX ameliorates RA activity by normalizing the distribution of Th17 and Treg, and their related cytokines, which may partly explain the mechanism of combined therapy of Etanercept plus MTX in RA treatment.