Peripheral blood CD4+ CD25+ CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response

Introduction: Tocilizumab (TCZ), an anti-interleukin--6 receptor antibody, is clinically effective against rheumatoid arthritis (RA), and several reports have indicated how TCZ influences a number of mechanisms underlying RA pathogenesis. However, it is still unclear whether TCZ affects inflammatory cells in peripheral blood and whether any such changes are associated with clinical response. We evaluated associations between proportions of subsets of peripheral immune cells and clinical response in patients with RA treated with TCZ. Methods: Thirty nine consecutive patients with RA who started to receive TCZ as their first biologic between March 2010 and April 2012 were enrolled. The proportions of several subsets of peripheral cells with their levels of expression of differentiation markers, activation markers and costimulatory molecules were measured sequentially from baseline to week 52 by flow cytometry analysis. Results: Clinical Disease Activity Index (CDAI) remission was achieved in 53.8% of patients at week 52 of TCZ therapy. The proportions of CD4(+) CD25(+)CD127(low) regulatory T cells (T-reg) and HLA-DR+ activated T-reg cells significantly increased with TCZ therapy (P< 0.001 and P< 0.001, respectively), whereas proportions of CD3(+)CD4(+)CXCR3(-)CCR6(+)CD161(+) T helper 17 cells did not change over the 52 weeks. The proportions of CD20(+)CD27(+) memory B cells, HLA-DR(+)CD147 and CD69(+)CD14(+) activated monocytes, and CD16(+)CD14(+) monocytes significantly decreased (P < 0.001, P< 0.001, P <0.001 and P <0001, respectively). Among them, only the change in Treg cells was inversely correlated with the change in CDAI score (p = -0.40, P = 0.011). The most dynamic increase in T-reg cells was observed in the CDAI remission group (P < 0.001). Conclusion: This study demonstrates that TCZ affected proportions of circulating immune cells in patients with RA. The proportion of Leg cells among CD4(+) cells correlated well with clinical response.