Peripheral blood CD4(+)CD25(+)CD127(low) regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response.

Jun Kikuchi,Yuko Kaneko,Naoshi Nishina,Keiko Yoshimoto,Misato Hashizume,Tsutomu Takeuchi

doi:10.1186/s13075-015-0526-4

Abstract

IntroductionTocilizumab (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.MethodsThirty-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.ResultsClinical Disease Activity Index (CDAI) remission was achieved in 53.8% of patients at week 52 of TCZ therapy. The proportions of CD4+CD25+CD127low regulatory T cells (Treg) and HLA-DR+ activated Treg 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+CD14+ and CD69+CD14+ activated monocytes, and CD16+CD14+ monocytes significantly decreased (P < 0.001, P < 0.001, P < 0.001 and P < 0.001, respectively). Among them, only the change in Treg cells was inversely correlated with the change in CDAI score (ρ = −0.40, P = 0.011). The most dynamic increase in Treg cells was observed in the CDAI remission group (P < 0.001).ConclusionThis study demonstrates that TCZ affected proportions of circulating immune cells in patients with RA. The proportion of Treg cells among CD4+ cells correlated well with clinical response.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0526-4) contains supplementary material, which is available to authorized users.

Highlights

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
A higher proportion of human leukocyte antigen (HLA)-DR+CD8+ T cells among the CD8+ T cells was significantly associated with higher C-reactive protein (CRP), Pt-VAS, Simplified Disease Activity Index (SDAI) and Health Assessment Questionnaire Disability Index (HAQ-DI), as well as a higher proportion of naïve and memory CD8+ T cells among the CD8+ T cells, was significantly associated with rheumatoid factor (RF), Anticitrullinated protein antibody (ACPA), swollen joint count (SJC), Clinical Disease Activity Index (CDAI) and SDAI (Additional file 1: Table S2)
A higher proportion of TH2 cells among the CD4+ T cells was significantly associated with tender joint count (TJC), Doctor’s visual analogue scale (D-VAS), Pt-VAS, CDAI and SDAI scores

Summary

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 It is still unclear whether TCZ affects inflammatory cells in peripheral blood and whether any such changes are associated with clinical response. Because in previous studies the number of patients, the period of study and the examined cell populations were limited, it is not clear whether there is a key population of peripheral immune cells that attenuates RA clinical symptoms through anti-IL-6R therapies [11,12,15] If these relationships could be clarified, it would enable medical researchers to comprehend the pathogenesis of RA from the view of lymphocyte populations and to find surrogate markers in order to choose an optimal therapeutic strategy for RA

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