Background Tocilizumab (TCZ) shows a great clinical effectiveness to rheumatoid arthritis (RA) and some reports indicates the mechanism by which TCZ impinge on the many aspects of RA pathogenesis. Nevertheless, it is not confirmed precisely whether TCZ affects inflammatory cells and anti-inflammatory cells in peripheral blood and whether the changes of these cell populations are associated with the clinical response to TCZ treatment.
Objectives To evaluate associations between the proportions of peripheral cells and clinical response in RA patients treated with TCZ.
Methods Consecutive RA patients who started to receive 8mg/kg of TCZ every 4 weeks as first biologics between March 2010 and April 2012 after giving a written informed consent were included in this study (n=39). The proportions of multiple subsets of peripheral cells at base line, week 24 and week 52 were sequentially measured by using the expression levels of differentiation markers, activation markers and co-stimulatory molecule markers in T cells, B cells, monocytes and NK cells defined in previous report .
Results Twenty-seven patients were monotherapy and 12 patients were combination therapy with MTX (8.0±0.4 mg/week). Mean disease duration was 4.7±3.3 years and CDAI was 19.6±9.3 at baseline. The proportions of cell populations were not correlated with age, disease duration and CDAI at baseline. After 52 weeks treatment, the rate of CDAI remission was achieved in up to 53.9%. The proportions of CD4+CD25+CD127low regulatory T cell (Treg) in CD4+ cells and HLA-DR+ activated Treg in Treg cells were significantly increased from baseline (Treg: p<0.0001, activated Treg: p=0.0008 by Wilcoxon rank test) over the treatment with TCZ, whereas Th17 cells defined by CD4+CD45RO+CD161+CCR6+ cells was not changed at all. The proportions of CD20+CD27+ memory B cells, HLA-DR+CD14+ activated monocytes, CD69+CD14+ activated monocytes and CD16+CD14+ non-classical monocytes were significantly decreased from baseline (memory B cell: p<0.0001, HLA-DR+ activated monocytes: p=0.0006, CD69+ activated monocytes: p<0.0001, non-classical monocytes: p<0.0001). There were no significant differences between monotherapy and combination therapy. Among Treg, activated Treg, memory B cells, activated monocytes and non-classical monocytes, only the change of Treg from baseline to 52 weeks after treatment was correlated with the change of CDAI from baseline after 52 weeks treatment with TCZ (rho=-0.40, p=0.0111 by spearman comparison test). The most dynamic change of Treg was observed in CDAI remission group after 52 weeks treatment with TCZ (p=0.0016 by Wilcoxon rank test).
Conclusions This study demonstrates that TCZ showed differential effects on the proportions of circulating immune cells in RA patients. And the proportion of CD4+CD25highCD127low regulatory T cells in CD4+ cells was significantly correlated with clinical response and would be a useful surrogate marker of clinical response to TCZ therapy.
Holden T. Maecker. et al. Standardizing immunophenotyping for Human Immunology Project. Nat Rev Immunol 2012;12:191-200.
Disclosure of Interest M. Hashizume: None declared, J. Kikuchi: None declared, K. Izumi: None declared, Y. Kaneko: None declared, K. Yoshimoto: None declared, T. Takeuchi Grant/research support: Abbott Japan Co., Ltd., Astellas Pharma Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Nippon Shinyaku Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis K.K., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical Co., Ltd.