Open Access Highly Accessed Research article

Comparative evaluation of the effects of treatment with tocilizumab and TNF-α inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients

Soken-Nakazawa J Song1, Mitsuhiro Iwahashi2, Naohisa Tomosugi3, Kazuko Uno4, Jiro Yamana2, Seizou Yamana2, Tomoyasu Isobe1, Hiroki Ito1, Hiroshi Kawabata5 and Kazuyuki Yoshizaki1*

Author Affiliations

1 Immuno-Medical Science, Division of Applied Chemistry, Graduate School of Engineering, Osaka University, Osaka, Japan

2 Higashihiroshima Memorial Hospital, Hiroshima, Japan

3 Division of Nephrology, Department of Internal Medicine, Kanazawa Medical University, Ishikawa, Japan

4 Division of Basic Research, Louis Pasteur Center for Medical Research, Kyoto, Japan

5 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

For all author emails, please log on.

Arthritis Research & Therapy 2013, 15:R141  doi:10.1186/ar4323

Published: 2 October 2013

Abstract

Introduction

Anemia of inflammation (AI) is a common complication of rheumatoid arthritis (RA) and has a negative impact on RA symptoms and quality of life. Upregulation of hepcidin by inflammatory cytokines has been implicated in AI. In this study, we evaluated and compared the effects of IL-6 and TNF-α blocking therapies on anemia, disease activity, and iron-related parameters including serum hepcidin in RA patients.

Methods

Patients (n = 93) were treated with an anti-IL-6 receptor antibody (tocilizumab) or TNF-α inhibitors for 16 weeks. Major disease activity indicators and iron-related parameters including serum hepcidin-25 were monitored before and 2, 4, 8, and 16 weeks after the initiation of treatment. Effects of tocilizumab and infliximab (anti-TNF-α antibody) on cytokine-induced hepcidin expression in hepatoma cells were analyzed by quantitative real-time PCR.

Results

Anemia at base line was present in 66% of patients. Baseline serum hepcidin-25 levels were correlated positively with serum ferritin, C-reactive protein (CRP), vascular endothelial growth factor (VEGF) levels and Disease Activity Score 28 (DAS28). Significant improvements in anemia and disease activity, and reductions in serum hepcidin-25 levels were observed within 2 weeks in both groups, and these effects were more pronounced in the tocilizumab group than in the TNF-α inhibitors group. Serum hepcidin-25 reduction by the TNF-α inhibitor therapy was accompanied by a decrease in serum IL-6, suggesting that the effect of TNF-α on the induction of hepcidin-25 was indirect. In in vitro experiments, stimulation with the cytokine combination of IL-6+TNF-α induced weaker hepcidin expression than did with IL-6 alone, and this induction was completely suppressed by tocilizumab but not by infliximab.

Conclusions

Hepcidin-mediated iron metabolism may contribute to the pathogenesis of RA-related anemia. In our cohort, tocilizumab was more effective than TNF-α inhibitors for improving anemia and normalizing iron metabolism in RA patients by inhibiting hepcidin production.