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.