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Abstract
IntroductionAnemia 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.MethodsPatients (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.ResultsAnemia 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.ConclusionsHepcidin-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.
Highlights
Anemia of inflammation (AI) is a common complication of rheumatoid arthritis (RA) and has a negative impact on RA symptoms and quality of life
We previously demonstrated that treatment with tocilizumab, by inhibiting hepcidin production, can reduce serum hepcidin and improve AI in patients with multicentric Castleman’s disease (MCD), a rare, interleukin 6 (IL-6)-mediated lymphoproliferative disorder [21]
Characteristics of the study population According to the World Health Organization definition of anemia (Hb levels lower than 13.0 g/dl for men and below 12.0 g/dl for women), 61 (66%) of the 93 active RA patients who participated in this study were anemic
Summary
Anemia of inflammation (AI) is a common complication of rheumatoid arthritis (RA) and has a negative impact on RA symptoms and quality of life. Treatments with anticytokine agents such as infliximab (anti-TNF-α), tocilizumab (anti-IL-6 receptor) and anakinra (anti-IL-1) have been shown to effectively ameliorate disease activity, inhibit joint destruction and significantly increase serum hemoglobin (Hb) levels in RA patients [8,9,10,11,12,13]. These findings suggest that the aforementioned biologic inhibitors have an antianemic effect as well as antirheumatic activities.
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