title: 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.
abstract: BACKGROUND
  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.
authors.forename: Soken-Nakazawa J
authors.initials: SN
authors.lastname: Song
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Iwahashi
authors.forename: Naohisa
authors.initials: N
authors.lastname: Tomosugi
authors.forename: Kazuko
authors.initials: K
authors.lastname: Uno
authors.forename: Jiro
authors.initials: J
authors.lastname: Yamana
authors.forename: Seizou
authors.initials: S
authors.lastname: Yamana
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Isobe
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawabata
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yoshizaki
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000097:blood / Q000517:prevention & control*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D002097:C-Reactive Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005293:Ferritins / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D064451:Hepcidins / Q000097:blood* / Q000235:genetics; D006801:Humans; D000069285:Infliximab; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D020298:U937 Cells; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D064451:Hepcidins; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C545475:hepcidin 25, human; D002097:C-Reactive Protein; D005293:Ferritins; D000069285:Infliximab; C502936:tocilizumab