Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis

Abstract

IntroductionOur objective was to determine the interrelationships of interleukin (IL)-6 receptor inhibition with haemoglobin, acute-phase reactants and iron metabolism markers (including hepcidin) in patients with rheumatoid arthritis (RA).MethodsData of patients receiving tocilizumab or placebo in the MEASURE study were analysed. We investigated associations at baseline and during tocilizumab treatment among haemoglobin, parameters of haemoglobin and iron homeostasis [ferritin, total iron-binding capacity (TIBC), hepcidin, haptoglobin], IL-6 and acute-phase reactants [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] to identify statistical correlates of rise in haemoglobin level.ResultsAt baseline, CRP and haptoglobin were inversely correlated (modestly) with haemoglobin levels. After treatment with tocilizumab, CRP, hepcidin, ferritin and haptoglobin levels fell alongside increases in TIBC and haemoglobin. The falls in CRP, hepcidin and haptoglobin levels in the first 2 weeks correlated with a week 12 rise in TIBC and haemoglobin.ConclusionsInflammatory anaemia improves in patients with RA treated with tocilizumab. This improvement correlates with the degree of suppression of systemic inflammation, reduction in hepcidin and haptoglobin and increase in iron-binding capacity. These clinical data provide evidence of a role for IL-6 signalling in the inflammatory anaemia of RA.

Hepcidin regulation in the anemia of inflammation

“…One strategy targets hepcidin production by inhibiting IL6-STAT3 signaling. The IL6 receptor antibody Tocilizumab reduced hepcidin and improved anemia and iron parameters in patients with rheumatoid arthritis [50-51]. The IL6 antibody Siltuximab lowered hepcidin and improved anemia in patients with multicentric Castleman’s Disease [52].…”

Pathophysiology of Iron Homeostasis during Inflammatory States

“…Subsequent experiments have confirmed IL-6-dependent up-regulation of hepcidin in mouse models of inflammatory bowel disease (IBD) and systemic bacterial, viral and parasitic infection (16-18). The importance of IL-6 in the elevated hepcidin levels associated with human inflammatory diseases is highlighted by the good correlation between serum or urine hepcidin levels and serum IL-6 concentrations in IBD, and by the fact that anti-IL-6 treatment in rheumatoid arthritis is associated with a decline in circulating hepcidin (19-22). Mechanistic experiments have demonstrated that IL-6 acts by binding to its receptor gp130 on hepatocytes, thereby activating signals that phosphorylate the transcription factor signal transducer and activator of transcription 3 (STAT3), which binds to the promoter of the hepcidin gene and increases its expression (15,23-25).…”

“…There is considerable variability in the hepcidin concentrations obtained with the different methods, even when using comparable samples, making further standardization essential before the tests can be implemented clinically (43). Nevertheless, serum or urine hepcidin levels have been shown to be significantly elevated in a number of human inflammatory conditions, including IBD, rheumatoid arthritis, malaria, human immunodeficiency virus infection and neonatal sepsis (19-22,44-47). …”

Modulation of hepcidin to treat iron deregulation: potential clinical applications

“…[107] Retrospective analysis of a phase 3B clinical trial for tocilizumab in rheumatoid arthritis patients (n = 70) further confirmed a reduction in hepcidin and increase in hgb. [108] Consistent in each of these studies was a rapid reduction in hepcidin followed by a prolonged, progressive increase in hgb.…”