Role of Cytokines in the Pathogenesis of Anemia of Chronic Disease in Rheumatoid Arthritis

Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, 451 10, Greece
Clinical Immunology (Impact Factor: 3.67). 09/1999; 92(2):153-160. DOI: 10.1006/clim.1999.4736


The aim of our study was to evaluate the role of proinflammatory cytokines: tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as the possible contribution of interleukin-10 (IL-10) in anemia of chronic disease (ACD) of rheumatoid arthritis (RA) patients. We measured the serum levels of TNFα, IL-1β, and IL-6 in 105 anemic and 127 nonanemic RA patients. We also investigated the effects of the above cytokines on the development of burst-forming units–erythroid (BFUe) and colony-forming units–erythroid (CFUe) in bone marrow cultures. Anemic patients had significantly higher serum levels of TNFα, IL-1β, and IL-6 compared to nonanemics. Serum IL-10 levels were low and there was no significant difference in IL-10 concentrations between anemic and nonanemic patients. Proinflammatory cytokines inhibited proliferation of BFUe and CFUe. IL-10 did not decrease the erythroid colony growth. Proinflammatory cytokines may play a role in the pathogenesis of ACD in RA patients. Low levels of IL-10 possibly contribute to the development of ACD.

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    • "Inflammation may also contributes to an increased RDW by impairing iron metabolism, inhibiting the production of or response to erythropoietin, and shortening red blood cell survival [22,23]. Additionally, inflammatory cytokines have been found to inhibit erythropoietin-induced erythrocyte maturation and induce the release of juvenile erythrocytes into circulation which lead to an increased RDW [24-26]. Interestingly, we have previously proposed that the inflammation may play a pathogenic role in isolated CAE [2]. "
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    ABSTRACT: Red cell distribution width (RDW) has been recognized as a novel marker for several cardiovascular diseases. The aim of this study was to evaluate the association between RDW levels and the presence of isolated coronary artery ectasia (CAE). We studied 414 subjects including 113 patients with isolated CAE (Group A), 144 patients with coronary artery disease (CAD, group B) and 157 angiographically normal controls (group C). Baseline clinical characteristics and laboratory findings including RDW were compared among three groups. The levels of RDW were significantly higher in group A and B compared with that in group C (12.97 +/- 1.4 and 12.88 +/- 1.0 vs 12.34 +/- 0.9, p = 0.020) while no difference was found between CAE and CAD (p = 0.17). Additionally, the levels of CRP were also higher in patients with CAE and CAD compared with normal controls (0.26 +/- 0.14 mg/L, 0.31 +/- 0.27 mg/L vs 0.20 +/- 0.06 mg/L, p = 0.04). The multivariate analysis indicated that RDW and CRP were the independent variables most strongly associated with the presence of isolated CAE and CAD. There was a positive correlation between levels of RDW and CRP in patients with isolated CAE (gamma=0.532, p = 0.001). Our data suggested that RDW may be a useful marker and independent predictor for the presence of isolated CAE.
    Journal of Translational Medicine 03/2014; 12(1):62. DOI:10.1186/1479-5876-12-62 · 3.93 Impact Factor
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    • "There is evidence, however, that RA patients with anemia have a more severe form of the disease and more serious joint damage [2-4]. Proinflammatory cytokines, particularly tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and IL-1 play important roles in the pathogenesis of RA and are thought to contribute to the development of RA-anemia by modulating iron metabolism and suppressing bone marrow erythropoiesis [5-7]. 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 [8-13]. "
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    ABSTRACT: 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. 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. 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. 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.
    Arthritis research & therapy 10/2013; 15(5):R141. DOI:10.1186/ar4323 · 3.75 Impact Factor
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    • "ACD is characterized by hypoferremia in the presence of adequate iron stores. ACD is an inflammatory anemia, and inflammatory cytokines are thought to play important roles in anemia in RA [54, 55]. In fact, TCZ therapy in RA patients rapidly improves anemia [40]. "
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    ABSTRACT: Several clinical studies have demonstrated that the humanized anti-interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) improves clinical symptoms and prevents progression of joint destruction in rheumatoid arthritis (RA). However, the precise mechanism by which IL-6 blockade leads to the improvement of RA is not well understood. IL-6 promotes synovitis by inducing neovascularization, infiltration of inflammatory cells, and synovial hyperplasia. IL-6 causes bone resorption by inducing osteoclast formation via the induction of RANKL in synovial cells, and cartilage degeneration by producing matrix metalloproteinases (MMPs) in synovial cells and chondrocytes. Moreover, IL-6 is involved in autoimmunity by altering the balance between T(h)17 cells and T(reg). IL-6 also acts on changing lipid concentrations in blood and on inducing the production of hepcidin which causes iron-deficient anemia. In conclusion, IL-6 is a major player in the pathogenesis of RA, and current evidence indicates that the blockade of IL-6 is a beneficial therapy for RA patients.
    05/2011; 2011(2090-1984):765624. DOI:10.1155/2011/765624
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