Availability of iron and degree of inflammation modifies the response to recombinant human erythropoietin when treating anemia of chronic disease in patients with rheumatoid arthritis

Abstract

Forty-six patients with rheumatoid arthritis (RA) and documented anemia of chronic disease (Hb < 100/110 g/l) were randomized to receive either human recombinant erythropoietin (r-HuEPO, n = 36, 300 U/kg body weight) or placebo (n = 10) for 12 weeks in a multicenter study. An adequate response was defined as elevation of Hb > or = 120 g/l. Relevant clinical and laboratory assessments were made to evaluate efficacy and secure safety. A significant elevation in Hb from week 10 onwards was noted in twenty-six patients (five drop-outs) out of nine patients receiving placebo (one drop-out) (12 +/- 1.2 g/l vs 4 +/- 0.5 g/l; Hb elevation from 95 g/l to 107 g/l vs 93 g/l to 97 g/l, P < 0.05). Only 14.6%, however, were considered responders according to preset criteria. In the responders a lower initial CRP, a significant reduction in ESR but not in CRP was seen compared to the remaining r-HuEPO group. A significant elevation of energy level was noted in the r-HuEPO group; otherwise, no differences in clinical variables were seen. No serious adverse effects were noted. When analyzing patients receiving oral iron in combination with r-HuEPO and adding five additional, openly selected patients receiving both adequate iron supplementation and r-HuEPO, there was a significant weekly elevation of Hb from week 8 onwards in favor of combination therapy over the ones only receiving r-HuEPO (18 +/- 1.1 g/l vs 7 +/- 1.1 g/l, P < 0.05). The initial six responders had now reached ten of whom seven belonged to the combination therapy group. Response to r-HuEPO in RA patients appears to be dependent on availability of iron and on the degree of inflammation. If r-HuEPO treatment is considered, iron deficiency should always be corrected and strenuous efforts should have been made to control the disease itself.

Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti–tumor necrosis factor-α antibody therapy

“…25 In keeping with previous reports suggesting normal EPO response to anemia in RA, 11,[40][41][42] our patients displayed normal endogenous EPO production indicating that a mechanism(s) other that EPO suppression affects BM erythroid cell survival. On the basis of our recent findings that increased local TNF-␣ production is related to the apoptotic depletion of BM progenitor cells in RA, 5 we examined whether TNF-␣ might play a causal role in patients' impaired erythropoiesis.…”

Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia

“…AI (also sometimes referred to as the anemia of chronic disease) has been reported in numerous patient populations [19][20][21][22][23][24] and is characterized by a relative resistance to erythropoiesis-stimulating agent (ESA; epoetin alfa or darbepoetin alfa) therapy. [25][26][27][28][29][30] In the current work, neutralization of hepcidin in vitro and in vivo illustrated that an antihepcidin therapy substantially modulated iron transport and effectively treated anemia in a mouse model of AI.…”

Anemia of aging and obstructive sleep apnea

“…Reduced efficiency of iron recycling from red blood cells (RBC), reduced RBC survival, enhanced apoptosis of erythroid precursors in the bone marrow, blunted secretion of erythropoietin, and impaired response to erythropoietin play important roles [16,17]. Elevated levels of inflammatory cytokines (interleukin (IL)-6, tumor necrosis factoralpha (TNF-alpha), C-reactive protein (CRP) are thought to be pivotal in the development of these processes and the anemia [18][19][20][21][22][23]. OSA is also an inflammatory disorder associated with increased levels of systemic IL-2, IL-6, TNF-alpha, and CRP [24][25][26][27][28][29].…”