The anemia of chronic disease (ACD) is commonly encountered in medical practice and can be the first sign of disease. Inflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin-6, and interferon γ are produced in the bone marrow or other organs of patients with chronic diseases. These cytokines have been implicated in the pathogenesis of ACD because they inhibit erythropoiesis while fostering the development and function of marrow cells involved in inflammation. Although these cytokines may have either direct or indirect effects on erythroid cells, a final common pathway for the inhibition is likely to be the induction of erythroid cell apoptosis. These proapoptotic cytokines would be counterbalanced by the antiapoptotic hormone erythropoietin. In vitro studies suggest a major role for TNFα in ACD. In vivo studies show a correlation between TNFα and the development of ACD. Clinical evidence for the relation between TNFα and ACD comes from studies of monoclonal antibodies to TNFα, which ameliorate signs and symptoms in chronic inflammatory diseases. Most clinical investigations of ACD have been performed in rheumatoid arthritis patients, and those treated with monoclonal antibodies to TNFα have a slight but definite improvement in ACD. In the article by Papadaki and colleagues (page 474), rheumatoid arthritis patients with ACD who were treated with monoclonal antibodies to TNFα showed improvement in their anemia that was not mediated through changes in erythropoietin. Before treatment, the patients with ACD had increased proportions of apoptosis in erythroid progenitor populations that were accompanied by decreased proportions of cells in the more differentiated erythroid precursor populations. Following treatment, apoptosis decreased while the proportions of erythroid progenitors and precursors in the bone marrow increased. These results indicate a proapoptotic role for TNFα in ACD, although additional factors are likely involved. For example, rheumatoid arthritis patients without ACD also had increased apoptosis and decreased proportions of erythroid progenitors when compared to normal controls. Furthermore, the decreased apoptosis and increased proportions of erythroid progenitors following treatment did not reach normal levels. Increased apoptosis above that attributable to TNFα may be related to other cytokines or to methotrexate received by the rheumatoid arthritis patients. Although future studies should help clarify our understanding of ACD, the results of Papadaki et al point to a prominent role of TNFα in the apoptosis of erythroid cells.

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