Blood, 15 July 2002, Vol. 100, No. 2, pp. 373-374
The anemia of chronic disease: TNF
involvement in erythroid
apoptosis
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 
(TNF), interleukin-6, and interferon 
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 TNF in ACD. In vivo studies show a correlation between
TNF and the development of ACD. Clinical evidence for the relation
between TNF and ACD comes from studies of monoclonal antibodies to
TNF, 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 TNF 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 TNF
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 TNF 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 TNF 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
TNF in the apoptosis of erythroid cells.
Mark J. Koury
Vanderbilt University School of Medicine
