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

Circumstantial evidence has implicated tumor necrosis factor a (TNF-alpha) in the pathogenesis of anemia of chronic disease (ACD) in rheumatoid arthritis (RA). We investigated the role of TNF-alpha in erythropoiesis of patients with active RA (n = 40) and the effect of anti-TNF-alpha antibody administration (cA2). Patients with RA had lower numbers of CD34(+)/CD71(+) and CD36(-)/glycophorin A(+) (glycoA(+)) bone marrow (BM) cells and increased proportions of apoptotic cells within the CD34(+)/CD71(+) and CD36(+)/glycoA(+) cell compartments, compared to healthy controls (n = 24). Erythroid burst-forming units (BFU-Es) obtained by BM mononuclear or purified CD34(+) cells were significantly lower in RA patients compared to controls. These abnormalities were more pronounced among patients with ACD. Increased TNF-alpha levels in patient long-term BM culture supernatants inversely correlated with BFU-Es and hemoglobin levels and positively with the percentage of apoptotic CD34(+)/CD71(+) and CD36(+)/glycoA(+) cells. Following cA2 therapy, a normalization was documented in the number of CD34(+)/CD71(+) and CD36(-)/glycoA(+) cells, the number of BFU-Es, and the proportion of apoptotic CD34+/CD71+ and CD36+/glycoA+ cells, which was associated with a significant increase in hemoglobin levels compared to baseline. Recovery from anemia was more prominent In patients with ACID. The exogenous addition of an anti-TNF-alpha. antibody In the cultures Increased BFU-E number In patients prior to cA2 treatment but not after treatment, further substantiating the Inhibitory role of TNF-alpha on patients' erythropoiesis. We conclude that TNIF-alpha-mediated apoptotic depletion of BM erythroid cells may account for ACD in RA and that cA2 administration may ameliorate ACD In these patients by down-regulating the apoptotic mechanisms involved in erythropoiesis.