title: Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy.
abstract: Circumstantial evidence has implicated tumor necrosis factor alpha (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 ACD. 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 TNF-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.
authors.affiliation: Department of Hematology and Rheumatology, University of Crete School of Medicine, Heraklion, Crete, Greece. epapadak@med.uoc.gr
authors.forename: Helen A
authors.initials: HA
authors.lastname: Papadaki
authors.forename: Heraklis D
authors.initials: HD
authors.lastname: Kritikos
authors.forename: Vasilis
authors.initials: V
authors.lastname: Valatas
authors.forename: Dimitrios T
authors.initials: DT
authors.lastname: Boumpas
authors.forename: George D
authors.initials: GD
authors.lastname: Eliopoulos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000740:Anemia / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000473:pathology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology*; D002908:Chronic Disease; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000473:pathology*; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab