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

• Published in: Blood 2002-07, Vol.100 (2), p.474-482
• Main Authors: Papadaki, Helen A., Kritikos, Heraklis D., Valatas, Vasilis, Boumpas, Dimitrios T., Eliopoulos, George D.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Anemia - drug therapy; Anemia - etiology; Anemia - pathology; Anemias. Hemoglobinopathies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antirheumatic Agents - administration & dosage; Antirheumatic Agents - pharmacology; Apoptosis - physiology; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - pathology; Biological and medical sciences; Bone Marrow Cells - drug effects; Bone Marrow Cells - pathology; Chronic Disease; Diseases of red blood cells; Diseases of the osteoarticular system; Erythroid Precursor Cells - drug effects; Erythroid Precursor Cells - pathology; Female; Hematologic and hematopoietic diseases; Humans; Inflammatory joint diseases; Infliximab; Male; Medical sciences; Middle Aged; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-01-0136

Circumstantial evidence has implicated tumor necrosis factor α (TNF-α) in the pathogenesis of anemia of chronic disease (ACD) in rheumatoid arthritis (RA). We investigated the role of TNF-α in erythropoiesis of patients with active RA (n = 40) and the effect of anti–TNF-α 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-α 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-α 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-α on patients' erythropoiesis. We conclude that TNF-α–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.