Pure red cell aplasia due to anti-erythropoietin antibodies
- Jeffrey S Berns, MD
Jeffrey S Berns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Dialysis
- Professor of Medicine
- Perelman School of Medicine at the University of Pennsylvania
- Section Editors
- Steve J Schwab, MD
Steve J Schwab, MD
- Editor-in-Chief — Nephrology
- Section Editor — Dialysis
- University of Tennessee Health Science Center
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Blood Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
Acquired pure red cell aplasia (PRCA) is a rare condition of profound anemia characterized by a very low reticulocyte count and the virtual absence of erythroid precursors in the bone marrow. All other cell lines are present and seem quantitatively and morphologically normal. Many cases of acquired PRCA are idiopathic. In others, underlying conditions, such as thymoma, myelodysplastic syndromes, lymphoma, leukemia, systemic autoimmune disorders, and viral infection (ie, parvovirus B19), or treatment with drugs, such as phenytoin or chloramphenicol, are identified . (See "Acquired pure red cell aplasia in the adult".)
PRCA has also been described in patients treated with recombinant human erythropoietin (EPO), resulting from the induction of antibodies directed against the EPO molecule . Most reported cases are in patients with chronic kidney disease (CKD).
PRCA due to anti-EPO antibodies in patients with chronic renal failure will be reviewed here. A discussion of other causes of acquired PRCA is presented separately. (See "Acquired pure red cell aplasia in the adult".)
ETIOLOGY AND PATHOGENESIS
Most cases of non-erythropoietin (EPO)-related pure red cell aplasia (PRCA) are mediated by immunoglobulin G (IgG) autoantibodies or cytotoxic T lymphocytes directed against erythroid precursor or progenitor cells [1,3]. Inhibition of erythropoiesis occurs primarily between the colony forming unit–erythroid (CFU-E) and proerythroblast stages. The proerythroblast is the first morphologically identifiable erythroid precursor in normal marrow and is virtually absent in the marrow of patients with PRCA. (See "Acquired pure red cell aplasia in the adult".)
PRCA due to autoantibodies against endogenous EPO is rare in patients who have never been treated with erythropoiesis-stimulating agents (ESAs) [4-6]. The serum of patients with EPO-related PRCA inhibits the growth of erythroid progenitor cells in bone marrow cultures . Neutralizing IgG antibodies to the protein component of exogenous recombinant EPO are found that crossreact with endogenous EPO.
- Fisch P, Handgretinger R, Schaefer HE. Pure red cell aplasia. Br J Haematol 2000; 111:1010.
- Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002; 346:469.
- Krantz S. Anemia due to bone marrow failure: diagnosis and treatment. Compr Ther 1980; 6:10.
- Peschle C, Marmont AM, Marone G, et al. Pure red cell aplasia: studies on an IgG serum inhibitor neutralizing erythropoietin. Br J Haematol 1975; 30:411.
- Bunn HF. Drug-induced autoimmune red-cell aplasia. N Engl J Med 2002; 346:522.
- Casadevall N, Dupuy E, Molho-Sabatier P, et al. Autoantibodies against erythropoietin in a patient with pure red-cell aplasia. N Engl J Med 1996; 334:630.
- Storring PL, Tiplady RJ, Gaines Das RE, et al. Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties. Br J Haematol 1998; 100:79.
- Rossert J, Casadevall N, Eckardt KU. Anti-erythropoietin antibodies and pure red cell aplasia. J Am Soc Nephrol 2004; 15:398.
- Eckardt KU, Casadevall N. Pure red-cell aplasia due to anti-erythropoietin antibodies. Nephrol Dial Transplant 2003; 18:865.
- Boven K, Stryker S, Knight J, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int 2005; 67:2346.
- Hermeling S, Schellekens H, Crommelin DJ, Jiskoot W. Micelle-associated protein in epoetin formulations: aA risk factor for immunogenicity? Pharm Res 2003; 20:1903.
- Boven K, Knight J, Bader F, et al. Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: solving the mystery. Nephrol Dial Transplant 2005; 20 Suppl 3:iii33.
- Schellekens H, Jiskoot W. Eprex-associated pure red cell aplasia and leachates. Nat Biotechnol 2006; 24:613.
- Sharma B, Ryan MH, Boven K. Reactions to Eprex's adverse reactions. Nat Biotechnol 2006; 24:1199.
- Quint L, Casadevall N, Giraudier S. Pure red cell aplasia in patients with refractory anaemia treated with two different recombinant erythropoietins. Br J Haematol 2004; 124:842.
- Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther 2002; 24:1720.
- Sibbald B. Eprex warning issued, but no ban. CMAJ 2004; 170:778.
- Cournoyer D, Toffelmire EB, Wells GA, et al. Anti-erythropoietin antibody-mediated pure red cell aplasia after treatment with recombinant erythropoietin products: recommendations for minimization of risk. J Am Soc Nephrol 2004; 15:2728.
- Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004; 351:1403.
- Prabhakar SS, Muhlfelder T. Antibodies to recombinant human erythropoietin causing pure red cell aplasia. Clin Nephrol 1997; 47:331.
- Peces R, de la Torre M, Alcázar R, Urra JM. Antibodies against recombinant human erythropoietin in a patient with erythropoietin-resistant anemia. N Engl J Med 1996; 335:523.
- Gershon SK, Luksenburg H, Coté TR, Braun MM. Pure red-cell aplasia and recombinant erythropoietin. N Engl J Med 2002; 346:1584.
- Macdougall IC. Antibody-mediated pure red cell aplasia (PRCA): epidemiology, immunogenicity and risks. Nephrol Dial Transplant 2005; 20 Suppl 4:iv9.
- Macdougall IC, Casadevall N, Locatelli F, et al. Incidence of erythropoietin antibody-mediated pure red cell aplasia: the Prospective Immunogenicity Surveillance Registry (PRIMS). Nephrol Dial Transplant 2015; 30:451.
- Macdougall IC. Pure red cell aplasia with anti-erythropoietin antibodies occurs more commonly with one formulation of epoetin alfa than another. Curr Med Res Opin 2004; 20:83.
- Amgen Statement on Pure Red Cell Aplasia www.amgen.com/clinicians/prca.html (Accessed on March 07, 2005).
- Health Canada, search term Aranasp www.hc-sc.gc.ca (Accessed on December 13, 2005).
- Jacob A, Sandhu K, Nicholas J, et al. Antibody-mediated pure red cell aplasia in a dialysis patient receiving darbepoetin alfa as the sole erythropoietic agent. Nephrol Dial Transplant 2006; 21:2963.
- Howman R, Kulkarni H. Antibody-mediated acquired pure red cell aplasia (PRCA) after treatment with darbepoetin. Nephrol Dial Transplant 2007; 22:1462.
- Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant 2001; 16 Suppl 3:3.
- Macdougall IC. Darbepoetin alfa: a new therapeutic agent for renal anemia. Kidney Int Suppl 2002; :55.
- Janssen Research and Development Case Reports www.jnjpharmarnd.com/company/n-casereports.html. (Accessed on December 13, 2005).
- Locatelli F, Del Vecchio L, Pozzoni P. Pure red-cell aplasia "epidemic"--mystery completely revealed? Perit Dial Int 2007; 27 Suppl 2:S303.
- McKoy JM, Stonecash RE, Cournoyer D, et al. Epoetin-associated pure red cell aplasia: past, present, and future considerations. Transfusion 2008; 48:1754.
- Alonso Melgar A, Melgosa Hijosa M, Pardo de la Vega R, et al. Antierythropoietin antibody-induced pure red cell aplasia: posttransplant evolution. Pediatr Nephrol 2004; 19:1059.
- Praditpornsilpa K, Tiranathanagul K, Kupatawintu P, et al. Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies. Kidney Int 2011; 80:88.
- Haag-Weber M, Eckardt KU, Hörl WH, et al. Safety, immunogenicity and efficacy of subcutaneous biosimilar epoetin-α (HX575) in non-dialysis patients with renal anemia: a multi-center, randomized, double-blind study. Clin Nephrol 2012; 77:8.
- Wu G, Wadgymar A, Wong G, et al. A cross-sectional immunosurveillance study of anti-EPO antibody levels in CRF patients receiving epoetin alfa in 5 Ontario Renal Centers. Am J Kidney Dis 2004; 44:264.
- Stoffel MP, Haverkamp H, Kromminga A, et al. Prevalence of anti-erythropoietin antibodies in hemodialysis patients without clinical signs of pure red cell aplasia. Comparison between hypo- and normoresponsive patients treated with epoetins for renal anemia. Nephron Clin Pract 2007; 105:c90.
- Chapter 1: Diagnosis and evaluation of anemia in CKD. Kidney Int Suppl (2011) 2012; 2:288.
- Casadevall N, Cournoyer D, Marsh J, et al. Recommendations on haematological criteria for the diagnosis of epoetin-induced pure red cell aplasia. Eur J Haematol 2004; 73:389.
- Weber G, Gross J, Kromminga A, et al. Allergic skin and systemic reactions in a patient with pure red cell aplasia and anti-erythropoietin antibodies challenged with different epoetins. J Am Soc Nephrol 2002; 13:2381.
- Pollock C, Johnson DW, Hörl WH, et al. Pure red cell aplasia induced by erythropoiesis-stimulating agents. Clin J Am Soc Nephrol 2008; 3:193.
- Swanson SJ, Ferbas J, Mayeux P, Casadevall N. Evaluation of methods to detect and characterize antibodies against recombinant human erythropoietin. Nephron Clin Pract 2004; 96:c88.
- Thorpe R, Swanson SJ. Assays for detecting and diagnosing antibody-mediated pure red cell aplasia (PRCA): an assessment of available procedures. Nephrol Dial Transplant 2005; 20 Suppl 4:iv16.
- Amgen, Inc., Medical Information. Direct communication, June 16, 2005.
- Asari A, Gokal R. Pure red cell aplasia secondary to epoetin alpha responding to Darbepoetin alpha in a patient on peritoneal dialysis. J Am Soc Nephrol 2004; 15:2204.
- Summers SA, Matijevic A, Almond MK. Successful re-introduction of recombinant human erythropoietin following antibody induced pure red cell aplasia. Nephrol Dial Transplant 2004; 19:2137.
- Macdougall IC, Roche A, Rossert J, et al. Re-challenging patients who developed pure red cell aplasia with epoetin: can it be done? Nephrol Dial Transplant 2004; 19:2901.
- Rossert J, Macdougall I, Casadevall N. Antibody-mediated pure red cell aplasia (PRCA) treatment and re-treatment: multiple options. Nephrol Dial Transplant 2005; 20 Suppl 4:iv23.
- Viron B, Dupuy CA, Kolta A, Casadevall N. Successful re-challenge with darbepoetin in a patient with rHu-EPO-induced pure red cell aplasia refractory to immunosuppressive drugs. Nephrol Dial Transplant 2008; 23:2416.
- Verhelst D, Rossert J, Casadevall N, et al. Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study. Lancet 2004; 363:1768.
- Chng WJ, Tan LK, Liu TC. Cyclosporine treatment for patients with CRF who developed pure red blood cell aplasia following EPO therapy. Am J Kidney Dis 2003; 41:692.
- Mandreoli M, Finelli C, Lopez A, et al. Successful resumption of epoetin alfa after rituximab treatment in a patient with pure red cell aplasia. Am J Kidney Dis 2004; 44:757.
- Comont T, Bournet B, Casadevall N, et al. Rituximab in pure red-cell aplasia secondary to anti-erythropoietin antibodies. Kidney Int 2014; 86:210.
- Bennett CL, Cournoyer D, Carson KR, et al. Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project. Blood 2005; 106:3343.
- Covic A, Cannata-Andia J, Cancarini G, et al. Biosimilars and biopharmaceuticals: what the nephrologists need to know--a position paper by the ERA-EDTA Council. Nephrol Dial Transplant 2008; 23:3731.
- Lim SK, Bee PC, Keng TC, Chong YB. Resolution of epoetin-induced pure red cell aplasia 2 years later, successful re-challenge with continuous erythropoiesis receptor stimulator. Clin Nephrol 2013; 80:227.
- Macdougall IC. Hematide, a novel peptide-based erythropoiesis-stimulating agent for the treatment of anemia. Curr Opin Investig Drugs 2008; 9:1034.
- Fan Q, Leuther KK, Holmes CP, et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol 2006; 34:1303.
- Woodburn KW, Fan Q, Winslow S, et al. Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia model. Exp Hematol 2007; 35:1201.
- Macdougall IC, Rossert J, Casadevall N, et al. A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med 2009; 361:1848.
- ETIOLOGY AND PATHOGENESIS
- Non-Eprex cases
- SCREENING FOR ANTI-EPO ANTIBODIES
- CLINICAL MANIFESTATIONS
- EVALUATION AND DIAGNOSIS
- Bone marrow aspirate
- Anti-EPO antibodies
- DIFFERENTIAL DIAGNOSIS
- Initial management
- Immunosuppressive therapy
- Continuous erythropoiesis receptor stimulator (CERA)
- SUMMARY AND RECOMMENDATIONS