Pure Red Cell Aplasia – Clinician Information
Anti-erythropoietin antibody associated pure red cell aplasia (PRCA) is a very rare cause of resistance characterised by transfusion dependency, low reticulocyte count, lack of proerythroid progenitor cells in the bone marrow and neutralising anti-erythropoietin antibodies(1).
ESA induced PRCA is a very rare condition. The overall incidence of reported cases between 1989 and June 2004 was 1.6 per 10,000 patient-years of subcutaneous exposure(2), and 0.02 per 10,000 patient-years of intravenous exposure(3). Nevertheless, most reported cases of anti-erythropoietin antibody-associated PRCA have occurred in CKD patients who have received the drug subcutaneously(4,5,6).
Pure red cell aplasia (PRCA) due to anti-erythropoietin (EPO) antibodies should be suspected in an individual who has previously responded to EPO if the hemoglobin (Hgb) level declines by >20 g/d per month or the reticulocyte count is <20,000/uL(5).
- Clinical Features
PRCA is specifically characterized by the following clinical features(6):
- A drop in Hb level of >7 to 10 g/L per week without transfusions or transfusion requirement of at least one unit per week to maintain adequate Hgb, despite continued use of ESA at high doses.
- Markedly reduced reticulocyte count (<10,000/uL).
- Normal platelet and white blood cell count.
- Elevated serum transferrin saturation and serum ferritin.
- Rarely, allergic urticarial skin reactions at sites of earlier subcutaneous EPO injections have been described(7).
The diagnosis of PRCA is established by:
- Bone marrow examination: which confirms severe hypoplasia of erythroid precursors (<5%).
- The presence of anti-erythropoietin antibodies
There are several available tests to detect antibodies to erythropoietin, with varying sensitivities and specificities (8).
Patients with suspected ESA induced PRCA who test positive using binding antibodies should have the diagnosis confirmed with the definitive testing for neutralizing antibodies (9).
Identification of an anti-EPO antibody is crucial to the diagnosis of PRCA.
There are several tests that can be used. These include:
- radioimmunoprecipitation assay,
- electrochemiluminescence bridging enzyme-linked immunosorbent assay
- surface plasmon resonance-based immunoassay.
The most validated test is the radioimmunoprecipitation assay . This test is very sensitive and can detect the presence of high-affinity anti-EPO IgG at concentrations as low as 10 ng/ml. This test can be undertaken for NHS patients only through collaboration with the PRCA Rare Disease Group. Nephrologists with potential cases should contact Ashraf.Mikhail@wales.nhs.uk to discuss it. At present the test is provided free of charge although this may change.
ESA induced PRCA is an immune mediated process. While spontaneous remissions after cessation of EPO therapy have been reported, immunosuppressive therapy is usually needed in most cases(10).
One study evaluated 170 CKD patients who developed epoetin-associated PRCA(11). Of the 34 patients who received epoetin after the onset of PRCA, 56% recovered epoetin responsiveness; the highest rate of epoetin responsiveness was observed among those who had no detectable anti-erythropoietin antibodies at the time of epoetin administration (89%). The study also reported that the highest recovery rates were among those treated with immunosuppressive therapy, particularly a combination of cyclophosphamide and prednisone(11).
Given these data, it is advisable that retreatment with ESA may be considered in patients with a history of PRCA only if anti-EPO antibody level is no longer detectable. In addition, if epoetin therapy is to be reconsidered for these patients, only the intravenous rather than the subcutaneous route should be considered for drug administration.
Treatment of patients with anaemia due to ESA induced PRCA was assessed(12) using a peptide based erythropoietin receptor agonist (peginesatide). During a median period of 28 months, 14 patients with established diagnosis of ESA induced pure red cell aplasia were treated with subcutaneous peginesatide every 4 months. After 12 weeks of therapy, 13 of the 14 patients no longer required regular transfusions. Unfortunately the drug is not currently available for clinical use.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Written by the Pure Red Cell Aplasia Rare Disease Group