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In the vast majority of patients with antibody (Ab)-mediated pure red cell aplasia (PRCA), simple withdrawal of the erythropoiesis-stimulating agent (ESA) does not effectively reverse PRCA. In contrast, immunosuppressive treatments can induce the disappearance of anti-erythropoietin Abs and a reversal of PRCA. Consensus opinion on the optimal therapy has not been established, but individual case reports or case series suggest that kidney transplantation or treatment with corticosteroids plus cyclophosphamide are the most effective therapies. However, treatment with cyclosporine is an interesting alternative, since it appears to be effective in at least two-thirds of patients and with minimal side effects. Due to the key role of ESAs in the management of patients with chronic kidney disease (CKD), some patients have been re-treated with an ESA following resolution of Ab-mediated PRCA. In all reported cases, this treatment increased haemoglobin levels, alleviated the need for transfusions and did not have side effects. However, one should be extremely cautious when deciding to re-treat a patient with ESA, due to the small number of reported cases and the possibility of publication bias. [ABSTRACT FROM AUTHOR]

Antibody (Ab)-mediated pure red cell aplasia (PRCA) is an immunological pathology associated with the production of neutralizing Abs that inhibit the erythropoietic activity of endogenous erythropoietin (EPO) and recombinant erythropoiesis-stimulating agents (ESAs). Although this disorder occurs very rarely, the number of reported cases has increased dramatically in recent years, predominantly in patients with chronic kidney disease (CKD)-associated anaemia receiving subcutaneous (s.c.) injections of one particular formulation of recombinant epoetin-a. This disorder is differentiated from classic forms of PRCA that are caused by chemical toxaemia (i.e. erythroblastopenia induced by chemical compounds), lymphoproliferative neoplasms, thymoma, human parvovirus B19 and certain autoimmune disorders. Patients with Ab-mediated PRCA develop resistance to EPO and severe anaemia that follows a period of successful erythropoietic response, and exhibit characteristic decreases in blood haemoglobin (Hb) level and in the number of circulating reticulocytes. However, it is not yet possible to predict which patients will develop PRCA or when in the course of their treatments PRCA may develop. Laboratory confirmation of Ab-mediated PRCA requires bone marrow examination demonstrating few or no erythroid precursors and the presence of serum anti-EPO Abs using a validated assay. These neutralizing anti-EPO Abs recognize the protein core of the EPO molecule; carbohydrate groups on EPO can affect the binding of Abs but are themselves not immunological determinants. Animal models are being developed to increase further our understanding of the immunological mechanisms underlying the onset and progression of Ab-mediated PRCA. [ABSTRACT FROM AUTHOR]

A substantial increase in the incidence of pure red cell aplasia (PRCA) associated with recombinant human erythropoietin (epoetin) treatment occurred in 1998. The upsurge of antibody-mediated PRCA was almost exclusively associated with chronic kidney disease patients who received subcutaneous epoetin therapy and the formulation of epoetin-a distributed outside the USA (EPREX/ERYPO). A systematic programme of technical, immunological and epidemiological investigations was initiated to identify the possible causes. The potential causes were evaluated on the basis of the following criteria: temporal correlation with the increase in incidence of PRCA, significant difference between EPREX/ERYPO and other epoetin products, sufficient concentration in the product to elicit a weak immune response, evidence of immunogenic activity in animals supportive, and consistent with available clinical data. Organic compounds that were leached from rubber stoppers through the action of polysorbate 80 were detected in pre-filled syringes with uncoated rubber stoppers containing polysorbate 80-formulated EPREX/ERYPO (introduced outside the USA in 1998). The leachates were not present when the stoppers were coated, in the product formulated with human serum albumin or in other epoetin products. The adjuvant activity of the leachates was demonstrated in mice. The incidence of PRCA was significantly higher in patients exposed to the polysorbate 80 formulation of epoetin-a delivered from pre-filled syringes with uncoated rubber stoppers, which were recalled in 2003, than in patients exposed to the same formulation from syringes with coated rubber stoppers. In conclusion, these data strongly suggest that leachates were the critical contributory factor in the increased incidence of antibody-mediated PRCA attributed to EPREX/ERYPO. [ABSTRACT FROM AUTHOR]

Recombinant human erythropoietin (epoetin) was first used for the treatment of renal anaemia in 1986. During the first 10 years of its use, epoetin-induced antibodies were a rare complication and only three cases of patients with epoetin-induced antibodies associated with pure red cell aplasia (PRCA) were published. Since 1998, however, there has been a significant increase in the number of patients developing severe anaemia during the course of epoetin treatment due to neutralizing antibodies. Patients with PRCA present with an absolute resistance to epoetin therapy and then rapidly develop severe anaemia with a very low reticulocyte count (<10 000/mm3). Consequently, patients become dependent on blood transfusions to maintain an acceptable level of haemoglobin. By December 2002, approximately 142 patients worldwide had been diagnosed with antibody-positive PRCA after receiving epoetin. The vast majority of these patients had been treated with the Eprex™/Erypo™ brand of epoetin alfa, but there were also some cases in which patients had been receiving epoetin beta (NeoRecormon™). To date, there have been no cases of antibody-mediated PRCA reported with the sole use of darbepoetin alfa (Aranesp® ). All patients with epoetin-induced anti-erythropoietin antibodies had received the drug subcutaneously (s.c.), and almost all had chronic kidney disease-related anaemia. To our knowledge, no patient treated exclusively by intravenous (i.v.) administration has developed anti-erythropoietin antibodies. The increase in reported cases coincides with the removal of human serum albumin from the ex-US formulation of epoetin alfa, in order to comply with new regulations from the European regulatory authorities. It has been proposed that the new formulation is less stable, allowing aggregates of erythropoietin molecules to form, which increases the probability of antibody formation. Treatment with epoetin must be discontinued if PRCA is suspected. Patients do not respond to an increase in dose. Furthermore, patients must not be switched to another form of erythropoietic therapy as the antibodies cross-react with all erythropoietic therapies available. In around 70% of cases, immunosuppressive regimens are effective in eliminating the antibodies; cessation of epoetin therapy without concomitant immunosuppression is rarely effective. Kidney transplantation seems to provide an immediate and effective cure. [ABSTRACT FROM AUTHOR]

Recombinant human erythropoietin (epoetin) was first used for the treatment of renal anaemia in 1986. During the first 10 years of its use, epoetin-induced antibodies were a rare complication and only three cases of patients with epoetin-induced antibodies associated with pure red cell aplasia (PRCA) were published. Since 1998, however, there has been a significant increase in the number of patients developing severe anaemia during the course of epoetin treatment due to neutralizing antibodies. Patients with PRCA present with an absolute resistance to epoetin therapy and then rapidly develop severe anaemia with a very low reticulocyte count (<10 000/mm3). Consequently, patients become dependent on blood transfusions to maintain an acceptable level of haemoglobin. By December 2002, approximately 142 patients worldwide had been diagnosed with antibody-positive PRCA after receiving epoetin. The vast majority of these patients had been treated with the Eprex™/Erypo™ brand of epoetin alfa, but there were also some cases in which patients had been receiving epoetin beta (NeoRecormon™). To date, there have been no cases of antibody-mediated PRCA reported with the sole use of darbepoetin alfa (Aranesp® ). All patients with epoetin-induced anti-erythropoietin antibodies had received the drug subcutaneously (s.c.), and almost all had chronic kidney disease-related anaemia. To our knowledge, no patient treated exclusively by intravenous (i.v.) administration has developed anti-erythropoietin antibodies. The increase in reported cases coincides with the removal of human serum albumin from the ex-US formulation of epoetin alfa, in order to comply with new regulations from the European regulatory authorities. It has been proposed that the new formulation is less stable, allowing aggregates of erythropoietin molecules to form, which increases the probability of antibody formation. Treatment with epoetin must be discontinued if PRCA is suspected. Patients do not respond to an increase in dose. Furthermore, patients must not be switched to another form of erythropoietic therapy as the antibodies cross-react with all erythropoietic therapies available. In around 70% of cases, immunosuppressive regimens are effective in eliminating the antibodies; cessation of epoetin therapy without concomitant immunosuppression is rarely effective. Kidney transplantation seems to provide an immediate and effective cure. [ABSTRACT FROM AUTHOR]

Antibodies develop to varying degrees during treatment with human proteins, including insulin, growth hormone, granulocyte-macrophage colony-stimulating factor, factor VIII, erythropoietin, and interferons. These antibodies may reduce the clinical efficacy of these agents by blocking or neutralizing their biologic activity and may have other biologic effects. For example, antibodies develop in 20 % to 40% of patients with severe hemophilia treated with human factor VIII; the presence of these antibodies can result in tolerance to the clotting effects of this agent. Similarly, a proportion of patients treated with interferon alpha develop antibodies, which inhibit its therapeutic effects. Therefore, it is important to test for neutralizing antibodies during treatment with these agents, particularly in patients who are unresponsive to treatment or have breakthrough disease. This article reviews the incidence and clinical impact of antibodies that develop in response to some of the commonly used protein therapeutic agents. [ABSTRACT FROM AUTHOR]