losartan-potassium and Red-Cell-Aplasia--Pure

A 76-year-old woman was referred to our hospital because of anemia. The laboratory findings revealed hemolysis. Although a direct Coombs test was negative, a high titer of RBC-bound IgG was detected, and a diagnosis of Coombs-negative autoimmune hemolytic anemia was made. She was successfully treated with prednisolone. One year and five months later, she again presented anemia and was diagnosed with pure red cell aplasia. Anti-erythropoietin receptor antibody was detected in the serum. She was treated with cyclosporine and obtained prompt recovery. We herein report this rare case and review the pertinent literature.

Topics: Aged; Anemia, Hemolytic, Autoimmune; Coombs Test; Cyclosporine; Erythropoietin; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Prednisolone; Receptors, Erythropoietin; Red-Cell Aplasia, Pure; Treatment Outcome

Pure red cell aplasia (PRCA) is a rare adverse effect of recombinant erythropoietin (rEPO). Affected patients rapidly become transfusion-dependent, with many requiring immunosuppressive therapy for remission. We report a confirmed case in an elderly female, possibly the first of its kind in New Zealand, who was started on rEPO for anaemia of chronic kidney disease. We also briefly review current literature on rEPO-associated PRCA.

Topics: Aged, 80 and over; Anemia; Erythropoietin; Female; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Erythropoiesis-stimulating agents (ESAs) have become a hallmark of anaemia therapy in patients with chronic kidney disease (CKD). Although different ESAs are available for the treatment of renal anaemia, each nephrologist should select a single ESA for an individual patient. Epoetin alfa and epoetin beta have been used 1-3 times weekly but extended-interval dosing up to every 4 weeks is also effective in a substantial majority of CKD patients. However, the epoetin dose necessary to achieve or maintain target haemoglobin (Hb) levels increases substantially as the dosing interval increases. Subcutaneous administration of short-acting ESAs is more effective than the intravenous route of administration. Darbepoetin alfa and the continuous erythropoietin receptor activator (CERA) have been developed as a treatment for anaemia with extended administration intervals (every 2 weeks and every 4 weeks, respectively). Dose requirements for these long-acting ESAs are independent of the route of administration. Patents of short-acting ESAs have expired, which has opened the field for biosimilars. Epoetin biosimilars approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) have been shown to have a comparable efficacy and safety profile to their originators. An alarming increase in pure red cell aplasia (PRCA) in Thailand with follow-on epoetins manufactured in Asia (but also those manufactured in Latin America) indicates that stringent country-specific approval and pharmacovigilance protocols for ESAs manufactured in non-North American and non-EU European countries are urgently needed. Two PRCA cases occurring with subcutaneous HX575 (one certain, one likely) indicate that chances of inducing a more immunogenic product are unpredictable, even with a biosimilar epoetin approved under the EMA biosimilar approval pathway. Phase III clinical trials with peginesatide, a pegylated synthetic peptide-based ESA without any homology to erythropoietin raised safety concerns in non-dialysis CKD patients but not in dialysis patients.

Topics: Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Peptides; Polyethylene Glycols; Randomized Controlled Trials as Topic; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic; Time Factors

Antibody-mediated pure red cell aplasia is a very rare but devastating condition affecting patients receiving treatment with erythropoiesis-stimulating agents. New cases continue to emerge, generally in clusters, consistent with an 'environmental' trigger to its pathogenesis. Defining the causes of antibody-mediated pure red cell aplasia is clearly of importance for patients with chronic kidney disease, but any developments in this area may also have relevance to other disease areas as therapeutic delivery of endogenous proteins rapidly increases. This review focuses on the current knowledge regarding the etiology of antibody-mediated pure red cell aplasia and the current approach to therapy.

Topics: Chemistry, Pharmaceutical; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Immune Tolerance; Protein Multimerization; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic; Time Factors

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Topics: Aspirin; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Gadolinium; Humans; Male; Nephrogenic Fibrosing Dermopathy; Prevalence; Prognosis; Red-Cell Aplasia, Pure; Reye Syndrome; Risk Assessment; South Carolina; Survival Rate

Myelodysplastic syndrome with erythroid hypoplasia or erythroblastopenia has not yet been clearly defined, and in most patients it is mistaken for acquired pure red cell aplasia. Including one additional patient reported in this article, a literature review revealed only 50 cases over the last 20 years. These patients were predominantly elderly males, all required regular packed red cell transfusions, and they had a poor prognosis, mainly because of acute transformation. The mechanisms of erythroid aplasia remain unclear. However, recent data suggest the association of an intrinsic stem cell defect with immunological implication.

Topics: Age Distribution; Blood Transfusion; Diagnosis, Differential; Erythroblasts; Erythropoietin; Evidence-Based Medicine; France; Humans; Myelodysplastic Syndromes; Prognosis; Red-Cell Aplasia, Pure; Risk Factors; Sex Distribution

Highly publicized safety issues of medicinal products in recent years and the accompanying political pressure have forced both the US FDA and the European Medicines Agency (EMA) to implement stronger regulations concerning pharmacovigilance. These legislative changes demand more proactive risk management strategies of both pharmaceutical companies and regulators to characterize and minimize known and potential safety concerns. Concurrently, comprehensive surveillance systems are implemented, intended to identify and confirm adverse drug reactions, including the creation of large pharmacovigilance databases and the cooperation with epidemiological centres. Although the ambitions are high, not much is known about how effective all these measures are, or will be. In this review we analyse how the pharmacovigilance community has acted upon two adverse events associated with the use of erythropoiesis-stimulating agents: the sudden increase in pure red cell aplasia and the possible risk of tumour progression associated with these products. These incidents provide important insight for improving pharmacovigilance, but also pose new challenges for regulatory decision making.

Topics: Adverse Drug Reaction Reporting Systems; Animals; Disease Progression; Erythropoietin; Europe; Government Regulation; Humans; Neoplasms; Recombinant Proteins; Red-Cell Aplasia, Pure; United States

Anaemia is a frequent complication of cancer. Recently, some concerns have appeared regarding the safety of erythropoiesis-stimulating agents (ESAs) for the treatment of anaemia in cancer patients. The current review will analyse the main arguments in favour of erythropoietin (EPO), as well as those against EPO in chemotherapy-induced anaemia and in cancer-related anaemia. The principal concerns are tumour progression, increased mortality and the risk of venous thromboembolic events (VTEs). Recent meta-analyses have come to divergent conclusions.. Several meta-analyses have reviewed the data regarding VTEs, EPO receptors on tumours and tumour progression as well as mortality.. As of now, ESAs should only be used within the indications as given in the various guidelines.

Topics: Anemia; Disease Progression; Erythropoietin; Hematinics; Humans; Hypertension; Neoplasms; Red-Cell Aplasia, Pure; Risk Assessment; Seizures

Pure red-cell aplasia (PRCA) is a serious, life threatening rare condition of multifactorial causes manifested as severe anemia with absence of erythroid precursors in the bone marrow. PRCA may be a consequence of antibody production against applied recombinant human erythropoietin (EPO). The first description of PRCA in the course of EPO therapy was performed in a patient receiving subcutaneously Eprex and in the next years after therapy with other erythropoiesis stimulating agents like erythropoietin beta, omega or darbepoetin. In the paper we describe epidemiology and diagnostic criteria of PRCA. The current treatment possibilities of this complication were described with special attention dedicated to different immunosuppressive agents and effectiveness of kidney transplantation with subsequent immunosuppression.

Topics: Antibodies; Epoetin Alfa; Erythropoietin; Humans; Immunosuppressive Agents; Kidney Transplantation; Recombinant Proteins; Red-Cell Aplasia, Pure

After the patents of biopharmaceuticals have expired, based on specific regulatory approval pathways copied products ("biosimilars" or "follow-on biologics") have been launched in the EU. This article summarizes experiences with hematopoietic medicines, namely the epoetins (two biosimilars traded under five different brand names) and the filgrastims (two biosimilars, six brand names). Physicians and pharmacists should be familiar with the legal and pharmacological specialities of biosimilars: The production process can differ from that of the original, clinical indications can be extrapolated, glycoproteins contain varying isoforms, the formulation may differ from the original, and biopharmaceuticals are potentially immunogenic. Only on proof of quality, efficacy and safety, biosimilars are a viable option because of their lower costs.

Topics: Anemia; Antineoplastic Agents; Biological Products; Chronic Disease; Drug Utilization; Erythropoietin; European Union; Filgrastim; Granulocyte Colony-Stimulating Factor; Guidelines as Topic; Humans; Isoantibodies; Kidney Diseases; Legislation, Drug; Marketing; Neoplasms; Patents as Topic; Polyethylene Glycols; Quality Control; Recombinant Proteins; Red-Cell Aplasia, Pure; Therapeutic Equivalency; World Health Organization

Topics: Anemia; Antibody Formation; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia in patients who are treated for anemia of chronic kidney disease with erythropoiesis-stimulating agents such as epoetin was first reported in 1998. Although the incidence of pure red cell aplasia peaked in 2002, it remains important for nephrologists to know how to investigate a suspected case of pure red cell aplasia and how to identify other causes of hyporesponsiveness to erythropoiesis-stimulating agents, which account for the vast majority of such cases. The authors reviewed the current status of information in the literature and drew on their personal experiences with patients regarding the diagnosis and management of epoetin-induced pure red cell aplasia. The mechanism for development of epoetin-induced pure red cell aplasia remains unconfirmed. It generally occurs after the production of neutralizing anti-erythropoietin antibodies. Elucidation of a suspected pure red cell aplasia case requires a systematic approach, beginning with simple measurements such as blood cell counts, because most cases of erythropoiesis-stimulating agent hyporesponsiveness are attributable to other causes. If these criteria indicate that the patient's response to erythropoiesis-stimulating agent therapy is very poor, then bone marrow examination and measurement of anti-erythropoietin antibodies is justified. If pure red cell aplasia is confirmed, then cessation of erythropoiesis-stimulating agent therapy and initiation of immunosuppressive therapy are recommended. Continued study of epoetin-induced pure red cell aplasia is needed to help nephrologists prevent or manage future cases and will have implications for the use of other protein-based therapeutic agents.

Topics: Anemia; Antibodies; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Red-Cell Aplasia, Pure

After almost 20 years, anemia in chronic kidney disease (CKD) and its treatment remain the focus of multiple questions for clinicians and investigators. The optimal hemoglobin (Hb) for patients with CKD is controversial and different targets are probably required for different populations. The current literature does not support an upper Hb target >12 g/dl and there is a clear demonstration of increased risk with Hb targets >13 g/dl. With this narrow target of 11-12 g/dl, fluctuations in Hb concentration are commonly observed in patients being treated with erythropoiesis-stimulating agents (ESAs). Studies to date provide a suggestion of an association between Hb cycling and mortality, but they have been primarily exploratory in nature and clinical trials comparing treatment strategies leading to different degrees of Hb variability are needed. The great majority of incidences of pure red cell aplasia (PRCA) was associated with ESA therapy and was first recognized several years ago after a change in the formulation in which human serum albumin was eliminated and replaced by polysorbate-80 in patients on epoetin alfa (Eprex). Years later, a registry (PRIMS) was established by the health authorities as part of a reapproval of the subcutaneous route to confirm that the cause of PRCA has been eliminated. The ongoing PRIMS study is a 3-year observation period prospective multicenter and international (Europe and Australia) registry that could serve as a model for assessment of the immunogenicity profiles of currently marketed and future ESAs. The association with a change in formulation makes PRCA of interest to the biotechnology industry as well as the medical community because it raises the broader question of the potential immunogenicity of biopharmaceuticals in general.

Topics: Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure

Since 1988, millions of patients have received epoetin products intravenously (IV) and subcutaneously. In 1998, epoetin-associated pure red cell aplasia (PRCA) was first reported and causation was attributed to formulations without human serum albumin (HSA), subcutaneous administration, and uncoated rubber stoppers.. Data on erythropoietin (EPO)-associated PRCA were obtained from the Food and Drug Administration (FDA), regulatory authorities in other countries, and the manufacturers of epoetin alfa, epoetin beta, and darbepoetin. The data included information on numbers of PRCA cases and estimated exposure-adjusted incidence rates by EPO product, anemia etiology, administration route, country of PRCA identification, and date reported.. In 1999, academicians in Paris identified 12 EPO-treated patients with antibody-mediated PRCA; 11 of these patients were on hemodialysis and had received subcutaneous Eprex (Johnson & Johnson). In 2002, authorities in Europe, Australia, Singapore, and Canada mandated Eprex by IV route to hemodialysis patients, and the relevant manufacturers added Teflon coating to prefilled syringes of Eprex; PRCA cases subsequently decreased by 90 percent. By 2003, 180 Eprex-associated PRCA cases were identified in Europe, Canada, Australia, and Asia, despite improvements in handling. Since 2002, FDA safety databases include information on 59 new cases of antibody-associated PRCA, primarily associated with subcutaneous epoetin alfa and darbepoetin that does not contain HSA.. Independent actions by regulatory authorities, manufacturers, and academic researchers identified significant numbers of PRCA cases between 1998 and 2003 and characterized the probable etiology. Today, antibody-mediated PRCA is an infrequent class toxicity occurring among some hemodialysis patients on EPOs.

Topics: Anemia; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Starting in 1998, the number of pure red-cell aplasia (PRCA) cases in patients treated with recombinant human erythropoietin (rHuEPO) increased dramatically. Most cases were observed in patients treated with epoetin alfa produced outside the United States. The peak was observed in 2002; since then, the PRCA incidence has declined. Many factors are likely to have contributed to this up-surge. The molecular structure of the various epoetins and patient characteristics do not seem to play a major role. The route of administration holds some importance, because most PRCA patients received rHuEPO subcutaneously. The peak of PRCA cases overlapped with the removal of human serum albumin from the Eprex formulation (Janssen-Pharmaceutica NV, Beerse, Belgium), for which polysorbate 80 and glycine were substituted. Polysorbate 80 may have increased the immunogenicity of Eprex by eliciting the formation of epoetin-containing micelles or by interacting with leachates released by the uncoated rubber stoppers of prefilled syringes. Compared with the previous formulation, the polysorbate 80 formulation has lower stability, making it more susceptible to stress conditions such as insufficient attention to the cold chain. This situation could facilitate protein denaturation or aggregate formation. Uncoated rubber stoppers were replaced with coated stoppers, and the cold chain was reinforced; the Eprex formulation has remained unchanged. Even though the incidence of PRCA returned to very low levels, discriminating the cause-effect relationship of a single action is difficult, given that all occurred with a similar chronology, and that PRCA develops after a relatively long exposure period. Careful observation of future trends of new PRCA cases is thus mandatory.

Topics: Chemistry, Pharmaceutical; Drug Contamination; Drug Storage; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors; Rubber; Syringes

Topics: Animals; Autoantibodies; Chemistry, Pharmaceutical; Epoetin Alfa; Erythropoietin; Humans; Learning; Recombinant Proteins; Red-Cell Aplasia, Pure

Antibody-mediated pure red cell aplasia is now recognized as a rare complication of erythropoiesis-stimulating agent therapy. The incidence of this adverse effect peaked in 2002, but new cases still appear sporadically. The aim of this review is to discuss the latest opinions regarding the detection and management of this condition.. The diagnosis of classical erythropoiesis-stimulating agent induced pure red cell aplasia is made by a constellation of clinical features, including severe transfusion-dependent anaemia, reticulocytopenia, low or absent erythroblasts in the bone marrow, and the presence of circulating antierythropoietin antibodies. Recently, some cases have been reported in which the bone marrow findings show red cell hypoplasia rather than aplasia; this may represent earlier presentations of the same condition.. Management of pure red cell aplasia as a complication of erythropoiesis-stimulating agent therapy consists of stopping the drug and implementing an immunosuppressive regimen to reduce or abolish erythropoietin antibody production. A recent animal study suggested that a possible alternative strategy may be to administer a novel peptide-based erythropoietin receptor agonist called Hematide that does not cross react with antierythropoietin antibodies, and will allow ongoing stimulation of erythropoiesis; this is the subject of a current clinical trial.

Topics: Epoetin Alfa; Erythropoietin; Humans; Immunosuppressive Agents; Peptides; Polyethylene Glycols; Recombinant Proteins; Red-Cell Aplasia, Pure

Rituximab, a monoclonal antibody directed against the CD20 molecule found on pre-B cells and mature B cells (but not on plasma cells), was introduced in the late 1990s for the treatment of non-Hodgkin's lymphoma. Recently, this antibody has been used to treat autoimmune diseases, especially those associated with a prominent humoral component and with potentially pathogenic autoantibodies. Small cohort studies have indicated that rituximab could have an important role in the management of these disorders. Rituximab has also been utilized in the transplant setting, to diminish levels of alloreactive antibodies in highly sensitized patients, to manage ABO-incompatible transplants, and to treat rejection associated with B cells and antibodies. The exact mechanism by which rituximab exerts its effects in autoimmunity and transplantation remains unclear, as specific autoantibody or alloantibody levels often seem not to diminish in parallel with clinical improvement. A role for rituximab in depleting B cells and compromising their antigen-presenting function seems likely; rituximab might also inhibit T-cell activation. A synergistic effect has been noted in vitro following administration of corticosteroids to B-cell lines, with accentuation of B-cell cytotoxicity; this observation might be relevant to certain studies, as some regimens have utilized both agents simultaneously. This article reviews the current use of rituximab in renal disease and transplantation, and includes discussion of the drug's potential role in novel therapeutic protocols.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Erythropoietin; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Graft Rejection; Humans; Immunologic Factors; Kidney Diseases; Kidney Transplantation; Lupus Erythematosus, Systemic; Lymphoproliferative Disorders; Recombinant Proteins; Red-Cell Aplasia, Pure; Rituximab; Vasculitis

Topics: Anemia; Anti-Bacterial Agents; Erythropoietin; Humans; Immunoassay; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure; Sensitivity and Specificity

The importance of recombinant human erythropoietin (epoetin) therapy has been clearly demonstrated in patients with anemia due to chronic kidney disease. The use of biopharmaceuticals to replace endogenous proteins, which may be inadequately low, carries the risk of stimulating the immune system to develop autoantibodies. Although these proteins are designed to closely mimic the endogenous proteins, they may have potential immunogenic properties. Erythropoietin produced by recombinant DNA technology is the most successful and efficacious agent for treating anemia. It was initially used in treating anemia in chronic kidney disease patients. Pure red cell aplasia (PRCA) ensuing from production of neutralizing anti-erythropoietin antibodies occurred very rarely with epoetin treatment. This agent was initially administered intravenously, but the mode of administration was progressively altered to subcutaneous without apparent increase in immune reaction. However, between 1998 and 2001, a sharp increase in the number of PRCA cases was seen. PRCA had been a very rare complication until this time. All of these patients had high affinity neutralizing anti-erythropoietin antibodies. This observation was made primarily in cases where one brand of epoetin, Eprex, was administered subcutaneously to patients with chronic kidney disease treated outside the United States, although a small number of cases among chronic kidney disease patients treated solely with epoetin beta were also identified. The marked increase in the number of Eprex cases was attributed to a change in the stabilizers, storage, and route of administration of Eprex to patients with chronic kidney disease. Since then changes have been made to the route of administration, storage, and handling of Eprex, and more recently to the rubber stoppers used in the prefilled syringes. Eprex was administered intravenously to chronic kidney disease patients and, with improved storage and handling, there was a subsequent dramatic reduction in the number of cases. More recently, the rubber stoppers have been replaced by Teflon-coated ones to prevent interactions with stabilizers and release of chemicals that have adjuvant properties. However, this concern is still relevant in the new generation of epoetin agents and generic formulations of epoetins. Epoetin treatment for anemia requires regular follow-up of hemoglobin levels but also of reticulocyte counts in chronic kidney disease patients.

Topics: Anemia; Antibodies; Autoimmune Diseases; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Recombinant human erythropoietin (epoetin) was first used for the treatment of anemia resulting from renal disease in 1986. During the first 10 years of its use, there were only three cases of epoetin-induced antibodies reported, which resulted in pure red cell aplasia (PRCA). Between 1998 and 2002, 191 chronic kidney disease patients developed PRCA during the course of epoetin treatment. Clinical characteristics of patients with PRCA include an absolute resistance to epoetin therapy, with a rapid development of severe anemia and very low reticulocyte count. In addition, patients developed high titre, high affinity neutralizing antibodies, which are detectable by immunoassays. The diagnosis of PRCA requires the onset of severe anemia, erythropoietin neutralizing antibodies in circulation, the lack of red cell precursors in the bone marrow aspirate, and normal to elevated transferrin saturation. Patients require blood transfusions to maintain an acceptable level of hemoglobin. Cessation of epoetin treatment alone does not improve PRCA. Patients have required immunosuppressive treatment. However, the most efficacious treatment has been kidney transplantation accompanied by immunosuppressive agents that prevent organ rejection. Evaluating patients receiving recombinant epeoetin therapy who experience a sudden loss of epoetin efficacy for the possibility of antibody-mediated PRCA is crucial. Timely identification and treatment of this rare syndrome can prevent the development of severe red blood cell transfusion requirements and the potential complications of iron overload, which results from these transfusions.

Topics: Anemia; Antibodies; Chronic Disease; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) is a relatively rare condition defined as severe anemia secondary to the virtual absence of red cell precursors in the bone marrow. The incidence of PRCA was associated with subcutaneous administration of epoetin alfa (human recombinant erythropoietin [rHuEPO]). PRCA occurs from the generation of antibodies against rHuEPO, which neutralize not only the recombinant protein, but also native erythropoietin, resulting in the absence of red cell precursors in the bone marrow. Drug-induced PRCA has very similar characteristics to idiopathic PRCA, making the patients transfusion-dependent. Prior to 1998 only four cases had been associated with administration of rHuEPO; however, post-1998 a sharp increase in incidence was reported outside the United States. A change in formulation in 1998 was thought to be the reason for the induction of PRCA. A number of possible mechanisms have been proposed. The modification in the drug formulation probably played a major role. A sharp decrease of PRCA cases has been reported after 2002 related to the change in the mode of administration from subcutaneous to intravenous. In addition to the modification to the route of administration, revised storage and handling protocols have contributed to the reduced incidence of PRCA in the last 3 years. Nevertheless, the usefulness of this drug to the chronic renal patients who suffer from anemia far outweighs the disadvantages. Maintaining target hemoglobin levels, monitoring the response to erythropoietin, and adjuvant therapy to rHuEPO are all critical issues in the clinical management of renal and cancer patients with anemia.

Topics: Anemia; Antibodies; Drug Administration Routes; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

In 2002, investigators from France reported 13 patients in whom pure red cell aplasia developed during treatment with recombinant human erythropoietin (epoetin). We reviewed 208 cases of this syndrome reported worldwide. Adverse event reports describing suspected and confirmed cases of epoetin-associated PRCA in websites maintained by the manufacturers and distributors of epoetin products and other publicly available sources were reviewed. Cases were reported from countries in Europe, North America, Asia, Australia and the United States (US). For >95% of the cases, EPREX had been administered subcutaneous to persons with chronic kidney disease (CKD) and anemia for a mean of nine months prior to diagnosis of PRCA. For 80% of persons with the syndrome, reversal of antibody production and recovery of reticulocytes occurred with discontinuation of epoetin and treatment with immunosuppressive agents. Patients with anemia of CKD who developed neutralizing anti-erythropoietin antibodies and pure red cell aplasia during treatment with epoetin have been identified in a number of countries. In non-US countries, switching renal dialysis patients from subcutaneous to intravenous administration of epoetin alpha and improved handling of the drug appear to have been successful strategies for reducing the occurrence of this toxicity. The decrease in cases occurred coincident with these varied changes, although it is difficult to prove causality. PRCA is a rare, but important side effect of epoetin therapy.

Topics: Adverse Drug Reaction Reporting Systems; Antibodies; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure

Antibody (Ab)-mediated pure red cell aplasia (PRCA) develops when patients mount a neutralizing Ab response to recombinant erythropoiesis-stimulating agents (ESAs) such as epoetin-alpha (EPO). These neutralizing Abs can also cross-neutralize endogenous EPO, leading to a state of absolute EPO resistance and transfusion dependence. The diagnosis of Ab-mediated PRCA in part relies on the sensitive and specific detection of serum anti-EPO Abs and a confirmatory examination of patients' bone marrow for lack of erythroid precursors. To date, a variety of assays have been used to detect anti-EPO Abs, including radioimmunoprecipitation (RIP) assay, enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR) and bioassays that measure neutralizing Abs. Each of these assays can yield informative results and possess characteristic benefits and limitations, so it is unclear whether or not a "superior" assay is required or possible. To date, a universal standardized assay has not yet been established that would facilitate the comparison of Ab data derived from different laboratories and retrospective analysis of stored sera. This review evaluates the results of studies measuring anti-EPO Abs with different assays and compares their relative advantages and disadvantages in terms of specificity, sensitivity, ease of use and ability to measure Ab-binding affinities and subclasses. These comparisons provide a basis for determining the optimal assay(s) for screening and/or analysis of patients' serum for anti-EPO Abs during treatment or after onset of Ab-mediated PRCA.

Topics: Antibodies; Biological Assay; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Humans; Radioimmunoprecipitation Assay; Recombinant Proteins; Red-Cell Aplasia, Pure

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.

Topics: Antibodies; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

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-alpha. 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.

Topics: Antibodies; Antibody Specificity; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

The imminent patent expiration of many biopharmaceutical products will produce the possibility for generic versions of these therapeutic agents (i.e. biosimilars). However, there are a number of issues that will make approval of biosimilars much more complicated than the approval of generic equivalents of conventional pharmaceuticals. These issues centre on the intrinsic complexity of biopharmaceutical agents, which are recombinant proteins in most cases, and the heterogeneity of proteins produced by different manufacturing processes (i.e. differences in host cells, purification and processing, formulation and packaging). The increased occurrence of antibody (Ab)-mediated pure red cell aplasia (PRCA) associated with a change in the formulation of one particular epoetin-alpha product highlights the potential for increased immunogenicity of recombinant proteins with different formulations, or those manufactured by different processes. Thus, verification of the similarity to or substitutability of biosimilars with reference innovator biopharmaceutical products will require much more than a demonstration of pharmacokinetic similarity, which is sufficient for conventional, small molecule generic agents. Regulatory requirements for the approval of biosimilars have not yet been fully established, but preliminary guidelines from the European Agency for the Evaluation of Medicinal Products (EMEA) state that the complexity of the product, the types of changes in the manufacturing process, and differences in quality, safety and efficacy must be taken into account when evaluating biosimilars. For most products, results of clinical trials demonstrating safety and efficacy are likely to be required. In addition, because of the unpredictability of the onset and incidence of immunogenicity, extended post-marketing surveillance is also important and may be required.

Topics: Antibodies; Biological Products; Drug and Narcotic Control; Erythropoietin; Humans; Product Surveillance, Postmarketing; Recombinant Proteins; Red-Cell Aplasia, Pure; Therapeutic Equivalency

Although epoetin-induced antibody (Ab)-mediated pure red cell aplasia (PRCA) was very rare prior to 1998, a large increase in the number of global cases was observed from 1999 to 2002 in patients treated with erythropoiesis-stimulating agents (ESAs) for the anaemia associated with chronic kidney disease (CKD). The number of global cases of this immunological form of PRCA has declined precipitously since 2003 following increased awareness of this disorder and changes in the handling and administration of the formulation of epoetin-alpha (EPO) that was associated with the majority of cases. Current recommendations state that patients should stop treatment immediately following a diagnosis of Ab-mediated PRCA and not resume treatment with the same or another ESA. The feasibility of re-treatment following remission from PRCA or during ongoing immunosuppressive therapy is currently under investigation. The immunological mechanism for developing Ab-mediated PRCA is unknown, but a variety of factors may increase the immunogenicity of epoetin or other ESAs. Product-related factors that have the potential to impact on immunogenicity include sequence variations in proteins, the degree and nature of protein glycosylation, the manufacturing process, handling and storage, and components and properties of the product formulation. Patient-related factors associated with developing Ab-mediated PRCA include skin reactions, immune status and treatment history. Increased awareness among physicians of the factors contributing to the development of PRCA and its distinguishing clinical features has coincided with studies aimed at identifying effective therapies for this disorder. A number of immunosuppressive therapies have been shown recently to reconstitute effectively the erythropoietic response in patients with PRCA. However, therapeutic approaches for this serious immunological reaction to recombinant ESAs remain investigative.

Topics: Antibodies; Drug Storage; Erythropoietin; Humans; Incidence; Micelles; Prevalence; Recombinant Proteins; Red-Cell Aplasia, Pure

During the first 10 yr of therapy with recombinant human erythropoietin ([EPO]), only three cases of antibody-associated pure red cell aplasia have been described in patients who were treated with EPO, whereas several millions of patients have received this treatment. Thus, the possibility for epoetin to induce the formation of anti-EPO antibodies was considered extremely low. However, since 1998, a significant increase in the number of cases of EPO-induced pure red cell aplasia has been found in patients with chronic kidney disease with a peak in 2001 and 2002. The incidence rate seems now to be back to the baseline level. The change in formulation of epoetin a sold outside the United States seems to be the cause of these antibodies.

Topics: Autoimmune Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Humans; Incidence; Male; Prognosis; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment

In patients with renal failure, severe anemia and associated fatigue, cognitive and sexual dysfunctions have a significant impact on the quality of life. Anemia also represents an important etiological factor in the development of left ventricular hypertrophy. An inadequate production of a glycoprotein hormone, erythropoietin (EPO), is the major cause of anemia in presence of a reduction in the glomerular filtration rate. EPO is the primary regulator of the growth and survival of the erythroid progenitor. The treatment of anemia in chronic renal failure has been revolutionized by the introduction of recombinant human EPO. The vast majority of patients responds very well to treatment, although 5-10% of patients shows some resistance to EPO, the most common cause of which is iron deficiency. Several studies have recently been started in order to investigate the effects of preventing renal anemia from ever developing in uremic patients. The hemoglobin concentration target in pre-dialysis and dialysis patients is the subject of continuous re-assessment.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Red-Cell Aplasia, Pure

European and US guidelines for renal anaemia management recommend subcutaneous (s.c.) epoetin as the preferred route of administration in pre-dialysis, peritoneal dialysis and haemodialysis patients. However, the restriction of Eprex/Erypro to intravenous (i.v.) administration in Europe has increased the interest of health care professionals regarding the optimal route of administration for all epoetin formulations. There are five major considerations for the 'optimal' route of epoetin administration: efficacy; dosing frequency; convenience; safety and tolerability; and cost. Although epoetin bioavailability is lower after s.c. administration, its efficacy is higher, owing to its prolonged elimination half-life compared with i.v. epoetin. Several studies and clinical surveys comparing s.c. and i.v. administration have demonstrated that equivalent target haemoglobin levels can be maintained at much lower doses of epoetin when administered s.c. Furthermore, s.c. epoetin dosing frequency can be reduced in some patients to once every 2 weeks, without compromising efficacy. Devices such as the Reco-Pen have been specifically designed to facilitate self-administration of s.c. epoetin-beta. An upsurge in the incidence of pure red cell aplasia (PRCA) was linked to the epoetin-alpha product Eprex/Erypo in Europe, and an increase in PRCA cases of the same magnitude was not seen in patients taking other epoetin products s.c. Therefore, PRCA should not be used as an argument against s.c. administration. The reduced dose with s.c. administration of epoetin-beta provides significant cost benefits, without compromising either safety or efficacy, and may also increase patient satisfaction and compliance with treatment.

Topics: Anemia; Drug Administration Schedule; Drug Costs; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

Acquired pure red cell aplasia (PRCA) is a rare condition. Traditionally it has been described in association with various etiologies such as parvovirus B19 infection, auto-immune disorders and drugs. Immunologically mediated PRCA is by far the commonest cause in adults, particularly since 1998, when a marked increased incidence of PRCA was noted in chronic renal failure patients receiving subcutaneous (SC) recombinant erythropoietin (rEpo). Typically these patients had been given erythropoietin for correction of anemia of renal failure and subsequently present with severe transfusion dependent anemia. Most cases were associated with SC administration of human serum albumin (HSA) free erythropoieitin alfa product (Eprex). Early recognition and withdrawal of erythropoietin therapy is essential. Treatment with immunosuppressive therapy, particularly in conjunction with renal transplant results in good response with resolution in the majority of cases. The pathogenesis is related to interaction of multiple factors such as formulation change and improper storage leading to increased immunogenicity of the recombinant product. The incidence peaked in 2001 and 2002, subsequently dropping considerably from 2003. This can be explained by the institution of measures such as more stringent handling and storage conditions, improvements in formulation of HSA free Eprex and switch to intravenous (IV) administration for Eprex in dialysis patients. The evidence to date on this condition is summarized in this review.

Topics: Autoimmune Diseases; Epoetin Alfa; Erythropoietin; Humans; Incidence; Kidney Failure, Chronic; Parvoviridae Infections; Parvovirus; Recombinant Proteins; Red-Cell Aplasia, Pure

Erythropoiesis-stimulating agents have dramatically changed the management of renal anaemia since their introduction almost 20 years ago. However, optimal dosing route and frequency are still a matter of debate. Intravenous application of recombinant human erythropoietin should be limited to haemodialysis patients and must be given three times weekly, as any reduction to this dosing frequency leads to a major increase in dose requirements. Administering recombinant human erythropoietin-beta once weekly via the subcutaneous route is effective. If conversion from the subcutaneous to the intravenous route is required, dose requirements for recombinant human erythropoietin therapy remain a subject of discussion.

Topics: Anemia; Chronic Disease; Drug Administration Schedule; Erythropoiesis; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

After 1998, the number of reported cases of pure red cell aplasia (PRCA) increased dramatically among patients with chronic renal failure treated with exogenous erythropoietin, although the incidence of this condition has now abated. Antibody-positive PRCA has been most commonly associated with use of the Eprex brand of epoetin-alpha. ESA (erythropoiesis-stimulating agent)-associated PRCA remains rare, and suspected cases should undergo a thorough diagnostic work-up before laboratory testing for anti-ESA antibody-positive status. This article provides an overview of the recent history and growing understanding of ESA-associated PRCA together with current approaches to the management of this rare side effect of an otherwise valuable therapy.

Topics: Epoetin Alfa; Erythropoietin; Humans; Incidence; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) is a rare haematological condition that is characterized by severe aregenerative anaemia due to an almost complete cessation of red blood cell production. While antibody-mediated PRCA was extremely rare before 1998, the incidence of this disorder increased sharply after 1998 in patients receiving subcutaneous epoetin alfa produced by Ortho-Biotech and marketed outside the USA. The diagnosis of antibody-mediated PRCA relies mostly on the results of bone marrow biopsy or aspirate, which shows an absence of erythroid precursors and/or red cell maturation arrest while counts of white cell and platelet precursors are normal, and on the identification of circulating anti-erythropoietin antibodies. Retrospective analysis of PRCA cases has shown that immunosuppressive therapy can induce a disappearance of anti-erythropoietin antibodies in most patients. Eur J Clin Invest 2005; 35 (Suppl. 3): 95-99.

Topics: Antibodies; Blood Cell Count; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Recombinant Proteins; Red-Cell Aplasia, Pure

Protein pharmaceuticals have matured into an important class of drugs, now comprising one in three novel drugs introduced on the market. However, significant gains are still to be made in reducing the costs of production, ensuring proper pharmacokinetics and efficacy, increasing patient compliance and convenience, and reducing side effects such as immunogenicity. This review summarises these issues and provides recent examples of methods to reduce costs, alter pharmacokinetics and increase patient compliance. It also discusses the increasing interest in understanding immunogenicity in order to prevent failure of the protein drug or serious life-threatening side effects due to autoimmunogenicity.

Topics: Animals; Antibody Formation; Chemistry, Pharmaceutical; Drug Administration Routes; Drug Delivery Systems; Drug Stability; Erythropoietin; Humans; Patient Compliance; Proteins; Recombinant Proteins; Red-Cell Aplasia, Pure

To compare rates of pure red cell aplasia (PRCA) over time in patients with chronic renal failure treated with subcutaneous injections of two brands of epoetin alfa (either Eprex or Epogen) or epoetin beta (NeoRecormon).. Cases of antibody-mediated PRCA associated with epoetin alfa-treated patients were obtained from public databases and company websites and limited to time periods when exposure data also were available The subcutaneous exposure rates per 100 000 patient-years were calculated for the periods 1989-1998 and 1999-2002.. The event rate for antibody-mediated PRCA for Epogen and Eprex were similar from 1989 to 1998, but the number of cases of Eprex-associated PRCA has increased markedly since 1999, even after accounting for subcutaneous exposure. In contrast, rates have remained low for Epogen and NeoRecormon.. The recent increase in PRCA appears to be product specific and cannot be explained solely as a consequence of increased use of the subcutaneous route of administration.

Topics: Epoetin Alfa; Erythropoietin; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Antibodies; Erythropoietin; Forecasting; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors

Topics: Antibody Specificity; Autoantibodies; Autoantigens; Autoimmune Diseases; Chemistry, Pharmaceutical; Drug Contamination; Epoetin Alfa; Erythropoietin; Europe; Humans; Immunosuppressive Agents; Injections, Subcutaneous; Prognosis; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors; Sorbitol; Treatment Outcome

The patents of the first generation of biopharmaceuticals derived from recombinant DNA such as interferons, growth hormone and epoietins are expiring, opening up the possibility for competitors to introduce biosimilar products. The concept of generics that applies to classical drugs and allows market admission on limited documentation cannot be extrapolated to these "off-patent biologics". Physicochemical characterization, bioassays and animals studies do not predict completely the efficacy and safety of therapeutic proteins. Clinical studies will nearly always be necessary to obtain marketing authorization for off-patent biologics. Immunogenicity is considered to be the main problem with therapeutic proteins. The recent upsurge of pure red cell aplasia (PRCA), a severe form of anemia associated with the use of epoietin-alpha, highlights both the unpredictability and the severe consequences of immunogenicity. A risk-based approach can be used to evaluate the potential induction of antibodies by off-patent biologics.

Topics: Animals; Antibodies; Biological Products; DNA, Recombinant; Epoetin Alfa; Erythropoietin; Humans; Patents as Topic; Proteins; Recombinant Proteins; Red-Cell Aplasia, Pure

A special form of anemia was observed during the treatment with recombinant human erythropoietin having been applied for more than 15 years. The pure red-cell anemia due to antibodies against erythropoietin was described in chronic renal failure patients. Since oncological patients are also treated with rhuEPO it is interesting to know whether this side effect could be observed in the patients with solid tumors as well. It should be considered in tumorous patients when coexistence of antibodies against rhuEPO with pure red-cell aplasia is demonstrated, and its other causes as immunological disease, thymoma, viral infections (eg. Parvovirus B12, Hepatitis B or C) are excluded. The author collected literature data and found the absence of reports on this side effect in cases of treatment with rhuEPO in cancer patients. The rhuEPO treatment is a safe method for the cure of cancer anemia as antibodies against rhuEPO have not been shown together with PRCA among cancer patients. The possible explanation could be the shorter application time in cancer compared to the chronic renal failure patients. The side effect observed in chronic renal failure patients calls the attention to the precise compliance with the instructions of the manufacturers.

Topics: Antineoplastic Agents; Drug Administration Schedule; Erythropoietin; Humans; Kidney Failure, Chronic; Neoplasms; Recombinant Proteins; Red-Cell Aplasia, Pure

Anti-erythropoietin (EPO)-induced pure red cell aplasia (PRCA) is an uncommon, potentially life-threatening condition in which the bone marrow stops manufacturing red blood cells. In the past few years, reports of drug-induced, anti-EPO antibody-mediated PRCA have increased substantially, with most cases attributed to the use of one erythropoiesis-stimulating protein, Eprex. A literature review was undertaken to document the reports of drug-induced PRCA, with all drugs and drug regimens. The sudden increase in reports of antibody-mediated PRCA is discussed.

Topics: Antibodies; Clinical Trials as Topic; Erythropoietin; Humans; Immunologic Factors; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) is a rare condition characterised by an arrest in red blood cell production, which may be congenital or acquired. Recombinant human erythropoietin (epoetin) was introduced in 1989 for the treatment of anaemia of chronic kidney disease patients and has maintained an excellent therapeutic and safety record while treating hundreds of thousands of patients. A very rare, but serious adverse event associated with epoetin administration is a condition in which patients develop neutralising anti-erythropoietin antibodies and, consequently, PRCA. This condition is referred to as epoetin-induced PRCA (epo-PRCA). Since it is a rare condition, many haematologists and nephrologists around the world see the condition infrequently and may be uncertain about the diagnosis. For this reason, an ad hoc international working group of expert haematologists and nephrologists met together to derive new recommendations for the haematological diagnosis of epo-PRCA. These recommendations, which represent the consensus opinions of the working group, address haematological approaches to monitor and investigate suspected epo-PRCA and should help physicians differentiate between PRCA and other bone marrow diseases, as well as, between PRCA and epo-PRCA.

Topics: Autoantibodies; Blood Cell Count; Bone Marrow Examination; Epoetin Alfa; Erythropoietin; Hematopoietic Stem Cells; Hemoglobins; Humans; Practice Guidelines as Topic; Recombinant Proteins; Red-Cell Aplasia, Pure

Due to appearance in the world scientific literature of reports on occurrence of pure red cell aplasia (PRCA) as an adverse effect of treatment with recombinant human erythropoietin administered for anemia correction in the course of chronic renal failure, the paper presents rules of diagnosis and treatment of this complication. PRCA is more frequently observed during subcutaneous administration of erythropoietin a than erythropoietin beta. According to currently available analysis, prophylaxis of PRCA may include changing of the route of erythropoietin alpha administration from subcutaneous to intravenous one.

Topics: Epoetin Alfa; Erythropoietin; Humans; Injections, Intravenous; Injections, Subcutaneous; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Anemia; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Hematologic Neoplasms; Humans; Lymphoproliferative Disorders; Myelodysplastic Syndromes; Prognosis; Quality of Life; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

Since recombinant gene technology was established to provide rare important regulatory proteins as recombinant molecules, cytokine therapies have widely developed and enormously contributed to the treatment of various diseases; nevertheless, it has been revealed that recombinant therapeutic molecules are not always perfect because of side-effects related to pharmacological functions of cytokines and/or potential antigenicity observed in some clinical cases. Although studies on the antigenicity of recombinant proteins have initiated, and observations in clinical studies have been accumulated over this decade, mechanisms of the autoantibody production are not clarified yet. Among various hematopoietic growth factors introduced into clinical trials, this report summarizes current issues of autoantibodies to primary regulators for terminal hematopoiesis.

Topics: Animals; Autoantibodies; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Erythropoietin; Humans; Immunogenetics; Injections, Subcutaneous; Kidney Failure, Chronic; Red-Cell Aplasia, Pure; Self Administration

Topics: Anemia; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Recombinant human erythropoietin (epoetin) is a highly active molecule and as such is used at very low therapeutic concentrations that require stabilisation. Commercially available epoetins differ in the stabilisers used in their formulations, which result in variations between epoetin preparations in storage and handling requirements. The stability and solubility of the epoetins are also affected by differences in the carbohydrate moieties that exist between them. However, it is the difference in stabilising agents that is thought to be the major cause of the upsurge in pure red cell aplasia (PRCA) cases observed predominantly with one epoetin alfa formulation, Eprex (Johnson & Johnson). In 1998 the European formulation of Eprex was changed with the replacement of human serum albumin (HSA), by polysorbate 80 and glycine. This formulation change coincided with an increased incidence of PRCA. In contrast, the incidence of PRCA has remained low with other HSA-containing epoetin alfa products and with epoetin beta. Therefore, it appears that the change in Eprex formulation has resulted in reduced protein stability and increased immunogenicity.

Topics: Antibody Formation; Chemistry, Pharmaceutical; Drug Administration Routes; Drug Stability; Drug Storage; Erythropoietin; Excipients; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Erythropoietic therapy has transformed the management of the anemia associated with chronic renal failure over the past decade. The first agents that proved effective in stimulating erythropoiesis were the epoetins (alfa and beta), which are recombinant human erythropoietins (EPOs). The EPO molecule was recently modified using site-directed mutagenesis to produce darbepoetin alfa with a longer circulating half-life in vivo. The development of epoetin-induced pure red cell aplasia associated with anti-EPO antibodies shook the nephrology community last year, and gradually new information is emerging on the cause of this rare but important condition. Pure red cell aplasia has provoked new discussions on the best route (intravenously or subcutaneously) for administering erythropoietic therapy. Further research has been published regarding some of the more traditional, although still hotly debated, issues concerning renal anemia management, such as target hemoglobin, factors affecting the response to EPO, and adjuvant therapy to EPO. This review addresses these topics and focuses largely on the publications relevant to these areas of clinical anemia management.

Topics: Anemia; Antibody Formation; Chemotherapy, Adjuvant; Erythropoietin; Hematocrit; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) is a relatively rare disease although multiple factors are implied in the pathogenesis of its development. A slow progressive normocytic-normochromic anemia and reticulocytopenia, without leukopenia and thrombocytopenia in a patient who, except pallor, does not show abnormal findings on physical examination, should arise the suspicion that he has PRCA. Search for underlying diseases or infections and intake of drugs may help for the establishment of the diagnosis of acquired PRCA. Lack of erythroblasts in the bone marrow with normal development of the other hemopoietic series, as well as high level of serum erythropoietin are important clues for the diagnosis. Elimination of potentially causative factors, administration of immunosuppressive agents and/or recombinant erythropoietin, preferably epoetin beta, may induce remission and complete recovery.

Topics: Adrenal Cortex Hormones; Blood Transfusion; Erythropoietin; Humans; Immunosuppressive Agents; Recombinant Proteins; Red-Cell Aplasia, Pure

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/mm(3)). 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.

Topics: Antibodies; Drug Hypersensitivity; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Since the nineties of the previous century, incidence of pure red-cell aplasia (PRCA) in patients with chronic renal failure (CRF) and renal anaemia treated with recombinant human erythropoietin (rHuEPO) has significantly increased. Due to the positive effects of rHuEPO on quality of life, lowering of morbidity and mortality of patients with CRF, such increased incidence has attained a widespread interest, though PRCA remains only a rare complication. The responsibility for the development of PRCA lies with the neutralizing anti-erythropoietin antibodies. The rise of antibodies and development of PRCA is related to the subcutaneous administration of erythropoietin and in the vast majority of patients to the treatment with Eprex, one of the epoetins alpha. At present, the most probable explanation is a change of the stabilizer in Eprex formulation, which is related to the increased immunogeneity of the product. The subcutaneous administration of rHuEPO, preferred for medical and economical reasons in both American and European guidelines, is known for its higher immunization power. Properties of the product, emphasized by the route of administration, can cause the rise of these antibodies. To prevent the rise of anti-erythropoietin antibodies and the development of PRCA, regulatory authorities and Eprex producers decided that Eprex cannot be administered to CRF patients subcutaneously, but only intravenously. Also the requirements on the handling of Eprex have become more stringent. Limitations do not concern either epoetin beta (NeoRecormon) or other epoetins alpha (of which the latter are not available in this country). Therapy of PRCA in patients treated with rHuEPO is based on suspension of rHuEPO and on the immunosuppressive therapy. Many questions concerning PRCA in CRF patients treated with rHuEPO remain unsolved. It is necessary to study further the ethiopathogenesis of this complication and possibly adjust preventive and therapeutic measures.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Erythropoietin (EPO) is a 165 amino-acid sequence glycoprotein which plays an important role in maintaining regular generation of erythrocytes, Jacobs et al. describe the cloning of the human EPO and recombinant EPO has been introduced for the treatment of anemia in patients with renal diseases. The extensive utilization of EPO can induce the production of neutralizing EPO antibodies, which have been proved in patients with the non-infectious form of pure red cell aplasia (NI-PRCA), an autoimmune disease characterized by a sudden inhibition of erythrocyte maturation and production. In this review, the literature concerning the molecular structure and the genetic profile of EPO as well as the relationship between neutralizing EPO antibodies and NI-PRCA have been analyzed.

Topics: Anemia; Animals; Autoantibodies; Autoimmune Diseases; Epitopes; Erythropoietin; Glycosylation; Growth Substances; Humans; Isoantibodies; Protein Conformation; Protein Processing, Post-Translational; Rabbits; Recombinant Proteins; Red-Cell Aplasia, Pure

Anemia is a frequent clinical feature with adverse prognostic effects in patients with chronic lymphocytic leukemia (CLL). It may complicate CLL at any time during the course of the disease. Different factors concur to the occurrence of anemia in CLL, as in other lymphoproliferative diseases: leukemic bone marrow infiltration, the myelosuppressive effect of chemotherapy and inhibiting cytokines, autoimmune phenomena, hypersplenism, a poor nutritional status that leads to folic acid, vitamin B12 and iron deficiency. In addition, a defective endogenous erythropoietin (EPO) production has also been described in patients with lymphoproliferative diseases. The severity of anemia, which may be worsened by an impaired cardiopulmonary function, may profoundly compromise the patients' quality of life and, indirectly, the outcome of cancer bearing patients. Several Authors have reported the clinical activity of recombinant human (rHu)EPO in anemic patients with lymphoproliferative diseases, including CLL. Low serum EPO levels at baseline and EPO levels inappropriately low for the degree of anemia help to identify patients who are likely to respond to EPO. A clear dose-dependent response to EPO has been reported by different Authors and it has been suggested that 5,000 IU should be considered as an appropriate initial dose for the majority of patients. rHuEPO represents a potentially effective and safe therapy for the management of anemia associated with lymphoproliferative diseases. The reduction of red blood cell transfusion requirement, the improvement of quality of life through the remission of fatigue-related anemia are two important results that should be considered in the management of patients with CLL. In prospect, the availability of new rHuEPO molecules with a more prolonged half-life may open new therapeutic avenues.

Topics: Anemia; Anemia, Hemolytic, Autoimmune; Antineoplastic Agents; Bone Marrow; Cytokines; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypersplenism; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoproliferative Disorders; Multicenter Studies as Topic; Nutrition Disorders; Radiotherapy; Randomized Controlled Trials as Topic; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

Immune-mediated acquired disorders of erythropoiesis can result in pure red cell aplasia or ineffective erythropoiesis. Erythropoiesis can be suppressed or impaired by humoral or cellular mechanisms. In vitro inhibition of erythroid colony growth by humoral factors or lymphocytes is a strong argument for the immune origin of the disease. Classical aetiologies are thymoma and hematological malignancies such as chronic lymphocytic leukaemia. Clonal proliferation of T cells has also been incriminated. Recently, acquired circulating autoantibodies directed against erythropoietin have been detected in a case of pure red cell aplasia. Autoimmune mechanisms have also been suggested in two dyserythropoietic syndromes recently described.

Topics: Anemia; Autoimmune Diseases; Cell Division; Erythropoiesis; Erythropoietin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Red-Cell Aplasia, Pure; T-Lymphocytes; Thymoma

A 40-year-old woman with acute myeloid leukemia in first remission developed pure red cell aplasia after a T cell-depleted ABO-incompatible bone marrow transplant from her HLA-identical sister. She remained transfusion-dependent for 11 months despite conversion of the ABO blood group to donor type, and titers of anti-donor isohemagglutinin being undetectable. Treatment with erythropoietin resulted in rapid improvement of the anemia with no further need for transfusions up to 21 months post-transplant. This case suggests that erythropoietin may provide effective therapy for pure red cell aplasia after ABO-incompatible bone marrow transplantation without the additional risks of further immunosuppression.

Topics: ABO Blood-Group System; Adult; Blood Group Incompatibility; Bone Marrow Transplantation; Erythropoietin; Female; Humans; Leukemia, Myelomonocytic, Acute; Lymphocyte Depletion; Red-Cell Aplasia, Pure; T-Lymphocytes; Transplantation, Homologous

We describe a 32-year-old woman who developed severe anemia due to pure red cell aplasia in the course of systemic lupus erythematosus (SLE). After failure of therapy with high doses of glucocorticoids and immunoglobulins, and despite high levels of endogenous erythropoietin, she was treated with human recombinant erythropoietin with dramatic and sustained improvement. Based on this case and on the literature review of erythropoietin therapy in pure red cell aplasia, we suggest that erythropoietin should be used in SLE associated pure red cell aplasia before cytotoxic therapy.

Topics: Adult; Erythropoietin; Female; Humans; Lupus Erythematosus, Systemic; Recombinant Proteins; Red-Cell Aplasia, Pure

We describe a 31-year-old patient with pure red cell aplasia of pregnancy, successfully managed with regular blood transfusions. In vitro studies showed specific inhibition of day 14 erythroid colonies (BFU-E) using serum and purified immunoglobulin G (IgG) obtained from the patient at diagnosis (before blood transfusion). The inhibition of BFU-E disappeared when haematological remission occurred 3 weeks after delivery and she remains clinically well with a normal haemoglobin 4 years later.

Topics: Adult; Blood Transfusion; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Pregnancy; Pregnancy Complications, Hematologic; Red-Cell Aplasia, Pure

Molecular analysis of the human erythropoietin receptor (EpoR) promises to yield a greater mechanistic understanding of erythropoiesis and disease states that affect red cell production. The cloned receptor molecule is a 66 kDa membrane protein that is structurally related to a large superfamily of haemopoietin/growth factor receptors. The 66 kDa EpoR alone is capable of binding to erythropoietin (Epo) with nanomolar affinity. The native EpoR may form dimers before or after binding Epo. EpoR dimers and/or associated molecules are probably necessary for high-affinity Epo binding. The 66 kDa EpoR probably exists as a protein complex with as yet unidentified proteins of 100 and 85 kDa. The molecular mechanism of Epo signal transduction remains largely undefined. The possible role of the EpoR in human diseases has been studied in a variety of clinical conditions. A structurally abnormal EpoR gene has been identified in a human erythroleukemia cell line. In polycythemia vera, red cell progenitors exhibit exaggerated sensitivity to Epo and express only low-affinity EpoR. Some cases of hereditary polycythemia may be due to a mutant EpoR conferring enhanced Epo sensitivity. Other pathologic conditions may also be associated with abnormalities of the EpoR or its associated molecules. Soluble, immunoreactive EpoR is detectable in human serum, but its physiological significance is unknown.

Topics: Animals; Cloning, Molecular; Cross-Linking Reagents; Erythropoiesis; Erythropoietin; Humans; Leukemia, Erythroblastic, Acute; Polycythemia; Protein Conformation; Receptors, Erythropoietin; Red-Cell Aplasia, Pure

To summarize the clinical characteristics of acquired pure red cell aplasia (PRCA) patients diagnosed in our hospital in the last 10 years.. The clinical features, immune state and treatment response of acquired PRCA patients diagnosed in our hospital from January 2007 to January 2017 were retrospectively analyzed.. The results showed that thymoma (13.21%) and parvovirus B19 (11.32%) were the most common causes for secondary PRCA. Ferritin (Fer) levels and erythropoietin (EPO) levels were increased in PRCA patients. The total CR and PR rate of immunosuppressive therapy in our studies was 68.29% and 12.20%, respectively. Patients with EPO level >400 U/L and Fer level >200 ng/ml had significantly lower CR rate than others. The patients with EPO level >400 U/L also had longer hemoglobin recovery time than patients with EPO level ≤400 U/L. Patients treated with corticosteroids (CS) + cyclosporine A (CsA) had lower relapse rate compared to the CS group (29.17% vs. 80.00%, P < .05).. Our data showed that patients with PRCA had high EPO and Fer levels. Thymoma and viral infections are the most common causes for secondary PRCA. The CS+ CsA group had lower relapse rate than CS group although response rate was similar. Increased EPO and Fer levels might be the negative factors for prognosis of acquired PRCA.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Erythropoietin; Female; Humans; Male; Middle Aged; Parvoviridae Infections; Parvovirus B19, Human; Red-Cell Aplasia, Pure; Retrospective Studies; Thymoma

We investigated whether a novel, synthetic, peptide-based erythropoietin-receptor agonist (Hematide, Affymax) can stimulate erythropoiesis in patients with anemia that is caused by antierythropoietin antibodies.. In this open-label, single-group trial, we enrolled patients with chronic kidney disease who had pure red-cell aplasia or hypoplasia due to antierythropoietin antibodies and treated them with a synthetic peptide-based erythropoietin-receptor agonist. The agonist was administered by subcutaneous injection at an initial dose of 0.05 mg per kilogram of body weight every 4 weeks. The primary end point was a hemoglobin concentration above 11 g per deciliter without the need for transfusions.. We treated 14 patients with the peptide agonist for a median of 28 months. The median hemoglobin concentration increased from 9.0 g per deciliter (with transfusion support in the case of 12 patients) before treatment to 11.4 g per deciliter at the time of the last administration of the agonist; transfusion requirements diminished within 12 weeks after the first dose, after which 13 of the 14 patients no longer required regular transfusions. Peak reticulocyte counts increased from a median of 10x10(9) per liter before treatment to peak counts of greater than 100x10(9) per liter. The level of antierythropoietin antibodies declined over the course of the study and became undetectable in six patients. One patient who initially responded to treatment had a diminished hematologic response a few months later despite increased doses of the agonist and required transfusions again; this patient was found to have antibodies against the agonist. One patient died 4 months after the last dose of the agonist, and a grade 3 or 4 adverse event occurred in seven other patients during the study period.. This novel agonist of the erythropoietin receptor can correct anemia in patients with pure red-cell aplasia caused by antierythropoietin antibodies. (ClinicalTrials.gov number, NCT00314795.).

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Receptors, Erythropoietin; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

The problem of pure red cell aplasia (PRCA) prompted nephrologists to revert to a wider intravenous (i.v.) utilization of erythropoeitin (Epo). Once weekly i.v. Epo administration has been suggested to be as effective as the twice/thrice weekly i.v. dose. The aim of the present study was to test whether once weekly i.v. Epo administration is equally as cost-effective as once weekly subcutaneous (s.c.) and 2-3 times weekly i.v. administration.. We prospectively studied 41 patients (23 males, aged 28-82 years), on renal replacement therapy for 18-286 months, stabilized on twice or thrice weekly s.c. Epo-alpha (basal). The patients were treated for three consecutive 6 month periods with once weekly s.c. (OWSC), once weekly i.v. (OWIV) and twice/thrice weekly i.v. (TWIV) Epo-alpha. The initial dose for each period was equal to the final dose of the previous one; when necessary, the dose was adjusted according to DOQY guidelines. Iron, folic acid and vitamin B(12) supplementations were given throughout all the study periods. At the end of each of the four study periods, the following parameters were evaluated: haemoglobin, haematocrit, hypochromic red blood cells (RBCs), iron, serum ferritin, transferrin, folate, vitamin B(12), C-reactive protein (CRP), Kt/V, parathyroid hormone (PTH) and weekly dose of Epo-alpha.. Thirty-three out of 41 enrolled patients completed the study (there were five deaths, two renal transplants and one transfer). No significant changes were observed as regards iron, serum ferritin, transferrin, folate, vitamin B(12), CRP, Kt/V or PTH level. Haemoglobin levels were not different at the end of the basal (11.7+/-1.21), OWSC (11.8+/-0.86) and TWIV (12.1+/-1.04) periods, while significantly lower levels were observed after the OWIV period (11.0+/-0.97, P<0.01). Weekly Epo consumption (Epo U/week/kg body weight/g haemoglobin) was: basal 11.57+/-5.96; OWSC 10.22+/-4.53; OWIV 15.99+/-7.7*(a); and TWIV 11.89+/-6.3*(a) (*P<0.01 vs basal; (a)P<0.01 vs OWSC).. From our results, the OWIV schedule seems to have less efficacy in the control of anaemia of chronic renal failure patients on dialysis treatment than either OWSC or TWIV schedules.

Topics: Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Anemia is a common complication of chronic kidney disease (CKD). Recombinant human erythropoietin (rHu-EPO) is used extensively in patients with CKD. However, anti-erythropoietin (anti-EPO) antibody has been reported during rHu-EPO treatment, which causes pure red cell aplasia (PRCA). We presented a case of 75-year-old man, who underwent hemodialysis for 2 years. He developed PRCA during rHu-EPO treatment. The rHu-EPO was immediately discontinued, and the patient was given roxadustat treatment. After 6 months of roxadustat treatment, the anti-EPO antibody was disappeared, and hemoglobin recovered normal range. The results suggest that roxadustat can be used to treat patients with anti-EPO antibody-mediated PRCA without immunosuppressive therapy.

Topics: Aged; Erythropoietin; Glycine; Humans; Isoquinolines; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Pure red cell aplasia (PRCA) associated with erythropoiesis-stimulating agents (ESAs), which were first reported in 1998, usually occurs with subcutaneous administration of epoetin alfa (Eprex

Topics: Anemia; Antibodies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Polyethylene Glycols; Prednisolone; Recombinant Proteins; Red-Cell Aplasia, Pure

BACKGROUND Pure red cell aplasia (PRCA) is an uncommon cause of anemia in end-stage kidney disease (ESKD). It is attributed to recombinant human erythropoietin (rHuEPO) administration. Although immunosuppression is the mainstay therapy, its effectiveness varies from 30% to 70%. PRCA in ESKD has been reported to improve following kidney transplantation. CASE REPORT A 46-year-old woman with ESKD secondary to lupus nephritis was treated for uremia at our center. She developed severe anemia. Bone marrow aspiration and biopsy revealed a reduction of erythroid precursors, consistent with PRCA. Because she had no sibling's blood group matched with her, ABO-incompatible kidney transplantation was an option for treatment. She underwent a desensitization protocol consisting of rituximab 375 mg/m2, tacrolimus, mycophenolate mofetil, and prednisolone 4 weeks before surgery, in addition to 3 sessions of double-filtration plasmapheresis (DFPP) every other day followed by intravenous immunoglobulin (IVIG) and 1 session of specific immunoadsorption (Glycosorb® B column) at pre-transplant day -1. She also received low-dose rabbit anti-thymocyte globulin (rATG) (Thymoglobulin®) (total 2.0 mg/kg). Maintenance therapy included tacrolimus, mycophenolate mofetil, and prednisolone. Allograft function normalized a few days after transplantation and her Hb gradually increased. CONCLUSIONS We report a rare case of PRCA in a patient with ESKD undergoing ABO-incompatible kidney transplantation. The outcome was satisfactory, with complete correction of anemia and kidney function.

Topics: ABO Blood-Group System; Blood Group Incompatibility; Erythropoietin; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prednisolone; Red-Cell Aplasia, Pure; Renal Dialysis; Tacrolimus; Thailand

Topics: Cyclosporine; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Erythropoietin; Glycine; Hemoglobins; Humans; Isoquinolines; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure

Recombinant human erythropoietin (rHuEPO) is a biopharmaceutical drug given to patients who have a low hemoglobin related to chronic kidney disease, cancer or anemia. However, some patients repeatedly receiving rHuEPO develop anti-rHuEPO neutralizing antibodies leading to the development of pure red cell aplasia (PRCA). The immunogenic antibody response activated by rHuEPO is believed to be triggered by T-cells recognizing EPO epitopes bound to MHC molecules displayed on the cell surface of APCs. Previous studies have reported an association between the development of anti-rHuEpo-associated PRCA and the HLA-DRB1*09 gene, which is reported to be entrenched in the Thai population. In this study, we used computational design to screen for immunogenic hotspots recognized by HLA-DRB1*09, and predicted seventeen mutants having anywhere between one through four mutations that reduce affinity for the allele, without disrupting the structural integrity and bioactivity. Five out of seventeen mutants were less immunogenic in vitro while retaining similar or slightly reduced bioactivity than rHuEPO. These engineered proteins could be the potential candidates to treat patients who are rHuEpo-dependent and express the HLA-DRB1*09 allele.

Topics: Alleles; Anemia; Antibody Formation; Cell Culture Techniques; Cell Line; Erythropoietin; Humans; Major Histocompatibility Complex; Protein Engineering; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Anti-erythropoietin antibody-related pure red cell aplasia (anti-EPO PRCA) is a severe complication in patients who receive erythropoiesis-stimulating agents for nephrogenic anemia. The standard therapy is withdrawl of EPO and immunosuppression. Here, we present successful treatment of anti-EPO PRCA with roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor. A 39-year-old woman with end-stage renal disease received recombinant human erythropoietin (rhEPO) subcutaneously. Unfortunately, she developed anti-EPO PRCA and her hemoglobin dropped continuously, whereas she rejected immunosuppressive therapy. The patient failed to achieve spontaneous hematologic recovery with cessation of rhEPO alone, and she became transfusion dependent. Thus, she accepted our advice to try roxadustat for nephrogenic anemia. Surprisingly, after starting roxadustat treatment, her reticulocyte and hemoglobin improved gradually. Four months later, the bone marrow aspiration smear demonstrated a return to normal in erythroid cells. Besides, her anti-erythropoietin antibody converted to negative. All in all, this case reveals the potential effect of roxadustat on anti-EPO PRCA.

Topics: Adult; Erythropoietin; Female; Glycine; Humans; Isoquinolines; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Our aim is to investigate the clinical characteristics of low- and intermediate-risk myelodysplastic syndrome (MDS) with pure red cell aplasia (PRCA).. We retrospectively reviewed the patients of low- and intermediate-risk MDS patients who had been diagnosed with PRCA in our hospital between January 2010 and December 2019.. There were 6 low- and intermediate-risk MDS patients with PRCA in our study, 1 male and 5 females, with a median age of 63.5 (50-75) years. It accounted for 7.7% (6/78) of all diagnosed PRCA cases and 1.67% (6/359) of diagnosed MDS cases during the same period. All patients were treated with multiple drugs, including recombinant human erythropoietin, cyclosporine, glucocorticoids, androgen, sirolimus, intravenous immunoglobulin and decitabine. Two patients achieved complete remission, two patients achieved partial remission and became blood transfusion independent. Two patients had no response and one patient died.. Low- and intermediate-risk MDS with PRCA was difficult to treat, but the prognosis was good.

Topics: Aged; Androgens; Cyclosporine; Erythropoietin; Female; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Red-Cell Aplasia, Pure; Retrospective Studies; Sirolimus

Acquired pure red cell aplasia (PRCA) is characterized by severe normocytic (rarely macrocytic) and normochromic anemia, a low reticulocytes count in peripheral blood, and near absence of erythroid precursors in the bone marrow, with a normal level of erythropoietin. We describe a case of the kidney transplant recipient, diagnosed with PRCA induced with parvovirus B19 infection. Our case demonstrates that although this complication is rare, it should be considered in a differential diagnosis of anemia diagnostics in immunocompromised patients. In our case reduced immune response resulted from post-transplant immunosuppressive therapy. In our patient, apart from infection by parvovirus B19, graft dysfunction due to polyomavirus BK virus infection was also detected together with histologic and serologic features of antibody-mediated renal graft rejection. Considering the entire clinical picture, intravenous immunoglobulin therapy (IVIg) was successfully introduced.

Topics: Antibodies, Viral; Erythema Infectiosum; Erythropoietin; Female; Graft Rejection; Humans; Immunocompromised Host; Immunoglobulins, Intravenous; Kidney Transplantation; Male; Middle Aged; Parvovirus B19, Human; Postoperative Complications; Red-Cell Aplasia, Pure

Erythropoietin-stimulating agents (ESAs) are used to treat anemia in patients with chronic kidney disease, enabling maintenance of stable hemoglobin levels and eliminating the need for multiple transfusions. Epoetin-beta pegol (C.E.R.A.) is a continuous erythropoietin receptor activator created by integrating a large methoxy-polyethylene-glycol-polymer chain into the erythropoietin molecule, which provides it with a longer half-life. On rare occasions, cases of antibody-mediated pure red cell aplasia (PRCA) related to ESAs are reported. They are characterized by abrupt onset of severe transfusion-dependent anemia, despite ESA therapy. We herein report a case of antibody-mediated PRCA in a dialysis patient receiving C.E.R.A.. A 44-year-old man with end-stage renal failure had been receiving continuous ambulatory peritoneal dialysis for 2 years. C.E.R.A. was administered subcutaneously as a sole ESA once a month at the hospital since 4 years ago for the treatment of renal anemia and his hemoglobin level was well controlled at 12 g/dl. From 10 months before diagnosis, however, his hemoglobin level suddenly declined, necessitating frequent transfusions. Based on the results of a bone marrow examination and detection of anti-C.E.R.A. antibodies, the patient was diagnosed with antibody-mediated PRCA. After successful elimination of the antibodies using oral prednisolone plus cyclosporine, the patient was re-administrated C.E.R.A. intravenously, as there are few reports of antibody-mediated PRCA related to ESA using that administration route. He responded to the C.E.R.A., and his anemia dramatically improved, eliminating the need for blood transfusions.. This is the first reported case of recovery from an antibody-mediated PRCA with C.E.R.A. after its re-administration following a reversal of the antibody. It has been suggested that the additional large pegylation chain makes C.E.R.A. less likely to trigger antibody generation than other ESAs. Following successful treatment of antibody-mediated PRCA using immunosuppressive therapy, C.E.R.A. can be re-administered intravenously to treat renal anemia.

Topics: Adult; Anemia; Antibodies; Cyclosporine; Erythropoietin; Glucocorticoids; Hematinics; Humans; Immunosuppressive Agents; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Polyethylene Glycols; Prednisolone; Red-Cell Aplasia, Pure; Renal Dialysis

The application of erythropoietin (EPO) can bring about a rare but serious complication called anti-EPO antibody-mediated pure red cell aplasia (PRCA). Once the disease is diagnosed, EPO administration should be stopped immediately. However, after the removal of the anti-EPO antibody, treating anaemia in these patients with chronic renal disease with EPO therapy is difficult, as restarting EPO therapy risks the recurrence of anti-EPO antibody-mediated PRCA. A 26-year-old man with anaemia related to renal failure, who was administered recombinant human EPO subcutaneously, developed anti-EPO antibody-mediated PRCA. After removal of antibodies by treatment with corticosteroids and cyclosporine, therapy for anaemia of chronic renal disease with roxadustat achieved good results. Roxadustat is a new type of drug for the treatment of anaemia, and it can stimulate endogenous EPO within or near the physiologic range and increase haemoglobin levels.

Topics: Adult; Erythropoietin; Glycine; Humans; Isoquinolines; Male; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

Thymoma is a type of rare tumor in the thymus gland, and among patients with thymoma, less than 10% will develop pure red cell aplasia (PRCA), whereas less than 5% of patients with PRCA have a thymoma. The optimal approach for PRCA in thymoma is immunosuppressive therapy, such as steroids, cyclosporine, and human antithymocyte globulin.. A sixty-one-year-old male was diagnosed with thymoma with PRCA after he complained fatigue, tinnitus, and weakness for 1 month, he received therapy with recombinant erythropoietin (rhEPO) for 1 month after the tumor was totally resected and readmitted with pulmonary embolism and received anticoagulation therapy with enoxaparin for 3 months.. Thymoma, pure red cell aplasia, pulmonary embolism.. He received cyclosporine A, prednisone and rhEPO treatment. Two months after the thymectomy and postoperative radiation, he was readmitted with pulmonary embolism.. Thymoma and pulmonary embolism become complete response (CR), PRCA become partial response (PR).. Clinicians should be alert to the possibility of the increased risk of thrombosis induced by rhEPO when it used to treat PRCA associated with thymoma. If other medication is effective for managing PRCA, rhEPO should be avoided.

Topics: Erythropoietin; Hematologic Agents; Humans; Male; Middle Aged; Pulmonary Embolism; Recombinant Proteins; Red-Cell Aplasia, Pure; Thymoma; Thymus Neoplasms

Immunogenicity is a major concern in the use of biological drugs. In particular, antibody-mediated pure red cell aplasia (PRCA) is a rare condition that is caused by administration of recombinant erythropoietin. There are numerous assay platforms for detect EPO anti-drug antibody (ADA), and most have appropriate assay sensitivity, but in need of improvement in terms of assay turnaround time and user accessibility. Here, the new method was developed based on lab-on-a-chip technology and bridging ELISA. The FREND™ Cartridge is equipped with a microfluidic lateral flow channel, enabling easy, fast and accurate immunoassays with small sample volumes. Biotinylated EPO was immobilized on the avidin-coated solid phase of the test zone in the FREND™ cartridge. Initially, ADA in the serum sample binds to the detector conjugate (EPO-HRP-anti HRP antibody-FL bead) in the conjugation zone, and it flows into the test zone prepared with capture complex (avidin-biotinylated EPO). Unbound detector complexes are captured in the reference zone. The FREND™ system detects and quantifies the fluorescence signals in each zone and then calculates the concentration of EPO ADA in the sample. The FREND™ EPO ADA kit may be useful in local clinics as a rapid method for monitoring patients administered recombinant erythropoietin.

Topics: Autoantibodies; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Humans; Lab-On-A-Chip Devices; Microfluidic Analytical Techniques; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Adolescent; Blood Transfusion; Drug Resistance; Erythema Infectiosum; Erythropoietin; Hematinics; Humans; Immunocompromised Host; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Nephritis, Hereditary; Opportunistic Infections; Red-Cell Aplasia, Pure; Treatment Outcome

Pure red cell aplasia is a rare condition associated with the use of recombinant human erythropoietin preparations. It has predominantly been associated with the subcutaneous use of a particular epoetin-α product, Eprex, and is rarely associated with intravenous use or with other commercially available products. Only a few cases of pure red cell aplasia secondary to epoetin-β have been reported. On account of its rarity, the condition can often be missed on initial presentation, leading to unnecessary investigations and delayed diagnosis. A high index of suspicion is required for timely diagnosis and proper management. We present a case of severe anaemia secondary to the subcutaneous use of epoetin-β (Recormon) and briefly discuss the pathogenesis, diagnosis and management.

Topics: Aged; Anemia; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

The European Medicines Agency recommends limiting the hemoglobin (Hb) concentration to 10 to 12 g/dL in adults with chronic kidney disease (CKD) receiving erythropoiesis-stimulating agents such as epoetin theta. This postauthorization study assessed the incidence and intensity of cardiovascular events, including ischemic stroke, in patients receiving epoetin theta for anemia associated with CKD. A secondary end point was adverse drug reactions, including pure red cell aplasia.. In this prospective, noninterventional, multinational cohort study, consecutive patients with advanced or end-stage renal disease and receiving epoetin theta were followed up for 6 months. Data on reportable adverse events (RAEs) (cardiac disorders, cardiac failure, myocardial infarction, and ischemic stroke and respective subterms), epoetin theta dosage, and Hb concentrations were collected. A post hoc exploratory analysis assessed the incidences of RAEs according to tertiles for individual mean Hb concentration (≤10.7, >10.7-11.47, and >11.47 g/dL for low, intermediate, and high, respectively) and mean weekly epoetin theta dosage (≤62, >62-125, and >125 IU/kg/wk for low, intermediate, and high).. Data from 1039 patients were included (577 men, 462 women; mean age, 68.7 years). A total of 101 RAEs were documented in 89 patients (8.6%), for an event rate of 0.1985/person-year. Sixty-four patients (6.1%) died; none of the deaths was considered related to epoetin theta use. The incidence of RAEs was lowest at intermediate Hb concentrations (6.2%) compared with low (11.3%) and high (7.8%) Hb concentrations. The incidence of ischemic stroke was 1.5% at high Hb concentrations versus 0.6% at both the low and intermediate Hb concentrations. The incidence of any RAE was greater in the high-dose group (10.1%) than in the intermediate-dose (8.0%) and low-dose (7.6%) groups. The risk for any cardiovascular RAE or ischemic stroke was greatest in the high-dose/high-Hb group (13.3%), followed by high dose/low Hb (12.6%) and low dose/low Hb (12.1%). The risks for RAEs were lowest at high dose/intermediate Hb (3.8%) and low dose/intermediate Hb (5.3%). The event rate of adverse drug reactions other than the predefined RAEs was 0.0161/person-year. No cases of pure red cell aplasia were reported.. The findings from the present study suggest that, for maintaining the optimal target Hb concentration (10-12 g/dL according to the current summary of product characteristics for epoetin theta; 10-11.5 g/dL according to the current guideline from Kidney Disease Improving Global Outcomes) in anemic adults with CKD, the lowest approved, effective dose epoetin theta should be used.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Cohort Studies; Erythropoietin; Female; Heart Failure; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic; Stroke; Young Adult

A panel of 9 fully human monoclonal antibodies against human erythropoietin (EPO) with defined characteristics (non-neutralizing, neutralizing, various isotypes, affinities) representative of those evident in antibody-mediated pure red cell aplasia (PRCA) and non-PRCA patients were formulated and lyophilized. The panel was evaluated in a multi-centre international collaborative study comprising eighteen different laboratories using different assay platforms including those in routine use. These included binding assays, some based on use of novel technologies and neutralization assays predominantly employing EPO responsive cell-lines. Results showed that detection and titre varied depending on antibody characteristics and the method used. Only selective assay platforms were capable of detecting the diverse repertoire of EPO antibodies in the panel indicating that some clinically relevant antibodies are likely to be missed in some assays. Importantly, the clinical samples from PRCA patients were distinguished as antibody-positive and the healthy donor serum as antibody negative across all different platforms tested. For neutralization, data was generally consistent across the assays for the different samples regardless of the cell-line and the assay conditions. The heterogeneity in data from the study clearly indicated the need for reference standards for consistency in detecting and measuring EPO antibodies across different assay platforms for monitoring the safety and efficacy of erythropoiesis stimulating agents. Therefore, the WHO ECBS at its meeting in October'15 established the EPO antibody panel, available from NIBSC, to facilitate decision-making on assay selection for testing antibodies against human EPO, for evaluating assay performance of antibody assays for clinical use, for assay validation and for standardization.

Topics: Antibodies; Antibodies, Monoclonal; Antibody Affinity; Erythropoietin; Humans; Immunoassay; Red-Cell Aplasia, Pure; Reference Standards; World Health Organization

Anti-erythropoietin (anti-EPO) antibody-related pure red cell aplasia (PRCA) is a rare but serious complication that can occur during the administration of erythropoiesis-stimulating agents. Treatment with the calcineurin inhibitor cyclosporine has shown benefits in patients with anti-EPO PRCA. The efficacy of tacrolimus, another calcineurin inhibitor, in patients with anti-EPO PRCA has not been determined. The present report is the first our knowledge to describe the successful treatment of a patient with anti-EPO PRCA using tacrolimus. A 73-year-old man was markedly anemic 8 months after starting epoetin beta treatment. He was diagnosed with anti-EPO PRCA. Cyclosporine was started, but he experienced side effects. He was switched from cyclosporine to tacrolimus. No side effects were observed, and his anti-EPO PRCA was improved 6 months later, despite the persistence of anti-EPO antibodies. Tacrolimus was continued until the disappearance of the antibodies. Following the cessation of tacrolimus, PRCA did not relapse. Antibody remained detectable at the time of clinical remission, indicating that immunosuppressive therapy should be continued while monitoring the antibody titer. When the antibody titer decreases to the negative range, cessation of the immunosuppressive therapy does not result in disease relapse.

Topics: Aged; Antibodies; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Male; Red-Cell Aplasia, Pure; Tacrolimus

Subcutaneous administration of Eprex(®) (epoetin alfa) in patients with chronic kidney disease (CKD) was contraindicated in the European Union between 2002 and 2006 after increased reports of anti-erythropoietin antibody-mediated pure red cell aplasia (PRCA). The Prospective Immunogenicity Surveillance Registry (PRIMS) was conducted to estimate the incidence of antibody-mediated PRCA with subcutaneous administration of a new coated-stopper syringe presentation of Eprex(®) and to compare this with the PRCA incidence with subcutaneous NeoRecormon(®) (epoetin beta) and Aranesp(®) (darbepoetin alfa).. PRIMS was a multicentre, multinational, non-interventional, parallel-group, immunogenicity surveillance registry. Adults with CKD receiving or about to initiate subcutaneous Eprex(®), NeoRecormon(®) or Aranesp(®) for anaemia were enrolled and followed for up to 3 years. Unexplained loss or lack of effect (LOE), including suspected PRCA, was reported, with antibody testing for confirmation of PRCA.. Of the 15 333 patients enrolled, 5948 received Eprex(®) (8377 patient-years) and 9356 received NeoRecormon(®)/Aranesp(®) (14 286 patient-years). No treatment data were available for 29 patients. Among 23 patients with LOE, five cases of PRCA were confirmed (Eprex(®), n = 3; NeoRecormon(®), n = 1; Aranesp(®), n = 1). Based on exposed time, PRCA incidence was 35.8/100 000 patient-years (95% CI 7.4-104.7) for Eprex(®) versus 14.0/100 000 patient-years (95% CI 1.7-50.6) for NeoRecormon(®)/Aranesp(®). The incidence of PRCA with Eprex(®) was not significantly different versus comparator ESAs (rate ratio: 2.56; 95% CI 0.43-15.31). An analysis based on observed time produced similar findings.. This large, prospective registry demonstrates that PRCA is rare with subcutaneous administration of either the new coated-stopper syringe presentation of Eprex(®), or NeoRecormon(®) or Aranesp(®).

Topics: Adult; Aged; Aged, 80 and over; Anemia; Autoantibodies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Humans; Incidence; Male; Middle Aged; Prognosis; Prospective Studies; Recombinant Proteins; Red-Cell Aplasia, Pure; Registries; Risk Assessment; Severity of Illness Index

Topics: Aged, 80 and over; Anemia; Antitubercular Agents; Bone Marrow Examination; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Isoniazid; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome; Tuberculosis, Pulmonary; Withholding Treatment

Topics: Anemia; Antibodies; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Red-Cell Aplasia, Pure; Renal Dialysis

Antibody-mediated pure red cell aplasia (PRCA) has been primarily observed in patients with chronic kidney disease treated with an erythropoiesis-stimulating agent (ESA); only a few anecdotal cases have been reported in other patient populations. We searched the Amgen Global Safety Adverse Event Database and identified 14 patients with hepatitis C who developed severe anemia, anti-erythropoietin antibodies, and bone marrow biopsy-proven PRCA, while receiving interferon therapy (with or without ribavirin) and an ESA. During the follow-up period and after ESA treatment stopped, 11 patients no longer required transfusions and 3 did. Analysis of antibody isotypes showed that, contrary to reports of patients with chronic kidney disease, immunoglobulin G1 was the predominant isotype rather than immunoglobulin G4 (immunoglobulin G4 was detected in only 1 of 6 patients). Epitope mapping showed the anti-erythropoietin antibodies bound domains required for receptor binding. Therefore, the potential benefits of ESA therapy must be weighed against the risk for PRCA in patients with hepatitis C who are receiving treatment with interferon and ribavirin.

Topics: Adult; Aged; Antibodies; Antiviral Agents; Epitope Mapping; Erythropoietin; Hematinics; Hepatitis C; Humans; Immunoglobulin G; Middle Aged; Red-Cell Aplasia, Pure

Approximately 10% of patients receiving recombinant human erythropoietin (rHuEPO) do not respond to the treatment. We evaluated parvovirus B19 (B19) and cytomegalovirus (CMV) infections and antierythropoietin (anti-EPO) antibodies as potential causes of anemia in dialyzed patients, hyporesponsive to rHuEPO.. Data from 120 dialyzed patients, receiving rHuEPO alfa, were collected: demographic characteristics, rHuEPO dose, duration of rHuEPO treatment and time on dialysis, etiology of chronic kidney disease and transfusion history. Serology and PCR were performed to address B19 and CMV infection status. An ELISA was developed to detect anti-EPO antibodies.. rHuEPO resistance correlated with high ferritin levels (p = 0.001) and short time on dialysis (p = 0.012). B19 DNA was found in 10 (8.3%) dialyzed patients and CMV DNA was detected in 33 (27.5%). There was no significant correlation between B19 infection and anemia,while a tendency of correlation between active CMV infection and hemoglobin levels or hematocrit value (p= 0.069 and p= 0.070, respectively) has been observed. Anti-EPO antibodies were not detected in any patient.. B19 infection is a rare complication in dialyzed patients and should be investigated after exclusion of other common causes, while CMV infection is rather common. The role of CMV infection in the hyporesponsiveness in dialyzed patients should be further evaluated in other studies. Our data suggest that anti-EPO antibodies are not involved in rHuEPO resistance in this population.

Topics: Adult; Aged; Antibodies, Neutralizing; Antiviral Agents; Case-Control Studies; Cytomegalovirus Infections; Drug Resistance, Viral; Epoetin Alfa; Erythema Infectiosum; Erythropoietin; Female; Humans; Male; Middle Aged; Parvovirus B19, Human; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Anti recombinant human erythropoietin (r-HuEpo) associated pure red cell aplasia (PRCA) is an immunologic adverse effect of using subcutaneous r-HuEpo. Immunosuppressive agents have been suggested as treatment of this serious complication. After the reversal of anti-r-HuEpo antibody, the patients continue to have renal anemia and require long-term blood transfusion, albeit less frequently than when the antibody is positive. It is controversial whether re-challenging the patients with r-HuEpo is appropriate because re-challenging may cause the reappearance of the antibody. To balance the risk of antir-HuEpo antibody reappearance and longterm blood transfusion complications, we re-challenged r-HuEpo in five anti-r-HuEpo associated PRCA cases after a successful reversal of antibody using prednisolone in combination with cyclophosphamide. The rechallenge was performed intravenously since there were no reports of anti-r-HuEpo associated PRCA cases using this administration route. The duration after the reversal of antibody was 2.4 months before the re-challenge. Two patients were immediately re-challenged as soon as the antibodies reversed. After rechallenge with intravenous r-HuEpo, all patients responded to r-HuEpo: target level of Hb was maintained, blood transfusion was not required, and anti-r-HuEpo was consistently negative. All patients were followed for at least 6 months after re-challenge. Our data suggest that re-challenge with intravenous r-HuEpo can successfully treat anti- r-HuEpo associated PRCA.

Topics: Adult; Erythropoietin; Female; Humans; Injections, Intravenous; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure

Antibody-mediated pure red cell aplasia (PRCA) is a rare complication of erythropoietin (EPO) therapy. Identification and demonstration of functional activity of EPO antibodies required to diagnose this condition is difficult and only performed in selected laboratories worldwide. In this article we report a recent cluster of three cases of antibody-mediated PRCA over a 16-month period in a single center associated with EPREX use. We also describe the use of a simple low-cost inhibitor assay that can be used to screen for PRCA in local laboratories.

Topics: Aged; Aged, 80 and over; Anemia; Antibodies, Neutralizing; Biomarkers; Calibration; Epoetin Alfa; Erythropoietin; Humans; Male; Predictive Value of Tests; Recombinant Proteins; Red-Cell Aplasia, Pure; Reference Standards; Serologic Tests

Topics: Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

Patients treated with erythropoietin-based erythropoiesis-stimulating agents (ESAs) can develop a rare but life-threatening condition called antibody-mediated pure red cell aplasia (amPRCA). The antibody characteristics in a nephrology patient with amPRCA include high antibody concentrations with neutralizing activity and a mixed IgG subclass including anti-ESA IgG4 antibodies. In contrast, anti-ESA IgG4 antibody is generally not detected in baseline samples and antibody-positive non-PRCA patients. Therefore, we validated a highly sensitive immunoassay on the ImmunoCAP 100 instrument to quantitate anti-ESA IgG4 antibodies using a human recombinant anti-epoetin alfa (EPO) IgG4 antibody as a calibrator. The biotinylated ESA was applied to a streptavidin ImmunoCAP, and bound anti-ESA IgG4 antibodies were detected using a β-galactosidase-conjugated mouse anti-human IgG4 antibody. The validated assay was used to detect anti-ESA IgG4 in amPRCA and non-PRCA patients. The immunoassay detected 15 ng/ml of human anti-EPO IgG4 antibody in the presence of a 200 M excess of human anti-ESA IgG1, IgG2, or IgM antibody and tolerated 2 μg/ml of soluble erythropoietin. All patient samples with confirmed amPRCA had measurable anti-ESA IgG4 antibodies. In addition, 94% (17/18) of non-PRCA patient samples were antibody negative or had below 15 ng/ml of anti-ESA IgG4 antibodies. This novel immunoassay can measure low-nanogram quantities of human anti-ESA IgG4 antibodies in the presence of other anti-ESA antibodies. An increased concentration of anti-ESA IgG4 antibody is associated with the development of amPRCA. We propose that the measurement of anti-ESA specific IgG4 antibodies may facilitate early detection of amPRCA in patients receiving all ESAs structurally related to human erythropoietin.

Topics: Antibodies, Neutralizing; Autoantibodies; Clinical Laboratory Techniques; Erythropoiesis; Erythropoietin; Humans; Immunoassay; Immunoglobulin G; Red-Cell Aplasia, Pure; Sensitivity and Specificity

Recombinant erythropoietin (rHuEPO) is used extensively to treat anaemia associated with chronic kidney disease. However, the development of neutralizing antibodies (NAbs) to rHuEPO can result in the development of antibody-mediated pure red cell aplasia (PRCA). The detection of NAb in patient sera by in vitro bioassay relies on the inhibition of a cellular response to rHuEPO. Current bioassays for rHuEPO measure proliferation in responsive cell lines such as the erythroleukaemic cell lines, UT-7 and UT-7/EPO, the latter sensitized to EPO. Using these cell lines, we show the dose-responsive induction of both PIM1 and EGR1 gene expression in UT-7 cells and of EGR1 in UT-7/EPO cells. The expression of EGR1 in UT-7/EPO cells in response to rHuEPO was comparable to the proliferative response measured by (3)H-thymidine incorporation and could be inhibited by serum from a patient with NAb-mediated PRCA in a dilution-dependent manner. Bioassays based on the induction of endogenous gene expression are comparable to current bioassays but are considerably quicker given that incubation time is decreased from 2-3 days to 50 min. Measurement of EGR1 gene expression in response to rHuEPO in UT-7/EPO cells offers a rapid, non-radioactive and automatable alternative to current assays for the detection of rHuEPO NAbs.

Topics: Animals; Antibodies, Neutralizing; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Early Growth Response Protein 1; Erythropoietin; Gene Expression; Humans; Immune Sera; Immunologic Techniques; Leukemia, Erythroblastic, Acute; Recombinant Proteins; Red-Cell Aplasia, Pure; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Serum; Sheep; Time Factors

Epoetin-induced pure red cell aplasia (PRCA) is most commonly associated with epoetin-a; nevertheless, its occurrence has been reported in epoetin-β and darbepoetin-a. We report a young hemodialysis patient who developed PRCA 2 years after receiving intravenous epoetin-β. Epoetin- induced PRCA was confirmed by bone marrow aspiration, associated with markedly elevated anti-erythropoietin antibody. He was treated with prednisolone and cyclophosphamide for 3 months but continued to be transfusion-dependent. 17 months after the development of PRCA, he was started on intravenous continuous erythropoiesis receptor stimulator (CERA) in view of frequent transfusions. He tolerated the CERA injection well and the hemoglobin level stabilized 7 months later. Repeat bone marrow aspiration confirmed complete resolution of PRCA with disappearance of anti-erythropoietin antibody. To date, he maintained a stable hemoglobin level and has been transfusion-independent for the past 1 year. This is the first in the literature that reported the utilization of CERA in epoetin-induced PRCA. Very low or undetectable level of anti-erythropoietin antibody might be the key to the success of re-challenge strategy in cases of epoetininduced PRCA. Thus, routine checking of anti-erythropoietin antibody before the rechallenge with an alternative erythropoietin product is highly recommended.

Topics: Adult; Blood Transfusion; Drug Administration Schedule; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Male; Polyethylene Glycols; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Time Factors; Treatment Outcome

The standard therapy for anti-erythropoietin (EPO) antibody-mediated pure red cell aplasia (PRCA) is cyclosporine (CyA) or prednisolone (PSL) 0.5-1.0 mg/kg. However, many patients with severe chronic kidney disease (CKD) and chronic heart failure cannot tolerate such an immunosuppressive regimen. An 86-year-old man with anemia related to CKD and chronic heart failure, who had received recombinant human erythropoietin subcutaneously, developed anti-EPO antibody-mediated PRCA. The patient was treated with CyA followed by PSL (1.0 mg/kg); however, he was unable to tolerate this drug regimen. The PSL dose was reduced to 0.2 mg/kg. Surprisingly, his reticulocyte count increased 3 months later, and RBC transfusion was no longer required. Low-dose PSL is a treatment option for patients with anti-EPO antibody-mediated PRCA who cannot tolerate CyA and PSL (0.5-1.0 mg/kg).

Topics: Aged, 80 and over; Antibodies; Erythropoietin; Humans; Immunosuppressive Agents; Male; Prednisolone; Red-Cell Aplasia, Pure; Treatment Outcome

We report a 73-year-old Japanese man with early onset pure red cell aplasia (PRCA) caused by subcutaneous administration of recombinant epoetin-β. Two months after the start of epoetin therapy, he developed PRCA. Anti-erythropoietin (EPO) antibody, detected in the patient's serum by enzyme immunoassay and radioimmunoprecipitation method, inhibited EPO-dependent growth of AS-E2 cells in vitro. Treatment with prednisone (1 mg/kg) significantly reduced antibody levels 3 months later. It is important to have an awareness of antibody-mediated PRCA. Our case shows that subcutaneous epoetin administration produces this complication in the early period of therapy.

Topics: Aged; Anemia; Antibodies; Erythropoietin; Humans; Injections, Subcutaneous; Male; Prednisolone; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

Antibody (Ab)-mediated pure red cell aplasia (PRCA) is a rare hematologic disorder. For the first time here, the authors report the use of combination therapy which consists of mycophenolate mofetil 500-1000 mg/day, intravenous cyclophosphamide 600 mg monthly and monthly intravenous methylprednisolone 1 gm/day for 2 days followed by oral prednisolone 10 mg/day. A 62-year-old woman developed Ab-mediated PRCA after using subcutaneous erythropoietin-beta 3000 U weekly for 14 months at the predialysis stage. Ab-mediated PRCA was diagnosed based on (1) the transfusion need of more than 1 unit/wk to keep hemoglobin level stable, (2) corrected reticulocyte count 0.36% and (3) < 5% erythroblasts with normal myeloid cells and megakaryocytes in bone marrow biopsy. Serum assay confirmed the anti-erythropoietin antibody of 230 ng/mL. The patient recovered from PRCA after the triple immunosuppressive therapy for 3 months. The rapid recovery occurred despite the fact that the patient was receiving intravenous erythropoietin-alpha while having the antibody in the serum. The present case describes the acceleration of the recovery and successful resumption of erythropoietin concurrently despite the positive serum anti-erythropoietin antibody.

Topics: Cyclophosphamide; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Middle Aged; Mycophenolic Acid; Prednisolone; Red-Cell Aplasia, Pure

The antibody characteristics in erythropoiesis-stimulating agent (ESA)-treated patients who develop antibody-mediated pure red cell aplasia (PRCA; amPRCA) can be described as high-affinity, neutralizing anti-ESA antibodies with a mixed immunoglobulin G (IgG) subclass. The characteristics of an early-onset anti-ESA antibody response are not well documented, especially in the months prior to the development of amPRCA. Therefore, a detailed characterization of anti-ESA antibodies was performed in patients in both clinical studies and in a post-market setting. Both baseline and post-dose samples were tested and antibody-positive samples were characterized. Antibody characteristics such as concentration, isotype and specificity were evaluated in subjects with non-neutralizing anti-ESA antibodies and subjects that developed neutralizing anti-ESA antibodies associated with amPRCA.. Serum samples were analyzed for the presence of anti-ESA antibodies, using a validated surface plasmon resonance (SPR)-based immunoassay or SPRIA.. Among the clinical studies, pre-existing non-neutralizing anti-ESA antibodies were found in 6% of the subjects from clinical studies in nephrology, oncology and congestive heart failure (CHF). After ESA treatment, 2.3% of the subjects developed binding, non-neutralizing antibodies with 0.1% confirmed as having an IgG isotype and were specific to the ESA protein. IgM antibodies were detected at baseline and post-ESA treatment and reported to be specific to the glycosylation of the ESA. No clinical study subjects progressed to amPRCA. In contrast, anti-ESA antibody-positive subjects from the post-market setting with a confirmed IgG subclass were specific to the ESA protein. Subjects that had progressed to amPRCA were noted to have high antibody concentrations with neutralizing activity and a diverse IgG subtype.. A low prevalence of non-neutralizing anti-ESA IgM specific to glycosylation on the ESA and IgG1 antibodies specific to the ESA protein was detected across all clinical patient populations. Patients with amPRCA were noted to have high IgG antibody concentrations, neutralizing antibodies and the presence of anti-ESA IgG4 antibodies.

Topics: Antibodies, Neutralizing; Antibody Specificity; Autoantibodies; Erythropoietin; Glycosylation; Hematinics; Humans; Immunoglobulin G; Immunoglobulin M; Product Surveillance, Postmarketing; Recombinant Proteins; Red-Cell Aplasia, Pure; Self Tolerance

Recombinant human erythropoietin (r-HuEpo) has been used for the treatment of renal anemia. With the loss of its patent protection, there has been an upsurge of more affordable biosimilar agents, increasing patient access to treatment for these conditions. The complexity of the manufacturing process for these recombinant proteins, however, can result in altered properties that may significantly affect patient safety. As it is not known whether various r-HuEpo products can be safely interchanged, we studied 30 patients with chronic kidney disease treated by subcutaneous injection with biosimilar r-HuEpo and who developed a sudden loss of efficacy. Sera from 23 of these patients were positive for r-HuEpo-neutralizing antibodies, and their bone marrow biopsies indicated pure red-cell aplasia, indicating the loss of erythroblasts. Sera and bone marrow biopsies from the remaining seven patients were negative for anti-r-HuEpo antibodies and red-cell aplasia, respectively. The cause for r-HuEpo hyporesponsiveness was occult gastrointestinal bleeding. Thus, subcutaneous injection of biosimilar r-HuEpo can cause adverse immunological effects. A large, long-term, pharmacovigilance study is necessary to monitor and ensure patient safety for these agents.

Topics: Adult; Aged; Anemia; Antibodies, Neutralizing; Erythropoietin; Female; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Pilot Projects; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors; Thailand

Functional cell-based assays are the preferred method to test for the presence of anti-rHuEPO neutralizing antibodies (NAbs). However, due to the unpredictable nature of test serum matrix effects on cell-based assays, confirmatory assays are essential for verifying NAb positive results observed during the course of sample testing. The cell-based assay used for the detection of NAbs described by Wei et al. [1] used 32D-EPOR cells, a murine myeloid cell line transfected with the human EPO receptor (EPOR). The 32D-EPOR cell line responded to either rHuEPO or murine interleukin 3 (mIL-3) with proliferation. NAbs were expected to only inhibit rHuEPO-induced cell proliferation and not mIL-3 induced proliferation. Due to reliance on proliferation, the results from this cell-based assay can be confounded by the presence of non-antibody inhibitory serum factors. This paper describes a strategy for confirming that the inhibition of rHuEPO-induced proliferation in a cell-based assay is only attributable to NAbs. The strategy of antibody depletion uses a resin mixture composed of Protein G Sepharose and Protein L Sepharose (Protein G/L resin) to significantly reduce the concentration of immunoglobulins of IgG, IgM and IgA isotypes from human serum prior to testing in the cell-based assay. If the reduction in immunoglobulins in a serum sample corresponds to a reduction in inhibition of EPO-induced proliferation, it would infer that EPO neutralizing activity is antibody-mediated and not due to non-antibody inhibitory serum factors.

Topics: Animals; Antibodies; Antibodies, Neutralizing; Biosensing Techniques; Cell Line; Cell Proliferation; Erythropoietin; Female; Humans; Immunoassay; Interleukin-3; Male; Mice; Receptors, Erythropoietin; Red-Cell Aplasia, Pure; Sepharose; Serum

Antibody (Ab)-mediated pure red cell aplasia (PRCA) is a rare but important side effect in patients with chronic kidney disease who receive recombinant human erythropoietin (rhEPO). Ab-mediated PRCA was first reported in the 1990s, and the incidence subsequently increased and reached a peak in 2001. After improvements in rhEPO products and the administration route, the incidence was reduced by 90%, and now Ab-mediated PRCA only develops in a limited number of patients who receive rhEPO subcutaneously for a long period. We describe here the clinical course of one such rare patient with Ab-mediated PRCA. The patient was a 70-year-old man with chronic renal failure secondary to diabetic nephropathy. He had not received rhEPO therapy before the initiation of hemodialysis. He started hemodialysis and began to receive rhEPO therapy intravenously. Three months later, his hemoglobin level started declining and he became transfusion dependent. A diagnosis of Ab-mediated PRCA was made by bone marrow examination and detection of anti-EPO Abs. He was successfully treated with cyclosporine and became independent of blood transfusions. This case is a reminder that vigilance is required regarding the development of Ab-mediated PRCA upon rhEPO therapy, regardless of the administration route.

Topics: Aged; Autoantibodies; Diabetic Nephropathies; Erythropoietin; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Recombinant human erythropoietin (rhEPO) has been successfully used for correcting renal anemia. However, recent studies have raised some concerns about the safety of rhEPO treatment due to its immunogenic side effect - pure red cell aplasia (PRCA). We now report a case of development of anti-EPO neutralizing antibodies (Abs) implicated in thrombocytopenia as well as erythrocytopenia. A 35-year-old man had a history of administering rhEPO (epoetin alfa, epoetin beta and darbepoetin alfa) for 2years to treat renal anemia. The hematological parameters were collected. Anti-EPO, anti-platelet, and anti-thrombopoietin (TPO) Ab assays were performed to test the presence of autoreactive Abs. After performing antibody assays due to severe resistance to rhEPO treatment, a high titer of anti-EPO neutralizing Abs was detected. However, unexpectedly, this patient also showed thrombocytopenia rather than PRCA. We investigated the cause of the marked thrombocytopenia and found anti-TPO Abs in patient serum. To our best knowledge, this is the first report of the development of anti-TPO Abs during rhEPO treatment for anemia.

Topics: Adult; Antibodies, Neutralizing; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Thrombocytopenia; Thrombopoietin; Treatment Outcome

We present a case of a young girl with end-stage renal disease secondary to anti-glomerular basement membrane disease who was receiving maintenance peritoneal dialysis and developed pure red cell aplasia secondary to anti-erythropoietin (EPO) antibodies. This occurred 13 months after the initiation of EPO alfa therapy for anemia. Initially, the patient required intermittent red blood cell transfusions. After immunosuppressive therapy had been initiated with corticosteroids and cyclosporine, the EPO antibody levels decreased precipitously, associated with an increased level of endogenous EPO production. For the following 6 months, the patient maintained adequate (>10 g/dL) hemoglobin levels and did not require red cell transfusions.

Topics: Anemia; Antibodies; Child, Preschool; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Time Factors; Treatment Outcome

Topics: Adrenal Cortex Hormones; Cyclophosphamide; Drug Costs; Drug Therapy, Combination; Erythropoietin; Hemoglobins; Humans; Receptors, Erythropoietin; Red-Cell Aplasia, Pure

Topics: Anemia; Antibodies; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Prednisone; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

An elderly patient with pure red cell aplasia (PRCA) with antierythropoietin (anti-EPO) antibodies is described. PRCA due to alloimmunization is a rare and severe complication of recombinant human erythropoietin (rHu-EPO) therapy. Most reported patients with PRCA were cured primarily by immunosuppressive drug therapy. The patient in this case, however, did not want to receive any immunosuppressive drugs. Therefore, rHu-EPO injection was simply discontinued, the severe anemia gradually improved, and the hemoglobin approached normal range. This case is very rare and significant in that there have been few such elderly patients with rHu-EPO-induced PRCA in whom PRCA remission was achieved, with decreasing antibody titers, after cessation of rHu-EPO alone. Further cases are needed to assess how PRCA should be treated in patients with anti-EPO antibodies.

Topics: Aged, 80 and over; Antibodies, Neutralizing; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Antibody-mediated pure red cell aplasia is a rare but serious event resulting from the induction of neutralizing erythropoietin (Epo)-specific antibodies provoked by treatment with recombinant Epo. Because of the crucial role of CD4 T cells in humoral response, we have quantified the number of Epo-specific CD4 T cells in the blood of normal donors by in vitro stimulation. An important repertoire of preexisting Epo-specific T cells was observed in almost half of the donors, comparable with that of non-self-proteins. This observation suggests that, at the steady state, endogenous Epo weakly contributes to tolerance induction and may be ignored by the immune system. As a result, circulating Epo-specific CD4 T cells could be prone to be activated by altered batches of Epo, providing them with costimulatory signals. Our data also highlight the relevance of T-cell assays performed with normal donors to evaluate the potential immunogenicity of therapeutic proteins.

Topics: Antibodies, Neutralizing; CD4-Positive T-Lymphocytes; Cells, Cultured; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Anti-erythropoietin antibodies usually cross-react with all kinds of recombinant erythropoietins; therefore, erythropoiesis-stimulating agent (ESA)-induced pure red-cell aplasia (PRCA) is not rescued by different ESAs. Here, we present a case of ESA-induced PRCA in a 36-yr-old woman with chronic kidney disease, whose anemic condition improved following reintroduction of darbepoetin-α. The patient developed progressive, severe anemia after the use of erythropoietin-α. As the anemia did not improve after the administration of either other erythropoietin-α products or erythropoietin-β, all ESAs were discontinued. Oxymetholone therapy failed to improve the transfusion-dependent anemia and a rechallenge with ESAs continuously failed to obtain a sustained response. However, her anemia improved following reintroduction of darbepoetin-α at 3 yr after the initial diagnosis. Interestingly, anti-erythropoietin antibodies were still detectable, although their concentration was too low for titration. In conclusion, darbepoetin-α can improve ESA-induced PRCA when the anti-erythropoietin antibody titer declines and its neutralizing capacity is lost.

Topics: Adult; Anemia; Antibodies; Bone Marrow Cells; Darbepoetin alfa; Drug Hypersensitivity; Erythropoietin; Female; Glomerulonephritis, IGA; Hematinics; Humans; Kidney Failure, Chronic; Oxymetholone; Recombinant Proteins; Red-Cell Aplasia, Pure

Anti-r-HuEpo associated PRCA developed in patients received subcutaneous injection of r-HuEpo for treatment of renal anemia in chronic kidney disease. This adverse immunological effect of r-HuEpo causes sudden loss of r-HuEpo efficacy, low circulating reticulocyte count and bone marrow biopsy shows an absence of erythroid precursor cells with normal cell population of non-erythroid lineage. There are postulation cause of anti-r-HuEpo associated PRCA including genetic factor, immunogenicity factor, storage and handlings factor and formulation of r-HuEpo product. Previous observation of our report showed an aggregation of HLA-DRB1*09 in four anti-r-HuEpo associated PRCA cases. This allele is rare in Caucasian (<1%) but more common in Thai population (8.4-12.5%). This study was aimed to investigate the possible association between HLA-DRB1*09 or other specific HLA and anti-r-HuEpo associated PRCA.. Twenty two cases of proven anti-r-HuEpo associated PRCA were recruited and studied retrospectively based on the incidence report of serious adverse drug reaction. The EDTA bloods were drawn for HLA typing using sequence specific primer polymerase chain reaction (SSP-PCR). The HLA data of 1,800 potential cadaveric kidney transplantation recipients in the waiting list as chronic kidney disease control and 1,500 potential bone marrow stem cell donors in national stem cell registry as healthy population control were retrieved from the database of Thai Red Cross for comparison.. The distribution of gene frequency of HLA-A, -B, -DR and -DQ alleles in anti-r-HuEpo associated PRCA cases showed high gene frequency of HLA-A*02, HLA-A*11 and HLA-A*24 for HLA-A loci, HLA-B*18, HLA-B*46, HLA-B*60 and HLA-B*62 for HLA-B loci, and HLA-DRB1*09, HLA-DRB1*12 and HLA-DRB1*15 for HLA-DR loci. There was a significant difference of HLA-DRB1*09 gene frequency (P < 0.001) which associated with HLA-DQB1*0309 between anti-r-HuEpo associated PRCA cases, and potential cadaveric kidney transplantation in the waiting list or potential national stem cell registry donor. The odd ratio of HLA-DRB1*09 allele for anti-r-HuEpo associated PRCA was 2.89 (95% CI: 1.88-4.46; p-value: <0.001).. Our data demonstrated the association of HLA-DRB1*09-DQB1*0309 and anti-r-HuEpo associated PRCA cases. This association may be used in identifying the risk of the patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Anemia; Antibodies, Anti-Idiotypic; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Gene Frequency; Genetic Predisposition to Disease; HLA-DQ Antigens; HLA-DQ beta-Chains; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Retrospective Studies; Risk Factors; Young Adult

Reports from the World Health Organization have suggested that counterfeit medicines pose a serious problem in developing countries. An investigation of anti-erythropoietin antibody-mediated pure red cell aplasia in Thailand found evidence of drug smuggling, which may have serious safety implications.. This study assessed the authenticity and quality of epoetin alfa samples in Thailand.. Samples of epoetin alfa-prefilled syringes were collected from the pharmacies at 2 major hospitals (62 samples), 8 retail pharmacies (41 samples), and Thai authorities (30 samples confiscated from smugglers at 2 airports, and 6 samples from a condominium used by smugglers). These samples were tested against the European Union Pharmacopeia specifications for aggregate content in epoetins of <2%. The integrity of epoetin alfa distribution channels, coldchain processes (maintenance at 2 degrees C-8 degrees C), primary and secondary packaging components (eg, batch number, expiration date, appearance, letter size), and company's confidential features (eg, nature of the ink, type and quality of the paper, other covered features) were also investigated. The main outcome measures were protein aggregate content, determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting; and isoform distribution, assessed by isoelectric focusing and Western blotting.. Epoetin alfa samples obtained from the company's cold-chain and authorized distribution channels met all quality standards, as did all epoetin alfa samples obtained from the hospital pharmacies. However, evidence showed that some samples were being smuggled or sold illegally through certain unauthorized retail pharmacies. The epoetin alfa samples obtained from both airports and the condominium were stored improperly at room temperature. Aggregate levels exceeded the specification of <2% in 11 samples from 2 of the retail pharmacies (range, 1.2%-3.1%), 15 samples from the Dongmuang Airport (range, 2.2%-17.0%), and all 6 samples from the condominium (range, 10.5%-19.8%). All samples from the 2 hospitals, 8 retail pharmacies, and Suvarnabhumi Airport had the authentic 6 isoform bands. Samples from Dongmuang Airport and the condominium appeared to have the 6 characteristic bands, but positive confirmation was difficult because of band smearing caused by a high level of aggregates. All features of primary and secondary packaging were found to be authentic.. This investigation found evidence that some epoetin alfa samples were smuggled into Thailand without proper cold chain, contained high levels of protein aggregates, and were sold illegally through certain retail pharmacies. The Thai authorities have intervened to stop such unauthorized products from reaching patients. Strenuous efforts must be made to prevent illegal cross-border smuggling of biopharmaceuticals without proper cold chain because of the serious safety implications for patients in developing countries.

Topics: Commerce; Crime; Drug and Narcotic Control; Drug Contamination; Drug Packaging; Drug Stability; Drug Storage; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Pharmacopoeias as Topic; Pharmacy; Quality Control; Recombinant Proteins; Red-Cell Aplasia, Pure; Syringes; Thailand

Topics: Anemia; Biopharmaceutics; Darbepoetin alfa; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Health Care Costs; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors

Topics: Erythropoietin; Humans; Receptors, Erythropoietin; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

Topics: Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Topics: Aged; Aged, 80 and over; Anemia; Cyclosporine; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) is a rare condition described in patients with chronic kidney disease during alpha-Epo treatment subcutaneous administered generated by anti-R-Epo antibodies. Recently two cases of PRCA have been reported in patients affected by myelodysplastic syndrome treated with R-Epo. We described one more case of PRCA in a patient with refractory anemia treated with R-Epo.

Topics: Adrenal Cortex Hormones; Aged; Blood Transfusion; Erythropoietin; Humans; Injections, Subcutaneous; Male; Myelodysplastic Syndromes; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

A 42-year-old woman with systemic lupus erythematosus was admitted to our hospital because of severe anemia. Her bone marrow was almost normocellular and erythroblasts were nearly absent. Laboratory data showed elevated levels of lactate dehydrogenase and positive findings on Coombs' tests. On the basis of these findings, her anemia was diagnosed as the overlap of pure red cell aplasia with autoimmune hemolytic anemia. Radioimmunoprecipitation assay revealed that her serum was positive for anti-erythropoietin antibodies before therapy. Furthermore, the autoantibodies inhibited proliferation of an erythropoietin-dependent cell line in a dose-dependent manner. Immunosuppressive treatment improved the anemia accompanied with disappearance of the autoantibodies.

Topics: Adult; Anemia, Hemolytic, Autoimmune; Antibody Specificity; Autoantibodies; Bone Marrow; Cell Division; Cell Line; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Methylprednisolone; Prednisolone; Red-Cell Aplasia, Pure

Biosimilars or follow-on biologics (FoB) are biopharmaceuticals that, unlike small molecule generic products, are copies of larger, much more complex proteins. As such, data generated from one biopharmaceutical cannot be extrapolated to another. Unlike small molecule generics, FoB require a full developmental programme, albeit smaller than for an originator product. This has been recognized by European regulatory authorities and it is becoming clear that accelerated processes for FoB marketing approval are not feasible.. To determine the balance between costs surrounding FoB (including relatively extensive developmental programmes and subsequent price to the market) and the necessity to ensure efficacy and safety.. It is important that FoB are sufficiently tested to ensure patient safety is not compromised. Conducting such a development programme followed by sound pharmacovigilance is very challenging and costly.. Cost-savings associated with FoB may be limited.

Topics: Biological Products; Cost Savings; Drug Approval; Drug Costs; Drugs, Generic; Epoetin Alfa; Erythropoietin; Humans; Product Surveillance, Postmarketing; Recombinant Proteins; Red-Cell Aplasia, Pure; Therapeutic Equivalency

Topics: Child; Erythropoietin; Humans; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Anemia; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic

Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event associated with recombinant human erythropoietin treatment (4.1 reports per 100,000 patient-years) in which patients produce antibodies to recombinant and endogenous erythropoietin, halting red blood cell production. In a previous case series, four Thai subjects with chronic kidney disease and Ab-positive PRCA were reported to have the HLA-DRB1*9 allele. To confirm a possible association of HLA-DRB1*9 and Ab-positive PRCA, we performed a pharmacogenomic analysis using subjects from an earlier case-control study of risk factors associated with Ab-positive PRCA, which had been performed using subjects from Europe or Canada. The primary goal of the analysis was to test the association between HLA-DRB1*9 and Ab-positive PRCA. A secondary goal was to perform an exploratory analysis in order to identify additional HLA alleles potentially associated with Ab-positive PRCA.. Subjects were taken from a case-control study of Ab-positive PRCA in chronic kidney disease patients treated in Europe or Canada. Ab-positive PRCA cases (n=24) were matched to controls (n=81) by timing of treatment exposure and, when possible, by location.. The allele frequency of HLA-DRB1*9 was 12.5% in cases vs 1.2% in controls (p=0.002). The frequency of the HLA-DRB1*9/other genotype was 25.0% in cases vs 2.5% in controls (p=0.004; OR: 10.8 [95% CI: 2.2-53.7]). Within the exploratory analysis, six additional HLA alleles (HLA-A*25, HLA-B*53, HLA-C*12, HLA-DQB1*3, HLA-DQB1*6 and HLA-DRB1*4) were also found to be associated with Ab-positive PRCA.. This study confirmed that HLA-DRB1*9 occurs at a significantly higher frequency in Ab-positive PRCA cases than in controls; however, within this sample set, carrying the *9 allele was neither necessary nor sufficient to cause Ab-positive PRCA.

Topics: Adult; Aged; Alleles; Autoantibodies; Case-Control Studies; Erythropoietin; Female; Gene Frequency; Genotype; HLA Antigens; HLA-C Antigens; HLA-DQ Antigens; HLA-DQ beta-Chains; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Male; Middle Aged; Odds Ratio; Recombinant Proteins; Red-Cell Aplasia, Pure; Retrospective Studies

Topics: Aged, 80 and over; Darbepoetin alfa; Drug Resistance; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

Topics: Antibodies, Monoclonal; Cyclosporine; Erythropoietin; Humans; Immunosuppressive Agents; Red-Cell Aplasia, Pure; Treatment Outcome

The prevalence of anti-erythropoietin antibodies in renal patients without clinical evidence of pure red cell aplasia (PRCA) who respond poorly to epoetin is unknown. This study tested for anti-erythropoietin antibodies in hemodialysis patients who were either hypo- or normoresponsive to epoetin treatment.. Epoetin hyporesponsiveness (hemoglobin < or =10.5 g/dl and epoetin > or =9,000 IU/week) and normoresponsiveness (hemoglobin >10.5 g/dl and epoetin <7,000 IU/week) were arbitrarily defined. Prevalence of anti-erythropoietin antibodies in hemodialysis patients without symptoms of PRCA was determined by screening sera of 536 patients from 35 German KfH dialysis units, using enzyme-linked immunosorbent assay (ELISA). Positive results were verified by radioimmunoprecipitation assay (RIP) and neutralizing activity was determined by bioassay.. Anti-erythropoietin antibodies were detected in 3 hyporesponsive and 3 normoresponsive patients using ELISA. One patient per group was verified as borderline by RIP testing; the other 4 were negative. The bioassay was negative for 1 patient; the other died unrelated to PRCA before testing. Follow-up with RIP testing after 15 months under continuous epoetin treatment was negative (4 patients, 2 deceased).. This survey did not identify anti-erythropoietin antibodies in hemodialysis patient's hyporesponsive to epoetin and does not support presumptive antibody screening as a routine work-up in these patients.

Topics: Aged; Anemia; Antibodies; Cohort Studies; Drug Resistance; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Male; Middle Aged; Radioimmunoprecipitation Assay; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Renal Insufficiency

Topics: Aged; Anemia; Antibodies; Chronic Disease; Cyclophosphamide; Darbepoetin alfa; Erythropoietin; Fatal Outcome; Hematinics; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Opportunistic Infections; Prednisolone; Red-Cell Aplasia, Pure

Topics: Aged; Anemia; Arthritis, Rheumatoid; Disease Progression; Disseminated Intravascular Coagulation; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

It has been reported in the Western literature that patients with chronic renal disease have developed anti-erythropoietin (EPO) antibody-related pure red cell aplasia (PRCA). To investigate the incidence of anti-EPO antibody-related PRCA in Japan, we designed a questionnaire survey based on previous reports of patients who had PRCA during treatment with EPO. Thirteen of 17 patients were evaluated in this study. In all 13 patients, EPO delivery was via injection, 9 subcutaneously, 2 intravenously and 2 with a combination of the 2 methods. Three of 4 patients treated with subcutaneous EPO administration were positive for anti-EPO antibodies, but all patients treated by intravenous injection were negative. The EPO was stopped in 8 patients after the onset of PRCA, and immunosuppressive therapy with prednisolone and/or cyclosporine was administered in 12 patients. An improvement in PRCA was obtained in 12 patients. It was suspected that previous reports in Japan may have included both anti-EPO antibody-associated PRCA and incidental cases. Furthermore, subcutaneous administration of EPO may effect the production of anti-EPO antibodies.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antibodies; Erythropoietin; Female; Humans; Immunosuppressive Agents; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Surveys and Questionnaires; Treatment Outcome

Immunogenicity profiles of recombinant therapeutic proteins are important to understand because antibodies raised against these molecules may have important clinical sequelae. The purpose of the present study was to demonstrate that a flow cytometric bead array could be used to detect clinically relevant antibodies with specificity to such therapeutics. We chose to evaluate well-characterized specimens from persons treated with epoetin alfa that developed antibody-mediated pure red blood cell aplasia as a means to demonstrate the utility of this platform. Our data show that this assay is capable of detecting anti-epoetin alfa antibodies with a relative antibody concentration of 50 ng/ml, where 25 of 25 sera spiked with antibodies at this concentration scored positive. Moreover, the assay was designed to include positive and negative control beads for each specimen that is processed to ensure the specificity of the signal when detected. Measurement of interassay precision supports quantitative estimates of relative antibody concentrations in the range of 313 to 5,000 ng/ml, where the percent coefficient of variation did not exceed 20%. With respect to clinical specimens, antibodies with specificity for epoetin alfa could be easily detected in a set of specimens from persons with pure red blood cell aplasia that had prior exposure to the EPREX brand of recombinant epoetin alfa. Further development and validation of this approach may facilitate successful widespread application of the method for detection of anti-epoetin alfa antibodies, as well as antibodies directed against other recombinant therapeutic proteins.

Topics: Autoantibodies; Epoetin Alfa; Erythropoietin; Feasibility Studies; Flow Cytometry; Humans; Immunoassay; Microspheres; Recombinant Proteins; Red-Cell Aplasia, Pure

To evaluate the potential of Hematide, a PEGylated, synthetic peptide-based erythropoiesis-stimulating agent that is in clinical development for the treatment of anemia associated with chronic kidney disease and cancer, to correct antierythropoietin antibody-associated pure red cell aplasia (PRCA).. The binding of anti-Hematide antibodies (mouse, rabbit, and monkey) to recombinant human erythropoietin (rHuEPO) and of anti-rHuEPO antibodies (mouse, goat, rat, and human) to Hematide were evaluated. An anti-EPO antibody-mediated anemia rat model was developed by subcutaneously administering rHuEPO to rats three times weekly for 4 weeks. Sixty percent of the animals developed PRCA as characterized by severe anemia, reduced reticulocytes, anti-EPO antibodies, and limited bone marrow erythroid precursors. The effect of Hematide administration on the PRCA rats was evaluated.. Antibodies to EPO do not cross react with Hematide and, conversely, antibodies to Hematide do not cross react with EPO. Hematide corrected antibody-induced anemia in a rat PRCA model.. The data support the potential of Hematide to correct anti-EPO antibody-associated PRCA in humans. In addition, the data suggest a negligible risk for development of anti-EPO antibody-induced PRCA secondary to Hematide administration.

Topics: Anemia; Animals; Antibodies; Bone Marrow; Colony-Forming Units Assay; Disease Models, Animal; Erythropoietin; Humans; Peptides; Polyethylene Glycols; Rabbits; Rats; Red-Cell Aplasia, Pure

After liver transplantation, reinfection of the newly engrafted liver with hepatitis C virus is essentially universal in patients who are viremic at the time of transplantation. Treatment with interferon preparations with or without ribavirin is recommended in patients with marked histologic injury; however, hematologic toxicity associated with therapy has been reported, which is usually treated with growth factor support, including erythropoietin analogues. We present the first reported case of anti-erythropoietin antibody-mediated pure red cell aplasia arising in the setting of hepatitis C virus therapy in a patient who underwent living donor liver transplantation.

Topics: Anemia; Antibodies; Antiviral Agents; Epoetin Alfa; Erythropoietin; Graft Rejection; Hematinics; Hepatitis C; Humans; Immunocompromised Host; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Polyethylene Glycols; Prednisone; Recombinant Proteins; Red-Cell Aplasia, Pure; Ribavirin; Secondary Prevention; Tacrolimus

We report a case of pure red cell aplasia (PRCA) subsequent to an allogeneic bone marrow transplantation with a major ABO mismatch, which was resistant to the standard treatment options such as plasma exchange, erythropoietin and changes in the immunosuppressive treatment. Accordingly, two cycles of Rituximab therapy were administered without success. The patient had a chronic graft-vs.-host disease of the liver, which meant that an additional donor leukocyte infusion could not be introduced. Instead, purified CD34(+) cells were administered after fludarabine and antithymocyte globulin therapy. As a result, the PRCA was resolved and the antidonor isohemagglutinin titer became undetectable.

Topics: ABO Blood-Group System; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD34; Bone Marrow Transplantation; Erythropoietin; Female; Humans; Leukocyte Transfusion; Medical Errors; Red-Cell Aplasia, Pure; Rituximab; Transplantation, Homologous; Vidarabine

Human parvovirus B19 (PVB 19) is responsible for pure red cell aplasia in immunocompromised patients, and particularly solid organ recipients. Intravenous immunoglobulins (IVIG) have been shown to be efficient to achieve the correction of anemia in association with the reduction of immunosuppression. We report a case of kidney transplant recipient with PVB 19-induced anemia that did not respond to recombinant human erythropoietin (rHuEPO) and to a first course of IVIG. After discontinuation of rHuEPO, a second course of IVIG was successful with the resolution of anemia. We discuss the role of rHuEPO that may facilitate PVB 19 replication in erythropoietin-sensitive human erythroid progenitor cells.

Topics: Drug Resistance; Erythropoietin; Female; Humans; Immunoglobulins, Intravenous; Kidney Transplantation; Middle Aged; Parvoviridae Infections; Parvovirus B19, Human; Recombinant Proteins; Red-Cell Aplasia, Pure; Virus Replication

The incidence of pure red cell aplasia (PRCA) in patients with chronic kidney disease associated with the subcutaneous (s.c.) administration of epoetin alfa (EPREX) began to increase in 1998. As part of an intensive investigation into the reasons for this increase, in vivo models were developed to assess the ability of potential causative factors to stimulate an immune response to recombinant human erythropoietin (rHuEPO). It was difficult to generate anti-EPO antibodies in mice. In animals injected with rHuEPO alone, anti-EPO antibodies were either absent or present at very low levels. The addition of an adjuvant to the immunization protocol was able to increase both the frequency of occurrence and titer of the immune response and resulted in the generation of anti-EPO antibodies that, in most cases, recognized both human and mouse EPO. Some mice exhibited a reduction in hematocrit, suggesting neutralization of endogenous EPO by anti-EPO antibodies. To evaluate the primary lead identified in the technical investigation, leachates from the uncoated syringe stoppers of EPREX syringes, a surrogate antigen (chicken egg albumin, OVA) was used to avoid possible interferences that could arise from the use of an endogenous protein like EPO. These leachates yielded a positive, concentration-dependent antibody response in the OVA animal model, demonstrating their adjuvant properties and providing support for the hypothesis generated through the technical investigation that leachates were capable of enhancing the immune response to rHuEPO.

Topics: Adjuvants, Immunologic; Animals; Drug Packaging; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Humans; Male; Mice; Models, Immunological; Ovalbumin; Recombinant Proteins; Red-Cell Aplasia, Pure; Syringes

Topics: Algorithms; Anemia, Aplastic; Bone Marrow Transplantation; Cyclosporine; Erythropoietin; Humans; Red-Cell Aplasia, Pure; Severity of Illness Index

Topics: Adverse Drug Reaction Reporting Systems; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment; Risk Factors

Topics: Adrenal Cortex Hormones; Erythropoietin; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Treatment Outcome

Topics: Antibodies; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Injections, Subcutaneous; Male; Middle Aged; Red-Cell Aplasia, Pure; Renal Dialysis; Time Factors

Topics: Animals; Epoetin Alfa; Erythropoietin; Humans; Incidence; Kidney Diseases; Mice; Ovalbumin; Recombinant Proteins; Red-Cell Aplasia, Pure; Structure-Activity Relationship

Pure red-cell aplasia is an isolated disorder of erythropoiesis that leads to the pment of severe, isolated anemia. In chronic kidney disease patients treated with n erythropoiesis stimulating agent (ESA), development of anti-erythropoietin antibodies s one of the leading causes of pure red-cell aplasia. It requires to stop treatment with ESA, but in the vast majority of cases immunosuppressive therapy is necessary to induce the disappearance of anti-erythropoietin antibodies. Isolated case reports suggest that, at least in some patients, treatments with ESA can be resumed after recovery from antibody-mediated pure red-cell aplasia.

Topics: Anemia; Antibodies; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) emerged recently as the potentially life-threatening condition secondary to anti-Epo antibodies. Vast majority of cases were reported from Western European countries and were secondary to subcutaneous injections of Epoietin alpha. Here we describe possibly for the first time in the literature the case of PRCA from Poland or even Central and Eastern Europe in patient treated exclusively with Epoietin beta from multi-dose vial. In the last section of the paper the current epidemiological, diagnostic and therapeutic aspect of PRCA were discussed.

Topics: Aged; Anemia; Autoantibodies; Bone Marrow Examination; Erythropoietin; Humans; Male; Poland; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

A 68-year-old male with chronic renal failure and anemia received recombinant human erythropoietin (rHuEPO), epoetin beta, for approximately 1 year. Although the agent was initially effective for improving anemia, anemia refractory to EPO administration appeared and then worsened later, and pure red-cell aplasia (PRCA) was diagnosed. Anti-EPO antibody was detected by radioimmunoprecipitation (RIP) assay in the patient's serum. The antibody inhibited the proliferation of EPO-dependent cell line in a dose-dependent manner neutralizing EPO activity. The antibody also reacted with the other epoetin alfa products. The antibody did not recognize the carbohydrate moieties or denatured epoetin beta. The result suggested that the antibody recognized the conformational epitope of epoetin beta peptide molecule. Withdrawal of EPO and administration of cyclosporine decreased the titers of antibody; however, erythroid progenitor has not yet regenerated although the requirement for red blood cell transfusion is decreasing.

Topics: Aged; Anemia; Antibodies; Asian People; Cross Reactions; Erythropoietin; Humans; Immunoprecipitation; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Adverse Drug Reaction Reporting Systems; Erythropoietin; Humans; Incidence; Recombinant Proteins; Red-Cell Aplasia, Pure; United States; United States Food and Drug Administration

Topics: Adolescent; Adult; Antibodies; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Remission Induction

Topics: Drug Hypersensitivity; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

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-alpha 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-alpha 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.

Topics: Anemia; Drug Contamination; Equipment and Supplies; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Rubber

Topics: Antibodies; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

The recent emergence of antibody (Ab)-mediated pure red cell aplasia (PRCA) resulting from administration of certain erythropoiesis-stimulating agents (ESAs) has heightened awareness of the potential for this disorder in patients receiving ESAs for anaemia associated with chronic kidney disease (CKD). The Spanish Society of Nephrology sponsored an independent registry for analysis of patients who developed epoetin-induced, Ab-mediated PRCA in Spain. Twelve patients from 11 regional hospitals were included in the Spanish PRCA registry from November 2000 to December 2002 that met the criteria for Ab-mediated PRCA. Patients were reported using a standardized form specifically developed for PRCA, and serum samples were analysed in a central laboratory at Reina Sofia University Hospital in Cordoba, Spain. The characteristics of these patients, their serological and haematological results, and the outcomes of immunosuppressive therapies are presented. The Spanish PRCA registry serves as a model for establishing an independent global PRCA registry sponsored by the various nephrology societies in European Union countries, and elsewhere and coordinated by key investigators from the respective countries.

Topics: Adult; Aged; Aged, 80 and over; Antibodies; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Registries; Spain

The incidence of pure red cell aplasia (PRCA) in chronic kidney disease patients treated with epoetins increased substantially in 1998, was shown to be antibody mediated, and was associated predominantly with subcutaneous administration of Eprex. A technical investigation identified organic compounds leached from uncoated rubber stoppers in prefilled syringes containing polysorbate 80 as the most probable cause of the increased immunogenicity.. This study investigated whether the incidence of PRCA was higher for exposure to the product form containing leachates than for leachate-free product forms. Antibody-mediated PRCA cases were classified according to indication, product form, and route of administration. Exposure estimates were obtained by country, indication, route of administration, and product form.. For 2001 to 2003, the PRCA incidence rate for patients with subcutaneous exposure to Eprex in prefilled syringes with polysorbate 80 and uncoated rubber stoppers (leachates present) was 4.61/10,000 patient years (95% CI 3.88-5.43) versus 0.26/10,000 patient years (95% CI 0.007-1.44) for syringes with coated stoppers (leachates absent). The rate difference was 4.35/10,000 patient years (95% CI 3.44-5.26; P < 0.0001); the rate ratio was 17 (95% CI 3.14-707). A substantial rate difference remained in sensitivity analyses that adjusted for exposure to multiple product forms.. The epidemiologic data, together with the chemical and immunologic data, support the hypothesis that leachates from uncoated rubber syringe stoppers caused the increased incidence of PRCA associated with Eprex. Currently, all Eprex prefilled syringes contain fluoro-resin coated stoppers, which has contributed to decreased incidence of PRCA with continued surveillance.

Topics: Chemistry, Pharmaceutical; Erythropoietin; Humans; Incidence; Polysorbates; Recombinant Proteins; Red-Cell Aplasia, Pure; Syringes

Anemia frequently complicates the treatment of chronic hepatitis C with interferon and ribavirin (RVN), requiring dose reduction and jeopardizing sustained virologic response. Increasingly, epoetin alfa is used to prevent anemia in this setting. Below, we report the first case of pure red cell aplasia (PRCA) in a patient with chronic hepatitis C who received epoetin alfa (Procrit) to manage anti-viral treatment-induced anemia. Red blood cell transfusion-dependence developed 16 wk after the patient was started on peginterferon alfa-2b and RVN for chronic hepatitis C despite the simultaneous administration of epoetin alfa and subsequent discontinuation of the antiviral medications. Bone marrow biopsy was consistent with PRCA. High-titer erythropoietin antibodies, assayed by two methods, appeared shortly after epoetin alfa was administered, and were associated with a decline in serum erythropoietin to undetectable levels. Erythropoietin antibodies directed toward epoetin alfa were shown to cross react with darbepoetin alfa (Aranesp), and a neutralization assay confirmed that they inhibited cell growth in the presence of erythropoietin. Transfusion-dependence resolved approximately 16 wk after discontinuing epoetin alfa, and 6 wk after starting danazol. PRCA caused by the development of erythropoietin antibodies is a potentially life-threatening complication of administering epoetin alfa to prevent the anemia associated with antiviral therapy in patients with chronic hepatitis C.

Topics: Antibodies; Danazol; Drug Hypersensitivity; Epoetin Alfa; Erythropoietin; Estrogen Antagonists; Follow-Up Studies; Hematinics; Hepatitis C, Chronic; Humans; Male; Middle Aged; Radioimmunoprecipitation Assay; Recombinant Proteins; Red-Cell Aplasia, Pure

Pure red cell aplasia (PRCA) is a rare, but important, complication of erythropoietin (EPO) replacement therapy in patients with renal disease. There is no consensus about the best way to treat this condition; however, recent reports indicated that immunosuppressive therapy is beneficial. We report a patient with EPO-induced PRCA treated with a regimen initially designed for antifactor VIII antibodies in patients with hemophilia. This regimen consists of immunoadsorption therapy using protein A columns, followed by oral prednisolone and single bolus infusions of intravenous immunoglobulin G and cyclophosphamide. Shortly after the course, a swift and rapid increase in reticulocyte count was evident; the patient became transfusion independent and has remained so during 2 years of follow-up. By means of this report, we wish to encourage others to consider this option when first-line treatments fail.

Topics: Anemia; Blood Transfusion; Cyclophosphamide; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Nephrosclerosis; Peritoneal Dialysis; Prednisolone; Recombinant Proteins; Red-Cell Aplasia, Pure; Remission Induction; Reticulocyte Count; Sorption Detoxification; Staphylococcal Protein A

The cause of antibody positive pure red cell aplasia associated with the subcutaneous administration of EPREX to patients with chronic kidney failure has been determined to be due to the leaching of weakly adjuvant compounds from the uncoated rubber stoppers that were formerly used in prefilled syringes. Other researchers have suggested that polysorbate 80 micelles containing erythropoietin may be a causative factor. The purpose of this work was to repeat previously published studies in a more controlled manner and to define the precise nature of the interactions between polysorbate 80 and erythropoietin.. The contents of EPREX prefilled syringes and laboratory-prepared, well-characterized formulations of EPREX were analyzed by size exclusion chromatography. Fractions were analyzed for the presence of erythropoietin by ELISA. EPREX formulations prepared with increasing amounts of polysorbate 80 were analyzed by light scattering.. Well-controlled chromatographic studies showed that when EPREX formulations containing no aggregate were analyzed by high-performance liquid chromatography, erythropoietin monomer could not be detected under the polysorbate 80 peak. Dimer and oligomers of erythropoietin coeluted under the polysorbate 80 peak as the molecular weights overlapped on the size exclusion chromatogram. Solution light scattering indicated that polysorbate 80 associates with erythropoietin in a defined stoichiometric ratio of 1:12.. Based on controlled studies, previous results suggesting that EPREX contains micelle-associated erythropoietin were incorrect. As with other surfactants and proteins, polysorbate 80 associates with erythropoietin in a defined stoichiometric ratio.

Topics: Chromatography, Gel; Chromatography, High Pressure Liquid; Drug Contamination; Enzyme-Linked Immunosorbent Assay; Epoetin Alfa; Erythropoietin; Excipients; Micelles; Molecular Weight; Polysorbates; Recombinant Proteins; Red-Cell Aplasia, Pure; Surface-Active Agents; Syringes

We report a 3-year case history that describes a 78-year-old woman with recurrent transfusion-dependent pure red cell aplasia (PRCA) secondary to recombinant epoetin use that was responsive to immunosuppressant therapy. The patient had kidney disease of unknown aetiology (estimated glomerular filtration rate of 13 ml/min/1.73 m2) and was not on dialysis. After 16 months of therapy with subcutaneous Eprex, she developed anti-erythropoietin antibody-confirmed PRCA and was started on high dose prednisone (50 mg per day). Within 5 months, the patient's serum was clear of antibodies and, under the cover of low dose prednisone (5-7.5 mg per day), therapy with a different erythropoiesis-stimulating compound (Aranesp) was initiated due to persistent fatigue and anaemia. At 3 months of therapy, the serum anti-erythropoietin antibodies remained negative and, due to the patient's requests, and after discussion, prednisone therapy was discontinued. Unfortunately, 3 months after cessation of prednisone, a recurrence of PRCA was confirmed by the development of profound anaemia and reappearance of anti-erythropoietin antibodies in the patient's serum. High dose prednisone (50 mg per day) was reinstituted, whereupon, 2 months later, antibodies were again confirmed to be negative. This case report demonstrates the responsiveness of PRCA to simple immunosuppressive therapy, and the ability to introduce different erythropoiesis-stimulating agents in the presence of such therapy. It appears that there may be problems associated with discontinuation of immunosuppressive therapy in the presence of sustained erythropoiesis-stimulating agent therapy in those in whom the condition has occurred previously.

Topics: Aged; Antibodies; Darbepoetin alfa; Erythropoietin; Female; Follow-Up Studies; Glucocorticoids; Humans; Kidney Failure, Chronic; Prednisone; Recurrence; Red-Cell Aplasia, Pure

Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States. Herein, we report on the long-term outcome of these individuals. For 170 chronic kidney disease patients who developed epoetin-associated PRCA and had 3 months or more follow-up information available, case reports from the Food and Drug Administration and epoetin manufacturers were reviewed for information on clinical characteristics of the patients, immunosuppressive treatments, epoetin responsiveness, and hematologic recovery. Overall, 64% of the PRCA patients received immunosuppressive therapy, including 19 who also underwent a renal transplantation. Thirty-seven percent experienced a hematologic recovery, with higher hematologic recovery rates among PRCA patients who received immunosuppressive therapy (57% vs 2%, P < .001). Among 34 patients who received epoetin after the onset of PRCA, 56% regained epoetin responsiveness. The highest rates of epoetin responsiveness were observed among persons whose antierythropoietin antibodies were undetectable when epoetin was administered (89%). Among chronic kidney disease patients with epoetin-associated PRCA, epoetin discontinuation and immunosuppressive therapy or renal transplantation is necessary for hematologic recovery. Reinitiation of epoetin therapy among individuals could be considered if antierythropoietin antibodies are undetectable.

Topics: Autoantibodies; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Immunosuppression Therapy; Kidney Diseases; Kidney Transplantation; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Retrospective Studies; Treatment Outcome; United States; United States Food and Drug Administration

Since 1998, an increase of anti-erythropoietin (anti-EPO) antibody-induced pure red cell aplasia (PRCA) has been reported. As data up to now consisted mostly of spontaneously reported cases the question arose about the frequency of this increase in EPO-induced PRCA. The objectives of this study were to determine the incidence and causes of recombinant EPO hyporesponse, of antibodies to EPO in patients on dialysis, and to relate the detection of anti-EPO antibodies to the presence of PRCA.. This multicenter cohort study used existing patient data and serum samples collected at 6-month intervals from 1677 patients with incident end-stage renal disease (ESRD) participating in The Netherlands Cooperative Study on the Adequacy of Dialysis-2 (NECOSAD-2).. Fifty-seven patients had an inadequate EPO response, which resulted in an incidence of 16.7 per 1000 patient-years on EPO while on dialysis. All available sera specimens (N = 232) of these patients were screened for anti-EPO antibodies. The sera specimens of two of these 57 patients tested positive. Of the 57 patients with inadequate EPO response, one had clinical PRCA (incidence 0.29 per 1000 patient-years on EPO and on dialysis). Of the 1346 patients without symptoms of inadequate EPO response, one patient tested borderline positive for anti-EPO antibodies. In total, three patients developed EPO antibodies during follow-up, leading to an estimated incidence of 1.27/1000 (95% CI 0.3 to 3.7/1000) patient-years since the start of dialysis.. The incidence of inadequate EPO response in our population of dialysis patients is in concordance with tentative calculations found in the literature. Furthermore, we found the incidence of EPO-induced PRCA and EPO antibodies to be low.

Topics: Adult; Aged; Anemia; Antibodies; Cohort Studies; Erythropoietin; Female; Follow-Up Studies; Humans; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Seroepidemiologic Studies

Topics: Erythropoietin; Humans; Red-Cell Aplasia, Pure

Topics: Anemia; Antibodies; Erythropoietin; Humans; Polymorphism, Genetic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Autoantibodies; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Prognosis; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Risk Assessment; Severity of Illness Index

Topics: Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment; Treatment Outcome

The use of recombinant human erythropoietin (rHuEPO) is a major advance in the treatment of patients with anemia caused by chronic renal failure (CRF). The development of antierythropoietin (anti-EPO) antibodies following treatment with rHuEPO has been observed in an increasing number of patients. This causes pure red cell aplasia (PRCA) and requires the definitive withdrawal of rHuEPO. Many patients require immunosuppressive therapy before anti-EPO antibodies disappear completely. We report a case of PRCA owing to anti-EPO in a 20-year-old hemodialyzed man who was receiving immunosuppressive therapy for a liver transplantation carried out in childhood. He required repeated red cell transfusions until a kidney transplantation was performed. He received an induction therapy with antithymocyte globulins and a maintenance regimen consisting of steroids, tacrolimus and mycophenolate mofetil. This new immunosuppressive treatment led to the complete disappearance of anti-EPO antibodies within a few weeks after the kidney transplantation. Erythropoiesis and endogenous erythropoietin synthesis were restored following transplantation, without leading to an increase in the titer of anti-EPO antibodies.

Topics: Antilymphocyte Serum; Autoantibodies; Child; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Red-Cell Aplasia, Pure; Renal Dialysis

A report of neutralizing antibodies to recombinant human erythropoietin (rHuEPO) in European dialysis patients raised concerns that US dialysis patients may be at similar risk. We investigated the frequency of diagnosis codes that include pure red cell aplasia (PRCA) in the Medicare end-stage renal disease data.. Medicare claims data were used to identify incident dialysis patients from 1995 through 1999 aged 67 years or older who did not have a diagnosis code for aplastic anemia (AA; which includes PRCA) or were not administered rHuEPO before dialysis therapy initiation. Patients were assessed for complicating conditions, rHuEPO dose, hematocrit level, blood transfusion, bone marrow testing, and AA diagnosis (maximal follow-up, 13 months).. Of 101,782 patients eligible for study, 9,896 patients had diagnosis codes for AA after dialysis therapy initiation, 3,894 patients underwent bone marrow tests (required for PRCA diagnosis), 19 patients had diagnosis codes for AA based on bone marrow examination and no other complicating conditions, and 5 patients were administered blood transfusion in 1 or more months during follow-up, of whom only 1 patient had persistent low hematocrit levels while being administered rHuEPO and blood transfusion. This latter patient was identified from a total of 101,782 patients, or 70,706.75 person-years of rHuEPO exposure.. Diagnosis codes in the Medicare data are inadequate for the conclusive study of PRCA in US dialysis patients. Despite limitations of this study, it appears that few cases of rHuEPO-associated PRCA have occurred in US Medicare dialysis patients. Additional investigation is needed to determine whether apparent differences between US complication rates and those elsewhere result from differences in the manufacturing and/or use of erythropoietin products.

Topics: Aged; Aged, 80 and over; Blood Transfusion; Bone Marrow Examination; Erythropoietin; Female; Hematocrit; Humans; International Classification of Diseases; Kidney Failure, Chronic; Male; Medicare; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Retrospective Studies; United States

There have been several recent reports of pure red-cell aplasia (PRCA) mediated by anti-erythropoietin antibodies (AEA) in patients with chronic renal failure treated with recombinant human erythropoietin (EPO). Among the factors thought to trigger this mechanism is the subcutaneous administration of EPO. Despite this being the normal route of administration in patients undergoing peritoneal dialysis (PD), to date there has only been 1 described case of PRCA due to AEA in PD. Herein, we report such a case involving a patient in whom a diagnosis of anemia due to PRCA was particularly difficult to make because of concomitant rectal bleeding.

Topics: Antibodies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Creutzfeldt-Jakob Syndrome; Drug and Narcotic Control; Erythropoietin; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; North America; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment

Topics: Aged; Anemia, Refractory; Erythropoietin; Humans; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

From May 1998 to November 2000, 13 European patients developed antibody-mediated pure red cell aplasia during treatment with recombinant human erythropoietin (rHuEPO), reinforcing the need for analytical testing for antibodies against erythropoietic agents. Specimens from 8 patients were provided for further antibody testing and characterization.. We evaluated 4 analytical methods with these sera: radioimmune precipitation (RIP), enzyme-linked immunosorbent assay (ELISA), biosensor immunoassay, and a bioassay for identification of neutralizing antibodies.. The RIP, biosensor immunoassay, and biological assay performed equally to detect and quantify anti-rHuEPO antibodies. The ELISA failed to detect antibodies in 2 patient samples. The biosensor immunoassay could determine antibody isotypes, subclasses, and dissociation rates and the bioassay could determine whether these antibodies were able to neutralize the biological effect of the drug; the other assays could not make this determination.. We recommend the use of the biosensor immunoassay followed by a bioassay to best identify and characterize anti-rHuEPO antibodies. The biosensor immunoassay allows for identification of all classes and subclasses of immunoglobulins and is a preferred method for the identification of lower-affinity antibodies. The bioassay is needed to determine if the antibodies identified have the capacity to neutralize a biological effect of the drug in a cell-based system.

Topics: Antibodies; Antibody Specificity; Biological Assay; Biosensing Techniques; Enzyme-Linked Immunosorbent Assay; Epoetin Alfa; Erythropoietin; Humans; Immunoassay; Radioimmunoprecipitation Assay; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Aged; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Pure red cell aplasia is a rare complication of recombinant human erythropoietin (rHuEPO) treatment, which physicians should consider once the more frequent causes of hyporegenerative anemia have been excluded. To our knowledge, no pediatric cases have been described. In our patient, cyclosporin A treatment enabled a reduction in the number of transfusions and the risk of hyperimmunization. After transplantation, our patient's hemoglobin level has remained normal and stable.

Topics: Adolescent; Antibodies; Erythropoietin; Humans; Kidney Transplantation; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Recombinant human erythropoietin is the standard treatment for anaemia related to chronic kidney disease, and its widespread use has been favoured by a very high therapeutic index. However, since 1998, more than 200 patients worldwide with chronic kidney disease treated in this way have developed neutralising antibodies to erythropoietin, causing pure red cell aplasia. We aimed to collate clinical and pathological features in patients unequivocally shown to have erythropoietin-induced pure red cell aplasia.. We retrospectively obtained data from the files of 47 patients with pure red cell aplasia. We assessed treatment and outcome of patients and defined recovery from pure red cell aplasia as an increase in reticulocyte counts to more than 20 000 per microL in patients who were no longer transfusion-dependent.. When patients developed pure red cell aplasia, all were receiving erythropoietin subcutaneously, and the product most typically prescribed was epoetin alfa (Eprex, Ortho Biotech). The median delay between start of erythropoietin treatment and occurrence of pure red cell aplasia was 11 months (IQR 7.5-14). Nine patients received no immunosuppressive treatment, and none of these recovered. Of 37 patients who received immunosuppressive therapy, 29 (78%) recovered. All six patients who received a kidney transplant recovered within 1 month, and recovery rates were between 56% and 88% in patients treated with corticosteroids, corticosteroids plus cyclophosphamide, or ciclosporin. No relapse of pure red cell aplasia happened after stopping immunosuppressive treatment, but no patient was rechallenged with erythropoietin.. Immunosuppressive treatment accelerates recovery from erythropoietin-induced pure red cell aplasia.

Topics: Adrenal Cortex Hormones; Aged; Anemia; Erythropoietin; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Retrospective Studies

An 88-year old Japanese female with pure red cell aplasia was treated safely and effectively by a combination of thymectomy, cyclosporin A, and erythropoietin. The thymoma was histologically classified as lymphocytic type or cortical type, which are uncommon in cases of a thymoma accompanied by pure red cell aplasia. Immunohistochemical analysis of the thymoma and bone marrow revealed a predominance of CD8(+) cells. Thymectomy alone was ineffective, but cyclosporin A treatment subsequent to thymectomy was safe and effective and resulted in the disappearance of a Vbeta12 bearing T-cell clone in the bone marrow. Additional treatment with erythropoietin enhanced the effects of cyclosporin A and restored the patient's hemoglobin to normal levels. The beneficial effect of cyclosporin A may be attributed not to a broad immunomodulatory effect, but to a local effect on a limited T-cell subset.

Topics: Aged, 80 and over; Bone Marrow Cells; Cyclosporine; Erythropoietin; Female; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure; Thymectomy; Thymoma

Topics: Anemia; Anemia, Sickle Cell; Arteriovenous Shunt, Surgical; Blood Transfusion; Chronic Disease; Darbepoetin alfa; Diabetic Nephropathies; Disease Progression; Erythropoiesis; Erythropoietin; Europe; Evidence-Based Medicine; Ferritins; Hematocrit; Hematologic Tests; Hemoglobinometry; Hemoglobins; Hemorheology; Humans; Iron; Kidney Failure, Chronic; Nutritional Physiological Phenomena; Oxidative Stress; Quality of Life; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Review Literature as Topic; Transferrin; Treatment Failure; Vitamin E

Pure red-cell aplasia (PRCA) after erythropoietin (Epo) administration due to the appearance of neutralizing anti-Epo antibodies has been reported in over 200 cases between 1998 and 2002. However, large intercountry disparities were observed in the occurrence of this syndrome.. On behalf of the Swiss Society of Nephrology, a survey was conducted in all the dialysis units of Switzerland in order to collect information on the occurrence, diagnostic and evolution data of the cases observed. A questionnaire was send to the nephrologists in charge of each of the 69 dialysis units in January 2003. The clinical and biological data of the suspected cases were analysed and compared with the data provided to health authorities and pharmaceutical companies.. A total of five cases were identified as true PRCA with demonstrated positive anti-Epo antibodies. They occurred between November 1998 and February 2002, were all treated by haemodialysis and had received Epo subcutaneously. The median appearance time of refractory anaemia after Epo initiation was 10 months (range: 7-54 months). Two cases had been treated exclusively with epoietin-alpha, one solely with epoietin-beta and the two others with a combination of both. With five cases out of a total of about 2500 dialysis patients and 2300 Epo-treated dialysis patients or an exposure rate to Epo of 9900 dialysis patient-years during a 4.3 year period, this prevalence is among the highest of those reported in European countries.. The prevalence of PRCA after Epo administration in dialysis patients appears particularly high in Switzerland. Among the potential explanations, the most plausible are the high percentage of dialysis patients treated with Epo, the almost exclusive subcutaneous administration, the larger market distribution of the epoietin-alpha brand, the eventual disruption of the cold chain and the setting-up of a systematic national survey.

Topics: Aged; Antibodies; Erythropoietin; Female; Humans; Male; Middle Aged; Prevalence; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Switzerland

Topics: Aged; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Reticulocyte Count

Topics: Aged; Aged, 80 and over; Antibodies; Cyclosporine; Darbepoetin alfa; Drug Resistance; Epoetin Alfa; Erythropoietin; Humans; Immunosuppressive Agents; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Reticulocyte Count; Retreatment

Epoetin alfa (Eprex*; Johnson & Johnson, Manati, PR) has been used successfully to correct the anemia of chronic renal failure for more than 12 years. Anti-erythropoietin (anti-EPO) antibodies have been reported in a small number of patients, resulting in a blood disorder, pure red cell aplasia (PRCA). To evaluate the utility of a large-scale anti-EPO antibody screening program in patients with chronic kidney disease (CKD) administered epoetin alfa, a study involving 5 large renal centers in southern Ontario, Canada, was conducted.. More than 1,500 hemodialysis, peritoneal dialysis, and predialysis patients were screened for the prevalence of anti-EPO antibodies by means of a radioimmunoprecipitation (RIP) assay. Serum samples were drawn and shipped to PPD Development (Richmond, VA) for the immunoprecipitation assay. Serum EPO levels also were measured. All samples that tested positive or borderline for antibodies were sent to MDS Pharma Services (Montreal, Canada) for the neutralization assay.. Of 1,531 samples tested, 1 patient tested low-positive and 3 borderline results were detected by means of RIP. PRCA previously was diagnosed in the patient with the low-positive antibody level; the patient was treated with cyclosporine and currently is being administered epoetin alfa with good response. The 3 patients with borderline antibody results manifested no clinical signs of PRCA. Neutralization assays performed on all 4 serum samples were negative for anti-EPO antibodies.. Results from this surveillance study show that the prevalence of antibody to EPO in patients with CKD administered epoetin alfa in 5 Canadian renal centers is low, and the value of a large-scale antibody screening program for PRCA cannot be justified.

Topics: Aged; Aged, 80 and over; Anemia; Autoantibodies; Autoimmune Diseases; Cross-Sectional Studies; Cyclosporine; Epoetin Alfa; Erythropoietin; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Mass Screening; Middle Aged; Ontario; Peritoneal Dialysis; Population Surveillance; Radioimmunoprecipitation Assay; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Recombinant Human Erythropoietin (EPO) is extensively used for anemia in renal failure patients. It is normally safe and effective, improving symptoms of anemia. We report here a case of renal anemia in a patient undergoing peritoneal dialysis (PD) for end stage renal failure from renovascular disease. He initially responded well to Epoetin alpha (Eprex) but subsequently developed EPO antibodies and pure red cell aplasia (PRCA), becoming blood transfusion dependent. Subsequently, he responded to Darbepoetin alpha (Aranesp), without any complications in the presence of persisting EPO antibodies. This positive response, which restored hemoglobin values to normal, occurred despite general belief that any form of EPO will cross-react to EPO antibodies. This is the first case report where PRCA with EPO antibodies responded well to another EPO preparation without intervention from immunosuppression therapy.

Topics: Aged; Aged, 80 and over; Anemia; Antibodies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Antibodies; Erythropoietin; Humans; Micelles; Proteins; Red-Cell Aplasia, Pure

Topics: Australia; Canada; Contraindications; Drug and Narcotic Control; Erythropoietin; Europe; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

An 80-year-old man with chronic renal failure (CRF) had pure red cell aplasia (PRCA) 9 months after starting the subcutaneous administration of recombinant human erythropoietin alfa (rHuEPO-alpha). Owing to the advanced renal failure, conventional immunosuppressive therapies were not practicable. It was decided to administer rituximab (4 cycles of 375 mg/m2/wk). PRCA was treated successfully with rituximab. The administration of rHuEPO-alpha then was resumed via the intravenous route with a satisfactory correction of anemia (12 months after the EPO-alpha rechallenge the patient is still transfusion independent). To the authors' knowledge, this is the first report of (1) a successful treatment with rituximab with CD20 depletion in a CRF patient with PRCA and (2) a successful intravenous resumption of the same rHuEPO-alpha.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Rituximab

Pure red cell aplasia (PRCA) caused by neutralising anti-erythropoietin antibodies is a very rare disease. Since 1998, an increased incidence of PRCA in patients with kidney failure following treatment with recombinant human erythropoietin (rhEpo) has been reported, mostly in Europe. In most cases, PRCA was cured by immunosuppressive therapy, immunoglobulins, plasmapheresis or renal transplantation. We report an exceptionally prolonged course of PRCA over 68 months despite renal transplantation and different immunosuppressive regimens.

Topics: Adult; Antibodies; Erythropoietin; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Recombinant Proteins; Red-Cell Aplasia, Pure; Time Factors; Treatment Failure

Topics: Adverse Drug Reaction Reporting Systems; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Between 1988 and 1998, antibody-associated pure red-cell aplasia was reported in three patients who had undergone treatment with recombinant human erythropoietin (epoetin). Between 1998 and 2000, 13 such cases were reported from France--12 in patients who had received the Eprex formulation of epoetin alfa and 1 in a patient who had received Neorecormon (a formulation of epoetin beta); both are products that are marketed outside the United States.. We obtained reports of epoetin-associated pure red-cell aplasia from the Food and Drug Administration and from the manufacturers of Eprex, Epogen (another formulation of epoetin alfa), and Neorecormon. The numbers of case reports and estimates of exposure-adjusted incidence were analyzed according to the product, the cause of anemia, the route of administration, the country in which pure red-cell aplasia was identified, and the date on which pure red-cell aplasia was reported.. Between January 1998 and April 2004, 175 cases of epoetin-associated pure red-cell aplasia were reported for Eprex, 11 cases for Neorecormon, and 5 cases for Epogen. Over half these cases had occurred in France, Canada, the United Kingdom, and Spain. Between 2001 and 2003, the estimated exposure-adjusted incidence was 18 cases per 100,000 patient-years for the Eprex formulation without human serum albumin, 6 per 100,000 patient-years for the Eprex formulation with human serum albumin, 1 case per 100,000 patient-years for Neorecormon, and 0.2 case per 100,000 patient-years for Epogen. After procedures were adopted to ensure appropriate storage, handling, and administration of Eprex to patients with chronic kidney disease, the exposure-adjusted incidence decreased by 83 percent worldwide.. After the peak incidence of Eprex-associated pure red-cell aplasia was reached in 2001, interventions designed in response to drug-monitoring programs worldwide resulted in a reduction of more than 80 percent in the incidence of pure red-cell aplasia due to Eprex.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure

Since 1998, there has been a marked increase in incidence of pure red cell aplasia secondary to development of anti-erythropoietin antibodies (Ab+ PRCA) in patients who have chronic kidney disease (CKD) and receive recombinant erythropoietin. The relationship between incidence of Ab+ PRCA and specific erythropoietin products has not been examined rigorously. Manufacturers provided data regarding exposure to erythropoietin products and incidence of Ab+ PRCA between January 1998 and March 2003 in patients with CKD. Assuming a Poisson distribution, a maximum likelihood estimate for the Poisson rate parameter was calculated for each product. A test for homogeneity of Poisson rates was conducted to compare likelihood estimates between products. Global incidence of Ab+ PRCA was relatively low. Likelihood estimates were not significantly different for Epogen, Procrit, and Aranesp, independent of their formulation or route of administration. Eprex lacking human serum albumin (HSA) and administered subcutaneously was associated with the greatest risk of Ab+ PRCA. HSA-containing Eprex administered subcutaneously was associated with a lower risk than HSA-free Eprex administered subcutaneously, but this risk exceeded that of intravenous Epogen and intravenous HSA-free Eprex. NeoRecormon administered subcutaneously was associated with less risk than subcutaneous HSA-free Eprex but more risk than intravenous Epogen. HSA-free Eprex should not be administered subcutaneously to patients with CKD due to increased risk of Ab+ PRCA. Although the subcutaneous administration of HSA-containing Eprex is riskier than intravenous Epogen and intravenous HSA-free Eprex, and the use of subcutaneous NeoRecormon is riskier than intravenous Epogen, there is currently no evidence that other products are safer.

Topics: Age Distribution; Autoantibodies; Cohort Studies; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Health Planning Guidelines; Humans; Kidney Failure, Chronic; Male; Prevalence; Primary Prevention; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment; Severity of Illness Index; Sex Distribution

Topics: Aged; Antibodies; Antibodies, Monoclonal; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Reticulocyte Count; Retreatment

We report a case of pure red cell aplasia (PRCA) following allogeneic stem cell transplantation (SCT) with major ABO mismatch which proved resistant to all standard treatment options such as change in immunosuppressive treatment, high-dose erythropoietin (EPO) or plasma exchange. We therefore proceeded to administer five cycles of Rituximab therapy, without success. Finally, escalating doses of donor-derived leukocyte infusion (DLI) resolved the PRCA of our patient 415 d after bone-marrow transplantation (BMT) and 140 d after the first infusion of donor leukocytes. A review of the literature shows the efficacy of various treatments; the role of DLI and other treatment options are discussed. Furthermore, the underlying pathophysiological mechanisms especially with regard to the role of NK cells in alloreactivity after allogeneic SCT are explained.

Topics: ABO Blood-Group System; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Blood Group Incompatibility; Blood Transfusion; Combined Modality Therapy; Cytarabine; Drug Resistance; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Immunosuppressive Agents; Killer Cells, Natural; Leukemia, Myelomonocytic, Acute; Leukocyte Transfusion; Male; Middle Aged; Plasmapheresis; Red-Cell Aplasia, Pure; Remission Induction; Rituximab; Transplantation, Homologous

Assays for the analysis of antierythropoietin antibodies (anti-EPO Abs) currently suffer from a high degree of nonspecificity or are cumbersome and time consuming to perform. They are therefore not well suited for the analysis of large numbers of human sera samples, a task that has become increasingly important due to an increase in the number of patients developing anti-EPO Abs. The objective of this study was to develop and validate a sensitive and specific ELISA for the determination of anti-EPO Abs that would suit these purposes. In this new double antigen bridging ELISA, anti-EPO Abs bind via one site to recombinant human erythropoietin (rhEPO)-biotin immobilized to streptavidin-coated microtiter plates (MTPs) and by a second site to rhEPO labelled with digoxigenin (DIG). The amount of bound antibody is determined using an anti-DIG antibody coupled to peroxidase. A rabbit polyclonal anti-EPO Ab purified by immunoadsorption is used as reference antibody preparation. The dynamic range of this ELISA was 1-75 ng/ml per assay calibrated with the reference antibody preparation. The assay was specific for anti-EPO Abs and did not react with other immunoglobulins (Ig) present in human serum. The lower limit of detection (LLD) of the assay was 0.5 ng/ml, and the lower limit of quantitation (LLQ) was 1.0 ng/ml. Anti-EPO Abs could be detected in the sera of pure red cell aplasia (PRCA) patients. In contrast to previous reports, no anti-EPO Abs could be detected in the sera of patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome (SS), or in the sera of dialysis patients.

Topics: Animals; Antibodies; Biotin; Digoxigenin; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Humans; Lupus Erythematosus, Systemic; Peroxidase; Rabbits; Recombinant Proteins; Red-Cell Aplasia, Pure; Reference Standards; Reference Values; Renal Dialysis; Reproducibility of Results; Sensitivity and Specificity; Sjogren's Syndrome; Streptavidin

Topics: Antibody Formation; Epoetin Alfa; Erythropoietin; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure

A 73-year-old man, a 73-year-old woman, and a 57-year-old man with anaemia due to renal insufficiency were treated with epoetin. After 6-12 months, the haemoglobin level decreased despite dosage increases, after which the patients became dependent on regular transfusions of concentrated erythrocytes. The older man died from peritonitis following diagnostic examination because of the anaemia. The woman died from septic shock, even though epoetin had been replaced by darbepoetin. The haemoglobin level in the younger man returned to normal after the presence of antibodies against epoetin had been demonstrated, he had stopped using the drug, and he had started on immunosuppressive therapy following kidney transplantation. Since 1998, the number of patients with epoetin resistance due to the development of antibodies against the drug (epoetin-induced pure red-cell aplasia) has increased. This complication should be considered in every patient treated with epoetin who experiences unexplained transfusion-dependent anaemia.

Topics: Aged; Anemia; Antibodies; Drug Hypersensitivity; Erythrocyte Transfusion; Erythropoietin; Fatal Outcome; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency

Topics: Erythropoietin; Humans; Injections, Intravenous; Injections, Subcutaneous; Recombinant Proteins; Red-Cell Aplasia, Pure

Human recombinant erythropoietin is the main treatment for anemia in renal patients. Recently, there have been case reports of pure red blood cell aplasia (PRCA) developing in renal patients administered erythropoietin, probably because of neutralizing antibodies detected in all these patients. All reports were from the West, and most patients were treated with erythropoietin-alpha. Cyclosporine is an immunosuppressive agent used to treat a spectrum of autoimmune conditions. We report a series of Chinese renal patients who developed PRCA after treatment with erythropoietin-alpha, suggesting that this is a problem worldwide. They were treated successfully with cyclosporine and became transfusion independent.

Topics: Aged; Asian People; Cyclosporine; Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Anemia; Critical Illness; Erythrocyte Transfusion; Erythropoietin; Hemoglobins; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Antibody Formation; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure; Time Factors

Topics: Aged; Anemia; Antibodies; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Anemia; Cost-Benefit Analysis; Erythropoietin; Humans; Injections, Intravenous; Injections, Subcutaneous; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

In 1993 a Concerted EU Action was started to coordinate research concerning the immunogenicity of biopharmaceuticals bringing together researchers from academia and industry. The main topic of this concerted action has been interferon alpha. The factors influencing its immunogenicity were studied. Blind panel testing of patients' sera showed large differences in reported titres as an important variable in different studies. The EMEA has requested the three marketing authorization holders of interferon beta to develop a common assay for antibodies to this product. The status of this project will be discussed. The occurrence of about 30 cases of pure red cell aplasia related to antibodies induced by erythropoietin treatment will also be reported.

Topics: Biological Factors; Biopharmaceutics; Erythropoietin; European Union; Humans; Interferon-beta; Marketing; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Epoetin Alfa; Erythropoietin; Excipients; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure; Serum Albumin

In a patient with chronic renal failure due to diabetes mellitus pure red-cell aplasia developed during treatment with erythropoietin (epoetin alfa). The treatment with erythropoietin was stopped and immunosuppressive therapy resulted in normalisation of the bone marrow function and increase of the Hb level to normal values. Pure red cell aplasia which develops during treatment with erythropoietin has recently been reported in a few other patients with anaemia due to chronic renal failure. Hitherto our patient is the first case reported in Denmark.

Topics: Epoetin Alfa; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Remission, Spontaneous

Topics: Anemia; Autoimmune Diseases; Clinical Trials as Topic; Doping in Sports; Erythropoietin; Humans; Kidney Diseases; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome; Uremia

We report the case of a woman with end-stage renal disease on maintenance hemodialysis and treated with recombinant human erythropoietin (epoetin alfa) administered subcutaneously, who developed a pure red cell aplasia secondary to the development of neutralizing antibodies anti-erythropoietin after 8 months of treatment. Despite epoetin withdrawal and immunosuppressive treatment with corticosteroids and gammaglobulins the patient still has high red blood cell transfusion requirements and undetectable plasma erythropoietin levels. Pure red cell aplasia secondary to the development of neutralizing antibodies anti-erythropoietin is a rare but severe complication associated with the use of recombinant human erythropoietin in uremic patients. In recent years, the incidence of this complication has sharply increased, specially associated with the use of epoetin alfa administered subcutaneously. For this reason, the Spanish Drug Agency has recently contraindicated treating uremic patients with epoetin alfa administered subcutaneously.

Topics: Adult; Autoantibodies; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Uremia

Topics: Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Antibody Formation; Chemistry, Pharmaceutical; Drug Administration Routes; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

A 68-year-old male had end-stage renal disease secondary to hypertension. He was placed on chronic dialytic therapy and was given recombinant human erythropoietin (epoetin) for renal anemia. One month later, rapidly progressing anemia was noted. The anemia was unresponsive to maximal doses of epoetin and the patient soon became transfusion-dependent. Erythroid hypoplasia was demonstrated by bone marrow biopsy. A detailed search for the cause of the erythroblastopenia revealed nothing. A diagnosis of acquired pure red cell aplasia was made. The use of immunosuppressive agents improved the patient's symptoms and laboratory data. Antibodies for erythropoietin (EPO) were negative after the treatment. It is suggested that patients with EPO-resistant anemia with no obvious etiology should be examined for underlying hematologic disorders.

Topics: Aged; Erythropoietin; Humans; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Topics: Anemia, Aplastic; Erythropoiesis; Erythropoietin; Humans; Neoplasms; Recombinant Proteins; Red-Cell Aplasia, Pure

A line of transgenic mice overexpressing erythropoietin was created. These mice retained their capacity to reduce their gastro-intestinal absorption of iron and to regulate the changes in their iron metabolism and they could serve as a model for the in vivo study of iron homeostasis and erythropoiesis. NEW INDICATIONS FOR RECOMBINANT HUMAN ERYTHROPOIETIN: After chronic terminal kidney failure, the treatment of chronic dialysed kidney failure patients and patients treated with azathioprine or patients having undergone surgery and requiring transfusion, other indications have been proposed. Such as anaemia in children following inadequate production of endogenous erythropoietin and/or direct inhibition of the erythroid cell line in the bone marrow or anaemia during pregnancy and, since the Sixties, anaemia during cancer. TO ASSESS THE PHYSIOPATHOLOGY OF ANEMIA:In anaemic patients suffering from a malignant blood disease, it would be useful to calculate the relationship between the predicted and observed rates of erythropoietin as well as the transferin serum receptors.

Topics: Adult; Anemia, Aplastic; Animals; Child; Erythropoiesis; Erythropoietin; Female; Humans; Male; Mice; Mice, Transgenic; Neoplasms; Pregnancy; Receptors, Transferrin; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

IMPROVED QUALITY OF LIFE WITH EPOETIN BETA: In a study against a placebo, there was evidence that the quality of life scores were significantly improved in patients treated with epoetin beta, whether they exhibited a solid tumour or a malignant lymphoma. The same was noted in children with cancer exhibiting severe neoplasia and treated with chemotherapy. The efficacy and tolerance to treatment were equivalent, whatever the administration regimen. IN PATIENTS SUFFERING FROM MYELODYSPLASTIC SYNDROMES: A particular entity among malignant blood diseases, myelodysplastic syndromes are at the origin of anaemia against which repeated transfusions and growth factors are proposed with varying results and disadvantages, and against which erythropoietin may be moderately effective (a mean of 25% in non-selected cohorts of patients). DEPENDING ON THE PROTOCOLS OF ERYTHROPOIETIN ADMINISTRATION IN CASES OF MYELODYSPLASTIC SYNDROMES: Recombinant human erythropoietin, irrespective of its concentration in myelodysplastic cell culture, does not appear capable of restoring normal erythropoiesis. The influence of prolonged treatment is not admitted by all. The effects of the addition of growth factors (notably G-CSF) are obvious but some are controversial because of the costs and the prolonged duration of such treatments.

Topics: Adult; Anemia, Aplastic; Blood Transfusion; Child; Erythropoiesis; Erythropoietin; Hemoglobinometry; Humans; Myelodysplastic Syndromes; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

PURE RED CELL APLASIA: Designated by the acronym PRCA or the term erythroblastopenia, pure red cell aplasia is characterised by severe anaemia with reticulocytopenia. It may occur in acute form induced by infectious agents, following drug toxicity or transplantation of allogeneic haematopoietic cells, associated with autoimmune haemolytic anaemia. The chronic form is rarely constitutional but can be acquired and is usually associated with blood or idiopathic diseases. IMMUNOLOGICAL INHIBITION OF ERYTHROPOIESIS: Among the mechanisms responsible for PRCA is immunological erythropoiesis inhibition. This may be of lymphocyte T cell origin or due to the presence of antibodies in the patient's serum. Although observations of PRCA with presence of neutralising antierythropoietin antibodies in patient's serum have multiplied over the past 5 years, they still remain extremely rare. From a therapeutic point of view, they require withdrawal of epoetin and often the administration of immunosuppressors and transfusion for symptomatic treatment. GROWTH FACTORS: The role of growth factors in restoring aplastic anaemia appears to be only partial, at random and temporary.

Topics: Acute Disease; Anemia, Aplastic; Autoantibodies; Chronic Disease; Erythropoietin; Humans; Immunosuppressive Agents; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors

THE DEBATE: Although some believe that rHu-EPO should not be widely used in malignant affections, others think that because of the varied impact of these anaemia, its wider use should be recommended. FOR A TARGET USE: Various observations (influence of the degree of extension of the myelomas to the skeleton and response to specific treatment in the case of myeloma, whatever the haemoglobin concentration, degree of prevention of rHu-EPO chemo-induced anaemia) are in favour of its use in selected patients. FOR A WIDER USE: The benefits of treatment with rHu-EPO are not limited to the symptomatology of anaemia but extend to its potential complications in the most fragile patients. Other than the risks of infection, the heavy costs of transfusions must also be taken into account.

Topics: Anemia, Aplastic; Blood Transfusion; Cost-Benefit Analysis; Erythropoietin; Hemoglobinometry; Humans; Multiple Myeloma; Neoplasms; Prognosis; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Anemia, Aplastic; Blood Transfusion; Erythropoietin; Humans; Neoplasms; Quality of Life; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Child; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Biotechnology; Drug Approval; Drug Industry; Drugs, Generic; Erythropoietin; European Union; Humans; Kidney Failure, Chronic; Micelles; Product Surveillance, Postmarketing; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Biotechnology; Drug Approval; Drug Industry; Drugs, Generic; Erythropoietin; European Union; Humans; Kidney Failure, Chronic; Micelles; Product Surveillance, Postmarketing; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Erythropoietin; Health Planning Guidelines; Humans; Injections, Intravenous; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Aged; Anemia; Autoantibodies; Diagnosis, Differential; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

A 66-year-old Japanese man developed severe anemia and erythroid hypoplasia in bone marrow without any significant underlying disease. The results of an antiglobulin test were strongly positive, and serum erythropoietin (Epo) was high. The patient was diagnosed as having acquired pure red cell aplasia (PRCA) and was treated with steroids. Anemia was subsided by reticulocyte production in parallel with a decrease in the titer of antiglobulin test and the level of Epo. We studied the immunological mechanism directed against erythroid cells in vitro by using the patient's serum. In vitro analysis indicated the presence of an inhibitor of erythroid precursors at onset, and its disappearance at remission, suggesting the presence of inhibitor against erythroid precursors.

Topics: Aged; Anti-Inflammatory Agents; Bone Marrow Examination; Coombs Test; Erythroid Precursor Cells; Erythropoietin; Humans; Male; Methylprednisolone; Prednisolone; Red-Cell Aplasia, Pure; Tumor Cells, Cultured

Recent concern has arisen about the development of neutralizing anti-erythropoietin (EPO) antibodies during the course of treatment with recombinant EPO. The underlying mechanisms are poorly understood. A patient was observed who developed wheals at the sites of subcutaneous injections of epoetin-alpha before the manifestation of pure red cell aplasia (PRCA). Intravenous application of different epoetins evoked skin reactions at the sites of former subcutaneous injections, indicating local persistence of sensitized cells, and eventually a systemic anaphylactoid response. Anti-EPO antibodies crossreactive with epoetin-beta and darbepoetin-alpha were demonstrated in patient serum. PRCA gradually improved after treatment with prednisolone.

Topics: Autoantibodies; Drug Eruptions; Erythropoietin; Humans; Injections, Subcutaneous; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Antibodies; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Antibodies; Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Receptors, Erythropoietin; Recombinant Proteins; Red-Cell Aplasia, Pure

ABO incompatibility in allogeneic bone marrow transplantation may be associated with incomplete or delayed erythroid engraftment, being pure red cell aplasia (PRCA) the most severe complication in this setting. Attempts for the treatment of PRCA have been made with erythropoietin or with plasmapheresis with relative success, and some authors have reported the reversibility of PRCA with antilymphocyte globulin (ALG or ATG), based on the assumption that PRCA might be immunologically mediated. We report herewith a patient with acute leukemia who developed post--BMT pure red cell aplasia. His sibling donor (sister) was HLA identical and ABO incompatible, having low agglutinin titers against donor's blood group. PRCA did not improve after treatment with erythropoietin or a boost of hematopoietic progenitor cells obtained from donor's peripheral blood but the problem was resolved completely after treatment with ALG.

Topics: ABO Blood-Group System; Adolescent; Antilymphocyte Serum; Blood Group Incompatibility; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Red-Cell Aplasia, Pure; Transplantation, Homologous

Within a period of three years, we identified 13 patients in whom pure red-cell aplasia developed during treatment with recombinant human erythropoietin (epoetin). We investigated whether there was an immunologic basis for the anemia in these patients.. Serum samples from the 13 patients with pure red-cell aplasia were tested for neutralizing antibodies that could inhibit erythroid-colony formation by normal bone marrow cells in vitro. The presence of antierythropoietin antibodies was identified by means of binding assays with the use of radiolabeled intact, deglycosylated, or denatured epoetin.. Serum from all 13 patients blocked the formation of erythroid colonies by normal bone marrow cells. The inhibition was reversed by epoetin. Antibodies from 12 of the 13 patients bound only conformational epitopes in the protein moiety of epoetin; serum from the remaining patient bound to both conformational and linear epitopes in erythropoietin. In all the patients, the antibody titer slowly decreased after the discontinuation of treatment with epoetin.. Neutralizing antierythropoietin antibodies and pure red-cell aplasia can develop in patients with the anemia of chronic renal failure during treatment with epoetin.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Bone Marrow Cells; Cell Division; Epoetin Alfa; Erythroid Precursor Cells; Erythropoietin; Humans; Iodine Radioisotopes; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Autoantibodies; Autoimmune Diseases; Epoetin Alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Canada; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Product Surveillance, Postmarketing; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Clinical Trials as Topic; Drug Industry; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Europe; Humans; Infusions, Intravenous; Prevalence; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment

Topics: Adult; Autoantibodies; Autoimmune Diseases; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Immunoglobulin G; Infant, Newborn; Isoantibodies; Red-Cell Aplasia, Pure; Risk; Safety

Topics: Aged; Anemia; Drug Hypersensitivity; Erythropoietin; Female; Humans; Red-Cell Aplasia, Pure

Topics: Adverse Drug Reaction Reporting Systems; Anemia; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; United States

Topics: Arteriosclerosis; Autoantibodies; Cardiovascular System; Erythropoietin; Humans; Kidney Failure, Chronic; Red-Cell Aplasia, Pure; Renal Dialysis

Topics: Acute Disease; Adult; Antibodies; Diagnosis, Differential; Erythropoietin; Female; Humans; Lupus Erythematosus, Systemic; Red-Cell Aplasia, Pure

Warm autoimmune hemolytic anemia (AIHA) is a condition in which peripheral red blood cell (RBC) destruction is induced by the presence of an autoantibody. Pure red cell aplasia (PRCA) represents an isolated process of decreased erythropoiesis. The combination of both is quite rare, with a very poor prognosis. We describe a patient with isolated splenic lymphoma whose presentation was a combination of AIHA and PRCA. The patient was resistant to all treatment.. Erythroid colony assays were performed, in order to compare the effect of the patient's serum on colonies with that of a normal control.. The patient's serum significantly suppressed normal erythroid colony growth. A red cell eluate revealed the presence of a warm autoantibody.. The patient's serum contained warm autoantibody responsible for peripheral RBC destruction and a humoral factor, perhaps the warm autoantibody, which suppressed bone marrow erythropoiesis. Establishing an early diagnosis, and treatment of the underlying disease might result in a better prognosis.

Topics: Anemia, Hemolytic, Autoimmune; Antineoplastic Agents; Autoantibodies; Cell Division; Coombs Test; Diagnosis, Differential; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Lymphoma; Middle Aged; Red-Cell Aplasia, Pure; Sepsis; Splenectomy; Splenic Neoplasms

We have characterized the proliferation kinetics of hematopoietic cells in long-term marrow cultures (LTMC) from five normal children and seven children with congenital bone marrow failure (four with Fanconi anemia [FA] and three with congenital pure red cell aplasia [PRCA]). Total nonadherent and adherent cells, as well as nonadherent progenitors, were determined weekly in the presence or in the absence of rhGM-CSF (10 ng/ml) or rhEPO (3 U/ml). As compared to normal LTMC, hematopoiesis was drastically reduced in cultures from FA patients. Myeloid and erythroid progenitor cells reached undetectable levels after only 3 and 1 weeks of culture, respectively. This was observed even in cultures supplemented with rhGM-CSF, in which no response to this cytokine occurred. In LTMC from PRCA children, the growth of erythroid and multipotent progenitors was also drastically reduced. Myelopoiesis, on the other hand, showed normal levels during the first three weeks of culture; however, from week 4, there was a significant decrease in the levels of both progenitor and mature cells, reaching undetectable levels several weeks before normal cells did. Response to rhGM-CSF and rhEPO was transient and deficient. Our results suggest that in FA, alterations at the level of primitive progenitor cells are so severe that myeloid, erythroid and multipotent progenitors are unable to proliferate in LTMC, even in the presence of rhGM-CSF. In patients with PRCA the erythroid arm of hematopoiesis is preferentially affected and addition of rhGM-CSF and/or rhEPO to these cultures had little or no effect on erythroid cell production. Interestingly, myelopoiesis in this culture system was deficient as well and response to rhGM-CSF was defective, suggesting that the myeloid lineage is also altered in congenital PRCA.

Topics: Bone Marrow Cells; Bone Marrow Diseases; Cell Adhesion; Cell Division; Cell Nucleus; Cells, Cultured; Child; Child, Preschool; Erythropoietin; Fanconi Anemia; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Kinetics; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Antigens, CD; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; CD4-CD8 Ratio; Cyclosporine; Erythropoietin; Hemoglobins; Humans; Immunoglobulins, Intravenous; Immunophenotyping; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Prednisone; Red-Cell Aplasia, Pure; Vidarabine

In this case report we describe two patients with pure red cell aplasia (PRCA) as an initial manifestation of systemic lupus erythematosus (SLE). Antibodies to erythropoietin were determined, by an ELISA method developed in our laboratory, in frozen serum obtained from one of the patients. A high titer of antibodies to erythropoietin was detected in serum obtained before treatment with high dose intravenous immunoglobulin (IVIG). The antibody titer declined after successful treatment. This observation suggests that antibodies to erythropoietin may contribute to the pathogenesis of SLE associated PRCA.

Topics: Adult; Antibodies; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Lupus Erythematosus, Systemic; Red-Cell Aplasia, Pure

To report a case of post-allogeneic peripheral blood stem cell transplantation (allo-PBSCT) pure red cell aplasia(PRCA) and the treatment outcome.. A patient with acute non-lymphoblastic leukemia(M2a) was treated with allo-PBSCT. His post-PBSCT PRCA was treated with plasmapheresis(2-3 times weekly) and Epo(3,000 U/day, subcutaneously).. Reticulocyte count (Ret) recovered to 0.01 at day +131 and hemoglobin reached 110 g/L at day +154. Erythroid cells in the bone marrow recovered to 0.25, and BFU-E and CFU-E within normal range. This normalized hematopoiesis remained for over 5 months after the cessation of Epo.. Post allo-PBSCT PRCA can be successfully treated with plasma exchange and Epo.

Topics: Adult; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Plasma Exchange; Red-Cell Aplasia, Pure

Recombinant human erythropoietin (rHuEPO) is used extensively in anemic patients on dialysis and other patients and is regarded as very safe and effective in the management of anemia in these patients. To date, there is no report on the development of antibodies to rHuEPO in the patients treated with this drug. We report here a patient who developed antibodies to rHuEPO and as a result developed pure red cell aplasia. A 63-year-old black male with end-stage renal disease secondary to hypertension was placed on chronic dialytic therapy and tolerated rHuEPO treatment well for two years. A rapidly progressive anemia was then noted which was unresponsive to maximal doses of rHuEPO and the patient soon became transfusion-dependent. Bone marrow examination revealed paucity of red cell precursors. A detailed search for the cause of this pure red cell aplasia was unrevealing. Serological tests for Parvovirus B19 infection were negative. Antibodies for rHuEPO were tested by radioimmuno-precipitation assay and were found positive. In the course of several months, the antibody titer declined spontaneously to negligible levels with simultaneous improvement in the anemia and reappearance of red cell precursors in the bone marrow. This is the first patient to be reported who formed antibodies to rHuEPO and as a consequence developed pure red cell aplasia. Thus we conclude that although very rare, antibody production to rHuEPO should be considered in evaluating patients with EPO-resistant anemia with no obvious etiology.

Topics: Antibody Formation; Erythropoietin; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Topics: Aged; Autoantibodies; Bone Marrow; Bone Marrow Cells; Erythropoietin; Female; Humans; Red-Cell Aplasia, Pure

Topics: Aged; Aged, 80 and over; Blood Transfusion; Chlorambucil; Cyclosporine; Erythropoietin; Follow-Up Studies; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Prednisone; Receptors, Transferrin; Recombinant Proteins; Red-Cell Aplasia, Pure; Reticulocyte Count

A 34-year-old man with acute myelocytic leukemia (AML: MO) and a 32-year-old woman with AML: M2 developed pure red cell aplasia (PRCA) after receiving a major ABO incompatible bone marrow transplant (BMT). The first patient responded to recombinant human erythropoietin (rhEPO) therapy, while the second did not. The second patient also received methylprednisolone (m-PSL) but developed reticulocytosis and hemolysis after the administration of m-PSL. Plasmapheresis was then performed and the patient promptly recovered from hemolysis and PRCA. We conclude that close attention must be paid when treating PRCA following major ABO-incompatible BMT with rhEPO and m-PSL, as there is always the potential for massive hemolysis.

Topics: ABO Blood-Group System; Acute Disease; Adult; Blood Group Incompatibility; Bone Marrow Transplantation; Erythropoietin; Female; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Models, Immunological; Recombinant Proteins; Red-Cell Aplasia, Pure; Remission Induction; Transplantation, Homologous

Systemic disorders, often immune in nature, can sometimes be associated with the presence of thymic pathology. Thymic enlargement due to lymphoid hyperplasia or thymoma is a common occurrence in patients with myasthenia gravis. In patients with pure red cell aplasia, at least 10% to 15% of patients are found to have thymoma, usually of spindle cell or medullary type. Pure red cell aplasia with demonstrable thymic enlargement due to lymphoid follicular hyperplasia is distinctly unusual, and has not been previously reported. The authors report such a case developing in a patient with end-stage renal failure maintained on hemodialysis and erythropoietin therapy. Because the red cell aplasia resolved after thymectomy, the disease process was considered etiologically related to the reactive lymphoid hyperplasia.

Topics: Adult; Drug Resistance; Erythropoietin; Female; Humans; Hyperplasia; Kidney Failure, Chronic; Red-Cell Aplasia, Pure; Thymoma; Thymus Gland

In most patients with Diamond-Blackfan anaemia (DBA) the addition of IL-3 to in vitro cultures increases the number of erythroid progenitors. However, a small proportion of patients show an erythroid response to in vivo administration of IL-3. We treated two adult patients with corticosteroid-refractory DBA, who had shown a clear in vitro erythroid response to IL-3, with increasing doses of IL-3 (from 2.5 to 10 micrograms/kg/d) by subcutaneous injections for 7 and 9 weeks. Monitoring of marrow and circulating progenitors showed a sustained elevation of BFU-E and CFU-E as well as an increase of other progenitors and CD34+ cells during therapy. However, this effect did not translate into a clear clinical response, although transfusion requirements decreased transiently in one patient. This report shows that a sustained elevation of erythroid progenitors induced by in vivo IL-3 administration may not translate into an increase of mature red cells production in DBA patients.

Topics: Adult; Bone Marrow; Dose-Response Relationship, Immunologic; Erythroid Precursor Cells; Erythropoietin; Fanconi Anemia; Female; Hematopoietic Stem Cells; Humans; Interleukin-3; Middle Aged; Red-Cell Aplasia, Pure

Pure erythrocyte aplasia is a recognised feature of systemic lupus erythematosus (SLE); here we report two cases, one predating the onset of SLE, the other following a long period of disease quiescence. One case demonstrates the typical features of this disorder and was successfully treated with prednisolone. The second case is unusual in being resistant to immunosuppressive treatment. Bone marrow culture from the second patient revealed an inhibition of BFU-E colony formation in the presence of the patient's serum, indicating that a serum inhibitor of haemopoiesis was present. Furthermore, following T cell depletion of this patient's marrow, there was an increase in BFU-E, CFU-G and CFU-GM colony growth implicating, in addition, a possible T cell-mediated inhibition of marrow haemopoiesis. This is a novel observation and may explain the resistance shown by this patient to standard treatment.

Topics: Adult; Blood Transfusion; Bone Marrow; Cells, Cultured; Colony-Forming Units Assay; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Hemoglobins; Humans; Interleukin-3; Lupus Erythematosus, Systemic; Puerperal Disorders; Red-Cell Aplasia, Pure

A male patient suffered chronic renal failure due to lupus nephritis and was undergoing hemodialysis. Six years after beginning hemodialysis, anemia developed, which improved by erythropoietin. Unresponsiveness to erythropoietin gradually appeared, and with a suspicion of pure red cell aplasia, he was treated with a high-dose corticosteroid but the unresponsiveness did not improve. Neither his serum nor lymphocytes inhibited erythropoiesis of either normal bone marrow stem cells or his own in vitro. These observations suggest an impaired hematopoietic microenvironment in his bone marrow.

Topics: Adrenal Cortex Hormones; Adult; Chronic Disease; Colony-Forming Units Assay; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Lupus Nephritis; Male; Red-Cell Aplasia, Pure; Renal Dialysis

Acquired pure red cell aplasia (PRCA) has been associated with various lymphoproliferative conditions but its occurrence with Hodgkin's disease is rare. We report a case of PRCA occurring immediately following the completion of induction chemotherapy in a patient with Stage IIIB nodular sclerosing Hodgkin's disease. In vitro erythroid colony studies documented evidence for T cell mediated suppression of erythropoiesis and lack of a serum inhibitor. Addition of cyclosporin to the in vitro cultures stimulated erythroid colony growth. Following in vivo treatment with cyclosporin peripheral blood CD4/CD8 ratios returned to normal. However, serum erythropoietin levels were inappropriately low. Subsequent treatment with erythropoietin induced a reticulocytosis and transfusion independence. Since discontinuing the erythropoietin, the patient has been able to maintain a hemoglobin of 100 g/L. This case illustrates that red cell aplasia occurring in the setting of Hodgkin's disease may be due to T cell mediated suppression of erythropoiesis. A response to cyclosporin may be masked by inappropriately low erythropoietin levels.

Topics: Adult; Colony-Forming Units Assay; Cyclosporine; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Hodgkin Disease; Humans; Red-Cell Aplasia, Pure; T-Lymphocytes

A case of pure red cell aplasia after major ABO-incompatible bone marrow transplantation with long duration of up to 482 days is presented. The patient exhibited resistance to treatment using intravenous gamma globulin, prednisolone and 8 week administration of erythropoietin. The patient finally responded to treatment using erythropoietin and methylprednisolone simultaneously. Because of its safety and efficacy, it might be worthwhile to try erythropoietin with methylprednisolone, if necessary, for pure red cell aplasia complicating major ABO-incompatible bone marrow transplantation.

Topics: ABO Blood-Group System; Adult; Bone Marrow Transplantation; Combined Modality Therapy; Drug Resistance; Drug Therapy, Combination; Erythropoietin; Histocompatibility; Humans; Immunoglobulins, Intravenous; Male; Methylprednisolone; Prednisolone; Red-Cell Aplasia, Pure; Time Factors

A patient with acquired pure red cell aplasia and agnogenic myeloid metaplasia (AMM) was treated with rHuEPO. She became transfusion independent. Weekly injections of rHuEPO have maintained the response without side-effects or disease progression. In addition, marrow fibrosis and splenomegaly have decreased. Therefore, rHuEPO may be effective therapy for some patients with acquired PRCA and/or AMM.

Topics: Aged; Blood Transfusion; Erythrocyte Count; Erythropoietin; Female; Humans; Primary Myelofibrosis; Red-Cell Aplasia, Pure; Reticulocytes; Time Factors

Allogeneic bone marrow transplants with major ABO incompatibility may be associated with delayed erythroid engraftment. A case of a male patient with erythroleukemia (blood group O) who received a bone marrow transplant from an HLA-identical sibling (blood group AB) is reported. The bone marrow transplantation was followed by normal myeloid and megakaryocytic engraftment, but pure red cell aplasia was present for more than 230 days after bone marrow transplant. Despite documentation of an elevated endogenous erythropoietin level (360 mU/mL; normal value, < 19 mU/mL) during the period of absent erythropoiesis, erythroid engraftment was observed soon after the initiation of human recombinant erythropoietin at a dose of 50 U per kg daily. This experience suggests that high-dose erythropoietin may stimulate sufficient production of erythroid precursors to overcome circulating inhibitors resulting in the correction of pure red cell aplasia.

Topics: ABO Blood-Group System; Adult; Blood Group Incompatibility; Bone Marrow Transplantation; Dose-Response Relationship, Drug; Erythropoietin; Humans; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Adult; Erythropoietin; Humans; Legislation, Drug; Male; Red-Cell Aplasia, Pure; United Kingdom

To assess the effects of decreased erythrocyte production on the levels of serum erythropoietin in children, we measured simultaneous hemoglobin concentrations and erythropoietin in 18 children with iron deficiency anemia, 17 children with transient erythroblastopenia of childhood (TEC), and 7 children with aplastic anemia. In all but two patients (one with TEC; one with aplastic anemia), erythropoietin was measured at diagnosis, before institution of specific therapy for the anemia. There was a statistically significant inverse linear correlation between log10 erythropoietin and hemoglobin values for all patient groups (r = 0.904 to 0.912; p less than 0.005). A comparison of the slopes of the regressions for each patient group by analysis of covariance revealed a significantly steeper slope for the iron deficiency group (-0.553) versus the TEC (-0.287) and aplastic anemia (-0.256) groups (p = 0.0001). The difference in erythropoietin levels appeared greatest in patients whose presenting hemoglobin level was greater than 5 gm/dl. Decline in serum erythropoietin levels was more precipitous in the less severely anemic patients with iron deficiency anemia than in the patients with TEC or aplastic anemia. These data reveal quantitative and qualitative differences in the relationship between serum erythropoietin and hemoglobin levels when children with severe iron deficiency anemia versus those with TEC or aplastic anemia are considered, even though all three conditions are characterized by hypoproliferation of erythrocytes.

Topics: Analysis of Variance; Anemia, Aplastic; Anemia, Hypochromic; Child; Child, Preschool; Erythropoietin; Hemoglobins; Humans; Infant; Red-Cell Aplasia, Pure

Serum erythropoietin (EPO) levels were determined by the recombigen EPO RIA kit (DPC) in normal subjects and patients with renal dysfunction, diabetes mellitus, hypothyroidism and a variety of hematological disorders. Mean (+/- SD) serum EPO levels were 18.6 +/- 5.6 mU/ml in 180 normal subjects and no sex difference was obtained. Serum EPO levels in older subjects were slightly greater than those in younger subjects. There was a negative correlation between serum EPO levels and Ht values in anemic patients with normal renal function, whereas serum EPO levels were within the normal range in anemic patients with renal disorders, suggesting that serum EPO levels were relatively low in patients with chronic renal failure. Serum EPO levels were rather increased in patients with diabetes mellitus and hypothyroidism. High serum EPO levels were obtained in patients with a variety of hematological disorders such as acute leukemia, multiple myeloma, myelodysplasia syndrome, aplastic anemia and pure red cell aplasia. In a patient with pure red cell aplasia treated with glucocorticoids, serum EPO levels were lowered before anemia was recovered and reticulocytes were increased. These findings indicate that measurement of serum EPO levels are useful for not only differential diagnosis of anemia but also clinical evaluation of the treatment.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Diabetes Mellitus; Erythropoietin; Female; Humans; Male; Middle Aged; Reagent Kits, Diagnostic; Red-Cell Aplasia, Pure; Reference Values

Topics: ABO Blood-Group System; Adult; Blood Group Incompatibility; Bone Marrow Transplantation; Erythropoietin; Humans; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Autoimmune Diseases; Drug Resistance; Erythropoietin; Female; Humans; Methylprednisolone; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Remission Induction

In vitro cultures of erythroid progenitors and radioimmunoassay of erythropoietin (Epo) are 2 recently available techniques. It is possible to assess their relevance in various hematological disorders. Erythroid cultures can be performed in the investigation of polycythemias, pure red cell aplasias (PRCA) and refractory anemias. In primary polycythemias "spontaneous" colonies appear in vitro whereas this phenomenon is never observed in secondary polycythemias. These so called "spontaneous" colonies have been demonstrated with a lower incidence in all myeloproliferative disorders. Therefore, if the absence of spontaneous colonies does not permit us to eliminate the presence of a myeloproliferative syndrome aside from polycythemia vera, their presence does seem pathognomonic of a myeloproliferative disorder. In acquired chronic pure red cell aplasia in adults, a strong correlation is found between the in vitro growth of erythroid colonies and the results of immuno-suppressive treatment. In refractory anemias erythroid cultures do not have either diagnostic, or prognostic interest. Serum epo level does not have a high discriminatory value in distinguishing between primary and secondary erythrocytosis. Indeed in PV, the Epo level is generally low or normal, in secondary polycythemias Epo level is high or normal. There is an important overlap between the two groups. Epo level determination can have a therapeutic incidence. Administration of recombinant Epo seems justified only in patients both sufficiently anemic to warrant transfusions and in whom Epo level is low in comparison with the degree of anemia.

Topics: Erythroid Precursor Cells; Erythropoietin; Hematologic Diseases; Humans; Immunosuppression Therapy; Polycythemia; Radioimmunoassay; Red-Cell Aplasia, Pure; Remission Induction; Reproducibility of Results

Erythropoietin titers when related to the hematocrit percentage and measured by bioassay in 33 normal volunteers and in 61 patients with anemias not complicated by renal or chronic disease were found to overlap with titers measured by radioimmunoassay in 20 normals and 28 patients with similar anemias. Erythropoietin titers measured by radioimmunoassay in 34 patients with rheumatoid arthritis, 25 patients with sickle cell anemia (58 separate samples), and 28 patients with erythroid hypoplasia caused by hematologic malignancies were compared with those in the control group of patients with uncomplicated anemias and found not to differ significantly from titers in this group. Erythropoietin titers measured by bioassay in 12 patients with aplastic anemia also fell within the range of those in the control group. Consequently, erythropoietin titers in these anemias appear to be determined primarily by the degree of anemia and not by any specific effect of these illnesses on the production of erythropoietin.

Topics: Anemia; Anemia, Aplastic; Anemia, Sickle Cell; Arthritis, Rheumatoid; Biological Assay; Erythropoietin; Female; Hematologic Diseases; Humans; Male; Radioimmunoassay; Red-Cell Aplasia, Pure

Topics: Autoimmune Diseases; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Immunization, Passive; Immunoglobulin G; Immunoglobulins, Intravenous; Infant; Injections, Intravenous; Red-Cell Aplasia, Pure

A short review is presented of the primary and the secondary types of therapy-refractory anemia. Special emphasis is placed on the newest results obtained with therapeutic plasmapheresis and with recombinant human erythropoietin.

Topics: Anemia, Refractory; Anemia, Sideroblastic; Erythropoietin; Humans; Plasmapheresis; Red-Cell Aplasia, Pure

A 17-year-old girl with a severe pure red cell aplasia (PRCA) and an appropriate elevation of erythropoietin titres was treated successfully with plasmapheresis, during which plasma was exchanged with human albumin and Ringer lactate. Before this treatment, therapeutic attempts with prednisolone, oxymetholone and infusions with fresh frozen plasma had all been without effect. Bone marrow culture studies revealed an inhibitory activity against BFU-E in the plasma, an activity which could not be demonstrated after the plasmapheresis. 22 months after the plasmapheresis the patient is still healthy without any medication. This case adds additional evidence for the presence of a pathogenetic erythroid inhibitory factor in the plasma of some patients with PRCA.

Topics: Adolescent; Bone Marrow Cells; Cells, Cultured; Erythropoietin; Female; Humans; Plasmapheresis; Red-Cell Aplasia, Pure