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A clinical review of antibody-mediated pure red cell aplasia.

Goal:

Recognize the clinical manifestations of and therapeutic options for rHuEPO-induced pure red cell aplasia (PRCA).

Objectives:

1. List the symptoms of PRCA and its causes.

2. Describe the epidemiologic pattern of rHuEPO-induced PRCA.

3. Discuss therapy for rHuEPO-induced PRCA.

Pure red cell aplasia (PRCA) is a severe, rare, and sometimes life-threatening form of anemia that can be caused by congenital or acquired disorders (Dessypris, 1991). A complete diagnosis of PRCA requires careful identification of the primary cause. A sharp increase in the incidence of PRCA has been observed in patients with chronic kidney disease (CKD) who are treated with recombinant human erythropoietin (rHuEPO) for chronic renal anemia (Bergrem, Danielson, Eckardt, Kurtz, & Stridsberg, 1993; Casadevall, 2002; Casadevall et al., 2002; Prabhakar & Muhlfelder, 1997). This form of PRCA has been determined to be an immunologic response to rHuEPO treatment that is characterized by the formation of antibodies (AB) that can bind rHuEPO and suppress its biologic activity (Casadevall et al., 1996; Peschle et al., 1975; Steinberg, Huang, Ljubich, & Lee-Huang, 1990). Although AB-mediated PRCA has been reported more frequently in patients with CKD treated with rHuEPO sold outside of the United States (U.S.) (Eprex[R], Ortho Biotech), the etiology and pathophysiology of this form of PRCA remain uncertain (Eckardt & Casadevall, 2003; Gershon, Luksenburg, Cote, & Braun, 2002; Rossert, Casadevall, & Eckardt, 2004). The recent emergence of rHuEPO-induced PRCA underscores the need for nephrology nurses and other health care providers to gain a better understanding of this form of PRCA, which can cause nonresponse to rHuEPO in patients with CKD-associated anemia and may well be classified as a "disease of medical progress."

This review provides a broad overview of the natural history, epidemiology, pathogenesis, and clinical manifestations of PRCA, with a focus on AB-mediated PRCA and its differentiating characteristics and options for therapy.

Natural History and Diagnosis

First described by Kaznelson in 1922 (Krantz, 1974), PRCA has a gradual onset, manifesting as a normochromic, normocytic anemia and reticulocytopenia with normal white blood cells and platelet count. This disorder is characterized histologically by erythroblastopenia in an otherwise normally appearing bone marrow (see Figure 1). Symptoms include weakness, lethargy, and pallor, which represent the consequences of anemia (Thompson & Gales, 1996) in patients who are transfusion-dependent (need of about 1 unit packed red blood cells per week). PRCA may occur as a congenital disorder or as an acquired primary or secondary disorder with varied causes (Dessypris, 1991; Dessypris, Baer, Sergent, & Krantz, 1984; Dessypris, Fogo, Russell, Engel, & Krantz, 1980; Young & Mortimer, 1984) (see Table 1). Approximately 5% of all cases of PRCA are drug induced (see Table 2). In general, the drug-induced form resolves following discontinuation of the causative medication. However, in cases of rHuEPO-induced PRCA, withdrawal from erythropoietic treatment does not usually resolve anemia (Casadevall, 2002; Verhelst et al., 2003). Because of the requirement for frequent blood transfusions and the complications often associated with them, management of persistent PRCA can be problematic.

[FIGURE 1 OMITTED]

rHuEPO-induced PRCA usually manifests as a sudden and severe anemia (Peces et al., 1996; Weber, Gross, Kromminga, Loew, & Eckardt, 2002). In this disorder, blood Hb decreases at an average rate of about 1 g/dL per week and circulating reticulocytes decrease to less than 10,000/[mm.sup.3] of blood (Rossert et al., 2004). Neutralizing ABs are produced that effectively neutralize the biological activity of endogenous rHuEPO as well as of all recombinant erythropoietic proteins (collectively referred to as "erythropoiesis stimulating agents" or ESAs). Thus, affected patients are rendered absolutely nonresponsive to increased drug doses or different ESP preparations, including epoetin beta (NeoRecormon[R], Roche Pharmaceuticals) and darbepoetin alfa (Aranesp[R], Amgen Inc.) (Eckardt & Casadevall 2003).

Diagnosis of Various Forms

The diagnosis of various forms of PRCA is usually made on the basis of a physical examination, a complete medical history, and the results of specific laboratory tests. Patients with rHuEPO-induced PRCA present with severe anemia, and an evaluation of the patient's medical history reveals an exposure to rHuEPO and absence of other possible etiologies (Casadevall, 2002. The definitive diagnosis of PRCA requires histological examination of a bone marrow aspirate or biopsy that reveals absence of erythroid precursor cells or maturation arrest Dessypris, 1991; Rossert et al., 2004. The diagnosis of AB-mediated PRCA requires the additional demonstration of binding or neutralizing anti-rHuEPO ABs in the patient's serum.

Several laboratory tests (assays) that measure anti-rHuEPO binding of neutralizing ABs have been used to confirm the diagnosis of AB-mediated PRCA. Currently, there are 3 types of serologic assays available: (a) enzyme-linked immunosorbent assays (ELISAs) (Castelli et al., 2000; Peces el al., 1996), (b) radioimmuno-precipitation (RIP)assays (Casadevall et al., 2002; Egrie, Cotes, Lane, Gaines Das, & Tam, 1987), and (c) the BIAcore surface plasmon resonance assay (Swanson, Ferbas, Mayeux, & Casadevall, 2004). Cell-based bioassays can be used to confirm that the ABs are neutralizing (Casadevall, 2002; Casadevall et al., 2002; Lacombe, Casadevall, Muller, & Varet, 1984). Each assay has its particular level of sensitivity and specificity for detecting anti-rHuEPO ABs, although the RIP assay has been used most often in reports of AB-mediated PRCA (Rossert et al., 2004). No single assay has yet been chosen as the standard method for measuring anti-rHuEPO ABs.

Epidemiology

rHuEPO-induced PRCA appears to follow an epidemiological pattern, in which the vast majority of cases have occurred in patients with CKD-associated renal anemia who received rHuEPO and responded well initially to rHuEPO, but then become refractory to continued or increased dosages of rHuEPO or other ESAs. A recent update cited 177 total AB-positive PRCA cases associated with the subcutaneous (SC) use of the Eprex[R] product alone, 18 cases with use of Eprex[R] plus 1 or more other ESAs, and an additional 63 cases still under investigation (Johnson & Johnson Pharmaceutical Research & Development, 2003). The majority of these cases occurred in Europe, Canada, and Australia.

rHuEPO reports on other ESPs have revealed only a relatively small number of AB-mediated PRCA cases in patients receiving either rHuEPO (Swissmedic, 2003), or another formulation of rHuEPO sold in the U.S. (Epogen[R], Amgen Inc./Prooit[R], Ortho Biotech) (Amgen Inc., 2003) (n = 8 and 6, respectively). No cases of AB-mediated PRCA have been reported to date in patients treated exclusively with darbepoetin alfa (Amgen Inc., 2003), administered either by the SC or intravenous (IV) routes, although AB formation is a possibility with any protein-based therapeutic. Data on PRCA cases associated with use of epoetin beta are current as of December 2002, and have not been updated since that time. PRCA case numbers with use of all other ESAs are current as of September 30, 2003.

The accrual rate of newly diagnosed cases of AB-mediated PRCA associated with SC use of Eprex[R] was greatest between 1998 and 2002, followed by a notable decrease in 2003 (see Figure 2). Cases of PRCA associated with the use of other ESPs have not increased at similar rates before or after 1998 (Amgen Inc., 2003).

Immunogenicity of ESAs

Recombinant erythropoietins have been used successfully for more than a decade for treating the anemia associated with CKD. Administration of ESAs to patients with CKD is an alternative treatment to transfusions. However, the demonstrated immunogenic potential of a number of other recombinant proteins (Vial & Descotes, 1995) suggests that ESAs may be immunogenic in a very small percentage of patients. The recent increase in the incidence of AB-mediated PRCA in patients with CKD has raised concern about the immunogenicity of ESAs (Casadevall, 2002; Casadevall et al., 2002).

Etiology

The causative factors associated with the production of anti-rHuEPO ABs in response to treatment with ESPs are not well understood, but the etiology of AB-mediated PRCA is probably multifactorial. Theoretic possibilities include product formulation, storage and handling, route of administration, and patients' treatment history (Rossert et al., 2004; Schellekens, 2003). Shortly after a change in the formulation of the Eprex[R] brand of rHuEPO sold outside the USA in 1998, there was an increased incidence of PRCA that continued through 2002, primarily in patients treated SC with this formulation of rHuEPO (Gershon et al., 2002; Rossert et al., 2004). The change in formulation of Eprex[R] followed recommendations in the European Union to remove human serum albumin stabilizer from injectable products because of concerns about transmission of infectious human viruses and Creutzfeldt-Jakob disease prions (Breckenridge, 2004). Other potential contributing factors include silicone oil used as syringe lubricant or contaminants released from the rubber stoppers that act as immunologic adjuvants, or which destabilize the product.

The SC route of administration alone cannot completely explain the rapid rise in PRCA cases, since all recombinant erythropoietic agents have been administered by this route in a relatively high proportion of patients over time outside the U.S. However, no cases of rHuEPO-induced PRCA have been described in patients treated with IV rHuEPO to date. In its summaries of cases of AB-mediated PRCA, Johnson & Johnson suggested that improper storage and handling of recombinant proteins may contribute to their immunogenicity (Johnson & Johnson Pharmaceutical Research & Development, 2003). The company stated that improvements have been made in their shipping and handling procedures, along with educational initiatives for end-users on proper handling of Eprex[R].

Pathogenesis

The development of rHuEPO-neutralizing ABs is one of the characteristic diagnostic features of rHuEPO -induced PRCA. Antibodies against one form of rHuEPO have been found to cross- react with other ESAs, which precludes further treatment following the development of AB-mediated PRCA. One recent study has shown that rHuEPO-neutralizing ABs bind to the portion on the rHuEPO molecule that binds to the cellular rHuEPO receptor (Elliott et al., 2003). Inhibition of rHuEPO binding or absence of rHuEPO leads to programmed cell death of erythroid progenitors (Koury & Bondurant, 1990).

Therapy

Appropriate therapy for rHuEPO-induced PRCA includes discontinuation of treatment with any rHuEPO and administration of blood transfusions as required. However, ABs are unlikely to disappear without immunosuppressive therapy. Renal transplantation appears to be the optimum therapy for AB-mediated PRCA, as a functioning transplanted kidney produces endogenous rHuEPO and eliminates the need for exogenous erythropoietic support (Eckardt & Casadevall, 2003) and associated immunosuppressive therapy stops the production of ABs. Immunosuppressive therapy with agents such as cyclosporine A or corticosteroids with or without cyclophosphamide have been reported to allow erythropoietic recovery in some patients (Casadevall, 2002; Clark, Dessypris, & Krantz, 1984; Verhelst et al., 2003). However, no consensus statements or guidelines have yet been published regarding appropriate immunosuppressive therapy for AB-mediated PRCA.

Nursing Implications

There are nursing implications for storage, administration, and patient education regarding rHuEPO as well as for observing patients for adverse affects, including PRCA. The rHuEPO products should be stored according to product labeling at a temperature of 28[degrees]C. Multidose vials instead of prefilled syringes are recommended to prevent possible reaction to the materials used in manufacturing the syringe.

Nurses need to explain the risks of rHuEPO before administration and immediately report all adverse events to the manufacturer and the FDA. If PRCA is suspected, rHuEPO therapy must be stopped. In addition, the antibodies will cross react with all currently available rHuEPO products; therefore, switching to another product is not recommended (Locatelli, Aljama, & Barany et al. (2004).

Conclusions

Nurses and clinicians should be aware of the possible development of AB-mediated PRCA in patients receiving rHuEPOP for CKD-associated anemia. Although the immunologic mechanisms underlying the development of this disorder remain unclear, health care providers must remain vigilant for the onset of AB-mediated PRCA, which can cause nonresponse to recombinant rHuEPO in patients with CKD who are anemic. Antibody-mediated PRCA is associated with a sudden decrease in blood Hb and circulating reticulocytes after an initial period of successful treatment that is accompanied by resistance to the therapeutic effects of ESAs. The clinical diagnosis of AB-mediated PRCA requires histologic examination of bone marrow and is supported by a positive serologic test for specific ABs against rHuEPO.

Since anti-rHuEPO ABs can cross-react with all ESA formulations, patients demonstrating ABs against one form of ESA should no longer be considered good candidates for switching to other ESA formulations. Although optimal treatment of AB-mediated PRCA has not been defined, evidence suggests that therapy with certain immunosuppressive drugs combined with corticosteroids may be effective in some patients.
Table 1

Various Etiologies of PRCA *

Congenital            Diamond-Blackfan Syndrome
                      (congenital hypoplastic anemia)

Acquired PRCA
  Primary Form
    Autoimmune        Rheumatoid arthritis
    disorders         Myasthenia gravis
                      Autoimmune hypothyroidism
                      Systemic lupus erythematosus
                      Anti-erythropoietin autoantibodies

    Other             Severe renal failure
                      Severe nutritional deficiencies

Secondary Form
  Infectious disease  Human parvovirus B19
                      Cytomegalovirus
                      Epstein-Barr virus
                      Mumps
                      Human immunodeficiency virus
                      Hepatitis A, B, and C

  Malignant disease   Thymoma
                      Chronic lymphocytic leukemia
                      Chronic granulocytic leukemia
                      Lymphoma
                      Multiple myeloma
                      Solid tumors

  Iatrogenic          Diphenylhydantoin
                      Azathioprine
                      Isoniazid
                      Recombinant erythropoietin-stimulating agents
                      Pregnancy

  Other               Histoincompatible transplantation

* Note: Adapted from Dessypris, E.N., Baer, M.R., Sergent, J.S., &
Krantz, S.B. (1984). Rheumatoid arthritis and pure red cell aplasia.
Annals of Internal Medicine, 100(2), 202-206; Dessypris, E.N. (1991).
The biology of pure red cell aplasia. Seminars in Hematology, 28(4),
275-284.

Table 2
Drugs Associated With the Development of PRCA *

Antibiotic                        Isoniazid
                                  Cephalothin
                                  Chloramphenicol
                                  Dapsone
                                  Penicillin

Antiepileptic                     Diphenylhydantoin
                                  Carbamazepine
                                  Sodium valproate

Antiinflammatory                  Fenoprofen
                                  Sulfasalazine

Cardiovascular                    Procainamide

Chemotherapeutic                  Rifampicin

Erythropoietic                    Recombinant erythropoietins

Other agents                      Azathioprine
                                  Chlorpropamide
                                  Allopurinol
                                  Methazolamide
                                  Penicillamine
                                  Phenobarbital

* Note: Adapted from Dessypris, E.N. (1991). The biology of
pure red cell aplasia. Seminars in Hematology, 28(4), 275-284
and Thompson, D.F., & Gales, M.A. (1996). Drug-induced pure red
cell aplasia. Pharmacotherapy, 16(6), 1002-1008.

Figure 2

Incidence of AB-mediated PRCA globally and in Europe from
2001 through July 2003.

                   Worldwide           Europe

Jan-Jul              1.67               2.38
2001

Jul-Dec              3.73               4.45
2001

Jan-Jul              3.32               3.04
2002

Jul-Dec              2.69               2.07
2002

Jan-Jul              0.89               1.13
2003

Note: Figure adapted from data provided by J&J on 4 December 2003.

Note: Table made from bar graph.


References

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This offering for 1.0 contact hour is being provided by the American Nephrology Nurses' Association (ANNA). ANNA is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. ANNA is a Provider approved by the California Board of Registered Nursing, provider number CEP 00910.

The Nephrology Nursing Certification Commission (NNCC) requires 60 contact hours for each recertification period for all nephrology nurses. Forty-five of these 60 hours must be specific to nephrology nursing practice. This CE article may be applied to the 45 required contact hours in nephrology nursing.

Susan Vogel, MHA, RN, CNN, the CEO and President of Renal Replacement Therapies, Encino, CA. She is also an Administrator at South Valley Regional Dialysis Center, Inc., Encino, CA; and a member of the Los Angeles chapter of ANNA.

Jerome Rossert, MD, PhD, is a Professor of Nephrology at the University Pierre and Marie Curie in Paris, France. He is also a Consulting Physician in the Department of Nephrology at Tenon Hospital, Paris, France; and a Senior Scientist at the National Institute for Health and Medical Research (INSERM), Paris, France.
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Title Annotation:Continuing Education
Author:Vogel, Susan; Rossert, Jerome
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:Jan 1, 2005
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