EPO-associated PRCA

Autoimmunity to erythropoietin (EPO) causing Pure Red Cell Aplasia (PRCA) has recently become an important problem for renal patients, and also provides a challenge to those seeking to understand autoimmunity. This short summary has been provided by nephrologists from King's College Hospital and the Edinburgh Renal Unit with particular interests in the treatment of renal anaemia and in autoimmunity. Note that it is primarily intended for those with prior medical knowledge.

Basic information for patients about renal anaemia and its treatment with recombinant erythropoietin (EPO) is vailable from other sources: for example from Cardiff, Baxter Healthcare's Kidneywise (UK), and (more detailed) from the Kidney Transplant/Dialysis Association Patient Handbook (Boston, USA; see their home page). Our own page is under construction

Background

Pure red cell aplasia (PRCA) caused by anti-EPO antibodies has been increasingly recognised worldwide since 1998, although rare instances of the phenomenon had been reported in the preceding decade since EPO became available for the treatment of the anaemia of chronic renal failure.

The cause of this increase is still not fully explained, but is under major investigation at present, including involvement of the regulatory authorities (such as FDA, MCA, etc.)

Some key information:

• There is "clustering" of cases in several European countries, e.g. France and the UK, while the incidence in other European countries (such as Germany and Italy) has remained low. The incidence is also very low in the USA.
• Almost all cases have been associated with subcutaneous administration of the drug.
• Epoetin alfa has been associated with most cases. The prescribing information for epoietin alfa in Europe (sold under the name Eprex) was altered in December 2002 to state that it should no longer be administered by subcutaneous injection. Link to Medicines Control Agency UK; link to Ortho Biotech
• In 2003 the number of new cases fell dramatically, following these changes. A very small number of further cases have been reported, usually associated with subcutaneous administration of other types of epoetin.
• The antibodies are neutralising, and will cross-react with all currently available erythropoietic agents (epoetin alfa and beta, and darbepoetin alfa), in addition to endogenous EPO.
• From the limited data available, the antibodies seem to be IgG in origin, sub-class G1 or G4.
• PRCA is diagnosed on a bone marrow aspirate or biopsy, while anti-EPO antibodies are detected by immunoassay or bioassay. When should these tests be done? - see below
• The most reliable assay for detecting clinically significant EPO antibodies is a radioimmunoprecipitation assay (RIP). ELISAs may also be able detect them, but they may give false positive or negative results - there is not adequate information to be able to assess this at present.

When to suspect EPO-associated PRCA

	On EPO for at least 3 months
	Sudden (over approximately 1-6 weeks) and severe (to transfusion dependence) unexplained fall in haemoglobin despite continuing treatment with EPO.
	Reticulocyte count low: <10 x 10(9) per litre is strongly associated; but any count below 30x10(9) per litre may be suspicious.
	Bone marrow (obligatory if diagnosis suspected) shows hypoplasia/aplasia of red cell lines only, without infiltration.
	Low probability of other causes: Previously stable Haemoglobin values with adequate iron stores WBC and platelet counts normal or only moderately depressed Parvovirus B19 IgM titres and PCR negative No evidence of thymoma No evidence of lymphoma, or solid tumour Hepatitis B, C and HIV status unchanged

EPO antibody detection offers the best way of differentiating autoimmunity to EPO from other causes of PRCA, although there are very few validated assays for this purpose. EPO antibody testing is not currently a suitable test for screening multiple samples when there is a low probability of PRCA, though establishing such an assay is desirable.

All three companies that supply EPO in the UK (Amgen, Ortho Biotech, and Roche) have offered to measure EPO antibodies for any suspected PRCA cases, but we are nervous of commercial involvement. The assays are undertaken in North America or Germany. See assays below.

Management of suspected and proven cases

Assess the probability that it is EPO-induced PRCA, including investigations outlined in the box above.

Discontinue EPO immediately unless the probability looks very low. Do not substitute other types of EPO.

Support with transfusion as required.

If investigations suggestive, request EPO antibody assay (as above, or see below)

Report probable cases to regulatory authorities (MCA in the UK) and the supplying company.

At present there is little reliable advice that can be given about therapy. Various immunosuppressive strategies have been used. The problem may resolve spontaneously over weeks to months. From anecdotal reports it is possible to make the following observations:

• Most patients have received corticosteroids, but at varying doses, and the rationale is not entirely clear.
• Cyclophosphamide treatment has been used in many cases that have been described as responding to therapy. The drug has a track record in other antibody-mediated diseases. There are a very few reports concerning mycophenolate mofetil, but this might also be effective on theoretical grounds.
• Cyclosporine (ciclosporin) has been used in several UK cases. Although it does not have a promising track record in other antibody-mediated disorders, it has been associated with improvement in some cases. In pre-dialysis ESRD it will worsen renal function and hypertension.
• Plasma exchange is a rational treatment if used in combination with cytotoxic therapy, but not if used alone. If you undertake this treatment, please keep the first bag of removed plasma, as it may be a valuable resource for establishing assays and investigating pathogenesis - contact neil.turner@ed.ac.uk for details of how to send to us.
• Transplantation has been associated with the best improvement rate (100%). It is not known why this has been so successful, but it is associated with immunosuppressive therapy, and a new source of native EPO. It is reasonable therefore to leave patients on the transplant list.

Current investigations in the UK

We have set up a joint approach to investigate this problem in the UK.

Investigation of clinical cases

We have visited and obtained full information on almost all proven or probable cases in the UK. This information includes bone marrow slides for review by an expert panel of haematologists led by Dr Judith Marsh at St. George's Hospital, London, and clinical and immunological data. Data on over 20 definite cases has been gathered, and was presented at the American Society of Nephrology meeting in November 2003. Background information on the UK investigation (pdf file).

Assays

Prof Mike Kemeny is offering testing for EPO antibodies in any suspected PRCA cases, using an immunoprecipitation assay with, in addition, the facility to sub-type the antibody, and also to screen for IgM antibodies.

These facilities will be offered to any UK nephrologist free-of-charge, provided the request is clinically indicated. Assays will be run independently of any company involvement (although they may attract unrestricted educational grant support from any of them). Contact us

In the near future we hope to be in a position to screen populations of patients for the presence of EPO antibodies, in the absence of clinical PRCA, particularly those switching from one brand of EPO to another, to see if we can detect a potential PRCA problem before it develops. Anyone wishing to provide samples for this more research-orientated approach would be very welcome to discuss this in the first instance.

Contact information

This page was first published in October 2002 and last revised on Thu, Dec 4, 2003. Its authors were Iain Macdougall, Anna Thompson and Neil Turner. Contact us at renal@ed.ac.uk with comments. NOTE that the accuracy of any statements in this information cannot be guaranteed. It is published in the belief that it is correct, and we endeavour to keep it so. However, over some subjects there are differing opinions, or differing degrees of certainty. Please bear this in mind. Prior medical knowledge is assumed, and this information is not suitable for those without such a background.