PURE RED CELL APLASIA INTRODUCTION u Pure red

PURE RED CELL APLASIA 신장내과 위 지 완

INTRODUCTION u Pure red cell aplasia (PRCA) § profound anemia § very low reticulocyte count § absence of erythroid precursors in the bone marrow § all other cell lines are present and seem quantitatively and morphologically normal § Idiopathic, thymoma, myelodysplastic syndromes, lymphoma, leukemia, systemic autoimmune disorders, viral infection (parvovirus B 19), or treatment with drugs such as phenytoin or chloramphenicol § Patients treated with recombinant human erythropoietin (EPO) ⇒ the induction of antibodies directed against the EPO molecule

ETIOLOGY AND PATHOGENESIS u Mediated by Ig. G autoantibodies or cytotoxic T lymphocytes directed against erythroid precursor or progenitor cells

ETIOLOGY AND PATHOGENESIS u There are several preparations of EPO (epoetin alfa, epoetin beta, epoetin omega), produced by various manufacturers around the world u The number of cases of epoetin-associated pure red-cell aplasia varied according to product, cause of anemia, route of administration, country N Engl J Med 2004; 351: 1403 -8

N Engl J Med 2004; 351: 1403 -8

ETIOLOGY AND PATHOGENESIS u Stabilizing agent : human serum albumin (HSA), polysorbate u In 1998 : HSA could transmit a variant of Creutzfeldt–Jakob disease u Eprex - polysorbate 80 > Neo. Recormon - polysorbate 20 u Eprex – uncoated rubber stopper syringe > coated rubber stopper syringe u Eprex > Neo. Recormon > Epogen > Aranesp ⇒ Uncoated rubber stoppers → fluororesin-coated stoppers Eprex with polysorbate : SC route → IV route N Engl J Med 2004; 351: 1403 -8

SCREENING FOR ANTI-EPO ANTIBODIES (Radioimmunoprecipitation Assay) u The 3 patients with borderline antibody results manifested no clinical signs of PRCA ⇒ value of a large-scale antibody screening program for PRCA cannot be justified Am J Kidney Dis 2004; 44: 264 -269

SCREENING FOR ANTI-EPO ANTIBODIES u Exposed to at least 8 weeks of erythropoiesis-stimulating agent (ESA) § Decline in hemoglobin level of > 0. 5 -1. 0 g/d. L per week, or transfusion requirement of at least one to two units per week to maintain adequate Hgb § Normal platelet and white blood cell (WBC) count § Absolute reticulocyte count of <10, 000/micro. L 2012 KDIGO guideline

DIAGNOSIS J Am Soc Nephrol 2004; 15: 398– 406

DIAGNOSIS u Bone marrow aspirate § severe erythroid hypoplasia, with <5% red blood cell precursors § platelet and white cell precursors are entirely normal

DIAGNOSIS u Anti-EPO antibodies § critical component of the diagnosis u Radioimmunoprecipitation assay (RIPA) § appears to be the most accurate test for detecting anti-EPO Ab § not standardized, may not detect low-affinity antibodies, requires radiolabeled antigen, time consuming and difficult to automate u Enzyme-linked immunosorbent assays (ELISA) § more widely available § lower sensitivity and specificity than the RIPA u Biosensor assay § not as readily available as the previous two assay § may provide better characterization of detected antibodies § may detect very low-affinity antibodies in baseline sera that never cause PRCA

DIAGNOSIS RIPA ELISA Biosensor Assay

TREATMENT – Initial management u Discontinue all recombinant erythropoietin products § anti-EPO antibodies crossreact not only with the endogenous hormone, but also with all recombinant EPO molecules, including darbepoetin alfa § rechallenge with EPO preparations may cause an anamnestic antibody response, making it less possible for the antibody to either spontaneously disappear or return to clinically unimportant levels § rechallenge with EPO may incite the formation of allergic skin and systemic reactions (eg, anaphylaxis), which might further complicate the patient's clinical picture u Transfusions for symptomatic anemia

TREATMENT – Immunosuppressive therapy u Since PRCA in this setting is immune mediated, the condition should respond to immunosuppressive therapy u Spontaneous remissions after cessation of EPO therapy occur, they appear to be rare Lancet 2004; 363: 1768– 71

TREATMENT – Immunosuppressive therapy u Continue treatment until antibody levels become undetectable or there is no response within three to four months of treatment initiation u Monitor Hgb weekly to assess for transfusion requirement and response to therapy u Monitor reticulocyte count and anti-EPO antibody levels every one to two weeks during treatment to assess response Blood 2005; 106: 3343 -3347

TREATMENT u Continuous erythropoiesis receptor stimulator (CERA) § single case report of use of intravenous CERA following ESA-induced PRCA without recurrence u Peginesatide § serious side effects and has been withdrawn from the market

1296921 김OO (61/F) u 2014/2/11 refractory anemia 주소로 전원 § 2013년 초부터 epokine 30000 U, 주 3회 투여 중 anemia 악화되어 수회 transfusion 시행 u 2014/2/11 본원 LAB § CBC 4400 -7. 5/21. 9 -138 k § PB morphology : mild anisocytosis § Ferritin 876. 06, Iron 172, UIBC 14, TIBC 186 § Corrected reticulocyte 0. 1%, absolute reticulocyte 2300/ l § ANA (-), Parvo virus B 19 Ig. G/M (-/-) § 2014/2/13 GFS: Chronic atrophic gastritis, Reflux esophagitis CFS: Chronic colon ulcers, r/o drug-induced

1296921 김OO (61/F) u 2014/2/13 BM aspiration § Erythropoiesis was markedly decreased enough to be scarcely observed. Granulopoiesis was adequate in number and usual in morphology. Megakaryocytes were increased in number and usual in morphology. Stainable iron was adequate in amount on aspirate smear.

1296921 김OO (61/F) u Transfusion § 1/8 1 pint, 1/24 1 pint, 1/27 1 pint, 2/17 2 pint § 3/12 2 pint, 3/31 1 pint, 4/2 1 pint, 4/16 1 pint, 4/21 1 pint u 2014/3/11 § CBC 3600 -6. 3/18. 5 -115 k ⇒ cyclosporine 100 mg bid 15 10 6. 3 8. 0 9. 7 10. 4 11. 2 Hb 5 0 03월 11일 03월 25일 04월 08일 04월 29일 6월 3일