Boven Katia, Knight John, Bader Fred, Rossert Jérome, Eckardt Kai-Uwe, Casadevall Nicole
Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 1 Place du Parvis Notre Dame, 75181 Paris Cedex 4, France.
Nephrol Dial Transplant. 2005 May;20 Suppl 3:iii33-40. doi: 10.1093/ndt/gfh1072.
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.
1998年，与重组人促红细胞生成素（依泊汀）治疗相关的纯红细胞再生障碍性贫血（PRCA）发病率大幅上升。抗体介导的PRCA激增几乎完全与接受皮下依泊汀治疗的慢性肾病患者以及在美国境外销售的α-依泊汀制剂（EPREX/ERYPO）有关。启动了一项技术、免疫学和流行病学调查的系统计划，以确定可能的原因。根据以下标准对潜在原因进行了评估：与PRCA发病率增加的时间相关性、EPREX/ERYPO与其他依泊汀产品之间的显著差异、产品中足以引发微弱免疫反应的浓度、动物体内免疫原性活性的支持证据以及与现有临床数据一致。在含有聚山梨酯80配方的EPREX/ERYPO（1998年在美国境外推出）的未涂层橡胶塞预填充注射器中，检测到通过聚山梨酯80作用从橡胶塞中浸出的有机化合物。当塞子涂层时、用人血清白蛋白配制的产品中或其他依泊汀产品中均未出现浸出物。浸出物的佐剂活性在小鼠中得到证实。2003年召回的未涂层橡胶塞预填充注射器中递送的α-依泊汀聚山梨酯80配方暴露患者的PRCA发病率显著高于涂层橡胶塞注射器中相同配方暴露患者。总之，这些数据强烈表明浸出物是EPREX/ERYPO所致抗体介导PRCA发病率增加的关键促成因素。
