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Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome
发布于：2013年7月8日 文字：【大】【中】【小】
N Engl J Med. 2013 Jun 6;368(23):2169-81. doi: 10.1056/NEJMoa1208981.
Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.
Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nürnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C.
Abstract
BACKGROUND:Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease.
METHODS:We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2).
RESULTS:A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period.
CONCLUSIONS:Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome.
aHUS发病与遗传或获得性的补体旁路调节异常致补体旁路在内皮细胞表面过度活化，通过补体活化片段（如C5a）及形成补体活化终末产物（膜攻击复合物，MAC）引起内皮细胞损伤，继而出现TMA病理、临床表现。Eculizumab是抗C5单抗，与C5结合后，能抑制C5转化酶对C5的降解，从而抑制C5a的产生及MAC的形成，达到治疗aHUS的作用。Eculizumab最开始于2007被批准用于治疗阵发性睡眠血红蛋白尿，2011美国FDA批准eculizumab用于治疗aHUS，随后欧洲也批准了eculizumab在aHUS中的应用。
既往eculizumab在aHUS中的有效性主要来自病例报道。本文是在12岁以上aHUS患者中进行的2个前瞻、开放性性II期临床试验：此2个临床试验患者均需除外ADAMTS13活性小于5%和产志贺样毒素大肠埃希菌感染。此临床试验于2011年3月结束。
结果：见附表。越早使用eculizumab可以使eGFR得到更明显改善；随着时间延长GFR呈逐渐增加趋势；即使在长期明显肾脏损伤患者肾功能仍然能持续改善。Eculizumab可以明显改善患者生活质量。无药物累积毒性或严重感染（包括脑膜炎球菌感染）。在Trial 1中24%、Trial 2 35%患者未发现补体基因突变或H因子自身抗体；此试验的阳性结果在发现或未发现补体异常患者中无差异，提示在aHUS患者无需在进行补体旁路基因检测后才开始eculizumab治疗。
| Trial | 入选条件 | 首要终点 | 次要终点 | 结果 |
| Trial 1 (n=17) | ≥4次血浆置换后仍存在TMA活动： （1）血小板减少 （2）肾脏损伤
| （1）血小板变化； （2）血小板和LDH正常（2次，至少间隔4周） | （1）无TMA相关事件； （2）GFR上升 （3）生活质量评估 | （1）至26周时血小板平均上升73×109/L。88%脱离血浆置换。 （2）随着时间延长GFR逐渐上升，4/5脱离透析。 |
| Trial 2 (n=20) | 病程长、慢性肾脏损伤、长期血浆置换/输注： （1）血浆置换或输注过程中血小板减少小于25%并维持至少8周 （2）肾脏损伤 | （1）无TMA相关事件（≥12周）： PLT下降不超过25%； 不需要血浆置换或输注； 不需要血液透析 （2）血小板和LDH正常（2次，至少间隔4周） | （1）GFR上升 （2）生活质量评估 | （1）至26周时80%患者达到首要终点；另外20%只是血小板下降超过25%（但仍在正常范围内）；100%患者脱离血浆置换/输注。 （2）随着时间延长GFR上升。 |
结论：eculizumab可以抑制补体介导的血栓性微血管病，同时可以明显改善肾功能。
http://www.ncbi.nlm.nih.gov/pubmed/23738544