Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study.
Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study.
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DOI：
10.1182/blood.2022018833
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发表时间：
2023-10-19
期刊：
影响因子：
20.3
通讯作者：
Kavanagh, David
中科院分区：
文献类型：
--
作者：
Brocklebank, Vicky;Walsh, Patrick R.;Smith-Jackson, Kate;Hallam, Thomas M.;Marchbank, Kevin J.;Wilson, Valerie;Bigirumurame, Theophile;Dutt, Tina;Montgomery, Emma K.;Malina, Michal;Wong, Edwin K. S.;Johnson, Sally;Sheerin, Neil S.;Kavanagh, David
我们证明在基因型匹配的补体介导的aHUS队列中，C5抑制导致无eskd生存的统计学改善。我们证明EXOSC3的双等位基因致病性突变会导致eculizumab无反应的aHUS。从历史上看，大多数补体介导的非典型溶血性尿毒症综合征（CaHUS）患者进展为终末期肾病（ESKD）。eculizumab单臂试验短时间随访显示疗效。据我们所知，我们首次在一个基因型匹配的CaHUS队列中证明，无eskd生存率的5年累积估计值从对照组的39.5%提高到eculizumab治疗组的85.5%（风险比4.95；95%可信区间[CI]， 2.75-8.90; P = 0.000；需要治疗的人数2.17 [95% CI, 1.81-2.73]）。依珠单抗治疗的结果与潜在的基因型相关。在多因素分析中，较低的血清肌酐、较低的血小板计数、较低的血压、较年轻的发病年龄以及较短的发病时间与6个月时估计的肾小球滤过率bbb60ml /min相关。在接受治疗的队列中，脑膜炎球菌感染率是普通人群背景感染率的550倍。eculizumab停药后的复发率对于具有致病性突变的患者为1 / 9.5人年，对于具有不确定意义的变异的患者为1 / 10.8人年。在没有罕见遗传变异的患者中，使用eculizumab治疗67.3人年无复发记录。6名停止使用Eculizumab的肾脏功能正常的患者重新开始使用Eculizumab，没有患者进展为ESKD。我们证明，编码RNA外泌体重要部分的RNA加工基因（包括EXOSC3）中的双等位基因致病性突变可导致eculizumab无反应的aHUS。隐性HSD11B2突变引起明显的矿皮质激素过量也可能出现血栓性微血管病。在本月的CME文章中，Brocklebank等人发表了一项英国大型队列研究的详细临床特征和完整的遗传分析，该队列患者疑似补体相关非典型溶血性尿毒症综合征（CaHUS），接受eculizumab治疗。作者证明了在基因型匹配的CaHUS患者中优于历史治疗的优势，证明了eculizumab停用后的结果是基因型依赖的，并且表明如果没有致病基因变异存在，复发的可能性很小。这些数据还揭示了eculizumab难治性CaHUS的一种新的致病遗传病变，并提供了一个基准，随着CaHUS治疗的其他选择的出现，应该证明是有用的。
We prove in genotype-matched complement-mediated aHUS cohorts that C5 inhibition results in a statistical improvement in ESKD-free survival. We demonstrate that biallelic pathogenic mutations in EXOSC3 cause eculizumab nonresponsive aHUS. Historically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials of eculizumab with a short follow-up suggested efficacy. We prove, for the first time to our knowledge, in a genotype matched CaHUS cohort that the 5-year cumulative estimate of ESKD-free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab-treated cohort (hazard ratio, 4.95; 95% confidence interval [CI], 2.75-8.90; P = .000; number needed to treat, 2.17 [95% CI, 1.81-2.73]). The outcome of eculizumab treatment is associated with the underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure, and younger age at presentation as well as shorter time between presentation and the first dose of eculizumab were associated with estimated glomerular filtration rate >60 ml/min at 6 months in multivariate analysis. The rate of meningococcal infection in the treated cohort was 550 times greater than the background rate in the general population. The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for patients with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. No relapses were recorded in 67.3 person years off eculizumab in those with no rare genetic variants. Eculizumab was restarted in 6 individuals with functioning kidneys in whom it had been stopped, with no individual progressing to ESKD. We demonstrated that biallelic pathogenic mutations in RNA-processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab nonresponsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with thrombotic microangiopathy. In this month’s CME article, Brocklebank et al present detailed clinical characteristics and complete genetic analyses of a large United Kingdom cohort of patients with suspected complement-associated atypical hemolytic uremic syndrome (CaHUS) treated with eculizumab. The authors demonstrate superiority over historical therapies in genotype-matched patients with CaHUS, document that outcome after eculizumab cessation is genotype-dependent, and show that relapse is very unlikely if no pathogenic gene variant is present. The data also reveal a new causative genetic lesion for eculizumab-refractory CaHUS and provide a benchmark that should prove useful as additional options for CaHUS treatment emerge.
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DOI：
10.4049/jimmunol.0804031
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ferreira VP;Herbert AP;Cortés C;McKee KA;Blaum BS;Esswein ST;Uhrín D;Barlow PN;Pangburn MK;Kavanagh D
通讯作者：
Kavanagh D
影响因子：
19.6
作者：
Cavero, Teresa;Arjona, Emilia;Praga, Manuel
通讯作者：
Praga, Manuel
影响因子：
20.3
作者：
Fakhouri, Fadi;Fila, Marc;Fremeaux-Bacchi, Veronique
通讯作者：
Fremeaux-Bacchi, Veronique
影响因子：
13.6
作者：
Challis, Rachel C.;Araujo, Geisilaine S. R.;Kavanagh, David
通讯作者：
Kavanagh, David
影响因子：
19.6
作者：
Greenbaum, Larry A.;Fila, Marc;Licht, Christoph
通讯作者：
Licht, Christoph