抗淀粉样蛋白-β免疫疗法III期临床试验中淀粉样蛋白相关影像异常的发生率：一项更新的荟萃分析。

Incidence of Amyloid-Related Imaging Abnormalities in Phase III Clinical Trials of Anti-Amyloid-β Immunotherapy: An Updated Meta-Analysis.

作者信息

Jeong So Yeong, Suh Chong Hyun, Lim Jae-Sung, Shim Woo Hyun, Heo Hwon, Choi Yangsean, Kim Ho Sung, Kim Sang Joon, Lee Jae-Hong

机构信息

Department of Radiology, Seoul National University Bundang Hospital, Seongnam, South Korea.

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; and.

出版信息

Neurology. 2025 Apr 22;104(8):e213483. doi: 10.1212/WNL.0000000000213483. Epub 2025 Mar 19.

DOI:10.1212/WNL.0000000000213483

PMID:40112274

Abstract

BACKGROUND AND OBJECTIVES

Amyloid-related imaging abnormalities (ARIA) are key safety considerations in anti-amyloid-β (Aβ) immunotherapy. ARIA can be categorized into 2 types: ARIA characterized by edema and effusion (ARIA-E) or microhemorrhages and superficial siderosis (ARIA-H). In this study, we assessed the incidence of ARIA in phase 3 randomized controlled trials (RCTs) of anti-Aβ immunotherapy and compared the incidence among different agents and ε4 carrier status.

METHODS

PubMed and Embase databases were searched for phase 3 RCTs of anti-Aβ immunotherapy published on or before May 23, 2024. The inclusion criteria were phase 3 trials of anti-Aβ immunotherapy for mild cognitive impairment due to Alzheimer disease (AD) or mild AD dementia, with sufficient data on ARIA-E/H. The pooled incidences of ARIA and subgroup analyses according to various agents and ε4 carrier status were calculated. A sensitivity analysis excluding outliers was performed. The pooled odds ratio (OR) of ARIA-E according to the ε4 carrier status was also calculated.

RESULTS

Nine phase 3 RCT cohorts from 8 eligible studies were identified, analyzing data from 6,315 patients. The pooled incidence of ARIA-E was 9.5% (95% CI 2.8%-27.3%), and the adjusted pooled incidence of ARIA-E was 25.5% (95% CI 20.4%-31.8%) in the sensitivity analysis. The pooled incidence of symptomatic ARIA-E was 6.7% (95% CI 3.5%-12.5%) and that of severe ARIA-E was 3.5% (95% CI 13.8%-8.4%). The pooled incidence of ARIA-H was 17.8% (95% CI 11.0%-27.5%), with the incidence of superficial siderosis was 9.3% (95% CI 6.1%-13.9%). The pooled incidence of isolated ARIA-H was 8.7% (95% CI 7.6%-10.1%). Subgroup analysis showed that homozygous ε4 carriers had significantly higher odds of developing ARIA-E (OR 5.6, 95% CI 3.8-8.2, < 0.001) than noncarriers. Heterozygous ε4 carriers also had significantly higher odds of developing ARIA-E (OR 1.9, 95% CI 1.5-2.4, < 0.001) than noncarriers.

DISCUSSION

Although limited by small sample size and cohort-level data, our meta-analysis shows the adjusted pooled incidence of ARIA-E was 25.5% and the pooled incidence of ARIA-H was 17.8% in the recent phase 3 RCTs of anti-Aβ immunotherapy. Homozygous ε4 carriers have a 5.6-fold higher risk of developing ARIA-E than noncarriers.

摘要

背景与目的

淀粉样蛋白相关影像异常（ARIA）是抗淀粉样β蛋白（Aβ）免疫治疗中的关键安全性考量因素。ARIA可分为2种类型：以水肿和积液为特征的ARIA（ARIA-E）或微出血和浅表性铁沉积（ARIA-H）。在本研究中，我们评估了抗Aβ免疫治疗3期随机对照试验（RCT）中ARIA的发生率，并比较了不同药物以及ε4携带者状态下的发生率。

方法

检索PubMed和Embase数据库，查找2024年5月23日或之前发表的抗Aβ免疫治疗3期RCT。纳入标准为针对阿尔茨海默病（AD）所致轻度认知障碍或轻度AD痴呆的抗Aβ免疫治疗3期试验，且有关于ARIA-E/H的充分数据。计算ARIA的合并发生率以及根据不同药物和ε4携带者状态进行的亚组分析。进行了排除异常值的敏感性分析。还计算了根据ε4携带者状态的ARIA-E合并比值比（OR）。

结果

从8项符合条件的研究中确定了9个3期RCT队列，分析了6315例患者的数据。ARIA-E的合并发生率为9.5%（95%CI 2.8%-27.3%），敏感性分析中ARIA-E的校正合并发生率为25.5%（95%CI 20.4%-31.8%）。有症状的ARIA-E合并发生率为6.7%（95%CI 3.5%-12.5%），严重ARIA-E的合并发生率为3.5%（95%CI 1.38%-8.4%）。ARIA-H的合并发生率为17.8%（95%CI 11.0%-27.5%），浅表性铁沉积的发生率为9.3%（95%CI 6.1%-13.9%）。孤立性ARIA-H的合并发生率为8.7%（95%CI 7.6%-10.1%）。亚组分析显示，纯合子ε4携带者发生ARIA-E的几率（OR 5.6，95%CI 3.8-8.2，<0.001）显著高于非携带者。杂合子ε4携带者发生ARIA-E的几率（OR 1.9，95%CI 1.5-2.4，<0.001）也显著高于非携带者。