AQP4抗体阳性NMOSD中的星形胶质细胞与轴索损伤生物标志物：来自PREVENT和CHAMPION-NMOSD研究的启示。
完整摘要 · 中文译文
背景与目的：胶质纤维酸性蛋白（GFAP）和神经丝轻链（NfL）分别是水通道蛋白-4抗体阳性视神经脊髓炎谱系疾病（AQP4-Ab+ NMOSD）中星形胶质细胞损伤和轴突损伤的生物标志物。我们评估了接受补体成分5抑制剂依库珠单抗或雷夫利珠单抗治疗期间血清GFAP和NfL水平，并利用PREVENT（依库珠单抗）和CHAMPION-NMOSD（雷夫利珠单抗）3期试验的样本，检验了治疗前生物标志物水平、临床特征与试验期间复发风险之间的关联。 方法：血清GFAP和NfL水平在PREVENT中进行了回顾性分析，在CHAMPION-NMOSD中进行了前瞻性分析，并与人口学匹配的外部健康供者水平进行比较。采用检验-验证策略，通过逻辑回归评估基线临床特征与高生物标志物水平（≥健康供者均值以上2个标准差）之间的关联。评估了整个治疗期间相对于治疗前基线的变化。检查了与裁定试验期间复发相关的生物标志物变化。采用Kaplan-Meier分析评估基线生物标志物水平与首次裁定试验期间复发时间之间的关联。 结果：可获得41例PREVENT和55例CHAMPION-NMOSD患者的样本。与健康供者相比，患者治疗前基线GFAP和NfL水平升高。高基线GFAP水平与初次发病年龄较大、距末次复发时间较短以及基线Hauser步行指数较高相关（Ha I) 评分。高基线NfL水平与年龄较大和较高的基线HAI评分相关。使用年龄调整Z评分评估了高基线GFAP和NfL水平，结论不会发生实质性改变。中位GFAP水平快速下降（4-6周内），并在依库珠单抗和雷夫利珠单抗治疗下均维持稳定。中位NfL水平在雷夫利珠单抗治疗下显著下降，但在依库珠单抗治疗下未显著下降。在PREVENT研究中，经裁定的事件内复发与安慰剂治疗患者GFAP水平升高相关，而依库珠单抗治疗患者的GFAP升高被减弱。 讨论：NMOSD患者血清GFAP和NfL水平升高，并与残疾的临床特征相关。补体成分5阻断在生物学上抑制NMOSD中的星形胶质细胞损伤，验证了GFAP作为药效学生物标志物和随机3期试验中靶点结合的机制性读出指标。这与不同化合物在各自独立3期试验中的早期发现一致。
完整摘要 · 英文原文
BACKGROUND AND OBJECTIVES: Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are biomarkers of astrocytic and axonal injury, respectively, in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-Ab+ NMOSD). We evaluated serum GFAP and NfL levels during treatment with complement component 5 inhibitors eculizumab or ravulizumab and examined associations between pretreatment biomarker levels, clinical characteristics, and on-trial relapse risk using samples from the PREVENT (eculizumab) and CHAMPION-NMOSD (ravulizumab) phase 3 trials. METHODS: Serum GFAP and NfL levels were analyzed retrospectively in PREVENT and prospectively in CHAMPION-NMOSD and compared with levels in demographically matched external healthy donors. Associations between baseline clinical characteristics and high biomarker levels (≥2 SDs above the healthy donor mean) were evaluated using logistic regression with a test-and-validate strategy. Changes throughout treatment were assessed relative to pretreatment baseline. Biomarker changes associated with adjudicated on-trial relapses were examined. Associations between baseline biomarker levels and time to first adjudicated on-trial relapse were assessed using Kaplan-Meier analyses. RESULTS: Samples were available from 41 PREVENT and 55 CHAMPION-NMOSD patients. Pretreatment baseline GFAP and NfL levels were elevated in patients compared with healthy donors. High baseline GFAP levels were associated with older age at initial presentation, less time since last relapse, and higher baseline Hauser Ambulation Index (HAI) score. High baseline NfL levels were associated with older age and higher baseline HAI score. High baseline GFAP and NfL levels using age-adjusted Z-scores were evaluated and would not have materially changed the conclusions. The median GFAP levels declined rapidly (within 4-6 weeks) and were sustained with both eculizumab and ravulizumab. The median NfL levels declined significantly with ravulizumab but not eculizumab. In PREVENT, adjudicated on-trial relapses were associated with increased GFAP levels in placebo-treated patients, while GFAP increases were attenuated in eculizumab-treated patients. DISCUSSION: Serum GFAP and NfL levels are elevated in patients with NMOSD and are associated with clinical features of disability. Complement component 5 blockade biologically suppresses astrocytic injury in NMOSD, validating GFAP as a pharmacodynamic biomarker and mechanistic readout of target engagement in randomized phase 3 trials. This aligns with earlier findings across different compounds in separate phase 3 trials.