Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan.
Enoki Eye Clinic, Sayama, Japan.
Front Immunol. 2021 Oct 13;12:738521. doi: 10.3389/fimmu.2021.738521. eCollection 2021.
Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in older people. Low-grade inflammation is well-known as one of the pathogenic mechanisms in nAMD. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for nAMD, although macula atrophy (MA) developed under anti-VEGF therapy causes irreversible visual function impairment and is recognized as a serious disorder. Here, we show specific expression patterns of aqueous humor (AH) cytokines in nAMD eyes developing MA under intravitreal injection of aflibercept (IVA) as an anti-VEGF antibody and present predictive cytokines as biomarkers for the incidence of MA in nAMD eyes under IVA treatment.
Twenty-eight nAMD patients received three consecutive monthly IVA, followed by a regimen for 2 years. AH specimens were collected before first IVA (pre-IVA) and before third IVA (post-IVA). AH cytokine levels, visual acuity (VA), and central retinal thickness (CRT) were measured.
Two-year incidence of MA was 21.4%. In nAMD eyes developing MA [MA (+) group], pre-IVA levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1β, VEGF and post-IVA level of MCP-1 were higher than those in nAMD eyes without MA [MA (-) group]. In hierarchical cluster analysis, pre-IVA MCP-1 and VEGF were grouped into the same subcluster, as were post-IVA MCP-1 and CRT. In principal component analysis, principal component loading (PCL) of pre-IVA interferon-γ-inducible protein 10 (IP-10) was 0.61, but PCL of post-IVA IP-10 decreased to -0.09. In receiver operating characteristic analysis and Kaplan-Meier curves, pre-IVA MCP-1, MIP-1β, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1β were detected as predictive factors for MA incidence. In 2-year clinical course, changes of VA in groups with high levels of pre-IVA MIP-1β (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group.
Substantial loss of IP-10 effects and persistent inflammation contribute to incidence of MA, and screening of AH cytokine levels could be a useful method to predict MA incidence in nAMD eyes under anti-VEGF therapy.
新生血管性年龄相关性黄斑变性（nAMD）是老年人致盲的主要原因之一。低度炎症是 nAMD 发病机制之一。抗血管内皮生长因子（VEGF）治疗是 nAMD 的一线治疗方法，尽管抗 VEGF 治疗下发生的黄斑萎缩（MA）导致不可逆转的视觉功能损害，被认为是一种严重的疾病。在这里，我们展示了在玻璃体内注射抗 VEGF 抗体阿柏西普（IVA）治疗 nAMD 时，发生 MA 的眼房水中特定的房水细胞因子表达模式，并提出了预测细胞因子作为 nAMD 眼IVA 治疗后 MA 发病的生物标志物。
28 名 nAMD 患者接受了连续 3 个月的每月一次 IVA，然后进行了 2 年的治疗方案。在首次 IVA 前（预-IVA）和第三次 IVA 前（后-IVA）采集房水标本。测量房水细胞因子水平、视力（VA）和中心视网膜厚度（CRT）。
2 年 MA 的发生率为 21.4%。在发生 MA 的 nAMD 眼中[MA（+）组]，与未发生 MA 的 nAMD 眼中[MA（-）组]相比，前 IVA 时单核细胞趋化蛋白-1（MCP-1）、巨噬细胞炎性蛋白（MIP）-1β、VEGF 的水平更高，后 IVA 时 MCP-1 水平更高。在层次聚类分析中，前 IVA MCP-1 和 VEGF 归为同一亚群，后 IVA MCP-1 和 CRT 也归为同一亚群。在主成分分析中，前 IVA 干扰素诱导蛋白 10（IP-10）的主成分负荷（PCL）为 0.61，但后 IVA IP-10 的 PCL 降低至-0.09。在受试者工作特征分析和 Kaplan-Meier 曲线中，前 IVA MCP-1、MIP-1β 和 VEGF 以及后 IVA 白细胞介素-6、MCP-1 和 MIP-1β 被检测为 MA 发生率的预测因素。在 2 年的临床病程中，前 IVA MIP-1β（超过 39.9 pg/ml）和 VEGF（超过 150.4 pg/ml）水平较高组的 VA 变化与 MA（+）组相当。
IP-10 作用的显著丧失和持续的炎症导致 MA 的发生，筛选房水细胞因子水平可能是预测 nAMD 眼抗 VEGF 治疗后 MA 发生率的有用方法。
