药物相关脱髓鞘：基于FAERS数据库的回顾性药物警戒研究

Drug-Related Demyelination: A Retrospective Pharmacovigilance Study Based on the FAERS Database

摘要: 目的：本研究旨在基于美国食品药品监督管理局不良事件报告系统(FAERS)数据库，识别与脱髓鞘不良事件关联性报告最频繁的药物。方法：采用不成比例分析法评估2004年第一季度至2024年第四季度期间上报至FAERS的药物相关脱髓鞘报告。通过火山图、单因素分析、LASSO回归及多因素回归分析探讨药物相关脱髓鞘的风险因素。采用Kaplan-Meier法评估脱髓鞘事件的累积发生率。结果：FAERS数据库共识别116,250例药物相关脱髓鞘不良事件报告。患者人口学特征显示，女性占比显著(85,027例，73.1%)。多因素回归分析确定女性性别及21种药物(包括那他珠单抗、干扰素β-1a、富马酸、芬戈莫德、醋酸格拉替雷)为显著风险因素。报告病例数最多的三种药物依次为：那他珠单抗(24,664例，报告比值比ROR = 34.55 [34.04~35.08])、干扰素β-1a (20,488例，ROR = 29.04 [28.58~29.51])和富马酸(11,507例，ROR = 20.97 [20.55~21.40])。报告最频繁的一级解剖治疗化学(ATC)类别为抗肿瘤药及免疫调节剂(n = 47, 62.7%)，其次为全身用抗感染药(n = 16, 21.3%)。药物相关脱髓鞘发生的中位时间为248天。25.18%的不良事件发生于用药后30天内，43.04%发生于用药360天后。结论：本研究结果有助于临床医生早期识别潜在的药物相关脱髓鞘高风险药物和人群(如女性)，并为阐明其发病机制提供重要线索。所发现的说明书风险信息缺失(如阿昔洛韦等4种药物)提示需关注非典型药物风险及更新药品说明书。

Abstract: Objective: This study aimed to identify the most frequently reported drugs associated with demyelinating adverse events using the FDA Adverse Event Reporting System (FAERS) database. Methods: Disproportionality analysis was employed to evaluate reports of drug-related demyelination submitted to FAERS from the first quarter of 2004 to the fourth quarter of 2024. Risk factors for drug-related demyelination were explored using volcano plots, univariate analysis, LASSO regression, and multivariate regression analysis. The Kaplan-Meier method was utilized to assess the cumulative incidence of demyelinating events. Results: A total of 116,250 reports of drug-related demyelination were identified. Patient demographics revealed a significant female predominance (85,027; 73.1%). Multivariate analysis identified female sex and 21 drugs (including natalizumab, interferon beta-1a, fumaric acid, fingolimod, glatiramer acetate) as significant risk factors. The three drugs with the highest number of reported cases were natalizumab (24,664 cases; reporting odds ratio [ROR] = 34.55 [34.04~35.08]), interferon beta-1a (20,488 cases; ROR = 29.04 [28.58~29.51]), and fumaric acid (11,507 cases; ROR = 20.97 [20.55~21.40]). The most frequently reported first-level Anatomical Therapeutic Chemical (ATC) categories were antineoplastic and immunomodulating agents (n = 47, 62.7%), followed by antiinfectives for systemic use (n = 16, 21.3%). The median time to onset of drug-related demyelination was 248 days. Notably, 25.18% of adverse events occurred within the first 30 days of drug exposure, while 43.04% occurred after 360 days. Conclusion: This study aids clinicians in early identification of drugs and populations (e.g., females) at high risk for drug-related demyelination and provides insights into its pathogenesis. The finding that demyelination risk was undocumented in the labeling for 4 identified drugs (e.g., aciclovir) highlights the need for vigilance regarding non-traditional agents and potential label updates.