Importance Tumor necrosis factor (TNF) inhibitors are common therapies for certain autoimmune diseases, such as rheumatoid arthritis. An association between TNF inhibitor exposure and inflammatory central nervous system (CNS) events has been postulated but is poorly understood.

Objective To evaluate whether TNF inhibitor exposure is associated with inflammatory demyelinating and nondemyelinating CNS events in patients with an indication for TNF inhibitor use and to describe the spectrum of those CNS events.

Design, Setting, and Participants A nested case-control study was conducted using the medical records of patients with autoimmune diseases treated at 3 Mayo Clinic locations (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida) between January 1, 2003, and February 20, 2019. Patients were included if their records reported International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnostic codes for US Food and Drug Administration–approved autoimmune disease indication for TNF inhibitor use (ie, rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, Crohn disease, and ulcerative colitis) and diagnostic codes for inflammatory CNS events of interest. Patients were matched 1:1 with control participants by year of birth, type of autoimmune disease, and sex.

Exposures TNF inhibitor exposure data were derived from the medical records along with type of TNF inhibitor, cumulative duration of exposure, and time of exposure.

Main Outcomes and Measures The main outcome was either inflammatory demyelinating (multiple sclerosis and other diseases such as optic neuritis) or nondemyelinating (meningitis, meningoencephalitis, encephalitis, neurosarcoidosis, and CNS vasculitis) CNS event. Association with TNF inhibitor was evaluated with conditional logistic regression and adjusted for disease duration to determine the odds ratios (ORs) and 95% CIs. Secondary analyses included stratification of outcome by inflammatory demyelinating and nondemyelinating CNS events and by autoimmune disease (rheumatoid arthritis and non–rheumatoid arthritis).

Results A total of 212 individuals were included: 106 patients with inflammatory CNS events and 106 control participants without such events. Of this total, 136 were female (64%); the median (interquartile range) age at disease onset for patients was 52 (43-62) years. Exposure to TNF inhibitors occurred in 64 patients (60%) and 42 control participants (40%) and was associated with an increased risk of any inflammatory CNS event (adjusted OR, 3.01; 95% CI, 1.55-5.82; P = .001). These results were similar when the outcome was stratified by demyelinating and nondemyelinating CNS events. Secondary analyses found the association was predominantly observed in patients with rheumatoid arthritis (adjusted OR, 4.82; 95% CI, 1.62-14.36; P = .005).

Conclusions and Relevance This study found that exposure to TNF inhibitors in patients with autoimmune diseases appeared to be associated with increased risk for inflammatory CNS events. Whether this association represents de novo or exacerbated inflammatory pathways requires further research.

重要性 肿瘤坏死因子（TNF）抑制剂是某些自身免疫性疾病（例如类风湿关节炎）的常用疗法。TNF抑制剂暴露与炎症性中枢神经系统（CNS）事件之间的关联已被假定，但知之甚少。

目的 评估暴露于TNF抑制剂的患者中TNF抑制剂暴露是否与炎症性脱髓鞘和非脱髓鞘性CNS事件相关，并描述这些CNS事件的范围。

设计，背景和参与者 一项嵌套病例对照研究是利用2003年1月1日至3月5日在明尼苏达州罗切斯特，亚利桑那州斯科茨代尔和佛罗里达州杰克逊维尔的3个梅奥诊所治疗的自身免疫性疾病患者的病历进行的。 2019年2月20日。如果患者的记录报告《国际疾病和相关健康问题统计分类第十次修订本》，美国食品和药物管理局的诊断代码-批准使用TNF抑制剂的自身免疫性疾病指征（即类风湿性关节炎，强直性脊柱炎，牛皮癣和银屑病关节炎，克罗恩病和溃疡性结肠炎）和相关的炎症性CNS事件的诊断代码。根据出生年份，自身免疫疾病的类型和性别，将患者与对照参与者1：1配对。

暴露 TNF抑制剂的暴露数据来自医疗记录，以及TNF抑制剂的类型，暴露的累积持续时间和暴露时间。

主要结果和措施 主要结果是炎性脱髓鞘（多发性硬化和其他疾病，如视神经炎）或非脱髓鞘（脑膜炎，脑膜脑炎，脑炎，神经结节病和CNS脉管炎）CNS事件。通过条件逻辑回归评估与TNF抑制剂的关联，并根据疾病持续时间进行调整，以确定比值比（OR）和95％CI。次要分析包括炎症性脱髓鞘和非脱髓鞘中枢神经系统事件以及自身免疫性疾病（类风湿关节炎和非类风湿关节炎）的结局分层。

结果 共纳入212人：106例具有炎症性中枢神经系统事件的患者和106例无此类事件的对照组。在这一总数中，有136名是女性（64％）；患者发病的中位年龄（四分位间距）为52（43-62）岁。TNF抑制剂的暴露发生在64位患者（60％）和42位对照参与者（40％）中，并且与任何炎性CNS事件的风险增加相关（校正后的OR，3.01； 95％CI，1.55-5.82；P  = 0.001） ）。当通过脱髓鞘和非脱髓鞘的中枢神经系统事件对结果进行分层时，这些结果是相似的。二级分析发现，这种关联主要在类风湿关节炎患者中观察到（校正后OR，4.82； 95％CI，1.62-14.36；P  = 0.005）。

结论与相关性 这项研究发现，自身免疫性疾病患者接触TNF抑制剂似乎与炎症性中枢神经系统事件的风险增加有关。这种关联是否代表从头开始或加剧的炎症途径尚需进一步研究。