Comparative Risk of Alzheimer Disease and Related Dementia Among Medicare Beneficiaries With Rheumatoid Arthritis Treated With Targeted Disease-Modifying Antirheumatic Agents.
Comparative Risk of Alzheimer Disease and Related Dementia Among Medicare Beneficiaries With Rheumatoid Arthritis Treated With Targeted Disease-Modifying Antirheumatic Agents.
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DOI：
10.1001/jamanetworkopen.2022.6567
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发表时间：
2022-04-01
影响因子：
13.8
通讯作者：
Thambisetty M
中科院分区：
文献类型：
--
作者：
Desai RJ;Varma VR;Gerhard T;Segal J;Mahesri M;Chin K;Horton DB;Kim SC;Schneeweiss S;Thambisetty M
靶向疾病改善抗风湿药物的使用与阿尔茨海默病和相关痴呆（ADRD）的风险相关吗？在这项包括22569对倾向评分匹配的患者的队列研究中，与开始使用abatacept（一种t细胞活化抑制剂）相比，开始使用Janus-kinase、白细胞介素-6或肿瘤坏死因子抑制剂与降低ADRD风险无关。这些结果不支持将靶向改善疾病的抗风湿药物作为ADRD的疾病改善候选药物。本队列研究比较了使用改善疾病的抗风湿药物的类风湿关节炎医保患者阿尔茨海默病和相关痴呆的发病率。在基于多组学表型的有效阿尔茨海默病药物再用途（DREAM）倡议中，细胞因子信号，包括肿瘤坏死因子（TNF）和白细胞介素(IL)-6，通过Janus-kinase （JAK）信号转导和转录途径激活因子，被假设可以降低阿尔茨海默病和相关痴呆（ADRD）的风险。评估托法替尼、托珠单抗或TNF抑制剂与阿巴接受治疗与adr发生风险之间的关系。这项队列研究是在2007年至2017年美国65岁及以上的类风湿关节炎患者中进行的。根据开始使用tofacitinib（一种JAK抑制剂）、tocilizumab（一种IL-6抑制剂）或TNF抑制剂与常用比较物abatacept（一种t细胞活化抑制剂）的比较，将患者分为3个队列。分析时间为2020年8月至2021年8月。主要结果是基于4种可选分析方案评估的诊断代码的ADRD发病情况：(1)治疗后随访法，(2)6个月的诱导期起始随访法，(3)将6个月的症状与诊断期结合起来，以解释ADRD发病的错误分类，(4)通过对症处方和诊断代码识别ADRD。通过倾向评分匹配调整79个暴露前特征后，通过Cox比例风险回归计算95% ci的风险比（hr）。在与使用abatacept的患者进行1:1的倾向评分匹配后，共评估了22 569对倾向评分匹配的患者，包括4224对托法替尼（平均[SD]年龄72.19[5.65]岁；6945[82.2%]名女性）、6369对托珠单抗（平均[SD]年龄72.01[5.46]岁；10 105[79.4%]名女性）和11 976对TNF抑制剂（平均[SD]年龄72.67[5.91]岁；19 710[82.3%]名女性）。在不同的分析方案中，ADRD的发病率从每1000人年2例到18例不等。ADRD与托法替尼（分析1:HR， 0.90 [95% CI, 0.55-1.51]；分析2:HR， 0.78 [95% CI, 0.53-1.13]；分析3:HR， 1.29 [95% CI, 0.72-2.33]；分析4:HR， 0.50 [95% CI, 0.21-1.20]）、托珠单抗（分析1:HR， 0.82 [95% CI, 0.55-1.21]；分析2:HR， 1.05 [95% CI, 0.81-1.35]；分析3:HR， 1.21 [95% CI, 0.75-1.96]；分析4:HR， 0.78 [95% CI, 0.44-1.39]）或TNF抑制剂(分析1:HR， 0.93 [95% CI, 0.72-1.20]；分析2:HR， 1.02 [95% CI, 0.86-1.20]；分析3:HR， 1.13 [95% CI, 0.86-1.48]；分析4:0.90 [95% CI, 0.60-1.37])。根据年龄、性别和基线心血管疾病进行的预先指定亚组分析的结果是一致的，除了心血管疾病患者，TNF抑制剂与阿巴他普发生ADRD的潜在风险较低，但仅在分析2和4中（分析1:HR， 0.76 [95% CI, 0.50-1.16]；分析2:HR， 0.74 [95% CI, 0.56-0.99]；分析3:HR， 1.03 [95% CI, 0.65-1.61]；分析4:HR， 0.45 [95% CI, 0.21-0.98]）。该队列研究未发现与阿巴接受相比，接受托法替尼、托珠单抗或TNF抑制剂治疗的患者发生不良反应的风险有任何关联。
Is use of targeted disease-modifying antirheumatic drugs associated with risk of Alzheimer disease and related dementia (ADRD)? In this cohort study including 22 569 propensity score–matched patient pairs, initiation of inhibitors of Janus-kinase, interleukin-6, or tumor necrosis factor was not associated with reduced risk of ADRD compared with initiation of abatacept, a T-cell activation inhibitor. These results do not support advancing targeted disease-modifying antirheumatic drugs as disease modifying candidates for ADRD. This cohort study compares incidence of Alzheimer disease and related dementia among Medicare patients with rheumatoid arthritis using disease-modifying antirheumatic drugs. Cytokine signaling, including tumor necrosis factor (TNF) and interleukin (IL)-6, through the Janus-kinase (JAK)–signal transducer and activator of transcription pathway, was hypothesized to attenuate the risk of Alzheimer disease and related dementia (ADRD) in the Drug Repurposing for Effective Alzheimer Medicines (DREAM) initiative based on multiomics phenotyping. To evaluate the association between treatment with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept and risk of incident ADRD. This cohort study was conducted among US Medicare fee-for-service patients with rheumatoid arthritis aged 65 years and older from 2007 to 2017. Patients were categorized into 3 cohorts based on initiation of tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors compared with a common comparator abatacept (a T-cell activation inhibitor). Analyses were conducted from August 2020 to August 2021. The main outcome was onset of ADRD based on diagnosis codes evaluated in 4 alternative analysis schemes: (1) an as-treated follow-up approach, (2) an as-started follow-up approach incorporating a 6-month induction period, (3) incorporating a 6-month symptom to diagnosis period to account for misclassification of ADRD onset, and (4) identifying ADRD through symptomatic prescriptions and diagnosis codes. Hazard ratios (HRs) with 95% CIs were calculated from Cox proportional hazard regression after adjustment for 79 preexposure characteristics through propensity score matching. After 1:1 propensity score matching to patients using abatacept, a total of 22 569 propensity score–matched patient pairs, including 4224 tofacitinib pairs (mean [SD] age 72.19 [5.65] years; 6945 [82.2%] women), 6369 tocilizumab pairs (mean [SD] age 72.01 [5.46] years; 10 105 [79.4%] women), and 11 976 TNF inhibitor pairs (mean [SD] age 72.67 [5.91] years; 19 710 [82.3%] women), were assessed. Incidence rates of ADRD varied from 2 to 18 per 1000 person-years across analyses schemes. There were no statistically significant associations of ADRD with tofacitinib (analysis 1: HR, 0.90 [95% CI, 0.55-1.51]; analysis 2: HR, 0.78 [95% CI, 0.53-1.13]; analysis 3: HR, 1.29 [95% CI, 0.72-2.33]; analysis 4: HR, 0.50 [95% CI, 0.21-1.20]), tocilizumab (analysis 1: HR, 0.82 [95% CI, 0.55-1.21]; analysis 2: HR, 1.05 [95% CI, 0.81-1.35]; analysis 3: HR, 1.21 [95% CI, 0.75-1.96]; analysis 4: HR, 0.78 [95% CI, 0.44-1.39]), or TNF inhibitors (analysis 1: HR, 0.93 [95% CI, 0.72-1.20]; analysis 2: HR, 1.02 [95% CI, 0.86-1.20]; analysis 3: HR, 1.13 [95% CI, 0.86-1.48]; analysis 4: 0.90 [95% CI, 0.60-1.37]) compared with abatacept. Results from prespecified subgroup analysis by age, sex, and baseline cardiovascular disease were consistent except in patients with cardiovascular disease, for whom there was a potentially lower risk of ADRD with TNF inhibitors vs abatacept, but only in analyses 2 and 4 (analysis 1: HR, 0.76 [95% CI, 0.50-1.16]; analysis 2: HR, 0.74 [95% CI, 0.56-0.99]; analysis 3: HR, 1.03 [95% CI, 0.65-1.61]; analysis 4: HR, 0.45 [95% CI, 0.21-0.98]). This cohort study did not find any association of risk of ADRD in patients treated with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept.
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影响因子：
39
作者：
Fralick, Michael;Kesselheim, Aaron S.;Schneeweiss, Sebastian
通讯作者：
Schneeweiss, Sebastian
影响因子：
16.2
作者：
Patorno, Elisabetta;Schneeweiss, Sebastian;Franklin, Jessica M.
通讯作者：
Franklin, Jessica M.
影响因子：
5
作者：
Fukuyama, Tomoki;Tschernig, Thomas;Baeumer, Wolfgang
通讯作者：
Baeumer, Wolfgang
DOI：
10.1093/gerona/glx229
发表时间：
2018-07-01
影响因子：
5.1
作者：
Kim, Dae Hyun;Schneeweiss, Sebastian;Avorn, Jerry
通讯作者：
Avorn, Jerry
DOI：
10.1002/trc2.12163
发表时间：
2021
期刊：
Alzheimer's & dementia (New York, N. Y.)
影响因子：
--
作者：
Kern DM;Lovestone S;Cepeda MS
通讯作者：
Cepeda MS