Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies
Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies
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DOI：
10.1001/jamaneurol.2019.3365
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发表时间：
2020-02-01
期刊：
影响因子：
29
通讯作者：
Frisell, Thomas
中科院分区：
文献类型：
--
作者：
Luna, Gustavo;Alping, Peter;Frisell, Thomas
问题：与多发性硬化症不同的疾病修饰治疗相关的感染风险是什么？调查结果：这项全国性的队列研究发现，多发性硬化症患者感染的风险普遍增加，这种风险部分取决于治疗的选择。注射疗法的感染率最低;在较新的治疗中，使用利妥昔单抗与严重感染率最高相关，但与芬戈莫德和那他珠单抗相比，使用疱疹抗病毒药物较少。根据这项研究的结果，医生和患者应该意识到与新的多发性硬化症治疗相关的感染风险，尤其是抗CD 20治疗。重要性：尽管与注射疗法干扰素β和醋酸格拉替雷（GA）相比，多发性硬化症（MS）的高效疾病修饰疗法与感染风险增加有关，但在现实世界人群中，潜在风险增加的程度尚未得到很好的确定。甚至更少的是已知的感染风险与利妥昔单抗，这是广泛使用的标签外治疗MS在Sweden.Objective：要检查严重感染的风险与疾病修饰治疗MS.设计，设置和参与者：这项全国性的基于登记的队列研究是在瑞典从2011年1月1日至2017年12月31日进行。使用了国家登记册和从公共卫生保健系统收集的前瞻性数据。所有瑞典复发缓解型MS患者的数据记录在瑞典MS登记册中，作为开始使用利妥昔单抗、那他珠单抗、芬戈莫德或干扰素β和GA治疗，以及年龄匹配和性别匹配的一般人群对照队列。严重感染定义为导致住院的所有感染。其他结果包括门诊使用抗生素或疱疹抗病毒药物治疗。调整后的风险比（HR）估计在考克斯regressions.Results：共6421例患者（3260服用利妥昔单抗，1588服用那他珠单抗，1535服用芬戈莫德，2217服用干扰素β/GA），加上一个比较队列的42645人。在6421例患者的8600次治疗事件中，治疗开始时的平均（SD）年龄范围为35. 0（10. 1）岁至40. 4（10. 6）岁; 6186例患者为女性。服用干扰素β和GA的MS患者的粗感染率高于普通人群（发生率，8.9 [95% CI，6.4-12.1] vs 5.2 [95% CI，4.8-5.5]/1000人-年），服用芬戈莫德的患者仍更高（发生率，14.3 [95%CI，10.8-18.5]/1000人-年）、那他珠单抗（发生率，11.4 [95%CI，8.3-15.3]/1000人-年）和利妥昔单抗（发生率，19.7 [95%CI，16.4-23.5]/1000人-年）。调整混杂因素后，与干扰素β和GA相比，利妥昔单抗（HR，1.70 [95% CI，1.11-2.61]）的发生率仍然显著较高，但芬戈莫德（HR，1.30 [95% CI，0.84-2.03]）或那他珠单抗（HR，1.12 [95% CI，0.71-1.77]）的发生率则不显著较高。相比之下，利妥昔单抗治疗期间疱疹抗病毒药物的使用与干扰素β和GA相似，低于那他珠单抗（HR，1.82 [1.34-2.46]）和芬戈莫德（HR，1.71 [95%CI，1.27-2.32]）。结论和相关性：MS患者感染的风险普遍增加，这因治疗而异。干扰素β和GA的感染率最低;在较新的治疗中，利妥昔单抗的超说明书使用与严重感染率最高相关。不同的风险特征应该为这些治疗的风险-获益评估提供信息。
Question: What is the risk of infections in association with different disease-modifying treatments for multiple sclerosis?Findings: This nationwide cohort study found that patients with multiple sclerosis are at a generally increased risk of infections, and this risk is partly dependent on the choice of treatment. The rate of infections was lowest with injectable therapies; among newer treatments, use of rituximab was associated with the highest rate of serious infections but less use of herpes antiviral medications compared with fingolimod and natalizumab.Meaning: Per the results of this study, physicians and patients should be aware of infection risks associated with newer multiple sclerosis treatments and perhaps particularly anti-CD20 therapies.This registry-based cohort study examines the risk of serious infections associated with disease-modifying treatments for multiple sclerosis in Sweden.Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.Design, Setting, and Participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA.Main Outcomes and Measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).Conclusions and Relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.