Filippini Graziella, Kruja Jera, Del Giovane Cinzia
Scientific Director's Office, Carlo Besta Foundation and Neurological Institute, Milan, Italy.
Neurology, UHC Mother Theresa, University of Medicine, Tirana, Albania.
Cochrane Database Syst Rev. 2025 Mar 11;3(3):CD013874. doi: 10.1002/14651858.CD013874.pub3.
Multiple sclerosis (MS) is the most common neurological cause of disability in young adults. Off-label rituximab for MS is used in most countries surveyed by the International Federation of MS, including high-income countries where on-label disease-modifying treatments (DMTs) are available. This updates the 2021 version of the review.
To assess the benefits and harms of rituximab as 'first choice' and 'switching' treatment for adults with any form of MS.
We searched CENTRAL, MEDLINE, Embase, CINAHL, and three trials registers on 31 December 2023, together with reference checking and contacting study authors to identify unpublished studies.
We included randomised controlled trials (RCTs) and controlled non-randomised studies of interventions (NRSIs) comparing rituximab with placebo or another DMT for adults with any form of MS.
We followed standard Cochrane methods. We used RoB 1 to assess risk of bias in RCTs and ROBINS-I in NRSIs. We assessed the certainty of evidence for critical and important prioritised outcomes using GRADE: disability worsening, relapse, serious adverse events (SAEs), health-related quality of life (HRQoL), common infections, cancer, and mortality. We conducted separate analyses for rituximab as 'first choice' or as 'switching' treatment, relapsing or progressive MS, comparison with placebo or another DMT, and RCTs or NRSIs.
In this update, the number of study participants increased from 16,429 (15 studies) to 37,443 (28 studies; 13 new studies: 1 RCT and 12 NRSIs). The studies were conducted worldwide; most originated from high-income countries (25 studies). Public institutions funded 22 (79%) of the studies. Most studies investigated the effects of rituximab on people with relapsing MS (19 studies; 27,500 (73%) participants). We identified 12 ongoing studies. Rituximab as 'first choice' for active relapsing MS None of the included studies compared rituximab to placebo. One RCT compared rituximab to dimethyl fumarate, with 24 months' follow-up. Rituximab may reduce the recurrence of relapse (odds ratio (OR) 0.16, 95% confidence interval (CI) 0.04 to 0.57; 195 participants; low-certainty evidence). The evidence is very uncertain on disability worsening and SAEs. Rituximab may result in little to no difference in upper respiratory tract infections (rate ratio (RR) 1.03, 95% CI 0.79 to 1.34; low-certainty evidence). The evidence is very uncertain for urinary tract, skin, and viral infections. HRQoL, cancer, and mortality were not reported. One NRSI compared rituximab to other DMTs, with 24 months' follow-up. Disability worsening was not reported. Compared with interferon beta or glatiramer acetate, rituximab likely delays relapse (hazard ratio (HR) 0.14, 95% CI 0.05 to 0.39; 1 study, 335 participants; moderate-certainty evidence). Compared with dimethyl fumarate and natalizumab, rituximab may delay relapse (dimethyl fumarate: HR 0.29, 95% CI 0.08 to 1.00; 1 study, 206 participants; low-certainty evidence; natalizumab: HR 0.24, 95% CI 0.06 to 1.00; 1 study, 170 participants; low-certainty evidence). The evidence for relapse is very uncertain when comparing rituximab to fingolimod. The effect on SAEs is uncertain due to very few events in all the comparison groups. No deaths were reported. HRQoL, common infections, and cancer were not reported. Rituximab as 'first choice' for primary progressive MS One RCT compared rituximab to placebo, with 24 months' follow-up. Rituximab likely results in little or no difference in disability worsening (OR 0.71, 95% CI 0.45 to 1.11; 439 participants; moderate-certainty evidence). The evidence is very uncertain on relapse, SAEs, common infections, cancer, and mortality. HRQoL was not reported. None of the included studies compared rituximab as 'first choice' treatment to other DMTs for primary or secondary progressive MS. Rituximab as 'switching' treatment for relapsing MS One small RCT compared rituximab to placebo, with 12 months' follow-up. Disability worsening was not reported. Rituximab may reduce recurrence of relapses (OR 0.38, 95% CI 0.16 to 0.93; 1 study, 104 participants; low-certainty evidence). The evidence is very uncertain regarding SAEs, common infections, cancer, and mortality. HRQoL was not reported. Twelve NRSIs compared rituximab to other DMTs, with 24 months' follow-up. The evidence on disability worsening is very uncertain in comparison with interferons or glatiramer acetate, natalizumab, alemtuzumab, and ocrelizumab. Rituximab likely delays time to relapse in comparison with interferons or glatiramer acetate (HR 0.18, 95% CI 0.07 to 0.49; 1 study, 1383 participants; moderate-certainty evidence), fingolimod (HR 0.08, 95% CI 0.02 to 0.32; 1 study, 256 participants; moderate-certainty evidence), and may result in little or no difference compared with natalizumab (HR 0.96, 95% CI 0.83 to 1.10; 3 studies, 1922 participants; low-certainty evidence). The evidence is very uncertain on relapse in comparison with alemtuzumab. There is uncertainty regarding SAEs when comparing rituximab to natalizumab and fingolimod. Rituximab likely increases serious common infections when compared with interferon beta or glatiramer acetate (OR 1.71, 95% CI 1.11 to 2.62; 1 study, 5477 participants; moderate-certainty evidence) and natalizumab (OR 1.58, 95% CI 1.08 to 2.32; 2 studies, 5001 participants; moderate-certainty evidence). The evidence for common infections is very uncertain when comparing rituximab to fingolimod and ocrelizumab. Rituximab may slightly reduce the risk of cancer compared with natalizumab (HR 0.79, 95% CI 0.62 to 0.99; 2 studies, 6202 participants; low-certainty evidence), whereas the evidence is very uncertain in comparison with fingolimod. The effect of rituximab on mortality is very uncertain due to very few events in all the comparison groups. HRQoL was not reported.
AUTHORS' CONCLUSIONS: For preventing relapses in relapsing MS, rituximab as 'first choice' and 'switching' treatment compares favourably with a wide range of approved DMTs. The protective effect of rituximab against disability worsening is uncertain. There is limited information to determine the effect of rituximab on primary progressive MS. There is limited evidence for long-term adverse events of rituximab in people with MS. Evidence for serious adverse events, cancer, and mortality was of very low certainty due to few events. There is an increased risk of serious (hospital-treated) infections with rituximab compared with other DMTs, although the absolute risk is low. High-quality (prospectively registered) NRSIs should be conducted to draw more reliable conclusions about the potential benefits and harms of rituximab in people with MS.
多发性硬化症（MS）是年轻成年人致残的最常见神经学病因。在国际多发性硬化症联合会调查的大多数国家，包括有标签适应证的疾病修饰治疗（DMT）药物可用的高收入国家，均使用利妥昔单抗治疗MS，但属于超适应证用药。本综述更新了2021年版本。
评估利妥昔单抗作为任何形式MS成人患者的“首选”和“转换”治疗的益处和危害。
我们于2023年12月31日检索了Cochrane系统评价数据库、MEDLINE、Embase、护理学与健康领域数据库（CINAHL）以及三个试验注册库，并进行参考文献核对以及与研究作者联系以识别未发表的研究。
我们纳入了随机对照试验（RCT）和干预性非随机对照研究（NRSC），这些研究比较了利妥昔单抗与安慰剂或其他DMT药物对任何形式MS成人患者的疗效。
我们遵循Cochrane标准方法。我们使用Cochrane偏倚风险评估工具1（RoB 1）评估RCT中的偏倚风险，使用非随机干预性研究的偏倚风险评估工具（ROBINS-I）评估NRSC中的偏倚风险。我们使用GRADE评估关键和重要优先结局的证据确定性：残疾恶化、复发、严重不良事件（SAE）、健康相关生活质量（HRQoL）、常见感染、癌症和死亡率。我们分别对利妥昔单抗作为“首选”或“转换”治疗、复发型或进展型MS、与安慰剂或其他DMT药物比较以及RCT或NRSC进行了分析。
在本次更新中，研究参与者数量从16429名（15项研究）增加到37443名（28项研究；13项新研究：1项RCT和12项NRSC）。这些研究在全球范围内开展；大多数研究来自高收入国家（25项研究）。22项（79%）研究由公共机构资助。大多数研究调查了利妥昔单抗对复发型MS患者的影响（19项研究；27500名（73%）参与者）。我们识别出12项正在进行的研究。
利妥昔单抗作为复发型MS的“首选”治疗：纳入的研究中没有一项将利妥昔单抗与安慰剂进行比较。一项RCT将利妥昔单抗与富马酸二甲酯进行比较，并进行了24个月随访。利妥昔单抗可能会降低复发率（比值比（OR）0.16，95%置信区间（CI）0.04至0.57；195名参与者；低确定性证据）。关于残疾恶化和SAE的证据非常不确定。利妥昔单抗可能对上呼吸道感染影响不大或无影响（率比（RR）1.03，95%CI 0.79至1.34；低确定性证据）。关于泌尿系统、皮肤和病毒感染的证据非常不确定。未报告HRQoL、癌症和死亡率。一项NRSC将利妥昔单抗与其他DMT药物进行比较，并进行了24个月随访。未报告残疾恶化情况。与干扰素β或醋酸格拉替雷相比，利妥昔单抗可能会延迟复发（风险比（HR）0.14，95%CI 0.05至0.39；1项研究，335名参与者；中度确定性证据）。与富马酸二甲酯和那他珠单抗相比，利妥昔单抗可能会延迟复发（富马酸二甲酯：HR 0.29，95%CI 0.08至1.00；1项研究，206名参与者；低确定性证据；那他珠单抗：HR 0.24，95%CI 0.06至1.00；1项研究，170名参与者；低确定性证据）。当将利妥昔单抗与芬戈莫德比较时，复发的证据非常不确定。由于所有比较组中的事件很少，因此对SAE的影响尚不确定。未报告死亡情况。未报告HRQoL、常见感染和癌症。
利妥昔单抗作为原发进展型MS的“首选”治疗：一项RCT将利妥昔单抗与安慰剂进行比较，并进行了24个月随访。利妥昔单抗可能对残疾恶化影响不大或无影响（OR 0.71，95%CI 0.45至1.11；439名参与者；中度确定性证据）。关于复发、SAE、常见感染、癌症和死亡率的证据非常不确定。未报告HRQoL。纳入的研究中没有一项将利妥昔单抗作为“首选”治疗与其他DMT药物用于原发或继发进展型MS进行比较。
利妥昔单抗作为复发型MS的“转换”治疗：一项小型RCT将利妥昔单抗与安慰剂进行比较，并进行了12个月随访。未报告残疾恶化情况。利妥昔单抗可能会降低复发率（OR 0.38，95%CI为0.16至0.93；1项研究，104名参与者；低确定性证据）。关于SAE、常见感染、癌症和死亡率的证据非常不确定。未报告HRQoL。12项NRSC将利妥昔单抗与其他DMT药物进行比较，并进行了24个月随访。与干扰素或醋酸格拉替雷相比时，残疾恶化的证据非常不确定。与那他珠单抗、阿仑单抗和奥瑞珠单抗相比时，利妥昔单抗可能会延迟复发时间。与干扰素或醋酸格拉替雷相比时，利妥昔单抗可能会延迟复发（HR 为0.18，95%CI为0.07至0.49；1项研究，1383名参与者；中度确定性证据），与芬戈莫德相比可能会延迟复发（HR 为0.08，95%CI为0.02至0.32；1项研究，256名参与者；中度确定性证据），与那他珠单抗相比可能影响不大或无影响（HR 为0.96，95%CI为0.83至1.10；3项研究，1922名参与者；低确定性证据）。与阿仑单抗相比时，复发的证据非常不确定。当将利妥昔单抗与那他珠单抗和芬戈莫德比较时，SAE的情况尚不确定。与干扰素β或醋酸格拉替雷相比时，利妥昔单抗可能会增加严重常见感染（OR 为1.71，95%CI为1.11至2.62；1项研究，5477名参与者；中度确定性证据），与那他珠单抗相比时也可能会增加严重常见感染（OR 为1.58，95%CI为1.08至2.32；2项研究，5001名参与者；中度确定性证据）。当将利妥昔单抗与芬戈莫德和奥瑞珠单抗比较时，常见感染的证据非常不确定。与那他珠单抗相比时，利妥昔单抗可能会略微降低癌症风险（HR 为0.79，95%CI为0.62至0.99；2项研究，6202名参与者；低确定性证据），与芬戈莫德相比时证据非常不确定。由于所有比较组中的事件很少，因此利妥昔单抗对死亡率的影响非常不确定。未报告HRQoL。
对于预防复发型MS的复发，利妥昔单抗作为“首选”和“转换”治疗与多种已批准的DMT药物相比具有优势。利妥昔单抗对残疾恶化的保护作用尚不确定。关于利妥昔单抗对原发进展型MS的影响，信息有限。关于利妥昔单抗在MS患者中的长期不良事件，证据有限。由于事件较少，严重不良事件、癌症和死亡率的证据确定性非常低。与其他DMT药物相比，利妥昔单抗导致严重（需住院治疗）感染的风险增加，尽管绝对风险较低。应开展高质量（前瞻性注册）的NRSC，以更可靠地评估利妥昔单抗对MS患者的潜在益处和危害。
