背景:不同的治疗策略可用于治疗复发缓解型多发性硬化症(RRMS)患者,包括免疫调节剂,免疫抑制剂和生物制剂。尽管与没有治疗相比,这些疗法中的每一种都降低了复发频率并减缓了残疾积累,他们的相对益处仍不清楚。这是2015年发布的Cochrane评论的更新。
目的:为了比较疗效和安全性,通过网络荟萃分析,干扰素β-1b,干扰素β-1a,醋酸格拉替雷,那他珠单抗,米托蒽醌,芬戈莫德,特立氟胺,富马酸二甲酯,阿仑单抗,聚乙二醇干扰素β-1a,daclizumab,拉喹莫德,硫唑嘌呤,免疫球蛋白,克拉屈滨,环磷酰胺,富马酸二肟酯,氟达拉滨,干扰素β1-a和β1-b,来氟米特,甲氨蝶呤,米诺环素,霉酚酸酯,Ofatumumab,奥扎曼德,ponesimod,利妥昔单抗,西波莫德和类固醇用于治疗RRMS患者。
方法:中央,MEDLINE,Embase,2021年9月21日搜索了两个试验登记册,并进行了参考检查,引文搜索和与研究作者联系以确定其他研究。2022年8月8日进行了充值搜索。
方法:随机对照试验(RCT)研究了一种或多种可用的免疫调节剂和免疫抑制剂作为单一疗法与安慰剂或另一种活性剂的比较,在患有RRMS的成年人中。
方法:两位作者独立选择研究并提取数据。我们考虑了直接和间接证据,并通过成对和网络荟萃分析进行了数据合成。通过等级方法评估证据的确定性。
结果:我们纳入了50项研究,涉及36,541名参与者(68.6%为女性,31.4%为男性)。中位治疗时间为24个月,和25(50%)的研究是安慰剂对照。考虑到偏见的风险,最常见的问题是赞助商在研究报告作者或数据管理和分析中的作用,对此,我们判断68%的研究存在其他偏倚的高风险.其他常见的担忧是绩效偏差(34%被认为具有高风险)和减员偏差(32%被认为具有高风险)。安慰剂用作网络分析的常用比较器。12个月以上的复发:18项研究提供了数据(9310名参与者)。那他珠单抗导致12个月时复发患者的大幅减少(RR0.52,95%CI0.43至0.63;高确定性证据)。芬戈莫德(RR0.48,95%CI0.39至0.57;中等确定性证据),达克利珠单抗(RR0.55,95%CI0.42至0.73;中等确定性证据),和免疫球蛋白(RR0.60,95%CI0.47~0.79;中度确定性证据)可能导致12个月时复发患者的大幅减少.超过24个月的复发:28项研究报告了数据(19,869名参与者)。克拉屈滨(RR0.53,95%CI0.44至0.64;高确定性证据),阿仑珠单抗(RR0.57,95%CI0.47~0.68;高确定性证据)和那他珠单抗(RR0.56,95%CI0.48~0.65;高确定性证据)导致24个月时复发人数大幅减少.芬戈莫德(RR0.54,95%CI0.48至0.60;中等确定性证据),富马酸二甲酯(RR0.62,95%CI0.55至0.70;中等确定性证据),和ponesimod(RR0.58,95%CI0.48~0.70;中度确定性证据)可能导致24个月时复发人数大幅减少.醋酸格拉替雷(RR0.84,95%,CI0.76至0.93;中度确定性证据)和干扰素β-1a(Avonex,Rebif)(RR0.84,95%CI0.78至0.91;中度确定性证据)可能会在24个月时适度减少复发患者。超过36个月的复发结果可从五项研究(3087名参与者)获得。与安慰剂相比,评估的治疗方法均未显示中度或高度确定性的证据。在31项研究(24,303名参与者)中评估了24个月内的残疾恶化。那他珠单抗可能导致24个月时残疾恶化的大幅减少(RR0.59,95%CI0.46至0.75;中度确定性证据)。在三项研究(2684名参与者)中评估了36个月以上的残疾恶化,但没有一项研究使用安慰剂作为比较物。43项研究(35,410名参与者)提供了因不良事件而停止治疗的数据。Alemtuzumab可能导致因不良事件导致的治疗中止略有减少(OR0.39,95%CI0.19至0.79;中度确定性证据)。Daclizumab(OR2.55,95%CI1.40至4.63;中等确定性证据),芬戈莫德(OR1.84,95%CI1.31至2.57;中等确定性证据),特立氟胺(OR1.82,95%CI1.19至2.79;中度确定性证据),干扰素β-1a(OR1.48,95%CI0.99至2.20;中等确定性证据),拉喹莫德(OR1.49,95%CI1.00至2.15;中等确定性证据),那他珠单抗(OR1.57,95%CI0.81至3.05),醋酸格拉替雷(OR1.48,95%CI1.01~2.14;中度确定性证据)可能导致因不良事件而停止治疗的人数略有增加.35项研究报告了严重不良事件(SAE)(33,998名参与者)。与安慰剂相比,接受干扰素β-1b治疗的RRMS患者的SAE可能略有减少(OR0.92,95%CI0.55至1.54;中度确定性证据)。
结论:我们非常有信心,与安慰剂相比,用那他珠单抗治疗两年,克拉屈滨,或阿仑珠单抗比其他DMT更能减少复发。我们适度相信,使用那他珠单抗的两年治疗可能会减缓残疾进展。与安慰剂相比,接受大多数评估的DMT治疗的RRMS患者由于AE而中断治疗的频率更高:我们适度相信芬戈莫德可能会发生这种情况,特立氟胺,干扰素β-1a,拉喹莫德,那他珠单抗和达克利珠单抗,而我们对其他DMT的确定性较低。我们还适度确定,与安慰剂相比,阿仑单抗治疗因不良事件导致的停药次数较少。并且适度确定干扰素β-1b可能导致经历严重不良事件的人的轻微减少,但我们对其他DMT的确定性较低。没有足够的证据来评估DMT在超过两年的时间内的疗效和安全性。这是一个相关的问题,慢性疾病,如MS,发展了几十年。超过一半的纳入研究是由制药公司赞助的,这可能影响了他们的结果。进一步的研究应该集中在活性剂之间的直接比较,至少随访三年,并评估其他患者相关结果,比如生活质量和认知状态,特别关注性别/性别对治疗效果的影响。
Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015.
To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS.
CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022.
Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS.
Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach.
We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence).
We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.