Interferon beta-1b

干扰素 β - 1b
  • 文章类型: Journal Article
    多发性硬化症(MS)治疗干预与免疫调节治疗在疾病早期阶段改善短期临床结果。本研究的目的是描述Betaferon®/Betaseron®在新兴MS初始治疗(BENEFIT)中随机分组的临床孤立综合征(CIS)患者的长期结果和医疗保健利用,平行组试验。在BENEFIT中,患者被分配到“早期”IFNB-1b治疗或安慰剂(“延迟”治疗)。2年后或转换为临床明确的多发性硬化症(CDMS),所有患者均接受IFNB-1b治疗,并在15年后重新评估.468名患者中,261人(55.8%)被纳入受益15人(161人[55.1%],100[56.8%]来自延迟治疗组)。在完整的利益分析集中,早期治疗组患者转CDMS的风险仍然较低(-30.5%;风险比0.695[95%CI,0.547-0.883];p=0.0029),复发风险比延迟治疗组低15.7%(p=0.1008).总的来说,25例患者(9.6%;早期9.9%,9.0%延迟)转化为继发性进行性多发性硬化症。在扩展的残疾状态量表评分或MRI指标中,残疾率保持较低且稳定,组间没有显着差异。在早期治疗组中,起搏听觉系列增加任务-3评分更好(对于15年以上的治疗效果,p=0.0036)。66.3%的患者在15年仍有工作,而基线为74.7%。总之,从初始随机化开始的15年结果支持IFNB-1b早期治疗的长期益处.
    Multiple sclerosis (MS) treatment intervention with immunomodulating therapy at early disease stage improves short term clinical outcomes. The objective of this study is to describe the long-term outcomes and healthcare utilization of patients with clinically isolated syndrome (CIS) included in the Betaferon®/Betaseron® in Newly Emerging MS for Initial Treatment (BENEFIT) randomized, parallel group trial. In BENEFIT patients were assigned to \"early\" IFNB-1b treatment or placebo (\"delayed\" treatment). After 2 years or conversion to clinically definite multiple sclerosis (CDMS), all patients were offered IFNB-1b and were reassessed 15 years later. Of 468 patients, 261 (55.8%) were enrolled into BENEFIT 15 (161 [55.1%] from the early, 100 [56.8%] from the delayed treatment arm). In the full BENEFIT analysis set, risk of conversion to CDMS remained lower in the early treatment group ( - 30.5%; hazard ratio 0.695 [95% CI, 0.547-0.883]; p = 0.0029) with a 15.7% lower risk of relapse than in the delayed treatment group (p = 0.1008). Overall, 25 patients (9.6%; 9.9% early, 9.0% delayed) converted to secondary progressive multiple sclerosis. Disability remained low and stable with no significant difference between groups in Expanded Disability Status Scale score or MRI metrics. Paced Auditory Serial Addition Task-3 scores were better in the early treatment group (p = 0.0036 for treatment effect over 15 years). 66.3% of patients were still employed at Year 15 versus 74.7% at baseline. In conclusion, results 15 years from initial randomization support long-term benefits of early treatment with IFNB-1b.
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  • 文章类型: Meta-Analysis
    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.
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  • 文章类型: Meta-Analysis
    背景:多发性硬化症(MS)是中枢神经系统的一种慢性疾病,主要影响年轻人(女性的发病率是男性的2至3倍),并在发病后导致严重的残疾。尽管人们认为MS患者的免疫疗法会降低疾病活动,他们的相对安全性仍然存在不确定性。
    目的:比较免疫疗法对MS或临床孤立综合征(CIS)患者的不良反应,并通过网络荟萃分析(NMA)根据不良反应的相对风险对这些治疗进行排名。
    方法:我们搜索了CENTRAL,PubMed,Embase,另外两个数据库和试验登记至2022年3月,同时进行参考文献检查和引文搜索以确定其他研究.
    方法:我们纳入了18岁或以上诊断为MS或CIS的参与者,根据任何公认的诊断标准,纳入随机对照试验(RCT)的患者,这些试验检查了MS或CIS中使用的一种或多种药物,并将它们与安慰剂或其他活性剂进行比较。我们排除了RCTs,其中将药物方案与没有其他活性剂或安慰剂作为对照的相同药物的不同方案进行比较。
    方法:我们使用标准Cochrane方法进行数据提取和成对荟萃分析。对于NMA,我们在R中使用netmeta命令套件来拟合随机效应NMA,假设研究之间的共同方差。我们使用CINeMA平台来评估NMA中证据体的确定性。与安慰剂相比,我们认为相对风险(RR)为1.5作为非劣效性安全阈值。我们根据等级评估了NMA中主要结局的证据的确定性,非常低,低,中等或高。
    结果:这项NMA纳入了123项试验,有57,682名参与者。84项研究提供了严重不良事件(SAE)报告,包括所有研究的57,682名参与者中51,833名(89.9%)参与者的5696(11%)事件。根据SAE的绝对频率,我们的非劣效性阈值(风险增加高达50%)意味着,与安慰剂相比,每18人中就有不超过1人出现SAE.低确定性证据表明,与安慰剂相比,三种药物可能会降低SAE(相对风险[RR],95%置信区间[CI]):干扰素β-1a(Avonex)(0.78,0.66至0.94);富马酸二甲酯(0.79,0.67至0.93),和醋酸格拉替雷(0.84,0.72至0.98)。与安慰剂相比,几种药物符合我们的非劣效性标准:特立氟胺的中度确定性证据(1.08,0.88至1.31);奥克瑞珠单抗的低度确定性证据(0.85,0.67至1.07),奥扎马德(0.88,0.59至1.33),干扰素β-1b(0.94,0.78至1.12),干扰素β-1a(Rebif)(0.96,0.80至1.15),那他珠单抗(0.97,0.79至1.19),芬戈莫德(1.05,0.92至1.20)和拉喹莫德(1.06,0.83至1.34);达克利珠单抗的确定性证据非常低(0.83,0.68至1.02)。由于其他药物的不精确,安慰剂的非劣效性未达到:克拉屈滨的低确定性证据(1.10,0.79至1.52),西波莫德(1.20,0.95至1.51),Ofatumumab(1.26,0.88至1.79)和利妥昔单抗(1.01,0.67至1.52);免疫球蛋白的极低确定性证据(1.05,0.33至3.32),富马酸二罗肟酯(1.05,0.23至4.69),聚乙二醇干扰素β-1a(1.07,0.66至1.74),阿仑单抗(1.16,0.85至1.60),干扰素(1.62,0.21至12.72)和硫唑嘌呤(3.62,0.76至17.19)。不良事件导致的退出报告来自105项研究(85.4%),包括所有研究中57,682名患者中的55,320名(95.9%)患者的3537(6.39%)事件。根据提款的绝对频率,我们的非劣效性阈值(高达50%的风险增加)意味着与安慰剂相比,每31人中不超过1人会退出.与安慰剂相比,没有药物减少由于不良事件导致的停药。有非常低的确定性证据(意味着估计不可靠)表明两种药物与安慰剂相比符合我们的非劣效性标准,假设95%CIRR上限为1.5:富马酸二罗肟酯(0.38,0.11~1.27)和阿仑珠单抗(0.63,0.33~1.19).由于以下药物的不精确,安慰剂的非劣效性未达到:ofatumumab的低确定性证据(1.50,0.87至2.59);甲氨蝶呤的极低确定性证据(0.94,0.02至46.70),皮质类固醇(1.05,0.16至7.14),奥扎马德(1.06,0.58至1.93),那他珠单抗(1.20,0.77至1.85),奥克瑞珠单抗(1.32,0.81至2.14),富马酸二甲酯(1.34,0.96至1.86),西波莫德(1.63,0.96至2.79),利妥昔单抗(1.63,0.53至5.00),克拉屈滨(1.80,0.89至3.62),米托蒽醌(2.11,0.50至8.87),干扰素(3.47,0.95至12.72),和环磷酰胺(3.86,0.45至33.50)。与安慰剂相比,由于不良事件,11种药物可能会增加停药:特立氟胺的低确定性证据(1.37,1.01至1.85),醋酸格拉替雷(1.76,1.36至2.26),芬戈莫德(1.79,1.40至2.28),干扰素β-1a(Rebif)(2.15,1.58至2.93),daclizumab(2.19,1.31至3.65)和干扰素β-1b(2.59,1.87至3.77);拉喹莫德的极低确定性证据(1.42,1.01至2.00),干扰素β-1a(Avonex)(1.54,1.13至2.10),免疫球蛋白(1.87,1.01至3.45),聚乙二醇干扰素β-1a(3.46,1.44至8.33)和硫唑嘌呤(6.95,2.57至18.78);然而,极不确定的证据是不可靠的。敏感性分析,仅包括低损耗偏倚的研究,药物剂量高于组中位数,或仅有复发缓解型MS或CIS的患者,通过先前的疾病改善治疗进行的亚组分析没有改变这些数字。排名没有药物在主要和次要结局的概率优于其他药物的上四分位数中产生一致的P评分。
    结论:我们发现,用于治疗MS的药物可能不会增加SAE的低和极低的确定性证据,但与安慰剂相比,可能会增加退出。结果表明,一线和二线药物之间以及口服之间在SAEs的发生没有重要差异。可注射,或者注射药物,与安慰剂相比。我们的审查,连同其他文学作品,从干预措施的随机对照试验证实不良事件报告质量差.至少,未来的研究应遵循CONSORT关于报告危害相关问题的建议。为了解决不利影响,未来的系统评价还应包括非随机研究.
    Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and causes significant disability after onset. Although it is accepted that immunotherapies for people with MS decrease disease activity, uncertainty regarding their relative safety remains.
    To compare adverse effects of immunotherapies for people with MS or clinically isolated syndrome (CIS), and to rank these treatments according to their relative risks of adverse effects through network meta-analyses (NMAs).
    We searched CENTRAL, PubMed, Embase, two other databases and trials registers up to March 2022, together with reference checking and citation searching to identify additional studies.
    We included participants 18 years of age or older with a diagnosis of MS or CIS, according to any accepted diagnostic criteria, who were included in randomized controlled trials (RCTs) that examined one or more of the agents used in MS or CIS, and compared them versus placebo or another active agent. We excluded RCTs in which a drug regimen was compared with a different regimen of the same drug without another active agent or placebo as a control arm.
    We used standard Cochrane methods for data extraction and pairwise meta-analyses. For NMAs, we used the netmeta suite of commands in R to fit random-effects NMAs assuming a common between-study variance. We used the CINeMA platform to GRADE the certainty of the body of evidence in NMAs. We considered a relative risk (RR) of 1.5 as a non-inferiority safety threshold compared to placebo. We assessed the certainty of evidence for primary outcomes within the NMA according to GRADE, as very low, low, moderate or high.
    This NMA included 123 trials with 57,682 participants. Serious adverse events (SAEs) Reporting of SAEs was available from 84 studies including 5696 (11%) events in 51,833 (89.9%) participants out of 57,682 participants in all studies. Based on the absolute frequency of SAEs, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 18 additional people would have a SAE compared to placebo. Low-certainty evidence suggested that three drugs may decrease SAEs compared to placebo (relative risk [RR], 95% confidence interval [CI]): interferon beta-1a (Avonex) (0.78, 0.66 to 0.94); dimethyl fumarate (0.79, 0.67 to 0.93), and glatiramer acetate (0.84, 0.72 to 0.98). Several drugs met our non-inferiority criterion versus placebo: moderate-certainty evidence for teriflunomide (1.08, 0.88 to 1.31); low-certainty evidence for ocrelizumab (0.85, 0.67 to 1.07), ozanimod (0.88, 0.59 to 1.33), interferon beta-1b (0.94, 0.78 to 1.12), interferon beta-1a (Rebif) (0.96, 0.80 to 1.15), natalizumab (0.97, 0.79 to 1.19), fingolimod (1.05, 0.92 to 1.20) and laquinimod (1.06, 0.83 to 1.34); very low-certainty evidence for daclizumab (0.83, 0.68 to 1.02). Non-inferiority with placebo was not met due to imprecision for the other drugs: low-certainty evidence for cladribine (1.10, 0.79 to 1.52), siponimod (1.20, 0.95 to 1.51), ofatumumab (1.26, 0.88 to 1.79) and rituximab (1.01, 0.67 to 1.52); very low-certainty evidence for immunoglobulins (1.05, 0.33 to 3.32), diroximel fumarate (1.05, 0.23 to 4.69), peg-interferon beta-1a (1.07, 0.66 to 1.74), alemtuzumab (1.16, 0.85 to 1.60), interferons (1.62, 0.21 to 12.72) and azathioprine (3.62, 0.76 to 17.19). Withdrawals due to adverse events Reporting of withdrawals due to AEs was available from 105 studies (85.4%) including 3537 (6.39%) events in 55,320 (95.9%) patients out of 57,682 patients in all studies. Based on the absolute frequency of withdrawals, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 31 additional people would withdraw compared to placebo. No drug reduced withdrawals due to adverse events when compared with placebo. There was very low-certainty evidence (meaning that estimates are not reliable) that two drugs met our non-inferiority criterion versus placebo, assuming an upper 95% CI RR limit of 1.5: diroximel fumarate (0.38, 0.11 to 1.27) and alemtuzumab (0.63, 0.33 to 1.19). Non-inferiority with placebo was not met due to imprecision for the following drugs: low-certainty evidence for ofatumumab (1.50, 0.87 to 2.59); very low-certainty evidence for methotrexate (0.94, 0.02 to 46.70), corticosteroids (1.05, 0.16 to 7.14), ozanimod (1.06, 0.58 to 1.93), natalizumab (1.20, 0.77 to 1.85), ocrelizumab (1.32, 0.81 to 2.14), dimethyl fumarate (1.34, 0.96 to 1.86), siponimod (1.63, 0.96 to 2.79), rituximab (1.63, 0.53 to 5.00), cladribine (1.80, 0.89 to 3.62), mitoxantrone (2.11, 0.50 to 8.87), interferons (3.47, 0.95 to 12.72), and cyclophosphamide (3.86, 0.45 to 33.50). Eleven drugs may have increased withdrawals due to adverse events compared with placebo: low-certainty evidence for teriflunomide (1.37, 1.01 to 1.85), glatiramer acetate (1.76, 1.36 to 2.26), fingolimod (1.79, 1.40 to 2.28), interferon beta-1a (Rebif) (2.15, 1.58 to 2.93), daclizumab (2.19, 1.31 to 3.65) and interferon beta-1b (2.59, 1.87 to 3.77); very low-certainty evidence for laquinimod (1.42, 1.01 to 2.00), interferon beta-1a (Avonex) (1.54, 1.13 to 2.10), immunoglobulins (1.87, 1.01 to 3.45), peg-interferon beta-1a (3.46, 1.44 to 8.33) and azathioprine (6.95, 2.57 to 18.78); however, very low-certainty evidence is unreliable. Sensitivity analyses including only studies with low attrition bias, drug dose above the group median, or only patients with relapsing remitting MS or CIS, and subgroup analyses by prior disease-modifying treatments did not change these figures. Rankings No drug yielded consistent P scores in the upper quartile of the probability of being better than others for primary and secondary outcomes.
    We found mostly low and very low-certainty evidence that drugs used to treat MS may not increase SAEs, but may increase withdrawals compared with placebo. The results suggest that there is no important difference in the occurrence of SAEs between first- and second-line drugs and between oral, injectable, or infused drugs, compared with placebo. Our review, along with other work in the literature, confirms poor-quality reporting of adverse events from RCTs of interventions. At the least, future studies should follow the CONSORT recommendations about reporting harm-related issues. To address adverse effects, future systematic reviews should also include non-randomized studies.
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  • 一名54岁的多发性硬化症患者接受干扰素-β(IFN-β)-1b治疗15年,出现持续高血压(240/124mmHg)和视网膜出血。她有蛋白尿,贫血,血小板减少症,血清肌酐水平升高,和触珠蛋白耗竭。静脉注射尼卡地平稳定了她的血压,但是她的肾功能和血小板计数恶化了.具有血小板反应蛋白1型基序13(ADAMTS13)活性的初始整合素样金属蛋白酶在没有其抑制剂的情况下是正常的28%。随后的裂孔细胞周围出现提示血栓性微血管病(TMA)。IFN-β-1b停止后,血小板计数增加,血压稳定了.ADAMTS13活性归一化,虽然肌酐水平没有。长期使用IFN-β后可能会出现TMA,而不会出现不良事件。
    A 54-year-old woman with multiple sclerosis treated with interferon-β (IFN-β)-1b for 15 years presented with sustained hypertension (240/124 mmHg) and retinal bleeding. She had proteinuria, anemia, thrombocytopenia, elevated serum creatinine levels, and haptoglobin depletion. Intravenous nicardipine stabilized her blood pressure, but her renal function and platelet count deteriorated. The initial disintegrin-like metalloprotease with thrombospondin type 1 motifs 13 (ADAMTS13) activity was 28% of normal without its inhibitor. The subsequent peripheral appearance of schistocytes suggested thrombotic microangiopathy (TMA). After IFN-β-1b cessation, the platelet count increased, and the blood pressure stabilized. The ADAMTS13 activity normalized, although the creatinine level did not. TMA may develop after the long-term use of IFN-β without adverse events.
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  • 文章类型: Journal Article
    COVID-19大流行在卫生部门造成了严重破坏。炎性细胞因子在疾病状态中起着重要作用。现有证据为药物的再利用提供了一些见解。这项荟萃分析和系统评价旨在探讨干扰素β-1b(IFNβ-1b)和标准治疗与仅标准治疗作为治疗重症COVID-19患者的治疗药物的疗效。在以下数据库中进行搜索:Cochrane中央对照试验登记册(CENTRAL),PubMed,Scopus,和谷歌学者,在2020年1月1日至2023年2月16日期间发布。所有纳入的三项研究均独立评估合格性。采用修改后的Cochrane数据提取形式。使用Cochrane偏倚风险工具评估三项纳入研究的质量。GradePro软件用于总结主要结局指标的质量分级。用IFNβ-1b治疗时,临床改善所需的时间为(MD:-3.28天;95%CI:-5.65,-0.91;P值=0.007)。住院时间(MD:-2.43天;95%CI:-4.45,-0.30;P值=0.03),和重症监护病房(ICU)的需要(RR:0.71;95%CI:0.52,0.97;P值=0.03)有统计学意义。干扰素β-1b被证明可以减少住院时间,临床状况的改善可能成为COVID-19治疗的基石。
    The COVID-19 pandemic has caused havoc in the health sector. Inflammatory cytokines play an important role in the disease condition. Existing evidence has provided certain insights into the repurposing of the drugs. This meta-analysis and systematic review aimed to explore the efficacy of the administration of interferon beta-1b (IFN β-1b) and standard care versus only standard care as the therapeutic agent for managing COVID-19 patients who are severely ill. The search was conducted in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Scopus, and Google Scholar, which were published during the period January 1, 2020, to February 16, 2023. All the included three studies were independently assessed for eligibility. The modified data extraction form of Cochrane were used. The quality of the three included studies was assessed using the Cochrane risk of bias tool. GradePro software was used to summarize the quality grading of the primary outcome measures. The time taken for clinical improvement was (MD: -3.28 days; 95% CI: -5.65, -0.91; P value = 0.007) when treated with IFN β-1b. The duration of hospital stays (MD: -2.43 days; 95% CI: -4.45, -0.30; P value = 0.03), and need for intensive care unit (ICU) admission (RR: 0.71; 95% CI: 0.52, 0.97; P value = 0.03) was statistically significant. Interferon beta-1b is proven to reduce the duration of hospital stay, and the improved clinical status may become a cornerstone of COVID-19 treatment.
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  • 文章类型: Journal Article
    背景:多发性硬化症(MS)患者的有限亚组表现为长期疾病演变,其特征是疾病进展有限,称为良性MS(BMS)。几丁质酶3样-1(CHI3L1)水平对炎症过程敏感,可能在MS的发病机理中起作用。在这次观测中,横断面研究,我们旨在评估血清CHI3L1和炎性细胞因子在接受干扰素β-1b治疗超过10年的BMS患者中的意义.
    方法:我们收集了17例BMS患者和17例健康对照(HC)的血清样本,以测量血清CHI3L1水平和Th17炎性细胞因子组。使用夹心ELISA方法分析CHI3L1的血清水平,并在Flexmap3D分析仪上使用多重XMap技术评估Th17面板。
    结果:血清CHI3L1水平与HC无显著差异。我们确定了CHI3L1水平与治疗期间复发之间的正相关。
    结论:我们的研究结果表明,BMS患者和HC之间的血清CHI3L1水平没有差异。然而,血清CHI3L1水平对临床炎症活动敏感,可能与BMS患者的复发有关。
    BACKGROUND: A limited subgroup of multiple sclerosis (MS) patients present with a longterm disease evolution characterized by a limited disease progression, known as benign MS (BMS). Chitinase 3-like-1 (CHI3L1) levels are sensitive to inflammatory processes and may play a role in the pathogenesis of MS. In this observational, cross-sectional study, we aimed to evaluate the implications of serum CHI3L1 and inflammatory cytokines in BMS patients treated with interferon β-1b for over a decade.
    METHODS: We collected serum samples from 17 BMS patients and 17 healthy controls (HC) to measure serum CHI3L1 levels and a Th17 panel of inflammatory cytokines. Serum levels of CHI3L1 were analysed using the sandwich ELISA method and the Th17 panel was assessed using the multiplex XMap technology on a Flexmap 3D Analyzer.
    RESULTS: Serum CHI3L1 levels did not differ significantly from HC. We identified a positive correlation between CHI3L1 levels and relapses during treatment.
    CONCLUSIONS: Our findings suggest that there are no differences in serum CHI3L1 levels between BMS patients and HC. However, serum CHI3L1 levels are sensitive to clinical inflammatory activity and may be associated with relapses in BMS patients.
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  • 文章类型: Randomized Controlled Trial
    I型干扰素(IFN)是呼吸道暴露于冠状病毒后诱导的必需抗病毒细胞因子。I型IFN信号传导的缺陷可在暴露于呼吸道病毒感染时导致严重的疾病,并且与更差的临床结果相关。据报道,I型IFN的中和自身抗体(自体抗体)是危及生命的COVID-19的危险因素,但尚未在严重中东呼吸综合征(MERS)患者中评估它们的存在。
    我们评估了在接受IFN-β1b和洛匹那韦-利托那韦治疗的安慰剂对照临床试验(MIRACLE试验)的MERS住院患者队列中I型IFN自体抗体的患病率。使用多重基于颗粒的测定法测试样品的I型IFN自体-Ab。
    在62名患者中,对于I型IFN的至少一种亚型,15(24.2%)的免疫球蛋白G自身Ab是阳性的。Auto-Abs阳性患者与auto-Abs阴性患者在年龄上没有差异,性别,或合并症。然而,auto-Abs阳性的患者中,大多数(93.3%)在纳入时是危重患者,被送进ICU,而auto-Abs阴性的患者中,这一比例为66%.两组之间IFN-β1b和洛匹那韦-利托那韦治疗的效果没有显着差异。
    这项研究证明了在患有MERS的住院患者中存在I型IFN自身抗体。
    Type I interferons (IFNs) are essential antiviral cytokines induced upon respiratory exposure to coronaviruses. Defects in type I IFN signaling can result in severe disease upon exposure to respiratory viral infection and are associated with worse clinical outcomes. Neutralizing autoantibodies (auto-Abs) to type I IFNs were reported as a risk factor for life-threatening COVID-19, but their presence has not been evaluated in patients with severe Middle East respiratory syndrome (MERS).
    We evaluated the prevalence of type I IFN auto-Abs in a cohort of hospitalized patients with MERS who were enrolled in a placebo-controlled clinical trial for treatment with IFN-β1b and lopinavir-ritonavir (MIRACLE trial). Samples were tested for type I IFN auto-Abs using a multiplex particle-based assay.
    Among the 62 enrolled patients, 15 (24.2%) were positive for immunoglobulin G auto-Abs for at least one subtype of type I IFNs. Auto-Abs positive patients were not different from auto-Abs negative patients in age, sex, or comorbidities. However, the majority (93.3%) of patients who were auto-Abs positive were critically ill and admitted to the ICU at the time of enrollment compared to 66% in the auto-Abs negative patients. The effect of treatment with IFN-β1b and lopinavir-ritonavir did not significantly differ between the two groups.
    This study demonstrates the presence of type I IFN auto-Abs in hospitalized patients with MERS.
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  • 文章类型: Journal Article
    全基因组关联研究(GWAS)已经验证了动脉粥样硬化与CDKN2A/B基因座的强关联,一个含有三个抑癌基因的位点:p14ARF,p15INK4b,和p16INK4a。GWAS后功能分析显示,CUX是p16INK4a的转录激活因子,通过其与动脉粥样硬化相关的CDKN2A/B基因座上的功能性SNP(fSNP)rs1537371的特异性结合,调节内皮衰老。在这项工作中,我们描述了SATB2,另一种与rs1537371特异性结合的转录因子。我们证明,即使CUX1和SATB2都是同源结构域转录因子,与CUX1不同,SATB2是p16INK4a的转录抑制因子,SATB2的过表达与CUX1竞争其与rs1537371的结合,从而抑制人内皮细胞(ECs)中p16INK4a和p16INK4a依赖性细胞衰老。令人惊讶的是,我们发现SATB2表达被CUX1转录抑制。因此,CUX1的上调抑制SATB2表达,增强CUX1与rs1537371的结合,随后微调p16INK4a表达。值得注意的是,我们还证明了IL-1β,衰老相关分泌表型(SASP)基因本身和动脉粥样硬化的生物标志物,还通过上调人EC中的CUX1和/或下调SATB2来诱导细胞衰老。提出了一个模型来调和我们的发现,该发现显示了如何通过与动脉粥样硬化相关的p16INK4a表达激活原发性和继发性衰老。
    Genome-wide association studies (GWAS) have validated a strong association of atherosclerosis with the CDKN2A/B locus, a locus harboring three tumor suppressor genes: p14ARF , p15INK4b , and p16INK4a . Post-GWAS functional analysis reveals that CUX is a transcriptional activator of p16INK4a via its specific binding to a functional SNP (fSNP) rs1537371 on the atherosclerosis-associated CDKN2A/B locus, regulating endothelial senescence. In this work, we characterize SATB2, another transcription factor that specifically binds to rs1537371. We demonstrate that even though both CUX1 and SATB2 are the homeodomain transcription factors, unlike CUX1, SATB2 is a transcriptional suppressor of p16INK4a and overexpression of SATB2 competes with CUX1 for its binding to rs1537371, which inhibits p16INK4a and p16INK4a -dependent cellular senescence in human endothelial cells (ECs). Surprisingly, we discovered that SATB2 expression is transcriptionally repressed by CUX1. Therefore, upregulation of CUX1 inhibits SATB2 expression, which enhances the binding of CUX1 to rs1537371 and subsequently fine-tunes p16INK4a expression. Remarkably, we also demonstrate that IL-1β, a senescence-associated secretory phenotype (SASP) gene itself and a biomarker for atherosclerosis, induces cellular senescence also by upregulating CUX1 and/or downregulating SATB2 in human ECs. A model is proposed to reconcile our findings showing how both primary and secondary senescence are activated via the atherosclerosis-associated p16INK4a expression.
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  • 文章类型: Journal Article
    背景:迄今为止,关于什么药物是治疗重症COVID-19患者的“最佳”药物,几乎没有达成一致。本研究旨在评估目前可用的不同药物治疗重症COVID-19的疗效和安全性。
    方法:我们在数据库中搜索了截至2022年2月28日发表的随机对照试验(RCT),没有语言限制。推荐用于患有严重COVID-19感染的患者(16岁或以上)的药物。我们提取了有关试验和患者特征的数据,和以下主要结果:全因死亡率(ACM),和治疗引起的不良事件(TEAE)。
    结果:我们通过数据库搜索和其他来源确定了4021份摘要,其中包括48份RCT,包括9147名参与者。对于ACM的减少,我们发现伊维菌素/多西环素,C-IVIG(即,超免疫抗COVID-19静脉注射免疫球蛋白),甲基强的松龙,干扰素-β/标准护理(SOC),干扰素-β-1b,恢复期血浆,remdesivir,洛匹那韦/利托那韦,免疫球蛋白γ,高剂量sarilumab(HS),auxora,与安慰剂组或SOC组相比,伊马替尼有效。我们发现秋水仙碱和干扰素-β/SOC仅与重症COVID-19患者的TEAE相关。
    结论:这项研究表明,伊维菌素/强力霉素,C-IVIG,甲基强的松龙,干扰素-β/SOC,干扰素-β-1b,恢复期血浆(CP),remdesivir,洛匹那韦/利托那韦,免疫球蛋白γ,HS,auxora,和伊马替尼治疗重症COVID-19患者有效。我们发现,大多数药物在治疗重症COVID-19方面是安全的。仍需要更大规模的RCT来证实本研究的结果。
    BACKGROUND: To date, there has been little agreement on what drug is the \"best\" drug for treating severe COVID-19 patients. This study aimed to assess the efficacy and safety of different medications available at present for severe COVID-19.
    METHODS: We searched databases for randomized controlled trials (RCTs) published up to February 28, 2022, with no language restrictions, of medications recommended for patients (aged 16 years or older) with severe COVID-19 infection. We extracted data on trials and patient characteristics, and the following primary outcomes: all-cause mortality (ACM), and treatment-emergent adverse events (TEAEs).
    RESULTS: We identified 4021 abstracts and of these included 48 RCTs comprising 9147 participants through database searches and other sources. For decrease in ACM, we found that ivermectin/doxycycline, C-IVIG (i.e., a hyperimmune anti-COVID-19 intravenous immunoglobulin), methylprednisolone, interferon-beta/standard-of-care (SOC), interferon-beta-1b, convalescent plasma, remdesivir, lopinavir/ritonavir, immunoglobulin gamma, high dosage sarilumab (HS), auxora, and imatinib were effective when compared with placebo or SOC group. We found that colchicine and interferon-beta/SOC were only associated with the TEAEs of severe COVID-19 patients.
    CONCLUSIONS: This study suggested that ivermectin/doxycycline, C-IVIG, methylprednisolone, interferon-beta/SOC, interferon-beta-1b, convalescent plasma (CP), remdesivir, lopinavir/ritonavir, immunoglobulin gamma, HS, auxora, and imatinib were efficacious for treating severe COVID-19 patients. We found that most medications were safe in treating severe COVID-19. More large-scale RCTs are still needed to confirm the results of this study.
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  • 文章类型: English Abstract
    OBJECTIVE: To assess the outcomes of long-term treatment in multiple sclerosis (MS) patients with Infibeta (interferon beta-1b).
    METHODS: The article presents the results a real-world, multicenter, retrospective, observational study of treatment with interferon beta-1b. We enrolled 332 patients with MS who had been receiving Infibeta for at least 8 years. 60.2% of them had a relapsing-remitting MS (RRMS). 73.2% patients received only interferon beta-1b that was initial DMT.
    RESULTS: During the first year of the treatment, 66% of the patients reported no relapses regardless of the MS type. No relapses in the 8th year of treatment were observed in 86.9% of patients with RRMS and 77.7% with secondary progressive MS (SPMS). The median number of relapses during the whole follow-up period in RRMS patients was 1. The time to first relapse in the subgroup of patients who received interferon beta as the first treatment was longer compared to other treatment (median 4 and 2, respectively, p=0.0017). 42% of patients with RRMS remained progression-free during 8 years of follow-up. The flu-like syndrome was observed in 61.7% for the first year of treatment; in 36.3% it was periodically and was mild in 71.3%.
    CONCLUSIONS: The study outcomes confirm a high clinical response to the long-term treatment with Infibeta in patients with RRMS and SPMS and demonstrate that interferon beta-1b is one an optimal option for the initial treatment of patients with moderate disease activity.
    UNASSIGNED: Оценить результаты долгосрочной терапии пациентов с рассеянным склерозом (РС) препаратом Инфибета (интерферон бета-1b).
    UNASSIGNED: Проведено многоцентровое ретроспективное исследование применения интерферона бета-1b в реальной клинической практике. Были включены 332 пациента (средний возраст 48,7±10,2 года) с РС, получавших терапию препаратом Инфибета в течение не менее 8 лет. У 60,2% пациентов отмечалось ремиттирующее течение РС (РРС). Значительная (73,2%) доля пациентов получали только интерферон бета-1b, который являлся для них стартовым препаратом, изменяющим течение РС.
    UNASSIGNED: В 1-й год лечения препаратом Инфибета обострений не отмечалось у 66% пациентов независимо от типа течения РС. Без обострений на 8-й год терапии оставались 86,9% пациентов с РРС и 77,7% — с вторично-прогрессирующим РС (ВПРС). За весь период наблюдения у пациентов с РРС Me количества обострений — 1. Показатели времени до первого обострения в подгруппе пациентов, получавших в качестве первого препарата интерферон бета, были значимо лучше по сравнению с теми, кто получал другое лечение (Me (95% ДИ): 4 (3—4), 2 (2—3) соответственно; p=0,0017). Оставались без прогрессирования по шкале EDSS в течение 8 лет наблюдения 42% пациентов с РРС. Гриппоподобный синдром чаще (61,7%) возникал в 1-й год терапии, у 36,3% пациентов фиксировался периодически и преимущественно (71,3%) был легкой степени тяжести.
    UNASSIGNED: Полученные результаты подтверждают высокий клинический эффект длительной терапии препаратом Инфибета пациентов с РРС и ВПРС и демонстрируют, что интерферон бета-1b представляет собой оптимальную опцию для стартовой терапии пациентов с умеренной активностью заболевания.
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