Pihl-Jensen Gorm, Tsakiri Anna, Frederiksen Jette Lautrup
Clinic of Optic Neuritis and Clinic of Multiple Sclerosis, Neurological Department, Glostrup Hospital, University of Copenhagen, Nordre Ringvej 57, 2600, Glostrup, Denmark,
CNS Drugs. 2015 Apr;29(4):277-91. doi: 10.1007/s40263-015-0239-x.
Multiple sclerosis (MS) is a chronic inflammatory disease that leads to progressive disability. Statins [hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors] are widely prescribed drugs in hypercholesterolemia. They exert immunomodulatory and neurotrophic effects and are attractive candidates for MS treatment due to reliable safety profiles and favorable costs. Studies of statins in a murine MS model and in open-label trials in MS have shown decreased disease severity.
Our objective was to assess current evidence to support statin treatment in MS and clinically isolated syndrome (CIS).
We conducted a systematic literature review of EMBASE, PubMed, and CINAHL databases, clinical trials registries, and unpublished conference meeting abstracts as well as reference lists between 1 and 8 June 2014 and repeated it on 1 December 2014. Randomized controlled trials (RCTs) of statins, in any form or dosage, as monotherapy or add-on to established therapy in relapsing-remitting MS (RRMS), progressive MS, and CIS were included. Data were extracted using pre-defined fields to measure study quality. Meta-analysis was performed with regards to pre-defined outcome measures of relapse activity, magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS) progression, and adverse events using a fixed-effects model due to low heterogeneity between studies.
Eight trials were included in the review [five of statin add-on to interferon (IFN)-β treatment in RRMS, one of statin monotherapy in CIS, one of statin monotherapy in optic neuritis (ON)/CIS, and one of statin monotherapy in secondary progressive MS (SPMS)]. Three trials with eligible characteristics had not been published in peer-reviewed journals and were therefore not included. Due to the low number of trials in CIS and SPMS, meta-analysis of primary outcomes was only performed for RRMS studies. Meta-analysis showed no significant effect of statin add-on to IFNβ therapy. Indeed, a trend towards an increase in disease activity was shown in the statin group with regards to new T2 lesions, proportion of patients with relapse, and whole brain atrophy but not for EDSS progression. In SPMS, statin monotherapy showed significant reduction in brain atrophy and disability progression but no effect on relapse rate. In CIS, a phase II trial showed no difference in relapse activity, MRI activity or risk of MS between statin monotherapy and placebo. In acute ON, statin monotherapy produced better visual outcome but no difference in relapse activity, MRI activity, or risk of MS.
The pleiotropic effects and effects in the murine model of MS could not be converted to a proven effect in relapsing MS and hence statin therapy either as a monotherapy or in combination with IFNβ treatment for RRMS, and statin monotherapy for CIS cannot at present be recommended. However, indications are that statins may be beneficial in SPMS. The benefit thereof and whether this is due to a direct immunomodulatory and neuroprotective effect warrant further studies.
多发性硬化症（MS）是一种导致进行性残疾的慢性炎症性疾病。他汀类药物[羟甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂]是高胆固醇血症中广泛使用的处方药。它们具有免疫调节和神经营养作用，由于可靠的安全性和良好的成本效益，是治疗MS的有吸引力的候选药物。在小鼠MS模型和MS开放标签试验中对他汀类药物的研究表明疾病严重程度降低。
我们的目的是评估支持他汀类药物治疗MS和临床孤立综合征（CIS）的现有证据。
我们对EMBASE、PubMed和CINAHL数据库、临床试验注册库以及未发表的会议摘要和参考文献列表进行了系统的文献综述，时间范围为2014年6月1日至8日，并于2014年12月1日重复进行。纳入了以任何形式或剂量使用他汀类药物作为复发缓解型MS（RRMS）、进展型MS和CIS的单一疗法或既定疗法的附加疗法的随机对照试验（RCT）。使用预定义字段提取数据以衡量研究质量。由于研究之间的异质性较低，因此使用固定效应模型对复发活动、磁共振成像（MRI）活动、扩展残疾状态量表（EDSS）进展和不良事件的预定义结局指标进行了荟萃分析。
该综述纳入了8项试验[5项在RRMS中他汀类药物附加于干扰素（IFN）-β治疗，1项在CIS中他汀类药物单一疗法，1项在视神经炎（ON）/CIS中他汀类药物单一疗法，1项在继发进展型MS（SPMS）中他汀类药物单一疗法]。3项具有合格特征的试验尚未在同行评审期刊上发表，因此未被纳入。由于CIS和SPMS中的试验数量较少，仅对RRMS研究进行了主要结局的荟萃分析。荟萃分析显示他汀类药物附加于IFNβ治疗没有显著效果。实际上，在他汀类药物组中，新发T2病变、复发患者比例和全脑萎缩方面显示出疾病活动增加的趋势，但EDSS进展方面没有。在SPMS中，他汀类药物单一疗法显示脑萎缩和残疾进展显著降低，但对复发率没有影响。在CIS中，一项II期试验显示他汀类药物单一疗法与安慰剂在复发活动、MRI活动或MS风险方面没有差异。在急性ON中，他汀类药物单一疗法产生了更好的视力结果，但在复发活动、MRI活动或MS风险方面没有差异。
MS小鼠模型中的多效性作用和效果无法转化为复发型MS中已证实的效果，因此目前不推荐将他汀类药物作为单一疗法或与IFNβ联合用于RRMS治疗，也不推荐将他汀类药物单一疗法用于CIS治疗。然而，有迹象表明他汀类药物可能对SPMS有益。其益处以及这是否归因于直接的免疫调节和神经保护作用值得进一步研究。
