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多发性硬化症:全球病例大约230万,中国男女患者比例1 : 1.5

Yuchen G. Yuchen G. 来源:医药魔方
2019-03-09
多发性硬化症
原文

多发性硬化症(Multiple Sclerosis,MS)是一种自身免疫系统病变,神经髓鞘的破损和剥落致使脊髓、大脑以及视神经功能受到损害,患者的神经系统残疾在发病一二十年后逐渐加重,会丧失自理能力、失明甚至失去生命。MS是一种罕见病,多发于20-40岁的中青年群体,又因全球大约四分之三的MS患者为女性,又被一些媒体称之为“美女病”。

 

比较有名的MS患者,比如上世纪著名的大提琴演奏家杰奎琳·杜·普蕾, 28岁便罹患MS,42岁英年早逝,其事迹后被拍成电影《她比烟花寂寞》。现年30岁的日裔德国籍钢琴家Alice Sara Ott也在今年初公开了自己身患MS的消息。

 

左:Alice Sara Ott   右:杜·普蕾

 

华盛顿大学卫生计量与评估研究所的全球疾病负担(Global Burden of Disease ,GBD)研究团队3月份在《Lancet Neurol》新发表了一篇文章,系统分析了1990-2016年间全球、地区、国家间的MS疾病负担水平,并统计了全世界各地区的患病率和发病率。2016年,全球MS病例约230万例,相应的年龄标化后的患病率自1990年来增长了10.4%。全球范围内年龄标化死亡率大幅度下降了11.5%, 年龄标化后的伤残调整寿命年(DALYs)变化不大(–4·2%, –16·4 to 0·8),因早亡的生命损失年(YLLs)在生命的第六个十年达到最大。GBD的报告指出:最近20年间许多地区的MS患病率大幅上升,部分原因由于MS患者的存活率大幅提高。全球MS疾病负担最重的地方在MS患病率高的地区,也就是某些欧美发达国家,这也是由于发展欠缺的地区还没有能力诊断和治疗MS [1]。

 

在最新的GBD报告发表之前,仅有的全球范围内的MS流行病学统计数据来源于MS 国际联合会(MS International Federation,MSIF)[2] 。该机构在2008年和2013年收录了MS全球流行病学地图集,但MSIF的数据并没有使用系统的建模方法来估算疾病发生率、死亡率以及风险因素。另一大问题是只有少数几个国家完成过MS流行病学调查,并缺少以种族划分的流行病学数据。GBD的系统性分析方法根据人口统计变量和地理位置对给定条件非常详细地量化了健康损失,模型使用贝叶斯元回归架构,包含了患病率、发病率、缓解率和死亡率。但唯一问题是由于使用的人群数据分散庞大,统计建模出的数据不确定性区间往往很大。

 

所有地区中,1990到2016年间MS年龄标化后的患病率在东亚和加拿大增长最多,增长率分别为44.8%和81.9%。1990年至2016年间患病率增长最大变化发生在社会人口指数SDI(包含了人均收入、受教育年限和生育率的综合指标)的中间分位,即中等发展程度的国家,模型统计出这一区段国家41.3%的增长率。死亡率在全球范围内则降低了11.5%,美国是所有国家中MS死亡率最高的国家:死亡率30.7% [1]。



MS的全球患病率性别比随着年龄增长显现出差异(上图)。在十岁内的儿童中,男孩和女孩的多发性硬化症患病率相似。曲线从青春期开始出现分歧,女孩的患病率比男孩高,这个规律一直持续到六十岁时,此时性别比(女:男)为2:1 。在老年人中,女性的患病率普遍持续攀升,但男性患病率逐渐下降。

 

主要的环境风险因素包括地理纬度(在更温和的气候条件下具有更高的发病率),这可能反映出阳光照射程度影响维生素D水平或也影响了这片区域普遍存在的病原体,尽管遗传也可能发挥了作用[3]。第二个与纬度相关的风险因素在GBD的模型中也得到了验证:纬度每增加一度,MS患病率增加1.03倍 [1]。

 

MS患病率地图 [2]:可以看出随着纬度增高,MS患病率也增高的趋势

 

 

GBD的分析结果显示,1990年至2016年间中国大陆和台湾地区的患病率分别增加了45.6%和49.5%,是整个东亚地区患病率增加最高的两个区域 [1]。

 

2016年,伊朗德黑兰大学的MS研究中心发表过一篇全亚洲MS流行病学系统综述,囊括了2016年前所有亚洲地区的MS流行病学数据,收录了至2016年为止中国地区的6项研究(见下图)[4]。

 


这组研究结果中值得注意的是性别比存在一定差异,这几项集中在北京、上海、苏州等中国特定城市内的研究结果显示:中国病例男女性别比(女:男)跨度很大,从最低1.2:1 到最高9:1,总体估计中国病例男女性别比(女:男)为1.5:1。同时,东亚病例男女性别比为3.4:1,其它东亚地区男女性别比(女:男)为:台湾3.4:1,日本2.1:1,香港3.2:1,韩国1.6:1。从中国的研究中发现,过去20年中MS疾病发病的平均年龄从1993年的46.4岁到2016年的32.6岁不等。

 

据其中一项研究的研究者记录,在患有MS的患者中,与西方国家相比,中国北方的视神经脊髓炎MS患者(Optic-spinal form of Multiple Sclerosis OSMS)数量更多,并且发病时的肢体无力是所有OSMS和CMS(Classical Multiple Sclerosis)患者中最常见的医学症状 [5]。

 

虽然这项元分析系统地囊括了亚洲地区的所有MS流行病学研究,但仍有大量地区的研究还未开始进行,因此泛亚地区各国的MS流行病学统计数据还是很稀缺。这项研究的另一个问题是收录的不同研究所采用的数据质量参差不齐,且只有小数目的病例被识别,诊断标准和发表方法并不统一,还受限于仅用英语发表的文献。

 

近几年,其它国家的MS流行病学研究也有新进展。 2013年发表在《Neurology》上的美国南加州MS族裔流行病学队列研究发现,非裔美国人的发病率在所有族裔中最高 (10.2, 95% confidence interval [CI] 8.4–12.4; p <0.0001) (见下图),非裔美国女性的发病率高达14.72/10万人,远高于白人女性的9.25/10万人、拉丁裔3.92/10万人和亚裔1.77/10万人 [6]。从丹麦MS医保系统的数据中分析发现,丹麦女性的MS发生率在1950年至2009年间翻了一倍,然而男性的MS发生率在此期间并无太大增长。环境的改变包括肥胖率升高,吸烟人群的增加,以及母乳喂养频率的变化都有可能造成MS女性发病率的快速增加 [1]。

 

                           

目前FDA批准用于治疗MS的药物有:Ocrevus® (ocrelizumab) 、 Zinbryta® (daclizumab) 、Tecfidera® (dimethyl fumarate) 、Tysabri®(natalizumab) 、Gilenya® (fingolimod) 、Lemtrada® (alemtuzumab) 、Rebif® (interferon beta-1a) 、Aubagio® (teriflunomide)。2018年3月,Biogen和AbbVie由于欧洲MS患者服用Zinbryta® 后出现炎症性脑炎等副作用,在全球市场撤出了该药,这距离Zinbryta®被FDA批准在美国用于治疗复发的MS才不到两年时间。2018年2月,FDA批准了Glatopa(醋酸格拉替雷注射剂)40mg的规格,每周3次给药,作为复发型MS的第二剂量选择;同年5月,FDA批准Gilenya®(芬戈莫德)作为特别适用于治疗儿科MS的第一款治疗。目前仍在进行的两大III期临床试验包括:诺华的III期EXPAND试验 - 用于评估受体调节剂siponimod治疗继发进展型多发性硬化症(SPMS)和MediciNova开发的口服治疗药物Ibudilast (MN-166),他们都在2018年公开了有效结果 [7-8]。

 

2018年7月,CFDA只用了58天就批准了赛诺菲的奥巴捷(特立氟胺片)在中国上市,这是在中国获批的首款用于治疗复发型MS的口服治疗药物。赛诺菲针对符合旗下治疗药物奥巴捷适应症的患者予以援助。符合条件的多发性硬化患者接受药品援助后,年药物治疗费用可降低40%以上,低保患者甚至可获得全免援助。2019年3月,首批21个罕见病减税药品中,默克雪兰诺的重组人干扰素β-1a 注射液 (Rebif®) 被收录。

 

目前,中国MS流行病学研究数据缺少。2018年,中华医学会神经病学分会已牵头进行首次大范围的MS患者生存现状调研,涉及全国28个省50家医院和1362名患者,报告预计很快出炉。GBD报告结果对医生、研究人员、政策制定者的重要启示意义是,在深究医疗服务需求时一定要考虑到MS病人数目增加的问题,开发治疗MS的药物,确保康复科和其它科的护理都是MS综合治疗的重要组成部分。为了未来得到更准确、强大的MS疾病治疗估算,非常需要更多国家的流行病学数据。


相关论文:

[1] Wallin MT, Culpepper WJ, Nichols E, et al. Global, regional, andnational burden of multiple sclerosis 1990–2016: a systematic analysis for theGlobal Burden of Disease Study 2016. TheLancet Neurology. 2019;18:269-285.

[2]MS International Atlas

[3]Reich     DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. The New England Journal of     Medicine. 2018;378:169-180.

[4]Eskandarieh     S, Heydarpour P, Minagar A, Pourmand S, Sahraian MA. Multiple Sclerosis     Epidemiology in East Asia, South East Asia and South Asia: A Systematic     Review. Neuroepidemiology.     2016;46:209.

[5]Li     T, Xiao H, Li S, Du X, Zhou J: Multiple sclerosis: clinical features and     MRI findings in northern China. Eur J Med Res 2014; 19: 20.

[6]Langer-Gould     A, Brara SM, Beaber BE, Zhang JL. Incidence of multiple sclerosis in     multiple racial and ethnic groups. Neurology.     2013;80:1734-1739.

[7]Kappos L, Bar-Or A, et al. Siponimod versus placebo in secondary     progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase    3 study. The Lancet.     2018;391:1263-1273.

[8]MediciNova Announces MN-166 (ibudilast) Demonstrated a 26% Reduction inConfirmed Disability Progression in the SPRINT-MS Phase 2b Trial in ProgressiveMS: Potential Best-in-Disease Drug 


机器翻译

Multiple Sclerosis (MS) is a disorder of the immune system in which the myelin sheaths of the nerves break and peel off causing the spinal cord.The brain and optic nerve function is impaired, and the patient's neurological disability gradually worsens after the onset of the disease for a decade or two, and the patient will lose the ability to take care of themselves.Blindness and even loss of life.MS is a rare disease, mostly in the young and middle-aged group of 20-40 years old, and because about three-quarters of MS patients worldwide are female, they are also called "beauty disease" by some media.

Well-known MS sufferers, such as the famous cellist Jacqueline Du Pree of the last century, who suffered from MS at the age of 28 and died young at the age of 42, were later filmed as "She is Lonelier than Fireworks."Alice Sara Ott, a 30-year-old German-Japanese pianist, also made public earlier this year.

Left: Alice Sara Ott Right: Du Pree

The Global Burden of Disease (GBD) research team at the University of Washington's Institute for Health Metrology and Assessment published a new article in March in Lancet Neurol that systematically analyzed the world between 1990 and 2016.Region.The burden of MS disease among countries, and statistics of the prevalence and incidence in various regions of the world.In 2016, there were about 2.3 million MS cases worldwide, and the corresponding age-standardized prevalence increased by 10.4% since 1990.Globally, age-standardized mortality rates declined by 11.5%, age-standardized disability-adjusted life years (DALYs) changed little (– 4.2%, – 16 · 4 to 0 · 8), and years of life lost due to premature death (YLLs) reached their maximum in the sixth decade of life.The GBD report notes that MS prevalence has increased substantially in many regions over the last 20 years, in part because of the substantial increase in survival rates.The highest burden of MS disease worldwide is in areas with high prevalence of MS, that is, some developed countries in Europe and America, which is also due to the lack of capacity to diagnose and treat MS in underdeveloped areas (1).

Before the publication of the latest GBD report, the only worldwide epidemiological statistics of MS were derived from the MS International Federation (MSIF) (2).The Institute included MS Global Epidemiology Atlas in 2008 and 2013, but the MSIF data did not use a systematic modeling approach to estimate disease incidence.Mortality and risk factors.Another big problem is that only a handful of countries have completed MS epidemiological surveys and lack ethnically disaggregated epidemiological data.The systematic analysis method of GBD quantifies health loss in detail according to demographic variables and geographical location.Incidence.Response and mortality rates.但唯一问题是由于使用的人群数据分散庞大,统计建模出的数据不确定性区间往往很大.

Among all regions, the age-standardized prevalence of MS increased the most in East Asia and Canada between 1990 and 2016, with growth rates of 44.8% and 81.9%, respectively.The greatest change in prevalence growth between 1990 and 2016 occurred in the SDI (which includes per capita income.For the middle quintile of years of schooling and fertility, or countries with moderate levels of development, the model estimates a 41.3 percent growth rate for this segment of the country.Mortality was reduced by 11.5% worldwide, with the United States having the highest MS mortality rate of any country: 30.7% [1].

The sex ratio of global prevalence of MS showed differences with age (above).Among children in their teens, the prevalence of multiple sclerosis was similar in boys and girls.The curve diverges from puberty, with a higher prevalence in girls than in boys, and this pattern persists until the sixth decade, when the sex ratio (female: male) is 2:1.In the elderly, the prevalence in women continues to climb, but in men it gradually declines.

Major environmental risk factors include geographic latitude (higher incidence in milder climates), which may reflect the extent of sunlight exposure affecting vitamin D levels or also affecting pathogens prevalent in this area, although genetics may also play a role (3).A second latitude-related risk factor was also validated in models of GBD: each degree increase in latitude was associated with a 1.03-fold increase in MS prevalence (1).

MS prevalence map [2]: It can be seen that as latitude increases, MS prevalence also tends to increase

The analysis results of GBD showed that the prevalence in mainland China and Taiwan increased by 45.6% and 49.5%, respectively, between 1990 and 2016, which were the two regions with the highest increase in prevalence throughout East Asia [1].

In 2016, the MS Research Center of Tehran University in Iran published a systematic review of MS epidemiology across Asia, which included MS epidemiology data from all Asian regions through 2016 and included 6 studies in China up to 2016 (see figure below) [4].

The results of this study are notable for some differences in sex ratios, which are concentrated in Beijing.Shanghai.The results of studies in specific cities in China, such as Suzhou, showed that the male-to-female sex ratio (female: male) of Chinese cases spanned a wide range, from a minimum of 1.2:1 to a maximum of 9:1, and the overall estimated male-to-female sex ratio (female: male) of Chinese cases was 1.5:1.Meanwhile, the sex ratio of East Asian cases was 3.4:1, and that of other East Asian cases (female: male) was 3.4:1 in Taiwan, 2.1:1 in Japan, 3.2:1 in Hong Kong, and 1.6:1 in Korea.The average age at onset of MS disease over the past 20 years ranged from 46.4 years in 1993 to 32.6 years in 2016, according to a Chinese study.

According to the investigators of one of the studies, among patients with MS, optic-spinal form of multiple sclerosis (OSMS) is more numerous in northern China compared to western countries, and limb weakness at onset is the most common medical symptom in all patients with OSMS and CMS (classic multiple sclerosis) (5).

Although this meta-analysis systematically includes all MS epidemiological studies in Asia, there are still a large number of studies in the region that have not yet begun, so the epidemiological statistics of MS in countries in the pan-Asian region are still very scarce.Another problem with this study is that the quality of the data used in the different studies included was variable, only a small number of cases were identified, diagnostic criteria and methods of publication were not uniform, and was limited by literature published in English only.

In recent years, there have been new advances in MS epidemiological studies in other countries.An ethnic-epidemiological cohort study of MS in Southern California, published in Neurology in 2013, found that African Americans had the highest incidence among all ethnicities (10.2, 95% confidence interval [CI] 8.4 – 12.4.The incidence in African-American women is as high as 14.72 per 100,000 people, much higher than the 9.25 per 100,000 in white women.3.92/100,000 Latinos and 1.77/100,000 Asians (6).Analysis of data from the Danish MS health insurance system found that the incidence of MS in Danish women doubled between 1950 and 2009, whereas the incidence of MS in men did not increase much during this period.Changes in the environment including elevated rates of obesity, an increase in the number of people who smoke, and changes in the frequency of breastfeeding have the potential to cause a rapid increase in the incidence of MS women (1).

Currently FDA-approved drugs for MS are: Ocrevus ® (ocrelizumab).ZINBRYTA ® (daclizumab).Tecfidera ® (dimethyl fumarate).Tysabri ® (natalizumab).Gilenya ® (fingolimod).LEMTRADA ® (alemtuzumab).REBIF ® (interferon beta-1a).Aubagio ® (teriflunomide).In March 2018, Biogen and AbbVie withdrew Zinbryta ® from the global market due to inflammatory encephalitis and other side effects in MS patients in Europe, less than two years after Zinbryta ® was approved by the FDA for the treatment of relapsing MS in the United States.In February 2018, the FDA approved the strength of Glatopa (glatiramer acetate injection) 40 mg, administered three times a week, as a second dose option for relapsing forms of MS.In May of the same year, the FDA approved Gilenya ® (fingolimod) as the first treatment specifically indicated for the treatment of pediatric MS.Two major ongoing Phase III trials include the Novartis Phase III EXPAND trial to evaluate the receptor modulator siponimod in secondary progressive multiple sclerosis (SPMS) and the oral therapy ibudilast (MN-166) developed by MediciNova, both of which published valid results in 2018 [7-8].

In July 2018, the CFDA approved Sanofi's Obazel (teriflunomide tablets) in China in only 58 days, which is the first oral drug approved in China for the treatment of relapsing MS.Sanofi is assisting patients who meet the indications for its treatment, Obarget.After eligible MS patients receive drug assistance, the annual cost of drug treatment can be reduced by more than 40%, and patients with subsistence allowances can even receive free assistance.In March 2019, Merck Serono's Recombinant Human Interferon Beta-1a Injection (Rebif ®) was included in the first batch of 21 rare disease tax relief drugs.

Currently, data from epidemiological studies of MS in China are lacking.In 2018, Chinese Society of Neurology has led the first large-scale investigation on the survival status of MS patients, involving 50 hospitals in 28 provinces and 1362 patients. The report is expected to be released soon.GBD reports the results to the physician.Researchers.The important enlightenment of policy-makers is that the increasing number of MS patients must be taken into account when investigating the demand for medical services. Developing drugs for MS and ensuring the care of rehabilitation and other departments are all important components of comprehensive MS treatment.More accurate for the future.There is a strong need for epidemiological data from more countries with strong estimates of MS disease treatment.

Related Papers:

[1] Wallin MT, Culpepper WJ, Nichols E, et al.Global, Regional, and National Burden of Multiple Sclerosis 1990 – 2016: a systematic analysis for the Global Burden of Disease Study 2016.The Lancet Neurology.2019.18:269-285.

2] MS International Atlas

3] Reich DS, Lucchinetti CF, Calabresi PA.Multiple Sclerosis.The New England Journal of Medicine.2018.378:169-180.

4] Eskandarieh S, Heydarpour P, Minagar A, Pourmand S, Sahraian MA.Multiple Sclerosis Epidemiology in East Asia, South East Asia and South Asia: A Systematic Review.Neuroepidemiology.2016.46:209.

5] Li T, Xiao H, Li S, Du X, Zhou J: Multiple sclerosis: clinical features and MRI findings in northern China.Eur J Med Res 2014.19:20.

6] Langer-Gould A, Brara SM, Beaber BE, Zhang JL.Incidence of multiple sclerosis in multiple racial and ethnic groups.Neurology.2013.80:1734-1739.

7] Kappos L, Bar-Or A, et al.Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomized, phase 3 study.The Lancet.2018.391:1263-1273.

8] MediciNova Announces MN-166 (ibudilast) Demonstrated a 26% Reduction inConfirmed Disability Progress in the SPRINT-MS Phase 2b Trial in ProgressiveMS: Potential Best-in-Disease Drug

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