Recent progress in epidemiology,clinical features,and therapy of multiple sclerosis in China

Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by inflammation, demyelination, and neurodegeneration. It mainly affects young adults, imposing a heavy burden on families and society. The epidemiology, clinical features, and management of MS are distinct among different countries. Although MS is a rare disease in China, there are 1.4 billion people in China, so the total number of MS patients is not small. Because of the lack of specific diagnostic biomarkers for MS, there is a high misdiagnosis rate in China, as in other regions. Due to different genetic backgrounds, the clinical manifestations of MS in Chinese are different from those in the West. Herein, this review aims to summarize the disease comprehensively, including clinical profile and the status of disease-modifying therapies in China based on published population-based observation and cohort studies, and also to compare with data from other countries and regions, thus providing help to develop diagnostic guideline and the novel therapeutic drugs. Meanwhile, we also discuss the problems and challenges we face, specifically for the diagnosis and treatment of MS in the middle- and low-income countries.

Keywords

China clinical features epidemiology multiple sclerosis therapy

Introduction

Multiple sclerosis (MS) is a classical inflammatory demyelinating disorder of the central nervous system (CNS), which commonly starts affecting young adults and lasting for a lifetime, leading to considerable social impact and economic burden.¹ It was earlier generally considered that MS mainly occurred in several parts of Europe and the United States as well as the high latitude regions. However, with the further improvement of diagnostic criteria increasing earlier diagnosis rate, a universal increase in the prevalence and incidence of MS in many regions has been reported during recent decades.^2,3 Till now, MS has been indicated to be a worldwide problem, with different prevalence and incidence across the globe.^4,5 According to a report from the atlas of MS third edition, the number of people with MS across the globe has increased from 2.3 million in 2013 to 2.8 million in 2020.⁶ An increasing number of studies have demonstrated that there are significant differences in MS in terms of epidemiology and clinical characteristic across diverse races and countries. At present, the cause of MS remains unclear; it is considered as a result of the complex interaction between genetic and environmental factors.⁷ So far, no specific diagnostic biomarkers have found in MS, and it is difficult for early identification. MS was historically believed as a T-cell-mediated disease, and most disease-modifying therapies (DMTs) focused on eliminating these pathogenic T cells.⁸ However, in recent years, there has been a tremendous change in understanding the immune mechanism of MS, away from T-cell-centered dogma to a recognition that B cells play a core role in MS pathogenesis.⁹ B-cell-depleting therapies upend the traditional idea of T-cell-based therapy and may play a crucial role in reducing relapses and delaying disability progress.¹⁰ Although a dozen different DMTs have been approved for MS therapy globally, only six of them are available in clinical application of China until now. Therefore, there is a lack of data related to the currently available medications for MS and their efficacy and safety in China.

As the most populous country with wide geographical distribution in the world, so far, the comprehensive and accurate description of MS in China is insufficient, and the reason is the uneven development of medical diagnosis in various regions. To fill the gap, in this review, we collected 92 studies published in English and Chinese regarding MS in China from 2011 to July of 2022 and conducted further analysis of these data of MS, including the epidemiology, clinical features, treatment, and prognosis, and also to compare comprehensively the data of MS in China to those in other races and countries. This article mainly focuses on identifying the actual picture of MS in China and providing the basis for future studies in the middle- and low-income countries.

Search strategy and results

In this literature review, all available studies on MS in Chinese population published in China National Knowledge Infrastructure, Wanfang and PubMed databases from 2011 to July of 2022 were collected. The using search terms were [(‘Multiple Sclerosis’ or ‘MS’) and (‘China’ or ‘Chinese’ or ‘Hongkong’ or ‘Taiwan’)]. The references of retrieved articles were also screened for avoiding missing potentially relevant studies. The types of studies included prospective, retrospective, cross-sectional, and case-control studies, and clinical trials, published in full-text with relevant information to extract. We did not collect the case reports, review articles, commentaries, and meta-analysis. Other papers with irrelevant or incomplete data were also excluded.

The initial search strategy identified 218 studies after reading abstract. After reviewing all retrieved articles by applying the above criteria, a total of 92 studies were cited in this review.^11–102 Of these 92 articles, 17 were reported in English, the resting 75 in Chinese. Of these selected studies, 87 were conducted in mainland China, 4 in Hong Kong, and 1 in Taiwan, including15,653 patients. For studies reporting qualitative and quantitative data, available information on demographics, clinical features, treatment, and results were further integrated and tabulated. The basic characteristics of the Chinese MS cohort are summarized in Table 1.

Table 1.

Demographics and clinical characteristics of MS patients in China.

MS features	Chinese cohort (n = 15,653)	References
Demographics
Age, years	41.53 adult; 8.05 children	Ren and Qiao,¹² Wang,¹⁵ Long et al.,¹⁷ Han and Liu,²² Wang,²⁵ Cheng et al.,²⁶ Ren et al.,²⁷ Li et al.,²⁸ Zhu et al.,²⁹ Duan,³⁰ Gong,³¹ Jia,³² Wang and Wei,³³ Chen,³⁴ Duan and Hua,³⁵ Kong,³⁶ Zhang,³⁷ He and Zou,³⁸ Liu and Huang,³⁹ Li and Zhou,⁴⁰ Xue,⁵⁰ Yang and Yang,⁵⁴ Zhang et al.,⁵⁹ Ruan,⁶³ Wang et al.,⁶⁵ Chen et al.,⁶⁶ Meng,⁶⁷ Zhou and Luo,⁷⁰ Bai,⁷⁵ Zhou and Fu,⁷⁷ Ouyang and Zhu,⁷⁸ Huang et al.,⁷⁹ Lin,⁸⁰ Shi,⁸² Liu et al.,⁸⁷ Long et al.,⁸⁹ Liu et al.,⁹² Chen et al.,⁹³ Zhang et al.,⁹⁵ Zhang et al.,⁹⁸ Xu et al.¹⁰¹
F/M ratio	10,482/5171 (2.0)	Cui et al.,¹¹ Ren and Qiao,¹² Guo et al.,¹³ Cheng and Li,¹⁴ Wang,¹⁵ Fan et al.,¹⁶ Long et al.,¹⁷ Liu and Feng,¹⁸ Qian,¹⁹ Li et al.,²⁰ Wang,²¹ Han and Liu,²² Zheng,²³ Wang et al.,²⁴ Wang,²⁵ Cheng et al.,²⁶ Ren et al.,²⁷ Li et al.,²⁸ Zhu et al.,²⁹ Duan,³⁰ Gong,³¹ Jia,³² Wang and Wei,³³ Chen,³⁴ Duan and Hua,³⁵ Kong,³⁶ Zhang,³⁷ He and Zou,³⁸ Liu and Huang,³⁹ Li and Zhou,⁴⁰ Qiu,⁴¹ Lin et al.,⁴² Song,⁴³ Lin et al.,⁴⁴ Zhao et al.,⁴⁵ Xu,⁴⁶ Liu et al.,⁴⁷ Zhu et al.,⁴⁸ Ma and Liu,⁴⁹ Xue,⁵⁰ Xie et al.,⁵¹ Chen et al.,⁵² Hu and Chang,⁵³ Yang and Yang,⁵⁴ Lu et al.,⁵⁵ Zhang,⁵⁶ Liu et al.,⁵⁷ Zhao et al.,⁵⁸ Zhang et al.,⁵⁹ Huang and Chen,⁶⁰ Su,⁶¹ Hu,⁶² Ruan,⁶³ Zeng et al.,⁶⁴ Wang et al.,⁶⁵ Chen et al.,⁶⁶ Meng,⁶⁷ Zhou and He,⁶⁸ Wu,⁶⁹ Zhou and Luo,⁷⁰ Zhang et al.,⁷¹ He et al.,⁷² Lv,⁷³ Li,⁷⁴ Bai,⁷⁵ Yin,⁷⁶ Zhou and Fu,⁷⁷ Ouyang and Zhu,⁷⁸ Huang et al.,⁷⁹ Lin,⁸⁰ Xing et al.,⁸¹ Shi,⁸² Wang,⁸³ Feng,⁸⁴ Han,⁸⁵ Chan et al.,⁸⁶ Liu et al.,⁸⁷ Chan et al.,⁸⁸ Long et al.,⁸⁹ Yang et al.,⁹⁰ Li et al.,⁹¹ Liu et al.,⁹² Chen et al.,⁹³ Liu et al.,⁹⁴ Zhang et al.,⁹⁵ Lu et al.,⁹⁶ Fang et al.,⁹⁷ Zhang et al.,⁹⁸ Zhao et al.,⁹⁹ Zheng et al.,¹⁰⁰ Xu et al.,¹⁰¹ Zhao et al.,¹⁰² Lai et al.¹⁰³
Clinical course of MS		Guo et al.,¹³ Fan et al.,¹⁶ Zheng,²³ Ren et al.,²⁷ Gong,³¹ Zhang,³⁷ Qiu,⁴¹ Lin et al.,⁴² Xu,⁴⁶ Ma and Liu,⁴⁹ Liu et al.,⁵⁷ Zhao et al.,⁵⁸ Zeng et al.,⁶⁴ Bai,⁷⁵ Ouyang and Zhu,⁷⁸ Li et al.,⁹¹ Zhang et al.,⁹⁵ Zhao et al.¹⁰²
RRMS (%)	85.2%
SPMS (%)	8.6%
PPMS (%)	6.2%
Clinical manifestations		Cui et al.,¹¹ Guo et al.,¹³ Wang,¹⁵ Fan et al.,¹⁶ Long et al.,¹⁷ Liu and Feng,¹⁸ Li et al.,²⁰ Wang,²¹ Zheng,²³ Wang et al.,²⁴ Wang,²⁵ Cheng et al.,²⁶ Ren et al.,²⁷ Zhu et al.,²⁹ Duan,³⁰ Gong,³¹ Jia,³² Wang and Wei,³³ Chen,³⁴ Duan and Hua,³⁵ Zhang,³⁷ He and Zou,³⁸ Liu and Huang,³⁹ Li and Zhou,⁴⁰ Qiu,⁴¹ Song,⁴³ Lin et al.,⁴⁴ Zhao et al.,⁴⁵ Ma and Liu,⁴⁹ Xue,⁵⁰ Xie et al.,⁵¹ Chen et al.,⁵² Hu and Chang,⁵³ Yang and Yang,⁵⁴ Lu et al.,⁵⁵ Liu et al.,⁵⁷ Zhao et al.,⁵⁸ Zhang et al.,⁵⁹ Huang and Chen,⁶⁰ Su,⁶¹ Zeng et al.,⁶⁴ Wang et al.,⁶⁵ Meng,⁶⁷ Zhang et al.,⁷¹ He et al.,⁷² Bai,⁷⁵ Yin,⁷⁶ Ouyang and Zhu,⁷⁸ Huang et al.,⁷⁹ Lin,⁸⁰ Xing et al.,⁸¹ Shi,⁸² Feng,⁸⁴ Han,⁸⁵ Li et al.,⁹¹ Liu et al.⁹²
Optic neuritis (%)	1193/4865 (24.5)
Limb weakness (%)	2070/4865 (42.5)
Sensory disturbances (%)	1741/4865 (35.8)
Sphincter dysfunction (%)	462/4865 (9.5)
Ataxia (%)	688/4865 (14.1)
Cognitive impairment (%)	202/4865 (4.2)
Epilepsy (%)	33/4865 (0.7)
Consciousness disturbance (%)	51/4865 (1.0)
Cranial nerve involvement (%)	610/4865 (12.5)
Eye movement-related nerves	518/4865 (10.6)
Facial weakness	27/4865 (0.6)
Bulbar palsy	50/4865 (1.1)
Comorbidity (%)		Liu and Feng,¹⁸ Wang,²¹ Zhang,⁵⁶ Liu et al.,⁵⁷ Ouyang and Zhu,⁷⁸ Feng,⁸⁴ Chan et al.⁸⁸
Autoimmune diseases
Systemic autoimmune diseases	37/496 (7.6)
MG	10/496 (2.0)
Nonautoimmune diseases
Hypertension	59/496 (11.9)
Coronary heart disease	20/496 (4.0)
CSF study
White cell count (>8 cells/mm³) (%)	260/1077 (24.1)	Wang,¹⁵ Wang,²⁵ Cheng et al.,²⁶ Ren et al.,²⁷ Li et al.,²⁸ Zhu et al.,²⁹ Duan,³⁰ Gong,³¹ Liu and Huang,³⁹ Zhao et al.,⁴⁵ Ma and Liu,⁴⁹ Xue,⁵⁰ Hu and Chang,⁵³ Yang and Yang,⁵⁴ Lu et al.,⁵⁵ Su,⁶¹ Chen et al.,⁶⁶ Zhou and Luo,⁷⁰ Bai,⁷⁵ Ouyang and Zhu,⁷⁸ Huang et al.,⁷⁹ Lin,⁸⁰ Feng,⁸⁴ Han,⁸⁵ Long et al.⁸⁹
Protein, g/L (interquartile range)	0.4–0.9	Wang,¹⁵ Zheng,²³ Ren et al.,²⁷ Zhu et al.,²⁹ Zhu et al.,⁴⁸ Hu and Chang,⁵³ Yang and Yang,⁵⁴ Lu et al.,⁵⁵ Su,⁶¹ Chen et al.,⁶⁶ Zhou and Luo,⁷⁰ Bai⁷⁵, Ouyang and Zhu,⁷⁸ Huang et al.,⁷⁹ Lin,⁸⁰ Feng,⁸⁴ Long et al.⁸⁹
IgG index >0.7 (%)	193/456 (20.4)	Zheng,²³ Li et al.,²⁸ Wang and Wei,³³ Duan and Hua,³⁵ Lin et al.,⁴⁴ Xue,⁵⁰ Lu et al.,⁵⁵ Bai,⁷⁵ Yin,⁷⁶ Ouyang and Zhu,⁷⁸ Han,⁸⁵ Liu et al.⁹²
OCB (%)	671/1380 (48.6)	Wang et al.,²⁴ Li et al.,²⁸ Duan,³⁰ Gong,³¹ Jia,³² Zhao et al.,⁴⁵ Hu and Chang,⁵³ Bai,⁷⁵ Chan et al.,⁸⁸ Long et al.,⁸⁹ Yang et al.,⁹⁰ Li et al.,⁹¹ Liu et al.,⁹² Lu et al.,⁹⁶ Zhao et al.⁹⁹
MRI features
Brain MRI abnormalities (%)		Cui et al.,¹¹ Guo et al.,¹³ Wang,¹⁵ Li et al.,²⁰ Zheng,²³ Ren et al.,²⁷ Li et al.,²⁸ Zhu et al.,²⁹ Duan,³⁰ Gong,³¹ Jia,³² Wang and Wei,³³ Duan and Hua,³⁵ Lin et al.,⁴² Lin et al.,⁴⁴ Xu,⁴⁶ Zhu et al.,⁴⁸ Xue,⁵⁰ Hu and Chang,⁵³ Huang and Chen,⁶⁰ Hu,⁶² Ruan,⁶³ Bai,⁷⁵ Yin,⁷⁶ Zhou and Fu,⁷⁷ Ouyang and Zhu,⁷⁸ Long et al.,⁸⁹ Zhao et al.⁹⁹
Periventricular lesions	1061/1635 (64.9)
Cortical lesions	633/1635 (38.7)
Cerebellar lesions	197/1635 (12.0)
Brainstem lesions	542/1635 (33.1)	Zheng,²³ Bai,⁷⁵ Ouyang and Zhu,⁷⁸ Long et al.⁸⁹
Midbrain	24/209 (11.5)
Pons	55/209 (26.3)
Medulla	27/209 (12.9)
Spinal cord MRI abnormalities (%)	778/1267 (61.4)	Qian,¹⁹ Jia,³² Wang and Wei,³³ Liu et al.,⁴⁷ Xue,⁵⁰ Ruan,⁶³ Zhou and Fu,⁷⁷ Huang et al.,⁷⁹ Lin⁸⁰, Feng,⁸⁴ Yang et al.⁹⁰
Cervical cord lesions	420/1267 (33.1)
Thoracic cord lesions	224/1267 (17.7)
Cervical and thoracic cord lesions	93/1267 (7.3)
Lumbar cord lesions	19/1267 (1.5)

Data are presented as n (%) or median [IQR].

Average age.

CSF, cerebrospinal fluid; IgG, immunoglobulin G; MG, myasthenia gravis; MRI, magnetic resonance imaging; MS, multiple sclerosis; OCB, oligoclonal bands; PPMS, primary progressive MS; RRMS, relapsing-remitting MS; SPMS, secondary progressive MS.

Epidemiology

Prevalence and incidence

The prevalence and incidence of MS seem to be increasing globally. The estimated global prevalence and incidence of MS in 2020 were, respectively, 35.9/100,000 and 2.1/100,000. However, the reported epidemiological data of MS varied greatly in different regions and countries of the world, which might be related to genetic and environmental factors and poor medical data collections. The highest prevalence was reported mainly in the Americas and Europe (117.49/100,000 and 142.81/100,000, respectively), while the lowest prevalence in Latin America (ranging from 2.0/100,000 to 69.0/100,000).¹⁰⁴ The reported prevalence of MS had a wide regional variation across Asia areas, ranging from 3 to 50 per 100,000 population, with the lowest levels reported in South East Asia (3.26/100,000).¹⁰⁵ Despite the difference in prevalence, recent studies have shown the obvious increase in prevalence in most regions, including some countries with low prevalence, such as Japan (18.6/100,000),¹⁰⁶ Korea (3.23/100,000),¹⁰⁷ and Pakistan (10.0/100,000).¹⁰⁸ The crude data across the globe can be available from the third edition of the Atlas of MS.¹⁰⁶

Despite lack of national data to reveal the real prevalence and incidence of MS in China, the latest MS data published by Multiple Sclerosis International Federation showed that there were nearly 42,440 MS patients in China in 2020.¹⁰⁹ We collected the published original articles, of which most were based on a single center from different regions, to assess MS epidemiology. For example, a population-based survey covering 18 districts conducted by Ruijin Hospital showed a prevalence of 1.39/100,000 individuals in Shanghai in 2007.¹¹⁰ In 2008, Lau et al.¹¹¹ reported the prevalence of 4.8 per 100,000 in Hong Kong. Recently, Xu et al.¹⁰¹ published representative national data by using National Medical Insurance Databases with the prevalence of 2.44/100,000, which was smaller than the reported from the third edition of the Atlas of MS with 3/100,000. The data showed that Liaoning Province had the highest prevalence with 3.13, followed by Zhejiang Province (2.89), Guangdong Province (2.66), Inner Mongolia Autonomous Region (2.38), and Chongqing Municipality (1.67).¹⁰¹ Liu et al.⁹⁴ reported that the MS prevalence in Shandong Province was estimated to be 5.2/100,000 using hospitalized data. From these data, we could see that the prevalence of MS in China followed a geographic distribution. MS incidence increases with latitude and altitude in China.¹¹² Specifically, some regions with high-latitudes, like Inner Mongolia had higher incidence compared to mid-latitudes and low-latitudes. Also, the risk of MS in the low-altitude eastern regions was lower than the high-altitude Western regions. The published data on the prevalence, the incidence, and the sex ratio of MS in different provinces are presented in Figure 1. Due to low incidence rate of MS in China, it is considered as a rare disease in China; however, the total number of MS patients is not small due to 1.4 billion people in China.

Figure 1.

The epidemiological characteristics of MS in different regions of China.

Epidemiology

MS is more predominant in females, similar to other autoimmune diseases of the nervous system, such as neuromyelitis optica spectrum disorder (NMOSD) and autoimmune encephalitis.^113–115 Many retrospective studies demonstrated that the prevalence of MS in women was two to three times higher than that in men.^116–118 In some regions, such as Malaysia and Thailand, the gender difference was more significant (5:1 and 6.2:1, respectively).^119,120 In this review, the F/M ratio was estimated to be 2.0 in China, after reviewing all data from 92 studies related to MS (Table 1). This result was similar to that reported in Italy and Kuwait.^121,122

China is divided into Northern and Southern parts by the Huai River and Qinling Mountains. We compared the numbers of female and male patients as well as the F/M ratio in Northern China with their counterparts in Southern China. As shown in Table 2, the total number of patients, as well as the number of female and male patients in the north, was significantly higher than that in the south. The data followed the laws of geographical distribution. As we know, geographical location plays an important role in the development of MS.¹²³ Both in Southern and Northern China, we found significantly more female MS patients than male patients. However, there was no significant correlation between sex ratio with latitude (1.79 in Northern China versus 1.82 in Southern China) (Table 2), consistent with previous reports.¹²⁴

Table 2.

Clinical features of patients with MS between geographical regions in China.

MS features	Northern China	Southern China	References
Demographics
F/M ratio	4495/2513 (1.79)	1991/1096 (1.82)	Cui et al.,¹¹ Ren and Qiao,¹² Guo et al.,¹³ Cheng and Li,¹⁴ Wang,¹⁵ Fan et al.,¹⁶ Long et al.,¹⁷ Liu and Feng,¹⁸ Qian,¹⁹ Li et al.,²⁰ Wang,²¹ Han and Liu,²² Zheng,²³ Wang et al.,²⁴ Wang,²⁵ Cheng et al.,²⁶ Ren et al.,²⁷ Li et al.,²⁸ Zhu et al.,²⁹ Duan,³⁰ Gong,³¹ Jia,³² Wang and Wei,³³ Chen,³⁴ Duan and Hua,³⁵ Kong,³⁶ Zhang,³⁷ He and Zou,³⁸ Liu and Huang,³⁹ Li and Zhou,⁴⁰ Qiu,⁴¹ Lin et al.,⁴² Song,⁴³ Lin et al.,⁴⁴ Zhao et al.,⁴⁵ Xu,⁴⁶ Liu et al.,⁴⁷ Zhu et al.,⁴⁸ Ma and Liu,⁴⁹ Xue,⁵⁰ Xie et al.,⁵¹ Chen et al.,⁵² Hu and Chang,⁵³ Yang and Yang,⁵⁴ Lu et al.,⁵⁵ Zhang,⁵⁶ Liu et al.,⁵⁷ Zhao et al.,⁵⁸ Zhang et al.,⁵⁹ Huang and Chen,⁶⁰ Su,⁶¹ Hu,⁶² Ruan,⁶³ Zeng et al.,⁶⁴ Wang et al.,⁶⁵ Chen et al.,⁶⁶ Meng,⁶⁷ Zhou and He,⁶⁸ Wu,⁶⁹ Zhou and Luo,⁷⁰ Zhang et al.,⁷¹ He et al.,⁷² Lv,⁷³ Li,⁷⁴ Bai,⁷⁵ Yin,⁷⁶ Zhou and Fu,⁷⁷ Ouyang and Zhu,⁷⁸ Huang et al.,⁷⁹ Lin,⁸⁰ Xing et al.,⁸¹ Shi,⁸² Wang,⁸³ Feng,⁸⁴ Han,⁸⁵ Chan et al.,⁸⁶ Liu et al.,⁸⁷ Chan et al.,⁸⁸ Long et al.,⁸⁹ Yang et al.,⁹⁰ Li et al.,⁹¹ Liu et al.,⁹² Chen et al.,⁹³ Liu et al.,⁹⁴ Zhang et al.,⁹⁵ Lu et al.,⁹⁶ Fang et al.,⁹⁷ Zhang et al.,⁹⁸ Zhao et al.,⁹⁹ Zheng et al.,¹⁰⁰ Xu et al.,¹⁰¹ Zhao et al.,¹⁰² Lai et al.¹⁰³
Clinical manifestations			Cui et al.,¹¹ Long et al.,¹⁷ Wang,²¹ Zheng,²³ Zhu et al.,²⁹ Gong,³¹ Wang and Wei,³³ Duan and Hua,³⁵ He and Zou,³⁸ Qiu,⁴¹ Zhao et al.,⁴⁵ Hu and Chang,⁵³ Yang and Yang,⁵⁴ Su,⁶¹ Zeng et al.,⁶⁴ Meng,⁶⁷ Yin,⁷⁶ Huang et al.,⁷⁹ Lin,⁸⁰
Optic neuritis (%)	401/2021 (19.8)	442/1913 (23.1)
Limb weakness (%)	772/2021 (38.2)	694/1913 (36.3)
Sensory disturbances (%)	707/2021 (35.0)	493/1913 (25.8)
Sphincter dysfunction (%)	133/2021 (6.7)	85/1913 (4.4)
Ataxia (%)	146/2021 (7.2)	143/1913 (7.5)
Cognitive impairment (%)	25/2021 (1.2)	47/1913 (2.5)
Epilepsy (%)	12/2021 (0.6)	21/1913 (1.0)
Consciousness disturbance (%)	23/2021 (1.1)	28/1913 (1.4)
Cranial nerve involvement (%)	241/2021 (12.4)	109/1913 (5.7)
CSF study			Cui et al.,¹¹ Wang,¹⁵ Liu and Feng,¹⁸ Zheng,²³ Wang,²⁵ Zhu et al.,²⁹ Duan,³⁰ Zhao et al.,⁴⁵ Zhu et al.,⁴⁸ Ma and Liu,⁴⁹ Hu and Chang,⁵³ Yang and Yang,⁵⁴ Su,⁶¹ Zhou and Luo,⁷⁰ Bai,⁷⁵ Ouyang and Zhu,⁷⁸ Huang et al.,⁷⁹ Lin,⁸⁰ Feng,⁸⁴ Long et al.⁸⁹
White cell count (>8 cells/mm³) (%)	101/457 (22.1)	159/620 (25.6)
Protein (>0.25 g/L)	162/598 (27.1)	170/703 (24.5)
IgG index >0.7 (%)	113/255 (44.3)	80/201 (39.8)
OCB (%)	169/476 (35.5)	502/904 (55.5)
MRI features
Brain MRI abnormalities (%)			Cui et al.,¹¹ Guo et al.,¹³ Wang,¹⁵ Li et al.,²⁰ Ren et al.,²⁷ Li et al.,²⁸ Zhu et al.,²⁹ Duan,³⁰ Gong,³¹ Jia,³² Wang and Wei,³³ Lin et al.,⁴² Lin et al.,⁴⁴ Xu,⁴⁶ Zhu et al.,⁴⁸ Hu and Chang,⁵³ Huang and Chen,⁶⁰ Hu,⁶² Ruan,⁶³ Bai,⁷⁵ Yin,⁷⁶ Zhou and Fu,⁷⁷ Ouyang and Zhu,⁷⁸ Long et al.,⁸⁹ Zhao et al.⁹⁹
Periventricular lesions	432/768 (56.3)	629/867 (59.1)
Cortical lesions	302/768 (39.3)	499/867 (57.5)
Cerebellar lesions	123/768 (16.0)	74/867 (8.5)
Brainstem lesions	302/768 (39.3)	240/867 (27.7)
Spinal cord MRI abnormalities (%)			Cui et al.,¹¹ Guo et al.,¹³ Qian,¹⁹ Li et al.,²⁰ Zheng,²³ Duan,³⁰ Duan and Hua,³⁵ Liu et al.,⁴⁷ Xue,⁵⁰ Su,⁶¹ Hu,⁶² Ruan,⁶³ Meng,⁶⁷ He et al.,⁷² Ouyang and Zhu,⁷⁸ Huang et al.,⁷⁹ Lin,⁸⁰ Feng,⁸⁴ Han,⁸⁵ Yang et al.,⁹⁰ Liu et al.⁹²
Cervical cord lesions	285/670 (42.5)	135/597 (22.6)
Thoracic cord lesions	135/670 (20.1)	109/597 (18.3)
Cervical and thoracic cord lesions	54/670 (8.0)	39/597 (6.5)
Lumbar cord lesions	11/670 (1.6)	8/597 (1.3)

Data are presented as n (%).

CSF, cerebrospinal fluid; IgG, immunoglobulin G; MRI, magnetic resonance imaging; MS, multiple sclerosis; OCB, oligoclonal bands.

MS mainly starts affecting patients at an age of 20–40 years.^3,125–127 The highest prevalence rates of pediatric multiple sclerosis is aged 13–16.¹²⁷ Up to 10% of MS patients present demyelinating before 18 years.¹²⁸ In China, the average age of MS often occurred in adults aged around 41.53 years and children aged around 8.05 years (Table 1).

Clinical features

Clinically isolated syndrome (CIS) is the occurrence of the initial demyelinating event with a high suspicion of development of MS.¹²⁹ Due to the lack of specific biomarkers, the diagnosis of MS is established in the fulfillment of dissemination in space (DIS) and time (DIT) demonstrated by the combination of clinical manifestations, imaging and cerebrospinal fluid (CSF) analysis [especially oligoclonal bands (OCBs)].¹³⁰ The development of McDonald’s criteria for MS and gradual improvement over time makes the diagnosis of MS more accurate and may allow the earlier diagnosis and treatment.

MS subtypes and course

According to the clinical course, several different phenotypes of MS have been defined: relapsing-remitting MS (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive MS (PPMS).

Almost 80–85% MS patients belong to RRMS.¹³¹ A study showed that almost 50% of RRMS patients could develop SPMS within 15 years.¹³² Of the 92 articles retrieved, only 30 articles reported relevant data (Table 1). According to the current data, RRMS is the most common phenotype in China and accounts for 85.2% of all MS patients, which is similar to the data from other regions, such as Argentina¹³³ and Lebanon.¹³⁴ Other phenotypes are SPMS and PPMS, with the percentage of 8.6% and 6.2%, respectively. In a 3-year follow-up study about CIS carried out in 2011 in China, 25.0% of patients finally converted to clinically definite MS (CDMS), with a higher conversion rate in females than males. Patients who had multifocal lesions had a greater likelihood of converting CDMS.⁸⁷ In a study including 249 patients with MS in 2008 in Shanghai, the proportion of RRMS, SPMS, and PPMS was 86.3%, 6.4%, and 1.6%, respectively. The remaining patients were hard to classify.¹³⁵ A two-center study conducted in 2019 reported that there were 115 patients (81.0%) with RRMS, 21 patients (15.0%) with PPMS, and 6 patients (4.0%) with SPMS.⁹⁶ In a prospective study in China including 365 patients followed up until reaching the expanded disability status scale of 6.0, 34 (9.3%) RRMS patients developed into the stage of SPMS, with a bit predominance in males (male:female = 10.9:8.5).⁹⁸

Clinical manifestations

The clinical features of an MS attack are various, depending on the regions of CNS targeted. The most common clinical phenotypes are optic neuritis (ON), transverse myelitis (TM), brainstem, and cerebellar syndromes. However, there exist other less common clinical manifestations related to cortical lesions, such as seizures and aphasia.¹²⁶

Optic neuritis

ON is a common initial presentation characterized by the subacute and unilateral attack with a gradual worsening of vision and photophobia, etc.^136–138 In 2013, a study reported that ON was the second most symptom in Latin American MS patients,¹³⁹ which was similar to the results from the cohort of Polish MS patients.¹⁴⁰ A study from Egypt showed that visual symptoms (21%) and motor dysfunction (21%) were the most common presenting features, and females were more prone to develop visual damage than males.¹⁴¹ However, we observed that ON was the third clinical presenting complaint in China (Table 1), which was consistent with the data in Mexico presented by Bertado-Cortés et al.¹⁴² In addition, in a study of 184 MS patients in South China, the results showed that there was no difference in the incidence of ON between OCB-positive and OCB-negative MS patients,⁹⁶ which was agreement with studies from other European countries, such as Serbia¹⁴³ and Greece.¹⁴⁴ A comparative study from Turkey demonstrated that there was no difference between OCB (+) and OCB (−) patients with respect to visual evoked potentials abnormalities.¹⁴⁵ And another Chinese study showed OCB had no effect on the final outcome of vision.¹⁴⁶

Transverse myelitis

Spinal cord involvement is the most common clinical manifestations of MS.¹⁴⁷ Compared to other continents, the advantage of the frequency of TM over that of visual disorders in Asia seems to be no significant.^{142,148–151} A study comparing clinical characteristics between the Middle East and North Africa patients and Indian patients versus patients with European descent showed the frequency of spinal cord symptoms was not different between these groups.¹⁵¹ A survey enrolled 142 MS patients in Pakistan showed that the most common initial symptoms were motor weakness (70%), followed by sensory symptoms (45%), while only 15% had bladder dysfunction.¹⁵² Kim et al.¹⁵³ also reported the low frequency of bladder/bowel dysfunction (9%) in Korea. However, in Indian, the most frequent initial presentation was motor weakness in almost 85.1% of MS patients. Sensory symptoms and bladder dysfunction were present in 41.6% and 65.1% of patients, respectively.¹⁵⁴ In a multicenter study from Brazil, the frequency of urinary system symptoms was 50%,¹⁵⁵ which was higher than the reported from a Chinese study, with the proportion of 3.3%.⁹² We found that limb weakness was the most common complaint and occurred in 42.5% of MS patients in China. Sensory disturbances and sphincter dysfunction occurred in 35.8% and 9.5% of the patients, respectively (Table 1).

Brainstem symptoms

Brainstem involvement in MS can cause ocular motility disorder such as diplopia and nystagmus, especially diplopia.¹⁵⁶ Internuclear ophthalmoplegia is a common acute ocular motor manifestation in MS, which can occur in approximately 33% of patients.¹⁵⁷ Brainstem involvement was reported in a study of 14,969 cases with MS at a proportion of 19.6%.¹⁵⁸ A single-center retrospective study in a cohort of 375 Polish MS patients reported that 9.3% of patients presented with diplopia, 5.9% with cranial nerves dysfunction.¹⁴⁰ One study from Northern China showed that 24.8% of MS had nystagmus, 6.8% had diplopia, and 10.3% had dysarthria.⁹¹ Generally, the cranial nerve involvement occurred in 12.5% of MS patients in China, mainly eye movement-related nerves (10.6%), followed by bulbar weakness (1.1%) and facial palsy (0.6%) (Table 1). Other less common symptoms included vertigo, trigeminal neuralgia, and vomiting. In addition, the frequency of cranial nerves dysfunction in Northern China was slightly higher than that in Southern China (12.4% and 5.7%, respectively) (Table 2). Both of them were mainly with ocular motility disorder.

Cerebellar symptoms

The injury of the cerebellum and its related pathways are also common in MS, especially in advanced disease states. Wilkins reported that the prevalence of cerebellar ataxia could be up to 80% in MS patients.¹⁵⁹ Tremor may affect limbs, head, and trunk. Postural or intention tremor is the most common type.¹⁶⁰ Severe tremor tends to be suggestive of poor prognosis. At the early stage of MS, the presence of cerebellar signs and symptoms tends to indicate the early occurrence of higher disability.¹⁶¹ In a study of 221 patients with early-onset MS,¹⁶² as one of the initial presentations, cerebellar signs occurred in 14.6% of all patients, which was consistent with the result reported by Kalincik et al.¹⁵⁸ that the cerebellar symptoms occurred in 10.1% of patients. Another previous study reported that tremor may occurred in up to 25−60% of MS patients.¹⁶³ Interestingly, a study from Saudi Arabia¹⁶⁴ showed that there was no difference of the frequency of cerebellar symptoms between males and females, while the result was distinct from other studies from Mexico¹⁴² and Egypt.¹⁴¹ They stated ataxia and tremors were more common in males than in females. We found that the frequency of ataxia in China was 14.1% (Table 1), which was comparable to the study from Jordan.¹⁶⁵ Patients from Northern China tend to have higher proportion of ataxia than patients from Southern China (7.2% versus 7.5%, respectively) (Table 2).

Cognitive impairment

Due to continuous axonal loss and atrophy of white matter and gray matter, MS patients have cognitive impairment (CI). The prevalence of CI in MS ranges from 40% to 65%¹⁶⁶ occurring in all MS phenotypes. However, it is more frequent and severe in progressive MS than in RRMS, which suggests that cognitive deficits tend to aggravate due to the exhaustion of nervous system reserve over time.¹⁶⁷ Some studies from European countries^168–170 and Latin America¹⁷¹ reported the prevalence of CI was between 34% and 65%. Generally, the older patients are likely to have worse cognitive performances than young patients, while CI is mostly directly related to MS itself and not similar to the decline in CI with general aging.^172,173 However, we found that only 4.2% of Chinese patients presented with CI (Table 1), which was very lower than the result from other Asia countries, such as Kuwait (23.3%)¹⁷⁴ and Korea (50%).¹⁷⁵ While a study with only very early MS patients showed the prevalence of CI was 11.6%.¹⁷⁶ We speculate that the low frequency of CI may be related to the stage of disease and selected testing methods and scales. In the early stage, these symptoms may be obscure and easily neglected.

Other symptoms

There are several other less common clinical syndromes, such as epilepsy and consciousness disturbance. Epilepsy is rare in MS and related to cortical or subcortical demyelinating lesions and atrophy of cortex and gray matter.¹⁷⁷ We found that epilepsy occurred in 0.7% of MS patients in China, smaller than that in Iran and Germany (2.3% and 2.6%, respectively).^178,179 Consciousness disturbance was also uncommon in Chinese patients with the prevalence of 1.0% (Table 1).

Comorbidity

Recently, many studies focus on the field of in MS.^180,181 Comorbidity is one of the clinical characteristics in MS patients and seems to be related to disability. Comorbidities of MS can be divided into two categories: autoimmune and nonautoimmune comorbidities.

Increasing evidence has shown that autoimmune comorbidities are prevalently presented in MS and associated with the disease progression. The frequency of autoimmune comorbidity ranged from 0% to 7.74%. The most prevalent autoimmune and neurological autoimmune comorbidities were psoriasis, thyroid disease, and myasthenia gravis (MG).^182,183 Danish reported that there was a significantly higher proportion with autoimmune diseases, including diabetes mellitus type I, Crohn’s disease, and systemic lupus erythematosus (SLE) in male patients with MS, than non-MS male controls. In this study, Crohn’s disease and ulcerative colitis were the most frequent autoimmune comorbidities in MS patients.¹⁸⁴ Another study comprising 2725 patients from Serbia demonstrated the prevalence of autoimmune disorders was 6.06% and the thyroid disease was the most common autoimmune disease.¹⁸⁵ However, we found that Sjogren syndrome and MG were the most common systemic and neurological autoimmune diseases, respectively, in China (Table 1), which was in consonance with the result from another Chinese study.⁹⁷

In addition to the autoimmune diseases, there is also a high prevalence of nonautoimmune diseases in MS. Hypertension, chronic lung disease, and hyperlipidemia are the most common nonautoimmune comorbidities.¹⁸⁶ Studies have suggested that these comorbidities are associated with the clinical course of the disease, disability progression, and higher increased mortality.^187,188 Increased risk of certain comorbidities may be the consequence of immunotherapy in MS patients.¹⁸⁵ In a Chinese study cohort, cardiovascular diseases, especially hypertension were the most common nonautoimmune diseases in MS patients.¹⁸⁹ Other studies from European and American countries also confirmed this point.^190–192 However, aging is largely correlated with the increased frequency of these comorbidities in MS patients.¹⁹³

Characteristics of CSF

Since the high heterogeneity of clinical manifestations, the diagnosis of MS is complex depending on the comprehensive consideration of clinical presentations, imaging, and laboratory findings. In most patients with MS, CSF can still provide valuable evidence.

We analyzed all data collected and found that a total of 24.1% of MS patients in China showed mildly raised white cell count. The frequency of raised protein was 25.5%, mainly in the range of 0.4–0.9 g/L (Table 1), and similar to the previously reported findings from China and other countries.^134,135,194 In addition, there seems to be no significant difference in the proportion of raised white cell count and protein between Northern with Southern China (Table 2).

Although only 70% of all MS patients exhibited elevated immunoglobulin G (IgG) index, it can take the integrity of the blood-brain barrier into consideration and is regarded as the valuable diagnostic hallmark in MS.¹⁹⁵ Olsson and Pettersson¹⁹⁶ found that the frequency of elevated IgG index in MS patients was higher than that in patients with other neurological diseases. However, in a previous study, IgG index >0.7 was observed in only 46.2% of patients,¹⁹⁷ while another study in Korea showed that this proportion was 60%. Interestingly, a study of Czech Republic displayed different IgG index in different types of MS, with 49.3% in CIS, 69.8% in RRMS, 63.5% in SPMS, and 66.6% in PPMS.¹⁹⁸ We found that the frequency of raised IgG index was 20.4% in China (Table 1). The frequency of elevated IgG index in Northern China was higher than that in Southern China (44.3% versus 39.8%, respectively) (Table 2).

Excessive intrathecal synthesis of IgG is also confirmed by detecting OCBs. Almost 95% of MS patients have OCBs in CSF in Sweden.¹⁹⁹ However, only 48.6% OCBs positive occurred in MS patients of China (Table 1), which was a little lower than that in other Asian countries, with 62% in Japan,²⁰⁰ 53% in Korea,¹⁵³ and slightly higher than 44.2% in Jordan,¹⁶⁵ but lower than that in Western countries.^201–203 When compared with Northern China, OCBs positive occurred more frequently in Southern China (35.5% versus 55.5%, respectively) (Table 2). Another study in China showed that patients with early-onset age tended to have OCBs in CSF than elder patients, while there was no association between OCBs status and the clinical findings.⁹⁶ Liu et al.⁸⁷ also observed a high conversion rate to CDMS in OCB-positive patients compared to OCB-negative patients although without obvious statistical significance. However, Kolcˇava et al.¹²⁹ demonstrated that during a follow-up lasting a mean of 27 months, OCB positivity was a strong predictor for the conversion of CIS to MS. Interestingly, the OCB positivity was correlated with latitude, that is, the probability of being OCB positive may increase with enhancing distance from the equator.^204,205 But the study from Argentina showed latitude seemingly regardless of OCB prevalence.²⁰⁶ This relationship should be investigated in more countries and larger patients.

Imaging features

Magnetic resonance imaging (MRI) is increasingly used to find the evidence that is suggestive of MS diagnosis, especially for patients with OCB and other tests negative results, and monitor its progression. As showed in standard MRI, the Dawson fingers of the periventricular lesions, ovoid lesions within characteristic locations, juxtacortical and infratentorial, and corpus callosum lesions are suggested as typical brain MRI findings, while short lesions (usually no more than three vertebral segments) with a clear boundary and mild edema, mainly involving the dorsolateral cord as specific spinal cord MRI findings. For most patients, the McDonald diagnostic criteria require demonstration of DIS and DIT with MRI findings. Given the relative low specificity and poor correlation with disability measures of conventional imaging, some specific MRI features, such as the central vein sign (CVS) and iron deposition, may provide new insight into the pathophysiology of MS and increase the specificity of MS diagnosis.

Brain

Periventricular lesion

Periventricular region seems to be more likely to subjected to demyelination.²⁰⁷ In 2020, a study evaluated lesions distribution to distinguish between NMOSD, MS, and myelin oligodendrocyte glycoprotein antibody-associated disorders. They found that 61 (61/71, 85.9%) of 71 MS patients have periventricular lesions. In another study, almost 96.0% of RRMS patients had specific periventricular lesions. However, periventricular lesions were observed in only 64.9% of MS patients in China (Table 1).^93,208 The low frequency of periventricular lesions is largely related to the MRI technique, since MS patients are mostly received MRI examination with two-dimensional (2D) imaging in many Chinese regions. There was also no difference in the distribution of periventricular lesions between MS patients with and without OCBs,⁹⁹ while an opposite result in Japan indicated that periventricular lesions were correlated with OCB state.²⁰⁹

Juxtacortical or cortical lesions

The juxtacortical or cortical lesion is a characteristic of MS and can be detected in almost 78% of MS patients and 20–72% of CIS patients.^210–213 In CIS patients, ⩾1 cortical lesion can increase the specificity to identify those who have the potential to convert to MS.²¹⁴ Moreover, the MRI evidence of cortical lesions is predictive for SPMS conversion. Patients with large cortical lesion counts have a high probability to develop SPMS.^215,216 Interestingly, it was found that male patients had more possibility to develop cortical lesions than females.²¹⁷ We found that cortical lesions were detected in 38.7% of MS patients (Table 1), which was higher than a study from Qatar²¹⁸ and another Chinese study,⁹³ but lower than Zhao et al.⁹⁹ reported.

Infratentorial lesions

Infratentorial lesions is one of the characteristic damage locations in MS. Favored targets of MS lesions are the brainstem and cerebellar peduncles, mainly brachium pontis.²¹⁹ Infratentorial lesions are more sensitive and specific for MS diagnosis than periventricular lesions.^208,220

The involvement of brainstem in MS is very common. Up to 58.0% of patients with MS can be detected with brainstem lesions.²²¹ Among three anatomic sites, the pons is more frequently involved. However, only 33.1% of Chinese patients had brainstem lesions (Table 1), which was lower than that in many Western countries.^222–225 The distribution of MRI lesions in the brainstem was 11.5% in the midbrain, 26.3% in the pons, and 12.9% in the medulla (Table 1). Although MRI lesions found in Japan were higher than our results, it was still lower than in Western countries.²²⁶ It is speculated that the ethnic factors may play an important role resulting in the difference. Of course, MRI’s program with different spatial resolutions can also contribute to this result.²²⁷ Besides, CIS patients both with symptomatic and asymptomatic brainstem lesions are more likely to develop MS than patients only with symptomatic brainstem lesions.²²⁸

Cerebellar injury is also common in MS, which is the origin of many manifestations. Lesions can affect any part of the cerebellum.²²⁹ Similar to the brainstem, there is a difference in the percentage of cerebellar involvement between different countries. In China, 12.0% of MS patients had cerebellum lesions (Table 1). We shared a similar result with a study in Japan,²²⁶ but the percentage was low significantly compared to white patients with MS.^230,231 This relationship needs to be confirmed by future studies.

Spinal cord

The typical spinal cord MRI findings in MS patients are featured with T1-hypointense and T2-hyperintensity.^232,233 Gadolinium-enhancing lesions in the spinal cord are less seen than in the brain and are usually accompanied by new clinical symptoms.

Types of spinal cord lesions vary depending on the MS subtype. As mentioned before, asymptomatic spinal cord lesions have been proposed in 30–40% of CIS patients. Focal lesions are more seen in RRMS patients.²²⁹ When RRMS patients progress to a secondary progressive course or patients start with a primary progressive course, spinal cord abnormalities tend to be diffuse and extensive, which is often correlated with spinal cord atrophy.^229,234 Abnormal spinal cord imaging was seen in 61.4% of MS patients in China (Table 1), which was lower than previously reported,^235,236 but similar to a previous study in China reported with a frequency of 63%.⁹² What is more, two Chinese studies have shown that there was no difference in the number of spinal cord lesions between OCB-positive and OCB-negative patients.^96,99 While postmortem studies demonstrated that demyelination affects the entire spinal cord,^237,238 MRI detection of such lesions is regularly more successful in the cervical proportion.^{234,239–242} In our study, among patients who had spinal cord abnormalities, cervical cord lesions were found in 33.1% of cases, thoracic cord in 17.7%, and 1.5% in lumbar cord. 7.3% of patients had both cervical and thoracic cord lesions (Table 1). However, there was a higher ratio of thoracic cord involvement than cervical cord in Korean.²⁴³ In a study of 202 patients with MS, cervical cord abnormalities were seen in 59% of patients; the percentage was higher than that of involved thoracic or lumbar cord.²⁴¹ Andreadou et al.¹⁴⁴ showed that OCB-positive patients had the higher frequency of cervical spinal cord lesions than OCB-negative patients. Nevertheless, the number of cervical spinal cord lesions did not differ by OCB status in Turkey.¹⁴⁵ Asian-type MS tends to have higher frequencies of spinal cord lesions as well as gadolinium-enhanced lesions than Western-type MS.²⁴⁴

Specific MRI features as biomarkers

Central vein sign

CVS is regarded as a kind of phenomenon of the MRI-detectable perivenular distribution of demyelinating lesions.²⁴⁵ As a newly proposed biomarker of inflammatory demyelination, the CVS is increasingly recommended for improving the accuracy of MS diagnosis.²⁴⁶ A number of groups have evaluated the CVS in various conditions, including Susac’s syndrome, NMOSD, and inflammatory vasculopathies, and increasing evidence has demonstrated CVS as a potential imaging marker to accurately distinguish MS from non-MS mimics.^247–250 Studies have identified that the CVS could be present in all subtypes of MS, and there was no difference between clinical phenotypes regarding the proportion of total lesions with a central vein.^251,252 In terms of the distribution, the CVS has a predilection for the periventricular region, which was consistent across studies.^253,254 However, large prospective studies are still needed to validate the clinical value of CVS as a novel indicator to support the diagnosis of MS. As in other middle- and low-income countries, so far, MRI examination with 2D imaging has been applying in China; therefore, the CVS as an important imaging marker could not be identified well, which is needed to be improved as soon as possible.

Iron deposition

Iron is an essential element that functions in normal neurobiological processes, including neurotransmitter synthesis and myelin production.²⁵⁵ In the aging process, iron can accumulate in brain tissue. However, it has demonstrated that abnormal deposition of iron in the brain may be related to neurodegeneration.²⁵⁶ MRI has been proposed as a powerful mean for quantifying iron deposition in brain lesions and typically exhibits a rim of hypointense signal fully or partially encircling lesions, the so-called iron rims (IRs).²⁵⁷ IRs can be detected by several MRI techniques, such as conventional T2-weighted MRI, susceptibility weighted imaging, and quantitative susceptibility mapping.²⁵⁸ Histopathological-imaging studies identified that, IRs in MS lesions are predominantly from activated microglia and macrophages and considered to represent chronic active lesions.²⁵⁹ IRs can be detected in different MS subtypes. Llufriu et al.²⁶⁰ found the detectable frequency of IRs in SPMS patients is higher than in RRMS patients, which is similar to the finding by Chawla et al.,²⁵⁰ but different from another study.²⁶¹ Importantly, age and sex differences may influence the occurrence of IRs in MS patients. IRLs are more common in young male MS patients,^251,262 and IRs may be also useful biomarkers for improving the accuracy of MS diagnosis. Many studies found that IRs are rare in non-MS inflammatory neurological diseases, including NMOSD,²⁶³ Susac syndrome,²⁶⁴ SLE, and other inflammatory demyelinating diseases of CNS.^265,266 Besides, IRs are also better markers for evaluating neurological disability and more brain atrophy.^267,268

Treatments

Management of MS requires to be integrated multidisciplinary approach and immunomodulating treatments. Many clinically conventional and novel medications with distinct targets have been approved for immunomodulatory and immunosuppressive treatments. In the acute phase, patients can be treated with corticosteroids to inhibit inflammatory and autoimmune activity. During the remission and relapse phases, all kinds of DMTs, especially several novel monoclonal antibodies (Mab), targeting different targets modify the process of MS reducing relapse by inhibiting or regulating immune response.²⁶⁹

Treatment of acute relapses

The aim of acute relapse treatment is to accelerate clinical recovery without effect on long-term prognosis. However, the relapse severity decides the need for acute treatment in MS. The standard treatment for MS relapses is the intravenous infusion of high-dose corticosteroids in a short time.²⁷⁰ If the initial response to steroids is inadequate, rescue treatment is available, including plasma exchange or intravenous immunoglobulin.²⁷¹

According to the Chinese expert consensus on MS diagnosis and treatment, the recommend first-line therapy in the acute phase is glucocorticoids. If the clinical neurological deficit recovered obviously, it can be stopped directly. The second-line therapy is plasma exchange.²⁷² A study explored the factors associated with the efficacy of glucocorticoid in Chinese patients with MS.²⁷³ The results showed that patients who were sensitive to glucocorticoid had higher expression of glucocorticoid receptor (GR)-α and lower expression of FK506 binding protein 5 (FKBP5), which might provide a novel therapeutic strategy for glucocorticoid-resistant patients with MS in the acute stage.

Treatment of remission

Conventional immunosuppressants

Since the introduction of interferon-β (IFN-β) into the Chinese medical market, people certainly start to be exposed to the concept of ‘DMTs’. However, before that, the lack of potent drugs for MS always makes patients as well as doctors helpless. Thus, Chinese doctors have no choice but to choose medicine best for patients among conventional immunosuppressants, which have been demonstrated to be effective in MS, such as azathioprine and mycophenolate mofetil. Despite adverse effects, they are widely used in MS patients in China due to the low price and confirmed effectiveness.²⁷⁴ A clinical trial for MS in Italy showed that azathioprine could function in reducing new brain inflammatory lesions.^275,276 A prospective double-masked trial enrolled 59 American MS patients displayed that treatment with azathioprine could significantly decline the risk of disability and relapse, leading to the delay of MS progress.²⁷⁷ However, there is some concern about its safety, mainly a possible increased risk of malignancy. But cumulative doses of 600 g seem to decline the incidence of side effects.²⁷⁸ A retrospective study also confirmed the effect of mycophenolate mofetil on MS. This study enrolled 344 MS patients (median follow-up 25.3 ± 1.1 months), and the result showed that during the 1-year control period, the recurrence rate significantly decreased and kept the disability at the initial level.²⁷⁹

Disease-modifying therapies

Over the last few years, the treatment of MS has experienced a revolution since the advent of more potent DMT drugs. All of these medicines have been identified to be effective in decreasing the frequency of relapses and accumulation of lesions, thereby slowing disease progression. Up to now, since the invention of the first immunomodulating IFN-β-1b in 1993, 15 DMTs have been currently approved in various regions worldwide for modifying the course of MS. To date, there have been only four licensed DMTs available in China: IFN-β, teriflunomide, fingolimod, and siponimod. A recent study on the survival analysis of MS patients showed that financial burden, symptom degree, and educational level all govern the treatment acceptance in Chinese patients with MS.²⁶⁹

IFN-β was added to the National Medical Insurance Drug List in 2017 in China. As a first-line treatment for MS, IFN-β can reduce the relapse rate, disability, and MRI prognostic indicators.²⁸⁰ Unfortunately, it has been excluded from National Medical Insurance Drug List. Due to the expensive cost and intolerance of injection administration, IFN-β is becoming less and less unaccepted by Chinese MS patients.

Teriflunomide, as the first orally DMTs approved in China, can suppress the proliferation of activated lymphocytes by inhibiting of the dihydroorotate dehydrogenase, hence reducing CNS lymphocyte infiltration.²⁸¹ The Phase III TOWER study of teriflunomide in China has been completed and showed the marked extent of efficacy and excellent safety in Chinese subjects.²⁸² Meanwhile, compared with IFN-β, teriflunomide is more cost-effective.²⁸³

With the increasing diagnostic rate of SPMS in China, the use of sphingosine 1-phosphate (S1P)-receptor modulators fingolimod and siponimod are increasing gradually. However, there is a lack of data related to the efficacy and safety of the S1P receptor modulators for MS in China because phase III clinical trials are still going now.

Recently, several new Mabs as DMTs have started to treat MS patients in China, such as anti-CD20 Mabs’s rituximab and ofatumumab, which are highly precise by specifically targeting molecules displayed on cells involved in distinct immune mechanisms of MS pathophysiology. So far, the efficacy and safety of Mabs in Chinese MS patients have not been reported.

Furthermore, transplantations of umbilical cord mesenchymal stem cells and autologous mesenchymal stem cell in MS were conducted in China and other countries, which requires further study to confirm its effectiveness and safety.^81,284

Prospect and challenges

The clinical research is gradually enriching our knowledge of MS; however, it remains a complex and challenging condition. The epidemiology, clinical features, and therapy of MS differ within distinct countries in the globe and Chinese different regions. In this review, we provide the overall profile of MS in China and global research advance on MS, which can help us to recognize risk factors, signs, and symptoms suggestive of MS in order to make early diagnosis, and appropriate and timely treatment. Although most kinds of existing DMTs can prevent relapse, hinder focal brain inflammation, and partly slow long-term progression, they are mainly available to RRMS patients and a minority of people with progressive forms of the disease. Therefore, an important topic for future studies would be to elucidate the mechanisms of neurodegeneration and explore available biomarkers to diagnose and monitor disease progression and, thus, to drive the development of new treatment combining neuroprotection with remyelination to promote lesion repair and prevent progressive accumulation of disability. However, there are some deficiencies and problems in China and other low- and middle-income countries in this regard as described above, which leads to misdiagnosis and delayed timely treatment. These challenges need national and international cooperation to solve in the future.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Tao Jin

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