Fast Facts: Multiple Sclerosis: A new era of disease modification and treatment

By S E Hughes and G. Macaron

Multiple sclerosis (MS) is a leading cause of disability in young adults, carrying a considerable individual and societal economic burden. The development of disease-modifying therapies and updates to diagnostic criteria are leading us into a new era for MS management, both in the earliest disease phases and progressive MS. In this completely revised/fully updated edition of Fast Facts: Multiple Sclerosis, we present the most recent evidence on disease pathogenesis and all clinical aspects of the condition, as well as the latest on disease-modifying therapies and other potential treatments. Given the need for multidisciplinary management of MS, we have written this resource for the benefit of all health professionals involved in MS care. Table of Contents: • Epidemiology and genetics • Pathology • The clinical picture • Treatment of relapses and symptoms • Disease-modifying treatment • Emerging therapies • Special MS populations • Lifestyle considerations and the multidisciplinary team • Advanced MS

• Language: English
• Publisher: S. Karger
• Release date: May 5, 2021
• ISBN: 9783318067996

Book preview

Introduction

Multiple sclerosis (MS) is a leading cause of disability in young adults, and it has a significant effect on patients’ quality of life, family plans and careers. By causing varying degrees of physical and cognitive disability, MS carries a considerable individual and societal economic burden.

Fortunately, we are entering a new era in the management of MS. Several recent studies support initiating treatment early in the disease course with higher-efficacy disease-modifying therapies in patients with relapsing-remitting MS. This approach has been associated with better long-term outcomes, specifically a lower risk of conversion to secondary progressive MS. Moreover, new molecules with the potential to induce myelin repair or halt the neurodegenerative process are in the pipeline for the treatment of progressive MS. Coupled with a recent update to the diagnostic criteria, clinicians can now diagnose and treat patients in the earliest phases of their disease.

In this new edition of Fast Facts: Multiple Sclerosis, we present the latest evidence on disease pathogenesis and all clinical aspects of the condition, as well as the latest on disease-modifying therapies and other potential treatments.

Given the need for multidisciplinary management of MS, we have written this resource for the benefit of all health professionals involved in the care of patients with this complex disease.

Acknowledgments. The authors wish to thank the authors of the third and fourth editions of this resource, Drs Michael Barnett, Omar Malik, Ann Donnelly, Mary Rensel and Orla Gray, for the strong foundation on which this new edition is based.

1Epidemiology and genetics

Multiple sclerosis (MS) is a neurological condition resulting from inflammation and degeneration within the central nervous system (CNS). This inflammation can affect different sites at different times, producing a variety of symptoms and signs. Periods of relapse and remission occur in the early stages of the disease, and in most patients a slowly progressive course ensues within one to two decades of disease onset. The cause of MS is unknown, but dysregulation of the immune system is central to the pathogenesis of the disease.

Epidemiology

MS is the leading cause of neurological disability in the young and middle-aged populations of the developed world. Survey figures from 2020 suggest that it affects 2.8 million people worldwide.¹ Given the lack of complete surveillance data in some countries, this is likely to be an underestimate.

Prevalence. The worldwide prevalence of MS appears to be increasing. This is related to many factors, including improved counting methods, better diagnosis, global population growth, people with MS living longer (through improved treatment and support) and a true increase in disease incidence, especially in females.

The number of people with MS in a given population at any one time is usually expressed as cases per 100 000 population. Prevalence varies worldwide, but MS is most prevalent in northern European populations, especially in individuals of Nordic descent, and is notably more prevalent in temperate than equatorial regions. While, globally, the median estimated prevalence of MS is 36 per 100 000,¹ in some countries, prevalence exceeds 300 per 100 000.

Regionally, the median estimated prevalence of MS is greatest in Europe and the Americas (133 and 112 per 100 000, respectively).¹ However, prevalence varies significantly both within regions and within countries. For example, in Europe, San Marino and Germany have the highest prevalence of MS in the world (337 and 303 per 100 000, respectively), whereas some European countries have prevalence figures below 40 per 100 000.¹

In the Global Burden of Disease Study 2016, the highest age-standardized MS prevalence estimates (given as per 100 000 population) were in high-income North America (164.6), western Europe (127.0) and Australasia (91.1), and the lowest were in eastern and central sub-Saharan Africa (3.3 and 2.8, respectively) and Oceania (2.0).²

Incidence. The number of new cases per 100 000 population per year can indicate changes in the risk of a disease within a population, and can signify whether the disease frequency is increasing in a population. It is not affected by changes in survival. The incidence of MS, which peaks at age 30, appears to be rising in both the northern and southern hemispheres, particularly in women. The median estimated global incidence of MS is 2.5 per 100 000 per year, but in some countries the incidence may exceed 10 per 100 000 per year.³

Geo-epidemiology of MS. The prevalence of MS is significantly associated with latitude, particularly in populations of European descent (Figure 1.1). The ‘latitudinal gradient’ in MS has been confirmed by independent studies in Australia, New Zealand and the USA, with exceptions in Sardinia and northern Scandinavia.⁴ In Australia, the age-standardized prevalence is highest in Tasmania, almost double that in Queensland.⁵ Genetic variation between geographically discrete populations has been invoked as one explanation for this observation, particularly within the human leukocyte antigen (HLA). However, a statistically significant relationship between MS prevalence and latitude persists in some European populations even after adjustment for HLA-DRB1 allele frequency,⁴ supporting a role for environmental factors that vary with latitude, such as ultraviolet (UV) light exposure, viral infections and vitamin D levels.

Sex. MS is more common in women than men, at a ratio of 2–3:1. In Denmark, where an MS registry has been ongoing since 1950, the incidence of MS has doubled in women, but has increased by only 24% in men.⁶ An increasing incidence in females only has been observed in several other northern hemisphere countries, including Canada,⁷ Finland⁸ and Japan.⁹ An exploratory analysis across different geographic areas worldwide also showed a latitudinal gradient to the increased sex ratio.¹⁰ The pediatric MS population has a prepubertal sex ratio of 1:1, pointing to a likely association between sex hormones and disease onset.¹¹

Figure 1.1 Geographic distribution of MS, showing a greater prevalence at high latitudes. Source: Atlas of MS, 3rd edition. Multiple Sclerosis International Federation, 2020.¹

Environmental risk factors include:

•UV radiation and season of birth

•levels of dietary vitamin D

•Epstein–Barr virus (EBV) infection

•smoking

•migration.

Ultraviolet radiation and season of birth. The latitudinal prevalence gradient for MS may be explained in part by a relationship to exposure to UV radiation from sunlight, as there is an association between low levels of UVB exposure and development of MS. This may explain the ‘season of birth effect’ whereby those born in spring (April) in countries in the northern hemisphere have a significantly higher relative risk of developing MS than those born in winter months (October).¹² This may be related to maternal exposure to UV light.

Dietary vitamin D. There is an association between low levels of vitamin D and a number of diseases, including MS. Diet, dietary supplements and ambient UV exposure are all sources of vitamin D. Populations exposed to limited sunlight but who consume diets rich in fatty fish (a good source of vitamin D) have lower MS prevalence rates than expected for their latitude.¹³ Prospective studies have shown that MS risk is lower in groups who take vitamin D supplements regularly.¹⁴ Higher vitamin D levels are associated with lower risk of relapse¹⁵ and slower rates of progression in MS. Studies in patients with clinically isolated syndromes have reported a delay before the second inflammatory episode in people with higher vitamin D levels.¹⁶,¹⁷

Epstein–Barr virus is a double-stranded DNA virus that is transmitted via saliva. EBV does not always cause illness, and early childhood infection with the virus is usually asymptomatic. The acute illness caused by EBV, infectious mononucleosis, often accompanies primary infection in adolescence or young adulthood. Individuals with MS are rarely seronegative for EBV, and there is a strong association between previous history of infectious mononucleosis and MS, with a twofold greater risk of MS in this group.¹⁸ There also appears to be a relationship between the titers of EBV immunoglobulin G (IgG) and the risk of MS.¹⁹ The nature of the association between EBV and MS is yet to be established, but the infection may trigger or potentiate autoimmunity.

Smoking. The relative risk of developing MS is around 1.5 times higher for smokers than non-smokers,²⁰ and there is a direct link between duration and intensity of smoking. Cultural trends that have led to an increase in the number of female smokers may be contributing to the rising incidence of MS in females (see page 10). However, the risk appears to be greater in male (threefold) than female (twofold) smokers. The risk of developing secondary progressive MS (see page 30) is higher in ‘ever smokers’ than ‘never smokers’.²⁰

Migration studies support a relationship between the country of origin and risk of MS. An individual’s age at the time of migration from a high-prevalence area to one of low prevalence appears to affect the risk for MS, with a critical time period that may extend into early adulthood.²¹ Although this observation lends indirect support to the hypothesis that environmental factors contribute to MS risk, the correlation between migration and MS risk is not necessarily maintained when people from communities that do not classically have a high MS prevalence, such as the Japanese, move to areas of high prevalence.²¹

Ethnicity. MS is more common in people with northern European ancestry. The incidence is lower in people of Asian/African or South American heritage.²² People of different ethnicities living in the same environment have different prevalence rates for MS. For example, in the UK, the prevalence of MS was found to be considerably lower in black (African or Caribbean descent) and south Asian (Indian, Bangladeshi, Pakistani or Sri Lankan descent) people living in east London than in white (British, American or European descent) people living in the same area. However, MS is several times more prevalent in black and south Asian people living in the UK than in those living in Africa and south Asia (although the data from less-developed countries are limited).²³ These findings highlight both the genetic contribution to MS susceptibility and the effect of environmental factors on MS risk.

Genetics

No single causative gene for MS has been identified. However, people with a family member with MS have a greater risk of developing the disease (Table 1.1).²⁴ Concordance between female monozygotic (identical) twins approaches 40%, while dizygotic (non-identical) twins have a concordance rate of approximately 4% and non-twin siblings have a relative risk 15–20 times that of the local population.²⁵ Although these figures also implicate environmental factors in the genesis of MS, studies of ‘non-biological siblings’, that is, siblings who share the same environment but have different biological parents, do not suggest an increased risk related solely to environment. It is therefore likely that an individual’s genetic background modulates susceptibility to environmental risk factors.

TABLE 1.1

Population-based prevalence in relatives of a person with MS

*Sibling with the same parents, where the parents are related.

Adapted from Ebers 2008.²⁴

There is a strong association between susceptibility to MS and specific HLA alleles that code for major histocompatibility complex (MHC) class II antigens. These antigens are expressed on antigen-presenting cells (including dendritic cells, macrophages and B lymphocytes). In northern Europeans, the HLA-DRB1*1501 allele (and HLA-DR15 haplotype) has shown a consistent association with MS and is said to increase the risk of MS threefold.²⁶ It may be that an effect of one gene is modified by several other genes (epistasis). Furthermore, epigenetic modulation of the MHC by environmental factors such as vitamin D, smoking, EBV infection and early-life hygiene may modify the effect of allelic variation at this site.

A number of other susceptibility loci have been identified; in a study of over 14 000 people with MS, the International Multiple Sclerosis Genetics Consortium expanded the number of genetic variations associated with MS to more than 100.²⁷ Most of the risk alleles associated with MS are related to function of the immune system. However, only around 25% of the disease heritability is explained by the MS risk loci identified to date.²⁶

An individual’s genetic background may also explain the varied response to immunotherapy. Pharmacogenomic studies are ongoing.

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