The Autoimmune Diseases || Multiple Sclerosis

Chapter 52

Multiple Sclerosis

Amanda L. Hernandez1, Kevin C. O’Connor2, and David A. Hafler3

1Department of Neurology, Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven CT, USA, 2Department of

Neurology, Human and Translational Immunology Program, Yale University School of Medicine, New Haven CT, USA, 3Department of Neurology,

Yale University School of Medicine, New Haven CT, USA

Chapter OutlineHistorical Background 735

Clinical Features 736

Imaging 737

Immunological Markers in Diagnosis 738

Pathology 738

Epidemiology of MS 739

Genetic Factors 739

Environmental Factors 740

Immune Pathogenesis 742

T Cell Pathogenesis 743

Immune Dysregulation 744

Autoantigens 745

Meningeal Ectopic B Cell Follicles 745

Treatment 745

Interferons 746

Glatiramer Acetate (Copaxone) 747

Natalizumab (Tysabri) 747

Mitoxantrone (Novantrone) 748

Fingolimod (Gilenya) 748

Teriflunomide (Aubagio) 748

Dimethyl Fumarate, BG-12 (Tecfidera) 748

Concluding Remarks 749

References 749

HISTORICAL BACKGROUND

It is widely held that the earliest known reference of

multiple sclerosis (MS) can be attributed to Scottish pathol-

ogist Robert Carswell (Murray, 2009). In his atlas,

Pathological Anatomy: Illustrations of the Elementary

Forms of Disease (1838), Carswell described two patients

affected by paralysis, both with lesions along the spinal

cord and lower brain stem accompanied by atrophy.

Carswell believed that the extensive paralysis the patients

suffered was directly related to the impressive pathology he

encountered (Behan, 1982). However compelling

Carswell’s account was, it was not until 30 years later that

MS was named by a French neurologist, Jean Martin

Charcot. Charcot first described a comprehensive account

of the features of MS in 1868 by correlating the clinical and

pathological features of the illness in patients he examined

both while they were alive and at autopsy. He noted the

accumulation of inflammatory cells in a perivascular

distribution, demyelination, and axonal sparing within the

lesions or “plaques” in the brain and spinal cord white

matter of patients with intermittent episodes of neurologic

dysfunction (Charcot, 1868a,b, 1877). This led to the term

“sclerose en plaques disseminees,” or multiple sclerosis.

Over the last 100 years there have been many important

historical milestones that have led to the fundamental under-

standing that MS is a multifocal inflammatory disease pri-

marily affecting central nervous system (CNS) white matter

resulting in progressive neurodegeneration in genetically sus-

ceptible hosts (recently reviewed in Nylander and Hafler,

2012). The hypothesis that MS is an autoimmune disease can

be attributed to observations by Thomas Rivers at the

Rockefeller Institute. In 1933 Rivers demonstrated that injec-

tion of rabbit brain and spinal cord into primates resulted in a

demyelinating disease in mammals (Rivers et al., 1933). This

disease, known as experimental autoimmune encephalomy-

elitis (EAE), is the result of immunization of CNS myelin

and has served as an important animal model for multiple

sclerosis.

In 1965, Schumacher et al. defined clinical diagnostic

criteria based on the notion that MS is a disease

disseminated in time and space throughout the CNS

735N. Rose & I. Mackay (Eds): The Autoimmune Diseases, Fifth edition. DOI: http://dx.doi.org/10.1016/B978-0-12-384929-8.00052-6

© 2014 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/B978-0-12-384929-8.00052-6

(Schumacker et al., 1965). Such criteria continue to be

utilized and revised today. Since then, the advent of mag-

netic resonance imaging and FDA approval of IFN-β1b,among other therapeutic agents, have revolutionized how

we examine and treat patients with MS (Young et al.,

1981; Arnason, 1993). During the past 20 years, MS has

evolved from a disease with no therapy to one with eight

approved therapies in the USA to date. These major

advances have established MS as a treatable neurological

illness. Nonetheless, the development of more effective

and safer treatments that can be used at the time of diag-

nosis for this potentially disabling illness is paramount,

and predicated on a more thorough understanding of the

underlying immunopathology. Advances in immunology

and neurology have provided clinicians with powerful

tools to better understand the underlying causes of MS,

leading to new therapeutic advances. The future calls for

extending the original observations of Carswell and

Charcot by continuing to define the molecular pathology

of MS in relation to growing knowledge surrounding

immune-related pathology and DNA haplotype structure

in addition to CNS and peripheral mRNA and protein

expression, leading to the generation of a new series of

disease-related hypotheses.

CLINICAL FEATURES

The signs and symptoms of MS are variable as the disease

can affect anywhere within the CNS. Demyelinating

lesions may develop at any site along myelinated CNS

white matter tracts, and symptoms of MS therefore

depend on the functions subserved by the pathways

involved. Although the primary insult involves demyelin-

ation, edema, inflammation, gliosis, and axonal loss all

contribute to the symptomatology of a lesion. The most

common symptoms and signs involve alteration or loss of

sensation due to involvement of spinothalamic or poste-

rior column fibers, visual loss from optic neuritis, limb

weakness and spasticity related to disruption of corticosp-

inal tracts, tremors and incoordination of gait or limbs

largely related to cerebellar or spinocerebellar fiber

involvement, and abnormalities of cranial nerve function

(such as double vision due to disturbance in conjugate eye

movement) secondary to brainstem lesions (Noseworthy

et al., 2000). Bowel, bladder, and sexual dysfunction

occur in over two-thirds of patients at some time during

the course of their illness (Betts et al., 1993; Mattson

et al., 1995) largely due to disruption in spinal cord path-

ways. Fatigue, depression, and cognitive changes are

common symptoms of elusive etiology that may signifi-

cantly interfere with daily functioning and are now being

recognized as significant contributors to disability

(Whitlock and Siskind, 1980; Freal et al., 1984;

Sadovnick et al., 1996). A correlation with progressive

brain atrophy, cognitive decline, and impairment on MRI

has implicated axonal loss as the pathologic substrate of

the cognitive deterioration in MS (Rao et al., 1989; Hohol

et al., 1997; Amato et al., 2004).

While MS can have variability in clinical presentation

and course of the illness, it can follow a number of rather

predictable courses. MS may be divided into four clinical

categories: clinically isolated syndromes (CIS), an early

form of MS, relapsing�remitting multiple sclerosis

(RRMS), which in a subgroup of patients becomes sec-

ondary progressive multiple sclerosis (SPMS), and

primary progressive multiple sclerosis (PPMS).

CIS generally occur in young adults, and are defined by

the presentation of a first episode of demyelination typically

in the form of optic neuritis, cerebellar, or brainstem syn-

drome. During an episode, neurological symptoms develop

over hours to several days, persist for days to several weeks

and gradually dissipate (Miller et al., 2012). In order for

such episodes of acute inflammatory CNS demyelinating

events to be considered CIS, they must last for at least 24

hours with no more than 30 days between attacks (Polman

et al., 2005). The resolution of symptoms appears to be due

to the reduction of inflammation and edema at the site of

the responsible lesion rather than to the reversal of demye-

lination, which may persist even in the absence of symp-

toms (McDonald et al., 2001). In a number of recent

prospective studies, patients experiencing an initial episode

suggestive of CNS demyelination and having MRI evidence

indicating the presence of lesions either at the time of or

within 3 months of the event is highly predictive for the

development of relapses and thus clinically definite multi-

ple sclerosis (CDMS). Without MRI lesions, the probability

of developing MS is substantially less. More than half of

those developing MS experienced the additional relapse

within 1 year of their first episode (Achiron and Barak,

2000; Fisniku et al., 2008). Thus, it seems reasonable to

label the first attack of what appears to be MS as CIS,

explaining to patients that there is a high likelihood of

developing multiple sclerosis (Rovira et al., 2009). This

indicates to the patient there is a good understanding of the

underlying problem, but the prognosis is not clear, allowing

patients who never have another attack to be saved from

carrying a diagnosis of MS (Miller et al., 2012).

If a patient with a CIS develops further episodes of

relapses followed by a recovery with a stable course

between relapses, patients are referred to as having

RRMS. Early in the course of MS, patients often make

complete recovery from relapses. As the disease goes on,

the recovery from a relapse diminishes, which causes a

patient to accrue disability. A relapsing�remitting onset

is observed in 85�90% of patients, with relapses often

lasting 4 weeks in duration. The outcome in patients with

RRMS is variable; untreated, previous reports suggested

that approximately 50% of all MS patients require the use

736 PART | 10 Central and Peripheral Nervous System

of a walking aid by 10 years after clinical onset

(Weinshenker, 1994). The consequences on prognosis of

newer treatment regimens are not completely delineated;

however, many studies indicate improvement of disability

status following continued treatment regimens (Bates,

2011). Increased attack frequency and poor recovery from

attacks in the first years of clinical disease predict a more

rapid deterioration (Confavreux and Vukusic, 2006).

Ultimately, approximately 40�50% of untreated relap-

sing�remitting patients stop having attacks and develop

what may be a neurodegenerative progressive disease

secondary to the chronic CNS inflammation, known

as secondary-progressive multiple sclerosis (SPMS)

(Confavreux et al., 2000). The evolution to this secondary

progressive form of the disease is associated with signifi-

cantly fewer gadolinium-enhanced lesions and a decrease in

brain parenchymal volume (Khoury et al., 1994; Filippi

et al., 1995; Weiner et al., 2000). Similarly, while earlier

relapsing�remitting MS is sensitive to immunosuppression

(Hohol et al., 1999), as times goes on, responsiveness to

immunotherapy decreases and disappears in secondary pro-

gressive disease (Rieckmann et al., 2004). Thus, rather than

conceiving of MS as first a relapsing�remitting and then a

secondary progressive disease, it could be hypothesized that

MS is a continuum where there are acute inflammatory

events early on with secondary induction of a neurodegener-

ative process refractory to immunologic intervention. This

hypothesis awaits experimental verification.

Primary progressive MS (PPMS) occurs in close to

15% of patients, and is characterized from the onset by

the absence of acute attacks and instead involves a grad-

ual clinical decline traditionally in the form of a progres-

sive myelopathy (Miller and Leary, 2007). Patients may

also present with a progressive cerebellar syndrome in the

form of ataxia. Clinically, this form of the disease is asso-

ciated with a lack of response to any form of immuno-

therapy. Researchers had therefore posited that PPMS

may in fact be a different disease than RRMS.

In the absence of a specific immune-based assay, the

diagnosis of MS continues to be predicated on the clinical

history and neurological exam demonstrating multiple

lesions disseminated in time and space within the CNS

(McDonald et al., 2001). Although using McDonald’s cri-

teria the diagnosis of MS can be made solely on the basis

of history of two relapses and objective findings on exam

of two lesions disseminated in the CNS (periventricular,

juxtracortical, infratentorial, or spinal cord), MRI of the

neuroaxis is often sought to confirm the diagnosis or to

rule out other mimics of the illness. The use of the MRI

and other imaging modalities has had a major impact on

early diagnosis by establishing newer criteria for the diag-

nosis of the disease as well as a means to determine prog-

nosis and monitor disease course and response to therapy.

T1-weighted scans generally provide appreciable contrast

between gray and white matter with water appearing dar-

ker and fat brighter. In T2-weighted scans fat is also

differentiated from water; however, fat appears darker

and water lighter in the image, making T2-weighted scans

well suited for imaging edema since CSF appears lighter

(Filippi and Agosta, 2009). As part of McDonald’s

criteria, new T1-weighted lesions or T2-weighted gado-

linium enhancing lesions on follow-up MRI scans may

serve as criteria for dissemination in space or time, thus

allowing the diagnosis fulfilling the criteria of MS to be

made with further confidence (Polman et al., 2011).

Imaging

MRI has gained a principal role in the assessment of MS

because it allows clinicians to readily obtain an understand-

ing of the pathophysiology of the lesions, CNS involvement,

and ultimately the overall illness without invasive proce-

dures. Currently, common MRI measures of disease burden

include the quantification of brain lesions using T1- and T2-

weighted images, gadolinium contrast, proton density, and

fluid attenuated inversion recovery sequences. Each of these

markers represents many possible histopathological corre-

lates, including: demyelination, edema, axonal loss, matrix

destruction, and inflammation (Filippi and Rocca, 2011).

The lesions on MRI are often ovoid in shape, ranging from

a few mm to more than 1 cm in size. Their location is cru-

cial, considering that MS lesions have a high propensity to

locate in the periventricular white matter, brainstem, and

cerebellum. Additionally, MRI and pathological data sug-

gest that evolution of MS lesions depends on whether they

occur during early versus chronic phases of the disease

course (Filippi et al., 2012).

Lesions on T2-weighted images are often clinically

silent and correlate weakly with a patient’s disability

despite correlating well with the location on plaques in

the CNS of postmortem MS patients (Newcombe et al.,

1991). Hypointense lesions on T1-weighted images may

be persistent or nonpersistent (Rovaris et al., 1999).

Persistent hypointense T1-weighted lesions represent

areas indicative of axonal loss and severe tissue destruc-

tion and correlate better than T2 lesion load with clinical

severity of the disease (van Waesberghe et al., 1999).

Multiple T2-weighted and/or gadolinium-enhancing

lesions on initial MRI scans indicative of diffuse cortical

lesions and atropy also predict a more severe subsequent

course related not only to physical disability but also to

diminished cognitive outcome (Calabrese et al., 2009;

Deloire et al., 2011). Nonpersistent hypointense lesions

on T1-weighted images represent reversible edema due to

abatement of inflammation. Post-contrast gadolinium

enhancement of lesions on T1-weighted images represents

acute disruption of the blood�brain barrier from inflamma-

tion. On average, disruption can last 3 weeks, but may range

737Chapter | 52 Multiple Sclerosis

anywhere from 2 to 6 weeks and is dependent on gadolin-

ium dose, the characteristics and delay of image acquisition,

and steroid treatment of acute attacks (Filippi, 2000).

Intermittent MRI imaging might underestimate severity

of disease burden since weekly MRI scanning suggests that a

significant proportion of MS lesions have very short-lived

enhancement (Cotton et al., 2003). Brain and spinal cord

atrophy may occur in MS and can represent loss of myelin,

oligodendrocytes, and axons, in addition to contraction of

astrocyte volume. Continued work in improving the use

of various imaging modalities to more accurately character-

ize active disease is imperative in moving forward.

IMMUNOLOGICAL MARKERS INDIAGNOSIS

CSF immunologic markers can function as adjuncts to

clinical findings when considering the diagnosis of MS.

The CSF of patients with MS typically shows normal glu-

cose, a few lymphocytes (mostly T cells), normal to

mildly elevated total protein, and oligoclonal immuno-

globulin bands (OCBs). OCBs are uncovered when CSF

from MS patients is electrophoresed. The cathode region

reveals a number of discrete bands that represent excess

antibody production by one or more clones of B cells.

Such bands are not evident when CSF from healthy con-

trols is electrophoresed. Often absent early in the disease,

OCBs can eventually be detected in over 90% of patients

with MS (Cruz et al., 1987; Mclean et al., 1990).

CSF OCBs have also been described in conditions

such as subacute sclerosing panencephalomyelitis (SSPE)

(Mattson et al., 1980), neurosyphilis (Pedersen et al.,

1982), varicella zoster virus (VZV) infection (Vartdal

et al., 1982), HIV infection (Skotzek et al., 1988), and in

multisystem autoimmune diseases, cerebrovascular acci-

dents, and up to 5% of normal individuals. Of note,

OCBs are continuously present in MS regardless of dis-

ease activity, whereas they are transient in other condi-

tions due to infection clearance (Link and Huang, 2006).

Furthermore, OCBs have been reported to correlate with

disease course and disability progression (Link and

Huang, 2006; Mandrioli et al., 2008) and with the conver-

sion to MS in patients with CIS and a negative MRI or an

MRI with few lesions (Tintore et al., 2008). In diseases

such as the viral encephalitides, OCBs commonly bind

virus determinants, in contrast to MS, where the antigen

against which the majority of bands are directed has not

been identified to date (Olek, 2000).

Due to intrathecal synthesis from plasma cells, CSF

immunoglobulin levels are also elevated in patients with

MS. The immunoglobulins are mainly composed of IgG,

with lesser amounts being IgM and IgA. Specifically,

studies have delineated differences between IgG and IgM

levels with the latter correlating more strongly with MS

disease course and IgG reflecting local B cell responses

accompanying CNS inflammation. Nearly 90% of

patients demonstrate elevated levels of CSF IgG produc-

tion when the IgG index formula (spinal fluid IgG/spinal

fluid albumin)/(serum IgG/serum albumin) is calculated.

A spinal fluid IgG index greater than 0.58 implies that

IgG are being synthesized in the CNS.

Apart from oligoclonal bands, numerous CSF markers

have demonstrated specificity for the MS disease process.

Several non-specific proteins may function as markers of

disease process, including: tau protein and myelin basic pro-

tein (MBP), in addition to light and heavy neurofilament

chains appearing during relapse and correlating with long-

term functional outcome and the likelihood of conversion

from CIS to RRMS (Graber and Dhib-Jalbut, 2011).

There are reports of serum and CSF anti-MBP, anti-

MOG, and anti-PLP autoantibodies (Warren and Catz, 1994;

Warren et al., 1994; Berger et al., 2003) in patients with MS.

Such studies have been challenged due to the possibility of

non-specific binding of low-affinity antibodies and observa-

tions that high-affinity antibodies against MOG epitopes are

only present in a small proportion of patients (Menge et al.,

2011). However, using sensitive solution phase assays, high-

affinity autoantibodies to MBP and MOG can be detected in

the serum and CSF of patients with acute disseminated

encephalomyelitis and MS (O’Connor et al., 2003, 2005,

2007; Zhou et al., 2006). A recent study aiming to character-

ize intrathecal MOG antibodies in MS indicated that the

rMOG index, a marker of intrathecal MOG antibody produc-

tion, may provide complementary information to routine

CSF testing in the diagnosis of MS (Klawiter et al., 2010).

Moreover, anti-MOG autoantibodies can be eluted from the

brain tissue of a subset of patients with MS (O’Connor et al.,

2005). Such markers support the ongoing hypothesis of MS

as a disease linked to immune dysfunction, ongoing inflam-

mation, and tissue damage and repair. A serum autoantibody,

neuromyelitis optica immunoglobulin (NMO-IgG), was iden-

tified in patients with neuromyelitis optica, an inflammatory

demyelinating disease similar to, and considered by some to

be a variant of, MS affecting the optic nerves and spinal

cord, thereby highlighting the importance of the differential

diagnosis between MS of NMO and NMO spectrum

disorders. NMO and the associated autoantibody (NMO-

IgG/anti-aquaporin 4) is discussed further in Chapter 57.

PATHOLOGY

Gross examination of MS brain tissue has largely been

limited to autopsy specimens of individuals with long-

standing disease. Such pathological examination reveals

multiple sharply demarcated gray colored plaques in the

CNS white matter with a predilection for the optic nerves

and white matter tracts of the periventricular regions,

brain stem, and spinal cord. The gray matter contains

less myelin, and thus lesions in the gray matter are


less conspicuous on gross examination (Geurts et al.,

2005). When examining the histological features of an MS

lesion there exist three major components: inflammation,

gliosis, and demyelination. The inflammation in lesions is

composed of lymphocytes, monocytes, and macrophages

whose proportions depend on the activity and age of the

lesion (Frohman et al., 2006). The second component of a

lesion occurs when reactive astrocytes and fibrillary glio-

sis are present in the lesion.

Demyelination is an important feature of the MS

lesion. Although MS is described as a disease causing a

loss of myelin, the notion of axonal loss has been sug-

gested as the major cause of irreversible disability in

patients with MS. Trapp et al. first reported that substan-

tial axonal injuries with axonal transections are also

abundant throughout active MS lesions, even in patients

in early stages of the disease process (Trapp et al.,

1998). Axonal reduction and acute damage have previ-

ously been correlated with demyelination and meningeal

inflammation (Ferguson et al., 1997). Interestingly, dif-

ferences in axonal loss exist among subsets of MS, with

the least axonal loss being demonstrated in PPMS and

the most pronounced in SPMS (Bitsch et al., 2000).

Notably, there have been case reports of early RRMS

presenting with inflammatory cortical demyelination

prior to the appearance of white matter lesions, indicating

possible inflammation being initiated at the subpial layer

(Popescu et al., 2011). Recent work aimed at elucidating

the pathogenesis of axonal damage and loss has impli-

cated several mechanisms including: inflammatory secre-

tions, Wallerian degeneration, disruption of axonal ion

concentrations, loss of myelin-derived support, damage

from nitric oxide and reactive oxygen species, energy

failure from mitochondrial dysfunction, and Ca21 accu-

mulation (Smith and Lassmann, 2002; Dutta and Trapp,

2007; Dziedzic et al., 2010).

MS lesions can also be classified from a pathogenesis

point of view into three types based on the age of the

lesion: active, chronic active, and chronic inactive

(Lassmann, 1998). Macrophages are most prominent in

the center of the active plaques and are seen to contain

myelin debris, while oligodendrocyte counts are reduced

and generally present in lesions demonstrating signs of

remyelination. Hypertrophic astrocytes and mild astroglial

scarring are also characteristic of active lesions (Frohman

et al., 2006). Lymphocytes may be found in normal

appearing white matter beyond the margin of active

demyelination (Prineas, 1975; Booss et al., 1983). The

inflammatory cell profile of active lesions is characterized

by perivascular infiltration of oligoclonal T cells

(Wucherpfennig et al., 1992b) consisting predominantly

of clonally expanded CD81 T cells in the plaque margins

and perivascular cuffs, and to a lesser extent of CD41

cells invading the normal appearing white matter around

the lesion (Traugott et al., 1983; Hauser et al., 1986;

Babbe et al., 2000). The inflammatory infiltrate may also

include monocytes, occasional B cells, γδ T cells,

and rare plasma cells (Booss et al., 1983; Wucherpfennig

et al., 1992a; Babbe et al., 2000). Remarkably, demyelin-

ation in acute lesions may be related to an antimyelin

antibody-mediated mechanism in which normal myelin is

coated with anti-MBP immunoglobulin or anti-MOG and

phagocytosed in the presence of complement by local

macrophages (Genain et al., 1999). Chronic-active lesions

are sharply demarcated with perivascular cuffs of infiltrat-

ing cells, lipid- and myelin-laden macrophages, activated

microglia, and hypertrophic astrocytes. These cells disap-

pear from the center core suggesting the presence of

ongoing inflammatory activity along the lesion edge.

Within the hypocellular core there are naked axons

embedded within a matrix of fibrous astrocytes, lipid-

laden macrophages, a few infiltrating leukocytes, and no

oligodendrocytes. The chronic-inactive plaque does not

have macrophages at the border or center of the plaque.

There is vast hypocellularity and no ongoing demyelin-

ation with histology demonstrating demyelinated axons

with fibrillary gliosis (Raine, 1991).

EPIDEMIOLOGY OF MS

The prevalence rates of MS in North America range

between 30 and 150/100,000. Based on a weighted mean

of several studies, the average annual incidence of MS in

the USA is 3.2/100,000 per year. The median age of onset

of symptoms is 23�24 years of age, with a peak age of

onset for women in the early twenties, and for men in the

late twenties (Schumacker et al., 1965; Paty et al., 1994).

As in most diseases classified as autoimmune, there is a

clear female predominance in MS cases, with a 3:2

female to male ratio (Olek, 2000). Studies of MS

incidence rates in migrants (Dean et al., 1976) and appar-

ent epidemics of MS at geographical locations (Kurtzke

et al., 1982), also discussed below, indicate a clear role

for environmental factors.

Genetic Factors

Studies in twins (Mackay and Myrianthopoulos, 1966;

Williams et al., 1980; Heltberg and Holm, 1982; Ebers

et al., 1986; Kinnunen et al., 1987; French Research

Group on MS, 1992; Mumford et al., 1992) demonstrate

shared genetic risk factors for MS. Most recently, work

involving genome-wide association studies (GWAS)

using single nucleotide polymorphisms (SNPs) from the

haplotype map (HapMap) project have provided insights

into the genetic associations involved in MS (Tishkoff

and Verrelli, 2003; Frazer et al., 2007; Patsopoulos et al.,

2011). While the risk of developing MS in the general

population is 1/750, our early understanding of the

genetic factors linked to MS has been derived from


epidemiological studies and disease concordance within

family members or twins. Such studies have demonstrated

that approximately 15�20% of patients have a family his-

tory of MS and when both parents are affected with MS,

9% of children develop the disease (Hogancamp et al.,

1997; Sadovnick et al., 1997; Sadovnick, 2006). Twin

studies have indicated that the monozygotic concordance

rate is 30% versus the dizygotic rate of 5% (Holmes

et al., 1967; Sadovnick et al., 1993). Nevertheless, large

extended pedigrees are relatively uncommon.

The sequencing of the human genome and the genera-

tion of the HapMap has finally allowed the identification

of the genetic architecture underlying risk for developing

MS by GWAS (Tishkoff and Verrelli, 2003). GWAS

have afforded an unbiased and widespread approach in

scanning the whole genome and identifying haplotypes

associated with risk of developing MS. They provide an

alternative approach to classic linkage analysis and have

greater statistical power to detect variants conferring a

modest disease risk (Risch and Merikangas, 1996; Yang

et al., 2005). These studies have provided convincing evi-

dence that MS fits into the autoimmune disease category

and is caused by common allelic variants each with only

subtle but important variations on function.

In 2007, the first GWAS in MS clearly identified sev-

eral gene regions. Subsequent GWAS and their corre-

sponding meta-analyses identified 14 regions with

genome-wide significance, several of which have been

previously identified; these regions include CD58, CD40,

CD6, IL-2RA, IL-7RA, EVI5, CLEC16A, TYK2 and

TNF-RSF1A, IRF8, and STAT3, all of which are of inter-

est due to their expression on regulatory T cells, and

proinflammatory Th17 cells, both CD41 subsets impli-

cated in MS later described in detail (Wellcome Trust

Case Control Consortium et al., 2007; Aulchenko et al.,

2008; Comabella et al., 2008; Australia and New Zealand

Multiple Sclerosis Genetics Consortium, 2009; Baranzini

et al., 2009; De Jager et al., 2009b; Jakkula et al., 2010;

Nischwitz et al., 2010; Sanna et al., 2010). Finally, a

recent international GWAS collaboration aimed at analyz-

ing over 9000 cases of MS succeeded in replicating many

of the earlier findings in addition to highlighting 29 novel

susceptibility loci, thereby identifying more than 50

regions of interest. Although each haplotype only repre-

sents a small influence on the risk of developing MS,

together they account for approximately half of the

genetic risk for MS (Sawcer et al., 2011) (Figure 52.1)

As expected, these SNPs, upon being related to the

known or likely function of nearby genes, are largely

associated with lymphocyte function, providing further

evidence of an immunopathogenesis of MS. A large

meta-analysis with replication is now in progress.

One of the additional aims of GWAS has been to refine

our understanding of the genetic risk associated with the

major histocompatibility complex (MHC) through looking

more closely at HLA types at six loci (A, B, C, DQA1,

DQB1, and DRB1) (Sawcer et al., 2011). Prior to GWAS,

our understanding of the association and linkage of MS

with respect to MHC was limited to alleles and haplotypes

on chromosome 6p21. Recently, studies have successfully

established HLA DRB*1501 as being the allele variant

involved in MS as opposed to HLA DQA1 or DQB1

(Brynedal et al., 2007; Lincoln et al., 2009). Further work

has implicated HLA-A2 as being negatively associated with

MS, thereby potentially serving as a protective allele with

consistent effects across cohorts.

Many of the alleles identified in MS are shared not only

among other autoimmune diseases but also are strongly

associated with immune pathways (Torkamani et al., 2008;

Xavier and Rioux, 2008; International Multiple Sclerosis

Genetics Consortium, 2009; Zhernakova et al., 2009). Given

these genetic commonalities, it is therefore not surprising

that MS and other autoimmune diseases share related defects

in immune function and regulation. Recent work aimed at

uncovering the intricacies of the relationships between auto-

immune diseases has confirmed commonality across seven

autoimmune diseases through identifying shared genes

among some but not all of the diseases (Cotsapas et al.,

2011). A model addressing the overarching interconnectivity

of various autoimmune disease mechanisms is likely to be

elucidated in the future. As MS is a complex disease, under-

standing which combinations of genes within the population

confer the greatest risk of developing autoimmune disease is

a central goal of present genetic research efforts.

Environmental Factors

Global maps of MS prevalence rates, constructed based

on multiple descriptive epidemiological studies, reveal a

non-random geographical distribution of the disease.

A diminishing north to south gradient of MS prevalence

was described in the Northern Hemisphere (Beebe et al.,

1967; Kurtzke, 1977; Kurtzke et al., 1979; Hammond

et al., 1987), with an opposite trend identified in the

Southern Hemisphere (Hammond et al., 1988;

Hogancamp et al., 1997; Kurtzke, 2000). Notably, there is

a marked absence of MS cases directly near the equator.

When taking continental differences into consideration,

there is increased prevalence of MS with large dispersion

in Western Europe and North America, both regions

being highly populated by Caucasians, whereas areas in

Central and Eastern Europe, Australia, and New Zealand

have lower prevalence with the lowest prevalence occur-

ring in Asia, the Middle East, and Africa. Such variation

calls into question the possibility that ethnicity might be

linked to the continental differences seen (Koch-

Henriksen and Sorensen, 2010).


FIGURE 52.1 Regions of genome showing association to MS. Genome regions showing association with MS. Evidence for association from lin-

ear mixed model analysis of the discovery data (threshold at a 2 log10 P value of 12) is shown at left. Non-MHC regions containing associated SNPs

are indicated in red and labeled with the rs number (green text for newly identified loci, black text for loci with strong evidence of association, and

gray text for previously reported loci) and risk allele of the most significant SNP. Asterisks indicate that the locus contains a secondary SNP signal.

(Continued)


The study of latitudinal differences has demonstrated

only modest effect in Europe and North America, but

none within Western Europe (Lauer, 1995; Weinshenker,

1996). The only clear trend of increased incidence can be

attributed to the Southern Hemisphere where the majority

of studies have come from New Zealand and Australia

(Skegg et al., 1987; Mcleod et al., 1994). Descendants liv-

ing New Zealand and Australia have a lower risk of MS

than those descendants living in the UK. These studies

are rather compelling because the populations in New

Zealand and Australia are relatively homogeneous due to

similar British ancestry. This general distribution likely

reflects a combination of genetic and environmental influ-

ences particularly with respect to exposure to sunlight

(Ebers, 2008).

Relatedly, environmental deficiencies have long been

associated with MS, as indicated by the inverse correlation

of the world prevalence of MS and environmental supply of

vitamin D. Vitamin D may be supplied from the environ-

ment via sunlight exposure or via dietary intake of vitamin

D3 (Vanamerongen et al., 2004; Ascherio et al., 2010). At

higher latitudes, the exposure to sunlight is insufficient to

produce vitamin D given the lower exposure to the sun in

winter months. Vitamin D and its immunomodulatory effect

has been established both in response to sunlight and in die-

tary vitamin D(3) intake (Smolders et al., 2008; Kragt et al.,

2009). Subtle defects in vitamin D metabolism have sug-

gested a possible genetic origin. Identification of a highly

conserved vitamin D responsive element in the promoter

region of the HLA-DRB*1501 haplotype has sparked ongo-

ing debate as to whether HLA-DRB*1501 might be involved

in the response to vitamin D particularly since studies sug-

gest that the beneficial effect of vitamin D on MS may in

fact be attenuated in those with the risk allele (Ramagopalan

et al., 2009; Simon et al., 2011). Nevertheless, few genetic

determinants have been identified.

Epstein�Barr virus (EBV) infection has been linked

to MS risk since exposure to EBV is associated with 1.5

times greater risk of developing MS. Over 99% of

individuals with MS have evidence of prior infection with

EBV in comparison to 90% in humans overall (Bagert,

2009). However, the role of EBV in the development of

MS is not known. EBV generally infects resting B lym-

phocytes transforming them into memory cells that sur-

vive long-term largely undetected by the immune system

(Thorley-Lawson and Gross, 2004). Interestingly, serosta-

tus in individuals with MS has demonstrated elevated

titers to EBV prior to the development of any neurologic

sequelae (Thacker et al., 2006). It has been suggested that

EBV may play a role in the pathogenesis of MS since

postmortem analysis of brains from patients with MS

have demonstrated diffuse EBV-association B cell dysre-

gulation among the varying types of MS (Serafini et al.,

2004). However, these results have been challenged due

to the inability to unequivocally identify EBV infection in

pathological tissues, particularly in respect to clinical sce-

narios unrelated to EBV-driven lymphomas or acute EBV

infections. Such difficulties may be linked to differences

in sensitivity and specificity of the detection methods

utilized (Lassmann et al., 2011).

IMMUNE PATHOGENESIS

Until recently, there were discussions as to whether MS is

a primary degenerative disease with secondary inflamma-

tion or an autoimmune disease with immune-mediated

destruction of the CNS. The sharing of almost half of the

allelic variants between MS and other autoimmune disor-

ders from the GWAS has to a large extent provided con-

vincing evidence for an autoimmune pathophysiology for

the disease (Hafler, 2012). Our current understanding of

MS strongly implicates involvement of the immune sys-

tem and autoreactive proinflammatory T cells that are

critical to the propagation of CNS tissue injury.

Elucidating the mechanism of disease initiation and how

it contributes to the transition from physiologic immuno-

surveillance to pathologic cascade continues to be an area

of ongoing investigation. Our foundation is based on

the understanding that peripherally activated cross-

reactive T cells migrate into the CNS of genetically sus-

ceptible hosts and mount proinflammatory responses to

myelin epitopes. Myelin-reactive T cells appear to be

both increased in frequency and activation state in indivi-

duals with MS (Raddassi et al., 2011), suggesting a

peripheral breach of tolerance to CNS antigen. However,

the presence of autoreactive cells in the periphery is an

insufficient explanation for the development of autoim-

mune disease given that myelin-reactive T cells can be

found in the peripheral blood of both healthy individuals

and patients with MS.

� Odds ratios (ORs; diamonds) and 95% confidence intervals (whiskers) are estimated from a meta-analysis of discovery and replication data (1 indi-

cates estimates for previously known loci from discovery data only). Risk allele frequency estimates in the control populations are indicated by verti-

cal bars (scale of 0 to 1, left to right). A candidate gene and the number of genes are reported for each region of association. Black dots indicate that

the candidate gene is physically the nearest gene included in the GO immune system process term. “Tags functional SNP” indicates whether the

most-significant SNP tags a SNP predicted to affect the function of the candidate gene. Where such an SNP exists, the gene is selected as the candi-

date gene; otherwise, the nearest gene is selected unless there are strong biological reasons for a different choice. The final column indicates whether

SNPs are correlated (r2. 0.1) with SNPs associated with other autoimmune diseases. CeD, celiac disease; CrD, Crohn’s disease; PS, psoriasis; RA,

rheumatoid arthritis; T1D, type 1 diabetes; UC, ulcerative colitis. Reproduced with permission from Nature (Sawcer et al., 2011).


T Cell Pathogenesis

Upon interaction of the T cell with the antigen-presenting

cell (APC), the antigen-specific T cells proliferate and

divide into subsets (see Figure 52.2). Of specific interest

to MS are the Th1, Th2, Th17, and regulatory T cell sub-

sets. T cells have been classified according to the cytokine

profiles that they produce upon activation (Abbas et al.,

1996; O’Garra, 1998; O’Shea and Paul, 2010). MHC class

II restricted CD41 T cells, producing IFN-γ, IL-2, lym-

photoxin (LT), and TNF-α, have been defined as Th1

(inflammatory) cells, and have demonstrated pathogenicity

in EAE models (Leonard et al., 1995; Segal et al., 1998;

Severson and Hafler, 2010). The Th1 cytokines activate

macrophages for cellular immunity with the assistance of

IgG1 secreted by B cells. In contrast, CD41 T cells pro-

ducing IL-4, IL-5, IL-10, or IL-13 have been termed Th2

(anti-inflammatory) cells, and have demonstrated a protec-

tive role in EAE (Khoury et al., 1992; Owens et al., 1994;

Begolka et al., 1998; Antel and Owens, 1999). Th2 cyto-

kines promote humoral immune responses alongside IgG4.

Th17 cells are thought to be proinflammatory in nature

and secrete the cytokines IL-17A, IL-17F, IL-21, and IL-

22, which have been strongly implicated in the pathogene-

sis of autoimmune diseases (Harrington et al., 2005).

Regulatory T cells (Tregs) are a subset of T cells that are

FIGURE 52.2 Pathophysiology of MS. Defects in peripheral immune regulation lower the activation barrier for autoreactive T cells. (A) In nor-

mal homeostasis, APCs digest microbial antigens or self proteins and present them to naıve T cells in the context of costimulatory molecules.

An appropriate cytokine milieu can drive differentiation of these naıve autoreactive T cells to a Th1 or Th17 cell phenotype; however, these poten-

tially pathogenic T cells are not activated due to the actions of peripheral regulatory immune cell populations, such as FoxP31 Tregs and Tr1 cells.

Via the actions of co-inhibitory molecules and cytokines such as IL-10 and TGF-β, autoreactive T cells become anergic and autoimmune disease is

prevented. Other mechanisms, such as thymic deletion and lack of costimulatory molecules on APCs, are also involved in controlling autoreactive T

cells. (B) MS patients have defects in peripheral immune regulation, including higher expression of costimulatory molecules on APCs, lower CTLA-4

levels, and lower IL-10 production. Additionally, MS patients have an increased frequency of IFN-γ-secreting Tregs relative to healthy controls.

Thus, the barrier for activation of autoreactive T cells is lowered for MS patients. Activated myelin-reactive T cells can then adhere to and extravasate

across the choroid plexus and BBB, where they can initiate an inflammatory milieu that gives license to further waves of inflammation and eventual

epitope spreading. Reproduced with permission from the Journal of Clinical Investigation (Nylander and Hafler, 2012).


involved in the regulation of the immune system, mainte-

nance of tolerance to self-antigens, and surveillance of

autoimmune disease. They can secrete a variety of cyto-

kines including, TGF-β, IL-10, and IFN-γ in addition to

utilizing FoxP3 as a transcription factor (Fontenot et al.,

2003; Hori et al., 2003). Current work involving Tregs has

linked this subset with immune dysregulation, a concept

which will be discussed later.

Several lines of evidence support the hypothesis that

Th1 cells may be pathogenic in MS. Th1 and Th2 cells

express distinct profiles of chemokine receptors, includ-

ing CXCR3/CCR5 and CCR3/CCR4, respectively

(Bonecchi et al., 2009). An increased proportion of

T cells from MS patients was shown to express the char-

acteristic Th1 chemokine receptor pattern and MS plaques

were found to express increased levels of the correspond-

ing chemokine (Siveke and Hamann, 1998; Balashov

et al., 1999; Sorensen et al., 1999). Analysis of cytokine

mRNA in CSF from MS patients showed a bias towards

Th1 cytokines (Blain et al., 1994). Immunohistochemical

studies of MS plaques in situ have demonstrated the pres-

ence of the proinflammatory cytokines TNF-α and IL-12

(Hofman et al., 1989; Selmaj et al., 1991; Windhagen

et al., 1995). Markedly, MBP-reactive T cells derived

from patients with MS secrete cytokines that are more

consistent with Th1-mediated response, whereas MBP-

reactive T cells from healthy individuals are more likely

to produce cytokines that characterize a Th2-mediated

response (Crawford et al., 2004). Interventions that shift

or deviate the cytokine responses away from a Th1 and

towards a Th2 profile have been deemed favorable.

Despite the prior suggestion that Th1 cells are unique

in driving the inflammatory response, recent work has

characterized the putative role of proinflammatory Th17

cells in establishing the MS phenotype. Studies implicate

pathogenic Th17 cells in gaining early access to the CNS

(Steinman, 2007; Reboldi et al., 2009). Entry to the

CNS is mediated via the choroid plexus, which, in addi-

tion to producing CSF, spans the blood�CSF barrier and

facilitates immune surveillance. The Th17 mechanism

implicates the CCR6/CCL20 axis in disease initiation as

defined in the EAE model, with Th17 cells expressing

CCR6 and choroid plexus endothelial cells expressing

CCL20. In applying this information to human disease, it

is likely that peripherally activated Th17 cells are able to

bind to adhesion molecules and chemokine receptors

expressed on the choroid plexus thereby migrating across

the blood2CSF barrier and gaining access to circulating

CSF. Dysregulated Th17 cells are subsequently able to

access perivascular tissue, initiating a cascade of proin-

flammatory events. Th17 cells secrete IL-23, which, in

EAE models, alongside the transcription factor RORγt,promotes production of GM-CSF. This induces a positive

feedback loop where further secretion of IL-23 occurs

and is implicated in the encephalogenicity and incidence

of axoglial damage (Codarri et al., 2011; El-Behi et al.,

2011). In relating Th17 cells to the formation of perivas-

cular infiltrates, it is possible that their secretion of IL-17

and IL-22 may increase blood�brain barrier permeability

and thus facilitate the influx of immune cells, such as

autoreactive Th17 cells, Th1 (IFN-γ secreting), γδ T cells,

cytotoxic CD81 cells, B cells, and immunoglobulin-

secreting plasma cells (Kebir et al., 2007). This leads to

the possibility of a two-step process for initiation of MS,

one in which Th17 cells prime the entrance of other

dysregulated immune cells and therefore creating the

appropriate inflammatory environment containing infil-

trates of cells that result in downstream damage of the

CNS (Nylander and Hafler, 2012).

Immune Dysregulation

In elaborating on the concept of immune dysregulation,

GWAS have shed light on the likely involvement of alle-

lic variants in diseases states. A number of these variants

involved genes for cytokine receptors and costimulatory

molecules and have been associated with defects in Treg

homeostasis. Costimulatory molecules have recently been

found to function as negative regulators of the immune

system. TIM-3 has been implicated in modulating Th1

and Th17 cytokine secretion and loss of TIM-3 functional

T cell regulation has been established in MS patients

(Koguchi et al., 2006; Yang et al., 2008; Hastings et al.,

2009). GWAS studies have linked CD226 to MS risk

(Hafler et al., 2009), and recent work has implicated the

CD226/TIGIT axis in regulating human T cell function

via a mechanism similar to that employed by

CD28/CTLA4, in which binding to B7 induces coexpres-

sion of inhibitory and excitatory signals that modulate

immune responses (Joller et al., 2011; Lozano et al.,

2012). Costimulation between CD58/CD2 appears to be

implicated in T cell receptor signaling, including activa-

tion of Tregs, and has been suggested to provide a protec-

tive effect for MS (De Jager et al., 2009a).

Recent studies have indicated that despite normal

frequency of Tregs in MS patients, their suppressive ability

is compromised and substantially decreased in response to

autoreactive T cells in comparison to healthy individuals

(Viglietta et al., 2004; Haas et al., 2005). Notably, Tregs

have demonstrated great functional plasticity. Their ability to

be reprogrammed suggests that Tregs may be able to func-

tion as a biomarker in MS (Nylander and Hafler, 2012). In

the presence of IL-1β and IL-6, Tregs are able to produce the

inflammatory cytokine IL-17, further implicating this subset

in autoimmune disease (Koenen et al., 2008; Ayyoub et al.,

2009; Beriou et al., 2009). Moreover, the notion of Treg

reprogramming has arisen due to the observation that patients

with RRMS have the ability to produce IFN-γ-secreting


Tregs, thereby characterizing a Th1-type Treg effector

phenotype. This finding was observed in vitro under IL-12

stimulation of Tregs and recapitulated in ex vivo Tregs

derived from patients with untreated RRMS. This role of

Th1�Treg effector cells was suggested by the use

of IFN-β, a first-line therapy for RRMS, which has been

shown to decrease IL-12 levels and normalize the ratio

of IFN-γ1Foxp31 Tregs to that of healthy controls

(Dominguez-Villar et al., 2011). Costimulatory molecules

and regulatory T cell plasticity in MS undoubtedly provide

fascinating clues into disease pathogenesis.

Autoantigens

Autoantigen-specific T cells have been identified both in

healthy individuals and in patients with MS. Their entrance

into the inflamed CNS environment is likely mediated by

the immune mechanisms posited above, whereupon enter-

ing, the autoreactive T cells are able to subsequently contrib-

ute to myelin destruction and axonal damage in addition to

secondary inflammation following activation by local

antigen-presenting cells. Attention has been directed towards

uncovering frequencies of autoantigen-specific T cell bind-

ing to myelin proteins including MOG, MBP, and proteoli-

pid in addition to heat shock protein αB-crystallin and

oligodendroglia-specific enzyme transaldolase in CD41

cells isolated from MS patients (Banki et al., 1994; Greer

and Pender, 2008). Anti-MOG has previously been isolated

from postmortem CNS tissue in MS patients (O’Connor

et al., 2005). In an assay based on self-assembly of radiola-

beled MHC tetramers, it was demonstrated that such tetra-

mers were more sensitive for MOG autoantibody detection.

Nevertheless, MOG-specific autoantibodies were found

more so in patients with acute disseminated encephalomyeli-

tis, than in adults with MS (O’Connor et al., 2007).

Likewise, the ability to detect and clone autoantigen-specific

T cells from blood has allowed further quantification of

MOG frequencies, work which demonstrated an increase in

MOG-specific T cells in MS patients in comparison to

healthy individuals (Raddassi et al., 2011).

Despite the inability to identify a putative role for envi-

ronmental triggers, infectious factors, or microbial antigens

in establishing MS risk, studies have suggested potential

cross-reactivity between epitopes with microbial antigens.

Finally, regardless of what antigen event initiates the self-

reactive cascade, epitope spreading is likely to contribute to

an array of activated immune cells that can respond to multi-

ple antigens. Nevertheless, no single antigen has been clearly

implicated in the pathogenesis of MS.

Meningeal Ectopic B Cell Follicles

Given the marked presence of OCBs and increased levels

of IgG within the CSF of individuals diagnosed with MS

in addition to the ongoing debate underlying the increased

incidence of EBV and its ability to prime the immune sys-

tem in individuals with MS, the notion of B cell involve-

ment has received great attention in playing a crucial role

in MS pathogenesis. There appears to be great connectiv-

ity between the cell population in the CNS and CSF since

clonally expanded B cells and plasmablast clones have

been associated with the observed intrathecal immuno-

globulin production (Lovato et al., 2011; Obermeier et al.,

2011). Recently published work indicates that related

B cell clones populate the meninges, leading to the

hypothesis that these aggregate structures can be related to

the B cell infiltrates found in MS lesions (Lovato et al.,

2011). Likewise, ectopic lymphoid follicles, strongly

resembling germinal centers, have been identified in the

meninges of SPMS patients (Serafini et al., 2004). These

follicles contain proliferating B cells, plasma cells, T cells,

and dendritic cells with the corresponding diffuse menin-

geal inflammation being suggested to play a role in the

manifestation of cerebral cortical gray matter pathology in

MS. Follicles have been located more frequently in the

deep sulci of the temporal cingulate, insula, and frontal

cortex (Howell et al., 2011). Apart from being associated

with cortical pathology, studies have implicated that men-

ingeal B cell follicles can be associated with early onset of

disease in patients with SPMS (Magliozzi et al., 2007).

Overall, such humoral activation within ectopic lymph tis-

sue and CSF has been postulated to play an imperative

role in disease progression secondary to the ongoing per-

sistence of antigens driving a constitutive inflammatory

and humoral response.

TREATMENT

Therapeutic approaches in MS may be broadly divided into

treatments that are symptomatic and/or supportive in nature,

and treatments that are directed at the underlying pathophys-

iology of the disorder. There are currently nine agents

approved by the United States Food and Drug

Administration (FDA) (see Table 52.1 for comparison of

FDA-approved therapies) as disease-modifying therapies

(DMT). They are expensive, with 10-year disease-related

costs averaging US$467,712 for patients on a single disease

modifying therapy (DMT) (Noyes et al., 2011). The vast

majority of these DMTs have been studied in RRMS and

CIS, and approved for such use, whereas the progressive

forms of MS do not respond to immunotherapies. Their cur-

rent use has marked a milestone for patient care.

Understanding pharmacologic mechanisms of action in a

number of MS DMTs has led to significant advancement in

elucidating MS pathogenesis. The growing number of thera-

pies being studied for the treatment of MS in addition to the

advent of oral therapy indicates great promise for the future.


Interferons

Compared to placebo-treated RRMS controls, treatment

with alternate-day subcutaneous injections of eight mil-

lion units of IFN-β1b (Betaserons) was shown to

decrease the primary efficacy outcome measure of

frequency of relapses by 34% after 2 years (The IFNB

Multiple Sclerosis Study Group, 1993). A significant

decrease in the accumulation of MRI lesions was

observed with treatment (Paty and Li, 1993) and 5-year

follow-up data reported that disease progression in the

IFN-β1b treated group was 35%, compared with 46% pro-

gression in the placebo group (IFNB Multiple Sclerosis

Study Group, 1995). A 30% decrease in the annual

exacerbation rate in the treated group was maintained.

IFN-β1a (Avonexs, weekly IM injections), a glycosy-

lated recombinant beta-interferon, was evaluated in a

2-year study of weekly intramuscular injections of six

million units (30 μg). The proportion of patients progres-

sing by the end of the trial was 21.9% in the treated group

compared to 34.9% in the placebo group. The annual

exacerbation rate was decreased by 32% in the treated

TABLE 52.1 FDA Approved Therapies for MS

Brand name Indications Results Mechanism of action

IFN-β1a (IMweekly)

Avonexs � Treatmentof RRMS

� Reduction of relapses byone-third

� Reduction of new MRI T2lesions and the volume ofenlarging T2 lesions

� Reduction in the number andvolume of Gd-enhancinglesions

� Slowing of brain atropy

� Acts on blood�brain barrier by interferingwith T cell adhesion to the endothelium bybinding VLA-4 on T cells or by inhibiting theT cell expression of MMP Reduction in T cellactivation by interfering with HLA class II andcostimulatory molecules B7/CD28 and CD40:CD40L

� Immune deviation of Th2 over Th1 cytokineprofile

� Normalizing ratio of IFN-γ1 Foxp31 Tregs

IFN-β1a (SC threetimes weekly)

Rebifs � Treatmentof RRMS

� Same as IFN-β1a � Same as IFN-β1a

IFN-β1b (SCevery other day)

Betaserons,Extavias

� Treatmentof RRMS

� Same as IFN-β1a � Same as IFN-β1a

Glatirameracetate (SC daily)

Copaxones � Treatmentof RRMS

� Reduction of relapses byone-third

� Reduction of 57% in thenumber and volume ofGd-enhancing lesions

� Induces cytokine shift from one that isproinflammatory to one that is anti-inflammatory and regulatory in nature

Natalizumab (IVmonthly infusion)

Tysabris � Treatmentof RRMS

� Reduced rate of relapse up to68% and the development ofnew MRI lesions

� Monoclonal antibody that blocks alpha4-integrin on surface T cells preventing themfrom crossing the blood�brain barrier

Mitoxantrone (IVinfusions every 3months)

Novantrones � Worseningforms ofRRMS

� SPMS

� Reduction in relapses by 67%� Slowed progression on EDSS,

ambulation index and MRIdisease activity

� Anti-neoplastic that intercalates DNA� Suppresses cellular and humoral immune

response

Fingolimod (givenorally once a day)

Gilenyas � Treatmentof RRMS

� Reduction of 54% in risk ofrelapse

� Lower risk of disabilityprogression by 30%

� S1P agonist, causing internalization of S1P1receptors on lymph-node T cells

� Subsequent decrease in migration of activationlymphocytes into circulation

Teriflunomide(given orally oncea day)

Aubagios � Treatmentof RRMS



� Inhibits de novo nucleotide synthesis� Decreases T cell and B cell proliferation� Interrupts T cell and APC interactions� Subsequently possesses anti-inflammatory

properties

BG-12, dimethylfumarate (givenorally twice aday)

Tecfideras � Treatmentof RRMS



� Inhibits immune cells and molecules� Decreases myelin damage in the CNS� Exhibits anti-oxidant properties that may be

protective against damage to the brain andspinal cord


group versus the placebo group. Treatment was also associ-

ated with a 40% reduction in mean MRI lesion load

(Jacobs et al., 1995, 1996). Clinical and MRI benefit of

IFN-β1a (Rebifs, subcutaneous, three times weekly) doses

for up to 4 years was demonstrated in PRISMS-4, thereby

suggesting that early treatment with IFN-β1a was of

increased benefit to patients with RRMS as compared with

those treated later in disease course (PRISMS, 2001).

β-Interferon therapy utilizes recombinant forms of

naturally occurring cytokines intrinsically possessing a wide

range of properties. The mechanism of action involving

β-interferons appears to be quite complex with the DMT

exerting its effects on the pathophysiology of MS at several

sites. Studies have suggested that β-interferons inhibit the

migration of activated inflammatory cells across the

blood�brain barrier (BBB) and into the CNS parenchyma

through decreasing the function of the vascular cell adhesion

molecule-1/very late activation antigen-4 cell adhesion axis

(see Natalizumab (Tysabris), below). IFN-β may potentially

intercept inflammatory cell adhesion and subsequent migra-

tion across the BBB (Calabresi et al., 1997; Graber et al.,

2005). The rapid effect of β-interferons on the gadolinium

enhancing lesions of MS represents a biological marker of

treatment response and establishes the BBB as an important

site of action of β-inteferon therapy (Stone et al., 1997).Studies have also suggested that the β-interferons may

exert their pharmacologic effects by shifting cytokines and

immune cell profiles in MS patients towards one that is

anti-inflammatory and protective (Brod et al., 1996). IFN-

β has also demonstrated ability to upregulate expression of

costimulatory molecules needed for antigen presentation

(CD80, CD86, and CD40) on monocytes, thus decreasing

the generation of autoreactive T cells and limiting T cell

activation. As addressed earlier, IFN-β has been impli-

cated in normalizing the ratio of IFN-γ1Foxp31 Tregs to

that of healthy controls and in decreasing IL-12 levels,

thereby potentially restoring the ability of Tregs to regu-

late immune cells (Dominguez-Villar et al., 2011).

Glatiramer Acetate (Copaxones)

Glatiramer acetate is the major noninterferon DMT used in

the treatment of MS. Treatment with glatiramer acetate/

copolymer 1 (Copaxone, GA, subcutaneous, daily) was asso-

ciated with a 2-year relapse rate reduction of 29% compared

to placebo control (Johnson et al., 1995). The clinical benefit

of GA for relapse rate in comparison to placebo was sus-

tained following an 11-month extension period utilizing the

same study design (Johnson et al., 1998). Subsequent studies

revealed a beneficial effect of GA in MRI with a 35% reduc-

tion in total gadolinium-enhancing lesions and 57%

reduction in new gadolinium-enhancing lesions, with an

overall decrease in T2 disease burden (Mancardi et al., 1998;

Comi et al., 2001).

GA is a random sequence polypeptide of the four

amino acids alanine (A), lysine (K), glutamate (E), and

tyrosine (Y). As a sequence of amino acids, GA has

been proposed to function as a T cell receptor antago-

nist to MBP/MHC at MBP-specific T cell receptors and

operate as an altered peptide ligand to the MBP

(Aharoni et al., 1999; Duda et al., 2000). Thus, research

suggests that GA elicits its effect on the immune system

by inducing deviation of cytokine production in

response to MBP from Th1 cytokines to Th2 cytokines,

a change that is characterized by increased secretion of

anti-inflammatory cytokines, with prolonged GA treat-

ment leading to a Th2 bias in MS patients (Miller et al.,

1998; Duda et al., 2000; Gran et al., 2000; Neuhaus

et al., 2000; Valenzuela et al., 2007;). Additionally, GA

has been implicated in altering the cytokine profile to

one that is more consistent with a regulatory population

(Hong et al., 2005). Furthermore, increases in FoxP31

expression in Tregs have been demonstrated following

GA, also supporting theories that GA facilitates a

regulatory population (Hong et al., 2005).

Natalizumab (Tysabris)

Natalizumab is a monoclonal antibody to the very late

activation antigen (VLA-4), the α4β7 integrin expressed

on activated T cells and monocytes, and is the

ligand for vascular cell adhesion molecule (VCAM)

expressed on CNS endothelial cells. Natalizumab,

by preventing adhesion of activated T cells to endo-

thelial cells, has been able to decrease influx of

potentially autoreactive T cells into perivascular tissue.

Natalizumab-treated patients have developed cases of

progressive multifocal leukoencephalopathy, a rare and

fatal disease caused by JC virus and characterized by

progressive inflammatory damage of CNS white matter.

This prompted both its manufacturer and the FDA to

review its utility in treating MS. Regardless, its clinical

benefits have been deemed to outweigh the risks

involved. Its use has been restricted to individuals with

highly active disease. Two trials involving RRMS

patients have demonstrated interesting clinical results.

The AFFIRM study compared natalizumab alone to

placebo and the SENTINEL study looked at adding

natalizumab to ongoing IFN-β1a therapy. The AFFIRM

trial demonstrated a 42% reduced risk of sustained pro-

gression of disability, a 68% reduction in rate of clinical

relapse at 1 year, and an 83% reduction in accumulation

of new or enlarging hyperintense lesions over 2 years

(Polman et al., 2006). Results of the SENTINEL trial

were similar to those of AFFIRM with the exception of

a 64% decreased risk of sustained disability progression

with natalizumab (Calabresi et al., 2007; Hutchinson

et al., 2009).


Mitoxantrone (Novantrones)

Mitoxantrone, a small molecule chemotherapeutic agent

able to cross the blood�brain barrier, functions as a type

II topoisomerase inhibitor, which disrupts DNA synthesis

and DNA repair, both events which function in an immu-

nosuppressant capacity thereby inhibiting T cell, B cell,

and macrophage proliferation. Overall, this leads to

enhanced T cell suppressor function, inhibition of B cell

function and antibody production, decreased secretion of

proinflammatory cytokines, and inhibition of

macrophage-mediated myelin degradation (Fox, 2004).

Mitoxantrone, administered intravenously, has been

approved by the FDA as treatment for patients with wors-

ening forms of MS including SPMS, worsening RRMS,

and PRMS. The MIMS trial indicated a 44% reduction in

time to first relapse; a 24% decrease in the expanded dis-

ability status scale, however, did not demonstrate a

positive impact on MRI disease burden (Hartung et al.,

2002; Krapf et al., 2005). Due to concerns related to

increased incidence of systolic dysfunction and therapy-

related acute leukemia, its use remains relatively limited

(Marriott et al., 2010).

Fingolimod (Gilenyas)

Fingolimod’s pharmacologic activity is targeted towards

lymphocyte migration out of lymph nodes. This action is

highly dependent on the engagement of a G-protein-

coupled receptor, S1P1, present on the surface of the lym-

phocytes. Fingolimod is structurally similar to S1P and can

function as an agonist by engaging four of the five known

S1P receptors (S1P1, S1P3, S1P4, S1P5). This leads to a

reduction in activated T cells that are able to exit the

lymph node and subsequently cross the blood�brain

barrier to exert their potential pathogenic effects on peri-

vascular tissue (Schwab and Cyster, 2007; Pham et al.,

2008). Studies have indicated the potential for S1P recep-

tors to be present on other cells, including neurons, micro-

glial cells, oligodendrocytes, and astrocytes, suggesting a

putative role for fingolimod in influencing myelin repair,

modulating survival of oligodendrocyte progenitor cells,

and directing astrocyte migration and proliferation

(Yamagata et al., 2003; Miron et al., 2008, 2010).

In September 2010 fingolimod became the first FDA-

approved first-line oral agent for the treatment of MS.

The FREEDOMS trial demonstrated, after 2 years, an

overall 54% decreased risk of relapse in the group treated

with fingolimod versus those taking placebo. The risk of

disability progression was 30% lower in patients receiving

the lower dose (0.5 mg) as opposed to placebo. With

regard to MRI disease burden, those taking fingolimod

presented with fewer new lesions and less brain tissue

atrophy. The TRANSFORMS trial aimed at characterizing

the efficacy of fingolimod versus intramuscular IFN-β1a(Avonexs). The group taking fingolimod had a 52%

lower risk of having a relapse than those taking IFN-β1a,with 82.5% of the fingolimod group and 70% of IFN-β1apresenting with no relapses during the 1-year study

period. Furthermore the group taking fingolimod had

fewer signs of MRI disease burden. There was no differ-

ence among the groups in the risk of disease progression

(Cohen et al., 2010). Although the arrival of fingolimod

has been met with great enthusiasm, the lack of clarity

surrounding long-term safety has led to caution as to its

utility as a first-line agent.

Teriflunomide (Aubagios)

Teriflunomide is the active metabolite of leflunomide, an

approved therapy for rheumatoid arthritis. It inhibits

de novo pyrimidine nucleotide synthesis and therefore

potently decreases T cell and B cell proliferation

(Hartung et al., 2010). Reports also indicate that terifluno-

mide may interrupt T cell and APC interactions in addi-

tion to possessing anti-inflammatory properties

(Zeyda et al., 2005; Gold and Wolinsky, 2011). The

TEMSO trial demonstrated a 31% reduction in annual

relapse rate, a 21% reduction in disability progression,

and a 76% reduction in number of new or enlarging T2

lesions on MRI in the higher dose cohort (O’Connor

et al., 2011). Teriflunomide was approved by the FDA in

September 2012 for patients with RRMS.

Dimethyl Fumarate, BG-12 (Tecfideras)

BG-12 is an oral formulation of fumaric acid, which is

metabolized to monomethyl fumarate. It was approved a

second-line agent in 2013. Other oral formulations of

fumaric acid have previously been used to treat psoriasis.

Both dimethyl fumarate and the active metabolite induce

activation of the nuclear factor E2-related factor-2 path-

way, which exerts neuroprotective effects and decreases

myelin damage in the CNS (Kappos et al., 2008; Fontoura

and Garren, 2010; Linker et al., 2011). Anti-inflammatory

mechanisms have also been attributed to dimethyl fuma-

rate (Gold, 2011). The DEFINE trial was completed in

2011. As a randomized, double-blind, placebo-controlled

phase III study, patients with RRMS were assigned to

receive either oral BG-12 at a dose of 240 mg twice or

thrice daily, or placebo. The primary end-point was the

proportion of patients who had a relapse 2 years later in

addition to disability progression and MRI disease burden.

The study demonstrated positive results with a significant

reduction in relapse rate (27% with BG-12 twice daily and

26% with BG-12 thrice daily vs. 46% with placebo), in the

rate of disability progression, in the number of new or

enlarging T2 lesions, and in new gadolinium-enhancing


lesions (Gold et al., 2012). The CONFIRM trial was also

completed in 2011. A phase III, randomized study, it

aimed to ascertain the efficacy and safety of BG-12 at a

dose of 240 twice or thrice daily in comparison to both

placebo and glatiramer acetate in patients with RRMS.

Similarly to the DEFINE trial, both BG-12 and glatiramer

acetate significantly reduced relapse rates and MRI disease

burden in relation to the placebo group (Fox et al., 2012).

In early 2013, BG-12 was approved as a first-line therapy

for adults with RRMS.

CONCLUDING REMARKS

Over the past decade, major strides have been made in our

understanding of the immunopathogenesis underlying the

development and course of MS, an autoimmune disease

that predominantly impacts the CNS by way of white mat-

ter damage and demyelination of neurons thought to be pri-

marily driven by T cell dysregulation, inflammation, and

immune dysfunction. Nevertheless, our ever-growing fund

of knowledge continues to inspire future directions. Novel

insights are providing hints for future prospects related to

early cortical demyelination, gray matter pathology, imag-

ing, and B cell involvement in MS further establishing this

disease as a multifocal entity. Overall, our increasing

knowledge pertaining to MS continues to be multifactorial.

The ability for clinicians and researchers to utilize our

understanding of the immunopathogenesis in relation to

known pharmacologic mechanisms, clinical findings, and

imaging modalities will be paramount in taking the neces-

sary steps towards eradicating MS.

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