multiple sclerosis: where will we be in 2020?

MOUNT SINAI JOURNAL OF MEDICINE 78:268–279, 2011 268

Multiple Sclerosis:Where Will We Be in 2020?

Aaron E. Miller, MD

Mount Sinai School of Medicine, New York, NY

OUTLINE

DIAGNOSIS

CAUSES AND RISK FACTORS

PROGNOSIS

TREATMENT

Treatment of Relapsing Forms ofMultiple Sclerosis

Treatment of Progressive Forms ofMultiple Sclerosis

Chronic Cerebrospinal VenousInsufficiency

CONCLUSION

ABSTRACT

The past decade has seen a surge of research inter-est in multiple sclerosis and an accelerated expan-sion of investigative efforts into multiple sclerosistherapeutics. Investigators have continued dissect-ing the complex immunological perturbations thatmay contribute to the disease and made majoradvances in understanding the genetics of multiplesclerosis. This article addresses current investiga-tive issues and offers predictions about where theunderstanding and treatment of multiple sclerosismay stand at the end of the 21st century’s seconddecade. Mt Sinai J Med 78:268–279, 2011. 2011Mount Sinai School of Medicine

Key Words: genetics, immunology, MS, multiplesclerosis, therapeutics.

In the perspective of history, a decade seems likemerely a fleeting moment. On the other hand, forpeople with a serious chronic disease it can seem

Address Correspondence to:

Aaron E. MillerMount Sinai School of Medicine

New York, NYEmail: [email protected]

like forever. Remarkable progress has been madewith regard to multiple sclerosis (MS), especially inthe area of therapeutics, in the last couple of decades.Will the next 10 years see similar advances? This arti-cle will address current issues regarding MS and offersome predictions about where we might be at theconclusion of the second decade of the 21st century.

DIAGNOSIS

For many decades, the diagnosis of MS has beenpredicated, irrespective of the specific criteria in aparticular diagnostic scheme, on the demonstrationof ‘‘dissemination in time and space.’’ This dictumrequires that symptoms or signs have to reflectdisease activity at multiple points in time and involve-ment of multiple discrete areas of the central nervoussystem (CNS). Virtually all proposed criteria for thediagnosis of MS also included the caveat that there isno better explanation for the clinical syndrome.

A major development in the diagnosis of MSwas the publication in 2001 of the diagnostic crite-ria established by an international panel convenedby the National Multiple Sclerosis Society, subse-quently known as the McDonald criteria after the latechairman of that panel, W. Ian McDonald.1 These cri-teria were the first to incorporate magnetic resonanceimaging (MRI) parameters into the diagnostic scheme,allowing their utilization for demonstration of dissem-ination in space or time, or both. The requirement fordissemination in space made use of criteria initiallysuggested by Barkhof and subsequently modifiedby Tintore. To fulfill the requirements (subsequentlywidely known as the Barkhof criteria) for dissemina-tion in space, the MRI had to demonstrate at least 3of the following 4 criteria:

1. ≥9 T2-hyperintense lesions or ≥1 gadolinium-enhancing lesions.

2. ≥1 infratentorial lesions.3. ≥1 juxtacortical lesions (ie, at the gray-white

junction).4. ≥3 periventricular lesions.

Published online in Wiley Online Library (wileyonlinelibrary.com).DOI:10.1002/msj.20242

2011 Mount Sinai School of Medicine

MOUNT SINAI JOURNAL OF MEDICINE 269

In 2005 the panel published revised criteria.2 Theseincluded some minor revisions in the use of MRIfor dissemination in space (allowing a spinal cordlesion to be counted as an infratentorial lesion andpermitting all discrete T2 lesions in the spinal cord tobe included among the 9 T2 hyperintensities neededto satisfy one of the requirement options), but alsoa major change that simplified the demonstration ofdissemination in time. Two options are available.The first is the demonstration of a new gadolinium-enhancing lesion on a scan performed at ≥3 monthsafter the initial onset of clinical symptoms (providedit was not in an area likely responsible for the clinicalsymptoms). The second option is the demonstrationof any new lesion on an MRI performed any timeafter a reference scan that was performed ≥30 daysafter the clinical onset. These changes were simplerto fulfill and allowed earlier diagnosis, increasingsensitivity while sacrificing very little in specificity.

Recently, a European MS MRI consortium (Mag-netic Imaging in MS [MAGNIMS]) proposed yetsimpler criteria3 designating dissemination in spacewhen the MRI shows ≥1 lesion in at least 2 of4 characteristic locations: juxtacortical, periventric-ular, infratentorial, or spinal cord. They simplifiedthe criteria for dissemination in time by acceptingthe occurrence of any new lesion developing at anytime after a reference scan that was performed atany time in reference to the initial clinical episode.Furthermore, the MAGNIMS criteria also permit thefulfillment of the criteria of dissemination in time bya single MRI scan that simultaneously demonstratesboth T2 hyperintense lesion(s) and ≥1 gadolinium-enhancing lesion, based on the presumption that thecontrast-enhancing lesion represents current diseaseactivity and the T2-hyperintense lesions representpast activity. Though this option for designatingdissemination in time has relatively low sensitivity(45%), it has good specificity (86%) and simplifiesthe diagnostic process when present.

The international panel met again in Dublin in2010 and made further revisions to the McDonaldcriteria which incorporated the MAGNIMS criteria.

I do not believe we will see further significantrevisions in the diagnostic process over the nextdecade. I do not expect that refinements in MRItechnology will lead to clinical utilization that wouldfurther alter the recommendations for disseminationin space and time. The only other development thatcould potentially alter the diagnostic scheme wouldbe the discovery of reliable biomarkers, somethingthat could be reliably measured in a bodily fluid,preferably blood or urine rather than cerebrospinal

I do not believe we will see furthersignificant revisions in thediagnostic process over the nextdecade.

fluid. Despite intense interest in this subject, nothinglooms on the horizon that will likely be of diagnosticvalue.

CAUSES AND RISK FACTORS

To give the bottom line first, I do not think we willbe substantially further along in a decade in ourunderstanding the root cause of MS, because I do notbelieve there is a single ‘‘cause’’ of MS. Increasingly

To give the bottom line first, I donot think we will be substantiallyfurther along in a decade in ourunderstanding the root cause ofmultiple sclerosis (MS), because Ido not believe there is a single‘‘cause’’ of MS.

the evidence suggests that the disease results froma complex interplay of genetic and environmentalfactors that are unlikely to be the same in any 2individuals. Specifically, investigators have searchedfor years for a specific viral etiology. Occasionalclaims of the identification of a particular agent havesubsequently been refuted, and, given the sophis-tication of modern biological techniques, it seemsvery unlikely that a novel causative agent will bediscovered. In recent years extensive attention hasbeen paid to the potential role of Epstein-Barr virus(EBV).4–8 Exposure to this virus does seem to conveysome increased risk for the development of MS. Forexample, MS is more common in patients who havehad clinical mononucleosis5,6 and the prevalence ofpositive serology to EBV is higher among patientswith MS than in controls.8 However, the near ubiq-uity of this viral infection and failure to find the virusitself in the brains of most patients with MS makes ithighly improbable that EBV is directly involved as acausal agent.

In the first decade of the 21st century, vita-min D has garnered considerable attention amongMS researchers. A variety of evidence suggests thatvitamin D deficiency may be a risk factor for thedevelopment of the disease.9,10 However, currentlythe data, principally on the basis of epidemiological

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270 A. E. MILLER: MULTIPLE SCLEROSIS: WHERE WILL WE BE IN 2020?

surveys or studies, only indicate potential associationbetween a lack of vitamin D, rather than a causalrole. In a large case-control study among US militarypersonnel, MS was significantly less prevalent in thegroup whose banked serum samples, obtained priorto the diagnosis of MS, were in the highest quintileof vitamin D levels.11

Latitudinal differences in the prevalence of MS,with the disease much more common in popula-tions living farther away from the equator, have longbeen recognized. One way to link this observationwith vitamin D is the suggestion that the latitudinaldifference reflects variation in the amount of sun-light, specifically ultraviolet (UV) light exposure, thepopulation receives. Individuals in more temperatelatitudes receive less UV exposure, in turn resultingin lower levels of vitamin D, because sunlight is amajor factor in the body’s synthesis of vitamin D. Sur-veys of individuals within the same geographical areasuggest that those individuals with more sun expo-sure are less likely to develop MS.12 In a Tasmanianstudy, the amount of UV exposure was estimatedbased on the extent of actinic damage to the skin,demonstrated on skin biopsy, and children who hadmore extensive actinic damage were less likely todevelop MS.13 Other epidemiological evidence does,however, cast some doubt on the role of vitamin D,or at least that of sun exposure. The prevalence of MSin the island nation of Malta is approximately 13 per100,000,14 which is dramatically different from that inEnna, Sicily, where the prevalence was determined tobe 120 per 100,000.15 It seems highly improbable thatthere is significant difference in average sun exposurebetween the populations living in these 2 closely geo-graphically situated Mediterranean islands, althoughother indeterminate risk factors may distinguish these2 populations.

It is virtually certainly that by 2020 we will nothave further definitive evidence about the role of vita-min D as an MS risk factor. That determination would

It is virtually certainly that by 2020we will not have further definitiveevidence about the role ofvitamin D as aMS risk factor. That determinationwould require followingan enormously large cohortfor several decades, a theoreticallyfeasible, but practicallydaunting and financiallyoverwhelming undertaking.

require following an enormously large cohort for sev-eral decades, a theoretically feasible, but practicallydaunting and financially overwhelming undertaking.

What about the role of supplemental vitamin Din reducing the relapse rate or disability progressionin people who already have MS? The answer tothis question is currently unknown. Many physicianscaring for people with MS have begun to recommendthat their patients take supplemental vitamin D. Ifone assumes that a minimum desired serum level ofvitamin D is 30 ng/mL, then one finds that one-thirdto one-half of the population in temperate countrieshas levels below 20 ng/mL.10 Generally speaking,supplementation with daily oral vitamin D between1000 and 4000 (average 2000) IU will bring mostpeople to at least the minimum level.

A trial to determine whether supplemental vita-min D is beneficial to people with MS would seemrelatively easy to design. Here, however, a major bar-rier to completion of a study of statistically adequatepower is likely to be cost. Given the widespread exis-tence of increasingly effective therapies, the demon-stration of the value of adding vitamin D will likelyrequire a study with a very large sample size. Amore manageable sample size would be sufficientin a randomized, placebo-controlled trial. However,such a trial would be currently unethical, at leastin most well-developed countries, because of theavailability of at least partially effective treatments.To perform an adequate trial in patients already ondisease-modifying therapy (DMT) would require avery large sum of money, the availability of whichis quite problematic in view of absence of a profitmotive for the demonstration of the utility of vita-min D supplementation. I predict, therefore, that thecurrent practice of recommending supplemental vita-min D for people with MS will continue, becauseof its apparent safety and potential benefit for suchother issues as bone health. However, I believe thatin 2020 we will neither know specifically whethersuch a recommendation has an impact on the courseof MS, nor what an ideal serum level is.

Recent years have seen an explosion of inter-est and research into genetic aspects of MS. Clearly,genetic influences are important for the develop-ment of MS. For example, the concordance rate inmonozygotic twins is approximately 30%, far exceed-ing the prevalence rate in the general population(eg, approximately 1/1000 in temperate latitudes ofthe Northern Hemisphere) or the lifetime risk infirst-degree relatives, including dizygotic twins, ofabout 2%–5%.16 The converse of this observation,of course, is that the discordance rate is 70%, indi-cating that any genetic risk must be augmented bysome presumably stochastic environmental event in

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order to trigger the development of MS in a particularindividual.

For many years, the importance of the associa-tion with major histocompatibility loci in MS has beenrecognized. Specifically, the relationship between MSand HLA DRB*1501 remains by far the most impor-tant genetic connection. Very recently, a series ofgenome-wide association studies (GWAS) conductedby a number of large international groups has uncov-ered ≥15 susceptibility alleles.17–19 Each of theseallelic variations conveys an added risk, but with verylow odds ratios, ranging from 1.04 to 1.33. Therefore,even the presence of many of these alleles in anindividual conveys little added risk, likely no morethan 2%.

Efforts are ongoing to make use of this geneticinformation in the clinical setting. Nonetheless, I sus-pect that the clinician in 2020 will still find little,if any, meaningful guidance from the genetic infor-mation about individual patients. Indeed, knowledge

Efforts are ongoing to make use ofgenetic information in the clinicalsetting. Nonetheless, I suspect thatthe clinician in 2020 will still findlittle, if any, meaningful guidancefrom the genetic informationabout individual patients.

of the strongest genetic association, that with HLADRB*1501, has been known for years and has had noimpact on clinical practice. Adding the limited impactof the other allelic risk loci seems unlikely to changethis situation. Perhaps the greatest importance to bederived from the GWAS so far has been the recog-nition that virtually all of the identified risk loci arerelated to the immunological system. This informa-tion may lead to further unraveling of the role of theimmune system in the pathogenesis of MS.

PROGNOSIS

Customarily, physicians answer MS patients whoinquire about their prognosis by professing theirinability to predict an individual’s course because thedisease has so much variability and ‘‘every patientis different.’’ To be sure, we currently lack the abil-ity to precisely forecast an individual’s course withMS, and that will likely remain true a decade fromnow. Nonetheless, with regard to other medical con-ditions, physicians commonly utilize statistical dataabout prognosis to make treatment decisions and

Table 1. Negative Prognostic Features in MS.

Clinical1. Motor, brainstem, or cerebellar involvement in initialattack2. Bladder or bowel involvement with initial attack3. Incomplete recovery from initial attack4. Short interval (<2 years) between first and secondattacks

MRI1. ≥10 T2-hyperintense lesions on initial MRI2. Posterior fossa involvement

Abbreviations: MRI, magnetic resonance imaging;MS, multiple sclerosis.

to offer patients some guidance about what theyare more or less likely to experience in the future.I believe that we already have considerable informa-tion available to inform prognosis (Table 1) and thatover the next decade we will continue to recognizeother clues to the expected course of MS. Utilizingthis information will become increasingly important,

I believe that we already haveconsiderable informationavailable to inform prognosis andthat over the next decade we willcontinue to recognize other cluesto the expected course of MS.

as physicians may need to choose between drugs thatare potentially more effective but carry greater riskand those whose efficacy may be lower but whosesafety profile is better.

Currently, even the very first episode of what islikely to be MS, the so-called clinically isolated syn-drome (CIS), offers some prognostic information. Thenature of that initial attack has implications. Patientswhose attack involves the brainstem or, especially,motor function, have a worse prognosis, on average,than those with sensory episodes. If the initial attackinvolves urinary dysfunction, admittedly a relativelyinfrequent occurrence, studies consistently demon-strate a worse prognosis. Multiple studies support theobservation that failure to make a complete recoveryfrom the initial clinical episode portends a bleakerfuture.20,21

Early MRI data are undergoing increasingscrutiny for prognostic implications. Recent studiessuggest that even the initial MRI can provide impor-tant information about the future. In a well-studiedBritish cohort, patients who had ≥10 T2-hyperintenselesions on their initial MRI scan fared considerablyworse than those with fewer lesions.22 Such patients

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had a median Expanded Disability Status Scale (EDSS)score of 6 (meaning they required unilateral assis-tance to walk) at 20 years. Nearly 50% of thesepatients had reached an EDSS of 6, compared with<20% of patients with ≤3 lesions. Another study hasshown that the presence of 3 or 4 positive Barkhofcriteria on the initial scan has a moderate correlationwith the EDSS at 5 years.

As the patient evolves to a diagnosis of definitiveMS, additional information may inform the progno-sis. Studies have consistently demonstrated that theinterval between the first 2 MS attacks augurs thefuture course.20,23 Those patients with a short initialinterattack interval (<2 years in most studies) have aworse prognosis than those who go a longer periodbetween the first and second attacks. In one of thelargest MS databases studied over a long period oftime, in Lyon, France, patients with an initial interat-tack interval of <2 years reached an EDSS score of4 (generally, a point at which the distance a personcan walk is clearly becoming limited) at a medianof 6.6 years, compared with 9.6 years to reach thatmilestone for those who went 2 to 5 years betweenattacks and 16.1 years for those who took >5 years.23

Putting such information together, then, as weapproach patients over the next decade, it seems thata more aggressive therapeutic approach would bewarranted, for example, for a patient with clinicallydefinite MS who has had an initial motor attack, leav-ing her with a residual paresis of 1 leg, followed by abrainstem attack 6 months later and whose initial MRImeets all 4 Barkhof criteria, with 20 T2-hyperintenselesions, including involvement of the brainstem andspinal cord. In contrast, a less-ominous course wouldbe implied in a patient who has had an episodeof mild optic neuritis with full recovery, followed7 years later by a minor sensory relapse, who hasa normal neurological examination and whose MRIreveals only 5 T2-hyperintense lesions confined tothe cerebral white matter.

During the next decade, new imaging techniqueswill evolve and improvements in current researchtechniques are likely to occur. However, given thecurrent lack of standardization of the specific imagingprotocols and their unavailability for routine clinicaluse, as well as the length of follow-up needed toacquire prognostic information, it is unlikely thatthey will contribute significantly to a better abilityto forecast individual outcomes by 2020. The questfor biomarkers as surrogates that would contributeto accurate forecasting of individual prognosis is avigorous area of investigation. Thus far, no strongcandidate has emerged, and I suspect that this holygrail will remain elusive over the next decade withregard to application to a specific MS patient.

TREATMENT

Treatment of Relapsing Forms ofMultiple Sclerosis

For more than a decade, the mainstay of treatmentto modify the course of MS has been injectable ther-apy with either interferon-β (IFN-β) or glatirameracetate (GA). Two other parenteral agents, mitox-antrone and natalizumab, are on the market, but aregenerally reserved for patients who are having anunsatisfactory response to or are not tolerating theself-injected DMTs. Three preparations of IFN-β areavailable (in historical order of US Food and DrugAdministration approval): subcutaneous (SC) IFN-β-1b, administered every other day; intramuscular (IM)IFN-β-1a, administered weekly; and SC IFN-β-1a,administered 3× weekly. Although the mechanismsof action of IFN-β and GA are imprecisely known,and their adverse-event profiles differ, the efficacyof the 2 classes of DMTs appears to be comparable,perhaps with the caveat that weekly IM IFN-β maybe somewhat less effective than the more frequentlyadministered IFN-β preparations. Mitoxantrone, animmunosuppressive agent, is currently the only drugapproved for the treatment of secondary progressiveMS (SPMS) without relapses (it is also approved forworsening relapsing forms). It is infrequently usedbecause of its potential for serious adverse events,including cardiotoxicity and drug-related leukemia.

Natalizumab is a monoclonal antibody directedagainst α4β1 integrin, an adhesion molecule on thesurface of lymphocytes.24 Interaction of this adhesionmolecule with its complementary receptor vascularcell adhesion protein 1 on the vascular endotheliumenables the lymphocyte to be arrested at the vascularwall, a necessary step for penetration into the CNS.Natalizumab was originally marketed in late 2004,but was voluntarily removed in early 2005 becauseof the discovery of 2 cases of progressive multifo-cal leukoencephalopathy (PML),25,26 an opportunisticviral infection of the brain caused by JC virus (JCV),in study patients treated with the drug for MS and anadditional case in an individual receiving the agent forCrohn’s disease. The drug was brought back to mar-ket in the summer of 2006 with a risk evaluation andmitigation strategy to try to facilitate the early recogni-tion of PML. Since its reintroduction, 75 more patientswith PML have been identified among >75,000 whohave received natalizumab. The risk of PML increaseswith duration of exposure, at least up to 2 yearsof treatment. No case of PML has yet occurredwith usage of natalizumab for <14 months, and theincidence for all patients receiving ≥24 infusionsis 1.97/1000 (95% confidence interval: 1.51–2.53).

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However, the rate does not appear to continue toincrease with exposure for >2 years. Because of thisrisk, use of natalizumab is recommended for patientswho are not having a satisfactory response to the first-line injectable therapies or are not tolerating them.

Use of a recently developed antibody assay forJCV suggests that only slightly more than half of thepatients treated with natalizumab have antibody toJCV.27

So far, in all 23 natalizumab-treated patients forwhom serum was available, antibody titers have beenpositive. If these observations hold up with furtherstudy, there would probably be a major impact onthe clinical use of natalizumab, as antibody negativ-ity would imply extremely low risk of PML (patientsdo convert to antibody positivity at a low annualrate, so repeated testing would be necessary). Con-versely, the presence of antibodies would mean thata patient on the drug was at a considerably higherrisk for PML than we currently believe, at least afterprolonged exposure to the treatment. Soon after theintroduction of IFN-β-1b, patients began to ask theirphysicians, ‘‘When will there be a pill?’’ Despite thevery benign safety profiles of IFN-β and GA, clearlymost patients would prefer to have an oral medi-cation. Many patients experience both physical andpsychological discomfort from the repeated injec-tions. Often, because of underlying changes to theSC tissue, patients experience increasing difficultywith their injections after prolonged usage. In par-ticular, GA may cause prominent focal lipoatrophy,sometimes resulting in cosmetically unsightly ‘‘div-ots’’ in the injected areas after extended treatment.This is especially true in women.

Fortunately, we are now seeing the dawn of oraltherapy for MS. The first oral agent, fingolimod, wasapproved by the FDA in September 2010. A new classof MS DMT, fingolimod is a sphingosine-1-phosphatereceptor (S1PR) modulator. The drug acts as a func-tional antagonist of the S1PR, thereby preventingegress of lymphocytes from the lymph nodes (albeitsparing central memory T cells) and thus keepingthem from doing damage in the CNS. Fingolimodmay also have a direct neuroprotective effect withinthe CNS.

Administered once daily, the drug was approvedbased on two positive phase III trials. The firstreported was a 1-year trial against an active compara-tor, weekly IM IFN-β-1a, in which patients receivingfingolimod at what is now the marketed dose of0.5 mg experienced fewer than half the numberof relapses that occurred in the IFN-β-1a group.28

The pivotal randomized, double-blind, placebo-controlled trial, known as the Efficacy and Safetyof Fingolimod in Patients With Relapsing-Remitting

Multiple Sclerosis (FREEDOMS) 1, resulted in a>50% reduction in annualized relapse rate for boththe 0.5-mg and 1.25-mg doses of fingolimod thatwere studied in the trial.29 The fingolimod-treatedpatients also experienced significant benefit on sev-eral MRI parameters, including new T2-lesion vol-ume, gadolinium-enhanced lesions, and brain vol-ume, as well as a statistically significant reduction insustained disability progression.

Fingolimod treatment was associated with somepotentially significant adverse events. Bradycardia,rarely clinically significant, occurred with the firstdose, and prescribing information instructs healthcareproviders to monitor patients for 6 hours at the initialdosing and also recommends obtaining an electro-cardiogram prior to prescribing the drug in patientsusing antiarrhythmics including β-blockers and cal-cium channel blockers, those with cardiac risk factors(second-degree or higher atrioventricular blocks, sicksinus syndrome, prolonged QT interval, ischemic car-diac disease, or congestive heart failure), and thosewho on examination have a slow or irregular heart-beat. Macular edema occurred in 0.4% of patients,albeit usually in the patients treated with the 1.25-mgdose of fingolimod, resulting in the recommendationthat patients undergo baseline ophthalmic evaluationand repeat examination 3 to 4 months later. Concernabout herpes infections, especially varicella zoster,has led to the recommendation that patients not bestarted on fingolimod unless they have had chickenpox or varicella immunization. Liver function testsand complete blood counts need to be monitored.

Cladribine, a purine nucleoside analogue thatis a potent lymphocyte-depleting agent, has had apositive phase III trial, reducing relapse rate by wellover 50% compared with placebo.30 The drug wasdosed for several days in each of 2 or 4 monthlycycles (low and high dose, respectively), and thentreatment was not repeated until 12 months afterthe initial cycle. The agent is currently approved inRussia and Australia, but the European MedicinesAgency recently rejected the application, citing con-cerns about 4 cases of cancer that occurred in thetrial. A decision by the FDA is pending.

Teriflunomide, a drug that interferes with pyrim-idine synthesis, met its primary endpoint of a reduc-tion of annualized relapse rate (ARR), as reportedat a recent international MS meeting. Both the 7-and 14-mg single daily doses tested achieved relapserate reductions of approximately 31%, as well as sig-nificant reductions in total T2-lesion volume.31 Thehigher dose also produced a statistically significantreduction of nearly 30% in the development of sus-tained disability progression. Confirmatory studies

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are in progress. The safety profile appears favorable,although elevations of liver enzymes may occur.

Two other oral agents, fumarate and laquini-mod, are nearing completion of phase III trials. Bothagents are likely to have good safety profiles, basedon their phase II data.32,33 In addition, fumarate hasbeen marketed in Germany for years for the treat-ment of psoriasis, without the significant occurrenceof serious adverse events. The exact mechanisms ofaction of these drugs is uncertain. The major ques-tion that must be answered is whether these agentswill prove effective. In the phase II trials, both agentsreduced MRI activity, although the laquinimod resultswere less pronounced than what has been seen withseveral other drugs. Each drug showed only a trendto reducing relapse activity in the phase II trials, butsuch studies are not powered to expect statisticallysignificant results on this parameter.

In addition to these promising oral agents, sev-eral parenteral monoclonal antibodies are undergo-ing phase III trials. Rituximab, a chimeric antibodydirected against the CD20 antigen on B cells, had apositive phase II trial several years ago.34 However,its further development for MS was halted in favor ofa more fully humanized anti-CD20 antibody knownas ocrelizumab. Results of a phase II trial of this agentwere recently reported and, like rituximab, producedrobust reduction in MRI activity and also statisti-cally significant reduction in relapse rate, despite thepower limitations of the phase II trial.35 The drug isexpected to soon undergo phase III testing.

Alemtuzumab, a monoclonal antibody directedagainst the CD52 antigen present on both T andB lymphocytes, is a potent immunosuppressiveagent. Because the treatment is associated withvery prolonged depletion of lymphocytes, it isadministered for several days followed by a hiatusof 1 year before the next course of therapy. Ina phase II/III trial against SC IFN-β-1a, treatmentwith the agent resulted in a remarkably lowARR of 0.11 in patients treated with 12 mg/dayand 0.05 in patients who received 24 mg/day.36

Unfortunately, the trial was marked by someserious adverse experiences. Most notably, 6 casesof immune thrombocytopenic purpura, the firstof which resulted in a fatal brain hemorrhage,occurred among the 222 patients who receivedalemtuzumab. In addition, 49 patients receiving themonoclonal antibody developed abnormalities ofthyroid function. Despite these risks, phase III trialsare currently in progress.

A third monoclonal antibody, daclizumab, is alsocurrently in phase III trials. This agent is directedagainst the α subunit (CD25) of the high-affinityinterleukin-2 receptor and results in inhibition of

activated T cells. Current evidence suggests thatCD25 antagonism causes expansion of a regulatorysubset of natural killer cells, CD56 bright cells, whichpresumably lyse autologous activated T cells. Ina phase II trial, the higher dose of daclizumab,2 mg/kg SC every 2 weeks, added to treatmentwith weekly IM IFN-β-a, reduced the number oftotal new and enlarging gadolinium-enhanced lesionsdeveloping between weeks 8 and 24 by 72%compared with the addition of placebo.37 A trend inARR favored daclizumab but did not reach statisticalsignificance.

Currently available and prospective DMTs aresummarized in Table 2. I believe that by 2020,oral treatment of MS will be the mainstay of ther-apy. I predict that S1PR modulation will ultimatelybe determined to be an effective and relativelysafe therapy. Fingolimod may be the most widelyused therapy; although, depending on the speedof development, it might be supplanted by morereceptor-selective S1PR modulators. Many patients,however, may initially be treated with an oral agentwith a better safety profile but perhaps somewhatlesser efficacy, such as teriflunomide, fumarate, orlaquinimod, and switched to the more potent agentif they experience breakthrough disease. I believethat cladribine, if approved, will be prescribed lessfrequently because of its very-long-lasting depletionof lymphocytes, as well as concerns about reproduc-tive risk. I also expect the monoclonal antibodiesto have a smaller role in the overall management

I believe that by 2020, oraltreatment of MS will be themainstay of therapy. Fingolimodmay be the most widely usedtherapy; although, depending onthe speed of development, it mightbe supplanted by morereceptor-selective S1PRmodulators. Many patients,however, may initially be treatedwith an oral agent with a bettersafety profile but perhapssomewhat lesser efficacy, such asteriflunomide, fumarate, orlaquinimod, and switched to themore potent agent if theyexperience breakthrough disease.

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Table 2. Current and Prospective MS DMTs.

Drug NameRoute of

Administration Mechanism of Action FDA Status

IFN-β-1a IM Multiple ApprovedIFN-β-1a SC Multiple ApprovedIFN-β-1b SC Multiple ApprovedGlatiramer acetate SC Switch from Th1 to Th2 predominance;

?Increase Treg cellsApproved

Mitoxantrone IV Multiple immunosuppressant functions,including inhibition of T-cell activation

Approved

Natalizumab IV Selective adhesion molecule inhibitor ApprovedFingolimod Oral S1PR modulator ApprovedCladribine Oral Purine nucleoside analogue; depletes

lymphocytesPending

Teriflunomide Oral Pyrimidine synthesis inhibition inlymphocytes

1 phase III trial positive

Laquinimod Oral ?Th1 to Th2 shift 1 phase III trial positiveFumarate (BG-12) Oral Uncertain Phase III trials pendingRituximab/ocrelizumab IV Anti-CD20 antibody; depletes B cells Phase II trial positiveAlemtuzumab IV Anti-CD52 antibody; depletes T and B

cellsPhase II/III trial positive;

phase III trial pendingDaclizumab SC Anti-CD25, component of high-affinity

IL-2 receptor; inhibits activated T cellsPhase III trials pending

Abbreviations: DMT, disease-modifying therapy; FDA, US Food and Drug Administration; IFN-β, interferon β;IL-2, interleukin-2; IM, intramuscular; IV, intravenous; MS, multiple sclerosis; S1PR, sphingosine-1-phosphate receptor;SC, subcutaneous; Th, T helper cell; Treg, regulatory T cells.

of MS, primarily because of greater concerns aboutthe potential for opportunistic infections (particularlywith ocrelizumab or alemtuzumab) or, particularly inthe case of alemtuzumab, other autoimmune phe-nomena. In addition, treatment with alemtuzumab isa double-edged sword. On the one hand, the treat-ment regimen is attractive, requiring only a few daysof intravenous infusion annually, but the fact thatthe effects of the treatment are of very prolongedduration and irreversible is concerning.

I anticipate that by 2020 the use of self-administered injectable medications–the IFN-βs orGA–will be minimal, principally because of theadvent of better-accepted oral agents that match orexceed these current frontline therapies in efficacy

I anticipate that by 2020 the useof self-administered injectablemedications–the interferons orglatiramer acetate–will beminimal, principally becauseof the advent of better-acceptedoral agents that match or exceedthese current frontline therapiesin efficacy while carrying anacceptable safety profile.

while carrying an acceptable safety profile. Possibly,combination therapy with one or another of the oralagents and either IFN-β or GA will be employed insome patients whose disease is not fully controlledby the single drug. Patients taking injectable ther-apy today almost universally would prefer the optionof oral therapy, or even infrequently administeredinfusions, as they almost invariably experience dis-comfort with the injections and increasing difficultybecause of tissue changes associated with prolongedusage of these drugs.

Treatment of Progressive Forms ofMultiple Sclerosis

Developing successful treatment of progressive formsof MS, both SPMS and primary progressive (PPMS),has been an unmet challenge and remains a crit-ical need. Currently mitoxantrone, an immunosup-pressive agent, is the only drug approved for thetreatment of SPMS (without relapses), and it is notwidely used because of the potential serious risks ofdrug-induced leukemia and cardiotoxicity.

No drug has so far had a positive trial forthe treatment of PPMS. A trial of GA showed atrend in favor of benefit, but could not demonstratestatistical significance. The trial was hamperedby the fact that the placebo group failed toprogress to the extent anticipated when the trial

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was powered.38 A post hoc analysis suggestedthat males had benefited from the treatment. Inanother recent trial for PPMS patients comparingrituximab with placebo, the primary endpoint ofconfirmed progression was not achieved.39 However,the data suggested benefit for younger patientsand those with continued evidence of inflammationas indicated by gadolinium-enhancing lesions onMRI.

The progressive stage of MS, be it in SPMS orPPMS, appears to be principally associated with aprocess that is neurodegenerative or influenced bythe innate immune system, rather than the more evi-dent inflammation that is seen in relapsing-remittingdisease. Nonetheless, some patients with SPMS docontinue to have relapses and to develop new lesionson MRI, including gadolinium-enhancing lesions. Inclinical trials of PPMS, some patients also continue todevelop enhancing lesions.

I predict that an ongoing trial of fingolimod inPPMS will be positive, resulting in the approval ofthe first drug for PPMS. I believe this not necessarily

I predict that an ongoing trial offingolimod in primary progressivemultiple sclerosis will be positive,resulting in the approval of thefirst drug for PPMS.

because fingolimod has a greater impact on neu-rodegeneration (though it may) than other agents,but rather because the design of the phase III trialsfavors the inclusion of patients with a more inflam-matory profile than other trials in PPMS have. Thetrial limits entry to patients who have had evidence ofPPMS for ≤10 years and also requires evidence of dis-ease progression in each of the 2 years prior to entry.These criteria favor a population with greater diseaseactivity and, I believe, will increase the likelihood ofa favorable outcome in the trial.

The prospects of success in SPMS are uncer-tain over the next decade. Progress has also beenhampered by the absence of surrogate markers forprogression, necessitating long follow-up of patientsin clinical trials. The search for predictive surro-gate markers for progression, either imaging mea-sures or biomarkers, will continue. Nonetheless,we are likely to see trials of some of the moreactive anti-inflammatory agents, which may again, forthe reasons cited above, possibly result in positivetrials.

Chronic Cerebrospinal VenousInsufficiency

In 2009, a vascular surgeon, Professor Paulo Zam-boni of Ferrara, Italy, reported an association of whathe claimed were venous abnormalities detected byultrasound in patients with MS.40 He defined the syn-drome of chronic cerebrospinal venous insufficiency(CCSVI) as the situation in which at least 2 of 5criteria were present:

• Reflux in internal jugular veins (IJV) or vertebralveins (VVs).

• Reflux in intracranial veins or sinuses.• Detection of stenoses in IJVs.• Absence of Doppler signal in IJV and/or VV.• Cross-sectional area of IJV greater sitting than

supine.

He claimed that CCSVI existed in 100% of 65 MSpatients and none of 235 control patients, and postu-lated that the condition caused MS. Zamboni furtherbased this speculation on the belief that CCSVI ledto the deposition of iron in the brain, which in turnpromoted an inflammatory, demyelinating process.In a subsequent paper, he reported that interven-tions to repair these venous abnormalities resultedin improvement in patients with MS, using a pro-cedure that he provocatively termed the ‘‘liberationprocedure.’’41 He did, however, note that ‘‘restenosis’’of the IJV occurred in 47% of cases.

The Zamboni claims created a firestorm in theMS community, fueled by the promotion of hisideas by the mainstream media, especially in Canada.Demands for the liberation procedure reached a feverpitch, fanned by huge numbers of Internet bloggers.The causal relationship between CCSVI and MS wasconsidered highly unlikely by most MS scientists andclinical specialists. The all-or-none results claimed byZamboni strained credulity. Critics pointed out thefact that ultrasound evaluation of the cerebral venoussystem was significantly operator-dependent and thatno uniform anatomy of that system existed. Theyemphasized the redundancy of the venous drainageof the brain and the fact that surgeons operating onthe head and neck, particularly for tumors, commonlyligated the IJVs without untoward effects. In addition,they noted the absence of the clinical signs usuallyassociated with blocked venous drainage and pointedout that, although iron deposition is increased in thebrains of people with MS, it is also found in patientswith other neurodegenerative diseases. It is also pos-sible that even if the association of CCSVI with MSwere true, it might be a result of the disease, ratherthan a cause.

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Despite this widespread skepticism, the NationalMultiple Sclerosis Society and the Multiple SclerosisSociety of Canada, driven by their desire to exploreany possibility of finding a cause or cure of MS andthe intensity of the demand for procedures to ‘‘open’’the veins, requested proposals to study CCSVI. Aninternational multidisciplinary panel recommendedfunding of several studies, currently underway,designed to confirm or refute the Zamboni findings,as well as to extend the studies to other methodsof investigating the venous system in patients withMS, including those very early in the course of thedisease.

Subsequent to the original Zamboni reports,deaths associated with the use of venous stentshave been reported, as well as some other seri-ous complications. The occurrence of a death fromintracerebral hemorrhage and the need for open heartsurgery because of migration of a stent to the heartled Stanford University to ban performance of theprocedure.42 Recently, another death occurred in apatient who underwent the procedure in Costa Rica.43

A number of investigators have now reported findingeither a much lower frequency of CCSVI in patientswith MS and a much greater number in controls, orno significant difference at all between MS patientsand control subjects.35,44,45

By 2020, the concept of CCSVI will likely havebeen discredited as a plausible cause of MS. Nonethe-less, as we have seen with other claims, such asthe refuted notion that dental amalgams cause MSand their removal effects improvement, I expect thatsome patients will continue to seek procedures to‘‘open’’ their venous systems. Furthermore, I expectthat within the next decade some other claim aboutthe cause and cure of MS will capture the pub-lic fancy, just as others have done over the years.Sadly, such situations tend to divert patients from

By 2020, the concept ofcerebrospinal venous insufficiencywill likely have been discreditedas a plausible cause of multiplesclerosis. Furthermore, I expectthat within the next decade someother claim about the cause andcure of multiple sclerosis willcapture the public fancy, just asothers have done over the years.

legitimate, scientifically proven treatments (evenif only partially successful) and may result in

expenditure of research dollars that could be betterused for other studies.

CONCLUSION

The past decade has seen a surge of research interestin MS and an incredible expansion of investigativeefforts in MS therapeutics. Continued dissectionof the complex immunological perturbations thatmay contribute to the disease has occurred. Majoradvances in understanding the genetics of MS havebeen made and are continuing rapidly. I expect thatthe current decade will be characterized by continuedintense exploration of this enigmatic disorder withfurther advances in our understanding of the diseaseand additional progress in its treatment.

DISCLOSURES

Potential conflict of interest: Nothing to report.

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multiple sclerosis: where will we be in 2020?

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