Faculty

David Bates(Scientific organiser)Department of NeurologyRoyal Victoria InfirmaryNewcastle Upon Tyne, UK

Orhan AktasDepartment of NeurologyHeinrich-Heine-UniversityDüsseldorf, Germany

Raed AlroughaniAmiri HospitalDasman Research InstituteKuwait City, Kuwait

Isa AlsharoqiDepartment of Clinical NeurosciencesSalmaniya medical complexManama, Bahrain

Roberto BergamaschiNational Neurological Institute C. MondinoPavia, Italy

Saeed BohlegaDepartment of NeurosciencesKing Faisal Specialist Hospital and Research CentreRiyadh, Saudi Arabia

Giancarlo ComiDepartment of NeurologyInstitute of Experimental NeurologyVita-Salute San Raffaele UniversityMilan, Italy

Nicola De StefanoNeurology and Neurometabolic UnitDepartment of Neurologicaland Behavioral SciencesUniversity of Siena, Siena, Italy

Gilles EdanCentre HospitalierUniversitaire de RennesRennes, France

Robert FoxMellen Center for MSCleveland ClinicCleveland, USA

Jihad InshasiNeurology DepartmentRashid HospitalDubai Health Authority (DHA)Dubai, UAE

Dawn LangdonDepartment of Psychology Royal Holloway University of LondonLondon, UK

Letizia LeocaniInstitute of Experimental NeurologyUniversity Vita-Salute IRCCSSan Raffaele Hospital, Milan, Italy

Filippo Martinelli BoneschiNeurological Complex Disorders Department of Neuro-rehabilitationINSPE Scientific Institute San RaffaeleMilan, Italy

Vittorio MartinelliNeurology UnitSan Raffaele Scientific InstituteVita-Salute San Raffaele UniversityMilan, Italy

Carlo PozzilliDepartment of Neurology and Psychiatry“La Sapienza” University of Rome, Rome, Italy

Peter RieckmannBamberg Hospital and University of Erlange Bamberg, Germany

Maria Assunta RoccaNeuroimaging Research UnitInstitute of Experimental NeurologyDivision of NeuroscienceSan Raffaele Scientific InstituteVita-Salute San Raffaele UniversityMilan, Italy

Mohammad Ali SahraianMS research centerTehran University of Medical SciencesTehran, Iran

Aksel SivaDepartment of NeurologyIstanbul UniversityIstanbul, Turkey

Ilham SlassiIbn Rochd HospitalCasablanca, Morocco

Alessandra SolariUnit of NeuroepidemiologyFoundation IRCCS Neurological Institute C. Besta Milan, Italy

Mar TintorèMultiple Sclerosis Centre of Catalonia (Cemcat) Neurology-Neuroimmunology Department Vall d’Hebron University Hospital Barcelona, Spain

Bassem YammoutMultiple Sclerosis Center Clinical Research American University of Beirut Medical Center Beirut, Lebanon

Rachel Clark, CEO of EXCEMED, opened the 2014 Annual Conference on multiple sclerosis (MS) and the scientificorganisers, David Bates (Royal Victoria Infirmary, Newcastle upon Tyne, UK), Giancarlo Comi (Institute of ExperimentalNeurology, Vita-Salute San Raffaele University, Milan, Italy) and Aksel Siva (Istanbul University, Istanbul, Turkey)welcomed around 260 participants to the Conference, which has been accredited for a maximum of 9 hours of EuropeanCME credits (ECMEC) and 9.75 CPD credit points by Dubai Health Authority. The local scientific organiser Jihad Inshasi(Rashid Hospital, Dubai Health Authority (DHA), Dubai, UAE) welcomed the participants to the city of Dubai.The improvements in both diagnosis and treatment of MS through exciting scientific discoveries in recent decades havechanged the medical approach to MS from disease- to patient-orientated, allowing patients to be involved in the decisionmaking process. There is now the opportunity to tailor treatment based on disease activity.This live educational conference aimed to explore the roles of genetics and environment in the pathogenesis of MS andexamine options within the patient-centred approach to clinical management (click here to see the full programme,abstracts and speaker biographies).

David BatesNewcastle, UK

HIGHLIGHTS

2014 Annual conference Multiple sclerosis: improving patient outcomesthrough scientific and clinical advances9-10 May 2014 - Dubai, UAE

MS is a multifactorial disease - evidence suggests that there is acomplex interplay between genes and the environment at work, andthat no single factor may be responsible. The disease course varieswidely among patients, and the move towards individualisedtreatment is a positive development in the treatment of this complexand debilitating disease.The conference programme was divided into three main plenarysessions: Pathogenesis and basic research, Clinical approachto MS, and Therapeutic management. As well as these sessions,the delegates took part in a rotation of interactive workshops, anda round table discussion.

Highlights of the meeting

The female: male ratio of MS cases is increasing

Environmental factors may be important in the epidemiology of MS

MRI is an important tool for MS diagnosis and a key component ofMS diagnostic criteria

2

Treatment goals are evolving in MS

Tailoring treatment based on BREMS

A new goal for MS treatment has emerged: to reach no evidentdisease activity (NEDA)

Predictors of response to treatment are necessary to optimisepatient management

Non-adherence to therapy is an important issue in the field of MS

Early treatment can delay relapses, disability, and brain volumeloss in the long term

MS patients are now active players in the decision making process

Be sure to look out for future Excemed events available on thewebsite here.

Session I: New insights in MS pathogenesis

The changing epidemiology of MSPresenter: Saeed Bohlega, Department of Neurosciences, King FaisalSpecialist Hospital and Research Centre, Riyadh, Saudi Arabia

• MS is increasing in prevalence in some parts of the Middle East MSis now 2.5 times more frequent in Palestinians than Kuwaitisaccording to comparative studies of MS prevalence in the region.

• Possible explanations for this phenomenon include the increasingpopulation, thus leading to a higher number of people at risk ofdeveloping MS.

• MS prevalence is also lower in regions with wide spread helminthinfections and poor sanitation.

• Recent studies have shown an increase in the female:male ratio ofMS cases (Figure 1), 1,2 highlighting the need to focus futurestudies on lifestyle changes among women, such as smoking,obesity and birth control.

Figure 1: Increase in the female to male ratio

2,5

2

1,5

0

1 Change in female: male ratio with repeated survey in thesame location

NorwaySwedenFinlandDenmarkSardiniaSicilySe

x in

cide

nce

ratio

1950 1960 1970 1980 1990 2000Period

Increase in female ratio

0

1.0

1.5

2.0

2.5

Sex

ratio

1950-59 1960-69 1970-79 1980-89 1990-99Time period

2 Increase in female: male ratio inDenmark since 1950A. Alonso, MA Herman, Neurology, 2008

N. Koch-Henricksen, P.S. Sorensen, Journal of Neurological Sciences, 2011

Learning objectives

By attending this live educational conference learners havebeen able to:

• Describe the latest advances in MS pathogenesis

• Explain the role of genetic susceptibility and environment inMS pathogenesis

• Select the most suitable treatment on the basis of diseasephase

• Identify the main predictors of disease evolution

• Summarize how to assess non responders to treatment andhow to change therapies

The role of infections and the environmentPresenter: Orhan Aktas, Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany

Why does the immune system get activated in MS?Trying to work out what activates the immune system in MS has longbeen a burning question for researchers, but the latest researchsuggests that there is a complex interplay between genes and theenvironment at work, and that no single factor may be responsible(Figure 2).

Environmental factors may be important in the epidemiologyof MS

• Migrants who move from an area where the disease is common toan area where it is rarer show a decrease in rate of disease and viceversa, and risk is largely established during the first two decades oflife.

• One hypothesis is that MS occurs after exposure to a commoninfectious agent, with candidates including Epstein-Barr virus (EBV).

3 The risk of MS is extremely low in individuals with EBV-negativeserostatus. 4

• Vitamin D may also influence MS pathogenesis by modulating theimmune system. 5

• Other non-genetic risk factors that have been identified includesmoking and obesity.

• New insights on epigenetic and epistasis have expanded knowledgeon the interactions between genes and environment in MS:

• While the functional role of identified MS risk variants is partiallyunderstood, the role of genetic factors in influencing the clinicalphenotypes of disease and response to treatment is still unclear

Genetics of MSPresenter: Filippo Martinelli Boneschi, Neurological ComplexDisorders, Department of Neuro-rehabilitation, INSPE ScientificInstitute San Raffaele, Milan, Italy

Genetics loads the gun and environment pulls the triggerDr. Francis Collins[ ]

Pharmacogenomics in multiple sclerosis: Getting the right medicine to the patientManuel Comabella 2008[ ]

3

Genes involved in the pathogenesis of MS were first identified in 2007from genome-wide association studies (GWAS). 6 Since then,research has gathered pace; as well as the genes related to immunesystem pathways which are known to drive MS, 7 more than ahundred risk variants for MS have been identified outside the HLAregion, and other low frequency and rare variants are expected to bediscovered in the future. 8

There are now 110 established multiple sclerosis risk variants outsidethe HLA region, but there are other low frequency and rare variants todiscover.• Non genetic risk factors for MS include vitamin D levels, smoking,

obesity and EBV infection.• There are other mechanisms which could explain the influence of

genetics on susceptibility to the disease (epigenetics, interactionbetween genetic and non-genetic factors).

• The functional role of identified MS risk variants is only partiallyunderstood.

• The role of genetic factors in influencing the clinical phenotypes ofdisease and response to treatment is still unclear.

Deciphering MS pathogenesis: the role of MRIPresenter: Maria Assunta Rocca, Neuroimaging Research Unit,Institute of Experimental Neurology, Division of Neuroscience, SanRaffaele Scientific Institute, Vita-Salute San Raffaele University, Milan,Italy

MRI: an important tool for MS diagnosis and a key componentof MS diagnostic criteria• MRI studies have given us new insights into the pathogenesis of MS

and factors associated with disease progression• MRI makes it possible to see dissemination in space (DIS) and time

(DIT) and to identify the neuroradiological red flags typical of otherconditions that may resemble MS in the clinic.

• Advanced MRI techniques can now identify lesions in brain regionsnot previously thought to be involved in the MS pathogenic process,such as normal appearing white and grey matter and cortical areas,adding more insights into MS pathogenesis (Figure 3).

• Leukocortical (type I) and subpial (III-IV) cortical lesions arepotential cortical biomarkers of cognitive and neurologicdisability 9

Results from this approach contribute to firmly establishthat genes and pathways involved in the immuneresponse are the major drivers of MS riskLeena Peltonen

[ ]

Figure 2: The interplay of genes and environment in MS

Multiple Sclerosis - A complex disease

Genes Environmentalfactors

Immune systemHLA-DRB1, HLA-DQB1,IL-2R, IL-7R ....(>140 SNPs)

Figure 3: Cortical lesions in MS

EDSSType I CLs: b=0.449 (p=0.02)Type III-IV CLs: b=0.670 (p=0.0001)

Cognitive performanceType I CLs: 6/11 variables (55%)Type III-IV CLs: 4/11 variables (36%)

The role of neurophysiology Presenter: Letizia Leocani, Institute of Experimental Neurology,University Vita-Salute IRCCS, San Raffaele Hospital, Milan, Italy

• MS-related damage is caused by segmental demyelination andaxonal degeneration:

• This can be measured and monitored by conduction velocity andamplitude, respectively.

• Delayed latency is most often detectable in asymptomaticpatients and predicts future axonal loss.

• Reduced amplitude is a sign of clinical impairment and becomespermanent when axonal loss occurs.

• Studies on optimising the use of neurophysiological techniques,particularly evoked potentials (EPs), show promise for identificationof patients who are more likely to develop future disability and whoneed intensive monitoring and treatment.

• Visual evoked potentials (VEPs) are usually absent inneuromyelitis optica (NMO)

• VEPs are less sensitive as an indicator in clinical isolatedsyndrome (CIS), but subclinical motor evoked potential (MEP)

4

abnormalities may positively predict future motor functioninvolvement.

• In fact, data suggest that MEPs may predict disability at 2 yearsin relapsing-remitting MS (RRMS) with 80% accuracy.

• Optic coherence tomography (OCT) has also emerged as areliable tool for diagnosis and monitoring of axonal loss after anepisode of optic neuritis (Figure 4). 10

Table 1: Comparing clinical utility of EPs in MS

DIAGNOSIS

• Detection of clinically silent lesions (anywhere in CNS)SCARCE

• Indication on underlying pathology (>>demyelination,<axonal damage/block) VERY GOOD

MONITORING (e.g. assessing treatment efficacy)

• Disease activity (lesions anywhere in CNS) SCARCE

• Relapse confirmation (vague symptoms) GOOD

• Disease progression (clinically relevant pathways) GOOD

• Functional improvement (clinically relevant pathways) GOOD

• Prediction of future disability progression (?)

Evolving Goals

Clinical disease:Progressionand relapses

MRI

CognitiveFunction/Qol

Reduce disease burden

(prognostic biomarkers)

Slow disabilityprogression

Suppressrelapses

Stopprogression

End relapses

Traditional Measures

Stop MRIprogression

Haltdiseaseactivityand

reducedisability

ImproveFunction/Qol

Patientwell-being

Evolving Treatment Goals

Session II: Clinical approaches to MS

TheMS management is now comprised of disease modification,maintaining and improving physical cognitive function, andquality of life.

In the near future we should be able to produce risk forecasts onindividual patient level, incorporating not only further clinicalaspects of the disease (e.g. cognitive impairment), but also genetic,immunological, neurophysiological and radiological findings.

120 pts

Chronic ON (> 3 months)similar VEP and OCT sensitivity

Sensitivity (%

)

Recent ON (<3 months)VEPs are more sensitive vs OCT

66,761,9

4,80

90

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0VEP and OCT OCT only VEP only VEP and/or

OCT

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40

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10

0

51,9

16,79,3

77,9

VEP and OCTVEPOCT

VEPOCT

OCT only VEP only VEP and/orOCT

Di Maggio et al,ECTRIMS 2013

Figure 4: Sensitivity of OCT and VEP in chronic or acute optic neuritis 10

61,168,5

66,7

6,7

NEDA at 2 years:

IFNb-1a (SC) 27%Alemtuzumab 39%

Fold-Increase 1.4

Treatment goals are evolving in MSTrying The course of MS has changed since the advent of disease-modifying agents. These new drugs provide many benefits forpatients, including fewer and less severe relapses, better recoveryafter relapses, prevented or postponed progression of disability,reduced accumulation of disease burden or decreased brain lesionactivity, and improved quality of life, cognitive functioning or lessfatigue. This has led to evolving treatment goals, with the well-beingof the patient now an important consideration in the therapeuticcontract:

Prognosis from natural historyPresenter: Roberto Bergamaschi, National Neurological Institute C.Mondino, Pavia, Italy

Tailoring treatment based on BREMS• There are several clinical factors that may help define MS prognosis

from natural history, particularly male gender, 11 and an older ageof onset of the relapsing-remitting phase of the disease. 12

• The Bayesian Risk Estimate for Multiple Sclerosis (BREMS) wasdiscussed as an important tool for predicting secondary progressionand to predict poor outcomes at an early stage, particularly whenassessing and comparing the effects of disease-modifying drugs. 13

• BREMS is based on clinical factors including gender, pure motoronset, sphincter involvement and number of motor relapses. TheBREMS might help tailor treatments for individuals based on thepresence or absence of negative prognostic factors.

Defining Breakthrough Disease Activity: Targeting Disease-Free StatusPresenter: Robert J. Fox, Mellen Center for MS, Cleveland Clinic,Cleveland, USA

In the last few years, a new goal for MS treatment hasemerged: to reach no evident disease activity (NEDA)• NEDA was first reported as a concept in 2009 14 and since then a

plethora of clinical trials have demonstrated the effectiveness ofdisease-modifying drugs according to this endpoint, which includesmeasures of:

• Number of clinical relapses

5

• MRI activity • Disability progression.

• Up to 40% of patients achieve NEDA in 2 years with currently-available drugs, but disability progression may be confounded byprevious injury (Figure 5) 15

• Treating to target requires individualised planning of treatments andassessment for each patient, taking into account severity, recoveryfrom relapses and lesion characteristics:

• Unresolved issues in individualising treatment include optimaldefinition of NEDA and breakthrough disease, incompleteassessment, and integration of NEDA with treatment risks.

How approaches to MS treatment have changed over theyears:

• Pre-1990s: “There’s nothing we can do”

• 1990s: There are treatments that will help some

• 2000s: If one treatment doesn’t seem to work, then change toa different one

• 2014: We’re aiming for no evident disease activity

Evolving Paradigm: Individualized Treatment Based on Projected Disease Course

Ongoing assessment

Stable on treatment?

Discuss therapy options with patient /

Choose therapy

Therapy Choice:• Therapy choice tailored to individual patient profile,

including MS prognosis and consideration of thecontext 0f MS disease progression when evaluatingrisk of treatmentno

yes

Gd=gadolinium; NAbs=neutralizing antibodies 10

Define the individual MSpatient profile

The Individual MS Patient:• MS prognosis• Patient preferences• Treatment history• Potential to remain adherent

• Biomarkers of reduceddrug activity and/orsafety– NAbs

• Tolerability

• Safety event

• Adherence

• Clinical– Relapse– Disability progression

• MRI– T2 lesions– T1 Gd-enhancing

lesions

Ongoing Assessment:

Figure 5: NEDA status in the CARE-MS-I study 15

Patie

nts

with

out A

ctiv

ity (%

)

SC IFNB-1aAlem 12 mg/ d

Predictivity of treatment responsePresenter: Mar Tintorè, Multiple Sclerosis Centre of Catalonia(Cemcat), Neurology-Neuroimmunology Department, Vall d’HebronUniversity Hospital, Barcelona, Spain

Predictors of response to treatment are necessary tooptimise patient management• Response to treatment is highly heterogeneous among MS patients

and therefore predictors of response to treatment are needed tooptimise patient management.

• Can we identify subgroups of patients who show different treatmenteffects? Clinical, MRI and biological parameters can all define thepredictivity of response to treatment.

• A later age at onset, a lower disability and a lower number of GADlesions at baseline MRI were predictors of treatment efficacy,

• 16 – BUT it is not clear whether these parameters are reallypredictors of treatment response or prognostic factors.

• Overall, clinical parameters show a low sensitivity in defining theprognosis.

• The risk of disability is greater in patients with increased MRIactivity. 17, 18

• Brain atrophy measurement is not always a reliable measure,due to technical difficulties and bias during the acquisition anddata analysis phases. 19

• Clinical evaluation and MRI studies together could be more useful indefining the prognosis (Figure 6).

How to keep patients on treatment Presenter: Carlo Pozzilli, Department of Neurology and Psychiatry,“La Sapienza” University of Rome, Rome, Italy

Non-adherence to therapy is an important issue in the fieldof MS• Patients don’t always take their medication because treatment

regimens may be complex, side effects can be intolerable, orpatients fail to understand the need for the medication.

• One in three MS patients discontinues interferon beta (IFNB)treatment within 3–5 years, 21 with 10–20% discontinuing withinthe first 3–6 months 22

6

• In comparison, drop-out rates in clinical trials are less frequent(8 14%; 2 3-year data)

• Early treatment is important to reduce inflammation and preventdisability and disease progression.

• To be effective, a treatment should be administered in the rightway and at the right dosage.

• It is important to share decisions about treatment with patientsand relatives.

• Symptoms should be managed as soon as they are identifiedbecause they may negatively impact on adherence to treatment.

Workshops

Throughout the meeting, six interactive workshop sessions wereavailable in rotation, so that participants were able to attend all ofthem, with the chance to share opinions and understanding of thesedifferent MS related topics:

Treatment initiation and therapeutic contractLed by: Carlo Pozzilli, Department of Neurology and Psychiatry,

“La Sapienza” University of Rome. Rome, Italy and Aksel Siva, Department of Neurology, Istanbul University,

Istanbul, TurkeyManagement of MS has been significantly improved by more recentlydeveloped second-line treatments, which include monoclonalantibodies and new oral agents, which show greater efficacy and

Successful long-term management of MS

• Patient selection for therapy: disease stage and course timing

• Patient education: realistic expectations (must believe thattherapies can make a difference)

• Reinforcing goals: perception of neurologist as supportive oftherapy

• Managing and explaining side effects

• Support through therapy initiation

• Available specialised support and advice

Figure 6: A monitoring algorithm for assessment of clinical response 20

Modified Rio Score=0No relapses and no

substantial new T2 activity*

Modified Rio Score=11 relapse and no relapses

and substantial new T2 activity*

Modified Rio Score=2 –3>1 relapse or 1 relapse andsubstantial new T2 activity*

No relapses and <2 new T2 lesions

≥1 relapse 02 ≥2 new T2 lesions

Responders

Nonresponders

1 year 1.5 years Follow-up

IFNbStart

Modified Rio Score

Reassessmentif Modified

Rio Score=1

* Substantial new T2 activity is defined as >4–5 new T2 lesions in 1 year of treatment, or >1–2 new T2 lesions if the reference MRI scan to assess new T2 lesion formation is obtained at least 6 months after initiating therapy.

Sormani MP, De Stefano N. Nat Rev Neurol. 2013;9:504-512; Sormani MP et al. Mult Scler. 2013;19:605-612;Freedman MS et al. Can J Neurol. Sci. 2013;40:307-323

probably better patient compliance compared with the injectables, butwhich may also carry novel safety and tolerability concerns. Newdrugs for MS need to be placed within this evolving marketplace,where ease of delivery together with efficacy and side effects needs tobe balanced against the known issues but also the known long-termsafety of standard injectables.

How to manage response to first-line therapiesLed by: Orhan Aktas, Department of Neurology, Heinrich-Heine-

University, Düsseldorf, Germany and Gilles Edan, Centre Hospitalier, Universitaire de Rennes,

Rennes, FranceThe workshop looked at aspects of first-line therapy for MS, includingindications for switching from one therapy to another. Theinvestigation of response to treatment should be carefully investigatedand non-responders clearly defined. Both clinical evaluation and MRIstudies should help neurologists make the right decision. Adherenceto treatment may profoundly influence the response to treatment andshould be assessed during the patient follow-up.

Therapeutic optionsLed by: Giancarlo Comi, Department of Neurology, Institute of

Experimental Neurology, Vita-Salute San RaffaeleUniversity, Milan, Italy

and Peter Rieckmann, Bamberg Hospital and University ofErlange, Bamberg, Germany

The experts looked at disease-modifying drugs old and new,illustrated with four clinical case vignettes to define scenarios in whichtherapeutic options are key questions at patient’s consultation,including Initial diagnosis, Discomfort with injections, Plannedpregnancy, and Breakthrough disease.

Role of MRI in monitoring treatmentLed by: Nicola De Stefano, Neurology and Neurometabolic Unit,

Department of Neurological and Behavioral Sciences,University of Siena, Siena, Italy

and Maria Assunta Rocca, Neuroimaging Research Unit,Institute of Experimental Neurology, Division ofNeuroscience, San Raffaele Scientific Institute, Vita-SaluteSan Raffaele University, Milan, Italy

The workshop looked at how MRI techniques have provided usefulmarkers to monitor treatment effect in MS clinical trials. Evaluation ofpotential new therapies for MS has been facilitated by the use ofstandardised MRI protocols in phase II and III trials, and thecombination of clinical measures of disease activity with imagingevidence of formation of new lesions seen with MRI may have a role inidentifying non-responders to first-line treatments. The routine use of MRI is therefore recommended to monitor diseaseactivity during treatment, both to facilitate early identification of thosepatients who could possibly benefit from a different therapeuticapproach, and to identify signs of side effects. It is likely that in thenear future, novel MR metrics to assess treatment response in clinicaltrials and in daily-life practice will be proposed, validated and used.

Genes and environmentLed by: Gilles Edan, Centre Hospitalier, Universitaire de Rennes,

Rennes, France and Filippo Martinelli Boneschi, S Centre, Division of

Neuroscience, Institute of Experimental Neurology (INSPE),Scientific Institute San Raffaele, Milan, Italy

The workshop reviewed the main findings on genetic susceptibilityand the role of environmental factors in disease onset andprogression. Evidence was presented that, while MS is a multifactorialdisease involving both genetic and environmental factors, geneticfactors outweigh environmental factors in disease pathogenesis. Thegroups looked at challenging areas likely to occur in the near future,

7

including interpretation of genome-wide association studies and thecontribution of genetics to clinical practice.

Patient engagement in the decision-making processLed by: Dawn Langdon, Department of Psychology, Royal Holloway

University of London, London, UK and Alessandra Solari, Unit of Neuroepidemiology, Foundation

IRCCS, Neurological Institute C. Besta, Milan, ItalyDawn Langdon and Alessandra Solari explored the role of the patientin MS management today, emphasising the importance of nurturingthe relationship between the patient and healthcare professionals(HCPs) for optimal management and outcomes. It is now recognisedthat patient engagement, and their involvement in decision making, isa key aspect of this partnership. MS poses certain challenges toengagement, with cognition, depression, fatigue and other symptomsrequiring skilful communication and understanding by HCPs tomaintain and support their engagement in decision making.

Roundtable discussion session

Patients’ perception and patient reported outcomes(PROs)

Introduced by Bassem Yamout, Multiple Sclerosis Center, ClinicalResearch, American University of Beirut Medical Center, Beirut,LebanonChairs: D. Bates (UK) and B. Yamout (Lebanon)

MS patients are now active players in the decision-making process:After the presentation by Bassem Yamout, key opinion leadersdiscussed emerging aspects in the management of MS during theroundtable:• Patients are having ever greater input into the decision making

process surrounding their disease management. Their perceptionabout the disease and the treatment response is a key componentof MS management. However, patients often don‘t understand therelevance of avoiding one relapse every 4 years, and doctors andpatients don’t always agree on what is important about theirdisease. Patients’ quality of life (QoL) is much more important tothem than clinicians have realised: 23

•• This cross-sectional study demonstrates that patients with MS

are less concerned than their clinicians about physical disabilityin their illness and more concerned about their quality of life.

• Significant predictors of quality of life in patients with MS includedepression, social support, religious beliefs, education andstandard of living. 24

0.1 1010.01 100

Odds ratio (95% CI)Clinicians(n=25)

Patients(n=42

Mental health 25 7

Physical function 22 20

Physical role limitation 17 21

Emotional role limitation 16 2

General health 14 4

Social function 14 13

Vitality 13 3

Bodily pain 5 4

More importantto patients

More importantto clinicians

• Patient education can reduce disease progression: 25

• The relapse rate was lower by 0.8 in educated patients through 2years of monitoring

• Traditionally, outcome scales based on the clinical perspective havebeen applied both in clinical practice and in the scientific setting, butcurrent outcome measurements do not allow the full benefit of newdrugs to be assessed.

• In order to make the role of patients more relevant, innovative,patient-centered outcome measures that go beyond relapsereduction and EDSS stabilization have been developed. The “MS inthe 21st Century” initiative 26 defines how multiple sclerosis (MS)treatment and standards of care should look today

• The panel of experts concluded that new endpoints in clinical trialsshould include patient-reported measures as well as functionalassessments and biomarkers. Incorporating PROs in patientmanagement will likely increase patient engagement andadherence to treatment.

• Debate continues on which PROS should be chosen for individualpatients, and how this new approach can be translated into routineclinical practice

• The need to include these measures as key endpoints in futureclinical trials was also highlighted during the roundtablediscussions.

• However, it was agreed that incorporating patient-reported outcomemeasures in patient follow-up is likely to increase patientengagement and adherence to treatment. Shared decision makingbetween patients with MS and their doctors is evolving.

Session III: Therapeutic management

This year, the thorny issue of when to initiate treatment was discussedin a workshop and also the topic of a lively debate. Giancarlo Comi(Vita-Salute San Raffaele University, Milan, Italy) urged those treatingMS patients to start treating immediately, while Aksel Siva (IstanbulUniversity, Istanbul, Turkey) made a compelling case to “wait andsee”.

Early treatment can delay relapses, disability, and brainvolume loss in the long term

2,7

3,2

rela

pse

rate

5

4

3

2

1

0

3,1

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Relapses before Relapses after

intervention group control group

The dilemma:

• giving “a long term treatment” to an individual who doesn’trequire it, or to whom such a treatment may worsen thedisease, is causing harm!

• withholding “a beneficial treatment” from an individual whorequires it, or to whom such a treatment may improve thedisease’s outcome, is also causing harm!

8

The case for early treatment is based on there being a “window ofopportunity” to prevent irreversible axonal damage. Early treatmentwill prevent the irreversible damage to the nervous sytem whichoccurs very early and is (at least partially) related to inflammation inMS. It is also well known that the early course of the diseaseinfluences long-term outcomes. Immunomodulatory treatments canreduce the inflammation that predominates in the early phases of thedisease, and patients with greater clinical activity during their firstyear of treatment were at increased risk of continuing with relapsesand/or sustained disability in the next 2 years. 27 Data from severalclinical trials show that treatments for MS are more effective in therelapsing remitting phase than in progressive phase of disease: 28

But… Not all patients with RIS or CIS will develop MSThe arguments to wait before treating focused on the fact that not

all patients are biologically equal and will vary in their responses andoutcomes. Therefore there is a case to be more selective beforemaking “life-time” treatment decisions.While neuroradiological examinations are now detecting increasednumbers of patients with radiologically isolated syndrome (RIS), manywill not go on to develop MS. 29 Is RIS the earliest stage of MS andshould individuals with RIS be considered for early treatment as well?

30 Similarly, not all patients with clinically-isolated syndromes (CIS)go on to develop MS, 31 and not all untreated CIS patients developMS or MS-related disability. 32 These studies provide evidence thata “benign MS” exists, and supports the strategy of wait and see,particularly in patients thought to be at lower risk of developing MS.

Assessing treatment failure

Also debating were Nicola De Stefano (Neurology andNeurometabolic Unit, Department of Neurological and BehavioralSciences, University of Siena, Siena, Italy) and Vittorio Martinelli(Neurology Unit, San Raffaele Scientific Institute, Vita-Salute SanRaffaele University, Milan, Italy), who explored MRI versus clinicalresponse to assess treatment failure. Nicola De Stefano highlighted the importance of MRI assessmentof lesions and brain atrophy to predict prognosis, as well as its key rolein the recently-developed Rio score to predict response to treatment.

33 Even when clinical signs are absent, MRI can detect braindamage. 34

The dilemma:

…if an area of the CNS is lesioned, another area can take overits functions…

There is adaptive reorganisation!

Figure 2 Therapy in MS: disease stage and therapeutic effects ofinterferon -b (IFNb)

Axonal loss

Disabilitythreshold

Disease stage

Potential therapeuticbenefit of IFNb

Mono-symptomaticMS RR to SP

RRMSBetaseron

AvonexRebif

EU-SPMSBetaferon Rebif SP

Avonex SPNA-SPMSBetaseron

RRMS SPMS Time

Vittorio Martinelli however argued that MRI studies are not fullyobjective and vary with technique, while clinical evaluation remainsthe only way of diagnosing and monitoring the many different forms ofMS and CIS. As discussed in one of the workshops at the meeting, clinicalevaluation and MRI studies together should help neurologists make

9

the right decision. Indeed, the modified Rio score is based on acombination of the two parameters, incorporating scoring for bothclinical relapses and new T2-hyperintense MRI lesions after 1 year oftreatment. 20

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