greater expectations: the future hopes of people with ... · adults from vitamin d deficiencies...

Greater Expectations: the Future Hopes of People with Multiple SclerosisThis report presents the key findings of a new international survey of the treatment related beliefs, priorities and expectations of people living with multiple sclerosis (the TaP-MS survey) and, against the background of the available literature, discusses their implications for health and social care policy makers. It concludes that increased access to more effective treatments, enhanced rehabilitative care and better social and economic support will curb disease progression, prevent disabilities and improve the quality of life of people living with all forms of MS, together with that of their partners, children and other family members

Summary• Multiplesclerosis (MS) is today themostprevalent formofseriousnon-traumaticdisability inyoungadults

inregionslikeNorthAmericaandEurope.Itdirectlyaffectsapproaching2.5millionpeopleworld-wide.MStypically starts asadiseasewhichcyclesbetweensymptomatic illnessand remission. In time it becomesprogressivewithoutremissions.

• AboutathirdofpeoplediagnosedwithMSdonotbecomeseverelyimpaired.Butwithouteffectivedisabilitydelayingtreatmentmostotherswillbecomewheelchairdependentwithin15-20years.PeoplelivingwithMS(PLwMS)experiencefluctuatingsymptoms,rangingfrompainandfatiguethroughtovisualdifficulties,bladdercontrolproblemsandlostcognitiveabilities.

• Treatments forMScan relieve immediatedistressorchange itsnaturalcourse.Diseaseprogression is therootdriverofMSrelatedsymptomsandharm.Diseasemodifyingtreatments(DMTs)thatslowtheevolutionofrelapsingremittingMS(RRMS)wereinitiallylicensedintheearly1990s.Anincreasedrangeofmedicinesforlimitingdiseaseprogressionisnowavailable.Allcarryrisksofsideeffectsthatmustbebalancedagainsttheirlikelybenefits.

• This report assesses evidence relating toMSprevention and care and analyses the findings theTaP-MSsurveyof the treatment relatedexpectationsandprioritiesofPLwMS. In thesummerof2017 researchersgatheredresponsesfrom1040individualsinAustralia,Canada,France,Germany,Italy,Spain,Sweden,theUKandtheUS.

• Constantlyvarying–andconsequentlyhighlyintrusive–symptomsmakeMSmoredifficulttolivewiththan‘static’formsofdisability.TheTaP-MSfindingsunderlinethesignificanceoffatiguecausedbyMSandtheimportancePLwMSattachtoreducingrelapserates,avoidingwheelchairdependenceandprotectingtheircognitiveabilities.Thehighestprioritytreatmentexpectationisslowingorstoppingdiseaseprogression,whichisthedriverofallMSsymptoms.

• OtherkeyexpectationshighlightedbytheTaP-MSsurveyarewantingmorevitalityandenergyandbeingabletomanagebladderandbowelcontrolproblemsmoreeffectively.Symptomslikeincontinence,pain,anxietyorvisualdifficultiesallrequireeffectivemanagement.FurthercareadvanceswillfreemorepeoplewithMStoachievetheirmostimportantgoalsinlife.

• Individuals livingwithMSwant freedom from thediseaseand its symptoms.Until effectivecuresbecomeavailableoptimisingMSoutcomeswilloftenrequireindividuallytailored,holistic,combinationsofpharmaceutical,psychological,socialandotherformsofcareandsupport.

• Noonewantssideeffectsfromanymedicaltreatment.Buttheycannotalwaysbeavoided.TheTaP-MS surveyfindingsindicatethatsideeffectandtreatmentharmavoidanceisformanyPLwMSa‘secondorder’prioritycomparedtocurbingdiseaseprogression.TheavailableevidenceindicatesthatmostPLwMSwillknowinglyacceptadegreeoftherapeuticriskinreturnforanimprovedchanceofstoppingdiseaseprogression.

Embargo: not for quotation before 00:01 hours Friday 8 December 2017.

2 GreaterExpectations

• TheTaP-MSresultsalsoindicatethat‘practicality’linkedconsiderationslikewhetherornotatherapyhastobeinjectedarealowerorderpriorityformostPLwMSthaneitherslowingdiseaseprogressionorsideeffectavoidance.Nevertheless, to theextent that convenience inuseaffectsmedicine taking, adherence relatedissuesmustbewellmanaged.

• SeventypercentofTaP-MSparticipantsagreedwiththestatement‘I expect that MS will be effectively curable in 20 years’.Over80percentofAmericansagreed.ButamongstUKrespondentsjust49percentagreed.Thiscouldreflectvaryingnationalapproachestohealthcarecostcontrolandadoptinginnovativetherapies.Lowexpectationsoftreatmentadvancesmaynegatively impactonlevelsofhopeandoptimismandimpaircopingabilities.

• ThereisevidenceofmajorvariationsinthestandardsofcareavailabletoMSpatientslivinginneighbouringcountries.ThesecanaffectbothearlydiagnosisratesandaccesstoDMTs.TheTaP-MSsurveyfoundthatreportedDMTuseamongst respondentswithRRMSwas justover70percent in theUKand theUS,ascomparedto83percentfortherestofthesamplecombined.(Thesurveydidnotdifferentiatebetweenolderandnewerdiseasemodifyingmedicineuse.)

• Bycontrast,90-95percentofAmericanswhosaidtheyhaveaprogressiveformofMSreportedtakingaDMT.This compares to 25-33per cent of Swedish respondents. Such figures suggest international differences inmedicalpracticeandthelevelofunderstandingpeopleindifferentcountrieshaveoftheMStreatmentstheyaretaking.Greater‘pharmaceuticalliteracy’isneededtooptimisethebenefitsrelativetothecostsofmedicinesuse.

Conclusions and Recommendations1. ImprovingthepreventionandtreatmentofMSisanimportanthealthobjective.ReducingtheburdensMS

imposeson individuals, familiesandcommunitieswill requireongoing investment inpublicandprivateresearchanduniversal access tohighqualityhealthandsocial care.Governmentsshouldcommit topursuingthesegoalsinwaysthatpermitmonitoring.

2. CarefundersshouldprovideadequatefacilitiesfortheearlyidentificationofMSandmonitoringtreatmentoutcomes.ThisincludesassuringgoodaccesstoMRIscanningandestablishingandmaintaininghighqualitydiseaseregistries.

3. Moreevidenceof the long termbenefitsandcostsofMSDMTusewill emerge.But there isalreadysufficientdatatosupporttheconclusionthatpeoplewithMSoughttobegivenaccessthetreatmentsthattheyandtheirneurologistsjudgewillofferthemthemaximumpossiblenetbenefit.

4. PLwMS and organisations representing them have a vital part to play in raisingMS care standards,preventingaccess inequalitiesandcontributingtopharmaceutical literacy.Carequalitydatashouldbegatheredandcommunicatedinwaysthatpermitmorerobustintra-andinter-nationalcomparisonsandinformhealthpolicydebateandindividualchoice.

5. Costconcernsneednotdelaythetimelyprovisionofeffectivecare.EconomistsandothersinvolvedinevaluatingtherapeuticadvancesoughttoensurethatthebenefitsofrelievingsymptomslikefatigueanddepressionandthesocietalcostsassociatedwithMSarecomprehensivelyassessed.

6. Medical,nursing,pharmaceutical,psychologicalandrehabilitativecareshouldbeprovidedinwaysthatmaximisetheirsynergisticvalueandofferpatientsanauditablerecordofcoherenttreatmentandsupport.

7. Nationalstandardsofsocialandeconomicprovisionforoffsettingtheimpactsofdisabilitiesonindividuals,familiesandcommunitiesshouldbeinplacethroughoutEuropeandsimilarregions.

8. ProgrammesaimedatraisingpublicawarenessofMSandthevalueofearlydiagnosisandtreatmentareneededtoimproveoutcomes.

9. PreventionprogrammesshouldhighlighttherolesofsmokingandadolescentobesityinMS,andofthelinksbetweenlowvitaminDlevelsandthedisease.Policiestoprotectchildren,adolescentsandyoungadultsfromvitaminDdeficienciesshouldberobustlyevaluated.

10. Governments and pharmaceutical companies ought to consider evidence linking Epstein Barr VirusinfectiontoMSandotherillnesses,andifnecessaryinvestjointlyinvaccinedevelopmentoralternativepublicprotectionprogrammes.

GreaterExpectations 3

IntroductionTheidentificationofmultiplesclerosis(MS)asadiscretediseaseisnormallyattributedtothepioneeringnineteenthcenturyFrenchneurologist,Jean-MartinCharcot.SomedescriptionsofwhatistodaycalledMSdatebacktowellbefore his time.But itwasCharcotwho in the1860scharacterised the symptoms of multiple sclerosis andlinkedhisclinicalobservationstopathologicalchangesseeninthebrainsandspinalcordsofpatientsaftertheirdeaths(Kumaretal,2011).

ThetermCharcot’striad(whichreferstoacombinationof ‘intentional tremor1’, abnormal eyemovements andstaccatospeech)isstillsometimesusedtodayinrelationtoMS,albeittheconditionisnowknowntocausemanyadditional forms of difficulty, disability and distress.Becauseitcanimpactonvirtuallyanypartofthenervoussystemwithvaryingdegreesofseverity,MS isoftenapotentcauseofuncertainty.Thisissonotonlyforthoseindividualswhoselivesaredirectlyaffectedbyit,butfordoctors and others seeking to diagnose the conditionandpredictitscourse.

In the150yearsor sosince theEnglish termmultiplesclerosiswasderivedfromCharcot’soriginalsclerose en plaques(nervoussystemlesionsandpatchesofdamage) much success has been achieved in discovering thecauses of and developing at least partially effectivetreatmentsformanycommonlyoccurringinfectionsandnon-communicabledisorders.Thelatterincludevasculardiseasessuchasatheromaanditsacuteconsequences;cancers like,forexample, leukaemiasandlymphomas;andmentalillnessessuchasdepression.

Even in the context of neurological diseases like thedementias(AloisAlzheimerfirstreportedontheconditionnamedafterhimin1906)therewaslimitedtherapeuticprogressinthelatterhalfofthetwentiethcentury.Butinthecaseofmultiplesclerosisprogresswasuntilrecentlyslow.Despiteitsemergenceasthemajorcauseofnon-traumaticmajorphysicaldisabilityamongstyoungadults–andparticularlyyoungwomen–agedupto50yearsinregionslikeEuropeandNorthAmericaitscausalityhasremainedunknownand itwasnotuntil the1990sthatthefirst(interferonbased)diseasemodifyingtreatments(DMTs)capableofslowingtheprogressionofthemostcommonformofMSbecameavailable.

Before then care standards were often poor. BecausethosedisabledbyMSwere–despitepalliativecareoptions– often regarded as medically untreatable they weresometimesadmittedto,andneglectedin,longtermcaresettingstypicallyusedto‘house’mucholderindividuals.

Even in the most affluent twentieth century societiesmuchoftheeconomicburdenimposedbyMShasfallen

1 Intentional(orcerebellar)tremorintensifiesasindividualsdeliberatelyreachoutforobjectstheysee.

on people livingwith the condition (PLwMS) and theirfamilies,ratherthanbeingmorefairlysharedwithhealthandsocialserviceprovidersandtheirwidercommunities.However,sincethestartofthiscenturytheintroductionof an expanding range of DMTs for multiple sclerosishashelpedtogeneraterisingexpectationsthatPLwMSshouldbeabletoenjoyamoresatisfactoryqualityoflifethaninthepast.Newhopesareemergingthatinfuturefunctionalcuresand/oreffectivepreventiveinterventionswillbedevelopedforallformsofMS.Suchtrendscouldin turn generate further changes in public and patientattitudesandservicestandards.

Thediagnostic techniquesandMStherapiespresentlyavailableareof varyingutility.Medicines forpreventingMS-relateddisabilitiescanonoccasionscauseserioussideeffects.Theiruseisalsoincreasinghealthcarecosts,particularlyinrelationtoearlystagediseasetreatmentsdelivered in theoutpatient setting (Kobelt et al, 2017).Butagainstthistheyofferthepromiseofareducedrateofdiseaseprogression(Frohmanetal,2006;Giovannonietal,2015)andlower–oratleastdelayed–laterstagetreatmentandsupportcosts.

Thefactthatoptimisingpharmaceuticalcareforpeoplewith MS requires achieving an agreed balance ofpossibleharmagainstlikelybenefitisalsodrivingcloserpatientinvolvementintherapeuticdecisionmaking.Thisshouldhelppromotefurther improvementsinthewaysthatbothpatientsandhealthprofessionalsaddressandcopewiththechallengesMSpresents.

Againstthisbackground,thisUCLSchoolofPharmacyreport offers an outline of what is known about thenatureandconsequencesofmultiple sclerosisandananalysisoftheissuesfacingwomenandmenlivingwithit. Itpresentsthefindingsofanewinternationalsurveyof the treatment beliefs, priorities and expectations ofpeoplelivingwiththedisease(theTaP-MSsurvey)anddiscusses their implications for health and social caredecisionmakers.Topicsexploredrangefromtheextenttowhichhopesoffuturefunctional‘cures’–almost70per cent of the TaP-MS respondents agreed with thestatement ‘I expect that MS will be effectively curable within 20 years’–arecreatingnewpatternsofservicedemand, throughtowhichsymptomsthose livingwiththeconditionmostwant tobealleviatedand the riskstheyarepreparedtoacceptinreturnforslowerdiseaseprogression.

ForuptoathirdofthepeoplewhoreceiveadiagnosisofMShavingthediseaseislikelytoprovetobearelativelybenign – if at times worrying and discomforting –experience.Yetforothersitisahighlyintrusiveconditionthat,evenifitsimpactsonlifeexpectancyarerelativelymodest,causesphysicalandmentalsufferinginuniquelydistressingwaysandoftenendsinprofounddisability.


MS in total affects approaching 2.5 million peopleacross the world2 (MSIF, 2013), together with asignificantly greater number of carers and other familymembers whose lives are impacted by it. Seen fromthis standpoint, investing in developing and assuringappropriate access to better treatments for multiplesclerosis isarguablyoneofhumanity’smore importantgoalsatthispointinhistory.Scientificunderstandingofthe immune system and other factors influencing thedevelopmentoftheconditionisnowatastageinwhichfurtherfundamentaltreatmentadvancesareincreasinglylikely to emerge. Achieving such progress will requirecontinuinginvestmentsofmoneyandhumanresources.But the longer termbenefits itwillbringwillbeofverymuchgreater–insomerespectsincalculable–value.

Multiple Sclerosis – a Progressive, Inflammatory and Demyelinating DiseaseMS is today regarded as a progressive, autoimmune/immune response modulated, inflammatory condition.Itinvolvesavarietyofbiologicalmechanisms,includingimmune system T cells attacking the myelin sheathsprotecting central nervous system neurones. This,together with other inflammatory processes involving‘scavenger’ cells such as macrophages/microglia(Luo et al, 2017) harms the thread-like axons whichpass impulsesfromonenervecell toanother.Affectedneurones eventually die. As the disease progressesoligodendrocytes responsible for generating myelinin the central nervous system are also killed, and thebrains and spinal columns of PLwMS incur increasingdamage.At first theremaybe sufficient reservebrain/nervous system capacity to compensate for suchharm.However,asneuronallossesbuilduppermanentdisabilitiesbecomemanifest.

For thepurposesof this analysis fourmain categoriesof MS exist, together with clinically or radiologically3isolated syndromes. The latter terms refer to theconditionof individualswhoshowclinicalsignsorMRI(magneticresonanceimaging)revealedlesionslikethoseassociatedwithMS,butwhocannotbedefinitelysaidtohavethecondition.Estimatesvaryandtheaccuracyof diagnostic processes is improving. But historicallyaroundahalfthepeoplesaidtohaveclinically isolatedsyndrome(CIS)havegoneontodevelopMS.

2 Ofwhomintheorderof500,000liveinEuropeandabout400,000liveintheUSandCanada

3 MRIscanninghassincethe1980semergedasakeytechnologyforidentifyingareasofdemyelisationinthebrain,and–viatheuseofgadoliniumasacontrastagent–differentiatingbetweenlongstandinglesionsandareasofcurrentlyactivedisease.MRI‘tests’donotexposeindividualstopotentiallydamagingformsofradiation,andcanthusbeconductedasfrequentlyasclinicalneedsandhealthserviceresourcespermit.

Atconfirmedonsetaround85percentofPLwMShavethe relapsing remitting formof the disease (RRMS), inwhichepisodesofsymptomatic illnessare followedbyperiodsoffullorpartialrecovery.Butwithin10-15yearsfromtheirinitialdiagnosisabouttwothirdsofpeoplewithRRMSwill, ifnoteffectivelytreated,developsecondaryprogressive multiple sclerosis (SPMS). During thissecondstagethediseasetakesacontinuingcourseofaccumulating neuronal losswhichmayormaynot bemarkedbyperiodsof exacerbation – seeFigure1.Atanygiventimeupto60percentofthetotalpopulationlivingwithMS has the relapsing remitting form. Some25-30percentwillhaveSPMS.

Bycontrast,about15percentofpeoplewithMSareatdiagnosiscategorisedashavingtheprimaryprogressive(PPMS– circa10per cent of the total number of theinitialdiagnosistotal)orprogressiverelapsing(PRMS–about5percent)formsofthedisease.InthistypeofMS,whichonaverageisfirstidentifiedinindividualsabout10years older than those receiving an initial diagnosis ofRRMS,therearenoperiodsofrecovery.Rather,thereisacontinuing(albeitoftengradual)increaseintheseverityof the condition.Because untreatedpeople livingwithPPMShave lifeexpectancies in theorderof5-6years

Brain atrophy

Neurological reserve

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Brain atrophy is faster than usual and proceeds throughout the disease course

Neurological reserve declines

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Relapses are acute attacks of symptoms

Progressive disease starts when neurological reserve is exhausted

New lesions appear, some lead to relapses

Progressive disease is typically characterized by losing the ability to walk

Recovery from relapses is often incomplete and can lead to

stepwise disability progression

RRMS RSPMS NRSPMS

The first interferon based RRMS disease modifying treatment was licensed by the FDA in 1993. The first medicine licensed for the treatment of progressive MS was licensed in the US in the Spring of 2017. In this diagram RSPMS refers to relapsing secondary progressive multiple sclerosis and NRSPMS stands for non-relapsing secondary progressive multiple sclerosis.

Time

Figure 1. Relapsing Remitting and Secondary Progressive MS

Source:AfterGiovannonietal,2015

Note: Primary Progressive and Progressive Relapsing MS following a continuing course of functional loss without remision from the time of their initial diagnosis. It is not known whether or not this reflects differences in underlying causality.


lessthanthoseofindividualswithRRMS/SPMS(whointurncurrentlyhaveprojected lifeexpectancies thatare3-4yearslessthanthepopulationaverage)theyatanyonetimeaccountforlittlemorethanatenthofthetotalnumberofidentifiedpatients.

MS is most frequently diagnosed in individuals agedbetween20and40 years.But around10per centof‘cases’ are first identified in children and adolescentsaged16orunder(Schreiner,2015).Thereisinadditionevidence thatduring the twentiethcentury the ratioofwomen to men with diagnosed MS increased (Harboet el, 2013; Kock-Henriksen and Soelberg Sorensen,2012). In typical northern European and Americancommunities women living with MS now outnumbermenwiththeconditionbybetween2and3toone.Itsrecordedprevalenceisinhigherrisksettingsbetween2and3per1000amongstfemales,comparedtocloseto1per1000formales.

Common symptoms

Because MS exacerbations have varying impacts ondifferent parts of the nervous system the symptomsexperienced can differ on more or less a day-to-daybasis. Short term fluctuations, coupled with long termuncertaintiesabouthowandatwhatspeedtheconditionwillprogress,makelivingwithMSverydifferentfromhaving‘stable’disabilitiessuchasamissinglimbor,say,alearningdifficulty.Periodsofrecoveryarefollowedbyrelapsesandnew,onoccasionspainfulandconfidencedraining,lossesofability.ItisthereforenotsurprisingthatpeoplewithMSareataraisedriskofpsychiatricandotherco-morbiditieslikedepressionandsevereanxiety.Eveniftheyarenot–as is thecasewithcognitivedeficits–causedbyMSatthe physiological level, suchmental health problems areintimatelylinkedtoitspersonalandsocialimpacts.

Figure 2a summarises some relatively long standinginformation relating to likelihood of people with MS

experiencingitsmorecommonsymptoms(Craytonetal,2004).Theyrangefromspasticity–musclecontractionsorextensionscausedbydamage topartsof thebrainand spinal column concerned with ‘motor control’,which can cause feelings of stiffness and movementabnormalities – through to paroxysmal symptoms likesuddenstabbingsensations.Othercommonsymptomsinclude pain; loss of bladder and bowel control; andsexualproblemssuchaserectiledysfunction.

Abnormalfeelingsoffatigueareoftenexperiencedbynotonlypeoplewithneurologicaldisordersbutalsopatientslivingwithcancerorlongtermconditionslikerheumatoidarthritis and renal failure (Whitehead et al, 2016). Themechanisms involved are not fully understood. Buttheyareprobablylinkedtoimmuneresponsescoupledwith brain and spinal column changes stemming fromprolongedexposurestostressanddistress(BraleyandChervin, 2010). Such neurological phenomena canalso affect sleeping patterns and pain thresholds. Inaddition some drug treatmentsmay cause feelings offatigue,whichcanalsofollowsurgicalinterventionsandtraumaticinjury.

Incancercarethereareimportantexamplesoffatiguebeingrecognisedasamajorproblemforpatients.Butits full significance has on occasions been neglectedin the MS context. Like pain, fatigue is a subjectiveexperience that (as opposed to factors such asimpairedmusclecontrol)clinicianscannotmeasureviadirectobservation.ThismighthelpexplainwhysomemedicalapproachesfailtorecognisetheimportanceoffatiguetopeoplewithMS.Inrealityitcan–astheTaP-MSsurveyresultsdiscussedlaterinthisreportconfirm–beamajorbarriertobeingabletoenjoynormalfamily,socialandworkinglives.

Unlike difficulties like, say, needing help with dressingor having to use a wheelchair, fatigue cannot beadapted to in ways that permit a satisfactory way oflife.This isanother reasonwhy its importancemaybeunder-estimatedby traditionalmedical (and economic)assessmentsthatusestaticand,fromasocialscienceperspective, disappointingly limited sets of measuressuchastheExpandedDisabilityStatusScaleortheEQ5D–seeBox1–toquantifycomplexphenomenalikeanindividual’s‘qualityoflife’(QoL).

OtherfrequentlyencounteredMSsymptomsincludelossofvision(typicallyinoneratherthanbotheyes),speechabnormalities and swallowing problems. The availableevidence indicates that for many PLwMS becomingwheelchair dependent is the disease progression stepthey say they most fear (Isaakson, 2006; Heesen etal, 2008). The data presented in Figure 2b comparesthekeyconcernsreportedbyasampleof justover80peoplewhohadadiagnosisofMSforfiveyearsorlesswith those of a similar sample of individuals who hadlivedwithMSforfifteenyearsormore.

Figure 2a. Percentages of People with MS likely to experience commonly occurring symptoms

Source:Craytonetal,2004

Notes: The graph illustrates the higher and lower symptom prevalence rates recorded in the studies reviewed.

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Both groups rated maintaining lower limb function astheir highest priority.But amongst thosewith a longerexperienceofMStheperceivedimportanceofvisualandcognitive (thinking and memory) problems was higherthan in the more recently diagnosed group. The levelofprioritygiven tomaintainingwalkingabilitieswasbycontrastloweramongstthosewhohadlivedwithMSforfifteenormoreyears.

InthecontextofwheelchairdependenceanothergroupofresearchersshowedthatpeoplewhohadrecentlybeendiagnosedwithMStendedtoover-estimatetheir2and5yearchanceofbecomingwheelchairdependent,buttounder-estimatetheirlife-timerisks(Janssensetal,2003).Onethirdofthoserespondingtothissurveysaidthattheythoughttheir10yearprobabilityofbecomingwheelchairdependentwas50percent.Theactualfigureinuntreatedpopulations is in the order of 20-25 per cent (see, forinstance,Myhretal,2001;Weinshenkeretal,1989).

At the same the time newly diagnosed individualscontributing to Janssens et al’s research similarlyestimated their lifetime risk of becoming wheelchairdependenttobe50percent.Theobservedproportionbeforetheadventofdiseasemodifyingtreatmentswas70percent.Akeyfindingofthisstudywasthatpeoplewhoover-estimatetherateoftheirillness’sprogressionto thegreatestextentare–perhapsnotsurprisingly–thosemostlikelytoexperienceanxietyanddepression,andtohavemoreextensiveproblemsthanotherswithMSinadaptingtolivingwiththecondition.

These results highlight the importance of supportivecommunication at around the time of diagnosis – seebelow. They are also indicative of the vulnerability ofPLwMSwithregardto theuncertainprognosisof theircondition, and the limitations of both research and

therapeuticapproacheswhichplaceunduerelianceonpatientsbeingabletomakejudgementsaboutproblemstheyhavenotdirectlyexperienced.

The environmental, genetic and lifestyle linked causes of MS

ItisoutsidethescopeofthisreporttodiscussindetailthecausesofMS,whicharenot yet fullyunderstood.ButtheincidenceandprevalenceofMShavelongbeenknowntobecorrelatedwithlatitude.ThiswasfirstnotedbyresearcherssurveyingUSArmyrecruitsshortlyafterWWI(Davenport,1922).Thefurthernorthandsouthontheglobepeople live inchildhoodandearlyadulthoodthemore likely they are to contract MS. In equatorialcommunitiesMSismuchmorerarelydiagnosed4.

Such discrepancies still exist today. MS incidence inCanadais,forinstance,higherthanthatfortheUS,andwithintheUSitisonaveragetwiceashighinnorthernStates than in those located below the 37th parallel(PietrangeloandHiguera,2015).SimilargradientsexistinAustralasiaandEurope,albeitexceptionsexist.Thereis,forexample,ahighrateofMSincidenceinSardinia.This is linkedtoaspecificgeneticvariantfoundinthatisland’spopulation(O’Gormanetal,2012).

ThesignificanceofMS’sgeographicdistributionbecamebetterunderstoodtheendofthe1950swhenAchesonetal (1960)observedthat itsoccurrencewasinverselyrelated to solar radiation levels. Low levels of sunlightexposure result in below average vitaminD synthesis,added towhich vitaminD is now known to affect theexpression of some genes responsible for modulatingimmunesystemfunctioning(Aranow,2011).

ItwasalsosoonafterWWIIthatevidenceindicatingthatmultiple sclerosis is an autoimmune disease becameavailable (Hafler, 2004). Other factors associated withMS’soccurrencerangefromwhetherornotindividualscarry certain immune response modifying genes5,through to the fact that in pregnancy (during which

4 EvenallowingfordiagnosticcapacityvariationsandthefactthatintheUSblackArmyrecruitshaverelativelyhighobservedMSrisksthisislikelytobearealobservation.ItmayberelatedtoearlierexposurestoinfectiousagentssuchasEBV–seemaintext–and/orvariablessuchasdifferingmicrobialandparasiticloads.Thelattermay,forinstance,helpaccountforotherlatitudelinkedepidemiologicalphenomenalikethefactthatTBvaccinationislessefficaciousinequatorialcountriesthaninthoselocatedclosertothepoles(Rennie,2017).

5 AnassociationbetweenmultiplesclerosisandtheMajorHistocompatibilityComplex/humanleukocyteantigensystemgeneslocatedonchromosome6wasfirstmutedinthe1970s(Naitoetal,1972).Forexample,EuropeanswithwhatiscalledtheHLA-DR15haplotypehavebeenreportedtobeatsignificantlyraisedriskofthedisease,andmayalsocontractitatayoungeraverageagethanotherswithMS.Therearenowwellover100genesthoughttocontributetotheoccurrenceofMS,althoughonlyabout15percentofPLwMShaverelativeswithMS(MST,2016).EvenanidenticaltwinwhohasasiblingwithMSonlyhasa20percentchanceofalsodevelopingthecondition.SuchobservationshighlightthelikelyroleofchanceasopposedtoconsistentlysharedenvironmentalexposuresintheaetiologyofMS..

Figure 2b. Levels of concern about symptom areas and disabilities expressed by people a) with less than 5 years of living with MS and b) with more than 15 years MS experience

Source:Heesonetal,2008

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Box 1. The EDSS and the EQ5D as measures of MS

There are a variety ofmeasures used to assess theimpactsofMS.Theonemostcommonlyemployedinclinical trials is called the Expanded Disability StatusScale or EDSS (National Multiple Sclerosis Society,2017).Withanassociated instrumentcalled theFSS(FunctionalSystemsScores) itwasfirstdeveloped inthe1950sand refined in the1980s.TheEDSS isanordinalratingscale–onewhichindicatesadirection–withthepointsalongitrangingfrom1(minimallossoffunction,nodisability) throughto5 (canwalkwithoutaidorrestforabout200meters,butdisabilitysevereenough to impair fulldailyactivities likebeingable toworkafulldaywithoutspecialprovisions)to7(unabletowalkunaidedformorethan5meters)and9(aso-called‘helplessbedpatient’).Point10onthescaleis–questionably–deathfromMS.

Appropriatelyused,theEDSShasconsiderablevalue.Kobelt et al (2017) showed that across Europe itcorrelates strongly with the likelihood of people withMS being in employment. These researchers alsofound that EQ5D (see below) and EDSS ratings forPLwMSmatchwellwitheachotherandwithpercapitacarecosts,albeitthatataroundpoint6.5(definedasneeding constant bilateral assistance – including theuseofcanes,crutchesorbraces–towalk20metersormore) thegradients of theEDSS versusQoLandcarecostcurvesbecomemarkedlysteeper.

Suchobservationsmeanthataonepointdifferenceinonepartof theEDSSdoesnotnecessarily representthesameintervalasaonepointdifferenceinanother.This canmake interpreting findingsbasedon its useproblematic,ascanvariationsintest-retestfindingsandlimitedinter-raterconsistency.ThefactthattheEDSSis mainly focused on ambulatory criteria means thatrelyingonitcouldonoccasionshaveledneurologistsandotherstounder-ratetheimportanceofMSlinkedsymptomssuchasfatigueoranxiety.

ScoresgeneratedviatheFSSandtheEDSSalsohavelittleornopower toexplainphenomenasuchas the

‘disability paradox’. The latter exists when severelydisabledindividualsreportahighqualityoflifebecauseof their psychological resilience and factors such astheir retaining social status via a valued role in life.Similarconcerns relate to the fact thatwhilephysicallimitationscanoftenbeaccommodatedovertime,thisisnotasoften thecasewithproblemssuchas,say,intermittentacutepain.

The Euroqual 5D (so termed because it has 5dimensions – mobility, self-care abilities, usualactivities, pain/discomfort and anxiety/depression) isaimed at providing a generic measure of the qualityof life of people with any disease in order to permitserviceprioritiestobesetandeconomicassessmentsof alternative treatments to be made. Since itsdevelopmentatthestartofthe1990sitsusehascometodominatehealtheconomicevaluationsintheUKandtoalesserextentothercountries.

Yet the EQ5D (the use of which typically involveshealthy people imagining what it is like to live withconditionslikeMSasdescribedtothembyexpertslikeneurologists)may also be relatively insensitive to thesignificanceofvariablessuchasprognosticuncertainty.Asanessentiallystaticand‘a-social’(thatis,individualexperiencefocused)measureitisalsoblindtomatterssuch as historical and scientific context and thevaryingcapacitiesofbiomedicaltechnologiestoevolvedynamicallyand fostersocialchangesrelevant to thewellbeing of minority groups and entire communities(Taylor,2016).

For the purposes of this report the keymessage tobe taken fromsuchobservations is thatPLwMSandthose seeking to support them should treat datageneratedbytools liketheEDSSandtheEQ5Dwithcaution, and be critical of their limitations. The needfor this isarguablyhighest incircumstances inwhichinadequate measurements may cause the value ofuseful innovations tobeunder-estimatedandaccesstobettercarecounter-productivelyrestricted.

immuneresponsesaredown-regulatedtoprotectbabiesin utero fromrejection)womenwithMStendtobefreeofrelapses.Bycontrast,whenestrogenandprogesteronelevels fall afterchildbirth theybecomeat raised riskofexacerbations.

There is additional data showing links to ‘life style’variables such as smoking6 and being overweight inadolescence, both of which can influence immune

6 OnesuggestedreasonfortheincreaseinMSprevalenceamongstwomenrecordedoverthelastcenturyincountriessuchastheUSandthoseofWesternEuropeis,inadditiontoaltereddiagnosticpractices,increasedcigarettesmoking.YetthisfactoralonecannotexplainwhymaleMSoccurrencerateshaveremainedmuchmorestable.WidersocialtrendslinkedtolifestylesandrolechangesmightwellhaveplayedanimportantpartininfluencinggenderrelatedshiftsintheincidenceofMS,butasyetnoclearmechanismhasbeenidentified(Sellneretal,2011).

responses via inflammatory mechanisms (Milner andBeck, 2012). Early life obesity and use of tobaccoincreasetheriskofdevelopingMS,andmightinadditioninfluenceitscourse(Olssonetal,2017).

Firstexposures toEpstein-Barrvirus inadolescenceandearlyadulthoodmayalsobeacauseofmultiplesclerosis–seePenderandBurrows(2014)andBox2.Atthepresentstage of history the complex interactions between thegenetic,environmentalandlifestylelinkedcausesofMSandotherautoimmuneconditionsarebecomingunderstood.Sotooistheworkingoftheimmunesystemasitbothpreventsandcausesdisease.ThisiscreatingnewopportunitiesfortherapeuticinnovationandimprovedoutcomesforpeoplelivingwithMS.Adequate levelsof investmentcouldalsobringeffectivepreventivetechnologies.


Box 2. Epstein-Barr Virus (EBV) Infection and MS – Future Prevention and Treatment Opportunities

ThecausesofMSarenotyetfullyunderstood.ButinthecaseofRRMSthey involve the functioningof theimmunesysteminawaythatleadsTlymphocytestodamagethemyelinsheathsprotectingcentralnervousneurones. They also involve genetic (and probablyepigenetic),environmentalandlifestylefactorsthatworksynergisticallytodrivethediseaseprocess.Establishedexamples of this relate to the relationships vitaminDsynthesisandconsumption(25-hydroxyvitaminDplaysaroleinregulatingtheexpressionofmanygeneslinkedtoMS–seeGourraudetal,2012)andthepresenceofcertainmajor histocompatibility complex (MHC) genevariantsinanindividual’sgenome.

One of these (called DRB1*15:01) is alone believedto raise the risk of developing MS by about threefold above the average in Europeans. At the sametime recent research on vitamin D amongst womenindicatesatwo-folddifference in the incidenceof thedisease between those with high recorded levels ofserumvitaminD–whoareatreducedrisk–andthosewithlowlevels(Mungeretal,2017).

Suggestionsthatinfectionssuchasmeaslesconstituteanothercauseorco-causeofMShavebeendisproved.ButthereisevidencethattheEpstein-Barrvirus(EBV)doesplaysucharole.EBVwasdiscoveredintheearly1960s by Professor Michael Epstein and Dr YvonneBarr, who were investigating Burkitt’s Lymphomaamongst young children in sub-Saharan Africa.EBV is now known to cause – in some instances inassociationwithotherinfectiousagents–awiderangeof leukaemias, lymphomas and other malignancies.Thevirusmaybegloballyresponsibleforupto200,000malignancyrelateddeathsayear.

EBV (which isalsoknownashumanherpesvirus IV)alsocausesglandularfever(infectiousmononucleosisor IM), the occurrence of which is linked to that ofMS.Inoveralltermsteenagersandyoungadultswhocontractglandularfever(earlierchildhoodexposuretoEBV appears less risky, inmuch the sameway thatpolio virus infection does not usually cause paralysis

in infants) have double the risk of developingMS ascompared with those without a history of IM. TherelativeriskfordevelopingMSisanorderofmagnitudegreater amongst individuals with key HLA typevariations combined with high EBV antibody titres.(See,forinstance,Sawceretal,2009;Sundqvistetal,2012;Moutsianasetal,2015;Münz,2016.)

In addition to her recentwork on vitaminD, anotherstudy by Munger et al (2011) found that amongstindividuals in the US armed forces with the highestlevelsofEBVrelatedantibodiestheriskofdevelopingMS was over 30 times that of those displaying noevidence of infection by the virus. In epidemiologicalresearch statistical relationships of this strength arenormallyevidenceofcausality(Wald,2017).

Itmaytakeseveralmoredecadesforalltheinteractionsleading to the occurrence of MS to be identified indetail.Questionsyettobeansweredinclude‘do other microbes like, for instance, human herpes virus VI act with EBV to help cause MS in some people?;’ ‘in the context of MS and other auto-immune conditions, what is the significance of B lymphocytetransformation associated with EBV infection?; and ‘do progressive forms of MS involve mechanisms other than those responsible for RRMS?’.ButeffortstoapplyknowledgeofthecausesofMSshouldbedelayeduntilallaspectsofitsaetiologyareunderstood.

There is apublic interest basedcase for investing inthe development of an EBV vaccine suitable for usein children, difficult and costly though thismightwellprove to be – see main text, page 26. Alongsidefurther efforts to reduce the prevalence of vitamin Dinsufficiencies (which affect many more people thanrare genetic variations) ways forward may includepro-activelyusingcombinationsofEBVantibodyandgenetic testing to identify individuals at high risk ofdeveloping MS. This could facilitate early treatmentand complement programmes aimed at findingmedicinesforprophylacticuseduringorafterepisodesofglandularfever.

Symptom relieving and disease modifying treatments

TreatmentsforMSareoftwobasictypes.First,therapiesthat canmake it easier to livewith the condition as itprogresses. Second, disease modifying therapies,designedtoslowand ideallyhalt thenaturalcourseofthedisorder.

Illustrations of the former range from antidepressantsand cognitive behavioural therapy for counteringthe psychiatric consequences of MS through toanticholinergic and other medicines that may relievebladder control and swallowing difficulties. Providingphysiotherapyand/orrehabilitativecarelikethatavailable

someEuropeanSpas,usingcannabistorelieveproblemssuchasspasticityandpain,and takingamantadine toreduce fatigue are additional examples of treatmentsthatfallintothiscategory.Thelattermightactonfatigueviaanantiviralmechanism,although it isalsousedasaParkinson’sDisease therapybecauseof itsability toincreasetheavailabilityofdopamineinthebrain.Thisislinkedtobothmoodandmovementcontrol.

Up until the end of the 1980s there were no diseasemodifying treatments forMS. But in the last 30 yearsaroundadozensuchmedicineshavebeen introducedtotheworldmarket.Theyinthemainworkbyinfluencingthe actions of cytokines (messenger substances)responsible for modulating immune responses or


reducing the numbers of T and/or B lymphocytesresponsible for the neurological damage people livingwithMS incur. At the same time there has also beenincreasing interest in the concept of preventing ordelayingtheonsetofthediseaseandperhapsslowingits course via lifestyle related interventions aimed atpreservingbraincapacity.Althoughthepopulationleveleffectivenessofsuchstrategies isunproven in theMScontext stopping smoking, moderating alcohol use,taking regular exercise and controlling weight are allcapableofgeneratinggeneralhealthbenefits.

Taking vitaminD supplements can alsoprovide healthbenefitsforsomeindividualsandgroups,mostnotablyamongstpeopleinlaterlifeandchildrenatriskofrickets.ThereisdatalinkingvitaminDlevelsandMSincidencerates(Mungeretal,2017)andinindividualsbeingtreatedforRRMSthereisanassociationbetweenlowlevelsof25-hydroxyvitamin D and relapse frequency (Rotsteinetal,2015).Thisdoesnotconstituteevidenceofdirectcausalityandthereisasyetnodefinitiveevidencethatusing supplementswill prevent or beneficially alter thecourse ofmultiple sclerosis. But from a precautionaryviewpoint the case for seeking to avoid vitamin Ddeficienciesinallchildren,adolescentsandyoungadultslooksstrong.

With regard to DMT use clinicians and PLwMS need,as noted in the introduction of this report, to balancetherisksofunwantedsideeffectsagaintsthedegreetowhichtheyarelikelytoslowtherateofMSprogressionand/or, in the context of RRMS, reduce the numberof relapses (ICER, 2017). Therapies that supress orotherwise alter immune responses can leave thosetakingthemvulnerablenotonlytoinfections(oneofthebestofknownofwhichisintheMScontextprogressivemultifocal leukoencephalopathy – PML) but also non-communicable conditions such as cancers. This isbecause protection from developing the latter in largepartdependsonimmuneresponsesthatstoptumoursdevelopingatanearlystage.

InthecaseofPML,whichiscausedbyamicrobecalledthe JC (John Cunningham) virus that is widely foundamongst–butisnormallysuccessfullyheldincheckby–healthy individuals,screening forJCVantibodiescannowhelpreducetheriskofthisside-effectoccurringinMSpatients.Otherformsofbiomarkertestingshouldinfuturebeabletoguardagainstotherunwantediatrogenic(treatmentinduced)events.

At worst, doubts and questions about the value ofnew or existing therapeutic options increase feelingsof uncertainty and fear, and underminewelfare. Someindividualsappeartobemoreconcernedwithavoidingdrugsideeffectsthantheyarewithslowingthenaturalcourse ofMS.Othersmay prefer not to have to faceexplicit treatment choices. But the available evidenceindicates that most PLwMS are – when given robust

information about their options – prepared to acceptwhatareinevery-daytermsrelativelyhighlevelsofriskinreturnforareducedprobabilityofdiseaseprogression.

Forinstance,inastudybyHeesenetal(2010)amongstasampleofpatientsandneurologists,participantsweregivencomprehensiveinformationaboutPMLrisks.Theirwillingnesstocontinueusingatreatmentonoccasionscapable of causing PMLwas subsequently assessed.Itwasfoundthatpatientswerewillingtoaccepthighertherapeutichazard levels thanclinicians, andalso thattheytendedtoregardMSasamoremalignantconditionthandidthephysicianstreatingthem.

AnotherstudybyJohnsonetal(2009)involvedover600peoplewithMSinaseriesofrisk-versus-benefit‘tradeoff’choices.Itwasobservedthatinreturnforacutinthenumberofrelapsesfrom4to1overafiveyearperiodand an extension in the delay between each stage ofdisabilityprogression(asassessedbyameasurecalledthePatient-DeterminedDiseaseStepsScaleorPDDSS)fromthree tofiveyears, respondentswereonaverageprepared to accept a circa 0.4 per cent (or 1 in 250)annualchanceofdeathfromsideeffects.

Such a risk level is well in excess of those actuallyassociatedwithlicensedMSmedicines.Resultslikethesesuggest that health professionals should be confidentthattheyareethicallyjustifiedininformingPLwMSaboutandproviding themwithdisabilitydelaying treatments,andinencouragingthosewhoareuncertaintoconsideracceptingtherapiesthatofferlongtermrewardsinreturnforlimitedchancesofharm.

The full value of starting optimally effective diseasemodifyingtreatmentassoonaspossibleaftertheinitialdiagnosis of MS, and making the latter as early aspossible, isyet tobedetermined7.But there isalreadyfrom a patient and wider public interest perspectivea powerful case for pursuing such options – see, forexample,Kanavosetal(2016).

Until recentlypeoplewithprogressiveformsofmultiplesclerosis had no licensed therapy available to themanywhereintheworld.Nevertheless,aproportionhavein recentyearsbeengivenwhatsomedoctorsbelievemightbeprovediseasemodifyingmedicinesonan‘off-label’(ieunlicensed)basisbytheirphysicians.

One drug which a number of responses to the TaP-MS survey described later in this report indicate is

7 Anew£10millioninvestigationintotheextenttowhichearlyaggressiveMStreatmentisbeneficialwasannouncedbytheMultipleSclerosisSocietyofGreatBritaininSeptember2017.Thisshouldbuildonexistingevidenceofreducedrelapseratesandslowerdiseaseprogression.InadditiontowantingmoreinformationaboutwhichtreatmentscanmosteffectivelycurbdiseaseprogressionandstopordelaydisabilitiesfromdevelopingPLwMSwishtoprioritiseresearchinfieldssuchasMSprevention;alleviatingfatigue;supportingselfcare;thevalue(ifany)ofvitaminDasaDMT;andpreventingoralleviatingsymptomslikemobilityproblems,impairedcognitionandMSassociatedpain.


occasionallyprescribedfor thispurpose isrituximab,amonoclonalantibody licensed inthe late1990sfor thetreatmentofconditionssuchaslymphomas.Thisproductisnowbecomingavailable in the formof relatively lowcostbio-similarpresentations.However,theonlymajortrialof it in thecontextofPPMSyieldeddisappointingresults(Hawkeretal,2009)8.

Building Confidence – Meeting the Challenges of MSModelsofdisabilitycanaidassessmentsoftheimpactsoflongtermconditionsandotherformsofillhealthandhelpdetermine thevalueofanddegreeofpriority thatshould be given to providing alternative forms of careand support for health and social service users. Forexample,theWHO(WHO,1980;Wood,1980)hasinthepastdifferentiatedbetweenimpairments(thebiomedicalchangescausedbyadiseasesuchas,say,opticnervedamage in thecaseofMS),disabilities (the immediate

8 RituximabisnotlicensedforthetreatmentofMS.ThisUCLSchoolofPharmacyreportdoesnotrecommenditsuseforthispurpose.However,itsmodeofaction–incommonwiththoseofsomelicensedDMTs–suggeststhatinMSBcells(groupsofwhicharepermanentlytransformedbyexposurestoEBVinfection)playaroleindirectingTcellandperhapsotherattacksonmyelin.See,forexample,Salzeretal,2016;Montalbanetal,2017;Hauseretal,2017.

functional consequences of such effects, like loss ofvision) andhandicaps (the eventual loss/deprivationofvaluedsocialroleslikebeingemployed).

This three level classification remains useful in that,for example, it underlines the fact that althoughunderstanding neurological and other disorders at thebiomedical and functional levels is vital if they are tomanaged effectively and for developingmore effectivefuturetreatmentsandpreventiveinterventions,optimisingoutcomes additionally requires social and politicalaction.Thisisneededtomaximisethechancespeoplewithdisabilitieshaveforenjoyinglifeviacommunitywidesupportive interventions which complement personalefforts(Simmons,2010).

Other potentially valuable approaches to understandingMSandways thatpeople livingwith itcanbeeffectivelysupported range from applying Maslow’s ‘hierarchy ofneed’ theory9 (Maslow, 1943) in the disability context tousing theadaptedpublichealthmodeloutlined inFigure3. The former in part involves ensuring that individuals’requirementsfor‘higherlevel’fulfilmentarenotignoredoractivelydeniedduringtheprovisionofbasicpersonalcare.

9 Maslowdidnotbasehisworkondirectempiricalobservations.Hedifferentiatedbetweenbasicneedsforsafetyandthoselinkedtophysiologicalfunctioning,suchashavingshelterandenoughtoeat;psychologicalneedssuchasthosefor‘belonging’andsocialesteem;andself-fulfilmentneedsrelatedtotheexpressionofcreativeabilities.Itissometimesthoughtthathebelievedthatbasicneedsshouldbeprioritisedoverothers.Butheonoccasionswarnedagainstthis,indicatingthatallindividualsseekingasatisfactoryliferequireself-realisationopportunitiesaswellasmoreimmediatenecessities.

Figure 3. A Public Health and Medical Sociology Oriented Model for Understanding MS

WID

ERSOC

IAL&ECONOMICENVIRONMENT

WOR

K&

LOCA

LCOMMUNITYENVIRONMEN

T

Objectivefactsregardingasociety’sdominantbeliefsaboutissuessuchasfairnessandthenatureofhealthandillness,theextentofandattitudestowardsincomeandhealthinequalitiesandgradientsinwealth,levelsofnationwideaccesstoserviceslikeeducation,legalframeworksrelatingtoareassuchasdisability,standardsofpublicdiscourseaboutsciencebasedtopics,prevalent

beliefsaboutthevalueandlikelihoodofbiomedicalprogress

LIFE

STYLE

&HOME&FAMILYENVIRO

NMEN

TOUTERSELF

INNERSELF

Subjectivelyexperiencedphenomenasuchaspain,fatigueanddisruptionstoanindividual’snarratives

aboutthemselves,theirjourneythroughlifeandstandingintheinternallyperceivedworld

Observablecharacteristicssuchasanindividual’sgender,age,weight,geneticendowmentandinherentoracquiredphysicalandmentalabilities

Habitssuchassmokingand/orexercisetaking,thequalityofaperson’sdomesticsettingandwhetherornotheorshehasa

partnerorchildrenandaccesstoinformalcarewhenneeded

Employmentandleisureactivityopportunities,experiencesofcommunityacceptanceorrejection,qualityofhealthandsocialcare,accesstomedicines,physicalsecurityandlocalareahousingstandards


The public health approach described by Figure 3 isbased on the work of researchers such as DahlgrenandWhitehead (1991; 1996) andBury (1982; 2017). Itcombinesanemphasisontheenvironmentaldeterminantsof illness occurrence and disease experience withsociologicalandpsychologicalinsightsintothedisruptiveimpactsofdisablingconditionsonindividuals’biographies,andtheinternalnarrativeswhichdefinetheiridentitiesandinfluencetheirpositioningintheworld.

Patients’thinkingaboutthemselvesisfrequentlyinvisibleto doctors and others providing day-to-day healthservices. Yet preserving each person’s biographicalintegrityandsenseofbeinginanacceptablerealitycanberegardedasacoreobjectiveofallgoodqualitycare.

Special dimensions of demyelinating disease

Models of disease and disability impact such as thatembedded in theEQ5D (seeBox1) are employed ineconomicevaluationsofwhatinterventionsoffersufficient‘valueformoney’tobejudgedcosteffective.However,as theBritishstatisticianGeorgeBoxhasbeenwidelyquotedassaying,‘all models are wrong, (even if) some are useful’.ThedangersofuncriticallyapplyingsimplifiedrepresentationsofdisabilityandlostopportunityinlifetodisordersasmultifacetedasMScentreonthefactthatimportantaspectsoftheburdensthey imposemaybeoverlooked.Anumberofspecificissuesrelatedtolivingwithmultiplesclerosisarethereforedescribedbelowinorder to provide further context within which to placethenewTaP-MSsurveyfindingspresented in thenextsectionofthisreport.

The unique challenges that fluctuating demyelinatingillnessescreaterelate,aspreviouslynoted,touncertaintyandthevariabilityofthedisabilitiesitcausescoupledwithitstoaconsiderableextentunpredictableprogression.Therearealsospecialissuesrelatingtofactorssuchashowitcanbediagnosedasaccuratelyandearlyaspossible;howpeoplecanmosteffectivelyseektocopewithitandlivehappilyasanindividualwhohappenstohaveMS,ratherthanbeingdefinedbytheirillness;andtheneedsofthosewhocareforindividualswithmultiplesclerosis.TheeconomicsofMSserviceprovisionarealsoworthconsiderationinthelightofthepressuresthatnewMStreatmentsareputtingonhealthcarebudgetsatatimeinwhichtheproportionofnationalwealthbeingspentonhealthandsocialcare is inmanycountriesunderclosescrutiny.

The importance of early diagnosis and effective communication

Historically,manyneurologistsandotherdoctorsappearto have believed that because only symptom relievingtherapieswereavailableitwasnotdesirabletoseekto

diagnoseMSasearlyaspossible,ortoexplainthefullimplicationsofhavingthediseasetopatientsbeforeitsdisablingconsequencesbegantoimpactupontheirlives.SuchbeliefswereoftenaccompaniedbyconsiderablepracticaldifficultiesinidentifyingtheconditioninitsinitialstagesbeforeMRIscanningwasavailable,andwhenthediagnosticcriteria inusewere lessfinely tuned than issotoday.

For some patients limited information provision mayofferbenefitsiftheyareenabledtoliveforanadditionalperiodwithoutworryandfear.Butforothersitcanleadtoavoidabledistressassociatedwith feelingsthattheyare being ignored or are becoming mentally ill, andbeingbesetby imaginaryconcerns.There is evidencethat a heavy emotional burden is often experiencedby individualswaiting foradiagnosisofMS(O’Connoretal,2004)and thatamajoritywould,evenbefore theavailability of the current range of DMTs, prefer earlierrather than later disclosure of information about theircondition(Janssensetal,2004).

The available literature offers reports of people withMS saying that receiving a positive diagnosis wasaccompaniedbyfeelingsofreliefbecausetheyatleastknewthereasonfortheirsymptomsandcouldstarttoaddress the problems likely to lie ahead of them in aconstructivemanner(MurphyMiller:1997;Russelletal,2006).EvenforpeopleatonetimesuspectedofhavingMSbutwhodidnotsubsequentlydevelopit,thosegivenuncertainlabelslike‘clinicallyisolatedsyndrome’followedonoccasionsby years inwhichno further informationwasforthcomingmayhavebeenforcedintomakinglifechangingdecisionsaboutmatters suchaswhetherornottohavechildrenthatcouldnotbereversedaftertheirsituationwaseventuallyclarified.

In thedevelopedworld today suchdifficulties are lesslikely to occur than in the past because of improveddiagnosticcriteria(Polmanetal,2011)andbetteraccesstoMRI scanning, even though therearemarked inter-and intra-nationalvariations intheavailabilityof latter–seeFigure4.RecentOECDdataindicatethattherearearoundfivetimesmoreMRIunitsperheadofpopulationinGermanythanin,say,theUKorRomania.VariationsinthenumbersofMRIscansundertakenappeartobeeven greater (OECD, 2016: Wilsden et al, 2014) andthere may in some settings be additional problemsassociatedwiththeavailableequipmentbeingoutdated(CIB,2017).

Earlierandmoreaccuratediseaseidentificationcoupledwith high quality progression monitoring opens theway to more effective treatment, aimed at stoppingobservable disease activity and preventing disabilities.ReceivingadiagnosisofMScanbeashockingeventleadingtointensefeelingsoffear,lossandabandonment(Johnson,2003).Yet there isevidence that shorteningthetimespentwaitingforadiagnosiscurbsanxietyand


generateslongtermbenefit.Providingeffectivesupportand comprehensive information at the time of firstdiagnosisalso improvespatients’subsequentchancesofcopingwellwiththeircondition(Thorneetal,2004).

The causal relationships between levels ofhealth knowledge and health behaviours are notas straightforward as is sometimes assumed.Nevertheless, there are observed links between thequalityoftheinformationPLwMSreceive,howmuchthey understand about their condition and howsuccessfully they cope with their diagnosis andMSsymptoms(Lodeetal,2007).Goodcommunicationandinformationprovisionpracticesforhealthprofessionalsinvolveusingclearbutnotsimplistic language;beingopenaboutthenatureofMSanditsuncertaincourse,whileatthesametimeshowingconfidentbiomedicalexpertise;andspendingsufficienttimetoensurethatpatients’questionsandconcernsarelistenedtoandaddressed as fully as possible – see, for instance,Kopkeetal(2014).

Coping strategies, personality types and MS outcomes

Disabilities caused by MS are often challenging tolive with. So too, for most people, is the prospect offurtherlossesofvaluedattributessuchasthecapacityfor independent mobility, or cognitive competencieslike those relating to memory. The distress that suchpossibilities generate can lead individuals with MS to‘live for the day’andavoidthinkingaboutthefuture.Asignificantproportionreportambiguitiesaboutwhethertheywouldlikeamorepreciseprognosisbecausetheyfearmorebadnews.

ForsomepeopletryingnottothinkaboutMSisbeneficial(Aronson, 1997). But, as with delaying or limitingdiagnosticdisclosures, there isempiricalevidence thatif such strategies lead to the habitual avoidance ofunwantedfeelingsandhence‘emotionfocused’copingstyles (asopposed toproblemorientedcoping,whichconcentrates on changing the individual and her orhis environment in order to overcome difficulties) theyundermine self-efficacy. This is associated with raisedrisks of psychological distress and psychiatric illness(Beattyetal,1998;Packenhametal,1999).Highlevelsof mental stress/distress may in turn impact on thenumbers of newnervous systems lesions (Mohr et al,2012).

Psychologists differentiate between coping styles andstrategiesthatarelearnedandcanbechangedrelativelyeasily andpersonality types,which aremore stable innature.Inthelattercontextsocalled‘blunters’–see,forinstance,Baker(1996)–trytoavoidreceivingpotentiallydistressing information. ‘Monitors’ on the other handtend to seek repeated updates about their condition’sprogressionand tobecontinuously searching for newinformationabouttheirsituation.ItislikelythatblunterslivingwithMSwillmoreoftenopt foremotion focusedcopingstrategiesthanmonitors,albeitrigidassumptionsabout anygiven individual’spreferredwaysof learningandhandlingdifficultinformationshouldbeavoided.

Inreality,thedividinglinesbetweenacquiredandmoredeep rooted behaviours and ways of thinking areblurred. Furthermore from a sociological perspectiveit is important not to exaggerate the extent to whichpeople can in any given social and economic contextchoose their approaches towardsdisease acceptanceand disability accommodation. But for the purposesofthisreportthemostimportantconclusiontodrawisthatwhereverpossiblecliniciansandothersseekingtosupport people livingwithmultiple sclerosis and otherlong term conditions should seek to adjust flexibly tothe needs and preferred learning and communicationstylesofeachindividualwithMSwithoutlosingsightofthedesirabilityoffosteringoptimallyeffectivebehaviourswhenopportunitiesarise.

Figure 4. Numbers of MRI Units per million population in Europe

Source:OECD,2016

0 10 20 30Permillionpopulation

GermanyItaly

GreeceFinlandCyprusAustria

DenmarkEU28Spain

SwedenIreland

NetherlandsLuxembourg

LatviaMalta

EstoniaFranceBelgiumLithuaniaCroatiaSlovenia

SlovakRepublicCzechRepublic

PortugalBulgariaPoland

UnitedKingdomRomaniaHungary

IcelandSwitzerland

TurkeyFYRofMacedonia

Serbia

30.525.224.3

23.319.919.7

15.415.415.314.7

13.412.912.612.511.711.410.910.810.610.4

8.78.37.47.17.16.76.1

4.73.0

21.420.9

9.82.92.8


Contrasting patient, clinician and carer views and needs

As already observed, doctors and other healthprofessionalscannotdirectlyseetheinnerthoughtsandsubjectivefeelingsofpatientsinthesamewaythattheycan observe and quantify physical symptoms like, forinstance,aninabilitytowalk.Itisnot,therefore,surprisingthat the available evidence indicates that neurologistsand other doctors tend to rate the importance of thephysicalaspectsofMSmorehighlythandotheirpatients.In relative terms the latter tend tobemoreconcernedwithproblemssuchasfatigue,emotionalandsocialrolelimitations,depressionandlossofvitality(Rothwelletal,1997).

Recent research by Tintore et al (2017) has alsoidentifiedpotentially importantdifferencesinperceptionbetweenpatientsandneurologistsconcerningtreatmentexpectations,selectionandsatisfaction.Thisstudyalsofound variations in attitudes towards issues such astreatmentcosts (whichmayperhapsbemore likely todeleteriouslyimpactonaproportionofpeoplelivingwithMSintheUSthaninmostotheraffluentcountries)andthesignificanceofsideeffects,togetherwithperceivedpatient‘failures’toaccepttheirillness.Suchfactorsaresignificantinthecontextofnon-adherencetomedicationregimens.PLwMSandneurologistsinadditionidentifieduncertainties as to whether therapies are working ashopedasa‘topchallenge’inrelationtotakingDMTs.

Withregardto theextent towhichthe982Europeansand Americans with MS who took part in this survey

said that they or their physicians controlled treatmentselection, there was a normally distributed responserelating to each main type of MS. Overall, just under40per centofPLwMS reported that their doctorwasthe sole or primary therapeutic decisionmaker. A likeproportionsaid that they, theDMTuser,hadbeen themaindecisionmaker.The remainderofa littleunderathirdof the totalsample reportedanequalpartnershipbetweenthemselvesandtheirphysicians.

RespondentswithRRMSweremarkedlymoresatisfiedwiththeirtreatmentthanthosewithSPMSandPPMS,pointing to the existence of unmet need. Like others,the authors of this study stressed the value of goodcommunication and active patient involvement in MScare decisions, not least because of its capacity toenhancetreatmentacceptanceandhenceitsoutcomes.

There are also significant differences between theperceptions and needs of people with MS and theirinformal carers. Individualsprovidingcareandsupportforpartnersorotherrelativeswithmultiplesclerosisarelikely tobemotivatedby feelingsof loveandduty.Buttheymayatthesametimeexperiencesadnessandlosscoupledwithareducedqualityoflifecomparedtotheirpeerswithoutsuchresponsibilities.Forthoseofworkingagehavingacaringrolemaybeassociatedwithcareerdisadvantages (Bassieetal,2016;Donzeetal,2016).Such problems raise risks of developing depressiveillnessesandotherformsofpsychiatricdistress.Figure5highlightsresearchfindingsontheunmetneedsreportedbycaregiversandcomparesthemwiththoseidentifiedbyPLwMS.

Figure 5. Contrasting Patterns of Unmet Need Reported by PLwMS and Care Givers

Source:Donzeetal,2016

Moreinformation

Moreresearch

Financialaid

Oraltherapy

Curativetreatment

Lessadverseevents

Fatiguetreatment

Psychologicalsupport

Prognosis

Moreunderstandingfromrelatives

Moresocialrelationships

Moreconvenienttreatments

Administrativeaid

Moreleisure

Analgesics

Professionalsupport

14.7% 31.0%

13.4% 19.0%

7.4% 15.5%

16.4% 5.2%

10.3% 10.3%

10.3% 10.3%

19.1%

1.5% 17.2%

8.8% 8.6%

4.4% 12.1%

4.4% 5.2%

8.6%

8.6%

2.9% 5.2%

7.4%

7.4%

Patients(N=68)

Caregivers(N=58)


These data re-emphasise from the viewpoint of thosewithMS the importance of relieving fatigue. From thecaregiverperspective theypoint to their requirementsforpsychologicalsupport,whichreflecttheirimportanceinmaintainingthemoraleofpeoplelivingwithdisabilitiesofalltypes.Iftheneedsofcarersareneglectedthiswillimpactonformalservicedemandpressuresandcosts.

Economic concerns

MS is a costly disease for both individuals andcommunities. A recent study by Kobelt et al (2017)foundaverageannualoutlaysonMSacrosstheEUtobe€23,000 (at2015PPPadjustedvalues)perpatientin relation to mild (EDSS 1-3) disease, €37,000 formoderate disease (EDSS 4-6.5) and €57,500 for theseverest(EDSS7-9)expressionsofthecondition.Withinthesetotalshealthcarecosts(includingpharmaceuticalspending)accountedfor68percent,47percentand26percentrespectively,representingsome€15,000ayearineachcase.

ThesedataareconsistentwithestimatesthatMSaccountsfor about 1 per cent of health service outlays in theEUnations and similar countries like Canada and Australia.Outside theUSthis isequivalent toaround0.1percentof GDP. Within this total, some 2-2.5 per cent of allpharmaceuticalcosts10(orapproximately0.03percentof

10Authors’estimatebasedonvarioussources.TheworldmarketforDMTsforMSispresentlyvaluedatabout$US20billion,outofaglobalpharmaceuticalsalestotalofcirca$US1.1trillion.PLwMSalsoconsumearangeofotherpharmaceuticalproducts.

theaveragenation’sGDP)maybebeingincurredinrelationto symptom relieving and disease modifying MS drugusage.However,Kobeltandhercolleagueswarn that inrealitypricediscountingmeansthatdrugcoststendtobeoverstatedcomparedwithotherhealthsectoroutlays.

Onepercentoftotalhealthspendingisaverysubstantialsumonaconditionthattypicallyaffectslittlemorethan0.2percentof theaverageEuropeanorsimilarpopulation.Yet it is below the direct and indirect financial burdensincurred by people with MS and their families in theshapeofinformalcareinputsandwagelosseslinkedtoproductionshortfalls.Otherkeyobservationsmadebytheauthorsof this largesurvey (whichgathered informationfromalmost17,000EuropeanswithMS)include:

• before the 1990s MS related health care costs were strongly skewed towards providing hospital and institutional care for those most disabled by the disease. The availability of DMTshaseffectivelyeliminated thisgradient.Their adventshould in time lower overall spending requirementsas the prices of treatments fall after the expiry ofintellectualproperty rightsandwhendisability levelsamongstolderMSpatientsdecline.ButpresentlytheoverallamountsspentonDMTsformultiplesclerosisare sometimes regarded as a problem for healthservicebudgetholders.IntheUK,forinstance(whereKobeltetalreported–for2015–onlyabouthalftheoveralllevelofDMTtakingobservedincountrieslikeFrance,Germany, Italy andSpainand two thirdsofthe access recorded in Sweden and Denmark) the

Box 3. The MS-TaP Survey Methodology

Workon theMS-TaPsurveybegan in theUCL-linkedmedicinesuseoptimisationcompanySpoonfulofSugarinearly2017.Socialmediasiteswerescrutinisedinordertogaininsightsintotheinterests,viewsandbeliefsofpeoplelivingwithMS.ArapidliteraturereviewwasalsoundertakenbySoS,inadditiontothesearchesseparatelyconductedforthepreparationofthisUCLSchoolofPharmacyreport.TheSoSworkinvolved31textsbeingreadinfullalongwiththeabstractsofsome200otheracademicpapersandreports.Asillustratedbelow,thisthenledontofourqualitativeinterviewsbeingundertakenwithpeoplelivingwithMSintheUK.

Followinganevaluationoftheinformationgatheredinthefirstthreestagesoutlinedabove,aninitialversionoftheonlinesurveyinstrumentwasdesignedandpiloted.Thefinalversionwassubsequentlyproduced.Itaskedatotalof15questionsandemployedprovenpriorityassessmenttechniquesaswellasprovisionsforenablingrespondentswhowerenottakingdiseasemodifyingtreatmentstoexplainwhythiswasthecase.

Surveyparticipantswererecruitedonlinethroughnationalpatientorganisations,charities,prominentpatientbloggersandonlineforums. IntheUKprospectiverespondentswerealsocontactedviathenetwork linksofthosepeoplewithMSwhointheearlystagesoftheprojecthadprovidedinsightsusedtosupportthedevelopmentofthesurveyinstrument.Overthesummerof2017atotalof1040completedresponseswerereturnedtoSoS.ThefinalversionofthefullSoSreportontheTaP-MSsurveyfindingsisavailableathttp://sos-adherence.co.uk/research/tap-ms

•SocialmedialisteningtogatherinsightsandassessMSperceptions

•Rapidliteraturesearch

•4in-depthsemistructuredinterviews

•Datacollationandsurveydesign

•Onlinesurveytool

•Datacollection,validationandanalysis


establishmentofNICE in1999was linked to (false)fearsthat interferonbasedtreatmentsforMSwould‘bankrupt the NHS’ (Taylor,2002;2016).

• health and other service provisions for people with MS vary significantly between nations in Europe and elsewhere. In Sweden, for example,there is an exceptional level of investment in socialsupport. Access to neurologists is high in settingslike Germany and France, while MS patients aremorelikelytoseespecialistMSnursesintheUKandnationssuchasDenmarkandTheNetherlands.

Theseauthorsconcludedthatforthefuturethereshouldbe more emphasis on studying the epidemiology ofMS and the quality of care available to people livingwith it by the level of disease severity, rather than bycondition ‘type’. They also stressed the importanceof understanding more about how fatigue, cognitionproblems, depression and anxiety affect employmentand other aspects of daily life, and how health carefunding differences impact on service standards inotherwisesimilarnations.

The MS Treatment Expectations and Priorities (TaP-MS) Survey – Key Findings

TheTaP-MS surveywas conducted in the summer of2017bytheUCLspin-outcompanySpoonful of Sugar(SoS), thenameofwhichreflects the titleofaseminalreportonmedicinestakingpublishedatthestartofthis

century (Audit Commission, 2001). SoS specialises inundertaking studies of health behaviour change andin facilitating improved medicine use. Details of theresearchmethods the TaP-MS survey teamemployedarepresentedinBox3.

Table1andFigures6aand6bprovidedatarelatingtothesampleof1040PLwMSgatheredduringthestudyperiod.Swedish,American,British,FrenchandGermanpatients togetheraccounted foralmost80percentofthe respondent total. The average participant was inher or his early 40s and females outnumberedmalesby 2.4:1. The typical individual reported that they hadbeendiagnosedwithMSforabout10years.Overall,55percentsaidtheyhadRRMS,and18percentSPMS.Another18percentofrespondentsindicatedthattheyhad either PPMS or PRMS – the absolute numbersrecordedwere145and43respectively.Theremaining8percentgave‘don’tknow’replies.

Over half the latter (55 out of 88) respondents wereSwedish.Asub-analysisofthisgroupdidnotshowittobedifferent fromtheoverallbodyofSwedishPLwMS.Itshouldnotbeassumed‘don’tknow’answersreflectignoranceoralackofunderstandingofMS.Itmaybe,for instance, that those saying theywere uncertain oftheir diagnosis were in transition between RRMS andSPMS(whichisatestingperiodforpatientsandcarersalike)orhadanother informedreasonnot toprovideaprecise answer. For example, the distinction betweenPPMSandPRMScanbedifficulttomake.

Country

Totalno.ofrespondents

male&femalecombined

%female

Averageageattimeofresponse

(M&F)

Averagetimesincediagnosis

(years)

%oftotal(including

‘don’tknow’)withRRMS

%withSPMS

%withPPMS,

includingPRMS

%don’tknow

Australia 28 93% 47.0 7.1 71.4% 10.7% 14.3% 3.6%

Canada 28 50% 42.0 9.6 50.0% 25.0% 25.0% 0.0%

France 102 58% 37.8 7.5 65.7% 7.8% 11.8% 14.7%

Germany 85 86% 36.2 7.7 68.2% 5.9% 14.1% 11.8%

Italy 18 72% 46.1 12.3 50.0% 11.1% 16.7% 22.2%

Spain 61 52% 47.7 15.1 60.7% 21.3% 14.8% 3.3%

Sweden 337 79% 50.9 11.8 43.9% 26.1% 13.6% 16.3%

UnitedKingdom 139 59% 42.0 9.3 76.3% 8.6% 15.1% 0.0%

UnitedStatesofAmerica 242 56% 39.2 7.6 49.6% 19.4% 30.6% 0.4%

1040

Totalsplitbygender

Male(allcountries) 308 43.4 8.9 48.7% 18.2% 27.3% 5.8%

Female(allcountries) 727 44.1 10.1 58.6% 17.7% 14.3% 9.4%

Preferrednottosay 5 42.5 6.5 60.0% 40.0%

Table 1. The TaP-MS Sample

Source:SpoonfulofSugar,2017


Table 2 provides a country by country breakdown ofthe self-reporteduseofDMTsbydiagnosis.Some81percentofallthosewhosaidtheyhadRRMSindicatedbeinginreceiptofadiseasemodifyingtherapy.Nationallevel figures ranged from 71 to 73 per cent being onDMTsintheUKandtheUSrespectivelythroughtowellover80percentincountriessuchasAustralia,Canada,FranceandSpain.

These national level statistics should not be over-interpreted.InthecaseofAustralia,forinstance,just28PLwMStookpart in theTaP-MSsurvey.Nevertheless,the fact that the US figure is comparable to that forthe UK and that the aggregated proportion of peoplewithRRMSwhoreportedbeingonDMTs inthesetwocountries isover10percent lessthantheaverageforall other countries combined raises questions aboutaccesstocare.

It suggests, for example, that some people in theUSRRMScommunitymaybebeingunder-treated,perhapsbecause of socio-economic inequalities linked to risktakinginthehealthandhealthcarecontexts.FromaUSpatientinterestandpublicpolicyperspectiveitmightbeworthfurtherinvestigatingthepossibilitythatindividualswho have – despite the medicines access supportprovisions available – perceived problemswith payingfor MS therapies or for other reasons have restrictedaccesstoservicesneededtofacilitatetheirusearebeingexposedtoanavoidablelongtermriskofdevelopingMSrelateddisabilities.

Despite the existence of the NHS in the UK there isalso evidence that British policies have on occasionsrequiredclinicianstomakesubjectivejudgementsaboutthe ‘suitability’ofpatients forMS treatment (Owensetal, 2013). Such observations cannot explain the lowoverall level ofDMTuse inBritain reportedby varioussources.ButtheyserveasawarningastohowsocialclassrelatedMStreatmentinequalitiescanbefosteredin systems that donot explicitly guarantee individuals’rightstotreatment.

Infact,thelevelsofUKpatientDMTusereportedbytheTaP-MSsurveyrespondentswerenotaslowassourcessuchas theEuropean Burden and Costs of MSstudy(Kobeltetal,2017)ordatalikethatquotedinGiovannonietal’sBrain Health: time matters in MS(2015)indicateisthecase.Itmaybethat,followingtheactiveinvolvementinhealthpolicydebatebyUKMSorganisationsandtherelease of revised clinical guidance by NICE in 2014,accesstoMSdiseasemodifyingtreatmentshasrecentlyimprovedinBritain.However,TaP-MSrespondentswerenotaskedtodifferentiatebetweenolderandnewerMSDMTuse.Fromaglobalpatient interestperspective itwould in future be desirable to have open access toreliable,up-to-date,figuresonallformsofadvancedMStreatmentusageonacountrybycountrybasis.

TurningtopeoplelivingwithSPMSandPPMS,Table2shows average reported levels of DMT use of 59 percentand57percentrespectively.Thesedataincludealimitednumberofrepliesfromindividualsindicatingtheyaretakingrituximabonanoff-labelbasis.InthecontextofSPMStreatmentonlyathirdofSwedishrespondentssaid they were using a DMT, compared with 96 percent ofUSpatients. In the case of PPMSandPRMStheoverallfiguresreferredtoabovewereskewedbythefactthatalthough89percentofAmericanrespondentssaid theyweretakingaDMT littlemorethana thirdofEuropeans with these diagnoses said that they wereusingone.

In Sweden and Spain less than a quarter of thosereportingadiagnosisofPPMSorPRMSsaidtheyweretaking a DMT. Once again, over-interpretation shouldbe avoided. During the period in which the TaP-MSinvestigationtookplace(thatis,thesummerof2017)onlythe American and Australian pharmaceutical marketscontainedaDMT licensed for any formofprogressivediseasetreatment.Yetthishadonlybeensoforaverylimited time period and cannot therefore account forsuchdiscrepantfindings.

Figure 6b. Distribution of Tap-MS Respondents by Time Since Reported Initial Diagnosis

Num

ber o

f res

pond

ents


350

300

250

200

150

100

50

0<1year 1-5 6-10 11-15 16-20 21-25 26-30 >30years

Figure 6a. Distribution of TaP-MS Respondents by Age


Respondent age (years)18-25 26-35 36-45 46-55 56-65 66-75 76or

above

350

300

250

200

150

100

50

0

Num

ber o

f res

pond

ents


OnepossibilityisthattheyreflectsignificantdifferencesinprescribingpracticesbetweendoctorsintheUSandothersettings.ButevenEuropeanandCanadianrespondentswhosaidtheyhadaprogressiveformofMSreportedasurprisinglyhighlevelofdiseasemodifyingmedicineuse.Alternative reasons for the reported figures range fromsamplingbiasesthroughtomuchhigherthanexpectedoff-labelprescribingratesorrespondentmisunderstandingsabouteitherthetreatmentsbeingtakenorthemeaningof ‘disease modification’. Further investigations of thepatternsofcareprovidedforpeoplewithPPMS/PRMSineachnationalsettingwillrequiredtofurtherexplainsuchobservationsandtheirwelfareimplications.

Existing therapy concerns and expectations

Figures7a,bandcofferover-viewsofthereasonsgivenbypeoplewithMS fornotusingDMTs. In thecaseofRRMSthemainfactorsinvolvedrelatedtotheperceivedriskofsufferingsideeffectsandlongtermharm(labelledConcerns) anda lackofbelief in theneed for therapy(labelledNeeds)11.Bycontrast, inboth theSPMSandPPMS/PRMScategoriesthemostsignificantbarrierstoaccessreportedbyrespondentswereunavailability(that

11Horne’sNecessityandConcernsFrameworkcanbeusedtopredictadherenceinmedicinestaking.IndividualswhobelievestronglythattakingMSDMTsorothermedicinesisnecessaryfortheirfuturewellbeingandwhohaverelativelylowlevelsofconcernaboutsideeffectsorotherpossiblecausesoftreatmentrelatedharmaremorelikelytoacceptandcontinueusingrecommendedmedicinesthatthosewithastrongconcerns/weaknecessitybalanceofmedicationassociatedbeliefs.

is, thebelief thatnosuitablemedicinefortreatingtheirconditionexists)followedbyConcernsandNeedslinkedexplanations.

The patterns of drug use and patient beliefs aboutproblems like side effects observed during the TaP-MS investigationwere by and large consistent acrossnational boundaries. However, the issues touched onabovemayreflectdifferencesinareaslike,forinstance,how Swedish neurologists and/or service fundersemploytreatmentsintheSecondaryProgressivesettingascomparedwithrelevantdecisionmakersinotherpartsofEurope. If this is so itmighthelpexplaindiagnosticambiguitiesattheRR/SPborderline.Were,forinstance,somepatientstransitioningfromRRMStoSPMStofearrestrictions in their ongoing therapeutic opportunitiestheymightbemoreinclinedtoexpressuncertaintyabouttheirdiagnosesthanPLwMSlivingelsewhere.

This particular hypothesis is by no means proven.Nevertheless, the TaP-MS findings point to a needto understand better the knowledge and beliefs thatpeoplewithPLwMShaveabouttakingDMTs.Theyalsosignal that itwouldbeuseful toexplorecross-nationalvariations in medical practices in greater depth. Tothe extent that therapeutic conservatism or liberalismimpactsonserviceusers’welfare,practicevariationsinareaslikefosteringearlyMSdiagnosisandtreatmentarenotmattersofconcerntothemedicalprofessionalone.Astherangeofeffectivetherapiesgrows,patientsandtheirrepresentativesacrosstheworldwillshareinterestsinensuringoptimalaccessanduse.

Table 2. Disease Modifying Treatment/Drug Use

Diagnosis RRMS SPMS PPMS+PRMS Don’tKnow

Country OnDMT All %DMT OnDMT All %DMT OnDMT All %DMT OnDMT All %DMT

Australia 19 20 95.0% 2 3 66.7% 2 4 50.0% 1 1 100.0%

Canada 12 14 85.7% 6 7 85.7% 4 7 57.1%

France 57 67 85.1% 7 8 87.5% 7 12 58.3% 12 15 80.0%

Germany 46 58 79.3% 3 5 60.0% 6 12 50.0% 6 10 60.0%

Italy 7 9 77.8% 2 1 3 33.3% 1 4 25.0%

Spain 36 37 97.3% 9 13 69.2% 2 9 22.2% 2 2 100.0%

Sweden 126 148 85.1% 29 88 33.0% 11 46 23.9% 36 55 65.5%

UnitedKingdom

76 106 71.7% 9 12 75.0% 9 21 42.9%

Total(USnotincl.)

379 459 82.6% 65 138 47.1% 42 114 36.8% 58 87 66.7%

UnitedStatesofAmerica

88 120 73.3% 45 47 95.7% 66 74 89.2% 1

GrandTotal 467 579 80.7% 110 185 59.5% 108 188 57.4% 58 88 65.9%



highlighttheimportancethatpeoplewithMSattachtocombatting fatigue, maintaining their walking/mobilitycapabilities and alleviating problems like bladder andbowelcontroldifficultiesandsightimpairments.

They also confirm that DMT users attach high prioritytoreducingrelapseratesandslowingor ideallyhaltingdiseaseprogression.InthatthelattercanbeseenastheultimatedriverofalltheunwantedaspectsofMS,theseresultsindicatethatstoppingdiseaseprogressionisthehighest priority expectation of patients taking DMTs.However,thisisnottodenytheimportanceforpatientsofotheraspectsofdiseaseandsymptomimprovementlikealleviatingfatigueand,ifandwhenpossible,reducinglevelsofdiseasefluctuation.

TheTaP-MSresponsesinadditionshowthatwhilepeoplewithMS,likeothers,donotwanttosufferunwantedsideeffectsasaresultoftakingmedicinesofanytype,mostarepreparedtoacceptadegreeofriskinreturnforsymptommoderationanddiseasestabilisation.TheresultsshowninFigure8confirmthat–althoughimportant–treatmentharm minimisation is for most people a second orderpriorityascomparedwithdiseasemodification.

These findings,which are again consistentwith thosecontained in the literature summarised earlier in thisreport,offerawarningabouttheundesirabilityofunduetherapeutic risk aversion. In bureaucratic and other‘statusandorderpreservation’ focusedsocialsystemsthere isoftenastrongdesire topreventactionswhichcould result in external criticism. But clinicians andservice managers should be aware of service users’preferences.Careshouldbe taken to fully respect therequirementsofpeopleseekingtomaximisethechancesof stoppingMSprogression as againstminimising thepossiblerisksoftreatment.

‘Practicality’linkedconsiderationslikethoseassociatedwithalternativemedicineadministrationroutes12canbeseenasthirdorderprioritiesforPLwMS.Thisisnottosaythatease-of-uselinkedfactorsdonotinfluencemedicinetaking, and sode facto therapeutic effectiveness. Butfrom a health policy viewpoint there is no patientexpectation based reason to prefer any one route orpattern of DMT administration over another, providedadherenceissuesarewellmanaged.

Inshort,‘what works best matters most to most people with MS’.Fromapharmaceuticalresearchanddevelopmentperspective this conclusion underlines the need forenhanced outcomes rather than improved medicinalproperties.However,iftherapeuticallyequivalentchoicesareavailablethenfactors likeconvenienceandfreedomfromevenminorsideeffectscanandshouldshapebothpatients’andclinicians’preferences.

12Suchas,forexample,whetherornotmedicinalproductscanbetakenorally–andifsohowmanytimesaday–ormustbedeliveredovertimeviainfusion.


Figure 7a Reasons for Not Using DMTs (RRMS)

Figure 7b Reasons for Not Using DMTs (SPMS)

Figure 7c Reasons for Not Using DMTs (PPMS and PRMS)

Greatestbarrier:concerns(51%)

Concerns 51%

Lack of perceived need 33%

Unavailable 12.5%

Other 3.5%

Greatestbarrier:availability(52%)

Concerns 16%


Unavailable 52%

Other 16%

Greatestbarrier:availability(44%)

Concerns 32%


Unavailable 44%

Other 9%

Turning to other expectations relating to currentlyavailable DMTs, Figures 8, 9 and 10 summarise therepliesgiventoasetofquestionsaimedatestablishingrespondents’prioritiesregardingthebenefitstheywantfromtheirmedicines.TheTaP-MSfindingsconfirmandaugment those of earlier research. They in particular


Figure 9. Symptom Improvement Expectations for DMTs

Source:SpoonfulofSugar,2017 Priority rank (max = 1, min = 7)

Improvementinspeechdifficulties

Improvementinmymemoryandthinking

Improvementintinglingandnumbness

Improvementinmybalanceordizziness

Betterbladderandbowelcontrol

Improvementinwalking

Improvementinmyvisionand/oreyemovement

7 6 5 4 3 2 1

AllothercountriesUnitedKingdomGermany

Withregardtothelowlevelofprioritygiventodoctors’opinions recorded in Figure 8, the interpretationoffered here is not that most people with MS do notvalue their neurologists’ or other doctors’ advice. It israther that theywant evidence based guidance ratherthanarbitrarydirectionormedical judgements thatarenot based on a respect for patients’ highest priorityexpectations.Thisimpliesthatotherprofessionalgroupssuchaspharmacists could in futureplay anextendedrole inprovidingmedicinesandothertreatmentrelatedinformationandfacilitatingtherapeuticchoices.

Finally,thedatageneratedbytheTaP-MSsurveysuggestthat(withthepossibleexceptionofAustralians)Englishspeakingcountry respondentsare,whencompared totheirmainlandEuropeanpeers,more likely tosay theyvalue symptom reduction as opposed to progressionslowing. These expectations are not fully independentofeachother.Yetevenso,thisapparentdifferencemay

be relevant to optimising care in contrasting culturalsettings. It is possible, for example, that they could insome cases relate to less adequate symptom controlcausingpatientsavoidabledistress.

The responses given to the question set covered inFigures 8, 9 and 10were in overall terms consistentacrossthecountriescovered.YetthepatternofBritishandtoalesserextenttheGermanprioritiesexpresseddiffered from that of the main body of respondents.Furtherresearchwouldbeneededtofullyvalidateand/orexplainthisobservation.ButintheUKcontextthereisevidenceindicatingthattheMScareprovidedcouldin certain respects have lagged behind that in someotherpartsoftheEU.ItmightbethatBritishtreatmentaccess and standards have been sufficiently differentfromthoseinsettingssuchas,say,Francetoaccountfor variations in expressed patient preferences andneeds.

Figure 8. Key Considerations/Expectations Related to Deciding Whether or Not to Start Taking a New DMT

Priority rank (max = 1, min = 8)Source:SpoonfulofSugar,2017

Mydoctor’sopinionaboutthetreatment

Howoftenthemedicationwouldhavetobetaken

Thewayinwhichthemedicationwouldbetaken

Thepossiblelong-termharmsfrommedication

ThepossiblesideeffectsImayexperiencefromthetreatment

Aslowingdownofmydiseaseprogression

ThepossiblereductionintherelapsesIexperience

Thepossiblereductionofsymptoms

7 6 5 4 3 2 1

Treatmentharmreduction/minimisation

Diseaseandsymptomimprovement

Practicalities

8


New treatment expectations

Just under three quarters of respondents to the TaP-MS survey said that they would expect side effectsfromanynewmedication, ranging fromahighofover90percent inGermanytoa lowofabout50percentin Spain. There is robust evidence that experiencingtreatment side-effects can alter individuals’ medicinestaking.Recentstudieshavealsohighlightedtheextentto which perceived personal sensitivities to treatmentsideeffectsareinfluencedbyfactorssuchasmediaandinformalreportsalongsideothersocialandbehaviouralvariables(Faasseetal,2015).Suchobservationspointto the importance of evidence based contributions topublic debates about health generally and medicinesuseinparticular.

ThedatageneratedbytheTaP-MSinvestigationindicatevery similar patterns of DMT use amongst peoplesayingtheyexpectnewmedicinestohavesideeffectsandthosesayingtheydonotexpectsideeffects.Thisobservationholds forall formsofMS. It indicates thatsimplyaskingpeoplelivingwiththediseasewhetherornottheyexpectnegativetreatmentconsequencesisnotlikelytobeaneffectivepredictorofmedicationrejection.

However,against this there isevidencethat individualswho have unrealistic expectations of medicines theyare takingmayover timebemore likely to stopusingthem than others, should problems occur (Zivadinovet al., 2003). There is therefore a case for seeking toimprovetheinformationandsupportavailabletopeoplewhoappearnottoknow(ortohavenotaccepted)thatDMTs forMS–alongwithallother treatments–carryrisksofharm.This,togetherwithotherinformationaboutthebenefitsoftreatmentandcopingwithMS,shouldbeofferedinwaysconsistentwitheachperson’spreferredlearningandcopingstyles.

Figure 11 provides an overview of the types of sideeffect TaP-MS respondents said they expected tosuffer.Stomachaches,nausea,headachesandmuscleattacks are associated with many forms of medicinaldruguse.However,themostcommonly identifiedsideeffect expectation was fatigue. A significant numberof respondents also citeddepression as anunwanted

consequenceof treatment.MSDMTscancausesucheffects. Yet as fatigue and depression are commonlyexperiencedfacetsofthediseaseitselftheseresponsessuggest theexistenceofanambiguity in themindsofsomepeoplewithMSastothedesirabilityofDMTuse.

Figure 11. Most Frequently Expected DMT Side Effects


Tiredness/Fatigue27%

Stomachupset17%

Nausea15%

Pain12%

Musclepain7%

Headache10%

Depression4%

Unsure4%Other5%

Itispossiblethatknowledgerelatingtothesideeffectsofestablishedtherapies(suchasinterferonbasedproductsthatcancauseflu-likesymptomsanddepression)mayonoccasionsbeingprojectedforwardintopeople’sthinkingabouttakingnew,previouslyuntried,treatments. Ifthishypothesiscanbevalidatedcliniciansandserviceusersshouldbewarnedof the risk thatmisplacedconcernscouldunderminebeneficialmedicinesuseand impedeefforts to enhance outcomes. The scale of the healthandfinancialcoststhiscouldresultinmaybesufficientto justify significantly increasedspendingon improvingmedicinestakingrelatedsupport.

Figures12and13describeexpectationsobservedinthecontextofthe impactsthatnewmedicinesshouldhaveonthequalityoflifeofpeoplewithMSandtheirabilitytoliveastheywantwithoutintrusivesymptomslimitingtheirfreedoms.Thesedataagainhighlight the importanceoffatigue reductionand thedegree towhichpeople livingwith MS seek more energy and mobility, coupled withfewerrelapsesandslowerorhalteddiseaseprogression.

Figure 10. Symptom Reduction Priorities


Fewersexualproblems

Reductionintremors/shaking

Reductioninpain

Reductioninspasmsandstiffness

Feelinglesstiredandfatigued

5 4 3 2 1

Priority rank (max = 1, min = 5)


Suchfindingsarenotunexpected.Butconsideredagainstthe background analysis offered earlier in this reporttheysignalthattomeettheexpectationsofPLwMSaswellaspossibletreatmentprovidersshouldnotconfinetheirattentiontomeetingbasiccareneeds.Theyoughtinadditionbeseeking tocare forpeoplewithMS inaholisticmannerthatenablesindividualstopursuealltheirgoalsinlife.Thisfavoursseekingtocombinethebenefitsofnursing,pharmaceutical,psychological, rehabilitativeandotherinterventionsinaco-ordinatedmanner.

Socially defined expectations

Following on from the above, the responses given inrelation to the four test statements shown in Figure14underlinethefactthatmost individualsarenotonlyconcernedwith their immediate wellbeing. Overall, 44percentofall those takingpart in theTaP-MSsurveyagreedor strongly agreedwith the statement ‘I would

prioritise a long life, regardless of any physical disabilities I might develop’.

Justover30percentdisagreed.Theremainderneitheragreednordisagreed.OnacountrybasisAmerican(71percent),Canadian (64percent),British (61percent)and Australian (57 per cent) respondents were mostlikely tosay that theywouldprioritisea long lifeaboveall other considerations.By contrast, less than30percentofthoselivinginFrance,Germany,Italy,SpainandSwedenexpressedagreementwiththisstatement.

‘Mainland’EuropeanswereabouttwiceaslikelyasweretheirEnglishspeakingcounter-partstoactivelydisagree.Thisobservationisagainsuggestiveofculturalvariationsthat could impactonhealth and social careprovision.AlthoughitsapplicabilityoutsidetheMScontextneedsfurther investigation itmight, for instance, offer insightastowhyservicefundersandotherhealthcarerelateddecision makers in settings such as France may beprepared to give more weight to quality of life linkedconsiderations independentlyofsurvivaldurationsthantheirequivalentsincountriesliketheUK.

Therewasstrongerandmoreuniformagreementwiththestatement‘I would prioritise a treatment that assures me that my MS will not progress any further over a medicine for symptom relief.’Overall,approachingfourfifths(78percent)ofrespondentssaidthattheyagreed,abouthalfofthemstrongly.Littlemorethanonepersonintwenty(circa6percent)saidthattheydisagreed.

Symptom relief and stopping or slowing diseaseprogressionareoftencloselyintertwined.Nevertheless,these responses validate findings about the value ofslowingorstoppingdiseaseprogressionreportedearlierand imply that, from a patient-centred standpoint,agencies like pharmaceutical companies and public

Figure 12: Quality of Life Improvements Most Expected from New Treatments


Moreactiveandenergetic43%

Improvedwellbeing12%

Independence13%

Lesspain9%

Bettersociallife7%

Idon’texpectanychanges8%

Bettersleep6%

Other3%

Figure 13: MS Symptom Improvements Most Expected from New Treatments


UnitedStatesofAmerica

UnitedKingdom

Sweden

Spain

Italy

Germany

France

Canada

Australia

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Fewersymptoms Idon’texpectanyimprovement Physicalsymptomsimprovement Lessrelapses

Moremobility Slowerdiseaseprogression Other Cognitiveandemotionalsymptomimprovement


research funders should concentrate their investmentsin projects aimed at developingmore effectivemeansof halting the disease processes at the heart of MS.However, ifalternativeopportunitiestotreatsymptomssuch as fatigue arise they should not be ignored, notleastbecause theymayhave importantapplications inareasoutsidetheMSsphere.

With regard to the statement ‘I would prioritise preventing MS in future generations over developing better treatments for people currently living with MS’56 per cent of all respondents expressed agreement.AtthenationallevelsupportforthisviewwasstrongestinFrance,where82percentof respondentswithMSindicatedpositivesupport.IntheUS76percentagreedorstronglyagreed.Theaveragelevelofconcurrenceinall the other countries included in the overall TaP-MSsamplewasintheorderof45percent.

One interpretation of this finding is that althoughAmericansmayreportavaluedrivendesiretostayaliveeven if they have to endure serious disability/distress,theyalsohaveastrongcollectiveethicfavouringfuturediseaseavoidance.The resultsoutlinedhere imply theexistence of similar national/cultural values relatingto population wide disease prevention in the FrenchRepublic, alongside a more nuanced approach topersonalsurvivalasagainstwell-being.

Finally, seven in every ten respondents (69 per cent)agreedorstronglyagreedwiththestatement‘I expect that MS will be effectively curable in 20 years’.AmongsttheoverallpopulationtakingpartintheTaP-MSsurveyonly12percentofrespondentsexpresseddisagreement,includingjust7percentoftheAmericansinvolved.

However, theproportiondisagreeing amongstPLwMSfrom the UK was 29 per cent. Just 49 per cent ofBritish respondents agreed. This is unlikely to be a

chanceobservation. In thecontextof individuals livingwith PPMS and PRMS, approaching 95 per cent ofAmericanswiththeseconditionssaidthattheythinkMSwillbeeffectivelycurableintwentyyears.Thiscompareswithafigureof76percentforpeoplewithPPMS/PRMSfromtheothercountriescoveredinthesurveywhosaidthey were taking a DMT. The figure for all those withdiagnosesofPPMSorPRMSlivingoutsidetheUSwhoexpectMStobeeffectivelycurableintwentyyearswas,forDMTusersandnon-userscombined,65percent.

Once again, research would be needed to verify thesignificance of these findings. Yet for the purposes ofthispolicyreporttwopossibilitiesareworthhighlighting.ThefirstisthattheUK’scentraltaxationbasedfundingapproach to health care has led to a relatively strongemphasisontheneedforrationingandcostlimitation,asopposedtobelievinginthepositivebenefitsofimprovingtreatmentoutcomesand fosteringpharmaceutical andotherformsofinnovation.

A consequence of attempts to achieve ‘therapeuticausterity’couldperhapshavebeenthat ithasnotonlyundermined public and patient confidence in servicestandards,butreducedexpectationsastothebenefitsoftreatmentsforconditionslikeMS.InthiscontextitmayberelevanttorecordthattheUnitedNations’Committeeon the Rights of Persons with Disabilities (2016) wasrecentlyhighlycriticalofUK,andinparticularlyEnglish,authoritiesforfailingtoprotectthewell-beingofpeoplewithdisablingdisordersandpermittinghealthandsocialcarestandardstobedegraded.

Asecond,linked,hypothesisisthatloweredexpectationsof therapeuticadvanceactivelyharmsome individuals.There is limited but nevertheless potentially importantqualitative evidence that having positive attitudestowards scientific progress and the ongoing evolutionof more effective treatments can help people with

Figure 14. Levels of Agreement and Disagreement with Test Statements


0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

IwouldprioritiseatreatmentthatassuresmethatmyMSwillnotprogressanyfurtheroveramedicinefor

symptomrelief

IexpectthatMSwillbeeffectivelycurablewithin20(twenty)years

IwouldprioritisepreventingMSinfuturegenerationsoverdevelopingbettertreatmentsforpeoplecurrently

livingwithMS

Iwouldprioritisealonglife,regardlessofanyphysicaldisabilitiesImightdevelop

Stronglyagree Agree Neitheragreenordisagree Disagree Stronglydisagree


conditionssuchasMSmaintainhopeandlivewiththeirillnessaswell aspossible – see, for instance,MurphyMiller(1997)andSoundyetal(2011).

Thereisaneedforappropriateeconomyandaffordabilityin all areas of health and social care. Yet maintaininggoodmoraleandoptimismamongstpeople livingwithprogressive,disablingand life threateningconditions isalsoimportant.Itinpartdependsonpromotinginformedunderstandingsofthevalueoftherapeuticdevelopmentslike those now taking place in theMS field. Agenciesthatmay be trying to limit public service spending viadelayingtheuptakeofnewtherapiesshouldtrytoavoiddoing so in ways that engender pessimism, damagefutureexpectationsandundermineday-to-daylevelsofconfidenceandhope.

Policy Issues and Political ChoicesThere are many examples of new medical andpharmaceutical technologieshaving long-term impactsextendingwellbeyondtheirvaluetopatientsseenonlyasisolated‘personalutilitymaximising’ individuals.Theintroductionoforalcontraceptives(OCPs)inthe1960sis one of the best known. In the decades since thenOCPshavecontributedtofreeingmanywomentotakepart inhigher educationandacquire social rolesonceenjoyedonlybymen(GoldinandKatz,2002).

Thishas inturnbroughtbenefits for theirpartnersandchildren.Vaccinesforconditionslikepolioandmedicinesused to prevent and treat conditions such as pepticulcerdiseaseandvasculardisordershavealsohavehadimportantimpactsthatmaybeinvisibletoobserverswhoareunduly reliantonshort termmeasuresof individualbenefitliketheEQ5D.

The introduction of more effective treatments andeventuallyfunctionalorcompletecuresforMSwillalsogenerate a range of individual and societal benefitsextendingbeyondconventionallymeasuredQoLgains,includingreducingthenumbersofpeoplelivingwhatmayberegardedasunfairlylimitedlives13.Itisalsoimportanttorecordthatfromalongertermeconomicperspectivethe prices of medicines decline as the patents andotherformsofintellectualpropertyprotectionneededtoencouragefurtherinvestmentinresearchandinnovationexpire. Competition between suppliers coupled withproductionandclinicalpracticeimprovementsenhancestheircosteffectiveness.

13TheuncertaintiesandfearssurroundingMScanimpedelongtermplanninginwaysthatharmnotonlyindividualsbutentirefamilies.Eveniftheclinicalbenefitsofbettertherapiesrelatetothestabilisationofdisabilitiesratherthaneliminatingthem,theirvaluecanbeconsiderable.Independentlyofthis,reducedlevelsofdiseaselinkedsocialinequalitycouldalsogenerateadditionalwelfaregainsforallcommunitymembers,includingthehealthyindividualsandgroups.

However, attractiveas this long termvision is therearea variety of barriers to its realisation. They range frompolicies which impede the introduction of better waysofpreventingandalleviatingdisease through toculturalbiasesthatdrawattentionawayfromthe importanceofreducing health inequalities andprotecting the interestsofminority groups affected by relatively rare conditionssuchas, for instance,PPMS.Thebrief analysisofferedbelowis intendedtobeofparticularrelevancetopolicymakersconcernedwithpromoting improvements inMSrelatedhealthoutcomes,andensuring thatpeoplewithalldisablingillnessesareasadvantagedaspossibleinlife.

Improving service performance

Opportunities for enhancing thebenefitsgeneratedbycurrentMSserviceprovisionsinclude:

• facilitating MS prevention or onset delay wheneverpossible;

• fostering early diagnosis and the prompt initiationof disease modifying treatment in order to slow orhalt disease progression and stopmajor disabilitiesemerging;

• psychologically supporting PLwMS at all stages oftheirdiseaseexperience;

• assuringoptimallyappropriatetherapyselectionatalltimes;

• combining medical, nursing, pharmaceutical,psychological and rehabilitative and social care inwaysthatmaximisetheirsynergisticvalueandprovidepatientswithanauditablerecordofcoherentsupport;and

• furtherstrengtheningsocialandeconomicprovisionsthat offset the impacts of disabilities on individuals,familiesandcommunities–inthiscontextnationalorsupra-national standards should be put in place inordertopermitperformanceevaluations.

At present there is no method of preventing MS thatiscomparableto,say,poliovaccinationand itsprovenvalueinguardingagainsttheilleffectsofpolioinfectionafterthefirstoneortwoyearsoflife.Butasdescribedearlier in this report, there isevidence thatnotstartingor stopping smoking as soon as possible, eatingwellandreducingobesityrates,takingregularexerciseandcontrolling blood pressure levels and allied vasculardiseaserisk factorscan–aswellasofferinggains likecutting type 2 diabetes rates –maintain ‘brain health’and reduce central nervous system tissue lossesthroughout life (Giovannoni at al, 2015). The timemaynow also have come for health professionals, parentsandpolicymakerstoactontheincreasingbodyofdatalinkingvitaminDdeficienciestoMS.


Theextenttowhich,incurrentcircumstances,increasedpublic awareness of such opportunities could lead tosignificantcutsindiseaseincidenceremainsdebateable.Yet the fact that lifestyle choices combined with theappropriate use of medicines can have importantpreventiveeffectscouldwellbeanimportantpointertothefutureofMSlinkedharmreduction.

Some observers involved in the provision of ‘evidencebasedcare’mayarguethatthebenefitsofpromptDMTuse are not as yet fully proven. Concerns about theeffectiveness and side effects of current therapies canincreasetheanxietyanduncertaintyfeltbysomepeoplewithMSwhentheyareasked if theywish toacceptorforego treatment. However, there is already a stronglogicalandvaluebasedcaseforquestioningtherapeuticconservatismandseeking tooptimise thechances thatpeoplewithearlystagemultiplesclerosishavetoavoidinfuturehavingtolivewithmajordisabilities.

Interventionsdesignedtosupportearlydiagnosisincludeintroducing school based and wider public (health)programmes aimed at raising MS awareness andcommunity-widewillingnesstoreportwhatmaybeinitialsymptoms. Investing more in the identification, wherepossible, of genetic risks and providing good universalaccess toMRI testingshouldalsohave thecapacity togenerateadditionalbenefit.Nationalpolicymakersmight,forinstance,inadditiontoestablishingorstrengtheningMSregistriesinordermonitortreatmentqualityandoutcomes,seektoinstitutefreestandingauditsthatcompareaccesstoMRIbaseddiagnosticanddiseaseprogressiontestingonalocalitybylocalitybasis.Disseminatingthefindingsofsuchprojectscouldhelpcreatethepoliticalwillneededto address service shortfalls linked to socio-economicdisadvantage.

Regionalandglobalhealthpolicymakersmayalsowishtocommissionandpublicisetheresultsofhighquality,statisticallyrobust,analysesoftheextenttowhich,evenafterGDPvariationsareaccountedfor,accesstotimelyMS diagnoses and optimally effective treatments is insome countries markedly better than in others. Suchstudiesarealreadyavailableintheoncologyfield,alongwithoutcomedata.

Another quality and performance improvement toolwouldbe tomonitor the time taken for people labelledas havingCISorRIS (clinically or radiologically isolatedsyndromes)toreceiveeitheraconfirmedMSdiagnosisorbetolddefinitivelythattheydonothavethecondition.TheviewsofthoseeventuallyfoundtobefreeofMSregardingthe support they received during periods of diagnosticuncertaintycouldbeparticularlyvaluable.

In addition to the stresses associated with their initialdiagnosis (Bogosian et al, 2009) people with RRMSare likely to have to face a series of ‘progressionpoints’ atwhich newdisabilities or symptoms appear.

They are eventually likely to have to ‘transition’ to anSPMS diagnosis. At worst, this can be experiencedas a form of personal failure or defeat, similar to thefeeling experienced by women initially diagnosed withapotentiallycurablebreastcancercanhaveiftheyaresubsequentlyfoundtohaveametastaticillness(Taylor,2017).TheTaP-MSfindingsreviewedpreviouslyhighlightthe importanceofbeingsensitive topatientschangingrequirements,aswellastotheirwishestobefreefromsymptomssuchasfatigueandbeingdeprivedofenergythroughoutalldiseasestages.

Thequalityofcommunicationandinformationprovisionthat exists between health care providers and serviceusers with MS can be a critical determinate of howwell such challenges, together with issues relating tounderstandingandadapting toprognostic information,are handled. One problem with quantitative researchcan be that pre-determined questions based onconventionalmedicalmodelsofdiseaseareunlikely torevealunanticipatedissues.

Some investigations show relatively high levels of MSpatient satisfaction regarding communication withdoctors (see, for instance, Messina et al, 2015). Butqualitativestudiessuggesttheexistenceofcomplexanddeep-rootedcommunicationdifficultiesbetweenhealthcareprofessionalsandpeoplelivingwithMS(Dennisonetal,2016).Thediscussionoffered inBox4 indicatesthat opportunities to investigate such problems andfosterappropriateservice improvementsdeservemoreattention. Techniques employed in the TaP-MS studycould in future be used to test communication qualitylinkedhypotheses.

Good quality pharmaceutical care also requires highstandards of communication and respect for patientpreferences, coupled with expert knowledge of thepharmacologicalandotherpropertiesofexistingandnewtherapies. Delivering pharmaceutical care well involvesbeing sensitive to both direct and indirect warnings ofunwanted drug interactions and side-effects as well assignsof reneweddiseaseactivity, anda commitment toprovidingwhatevertherapiesbestmeettheneedsofeachindividualateachpointintheirillness.

Inthecontextofcombiningdifferentformsoftreatment,care and support as effectively possible, the availableresearch shows that even in adjacent countries theservicemixesofferedtopeoplewithMSvarywidely.Forexample,Swedeninvestsmoreinsocialcarerelativetohealthcarethanothernations;inDenmarkpeoplewithMSappeartohaveanunusuallyhighrateofspecialistnurse contacts; inGermany peoplewithMS see theirneurologistsmorefrequentlythandootherEuropeanMSpatients;andinHungaryandPolandtherearehighratesofhospitaladmission(Kobeltetal,2017).


Box 4. Opportunities for Better Communication

Because of the nature of MS as a fluctuating,progressive conditionwith varying symptomsandanuncertain course, good supportive communicationbetween health and social care professionals andwomen and men with the condition has a specialparttoplayinoptimisingoutcomes.IfPLwMScanbehelpedthroughchallengeslikethosesurroundingtheirinitialdiagnosisinwaysthatenablethemtoacceptthediseasewithaslittleavoidabledistressaspossibleandplanconstructivelyforthefuturetheyarelikelytoenjoya better quality of life than thosewho to ‘blank out’awarenessoftheirsituation–see, forexample,NICE(2014).

However, individualswithestablishedwaysofcopingthat involve ‘blunting’ (defined as flattening theirresponses via denial and other avoidance strategies)can find it very difficult to change their approaches.Those who constantly seek to be present focusedand‘live for the day’mayseeitasthemostviablewayforwardinwhattheymightotherwiseexperienceasahopelesssituation.Theymightinpracticeprefernottoconsidertheirlikelyfuture,evenifwhenaskedtheysaytheywantprognosticinformation.

The development of more reliable instruments forpredictingthepathofMSisthereforeinsomerespectsproblematic.Insensitivecommunicationscould,evenifwell intended, domore harm than good. Awarenessofthispossibilitymightinturndiscourageprofessionalattemptstoshareknowledgeandusefulinsights.

A qualitative study byDennison et al (2017) on howpeople with MS experience prognostic uncertaintyandacquireinformationaboutthelikelycourseoftheirillness illustrates this dilemma. It foundevidence that

although patients develop expectations about theirdiseasetrajectoriestheyoftendosowithminimalinputfromhealthprofessionals.Thiscancreateambiguousfeelings.Itmight,evenasnewtherapeuticoptionswithimproved capacities to prevent disease progressionemerge,limitthedevelopmentofenhancedtreatmentexpectationsand impedetheoptimaluseofeffectiveDMTs.

Asnoted in themain text, goodcommunicationandinformation provision practices involve using clearlanguagewhilenot ‘talkingdown’;beingopenaboutthenatureofMSanditsvariablecourse,whileatthesame time showing confident biomedical expertise;andspendingenoughtimetoensurethatthequestionsandconcernsofindividualswithMSare‘visiblylistenedto’ and addressed empathetically. This requires theskills needed to assess the personal learning stylesof each service user (for instance, ‘blunters’ mayrespondwell to generalised information,while otherswant direct, fully personalised, messages) and craftcommunicationsappropriately.

On the service user side an understanding of theproblemsthattalkinginafullyengagedwayaboutMSmaypresentforbothinformalandformalcarersshouldprove valuable. But for the purposes of this reportthe main point to emphasise is that as diagnostic,prognostic and therapeutic technologies go onimproving therewillbeacontinuingneed to invest inhighqualitycommunicationbetweenpeoplewhohaveMS and their professional advisors and supporters.This will include developing and using instrumentsthat reveal individuals’ preferredways of coping andexchangingconfidencesabouttheirinnerthoughtsandexperiences.

Alongsidesuchvariationstherearedangersof‘siloed’service provisions and of inadequate levels of cross-national research into which patterns of service arelikely tobe affordable andmost satisfactory from thepatient/user viewpoint. It might be of global value,for instance, to peoplewithMS ifmoremedical andallied researchwere to be focused on evaluating theextent to which the forms of social care provided inSwedeninfluencehealthserviceuseandthelikelihoodofpatientswithRRMSandotherfluctuatingdisordersrequiring emergency health care admissions duringrelapses. Understanding more about how culturaldifferences shapehealth and social carepolicies andpublic beliefs about the value of innovations in areassuch as genetics and treating non-communicabledisease could open the way to both enhancedwell-beingandefficiencygains.

Funding innovation aimed at resolving unmet needs

Despite the advances of recent years there are stillmany ways in which the technologies presentlyavailable for diagnosing and treatingmultiple sclerosisrequire improvement (MehrandZimmerman,2015). Inaddition to thebroadgoals of diseaseprevention andfinding more effective ways of halting or slowing MSprogression,prioritiesrangefromdevelopingbetterwaysof countering fatigue to identifyingnewbiomarkers foruseinpersonalisingtherapeuticregimensandminimisingthedanger that treatmentswill cause iatrogenicharm.Advances are also needed in areas like improving themeasurementofthefunctionalandpatientexperiencedoutcomes ofMS therapy provision, and in supportingadherencetopatientagreedmedicationregimens.

ItwouldbebeyondthescopeofthisreviewtoattempttoofferatechnicalevaluationofemergentopportunitiesfortreatingMScoveringareassuchasgenetherapyand


immunotherapy14or–astouchedoninBox2,page8–developinga vaccine thatmightprevent cases fromoccurring.Butitisrelevanttohighlighttwosetsofpointsrelatingtothefundingofhealthsectorrelatedresearchanddevelopment.

The complexity of the causes and impacts ofmultiplesclerosis isagood illustrationof the fact thatbecausemuch ‘low hanging biomedical fruit’ has already beenpicked the research challenges facing agencies suchas Universities and pharmaceutical companies todayaregreater than in thepast.Theyarealso likely tobemuch more expensive to resolve than was the casein the twentieth century, partly because regulatoryrequirements were not as extensive then as they aretoday and partly because of the sophistication of theresearchmethodologiesnowrequired.

Even if it were demonstrated that, for example,immunisationagainstEpstein-Barrvirus infectioncouldplayanimportantfuturepart inprotectingchildrenandyoungadultsfromMS,developingavaccineapprovedformasspaediatricusemighttakeseveraldecadesandcostmore thanabillionEurosorUSDollars. It is lessthancertainthattrialscouldbeconductedassafelyasregulatorswoulddemand.Buteven if thisbarrierwereto be overcome the financial risks involved would bevery considerable. Alone, even the largest of privatecompaniesmightbeunwillingorunabletoacceptthem.

It ispossiblethatsimilardifficultieswillbeencounteredif andwhen attempts aremade to develop alternativeways forward, such as producing potentially curativeimmunotherapiesforpeoplewithMS.The‘moon-shot’scaleofthetasksandchallengesinvolvedsuggeststhatnewformsofGovernmentalandindustrialcollaborationmayberequiredifpublicandpatientexpectationsofafunctionalcureforconditionslikeMSaretobemetbyorbeforethemiddleofthiscentury(EuropeanCommission,2016;Bell,2017).

Following on from this, some commentators fear thepricesofnewmedicinesareorwillbecomeunsustainablyhighandthatassuringuniversalaccesstoallinneedisnotpossible.ButfromtheviewpointofpeoplewithMSandotherswishingtoseecontinuingtherapeuticinnovationinareaslikeneurologyandimmunologytherearestrongarguments in favour of building as constructively aspossibleontheexisting IP (intellectualproperty)basedmodel of ‘market funded’ private sector therapeuticinnovation backed by publicly funded fundamentalresearch.Inthiscontextitisrelevanttorecordthat:

• the overall proportion of health spending devotedtopharmaceuticaloutlayshasbeen relatively stablein theOECDnations forseveraldecades.Sincethe

14Whichmight,forinstance,eventuallyinvolveremovingimmunesystemcellsfrompatients,enhancingtheirbiologicalpropertiesandthenre-introducingtheminthehopeofeliminatingMS.

economiccrisis of 2008/9 it has inmany instancesfallen (OECD, 2015). Pharmaceutical spending iscurrentlybelievedtoaccountforabout15percentoftheaverageOECDcountry’shealthcarecosts (thatis,around1.5percentofGDP)althoughbecauseofdiscountingthismaybeanover-estimate;

• key aspects of pharmaceutical sector economicsincludethefactthat,asalreadyalludedto,thepricesof products likemedicines normally fall significantlyaftertheyloseIPprotection.Itisalsoofnotethatinrecent years increases in theaverage launchpricesof innovativeproducts havebeenoffset by the factthattheirvolumesalesareoftenlowerthanthoseofpreviousgenerationsofnovelpharmaceuticals;and

• asandwhennewbiologicalsciencebasedmethodsofpreventingorcuringNCDslikeMSbecomeavailabletheage-specificcostsofhealthcarewillovertimefall,despitethefactthatallnewproducts(fromelectronicgoodstonovelformsoftransport)arerelativelyexpensiveatthepoint of market entry as compared with establishedtechnologies.Shorttermfinancialbarrierstotheuseofbeneficialinnovationsshouldnotbepermittedtounfairlydelaylessadvantagedconsumers’accesstothem,orobscurethelongtermsocialandeconomicgainstheywillprovideforentirecommunities.

Theseandalliedobservationsindicatethatsupplyingbettertreatmentstoallinneedwouldbeaffordablewithsufficientpoliticalwill.Onewayoranotherresearchanddevelopmentand theassociatedcostsof ‘riskcapital’ (that is,moneyinvestedinareasinwhichanyoneprojecthasonlyalowchanceofyieldingreturns)willhavetobemetifsocietieswish to benefit from ongoing bio-pharmaceutical andbio-medicaladvances.But theamounts involvedarenotprohibitivelylarge,andwillovertimebecounter-balancedbytheeconomiesgeneratedbybetterhealthoutcomes.

‘Patient led’ scientific and service development

PeoplelivingwithconditionslikeRRMS,SPMSandPPMScanofferuniqueinsights into livingwiththeirdisorderstoprofessionalandotheraudiences.Themorethatrobustlyappointed patient representatives are in a positionto witness and influence how research and resourceallocationdecisionsaremadethemoretheyshouldbeabletoprevent institutionalised injustices andprotect nationalandglobalpublicinterestsinthepreventionandalleviationofmental and physical disabilities and social handicaps.Theycanalsoplaykeyrolesinareaslikepromotinggreaterpharmaceutical literacy and informing public debate onissues such as understanding medicines side effects inwaysthatdonotdiscouragetheirbeneficialuse.

Critics of patient involvement in areas such as thegovernance of clinical trials and the management of


healthandsocialcaresometimesquestiontheexpertiseand objectivity of those livingwith conditions likeMS.Itmaybeclaimedthat inputs frompatientgroupsandindividualswithdisablingconditionsintopolicydebatescanleadtodecisionmakingbeingdistortedby‘specialpleading’. Itmight also be implied that patient groupsthat receive funding from sources like research basedpharmaceutical companies are serving sectional ends.(See,forexample,ArieandMahoney,2014.)

The opportunity cost of the latter could – assumingfixed health sector resource allocations – be that othergroups with legitimate claims to better care sufferneglect.Transparencyandmanagingconflictsofinterestappropriatelyarethereforeimportant.However,thisisnottosaythatpeoplewithconditionssuchasMSshouldnotpressasrobustlyaspossibleforgoodcarestandardsandongoing research that could in future benefit the entirecommunity. In response to concerns about acceptingindustry linked funding, advocates of better caremightpoint out that accepting public funding can also carryrisksshould,forinstance,itonoccasionsbeassociatedwithpressurestoacceptquestionablelimitsonaccesstopharmaceuticalorotherformsofcare.

Theburdensimposedbymultiplesclerosisonindividualsandfamiliesarestillnotwidelyunderstoodbymanyofthose who come into contact with people living withthe disease, even in themost economically advancedpartsoftheworld.Nor–arguably–isthefullpotentialofimmunologicallybasedandotherformsofbiomedicalinnovation to benefit humanity as a whole as widelyappreciatedasitoughttobe.

The view taken here is that MS patient groups have,alongwith independent individualsworking tomake adifference,avitalroletoplayincorrectingthissituationandpromotingbetteroutcomes.Competentandwell-motivated service user representation can also makevaluablecontributionsinareassuchas,say,establishingdisease registries and the data bases needed formonitoringvariationsindiagnosticserviceperformanceandtreatmentoutcomes.

Conflicts of interest of all types should be addressedwheneverthereisreasonforfearingharm.Thisappliesto everyone in society, from health professionals toeconomists, journalists and politicians. But awarenessof this should not discourage advocacy groups fromjoining with other stakeholders with whom they sharecommonintereststopressforbettersupportforpeoplewithMS.Thefactthatworkingtobuildgreaterserviceexpectationsmightcausepeoplewithdifferentprioritiesto ask critical questions when demands for furtherinvestment are successfully expressed is not a reasonforpatientgroups tostopcalling for thebestpossiblehealthandsocialcare.

ConclusionCharles Dickens published Great Expectations at thestart of 1860s, the decade in which in Paris Charcotconductedhispioneeringworkonmultiplesclerosis.AcoremessageofDicken’snovelisthatalthoughitmaybehighlydesirabletoapproachlifewithenthusiasmandhope, chance often leads to unfairness and injustice.Evenforthemostfortunate,earlyexpectationsarerarelyfullyrealised.

ThecontinuingburdensimposedonindividualswhoasadolescentsoryoungadultsdevelopMSare,150yearsaftertheeraofCharcotandDickens,arobustillustrationofthetruthofthisinsightintothehumancondition.Yetimportanttherapeuticprogresshasrecentlybeenmade,andfurtheradvancesaretobeexpectedasthetwentyfirstcenturyunfolds.Accesstomoreeffectivetreatmentscoupledwithappropriatesocialandeconomicsupportcan and should curb disease progression, preventdisabilitiesandimprovethequalityoflifeforpeoplelivingwithallformsofmultiplesclerosis.

Such advanceswill also enhance thewellbeing of thepartners,children,parentsandotherrelativesofpeoplelivingwithMS.Thankstotheprogressalreadyachievedsince the 1990s people living with MS in regions likeEurope, North America and Australasia are now in abetterpositionthaneverbeforetoenjoytheir livesandplayactivepartsinpromotingongoingimprovementsintheir own treatment andcare, aswell as thatof othermembersofsociety.

For individuals who already have established MSrelateddisabilitiesthe importanceofdiseasemodifyingtreatmentsaloneshouldnotbeoverstated.Theyneedaccess not only to good quality pharmaceutical carecapableofslowingorstoppingthefurtherprogressionoftheirillnessbutotherformsofsupportaimedatprovidingthemandtheircarerswithanoptimalqualityoflife.YetasscientificandtherapeuticdevelopmentscontinuepeoplewithearlystageMSwillbeabletoexpectwithincreasingconfidenceabetterfuturederivedmoreexclusivelyfromagrowingcapacitytocontrolthefundamentalbiologicalmechanismslyingattheheartofthedisorder.

Pharmaceutical and other advances against disablingconditionslikeMSoughtalso,inadditiontotheirbenefitsfor individuals, help make societies more equal, andeveryoneinthemcollectivelylessvulnerabletorandommisfortunes.Seen from thisperspective improvingMSprevention anddevelopingbetter treatments should inthefinalanalysisberegardedaseverybody’sbusiness,not just thatof thosemostat riskof having their livesdefinedbyadiseasewithwhich theyhave throughnofaultoftheirsbeenobligedlive.


References and Further ReadingAchesonE.D.,BachrachC.A.andWrightF.M.(1960)Somecommentsonthere;tionshipofthedistributionofmultiplesclerosistolatitude,solarradiation,andothervariables.Acta Psychiatrica Scandinavica supplement35,132-147

AirasL.(2015).Hormonalandgender-relatedimmunechangesinmultiplesclerosis.Acta Neurologica Scandinavica, 132(199),62-70.doi:10.1111/ane.12433

AranowC.(2011)VitaminDandtheImmuneSystem.Journ Investigative Med59(6)881-886

AransonK.J.(1997)Qualityoflifeamongpersonswithmultiplesclerosisandtheircaregivers.Neurology48(1),74-80

ArieS.andMahonyC.(2014)ShouldPatientGroupsbeMoreTransparentAbouttheirFunding?British Med Journ 349 doi:https://doi.org/10.1136/bmj.g5892

AuditCommission(2001)ASpoonfulofSugar.London:TheAuditCommissionforEnglandandWales

Ascherio,A.,MungerK.L.etal.(2012).“Theinitiationandpreventionofmultiplesclerosis.”Nat Rev Neurol8(11):602-612.

Baker,L.M.(1996).Astudyofthenatureofinformationneededbywomenwithmultiplesclerosis.Library & Information Science Research, 18(1),67-81.

Baker,L.M.(1998).Sensemalkinginmultiplesclerosis:theInformationneedsofpeopleduringanacuteexacerbation.Qualitative Health Research, 8(1),106-120.

BassiM.,FalautanoM.,CiliaSetal(2016)IllnessPerceptionandWell-beingamongPersonswithMultipleSclerosisandtheirCaregivers.JournClinPsychinMedSettings23(1)33-52

BeattyW.W.,HamesK.A.,BiancoC.R.etal(1998)Correlatesofcopingstyleinpatientswithmultiplesclerosis.MultipleSclerosisjournal4(5),440-443

BellJ.(2017)LifeSciences:IndustrialStrategy.London:OfficeforLifeSciences

Boeije,H.R.andJanssens,A.C.J.(2004).‘Itmighthappenoritmightnot’:howpatientswithmultiplesclerosisexplaintheirperceptionofprognosticrisk.Social Science and Medicine, 59(4),861-868.

BogosianA.,Moss-MorrisR.,YardleyL.andDennisonL.(2009).ExperiencesofthePartnersofPeopleintheEarlyStagesofMultipleSclerosis.MultipleSclerosisJournal15(7),876-884

Bove,R.,Alwan,S.,Friedman,J.M.etal(2014).Managementofmultiplesclerosisduringpregnancyandthereproductiveyears:asystematicreview.Obstetrics and Gynecology, 124(6),1157-1168.

BraleyT.J.andChervinR.D.(2010)FatigueinMultipleSclerosis:Mechanisms,Evaluation,andTreatment.Sleep33(8)1061-1067

BuryM.(1982)ChronicIllnessasbiographicaldisruption.Sociology of Health and Illness4(2)167-182

BuryM(2017)Personalcommunication

CIB(2017).Magnetic Resonance Imaging (MRI) Equipment, Operations and Planning in the NHS.Available at https://www.rcr.ac.uk/sites/default/files/cib_mri_equipment_report.pdf Last accessed October 2017

Compston,A.andColes,A.(2008).Multiplesclerosis.Lancet, 372(9648),1502-1517.doi:10.1016/s0140-6736(08)61620-7

Confavreux,C.,Hutchinson,M.,Hours,M.M.,Cortinovis-Tourniaire,P.,&Moreau,T.(1998).Rateofpregnancy-relatedrelapseinmultiplesclerosis.PregnancyinMultipleSclerosisGroup.New England Journal of Medicine, 339(5),285-291.doi:10.1056/nejm199807303390501

Crayton,H.,Heyman,R.A.andRossman,H.S.(2004).Amultimodalapproachtomanagingthesymptomsofmultiplesclerosis.Neurology, 63(11suppl5),S12-S18.

Dahlgren,G.andWhitehead,M.(1991)Policiesandstrategiestopromotesocialequityinhealth,Stockholm:InstituteofFuturesStudies.

DahlgenG.andWhiteheadM.(2006).EuropeanStrategiesforTacklingSocialInequalitiesinHealth–LevellingUp,PartII.Copenhagen:WHORegionalOfficeforEurope.

DavenportC.(1922)Multiplesclerosis:Fromthestandpointofgeographicaldistributionandrace.Arch Neurology and Psychiatry8,51-58

Daumer,M.,Neuhaus,A.,Lederer,C.,Scholz,M.etal(2007).Prognosisoftheindividualcourseofdisease-stepsindevelopingadecisionsupporttoolforMultipleSclerosis.BMC Medical Informatics and Decision Making, 7(1),11.

Degenhardt,A.,Ramagopalan,S.V.,Scalfari,A.andEbers,G.C.(2009).Clinicalprognosticfactorsinmultiplesclerosis:anaturalhistoryreview.Nature Reviews: Neurology, 5(12),672-682.doi:10.1038/nrneurol.2009.178

Dennison,L.,Smith,E.M.,Bradbury,K.,andGalea,I.(2016).HowDoPeoplewithMultipleSclerosisExperiencePrognosticUncertaintyandPrognosisCommunication?AQualitativeStudy.PloS One, 11(7).doi:10.1371/journal.pone.0158982

Devins,G.M.,Edworthy,S.M.,Klein,G.M.etal(1993).Differencesinillnessintrusivenessacrossrheumatoidarthritis,end-stagerenaldisease,andmultiplesclerosis.The Journal of nervous and mental disease, 181(6),377-381.

D’hooghe,M.B.,andNagels,G.(2010).Long-termeffectsofchildbirthinMS.Journal of Neurology, Neurosurgery and Psychiatry, 81(1),38-41.

DonzeC.,LenneB.,DelegliseJ.etal(2016).EVASEP:ANoninterventionaltudyDescribingthePerceptionsofNeurologists,PatientsandCaregiversinCaregivers’RoleintheSupportofPatientsSufferingfromMultipleSclerosisTreatedwithSubcutaniousInterferonBeta1A.Mult Scler Int4986073.doi: 10.1155/2016/4986073

Elian,M.andDean,G.(1985).Totellornottotellthediagnosisofmultiplesclerosis.The Lancet, 326(8445),27-28.


EuropeanCommission(2014).ThePharmaceuticalIndustry:AStrategicSectorfortheEuropeanEconomy.Commissionstaffworkingdocument.Brussels:theEuropeanCommission.

Faasse,K.,Grey,A.,HorneR.andPetrieKJ2015Highperceivedsensitivitytomedicinesisassociatedwithhighermedicalcareutilisation,increasedsymptomreportingandgreaterinformation-seekingaboutmedication.See comment in PubMed Commons belowPharmacoepidemiol and Drug Safety24(6):592-9.doi:10.1002/pds.3751.

Frohman,E.M.,Stuve,O.,Havrdova,E.etal(2006).Therapeuticconsiderationsfordiseaseprogressioninmultiplesclerosis:evidence,experience,andfutureexpectations.Archives of Neurology, 62(10),1519-1530.doi:10.1001/archneur.62.10.1519

GiovannoniG.,ButzkuevenH.,Dhib-JalbutSetal(2015)Brainhealth:timemattersinmultiplesclerosis.Oxford:OxfordPharmagenesisLtd

Goldin,C.andKatz,L.(2002)ThePowerofthePill:OralContraceptivesandWomen’sCareerandMarriageDecisions.Journal of Political Economy110, 730-770.

GourraudP.A.,HarboH.F.,HauserS.L.andBaranziniS.E.(2012).Thegeneticsofmultiplesclerosis:anup-to-datereview. Immunol Rev248(1):87-103.doi:10.1111/j.1600-065X.2012.01134.

Gottberg,K.,Gardulf,A.andFredrikson,S.(2000).Interferon-betatreatmentforpatientswithmultiplesclerosis:thepatients’perceptionsoftheside-effects.Multiple Sclerosis Journal, 6(5),349-354.

HaflerD.A.(2004).MultipleSclerosis.J Clin Invest113(6):788-94

Handel,A.E.,WilliamsonA.J.etal.(2010).Anupdatedmeta-analysisofriskofmultiplesclerosisfollowinginfectiousmononucleosis.PLoS ONE5(9).

HarboH.F.,GoldR.andTintoréM.(2013).SexandgenderissuesinMultipleSclerosis.Ther Adv Neurol Disord.6(4):237–248

HauserS.L.,Bar-OrG.,ComiG.etal(2017)OcrelizumabversusInterferonBeta-1ainRelapsingMultipleSclerosis.N Engl J Med 376:221-34doi:10.1056/NEJMoa1601277

Hawker,K.,O’Connor,P.,Freedman,M.S.etal(2009).Rituximabinpatientswithprimaryprogressivemultiplesclerosis:Resultsofarandomizeddouble-blindplacebo-controlledmulticentertrial.See comment in PubMed Commons belowAnn Neurol.66(4):460-71.doi:10.1002/ana.21867

Heesen,C.,Böhm,J.,Reich,C.etal(2008).Patientperceptionofbodilyfunctionsinmultiplesclerosis:gaitandvisualfunctionarethemostvaluable.Multiple Sclerosis14(7):988-91.doi:10.1177/1352458508088916.

Heesen,C.,Kasper,J.,Segal,J.etal(2004).Decisionalrolepreferences,riskknowledgeandinformationinterestsinpatientswithmultiplesclerosis.Multiple Sclerosis Journal, 10(6),643-650.

Heesen,C.,Böhm,J.,Reich,C.etal(2008).Patientperceptionofbodilyfunctionsinmultiplesclerosis:gaitandvisualfunctionarethemostvaluable.Multiple Sclerosis.

Heesen,C.,Kleiter,I.,Nguyen,F.etal.(2010).Riskperceptioninnatalizumab-treatedmultiplesclerosispatientsandtheirneurologists.Multiple Sclerosis Journal, 16(12),1507-1512.

ICER(2017).Disease-ModifyingTherapiesforRelapsing-RemittingandPrimary-ProgressiveMultipleSclerosis:EffectivenessandValue.InstituteforClinicalandEconomicReview

Isaaksson,A.K.(2006).Fromsymptomtodiagnosis:illnessexperiencesofmultiplesclerosispatients.The Journal of neuroscience nursing, 38(4),229.

Janssens,A.,DeBoer,J.,VanDoorn,P.etal(2003).Expectationsofwheelchair‐dependencyinrecentlydiagnosedpatientswithmultiplesclerosisandtheirpartners.European Journal of Neurology, 10(3),287-293.

Janssens,A.C.J.,vanDoorn,P.A.,deBoer,J.B.etal(2004).Perceptionofprognosticriskinpatientswithmultiplesclerosis:therelationshipwithanxiety,depression,anddisease-relateddistress.Journal of Clinical Epidemiology, 57(2),180-186.

Johnson,J.(2003).Onreceivingthediagnosisofmultiplesclerosis:managingthetransition.Multiple Sclerosis, 9(1),82-88.doi:10.1191/1352458503ms856oa

Johnson,F.R.,VanHoutven,G.,Özdemir,S.etal(2009).Multiplesclerosispatients—benefit-riskpreferences:seriousadverseeventrisksversustreatmentefficacy.Journal of Neurology, 256(4),554.

KanavosP.,TinelliM.,Efthymiadou O.etal(2016)TheInternationalMultiPlESclerosisStudy(IMPrESS).London:TheLondonSchoolofEconomics

Kasper,J.,Köpke,S.,Mühlhauser,I.andHeesen,C.(2006).Evidence-basedpatientinformationabouttreatmentofmultiplesclerosis—aphaseonestudyoncomprehensionandemotionalresponses.Patient Education and Counseling, 62(1),56-63.

KobeltG.,ThompsonA.,.BergJetal(2016).NewinsightsintotheburdenandcostsofmultiplesclerosisinEurope.Multiple Sclerosis23(8):1123-1136.doi:10.1177/1352458517694432

Koch-HenriksenN.andSoelbergSorensenP.(2010)Thechangingdemographicpatternofmultiplesclerosisepidemiology.Lancet Neurol 9 520-532

Köpke,S.,Solari,A.,Khan,F.,Heesen,C.,&Giordano,A.(2014).Informationprovisionforpeoplewithmultiplesclerosis.The Cochrane Library.

KumarD.R.,AsliniaF.,YaleS.H.andMazzaJ.J.(2011)Jean-MartinCharcot:TheFatherofNeurology.ClinMedRes9(1):46–49.

Lebrun,C.,LePage,E.,Kantarci,O.etal(2012).Impactofpregnancyonconversiontoclinicallyisolatedsyndromeinaradiologicallyisolatedsyndromecohort.Multiple Sclerosis Journal, 18(9),1297-1302.

Lublin,F.D.andReingold,S.C.(1996).Definingtheclinicalcourseofmultiplesclerosis:resultsofaninternationalsurvey.NationalMultipleSclerosisSociety(USA)AdvisoryCommitteeonClinicalTrialsofNewAgentsinMultipleSclerosis.Neurology, 46(4),907-911.


Lublin,F.D.,Reingold,S.C.,Cohen,J.A.etal(2013)Definingtheclinicalcourseofmultiplesclerosis:the2013revisions.Neurology, 83(3),278-286.doi:10.1212/wnl.0000000000000560

MaslowA.H.(1943).Atheoryofhumanmotivation.Psychological Review. 50 (4): 370 – 96. doi: 10.1037/h0054346

MehrS.R.andZimmerman,M.P.(2015).ReviewingtheUnmetNeedsofPatientswithMultipleSclerosis.Am Health Drug Benefits, 8(8),426-431.

Messina,M.J.,DallaCosta,G.,Rodegher,M.etal(2015).TheCommunicationofMultipleSclerosisDiagnosis:ThePatients’Perspective.Mult Scler Int, 2015,353828.doi:10.1155/2015/353828

MilnerJ.J.andBeckM.A.(2012)Theimpactofobesityontheimmuneresponsetoinfection.Proc Nutr Soc71(2):298-306.doi:10.1017/S0029665112000158

Mitchell,A.J.,Benito-León,J.,González,J.-M.M.andRivera-Navarro,J.(2005).Qualityoflifeanditsassessmentinmultiplesclerosis:integratingphysicalandpsychologicalcomponentsofwellbeing.The Lancet Neurology, 4(9),556-566.

Mohr,D.,Goodkin,D.,Likosk,W.etal.(1996).Therapeuticexpectationsofpatientswithmultiplesclerosisuponinitiatinginterferonbeta-lb:Relationshiptoadherencetotreatment.Multiple Sclerosis Journal, 2(5),222-226.

MontalbanX.,HouserS.L.etal(2017).OcrelizumabversusplaceboinPrimaryProgressiveMultipleSclerosis.N Engl J Med376:209-220DOI:10.1056/NEJMoa1606468

Moutsianas,L.,JostinsL.etal.(2015).ClassIIHLAinteractionsmodulategeneticriskformultiplesclerosis.Nat Genet47(10):1107-1113.

MSIF(2013).AtlasofMultipleSclerosis.Avialableathttps://www.msif.org/about-us/advocacy/atlas/LastaccessedSeptember2017

MST(2016)RisksofDevelopingMultipleSclerosis.Availableathttps://www.mstrust.org.uk/a-z/risk-developing-msLastaccessedOctober2017

MungerK.L.,LevinL.Ietal(2011).Anti-Epstein-Barrvirusantibodiesasserologicalmarkersofmultiplesclerosis:aprospectivestudyamongUnitedStatesmilitarypersonnel.Mult Scler17(10):1185-93.doi:10.1177/1352458511408991

MungerK.L.,HongellK.,AivoJ.etal(2017)25-HydroxyvitaminDdeficiencyandriskofMSamongwomenintheFinnishMaternityCohort.Neurology89:1–6

Münz,C.,LünemannJ.D.etal.(2009).Antiviralimmuneresponses:triggersofortriggeredbyautoimmunity?Nat Rev Immunol9(4):246-258.

MünzC.(2016).Personalcommunication

MurphyMillerC.(1997).Thelivedexperienceofrelapsingmultiplesclerosis:aphenomenologicalstudy.Journal of Neuroscience Nursing, 29(5),291-304

MyhrK.,RiiseT.,VedelerCetal(2001).DisabilityandPrognosisinMultipleSclerosis:demographicandclinicalvariablesimportantfortheabilitytowalkandawardingofdisabilitypensions.Multiple Sclerosis Journal7(1)59-65

NationalMultipleSclerosisSociety(2017).FunctionalSystemsScores(FSS)andExpandedDisabilityStatusScale(EDSS).Availableat:

https://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-Researchers/Clinical-Study-Measures/Functional-Systems-Scores-(FSS)-and-Expanded-DisabLastretrievedSeptember2017

Naito,S.,Namerow,N.,Mickey,M.R.andTerasakiP.I.(1972).Multiplesclerosis:associationwithHL-A3.Tissue Antigens 2(1):1-4

NielsenT.R.,RostgaardK.etal(2007)“Multiplesclerosisafterinfectiousmononucleosis.”Arch Neurol 64(1):72-75

NielsenT.,RostgaardK.etal.(2009).EffectsofinfectiousmononucleosisandHLA-DRB1*15inmultiplesclerosis.Mult Scler15(4):431-6.

O’ConnorP.,DetskyA.S.,TanseyC.andKucharczykW.(1994)Effectofdiagnostictestingformultiplesclerosisonpatienthealthperceptions.ArchivesofNeurology51(1)46-51

OECD (2015).Health at a Glance 2015: OECD Indicators.Paris:OECDPublishing.

OECD(2016).Health at a Glance 2016: OECD Indicators.Paris:OECDPublishing.

Olsson,T.,BarcellosL.F.etal.(2017).Interactionsbetweengenetic,lifestyleandenvironmentalriskfactorsformultiplesclerosis.Nat Rev Neurol13(1):25-36.

O’GormanC.,LucasR.andTaylorB.(2012)EnvironmentalRiskFactorsforMultipleSclerosis:AReviewwithaFocusonMolecularMechanisms.Int Journal of Mol Science13,11718-11752

O’Rourke,K.E.,&Hutchinson,M.(2005).Stoppingbeta-interferontherapyinmultiplesclerosis:ananalysisofstoppingpatterns.Multiple Sclerosis Journal, 11(1),46-50.

Pakenham,K.I.(1999).Adjustmenttomultiplesclerosis:Applicationofastressandcopingmodel.Health Psychology, 18(4),383

Pender,M.P.andBurrows,S.R.(2014)Epstein–Barrvirusandmultiplesclerosis:potentialopportunitiesforimmunotherapy.ClinTransImmunology31,3(10)e27doi:10.1038cti.2014.25

Peterson,E.W.,Cho,C.C.,&Finlayson,M.L.(2007).Fearoffallingandassociatedactivitycurtailmentamongmiddleagedandolderadultswithmultiplesclerosis.Multiple Sclerosis Journal, 13(9),1168-1175.

Pietrangelo,A.andHiguera,V.(2015)MultipleSclerosisbytheNumbers:Facts,Statistics,andYou.Healthline.https://www.healthline.com/health/multiple-sclerosis/facts-statistics-infographicLastaccesedOctober2017

Polman,C.H.,Reingold,S.C.,Banwell,B.etal(2011).Diagnosticcriteriaformultiplesclerosis:2010revisionstotheMcDonaldcriteria.Annals of Neurology, 69(2),292-302.


ProsserL.A.,KuntzK.M.,Bar-OrA.andWeinsteinM.C.(2002).Therelationshipbetweenriskattitudeandtreatmentchoiceinpatientswithrelapsing-remittingmultiplesclerosis.Med Decis Making22(6):506-13

RennieT.(2017)Personalcommunication

Rothwell,P.M.,McDowell,Z.,Wong,C.andDorman,P.(1997).Doctorsandpatientsdon’tagree:crosssectionalstudyofpatients’anddoctors’perceptionsandassessmentsofdisabilityinmultiplesclerosis.BMJ, 314(7094),1580.

RotsteinD.L.,HealyB.C.,MalikM.T.etal(2015)EffectofvitaminDonMSactivitybydisease-modifyingtherapyclass.SeecommentinPubMedCommonsbelowNeurol, Neuroimmunol and Neuroinflamm29;2(6):e167.doi:10.1212/NXI.0000000000000167

Russell,W.R.(1971).Multiplesclerosis:occupationandsocialgroupatonset.The Lancet, 298(7729),832-834

SalzerJ.,SvenningssonR.,AlpingPetal(2016).Rituximabinmultiplesclerosis:Aretrospectiveobservationalstudyonsafetyandefficacy.Neurology15;87(20):2074-

SaposnikG.,SempereA.P.,RaptisR.etal(2016).Decisionmakingunderuncertainty,therapeuticinertia,andphysicians’riskpreferencesinthemanagementofmultiplesclerosis(DIScUTIRMS).BMC Neurology, 16,58.doi:10.1186/s12883-016-0577-42081

SawcerS.,HellenthalG.etal.(2011).Geneticriskandaprimaryroleforcell-mediatedimmunemechanismsinmultiplesclerosis.Nature476(7359):214-219.

SchreinerT.L.andWaubantE.L.,2015PediatricMultipleSclerosis.Medscape

http://emedicine.medscape.com/article/2091406-overviewLastretrievedSeptember2017

Sellner,J.,Kraus,J.,Awad,A.etal(2011).Theincreasingincidenceandprevalenceoffemalemultiplesclerosis—acriticalanalysisofpotentialenvironmentalfactors.Autoimmunity reviews, 10(8),495-502.

Simmons,R.D.(2010).Lifeissuesinmultiplesclerosis.Nature Reviews Neurology, 6(11),603-610.

Solari,A.(2014).Effectivecommunicationatthepointofmultiplesclerosisdiagnosis.Multiple Sclerosis Journal, 20(4),397-402.

Soundy,A.,Benson,J.,Dawes,H.etal(2012).UnderstandinghopeinpatientswithMultipleSclerosis.Physiotherapy, 98(4),344-350.

Strautins,K.,TschochnerM.etal.(2014).CombiningHLA-DRriskallelesandanti-Epstein-Barrvirusantibodyprofilestostratifymultiplesclerosisrisk.Mult Scler20(3):286-294.

Sundqvist,E.,SundstromP.etal.(2012).Epstein-Barrvirusandmultiplesclerosis:interactionwithHLA.Genes Immun13(1):14-20.

Synnot,A.J.,Hill,S.J.,Garner,K.A.etal(2016).Onlinehealthinformationseeking:howpeoplewithmultiplesclerosisfind,assessandintegratetreatmentinformationtomanagetheirhealth.Health Expectations, 19(3),727-737.

TaylorD.G.(2002)FundingMedicinesforPeoplewithMultipleSclerosis. British Medical Journal2001;322:1379-80

TaylorD.G(2016)AffordingtheFuture?London:theUCLSchoolofPharmacy.Availableathttps://www.ucl.ac.uk/pharmacy/departments/practice-policy/affording-the-future.pdfLastretrievedSeptember2017

TaylorD.G.(2017)TheRealityofEconomicsforOncologists.Breast.SeecommentinPubMedCommonsbelow33:183-190.doi:10.1016/j.breast.2017.03.014

ThorneS.,Con,A.,McGuinness,L.,McPherson,G.,&Harris,S.R.(2004).Healthcarecommunicationissuesinmultiplesclerosis:aninterpretivedescription.Qualitative Health Research, 14(1),5-22.

TintoreM.,Rovira,A.,Rio,J.etal(2015).Defininghigh,mediumandlowimpactprognosticfactorsfordevelopingmultiplesclerosis.Brain, 138(Pt7),1863-1874.doi:10.1093/brain/awv105

TintoreM.,Alexander,M.,Costello,K.etal(2017).Thestateofmultiplesclerosis:currentinsightintothepatient/healthcareproviderrelationship,treatmentchallengesandsatisfaction.Patient Prefer Adherence 11,33-45.doi:10.2147/ppa.s115090

UNCRDP(2016)Inquiry concerning the United Kingdom of Great Britain and Northern Ireland carried out by the Committee under article 6 of the Optional Protocol to the Convention: Report of the Committee.Availableathttp://www.ohchr.org/EN/HRBodies/CRPD/Pages/InquiryProcedure.aspxLastretrievedSeptember2017

Weinshenker,B.G.,Bass,B.etal(1989).Thenaturalhistoryofmultiplesclerosis:ageographicallybasedstudy:I.Clinicalcourseanddisability.Brain, 112(1),133-146.

WhiteheadL.C.,UnahiK.,BurrellB.andCroweM.T.(2016).TheExperienceofFatigueAcrossLong-TermConditions:AQualitativeMeta-Synthesis.JournalofPainSymptomManagement.52(1):131-143.e1.doi:10.1016/j.jpainsymman.2016.02.013.

WilsdenT.,BarronA.,Mitchell-HeggsA.andGinozaS.(2014).AccesstoMedicinesforMultipleSclerosis:ChallengesandOpportunities.London:CharlesRiversAssociates

WoodP(1980)Thelanguageofdisablement:Aglossaryrelatingtodiseaseanditsconsequences.Int Rehabil Med2:86-92

WHO(1980).InternationalClassificationofImpairments,DisabilitiesandHandicaps.Geneva:theWorldHealthOrganisation

Zivadinov,R.,Zorzon,M.,Tommasi,M.A.etal(2003).Alongitudinalstudyofqualityoflifeandsideeffectsinpatientswithmultiplesclerosistreatedwithinterferonbeta-1a.Journal of the Neurological Sciences, 216(1),113-118.

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Treatment Expectations and Priorities of People with MS

Prepared by Spoonful of Sugar97 Tottenham Court RoadLondon W1T 4TPDate: October 2017

Greater Expectations was researched and written by Dr Monika Heller andProfessorDavidTaylor. ItwascommissionedbyDrTomKennyofSpoonful of Sugar via UCL Consultants. Spoonful of Sugar was funded through a grantawardedtotheUniversityofBournemouthbyF.Hoffmann-LaRoche.

ThemembersoftheSpoonful of Sugarteamthatundertookthe2017Treatment Expectations and Priorities of People with Multiple Sclerosis (TaP-MS) surveyincludedJordiGuitart,ManjulaHalai,TomKenny,HelenLycett,andChloeTuck

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