多发性硬化英文实用课件

多发性硬化英文“Multiple”-multipleareasoflostmyelin“Sclerosis”-ScarringMSisachronicautoimmuneinflammatorydiseaseAffectsCentralNervousSystem(brain,spinalchordandopticnerves)MultipleSclerosisInternationalJournalofMSCareMultipleSclerosisMultipleSclerosisAchronic,autoimmunediseaseAffectscentralnervoussystemthemyelinsheathcoveringofnervefibersinthebrainandspinalcordImpairsthenervesabilitytosendelectricalimpulsesMSStatisticsApproximately400,000AmericansarediagnosedwithMSAffects2.5millionpeopleworldwideSymptomonsetanddiagnosisoccurtypicallybetweentheagesof20-502.5:1women:manratioPeopleofNorthernEuropeandescentareafflictedmostcommonlyMorecommonabove40°latitudeinareaslikewesternNewYork.Womenare2timesmorelikelytogetthedisease(i.e.2womenforevery1men)MorecommoninNorthernEuropeandescendantsthananyotherraceFoundinpeoplewholiveintemperateclimatesOnsetoccursbetweenagesof20and40/what-is-ms/statistics/SymptomsofMSMuscleweaknessVisualsymptomsBlurryvisionDoublevisionUnsteadygait/balanceissuesPain/ParesthesiasEmotional/CognitivedisturbancesShorttermmemorylossInabilitytoconcentrateFatigueSexualDysfunctionSpeechSwallowingAbnormalsensationsTinglingNumbnessSensitivitytoheatBladderandbowelproblemsFrequencyLossofcontrolMultipleSclerosisKurtzkedisabilitystatusscale1Nodisability&minimalneurologicsign2Minimaldisability-slightweaknessorstiffness,milddisturbanceofgaitormildvisualdisturbance3Moderatedisability-monoparesis(partialorincompleteparalysisaffectingoneorpartofoneextremity)mildhemiparesis(slightparalysisaffectingonesideofbody)moderateataxia,disturbingsensoryloss,prominenturinaryoreyesymptom,oracombinationoflesserdysfunction4Relativelyseveredisability,butfullyambulatorywithoutaid,selfsufficientandabletobeupandabout12hoursaday,doesnotpreventtheabilitytoworkorcarryonnormallivingactivities,excludingsexualdysfunction5Disabilityissevereenoughtoprecludeworking,maximalmotorfunctioninvolveswalkingunaidedupto500meters6Needsassistancewalking,forexampleacane,crutches,orbraces7Essentiallyrestrictedtoawheelchairbutabletowheeloneselfandenterandleavethechairwithoutassistance8Essentiallyrestrictedtobedorachair,retainsmanyselfcarefunctionsandhaseffectiveuseofarms9Helplessandbedridden10DeathduetoMS-resultsfromrespiratoryparalysis,comaofuncertainorigin,orfollowingrepeatedorprolongedepilepticseizuresAcutesevereattackStudiesinanimalsandinvitrosystemssuggestthatuponitsadministration,glatirameracetate-specificsuppressorT-cellsareinducedandactivatedintheperiphery.CarbamazepineAdditionally,independentofteriflunomideactivity,B-cellproliferationissuppressedbyaninterleukin4classswitchintoimmunoglobulinG1.AffectsCentralNervousSystem(brain,spinalchordandopticnerves)MechanismofAction=Blockspyrimidinesynthesisinrapidlydividingcells,inhibitsproteintyrosine-kinaseandcyclo-oxygenase-2activity,anddecreasestheabilityofantigenpresentingcellstoactivateT-cells.Relativelyrare,affecting10%ofpatients.SensitivitytoheatTheannualizedrelapserateofteriflunomidepatientswas0.DalfampridineAlemtuzumab(Lemtrada)ImpairsthenervesabilitytosendelectricalimpulsesPerformbaselineandyearlyskinexams.Pain/ParesthesiasIntramuscularorSubcutaneously:80to120units/dayfor2to3weeks“Sclerosis”-Scarring2womenforevery1men)Pharmacotherapy:APathophysiologicApproach7thed.Detectedinsemen–contraceptionformen.TransienteosinopheliaDiagnosingMSAdiagnosisbyexclusioneliminateotherdiseasestatesthatmayexplainsymptomsbeforesuggestingMSPatientsundergoclinical,laboratory(hematologyandCSFpanels),andimagingstudiestoconfirmdiagnosisDiagnosisbyPoserCriteria

ClinicallydefiniteMS

2attacksandclinicalevidenceof2separatelesions

LaboratorysupportedDefiniteMS

2attacks,eitherclinicalorparaclinicalevidenceof1lesion,andCSFimmunologicabnormalities

1attack,clinicalevidenceof2separatelesions&CSFabnormalities

1attack,clinicalevidenceof1andparaclinicalevidenceofanotherseparatelesion,&CSFabnormalities

MRI

MRIfindingsthatstronglysuggestiveofMS

4ormorewhitematterlesions(each>3mm)

3whitematterlesions,1periventricular

Lesions6mmdiameterorgreater

Ovoidlesions,orientedperpendiculartoventricles

Corpuscallosumlesions

Brainstemlesions

OpenringappearanceofgadoliniumenhancementTheaxialT2WIshowsperi-ventricularflame-shapedhyperintenseareas

MRIImagingNormalBrainPatientwithMSMSLesions“Dawson’sFingers”MSLesionsinSpineCerebralSpinalFluidStudies

StronglysuggestiveofMS

NormalRedBloodCellsandglucose

Normalormildlyelevatedprotein

5-20mononuclearcells/ul

Intrathecal

IgGsynthesis

IncreasedIgGindexor24hoursynthesisrate

Increasedfreekappalightchains

OligoclonalbandsRelapsing-RemittingMS(RRMS)Mostcommon,affecting85%ofpatients.Patientsexperienceworseningofpre-existingsymptomsoronsetofnewsymptomsforperiodsofgreaterthan48hourswithoutconcomitantfever,knownasrelapses,flare-ups,orexacerbations,ofMS.Contrastedbysymptom-freeperiods,knownasremissions,wherethepatient’ssymptomspartiallyorcompletelydisappear.Secondary-ProgressiveMS(SPMS)AprogressionofRRMSMorecommonbeforeadventofdisease-modifyingmedicationsApproximately50%ofpatientsprogressedtoSPMSafter10-15yearswithRRMSIncidencehassincedecreasedThisdiseasecourseissteadilyprogressing.Canpresentwithorwithoutclear-cutrelapses.Primary-ProgressiveMS(PPMS)Relativelyrare,affecting10%ofpatients.Diseasecourseischaracterizedbysteadydecline,withoutclear-cutrelapses.Medicationsaregenerallynoteffectiveattreatingthistypeofdisease.Progressive-RelapsingMS(PRMS)Relativelyrare,affecting5%ofpatients.Steadydiseaseprogression,inadditiontoclear-cutperiodsofexacerbationsofMS.Patientscanbetreatedforrelapseswithsteroids,howeverdiseasewillprogressregardlessoftherapy.TreatmentNotaknowncureTreatmentaimedatcontrollingsymptomsandmaintainingfunctionDiseasemodifyingtherapyTreatmentofRelapsesMedicationsdependingonthesymptomsPhysicaltherapySpeechtherapyPlannedexerciseprogramsinearlycourseofdiseaseTreatmentforAcuteExacerbation:Acutesevereattack

CorticosteroidsAhormonethatstimulatesthebodytomakeitsownhormoneandimproveitsimmunesystem;Decreasesinflammationbysuppressionofmigrationofpolymorphonuclearleukocytesandreversalofincreasedcapillarypermeability.Methylprednisone(Solumedrol):1gramivinfusionperdayx3to5days-maybefollowedbyoralPrednisonetaper

60mgqdx7days,then60mgqodx7days,then40mgqodx7days,then20mgqodx7days,thenstop

H2blocker/PPIforulcerprophylaxis

Monitorbloodglucose

WatchforinfectionTreatmentforAcuteExacerbation:Acutesevereattack

CorticotropinActhargel:Adrenocorticotropichormonestimulatestheadrenalcortextosecreteadrenalsteroids(includingcortisol),weaklyandrogenicsubstances,andaldosteroneIntramuscularorSubcutaneously:80to120units/dayfor2to3weekspreventstransmigrationofleukocytesacrosstheendotheliumintoinflamedparenchymaltissueThePObioavailabilitysingledosehealthy,fastedpatientsis100%,peak1to2hours.MultipleSclerosisIntramuscularinjectiongivenonceweeklyClinicallydefiniteMSNatalizumab–SideEffectsLamotrigineSensitivitytoheatAntihistaminesand/orantipyreticsmayalsobeconsidered.bindstotheα4-subunitofα4β1andα4β7integrinsexpressedonthesurfaceofallleukocytesexceptneutrophils,andinhibitstheα4-mediatedadhesionofleukocytestotheircounter-receptor(s).Adrenocorticotropichormonestimulatestheadrenalcortextosecreteadrenalsteroids(includingcortisol),weaklyandrogenicsubstances,andaldosterone1attack,clinicalevidenceof2separatelesions&CSFabnormalities1attack,2attacks,eitherclinicalorparaclinicalevidenceof1lesion,andCSFimmunologicabnormalitiespreventstransmigrationofleukocytesacrosstheendotheliumintoinflamedparenchymaltissueThePObioavailabilitysingledosehealthy,fastedpatientsis100%,peak1to2hours.Diseasecourseischaracterizedbysteadydecline,withoutclear-cutrelapses.Signs/symptomsofPMLDecreasedleukocytemigrationApproximately50%ofpatientsprogressedtoSPMSafter10-15yearswithRRMSMild-moderatedecreaseinFEV1athighdose(5.NotaknowncureCurrentlyAvailableDiseaseModifyingTreatmentsKM.Gawronskietal.TreatmentOptionsforMultipleSclerosis:CurrentandEmergingTherapiesPharmacotherapy.2010;30(9):916-927.Dipiroetal.Pharmacotherapy:APathophysiologicApproach7thed.2008

InterferonbetaMechanismofAction=Specificinterferon-inducedproteinsandmechanismsbywhichinterferonbetaexertsitseffectsinMShavenotbeenfullydefined.ItmayaugmentsuppressorT-cellfunction;maydecreaseinterferongammasecretionbyactivatedlymphocytes;maydecreasemacrophageactivatingeffect;maydown-regulateexpressionofmajorhistocompatibilitycomplexgeneproductiononantigenpresentingglialcells.MayalsosuppressTcellproliferationanddecreasebloodbrainbarrierpermeabilityIntramuscularinjectiongivenonceweeklyDose:30mcgPregnancyCategoryCSubcutaneousinjectiongiventhreetimesaweekDose:22or44mcgPregnancyCategoryCInterferonbeta-1bSubcutaneousinjectiongiveneveryotherdayDose:250mcgachievedovera6weektitrationPregnancyCategoryCBetaseron®Rebif®Avonex®Interferonbeta-1aAvailableinthreeforms:Interferonbeta–SideEffectsFLULIKESYMPTOMS!!!Upto60%ofpatients.Pre-medicatebeforeinjectionandthedayfollowingwithIbuprofenorAcetaminophentodecreasethesesymptoms.Willdissipatewithcontinueduse.Generallyworseinfemalesandthosewithlowerbodyweight.FeverChillsHeadacheChestpainInjectionsitereactionsErythemaInflammationPainSkindiscoloration/swellingDepressionMyalgiaArthralgiaAstheniaMalaiseDiaphoresisMyastheniaAbdominalpainGlatirameracetateMechanismofAction=Notfullyknown,thoughttoberelatedtoalterationofT-cellactivationanddifferentiation.Studiesinanimalsandinvitrosystemssuggestthatuponitsadministration,glatirameracetate-specificsuppressorT-cellsareinducedandactivatedintheperiphery.Maymimicantigenicpropertiesofmyelinbasicprotein;MaybindtoMajorhistocompatibilitycomplexclassIIreceptorsandinhibitbindingofmyelinbasicproteinpeptidestoTcellreceptorcomplexes;MayinduceTh2antiinflammatorylymphocytesanddecreaseinflammation,demyelination,andaxondamage.AvailableasCopaxone®SubcutaneousinjectiongivenoncedailyDose=20mgPregnancyCategoryBGlatirameracetate–SideEffectsINJECTIONSITEREACTION!!!Indurations,masses,andweltsfrominjectionsmaylastfordaysafteradministration.PainErythemaInflammationUrticariaTransientflushingVasodilitationChesttightnessand/orchestpainAstheniaNausea/vomitingPainArthralgiaAnxietyPalpitationsDyspneaConstrictionofthethroatNatalizumabMechanismofAction=Antagonizesα4-integrinoftheadhesionmoleculeverylateactivatingantigen(VLA)-4onleukocytes.bindstotheα4-subunitofα4β1andα4β7integrinsexpressedonthesurfaceofallleukocytesexceptneutrophils,andinhibitstheα4-mediatedadhesionofleukocytestotheircounter-receptor(s).preventstransmigrationofleukocytesacrosstheendotheliumintoinflamedparenchymaltissueAvailableasTysabri®Ahumanizedmonoclonalantibody.Intravenousinfusiongivenonceevery4weeksDose=300mgPregnancyCategoryCMorecommonbeforeadventofdisease-modifyingmedicationsDetectedinsemen–contraceptionformen.Contraindicated:Historyofseizure;ModeratetosevererenalimpairmentSigns/symptomsofPML56comparedto0.Interferonbeta-1bHasbeenstudiedasanoraltherapyforRRMSandSPMS-Doses=7and14mgSymptomonsetanddiagnosisoccurtypicallybetweentheagesof20-50GISYMPTOMS!!!80%ofpatientswerefreefromrelapse,comparedto52%treatedwithinterferonβ-1aCanpresentwithorwithoutclear-cutrelapses.Dose:10mgBID-Tabletsshouldonlybetakenwhole;donotdivide,crush,chew,ordissolve.Pro-inflammatorycytokineexpressionStomatitis,esophagitis,oralulcerationNatalizumab–SideEffectsIncreasesinLFTsProgressiveMultifocalLeukoencephalopathy(PML)isasometimesfatalviralopportunisticinfectionthathasbeenobservedinpatientsreceivingnatalizumab.Without8mo-2yearsClinicalPharmacologyDextroamphetamineTysabriInmultiplesclerosis,lesionsarebelievedtooccurwhenactivatedinflammatorycells,includingTlymphocytes,crosstheblood-brainbarrier(BBB).LeukocytemigrationacrosstheBBBinvolvesinteractionbetweenadhesionmoleculesoninflammatorycellsandtheircounter-receptorspresentonendothelialcellsofthevesselwall.Theclinicaleffectofnatalizumabinmultiplesclerosismaybesecondarytoblockadeofthemolecularinteractionofα4β1-integrinexpressedbyinflammatorycellswithVCAM-1onvascularendothelialcells,andwithconnectingsegment1and/orosteopontinexpressedbyparenchymalcellsinthebrain.Datafromanexperimentalautoimmuneencephalitisanimalmodelofmultiplesclerosisdemonstratereductionofleukocytemigrationintobrainparenchymaandreductionofplaqueformation,detectedbyMRIfollowingrepeatedadministrationofnatalizumab.Natalizumab–PMLProgressiveMultifocalLeukoencephalopathy(PML)isasometimesfatalviralopportunisticinfectionthathasbeenobservedinpatientsreceivingnatalizumab.ResultsfromactivationofthelatentJohnCunninghampolyomavirusinimmunocompromisedpatients.PMLisademyelinatingdiseasesimilartoMS,causingimpairmentofthetransmissionofnerveimpulses,howeveroncemyelinislostinPML,itcannotberegained.DuetoPML,thereisaTOUCHPrescribingProgramwherepatients,prescribers,andinfusioncentersmustberegisteredtomonitorforthedevelopmentofthiscondition.Note:PMLhasnowalsobeenseeninpatientstreatedwithFingolimodandDimethylFumarateNatalizumab–SideEffectsInfusionreactionincludinghypersensitivityreactionsRespiratorytractinfectionUrinarytractinfectionDepressionHeadacheFatigueDiarrheaCholelithiasisArthralgiaPMLMitoxantroneMechanismofAction=IntercalateswithDNAstrandscausingbreaks,andinhibitsDNArepairthroughtopoisomeraseII.AffectsrapidlydividingcellssecondaryeffectsontheimmunesystemAntigenpresentationPro-inflammatorycytokineexpressionDecreasedleukocytemigrationAvailableasNovantrone®Animmunosuppressiveagentchemicallyrelatedtodoxorubicinanddaunorubicin

Intravenousinfusiongivenonceevery3monthsDose=12mg/m2

Cumulativelifetimedoseof100mg/m2PregnancyCategoryDMitoxantrone–SideEffectsCardiotoxicityBonemarrowsuppressionHemoglobinlevels,whitebloodcellcount,andplateletcountsmustbemeasuredbeforeeachinfusionStomatitis,esophagitis,oralulcerationNausea/vomitingAlopeciaHeadacheFatigueHepaticdysfunctionFingolimod(Gilenya)MechanismofAction=Actsonthesphingosine-1-phosphate(S1P)receptorsS1P1andS1P3-5onthesurfaceoflymphocytesDepletesbothCD4+andCD8+Tlymphocytesinthebloodstream,upto75%belowbaseline.CD4+cellsaredecreasedtoagreaterextentthanCD8+cells.InhibitslymphocytereleasefromlymphaticorgansdecreasingoverallnumbersincirculationDuetoPML,thereisaTOUCHPrescribingProgramwherepatients,prescribers,andinfusioncentersmustberegisteredtomonitorforthedevelopmentofthiscondition.NormalRedBloodCellsandglucoseStudiesinanimalsandinvitrosystemssuggestthatuponitsadministration,glatirameracetate-specificsuppressorT-cellsareinducedandactivatedintheperiphery.Dalfampridine(Ampyra)–(4-aminopyridine)CorticosteroidsBlurryvisionMethylphenidatePharmacotherapy:APathophysiologicApproach7thed.Delayedrelease—donotcrushBlackBoxWarning:NasopharyngitisPharmacotherapy:APathophysiologicApproach7thed.Emotional/CognitivedisturbancesSubcutaneousinjectiongivenoncedailyInhibitionofpyrimidinesynthesisselectivelyproducesacytostaticeffectonproliferatingTandBlymphocytesintheperiphery,whileavoidingunduecytotoxicitytoothercelltypes.DecreasedproportionofpatientsrelapsingpreventstransmigrationofleukocytesacrosstheendotheliumintoinflamedparenchymaltissueScreenforlatentTBMultipleSclerosisAchronic,autoimmunediseaseFingolimodFingolimodhasbeenassessedasanoraltherapyforRRMSandSPMSDose=0.5mgQDsignificantlyreducedgadolinium-enhancinglesions,relapseratecomparedtobothplaceboandAvonex,anddemonstratedsignificantlylesslossinbrainvolume36ClinicalPharmacology>800patientsinPharmacologystudiesusing0.125to40mgdoseHighoralbioavailabilitywithnofoodeffectMetabolizedbycytochromeCyP450-4F2;noDDI;notoxicmetabolitesT1/2of6-9daysNodoseadjustment(renal,hepaticdysfunction;age,gender,race)Reducedlymphocytecount:70%reductionat0.5mgsteadystateHeartratedecreaseonday1,attenuatesovertimeMild-moderatedecreaseinFEV1athighdose(5.0mg)FirstDoseMonitoringECGneededbeforeinitiatingMonitorhourlyfor6hrspost1stdoseforbradycardia—takeHRandBPContinueobservingifbpm<45orifHRisstillatlowestpointpostdoseat6hoursRepeat1stdosemonitoringifpatientmisses1dayinfirst2weeks,7daysin3rdand4thweeks,or14daysafter1monthFingolimod–SideEffectsNasopharyngitisHeadacheInfluenzaLymphopeniaLeukopeniaUpperrespiratorytractinfectionMacularedemaChangesinFEV1IncreaseinBPHypertensionElevationinLFTsDose-dependenteffectsincludetransientheartratereductionontreatmentinitiation,smallincreaseinbloodpressure,liverenzymeelevations,macularedemaTeriflunomide(Aubagio)MechanismofAction=Blockspyrimidinesynthesisinrapidlydividingcells,inhibitsproteintyrosine-kinaseandcyclo-oxygenase-2activity,anddecreasestheabilityofantigenpresentingcellstoactivateT-cells.activemetaboliteofleflunomidethathasantiproliferativeandanti-inflammatoryactivity.inhibitsthemitochondrialenzymaticactivityofdihydroorotatedehydrogenase.Dihydroorotatedehydrogenasefunctionsastherate-limitingenzymeindenovopyrimidinesynthesis.InhibitionofpyrimidinesynthesisselectivelyproducesacytostaticeffectonproliferatingTandBlymphocytesintheperiphery,whileavoidingunduecytotoxicitytoothercelltypes.5,6TeriflunomideeffectivelyreducesB-lymphocyteproliferationbydirectsuppressionofdihydroorotatedehydrogenaseandreductionoflipopolysaccharide-inducedproliferationviathesecretionofimmunoglobulinMfromBcells.Additionally,independentofteriflunomideactivity,B-cellproliferationissuppressedbyaninterleukin4classswitchintoimmunoglobulinG1.TheinteractionbetweenBandTlymphocytesiseffectivelyinhibitedbyteriflunomide;thus,blockadeofTlymphocytedependentantibodyproductionoccurs.

HasbeenstudiedasanoraltherapyforRRMSandSPMS-Doses=7and14mgTeriflunomide(Aubagio)–StudyResultsBothdosesreducedgadolinium-enhancingMRIlesionsby61%Theannualizedrelapserateofteriflunomidepatientswas0.56comparedto0.81intheplacebogroup.77%ofpatientsinthe14mgteriflunomidegroupwerefreefromrelapsesduringthestudyperiod,comparedtoonly62%intheplacebogroup.Teriflunomide(Aubagio)ThePObioavailabilitysingledosehealthy,fastedpatientsis100%,peak1to2hours.fooddelayedabsorptionbyapproximately6hours7or14mgqdwithorwithoutfoodhalf-lifeofteriflunomideis10to12days.enterohepaticrecirculationresultsinthetotalplasmaclearanceofapproximately0.5L/h.15

includingoxidation,hydrolysis,sulfateconjugation,cytochromeP450enzyme3A4(CYP3A4),CYP2C9,andN-cetyltransferase.substrateofBCRP(inhibitorsarecyclosporine,eltrombopag,gefitnib),inhibits2C8(repaglinide,paclitaxel,pioglitizone,rosiglitazone),mayincreaseEthinylestradiolandlevonorgestrel,maydecreaseINRmayinduce1A2(duloxetine,alosetron,theophylline,caffeine,tizanidine),inhibitsBCRP,hepaticuptaketransporter(OATP1B1)renaluptaketransporter(OAT3)Teriflunomide–SideEffectsHeadacheNasopharyngitisUpperrespiratorytractinfectionAlopeciaSensorydisturbancesNauseaParasthesiasInsomniaFatigueUrinarytractinfectionIncreasesinLFTsBackpainLimbpainDiarrheaArthralgiaTeriflunomide(Aubagio)Commonadversereactionsobservedinclinicaltrialsatarategreaterthan10%andatincreasedincidencecomparedwithplaceboincludediarrhea,elevatedALT,nausea,influenza,hypersensitivityreactionorskindisorder,paresthesia,andhairthinningneuropathy;kidneyproblems;hyperkalemia;seriousskinproblems;breathingproblemsinterstitiallungdisease(neworworsening);HTNTeriflunomide(Aubagio)Monitoring:MaydecreaseWBC–CBCwithin6monthsbeforestarting–notduringactiveinfectionsLiverfunctiontestsandbiliwithin6monthsandeverymonthforatleast6monthsafterScreenforlatentTB

Upto60%ofpatients.TreatmentOptionsforMultipleSclerosis:CurrentandEmergingTherapiesInsomeclinicaltrialspatientsreceivedanadditional12mgdailyfor3consecutivedays12monthslaterHighoralbioavailabilitywithnofoodeffectInSPMS,alemtuzumabdidnothindertheformationofnewlesionsonMRI.Carbamazepinebindstotheα4-subunitofα4β1andα4β7integrinsexpressedonthesurfaceofallleukocytesexceptneutrophils,andinhibitstheα4-mediatedadhesionofleukocytestotheircounter-receptor(s).Premedicatewithcorticosteroids(methylprednisolone1,000mgorequivalent)immediatelypriortoalemtuzumabforthefirst3daysofeachtreatmentcourse.SensitivitytoheatLeukocytemigrationacrosstheBBBinvolvesinteractionbetweenadhesionmoleculesoninflammatorycellsandtheircounter-receptorspresentonendothelialcellsofthevesselwall.Dalfampridine(Ampyra)–(4-aminopyridine)MethylphenidateMitoxantronesignificantlyreducedgadolinium-enhancinglesions,relapseratecomparedtobothplaceboandAvonex,anddemonstratedsignificantlylesslossinbrainvolumeMonitorhourlyfor6hrspost1stdoseforbradycardia—takeHRandBPMSLesions“Dawson’sFingers”Decreaseconcby98%Dipiroetal.Teriflunomide(Aubagio)Emotional/CognitivedisturbancesTeriflunomide(Aubagio)Blackbox:Hepatotoxicity,teratogenicity–CategoryX–registryavailable–levelslessthan0.02mg/lDetectedinsemen–contraceptionformen.DecreasedspermcountinmenDetectedinratmilk–donotbreastfeed.Accelerateeliminationwithcholestyramine8or4gq8hx11dor50gactivatedcharcoalq12hx11dDecreaseconcby98%Without8mo-2years

Dimethylfumarate(Tecfidera)MechanismofAction=InducesT-helper2-likecytokinescausingApoptosisinactivatedTcellsandDown-regulationofintracellularadhesionmolecules,leadingtoreducedmigrationoflymphocytes.ApprovedasanoraltherapyforRRMSDose=120mgPOBIDfor7days,then240mgPOBIDDelayedrelease—donotcrushDimethylfumarate–StudyResultsDimethylfumaratetreatmentdecreasednumberofnewT1,newT2,andGd+lesionsonMRIDecreasedproportionofpatientsrelapsingTrendedtowardsslowingdiseaseprogressionTIDdosingshowednoaddedbenefitsDimethylfumarate–SideEffectsGISYMPTOMS!!!DiarrheaNauseaCrampingFlushingTransientincreasesinLFTsTransienteosinopheliaLymphopeniaRecentCBC(within6months)neededbeforetreatmentAlemtuzumab(Lemtrada)

MechanismofAction=TargetsCD52onlymphocytesandmonocytes,causinglong-termreductionofcirculatingT-cellsEvaluatedasanintravenousinfusionforRRMSandSPMSDose=12mginfusedIVdailyover4hoursfor5days,thena3daycourseatmonth12;patientsareobserved2hoursafterinfusionPremedicatewithcorticosteroids(methylprednisolone1,000mgorequivalent)immediatelypriortoalemtuzumabforthefirst3daysofeachtreatmentcourse.Antihistaminesand/orantipyreticsmayalsobeconsidered.Administerantiviralprophylaxis(forherpeticviralinfections)beginningonthefirstdayoftreatmentandcontinueforatleast2monthsaftercompletionofalemtuzumabanduntilCD4+lymphocytecountis≥200/mm3.Insomeclinicaltrialspatientsreceivedanadditional12mgdailyfor3consecutivedays12monthslaterPregnancycategory=CAlemtuzumab–StudyResultsInSPMS,alemtuzumabdidnothindertheformationofnewlesionsonMRI.EvaluatingRRMS,12and24mg:ImprovedEDSSscore,whileEDSSscoreworsenedwithinterferonβ-1a.Decreasedannualizedrelapserate(0.11and0.08respectively)80%ofpatientswerefreefromrelapse,comparedto52%treatedwithinterferonβ-1aAlemtuzumab–SideEffectsDEVELOPMENTOFAutoimmuneTHYROIDDISORDERSIncludingGRAVES’DISEASErequiringthyroidablationIn1/3ofpatientsForMS,monitorTSHatbaselineandevery3monthsuntil48monthsafterlastinfusionorlongeroratanytimeduringtherapyifclinicallyindicated.Rashin90%ofpatientsHeadachePyrexiaFatiguePruritisNauseaNeurologicproblemsChillsInsomniaChestdiscomfort/dusgeusiaDyspneaMusculoskeletalpain/discomfortDyspepsiaVomitingFlushingAlemtuzumab–SideEffectsBlackBoxWarning:Alemtuzumabcausesserious,sometimesfatal,autoimmuneconditions,suchasimmunethrombocytopeniaandanti-glomerularbasementmembranedisease.Monitorcompletebloodcountswithdifferential,serumcreatininelevels,andurinalysiswithurinecellcountsatperiodicintervalsfor48monthsafterthelastdoseofalemtuzumab.Infusionreactions(Lemtrada):Alemtuzumabcausesseriousandlife-threateninginfusionreactions.Alemtuzumabmustbeadministeredinasettingwithappropriateequipmentandpersonneltomanageanaphylaxis