2The Talk The basics - a little revision The state of play regarding disease modifying therapiesWhat are they?What do they do?Who would benefit?
3The Basics - Revision A central nervous system disease. Episodes affecting different parts of the central nervous system at different times.Inflammation, leading to demyelination and temporary conduction block, symptomatic only if it occurs in an eloquent area
4Some Definitions A Relapse:- Clinically Isolated Syndrome:- Onset of new neurological symptoms, or a substantial deterioration of previous symptoms, lasting more than 24 hours, not explicable on the basis of infection or other processClinically Isolated Syndrome:-Single neurological episode without clinical evidence of previous episodes, with a normal MRI scan has a ~20% chance of progressing to MS, with and abnormal scan fulfilling certain criteria has an 85% chance of developing MS
5Some more definitionsRelapsing Remitting :- disease characterised by relapses with substantial regression of symptoms afterwards – 70% start like thisPrimary Progressive :- gradual progressive disease from onset without relapses. ~15% of MS casesSecondary Progressive :- progressive disease following period or relapsing remitting disease
6RelapsingRemittingProgressivePhaseDisabilityClinicalCourseAxon LossClinical ThresholdWhite Matter LesionsGrey Matter LesionsDisability Accrued from Relapses“Inflammation”
8Recognising the disease Time course is keyOnset over hours to days, recover over weeksTypical relapsesOptic neuritisSpinal relapse (ascending sensory disturbance, tight band sensations, urgency, tripping over cracks in pavement)Trigeminal neuralgia in young womenVertigo+, “Bell’s Palsy”+, diplopia (eg INO) etcUhthoff’s and Lhermitte’s
9The acute relapse Acute Relapse Clinic Can the patient cope at home with help?No - admitYesIs there evidence of infection?Check Chest, MSU, FBC & CRPawait results…Yes – treatNoAre they significantly disabled by the relapseand not showing signs of improvement?Eg –unable to work, care for themselves etcYesConsider high dose steroidsOral Methylpred 500mg/day x5daysOr IVMP 1g/day x3daysNoPhysio/OT if needed
10Steroids in Acute Relapses Speed recovery from an acute relapsePossibly by only a few daysDo not alter the outcome at 6 monthsIf relapse severe + not improving in a few daysExclude infectionNeed adequate doses (>60mg)IV methyl pred 1g 3/7 or 500mg po for 5/7Gastric protection if a risk factorsAvoid oral tail-off unless prev. bad withdrawalAvoid long term steroidsCounsel about long term side effects (inc weakness, avascular necrosis)
11Disease Modifying Treatments When to treat?Who to treat?
12Who Is Most At Risk?Frequency of relapses in the first year(s) appear(s) to predict long-term disabilityWeinshenker et al Brain ‘89 112(6)Scalfari et al Brain ‘10 133(7)Frequent relapses in established disease correlate poorly with later disabilityConfavreux et al Brain ’03 126(4)MRI activity early has some predictive valueBrex et al NEJM ‘02 346(3)
13When to treat?Potent immune modulation (alemtuzumab) given early in the disease appears not just to stop relapses but to halt progression in the medium term (~5 years)Coles et al NEJM ‘08 359(17)The same treatment in patients with established secondary progression stops relapses but fails to halt progressionColes et al Annals Neurol. ‘99 46
14Overview of Treatments DrugRelapse Rate ReductionSafety IssuesSide effects/ ConvenienceAvailabilityBeta-Interferon30%(LFTs)‘flu’ & inj. sitesWidelyGlatiramerInjection sitesMitoxantrone~65%Leakaemia,cardiotoxicityInfusionsUnlicensedNatalizumab68%PML 0.1%/yrMthly infusionsWidely ‘07Alemtuzumab80%+Autoimmunity2 courses infus.Cladribine55%Infections VZV ?cancers+Oral - coursesRejected by EMAFingolomodInfections, ophth, HTDaily oral (?I/P)? Late 2011
15IFN & GlatiramerRelapsing Remitting (or early progression with dominant relapses)2 significant relapses in 2 yearsReduce relapse rate by ~30%Safe, but ‘flu-like side effects troublesomeEffect on progression remains unprovenPointers towards some effect if treatment commenced earlyNew ABN guidelines?
16Natalizumab Tysabri Integrin α4 blockade Stops circulating lymphocytes entering the CNSWell tolerated monthly infusionsEffective relapse suppression (68% cf placebo)Risk of PML appears to increase with time on treatment:-Very low in first yearBy 2 years around 1 in 1000 per year of treatmentStratifying risk based on PML serology(40% negative)Risk of rebound disease activity when stopped
17MitoxantroneOriginally suggested for highly active RRMS and possibly early progression50% reduction in relapse rateCardiotoxicity, less common with newer regimesRisk of Leukaemia – particularly Promyelocytic leukaemia ?0.3%++
18Alemtuzumab Campath Anti CD52 monoclonal depletes all lymphocytes, Prolonged immunomodulation2+ courses of infusions, with long-term controlHighly effective relapse reduction (78% cf IFNβ1a)Stops progressive disability when given early30% risk of AutoimmunityITPThyroidPhase 3 trials (vs IFN-β1a) due FDA “fast track”
19Campath (Alemtuzumab) Unlicensed, and cheap! (at present)“resets” the immune systemNo effect on establishes progressionMarked reduction in relapse rate for those with highly active disease – 74% cf IFNMost convincing effect on progression of any drug, when started early enough25% occurrence of other autoimmune disease (Graves, ITP etc)
20FREEDOMSTRANSFORMSPlacebo0.40 /yr0.5 mg Fingolimod0.18 /yr0.16 /yr1.25 mg Fingolimod0.20 /yrIFN-β1a (Avonex)0.33 /yrFingolimodSphingosine analogue – stops lymphocytes leaving lymph nodes, and thus accessing CNSDaily oral tablet, first dose given in hospital due to potential for bradycardia and AV blockRelapse reduction 55% (0.18 cf 0.4 relapse/yr)Macular oedema (?high dose only)Hypertension2 deaths from HSV/ZVZ encephalitisApproved by FDA – NICE review after July ‘11
22Future Prospects Drug Mode of Action Phase III Studies Completion Date TeriflunomideDiHydroOrotateDehydrog. inhibitor↓Dividing CellsTEMSO: v placeboTOWER: v placeboTENERE: add-on IFNTOPIC: in CISECTRIMS next wkSeptember 2011BG-12Dimethyl fumarateNrf2 transcriptional activator?neuroprotectionDEFINE: v placeboCONFIRM: v glatir.December 2010April 2011LaquinimodCytokine modulator↓L’cytes into CNSALLEGRO: v placeboBRAVO: v IFNβ1aFebruary 2011November 2011RituximabDepletes B cellsAnn Neurol 66(4)Published ‘09DaclizumabIL-2 blocking mAb ↑NK cellsSELECT: v placeboDECIDE: v IFNβ1aJanuary 2014