Multiple Sclerosis

Dr Chris. HalfpennyConsultant Neurologist,

Southampton & Portsmouth

The Talk

The basics - a little revision

The state of play regarding disease modifying therapies– What are they?– What do they do?– Who would benefit?

The 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

Some Definitions

A Relapse:- 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 process

Clinically 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

Some more definitions

Relapsing Remitting :- disease characterised by relapses with substantial regression of symptoms afterwards – 70% start like this

Primary Progressive :- gradual progressive disease from onset without relapses. ~15% of MS cases

Secondary Progressive :- progressive disease following period or relapsing remitting disease

“Inflammation”

Clinical Threshold

Axon Loss

RelapsingRemitting

White Matter Lesions

Grey Matter Lesions

Disability Accrued from Relapses

ClinicalCourse

ProgressivePhase

Dis

abili

ty

Oligodendrocyte Damage

Apoptotic Myelin Membranes

Macrophages phagocytoseMyelin sheaths

Denuded Axons

Chronic Demyelinated Axons

Accumulatingaxon loss

Progressive Disability

AcuteInflammation

?

Conduction BlockRemyelination

Slow, InsecureConduction

Transient Symptoms

AcuteRelapse

AxonProtected

Chronic Inflammationwithin BBB

Recognising the disease

Time course is key– Onset over hours to days, recover over weeks

Typical relapses– Optic neuritis – Spinal relapse (ascending sensory disturbance, tight band

sensations, urgency, tripping over cracks in pavement)

– Trigeminal neuralgia in young women– Vertigo+, “Bell’s Palsy”+, diplopia (eg INO) etc

Uhthoff’s and Lhermitte’s

The acute relapse

Can the patient cope at home with help?

No - admit Yes

Is there evidence of infection?Check Chest, MSU, FBC & CRP

await results…

Yes – treat No

Are they significantly disabled by the relapse and not showing signs of improvement?

Eg –unable to work, care for themselves etc

YesConsider high dose steroids

Oral Methylpred 500mg/day x5daysOr IVMP 1g/day x3days

NoPhysio/OT if needed

AcuteRelapse

Clinic

Steroids in Acute Relapses

Speed recovery from an acute relapse– Possibly by only a few days

Do not alter the outcome at 6 monthsIf relapse severe + not improving in a few days– Exclude infection – Need 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 withdrawal

– Avoid long term steroids– Counsel about long term side effects (inc weakness,

avascular necrosis)

Disease Modifying Treatments

When to treat?

Who to treat?

Who Is Most At Risk?

Frequency of relapses in the first year(s) appear(s) to predict long-term disability

Weinshenker et al Brain ‘89 112(6)

Scalfari et al Brain ‘10 133(7)

Frequent relapses in established disease correlate poorly with later disability

Confavreux et al Brain ’03 126(4)

Scalfari et al Brain ‘10 133(7)

MRI activity early has some predictive value Brex et al NEJM ‘02 346(3)

When 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 progression

Coles et al Annals Neurol. ‘99 46

Overview of TreatmentsDrug Relapse Rate

ReductionSafety Issues Side effects/

ConvenienceAvailability

Beta-Interferon

30% (LFTs) ‘flu’ & inj. sites Widely

Glatiramer 30% Injection sites Widely

Mitoxantrone ~65% Leakaemia,cardiotoxicity

Infusions Unlicensed

Natalizumab 68% PML 0.1%/yr Mthly infusions

Widely ‘07

Alemtuzumab 80%+ Autoimmunity 2 courses infus.

Unlicensed

Cladribine 55% Infections VZV ?cancers+

Oral - courses Rejected by EMA

Fingolomod 55% Infections, ophth, HT

Daily oral (?I/P)

? Late 2011

IFN & Glatiramer

Relapsing Remitting (or early progression with dominant relapses)2 significant relapses in 2 years– Reduce relapse rate by ~30%– Safe, but ‘flu-like side effects troublesome– Effect on progression remains unproven

Pointers towards some effect if treatment commenced early

New ABN guidelines?

Natalizumab Tysabri

Integrin α4 blockade

Stops circulating lymphocytes entering the CNS

Well tolerated monthly infusions

Effective relapse suppression (68% cf placebo)

Risk of PML appears to increase with time on treatment:-

Very low in first year

By 2 years around 1 in 1000 per year of treatment

Stratifying risk based on PML serology(40% negative)

Risk of rebound disease activity when stopped

Mitoxantrone

Originally suggested for highly active RRMS and possibly early progression

50% reduction in relapse rate

Cardiotoxicity, less common with newer regimes

Risk of Leukaemia – particularly Promyelocytic leukaemia ?0.3%++

Alemtuzumab Campath

Anti CD52 monoclonal depletes all lymphocytes,

Prolonged immunomodulation

2+ courses of infusions, with long-term control

Highly effective relapse reduction (78% cf IFNβ1a)

Stops progressive disability when given early

30% risk of AutoimmunityITP

Thyroid

Phase 3 trials (vs IFN-β1a) due 2012. FDA “fast track”

Campath (Alemtuzumab)

– Unlicensed, and cheap! (at present)– “resets” the immune system

No 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)

Fingolimod

Sphingosine analogue – stops lymphocytes leaving lymph nodes, and thus accessing CNS

Daily oral tablet, first dose given in hospital due to potential for bradycardia and AV block

Relapse reduction 55% (0.18 cf 0.4 relapse/yr)

Macular oedema (?high dose only)

Hypertension

2 deaths from HSV/ZVZ encephalitis

Approved by FDA – NICE review after July ‘11

FREEDOMS TRANSFORMS

Placebo 0.40 /yr

0.5 mg Fingolimod 0.18 /yr 0.16 /yr

1.25 mg Fingolimod

0.16 /yr 0.20 /yr

IFN-β1a (Avonex) 0.33 /yr

Cladribine

Purine analogue, preferentially depleting lymphocytes,

Leads to prolonged immune modulation

Short oral course at yearly intervals

Relapse reduction 58% (0.14 cf 0.34)

Infections – zoster

Tumours – uterine fibroids, ?cancers

Rejected by European Medicines Agency– “Risks outweigh benefits”

CLARITY

Placebo 0.33 /yr

Cladribine 3.5 mg/kg 0.14 /yr

Cladribine 5.25 mg/kg 0.15 /yr

Future ProspectsDrug Mode of Action Phase III Studies Completion Date

Teriflunomide DiHydroOrotateDehydrog. inhibitor↓Dividing Cells

TEMSO: v placeboTOWER: v placeboTENERE: add-on IFNTOPIC: in CIS

ECTRIMS next wkSeptember 2011

BG-12Dimethyl fumarate

Nrf2 transcriptional activator ?neuroprotection

DEFINE: v placeboCONFIRM: v glatir.

December 2010April 2011

Laquinimod Cytokine modulator↓L’cytes into CNS

ALLEGRO: v placeboBRAVO: v IFNβ1a

February 2011November 2011

Rituximab Depletes B cells Ann Neurol 66(4) Published ‘09

Daclizumab IL-2 blocking mAb ↑NK cells

SELECT: v placeboDECIDE: v IFNβ1a

November 2011January 2014