Transcript Multiple Sclerosis Basic Principles and New Developments

Multiple Sclerosis
Dr Chris. Halfpenny
Consultant 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
Disability
Relapsing
Remitting
Progressive
Phase
Clinical
Course
Axon Loss
Clinical Threshold
White Matter Lesions
Grey Matter Lesions
“Inflammation”
Disability Accrued from Relapses
?
Oligodendrocyte Damage
Apoptotic Myelin Membranes
Acute
Inflammation
Remyelination
Axon
Protected
Chronic
Inflammation
within BBB
Acute
Relapse
Macrophages phagocytose
Myelin sheaths
Denuded Axons
Conduction Block
Chronic Demyelinated Axons
Slow, Insecure
Conduction
Accumulating
axon loss
Transient Symptoms
Progressive Disability
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
Yes
Consider high dose steroids
Oral Methylpred 500mg/day x5days
Or IVMP 1g/day x3days
No
Physio/OT if needed
Acute
Relapse
Clinic
Steroids in Acute Relapses
Speed recovery from an acute relapse
– Possibly by only a few days
Do not alter the outcome at 6 months
If relapse severe + not improving in a few days
– Exclude infection
– Need adequate doses (>60mg)
IV methyl pred 1g 3/7 or 500mg po for 5/7
Gastric protection if a risk factors
Avoid 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 Treatments
Drug
Relapse Rate Safety Issues Side effects/
Reduction
Convenience
BetaInterferon
30%
Glatiramer
30%
Mitoxantrone
~65%
Natalizumab
(LFTs)
Availability
‘flu’ & inj. sites Widely
Injection sites
Widely
Leakaemia,
cardiotoxicity
Infusions
Unlicensed
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 Autoimmunity
ITP
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 progression
Marked reduction in relapse rate for those
with highly active disease – 74% cf IFN
Most convincing effect on progression of
any drug, when started early enough
25% occurrence of other autoimmune
disease (Graves, ITP etc)
FREEDOMS TRANSFORM
S
Fingolimod
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
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
CLARITY
Cladribine
Placebo
0.33 /yr
Cladribine 3.5 mg/kg
0.14 /yr
Cladribine 5.25 mg/kg
0.15 /yr
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”
Future Prospects
Drug
Mode of Action
Phase III Studies
Completion Date
Teriflunomide
DiHydroOrotate
TEMSO: v
ECTRIMS next wk
Dehydrog. inhibitor placebo
September 2011
↓Dividing Cells
TOWER: v placebo
TENERE: add-on
IFN
TOPIC: in CIS
BG-12
Dimethyl fumarate
Nrf2 transcriptional DEFINE: v placebo December 2010
activator
CONFIRM: v glatir. April 2011
?neuroprotection
Laquinimod
Cytokine
modulator
↓L’cytes into CNS
ALLEGRO: v
placebo
BRAVO: v IFNβ1a
February 2011
November 2011
Rituximab
Depletes B cells
Ann Neurol 66(4)
Published ‘09
Daclizumab
IL-2 blocking mAb
↑NK cells
SELECT: v
November 2011
placebo
January 2014
DECIDE: v IFNβ1a