Why haven’t we cured MS yet?
Gavin Giovannoni
Barts and The London
To cure MS do we need to know the cause?
EBV
Vitamin D
Genes
Smoking
We work on the hypothesis that MS is an autoimmune disease.
Genes
Environment
Multiple
Sclerosis
The autoimmune hypothesis
Genes
Environment
Multiple
Sclerosis
Disability
What does a cure mean?
Time
What does a cure mean?
1
3
delayed worsening
2
stabilised
improved function
4
recovered function
The therapeutic window for recovery
PPMS
RIS
RRMS
CIS
R-SPMS
SPMS
Disease Severity
Inflammation
Nerve cell loss
Asymptomatic
disease
Brain volume loss
1st clinical
attack
Relapses
1st MRI
lesion
EDSS < 4.0 / ? Age < 40
MRI Lesions
Time (Years)
RIS = radiologically isolated syndrome (asymptomatic MS)
CIS = clinically isolated syndrome
RRMS = relapsing-remitting MS
R-SPMS = relapsing secondary progressive MS
SPMS = secondary progressive MS
PPMS = primary progressive MS
Survival Curves
100%
Benign MS
85%
Natural
history
Delayed onset of SPMS
50%
Proportioned of treated
MSers are cured
30%
Unrealistic
expectation
0%
15yrs
25yrs
40yrs
50yrs
Defining a cure: a working definition
100%
85%
Natural
history
50%
Proportioned of treated
MSers are cured
30%
0%
15yrs
NEDA = no evident disease activity
25yrs
40yrs
50yrs
The autoimmune hypothesis
Genes
Environment
Multiple
Sclerosis
Professor Baker’s
Animal model of MS
Day 0
Clinical Score
Day 7
0
1
Normal
(1)
Limp tail
Remission
2
Impaired
righting reflex
3
partial paralysis
4
hindlimb paralysis
5
Moribund
Slide courtesy David Baker
Curing animal MS
Can we repeat the animal experiment in MS?
survival analysis
“highly effective treatments”
MS is an autoimmune
disease hypothesis
Genes
Environ
-ment
Multiple
Sclerosis
15-20 year
experiment
Moving the target: the MS Iceberg
Relapses
Unreported relapses
Clinical activity
Clinical disease worsening
Subclinical relapses: focal MRI activity
Focal MRI activity
Focal gray and white matter lesions
not detected by MRI
Brain atrophy
Hidden focal and diffuse MRI activity
Spinal fluid neurofilament levels
Biomarkers
Microscopic or biochemical pathology
Moving the target: end-organ damage
Control
Multiple sclerosis
NEDA
Treat-2-target
No evidence of disease activity defined as:1,2
× No relapses
× No sustained worsening of disability
× No MRI activity
×
No new or enlarging T2 lesions
×
No Gd-enhancing lesions
Brain volume loss should be included in our definition for NEDA
Gd, gadolinium.
1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Have we got it wrong?
EBV
Vitamin D
Genes
Smoking
Is MS due to a virus?
Charcot Project
INSPIRE Trial (Raltegravir)
Genes
Environ
-ment
Etc. etc. etc.
Multiple
Sclerosis
Why haven’t we cured MS yet?
We may have, we need time to tell, or alternatively a black
swan may fly in to the change the time-line.