5th uclp ms research day curing ms
TRANSCRIPT
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
Smoking Genes
We work on the hypothesis that MS is an autoimmune disease.
Multiple
Sclerosis
Environ-ment
Genes
The autoimmune hypothesis
Multiple
Sclerosis
Environ-ment
Genes
What does a cure mean?
Dis
abili
ty
Time
delayed worsening 1 stabilised 2
improved function 3 recovered function 4
What does a cure mean?
MRI Lesions
1st clinical attack
Time (Years)
Asymptomatic disease
Inflammation
Brain volume loss
Nerve cell loss
Dis
eas
e S
eve
rity
SPMS RRMS
1st MRI lesion
Relapses
CIS RIS R-SPMS
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
PPMS
The therapeutic window for recovery
MRI Lesions
1st clinical attack
Time (Years)
Asymptomatic disease
Inflammation
Brain volume loss
Nerve cell loss
Dis
eas
e S
eve
rity
SPMS RRMS
1st MRI lesion
Relapses
CIS RIS R-SPMS
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
PPMS
EDSS < 4.0 / ? Age < 40
The therapeutic window for recovery
Survival Curves
85%
50%
30%
0%
15yrs 25yrs 40yrs 50yrs
100% Benign MS
Proportioned of treated MSers are cured
Natural history
Unrealistic expectation
Delayed onset of SPMS
Defining a cure: a working definition
85%
50%
30%
0%
15yrs 25yrs 40yrs 50yrs
100%
Proportioned of treated MSers are cured
Natural history
NEDA = no evident disease activity
The autoimmune hypothesis
Multiple
Sclerosis
Environ-ment
Genes
Day 7
Limp tail
Impaired righting reflex
hindlimb paralysis
Moribund
partial paralysis
Normal
Remission
0
1
2
3
4
5
(1)
Clinical Score Professor Baker’s
Animal model of MS
Day 0
Slide courtesy David Baker
Curing animal MS
survival analysis
“highly effective treatments”
MS is an autoimmune disease hypothesis
15-20 year experiment
Can we repeat the animal experiment in MS?
Multiple
Sclerosis
Environ-ment
Genes
Relapses
Unreported relapses
Clinical disease worsening
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
Moving the target: the MS Iceberg
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
Control Multiple sclerosis
Moving the target: end-organ damage
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.
Treat-2-target
Brain volume loss should be included in our definition for NEDA
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
Have we got it wrong?
EBV Vitamin D
Smoking Genes
Multiple
Sclerosis
Environ-ment
Genes
Is MS due to a virus?
Charcot Project
INSPIRE Trial (Raltegravir)
Etc. etc. etc.
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.