What are we actually measuring in MS? “Preventing end-organ damage: Saving Brain” Gavin Giovannoni
What are we actually measuring in MS?
“Preventing end-organ damage: Saving Brain”
Gavin Giovannoni
Disclosure
Gavin Giovannoni: has provided consultation to Bayer Schering Healthcare, Biogen Idec, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Protein Discovery Laboratories, Teva Aventis, UCB Pharma, Ironwood, Eisai, Vertex, Roche, Synthon, Canbex. He has received grant support from Bayer Schering Healthcare, Biogen Idec, Merck Serono, Merz, Novartis, Teva Aventis, GW Pharma.
Prevention
Diagnosis
DMT Symptomatic
Therapist
Terminal
Counselling A clinical perspective of multiple sclerosis
Epstein–Barr virus
Genetics
Vitamin D
Smoking
Risks
Adverse events
Differential diagnosis
MRI
Evoked potentials
Lumbar puncture
Blood tests
Diagnostic criteria
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
Pain Swallowing
Spasticity Falls
Balance problems Insomnia
Restless legs Fertility
Clinical trials
Gait
Pressure sores
Oscillopsia
Emotional lability
Seizures
Gastrostomy
Rehab
Suprapubic catheter
Intrathecal baclofen
Physio- therapy
Speech therapy
Occupational Therapy
Functional neurosurgery
Colostomy
Tendonotomy
Studying
Employment Relationships
Travel
Vaccination
Anxiety
Driving
Nurse specialists
Family counselling
Relapses
1st line
2nd line
Maintenance Escalation Induction
Monitoring
Disease-free
Disease progression
DMTs
Side effects
Advanced directive
Exercise
Diet
Alternative medicine
Pregnancy Breast- feeding
Research
Insurance
Visual loss
Palliative care
Assisted suicide
Social services
Legal aid
Genetic counselling
Intrathecal phenol
Fractures
Movement disorders
Osteopaenia
Brain atrophy
Hearing loss
Tinnitus
Photophobia
Hiccoughs
DVLA
Neuroprotection
Psychosis
Depersonalisation
Brain health
Cognitive reserve
Sudden death
Suicide
OCD
Narcolepsy
Apnoea Carers
Respite
Hospice
Respite
Dignitas
Advanced directive
Rhiztomy
Wheelchair
Walking aids
Blood/Organ donation
Brain donation
Exercise therapy
NABs
Autoimmunity
Infections
Outcome measures
Web Resources
Pathogenesis
Double vision
What is MS?
NEDA
T2T OCT
Neurofilaments
JCV status Pharma
Anaesthesia
Natural history
Delayed intervention
Later treatment
Treatment at diagnosis
Early intervention
Time Disease onset
Dis
abili
ty
Time is brain
Theoretical model: treat early and effectively
Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial
Survival from pivotal randomized controlled trial randomization over 21 years is shown for interferon β-1b (IFNβ-1b) 250 μg vs. placebo (A) and IFNβ-1b 50 μg vs. placebo (B). Time from onset of clinical symptoms to death is shown for IFNβ-1b 250 μg vs. placebo (C) and IFNβ-1b 50 μg vs. placebo (D). Hazard ratios (HRs) and 95% confidence intervals (CIs) are estimated using Cox proportional hazard models without stratification. Goodin DS, et al. Neurology 2012; 78:1315–1322
Pro
po
rtio
n o
f p
atie
nts
w
ho
are
sti
ll al
ive
(%)
Time (y) At risk (n): IFNβ-1b 50 µg Placebo
125 125 123 73 48 125 116 32 13 31 69 118 123 123 121 107 24 12
IFNβ-1b 50 µg Placebo
HR = 0.545 (95% CI 0.321–0.924) 45.5% reduction in hazard rate Log-rank, P = 0.0223
100 95
85
75 70
60 55
45
90
80
65
50
0 5 15 20 25 10 30 35 40
Pro
po
rtio
n o
f p
atie
nts
w
ho
are
sti
ll al
ive
(%)
Time (y) At risk (n): IFNβ-1b 250 µg Placebo
124 124 122 93 52 122 120 35 9 31 69 118 123 123 121 107 24 12
IFNβ-1b 250 µg Placebo
HR = 0.495 (95% CI 0.289–0.847) 50.5% reduction in hazard rate Log-rank, P = 0.0089
100 95
85
75 70
60 55
45
90
80
65
50
0 5 15 20 25 10 30 35 40
Pro
po
rtio
n o
f p
atie
nts
w
ho
are
sti
ll al
ive
(%)
Time (y) At risk (n): IFNβ-1b 250 µg Placebo
124 124 121 118 104 88 109 117 120 123
IFNβ-1b 250 µg Placebo
HR = 0.532 (95% CI 0.314–0.902) 46.8% reduction in hazard rate Log-rank, P = 0.0173
100
95
90
85
80
75
70
65
0 5 10 15 20
Pro
po
rtio
n o
f p
atie
nts
w
ho
are
sti
ll al
ive
(%)
Time (y) At risk (n): IFNβ-1b 50 µg Placebo
125 122 120 113 109 88 109 117 120 123
IFNβ-1b 50 µg Placebo
HR = 0.540 (95% CI 0.318–0.915) 46.0% reduction in hazard rate Log-rank, P = 0.0202
100
95
90
85
80
75
70
65
0 5 10 15 20
A B
C D
38-year-old teacher with relapsing–remitting MS under the care of a hospital in central London
• Glatiramer acetate treatment for 3 years (good adherence and tolerance)
• Relapse with a mild left sensory loss
• Referred to me for a second opinion
• Switched to interferon β (intramuscular interferon β-1a; www.msdecisions.org.uk)
• Mild persistent flu-like side effects and lymphopenia
• 12/12’s neutralizing antibodies screen negative
• Volunteered for new research programme, which included a gadolinium-enhanced MRI protocol
Teacher
Teacher
38-year-old teacher with relapsing–remitting MS
• As a result of fatigue and cognitive problems she is forced to take early retirement
• Although fully functional she develops depression and anxiety
• In her spare time she spends a lot of time on the web and becomes an expert patient
X
How bad is MS?
Consequences of increasing EDSS scores: loss of employment1
The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger. * In a Danish cohort study, the median time to early pension was 10 years for patients and 24 years for controls 1. Kobelt G, et al. J Neurol Neurosurg Psychiatry 2006; 77:918–926; 2. Pfleger CC, et al. Mult Scler 2010;16:121–126.
Spain Sweden Switzerland United Kingdom
Netherlands Italy Germany Belgium Austria
Work capacity by disability level
~10 yrs*,2
0
10
20
30
40
50
60
70
80
90
0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0
EDSS Score
Pro
po
rtio
n o
f p
atie
nts
≤6
5 y
ear
s o
ld
wo
rkin
g (%
)
Gambler’s Dilemma
Benign MS
What is benign MS?
Amato MP, et al. J Neurol 2006; 253:1054–1059
163 patients with “benign” MS
(disease duration ≥15 years and EDSS ≤3.5):
45% cognitive impairment
49% fatigue
54% depression
Maria Pia Amato
Valentina Zipoli
Benedetta Goretti
Emilio Portaccio
Maria Fara De Caro
Laura Ricchiuti
Gianfranco Siracusa
Medena Masini
Sandro Sorbi
Maria Trojano
Impact of MS: cognitive functioning in the CIS stage
Feuillet L, et al. Mult Scler 2007; 13:124–127
Pat
ien
ts f
ailin
g
≥ 2
co
gnit
ive
te
sts
57%
7%
0%
10%
20%
30%
40%
50%
60%
CIS patientsn = 40
Healthy controlsn = 30
P < 0.0001
Deficits were found mainly in memory, speed of
information processing, attention and executive
functioning
Relapses
Weinshenker BG, et al. Brain 1989; 112:1419–1428
Pe
rce
nta
ge o
f p
atie
nts
*
Time from onset of MS (yrs)
0 10 20 30 40 50
100
80
60
40
20
0
0–1 attacks in first 2 years
2–4 attacks in first 2 years
≥5 attacks in first 2 years
* The percentage of patients not having reached DSS 6 is shown after stratification according to the number of attacks in the first 2 years from onset of MS. The difference between the groups is significant (P < 0.0001). Patients with chronically progressive MS were excluded.
Predictors of long-term outcomes in MSers treated with IFNβ-1a
Bermel RA, et al. Ann Neurol 2013; 73:95–103
15 years 2 years
Treatment chosen by the treating physician
ASSURANCE study: long-term clinical follow-up
MSCRG study: MRI at baseline, Year 1 and Year 2
Placebo
IM IFNβ-1a 30 μg qwk
Predictors of long-term outcomes in MSers treated with IFNβ-1a
Bermel RA, et al. Ann Neurol 2013; 73:95–103
IM IF
Nβ
-1a
P
lace
bo
OR of advancing into the worst quartile of EDSS change after 15 years
40 30 20 10 1
Early disease activity*
New T2
Relapse
Gd+
New T2
Relapse
Gd+
OR (confidence interval)
2.62 (0.93, 7.43)
1.53 (0.56, 4.19)
1.79 (0.62, 5.16)
2.89 (0.88, 9.54)
4.44 (1.43, 13.85)
8.96 (2.53, 31.65)
P value
0.069
0.408
0.284
0.080
0.010
< 0.001
Gd+, gadolinium-enhancing; IM, intramuscular; OR, odds ratio. * ≥2 gadolinium-enhancing lesions (cumulative) on year 1 and/or year 2 MRI; ≥3 new T2 lesions on Year 2 MRI compared with baseline; and ≥2 relapses over 2 years.
27 29 30
42 44
41
0
5
10
15
20
25
30
35
40
45
50
30–59 60–89 ≥90
≥1.0 EDSS point
≥0.5 EDSS point
Relapses and residual deficits
Lublin FD, et al. Neurology 2003; 61:1528–1532
Patients with a change in EDSS score of ≥1.0 or ≥0.5 after relapse
Pat
ien
ts (
%)
Days after exacerbation
(n = 62) (n = 85) (n = 77)
Disease progression
Relationship between early clinical characteristics and long-term disability outcomes: 16-year cohort study (follow-up) of the
pivotal IFNβ-1b trial
Physical outcome = either SPMS or EDSS = 6; † Cognitive outcome = cognitive performance index; BOD, burden of disease; EDSS, Expanded Disability Status Scale score; LTF, long-term follow-up; RCT, randomized controlled trial; SPMS, secondary progressive multiple sclerosis Goodin DS, et al. J Neurol Neurosurg Psychiatry 2012; 83:282–287
Multiple regression model for outcome at long-term follow-up derived with stepwise model selection procedure: fitted regression model including predictors with P ≤ 0.5 to enter; P < 0.1 to stay in the model.
Estimate SE P value
Physical outcome* model fit (logistic regression): R2 = 0.51
Baseline variables
Intercept –5.3 0.91 < 0.0001
EDSS at baseline 1.2 0.22 < 0.0001
MRI T2 BOD at baseline (cm2) 0.05 0.02 0.001
Gender 0.93 0.47 0.045
On-RCT variables
Actual EDSS change from baseline 0.86 0.21 < 0.0001
Annualized relapse rate 0.52 0.23 0.025
Cognitive outcome† model fit (linear regression): R2 = 0.49
Baseline variables
Intercept –11.2 3.98 0.006
EDSS at baseline –0.99 0.25 < 0.0001
Pre-morbid IQ 0.12 0.035 0.0007
MRI T2 BOD at baseline (cm2) –0.05 0.02 0.018
Third ventricular width at baseline (mm) –0.41 0.16 0.014
On-RCT variables
Actual EDSS change from baseline –0.67 0.24 0.007
Change, third ventricular width (mm) –0.87 0.33 0.009
Strongest predictor of disability progression on IFNβ therapy is progression itself
* EDSS score ≥6.0 or increase in at least three EDSS steps. Río J, et al. Ann Neurol 2006; 59:344–352
Disease activity during 2 years of treatment and prediction of disability progression* at 6 years
Group Sensitivity (%)
(CI) Specificity (%)
(CI)
A. An increase of at least one EDSS step confirmed at 6 months 85 (64–95) 93 (86–97)
B. Occurrence of any relapse 80 (58–92) 51 (41–61)
C. Occurrence of two or more relapses 45 (26–66) 81 (72–82)
D. A decrease in relapse rate less than 30% compared with 2 years before therapy
40 (22–61) 86 (77–91)
E. A decrease in relapse rate less than 50% compared with 2 years before therapy
40 (22–61) 81 (72–88)
F. No decrease or identical relapse rate compared with 2 years before therapy
35 (18–57) 88 (79–93)
G. Definition A or B 90 (70–97) 48 (38–58)
H. Definition A or E 85 (64–95) 76 (66–83)
I. Definition A and B 75 (53–89) 97 (91–99)
J. Definition A and E 40 (22–61) 99 (94–99)
What to measure?
Normal neurological examination
No disability
Minimal disability
Moderate disability
Relatively severe disability
Disability precludes full daily activities
Assistance required to walk Restricted
to a wheelchair
Restricted to bed or chair Confined
to bed
Death
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0
Adapted from http://www.msdecisions.org.uk/. Accessed 15 April 2014. Previously adapted from Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33: 1444-52.
Yes – I do an EDSS whenever I see a patient 14 25%
Yes – I do an EDSS annually 10 18%
Yes – I occasionally do an EDSS 20 36%
No – I never do an EDSS 3 5%
Other 9 16% Yes – I do an EDSS whenever I see a
patient [14] Yes – I do an EDSS
annually [10]
Yes – I occasionally do an EDSS [20]
No – I never do an EDSS [3]
Other [9]
Survey of UK MSologists
Schmierer K, et al. ABN 2014; unpublished.
Clinical – In your routine MS clinical practice, do you use the EDSS?
Clinical – If you do an EDSS in your routine clinical practice, do you walk the patients to assess their walking distance?
Yes [9]
No [20]
Sometimes [22]
Other [5] Yes 9 16%
No 20 36%
Sometimes 22 39%
Other 5 9%
Validating a novel web-based method to capture disease progression outcomes in multiple sclerosis
The midpoint of the diamonds is the mean difference between the two EDSS scores, the upper and lower lines within the diamonds are the 95 % confidence interval. The width of the diamond indicates the sample size, the dots the actual values. The horizontal line at 0.46 indicates the mean difference between the two scores. The graph indicates the greater variation at lower EDSS scores, with greater agreement at scores >5. Leddy S, et al. J Neurol 2013; 260:2505–2510
ORIGINAL COMMUNICATION
we
b-
EDSS
– P
-ED
SS
P-EDSS
–4
–3
–2
–1
0
1
2
3
4
0 1 1.5 2 2.5 3 3.5 4 4.5 5.5 6 6.5 7 8
Monitoring your own disease
http://www.patientslikeme.com/
Teacher
38-year-old teacher with relapsing–remitting MS
• As a result of fatigue and cognitive problems she is forced to take early retirement
• Although fully functional she develops depression and anxiety
• In her spare time she spends a lot of time on the web and becomes an expert patient
• Possible undocumented relapses
– Several episodes of pins and needles and numbness in her feet – An episode of urinary frequency and urgency – Cognitive impairment waxed and waned
X
Teacher X
No Evidence of Disease Activity: 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
Should brain volume loss and a patient-related outcome measure be included in our definition for ‘no evidence of disease activity’?
‘No evidence of disease activity’ defined as:1,2
No relapses
No focal MRI activity – sub clinical relapses
No new or enlarging T2 lesions
No Gd-enhancing lesions
No sustained disability progression
Control Multiple sclerosis
End-organ damage: saving brain
Conclusions
• Treat early and effectively
• The gambler’s dilemma
– What is benign MS?
• Relapses and disease progression count
– Relapses are often missed
– Poor recovery from relapses is a cause of disease progression
– EDSS is not routinely done, and if done it is not reliable
– Need sensitive and objective measures such as MRI and PROMS
• Need to target both inflammation and neurodegeneration
– Treat-2-target NEDA
– Do we need to expand our current definition of NEDA?
– Do we need to focus on end-organ damage and saving brain?