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GAVIN GIOVANNONI BARTS and THE LONDON
Early Clinical Predictors for Long-
Term Prognosis: Goals of Therapy
1
2
How serious a disease
is multiple sclerosis?
3
Lifespan in MS Patients Is Shortened by 8 to 12 Years
• Survival probability of Norwegian patients with relapsing-remitting MS (RRMS)
(Hordaland County, Western Norway, 1953–2003)
4
RRMS % s
urv
ival
MS=multiple sclerosis; CI=confidence interval.
Population-Based MS Mortality Studies
First Author
Population
and Time Period
Size
of Cohort
Standardized
Mortality Ratio Additional Survival Measures
GryttenTorkildsen
Mult Scler 2008
Western Norway
1953–2003 878
2.66
(95% CI: 2.31–3.06)
• Median survival time from onset: 41 years MS vs 49 years general population
− 8 years life lost in MS
Smestad
Mult Scler 2009
Oslo
1940–1980 368
2.47
(95% CI: 2.09–2.90)
• Reduction of median life expectancy vs general population
− Female: 11.2 years
− Male: 7.4 years
Bronnum-Hansen
Brain 2004
Danish MS Registry
1949–1996 9881
2.89
(95% CI: 2.81±2.98)
• Median survival time (from disease onset) vs general population:
− ≈10 years life lost in MS
Hirst
JNNP 2008
South Wales
1985–2006 373
2.79
(95% CI: 2.44 to 3.18)
• Median age of death: 63.1 years MS vs 70.6 years general population
− 7.5 years life lost in MS
Sumelahti
Mult Scler 2010
Finland
1964–1993 1595
2.8
(95% CI: 2.6–3.1)
• Survival decreases with disease progression
− SMR, 2–9.9 years after diagnosis: 2.4
− SMR, ≥10 years after diagnosis: 3.1
Wallin
Brain 2000
USA
1956–1996 2489
2.18
(Not specified)
• Healthy soldier effect speculated to have a
favorable effect on survival
Leray
Mult Scler 2007
West France
1976–2004 1879
1.3
(95% CI: 1.01–1.7)
• Mean follow-up duration=12.7 years from
clinical onset; may be basing estimate on
relatively immature dataset
5
SMR=standardized mortality ratio.
The Survival Disadvantage in MS Is Greater Than in
Some Other Chronic Diseases Standardized Mortality Ratios in Chronic Diseases
6
Disease SMR (RANGE)
Cardiovascular disease1* 1.34 (1.23–1.44)
Ischemic stroke2† 1.75(1.38–2.19)
Early breast cancer3 2.0 (1.6–2.7)
Crohn’s disease4 2.8
MS5 2.8 (2.6–3.1)
MS (2–9.9 years after diagnosis)5 2.4 (1.9–2.9)
MS (≥10 years after diagnosis)5 3.1 (2.8–3.4)
Parkinson’s disease6 3.66 (3.37–3.95)
Type 2 diabetes1 4.47 (3.91–5.10)
*In patients with type 2 diabetes; †in patients with valvular heart disease in Olmsted County, Minnesota.
1. De Marco R et al Diabetes Care. 1999;22:756-761; 2. Petty GW et al. Mayo Clin Proc. 2005;80:1001-1008; 3. Hooning MJ et al. Int J Radiat Oncol Biol Phys.
2006;64:1081-1091; 4. South East England Public Health Observatory, Mortality trends. 2006; 5. Sumelahti ML et al. Mult Scler. 2010;16:1437-1442;
6. Hristova DR. Folia Medica. 2009;51:40-45.
21-Year Long-term Follow-up of IFNβ-1b Study Time
From Study Randomization to Death
Early treatment (3 years) with IFNβ-1b was associated with a 47% reduction
in the risk of dying over 21 years compared with initial placebo treatment
IFNβ=interferon beta; HR=hazard ratio.
Source: Goodin et al Neurology. 2012;78:1315–1322.
At risk:
IFNβ-1b 250 µg
Placebo
124
123
124
120
121
117
118
109
104
88
HR=0.532 (95% CI: 0.314–0.902)
46.8% reduction in hazard ratio
Log rank, P=0.0173
IFNB-1b 250 µg
Placebo
65%
70%
75%
80%
85%
90%
95%
100%
0 2 4 6 8 10 12 14 16 18 20 22
Pro
po
rtio
n o
f p
ati
en
ts w
ho
are
sti
ll a
live
Time (Years)
7
Uti
lity
EDSS Status
EDSS and utility* show a significant
inverse relationship1,†
*Utility measures are derived from EQ-5D using the EuroQoL instrument; †error bars depict 95% confidence intervals. Half points on
EDSS are not shown on graph axis, except at EDSS 6.5.
EDSS=Expanded Disability Status Scale; WHO=World Health Organization; MSIF=Multiple Sclerosis International Federation.
1. Adapted from Orme M et al. Value In Health. 2007;10:54-60. 2. WHO and MSIF.
http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747. Accessed October 6, 2010.
3. Confavreaux, Compston. McAlpine’s multiple Sclerosis. 4th edn. Churchill Livingstone Elsevier; 2006. p. 183–272. 4. Compston A,
Coles A. Lancet 2008; 372:1502-1517.
• MS is one of the most common
causes of neurological disability
in young adults2
• Natural history studies indicate
that it takes a median time of 8,
20, and 30 years to reach the
irreversible disability levels of
EDSS 4, 6, and 7, respectively3
The Effect of MS on Quality of Life
8
The Effects of MS on Unemployment
9
Pfleger CC et al. Mult Scler. 2010;16:121-126.
Healthcare Costs Are Linked to Disability
10
Costs are given in € (euros).
OTC=over-the-counter.
Berg J et al. Eur J Health Econ 2006;7(Suppl 2):S75−85.
Total mean annual cost per patient €53,601
Informal care
(disposable income)
(9.2)
Ambulatory care
(5.6)
Disease-modifying
drugs (10.6)
Other prescription and
OTC drugs (1.6)
Tests (0.4)
Investments (2.0)
Long-term sick leave and
early retirement (30.0)
Short-term absence
(2.0)
Services
(28.5)
Inpatient care
(10.2)
The Effects of MS on Divorce and Separation
11
Pfleger CC et al. Mult Scler. 2010;16:878-882
CIS Patients
n = 40
Impact of MS: Cognitive Functioning in the CIS Stage
Cognitive Test Performance in an Exploratory Study*
12
57%
7%
-20%
0%
20%
40%
60%
*40 untreated CIS patients who fulfilled the McDonald dissemination in space criterion compared to a cohort of 30 matched healthy
controls. An extensive battery of neuropsychological tests was used to explore verbal and non-verbal memory, attention, concentration,
speed of information processing, language and abstract reasoning. Cognitive impairment was present when at least 2 different
neuropsychological tests were failed.
CIS=clinically isolated syndrome.
Feuillet l et al. Mult Scler. 2007;13:3124-127.
Healthy Controls
n = 30
p < 0.0001
Deficits were found mainly in
memory, speed of information
processing, attention, and
executive functioning
Pati
en
ts f
ailin
g
≥2 c
og
nit
ive t
ests
What Is Benign MS?
13
163 patients with “benign” MS
(disease duration >15 years and
EDSS <3.5):
1. 45% cognitive impairment
2. 49% fatigue
3. 54% depression
Prognostic factors
14
Clinical Prognostic Factors
Good Prognosis
• Optic neuritis
• Isolated sensory symptoms
• Long interval to
second relapse
• No disability after
5 years
• Normal MRI or low lesion load
Poor Prognosis
• Multifocal CIS
• Efferent systems affected
• High relapse rate in first 2–5
years
• Substantial disability after 5
years
• Abnormal MRI with large lesion
load
MRI=magnetic resonance imaging.
Miller D et al. Lancet Neurol. 2005;4:281-288.
15
0
20
40
60
80
100
0 5 10 15 20
Pa
tie
nts
Co
nve
rtin
g t
o C
DM
S (
%)
Years
0 Lesions
1–3 Lesions
4–10 Lesions
>10 Lesions
Baseline Number of Brain Lesions Predicts
Conversion to CDMS
16
The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study.
The exact relationship between MRI findings and the clinical status of the patient is unknown.
CDMS=clinically definite MS.
Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503;
Brex PA et al. N Engl J Med. 2002;346:158-164; Tintore M et al. Neurology. 2006;67:968-972.
Cu
mu
lati
ve
Pro
ba
bilit
y D
eve
lop
ing
CD
MS
0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60 72 84 96 108 120
Time Since First Attack (months)
0 Lesions
4–9 Lesions
No. of Lesions at Baseline
≥10 Lesions
1–4 Lesions
No. of Lesions at Baseline
Queen Square Study Tintore Study
0
10
20
30
40
50
60
70
80
0 5 10 15 20
Pa
tie
nts
Co
nve
rtin
g t
o E
DS
S ≥
3.0
(%
)
Years
0 Lesions
1–3 Lesions
4–10 Lesions
>10 Lesions
The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study.
The exact relationship between MRI findings and the clinical status of the patient is unknown.
Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503;
Brex PA et al. N Engl J Med. 2002;346:158-164; Tintore M et al. Neurology. 2006;67:968-972.
Baseline Number of Brain Lesions Predicts
Progression to EDSS Score ≥3.0
17
Cu
mu
lati
ve
Pro
ba
bilit
y R
ea
ch
ing
ED
SS
3.0
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60 72 84 96 108 120
Time Since First Attack (months)
0 lesions
Queen Square Study Tintore Study
0 Lesions
4–9 Lesions
No. of Lesions at
Baseline
≥10 Lesions
1–4 Lesions
No. of Lesions at Baseline
Presence of Infratentorial Lesions Increases the
Risk for Disability
18
Tintoré M et al. Neurology 2010; 75:1933-1938.
Basal MR
in CIS
Relapses Can Result in Residual Deficits
• MS exacerbations can produce a measurable and sustained effect
on accrued impairment and disability1
• Therefore, treatments that reduce the frequency of relapses should
be beneficial
19
1. Lublin FD et al. Neurology. 2003;61:1528-1532.
27 29 30
42 44 41
0
10
20
30
40
50
30–59 60–89 ≥90
Pati
en
ts (
%)
Days After Exacerbation
Patients (%) with a ≥1.0 or ≥0.5 Change in EDSS Score After Relapse
≥1.0 EDSS Point
≥0.5 EDSS Point
Adapted from Lublin et al 2003.
Treatment strategy
20
Theoretical Model: Treat Early and Aggressively
21
Time
Disease Onset
Treatment
at diagnosis
Natural course
of disease
Later intervention
Intervention
at diagnosis
Dis
ab
ilit
y
Later
treatment
Prognostic Factors on Treatment
Response to Therapy
22
Breakthrough Disease After Treatment Initiation
• Patients with breakthrough disease can be identified with
• Clinical measures
• Relapses
• EDSS progression
• MRI measures
• T2 and Gd+ lesions
• Biological markers
• IFNβ neutralizing antibodies (NAbs)/lack of MxA induction
• Anti-natalizumab Abs
23
Gd+=gadolinium-enhancing; MxA=myxovirus protein; Ab=antibody.
Relapse on IFNβ Therapy Increases Risk of
Sustained Disability Progression
• Risk is not much greater for 2 or more relapses
• Sensitivity is only 50%
24 SE=standard error.
Bosca I et al. Mult Scler. 2008;14:636-639.
HR SE P Value 95% CI
No relapses
(reference=1) 1
One relapse 3.41 1.47 0.005 1.46–7.98
Two or more relapses 4.37 1.74 0.000 1.90–9.57
HR of EDSS Increase in Patients with No Relapses, 1 Relapse, and 2 or More Relapses During the First
2 Years of IFN Treatment
One New T2 Lesion
2 or More New T2 Lesions
Dobson et al. unpublished data.
MRI to Monitor Treatment Response to IFNβ: a
Systematic Review
25
MRI to Monitor Treatment Response to IFNβ: a
Systematic Review (cont.)
26
One New Gd+ Lesion
2 or More Gd+ Lesions
Dobson et al. unpublished data.
Predictors of Long-term Outcome in Multiple Sclerosis
Patients Treated with IFNβ
27
Bermel RA et al. Ann Neurol. 2013;73:95-103.
Predictors of Long-term Outcome in Multiple Sclerosis
Patients Treated with IFNβ (cont.)
28
Bermel RA et al. Ann Neurol. 2013;73:95-103.
Strongest Predictor of Disability Progression on
IFNβ Therapy Is Progression Itself
Disease Activity During 2 Years of Treatment and Prediction of Disability
Progression* at 6 Years
29
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)
*EDSS ≥6.0 or increase in at least three EDSS steps.
Rio J et al. Ann Neurol. 2006;59:344-352.
Clinical Importance of Neutralizing Antibodies Against
IFNβ in Patients with RRMS
30
Sorensen PS et al. Lancet. 2003;362:1184-1191.
Mean Change in EDSS
31
Malluci S et al. Neurology. 2004;62:2031-2037.
The Incidence and Significance of Anti-Natalizumab
Antibodies: Results from AFFIRM and SENTINEL
Ab−=antibody negative; Ab+=antibody positive.
Calabresi P et al. Neurology. 2007;69:1391-1403. 32
Placebo
Ab–
Transiently Ab+
Persistently Ab+
315
568
20
37
296
550
19
32
283
538
18
26
264
526
16
25
248
506
16
24
240
487
16
22
229
480
15
22
216
470
14
16
208
460
14
16
200
449
14
15
Number at Risk
0 12 24 36 48 60 72 84 96 108 120
Week
0
0.1
0.2
0.3
0.4
0.5
Cu
mu
lati
ve
Pro
po
rtio
n o
f P
ati
en
ts
wit
h S
us
tain
ed
Dis
ab
ilit
y P
rog
res
sio
n
(ED
SS
)
17%
Placebo
Ab–
Transiently Ab+
Persistently Ab+
17%
29%
34%*†
*P≤0.05 vs Ab– patients; †P=0.66 vs placebo
The Incidence and Significance of Anti-Natalizumab
Antibodies: Results from AFFIRM and SENTINEL (cont.)
33
Values are n (%).
*P<0.05 vs persistently Ab+; †P<0.01 vs persistently Ab+; ‡P<0.001 vs persistently Ab+.
Calabresi P et al. Neurology. 2007;69:1391-1403.
Ab–
(n=568)
Transiently Ab+
(n=20)
Persistently Ab+
(n=37)
Natalizumab monotherapy
Headache 4 (24)† 0* 19 (7)
Urticaria <1 (4)‡ 5 (1) 14 (5)
Nausea 1 (8)‡ 0 16 (6)
Rigors <1 (1)‡ 0 11 (4)
Natalizumab add-on therapy (n=515) (n=32) (n=38)
Rigors <1 (1)‡ 0‡ 29 (11)
Nausea 1 (7)‡ 0* 18 (7)
Headache 4 (20)* 3 (1) 13 (5)
Pruritus ≤1 (4)† 3 (1) 11 (4)
Flushing ≤1 (3)‡ 0 13 (5)
Urticaria ≤1 (2)‡ 0 13 (5)
Tachycardia 0‡ 0 11 (4)
Dizziness 3 (15) 0 8 (3)
Pyrexia <1 (3)† 0 8 (3)
Incidence of Common Infusion-Related Adverse Events by Antibody Status in AFFIRM and SENTINEL
Emerging concepts in MS
NEDA; no evidence of disease activity
TTT; treat-to-target
Treat-2-target
No Evidence of Disease Activity
Treat-2-Target Proposed NEDA* Treatment Algorithm for
Relapsing MS
36
NEDA=no evidence of disease
activity.
Conclusions
• MS is a bad disease
• Disability (physical and cognitive)
• High societal costs (unemployment, healthcare costs, divorce)
• Survival compromised
• Treat early and aggressively
• Prognostic factors
• Clinical findings, MRI activity, OCBs, and other emerging biomarkers
• Treatment response markers
• Clinical (relapses and disability progression)
• MRI (T2 and Gd+ lesions)
• NAbs (efficacy and safety)
• Treat-2-Target
• NEDA
37
OCB=oligoclonal band.