The Science and Medicine of
Multiple Sclerosis
When, Why and How of
Multiple Sclerosis Neurotherapy
P.K. Coyle, MD
Professor and Acting Chair
Department of Neurology
Director, MS Comprehensive Care Center
SUNY at Stony Brook
Stony Brook, NY
MS Neurotherapy Basics
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Wellness program
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Diet, exercise, sleep, weight, alcohol/ tobacco
Health maintenance
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Vitamin D and B12, bone density, blood pressure, lipids,
glucose, breast/prostate/ colon screening
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Optimized symptomatic management
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Disease modifying therapies (DMTs)
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most patients eligible, no absolute contraindications
MS Neurotherapy: WHEN?
► Considerations
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Clinical subtype
Disease activity level
Disease timepoint/ duration
► Clinical
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subtype
All relapsing forms of MS
Progressive MS has no proven DMTs (?GA;
anti-CD 20; FTY 720; MBP analog)
MS Neurotherapy: WHEN?
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Disease activity level
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All early MS is active (no remissions/ burnout)
Damage process (macroscopic/ microscopic) often
occult
Benign MS <5%
Disease timepoint/ duration
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Definite relapsing MS
Clinically isolated syndrome (CIS)/ first attack- high
risk MS
Radiologically isolated syndrome (RIS)
Multiple positive phase III trials in relapsing MS and
CIS
CIS/ First Attack High Risk MS
► Appropriate
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15 to 45/50 years
► Suggestive
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age
clinical syndrome
Monocular optic neuritis
Incomplete transverse myelitis
Isolated brainstem/ cerebellar syndrome
Multifocal CNS syndrome
Paroxysmal attacks
CIS/ First Attack High Risk MS
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Abnormal MRI
● silent lesion(s) suggestive for MS
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No better diagnosis
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Above criteria identity first relapse MS
RIS
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Routine MRI is abnormal and suggestive for MS
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No prior history consistent with MS
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Issue involves presymptomatic MS vs.
asymptomatic MS vs. not MS
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No accepted management protocol
MS Neurotherapy: WHY?
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Most (>95%) untreated MS patients develop
disability
● Physical, cognitive, vocational
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Ongoing accumulating macroscopic and
microscopic injury
● Accelerated CNS tissue volume loss
● Permanent damage involved
MS Neurotherapy: WHY?
► DMTs
decrease this injury/ disability
process
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Starting DMT immediately, esp in functionally
intact patients, gives better long term outcomes
► First
► This
line DMTs are safe and well tolerated
approach (aggressive early therapy)
endorsed for other organ-specific immune
mediated disorders
MS Neurotherapy: HOW?
► DMT
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choice based on
Disease features (subtype, duration,
prognostic profile, clinical/ MRI features)
Drug features (efficacy, tolerability, dosing/
administration, convenience, risk/ benefit
ratio, screening, cost)
Patient characteristics (comorbidity, lifestyle,
expectations, pregnancy concerns)
MS Neurotherapy: HOW?
► First/
second line DMTs based on risk
benefit ratio
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First line: GA, IFNβs; similar clinical efficacy;
no short or long term safety issues
Second line: Natalizumab, mitoxantrone;
safety issues involve PML, cardiomyopathy/
treatment related leukemia
MS Neurotherapy: HOW?
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Critical compliance issue
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Education and training (realistic expectations,
management of side effects)
Support services
Open communications
Treatment of depression
MS Neurotherapy: HOW?
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Continued monitoring
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Regular assessments
Evaluation for relapses, sustained worsening,
MRI activity
Breakthrough disease activity evaluation, for
suboptimal response/ treatment failure
Nova Scotia MS Cohort*
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1980 to 2004 data (treatment era 1988-2004)
Three populations
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•
•
•
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Relapsing MS (N=390)
SPMS (N=200)
Relapsing onset MS (N=590)
Pretreatment annual EDSS increases were
0.10, 0.31, 0.16
Treatment significantly lessened EDSS annual
worsening (relative size effect- 112%, 21%,
105%)
Neurology 2007;69:1498
Italian MS Cohort*
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N=1,504 relapsing MS patients
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1,103 on IFNβ
401 untreated
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Followed up to 7 years
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Propensity score inverse weighting used to
evaluate
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Transition to SPMS
EDSS 4 and 6
Ann Neurol 2007;61:300
Italian MS Cohort*
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Treated group significantly less likely to reach
disability markers
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After 7 years SPMS in 8% vs. 20.2%
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EDSS 4 in 20.5% vs. 28%; EDSS 6 in 7.7% vs.
12.4%
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Conclusion: DMT slows disability progression
in relapsing MS
Ann Neurol 2007;61:300
IFNß-1a im Long-term Follow-up
8 Year Analysis
Time to EDSS ≥ 6.0
22%
▼
Rudick et al. MS 11:626, 2005
31%
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ASSURANCE
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15-year long-term follow-up of pivotal IM IFNβ1a
relapsing trial (MSCRG)
● Involved 2-year completers
● Open label, retrospective, patient reported
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N=136 (of 172) participated
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46% currently on IM IFNβ1a (median duration 13.3
years)
ASSURANCE
► Those
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on IM IFNβ1a showed
↓ Mean EDSS change (2.3 vs. 3.3, p=0.011)
↓ EDSS 4 (64% vs. 83%, p=0.06)
↓ EDSS 6 (32% vs. 62%, p=0.008)
↓ EDSS 7 (9% vs. 33%, p=0.008)
Better physical score on SF36 (p<0.0001),
greater independence (p=0.0019; p=0.031)
PRISMS Long Term Follow-up*
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8-year follow-up of PRISMS SC IFNβ1a pivotal
relapsing trial
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382 of 560 subjects (68.2%) evaluated
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275 (72%) still receiving IFNβ1a
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Subjects initially randomized to 44mcg
showed best EDSS, relapse rate, T2 burden
of disease at 8 years
-no brain atrophy difference
19.7% progressed to SPMS
Neurology 2006;67:944
IFNß-1a sq Long-term Follow-up
8 Year Analysis
% Free of 3 month Sustained
EDSS Progression
Time to Accumulated Disability
44 µg
22µg
Late Rx
All
134
138
134
396
Reached EDSS
4.0
23.9%
28.9%
27.6%
26.8%
Time to 20th %tile
5.8 yr
4.6 yr
3.5 yr
4.8 yr
N at Risk
19.7% of all subjects in LTFU developed SPMS (12 months of ≥ 1.0
EDSS change without relapse)
Kappos et al. Neurology 67:944, 2006
16 Year Follow-Up
Pivotal Study (n=372)
IFNβ-1b 250 µg
124
56
IFNβ-1b 50 µg
125
52
Placebo
123
58
1988 1990
Patients under regular medical care - no trial
1993
Cross-sectional investigation of:
- clinical outcomes (disability, relapse rate)
- imaging (brain and spinal MRI)
- cognition and mood
- QoL, resource use
- lab parameter including NAb's and PgX
Goodin et al., Early treatment with interferon beta-1b associated with improved long-term
outcome in multiple sclerosis. Multiple Sclerosis; 2008: 14 (Suppl 1), P52
LTF
2005
16-Year LTF: Patient Disposition in the
Intent-to-Treat Population
Proportion of Patients
16.3%
7.2%
13.6%
11.4%
4.8%
10.5%
Deceased
84.7%
Not found
79.2%
Alive
72.4%
Placebo
n = 123
Ebers G. Presented at ECTRIMS 2006, Madrid, Spain.
INFB-1b
50 µg
n = 125
IFNB-1b
250 µg
n = 124
16-Year LTF: Other findings
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The most important predictors for better long-term outcomes from
the IFNB-1b 16-year LTF study were
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Low EDSS (<2) at study entry
High exposure to IFNB-1b
• The risk of any negative outcome* was reduced by 60% with high compared
to low exposure
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Safety and tolerability
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No new or unexpected side effects
Flu-like symptoms , injection site reactions and NAbs continued at a
low level
*EDSS 6; SPMS; EDSS 6/SPMS, Wheelchair
Goodin et al., Early treatment with interferon beta-1b associated with improved long-term
outcome in multiple sclerosis. Multiple Sclerosis; 2008: 14 (Suppl 1), P52
GA 10-Year Follow-up
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Prospective follow-up from pivotal relapsing trial
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N=108 remained in study; N=124 withdrew (N=50
returned for LTFU)
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EDSS ↑ by 0.50 ± 1.65 in ongoing cohort vs. 2.24 ±
1.86 in withdrawn cohort
-EDSS stable or improved in 62% vs. 28%
-EDSS 4 (24.8% vs 68%)
-EDSS 6 (1% vs 10%)
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Relapse reduction >80%; ARR ~ 0.2
Summary
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There is strong justification for treating relapsing forms
of MS (including first attack)
- Increasing rationale for “the earlier the better”
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There is accumulating data to support that treatment is
changing MS natural history
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Accumulating long term follow-up studies all support
early treatment
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Therapy is optimized by tailoring DMD choice,
providing support services, and ongoing follow-up
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This modern treatment era is changing the face of MS