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ASN MS Update
2015 Annual Meeting
Carefree, AZ
Guy Buckle, MD, MPH
Director of Neuroimaging Research
Andrew C. Carlos MS Institute at Shepherd Center
Atlanta, GA
Learning Objectives
• Discuss how new information on the
immunopathology of MS affects understanding of the
disease process
• Employ current information on the use of MRI to
improve diagnosis, treatment, and monitoring of
patients with MS
Overview
• MS History and Epidemiology
• MS Presentation and Diagnostic Criteria
• Emerging Prognostic Tools
St. Lidwina of Schiedam (1380-1433)
St Lidwina’s disease began soon
after a fall while skating, at the age
of 16. From that time onwards, she
developed walking difficulties,
headaches and violent pains in her
teeth. By the age of 19, both her
legs were paralyzed and her vision
was disturbed. Over the next 34
years, Lidwina's condition slowly
deteriorated, although with
apparent periods of remission, until
eventually she died at the age of
53.
Robert Carswell (1793-1857)
"a peculiar diseased state
of the chord and pons
Varolii, accompanied
with atrophy of the
discoloured portions"
Jean Cruveilhier (1791 – 1874)
"had been ill six years
without cause … she
noticed that the left leg
resisted her will to such
a degree that she fell in
the street"
DR. JEAN MARTIN CHARCOT
(1825-1893)
Nikola Tesla (1856-1943)
“The operator’s body,
in this experiment, is
charged to a high
potential by means of
a coil responsive to
the waves transmitted
to it from a distant
oscillator.” Electrical
Review, March 29,1899
First MRI in MS
Ian R Young
• "[MRI] scanning
promises to be of
value in patients
presenting with
symptoms and signs
referable to the brain
and ... spinal cord ."
Reproduced with permission from
Nuclear magnetic resonance
imaging of the brain in Multiple
Sclerosis, IR Young et al., The
Lancet, Nov 14, 1981, p1063-5
Copyright The Lancet Ltd, 1981
Gadolinium (Gd) enhancement
Robert Grossman
• Introduction of Gd
as a contrast
agent.
•
•
Robert Grossman, a radiologist
working in Philadelphia, found
that when using the enhancing
agent gadolinium-DPTA, some
MRI lesions enhance while
others do not.
Grossman recognized that the
Gd enhancement identified
breakdown of the blood-brain
barrier, indicating areas of
active inflammation.
Epidemiology of MS
• The most common chronic disabling disease affecting
the CNS in young adults
• MS strikes individuals between the ages 20-50
• ~400,000 cases in the US (1:1000)
• ~2 million cases worldwide
• Risk factors
– First degree relative with MS (25% with identical twin)
– Distance from the equator
– Caucasian
– Women (~ 2.5:1)
– HLA-DR*1501 (OR = 3.2)
http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-getsms/index.aspx. Accessed October, 2013.
Pathogenesis of MS
Infectious
Agent
Genetic
Predisposition
Abnormal Immunologic Response
O'Gorman C, et al. Int J Mol Sci. 2012;13(9):11718-11752.
Environmental
Factors
MS
Immune Pathways
Linker RA, et al. Trends Pharmacol Sci. 2008;29(11):558-565.
Claussen MC, Korn T. Clin Immunol. 2012;142(1):49-56.
Davila L, et al. Nat Rev Rheumatol. 2011;7(9):537-550.
MS: Prevalence
Average World UV Index
http://www.temis.nl/uvradiation/UVindex.html. Accessed October 2013.
Vitamin D Status is Associated With
New Brain MRI Activity
Mowry EM, et al. Ann Neurol. 2012;72(2):234-240.
Natural History of MS
Measures of brain volume
Relapses and impairment
MRI burden of disease
MRI activity
Preclinical
(RIS)
CIS
Secondary-Progressive
RRMS
Time
Comi. Opin Neurol. 2000;13:235; Munschauer. Clin Ther. 1997;19:868; Weinshenker. Brain. 1989;112:1422.
Multiple Sclerosis: Diagnosis and Monitoring
• RIS: Definition and natural history
• CIS: Early Findings and predictive value
• CDMS and RRMS: Diagnostic Criteria
• Effect of DMTs on MRI
RIS Criteria
Okuda D T et al. Neurology 2009;72:800-805
RIS: Typical Findings
Figure 1 Cross-sectional and longitudinal
MR images from select RIS cases (A)
Axial 3.0 T proton density image
demonstrating a juxtacortical and
multiple, ovoid, periventricular foci of T2
prolongation (arrows).
Okuda D T et al. Neurology 2009;72:800-805
© 2013 American Academy of Neurology
RIS: Natural History
Figure 2 Kaplan-Meier curves
for clinical and radiologic
endpoints Kaplan-Meier
curves for patients with
endpoints including (A) tie to
first clinical event and (B)
time to first new T2-weighted
focus on subsequent brain
MRI studies.
Okuda D T et al. Neurology 2009;72:800-805
© 2013 American Academy of Neurology
RIS: Predictive Value of Spinal Cord Imaging
Asymptomatic cervical spinal cord lesion in a subject with radiologically isolated
syndrome (A) Sagittal T2-weighted MRI of the cervical spine demonstrating a
focus of high signal abnormality at C2.
Okuda D et al. Neurology 2011;76:686-692
© 2013 American Academy of Neurology
3 Cases
26 y/o Woman w/ numbness, tingling and HA:
Neurologic Exam, LP, EPs, S.C. imaging all WNL
Clinically Isolated
Syndrome: Optic Neuritis
• 26 year-old woman with
acute onset of
monocular visual loss
O.S. with pain on eye
movement.
• Examination: Mild
papilledema; Acuity of
20/200 w/ red desat.
central scotoma and
RAPD. Remainder of
exam is normal.
Clinically Isolated Syndrome 2: Initial
Findings on FLAIR MRI
FLAIR = fluid-attenuated inversion recovery
Clinically Isolated Syndrome 2:
Transverse Myelitis
• 23-year-old woman with gradual
onset of tingling and numbness in
her feet that ascends to the
umbilicus over the next 4 days.
• Exam shows a T8 sensory level to
LT and temp. and reduced
vibratory sensation with hyperreflexia in the LE’s. The remainder
of the neurological examination is
normal.
T2
T1 + Gd
Clinically Isolated Syndrome 2:
Initial Findings on Proton Density MRI
Proton Density
T1 w/Gd
Medical History
• Patient is active and appears to be in good health.
• No personal history of previous neurological
disease.
• There is no family history of neurological or
autoimmune disease.
• Patient does not report any other symptoms.
Basic Differential
Diagnosis TM
• Metabolic — B12 Copper deficiency
• Infectious — Lyme, syphilis, HIV, HTLV-1
• Vascular — arteriovenous malformation (AVM)
• Malignancy — intramedullary or extrinsic tumor
• Inflammatory/autoimmune — SLE, Sjögren's,
sarcoidosis, APLS, NMO
• Structural — cervical spondylosis
Clinically Isolated Syndrome:
Discussion Points
• Which patient has multiple sclerosis
(MS)?
• Would you recommend treatment for
this patient?
– If yes, what type of treatment should
be offered?
– If no, how should this patient be
followed?
Clinically Isolated
Syndrome (CIS)
Patients who present with clinically isolated
syndrome (CIS) should be managed based on their
risk of progression to MS:
• In the Optic Neuritis Trial, risk at 10 years was:
– 56% for patients with ≥1 lesion
– 22% for patients with no lesions
• In patients with CIS and no lesions, risk of MS at
14 years was:
– 19% for clinically definite (CD) MS
Brex et al. N Engl J Med. 2002;346:158-164.
Optic Neuritis Study Group. Arch Ophthalmol. 2003;121:944-949.
Median EDSS Score at Year 14
Number and Volume of T2 Lesions at
Presentation Predict Disability
7
6
6
5
4
4
3
2
1.75
2
0
(0 cm3)
1 to 3
(0.6 cm3)
1
0
4 to 10
(0.9 cm3)
>10
(5.6 cm3)
Number (Median Volume) of T2 Weighted Lesions at Presentation
Brex. N Engl J Med. 2002;346:158.
Baseline Brain MRI Lesion Number
20-Year Clinical Status
Fisniku LK. Brain 2008;131:808-817.
Multiple Sclerosis:
Evolution of Diagnostic Criteria
Poser Criteria Define MS as
“Clinically Definite” or “Probable”
8
• Clinically definite MS
– A1: 2 attacks + 2 lesions
– A2: 2 attacks + 1 lesion + 1 paraclinical lesion
• Laboratory-supported definite MS
– B1: 2 attacks + 1 lesion or 1 paraclinical lesion + abnormal CSF
– B2: 1 attack + 2 lesions + abnormal CSF
– B3: 1 attack + 1 lesion + 1 paraclinical lesion + abnormal CSF
• Poser criteria also includes 2 additional categories
– Clinically probable MS
– Laboratory-supported probable MS
Poser CM et al. Ann Neurol. 1983;13(3):227-231.
Diagnosis of Multiple Sclerosis: McDonald Criteria
•
•
•
•
•
Objective evidence of dissemination in space (DIS) and dissemination in
time (DIT) is essential.
Alternative diagnostic considerations must be excluded (no better
explanation).
Clinical evidence must be based on objective
clinical signs (not solely on pt’s provided history).
MRI, CSF, and visual evoked potentials may be helpful for diagnosis when
clinical presentation is
not diagnostic (SSEPs and BAERs discarded).
Following evaluation, diagnosis will be: MS, not MS, or possible MS (no
laboratory-supported, clinically probable MS, etc.).
McDonald WI, et al. Ann Neurol. 2001;50:121-127.
McDonald Criteria 2001
CLINICAL
(ATTACKS)
OBJECTIVE
LESIONS
ADDITIONAL REQUIREMENTS TO MAKE DIAGNOSIS
2 or more
2 or more
• None; clinical evidence will suffice (additional evidence desirable but must be consistent
with MS)
2 or more
1
1
2 or more
1 monosymptomatic
0 (progression
from onset)
• Dissemination in space by MRI or positive CSF and 2 or more MRI lesions consistent with
MS or further clinical attack involving different site
• Dissemination in time by MRI or second clinical attack
1
• Dissemination in space by MRI or positive CSF and 2 or more MRI lesions consistent with
MS
AND
• Dissemination in time by MRI or second clinical attack
1
• Positive CSF
AND
• Dissemination in space by MRI evidence of 9 or more T2 brain lesions
or 2 or more cord lesions or 4–8 brain and 1 cord lesion
or positive VEP with 4–8 MRI lesions
or positive VEP with less than 4 brain lesions plus 1 cord lesion
AND
• Dissemination in time by MRI or continued progression for 1 year
McDonald Criteria: Dissemination in Space
MRI evidence of dissemination in space
Three of the following:
• One Gd-enhancing lesion or 9 T2-hyperintense lesions
• At least 1 infratentorial lesion
• At least 1 juxtacortical lesion
• At least 3 periventricular lesions
Note: 1 spinal cord lesion can be substituted for 1 brain lesion.
McDonald WI, et al. Ann Neurol. 2001;50:121-127.
2005 Criteria for Demonstration of Dissemination in
Space (DIS)
ORIGINAL MCDONALD
Three out of four of the following:
1. One Gd-enhancing lesion or nine T2
hyperintense lesions if there is no Gdenhancing lesion
2. At least one infratentorial lesion
3. At least one juxtacortical lesion
4. At least three periventricular lesions
NOTE: One spinal cord lesion can substitute for
one brain lesion
THE 2005 REVISIONS
Three out of four of the following:
1. One Gd-enhancing lesion or
nine T2 hyperintense lesions if
there is no Gd-enhancing lesion
2. At least one infratentorial
lesion
3. At least one juxtacortical
lesion
4. At least three periventricular
lesions
NOTE: A spinal cord lesion can be
considered equivalent to a
brain infratentorial lesion: an
enhancing spinal cord lesion
is considered to be equivalent
to an enhancing brain lesion,
and individual spinal cord
lesions can contribute along
with individual brain lesions to
reach the required number of
T2 lesions.
Table 1 - MRI Criteria for Dissemination of Lesions in
Time (DIT)
ORIGINAL 2001 MCDONALD CRITERION
1. If a first scan occurs 3 months or
more after the onset of the clinical
event, the presence of a Gdenhancing lesion is sufficient to
demonstrate dissemination in time,
provided that it is not at the site
implicated in the original clinical
event. If there is no enhancing
lesion at this time, a follow-up scan
is required. The timing of this
follow-up scan is not crucial but 3
months is recommended. A new
T2- or Gd-enhancing lesion at this
time then fulfills the criterion for
dissemination in time.
1. If the first scan is performed less
than 3 months after the onset of the
clinical event, a second scan done 3
months or more after the clinical
event showing a new Gd-enhancing
lesion provides sufficient evidence
for dissemination in time.
However, if no enhancing lesion is
seen at this second scan, a further
scan not less than 3 months after
the first scan that shows a new T2
lesion or an enhancing lesion will
suffice.
MRI Criteria for Dissemination of Lesions in Time (DIT)
THE 2005 REVISIONS
1.
Detecting Gd
enhancement at least
3 months after the
onset of the initial
clinical event, if not at
the site corresponding
to the initial event.
2.
Detecting a NEW T2 lesion
if it appears at any time
compared to a reference
scan done at least 30 days
after the onset of the initial
clinical event.
McDonald 20011,2
≥ 3 of:

Dissemin
ation in
Space
(on Either
Baselines
or FollowUp
Magnetic
Resonan
ce
Imaging
[MRI])
McDonald 20051,3
≥ 3 of:
McDonald 2010
≥ 1 lesion in each of ≥ 2
characteristic locations
≥ 9 T2 lesions or ≥ 1
gadolinium-enhancing lesion
≥ 9 T2 lesions or
≥ 1 gadoliniumenhancing lesion
Periventricular
≥ 3 periventricular lesions
≥ 3 periventricular
lesions
Juxtacortical
≥ 1 juxtacortical lesion
≥ 1 juxtacortical lesion
Posterior fossa
≥ 1 posterior fossa lesion
≥ 1 posterior fossa
lesion
Spinal cord
1 cord lesion can replace 1
brain lesion
Any number of lesions
can be included in
lesion count
All lesions in symptomatic
regions excluded in brain
stem and spinal cord
syndromes
1)
≥ 1 gadolinium-enhancing
lesion ≥ 3 months after CIS
onset (if not related to CIS)
2)
A new T2 lesion with
reference to a prior scan
obtained
≥ 3 months
after CIS
1)
≥ 1 gadoliniumenhancing lesion ≥ 3
months after CIS
onset (if not related
to CIS)
2)
A new T2 lesion with
reference to a prior
scan obtained ≥ 30
days after CIS
Dissemination in
Time
1)
Simultaneous presence
of asymptomatic
gadolinium-enhancing
and nonenhancing
lesions at any time
2)
A new T2 and/or
gadolinium-enhancing
lesion on follow-up MRI
irrespective of timing of
baseline scan
A 32-year-old woman with left heminumbness and left leg weakness. No prior
Patient
Meets
Criteria
for MS Using
thesensation
MAGNIMS
medical
history.
Examination
demonstrates
diminished
in the 2010
left
upper and lower extremities; mild weakness
Criteriaof the left leg with extensor
plantar response and asymmetrically hyperreflexic. Brain MRI shows:
Posterior fossa lesion
Juxtacortical lesion
Asymptomatic gadoliniumenhancing lesion
Periventricular lesion
Asymptomatic T2 lesion
Images courtesy of Omar Khan, MD.
Predicting Conversion From
CIS to CDMS
Criteria
Specificity
(95% CI)
Sensitivity
(95% CI)
Positive Predictive
Value
(95% CI)
McDonald (2001)
91.1% (85-95)
47.1% (36-58)
78.4% (65-89)
McDonald (2005)
87.8% (81-93)
60.0% (49-70)
77.3% (65-87)
MAGNIMS 2010
87.0% (80-92)
71.8% (61-81)
79.2% (68-88)
CDMS: clinically defined MS
Montalban X, et al. Neurology. 2010;74:427-434.
Importance of New MAGNIMS/
McDonald MRI Criteria
•
•
•
•
User-friendly
Clinically oriented
Lead to earlier diagnosis
Sensitivity and specificity are comparable to
existing diagnostic criteria
• May reduce repeat MRI scans
• Caution: consider other possibilities in the
differential diagnosis. Careful interpretation of the
MRI scans will be critical
Why Treat Early?
• Relapses and impairment parallel the MRI burden
of disease.1-3
• Axonal damage occurs early and may cause
permanent neurological dysfunction.4
• Number of MRI lesions are predictive of future
disability.5
• Preventing development of lesions may prevent
progression of disability in patients.6
• Preventing early relapses may prevent long-term
disability in patients.3
1. Comi. Curr Opin Neurol. 2000;13:235; 2. Munschauer. Clin Ther. 1997;19:868; 3. Weinshenker. Brain. 1989;112:1422; 4.
Trapp. N Engl J Med. 1998;338:278; 5. Brex. N Engl J Med. 2002;346:158; 6. O’Riordan. Brain. 1998;121:495.
Early Relapses Affect LongTerm Disability
100
Low (0―1 attacks in 2 years)
Intermediate (2―4 attacks in 2 years)
High (>5 in 2 years)
Patients (%)
80
60
40
20
0
0
10
20
30
40
50
Time From Onset of MS (years)
Actuarial analysis of disability: percentage of patients not having reached EDSS 6:
difference between the groups significant (P<0.0001).
Weinshenker. Brain. 1989;112:1422.
Axons Are Transected in MS
Plaques and in NAWM
SMI-32 (non-phosphorylated neurofilament)
Trapp. N Engl J Med. 1998;338:278.
Number of Transected Axons Increases with Level
of Activity in MS Lesions
12,000
11,236
10,000
8,000
6,000
3,138
4,000
875
2,000
17
0.7
NAWM
Control
white
0
Active
Chronic
active
edge
(NAWM: normal-appearing white matter)
Trapp BD, et al. N Engl J Med. 1998;338:278-285.
Chronic
active core
Prognosis Summary
• High volume and high number of T2 brain lesions at
presentation predicts a worse future course
• Early relapse rate and disability accumulation is
correlated with a worse future disease course
• Serum and CSF biomarkers may refine disease course
prediction, but to date none have been validated other
than presence of OCBs in CSF.
• MRI is our “Biomarker” in MS.
MRI Lesions at 12 Month F/U Scan
Indicate Treatment Failure
MRI Lesions at 12 Months
• 394 patients
• Mean follow-up 4.8
years
• 30.4% poor responders
Responders
Poor responders (sustained
progression ≥ 1 point on EDSS)
Prosperini L, et al. Eur J Neurol. 2009;16:1202-1209.
Multiple Sclerosis:
Effects of DMTs on MRI
MRI Defined Burden of Disease
• Traditionally defined as total volume of
hyperintense lesion on T2-weighted images.
• Also defined as sum of T2 hyperintense and
T1 hypointense lesion volume.
• Number of new gad-enhancing lesions
• Number of new T2 or enlarging and/or gadenhancing lesions (Combined unique lesions)
• Brain volume (atrophy)
Personal communication from Dr. Bakshi.
IFN Beta-1b SC (Betaseron):
T2 Burden of Disease
Median % Change from Baseline
p=0.0363
p=0.0002
p=0.0055
p=0.0015
p=0.0012
n=75
n=72 n=62 n=77
n=72 n=61 n=73
aTreatment administered every other day
IFNB=interferon beta; MIU=million international units; SC=subcutaneous
IFNB MS Study Group et al. Neurology 1995;45:1277-85.
n=70 n=59 n=73
n=72 n=61
n=14 n=16 n=19
91.4% reduction
p<0.0001
IFNB-1b 8 MIU sq QOD
Pretreatment (n=27)
160
Total Contrast-enhancing Lesions
Mean New Contrast-enhancing Lesion
Frequency
Interferon Beta-1b (Betaseron):
Gd-enhancing Lesions
140
120
100
80
60
40
20
0
1
2
3
4
5
6
7
Month
Stone LA et al. Neurology 1997;49:862-69.
8
9
10
11
12
European/Canadian MRI Trial
Median % Change in T2
Lesion Volume (Baseline to 9
Months)
Glatiramer Acetate (CopaxoneTM):
T2 Burden of Disease
Comi G et al. Ann Neurol 2001;49:290-97.
40.3% reduction
p=0.001
n=120
n=119
European/Canadian Trial
Glatiramer Acetate (Copaxone):
Gd-enhancing Lesions Over 9 months
Cumulative Median Enhancing
Lesion Volume (mL)
Cumulative monthly change from baseline in Gd-enhancing lesion volume showed a
significant treatment effect in favor of glatiramer acetate compared with placebo
3.0
Placebo (n=120)
Glatiramer acetate (n=119)
2.5
2.0
p<0.05
1.5
p<0.05
1.0
0.5
0
0
1
2
3
4
5
Month
Comi G et al. Ann Neurol 2001;49:290-97.
6
7
8
9
AFFIRM Trial
Natalizumab (Tysabri):
T2 Lesion Counts over 2 Years
Median No. of New or Enlarging
T2 Lesions
Placebo (n=315)
Miller DH et al. Neurology 2007;68:1390-401.
Natalizumab (n=627)
83% reduction
p<0.001
AFFIRM Trial
Natalizumab (Tysabri):
T2 Lesion Load over 2 Years
Placebo (n=315)
Mean Change in T2
Hyperintense Lesion Volume
(mm3)
Natalizumab (n=627)
Miller DH et al. Neurology 2007;68:1390-401.
p<0.001
AFFIRM Trial
Mean No. of Gd-enhancing Lesions
Natalizumab (Tysabri):
Gd-enhancing Lesions
Miller DH et al. Neurology 2007;68:1390-401.
92.3% reduction
(p<0.001)
91.6% reduction
(p<0.001)
Natalizumab: Mechanism of Action
Prescribing information for natalizumab (Tysabri®). Available at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Tysabri clinical efficacy
67% relative reduction in relapses at 2
yrs (P <0.001)
®
Natalizumab: Risk Management
– Infusion-related reactions
– Neutralizing antibodies
– Hepatotoxicity
– Opportunistic infections

Progressive Multifocal
Leukoencephalopathy (PML)
Polman CH, et al. N Eng J Med. 2006;354(9):899-910.
Factors that Increase PML Risk
– JCV exposure indicated by anti-JCV antibody
positive status
– Receiving an immunosuppressant prior to
receiving natalizumab
– Natalizumab treatment duration (especially >2
years)
JCV = John Cunningham virus
Prescribing information for natalizumab (Tysabri®). Available at
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Soelberg Sorensen P, et al. Mult Scler. 2012;18(2):143-152.
Fox RJ. Rudick RA. Neurology. 2012;78(6):436-437.
Bloomgren G, et al. New Eng J Med. 2012;366:1870-1880.
Natalizumab-Associated PML:
Updated Incidence by Treatment Epoch
As of 12/31/12, ~112,200 patients have received natalizumab in the post-marketing setting worldwide
As of 5/13/13, there have been 347 confirmed cases of PML worldwide
Biogen Idec. Data on file.
List of PML diseases under Tysabri. Available at: http://chefarztfrau.de/?page_id=716.
Current Stratification of
Natalizumab-Associated PML Risk
Anti-JCV Antibody Status
Positive
Negative
Prior IS Use
NTZ
Exposure
0.07/1,000
95% CI 0–0.38
NO
YES
1–24 months
0.6/1,000 patients
(95% CI 0.4–0.9)
1.8/1,000 patients
(95% CI 1.1–2.8)
> 24 months
5.2/1,000 patients
95% CI 4.3–6.2)
10.6/1,000 patients
(95% CI 8.1–13.8)
JCV = John Cunningham virus; IS = immunosuppressant.
Dong-Si T, et al. Presented at AAN; March 16–23, 2013; San Diego, CA. Abstract P04.271.
Foley J. Presented at AAN; March 16–23, 2013; San Diego, CA. Abstract S30.002.
Newer Therapies for MS
• Oral Medications
– fingolimod (Gilenya)
– teriflunimide (Aubagio)
– dimethyl fumarate (Tecfidera)
• Monoclonal Antibodies
– alemtuzumab (Lemtrada)
Fingolimod: Mechanism of Action
Activation
S1P
Proliferation and
differentiation
Lymphatic sinus
Afferent lymphatic vessel
Activated T cells
S1P1 receptor
Naïve T cell
Sinus-lining endothelium
Efferent lymphatic vessel
Lymph node
S1P1
downregulation
Fingolimod
S1P = sphingosine-1 phosphate
Horga A, Montalban X. Expert Rev Neurother. 2008;8:699-714.
Sinus-lining endothelial cell
barrier enhancement
Reduced T cell egress
FREEDOMS Trial
Mean No. of New or Enlarging
T2 Lesions
Fingolimod (Gilenya): T2 Lesions at 24
Months
Kappos L et al. N Engl J Med 2010;362:387-401.
-74%
p<0.001
-74%
p<0.001
FREEDOMS Trial
Mean No. of Gd-enhancing Lesions
Fingolimod (Gilenya):
Gd-enhancing Lesions over 24 Months
Kappos L et al. N Engl J Med 2010;362:387-401.
82%
reduction
(p<0.001)
Teriflunomide (Aubagio) Phase 2 Study:
Primary Efficacy Endpoint
•
•
•
Teriflunomide (7 or 14 mg/day)
was generally well tolerated and
reduced MRI activity vs. placebo1
These findings led to the initiation
of the phase 3 program
Patients completing this study
were eligible for entry into a
long-term open-label extension;
8-year follow-up available2,3
Mean No. of Unique Active
Lesions per Scan
Significant reduction in number of
combined unique active lesions
RR: 61.3%
RR: 61.1%
*
†
Teriflunomide
*p<0.03 placebo vs. 7 mg
†p<0.01 placebo vs. 14 mg
RR=relative reduction
1. O'Connor PW et al. Neurology 2006;66(6):894-900; 2. Li D et al. ECTRIMS 2010; 3. Confavreux C et al. Mult Scler
2012;18(9):1278-89.
TEMSO Trial
Teriflunomide (Aubagio):
Gd-enhancing Lesions
Mean No. of T1
Gd-enhancing Lesions per Scan
Proportion of Patients Free from
T1 Gd-enhancing Lesions (%)
1.4
1.2
1.0
RRR: 57.2%a (p<0.001)
1.33
(n=363)
0.8
0.6
0.57
(n=365)
0.4
0.2
0
0.26
(n=358)
Placebo
(n=363)
7 mg
(n=365)
14 mg
(n=358)
Teriflunomide
aDerived
p<0.001
Proportion of Patients (%)
Mean No. of Lesions Per Scan
RRR: 80.4%a (p<0.001)
70
p<0.001
60
64.1
(n=358)
50
40
30
39
(n=363)
51.4
(n=365)
20
10
0
Placebo
(n=363)
7 mg
(n=365)
14 mg
(n=358)
Teriflunomide
from a Poisson regression model with robust error variance; the model included treatment, EDSS strata, region, and baseline number
of unique active lesions as covariates and log-transformed number of scans as an offset variable. Data presented for the modified intent-to-treat
population.
O’Connor P et al. N Engl J Med 2011;365:1293-303.
Dimethyl Fumarate (BG-12/Tecfidera):
T2 Lesions at 2 Years
20
16
17
85%
p<0.001
74%
p<0.001
12
8
4
4.4
2.6
0
Placebo
n=165
BG-12 240
mg BID
BG-12 240
mg TID
n=152
n=152
CONFIRM2
(Secondary efficacy endpoint)
Adjusted Mean No. of
New/Newly Enlarging T2 Lesions
Adjusted Mean No. of
New/Newly Enlarging T2 Lesions
DEFINE1
(Secondary efficacy endpoint)
20
17.4
15
71%
p<0.001
73%
p<0.001
54%
p<0.001
10
8.0
5
5.1
4.7
0
1. Gold R et al. N Engl J Med 2012;367:1098-107; 2. Fox RJ et al. N Engl J Med 2012;367:1087-97.
Placebo BG-12
BG-12 Glatiramer
240 mg BID 240 mg TID acetate
n=139
n=140
n=140
n=153
Dimethyl Fumarate (BG-12/Tecfidera):
Gd-enhancing Lesions at 2 Years
DEFINE1
(Secondary efficacy endpoint)
CONFIRM2
(Tertiary efficacy endpoint)
90%
p<0.001
73%
p<0.001
Mean No. of Gd+ Lesions
Mean No. of Gd+ Lesions
2.0
2
74%
p<0.001
65%
p<0.001
61%
p=0.002
1.5
1.0
0.7
0.5
0.5
0.4
0.0
Placebo BG-12 240 BG-12 240 Glatiramer
mg BID
mg TID
acetate
n=165
n=152
n=152
n=139
n=140
n=140
Compared with placebo, BG-12 BID and TID significantly reduced the mean number of
new Gd+ lesions at 2 years in both DEFINE and CONFIRM trials
1. Gold R et al. N Engl J Med 20y12;367:1098-107; 2. Fox RJ et al. N Engl J Med 2012;367:1087-97.
n=153
Median % Change in T2 Lesion Load
Alemtuzumab (Lemtrada): Phase 2
CAMMS223:
T2 Burden of Disease Over 36 Months
Coles J et al. N Engl J Med 2008;359:1786-801.
p=0.03
p=0.01
Alemtuzumab (Lemtrada):
Gd-enhancing Lesions
CARE-MS II2
CARE-MS I1
p=0.17
p=0.77
p=0.51
p=0.009
52% reduction
p=0.02
SC IFNB-1a (n=187)
Alemtuzumab 12 mg (n=376)
1. Arnold DL et al. AAN 2012, S11.006; 2. Arnold DL et al. ECTRIMS 2012, P877.
SC IFNB-1a (n=202)
Alemtuzumab 12 mg (n=426)
Alemtuzumab CAMMS223 Study: Safety
• Principal AEs associated with alemtuzumab included:
– Infusion reactions
– Mild-to-moderate infections
– Autoimmunity

Immune thrombocytopenia (ITP approx. 1%)

Thyroid disorders (28% vs 3% for IFNβ-1a)

Glomerulonephropathy (Goodpasture
syndrome).
Coles A. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, 2009. Poster # 890.
p=0.5
p=0.2
p=0.2
OCR=ocrelizumab
Kappos L et al. Lancet 2011;378;1779-87.
Total number of new or enlarging T2 lesions
at Week 24
Mean change in volume of T2 lesions from
baseline to Week 24
Ocrelizumab:
T2 Hyperintense Lesions at 24 Weeks
p=0.3
p<0.0001
p<0.0001
Ocrelizumab:
Gd-enhancing lesions over 24 weeks
Mean (SD)
Gd-enhancing Lesions
25
*p<0.0001 vs. placebo
20
15
10
5
89% reduction
vs. placebo
Median
6.9
5.5
*
0
96% reduction
vs. placebo
0.6
*
0.2
1.6
0.0
0.0
1.0
Placebo
(n=54)
OCR 600 mg
(n=55)
OCR 2000 mg
(n=55)
IFNB-1a IM
(n=54)
At Weeks 12, 16, 20 and 24 (ITT): average imputation
Van Elteren test is stratified by geographical region and baseline presence of Gd-enhancing lesions (absent or present)
IFNB-1a arm was open-label; all efficacy comparisons were exploratory
OCR=ocrelizumab
Kappos L et al. Lancet 2011;378:1779-87.
Risk-Benefit Assessment
• Risk-Benefit assessments should include:
– The benefits of therapies
– The risks of those therapies
– The risks of not treating or
under-treating the disease itself
 Quality of life
 Long-term outcomes
 Patient’s history of disease and
disease activity
 Costs
Risk-Benefit information should be communicated to patients!
One More Experimental Symptomatic Therapy…
Conclusions
• MRI is a powerful and sensitive tool for diagnosing MS but lacks
pathological specificity.
• MRI is a valuable surrogate marker of biological disease activity
and severity.
• The continuing worsening of MRI findings, even if clinically silent,
significantly impacts on long term clinical outcomes.
• Conventional MRI measures (T2 lesions and Gad. Enhancement)
represent only the “tip of the iceberg,” in terms of disease activity.
• Newer techniques hold greater promise for following both
inflammation and neurodegeneration throughout all stages of the
disease process.
Thank you for your attention
Any Questions?