Transcript Glatiramer Acetate Effects on MS Pathology

Multiple Sclerosis
John M. Bertoni, M.D., Ph.D.
Creighton University
Diagnosis of MS
 MS is a clinical diagnosis
 Supported by
–Imaging
–Spinal fluid analysis
Multiple Sclerosis – A to Z
1.
MS Pathology
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•
2.
Immunomodulatory Therapies (IMTs)
•
•
•
3.
Conventional MRI (T1, T2)
Non-conventional MRI (MRS, MTI, Brain Atrophy)
Clinical Data
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•
5.
Glatiramer Acetate (Copaxone®)
Beta Interferons (Avonex®, Betaseron®, Rebif®)
Natalizumab (Tysabri®) – NOT CURRENTLY AVAILABLE
Magnetic Resonance Imaging (MRI)
•
•
4.
Inflammation
Neurodegeneration
Pivotal Trials
Open-Label Comparative Trial
Safety & Tolerability of the IMTs
Inflammation and Axonal Loss in MS
Repairing-Remitting
Secondary Progression
Clinical Disability
Clinical
Threshold
Brain Volume
Inflammation
Axonal Loss
Frequent inflammation,
demyelination, axonal
transection, plasticity,
and remyelination
Continuing inflammation,
persistent demyelination
Adapted with permission from Elsevier (The Lancet. 2002;359:1221-1231).
Infrequent inflammation,
chronic axonal
degeneration, gliosis
Progression of Disability
Occurrence, Extent of Severity
MS Courses as Redefined by MRI
SPMS
Clinical Impairment
MRI-Defined Plaque Burden
Late
RRMS
Enhancements
Early
RRMS
Time
Adapted with kind permission from Dr. J.S. Wolinsky.
MS Is More Than a Demyelinating Disease
A
Action potential
Normal
Myelinated
Axon
Axon
B
Demyelination
Postsynaptic
neuron
Myelin
sheath
Acutely
Demyelinated
Axon
Sodium
channels
C Chronically
Demyelinated
Axon
Action potential
Conduction restored by
Increase in density of
sodium channels
Postsynaptic
neuron
D
Degenerated
Axon
Adapted with permission from Waxman SG. N Engl J Med. 1998;338:323-325.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.
End of
transected
axon
Axonal Transection in MS Lesions
64m
Reprinted with permission from Trapp BD et al. N Engl J Med. 1998;338:278-285.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.
45m
MS Pathogenesis
Autoreactive T Cells
Danger Signal
or Trigger
T
T
T
Activation, Differentiation,
Clonal Expansion
T
T
Adhesion/Attraction
T
Periphery
Transmigration
T
BBB
B
Antibodies
IFN-
T
Local Reactivation
CNS
APC
M
NO
TNF-
APC
Release of Cytokines;
Recruitment of M
T
TNF-
Demyelination and Axon Loss
Adapted with kind permission from Prof. R. Hohlfeld.
MS: A Disease of Severe Myelin,
Axonal, and Neuronal Losses
Normal White Matter
Plaque
Lymphocytes
Neurons
Myelin
Axons
Astrocytes
Adapted with kind permission from Dr. W. Brück.
Macrophages
The Dual Nature of Inflammation in MS
Pro-inflammatory and
Neurotoxic Factors
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



Th1 cytokines
TNF-
IL-2
Nitric oxide
Reactive oxygen species
Glutamate
Antibodies and complement
Cell-mediated neurotoxicity
TISSUE DAMAGE
Anti-inflammatory and
Neuroprotective Factors
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

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Th2 cytokines
TGF-
IL-10
Neurotrophic factors
– BDNF
– NGF
– NT-3
– CNTF
– GDNF
TISSUE PROTECTION
Detrimental Inflammation in MS
 Evidence from animal models implicates
activated T cells in initiating MS pathology
 Subsequent injury to CNS is mediated by
T cells, B cells, and macrophages/microglia
 Inflammatory components destroy myelin
and oligodendrocytes
 Inflammation is associated with axonal damage
Neuhaus O et al. Trends Pharmcol Sci. 2003;24:131-138.
Inflammatory Cells May Downregulate
Detrimental Inflammation
 Inflammatory cells produce growth factors
 Inflammatory cells remove myelin-associated
inhibitory molecules
 Inflammatory cells may adapt a protective
suppressor phenotype
Martino G et al. Lancet Neurology. 2002;1:499-509.
Multiple Sclerosis – A to Z
1.
MS Pathology
•
•
2.
Immunomodulatory Therapies (IMTs)
•
•
•
3.
Conventional MRI (T1, T2)
Non-conventional MRI (MRS, MTI, Brain Atrophy)
Clinical Data
•
•
5.
Glatiramer Acetate (Copaxone®)
Beta Interferons (Avonex®, Betaseron®, Rebif®)
Natalizumab (Tysabri®) – NOT CURRENTLY AVAILABLE
Magnetic Resonance Imaging (MRI)
•
•
4.
Inflammation
Neurodegeneration
Pivotal Trials
Open-Label Comparative Trial
Safety & Tolerability of the IMTs
Immunomodulatory Therapies
Glatiramer
IFN -1b
Acetate
(Betaseron®)
(Copaxone®)
IFN -1a
(Rebif®)
IFN -1a
(Avonex®)
Natalizumab
(Tysabri®)
Type
Polypeptide Recombinant
mixture
protein
Recombinant
protein
Recombinant
protein
Recombinant
monoclonal
antibody
FDA
Indication
Reduction
Reduce the
of the
frequency
frequency of of clinical
relapse
exacerbation
Decrease the
frequency
of clinical
exacerbation
Decrease the
frequency
of clinical
exacerbation
Reduce the
frequency
of clinical
exacerbation
Slow
accumulation
of disability
Slow
accumulation
of disability
Dosage and
Administration
SC
SC
SC
IM
IV infusion
Daily
QOD
3 X Wk
Weekly
Q 4 Weeks
20 mg
250 µg (8
MIU)
22 µg
30 µg
300 mg
44 µg
Periphery
AntigenPresenting
Cell
TCR
GA Therapy
Macrophage
MHC
Blood-Brain Barrier
Mode of Action of Glatiramer Acetate:
Bystander Suppression and Neuroprotection
Glatiramer
Acetate
CNS
Microglia
MHC
CNS Ag
Bystander
Suppression
TCR
TCR
Glatiramer
AcetateSpecific
T Cell
Anti-inflammatory
Cytokines
BDNF
Th1
Th2
Neurotrophins
Th2
Neuroprotection
Adapted with permission from Neuhaus O et al. Neurology. 2001;56:702-708.
Ziemssen T et al. Brain. 2002;125:2381-2391.
Progression to Disability—EDSS Steps
Walking ability
10.0 = Death due to MS
9.0 - 9.5 = Completely dependent
Confined to a
wheelchair or bed
8.0 - 8.5 = Confined to bed or chair
7.0 - 7.5 = Confined to wheelchair
6.0 - 6.5 = Walking assistance is needed
5.0 - 5.5 = Increasing limitation in ability to walk
4.0 - 4.5 = Disability is moderate
3.0 - 3.5 = Disability is mild to moderate
Walks with aid
(< 5 yards)
Walks with
assistance
(22 - 110 yards or
more)
Walks unaided (110 220
yards or more)
Walks unaided (330 550
yards or more)
2.0 - 2.5 = Disability is minimal
1.0 - 1.5 = No disability
Fully ambulatory
0 = Normal neurologic exam
Long-term Disability: Time from
Onset of MS to EDSS 4
1 = 0–19 years old
2 = 20–29 years old
3 = 30–39 years old
4 = 40–49 years old
5 = 40 years old
Confavreux C et al. Brain 2003;126:770–82
Imaging in Multiple Sclerosis
Examples of Atrophy in MS
31 y/o male
Healthy control
36 y/o woman
RR MS (2 y)
Rudick et al. Neurology. 1999;53:1698-1704.
43 y/o woman
SP MS (19 y)
Diagnosis and Monitoring MS
 Subjective:
– detects minor sensory, visual, vestibuloauditory
lesions
 Clinical exam:
– Motor and sensory tracts, brainstem tegmentum
– Sensitive to multifocal, microscopic disease
 Electrophysiology:
– Characterizes, localizes, detects silent disease in
sensory tracts, sensitive to microscopic disease
 CSF Exam:
MRI detects ‘silent activity’
 There are approximately 7-10+ brain
lesions for every clinical event
 The symptomatic lesion is seen only
20% of time
 Spinal cord MRI is insensitive for
lesions
– Unless special techniques used and
carefully inspected by reader
Typical callosal lesions
Brainstem lesion – Facial Myokymia
Proton density
GAD
T2 FLAIR (adjusted)
21 year old, mother with MS, presents with facial myokymia
Positive oligoclonal bands and elevated IgG index
Negative otherwise MRI
T1 post
Optic nerve lesion – asymptomatic prior optic
neuritis
Proton density
Optic neuritis 8 years before, complete recovery
Proton density usually sees better than T2
T2 FLAIR
MRI spinal cord – Acute lesions, low contrast
 T2
T1 post GAD
PD
STIR
 These are very edematous (mass, STIR)
 PD is more extensive than T2 (also old gliosis)
Heterogeneous Pathology of T2 hyperintense lesions
Evolution of MS Lesions
Axonal Loss
BBB Disruption
Inflammation
Increased Inflammation
Demyelination
Reactivated Lesions
Gliosis
Axonal Loss
Adopted from Paty and Ebers
Dawson’s fingers,Black holes
Seeing the brain as never before
SHORT FIBRES
Superior Longitudinal Fasciculus
BROCA‘S
WERNICKE’S
AREA
AREA
LONG
FIBRES
SHORT
FIBRES
INSULAR
FIBRES
TEMPORAL
FIBRES
Diffusion Tractography
Images Courtesy of:
Dr. Derek Jones, Institute of Psychiatry, London UK
LONG FIBRES
THE END