european charcot foundation laboratory measures - giovannoni
TRANSCRIPT
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MS variability and prognostic implications Laboratory
Gavin Giovannoni
Barts and The London School of Medicine and Dentistry
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Disclosures
Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
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Why the laboratory?
• Diagnostic testing
– Positive & negative predictive testing
• Pathogenesis
– Immunology
– Aetiology
– Disease progression & recovery
– Disease heterogeneity
• Pharmacovigilance
• Monitor disease processes
– Prognosis (high vs. low risk patients)
– Monitoring effect of therapeutic interventions
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Diagnostic & pathogenic markers
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The evolving clinical definition of MS
1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report
by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N
Y Acad Sci 1965;122:552-68.
2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
Ann Neurol 1983;13:227-31.
3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from
the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.
4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald
Criteria". Ann Neurol 2005;58:840-6.
5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald
criteria. Ann Neurol. 2011;69:292-302.
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Will Rogers Phenomenon in Multiple Sclerosis
1879 - 1935
“When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”
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Will Rogers Phenomenon in Multiple Sclerosis
Sormani et al. Ann Neurol 2008;64:428–433.
Poser
McDonald
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Inactive CIS
Active CIS RRMS
MS diagnosed according the old Poser Criteria
Inactive CIS
Less active RRMS
More Active RRMS
MS diagnosed according the New McDonald Criteria
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Intrathecal synthesis of IgG
Images courtesy of Alastair Compston and Ed Thompson.
Kabat et al. J Clin Invest. 1942 Sep;21(5):571-7. Carl Lange – Colloidal Gold Curve
Isoelectric focusing with immunfixation
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Diagnostic criteria for Primary Progressive MS
Polman et al. Ann Neurol 2005;58:840-6.
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Accumulation of disability in PPMS: stratified by intrathecal IgG abnormalities
Proportion Progressing as Percent
Epoch CSF- CSF+
6 mo 7.3 9.8
12 mo 15.0 20.4
18 mo 22.8 28.1
24 mo 25.4 34.3
Years to Progression
2.43 2.26
Based on data from a second meeting of the DSMB and assume no therapeutic effect
Slide courtesy of Jerry Wolinsky
0 1 2 3 Years
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n P
rogr
essi
ng
Positive Negative
CSF
P =0.03
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PPMS diagnosed according the original McDonald/Thompson criteria
PPMS diagnosed according the New Polman-McDonald Criteria
Not MS Not MS OCB-ve
OCB+ PPMS
Not MS OCB-ve
PPMS OCB+ PPMS
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Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.
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What constitutes a useful diagnostic test or set of criteria?
TARGET DISORDER
PRESENT ABSENT
DIAGNOSTIC TEST RESULT
+ a b a + b
- c d c + d
a + c b + d a + b + c + d
From these we determine the sensitivity and specificity as follows: SENSITIVITY = a/(a+c) > 80% SPECIFICITY = d/(b+d) > 80%
Neurobiol Aging 1998; 19:109-116.
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Multiple sclerosis definition
Pathological Definition: Inflammatory disease of the CNS
characterised by demyelination and variable degrees of
axonal loss and gliosis.
Clinical Definition: Objective CNS dysfunction, i.e.
involvement of two or more white matter structures
(space) separated by time, with no other aetiology.
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CDMS n=518
MS n=485 (94%)
Not MS n=33(6%)
A clinico-pathoanatomical study of multiple sclerosis diagnosis
SENSITIVITY = True+ve /(True+ve + False-ve)
Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.
• Eye Department, Hvidovre Hospital, Denmark
• Neuropathological examination of 518 consecutive patients with CDMS
Clinically probable MS, n=33 MS, n=33 (66%)
Not MS, n=11(33%)
Clinical or ante-mortem Pathological or post-mortem
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A clinico-pathoanatomical study of multiple sclerosis diagnosis.
SPECIFICITY = True-ve /(True-ve + False+ve)?
Danish post-mortem series of silent MS:
• Hvidovre, 5 cases out of 2,600 PMs
• Aarhus, 4 cases out of 6,500
• Bispebjerg 3 cases out of 7,000
Frequency of MS diagnosed at PM = 0.08%
Estimated 40 cases per year die with silent MS
25% of cases of MS were undiagnosed in life (asymptomatic or benign cases)
Routine post-mortems n =16,100
Engell T. Acta Neurol Scand. 1989 May;79(5):428-30..
Silent MS n=12 (0.08%)
~ 25% MS undiagnosed in life
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“Inflammation”
“Oligodendrocyte Toxicity &
Demyelination”
Axonal Toxicity (conduction block)
Axonal & Neuronal Loss
Gliosis
Remyelination & Axonal Recovery
“Inflammation”
Central Adaptation &
Plasticity
Key pathological processes in MS
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Prognostic markers
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Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology
Magliozzi et al. Brain 2007; 130:1089-1104.
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Intrathecal synthesis of IgG
Images courtesy of Alastair Compston and Ed Thompson.
Kabat et al. J Clin Invest. 1942 Sep;21(5):571-7. Carl Lange – Colloidal Gold Curve
Isoelectric focusing with immunfixation
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CSF oligoclonal band patterns reveal disease heterogeneity in MS
Villar et al. Journal of Neuroimmunology 211 (2009) 101–104
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Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
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Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
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Natalizumab treatment of progressive MS reduces inflammation and tissue damage: CSF markers of axonal damage
Romme Christensen et al. ECTRIMS 2012.
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-1.0%
-0.8%
-0.6%
-0.4%
-0.2%
0.0% Years 0-2
-0.82%
-0.80%
P=0.822
Placebo (N=315) Natalizumab (N=627)
Year 0-1* Year 1-2
-0.40%
-0.56%
-0.43%
-0.24%
P=0.004
P=0.002
Miller DH et al. Neurology 2007;68:1390-1401.
Natalizumab and brain atrophy Mean (SE) percentage change in BPF
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Bas
elin
e
Follow-u
p
0
500
1000
1500
2000
2500
NfL
(p
g/m
l)
Bas
elin
e
Follow-u
p
0
1000
2000
10000
NfL
(p
g/m
l)
Cerebrospinal fluid NfL Fingolimod 0.5mg/1.25 mg versus placebo treated patients
p<0.001
Fingolimod, n=23 Placebo, n=12
p=0.470
Fingolimod 0.5 mg Fingolimod 1.25 mg
Baseline Follow-up Baseline Follow-up
Median (pg/ml)
644 321 (-50%) 886 738 (-17%)
*Non-parametric Wilcoxon matched pairs test; p value is calculated with inclusion of outliers Dr Jens Khule, ECTRIMS 2013
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Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM
FREEDOMS, 2 years
Fingolimod 0.5 mg (n = 356)
Placebo (n = 329)
***
* **
6 0 12 24
Time (months)
0
-0.4
-0.8
-1.2
-1.6
-2.0
−38%
vs placebo p<0.001
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
TRANSFORMS, 1 year
0 12
Time (months)
0.0
-0.4
-0.6
-1.0
IFNb-1a IM (n = 359)
Fingolimod 0.5 mg (n = 368)
−40%
vs IFNb-1a IM p<0.001
*** -0.2
-0.8
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
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Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis
Comabella et al. Brain 2010: 133; 1082–1093.
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Very low risk
age place of residence
outdoor activity / sun exposure / sun screen diet / vitamin D supplements
age of exposure to EBV smoking
At risk High Risk
Low risk
RIS CIS MS
family history genetics
sex month of birth place of birth
Unfavourable disease-modifying factors dynamic risk factors static risk factors
dynamic protective factors static protective factors
MRI / evoked potentials changes
Peripheral immunological changes T-regs (), NK cells, CD8 ()
Clinical disease
In utero childhood Adolescence / early adulthood adulthood
1. Declining Physiology – “peripheral immunological endophenotype” 2. Biological disease threshold – “CNS endophenotype” 3. Asymptomatic disease – RIS (abnormal MRI and/or evoked potentials) 4. Clinical disease
a. Clinically isolated syndrome (CIS) b. Relapsing MS c. Relapsing secondary progressive MS d. Non-relapsing secondary progressive MS
Favourable disease-modifying factors
protective HLA haplotypes
CNS changes (OCBs and microscopic pathology)
2
3
2 4b 2 4c 2 4d
2 4a
1
The MS ‘Endophenotype’
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ECTRIMS 2012
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d25-OH D3
Cox univariate HR 95% CI P value
Q1 1.00
Q2 0.74 0.60-0.92 0.008
Q3 0.69 0.55-0.90 0.001
Q4 0.74 0.60-0.92 0.007
Median Survival (days)
Log-rank p
> Median 1267
0.021 < Median 973
Dr Jens Khule, ECTRIMS 2013
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EBNA-1 IgG*
Cox univariate HR 95% CI P value
EBNA-1 nOD 1.01 0.996-1.029 0.137
* similar results in OCB pos and MRI T2 pos patients only
Median Survival (days) Log-rank p
< Median 1247
0.216 > Median 1032
Dr Jens Khule, ECTRIMS 2013
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Conclusion
• Diagnostic/prognostic biomarkers
• Intrathecal OCBs (IgG, ? IgM & ? anti-lipid OCBs)
• IgG Index
• vD levels
• ? Chitinase
• ? EBV serology
• Potential surrogate treatment markers • ? CSF neurofilament levels
• ? GFAP
• ? MBP
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Acknowledgements
• Giovannoni
– Sharmilee Gnanapavan
• David Baker
– Gareth Pryce
– Sarah Al-Izki
• Sam Jackson
– Katie Lidster
• Yuti Chernajovsky
– Alex Annenkov
– Anne Rigby
– Michelle Sclanders
• Larry Steinman
– Peggy Ho
• Charles ffrench-Constant – Robin Franklin
• Siddharthan Chandran – David Hampton
• Ian Duncan – Sam Jackson
• Peter Calabresi – Avi Nath
• Raj Kapoor • John Zajicek • Doug Brown • UK MS Clinical Trial Network • BioMS
• Co-investigators
– NABINMS – Affirm study – Care MS 1 & 2 studies – Select trial