disease-activity free status talk - cleveland clinic 20 sept 2012
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What would disease free status look like in MS and what is the evidence that we can achieve it?
Gavin Giovannoni
Barts and The London School of Medicine and Dentistry
What would disease free status look like in MS and what is the
evidence that we can achieve it?
What would disease free status look like in MS and what is the
evidence that we can achieve it?
What is a disease?
What is a disease/what is MS?
A. Conventional definition
• E.g. “hepatitis is inflammation of the liver”
B. Pre-theoretical definition
• “SLE is characterised by the ARA criteria”
• Indirect definition
• Usually “polythetic”
• Inclusive definition using multiple characteristics
• According to Wittgenstein's model of a "long rope twisted together out of
many shorter fibres.“*
C. Theoretical definition
• E.g. “Down’s syndrome is trisomy 21”.
• Usually “monothetic”.
*Ludwig Wittgenstein a controversial 20th-century analytical philosopher (1889-1951).
Ludwig Wittgenstein
1889-1951
What is multiple sclerosis?
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.
What constitutes a useful set of diagnostic 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.
A clinico-pathoanatomical study of MS diagnosis
SPECIFICITY = True-ve /(True-ve + False+ve) ?
25% of cases diagnosed with MS on post-mortem are undiagnosed in life
– asymptomatic
– benign cases
Engell T. Acta Neurol Scand. 1989 May;79(5):428-30.
The evolving clinical definition of MS is changing the natural history of MS
1. Schumacker, 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.
Will Rogers phenomenon in MS
1879 - 1935
“When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”
Inactive CIS Active CIS RRMS
MS diagnosed according the old Poser Criteria
MS diagnosed according the old Poser Criteria
Inactive CIS Active CIS RRMS
Inactive CIS
Less active RRMS
More Active RRMS
MS diagnosed according the New McDonald Criteria
Will Rogers Phenomenon in Multiple Sclerosis
Sormani et al. Ann Neurol 2008;64:428–433.
Poser
McDonald
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” - Giovannoni et al. Lancet Neurol. 2010 Jul;9(7):727-39.
The evolving clinical definition of MS
1. Schumacker, 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.
6. Polman, et al. ……………2016? RIS or asymptomatic/presymptomatic MS
What would disease free status look like in MS and what is the
evidence that we can achieve it?
What do you want to measure?
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis - biology
- clinical outcomes
- biomarkers
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
e.g. neurofilaments
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
e.g. neurofilaments
Clinical Attack
Disease Progression
Clinical Recovery - biology
- clinical outcomes
- biomarkers
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
e.g. neurofilaments
Clinical Attack
Disease Progression
Clinical Recovery
? - biology
- clinical outcomes
- biomarkers
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
e.g. neurofilaments
Clinical Attack
Disease Progression
Clinical Recovery
?
- biology
- clinical outcomes
- biomarkers
Gd
T2
CU
R
DP
Gd
T2
CU
R
DP
Effect of natalizumab on clinical and radiological disease activity in MS: a retrospective
analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) study
Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.
35% vs. 64% Δ = 29%
14% vs. 58% Δ = 44%
Gd
T2
CU
R
DP
15% vs 47% Δ 32%
13% vs 68% Δ 55%
6% vs 37% Δ 31%
Effect of natalizumab on clinical and radiological disease activity in MS: a retrospective
analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) study
Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.
A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis
Gd
T2
CU
R
DP
Polman et al. N Engl J Med 2006;354:899-910.
Clinical implications
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
• IFNb neutralizing antibodies (NAbs)/lack of MxA induction
• Anti-natalizumab Abs
Relapse on IFNβ therapy increases risk of sustained disability progression
• Risk is not much greater for 2 relapses or more
• Sensitivity is only 50%
Bosca et al. Mult Scler 2008;14:636-39. 33
One new T2 lesion
2 or more new T2 lesions
Dobson et al. Submitted 2012.
MRI to monitor treatment response to IFN-beta: a systematic review
Measurement sensitivity?
MRI to monitor treatment response to IFN-beta: a systematic review
One new Gd+ lesion
2 or more Gd+ lesions
Dobson et al. Submitted 2012. 35
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
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 3 EDSS steps.
Rio et al. Ann Neurol. 2006;59:344.
Post-hoc analysis, disease-activity free: Patients with no relapse, no sustained disability
progression and no new MRI lesion activity
Placebo
(n=379*)
15.8
44.2 45.7
Weeks 0–96
3.5 mg/kg
(n=403*)
5.25 mg/kg
(n=411*)
56.1
23.9
54.2
Weeks 0–48
Placebo
(n=360*)
3.5 mg/kg
(n=384*)
5.25 mg/kg
(n=396*)
Placebo
(n=373*)
38.9
67.369.7
3.5 mg/kg
(n=395*)
80
60
40
20
0 5.25 mg/kg
(n=406*)
Weeks 0–24
Pati
en
ts d
isease a
cti
vit
y-f
ree (
%)
p<0.001 p<0.001 p<0.001
Cladribine tablets Cladribine tablets Cladribine tablets
OR = odds ratio *Based on observed data; no imputation used
Gd
CU
R
DP T2
OR (95% CI): 3.31 (2.46, 4.46)
OR (95% CI): 3.68 (2.73, 4.97)
OR (95% CI): 3.80 (2.77, 5.22)
OR (95% CI): 4.13 (3.02, 5.66)
OR (95% CI): 4.26 (3.03, 5.99)
OR (95% CI): 4.58 (3.26, 6.43)
Fingolimod treatment increases the proportion of patients who are free from disease
activity in multiple sclerosis; results from a phase 3, placebo-controlled study (FREEDOMS)
Kappos et al., AAN 2011
Gd
CU
R DP
T2
BG-12 Increases the Proportion of Patients Free of Clinical and Radiologic Disease Activity in Relapsing–Remitting Multiple Sclerosis: Findings from a DEFINE Post Hoc Analysis
Giovannoni et al., AAN 2012
Gd
CU
R
DP
T2
Fingolimod Treatment Increases the Proportion of Patients who are Free from Disease Activity in Multiple Sclerosis
Compared to Interferon beta-1a: Results from a Phase 3 Active-Controlled Study (TRANSFORMS)
Khatri et al. AAN 2012.
Gd
CU
R
DP T2
41
Disease Activity-Free Status in Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I (CARE-MS I) - Phase 3 Study
Odds of experiencing MS disease activity for SC IFNB-1a patients was 1.75 times higher than alemtuzumab patients; odds ratio=1.75 (95% CI: 1.17, 2.61), p=0.0064
CDA-Free MRI Activity–Free MS Disease
Activity-Free
p<0.0001
p=0.0388
p=0.0064
Giovannoni et al. ENS 2012
Gd
CU
R
DP T2
Power calculations from CLARITY study
Absolute difference 90% power
treatment rate - placebo rate
10% 20% 30%
Placebo rate
1 group 1 group 1 group
15% 354 108 54
+10% 389 118 59
30% 496 134 63
+10% 546 147 69
Giovannoni et al. Unpublished observations
Gd
CU
R DP
T2
Current Dogma
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
e.g. neurofilaments
Clinical Attack
Disease Progression
Clinical Recovery
?
? ?
? ?
- biology
- clinical outcomes
- biomarkers
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
Post-inflammatory neurodegeneration
Gunnarsson et al. Ann Neurol 2010.
Axonal Damage in Relapsing Multiple Sclerosis is Markedly Reduced by Natalizumab
Conclusions / Questions
• What would disease free-status look like?
• Absence of any clinical and biomarker evidence of disease activity
• Current definition = relapse, disease-progression, Gd-enhancing lesions and new T2 lesions
• What about brain atrophy and CSF neurofilament levels?
• Should the definition be stage specific?
• CIS/RRMS vs. R-SPMS vs. NR-SP/PPMS
• What do we do about post-inflammatory neurodegeneraton?
• What about the potential effects of superimposed accelerated or premature aging?
• How do we define an appropriate baseline for comparison?
• We need to optimise the time fore re-base lining MRI when looking for a change; this may need to be agent specific.
• How do we deal with the difference between maintenance and induction therapies?
• Maintenance - absence of DAF status indicated non-response
• Induction – absence of DAF status indicates a time to retreat.
• How do we standardise (or improve) on the metrics?
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
e.g. neurofilaments
Clinical Attack
Disease Progression
Clinical Recovery
- biology
- clinical outcomes
- biomarkers
Do we need to challenge the dogma?
Do we need to challenge the dogma?
immune activation innate and adaptive responses
focal inflammation
BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity & remyelination
delayed neuroaxonal loss and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
e.g. neurofilaments
Clinical Attack
Disease Progression
Clinical Recovery
Viral infection
What will a cure in MS look like?
www.ms-res.org
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