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Biomarkers in clinical practice & novel biomarkers
Gavin Giovannoni
Barts and The London
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Why MS biomarkers?
• 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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Q: Who still does diagnostic lumbar punctures?
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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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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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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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A clinico-pathoanatomical study of multiple sclerosis diagnosis
SENSITIVITY = True+ve /(True+ve + False-ve)
Eye Department, Hvidovre Hospital, Denmark.
• Neuropathological examination of 518 consecutive patients with clinically definite MS revealed a correct diagnosis in 485 cases (94%).
• Clinical diagnosis had been established by a neurologist in all cases.
• Erroneous diagnosis included a variety of other neurological disorders.
• Also investigated was a randomly selected series of 33 patients with a clinical diagnosis of probable MS:
– post mortem confirmation of MS was obtained in circa 66%.
– The remainder the error pattern was similar to the above.
Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.
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Lennon et al. Lancet 2004;364:2106-12.
NMO
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Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.
PML complicating treatment with natalizumab and IFNb-1a for MS
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Pathogenic markers
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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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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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Brain atrophy
Slider courtesy of Dr Nic Losseff, Institute of Numerology, Queen Square.
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Control Multiple sclerosis
Brain atrophy
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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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Gunnarsson et al. Ann Neurol 2010; Epub.
CSF NFL
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Natalizumab treatment of progressive multiple sclerosis reduces
inflammation and tissue damage
- results of a phase 2A proof-of-concept study
ClinicalTrials.gov Identifier: NCT01077466
J. Romme Christensen1, R. Ratzer1, L. Börnsen1, E. Garde2, M. Lyksborg2, H.R. Siebner2, T.B. Dyrby2, P. Soelberg Sørensen1 and F. Sellebjerg1
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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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Q: Who routinely measures vD levels?
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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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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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Vitamin D as an Early Predictor of Multiple Sclerosis Activity and Progression
Ascherio et al. JAMA Neurol. 2014 Jan 20.
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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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Pharmacovigilance markers
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Q: Who routinely does a serum protein electrophoresis before starting IFN-beta?
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What is the diagnosis?
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Take special care with Interferon-beta-1b: If you might have a disorder of the immune system in which abnormal proteins are found in the blood (monoclonal gammopathy), you must check this with your doctor before you use interferon beta-1b. Patients who have the rare condition known as monoclonal gammopathy may develop problems with their small blood vessels (capillaries) leading to shock (collapse) which can be fatal, when they use medicines like interferon-beta-1b. See also 4. Possible side effects.
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?
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Natalizumab
Progressive multifocal leukoencephalopathy (PML)
Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.
439 cases – 4th February 2014 20% mortality 80% alive
Mild disability – 10% Moderate disability – 50% Severe disability – 40%
5% NAbs – infusion reactions
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Natalizumab PML risk stratification tool
Anti-JC virus antibody status
Negative Positive
Prior immunosuppressant use
Natalizumab treatment
>2 Years
Natalizumab treatment
>2 Years
No Yes
No Yes No Yes
Lowest Highest Relative PML Risk
< 1 in 10,000 1 in 94 1 in 256 1 in 668 1 in 1887
Mitoxantrone
Azathioprine
Methotrexate
Cyclophosphamide
Mycophenolate
Cladribine
Rituximab
Etc.
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Q: When requesting JCV serology who looks at the antibody index or titre?
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PML risk estimates for anti-JCV antibody index thresholds were calculated based on the current PML risk stratification algorithm (September 2012)
and predicted probabilities (using data from patients with no prior IS use: 2242 non-PML patients and 51 patients who developed PML using all
available anti-JCV antibody index data at least 6 months prior to PML diagnosis) for the population at or below that particular index (0.9−1.5) and
for the population above an index of 1.5. For index thresholds below 0.9, patient numbers were insufficient to allow for calculation of risk estimates.
Anti-JCV antibody index values may differentiate PML risk for those with no prior immunosuppression
Index 1−24 months
≤0.9 0.1 (0, 0.41)
≤1.1 0.1 (0, 0.34)
≤1.3 0.1 (0.01, 0.39)
≤1.5 0.1 (0.03, 0.42)
>1.5 1.0 (0.64, 1.41)
50
PML risk estimates (95% CI) per 1000 patients with no prior IS use
Plavina T et al. Poster DX51, CMSC May 29–June 1 2013, Orlando, USA; Ticho B. et al, Presented at ENS, June 8–11 2013, Barcelona, Spain O228.
50
25−48 months 49−72 months
0.3 (0.04, 1.13)
0.4 (0.01, 2.15)
0.7 (0.21, 1.53)
0.7 (0.08, 2.34)
1.0 (0.48, 1.98)
1.2 (0.31, 2.94)
1.2 (0.64, 2.15)
1.3 (0.41, 2.96)
8.1 (6.64, 9.80)
8.5 (6.22, 11.38)
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Predicting autoimmunity following treatment of MS with alemtuzumab
• 30% of alemtuzumab-treated pts develop autoimmune side-effects (primarily thyroid disease and idiopathic thrombocytopenia)
• Aim: To define predictive factors for autoimmune side-effects
• Sera of 141 pts screened at baseline for 8 different cytokines/chemokines
A combined IL-21/IL-7 test on pre-treatment serum may be useful to identify patients at low risk of developing autoimmunity following treatment with alemtuzumab
Jones JL, et al. ECTRIMS 2011, Amsterdam. P1009
Sensitivity NPV Specificity PPV
IL-21 alone 81 84 70 66
IL-7 alone 76 76 54 54
CCL21 alone 63 65 49 47
IL-21 or IL-7 98 97 41 55
IL-21 OR IL-7 OR CCL21
98 91 12 45
Given that pts may elect to receive treatment based
on results of this test – most weight given to
minimizing false negative results. Combining IL-21
and IL-7 into a single test offers improved test
accuracy over IL-21 alone. CCL21 did not improve
test accuracy
0
10
20
30
40
IL-7
Autoimmunity No autoimmunity
0
500
1000
1500
IL-2
1
1.0
Sen
sit
ivit
y
0.8
0.6
0.4
0.2
0.0 0.0 0.2 0.4 0.6 0.8 1.0
1.0
Sen
sit
ivit
y
0.8
0.6
0.4
0.2
0.0 0.0 0.2 0.4 0.6 0.8 1.0
1-Specificity
IL-21 and IL-7 levels in sera
of pts who did or did not
develop autoimmunity
Receiver operating
characteristic (ROC) curves
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Neurology 2012;78(Suppl.): [S41.006]
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Case study: ITP in alemtuzumab treated patient
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Anti-natalizumab Antibodies
Number of Patients at Risk
Placebo
Antibody Negative
Transiently Positive
Persistently Positive
315
568
20
37
296
550
19
32
283
538
18
26
264
526
16
25
248
506
16
24
240
487
16
22
229
480
15
22
216
470
14
19
208
460
14
16
200
449
14
15
Weeks
0.0
0.1
0.2
0.3
0.4
0.5
0 12 24 36 48 60 72 84 96 108 120
29%
Placebo
17%
Antibody Negative
17%
Transiently Antibody Positive
34%Persistently Antibody Positive
Cu
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Pro
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ati
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wit
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us
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Pro
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DS
S) *,†
*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placebo
Number of Patients at Risk
Placebo
Antibody Negative
Transiently Positive
Persistently Positive
315
568
20
37
296
550
19
32
283
538
18
26
264
526
16
25
248
506
16
24
240
487
16
22
229
480
15
22
216
470
14
19
208
460
14
16
200
449
14
15
Weeks
0.0
0.1
0.2
0.3
0.4
0.5
0 12 24 36 48 60 72 84 96 108 120
29%
Placebo
17%
Antibody Negative
17%
Transiently Antibody Positive
34%Persistently Antibody Positive
Cu
mu
lati
ve
Pro
po
rtio
n o
f P
ati
en
ts
wit
h S
us
tain
ed
Dis
ab
ilit
y
Pro
gre
ss
ion
(E
DS
S) *,†
*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placebo
0.73
0.220.16
0.48*
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Ad
jus
ted
An
nu
ali
ze
d R
ela
pse
Ra
te (
95
% C
I)
Placebo
(n=315)
Antibody Negative
(n=568)
Transiently
Antibody Positive
( n=20)
Persistently
Antibody Positive
(n=37)
*p=0.009 vs. antibody-negative patients
0.73
0.220.16
0.48*
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Ad
jus
ted
An
nu
ali
ze
d R
ela
pse
Ra
te (
95
% C
I)
Placebo
(n=315)
Antibody Negative
(n=568)
Transiently
Antibody Positive
( n=20)
Persistently
Antibody Positive
(n=37)
*p=0.009 vs. antibody-negative patients
Calabresi et al, Neurol 2007
Impact of anti-natalizumab antibodies on . . . . .
Annualized relapse rate Progressive disability
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Natalizumab infusion reactions
• Acute hypersensitivity reactions are well-recognized
• Generalized urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, dyspnea, chest pain
• Onset generally during or within 1 hour of second infusion
• Incidence ~4%
• severe anaphylactic/anaphylactoid reactions <1%
• Most reactions are associated with anti-natalizumab antibodies
• Treatment:
• immediate and permanent cessation of natalizumab
• antihistamines
Rudick et al, NEJM 2006
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Monitoring effect of therapeutic interventions
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Reduced efficacy due to NAbs – systematic review
Farrell & Giovannoni, Multiple Sclerosis 2007; 13: 567-577.
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Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis
Sorensen et al. Lancet 2003; 362: 1184–91.
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Jacob Elkins, James Sheridan, Lakshmi Amaravadi, Katherine Riester, Gilmore O’Neill
Neurology 2012;78(Suppl.): S31.004
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Prognostic markers
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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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Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.
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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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Conclusion • Diagnostic/prognostic biomarkers
• Intrathecal OCBs
• IgG Index
• Pharmacovigilance
• Baseline screening
• Monoclonal gammaopathy (IFNbeta)
• Serology – VZV, JCV (immunosuppression)
• Monitoring
• FBC, LFTs, U&E, TFTs
• Monthly platelets and possibly urine (alemtuzmab)
• Serology – JCV (natalizumab)
• CD56-bright cells (daclizumab)
• NABs (IFNbeta and natalizumab)
• Potential surrogate treatment markers
• CSF neurofilament levels
• Potential future baseline response markers
• Type 1 interferon signature
• PBMC transcriptomic profiles
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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
• NABINMS • Affirm study • Care MS 1 & 2 studies • Select trial