emerging research into the causes of ms
TRANSCRIPT
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Emerging areas of research into the causes of MS
Professor Gavin Giovannoni Professor of Clinical Neurology & Chair of Neurology
Blizard Institute, Barts and The London School of Medicine and Dentistry, London
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Complex diseases
Genes
Epigenetics
Environment
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Causation theory
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Causation
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Giovannoni & Cutter; Lancet Neurol 2006; 5: 887–94.
Diffusion Curve
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Causation - Koch’s Postulates
1. The specific organism should be shown to be present in all cases of animals suffering from a specific disease but should not be found in healthy animals.
2. The specific microorganism should be isolated from the diseased animal and grown in pure culture on artificial laboratory media.
3. This freshly isolated microorganism, when inoculated into a healthy laboratory animal, should cause the same disease seen in the original animal.
4. The microorganism should be reisolated in pure culture from the experimental infection. 1843-1910
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Sir Bradford-Hill: Criteria for Causation
Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.
1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS
2. STRENGTH OF ASSOCIATION
3. TEMPORAL SEQUENCE
4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP)
5. SPECIFICITY
6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE
7. BIOLOGICAL PLAUSABILITY
8. REASONING BY ANALOGY
9. EXPERIMENTAL EVIDENCE
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Causation and Disease:
A Chronological Journey
Alfred S. Evans
Hardcover / Plenum Pub Corp
March 1993 / 0306442833
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“Evidence” or “lack of evidence”
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99.2% vs. 90.2%
.
Ascherio et al, 2000
Sero-positivity among MS patients compared with controls by study
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The risk of developing MS in individuals seronegative for EBV: a meta-analysis
Pakpoor et al., MSJ 2012
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Infectious mononucleosis
Handel et al. 2010.
Small OR
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Concealed effects of gene-environment interactions in genome-wide association
Handel, Williamson, Lincoln & Ramagopalan, MSARD 2012
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EBV antibody titres: anti-EBNA1
.
Levin et al, 2005
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Odds ratio of MS in subjects seronegative for EBV
Ascherio et al, 2007
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Distribution of MS in England
Ramagopalan et al., JNNP 2011.
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Distribution of IM in England
Ramagopalan et al., JNNP 2011.
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Correlation Between Distribution of IM and MS in England
Females- Pearson R= 0.70, p=0.000025
Males- Pearson R= 0.55, p=0.003
Correlations don’t imply causation Ramagopalan et al., JNNP 2011.
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Primary infection with the EBV and risk of MS
• Nested case-control study including from over 8 million military personnel with serum stored in the Department of Defense Serum Repository.
Levin et al. Ann Neurol 2010.
MS
Controls N = 610
N = 305 10/305 (3.3%) EBV –ve
32/610 (5.2%) EBV –ve 10/28 (35.7%) EBV –ve
10/10 (100%) EBV –ve
• MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection.
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The ugly fact
“The great tragedy of Science; the slaying of a beautiful hypothesis by an ugly fact.” Thomas Henry Huxley
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Viral serologies in children with MS
Banwell et al. Lancet Neurology, Sept. 2007
?
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Congruency
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Compston & Coles, Lancet 2008.
Epidemiology: worldwide distribution & migration studies
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Latitude & link with vD & UVB
1Jablonski NG, Chaplin G. J Hum Evol 2000;39:57–106. 2Chaplin G. Am J Phys Anthropol 2004;125:292–302.
45
55
70
47 76
71 78
51 53 51
59
77
62
88
103
98 100
84
82
93
87
95
MS Prevalence by Department Against UVMED Minimum
3–4
4–6
6–7
Department UVMed MIN
7–9
10–11
11–13
14–16
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Relationship of MS Prevalence to Ultraviolet exposure
Ramagopalan et al, 2011
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Prevalence of MS in Norway
• Prevalence data for counties in Norway (/105):
A Finnmark1 (2003) >83
B Troms1 (2003) >104
C Nordland (1999) 106
D Nord Trøndelag (1999) 164
E Oppland (2002) 190
F Hordaland (2003) 151
G Oslo (2005) 154
• In Norway, MS prevalence does not rise with increasing latitude, unlike other northern European countries and the USA
• As expected, measured UV radiation levels decrease with increasing latitude
1Kampman MT et al. J Neurol 2007;254:471–477.
A
B
C
D
E
F G
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Fish consumption?
Kampman et al, 2007
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Can serum levels of 25(OH)D3 predict MS risk?
• Nested case-control study including from over 7 million military personnel with serum stored in the Department of Defense Serum Repository.
MS
Controls N = 296
N = 148 25-OH vD3
25-OH vD3
quintiles
• RR of MS significantly decreased with increasing levels of 25-OH-vD
• OR for a 50-nmol/L increase in 25-OH-vD was 0.59 (95%CI = 0.36-0.97)
• RR lowest quintile (<63.3 nmol/L) as the reference, the ORs for each subsequent quintile were 0.57, 0.57, 0.74, and 0.38 (P = .02 for trend across quintiles)
• OR for the highest quintile, corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L, was significantly different from 1.00 (OR = 0.38; 95%CI = 0.19-0.75; P = .006)
Munger KL et al. JAMA 2006;296:2832–2838.
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Can vD supplements prevent MS?
• Nurses' Health Study
• NHS I - 92,253 women followed from 1980 to 2000
• NHS II - 95,310 women followed from 1991 to 2001
• Diet assessed at baseline & every 4 years thereafter
Munger KL et al. Neurology. 2004 Jan 13;62(1):60-5.
• Results
• RR highest quintile of total vitamin D intake to the lowest quintile was 0.67 (95% CI = 0.40 to 1.12; p for trend = 0.03)
• RR comparing women with intake of >or=400 IU/day with women with no supplemental vitamin D intake was 0.59 (95% CI = 0.38 to 0.91; p for trend = 0.006)
MS N = 173
1st 2nd 3rd 4th 5th
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What dose of vD?
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Veith Am J Clin Nutr 1999;69:842–56.
Level of vD supplementation
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Genetics of MS: the rate of MS in females is increasing
1Orton SM et al. Lancet Neurol 2006;5:932–936.
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Sex- Ratio of IM Admission by Age in England
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Fem
ale
:Mal
e r
atio
Age group at admission
Sreeram Ramagopalan et al., unpublished data.
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0.06
0.065
0.07
0.075
0.08
0.085
0.09
0.095
0.1
0.105
1996 1998 2000 2002 2004 2006 2008 2010
L/in
div
idu
al
Ramagopalan & Giovannoni, submitted.
Sunscreen sales per capita in the USA (1997-2008)
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A study of childhood environmental factors in Norway
Odds ratio for MS and summer outdoor activities
Kampman MT et al. J Neurol 2007;254:471–477.
Unadjusted odds ratio P- value Adjusted odds ratio* P- value
Summer outdoor activities
OR† 95% CI OR† 95% CI
Age 16–20 0.54 0.38–0.75 0.001 0.55 0.39–0.78 0.001
Age 11–15 0.70 0.52–0.96 0.025 0.74 0.54–1.01 0.055
Age 6–10 0.69 0.51–0.93 0.013 0.71 0.52–0.96 0.025
The regression analysis included 111 patients and 246 controls with complete data for all variables. *Adjusted for use of cod-liver oil supplementation and meals of boiled or fried fish. †Odds ratio per one unit change in summer outdoor activities.
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Smoking is a risk factor for multiple sclerosis
Handel et al. PLoS One. 2011 Jan 13;6(1):e16149.
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Prevalence of Smoking in England
Source: Office of National Statistics
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Compston & Coles, Lancet 2008.
MS Familial Risk
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Month of Birth
1Willer CJ et al. BMJ 2005;330:120–125.
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Parent-of-origin effects
Ebers et al. Lancet. 2004;363(9423):1773–1774.
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IMSGC 2007
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GWAS results in MS 110 SNPs / 103 loci
.
IMSGC & WTCCC2, 2011 IMSGC 2013
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IMSGC NEJM, 2007 IMSGC & WTCCC2 Nature, 2011
Immune function candidate loci
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GWAS results in context
0
100
200
300
400
500
600
% R
isk
Incr
eas
e
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Fine-mapping the genetic association of the MHC in MS: HLA and non-HLA effects
Patsopoulos et al. PLoS Genet. 2013 Nov;9(11):e1003926.
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Ramagopalan et al. Arch Neurol 2011; 68:469-72.
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Gene-environment interactions
Ramagopalan & Giovannoni; Lancet Neurol. 2009
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Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis
Hedstrom et al. Brain 2011:134;653–664.
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Biological plausability
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EBV & Disease Activity
Farrell et al. Neurology 2009
EBNA-1
NOT VCA or EA
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International CIS study: EBNA-1 IgG and conversion to CDMS*
Cox univariate HR 95% CI P value
EBNA-1 nOD 1.01 0.996-1.029 0.137
* similar results in OCB+ve and MRI T2 +ve patients only
Median Survival (days) Log-rank p
< Median 1247
0.216 > Median 1032
Dr Jens Khule, ECTRIMS 2013
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Dysregulated EBV infection in the MS brain
Serafini et al. J Exp Med. 2007 Nov 26;204(12):2899-912.
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Negative follow-up studies
1. Torkildsen O, et al. Upregulation of Immunoglobulin-related Genes in
Cortical Sections from Multiple Sclerosis Patients. Brain Pathol. 2009 Oct 16.
[Epub ahead of print]
2. Willis SN, et al. Epstein-Barr virus infection is not a characteristic feature of
multiple sclerosis brain. Brain. 2009 Dec;132(Pt 12):3318-28.
3. Peferoen LA, et al. Epstein Barr virus is not a characteristic feature in the
central nervous system in established multiple sclerosis. Brain. 2010
May;133(Pt 5):e137. Epub 2009 Nov 16.
4. Hans Lassman et al, personal communication.
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Innate immune activation is a hallmark of the active MS lesions
Tzartos et al., Neurology 2012.
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Intrathecal oligoclonal IgG bands (OCBs)
1. Rand KH, et al. (1998) Molecular approach to find target(s) for oligoclonal bands in multiple sclerosis. J Neurol Neurosurg Psychiatry 65:48-55.
2. Bray PF, et al. (1992) Antibodies against Epstein-Barr nuclear antigen (EBNA) in multiple sclerosis CSF, and two pentapeptide sequence identities between EBNA and myelin basic protein. Neurology 42:1798-804.
3. Cepok S, et al. (2005) Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 115:1352-60.
4. Rand KH, et al. (2000) Epstein-Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J Neurol Sci 173:32-9.
C+ / S-
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Analogy
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Japanese macaque encephalomyelitis: spontaneous MS–like disease in a nonhuman primate
Axthelm et al. Ann Neurol 2011.
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Experimental evidence
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N Engl J Med 2008;358:676-88.
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Ocrelizumab Significantly Reduced
ARR by Week 24 (ITT)
Placebo
(n=54)
IFN-β1a
(n=54)
p=0.0019
p=0.0136
OCR 600 mg
arm (n=55)
OCR 1000 mg
arm (n=55)
0.213 0.127
0.557 62% 77%
Ad
jus
ted
AR
R*
(95
% C
I)
*Adjusted for geographical region. CI, confidence interval.
0.364
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The Reduction in Gd-Enhancing T1 Lesions
by OCR Is Maintained Through 144 Weeks
Primary endpoint:
OCR vs placebo1
Weeks
* *
1. Kappos L, et al. Lancet. 2011;378(9805):1779–87; 2. Kappos L, et al. Abstract presented (P362) ECTRIMS 2012 , October 12
OCR 600 mg arm (n=55)
OCR 1000 mg arm (n=55)
Placebo (n=54)
IFN-β1a (n=54)
- ‘Core Study' (0–96 weeks)
- ‘Follow-Up' (97–144 weeks)a
*p<0.0001 for both OCR doses vs placebo, N (for primary analysis): Placebo=54, OCR 600 mg=51, OCR 1000 mg=52, IFN-β1a=522
aPatients who withdrew during earlier treatment cycles were also included in the follow-up periods
Patients with baseline MRI
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Summimg-up
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A causal cascade for multiple sclerosis?
.
Ramagopalan et al, 2010
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VS.
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Sir Bradford-Hill: Criteria for Causation Is EBV the cause of MS?
Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.
1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS - Yes (not 100%)
2. STRENGTH OF ASSOCIATION – ? / Yes (RR ~ 2 to 3)
3. TEMPORAL SEQUENCE - Yes
4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP) - ? (not relevant to infections)
5. SPECIFICITY – No (not 100% other putative autoimmune diseases also associated with EBV)
6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE - Yes
7. BIOLOGICAL PLAUSABILITY - Yes
8. REASONING BY ANALOGY - Yes
9. EXPERIMENTAL EVIDENCE - ?
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Kakalacheva et al, 2011
How does EBV increase MS risk?
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Conclusions • Genetics
• Increased familial risk proportional to degree of relatedness
• The effect of the HLA dwarfs that of any other region (at least 6 loci)
• 102 imputed genes, of modest effect, now have convincing evidence for involvement in MS
• Genetics support an immunological basis to the aetiology of MS
• Epigenetics • Month of birth effect
• Dizygotic twin vs. sibling concordance rate
• Parent of orgin effect
• vD and EBV biology
• Environment • vD; latitude, migration, outdoor activity, Vd levels, fish consumption, etc.
? epigenetic / immunological mechanisms
• EBV ? Cause; ? biological mechanisms
• Smoking ? Post-translational modification of putative autoantigens
• Is MS a preventable disease? YES!!!!
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Acknowledgements
• Ute Meier
• Monica Marta
• Sreeram Ramagopalan
• Ruth Dobson
• George Ebers
• Jo Topping
• Georgina Burrow
• Julian Gold
• Rachel Farrell
• Cosimo Maggiore
• Jaap Middeldorp
• Sandra Amor
• Dorothy Crawford
• Karen McCauley
• Adam Handel
• Giulio DeSanto
• Hadi Amir-Maghzi
• Chris Hawkes
• Klaus Schmierer
• David Baker
• Jens Kuhle
• Arie Gafson
• Julia Pakpoor