prevention ms trials
TRANSCRIPT
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MS Prevention
Gavin Giovannoni
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EBV Vitamin D
SmokingGenes
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Very low risk
ageplace of residence
outdoor activity / sun exposure / sun screendiet / vitamin D supplements
age of exposure to EBVsmoking
At risk High Risk
Low risk
RIS CIS MS
family historygenetics
sexmonth of birthplace of birth
Unfavourable disease-modifying factorsdynamic risk factorsstatic risk factors
dynamic protective factorsstatic protective factors
MRI / evoked potentials changes
Peripheral immunological changesT-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 MSc. Relapsing secondary progressive MSd. Non-relapsing secondary progressive MS
Favourable disease-modifying factors
protective HLA haplotypes
CNS changes(OCBs and microscopic pathology)
2
3
24b 24c 24d
24a
1
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Smoking
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Statistics on Smoking, England 2013. Health & Social Care Information Centre. Table 2.1.
Prevalence of cigarette smoking among young adults - England
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www.digestingscience.co.uk
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vD
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Population
vs.
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Questions
• Age group– In utero, childhood, adolescence, adulthood
• Dose– Fixed-dosing– Target (what target? Population mean vs. Evolutionary Medicine)– Food fortification
• Comparator– Placebo– Active (400U/day)
• Outcome– MS vs. basket of related diseases (T1DM > MS, etc.)
• Adherence• Case definitions• Logistics
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Old-World PrimatesHumans exposing full
skin surface to Sunshine’s UVB
Winter 43o N Latitude
“Normal”0
40
120
160
Vitamin D Status in Primates and Early Humans
Sources, include Cosman, Osteoporosis Int 2000; Fuleihan NEJM 1999; Scharla Osteoporosis Int 1998; Vieth AJCN 1999, 2000
80
Physiological adult intake
Blood Levels when taking 25 mcg/d
1000 IU/day
Northern PeopleTaking
100 mcg/d 4000 IU/day
Slide adapted from Reinhold Vieth
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Maasai median 25(OH)D = 104 nmol/L = 41 ng/mL
Luxwolda et al. British Journal of Nutrition (2012), 108, 1557–1561
40 ng/mL
Slide adapted from Reinhold Vieth
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Veith Am J Clin Nutr 1999;69:842–56.
Level of vD supplementation
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At risk High Risk RIS CIS MS
In utero childhood Adolescence / early adulthood adulthood
High riskLow risk
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High risk
Cohort 1 – in utero (pregnancy)
Cohort 2 – Childhood
Cohort 3 – Adolescence
Cohort 4 – Early adulthoodvs.
Cohorts 5-8 – Comparator population (historical or contemporary)
+ve family history – 1° & 2° relatives
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Risk of MS to children
Borisow et al. EPMA J. 2012 Jun 22;3(1):9.
RR ~ 7.5
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Sex
Orton et al, 2006; Koch-Henriksen and Sorenson 2010
The rate of MS in females is increasing rapidly while the male rate of MS has remained stable.
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.
Peak age of MS onset is between 20-40 years old
Paty and Ebers, 1998
~70% → ~6 year follow-up ~20% of incidence cases
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Population Demographic Profile
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High risk
+ve family history – 1° & 2° relatives
Prevalence: 150/100,000 (1in 500-1,000)Incidence: 7.5/100,000 (6-9/100,000) Sex ratio: females:male: 3:1Relative risk: x7.5 (1° & 2° relatives)Prevalence in at risk: 1125/100,000
Age: 16-36 → ~70% = 788 incident cases/100,000~39.4 incident case/100,000/yr~4 incident case/10,000/yr
2-years ≥5-years
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Does the risk score provide an estimate of MS risk?
Area under
curve (95% CI)
Risk score including genetic contribution
from HLA-DRB15*1501 only
0.77
(0.70 – 0.84)
Risk score including genetic contribution
from all MS risk alleles
0.80
(0.74 – 0.87)
Risk score including genetic contribution
from HLA-DRB1*1501 only; excluding
serum 25-OHvD level
0.80
(0.73 – 0.87)
Risk score including genetic contribution
from all MS risk alleles; excluding serum
25-OHvD level
0.82
(0.75 – 0.88)
Ruth Dobson, unpublished data
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Odds ratio of having MS varies according to risk score category
Risk score calculated using full genetic information
Markedly increased risk of being in the top risk score category compared to the lowest risk score category (OR 1296.00; 95% CI 78 – 21,527;p<0.00001)
Ruth Dobson, unpublished data
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Google or Big Data StudyGary Cutter – 10,000,000 study
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10,000,000
Randomisation
400U 2,000U 10,000U
Annual end-of-winter blood spots
Biobank
Follow-up x 10 years
Annual health questionnaire Events Confirmation
Inclusion/Exclusion
Online volunteeringPublic engagement
Multiple nested case-control study
PR / Media
Social Media
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EBV
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Population based vaccine
vs.
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Questions
• Need a vaccine– GSK / Medimmune gp350– NIH new initiative
• Age group– Childhood, adolescence, early adulthood
• Vaccine programme– Piggy-back on HPV programme
• Comparator– Placebo
• Primary outcome– IM
• Secondary outcome– Population surveillance (autoimmune / oncology)
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High risk
Infant/childhood vs. early adulthood & adolescence (EBV –ve)
vs.
Active comparator (EBV –ve)
General Population
vs.
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PD
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High riskLow risk
Intermediate Phenotypes1. Smell (UPSIT)2. REM-sleep behavioural disorder3. Tapping speed (BRAIN TEST)4. Genomics (LRRK2 / GBA)PD Phenotypes1. Clinical (UPDR / PD)2. Imaging (US / DAT)
High vs. Low risk
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Conclusion
• Is MS preventable? Yes
• Smoking
• 20% of cases in general population
• 40% familial cases
• Vitamin D
• General population
• At risk
• Enrichment (endophenotype)
• EBV
• Vaccination
• prevent wildtype infection
• wildtype early infection (vD replete)
• IM
• Prevention (vaccine)
• Treatment
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Acknowledgements
Rachel FarrellRuth DobsonJens KuhleJulian GoldDavid HoldenUte MeierSreeram Ramagapolan
Dorothy CrawfordKaren McAulayDavid MillerBasil SharrackGeorge Ebers