The Environment and MS

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The Environment and MS

  1. 1. How and when to intervene to prevent multiple sclerosis; targeting the environment? Professor Gavin Giovannoni Professor of Clinical Neurology & Chair of Neurology Blizard Institute, Barts and The London School of Medicine and Dentistry, London
  2. 2. Multiple sclerosis is a complex disease Epigenetics 1. 2. 3. 4. Month of birth Maternal parentof origin effect Dizygotic vs. sibling concordance rates vD, EBV & smoking Genes Chance Environment 1. 2. 3. EBV vD Smoking 1. 2. HLA Etc.
  3. 3. EBV
  4. 4. Sero-positivity among MS patients compared with controls by study 99.2% vs. 90.2% . Ascherio et al, 2000
  5. 5. Infectious mononucleosis Small OR Handel et al. 2010.
  6. 6. Odds ratio of MS in subjects seronegative for EBV Ascherio et al, 2007
  7. 7. Distribution of MS in England Ramagopalan et al., JNNP 2011.
  8. 8. Distribution of IM in England Ramagopalan et al., JNNP 2011.
  9. 9. 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.
  10. 10. 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. 32/610 (5.2%) EBV –ve 10/28 (35.7%) EBV –ve Controls N = 610 10/305 (3.3%) EBV –ve 10/10 (100%) EBV –ve MS N = 305 • MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection. Levin et al. Ann Neurol 2010.
  11. 11. The ugly fact “The great tragedy of Science; the slaying of a beautiful hypothesis by an ugly fact.” Thomas Henry Huxley
  12. 12. Viral serologies in children with MS ? Banwell et al. Lancet Neurology, Sept. 2007
  13. 13. The risk of developing MS in individuals seronegative for EBV: a meta-analysis Pakpoor et al., MSJ 2012
  14. 14. EBV antibody titres: anti-EBNA1 . Levin et al, 2005
  15. 15. EBV & Disease Activity EBNA-1 NOT VCA or EA Farrell et al. Neurology 2009
  16. 16. International CIS study: EBNA-1 IgG and conversion to CDMS* Cox univariate HR 95% CI EBNA-1 nOD 1.01 0.996-1.029 0.137 Median Survival (days) P value * similar results in OCB+ve and MRI T2 +ve patients only < Median 1247 > Median 1032 Log-rank p 0.216 Dr Jens Khule, ECTRIMS 2013
  17. 17. N Engl J Med 2008;358:676-88.
  18. 18. The Reduction in Gd-Enhancing T1 Lesions by OCR Is Maintained Through 144 Weeks Patients with baseline MRI Placebo (n=54) OCR 600 mg arm (n=55) OCR 1000 mg arm (n=55) IFN-β1a (n=54) Primary endpoint: OCR vs placebo1 - ‘Core Study' (0–96 weeks) - ‘Follow-Up' (97–144 weeks)a * * Weeks *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 1. Kappos L, et al. Lancet. 2011;378(9805):1779–87; 2. Kappos L, et al. Abstract presented (P362) ECTRIMS 2012 , October 12
  19. 19. vD
  20. 20. Epidemiology: worldwide distribution & migration studies Compston & Coles, Lancet 2008.
  21. 21. Latitude & link with vD & UVB MS Prevalence by Department Against UVMED Minimum 93 103 82 77 100 88 98 87 62 59 Department UVMed MIN 3–4 4–6 6–7 7–9 84 47 76 70 78 95 71 55 51 53 51 10–11 11–13 14–16 45 1Jablonski NG, Chaplin G. J Hum Evol 2000;39:57–106. Am J Phys Anthropol 2004;125:292–302. 2Chaplin G.
  22. 22. Relationship of MS Prevalence to Ultraviolet exposure Ramagopalan et al, 2011
  23. 23. 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 A B C D E F G 1Kampman MT et al. J Neurol 2007;254:471–477.
  24. 24. Fish consumption? Kampman et al, 2007
  25. 25. A study of childhood environmental factors in Norway Odds ratio for MS and summer outdoor activities Unadjusted odds ratio Summer outdoor activities OR† 95% CI Age 16–20 0.54 0.38–0.75 Age 11–15 0.70 Age 6–10 0.69 P- value Adjusted odds ratio* P- value OR† 95% CI 0.001 0.55 0.39–0.78 0.001 0.52–0.96 0.025 0.74 0.54–1.01 0.055 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. Kampman MT et al. J Neurol 2007;254:471–477.
  26. 26. 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. Controls N = 296 MS 25-OH vD3 N = 148 quintiles 25-OH vD3 • 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.
  27. 27. 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 MS 1st 2nd 3rd 4th N = 173 5th 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) Munger KL et al. Neurology. 2004 Jan 13;62(1):60-5.
  28. 28. What dose of vD?
  29. 29. Level of vD supplementation Veith Am J Clin Nutr 1999;69:842–56.
  30. 30. Level of vD supplementation Veith Am J Clin Nutr 1999;69:842–56.
  31. 31. Cultural changes
  32. 32. Genetics of MS: the rate of MS in females is increasing 1Orton SM et al. Lancet Neurol 2006;5:932–936.
  33. 33. Sunscreen sales per capita in the USA (1997-2008) 0.105 0.1 L/individual 0.095 0.09 0.085 0.08 0.075 0.07 0.065 0.06 1996 1998 2000 2002 2004 2006 2008 2010 Ramagopalan & Giovannoni, submitted.
  34. 34. Smoking
  35. 35. Smoking is a risk factor for multiple sclerosis Handel et al. PLoS One. 2011 Jan 13;6(1):e16149.
  36. 36. Prevalence of Smoking in England Source: Office of National Statistics
  37. 37. When to supplement?
  38. 38. Month of Birth 1Willer CJ et al. BMJ 2005;330:120–125.
  39. 39. MS Familial Risk Compston & Coles, Lancet 2008.
  40. 40. Parent-of-origin effects Ebers et al. Lancet. 2004;363(9423):1773–1774.
  41. 41. Analogy
  42. 42. Japanese macaque encephalomyelitis: spontaneous MS–like disease in a nonhuman primate Axthelm et al. Ann Neurol 2011.
  43. 43. Prevention strategies
  44. 44. A causal cascade for multiple sclerosis? vD supplementation Smoking prevention EBV vaccination IM prevention and treatment EBV therapies . Ramagopalan et al, 2010
  45. 45. Causation theory
  46. 46. Sir Bradford-Hill: Criteria for Causation 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 Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.
  47. 47. Sir Bradford-Hill: Criteria for Causation Is EBV the cause of MS? 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 - ? Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1966; 58:295.
  48. 48. VS.
  49. 49. Conclusions • Genetics • • • • • Epigenetics • • • • • 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 Month of birth effect Dizygotic twin vs. sibling concordance rate Parent of orgin effect vD, EBV and smoking 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!!!!
  50. 50. 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

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