Multiple Sclerosis: a NZ Perspective. Dr Deborah Mason Neurologist Christchurch Hospital

Multiple Sclerosis: a NZ Perspective Dr Deborah Mason Neurologist Christchurch Hospital

Multiple Sclerosis in NZ What is MS Epidemiology of MS in NZ Impact of the disease on PwMS Genetic and Environmental Aspects Future Studies

Multiple Sclerosis An inflammatory disease affecting the brain, spinal cord and optic nerves.

Immune Cell Migration into Inflammatory Sites Prostaglandins TNF IL-1 Leukotrienes Chemokines BLOOD VESSEL Inflamed Tissue Free radicals Metalloproteases PAF Nitric Oxide Lipoxins

MRI Brain

PATHOLOGICAL DATA Neuropathology in cortical lesions Peterson J et al. Ann Neurol 2001

MRI and clinical pattern in MS Progression Disability Disease severity Relapse MRI Active lesions Time (years)

MS Prevalence in NZ Region Study Period Prevalence rate per 100,000 population Bay of Plenty region (Chancellor et al, 2003) Wellington region (Hornabrook,1971) Wellington region (Miller et al, 1986) Wellington region (Miller et al, 1992) Christchurch (Cunningham, 1972) Waikato Otago-Southland (Skegg et al, 1987) 2001 50 1968 38 1983 58 61 1971 37 1981 23.6 68.5

MS Prevalence Study The New Zealand MS Prevalence Study Group. A/Prof Bruce Taylor Dr Deborah Mason Dr Ernie Willoughby Dr Glynnis Clarke Dr David Abernethy Dr John Pearson Dr Clive Sabel

NZMS Prevalence Study Notifications 13,803 Unique Individuals 5,901 Confirmed MS 2917

MS Prevalence Study Prevalence 72.4 per 100,000 F/M ratio of 3:1

MS Prevalence Study Prevalence 24.2 per 100,000 F/M ratio of 2.1:1

Prevalence and Number of cases by 5yr age groups 450 400 350 300 250 200 150 100 50 0 Number of Cases of MS Prevalence 0-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75+

Impact of the Disease MS The Extended Disability Status Score (Kurtzke 1983) An EDSS of <3 denotes mild disability Scores between 3 and 5.5 represent moderate disability (pts still able to walk independently) 6 and 7.5 patients require aids to walk 8 and 9.5 severe disability (restricted to bed or chair)

EDSS Grouping 900 800 700 600 500 400 300 200 100 0 <3 3-5.5 6-7.5 8+

Impact of the Disease MS Not surprisingly this has a large impact on socioeconomic status particular employment status Whilst over 90% of working age MS cohort had a work history Over half not working c.f 22% general population 55% stopped work within 4 years of diagnosis Median annual personal income $20,000 (34,750) 30% receiving an invalid s benefit

MS Prevalence Region Prevalence rate per 100,000 population 2006 prevalence ASP rate per 100,000 population (95% CI) Bay of Plenty region 50 50.0 (41.4-58.5) Wellington region 38 86.2 (77.6-94.9) Wellington region Wellington region 58 61 86.2 (77.6-94.9) Christchurch 37 103 (95 112) Waikato 23.6 46.4 (39.6-53.3) Otago-Southland 68.5 127 (108 146)

150 100 50 0 MS prevalence by region Prevalence w ith 95% CI Prevalence increases by 10.8 0.9 per degree of Latitude South of 37 p<0.002 36.7 37.9 39.7 41.2 43.6 45.8 Latitude at Population Weighted Centroid Age standardised prevalence (per 100,000) Nth/Auckland Waikato/BOP Tarnaki/HB Well/Nel/Mar Canterbury/WC Otago/South

Cloud corrected Erythemal UV dose Southern HemisphereWinter

Cloud corrected Erythemal UV dose Southern Hemisphere Summer

Vitamins Casmir Funk Polish biochemist 1912 Isolated thiamine Vital amines molecules not made in the body but vital to it in small amounts Scurvy, Pellagra and rickets. Vitamin D hormone

Vitamin D Metabolism

Vitamin D It seems logical to consider intervention strategies - Relevant age or timing of the exposure - Dose and type -Safety Impact on MS risk Efficacy in slowing progression

PreVANZ Study Randomized, Double-Blind, Placebo-Controlled, Trial of Vitamin D 3 in Patients with a First Demyelinating Event. To determine the efficacy of oral, daily, Vitamin D 3 (1000IU, 5000IU, 10,000IU) compared with placebo Reducing the risk of disease activity in the 12 months following first attack.

Infectious agents MS Genetic Factors Environmental Factors

What is the gene effect? Twin Studies No single gene has been identified Multiple genes

The Australia and New Zealand MS Genetics Consortium 11 institutions 4,500 people with MS 40+ researchers $1.5M MS Research Australia / ARC University of Queensland University of Auckland Griffith University Sir Charles Gardiner Hospital Flinders University University of Melbourne Walter & Eliza Hall Institute University of Newcastle Westmead Millennium Institute University of Otago Menzies Research Institute

Conclusions from our study (published 2009) Identified a possible genetic link between vitamin D metabolism and risk of MS can modulation of this pathway be used to treat MS, and other autoimmune diseases?

Vitamin D metabolism

MS Research: The Future NZ MS Incidence study began June 1 st 2012 MRI study began January 2012

A/Prof Bruce Taylor Dr Ernie Willoughby Dr Glynnis Clarke Dr David Abernethy Dr John Pearson Dr Clive Sabel Prof David Miller Dr Sridhar Alla Dr Laetitia Debernard Dr Saskia Van Stockum Ms Jane Eagle Dr John Dalrymple-Alford Dr Tracey Melzer Thank you

Ethnicity MS Study 2006 NZ Census Ethnic group 1 N % N % NZ European 1,874 92.8 2,609,589 67.6 Maori 61 3.0 565,329 14.6 Pacific 2 0.1 265,974 6.9 Asian 13 0.6 354,549 9.2 Other 169 8.4 430,881 11.2 Total 2,019 3,860,163 responses Not stated 2 877 167,784 Total people 2,896 4,027,947

Single Nucleotide Polymorphisms (SNPs) TTCCCTAGGTG TTCCTTAGGTG Human DNA sequence: 3 billion (nucleotides) One SNP every 300 nucleotides Around 10 million SNPs

Conclusions from our study (published 2009) Further evidence for genetic overlap between organ specific autoimmune diseases Identified a possible genetic link between vitamin D metabolism and risk of MS can modulation of this pathway be used to treat MS, and other autoimmune diseases? CD40 signalling is important in MS: working in the opposite direction compared to other autoimmune diseases

Phase 2: results in two chromosome regions replicated P=0.0001 CD40 most likely gene

Country Prevalence PwMS Denmark 149 8000 Slovakia 147 8000 Belgium + Luxemburg 146 15000 Czech Republic 146 15000 Finland 145 7500 Germany 144 120000 Norway 144 6500 Ireland 142 5500 Russia 138 200000 Switzerland 137 10000 Sweden 135 12000 UK 134 80000 USA 125 350000 Canada 125 40000 Slovenia 124 2400 Austria 104 8500

Country Prevalence PwMS Netherlands 100 16000 France 100 60000 Italy 87 50000 Hungary 84 8500 Australia 82 16000 Israel 82 5000 Spain 62 25000 Portugal 50 5000 Greece 32 3500 Turkey 31 21000 Japan 8 10000

MS in Maori Prevalence 24.2 per 100,000 F/M ratio of 2.1:1

P=4.1 x 10-6 P=0.00001 P=0.0001 CYP27B1