Ms society prevention workshop november 2015

MS Society Prevention Workshop Report

Contents

Executive Summary ................................................................................................................................. 3

Introduction ............................................................................................................................................ 4

Session 1: Lifestyle factors: Vitamin D, UV exposure and smoking ............................................. 5

An overview of the evidence of vitamin D as a risk factor for development of MS emerging

evidence ............................................................................................................................................ 5

Evidence for vitamin D and sunlight as risk factors of MS: data and perspectives from

Australia ............................................................................................................................................. 7

Vitamin D deficiency as a risk factor for Type 1 Diabetes ......................................................... 8

Smoking as a risk factor for MS ..................................................................................................... 9

Session 2: Therapeutics – infections and vaccines ...................................................................... 10

EBV as a risk factor for MS: an overview of the evidence ....................................................... 10

Understanding the role of EBV in MS ......................................................................................... 11

EBV-host interactions and the possible role of Bacille Calmette Guerin vaccine in MS

prevention ........................................................................................................................................ 11

Session 3: Challenges and opportunities in trial design .............................................................. 13

Challenges and opportunities in trial design .............................................................................. 13

Challenges and considerations for prevention trials ................................................................. 14

Recommendations ............................................................................................................................. 14

References .......................................................................................................................................... 15

Appendix I ............................................................................................................................................ 16

Executive Summary Research into preventing MS is a high priority for people with MS. The MS Society

prevention workshop brought together around 50 delegates from around the world to

discuss the future of research into the prevention of MS.

Professor Ascherio provided an overview to delegates of the prevalence of MS,

presenting studies that showed evidence for a latitude gradient. He also summarised

research into MS incidence with regards to gender and ethnicity.

Session one focused on lifestyle factors such as vitamin D, UV exposure and

smoking. Professor Ascherio presented evidence on vitamin D deficiency as a risk

factor for development of MS and Professor Lucas presented evidence of low UV

exposure as a risk factor, separate to but including vitamin D deficiency. Professor

Todd then summarised research conducted into vitamin D deficiency as a risk factor

for type 1 diabetes. Professor Constantinescu presented the evidence for smoking

as a risk factor for MS.

Session two focused on therapeutics with regards to infections and vaccines. Dr

Gran provided an overview of the evidence for EBV as a risk factor for MS. Professor

Rickinson expanded on the role of EBV in MS and Dr Salvetti suggested a possible

role of Bacille Calmette Guerin (BCG) vaccine in MS prevention.

The final session, session three, was an open discussion during which the group considered the challenges and opportunities in trial design. The group produced the following recommendations for research funders interested in prevention of MS:

The MS Society and other MS charities should review their messaging around smoking and lifestyle to ensure that these recommendations are clear to first and second degree relatives of people with MS.

The MS Society should explore setting up an international working group looking at developing prevention trials in MS including identifying funding sources for such trials.

The MS Society should follow the plans of EBV vaccine trials in the USA and investigate whether MS prevention could be included within the scope of these trials.

More research should focus on the fundamental biology involved in various risk factors associated with MS as well as evaluating emerging theories such as the influence of gut bacteria on the risk of developing MS.

Introduction

The MS Society held an international workshop on prevention of MS in London on

the 11th and 12th of November. The workshop was organised in response to a need

to further research into primary prevention of MS and to develop plans to address

this unmet need. Around 50 delegates from around the world attended the workshop

to contribute their views on the future of research into prevention of MS.

Delegates were welcomed by Professor Sir Andy Haines of the London School of

Hygiene and Tropical Medicine, Co-Chair of the MS Society’s Research Strategy

Committee. He spoke about the MS Society’s Research Strategy (2013-2017) its

focus on prevention, as well as the causes and risk factors of MS.

Through their collaboration with the James Lind Alliance (JLA) Priority Setting

Partnership, the MS Society has identified the top 10 research priorities for people

affected by MS and healthcare professionals. Understanding how MS can be

prevented was the second highest ranked priority, after understanding which

treatments are effective to slow, stop or reverse the accumulation of disability

associated with MS.

Therefore there is a clear direction from people with MS that further research is

needed in this area.

The workshop had three clear aims:

1. Engage the research community on areas of prevention research

2. Build relationships and learn from prevention research in other fields

3. Provide actionable recommendations for research funders on furthering

research in this area

Professor Haines invited Professor Alberto Ascherio from Harvard University to give

an overview of the epidemiology of MS.

Professor Ascherio gave an overview of the research that has been conducted on

the prevalence of MS. He showed data indicating that latitude is a strong predictor of

prevalence of MS, but highlighted that the picture is actually very complex, with a

number of risk factors playing a role in the development of MS.

He showed data from migrant studies demonstrating that prevalence of MS changes

with migration from countries of high risk to countries of lower risk. Gale et al., (1995)

showed this reduction in MS risk is stronger for migration in childhood (< 15 years).

Furthermore, migrant studies conducted in US Army Veterans, have shown that the

risk of MS is approximately one half for individuals that are born in the north of the

US and move south, compared to those that remain in the north (Kurtze et al., 1985).

Professor Ascherio showed that the incidence of MS is highest in Caucasian females

(Wallin et al., 2012).

He also discussed recent trends in the female to male ratio of MS cases . He

highlighted that the Danish MS Registry is the oldest and most complete data set

available to date. Recent data from the Registry suggest an increase in the female:

male ratio, which has been demonstrated in other countries such as Canada.

However, some countries, such as Sweden, do not find this increase.

A Canadian study showed that cigarette smoking has decreased in men and women,

however because in the 1920-30’s nearly all men smoked, the ratio of F: M smokers

has effectively increased. He suggested that smoking cessation in men could be

masking an increase in incidence of MS in men caused by risk factors such as

vitamin D deficiency.

Session 1: Lifestyle factors: Vitamin D, UV exposure and smoking

Chair: Professor David Miller, University College London

An overview of the evidence of vitamin D deficiency as a risk factor for

development of MS emerging evidence

Professor Alberto Ascherio, Harvard University

Professor Ascherio presented an overview of vitamin D and MS risk. The main

sources of vitamin D are sunlight exposure and dietary vitamin D. Studies show that

the active form of vitamin D regulates the immune responses which may influence an

individual’s risk of developing MS. He pointed out, however, that this does not give

an indication what kind of dosage of vitamin D would be required to prevent MS in

humans.

Three examples of longitudinal studies in humans that Professor Ascherio

highlighted are:

A nested case-control study conducted in a cohort of nurses, found that women

regularly taking 400IU/d of vitamin D had 40% less risk of developing MS

compared to women with no supplemental vitamin D intake (Munger et al., 2004).

A nested case-control study using the Department of Defence Serum Repository

(DoDSR) found among people with Caucasian backgrounds that the risk of MS

significantly decreased with increasing levels of 25-hydroxyvitamin D (25(OH)D)

– the usual measure of vitamin D status. However they didn’t find an association

between levels of 25(OH)D and MS in people with African American backgrounds

(Munger et al., 2006).

In Swedish cohorts, levels of 25(OH)D ≥75 (vs <75) nmol/L in prospectively

collected blood samples were associated with a 60% lower risk of MS (Salzer et

al., 2012).

Recent data by Mokry et al. (2015) showed that genetic variants associated with

lowered 25(OH)D levels are associated with a 2-fold increase in risk of MS. He

pointed out that the results of this study provide strong evidence that there is an

association between MS risk and lower 25(OH)D levels, irrespective of other factors

such as (lack of) UV light exposure.

Additionally, Professor Ascherio pointed out that there is evidence that a high BMI

during childhood is associated with increased risk of MS (Munger et al., 2009). A

study by Ekwaru et al., (2014) showed that obesity can lower the achieved 25(OH)D

level following vitamin D supplements, or that a higher dose of vitamin D

supplementation is required to raise 25(OH)D levels with increasing BMI. Ekwaru et

al. recommend vitamin D supplementation to be 2 to 3 times higher for obese

individuals and 1.5 times higher for overweight individuals, relative to normal weight

individuals.

Professor Ascherio highlighted a lack of human experimental studies looking

systematically at vitamin D supplementation and the need for large scale rigorous

intervention studies in the future.

Discussion

Delegates highlighted that 25(OH)D levels have increased in certain parts of the

world such as USA, but questioned whether there is any evidence that 25(OH)D

levels have changed in the population as a whole.

Professor Ascherio mentioned that there is a lot of variability in the way vitamin D (in

the form of 25-hydroxy vitamin D) is measured. Most papers measure the total

25(OH)D level, but the results are affected by the laboratory method.

Delegates discussed whether there was an association between the F: M ratio and

25(OH)D levels, as there is a theory that women use more sunblock than men and

have lower levels of 25(OH)D, increasing their MS risk.

Professor Ascherio explained that there is no data supporting this theory in the US

and Canada as it has not been shown that men have higher levels of 25(OH)D than

women in these countries. One delegate commented that in Australia there is an

increasing F: M ratio further south, therefore there may be an association between

the F: M ratio and vitamin D.

Evidence for vitamin D and sunlight as risk factors of MS: data and

perspectives from Australia

Professor Robyn Lucas, Australian National University

Professor Lucas described the strong latitude gradient in MS in Australia. In 1981 a

study showed a 7 fold increase in MS prevalence from Queensland to Tasmania

(McLeod et al., 1994). This latitudinal variation in MS remained the same in 2006

(Taylor et al., 2010). In contrast, studies conducted in the USA suggest that the

latitudinal gradient in the USA may be reducing.

Professor Lucas described a multicentre incident case-control study, the

‘Ausimmune Study’, which found higher levels of sun exposure and higher levels of

serum vitamin D status were independently associated with reduced risk of first

demyelinating events (FDEs) (Lucas et al., 2011).

Multi-ethnic studies carried out in the USA show that people with African

backgrounds do not have a lower risk of MS. A recent incident case-control study

shows that higher 25(OH)D has a protective effect in people with Caucasian

background, but not people with Hispanic or African backgrounds. In particular the

findings do not follow a skin tone gradient consistent with lower levels of 25(OH)D,

i.e. skin tone is increasingly dark from Caucasian to Hispanic to African, and

25(OH)D levels would be expected to decrease according to this gradient. However

risk does not increase according to this same gradient, suggesting a more complex

relationship between 25(OH)D and MS risk.

Professor Lucas highlighted the fact that there are many UV-induced molecules,

some of which also cause immune suppression. Over 95% of UV we are exposed to

is UV-A, and we have a small amount of UV-B (which generates vitamin D).

Professor Lucas noted it was interesting that most immune suppression is UV-A

induced, and is therefore not a vitamin D effect.

Professor Lucas discussed other pathways which may play a role in the effects of

UVR on immune and other biological processes. These include DNA damage,

increased secretion of nitric oxide, PGE2, and -melanocyte stimulating hormone (-

MSH) and isomerisation of trans-urocanic acid to the cis form (cis-UCA). Each of

these factors has been shown to have effects on immune function.

Professor Lucas described the on-going PrevANZ trial in Australia funded by MS

Research Australia. The randomised double blind placebo-controlled trial is

investigating vitamin D supplementation as a mechanism to prevent progression

from clinically isolated syndrome (CIS) to MS. Individuals are randomised to receive

three different doses of vitamin D3 (1000, 5000, 10,000 IU/ day) or placebo for 48

weeks. The investigators then measure sun exposure, skin pigmentation, calcium

intake (and serum calcium). The investigators have found a challenge in recruiting

patients to the trial, with a relatively small population in Australia.

The PhoCIS trial is looking at UV-B phototherapy to prevent progression from CIS to

MS. Participants are vitamin D sufficient and given phototherapy 3 times a week for

8 weeks. The investigators then measure vitamin D status, skin pigmentation,

calcium intake and immune markers.

Delegates mentioned that the NIHR have collaborated with the National Health and

Medical Research Council in Australia and opportunities for collaboration in the

future should be explored.

Vitamin D deficiency as a risk factor for Type 1 Diabetes

Professor John Todd, Cambridge University

Professor Todd explained that there is a long history of association between type 1

diabetes and vitamin D. A study by Cooper et al., (2011) showed inherited variation

in vitamin D genes are associated with predisposition to type 1 diabetes. Studies

have shown the incidence of childhood type 1 diabetes is seasonal (more commonly

diagnosed in January and February than the summer months) (Imkampe and

Gulliford, 2011). There is also evidence that certain cord blood islet autoantibodies

have a seasonal association with the type 1 diabetes high-risk genotype (Lynch et

al., 2008). And, as is the case for multiple sclerosis, there is a strong north-south

gradient of disease incidence, with northern European countries having the highest.

Type 1 diabetes is an autoimmune attack against insulin producing cells and its

precursors during the neonatal and perinatal period. Median age of diagnosis is 11

years old.

A Finnish group have identified an increase in serum 25(OH)D concentrations

preceded a plateau in type 1 diabetes incidence in Finnish children.

The group discussed the fact that the peak appearance of autoantibodies to insulin is

at 9 months of age. Therefore it is important to assess 25(OH)D levels in the

neonatal and perinatal periods, in order to identify their importance for the later

development of type 1 diabetes. It was discussed that pregnant women are given

vitamin D supplements during pregnancy.

The group discussed whether it could be useful for MS researchers to consider

conducting studies in unaffected siblings to try to identify early markers of the

condition. However, there would be challenges with carrying out this type of study in

people with MS because there are only 40-50 children diagnosed with MS in the UK

per year. Most individuals are diagnosed between the ages of 20-40 years.

Nevertheless, it would be of considerable value to study these children.

The group wondered whether autoimmune diseases should be studied in

combination to understand the common mechanisms of autoimmunity. For example,

some autoimmune diseases cluster and seem to share some common mechanisms.

This approach can be taken in parallel with the study of susceptibility genes that are

unique to a disease.

Smoking as a risk factor for MS

Professor Cris Constantinescu

Professor Constantinescu suggests that by looking at epidemiological evidence,

especially the role of viruses, role of protective factors and geographical distribution

we will be able to improve our understanding of MS and potentially develop new

treatments.

Epidemiological studies suggest tobacco smoking is a significant trigger in the

development of MS.

Tobacco smoking increases the risk of MS by 50% (Handel et al., 2011)

Presence of DRB1*15 and absence of A*02 and smoking is shown to

increase the risk of MS by 13.5 times (Hedstrom et al., 2011)

Snuff-takers have a decreased risk of developing MS compared with those

that have never used moist snuff (Hedstrom et al., 2013)

The risk of MS for ever-smokers was only significant among the cases with

high anti-EBNA titers (Simon et al., 2010)

Research suggests there is a synergistic environmental and genetic effect on the risk

of MS. Smoking increases the risk, whereas nicotine itself (as in unsmoked snuff)

may in fact be protective.

The first meta-analysis related to smoking and the causes of MS was conducted in

2007, which looked at a small number of studies and suggested the increased risk of

developing MS in smokers was 25% (Hawkes MSJ 2007). This was updated in 2011

with 10 studies and they concluded the risk increased to 50% (Handel et al 2011

PlosOne).

A cohort of over 1000 patients studied at University of Nottingham (mean age at the

start of smoking was 17.5 years old patients smoked for an average duration of 22.8

years, average smoking intensity was 18.7 cigarettes per day) was used to carry out

a case-control study to look at tobacco smoking and risk of MS. They found regular

smokers were 64% more likely to develop MS than non-smokers and ever-smoking

was associated with 44% increase in risk of MS.

They also used the cohort to look at tobacco smoking and risk of MS progression.

They found current smokers had 2.38 times higher risk of developing SP MS.

Finally, they also used the cohort to look at tobacco smoking and risk of premature

death. As expected the prevalence of concomitant comorbid diseases was

significantly higher in ever-smokers.

It was questioned whether there has been an intervention trial looking at smoking

cessation to provide further evidence.

Professor Constantinescu noted there are very few smoking cessation studies, none

of which was a prospective trial in MS, and most of the evidence has been

observational studies of people stopping smoking. He did highlight that qualitative

research shows MS patients are more motivated to stop smoking than the general

population, and thus designing a cessation intervention trial is feasible.

Session 2: Therapeutics – infections and vaccines

Chair: Professor Richard Reynolds, Imperial College London

EBV as a risk factor for MS: an overview of the evidence

Dr Bruno Gran

Dr Gran discussed the evidence for EBV as a major environmental risk factor for MS.

Studies have shown that anti-EBNA IgG titres directly correlate with the risk of

developing MS.

More than 90% of the adult population are EBV positive. Infectious mononucleosis

(IM) is a relatively infrequent, symptomatic consequence of late EBV infection (early

in life the infection is often asymptomatic). It is associated with an increased risk of

MS as well as EBV-related malignancies.

Furthermore, in the adult population MS only develops exceptionally in the absence

of EBV infection. There is an approximate 15x reduced risk of developing MS in

those without serological evidence of past EBV infection (Pakpoor et al., 2012).

A longitudinal study showed that EBV-seronegative individuals do not develop MS

until after seroconversion (Munger et al., 2015).

Studies have shown that genes associated with MS are highly expressed in B and T

cells. B cells are potent antigen-presenting cells, therefore immune mediated effects

have been proposed. Several mechanisms of action have been proposed for the

effect of EBV on B and T cells, including molecular mimicry (Lunemann et al., 2008)

and increased frequency and proliferation of T cells reactive to EBNA-1 peptide

(Lunemann et al., 2006).

Several mechanisms of action have been proposed for the role of EBV in the brain,

including a possible role for the virus in the formation of ectopic lymphoid follicles

(Serafini et al., 2007) and activation of the innate immune system through Toll-like

receptor 3 (TLR3) (Tzartos et al., 2012).

Dr Gran argued if we were to have a safe preventative vaccine to EBV, MS

incidence would decrease accordingly. Some encouraging results have been

published which have looked at the recombinant gp350 vaccine in healthy young

EBV-negative adults, with a decreased incidence of infectious mononucleosis (IM) in

those who received the vaccine (Sokal et al., 2007).

The group discussed the challenges of identifying people at high risk of developing

MS, which typically include first-degree relatives of patients. The Genes and

Environment in Multiple Sclerosis GEMS study is being carried out in the US over 20

years and aims to capture the transition from health to MS and test primary

prevention strategies. The next phase would be to leverage GEMS and expand the

study internationally to accelerate progress of discovery, facilitate the execution of

primary prevention studies, and provide critical information regarding the

generalizability of the interim GEMS results in the US (Xia et al., 2016).

Dr Gran was asked what the average age of seroconversion to EBV is. Dr Gran said

the age is usually below 10, but it varies in different parts of the world. For example

in Africa children are much younger, but in Scandinavia they are older (Chabay and

Preciado, 2013). In countries in which MS is more prevalent, preventative vaccines

could target children at a relatively older age. Based on robust epidemiological

observations, prevention of seroconversion, or in fact even just reduction of the

incidence of IM, would be expected to significantly lower the incidence of MS

(Thacker et al, 2006).

Understanding the role of Epstein-Barr virus (EBV) in MS

Professor Alan Rickinson, University of Birmingham

Professor Alan Rickinson presented on the topic ‘Understanding the role of EBV in

MS’. A comprehensive review on the immunology of EBV infection as it relates to

immune-mediated diseases and cancer was published by his group last year (Taylor

et al., Annu Rev Immunol. 2015;33:787-821).

EBV-host interactions and the possible role of Bacille Calmette Guerin vaccine

in MS prevention

Dr Marco Salvetti

Dr Salvetti explained that half a dozen published studies show mixed results about

whether some EBV strains carry more risk than others. Following a study using

EBNA2 variants in patients with MS and healthy donors HDs, Dr Salvetti concluded

that the potential for using variants to predict MS risk was fairly good.

There is a theory that if EBV contributes to MS pathogenesis it may do so by

interacting with disease predisposing genes. In order to test this, Dr Salvetti and his

team created ‘candidate interactomes’ (group of genes whose products are known to

physically interact with environmental factors that may be relevant for MS aetiology).

Aggregate analysis indicated three viruses interact with MS predisposing genes -

EBV, hepatitis B virus (HBV) and human immunodeficiency virus (HIV).

Having identified that EBV interacts with MS-predisposing genes, it was then queried

whether EBV influences the expression of MS associated genes. EBNA2 was used

as a candidate for these studies. They found EBNA2/ RBPJ binding occurs within

MS regions more than expected by chance. Excess enrichment was also seen for

systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), but not for

ulcerative colitis (UC) and obesity. EBNA2 overlaps with VDR genomic occupancy.

EBNA2-VDR joint occupancy sites occur in MS regions but not in SLE and AR

regions.

Dr Salvetti explained that RBPJ is a downstream effector in Notch signalling. A paper

showed that BCG upregulated Notch-1 activity. Therefore, this suggests BCG may

restore ‘normal’ Notch signalling.

Studies have shown that MRI activity (in new and enhancing lesions) is reduced

following BCG vaccination.

A multicentre, double-blind placebo-controlled trial was conducted to assess the

effects of BCG in patients with the first demyelinating event in the CNS. 100

participants with CIS were given a single dose of BCG or placebo. The following

procedures were then carried out - blood tests, electrocardiogram, X-ray chest and

Mantoux reaction at baseline. Clinical examination and MRI scans were also done at

months 6, 12, 24, 36 after BCG or placebo.

The group discussed whether a strategy like this could initially be employed as a

secondary prevention approach, and then transferred to primary prevention.

The group asked when they were looking at the alleles and MS risk, did they look at

disease course? Dr Salvetti explained this was not possible with the numbers they

had. BCG, as compared to placebo, was associated with significantly reduced

development of gadolinium-enhancing lesions in people with CIS for a 6-month

period before starting immunomodulating therapy (Class I evidence) (Ristori G et al.,

1999; Ristori G et al., 2014).

Dr Salvetti was asked whether all the people given BCG had not been given it

before.

The group confirmed that individuals are no longer given BCG at 13 years old.

However some babies are given the vaccine depending on the area in the UK.

It was agreed that it would be interesting to know what impact this change in

vaccination routine may have had on MS incidence in the UK.

Session 3: Challenges and opportunities in trial design

Chair: Professor Sue Pavitt, University of Leeds

Challenges and opportunities in trial design

Professor Sue Pavitt

Professor Pavitt described the UK NIHR research pathway that had relevance to this

area of research and highlighted the likelihood that budgets for research in the UK

are likely to be tight following the pending comprehensive spending review.

Therefore, we want a bold, innovative design that offers efficiency whilst being

achievable.

She outlined the different types and phases of clinical trials. She discussed the

difference between preventative and prophylaxis trials, as well as the fact that these

trials pose ethical and methodological challenges. These include ethical issues such

as weighing up individual risks/ cost/ inconvenience vs collective benefit, when there

is no immediate therapeutic compensation/gain.

The most important factor is to get the right research question. The following criteria

need to be fulfilled: the proposed trial has a strong rationale, is achievable, is within

remit of the funder, is hypothesis-driven and value for money.

With MS, it is important to address the following methodological considerations:

Primary or secondary prevention? (Primary prevention may be difficult)

Which population?

How early do we start? (Diabetes immune biology suggests

intervention at birth – 9 months for vitamin D supplementation)

Is CIS a suitable starting population for preventing MS?

Can we enrich target population - stratification factors for “high risk

identified” such as by targeting on any genes associated with

predisposition to autoimmune diseases/ MS /seasonality genes/EBV-

mono/geography?

Where do we start: Twins? Unaffected sibling cohort? Paediatric

studies?

Recruitment of participants

Retention of participants

Sample size calculation – is it achievable?

Data collection, e.g. number of measures

Specification of intervention

Delivery of intervention (feasibility, acceptability etc)

Value for money - Costs in comparison with the expected efficacy

Opportunity for funding collaborations were highlighted e.g. NIHR has an

arrangement with the Australian MRC for commissioning joint priority areas

for research. Opportunities for obtaining useful demographic data from UK GP

databases or USA Kaiser Permanente collaborations were noted.

We need to consider what underpinning work will be needed to strengthen a grant

application.

Challenges and considerations for prevention trials

Professor Gavin Giovannoni

Professor Gavin Giovannoni presented on the topic ‘Challenges and considerations

for prevention trials’.

Recommendations

The group came together to discuss next steps for prevention research and to

produce some recommendations for research funders interested in prevention of

MS.

Though we don’t know the specific causes of MS, it is generally accepted that living an active, healthy lifestyle may reduce the risk of developing MS in individuals at high risk. The group recommended that people with first and second degree relatives avoid smoking and ensure they are not deficient in vitamin D. The MS Society and other MS charities should review their messaging around smoking and lifestyle to ensure that these recommendations are clear.

Further work is needed to develop and refine ideas for prevention trials in MS. The group recommended that the MS Society explore setting up a working group looking at developing prevention trials in MS including identifying funding sources for such trials. The group recommended that any such working group should be multi-disciplinary.

There is some opportunity with several EBV vaccine trials being planned in the USA that MS be included within the scope of these trials. The group recommended that the MS Society follow up on the plans of these trials.

The group discussed the need to understand more of the fundamental biology involved in various risk factors associated with MS. The group specifically discussed the relationship between Infectious Mononucleosis and MS as well as emerging theories such as the influence of gut bacteria on the risk of

developing MS. The group recommended that more research into the fundamental biology of these factors is completed.

Acknowledgements

The meeting was developed in partnership with the Canadian MS Society, Italian MS

Society, MS Research Australia, MS International Federation and the National MS

Society. We are very grateful to Genzyme for providing a grant contributing to the

costs of the meeting.

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Appendix I

Draft statement from attendees at the meeting on lifestyle factors that could reduce

the risk of MS:

1. If you are smoker, stop smoking and try to minimize exposure to tobacco

smoke. This applies at all ages.

2. The most important step that you can take to reduce your risk of developing

MS is to make sure that you have adequate levels of vitamin D. Individuals

with low circulating levels of 25(OH)D have a markedly increased risk of MS.

Most people in the UK have 25(OH)D levels well below 100 nmol/L (40

ng/dL), which is the level associated with the lowest MS risk . We therefore

recommend that in the UK all individuals aged 13 and above take 3,000 IU of

oral vitamin D3 per day. This dose should be increased to 4,000 IU/day in

individuals 13 and older who are obese (body mass index > 30). These doses

do not have any known adverse effect in healthy individuals, and therefore do

not require monitoring of blood levels. An exception are persons affected by

rare diseases associated with hypercalcemia or who take high doses of

calcium supplements; these individuals should consult their physician to

make sure that there are no contraindications to vitamin D supplementation.

Data on vitamin D level in early childhood and MS risk are still insufficient to

support specific recommendations for MS prevention. Under the age of

13, vitamin D supplements should therefore be administered as needed to

prevent vitamin D deficiency or insufficiency according to current guidelines.

3. Obesity in children and adolescents is an important risk factor for MS. If you

are a parent, try to help your children to maintain a healthy diet and exercise

daily to prevent obesity.

By Sarah Nicholson, Acting Research Manager, The MS Society