Vitamin D, smoking and obesity: what do we know about their role in causing MS? 

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Although the etiological mechanisms of multiple sclerosis (MS) are not fully understood, we know that it is a multifactorial disease linked to the interaction between genetic susceptibility and environmental or lifestyle factors. In addition, interaction with HLA genes has been proven for certain factors such as smoking or obesity, suggesting pathogenic mechanisms that involve the adaptive immune system (1).

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Role of vitamin D

Scientists have looked at the role played by vitamin D (vitD) deficiency in MS etiopathogenesis in the 1970s, focusing on two elements: epidemiological on the one hand, with a higher MS prevalence in regions with weaker UV exposure, and immunological on the other, with the active form of vitD playing a role in lymphocyte activation and proliferation, the production of specific antibodies and immune response regulation (2). 

Thanks to records from Scandinavia (3), it has been possible to establish an inverse correlation between the risk of developing MS as an adult and the level of vitD at birth, if not in utero. Although these records (as well as others) suggested that vitD supplements could be beneficial for relapse rates and MRI radiological activity, these results were invalidated in other studies. The contradictory nature of this data underscores the need for additional studies with standardised methodologies, appropriate timing for intervention and recommendations for target vitD levels. Nevertheless, if oral supplementation has no harmful effect, it appears reasonable to recommend treating patients for vitD deficiency.

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Role of smoking

Active smoking that irritates the airways triggers a pro-inflammatory immune profile that favours the development of MS in those with risk genes. Accordingly, a Swedish study on patients with genetic risk factors (HLA-DRB1*15 positive and HLA-A*02 negative) found that the risk of developing MS was 4.9 in non-smokers compared with 13.5 in smokers. 

Active smoking therefore increases the risk of developing MS, and this risk is dose-dependent (duration of smoking and number of cigarettes smoked/daily intake) (1). 

The Swedish records also showed, amongst other things, that passive smoking increased the risk of developing MS by a factor of 1.3 in proportion to the duration of exposure (4). 

Once MS manifests, smoking continues to negatively influence disease prognosis: shorter period of time before a second relapse, higher number of relapses, higher number of brain lesions on MRI and earlier progression (around 10 years earlier) to secondary progressive MS (1). 

Lastly, smoking increases the risk of developing neutralising antibodies to certain immunomodulating drugs (such as interferon and natalizumab), which may affect their effectiveness (1). 

The effect of smoking cessation is less well documented; however, a few studies suggest a beneficial effect on gait dysfunction, independently of the effects on anxiety and depression. (5).

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Role of obesity

Many studies have shown that a high body mass index in adolescents or young adults is associated with an increase, and as much as a doubling, of the risk of developing MS (6). This association was stronger among adolescents. The causes of this interaction are still poorly understood, but a role may be played by genetics (modulated by adipokines) or gut microbiota. More recently, it has been suggested that obesity is an aggravating factor in terms of disability in MS progression, independent of other risk factors (7).

As a result, MS therapy nowadays must involve appropriate immunomodulators or immunosuppressants as well as lifestyle modifications.

Smoking cessation and obesity reduction are part of the arsenal of immunomodulatory interventions, which may also be termed ‘immunoprotective’, that should be implemented at the time of diagnosis.

More generally, smoking prevention (including passive smoking) and obesity prevention as early as possible could play a role in disease prevention, in particular in patients who present genetic risk factors or have a family history of MS.

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Professor Souraya El Sankari MD, PhD

Neurology

Cliniques Universitaires Saint-Luc 

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Références

1- Lars Alfredsson, Tomas Olsson. Lifestyle and environmental factors in Multiple Sclerosis. Cold Spring Harb Perspect Med . 2019 Apr;9(4):a028944. 

2- Martina B. Sintzel . Mark Rametta . Anthony T. Reder.  Vitamin D and Multiple Sclerosis: A Comprehensive Review. Neurol Ther (2018) 7:59–85.

3- Nete Munk Nielsen, Kassandra L Munger, Nils Koch-Henriksen, David M Hougaard et al. Neonatal vitamin D status and risk of multiple sclerosis: a population-based case-control study. Neurology. 2017 Jan 3;88(1):44-51.

4-AK Hedstrom, M Baarnhielm, T Olsson, L Alfredsson. Exposure to environmental tobacco smoke is associated with increased risk for MS. Mult Scler. 2011;17(7):788–93.

5-Jeff Rodgers, Tim Friede, Frederick W Vonberg, Cris S Constantinescu et al. The impact of smoking cessation on multiple sclerosis disease progression. Brain. 2021 Oct 8;145(4):1368–1378. 

6-Rune A Aa Hoglund, Haakon E Meyer, Hein Stigum, Oivind Torkildsen et al. Association of Body Mass Index in adolescence and young adulthood and long term risk of multiple sclerosis: a population-based study. Neurology . 2021 Dec 7;97(23):e2253-e2261.

7- Isabel Lutfullin, Maria Eveslage, Stefan Bittner, Gisela Antony et al. Association of obesity with disease outcome in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2023 Jan;94(1):57-61.