Data Suggest Causal Link Between Tobacco Smoking and Risk of Multiple Sclerosis

The overall attributable fraction of multiple sclerosis due was 13.1%, in comparison with just 0.6% of ex-smokers, indicating the beneficial effects of smoking cessation.

Ali Manouchehrinia, PhD

According to findings from a recently published case-control study, tobacco smoking, a modifiable environmental factor, is linked with the risk of multiple sclerosis (MS) and is most likely causal. Based on this concept, the study indicated that at least 13% of cases of MS could be prevented through the avoidance of tobacco smoking.1

Led by Ali Manouchehrinia, PhD, postdoctoral researcher, Karolinska Institutet, the study included 9419 individuals with MS participating in 2 large Swedish cohorts and 9419 controls matched for age, gender, and residential area at the time of disease diagnosis. “Smokers” were defined as those who had ever smoked cigarettes regularly before MS onset or the equivalent age in controls.

To determine the population attributable fraction (AF) of MS due to smoking, investigators used a method suggested by Dahlqwist et al.2 The method calculated confounder adjusted AF estimates for case-control study design. For each case of MS, the study authors identified one exact calendar year of birth and sex-matched control while adjusting all the models for the calendar year of birth in 5 groups. In addition to calculating overall and sex-stratified AF, a separate analysis calculated AF by stratifying human leucocyte antigen (HLA) and non-HLA genetic burden.

In total, 44.1% of persons with MS and 35.9% of controls had ever smoked prior to disease onset or index age. At the time of MS onset, 38.1% of cases and 29.2% of controls were still smoking (current smokers). The overall AF of MS because of smoking was 13.1% (95%, 10.7-15.4). Women, whom made up 72% of the population, had an AF of 10.6% (95% CI, 7.4-13.7), while men demonstrated an AF of 19.1% (95% CI, 13.1-25.1).

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The risk of MS in ever-smokers was increased by 41% (95% CI, 1.33-1.50) compared to never-smokers. Notably, the AF was less than 1% (AF, 0.6%; 95% CI, 0-2) in ex-smokers, indicating the beneficial effects of smoking cessation.

"Considering the prevalence of the disease, this represents a very large group of people in absolute numbers who would never develop MS," Manouchehrinia et al wrote. "We believe that, from a global perspective, these numbers may represent an underestimate. The study was based on a well-characterized sample of Swedish population. In Sweden, the prevalence of MS is high, and the prevalence of smoking is low. As the AF increases with the prevalence of smoking, we believe that the AF in a country with a high prevalence of smoking could be considerably higher."

The group investigators also noted that "exposure to cigarette smoke is an important modifiable environmental risk factor for MS development and its clinical course," adding that the available literature suggests a 50% higher risk of developing MS in ever-smokers compared to never-smokers.

The mean number of pack-years smoked was statistically significant between individuals with MS (4.2 [SD, 7.2]) and their controls (3.2 [SD, 6.7]; P <.001). Cases of MS smoked on average 5.7 (SD,7.5) cigarettes per day for the duration of 6.2 (SD, 9.1) years, whereas controls smoked an average of 4.4 (SD, 6.9) cigarettes for a duration of 4.9 (SD, 8.6) years. Among individuals who smoked above the median pack-years, the AF was 9.3% (95% CI, 7.1-11.5) compared to 7.1% (95% CI, 4.9-9.3) in those who smoked below the median smoking intensity.

The HLA and non-HLA genetic risk scores were available in 5916 controls and 6885 individuals with MS. In those having HLA and non-HLA risk scores above the median levels of controls, the AF was 11.4% (95% CI, 6.8-15.9) and 12% (95% CI, 7.7-16.3), respectively. These AFs increased to 17.6% (95% CI, 10.2-24.9) and 18.6% (95% CI, 5.5-31.6) for those with HLA and non-HLA risk scores below the median levels in controls.

"In conclusion, integrated efforts need to be aimed not only at smoking cessation but crucially also at smoking prevention. The former will make relapses and disability progression in MS in part preventable, while the latter will make a substantial proportion of MS a preventable disease," the study investigators concluded.

1. Manouchehrinia A, Huang J, Hillert J, et al. Smoking attributable risk in multiple sclerosis. Front Immunol. Published online March 3, 2022. doi:10.3389/fimmu.2022.840158
2. Dahlqwist E, Zetterqvist J, Pawitan Y, Sjölander A. Model-Based Estimation of the Attributable Fraction for Cross-Sectional, Case–Control and Cohort Studies Using the R Package AF. Eur J Epidemiol (2016) 316(31):575-582. doi: 10.1007/S10654-016-0137-7
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