Associations of smoking, infections, early-life exposures, and concussion with progressive-onset versus relapse-onset...

Among environmental factors associated with multiple sclerosis (MS) susceptibility, few studies have examined different onset types. It remains unclear whether risk factors for primary progressive MS (PPMS) are comparable to those for relapse-onset MS (RMS). This study aimed to explore the association between selected environmental factors and PPMS risk, and compare their effect sizes with RMS.

We used a case-control design with participants from two datasets: the Primary-Progressive MS Study (2015-2021) and the Australian Multi-center Study of Environment and Immune Function (2003-2006). Questionnaires collected data on smoking, infectious and concussion history before MS onset, supplement intake before age 15, and breastfeeding history. Unconditional, conditional, and weighted multivariable logistic regression evaluated associations with PPMS and RMS onset risk.

A significant positive association was observed between tobacco smoking prior to onset (≥20 pack-years: odds ratio (OR)=1.75, 95% confidence interval (CI)=0.96-3.20, P for trend=0.03) and history of infectious mononucleosis before MS onset (OR=1.74, 95% CI=1.05-2.88) in PPMS. Having vitamin supplements before age 15 (OR=0.52, 95% CI=0.31-0.87) and being breastfed during infancy (>6 months vs. never: OR=0.52, 95% CI=0.27-0.98) were associated with reduced PPMS risk. For RMS, tobacco smoking prior to onset (ever smoker OR=1.62, 95% CI=1.15-2.30; ≥20 pack-years: OR=2.17, 95% CI=1.20-3.80, P for trend=0.007) and infectious mononucleosis (OR=1.76, 95% CI=1.19-2.61) were also significantly associated with increased risk, with no difference in effect sizes compared to PPMS. Other infections, supplement intake, and being breastfed were not associated with RMS risk. Marijuana smoking and concussion history were not associated with either PPMS or RMS.

PPMS shares some common risk factors with RMS, such as tobacco smoking and infectious mononucleosis, with similar effect sizes. This suggests PPMS and RMS may share underlying disease mechanisms. Further studies are needed to validate the role of other factors associated with PPMS onset.