Environmental and lifestyle factors in multiple sclerosis progression

Multiple sclerosis (MS) is characterized by marked heterogeneity in inflammatory activity, disability accumulation, and long-term clinical outcomes. Although disease-modifying therapies have substantially improved control of inflammatory disease activity, disability progression remains incompletely explained by treatment exposure and conventional clinical predictors. Environmental and lifestyle factors are increasingly recognized as potential modifiers of disease course after MS onset, but they are often studied in isolation. In this review, we examine evidence linking persistent viral infections, inhalational exposures, sun exposure and vitamin D, obesity, diet and the gut microbiota, physical activity and sleep characteristics to MS disease activity and progression. Across these exposures, several shared pathways emerge, including chronic innate immune activation, persistent adaptive immune stimulation and impaired immune regulation, metabolic and mitochondrial dysfunction, oxidative stress, and altered capacity for tissue repair and neuroimmune resilience. We also discuss evidence that environmental effects may depend on host genetic background, particularly human leukocyte antigen (HLA) class I and class II variation. Although causal evidence remains incomplete and many studies are limited by reverse causation, residual confounding, and exposure misclassification, integrating environmental, genetic, immune, and metabolic data may help explain heterogeneity in MS outcomes and identify opportunities for more personalized prevention and intervention after disease onset.