Smoking, Comorbidities, and Low Sun Exposure Are Associated with Clinical and Radiological Outcomes in Patients with Multiple Sclerosis-A Four-Year Observational Cohort Study.

Background: While disease-modifying therapies reduce inflammatory activity in multiple sclerosis (MS), long-term disability progression remains insufficiently controlled. Increasing evidence points to modifiable environmental and lifestyle factors-such as smoking, sun exposure, comorbidities, and obesity-as contributors to neurodegeneration and progression independent of relapse activity. Objective: To evaluate the associations between smoking, comorbid conditions, sun exposure, and obesity on clinical and radiological progression in patients with relapsing-remitting MS (RRMS) over a 48-month observational period. Methods: We performed a retrospective secondary analysis of a previously described longitudinal cohort of 132 patients with RRMS who were monitored over four years with serial assessments of EDSS, magnetic resonance imaging (MRI) inflammatory activity as gadolinium-enhancing lesions (GELs), new or enlarged T2-weighted lesions, serum 25(OH)D levels, and linear brain atrophy metrics. Sun exposure, smoking status, obesity, and comorbidity burden were recorded at each time point. Results: Low sun exposure was associated with higher EDSS trajectories and lower serum 25(OH)D levels (p < 0.01). Smoking was associated with a higher probability of GELs (p < 0.05), while comorbidities were associated with relapse occurrence and GELs. Obesity was associated with vitamin D insufficiency but not clearly with clinical relapse activity, GELs, or EDSS trajectories. MRI-based indices confirmed increasing brain atrophy during follow-up, particularly in patients with multiple risk factors. Conclusions: Our findings suggest that selected modifiable lifestyle and clinical factors are associated with distinct clinical and radiological outcomes in RRMS. Integrating sun-safe outdoor activity, smoking cessation, comorbidity management, and weight control into MS care may support comprehensive risk management alongside pharmacological therapy.