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.