Baseline predictors of sustained fatigue onset in multiple sclerosis: A longitudinal survival analysis of the MS PATHS cohort.

Fatigue is a common and debilitating symptom of multiple sclerosis (MS). While some patients experience fatigue prior to or at the time of diagnosis, a proportion develop this symptom during the disease course. This study aimed to identify factors associated with the future development of sustained fatigue in patients who were fatigue-free at baseline. We analyzed longitudinal data from a large, real-world cohort of people with MS, drawn from the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) across 10 healthcare associations. Using Neuro-QoL-recommended T-score cut-points, participants' fatigue levels at baseline were categorized as "no fatigue" (T-score ≤ sample mean + 0.5 SD) or "fatigued" (T-score > sample mean + 0.5 SD). A multivariable time-to-event analysis was employed to determine predictors of 3-month sustained fatigue. Of the 6,327 fatigue-free participants included, 23.1 % developed sustained fatigue during an average (SD) of 2.5 (2.3) years of follow-up. Factors significantly associated with an increased risk of developing sustained fatigue included higher baseline physical disability (PDDS; HR = 1.38, 95 % CI: 1.15-1.67), depression (HR = 1.03, 95 % CI: 1.01-1.04), and anxiety (HR = 1.04, 95 % CI: 1.03-1.06). Conversely, better baseline cognitive function (HR = 0.96, 95 % CI: 0.95-0.97) was protective. Restricted Mean Survival Time (RMST) analysis showed that participants with a baseline PDDS ≤ 5 experienced an eight-month longer delay in the development of sustained fatigue (95 % CI: 5.0-11.1, P < 0.001) compared to those with a PDDS > 5. Similarly, participants without baseline depression had a 17.4-month longer delay (95 % CI: 15.6-19.1, P < 0.001) compared to those with depression. In conclusion, nearly a quarter of initially fatigue-free patients developed sustained fatigue during medium-term follow-up. Baseline physical disability, depression, anxiety, and cognitive function were significant predictors of this outcome. These findings may guide interventions aimed at reducing the burden of fatigue, a disabling symptom in MS.