Development of early progression independent of relapse activity significantly impacts on disability accumulation in patients with multiple sclerosis

Background: Disability accumulation in multiple sclerosis (MS) is driven by relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). Early PIRA (EP), occurring within five years of disease onset, has been proposed as a critical marker of poor prognosis. However, risk factors for EP remain poorly defined. Objective: To identify clinical and demographic factors associated with EP and assess its impact on long-term disability accumulation. Methods: This retrospective cohort study included 143 relapsing-remitting MS patients with disability progression (EDSS 4, 6, or 8) primarily due to PIRA. Patients were categorized as EP (PIRA within five years of onset) or late PIRA (LP, after five years). Cox regression and Kaplan-Meier survival analyses assessed risk factors and disability progression. Results: EP was identified in 39/77 (51 %) of PIRA patients. EP patients were older at diagnosis (38.6 vs. 34 years, p = 0.01), predominantly female (p = 0.02), and more likely to have spinal cord onset symptoms (p < 0.01). EP patients reached EDSS 4, 6, and 8 significantly faster than LP patients (p < 0.01). In multivariate analysis, spinal cord onset was the strongest predictor of EP (HR=2.1, 95 %CI=1.05-4.44, p = 0.03). Conclusions: EP occurs in half of PIRA patients and is associated with spinal cord onset and older age at diagnosis. These findings highlight the need for early identification and aggressive treatment to mitigate long-term disability. Further research is required to refine predictive models and optimize therapeutic strategies for high-risk patients.