Pre-diagnostic relapse burden predicts disability severity in multiple sclerosis: a dose-response relationship

Abstract

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease and a leading cause of neurological disability in young adults. Although inflammatory activity early in the disease has been linked to worse outcomes, the independent impact of relapse burden before diagnosis on long-term disability remains unclear. Objective: To evaluate whether relapse burden prior to diagnosis independently predicts disability severity in patients with multiple sclerosis. Methods: We performed a cross-sectional analysis of a single-center multiple sclerosis cohort. Pre-diagnostic inflammatory burden was defined as the number of relapses preceding diagnosis and analyzed both continuously and categorically (0-1, 2-3, ≥4). Disability was assessed using the Expanded Disability Status Scale (EDSS) and categorized into clinically relevant thresholds (0-2.5, 3-5.5, ≥6). Ordinal logistic regression models estimated adjusted odds ratios (OR) for higher disability categories controlling for sex, clinical phenotype, and lesion topography. Results: Among 365 patients with complete data, each additional relapse prior to diagnosis increased the odds of worse disability by 23%. (adjusted OR 1.23, 95% CI 1.09-1.38, p<0.001). This association remained significant after adjustment for lesion topography (OR 1.22, 95% CI 1.09-1.38, p<0.001). Dose-response analyses showed that patients with ≥4 relapses had markedly higher odds of disability compared with those with 0-1 relapse (OR 3.38, 95% CI 1.67-6.86, p<0.001). Lesion topography was not independently associated with disability severity. Conclusion: Pre-diagnostic relapse burden was independently associated with disability severity in MS and demonstrated a clear dose-response relationship. These findings suggest that cumulative inflammatory activity before diagnosis may play a key role in early disability accumulation and highlight the potential impact of earlier recognition and treatment.