Objective: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis, we modelled disability outcomes in 14,717 patients.

Methods: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity.

Results: 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43-0.82, p=0.0016), worsening of disability (0.56, 0.38-0.82, p=0.0026) and progress to EDSS step 6 (0.33, 0.19-0.59, p=0.00019). Among 1085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p=10^-9) and worsening of disability (0.81, 0.67-0.99, p=0.043).

Conclusions: Continued treatment with multiple sclerosis immunotherapies reduces disability accrual by 19-44% (95%CI 1-62%), the risk of need of a walking aid by 67% (95%CI 41-81%) and the frequency of relapses by 40-41% (95%CI 18-57%) over 15 years. This study provides the evidence that disease modifying therapies are effective in improving disability outcomes in relapsing-remitting multiple sclerosis over the long-term.

Classification of Evidence: This study provides class IV evidence that for patients with relapsing-remitting multiple sclerosis, long-term exposure to immunotherapy prevents neurological disability.