Study reveals the various ways patients with multiple sclerosis acquire disability

A new study conducted by researchers from the Corrine Goldsmith Dickinson Center for Multiple Sclerosis at Icahn School of Medicine at Mount Sinai in collaboration with Novartis, the University of Oxford and key MS experts across the globe, has revealed detailed information on the various ways patients with multiple sclerosis (MS) acquire disability. Analyzing both the role of relapses on long-term outcomes and the role of worsening that occurs independent of relapse activity, the study, published February 1 in Brain, also shows the benefit of treatment on longer term outcomes.

Patients with MS acquire disability either through relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA). This study addresses the relative contribution of relapses to disability worsening over the course of the disease, how early progression begins, and the extent to which MS therapies delay disability accumulation.

Utilizing the Novartis-Oxford MS data pool (NO.MS), spanning all MS phenotypes (pediatric MS, relapsing remitting MS [RRMS], secondary progressive MS [SPMS], primary progressive MS [PPMS]), the study team evaluated clinical and MRI data from more than 27,000 patients who had been followed for up to 15 years. They analyzed three datasets: (A) A full analysis dataset containing all observational and randomized controlled clinical trials in which disability relapses were assessed; (B) All phase 3 clinical trials; and (C) All placebo-controlled phase 3 clinical trials. They determined the relative importance of RAW and PIRA, investigated the role of relapses on all-cause disability worsening, and observed the impact of the mechanism of worsening and disease modifying therapies on the time to reach milestone disability levels.

The research analysis revealed that PIRA started early in MS, occurred in all phenotypes, and became the principal driver of disability accumulation in the progressive phase of the disease. Relapses significantly increased the hazard of all-cause disability worsening events: Following a year in which relapses occurred (vs. a year without relapses), the hazard increased by 31–48%; all p < 0.001. Pre-existing disability and older age were the principal risk factors for incomplete relapse recovery. For placebo-treated patients with minimal disability (EDSS 1) it took 8.95 years until increased limitation in walking ability (EDSS 4) and 18.48 years to require walking assistance (EDSS 6). Treating patients with disease modifying therapies delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and by 3.09 years (2.60, 3.72), respectively. In RRMS, patients who worsened exclusively due to RAW events took a similar time to reach milestone EDSS values compared with those with PIRA events; the fastest transitions were observed in patients with PIRA and superimposed relapses.

Our data confirm relapses contribute to the accumulation of disability, primarily early in multiple sclerosis and that progression independent of relapse activity can start early in relapsing, remitting MS and becomes the dominant driver of disability accumulation as the disease evolves. Pre-existing disability and older age are the principal risk factors for further disability accumulation. Importantly, using disease modifying therapies delays disability accrual by years, with the potential to gain time being the hightest in the early stage of multiple sclerosis."

Fred Lublin,MD, lead author of the study and Saunders Family Professor of Neurology and Director of The Corinne Goldsmith Dickinson Center for Multiple Sclerosis at the Icahn School of Medicine at Mount Sinai