How patients with multiple sclerosis acquire disability.

Area of Science:

• Neurology
• Clinical Research
• Epidemiology

Background:

• Multiple sclerosis (MS) disability accrues via relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA).
• Understanding the interplay between RAW, PIRA, and disease-modifying therapies (DMTs) is crucial for MS management.

Purpose of the Study:

• To quantify the relative contributions of RAW and PIRA to disability worsening in MS.
• To determine the onset of PIRA and its role across MS phenotypes.
• To assess the impact of DMTs on delaying disability accumulation.

Main Methods:

• Analysis of the Novartis-Oxford MS (NO.MS) data pool (>27,000 patients, ~200,000 EDSS transitions).
• Utilized Andersen-Gill models to assess relapse impact on disability.
• Employed time-continuous Markov models to evaluate time to disability milestones with/without DMTs.

Main Results:

• PIRA begins early, affects all MS phenotypes, and becomes the primary driver of disability progression.
• Relapses significantly increase the hazard of disability worsening (31-48% increase post-relapse year).
• DMTs delay key disability milestones (e.g., EDSS 4, EDSS 6) by approximately 3-3.5 years.

Conclusions:

• PIRA is a critical component of MS disability, evident from early disease stages.
• Relapses contribute significantly to disability, particularly early in the disease course.
• DMTs offer substantial benefits by delaying disability accrual, with greater impact when used early.