Relapse-associated versus relapse-independent progression determines disability trajectories in multiple sclerosis...

Area of Science:

• Neurology
• Immunology
• Clinical Research

Background:

• The two-stage disability progression model in multiple sclerosis (MS) suggests early inflammation impacts moderate disability (EDSS 3.0) timing, with later progression being relapse-independent.
• The persistence of this model under high-efficacy disease-modifying therapies (DMTs) remains uncertain.

Purpose of the Study:

• To determine if disability progression to sustained EDSS 3.0 via relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA) affects subsequent disability accumulation.
• To evaluate the long-term impact of DMTs on MS progression.

Main Methods:

• A prospective analysis of 269 relapsing-remitting MS patients followed from disease onset to sustained EDSS 3.0 (≥12 months) for a mean of 20.8 years.
• Disability progression to EDSS 3.0 was categorized as RAW or PIRA (PIRMA required absence of MRI activity).
• Kaplan-Meier survival and Cox regression analyses assessed progression to EDSS 4.0, 6.0, and secondary progressive MS (SPMS), adjusting for covariates and DMT exposure.

Main Results:

• 159 patients (59%) reached EDSS 3.0 via PIRA, and 110 (41%) via RAW.
• RAW patients reached EDSS 3.0 earlier (median 8.0 vs. 11.0 years) and at a younger age (41.1 vs. 46.7 years) than PIRA patients.
• Progression from EDSS 3.0 to 6.0 was comparable between groups, but SPMS conversion was higher in the PIRA group (64.7% vs. 35.5%). Older age and male sex predicted faster progression; initial DMT class did not significantly impact long-term outcomes.

Conclusions:

• The findings support a persistent two-stage MS progression model in contemporary treated patients, where RAW accelerates early disability, and post-EDSS 3.0 progression converges.
• Preventing relapse-associated disability and identifying silent PIRA are crucial for preserving long-term neurological function in MS patients.