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

Multiple sclerosis (MS) exhibits a two-stage disability progression model in which early inflammatory activity influences the timing of moderate disability (EDSS 3.0), whereas subsequent progression is largely relapse-independent. It remains unclear whether this paradigm persists in the era of high-efficacy disease-modifying therapies (DMTs).

To assess whether attainment of sustained EDSS 3.0 via relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA) influences subsequent disability accumulation and to evaluate the impact of DMTs on long-term outcomes.

We conducted a prospective analysis of 269 relapsing-remitting MS patients followed from disease onset to sustained EDSS 3.0 (≥12 months) and followed for a mean 20.8 years from disease onset. Disability progression to EDSS 3.0 was categorized as RAW or PIRA. PIRMA additionally required absence of MRI inflammatory activity. Kaplan-Meier survival and Cox regression analyses were performed for progression to EDSS 4.0, 6.0, and secondary progressive MS (SPMS), adjusting for age, sex, time from disease onset to treatment initiation and DMT exposure.

Of 269 patients, 159 (59%) reached EDSS 3.0 via PIRA and 110 (41%) via RAW. RAW patients attained EDSS 3.0 earlier (median 8.0 vs. 11.0 years) and at younger age (41.1 vs. 46.7 years) than PIRA patients, but time of progression from EDSS 3.0 to 6.0 was comparable. Conversion to SPMS occurred more frequently in the PIRA group (64.7% vs. 35.5%). Multivariable models identified older age and male sex as independent predictors of faster progression. Initial DMT class was not significantly associated with long-term outcomes.

In contemporary treated MS, RAW accelerates early disability accumulation, whereas post-EDSS 3.0 progression converges between RAW and PIRA, supporting a persistent two-stage model of disease evolution. Early intervention to prevent relapse-associated disability and recognition of silent PIRA are critical to preserving long-term neurological function.