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

Carmen Alcalá-Vicente1, Jordi Tortosa-Carreres2, Laura Cubas-Núñez3

  • 1Neuroimmunology Research Group, Health Research Institute La Fe, Avinguda de Fernando Abril Martorell 106, Quatre Carreres 46026 Valencia, Spain; Neurology Department, University Hospital of La Ribera, km 1, Corbera Road, 46600 Alzira, Valencia, Spain.

Multiple Sclerosis and Related Disorders
|June 4, 2026
PubMed
Abstract

Insights

Relapse-associated worsening (RAW) speeds early multiple sclerosis (MS) disability, but later progression is similar for RAW and progression independent of relapse activity (PIRA). Early intervention is key for long-term neurological function.

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.
Keywords:
Disability progressionDisease-modifying therapiesMultiple sclerosisProgression independent of relapse activityRelapse-associated worsening

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