OBJECTIVE: The objective of this study was to investigate the ability of patient-reported/administered outcomes to capture disability worsening and progression independent of relapse activity (PIRA) in multiple sclerosis (MS).

METHODS: We included patients from the longitudinal multicenter MS PATHS cohort with ≥3 assessments and >6 months follow-up. PIRA was defined on the patient-determined disease steps (PDDS) and self-administered tests assessing walking speed, manual dexterity, and processing speed, in the absence of self-reported relapses. We assessed (i) prevalence of PDDS/self-administered test-based disability worsening and PIRA definitions; (ii) their concurrent validity, through the association with worsening and PIRA definitions based on the expanded disability status scale (EDSS; Barcelona subcohort); and (iii) their clinical meaningfulness, through the correlation with brain magnetic resonance imaging (MRI) and quality-of-life (QoL) data trajectories.

RESULTS: We included 9,088 patients (73% female patients; age = 46.8 years; disease duration = 14.2 years). Over a 3-year follow-up, 4,066 (45%) patients worsened on ≥1 patient-reported/administered outcome, of which 2,357 (58%) developed PIRA. In the Barcelona subcohort (N = 279), 68 (24%) patients developed EDSS-based worsening, of which 30 (44%) developed EDSS-based PIRA; 99 of 279 (35%) worsened on ≥1 patient-reported/administered test, of which 78 of 99 (79%) had PIRA. Worsening (but not PIRA) on PDDS was associated with EDSS-based worsening (odds ratio = 3.03 [1.42; 6.43], p = 0.004). PDDS/self-administered-test-based worsening or PIRA strongly correlated with accelerated brain atrophy and T2 lesion volume increase compared to non-worseners (p < 0.05), and showed worse QoL (p < 0.05).

INTERPRETATION: Despite only partial agreement with EDSS-based definitions, PDDS/self-administered test-based worsening and PIRA definitions were clinically meaningful, by identifying patients with greater brain damage and poorer QoL, supporting their use in clinical practice. ANN NEUROL 2026.