Progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) are primary mechanisms of irreversible disability accumulation in multiple sclerosis (MS). Various PIRA definitions have been proposed, limiting cross-study comparability. We aimed to determine a clinically applicable PIRA definition by analyzing 18 different models using real-world data.

Inconsistent PIRA definitions hamper comparative research and meta-analyses. Most existing studies rely on clinical trial data rather than real-world populations. Systematic comparison of detection methodologies is needed to establish evidence-based standardization.

We included 392 relapsing-remitting MS patients meeting 2017 McDonald criteria, examined within one year of disease onset, with ≥2 years follow-up. We developed an algorithm enriching longitudinal EDSS data at 90-day intervals. Eighteen PIRA detection models were systematically compared across three parameters: (1) confirmation time (6 months, 12 months, end-of-follow-up), (2) confirmation type (threshold-based vs. absolute), and (3) relapse-free criteria (90 days post-relapse, no relapses baseline-to-worsening, no relapses baseline-to-confirmation). Annualized PIRA rates (APR) were calculated as events per patient-year.

Among 392 patients (257 female, 135 male), median follow-up was 6.4 years (IQR: 7.0) and median age at disease onset was 26.4 years (IQR: 11.3). During up to 5 years of follow-up (1,592.5 patient-years), PIRA incidence ranged from 2.0% to 9.9% across definitions, while APR ranged from 0.0057 to 0.0270 events per patient-year. Relapse-free criteria showed the largest effect on PIRA detection (relative impact 72.3%), while confirmation time and type showed 50.6% and 4.0% impacts. For clinical practice, we identified a model using 12-month threshold-based confirmation with baseline-to-worsening relapse-free criteria as the most applicable. This model yielded 4.3% PIRA incidence, 7.7% RAW incidence, and APR of 0.0126.

We propose 12-month threshold-based confirmation with baseline-to-worsening relapse-free criteria as the most clinically applicable PIRA definition in early MS. This model can contribute to more consistent and comparable PIRA detection in clinical practice.