Toward a Unified Definition of Progression Independent of Relapse Activity in Multiple Sclerosis

Progression independent of relapse activity (PIRA) is the main driver of disability accumulation in relapsing multiple sclerosis (MS). We tested various PIRA definitions against the risk of long-term disability. Patients with relapsing MS, first visit ≥January 1, 2000, ≥3 visits with Expanded Disability Status Scale (EDSS), and ≥5-year follow-up were extracted from the Italian MS and Related Disorders Register on September 29, 2023. Eighteen PIRA definitions were obtained combining fixed or roving baseline, 24-week, 48-week confirmed or sustained disability accrual, no relapses ≤90 days before/≤30 days after the event (90d), ≤180 days before/≤30 days after the event, or absence of relapses from baseline to confirmation score (ABS). Predictive performance against the reaching of EDSS = 6.0 was calculated. A total of 30,203 patients were included. After a follow-up of 11.3 ± 4.3 years, PIRA ranged from 38.8% to 74.1%. EDSS = 6.0 was detected in 4,401 (15%) patients. Sensitivity of PIRA definitions against EDSS = 6.0 was higher using the 90d criterion (66.7%-69.4%), while the ABS criterion increased specificity (55.3%-62.2%). The definition of PIRA combining roving baseline, no relapses 90 days before and 30 days after the event and 24-week confirmation achieved the best predictive value and feasibility, supporting its use in routine practice and research.