Defining Progression Independent of Relapsing Activity and Insights into Early Multiple Sclerosis Progression: Emilio Portaccio, MD

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"Progression is present even in the earliest phases of the disease, and in some cases, it can be detected in the preclinical phase."

Progression independent of relapse activity (PIRA) has emerged as a critical driver of disability accrual in relapsing multiple sclerosis (MS), yet the establishment of a reliable definition remains contentious. A recent cohort study using data from the Italian Multiple Sclerosis Register sought to address this gap by assessing the sensitivity, specificity, and predictive accuracy of various PIRA definitions against a hard disability outcome, the attainment of an Expanded Disability Status Scale (EDSS) score of 6. The findings revealed that PIRA definitions employing a roving baseline and a 24-week confirmation of disability progression, with no relapses in 90 days before or 30 days after the onset of confirmed disability accrual (CDA), demonstrated the highest predictive performance, offering a practical framework for clinical and research applications.

Overall, the study included 32,905 patients with MS who were followed for an average of 11.3 years, applying different definitions of PIRA based on fixed versus roving baselines, sustained versus 24-week CDA confirmations, and specific time intervals for relapse exclusion. The results highlighted that using a roving baseline increased the detection of CDA by 14-16% compared with a fixed baseline. Definitions incorporating a 24-week confirmation period showed strong predictive value (sensitivity 69%, negative predictive value 68%), underscoring their feasibility for clinical practice. In contrast, definitions requiring no relapses from baseline to CDA confirmation exhibited lower sensitivity. These insights emphasize the need for tailored definitions aligned with specific clinical or research objectives, improving the precision of disability progression assessments in MS.

At the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, September 18-20, in Copenhagen, Denmark, Emilio Portaccio, MD, professor of neurology at the University of Florence, presented these pivotal findings. In an interview with NeurologyLive^® at the Congress, Portaccio discussed the clinical implications of standardizing PIRA definitions, the challenges in balancing sensitivity and specificity for different objectives, and the broader impact of understanding early disease mechanisms like smoldering MS. He also emphasized the importance of these advancements in refining patient management strategies and shaping future research directions to enhance long-term outcomes in MS.

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REFERENCES
1. Portaccio E, Betti M, de meo e, et al. Towards an unified definition of progression independent of relapse activity in relapsing multiple sclerosis Towards an unified definition of progression independent of relapse activity in relapsing multiple sclerosis. Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark. Abstract 2078.