To determine whether progression independent of relapse (PIRA) and conventional MRI (cMRI) activities in multiple sclerosis (MS) can be detected in active relapsing-remitting MS (RRMS) cohorts across clinical trials of approved disease-modifying therapies (DMTs).

PIRA, with or without cMRI activity, characterizes progressive MS (PMS) but has also been reported in recent RRMS clinical trial cohorts and retrospective databases. These analyses are challenging and require reliable data. Whether PIRA occurred in older DMT cohorts, including pediatric populations, remains uncertain. Model-based predictions of DMT effects may help address this question.   

Two models were generated to analyze the detectability of Clinical Events (CE) and cMRI Events (ME). An Anatomical Model subdivided the CNS into brain and spinal cord, with clinical detection thresholds (brain > spinal cord) set higher than MRI thresholds. A Functional Model subdivided the CNS into eloquent areas (variable thresholds) and non-eloquent areas (clinical > MRI thresholds). The effects of DMTs on the relative reductions of CE and ME (RRCE,RRME) in the models were compared to the relative reductions of relapses and T2 lesions (RRRR,RRT2) in DMT trial cohorts (17 adult  1 pediatric) using Enhanced Mahalanobis distance analysis.

In all 17 adult cohorts, the RRRR/RRT2 pattern was more likely to match the Functional Model (lower clinical than MRI thresholds) than the Anatomical Model (p<0.01). In contrast, the pediatric cohort was more likely to match to the Anatomical Model (p<0.01). A lower detection threshold for clinical than for MRI events is indicative of clinical activity without MRI correlates, a feature of PIRA. 

PIRA was observed in adult RRMS DMT trial cohorts but not in a pediatric cohort, which represents the early stages of the disease. These findings suggest that PIRA is not intrinsic to MS but is acquired, possibly arising from disease-related CNS injuries. Reserve depletion was suggested to explain this process.