Using the Progression Independent of Relapse Activity Framework to Unveil the Pathobiological Foundations of Multiple Sclerosis

Abstract

Progression independent of relapse activity (PIRA), a recent concept to formalize disability accrual in multiple sclerosis (MS) independent of relapses, has gained popularity as a potential clinical trial outcome. We discuss its shortcomings and appraise the challenges of implementing it in clinical settings, experimental trials, and research. The current definition of PIRA assumes that acute inflammation, which can manifest as a relapse, and neurodegeneration, manifesting as progressive disability accrual, can be disentangled by introducing specific time windows between the onset of relapses and the observed increase in disability. The term PIRMA (progression independent of relapse and MRI activity) was recently introduced to indicate disability accrual in the absence of both clinical relapses and new brain and spinal cord MRI lesions. Assessing PIRMA in clinical practice is highly challenging because it necessitates frequent clinical assessments and brain and spinal cord MRI scans. PIRA is commonly assessed using Expanded Disability Status Scale, a scale heavily weighted toward motor disability, whereas a more granular assessment of disability deterioration, including cognitive decline, using composite measures or other tools, such as digital tools, would possess greater utility. Similarly, using PIRA as an outcome measure in randomized clinical trials is also challenging and requires methodological considerations. The underpinning pathobiology of disability accumulation, that is not associated with relapses, may encompass chronic active lesions (slowly expanding lesions and paramagnetic rim lesions), cortical lesions, brain and spinal cord atrophy, particularly in the gray matter, diffuse and focal microglial activation, persistent leptomeningeal enhancement, and white matter tract damage. We propose to use PIRA to understand the main determinant of disability accrual in observational, cohort studies, where regular MRI scans are not included, and introduce the term of "advanced-PIRMA" to investigate the contributions to disability accrual of the abovementioned processes, using conventional and advanced imaging. This is supported by the knowledge that MRI reflects the MS pathogenic mechanisms better than purely clinical descriptors. Any residual disability accrual, which remains unexplained after considering all these mechanisms with imaging, will highlight future research priorities to help complete our understanding of MS pathogenesis.

Figure 1. Annual Frequency of PIRA Events Reported by Previous Studies

This figure represents the percentage of people with MS who develop at least 1 PIRA event a year, as reported by previous studies. Each study is represented by an arrow, whose length indicates the median time of the study follow-up. The position of the start of the arrow along the x-axis represents the median/mean (as available) disease duration of the patients at study entry. The references are given in the eTable 1. MS = multiple sclerosis; NEDA = no evidence of disease activity; PIRA = progression independent of relapse activity.

Figure 2. Schematic Representation of PIRA

PIRA is the increase in disability of the event score (most commonly EDSS) compared with baseline score. Absence of relapses is required between 90 days before and 30 days after the event score and at the time of the confirmation score. EDSS = Expanded Disability Status Scale; PIRA = progression independent of relapse activity.

Figure 3. Examples of Slowly Expanding Lesions and a Paramagnetic Rim Lesion

Axial FLAIR images showing slowly expanding lesions in the periventricular regions developing between baseline (A and B) and 2-year follow-up (C and D). The red arrows indicate the direction of the lesion expansion. Note also the increase in hypointensity indicating progressive tissue destruction. Axial FLAIR image (F) and SWI (G) showing a paramagnetic rim lesion (yellow arrow). (E) Axial T1-weighted image showing an hypointense lesion in the corona radiata at baseline (H) (yellow arrow) and 2 years follow-up (I) (yellow arrow), with corresponding deformation map (L), which shows in red a concentric expansion of the lesion over time (called slowly expanding lesion) (positive Jacobian >0) and in blue a shrinkage (Jacobian ≤0). FLAIR = fluid-attenuated inversion recovery; SWI = susceptibility-weighted imaging.

Figure 4. Examples of Brain Atrophy, Slowly Expanding Lesions, Spinal Cord Segmentation, Cortical Lesions, and Leptomeningeal Enhancement

(A) Axial T1-weighted images acquired between 1995 (first image on the left) and 2005 (last image on the right) showing progressing development of brain atrophy (increase size of the ventricles and widening cortical sulci) and slowly expanding lesions (yellow arrows). (B) Sagittal T2-weighted image showing one of the steps required for computation of spinal cord longitudinal atrophy, which involves segmentation of the spinal cord (area in red) which is separated from the cerebro-spinal fluid. (C) Axial DIR image showing a couple of intracortical lesions (yellow arrows). (D) Axial and (E) coronal contrast-enhanced 3D T2-FLAIR images showing a high-signal linear hyperintensity (yellow arrow) in the right central sulcus, indicating leptomeningeal enhancement. DIR = double inversion recovery; FLAIR = fluid-attenuated inversion recovery.