PIRA Identified as the Most Common Form of Disability Accumulation in Multiple Sclerosis


Researchers proposed a harmonized definition of progression independent of relapse activity that may improve the comparability of results in current and future study cohorts, according to a newly published systematic review.

Ludwig Kappos, MD, professor of neurology, University of Basel

Ludwig Kappos, MD

Newly published in JAMA Neurology, a systematic review showed that progression independent of relapse activity (PIRA) is the most frequent manifestation of disability accumulation across the full spectrum of traditional multiple sclerosis (MS) phenotypes, including clinically isolated syndrome and early relapsing-remitting multiple sclerosis (RRMS). Thus, acknowledging the occurrence of PIRA may lead to a better understanding disease to develop more targeted interventions and that a harmonized definition could improve comparability of results in future studies.1

Among 48 analyzed studies, PIRA was reported to occur in roughly 5% of all patients with RRMS per annum, causing at least 50% of all disability accrual events in typical RRMS. Notably, the number of PIRA cases reported compared with relapse-associated worsening increased with age and longer disease duration. Despite lower absolute event numbers, the proportion of PIRA increased among patients with potent suppression of relapses by highly effective disease-modifying therapy. In the studies analyzed, the definition of PIRA was used in multiple different variations which authors noted rendered the comparability of studies.

“Observational and controlled clinical trials provide unequivocal evidence that PIRA is the most frequent manifestation of disability accumulation across the full spectrum of traditional MS phenotypes, including CIS and early RRMS, thus challenging the conceptual distinction between relapsing and progressive disease courses or stages,” senior author Ludwig Kappos, MD, professor of neurology, University of Basel, and colleagues wrote.1 “Systematic follow-up and advancing control of acute inflammatory disease activity through effective DMTs helped to uncover the phenomenon of PIRA and bring it to the attention of researchers and clinicians.”

In this systematic review, investigators summarized the current evidence about PIRA in terms of the terminologies used in its context and proposed a harmonized definition to be used in clinical practice and future clinical trials. Researchers gathered 119 studies using the search terms multiple sclerosis, PIRA, progression independent of relapse activity, silent progression, and progression unrelated to relapses. The databases used to collect the information of the studies were from PubMed, Embase, Cochrane, and Web of Science, published between January 1990 and December 2022.

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“We propose to use the term disability accrual to describe any observed increase of disability within context of PIRA. The definition of PIRA represents a trade-off of specificity and sensitivity. If a higher specificity for PIRA is desired in a study, we recommend that disability accrual events are only considered as PIRA events in the absence of relapses between baseline/reference score and confirmation score. To ensure reliable data, we recommend using data sets with regularly scheduled standardized clinical assessments with average intervals of 6 months and not exceeding 12 months,” Kappos et al noted.1

All told, investigators concluded that the proposed harmonized definition may balance sensitivity and specificity and improve the comparability of results in current and future cohorts and data sets. Despite the benefits of this harmonized definition, several limitations still exist, including that PIRA may frequently remain undetected because of the low granularity of our clinical measures. Also, the relationship between the different types of PIRA should be further assessed using conventional and advanced imaging techniques of the brain as well as the spinal cord to enhance the understanding of the relation of subclinical inflammation and clinical PIRA.

“For incorporating MRI data into the PIRA definition, new and/or enlarging T2 lesions and/or gadolinium-enhancing T1 lesions should be used as imaging signs of acute MRI activity, both on brain and spinal cord MRI. To be temporally associated with a clinical event, these signs must be detected in an MRI acquired within 90 days before or after the event. The terms PIRMA, pure PIRA, and nonactive PIRA can be used interchangeably, although the term PIRMA may be preferable as it most accurately describes the situation,” Kappos et al noted.1 “To be labeled as PIRMA, there should not be any signs of acute MRI activity on spinal and brain MRI within 90 days before the event date and a second spinal and brain MRI within 90 days after the confirmation date.”

Authors also noted that a concept of progression independent of any disease activity needs to be explored to precisely better identify worsening that may be exclusively related to a neurodegenerative component as well as considering the compensation and reorganization capacity of the central nervous system. In addition, the investigators recommended that the utility of diagnostic and treatment algorithms based on such multimodal classifications should be analyzed through combining the advantages of real-world evidence and randomized prospective trial design in clinical trials.

1. Müller J, Cagol A, Lorscheider J, et al. Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis: A Systematic Review. JAMA Neurol. 2023;10.1001/jamaneurol.2023.3331. doi:10.1001/jamaneurol.2023.3331
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