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Observed Differences in PIRA Definition Call for More Standardized Agreement on Term
Key Takeaways
- Variability in PIRA incidence and persistence is influenced by definition parameters, highlighting the need for a standardized definition in MS research.
- The study analyzed 33,303 patients, revealing that baseline disability and confirmation period significantly affect PIRA detection.
A recent large cohort analysis of global MS registry data reported that the incidence and persistence of progression independent of relapse activity varied widely depending on how it was defined.
Jannis Müller, MD, MSc
(Credit: LinkedIn)
Newly published in JAMA Neurology, a retrospective cohort study using MSBase registry data that compared 360 definitions of progression independent of relapse activity (PIRA) in patients with relapsing-remitting multiple sclerosis (MS) reported substantial differences in PIRA incidence and persistence depending on definition parameters.The study suggests that a proposed standardized definition could improve consistency and comparability across future MS research.1
Overall, the analysis comprised 33,303 patients with clinically definite relapsing-remitting MS from 186 centers in 43 countries, drawn from a total pool of 87,239 patients in the MSBase registry between July 2004 and July 2023.2 Authors noted that patients included in the analysis had an average of 15.1 visits across 8.9 years, and 84.2% were diagnosed with relapsing-remitting MS.
Investigators tested PIRA incidence and persistence using combinations of criteria such as baseline disability, confirmation period, magnitude of worsening, and freedom from relapse at both worsening and confirmation time points. Across all definitions, researchers reported that PIRA incidence ranged from 0.141 to 0.658 events per decade, and persistence ranged from 0.753 to 0.919 over at least 5 years.
“In our assessment of different definitions of PIRA and its components, we have demonstrated that both identification and persistence of PIRA are dependent on the specific definition used. In particular, the method of defining disability baseline determines the incidence of identified PIRA events, while the duration of the confirmation period determines both incidence and persistence of PIRA,” lead author Jannis Müller, MD, MSc, neurologist and researcher at University of Basel, and colleagues wrote.1 “Comparatively less prominent variability in the incidence and persistence of identified PIRA events is attributed to the various definitions of freedom from relapses prior to initial disability worsening and its confirmation and the minimum disability threshold for confirmation of PIRA.”
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All told, participants included 24,152 women (72.5%) and 9151 men (27.5%), with a mean age of 36.4 years at their first visit and a median Expanded Disability Status Scale (EDSS) score of 2.0. Investigators noted that the definitions of PIRA varied by how baseline disability was treated (e.g., fixed or rebaselined after events), confirmation duration (6, 12, or 24 months), and relapse-free periods surrounding worsening and confirmation events.
Additional findings showed that both the baseline strategy and the length of the confirmation period significantly impacted PIRA detection. Among the tested definitions, 1 yielded a balanced estimate of both incidence and persistence. This definition meant that it required significant EDSS worsening from a baseline reset after each PIRA, relapse, or improvement; no relapse since the last EDSS assessment; and confirmation with EDSS scores that remained above the worsening threshold for 12 months, without relapse in 30 days prior.
Investigators acknowledged several limitations of the study, including the use of the EDSS, which may have overlooked nonmotor symptoms and introduced variability. The comparison framework may not have fully captured interactions among criteria, and treatment status was not considered, which could have influenced PIRA estimates. The definition also depended on standardized relapse identification and may have missed cases where relapse and progression overlapped. Additionally, imaging and biomarker data were not included, which might have improved the assessment of PIRA.
“Based on our analysis, we propose a PIRA definition that incorporates re-baselining after PIRA events, relapses, and EDSS score improvements, with disability worsening that occurs in absence of relapse since the previous EDSS score, that remains above the EDSS worsening threshold for at least 12 months, and where only confirmation EDSS scores recorded more than 30 days after preceding relapses are considered,” Müller et al noted.1 “This approach balances the sensitivity and specificity to disability worsening that is likely to persist for at least 5 years, with applicability across a broad spectrum of study designs.”
