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Toward a Unified Definition of Progression Independent of Relapse Activity in Multiple Sclerosis
Emilio Portaccio1, Matteo Betti1, Ermelinda De Meo1
1Department of NEUROFARBA, University of Florence, Italy.
Objectives:
Progression independent of relapse activity (PIRA) is the main driver of disability accumulation in relapsing multiple sclerosis (MS). We tested various PIRA definitions against the risk of long-term disability.
Methods:
Patients with relapsing MS, first visit ≥January 1, 2000, ≥3 visits with Expanded Disability Status Scale (EDSS), and ≥5-year follow-up were extracted from the Italian MS and Related Disorders Register on September 29, 2023. Eighteen PIRA definitions were obtained combining fixed or roving baseline, 24-week, 48-week confirmed or sustained disability accrual, no relapses ≤90 days before/≤30 days after the event (90d), ≤180 days before/≤30 days after the event, or absence of relapses from baseline to confirmation score (ABS). Predictive performance against the reaching of EDSS = 6.0 was calculated.
Results:
A total of 30,203 patients were included. After a follow-up of 11.3 ± 4.3 years, PIRA ranged from 38.8% to 74.1%. EDSS = 6.0 was detected in 4,401 (15%) patients. Sensitivity of PIRA definitions against EDSS = 6.0 was higher using the 90d criterion (66.7%-69.4%), while the ABS criterion increased specificity (55.3%-62.2%).
Discussion:
The definition of PIRA combining roving baseline, no relapses 90 days before and 30 days after the event and 24-week confirmation achieved the best predictive value and feasibility, supporting its use in routine practice and research.
Insights
Progression Independent of Relapse Activity (PIRA) significantly impacts disability in relapsing multiple sclerosis (MS). A definition combining roving baseline, specific relapse exclusion, and 24-week confirmation best predicts long-term disability.
Area of Science:
- Neurology
- Clinical Research
- Multiple Sclerosis Therapeutics
Background:
- Progression Independent of Relapse Activity (PIRA) is a key factor in disability accumulation for patients with relapsing multiple sclerosis (MS).
- Accurate identification and definition of PIRA are crucial for predicting long-term disability outcomes in MS.
- Existing definitions of PIRA vary, necessitating an evaluation of their predictive performance.
Purpose of the Study:
- To evaluate eighteen distinct definitions of PIRA based on different criteria for disability confirmation and relapse exclusion.
- To determine which PIRA definition most accurately predicts the risk of reaching a significant disability level (EDSS = 6.0).
- To identify a feasible and predictive PIRA definition for use in clinical practice and research.
Main Methods:
- Retrospective analysis of 30,203 patients with relapsing MS from the Italian MS and Related Disorders Register.
- Inclusion criteria: first visit on or after January 1, 2000, at least three visits with Expanded Disability Status Scale (EDSS) assessments, and a minimum 5-year follow-up.
- Eighteen PIRA definitions were tested, varying baseline criteria, confirmation windows (24 or 48 weeks), relapse exclusion periods (90 or 180 days), and absence of relapses (ABS).
Main Results:
- Over an 11.3-year follow-up, PIRA prevalence ranged from 38.8% to 74.1% across definitions.
- 15% of patients reached an EDSS score of 6.0.
- The 90-day relapse exclusion criterion (90d) yielded higher sensitivity (66.7%-69.4%), while the absence of relapses (ABS) criterion improved specificity (55.3%-62.2%).
Conclusions:
- A PIRA definition incorporating a roving baseline, exclusion of relapses within 90 days before and 30 days after the event, and 24-week confirmation demonstrated the best predictive value.
- This optimized PIRA definition offers high feasibility and predictive accuracy for long-term disability in relapsing MS.
- The findings support the adoption of this refined PIRA definition in routine clinical monitoring and scientific investigations of MS progression.
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