What a mess in defining MS

Disability accumulation what drives it? Relapse associated worsening (RAW) or progression independent of relapse activity (PIRA). It says here most of it is due to PIRA but PIRA typically covers all worsening about 30 days after a relapse…One can argue that a significant part of worsening has lesion formation as a root trigger and that the slow worsening has its origins in lesion formation which are clinical or subclinical relapses. So elements of PIRA are actually RAW. Now it doesn’t matter what you call it. It is what you do about it that matters. Natalizumab can inhibit PIRA and it’s actions are outside of the CNS, so it says something about PIRA. However, elements of the worsening have, I believe, distinct pathology from relapsing lesion formation. This needs different treatment approaches.

Bsteh G, Marti S, Hammer H, Krajnc N, Guger M, Di Pauli F, Kraus J, Enzinger C, Chan A, Berger T, Hegen H, Hoepner R. Dissecting definitions of disability accrual in relapsing multiple sclerosis-Have we reached standardization yet? Mult Scler. 2025 Dec 6:13524585251396283. 

Background: Distinguishing relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) has reshaped understanding of disability accumulation in relapsing multiple sclerosis (RMS). The influence of differing definitions of disability accrual on event rates and RAW/PIRA proportions remains uncertain.

Methods: This observational cohort study used Austrian MS Treatment Registry data (2010-2024). A custom algorithm evaluated 1440 definitional variants of disability accrual with varying confirmation duration, baseline modeling, and RAW/PIRA classification, including recently proposed “standardized” criteria.

Results: We included 3273 RMS patients (mean age 37.5 years; 67.8% female) with ⩾24 months follow-up, ⩾3 Expanded Disability Status Scale (EDSS) scores, and ⩾1 EDSS score per year, contributing 3525 follow-up periods. Depending on definition, disability accrual varied between 15.7% and 41.6% of follow-ups. PIRA accounted for 56.1%-86.3% of events across definitions, while up to 8.4% were ambiguously classified, mainly due to post-relapse re-baselining or relapses during the confirmation period. Even under “standardized” criteria, 144 definitional combinations remained, with event rates ranging from 19.1% to 21.7% and PIRA contribution varying widely from 59.8% to 85.8%.

Conclusion: PIRA predominantly drives disability accrual, yet definitional variation substantially influenced event rates and RAW/PIRA proportions. Transparent reporting and further optimization of definitions are critical for improving comparability, interpretation, and clinical relevance in MS research and care.