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Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in
Noemi Montobbio1, Cinzia Cordioli2, Alessio Signori1
1Department of Health Sciences, University of Genoa, Genoa, Italy.
Objective:
The introduction of disease-modifying therapies for multiple sclerosis (MS) has led to a deceleration of disease course over the years. Although decreased relapse rate constitutes a factor, the role of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) in MS course deceleration is still unclear.
Methods:
We retrospectively examined long-term Expanded Disability Status Scale (EDSS) progression in patients referred to the MS Center of Montichiari (Italy) and diagnosed with relapsing-remitting MS from 1980 to 2022. To isolate PIRA, we deducted all EDSS changes associated with relapses from overall EDSS change. We compared the relative contribution of PIRA and RAW to EDSS progression in patients diagnosed in different periods using mixed-effects models.
Results:
A total of 1,405 patients were included in the study, of whom 231 were diagnosed in 1980-1996 (pre-treatment era), 577 in 1997-2008 (injectable disease-modifying therapy era), and 597 after 2008 (oral drugs, monoclonal antibodies, and anti-CD20 era). Across ages, both PIRA and RAW were reduced in patients diagnosed in more recent periods as compared with earlier periods. The average contribution of PIRA to overall EDSS progression was already predominant in patients diagnosed in 1980-1996 (78%) and in 1997-2008 (76%), but it was significantly increased (p = 0.0009) in patients diagnosed in later years (87%).
Interpretation:
The deceleration of MS course observed throughout the years is determined not only by fewer RAW events, but also by a reduction in PIRA. However, the shift toward a mostly relapse-independent progression highlights the importance of evaluating new therapies based on their effect on PIRA. ANN NEUROL 2024.
Insights
Disease-modifying therapies have slowed multiple sclerosis (MS) progression by reducing both relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). PIRA increasingly drives MS progression, emphasizing the need for therapies targeting it.
Area of Science:
- Neurology
- Immunology
Background:
- Disease-modifying therapies (DMTs) have decelerated multiple sclerosis (MS) progression.
- The specific contributions of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to this deceleration are not fully understood.
Purpose of the Study:
- To investigate the evolving roles of RAW and PIRA in MS course deceleration over time.
- To assess the impact of different eras of DMTs on the relative contributions of RAW and PIRA to disability progression.
Main Methods:
- Retrospective analysis of long-term Expanded Disability Status Scale (EDSS) progression in 1,405 relapsing-remitting MS patients diagnosed between 1980 and 2022.
- Isolation of PIRA by deducting relapse-associated EDSS changes from overall EDSS change.
- Comparison of PIRA and RAW contributions using mixed-effects models across diagnostic eras (pre-treatment, injectable DMTs, modern DMTs).
Main Results:
- Both PIRA and RAW showed reductions in patients diagnosed in more recent periods.
- PIRA was the predominant driver of EDSS progression across all eras, accounting for 78% (1980-1996) and 76% (1997-2008).
- PIRA's contribution significantly increased to 87% in patients diagnosed after 2008 (p=0.0009).
Conclusions:
- MS course deceleration is attributed to reductions in both RAW and PIRA.
- The increasing dominance of PIRA highlights the critical need to develop and evaluate new therapies targeting relapse-independent progression.
- Future MS treatment strategies must consider PIRA's significant and growing impact on long-term disability.
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