Key result
The contribution of progression independent of relapse activity to overall disability progression increased significantly in patients diagnosed after 2008 (87%) compared to earlier eras (76-78%, p=0.0009).
Why the study?
Does the era of diagnosis and available disease-modifying therapies affect the relative contribution of relapse-associated worsening versus progression independent of relapse activity to overall disability progression in multiple sclerosis?
Cohort (n=1,405)
No
Does the era of diagnosis and available disease-modifying therapies affect the relative contribution of relapse-associated worsening versus progression independent of relapse activity to overall disability progression in multiple sclerosis?
Absolute Event Rate: 87% vs 78%
p-value: p=0.0009
The deceleration of MS course over recent decades is driven by reductions in both relapse-associated worsening and progression independent of relapse activity, though the latter now accounts for a significantly larger proportion (87%) of overall disability progression.
PIRA now predominates MS disability accrual despite DMT-era gains; leaves open whether PIRA-targeted therapies will further decelerate progression in prospective studies.
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.
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Montobbio et al. (2024) conducted a cohort in Relapsing-remitting multiple sclerosis (n=1,405). Diagnosis in later years (after 2008) vs. Diagnosis in earlier years (1980-1996 and 1997-2008) was evaluated on Average contribution of progression independent of relapse activity (PIRA) to overall EDSS progression (p=0.0009). The contribution of progression independent of relapse activity to overall disability progression increased significantly in patients diagnosed after 2008 (87%) compared to earlier eras (76-78%, p=0.0009).
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