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Observational Study
. 2025 Oct;12(10):2012-2019.
doi: 10.1002/acn3.70131. Epub 2025 Jul 6.

Early Intensive Versus Escalation Approach: Ten-Year Impact on Disability in Relapsing Multiple Sclerosis

Pietro Iaffaldano  1 , Giuseppe Lucisano  2 , Tommaso Guerra  1 , Francesca Caputo  1 , Marta Simone  3 , Massimiliano Copetti  4 , Damiano Paolicelli  1 , Emilio Portaccio  5 , Francesco Patti  6 , Paola Perini  7 , Vincenzo Brescia Morra  8 , Alessia Di Sapio  9 , Matilde Inglese  10   11 , Carlo Pozzilli  12 , Giacomo Lus  13 , Giuseppe Salemi  14 , Erica Curti  15 , Giovanna De Luca  16 , Paola Valentino  17 , Eleonora Cocco  18 , Paola Cavalla  19 , Carlo Avolio  20 , Alessandra Lugaresi  21   22 , Antonio Gallo  23 , Pietro Annovazzi  24 , Maria A Rocca  25   26   27 , Clara Grazia Chisari  6 , Massimo Filippi  25   26   27 , Maria Pia Amato  5   28 , Maria Trojano  1 ; Italian MS Register
Collaborators, Affiliations
Observational Study

Early Intensive Versus Escalation Approach: Ten-Year Impact on Disability in Relapsing Multiple Sclerosis

Pietro Iaffaldano et al. Ann Clin Transl Neurol. 2025 Oct.

Abstract

Objective: To evaluate the long-term impact of early intensive treatment (EIT) versus escalation (ESC) strategies using high-efficacy disease-modifying therapies (HE-DMTs) on disability progression in relapsing multiple sclerosis (RMS).

Methods: This observational study included 4878 RMS patients from the Italian Multiple Sclerosis Register. Eligible participants initiated their first disease-modifying therapy (DMT) within 3 years of disease onset and had ≥ 5 years of follow-up with at least three Expanded Disability Status Scale (EDSS) evaluations. Patients were categorized into the EIT group if they started with HE-DMTs and into the ESC group if HE-DMTs were initiated after ≥ 1 year of moderate-efficacy therapy. Propensity score matching was performed to balance baseline characteristics. Outcomes included disability trajectories assessed using linear mixed models for repeated measures and risks of confirmed disability accrual (CDA), progression independent of relapse activity (PIRA), and relapse-associated worsening (RAW) evaluated using Cox proportional hazards models.

Results: Post-matching analysis of 908 pairs revealed significantly slower disability progression in the EIT group compared to the ESC group. At 10 years, the delta-EDSS difference between groups was -0.63 (95% CI: -0.83 to -0.43; p < 0.0001). ESC was associated with higher risks of CDA (HR 1.36, 95% CI: 1.20-1.54; p < 0.0001), PIRA (HR 1.22, 95% CI: 1.05-1.40; p = 0.0074), and RAW (HR 1.55, 95% CI: 1.17-2.05; p = 0.0021).

Interpretation: EIT significantly reduces long-term disability progression in RMS compared to ESC. These findings underscore the potential of EIT to optimize long-term outcomes in RMS patients.

Keywords: PIRA; disability trajectories; multiple sclerosis.

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Conflict of interest statement

The authors declare no conflicts of interest with respect to the contents of the current study, but note that the patients in the study were treated with a number of disease‐modifying drugs and that the authors have received advisory board, membership, speakers honoraria, travel support, research grants, consulting fees, or clinical trial support from the manufacturers of those drugs, including Actelion, Allergan, Almirall, Alexion, Bayer Schering, Biogen, Celgene, Excemed, Genzyme, Forward Pharma, Horizon, Ipsen, Medday, Merck Serono, Mylan, Novartis, Sanofi, Roche, Teva, and their local affiliates.

Figures

FIGURE 1
FIGURE 1
Flowchart of patients' selection procedure.
FIGURE 2
FIGURE 2
Comparison between the disability trajectories of ESC and EIT groups built through the estimated EDSS scores by semesters of follow‐up.
FIGURE 3
FIGURE 3
Kaplan–Meier curves for the probabilities of reaching the outcomes CDA (A), PIRA (B), and RAW (C).
See this image and copyright information in PMC

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