Sex differences in relapse-independent and relapse-associated disability progression in relapsing-remitting multiple sclerosis: a real-world inverse-probability weighted study

Matteo Foschi; Damiano Marastoni; Ivan Panzera; Luca Mancinelli; Cristiana Ganino; Gianmarco Abbadessa; Lucio D'Anna; Francesca Gabriele; Simona Sacco; Elisabetta Signoriello; Alessandra Lugaresi; Elena Tsantes; Maria Grazia Piscaglia; Andrea Surcinelli

doi:10.1177/17562864251376807

Sex differences in relapse-independent and relapse-associated disability progression in relapsing-remitting multiple sclerosis: a real-world inverse-probability weighted study

Ther Adv Neurol Disord. 2025 Sep 23:18:17562864251376807. doi: 10.1177/17562864251376807. eCollection 2025.

Authors

Affiliations

¹ Department of Neuroscience, Multiple Sclerosis Center-Neurology Unit, S. Maria delle Croci Hospital, AUSL Romagna, Viale Vincenzo Randi 5, Ravenna 48121, Italy.
² Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
³ Neurology B, Department of Neurosciences, University of Verona, Verona, Italy.
⁴ Department of Neuroscience, Multiple Sclerosis Center-Neurology Unit, S. Maria delle Croci Hospital, AUSL Romagna, Ravenna, Italy.
⁵ Department of Neuroscience, Multiple Sclerosis Center-Neurology Unit, Maurizio Bufalini Hospital, AUSL Romagna, Cesena, Italy.
⁶ Department of Neuroscience, Multiple Sclerosis Center-Neurology Unit, Infermi Hospital, AUSL Romagna, Rimini, Italy.
⁷ Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy.
⁸ Department of Brain Sciences, Imperial College London, London, UK.
⁹ Second Division of Neurology, University of Campania "Luigi Vanvitelli," Naples, Italy.
¹⁰ Department of Biomedical and Neuromotor Science, University of Bologna, Bologna, Italy.
¹¹ IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
¹² Neurology Unit, Department of General and Specialized Medicine, Parma University Hospital, Parma, Italy.

Abstract

Background: Sex differences in multiple sclerosis (MS) progression are poorly characterized, especially for disability worsening independent of relapses.

Objectives: To assess sex-specific risks of progression independent of relapse activity (PIRA), relapse and magnetic resonance imaging (MRI) activity (PIRMA), and relapse-associated worsening (RAW) in a real-world MS cohort, quantify each event's contribution to disability accumulation, and explore variation across clinical subgroups.

Design: Inverse probability-weighted analysis of adults with relapsing-remitting MS ambispectively enrolled in a local registry who had their first recorded neurological evaluation within 12 months of MS onset.

Methods: We used weighted conditional proportional hazard models for recurrent events, adjusted for visit/MRI frequency, to compare risks between sexes. We also tested the homogeneity of sex effects across prespecified subgroups: age at MS onset, symptom location at onset, presence of ⩾10 T2-hyperintense brain lesions, ⩾1 spinal T2 lesion, ⩾1 Gadolinium-enhancing brain lesion at baseline, initial MS treatment type, and percentage of follow-up time on disease-modifying therapy (DMT).

Results: We included 492 people with MS (median age 44.0 years, interquartile range (IQR) 35.0-53.6; 68.9% women), followed for a median of 5.1 years (IQR 3.1-7.2). In the weighted cohort, women had higher hazards of PIRA (hazard ratio (HR) 2.44, 95% confidence interval (CI) 1.56-3.70; p < 0.001) and PIRMA (HR 2.13, 95% CI 1.25-3.70; p < 0.001), mainly postmenopausal (56.6% and 52.4%). RAW risk was similar (HR 1.07, 95% CI 0.54-2.11; p = 0.843), despite higher relapse rates in women (0.13 ± 0.18 vs 0.06 ± 0.16; p < 0.001). Men had greater Expanded Disability Status Scale worsening per PIRA (+0.29 ± 0.71 vs +0.16 ± 0.53; p = 0.023) and PIRMA (+0.25 ± 0.71 vs +0.09 ± 0.38; p = 0.001). Age ⩾50 at onset increased PIRA/PIRMA risk without sex interaction. Significant sex interaction was seen for onset symptom location (p < 0.001 for both outcomes) and initial DMT (p = 0.013 for PIRA; p = 0.022 for PIRMA).

Conclusion: Women, especially postmenopausal, had higher PIRA/PIRMA risk, but disability worsening per event was greater in men, associations varied by onset phenotype and initial DMT strategy.

Keywords: disability; multiple sclerosis; progression independent of relapse activity; progression independent of relapse and MRI activity; relapse-associated worsening; sex.