Therapeutic advances in neurological disorders · 2025
Sex differences in relapse-independent and relapse-associated disability progression in relapsing-remitting multiple sclerosis: a real-world inverse-probability weighted study.
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Foschi Matteo, Marastoni Damiano, Panzera Ivan, Mancinelli Luca, Ganino Cristiana, Abbadessa Gianmarco, D'Anna Lucio, Gabriele Francesca, Sacco Simona, Signoriello Elisabetta, Lugaresi Alessandra, Tsantes Elena, Piscaglia Maria Grazia, Surcinelli Andrea
Аннотация
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.
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.