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Updated: Jan 16, 2026
A Method of Trigonometric Modelling of Seasonal Variation Demonstrated with Multiple Sclerosis Relapse Data
Published on: December 9, 2015
Sex differences in relapse-independent and relapse-associated disability progression in relapsing-remitting multiple
Matteo Foschi1,2, Damiano Marastoni3, Ivan Panzera4
1Department of Neuroscience, Multiple Sclerosis Center-Neurology Unit, S. Maria delle Croci Hospital, AUSL Romagna, Viale Vincenzo Randi 5, Ravenna 48121, Italy.
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.
Insights
Women with multiple sclerosis (MS) face higher risks of progression independent of relapse activity (PIRA) and magnetic resonance imaging (MRI) activity (PIRMA), particularly postmenopausal individuals. However, men experience greater disability worsening from these events, with variations based on initial symptoms and treatment.
Area of Science:
- Neurology
- Neuroimmunology
- Epidemiology
Background:
- Sex differences in multiple sclerosis (MS) progression are not well understood, especially concerning disability worsening unrelated to relapses.
- Characterizing these differences is crucial for personalized MS management and understanding disease trajectories.
Purpose of the Study:
- To evaluate sex-specific risks of progression independent of relapse activity (PIRA) and magnetic resonance imaging (MRI) activity (PIRMA) in a real-world MS cohort.
- To quantify the contribution of PIRA, PIRMA, and relapse-associated worsening (RAW) to disability accumulation.
- To explore how these sex-specific effects vary across different clinical subgroups.
Main Methods:
- An inverse probability-weighted analysis was conducted on adults with relapsing-remitting MS.
- Weighted conditional proportional hazard models for recurrent events were used to compare sex-specific risks.
- Analyses were adjusted for visit/MRI frequency and examined interactions across subgroups (age, symptom location, lesion load, treatment).
Main Results:
- Women exhibited significantly higher hazards for PIRA and PIRMA, with a pronounced effect in postmenopausal women.
- Relapse-associated worsening (RAW) risk was similar between sexes, despite women having higher relapse rates.
- Men experienced greater Expanded Disability Status Scale (EDSS) worsening per PIRA and PIRMA event.
- Sex interactions were significant for onset symptom location and initial disease-modifying therapy (DMT) choice.
Conclusions:
- Women, particularly postmenopausal, face elevated risks of PIRA and PIRMA in MS.
- Disability worsening per PIRA/PIRMA event is more substantial in men.
- The impact of sex on MS progression varies based on initial clinical presentation and treatment strategies.
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