The difference in inflammatory disease activity between men and women faded after the age of 50 years, whereas the sex difference in the neurodegenerative component of MS became apparent after the age of 45 years and deepened with older age.
Findings from a nationwide study of patients with relapsing multiple sclerosis (MS) showed statistically significant differences between the sexes, as women demonstrated more inflammatory disease activity while men accrued more disability with time than women. The difference in inflammatory disease activity subsided following the age of 50 years, suggesting that sex hormones may play a role in the earlier stages.1
The trial included 3028 men and 6619 women on a disease-modifying therapy (DMT) from the Danish MS Registry (DMSR) who had clinical onset of relapsing MS or clinically isolated syndrome (CIS) since 1996. Patients were indexed by date of birth, date of onset, and date of entry, which was the date of the commencement of the first DMT. From this time, relapses and Expanded Disability Status Scale (EDSS) scores were recorded systematically.
Lead investigator Melinda Magyari, MD, PhD, clinical research professor, University of Copenhagen, and colleagues used weighted general linear models to analyze relapse rates and changes on EDSS. The end of follow-up was July 23, 2021, or at the final discontinuation of DMT, whichever came first. Patients were followed irrespective of temporary discontinuation of treatment. Men who stopped treatment before the end of follow-up had a mean of last recorded EDSS score of 3.62 as opposed to 2.76 in men who were still on treatment at the follow-up date.
Stabilized inverse probability treatment weights (sIPTWs) truncated by the 1/99 percentiles led to a female-male relapse ratio of 1.16 (95% CI, 1.10-1.22), with estimated annualized relapse rates (ARRs) of 0.32 (95% CI, 0.31-0.33) for women and 0.28 (95% CI, 0.27-0.29) for men, which was statistically significant (P <.001). ARRs in both men and women decreased with time since onset; however, after 50 years, the sex difference disappeared. In a subgroup of individuals with clinical onset at age 50 years old or later, the female-male relapse ratio was 1.08 (95% CI, 0.94-1.26; P = .26).
Throughout the observation period, men deteriorated by 0.065 EDSS points per year (95% CI, 0.054-0.075) compared with women, who showed worsening by 0.049 EDSS points per year (95% CI, 0.042-0.056). This led to a male-female ratio of 1.0216 (95% CI, 1.003-1.029), which was statistically significant (P = .0017). Similar to what was observed with ARRs, there were no differences in increases of EDSS scores between men and women over the age of 50 years. In this subgroup, the mean annualized increase in EDSS was 0.154 in women and 0.139 in men.
Men demonstrated a higher cumulative probability of reaching the confirmed and sustained end points of EDSS 3.0, EDSS 4.0, and EDSS 6.0 than women, regardless of whether onset or age 20 years was the starting point. The cumulative probability of not reaching EDSS 2.0 by year 20, or what the investigators defined as “benign MS,” was 22.5% (95% CI, 21.0-24.0) in women and 13.1% (95% CI, 10.7-15.4) in men.
The second, retrospective, and descriptive part of the study included all patients with MS in Denmark who were prevalent in 1949, and all patients with onset or diagnosis of MS from 1948 onward. Since 1948, the DMSR registered 31,175 records of patients with onset of MS and 12,624 patients had a diagnosis classified as "definite MS" after initial course was unknown. The initial course of the remaining patients with MS was relapsing in 87.9% and primary progressive (PPMS) in 12.1% of the cases.
For the whole cohort and period observed, the retrospective mean time from diagnosis back to onset was 5.03 (95% CI, 4.92-5.15) years in men and 5.10 (95% CI, 5.00-5.18) years in women; however, this diagnostic delay decreased with time. For patients diagnosed between 2010-2019, it was 4.00 (95% CI, 3.77-4.26) years in men and 4.19 (95% CI, 4.00-4.37) years in women. "The reason for why it is higher in this part of the study than in the follow-up study is that we also included patients with PPMS and those who had not received DMT for other reasons," Magyari et al noted.