Abstract
Background
Individual disease-modifying treatment (DMT) decisions might differ between female and male people with MS (pwMS).
Objective
To identify sex-related differences in DMT strategies over the past decades in a real-world setting.
Methods
In this cohort study, data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR), a nationwide prospectively collected registry mandatory for reimbursement, were retrospectively analyzed. Of 4840 pwMS, those with relapsing–remitting MS, aged at least 18 years, who started DMT and had at least two clinical visits, were identified. At baseline, demographics, Expanded Disability Status Scale (EDSS) score, annualized relapse rate (ARR) in the prior 12 months and MRI lesion load were assessed. At follow-up, ARR, EDSS scores, and DMT were determined.
Results
A total of 4224 pwMS were included into the study and had a median of 10 (IQR 5–18) clinical visits over an observation period of 3.5 (IQR 1.5–6.1) years. Multivariable Cox regression analysis revealed that the probability of DMT escalation due to relapse activity was lower in female than male pwMS (HR 4.1 vs. 8.3 per ARR). Probability of discontinuing moderate-effective DMT was higher in female pwMS when they were younger (HR 1.03 per year), and lower in male pwMS at higher age (HR 0.92). Similarly, female pwMS were more likely to stop highly effective DMT than male pwMS (HR 1.7). Among others, the most frequent reason for DMT discontinuation was family planning in female pwMS. All sex-related effects were independent of disease activity, such as MRI lesion load, baseline ARR or EDSS.
Conclusions
Real-world treatment decisions are influenced by sex-related aspects. Awareness of these associations should prevent unwarranted differences in MS care.
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Introduction
A female predominance in relapsing multiple sclerosis (RMS) is well known with a female: male ratio of 2.3–3.5:1 which even showed an increase in the last decades [1, 2]. To date, several differences in MS disease course depending on the biological sex were described, e.g., women are younger at disease onset [3], show a higher relapse activity [4], develop secondary progressive MS (SPMS) later during the disease course [5], and have slower disability progression [6]. Only a limited number of clinical trials performed sex-specific subgroup analysis regarding the efficacy of disease-modifying treatments (DMT), even though a recent meta-analysis found no clear sex-based difference of DMT response with regard to clinical outcomes [2, Fig. 4).
Time to mDMT discontinuation depending on patients’ sex and age. To visualize the interaction effect of sex and age on the probability of treatment discontinuation, we computed the estimated Cox regression survival probabilities for male (left panel) and female pwMS (right panel), each separately for mature (age set at 55 years) and young pwMS (age set at 25 years). In addition, DMT was set to “DMF”, pre-treatment “yes”, baseline MRI T2 lesion load “ > 9”, EDSS progression “no” and ARR on DMT “0”. All other parameters (disease duration, pre-ARR, baseline EDSS) were set to their median values. ARR, annualized relapse rate; DMF, dimethyl fumarate; DMT, disease-modifying treatment; EDSS, Expanded Disability Status Scale; mDMT, moderate-efficacy DMT
Reasons for stop** mDMT were family planning (n = 24; 33%), patient`s request (n = 19; 26%) disease stability (n = 8; 11%), and disease progression (n = 5; 7%). In 17 pwMS (26%), DMT was stopped due to AEs. Compared to the average female predominance of approximately 70%, family planning as reason for mDMT stop** was dominated by female pwMS (100%), while disease progression by male sex (80%) (Table e-8).
DMT de-escalation at similar frequencies in women and men with MS
Of 1836 pwMS receiving NTZ or FTY over a period of at least 12 months, 78 (4.2%) were deescalated to a mDMT. Patients receiving ALZ, CLB, or OCR were not included in the analysis due to lack of de-escalating patients (Fig. 1). Twenty-nine (37%) switched from FTY and 49 (63%) from NTZ (Table e-9). Distribution of demographic and clinical characteristics between female and male pwMS is given in Table e-10.
Most frequent reasons for de-escalation were JCV positivity (n = 38; 49%) and adverse events (n = 27; 36%) followed by pwMS’ request (n = 8; 11%), transition to SPMS (n = 4; 4%), and other reasons (n = 1; 1%).
Multivariable Cox regression analysis showed that pwMS with lack of EDSS progression (β = − 0.7, [− 1.2, − 0.2]) was more likely de-escalated (Table 3). No interaction effects with sex were statistically significant.
Women with MS more frequently stopped high-efficacy DMT
Of 1941 pwMS with hDMT (Fig. 1), 231 (12%) stopped DMT (Table e-11). Distribution of demographic and clinical characteristics between female and male pwMS is given in Table e-12.
Multivariable Cox regression revealed that EDSS progression (β = 0.6, [0.3, 0.9]) during DMT was associated with DMT stop. Higher relapse rate was associated with lower HR for DMT stop (β = − 1.0, [− 1.7, − 0.2]); however, this effect was reversed in a subgroup of pwMS who requested DMT stop due to various reasons including adverse events, family planning or specific patient request (Table 4). Overall, females had an increased HR of 1.7 to quit hDMT (β = 0.5, [0.2, 0.9]).
The most frequent reasons for stop** hDMT were JCV positivity (n = 32; 14%), adverse events (n = 31; 13%), progression (n = 31; 13%), pwMS’ request (n = 43; 19%), family planning (n = 74; 32%), neutralizing antibodies (n = 1; 0.4%), progressive multifocal leukoencephalopathy (n = 7; 3%), stability (n = 3; 1%), and other reasons (n = 9; 4%). Compared to the average female predominance of approximately 70%, family planning was the reason for hDMT stop** clearly dominated by a sex effect, as all of these individuals were female (Table e-13).
Discussion
Real-world data regarding sex-related differences in MS treatment strategies are scarce. The results of our study should create awareness of potential sex-related treatment differences and avoid unwarranted differences in MS care.
In our study, we observed that female pwMS had a longer time to DMT start independent of age, clinical disease activity (ARR, EDSS) and MRI lesion load. Female pwMS also had delayed treatment escalation despite relapses compared to male pwMS. An increase in ARR by 1 means an approximately 8 times higher probability to escalate DMT in men, but only 4 times higher probability in women. In addition, discontinuation of mDMT was more likely in females, especially when they were younger, and the probability to stop hDMT was higher in female compared to male pwMS.
Similar results were found in the Danish Multiple Sclerosis Registry [26]. Men were more likely to receive hDMT right from the start (odds ratio 1.53) and were more likely to be escalated to hDMT (odds ratio 2.03) than women. Sex differences in treatment discontinuation or de-escalation were not examined in this study. Supporting the results of our study, further work reported that women received hDMT less frequently than men (odds ratio 0.92) [27]. In addition, consistent with our results, this study showed that younger age, higher relapse rate, and higher EDSS scores were also associated with a higher likelihood of hDMT [27]. Furthermore, in 499 pwMS receiving interferon-beta as first DMT, interferon-beta discontinuation was more frequent in female pwMS than in male pwMS (HR 1.42) [28].These results were confirmed by another study, which showed that women were more likely to stop interferon-beta or glatiramer acetate initiated after MS diagnosis than men [29]. The limitation of these studies is that there are no data for hDMT discontinuation.
One reason for different treatment strategies and different weighting of disease activity is family planning. In our study, family planning was one of the most common reasons to discontinue a DMT. The AMSTR started in 2006 [10]. At that time and in subsequent years, there was insufficient evidence of fetal risk and use of DMT. Thus, all DMT had a contraindication in pregnancy and were discontinued before conception or in early pregnancy [30]. Due to increasing data from pregnancy registries, it is now possible to continue certain therapies depending on the activity of the disease and individual benefit–risk evaluation [9].
E.g., in the case of NTZ treatment, bearing a high risk of disease reactivation or even rebound activity, treatment interruption should be avoided to prevent women from further, potentially debilitating disease activity [31]. Whereas in pwMS treated with NTZ (depending on the activity of the disease), it is possible to continue the therapy with a different treatment interval, S1P receptor modulators (where rebound or a high risk of disease reactivation is also described [32]) must be discontinued due to their potential teratogenic effect [33]. Few data are available regarding treatment with CD20 antibodies and pregnancy. Although continuous administration of CD20 antibodies is necessary to suppress disease activity, no excessive disease activity after discontinuation has been observed so far [34]. In contrast to hDMT, discontinuation of mDMT in women with a stable course of disease without clinical or radiological disease activity is considered relatively safe [35].
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HH has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Sanofi-Genzyme, Siemens, Teva, and received honoraria for acting as consultant for Biogen, Bristol Myers Squibb, Novartis, Roche, Sanofi-Genzyme and Teva. He is associate editor of Frontiers in Neurology. KB has participated in meetings sponsored by, received speaking honoraria or travel funding from Roche, Biogen, Sanofi and Teva. FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene-BMS, Genzyme-Sanofi, Horizon, Merck, Novartis Pharma, Roche, and Teva. His institution has received research grants from Biogen and Genzyme Sanofi. He is section editor of the MSARD Journal (Multiple Sclerosis and Related Disorders) and review editor of Frontiers Neurology. TB has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Biogen, Bionorica, BMS/Celgene, Eisai, Horizon, Jazz Pharmaceuticals, Janssen-Cilag, MedDay, Merck, Novartis, Roche, Sanofi Aventis/Genzyme, Sandoz, TG Therapeutics, TEVA and UCB. His institution has received financial support in the last 2 years by unrestricted research grants (Biogen, BMS/Celgene, Novartis, Sanofi Aventis/Genzyme, Roche, TEVA) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, BMS/Celgene, Merck, Novartis, Roche, Sanofi Aventis/Genzyme, TEVA. CE received funding for travel and speaker honoraria from Biogen, Bayer, Celgene, Merck, Novartis, Roche, Shire, Genzyme, and Teva Pharmaceutical Industries Ltd./sanofi-aventis; re- search support from Merck Serono, Biogen, and Teva Pharmaceutical Industries Ltd./sanofi-aventis; serving on scientific advisory boards for Bayer, Biogen, Celgene, Merck, Novartis, Roche and Teva Pharmaceutical Industries Ltd./sanofi-aventis. MG received support and honoraria for research, consultation, lectures and education from Alexion, Almirall, Bayer, Biogen, Bristol-Myers-Squibb, Celgene, Genzyme, Horizon, Janssen-Cilag, MedDay, Merck, Novartis, Roche, Sanofi Aventis and TEVA ratiopharm. JK received consulting and/or research funding and/ or educational support from Almirall, Bayer, Biogen, Celgene/ Bristol Myers Squibb, MedDay, Medtronic, Merck, Novartis, Roche, Sanofi- Aventis, Shire, and TEVA ratiopharm. JW has nothing to disclose. FDP has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Roche and Teva. Below is the link to the electronic supplementary material. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Hegen, H., Berek, K., Deisenhammer, F. et al. Sex impacts treatment decisions in multiple sclerosis.
J Neurol 271, 3256–3267 (2024). https://doi.org/10.1007/s00415-024-12270-y Received: Revised: Accepted: Published: Issue Date: DOI: https://doi.org/10.1007/s00415-024-12270-yAbbreviations
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