
==== Front
Eur J Neurol
Eur J Neurol
10.1111/(ISSN)1468-1331
ENE
European Journal of Neurology
1351-5101
1468-1331
John Wiley and Sons Inc. Hoboken

38925580
10.1111/ene.16396
ENE16396
EJoN-24-0465.R1
Short Communication
Multiple Sclerosis
Sex‐ and age‐related shift of relapse phenotypes in a cohort of relapsing multiple sclerosis patients: Post hoc analysis from the OPERA phase 3 trials
Sex‐ and age‐related shift of relapse phenotypes in a cohort of relapsing multiple sclerosis patients: Post hoc analysis from the OPERA phase 3 trials
Leon Betancourt et al.
Leon Betancourt A. 1
Hoepner Robert https://orcid.org/0000-0002-0115-7021
1
Hammer Helly 1
Chan Andrew 1
Salmen Anke https://orcid.org/0000-0002-4751-299X
1 2 anke.salmen@rub.de

1 Department of Neurology, Inselspital, Bern University Hospital University of Bern Bern Switzerland
2 Department of Neurology, St. Josef Hospital Ruhr University Bochum Bochum Germany
* Correspondence
Anke Salmen, Department of Neurology, St. Josef Hospital Bochum, Ruhr University Bochum, Gudrunstrasse 56, Bochum 44791, Germany.
Email: anke.salmen@rub.de

26 6 2024
10 2024
31 10 10.1111/ene.v31.10 e1639601 5 2024
08 3 2024
13 6 2024
© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Abstract

Background and purpose

Relapse presentation in relapsing multiple sclerosis (RMS) differs between sexes, leading to differential outcomes. An influence of age seems likely but is less well investigated separately for women and men.

Methods

Using the large well‐defined dataset of the pivotal trials of ocrelizumab in RMS, OPERA I and II, and their open‐label extension, we performed a post hoc analysis to investigate relapse phenotypes for sex‐ and age‐related differences in n = 929 relapses in 534 subjects (171 men, 363 women). Frequencies of affected functional systems were analyzed separated by sex and for three age strata (<35, 35–44, ≥45 years). Exact p‐values are given for this exploratory analysis.

Results

Frequencies of mono‐ versus polysymptomatic relapse presentations were different neither between sexes nor in different age groups. Cerebellar symptoms were more frequent in relapses in men (female [f]: 23.1%, male [m]: 33.0%, p = 0.002), and women's relapses included more sensory (f: 53.8%, m: 32.3%, p < 0.001) and fatigue symptoms (f: 22.6%, m: 14.7%, p = 0.006). Whereas the sex difference for sensory involvement was present over all age groups (<35 years: f: 58.3%, m: 30.4%, p < 0.001; 35–44 years: f: 53.7%, m: 36.0%, p = 0.003; ≥45 years: f: 47.8%, m: 28.8%, p = 0.009), the difference for cerebellar involvement diminished with age (<35 years: f: 20.1%, m: 33.3%, p = 0.009; 35–44 years: f: 22.7%, m: 34.2%, p = 0.034; ≥45 years: f: 27.8%, m: 30.3%, p = 0.750). Relapse presentation seemed to shift with age in women only.

Conclusions

We describe sex‐specific relapse presentations and an influence of age only for women. Underlying causal factors warrant further investigations.

age
MS
relapse
sex
symptoms
source-schema-version-number2.0
cover-dateOctober 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:20.09.2024
Leon Betancourt A , Hoepner R , Hammer H , Chan A , Salmen A . Sex‐ and age‐related shift of relapse phenotypes in a cohort of relapsing multiple sclerosis patients: Post hoc analysis from the OPERA phase 3 trials. Eur J Neurol. 2024;31 :e16396. doi:10.1111/ene.16396

A. Leon Betancourt and Robert Hoepner contributed equally to this study.
==== Body
pmcINTRODUCTION

Multiple sclerosis (MS) relapses present differently between sexes; although women experience higher relapse rates [1, 2], men are prone to faster disability accumulation in relapse onset MS, but not in primary progressive disease [3]. An interplay between sex‐ and age‐related factors is likely.

A previous subgroup analysis of the pivotal trials of ocrelizumab versus interferon‐beta 1a (IFNb) in relapsing MS (RMS), OPERA I and II, has already demonstrated efficacy of ocrelizumab in reduction of annualized relapse rates for both sexes. Effects were less pronounced in patients aged 40 years or older in comparison to IFNb but were not analyzed separately by sex. The effects on confirmed disability progression were maintained over both sexes and the two age strata, but again, no sex‐specific analysis of age strata has been performed for disability progression [4, 5].

Using the large dataset of OPERA I and II and their open label extension in RMS, we set out to investigate relapse phenotypes for sex‐ and age‐related differences as a post hoc analysis.

METHODS

All RMS patients who experienced relapses during the core trial and/or open‐label extension were analyzed. Adverse events classified as “relapse” were taken into account irrespective of whether these events represented a protocol‐defined relapse (PDR). In a first step, the total number of recorded relapse events (n = 929 in 534 subjects, 171 male and 363 female persons) was investigated for the affected functional system (classified by Expanded Disability Status Scale [EDSS] functional system categories plus “fatigue” and “other” assessed with “yes/no” by the investigators) stratified by sex. In a second step, three age strata were added to the analysis (<35, 35–44, ≥45 years). With regard to the mean age distribution and inclusion criteria (limited to maximum 55 years of age) [5], the group of ≥45 years was most suited to serve as a proxy for the perimenopausal phase [6] with acceptable group sizes.

Treatment groups (ocrelizumab vs. IFNb at the time of event) were analyzed separately for presence of mono‐ or polysymptomatic relapses.

Frequency comparison was performed using Fisher exact test (SPSS v29.0.2.0, IBM, Armonk, NY). For this exploratory analysis in patient subgroups, all unadjusted p‐values are given in Tables 1, 2, 3. Probability values of <0.05 are marked in bold; p‐values of <0.00625 representing Bonferroni correction for eight tests (i.e., eight functional domains excluding the test of mono‐ vs. polysymptomatic) within each set of analyses are marked with an asterisk.

TABLE 1 Absolute and relative frequencies of symptoms reported for relapse events by sex.

Event	Male, n = 279 (30.0%), n (%)	Female, n = 650 (70.0%), n (%)	p	
Monosymptomatic	129 (46.2)	269 (41.4)	0.193	
Polysymptomatic	150 (53.8)	381 (58.6)	
Visual, yes	49 (17.6)	120 (18.5)	0.781	
Visual, no	230 (82.4)	530 (81.5)	
Brainstem, yes	52 (18.6)	101 (15.5)	0.248	
Brainstem, no	227 (81.4)	549 (84.5)	
Pyramidal, yes	132 (47.3)	290 (44.6)	0.473	
Pyramidal, no	147 (52.7)	360 (55.4)	
Cerebellar, yes	92 (33.0)	150 (23.1)	0.002*	
Cerebellar, no	187 (67.0)	500 (76.9)	
Sensory, yes	90 (32.3)	350 (53.8)	<0.001*	
Sensory, no	189 (67.7)	300 (46.8)	
Cerebral, yes	28 (10.0)	66 (10.2)	1.000	
Cerebral, no	251 (90.0)	584 (89.8)	
Fatigue, yes	41 (14.7)	147 (22.6)	0.006*	
Fatigue, no	238 (85.3)	503 (77.4)	
Other symptoms, yes	44 (15.8)	83 (12.8)	0.252	
Other symptoms, no	235 (84.2)	567 (87.2)	
Note: Probability values of <0.05 are marked in bold; p‐values after Bonferroni correction are marked with an asterisk (indicating p < 0.00625). "Other symptoms" include bowel/bladder and unspecified symptom descriptions (e.g., dizziness/vertigo, pain, speech and walking difficulties, unknown).

RESULTS

The majority of participants experienced a single relapse during observation (1 relapse: women: 203/363 [55.9%], men: 99/171 [57.9%]; 2 relapses: women: 85/363 [23.4%], men: 46/171 [26.9%]; 3 relapses: women: 44/363 [12.1%], men: 14/171 [8.2%]; 4 relapses: women: 16/363 [4.4%], men: 8/171 [4.7%]; ≥5 relapses: women: 15/363 [4.1%], men: 4/171 [2.3%]).

Absolute and relative frequencies of relapse symptoms are given in Tables 1, 2, 3, displayed separately by sex (Table 1), by sex for each age group (Table 2), and by sex for each treatment group (Table 3). No relevant differences were found in the frequency of mono‐ versus polysymptomatic relapse presentations for sex, age, or treatment groups. However, some relapse symptoms differ between sexes (Figure 1a).

TABLE 2 Absolute and relative frequencies of symptoms reported for relapse events by age strata.

Event	Male, <35 years, n = 102 (28.7%), n (%)	Female, <35 years, n = 254 (71.3%), n (%)	p	Male, 35–44 years, n = 111 (33.9%), n (%)	Female, 35–44 years, n = 216 (66.1%), n (%)	p	Male, ≥45 years, n = 66 (26.8%), n (%)	Female, ≥45 years, n = 180 (73.2%), n (%)	p	
Monosymptomatic	47 (46.1)	113 (44.5)	0.814	56 (50.5)	89 (41.2)	0.127	26 (39.4)	67 (37.2)	0.768	
Polysymptomatic	55 (53.9)	141 (55.5)	55 (49.5)	127 (58.8)	40 (60.6)	113 (62.8)	
Visual, yes	25 (24.5)	61 (24.0)	1.000	13 (11.7)	32 (14.8)	0.500	11 (16.7)	27 (15.0)	0.842	
Visual, no	77 (75.5)	193 (76.0)	98 (88.3)	184 (85.2)	55 (83.3)	153 (81.5)	
Brainstem, yes	22 (21.6)	34 (13.4)	0.075	21 (18.9)	38 (17.6)	0.763	9 (13.6)	29 (16.1)	0.695	
Brainstem, no	80 (78.4)	220 (86.6)	90 (81.1)	178 (82.4)	57 (86.4)	151 (83.9)	
Pyramidal, yes	42 (41.2)	101 (39.8)	0.812	58 (52.3)	91 (42.1)	0.101	32 (48.5)	98 (54.4)	0.472	
Pyramidal, no	60 (58.8)	153 (60.2)	53 (47.7)	125 (57.9)	34 (51.5)	82 (45.6)	
Cerebellar, yes	34 (33.3)	51 (20.1)	0.009	38 (34.2)	49 (22.7)	0.034	20 (30.3)	50 (27.8)	0.750	
Cerebellar, no	68 (66.7)	203 (79.9)	73 (65.8)	167 (77.3)	46 (69.7)	130 (72.2)	
Sensory, yes	31 (30.4)	148 (58.3)	<0.001*	40 (36.0)	116 (53.7)	0.003*	19 (28.8)	86 (47.8)	0.009	
Sensory, no	71 (69.6)	106 (41.7)	71 (64.0)	100 (46.3)	47 (71.2)	94 (52.2)	
Cerebral, yes	12 (11.8)	23 (9.1)	0.436	9 (8.1)	26 (12.0)	0.346	7 (10.6)	17 (9.4)	0.810	
Cerebral, no	90 (88.2)	231 (90.9)	102 (91.9)	190 (88.0)	59 (89.4)	163 (90.6)	
Fatigue, yes	16 (15.7)	50 (19.7)	0.452	14 (12.6)	59 (27.3)	0.003*	11 (16.7)	38 (21.1)	0.477	
Fatigue, no	86 (84.3)	204 (80.3)	97 (87.4)	157 (72.7)	55 (83.3)	142 (78.9)	
Other symptoms, yes	12 (11.8)	22 (8.7)	0.425	19 (17.1)	32 (14.8)	0.630	13 (19.7)	29 (16.1)	0.567	
Other symptoms, no	90 (88.2)	232 (91.3)	92 (82.9)	184 (85.2)	53 (80.3)	151 (83.9)	
Note: Probability values of <0.05 are marked in bold; p‐values after Bonferroni correction are marked with an asterisk (indicating p < 0.00625). "Other symptoms" include bowel/bladder and unspecified symptom descriptions (e.g., dizziness/vertigo, pain, speech and walking difficulties, unknown).

TABLE 3 Absolute and relative frequencies of symptoms reported for relapse events by treatment group.

Event	Male, n (%)	Female, n (%)	p	
OCR	134 (30.9)	299 (69.1)		
Monosymptomatic	58 (43.3)	119 (39.8)	0.526	
Polysymptomatic	76 (56.7)	180 (60.2)	
IFNb	137 (30.5)	312 (69.5)		
Monosymptomatic	65 (47.4)	130 (41.7)	0.258	
Polysymptomatic	72 (52.6)	182 (58.3)	
Abbreviations: IFNb, interferon‐beta; OCR, ocrelizumab.

FIGURE 1 (a) Frequencies (percentage) of different symptoms during relapse stratified by sex in n = 929 relapse events. (b) Frequencies (percentage) of different symptoms during relapse stratified by age groups for male sex (n = 279 events; left panel; blue) and female sex (n = 650 events; right panel; green).

Whereas cerebellar symptoms were more frequent in relapses in men (female [f]: 23.1%, male [m]: 33.0%, p = 0.002), women's relapses included more sensory (f: 53.8%, m: 32.3%, p < 0.001) and fatigue symptoms (f: 22.6%, m: 14.7%, p = 0.006).

Comparing sexes within the different age groups, the sex difference for cerebellar symptoms was only significantly present in the two younger age groups, but not in the age group ≥45 years (<35 years: f: 20.1%, m: 33.3%, p = 0.009; 35–44 years: f: 22.7%, m: 34.2%, p = 0.034; ≥45 years: f: 27.8%, m: 30.3%, p = 0.750). The sex difference for sensory symptoms was present over all age groups (<35 years: f: 58.3%, m: 30.4%, p < 0.001; 35–44 years: f: 53.7%, m: 36.0%, p = 0.003; ≥45 years: f: 47.8%, m: 28.8%, p = 0.009). For fatigue, the medium age stratum seemingly mainly drove the sex difference of the whole group (<35 years: f: 19.7%, m: 15.7%, p = 0.452; 35–44 years: f: 27.3%, m: 12.6%, p = 0.003; ≥45 years: f: 21.1%, m: 16.7%, p = 0.477).

Visualizing age strata by sex, no consistent age‐related pattern could be observed for men, whereas in women, the frequencies of sensory symptoms seemed to lower with age, although they increased for cerebellar and pyramidal involvement during relapse (Table 2, Figure 1b).

DISCUSSION

We describe a sex‐specific relapse presentation with more common sensory and fatigue symptoms during relapse in women and more common cerebellar involvement in men. These differences seem to be influenced by age. Our visualization demonstrates patterns in the shift with age for women, especially for sensory, cerebellar, and pyramidal involvement, unlike for men.

Our observation using a large well‐controlled dataset corroborates data from the large MSBase dataset with very similar observations regarding sex‐specific and age‐dependent relapse phenotypes [7]. Yet, whether the age‐dependent effects were different between sexes has not been analyzed.

Similarly, age differences have been demonstrated earlier. However, age‐related differences have been classified as being independent of sex only, as after adjustment for sex, results remained significant [8].

Both in observational and in phase 3 settings, less severe events may be underreported. To address this, we have here included all events classified as relapse irrespective of the fulfillment of study‐specific PDR requirements and assessed the presence versus absence of involvement of the particular functional system instead of functional system scores or total EDSS. Particularly the latter would have very likely been additionally influenced by treatment as demonstrated earlier for the OPERA trials [9] although not analyzed distinctly by sex. As treatment effects were not our main question, we have thus tried to choose the approach most likely capturing any potential symptoms presenting as a relapse as evaluated by the actual trial investigator.

We deem it important to share the crude observation of interrelated sex and age differences in relapse presentations from this dataset to foster additional research in this important field of both sex‐ and gender‐specific but also age‐related medicine.

An age‐related shift of relapse symptoms in the female group of patients might be explained by the life cycle and hormonal changes [10], which we have not at all addressed here, and which are less well understood for men. Menopause‐associated reduction of gonadal steroid production has been proposed as a potential explanation for advanced neurodegeneration measured by EDSS and volumetric magnetic resonance imaging in women with MS [11]. Plasma anti‐Mullerian hormone (AMH) measurements were herein used to assess ovarian aging. To be able to investigate such factors in a data‐driven approach, future large studies including phase 3 trials assessing novel treatments should be prompted to include such variables and laboratory assessments for sex and gender medicine approaches.

A large multinational analysis has demonstrated that women are less likely to receive disease‐modifying treatment (DMT), particularly in two age spans (i.e., late 20s to early 40s and late 50s to late 60s), even after adjustment for additional confounders known to be mediated by sex [12]. As these and our data only describe the status quo on a cross‐sectional basis, it remains speculative whether a lack of DMT over longer periods of time in women may represent another cause of the phenotypical shift described here, which might be prevented with adapted treatment algorithms both during the reproductive and the perimenopausal phase. This may only be answered in specific longitudinal settings.

This short notion cannot replace distinct research to be invested in this area and bears several limitations. Nonetheless, these kinds of datasets represent a major source of data to first investigate the question of sex differences until prospective specific studies arise.

Despite the large dataset, as a post hoc analysis, our results need to be interpreted with caution. The trials were not powered to specifically assess our research question. The male subgroups are considerably smaller, in particular for some symptom classes and the age category ≥45 years. Relapse events were thus included instead of a sole event for each participant, which may serve as a potential bias due to individual symptom predominance [7]. However, this potential bias should possibly be similarly distributed within the female and male groups. A number of single tests has been performed. This is why we chose to present all raw p‐values for transparency to the readers. We have not assessed relapse severity, but merely frequencies of symptom classes without additional information on the detailed kinds of symptoms. It may be that relapse severity harbors additional sex and age differences and that severity is actually altered by the two treatment arms.

We hope to inspire other researchers to invest effort to further corroborate our exploratory findings using more specific settings. These should include large‐scale studies on a longitudinal basis and implement an improved collection of sex‐related data (e.g., AMH measurement and hormonal status, reproductive life cycle, hormonal interventions). The obligatory requirement of an implementation (e.g., in phase 3 settings) might accelerate the availability of such data, which should be made open for researchers outside the trials as provided for our analysis.

AUTHOR CONTRIBUTIONS

A. Leon Betancourt: Conceptualization; writing–original draft; writing–review and editing. Robert Hoepner: Writing–review and editing; formal analysis; methodology; data curation. Helly Hammer: Writing–review and editing; formal analysis. Andrew Chan: Writing–review and editing; supervision. Anke Salmen: Conceptualization (lead); data curation; visualization; formal analysis; methodology; writing–original draft; writing–review and editing.

CONFLICT OF INTEREST STATEMENT

A.L.B. has received speaker/advisor honorary from Sanofi and Teva. He has received travel grants from Almirall and Sanofi. R.H. has received speaker/advisor honoraria from Merck, Novartis, Roche, Biogen, Alexion, Sanofi, Janssen, Bristol‐Myers Squibb, Teva/Mepha, and Almirall. He has received research support within the past 5 years from Roche, Merck, Sanofi, Biogen, Chiesi, and Bristol‐Myers Squibb. He also has received research grants from the Swiss MS Society and is a member of the advisory board of the Swiss and International MS Society. He also serves as associated editor for the Journal of Central Nervous System Disease. All conflicts are not related to this work. H.H. has received speaker/advisor honoraria from Merck, Biogen, Janssen, and Teva. She has received research support within the past 5 years from Biogen. She has received travel grants from Almirall, Biogen, Roche, Janssen, and Merck. A.C. has served on advisory boards for and received funding for travel or speaker honoraria from Actelion‐Janssen, Almirall, Bayer, Biogen, Celgene, Sanofi Genzyme, Merck, Novartis, Roche, and Teva, and has received research support from Biogen, Genzyme, and UCB. A.C. is an associate editor of the European Journal of Neurology and serves on the editorial board for Clinical and Translational Neuroscience and as topic editor for the Journal of International Medical Research. He reports no conflicts of interest related to this article. A.S. has received speaker honoraria for activities with Bristol‐Myers Squibb, CSL Behring, Novartis, and Roche, and research support from the Baasch Medicus Foundation, the Medical Faculty of the University of Bern, and the Swiss MS Society, all not related to this article.

ACKNOWLEDGMENTS

We thank Roche Pharma (Schweiz) for granting access to the data of OPERA I/II and open‐label extension for this analysis. All analyses have been performed independently of Roche Pharma.

DATA AVAILABILITY STATEMENT

All aggregated data needed to reproduce these analyses are provided within Tables 1, 2, 3. Additional data requests should be addressed to the sponsor of the initial studies, Roche Pharma.
==== Refs
REFERENCES

1 Kalincik T , Vivek V , Jokubaitis V , et al. Sex as a determinant of relapse incidence and progressive course of multiple sclerosis. Brain. 2013;136 :3609‐3617.24142147
2 Tremlett H , Zhao Y , Joseph J , Devonshire V , Neurologists UC . Relapses in multiple sclerosis are age‐ and time‐dependent. J Neurol Neurosurg Psychiatry. 2008;79 :1368‐1374.18535026
3 Ribbons KA , McElduff P , Boz C , et al. Male sex is independently associated with faster disability accumulation in relapse‐onset MS but not in primary progressive MS. PLoS One. 2015;10 :e0122686.26046348
4 Turner B , Cree BAC , Kappos L , et al. Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis. J Neurol. 2019;266 :1182‐1193.30820738
5 Hauser SL , Bar‐Or A , Comi G , et al. Ocrelizumab versus interferon Beta‐1a in relapsing multiple sclerosis. N Engl J Med. 2017;376 :221‐234.28002679
6 Brinton RD , Yao J , Yin F , Mack WJ , Cadenas E . Perimenopause as a neurological transition state. Nat Rev Endocrinol. 2015;11 :393‐405.26007613
7 Kalincik T , Buzzard K , Jokubaitis V , et al. Risk of relapse phenotype recurrence in multiple sclerosis. Mult Scler. 2014;20 :1511‐1522.24777276
8 Cossburn M , Ingram G , Hirst C , Ben‐Shlomo Y , Pickersgill TP , Robertson NP . Age at onset as a determinant of presenting phenotype and initial relapse recovery in multiple sclerosis. Mult Scler. 2012;18 :45‐54.21865412
9 Kappos L , Wolinsky JS , Giovannoni G , et al. Contribution of relapse‐independent progression vs relapse‐associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials. JAMA Neurol. 2020;77 :1132‐1140.32511687
10 Ysrraelit MC , Correale J . Impact of sex hormones on immune function and multiple sclerosis development. Immunology. 2019;156 :9‐22.30222193
11 Graves JS , Henry RG , Cree BAC , et al. Ovarian aging is associated with gray matter volume and disability in women with MS. Neurology. 2018;90 :e254‐e260.29273686
12 Leavitt VM , Dworkin JD , Galioto R , Ratzan AS . Disparities in DMT treatment: demographic and neurocognitive differences between MS patients currently treated versus not treated with disease‐modifying therapies. Mult Scler Relat Disord. 2024;85 :105508.38452646
