Title
Sex as a determinant of relapse incidence and progressive course of multiple sclerosis
Running title
Multiple sclerosis relapses: sex and age
Authors and affiliations
Tomas Kalincik; Department of Medicine, University of Melbourne, Melbourne, Australia;
Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia
Vino Vivek; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia
Vilija Jokubaitis; Department of Medicine, University of Melbourne, Melbourne, Australia
Jeannette Lechner-Scott; John Hunter Hospital, Newcastle, Australia
Maria Trojano; Department of Basic Medical Sciences, Neuroscience and Sense Organs,
University of Bari, Bari, Italy
Guillermo Izquierdo; Hospital Universitario Virgen Macarena, Sevilla, Spain
Alessandra Lugaresi; MS Center, Department of Neuroscience and Imaging, University ‘G.
d’Annunzio’, Chieti, Italy
Francois Grand’Maison; Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec, Canada
Raymond Hupperts; Orbis Medicle Center, Sittard, The Netherlands
Celia Oreja-Guevara; University Hospital San Carlos, IdISSC, Madrid, Spain
Roberto Bergamaschi; Neurological Institute IRCCS Mondino, Pavia, Italy
Gerardo Iuliano; Ospedali Riuniti di Salerno, Salerno, Italy
Raed Alroughani; Amiri Hospital, Kuwait City, Kuwait
Vincent Van Pesch; Cliniques Universitaires Saint-Luc, Brussels, Belgium
Maria Pia Amato; Department NEUROFARBA, Section of Neurosciences, University of
Florence, Florence, Italy
Mark Slee; Flinders University and Medical Centre, Adelaide, Australia
Freek Verheul; Groen Hart Ziekenhuis, Gouda, The Netherlands
Ricardo Fernandez-Bolanos; Hospital Universitario Virgen de Valme, Seville, Spain
Marcela Fiol; FLENI, Buenos Aires, Argentina
Daniele La Spitaleri; AORN San Giuseppe Moscati, Avellino, Italy
Edgardo Cristiano; Hospital Italiano, Buenos Aires, Argentina
Orla Gray; Craigavon Area Hospital, Portadown, UK
Jose Antonio Cabrera-Gomez; Centro Internacional de Restauracion Neurologica, Havana,
Cuba
Vahid Shaygannejad; Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
Joseph Herbert; New York University Hospital for Joint Diseases, New York, USA
Steve Vucic; Westmead Hospital, Sydney, Australia
Merilee Needham; Royal North Shore Hospital, Sydney, Australia
Tatjana Petkovska-Boskova; Clinic of Neurology Clinical Center, Skopje, Macedonia
Carmen-Adella Sirbu; Central Clinical Emergency Military Hospital, Bucharest, Romania
Pierre Duquette; Hôpital Notre Dame, Montreal, Canada
Marc Girard; Hôpital Notre Dame, Montreal, Canada
Pierre Grammond; Hotel-Dieu de Levis, Quebec, Canada
Cavit Boz; Karadeniz Technical University, Trabzon, Turkey
Giorgio Giuliani; Ospedale di Macerata, Macerata, Italy
Maria Edite Rio; Hospital CUF, Porto, Portugal
Michael Barnett; Brain and Mind Research Institute, Sydney, Australia
Shlomo Flechter; Assaf Harofeh Medical Center, Beer-Yaakov, Israel
Fraser Moore; Jewish General Hospital, Montreal, Canada
Bhim Singhal; Bombay Hospital Institute of Medical Sciences, Mumbai, India
Elizabeth Alejandra Bacile; Instituto de Neurociencias Cordoba, Cordoba, Argentina
Maria Laura Saladino; INEBA, Buenos Aires, Argentina
Cameron Shaw; Geelong Hospital, Geelong, Australia
Eli Skromne; Hospital Angeles Mexico City, Lomas, Mexico
Dieter Poehlau; Multiple Sclerosis Centre Kamillus-Klinik, Asbach, Germany
Norbert Vella; Mater Dei Hospital, Malta
Timothy Spelman; Department of Neurology, Royal Melbourne Hospital, Melbourne,
Australia
Danny Liew; Melbourne EpiCentre, University of Melbourne and Melbourne Health,
Melbourne, Australia
Trevor J Kilpatrick*; Centre for Neuroscience Research and the Melbourne Neuroscience
Institute, University of Melbourne, Melbourne, Australia; Department of Neurology,
Royal Melbourne Hospital, Melbourne, Australia;
Helmut Butzkueven*; Department of Medicine, University of Melbourne, Melbourne,
Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia;
and Department of Neurology, Box Hill Hospital, Monash University, Box Hill, Australia
on behalf of the MSBase Study Group†
*These authors contributed equally to the manuscript.
†Contributing members of the MSBase Study Group are listed in the Acknowledgements.
Corresponding author: Tomas Kalincik; L4 Centre, Melbourne Brain Centre at Royal
Melbourne Hospital, Grattan St, Parkville VIC 3050, Australia; Tel: +61 3 9342 4404, Fax: +61
3 9349 5997
Keywords:
multiple sclerosis, sex, risk factors, MSBase, prediction
Word count – manuscript: 3941
SUMMARY
Objectives
To evaluate sex differences in the incidence of multiple sclerosis relapses. To assess the
relationship between sex and primary progressive disease course. To compare effects of age
and disease duration on relapse incidence.
Methods
Annualised relapse rates were calculated using the MSBase registry. Patients with
incomplete data or less than one year of follow-up were excluded. Patients with primary
progressive multiple sclerosis were only included in the sex ratio analysis. Relapse
incidences over 40 years of multiple sclerosis or 70 years of age were compared between
females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified
by annual relapse count were evaluated across disease duration and patient age and
compared between relapse-onset and primary progressive multiple sclerosis.
Results
The study cohort consisted of 11,570 eligible patients with relapse-onset and 881 patients
with primary progressive multiple sclerosis. Among the relapse-onset patients (82,552
patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in
females compared to males. Within the initial five years, the female-to-male ratio increased
from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The
magnitude of this sex effect increased at longer disease duration and older age (p < 10-12).
However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero
relapses in any given year was double that of the patients with primary progressive multiple
sclerosis. Patient age was a more important determinant of decline in relapse incidence
than disease duration (p < 10-12).
Conclusions
Females are predisposed to higher relapse activity than males. However, this difference
does not explain the markedly lower female-to-male sex ratio in primary progressive
multiple sclerosis. Decline in relapse activity over time is more closely related to patient age
than disease duration.
INTRODUCTION
Episodic exacerbations are defining phenomena for relapsing-remitting multiple sclerosis
(MS) and can be directly associated with residual disability (Hirst et al., 2008). Even though
the evidence remains inconclusive (Hutchinson, 2011), an association between high relapse
rate in the first two years after disease onset and later accumulation of irreversible
neurological impairment has been suggested (Kalincik et al., 2012; Scalfari et al., 2010).
There have been only a limited number of studies delineating predictors of relapse activity,
with only one study examining a large retrospective cohort (Held et al., 2005; Mowry et al.,
2009; Tremlett et al., 2009). These studies suggested several predisposing factors, such as
sex, age, ethnicity and time from MS onset. However, their outcomes, in particular those
related to effect of sex on relapse incidence, have often been discordant.
There is a marked predominance of women among MS patients with relapse-onset course.
The sex ratios are 3:1 in relapsing-remitting and 3:2 in secondary progressive MS, but in
primary progressive MS the both sexes are represented equally (Alonso and Hernan, 2008;
Confavreux and Vukusic, 2006b; Koch-Henriksen and Sorensen, 2010; Runmarker and
Andersen, 1993).
We have used MSBase, a longitudinal, international, observational registry of patients with
MS, to evaluate the effect of sex on relapse activity up to 40 years of MS duration or 70
years of age. We have directly compared the impacts of age and disease duration on relapse
frequency in a predominantly contemporary MS cohort. We have also tested the hypothesis
that the female-to-male ratio increases gradually with relapse MS activity and that the
primary progressive disease represents a non-relapsing extreme along this continuum.
PATIENTS AND METHODS
Ethics statement
The MSBase registry (Butzkueven et al., 2006) was approved by the Melbourne Health
Human Research Ethics Committee, and by the local ethics committees in all participating
centres (or exemptions granted, according to applicable local laws and regulations). If
required, written informed consent was obtained from enrolled patients, in accordance with
the Declaration of Helsinki.
Patients and follow-up
Longitudinal clinical data from 18,885 patients from 55 MS centres in 25 countries were
extracted from the MSBase registry in February 2012. Data recorded between years 1951
and 2012 were used. The majority of the patients were enrolled in the MSBase registry in
year 2000 or later (75%), with 20% enrolled in years 1990-2000, 3% enrolled in years 19801990 and only 0.9% of patients enrolled before 1980. The participating centres contributed
between 2 and 1239 cases fulfilling the study inclusion criteria, with recorded ARR in
relapse-onset MS ranging from 0.1 to 2 and female-to-male ratio ranging from 0.9:1 to
4.4:1. The country-specific ranges were 2-3282 for the number of eligible patients, 0.2-2 for
ARR in relapse-onset MS and 0.9-4.4:1 for female-to-male ratio. Patients with incomplete
data (i.e. not fulfilling the minimal dataset requirement, see below) or less than one year of
recorded clinical follow-up were excluded. The minimal dataset consisted of patient date of
birth, sex, MS centre, dates of MS onset and clinical follow-up, disease course and disability
(at inclusion and censoring), start and end dates of disease modifying treatment exposure
and list of clinical relapses (including date of onset and relapse treatment status). Patients
with relapse-onset MS (i.e. clinically isolated syndrome, relapsing-remitting MS, secondary
progressive MS or relapsing-progressive MS) were included in all analyses. Patients with
primary progressive MS were only included in the analyses comparing female-to-male ratios
between relapse-onset and primary progressive MS (see below). Finally, patients with
relapse-onset MS and at least 10 years of recorded follow up, and all patients with primary
progressive MS were included in a subgroup analysis of female-to-male ratios stratified by
relapse activity.
The analysed data were recorded as part of routine clinical practice. The usual data entry
practice at most centres was real time or near-real time data entry in relation to clinical
visits. The MSBase protocol stipulates minimum annual updates of the minimum dataset,
but patients with less frequent visits were not excluded from the analysis. Data entry portal
was either the iMed patient record system or the MSBase online data entry system.
A relapse was defined as occurrence of new symptoms or exacerbation of existing
symptoms persisting for at least 24 hours, in the absence of concurrent illness or fever, and
occurring at least 30 days after a previous relapse (Schumacher et al., 1965). Date of onset
was recorded for each clinical relapse. Formal scoring of relapse-associated disability was
not required upon relapse entry. Disability was scored by accredited scorers (online
Neurostatus certification was required at each centre) using the Expanded Disability Status
Scale (EDSS). Duration of MS was calculated as the time from the patient-reported first
clinical manifestation of the disease and relapsing / progressive onset of disease was
assessed by participating neurologists. Primary progressive MS was defined as the disease
with at least one year of disease progression from its first clinical manifestation and with
zero recorded relapses. In each patient, unadjusted annualised relapse rates (ARRs)
stratified by disease duration or patient age were calculated by including the initial relapse
and the number of relapses for years for which clinical data were available. Censoring was
defined to occur on the day of the last recorded clinical visit. Information about patient
death and its relation to MS was not collected in the database.
To assure quality of the analysed data, only information from centres contributing at least
10 active records (i.e. cases with regular annual updates of clinical information) to the
MSBase registry was used, as stipulated in the study protocol. A date of onset was required
for all recorded events, including relapses, visit (with or without EDSS score), changes in
disease course and changes in treatment. Prior to the analysis the recorded data were
verified using a series of automated procedures to identify any invalid or inconsistent
entries.
Statistical analysis
Statistical analyses were carried out using Statistica 10 (Statsoft, Tulsa, OK, USA) and R
(http://www.R-project.org). All hypotheses were tested at the two-tailed 0.05 level of
statistical significance, after applying the Benjamini-Hochberg correction for multiple
hypothesis testing. Two proportional hazards models with robust variance estimation
(Andersen-Gill) and Efron approximation method, adjusted either for patient age or disease
duration, were used to estimate cumulative hazard* of relapses for each sex. The outcome
variable was time to relapse with multiple entries per patient allowed. The models were
adjusted for pregnancy (proportion of time pregnant from the study enrolment or the
previous recorded event to the next event/censoring, treated as time-varying variable) and
immunomodulatory therapy, when any change in therapy with or without relapse was
treated as a relapse (response) or non-relapse (censoring) event. The immunomodulatory
agents considered were interferon β-1a 22 μg or 44 μg subcutaneous injection thrice
weekly, interferon β-1a 30 μg intramuscular injection once weekly, interferon β-1b 250 μg
subcutaneous injection every other day, glatiramer acetate 20 mg subcutaneous injection
daily, natalizumab 300 mg intravenous infusion once monthly, fingolimod 0.5 mg orally once
daily, dimethyl fumarate 240 mg orally twice or thrice daily, cladribine 10 mg orally once
monthly for two months, and teriflunomide 7 mg or 14 mg orally once daily.
Two Tweedie models with index parameters 1.5 (i.e. compound Poisson-Gamma models)
adjusted for sex, pregnancy and treatment (the latter two variables expressed as the
proportion of time pregnant or treated with disease modifying agent, respectively,
throughout the recorded follow-up) were built to evaluate separately the effects of age and
disease duration on ARR. Each patient contributed a single entry of overall ARR calculated as
the number of relapses divided by the duration of the follow-up. A similar final Tweedie
model including both age and disease duration was used to compare the effects of age and
disease duration.
We evaluated the effect of relapse count on female-to-male ratio at any completed
observational year using two logistic mixed effect models. The outcome in these models was
the probability of being female (i.e. the female gender recorded in individual patients), with
multiple entries per patient allowed (one entry per completed year of follow-up /
chronological age) and the random effect being the patient unique identifier. The predictors
of interest were the number of relapses recorded in any completed follow-up year, patient
age or MS duration (either age or MS duration was used in either model), and their
interaction term. The models were adjusted for age at MS onset, disease course, pregnancy
(proportion of time in any completed year) and immunomodulatory therapy (proportion of
time in any completed year).
RESULTS
Of the 18,885 patients in the MSBase registry (17,021 with relapse-onset MS, 1018 with
primary progressive MS and 846 with the information about disease course missing), data
from 11,570 relapse-onset and 881 (7%) primary progressive patients fulfilled the inclusion
criteria (Figure 1). The female-to-male ratio among the excluded patients (n = 6434) was
2.4:1 (4516 females, 1918 males, in no instance the information about patient sex was
missing). Tables 1 and 2 show demographic and clinical characteristics of the included
patients with relapse-onset and primary progressive MS, respectively. Patient characteristics
were comparable between females and males, including visit frequency, with only
marginally shorter disease duration and larger end-of-follow-up disability among males.
Numbers of patients with relapse-onset MS included in the analysis stratified by disease
duration and age are shown in Figure 2A and B. In 82,552 patient-years of observation
recorded among the relapse-onset patients, 48,362 relapses were recorded. Of these, 42%
were concurrent with clinical visits. Figure 2C and D shows unadjusted ARR with respect to
disease duration and age. Within the first year of MS, the relapse rate was relatively high
(1.1 relapse / year), which was a result of its inflation by inclusion of the first recorded
relapse. Thereafter, the ARR gradually decreased from 0.5 at 2 years to 0.1 at 40 years. Also,
a marked decline in ARR with age was seen, when ARR decreased from 0.9 at the age 17 to
0.1 at the age 70. Importantly, females tended to show higher unadjusted ARR during the
initial 18 years of MS duration and between 27 and 49 years of age. These differences were
further enhanced by adjusting the ARR for MS duration / patient age, pregnancy and
treatment (Figure 2E and F). Females showed consistently higher adjusted ARR (on average
by 17.7%, 95% confidence interval = 15.1 – 20.3%) than males throughout the disease
duration and at every chronological age (risk ratio = 1.08, 95% confidence interval = 1.06 –
1.11, p ≤10-16, Tweedie models), with a relative decrease in this difference at long MS
durations or at an older age. Accordingly, the cumulative hazard of relapses (see Figure 2G
and H) was consistently higher among females and reached 9.3 (95% confidence interval =
9.1-9.5) in women and 8.4 (95% confidence interval = 8.1-8.7) in men at 40 years after MS
onset (hazard ratio = 1.1, 95% confidence interval = 1.05 - 1.14, p = 10-5, Andersen-Gill
model). At the age of 70, the cumulative hazard reached 28.5 (95% confidence interval =
26.6-30.7) in women and 26.7 (95% confidence interval = 24.7 – 28.8) in men (hazard ratio =
1.1, 95% confidence interval = 1.07 - 1.14, p < 10-12, Andersen-Gill model).
These observations in relapse-onset MS were further confirmed by the fact that the femaleto-male ratio was higher among the patients with higher annual relapse count (see Figure 3,
β = 0.03, p < 10-12, logistic mixed models). Within the initial five years of disease onset, the
ratio increased from 2.3:1 in patients with no relapses to 3.3:1 in patients with at least four
relapses per year. Interestingly, this effect was accentuated by longer disease duration, as
the sex ratio among the frequently relapsing patients exceeded 4:1 (interaction term p < 1012,
logistic mixed model). A similar interaction effect was seen for age (p < 10-12, logistic
mixed model). Overall, the sex ratios stratified by disease course were 2.1:1 for clinically
isolated syndrome (as defined by the McDonald 2005 criteria (Polman et al., 2005)), 2.8:1
for relapsing remitting MS, 2.2:1 for secondary progressive MS and 1.3:1 for relapsing
progressive MS. Compared to the patients with relapse-onset MS, the population diagnosed
with primary progressive disease showed a significantly lower female-to-male ratio across
all disease durations or patient age groups - approximately 1.2:1 (β = 1.13 – 1.16, p < 10-12,
logistic mixed model; see Figure 3). In fact, the female-to-male ratio in patients with relapseonset MS and zero relapses in any given year was 2:1 and therefore almost double that of
the patients with primary progressive MS. In a subgroup analysis including 2969 patients
with relapse-onset MS and data recorded over at least 10 years, the sex ratio increased from
2.2:1 in those with zero overall relapses† to 3.2:1 in those with 8 or more relapses captured
during their 10-year follow-up (see Figure 4). In 881 patients with primary progressive MS
(and therefore no recorded relapses) regardless of the duration of their follow-up, the
female-to-male ratio was 1.2:1.
Among the patients with relapse-onset MS, the incidence of relapses declined with both MS
duration (by 0.01 per year, 95% confidence interval = 0.0001 – 0.03) and patient age (by
0.01 per year, 95% confidence interval = 0.006 – 0.02). This was confirmed by the adjusted
Andersen-Gill models (MS duration: hazard ratio = 0.87, 95% confidence interval = 0.864 –
0.872, p < 10-12; age: hazard ratio = 0.95, 95% confidence interval = 0.949 – 0.953, p < 10-12).
The two separate Tweedie models (dispersion parameters = 0.52 and 0.51) further
confirmed the significant effects of MS duration (rate ratio = 0.99, 95% confidence interval =
0.992 – 0.996, p = 10-11) and age (rate ratio = 0.98, 95% confidence interval = 0.982 – 0.985,
p < 10-12) on ARR. Interestingly, in the final Tweedie model containing both MS duration and
patient age (dispersion parameter = 0.51), only the patient age was found to have an
independent negative association with ARR (rate ratio = 0.98, 95% confidence interval =
0.979 – 0.983, p < 10-12).
DISCUSSION
In a large mostly contemporary population of patients followed in the MSBase registry,
women have a higher relapse rate than men throughout the course of MS. The sex ratio in
progressive-onset forms of MS is markedly different from that in relapse onset MS and is
discrete from the gradient determined by the relapse frequency. We have confirmed a
strong inverse relationship between relapse frequency and either disease duration or age.
Of these two collinear factors, chronological age is more closely related to the relapse
incidence.
In the only available retrospective cohort study of predictors of relapse incidence, Tremlett
and colleagues showed that women had 14.3% higher ARR than men (Tremlett et al., 2008).
We have confirmed this observation by demonstrating a similar sex effect of 17.7%.
Compared to Tremlett et al., our recorded ARR was approximately double (0.59 vs. 0.23,
range 0.1-0.9 vs. 0.08-0.29 depending on patient age, respectively), despite the presumed
higher proportion of patients receiving disease modifying treatment. This could be
attributed to the inclusion of the first clinical episodes in the relapse count in our study and
the near real-time data entry in the MSBase registry, which could have partially ameliorated
the expected under-reporting of relapses.
Other literature reporting incidence of relapses in MS only describes relatively short followup periods. A series of studies identified young age (Mowry et al., 2009; West et al., 2006)
and short disease duration (Held et al., 2005) but not sex as being independently predictive
of higher relapse incidence during one-year observational periods. The discrepancies
between these studies and our present analysis could be explained by the differences in
statistical power determined by the size of the cohorts and the analytical designs. With
respect to the low effect-to-noise ratio, the other studies were most probably
underpowered to assess the effect of sex, as they only evaluated information derived from
105 – 727 patient-years.
We have seen that women are over-represented among patients with high relapse
frequency, in particular later in the disease course and at older chronological age. This
suggests that the attenuation of clinically apparent episodic inflammatory activity is delayed
in women compared to men. In addition, higher mortality from MS-unrelated causes in men
could potentially contribute to this phenomenon; however, the lack of detailed mortality
data in the MSBase registry prevented the evaluation of this potential confounder.
Importantly, the follow-up duration, which did not differ between the enrolled women and
men, did not support sex-dependent study drop-out.
The difference in relapse risk associated with sex probably only plays a small role in
explaining the reported differences in sex ratios between patients with relapse- and
progressive-onset MS (Confavreux and Vukusic, 2006b; Kampman et al., 2013). Since men
show less frequent relapse activity throughout the disease course and life span, one could
argue that their disease is more likely to be classified as progressive. However, the sex ratio
among patients with primary progressive MS is still very distinct from that among patients
with relapse-onset MS and no relapse activity observed during the study period (see Figures
3 and 4). Thus, we rejected the hypothesis that sex difference in propensity to relapses is
fully accountable for the different sex ratios between relapse- and progressive-onset MS.
From this perspective, primary progressive MS can not be viewed as a mere extreme along
the continuum of relapse activity in relapsing-remitting MS.
It is of further interest how the relapse incidence interacts with progression of disability. It
has been previously suggested that early relapses may be associated with the development
of permanent disability (Hirst et al., 2008; Kalincik et al., 2012; Leray et al., 2010; Lublin et
al., 2003; Scalfari et al., 2010; Tremlett et al., 2009). There is also evidence both supporting
(Confavreux and Vukusic, 2006a; Confavreux et al., 2003; Leray et al., 2010) and opposing
(Amato et al., 1999; Simone et al., 2002; Trojano et al., 1995) the common view of faster
disability accrual in men. Clearly, the associations between sex and disability warrant further
clarification in observational studies, with the perspective of elucidating the complex
interactions between sex, relapses and disability.
MS duration and patient age are two largely collinear variables, whose effect on disease
outcomes is difficult to differentiate. Whether the MS relapse activity is determined
predominantly by the time from MS onset, or by patient age, is not known. While some
works identified disease duration as an independent predictor of relapse incidence (Held et
al., 2005), others reported independent effect of age (Inusah et al., 2010). Tremlett et al.
described a faster decline in ARR with disease duration in patients with later MS onset. It is
possible, that this interaction effect was in fact driven by the effect of age, but a direct
statistical comparison between the effects of age and disease duration was not reported
(Tremlett et al., 2008). In our present study, we have directly compared these two collinear
variables using a multivariate Tweedie model. Our analysis indicates a dominant role of
chronological age (approximately 2% per year decrease in ARR) over that of disease duration
(approximately 1% per year decrease in ARR). This observation is complementary to
previous works, which demonstrated that age at onset of progressive phase is remarkably
similar between patients with primary progressive vs. relapsing-remitting / secondary
progressive disease course, suggesting that presence and duration of relapsing phase is, to a
great extent, defined by patient age (Confavreux and Vukusic, 2006b; Leray et al., 2010;
Scalfari et al., 2011).
Our analysis was carried out in a large international observational cohort - the MSBase
registry. The studied population was representative of patient populations managed at large
academic MS centres, which might limit generalisation of our observations to a prevalent
population. Inclusion in the MSBase might have posed a risk of recruitment bias; this was
subject to the criteria for patient inclusion at the participating centres. Also, preferential
data entry of patients with relapse-onset disease course at the study sites could have
resulted in a relative under-representation of patients with primary progressive disease
(which in our study was approximately 7%). Selection bias was potentially introduced by the
applied inclusion criteria. However, the fact that female-to-male ratios were comparable
between the excluded and included populations rendered this situation unlikely. Survival
bias could potentially have been introduced in case that the patients with more pronounced
disability were more often lost to follow-up. This hypothetical situation might favour the sex
with slower disability accrual. On the other hand, given the parallel patient disposition of
both sexes with respect to disease duration and patient age, the survival bias was
improbable (see Figures 2A and B). The information prior to year 2000 represented data
transferred from other clinical databases, and constituted only a small proportion of the
evaluated data. The ARR and subsequently the differences studied in our analysis could have
been underestimated by the possible relapse under-reporting. The differences in relapse
reporting at the participating centres, as implied by the variability in the centre-specific
ARRs, could have inflated the under-reporting error. On the other hand, the fact that only
42% of the recorded relapses were concurrent with a recorded clinical visit and that EDSS
validation of relapses was not required indicates that relapse over-reporting could have
occurred. For all of these potential confounders, we presume that their influence applied
consistently across the studied population, regardless of patient sex, age or disease
duration. It should be noted that our analysis contained remarkable statistical power
provided by 82,552 patient-years from a longitudinal patient follow-up with the mean
follow-up period being 6 years. Overall, we were able to analyse ARR over 40 years of
disease duration and 70 years of age.
In this study we evaluated effect of sex on the incidence of MS relapses throughout the
disease- and life span and in the relapse-onset versus primary progressive course in a
longitudinally followed large patient population. Its outcomes help elucidate patterns of MS
activity determined by sex and in the future might lead to our improved understanding of
MS etiopathogenesis.
FUNDING
The work was supported by the Multiple Sclerosis Research Australia Postdoctoral
Fellowship to TK [11-054], NHMRC Career Development Award (Clinical) to HB [ID628856],
NHMRC Project Grant [1032484], NHMRC Centre for Research Excellence [Grant ID
1001216] and the MSBase Foundation. The MSBase Foundation is a not-for-profit
organization that receives support from Merck Serono, Biogen Idec, Novartis Pharma,
Bayer-Schering, Sanofi-Aventis and BioCSL.
ACKNOWLEDGEMENTS
MSBase study group contributors: From MS-Centrum Nijmegen, The Netherlands, Dr Cees
Zwanikken; from Francicus Ziekenhuis, The Netherlands, Ms Leontien den Braber-Moerland;
from Jeroen Bosch Ziekenhuis, The Netherlands, Dr Erik van Munster; from Centre
hospitalier del’Universite de Montreal, Hopital Notre-Dame, Canada, Dr Elaine Roger and Dr
Pierre Despault; from the Royal Melbourne Hospital, Australia, Dr Mark Marriott, Dr Anneke
Van der Walt, Dr John King , Dr Katherine Buzzard, Dr Jill Byron and Ms Lisa Morgan; from
Box Hill Hospital, Monash University, Australia, Dr Olga Skibina and Ms Jodi Haartsen; from
St Vincent’s Hospital, Australia, Dr Mark Paine; from Department of Neuroscience and
Imaging, University ‘G. d’Annunzio’, Italy, Dr Giovanna De Luca, Dr Valeria Di Tommaso, Dr
Daniela Travaglini, Dr Erika Pietrolongo, Dr Maria di Ioia and Dr Deborah Farina; from
Hospital Italiano, Argentina, Dr Juan Ignacio Rojas and Dr Liliana Patrucco; from Consultorio
Privado, Buenos Aires, Argentina, Dr Aldo Savino; from Hopital Tenon, Paris, France, Dr
Etienne Roullet; from FLENI, Argentina, Dr Jorge Correale and Dr Celica Ysrraelit; from
Ospedale di Macerata, Italy, Dr Elisabetta Cartechini and Mr Eugenio Pucci; from John
Hunter Hospital, Australia, Dr David Williams and Dr Lisa Dark; from Sheba Medical Center,
Tel Hashomer, Israel, Dr Joab Chapman; from Hospital Fernandez, Argentina, Dr Norma Deri;
from Hospital Ecoville, Brazil, Dr Walter Oleschko Arruda; from HIGA Gral. San Martin La
Plata, Argentina, Dr Santiago Vetere; from Jahn Ferenc Teaching Hospital, Hungary, Dr Csilla
Rozsa and Dr Krisztian Kasa; and from Thomas Jefferson University, Philadelphia, USA, Dr
Donald McCarren.
NOTES
*Cumulative hazard function is interpreted as the most probable count of repeatable events
that would be expected for each individual by defined time, if the exposure to the risk
started at time 0.
†In
these patients, the start of the 10-year follow-up period did not coincide with their
disease onset. The diagnosis of relapsing-remitting MS was based on their relapse activity
preceding the recorded follow-up.
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TABLES
Table 1
Characteristics of the studied population with relapsing MS course
females
males
8295
3275
- at inclusion, years
37.0 ± 11.2
37.2 ± 11.2
0.02
- at censoring, years
44.1 ± 11.7
44.4 ± 11.5
0.02
Caucasian, number (%)
5102 (62%)
1992 (61%)
Hispanic, number (%)
123 (2%)
64 (2%)
Asian, number (%)
269 (3%)
7 (2%)
African, number (%)
44 (0.5%)
12 (0.4%)
other, number (%)
227 (3%)
117 (4%)
not specified, number (%)
2530 (31%)
1023 (31%)
5.8 (3, 9.5)
5.9 (3.1, 9.7)
0.01
- at inclusion, years*
2.9 (0.4, 9.3)
2.5 (0.4, 8.5)
0.11
- at censoring, years*
11.3 ( 6.2, 18.1)
10.8 (6.1, 17.5)
0.04
35725
12637
patients, number
Cohen’s d
age
ethnicity
follow-up duration, years*
disease duration
relapses, number
disease course
- at inclusion
CIS, number (%)
2981 (36%)
1240 (38%)
RRMS, number (%)
4731 (57%)
1721 (53%)
SPMS, number (%)
412 (5%)
182 (6%)
RPMS, number (%)
171 (2%)
132 (4%)
CIS, number (%)
1521 (18%)
669 (20%)
RRMS, number (%)
5488 (66%)
1984 (61%)
SPMS, number (%)
1115 (13%)
490 (15%)
RPMS, number (%)
171 (2%)
132 (4%)
- at inclusion, EDSS*
2 (1.5, 3.5)
2.5 (1.5, 4)
0.08
- at censoring, EDSS*
2.5 (1.5, 5)
3 (1.5, 6)
0.14
3956 (48%)
1617 (49%)
- at censoring
disability
received DMDs, number (%)
*, median (interquartile range); otherwise mean ± standard deviation are shown
CIS, clinically isolated syndrome; DMDs, disease modifying drugs; EDSS, Extended Disability Status
Scale; RPMS, relapsing-progressive multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis;
SPMS, secondary progressive multiple sclerosis
Table 2
Characteristics of the group with primary progressive MS course
patients, number(females, %)
881 (55%)
age
- at inclusion, years
49.4 ± 11.0
- at censoring, years
53.9 ± 11.2
follow-up duration, years*
2.6 (0.5, 7.0)
disease duration
- at inclusion, years*
5.8 (2.6, 11.4)
- at censoring, years*
10.8 (6.2, 17.5)
disability
- at inclusion, EDSS*
5 (3.5, 6.5)
- at censoring, EDSS*
6 (4, 7)
received DMDs, number (%)
190 (22%)
*, median (interquartile range); otherwise mean ± standard deviation are shown
DMDs, disease modifying drugs; EDSS, Extended Disability Status Scale
FIGURE LEGENDS
Figure 1
CONSORT flowchart of patient disposition
CIS, clinically isolated syndrome; MS, multiple sclerosis; PPMS primary progressive MS;
RPMS, relapsing-progressive multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SPMS,
secondary progressive multiple sclerosis
Figure 2
Incidence of relapses in women and men with relapse-onset disease course, stratified by
disease duration and chronological age
Patient disposition (A-B) is only shown for patients with complete respective observational
years. Annualised relapse rate unadjusted for other potential confounders (C-D) and
adjusted for age (E) or disease duration (F), treatment and pregnancy using Tweedie models
(E-F). Each patient contributed a single ARR at censoring. P-values for effects of sex, disease
duration and age are shown (Tweedie regression). Cumulative hazard functions for relapses
in female and male sub-populations, adjusted for age (G) or disease duration (H), treatment
and pregnancy using Andersen-Gill models (G-H), with each patient contributing multiple
time-to-relapse entries.
All results are stratified by disease duration (A, C, E, G) and patient age (B, D, F, H). Error
bars and dashed lines show 95% confidence intervals.
Figure 3
Female-to-male ratios stratified by disease duration and chronological age
Unadjusted distributions of the female-to-male (F:M) ratios by disease duration (A) and
patient age (B) are shown for patients with relapse-onset MS (blue marks) stratified by
annual relapse number and patients with primary progressive MS (yellow marks). Each point
represents a F:M ratio among the patients with corresponding number of relapses in a
completed observational year. Numbers of patients per timepoint are indicated. Patients
were allowed to contribute entries at multiple years. Estimated mean is shown as distanceweighted least squares surface (relapse-onset MS) and red least squares line (primary
progressive MS).The mean estimation does not extend beyond 2 relapses in patients with
more than 20 years of MS duration or 50 years of age, as the amount of the corresponding
data was insufficient.
Figure 4
Female-to-male ratios in relapse- vs. progressive-onset MS
Female-to-male ratios (F:M) by total number of relapses recorded over a 10-year follow-up
period. Patients with relapsing-remitting (n = 2969) and primary progressive MS course (n =
881) with 10-year follow-up data available are compared. Circle sizes indicate number of
patients within each stratum.