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Rejected
ATC codes:
L04AA27
EMLc
Indication
Relapsing-remitting multiple sclerosis
ICD11 code:
8A40.0
INN
Fingolimod
Medicine type
Chemical agent
List type
Complementary
(EML)
(EMLc)
(EMLc)
Formulations
Oral > Solid:
0.25 mg ;
0.5 mg
EML status history
Application rejected in 2019
(TRS
1021)
Sex
All
Age
Also recommended for children
Therapeutic alternatives
The recommendation is for this specific medicine
Patent information
Read more
about patents.
Wikipedia
DrugBank
Expert Committee recommendation
The Expert Committee acknowledged the important public health burden of MS
and the need for effective and affordable treatments and noted the large number
of supporting letters that were received in relation to the application.
The Committee appreciated the approach taken in the application to
propose a limited number of essential medicines for MS, but noted that the
superiority of the presented medicines over other therapeutic options in terms of
benefits, harms and affordability did not clearly emerge.
The Committee noted that some commonly used treatments were not
included (e.g. azathioprine, natalizumab, dimethyl fumarate, cladribine) or were
not given full consideration (rituximab) and the reasons for their exclusion were
not clear. The Committee also noted ongoing development in international MS
guidelines and would welcome a revised application for EML inclusion in the
future that considers the relative roles of all available medicines for MS.
In particular, the Committee noted the evidence presented in the
application in relation to rituximab. The Committee agreed that rituximab could
have a relevant clinical role in treatment of MS, and recommended that any future
application should include evidence for rituximab versus active comparators, not
just placebo.
The Committee, therefore, did not recommend the addition of glatiramer
acetate, fingolimod and ocrelizumab to the Model Lists at this time, and would
welcome a revised application which comprehensively reviews the relative roles
of relevant available medicines for MS.
Background
The application requested the addition of glatiramer acetate, fingolimod and
ocrelizumab to the complementary list of the EML and EMLc for use in the
treatment of multiple sclerosis.
In 2015, the Expert Committee reviewed an application requesting addition
of azathioprine to the EML for the treatment of multiple sclerosis (MS).
The Committee acknowledged the significant public health burden of MS
but noted the availability of a number of well-established and more recent
immunomodulating medicines for this condition. The Committee therefore
recommended that a comprehensive review be undertaken of all medicines used
for the management of relapsing–remitting and other forms of MS for future
consideration (1).
The Multiple Sclerosis International Federation (MSIF) is a non-state
actor in official relations with WHO. They convened a taskforce of global experts
in MS research and care to submit an application for disease-modifying therapies
(DMTs) for the treatment of MS to be included on the EML. All approved DMTs
used for the treatment of MS were summarized by comparative effectiveness
in a variety of clinical settings based on the recently published ECTRIMS/
EAN (European Committee for Treatment and Research for Multiple Sclerosis/
European Association of Neurology) Guideline on the pharmacological treatment
of people with MS (2). A comparison was also made with the American Academy
of Neurology guidelines on DMTs in MS (3).
Of the multiple therapies used for treating MS, the application
prioritized three medications to be included on the EML. Prioritization was
based on their efficacy/safety profiles, tolerability/liveability, monitoring needs,
route of administration, licensed use in paediatric-onset and primary progressive
MS, safety profile in pregnancy, and availability of generic and/or biosimilar
substitutes.
Public health relevance
Multiple sclerosis is an immune-mediated disorder of the central nervous system
(grey and white matter) characterized by inflammation, demyelination and
degenerative changes including neuroaxonal loss and progressive brain and spinal
cord atrophy. Approximately 85% of those with MS initially experience relapses
and remissions of neurological symptoms, (relapsing–remitting MS, RRMS), with
relapses often associated with new areas of central nervous system inflammation.
Gradual worsening in this population, with or without additional inflammatory
events, is known as secondary progressive MS. Progressive changes can occur at
any time in the disease course, but usually become more prominent over time.
Approximately 15% of people diagnosed with MS have a progressive course from
disease onset (primary progressive MS). Some with primary progressive MS may
have typical relapses later in their disease course, after a progressive course has
been established (4, 5).
In 2013, there were more than 2.3 million people with MS worldwide
(6, 7). The incidence and prevalence of MS are rising, with studies showing
significantly larger numbers than was previously estimated (8–15). Women are
disproportionally affected, with prevalence in females two to three times that in
males (7, 16). Although the cause is not fully understood, MS is considered to
have complex causality blending genetic risk and environmental factors. People
can be diagnosed throughout the age range, though MS is most often diagnosed
between the ages of 20 and 50 years. Onset may also occur in childhood, and
it is estimated that 3% to 10% of all individuals with MS experience their first
attack prior to age 18 years (17). The incidence of paediatric-onset MS in
North American and European studies has been reported to be between 0.13 to
0.6 cases per 100 000 children (18).
Symptoms of MS negatively impact functional abilities and quality of life,
and often include overwhelming fatigue, mood and cognitive changes, mobility
impairment, sensory impairment, visual disturbances, sexual dysfunction, and
impaired bowel and bladder control. People with MS report lower health-related
quality of life compared to other populations – including those with other
chronic illnesses. The prevalence of depression is estimated to be 70% in people
with MS (19).
The goal of treatment is to reduce the long-term burden of the disease,
i.e. to delay disability progression and to prevent secondary progressive MS
(20). Quality of life and the socioeconomic burden of MS are closely linked to
disability, therefore, delaying and preventing disability worsening will have a
major impact for individuals with the disease and for society (21).
Benefits
Glatiramer acetate
Three trials (3217 patients) compared glatiramer acetate with placebo in patients
with RRMS with follow up ranging from 52 to 104 weeks (22–24). Compared
to placebo, glatiramer acetate lowered annualized relapse rates for follow ups of
52–96 weeks (mean difference (MD) −0.14, 95%CI −0.21 to −0.06, moderate
quality evidence, n=2117, two studies) and resulted in more patients free from
relapse at one to two years follow up (RR 1.17, 95%CI 1.10 to 1.24, moderate
quality evidence, n=2360, three studies). Glatiramer acetate was also shown to
result in a lower number of cumulative gadolinium-enhancing (GAD) lesions
(MD −0.73, 95%CI −1.15 to −0.31, high quality evidence, n=1325, one
study) and new or newly enlarging T2 lesions at 6 and 12 months follow up
(MD −1.94, 95%CI −3.03 to −0.85, high quality evidence, n=1325, one study)).
Low quality evidence showed a non-statistically significant effect on disability at
two years follow up (RR 0.86, 95%CI 0.66 to 1.11, n=964, two studies).
Four trials compared glatiramer acetate to interferon in patients with
RRMS (25–28). At two years’ follow up, the number of participants free from
relapse did not significantly differ (RR 0.98, 95%CI 0.90 to 1.06, moderate quality
evidence, n=2175, 3 studies), nor did extent of disability worsening (RR 1.07,
95%CI 0.83 to 1.31, one study).
One trial (970 patients) compared glatiramer acetate to placebo for
patients with primary-progressive MS (29). There was a non-significant effect on
the number of participants with disability worsening (RR 0.87, 95%CI 0.75 to
1.02) and longer time to disability worsening (HR 0.87, 95%CI 0.71 to 1.07) in
the glatiramer acetate group.
Fingolimod
Two trials compared fingolimod with placebo in patients with RRMS, with
two years follow up (30, 31). A larger proportion of patients were free from
relapse at two years in the fingolimod arm (RR 1.44, 95%CI 1.28 to 1.63,
moderate quality evidence, n=2355). The annualized relapse rate was also lower
in the fingolimod arm (MD −0.21, 95%CI −0.25 to −0.16, moderate quality
evidence). Fingolimod-treated patients had a lower risk of disability worsening
compared to placebo (RR 0.71, 95%CI 0.56 to 0.90, moderate quality evidence,
n=2355). Patients also had fewer new or newly enlarged T2 lesions (RR 2.16,
95%CI 1.77 to 2.63, moderate quality evidence, n=1192) and fewer GAD lesions
(MD −0.87, 95%CI −1.10 to −0.64, moderate quality evidence, n=1216, two
studies) at two years follow up. According to one study, fingolimod reduced
percent change in brain volume at one to two years follow up (MD 0.3, 95%CI
0.16 to 0.44, moderate quality evidence, n=685).
One trial compared fingolimod with interferon in patients with RRMS
(32). Moderate quality evidence showed that participants in the fingolimod
arm had lower annualized relapse rates (MD −0.17, 95%CI −0.26 to −0.08,
n=860), and more participants were free from relapse at one year (RR 1.19,
95%CI 1.11 to 1.29, n=860) than the interferon group. Fingolimod was also
associated with fewer new or newly enlarged T2 lesions (MD −0.90, 95%CI
−1.62 to −0.18, n=733) and GAD lesions (MD −0.28, 95%CI −0.50 to −0.06,
n=728). There was no significant difference in extent of disability progression
between fingolimod and interferon in the trial.
A Phase III trial investigated the safety and efficacy of fingolimod versus
interferon beta-1a, in 215 children and adolescents (ages 10 to 17) with MS.
Fingolimod significantly reduced annualized relapse rates by 82% (absolute
difference, 0.55; 95%CI 0.36 to 0.74; relapses RR 0.18, 95%CI 0.11 to 0.30) over
a period of up to two years compared to interferon beta-1a; reduced the number
of new or newly enlarged T2 lesions up to 24 months by 53% (RR 0.47, 95%CI
0.36 to 0.62) and reduced the average number of gadolinium-enhancing T1
(Gd+) lesions per scan at 24 months by 66.0% (RR 0.34, 95%CI 0.22 to 0.54).
Fingolimod was associated with a higher rate of serious adverse events (16.8% vs
6.5%) (33).
One trial (970 participants) compared fingolimod with placebo in
patients with primary-progressive MS (34). There was no difference in disability
progression at 156 weeks follow up between fingolimod or placebo (RR 0.93,
95%CI 0.80 to 1.08, moderate quality evidence). The adjusted annualized relapse
rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute
difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary
end point of the annualized rate of new or newly enlarged lesions on T2-weighted
magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with
interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%;
P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in
88.8% of patients who received fingolimod and 95.3% of those who received
interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in
the fingolimod group and included infection (in four patients) and leukopenia
(in two patients). Six patients had convulsions. Serious adverse events occurred
in seven patients (6.5%) in the interferon beta-1a group and included infection
(in two patients) and supraventricular tachycardia (in one patient).
Ocrelizumab
A Phase II trial compared ocrelizumab (low and high dose) and placebo in
patients with RRMS. At the end of the 24 weeks participants in both ocrelizumab
groups had lower numbers of active brain lesions compared to the placebo group
(89%, 95%CI 68 to 97, lower in low dose ocrelizumab group and 96%, 95%CI
89 to 99, lower in high dose ocrelizumab group). Annualized relapse rates over
the 24 weeks were 0.13 (95%CI 0.03 to 0.29) in the low dose ocrelizumab group
and 0.17 (95%CI 0.05 to 0.35) in the high dose ocrelizumab group compared to
the 0.64 rate (95%CI 0.43 to 0.94) of the placebo group. Findings also showed that
both doses of ocrelizumab were effective in reducing MRI and clinical disease
activity (35).
Two Phase III clinical trials, OPERA I and OPERA II, compared the
effects of ocrelizumab (600 mg every 24 weeks) with interferon beta-1b (44 µg
three times a week) for 96 weeks. Clinical outcomes from 1656 participants
show significantly reduced annualized relapse rates with ocrelizumab compared
to interferon beta-1a at two years (MD −0.13, 95%CI −0.18 to −0.08) thus
meeting its primary endpoint. Secondary outcomes showed ocrelizumab had
lower rate of disability progression. For the total trial period of 96 weeks, the
rate of disability progression at 24 weeks was 6.9% vs 10.5% in the ocrelizumab
and interferon beta-1a groups, respectively (HR 0.60; 95%CI 0.43 to 0.84).
Patients in the ocrelizumab group also had fewer GAD lesions (36).
One trial compared ocrelizumab to placebo in patients with primary
progressive MS. The ocrelizumab group had a greater time to disability
progression at 120 weeks follow up when confirmed at both 12 weeks (HR 0.76,
95%CI 0.59 to 0.98, high quality evidence, n=732) and 24 weeks (HR 0.75,
95%CI 0.58 to 0.97, high quality evidence, n=732) (37).
Rituximab
A 2013 Cochrane systematic review found one trial comparing rituximab to
placebo in 104 adult patients with RRMS (38). The mean number of total GAD
lesions, the primary endpoint of this double-blind Phase II trial, was significantly
decreased in patients receiving rituximab after 12, 16, 20 and 24 weeks (−5.0,
95%CI −9.99 to −0.01). The proportion of patients with relapses was significantly
reduced in the rituximab group, both after 24 weeks (14.5% vs 34.3% in the
placebo group; p=0.02) and 48 weeks (20.3% vs 40.0%, p=0.04) (39). A Phase II
open-label study of 26 patients with RRMS receiving rituximab at baseline and
six months found that mean annualised relapse rate reduced from 1.27 to 0.23,
and mean number of GAD lesions reduced from 1.31 to 0.05 at week 48 and 0.0
at week 72. Mean number of new or newly enhancing T2 lesions also decreased
from 0.92 at week 4 to 0.0 at week 72 (40).
A randomized controlled trial (439 participants) compared rituximab
versus placebo in patients with primary progressive MS (41). Patients were
randomized (2:1) to receive two intravenous doses (two weeks apart) of
rituximab (n=292) or placebo (n=147) infusions every 24 weeks, for 96 weeks.
Results showed that fewer in the rituximab group (30.2%) experienced 12 weeks
confirmed disease progression during 96 weeks compared to 38.5% in the
placebo group, but the difference did not reach statistical significance (p=0.14).
However, in a predefined sub-analysis, rituximab showed a significant effect
in patients with active MRI lesions or aged less than 51 years. This effect was
comparable with the effect seen in the ocrelizumab trial, which only included
patients below the age of 55.
Real-world data on treatment with rituximab in MS was available from a
study that examined the disease course of 822 MS patients, 557 with RRMS, 198
with secondary progressive MS and 67 with primary progressive MS, who were
followed for a mean duration of 22 months (42). RRMS patients treated with
rituximab had a yearly relapse rate of 0.044 during the study period. In total,
5.2% of the patients stopped treatment because of side-effects or disease activity.
The ratio of GAD lesions per MRI dropped significantly from approximately
three months after treatment initiation, and was in total 0.054, present in 2.2%
of MRIs. Moreover, the registry data suggest that the treatment efficacy of
rituximab in RRMS could exceed the effect of fingolimod, dimethyl fumarate
and beta-interferons. In addition, adherence was higher and side-effects were
comparable to all other drugs (43, 44).
Harms
The application presented a summary description of adverse events associated
with glatiramer acetate, fingolimod and ocrelizumab, and their associated
frequencies, as reported in the respective approved prescribing information
documents.
Common and very common adverse events associated with glatiramer
acetate include injection site reactions, lipoatrophy, vasodilation, rash, dyspnoea,
chest pain and lymphadenopathy.
Common and very common adverse events associated with fingolimod
include headache, influenza, diarrhoea, back pain, elevated liver enzymes, cough,
first-dose bradycardia, macular oedema, lymphopenia and bronchitis.
Common and very common adverse events associated with ocrelizumab
include infusion reactions and infections. Ocrelizumab has also been associated
with a possible increased risk of malignancies.
Additional evidence
Glatiramer acetate
A 2016 Cochrane systematic review of six trials (2904 participants) compared
the safety and efficacy of glatiramer acetate and beta-interferons (45). Both
medicines showed similar clinical efficacy at 24 months (three studies) for
number of participants with relapse (RR 1.04, 95%CI 0.87 to 1.24) or confirmed
progression (RR 1.11, 95%CI 0.91 to 1.35). At 36 months, results from a single
study suggested that relapse rates were higher in the IFN group than in the GA
group (RR 1.40, 95%CI 1.13 to 1.74). However, greater and faster reduction in
MRI lesion load accrual was observed in IFN‐treated compared with GA‐treated
participants with MS (MD for T2 weighted lesion volume −0.58, 95%CI −0.99
to −0.18). Reviewers interpretation of overall evidence quality was cautious: the
number of studies and participants was limited, the heterogeneity among studies
was high and the clinical relevance of scales to measure disease progression was
considered doubtful. The number of participants who withdrew from or dropped
out of the study because of adverse events was available for four studies (2685
participants; 93%). No differences were found between the two treatment groups
(RR 0.95, 95%CI 0.64 to 1.40). Results were similar for severe adverse events
(RR 0.99, 95%CI 0.63 to 1.56).
A 2018 network meta-analysis including direct and indirect evidence,
including 24 trials published between 1987 and 2015, yielded a more precise
estimate of effectiveness for both interferon beta-1a once a week versus placebo
(HR 0.73, 95%CI 0.53 to 1.00) and glatiramer acetate (HR 0.76, 95%CI 0.60
to 0.97) at three months (46). There was little evidence of superiority of one
drug over another but ranking of the medicines suggested that interferon
beta-1a three times weekly had the highest cumulative probability of superiority.
Interpretation of these findings should take into consideration the short length
of follow up, the high risk of bias across studies, and the potential differences
among trials that may act as effect modifiers and introduce bias in the network
meta-analysis. This review also considered discontinuation due to adverse
events, at different follow up times. Evidence that one medicine was more likely
to lead to discontinuation than another was limited, as the confidence intervals
were wide: more discontinuation were observed with interferon beta-1a three
times weekly versus placebo (RR 2.49, 95%CI 0.89 to 6.95) and with glatiramer
acetate (RR 2.36, 95%CI 0.74 to 7.53).
Fingolimod
A 2016 Cochrane systematic review of six trials (5512 participants) compared
the safety and efficacy of fingolimod versus placebo or other disease modifying
treatment for RRMS (47). Compared to placebo, fingolimod at 24 months
increased the probability of being relapse‐free (RR 1.44, 95%CI 1.28 to 1.63);
moderate quality of evidence), little or no difference in preventing disability
progression was observed (RR 1.07, 95%CI 1.02 to 1.11; primary clinical
endpoints; low quality evidence). Benefit was observed for other measures
of inflammatory disease activity including annualized relapse rate and GAD
lesions. No significant increased risk of discontinuation due to adverse events
was observed for fingolimod at recommended dose compared to placebo at six
and 24 months. No significant increased risk of discontinuation due to serious
adverse events was observed for fingolimod 0.5 mg compared to placebo at six
and 24 months. A significant increased risk of discontinuation due to serious
adverse events was found for fingolimod 5.0 mg (RR 2.77, 95%CI 1.04 to 7.38)
compared to placebo at six months.
Compared to intramuscular interferon beta‐1a, there was moderate
quality evidence fingolimod 0.5 mg at one year slightly increased the number of
participants free from relapse (RR 1.18, 95%CI 1.09 to 1.27) or from GAD lesions
(RR 1.12, 95%CI 1.05 to 1.19), and decreased the relapse rate (rate ratio 0.48,
95%CI 0.34 to 0.70). There was no observed advantage for preventing disability
progression (RR 1.02, 95%CI 0.99 to 1.06; low quality evidence).
There was a greater likelihood of participants discontinuing fingolimod,
compared to other DMTs, due to adverse events at six months (RR 3.21, 95%CI
1.16 to 8.86), but there was no significant difference versus interferon beta‐1a at
12 months (RR 1.51, 95%CI 0.81 to 2.80; moderate quality evidence). A higher
incidence of adverse events was suggestive of the lower tolerability rate of
fingolimod compared to interferon‐beta 1a.
Cost / cost effectiveness
The cost-effectiveness of disease modifying treatments for MS have been assessed
in multiple systematic reviews involving studies conducted in high-income
countries in Europe and North America (48–51). The studies reported that DMTs
(including glatiramer acetate, fingolimod, ocrelizumab and rituximab) were
potentially cost-effective but several studies reported costs that were likely to be
above particular countries’ willingness to pay thresholds. Limitations of these
studies noted in these reviews included the lack of head-to-head comparisons
between different DMTs, variation in time-horizons, and variation in end-points.
There were no cost-effectiveness studies identified from LMICs.
Though there is significant variance globally, a North American study
suggested that approximately 60% of people with MS are unemployed (52),
accounting for about one third of the total economic burden of MS (53). In
addition to a loss in productivity, people with MS will have additional care
needs with advancing age and disease severity. The economic burden of MS
per patient and year ranges from approximately US$ 24 666 to US$ 51 678 (54).
These amounts represent direct costs, which include in and out patient care,
medications, medical procedures and social services as well as indirect costs
related to loss of employment, disability benefits, early pension plans, and loss of
productivity for spouses or family members providing informal care and death.
Given the most frequent age of presentation (young adults), it is important to
note that MS has both physical and cognitive impact, and also impacts the family
development of the patients, as well as, determines a socioeconomic impact on
society as a whole.
WHO guidelines
None available.
Availability
Glatiramer acetate has marketing approval in many countries. Generic versions
of glatiramer acetate are available in some countries – for example, in India,
the Russian Federation and the United States. Secondary patents concerning
glatiramer acetate are active in some jurisdictions.
Fingolimod also has marketing approval in many countries. Price and
availability of fingolimod vary globally. Generic versions are available. The
main product patent on fingolimod appears not to have been filed in the LMIC
jurisdictions surveyed and expires between 2016 and 2018 in some European
countries and 2019 in the United States.
Ocrelizumab has marketing approval in 68 high- and middle-income
countries. Ocrelizumab is protected by a product patent expiring in 2023 in
many jurisdictions. It is likely that biosimilar ocrelizumab cannot enter the
market where this patent has been granted before 2023.
Rituximab has marketing approval for indications other than multiple
sclerosis in high-, middle- and low-income countries. Biosimilar versions of
rituximab have been approved in numerous countries, including Australia,
Bolivia, Chile, India, Peru, the Republic of Korea, and the European Union.
Other considerations
Use in pregnancy
A pregnancy registry maintained by the marketing company of branded
glatiramer acetate captured over 7000 pregnancies exposed to glatiramer acetate.
It did not find an increase in spontaneous abortions, premature births, neonatal
complications or birth defects (55). No significant differences were observed in
birth weight of babies born to mothers exposed to glatiramer during pregnancy
compared with mothers not exposed to glatiramer acetate during pregnancy.
Evidence supports the use of branded glatiramer acetate in pregnant women
who are recommended to remain on treatment to manage disease activity.
Fingolimod is a teratogen class C agent and should be considered an
absolute contraindication in pregnancy and breastfeeding based on its known
teratogenicity in animal studies and post-marketing data.
Ocrelizumab is known to cross the placental barrier and is recommended
to be avoided during pregnancy unless the potential benefit to the mother
outweighs the potential risk to the fetus. There are no adequate data on the
developmental risk associated with use of ocrelizumab in pregnant women.
For rituximab, a large cohort study found that out of 153 pregnancies,
90 resulted in live births (56). Twenty-two infants were born prematurely;
with one neonatal death at six weeks. Eleven neonates had haematologic
abnormalities; none had corresponding infections. Two congenital malformations
were identified.
The European League Against Rheumatism (EULAR) considered use of
rituximab before pregnancy and during pregnancy (57). Based on a systematic
literature and consensus among experts, the recommendation considered that
rituximab should be replaced by other medication before conception. It should
be used during pregnancy only when no other pregnancy-compatible drug can
effectively control maternal disease.
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2015 (including
the 19th WHO Model List of Essential Medicines and the 5th WHO Model List of Essential Medicines
for Children) (WHO Technical Report Series, No. 994). Geneva: World Health Organization; 2015.
Available from https://apps.who.int/iris/bitstream/handle/10665/189763/9789241209946_eng.
pdf, accessed 30 October 2019.
2. Montalban X, Gold R, Thompson AJ, Otero-Romero S, Amato MP, Chandraratna D et al. ECTRIMS/
EAN Guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler.
2018;24(2):96–120.
3. Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS et al. Practice guideline
recommendations summary: Disease-modifying therapies for adults with multiple sclerosis:
Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the
American Academy of Neurology. Neurology. 2018;90(17):777–88.
4. Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol. 2014;72 Suppl 1:1–5.
5. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M et al. The relation
between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(Pt
5):1175–89.
6. Browne P, Chandraratna D, Angood C, Tremlett H, Baker C, Taylor BV et al. Atlas of Multiple Sclerosis
2013: A growing global problem with widespread inequity. Neurology. 2014;83(11):1022–4.
7. Atlas of MS 2013: mapping multiple sclerosis around the world. London: Multiple Sclerosis
International Federation; 2013. Available from: http://www.msif.org/about-us/advocacy/reportsand-resources/, accessed 29 September 2019.
8. Marrie RA, Yu N, Blanchard J, Leung S, Elliott L. The rising prevalence and changing age distribution
of multiple sclerosis in Manitoba. Neurology. 2010;74(6):465–71.
9. Mackenzie IS, Morant SV, Bloomfield GA, MacDonald TM, O’Riordan J. Incidence and prevalence
of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research
Database. J Neurol Neurosurg Psychiatry. 2014;85(1):76–84.
10. Benito-Leon J. Multiple sclerosis: is prevalence rising and if so why? Neuroepidemiology.
2011;37(3-4):236–7.
11. Amankwah N, Marrie RA, Bancej C, Garner R, Manuel DG, Wall R et al. Multiple sclerosis in Canada
2011 to 2031: results of a microsimulation modelling study of epidemiological and economic
impacts. Health Promot Chronic Dis Prev Can. 2017;37(2):37–48.
12. Sahraian MA, Sahebkar M, Dehghani R, Derakhshan-Jazari M, Kazami-Moghaddam V, Kouchaki E.
Multiple sclerosis-A disease on a dramatically rising trend in Iran: Review of possible reasons. Iran
J Neurol. 2017;16(1):34–40.
13. Chinea A, Rios-Bedoya CF, Vicente I, Rubi C, Garcia G, Rivera A et al. Increasing Incidence and
Prevalence of Multiple Sclerosis in Puerto Rico (2013-2016). Neuroepidemiology. 2017;49(3-
4):106–12.
14. Brola W, Sobolewski P, Flaga S, Fudala M, Jantarski K. Increasing prevalence and incidence of
multiple sclerosis in Poland. Neurol Neurochir Pol. 2017;51(1):82–5.
15. Bezzini D, Policardo L, Profili F, Meucci G, Ulivelli M, Bartalini S et al. Multiple sclerosis incidence
in Tuscany from administrative data. Neurol Sci. 2018;39(11):1881–5.
16. Ascherio A, Munger KL. Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention-An
Update. Semin Neurol. 2016;36(2):103–14.
17. Chitnis T. Disease-modifying therapy of pediatric multiple sclerosis. Neurotherapeutics. 2013;
10(1):89–96.
18. Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B. Multiple sclerosis in
children: an update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol.
2014;13(9):936–48.
19. Marrie RA, Fisk JD, Tremlett H, Wolfson C, Warren S, Tennakoon A et al. Differences in the burden
of psychiatric comorbidity in MS vs the general population. Neurology. 2015;85(22):1972–9.
20. Giovannoni G, Butzkueven H, Dhib-Jalbut S, Hobart J, Kobelt G, Pepper G et al. Brain health: time
matters in multiple sclerosis. Mult Scler Relat Disord. 2016;9 Suppl 1:S5–s48.
21. Kobelt G, Thompson A, Berg J, Gannedahl M, Eriksson J. New insights into the burden and costs
of multiple sclerosis in Europe. Mult Scler. 2017;23(8):1123–36.
22. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP et al. Copolymer 1 reduces
relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase
III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study
Group. Neurology. 1995;45(7):1268–76.
23. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M et al. Placebo-controlled phase 3
study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087–97.
24. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R. Three times weekly glatiramer acetate in
relapsing-remitting multiple sclerosis. Ann Neurol. 2013;73(6):705–13.
25. Mikol DD, Barkhof F, Chang P, Coyle PK, Jeffery DR, Schwid SR et al. Comparison of subcutaneous
interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif
vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised,
parallel, open-label trial. Lancet Neurol. 2008;7(10):903–14.
26. Cadavid D, Wolansky LJ, Skurnick J, Lincoln J, Cheriyan J, Szczepanowski K et al. Efficacy of
treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME
study. Neurology. 2009;72(23):1976–83.
27. Calabrese M, Bernardi V, Atzori M, Mattisi I, Favaretto A, Rinaldi F et al. Effect of disease-modifying
drugs on cortical lesions and atrophy in relapsing-remitting multiple sclerosis. Mult Scler.
2012;18(4):418–24.
28. O’Connor P, Filippi M, Arnason B, Comi G, Cook S, Goodin D et al. 250 microg or 500 microg
interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a
prospective, randomised, multicentre study. Lancet Neurol. 2009;8(10):889–97.
29. Wolinsky JS, Narayana PA, O’Connor P, Coyle PK, Ford C, Johnson K et al. Glatiramer acetate in
primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind,
placebo-controlled trial. Ann Neurol. 2007;61(1):14–24.
30. Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P et al. A placebo-controlled trial
of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401.
31. Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT et al. Safety and efficacy of
fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind,
randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(6):545–56.
32. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X et al. Oral fingolimod or
intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.
33. Chitnis T, Arnold DL, Banwell B, Bruck W, Ghezzi A, Giovannoni G et al. Trial of Fingolimod versus
Interferon Beta-1a in Pediatric Multiple Sclerosis. N Engl J Med. 2018;379(11):1017–27.
34. Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H et al. Oral fingolimod in
primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebocontrolled trial. Lancet. 2016;387(10023):1075–84.
35. Kappos L, Li D, Calabresi PA, O'Connor P, Bar-Or A, Barkhof F et al. Ocrelizumab in relapsingremitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet.
2011;378(9805):1779–87.
36. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B et al. Ocrelizumab versus
Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017;376(3):221–34.
37. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G et al. Ocrelizumab versus Placebo
in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017;376(3):209–20.
38. He D, Guo R, Zhang F, Zhang C, Dong S, Zhou H. Rituximab for relapsing-remitting multiple
sclerosis. Cochrane Database Syst Rev. 2013(12):CD009130.
39. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ et al. B-cell depletion with rituximab in
relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676–88.
40. Bar-Or A, Calabresi PA, Arnold D, Markowitz C, Shafer S, Kasper LH et al. Rituximab in relapsingremitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol. 2008;63(3):395–400.
41. Hawker K, O’Connor P, Freedman MS, Calabresi PA, Antel J, Simon J et al. Rituximab in patients with
primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled
multicenter trial. Ann Neurol. 2009;66(4):460–71.
42. Salzer J, Svenningsson R, Alping P, Novakova L, Bjorck A, Fink K et al. Rituximab in multiple sclerosis:
A retrospective observational study on safety and efficacy. Neurology. 2016;87(20):2074–81.
43. Granqvist M, Boremalm M, Poorghobad A, Svenningsson A, Salzer J, Frisell T et al. Comparative
Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis. JAMA
Neurol. 2018;75(3):320–7.
44. Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Bjorck A et al. Rituximab versus
fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 2016;79(6):950–8.
45. La Mantia L, Di Pietrantonj C, Rovaris M, Rigon G, Frau S, Berardo F et al. Interferons-beta versus
glatiramer acetate for relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev.
2016;11:CD009333.
46. Melendez-Torres GJ, Armoiry X, Court R, Patterson J, Kan A, Auguste P et al. Comparative
effectiveness of beta-interferons and glatiramer acetate for relapsing-remitting multiple sclerosis:
systematic review and network meta-analysis of trials including recommended dosages. BMC
Neurol. 2018;18(1):162.
47. La Mantia L, Tramacere I, Firwana B, Pacchetti I, Palumbo R, Filippini G. Fingolimod for relapsingremitting multiple sclerosis. Cochrane Database Syst Rev. 2016;4:CD009371.
48. Sharac J, McCrone P, Sabes-Figuera R. Pharmacoeconomic considerations in the treatment of
multiple sclerosis. Drugs. 2010;70(13):1677–91.
49. Hawton A, Shearer J, Goodwin E, Green C. Squinting through layers of fog: assessing the
cost effectiveness of treatments for multiple sclerosis. Appl Health Econ Health Policy. 2013;
11(4):331–41.
50. Thompson JP, Abdolahi A, Noyes K. Modelling the cost effectiveness of disease-modifying
treatments for multiple sclerosis: issues to consider. Pharmacoeconomics. 2013;31(6):455–69.
51. Hernandez L, O'Donnell M, Postma M. Modeling Approaches in Cost-Effectiveness Analysis of
Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: An Updated Systematic
Review and Recommendations for Future Economic Evaluations. Pharmacoeconomics. 2018;
36(10):1223–52.
52. Dobrescu A, Dinh T, Stonebridge C. Multiple Sclerosis in the Workplace: Making the Case for
Enhancing Employment and Income Supports. Ottawa: The Conference Board of Canada; 2018.
Available from https://www.conferenceboard.ca/e-library/abstract.aspx?did=9611, accessed 29
September 2019.
53. Dinh T, Astles P, Turpin K. Multiple Sclerosis in the Workplace: Supporting Successful Employment
Experiences. Ottawa: The Conference Board of Canada, 2016. Available from: https://www.
conferenceboard.ca/e-library/abstract.aspx?did=7921, accessed 29 September 2019.
54. Ernstsson O, Gyllensten H, Alexanderson K, Tinghog P, Friberg E, Norlund A. Cost of Illness of
Multiple Sclerosis - A Systematic Review. PLoS One. 2016;11(7):e0159129.
55. Sandberg-Wollheim M, Neudorfer O, Grinspan A, Weinstock-Guttman B, Haas J, Izquierdo G et al.
Pregnancy Outcomes from the Branded Glatiramer Acetate Pregnancy Database. Int J MS Care.
2018;20(1):9–14.
56. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to
rituximab. Blood. 2011;117(5):1499–506.
57. Gotestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C et al. The
EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy
and lactation. Ann Rheum Dis. 2016;75(5):795–810.