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CNS & Neurological Disorders - Drug Targets, 2012, 11, 000-000
1
Disease Modifying Drugs in Multiple Sclerosis: Mechanisms of Action and New
Drugs in the Horizon
Monica Marta*,1 and Gavin Giovannoni1
1
Queen Mary University of London, Blizard Institute,
Barts & The London School of Medicine and Dentistry, London, UK
Abstract: The term “disease modifying drugs” (DMD) is taken from rheumatologists who coined it after the use of
immunosuppressive drugs and, more recently, the association of “biological drugs” that changed the degenerative course of
rheumatic disease.
In the treatment of multiple sclerosis (MS), the advent of interferon (IFN), which caused a reduction in the number of
relapses and possibly improvement in disability outcomes, was the first strategy to prevent inflammatory damage in the
central nervous system (CNS). Soon after, glatiramer acetate showed similar results. It would be more than a decade
before natalizumab was licensed, showing a much better efficiency in relapse reduction than was seen after first-line
therapies failed. The pipeline is now much larger with several drugs on the horizon. Overall, the anti-inflammatory
strategy has been mostly successful but drugs that have protection and repair mechanisms are still missing.
Keywords: multiple sclerosis, treatments, mechanisms of action
FIRST-LINE DISEASE MODIFYING DRUGS
Mechanisms of Action
Interferon-
Since IFN- was shown to have a beneficial effect in MS,
its mechanisms of action have been investigated, but the
biological effects are wide and can be opposing in different
cell types.
Interferons are naturally occurring glycoproteins that
function as signals between cells -hence called cytokines.
They have roles in hematopoiesis and innate and acquired
immunity to infection, cancer and autoimmunity through the
activation of immune cells, increased recognition of infected
or tumour cells by upregulation of antigen presentation and
other mechanisms. In humans, IFNs are divided into three
groups: type I IFNs include IFN- , IFN- and IFN-, type II
IFNs include IFN- , and type III IFNs include IL10R2 and
CRF2-12 [1].
The IFNs pathways are central to innate immunity
mechanisms and are activated upon ligation of pathogen- and
danger-associated molecular patterns (PAMP and DAMP) to
pattern recognition receptors (PRR). The toll-like receptor
(TLR)-dependent expression of IFN- is one of the links
between innate and adaptive immunity, as type I IFN
(IFNAR1 and IFNAR2c) are present in antigen presenting
cells but also T-cells. Type I IFNs also induce the synthesis
of several key antiviral mediators including
2'-5'
oligoadenylate synthetase (2'-5'OAS),
2-microglobulin,
neopterin and protein kinase receptor (PKR).
For commercial use, human IFN- 1a is produced in
mammalian cells (Chinese Hamster Ovary cells), has 166
residues and is glycosylated like mammalian proteins. On the
other hand, human IFN- 1b is produced in E. coli, has no
carbohydrates on any of the 165 residues, and there is a
substitution of cysteine 17 with serine in comparison with the
naturally occurring IFN- 1a.
*Address correspondence to this author at the Barts & The London School of
Medicine and Dentistry, London, UK; Tel: ++44 20 78822677; Fax: +44 20
78822180; E-mail: [email protected]
1871-5273/12 $58.00+.00
Overall, we currently consider there are inhibitory effects on
proliferation of leukocytes and less efficient antigen
presentation. Furthermore, IFN- modulates the profile of
cytokine production toward that of the anti-inflammatory
phenotype, and this appears to occur not only in the systemic
compartment but also within the CNS. Finally, IFN- can
reduce T-cell migration by inhibiting the activity of T-cell
matrix metalloproteinases (MMP) [2].
In vitro studies show that IFN- inhibits the proliferation
of T-cells, and reduces T-cell production of IFN- and
tumour necrosis factor (TNF)-[3]. Surprisingly, it increases
interleukin
(IL)-6 production in peripheral blood
mononuclear cells (PBMC) of MS patients [4] but decreases
the number of circulating IFN- and IL-4 producing T-cells
over time [5], simultaneously prolonging the survival of
memory T-cells. When subsets of PBMCs were analyzed,
IFN- showed regulatory effects on CD4+ T-cells
production of osteopontin, IL-17 and IL-21 in MS
patients when compared with healthy controls (HC) [5]. A
major change in the interpretation of the studies came when
the T-helper (Th) 1 versus Th2 dogma was challenged and
Th17 cells were shown to be involved in the pathology of
MS. In a longitudinal follow-up of 18 MS patients treated
with IFN- , Th17 cells were generally inhibited by IFNand their numbers were higher in active in comparison with
inactive MS [6]. In response to IFN- , IFN- receptor 1
expression, STAT (signal transducers and activators of
transcription)-1 activation, and apoptosis were significantly
greater in Th17 than Th1 cells. A recent study detected
induction of apoptosis in specific leukocyte subsets and
enhanced expression of TNFSF10
(TRAIL) (which
© 2012 Bentham Science Publishers
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CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5
sensitizes cells to apoptosis) on monocytes and granulocytes was
proposed as a response marker [7]. Changes were detected not
only
at
the
cellular
level
but
could also be detected in serum samples.
A
one
year
prospective study showed that serum MMP-8, MMP-9, IL12p40 and IL-23, but not IL-17, were decreased in MS
patients treated with IFN-1b; this laboratorial feature
correlated with a decrease in the number of contrastenhanced T1 magnetic resonance imaging (MRI) lesions [8].
IFNdecrease
the
permeability
of
the
blood brain barrier (BBB). Serum from IFN- 1b-treated
patients with early MS stabilized an in vitro model of the
BBB [9]. Indeed, IFNregulates CD73 and adenosine
expression on the BBB [10]. Importantly, the mechanisms of
reduction of lymphocyte transmigration through the BBB are
currently better understood and are affected by IFN- .
Transmigration involves increased expression of ecto-5'nucleotidase both on the BBB and astrocytes. CD73 is
required for efficient entry of lymphocytes into the CNS
system during experimental autoimmune encephalomyelitis
(EAE) and is strongly expressed in the microvasculature in
postmortem MS brains [11].
After many studies in MS and experimental autoimmune
encephalomyelitis (EAE), the reason why IFN- works in
some MS patients but not on others is still unknown. In fact,
except for some recent publications [12-14] that identify an
IFN pathway signature in MS patients who are nonresponders or responders, the initiation of therapy is still a
trial.
Clinical Trials of IFN- in Patients with Relapsing MS
(Table 1)
The initial clinical trial for IFN- in relapsing-remitting
(RR)MS eventually led to the licensing of IFN- 1b 250 μg
subcutaneous every other day (SC eod) (Betaseron in USA
and Betaferon in Europe) in this stage of disease [15, 16]. A
trial with IFN-1a 30 μg intramuscular (IM) weekly
(Avonex ) followed and the results were similarly
encouraging [17-19], with the benefit of being a drug closer
to the naturally occurring IFNs but also with a once weekly
formulation that constitutes an appealing feature. The same
IFN- 1a 22-44 μg three times per week (ttw) was later used
in a high dose/ high frequency (HD-HF) scheme formulation
(Rebif ); the clinical trial enrolled the largest number of
RRMS patients and had positive effects in relapse rate and
MRI markers) [20, 21]. Another trial was performed to
compare the effect of the two formulations of IFN- 1a,
Avonex and Rebif . Only when higher dose/ higher
frequency Rebif showed better results was it licensed by the
Food and Drug Administration (FDA) [22]. The long-term
follow up studies tend to follow mostly patients who stayed
on medication, who were the ones who were most likely to
have benefited from the drug [23-24].
In clinical practice, the safety of all IFN- drugs in the
short term is a critical point. There are risks of lymphopenia
and rarely neutropenia, which are not associated with a
higher frequency of viral, bacterial or fungal infections.
There is a risk of hepatic toxicity that is usually mild but can
be severe when not detected and may need steroid treatment.
Marta et al.
Regular blood tests, including full blood counts and liver
function tests, are required and when an abnormality is
detected and deemed clinically significant, the dose is
reduced or the medication is temporarily suspended. In most
cases, IFN- can be reintroduced when the values return to
normal.
The most common side-effects, almost in every person in the
initial injections, are flu-like symptoms. These can be
improved with pain killers, and anti-pyrexials such as nonsteroidal anti-inflammatories and paracetamol, and tend to
improve after about 3 months, but constitute an important
cause for discontinuation of therapy. Injection site reactions are
also very common, with different size erythematous and
oedematous lesions that can be pruriginous and last 2-20
days, very rarely leaving any scars. Strategies that include
rotation of injection sites, room temperature injections for
formulations that need to be kept cold, local ice postinjection and moisturizing creams are helpful.
The benefit of IFN- drugs in RRMS patients is accepted
by most neurologists and the regulatory authorities, and
current trials in these patients rarely use placebo arms.
The benefit for individual patients is sometimes difficult to
assess as the course of MS is unpredictable and disease can
be clinically dormant for several years. Also, there is no data
to predict a positive response or failure of treatment
beforehand. A close clinical and imaging observation after
about one year can predict the longer term benefit: new
significant clinical relapses, new MRI lesions and the
occurrence of both are signs of treatment failure and good
indicators for a medication switch.
Clinical Trials of IFN- in Patients with Clinically Isolated
Syndrome (Table 2)
The effect of IFN- s in patients with clinically isolated
syndrome (CIS) suggestive of MS has been tested and the
clinical trials described below have shown general benefits
in the rate of conversion to clinically definitive (CD) MS,
time to conversion to CDMS, and MRI markers. Depending
on the countries, the results have been more difficult to
translate to clinical practise.
A
placebo-controlled
trial
of
IFN-1b (Betaseron /Betaferon ) early after CIS compared
with IFN-1b after CDMS showed benefit of early
treatment in measures related to conversion to CDMS.
Important information was gained from a late subgroup
analysis [23, 27] that showed that the risk of developing CDMS
was greater in patients who were on placebo (45%), who had
positive CSF (49%), had needed high dose steroid treatment
for the attack (48%) or if they were younger (<30 years 60%). The characteristics of the MRI that increased the risk
of CDMS for patients who were on placebo were: nine or
more MRI T2-lesions (48%) or one or more Gad-enhancing
T1 lesions (52%) or higher if they had both (75%).
Interestingly, five years after enrolment, a delay in treatment
by up to two years did not affect long-term disability
outcomes [26, 29-30]. IFN- 1a (Avonex ) was compared with
placebo after a CIS with characteristics of demyelination and
at least two characteristic T2 brain MRI lesions in the
CHAMPS study [27]. The trial was stopped after a preplanned interim analysis showed benefit of the active arm in
the delayed development of CDMS and less brain MRI
Recent Gains in Clinical Multiple Sclerosis Research
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5
3
Table 1. Clinical Trials of IFN- in Patients with Relapsing MS
1. Betaferon - IFN- 1b
Randomized
Double-blind
Placebocontrolled
372 RRMS
patients
EDSS <5.5
2 attacks in
prior 2 years
Placebo or
1.6MIU=50μg
8MIU=250μg
SC EOD
2 years
2 attacks in
prior 3 years
Placebo or
IFN 1-a
6MIU=30μg/wee
k IM
2 years
But only
172 at 2
years
Relapse rate reduction
IFN 1-b vs placebo: 34%, p<0.0001
MRI medium number T2
active lesions: -83%,
p<0.009
15-16
MRI T2 median disease
burden
-17.3%, p<0.16
2. Avonex - IFN- 1a
Multicentre
Randomized
Placebocontrolled
301 RRMS
patients
EDSS 1-3.5
1-point EDSS progression
rate: -37% p<0.02
Relapse rate reduction: 18% p<0.04
MRI medium number of
Gad enhancing lesions: 33%, p<0.05
MRI total volume of T2
lesion: ns
17-19
3. Rebif - IFN- 1a PRISMS (Prevention of Relapses and Disability by IFNbeta1a Subcutaneously in Multiple Sclerosis)
Multicentre
Randomized
Double-blind
Placebocontrolled
Blinded
Long-term
follow-up
Unblinded
560 RRMS
patients
EDSS <5.5
2 attacks in
prior 2 years
Placebo or
6MIU=22μg or
12MIU=44μg
ttw
Placebo
started on
44μg TTW
2 years
4 years
7-8 years
post
baseline
382/560
initial RRMS
Relapse rate reduction
44μg TTW vs placebo: 32%, p<0.005
1-point EDSS progression
rate: -30% p<0.05
Sustained clinical (relapse
rate and disability
progression) benefit from
the two doses
Patients earlier on 44μg
TTW showed lower
EDSS progression and
relapse rate
75/381 were SPMS
MRI medium number of
active T2 lesions: -78%,
p<0.0001
20
Volume of T2 white
matter disease: -14.7%,
p<0.0001
Sustained MRI benefit
from
both
doses
but
21
better with 44μg TTW
Patients earlier on 44μg
TTW showed lower T2
burden of disease
23
4. Rebif - IFN 1-a EVIDENCE (Evidence of Interferon Dose Response: European North American Comparative Efficacy)
Randomized
Controlled
Assessor
blinded
Parallel-group
677 RRMS
patients
EDSS<6.0
2 attacks in
prior 2 years
IFN 1-a
44μg ttw
SC
vs
30μg/week IM
24 and 48
weeks
24 weeks: 75% patients
on 44μg TTW vs 63%
patients on IM
30μg/week were relapse
free
48 weeks: the odds-ratio
of remaining relapse free
on 44μg TTW decreased
from 90% at 24 weeks to
50%
Combined MRI measure
(new or enlarging T2
lesions and T1 Gadenhancing lesions) and
use of steroids, time to
first relapse and
disability progression
were improved on higher
dose
22
5. Copaxone - Glatiramer Acetate (GA)
Randomized
Double-blind
Placebocontrolled
Multicentre
251 RRMS
patients
All on 20mg GA
SC
blinded
Open-label
Placebo or
20mg GA SC
208 MS
patients
All on 20mg GA
SC
2 years
Reduction in relapse rate
(29%, p=0.07),
annualized rate was 0.59
on GA and 0.84 on
placebo
Reduced median time to
first relapse
Further
1-11
months
Confirmed reduced
relapse rate (the relapse
rate for the switch from
placebo to GA decreased)
and slower neurological
disability
35
Risk of T1 Gadenhancing lesions was
2.5 higher and cerebral
atrophy worse for
patients on prior placebo
36
MRI features of 69
patients who were
initially on GA and 66
36 months
37-38
patients initially on
placebo with no major
differences
4
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5
Runia et al.
(Table 1) contd…..
6. Copaxone - Glatiramer Acetate (GA)
Randomized
Double-blind
Placebocontrolled
Long term
follow-up
239 RRMS
patients
At least 1
relapse in prior
2 years and T1
Gadenhancing
lesion
142 patients
73 patient
initially treated
with GA
Placebo or
20mgGA SC
9/12
blinded
followed
by 9/12
open label
with 224
patients
All on 20mgGA
Mean 5.8
years (5.36.4)
Total number of Gadenhancing lesions on
monthly brain MRI (1ry
end-point) was reduced
(-10.8%, p=0.003) in GA
treated group. Benefit for
39
GA group in proportion of
patients with Gadenhancing lesions, number of
new T2 lesions and
change in volume of
T1-weighted lesions.
Proportion of patients who
had EDSS<6.0 was lower
in group initially treated
with placebo.
MRI measures similar in
group initially on GA and
initially on placebo.
40
the 96 patients on IFN- 1b
showed less new MRI
active lesions
34,44
Head-to-Head Studies
7. INCOMIN
Randomized
open-label
IFN- 1b 250μg
EOD SC vs IFN1a 30μg week IM
RRMS
No differences between the
two therapies during the
initial 6 months; the benefit
2 years
of the high dose-high
frequency only detected at
one and two years
8. EVIDENCE
IFN- 1a
44μg SC ttw and
IFN- 1a
30μg/week IM
Randomized
open-label
1-2 years
Significant benefit of IFN1a 44μg SC ttw IFN- 1a
over 30μg/week IM during
22
the initial 24 weeks, but not
maintained for the
following 24 weeks
9. Danish Study
Randomized
Open-label
303 RRMS
patients
of IFN- : 8 MIU 1b SC every other
day with 6 MIU
IFN- 1a SC every
week
No difference was recorded
in any clinical outcome
measure between the two
doses of IFN-
MRI outcomes suggested
that the higher dose of
45
IFN- 1b might be superior
10. REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease)
Randomized
Open-label
Sub-study
764 RRMS
patients
230 patients
one or more
relapses in the
prior 12
months
no significant difference in
the time to first relapse
IFN- 1a 44 μg SC
ttw or GA 20μg
SC daily
46
(hazard ratio 0.94, 95% CI
0.74 to 1.21; p=0.64)
patients on IFN- 1a had
significantly fewer brain
Gad-enhancing T1 MRI
lesions than patients on
GA (0.24 vs 0.41 lesions
per patient per scan, 95%
CI -0.4 to 0.1; p=0.0002)
In REGARD
study
11. BEYOND
Prospective
randomized
IFN- 1b SC eod
250μg or 500μg vs
GA 20μg SC daily
2244 RRMS
patients
2-3.5 years
No differences in relapse
risk, EDSS progression,
T1-hypointense lesion
47
volume, or normalised
brain volume among
treatment groups
12. BECOME
Randomized
75 RRMS or
CIS patients
triple-dose
Gadolinium
and 3-Tesla
MRI
IFN- 1b SC eod
250μg vs GA 20μg
SC daily
2 years
No differences in clinical
exacerbations over 2 years
No significant differences
in combined active lesions:
all enhancing lesions and
non-enhancing new
T2/fluid-attenuated
inversion recovery lesions.
48
Recent Gains in Clinical Multiple Sclerosis Research
changes. This study showed the benefit of IFN- 1a
independent of clinical syndrome, brain MRI or combined
clinical-MRI outcomes [28]. More than half of the patients
from both the delayed (DT) and immediate treatment (IT)
groups enrolled in the CHAMPIONS study that compared
clinical features and MRI characteristics of patients 5 years
post-CHAMPS randomization. Overall, 28% of patients who
enrolled in CHAMPIONS had developed CDMS during the
2 years of CHAMPS study. The cumulative probability of
developing CDMS was lower for the IT group (36%  9
versus 49%  10; p<0.03) and few patients in either group
developed major disability after 5 years; most patients (71%)
had an (expanded disability scale score) EDSS < 1.5 and
13% had an EDSS> 2.5 [29]. Over the years there have been
changes to the definition of CIS and the risk of development
of CDMS that some clinical and MRI features entail. This
prompted a reanalysis of CHAMPS data, which confirmed
the beneficial effect of IFN1a in delaying conversion to
CDMS irrespective of the characteristics of CIS [30]. The
following trial in CIS (ETOMS or Early Treatment Of
Multiple
sclerosis Study group) [31] randomized patients to 22 μg
IFN- 1a SC ttw (not 44 μg) or placebo. Patients in the active
arm group had a lower conversion to CDMS and better
Scripps Neurologic Rating Scale score and MRI measures.
For the first time, MRI measures showed a reduction of the
progressive brain volume loss with early treatment [32],
although this was only detected in a post-hoc study. The
results from ETOMS were quite noteworthy as the patients
enrolled had more active disease (multifocal onset was
possible and MRI with more lesions), the patients were
followed longer, and the efficacy was maintained.
There is an ongoing debate whether a high dose-high
frequency (HD-HF) of IFN- causes a significant difference
in the efficacy of therapy both for RRMS and CIS. ETOMS
used a lower dose of IFN- than that approved for use in
RRMS and showed that it is effective in CIS patients, in
contrast to data obtained in RRMS patients. Data from the
two years REFLEX phase III study (Rebif Flexible Dosing
in Early MS - a single clinical event suggestive of MS, and
at least two clinically silent T2 lesions on brain MRI) show
the benefit of even lower doses, as both doses delayed
clinical relapses and MRI activity [33]. The INCOMIN [34]
and EVIDENCE [22] studies, described below, show a
limited benefit from HD-HF that was not statistically sound.
In clinical practice it is most often a compromise between
the formulations that best adapt to the balance between
perception of risk and life-style choices that dictates which
formulation to choose.
Glatiramer Acetate in MS and CIS (Tables 1 and 2)
Glatiramer acetate (GA - Copaxone ) is a random
polymer of glutamate, lysine, alanine and tyrosine, four
amino acids found in myelin basic protein. The proposed
mechanisms of action for GA include shifts of T-cells from
pro-inflammatory Th1 phenotype to Th2 less aggressive
phenotypes that suppress the inflammatory response; and a
possible diversion of an autoimmune response against
myelin. The function of the BBB does not seem affected.
Overall, there are very few scientific clues as to the effect of
GA in MS.
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5
5
The efficacy of GA in patients with RRMS was shown in
several trials detailed in Table 1. The initial placebocontrolled trial in RRMS patients showed a 29% reduction
(p=0.07) of relapse rate in the patients who were on GA. The
proportion of patients who did not have a relapse and the
median time to first relapse was improved by GA, and the
risk of worsening neurological disability was worse in the
placebo group [35]. This study had a blinded extension phase
where the benefit of GA was confirmed for reduced relapse
rate and slowing of neurological disability [36]. An openlabel extension study followed all 208 RRMS patients on
GA every six months and/or when a relapse was suspected
[37]. Interestingly, the mean annualized relapse rate (ARR)
of the patients who had GA initially was 0.42 (95%
confidence interval (CI)=0.34 - 0.51) and the rate/year
dropped to 0.23 on the 6th year [38]. The available brain MRI
scans showed no major differences between the two groups.
Furthermore, the ongoing follow-up study to this original
pivotal GA trial, now extending beyond 15 years, continues
to support the safety of GA. A second placebo-controlled
trial of GA assessed RRMS patients clinically and with MRI
monthly over nine months and again showed a reduction in
relapse rate by 33%, as well as a reduction in number of
Gad- enhancing T1 and other MRI lesions [39]. Finally,
long-term follow-up clinical and MRI evaluations were done
after a mean of 5.8 years. The MRI measures were similar in
both initially GA treated and initially placebo groups, but the
proportion of patients who had EDSS <6.0 was lower in the
latter group (P=0.034) [40].
The efficacy of GA in patients with CIS was established
recently (the PreCISe trial) (Table 2). Patients with a CIS
with unifocal manifestation and at least two T2-weighted
brain MRI lesions >5 mm were assessed for 36 months or up to
CDMS conversion. GA reduced the risk to CDMS
conversion by 45% compared to placebo (hazard ratio 0.55,
95% CI 0.40-0.77; p=0.0005) [41].
It is worth noting that for some experts, the evidence that
early treatment (after CIS) with GA or IFN- reduces
conversion to CDMS, relapse rate and evidence for MS
activity on MRI, does not outweigh the side-effects and
costs. This is mainly because of the lack of strong evidence
that supports a reduced disability progression in the longterm.
Head-to-Head Studies (Table 1)
Studies that directly compare two drugs are considered
the best way to determine which has the best efficacy. These
studies are usually flawed by the natural assumption that one
is better and there can be a bias towards the favourite drug.
In particular in MS, borderline events are the responsibility
and interpretation ultimately of the investigators, even after
blinded assessors are used [42]. Further, the ARR of patients
on IFN- in the initial trials was between 0 6 and 0 8; in
subsequent trials, patients on IFN- have relapse rates of
0 2-0 3 per year. This can reflect the fact that MS patients are
being enrolled and exposed to treatments earlier or with milder
disease in view of the relatively mild long-term associated
risks [43], and has necessarily affected the power calculations of
recent studies.
6
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5
Runia et al.
Table 2. Clinical Trials of IFN- in Patients with Clinical Isolated Syndrome
1. Betaferon IFN- 1b BENEFIT (Betaseron in Newly Emerging MS for Initial Treatment)
Multicentre
Randomized
Blinded
Follow-up at the
end
468 CIS patients
EDSS <5.5
2 attacks in prior
2 years
358 postBENEFIT
patients
Placebo until relapse
(176)
2-3.5 years
IFNb1b 250μg
Sub-cut EOD (292)
123 Initial placebo
235 initial IFNb1b
Relapse rate
reduction IFN vs
placebo: -34%,
p<0.0001
5 years after initial
randomization
MRI medium
number T2 active
lesions: -83%,
p<0.009
24
MRI T2 median
disease burden
-17.3%, p<0.16
Early
treatment
reduced risk of
CDMS by 37%
(HR- 0.63, 95% CI
0.48-0.83,
p=0.003). No
change in disability
outcome for
delayed treatment
26
2. Avonex IFN- 1a CHAMPS (Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study)
Randomized
Double-blind
383 CIS patients
>1 characteristic
T2 lesion in brain
MRI
High dose IV steroid
in all
Placebo (DT)
30μg/week IM (IT)
Stopped after
planned interim
analysis
Lower probability
to develop CDMS
in IFNb1a (0.56%,
95% CI 0.38-0.81,
p=0.002)
Reduction of
volume of brain
T2 lesions
(p<0.001) and
fewer T1 Gadenhancing
lesions
27-28
IT after
monofocal CIS
delayed CDMS
(p=0.0013)
irrespective of
presence of T1
Gad-enhancing
lesions
29-30
Reduction of
progression of
brain volume loss
with early
treatment
31-32
Avonex CHAMPIONS (Post-CHAMPS)
203 postCHAMPS
patients
Included patients
who had stopped
IFNb1a and 28%
were CDMS after
CHAMPS
DT (100 of 190) and
IT (103 of 193)
CHAMPS patients
5 years after initial
randomization
Lower probability
to develop CDMS
(IT= 36% 9 vs
DT= 49%  10;
p<0.03)
Disability levels
(EDSS) were low in
both groups (71%
had EDSS<1.5)
3. Rebif IFN- 1a ETOMS (Early Treatment of Multiple Sclerosis Study Group)
Lower probability
to convert to CDMS
with IFNb1a (34%
vs 45%, p=0.047)
Longer time to
convert to CDMS
on IFNb1a (569 vs
252 days)
Placebo
309 patients with
CIS suggestive of
MS
6MIU=22μg
Sub-cut TTW
TTW=3X/week
4. Copaxone - Glatiramer Acetate (GA) - PreCISe Trial
Multicentre
Randomized
Double-blind
481 CIS patients
with focal
manifestation
>1 T2 brain
lesions (at least
6mm diameter)
20mg GA sub-cut
daily
INCOMIN [34] compared IFN- 1b (Betaferon ) with
IFN- 1a (Avonex
) in RRMS patients for 2-years and
EVIDENCE [22] compared two IFN- 1a treatment regimens
in MS (44 μg Rebif and 30 μg Avonex ) for 1-2 years.
INCOMIN showed the benefit of the HD-HF at one and two
years, not 6 months, and the clinical results were supported
36 months or up to
CDMS conversion
Risk of CDMS
conversion was
decreased by 45%
(HR 0.55, 95% CI
0.40-0.77,
p=0.0005) in GA
treated group vs
placebo
41
by MRI outcomes [44,52]. Significantly though, important
differences existed in the baseline demographic and clinical
characteristics of the patients, which biased the interpretation
of results. In EVIDENCE, the benefit of HD-HF occurred
during the initial 24 weeks, but was not maintained for the
following 24 weeks. The Danish open-label study [45]
Recent Gains in Clinical Multiple Sclerosis Research
compared two doses of IFN- : 8 MIU -1b SC eod with 6
MIU IFN- 1a SC every week in 303 RRMS patients but
only the MRI outcomes suggested the higher dose of IFN1b might be superior and no differences were seen in
clinical outcomes. Some investigators claim the lack of
differences were due to bias regarding the equivalence of the
different formulations [42].
Studies comparing different doses and formulations of
IFN- with GA, such as the REGARD [46], the BEYOND
[47] or the BECOME [48] studies, did not detect significant
differences in efficacy between IFN- or GA in clinical
measures and only in MRI characteristics in some studies.
Some studies suggest that the inflammatory activity
driving the relapses is independent of the degenerative
pathology that drives disability [49, 50] and IFNs or GA
mainly affect relapses and MRI measures hence have very
limited effect on MS course. On the other hand, in our
opinion and those of others, there is an early window of
opportunity to change the course of disease [51].
In general, it seems fair to claim that IFN- s and GA all
reduce the relapse rate in RRMS, and delay the conversion
of CIS to CDMS. Considering the perceived but not proven
benefit with HD-HF IFN- s [52, 53] and a similar effect
compared to GA, most neurologists would not strongly
influence the choice of one formulation of IFN- or GA by
people with RRMS.
In clinical practice, it is impossible to determine if a
patient will do well on one medication, so it is important to
detect failure of treatment as early as possible. A number of
studies have demonstrated a relationship between the
development of new MRI lesions and a suboptimal clinical
response to IFN- treatment. Among a cohort of more than
400 RRMS patients, the ones who developed new T2 lesions
on MRI after one year of therapy had an increased risk of
poor response to treatment (hazard ratio 16.8; P <0.001).
The level of risk increased with the number of lesions
observed independently of new relapses or disability
progression [54, 55]. Not surprisingly, the presence of
neutralizing antibodies (Nabs) to IFN- is associated with
MRI evidence of disease activity such as Gad-enhancing T1
lesions and new or enlarging T2 lesions on MRI [44].
DRUGS USED IN SECOND LINE TREATMENT
Natalizumab (Tysabri )
The first humanized monoclonal antibody to be licensed
in RRMS, natalizumab was designed to recognize and block
the cellular adhesion molecule 4-integrin on the surface of
inflammatory cells. The integrin interacts with vascular cell
adhesion protein (VCAM)-1 on endothelial cells of the brain
(and gut) vessels to slow the movement of lymphocytes and
allow them to cross the endothelium. Natalizumab is
administered monthly through an intravenous infusion and
has been licensed for relapsing MS. In the UK, NICE
approved the use of natalizumab every 4 weeks for highly
active MS (as defined by two significant relapses in the prior
12 months) and it can be used as first line therapy.
Natalizumab decreases the numbers of CD4+ and CD8+
T-cells, CD19+ B-cells, and CD138+ plasma cells in the
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5
7
cerebrospinal fluid (CSF) of MS patients and the effect is
maintained 6 months after discontinuation [56-59]. When
natalizumab is used for longer than 30 months, the PBMC
composition in MS patients can shows an increase of T-,
NK- or particularly B-cells, probably due to an induced
release of lymphoid- but not myeloid precursor cells. The
recent thymic emigrants, naïve, effector or memory T-cells,
remained unchanged, but there were more memory- and
marginal zone-like, but not naïve B-cells, reflecting the
ability of natalizumab to influence B-cell migration and
homeostasis through the splenic marginal zone [60, 61].
The clinical trials enrolled people with active RRMS (at
least one clinical relapse during the prior year) and an EDSS
between 0 and 5. Natalizumab was shown to reduce relapses
by 68% compared to placebo and slowed the progression of
disability [62-64]. Subsequent studies showed reduced visual
loss, more disease-free individuals, better assessments of
health-related quality of life, reduced cognitive decline in
some individuals with MS, reduced hospitalizations and
steroid use and fewer new MRI lesions [64-68], as well as
improvement in several MRI measures
[65, 69].
Natalizumab was approved in 2004 by the FDA after the
release of the interim results but after three deaths due to
progressive multifocal leukoencephalopathy (PML), it was
suspended. After a safety review and no further deaths, the
drug was returned to the US market in 2006 and European
market in 2007 under a special prescription program.
Significantly, it is effective in MS patients who did not
respond or responded poorly to IFN and GA, as a second line
therapy and in highly-active MS in particular [70-72].
Approximately 6% of individuals on natalizumab develop
persistent antibodies to the drug, which reduces its efficacy
[73] and causes infusion reactions. Unfortunately, the effect
of natalizumab is not sustained after drug cessation but the
evidence for rebound activity is not significant [74].
According to Biogen-Idec monthly natalizumab safety
update and PML risk stratification programme, there were
193 cases of PML as of 1 st December 2011, with death
resulting in 20% of the cases.
The expected benefits of natalizumab treatment have to
be weighed and the risk of PML can be stratified [75].
People who have undetectable anti-JCV antibodies (JCV is
the virus that causes an asymptomatic infection and that in
immunosuppressive conditions can cause PML) have a
negligible risk of developing PML. People who are JCV
antibody positive and who have received immunosuppressive drugs, such as mitoxantrone or cyclophosphamide, are
at much higher risk. For MS patients who have not taken
such drugs, the risk is higher after two years of uninterrupted
infusions. In the STRATIFY-1 study of the prevalence of
anti-JCV antibodies in MS patients, a rate of 50-60% and an
association of increasing age and male gender was detected
but not natalizumab treatment nor prior immunosuppression
[76].
Despite the risk of PML, natalizumab remains an
extremely effective drug for RRMS and it is as effective in a
regular clinical environment as seen in pivotal and post
hoc studies [77]. Further, natalizumab is effective as second
line therapy in the treatment of relapsing remitting multiple
sclerosis [71, 72, 78].
8
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5
Fingolimod (FTY720 or Gilenya®)
Fingolimod is the first oral therapy for RRMS licensed
by the FDA and European Medicines Agency (EMA) for
second line treatment. It is a structural analogue of
sphingosine that needs to be phosphorylated in the cell by
sphingosine kinase 2 [79]. The effect on RRMS depends on
the activity on one of the five sphingosine-1-phosphate
receptors, S1PR1, defining it as an S1PR modulator, as seen
in animal models [80]. It involves the sequestration of
lymphocytes in lymph nodes, preventing egression from
most secondary lymphoid organs and trafficking into the
CNS [81, 82]. The recognized side-effects, which include
viral infections, macular oedema and brady-arrhythmia, can
be understood by potent lymphopenia, vascular leak
phenomena, and presence of S1PRs in the cardiovascular
system, respectively [83].
The results of two clinical trials led to fingolimod
approval by the FDA and EMA as a second-line drug for
highly active RRMS. A 24-month, double-blind study
enrolled 1272 active (one or more relapses in the previous
year or two or more in the previous two years) RRMS
patients, with a EDSS below 6.0. Patients were randomized
to 0.5 mg or 1.25 mg daily fingolimod or placebo. Patients
on fingolimod had reduced risk of disability progression over
the 24-month period (17.7% and 16.6% vs 24.1%) and both
doses were superior to placebo in brain MRI new or enlarged
lesions on T2-weighted images, Gad-enhancing lesions, and
brain-volume loss (p<0.001 for all comparisons) [84]. The
second study, TRANSFORMS [85], followed 1292 RRMS
patients randomized to 1.25 or 0.5 mg fingolimod daily or 30
g IM IFN- 1a weekly. The ARR was lower in both
fingolimod groups than IFN- 1a (p<0.001 for both
comparisons), fingolimod had greater efficacy on relapse
rates than IFN-1a, and the MRI findings supported the
clinical results. Unlike the 24 months study, there were no
significant differences in disability progression. Two fatal
infections (one disseminated primary varicella zoster and one
herpes simplex encephalitis) occurred in the high dose group
[85]. An extension study [86] after TRANSFORMS
followed patients for a further 24 months of fingolimod and
showed persistent benefits in ARR; for the patients who
initially had IFN-1a, clinical and MRI measures improved
when compared with the previous 12 months of IFN [86].
The effect that fingolimod has on PBMCs and CSF cells
was investigated in studies with healthy people and MS
patients. The peripheral blood T-cell population of 16 MS
patients treated with fingolimod showed a reduction of 80% of
CD4+ and 60% of CD8+ when compared to PBMCs from IFN treated
and
untreated
patients.
The
naive
(CCR7+CD45RA+) and central memory (CCR7+CD45RA-)
T(TCM) were selectively reduced and the
effector memory (EM)
(CCR7-CD45RA- and CCR7CD45RA+) Twere relatively increased. Remaining
peripheral blood T-cells secreted less IL-2 and proliferated
less but promptly secreted IFN- . This is presumably
because naive Tand TCM express the homing receptor
CCR7, allowing recirculation to secondary lymphoid tissues.
These effects were not reproduced in an in vitro study of
fingolimod [87]. The CD8+ T-cell population was enriched
with CD27- CD28- (late effector) memory
[88]. Th17
cells, phenotypically characterized as TCM, were reduced in
Runia et al.
blood of treated people, probably retained in secondary
lymphoid organs [89]. CD56(bright) and CD56(dim) NKsubsets from healthy people exposed to fingolimod
showed reduced migration but similar ability to secrete
cytokines when compared to NK-cells from people not
exposed [90]. The effect on CSF cells is distinct from the
effect on peripheral blood cells. The CSF lymphocyte counts
are significantly reduced, but the oligoclonal bands and
intrathecal IgG synthesis are unchanged. he proportion of
CSF CD4+ T-cells decreased but less than in the peripheral
blood. While
strongly reduced B-cells in the
periphery, it had little impact on B-cells in the CSF. The
percentage of CSF CD8+ T-cells, NK-cells, and monocytes
increased compared to treatment-naive patients [91]. Early
reports showed a rapid reconstitution of the peripheral blood
cells populations. This view was challenged by a recent
report showing two of five MS patients to be lymphopenic 9
and 34 months after fingolimod discontinuation following
prolonged treatment (1-5 years) [92].
Fingolimod is an effective drug in RRMS that reduced not
only the relapse rate and MRI markers of activity but also
reduced disability progression and brain volume loss,
suggesting preservation of tissue. It is a great addition to the
available MS drugs, but the novelty and small numbers
treated so far warrant increased attention to side-effects and a
wise risk assessment consideration.
UNLICENSED ORAL THERAPIES IN THE PIPELINE
Positive results were reported for new oral drugs cladribine, laquinimod, teriflunomide and dimethyl
fumarate/BG12 - in phase II or phase III studies; data is still
scarce and safety issues are unknown for most, so the role
these drugs will play in the treatment for MS is still
provisional. The results from long-term safety studies and the
potential for some neuroprotective effects the drugs may have
will be of particular importance [93].
The development of cladribine for RRMS was halted by
Merck-Serono following regulatory agencies requests for
further clinical trials, despite the encouraging results from
the phase III CLARITY study [94-96]; it is still licensed for
hairy cell leukemia. Teva Pharmaceutical Industries
announced it will not be filing for FDA approval of
laquinimod in the near future, following disappointing initial
results from the Phase III BRAVO and ALLEGRO studies,
showing a failure to meet the primary endpoint, the reduction
of ARR, despite promising results in the MRI activity
markers in the phase II trials [97, 98], and being safe and
well tolerated.
BG-12 (Dimethyl Fumarate - Biogen Idec)
Dimethyl fumarate is a fumaric acid ester that was used to
treat psoriasis in some European countries. The
mechanism of action is not completely elucidated but
involves changes in the inflammatory profile of peripheral
blood lymphocytes and the cytokines they secrete. The direct
protective effect on neurons is still controversial, but
dimethyl fumarate can cross the BBB.
In a phase II trial, 257 RRMS patients were randomized
to receive 120 mg BG-12 once daily, 120 mg three times
Recent Gains in Clinical Multiple Sclerosis Research
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5
9
daily (tid) or 240 mg tid or placebo for 24 weeks. There was
a 24 week safety extension period where the patients on
placebo received 24 mg BG-12 tid. This dose reduced the
total number of new Gad-enhancing T1 MRI lesions by 69%
from week 12 to 24 compared with placebo (1.4 vs 4.5,
p<0.0001), as well as reduced the number of new or
enlarging T2- (p=0.0006) and new T1- (p=0.014) lesions
compared with placebo. Clinically, BG-12 reduced ARR by
32% (0.44 vs 0.65 for placebo; p=0.272). The adverse event
profile was mild with abdominal pain and flushing,
headaches and fatigue [99]. The brain MRI of 38 RRMS
patients initially on placebo and 18 patients on 240 mg BG12 tid who had a least one new Gad-enhancing lesion from
week 4 to 12 were retrospectively studied. When compared
with placebo, BG-12 not only reduced the frequency of new
Gad-enhancing lesions, but also reduced probability that they
would evolve to T1-hypointense lesions [100, 101].
MONOCLONAL ANTIBODIES
The results from DEFINE and CONFIRM confirmed the
reduced ARR of over 50% when compared to placebo and
by 29% when compared to GA, respectively. In the DEFINE
study, but not the CONFIRM, the disability progression was
reduced by 38%. There seems to be a dose dependent
efficacy, with higher doses achieving better results. The
publication of the results and detailed analyses are eagerly
awaited, and this may become a very important new drug
because of a combination of efficacy and a good safety
profile and experience in use.
The development of alemtuzumab for RRMS has been a
long-term project that met many hurdles. The success
perceived in series and descriptions of individual patients
treated off-license was finally recognized with the
publication of the results of the phase II, CAMMS 223 trial.
This was a blinded study of 334 treatment naïve early RRMS
patients (less than 3 years disease duration) involving
previously untreated, early RRMS subjects who were
randomized to receive44 g SC TIW IFN- 1a or annual
intravenous infusions of 12 or 24 mg of alemtuzumab for 36
months. Alemtuzumab significantly reduced the rate of
sustained accumulation of disability, as compared with IFN1a (p<0.001) and the ARR (p<0.001). The brain MRI T2
lesion burden was reduced and from month 12 to 36, brain
volume increased in the alemtuzumab group but decreased in
the interferon beta-1a group (P=0.02). The serious adverse
events included 23% autoimmune thyroid disorders, 3%
immune thrombocytopenic purpura (ITP) and infections
(66% vs 47%). The two doses showed similar results [106108]. The profile of antibody mediated autoimmune
disorders arising post-alemtuzumab was confirmed [109] and
is possibly associated with pre-treatment levels of IL-21
[110].
Teriflunomide (Aubagio® - Sanofi Aventis)
Teriflunomide is the active metabolite of leflunomide, a
standard rheumatoid arthritis drug. Its specific mechanism of
action is to inhibit pyrimidine synthesis, which reduces
proliferation of T and B peripheral blood lymphocytes,
particularly activated T cells [102]. The mechanism of action
may involve blockage of the transcription factor NF- B and
inhibition of tyrosine kinase enzymes (the latter at higher
than tested doses).
The recent phase III, double blind, TEMSO study of
teriflunomide in RRMS, randomized 1088 RRMS patients
with EDSS lower than 6.0 and at least one relapse in the
previous year, to 14 mg and 7 mg daily teriflunomide or
placebo for 108 weeks [103].
significantly
reduced relapse rates, disability progression (at 14 mg) and
brain MRI markers of activity, as compared with placebo
[104]. The drug was well tolerated, but adverse events
included nausea and diarrhoea, hair thinning and
abnormalities in liver function tests. Two more phase III
studies of teriflunomide in RRMS, TOWER and TENERE,
are ongoing. The TENERE compares 7 mg and 14 mg
teriflunomide with SC ttw IFN- 1a in 300 MS patients over
48 weeks. The primary outcome is the time to treatment
failure: the first occurrence of a relapse or withdrawal from the
study. Estimated completion date is July 2012. The
TOWER study is a double blind trial where 1110 MS
patients were randomized to 7 mg or 14 mg teriflunomide or
placebo for 48 weeks. The primary outcome measure of this
study will be the number of relapses per year and the
estimated completion date is February 2013.
Alemtuzumab (Lemtrada® - Sanofi Genzyme)
Alemtuzumab is a humanized monoclonal antibody that
targets glycoprotein CD52 on the surface of mature
lymphocytes but not stem cells. The profound depletion of
B- and T-cells is reversed earlier (around month 3) and with
a degree of overshoot for B-cells. The CD4+ and CD8+
lymphopenia is sustained for 3-9 months and in some cases
is permanent [105]. The targeted cells undergo apoptosis
through antibody-dependent cell-mediated cytotoxicity, the
mechanism probably responsible for the infusion sideeffects. Alemtuzumab is approved for chronic lymphocytic
leukemia, cutaneous T-cell lymphoma and T-cell lymphoma
and is sometimes used in conditioning regimens for bone
marrow transplantation, kidney transplantation and Islet cell
transplantation.
There were two phase III trials, CARE-MS I that
recruited early treatment naïve RRMS patients and CAREMS II that recruited 840 patients who had at least one
breakthrough relapse on other therapies in the previous year.
The results of CARE-MS II have just been released and the
study met both its co-primary end-points: significantly
decreased relapse rate and decreased sustained accumulation
of disability in RRMS patients on alemtuzumab (5
consecutive days of 12 mg/day on the first year and 3
consecutive days of 12 mg/day on the second year) when
compared with SC TIW IFN- 1a. In the CARE-MS II trial,
the relapse rate was significantly reduced when compared to
IFN- 1a, but the reduction in disability progression was not
significant. The proportion of patients who remained relapse
free after two years was over 75%. Common adverse events
were infusion associated reactions: headache, rash, nausea,
hives, fever, itching, insomnia, and fatigue. Infections were
common in both groups with a higher incidence in the
10
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5
alemtuzumab group and included upper respiratory and
urinary infections and reactivation of herpes simplex. About
16% of alemtuzumab-treated patients developed an
autoimmune
thyroid-related
adverse
event
and
approximately
one
percent
developed
immune
thrombocytopenia during the two-year study period.
Alemtuzumab offered great results in the phase II trial but
there was a degree of disappointment after the phase III results
were made public. It is still the drug with best reduction
of relapse rate and one that offers the possibility of being disease
free for longer. The benefits seem to be more significant when
used early in disease but the risks and longterm side-effects may cause the regulatory authorities to
limit its use to second-line therapy.
Daclizumab (Zenapax® - Hoffmann-La Roche)
Daclizumab, a humanized anti-CD25 monoclonal
antibody, reduced MS disease activity in inital nonrandomized studies. In a phase II randomized, double-blind,
placebo-controlled study, 230 RRMS patients who were on
IFN- 1a were randomized to receive add-on SC daclizumab
2 mg/kg every 2 weeks, daclizumab 1 mg/kg every 4 weeks, or
placebo for 24 weeks. The association reduced the number of
new or enlarged Gad-enhancing T1 brain MRI lesions
compared with IFN- 1a alone but the significance was
limited [111]. The phase III trial is still ongoing.
Anti-CD20 Monoclonal Antibodies: Rituximab and
Ocrelizumab - (Hoffmann-La Roche's Subsidiary
Genentech, and Biogen Idec)
Studies of rituximab (a chimeric anti-CD20 mousehuman monoclonal antibody) in RRMS, active naïve patients
showed a degree of benefit with an apparent reduction in
relapses [112] This was also observed over 72 weeks
compared with the year before therapy with fewer new Gadenhancing T1 or new T2 lesions [113, 114]. This benefit was
again detected in breakthrough MS activity [115].
The development of rituximab was halted and a
programme to investigate ocrelizumab, another humanized
anti-CD20 monoclonal antibody was initiated. In a phase II,
examining physician blinded study, 218 RRMS patients were
randomized to receive 600 mg, 2000 mg in two doses (day 1
and day 15) or 30 μg IM IFN- 1a weekly or placebo. At
week 24, patients in the initial placebo, 600 mg ocrelizumab
and IFN- 1a groups received ocrelizumab 600 mg; the 2000
mg group received 1000 mg. At week 24, the number of
Gad-enhancing T1 lesions was 89% lower in the 600 mg
ocrelizumab group than in the placebo group (p<0 0001),
and 96% lower in the 2000 mg group (p<0 0001). There
were pronounced effects of B-cell depletion with both
ocrelizumab doses, on MRI and around 80% relapse
reduction [116].
The development of ocrelizumab is pursued in both RR and
progressive MS, but was stopped in rheumatoid arthritis and
lupus because of several fatal opportunistic infections. The
results in MS were extremely promising and we expect to learn
a great deal more in terms of pathology of MS from the use of
B-cell therapies.
Runia et al.
CONCLUSION
These are exciting times with several important
breakthroughs in the treatment of RRMS patients. New
drugs with increased efficacy and different safety profiles are
in the pipeline and the accumulated knowledge will ensure
that the risks associated with the new drugs will be limited
and worth taking. It is of major importance to switch our
efforts to the development of drugs and strategies that offer
neuroprotection and eventually repair for MS: what we can
offer MS patients who suffer with progressive disease is still
extremely limited and provides no significant changes in
disease course.
ABBREVIATIONS
2’-5' Oligoadenylate synthetase
2'-5'OAS
=
ARR
= Annualized relapse rate
BBB
= Blood brain barrier
CD
= Clinically definitive
CIS
= Clinically isolated syndrome
CNS
= Central nervous system
CI
= Confidence interval
CSF
= Cerebrospinal fluid
DAMP
= Danger-associated molecular patterns
DT
= Delayed treatment
DMD
= Disease modifying drug
EMA
= European Medicines Agency
Eod
= Every other day
EDSS
= Expanded disability scale score
EAE
= Experimental autoimmune encephalomyelitis
FDA
= Food and Drug Administration
GA
= Glatiramer acetate
HC
= Healthy controls
HD-HF
= High dose/high frequency
IgG
= Immunoglobulins
IT
= Immediate treatment
IFN
= Interferon
IL
= Interleukin
IM
= Intra-muscular
MRI
= Magnetic resonance imaging
MMP
= Matrix metalloproteinases
MS
= Multiple sclerosis
NK
= Natural killer
PAMP
= Pathogen-associated molecular patterns
PRR
= Pattern recognition receptors
PBMC
= Peripheral blood mononuclear cells
PML
= Progressive multifocal leukoencephalopathy
Recent Gains in Clinical Multiple Sclerosis Research
PKR
= Protein kinase receptor
RR
= Relapsing-remitting
S1PR
= Sphingosine-1-phosphate receptors
SC
= Subcutaneous
STAT
= Signal Transducers and Activators of
Transcription
Th
= T-helper
Tid
= Three times daily
Ttw
= Three times per week
TLR
= Toll-like receptor
TNF
= Tumour necrosis factor
VCAM
= Vascular cell adhesion protein
CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5
[14]
[15]
[16]
[17]
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Accepted: April 30, 2012
DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the
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PMID: 22583439