Multiple Sclerosis Journal

19(11) 1428 1436

The Author(s) 2013
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DOI: 10.1177/1352458513502572
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MULTIPLE
SCLEROSIS MSJ
JOURNAL
Introduction
There is no other neurological disease in the last 20 years
that can equal multiple sclerosis (MS) for progress in treat-
ment. Since the publication in 1993 of the efficacy of inter-
feron (IFN)1b in relapsingremitting multiple sclerosis
(RRMS),
1,2
there has been growing evidence that drugs
with differing mechanisms of action which target the
immunological changes leading to inflammation in the cen-
tral nervous system (CNS) can variably reduce both clinical
and magnetic resonance imaging (MRI) measures of dis-
ease activity.
3
Large effects on the relapse rate have usually
been associated with a significant decrease in the risk of
disability progression.
46
More recently, the concept of
early treatment
7
has gained acceptance in the MS commu-
nity after evidence that the same agents shown to be effec-
tive in the relapsingremitting phase of the disease are also
able to significantly delay the occurrence of a second attack
in patients following a first demyelinating clinical epi-
sode.
8,9
There is converging evidence that drugs used to
treat RRMS patients have greater beneficial effects if used
immediately after the first attack.
10
Soon after the efficacy of interferons in RRMS was
demonstrated, clinical trials were started in secondary
progressive multiple sclerosis (SPMS) in both North
America and Europe. These clinical trials produced essen-
tially negative results, with the exception of the European
clinical trial on the effects of IFN1b
11
and the MIMS
trial exploring the effects of mitoxantrone.
12
All clinical
trials performed in primary progressive multiple sclerosis
(PPMS) have failed. The observation of a differing
response to the same treatment in the different phases of
MS provides clear evidence that pathophysiological
mechanisms change along the course of the disease and
calls for new therapeutic strategies for progressive dis-
ease. It is now considered that the progressive phase of
MS is dominated by neurodegenerative phenomena,
13
at
least partially determined by compartmentalized inflam-
mation in the CNS driven by microglial activation.
14,15

Brain MRI has recently contributed to a better under-
standing of the mechanisms underlying neurodegenera-
tion in MS. Firstly, many studies using magnetization
transfer ratio, diffusion tensor imaging and magnetic reso-
nance spectroscopy have shown widespread changes in
the so-called 'normal-appearing' tissues of the brain and
spinal cord in the white, and especially gray, matter of
Disease-modifying treatments for
progressive multiple sclerosis
Giancarlo Comi
Abstract
The last 20 years have seen major progress in the treatment of relapsingremitting multiple sclerosis (RRMS) using a
variety of drugs targeting immune dysfunction. In contrast, all clinical trials of such agents in primary progressive multiple
sclerosis (PPMS) have failed and there is limited evidence of their efficacy in secondary progressive disease. Evolving
concepts of the complex interplay between inflammatory and neurodegenerative processes across the course of multiple
sclerosis (MS) may explain this discrepancy. This paper will provide an up-to-date overview of the rationale and results
of the published clinical trials that have sought to alter the trajectory of both primary and secondary MS, considering
studies involving drugs with a primary immune target and also those aiming for neuroprotection. Future areas of study
will be discussed, building on these results combined with the experience of treating RRMS and new concepts emerging
from laboratory science and animal models.
Keywords
Multiple sclerosis, progressive multiple sclerosis, disease-modifying therapies
Date received: 1 August 2013; accepted: 1 August 2013
Department of Neurology, Universit Vita-Salute San Raffaele, Italy .
Corresponding author:
Giancarlo Comi, Department of Neurology and INSPE, Vita-Salute San
Raffaele University, Via Olgettina, 48, 20132 Milan, Italy.
Email: g.comi@hsr.it
502572MSJ191110.1177/1352458513502572Multiple Sclerosis JournalComi
2013
Topical Review
Comi 1429
progressive MS patients.
1618
Such changes may be
explained by a diffuse neurodegenerative process, how-
ever it has recently been demonstrated that anterograde
and retrograde degeneration of interconnected brain
areas
19,20
may also play a role. Secondly, gray matter dam-
age plays an important role in the accumulation of disabil-
ity in the progressive phase
21,22
and the number of cortical
lesions increases at a significantly greater rate in patients
with actively progressive disease, correlating with increas-
ing Expanded Disability Status Scale (EDSS) score and
cognitive dysfunction.
23,24
Among the three types of corti-
cal lesions, subpial lesions are the most frequent and can
be very extensive, affecting >60% of the cortical ribbon in
the cerebrum,
25
cerebellum
26
and hippocampus.
27
This
type of cortical lesion has been attributed to diffuse
meningeal inflammation. These subpial lesions are quite
frequent in progressive MS,
28,29
sometimes organized in
follicle-like structures in SPMS
30,31
but not in PPMS,
29

and have also recently been reported to occur in early MS
cases.
32
These observations suggest that both cortical
lesions and meningeal inflammation play a role in increas-
ing disability, although are not specific to the progressive
phase of MS.
Links between the early inflammatory phase and late
degenerative phase are not clear, however the exhaustion of
remyelination processes,
33
the secondary degeneration of
demyelinated axons due to abnormal axonal excitability
34

and mitochondrial failure
35
are probably contributing fac-
tors. Finally, it should be considered that the redundancy of
the nervous system and its large plasticity may protect from
functional impairment even in presence of significant tissue
damage; however when a critical threshold is reached, even
minor further damage may result in irreversible neurologi-
cal abnormalities.
In Table 1 the key differences between progressive and
relapsing MS are summarised.
In this review we will focus on the results of phase IIIII
clinical trials exploring disease modifying treatments for
progressive MS with a few notes about future develop-
ments in this area. There is some evidence that, even though
PPMS and SPMS have a similar evolution in the progres-
sive phase
36
and a similar genetic basis,
37
they may differ in
other aspects.
38
As such, we will discuss their treatment
separately.
Anti-inflammatory treatments
SPMS. Two treatments have been approved for SPMS
patients in Europe and North America: IFN-1b
39
and mito-
xantrone.
40
The European Trial in SPMS (EUSPMS), test-
ing IFN1b against placebo, recruited 718 patients. There
was a 22% reduction in the proportion of patients with three
months confirmed disability progression which was inde-
pendent of baseline EDSS, pre-entry relapse rate and the
occurrence of relapses during the study. There was a sig-
nificant reduction in clinical and MRI activity, of the same
magnitude observed in the pivotal clinical trial in RRMS.
Unfortunately, a subsequent study performed in North
America failed to confirm the effect of IFN-1b on disabil-
ity progression, even if the efficacy on clinical and MRI
measures of disease activity was confirmed.
41
A compari-
son between the two studies shows a younger and more
active population in the EUSPMS trial, in line with a better
response to anti-inflammatory treatments in patients with
more active disease. Moreover, it is probable that a higher
relapse rate on study may have driven the EDSS changes -
the annualised relapse rate of 0.64 observed in the placebo
arm of the EUSPMS trial is a value not observed even in
pure RRMS clinical trials today.
Subcutaneous IFN-1a has been tested in two clinical
trials in SPMS. In SPCTRIMS, a multicentre European,
Canadian and Australian trial, 618 patients were ran-
domised to placebo or two doses of IFN-1a, 22 or 44 g
s/c three times/wk. The risk of disability progression did
not differ between treatment arms, however both doses sig-
nificantly reduced the relapse rate and the number of active
MRI lesions.
42
In a second trial performed in Northern
European countries, the 22 g dose was tested against pla-
cebo. Again, no effect on disability progression was seen.
Moreover, in this study, there was no effect on annualised
relapse rate; brain MRI was not performed.
43
Only one trial has been performed to explore the effi-
cacy of intramuscular IFN-1a in SPMS, the IMPACT trial,
showing no significant modification of the risk of disability
progression despite a significant reduction in clinical
relapse and MRI activity.
44
A recent Cochrane review has concluded that there is no
effect of IFNs in reducing the risk of sustained six-month
EDSS progression in SPMS patients, however there is a
Table 1. Key aspects of progressive multiple sclerosis distinguishing it from relapsingremitting multiple sclerosis (RRMS).
Time to disability progression is not driven by relapse rate, frequency or severity
Fewer gadolinium enhancing lesions (signifying fewer blood-brain barrier breaches)
Less peripheral immune cell activation
Compartmentalised inflammation within the central nervous system (CNS)
Fewer active plaques
Anti-inflammatory therapies less effective or ineffective
More atrophy, axonal loss and cortical pathology
Universal progressive spinal disease
1430 Multiple Sclerosis Journal 19(11)
Table 2. Drugs tested in phase III clinical trials in progressive
mutliple sclerosis.
SPMS
Cladribine
Cyclophosphamide
Dirucotide
Dronabinol
Interferon-beta1a i.m. (avonex)
Interferon-beta1a s/c (rebif)
Interferon-beta-1b s/c (betaferon/betaseron)
Intravenous immunoglobulin
Lamotrigine
Mitoxantrone
PPMS
Dronabinol
Glatiramer acetate
Interferon-beta1a (avonex)
Interferon-beta1b (betaferon/betaseron)
Rituximab
significant decrease of the risk of three-month confirmed
disability progression, reflecting relapse-related disability
changes.
45
Based on these results the clinical use of IFN in SPMS
patients is restricted to the use of IFN1b in patients with
persisting attacks, mostly those with low levels of disabil-
ity. The rationale for this is twofold: (a) these patients still
have some level of ongoing inflammatory activity which
may respond to the drug; (b) IFNs increase spasticity and
the potential advantages of protection from new lesions are
countered by adverse effects on the motor system.
Mitoxantrone is an anti-neoplastic anthracenedione
derivative which inhibits DNA replication, DNA-dependent
RNA synthesis and DNA repair, resulting in a marked
reduction of B and T cell numbers. Mitoxantrone is a very
small molecule, able to cross the bloodbrain barrier and
interact with cells in the CNS.
46,47
The most important limi-
tation in its use is its long-term safety, mainly related to the
risk of cardiotoxicity and acute leukaemia.
48,49
In the MIMS
trial, 194 patients with worsening RRMS or SPMS were
assigned placebo or mitoxantrone, 12 mg/m
2
intravenously
every three months for 24 months. About half of the patients
were classified as SPMS. At 24 months, the mitoxantrone
group experienced benefit compared to the placebo group
for disability progression confirmed at three and six
months.
40
However, the proportion of patients who pro-
gressed overall was low (19% placebo vs 7% mitoxantrone)
and a separate statistical analysis of the SPMS patients was
not performed. Effects on the relapse rate and MRI param-
eters were positive in the mitoxantrone arm compared to
placebo. The type of patients included in the MIMS trial
does not allow conclusions to be drawn on the efficacy of
mitoxantrone in SPMS patients without attacks.
Interestingly, a recent open study comparing the efficacy of
the drug in RRMS and SPMS showed a significantly higher
proportion of patients free from disability progression in
the RRMS group compared to the SPMS group,
50
in line
with observations using IFN.
Other treatments have been tested in phase IIIII clinical
trial in SPMS patients or in mixed progressive MS popula-
tions, all with negative results (Tables 2 and 3). Glatiramer
acetate (GA) showed no effects on disability in a study per-
formed in 106 progressive MS patients.
51
The effect of high
dose intravenous immunoglobulin (IVIg) was tested in two
studies. In a large multicentre phase III clinical trial (ESIMS
trial) no effect was seen on clinical and MRI measures of
disease activity and disease burden, including brain atro-
phy.
52
In a second multicentre clinical trial in progressive
MS patients (the vast majority SPMS), IVIg led to a sig-
nificant reduction in the proportion of patients with con-
firmed disability progression, however some methodological
aspects limit the value of the results.
53
Cyclophosphamide and methotrexate have been used for
more than 30 years in progressive MS on the basis of mar-
ginal positive effects seen in old studies.
5458
Patients in the
early progressive phase with clinical and MRI evidence of
persistent inflammatory activity seem to respond to this
therapeutic approach. Cladribine is a powerful immunosup-
pressive agent, moderately effective in RRMS,
59
even if it
has not been approved in the European Union and USA due
to a presumed unfavourable safety profile. Cladribine has
been tested in progressive MS in two phase III clinical tri-
als. In the first trial, cladribine significantly reduced the
risk of disability progression with a marked reduction of
MRI activity.
60
In a second clinical trial, two doses of the
drug were tested against placebo in a mixed population of
PPMS and SPMS patients: no effects were observed on the
primary end point, disability progression although, again, a
marked reduction in MRI activity was evident.
61,62
The
small sample size and the short duration of the two trials,
one year, along with the low proportion of patients with
active disease in the second may partially explain the dis-
crepancy between the results. Alemtuzumab is a humanized
IgG1 monoclonal antibody targeting CD52, a glycoprotein
expressed widely throughout the immune system on T and
B lymphocytes, natural killer (NK) cells, dendritic cells,
most monocytes and macrophages.
63
Two phase III clinical
trials have shown a clear superiority versus IFN-1a sc in
RRMS.
64,65
In contrast, despite its profound effect in inhib-
iting the formation of active lesions on MRI, alemtuzumab
did not halt the progression of disability or the development
of brain atrophy in SPMS patients.
66
High-dose immuno-
suppressive regimens followed by autologous hematopoi-
etic cell transplantation (AHCT) rescue is effective in
controlling inflammatory activity in some autoimmune dis-
eases including MS.
67
The effects of AHCT in progressive
MS have been explored in many small uncontrolled studies
which have consistently shown that when patients are
treated in the advanced phase of the disease, the decline in
neurological function continues even when there is little
Comi 1431
clinical and MRI evidence of ongoing inflammation.
68,69
In
a recent long-term follow-up report, disease progression-
free survival at 15 years was 44% for individuals with
active CNS disease pre-transplant and only 10% for those
without,
70
suggesting that even extreme immunosuppres-
sion fails if applied too late in the disease evolution.
Antibody targeting of myelin components may be
important to disease progression,
71
so tolerization to one or
more epitopes may be effective in MS. MBP8298 (diruco-
tide) is a synthetic peptide with an amino acid sequence
corresponding to amino acids 8298 of myelin basic pro-
tein (MBP). MBP8298 has been tested in a phase III clini-
cal trial in SPMS with no effects seen on disability
progression or disease activity.
72
PPMS. There are no approved treatments for PPMS. All
phase III clinical trials have had negative results, even if the
possibility of a positive effect on specific subgroups has
emerged in post hoc analyses of some studies.
IFN has been tested in two clinical trials. In the first
two-year study, IFN-1a i.m. was tested against placebo in
a small group of 50 patients.
73
No significant effect emerged
on the risk of confirmed disability progression or on the
evolution of brain atrophy. In the second study, 73 PPMS
patients were included in a double blind phase III clinical
trial exploring the effects of IFN-1b against placebo.
There was a trend towards a decrease in the proportion of
patients with confirmed disability progression, from 38%
in the placebo arm to 28% in the IFN-1b arm (26%).
There was a significant reduction in new T2 and new T1
lesions in the active treatment arm but no effect on brain or
spinal cord atrophy.
74
The PROMiSe trial recruited 934 PPMS patients to
evaluate the effects of GA versus placebo on disability. The
study was terminated by the data safety monitoring com-
mittee for futility when more than two-thirds of the patients
had completed at least two years.
75
No effects were
observed on time to confirmed EDSS progression (hazard
ratio 0.87). In a post hoc analysis there was a significant
increase of time to disability progression in males treated
with GA compared to males randomised to placebo
(p=0.02) but no similar difference was seen in females.
Interestingly, the number of gadolinium (Gd)-enhancing
lesions at year 1, but not at year 2, was also significantly
decreased (p<0.005) and the increase in T2 lesion volume
was significantly less in the GA arm at year 2. However, the
T2 lesion volume change was significant in females only.
76
Rituximab, a B-cell depleting monoclonal antibody, was
investigated in 439 patients with PPMS.
77
No significant
effects were observed at the primary end point which was
the time to confirmed disability progression. Pre-planned
subgroup analysis revealed a significant prolongation in the
time to disability progression in younger patients with
active disease at entry revealed by the presence of
Gd-enhancing lesions. The speed of disability progression
was much faster in younger and baseline-active patients
than in older and baseline-inactive patients. The efficacy of
rituximab in this subgroup of patients may be explained by
the strong anti-inflammatory effects of the drug, already
seen in RRMS patients.
78
No effects were observed on
brain atrophy, however brain volume changes in subgroups
of patients were not reported. These observations are fully
in line with what has been seen in SPMS: a dissociated
effect of anti-inflammatory treatments on disease activity
and disease progression.
Neuroprotective treatments
There are two main reasons why neuroprotective strategies
may have a role in progressive MS: (a) mechanisms under-
lying the progressive phase of MS are at least partially
independent from ongoing inflammation; (b) neuroprotec-
tion could be be combined with anti-inflammatory treat-
ments. Neuroprotection is a very broad concept, including
the preservation of the integrity of myelin, axons, neurons
and glial cells.
Some drugs have been shown to be effective neuropro-
tective agents in different animal experimental autoimmune
encephalomyelitis (EAE) models, but only very few have
been tested in clinical MS. Erythropoietin (EPO) is an anti-
apoptotic and anti-oxidative agent that promotes neurite
outgrowth, axonal repair, neurogenesis and angiogene-
sis.
79,80
EPO increases functional recovery in EAE.
81
In
MS, initial signs
82
of a possible effect on disability progres-
sion and cognition were not followed by further investiga-
tions. In a small pilot trial in 16 patients with PPMS the
glutamate-antagonist riluzole showed neuroprotective
effects on MRI parameters, revealing a stabilization of
T1-hypointense lesion volume and cervical cord area.
83

Another potentially neuroprotective drug is the sodium and
calcium channel blocker, lamotrigine. Excessive accumula-
tion of sodium ions may occur in axons affected by inflam-
mation or demyelination, which might make these axons
vulnerable to injury by favouring calcium accumulation
through the sodiumcalcium exchanger.
84
Partial blockade
of voltage-gated sodium channels may result in a neuropro-
tective effect, as suggested by observations in both EAE
Table 3. Interventions in ongoing/planned phase III clinical trials
in progressive multiple sclerosis.
Axon outgrowth inhibitors
Anti-nogo-a antibody
Anti-lingo antibody
Fingolimod
Fumarate
Laquinimod
Magnetic /electrical brain stimulation
Mesenchymal stem cells
Natalizumab
Ocrelizumab
1432 Multiple Sclerosis Journal 19(11)
and other experimental models of inflammatory axonal
injury.
85,86
In a phase II clinical trial of lamotrigine, brain
atrophy, the primary end point of the study, progressed at a
similar annual rate in the active and placebo arms.
87
No sig-
nificant effect of lamotrigine was seen on spinal cord atro-
phy or on MRI measures of disease activity and disease
burden.
Recently, preliminary results of a phase II clinical trial
on the effects of simvastatin in patients with SPMS have
been presented.
88
Confirmed disability progression and the
rate of brain atrophy were both significantly reduced by
simvastatin compared to placebo. This surprising result,
considering the previously negative results of a clinical trial
with statins in progressive MS, needs to be confirmed by
larger studies.
In addition to these protective strategies targeted directly
at the neurones, it might be possible to promote neuropro-
tection indirectly through manipulation of the innate
immune system. Cells playing a direct or indirect role in the
innate immune system, such as activated microglia, den-
dritic cells and astrocytes are recognised to have a role in
the mechanisms of progression. Some drugs, such as sphin-
gosine-1-phosphate agonists, laquinimod, fumarate, natali-
zumab and ocrelizumab which have already demonstrated a
significant anti-inflammatory effect are now being tested,
or are under consideration to be tested, in phase IIIII clin-
ical trials in progressive MS patients. Some other drugs,
such as minocycline, which have failed in RRMS, have
revealed effects on disease progression in EAE models.
89

The ability to prevent disease progression in PPMS and
SPMS is also being evaluated for cannabis extracts based
on the observation that the activation of the cannabinoid
receptor type 1 results in some degree of neuroprotection,
slowing down the atrophy associated with EAE
90
and
decreasing microglia-mediated nervous tissue damage.
91

Moreover, a role for cannabinoids is further suggested by
the report of Rossi et al.
92
that MS patients homozygous for
long AAT repeats in the cannabinoid CB1 receptor gene
have more severe disease and a higher risk of disease pro-
gression. In a follow-up for up to 12 months of the main
Cannabinoids in Multiple Sclerosis (CAMS) study, there
was marginal evidence for a treatment effect of 9- tetrahy-
drocannabinol on some aspects of disability. The short
duration of the trial limited the value of the observation
which nevertheless encouraged further study of the can-
nabinoids in progressive MS. Very recently,
93
in a double-
blind, placebo-controlled, multicentre phase III clinical
trial, the CUPID study, oral dronabinol (9 tetrahydrocan-
nabinol) had no effect on EDSS progression in patients
with progressive MS. No effects were also observed on
other measures of disability, quality of life or brain atrophy.
Mesenchymal stem cells are pluripotent cells that can be
derived and expanded from various adult tissues (e.g. bone
marrow or adipose tissue) or fetal tissue (e.g. placenta) and
can differentiate into cells of mesodermal origin (e.g. bone,
cartilage or fat). The potential role of mesenchymal stem
cells for neuroprotection in multiple sclerosis has been
reviewed.
9496
The recent evidence of an improvement in
visual function in 10 SPMS patients included in an open
label, phase IIa proof-of-concept study using autologous
mesenchymal stem cells is of great importance, not only
because it is the first evidence of the possibility to enhance
repair, but also because of the demonstration that, with
appropriate biomarkers, it is possible to discriminate neuro-
protective properties of a treatment.
97
Another three open
label studies
98100
provide some evidence of efficacy on
clinical and MRI parameters, however the small number of
patients recruited and the weakness of the study design
make these results essentially anecdotal. A multicentre,
multinational, phase II, double-blind, randomised, crosso-
ver trial has recently started to evaluate the safety and effi-
cacy of these cells in active RR and progressive MS
patients.
101
Another exciting approach is to promote remyelination
in order to prevent axonal loss. It is beyond the scope of this
review to discuss fully strategies to promote/improve remy-
elination with chemical or cellular approaches. The reasons
why remyelination is impaired in MS are not completely
understood, but one likely mechanism is the inhibition of
oligodendrocyte precursor cells within chronic MS
plaques.
102,103
Proteomic analysis of chronic plaques (e.g.
Han et al.
104
) will be important to identify the factors that
block oligodendrocyte differentiation. One key factor that
has already been identified is LINGO-1 (leucine-rich repeat
and Ig-like domain-containing Nogo receptor-interacting
protein 1). LINGO-1 antagonism has recently shown the
potential to enhance remyelination.
105
Phase II clinical tri-
als are ongoing to test the neuroprotective and remyelina-
tion effects of a monoclonal antibody against LINGO-1.
106
Conclusions
In contrast to the advances in the treatment of relapsing
MS, which have positively influenced the lives of patients
in the early and intermediate phase of the disease, almost
nothing has been achieved in the treatment of patients who
have the progressive form of the disease. The major reason
for this failure is that most, if not all, treatments tested in
progressive MS have had as their main target derangement
of the immune system in the periphery, which is probably
playing only a minor role in the accumulation of nerve tis-
sue damage accumulated in the progressive phase. A better
understanding of the pathophysiology of the progressive
phase of the disease is central to the development of new
treatments. We have learnt from treating RRMS that tack-
ling pathological processes early in their evolution results
in greater clinical benefit. In an analogous way, it is possi-
ble that treatment of progressive MS with appropriate inter-
ventions targeting the specific pathogenic mechanisms of
progression (potentially alterations in innate immunity)
Comi 1433
should be started very early, probably in the relapsing phase
of the disease, with a combination of drugs targeting both
peripheral and the central immune dysfunction.
A recent initiative promoted by a concerted action of
various national MS societies and supported by the
International MS Federation, the MS Progressive Initiative,
is committed to engage the MS research community through
an international effort to fund a spectrum of research activi-
ties relevant to progressive MS with the ultimate goal of
expediting the development of disease-modifying and
symptom-relief treatments for this stage of the disease.
Conflict of interest
Giancarlo Comi has received, in past years, compensation for con-
sulting services from Novartis, Teva Pharmaceutical Industries,
Sanofi, Genzyme, Merck Serono, Biogen, Bayer, Actelion and
Almirall; he has also received compensation for speaking activi-
ties from Novartis, Teva Pharmaceutical Industries, Sanofi,
Genzyme, Merck Serono, Biogen and Bayer.
Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
References
1. Paty DW and Li DK. UBC MS/MRI Study Group and the
IFNB Multiple Sclerosis Study Group. Interferon beta-1b is
effective in relapsingremitting multiple sclerosis. II. MRI
analysis results of a multicenter, randomized, double-blind,
placebo-controlled trial. Neurology 1993; 43: 662667.
2. The IFNB Multiple Sclerosis Study Group. Interferon beta-
1b is effective in relapsingremitting multiple sclerosis. I.
Clinical results of a multicenter, randomized, double-blind,
placebo-controlled trial. Neurology 1993; 43: 655661.
3. Gold R and Montalban X. Multiple sclerosis: More pieces of
the immunological puzzle. Lancet Neurol 2012; 11: 910.
4. Cohen JA, Barkhof F, Comi G, et al. Fingolimod versus
intramuscular interferon in patient subgroups from TRANS-
FORMS. J Neurol 2013
5. Phillips JT, Giovannoni G, Lublin FD, et al. Sustained
improvement in Expanded Disability Status Scale as a new
efficacy measure of neurological change in multiple sclerosis:
Treatment effects with natalizumab in patients with relapsing
multiple sclerosis. Mult Scler 2011; 17: 970979.
6. Zipoli V, Portaccio E, Hakiki B, et al. Intravenous mitoxan-
trone and cyclophosphamide as a second-line therapy in mul-
tiple sclerosis: An open-label comparative study of efficacy
and safety. J Neurol Sci 2008; 266: 2530.
7. Comi G. Clinically isolated syndrome: The rationale for early
treatment. Nat Clin Pract Neurol 2008; 4: 234235.
8. Comi G, Martinelli V, Rodegher M, et al. Effects of early
treatment with glatiramer acetate in patients with clinically
isolated syndrome. Mult Scler 2012
9. Comi G, Martinelli V, Rodegher M, et al; PreCISe study
group. Effect of glatiramer acetate on conversion to clinically
definite multiple sclerosis in patients with clinically isolated
syndrome (PreCISe study): A randomised, double-blind, pla-
cebo-controlled trial. Lancet 2009; 374: 15031511.
10. Comi G, Filippi M, Barkhof F, et al; Early Treatment of
Multiple Sclerosis Study Group. Effect of early interferon
treatment on conversion to definite multiple sclerosis: A ran-
domised study. Lancet 2001; 357: 15761582.
11. European Study Group on interferon beta-1b in secondary
progressive MS. Placebo-controlled multicentre randomised
trial of interferon beta-1b in treatment of secondary progres-
sive multiple sclerosis. Lancet 1998; 352: 14911497.
12. Krapf H, Morrissey SP, Zenker O, et al, MIMS Study Group.
Effect of mitoxantrone on MRI in progressive MS: Results of
the MIMS trial. Neurology 2005; 65: 690695.
13. Martinelli-Boneschi F, Esposito F, Scalabrini D, et al. Lack
of replication of KIF1B gene in an Italian primary progressive
multiple sclerosis cohort. Eur J Neurol 2010; 17: 740745.
14. Howell OW, Palser A, Polito A, et al. Disruption of neurofas-
cin localization reveals early change preceding demyelination
and remyelination in multiple sclerosis. Brain 2006; 129:
31733185.
15. Meinl E, Krumbholz M, Derfuss T, et al. Compartmentaliza-
tion of inflammation in the CNS: A major mechanism driving
progressive multiple sclerosis. J Neurol Sci 2008; 274: 4244.
16. Filippi M, Rovaris M and Rocca MA. Imaging primary pro-
gressive multiple sclerosis: The contribution of structural,
metabolic, and functional MRI techniques. Mult Scler 2004;
10: S36S44.
17. Agosta F, Absinta M, Sormani MP, et al. In vivo assessment
of cervical cord damage in MS patients: A longitudinal diffu-
sion tensor MRI study. Brain 2007; 130: 22112219.
18. Rovaris M, Judica E, Sastre-Garriga J, et al. Large-scale, mul-
ticentre, quantitative MRI study of brain and cord damage in
primary progressive multiple sclerosis. Mult Scler 2008; 14:
455464.
19. Sepulcre J, Masdeu JC, Goni J, et al. Fatigue in multiple scle-
rosis is associated with the disruption of frontal and parietal
pathways. Mult Scler 2009; 15: 337344.
20. Kolasinski J, Stagg CJ, Chance SA, et al. A combined post-
mortem magnetic resonance imaging and quantitative his-
tological study of multiple sclerosis pathology. Brain 2012;
135: 29382951.
21. Fisher E, Lee JC, Nakamura K, et al. Gray matter atrophy in
multiple sclerosis: A longitudinal study. Ann Neurol 2008; 64:
255265.
22. Fisniku LK, Chard DT, Jackson JS, et al. Gray matter atro-
phy is related to long-term disability in multiple sclerosis. Ann
Neurol 2008; 64: 247254.
23. Calabrese P and Penner IK. Cognitive dysfunctions in mul-
tiple sclerosis a 'multiple disconnection syndrome'? J Neurol
2007; 254: S18S21.
24. Calabrese M, Rinaldi F, Mattisi I, et al. Widespread cortical
thinning characterizes patients with MS with mild cognitive
impairment. Neurology 2010; 74: 321328.
25. Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Corti-
cal demyelination and diffuse white matter injury in multiple
sclerosis. Brain 2005; 128: 27052712.
26. Kutzelnigg A, Faber-Rod JC, Bauer J, et al. Widespread
demyelination in the cerebellar cortex in multiple sclerosis.
Brain Pathol 2007; 17: 3844.
27. Geurts JJ, Bo L, Roosendaal SD, et al. Extensive hippocampal
demyelination in multiple sclerosis. J Neuropathol Exp Neu-
rol 2007; 66: 819827.
1434 Multiple Sclerosis Journal 19(11)
28. Howell OW, Reeves CA, Nicholas R, et al. Meningeal inflam-
mation is widespread and linked to cortical pathology in mul-
tiple sclerosis. Brain 2011; 134: 27552771.
29. Choi SR, Howell OW, Carassiti D, et al. Meningeal inflam-
mation plays a role in the pathology of primary progressive
multiple sclerosis. Brain 2012; 135: 29252937.
30. Magliozzi R, Howell O, Vora A, et al. Meningeal B-cell fol-
licles in secondary progressive multiple sclerosis associate
with early onset of disease and severe cortical pathology.
Brain 2007; 130: 10891104.
31. Magliozzi R, Howell OW, Reeves C, et al. A gradient of neu-
ronal loss and meningeal inflammation in multiple sclerosis.
Ann Neurol 2010; 68: 477493.
32. Luchinetti CF, Popescu BF, Bunyan RF, et al. Inflammatory
cortical demyelination in early multiple sclerosis. N Engl J
Med 2011; 365: 21882197.
33. Chang A, Staugaitis SM, Dutta R, et al. Cortical remyelin-
ation: A new target for repair therapies in multiple sclerosis.
Ann Neurol 2012; 72: 918926.
34. Waxman SG. Axonal dysfunction in chronic multiple sclero-
sis: Meltdown in the membrane. Ann Neurol 2008; 63: 411
413.
35. Dutta R, McDounough J, Yin X, et al. Mitochondrial dysfunc-
tion as a cause of axonal degeneration in multiple sclerosis
patients. Ann Neurol 2006; 59: 478489.
36. Orbach R, Zhao Z, Wang YC, et al. Comparison of disease
activity in SPMS and PPMS in the context of multicenter
clinical trials. PLoS One 2012; 7: e45409.
37. Lassmann H, van Horssen J and Mahad D. Progressive mul-
tiple sclerosis: Pathology and pathogenesis. Nat Rev Neurol
2012; 8: 647656.
38. Bramow S, Frischer JM, Lassmann H, et al. Demyelination
versus remyelination in progressive multiple sclerosis. Brain
2010; 133: 29832998.
39. Kappos L, Weinshenker B, Pozzilli C, et al.; European (EU-
SPMS) Interferon beta-1b in Secondary Progressive Multiple
Sclerosis Trial Steering Committee and Independent Advi-
sory Board; North American (NA-SPMS) Interferon beta-1b
in Secondary Progressive Multiple Sclerosis Trial Steering
Committee and Independent Advisory Board. Interferon beta-
1b in secondary progressive MS: A combined analysis of the
two trials. Neurology 2004; 23; 63: 17791787.
40. Hartung HP, Gonsette R, Knig N, et al.; Mitoxantrone in
Multiple Sclerosis Study Group (MIMS). Mitoxantrone in
progressive multiple sclerosis: A placebo-controlled, dou-
ble-blind, randomised multicentre trial. Lancet 2002; 360:
20182025.
41. Goodin DS, Traboulsee A, Knappertz V, et al.; 16-year long
term follow-up study investigators. Relationship between
early clinical characteristics and long term disability out-
comes: 16 year cohort study (follow-up) of the pivotal inter-
feron beta-1b trial in multiple sclerosis. J Neurol Neurosurg
Psychiatry 2012; 83: 282287.
42. Secondary progressive efficacy clinical trial of recombinant
interferon-beta-1a in MS (SPECTRIMS) study group. Ran-
domized controlled trial of interferon beta-1a in secondary pro-
gressive MS: Clinical results. Neurology 2001; 56: 14961504.
43. Andersen O, Elovaara I, Frkkil M, et al. Multicentre, ran-
domised, double-blind, placebo controlled, phase III study of
weekly, low dose, subcutaneous interferon beta-1a in secondary
progressive multiple sclerosis. J Neurol Neurosurg Psychiatry
2004; 75: 706710.
44. Cohen JA, Cutter GR, Fischer JS, et al.; IMPACT investiga-
tors. Benefit of interferon beta-1a on MSFC progression in
secondary progressive MS. Neurology 2002; 59: 679687.
45. La Mantia L, Vacchi L, Di Pietrantonj C, et al. Interferon beta
for secondary progressive multiple sclerosis. Cochrane Data-
base Syst Rev 2012; 1: CD005181.
46. Fidler JM, DeJoy SQ and Gibbons JJ Jr. Selective immuno-
modulation by the antineoplastic agent mitoxantrone. I. Sup-
pression of B lymphocyte function. J Immunol 1986; 137:
727732.
47. Morissey SP, Le Page E and Edan G. Mitoxantrone in the
treatment of multiple sclerosis. Int MS J 2005; 12: 7487.
48. Cohen BA and Mikol DD. Mitoxantrone treatment of mul-
tiple sclerosis: Safety considerations. Neurology 2004; 63:
S28S32.
49. Martinelli V, Cocco E, Capra R, et al.; Italian Mitoxantrone
Group. Acute myeloid leukemia in Italian patients with mul-
tiple sclerosis treated with mitoxantrone. Neurology 2011; 77:
18871995.
50. Esposito F, Radaelli M, Martinelli V, et al. Comparative study
of mitoxantrone efficacy profile in patients with relapsing
remitting and secondary progressive multiple sclerosis. Mult
Scler 2010; 16: 14901499.
51. Bornstein MB, Miller A, Slagle S, et al. A placebo-controlled,
double-blind, randomized, two-center, pilot trial of Cop 1 in
chronic progressive multiple sclerosis. Neurology 1991; 41:
533539.
52. Fazekas F, Sorensen PS, Filippi M, et al. MRI results from the
European Study on Intravenous Immunoglobulin in Second-
ary Progressive Multiple Sclerosis (ESIMS). Mult Scler 2005;
11: 433440.
53. Pohlau D, Przuntek H, Sailer M, et al. Intravenous immuno-
globulin in primary and secondary chronic progressive mul-
tiple sclerosis: A randomized placebo controlled multicentre
study. Mult Scler 2007; 13: 11071117.
54. Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al.
Low-dose (7.5 mg) oral methotrexate reduces the rate of pro-
gression in chronic progressive multiple sclerosis. Ann Neurol
1995; 37: 3040.
55. Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al.
Low-dose oral methotrexate in chronic progressive multiple
sclerosis: Analyses of serial MRIs. Neurology 1996; 47:
11531157.
56. The Canadian Cooperative Multiple Sclerosis Study Group.
The Canadian cooperative trial of cyclophosphamide and
plasma exchange in progressive multiple. Lancet 1991; 337:
441446.
57. Weiner HL, Mackin GA, Oray EJ, et al. Intermittent cyclo-
phosphamide pulse therapy in progressive multiple sclerosis:
Final report of the Northeast Cooperative Multiple Sclerosis
Treatment Group. Neurology 1993; 43: 910918.
58. Zephir H, de Seze J, Duhamel A, et al. Treatment of progres-
sive forms of multiple sclerosis by cyclophosphamide: A
cohort study of 490 patients. J Neurol Sci 2004; 218: 7377.
59. Giovannoni G, Comi G, Cook S, et al.; CLARITY Study
Group. A placebo-controlled trial of oral Cladribine for
relapsingremitting multiple sclerosis. N Engl J Med 2010;
362: 416426.
Comi 1435
60. Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment
of chronic progressive multiple sclerosis. Lancet 1994; 344:
913.
61. Rice GP, Filippi M and Comi G. Cladribine and progressive
MS: Clinical and MRI outcomes of a multicenter controlled
trial. Cladribine MRI Study Group. Neurology 2000; 54:
11451155.
62. Filippi M, Rovaris M, Iannucci G, et al. Whole brain volume
changes in patients with progressive MS treated with cladrib-
ine. Neurology 2000; 55: 17141718.
63. Ratzinger G, Reagan JL, Heller G, et al. Differential CD52
expression by distinct myeloid dendritic cell subsets: Implica-
tions for alemtuzumab activity at the level of antigen presen-
tation in allogenic graft-host interactions in transplantation.
Blood 2003; 101: 14221429.
64. Coles AJ, Twyman CL, Arnold DL, et al.; CARE-MS II
investigators. Alemtuzumab for patients with relapsing mul-
tiple sclerosis after disease-modifying therapy: A randomised
controlled phase 3 trial. Lancet 2012; 380: 18291839.
65. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective
than interferon beta-1a at 5-year follow-up of CAMMS223
clinical trial. Neurology 2012; 78: 10691078.
66. Paolillo A, Coles AJ, Molyneux PD, et al. Quantitative MRI
in patients with secondary progressive MS treated with mono-
clonal antibody Campath 1H. Neurology 1999; 53: 751757.
67. Reston JT, Uhl S, Treadwell JR, et al. Autologous hematopoi-
etic cell transplantation for multiple sclerosis: A systematic
review. Mult Scler 2011; 17: 204213.
68. Mancardi G and Saccardi R. Autologous haematopoietic
stem-cell transplantation in multiple sclerosis. Lancet Neurol
2008; 7: 626636.
69. Bowen JD, Kraft GH, Wundes A, et al. Autologous hemato-
poietic cell transplantation following high-dose immunosup-
pressive therapy for advanced multiple sclerosis: Long term
results. Bone Marrow Transplant 2012; 47: 946951.
70. Fassas A, Kimiskidis VK, Sakellari I, et al. Long-term results
of stem cell transplantation for MS: A single-center experi-
ence. Neurology 2011; 76: 10661070.
71. Holmony T. Immunopathogenesis of multiple sclerosis: Con-
cepts and controversies. Acta Neurol Scand Suppl 2007; 187:
3945.
72. Freedman MS, Bar-Or A, Oger J, et al.; MAESTRO-01 Inves-
tigators. A phase III study evaluating the efficacy and safety
of MBP8298 in secondary progressive MS. Neurology 2011;
77: 15511560.
73. Leary SM, Miller DH, Stevenson VL, et al. Interferon beta-
1a in primary progressive MS: An exploratory, randomized,
controlled trial. Neurology 2003; 60: 4451.
74. Montalban X, Sastre-Garriga J, Tintor M, et al. A single-
center, randomized, double-blind, placebo-controlled study
of interferon beta-1b on primary progressive and transitional
multiple sclerosis. Mult Scler 2009; 15: 11951205.
75. Wolinsky JS, Narayana PA, OConnor P, et al.; PROMiSe Trial
Study Group. Glatiramer acetate in primary progressive mul-
tiple sclerosis: Results of a multinational, multicenter, double-
blind, placebo-controlled trial. Ann Neurol 2007; 61: 1424.
76. Wolinsky JS, Shochat T, Weiss S, et al.; PROMiSe Trial
Study Group. Glatiramer acetate treatment in PPMS; why
males appear to respond favourably. J Neurol Sci 2009; 286:
9298.
77. Hawker K, OConnor P, Freedman MS, et al.; OLYMPUS
trial group. Rituximab in patients with primary progressive
multiple sclerosis: Results of a randomized double-blind
placebo-controlled multicenter trial. Ann Neurol 2009; 66:
460471.
78. Hauser SL, Waubant E, Arnold DL, et al.; HERMES Trial
Group. B-Cell depletion with rituximab in relapsingremit-
ting multiple sclerosis. New Engl J Med 2008; 358: 676688.
79. Konishi Y, Chui DH, Hirose H, et al. Trophic effect of eryth-
ropoietin and other hematopoietic factors on central choliner-
gic neurons in vitro and in vivo. Brain Res 1993; 609: 2935.
80. Campana WM and Myers RR. Erythropoietin and erythropoi-
etin receptors in the peripheral nervous system: Changes after
nerve injury. Faseb J 2001; 15: 18041806.
81. Zhang J, Li Y, Cui Y, et al. Erythropoietin treatment improves
neurological functional recovery in EAE mice. Brain Res
2005; 1034: 3439.
82. Ehrenreich H, Fischer B, Norra C, et al. Exploring recom-
binant human erythropoietin in chronic progressive multiple
sclerosis. Brain 2007; 130: 25772588.
83. Kalkers NF, Barkhof F, Bergers E, et al. The effect of the
neuroprotective agent riluzole on MRI parameters in primary
progressive multiple sclerosis: A pilot study. Mult Scler 2002;
8: 532533.
84. Kapoor R, Davies M, Blaker PA, et al. Blockers of sodium
and calcium entry protect axons from nitric oxide-mediated
degeneration. Ann Neurol 2003; 53: 174180.
85. Bechtold DA, Kappor R and Smith KJ. Axonal protection
using flecainide in experimental autoimmune encephalomy-
elitis. Ann Neurol 2004; 55: 607616.
86. Bechtold DA, Yue X, Evans RM, et al. Axonal protection
in experimental autoimmune neuritis by the sodium channel
blocking agent fleacainide. Brain 2005; 128: 1828.
87. Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuro-
protection in secondary progressive multiple sclerosis: A
randomised, double-blind, placebo-controlled, parallel-group
trial. Lancet Neurol 2010; 9: 681688.
88. Chataway, et al.The MS-STAT trial: High dose simvastatin
demonstrates neuroprotection without immune-modulation in
secondary progressive multiple sclerosis (SPMS) a phase II
trial. ECTRIMS 2012; abstract 38a.
89. Giuliani F, F SA, Metz LM, et al. Effective combination of
minocycline and interferon-beta in a model of multiple scle-
rosis. J Neuroimmunol 2005; 165: 8391.
90. Haaseldam H and Johansen FF. Cannabinoid treatment ren-
ders neurons less vulnerable than oligodendrocytes in experi-
mental autoimmune encephalomyelitis. Int J Neurosci 2011;
121: 510520.
91. Chung YC, Bok E, Huh SH, et al. Cannabinoid receptor type
1 protects nigrostriatal dopaminergic neurons against MPTP
neurotoxicity by inhibiting microglial activation. J Immunol
2011; 187: 65086517.
92. Rossi S, Buttari F, Studer V, et al. The (AAT)n repeat of the
cannabinoid CB1 receptor gene influences disease progres-
sion in relapsingremitting multiple sclerosis. Mult Scler
2011; 17: 281288.
93. Zajicek J, Ball S, Wright D, et al., on behalf of CUPID
investigator group. Effect of dronabinol on progression in
progressive multiple sclerosis (CUPID): A randomised, pla-
cebo-controlled trial. Lancet Neurology 2013:
1436 Multiple Sclerosis Journal 19(11)
94. Martino G, Franklin RJ, Baron Van Evercooren A, et al.;
Stem Cells in Multiple Sclerosis (STEMS) Consensus Group.
Stem cell transplantation in multiple sclerosis: Current status
and future prospects. Nat Rev Neurol 2010; 6: 247255.
95. Uccelli A, Pistoia V and Moretta L. Mesenchymal stem cells:
A new strategy for immunosuppression? Trends Immunol
2007; 28: 219226.
96. Freedman MS, Bar-Or A, Atkins HL, et al.; MSCT Study Group.
The therapeutic potential of mesenchymal stem cell transplanta-
tion as a treatment for multiple sclerosis: Consensus report of the
international MSCT Study Group. Mult Scler 2010; 16: 503510.
97. Connik P, Kolappan M, Crawley C, et al. Autologous mesen-
chymal stem cells for the treatment of secondary progressive
multiple sclerosis: An open-label phase 2a proof-of-concept
study. Lancet Neurol 2012; 11: 150156.
98. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al.
Safety and immunological effects of mesenchymal stem cell
transplantation in patients with multiple sclerosis and amyo-
trophic lateral sclerosis. Arch Neurol 2010; 67: 11871194.
99. Mohyeddin Bonab M, Yazdanbakhsh S, Lotfi J, et al. Does
mesenchymal stem cell therapy help multiple sclerosis patients?
Report of pilot study. Iran J Immunol 2007; 4: 5057.
100. Yamouth B, Hourani R, Salti H, et al. Bone marrow mes-
enchymal stem cell transplantation in patients with mul-
tiple sclerosis: A pilot study. Neuroimmunol 2010; 227:
185189.
101. Uccelli A, Laroni A and Freedman MS. Mesenchymal stem
cell as treatment for MS progress to date. Mult Scler 2013;
19: 515519.
102. Hanafy KA and Sloane JA. Regulation of remyelination in
multiple sclerosis. FEBS Lett 2011; 585: 38213828.
103. Sabo JK and Cate HS. Signalling pathways that inhibit the
capacity of precursor cells for myelin repair. Int J Mol Sci
2013;14: 10311049.
104. Han MH, Hwang S, Roy DB, et al. Proteomic analysis of
active multiple sclerosis lesions reveals therapeutic targets.
Nature 2008; 451: 10761081.
105. Rudick RA, Mi S and Sandrock AW Jr. LINGO-1 antag-
onists as therapy for multiple sclerosis: In vitro and in
vivo evidence. Expert Opin Biol Ther 2008; 8: 1561
1570.
106. Mi S, Blake Pepinski R and Cadavid D. Blocking LINGO-1
as a therapy to promote CNS repair: From concept to the
clinic. CNS Drugs 2013; 27: 493503.