The World Congress (ECTRIMS + ACTRIMS + LACTRIMS)
on treatment and research in MS gathered 5000
MS clinicians and researchers from around the
world in Montreal from September 17 to 20.
Presentations from leading MS researchers highlighted
the changing landscape of MS, new insights
into risk factors and progress in the search
for better treatments.
Details
Below are summaries from some of the many
varied topics that were presented:
Vitamin D
Investigating the sunlight/vitamin D question
from the angle of a high-incidence area,
researchers at the Hospital for Sick Children
(Toronto, Ontario) reviewed records of 35
children with MS from Canada whose serum
levels of vitamin D had been tested. Naila
Makhani, MD, described finding that only
34% had serum levels considered "adequate" (greater
than 70 nmol/L 25-hydroxyvitamin D), while
65% were either "insufficient" (31-69
nmol/L) or deficient (0-30 nmol/L). Future
studies are needed to determine whether vitamin
D supplementation alters disease susceptibility
or course.
In a related study investigating the possible
link between vitamin D and risk of MS, reported
earlier during the congress, Heather Hanwell,
MS (University of Toronto) and colleagues in
the Canadian National Pediatric Demyelinating
Disease Network investigated 117 children at
high risk for MS - youngsters who have had
one neurologic episode. They took blood samples
and then followed the children for one year
or so to determine whether they developed definite
MS (as determined by experiencing a second
episode). They found that vitamin D levels
were significantly lower in the 16% of the
children who developed MS.
Growing evidence is linking increased levels
of vitamin D to decreased MS risk, but one
question is, will vitamin D supplements protect
people from developing MS? First, we'd need
to know the safety of increasing supplementation
in people with MS. Jodie Burton, MD (St. Michael's
Hospital, Toronto), and colleagues compared
administering escalating doses of vitamin D3
(the equivalent of 4,000 to 40,000 international
units per day) to 25 people with MS over 52
weeks, with 24 untreated controls. Calcium
levels remained within normal limits. Immune
system analysis showed that reactivity of T
cells - major players in the MS attack - was
reduced. Trends toward clinical improvement
were noted, but they were not significant.
The group is now planning a phase II study
of vitamin D supplementation that will focus
on MRI and clinical endpoints.
Note: Further studies are needed to determine
whether vitamin supplements could reduce the
risk of MS, and there is insufficient evidence
yet that vitamin D supplements can affect the
course of MS once it has begun. Currently,
there are well-designed trials in progress
that may clarify the potential value and possible
risks of vitamin D supplementation in MS within
a few years.
Repairing and Protecting Against MS Damage
Repairing disease damage is an elusive goal
of MS research - thanks to treatments currently
on the market, we can often do a reasonable
job of stopping the immune attack on the
brain and spinal cord, but we still can't
repair the damage it causes. Today, research
teams from around the world reported their
strides forward in this important aim.
One experimental strategy under study for
repairing tissue damage in MS is cell transplants,
such as "mesenchymal stem cells" which
are derived from bone marrow. Antonio Uccelli,
MD (University of Genoa) studied whether mesenchymal
cell transplants would affect the immune attack
as well as tissue damage in mice with the MS-like
disease EAE. Despite finding little evidence
that these cells developed into actual replacement
nerve cells, they found evidence that brain
tissue was protected from disease, as well
as an increase in T cells that regulate the
immune attack and a decrease of pro-inflammatory
cells. Results of an early clinical trial of
mesenchymal stem cells are slated to be presented
on Friday.
People with MS have varying symptoms, which
means that the underlying damage probably differs
as well, and understanding these differences
is a vital first step to devising repair strategies.
A. Giorgio, MD (University of Siena, Italy)
and colleagues examined changes in brain volume
over an average time period of 18 months using
MRI in 963 people with different types of early
and later MS who were involved in placebo arms
of clinical trials or who were not taking any
disease-modifying therapy. Using a new technique
to analyze brain atrophy, the investigators
reported that reductions in brain volume were
similar in people in the earliest stages of
MS and those in late stages. They concluded
that this damage occurs steadily during the
disease's evolution. Further work is needed
to verify these findings over longer periods
of time.
Ikuo Tsunoda, MD, PhD, and colleagues (University
of Utah, Salt Lake City) administered resveratrol,
a component of red wine, to mice with an
MS-like disease induced by a virus. Resveratrol
enhances the activity of SIRT1, a molecule
that might help to preserve nerve fibers.
In this National MS Society-funded effort,
treated mice gained more weight than untreated
mice, a sign of clinical improvement which
the researchers say might be attributed to
nerve protection. In mice infected with a
low dose of virus, fewer died with resveratrol
treatment. The team is proceeding with the
pathologic studies necessary to confirm this
hypothesis.
Exercise and Fatigue
Although exercise is helpful in managing
many MS symptoms, research on the type and
intensity
of this exercise continues. Heather Hayes,
DPT, and colleagues (University of Utah)
were funded by the National MS Society to compare
a standard exercise program with a high-intensity
resistance training program in 19 people
with
moderately severe MS. There were no significant
differences in the improvement of strength
or mobility between the two programs; fatigue
improved significantly in both groups. The
results showed no significant additional
benefit of this high-intensity program for
people with
moderately severe MS - such studies help
to direct exercise protocols for people with
this
disease.
Reports about Pediatric MS
Studies from National MS Society-supported
Pediatric MS Centers of Excellence and
others focus on characterizing MS in this understudied
population. John R. Rinker, MD, and others
from the University of Alabama-based Center
reported that African-American children
with
MS in general experience more severe disease
than children with MS from other racial
or ethnic groups. The same team reported that
out of 45 pediatric MS patients referred
to their center over several months, two-thirds
had psychiatric disorders in addition to
MS. The most common was depression (64%),
followed by anxiety and attention deficit
hyperactivity disorder. A significant percentage
of adults with MS also experience psychiatric
disorders such as depression.
Researchers at the National MS Society-funded
Pediatric Center of Excellence in Stony Brook,
New York, reported on a study of fatigue in
51 children with pediatric MS. William Macallister,
PhD, reported that fatigue was a major MS symptom
for 43% of these children, who can experience
this symptom even early in the disease and
in the absence of other significant neurologic
impairments. Fatigue can impact school performance
and other quality of life issues
Women and MS
MS typically initially affects women of childbearing
age. When young women receive a diagnosis
of MS, they frequently have questions about
the
effects of the disease on childbearing --
and vice versa, making this a crucial area
for
research. Some brief findings reported today
in this area include:
Dr. M. Mendibe, and colleagues (Hospital de
Cruces, Baracaldo, Spain) analyzed the evolution
of disability in 451 women with MS and showed
that having children did not affect the development
of disability. Annette Wundes, MD, and colleagues
(University of Washington, Seattle) analyzed
data from 391 women with MS and showed that
significantly fewer have children than the
U.S. national average. It is not clear whether
this is the result of biological factors or
choice. Chiara Rivoiro, MD, and colleagues
(S. Luigi Gonzaga Hospital, Orbassano, Italy)
administered gonadotrophin releasing hormone
(GnRH)-analogue treatment to 12 women undergoing
treatment with mitoxantrone to prevent onset
of premature ovarian failure - a common long-term
consequence of similar chemotherapeutic agents.
So far, six women have completed treatment
with both agents and have returned to normal
menstrual cycles.
Reports on Emerging Therapies
More patients remained relapse-free and stable
while taking experimental alemtuzumab (Genzyme
Corporation) compared with those taking a standard
interferon, supporting other beneficial measures
previously reported from a Phase 2 study of
the annual IV infusion, now in Phase 3 trials.
Krzysztof Selmaj, MD, PhD (Klinika J Katedra
Neurologii Akademii, Lodz, Poland) presented
data on the Phase 2 study, which evaluated
high and low doses of this immune-suppressing
monoclonal antibody compared with Rebif® (interferon
beta-1a, EMD Serono, Inc. and Pfizer, Inc.)
in people with relapsing-remitting MS who had
never taken any other disease-modifying therapies.
Immune thrombocytopenic purpura, thyroid adverse
events, and infections occurred more frequently
in the alemtuzumab groups.
First results from a one-year, multi-center
trial of T-cell vaccination (Tovaxin, Opexa
Therapeutics) were presented by Edward Fox,
MD, PhD (University of Texas Medical Branch,
Round Rock Texas). The placebo-controlled study
involved 140 patients with relapsing-remitting
MS and 10 patients who had experienced a neurological
episode (CIS) that put them at possible risk
for being diagnosed with MS. Those on treatment
received five monthly subcutaneous injections
of their own attenuated immune T cells and
followed for one year. The treatment was found
to be safe, but did not achieve statistical
significance in the primary endpoint evaluating
the cumulative number of active MRI lesions
(gadolinium-enhanced) in those on active therapy
versus those on placebo. Dr. Fox stated that
additional evaluations of the immunological
and other effects of the treatment are ongoing,
with an eye toward the design of further clinical
trials.
A recent study found that one course of the
IV drug Rituxan® (rituximab, Genentech
and Biogen Idec) reduced disease activity and
relapses for 48 weeks in people with relapsing-remitting
MS. Today Robert Naismith, MD (Washington University,
St. Louis, Mo.) presented results of an investigator-initiated
study supported in part by the National MS
Society (USA) suggesting that this drug, which
depletes immune B cells, has potential for
treating "breakthrough" disease activity
in people still taking a standard MS therapy.
Twenty-six people who were on disease-modifying
therapies but showing active MRI-detected lesions
received four doses of rituximab while staying
on their other therapy. At the end of 24 weeks,
their disability status score (EDSS) remained
unchanged, but another functional measure called
the MS Functional Composite (MSFC) improved
over baseline.). In an earlier presentation
by the same group, they also reported finding,
to their surprise, that rituximab not only
depleted B cells, but also T cells.
Disappointing results from a trial of the
IV drug Rituxan® (rituximab, Genentech
and Biogen Idec), which depletes immune B cells
from circulation, may provide possible clues
to future clinical trials in primary-progressive
MS, a course of MS for which no treatments
are currently on the market. Kathleen Hawker,
MD (Ohio State University, Columbus, Oh.) presented
results of a trial involving 439 people with
primary-progressive MS, showing that the drug
did not slow disease progression when compared
with inactive placebo, the primary endpoint
of the study.
However, secondary outcome measures using
MRI showed the median change in lesion volume
from baseline to week 96 was significantly
lower in patients on therapy. Looking at subgroups
of participants, the investigators found that
those who were younger and showed MRI signs
of active inflammatory lesions (gadolinium
enhancement) appeared to benefit most from
the therapy. This suggests some impact on underlying
disease activity that should be factored into
future trials of therapies for this progressive
form of the disease.
According to investigators reporting the first
results from an early, uncontrolled trial
of injections of mesenchymal stem cells (grown
from the patients' own bone marrow) in a
small number of individuals with MS and ALS,
this approach may warrant longer, controlled
investigations. Dimitrios Karussis, MD, PhD
(Hadassah-Hebrew University, Jerusalem) reported
that 15 individuals with advanced MS and
14 with advanced ALS received intrathecal
and intravenous injections of the cells.
According to the report, the ALS patients
remained stable for 6 months and MS patients
showed improvement on disability status scores
(EDSS) at 3 months and 6 months. Twenty patients
experienced mild fever and transient meningeal
irritation.
Results of a small-scale safety trial of the
experimental peptide therapy ATX-MS-1467 were
presented by David C. Wraith, PhD (University
of Bristol, UK). This compound is a "cocktail" of
four peptides derived from human myelin basic
protein, a major component of the myelin that
is attacked in MS. The vaccine was tested in
6 people with secondary-progressive MS and
was well tolerated. Lab tests also showed that
it suppressed responses to MBP by immune T
cells of the participants. This preliminary
study was funded by Apitope Ltd. According
to Dr. Wraith, the company hopes to conduct
a larger clinical trial in the future.
Results of a second Phase 3 trial of sustained-release
Fampridine (Acorda Therapeutics) showed that
this symptomatic therapy could temporarily
improve walking speed and leg strength in a
subgroup of people with all types of MS. Andrew
Goodman, MD (University of Rochester, New York)
presented results of this trial of Fampridine-SR,
a sustained-release formula of 4-aminopyridine
that temporarily enhances nerve signaling.
For nine weeks 120 people received fampridine
versus 119 on placebo. The primary outcome
measured was improvement in the time taken
to walk 25 feet. About 43% of those on treatment
showed consistent improvement in walking speed,
versus about 9% of those on placebo. Among
responders, speed improved by about 25% from
baseline. The drug was well tolerated. According
to the company, these results, combined with
previous testing, will serve as the basis of
an application for marketing approval.
In the first attempt to apply a new "antisense" approach
to treating MS, ATL1102 showed significant
reduction in the accumulation of new active
brain lesions over 8 weeks of treatment in
a European Phase 2 trial. The study, presented
by Volker Limmroth, MD, PhD (University of
Cologne, Germany), was a placebo-controlled
trial involving 77 people with relapsing-remitting
MS who received twice weekly subcutaneous injections
of the active agent or placebo. This proof-of-concept
study requires followup with larger, longer
clinical trials to verify this compound's clinical
effectiveness and safety. ATL1102 targets CD49d,
a subunit of a T cell adhesion molecule that
permits immune cells to migrate into the central
nervous system.
MS and Cognitive Impairment
Cognitive dysfunction, a troubling symptom
that often involves problems with memory,
attention, and information processing speed,
can impact
people with MS even early on in the disease
course. Studies are underway in understanding
the biological basis for these problems and
in addressing them through cognitive rehabilitation.
A study using an advanced magnetic resonance
imaging technique (double inversion recovery)
to evaluate the presence of lesions, or damaged
areas, in the gray matter parts of the brain
(cortex), and their possible association with
congitive problems was described by Massimiliono
Calabrese (University of Padova, Italy). The
team administered cognitive tests and also
evaluated fatigue and depression in 70 people
with MS, and compared the results to their
images of intracortical lesions. They found
that cognitive impairment, but not fatigue
or depression, was associated with high volumes
of intracortical lesions.
In a related study, Flavia Nelson, MD (University
of Texas Helath Science Center, Houston, Texas)
and colleagues also showed a link between intracortical
lesions and cognitive impairment. These types
of lesions are not well detected using conventional
MR imaging. More research is needed on the
detection, treatment and prevention of cognitive
impairment in MS.
The four days of the World Congress offered
an impressive glimpse into the fast-moving
progress being made by investigators around
the world, in many different fields, toward
better treatments and quality of life, prevention
and a cure for multiple sclerosis.
With information from the National MS Society
(USA)
National Research and Programs
Clinical Programs
Offert en français.
Disclaimer
The Multiple Sclerosis Society of Canada is an independent, voluntary health
agency and does not approve, endorse or recommend any specific product or therapy,
but provides information to assist individuals in making their own decisions.
