Last month more than 10,000 researchers and practicing neurologists from around the world gathered at the 63rd Annual Meeting of the American Academy of Neurology (AAN) in Honolulu. Over 500 presentations related to multiple sclerosis. National MS Society grantees/MS Society of Canada grantees were among those presenting novel findings on many different approaches to stopping MS, restoring function, and ending the disease forever. Here are some highlights.
Research Toward Stopping MS
— Experimental Therapies in the Pipeline
Laquinimod: First results from the large, international phase III clinical trial of laquinimod (Teva Pharmaceuticals) in relapsing-remitting MS were presented by Giancarlo Comi, MD (University of Milan). Another large trial of this experimental immune therapy is still underway:
- After two years, laquinimod reduced the annual relapse rate
in those completing the trial by 23%, compared to those on
placebo.
- Other secondary outcomes included reducing the risk of
disease progression (by 36%) and brain atrophy (by 33.8%), and
reducing the accumulation of brain lesions detected with MRI.
- No serious infections were reported; the most common adverse events were back pain and abdominal pain, and elevations in liver enzymes, but no serious liver damage was reported. (Late-Breaking News – Abstract not currently available)
Other presentations and posters provided further evaluations and extension results from clinical trials previously reported, including cladribine, teriflunomide, and alemtuzumab, and ocrelizumab, generally supporting their benefits and safety previously reported at other conferences such as ECTRIMS and other conferences.
Primary-progressive MS: A poster presentation by Xavier Montalban, MD (Hospital Universitari Vall d’Hebron, Barcelona) and colleagues outlined a planned phase III international clinical trial of ocrelizumab (Roche and Biogen Idec) that will involve 630 people with primary-progressive MS, called the ORATORIO study. This is a monoclonal antibody similar to rituximab which targets immune B cells, which is given as infrequent cycles of intravenous infusions. It is also being studied in relapsing MS. (Abstract P04.186)
Research Toward Stopping MS
— Current MS Therapies
Many presentations focused on follow-up safety and benefits of approved therapies, generally supporting and expanding on original findings of their benefit for treating MS. For example:
Early vs. delayed treatment: A poster by an international team presented follow-up results of the large-scale PreCISe clinical trial that had shown that glatiramer acetate (Copaxone, ® Teva Pharmaceuticals) could delay the development of definite MS in people who had experienced a single neurological episode (CIS).
- After participants on placebo experienced a second attack
that confirmed an MS diagnosis, they were eligible to go on
glatiramer acetate.
- Five years after the original trial began, the risk of developing definite MS was reduced by 41% in those who had received early treatment, and those who received early treatment versus delayed treatment after placebo were significantly more likely to show less disease burden on MRI and less brain atrophy. (PD6.006)
Long-term impacts of therapy: A poster by another international team described an effort to locate and ascertain the status of 372 people with MS who were originally enrolled 21 years ago in a placebo-controlled clinical trial of interferon beta-1b (Betaseron,® Bayer HealthCare Pharmaceuticals, Inc.).
- They managed to identify the status of 98.4% of the original
participants, one-third of whom were on placebo during the trial.
This high rate of ascertainment adds significance to this
clinical trial follow-up study.
- After 21 years, 21.8% of the participants had died of various
causes.
- Those who had been on active therapy during the trial were
more likely to be alive 21 years later than those who had been on
placebo.
- The investigators noted that more research is needed to understand the biological basis for these outcomes. (Abstract P07.163)
Natalizumab and PML: Several platform presentations focused on studies determining outcomes of people taking natalizumab (Tysabri,® Biogen Idec and Elan) who have developed progressive multifocal leukoencephalopathy (PML), and whether a blood test that can show whether a person has been exposed to the JC virus can predict that person’s risk of developing PML. (Read more about natalizumab and PML). Meena Subramanyam, PhD (Biogen Idec) and colleagues focused on blood or serum samples taken from 25 people before they developed PML.
- All of those samples tested positive for the JC virus using a two-step laboratory test for antibodies. (Abstract S51.003)
Lucia Moiola, MD (University Hospital San Raffaele, Milan) and colleagues used the two-step laboratory assay to determine prevalence of antibodies for JC virus in 376 Tysabri-treated individuals in Italy in a study supported by Biogen Idec and Elan.
- About 57% had the antibodies.
- Women had lower rates than men (52% vs 68%). (S30.007)
Biogen-Idec is conducting large-scale studies to determine whether they can develop strong predictors of an individual’s risk of PML that could be used to better inform decisions about therapy.
Ralf Gold, MD (Ruhr-University Bochum, Germany) and colleagues described outcomes of those people who developed PML and survived (as of March 4, 2011, 81 out of 102 survived).
- Generally, the survivors were younger, had faster diagnoses
of PML, and had less widespread MRI evidence of PML.
- They conclude that early diagnosis of PML and aggressive management of PML and subsequent IRIS may improve outcomes. (Abstract S51.002)
Research Toward Stopping MS
— Understanding What Goes Wrong
Pregnancy, MS activity and breastfeeding: Many people with MS are women of childbearing age, and while pregnancy generally reduces a woman’s MS symptoms, there is an increased risk of relapse during the first few months after giving birth. Conflicting findings were reported around how to prevent postpartum relapses:
- Emilio Portaccio, MD (University of Florence) described
results from an ongoing study of pregnancy and MS in Italy. Only
16% of the women started MS therapy early after delivery, and
about 44% experienced at least one MS relapse within 12 months
after delivery. Contrary to other studies, they did not find that
breastfeeding was protective against postpartum relapse, and
found that disability progression was associated with postpartum
relapses. They reported that frequent relapses before pregnancy
and delivery predicted post-delivery relapses, and suggested
early therapy postpartum to protect against relapse. (Abstract
S20.001)
- Kerstin Hellwig, MD (Ruhr University, Bochum, Germany) described a nationwide MS pregnancy registry in Germany. (Abstract 20.002) They found that exclusive breastfeeding (without formula supplements) seemed to be beneficial against postpartum relapses for 6 months postpartum. (Abstract 20.003)
Physical basis of MS depression?: Previous studies have identified pathological loss of tissue in a specific region in the brain involved in controlling mood, called the hippocampus, in people with MS. Nancy Sicotte, MD (Cedars-Sinai Medical Center, Los Angeles) and a multinational team investigated how this phenomenon might be linked to MS depression in 109 women with MS who were enrolled in a stress intervention study.
- Depression for all participants was evaluated using standard
scales, and 61 were classified as having low levels of depression
and 48 as having high depression. The groups were similar in
terms of disease duration, disability and use of MS
therapies.
- Imaging this brain region using MRI, they found a significant
link between high depression and more tissue loss and patterns of
loss in specific areas of the hippocampus.
- This study offers clues to a biological basis of MS depression, which may help inform intervention strategies. (Abstract S11.002)
Myelin abnormalities: Previous work has suggested that clinical progression may be more common in people with MS whose brain MRIs show something called “diffusely abnormal white matter,” or DAWM. In a study supported by the MS Society of Canada, G. R. Wayne Moore, MD, FRCPC (University of British Columbia. Vancouver) and colleagues studied brain tissues and compared them microscopically against MRIs of the same brain regions to understand the biology behind these images.
- They found at the microscopic level there was loss of the
fatty portions of myelin (phospholipids), with the myelin protein
MBP relatively intact, in the DAWM areas seen on MRI.
- This myelin phospholipid loss appeared to pre-date any loss
of nerve fibers (axons).
- They note the possibility that abnormalities in the fatty portions of myelin may play a role in progression in people with MS showing signs of DAWM. (Abstract S50.007)
Role of B cells in MS: For several years there has been higher awareness of the role of immune system B cells in the nervous system damage that occurs in MS. Investigating their role further, Robert Lisak, MD (Wayne State University, Detroit) and colleagues in Detroit and Montreal, Canada took B cells from people with MS and from healthy controls and cultured them without and with stimulation with various factors relevant to the disease-related activation.
- They added molecules secreted by the B cells to cell cultures
of myelin-making cells (oligodendrocytes) and other glial cells
from rats.
- Molecules from MS B cells were significantly more toxic to
oligodendrocytes and not to other glial cells, and this toxicity
was not related to immunoglobulin production.
- Further research is ongoing to determine the nature of this toxicity and its relevance to disease activity. (Abstract S50.006)
A separate study led by Halina Offner (Oregon Health & Science University/Portland VA Medical Center), funded by the NIH, National MS Society, and Dept. of Veterans’ Affairs, explored how immune B cells behave when the sex hormone estrogen is playing its typically protective role against MS-like EAE in mice.
- They found that estrogen could not protect against EAE in
mice that had been engineered to lack B cells.
- They suggest that B cells influenced by estrogen may play a regulatory, rather than destructive, role in MS. (Abstract P05.027)
Research Toward Restoring Function
Repairing myelin: Some myelin repair occurs in response to damage to the nervous systems in people with MS, but it is not clear whether this repair is accomplished by myelin-making oligodendrocytes near the damage or by newly recruited immature glial precursor cells. Qiao-Ling Cui, MD, PhD (Montreal Neurological Institute, McGill University) and colleagues used neurons grown in lab cultures to compare the capacity of mature oligodendrocytes versus immature oligodendrocyte precursor cells (OPCs) to enwrap axons (nerve fibers).
- They found that the OPCs showed far better capacity to cover
axons with myelin, lending evidence to the idea that OPCs are a
major source of myelin repair.
- The factors that restrict the repair ability of mature
oligodendrocytes are still undefined.
- This study, funded by the MS Society of Canada and Canadian Stem Cell Network, adds clues to stimulating myelin repair in people with MS. (Abstract S50.004)
Ginkgo trial: Disappointing results of a placebo-controlled, 12-week trial testing the ability of Ginkgo biloba to improve cognitive function in people with MS were reported during a platform presentation by Jesus Lovera, MD (Louisiana State University, New Orleans) and colleagues.
- The study, funded by the Department of Veterans Affairs,
involved 121 people with all types of MS whose cognitive tests
showed some thinking impairment.
- After 12 weeks, no differences were seen between those on
Ginkgo and those taking placebo in any of the outcomes including
learning tests and family reports.
- The authors point out that this study was not designed to determine the long-term impact of Ginkgo. (Abstract S41.004)
Ampyra for walking: Further evaluations of clinical trials that led to the U.S. FDA approval of dalfampridine to improve walking (Ampyra - http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/treatments/medications/dalfampridine/index.aspx) were presented, including a poster by Andrew Goodman, MD (University of Rochester), funded by Acorda Therapeutics and Biogen Idec, examining whether people with severe walking impairment (greater than or equal to a score of 6 EDSS) and those with spasticity and muscle weakness benefited at the same level as others included in three clinical trials.
- The results from all participants from three clinical trials
suggested that 37% responded to treatment by walking faster,
versus 9% who were on inactive placebo.
- In these subgroups with severe walking impairment, 38% of
those with higher EDSS responded to treatment (versus 9.2% of
those on placebo) and in those with spasticity and weakness, 33%
were responders (versus 3.7% on placebo).
- Since these results are similar to those of the combined
clinical trials, they suggest that dalfampridine can improve
walking even in those with severe walking impairment. (Abstract
P07.172)
Treating sleep disorders: Daria A. Trojan, MD, MSc (McGill University Health Centre, Montreal) and team evaluated whether treating sleep disorders experienced by people with MS could improve symptoms and quality of life. In a study supported by the MS Society of Canada, sleep quality was evaluated by questionnaires and overnight polysomnography. All participants who had sleep problems were offered treatment.
- Of 56 people who completed the follow-up evaluation, 21 were
treated for sleep apnea, 3 for restless legs syndrome, and 1 for
insomnia; 35 were not treated for sleep disorders (including 18
who had sleep disorders but were not treated and 17 who had no
sleep disorders).
- Compared to all others, those who were treated for sleep disorders showed significant improvements on measures of physical and mental fatigue, sleepiness and sleep quality. (Abstract P03.227)
Thinking and warm weather: A poster by National MS Society rehabilitation fellow Victoria Leavitt, PhD (Kessler Foundation Research Center, West Orange, NJ) and colleagues tested the impact of air temperature on outcomes of cognitive testing, since heat causes many people with MS to experience worsening of other MS symptoms:
- 40 people with MS and 40 healthy controls were enrolled
throughout the calendar year, and air temperature was recorded
for days of participation. Cognitive tests of memory, processing
and learning were administered, and those with MS also had MRIs
to measure brain atrophy.
- Consistent with other MS symptoms, those with MS did worse on
cognitive tests as temperatures got hotter, even when controlling
for MRI findings of brain atrophy.
- They note that patient awareness of heat-related cognitive problems may guide life decisions, and that investigators planning clinical trials involving cognitive testing should account for the impact of warm weather. (Abstract P01.247)
Quality of life: What determines whether a person with MS has quality of life (QOL)? To help answer this question, Bassem Yamout, MD (American University of Beirut Medical Center, Beirut, Lebanon) and colleagues studied 201 people with MS using questionnaires and measures of symptoms, mental health and physical disability.
- Overall in this sample of people, QOL was influenced less by
physical factors and more by social factors, the 5 main factors
being depression, social support, religiosity, amount of
education and living area (rural/urban).
- They found the highest levels of QOL among people who were
religious, had higher education levels, and lived in urban
areas.
- They suggest that putting emphasis on physical disability alone may not improve QOL in people with MS. (Abstract P06.074)
In a separate study, Charles D. Kassardjian, MD (St. Michael’s
Hospital, Toronto) and colleagues found that higher levels of
fatigue, pain, bladder dysfunction and mental health problems
main factors associated with poor QOL in all types of MS, with
those with lower levels of disability impacted more than those
with more disability. They conclude that targeting these symptoms
early on may help maximize QOL. (Abstract P07.156)
Research Toward Restoring Function
— CCSVI and MS
Five studies, including three posters and two platform
presentations, related to studies of CCSVI (chronic cerebrospinal
venous insufficiency) and MS. Read more about CCSVI (MS Society of Canada CCSVI information and www.ccsvi.org)
Mei Lu, MD (Cleveland Clinic Cerebrovascular Center), a member of one of seven teams being supported to investigate CCSVI by the National MS Society (USA) and the MS Society of Canada, was lead author of a poster on factors, both physiological and technical, that can complicate screening for vein blockages using Doppler sonography (ultrasound) technology:
- They found that findings were often dependent on which
operator conducted the ultrasound evaluation.
- The team reported that heartbeat irregularities, stages of
breathing, head position and pressure applied by the operator
could alter results.
- The team also reported that the state of hydration of the
subject (whether they drank adequate amounts of fluids) could
also impact results of several of the criteria used to determine
CCSVI.
- They concluded that these complications may help explain the mixed results reported thus far related to CCSVI and MS, and that having consensus guidelines would help improve the standardization of ultrasound assessments related to CCSVI. (Abstract P01.263)
A platform presentation by the team of Florian Connolly, MD (Humboldt University, Berlin) described a study that measured venous blood flow and narrowing with Doppler sonography in 96 people with MS (75 relapsing-remitting, 21 secondary-progressive) and 20 healthy controls.
- As in a previous study published in 2010, in this larger
sample of people they were unable to detect individuals who met
more than one criterion for CCSVI.
- Except for one person with MS, blood flow direction was
normal in internal jugular vein and vertebral veins.
- As in the previous study, the team found that blood volume flow tended to be higher in the upright position in people with MS compared to the healthy controls. (Abstract S01.001)
A poster from Yuval Karmon, MD, Robert Zivadinov, MD, and colleagues (University of Buffalo) focused on details from Phase I of what is planned as a controlled clinical trial of angioplasty to treat CCSVI (PREMiSe trial). This phase was an open-label evaluation comparing the use of three imaging methods (Doppler sonography, intravascular ultrasound, and catheter venography) to detect valve abnormalities of the internal jugular vein in 10 people with relapsing MS who fulfilled criteria for CCSVI.
- They found that Doppler sonography was a sensitive tool for
detecting internal jugular valve abnormalities, and that its
findings were comparable to invasive intravascular
ultrasound.
- They found valve dysmobility frequently in this sample of
patients diagnosed with CCSVI.
- According to the investigators, the next phase will include more people and will be a blinded and controlled study of angioplasty. Results of that trial will be released after they have completed the study. (Abstract P04.187)
A platform presentation from Katayoun Alikhanim MD (University of Calgary) and colleagues from across Canada focused on a study of the frequency of neck vein abnormalities in 67 people who visited an MS clinic (34 MS, 20 not MS, 7 possible MS, 6 CIS) using contrast-enhanced MR venography.
- The radiologist was blinded as to the condition of each
patient.
- Abnormalities were found in 7 out of 34 with MS, 4 out of 20
not MS, 0 out of 7 possible MS and 1 out of 6 CIS.
- Those with MS with vein abnormalities were more likely to be older (average age about 52 years) and to have more disability (average EDSS 6.17) compared to those with normal veins (46 years, 3.57 EDSS). (Abstract S01.006)
A poster from Kresimir Dolic, MD, and colleagues (University of Buffalo) described a study to compare vein findings using Doppler sonography and MR venography and determine whether they were complementary. The study included 150 people with MS (104 relapsing-remitting, 38 secondary-progressive, 8 primary-progressive) and 63 healthy controls matched for age and sex.
- They found that Doppler sonography was more sensitive for
detecting internal jugular vein flow abnormalities, while MR
venography was more sensitive for detecting collateral veins.
- 98 (67.12%) of people with MS and 18 (28.57%) of healthy
controls met criteria for CCSVI.
- People with MS had evidence of collateral veins more often than healthy controls. (Abstract P05.071)
Research Toward Ending MS Forever
MS genes: Dr. Stephen L. Hauser (University of California, San Francisco) gave a plenary session talk about immense strides and emerging opportunities to better understand and treat MS. He is a founding member of the International Consortium on MS Genetics, which recently completed a genome-wide scan of 10,000 people with MS.
- He noted that, of 57 gene variants identified as being risk
factors in MS through the genome-wide screening projects, none
appear to relate to nerve degeneration, and most relate to immune
system activity.
- Importantly, no gene differences have been found between
people with primary-progressive MS versus people with
relapsing-remitting MS, which could be seen as evidence against
their being separate diseases.
- A large-scale genome-wide screening study to confirm and expand these findings in 10,000 more people with MS is getting underway with support from the National MS Society. Researchers have already begun the spade work of figuring out how specific genes may contribute to disease for clues to ways to block activity.
Gene impacts on severity: Ellen Mowry, MD (University of California, San Francisco), a former Sylvia Lawry Physician Fellow of the National MS Society, and colleagues at five MS centers studied whether genes linked to MS susceptibility may also be linked to disease severity or the ability to recover from early MS attacks. They determined the severity and recovery of the first two attacks of 353 people, and scanned their genes for the presence of specific MS-linked genes.
- One gene (MPHOSPH9 polymorphism) was linked to
greater attack severity, and another (CD58) was linked
to reduced attack severity.
- Another gene (CD6 polymorphism) was linked to
greater first attack severity and greater risk of incomplete
recovery from first and second attacks.
-
EVI5 and GPC5 were associated with worse
recovery from the first attack, second attack, or both.
- Further research to understand gene influences characterization of such genes may lead to a better understanding of the cause of MS even personalized approach to treatment. (Abstract S10.003)
Early risk factors: A study funded by MS societies in Canada and Italy investigated factors during pregnancy that may influence whether, after birth, the child eventually develops MS. Giulio Disanto, MD (University of Oxford, United Kingdom) and colleagues investigated exposure to sunlight and serum vitamin D levels during gestation in two groups of MS patients born in Scotland and England, compared to the general population.
- Contrary to some previous studies, they found that in the
United Kingdom, the child’s risk of MS is lower when the mother
had increased exposure to sunlight exposure in the second
trimester of pregnancy, and the risk of MS is higher when the
mother had lower vitamin D levels in the third trimester.
- The investigators note that having a better understanding of the timing of vitamin D action on fetal development will be important for future strategies of disease prevention. (Late-Breaking Abstract P05.289 – not online)
Berit Rosche, MD (Charite-University Medicine Berlin, Germany) and colleagues administered a questionnaire to 246 people with MS and 296 controls regarding environmental factors, such as infectious agents, encountered in their childhood.
- They found that among those surveyed, people with at least 2
older siblings, who attended day care, who grew up in cities with
more than 100,000 inhabitants, or who were breastfed tended to be
protected against developing autoimmune diseases including
MS.
- Further research is needed to understand how these factors may influence MS risk. (Abstract S10.005)
Risk factors in pediatric MS: Members of the National MS Society-supported Pediatric MS Network at the University of California, San Francisco and at Stony Brook, New York, investigated early risk factors in 140 children with MS or CIS (clinically isolated syndrome, often a prequel to developing definite MS). Ellen Mowry, MD (UCSF) and colleagues looked at vitamin D levels and antibodies to Epstein-Barr virus, cytomegalovirus, and herpes simplex virus-1 or-2.
- They found that vitamin D levels were weakly linked with
antibody levels to cytomegalovirus but not the other viruses, but
also found some interactions between vitamin D status and disease
state.
- Those with sufficient levels of vitamin D (greater than or
equal to 30 ng/mL), patients had higher antibody levels to
Epstein-Barr virus than controls.
- These and other findings on risks and exposures will be explored in a larger-scale study getting underway by the network with an NIH grant. (Abstract S10.007)
MS research today.
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Pharmaceuticals
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Tysabri is a registered trademark of Biogen Idec and Elan