In a large-scale, genome-wide analysis of more than 110,000 samples, researchers identified 200 genetic loci associated with multiple sclerosis. The study authors said that while the research highlights the role of several different immune cells that contribute to the initiation of this inflammatory disease, the mechanisms that lead this inflammatory disease to target the brain and spinal cord remain unclear.
By comparing the genomes of people with and without MS, the researchers identified 200 variants that were significantly more common among those with the disease. Most of these variants implicate genes that are associated with immune cells and immune system function, including a few potentially specific to brain-related functions.
Interestingly, many of the genes identified were known to also be involved in other autoimmune diseases, such as rheumatoid arthritis, Type I diabetes, and ulcerative colitis. This raises intriguing questions about why these diseases target different organs and have different clinical manifestations.
The findings were presented at the American Society of Human Genetics (ASHG) 2016 annual meeting in Vancouver, B.C.

Results from clinical trials, including new approaches to treating progressive MS, lifestyle and wellness research and myelin repair strategies were among more than 2,000 presentations made at the European Committee for Treatment and Research in MS (ECTRIMS) meeting held in London, England in September.
The world’s largest gathering of MS researchers convened more than 9,000 scientists and clinicians and industry representatives from across the globe, including many National MS Society-funded researchers, meeting and presenting on cutting-edge MS research progress. In addition, the European Rehabilitation in MS network met jointly with ECTRIMS this year.

• Read blogs and announcements from the meeting
• Explore scientific summaries (abstracts) on the ECTRIMS Website 

During the conference, the International Progressive MS Alliance announced new investments of over $14 million US dollars to support three Collaborative Network Awards. These international teams were selected to accelerate the pace of research in key areas to speed new therapies for progressive MS.

Below are highlights of presentations focused on stopping MS, restoring function, and ending MS forever. In most cases, studies presented are considered preliminary. Many will be analyzed more thoroughly, and likely published in peer-reviewed journals.

STOPPING MS

Many presentations showed continued benefits of available therapies and longer-term safety information, as well as more evidence that early and ongoing treatment with a disease-modifying therapy has long-term benefits for controlling disease activity, delaying accumulation of disability, and protecting quality of life.

Siponimod in secondary progressive MS: More details were presented from a 60-month, phase 3 clinical trial of the experimental oral therapy siponimod (Novartis Pharmaceuticals AG) involving 1,651 people with secondary progressive MS. The trial met its primary endpoint, with those on active treatment showing a modest 21% reduced risk of disability progression compared to those on placebo. Secondary endpoints suggested that those on active therapy had 23.4% lower average change in brain volume and reduced MRI-detected lesion volume. The medication showed a similar safety profile to others that work by preventing white blood cells from entering the central nervous system. (Abstract #250)

More details from trial of lipoic acid in secondary progressive MS: Dr. Rebecca Spain and colleagues (Oregon Health & Science University) presented results from a small, controlled clinical trial on the oral anti-oxidant supplement called lipoic acid in people with secondary progressive MS. The lipoic acid group had 66% less brain tissue shrinkage, or atrophy, than the group taking inactive placebo pills. This pilot study suggests potential benefits if they hold up in a larger trial. (Abstract #222)

New results on gut bacteria: Efforts are advancing to pinpoint bacteria in the gut that may drive inflammatory immune system activity in MS and others that can suppress it, which may open the door to novel probiotic or other therapeutic approaches to treating MS.

• Drs. Yan Wang, Lloyd Kasper and colleagues (Dartmouth Medical School and Eastern Washington University) reported that treating mice with the gut-related molecule called polysaccharide A (PSA) expanded a type of immune cells called “Regulatory B cells” (Bregs) which promote an immune response that prevents mice from getting MS-like disease. (Abstract #181) Members of this team also reported that PSA had positive effects in mice with progressive MS-like disease. (Abstract #P465) 
• Dr. Sergio Baranzini (University of California, San Francisco) and other collaborators in the National MS Society-supported MS Microbiome Consortium are analyzing gut bacteria to unearth clues about MS susceptibility and progression. They analyzed bacteria in stool samples from 64 people with MS who had received treatment for MS, and 68 people without MS. Certain bacteria were increased in people with MS, and those bacteria increased immune cells (T helper 1 cells) that are major players in MS immune attacks. Another type of bacteria that could suppress the immune attack was reduced. (Abstract #179) 

Disappointing results for nerve-protection approaches: A small two-year clinical trial of fluoxetine (same compound as the anti-depressant Prozac) did not meet its goal of improving walking speed in people with progressive MS. The multi-center team from Belgium is still analyzing other results, such as changes in MRI and cognition. (Abstract #253) Likewise, a trial conducted at the University of Oxford tested the ability of amiloride to protect against nerve damage in people with acute optic neuritis (often an early sign of MS) failed to show any neuroprotective benefit. (Abstract #102) Additional trials of neuroprotective approaches to MS are ongoing.

Vitamin D deficiency and smoking linked to progression: Dr. Maria Isabel Zuluaga and team (Vall d’Hebron University, Barcelona) explored the independent impacts of smoking and vitamin D deficiency in a large group of people followed over time. They found that those with severe vitamin D deficiency (defined as blood levels at less than 8 ng/ml) showed an increased risk for MS disability, and active smokers also had an increased risk for disability progression. (Abstract #252) Graduate student Ms. Eva Rosa Petersen (Danish MS Center, Copenhagen) also found that smoking intensity was linked with higher frequency of relapses among people taking interferon beta. Smoking one pack of cigarettes per day increased relapse rates by 25%. (Abstract #178)

Vitamin D added to Rebif: A large international trial did not show a statistical difference between treatment groups after adding vitamin D (14,000 IU [350 µg] vitamin D3 daily) or placebo to Rebif therapy in relapsing MS, in terms of the percent of participants who were free from disease activity after 48 weeks. Dr. Raymond Hupperts (Orbis Medical Centre, Sittard-Geleen, The Netherlands), who presented results, noted that both groups were stable, which likely contributed to the inconclusive results. (Abstract #166)

Biomarkers under development: Teams are making headway toward having a simple test that can predict a person’s disease course, progression and response to therapy. Dr. Bibiana Bielekova (National Institute of Neurological Diseases and Stroke) and team examined proteins in the spinal fluid of people with neurological diseases, including all types of MS, and identified a “signature” of markers that distinguished MS from other diseases, and also differentiated relapsing MS from progressive MS. (Abstract #219). Other investigators also reported progress in this area, including advances using “neurofilament light chain” as a biomarker. (Such as Abstracts #183, #249) These early results need further development but indicate that  sensitive biomarkers for predicting disease course and response to therapy may become useful tools for the clinical management of MS.

RESTORING FUNCTION – WELLNESS, LIFESTYLE, SYMPTOMS

Home-based rehabilitation can work: With funding from the National MS Society, Dr. Gabriel Pardo (Oklahoma Medical Research Foundation) and colleagues compared the benefits of three approaches to rehabilitation for gait and balance in a small study: unsupervised home-based exercise 5 times/week; home-based exercise supervised remotely by a physical therapist 2-3 times per week via audio and visual conferencing; and home-based exercise plus in-person physical therapy 2-3 times/week. They found that all participants improved, and that the telerehabilitation program worked as well as the onsite program to improve gait and balance. Further research in larger trials could make telerehabilitation a cost-effective and more accessible alternative for people with MS. (Abstract #120)

Tackling fatigue: Dr. Vincent de Groot (VU University Medical Center, Amsterdam) reported results from three clinical trials testing different strategies over 16 weeks to lessen fatigue, in 90 people with MS: aerobic training, cognitive behavioral therapy, and energy conservation management. Only cognitive behavioral therapy effectively reduced severe fatigue in this short-term study. This is a commonly available type of psychotherapy. (Abstract #142) Read more about managing fatigue

Pain more common than previously reported: Dr. Carolyn Young (University of Liverpool) and colleagues found that nearly 66% of over 700 people with MS reported nerve pain. Higher levels were found in those who had MS for a longer time, had more severe disability, or were not working. (Abstract #P337) Read more about addressing pain in MS

New trial confirms Ampyra (fampridine) benefits: Dr. Jeremy Hobart (Plymouth Hospitals NHS Trust) presented results from a large clinical trial of fampridine, a twice-a-day oral therapy that was previously approved for its ability to improve walking.. This trial wanted to show evidence that its benefits include meaningful functional improvements for people. The results over 6 months showed that 43% of those on active therapy had significantly better self-reported walking ability, mobility, and balance than those on placebo, with no new safety issues reported. (Abstract #254)

Cognitive rehabilitation enhances brain connections: Several studies showed that rehabilitation to improve cognition goes hand-in-hand with changes in brain connectivity (how areas of the brain interact). While many of these treatments are still experimental, some are available from rehabilitation specialists such as speech pathologists or neuropsychologists. Discuss options with your MS doctor:

• Dr. Brian Sandroff (Kessler Foundation, West Orange, NJ) and colleagues showed that treadmill training improved information processing speed and brain connectivity in a small pilot study funded by the Society. (Abstract #P796) 
• Dr. Pietro Iaffaldano (University of Bari, Italy) and colleagues showed that a home-based computerized training program that targeted specific cognitive issues improved overall cognitive function significantly more than a non-specific program. Also, those who had less function in certain brain areas showed greater improvement after cognitive training. (Abstract #145) 
• Oiane Rilo (University of Deusto, Bilbao, Spain) and colleagues showed that a three-month, group-based cognitive rehabilitation program improved working memory, information processing speed, verbal memory and executive function (which is important in problem solving and planning), and altered brain connectivity. (Abstract #144)  

Emerging treatment for muscle spasticity: Dr. Daniel Kantor (Kantor Neurology, Ponte Vedra Beach, FL) and colleagues report that in a trial of 354 people with relapsing-remitting or secondary progressive MS, Arbaclofen Extended Release Tablets (Osmotica Pharmaceuticals) significantly reduced spasticity compared to baclofen. The extended-release tablets caused significantly less sleepiness, drowsiness and dizziness than baclofen. (Abstract #128) The company reports that it has filed for FDA approval of Arbaclofen.

RESTORING FUNCTION – NERVOUS SYSTEM REPAIR

More Anti-LINGO Results: In June 2016 Biogen announced that its phase 2 clinical trial of anti-LINGO (proposed name opicinumab), an approach to repair myelin, did not meet its primary endpoint of improvement in physical function, cognitive function, or disability. The trial involved 418 people with relapsing MS who were taking interferon beta-1a (Avonex) plus one of several doses of intravenous opicinumab or placebo for 72 weeks. Dr. Diego Cadavid from the company described ongoing evaluations from the extensive testing and monitoring during the trial, which are helping to pinpoint the patient population, dosage and outcome measures that would inform the design of any future trials of anti-LINGO.  (Abstract #192)

Myelin repair in pediatric and adult MS: Dr. Sabine Pfeifenbring (University of Göttingen, Germany) and an international team analyzed brain biopsies from children who had been diagnosed with MS and compared the extent of damage and natural myelin repair against those of adults with MS. They found that children showed less damage to myelin-making cells and more evidence of myelin repair than adults. However, some myelin repair was found to occur at virtually all ages in MS. (Abstract #194)

Exercise enhances myelin repair in mice: To investigate some reasons why exercise promotes benefits in people with MS, Drs. S. Jensen and Wee Yong (University of Calgary) did a study where mice with myelin damage in their spinal cords used running wheels soon after the injury. They reported finding more evidence of generation of myelin-making cells and myelin repair in the active mice than those that did not use the running wheels after injury. (Abstract: #P1210)

Emerging approaches to protection and repair:  Dr. Martin Sanders (Io therapeutics) presented results from mice suggesting that the compound IRX4204 promotes repair of damaged myelin in mice. He noted that previous studies suggested that IRX4204 also showed signs of reducing immune attacks and protecting against nerve loss. This work was supported in part by a National MS Society’s Fast Forward investment. (Abstract #193)

Drs. Sarah Starossom, Samia Khoury and team (Brigham and Women’s Hospital, Boston) reported on studies of Chi3l3, a naturally occurring molecule in the brain that can stimulate the transformation of resident stem cells into myelin-making cells. The team noted that it plays an important role in recovery from the MS-like disease in mice, and may have potential for development as a new treatment approach in MS. (Abstract #195)
 

• Breathing easier -- “Respiratory dysfunction begins very early in the disease process,” noted physical therapist Donna Fry, PhD (University of Michigan-Flint). But, she said, respiratory exercises can improve strength in respiratory muscles even late in the disease. Dr. Fry’s team has shown these improvements using “threshold inspiratory muscle trainers,” inexpensive devices that can help breathing muscles to get stronger. “Most clinicians are not aware of the potential early involvement of the respiratory system in people with MS and of accessible, inexpensive equipment that can enhance muscle strength,” she added. 
• Muscle spasticity -- “Quite a few people with MS are experiencing significant problems from spasticity,” said neurologist Francois Bethoux, MD (Cleveland Clinic). Spasticity may be as mild as the feeling of tightness of muscles or may be so severe as to produce painful, uncontrollable spasms in the extremities, usually the legs. Dr. Bethoux believes spasticity can often be managed without specialized care. “Optimal care would involve an early diagnosis, setting realistic goals, and re-evaluation,” he said. Plus, stretching is vital, even if mobility is impaired

• Read a news story about this article in Scientific American: Unproven Stem Cell Clinics Proliferate in the U.S.

• Read the original journal paper in Cell Stem Cell: Selling Stem Cells in the USA: Assessing the Direct-to-Consumer Industry

• Read more about stem cells and MS, and Stem Cell Clinics

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• Researchers in Canada have published results of a long-term trial of an individuals’ own (autologous) hematopoietic (blood cell-producing) stem cell transplantation. The study involved 24 people with aggressive relapsing-remitting MS whose disease was not controlled with available therapies.
• Three years after the procedure, 70% remained free of disease activity, with no relapses, no new MRI-detected inflammatory brain lesions, and no signs of progression.
• None of the surviving participants, who were followed for 4 to 13 years after the procedure, experienced clinical relapses or required MS disease-modifying therapies to control their disease, and 40% experienced reductions in disability.
• One of the participants died and another required intensive hospital care for liver complications. All participants developed fevers, which were frequently associated with infections, and other toxicities.
• Additional research is focusing on figuring out who might benefit from this procedure and how to reduce its risks. 

• None experienced clinical relapse, had new active inflammatory MRI brain lesions, or required MS disease-modifying therapies to control their disease.
• The average rate of brain atrophy (shrinkage), a measure that has been linked to MS progression, returned to levels associated with normal aging.
• 40 percent experienced some lasting reversal of disability such as vision loss, muscle weakness and balance problems.
• Some were able to return to work or school. 

• A study of 676 people with MS treated with the MS therapy mitoxantrone in Germany reveals that the rates of acute myeloid leukemia (a type of cancer) and colorectal cancer were significantly increased above what would be expected in the general population there. Rates of other cancers were not increased.
• The authors note that if the findings are confirmed, recommending colonoscopy after treatment may be advisable, since if found early enough, colorectal cancer is curable.
• The team (led by Dr. Mathias Buttmann, University of Würzburg, Germany) has published results in Neurology (published early online, May 11, 2016).

Details
Background: Mitoxantrone is a powerful immune-suppressing therapy. Prior to its approval for use in MS, it was used only to treat certain forms of cancer. It acts in MS by suppressing the activity of immune T cells, B cells, and macrophages that are thought to lead the attack on nerve-insulating myelin. The U.S. Food and Drug Administration approved mitoxantrone for reducing neurologic disability and/or the frequency of relapses in people with secondary progressive MS or worsening relapsing-remitting MS. The total lifetime dose is limited to avoid possible heart damage. Acute myeloid leukemia has been previously reported in people treated with mitoxantrone for MS or cancer.

The Study: Investigators identified 677 people with MS seen at the University of Würzburg MS center between January 1994 and December 2007 who had received mitoxantrone. They were able to follow up with 676 of these patients.

The results show that 37 people developed cancer after taking mitoxantrone, including nine cases of breast cancer, seven cases of colorectal cancer, and four cases of acute myeloid leukemia. The rate of acute myeloid leukemia was 10 times that seen in the general population in Germany. The rate of colorectal cancer was three times that seen in the general population in Germany. The rate of breast and other cancers was not increased over that seen in the general population in Germany. Older age at treatment was associated with increased risk of cancer, but not prior use of other immunosuppressive treatments, or duration of treatment with mitoxantrone.

The team (led by Dr. Mathias Buttmann, University of Würzburg, Germany) has published results in Neurology (published early online, May 11, 2016).

Comment: The authors state that if the findings are confirmed, “posttreatment colonoscopy might improve the risk-benefit ratio of this highly active immunosuppressive drug,” since if found early enough, colorectal cancer is curable. They also note that mitoxantrone is currently the only MS therapy approved for treating secondary progressive MS, and that the overall rate of cancers may still justify the use of mitoxantrone in people who are severely affected with MS and where there are no better treatment options available.

Read more about mitoxantrone
Read more about treating secondary progressive MS
Read more about making treatment decisions in MS

• In a small, phase II clinical trial, the oral antihistamine clemastine modestly improved the transmission of electrical signals in the optic nerve in participants with MS who had optic nerve damage.
• The improved transmission indicates that nerve-insulating myelin was repaired along the nerve pathways.
• Clemastine is an over-the-counter allergy medication. Doses in this trial exceeded the maximum recommended for over-the-counter use. Clemastine affects a range of targets in the body, and involves the risk for side effects, particularly at increased dosages.
• This team is planning an additional trial to further determine the safety and effectiveness of clemastine, as well as studies to identify compounds that may enhance myelin repair and cause fewer side effects.
• Clemastine was identified as having possible myelin-repairing properties through innovative preclinical research conducted by National MS Society-funded Jonah Chan, PhD, who went on to become first recipient of the Barancik Prize for Innovation in MS Research for this pioneering work.
• Preliminary results will be presented by the clinical trial’s lead investigator Ari Green, MD (University of California, San Francisco), at the annual meeting of the American Academy of Neurology being held in Vancouver, Canada, April 15 to 21.

• Read more on Endocrinology Advisor
• Read the free-access journal article

• Read more on CBS News
• Read the free-access journal article 

Read more about risk factors for MS

• Researchers have found evidence that microscopic connectors in the brain called “synapses” are directly damaged during the course of MS-like disease in mice, in an area of the brain linked to cognitive function.
• The damage appeared to be unrelated to myelin damage, and was linked  to a specific molecule called platelet-activating factor receptor.
• Further research will determine whether treatment that protects synapses in the hippocampus may preserve cognitive function in people with MS. The team is pursuing therapeutic candidates based on these findings.
• This research was funded in part by a National MS Society-American Brain Foundation (American Academy of Neurology) Clinician Scientist Development Award to Dr. Matthew Bellizzi.
• The team (Drs. Bellizzi, Harris Gelbard, and colleagues, from the University of Rochester Medical Center, in New York) has published results in The Journal of Neuroscience. (2016 Jan 27;36(4):1336-46.) 

A new study finds that the more lesions spotted on an MRI, the worse the taste function of the patient with multiple sclerosis. They also found that women did better men on taste measures.
The researchers, led by Richard Doty, director of the University of Pennsylvania's Smell and Taste Center, administered a standard taste test (sweet, sour, bitter, and salty) to 73 MS patients and 73 controls subjects, along with MRI of 52 brain regions known to be affected by MS in both groups. They found that the disease significantly influenced the ability to identify tastes, especially salty and sweet. Fifteen to 32 percent of MS patients – which is nearly twice as high as previous studies found – had taste scores below the 5th percentile of controls. What's more, taste scores were inversely correlated with lesion amounts and volumes in the large sectors of the frontal and temporal lobes, the higher regions of the brain, identified on the MRI.
Regardless of subject group, women outperformed men on taste measures, which mirrors what previous taste studies have found. It is likely because women have more taste papillae and taste buds than men, the researchers said.
"It appears that a sizable number of these patients exhibit taste deficits, more so than originally thought. This suggests that altered taste function, though less noticeable than changes in vision, is a relatively common feature in MS. Future studies investigating the relationship between taste and MS may help better diagnose and understand the disease, as well as better manage symptoms," Doty said.
The findings were reported in the Journal of Neurology.

• This treatment, called autologous haematopoietic stem cell transplant (HSCT), attempts to “reboot” the immune system, which is believed to launch attacks on the brain and spinal cord in people with MS.
• HSCT is under investigation in clinical trials in Canada, the United States, Europe and elsewhere. Clinical trials are needed to fully understand the benefits and risks of HSCT in MS, and who might benefit most from this approach, since it does not seem to be effective in all types of MS.
• In HSCT, stem cells from a person’s own bone marrow or blood are stored, and the rest of the individual’s immune cells are depleted usually by chemotherapy. Then the stored stem cells are reintroduced and over time they produce new cells that repopulate the body with immune cells.
• There is exciting progress being made through innovative research related to the potential of many types of stem cells both for slowing MS disease activity and for repairing damage to the nervous system.
• At present, there are no approved stem cell therapies for MS. Stem cell therapy is in the experimental stage, and it’s important for people to have the best available information to understand this exciting area of research and make decisions related to this complex issue.
• In November 2015, the International Conference on Cell-Based Therapy for Multiple Sclerosis was convened by the National MS Society and the European Committee for Treatment and Research in Multiple Sclerosis, bringing leading researchers and clinicians together to confer on clinical trials needed to provide answers about which types of cells, which route of delivery, and which types and stages of disease, would be the most promising approach for treating MS. A summary and consensus on next steps will be published by the conference organizers, with recommendations to help speed the development of new cell-based treatment solutions.
• With the urgent need for more effective treatments for MS, particularly for those with more progressive forms of the disease, we believe that the potential of all types of cell therapies must be explored. The Society is currently supporting 12 research projects exploring various types of stem cells, including cells derived from bone marrow, fat and skin, and has supported 68 stem cell studies over the past 10 years.

• High-dose vitamin D supplementation increased vitamin D levels in the blood, was safe and tolerable, and reduced the proportion of immune cells that are thought to drive disease, in a small study of 40 people with relapsing-remitting MS.
• The trial was too small to detect differences in disease activity, but a larger Society sponsored trial of vitamin D supplementation is currently recruiting participants.
• The team (Elias S. Sotirchos, MD, Pavan Bhargava, MD, Peter A. Calabresi, MD, and colleagues, Johns Hopkins University School of Medicine, Baltimore) has published results in Neurology. Dr. Bhargava was funded by a Sylvia Lawry Physician Fellowship from the National MS Society.