Background: An important question in the treatment of MS is whether to start treatment for relapsing MS with a powerful therapy at the outset (called induction therapy), or to take a more traditional approach of starting with less powerful therapy and ramping up to a more powerful approach if relapses or other signs of disease activity continue (called escalation therapy).
Researchers from the Karolinska Institute (Stockholm, Sweden) set out to compare outcomes of people receiving induction therapy with a drug called rituximab, which is not specifically approved for the treatment of MS, compared to those receiving escalation therapy with one of the approved disease-modifying therapies. The investigators tracked whether the participants remained on therapy or discontinued it, which is an indirect measure of how well the treatment performed.
Rituximab: Rituximab is a monoclonal antibody (a protein made in the laboratory) that targets a specific protein (“CD20”) on the surface of immune B cells. B cells are known to be involved in the inflammation and damage to the brain and spinal cord in MS. Rituximab is FDA-approved for the treatment of several conditions including some cancers and rheumatoid arthritis, and it has been used “off-label” to treat several immune-mediated conditions, including MS. Rituximab is given by intravenous (into a vein) infusions every six months. A similar B-cell therapy approach that is manufactured differently, called ocrelizumab, was approved by the FDA in 2017 for the treatment of relapsing MS and primary progressive MS.
The Study: The researchers used data from the Swedish MS Registry and medical records of 494 people from two counties in Sweden who had been recently diagnosed with relapsing-remitting MS. About 24% had been started on rituximab; other initial therapies included injectable therapies (such as interferons and glatiramer acetate = 43.5%), oral therapies (dimethyl fumarate =17.4% and fingolimod =3.4%), and natalizumab given by IV infusion (24.3%). The key outcome measured was the proportion of people who discontinued specific therapies.
Results: A higher proportion of people given rituximab remained on it, compared to those who received other initial therapies. The reasons for therapy discontinuation differed by type of treatment, but the most common reasons were side effects, disease activity or pregnancy. The authors also reported a trend for increased relapses and brain lesions in participants using treatments other than rituximab.
This study was funded by the Swedish Medical Research Council and others. The report, by Drs. Fredrik Piehl, Mathias Grandqvist and others (Karolinska Institute), was published online January 8, 2018 in JAMA Neurology.
Comment: Understanding which individuals do best on what therapies is important for enabling people with MS to make the best treatment choices. Unlike well-designed clinical trials that have protocols for patient selection and assessment of outcomes, and that randomly assign participants to treatment groups, this observational study was not able to account for factors that determined why any particular therapy was prescribed for any individual, or for all factors that may have triggered an individual or doctor to discontinue a particular therapy. Results of controlled trials – several of which are now underway – are needed to understand the comparative effectiveness of MS therapies.
Background: Several recent studies have suggested that dietary salt (sodium chloride) could potentially influence MS disease activity and progression. For example, one study of 70 people with relapsing-remitting MS, who were followed for two years, found that higher levels of salt measured in urine samples were associated with a higher rate of relapses and larger brain MRI lesions. In addition, mice fed a high-salt diet developed a more aggressive course of EAE, a laboratory model of MS. But two studies in pediatric MS did not find a relationship between self-reported salt intake and MS risk or relapse rates. Resolving this question is important because it offers the possibility that reducing salt intake might improve a person’s overall health and their course of MS.
This Study: In work partly funded by the National MS Society, researchers set out to determine if a high-salt diet is associated with faster conversion from a first neurologic episode (known as clinically isolated syndrome or CIS) to a diagnosis of definite multiple sclerosis, or with MS disease activity. Kathryn C. Fitzgerald, ScD (Johns Hopkins School of Medicine), Alberto Ascherio, MD, DrPH (Harvard T. H. Chan School of Public Health) and colleagues took advantage of data accumulated from a previous clinical trial involving 465 participants who participated in a trial called BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) over 5 years. The trial compared benefits of giving interferon to individuals with CIS early versus later. Each person provided an average of 14 urine samples throughout the five-year follow-up. The researchers estimated average long-term sodium intake from the multiple urine samples, adjusting for age, sex, height, weight, where participants lived, and many other variables.
Results: Researchers found that neither average nor high urine sodium levels were associated with conversion to definite MS. They also weren’t associated with new MRI lesions at any point in the five years, relapse rates, or progression of disability. These results suggest that high sodium intake does not play a major role in influencing MS disease course or activity in people treated with interferon, at least in the early stages of the disease.
While the study has several strengths, including its length, large sample size, and systematic collection of data, it has limitations: BENEFIT participants were treated nearly uniformly with interferon, and the results may not apply to people on other therapies or no therapy. In addition, participants in the BENEFIT trial were primarily Caucasian and resided in Europe and Canada, and it isn’t known if similar results would apply to other populations and ethnicities. The results also don’t answer the question of whether salt intake affects the risk of developing MS in the first place.
The study, “Sodium Intake and Multiple Sclerosis Activity and Progression in BENEFIT,” was published in the July 2017 issue of the Annals of Neurology (2017;82:20-29).
Comment: Although this study does not support a link between high-salt intake and MS disease activity, research suggests that most Americans eat more salt than is recommended by federal guidelines. Even in the absence of direct evidence that MS immune activity is influenced by salt, reducing dietary salt is considered by most to be beneficial to the heart and circulatory system.
Read More: Diet, along with exercise, cognitive health, and other healthy behaviors can make a big difference to how you feel as you deal with MS. Learn more about living well with MS
Primary progressive MS is characterized by steadily worsening neurologic function from the onset of the disease. There are still many gaps in the knowledge we have about what differentiates relapsing-remitting from primary progressive MS, and the underlying mechanisms of primary progressive MS. The MS Genetics Group at the University of California San Francisco is recruiting people with primary progressive MS for a research study involving a one-time blood sample donation with the goal of identifying genetic factors driving the course of the disease. The team also is looking for people without MS who are not related to serve as controls. The team hopes to identify the major genetic factors that play a role in disease presentation and progression. Please note: you do not have to be located in or travel to California to participate. Everything for the study can be done remotely and is free of charge to participants.
Rationale: Specific subtle variations in the human genome are known to play a role in determining who is susceptible to developing multiple sclerosis, and may also influence the course of the disease. People living with MS can make a difference in studies searching for these genes by donating their DNA with a blood sample. Identifying the exact location and role of MS genes could help determine who is at risk for developing the disease and can provide clues to its cause, prevention, and lead to better treatments.
Details: Once an individual has completed the initial online intake form, they will receive a call from the study coordinator to discuss details and answer any questions. The consent form and health information privacy form can be signed electronically. Participants will then be emailed a link to two additional short online surveys and sent a blood-collection kit. The kit includes everything necessary for the blood draw, which can be taken to your local Quest Diagnostics Lab and returned in a prepaid envelope to the lab at UCSF. There is no cost to participants.
Contact: To participate or request additional information, please complete a brief intake survey.
OR you may contact UCSF directly:
Clinical Research Coordinator
UCSF Multiple Sclerosis Genetic Susceptibility Project
675 Nelson Rising Lane, Suite 235A, Box 3206
San Francisco, CA 94158
Toll Free Phone: 1-866-MS-Genes (1-866-674-3637) or Office Phone: (415) 502-7202
Background: While scientists still don’t know what causes multiple sclerosis, they do know that immune-system attacks are involved, resulting in damage to the myelin that insulates nerve fibers and to nerve cells and fibers themselves. Immune T cells have typically been named as culprits, but it has become clear that immune B cells, another type of white blood cell, are also involved in MS. Research and studies on B cells, including early studies supported by the National MS Society, eventually led to successful clinical trials and approval of Ocrevus™ (ocrelizumab – Genentech, a member of the Roche Group) to treat people with primary progressive and relapsing-remitting MS. Ocrevus depletes certain B cells.
The Study: The current study builds on the researchers’ earlier findings that B cells from the blood of people with relapsing-remitting MS – but not blood from healthy individuals – are toxic to certain cells that build myelin. In this study, the team isolated B cells in the laboratory from the blood of 13 women and men with relapsing-remitting MS who were not receiving disease-modifying treatment or recent steroids, and 13 controls without MS.
The researchers found that products released by B cells from the people with MS were toxic to both rat and human nerve cells grown in lab dishes, while cells from the controls did not incur the same damage. The nerve cells died from apoptosis – a type of self-destruct program – and not, as might be expected, from cell disintegration, or from immunoglobulins (antibodies) that have been identified as culprits in the MS attack.
Drs Robert P Lisak, Joyce Benjamins (Wayne State University), Amit Bar-Or (McGill University and currently at University of Pennsylvania) and colleagues published their findings in the Journal of Neuroimmunology (2017 Aug 15;309:88-99, published online May 17). This study was supported by the National MS Society (USA), the Research Foundation of the MS Society of Canada, and others.
Next Steps: This study offers new insight into how B cells may contribute to nervous system damage in MS. The team is now conducting further studies to identify the toxic factor or factors secreted by the B cells, and when and how they may act in people with MS. They are using “proteomics” for this work, advanced technologies the can identify and quantify numerous molecules simultaneously, along with other approaches. They also plan to answer questions such as whether the toxic B cells are unique to MS or are found in other immune mediated disease, which subsets of B cells produce the toxic effects and whether they are also evident in people with progressive MS.
Researchers in the U.K. have evaluated additional findings about the immune-system impacts of Lemtrada® (alemtuzimab, Sanofi Genzyme), a disease-modifying therapy for treating people with relapsing MS.
The team used data from phase 3 clinical trials submitted to the European Medicines Agency during the drug’s successful approval process. Some of this data was previously reported at medical meetings and in Lemtrada’s prescribing information.
Among their findings, they report that Lemtrada caused long-term reduction of specific immune cells (memory B and T cells, including regulatory T cells). They also found that the body rapidly repopulated an overabundance of immature B cells.
They propose that the blockade of memory B and T cells drives the beneficial effects of Lemtrada.
They also speculate that the known potential side effect for autoimmune thyroid disease and other autoimmune disorders may be triggered by the overabundance of immature B cells that occurs when there are few regulatory T cells to keep them in check.
Studies like this one, which reveal more information about a therapy’s mode of action, are important and may also lead to insights about how to reduce side effects.
Drs. Klaus Schmierer, David Baker and others at the Queen Mary University of London report their findings in JAMA Neurology, published online June 12, 2017.
Lemtrada is a registered trademark of Sanofi Genzyme
“Dawson’s fingers” is the name for the lesions around the ventricle-based brain veins of patients with multiple sclerosis. The condition is thought to be the result of inflammation or mechanical damage by blood pressure around long axis of medular veins.
Dawson’s fingers spread along, and from, large periventricular collecting veins, and are attributed to perivenular inflammation.
Lesions far away from these veins are known as Steiner’s splashes.
Sometimes experimental autoimmune encephalomyelitis has been triggered in humans by accident or medical mistake. The damage in these cases fulfils all the pathological diagnostic criteria of MS and can therefore be classified as MS in its own right. The lesions were classified as pattern II in the Lucchinetti system. This case of human EAE also showed Dawson fingers.
This month in Lancet Neurology, a Canadian research team reports there is a pre-clinical phase in MS. The study used health administration records from four Canadian provinces (British Columbia, Saskatchewan, Manitoba, and Nova Scotia). Due to the nature of the Canadian health-care system, these provinces have computerized health-care records on >99% of residents, including hospital discharges, physician billing, prescription on records, and dates of all medical visits – all records can be linked by a unique health-care number assigned to individuals. Using these records, medical histories for 14,428 MS cases and 72,059 controls were included for this study. They compared health-care utilization in the same five-year period prior MS diagnosis between cases and temporally matched controls.
Interestingly, five years before a MS diagnosis, the number of hospital admissions for people who eventually developed MS was 26% higher than controls, and this increased to 78% higher a year before MS diagnosis. A similar pattern was observed for physician billing (5 years before diagnosis: 24% higher in people with MS than controls; 1 year before diagnosis: 88% higher in people with MS than controls). There was also a substantial increase in the number of prescribed drug classes in people with MS compared to controls (5 years before diagnosis: 23% higher; 1 year before diagnosis: 49% higher). These results clearly demonstrate a pre-clinical stage for MS where subtle symptoms exist before clinically definitive symptoms (also known as a prodromal stage). With further research, we can explore these subtle symptoms and hopefully diagnose MS earlier and initiate therapeutics earlier, slowing the rate of progression of MS.
From: When do MS symptoms start? By Farren Briggs PhD, ScM; The Accelerated Care Project for Multiple Sclerosis
Background: Repetitive Transcranial Magnet Stimulation (rTMS) was approved by the FDA as a treatment for major depression. A device that generates electromagnet pulses is placed on the scalp with the idea of stimulating specific brain activity. Studies have shown that people with MS who received rTMS showed significant decreases in depression. This team looked at whether rTMS improved working memory (short-term memory needed for tasks such as mental arithmetic), which can be affected in people with MS.
The Study: Investigators administered rTMS – or a “sham” version of lower intensity – to an area of the brain associated with working memory in17 people with MS and 11 healthy controls. None of the participants showed signs of impaired memory at the outset of the study. A potential adverse event of rTMS is seizures, so participants were excluded if they were taking medicine that put them at risk for seizures, or had MS brain lesions in particular areas. Before and after, participants underwent imaging and extensive neuropsychological testing aimed at investigating memory. They also completed a working memory task while undergoing functional MRI, which measures brain activity during tasks.
At the beginning of the study, there were no differences in working memory between people with MS and controls. After treatment, the results suggested improvements among people with MS in working memory, brain activity, and “connectivity” (how parts of the brain interact with one another). These changes were not seen in controls.
The team (Hanneke Hulst, MD, of VU Medical Center in Amsterdam, and others) has published results in Journal of Neurology, Neurosurgery, and Psychiatry
Next Steps: The authors comment that this small study implies that rTMS may play a future role in cognitive rehabilitation in people with MS. However, the study is limited by the small sample size and the fact that participants did not have obvious cognitive problems. Further studies that address these factors are necessary to confirm the safety and effectiveness of this intervention for people with MS and its long-term impact on day to day activities.
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.
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.
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.
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:
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)