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.
“These results sound like a very promising step toward a potential new therapy for people with progressive forms of MS, for whom there are few treatment options,” said Dr. Bruce Bebo, Executive Vice President, Research, National MS Society.
Background: Ibudilast (MN-166, MediciNova, Inc.) inhibits an enzyme called phosphodiesterase, resulting in suppression of inflammation. While considered a “New Molecular Entity” in the United States and Europe, ibudilast is marketed in Japan and Korea to treat cerebrovascular disorders and asthma. It is being also being investigated in the U.S. for its potential to treat ALS and drug addiction.
The study was principally funded by NeuroNEXT Network, a clinical trials initiative of the National Institutes of Health, with additional support by MediciNova, the company that will supply ibudilast. The National MS Society also provided funding support because of its focus on progressive MS and because the trial’s design may answer important questions about the best ways to measure the benefits of therapies aimed at protecting the nervous system from MS.
The study: The trial, known as “SPRINT-MS,” was led by Principal Investigator Robert Fox, M.D., M.S., FAAN, Staff Neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic. It was conducted at the Cleveland Clinic and 27 other sites across the U.S. The trial involved 255 people with primary or secondary progressive MS. The primary outcome measure was change in brain atrophy (as measured by an MRI analysis technique called brain parenchymal fraction) after 96 weeks. Brain atrophy (shrinkage) has been linked to cognitive and physical disability in MS. Other imaging, safety, clinical and quality of life outcomes were also measured.
The results announced in a press release from MediciNova concluded that ibudilast was well tolerated and significantly slowed the rate of brain atrophy compared to placebo. Further details are schedule to be presented on Saturday, October 28th at the MSParis2017 – 7th Joint ECTRIMS-ACTRIMS Meeting.
What’s Next? These phase 2 results may lead the way to the testing of ibudilast in larger phase 3 trial(s), which would be needed before the company could apply for marketing approval from the FDA, the European Medicines Agency or other regulatory agencies. Ibudilast was designated by the U.S. Food and Drug Administration as a “Fast Track Product” which could speed its future development as a possible treatment of progressive MS.
Background: Researchers believe that several genetic and environmental factors influence whether a person will get MS. These factors may also impact the severity of the disease. Scientists are eager to find risk factors for MS that can be modified to possibly prevent MS and reduce disease activity. Research is increasingly pointing to reduced levels of vitamin D in the blood as a risk factor for developing MS, and studies are underway to determine if vitamin D levels influence MS disease activity.
This Study: This study — the largest such study to date – took advantage of a unique resource: stored blood samples from 800,000 Finnish women who had undergone routine prenatal testing during pregnancy. The study was designed to determine whether and to what extent vitamin D deficiency is associated with future risk of developing MS. The team identified 1,092 of the women who were later diagnosed with MS. The researchers compared their vitamin D levels to those of 2,123 women who were about the same age and lived in the same area but did not develop MS. Of those women whose medical records were available for examination, an average of 9.5 years had lapsed between the time of the first blood sample and the date of an MS diagnosis. For this study, classifications of blood levels of vitamin D (25-hydroxyvitamin D) included “deficient” (less than 30 nmol/L) and “adequate” (greater than or equal to 50 nmol/L).
Results: The team found that overall as vitamin D levels increased, the risk of later developing MS decreased. Women with the greatest deficiency in vitamin D had a twofold increase in the risk of developing MS, and those with the highest vitamin D levels had the lowest risk of a later MS diagnosis. Most of the women in the study were considered to have deficient or insufficient levels of vitamin D. Of the women who developed MS, 58 percent had deficient levels of vitamin D, compared to 52 percent of the women who did not develop the disease.
The researchers conclude that the results directly support vitamin D deficiency as a risk factor for MS and that correcting this among reproductive age women may reduce their future risk of developing MS. In addition, a previous study of this same group of women found that maternal vitamin D deficiency during pregnancy doubled the risk of MS in their offspring, and a Danish study found that low vitamin D levels in infants was associated with an increased MS risk in adulthood, suggesting that improving a woman’s vitamin D levels during pregnancy may also reduce the risk of MS in her children.
The study, by a team including Drs. Kassandra Munger and Alberto Ascherio (Harvard T. H. Chan School of Public Health in Boston), was published on September 13, 2017 in Neurology.
Comment: This largest study of its kind to date adds to growing evidence that low levels of vitamin D increase the likelihood of developing MS. Since this study included only women, who were mostly white, the results may not apply to men or to other racial groups. It also did not account for other potential risk factors that may have played a role.
An editorial in the same issue of Neurology by Drs. Ruth Ann Marrie Christopher Beck addresses the question of whether there is enough evidence now to make sweeping recommendations on vitamin D supplementation. They note, “Vitamin D supplementation is a simple intervention that would be highly cost-effective even if it prevents only a proportion of MS cases…,” concluding, “It is time to take an active approach to preventing MS, at a minimum targeting those individuals with an elevated risk of MS, including smokers, the obese, and those with a family history of MS.” Read more more about Vitamin D and MS
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