Tag: multiple sclerosis

Reduced Risk of Relapse in MS Sufferers Taking Cladribine

A healthy neuron.
A healthy neuron. Credit: NIH

A study using real-world data has shown that multiple sclerosis (MS) sufferers taking cladribine were less likely to experience disease relapse than those who took other oral disease-modifying therapies.

Relapse and discontinuation outcomes favoured cladribine tablets over oral fingolimod, dimethyl fumarate, and teriflunomide. The findings were reported Helmut Butzkueven, PhD, of Monash University at ACTRIMS Forum 2022, the annual meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis.

For the study, researchers drew on data from the MSBase registry of more than 79 000 people with MS worldwide. Few clinical trials or real-world studies are available that compare the effectiveness of cladribine tablets to other oral disease-modifying therapies, the researchers noted.

“Many treatment choices that patients and their care teams have to make are not or not yet examined in classical randomised trials,” Dr Butzkueven told MedPage Today. “Sophisticated analysis of data gathered systematically and prospectively in clinical care is proving a valuable alternative to examine and compare the outcomes of different treatment choices in all kinds of scenarios.”

“Oral agents for use in relapsing MS are very convenient and effective treatment choices,” he added. “This work directly compares outcomes for people with MS who chose cladribine tablets versus other oral drugs.”

The chemotherapy drug cladribine, was recently approved by the FDA for active secondary progressive disease and relapsing MS. This was based on results from trial data showing that cladribine significantly decreased the number of MS relapses and reduced the progression of disability compared with placebo.

GLIMPSE was a longitudinal study that included data for 3475 MS patients on either cladribine, fingolimod, dimethyl fumarate or teriflunomide.

The 633 patients taking cladribine were propensity-score matched with those taking oral comparators on various factors such as age, sex and country.

In pairwise comparisons, cladribine versus fingolimod had 520 matched participants per group: the annualised relapse rate (ARR) was 0.09 compared with 0.15, respectively, the hazard ratio (HR) for time to first relapse was 0.60, and the HR for time to discontinuation was 0.22.

For cladribine versus dimethyl fumarate (450 people per group), the ARR was 0.10 compared with 0.15 the HR for time to first relapse was 0.58, and the HR for time to discontinuation was 0.10.

The cladribine versus teriflunomide (458 people per group) comparisons showed that the ARR was 0.09 compared with 0.17, the HR for time to first relapse was 0.33, and the HR for time to discontinuation was 0.10.

Source: MedPage Today

Link Between Consuming Dairy Products and MS Flareups Explained

Source: Pixabay CC0

The reason why multiple sclerosis (MS) sufferers often complain of more severe disease symptoms after consuming dairy products may be down to the milk protein casein, which can trigger inflammation targeting the myelin sheath, according to a study published in the journal PNAS.

This link was demonstrated in mice, but there was evidence of a similar mechanism in humans. The researchers therefore recommend that certain groups of MS sufferers avoid dairy products.

“We hear again and again from sufferers that they feel worse when they consume milk, cottage cheese or yoghurt,” explained Professor Stefanie Kürten from the Institute of Anatomy at University Hospital Bonn. “We are interested in the cause of this correlation.”

The professor of neuroanatomy is considered a renowned expert on multiple sclerosis. “We injected mice with different proteins from cow’s milk,” she said. “We wanted to find out if there was a constituent that they were responding to with symptoms of disease.”

When they administered the cow’s milk constituent casein together with an effect enhancer to the animals, the mice went on to develop neurological disorders. Electron microscopy showed damage to the insulating myelin sheath, which normally prevents short circuits and significantly accelerates stimulus conduction.

In multiple sclerosis, the body’s immune system destroys the myelin sheath. Consequences range from paresthaesia and vision problems to movement disorders. With patients ending up in a wheelchair. In mice, the myelin sheath was also massively perforated, apparently triggered by casein administration. “We suspected that the reason was a misdirected immune response, similar to that seen in MS patients,” explained Rittika Chunder, a postdoctoral fellow in Prof. Kürten’s research group. “The body’s defenses actually attack the casein, but in the process they also destroy proteins involved in the formation of myelin.”

Such cross-reactivity can occur when two molecules share some similar parts, causing the immune system to mistake them for each other. “We compared casein to different molecules that are important for myelin production,” Dr Chunder said. “In the process, we came across a protein called MAG. It looks markedly similar to casein in some respects – so much so that antibodies to casein were also active against MAG in the lab animals.”

This means that in the casein-treated mice, the body’s own defences were also directed against MAG, destabilising the myelin. But to what extent can the results be transferred to people with MS? To answer this question, the researchers added casein antibodies from mice to human brain tissue. These did indeed accumulate in the cells responsible for myelin production in the brain.

The study found that the antibody-producing B cells in the blood of people with MS respond particularly strongly to casein. It is possible that at some point while consuming milk, the affected individuals developed an allergy to casein. Now, on consuming dairy products, the immune system produces masses of casein antibodies, which due to cross-reactivity with MAG, also damage the myelin sheath.

However, this only affects MS patients who are allergic to cow’s milk casein. “We are currently developing a self-test with which affected individuals can check whether they carry corresponding antibodies,” said Prof Kürten. “At least this subgroup should refrain from consuming milk, yogurt, or cottage cheese.”

It is possible that cow’s milk also increases the risk of developing MS in healthy individuals. Because casein can also trigger allergies in them – which is probably not even that rare. Once such an immune response exists, cross-reactivity with myelin can in theory occur. However, this does not mean that hypersensitivity to casein necessarily leads to the development of multiple sclerosis, Prof Kürten stressed. This would presumably require other risk factors. This connection is concerning worrying, said Prof Kürten, as “Studies indicate that MS rates are elevated in populations where a lot of cow’s milk is consumed.”

Source: University of Bonn

In MS, Twin Study Reveals Disease-causing T Cells

Source: Pixabay CC0

By studying the immune system of pairs of monozygotic twins to rule out genetics in cases of multiple sclerosis, researchers may have discovered a smoking gun: precursor cells of the disease-causing T cells.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system CNS and the most common cause of neurological impairment in young adults. In MS, the patient’s own immune system attacks the CNS, resulting in cumulative neurological damage. The cause of MS still unclear but a variety of genetic risk factors and environmental influences have already been linked to the disease.

Genetics have already been found to be a necessary condition for developing multiple sclerosis. “Based on our study, we were able to show that about half of the composition of our immune system is determined by genetics,” said Florian Ingelfinger, a PhD candidate at the UZH Institute of Experimental Immunology. The study shows that these genetic influences, while always present in MS patients, are not on their own sufficient to trigger multiple sclerosis. In the study, 61 pairs of monozygotic twins where one twin is affected by MS whereas the co-twin is healthy were examined. From a genetic point of view, the twins were thus identical. “Although the healthy twins also had the maximum genetic risk for MS, they showed no clinical signs of the disease,” said Lisa Ann Gerdes.

With this cohort of twins, the researchers were  tease out environmental differences. “We are exploring the central question of how the immune system of two genetically identical individuals leads to significant inflammation and massive nerve damage in one case, and no damage at all in the other,” explained Professor Burkhard Becher, leader of the research team. Using identical twins let the researchers block out the genetic influence and focus on the immune system changes that were ultimately responsible for triggering MS in one twin.

The researchers harnessed state-of-the-art technologies to describe the immune profiles of the twin pairs in great detail. “We use a combination of mass cytometry and the latest methods in genetics paired with machine learning to not only identify characteristic proteins in the immune cells of the sick twin in each case, but also to decode the totality of all the genes that are switched on in these cells,” Florian Ingelfinger explained. 

“Surprisingly, we found the biggest differences in the immune profiles of MS affected twins to be in the cytokine receptors, ie the way immune cells communicate with one another. The cytokine network is like the language of the immune system,” said Ingelfinger. Increased sensitivity to certain cytokines leads to greater T cell activation in the bloodsteams of patients with multiple sclerosis. These T cells are more likely to migrate into the CNS and cause damage there. The identified cells were found to have the characteristics of recently activated cells, which were in the process of developing into fully functional T cells. “We may have discovered the cellular big bang of MS here – precursor cells that give rise to disease-causing T cells,” said Prof Becher.

“The findings of this study are particularly valuable in comparison to previous studies of MS which do not control for genetic predisposition,” said Prof Becher. “We are thus able to find out which part of the immune dysfunction in MS is influenced by genetic components and which by environmental factors. This is of fundamental importance in understanding the development of the disease.”

The study findings were reported in Nature.

Source: University of Zurich

Meat, Gut Bacteria and Multiple Sclerosis

Gut microbiome. Credit: Darryl Leja, NIH

There appears to be a link between eating meat, gut bacteria and multiple sclerosis, according to new research published in EBioMedicine. The study teased out subtle connections that could lead to a better understanding of the causes of the disease.

The autoimmune disease multiple sclerosis (MS) is more prevalent in specific regions, particularly the northern mid-latitudes, suggesting that geography is somehow linked to the disease, perhaps involving diet. However, the exact relationships between diet, immune response, and MS has been a mystery. What exactly triggers the body to attack the myelin sheaths in MS in the first place is unknown.

Growing evidence suggests that bacteria might play a role. Gut bacteria affect the immune system, and diet affects the gut. Researchers studied the gut microbiome, immune systems, diet, and blood metabolites in 25 MS patients and 24 healthy controls to look for any subtle but important correlations.

“We found a number of gut bacteria associated with MS and severity of disability of MS patients,” said Dr Yanjiao Zhou. “We also found increased autoimmune markers and signature metabolites in MS. But what is really interesting is how these systems connect with each other, and how diet is involved in these connections. Using multi-OMICS approaches, we try to close the loop and show the associations between multiple systems.”

Meat eating was the strongest link in their analysis, where higher meat consumption saw a decrease in the population of Bacteroides thetaiotaomicron, a bacteria associated with digesting carbohydrates from vegetables.

Higher meat consumption, seen in the MS patients, was also linked to an increase in T-helper 17 cells in the immune system, and an increase in S-adenosyl-L-methionine (SAM) in their blood.

Meat eating was not a predictor of MS. But the evidence suggested that, in MS, something causes gut bacteria to disassociate with the immune system, leading to heightened T-helper 17 cells and autoimmune attacks on the nervous system. And it tends to be associated with eating meat.

Future research aims to recruit more volunteers, including those with more severe MS. Eventually they hope to understand more of the cause-and-effect between diet, bacterial ecosystems in the gut, and immune response, and potentially help prevent or mitigate MS symptoms in people suffering from the disease.

Source: University of Connecticut

MS Likely Caused by Epstein-Barr Virus

Source: NCI on Unsplash

Multiple sclerosis (MS) is likely caused by infection with the Epstein-Barr virus (EBV), according to a new Harvard University study.

“The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality,” said senior author Professor Alberto Ascherio. “This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.” The findings were published in Science.

Currently incurable, MS is a chronic inflammatory disease of the central nervous system that attacks the myelin sheaths protecting neurons in the brain and spinal cord. One of the top suspects for its cause is EBV, a herpes virus that can cause infectious mononucleosis and establishes a latent, lifelong infection of the host. Establishing a causal relationship between the virus and the disease has been hard because EBV infects approximately 95% of adults, MS is relatively rare, and the onset of MS symptoms begins about ten years after EBV infection. To determine the connection between EBV and MS, the researchers conducted a study among over 10 million US military personnel, identifying 955 who were diagnosed with MS during their period of service.

The team analysed serum samples taken twice a year by the military and determined the soldiers’ EBV status at time of first sample and the relationship between EBV infection and MS onset during the period of active duty. In this cohort, the risk of MS increased 32-fold after infection with EBV but remained unchanged after infection with other viruses. Serum levels of neurofilament light chain, a biomarker of the nerve degeneration typical in MS, increased only after EBV infection. The findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

The delay between EBV infection and the onset of MS may be partly a result of the disease’s symptoms being undetected early on and partly the evolving relationship between EBV and the host’s immune system, which is repeatedly stimulated whenever latent virus reactivates.

“Currently there is no way to effectively prevent or treat EBV infection, but an EBV vaccine or targeting the virus with EBV-specific antiviral drugs could ultimately prevent or cure MS,” Prof Ascherio said.

Source: Harvard University

Hydroxychloroquine Effective in Slowing MS

A healthy neuron.
A healthy neuron. Credit: NIH

Promising results for a generic antimalarial drug, hydroxychloroquine, have been seen when used to treat the evolution of disability of primary progressive multiple sclerosis (MS), the least treatable form of the autoimmune disease.

Research teams led by Dr Marcus Koch, MD, PhD, and Dr Wee Yong, PhD, found that hydroxychloroquine helped to slow the progression of disability during the 18-month study involving participants at the MS clinic in Calgary. The research was published in Annals of Neurology.

“With primary progressive MS, there is no good treatment to stop or reverse the progression of disease. The disability progressively worsens through time,” said Dr Koch. “Dr Yong’s research team, with whom we closely collaborate, has been screening a large number of generic drugs over several years and the results with hydroxychloroquine show some promise. Our trial is a preliminary success that needs further research. We hope sharing these results will help inspire that work, specifically larger scale clinical trials into the future.”

The experimental study followed 35 people, at least 40% of whom, or 14 participants, were expected to experience a significant worsening of their walking function, but at the end of the trial only eight participants had worsened.

Hydroxychloroquine is an anti-malaria medication more commonly used to manage the symptoms of rheumatoid arthritis and autoimmune conditions such as lupus. It was selected as it is use in rheumatological diseases is widespread and is generally well-tolerated.

“Based on research in our lab on models of MS, we predicted that hydroxychloroquine would reduce disability in people living with MS. Calgary has a vibrant bench-to-bedside MS program and the work from Dr Koch’s trial offers further evidence which we were pleased to see,” said Prof Yong.

To date, the cause of MS is unknown. This autoimmune disease generally long-lasting, often affecting the brain, spinal cord and the optic nerves in your eyes. It can cause problems with vision, balance and muscle control, although the effects are different for every patient with the disease.

Dr Koch and the research team have been studying the impact of hydroxychloroquine on primary progressive MS for several years and that work continues, including its potential to achieve even greater results as a therapy in combination with select other generic drugs.

Source: EurekAlert!

Green Light for New Device for MS Treatment

The American Food & Drug Administration has approved a new device for treating gait deficits in multiple sclerosis (MS) patients.

The Portable Neuromodulation Stimulator (PoNS), generates electrical pulses on the tongue to stimulate trigeminal and facial nerves to treat motor deficits. The FDA said that for it to be available by prescription, must be part of a supervised therapeutic exercise program in MS patients 22 and older. The device was authorised through the FDA’s ‘de novo’ premarket review pathway for new devices which pose do not pose significant risks of adverse effects.

In a statement, Christopher Loftus, MD, acting director of the Office of Neurological and Physical Medicine Devices in the FDA’s Center for Devices and Radiological Health, said: “MS is one of the most common neurological diseases in young adults. Today’s authorisation offers a valuable new aid in physical therapy and increases the value of additional therapies for those who live with MS on a daily basis.”

Onset of MS symptoms, which can include difficulties with walking and balance, typically occurs between 20 and 40, with greater frequency in women.

The PoNS device electrical stimulates the dorsal surface of the patient’s tongue. A control unit is worn around the neck which sends signals to a mouthpiece which the patient keeps in place with lips and teeth. Later, usage data can be viewed by a therapist to spot “potential areas of missed or shortened sessions,” the FDA noted.

The FDA gave their approval based on two clinical studies. One involved 20 MS patients with gait deficits (half with PoNS; half with a sham device). Th FDA said that the PoNS group showed “statistically significant and clinically significant” improvement in Dynamic Gait Index (DGI) scores at 14 weeks not seen in the sham device group.

The other study, with 14 patients, showed improvements from baseline in sensory organisation task scores (but not in DGI scores) at 14 weeks. There were no serious safety or adverse effects reported.

Among the FDA’s cautions, the FDA stated that the PoNS device should not be used by patients with penetrating brain injuries, neurodegenerative diseases, oral health problems, chronic infectious diseases, unmanaged hypertension or diabetes, pacemakers, or a history of seizures.

Source: MedPage Today

With Climate Change, Heat May Worsen Multiple Sclerosis Symptoms

As average global temperatures increase due to climate change, multiple sclerosis (MS) patients can experience worsening symptoms resulting in an increase in hospital visits.

Some 60% to 80% of MS patients experience heat sensitivity. Increased body temperature slows or stops nerve signals in damaged nerves, which has a number of impacts such as blurred vision and other neurological effects. Heat sensitivity is also correlated with fatigue. Together with fatigue, divided attention from heat sensitivity can contribute to falls.

“We know that heat sensitivity is common in multiple sclerosis, and climate scientists expect that periods of anomalously warm weather will become more frequent with climate change,” said study author Holly Elser, PhD. of Stanford University School of Medicine. “Our study suggests that warming trends could have serious health implications over the long term for people living with MS.”

The study defined anomalously warm weather as a month in which local average temperatures were higher than the long-term average temperature for that month by at least 1.5C.

The researchers drew data on insurance claims for 106 225 people with MS living in the US, and then calculated the estimated effect of anomalously warm weather on MS-related emergency department, inpatient and outpatient visits. Then, the number of medical visits for each person during anomalously warm weather periods was compared to those for periods of normal weather periods.

During anomalously warm weather periods, there was a 4% increased chance of an emergency department visit compared to periods of normal weather. Participants had a 3% increased chance of having an inpatient visit and a 1% increased chance of having an outpatient visit during anomalously warm periods compared to periods of normal weather.

Researchers estimate that during the follow-up period, anomalously warm weather periods were linked to an estimated excess of at least 592 emergency department visits, 1260 inpatient visits and 1960 outpatient visits related to MS.

“While the relative increase in risk of visits is small, the associated absolute effect on people with MS and the health care system is meaningful,” concluded Dr Elser.

Source: Medical Xpress

Promising Drug May Worsen Instead of Treat Multiple Sclerosis

A drug, TEPP-46,  that is being assessed to treat multiple sclerosis (MS) may in fact be worsening the progression of the disease, wrote University of Virginia on the Medical Xpress website.

MS is a debilitating disease which affects over one million people in America, in which the immune system attacks the myelin sheath, creating a range of effects in sufferers, from muscle spasms to numbness.

Presently available drugs to treat MS often have unwanted side effects, such as weakening the immune system. Originally developed to fight cancer, TEPP-46 is small-molecule drug that targets the changes in cellular metabolism that occur in both cancer and MS. However, the drug has been shown to produce off-target effects. In the mouse model used by the researchers, the inflammation was directed away from the spinal cord and into the brain. The researchers believed that this was the result of the drug harmfully changing T cells, but could not explain why. 

“It was not at all what we expected,” said MS researcher Alban Gaultier, PhD, of University of Virginia. “The take-home message is that we should be very careful and do more fundamental research before we propose to take this to clinical trials.”