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SAGE Journals: Your gateway to world-class journal research

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Subscription and open access journals from SAGE Publishing, the world's leading independent academic publisher.

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Agency for Toxic Substances and Disease Registry

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The Agency for Toxic Substances and Disease Registry (ATSDR), based in Atlanta, Georgia, is a federal public health agency of the U.S. Department of Health and Human Services. ATSDR serves the public by using the best science, taking responsive public health actions, and providing trusted health information to prevent harmful exposures and diseases related to toxic substances.

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A cluster of MS is the perception that a very high number of cases of MS have occurred over a specific time period and/or in a certain area.

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Multiple sclerosis: battle b-neath the surface

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The cells of the immune system are like different types of martial artists, each with their own job to do to protect the body. In multiple sclerosis (MS), the immune system turns against a person's central nervous system (CNS) and interrupts communications within the brain, and between the CNS and the body.

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Are the Prevalence and Incidence of Multiple Sclerosis Changing?

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Are the Prevalence and Incidence of Multiple Sclerosis Changing?

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Multiple Sclerosis medical animation - Polygon Medical Animation

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Multiple sclerosis (MS) is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. This medical animation shows how T cells cross the blood brain barrier and attacks the myelin.

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Want to learn more?

Roughly 17 litres of the filtered plasma are reabsorbed directly into the blood vessels, while the remaining three litres remain in the interstitial fluid. One of the main functions of the lymph system is to provide a return route to the blood for the surplus three litres.

The lymph in the tissues is moved along the lymphatic vessel network by either intrinsic contractions of the lymphatic passages or by extrinsic compression of the lymphatic vessels via external tissue forces (e.g. the contractions of skeletal muscles

The organization of lymph glands and drainage follows the organization of the body into external and internal regions; therefore, the lymphatic drainage of the head, limbs, and body cavity walls follows an external route, and the lymphatic drainage of the thorax, abdomen, and pelvic cavities follows an internal route. Eventually, the lymph vessels empty into the lymphatic ducts ( thoraic duct), which drain into one of the two subclavian veins, near their junction with the internal jugular veins

Lymph glands are where lymphocyte-mediated immune reactions are started

Memory B cells and plasma cells (antibody making cells) forming in the germinal centres
Then we have been talking about memory B cells and whilst we have been saying that memory B cells and antibody forming cells are formed in the germinal centres (GC), looking at that the expression of CD27 (CD27+), there are a few in the germinal centres. They accumulate in the marginal zone surrounded by the T cells, so they shuttle out of the germinal centre.

This can be see in histology. CD20 binds B cells but not plasma cells so you can see most of the cells in the germinal centre have CD20 so they are not plasma cells. CD27 is on the memory B cells but can be found on activated T cells. CD1c is a molecule associated with a form of antigen presentation.IgD is immunoglobulin D which is on B cells and is lost once memory cells class switch to produce IgA, IgG and IgE. So you can see the memory B cells are largely outside the follicle.

Where are the plasma cells?
Based on the fancy diagrams and all the hoo hah about ectopic follicles in the brain of MS, I was also under the assumption that the plasma cells would be located inside the follicle.
These cells stain with CD138.
When I had a look at the distribution of CD138 in lymphoid tissue I got a shock. The plasma cells are a few cells scattered outside the follicles and B cell areas.
Like the memory cells the plasma cells must rapidly leave the follicles where they are formed and the plasma cells then are found outside the follicles!

Here they are in the spleen, so you can see they are not really in the follicles. This is a revelation to me, because we are probably wasting our time looking for follicles, the plasma cells may be the odd cell next to a macrophage/microglia pumping out antibodies.

So maybe those pesky pathologists have done it again:-)....We are looking for the wrong thing.
I'll have to do some more reading. It's good that we learn together.
Some of you can hopefully spot my mistakes and misunderstandings.

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Want to learn more? Roughly 17 litres of the filtered plasma are reabsorbed directly into the blood vessels, while the remaining three litres remain in the interstitial fluid. One of the main functions of the lymph system is to provide a return route to the blood for the surplus three litres.

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The anti-α4 monoclonal antibody natalizumab inhibits lymphocyte extravasation into the central nervous system and increases peripheral T and B lymphocytes in multiple sclerosis patients. To investigate whether the lymphocyte accumulation was due to a higher lymphocyte production, an altered homeostasis, or a differential transmigration of lymphocyte subsets through endothelia, T-cell receptor excision circles and kappa-deleting recombination excision circles were quantified before and after treatment, T-cell receptor repertoire was analyzed by spectratyping, and T- and B-lymphocyte subset migration was studied using transwell coated with vascular and lymphatic endothelial cells. We found that the number of newly produced T and B lymphocytes is increased because of a high release and of a low propensity of naïve subsets to migrate across endothelial cells. In some patients this resulted in an enlargement of T-cell heterogeneity. Because new lymphocyte production ensures the integrity of immune surveillance, its quantification could be used to monitor natalizumab therapy safety.

Lymphocytes (blue)and red blood cells (red) in the microscope

The mechanism that causes the increase in the number of lymphocytes in the peripheral blood of MSers on natalizumab (Tysabri) was studied with a in vitro system that mimics blood vessels. So the lymphocytes are not the ones that would have gone to the brain and spinal cord... but they are new lymphocytes that cannot cross the walls of blood vessels as easily. So far, there are no safety concerns with this raised number of lymphocytes.

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Research: New white blood cells after Tysabri

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The anti-α4 monoclonal antibody natalizumab inhibits lymphocyte extravasation into the central nervous system and increases peripheral T and B lymphocytes in multiple sclerosis patients.

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Learn how #NeuroQuant can help physicians monitor #MS brain volume changes. Visit us at #ECTRIMS2015 - Stand D16 http://t.co/oWsfDbzIGp

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Learn how #NeuroQuant can help physicians monitor #MS brain volume changes. Visit us at #ECTRIMS2015 - Stand D16 http://t.co/oWsfDbzIGp

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HOW THE MULTIPLE SCLEROSIS PATIENTS FEEL UPON BEING DIAGNOSED AS MS AND DURING TREATMENT

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"A Dream to Walk. A Fight to Live": MS Short Documentary

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As a personal fitness trainer and a health therapist coach, Christina Aivazoglou ate, breathed and slept nutrition-that is, until August 16, 2006, when she was diagnosed with primary progressive multiple sclerosis. Within just eight years, she has watched her body rapidly deteriorate. The documentary, "A Dream to Walk.

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Bo Veisland, MI&I/Science Source

The trillions of bacteria that live in our intestines, known collectively as the gut microbiome, have been linked to maladies from eye disease to rheumatoid arthritis. Now, two new studies have added another disease: multiple sclerosis (MS), an autoimmune disorder that strips away nerve cells' protective covers, leading to muscle weakness, blindness, and even death. What's more, the studies suggest how our gut microbes make the immune system turn against nerve cells-a finding that could lead to treatments, like drugs based on microbial byproducts, that might improve the course of the disease.

MS affects 2.5 million people worldwide, but little is known about what causes the disease, which progressively disrupts information flow from and within the brain. Most researchers think it starts when genetically predisposed people encounter an as-yet-unknown environmental trigger. Previous studies have identified particular bacteria present in increased amounts in the guts of MS patients. But the new papers "took it to the next level" in trying to understand how these bacteria affect the immune system, says Francisco Quintana, a neuroimmunologist at Brigham and Women's Hospital in Boston not involved with the work. "These are going to be landmark studies."

In the first paper, a team of researchers led by Sergio Baranzini, a human geneticist at the University of California, San Francisco, analyzed the microbiomes of 71 people with MS and 71 healthy individuals, aged 19 to 71. They found that two bacterial groups, Acinetobacter and Akkermansia, were four times more abundant in MS patients than in individuals with no disease. Another group, Parabacteroides, was four times as abundant in healthy people.

The researchers then took naïve immune cells-which transform into different types based on the invaders they encounter-from the blood of healthy individuals and exposed them to bacteria in the guts of MS patients. In the presence of Acinetobacter and Akkermansia, they became a particular type of T helper cell, which trigger inflammation and help the immune system kill off invaders or infected cells, the researchers report today in the Proceedings of the National Academy of Sciences ( PNAS). But Acinetobacter also ramped down the production of regulatory T cells, which help prevent autoimmune diseases by dampening the immune response.

The researchers observed similar differences when they transferred the MS gut bacteria to germ-free mice and induced brain inflammation. Within 20 days, the mice receiving gut bacteria from MS donors developed severe brain inflammation. "But when we transferred the gut microbes from healthy people, the mice didn't get nearly as sick," Baranzini says.

In a related study also published today in PNAS, immunologists led by Gurumoorthy Krishnamoorthy and Hartmut Wekerle of the Max Planck Institute of Neurobiology in Martinsried, Germany, examined the gut microbiomes of 34 sets of identical twins, aged 21 to 63, in which only one twin had MS. They found that Akkermansia was slightly but significantly more abundant in MS patients than in their healthy twins. When the researchers transferred gut microbes from the twins into mice predisposed to develop a disease similar to MS, they found that after 12 weeks, three times as many mice receiving bacteria from MS patients developed brain inflammation as those receiving microbes from healthy donors. Gut bacteria from MS patients also seemed to block the production of molecules, like the cytokine IL-10, that reduce inflammation.

Both studies analyze a relatively small number of individuals, notes Javier Ochoa-Reparaz, an immunologist at Eastern Washington University in Cheney who was not involved with either team. However, they provide "exciting new evidence" that some intestinal microbes might inhibit key anti-inflammatory molecules and help trigger MS, he says, together with other genetic and environmental factors.

Understanding how intestinal bugs alter the immune response of MS patients could help develop treatments, such as cocktails of anti-inflammatory bacteria or drugs, Quintana says. But more work is needed to pinpoint the molecules produced by gut bacteria that alter the MS patients' immune system, the authors of both studies note. "Therapeutic applications are in everyone's mind," Baranzini says. "But it's still too early to think about that."

doi:10.1126/science.aap9323

More from News

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Gut microbes could help trigger multiple sclerosis

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The trillions of bacteria that live in our intestines, known collectively as the gut microbiome, have been linked to maladies from eye disease to rheumatoid arthritis. Now, two new studies have added another disease: multiple sclerosis (MS), an autoimmune disorder that strips away nerve cells' protective covers, leading to muscle weakness, blindness, and even death.

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"Hot Spots: Clusters of MS are scattered across the U.S., often in regions of heavy industry or agriculture."

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The unique beauty of the Palouse has inspired glorious names - Paradise Creek... Paradise Ridge... Paradise Street. Yet people in the small towns dotting this bit of heaven also live with a vague uneasiness - the hidden and unpredictable threat of multiple sclerosis.

That threat drew researcher Brett Parmenter to WSU in 2006. As assistant professor in the Department of Psychology, she is in eastern Washington - one of the nation's hot spots for MS - for the singular chance to help answer questions about this puzzling disease.

What is MS?
MS is a debilitating neurological disorder that reportedly affects more than 400,000 people in the U.S. and up to 2.5 million worldwide.

Its name refers to the many scar-like lesions that form on nerve cells - or axons. Axons conduct electrical impulses throughout the body and are covered with an insulating sheath of fatty material called myelin.

For unknown reasons, the body's immune system may turn against myelin and attempt to destroy it with white blood cells. These cells secrete an array of inflammatory compounds that eventually strip away the myelin, leaving damaged axons behind.

MS can cause symptoms such as fatigue, numbness, impaired vision, loss of balance, bladder dysfunction, paralysis and even death.

Silent symptoms
"We are still just learning how MS affects the brain," said Parmenter. "Research shows that MS doesn't just affect the white matter (myelin), but also attacks the deep grey matter structures like the thalamus. Each person is affected differently - and we can't predict which symptoms an individual might have.

"One of the more common symptoms of MS is cognitive impairment, which affects about 30 to 70 percent of patients," she said. "My research is focused on trying to find out why some people have cognitive impairment and others don't."

She also is looking into the relationship between that and MS-related fatigue - one of the "silent" symptoms, along with slowed thinking and tingling or numbness, that are not apparent to others. About 90 percent of patients rate fatigue as one of the most debilitating symptoms of MS, she said.

Important research
Collaborating with Parmenter on these studies is Roy Kanter, neurologist at the Holy Family Hospital MS Center in Spokane. (See ONLINE @ www.holy-family.org/Services/MultipleSclerosis.asp)

Kanter said that in recent years, it has become more apparent that MS patients face subtle but significant cognitive problems.

"There is often a kind of memory loss as well as decreased ability to concentrate. There also can be problems with processing speed and multitasking," he said.

"Brett's research is important, as there are few others investigating the area of cognitive impairment in MS," Kanter said. "Though we don't know how to prevent MS, our knowledge base of the disease has grown dramatically.

"We should be able to greatly slow down the progression of disability in the future. We may even come up with a cure in the next 10 to 12 years," he said.

Uncertain causes
The cause of MS remains uncertain.

"We know that it increases the further away from the equator you live," Parmenter said. "It affects more women than men, especially those of northern European heritage.

"Most people are diagnosed between the ages of 20 and 40 but some aren't diagnosed until their 50s or 60s. And there can also be pediatric onset of MS in children or teenagers."

Though research has revealed a genetic component to MS, it can only account for about a quarter of the cases. More likely, MS is caused by a combination of factors including genetics, diet, latitude/sunlight exposure and environmental contamination.

Hot spots
Clusters of MS are scattered across the U.S., often in regions of heavy industry or agriculture.

"Buffalo, New York, is a hot spot," said Parmenter. "As part of the rust belt, it is an area with a lot of industry and pollutants, although how these may be related to the disease is unknown.

"There are also hot spots in Kansas, Minnesota and North Dakota as well as locations in Missouri," she said.

"We don't have a certain hypothesis for why the Palouse area is so highly affected. It could be populations here have a genetic predisposition, which is triggered by something in the environment." Conventional wisdom has speculated that "something" might be agricultural chemicals and pesticides, or perhaps fallout from the Hanford nuclear projects that took place in the 1950s.

There are no published studies documenting the prevalence of MS in eastern Washington; however, a research team headed by William Lambert of the Oregon Health and Sciences University is in the process of collecting relevant data. Team members are counting actual numbers of cases of MS by age and gender for each county in eastern Washington. Their analysis is under evaluation by the Centers for Disease Control and is due to be released to the public in early 2008.

Call for volunteers
Parmenter is conducting studies on cognitive impairment associated with MS and is calling for volunteers over age 18 - both people with MS and those without it to serve as controls.

For one study investigating the role of sex hormones in MS, she is asking for women age 55 and younger. They will take part in blood draws and cognitive tests.

In another study on brain processing speed, Parmenter is looking for volunteers of both sexes to take part in tests evaluating memory and problem solving.

Millie (not her real name) was diagnosed with MS three years ago at age 54, but her neurologist feels she probably has had it since she was 27. She recently graduated from WSU and is working on a master's degree. As a participant in Brett Parmenter's study on multiple sclerosis, Millie agreed to talk about her condition using an assumed name.

"There is a stigma about MS," she said, "and people can be judged incorrectly sometimes, so I really need to think about whom to tell. Even with laws to protect us, there are ways ...for people... to get around them."

Looking back, Millie can see the signs of MS. She would feel fine one minute and the next lie down with extreme fatigue. She began having memory problems.

Her doctors typically said, "You have two kids, a lot of stress, you're active...it's normal."

It wasn't until she came to the Palouse and found herself unable to do a simple class assignment that she called her nurse practitioner in a panic and was subsequently diagnosed through an MRI.

"I'm so thankful she took the time to get to know me and listen to me," said Millie. "I knew I wasn't crazy."

With treatment, Millie's condition has remained fairly stable. But obtaining the medication is difficult. Only certain insurance companies will cover the cost of what may be a $2,000 per month drug bill.

Her insurance, Washington Basic Health Care, would pay only about $30 of the cost. With perseverance, Millie received funding from a nonprofit organization associated with the drug she takes, called Copaxone ©. Without that, she would have to go without medication.

"People with MS have to pay their health insurance before they buy food or pay rent," Millie said. "We can't lose it for 10 minutes or we can't get reinsured - we are considered a bad risk."

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The Palouse known as an MS hot spot | WSU News | Washington State University

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The unique beauty of the Palouse has inspired glorious names - Paradise Creek... Paradise Ridge... Paradise Street. Yet people in the small towns dotting this bit of heaven also live with a vague uneasiness - the hidden and unpredictable threat of multiple sclerosis. That threat drew researcher Brett Parmenter to WSU in 2006.

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Washington is a Hotbed for Three Dangerous Diseases

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Washington is a Hotbed for Three Dangerous Diseases

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"We outpace the nation in debilitating, and sometimes deadly, diseases. Washington is a hot spot for multiple sclerosis, has the sixth-highest rate of melanoma skin cancer and is number 15 nationwide in tuberculosis."

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We take pride in it: Our state regularly earns top honors as one of the most livable in the country, thanks to our old-growth forests, vast waterways, and our literary and recreational lifestyles. But Washington state also tops a few not-so-pleasant lists: We outpace the nation in debilitating, and sometimes deadly, diseases. Washington is a hot spot for multiple sclerosis, has the sixth-highest rate of melanoma skin cancer and is number 15 nationwide in tuberculosis.

Is it the air we breathe? The water we drink? The food we eat? Scientists, doctors and medical researchers are searching for answers-and not always finding them.

The National Multiple Sclerosis Society says multiple sclerosis is more prevalent in the Pacific Northwest than almost anywhere else on earth-there are about 12,000 known cases here. There's no known cure, no known cause and no proven explanation for its prominence in Washington. "If I knew why, I would get a free trip to Stockholm to pick up my Nobel Prize," says Dr. James Bowen, medical director of the Multiple Sclerosis Center at Swedish Medical Center's Neuroscience Institute and board member of the National Multiple Sclerosis Society.

What we do know is that every hour of every day, someone is diagnosed with this debilitating disease of the central nervous system. More than 400,000 people in the U.S.-2.5 million people worldwide-are affected by MS. An often-progressive disease that attacks the brain, optic nerves and spinal cord, MS symptoms vary from person to person: Some have numbness in their arms and legs, others lose their eyesight or balance, and some can become paralyzed and in very rare cases, even die. The complex disease is like a giant unsolved jigsaw puzzle: Dozens of factors-such as lack of vitamin D, diet, childhood viruses, gender, genetics, age and geography-are believed to contribute to it, but have yet to be fully understood and formally linked. Do our high-fat/dairy-rich diets and the vitamin D-depleting sunscreen we are obsessed with contribute to MS?

It has long been established that MS is more prevalent in communities in the far northern and southern latitudes, possibly due to less sunlight and more vitamin D deficiencies. "It's not known whether the low vitamin D levels contribute to causing MS, or whether having MS causes people to avoid sunlight [because of overheating issues], causing the low vitamin D levels," Dr. Bowen says. Another factor, he adds, is ethnic background. MS is more common in people of northern European heritage, such as Washington's large populations of Scandinavian and Germanic heritage. And it affects women three times as often as men.

Another disease that's vexing scientists in our state is viewed by many as a thing of the past: tuberculosis (TB). Despite a national drop for 18 consecutive years, the number of TB infections has been on the rise in Washington, with 256 cases reported in 2009, up from 228 cases the previous year. In Seattle/King County, there were 130 cases reported in 2009-that's about seven per 100,000 people, compared with the national rate of 3.8 cases per 100,000. In 2010, the TB rates decreased slightly to 239 cases statewide, and 116 in Seattle/King County. But health officials point to a troubling new trend: A more infectious strain-previously found mostly among the local homeless population-is now being transmitted among the broader community in King County.

"TB is a global disease," says Dr. Masa Narita, TB control officer for Public Health-Seattle & King County. About one-third of the world's population is infected with TB, and 2 million people die from it every year-but it's almost always curable. Antibiotics can generally cure the disease over a six- to nine-month period; drug-resistant forms of TB can take years to cure and cost as much as $250,000 per patient.

While anyone can get it, TB mainly affects foreign-born people from countries where the infection is widespread. Here in Seattle, we're especially vulnerable because of our diverse population-more than 80 percent of King County's active cases (about 120 to 150 per year) involve people born outside the United States, primarily in South and Southeast Asia, East Africa and Central America. Also, people with HIV/AIDS, those younger than 5 and older than 50, and those with weakened immune systems are at increased risk for TB.

A bacterial infection that usually affects the lungs, TB is spread in the air when an infected person coughs. Symptoms include fever, night sweats, fatigue, weight loss and a persistent cough, but it's possible to be infected with TB and have no symptoms-a fact that makes controlling the spread of the disease all the more difficult.

A third disease, melanoma, isn't caught from other people, but this deadliest form of skin cancer is wreaking health havoc in our state, which has the sixth-highest rate in the nation. Washington's skin cancer rate is 23 percent higher than the national average, according to the state Department of Health's Cancer Registry. It is the fourth-leading type of cancer in our state, with 2,687 new cases and 206 deaths reported in 2007, the most recent year for which statistics are available.

Skin cancer is the most common cancer in the U.S, with more than 2 million new cases diagnosed each year. According to the American Cancer Society, someone is diagnosed with melanoma in the U.S. every eight minutes-and someone dies from it every hour. In our state, about 200 people die from melanoma every year.

Why are the rates so high here, with Seattle being one of the least sunny places in the country? Unprotected exposure to the sun's ultraviolet light is the biggest known cause of melanoma. "In our cloudy climate, some people tend to get very pale in the winter and then can be prone to burn when they are in the sun," says Juliet VanEenwyk, epidemiologist for noninfectious conditions at the Washington State Department of Health. "Burning at a young age may be particularly harmful." Seattle's cloudy skies also give us a false sense of security, fooling us into thinking we don't need sunscreen. Those with fair skin, freckles or unusual moles, or those with a family history of melanoma are at an increased risk. Melanoma is more than 10 times more common in whites than in African Americans and is highly curable when detected early.

What can be done to avoid these illnesses? Avoiding contact with TB-infected people (until they've been treated) can help prevent TB. But the best defenses against melanoma and MS are as yet unclear, and perhaps in conflict (more sun exposure, or less?). Here in Washington, the troubling mysteries persist.

Local Resources
The Seattle area has many resources, clinics, support groups, educational programs and fundraising events addressing tuberculosis, multiple sclerosis and skin cancer.

Tuberculosis
Public Health - Seattle & King County Tuberculosis Control Program
Harborview Medical Center
325 Ninth Ave.
206.744.4579
Open Monday, Tuesday, Thursday and Friday, 8 a.m.-4:30 p.m.
The county's TB website has information for clinics, testing procedures and other TB-related programs; kingcounty.gov/healthservices/; search "TB control"

Washington State Department of Health Tuberculosis Control Services
Olympia
111 Israel Road SE
360.236.3447
doh.wa.gov/cfh/TB

Multiple Sclerosis
National Multiple Sclerosis Society, Greater Northwest Chapter
192 Nickerson St., Suite 100
800.344.4867; 206.284.4254
nationalmssociety.org

Skin Cancer
The Environmental Protection Agency
Washington state has partnered with the EPA to bring its SunWise program to local classrooms. The environmental and health education program aims to teach children and their caregivers how to protect themselves from overexposure to the sun through the use of classroom-, school- and community-based groups; epa.gov/sunwise/

Cancer Care Alliance (CCA)
The CCA offers information on skin cancer, including symptoms and risk factors, on its website; seattlecca.org; search "skin cancer"

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Washington is a Hotbed for Three Dangerous Diseases

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We take pride in it: Our state regularly earns top honors as one of the most livable in the country, thanks to our old-growth forests, vast waterways, and our literary and recreational lifestyles. But Washington state also tops a few not-so-pleasant lists: We outpace the nation in debilitating, and sometimes deadly, diseases.

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The major resource for individuals with concerns or questions about an MS cluster in their community is the local public health department. Public health officials are qualified to investigate suspected clusters. If they lack adequate staffing and funding to analyze situations that they consider to be of concern, they may refer cases to the federal Agency for Toxic Substances and Disease Registry at 888-422-8737 or ATSDRIC@cdc.gov.

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A cluster of MS is the perception that a very high number of cases of MS have occurred over a specific time period and/or in a certain area.

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Multiple Sclerosis Cases Higher in E. WA

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Multiple Sclerosis Cases Higher in E. WA

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Multiple Sclerosis Cases Higher In Eastern Washington

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The Palouse area of eastern Washington is one of the nation's hot spots in terms of reported cases of MS. Glenn Mosley reports.

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Juicing Helps Incurable Diseases like Multiple Sclerosis..check out uicing Recipes for Multiple Sclerosis

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Multiple sclerosis: Patients may benefit from over-the-counter therapy

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Multiple sclerosis: Patients may benefit from over-the-counter therapy

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Results will be tested in large-scale clinical trial

Date:

June 30, 2017

Source:

Oregon Health & Science University

Summary:

Over-the-counter antioxidant lipoic acid holds promise for treating patients with secondary progressive multiple sclerosis, a pilot study suggests. Researchers are using the findings from the pilot trial to design the expanded multi-site clinical trial to begin later this year in Portland and other sites that have yet to be finalized.

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Treatment options currently are limited for people suffering from secondary progressive multiple sclerosis. However, an OHSU pilot study suggests over-the-counter antioxidant lipoic acid holds promise in improving patients' lives.

The research was published June 28 in the journal Neuroimmunology & Neuroinflammation.

The randomized double-blind study involved 51 participants who completed the two-year trial. Twenty-seven people were given a 1,200-milogram daily dose of lipoic acid, with the remaining 24 participants given a placebo. Researchers are using the findings from the pilot trial to design the expanded multi-site clinical trial to begin later this year in Portland and other sites that have yet to be finalized.

"These are high doses," said lead author Rebecca Spain, M.D., M.S.P.H., an assistant professor of neurology in the OHSU School of Medicine. "And while it seems safe, we won't know whether it actually improves the lives of people with MS until we can replicate the results in the pilot study through a much bigger clinical trial. Fortunately, we're going to be able to answer that question with the participation of kind volunteers."

MS is a chronic condition that affects an estimated 2.3 million people worldwide. In MS, the sheath covering nerve fibers in the brain and spinal cord becomes damaged, slowing or blocking electrical signals from the brain reaching the eyes, muscles and other parts of the body.

The major finding of the pilot study involved measuring the degree to which lipoic acid arrested the rate of whole brain atrophy, as measured through magnetic resonance imaging.

The study revealed a 68 percent improvement over the placebo in slowing the rate of whole brain atrophy in patients with secondary progressive MS. For the sake of comparison, a clinical trial involving the recent FDA-approved pharmaceutical Ocrevus showed an 18 percent improvement over a placebo in slowing the rate of whole brain atrophy for patients with primary progressive forms of the disease.

In addition, the pilot study suggested improved walking times and fewer falls among study participants who took a daily dose of lipoic acid compared with those who received the placebo. Researchers are eager to test those outcomes in the larger clinical trial.

A companion study, published concurrently by Neuroimmunology & Neuroinflammation, measured the rate of absorption and clearance of lipoic acid through periodic blood tests of pilot study participants. The results will help to inform the design of additional clinical trials.

Lipoic acid was determined to be safe and well-tolerated by pilot study participants. Stomach upset was the most frequent side effect.

Journal Reference:

Rebecca Spain, Katherine Powers, Charles Murchison, Elizabeth Heriza, Kimberly Winges, Vijayshree Yadav, Michelle Cameron, Ed Kim, Fay Horak, Jack Simon, Dennis Bourdette. Lipoic acid in secondary progressive MS. Neurology - Neuroimmunology Neuroinflammation, 2017; 4 (5): e374 DOI: 10.1212/NXI.0000000000000374

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multiple sclerosis research; gastrointestinal problems; heartburn; today's healthcare; diseases and conditions; vitamin b; medical devices; fitness

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Multiple sclerosis: Patients may benefit from over-the-counter therapy: Results will be tested in large-scale clinical trial

# data[].attributes.attachment_link.description
Over-the-counter antioxidant lipoic acid holds promise for treating patients with secondary progressive multiple sclerosis, a pilot study suggests. Researchers are using the findings from the pilot trial to design the expanded multi-site clinical trial to begin later this year in Portland and other sites that have yet to be finalized.

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Human gut microbe may lead to treatment for multiple sclerosis

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Human gut microbe may lead to treatment for multiple sclerosis

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Date:

August 8, 2017

Source:

Mayo Clinic

Summary:

A human gut microbe may help treat autoimmune diseases, such as multiple sclerosis, report scientists in a new article.

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Mayo Clinic researchers, along with colleagues at the University of Iowa, report that a human gut microbe discovered at Mayo Clinic may help treat autoimmune diseases, such as multiple sclerosis. The findings appear in Cell Reports.

While probiotics have been used for millennia, there are little data showing how a bacterium can provide benefit against a disease outside the gut. This research team tested gut microbial samples from patients on a mouse model of MS. Of three bacterial strains, they discovered that one microbe, Prevotella histicola, effectively suppressed immune disease in the preclinical model of MS.

"This is an early discovery but an avenue that bears further study," says Joseph Murray, M.D., a Mayo Clinic gastroenterologist and senior author of the article. "If we can use the microbes already in the human body to treat human disease beyond the gut itself, we may be onto a new era of medicine. We are talking about bugs as drugs." Dr. Murray coined the term "brug" to refer to this approach.

The researchers found that P. histicola, which is cultured from the human intestine, caused a decrease in two types of pro-inflammatory cells, while increasing families of cells that fight disease: T-cells, dendritic cells and a type of macrophage.

The team concludes that, in the future, this type of gut microbe may play a role in treating MS, which is caused by an attack by the immune system on the myelin sheath, a natural insulation that covers the nerves in the brain and spinal cord.

"Our work is a classic example of a bedside to bench and potentially back to bedside study. Recent MS microbiome studies have shown the lack of Prevotella genus in patients with the disease and an increase when patients were treated with disease-modifying drugs," says Ashutosh Mangalam, Ph.D., first author and assistant professor of pathology at University of Iowa Carver College of Medicine, and principal investigator of the study. "And it's not just for MS, because this may have a similar modulating effect on other nervous system and autoimmune diseases."

Journal Reference:

Ashutosh Mangalam, Shailesh K. Shahi, David Luckey, Melissa Karau, Eric Marietta, Ningling Luo, Rok Seon Choung, Josephine Ju, Ramakrishna Sompallae, Katherine Gibson-Corley, Robin Patel, Moses Rodriguez, Chella David, Veena Taneja, Joseph Murray. Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease. Cell Reports, 2017; 20 (6): 1269 DOI: 10.1016/j.celrep.2017.07.031

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immune system; diseases and conditions; lymphoma; gastrointestinal problems; multiple sclerosis; disorders and syndromes; alzheimer's; caregiving

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Human gut microbe may lead to treatment for multiple sclerosis

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Mayo Clinic researchers, along with colleagues at the University of Iowa, report that a human gut microbe discovered at Mayo Clinic may help treat autoimmune diseases, such as multiple sclerosis. The findings appear in Cell Reports. While probiotics have been used for millennia, there are little data showing how a bacterium can provide benefit against a disease outside the gut.

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Common acne medication offers new treatment for multiple sclerosis

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Common acne medication offers new treatment for multiple sclerosis

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Study results offer safe and affordable treatment option
Date:

June 1, 2017

Source:

University of Calgary

Summary:

A research team has published important research which will benefit individuals who are in the early stages of multiple sclerosis (MS). Their study results show that a common acne medication, minocycline, can help prevent MS symptoms from developing into full-blown MS in patients who are in the early stages of the disease.

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A Canadian clinical trial led by researchers at the University of Calgary's Hotchkiss Brain Institute (HBI), at the Cumming School of Medicine (CSM), shows that minocycline, a common acne medication, can slow the progress of relapsing-remitting multiple sclerosis (MS) in people who have recently experienced their first symptoms.

In addition to being an unexpected discovery -- an acne drug benefitting a neurological disorder -- the discovery is significant as it offers a safe and affordable treatment option for those with early onset MS. This discovery could impact thousands of newly diagnosed MS patients around the world.

The results of the Phase 3 clinical trial were published in the New England Journal of Medicine. The trial included 142 participants between the ages of 18 and 60 across 12 Canadian sites including: Vancouver, Burnaby, Calgary, Edmonton, Winnipeg, Ottawa, Toronto, London, Montreal, Quebec City and Halifax.

MS is thought to be an autoimmune disease of the central nervous system (brain, spinal cord). The disease attacks myelin, the protective covering of the nerves, causing inflammation and often damaging the myelin. The drug works by reducing the inflammation.

In Canada, the cost of current therapies for relapsing-remitting MS typically falls in the range of $20,000 to $40,000 per year; the minocycline treatment would cost a fraction of that at about $600 per year. In the United States, MS treatment often costs about three times as much as in Canada. Researchers say the potential cost saving will be tremendous and will improve access to treatment for people with MS.

Researchers and doctors are excited about the discovery, as there are no oral therapies approved in Canada for use at this very early stage of the disease.

The drug itself has been around for 50 years, and it doesn't need further Health Canada approval to be used as an off label prescription for MS.

"The clinical results are compelling," says HBI member Dr. Luanne Metz, the study's lead author, who is also a professor in the Department of Clinical Neurosciences at the CSM and an Alberta Health Services neurologist. "Based on these findings, neurologists will be able to prescribe minocycline for people experiencing their first symptoms of demyelination if an MRI suggests the cause will likely prove to be MS."

"Patients will now have yet another treatment option, one that does not require injections, monitoring lab work, or special authorization by their insurance company; provided they have adequate coverage to begin with. These processes can delay treatment initiation for three to four months whereas minocycline can be started immediately."

Current care for many individuals experiencing a first clinical attack suggestive of relapsing-remitting MS involves a brain MRI at about six months to determine if MS can be confirmed or treatment with injectable medications to reduce the chance that their condition will evolve to confirm MS.

"We have not cured MS, but this trial makes future treatment easy and affordable. It has global impact because there are countries where people with MS cannot be treated because of the very high cost," says V. Wee Yong, PhD, a study author from the HBI and professor in the Department of Clinical Neurosciences.

Jill, 34, experienced her first sign that she could be developing MS at 27. She woke up with tingling in her hand, the numbness spread to 50 per cent of her body before she received confirmation that lesions had formed on her brain and spine. She volunteered for the two-year clinical trial and kept taking the drug after the trial ended. "Joining the trial was an easy decision and the support I received throughout the process was excellent. I believe in research. How else are we going to learn?"

Jill is now symptom free and has not been diagnosed with MS. After being on the drug for six years, Jill consulted with her physician and decided to stop taking the medication. "It is an antibiotic, and I wanted to give my body a break from all medication. I may go back on minocycline at some point. It's great to have this option."

The trial was funded by the Multiple Sclerosis Society of Canada and its affiliated Multiple Sclerosis Scientific Research Foundation (MSSRF). Participants in the trial who were experiencing their first demyelinating symptoms were randomized to receive 100 mg twice daily of the oral minocycline or placebo. Over six months of treatment, there was a 27.6 per cent reduction of becoming full blown MS. (The risk was 61 per cent in the placebo group and 33.4 percent in the minocycline group.) This is similar to the effects of current therapies.

"This is truly a Canadian success story in research that the MS Society of Canada and MSSRF are proud to be a part of," says Dr. Karen Lee, vice president of research at the MS Society of Canada. "These are some of the world's most experienced researchers and neurologists, who have taken an idea and brought it from bench to bedside. We are very encouraged by the results of the clinical trial and pleased that people living with MS will be provided a safe and beneficial treatment option as early in the disease as possible."

This remarkable outcome for individuals experiencing demyelinating symptoms worldwide has been over 18 years in the making. Yong, a neuroscientist, initially had the idea to test the acne medicine in an animal model since minocycline has many anti-inflammatory properties that he thought could be useful in treating MS. Soon after obtaining successful research results, in studies also supported by the MS Society of Canada and MSSRF, Yong teamed up with Metz who led the transition into a pilot clinical trial, then a Phase 2, and finally the definitive Phase 3 trial. "This study highlights the benefits of evaluating existing therapies for other indications. Minocycline is an existing acne medication which is safe, and well-tolerated and it is available for immediate clinical use," says Manitoba neurologist, Dr. Ruth Ann Marrie.

"Research has a profound impact on brain and mental health care. Drs. Yong and Metz have provided a remarkable example of how new brain health knowledge can be generated when the laboratory is bridged to the clinic," says HBI Director Samuel Weiss, PhD. "This is a spectacular outcome that will positively impact people's lives worldwide -- and is a testament to the power of research excellence at the HBI and CSM."

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pharmacology; multiple sclerosis research; mental health research; diseases and conditions; mental health; depression; multiple sclerosis; alzheimer's

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Common acne medication offers new treatment for multiple sclerosis: Study results offer safe and affordable treatment option

# data[].attributes.attachment_link.description
A research team has published important research which will benefit individuals who are in the early stages of multiple sclerosis (MS). Their study results show that a common acne medication, minocycline, can help prevent MS symptoms from developing into full-blown MS in patients who are in the early stages of the disease.

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Incidence and prevalence of multiple sclerosis in the UK 1990–2010: a descriptive study in the General Practice Research Database

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Incidence and prevalence of multiple sclerosis in the UK 1990–2010: a descriptive study in the General Practice Research Database

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Background

Individuals with multiple sclerosis (MS) can experience high levels of disability and impaired quality of life for prolonged periods. The costs of the disease in the UK, including health and social care and productivity losses, are high and correlate with disease severity. It is important to have accurate and up to date information on the prevalence of MS in the UK in order to understand the impact of this disease and to ensure that adequate resources are provided nationally and regionally for people affected by MS. National studies have been carried out in the past, but recent data are lacking. To address this need, work on compiling an online national MS register began in 2011 ( http://www.ukmsregister.org). A dedicated Scottish National MS Register for incident MS cases was established in 2010.

The General Practice Research Database (GPRD) is a longitudinal database containing details of patients' demographics, medical diagnoses, referrals to consultants and hospitals, and primary care prescriptions from a representative sample of general practices in the UK. Two previous studies have used the GPRD to study the epidemiology of MS in the UK, the first reporting for the period 1993-2000. A more recent study investigated the prevalence of MS between 2000 and 2008 stratified by age, sex, geographical region and calendar year.

Methods

Study design

This was a population-based study using the GPRD. The study protocol was reviewed and approved by the Independent Scientific Advisory Committee (ISAC) of GPRD. No further ethical approval is required for studies using GPRD that do not involve patient contact.

Hypothesis

This was a descriptive study. Its aim was to estimate the incidence and prevalence of MS by age in men and women and to describe secular trends and geographic variations within the UK between 1990 and 2010.

Study population

The study population included all patients with acceptable data who contributed follow-up time to the database after 1990. GPRD defines a patient's data as unacceptable if there is evidence of poor data recording, non-contiguous follow-up or if their registration with the practice is temporary. Eligible follow-up time for each patient started with their practice's 'up-to-standard' (UTS) date or the patient's date of registration with the practice if this was later. GPRD applies standard criteria to define the date at which any individual practice's data become 'UTS' to ensure quality of data.

The first 2 years of follow-up time for each patient were treated as a screening period, and incidence and prevalence rates were calculated for follow-up time after the screening period. We chose this screening period because preliminary analyses showed that incidence rates were high in the first 2 years of follow-up and prevalence rates were low, particularly in the first year. This is probably due to inclusion of patients with prevalent disease whose initial diagnosis pre-dated the computerisation of their practice's records.

The follow-up period ended with the earlier of either their transfer-out date or their practice's last data collection date.

Outcomes

For GPRD, Read codes for confirmed diagnoses of MS (ie, codes beginning F20) were used. For Hospital Episode Statistics (HES) the International Classification of Diseases (ICD10) code for MS (G35) was used. Incident cases were defined as the first occurrence of a code for MS if it occurred after the 2-year screening period.

Statistical analysis

The analysis plan is shown in .

GPRD

For every patient, the number of days of follow-up available on the GPRD was calculated for each year from 1990 to 2010. We determined whether patients had any prior diagnosis of MS in the GPRD on the 1st January each year and, if not, whether any incident diagnosis occurred during the year.

Incidence rates were estimated from Poisson regression models with log(time at risk) as an offset variable. Prevalence rates were estimated from logistic regression models. The explanatory variables in the models were age, year and region. Geographical regions were defined as Scotland, Wales, Northern Ireland and the 10 Strategic Health Authorities of England. Data for men and women were analysed separately.

Mortality rates were analysed using logistic regression models.

Hospital episode statistics

HES data were available for about 44% of patients in the GPRD from 1997 to 2010. We estimated the prevalence and incidence of MS in these patients over this period of time using GPRD data only, as described above. We compared these rates with those calculated for the same patients using the additional diagnoses obtained from HES. Age-specific rates of under-recording of MS in the GPRD were estimated from inverse polynomials fitted to the ratios of cases identified from HES and the GPRD together versus the GPRD alone. These rates were used to adjust estimates of incidence and prevalence rates for the whole GPRD population.

Office for National Statistics

We applied these adjusted age-specific and gender-specific incidence and prevalence rates to population statistics obtained from the Office for National Statistics (ONS) for the UK population to estimate the absolute numbers of new and prevalent cases of MS in the UK population in 2010. We obtained sex-specific and age-specific mortality rates for England and Wales in 2000 and 2010 from the ONS and used them to calculate period life expectancy at birth in those years. To estimate the numbers of incident and prevalent cases of MS in the UK population in 2010 for men and women in each decade of life, we calculated incidence and prevalence rates in the entire GPRD population and applied age-specific correction factors to account for under-reporting in GP records alone. We applied the corrected rates in 2010 to the total national UK population based on ONS figures.

Results

The numbers of patients with UTS follow-up time on the GPRD increased from 1.1 million in 1990 to at least 4.0 million between 2006 and 2010. The GPRD population included about 8% of the UK population in 2010, and their age and sex distributions were similar to those of the whole population ().

Table 1

Secular trends

The prevalence of MS increased by about 2.4% per year (95% CI 2.3% to 2.6%) in men and women over the study period (A) and reached 285.8 per 100 000 in women (95% CI 278.7 to 293.1) and 113.1 per 100 000 in men (95% CI 108.6 to 117.7) in 2010. The prevalence rates that are below the trend line in the early 1990s may be an artefact due to patients being first diagnosed before their entry to the database, despite the 2-year screening period. There was no change in MS prevalence in patients below the age of 50, but annual rates of increase were over 4% in patients aged ≥60 years (B).

There was a consistent downward trend in the incidence of MS in the whole study population over the 20-year study period (A). In 2010, MS incidence in women fell to 11.52 per 100 000/year (95% CI 10.96 to 12.11) and in men to 4.84 per 100 000/year (95% CI 4.54 to 5.16). The rate of decline between 1990 and 2010 was 1.51% per year (95% CI 0.99% to 2.07%) and did not differ between men and women (p=0.682) or with age (p=0.494) (B). This implies that the female-to-male ratio among incident cases, approximately 2.4, did not change significantly over the study period.

Mortality rates fell in the GPRD population over the study period. In the 70-79-year age group, for example, they fell from 5.41% per year (95% CI 5.25% to 5.58%) in 1990 to 2.82% per year (95% CI 2.76% to 2.87%) in 2010 in men and from 3.15% per year (95% CI 3.04% to 3.26%) to 1.88% per year (95% CI 1.84% to 1.92%) in women over the same time period. Among other age groups, the proportional decline was similar. The mortality rate among patients with MS was more than twice that of other patients in all age groups and in both sexes, but also declined at a similar proportional rate.

Life expectancy rose from 75.6 to 78.3 years in men and from 79.9 to 81.8 years in women. We applied the age-specific mortality ratios for people with and without MS observed in the present study to estimate changes in life expectancies in people with MS over the same decade. They increased from 61.4 to 65.4 years in men and from 68.7 to 71.6 years in women.

Age trends

The peak incidence of MS occurred at the age of 40 years in women and 45 years in men (A), while peak prevalence rates occurred at the ages of 56 years and 59 years, respectively, (B).

Regional variation

There was significant variation in the incidence and the prevalence of MS between regions of the UK (p<0.001) (see online supplementary Figures 5a and 5b). The highest prevalence and incidence rates were observed in Scotland. Among the other 12 regions of the UK, latitude accounted for 13.8% (men) and 4.0% (women) of the variation in incidence rates, and 2.0% (men) and 0.2% (women) of the variation in prevalence rates, none of which was statistically significant.

Hospital episode statistics

Between 1997 and 2010 GPRD and HES data were available for a subset of patients (approximately 44%, ). and show the age-specific and sex-specific prevalence and incidence rates of MS in this subgroup of patients based on the GPRD alone, and the rates when the additional diagnoses recorded in HES are included. HES identified an additional 744 prevalent cases and 121 incident cases in men and 1521 prevalent cases and 227 incident cases in women. GPRD alone underestimated the prevalence of MS by 7.0% in men and 5.5% in women and incidence by 21.3% in men and 17.2% in women over the period 1997-2010. Age-specific correction factors were estimated.

Table 3

Table 4

Overall estimates of the UK MS population in 2010

shows overall estimates of the numbers of incident and prevalent cases of MS in the UK population in 2010 for men and women in each decade of life. We estimate that 126 669 people were living with MS in the UK at the beginning of 2010 (203.4 per 100 000 population) and that 6003 new cases were diagnosed during that year (9.64 per 100 000/year). Women accounted for 72% of prevalent and 71% of incident cases. We also estimated the numbers of incident and prevalent cases of MS in the four countries which comprise the UK ().

Table 5

Discussion

Principal findings of the study

We estimate that the prevalence of MS in the UK in 2010, including diagnoses obtained from HES, was 289.0 per 100 000 in women and 115.0 per 100 000 in men. The overall prevalence of MS increased by approximately 2.4% per year between 1990 and 2010 in women and men. This increase in prevalence was due to a convergence of absolute mortality rates in patients with and without MS, the result of mortality rates falling by about 3% per year in both groups. There was no change in MS prevalence in patients below the age of 50, but annual rates of increase were over 4% in patients aged ≥60 years. We observed a decline in the rate at which new cases of MS were diagnosed, and the rising prevalence rate can likely be accounted for by trends in mortality rates. There was a consistent downward trend in overall incidence of MS in the whole study population over the 20-year study period, and the rate of decline did not differ between men and women or with age. It is possible that this is due to new diagnostic techniques which reduced the risk of false positive diagnoses over the study period. The maximum incidence of MS occurred at age 40 years (women) to 45 years (men). We were not able to analyse the effects of prior pregnancy on the age of onset of MS in women in this study, although it has previously been reported that pregnancy reduces the risk of onset of MS. We found significant regional variation in incidence and prevalence rates in the UK. We found the highest incidence and prevalence rates among the 13 regions of the UK in Scotland, but no trend with latitude among the other 12 regions. This suggests that the difference between Scotland and other regions of the UK is probably not the result of a consistent trend with latitude, but may involve factors not associated with latitude. We were not able to analyse the different regions of Scotland separately using the GPRD.

Strengths and weaknesses of the study

A major strength of this study is that it covers a representative sample of GPs spread geographically throughout the UK, and a patient population with age and sex distributions similar to those of the general UK population. The study population of some 4 million patients provides greater statistical precision than earlier regional surveys. Our analyses depend upon the accuracy of diagnosis and recording of MS by GPs: there may have been miscoding of tentative MS diagnoses as definite MS cases, leading to an overestimate in the number of MS cases, or under-recording may have led to an underestimate in the number of cases. In a systematic review of 212 publications using the GPRD, Herrett et al reported that the median proportion of cases with a confirmed diagnosis based on additional internal or external validation was 89% across all disease groups and 81% for nervous system diseases but there has not yet been a validation of MS diagnoses specifically within GPRD. We addressed some of the limitations of the GPRD records by also using HES, which allowed us to estimate the extent of under-recording of MS in the GPRD.

Relation to other studies

The prevalence rates we found are slightly higher than the rates reported by Thomas et al in 2007, also using the GPRD: 281.0 per 100 000 (95% CI 273.0 to 289.0) among women and 108.0 per 100 000 (95% CI 103.0 to 113.0) among men, with the highest prevalence in those aged 55-64 years. This study and our study found maximum prevalence for MS in patients around the age of 60.

Alonso and colleagues reported incidence rates of 7.2 (95% CI 6.5 to 7.7) per 100 000 person-years in women and 3.1 (95% CI 2.6 to 3.5) in men in the UK between 1993 and 2000 in their GPRD study, which are somewhat lower than our findings. The UK has a relatively high incidence of MS compared to other countries. An overall incidence rate of MS of 3.6 per 100 000 person-years in women and 2.0 in men was reported in a review of studies of the incidence of MS published between 1966 and 2007.

The downward trend in incidence that we found is in contrast to studies in Denmark, where the female incidence of MS has almost doubled since the 1970s while male incidence has remained constant. These authors found a general, but not ubiquitous, increase in MS incidence in Western Europe and North America. However, they point out that many of the studies included only small numbers of cases and random variations may have contributed to the irregular patterns observed. Moreover, separate surveys carried out and analysed at different times may be subject to methodological differences. It is not clear why our study has detected a decreasing incidence while others have suggested increasing incidence. Changes in awareness of MS and the challenges of diagnosing MS may account for changes incidence over time. However, we could identify no specific reason why the methodology or data source we used should have had an impact on our finding of decreasing incidence of MS over the period of the study.

Sex ratio in MS

In the current study, the mean female-to-male ratio for MS was 2.4 and there was no trend with time over the 20-year study period. In their 2008 review of published studies on the incidence of MS, Alonso and Hernán reported that the female-to-male ratio increased from 1.4 in 1955 to 2.3 in 2000. This increase in the sex ratio for MS is not ubiquitous, however, and there are striking geographic variations. For example, a recent analysis of trends in the sex ratio in MS for individuals born between 1930 and 1989 found a marked increase in Northern Europe (not including the UK) (from 2.09 to 3.77), but only a moderate increase in Southern Europe (from 1.46 to 2.31). In contrast, a study in Sweden found a mean female-to-male ratio for MS of 2.62, with no clear trend with year of birth for individuals born between 1931 and 1985. A recent review reported a significant increase in the MS prevalence female-to-male sex ratio in the UK between 1949 and 2009-a much longer time period than our study. It is possible that this historical trend in female-to-male sex ratio for MS has now stabilised. This may be partly accounted for by changing health-related behaviours of men in recent years, perhaps having more contact with medical services than was the case historically. We are not able to identify any particular reason why the study methodology or data source could have confounded our findings regarding sex-ratio.

Regional variations in MS

A recent study using HES data for the period 1999-2005 showed regional variations in hospital admission rates for MS in England. This study found significantly higher MS admissions in more northern regions of England even after adjusting for social deprivation and UK birthplace. Early studies on MS suggested a trend with latitude with increasing prevalence in more temperate climates in Northern and Southern hemispheres. However, the idea that there is a relationship between latitude and MS incidence or prevalence in Western Europe has been dismissed recently by some authors. In contrast, Simpson and colleagues reported that there was a statistically significant positive association between MS prevalence and latitude globally, although there were some exceptions to the latitudinal gradient in some parts of Europe.

Regional variation in MS epidemiology may be due to genetic or environmental factors and interactions between them. A study in Ireland found that the HLA DRB1*15 allele associated with MS susceptibility is more common in areas of higher prevalence. The exact role of such factors in the epidemiology of MS remains to be ascertained. One recent study found that the distribution of HLA DRB1 accounted for 52% of the variation in MS prevalence by latitude in Europe, whereas another study suggested that non-HLA DRB1 factors play an important role in regional MS variations in Europe. For example, it has been suggested that lack of vitamin D may increase susceptibility to MS. This is supported by studies on the effect of month of birth on subsequent risk of MS in Northern and Southern hemispheres. Vitamin D also reversibly blocks the progression of experimental autoimmune encephalomyelitis, a mouse model of MS. Further evidence comes from a recent genetic study which demonstrated a causative role for the CYP27B1 gene, which encodes the vitamin D-activating 1-α hydroxylase enzyme. Such factors may have a role in increasing the incidence of MS in Scotland relative to other parts of the UK. Further studies are needed to investigate the causative factors of MS, particularly the role of Vitamin D, genetic susceptibility factors and infective agents.

Conclusions

This study provides a comprehensive picture of the prevalence and incidence of MS throughout the UK over two decades. It shows that more than 6000 people in the UK were newly diagnosed with MS in 2010 and that patients with MS are living longer, leading to a rising population living with the disease. This has important implications for resource provision in the UK.

Footnotes

Contributors: All authors were involved in drafting and reviewing the manuscript. Statistical analysis was carried out by SVM. The guarantor for the study is ISM.

Funding: This study was funded by a grant from the Multiple Sclerosis National Therapy Centres (MSNTC), Registered Charity No.1 031 690. This grant supported study meetings but MSNTC had no input into the design of the study, collection, analysis or interpretation of the data or in the decision to submit the paper for publication.

Competing interests: All authors have completed the Unified Competing Interests form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that (1) the authors have no support from any company for the submitted work; (2) JOR has been involved as principal investigator in clinical trials, a consultant on advisory boards and invited guest speaker for Biogen Idec, Merc Serono, Bayer Schering, Teva Pharmaceuticals and Novartis; TM has been a consultant on advisory boards for Novartis in the area of multiple sclerosis and has other potential competing interests but not in this therapeutic area; IM holds research grants from Novartis and Menarini in different therapeutic areas; GB and SM have no specified relationships with companies that might have an interest in the submitted work in the previous 3 years; (3) the authors' spouses, partners or children have no financial relationships that may be relevant to the submitted work; (4) GB was a trustee of MSNTC from June 2008 to June 2012 and now acts as a consultant for MSNTC (both positions were unpaid). The other authors have no non-financial interests that may be relevant to the submitted work.

Ethics approval: ISAC approval.

Provenance and peer review: Not commissioned; externally peer reviewed.

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Research paper: Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research Database

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To estimate the incidence and prevalence of multiple sclerosis (MS) by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 and hence to provide updated information on the impact of MS throughout ...

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PMC: Multiple Sclerosis and Risk of Infection-Related Hospitalization and Death in US Veterans

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PMC: Multiple Sclerosis and Risk of Infection-Related Hospitalization and Death in US Veterans

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This study provides evidence that VA patients with MS are more likely than those without MS to be hospitalized and die of infection.

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From ECTRIMS: New Results on Gut Bacteria and MS

The ECTRIMS meeting has been a great place to connect with researchers on what's truly exciting in MS research. I've especially enjoyed hearing about an area of investigation that is moving forward quickly - from initial observations toward treatments or solutions for people with MS. From what I've heard this week, researchers who are looking at the gut microbiome and its role in the MS immune attack are doing just that. Feel free to browse the abstracts (summaries of conference presentations) here.

Drs. Yan Wang, Lloyd Kasper and colleagues from Dartmouth Medical School and Eastern Washington University built on previous work, which had shown that modulating gut bacteria during MS-like disease in mice induced specific immune cells (called Bregs - or regulatory B cells), and these Bregs reduced disease severity. At ECTRIMS, they reported that treating mice with the gut-related molecule called polysaccharide A (PSA) expanded Bregs; these cells promoted an immune response that prevented the mice from getting MS-like disease. PSA is released by specific species of gut bacteria (Bacteroides) that "colonize" the guts of almost 95% of people worldwide. Partly funded by the National MS Society, this exciting work brings us one step closer to future clinical studies to explore how PSA may help to stop the immune attack in people with MS. (Abstract 181) Members of this team also reported that PSA was effective in mice with progressive MS-like disease. (Abstract P465)

Drs. Egle Cekanaviciute, Sergio Baranzini and other collaborators in the MS Microbiome Consortium are rigorously analyzing gut bacteria to unearth clues about MS susceptibility and progression. At ECTRIMS, they reported on an analysis of 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 T helper 1 (Th1) cells - major players in the MS immune attack. Meanwhile, another type of bacteria - which was reduced in people with MS - induced cells that could turn down the immune attack. (Abstract 179) If we can pinpoint certain bacteria that may drive immune system activity in MS and others that can suppress it, this research may open the door to novel therapeutic approaches based on manipulating these gut bacteria.

Young investigator Dr. Gloria Dalla Costa and colleagues from San Raffaele Hospital in Milan showed that Th17 cells, important culprits in the MS immune attack, are increased in the intestinal lining of people with MS compared with people who do not have the disease. Their next goal is to determine how manipulating gut bacteria or diet might affect the generation of these intestinal Th17 cells, and the development of MS. (Abstract 73)

The interaction between the gut and the immune attack in MS may begin quite early, says Dr. Helen Tremlett (University of British Columbia) and collaborators from the U.S. Network of Pediatric MS Centers. They examined gut bacteria and immune markers in 15 children with MS and nine children without MS. In children with MS, they found links between types of gut bacteria and specific immune markers. For example, increases in Bacteroides meant decreases in Th17 cells, which are thought to help drive attacks. (Abstract P287) Studying MS in this early stage is important to identify the first steps of gut microbiome involvement in MS.

The microbiome is a relatively new area of research for the MS community - but I'm excited to see how far this field has come in a short amount of time. I'm eager for this progress to be propelled into treatments and solutions that will stop the disease.

1 Appreciate this

Elisabeth Mari, PhD

Dr. Elisabeth Mari is Director of Biomedical Research at the National MS Society. Her responsibilities include supporting the Society's biomedical research grant portfolio and the International Progressive MS Alliance. An immunologist by training, she attended the University of Delaware and then earned her PhD at Imperial College London. Dr. Mari did a postdoctoral research fellowship at Thomas Jefferson University in Philadelphia. She joined the Society in 2016 and brings over 13 years of experience in biomedical research.

From ECTRIMS: New Results on Gut Bacteria and MS

The ECTRIMS meeting has been a great place to connect with researchers on what's truly exciting in MS research. I've especially enjoyed hearing about an area of investigation that is moving forward quickly - from initial observations toward treatments or solutions for people with MS. From what I've heard this week, researchers who are looking at the gut microbiome and its role in the MS immune attack are doing just that. Feel free to browse the abstracts (summaries of conference presentations) here.

Drs. Yan Wang, Lloyd Kasper and colleagues from Dartmouth Medical School and Eastern Washington University built on previous work, which had shown that modulating gut bacteria during MS-like disease in mice induced specific immune cells (called Bregs - or regulatory B cells), and these Bregs reduced disease severity. At ECTRIMS, they reported that treating mice with the gut-related molecule called polysaccharide A (PSA) expanded Bregs; these cells promoted an immune response that prevented the mice from getting MS-like disease. PSA is released by specific species of gut bacteria (Bacteroides) that "colonize" the guts of almost 95% of people worldwide. Partly funded by the National MS Society, this exciting work brings us one step closer to future clinical studies to explore how PSA may help to stop the immune attack in people with MS. (Abstract 181) Members of this team also reported that PSA was effective in mice with progressive MS-like disease. (Abstract P465)

Drs. Egle Cekanaviciute, Sergio Baranzini and other collaborators in the MS Microbiome Consortium are rigorously analyzing gut bacteria to unearth clues about MS susceptibility and progression. At ECTRIMS, they reported on an analysis of 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 T helper 1 (Th1) cells - major players in the MS immune attack. Meanwhile, another type of bacteria - which was reduced in people with MS - induced cells that could turn down the immune attack. (Abstract 179) If we can pinpoint certain bacteria that may drive immune system activity in MS and others that can suppress it, this research may open the door to novel therapeutic approaches based on manipulating these gut bacteria.

Young investigator Dr. Gloria Dalla Costa and colleagues from San Raffaele Hospital in Milan showed that Th17 cells, important culprits in the MS immune attack, are increased in the intestinal lining of people with MS compared with people who do not have the disease. Their next goal is to determine how manipulating gut bacteria or diet might affect the generation of these intestinal Th17 cells, and the development of MS. (Abstract 73)

The interaction between the gut and the immune attack in MS may begin quite early, says Dr. Helen Tremlett (University of British Columbia) and collaborators from the U.S. Network of Pediatric MS Centers. They examined gut bacteria and immune markers in 15 children with MS and nine children without MS. In children with MS, they found links between types of gut bacteria and specific immune markers. For example, increases in Bacteroides meant decreases in Th17 cells, which are thought to help drive attacks. (Abstract P287) Studying MS in this early stage is important to identify the first steps of gut microbiome involvement in MS.

The microbiome is a relatively new area of research for the MS community - but I'm excited to see how far this field has come in a short amount of time. I'm eager for this progress to be propelled into treatments and solutions that will stop the disease.

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Elisabeth Mari, PhD

Dr. Elisabeth Mari is Director of Biomedical Research at the National MS Society. Her responsibilities include supporting the Society's biomedical research grant portfolio and the International Progressive MS Alliance. An immunologist by training, she attended the University of Delaware and then earned her PhD at Imperial College London. Dr. Mari did a postdoctoral research fellowship at Thomas Jefferson University in Philadelphia. She joined the Society in 2016 and brings over 13 years of experience in biomedical research.

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From ECTRIMS: New Results on Gut Bacteria and MS: MS Connection

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From ECTRIMS: New Results on Gut Bacteria and MS The ECTRIMS meeting has been a great place to connect with researchers on what's truly exciting in MS research.