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Unique type of immune cell contributes to multiple sclerosis (MS

Researchers at the National Institutes of Health have found evidence that a unique type of immune cell contributes to multiple sclerosis (MS). Their discovery helps define the effects of one of the newest drugs under investigation for treating MS — daclizumab — and could lead to a new class of drugs for treating MS and other autoimmune disorders.
In these disorders, the immune system turns against the body's own tissues. Ongoing clinical trials have shown that daclizumab appears to help quiet the autoimmune response in MS patients, but its precise effects on the legions of cells that make up the immune system are not fully understood.
The new study, published in Science Translational Medicine, shows that one effect of daclizumab is to thin the ranks of lymphoid tissue inducer (LTi) cells. These cells are known to promote the development of lymph nodes and related tissues during fetal life, but their role during adulthood has been unclear. The new study marks the first time that LTi cells have been implicated in any human autoimmune disorder.
"While further study is required to confirm the role of LTi cells in autoimmunity, our results point to the cells as a promising target for the development of new drugs to treat autoimmune disorders," said Bibiana Bielekova, M.D., an investigator at NIH's National Institute of Neurological Disorders and Stroke (NINDS).
Dr. Bielekova and her team found that among MS patients participating in clinical trials of daclizumab, the number of LTi cells was elevated in patients not receiving daclizumab compared to those on the drug. Patients receiving daclizumab also had reduced signs of inflammation in the cerebrospinal fluid (CSF) that surrounds the brain. And the researchers found that daclizumab appears to steer the body away from producing LTi cells, in favor of another cell type that counteracts autoimmunity.
In MS, the immune system attacks myelin, a material that insulates nerve fibers running throughout the brain and spinal cord. This typically leads to vision loss, and other sensory changes such as numbness and tingling, weakness, and fatigue. The disorder affects approximately 400,000 people in the United States. In about 85 percent of patients, MS starts as a relapsing-remitting form, in which symptoms come and go. Many patients eventually develop secondary progressive MS, in which symptom flare-ups are followed by worsening disability. Many medications are available to decrease the number of flare-ups, but no medication is effective at slowing the course of progressive MS.
The newer, sophisticated drugs for relapsing-remitting MS target key cells and molecules responsible for triggering and maintaining autoimmunity. Cytotoxic T cells, the immune system's specialized mobile infantry, are known to lead the attack. Antibodies, the immune system's guided missiles, appear to help reinforce it.
Daclizumab is a lab-engineered antibody, or monoclonal antibody, that alters signaling by interleukin-2 (IL-2), a key factor that mobilizes T cells. In a large clinical trial (NCT00109161), it has shown promise as an add-on therapy for patients taking the approved MS drug interferon-beta. Another ongoing trial (NCT00390221) is investigating whether or not daclizumab is effective as a stand-alone therapy for reducing relapses in MS.
The drug was designed to suppress T cell responses to IL-2, and it does so — but Dr. Bielekova had found previously that this suppression is indirect and depends on other immune cells. For example, one effect of daclizumab is to stimulate the non-specialized counterparts of T cells, called natural killer cells. These cells in turn suppress T cell activity.
In their new study, Dr. Bielekova and her team discovered that daclizumab's stimulatory effect on natural killer cells is paired with an inhibitory effect on LTi cells. They found evidence that the drug, via its effects on IL-2 signaling, acts on a type of stem cell. The drug appears to decrease the likelihood that this stem cell will develop into LTi cells, and sway it toward becoming natural killer cells.
"This helps explain why natural killer cells are activated and their numbers are expanded by daclizumab therapy," Dr. Bielekova said. Meanwhile, she said, the drop in LTi cells was "intriguing" in itself, given the cells' role in lymph node development.
Lymph nodes — found conspicuously in the armpits, neck and groin — are patches of tissue where T cells and antibody-producing B cells set up camp. Inside the nodes, T cells and B cells are found in clusters called lymphoid follicles, where they wait for a signal that the body is under siege from infection. In autoimmune disorders, abnormal lymphoid follicles can develop and contribute to the autoimmune response. Secondary progressive MS, in particular, is associated with abnormal lymphoid follicles in the connective tissues (or meninges) surrounding the brain. These are believed to contribute to chronic brain inflammation in MS, eventually leading to shrinkage of the brain.
Dr. Bielekova and her team reasoned that daclizumab, by suppressing LTi cells, should reduce the growth of lymphoid follicles. Since it is not possible to visualize these follicles in the live brain, the researchers measured the effects of daclizumab on markers of inflammation in the CSF. They found that CXCL13, a protein linked to lymphoid growth, and the IgG index, a measure of antibody production, decreased by an average of 50.4 percent and 13.5 percent, respectively, in trial participants who took the drug for six and half months.
"To our knowledge, no other MS therapy reduces IgG index," Dr. Bielekova said.
She cautioned that these data provide only an indirect link between LTi cells and brain inflammation in MS. If further research confirms that the cells play an important role in MS or other autoimmune disorders, "pursuing the development of new drugs to selectively inhibit LTi cells could be a useful therapeutic strategy," she said.
This study was funded by the NIH-NINDS intramural research program. The lead authors were Justin Perry and Sungpil Han. Mr. Perry was a fellow in NIH's Postbaccalaureate Intramural Research Training Award program, and is currently a Ph.D. student in the neuroscience program at Washington University in St. Louis. Mr. Han is an M.D.-Ph.D. student at Pusan National University in South Korea, and is supported in part by a fellowship from the Korea Research Foundation to study at NIH. Patient data were derived from a small completed trial (NCT00071838) which showed that daclizumab may reduce lesions in relapsing-remitting MS, and from an ongoing trial to investigate the drug's mode of action (NCT01143441).
NINDS (http://www.ninds.nih.gov) is the nation’s leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease – a burden borne by every age group, by every segment of society, by people all over the world.

Nickum's Nook: THE PATH vol.2, number 1

Nickum's Nook: THE PATH vol.2, number 1:                                   TABLE OF CONTENTS                              Volume 2, Number 1   Summer, 2012 D. E. Z. Butl...

Mom's Story

I am working on a second edition of Mom's Story, A Child Learns About MS. It will be at Amazon this fall.

Mom's Story

I am working on a second edition of Mom's Story, A Child Learns About MS. It will be at Amazon this fall.

Aimspro - Oxford Optic Neuritis Trial

Dramatic Improvement’ in Eyesight Problems with Aimspro

The results of the optic neuritis trial in Oxford are very good. Patients’ vision improved significantly following treatment with Aimspro.

The Multiple Sclerosis patients who took part in the double blind trial at the John Radcliffe Hospital showed improvement in visual field scores over a two week course of treatment.

These highly significant improvements in the patients’ sight were observed after only three injections, so the possibility of a placebo effect was excluded. There were no side effects.

This is the first time that any treatment has been shown conclusively to reduce an aspect of disability in the chronic phases of MS to this degree.

Dr BryanYoul, a consultant in Clinical Neurophysiology at the Royal Free Hospital in London, whose own findings on Aimspro in MS and other neurological conditions are about to be published, said: “These trial results are hugely significant and have wider implications for the treatment of MS."

U.S. Supreme Court rules on the Patient Protection and Affordable Care Act

The National Multiple Sclerosis Society supports the decision of the United States Supreme Court regarding the Patient Protection and Affordable Care Act.  This ruling will have a significant, positive impact on many, including the millions of Americans affected by multiple sclerosis. 

Below are some of the provisions of the law that the National MS Society believes will have the biggest impact on people with MS and their families:

• Prohibition of coverage denials based on pre-existing conditions:  Too many people living with MS had been routinely denied insurance after receiving their diagnosis, preventing them from getting the care they need.
• Prohibition of lifetime limits:  Routine, often costly care is needed to manage MS. This may cause those living with severe forms of the disease to reach their lifetime limit early in life. Elimination of that limit was critically important for continued care.
• Elimination of annual limits:  Similar to “lifetime limits,” many patients reach their annual limit of coverage because of the cost of care for MS. These arbitrary limits should not prevent those in need from receiving care. 
• Extension of parent’s insurance to 26:  Many people with MS are diagnosed in their 20s and may still be in school or lacking a full time job to help pay for their care. This provision ensures that they can continue coverage under their parent’s policy.
• Closing the Medicare Part D Coverage Gap:  Disease Modifying Therapies for someone with MS can cost as much as $4,000 per month, which is out of reach for the average American; therefore, gradually closing the coverage gap has provided financial relief for those who depend on Medicare for prescription coverage.
• Pathway for Biosimilars:  The law provides a pathway for biosimilars which provides some hope of lower cost therapies in the future.  The FDA had recently indicated it would not have pursued this pathway without the legislative mandate therefore, it will continue to be developed--which is good news for anyone who uses biologic therapies.

Study Identifies Gene Linked to Vitamin D Deficiency

A recent study at Oxford University in England and published in Annals of Neurology, has identified a gene that causes vitamin D deficiency, a condition suspected of having a role in the development of MS.
The study examined the DNA of a group of people with MS who also have a large number of family members with the disease. All the DNA samples showed a distortion of the CYP27B1 gene which controls vitamin D levels in the body. And in a few rare cases where the DNA showed two copies of the distorted gene, the person was found to have a genetic form of rickets caused by vitamin D deficiency as well as MS.
The cause of myelin damage related to MS is still hotly debated: some believe it to be an autoimmune disease while others cite viruses or the environment as the culprit. There is growing evidence however of a correlation between MS and vitamin D deficiency. Epidemiological studies also show that populations closer to the equator and the sun, have far fewer case of MS than populations closer to the north or south poles. Researchers at Oxford University have now taken this premise a step further by showing that vitamin D deficiency and therefore possibly MS could have a genetic cause.
Despite this pivotal link, not all people with vitamin D deficiency develop MS. More research is needed to fully understand why. However, a distortion of the CYP27B1 gene is increasingly apparent in MS cases and it’s possible that the gene generates other, yet undetected, complications that lead to the disease—such as genetically caused rickets.
“Although vitamin D deficiency doesn’t always cause MS, it unveiled a critical genetic source that could be causing other problems that lead to MS,” says Jeffrey Epstein, whose foundation partially supported the study. “Even if we don’t understand all of the implications of that gene’s distortion, research can focus on gene therapy, and that will accelerate a cure.”
The study was partly funded by the National Multiple Sclerosis Society, The Wellcome Trust and the support of science investor, Jeffrey Epstein and The Jeffrey Epstein VI Foundation.

Teriflunomide Pill Reduces Relapses

In a clinical trial involving 1,169 people with relapsing-remitting multiple sclerosis, oral teriflunomide (Genzyme/Sanofi-Aventis) reduced relapses compared with placebo over at least 48 weeks, according to a company press release dated June 1, 2012. Of two different doses tested during the TOWER trial, the higher dose also slowed progression of disability. This is the third completed of five phase III studies involving teriflunomide in multiple sclerosis. An application for marketing approval of teriflunomide was accepted for review by the U.S. Food and Drug Administration in October 2011.

New blog for Mom's Story

Please visit my new Mom's  Story blog at: http://wp.me/P2l34j-l

Please follow me...

Mom's Story and multiple sclerosis has moved to: http://momsstoryandmultiplesclerosis.com/. Please follow me at the new blogsite.

National MS Society-funded study suggests balance/ eye movement training improves fatigue, balance and other symptoms in people with MS

A recent controlled study suggests that a 6-week balance and eye movement-focused exercise program improved balance, reduced fatigue, and reduced disability due to dizziness or disequilibrium in a group of people with MS, lasting for at least 4 weeks following supervised training. Larger and longer studies are needed to determine how long the benefits last, and which people with MS would be most likely to respond to the training program. The study, by Jeffrey Hebert, PT, PhD (University of Colorado, Aurora) and colleagues, was reported in the journal Physical Therapy in August, 2011 and was partially funded by a pilot research grant from the National MS Society.


Background: Fatigue and impaired balance are two common and troublesome symptoms experienced by people with MS. Current treatments vary greatly in effectiveness. This study is the first to examine the effects of an exercise program involving balance and eye movement training – or “vestibular rehabilitation” -- in people with MS to see if it improves both fatigue and balance.

The study: For this controlled study, 38 people with MS were divided into three groups: one group did not participate in an exercise program and only received normal MS medical care; one group participated in a general exercise program involving endurance and stretching; and one group participated in the vestibular rehabilitation program specifically designed to improve balance. The endurance and stretching exercises included bicycle riding and exercise designed to stretch various muscles. The vestibular rehabilitation program included balance exercises on various surfaces (firm surface, foam cushion, trampoline, tiltboard), arm movements while kneeling, head movements on a trampoline and while fixating on different objects, ball catching while walking. The vestibular rehabilitation program also included 3 types of eye movement exercises. Both exercise programs were performed for 60 minutes twice a week in the clinic. A daily home exercise program, consisting of a subset of exercises performed in the clinic, was also assigned to each participant. The exercise training programs lasted for 6 weeks.


Effects on balance, fatigue, dizziness/equilibrium, depression, and walking ability were examined at the end of the 6 weeks and also 4 weeks after the exercise program had ended. At the end of the 6-week period, the group that underwent the vestibular rehabilitation program showed improved balance, reduced fatigue, and reduced disability due to dizziness or disequilibrium. Depression and walking ability were minimally improved. Neither of the control groups showed improvement in balance, fatigue, or dizziness/disequilibrium disability. Four weeks after the exercise program ended, those in the vestibular rehabilitation program group continued to show benefit.

It should be noted that in this study, the bicycle riding was not designed as an aerobic exercise, and thus these findings do not counter prior research studies that have shown benefits of aerobic exercise on MS fatigue. In their paper, the researchers suggest that the vestibular rehabilitation program reteaches the brain how to maintain balance when performing activities during standing or walking, after such abilities are impaired by MS, leading to improved balance, fatigue and dizziness.

Future studies should include more participants and a longer follow-up to determine how long the benefit lasts and which people with MS would most likely respond to this program. Proposals for these investigations are underway.

Based on these preliminary results, balance and eye movement training may help people with MS who are experiencing fatigue and balance problems. Those wishing to explore this option should consult with their neurologists, local rehabilitation facilities or hospitals to see whether this type of training is available.

Study: Woman’s Risk of Having a First Neurologic Event, Which Often Leads to MS, Decreased with Increased Number of Pregnancies

Women’s risk for developing clinically isolated syndrome, which often leads to multiple sclerosis, was shown to decrease with increased number of pregnancies in a comprehensive study undertaken in Australia. Clinically isolated syndrome (CIS) is a first neurologic episode caused by inflammation or damage to nerve fiber-insulating myelin in the brain or spinal cord. Although the results of this Ausimmune Study need to be confirmed, the findings encourage further exploration of potential treatments such as sex hormones, which may mimic pregnancy’s benefits in women with MS. The sex hormone estriol is currently in clinical trials, supported by the National MS Society and the National Institutes of Health, to treat women MS.


Anne-Louise Ponsonby, PhD (Murdoch Childrens Research Institute, Melbourne) and colleagues across Australia report their findings in Neurology (2011;76:540-548). This study was supported by a research grant from the National MS Society to Anthony McMichael, PhD, the National Health and Medical Research Council of Australia, and MS Research Australia.

Background: Before 1950, most women with MS were counseled to avoid pregnancy because of the belief that it might make their MS worse. Over the past 40 years, studies in hundreds of women with MS have almost all reached the opposite conclusion: that pregnancy reduces the number of MS exacerbations, especially in the second and third trimesters.

The Ausimmune Study was undertaken to investigate whether increased exposure to sunlight and vitamin D may be protective against MS in people who had not yet been diagnosed with MS, but who had experienced a CIS. Read more about previously released findings. In the current study, the team used this unique population to study whether the number of pregnancies or offspring affects the risk for developing a CIS.

The Study: Investigators looked at the records of 282 men and women who had developed a CIS, and compared the number of children – and in women, the number of pregnancies – with controls who did not develop CIS.

Women who had one pregnancy were nearly half as likely to develop CIS, and those with three or more pregnancies had more than one fourth the risk of developing CIS compared with controls. Other factors considered – such as sun exposure and immune-system-related genes associated with MS – did not otherwise explain these associations. There was no association between risk of CIS and the number of children in men.

Comment: In an accompanying editorial, Martin Daumer, PhD, Brian G. Weinshenker, MD, and Rhonda Voskuhl, MD, comment that these findings need to be replicated in other countries to be validated, and caution that the study does not address whether pregnancy affects the long-term course of MS or development of disability.

Even with these caveats, the editorial authors say that because of studies such as this one, there is a compelling need for research to develop therapeutic approaches that mimic pregnancy’s benefits in women with MS. Dr. Voskuhl is now leading a team of investigators at seven medical centers to conduct a two-year, controlled clinical trial of estriol – a sex hormone that is increased during pregnancy – added to standard therapy to treat MS in 150 women with relapsing-remitting MS. This study recently completed enrollment.

This study provides additional evidence of a link between gender and autoimmunity. Read more about the Society’s efforts to study this link for clues to stopping MS in its tracks and ending it forever.

New Drugs Raise Hope for Patients With M.S.

.By LAURIE TARKAN



 Three years ago, Kristie Salerno Kent, a singer-songwriter, was standing in a security line at the airport on her way home from a gig when her legs went numb. “From the waist down, it felt as though I was trying to walk through a bowl of oatmeal,” said the 38-year-old musician, who has multiple sclerosis.

She inched her way to a security officer, who called for a wheelchair and helped remove her shoes and belt to get her through security. Frightened and embarrassed, she was taken to her gate in a wheelchair.

Three months later, she experienced another flare-up. While giving a live television interview about a short film she had made on living with M.S., she suddenly lost her ability to speak. “It was as if my mouth was packed with marbles,” she said. “I kept trying to say, ‘I’m sorry,’ to the reporter, but nothing came out that made sense.”

The medication she was taking to prevent these attacks was losing its effect, so her doctor suggested she switch to Tysabri, one of the newer, more potent “disease-modifying drugs,” which reduce the severity and frequency of relapses. She also began taking Ampyra, which early last year became the first drug approved to treat any M.S. symptom. She hasn’t had a flare-up since.

After decades of basic research on M.S., the last five years have brought a rapid rollout of new and sophisticated drugs that are changing how this disease is managed and offering patients new hope.

“We have a disease that’s gone from having no treatments 20 years ago to having multiple treatment options,” said Dr. Timothy Coetzee, the chief research officer at the National Multiple Sclerosis Society. “There is a growing recognition that M.S. is becoming a manageable disease.”

In M.S., the body’s immune system damages neurons in the brain and spinal cord, attacking the myelin sheath that insulates these nerves. About 85 percent of patients start out with what is called relapsing-remitting M.S., characterized by flare-ups or attacks that cause lesions to form on the brain and that affect the ability to walk, to see and to control the bladder, among other neurological impairments.

These attacks are short-lived, and patients typically recover from them. But more than half of patients eventually develop a progressive form of M.S., causing the permanent loss of these functions.

Once that happens, many of the treatments are ineffective. But the new drugs may slow, perhaps even prevent, the progression that was once considered inevitable for many patients.

“The drugs we now have are shifting what the natural history of the disease looks like,” said Dr. Coetzee.

Doctors can now choose from eight disease-modifying drugs, which reduce relapses and thereby slow the progression of the disease. Some of the drugs also prevent brain neurons from dying off, now thought to be a major cause of permanent disability.

There have also been advances in treating specific symptoms of M.S. Within the past two years, three medications have been approved specifically for M.S. symptoms: Ampyra to improve walking, Nuedexta for uncontrollable laughing or crying, and Botox for urinary incontinence and spasticity in upper limbs.

“We’re shooting for disease-free status, where someone with M.S. is on a medicine and has no sign of M.S.,” said Dr. Richard Rudick, director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

The first generation of M.S. drugs included mostly immune-suppressing interferons delivered via injection or infusion. These are still the most widely used, reducing relapses by about one-third. The new drugs are more sophisticated, targeting specific molecules involved in the disease, rather than simply tamping down the immune system to reduce inflammation in the brain.

Just last year, the first oral drug for M.S., Gilenya, gained approval with data showing it cut the relapse rate by 55 percent. Gilenya causes inflammatory cells called lymphocytes to get trapped in lymph nodes so they don’t travel to the brain, where they would damage neurons.

Patients need to be monitored for several potentially serious side effects, including a slowed heart rate and liver and vision problems. One patient recently died 24 hours after starting on Gilenya; the Food and Drug Administration is investigating the cause of the death.

The most potent drug, Tysabri, reduces the relapse rate by about 70 percent, but it comes with a small risk of a fatal brain infection caused by a common virus. Patients may be screened for antibodies to the virus; the risk of infection is considered quite low in those with no sign of the antibodies, and they are given the drug.

At least four other drugs with different mechanisms are in Phase 3 clinical trials and could win approval within the next year, experts say. Some work by protecting nerves from damage.

“There’s a lot of focus on developing drugs that inhibit or stop this neurodegeneration, which we believe is the underlying cause for difficulty walking, leading people to require a wheelchair,” said Dr. Rudick.

One of the new neuroprotective drugs, called BG-12, captured wide attention at an annual international conference on M.S. in Amsterdam in October. Researchers reported a 53 percent reduction in relapses in patients taking it and a greater than 30 percent reduction of permanent disability progression over a two-year period. It also appears to have fewer risks than equally potent drugs like Gilenya.

“This might be the drug that would completely displace the interferons,” said Dr. Timothy L. Vollmer, director of neurology clinical research at the University of Colorado.

Although many doctors start patients on interferons first because of lower risks, there is a growing recognition that treating patients aggressively and early with the newer medications can preserve brain neurons and possibly prevent the progression of the disease.

But treating M.S. is still difficult. Many treatments come with serious side effects and other risks, and some people simply don’t respond to them. Patients progress at different rates, and the symptoms vary from one patient to another. Some people cannot tolerate certain medications.

“The biggest frustration is the huge uncertainty,” said Dr. Jerome J. Graber, an assistant professor of neurology at Montefiore Medical Center in the Bronx. “I still can’t predict who will progress and what’s the best way to treat someone.”

Still, some patients are beginning to see a more hopeful prognosis. After Ms. Salerno Kent started taking Tysabri and Ampyra, her walking improved enough for her to go hiking with husband and son, her speech issues resolved, and she felt much more confident when singing on stage.

“We have so many more options now, and I realize that we no longer have to give up the quality of life because we have M.S.,” she said. “We’ve always expected to deteriorate with time, but I realize that this is not acceptable anymore.”

Virtual Insight Panel

WEGO Health will be hosting a sponsored virtual Insight Panel for active members of the online Multiple Sclerosis (MS) Community. This panel will focus on the needs of the online community and review of Multiple Sclerosis tools and resources. All participants will receive a $25 Amazon.com gift card for their participation. http://bit.ly/ppYhDf

ABC News highlights treatment advances for MS

ABC News highlights treatment advances for MS. Watch the video (.wmv) and Read the article http://abcnews.go.com/Health/Wellness/multiple-sclerosis-sees-explosion-treatment-advances/story?id=15290688