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Neurology Now:
doi: 10.1097/01.NNN.0000453357.55519.37
Departments: New Frontiers

Making Progress on MS: A statin slows brain atrophy in secondary-progressive multiple sclerosis.

Dolan, Darrach

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High doses of the widely used drug simvastatin (brand name Zocor) slowed brain atrophy—defined as a decrease in brain volume—in patients with secondary progressive multiple sclerosis (MS) by 43 percent, according to results of a study published in the medical journal The Lancet on March 19, 2014. (Simvastatin is one of several statins, a class of drugs used to lower cholesterol.) This is the first time a treatment has been shown to slow the course of secondary progressive MS. (See box, “Multiple Sclerosis: The Basics” for a description of the different forms of MS.)

“The study suggests that we may be able to slow down secondary-progressive MS,” says co-author Richard Nicholas, MD, an MS researcher at Imperial College, London. “When we designed this study, we thought, ‘Simvastatin is a relatively safe drug that patients with secondary-progressive MS could potentially take at the beginning of their illness.’ Treatment with simvastatin had a small but significant effect over two years. Over 10 or 20 years, it may make a bigger difference—and the drug has already been used safely over that length of time.”

The study was a randomized, double-blind, placebo-controlled trial involving 140 patients aged 18–65 over two years. (In a randomized, placebo-controlled trial, participants are assigned randomly to receive either the treatment or a placebo, which looks just like the treatment but has no active ingredients.) Patients were assigned to receive either 80 mg simvastatin or a placebo.

“If these results can be replicated in future trials, this may be a glimmer of hope that the disease course of secondary-progressive MS is treatable,” says Richard M. Ransohoff, MD, director of the Neuroinflammation Research Center at the Cleveland Clinic Lerner Research Institute, staff neurologist at the Cleveland Clinic's Mellen Center for MS Treatment and Research, and professor of molecular medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

Before the 1990s, treatments were available only for the symptoms of relapsing-remitting MS, similar to the current situation for progressive forms of MS. “Before the advent of immune-modulating drugs, only 40 percent of people with MS would still be at work four years after diagnosis,” Dr. Nicholas says.

But in the early 1990s, treatment for people with relapsing-remitting MS was revolutionized with the introduction of drugs such as beta-interferons and glatiramer acetate (and later, natalizumab and fingolimod). These drugs are immune modulating, which means they adjust the activity of the body's immune system to a desired level.

“Relapsing-remitting MS is now treatable. For many people, it's a manageable condition,” says Dr. Ransohoff. The hope is that a similar revolution may occur in treatment for the other forms of MS.

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BRAIN SHRINKAGE

“Preserving brain volume is associated with clinical benefit,” says Timothy Vollmer, MD, professor and director of clinical research at the University of Colorado School of Medicine. Recent data has shown that shrinkage of brain volume is the best predictor of disease progression and disability in MS. “Decreased brain volume is a much better predictor of disability in MS than all other indicators,” Dr. Vollmer notes, “and preserving brain volume is a key target for developing treatments.” Disability in MS can include difficulty walking or balancing, muscle fatigue, and difficulties with memory retention and concentration.

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Multiple Sclerosis: The Basics
What is multiple sclerosis?

Multiple sclerosis (MS) is a chronic neurologic disease that affects the central nervous system, which is made up of the brain, spinal cord, and optic nerves. MS damages the material that surrounds and protects nerve cells, called the myelin sheath. This damage slows down or blocks messages between the brain and the body.

MS is classified into four types by the progression of disease:

  • ▸ Relapsing-remitting MS is characterized by periods of symptom flare-up (relapse) followed by periods of recovery (remission).
  • ▸ Secondary-progressive MS often develops in people who have relapsing-remitting MS. In secondary-progressive MS, relapses and partial recoveries occur, but the disability doesn't fade away between cycles. Instead, it progressively worsens.
  • ▸ Primary-progressive MS progresses slowly and steadily from its onset, without periods of remission. Symptoms generally do not decrease in intensity.
  • ▸ Progressive-relapsing MS is a relatively rare type of MS in which people experience both steadily worsening symptoms and attacks during periods of remission.
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What are the symptoms of multiple sclerosis?

Symptoms can include tingling, numbness, loss of balance, blurred or double vision, and weakness in one or more limbs. Muscle stiffness, pain, urinary incontinence, and cognitive problems may develop as MS progresses.

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How is multiple sclerosis treated?

While no cure for MS exists, the relapsing-remitting form of the disease is treatable. Nine drugs are approved by the U.S. Food and Drug Administration to slow progression of relapsing-remitting MS: beta interferons (brand names Avonex, Betaseron, Extavia, Rebif); glatiramer acetate (Copaxone); fingolimod (Gilenya); natalizumab (Tysabri); mitoxantrone (Novantrone); and teriflunomide (Aubagio). Symptom-relieving therapies are available for the other forms of MS.

The number and severity of flare-ups, in contrast, are not reliable indicators of disease progression and degree or type of disability, experts say. The reason is that much of the damage in MS occurs subclinically—it isn't felt or noticed by the patient or doctor until long after it has occurred. “Think of symptoms as the tip of the iceberg,” explains Dr. Ransohoff. “For instance, brain lesions found on autopsy exceed the number of attacks that were counted during a patient's life by at least 10 times.”

Even the number or size of brain lesions picked up by magnetic resonance imaging (MRI) doesn't tell the whole story. “Lesions tell us something abnormal is going on, but they don't tell you if it's good, bad, or indifferent. Brain atrophy, on the other hand, is mostly bad,” says Dr. Ransohoff.

According to Dr. Vollmer, inflammatory activity and the number of new or enlarging brain lesions is often less in the later progressive forms of the disease than in the earlier, less symptomatic forms—the opposite of what one might expect.

“When patients with relapsing-remitting MS are stable between relapses, the assumption is that the disease is stable. That is definitely not the case: 90 to 95 percent of the inflammatory events in the brain occur subclinically in MS. The patient doesn't recognize them,” says Dr. Vollmer. “These inflammatory events damage and shrink the brain. So this study has begun to answer a key question for doctors who treat and study MS, which is whether the goal of therapy from the very beginning should be to minimize loss of brain volume.”

“The reason patients look like they are stable between relapses—even though the disease is quite active—is brain reserve,” Dr. Vollmer explains. “The ongoing damage is masked because function shifts to undamaged areas of the brain. But as patients move to the progressive stage of the disease, that reserve is used up.”

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REDUCING BRAIN SHRINKAGE

Secondary progressive MS doesn't respond to the immune-modulating treatments used in the relapsing-remitting form. And while some of the newer drugs do slow brain atrophy in relapsing-remitting MS, none stop it altogether, and none stop it in secondary-progressive MS. This is another reason why simvastatin may have implications for treating MS in all its forms.

Unlike immune-modulating drugs, the high dose of simvastatin reduces brain atrophy without affecting the immune system. Simvastatin likely works in more than one way—by improving blood flow and reducing inflammation, experts say. “So you are affecting two different biological processes—vascular and inflammatory,” Dr. Ransohoff says. “I don't know how to tease out these different effects, and frankly, I'm not sure if it matters. If people do better on statins, do we care if it's because we improve blood flow or reduce inflammation?”

This different mechanism of action may make simvastatin an excellent candidate for add-on therapy to existing disease-modifying treatments, according to Dr. Vollmer. “Most conventional therapies work outside the blood-brain barrier [which allows some but not all materials in the bloodstream to cross, protecting the brain from foreign substances]. Simvastatin works within the blood-brain barrier. By using it as an add-on to current immune-modulating drugs, we might be able to target the disease in two separate and critical ways,” he says.

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THE NEXT STEP

The next step will be to see if they can replicate the results in a similar group of patients, according to Dr. Nicholas.

By limiting future trials to people with progressive MS who are not on disease-modulating therapies, Dr. Ransohoff notes, it should be easier and quicker to isolate and determine the effects of simvastatin.

According to Dr. Vollmer, the results of the study warrant a phase 3 trial of a much larger number of people, including newly diagnosed patients with relapsing-remitting MS. “I think we should rapidly move to formal studies of early add-on statins in patients who are taking other disease-modifying therapies,” he says.

However, experts also caution that statins are known to have rare but potentially serious adverse side effects. According to the U.S. Food and Drug Administration (FDA), statins have been associated with a rare type of liver injury and a slight increase in the risk for Type 2 diabetes. In combination with certain drugs, they can cause muscle weakness (myopathy). The FDA is also investigating claims of some patients developing cognitive problems while on statins, although these appear to be reversible and quite rare. Most importantly, experts say, we don't know how simvastatin or other statins will interact with the drugs currently approved to treat MS.

Dr. Vollmer warns against assuming statins will have the same benefit in all patients and for all types of MS—or of prescribing them outside of a clinical trial. “I don't think doctors should add statins outside of a formal trial. We often miss serious problems and side effects by doing that.”

© 2014 American Academy of Neurology

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