Why MS Patients May Benefit from Aggressive Early Treatment

Why MS Patients May Benefit from Aggressive Early Treatment
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​Research shows that treatment at the first sign of disease may be best for most patients with multiple sclerosis. Our experts explain why and describe some exceptions.

​Sheila Halloran Skowyra was coming up on one of her busiest weeks at work when she woke up with numbness in her legs and feet. "It was more like pins and needles. I could walk around fine, so I figured it was just a pinched nerve," says Skowyra, 37, an assignment editor at a Boston TV station and mother of two young children.

​Illustration by Jorge Colombo

​​The symptoms persisted, but Skowyra powered through, overseeing coverage of the Boston Marathon and celebrating Easter and her younger daughter's fourth birthday. When she went to the doctor's office midweek, an exam and bloodwork found nothing alarming.

But by the following Monday, Skowyra could barely walk and felt like she had a band wrapped around her waist. She dropped her children off at school and headed straight to the hospital.

A subsequent MRI showed she had multiple lesions on her spinal cord, as well as older-looking lesions on her brain—telltale signs of multiple sclerosis (MS). Although Skowyra had worked on some stories about MS, she knew few specifics of the disease. She was soon to learn that MS is a chronic condition in which the immune system produces inflammation in the central nervous system, resulting in damaged nerves, potentially significant disability, and increased risk of mortality.

Disease severity and symptoms vary from person to person, but MS commonly causes problems with vision, walking, and balance, as well as unusual fatigue, pain, muscle weakness or spasms, numbness and tingling, bladder or bowel dysfunction, and cognitive and emotional changes such as depression and anxiety.

Skowyra was told she had relapsing-remitting MS (the most common form of the disease), in which attacks, or flare-ups, can occur at any time, followed by periods of partial or complete remission. "I was worried about the effect it would have on my children if I became immobile or disabled," Skowyra says. That concern informed her decisions when it came time to pick a medication.

Her neurologist recommended two disease-modifying therapies (DMTs): a daily pill that has been around for about nine years and a newer drug that is administered twice a year through intravenous infusions. Skowyra chose the latter because it had proved highly effective in clinical trials at preventing attacks and seemed like it would suit her busy schedule. She had her first infusion in June. "I wanted to get ahead of this [disease] and treat it aggressively," Skowyra says. "I wasn't willing to wait and see if I had another attack."

Dan Scher, 45, of Mansfield, MA, had a different experience. Diagnosed 15 years ago, the former emergency department physician had first noticed something strange when he looked up from playing the piano and saw two of his daughters—he has only one—climbing the stairs. He realized he was having double vision. He went to a neurologist, but at the time his clinical and MRI findings didn't meet the diagnostic definition for MS, so his doctor took a wait-and-see approach. After Scher developed numbness in his pinkie finger about six months later, he was reevaluated and started on an injectable MS medication. He is now on his fifth drug, but he doesn't see that as a sign of failure.

"As my MS has evolved, so have treatment options," says Scher, who has relapsing-remitting MS. He says he's doing well on his current medication, an infusion therapy, and hopes to stay on it as long as possible. Scher's main symptoms are fatigue, heavy legs, some mental fogginess, and emotional ups and downs. He handles them by going to support groups and MS events and staying active.

As these stories illustrate, finding the medication that works best for any given patient may involve trial and error. And considerations may evolve as the disease progresses and more treatments become available. Patients have a total of 17 options approved by the US Food and Drug Administration (FDA) for treating relapsing-remitting MS. Siponimod (Mayzent) and cladribine (Mavenclad), two new oral drugs indicated for both relapsing-remitting MS and active secondary progressive MS (a stage that follows relapsing-remitting and is characterized by a worsening of neurologic function over time), were approved in March. Ocrelizumab (Ocrevus) was approved for primary progressive MS as well as the relapsing-remitting form of the disease in 2017.

Unlike when Scher experienced his first symptoms, doctors today are less likely to wait to start treatment. Research shows that treating MS with an immune-suppressant therapy beginning with the first attack not only may prevent future flare-ups but also may slow disease progression. The American Academy of Neurology issued a new guideline in 2018 noting that evidence from studies supports counseling patients about DMTs as early as possible. Medications can't reverse the damage to the central nervous system, but they can prevent more, says Alexander Rae-Grant, MD, FAAN, the main author of the guideline.

Still, it's hard to keep up with the rapidly changing MS drug landscape, says Dr. Rae-Grant, professor of medicine at the Cleveland Clinic Lerner College of Medicine and a staff physician at the Mellen Center for MS in Ohio. He encourages patients and doctors to consider all options and evaluate the advantages and disadvantages of each one. "I tell patients to choose a medication they feel comfortable with, and we'll see how they do. If it isn't right, we have other choices."

Those choices can be daunting, however, especially right after a diagnosis, says Rebecca Spain, MD, MSPH, associate director of clinical affairs at the VA Portland Health Care System in Oregon. Drug names aren't familiar and medications come in various modes of delivery (pills, injections, infusions) and dosing schedules. Some have well-established track records on effectiveness, safety, and side effects. In general, newer MS drugs tend to be more efficacious but carry more serious risks. Doctors sometimes use the word "aggressive" to describe newer MS drugs, but that doesn't mean they aren't good options for some patients. 

Dr. Spain, who is also associate professor of neurology at Oregon Health & Science University in Portland, usually tells her patients that treating sooner may reduce long-term disability. She reviews initial symptoms, overall medical history, preferences, lifestyle—and cost. Patients' insurance may not cover a drug, which can cost tens of thousands of dollars annually. She also reminds patients that clinical studies show only how a group of carefully selected patients did on the drug but can't predict how any individual patient will fare. Another important factor is whether to start newly diagnosed patients on the most effective (and riskier) DMTs or escalate from older, safer drugs as needed. Two ongoing clinical trials—TREAT-MS and DELIVER-MS at Johns Hopkins and the Cleveland Clinic, respectively—are addressing this important question.

A 2016 study called BENEFIT, published in Neurology, helped support the now widely held view that treatment should start at the earliest signs of disease. Researchers tracked more than 200 patients with clinically isolated syndrome (a first episode of MS-like neurologic symptoms that lasts at least 24 hours) and at least two asymptomatic MRI lesions. Patients were randomized to injections of interferon beta-1b or to a placebo. After two years, or at the time of a second relapse, all patients could take interferon or start on another DMT.

After 11 years of follow-up, researchers found that patients who began treatment at the first signs of disease were 34.5 percent less likely to have a recurrent attack. In addition, the annual risk of relapse was reduced by just over 19 percent. The researchers concluded that treating early with interferon beta-1b had a long-lasting beneficial effect on disease progression.

While research suggests that treating early and more aggressively may reduce long-term disability, few head-to-head comparison studies of drugs have been conducted, says Brian G. Weinshenker, MD, FAAN, professor of neurology at Mayo Clinic in Rochester, MN, who coauthored an editorial accompanying the BENEFIT study. And it's hard for researchers to track patients for the many years of MS progression to see which drug might best keep disability in check over the long haul.

"We now tend to offer treatment to any patient who has evidence of active multiple sclerosis regardless of attack frequency or severity, in large part because of what we've learned about brain atrophy occurring at an early point and because of the apparent long-term benefits of treatment," says Dr. Weinshenker. A retrospective study published in the Annals of Neurology in 2018 looked at MRI scans of MS patients and found that deep gray matter atrophy contributed to disability.

Treating early is good practice, says John Corboy, MD, FAAN, professor of neurology at University of Colorado Denver and co-director of the Rocky Mountain MS Center. "I think we should embrace the concept of more effective treatments at the onset," he says. Dr. Corboy worries that some doctors focus too much on the risks of medications and not enough on the risks of the disease itself, which often has life-altering consequences. "It is incredibly important that patients understand the nature of the disease, not just the possible problems with the medications," he says.

Despite the research, some neurologists think delaying therapy is still reasonable depending on the circumstances. "It may be appropriate for some patients with clinically isolated syndrome who have very few lesions on an MRI scan and it is unclear whether they are going to relapse," says Dr. Weinshenker. "It might also be appropriate in patients who are diagnosed years after their first symptom and the course appears to have been very mild with few lesions."

Dr. Corboy is beginning to consider whether certain older patients may be able to discontinue DMTs if their disease has been stable for years. Research shows that older MS patients tend to have less inflammatory activity than younger patients, and DMTs tend to benefit younger patients more. In a new study, Dr. Corboy hopes to answer two questions: "Is it necessary to continue these medications in older patients, and is it safe to stop them?"

There isn't one correct approach to treating MS, agrees Tanuja Chitnis, MD, FAAN, director of the CLIMB longitudinal studies on MS at Brigham and Women's Hospital in Boston. "Emerging research over the past five or 10 years shows different courses in MS," she says. Whether they are mild or more aggressive can influence choice of treatment.

Other factors in the decision include whether a woman is contemplating pregnancy and if a patient is doing well on an older drug, says Dr. Chitnis, also professor of neurology at Harvard Medical School. It can take multiple appointments and weeks for a patient to reach a decision, and even then nothing is set in stone. She tells her patients to try a drug until it no longer feels comfortable or ongoing monitoring indicates the drug isn't working anymore. "If patients want to switch, they can. That's the beauty of having many options," she says. Meanwhile, Dr. Chitnis is conducting research to identify MS biomarkers in the blood and spinal fluid that could help determine whether a therapy is keeping inflammatory aspects of MS under control.

More answers on treatment approaches will come as other clinical trial results emerge. For instance, a study published in January in the Journal of the American Medical Association (JAMA) found that among 1,555 patients with relapsing-remitting MS, those who were initially treated with the oral medication fingolimod (Gilenya) or infusions of natalizumab (Tysabri) or alemtuzumab (Lemtrada) had a lower risk of advancing to secondary progressive MS when compared with patients who started on interferon beta-1a (Rebif, Avonex) or glatiramer acetate (Copaxone), which are older injectable drugs. Because the study was not a randomized-controlled trial, experts say it should not be considered the final word.

In the meantime, MS patients bring their own sensibilities and priorities to treatment decisions. For Trish Palmer, a visiting nurse who lives near Seattle, it was important to pick a medication as soon as possible after her diagnosis of MS five years ago. She recalls feeling acknowledged when her neurologist asked what she was most anxious about. "I was most worried about disability and was willing to take anything to delay that," she says.

Palmer, 35, has switched drugs along the way. She's now taking one of the newer infusion therapies, and is doing well aside from some minor swallowing difficulties that have lingered after her first attack. While she thinks it is important to do research and talk to other MS patients, she tries not to let others' opinions sway her. "I would say everyone's journey is his or her own," she says. "Make sure you can talk it through with a doctor you trust, and then do what is best for your lifestyle and family."

Cathy Cook, 65, who runs Minnie's Bake Shop in New York City, says she met with three different neurologists after she developed numbness from the waist down and an MRI showed lesions indicative of MS. "I was looking for a doctor with whom I was comfortable and could ask questions of," Cook says. She's been on three different therapies over the past seven years and now gets twice-yearly infusions of a newer medication. She has some tingling or prickling sensations and sometimes experiences problems with balance, but says she manages fine in a job that requires being on her feet all day. "My body is an incredible machine because it's figured out how to compensate for my symptoms of MS."

Three Categories Of MS MedicationsTreatments can be grouped into three categories, based on their efficacy and safety. This overview comes from Rebecca Spain, MD, MSPH, associate director of clinical affairs at the VA Portland Health Care System in Oregon.

• Category 1 These drugs include older injectables such as interferon beta-1b (Betaseron and Extavia), interferon beta-1a (Avonex, Plegridy, Rebif), and the generic form of Copaxone called glatiramer acetate (Mylan, Glatopa). They have proven track records but more limited efficacy, reducing the risk of attacks by about 35 percent overall, Dr. Spain says.
• Category 2 This grouping contains oral medications like fingolimod (Gilenya), dimethyl fumarate (Tecfidera), teriflunomide (Aubagio), siponimod (Mayzent), and cladribine (Mavenclad), which are more effective than the older injectables, though few comparative trials have been conducted. Dimethyl fumarate has been shown to reduce attacks by 50 percent and fingolimod by 54 percent, Dr. Spain says. They also have some troubling risks. In a small number of cases, fingolimod and dimethyl fumarate have been associated with progressive multifocal leukoencephalopathy (PML), a rare but potentially deadly brain disease. Patients are monitored for signs of the virus that can cause PML.
• Category 3 Alemtuzumab (Lemtrada), ocrelizumab (Ocrevus), and natalizumab (Tysabri) are in the third group. Administered through infusions on varying schedules, these drugs reduced the risk of a flare-up by 50 to 65 percent in clinical trials, says Dr. Spain. They also have serious risks, such as autoimmune diseases, PML, infections, and cancer.

Four Ways To Handle The Expense Of MS DrugsAlmost all disease-modifying therapies (DMTs) used to treat multiple sclerosis (MS) cost between $5,000 and $7,000 per month, and for many patients price can be a deciding factor in choosing an appropriate therapy. Daniel Hartung, PharmD, MPH, associate professor at Oregon Health & Science University College of Pharmacy in Portland, whose research has focused on the cost of MS drugs, offers this advice for how patients can afford them.

1. Understand your insurance. Find out what your insurance policy covers and how much of a co-pay and deductible you are responsible for, so you know what your out-of-pocket costs will be.
2. Consider generics. Before 2015, all DMTs cost the same. Since then, two generic versions of Copaxone, a commonly prescribed injectable drug, have appeared on the market, which dropped the price by as much as 60 percent (from $5,000 to $2,000 a month). "Copaxone is one of the most highly prescribed drugs, with a strong track record of safety and efficacy, so the fact that this is the low-cost alternative is good news," says Dr. Hartung. Be sure to discuss generics with your neurologist; not all patients are candidates for these drugs, and patients used to an oral medication may not be comfortable taking an injectable. In general, though, the generic should be as efficacious and safe as the brand name, Dr. Hartung says. "Stringent regulations ensure that generic medications are identical to their branded counterparts."
3. Coordinate with your doctor. If your insurance company says it won't cover a particular DMT, your doctor can provide documentation that it is the appropriate medication for you and your insurance company may agree to cover the exception. "Although it can be administratively onerous, most neurology offices do this on a regular basis," says Dr. Hartung.
4. Explore patient assistance programs. Look into any programs your insurance company may have that provide reduced-cost or free medications for qualifying patients. Talk to your neurologist about them or check the National Multiple Sclerosis Society website, which has information about such programs for every product, or the drug manufacturer's website.

The Basics Of Self-Care For Multiple SclerosisAfter a diagnosis of multiple sclerosis (MS), patients are typically encouraged to take a three-pronged approach to treating their condition: Choose a disease-modifying therapy; consider medication for related symptoms, such as depression or anxiety; and practice self-care, says Rebecca Spain, MD, MSPH, associate professor of neurology at Oregon Health & Science University in Portland. Self-care means doing things for yourself that will keep you as healthy as possible despite having a chronic, potentially progressive disease. Here's what doctors recommend.
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• Diet. Despite several clinical trials, no diet has emerged that can slow or prevent the progression of MS. Neurologists suggest following the same heart-healthy, high-fiber, low-fat diet recommended for all adults.
• Sleep. In general, doctors recommend seven to nine hours of sleep a night for adults.
• Exercise. Staying active is important for maintaining strength, mobility, balance, flexibility, and endurance. Exercise can boost your mood, too. Ask your doctor or physical therapist for an exercise plan appropriate for your fitness level and symptoms.
• Stress reduction. Practices such as yoga, meditation, and deep breathing exercises may help you relax, but no direct evidence says they are beneficial for MS. Find what works best for you to keep stress levels low.

Proceed Cautiously With Alternative Treatments For MSAs a way to stay healthy or to target certain symptoms, some patients with multiple sclerosis (MS) take vitamins and supplements or have acupuncture. Before doing so, patients should talk to their doctors, says Vijayshree Yadav, MD, FAAN, associate professor of neurology at Oregon Health & Science University School of Medicine in Portland. Evidence for many alternative therapies is weak or lacking altogether, says Dr. Yadav, who is the author of a 2014 guideline from the American Academy of Neurology (AAN) that reviewed the studies on such treatments for MS.

The guideline, which covered everything from ginkgo biloba supplements to magnet therapy, concluded that more research is needed to study the effects of so-called complementary approaches and their possible interactions with FDA-approved drugs.

Opinions about non-medication approaches can change as more research emerges. Vitamin D is a good example: While early research said vitamin D supplements may be a good idea, a recent analysis of previously published studies, reported in the Cochrane Library in 2017, found that they did not reduce MS flare-ups, disease progression, or the number of new lesions.

The National Multiple Sclerosis Society advises all patients to be up front with their health providers about any medications or nonprescription therapies they take so their doctors can advise them on possible side effects or potential drug interactions—and about new research.

Here are some highlights from the AAN guideline.
Cannabis. Dr. Yadav says her patients often ask about cannabis, which is legal for recreational use in Oregon. Although she does not prescribe marijuana, she points to the guideline, which found "strong evidence" that oral cannabis extract reduces patient-reported symptoms of spasticity and pain (excluding central nervous system pain) and moderate evidence for oromucosal cannabis spray (nabiximols) in reducing symptoms of spasticity, pain, or urinary frequency, all of which can be treated effectively with standard medication.

Fish oil. Taking fish oil (omega-3 fatty acids) supplements on a low-fat diet is probably ineffective for reducing relapses, disability, or MRI lesions or for improving fatigue or quality of life in MS, according to the guideline.
Ginkgo biloba. The guideline found strong evidence against the claim that this herb can improve cognitive function in patients with MS, says Dr. Yadav.
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Cannabis icon by Pete Baker, Fish icon by Linseed Studio, Ginkgo biloba icon by Tiro, all icons from The Noun Project

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