Here is My Question:
I have RRMS. I don't want to take medications. What's the biggest risk if I don't?

Answer:
Disease modifying therapies (DMTs) for MS are 1) expensive, 2) associated with a variety of side effects and potential safety risks, and 3) are partially effective.  With this understanding, your question is one I hear frequently in clinic.  The major risk of deferring DMT for relapsing-remitting MS is an increased likelihood of clinical relapses in the future that can disrupt your day-to-day function, and short- and long-term disability.  Let me explain…

We have a great deal of natural history data on MS (this is information on the average experience of patients with MS who were not exposed to therapy).  This information is available to us because it wasn’t until the mid-1990’s that we had our first approved DMT for clinical use.  What we have learned is that patients with early and frequent clinical relapses are at a higher risk of developing walking disability (for instance, the average individual with greater than 5 clinical attacks in the first 2 years of MS will need a cane to walk by 6 to 7 years into their disease course; while the average patient with 0 or 1 clinical attack will need a cane by the 20 year mark).  We have also learned that the initial MRI brain scan after the first clinic event of MS can tell us about the likelihood of disability in the future—the more scars of MS that are seen on this first scan, the greater the probability for disability sooner rather than later.  Keep in mind that these numbers reflect MS patients who did not have DMT options.

At the time of this blog post, we have ten FDA-approved DMTs, with more being reviewed.  In nearly every case, these therapies have repeatedly shown effectiveness in 3 main measurements:  1) less clinical relapses or attacks compared to placebo, 2) reduced number of new, enlarging, or enhancing scars on the brain MRI scan, and 3) a reduction is short-term disability compared to placebo.

Critics have long pointed out that the DMTs are not cures, are expensive, have variable safety risks, and have not been proven to make a difference in the long-term.  While it is true that all DMTs are partially effective—meaning that the data does not show that they cut down new relapses, MRI lesions, and disability by 100%—they have recently demonstrated effectiveness in the long-term.  In 2012, a paper was published in the journal Neurology that presented long term follow-up data on the first approved DMT called betaseron.  This 21-year study followed the originally randomized study participants (an early treatment group that was randomized to betaseron from the beginning, and a late treatment group that comprised individuals that were originally randomized to placebo but were given the opportunity to take betaseron after the initial clinical trial ended 3 years later).  This paper showed that there were more people alive from the early treatment group 21 years later compared to those in the late treatment group.  You can read more about this at http://msj.sagepub.com/content/19/5/522.full.  This study confirmed our suspicions that DMT does help in the long term and does underscore the need to treat early rather than waiting—because there appears to be a window of opportunity to alter the course of the disease for the better.

Many of the barriers to initiating a DMT for relapsing-remitting MS patients have been removed.  There are financial and co-pay assistance programs in place to make DMTs affordable for patients, risk mitigating protocols for DMTs, and experienced MS clinicians that can help you in choosing a reasonable DMT that can fit your goals and lifestyle, and outline a plan to make sure the medication is doing what we expect it to do and make it tolerable for the patient.

While the majority of my patients ultimately decide to start a DMT after considering this information, some choose to defer treatment.  That is certainly each individual’s prerogative.  Before making the decision, everyone should recognize the fact that we do not yet have a therapy that can reverse or repair tissue damage already incurred due to MS inflammation, nor do we have a therapy at the moment that reverses sustained disability.  What we are left with are DMTs whose purpose is to get in front of the disease and impact it for the better, and hopefully avoid significant disability in the future.

-ASN

This is a question I get several times a week and my answer has changed over time with the availability of newer therapies and more information on identifying individual risk factors for the development of Progressive Multifocal Leukoencephalopathy (PML), the complication of treatment with this highly effective drug that we are all trying to avoid. [If you do not know much about Tysabri or PML, I recommend you search our site for a refresher course and then return to this blog].

To better understand if Tysabri therapy is good for you, it is informative to take a short walk down memory lane. When Tysabri first returned to the market place in 2006 and MS specialists started treating patients under the TOUCH program, the risk of PML was estimated at 1/1000.  Very quickly we learned about additional risks factors for PML; these new risk factors included,

1. Duration of therapy greater than 2 years and
2. Prior treatment with an immunosuppressant drug  (such as cyclophosphamide, mitoxantrone, azathioprine or Imuran, methotrexate, mycophenolate or cellcept)
   

This was followed by the development of a blood test to determine if your body was making antibodies against the virus that is associated with the development of PML, called the JC virus. Initially, results from the this blood test were reported as either positive or negative; those with a positive test (56% of people) seemed to have almost all the risk of developing PM, whereas those who were negative on this test  (44%) had a negligible risk of developing PML.  To make matters slightly more complicated, those who were negative on the JC virus antibody test could become positive later (about a 2% yearly conversion rate over the short term). The initial testing showed that about 40% of people with MS were negative on this test and 60% positive. For many neurologist and patients who were risk adverse, this eliminated Tysabri as a treatment option in at least 60% of patients who they felt were good candidates by other criteria.

Around this time other highly effective therapies were becoming available for people with MS with their own set of risk factors, particularly Fingolimod (Gilenya) with its risk of cardiac complications, macular edema and reactivation of herpetic infections like shingles.  We now have Tecfidera that appears relatively safe and effective, but associated with some unpleasant GI side effects in about 20% of people at the start of treatment.

Thankfully, we have further refined the risk stratification for people wishing to consider Tysabri therapy and the FDA recently approved the use of Tysabri as a first line agent (people with no prior disease modifying therapy) in well selected relapsing MS patients.  The main change in our risk stratification is based on a free test that measures the actual amount of antibodies your body makes against the JC virus, called the JC Virus antibody index.  We no longer consider patients as simply positive or negative for JC antibodies. This new information on stratifying risk by JC virus index in addition to the prior known risk factors, which include duration of therapy and prior immunosuppressant use, forms the basis of assessing your risk of developing PML on Tysabri therapy.  More importantly, the new risk stratification scheme reclassifies approximately 25% of the patients previously considered JC virus antibody positive as a relatively lower risk group who may now consider Tysabri therapy.

Please see the attached figure to see the entire stratification scheme. Once you know your JC Virus index value  (which you can get from your doctor) you can determine whether it is too risky for you to consider Tysabri by simply looking at the chart.  First some highlights:

1. If you are JC virus antibody negative the index value is not reported and your risk of PML is extraordinarily low (< 1 in 10,000).  You are definitely the type of patient who should consider Tysabri as an option right from the start. Other factors will determine the best choice of the therapy.
2. If you are JC Virus positive with any index level and you previously received immunosuppressant treatment, your risk of PML is very high after 2 years, and you should only consider Tysabri under extraordinary circumstances.
3. JC Virus index levels less than 1.5 in patients with no prior history of immunosuppressant use confers a variable risk of PML over time.  Generally, JC virus index levels less than 1.0 are associated with a low enough risk of PML  for me to consider Tysabri as a first line treatment in my patients with risk factors for short term MS disease progression. I generally consider Tysabri only a second line therapy for those with antibody index values between 1 and 1.5, and only as a last option for those with consistent JC virus index values greater than 1.5.
   

So how do I make these judgments? First, I think it is reasonable to consider an MS therapy as first line in almost all patients if a severe risk of that therapy occurs in less than 1 in 10,000 people.  I would consider the therapy first line in selected patients with significant MS disease activity if the risk of PML were less than 1 in 2500 (see table. This would mean a JC virus index value of < 0.9). This is mostly because we have other therapies available that may work and have a lower risk profile. For higher risks of PML, I am inclined to consider therapy only as second or third line but will still use Tysabri in selected cases.

So what is your risk profile? What are your thoughts on the risks associated with either Tysabri or any other MS disease modifying therapy?

 -- Dr. Kinkel

PLEASE NOTE:  The medical information on this site is provided as an information resource only, and is not to be used or relied on for any diagnostic or treatment purposes. The information and opinions provided do not create any patient-physician relationship, and should not be used as a substitute for professional diagnosis and treatment.  Please consult your health care provider before making any healthcare decisions or for guidance about a specific medical condition.