Q&A: What Do the Latest Data Mean for Practice in MS?

Course Director

Aaron Boster, MD

Aaron Boster, MD
The Ohio State University Multiple Sclerosis Center
The Ohio State University Medical Center
Columbus, Ohio

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Part 1 of a 2-part series

Dr. Boster provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


Successful management of multiple sclerosis (MS) has changed dramatically and rapidly in the past several years. The availability of oral therapies has greatly increased the range of effective treatment options, but may raise questions regarding how and when to incorporate these agents into practice. In addition to questions about the safety and efficacy of oral therapies, clinicians may have questions about how to sequence therapy, and how to create individualized regimens that address specific patient situations. In this activity, Dr. Aaron Boster answers some of these key questions and offers practical insights into individualizing therapy with new agents in patients with MS.


This activity is supported by educational grants from Teva CNS and Genzyme, a Sanofi Company.

Course Director
Aaron Boster, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Biogen Idec; EMD Serono, Inc.; Genentech, Inc.; Medtronic, Inc.; Novartis Corporation; and Teva Neuroscience, Inc.
Grant/Research Support from Actelion Pharmaceuticals US, Inc.; Biogen Idec; CNS Therapeutics, Inc.; DioGenix Inc.; EMD Serono, Inc.; Hoffmann-La Roche Inc.; Jazz Pharmaceuticals; Novartis Corporation; and Sun Pharmaceutical Industries Limited.
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Annette Wiggins
Answers in CME, Inc.
Annette Wiggins has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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What is the best or safest sequence to integrate oral therapies for MS? I’m particularly concerned with logistics and the safety of switching from one drug to another.

Dr. Boster: There are many factors that we have to consider in each individual patient. The first question is, "What drug were they on and what are the risk factors, the side-effect profiles of that drug? And in particular, when they stop the drug, are there any issues—in other words, do you need a washout period? The second issue is what are they starting and are there any unique issues related to starting a medication? Are there any safety checks or tolerability issues that need to be considered? The third issue is the patient themselves and their comorbid medical conditions. So those are the three factors that we have to consider with each and every patient.

Let me talk about a couple of examples. When a patient is taking glatiramer acetate and they're transitioning to an oral therapy—whether the oral therapy be dimethyl fumarate or fingolimod or teriflunomide—that's probably one of the easier switches from the injectable side. There are some practices that prefer to stop the glatiramer acetate a month before starting the next drug. In my own practice, we don't do that. I can't find an immunologic reason or a mechanistic reason why that's necessary. And so stopping glatiramer acetate is nothing more than stopping it and starting the next medicine.

With the interferons, it's almost as straightforward. Again, the party line is to stop the medicine for a month or so before starting the new medicine. I like to, instead, pay attention to risks and what the switch would entail.

We know that interferons can sometimes tickle the liver enzymes and lower bone marrow function, although they generally don't do that very much, and when they do, it's typically not a very robust effect. So, in my practice, I'm not as worried to be frank, about how long I stop the interferon. Instead, I turn to what I am starting. If you're going to start dimethyl fumarate, dimethyl fumarate tends to drop the white [blood cell] count by about 20% or 30%.1 And so you don't want a suppressed immune response. I don't have much of an issue with that with the interferons and glatiramer acetate, but you do want a fresh CBC. The FDA does not suggest that you have liver enzymes [testing] for dimethyl fumarate; [in] our own personal practice, we like to check them.

If you're switching to teriflunomide, then you're most certainly going to be looking at their liver enzymes anyway, and you're going to screen for tuberculosis and obviously for pregnancy, although in my own personal practice, it doesn't change how I stop the injectables.

Starting fingolimod is a bit of a different endeavor, with the safety checks required for starting this agent . When one starts fingolimod, as we're aware, we have to do an EKG and make sure that they don't have certain heart medicines or certain cardiovascular conditions, which may put them at increased risk for a cardiac problem. I still request that my patients have a thorough skin exam, although the risk for skin cancer is very, very low. I require that my patients have an ophthalmologic examination to make sure that they don't have concerns for macular edema. We also have to make sure that they have fresh LFTs and a CBC to start from. Lastly, we need to make sure that they demonstrate immunity to varicella zoster. Now given that it takes about a month or so to go through the rigor of doing all that prescreening, on average, not uncommonly we'll have a patient stop the medicine at the time they sign up for their fingolimod and then they go through their testing for about a month and start the drug. We do have patients that will continue to take their injectable up until the time they switch to fingolimod because they're not comfortable being off therapy for any given period of time.

When one switches from natalizumab infusions to a pill—if you stop the drug, based on the clinical data, it's going to be relatively biologically active and still kind of functioning for about three months. And so we want to wash people off of their natalizumab, but in a safe fashion. Typically, we stop the medication—this is our own chili recipe, not dogma—and we give them 1 g of steroids monthly for three consecutive months. The rationale is that we keep their disease at bay and we allow them to wash off the natalizumab in a safe fashion. At month three, we'll start them on their new drug. If they're switching to fingolimod, they're, of course, going to need to do all the prescreening.

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My patient is John Cunningham virus (JCV) [antibody]-positive and having ongoing relapses on interferon beta-1b. Would you consider adding or changing to an oral agent or moving to natalizumab?

Dr. Boster: So, I'm not going to add anything. I don't personally endorse stacking medicines, and that's both for lack of evidence for combinations and because of price, if you will. As far as switching, let's first talk about natalizumab. Now if someone is JCV antibody-positive, there are two questions that I have to ask them: First, "Have they ever been exposed to prior immunosuppression?" If they've been exposed to prior immunosuppression and they're JCV antibody-positive, they have two risk factors for PML; that might limit the duration of time that we consider putting them on therapy because after the 24th infusion—so entering the third year—the risk for PML goes up substantially.2

If they have not had immunosuppression and they are JCV antibody-positive, my next question is, “What is the optical density (OD) of the second generation JCV-antibody test?” The second generation test gives us an optical density which you can conceptualize like a titer. There is emerging data that suggests that if you have a high-positive titer, those patients are generally at risk for PML. If you are JCV antibody-positive with a high titer, I will be less inclined to put you on natalizumab. If I did do it, I would do it for two years only.3

Conversely, if you're JCV antibody-positive, but you're "low positive," it turns out that these patients have a very low risk, all things considered, of developing PML.3 If a patient was failing interferon and they were a low-positive JCV-antibody patient, I would feel comfortable putting them on natalizumab, although I am going to screen them with very frequent MRIs. There is emerging data that suggest that asymptomatically-captured PML—those patients when identified early and treated aggressively may stand a better chance of doing well.4 So I want to screen them with MRIs as frequently as every three months so that I can capture asymptomatic lesions of PML.

Going on to a pill is another option. As we just talked about, we have three pills to choose from. So, if the patient has certain risk factors, it’s going to help you in your decision-making process. For example, if a patient has serious cardiovascular risk factors or has risks for macular edema, you may not opt to put them onto fingolimod, just because there are risks in starting that medicine. If the person is of child-bearing potential with plans of conception in the next couple of years, they may choose not to go onto teriflunomide. Again, this becomes very individualized.

There isn't one size fits all and when a patient fails interferon, my practice in clinic is to hit pause, open up the books, so to speak, review all of the available options, and then based on efficacy, safety, tolerability, and individual patient factors, we're going to pick a custom-tailored drug for that individual.

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Would you switch a patient who is doing well on interferon to an oral therapy? If so, which one?

Dr. Boster: The question is, "What do you mean by doing well?" I presume that the drug is keeping their disease at bay; they're not having attacks; they're not accruing disability on examination; they're not cognitively impaired; and they're not having new spots show up on their MRI. So if that's the definition, the party line has traditionally been, "If it ain't broke, don't fix it."

There is another question that I think bears asking, that's the question of tolerability. Now that we have pills that are available, I'll ask people, "How well are you tolerating your injectable?" And they'll say, "I'm tolerating it fine." I draw a line on a piece of paper, and I say, "On the left side of the line is ‘I'm doing fine because I'm an adult and I'm a father of three and I know I need to take my medicine to keep healthy, but doc, I hate it with a passion and it ruins the quality of my life’.” Then on the other side of the line, I say, “This is a patient who says ‘I'm doing fine, I don't even think about it. I brush my teeth. I give myself my injection. And I could care less about the issues related to tolerability because I'm doing great’."

So in the first patient, I think that a pill is a reasonable thing to discuss. In the second patient, I'm not going to switch them to a different therapy. Not only are they being well controlled from an efficacy standpoint, but they're also tolerating their therapy without problem.

The reason I bring this up is because if a patient is not tolerating their injection, they're less likely to take their injection and nonadherence, as we know, is a major issue amongst MS therapies. When you look at data [in] patients who have been on injections for two years, only just shy of 50% are taking their medicines as prescribed.5-8 And so delving into how well they're putting up with their therapy in a real, genuine exchange is important. And that's going to help drive the decision as to whether we switch or not.

The second part of the question, which is "Which one do you switch it to," my answer is the same as above, which is there isn't one size fits all. You have to consider several factors. You have to consider the dosing schedule; you have to consider the monitoring. All of these factors for the individual patient have to be considered when picking that next medicine.

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  1. Tecfidera (dimethyl fumarate) Label: US Food and Drug Administration (FDA) website. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf. Accessed July 23, 2013.
  2. Bloomgren G et al. N Engl J Med. 2012;366:1870-1880.
  3. Plavina T et al. 5th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis (CMSC-ACTRIMS 2013). Abstract DX51.
  4. Dong-Si T et al. 65th Annual Meeting of the American Academy of Neurology (AAN 2013). Abstract P04.268.
  5. R?o J et al. Mult Scler. 2005;11:306-309.
  6. Haas J, Firzlaff M. Eur J Neurol. 2005;12:425-431.
  7. O'Rourke KE, Hutchinson M. Mult Scler. 2005;11:46-50.
  8. Ruggieri RM et al. Neurol Sci. 2003;24:361-364.

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Teva CNSGenzyme, a Sanofi Company

This activity is supported by educational grants from Teva CNS and Genzyme, a Sanofi Company.

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