Cases in Multiple Sclerosis: Applying Best Practices to Patient Care

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 3 of a 3-part series

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


The current trend in multiple sclerosis is to treat earlier and more aggressively. In addition to recently approved agents, a number of emerging therapies are being studied in an effort to add to the armamentarium. Understanding how and when to incorporate these agents into practice is critical to ensuring that patients derive the greatest benefit with minimal risk. In this activity, Dr. Aaron Boster provides clinical insights on the clinical implications of recently approved and emerging therapies and explores their potential role in the management of patients with MS.


This activity is supported by educational grants from Teva CNS, Novartis Pharmaceuticals Corporation and Genzyme, a Sanofi Company. Additional support provided by Penn State College of Medicine and Answers in CME.

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.
Medical Director
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 treatment is best for a newly diagnosed patient with clinically isolated syndrome (CIS)?

Dr. Boster: With the newest diagnostic criteria1, we're diagnosing MS very, very early; and in the last 10 years we've learned that if you put people on therapy sooner, they do better long term. CIS is just the beginnings of what's going to go on to be MS. So, putting these people on therapy, in my opinion, is very important.

Now, you're weighing some risk and benefit here. My standard practice, up until the oral agents came about, was to use glatiramer acetate first-line for CIS. The PreCISe trial supports its use, and glatiramer acetate has a very attractive side-effect profile.2 And, when you have a patient with CIS, they don't necessarily fully understand the disease process; they most often are asymptomatic after they recover. And so asking them to buy into a therapy that they'll take for the rest of their lives, early on in this condition, is challenging. And if there are a lot of side effects, there's a high likelihood that they're going to be nonadherent. And so, I've had success in my own personal clinic managing CIS, particularly CIS at high risk, by starting glatiramer [acetate].

One could consider interferons. My opinion is that the side-effect profile with the interferons—with flu-like symptoms and possible worsening of depression and spasticity, and headaches—may make them slightly less attractive, although they’re still a viable option.

The oral agents are game-changers in some capacity. Patients generally feel more comfortable taking a pill than a shot. And when you're dealing with a CIS population, these are people that aren't completely invested in their disease yet; some of them don't really believe yet that they're going to go on to have MS. When I look at the oral agents available, dimethyl fumarate is very attractive. It has good data in a population of very young, new MS patients, not CIS but a similar population. And at first blush, it appears to be very safe and well tolerated. If you look at the DEFINE and the CONFIRM trials3,4, the pivotal trials that led to the FDA approval of dimethyl fumarate, the majority of those patients were treatment-naïve. And the majority of the patients had relatively early disease.

I would be less comfortable starting teriflunomide in a CIS patient. We don't know how that patient is going to go on to develop and how aggressive their disease will be. In my opinion, given that teriflunomide is an immunosuppressant, this may close a door for natalizumab downstream. And I think the ordering of drugs becomes very important.

One could consider placing a CIS patient on fingolimod.5 It's a highly effective medicine. The one challenge in the CIS population is the number of safety checks that have to be done before starting the drug. If the patient is willing to go through the rigor of the evaluation, then I think that fingolimod is an option.

In summary, when I'm looking at a CIS patient, particularly a CIS patient at risk, the two drugs that I'm more likely to reach for would be glatiramer acetate and dimethyl fumarate as a viable option.

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My patient is a single father who is having breakthrough disease on second-line glatiramer acetate. He is very concerned about safety (even rare events) because he "needs to be around to take care of his kids." What are his options?

Dr Boster: The patient had breakthrough disease on interferon and then was switched to glatiramer acetate. This is a very common scenario, unfortunately, and we have to pick apart a couple of different things.

First of all, glatiramer acetate and the interferon class of medicines are mild-to-moderately effective, but our expectations are that we would see an attack no frequently than maybe one every three years. If you’ve failed one interferon, a lot of people may switch between low[-dose] interferon to high-dose interferon, but I leave the class. And switching to glatiramer acetate or vice versa, there are good data to support switching between those classes.6,7

Here we have a scenario where he's "burned through first-line agents." Independent of the fact that he's a single father, that's a bad prognostic situation to be in. So, I think it's appropriate in this case to be somewhat aggressive.

The other thing to consider is he wants to be around for his kids. I reinforce to him that he wants to be functional around his kids—so, it's more than just, "I want to be around." It's, "I want to be around and I want to be able to play ball."

So, my first-line approach to this gentleman would be to test his JC-virus antibody status. If he was JC-virus antibody negative, meaning that his risk of developing the PML infection is roughly 1 in 11,0008, I would strongly endorse starting natalizumab in this gentleman. We now have amassed a good deal of data suggestive that natalizumab is a highly effective therapy and has been used in this capacity both in trials and also in clinical practice quite successfully.9,10 Even if he was JC-virus antibody positive, I would still have a discussion with him about his risk profile and consider putting him on natalizumab, for two years, never having had an immunosuppression. If he was JC-virus antibody positive, his risk of developing PML in the first two years is roughly 1 in 1,000.8 We have to weigh the risk of ongoing disease activity against a theoretical risk that's 1 in 1,000.

You think about three oral agents for this guy. When I look at the TENERE trial11,12, which compared high-dose interferon beta-1a subQ [subcutaneous] against teriflunomide, they were not able to show superiority. And one could argue about making yet another lateral move, excuse the expression, from glatiramer [acetate] to teriflunomide. Here's a gentleman who has already [had] disease activity sneak by on two first-line agents. And whereas teriflunomide might be successful in controlling his disease, I don't want to wait another year or two to clarify that point. And so, I would not consider that as a next step for him. Moreover, it may close doors downstream if we ever did need to visit natalizumab.

One could consider fingolimod. We now have 63,000-some people who've been exposed to fingolimod post-marketing. We have some good trials, FREEDOMS I and II and TRANSFORMS.5,13,14 And there are subgroup analyses, although post hoc, suggestive that patients that have not responded to other therapies may respond to fingolimod. He's going to have to grapple with some of the safety screening tests. I like to remind patients that once you pass the safety hoop, once we figure out that cardiovascular things are okay, they're okay.

Now, considering dimethyl fumarate is a question mark in my mind. We do know that about 30% of patients in the pivotal trials had been exposed to previous medicines. But I don't think that we have very robust data yet in treatment-refractory patients, about how they would respond.

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My patient is a 30-year-old woman with active MS. She plans to become pregnant in the coming year. What are treatment considerations for now and during pregnancy?

Dr. Boster: This is a very critical question: [about] 70% of women with MS are of childbearing potential.15,16  Now, the party-line, if you will, is that we stop all forms of disease-modifying therapy at the initiation of attempts at conception, and that we remain off disease-modifying therapy throughout attempts at conception; while carrying the pregnancy; [at] delivery obviously; and then during breast-feeding. And that's borne out of teratogenicity concerns.    

The MS therapeutics that are currently available include two Category X medicines—mitoxantrone and teriflunomide; a bunch of Category C medicines; and one Category B, which is glatiramer acetate.17 Even with glatiramer, the party-line is to stop the medicine. There is a movement, although very much off-label and very contentious, to use glatiramer acetate during attempts at conception and during pregnancy. There's a paper soon to be published looking at a cohort of successful pregnancies on glatiramer [acetate]. And I think that it is reasonable to have a conversation [about it].       

Now, in this woman, we're told that she's active, and that's concerning. And so, depending on the degree of comfort of the patient, the ‘MS-ologist’, and the obstetrician, you may engage in an off-label conversation about whether or not we would keep someone on glatiramer [acetate] long-term, during pregnancy, given that it's Category B, although I want to reinforce that this is off-label.

Another way of thinking about this is what are the long-term plans and what's the long-term risk of disease progression? It would be ideal if this patient allowed us to treat her MS, to hold off on pregnancy. And I would ask her for one year of disease stability, not treatment, but stability because maybe it'll take us a year to get her stable. And I would feel much more confident and comfortable if she had a year of quiet disease, meaning no attacks, no progression on MRI, and no progression on clinical exam and then, "give the green light" to try to conceive. Now, of course, it's not about me; it's about her. And she has to fit her MS therapy and treatment into the context of her life overall.

A couple of things that we definitely would not want to do: So, teriflunomide is a drug which is Category X. In order to become pregnant, we would want the drug to be cleared from the body. Similarly, other chemotherapeutic agents would be less than favorable.

I also like to think about how long it takes to get someone off a drug. We know that to unbind all your VLA-4 receptors with natalizumab, it'll take three months. We know that in fingolimod, to reverse the sequestration of the T-cells from secondary lymphoid organs, it takes two to three months.18 And so, these are important factors to keep in mind before you allow them to attempt conception.

The last thing that I'll say is there is a small literature with using IVIg in the setting of MS and pregnancy. It's not Class I evidence by any means; however, there is some evidence to support the use of IVIg during pregnancy and immediately following conception, in what I commonly refer to as the "fourth trimester."

Now, not uncommonly a patient shows up in my clinic and routinely what happens is we have a lovely visit. And as the patient is leaving the room, they say to me, "Oh, I forgot, doctor. I'm pregnant."  Now, in that case, if they are on teriflunomide, it is imperative that they wash off the drug quickly. And there's a rapid elimination protocol, either by using activated charcoal or cholestyramine, to try to clear it from their body quickly.

Some MS clinicians, when a patient on glatiramer [acetate] becomes pregnant, they leave them on. Others will simply say, "Okay, now it's time to stop." With interferons, we simply stop the medicine then. It's a little trickier with natalizumab and with fingolimod because it takes a while to wash off. And so, we would stop the drug at the time that we learned that they're pregnant. There are registries for all of these drugs, so that women who become pregnant can be followed. And then we would just have to watch them carefully.

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  1. Polman CH et al. Ann Neurol. 2011;69:292-302.
  2. Comi G et al. Lancet. 2009;374:1503-1511.
  3. Gold R et al. N Engl J Med. 2012;367:1098-1107.
  4. Fox RJ et al. N Engl J Med. 2012;367:1087-1097.
  5. Kappos L et al. N Engl J Med. 2010;362:387-401. doi: 10.1056/NEJMoa0909494.
  6. Caon C. J Neurol Sci. 2009;277 (Suppl 1):S33-6. doi: 10.1016/S0022-510X(09)70010-3.
  7. Gajofatto A et al. Mult Scler. 2009;15:50-58. doi: 10.1177/1352458508096687.
  8. Sørensen PS et al. Mult Scler. 2012;18:143-152. doi: 10.1177/1352458511435105.
  9. Rudick RA et al. N Engl J Med. 2006;354:911-923.
  10. Polman CH et al. N Engl J Med. 2006;354:899‐910.
  11., website. Accessed June 3, 2013.
  12. Genzyme, press release. Accessed June 3, 2013.
  13. Radue EW et al. Arch Neurol. 2012;69:1259-1269.
  14. Cohen JA et al. N Engl J Med. 2010;362:402-415. doi: 10.1056/NEJMoa0907839.
  15. MS Alliance, website. Accessed September 24, 2013.
  16. National MS Society, website. Accessed September 24, 2013.
  17. Copaxone (glatiramer acetate), prescribing information. Accessed June 5, 2013.
  18. Gilenya (fingolimod), prescribing information. Accessed June 5, 2013.

The materials presented here are used with the permission of the authors and/or other sources.
These materials do not necessarily reflect the views of Answers in CME or any of its supporters.

This activity is supported by educational grants from Teva CNS, Novartis Pharmaceuticals Corporation and Genzyme, a Sanofi Company
Additional support provided by Penn State College of Medicine and Answers in CME.

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New and Emerging Therapies for the Treatment of Multiple Sclerosis: What is Their Potential Role in Patient Management?

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