Practical Guidance for Overcoming Challenging Patient-Care Issues in MS

Course Director

Daniel Ontaneda, MD, MS

Daniel Ontaneda, MD, MS
Cleveland Clinic Lerner College of Medicine
Case Western Reserve University
Cleveland, Ohio


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Part 2 of a 2-part series

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

Overview

The availability of novel therapies for multiple sclerosis (MS) has greatly increased the range of effective treatment options, but with these new options come questions regarding how and when to incorporate these agents into practice and how to optimally use them to maximize the benefits and minimize the risks to patients. In this activity, Dr. Daniel Ontaneda discusses brief MS case scenarios and provides practical guidance on how to deal with common patient-care challenges in everyday practice.


Disclosures

This activity is supported by educational grants from Biogen Idec and Novartis Pharmaceuticals Corporation.

Course Director
Daniel Ontaneda, MD, MS, has a financial interest/relationship or affiliation in the form of:
Consultant for Acorda Therapeutics; Biogen Idec; and Novartis Corporation.
Medical Director
Kadrin Wilfong, MD
Answers in CME, Inc.
Kadrin Wilfong, MD, 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 distinguishes one oral MS therapy from another? How can we determine which patients are better suited for oral versus parenteral therapy? And are there "best" candidates for a particular oral therapy?

Dr. Ontaneda: The selection of disease-modifying agents in multiple sclerosis [MS] is a significant challenge for a neurologist. And probably the best answer is that the selection of treatment should be individualized. The neurologist should take a careful look at several different factors to make a treatment decision. These include: 1) Disease activity: MRI disease activity, relapse disease activity, and progression of disability or accrual of disability activity. 2) Prior treatment response: What medications has the patient previously been on? Did they respond to those treatments? Did they fail those treatments? Did they have side effects to those treatments? 3) What are the patient baseline characteristics? We look at these increasingly to identify which patients are at higher risks of developing certain complications on specific agents. And, 4) what is the patient risk-benefit profile? This is a very important question that sometimes takes some time to answer. The neurologist should form some rapport with the patient and understand how aggressive the patient wants to be with their treatment.

Disease activity is probably what is easiest to identify for most neurologists. This includes understanding of the relapse rate, MRI lesion activity, disability progression, and atrophy measures. So treatment should be selected to manage the inflammatory activity a given patient has. Now, although this is sometimes difficult to do, certainly a patient with one enhancing lesion is not going to be the same as a patient with 10 enhancing lesions, and selection of treatment should target agents that have very powerful anti-inflammatory effects and also take into account how quickly those medications will start working.

Prior treatment response will give the clinician a good idea about how aggressive the disease might be and how they might respond to subsequent therapies. For example, a patient who has failed natalizumab is probably not the same as a patient who has failed one of the injectable therapies.

Oral agents should be selected which have the best likelihood of controlling disease activity. An understanding of the effectiveness of each medication compared to placebo will be helpful to make the selection. Now, by no means am I saying that we should compare the effect of medications against placebo, against each other—we know that methodologically that has its concerns [without head-to-head clinical trials]. But we should have an idea of what the overall estimate of effect of each medication is in order to pick the medication which is likely to control disease activity.

Patient baseline characteristics are very important in selecting disease-modifying agents. For example, some medications have significant teratogenic effects and, therefore, should be used with caution or even avoided in women who are at risk of becoming pregnant.1-3 Given cardiac side effects and macular edema, for example, fingolimod might not be the best choice in a 65-year-old patient with diabetes and coronary artery disease.1,4-6 Gastric side effects—gastric intolerance, nausea, vomiting, and diarrhea—can be an issue with dimethyl fumarate.2,7-10 And, therefore, patients with active GI disease, such as peptic ulcer or GERD, may have significant tolerability problems, and that should be taken into the equation of selecting an appropriate agent. Age, gender, and underlying medical conditions will help clinicians select a treatment that is both well-tolerated and minimize potential side effects.

Clinicians also need to understand the risk aversion of their patients. Some individuals are willing to take considerable risks, while others are not. Evidence suggests that patients with increasing disability are more likely to take higher risks when deciding on a disease-modifying agent. The novelty of a given medication might be an issue for a very risk-averse patient, but may not be a problem for someone who wants complete disease control despite higher risks.11,12

Taking all these factors into consideration will help the clinician and patient decide on an appropriate treatment. As the armamentarium of MS therapies increases, the neurologist will have to be able to guide patient decision, while at the same time understanding patient wishes.

Frequently, I am asked about the role of oral therapies as first-line agents. My current clinical practice is to offer patients a treatment individualized to their given characteristics. And many times oral agents are good fits for individual patient needs. As we gain experience with oral therapies, and if these prove to be safe in their use, it is likely that oral therapies will be used with increasing frequency as first-line agents.

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My patient is a 28-year-old woman who has been treated for MS for the past seven years; she is fully ambulatory. She was previously on interferon beta-1a, then natalizumab for two years, after which the JCV-antibody test came out, so she was stopped and placed on teriflunomide. She presents with her first major relapse in at least five years with right-sided weakness, and MRI shows tumefactive MS lesions. What therapy would you recommend now?

Dr. Ontaneda: The case illustrates a rather common clinical scenario, which is return of disease activity when stopping natalizumab.13 Now, I will work under the assumption that the patient is JC-virus–positive. The first choice of therapy in this case certainly would be a course of intravenous methylprednisolone; this will help with a prompt recovery of the relapse. Following steroids, one would choose a fourth disease-modifying agent for this patient.

There is no good clinical trial data that will guide us with which medication is best in this individual patient. Given that this patient has previously failed a first-line treatment such as interferon, I would think that the likelihood that [considering] another injectable agent—that is, another interferon or glatiramer acetate—the ability of one of those medications to control disease activity is probably pretty low.14

Having said that, basically we have two remaining options: That would be either fingolimod or dimethyl fumarate.5,9,10,13,15-19 The selection between these two medications is somewhat difficult. Clinical trial data show very similar efficacy in terms of relapses and MRI lesion control. I would probably pick the medication that the patient is most likely to tolerate, and the medication that would have the lowest risk of side effects based on the adverse-effect profile of the patient. Considerations would include history of GI disease, previous GI intolerance to medications, history of cardiac arrhythmia, presence of syncope, liver disease, presence of a history of diabetes, and use of concomitant medications.

A third, and somewhat more aggressive, option would be re-initiation of natalizumab. Although this certainly would not be my first recommendation, at our center, we have patients who wish to continue natalizumab despite risk of PML [or progressive multifocal leukoencephalopathy]. Using natalizumab in a JC-virus–positive patient many times is a decision the patient will make, and as clinicians, it is our job to make sure that the patient fully understands the risks associated with ongoing natalizumab treatment despite positive JCV status. In this patient, this would be very high-risk, as the patient has already been on a number of different MS medications, and this includes [2 years of] natalizumab. So, probably I would dissuade the patient against it. But I want to illustrate the fact that patients typically will make their own decisions regarding disease-modifying agents, and if a patient understands the risks and—despite understanding the risks wants to make a given decision—many times we have to comply with [what] the patient wishes.11,12

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Patients who want to become pregnant ask for advice regarding treatment. I typically take them off an interferon for three months before they try to conceive and then re-start the medication after delivery (unless they are breastfeeding). How should this advice change with the oral agents?

Dr. Ontaneda: This is an excellent question that many neurologists and patients face frequently. There are several points to be discussed in relation to pregnancy and disease-modifying medication. The first involves choosing when to become pregnant. In most patients with multiple sclerosis, my recommendation is that their pregnancy takes precedence over their MS. It is well-known that pregnancy confers protection for multiple sclerosis.20

Narrator: For example, pregnancy in MS patients has been associated with a reduced relapse rate and a reduction of neurological symptoms, especially in the third trimester.20

Dr. Ontaneda: Although the effects of female hormones are thought to be involved, the exact mechanisms through which pregnancy protects against MS are not clearly known.

I generally counsel the patients that if they wish to become pregnant, during pregnancy they will have one of the best MS treatments known, which is pregnancy itself. If they are currently on a disease-modifying agent, I typically would ask them to stop the disease-modifying agent prior to conception. One month off medication should be okay for most agents. The exception would be with teriflunomide, which is a Category X medication in pregnancy.3 For teriflunomide, a rapid elimination procedure is recommended and confirmation of medication levels in blood is desirable before conception.

The other oral therapies, fingolimod or dimethyl fumarate, are FDA Category C in pregnancy.1,2 For dimethyl fumarate, the medication has a very short half-life and is typically eliminated relatively quickly. And therefore, a very short washout period between medication termination and conception is appropriate.2 For fingolimod, some recommendations ask that patients be off medication for two months prior to conceiving, given that the medication does tend to have lingering effects in the body for at least that amount of time.1 It is important to note that in MS there is one Category B medication, which is glatiramer acetate.21

In pregnant MS patients, the literature, however, also indicates that there is an increased risk of relapse after delivery.22,23 If this does occur, I typically treat with steroids and counsel the patient to start disease-modifying treatment after that. The use of steroids or plasma exchange prophylactically has been studied, but at our center we do not generally recommend this. The rationale is that most women actually do not experience relapses postpartum, and therefore treatment may pose unwanted risks and costs. I also recommend that if patients wish to breastfeed, they can do so. And after breastfeeding is concluded, they can begin a disease-modifying therapy once again.

In certain patients with aggressive disease, it may be appropriate to stabilize the disease clinically before attempting pregnancy. However, this decision must be made on a case-by-case basis. Factors to consider will include patient age, history of previous pregnancies, [and] family plans going forward. For example, a patient who is in her early 20s who has not had babies and has a very aggressive MS disease course, it might be recommendable for that patient to have therapy, control the disease activity, and then move on to pregnancy. This woman has many years going forward where she will be able to become pregnant. In other situations, for example, when a woman is approaching an age where pregnancy becomes riskier, one might want to get pregnancy done as quickly as possible.

Another point of interest is outcomes in pregnancies that have been completed while on disease-modifying agents. While we don't have much data on oral agents,24 we certainly do have data on injectable therapies. There have been several studies examining patients who have remained pregnant in long-term follow-up, especially on glatiramer acetate. It appears that [in] patients who have become pregnant and stayed pregnant while on glatiramer acetate, babies seem to do well. There do not seem to be any major risks associated with that. However, there is always the unknown.25,26 Given the patient numbers are small, we typically recommend patients stopping disease-modifying agents.

Ultimately, pregnancy is a very delicate situation and given there is not a lot of scientific evidence about the safety of our medications, we tend to err on the side of caution, recommending that patients stay off medication during pregnancy and also during breastfeeding.

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References

  1. GILENYA (fingolimod) Prescribing Information. http://www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf. Accessed November 7, 2013.
  2. TECFIDERA (dimethyl fumarate) Prescribing Information. http://www.tecfidera.com/pdfs/full-prescribing-information.pdf. Accessed November 7, 2013.
  3. AUBAGIO (teriflunomide) Prescribing Information. http://products.sanofi.us/aubagio/aubagio.pdf. Accessed November 7, 2013.
  4. Willis MA, Cohen JA. Semin Neurol. 2013;33:37-44.
  5. Cohen JA et al. N Engl J Med. 2010;362:402-415.
  6. FDA Drug Safety Communication: Revised recommendations for cardiovascular monitoring and use of multiple sclerosis drug Gilenya (fingolimod).
    http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm. Accessed November 7, 2013.
  7. Linker RA, Gold R. Curr Neurol Neurosci Rep. 2013;13:394.
  8. Stangel M, Linker RA. Expert Rev Clin Pharmacol. 2013;6:355-362.
  9. Fox RJ et al. N Engl J Med. 2012;367:1087-1097. Erratum in: N Engl J Med. 2012;367:1673.
  10. Gold R et al. N Engl J Med. 2012;367:1098-1107. Erratum in: N Engl J Med. 2012;367:2362.
  11. Ontaneda D, Fox RJ. Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):1092-1099.
  12. Lugaresi A et al. Neuropsychiatr Dis Treat. 2013;9:893-914.
  13. Spelman T et al. 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2013). Abstract 179.
  14. Havla J et al. Ther Clin Risk Manag. 2013;9:361-369.
  15. Kappos L et al. N Engl J Med. 2010;362:387-401.
  16. Kappos L et al. N Engl J Med. 2006;355:1124-1140.
  17. Voldsgaard A et al. ECTRIMS 2013. Abstract 178.
  18. Gold R et al. ECTRIMS 2013. Poster 538.
  19. Phillips JT et al. ECTRIMS 2013. Poster 996.
  20. D'hooghe MB et al. Gynecol Obstet Invest. 2013;75:73-84.
  21. COPAXONE (glatiramer acetate injection) Prescribing Information. http://copaxone.com/pdfs/PrescribingInformation.aspx. Accessed November 7, 2013.
  22. Finkelsztejn A et al. BJOG. 2011;118:790-797.
  23. Hughes SE et al. [published online ahead of print October 9, 2013]. Mult Scler. doi:10.1177/1352458513507816.
  24. Hellwig K et al. ECTRIMS 2013. Abstract 114.
  25. Fragoso YD et al. CNS Drugs. 2013;27:955-961.
  26. Lu E et al. Neurology. 2012;79:1130-1135.

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Biogen IdecNovartis Pharmaceuticals Corporation

This activity is supported by educational grants from Biogen Idec and Novartis Pharmaceuticals Corporation.

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