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Switching Therapies in MS: What Are the Options?

Clyde E. Markowitz, MD

Department of Neurology and the Multiple Sclerosis Center, the Hospital of the University of Pennsylvania, Philadelphia

Although current disease-modifying treatments for relapsing forms of MS cannot completely stop disease activity, they can slow disability progression and cognitive decline, minimize the occurrence and duration of relapses, and prevent new lesions from forming. However, relapses or a suboptimal response to the medication as indicated by clinical or imaging evidence of disease activity (AV 1),1 also known as breakthrough disease, is common.2 For example, a review2 of relapsing-remitting MS found that, within 2 years of beginning treatment with a first-line agent, approximately two-thirds of patients relapsed or developed at least 1 new MRI lesion. To address breakthrough disease, clinicians should first assess patients with MS for treatment adherence, monitor their disease course throughout treatment to identify disease activity, and then intervene with appropriate treatment strategies.

AV 1. Proposed Consensus Criteria for Identifying Patients With Suboptimal Response (0:45)

AV 1. Proposed Consensus Criteria for Identifying Patients With Suboptimal Response
Assessing Adherence

If a patient is experiencing breakthrough disease, clinicians must first determine if relapses or new MRI lesions are the result of nonadherence before making any treatment adjustments, such as dose increases, that could compromise the patient’s safety. Some patient factors that can affect adherence include cognitive impairment, depression, anxiety, fatigue, and attitudes and beliefs about medications. For example, patients may not understand that medication can help control their disease, they may have a pessimistic outlook about their condition, or they may have unrealistic expectations about a medication’s capabilities. Patients may also experience intolerable side effects that can lead to discontinuation, so clinicians should effectively assess for and manage any adverse effects. By providing education on treatment goals, discussing patients’ expectations, and treating adverse effects, clinicians can create a strong alliance with patients and improve their adherence. A multidisciplinary approach is also needed so that patients have access to specialists (eg, physical therapists, psychologists, urologists) who have a firm understanding of MS and also encourage treatment compliance.

Ongoing Monitoring

After assessing adherence, clinicians can begin or continue to monitor patients’ treatment response. Determinations of suboptimal response are based on changes in relapse frequency, level of disability, neurological exams, disease progression, MRI scans, and adverse events experienced.2 Based on these areas, clinicians can ascertain if a patient’s MS is being adequately managed and what treatment interventions are necessary if breakthrough disease occurs.

Clinical monitoring. To monitor response to treatment, clinicians should track patients’ relapse frequency and severity, progression of disability, and transition from a relapsing to a progressive disease course.3 Monitoring the severity of relapses can help clinicians determine patients’ level of disability. For example, a mild clinical sensory complaint may not be as concerning as a motor complaint that affects a patient’s ability to work, drive, or walk. Additionally, after a relapse, patients may not recover to their previous level of functioning. Their progression of disability may be measured by administering the EDSS and tracking patients’ scores. A common criterion for breakthrough disease in clinical studies is a 1-point or more increase in EDSS scores over a certain time frame (eg, 6 months),3 which represents a substantial change in neurologic function.4

MRI monitoring. Whether or not patients demonstrate clinical evidence of breakthrough disease, MRI scans can detect disease activity by mapping existing and newly formed brain and spinal cord lesions, including hyperintense lesions on T2-weighted images, hypointense lesions on T1-weighted images, and gadolinium-enhanced lesions on post-contrast images.3 Clinicians can use MRI scans to track the number, volume, and location of lesions to monitor disease worsening. New MRI metrics are being explored, such as MRI measurement of gray matter atrophy, but are not yet used clinically.3

Adjusting Treatment

If clinicians determine that a patient is experiencing breakthrough disease, treatment adjustments may be necessary (AV 2).4 For patients with relapses and lesion activity, clinicians may consider adjusting the treatment dose, switching medications, or adding other agents as combination therapy.3,4

AV 2. Steps in Assessing Treatment Response in Patients With Multiple Sclerosis (0:34)

AV 2. Steps in Assessing Treatment Response in Patients With Multiple Sclerosis

Adjusting the dosage. Depending on the first-line medication, patients may require a dosage change to manage breakthrough disease. For interferon-beta (IFNβ), a type of first-line medication, the optimal dose varies from patient to patient. For those not responding to low-dose IFNβ (once-weekly IM), increasing the dose may be useful in selected cases, but may have little long-term effect on reducing relapses or disability.3

Note: The occurrence of neutralizing antibodies (NAbs), especially at high titers, can limit efficacy of IFNβ on delaying relapses and preventing new lesions from forming.2 Clinicians can monitor NAbs, which occur more frequently in patients taking subcutaneous rather than IM IFNβ and which usually appear between 6 and 24 months after treatment initiation.2

Switching agents. Patients with concerning breakthrough disease, such as those who have had cumulative disability from multiple relapses, may be switched to a medication that will better prevent attacks despite having a greater risk of adverse events.3 Injectable IFNβ and glatiramer acetate (GA) are moderately effective but are safer than IV natalizumab, which is more effective but carries more serious risks.2 Some patients may prefer the ease of use of oral medications, which have known short-term adverse effects but unknown long-term risks.

A large, open-label study5 (N = 4,754) evaluated the 4 available IFNβ therapies in relapsing forms of MS. Results showed that switching between IFNβ regimens was not beneficial for disease outcomes, and the effectiveness of the 4 treatments was similar, although benefits were noticeable when IFNβ was used as first-line rather than follow-up treatment.5

Another study6 showed that patients with suboptimal response to initial disease-modifying therapy experienced fewer relapses after switching between first-line medications or from first-line to second-line medications, illustrating that this strategy may be appropriate to reduce signs of disease activity.6

Escalating to a second-line treatment may be more beneficial than switching between first-line treatments for patients with suboptimal response. For example, an open-label cohort study7 found significant relapse rate reductions for patients with breakthrough disease who switched from first-line therapy to natalizumab or an immunosuppressant (P < .001 for both) but not for nonswitchers (P = .87) (AV 3).7 In a study by Prosperini and colleagues,8 patients with breakthrough disease (2 relapses or 1 relapse and residual disability) on first-line treatment switched to another first-line medication or escalated to second-line treatment with natalizumab. Although no differences were observed at 12 months between the 2 groups, more patients who switched to natalizumab had reduced relapses (P = .0001), disability progression (P = .0045), and MRI activity (P = .0003) compared with patients who switched among first-line immunomodulators, suggesting that natalizumab may be a more effective switching strategy than changing to another first-line therapy.8

AV 3. Relapse Rate Reductions for Patients In the Post-Switch Period (0:33)

AV 3. Relapse Rate Reductions for Patients In the Post-Switch Period

Note: When prescribing natalizumab, clinicians must inform patients of the risk of PML, a potentially fatal viral infection.9 Patients should be tested for JCV antibodies before initiating treatment with this agent. Additionally, anti-natalizumab antibodies may block the agent’s effectiveness and occur in about 6% of patients taking natalizumab.2

Switching to oral agents. Three oral medications are now available, and their ease of use and more favorable side effect profiles may be an appealing option for patients with suboptimal response to injectable or IV medications. Although long-term efficacy data are currently unavailable for switching to oral medications, the 3 approved agents have been shown to be effective for reducing relapses, MRI lesions, and disability in patients with relapsing MS.10 For patients with breakthrough disease or intolerance to injectable medications, switching to an oral agent may be an appropriate strategy, but clinicians must consider the risks and benefits of each agent as well as the patient’s preference.

Fingolimod was the first oral agent approved for the treatment of MS, based on phase 3 trials showing that fingolimod reduced relapses by about 50% compared with placebo or weekly IM IFNβ-1a.11 A retrospective study12 that examined patients with MS switching from IFNβ to either GA or fingolimod found that fewer patients had at least 1 relapse in the fingolimod group (13%) than in the GA group (25%). Patients who switched to fingolimod also had a 59% lower probability of relapse and 62% fewer relapses per year compared with those who switched to GA.12 Studies13,14 have also evaluated patients switching from natalizumab to fingolimod. Because between 20% and 30% of patients relapsed either during the washout period or the first 6 months of fingolimod treatment, a washout period of less than 2 to 3 months is recommended to decrease the risk of relapse.

Some concerns related to fingolimod are cardiac issues, macular edema, respiratory effects, liver toxicity, immunosuppression, and fetal risk.15 Clinicians should also assess patients’ prior exposure to various infections (eg, herpes, chicken pox) and ensure proper immunization before beginning this treatment. Fingolimod may be a viable switch option as long as clinicians complete appropriate baseline assessments, first-dose monitoring, and washout periods to minimize risks.11

Like fingolimod, teriflunomide is a once-daily oral formulation, and it has been shown to reduce relapse rates by about one-third.16 Patients must have a TB test before starting treatment and require liver and blood pressure monitoring throughout treatment. Serious side effects of this medication include severe liver injury, immunosuppression, acute renal failure, peripheral neuropathy, hypertension, and respiratory effects. Alopecia is a less serious side effect of this drug, but patients should still be aware of this risk.16 Teriflunomide is contraindicated in patients with severe hepatic impairment and in men and women who want to have children. Discontinuation due to liver problems or pregnancy may be followed by an accelerated elimination procedure using cholestyramine or activated charcoal.16

The third available oral agent for treating relapsing forms of MS is dimethyl fumarate (taken twice daily), which reduced annualized relapse rates by about half in clinical trials.17 Warnings of this medication are for lymphopenia and flushing, and common side effects are GI problems, such as nausea, diarrhea, and abdominal discomfort.17 Some of these can be managed with NSAID pretreatment, and taking the medication with food may help.17 A main concern is the 4 cases of PML reported in patients taking fumarates used to treat psoriasis.18 Overall, dimethyl fumarate requires less monitoring than other medications, but annual monitoring for white blood cell count is recommended.17

Combination therapies. For patients who have some response to first-line treatment and want to maintain that response, adding an agent to their current regimen is an option. Benefits of combination therapy in MS include the usefulness in treating comorbid disorders, a variety and large number of available adjunctive agents, the possibility of increased efficacy via different mechanisms of action, and the potential for reducing adverse events or toxicity by using lower doses of each agent or by choosing agents specifically to combat existing side effects.19 Some agents can also be added to disease-modifying therapy to combat specific MS symptoms, such as dalfampridine for walking. However, in terms of breakthrough disease, efficacy has not yet been established for combining disease-modifying agents.

Most adjunctive strategies involve combining IFNβ or GA with each other or with natalizumab or mitoxantrone.19 A double-blind, randomized, controlled study20 examined whether combined IM IFNβ-1a and GA was more effective than either medication alone for relapsing-remitting MS. Over 3 years, the combination did not have a statistically superior annualized relapse rate than the individual agents (P = .27), although the combination and GA were better than IFNβ-1a in reducing the risk of relapse by 31% and 25%, respectively. Combination therapy also reduced new lesion activity and total lesion volumes compared with the individual agents.20

Disease-modifying therapies, mainly IFNβ and GA, have also been combined with corticosteroids, methotrexate, azathioprine, and cyclophosphamide.19 A review19 of adjunctive agents (ie, methylprednisolone, natalizumab, cyclophosphamide, and mitoxantrone) concluded that, while some preliminary studies found favorable results for agents added to IFNβ treatment, larger, randomized, controlled trials have shown negative or conflicting results, which casts uncertainty on the usefulness of combination therapy. Generally, combining medications in MS is less common than monotherapy now because of the greater number of disease-modifying treatments.

Conclusion

Clinicians must assess adherence before determining that a patient is experiencing breakthrough disease. Several clinical and MRI measures can be used to monitor patients’ response to treatment, although individual factors such as relapse recovery and level of disability play an important role in making treatment decisions. For patients with suboptimal response or breakthrough disease, clinicians can adjust the dose, switch the disease-modifying treatment, or add an agent to the current treatment. Switching has better evidence than increasing dosages or combining agents. Switching from first-line treatments (IFNβ, GA) to second-line treatments (natalizumab, mitoxantrone) or to an oral medication (fingolimod, teriflunomide, dimethyl fumarate) requires knowledge of the risks and benefits associated with each agent. With more available treatments for MS, clinicians can intervene early to optimize and individualize therapy and improve outcomes for patients with MS.

Clinical Points
  • Monitor adherence in your patients with MS
  • Use clinical and MRI measures to assess treatment response
  • Consider adjusting medication dose, switching disease-modifying therapies, or combining treatments to manage breakthrough disease
Drug Names

azathioprine (Azasan, Imuran, and others), cyclophosphamide (Cytoxan and others), dalfampridine (Ampyra), dimethyl fumarate (Tecfidera), fingolimod (Gilenya), glatiramer acetate (Copaxone), interferon β-1a (Avonex and Rebif), interferon β-1b (Betaseron and Extavia), methylprednisolone (Medrol, SoluMedrol, and others), methotrexate (Otrexup, Trexall, and others), mycophenolate mofetil (Cellcept and others), natalizumab (Tysabri), teriflunomide (Aubagio)

Abbreviations

EDSS = Expanded Disability Status Scale, GA = glatiramer acetate, GI = gastrointestinal, IFNβ = interferon beta, IM = intramuscular, IV = intravenous, JCV = John Cunningham virus, MRI = magnetic resonance imaging, MS = multiple sclerosis, NAbs = neutralizing antibodies, NSAID = nonsteroidal anti-inflammatory drug, PML = progressive multifocal leukoencephalopathy, TB = tuberculosis

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References
  1. Cohen BA, Khan O, Jeffery DR, et al. Identifying and treating patients with suboptimal responses. Neurology. 2004;63(12 suppl 6):S33–S40. PubMed
  2. Rudick RA, Polman CH. Current approaches to the identification and management of breakthrough disease in patients with multiple sclerosis. Lancet Neurol. 2009;8(6):545–559. PubMed
  3. Fox EJ, Havrdova E. Breakthrough disease in multiple sclerosis: the problem and treatment options. European Neurol Rev. 2013;7(suppl 2):24–31. Full Text
  4. Río J, Comabella M, Montalban X. Predicting responders to therapies for multiple sclerosis. Nat Rev Neurol. 2009;5(10):553–560. PubMed
  5. Limmroth V, Maless R, Zettl UK, et al, for the QUASIMS Study Group. Quality Assessment in Multiple Sclerosis Therapy (QUASIMS): a comparison of interferon beta therapies for relapsing-remitting multiple sclerosis. J Neurol. 2007;254(1):67–77. PubMed
  6. Río J, Tintoré M, Sastre-Garriga J, et al. Change in the clinical activity of multiple sclerosis after treatment switch for suboptimal response. Eur J Neurol. 2012;19(6):899–904. PubMed
  7. Castillo-Trivino T, Mowry EM, Gajofatto A, et al. Switching multiple sclerosis patients with breakthrough disease to second-line therapy. PLoS One. 2011;6(2):e16664. PubMed
  8. Prosperini L, Gianni C, Leonardi L, et al. Escalation to natalizumab or switching among immunomodulators in relapsing multiple sclerosis. Mult Scler. 2012;18(1):64–71. PubMed
  9. Tysabri (natalizumab) [package insert]. Cambridge, MA: Elan Pharmaceuticals, Inc; 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=6fa00cb8-4229-4770-9d2a-d4a8542b3180. Accessed August 7, 2014.
  10. Thöne J, Ellrichmann G. Oral available agents in the treatment of relapsing remitting multiple sclerosis: an overview of merits and culprits. Drug Healthc Patient Saf. 2013;5:37–47. PubMed
  11. Singer BA. Initiating oral fingolimod treatment in patients with multiple sclerosis. Ther Adv Neurol Disord. 2013;6(4):269–275. PubMed
  12. Bergvall N, Makin C, Lahoz R, et al. Relapse rates in patients with multiple sclerosis switching from interferon to fingolimod or glatiramer acetate: a US claims database study. PLoS One. 2014;9(2):e88472. PubMed
  13. Jokubaitis VG, Li V, Kalincik T, et al, for the MSBase Study Group. Fingolimod after natalizumab and the risk of short-term relapse. Neurology. 2014;82(14):1204–1211. PubMed
  14. Cohen M, Maillart E, Tourbah A, et al. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436–441. PubMed
  15. Gilenya (fingolimod)[package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cc9e1c8c-0e2b-44e2-878b-27057f786be9. Accessed August 7, 2014.
  16. Aubagio (teriflunomide)[package insert]. Cambridge, MA: Genzyme Corp; 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4650d12c-b9c8-4525-b07f-a2d773eca155. Accessed August 7, 2014.
  17. Tecfidera (dimethyl fumarate)[package insert]. Cambridge, MA: Biogen Idec Inc; 2013. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=665d7e74-036c-5f68-5b67-ab84b9b49151. Accessed August 7, 2014.
  18. Sweetser MT, Dawson KT, Bozic C. Manufacturer’s response to case reports of PML. N Engl J Med. 2013;368(17):1659–1661. PubMed
  19. Conway D, Cohen JA. Combination therapy in multiple sclerosis. Lancet Neurol. 2010;9(3):299–308. PubMed
  20. Lublin FD, Cofield SS, Cutter GR, et al, for the CombiRx Investigators. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73(3):327–340. PubMed
From the Series:
The Impact of Oral Medications on the Treatment of Multiple Sclerosis

Supported by educational grants from Genzyme, a Sanofi Company, and Novartis Pharmaceuticals Corporation.

CME Background Information

Supported by educational grants from Genzyme, a Sanofi Company, and Novartis Pharmaceuticals Corporation.

Participants may receive credit by reading the activity, correctly answering the posttest question, and completing the evaluation.

Objective

After completing this educational activity, you should be able to:

  • Compare new oral treatment options for MS with each other and with injectable treatments

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosures are as follows:

Dr Markowitz is a consultant for Biogen Idec, Teva, Bayer, Novartis, Genzyme, and Roche.

The chair for this activity, Harold Moses, Jr, MD, is a consultant for Bayer, Biogen Idec, Genzyme, Teva, and Questcor; has received grant/research support from Novartis, NIH, Biogen Idec, Sanofi, and Genzyme; and is a member of the speakers/advisory boards for Questcor, Avanir, Teva, Biogen Idec, and Bayer.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This Neurology Report was published in December 2014 and is eligible for AMA PRA Category 1 Credit™ through December 31, 2017. The latest review of this material was August 2014.

Statement of Need and Purpose

Multiple sclerosis (MS) affects over 2 million people worldwide and results in reduced quality of life, cognitive impairment, and physical disabilities. The medications initially approved for MS required patients to either self-administer injections or receive hospital-based intravenous infusions. However, the US Food and Drug Administration (FDA) has recently approved oral medications for MS, which has changed patients’ outlook toward MS therapies, and using oral medications may have a positive impact on their quality of life. Oral agents have several benefits, including convenience, ease of use, and greater comfort with taking a pill versus administering an injection, but carry risks as well, especially for potentially serious side effects. Further, long-term safety and efficacy of these new agents remain unknown. Therefore, switching patients to oral medications on the basis of convenience is not a sufficient reason for the change. Because the landscape of MS treatment is changing rapidly, health care providers need information on all of the available treatments to help their patients receive optimal care. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on MS.

Disclosure of Off-Label Usage

Dr Markowitz has determined that azathioprine, cyclophosphamide, methotrexate, and mycophenolate mofetil are not approved by the US Food and Drug Administration for the treatment of MS.

Review Process

The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.

Acknowledgment

This Neurology Report is derived from the planning teleconference series “The Impact of Oral Medications on the Treatment of Multiple Sclerosis,” which was held in November 2013 and March 2014 and supported by educational grants from Genzyme, a Sanofi Company, and Novartis Pharmaceuticals Corporation. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.