Current Standards of Treatment in MS and the Role of Oral Agents
Harold Moses, Jr, MD
Multiple sclerosis (MS) is a debilitating disease affecting at least 30 per 100,000 people worldwide.1 Although MS cannot be cured, the relapsing forms of the illness respond to disease-modifying treatments; relapses (also called attacks or exacerbations) often require separate, short-term treatment. While only injections and IV infusions have been historically used to treat MS, newer, FDA-approved oral agents are now available. These oral agents offer several advantages and disadvantages that must be considered along with other factors that influence treatment decisions.
Agents for MS Relapses
Before the development of disease-modifying drugs, treatment of acute relapses was the only therapy available for people with MS.2 Corticosteroids were, and still are, the main treatment for acute relapses. These agents are used for a few days to 2 weeks, but no consensus exists on the optimal regimen.3 Corticosteroids are involved in a wide range of physiological processes, including stress responses, immune responses, and inflammation regulation. Steroids are used to treat MS by diminishing inflammation. Although IV methylprednisolone is commonly used, evidence4 suggests that outcomes with oral agents are similar to those with IV agents. Oral preparations, including prednisone, are typically more convenient and less expensive than the IV infusions.5 Also available is adrenocorticotropic hormone (ACTH), which is used in patients whose attacks are refractory to standard steroid therapy.2
Side effects of steroids and ACTH may develop, and discussing these potential issues with patients is important. In the short-term, patients can develop glaucoma, increased blood pressure and blood glucose levels, mood swings, weight gain, lipodystrophy, Cushingoid appearance, peptic ulcers, and fluid retention, including swelling in the lower legs.2 In the long-term, some patients may develop cataracts, hyperglycemia, an increased risk of infection, osteopenia, osteoporosis, dyslipidemia, and avascular necrosis.2 Over time, patients may also experience suppressed adrenal gland hormone production, thinning skin, easy bruising, and slower wound healing.6
Disease-Modifying Agents for Relapsing MS
For a long time, the only available treatment for MS was the management of acute relapses.2 Now, a main consideration is to reduce the occurrence of relapses through the use of disease-modifying drugs.7 In addition to reducing the underlying inflammatory process, treatment should result in fewer new lesions within the brain and spinal cord. This goal includes reducing new T2 lesions, GAD-enhancing T1 lesions, and T1 hypointense lesions shown on MRI and, ultimately, diminishing brain and spinal cord atrophy.8 Treatment goals should still include reducing short-term disability, both in terms of relapse duration and intensity. Finally, the major long-term objective for patients is to prevent disability. This objective seems to be achieved in some patients with the current disease-modifying therapies, but, hopefully, with newer treatment agents, more patients will achieve this goal in the future.
A number of approved disease-modifying therapies exist for relapsing MS (AV 1),9–11 4 of which are forms of IFNβ (either intramuscular or subcutaneous injections).12 Glatiramer acetate is also approved (subcutaneous), as are the IV infusible drugs mitoxantrone and natalizumab. Mitoxantrone is the only drug that is also approved for secondary progressive MS. Approved oral disease-modifying drugs are fingolimod, teriflunomide, and dimethyl fumarate. Because disease-modifying therapies do not change existing symptoms, patients often receive symptom-specific treatments (eg, dalfampridine for walking).7
Patients with a first attack suggestive of MS and objective clinical evidence of a lesion are characterized as having clinically isolated syndrome (CIS).13 If further attacks and/or lesions occur, the patient can be diagnosed with clinically definite MS.13 Patients with CIS should be treated with disease-modifying agents, some of which are FDA-approved for this indication, because evidence indicates that disability may be delayed and conversion to clinically definite MS may be prevented.14,15 These agents have well-established efficacy and safety profiles, and, for some insurers, are the only treatment options that may be offered to patients with early MS.
Advantages and Disadvantages of Oral Agents for MS
Advantages. For many patients, the idea of oral therapies is more comfortable than injections or IVs from an emotional standpoint, especially for patients who have otherwise been healthy. Oral medications offer a number of other potential advantages9:
- easy to ingest
- easy to transport
- less painful than injections or IVs
- No training necessary
- Easy access
Disadvantages. While oral MS medications may be easier for patients to take, clinicians must consider the following disadvantages and discuss them with their patients:
- new medications are actually priced higher than older medications, regardless of the mode of administration.
- cost comparisons need to be made individually.
- more research is needed on cost-effectiveness.16
- no evidence points to pills being safer than shots.
- long-term data are lacking on new oral therapies, while the older agents have better-known long-term safety profiles.17
- all of the oral agents approved for MS thus far have had varying degrees of tolerability issues.
- safety issues may preclude rapid transition to or initiation of another therapy.9
- prescreening and monitoring are needed with newer, oral agents.
- monitoring may require more visits to a clinic or physician’s office.
Factors That Influence Treatment Decisions
Guidelines18 for the use of disease-modifying therapies have not been updated since several new agents became available. Older therapies, including glatiramer acetate, IFNβ, and natalizumab, have a considerable advantage with regard to time on therapies and clinical experience. Most clinicians feel that they know what many patients may experience as they start one of these drugs. For example, natalizumab has a risk of PML, but the JCV antibody test can identify those with the highest PML risk.7 Some physicians and patients prefer to continue more established therapies despite the availability of newer, oral therapies. However, newly diagnosed patients may prefer an oral treatment, and many established patients may eventually make the transition from injections and IVs to oral medications.
A variety of different factors influence treatment decisions. For health care providers, medical considerations include the burden of disease, both clinically as well as reflected on MRI scans. On MRIs, for example, GAD-enhancing lesions are important for understanding how active a patient’s MS is at that moment in time.8 Disease course, both short-term and long-term, should be a major consideration. The number of relapses, particularly within the first 2 years after diagnosis, can help determine whether a treatment is efficacious or needs to be changed.
From patients’ perspectives, how the treatment impacts their lifestyle is crucial, as well as their expectations about what treatment will accomplish for them. Treatment choices should reflect patients’ capabilities in understanding and dealing with their chronic illness. Another factor in treatment choices is the support system that patients have through family and community relationships (AV 2).19
Research has shown that patients with MS relapses benefit from short-term steroid therapy while long-term use of disease-modifying therapy may decrease relapses and disability. Patients with early MS or CIS also benefit from therapy. Newer oral disease-modifying therapies can be an appropriate option for certain patients with MS. While oral treatments may be more desirable than injectable therapies, they also have disadvantages that must be discussed with patients along with other factors related to side effects and patient preferences. More research and data are needed on oral treatments for MS regarding efficacy and long-term safety.
- Treat MS attacks with short-term corticosteroids
- Treat CIS and MS with disease-modifying drugs
- Consider efficacy, safety, and tolerability when working with patients to select infusion, injection, or oral disease-modifying drugs
- Watch for long-term data on oral agents for MS treatment
ACTH = adrenocorticotropic hormone
CIS = clinically isolated syndrome
FDA = US Food and Drug Administration
GAD = gadolinium
IFNβ = interferon beta
IV = intravenous
JCV= John Cunningham virus
MRI = magnetic resonance imaging
MS = multiple sclerosis
PML = progressive multifocal leukoencephalopathy
dalfampridine (Ampyra), dimethyl fumarate (Tecfidera), fingolimod (Gilenya), glatiramer acetate (Copaxone), interferon β-1a (Avonex and Rebif), interferon β-1b (Betaseron and Extavia), natalizumab (Tysabri), teriflunomide (Aubagio)
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CME Background Information
Supported by an educational grant from Genzyme, a Sanofi Company, and Novartis Pharmaceuticals Corporation.
After completing this educational activity, you should be able to:
- Assess whether a patient’s quality of life may
benefit from switching to an oral MS agent from a self-injectable one
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 disclosure is as follows:
Dr Moses is a consultant for Bayer, Biogen, Genzyme, Teva, and Questcor; has received grant/research support from Novartis, NIH, Biogen, Sanofi, and Genzyme; and is a member of the speaker’s/advisory boards for Questcor, Avanir, Teva, Biogen, and Bayer.
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.
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 May 2014 and is eligible for AMA PRA Category 1 Credit™ through May 31, 2017. The latest review of this material was April 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 Moses has determined that, to the best of his knowledge, no investigational information about pharmaceutical agents that is outside US Food and Drug Administration-approved labeling has been presented in this activity.
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.
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.