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Program Overview

As pharmacists assume a more active role as part of the multidisciplinary multiple sclerosis (MS) care team, providing individualized, safe, and effective care for patients with MS can be challenging. This activity will provide pharmacists with the tools they need to maximize treatment outcomes and provide continuity of care for patients with MS, including disease pathophysiology and therapeutic targets, current recommendations for the use of disease-modifying therapies (DMTs) in adults, and safety and efficacy data for emerging agents.

Overview of Multiple Sclerosis

MS is a chronic inflammatory disease of the central nervous system (CNS) characterized by myelin destruction and axonal transection caused by the body’s immune system.^1-5 Widely considered an autoimmune disease, it is one of the leading causes of nontraumatic neurologic disability in young adults in the United States (US) and many other countries. Current prevalence estimates of MS in the US is close to one million people.^6-8 Diagnosis usually occurs between the age of 15 and 50 years, with the peak incidence occurring in the fourth decade of life. Women are two to three times as likely as men to develop MS.⁵ The most important determinants of disease risk are environmental influences (ie, prior infection with Epstein-Barr virus or human herpes virus 6, vitamin D deficiency, cigarette smoking), age, genetics, and immune dysregulation.^1-3,9 The global distribution of MS suggests that geography is also an important risk factor for disease onset. Overall, MS disease prevalence is higher in latitudes further from the equator.^5,10 However, substantial increases in MS incidence in Mediterranean regions and among females living in urbanized areas suggest a waning latitude gradient.¹¹

MS is a progressive disease in which an abnormal immune response causes irreversible damage to the CNS. The disease process is initiated when activated immune cells gain access to the CNS through a breach in the blood-brain barrier and trigger an inflammatory process that results in myelin degradation and transection of neurons.¹² Irreversible injury results when inflammatory disease activity outpaces the innate compensatory repair mechanisms and remodeling of the CNS. B cells and T cells are the major influencers of neuroinflammation. As such, they are the main therapeutic targets in the treatment of MS. 

MS has an unpredictable course with variable symptoms that can impact mobility and neurologic function.⁶ Disease activity is associated with long-term permanent disability and can be measured clinically or radiologically with magnetic resonance imaging (MRI).^13,14 Clinically isolated syndrome (CIS) is a term used to describe the first clinical episode that appears to be MS. The symptoms of CIS are caused by inflammation and/or demyelination in the CNS. CIS lasts for at least 24 hours and, depending on the patient’s clinical scenario, may require treatment. The clinical presentation of MS can be extremely variable between patients and is classified into relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). RRMS is characterized by distinct periods of new or increasing neurological symptoms (relapses) followed by periods of partial or complete recovery (remissions). Unlike RRMS, PPMS is characterized by a gradual worsening of symptoms and disability progression without distinct periods of relapse and remission. Within 15 to 20 years of onset, approximately 80% of people initially diagnosed with RRMS will develop SPMS, which is defined as a sustained period of gradual worsening of MS symptoms and disability over the course of 6 to 12 months. This worsening of neurological impairment is independent of relapse, although people with SPMS can still experience relapses. RRMS, the most common type, affects 85% of the MS population and therefore will be the focus of the remainder of this program.^15,16

The main goals of MS management are to slow disease activity and prevent the development of new lesions, delay progression of disability, manage symptoms, and maintain an acceptable quality of life.¹⁷ Treatment should be started as soon as a clinical diagnosis of MS is made, ideally within the first 5 years of clinical symptom onset.¹⁸ In RRMS, relapses indicate active disease and are typically followed by a period of remission. The duration, type of symptoms, and severity of a relapse varies. Accumulation of disability occurs when an individual does not fully recover from a relapse. Relapses are most common after onset of disease and diminish over time; the highest rates of relapse are seen within the first five years of diagnosis.¹⁸ Early initiation of DMT and identification of breakthrough disease (ie, clinical or radiological evidence of disease activity or progression, despite treatment) is critical for mitigating irreversible neurodegeneration and disability accumulation. Recent studies have shown that individuals with ongoing relapses or those who transition rapidly to SPMS experience a faster accumulation of disability in the absence of DMTs.^19-21

Goals of DMT and Current Treatment Recommendations

MS treatment may vary between institutions and across providers, depending on provider experience and preference, as well as local resources. Nonetheless, a three-pronged treatment approach is recommended for patients presenting with MS or CIS: 1) short-term treatment of an exacerbation, 2) long-term treatment of the disease itself with DMT, and 3) symptomatic treatment (ie, depression, cognitive changes, bladder dysfunction, spasticity, sensory symptoms, fatigue, walking speed), throughout the course of the disease.¹⁷ An MS treatment plan should be individualized based on patient factors and disease characteristics. It is important to include the patient in all treatment decisions and to ensure the plan is aligned with their personal expectations, treatment goals, values, and preferences. Through shared decision-making, a patient is more likely to adhere to their regimen, which is crucial to their overall treatment outcomes.¹⁸

The American Academy of Neurology (AAN) published evidence-based practice guidelines that recommend initiating DMT in patients presenting with a first demyelinating event and who are considered high risk for MS based on the presence of brain MRI lesions.¹⁸ When making decisions about initiating DMT in patients presenting with CIS, the patient and provider should discuss the risks and benefits of starting therapy. Other considerations should include presence of comorbid conditions (ie, depression, smoking) that are known to be associated with worse MS outcomes; evaluation of reproductive plans for patients of child-bearing age; assessing for barriers to adherence (ie, cost, patient understanding, readiness); and potential DMT adverse events.

Newly reported symptoms of MS or worsening of old symptoms can be identified as an exacerbation (also referred to as a flare-up, attack, or relapse). Exacerbations, which are caused by inflammation in the CNS and damage to the myelin sheath, can present as one or more primary symptoms such as fatigue, balance issues, paresthesia, or visual complaints. To be objectively defined as a true exacerbation, the attack must last for at least 24 hours and take place at least 30 days from the previous attack.²² Exacerbations can last from a few days up to several weeks, and in some cases, even months. These attacks demonstrate both inter- and intra-patient variability and can range from mild to severe. The degree to which a relapse can interfere with a patient’s ability to function in their personal and professional life is also variable. If an exacerbation presents as mild and has little effect on the patient’s activities, the symptoms can generally go without treatment and will eventually resolve on their own. Conversely, if a patient presents with a severe exacerbation that interferes with the patient’s ability to function or compromises their safety, it is recommended to treat with a high-dose corticosteroid (eg, methylprednisolone injection or oral prednisone) for three to five days to quickly resolve the causative inflammation.^23,24

There are several self-injectable, oral, and infusion DMTs currently available for the treatment of MS and several more are in development (Tables 1 and 2).²⁵ With so many treatment options available, MS care providers are challenged to balance the risks and benefits of available DMTs. In the pivotal clinical trials, treatment with self-injectable DMTs decreased the annualized relapse rate by approximately 33%, with minimal side effects.^26-30 The efficacy of oral and infusion DMTs are much greater; however, they are associated with a higher risk of serious side effects. For example, natalizumab, the first infusion DMT, resulted in the largest decrease in annualized relapse rate (approximately 68%) in the pivotal clinical trials,³¹ however, it is associated with life-threatening progressive multifocal leukoencephalopathy (PML). The exception to this generalization regarding the efficacy and safety of the newer DMTs is the oral DMT, teriflunomide. The efficacy of teriflunomide is close to that of a self-injected DMT; however, it can cause life-threatening liver damage. The mechanism of action and side-effect profile of currently available DMTs are listed in detail in Table 1.²⁵

Despite the expanded number of therapies now approved for MS, the heterogeneity of disease symptoms and progression makes treatment selection and optimization very challenging. In an effort to reduce variation in clinical practice and to simplify treatment decisions, the updated AAN guidelines also included recommendations for sequencing, switching, and stopping DMTs in adults with MS.¹⁸ These guidelines recommend switching DMTs if the drug causes intolerable or life-threatening side effects (eg, fatigue, pain, opportunistic infections, persistent laboratory abnormalities), the patient shows signs of breakthrough disease (ie, exacerbations or changes in disease activity despite DMT optimization and adherence to therapy), there is a change in the patient’s PML risk, or for pregnancy planning. The guidelines on stopping a DMT are not as clear-cut, as no clinical trials have addressed this question in its entirety; however, depending upon the clinical context, the decision to stop therapy may be appropriate in individuals who have no evidence of disease activity or progression.

When MS care providers evaluate DMTs for discussion with patients or in order to make a therapeutic recommendation to another healthcare practitioner, it is important to know which endpoints of the pivotal clinical trials were measured and reported. Most MS clinical trials evaluate the number of new gadolinium-enhancing lesions (ie, new active lesions), the number and size of white matter lesions (ie, demyelinated neurons which are the hallmark of the disease), black holes (ie, permanent neuron damage leading to disability), brain volume (ie, shrinkage of the brain leading to cognitive dysfunction), in addition to the annualized relapse rate (the average number of relapses a group of patients enrolled in a clinical study has in one year). 

When selecting therapies, it is also important to consider the MS subtype. Currently, there are limited treatment options for PPMS, compared with DMTs indicated for the treatment of RRMS. Ocrelizumab is the only FDA-approved DMT for both PPMS and relapsing forms of MS. In the pivotal clinical trials, the primary endpoint of the study was confirmed disability progression.³² The traditional outcome measurement of annualized relapse rate is not applicable to patients with PPMS since, by definition of the disease type, these patients are not experiencing relapses. With so many factors to consider, balancing disease severity and serious side effects of the oral and infusion DMTs with the patient’s treatment goals can be very challenging. Regardless of MS subtype, it is critical that the patient be part of the discussion about which agent to select. 

The Role of the Pharmacist in the Multidisciplinary Management of MS

Based on the complexity of MS and its comorbidities, a multidisciplinary approach is necessary to provide quality patient care. The role of the pharmacist in managing patients with MS continues to evolve as more DMTs enter the market. For patients coming in for their initial assessments and receiving a diagnosis of MS for the first time, this can be a very emotional experience. The standard of care in MS is to create a patient-centered approach. Studies have shown that involving patients in the decision-making process improves adherence.^{33, 34}

As the medication experts, pharmacists can provide several beneficial services across the continuum of care to those patients at any stage in their MS care, thus improving their treatment outcomes overall. In order to do this effectively, a comprehensive medication review should be conducted by a knowledgeable pharmacist so that the discussion of therapeutic options can be tailored to each individual patient. Along with reviewing the patient’s current medication regimen and assessing for pertinent drug-drug interactions, it is also important to identify any contraindications to potential DMT options, such as concurrently taking a class I or class III antiarrhythmic agent with fingolimod.³⁵

Depending on the patient’s stage of treatment it may also be necessary to identify which DMTs the patient has tried in the past and document the reason for failure, such as disease progression or intolerable side effects.³⁵ This information will help narrow down reasonable options for each patient individually. The selection of DMT should be based on available efficacy data, safety profile, and patient’s insurance coverage as these components will help the pharmacist assist neurologists with determining a treatment plan that is both appropriate and cost-effective.^36,37

Another important intervention a pharmacist can make before a medication is selected is to assess any potential barriers to adherence or any education and training the patient and/or caregivers may require.³⁸ As discussed previously, adherence is one of the most important determinants of a patient’s disease course so identifying and addressing any barriers up front will help set patients up for successful treatment outcomes.

DMTs are the cornerstone of MS treatment, however, they prove costly to patients. Average acquisition costs of DMTs reported in Micromedex 2019 are between $83,000 and $110,000 per year.³⁹ It is possible to get financial assistance through the patient’s insurance company, but this process can be confusing and take a substantial amount of time and energy. This is a unique opportunity for pharmacists to step into a patient advocacy role by providing their extensive knowledge of the insurance benefit system and ensuring that patients can receive these medications in an affordable and timely manner.³⁵

During the discussion of which DMT should be initiated, an investigation of insurance benefits should be conducted to help facilitate the selection, determine any preferred medication or dispensing pharmacy location(s), and referral to any medication assistance programs.^25,35 Pharmacists can use their medical expertise to identify the most cost-effective options based on individual patients’ insurance coverage and provide further explanation of benefits to patients and providers.³⁴ Sometimes the process of getting a medication covered by insurance requires a prior authorization request to be completed and submitted, especially if the chosen medication is not on the insurance company’s preferred drug list. Pharmacists can help assist in this complex process by providing written justification for medical necessity on the patient’s behalf.

Access to some DMTs, including natalizumab and alemtuzumab, is restricted to specialty pharmacies as part of the Risk Evaluation and Mitigation Strategy (REMS) drug safety program.³⁵ This may require a referral form to be completed and sent to the manufacturer support network, which pharmacists can also help facilitate. A pharmacist integrated into an MS clinic can ensure coordination of access to medication(s) and resources as well as communicate any challenges encountered along the way to the neurologist and the patient. A medication guide must be distributed along with some of the MS DMTs, including fingolimod and teriflunomide, to ensure that important drug safety information is communicated to the patient.

Pharmacists can also aid in the decision process by providing medication expertise through comprehensive medication education and counseling to both MS care providers and their patients. Meeting with patients one-on-one enables the pharmacist to discuss which medications are being considered and any alternative agents, the importance of treating early, and the importance of strict adherence to therapy. This also provides an opportunity for the pharmacist to address any questions the patient may have.

It is important to provide comprehensive patient counseling on general medication information, such as the name of the medication, dose, method of administration, potential side effects the patient may experience, and monitoring parameters that are required with the selected agent.^25,35 This gives the patient the opportunity to ask any medication-related questions they may have. Through this discussion, the pharmacist can assist MS care providers with coordinating initiation and ongoing management of medication. It is also an opportunity for the pharmacist to provide the patient with written and verbal patient education tools that can address any aspect of treatment or the disease course itself. Since many DMTs are injectable, educational materials can highlight proper injection techniques, which can be taught hands-on during an appointment with the pharmacist and revisited or retaught at any follow-up appointments.²⁵ Written educational materials can also help reinforce the importance of adherence and provide various ways to achieve this. Tailoring the educational materials to the needs of each patient will help individualize care and overall improve their clinical outcomes.

One of the most critical areas pharmacists can provide their expertise is through drug evaluation and monitoring, counseling on medication adverse events, and preventing potential drug-drug interactions. Before the initiation of a DMT, the pharmacist can assist MS care providers by ensuring the specific screening tests (eg, complete blood count (CBC), liver function tests (LFTs), electrocardiogram (EKG), pulmonary and cardiac function tests) are completed. More specific testing like the JC virus antibody test must also be performed prior to starting treatment with agents like natalizumab which carry a high risk of developing PML. For certain agents, a chart review by a pharmacist can determine if the required vaccinations have been administered within a safe time frame prior to administration of the DMT in order to prevent known complications or adverse events.^33,35 For DMTs with specific monitoring parameters, such as fingolimod, the pharmacist can help facilitate the mandatory first-dose observation period and ensure that all of the required documentation is completed accurately.^33,35

Individualized medication counseling should encompass the appropriate use of agents, potential drug-drug interactions, possible medication-specific side effects, and recognizing serious adverse events that should be reported to MS care providers. The pharmacist’s role can continue throughout the entire treatment process by evaluating the patient’s response and tolerance to their prescribed DMT and by verifying that patients are evaluated for treatment safety and efficacy at all follow-up visits. If a patient does experience a side effect of their DMT, the pharmacist can suggest interventions to MS care providers to manage these symptoms, such as adjusting interferons to improve patient tolerability to flu-like symptoms.³³ Additionally, pharmacists can continually monitor drug-drug interactions with the patient's current medication regimen and with any future medications that may need to be added or switched. By assisting with the prevention and management of adverse events and drug-drug interactions this will increase the likelihood of patient adherence to their DMT.

Once the patient is on an individualized medication regimen that is covered by insurance and the appropriate monitoring parameters are set in place, pharmacists should continually evaluate the drug safety of the selected medication as well as adherence. Pharmacist follow-up visits are often scheduled between neurology visits and are very helpful to evaluate and discuss any side effects that may have occurred since initiation. If any re-education is necessary (such as proper injection technique), this can be performed at any follow-up visits the patient has. Pharmacists are also able to appropriately identify patients who may recently have been hospitalized and would benefit from a prompt appointment with their MS care provider.

For female patients of childbearing age, it is important to educate on the fetal risk of specific DMTs, as some of the medications for MS carry a risk of fetal harm.³⁵ A thorough discussion about contraception or pregnancy planning is essential for helping patients carry out pregnancy plans in the safest way possible. If a washout period is needed due to the long half-life of the medication, the pharmacist can assist in the safe discontinuation of therapy. Furthermore, the pharmacist can recommend the safest DMT to use if the patient requires treatment during pregnancy.

Another aspect of safety and overall outcome of treatment is strict adherence to the medication regimen. Pharmacists can help by assessing any barriers to use, providing refill management or reminder phone calls, or helping to provide recommendations for therapy modifications that might increase patient adherence.^31-33 In some pharmacist-integrated clinic models, > 90% patient adherence is achieved by offering on-site pharmacy services.^35,38

Integration of a pharmacist into the interdisciplinary team when treating patients with MS can improve patient outcomes in several ways. Pharmacists can provide disease and medication counseling, evaluate and prevent adverse events and assist with how to mitigate them, assess and address patient barriers to adherence, ensure that ongoing safety monitoring is performed adequately, and facilitate insurance coverage and accessibility to therapeutic options. Providing these services can improve efficiency and communication between patients, MS care providers, and insurance providers, which is invaluable to this patient population.

References

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