RxCe - Multiple Facets of Multiple Sclerosis Materials

THE MULTIPLE FACETS OF MULTIPLE SCLEROSIS

Faculty:

L. Austin Fredrickson, MD, FACP

L. Austin Fredrickson is an Associate Professor of Internal Medicine at Northeast Ohio Medical University, where he serves as core faculty and teaches diagnostics, therapeutics, clinical skills, and health humanities. He is board-certified in general internal medicine and practices rural primary care. 

Jennifer Salvon, RPH

Jennifer Salvon is a clinical pharmacist and freelance medical writer at Salvon Scientific, based in Massachusetts. During her career, she has practiced in a variety of venues, including the hospital, retail, managed care, teaching, and clinical research settings. As a lifelong learner, Jennifer enjoys researching and writing to educate herself and others.

Liz Fredrickson, PharmD, BCPS

Liz Fredrickson, PharmD, BCPS, is an Associate Professor of Pharmacy Practice and Pharmaceutical Sciences at the Northeast Ohio Medical University (NEOMED) College of Pharmacy, where she is course director of the Parenteral Products and Basic Pharmaceutics Lab courses.

Kristina (Tia) Neu, RN

Kristina (Tia) Neu is a licensed Registered Nurse and author currently developing in-service training for healthcare professionals. She is a National Board-Certified Health & Wellness and Lifestyle Medicine Coach. Her work experience includes several areas of the healthcare profession, such as psychiatric nursing, medical nursing, motivational health coaching, chronic case management, dental hygiene, cardiac technician, surgical technician, and clinical director of a Clinically Integrated Network (CIN).

Pamela Sardo, PharmD, BS

Pamela Sardo, PharmD, BS, is a freelance medical writer and licensed pharmacist. She is the founder and principal at Sardo Solutions in Texas. Pam received her BS from the University of Connecticut and her PharmD from the University of Rhode Island. Pam’s career spans many years in retail, clinics, hospitals, long-term care, Veterans Affairs, and managed health care responsibilities across a broad range of therapeutic classes and disease states.

Abstract

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, progressive central nervous system (CNS) disease that leads to irreversible disability. MS affects people of all ages, is commonly diagnosed in early adulthood, and is the leading cause of non-traumatic neurological disability in young adults. An abnormal immune response causes inflammation in MS. As knowledge of the disease has evolved, treatment options and approaches have shifted and improved. Disease-modifying therapies (DMTs) modify the disease course by reducing relapse rate and disability progression. Different mechanisms of action, routes of administration, dosing regimens, and DMT safety concerns offer healthcare providers and patients many treatment options. A knowledgeable, informed healthcare team is prepared to manage, educate, and counsel patients on MS.

Accreditation Statements

In support of improving patient care, RxCe.com LLC is jointly accredited by the Accreditation Council^TM for Continuing Medical Education (ACCME^®), the Accreditation Council for Pharmacy Education (ACPE^®), and the American Nurses Credentialing Center (ANCC^®), to provide continuing education for the healthcare team.

Joint Universal Activity Number: The Joint Accreditation Universal Activity Numbers assigned to this activity are as follows:

Pharmacists: JA4008424-0000-26-165-H01-P

Pharmacy Technicians: JA4008424-0000-26-165-H01-T

Credits: 2 contact hour(s) (0.2 CEU(s)) of continuing education credit.

Credit Types:

Pharmacy - 2 Credits

Type of Activity: Application

Media: Computer-Based Training (i.e., online courses)

Estimated time to complete activity: 2 contact hour(s) (0.2 CEU(s)), including Activity Pre-Test, Post-Test, and Activity Evaluation.

Release Date: July 14, 2026 Expiration Date: May 25, 2027

Target Audience: This educational activity is for Physicians, Physician Assistants, and Pharmacists.

How to Earn Credit: From July 14, 2026, through May 25, 2027, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Take the “Educational Activity Pre-Test;”

Study the section entitled “Educational Activity;” and

Complete the Educational Activity Post-Test and Activity Evaluation. The Educational Activity Post-Test will be graded automatically. Following successful completion of the Educational Activity Post-Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

CE Credits: Credits for this course will be uploaded to CPE Monitor^® for pharmacists and pharmacy technicians.

Statement of Need

Multiple sclerosis (MS) management has evolved rapidly, driven by advances in diagnostic criteria, earlier intervention strategies, and an expanding array of disease-modifying therapies. Current standards of care emphasize prompt diagnosis using updated McDonald criteria, individualized treatment selection based on disease activity and patient-specific factors, ongoing monitoring for efficacy and safety, and proactive management of symptoms and comorbidities. Despite these advances, significant practice gaps remain. This educational activity is designed to bridge these gaps by providing clinicians with current, evidence-based information on MS diagnosis, treatment, monitoring, and long-term management.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Describe the different treatment approaches for relapsing-remitting multiple sclerosis

Identify mechanisms of action associated with current and emerging disease-modifying therapies

Recall common safety considerations associated with treatments for multiple sclerosis

Discuss counseling opportunities for people with multiple sclerosis

Disclosures

The following individuals were involved in planning, developing, and/or authoring this activity: L. Austin Fredrickson, MD, FACP; Jennifer Salvon, RPH; Kristina (Tia) Neu, RN; and Pamela Sardo, PharmD, BS. None of the individuals involved in developing this activity has a conflict of interest or financial relationships related to the subject matter. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity.

Educational Activity Pre-Test

Which of the following describes the overall treatment recommendations for MS?

The treatment approach to MS is clear-cut, with a defined step-wise approach.

Treatment recommendations only involve therapy with a DMT.

Treatment begins with lifestyle modifications, only starting DMT when the disease progresses.

Individualized therapy is key, involving lifestyle modifications, DMTs, and symptom management.

Which of the following disease-modifying therapies (DMTs) requires patient registration with a Risk Evaluation and Mitigation Strategy (REMS) program?

Alemtuzumab

Ocrelizumab

Fingolimod

Teriflunomide

______________ is a DMT that is associated with a high risk of progressive multifocal leukoencephalopathy (PML).

Glatiramer

Ofatumumab

*Natalizumab

Ponesimod

Educational Activity

The Multiple Facets of Multiple Sclerosis

Introduction

Multiple sclerosis (MS) is a chronic, progressive, immune-mediated inflammatory disease of the central nervous system (CNS). Multiple sclerosis damages the myelin sheaths of neurons and axons, resulting in motor and cognitive impairments.¹ Observation of neurodegenerative symptoms suggestive of MS dates back to the late 1300s. In 1868, Jean-Martin Charcot, a French neurologist, first described MS. Early treatments included arsenic, mercury, and deadly nightshade.² Thankfully, current therapy is less dangerous and more effective. Over twenty Food and Drug Administration (FDA)-approved disease-modifying therapies (DMTs) exist for MS treatment. DMTs differ in mechanism of action, route of administration, dosing schedule, efficacy, and side-effect profile.

Prevalence of Multiple Sclerosis

Multiple sclerosis affects approximately 1 million people in the United States and 2.8 million worldwide.³ Prevalence is highest in North America, Western Europe, and Australasia, steadily increasing over the last few decades.⁴ The average age of MS diagnosis is between 20 and 40 years of age, making MS the most common disabling disease of young adults.¹ Disease progression impacts activities of daily living, work productivity, and mental health, resulting in substantial burdens to patients and caregivers.⁵

The economic impact of MS is considerable, estimated at $85.4 billion.⁶ Direct medical costs, including retail prescriptions, outpatient care, and clinic-administered medications and care, are the primary contributors to healthcare expenses. Disease-modifying therapies account for the largest proportion of this cost.⁶ Indirect costs include presenteeism, absenteeism, early retirement, and informal care due to worsening disability.⁷ Patients with relapses and greater disability incur higher costs, resource use, and work impairment.⁷

Pathophysiology of Multiple Sclerosis

The cause of MS is unclear. Patient presentation and symptoms vary according to lesion severity and location within the CNS. Both genetic and environmental factors are associated with MS. The following risk factors are associated with MS development:^8,9

Vitamin D deficiency

Gender (more common in females)

UVB exposure

Epstein-Barr virus (EBV) infection

Obesity

Smoking

An abnormal immune response causes inflammation in MS. The adaptive and innate immune responses play roles in MS pathogenesis, involving T cells, B cells, and antibodies. T cells are activated in the lymph system. In MS, T cells enter the CNS via the bloodstream, causing inflammation and damage. This damages nerve fibers, myelin, and the cells that produce it. Both helper and cytotoxic T cells have been found in MS lesions. Helper T cells fail to function correctly in MS, leading to further damage. Cytotoxic T cells directly attack and destroy cells. Drugs limiting T-cell CNS access can reduce or eliminate new MS lesions. B cells are activated by T cells and produce antibodies that fight infections and other abnormal substances. The role of B-cells remains incompletely understood, but early success with B-cell-depleting therapies highlights their importance and has prompted further investigation.^10,11

Presentation

Clinical symptoms of MS may present suddenly or gradually and can be severe or mild, going unnoticed for years.¹⁰ MS often starts with a single event called a clinically isolated syndrome (CIS).¹² In a CIS, patients experience neurological symptoms lasting at least 24 hours without active infection and may or may not recover.¹² Symptoms of MS include the following:¹⁰

Sensory loss or tingling

Painful loss of vision (optic neuritis)

Facial weakness

Limb weakness

Brain fog, difficulty multitasking

Heat sensitivity

Fatigue

Dizziness

Hearing loss

Multiple sclerosis is classified into different types based on clinical presentation. Types are defined by assessing several factors, including disease progression severity, relapses, and the number of demyelinating lesions found via magnetic resonance imaging (MRI).¹ The most common type is relapsing-remitting MS (RRMS). RRMS is characterized by periods of neurological dysfunction followed by partial or complete recovery.¹ As the disease advances, the extent of recovery lessens, leading to increased disability.¹ Approximately 20% of patients transition to uninterrupted progression or secondary progressive MS (SPMS).^1,10 Patients experiencing progression from the outset have primary progressive MS (PPMS).¹⁰ PPMS occurs in 15% of patients.¹ This activity will focus on treatment approaches and considerations in RRMS treatment.

Diagnosis

Diagnosing MS is complex, involving a neurological exam, imaging, and laboratory findings. Magnetic resonance imaging (MRI) is a key diagnostic test in MS. Results are evaluated using the McDonald Criteria for Diagnosis of Multiple Sclerosis. The McDonald Criteria considers the number of attacks, MRI lesions, and evidence of dissemination in space and time. Increased lesion size and number indicate spatial dissemination. Dissemination in time is defined as multiple, distinct attacks at different times.¹

RRMS Treatment

Many diseases, such as hypertension and diabetes, have clearly defined treatment approaches. The treatment approach to RRMS is not as clear or as structured, as it is still evolving. Individualized treatment plans are essential due to the complexity, variable presentation, and progression of MS.¹³ A comprehensive treatment plan includes DMTs, symptom management, lifestyle modifications, psychological support, and rehabilitation.¹

In 2018, the American Academy of Neurology published practice guideline recommendations for DMTs.¹⁴ The guideline contains thirty recommendations encompassing DMT initiation, switching, and discontinuation. A full discussion of the guidelines is beyond the scope of this activity. Highlights of the recommendations include:¹⁴

Prescribing a DMT in patients with a CIS and two or more brain lesions after discussing DMT’s benefits and risks

Offering DMTs to RRMS patients with recent clinical relapses or new MRI activity

Using alemtuzumab, fingolimod, and natalizumab in patients with highly active MS

Encouraging pharmaceutical support programs for patients on DMTs

Switching DMTs in the following situations:

Suboptimal response to therapy

Medication-related adverse effects

Laboratory abnormalities

Poor patient adherence

There are two main treatment approaches for RRMS: escalation and early treatment with highly effective therapies (HET).^1,15,16 Escalation therapy prioritizes safety, starting with a lower-efficacy drug with a more favorable adverse effect profile. If the patient experiences disease progression, relapse, MRI changes, or disability, therapy is switched to a more efficacious agent. While minimizing risk, this approach may result in disease and disability progression.^1,17

Early treatment with HET starts with a high-efficacy drug at diagnosis. Experts believe that early HET initiation may alter the disease progression, preventing irreversible damage and minimizing future disability. The limitation of this approach is that it increases patients' risk of adverse events. Observational studies suggest that early use of highly effective therapies improves long-term patient outcomes.^1,10

There is no clear definition that designates a DMT as an HET, though several publications discuss HETs. Disease-modifying therapies considered HETs include natalizumab, the S1P receptor modulators, and the anti-CD20 monoclonal antibodies.^10,15,16,18

Efficacy Measurements

The efficacy of DMTs is measured by a reduction in annualized relapse rate (ARR).¹⁸ In studies, the HETs have an average ARR greater than 50% when compared to placebo or interferon therapy.¹⁸

A newer outcome measurement in evaluating DMTs is no evidence of disease activity (NEDA).¹⁹ NEDA-3 is the most commonly used measurement. NEDA-3 indicates no relapses, disability progression, or new MRI activity. NEDA-4 reports no additional brain volume loss. NEDA is currently used in clinical trials and is gaining interest among healthcare providers for assisting in treatment decisions.¹⁹

Worsening disability is the primary cause of indirect costs and is the most troublesome aspect of MS for patients. The Expanded Disability Status Scale (EDSS) measures disability severity.²⁰ Many functions are evaluated during a neurological examination, including muscle weakness, balance, coordination, tremor, eyesight, speech, and swallowing. The EDSS uses a scale of 0 to 10, with 0 indicating normal neurological function. A score of five indicates disability affecting the activities of daily living, and ten indicates death due to MS.²⁰

Progressive Multifocal Leukoencephalopathy

Progressive multifocal encephalopathy (PML) is a rare infection caused by the John Cunningham virus (JCV). The virus attacks the myelin sheath in the CNS, leading to demyelination. Up to 90% of healthy adults carry inactive JCV virus. Reactivation of the JC virus can have serious consequences for immunocompromised individuals. Patients with MS taking immunosuppressive therapy are a high-risk group for developing PML.²¹

Progressive multifocal encephalopathy presents with a wide range of symptoms, including ataxia, gait disturbances, double vision, and altered mental status. It is diagnosed using a combination of clinical and imaging findings. Management of PML involves stopping the causative agent and providing supportive care. Several DMTs are associated with PML, including natalizumab, fingolimod, dimethyl fumarate, ocrelizumab, and alemtuzumab. The risk of developing PML is an important consideration when initiating and evaluating MS therapy.²¹

Disease-Modifying Therapies

Disease-modifying therapies modulate and suppress immune function, decreasing relapse rate, MRI lesion accumulation, delaying disease progression, and worsening disability.¹⁰ Over 20 different DMTs are available for MS treatment. They differ in mechanism of action, administration, dosing, efficacy, safety, and adverse effects. The first DMT, interferon β-1b, gained approval in 1993. Before 1993, immunosuppressive drugs such as azathioprine and methotrexate were used with limited success.¹ The number of available DMTs offers the opportunity for individualized patient care but can also be overwhelming. Table 1 lists FDA-approved DMTs for RRMS treatment with dosing and administration notes. Table 2 lists monitoring and safety concerns for available DMTs. Below is a brief discussion of each drug class, including its efficacy and treatment considerations.

Table 1

Disease-Modifying Therapies for Relapsing-Remitting

Multiple Sclerosis^22-42

Generic	Brand (approval)	Route	Initial dosing	Maintenance dosing	Administration Notes
Interferons
Interferon β-1b	Betaseron (1993) Extavia (2009)	SC	0.0625 mg every other day, increase over a 6-week period	0.25 mg every other day	Must be diluted with the supplied diluent
Interferon β-1a	Avonex (1996)	IM	7.5 mcg first week; increase by 7.5 mcg each week for 3 weeks	30 mcg once weekly
Interferon β-1a	Rebif (2002)	SC	Start at 20% of the maintenance dose; increase over a 4-week period	22 mcg or 44 mcg, three times per week	Analgesics and/or antipyretics may help with flu-like adverse effects
Peginterferon β-1a	Plegridy (2014)	SC, IM	Day 1: 63 mcg Day 15: 94 mcg Day 29: 125 micrograms	125 mcg every 14 days	Analgesics and/or antipyretics may help with flu-like adverse effects
Amino acid copolymer
Glatiramer acetate	Copaxone (1996) Glatopa (2015, 2018)	SC	N/A	20 mg QD OR 40 mg, three times a week	Bring to room temperature before administration; doses are not interchangeable
Sphingosine-1 phosphate receptor modulators
Fingolimod	Gilenya (2010)	PO	N/A	> 40 kg = 0.5 mg once daily ≦ 40 kg = 0.25 mg once daily	Administer with or without food
Siponimod	Mayzent (2019)	PO	5-day titration: Day 1 & 2: 0.25 mg Day 3: 0.50 mg Day 4: 0.75 mg Day 5: 1.25 mg	2 mg once daily starting on Day 6	· Administer tablets whole; do not split or crush · Dosing adjustments required if patient has CYP2C9 1/3 or 2/3 · Use is contraindicated CYP2C9 3/3
Ozanimod	Zeposia (2020)	PO	Days 1-4: 0.23 mg once daily Days 5-7: 0.46 mg once daily	0.92 mg once daily starting Day 8	Dose adjustment for hepatic impairment and if dose interruption
Ponesimod	Ponvory (2021)	PO	2 mg QD, titrated over a 14-day period to 20 mg once daily	20 mg once daily
Fumarates
Dimethyl fumarate	Tecfidera (2013)	PO	120 mg BID for 7 days	240 mg BID	Administer with or without food
Diroximel fumarate	Vumerity (2019)	PO	231 mg BID for 7 days	462 mg BID	· Do not crush, chew, or sprinkle · Avoid administration with high-fat or high-calorie food or snack · Avoid alcohol
Monomethyl fumarate	Bafiertam (2020)	PO	95 mg BID for 7 days	190 mg BID	· Do not crush, chew, or sprinkle · Administer with or without food
Purine analog
Teriflunomide	Aubagio (2012)	PO	N/A	7 mg or 14 mg once daily	Administer with or without food
Pyrimidine synthesis inhibitor
Cladribine	Mavenclad (2019)	PO	N/A	3.5 mg/kg of body weight divided into two yearly treatment courses. Each treatment course is divided into two treatment cycles of 4-5 days, 14 days apart	Separate administration from other oral meds by 3 hours
Monoclonal antibodies
Natalizumab	Tysabri (2004)	IV infusion	N/A	300 mg over one hour every four weeks	Do not give as an IV push or bolus
Alemtuzumab	Lemtrada (2014)	IV infusion		Year 1: 12 mg/day for 5 consecutive days Year 2: 12 mg/day for 3 consecutive days Years 3 & 4: no treatment	· Infuse over 4 hours · Premedicate with corticosteroids for 3 days prior to the treatment course · Acyclovir prophylaxis during the first 2 months after infusion or until the CD4 lymphocyte count is less than 200 cells/mcL
Ocrelizumab	Ocrevus (2016)	IV infusion	First dose = 300 mg; followed by a second 300 mg dose two weeks later	600 mg every 6 months	Premedicate with a corticosteroid and an antihistamine
Ofatumumab	Kesimpta (2020)	SC	Week 0, 1, & 2: 20 mg	Starting on week 4: 20 mg once monthly
Ublituximab	Briumvi (2022)	IV infusion	1st = 150 mg 2nd = 450 mg, 2 weeks after the first dose	450 mg every 24 weeks, starting 24 weeks after the first infusion	Premedicate with a corticosteroid and an antihistamine
SQ = subcutaneous; IM = intramuscular; PO = oral; BID = twice daily; QD = once daily; IV = intravenous

Interferons and Glatiramer

Interferon β therapies and glatiramer were the first approved medications for RRMS treatment. The exact mechanism of action of interferon β is unknown, but it likely involves immunomodulation, decreasing T-cell migration and proliferation. This results in an anti-inflammatory effect, reducing relapse rate, lesion formation, and disability progression.¹⁰ Currently approved products include interferon β-1b, interferon β-1a, and peginterferon. In clinical trials, interferon β-1b reduced ARR by 29-34% compared to placebo. The long-term safety of interferons has been established in several trials.¹⁸

Sphingosine-1-phosphate Receptor Modulators (S1PRM)

Sphingosine-1-phosphate receptors (S1PRs) are widely distributed throughout the body and regulate several immunological, cardiovascular, and neurological functions. They are integral to the production of immune mediators and to the regulation of local and systemic inflammatory processes. There are five subtypes of S1PRs. The S1RP subtype 1 is expressed on the surface of lymphocytes. Inhibition of S1RP1 results in the sequestering of lymphocytes in lymph nodes, preventing CNS migration.⁴³

Four FDA-approved S1PRMs exist to treat MS: fingolimod, siponimod, ozanimod, and ponesimod. The S1PRMs differ in their affinity for the various S1PR subtypes and offer the advantages of oral administration and improved efficacy over interferons and glatiramer.¹⁸ In clinical trials, fingolimod reduced ARR by 48-55% compared to placebo and interferon β-1a.¹⁸

The first dose of fingolimod acts as an S1PR agonist, leading to bradycardia and heart block. Subsequent doses downregulate the receptor, and cardiac effects resolve. For this reason, all patients require first-dose observation with fingolimod for at least 6 hours.¹ First-dose observation is not required for siponimod and ozanimod in the absence of cardiac history.¹

Siponimod is metabolized by the cytochrome P450 system, primarily by CYP2C9. Siponimod requires CYP2C9 genetic testing before treatment to determine titration and dosing schedule. An ophthalmic assessment is recommended for patients on ozanimod with a history of macular edema or uveitis.¹

Fumarates

The fumarates approved for treating MS include dimethyl fumarate, diroximel fumarate, and monomethyl fumarate. The exact mechanism of action of fumarates is unknown, but it is thought to involve activation of the nuclear (erythroid-derived-2)-like 2 pathway. Fumarates have anti-inflammatory and cytoprotective effects. Dimethyl fumarate and diroximel fumarate are metabolized to the active form, monomethyl fumarate.¹⁰ Dimethyl fumarate showed a 44-53% reduction in ARR compared to placebo.¹⁸

Teriflunomide

Teriflunomide is a once-daily oral immunomodulator. Teriflunomide is the active metabolite of leflunomide and is a pyrimidine synthesis inhibitor. Teriflunomide reduces the number of activated T and B cells available to enter the CNS.¹⁰ Considered a modestly effective DMT, teriflunomide produced a 22-36% reduction in ARR compared to placebo.¹⁸

Cladribine

A purine nucleoside analog, cladribine, was initially developed to treat hematological malignancies. Cladribine exerts a cytotoxic effect on T-cells and B-cells, resulting in lymphocyte depletion.³⁷ Compared to placebo, cladribine reduced ARR by 55-58%, making it a highly effective therapy. Cladribine has a low treatment burden consisting of 2 short courses one year apart, followed by two years of no treatment.³⁷ Serious adverse events limit the use of cladribine.¹⁰

Monoclonal Antibodies

Many DMTs used to treat RRMS are monoclonal antibodies (mAb). Most available mAbs are administered by infusion, and all possess a higher efficacy profile than injectable and oral DMTs. Monoclonal antibody therapy commonly causes infusion reactions involving headache, nausea, itching, and flushing. Premedication with corticosteroids, antihistamines, and antipyretics mitigates infusion reaction symptoms.¹ Due to the risk of serious adverse effects, two mAbs, natalizumab and alemtuzumab, require prescriber and patient registration with the respective Risk Evaluation and Mitigation Strategy (REMS) program.⁴⁴ This program is FDA-mandated to evaluate the safety of a medication with serious safety concerns. This helps ensure that the benefits of a drug outweigh its risks.

There are three mAbs available that target the CD20 antigen on B and T cells: ocrelizumab, ofatumumab, and ublituximab. All are approved to treat CIS, RRMS, and SPMS. Ocrelizumab has an additional indication for the treatment of PPMS. By selectively depleting CD20 B and T cells, anti-CD20 mAbs disrupt lymphocyte CNS migration, suppressing the inflammatory process.¹ Comparative clinical trials demonstrate the high efficacy of mAbs.¹⁸ Compared with interferon β-1a, ocrelizumab therapy resulted in a 47% reduction in ARR.¹⁸ Efficacy trials comparing ofatumumab and ublituximab with teriflunomide resulted in similar ARR reductions: 50-60% for ofatumumab and 49-59% for ublituximab.¹⁸

Natalizumab is an mAb that binds to the alpha-4 subunit of integrins on lymphocytes, thereby limiting their CNS access.³⁸ Efficacy trials compared natalizumab with placebo, resulting in a 68% reduction in ARR.¹⁸ Due to the risk of PML, natalizumab is only available through a REMS program, the TOUCH Prescribing Program.³⁸

Alemtuzumab induces cell cytolysis by binding to the CD52 antigen on B and T cells, resulting in a 68% reduction in ARR compared with placebo.¹⁸ Alemtuzumab is associated with serious autoimmune effects, including hypo- and hyperthyroidism and immune thrombocytopenia.¹ As a result, it is usually reserved for treatment in patients with inadequate responses to two or more DMTs.

Table 2

Safety and Monitoring of DMTs in RRMS^1,22-42

Generic

Monitoring

Contraindications

Adverse Reactions

PML

Interferons

Interferon β-1b

CBC with differential and LFT at baseline, 1, 3, and 6 months

Thyroid function tests every 6 months

Signs and symptoms of depression

Known sensitivity to interferon β, or peginterferon, or any formulation component

Injection site reactions

Flu-like symptoms

Elevated liver enzymes

Leukopenia

Antibody development

No risk reported

Interferon β-1a

Injection site reactions

Flu-like symptoms

Elevated liver enzymes

Leukopenia

Anemia

Peginterferon β-1a

Injection site reactions

Flu-like symptoms

Elevated liver enzymes

Antibody development

Amino acid copolymer

Glatiramer acetate

None

Known sensitivity to glatiramer acetate or mannitol

Injection site reactions

Lipoatrophy

Post-injection reactions: chest pain, flushing, dyspnea, palpitations

No risk reported

S1P receptor modulators

Fingolimod

EKG, BP, and HR at baseline

First dose cardiac monitoring for 6 hours

LFT at baseline and every 6 months

CBC with lymphocyte counts at baseline and every 3 months

Ophthalmic exam at baseline and every 3-4 months

History of MI, unstable angina, stroke, TIA, heart failure

AV block without pacemaker treatment

Baseline QTC interval ≧500 msec

Concurrent use of class IA or III antiarrhythmic

Headache

Elevated LFTs

Diarrhea

Cough

Influenza

Leukopenia

Lymphocyto-penia

Bradycardia

AV block

Macular edema

Cases of PML reported

Monitoring for signs of PML is advised

Siponimod

EKG, BP, and HR at baseline

Patients with a history of heart conditions are monitored for 6 hours after the first dose

LFT at baseline and every 6 months

CBC with lymphocyte counts at baseline and every 3 months

Ophthalmic exam at baseline and every 3-4 months

CYP2C9 *3/*3 genotype

History of MI, unstable angina, stroke, TIA, heart failure

AV block without pacemaker treatment

Headache

Hypertension

Elevated LFTs

Cases of PML reported

Monitoring for signs of PML is advised

Ozanimod

EKG, BP, and HR at baseline

CBC with lymphocyte counts at baseline and every 3 months

Ophthalmic exam at baseline and every 3-4 months

History of MI, unstable angina, stroke, TIA, heart failure

AV block without pacemaker treatment

Severe, untreated sleep apnea

Concurrent use of MAOI

Upper respiratory infection

Elevated LFTs

Orthostatic hypotension

Urinary tract infection

Back pain

Hypertension

Cases of PML reported

Monitoring for signs of PML advised

Ponesimod

EKG, BP, and HR at baseline

Patients with a history of heart conditions must be monitored for 4 hours after the first dose

CBC with lymphocyte counts at baseline and every 3 months

Ophthalmic exam at baseline and every 3-4 months

History of MI, unstable angina, stroke, TIA, heart failure

AV block without pacemaker treatment

Upper respiratory tract infection

Elevated LFTs

Hypertension

No incidences of PML reported to date

Monitoring for PML advised

Fumarates

Dimethyl fumarate

CBC with lymphocyte counts at baseline and every 3 months

LFT at baseline and periodically during treatment

Known hypersensitivity to any of the fumarates

Coadministration with another fumarate

Flushing

Abdominal pain

Diarrhea

Nausea

Cases of PML reported

Monitoring for signs of PML advised

Diroximel fumarate

Monomethyl fumarate

Purine analog

Teriflunomide

CBC within 6 months of initiation and periodically during treatment

Serum creatinine, transaminase, and bilirubin monthly during the first 6 months

Hepatotoxicity

Fetal toxicity

Severe hepatic impairment

Pregnancy

Hypersensitivity

Current leflunomide treatment

Headache

Diarrhea

Nausea

Alopecia

Elevated LFTs

No risk reported

Pyrimidine synthesis inhibitor

Cladribine

CBC with lymphocyte count at baseline, 2, and 6 months

LFT at baseline and when clinically necessary during treatment

Screen for HIV, tuberculosis, HBV, and HCV before each treatment cycle

Patients with current malignancy

Pregnancy and breastfeeding

HIV infection

Active chronic infections

Hypersensitivity to cladribine

Upper respiratory infection

Headache

Lymphopenia

No cases of PML reported

Monoclonal antibodies

Natalizumab

CBC and LFT at baseline and periodically during treatment

Hypersensitivity monitoring during and for 1 hour after infusion

Patients who have had PML

Hypersensitivity to natalizumab

Headache

Fatigue

Joint pain

Urinary tract infection

Lower respiratory infection

Gastroenteritis

Vaginitis

Depression

Abdominal discomfort

Diarrhea

Rash

Cases of PML reported

Only available through TOUCH prescribing program

Alemtuzumab

CBC with differential, LFT, urinalysis before initiation, then monthly until 48 months after the last infusion

Thyroid function test before initiation, then every 3 months until 48 months after the last infusion

EKG before initiation

Patient observation at least 2 hours after each infusion

May cause serious, possibly fatal autoimmune conditions, infusion reactions, stroke, or malignancy

HIV infection

Active infection

Hypersensitivity to alemtuzumab

Infusion-related reactions

Lymphocyto-penia

Fungal infection

Thyroid disease

Fatigue

Rash

Headache

Cases of PML reported

Monitoring for signs of PML is advised

Ocrelizumab

Initial CBC with differential, LFTs, hepatitis panel

CBC with differential and LFTs annually

HBV screening before treatment

Monitor for infusion reactions for 1 hour after completion of the first 2 infusions

Infusion-related reactions

Upper respiratory infections

Herpes infections

Cases of PML reported

Monitoring for signs of PML is advised

Ofatumumab

CBC with differential and renal function

HBV screening

Serum immunoglobulins at baseline and during treatment

Active HBV infection

Injection site reactions

Infection

Upper respiratory infection

Headache

No cases of PML reported

Ublituximab

HBV screening

Serum immunoglobulin levels at baseline and during treatment

Monitor for infusion reaction at least 1 hour after completion of the first 2 infusions

Active HBV infection

History of life-threatening reaction to ublituximab

Infusion reactions

Upper respiratory infections

No incidences of PML reported to date

Monitoring for PML is advised

PML = progressive multifocal leukoencephalopathy; CBC = complete blood count; LFT = liver function tests; EKG = electrocardiogram; BP = blood pressure; HR = heart rate; MI = myocardial infarction; TIA = transient ischemic attack; AV = atrioventricular; HIV = human immunodeficiency virus; HBV = hepatitis B virus

Symptom Management, Supportive Care, and Lifestyle Modifications

Various medications and therapies are available to manage MS symptoms such as spasticity and spasms, gait impairment, tremor, bladder dysfunction, depression, and cognitive impairment. Table 3 lists some of the medications used to manage symptoms.

Physical, occupational, and speech therapy can help improve mobility and function. Rehabilitation programs focus on maximizing function and independence through exercise, mobility aids, and adaptive techniques. Healthy lifestyle habits such as regular exercise, a balanced diet, stress management, and adequate rest can help manage symptoms and improve overall well-being. Psychosocial support, counseling, and support groups provide emotional support, education, and resources for patients living with MS and their caregivers.¹

Table 3

Medications used to support symptom management in MS^1,10

Symptom	Pharmacological Treatments	Nonpharmacological Treatments
Spasticity and spasms	· Baclofen · Tizanidine · Gabapentin · Benzodiazepines	· Physiotherapy · Occupational therapy
Gait impairment	· Dalfampridine	· Physiotherapy · Adaptive devices · Functional electrical stimulation
Tremor	· Propranolol · Carbamazepine · Primidone · Gabapentin	· Physiotherapy · Occupational therapy · Wrist weights · Joint stabilization exercises
Bladder dysfunction	· Mirabegron · Oxybutynin · Tolterodine	· Pelvic floor exercises · Electrical stimulation · Fluid intake management
Depression	· Fluoxetine · Sertraline · Escitalopram · Bupropion · Venlafaxine	· Psychotherapy · Counseling
Cognitive impairment	· Lisdexamfetamine	· Attention training · Memory training

Front Line Support from the Pharmacy Team

Pharmacists and pharmacy technicians are among the most accessible healthcare providers. People routinely turn to neighborhood pharmacies for advice on many health topics. The complicated nature of MS creates an environment ripe for patient confusion and treatment adherence issues. An MS diagnosis is a stressful event; patients may remember only some of the information provided at the time of diagnosis. Patients with MS need extensive education about disease management and possible adverse effects. A knowledgeable pharmacy team can answer questions, helping patients to understand the risks and benefits of MS treatments better.

The following are important points to consider when counseling patients with MS:

When talking with a patient, it’s important to acknowledge the silent progression and invisibility of MS without making assumptions about how a patient feels.

Showing empathy to someone with MS involves understanding their experiences, challenges, and emotions while offering support and compassion. Remind patients that MS is a progressive disease and treatment adherence is critical to managing the symptoms of the disease and slowing down its progression.

Talk with MS patients when they come in, ask how they are doing, and touch base about periodic monitoring.

Discuss the role of individual treatment plans with patients so they know there is more than one approach.

Stay current on DMTs, dosage forms, titration, administration techniques, and potential adverse reactions.

Encourage patients to stop smoking and remain active, engaging in physical and mental activities.

The high cost of DMTs often results in higher out-of-pocket costs for patients, including copays and deductibles. This could lead to poor adherence, resulting in relapses, hospitalization, and worsening disability. The pharmacy team can assist MS patients with signing up for copay cards or other financial assistance.

Summary

Multiple sclerosis is a progressive and debilitating disease with no clear cause. It presents differently in each patient. Treatment is individualized, multifaceted, and long-term. There is no cure for multiple sclerosis. Patients with MS face lifelong challenges, including disability and cognitive impairment. Newer DMTs offer higher efficacy and easier administration but may be associated with potentially severe adverse effects.

The treatment of multiple sclerosis can seem intimidating due to the number of approved disease-modifying therapies. However, the approach to treatment is shifting, and the recent approval of several new highly efficacious therapies provides hope for patients. These drugs are the mainstay of MS treatment and work to reduce the frequency and severity of relapses, slow down the progression of disability, and decrease the number of lesions in the brain.

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DISCLAIMER

The information provided in this course is general in nature, and it is designed solely to provide participants with continuing education credit(s). This course and materials are not meant to substitute for the independent, professional judgment of any participant regarding that participant’s professional practice, including but not limited to patient assessment, diagnosis, treatment, and/or health management. Medical and pharmacy practices, rules, and laws vary from state to state, and this course does not cover the laws of each state; therefore, participants must consult the laws of their state as they relate to their professional practice.

Healthcare professionals must consult their employer, healthcare facility, hospital, or other organization for guidelines, protocols, and procedures to follow. The information provided in this course does not replace those guidelines, protocols, and procedures, but is for academic purposes only, and this course’s limited purpose is for the completion of continuing education credits.

Participants are advised and acknowledge that information related to medications, their administration, dosing, contraindications, adverse reactions, interactions, warnings, precautions, or accepted uses is constantly changing. Any person taking this course understands that such a person must make an independent review of medication information before any patient assessment, diagnosis, treatment and/or health management. Any discussion of off-label use of any medication, device, or procedure is informational only, and such uses are not endorsed hereby.

Nothing contained in this course represents the opinions, views, judgments, or conclusions of RxCe.com LLC. RxCe.com LLC is not liable or responsible to any person for any inaccuracy, error, or omission with respect to this course or course material.

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