Multiple sclerosis is a chronic, unpredictable, and disabling disease. Significant advances have been made in recent years supporting an earlier, more accurate, diagnosis and have led to more than 15 disease-modifying therapies approved by the Food and Drug Administration for relapsing forms of multiple sclerosis. Disease-modifying therapies are now being classified into categories based on level of efficacy. Strategies to use disease-modifying therapies earlier and in a more customizable manner are also emerging. A clinical case study will be used throughout this pearl to review the disease-modifying therapies and use patient-specific factors to develop and provide recommendations on therapeutic strategies for individuals with relapsing forms of multiple sclerosis.

Multiple sclerosis (MS) is characterized by immune-mediated, demyelinating attacks on the central nervous system (CNS) resulting in fully or partially reversible neurologic syndromes or relapses. An MS relapse typically comes on acutely or subacutely, lasts days to weeks, and gradually remits. Radiographic evidence of inflammatory attacks can be seen anywhere in the white and grey matter of the CNS. Symptoms reflect lesion locations although silent lesions occur as well. Acute optic neuritis is the most common neurologic syndrome at onset.1-4  Other symptoms may occur throughout the disease such as cognitive impairment, fatigue, bowel and bladder disturbances, and spasticity.2-4 

Nearly one million persons are currently living with MS in the United States.5  Multiple sclerosis is most commonly diagnosed in females and at age 20 to 50 years.6  More than 80% of persons with MS (pwMS) have relapsing remitting MS (RRMS). Approximately 15% to 30% of pwMS will gradually evolve from RR to secondary progressive (SP) 15 to 20 years after onset. Previous natural history studies reported that 25% to 40% of pwMS develop SPMS, likely reflecting the lack of earlier diagnosis and use of DMTs. Roughly 15% of pwMS have a primary progressive (PP) course from the onset.7-10 

A relapsing or progressive phenotype has been used since 1996 to describe a person's MS. In 2013, these phenotypes were modernized to better inform prognostication and treatment decision making by addressing limitations of the older phenotypes (Table 1).9,10  The core clinical phenotypes of RR, SP, PP were retained, clinically isolated syndrome was officially added, but the confusing progressive relapsing phenotype was removed. Radiologically isolated syndrome or the incidental findings of MS-like lesions on brain magnetic resonance imaging (MRI), was not added since MRI findings without clinical evidence of demyelination may be nonspecific. Descriptive modifiers were introduced to provide more clinically useful information when communicating phenotype including active and not active to describe disease activity (recent relapse or CNS imaging activity) and with progression and without progression to describe disease worsening. As of May of 2019, the Food and Drug Administration (FDA) approved labeling of every DMT has been updated with these modifiers.

TABLE 1

The 2013 update to the phenotypic classifications of MS10 

The 2013 update to the phenotypic classifications of MS10
The 2013 update to the phenotypic classifications of MS10

The McDonald's diagnostic criteria routinely undergoes revisions aligning the criteria with advancements in clinical and imaging technologies. Diagnosis is based on parameters such as medical history and neurological exam, as well as paraclinical parameters such as MRI, cerebrospinal fluid showing oligoclonal banding (sign of CNS inflammation), and evoked potentials (a measure of electrical activity in the brain). MRI remains the most sensitive tool available for determining events that meet diagnostic criteria for dissemination in time and space. The 2017 McDonald's diagnostic criteria11  revision allows for earlier diagnosis of MS in individuals with typical clinically isolated syndrome if either imaging shows both symptomatic and asymptomatic MRI lesions or if cerebrospinal fluid is positive for oligoclonal banding. MRI scans may be used to obtain objective evidence to track treatment efficacy and adverse effects (Table 2).12 

TABLE 2

Various types of magnetic resonance imaging scans and what they show12 

Various types of magnetic resonance imaging scans and what they show12
Various types of magnetic resonance imaging scans and what they show12

Patient Case Part 1: Risk Factors

A 27-year-old presents to the clinic with new onset numbness and tingling of the left buttock, leg, and foot along with lightheadedness and fecal incontinence. Brain MRI showed 2 new T2-lesions and cervical spine MRI showed 1 new T2-lesion, resulting in a diagnosis of RRMS. The patient exercises 4 times weekly, smokes 1 pack per day, has 2 to 3 alcoholic beverages per month, and expresses interested in natural remedies and lifestyle changes when discussing treatment options.

Take Home Points
  • Treatment of multiple sclerosis is centered around disease-modifying therapies (DMTs) that are either immunomodulating or immunosuppressive by mechanism. DMTs are further classified into modestly or highly effective based on annualized relapse reduction, decrease in new magnetic resonance imaging lesions, and decreased disability progression over time.

  • Treatment strategies are evolving. Current published data suggests using a risk-stratified approach to determine an escalation or induction therapy approach.

  • Risk of adverse effects, financial burden to the patient, and family planning desires should also be considered when choosing a DMT.

  • Newer DMTs have challenges associated with their management such as screening and monitoring requirements and significant infectious risks compared to the older self-injectable, immunomodulating DMTs.

The incidence of MS in the United States is greater at higher latitudes.5  This prevalence gradient may be related to less ultraviolet B-induced vitamin D production in the skin due to less sun exposure. Vitamin D appears to have protective anti-inflammatory and immunoregulatory effects.2  Other immunologic, infectious, genetic, and environmental etiological factors have also been identified.1-4  Patients should be educated on the etiological factors that are modifiable if applicable, where intervention may either lower the risk of developing MS or if diagnosed, may weaken its influence on the rate of disease progression (Table 3).13,14 

TABLE 3

Potentially modifiable environmental etiologic factors13,14 

Potentially modifiable environmental etiologic factors13,14
Potentially modifiable environmental etiologic factors13,14

Predicting the course of a pwMS is difficult since the disease manifests heterogeneously from one individual to another. Several factors can discern which pwMS may be at greater risk for a more aggressive course.15,16  The strongest and most consistent negative prognostic factors include: frequent relapses during the first 2 to 5 years postonset, short interval between relapses, incomplete relapse recovery, sphincter-type symptoms (ie, bowel, bladder), progression at onset, and rapidly worsening disability.15,16  Imaging characteristics include increasing size of T2 lesion burden from baseline, GAD lesions, cerebellar and/or spinal cord lesions, and brain atrophy.16  Identifying the presence of negative prognostic factors and, thereby, patients at greater risk of disease worsening, informs clinicians which patients may benefit from earlier initiation of higher efficacy DMT.

Patient Case Part 2: Too Many Choices

Based on formulary options, copay assistance programs, and patient preference for route of administration, interferon-betas, fingolimod, and teriflunomide are DMT options discussed with the patient during a shared-decision making conversation.

The newer DMTs affect immune system functioning more directly compared to older self-injectable DMTs by targeting T-cell activation, T-cell migration, T- and/or B-cell depletion. When selecting a DMT, consider patient-specific factors and treatment approach. In the case example, affordability as well as oral and injectable options were discussed given the patient did not want to consider an infused therapy option. Although self-injectable interferon-betas were the mainstay of MS management for many years, the self-injectable administration may not be ideal, primarily because of the risk of flu-like symptoms and injection-site reactions. Teriflunomide and fingolimod provide oral options but differ in their efficacy, safety, and side effect profiles (Table 4).17-29  While teriflunomide does have a risk of some worrisome side effects, (eg, hepatotoxicity, leukopenia, paresthesia), overall it has demonstrated similar or better tolerability compared to other oral DMTs in observational studies.30,31  The most important clinical risks with teriflunomide include hepatotoxicity (managed with routine laboratory monitoring), and teratogenicity. Another important factor for DMT decision-making is desire/plan for pregnancy. While specific management strategies for managing MS in preparation of and during pregnancy are out of the scope of this review, contraception and family planning should be discussed with every patient. Although safety of DMT use in pregnancy varies among agents, experts recommend highly effective contraception should be considered in all patients starting DMTs.32 

TABLE 4

Disease-modifying therapies17-29 

Disease-modifying therapies17-29
Disease-modifying therapies17-29

The variable efficacy and side effect profiles of currently approved DMTs (Table 4) have introduced the idea of personalizing MS care.

Based on the available evidence, there is a generally accepted categorization of modestly effective (ME)-DMTs versus highly effective (HE)-DMTs (Table 4), however controversy and differences in clinical opinion still exists.15,33  The increased efficacy of many of the newer DMTs exposes pwMS to DMTs with higher risks (eg, adverse effect potential, more complex safety monitoring needed). This increased risk potential is related to the newer agents having more immunosuppressing mechanisms (suppressing the immune response) versus the immunomodulating mechanisms (adjusting level of immune response) of the first available DMTs.

Determining ME-DMT versus HE-DMT for relapsing type of MS is not entirely straightforward given an overall lack of head-to-head trials between newer and older DMTs. Previous head-to-head trials34-38  between older self-injectable agents have shown similar efficacy across agents. While one trial38  showed superiority of one interferon-beta over another (eg, high-dose interferon vs low-dose interferon) this trial had design limitations lessening the strength of the result. The available phase III head-to-head trials and comparative effectiveness research between interferon-betas and the oral DMTs suggest teriflunomide is as effective as the interferon-betas and fingolimod is more effective than interferon-betas.39,40  The placebo-controlled studies24-27  of dimethyl fumarate included glatiramer acetate as a reference comparator, and thus were not designed to test the superiority or noninferiority of dimethyl fumarate versus glatiramer acetate. Prospective head-to-head studies among the HE-DMTs remain absent. Fortunately, observational and comparative effectiveness studies30,31,39,44,45  showing HE-DMTs are more effective than ME-DMTs and describing long-term safety are providing real world data and supplementing the evidence given the limited number of head-to-head phase III trials.

With limited head-to-head data, clinicians are also left with comparing DMT efficacy outcomes such as annualized relapse reduction, incidence of new brain lesions on MRI, and disability scores, across placebo-controlled clinical trials. This practice comes with its own set of confounding factors and limitations making it difficult to compare these agents. For example, clinical trials vary by patient population and inclusion/exclusion criteria. Additionally, the diagnostic criteria for MS and definition of clinical relapse have changed and evolved over the years, making it difficult to compare recent studies to older clinical trials.

Patient Case Part 3: To Induce or Not to Induce

At the next clinic visit, the clinician and the patient discussed the goals and expectations of therapy and compared the efficacy and safety of the DMT options.

Given the approval of more efficacious DMTs, a broad evolution of the current MS treatment paradigm is underway. The key evolving concepts include treatment initiation and goals, stratifying treatment on disease phenotype and DMT efficacy, and managing use of riskier DMTs.

Prior to the availability of HE-DMTs, treatment response was demonstrated by achieving limited reduction in relapse rates and minimal effects on disability accumulation. Following the approval of HE-DMTs, the goals of treatment response have started to shift from reluctant acceptance of a partial response to the expectation of achieving as close to complete cessation of disease activity and progression as possible.46  The no evidence of disease activity (NEDA) treatment goal remains controversial because of a lack of definition for how to measure disability progression clinically, MRI sensitivity for detecting lesions associated with disability, and real-world application.46  The most agreed upon definition includes the absence of relapses, no confirmed disability progression, and no new GAD lesions or new or worsened T2 lesions.46,47  Using NEDA as a treatment goal means any evidence of relapse, progression, and/or active lesions should prompt reconsideration of the current DMT. Two therapeutic strategies are being examined to determine which best achieves a NEDA-like target.

The escalation strategy means starting with safer ME-DMTs and then transitioning to higher risk HE-DMTs only if disease breakthrough occurs. The argument against this strategy is that the early use of subpotent DMTs may expose individuals unnecessarily to the loss of functional years from disability accumulation because relapses are frequently underreported and silent lesions often occur.48,49 

The induction strategy means that the higher risk, HE-DMTs are started immediately following diagnosis, in order to achieve the NEDA-like target as early as possible. Alemtuzumab and cladribine are considered induction-specific DMTs given their relatively rapid suppression of multiple cell lines and persistent immunosuppression. Repopulation of these cell lines may take months to years thus, fostering long term suppression of disease activity. Induction therapy is then followed by long-term maintenance treatment, such as with a ME-DMT.50  Rituximab and ocrelizumab are also HE-DMTs, though these agents have partial induction effects. While they do not suppress multiple immune cell lines, their duration of effect is prolonged and repeat dosing can be given at extended intervals (ie, every 9 to 12 months or longer if needed) over time. Natalizumab and fingolimod are HE-DMTs and are used as initial treatments for aggressive disease in a manner similar to induction-specific DMTs, but they do not have true induction effects. Both natalizumab and fingolimod (and likely siponimod) appear to have rapidly reversible effects that predispose patients to a rebound of disease activity upon discontinuation.50  The overall concern with the induction approach is that an otherwise young, healthy person may be exposed to serious adverse effects including risk of opportunistic infections.

The recently updated treatment guidelines published by the American Academy of Neurology (AAN)51  and the European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) in cooperation with the European Academy of Neurology (EAN)43  do not advocate for any particular therapeutic strategy. Both advise treating individuals with clinically isolated syndrome who have MS-like lesions with an injectable DMT. Both recommend treating RRMS as early as possible to improve outcomes based on data from trials of individuals with clinically isolated syndrome who had MS-like lesions and trials showing DMT efficacy is greatest when using the HE DMTs early in the disease.33,52,53  And both guidelines address switching DMTs. EAN/ECTRIMS endorses switching therapy for pwMS on a self-injectable who experience breakthrough disease activity (relapses, disability progression, or MRI activity) to a HE-DMT rather than between self-injectables. Without providing a definition of highly active MS, the AAN advises identifying persons with highly active MS and treating individuals with DMTs they consider having greater efficacy but did not use the term highly effective.51  Neither of these guidelines provide specific treatment algorithms for personalization. The MS Coalition, an affiliation of independent MS organizations including the National Multiple Sclerosis Society, updated their consensus paper in 2019. The consensus paper1  advocates for initiating DMT early, recognizes specific DMTs as HE-DMTs and supports using HE-DMTs if disease is highly active and opposes any restrictions to therapy choice. Neither AAN nor EAN/ECTRIM guidelines support one strategy (escalation or induction) over the other, and both strategies are an option. Use of a ME-DMT at onset (escalation strategy) can be considered either for patients presenting with milder symptoms (ie, optic neuritis or numbness/tingling sensory symptoms), who have no negative prognostic factors, for patients already stable on ME-DMTs who have no negative prognostic factors, or for patients who are risk averse. Consider escalating to a HE-DMT when a new relapse and/or new MRI lesion(s) occur. Additionally, inform the patient that even though the disease may appear dormant, silent inflammatory attacks and progression may be ongoing.15,16  For pwMS with any negative prognostic factor, we suggest HE-DMT from the start (induction strategy) along with education of the risks and careful monitoring of side effects.

Patient Case Part 4: De-Risking the Risk

The clinician supports the choice of fingolimod as an induction therapy given findings of spinal cord lesions and sphincter symptoms (fecal incontinence). Appropriate screening is completed and fingolimod is initiated with the recommended first dose observation (FDO) including a baseline electrocardiogram, blood pressure, and heart rate followed by blood pressure and heart rate checks hourly for 6 hours after the first dose is taken, and finally a repeat electrocardiogram at the 6 hour mark. The FDO of fingolimod is tolerated and treatment is started, after which the clinical pharmacy specialist assists with implementation of safety monitoring.

The clinical pharmacy specialist recommends absolute lymphocyte count (ALC) and liver function test (LFT) monitoring every 6 months while on fingolimod. At 6 months postinitiation, LFTs remain normal however, ALC falls to 300/μL. The patient denies any signs or symptoms of infection. The primary care provider orders a repeat complete blood count in 2 weeks and shows stable ALC, which remained at 300/μL.

Absolute lymphocyte count reduction is expected with fingolimod based on the mechanism of action of sequestering lymphocytes in lymphoid tissue and should not prompt therapy discontinuation. The lowest acceptable level of lymphopenia has been set to 200/μL because during clinical trials opportunistic infections were not seen even when the ALC dropped to this value. However risk of infection is unknown when ALCs are below this threshold as continuing fingolimod in this setting has not been extensively studied.54  If ALC values fall persistently below 200/μL, an alternative DMT should be considered. Holding fingolimod therapy to allow ALC to increase within an acceptable range may be tried. However, if treatment is interrupted for more than 14 days, FDO for cardiac changes is recommended upon reinitiation.

Siponimod and dimethyl fumarate can also reduce ALC.21,26  Because of a similar mechanism of action to fingolimod, ALC reduction with siponimod is expected and thus management recommendations are similar. Lymphopenia with dimethyl fumarate is less common. Unlike fingolimod or siponimod where ALC returns to baseline soon after discontinuation, prolonged lymphopenia after discontinuation may occur with dimethyl fumarate.26  In addition, rare cases of progressive multifocal leukoencephalopathy (PML; a sometimes fatal opportunistic viral infection of the CNS) has been linked to dimethyl fumarate-induced lymphopenia, and a case of PML which occurred after an ALC of less than 500/μL that persisted for greater than 6 months prompted a FDA label change in 2014, which expands on lymphocyte monitoring recommendations.26  While severe lymphopenia as a risk factor for PML remains controversial, it does highlight the importance of appropriate laboratory monitoring and follow up.55 

Patient Case Part 5: Rebound Relationships

After 3 years on fingolimod the patient has had no relapses, no radiographic or clinical progression of disease, and ALCs have remained at or above 200/μL without any recent illnesses. Upon follow-up, the patient shares plans to relocate out of state for a new job opportunity in 2 months. This move will involve changing insurance providers and finding a new clinician. The patient is nervous about how to continue taking fingolimod until seen by a new clinician.

Fingolimod should not be abruptly discontinued without a plan to transition to an alternative DMT because of risk of rebound in persons with relapsing MS. Clinical rebound syndrome has been reported within 4 to 16 weeks of patients stopping fingolimod and is consistent with signs/symptoms of a severe clinical relapse such as drastic increases in new and/or enhancing lesions on MRI and new or worsening MS symptoms.23,56  Similarly, risk of disease rebound after discontinuation is also high with natalizumab as a number of case studies have reported an increase in disease activity beyond that of prenatalizumab levels.17,57,58  While the most effective management strategy to prevent rebound syndrome remains unclear, expert clinicians recommend transitioning to an alternative HE-DMT before the effects of fingolimod or natalizumab wear off. Based on experience, it is the authors' practice to transition patients to a HE-DMT within 4 to 8 weeks after the last natalizumab infusion and within 4 weeks after the last fingolimod dose.

Since the patient will soon be without a clinician and possibly without fingolimod for an unknown length of time, switching to alternative HE-DMT prior to losing current insurance coverage would be ideal. Based on clinical experience, an anti-CD20 agent may be the best option given it may help prevent clinical rebound syndrome after discontinuing fingolimod. Anti-CD20 agents are HE-DMTs with clinical effects lasting for at least 6 months after receiving a dose, which allows the patient time to establish care. While the anti-CD20 agent, ocrelizumab, is FDA-approved for MS, rituximab was the precursor to its development and has been used off-label for many years in European countries and later in the United States.59  Either option would be appropriate, and choice would most likely be dictated by insurance coverage, copay, and provider preference.

The management of MS continues to rapidly evolve. Treatment options with greater efficacy and potential for altering the course are now available. Shared decision making and patient preferences remain key factors in DMT selection. However, treatment customization should also consider patient-specific negative prognostic factors both at diagnosis and throughout the course of treatment. Identification of these factors can further stratify therapy approach using the HE-DMTs, which then requires that benefits be balanced with sometimes very serious risks. Ongoing research will provide more direction as to which strategy is the safest and most effective for achieving a NEDA-like goal of treatment.

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Author notes

1(Corresponding author) Clinical Pharmacy Specialist in Neurology, Kaiser Permanente, Denver, Colorado; part-time Editorial Advisory Panel Consultant, Clinical Effectiveness, Wolters Kluwer Health, Hudson, Ohio, [email protected]

2Clinical Pharmacy Specialist in Neurology, Kaiser Permanente, Denver, Colorado

Competing Interests

Disclosures: S.K. is a consultant and serves as a part-time Clinical Specialist-Neurology with Wolters Kluwer Health. N.H. has nothing personal to disclose. Psychopharmacology Pearls are review articles intended to highlight both the evidence base available and/or controversial areas of clinical care for psychiatric and neurologic conditions as well as strategies of clinical decision-making used by expert clinicians. As pearls, articles reflect the views and practice of each author as substantiated with evidence-based facts as well as opinion and experience. Articles are edited by members of the Psychopharmacology Pearls Editorial Board as well as peer reviewed by MHC reviewers. This article was developed as part of the 2019 Psychopharmacology Pearls product for BCPP recertification credit. The course information and testing center is at https://cpnp.org/379404.

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