Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

39. Multiple Sclerosis

Jacquelyn L. Bainbridge, Augusto Miravalle, and John R. Corboy


KEY CONCEPTS

 Images The etiology of multiple sclerosis (MS) is unknown, but it appears to be autoimmune in nature. Currently there is no cure.

 Images MS is characterized by CNS demyelination and axonal damage.

 Images MS is classified by the nature of progression over time into several categories, which have different clinical presentations and responses to therapy.

 Images Although studies do not support the general use of any of the FDA-approved disease-modifying therapies (DMTs) in patients with progressive forms of the illness, information derived from multiple studies suggests younger patients with progressive illness and those with either superimposed acute relapses or enhancing lesions on magnetic resonance imaging (MRI) scans may benefit from some of the presently used DMTs.

 Images Diagnosis of MS requires evidence of dissemination of lesions over time and in multiple parts of the CNS and/or optic nerve, and is made primarily on the basis of clinical symptoms and examination. Diagnostic criteria also allow for the use of MRI, spinal fluid evaluation, optical coherence tomography, and evoked potentials to aid in the diagnosis.

 Images Exacerbations or relapses of MS can be disabling. When this is the case exacerbations and relapses are treated with high-dose glucocorticoids, such as methylprednisolone IV, with onset of clinical response typically within 3 to 5 days.

 Images Treatment of relapsing-remitting multiple sclerosis (RRMS) with the DMTs interferon-β (IFN-β) (Avonex, Betaseron, Rebif, Extavia), glatiramer acetate (Copaxone), natalizumab (Tysabri), mitoxantrone (Novantrone), fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera) can reduce annual relapse rate, lessen severity of relapses, slow progression of changes on MRI scans, slow progression of disability, and slow cognitive decline. In addition, they have been shown to reduce the likelihood of developing a second attack after a first clinically isolated syndrome (CIS) consistent with MS.

 Images In most cases, treatment with DMTs should begin promptly after the diagnosis of relapsing-remitting MS, or after a CIS if the brain MRI is suggestive of high risk of further attacks. Natalizumab and other choices that have been associated with problematic adverse events should be reserved for those patients who have failed one or more standard therapies and those with poor prognostic signs.

 Images The definition of treatment inadequacy for RRMS remains unclear, and therapy changes after “treatment failure” should be individualized.

 Images Patients suffering with MS frequently have symptoms such as spasticity, bladder dysfunction, fatigue, neuropathic pain, cognitive dysfunction, and depression that can require treatment. Patients must be counseled that therapies such as IFN-β and glatiramer acetate will not relieve these symptoms. Depression is common in MS and can pose the risk of suicide.


Multiple sclerosis (MS) is an inflammatory disease of the CNS that affects approximately 1 in 200 women and fewer men in the United States.1 The term “multiple sclerosis” refers to two characteristics of the disease: numerous affected areas of the brain and spinal cord (CNS) producing multiple neurologic symptoms that accrue over time, and the characteristic plaques or sclerosed areas that are the hallmark of the disease.

Images Although MS was first described almost 140 years ago, the cause remains a mystery, and a cure is still unavailable. Nevertheless, many advances have been made in treating and managing the disease complications and improving the quality-of-life of affected individuals.

EPIDEMIOLOGY

Epidemiologic aspects of MS have been reviewed in many publications.15 MS affects approximately 400,000 people in the United States and 2.5 million people worldwide.6 MS is usually diagnosed between the ages of 15 and 45 years; peak incidence occurs in the fourth decade. Approximately 10,000 new cases are diagnosed per year in the United States. Women are afflicted more than men by a ratio of 2:1. Men usually develop the first signs of MS at a later age than women, and are more likely to develop a progressive form of the disease. The most important factors in determination of risk for developing the disease are geography, age, environmental influences, and genetics. In general, disease prevalence is higher the greater the distance from the equator; within the United States the prevalence of MS is higher in states above the 37th parallel. Recent studies, however, suggest a waning latitude gradient as demonstrated by a substantial increase in MS incidence in Mediterranean regions. Rising incidence of MS in females appears to be associated with urbanization. As an example, recent reports suggest that MS incidence markedly rose on Crete among female subjects residing in urban settings or relocating at a young age from rural areas; this suggests that an environmental factor yet to be identified might play a role in changing disease susceptibility.7

MS occurs more frequently in whites of Scandinavian ancestry than in other ethnic groups. In addition, an inverse relationship between MS risk and 25-hydroxyvitamin D levels has been proposed.1,8

Etiology

It is thought that genetically susceptible individuals ≤15 years of age who have lived in a high-risk area for at least 2 years and were exposed to a crucial environmental agent are at risk for developing MS. Interestingly, an individual who migrates from a low- to high-risk area prior to the age of 15 years acquires the same chance of developing MS as those who live in a high-risk area all their lives.2 If the move is made from a high- to a low-risk area, the individual retains the high risk if the move is made after the age of 15 years, but acquires the lower risk if the move is made prior to this age.2 Smoking cigarettes has been associated with both an increased risk of developing MS and with more severe progression of disability.5,9

Viral or bacterial infections may be an important environmental cause of MS. Although no clear association has been identified, certain infections might participate in the pathogenesis of MS by initiating or activating autoreactive immune cells in genetically susceptible individuals, leading to subsequent demyelination. Evidence to support a viral etiology includes increased immunoglobulin G (IgG) synthesis in the CNS, increased antibody titers to certain viruses, and epidemiologic studies that indicate a childhood exposure factor, suggesting that “viral” infections may precipitate exacerbations. In addition, viruses have been shown to cause diseases with prolonged incubation periods, myelin destruction, and a relapsing-remitting course in both humans and experimental animal models.1,10

Although numerous viruses have a proposed association with MS, the greatest evidence supports Epstein–Barr virus (EBV). Links of EBV infection to MS pathology are yet largely hypothetical. Autoreactive T-cells could be activated by EBV through molecular mimicry, whereby sequence similarities between EBV and self-peptides are sufficient to result in the cross-activation of autoreactive T- or B-cells. Other potential mechanisms of demyelination include enhanced breakdown and presentation of self-antigens, expression of viral superantigens, or bystander activation.11 Antibody titers to Epstein–Barr nuclear antigen (EBNA) complex are higher in MS patients versus controls, especially if blood is collected ≥5 years before onset. These titers increase over time in MS patients (controls are unchanged), and a fourfold increase in EBNA titers over time results in a threefold increased risk of developing MS (almost an 18-fold increase in those with first samples before age 20).12 Interestingly, one paper notes individuals positive for HLA DRB1*1501 have a 24-fold increased risk of developing MS when they also have antibodies to certain epitopes within EBNA-1 compared with others.13 This is consistent with a genetic-environmental interaction. In addition, anti-EBNA titers have been associated with relapsing-remitting multiple sclerosis (RRMS), conversion of clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS, confirmed diagnosis of MS), and with magnetic resonance imaging (MRI) measures such as gadolinium-enhancing lesions, change in T2 lesion volume (r = 0.27; P = 0.044), and Expanded Disability Status Scale (EDSS) score (r = 0.3; P = 0.035). Zivadinov et al. also found anti-EBNA and anti-vascular cell adhesion (VCA) titers associated with gray matter atrophy in MS.14While Serafini et al. have claimed to identify evidence of abortive infection in a significant number of MS patients,15 others have not been able to replicate these findings.16 The majority of data would lead to a conclusion that exposure to EBV is somehow associated with developing MS, but does not support the concept of an active or aborting EBV infection directly causing MS.

The familial recurrence rate of MS is approximately 5%, with siblings being the most commonly reported relationship,4 and a concordance rate among monozygotic twins of approximately 25%. This is consistent with the idea that an environmental agent is important in the etiology of MS, but also suggests a role for one or more genes. Genes that lie within the major histocompatibility complex (MHC), which is located on the sixth chromosome in humans, have been linked to MS.1,4 Recent data show a significant association of risk with mutations in the interleukin-2α (IL-2α) and interleukin-7α (IL-7α) receptor genes.1719 African Americans are significantly less likely to be diagnosed with MS compared with whites, although there is emerging evidence that they are more likely to have a severe disease course20 and respond less well to interferon (IFN) therapy.21 A locus on chromosome 1 may be associated with increased susceptibility in African Americans.22

PATHOPHYSIOLOGY

Images The basic physiologic derangement in MS is stripping of the myelin sheath surrounding CNS axons. This activity is associated with an inflammatory, perivenular infiltrate consisting of T and B lymphocytes, macrophages, antibodies, and complement.10 Demyelination renders axons susceptible to damage, which becomes irreversible when they are severed. Irreversible axonal damage correlates with disability and can be visualized as hypointense lesions, or “black holes,” on T1-weighted MRI.23,24

It is well accepted that MS lesions are heterogeneous, which may be due in part to differences in the stage of evolution of the lesions over time, differences in underlying immunopathogenesis, or a combination. Briefly stated, acute lesions show demyelination and axonal destruction with lymphocytic activity consistent with an inflammatory state. In contrast, more chronic lesions display less inflammatory lymphocytes with active remyelination.10Although traditional descriptions have focused on white matter as the sole location of MS lesions, more recent studies have clearly identified cortical and subcortical gray matter lesions both pathologically25 and radiographically.26 In addition, a subset of patients with progressive MS are noted to have abnormalities consistent with B-cell follicles in the meninges.27

Just as the full dimensions of the neuropathology are uncertain, so is the pathogenesis of the MS lesion. Substantial evidence suggests it is an autoimmune process directed against myelin and oligodendrocytes, the cells that make myelin10 (Fig. 39-1). A new concept of T-cell entry into the CNS suggests that the initial lymphocyte invasion in MS may proceed through the ventricles, toward the choroid plexus along a CCL 20 gradient that attracts activated Th17 cells.28 The actual mediator of myelin and axonal destruction has not been established, but may reflect a combination of macrophages, antibodies, destructive cytokines, and reactive oxygen intermediates. The exact trigger for activation of T-cells in the periphery remains unclear, but the T-cells in MS patients recognize myelin basic protein (MBP), proteolipid protein, myelin oligodendrocyte glycoprotein, and myelin-associated glycoprotein. T-helper subtypes can be either pathogenic or protective in MS. Furthermore, theory holds that certain T-cell subsets are not terminally differentiated, but instead engender a level of plasticity that allows for their conversion from pathogenic to protective and vice versa under certain conditions (Fig. 39-2).29 In patients with stable or mild disease, increased numbers of cells are found that express messenger RNA (mRNA) for transforming growth factor-β (TGF-β) and interleukin-10 (IL-10) compared with patients with severe disease. Conversely, a reduction in the number of T-regulatory (Treg) cells, which exhibit suppressor activity, is associated with active MS and can be found in patients with progressive disease. It should be noted, however, that Treg ratios do not always correlate with disease activity. Of note, experimental evidence associates high 25-hydroxyvitamin D levels with improved Treg function, favoring the Th2 phenotype in the Th1/Th2 balance.30 Finally, the significance of one of the immunological hallmarks of MS, the intrathecal synthesis of multiple clones of immunoglobulins, remains unclear. The antigen(s) against which these immunoglobulins are directed remain unknown, but do not appear to include common CNS myelin antigens.31 The complex interplay of a variety of cells, antibodies, and cytokines remains to be elucidated.

Images

FIGURE 39-1 Autoimmune theory of the pathogenesis of multiple sclerosis (MS). In MS, the immunogenic cells tend to be more myelin-reactive, and these T-cells produce cytokines mimicking a Th1-mediated proinflammatory reaction. T-helper cells (CD4+) appear to be key initiators of myelin destruction in MS. These autoreactive CD4+ cells, especially of the T-helper cell type 1 (Th1) subtype, are activated in the periphery, perhaps following a viral infection. The activation of T- and B-cells requires two signals. The first signal is the interaction between MHC and APC (macrophage, dendritic cell, B-cell). The second signal consists of the binding between B7 on the APC and CD28 on the T-cell for T-cell activation. Similarly, CD40 expressed on APCs and CD40L expressed on T-cells interact to signal the proliferation of B-cells within the blood–brain barrier following the entry to T-cells. The T-cells in the periphery express adhesion molecules on their surfaces that allow them to attach and roll along the endothelial cells that constitute the blood–brain barrier. The activated T-cells also produce MMP that help to create openings in the blood–brain barrier, allowing entry of the activated T-cells past the blood–brain barrier and into the CNS. Once inside the CNS, the T-cells produce proinflammatory cytokines, especially interleukins (ILs) 1, 2, 12, 17, and 23, tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ), which further create openings in the blood–brain barrier, allowing entry of B-cells, complement, macrophages, and antibodies. The T-cells also interact within the CNS with the resident microglia, astrocytes, and macrophages, further enhancing production of proinflammatory cytokines and other potential mediators of CNS damage, including reactive oxygen intermediates and nitric oxide. The role of modulating, or downregulating, cytokines such as IL-4, IL-5, IL-10, and transforming growth factor-β (TGF-β) also has been described. These cytokines are the products of CD4+, CD8+, and Th1-cells.10New pathogenic mechanisms involve, but are not limited to, receptor-ligand mediated T-cell entry via choroid plexus (CCR6-CCL20 axis),28 coupling of key receptor-ligands for inhibition of myelination/demyelination (LINGO-1/NOGO66/p75 or TROY complex, Jagged-Notch signaling).(Ag, antigens; APC, antigen presenting cell; DC, dendrite cell; IgG, immunoglobulin G; MΦ, macrophage; Na+, sodium ion; MMP, matrix metalloproteinases; MHC, major histocompatibility complex; OPC, oligodendrocyte precursor cell; VLA, very late antigen; VCAM, vascular cell adhesion molecule.)

Images

FIGURE 39-2 Upon interaction with an antigen-laden APC and specific cytokines, the innate T-cells undergo differentiation into a few lineages (subtypes). Four subtypes significant for MS pathophysiology are illustrated here (Th1, Th2, Th17, and Treg). Th1 and Th17 are proinflammatory, Th2 is anti-inflammatory, and Treg is regulatory. Th1 and Th2 are mutually suppressive and are relatively stable differentiated subtypes. In contrast, Th17 and Treg subtypes are recently found to exhibit “plasticity.” In other words, they can undergo phenotypic conversion to another T-cell subtype (Th1 or Th2) in the presence of specific cytokine conditions. This plasticity of Th17 and Treg is the immunologic basis for development of therapeutic agents to favor the production of suitable Th subtypes for combating microbial invasion and also concurrently achieving neurocellular recovery after an infection.29 (APC, antigen presenting cell.)


CLINICAL PRESENTATION Multiple Sclerosis

General

    • Most patients with MS present with nonspecific complaints. Many have problems with their vision or paresthesias

Primary Symptoms/Signs

    • Visual complaints/optic neuritis

    • Gait problems and falls

    • Paresthesias

    • Pain

    • Spasticity

    • Weakness

    • Ataxia

    • Speech difficulty

    • Psychological changes

    • Cognitive changes

    • Fatigue

    • Bowel/bladder dysfunction

    • Sexual dysfunction

    • Tremor

Laboratory Tests

    • MS is a diagnosis of exclusion

    • MRI

    • CSF studies

    • Evoked potentials

Secondary Symptoms

    • Recurrent UTIs

    • Urinary calculi

    • Decubiti and osteomyelitis

    • Osteoporosis

    • Respiratory infections

    • Poor nutrition

    • Depression

Tertiary Symptoms

    • Financial problems

    • Personal/social problems

    • Vocational problems

    • Emotional problems

CLINICAL PRESENTATION AND COURSE OF ILLNESS

Images The clinical presentation of MS is extremely variable among patients and typically varies over time in a given patient. The signs and symptoms of MS can be divided into three categories. Primary symptoms are a direct consequence of conduction disturbances produced by demyelination and axonal damage, and reflect the area of the CNS that is damaged. Secondary symptoms are complications resulting from primary symptoms. For example, urinary retention, a primary symptom, can lead to frequent urinary tract infections (UTIs), a secondary symptom. Tertiary symptoms relate to the effect of the disease on the patient’s everyday life.32

The clinical course of CDMS is classified into four categories.33 At the onset of symptoms, about 85% of patients have exacerbations—new symptoms lasting at least 24 hours and separated from other new symptoms by at least 30 days—followed by remissions (complete or incomplete). Exacerbations are frequently referred to as relapses or attacks. This course is called RRMS; the first clinical presentation is typically CIS. During the RRMS phase, there is a correlation between new brain MRI lesions and clinical attacks, but typically there are many more new MRI lesions than new clinical symptoms. In RRMS patients, attack frequency tends to decrease over time and becomes independent of the development of progressive disabilities.34 Neurologic recovery following an exacerbation is often quite good early in the disease course, but following repeated relapses, recovery tends to be less complete. In addition, there is a new concept of a radiologically isolated syndrome (RIS), referring to individuals who have clinical scenarios not typical of MS, yet obtain MRI scans for other reasons (e.g., headache) and have radiological signs suggestive of MS. Some percentage of these patients convert to RRMS over time,35 although when to start treatment remains unclear and varies by practice.

Up to 10% to 20% of RRMS patients have a benign course, characterized by few relapses, often sensory, with minimal disability accruing over time. Most RRMS patients eventually enter a progressive phase in which attacks and remissions are difficult to identify. This is referred to as secondary-progressive multiple sclerosis (SPMS). Disability tends to accumulate more significantly during this phase of the illness. New brain MRI lesions, especially those seen only after the injection of contrast material, are less common, and brain atrophy and T1 holes increase.36

Images Approximately 15% of patients never have attacks and remissions but have progressive disease from the outset, known as primary-progressive multiple sclerosis (PPMS). These patients will have symptoms, especially spastic paraparesis that may worsen rapidly or relatively slowly over time, and accrue progressively more disability. Patients with PPMS are diagnosed at a later age, with the number of males roughly equal to that of females. In general, PPMS patients tend to have a worse prognosis than those who present initially with RRMS, although more recent data suggest progression is variable.37Many clinical trials have suggested that a significant portion of patients with PPMS do not receive benefit from studied therapies. However, a recent article using rituximab suggests a subgroup of PPMS patients who are <51 years of age and have at least one gadolinium-enhancing lesion may benefit from this therapy.38 Finally, a small percentage of patients may have a mixture of both progression and relapses, referred to as progressive-relapsing multiple sclerosis (PRMS). These patients are generally treated as relapsing patients.

Progression of the illness throughout the lifetime can be measured in many ways. The most widely used clinical rating scale is the EDSS, which uses a numerical value ranging from 0 (no disability) to 10 (death) to evaluate neurologic functions.39 The limitations of this scale are the relative insensitivity to clinical changes not involving impairment of ambulation, such as changes in cognition, fatigue, and affect. Other tools, such as the multiple sclerosis functional composite (MSFC), are being evaluated for increased sensitivity and utility in describing changes in MS-related disability over time.40 Increasingly, MRI is being used as an index of both disease activity and progression.10Specifically, the appearance of new lesions or changes in lesion number, size, and volume are being used as outcome measures in research studies. Optical coherence tomography measures the retinal neural fiber layer thickness, and may also be a measurable sign of pathological progression over time.41

The unpredictable nature of MS makes it impossible to anticipate when an exacerbation will occur. However, certain factors, including infections, heat (including fever), sleep deprivation, stress, malnutrition, anemia, concurrent organ dysfunction, exertion, and childbirth, may aggravate symptoms or lead to an attack. Interestingly, many patients experience a significant reduction in relapses during the third trimester of pregnancy, followed by a relative increase postpartum.42 Between 60% and 80% of individuals diagnosed with the MS have been reported to be sensitive to environmental heat.

Clinically, increased body temperature might result in worsening of previous neurological deficits, including fatigue and decreased muscular endurance. Blurred vision, known as Uthoff’s phenomenon, is caused by increased body temperature due to physical exercise or physical restraint. Body temperature influences nerve impulses, which are blocked or slowed down in a damaged nerve. After normalization of the temperature, signs and symptoms improve or disappear.

MS usually does not directly diminish life expectancy. The development of secondary complications such as pneumonia or septicemia (secondary to aspiration in those with swallowing difficulties, decubitus ulcers, or UTIs) or rapid progression of primary lesions affecting respiratory function can lead to a shorter than expected life span. Most of the decrease in life span is seen in patients with rapidly progressive disease. Suicide rates as high as seven times that seen in the general population have been reported.43 Clinical and demographic factors used to predict prognosis of MS are listed in Table 39-1.5,44 Several MRI features also have been shown to correlate with progression of disease (see below).4547

TABLE 39-1 Prognostic Indicators in Multiple Sclerosis

Images

DIAGNOSIS

Images MS is a diagnosis of exclusion; symptoms frequently can be attributed to other neurologic diseases, just as many syndromes can mimic MS. Some patients may have typical symptoms consistent with classic CIS, whereas others may have symptoms that are more vague. The diagnosis remains primarily a clinical one that requires demonstration of “lesions separated in space and time,” referring to the occurrence of at least two episodes of neurologic disturbance reflecting distinct sites of CNS damage that cannot be explained by another mechanism.50 An international panel of MS experts established the McDonald criteria,50 which allows brain MRI lesions, cerebrospinal fluid (CSF) abnormalities, and visual-evoked potential (VEP) studies to substitute for clinical lesions in defining “separated in space and time.” A reevaluation of the McDonald criteria has simplified the use of these laboratory studies.45In the new scheme, diagnostic categories are MS, possible MS (for those individuals at high risk of developing MS), and not MS; these new criteria allow for earlier diagnosis.45 Newer, simpler MRI criteria defining dissemination in time and space may be somewhat more sensitive and equally specific.5153A consensus panel of the American Association of Neurology endorses the utility of MRI for diagnostic purpose,47 and the U.S. FDA has approved several of the immunotherapies to be used after a single attack (CIS) of demyelination in the context of an appropriately abnormal brain MRI. A proposed set of criteria now being considered will allow for earlier diagnosis in patients with CIS to establish “dissemination in time and space” with a single MRI. Therefore, patients will need to have lesions in different areas of their CNS with at least one enhancing lesion that correlates with clinical symptomatology. By fulfilling these criteria, a patient can be diagnosed with CDMS.

Laboratory Studies

To date, there are no tests specific for MS. Evidence provided by MRI of the brain and spine,46,47 CSF evaluation (presence of increased oligoclonal bands and increased IgG), evoked potentials,45,50 and optic coherence tomography,54 used in conjunction with the physical examination and history, aids in establishing the diagnosis of MS. MRI, the most valuable diagnostic tool, produces images of the brain and spine that reflect damage that is characteristic of MS plaques in multiple areas of the CNS. MRI is the preferred technique for establishing a diagnosis, prognosis, and for following disease progression. Optic neuritis, a lesion or lesions on the optic nerve, is a common first symptom of MS. A greater number of T2-weighted lesions (called T2 burden of disease) on MRI following optic neuritis or CIS appears to correlate with the development of disability and progression to CDMS.46Lesions that enhance after injection of the contrast material gadolinium indicate new lesions and disruption of the blood–brain barrier and are associated with early conversion to CDMS in CIS patients.46,55 However, they do not correlate well over time with progression of disability. Brain atrophy, even early in the course of the illness, probably correlates better with progression of disability.47

DIFFERENTIAL DIAGNOSIS

Because a number of disorders can mimic MS, most patients are screened with blood tests for rheumatologic, collagen-vascular, infectious, and sometimes inherited metabolic diseases. Electromyography may help in diagnosing amyotrophic lateral sclerosis and neuropathies.

MRI, used to rule out tumors and cervical spondylosis, may also lead to evaluations for MS in many patients with little or no clinical history of MS. While some of these patients may have MRI scans suggestive of MS (so-called RIS), most have nonspecific MRI scans with identifiable causes for their scan abnormalities, including age greater than 50 years, hypertension, and migraine.56 The use of established criteria for distinguishing MS lesions from other etiologies enhances diagnostic accuracy.

TREATMENT

Treatment of MS falls into three broad categories: treatment of exacerbations, disease-modifying therapies (DMTs), and symptomatic therapies. Treatment of exacerbations will shorten the duration and possibly decrease the severity of the attack. DMTs alter the course of the illness, and diminish progressive disability over time. Symptomatic management of the disease is of utmost importance to maintain the patient’s quality-of-life. Although different treatment modalities have been studied in the last 30 years, many older trials had flawed designs. As there are no universally accepted treatment algorithms, treatments vary among clinicians and centers. Perhaps more importantly, treatment decisions are frequently based on the wishes and goals of individual patients rather than evidence-based algorithms. One potential algorithm for the immunotherapy of CDMS is shown in Figure 39-3.

Images

FIGURE 39-3 Algorithm for management of clinically definite multiple sclerosis. (ABC-R, interferon β1a [Avonex], interferon β1b [Betaseron, Extavia], glatiramer acetate [Copaxone], and interferon β1a[Rebif]; IVIG, intravenous immunoglobulin.)

Desired Outcomes

The main goals of treatment are to improve patients overall quality-of-life and minimize long-term disability. Treatment goals are attained by altering MS exacerbations or relapses, decreasing the number of white matter lesions and black holes on MRI, averting brain atrophy, and ultimately halting disease progression. This can be achieved by early recognition of the disease (CIS) and immediate utilization of FDA-approved drugs.

General Approach to Treatment

The severity of symptoms at initial presentation will determine whether an induction or escalation algorithm will be assigned to an individual patient. When FDA-approved drugs do not alter the naturally progressive disease, investigational agents or non–FDA-approved medications, such as rituximab, may be used. As a general rule, MS affects patients in their most productive years of life. Practitioners must work with their patients to set realistic expectations over their lifetime and develop a long-term treatment and management plan. Patients may require external support and assistance to accept their diagnosis. With disease progression, patients are likely to acquire secondary and tertiary symptoms of MS. In clinical trials, high nonadherence rates are reported as an important issue for potential treatment failure. Potential reasons identified for nonadherence are lack of perceived benefit, cost, adverse effects, depression, and fear of needles. With proper patient education and therapy management, treatment failure due to nonadherence can be avoided. Specialty pharmacies may be useful to address patient concerns. With the advance of FDA-approved medications to treat MS, patients are experiencing fewer relapses, slower disease progression, and improved quality-of-life.

Treatment of Exacerbations

Images Exacerbations are the hallmark of early RRMS. Although recovery after relapses is in general complete, over time a substantial accumulation of disability occurs. Controversy exists about the relationship between relapses and subsequent accumulation of disability. Frequent relapses (more than three relapses per year in the first 2 years after diagnosis), particularly in early phases of the disease, have shown consistent positive correlation with later development of neurological disability. Generally, mild exacerbations that do not produce functional decline may not require treatment. Decisions to treat relapses are usually substantiated by patient’s expectations, prior experience with corticosteroids, and predicted course of recovery. Generally accepted indications are based on mono- or polysymptomatic presentations; relapses that localize to the optic nerve, spinal cord, or brainstem; functional limitations that affect activities of daily living; and symptoms that continue to worsen over a period of 2 weeks. When functional ability is affected, the standard intervention is IV injection of high-dose corticosteroids. The American Academy of Neurology recommends that if treatment with steroids is warranted, it is best to use IV methylprednisolone.57 The mechanism of action for corticosteroids in MS is unknown, but it is speculated that steroids improve recovery by decreasing edema in the area of demyelination. IV methylprednisolone has been shown to shorten the duration of exacerbations; it may also delay repeat attacks for up to 2 years after optic neuritis,57 although it has not been shown to definitively affect disease progression.58 More recently, some practitioners are using high doses of oral methylprednisolone, mixing the lyophilized powder or crushed oral tablets in flavored drinks such as smoothies, but there are no comparative data to establish that this is an equivalent way to deliver the medication. In some circumstances, equipotent doses of oral prednisone can be substituted for IV methylprednisolone. Interestingly, adrenocorticotropic hormone (ACTH) is the only agent that is FDA approved for treatment of MS exacerbation treatment, although it is rarely used due to cost and availability.

Methylprednisolone doses range from 500 to 1,000 mg/day, given IV. Duration of therapy is variable and can range from 3 to (rarely) 10 days, depending on clinical response. Functional recovery after an exacerbation is more rapid if corticosteroids are initiated within 2 weeks of symptom onset. If improvement occurs, it usually begins after 3 to 5 days. Short-term use is often accompanied by sleep disturbance, a metallic taste, and rarely, GI upset. Patients with diabetes mellitus or a predilection to diabetes mellitus may have significant elevations of blood sugar, requiring the use of insulin. Longer durations of IV methylprednisolone therapy are associated with acne and fungal infections, mood alteration, and rarely, GI hemorrhage (especially in hospitalized patients or in those taking aspirin). If methylprednisolone is not available, equipotent doses of dexamethasone have been used as a substitute, although this is not well supported in the literature.

A small number of patients have more severe attacks, manifested by hemiplegia, paraplegia, or quadriplegia. If these patients fail to improve with aggressive steroid therapy, plasma exchange every other day for seven treatments can be beneficial for approximately 40% of patients, or intravenous immunoglobulin (IVIG) can be given.

A “pseudo-exacerbation” is an episode with symptoms consistent with an exacerbation, but precipitated by something other than the natural course of the disease. A pseudo-exacerbation can be precipitated by heat, infections (e.g., UTIs), or stress (emotional or physical); these must be ruled out before treatment is initiated or DMTs altered.

Disease-Modifying Therapy

Images Indications and dosing of DMTs is shown in Table 39-2. MS is a complex, heterogeneous disease with clear variability in pathogenesis between patients and within patients over time. As a result, treatment decisions are usually based on clinical predictors of disease severity, our incomplete understanding of the mechanism of action of currently available therapies, and the safety and tolerability profile of the medications. There is some degree of agreement that use of escalation approaches early in the course of the disease, with safer yet partially effective medications, is useful. These concepts lead to various categories of therapies: first-, second-, and potentially third-line medications. Currently, FDA-approved first-line therapies (self-injected medications that decrease annualized relapse rate by about 30% and decrease the formation of new white matter lesion) include three IFN formulations (four brand names), and glatiramer acetate (a non-IFN). The first-line DMTs are not immediately efficacious for patient symptoms. However, their efficacy is noted approximately 1 to 2 years after starting therapy. Fingolimod, natalizumab, and mitoxantrone, also approved for the treatment of MS patients, are used in cases of inadequate response or intolerance to first-line agents. The FDA has approved natalizumab, fingolimod, teriflunomide, and dimethyl fumarate for the treatment of relapsing forms of MS. Mitoxantrone has an FDA indication for progressive or worsening MS.

TABLE 39-2 Disease Modifying Therapy

Images

Images In some patients with poor prognostic factors and poor clinical presentation, natalizumab, fingolimod, potentially teriflunomide, and dimethyl fumarate may be prescribed as first-line therapy. This type of algorithm would be considered an induction therapy, where you concentrate all therapeutic efforts in the early phases of disease. Drugs used to treat MS can be considered either immunomodulatory (able to alter the immune signals without cytotoxic effect or bone marrow suppression) or immunosuppressive (able to alter the immune system through a direct cytotoxic activity or bone marrow suppression). However, these agents have a higher risk-to-benefit ratio based on their safety profile.59 Adverse drug reactions and monitoring parameters of DMTs are shown in Table 39-3.

TABLE 39-3 Adverse Drug Reactions and Monitoring Parameters

Images


Clinical Controversy…

With the development of highly effective therapies, neurologists are faced with the task of identifying clinical or paraclinical markers of response to therapies. In general there is acceptance on defining treatment success, and that is by the absence of any clinical evidence of progression (e.g., relapses, progression of disability, and new MRI findings). However, there is significant controversy on the definition of treatment failure. Biomarkers of response to various therapies are in development and soon will be validated for clinical use. In addition, there is little evidence to support the clinical decision on when to discontinue therapies in patients who are clinically stable for prolonged periods of time.

Interferon-β1b and Interferon-β1a

IFN-β1b (Betaseron and Extavia) was the first agent proven to favorably alter the natural course of the illness.60 In Table 39-4, DMTs are listed with evidence-based recommendations from the American Academy of Neurology.60Although the exact mechanism of action is unknown, IFN-β1b’s effect in MS may be caused by its immunomodulating properties, including the ability to augment suppressor cell function and reduce IFN-γ secretion by activated lymphocytes, its macrophage-activating effect, and its ability to downregulate the expression of IFN-γ–induced class II MHC gene products on antigen-presenting glial cells. IFN suppresses T-cell proliferation and may decrease blood–brain barrier permeability by decreasing matrix metalloproteinases.60 IFN-β also increases the production of regulatory CD56 (bright) natural killer cells and Treg cells.61 In general, all IFNs exert these actions in the periphery and at the blood–brain barrier level.

TABLE 39-4 Evidenced-Based Recommendations for Disease Modifying Treatment of Multiple Sclerosis

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IFN-β1b is a nonglycosylated synthetic analog of recombinant IFN-β that is produced in Escherichia coli. IFN-β1b is administered subcutaneously every other day at a dose of 250 mcg (8 million international units). Clinical trials have demonstrated that at these doses, IFN-β1b significantly reduces annual relapse rate and MRI burden of disease compared with placebo. No significant differences were noted between the IFN- and placebo-treated groups with respect to clinical disability.60 Betaseron is packaged in partially premixed syringes with a new formulation that does not require refrigeration and can be used with an autoinjector. In 2009, an additional IFN product was introduced with the trade name Extavia; Extavia is the same medicinal product as Betaseron.

IFN-β1a (Avonex and Rebif) is a natural-sequence glycosylated IFN produced in Chinese hamster ovary cells. Avonex is administered as a 30-mcg dose (6 million international units) intramuscularly once weekly. The prefilled syringes (33 mcg/0.5 mL, four per package) should be refrigerated, but can be kept at room temperature for 30 days. Rebif is made in a very similar fashion to Avonex but given as either 22 or 44 mcg (0.5 mL) subcutaneously three times weekly. It is supplied in a 0.5-mL prefilled syringe with an autoinjector. Rebif should also be kept refrigerated, but is stable at room temperature for 30 days. A new formulation may have lower immunogenicity and a slightly better side-effect profile.62

When given 30 mcg intramuscularly once weekly for 2 years, patients receiving IFN-β1a (Avonex) demonstrated, compared with placebo, statistically significant reductions (approximately one-third) in annual relapse rate as well as disease progression, defined as a confirmed decrease of one point on the EDSS.63 When disease progression was assessed by MRI studies, patients receiving active drug had significantly fewer new enhancing lesions compared with placebo-treated patients. Similar results were seen with higher dose (44 mcg), more frequent administration (three times weekly), and subcutaneous injection of IFN-β1a (Rebif).60 Other studies reveal significant effects on slowing brain atrophy64 and the progression of cognitive decline63 in patients treated with Avonex. Taken together, these observations show that IFN-β possesses significant disease-modifying activity.

Side effects are similar with all the IFNs. Baseline complete blood counts, platelet determinations, and liver function tests should be documented before starting therapy, at 1 month, then every 3 months for 1 year, and every 6 months thereafter. Small percentages of patients develop depressed cell counts and liver enzyme elevations that are usually transient and respond to discontinuation of therapy. Rarely patients have developed true liver failure requiring liver transplant, and package inserts for IFN-β products have been altered to reflect this risk. The most common adverse effects include injection-site redness, swelling, menstrual irregularities, flu-like symptoms (e.g., fever, chills, and myalgias), and rarely necrosis. These symptoms can be mild or severe and are seen in most patients. The flu-like side effects typically occur for up to 24 hours after injection and typically abate within 1 to 3 months after starting the injections, but they persist in some patients. Injection-site reactions are probably worse with IFN-β1b, can occur at any time, and can be lessened by using appropriate injection technique, including site rotation (thighs and buttocks), topical lidocaine, application of ice before and after the injection, or use of an autoinjector (usually free from drug manufacturer). Injecting the medications at body temperature (place under armpits to warm) will decrease injection-site pain. By taking the injection at night prior to bed time the patient may sleep through most of the flu-like symptoms; nonsteroidal anti-inflammatory agents or acetaminophen taken before and at regular intervals for 24 hours after administration may alleviate the flu-like symptoms. Initiation of one-quarter or one-half the standard dose, with increase to full dosage over 1 to 2 months, also may be beneficial in reducing flu-like side effects.65 Some authors suggest that because of the transient immune activation that can occur following the introduction of IFN-β, a short burst of oral prednisone can alleviate some adverse effects.65

Less commonly reported and transient side effects include shortness of breath, tachycardia, thyroid dysfunction, and neutralizing antibodies. Although depression is a common finding in MS patients, all the IFNs, especially IFN-β1b, can produce depressive symptoms. Clinicians must monitor patients carefully for signs of depression and treat accordingly. Patients who develop depression should be monitored closely for suicide risk. Most patients will not feel better or have improvement in symptoms when taking IFNs, and many will experience side effects; thus, adherence can become a major issue. Finally, safety data on IFN-β in pregnancy and lactation are lacking. Abortifacient activity in primates has been noted, and until adequate safety data are available, women should be counseled as to appropriate contraception while using these products. In general, pregnancy tends to protect patients from MS exacerbation.

Although the adverse-effect profile of IFN-β1a resembles that of IFN-β1b, intramuscular IFN-β1a (Avonex) may hold several advantages, including fewer local injection-site reactions and once-weekly administration versus subcutaneous injection every other day (or 3 days per week) with Rebif.

Glatiramer Acetate (Copaxone)

Glatiramer acetate (Copaxone, formerly known as copolymer-1) is a synthetic polypeptide consisting of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine. Although the precise mechanism of action of this compound is unknown, glatiramer acetate appears to mimic the antigenic properties of MBP.66 This agent also may act by directly binding to MHC class II receptors and inhibiting binding of MBP peptides to T-cell receptor complexes.66 Glatiramer acetate has demonstrated that it induces Th2 (anti-inflammatory) lymphocytes in experimental allergic encephalomyelitis.66 This is thought to contribute to “bystander” suppression at the site of the MS lesion and thereby reduction of inflammation, demyelination, and axonal damage.60 Glatiramer acetate may also suppress T-cell activation; recent studies suggest that it may be associated with a neuroprotective effect by inducing brain-derived neurotrophic factor.67

Given as a daily 20-mg subcutaneous dose, glatiramer acetate appears to have a relatively mild adverse effect profile. Mild pain and pruritus at the injection site are the most frequent patient complaints. Approximately 10% of patients experience a one-time transient reaction consisting of chest tightness, flushing, and dyspnea beginning several minutes after injection and lasting usually no longer than 20 minutes. The postinjection reaction can occur with any dose, and is not limited to the first injection. If patients have no history or evidence of coronary artery disease, they may be assured these reactions are almost always self-limited and benign. Several adverse effects associated with the IFNs, including flu-like symptoms and depression, do not appear to be provoked by glatiramer acetate. Multicenter trials with glatiramer acetate have demonstrated significant reductions in mean annual relapse rate (approximately 29%), comparable with the IFNs.60 An extension trial, completed after the original, pivotal 2-year study, suggests that glatiramer acetate may slow the progression of disability in patients with RRMS.60 Glatiramer acetate also delays development of T1 holes on brain MRIs;68 long-term uncontrolled data show that it remains safe and effective for individuals who continue to take it over 10 years.69 Glatiramer acetate is available as 20 mg/mL prefilled syringes, and needs to be stored in the refrigerator but can be kept at room temperature for up to 1 week.

Natalizumab (Tysabri)

Natalizumab is a partially humanized monoclonal antibody directed at the cell surface adhesion molecule α4β-integrin (also known as very-late antigen 1, VLA-1). Natalizumab works by attaching to VLA-1 and blocking its interaction with its ligand on CNS endothelium vascular cell adhesion molecule (VCAM-1). Thus, activated lymphocytes are denied entry past the blood–brain barrier. In a phase II study, compared with placebo, natalizumab significantly reduced the number of new gadolinium-enhancing lesions by more than 90%, and diminished relapses as well.70 In a 2-year phase III trial (A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis [AFFIRM]), compared with placebo, annual relapse rate was reduced by more than 60%, gadolinium-enhancing lesions were lessened by more than 90%, and progression of disability was significantly delayed.71In a separate 2-year, phase III trial (The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis [SENTINEL]) in patients already taking IFN-β1a (Avonex), those who had natalizumab added had a relapse rate reduction of more than 50% and gadolinium-enhancing lesion reduction of 84% compared with patients who continued with IFN-β1a alone.72 In these trials, natalizumab was injected IV every 4 weeks and was relatively well tolerated, although approximately 1% of patients developed infusion reactions, and 6% developed neutralizing antibodies that diminished the efficacy of the drug.

On November 23, 2004, the FDA approved natalizumab for use in relapsing MS in patients with inadequate response or intolerance to other MS therapies with the stipulation that the studies would continue. In February 2005, Biogen and Elan voluntarily removed natalizumab from the market after receiving reports of two patients (one patient from the SENTINEL trial, and one patient in a Crohn’s disease study), who died after developing progressive multifocal leukoencephalopathy (PML), a rare brain infection most commonly seen in patients with human immunodeficiency virus.7375 One other patient who developed PML in the SENTINEL trial survived.7375 Further safety analysis did not identify other cases, so on March 9, 2006, an FDA advisory panel reviewing the data suggested reapproval of natalizumab for use in relapsing patients with a mandatory Risk Evaluation and Mitigation Strategy (REMS) program called TOUCH. On June 5, 2006, the FDA reapproved use of natalizumab in the United States with a black-box warning about PML. As of September 2012, 271 cases of PML have been identified, all in patients using the medication for 8 months or longer. The estimated risk for developing PML is low. Three factors appear to impact the overall risk of developing PML while receiving natalizumab therapy: duration of treatment (24 months or longer), history of John Cunningham virus (JCV) infection, and prior use of immunosuppressive therapies (mycophenolate mofetil, alemtuzumab, efalizumab, and rituximab).76,77 A two-step enzyme-linked immunosorbent assay (ELISA, STRATIFY TEST) is available for qualitative detection of serum antibodies to the JCV, offering a false-negative rate of 2.5%.76,77

Plasma exchange (PLEX) has been utilized to help clear the drug more rapidly from the blood of patients who develop PML.78 An acute syndrome, referred to as immune reconstitution inflammatory syndrome, has been associated with acute neurological deterioration after PLEX, requiring the use of steroids.79

Natalizumab is indicated for relapsing forms of MS to delay the accumulation of physical disability and decrease the number of relapses in patients who have a documented inadequate response or intolerance to traditional MS therapies. Patients receiving natalizumab must be enrolled in the TOUCH program. The overall predicted seroconversion rate for JCV is 2% to 3% per year. For that reason, the current recommendation is to screen patients at baseline and every 6 months with a JCV test while receiving natalizumab therapy.80

Fingolimod (Gilenya)

Approved September 21, 2010, fingolimod is the first oral DMT for MS. It has a unique mechanism of action as a sphingosine 1-phosphate receptor agonist. Fingolimod exhibits its immunosuppressant properties by sequestering circulating lymphocytes into secondary lymphoid organs and reduces the infiltration of T lymphocytes and macrophages into the CNS. It may have neuroprotective effects. In clinical trials it decreased annualized relapse rates by approximately 52% compared to IFN-β1a. After 7 years of continuous fingolimod therapy, approximately 92% of patients were free of gadolinium-enhancing lesions, although these data used the 1.25 mg dose. The recommended dose approved by the FDA is 0.5 mg once daily.

Major side effects include pronounced first dose bradycardia and, rarely, bradyarrhythmia or atrioventricular block, infections, macular edema, a decrease in forced expiratory volume over 1 second in patients with previously compromised lung function, elevation of liver enzymes, and a sustained increase of approximately 1 to 2 mm Hg in systolic and diastolic blood pressure. Rare cases of lymphoma have also been identified. The reversal of lymphopenia can take 2 to 4 weeks after discontinuation of the drug. The cumulative number of deaths in patients receiving fingolimod, either during clinical trials or postmarketing use, is 31 patients as of February 2012. Extensive evaluation of patient deaths of apparently cardiovascular or unknown origin concluded that for each of the deaths, any contribution of fingolimod treatment was unclear, and the rate of death among MS patients treated with fingolimod was not higher than the rate of death for MS patients not receiving the drug. Nevertheless, the FDA announced a series of label updates. It is recommended that all patients starting fingolimod treatment be monitored for signs of bradycardia for at least 6 hours after the first dose. The FDA also recommends hourly pulse and blood pressure monitoring for all patients starting treatment, with electrocardiogram monitoring prior to dosing and at the end of the observation period; monitoring should continue until all symptoms resolve. The period should extend past 6 hours in patients at higher risk, in some cases overnight. Additionally, the package insert requires a new 6-hour observation period in patients who have discontinued and wish to restart therapy. The recommendation varies depending on the time of discontinuation and days of therapy missed. To reduce risks related to bradycardia or atrioventricular block, extended monitoring is now recommended in patients with certain preexisting conditions such as QT prolongation. This is also a concern in patients receiving concomitant drugs that slow the heart rate or atrioventricular conduction, drugs that cause QT interval prolongation, and those who have a known risk for torsades. The following class Ia and class III antiarrhythmic agents are contraindicated with concurrent use of fingolimod: quinidine, procainamide, disopyramide, amiodarone, bretylium, sotalol, ibutilide, azimilide, dofetilide, and dronedarone.81

Additional monitoring recommendations include baseline complete blood counts, liver function tests, ophthalmologic examinations, and electrocardiogram in patients with known heart problems. To date, one important drug interaction has been reported with concomitant use of ketoconazole and fingolimod. Ketoconazole has been shown to increase the area under the curve by 70%. If a live vaccine is to be administered to a patient (Zostavax, Flumist, YF-VAX, etc.), consider doing so prior to starting fingolimod or wait until 2 months after discontinuation. The degree to which fingolimod’s oral delivery may alter the likelihood of a patient using, or continuing to use, a self-injectable medication remains to be seen.

Teriflunomide (Aubagio)

Teriflunomide (Aubagio) is an immunomodulatory agent, which was FDA approved on September 12, 2012 for the treatment of relapsing forms of MS. The medication works by inhibiting dihydroorotate dehydrogenase to prevent the proliferation of peripheral lymphocytes (T and B cells). The reduction of activated lymphocytes in the CNS reduces the inflammation and demyelination, which occurs in patients with MS. Teriflunomide is the active metabolite of leflunomide, an agent approved for the treatment of rheumatoid arthritis; however, teriflunomide is dosed as 7 or 14 mg orally once daily. This medication is available for distribution by specialty pharmacies.

O’Connor et al. studied 1,088 patients with CDMS. The patients were randomized to receive 7 or 14 mg of teriflunomide or placebo. Patients receiving 7 and 14 mg daily of teriflunomide had a statistically significant reduction in annualized relapse rate compared with placebo (relative risk reductions: 31.2% and 31.5%; P = 0.0002 and 0.0005, respectively). The risk of disability progression was statistically significantly reduced for those receiving 14 mg of teriflunomide daily (hazard ratio reduction: 29.8%; P = 0.0279).82

In a 36-week randomized, double-blinded, placebo-controlled study in MS subjects with relapse, 179 patients were randomized to 7 or 14 mg of teriflunomide or placebo. The primary outcome was the average number of unique active lesions per MRI scan during treatment. A statistically significant reduction in the primary endpoint was reported for both 7 and 14 mg of teriflunomide compared with placebo (0.98 and 1.06; P = 0.0052 and 0.0234, respectively).83

Key pharmacokinetic parameters of teriflunomide are displayed in Table 39-5. Although teriflunomide is not metabolized by CYP 450 enzymes, it inhibits CYP2C8 and induces CYP1A2. This medication is also a substrate for the breast cancer resistant protein (BCRP). Thus, inhibitors of BCRP (cyclosporine) may increase serum concentrations of teriflunomide. Additionally, teriflunomide inhibits OATP1B1 and OAT3. However, the significance of these drug interactions is unknown at this time. Studies found that concomitant use of warfarin and teriflunomide resulted in a 25% decrease in international normalized ratio (INR), rendering the need for close monitoring. When teriflunomide is coadministered with estradiol and levonorgestrel, the mean maximum serum concentration and area under the curve are increased.

TABLE 39-5 Pharmacokinetic Parameters of Teriflunomide

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The most common adverse effects seen with teriflunomide are increases in liver function tests, alopecia, nausea, diarrhea, influenza, headache, and paresthesias.

Teriflunomide carries a black-box warning because of the risk of hepatotoxicity and teratogenicity (based on animal data). Monitoring for teriflunomide includes liver function tests (within 6 months prior to initiating teriflunomide and monthly for the first 6 months). Animal studies have found that oral teriflunomide resulted in fetal malformations and embryolethality in female rats as well as reduced sperm count in male rats. Based on these data, teriflunomide is not recommended in pregnancy. Females taking this medication should be placed on birth control. Patients who become pregnant during therapy or within 2 years after discontinuation of therapy should enroll in the Aubagio Pregnancy Registry and consider a cholestyramine washout. Additionally, men taking this medication with partners who wish to become pregnant may consider a cholestyramine washout to reduce serum drug levels as this drug may remain in the blood for up to 2 years after discontinuation. Teriflunomide may activate tuberculosis so a negative skin test or treatment of the disease must be documented prior to starting therapy. Overall, teriflunomide’s efficacy is about that of the IFN products and glatiramer acetate.

Dimethyl Fumarate (Tecfidera)

Dimethyl fumarate has an unknown mechanism of action; however, it is an in vitro nicotinic acid receptor agonist and an in vivo activator of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is involved in cellular response to oxidative stress. It is approved by the FDA for relapsing forms of MS. Dimethyl fumarate is metabolized by esterases in the GI tract, blood, and tissues. There are no known drug interactions. It is classified in pregnancy category C. Dimethyl fumarate is dosed initially at 120 mg (delayed release) orally twice daily. After 7 days, the dose should be increased to 240 mg (delayed release) orally twice daily. Laboratory monitoring includes a complete blood count prior to starting therapy and within 6 months of initiating treatment and annually. Side effects include lymphocytopenia (2% to 6%), increased liver function tests, and flushing (40%), which should improve over 1 month and is decreased by taking it with food. Rash, abdominal pain, diarrhea, nausea, and vomiting have also been reported. GI side effects decrease over 1 month.

In the “Efficacy and Safety Study of Oral Dimethyl Fumarate (BG-12) with Active Reference in Relapsing Remitting Multiple Sclerosis (CONFIRM)” dimethyl fumarate decreased the annualized relapse rate by 44% and 51% with twice daily or three times daily dosing, respectively. In “The Determination of the Efficacy and Safety of Oral BG-12 in Relapsing-Remitting MS” the annualized relapse rate decreased by 47% and 52% with 240 mg twice daily or three times daily dosing, respectively.

Mitoxantrone (Novantrone)

Mitoxantrone (Novantrone), a member of the anthracenedione family, is approved by the FDA for reducing neurologic disability and the frequency of clinical relapses in patients with SPMS (chronic), PRMS, or worsening RRMS.84The MRI outcomes, however, were not as robust as those typically seen in the trials of relapsing patients alone.85 Mitoxantrone is administered as a brief (5- to 15-minute) IV infusion dosed at 12 mg/m2 every 3 months. An evaluation of left ventricular ejection fraction and electrocardiogram are required prior to administration of each dose, and if signs or symptoms of congestive heart failure develop. The maximum allowable lifetime cumulative dose of mitoxantrone is 140 mg/m2. Other potential side effects noted are nausea, alopecia, menstrual disorder, amenorrhea, upper respiratory tract infection, UTIs, and leukemia. The role that mitoxantrone will ultimately play in the treatment of MS remains unclear because potential cardiac toxicity limits its long-term use. More recent estimates also suggest the risk of leukemia may be as high as 1 in 145 patients, which has significantly decreased interest in its use for MS patients.86 In addition, although patients with SPMS were included in the mitoxantrone in multiple sclerosis (MIMS—effect of mitoxantrone on MRI in progressive MS) trial, resulting in FDA approval for use in SPMS, there was no substudy documenting slowing of progression specifically in this subgroup of patients.84,85 Thus, support for use of mitoxantrone in this context is less strong.86

Remaining Questions for Disease-Modifying Therapy

Images Despite encouraging results from well-conducted clinical trials, several relevant issues remain. The most important question in the use of the DMTs is when to begin therapy. The Medical Advisory Board of the National Multiple Sclerosis Society has adopted recommendations regarding the use of the current MS DMTs (Table 39-6).87

TABLE 39-6 Disease Management Consensus Statement

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Decisions about the use of any medication rest on determination of the severity of the illness, the efficacy of the medication, and the side effects and costs related to the therapy. Clearly, these drugs slow the course of the illness but do not suppress it completely, and in some individuals, there is no apparent benefit. There is now, however, overwhelming evidence that the vast majority of untreated patients will have progressive disease over time. Pathologic data clearly show that even in acute lesions there is significant axonal damage that is essentially irreversible. MRI data show that 80% to 90% of all new enhancing lesions are asymptomatic, suggesting that a “quiet” clinical course does not necessarily mean there is not ongoing disease activity that ultimately will be reflected in cognitive problems and progressive spastic paraparesis.

Furthermore, it is now known that very early therapy is effective. In patients with CIS and two or more T2 lesions on brain MRI (i.e., at high risk for developing CDMS), placebo-controlled studies with all three of the IFN agents and glatiramer acetate have shown significant delay in a second attack and positive outcomes on a variety of MRI measures (BENEFIT, Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment; CHAMPS, Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study; and ETOMS, Early Treatment of Multiple Sclerosis).60,88 Thus, very early therapy is potentially warranted, and IFN-β1b, IFN-β1a (Avonex), and glatiramer acetate are approved by the FDA for use after CIS in those patients with abnormal MRIs consistent with demyelination, suggestive of high risk of further demyelinating events. The National Multiple Sclerosis Society recommends that patients with relapsing disease should be placed on Avonex, Betaseron (or Extavia), Copaxone, or Rebif (ABC-R) therapy immediately after the diagnosis.87

A second major issue is which drug to use in which patient. There has not been a single, randomized study comparing all four ABC-R drugs with one another in a similar patient population at the same time.89The pivotal placebo-controlled trials produced results that were more similar than different when comparing across trials, including a nearly identical one-third reduction in relapse rate for all four drugs over 2 years. A small number of studies have suggested higher dose, more frequent administration of IFN may be more efficacious than lower dose, less frequent administration,90,91 but these differences appear modest. Other studies argue against this,92,93 and recent studies note no significant difference in outcomes between standard and double dose IFN-β1b and glatiramer acetate,94 and no difference between IFN-β1a (Rebif) and glatiramer acetate.95

A concern with all three IFN products that further muddies our understanding of the clinical differences between the IFN products is the development of neutralizing antibodies. In clinical trials, 30% to 40% of patients receiving IFN-β1b developed antibodies directed against the drug.97 In these patients, the exacerbation rate was similar to that in placebo-treated patients. In patients on IFN-β1b, neutralizing antibodies can occur as early as 3 to 6 months and as late as 18 months. This product tends to be the most antigenic.96 With IFN-β1a, neutralizing antibodies were found in 22% of early trials of Avonex, but later studies reported that only 2% to 5% of treated patients developed antibodies; this decrease was caused by a formulation change of the drug making it the least antigenic.93,96 Percentages of antibody formation for Rebif (approximately 12%) are intermediate, therefore moderately antigenic, and this can occur in the first 9 to 15 months of treatment, which is the same time frame for antibody production with Avonex.60,96,97 The long-term clinical significance of these findings, however, is still not completely clear, although three recent studies have further confirmed the effect of neutralizing antibodies on relapses, MRI lesions, and progression of disability.97100 Whether these antibodies are truly cross-reactive between products is unknown, as is the duration during which antibodies can be detected. There are no general consensus guidelines regarding when to test for neutralizing antibodies, which assay to use, or what titer cutoff to apply to patients in clinical settings.101 An important question is whether production of antibodies might be diminished with treatments such as corticosteroids. Another concern of practitioners is the relationship between active ingredients and varying excipients or particulate matter of IFN therapies and the production of neutralizing antibodies. Neutralizing antibodies are seen in approximately 6% of patients treated with natalizumab, and the antibodies seem to diminish efficacy.72

Images We now have experience for more than a decade with MS patients taking DMTs, yet continuing to have more relapses, more lesions on MRI, more disability, and ongoing slippage into SPMS.102 There is no accepted definition of treatment inadequacy, although the Canadian Multiple Sclerosis Research Council has suggested a relatively simple approach that incorporates the elements of relapse rate, new MRI lesions, and change on the EDSS.103If a patient develops significant and persistent IFN antibodies, movement to a non-IFN (glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, mitoxantrone, or possibly rituximab104) is reasonable. When failing low-dose IFN, options include changing to a higher dose, more frequent administration of IFN, or changing to a non-IFN. A second option is addition of an immunosuppressant agent, such as monthly methylprednisolone,105azathioprine, methotrexate, or mycophenolate. As noted above, the addition of natalizumab to IFN-β1a was effective, but produced rare cases of PML, and thus, this combination should not be used. The addition of a statin agent may worsen MS106 although these results are not definitive.

Symptomatic Management

Images Many of the symptoms of MS do not require pharmacologic management or do not respond to it. This section addresses the primary symptoms in which pharmacologic management may be of benefit (Table 39-7).32,103,107110,112 See the preceding section on the treatment of exacerbations for a discussion of optic neuritis.

TABLE 39-7 Treatment of Selected Primary MS Symptoms

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Clinical Controversy…

In MS, there is no clear role for combination DMTs. Because of potential additive immunosuppression, all DMTs are currently used as monotherapy. There may be theoretical potential therapeutic benefit in adding an immunomodulator and an immunosuppressive agent, but the risk can be far greater (e.g., natalizumab plus interferon showed increased risk of PML). A recent clinical trial utilizing interferon and glatiramer acetate (CombiRX) demonstrated that there is minimal benefit of using the two in combination. However, other potential DMT combinations are yet to be studied.

Gait Difficulties and Spasticity

Problems with gait can be caused by spasticity, weakness, ataxia, defective proprioception, or a combination of these factors. Spasticity often presents late in disease and is amenable to pharmacologic intervention, whereas physical therapy may be required in treating gait disturbances caused by other factors. Spasticity is encountered commonly and tends to affect the legs more markedly than the arms. Spasticity can result in falls; however, in the later stages of the disease, the increased muscle tone of a spastic limb often lends pseudo strength to patients with underlying weakness. Therefore, when using muscle relaxants, one must be careful not to decrease the tone to an extent that ambulation is actually hindered.32,107 Baclofen (Lioresal), a γ-aminobutyric acid (GABA) analog, is the preferred agent and usually is started in dosages of 10 mg three times daily and titrated upward to achieve the desired response. Most patients achieve a satisfactory response with dosages between 40 and 80 mg/day; however, dosages higher than the recommended daily maximum of 80 mg are required by some patients.32,107 A wearing-off is common, due to the relatively short duration of action. A longer-acting version of Lioresal is under study. Continuous intrathecal administration of baclofen may be an option for patients unable to tolerate or unresponsive to oral therapy. Baclofen should not be discontinued abruptly to avoid the possibility of seizures.107 Small doses of diazepam (Valium) (e.g., 0.5 to 1 mg) often are added to baclofen in patients in whom optimal response has not been achieved.

Another effective agent with a different mechanism of action is tizanidine (Zanaflex). This short-acting, α-adrenergic agonist acts in the CNS to reduce spasticity by increasing presynaptic inhibition of motor neurons. It appears to have efficacy comparable with that of baclofen.107 Dosage must be titrated slowly over 2 to 4 weeks, starting with 4 mg at bedtime, with adjustments based on clinical response. Effective tolerated dosages have ranged from 2 to 36 mg/day. Sedation, dizziness, and dry mouth are the most commonly reported adverse effects, but hypotension also can occur, as well as a rare but severe hepatotoxicity. Tizanidine can be added in small dosages to baclofen, sometimes creating better results and making possible smaller doses of each drug.

In patients who are unable to tolerate baclofen or tizanidine, diazepam (Valium; 2 to 10 mg/day), clonazepam (Klonopin; 1 to 3 mg/day), or dantrolene sodium (Dantrium; 100 to 400 mg/day) may be considered as alternatives, but they generally are less effective than either baclofen or tizanidine. Mild spasticity also may respond to moderately high doses of gabapentin (Neurontin; 1,800 to 3,600 mg/day). Tiagabine (Gabitril 8 to 56 mg/day) may be useful in some patients with spasticity, but side effects can prohibit its use. Pregabalin (Lyrica; 75 to 300 mg/day) has similar features and mechanism of actions as gabapentin, although pregabalin is approximately three times more potent and does not saturate the L-transporter system in the GI tract, so it may prove useful in the treatment of spasticity in MS patients.

Botulinum toxin type A (Botox; dose depending on the muscles injected) has been shown to be effective in improving spasticity.32 The amount of toxin required to exert an effect on spasticity is often too excessive to use safely in the larger muscles; therefore, its use is best limited to smaller areas of focal muscle spasm.

An alternative approach to gait disruption employs K+ channel blockers such as 4-aminopyridine (4-AP). However, at the FDA-approved dose, the blockade of K+ channels is negligible. Regardless, dalfampridine can potentiate synaptic transmission and increase muscle twitch tension. Recent studies have shown that 4-AP may modestly improve walking speed.108,109 In early 2010, the FDA approved the use of a long-acting proprietary version of 4-AP, dalfampridine (Ampyra; 20 mg/day), for use in the United States. Dalfampridine is approved as a treatment to improve walking in patients with MS. It has been shown to increase walking speed by approximately 25% in responders.108,109 In other countries, dalfampridine is referred to as fampridine.109 A REMS program is in place to manage risks associated with dalfampridine use.

Safety concerns with the use of dalfampridine include the risk of seizures, particularly when patients exceed the maximum dose of 10 mg twice daily. The medication is contraindicated in patients with a history of seizures. It is important that patients are educated on not taking compounded 4-AP with dalfampridine, which is an extended release product. Additionally, the drug should not be chewed, crushed, or cut. If the patient misses a dose, they should take it immediately upon recognition and never double up on the dose, due to the risk of seizures. Commonly reported side effects of dalfampridine include UTIs, insomnia, dizziness, headaches, and balance disorders.

Tremor

Cerebellar symptoms such as tremor can be troubling and difficult to control. Medications that can be helpful include propranolol, primidone, and isoniazid.

Bowel and Bladder Symptoms

Patients commonly complain of incontinence, urgency, frequency, and nocturia, which are indications of a hyperreflexic bladder (i.e., inability to store urine). A number of anticholinergic agents, including oxybutynin chloride (Ditropan; 10 to 20 mg/day), tolterodine (Detrol; 2 to 4 mg/day), propantheline bromide (Pro-Banthine; 45 to 90 mg/day), hyoscyamine (Levsin; 0.75 to 1.5 mg/day), and dicyclomine hydrochloride (Bentyl; 30 to 80 mg/day) are used to treat this problem if symptoms are mild. Ditropan is available in an extended-release formulation (5 and 10 mg). In addition, tricyclic antidepressants, such as imipramine (Tofranil) and amitriptyline (Elavil), have been used for their anticholinergic properties to treat this condition. With all anticholinergic agents, great care must be used to avoid falls, decreased cognition, and constipation, which is worsened by the patient’s natural instinct to limit fluid intake. Antimuscarinic agents such as trospium chloride (Sanctura; 40 mg/day), solifenacin succinate (Vesicare; 5 to 10 mg/day), darifenacin hydrobromide (Enablex; 7.5 to 15 mg/day), and fesoterodine (Toviaz; 4 to 8 mg/day) are also used to treat incontinence. In June 2012, the FDA approved mirabegron (Myrbetriq), a β3adrenergic agonist for the treatment of overactive bladder. As an alternative, the synthetic antidiuretic hormone preparation desmopressin acetate (DDAVP; 0.2 to 0.6 mg/day) has been reported to be effective in the treatment of urgency and incontinence. Use of DDAVP is best limited to bedtime to improve sleep and prevent significant problems with hyponatremia and seizures if overused. Patients with significant sphincter detrusor dyssynergia may benefit from the oral use of α-adrenergic blockers such as prazosin (Minipress; 10 to 40 mg/day), tamsulosin (Flomax), or intramuscular use of botulinum toxin type A (Botox; dose depends on the muscles injected) to relax the internal sphincter.

Intermittent self-catheterization and the crede maneuver with or without a concomitant anticholinergic agent is recommended in patients with large postvoid residual volumes (>100 mL) or when the urinary problem is hyporeflexic in nature (failure to empty). Cholinergic agents (bethanechol) may be useful in patients with a hyporeflexive bladder. Patients with large postvoid residual volumes are at risk for developing UTIs and often are prescribed urinary acidifiers such as vitamin C or antiseptics such as methenamine mandelate to prevent infections. Antibiotics used for UTI prophylaxis include sulfamethoxazole/trimethoprim, cephalexin, cinoxacin, and nitrofurantoin.

Constipation is the most common bowel complaint. Many medications (e.g., narcotics, anticholinergics) in common use may worsen this problem, as may voluntary water restriction in those patients with urinary urgency and incontinence. Increases in dietary fiber and hydration may alleviate this problem, but in some instances laxatives or enemas may be necessary.

Major Depression

Major depression is common in patients with MS, and the risk of suicide may be increased markedly compared with healthy subjects.110 Patients should be monitored closely for the development of major depressive symptomatology and treated accordingly (see Chap. 51). IFN products and natalizumab should be used cautiously in patients with significant depression.

Sensory Symptoms

Numbness and paresthesia are frequent sensory complaints but usually do not require treatment. Some MS patients may develop acute or chronic pain syndromes107 such as trigeminal neuralgia and painful dysesthesias, for which treatment is necessary. Carbamazepine (Tegretol; 400 to 1,200 mg/day) is the preferred agent for the treatment of trigeminal neuralgia. Other agents also commonly used for neuropathic pain include amitriptyline and related tricyclic antidepressants, gabapentin, pregabalin, and duloxetine.

Sexual Dysfunction

Sexual dysfunction in both men and women are common in MS, and counseling should be offered to both partners. Sildenafil citrate (Viagra), tadalafil (Cialis), and vardenafil (Levitra) are very effective for men with MS who have erectile dysfunction. Other options for men include alprostadil injection (Caverject) or intraurethral suppositories (MUSE). Viagra is currently being studied in females with MS and sexual dysfunction. In patients needing antidepressant therapy for whom sexual dysfunction is a concern, bupropion is preferable to selective serotonin reuptake inhibitors as it has a much lower incidence of sexual side effects.

Fatigue

Fatigue, one of the most common complaints in MS patients, can be severely disabling, but treatment is often overlooked. Typically present in the mid to late afternoon, it can increase with heat exposure, exertion, intercurrent infection, spasticity, weakness, and depression. Amantadine hydrochloride (100 mg twice daily) is used often and may offer significant relief.32,103 Methylphenidate (Ritalin) and related products, and dextroamphetamine (Dexedrine) are used commonly for fatigue in MS. Modafinil (Provigil), at 200 mg daily, up to 400 mg daily may be helpful for MS-related fatigue. The R-enantiomer of modafinil is armodafinil (Nuvigil) dosed at 150 or 250 mg daily, which reaches peak concentrations more quickly with potentially fewer side effects than modafinil. In patients suffering from both depression and fatigue, a more activating antidepressant such as fluoxetine may be employed.

Cognition

Cognitive dysfunction is common in MS, affecting up to 50% or more of patients. It generally manifests itself as word-finding difficulties and problems with concentration and short-term memory. Cognitive dysfunction can be treated with stimulants or cholinesterase inhibitors.

Pseudobulbar Palsy

Pseudobulbar palsy is a condition, which is caused by progressive degeneration of the corticobulbar tract in patients with MS. Patients with this condition have dysarthria, dysphonia, and dysphagia. Additionally, sudden, uncontrollable, emotional outbursts such as crying or laughing occur inappropriately. Dextromethorphan/quinidine 20 mg/10 mg is used for the treatment of this pseudobulbar affect. The recommended dosing for this combination medication is one capsule daily for 1 week, followed by one capsule twice daily. Although the mechanism of action is unknown, the rationale for utilization of this combination drugs is that dextromethorphan is rapidly metabolized by CYP2D6, and quinidine inhibits the CYP2D6 enzyme to increase the serum concentration of dextromethorphan.

Complementary and Alternative Therapies for MS

A large percentage of patients with MS use complementary and alternative medicine (CAM) instead of, or in addition to, disease-modifying and symptomatic therapies. Common CAM therapies include diet and dietary supplements, such as vitamins, minerals, and herbs. Antioxidant supplements vitamin A, C, E, α-lipoic acid, coenzyme Q10, grape seed, pine bark extracts, mangosteen, and acai have suggestive evidence of benefiting MS patients. However, for patients with MS, there is a theoretical risk associated with taking antioxidant supplements owing to their ability to stimulate the immune system (T-cells and macrophages). Stimulating the immune system in patients with MS could be counterproductive, possibly worsening or exacerbating their disease, and may counteract the effects of immunomodulators. Other immune-stimulating supplements that should be used with caution are garlic, ginseng (Asian and Siberian), Echinacea, cat’s claw, astragalus, alfalfa, and stinging nettle. A few agents that may pose a problem in MS, but may have benefit when taken in moderation, are zinc, melatonin (for insomnia), and dehydroepiandrosterone.111

In general, insufficient data support the effectiveness and safety of CAM therapies for MS. However, for patients with MS who are willing to try new approaches with limited evidence, CAM may be a consideration in some cases. Healthcare providers can be a source of objective information regarding the use of CAM for MS and can assist their patients in making the best decision.111

Vaccine Recommendations

A yearly flu shot is recommended for all patients with MS, including patients on any of the DMTs. The intranasal influenza vaccine, FluMist, which is a live, attenuated vaccine, is not recommended for patients with MS, however. As DMTs suppress the immune system, a patient taking one of these medications is at increased risk for developing an infection of the strain of virus given in the vaccine. Live virus vaccines are also more likely to cause an increase in MS disease activity than inactivated virus vaccines. Finally, it is unknown whether there are any direct interactions between DMTs and the intranasal influenza vaccine.112 This information can likely be extrapolated to other vaccines, so if a patient is in need of a vaccination of any kind, “killed” virus vaccines are recommended.

Patients opting to take fingolimod who are varicella zoster virus antibody negative should consider receiving the varicella zoster virus immunization (even though it is a live attenuated vaccine) at least 2 months prior to beginning fingolimod. This should allow time to mount an antibody response prior to immunosuppression with fingolimod.

PERSONALIZED PHARMACOTHERAPY

The initial presentation of MS differs between individuals. When a patient is newly diagnosed modifiable risk factors may be considered prior to selecting therapy. Some of these modifiable risk factors include vitamin D deficiency, excess body weight, and smoking. Vitamin D deficiency has been associated with the risk of developing MS, and higher vitamin D levels may reduce MRI brain activity and thus reduce relapse rates.8 Excess body weight is also associated with a higher risk of developing MS.113 Smoking is associated with the development of MS, disability, MRI abnormalities, and conversion to CDMS (51% to 75% in 3 years).9,114

Treatments available for MS need to be individualized based on the initial symptomatology, MRI presentation, and the risk associated with the chosen therapy. Essentially when patients present, they can be given a modestly effective therapy with a low side effect profile (e.g., IFNs and glatiramer acetate) or a more aggressive therapy with a higher risk profile (natalizumab, fingolimod, or dimethyl fumarate). The weighing of the risks and benefits is ultimately dependent on a patient’s presentation or progression of disease.

The importance of adherence cannot be underestimated in patients taking first-line DMTs. Nonadherence has been reported anywhere between 17% and 50%. The reason many patients stop taking their first-line DMTs is multifactorial, and includes perceived lack of efficacy, side effects, fear of needles, and depression. Patients who remain adherent to their first-line DMTs generally remain employed full-time in the work force compared with those who are nonadherent. It is crucial that we emphasize and establish realistic expectations for our patients on first-line DMTs. Overall, untreated MS patients generally relapse about every 6 months, whereas treated patients relapse about every 2 to 5 years. Adherence is the key to successful treatment of MS.

EVALUATION OF THERAPEUTIC OUTCOMES

Response to treatment of acute exacerbations of MS is commonly seen within days. With respect to DMTs, it is important for the clinician to recognize that over the short term (days to weeks), little or no apparent benefit may be noted by either patient or clinician. Evaluation of therapeutic outcomes, such as decreased MS exacerbations and hospitalizations or perhaps slowed disease progression and disability (as measured using scales such as EDSS), must be conducted over a period of months to years. Patients should be provided with realistic goals and expectations of these treatment options and encouraged to participate in the evaluation of therapeutic response. Initially, it may be important to reevaluate patients at relatively short time intervals to monitor for adverse effects.

Safety monitoring of patients on IFN includes regular laboratory monitoring, patient observation, and questioning for adverse effects or changing disability, and regular neurologic examinations. Specific laboratory monitoring for individuals on IFN therapy should include a complete blood count, platelet count, and liver function tests. These should be completed at baseline, every 3 months for 1 year, and every 6 months thereafter. Glatiramer acetate requires no laboratory monitoring. Teriflunomide requires a transaminase, bilirubin, complete blood count, tuberculin skin test, and blood pressure prior to initiating therapy and alanine aminotransferase monthly for 6 months after starting. Teriflunomide is associated with renal failure and increased potassium; therefore, patients should be monitored as needed. Dimethyl fumarate requires a complete blood count prior to starting therapy and within 6 months of treatment initiation and annually and liver function tests. Natalizumab and fingolimod have REMS programs to monitor safety. In addition to counseling patients regarding the adverse effects associated with these drugs, clinicians should actively encourage patients to comply with their prescribed regimens.

ABBREVIATIONS

Images

Images

ACKNOWLEDGMENTS

The authors acknowledge Caleb Y. Oh, PharmD, Anne E. Eudy, PharmD, Karrine D. Roberts, PharmD candidate, Lisa Hong, PharmD candidate, and Joan Kaufman, illustrator, for their contributions to this chapter.

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