Current and Emerging Therapies for Multiple Sclerosis

Current and Emerging Therapies for Multiple Sclerosis

William Meador, MD

University of Alabama at Birmingham School of Medicine, Birmingham, Alabama

Over the past 21 years, nine treatments for multiple sclerosis (MS) have been approved by the US Food and Drug Administration (FDA), with three drugs given marketing clearance between 2010 and 2013. These additions to our armamentarium have made our choice of disease-modifying therapy for MS patients increasingly complex. Established agents are safe and reasonably effective, whereas newer agents carry more risk but may offer more benefit. A B-cell therapy probably will be approved by the FDA in the next few years, and ongoing neuroprotective or neuroreparative trials may produce a treatment option for progressive disease.

William Meador, MDRisk stratification of multiple sclerosis (MS) patients for treatment with an appropriate disease-modifying therapy (DMT) includes early assessment of disease severity, consideration of an individual's risk tolerance, and recognition of potential risks that may result from the use of a particular medication. The type of MS involved greatly influences therapeutic options, and relapsing-remitting MS (RRMS) presents its own unique challenges. Many neurologists use a first- and second-line approach—a DMT with a low-risk safety profile is started, and if treatment failure occurs, a second-line therapy with potentially more risk is considered. Many potential therapeutic options that are currently being evaluated target B cells, hone in on neuroprotective targets, and feature neuroreparative goals.

At a symposium held during the 66th Annual Meeting of the American Academy of Neurology, experts on the many dimensions of MS discussed treatment of relapsing disease, diagnostic and prognostic issues, different directions and targets for therapy, and the treatment of MS in younger patients. The symposium was co-chaired by Robert Fox, MD, FAAN, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, Cleveland, Ohio, and Eric Klawiter, MD, of the Department of Neurology at Massachusetts General Hospital, Boston.

TREATING RRMS: CHOOSING AMONG THE OPTIONS
Based on a presentation by Myla D. Goldman, MD, MSc, Assistant Professor of Neurology and Director of the James Q. Miller Multiple Sclerosis Clinic, University of Virginia, Charlottesville, Virginia.

Table 1Before 1993, the US Food and Drug Administration (FDA) had not approved any therapies for MS. Currently, nine drugs have been approved (Table 1), making our treatment decisions increasingly more complex. Many agents have been proven beneficial in studies with endpoints assessing the inflammatory components of MS, but no drug has been FDA approved for progressive disease. Therefore, determination of individual treatment goals should be based on the goal of "no evidence of inflammatory disease activity" (NEIDA), which better incorporates trial results into our clinical decision-making. This goal considers clinical relapses, enhancing lesions on magnetic resonance imaging (MRI), and detection of new T2 lesions as a possible indicator of therapeutic failure.

The Process of Decision-Making
When deciding on a DMT, 86% of neurologists report that efficacy is most important.1 Clinical trials in MS patients that have been conducted over the past 19 years have shown increasingly reduced annualized relapse rates (ARRs) in both treatment and placebo arms. Thus, it is difficult—many feel impossible—to compare different DMTs based solely on relapse reduction rates reported during large clinical trials. The only effective method of comparing these agents would be to design and perform head-to-head efficacy trials. Of 28 possible combinations, only 7 head-to-head trials have been performed, and these studies generally have not demonstrated significant differences among different DMTs. An extension of the TRANSFORMS study2 showed that patients who switched from intramuscular interferon β-1a to fingolimod experienced a reduction in ARR from 0.33 to 0.18.

Although efficacy most influences a physician's choice of DMT, safety tends to be the second most common consideration.1 Heesen et al3 showed that patients are generally less risk-averse than are their physicians during the DMT selection process. Actually, 80% of patients were willing to accept a risk of serious adverse event ≥ 1:100 when choosing a DMT, whereas most physicians surveyed placed their acceptable risk between 2:10,000 and 1:100. These results suggest that the risk tolerance of individual patients should be explored and considered when a DMT is being chosen.

Other factors that may drive our treatment decision include disease severity at the time of decision, pregnancy and family planning, tolerability, compliance, monitoring, cost, and comorbidities. Our ability to assess disease severity in the early stages of MS is flawed, yet factors such as initial frequency of relapses, impairment of activities of daily living (ADL), degree of recovery from relapses, and motor versus sensory involvement should be considered when patients are stratified to low-, medium-, and high-risk groups. The risk tolerance of both treating physicians and patients may differ when disease severity is included in this assessment. In addition, the likelihood of pregnancy should be assessed in each patient.

Further, the development of so many treatments for relapsing forms of MS over the past 21 years has been exciting and has contributed to a much more complex DMT decision.

TREATING RRMS: RISK STRATIFICATION AND MITIGATION
Based on a presentation by Bruce A.C. Cree, MD, PhD, Associate Professor of Neurology, University of California at San Francisco School of Medicine, San Francisco, California.

Currently, physicians have practical and commonly used methods for selecting DMTs to treat MS. An easily implemented two-tiered approach involving first- and second-line agents takes advantage of use of DMTs with better risk profiles initially; if these treatments are ineffective, escalation to an agent that may offer more benefit but that poses a greater risk of serious adverse effects may be tried. In typical practice, first-line agents might be the interferons or glatiramer acetate; these medications have been used in MS patients for two decades and have been associated with minimal serious adverse events. If use of these agents does not control a patient's disease, then that individual might try a DMT that may be more effective but more risky, such as natalizumab, fingolimod, or teriflunomide.

This two-tiered approach probably is used commonly in the United States, but it has some major disadvantages. Patients with more aggressive disease upfront may have unnecessary exposure to disease activity if a less effective DMT with a better side-effect profile is used. In addition, this approach does not account for the patient's individual risk tolerance—it would more directly reflect the risk tolerance of the treating physician who is determining which drug to use first.

Choices for DMT
Interferons tend to cause side effects that include flu-like symptoms, injection-site reactions, depression, and transaminitis. Over the 20 years since their introduction, interferons have only rarely caused serious adverse events. Likewise, glatiramer acetate has been widely used for MS for almost 20 years; it features a relatively benign side-effect profile that includes injection-site reactions, lipoatrophy, and a less-common post-injection systemic reaction resembling a panic attack. Due to their prolonged and widespread use, effectiveness, and minimal serious adverse events, these agents are ideal first-line choices for DMT.

Natalizumab, a monoclonal antibody, exerts its therapeutic benefit by blocking lymphocytes from entering the central nervous system (CNS). When compared with placebo, natalizumab therapy resulted in a significant reduction in relapse rates (68%) and disability (hazard ratio = 42%).4 Natalizumab is infused every 28 days. The drug held great promise for managing MS until a risk of progressive multifocal leukoencephalopathy (PML) was discovered. Natalizumab was withdrawn from the market, but it was then reapproved with a black-box warning concerning the risk of PML.

Over the years, patients have been risk-stratified for PML according to John Cunningham virus (JCV) antibody status, history of immune suppression, and duration of treatment (Table 2).5 However, JCV antibody seronegativity is not completely protective from PML—there have been two known cases of PML in patients who were JCV antibody negative.

Table 2

Villar6 evaluated 367 patients given natalizumab; among 23 who developed PML, lipid-specific immunoglobulin-M bands in the cerebrospinal fluid (CSF) were thought to correlate with a reduced risk of PML. Patients with CSF containing these bands seemed to have a PML risk similar to that of patients who are JCV antibody negative, even though some of this cohort were JCV antibody positive.

Fingolimod, the first FDA-approved oral agent to treat MS, was approved in 2010 for relapsing forms of the disease. In the pivotal FREEDOMS trial,7 fingolimod therapy reduced the ARR by 54% and accumulated disability by 30% when compared with placebo. Fingolimod inhibits sphingosine 1-phosphate receptors, which prevents egress of lymphocytes from lymphoid tissue. However, because these receptors are present in other parts of the body, fingolimod therapy can cause bradycardia, de novo hypertension, and macular edema. With the initial dose, patients may experience significant bradycardia; after receiving that first dose, patients should undergo electrocardiographic examination before and after a 6-hour monitoring period.

Varicella zoster virus reactivation also is possible with fingolimod therapy. Patients who do not have adequate titers of varicella zoster virus immunoglobulin G on serum testing should receive immunization 30 days prior to starting therapy. Monitoring for side effects is recommended, but no exact parameters regarding the frequency of monitoring are available.

Teriflunomide was approved by the FDA in 2011 for the treatment of relapsing forms of MS. This oral drug may exert its beneficial action as an antimetabolite that inhibits DNA synthesis. In clinical trials, its use resulted in a 32% reduction in ARR and a 30% reduction in disability when compared with placebo.8 The medication can cause reactivation of latent tuberculosis, alopecia, and transaminitis.

Teriflunomide has a Pregnancy Category X status; rapid elimination protocols are available if a patient on teriflunomide becomes pregnant. Henson et al9 reported on 70 pregnancies occurring while on teriflunomide and 22 men who fathered children on treatment; as of early 2014, the offspring have shown no structural or functional deficits. However, spontaneous abortions occurred at a rate of about 19%, which is similar to the rate observed among pregnant women who do not have MS.

Dimethyl fumarate, the most recently approved oral medication, was approved by the FDA in 2013 based on the results of two large trials showing significant benefit versus placebo in MS patients. Treatment with dimethyl fumarate resulted in a 47% relative reduction in ARR and a 59% reduction in disability progression when compared with placebo.10 Common side effects include a diffuse flushing reaction and gastrointestinal (GI) distress; rare side effects include lymphopenia and a theoretical risk of PML and renal cell carcinoma, which have occurred when a similar medication was used to treat psoriasis. Taking aspirin before each dose can reduce flushing, and drug administration with a meal can reduce GI distress.

B-cell therapy in MS has gained significant traction over the past few years, with several trials showing promising results. Ofatumumab is an anti-CD20 monoclonal antibody that profoundly reduces circulating B lymphocytes. In the MIRROR study,11 ofatumumab was compared with placebo in 232 RRMS patients. From week 0 to week 12 of treatment, a 65% reduction in the number of gadolinium-enhancing lesions was observed among the five groups treated with ofatumumab when compared with the group receiving placebo. Analysis of MRI scans taken during weeks 4–12 showed that ofatumumab-treated patients experienced an astonishing 90% reduction in gadolinium-enhancing lesions when compared with the placebo group. Of note, however, 52% of patients treated with ofatumumab had injection-related reactions, and five serious adverse events occurred.

Physicians should use caution when considering using the most effective medicine initially, despite its risk profile. Starting with the most effective DMT makes it difficult to find an alternative if the treatment fails. In addition, our ability to accurately predict patient response to these drugs is limited. Some physicians believe that brief, aggressive induction therapy followed by an ongoing DMT with a more tolerable side-effect profile may reduce risk while maximizing benefit. This approach warrants further investigation. Currently, it is acceptable to choose an initial DMT with a reasonable benefit and side-effect profile and to continue ongoing treatment until clinical or radiographic disease progression prompts consideration of a different therapy.

IS NO EVIDENCE OF MS DISEASE ACTIVITY AN ACHIEVABLE GOAL?
Based on a presentation by Robert Bermel, MD, Medical Director of the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, Ohio.

Appropriate goals to guide treatment of patients with MS are controversial. Using the treatment of rheumatoid arthritis as an example, results of the TICORA trial12 showed that earlier, more intensive therapy in a population of patients with an autoimmune disease may result in significant long-term benefit in multiple outcome measures. Therefore, early and aggressive treatment in MS patients based on NEIDA may be the most appropriate approach to take.

The first published discussion of NEIDA involved "disease-free status" used in the AFFIRM trial of natalizumab versus placebo.13 Disease-free status was defined as the absence of relapses, progression of disability, enhancing lesions, and new T2 lesions on MRI. At the end of the 2-year trial, 7% of the placebo group and 37% of natalizumab-treated patients maintained a disease-free status. However, disease-free status may be an inaccurate term, since histopathologic disease activity cannot be ruled out completely, and surrogate markers for disease activity (eg, MRI) are being used. NEIDA, on the other hand, implies that the treating physician is monitoring the patient for evidence of disease activity and cannot find any such evidence.

Should NEIDA Be Considered Clinically Meaningful?

Data from the 2-year AFFIRM trial showed that NEIDA correlated well with brain atrophy, cognition, ambulation scores, visual function, disability scores, and patient-reported outcomes. Likewise, NEIDA patients had more improvement in paced auditory serial addition test (PASAT) scores.

Bermel et al14 found improved Expanded Disability Status Scale (EDSS) scores in patients achieving NEIDA in the AFFIRM trial to persist for up to 192 weeks; MRI activity seems to play a key function in NEIDA and may be a strong predictor of poor outcome. In patients on interferon therapy, early MRI activity carried an odds ratio (OR) of 8.96 for poor long-term outcome, whereas new T2 lesions and clinical relapses only held ORs of 2.89 and 4.44, respectively. Similarly, using a Modified Rio Score, Sormani et al15 reported that early disease activity on MRI predicted the probability of disability over time. Prosperini et al16 found that detection of three or more new MRI lesions in the first year of interferon treatment predicted EDSS worsening, with a hazard ratio of 30.

These findings seem to show that short-term NEIDA may result in sustained benefit, and MRI is an instrumental tool in defining NEIDA. We can incorporate the concept of NEIDA into our assessment of clinical trial results by comparing NEIDA rates in treated and placebo groups (Table 3).

Table 3

TREATING MS IN 2020: REMYELINATION, PROGRESSIVE MS, AND BEYOND
Based on a presentation by Catherine Lubetzki, MD, PhD, Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France.

We have been unable to offer any MS treatment that can effectively stop progressive disease or promote repair of the CNS. Aside from one subgroup of rituximab-treated patients and one European trial that evaluated interferon β-1b, no DMT has shown any benefit in patients with progressive forms of MS. A great deal of progressive damage occurs via chronic demyelination and subsequent axonal loss; some experts believe that remyelination may reduce these degenerative changes. Basic science research principles currently are being used to better delineate how myelin repair occurs and to discover therapeutic targets and meaningful medications to help repair previously injured nervous system tissue. Both neuroprotection and remyelination therapies hold great promise for all patients suffering from MS, especially for those with progressive forms of MS.

Since the mid-1960s, remyelination has been known to occur in MS patients. Remyelination can reduce axonal loss during injury, but it does not seem to be completely protective. Oligodendrocytes myelinate axons within the CNS and can serve to remyelinate if they are activated. Oligodendrocyte progenitor cells (OPCs) reside in young and adult brains and can differentiate to form activated oligodendrocytes. After an injury, such as an area of demyelination, the OPCs initially activate and then migrate to the area of injury; they mature into oligodendrocytes and finally begin to remyelinate the local axons. Potential therapeutic targets could modulate any of these steps to improve activation, recruitment, maturation, or remyelination as they relate to OPCs and oligodendrocytes.

Manipulating Genetic Roots of MS
Dr. Lubetzki's work has focused on two primary areas: activation and migration. CCL2 and IL1B receptors seem to be active during OPC activation. Investigators in her laboratory induced myelin injury with cuprizone and showed that CCL2 and IL1B were upregulated. They also showed that activation of NETRIN1 and SEMA3A receptors repels OPCs, whereas activation of SEMA3F receptors attracts OPCs. In human MS lesions and in experimental models, OPCs express these receptors. Through the use of a lentivirus, these investigators upregulated the genes that control these receptors, resulting in increased migration of OPCs into a demyelinated area of injury. Multiple laboratories have shown that an increased density of OPCs in areas of injury correlate with an increase in the number of axons undergoing remyelination.

Cell Maturation and Gene Activity
An area of particular excitement relates to the process of maturation of OPCs into oligodendrocytes. When activated, the LINGO1 receptor blocks the OPC from maturing into an oligodendrocyte. Reducing LINGO1 receptor activity may increase the number of mature oligodendrocytes present in the area of injury and, in turn, increase the amount of remyelination.

An anti-LINGO1 monoclonal antibody has been produced; two phase 2 trials of this potential DMT in patients with MS and optic neuritis are ongoing. Investigators affiliated with the Relapsing-Remitting Multiple Sclerosis Synergy trial plan to enroll 400 patients who will be followed for 18 months. The optic neuritis trial plans to enroll 80 patients and follow them for 6 months.

The active metabolite of fingolimod may increase OPC maturation into oligodendrocytes via the ERK1/2 and p28MAPK pathways and may increase the number of mature oligodendrocytes.17 Thus, fingolimod may have direct modulatory activity on the OPC maturation process.

Neuroprotection also may impart possible benefit in patients with all forms of MS, but especially those with progressive disease. Two ongoing trials are evaluating possible neuroprotective agents in patients with progressive forms of MS. SPRINT-MS is a phase 2 trial that is comparing ibudilast with placebo in patients with progressive forms of MS. This trial will enroll 250 patients and have 2 years of follow-up. Similarly, MS-SMART is a phase 2 trial being conducted in the United Kingdom that will evaluate three drugs versus placebo in patients with primary progressive MS. In all, 440 patients will be enrolled; those in the active arms will receive riluzole, amiloride, or ibudilast.

TREATING PEDIATRIC MS: IS IT DIFFERENT FROM TREATING ADULTS?
Based on a presentation by Tanuja Chitnis, MD, Director of the Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, Massachusetts.

Over the past decade, patients who had been diagnosed with acute disseminated encephalomyelitis during the 1990s increasingly have been considered to have pediatric-onset MS (POMS). In many respects, POMS is similar to adult-onset disease, although a few key differences are apparent. Adult-onset MS and POMS share defining characteristics, such as relapses, disease progression, risk factors, and response to medications. However, POMS seems to have more of an inflammatory component, more frequent relapses, and more MRI activity. Also, POMS is related to a more robust response of interleukin (IL)-17–producing effector T helper cells, more cognitive effects, different pharmacokinetics, and a higher prevalence of myelin oligodendrocyte glycoprotein (MOG) antibodies.

Benson et al18 have shown that relapses are more frequent in POMS. Children tend to have slower accumulation of disability when measured with the EDSS. At any given age, however, POMS patients have higher rates of disability than do their adult counterparts. Approximately 35% of pediatric MS patients have significant cognitive impairment, which increases with time.19 POMS patients have a greater T-cell response to myelin peptides than do their adult MS counterparts or children and adults without MS.20 The disease progression in children is compounded by the fact that CNS myelination is not complete until the third decade of life.

Pediatric MS patients require different management of their disease. They need reinforcement of medication adherence, involvement of the entire family, and more frequent visits, since they tend to underreport new symptoms. Allowing children with MS and their families to socialize and interact with other families who are living with the same disease helps them to cope with their illness. Interferons and glatiramer acetate generally are first-line agents titrated to adult doses in children, as tolerated, but only limited data support these treatments in children, and none of these therapies is FDA-approved. The clinical effectiveness of these medications in children appears to be similar to that in adults in smaller cohorts.21 One of the largest studies in POMS was the REPLAY study, which evaluated subcutaneous administration of interferon β-1a in 307 pediatric patients.22 Retrospective analysis showed few serious adverse events, on the order of < 1%, but the ARR on treatment was still 0.45.

A collaborative study of pediatric MS centers followed 210 patients for an average of 4 years; 56% received one treatment over this period, 25% received two, and 19% received at least three.23 Natalizumab was used in 55 patients; it significantly reduced clinical disease activity and resulted in a less robust decrease in MRI measures.24

Few prospective trials, and virtually no randomized clinical trials, support the use of DMT in pediatric-onset disease, but new legislation may change protocols. In 2007, the US Congress passed the Pediatric Research Equity Act, which mandated that any investigational new drug (IND) study should evaluate the effectiveness in children. The sponsoring pharmaceutical company can apply for a waiver to extend its exclusive patent rights for 6 months beyond the expected time frame if they test the drug in pediatric patients. However, there are only an estimated 2,000–4,000 cases of pediatric MS worldwide, which makes prospective randomized clinical trials difficult to complete.

After 2000, the International Pediatric Multiple Sclerosis Study Group (IPMSSG) was established. This group focuses on the "evaluation of new and existing therapeutics for pediatric MS," according to its consensus statement.25 The plan is to carefully design randomized clinical trials using therapies that have shown promise in adult phase 3 studies, to better establish useful treatments in pediatric patients, and to use the growing number of centers participating in POMS management and research.

NEW RESEARCH AND FUTURE DIRECTIONS
Ehler et al26 evaluated a retrospective cohort of 90 glucocorticoid-unresponsive patients with MS relapses. Gadolinium-enhancing lesions were the only significant predictor of response to therapeutic plasma exchange in this cohort; there were no significant differences in terms of other potential predictors such as time from relapse onset, diagnosis, and age. This cohort included 21 patients with clinically isolated syndrome, 46 with RRMS, 18 with secondary-progressive MS, and 5 with primary-progressive MS. Adverse events associated with plasma exchange occurred in 18% of patients.

Vitamin D has been an area of particular interest in the MS community, since it modulates the immune system. A deficiency in vitamin D correlates with disease severity and is a risk factor for developing MS.27 Vitamin D status was evaluated in patients treated with either glatiramer acetate or interferon β in the CLIMB study28 cohort. Vitamin D levels obtained within 18 months of starting therapy were assessed in 151 patients on glatiramer acetate and 96 patients on interferon β. Higher levels of vitamin D correlated with a longer time to first event for the interferon β group, but it did not correlate with time to first event for glatiramer acetate. This suggests that the relevance of vitamin D status in MS patients may be modified by ongoing DMT.

Ongoing research continues to attempt to modulate the immune system to reduce disease activity in MS and MS models. Mayo et al29 showed that use of a nasal spray with anti-CD3 could alter the disease course in a mouse model of progressive MS. The response occurred in an IL-10–dependent manner; the benefit was abolished if IL-10 was blocked. This research needs further validation and study, but it may offer a unique mechanism of action for a future MS therapeutic approach.

Despite our best care efforts, many patients develop significant disability and progressive disease. Rehabilitation often is instrumental in allowing patients to maintain their independence. Constraint-induced (CI) therapy has been beneficial in stroke and cerebral palsy patients. Mark et al30 evaluated its usefulness in patients with progressive MS by randomizing 20 adults to undergo either 35 hours of CI therapy or 35 hours of complementary and alternative medicine (CAM). They evaluated outcomes with the motor activity log and with cortical gray-matter volume using voxel-based imaging scores. Use of CI resulted in significantly more benefit in both outcomes than did CAM, and it appeared to counteract some of the progressive functional loss and CNS degeneration that occur in progressive MS.

Sanders et al31 evaluated the compound IRX4204 in experimental autoimmune encephalitis (EAE), a mouse model for MS. The compound is an optically purified isomer of a synthetic molecule that has high affinity for the homodimerized RXR receptor. This compound has been well studied in over 70 humans with cancer, but it has only undergone study in neurologic disease (ie, Parkinson's and Alzheimer's diseases) more recently. It significantly reduced disease activity in EAE mice; its use may promote T-regulatory cells and inhibit T-helper 17 cells, a theoretically favorable action in reducing MS pathogenesis. This compound may impart immunomodulatory effects and increase remyelination after injury.

Vosckuhl and others32 presented data from a study of estriol used to modify MS disease activity. Relapses in pregnant MS patients are reduced by more than 70% during the third trimester; during this time, females are exposed to high levels of estriol. The hormone may mediate its effects in an anti-inflammatory manner to prevent fetal rejection. The design was a double-blind, placebo-controlled, 2-year study comparing patients taking glatiramer acetate plus placebo with those taking glatiramer acetate plus oral estriol; patients in the latter group also received periodic progesterone to protect the uterus.

No significant safety issues were noted during the study. Relapse rates in the estriol plus glatiramer acetate group were 47% lower than were those in the group using only glatiramer acetate during the first 12 months. However, the difference between the two groups seemed to wane over the 13–24 months of treatment. The investigators attributed this finding to a maximum effect of glatiramer acetate occurring during the second year, but it also may have represented a wearing off of the estriol effect. Cognitive outcomes were more robust and persisted into the second year. Patients given glatiramer acetate plus estriol who had PASAT scores below 55 at baseline had a significant increase in PASAT scores that persisted throughout the trial.

Viglietta et al33 presented results from the EXPLORE study that assessed the safety and tolerability of combining dimethyl fumarate with either glatiramer acetate or interferon β. This study enrolled patients who had been on the same treatment for over a year; they remained on monotherapy for 2 months, after which dimethyl fumarate was added, and they were followed for 6 months. Side effects were similar to those of dimethyl fumarate monotherapy, with three serious adverse events of worsening diabetes, clostridial infection, and significant GI distress resulting in discontinuation. Mean leukocyte counts were within normal limits, and transaminitis was mild. Treatment effect, which was not a primary outcome, seemed similar to that of dimethyl fumarate monotherapy.

Schippling and others34 evaluated the use of transcranial magnetic stimulation (TMS) in patients with MS. This therapeutic modality currently is used to treat depression and other neuropsychiatric disorders, and it has been tested in various neurologic diseases. Of 28 participants, 10 were given sham therapy, 9 were given TMS to the prefrontal cortex, and 9 were given TMS to the motor cortex. Statistically significant improvement in fatigue and depression occurred within 2 weeks of the start of TMS when the motor cortex was stimulated but not when the prefrontal cortex was stimulated. There were no significant adverse events, and the most common side effect of active treatment was lower extremity paresthesias, which may have been related to underlying MS lesions.

Birnbaum et al35 presented results from a prospective trial evaluating the cessation of DMT in patients with progressive MS. This study investigated whether or not patients with SPMS benefit from DMT that tends to reduce relapse rates; in addition, it sought to identify patients who could stop DMT without adverse events. The first group was comprised of patients who with stable disease for 8–10 years; their treating physician proposed that they stop therapy, and those who agreed were enrolled. The second group was made up of patients who initiated the discussion about stopping therapy without prompting from their physician. Of 62 patients in group 1, symptoms in 4 worsened after DMT was stopped; the median age in these patients was 54 years, whereas those whose symptoms did not worsen had a median age of 62 years. All had been stable on treatment for a similar length of time. In the second group, 4 of 10 patients worsened; however, the age difference was not similar to that in group 1. Thus, younger patients and those who voluntarily wish to stop therapy may be at higher risk of disease progression after DMT ends than are older patients who are asked to stop by their treating physicians.

CONCLUSION
Physicians must find an appropriate risk tolerance for choosing new therapies that incorporate a patient's disease severity and individualized risk tolerance. The DMT should be initiated with a goal of NEIDA. If treatment failure occurs, reassessment of risk tolerance is prudent before a second therapy is chosen.

Ongoing work aims to further elucidate targets for treatments that focus on myelin repair or neuroprotection to benefit all patients with MS but especially those with progressive disease. With these approaches, a growing supply of many DMT options hopefully will continue to improve management of MS patients and may even lead to reversal of the disease in the future.

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Dr. Meador is a National Multiple Sclerosis Society Clinical Care Fellow in Neuroimmunology at the University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.

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