After reading “A Data-Driven Approach to Improving Clinical and Economic Outcomes in Multiple Sclerosis,” complete the program evaluation and select the single best answer to each of the posttest questions.

	Participants must read each article in this supplement, complete the online posttest achieving a passing score of 70% or higher, and complete an online evaluation and request for credit. Detailed instructions on obtaining CE credit are included following the sample online posttest.

Articles

CE/CME QUIZ

Post Test: A Data-Driven Approach to Improving Clinical and Economic Outcomes in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic disease of the central nervous system usually diagnosed in the second or third decade of life; MS is more common among women than men by a ratio of 3 to 1. With its relatively early age of onset and symptoms that impair patients’ quality of life, MS requires lifelong, dynamic treatment, and places a substantial economic burden on individuals, healthcare systems, and society. The costs associated with providing benefits for MS therapy are growing rapidly and the increasing complexity of the MS market is impacting disease management for payers. Employers are also increasingly aware of the costs associated with MS and are asking health plans to advise on the most appropriate and cost-effective ways to manage both pharmacologic and non-pharmacologic therapies for MS. Health plans, by necessity, must therefore balance appropriate access to treatments for MS with the need to manage rising treatment costs. To meet this goal, payers require population-based solutions, guidelines, and treatment algorithms for the management of MS that can be used in clinical and formulary management decision making in the context of an evolving therapeutic landscape. Further, comparative studies are necessary for payers to determine which agents may work best on a population basis. Due to the current lack of appropriate clinical guidance and insufficient head-to-head data on disease-modifying drugs, strategies for health plans and clinical management have been designed using the best available evidence. Undoubtedly, management of this class will continue to evolve with the launch of newer agents.

Multiple sclerosis (MS) is a disease of the central nervous system that is diagnosed in 2 to 3 times as many women as men, most of whom are between the ages of 20 and 50 years.

 Because MS is characterized by inflammation and breakdown of the protective insulation surrounding nerve fibers (myelin), signals from within the brain and between the brain and body are disrupted, resulting in a variety of debilitating symptoms.

 Not only does MS degrade patient health-related quality of life (HRQoL),

 but the condition is also associated with a high economic burden for individuals, healthcare systems, and society.

 The overall burden of MS is substantial due to its early age of onset and its incurable, generally non-terminal nature, which necessitates lifelong treatment.

Payers have witnessed a rapid evolution of therapeutic treatment options for MS in recent years, as well as an increase in treatment costs over that time.

 Their clients, such as employers, have also experienced a significant rise in costs for patients with MS, and are asking payers to “justify” these growing expenses.8 Therefore, the treatment of MS is closely evaluated by payers, and as such, their needs for appropriately treating this illness include strategies that are population based, such as guidelines for the optimal management of patients that can be used in clinical and formulary management decision making, and methodologies to determine which agents will work effectively on individual patients from both the clinical and cost standpoints.

Managed care professionals and organizations must take into account that MS and its symptoms are associated with substantial personal, professional, and economic burdens. There are 4 subtypes of MS: (1) relapse-remitting (RRMS), (2) primary-progressive, (3) secondary-progressive (SPMS), and (4) progressive-relapsing (PRMS).11 The relapsing form of MS is the most commonly diagnosed form of MS and is marked by flare-ups, referred to as relapses or exacerbations, which are characterized by episodes of acute worsening of neurologic function.

 These flare-ups are followed by partial or complete recovery periods, referred to as remissions, that occur between attacks and are free of disease progression.

 Of the remaining subtypes of MS, SPMS and PRMS have unpredictable relapses and can result in a steady worsening and progression of the disease course, with approximately 50% and 90% of patients afflicted by RRMS progressing to SPMS after 10 years and 25 years, respectively.

 The very nature of MS makes the disease not only quite costly but also detrimental to patient HRQoL due to significant negative impact on physical functioning, vitality, and general health.

 Therefore, it is incumbent upon both managed care and healthcare authorities to develop effective strategies that increase patient HRQoL as well as reduce costs.

A decade ago, the average cost per patient in the United States who required hospitalization to manage the characteristic relapses of MS was $12,870 (in 2002 dollars).

 Subsequent US-based studies have reported similar if not greater total average annual costs for patients with MS, which were largely attributable to the high cost of prescription medications.

 Additionally, the results of the recently published MS Benchmarks Analysis revealed that the cost burden of MS varied according to the types of comorbidities and complications associated with MS such that costs (in 2009 dollars) were highest for those patients with ataxia ($31,483), followed by abnormality of gait ($31,175), muscle weakness ($29,104), spasms ($28,843), urinary incontinence ($28,561), and optic neuritis ($28,353).

 It should be noted that disease-modifying drugs (DMDs) accounted for 95% of the total annual pharmacy costs per patient, and 69% of the total costs for managing MS.

 Furthermore, 2 studies have reported a relationship between disease severity, impairments in HRQoL, and economic burden such that reductions in quality-adjusted life-years translated to estimated intangible costs that ranged from $7000 to $15,315 per patient, respectively.

MS also places a high burden on occupational factors that affect patients, employers, and society as a whole. The results of several longitudinal studies have demonstrated that MS is tied to high unemployment rates, such that only 40% to 70% of persons with MS remain employed.

 Even for those patients who maintain employment, the impact of absenteeism and its consequences has been found to be quite high. The results of one study published in 2009 determined that, depending on the agent used for treatment, the annual number of days of sick leave used by employees with MS ranged from 2.98 to 8.13 days, with combined sick leave and short-term disability times ranging from 7.33 to 20.67 days, and costs associated with sick leave ranging from $523 to $1431 (inflation-adjusted to 2007 dollars).

 It is interesting to note that treatment may affect these outcomes. In a study of employees with untreated MS versus individuals who had at least 1 DMD claim, the risk-adjusted total annual medical and indirect costs were $6187 versus $4393 and $3053 versus $2252, respectively, with expenditures for treated employees found to be significantly lower (

 Lastly, those responsible for providing care to patients with MS, such as parents, grandparents, spouses/partners, and other household members, may also experience a substantial negative impact on their own HRQoL due to spillover disutility and other collateral consequences.

Medical and Pharmacy Cost Trends and the Employer Perspective

In 2012, 4 specialty classes accounted for over 75% of spend for specialty drugs: (1) inflammatory conditions, (2) MS, (3) cancer, and (4) human immunodeficiency virus.

 Moreover, in recent years, the healthcare and managed care communities have witnessed a progressive shift in spend away from medical benefits and toward pharmacy benefits, especially for newer oral agents that treat cancer or manage MS. Specialty pharmacy is the largest driver of cost increases for pharmacy in 2013,

 and based on pharmacy reports, employers are witnessing an undeniable growth of specialty pharmaceutical costs.

According to a report prepared by Express Scripts, Inc, the average cost per prescription for an MS agent for an employer is $3583.

 Further, drugs for the treatment of MS accounted for almost $38 in per member per year (PMPY) drug spend during 2012.

 In a plan of 1 million members, that equates to an increased drug spend of approximately $38 million for the management of MS alone. In 2012, PMPY spend for MS grew 17.9% to $8.09, and with the introduction of 2 new oral agents for MS into the therapeutic market in 2012 and 2013, as well as an ever-growing drug pipeline, this figure is expected to increase further.

 Unfortunately, despite the detrimental clinical consequences of inappropriately managed MS and the high costs associated with the disease, an estimated 26.3% of patients with MS remain nonadherent to their therapies,

 which highlights the irrefutable need to address educational gaps and to improve current strategies in the managed care and healthcare arenas.

The Current Therapeutic Landscape and the Health Plan Perspective for MS

The first agent for MS approved by the US Food and Drug Administration (FDA) was made available in 1993 and was quickly followed by the addition of 5 more agents (

 Between 2005 and 2008, no additional agents were approved by the FDA, but between 2009 and 2013, the number of FDA-approved agents available to treat MS has nearly doubled.

 One of the more profound differences between the first and second generations of approved agents for MS was the introduction of medications that could be administered orally. Prior to 2010 and before oral agents for MS were available, clinicians and their patients could only select injectable first-line treatments from among the 3 available interferon-beta formulations (IFNs) and glatiramer acetate (GA).

Improving clinical outcomes and QOL for patients with MS is a top priority for health plans. However, with the introduction of newer therapies, health plan decision makers are faced with growing complexity in the MS space. Already, the management of MS may require the use of several agents of various drug classes to combat comorbid conditions and complications, including agents for the management of migraine, antidepressants, narcotic analgesics, corticosteroids, antispasmodic agents, anticonvulsants, nonsteroidal anti-inflammatory drugs, and benzodiazepines.

 Current health plan strategies for managing the optimal utilization of agents for MS include: (1) prior authorizations (PAs) that account for the appropriateness of the medication, the setting of care, and the duration of therapy; (2) initial clinical management with 1 or more preferred first-line agents; (3) the use of online “step edits” to automate clinical management; (4) case/therapy management for which patient compliance is of particular importance; (5) cost-effectiveness analysis, which is still a process in development; (6) benefit designs with cost sharing by the beneficiary; and (7) risk evaluation and management programs.

Health plans are also sensitive to the needs of employers to attract and maintain a productive workforce. Although treatment guidelines for MS have been put forth by several institutions and organizations, these guidelines are not necessarily beneficial for developing a health plan’s clinical management program. Health plans need to consider important clinical issues by asking the right questions, examples of which can be found in the 

. When faced with the paucity of head-to-head comparative trials, those responsible for developing clinical management programs must rely on current clinical management strategies. Clinical algorithms may be considered more helpful when developing these clinical management programs, as guidelines tend to provide general statements or overviews of concepts, but algorithms will contain details and specific instructions for individual clinical decisions.

One recent study was conducted in an effort to develop a uniform set of payer guidelines.

 The study involved 14 panel members who were experts in managed care, 8 of whom were pharmacy directors and 6 were medical directors, representing 12 US health plans, 1 specialty pharmacy, and 1 consulting company. All of the panelists were presently or previously involved in the formulary decision making process at their organizations. The panelists participated in 2 rounds of web-based questionnaires, with the first consisting of mostly open-ended questions and the second consisting of mostly closed-ended questions, before gathering for a live consensus meeting. A “consensus” was defined as a mean response of at least 3.3 or 100% of responses being either “agree” or “strongly agree” using a 4-item Likert scale (1 = strongly disagree, 2 = disagree, 3 = agree, 4 = strongly agree). After 3 phases, the panelists reached consensus on 25 statements, which included33:

		The initiation of DMD therapy for patients with clinically isolated syndrome is a provider decision, but most patients with clinically definite MS should be treated with a DMD

		Both GA and a preferred IFN should be on a health plan’s formulary

		Patients with MS should have preferred access to platform therapies

		Access to non-preferred IFNs should be restricted by step therapy or the use of a preferred agent first

		Health plans should have a preferred high-dose/high-frequency IFN on formulary, but should take efficacy, safety, cost, and contracting into consideration when selecting the preferred high-dose/high-frequency IFN

		Access to natalizumab should be limited to use for the FDA-approved indication

		Access to fingolimod in combination with injectable DMDs should be limited until additional safety information is available

		Payers should identify the need for patient compliance and support while on DMDs

When considering the role of pharmacy and therapeutics (P&T) committees in health plans, institutions, and hospital systems, it is important to define a few common terms. A formulary is a continuously updated list of medications and related information that represents the clinical judgment of physicians, pharmacists, and other experts in the diagnosis, prophylaxis, and/or treatment of disease and promotion of health.

 A formulary system is an ongoing process through which healthcare organizations establish policies regarding the prudent use of drugs, therapies, and drug-related products, and identify the agents that are most clinically appropriate and costeffective to best serve the health interests of a given patient population. The P&T committee is responsible for managing the formulary system, and typically comprises plan medical directors, pharmacy directors, pharmacy staff, actively practicing physicians, and other healthcare professionals and staff who participate in the medication use process. Further, the P&T committee bases its decisions on 3 core principles: (1) safety; (2) efficacy; and (3) cost/value.

 Generally, P&T committees will focus on the issues concerning safety and efficacy, and decisions can be categorized as clinically superior, clinically equivalent, or clinically inferior. Prior to 2009, all of the agents for MS were featured on many payers’ formularies and were readily available, with clinical management strategies typically consisting of a PA to verify RRMS and the prescribing physician. The addition of the newer agents since 2009 has introduced further complexity into the P&T decision-making process, and now those committees are looking to support their healthcare decisions with more relevant data. In the absence of adequate comparative data and clinical trials, committees are seeking to balance safety, efficacy, and the burden of therapy as one way of managing the MS formulary (

It is important to note that as benefits in a health plan are altered, patient and provider access will also change accordingly. Many plans have evolved from a typical 3-tier formulary (ie, generic, formulary, non-formulary) to a 4- or more-tier formulary (ie, generic, preferred branded, nonpreferred branded, specialty).

 Specialty drugs have varying definitions, but often, cost (>$600/month) is an important determining factor in its placement on a formulary tier.

 Drugs in the specialty tier will generally have higher patient out-of-pocket (OOP) costs and are usually coinsurance based. Newer benefit designs have increased member cost share through deductibles and coinsurance. Further, coinsurance tiers may or may not have a cap or maximum OOP limit, depending on the benefit design that is purchased by the client or beneficiary. It is important to remember that patients with MS will require lifelong therapy. Unfortunately, member cost-sharing practices, such as the absence of a cap on OOP expenses, may limit patient access to necessary treatments and create a substantial cost liability. A recent study showed that adherence to therapy is likely to decrease as member OOP costs increase, such that a 10% increase in cost sharing leads to an 8.6% decline in adherence.

The cost of providing health plan benefits and insurance coverage for MS therapy is one of the fastest growing sectors of healthcare spending today. The increasing complexity of the MS market is accompanied by increasing complexity for payers. Employers are aware of the rapidly growing costs of DMDs distributed through specialty pharmacies and have requested the development of actionable plans that put forth comprehensive management strategies. These plans must balance appropriate access to treatments for MS with the need to manage the high price tag of the therapeutic category. As management strategies for MS evolve, payers are constantly seeking population-based solutions to manage the disease.

As noted in articles 1 and 2 in this supplement,

 optimal therapies for MS must be tailored to individual patients, and current treatment guidelines maintain an essential role in managing initial treatment decisions and switches in therapies when needed. However, during a time in which the therapeutic environment and drug pipeline for MS is rapidly evolving, further research and application of prognostic indicators and treatment biomarkers in clinical practice will provide the necessary guidance and insight to formulate standardized treatment algorithms for MS and drive best practices that correlate with the dynamic picture of MS. Further, improved comparative studies will allow payers to differentiate agents from within the same drug class and to determine, on a population basis, which agents will work best for whom, under which circumstances, and the most cost-effectively, thus driving improved treatment efficacy, safety, adherence, and ultimately, reduced overall costs. As the clinical landscape for MS continues to expand and grow in complexity, the managed care arena must adapt accordingly and promote the prudent utilization of costly therapeutic agents to achieve optimal clinical and economic outcomes for both patients and providers.

 This activity is supported by educational grants from Bayer HealthCare Pharmaceuticals; Biogen Idec; EMD Serono, Inc; Genzyme

Corporation; and Questcor Pharmaceuticals, Inc.

 Dr Owens reports serving as a consultant/paid advisory board member for Biogen Idec, Genzyme Corporation, and Novartis. He also reports meeting/conference attendance sponsored by Biogen Idec and Genzyme Corporation.

Concept and design; critical revision of the manuscript for important intellectual content; administrative/technical support; and supervision.

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ARTICLES

Managed Care Aspects of Managing Multiple Sclerosis

Patients with multiple sclerosis (MS), a disease of the central nervous system that disrupts signals within the brain and also the signals between the brain and body, will likely experience symptoms that may negatively impact their quality of life (QOL). Due to the complexity of MS and its disease burden, multidisciplinary management that combines pharmacologic and nonpharmacologic strategies with patient education is necessary. Diagnosing relapses of MS in clinical practice can be difficult due to the multiple subtypes of MS, variations of symptomatology, and pseudo-relapses. Managing relapses also presents its own set of challenges, for example, evaluating if treatment is appropriate and determining which agent would be most effective for a patient if treatment is recommended. Patient education is essential for achieving optimal outcomes for patients with MS and improving patient QOL, and should increase awareness of: (1) the disease itself and its progression; (2) the signs and symptoms of MS; (3) current treatment strategies and plan of care; (4) the recognition and management of relapses; (5) the value of treatment adherence and impact of nonadherence; and (6) hope for the future. The management of active MS may be further complicated by the complex variety of pharmacotherapeutic options, and in some instances, by having to switch between agents and drug classes. Newer agents in development (eg, alemtuzumab, ocrelizumab, laquinimod) offer the opportunity to expand the therapeutic armamentarium, although further long-term data are required to evaluate any safety concerns associated with newer agents.

According to the National Multiple Sclerosis Society, multiple sclerosis (MS) is a disease of the central nervous system (CNS) that disrupts signals within the brain and also the signals between the brain and the body.

 Due to the CNS pathophysiology that characterizes MS, individuals afflicted by the disease will likely experience symptoms that range from numbness and tingling to blindness and paralysis.

 Although MS itself is not typically fatal, the neurological disease is incurable and can have a profoundly negative impact on patient quality of life (QOL).

 Fortunately, MS is now a treatable condition and many new pharmacotherapies have entered the market in recent years, with additional agents currently in late-stage development.

MS is a complex disease with various symptoms that impact many human functions. As such, a multidisciplinary approach that combines pharmacologic and nonpharmacologic management, patient education strategies designed to minimize adverse effects of medications (

) and to increase treatment adherence, patient support groups, and an emphasis on maintaining open and effective lines of communication between the patients and healthcare professionals is essential.

 According to Ross, every patient with MS should have a primary care physician and a neurologist in the multidisciplinary team to oversee their care. Nurses are also important members of this team, as patients with MS frequently look to their nurses for additional information regarding the disease and their care. The nurse is the facilitator for patient autonomy, teaching self-directed learning techniques and empowering patients to take responsibility for the treatment of their disease. In addition, the management of primary, secondary, and tertiary symptoms of MS may involve specialists from many areas, such as physical therapists, psychologists/ neuropsychologists, occupational therapists, urologists/neurourologists, and vocational rehabilitation counselors (

Relapsing-remitting multiple sclerosis (RRMS) is the most common subtype of MS, accounting for 85% of MS cases at initial diagnosis. Patients with RRMS will experience relapses (also called attacks, exacerbations, or flare-ups) separated by periods of full or partial recovery.

 According to the 2010 revision of the McDonald criteria for the diagnosis of MS, relapses are defined as “patient-reported or objectively observed events that are typical of an acute inflammatory demyelinating event in the CNS, current or historical, with a duration of at least 24 hours, in the absence of fever or infection.”

 Furthermore, paroxysmal symptoms, historical or current, may also be considered relapses if they consist of multiple episodes that occur over a minimum of 24 hours.

 The potential signs and symptoms of relapse are numerous and will vary in presentation depending upon the location of the demyelinating event and inflammation.

 Any disability that results from a relapse of MS can persist for several weeks or for months,

 although recovery time may be hastened through pharmacologic intervention.

The diagnosis and treatment of MS relapses in clinical practice is challenging, as there are multiple manifestations of relapse, such as optic neuritis, paroxysms, and myelitis, and symptoms of relapse can vary even within each particular manifestation.

 Adding further complication to the treatment of relapses is the common misconception among many patients that disease remission is a symptom-free period, even though most individuals will always be symptomatic in some form.

 While fluctuations in symptoms, such as fatigue, may be caused by factors as common as stress or sleep deprivation, and may be mistaken for a relapse in MS,

 pseudo-relapses and infections can also make the diagnosis of an actual relapse more difficult. For instance, the transient worsening of symptoms due to overexposure to heat or overexertion are not representative of actual relapses of MS, but are most likely attributable to conduction blocks within demyelinated axons.

 Infections such as viral upper respiratory infections and simple urinary tract infections are often associated with pseudo-relapses in patients with MS

; however, systemic infections may provoke actual relapses by introducing a proinflammatory bias in immune responsiveness that is capable of triggering disease activity and exacerbations.

If a true clinical relapse is suspected in a patient with MS, the clinician must decide if the relapse is to be treated at all, and if so, which treatment should be selected. Investigators have studied the effects of corticosteroids on both short- and long-term recovery from optic neuritis in patients with MS, and the results have demonstrated significant improvements in short-term outcomes; however, no long-term benefits in terms of attaining pre-relapse functioning have been observed.

 Therefore, the decision to treat a relapse in MS often depends on the functional impact that the relapse may have on the patient’s daily life. Typically, the standard of care and first-line treatment option for relapses in MS is 3 to 5 days of intravenous methylprednisolone (500-1000 mg/d), with or without an oral taper, or a high-dose oral steroid.

 Because high-dose oral and intravenous steroid regimens have shown similar efficacy in treating MS relapses,

 the decision of which agent to use is normally determined by patient and clinician preferences. Other treatments for relapses of MS include adrenocorticotrophic hormone, intravenous immunoglobulin, and plasma exchange; however, these treatments are usually reserved for those who are unresponsive to first-line therapies.

 It is important to note that combining comprehensive rehabilitation with standard, intravenous methylprednisolone therapy may result in improved performance on measures of disability and QOL over a 3-month period following a relapse in patients with MS.

Epidemiologically, the majority of patients diagnosed with MS are between the ages of 20 and 50 years, and the disease is diagnosed in 2 to 3 times as many women as men.

 The newly diagnosed patient with MS is often in his or her peak productive years—young (between the ages of 20 and 50 years) and of the age to possibly start a career and/ or a family.

 For these patients, concerns about disability and a fear for their future are common.

 These circumstances provide an opportunity for healthcare professionals to educate patients with MS regarding a variety of topics to ensure informed treatment decisions, to maintain selfcare, and to take control of their lives.

 Patients with MS require education that clearly explains the facts regarding the possible course and nature of the disease, its symptoms, and the importance of diagnostic tests.

 Another important area of education concerns assisting patients in finding support groups and developing appropriate support systems.

 Education regarding the nature of rehabilitative services and how to find those services will also be necessary.

 Regarding the treatment of MS, patient education topics include the plan of care, the potential side effects of pharmacotherapies and efforts needed to mitigate those effects, injection anxiety, social isolation, and treatment expectations.

 Patient education regarding realistic treatment expectations may be the most critical area of education,23 and is necessary for treatment adherence and the success of long-term disease management. Patients should know that pharmacotherapies for MS are, at the moment, not designed to be curative, but can slow the progression of the disease and improve patient QOL. In addition, education regarding the risks of not treating MS or delaying treatment for MS should be provided to patients. It is important to keep in mind the 4 main goals of MS management: (1) modifying/reducing relapses and delaying progression to disability; (2) treating relapses; (3) managing symptoms; and (4) maintaining an acceptable QOL. It should also be noted that inspiring hope for the future is also a critical component of patient education, as it can energize patients with MS and make healthy coping more feasible.

The management strategy for a patient with MS should be tailored based on the specific state of their disease, the therapeutic regimen, and the patient’s individual characteristics. Treatment decisions for MS are often quite complex and should be made by balancing disease-related therapeutic considerations with patient circumstances, which may include convenience, cost, patient preference, response, and tolerability (

). Treatment decisions should also take into account the patient’s goals and lifestyle in an effort to promote optimal adherence and persistence to therapy, while maintaining a balance between safety and efficacy for a chosen regimen. Additionally, patients should be aware of the availability of disease-modifying therapies (DMTs) for RRMS, and that therapy should be initiated as early as possible to reduce the frequency of relapses and to delay disease progression. Ultimately, the goals of treatment are to prevent further disability and to preserve function, and it is evident that successful management of MS is contingent upon a complex multitude of clinical, social, and cognitive factors.

Adherence, which is defined as the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen,25 involves partnership, mutually established goals, and a therapeutic alliance as core elements. Unfortunately, there are numerous barriers to treatment adherence in MS, including communication problems, knowledge deficits, physical impairments, social and cultural variables, financial concerns, emotional distress, psychiatric disorders, and cognitive deficits.

 MS is a highly complicated disease and despite its substantial clinical and significant burden, MS may not be well understood among the patient population. Other common issues that affect treatment adherence include the fear of needles, which complicates or even prevents the use of injectable therapies, and misconceptions of low treatment efficacy. Fortunately, with the recent introduction of noninvasive oral agents for MS into the drug market, patients, especially those uncomfortable with the use of injectable DMTs, may be afforded a more positive outlook on disease management and a more flexible, “on-the-go” lifestyle, which may consequently improve adherence to DMTs. However, similar to injectable therapies for MS, even patients on oral agents may become less adherent to treatment regimens if treatment is perceived to be less effective.

A study published in 1997 by the Archives of Neurology found that up to 41% of patients reported new or increased depression within 6 months of starting interferon treatment, and demonstrated that patients experiencing symptoms of depression were more likely than those without symptoms of depression to discontinue treatment with interferon for MS. Of the patients who had experienced depression, significantly more patients who received psychotherapy or management with antidepressant medication continued treatment with interferon compared with patients who did not receive treatment for their depression (86% vs 35%; 

 The authors of the study suggested that treating patient-reported depression may increase adherence to DMTs.

More recently, the authors of a review published in 2007 by The Journal of Neurological Sciences noted that the most frequent cause of stopping treatment is perceived lack of efficacy, and that most withdrawals from treatment occurred during the first year.

 This information illustrates the importance of patient education and the implementation of strategies to promote adherence, which include setting realistic expectations, explaining the critical role of adherence in treatment outcomes, recognizing and addressing barriers to optimal adherence, accounting for ethno-cultural barriers, advocating for patients by assisting with reimbursement, identifying available resources, and involving family members and loved ones.

The pharmacologic management of active MS typically begins with the administration of immunomodulatory diseasemodifying drugs (DMDs); however, not all patients will have an optimal response to initial therapy. For patients with persistent relapses or disease activity observed via magnetic resonance imaging (MRI), or those who have difficulty tolerating or adhering to their treatment regimen, switching agents may be the best option. A proposed algorithm from Spain has suggested that the first step in a switching strategy would be to switch from one first-line agent (ie, interferon betas, glatiramer acetate [GA], fingolimod, natalizumab) to another.

 For example, patients initially treated with interferon betas may have their drug dosage or frequency increased, or those already on high-dose interferon beta may be switched to GA.

 Similarly, patients who have been treated suboptimally with GA may be switched to an interferon beta.28 In cases where the aforementioned recommendations are ineffective, switching to a second-line agent (ie, natalizumab or fingolimod) is suggested; however, while the second-line agent may be more effective, toxicity to the patient is also increased.

 Fortunately, washout periods between switches are rarely needed, with the exception of switching from an immunosuppressive DMD to natalizumab, which requires immune system recovery.

 Treatment cost is also an important consideration when deciding on therapeutic switches. Evidence suggests that non-pharmaceutical medical costs are greater for those who switch treatments for MS compared with persistent users of initial therapy.

 Additionally, a study published in 2010 found that the initiation of therapy with fingolimod with continuous use for 2 years was associated with a lower cost per relapse avoided compared with treatment with an interferon beta (intramuscular interferon beta-1a) for 1 year followed by a switch to fingolimod.

Although several DMDs have demonstrated significant efficacy on clinical and MRI disease activity and are currently available for the treatment of patients with MS, more effective and tolerable therapies are still needed.

 Therefore, the drug pipeline for MS therapy continues to evolve to suit the needs of the patients and providers, with 3 DMDs (alemtuzumab, ocrelizumab, and laquinimod) currently in advanced development. The humanized monoclonal antibody alemtuzumab targets the glycoprotein antigen CD52, which is located on the surface of mature T and B lymphocytes and monocytes. The results of a study published in 2010 found that alemtuzumab induced the production of neurotrophic factors in reconstituted autoreactive T cells.

 The results of one phase III trial of laquinimod, a synthetic, orally active, small-molecule, anti-inflammatory agent, showed that it was unable to significantly reduce relapses among patients with MS beyond those seen with placebo.

 However, final results of another phase III trial showed that oral laquinimod administered once daily was able to slow the progression of disability and reduce the rate of relapse in patients with RRMS.

Investigational agents offer hope for improved patient outcomes, but are also associated with new challenges, and prominent among those challenges are safety concerns. While research and development for MS continues to move forward, patients receiving alemtuzumab in its phase III trials were required to undergo 1 month of prophylaxis with oral acyclovir after each infusion cycle due to concerns regarding opportunistic infections, and phase III trials with ocrelizumab for rheumatoid arthritis and lupus nephritis were partially or completely put on hold in 2010 due to opportunistic infections.

 Malignancies are another concern, as a case of melanoma has been reported following treatment with alemtuzumab.37 For those treated with alemtuzumab, lymphocytopenia is an additional safety issue due to prolonged lymphocyte depletion that may last for years following a single dose.

 Further, treatment with alemtuzumab has been associated with emergent autoimmune diseases in the form of antibody-mediated autoimmune complications, such as thyroid disorders, immune thrombocytopenic purpura, and Goodpasture syndrome.

Beyond the issues of safety, the selection of first-line therapies will undoubtedly become even more complicated due to the broadened scope of relative efficacy, different mechanisms of action, and various risk profiles. The decision-making process for treatment selection, sequencing, and combination for optimal benefits will undoubtedly increase in complexity as the agents currently in development for MS make their way into the market.

The complexity of MS and the diversity of its signs and symptoms require a multidisciplinary approach to treatment that combines pharmacologic and nonpharmacologic strategies, as well as improved patient education. The diagnosis and treatment of relapses in clinical practice presents a host of challenges due to the multiple manifestations of relapses, the variations of signs and symptoms within each particular relapse manifestation, and the presence of pseudo-relapses and infections. Whether or not treatment for relapse should be initiated is also a controversial topic, and if the relapse is to be treated, the selection of a treatment option requires careful and informed consideration. The treatment of active disease can also be further complicated based on the number and type of pharmacotherapeutic options available. Ultimately, a treatment decision should be personalized to the patient and contingent upon the balance between its risks and benefits. With the newer agents that are currently in the drug development pipeline, the expanded therapeutic armamentarium offers clinically beneficial opportunities, but also presents substantial challenges to clinicians and providers due to new questions regarding appropriate use and positioning in therapeutic algorithms. As such, additional long-term studies and clinical data will be required to elucidate any safety efficacy concerns associated with these newer agents for MS.

Ms Perrin Ross reports serving as a consultant/paid advisory board member for Acorda Therapeutics; EMD Serono, Inc; Genzyme Corporation; Novartis; and Teva. She also reports receiving lecture fees from Acorda Therapeutics; Biogen Idec; EMD Serono, Inc; Novartis; Pfizer, Inc; and Teva.

Concept and design; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

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