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Treatment of relapsing-remitting multiple sclerosis

current approaches and unmet needs

Miller, Aaron E.a; Rhoades, Robert W.b

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Current Opinion in Neurology: February 2012 - Volume 25 - Issue - p S4-S10
doi: 10.1097/01.wco.0000413319.87092.19
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Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating disease that attacks the central nervous system (CNS) [1]. MS generally takes one of four clinical courses: a relapsing-remitting course characterized by unpredictable exacerbations of existing symptoms or appearance of new symptoms [relapsing-remitting MS (RRMS)]; an initially relapsing-remitting course that ultimately becomes steadily progressive (secondary progressive MS); a form that is progressive from the onset without relapses (primary progressive MS); and rarely a course that is progressive from onset but is then punctuated by relapses (progressive-relapsing MS) [2]. Approximately, 85% of patients initially manifest a relapsing-remitting course, with 10–15% demonstrating the primary progressive form [1]. This article reviews the epidemiology of MS, societal cost and patient burden associated with MS, the benefits and limitations of current therapies, and unmet patient needs. This article complements a recent review that focuses on advances in MS therapy and predictions regarding treatment by 2020 [3].


MS affects about 400 000 people in the United States and approximately 2.5 million people worldwide [1]. The disease affects persons of all ages, but symptoms are most likely to appear in individuals 20–50 years of age [4]. The prevalence of MS in women is approximately two to three times that in men [1].


It has been estimated that the total direct and indirect costs of MS in the United States is $28 billion each year [4]. A recent evaluation of healthcare costs for 1411 newly diagnosed patients with MS vs. 7055 healthy controls indicated that MS patients were significantly more likely to be hospitalized (15.2 vs. 4.3%), have at least one emergency department visit (25.5 vs. 12.2%) and at least one visit for physical, occupational, or speech therapy (23.7 vs. 9.9%) over a 1-year follow-up period. The mean overall annual cost of care for a patient with MS was $18 829 vs. 4038 for a healthy control individual, excluding MS treatment drugs [5▪].

Box 1
Box 1:
no caption available

Both the direct and indirect costs of MS increase dramatically as the disease progresses. The annual cost for a patient with an Expanded Disability Status Score (EDSS) of 0.2–2.5 was $5740; and the respective values for patients with scores of 3.0–5.5, 6.0–7.5, and 8.0–9.5 were $11 114, $26 365, and $46 366, respectively (Fig. 1) [6]. Another survey carried out in the United States indicated that the total annual per patient cost of MS was $47 215 with 53% attributed to direct medical and nonmedical costs, 37% to production losses, and 10% to informal care [7].

Cost of multiple sclerosis increases with Expanded Disability Status Score (Data from Ref. [6]).

The high productivity losses for patients with MS result in large measure from the very high unemployment rate in this group. A cross-sectional and longitudinal investigation of work loss in 8867 patients with MS indicated that 56–58% of them were not employed and that unemployment was associated with a progressive disease course, longer symptom duration, and greater level of disability. Specific problems in mobility, hand function, fatigue, and cognitive performance were also associated with increased risk for unemployment [8].

The high cost of MS has significant effects on patients and their families. A survey of 983 working-age patients with MS in the United States indicated that 16.4% had considerable difficulty paying for healthcare, 27.4% put off or postponed seeking needed healthcare because of costs, and 26.6% reported considerable worries about affording such basic necessities as food, utilities, and housing [9]. Results from another survey of 411 MS patients indicated that 37% had experienced a decline in their standard of living since being diagnosed with the disease [10].


The lesions of MS can occur in many parts of the CNS and result in a wide range of symptoms including fatigue, visual impairment, vertigo, and sensory impairment [11,12]. MS may be a devastating disorder with progressive accumulations of motor, sensory, and cognitive disabilities and impaired quality of life (QOL) [13–18].

Interpersonal relationships and social functioning are also greatly impaired in patients with MS. Results from a cohort of 371 patients with RRMS or progressive MS indicated that about one-fourth of those with relapsing-remitting disease and over 70% of those with progressive disease were separated or divorced following their diagnosis. Both friendship and other family relationships were also affected by the disease [19]. Loneliness is often a poorly recognized component of the experience of MS that may result from changes in social networks that occur during the course of chronic illness. A survey of 659 women with MS indicated that more than 50% felt lonely, and this was significantly associated with low levels of social support, increased social demands of illness, higher functional limitation, and lower perceived health status [20].

MS exacts significant physical, psychological, and economic tolls on patients’ families and caregivers, and this burden rises as the disease progresses and the patients’ conditions worsen. Caregivers may spend as much as 3.5 h per day aiding patients with MS and this assistance is viewed as essential for 70% of patients [21,22]. As the MS patient's disease progresses, ability for self-care declines and the increasing requirement for daily assistance can take a rising physical and economic toll on caregivers [23]. Worsening MS in the patient has been shown to be correlated with declining physical and mental health in the caregiver [24]. The impact of MS on caregiver QOL has been demonstrated in a survey of 445 MS patients and their caregivers. Care giving was associated with significant reductions in mental health, vitality, and general health scores for caregivers vs. a normative control group. Patient Beck Depression Inventory score was a significant predictor of almost all caregiver SF-36 dimension scores; and EDSS, disease duration and course, and patient therapeutic characteristics also predicted declines in some dimensions of caregiver QOL [25]. Results from another survey showed that the distress for caregivers also increased with the emergence of cognitive and psychiatric conditions in the patient in addition to decline in EDSSs [26].

Evidence also indicates that MS is associated with increased mortality and shortened lifespan. Results from a cohort of 878 patients with MS indicated that median survival after diagnosis was 41 vs. 49 years for otherwise-matched patients without MS. The standardized mortality ratio was increased 2.7 fold in the MS patients vs. the control individuals [27]. A review of results from multiple studies indicated that patients with MS lose 5–10 years of life [28].


At present, no cure exists for MS and the goals of treatment are to arrest or slow the progression of disability, decrease relapse rate, manage symptoms, slow subclinical disease progression demonstrated by imaging techniques (e.g., MRI), and maintain or improve QOL [29–31].

The most commonly used MS treatments are immunomodulating agents, interferon (IFN)-β-1a, IFN-β-1b, glatiramer acetate, natalizumab, and fingolimod [32–34]. These therapies have been demonstrated to have efficacy superior to placebo. A summary of prospective, randomized, head-to-head trials assessing the comparative efficacy of IFNs and glatiramer acetate is shown in Table 1[35–41]. There have been no randomized trials to date that compared natalizumab or fingolimod with IFNs or glatiramer acetate.

Table 1
Table 1:
Summary of prospective, randomized, head-to-head trials of disease-modifying therapies for RRMS

Freedman et al.[33] reviewed the efficacy of these agents, except fingolimod, using combined information from randomized, placebo-controlled, double-blind studies and provided information about endpoints that included proportion of relapse-free patients at 1 and 2 years; annualized relapse rate at 2 years; proportion of progression-free patients at 2 years, and proportion of patients free of gadolinium-enhancing lesions at 1 year or 9 months. The results from this analysis support the efficacy of all of these MS therapies. Fingolimod was approved after the comparative analysis carried out by Freedman, but it has been directly compared with intramuscular (i.m.) IFN-β-1a in a 12-month, double-blind, double-dummy study. The trial included 1292 patients with RRMS who had a recent history of at least one relapse during the previous year or at least two documented relapses during the previous 2 years prior to entry. Study results showed that the annualized relapse rate was significantly lower for fingolimod (0.20 for 1.25 mg/day and 0.16 for 0.5 mg/day) vs. i.m. IFN-β-1a (0.33; P < 0.001). However, there were no significant differences among groups for progression of disability as measured by EDSSs [34]. Adverse events noted among patients receiving fingolimod were systemic herpesvirus infections, macular edema, and hypertension.


Although the agents described in the preceding section have all been shown to decrease the risk for relapse and slow disease progression in patients with RRMS, stopping or even reversing disability progression remains an unmet need in many patients [42–45]. Further, MS is a heterogeneous disease and some patients may not respond adequately to treatment for reasons that remain to be elucidated [46,47].

Adverse events associated with medical treatment can negatively impact adherence to therapy across a wide range of chronic diseases and this is also the case with MS. Adverse events noted for IFN-βs include injection site reactions, flu-like symptoms, and depression [48]. The most common systemic adverse event observed in patients taking IFN-βs is flu-like symptoms. These symptoms are most common during the first few months of treatment. They usually appear 2–6 h after injection and resolve within 24 h [49]. Injection site reactions are relatively common with all the agents delivered by subcutaneous injection, but occur less often for the IFN-β-1a preparation delivered via i.m. injection [48]. Liver function abnormalities have been noted in patients taking all IFN-βs and in patients receiving fingolimod [45,50]. Results from one clinical trial indicated that i.m. IFN-β-1a was associated with a significantly lower incidence of abnormal liver function test results than subcutaneous IFN-β-1a (9 vs. 18%, P = 0.002) [36]. Natalizumab is generally well tolerated, but is associated with a small risk for the development of potentially fatal progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain from reactivation of polyomavirus JC. Although the risk of PML with natalizumab is a concern, the ability to identify patients at risk has advanced with the findings that antibody to JC virus (JCV) and prior immunosuppressive therapy are associated with a significantly increased risk for PML in patients receiving natalizumab [51]. A serologic test for antibody to JC virus can identify patients who are seropositive and at elevated risk of PML [52]. Risk of PML can be stratified by JCV antibody status and immunosuppressive use and quantified by duration of natalizumab exposure. Current models estimated PML risks to range from 0.1 per 1000 for those JCV-antibody negative with no prior immunosuppressive use to 8.1 per 1000 in those JCV-antibody positive with prior immunosuppressive use and over 2 years of natalizumab exposure [53].

Women with MS who wish to become pregnant and/or breastfeed also need options that will permit them to stay on treatment; and a need remains for therapies that are approved for use during pregnancy and during breastfeeding. Fortunately, the risk for relapses is decreased during pregnancy, but is increased postpartum [54].


A variety of different measures have been used to quantify how well a patient follows a prescribed treatment regimen. Adherence to therapy is defined as the percentage of prescribed medication taken, and persistence is defined as continuing to take prescribed drugs [55].

Failures of persistence with and adherence to disease-modifying therapy are both important problems for patients with MS. Results from one study indicated that one-third of patients taking IFN-β interrupted treatment for more than 1 month over 5 years of follow-up and that more than 9% discontinued within 6 months [56]. Results from a more recent study of 6680 MS patients receiving disease-modifying treatments indicated that those taking i.m. IFN-β-1a possessed their medication for 77% of the days observed vs. 70% for subcutaneous IFN-β-1b, 72% for glatiramer acetate, and 74% for subcutaneous IFN-β-1a [57▪]. Time to nonpersistence with i.m. IFN-β-1a and subcutaneous IFN-β-1a is shown in Fig. 2. The time for 50% of patients to stop treatment was about 600 days after the index prescription [57▪]. Results from another study of 358 patients with MS whose healthcare claims were evaluated for 1 year indicated persistence rates of 60.3% for i.m. IFN-β-1a, 42.9% for subcutaneous IFN-β-1b, 42.7% for glatiramer acetate, and 45% for subcutaneous IFN-β-1a [58].

Kaplan–Meier failure curve of nonpersistence in multiple sclerosis patients receiving either intramascular IFN-β-1a or subcutaneous IFN-β1a [57▪]. Reprinted from [57▪] with permission from Dove Medical Press Ltd.

Patients with MS cite many different reasons for discontinuing treatment. The most common reasons for interrupting therapy among patients taking IFN-βs are perceived lack of efficacy (30%), injection site reactions (12%), flu-like symptoms (10%), depression (9%), headache (8%), liver function test abnormalities (7%), and fatigue (6%) [55]. Requirement for injection has also been noted as a barrier to adherence in patients with MS taking disease-modifying therapy [59].

There is no published information about adherence to treatment with either natalizumab or fingolimod outside the setting of controlled clinical trials. However, patients who discontinue natalizumab may experience an aggressive return of disease activity shortly after discontinuation that is believed to reflect immune system reconstitution [60].

Poor adherence to disease-modifying therapy for MS patients is associated with both poorer treatment outcomes and increased cost of care. Results from a retrospective cohort study of 1606 MS patients indicated that those who were adherent to treatment (medication possession on ≥85% of days prescribed) had significantly lower risk for relapses [risk ratio = 0.89; 95% confidence interval (CI) = 0.81–0.97], emergency department visits (risk ratio = 0.78; 95% CI = 0.61–0.99), and hospitalizations (risk ratio = 0.79; 95% CI = 0.65–0.98) vs. nonadherent patients [61▪▪]. Results from a second study that included 2446 patients with MS prescribed disease-modifying therapy indicated that 59.6% were adherent to treatment (defined as possessing medication on ≥80% of days prescribed). Adherent patients were significantly less likely than nonadherent patients to have MS-related hospitalization [odds ratio (OR) = 0.63, 95% CI = 0.47–0.83] or MS relapses (OR = 0.71, 95% CI = 0.59–0.85). The average cost of care for the adherent patients was $3380 vs. 4348 for those who were nonadherent (P = 0.003) [62▪▪].


MS is a progressive and highly debilitating disease that results in high burdens for both individual patients and society. Current disease-modifying therapies for MS are effective for decreasing relapses and slowing progression, but a need for interventions that can completely arrest or even reverse progressive disability in these patients, remains.

Clinicians should consider treatment goals and carefully evaluate benefits of and patient adherence to current therapy. Goal assessment and individualization of therapy should include consideration of current disease activity and disability, patient lifestyle and expected longevity, patient's preference for route of treatment administration, patient's ability to self-treat or need for therapy to be delivered by a healthcare professional, and reproductive status and expectations.



Conflicts of interest

A.E.M. has received consulting fees from Acorda, Avanir, Biogen Idec, BioMarin, Chelsea Therapeutics, Daiichi Sankyo, EMD Serono, Glaxo, Merck Serono, Novartis, Nuron Biotech, Ono, LA-SER and Sanofi-aventis; fees for non-CME/CE services directly from a commercial interest or their agents (eg, speakers’ bureaus) from Acorda, Biogen Idec, EMD Serono, Pfizer, and Teva; and contracted research support from Acorda, Biogen Idec, Genentech, Genzyme, Novartis, Roche, Sanofi-aventis, and Teva. R.R. has no conflict of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest


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adherence; cost; quality of life

© 2012 Lippincott Williams & Wilkins, Inc.