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Treatment of relapsing-remitting multiple sclerosis in adults
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Disclosures: Michael J Olek, DO Nothing to disclose. Francisco Gonzalez-Scarano, MD Employment: University of Texas Health Science Center, San Antonio; University of Pennsylvania. Equity Ownership/Stock Options: Multiple, but traded by advisors without my input [Pharmaceutical]. Other Financial Interests: NeuroLink [Venture Capital]. John F Dashe, MD, PhD Employee of UpToDate, Inc.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2015. | This topic last updated: Feb 10, 2015.

INTRODUCTION — Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) that is a leading cause of disability in young adults. The annual mean cost, including patient care, alterations to home and vehicle, medications, purchase of special equipment, and loss of earnings, is $47,000 per patient in 2004 dollars [1]. This translates into a national annual cost of $13 billion in the United States and a mean lifetime cost per case of $3.4 million.

The treatment of MS varies depending upon individual disease characteristics.

Relapsing-remitting MS (RRMS) is characterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery. There is no disease progression during the periods between disease relapses.

Primary progressive MS (PPMS) is characterized by disease progression from onset with occasional plateaus, temporary minor improvements, and acute relapses allowed.

Secondary progressive MS (SPMS) is characterized by an initial relapsing-remitting disease course followed by progression with or without occasional relapses, minor remissions, and plateaus.

The treatment of relapsing forms of MS is reviewed here. The treatment of progressive forms of MS is reviewed elsewhere. (See "Treatment of progressive multiple sclerosis in adults".)

Other aspects of MS are discussed separately:

(See "Pathogenesis and epidemiology of multiple sclerosis".)

(See "Clinical course and classification of multiple sclerosis".)

(See "Clinical features of multiple sclerosis in adults".)

(See "Symptom management of multiple sclerosis in adults".)

(See "Diagnosis of multiple sclerosis in adults".)

ACUTE ATTACKS — Acute attacks (relapses) of MS are typically treated with glucocorticoids. Indications for treatment of a relapse include functionally disabling symptoms with objective evidence of neurologic impairment. This is reviewed in detail separately. (See "Treatment of acute exacerbations of multiple sclerosis in adults".)

GENERAL PRINCIPLES OF DISEASE MODIFYING THERAPY — Certain immunomodulatory agents, including interferon beta preparations, glatiramer acetate, natalizumab, fingolimod, and teriflunomide, have shown several important beneficial effects for patients with relapsing-remitting multiple sclerosis (RRMS):

A decreased relapse rate

A slower accumulation of brain lesions on MRI

Thus, everyone with a diagnosis of definite RRMS should begin disease modifying therapy. However, the impact of these disease modifying therapies on the progression of brain atrophy in MS is still unclear, as some studies have reported decreased atrophy with treatment [2-4], while others have not [5,6].

We now know that most of the immune response in MS occurs early in the disease course. This is demonstrated by the findings that most of the gadolinium-enhanced lesions occur early in MS and that the relapse rate slows over the natural history of the disease. The later stages of MS are typically less inflammatory and more degenerative.

Therefore, treatment of MS should be early and aggressive. Evidence supporting this strategy can be found in clinical trials showing that early treatment with interferons reduces the attack rate, whether measured clinically or by MRI, in patients with clinically isolated syndromes suggestive of multiple sclerosis. (See "Clinically isolated syndromes suggestive of multiple sclerosis", section on 'Treatment'.)

The variety of patient disabilities and variation in the course of MS make the choice of treatment for the individual patient difficult. While the choice of disease modifying therapy typically relies upon the results of controlled trials, patients may differ markedly from those that have been treated in clinical trials.

INTERFERONS — A number of different interferon beta (IFNB) preparations have been investigated for treatment of relapsing-remitting multiple sclerosis (RRMS). A discussion of the different types of interferon and evidence of their effectiveness is presented below.

Interferon beta-1b (Betaseron) — The first disease modifying medication approved for use in MS was recombinant interferon beta-1b (Betaseron). The drug is a cytokine that modulates immune responsiveness, although its precise mechanism of action in MS is unknown [7].

The efficacy of interferon beta-1b was demonstrated in a double-blind, placebo-controlled trial of 372 patients with RRMS who were randomly assigned to treatment with either interferon beta-1b 50 mcg every other day, interferon beta-1b 250 mcg every other day, or placebo [8].

After two years, the annual exacerbation rate was significantly lower for both interferon beta-1b treatment groups and appeared to be dose related; the frequency of relapses was 1.27/year in the placebo group, compared with 1.17/year and 0.84/year in the low and high-dose interferon beta-1b groups, respectively [8].

At five-year follow-up, the incidence of disease progression was lower in the high-dose (250 mcg) interferon beta-1b group compared with the placebo group (35 versus 46 percent) [9]. There was also a 30 percent decrease in the annual exacerbation rate in the high-dose interferon beta-1b group over five years. Although this was not statistically significant, the treatment benefit trend was maintained. There was no significant increase in the median brain MRI lesion burden (3.6 percent) in the interferon beta-1b group, while the placebo group had a 30 percent increase in median MRI lesion burden over five years.

At a median of 21 year follow-up with nearly complete ascertainment (98 percent) of patients, the rate of all-cause mortality was significantly lower for those originally assigned to low and high dose interferon beta-1b treatment (17.9 and 18 percent, versus 30.6 percent for those originally assigned to placebo) [10]. Patients in this trial received the assigned treatment for up to five years, and subsequent use of disease modifying therapy was optional and unmasked. Therefore, these data suggest that earlier and/or longer exposure to interferon beta-1b treatment improves survival for patients with MS.

Interferon beta-1b also appears to be effective for RRMS in Japanese populations, where the frequency of the optic-spinal variant of MS is much higher than in Western populations. (See "Diagnosis of multiple sclerosis in adults", section on 'Neuromyelitis optica'.)

In a randomized clinical trial of 205 Japanese patients with RRMS that was not placebo controlled, treatment with interferon beta-1b 250 mcg every other day was associated with a significant reduction in the annual relapse rate compared with the "control" group that received interferon beta-1b 50 mcg every other day [11]. A subgroup analysis suggested that interferon beta-1b efficacy was similar for patients with optic-spinal variant (about 21 percent of the study population) and classic MS. However, the study was not powered to confirm treatment efficacy in subgroups.

Interferon beta-1b is administered every other day subcutaneously by self injection. The side effect profile was similar to the other interferons (see 'Side effects of interferons' below). Not all patients respond to the drug, and with time all patients have had additional attacks. In addition, 34 percent of patients developed neutralizing antibodies that could reduce the drug's clinical efficacy [12]. (See 'Neutralizing antibodies' below.)

The INCOMIN study compared interferon beta-1b with intramuscular interferon beta-1a in 188 patients with RRMS and found the former to be more effective on both clinical and MRI outcomes [13]. The trial design did not include blinding, but careful randomization was performed and clinical results were consistent with MRI results, the latter of which were obtained from a blinded analysis. Over two years, significantly more patients receiving interferon beta-1b remained relapse-free than those assigned to interferon beta-1a (51 versus 36 percent, relative risk of relapse 0.76, 95% CI 0.59-0.9); similarly, more patients receiving interferon beta-1b remained free from new T2 lesions on MRI (55 versus 26 percent, relative risk of new T2 lesion 0.6, CI 0.45-0.8).

In contrast to the INCOMIN results, a multicenter open-label randomized Danish trial involving 310 patients with RRMS compared subcutaneous interferon beta-1a (Rebif) 22 mcg once weekly with subcutaneous interferon beta-1b (Betaseron) 250 mcg every other day and found that the annual relapse rates were nearly equal in the two treatment groups [14].

Interferon beta-1a (Avonex) — The efficacy of intramuscular (IM) interferon beta-1a (Avonex) in patients with RRMS was demonstrated in a randomized, double-blind study of 301 patients [15]. Weekly intramuscular injections of 6 million units (30 mcg) of Avonex or placebo were administered [15]. Over two years, treatment with Avonex resulted in a reduction in the annual exacerbation rate compared with placebo (0.61 and 0.9, respectively), a decrease in MRI lesion volume (mean 74 versus 122), and fewer patients progressing by one point on the Expanded Disability Status Scale (EDSS) (22 versus 35 percent). In a subsequent randomized, double-blind study, a higher dose of Avonex (60 mcg per week) was not superior to 30 mcg [16]. As mentioned above, Avonex may also have beneficial effects on cognitive function [17].

Adverse effects with Avonex are similar to those with other interferons (see 'Side effects of interferons' below). Approximately 2 to 5 percent of patients develop neutralizing antibodies that may limit efficacy over time (see 'Neutralizing antibodies' below).

Interferon beta-1a (Rebif) — The benefit of subcutaneous interferon beta-1a (Rebif) was established by the double-blind PRISMS trial that randomly assigned 560 patients with RRMS to placebo, 22 mcg, or 44 mcg of Rebif three times per week for two years [12]. Treatment with 22 or 44 mcg was associated with a significant reduction in relapse rate (27 and 33 percent, respectively) compared with placebo. Treatment also reduced the MRI lesion burden in the low- and high-dose treatment groups (1.2 and 3.8 percent) versus an increase in the placebo group (10.9 percent).

The side effect profile was similar to the other interferons (see 'Side effects of interferons' below). Approximately 24 percent of the 22 mcg group and 13 percent of the 44 mcg group were positive for neutralizing antibodies, but this did not affect the mean relapse count (see 'Neutralizing antibodies' below).

In an extension of the PRISMS study, patients originally randomized to placebo began treatment with one of two doses of Rebif, while those originally randomized to Rebif continued the drug [18]. Patients who received Rebif therapy for the entire four years had significantly less change in impairment, disability, and MRI measures of pathology than patients who initially received placebo; the latter group never regained the losses associated with delaying interferon therapy.

In a later PRISMS extension study that followed 68 percent of the original trial cohort for either seven or eight years, patients who received Rebif therapy three times a week at either dose (44 mcg or 22 mcg) for the entire study period had a significantly lower relapse rate than patients who initially received placebo [19]. Patients originally assigned to the Rebif 44 mcg group, but not those originally assigned to the 22 mcg group, had a significantly lower MRI burden of disease than patients who initially received placebo.

These findings from the PRISMS extension studies suggest, but do not establish, that earlier subcutaneous interferon beta-1a therapy in patients with RRMS results in sustained long-term benefits compared with later therapy. Definitive conclusions are precluded by limitations of these studies, including lack of a control group, open label treatment with unblinded and retrospective assessment of clinical events, and large numbers of patients lost to follow-up [20].

A head to head comparison study (the EVIDENCE trial) enrolled 677 patients who were randomly assigned to receive Rebif (44 mcg three times weekly injection) or Avonex (30 mcg once weekly injection) [21]. Relapse was less frequent with Rebif (25 versus 37 percent), and the mean number of active unique MRI lesions per patient per scan was fewer (0.17 versus 0.33). However, treatment with Rebif was associated with a substantially higher rate of developing neutralizing antibodies (25 versus 2 percent). The percentage of relapse-free patients, the primary outcome measure, was significantly decreased in the Rebif patients with neutralizing antibodies.

In addition to concerns regarding neutralizing antibody formation, there were several criticisms of the EVIDENCE trial: the subjects were not blind to treatment assignment, the duration was relatively short (six months), disability was not used as an outcome measure, and different doses, frequencies, and routes of administration were compared [22,23].

In an extension of the EVIDENCE trial, patients who changed from low-dose interferon beta-1a (30 mcg once weekly injection) to high-dose interferon beta-1a (44 mcg three times weekly injection) experienced a statistically significant (50 percent) decrease in the annualized relapse rate, while patients continuing on high-dose interferon beta-1a experienced a nonsignificant (26 percent) decrease [24]. The higher dose of interferon beta-1a was associated with an increased rate of adverse effects.

Peginterferon beta-1a — Pegylated interferon beta-1a is formed by attaching a polyethylene glycol (PEG) group to the N terminus of interferon beta-1a [25]. Pegylation can improve some pharmacodynamic properties, including a longer half-life and consequently a reduced dosing frequency [25,26]. Peginterferon beta-1a was approved for the treatment of RRMS in Europe and the United States based upon findings from the ADVANCE trial, which randomly assigned 1512 adults with RRMS in a 1:1:1 ratio to treatment with subcutaneous peginterferon 125 mcg once every two weeks, peginterferon 125 mcg once every four weeks, or placebo [27]. At 48 weeks, the annualized relapse rates for the peginterferon every two-week group, the every four-week group, and placebo group were 0.256, 0.288, and 0.397, respectively. The corresponding relative risk reduction for the group receiving pegylated interferon every two weeks versus the placebo group was 0.64 (95% CI 0.50-0.83), while the absolute risk reduction was 0.14. Peginterferon treatment also led to statistically significant improvements on a number of other outcome measures, including a slight reduction in sustained disability progression and a reduction in several MRI measures of brain lesion activity. The preparation was generally well tolerated; the most common adverse events were injection-site reactions, influenza-like illness, and headache.

These results suggest that peginterferon beta-1a is effective for the treatment of RRMS. Because it requires fewer injections, peginterferon beta-1a may be better tolerated than nonpegylated interferon beta formulations. However there are no data directly comparing pegylated with non-pegylated formulations, and longer-term studies are needed to confirm the benefit and safety of peginterferon beyond the first year.

Long term benefit — The benefit of long-term treatment with interferon beta (IFNB) preparations for RRMS remains unproven. As reviewed above, randomized controlled trials of these agents provide evidence of benefit only for the relatively short duration (generally two years) of the trials. Results from a number of clinical trial extension studies suggest that there is continued benefit of IFNB treatment beyond two years [10,18,19]. However, definitive conclusions are precluded by limitations of these studies, which involve uncontrolled open-label treatment with unblinded and retrospective assessment of clinical events, and often large numbers of patients lost to follow-up. Long-term blinded randomized controlled trials of IFNB therapy for RRMS are ideally suited to settling this issue, but are considered impractical and possibly unethical [28].

Long-term observational studies are more practical but are similarly limited by nonrandomized retrospective methodology. These studies too have provided no convincing evidence that IFNB treatment for MS prevents long-term disability.

Propensity score weighting, a statistical method proposed to reduce the effects of bias in observational studies [29-31], was employed in an uncontrolled prospective observational study of 1504 patients with RRMS, in which 1103 patients were treated with various IFNBs (Betaferon, Avonex, and two different dose regimens of Rebif) and 401 were untreated [32]. At a median follow-up of 5.7 years, IFNB treatment compared with no IFNB treatment was associated with a significant reduction in the probability of worsening to secondary progressive MS (hazard ratio [HR] 0.38, 95% CI 0.24-0.58), and significant reductions in the probability of progressing to an Expanded Disability Status Scale (EDSS) score of ≥4 (HR 0.7, 95% CI 0.53-0.94) or EDSS ≥6 (HR 0.6, 95% CI 0.38-0.95). However, this study was criticized for being subject to "immortal time bias" related to different definitions of cohort entry for treated and untreated groups [33]. Patients not treated with IFNB were entered at the time of their first admission to the MS center, whereas treated patients were entered at the time of first administration of IFNB after admission; the time between admission and first administration of IFNB constitutes "immortal time," during which no outcome event could occur without excluding the patient from analysis. In contrast, the IFNB-untreated patients could experience outcome events immediately after admission, thereby artificially inflating the outcome rate for untreated patients.

A subsequent uncontrolled observational study analyzed patients with RRMS registered in a database, including 868 treated with IFNBs, 829 contemporary controls eligible for but not treated with IFNBs, and 959 historical controls eligible for IFNBs prior to approval (April 1985 to June 1995) and therefore not treated [34]. The median follow-up times for the treated, contemporary, and historical control groups were 5.1, 4.0, and 10.8 years, respectively. In adjusted regression analysis, with IFNB exposure as a time-dependent variable, there was no statistically significant relationship between IFNB-exposed time and the risk of reaching an EDSS score of 6 (ie, loss of ability to walk 100 m unaided) when the IFNB-treated patients were compared with contemporary controls (HR 1.30, 95% CI 0.92-1.83) or historical controls (HR 0.77, 95% CI 0.58-1.02). The findings were similar when the analysis included propensity score adjustment. The trend towards a more favorable outcome for the contemporary control group may be attributable to "indication bias," whereby patients with mild disease were not treated with IFNBs [34]. Additional limitations of this study include the inability to account for the impact of IFNB neutralizing antibodies, to compare outcomes associated with different IFNBs, or to consider the effect of switching among IFNBs.

Side effects of interferons — Interferons have significant side effects. Reactions at the injection site are common and can include injection site necrosis. Flu-like symptoms are also common and may be treated with ibuprofen, acetaminophen, and glucocorticoids [35]. Acetaminophen may also be used to treat these symptoms, but its routine use should probably be avoided as it may increase the risk of liver dysfunction associated with IFNB use. Flu-like symptoms and depression tend to diminish with time.

There is a high prevalence of mainly asymptomatic liver dysfunction associated with IFNB therapy:

A postmarketing retrospective review of patients with MS prescribed a beta-interferon found new elevations of alanine aminotransferase (ALT) in 243 (37 percent) of 659 patients [36]. All of the IFNB drugs caused elevated ALT levels. Their relative effect on ALT was approximated as interferon beta-1b SC (Betaseron) = interferon beta-1a SC (Rebif) > interferon beta-1a IM (Avonex). Liver function test abnormalities were typically minimal, but they were mild to moderate in 4 to 7 percent and severe in 1 to 2 percent. The risk was increased with male sex, obesity, alcohol use, and simultaneous use of other medications (eg, acetaminophen).

An analysis of pooled data from six clinical trials of interferon beta-1a in patients with MS, as well as postmarketing surveillance data, found asymptomatic and dose-related elevations of ALT at 24 months in up to 67 percent of patients taking interferon beta-1a [37]. More than 50 percent of elevations in liver enzymes occurred during the first three months of treatment, and more than 75 percent occurred during the first six months. Most of the elevated liver enzyme levels resolved spontaneously or with dosage adjustment. By two years, abnormal liver enzyme levels in those receiving interferon beta-1a (Rebif) 44 mcg three times weekly declined to 11 percent, compared with 6 percent of placebo-treated patients. Hepatic adverse effects led to discontinuation of interferon beta-1a treatment in only 0.4 percent of patients.

Serious hepatotoxicity associated with IFNB is rare. Nevertheless, the potential risk of using Avonex in combination with known hepatotoxic drugs or other products (eg, alcohol) should be considered prior to interferon beta-1a administration, or when adding new agents to the regimen of patients already on interferon beta-1a.

Other reactions possibly related to IFNB therapy have been reported, including leukopenia, anemia, and suicide. A partially reversible polyneuropathy was described in a small series of patients with MS who were treated with IFNB therapy [38]. In addition, there have been a few reports of thrombotic microangiopathy associated with the use of interferon beta-1a (Rebif) [39,40].

Periodic monitoring of complete blood count, liver function and thyroid function is suggested for patients on IFNB therapy, but the optimal frequency of monitoring has not been established. It is unclear whether monitoring these laboratory studies is helpful for detecting and avoiding the rare cases of serious IFNB-related toxicity. We suggest checking liver function tests monthly for six months after initiating therapy. We also suggest decreasing the IFNB dose by 50 percent if leukopenia develops or if transaminases are persistently elevated (three to five times normal) in the absence of another identifiable cause (eg, illness, a new medication, or alcohol intake). Monitoring should then be continued for another six months.

Interferon response status — Responsiveness to IFNB treatment may vary among treated individuals. Patients with MS who have ongoing disease activity despite IFNB treatment have been termed nonresponders, but this classification is not clearly defined given the highly variable course of MS disease activity and the modest effectiveness of IFNB treatment.

No validated measures exist to classify IFNB responsiveness. A study of 200 patients with RRMS and 62 patients with relapsing secondary progressive multiple sclerosis (SPMS) found that older age and longer disease duration were associated with responsiveness [41]. Responders with RRMS had a higher relapse rate during the year prior to IFNB therapy, and responders with SPMS had a higher EDSS score at initiation of IFNB treatment. The authors concluded that patients with relapsing MS who respond to IFNB have more inflammatory and less neurodegenerative disease at the time IFNB is initiated than do nonresponders [41].

Potential biologic [42-47] and radiologic [46,48] markers of IFNB responsiveness have also been examined, such as myxovirus resistance protein A (MxA). The clinical utility of these markers remains to be proven.

Results from a small randomized trial suggest that the addition of statin therapy leads to increased disease activity in patients with RRMS who are on IFNB treatment, but more data are needed clarify the effect of statins in patients with MS. (See 'Statins' below.)

Neutralizing antibodies — Accumulating evidence suggests that the development of neutralizing antibodies (NAbs) can limit the effectiveness of interferons as measured by MRI activity, relapses, and disease progression [49-53]. All of the interferons are capable of stimulating the production of NAbs, which reduce the bioavailability of interferon [54].

The rate of NAb formation varies with the type of interferon, the dosing regimen, and duration of IFNB therapy, as supported by the following observations [55,56]:

In a comparative study that tested sera from 125 patients, the risk of antibody formation over 18 months of treatment was highest with interferon beta-1b (Betaseron), intermediate with interferon beta-1a (Rebif), and lowest with interferon beta-1a (Avonex) (31, 15, and 2 percent, respectively) [55].

In a study of 455 patients with MS treated with different IFNB preparations and followed from six up to 78 months, the probability of remaining free of a positive NAb test decreased over time [56]. Overall, NAb status was definitely positive (at least two consecutive positive samples) in 41 percent, fluctuating in 7 percent, and persistently negative in 52 percent. The cumulative probability of becoming definitely Nab positive was about 60 percent for interferon beta-1b (Betaseron) and interferon beta-1a (Rebif) treatment, while the probability was significantly lower for interferon beta-1a (Avonex) at about 20 percent.

Of those who were definitely NAb positive, spontaneous reversion to NAb negative status over several years occurred in 34 percent [6]. Reversion to NAb negative status was significantly more likely to occur with interferon beta-1b (Betaseron) than interferon beta-1a (Rebif) (52 versus 19 percent, respectively). Only seven patients treated with interferon beta-1a (Avonex) were definitely NAb positive, precluding their inclusion in this analysis.

Patients who remained NAb negative for at least 24 months of IFNB therapy were unlikely to develop NAb positivity [56].

The administration of larger protein loads associated with interferon beta-1b (Betaseron) treatment may be more likely to lead to the reestablishment of immune tolerance and reversion to negative NAb status [57].

These findings may have implications for the choice of therapy. While using interferon beta-1a (Avonex) administered once weekly to avoid the NAb problem is a viable strategy, interferon beta-1a (Avonex) has a lower cumulative biologic activity than both interferon beta-1a (Rebif) administered three times a week or interferon beta-1b (Betaseron) administered every other day, suggesting that there is no single drug that has optimal effectiveness with minimal NAb formation [58].

Neutralizing antibody and MxA testing — The negative impact of NAbs on relapses and disease progression has led some experts to call for NAb testing in clinical practice at 12 and 24 months of interferon beta (IFNB) therapy [59,60]. The proposed role of testing would be mainly predictive, with positive NAb status identifying patients who are more likely to fail IFNB therapy than those who are NAb negative. However, national guidelines and expert opinion are conflicting regarding the utility of NAb testing.

An evidence-based review of NAbs published in 2007 by the American Academy of Neurology (AAN) concluded that there is insufficient information on the utilization of NAb testing to provide recommendations regarding which test to use, when to test, how many tests are needed, and what cutoff titer to apply [53].

Evidence-based guidelines from the European Federation of Neurological Societies (EFNS) published in 2005 recommend that all patients undergo NAb testing at 12 and 24 months [61]. The EFNS further recommends discontinuing IFNB therapy in patients with sustained high NAb titers at repeated measurements with three to six month intervals.

A European expert panel report published in 2010 concluded that information about NAbs and markers of IFNB biologic activity such as myxovirus resistance protein A (MxA) can be used to guide individual treatment decisions as follows [62]:

NAb and MxA measurements should have "therapeutic consequences," even for stable patients with low MS disease activity. For those with sustained high NAb titers and/or a lack of MxA bioactivity, a switch to non-IFNB therapy should be considered.

In the setting of intermediate MS disease activity, continuation of IFNB therapy could be considered for patients who are NAb-negative, whereas a switch to non-IFNB therapy should be suggested for those with high NAb titers and/or lack of MxA bioactivity.

In the setting of high disease activity, therapy should be changed independent of Nab or MxA results. For patients who have NAb titers, a switch to a non-IFNB therapy would be indicated. For those with absent Nab titers, some panel members felt that a switch to another IFNB product (ie, from a low dose/frequency IFNB to a higher dose/frequency IFNB) could still be an option.

In our view, further trials incorporating therapeutic interventions based on NAb status seem warranted before Nab or MxA testing can be widely recommended for patients with MS receiving IFNB therapy.

Clinically isolated syndromes — Interferon beta-1a (Avonex and Rebif) and interferon beta-1b (Betaseron/Betaferon) treatment has shown benefit in randomized controlled trials for patients experiencing a first clinical demyelinating event suggestive of MS. This issue is discussed in detail elsewhere. (See "Clinically isolated syndromes suggestive of multiple sclerosis", section on 'Treatment'.)

GLATIRAMER — Glatiramer acetate (copolymer 1) is a mixture of random polymers of four amino acids. The mixture is antigenically similar to myelin basic protein, a component of the myelin sheath of nerves. In experimental models, the immunomodulatory mechanism of action for glatiramer involves binding to major histocompatibility complex molecules and consequent competition with various myelin antigens for their presentation to T cells [63]. In addition, glatiramer is a potent inducer of specific T helper 2 type suppressor cells that migrate to the brain and lead to bystander suppression; these cells also express antiinflammatory cytokines.

The following trials demonstrated the effectiveness of glatiramer in RRMS [64]:

The benefit of glatiramer acetate was first established in a double-blind trial of 251 patients with RRMS [65]. At two years, patients treated with glatiramer acetate (20 mg subcutaneously daily) had a significantly lower relapse rate than those receiving placebo (1.19 versus 1.68) [65]. Furthermore, over 140 weeks, a significantly larger proportion of patients in the placebo group experienced increased disability by ≥1.5 steps on the Expanded Disability Status Scale (EDSS) compared with the treatment group (41 versus 22 percent) [66].

Another trial with 239 patients found that glatiramer acetate treatment led to a significant reduction in the number of new T2 lesions on brain MRI [67].

Dosing and side effects of glatiramer — Glatiramer acetate is administered at 20 mg daily by subcutaneous injection. Alternate dosing regimens (ie, 40 mg subcutaneously three times a week [68]) may also be effective but are not as well studied.

Side effects of glatiramer acetate include local injection site reactions and transient systemic postinjection reactions such as chest pain, flushing, dyspnea, palpitations, and/or anxiety. No laboratory monitoring is necessary. Neutralizing antibodies to glatiramer acetate have been detected in some studies but their clinical significance is unknown [69]. Desensitization to glatiramer acetate has been successfully performed in patients with either systemic allergic reactions or recurrent local reactions [70].

Glatiramer acetate is categorized as pregnancy category B, while both Avonex and Betaseron are category C (table 1). However, the clinical importance of this difference may be small, since treatment with all three drugs is discontinued when pregnancy occurs, and relapses during pregnancy are treated with intravenous (IV) glucocorticoids.

Trials comparing interferons with glatiramer — The available evidence from controlled trials suggests that interferons and glatiramer have similar clinical utility [71]. As an example, the blinded BEYOND trial randomly assigned patients with early RRMS in a 2:2:1 ratio to either interferon beta-1b (n = 1796) at 250 mcg or 500 mcg or to glatiramer acetate (n = 448) [72]. Patients were followed for at least two years. There were no differences among treatment groups for relapse risk, disease progression, or MRI measures of lesion burden. Flu-like symptoms were more common with interferon beta-1b, while injection site reactions were more frequent with glatiramer acetate.

ALEMTUZUMAB — Alemtuzumab is a humanized monoclonal antibody that causes depletion of CD52-expressing T cells, natural killer cells, and monocytes. Data from randomized controlled trials show that alemtuzumab is more effective than interferon beta-1a for reducing the relapse rate in relapsing-remitting MS (RRMS). This benefit is associated with a small increased risk of potentially serious infections and autoimmune disorders, including immune thrombocytopenia (ITP) [73-75].

CARE-MS I was a rater-blind trial that evaluated over 550 adults with RRMS, low disability levels, and no prior disease modifying therapy [74]. Subjects were randomly assigned to either alemtuzumab or subcutaneous interferon beta-1a (44 mcg three times per week) in a 2:1 ratio. Alemtuzumab was infused intravenously at 12 mg daily for five days at the start of treatment and for three days at 12 months. At two years, alemtuzumab significantly reduced the proportion of patients with any relapse (22 percent, versus 40 percent for interferon beta-1a, rate ratio 0.45, 95% CI 0.23-0.63) and the annualized relapse rate (0.18 versus 0.39). However, there was no significant difference between groups for sustained accumulation of disability (8 versus 11 percent). Imaging outcomes were mixed; there was no significant difference between groups for median change in volume of T2-hyperintense brain lesions, but the alemtuzumab group had significantly fewer new or enlarging T2-hyperintense lesions, and fewer gadolinium-enhancing lesions.

The similar CARE-MS II trial evaluated nearly 800 adults with RRMS and at least one relapse while on treatment with interferon beta-1a or glatiramer [75]. At two years, alemtuzumab significantly reduced the proportion of patients with any relapse (35 percent, versus 53 percent for interferon beta-1a, rate ratio 0.52 (95% CI 0.39-0.65) and the annualized relapse rate (0.26 versus 0.52). Unlike CARE-MS I, the alemtuzumab group in CARE-MS II had a significantly lower rate of sustained accumulation of disability (13 versus 20 percent, hazard ratio 0.58, 95% CI 0.38-0.87). Similar to CARE-MS I, the imaging outcomes in CARE-MS II showed no significant difference between groups for median change in volume of T2-hyperintense brain lesions, but the alemtuzumab group had significantly fewer new or enlarging T2-hyperintense lesions, and fewer gadolinium-enhancing lesions

The main side effects of alemtuzumab in these and earlier trials were infusion reactions, infections, and autoimmune disorders [73-76]. Infusion reactions occurred in approximately 90 percent of patients and were characterized by headache, rash, nausea, and fever. Infections, though generally not severe, were observed in two-thirds or more of the patients treated with alemtuzumab. Herpes viral infections occurred in 16 to 18 percent, leading to a change in the protocol of the in-progress CARE-MS trials with the addition of prophylactic acyclovir treatment during alemtuzumab infusion and for 28 days after infusion [74,75]. Thyroid autoimmunity was seen in 16 to 18 percent of patients at two years after alemtuzumab treatment [74,75], and in 30 percent with longer follow-up [76]. Immune thrombocytopenia developed in 1 percent of patients at two years [74,75], and in 3 percent at three years [73,76].

Alemtuzumab received marketing approval for the treatment of RRMS in Europe in September 2013 [77], and was also approved in Canada, Australia, and Mexico. In the United States, the drug was approved in November 2014 [78]. Although its precise role in the management of RRMS is not yet settled, alemtuzumab will be a second-line agent for patients with RRMS who have an inadequate response to treatment with interferons and glatiramer or other medications. In the United States, treatment with alemtuzumab requires special registration through a restricted distribution program (the Lemtrada Restricted Evaluation and Mitigation Strategy or REMS) for both the center and patient in order to ensure adequate follow-up [79].

Alemtuzumab is administered via intravenous (IV) infusion at 12 mg daily for five consecutive days (total 60 mg) at the start of treatment followed 12 months later by 12 mg daily for three consecutive days (total 36 mg). Patients in the clinical trials received premedication with glucocorticoids (1 g of methylprednisolone) for the first three days of therapy. Alemtuzumab therapy requires monitoring for infusion reactions and prophylaxis for herpes virus infections (oral acyclovir 200 mg twice daily) and Pneumocystis jirovecii pneumonia (PCP) (eg, trimethoprim-sulfamethoxazole 80 to 160 mg daily) during treatment and for several weeks after treatment. (See "Treatment and prevention of Pneumocystis pneumonia in non-HIV-infected patients", section on 'Prophylaxis'.)

Prolonged surveillance for bone marrow suppression, infections, and autoimmune disorders such as immune thrombocytopenia is also necessary.

DIMETHYL FUMARATE — Fumarates may have neuroprotective and immunomodulatory properties. In two large trials, an oral formulation of dimethyl fumarate (BG-12) significantly reduced relapse rates and the development of new brain lesions on MRI in patients with active MS [80,81], and results from one of these trials suggest that BG-12 reduces the rate of disability progression [81].

The CONFIRM trial randomly assigned over 1400 adults with relapsing-remitting multiple sclerosis (RRMS) to treatment with oral BG-12 at 480 mg daily in two divided doses, oral BG-12 at 720 mg daily in three divided doses, subcutaneous glatiramer acetate 20 mg daily, or placebo in a 1:1:1:1 ratio [80]. At two years compared with placebo, the annualized relapse rate was significantly lower in groups assigned to BG-12 480 mg daily, BG-12 720 mg daily, and glatiramer (0.22, 0.20, and 0.29, versus 0.40 for placebo). In addition, the number of new or enlarging brain lesions by MRI was significantly reduced for groups assigned to both doses of BG-12 and to glatiramer compared with placebo. There was a trend towards lower rates of disability progression with BG-12 and glatiramer treatment, but the differences compared with placebo were not statistically significant. In post hoc analyses comparing BG-12 with glatiramer, there were no significant differences in relapse rates or MRI outcomes.

The DEFINE trial randomly assigned over 1200 adults with RRMS to oral BG-12 at 480 mg daily in two divided doses, oral BG-12 at 720 mg daily in three divided doses, or placebo [81]. At two years, treatment with BG-12 480 mg daily and 720 mg daily resulted in significant reductions in the proportion of patients who had a relapse (27 and 26 percent, versus 46 percent for placebo), the annualized relapse rate (0.17 and 0.19, versus 0.36 for placebo), and the proportion of patients with progression of disability (16 and 18 percent, versus 27 percent for placebo). BG-12 treatment also significantly reduced the number of new brain lesions on MRI.

The most common side effects of BG-12 in these trials were flushing and gastrointestinal symptoms, including diarrhea, nausea, and abdominal pain.

Dimethyl fumarate was approved for marketing in the United States, Canada, and Australia in 2013, and in the European Union in 2014 [82,83]. The starting dose for oral dimethyl fumarate is 240 mg daily given in two divided doses. After seven days, the dose should be increased to 480 mg daily in two divided doses. Treatment with dimethyl fumarate may decrease lymphocyte counts, so patients should have a complete blood count obtained within six months of starting the medication and at least annually or as clinically indicated during the course of treatment. Dimethyl fumarate should be discontinued if lymphocytopenia develops. There is a case report of a patient taking dimethyl fumarate for over four years who developed a fatal case of progressive multifocal leukoencephalopathy (PML) in the setting of severe, prolonged lymphocytopenia [84,85]. Dimethyl fumarate has not been studied in patient with pre-existing low lymphocyte counts.

FINGOLIMOD — Fingolimod is sphingosine analogue that modulates the sphingosine-1-phosphate receptor and thereby alters lymphocyte migration, resulting in sequestration of lymphocytes in lymph nodes [86]. There is evidence from two large controlled trials that fingolimod is effective for reducing the relapse rate in patients with relapsing-remitting MS (RRMS). However, this benefit is associated with an increased risk of life-threatening infection.

The FREEDOMS trial randomly assigned 1272 adults with RRMS to treatment in a 1:1:1 ratio with either oral fingolimod (0.5 mg daily or 1.25 mg daily) or placebo [87]. At 24 months, the following observations were reported:

The annualized relapse rate, the primary outcome measure, was significantly reduced on intention-to-treat analysis for both the high and low fingolimod groups compared with placebo (0.18, 0.16, and 0.40 respectively). In addition, fingolimod treatment resulted in statistically significant reductions in both the risk of sustained disability progression and new lesions on brain MRI.

The incidence of serious infections and herpes virus infections were similar in the fingolimod and placebo groups.

Macular edema developed in seven patients in the high-dose fingolimod group.

The TRANSFORMS trial randomly assigned over 1200 adults with RRMS to treatment with either oral fingolimod (0.5 mg daily or 1.25 mg daily) or intramuscular interferon beta-1a (30 mcg weekly) in a 1:1:1 ratio [88]. At 12 months, the following outcomes were noted:

In the cohort of subjects who received at least one dose of a study drug, the annualized relapse rate, the primary end point, was significantly lower in both the high and low dose fingolimod groups than in the interferon beta-1a group (0.20, 0.16, and 0.33, respectively). MRI measures also favored fingolimod. Progression of disability was infrequent in all three groups.

There were more serious adverse events in the fingolimod groups. These included two deaths in the high-dose fingolimod group (one from disseminated varicella-zoster infection and the other from herpes simplex encephalitis) versus none for interferon beta-1a group. In addition, 12 patients on fingolimod developed skin or breast cancer (versus one in interferon beta-1a group), and 19 developed dose-related bradycardia or atrioventricular block (versus none assigned to interferon beta-1a).

In a preliminary randomized trial that evaluated 255 patients with relapsing MS, treatment with oral fingolimod (1.25 mg daily or 5.0 mg daily) resulted in a significant reduction in the total number of gadolinium-enhancing lesions on brain MRI at six months (the primary endpoint) compared with placebo [89]. One patient in the fingolimod treatment group developed a reversible posterior leukoencephalopathy.

Thus, oral fingolimod is an effective disease-modifying agent for RRMS, but its use is associated with a risk of varicella-zoster virus infections, potentially fatal, and tumor development.

In subsequent reports, fingolimod treatment has been linked to the following adverse events:

Additional varicella-zoster virus (VZV) infections [90,91]. In pooled data from randomized trials, the incidence of VZV infections, though low overall, was higher in patients assigned to fingolimod compared with those assigned to placebo (11 versus 6 per 1000 patient-years); in postmarketing data from over 60,000 patients who received fingolimod, the incidence of VZV was 7 per 1000 patient-years [92].

Paradoxical worsening of MS disease activity with severe MS relapses (some following cessation of natalizumab) or the development of tumefactive MS lesions [93-95]. In one case, marked exacerbation of MS activity was observed after fingolimod was withdrawn due to the development of severe herpes zoster infection [90].

Progressive multifocal leukoencephalopathy (PML) in a patient diagnosed with possible MS who had not received natalizumab but had treated with fingolimod for nearly eight months [96]. The patient had also been treated with interferon beta-1a and azathioprine for one month prior to starting fingolimod and had received multiple courses of glucocorticoids before and during fingolimod treatment. Therefore, it is not clear if the development of PML was related to fingolimod treatment.

These reports suggest but do not establish that fingolimod can cause or contribute to paradoxical worsening of MS disease activity, and further support the likelihood that the immunomodulating and lymphocytopenic effects of fingolimod increase the risk of viral infection.

Another concern is that 11 deaths (4 due to cardiac events and 7 unexplained) were linked to the use of fingolimod internationally as of late February 2012 [97,98]. A preliminary review by the FDA concluded that the contribution of fingolimod to these deaths is unclear, and that the number of reported deaths due to cardiovascular or unknown origin did not appear to be higher than in patients with MS who were not taking fingolimod [99].

Thus, additional data are needed to determine both the risk profile and the optimal dose of oral fingolimod for RRMS.

Clinical use of fingolimod — Even before concerns arose about the fingolimod-linked deaths discussed above, some experts believed that fingolimod should be reserved for patients who have an inadequate response to treatment with beta interferons or glatiramer acetate, at least until long-term safety data are available for fingolimod [100].

Contraindications to fingolimod include patients with recent (within six months) myocardial infarction, unstable angina, stroke, TIA, or heart failure, a history of second or third degree atrioventricular block or sick sinus syndrome (unless treated with a pacemaker), a prolonged QT interval at baseline, or treatment with anti-arrhythmic drugs [99,101]. Since the trials of fingolimod excluded patients with diabetes, we suggest not using fingolimod to treat patients who have diabetes.

The most common side effects associated with fingolimod include headache, influenza, diarrhea, back pain, elevated liver enzymes, and cough [101]. Less common but potentially serious adverse events associated with fingolimod include bradyarrhythmia and atrioventricular block (potentially fatal), macular edema [102], diminished respiratory function, and tumor development.

Before starting fingolimod, patients should have the following [101]:

Complete blood count and liver function test (LFT) results within six months

Electrocardiogram (ECG)

Ophthalmologic examination

Varicella serology and varicella zoster virus vaccination if antibody negative for those without a history of chicken pox or prior vaccination; fingolimod should not be started until one month after vaccination

Women of childbearing potential should be informed of risk for adverse fetal outcomes

In addition, we suggest a skin examination at baseline to screen for evidence of precancerous skin lesions.

The first dose of fingolimod should be given in a setting where symptomatic bradycardia can be managed [99,101]. At treatment initiation, baseline pulse and blood pressure should be measured. These measurements should be repeated hourly for six hours after the first dose while the patient is observed for signs of bradycardia or atrioventricular block, and an ECG should be obtained at the end of the six hour observation period. For patients who are at higher risk for bradycardia or who may not tolerate it, cardiovascular monitoring should be extended overnight using continuous ECG monitoring. Patients who develop symptomatic bradycardia or atrioventricular block (second degree or higher) should be managed appropriately and monitored with continuous ECG until the symptoms resolve.

During fingolimod treatment (and for two months after stopping), patients should be monitored for symptoms and signs of infection, and live attenuated vaccines should be avoided [101]. Ophthalmologic examination should be repeated three to four months after starting fingolimod, and routinely in patients with diabetes mellitus or a history of uveitis. Pulmonary function testing with spirometry and diffusion lung capacity for carbon monoxide (DLCO) should be obtained if indicated clinically, and LFTs should be monitored for patients with symptoms suggestive of hepatic dysfunction.

Fingolimod is pregnancy class C and should be stopped two months prior to conception.

NATALIZUMAB — Natalizumab is an effective drug for the treatment of relapsing-remitting MS (RRMS). However, it not a first-line agent because its use is rarely associated with the development of progressive multifocal leukoencephalopathy, a potentially fatal complication. Natalizumab should be reserved for patients with active RRMS that is refractory or resistant to beta interferons and glatiramer acetate, and for patients who are intolerant of these medications [103]. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults" and 'Refractory disease' below.)

TERIFLUNOMIDE — The immunomodulator teriflunomide is the active metabolite of leflunomide that inhibits pyrimidine biosynthesis and disrupts the interaction of T cells with antigen presenting cells [104].

In a preliminary randomized controlled trial involving 179 patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS), oral teriflunomide was effective in reducing MRI lesions compared with placebo and was well tolerated [105].

A larger trial of 1088 adults (ages 18 to 55) with relapsing MS found that teriflunomide (either 7 mg or 14 mg once daily for just over two years) significantly reduced the annualized relapse rate by approximately 31 percent compared with placebo [106]. In addition, teriflunomide at the higher dose (14 mg daily) significantly reduced disability progression compared with placebo (27 versus 20 percent) and improved MRI measures of MS disease activity. This trial has been criticized due to a relatively high dropout rate (approximately 27 percent) [107].

The most common adverse effects of teriflunomide were diarrhea, nausea, hair thinning, and elevated alanine aminotransferase (ALT) levels [105,106].

Because of the risk of hepatotoxicity, patients with known liver disease should not be treated with teriflunomide. The manufacturer recommends obtaining baseline transaminase and bilirubin levels before starting treatment with teriflunomide, and to monitor ALT levels monthly for at least six months once treatment is started. The drug should be discontinued if drug-induced liver injury is suspected.

Teriflunomide is pregnancy category X [108]. Due to the risk of teratogenicity, teriflunomide is contraindicated for women who are pregnant or trying to conceive, and women of childbearing age must have a negative pregnancy test before starting the drug. Teriflunomide is also found in semen [109]. Thus, men and women who wish to conceive a child should discontinue teriflunomide and undergo an accelerated drug elimination procedure using cholestyramine or activated charcoal powder for 11 days. Otherwise, teriflunomide may remain in the serum for up to 2 years. Pregnancy should be avoided until the serum concentration of teriflunomide is <0.02 mg/L.

We suggest oral teriflunomide 7 mg daily for men or postmenopausal women with RRMS who don’t want treatment with the better established MS therapies (eg, interferons and glatiramer acetate) that require injection.

MITOXANTRONE — Mitoxantrone is approved for use in both relapsing-remitting and progressive forms of MS. However, guidelines published in 2003 by the American Academy of Neurology recommended that, because of cardiac toxicity and the limited evidence of benefit, mitoxantrone should be reserved for patients with rapidly advancing disease who have failed other therapies [110]. In addition, mitoxantrone treatment is associated with a low risk of developing therapy-related acute leukemia [111-113]. (See "Treatment of progressive multiple sclerosis in adults", section on 'Mitoxantrone'.)

Patients older than age 50, those with long-standing disability, and those with substantial spinal cord atrophy may be less likely to respond to intense immunosuppression with agents such as mitoxantrone than patients without these characteristics [114].


Azathioprine — Early trials of azathioprine for MS were small and conflicting [115-117]. Nevertheless, in a meta-analysis that identified five randomized controlled trials involving 698 patients with MS, azathioprine compared with placebo was associated with a statistically significant reduction in the number of patients who had MS relapses during the first, second, and third years of treatment; relative risk reductions for these periods were 20, 23, and 18 percent, respectively [118]. Approximately 55 percent of the pooled patients included in the meta-analysis had relapsing-remitting MS (RRMS), while the remainder had progressive forms of MS; all of the trials were published prior to 1994.

Few studies have evaluated azathioprine for MS in the modern MRI era. One small, open-label study found that azathioprine up to 3 mg/kg per day was well tolerated and reduced the rate of new gadolinium-enhancing brain lesions in patients with RRMS [119]. The benefit and tolerability of azathioprine for patients with RRMS requires confirmation in larger blinded, randomized trials.

CCSVI treatment — Venous angioplasty and venous stent placement have been proposed as a treatment for chronic cerebrospinal venous insufficiency (CCSVI), a controversial condition, largely disproven, characterized by putative anomalies of cerebrospinal veins that interfere with venous drainage from the brain. (See "Pathogenesis and epidemiology of multiple sclerosis", section on 'Alternate theories'.)

Endovascular interventions for CCSVI, sometimes referred to as "liberation procedures," are also largely disproven. In a double-blind, controlled trial that randomly assigned patients with MS to venous angioplasty (n = 9) or sham angioplasty (n = 10), there was no benefit of the procedure [120]. Earlier open-label studies reported that percutaneous transluminal venoplasty was associated with significant improvement in some MS outcome measures [121,122]. The methodologic limitations of these studies include small patient numbers, lack of control groups, and open-label designs [123]. In addition, such endovascular interventions are not benign, and there were several reports of death following stent placement for the treatment of CCSVI [124-126].

Given the evidence that invasive treatments for CCSVI are not beneficial, and reports of harm with such treatments, we recommend not using endovascular venoplasty or stenting procedures to treat patients with MS for presumed CCSVI [127].

Cladribine — Cladribine, an immunosuppressive agent that targets lymphocyte subtypes, appears to reduce the relapse rate in patients with RRMS. However, this benefit may be associated with an increased risk of life-threatening infection. Supporting evidence comes from the CLARITY trial of 1326 adults with RRMS [128]. Subjects were randomly assigned in a 1:1:1 ratio to treatment with either oral cladribine (3.5 mg/kg or 5.25 mg/kg) or placebo. At 96 weeks, the following observations were reported:

The annualized relapse rate, the primary outcome measure, was significantly reduced on intention-to-treat analysis for both the high and low cladribine groups (0.14 and 0.15 versus 0.33 with placebo). In addition, cladribine resulted in statistically significant reductions in both the risk of sustained disability progression and brain lesion count on MRI.

Lymphocytopenia, generally mild to moderate, was more frequent among those assigned to the high and low dose cladribine groups (32 and 22 versus 2 percent with placebo).

One patient treated in the cladribine group developed a fatal reactivation of latent tuberculosis, while 20 developed nonfatal reactivation of latent herpes zoster infection. In addition, benign or malignant neoplasms developed in 10 patients assigned to cladribine and none assigned to placebo. One patient in the cladribine group died of pancreatic cancer. Overall, the incidence of serious adverse events was higher in the cladribine than placebo groups (9 versus 6 percent).

Thus, oral cladribine is a promising disease-modifying agent for RRMS, but further research is needed to better define the risk of infection and tumor development associated with its use.

The evidence regarding cladribine for progressive forms of MS is reviewed separately. (See "Treatment of progressive multiple sclerosis in adults", section on 'Cladribine'.)

Cyclophosphamide — Limited observational evidence supports the use of pulse (eg, monthly) intravenous (IV) cyclophosphamide for RRMS [129]. There is a greater experience with pulse cyclophosphamide for progressive forms of MS, but data are conflicting regarding benefit. (See "Treatment of progressive multiple sclerosis in adults", section on 'Cyclophosphamide'.)

Another option under investigation employs high-dose cyclophosphamide as immunoablative treatment without bone marrow transplantation [130,131]. In an open-label study, nine patients with active inflammatory RRMS were treated with IV cyclophosphamide (50 mg/kg daily) for four days, followed by granulocyte colony-stimulating factor [131]. At a mean follow-up of 23 months, there was a statistically significant improvement in disability and a reduction in the mean number of gadolinium enhancing lesions compared with pretreatment, and there were no serious adverse events. However, two patients developed MS exacerbations and required rescue treatment with other immunomodulatory drugs. Larger studies are needed to determine the effectiveness and safety of this approach, and it is not recommended for use outside of clinical trials.

Daclizumab — Daclizumab is a humanized monoclonal antibody that has specific binding activity for the alpha chain component of the high-affinity interleukin 2 receptor.

Preliminary data from a phase 2 randomized controlled trial [132] and small open label studies [133-136] in patients with RRMS and secondary progressive MS suggest that adjunct daclizumab treatment is well tolerated and is associated with reductions in MRI evidence of disease activity.

The SELECT trial, which evaluated daclizumab monotherapy, randomly assigned over 600 adults with RRMS to treatment every four weeks with subcutaneous injections of daclizumab 300 mg, daclizumab 150 mg, or placebo in a 1:1:1 ratio [137]. The daclizumab high-yield process formulation used in the trial has an identical amino-acid sequence as previous versions of daclizumab but a different glycosylation profile with a reduced antibody-dependent cellular cytotoxicity activity. At one year compared with placebo, the annualized relapse rate was significantly lower in groups assigned to daclizumab 150 mg and daclizumab 300 mg (0.21 and 0.23, versus 0.46 for placebo), corresponding to reductions of 54 percent and 50 percent, respectively. In addition, patients in the daclizumab 150 mg and 300 mg groups had significant reductions in the risk of three-month sustained disability progression (hazard ratios 0.43 and 0.57). While daclizumab was generally well-tolerated in this trial, the rate of serious infections in patients assigned to daclizumab was 2 percent, compared with no serious infections for patients assigned to placebo. One patient receiving daclizumab died from complications of a psoas abscess. In addition, more patients in the daclizumab groups had cutaneous events than in the placebo groups, and more patients in the daclizumab groups had hepatic enzyme elevations >5 times the upper limit of normal.

The findings of these studies are promising, particularly those suggesting that daclizumab reduces disability progression in patients with RRMS. However, longer-term trials are needed to confirm the efficacy and safety of daclizumab [138].

Dalfampridine — Dalfampridine (4-aminopyridine; fampridine), a potassium channel blocker, may improve walking speed in some patients with MS. This issue is discussed separately. (See "Symptom management of multiple sclerosis in adults", section on 'Dalfampridine'.)

Glucocorticoids in combination therapy — Monthly intravenous (IV) glucocorticoid bolus, typically 1000 mg of methylprednisolone, is used at many institutions for the treatment of primary or secondary progressive MS alone or in combination with other immunomodulatory or immunosuppressive medications. However, randomized trial data are limited and conflicting with respect to the use of oral or parenteral glucocorticoids in combination with interferon beta preparations for RRMS.

The MECOMBIN trial enrolled 341 treatment-naïve adults with RRMS [139]. All patients were started on interferon beta-1a treatment and after three months were randomly assigned to adjunct treatment with monthly pulses (three consecutive days per month) of oral methylprednisolone (500 mg/day) or placebo. Treatment continued for three to four years. At follow-up, the proportion of patients with sustained disability progression, the primary outcome, was no different for the methylprednisolone and placebo groups (26 versus 27 percent). The methylprednisolone group did have significant benefit on some of the secondary outcomes, including a reduction in the annualized documented relapse rate (0.21 versus 0.33, hazard ratio [HR] 0.63, 95% CI 0.47-0.84). More patients from the methylprednisolone group discontinued therapy or were lost to follow-up compared with the placebo group (51 versus 39 percent), particularly in the first year of the study, suggesting that combination therapy was not as well-tolerated.

In the ACT trial, 313 patients with RRMS and continued disease activity on intramuscular interferon beta-1a were randomly assigned to adjunctive treatment with either oral methotrexate (20 mg once a week), IV methylprednisolone (1000 mg daily for three days every other month), or both [140]. At one year, there was no statistically significant benefit for either adjunctive therapy, although there were trends suggesting modest benefit for IV methylprednisolone on some outcomes.

In the NORMIMS trial, discontinued prematurely due to slow recruitment, 130 adults with RRMS and recent relapse on subcutaneous interferon beta-1a were randomly assigned to 96 weeks of adjunctive treatment with either oral methylprednisolone (200 mg for five consecutive days every four weeks) or matching placebo [141]. On intention-to-treat analysis, oral methylprednisolone led to a significant reduction in mean yearly relapse rate (0.22 versus 0.59 with placebo, relative risk reduction 62 percent, 95% CI 39-77 percent). However, small patient numbers and a high dropout rate preclude definitive conclusions.

Thus, the role of glucocorticoids combined with beta interferons for the treatment of RRMS remains uncertain.

Intravenous immune globulin — Although data are equivocal, there is no compelling evidence that intravenous immune globulin (IVIG) is effective for patients with RRMS:

Some [142-145], but not all [146] early clinical trials reported beneficial effects for IVIG in RRMS. A systematic review that analyzed these trials concluded that IVIG is effective for reducing the proportion of patients with relapses, for reducing the mean number of annual exacerbations, and for improving disability in RRMS [147].

The 2002 American Academy of Neurology (AAN) guidelines [148], looking at essentially the same data [142-144], noted that trials of IVIG generally involved small numbers of patients, lacked complete data on clinical and MRI outcomes, or used questionable methodology [148]. The AAN concluded that IVIG is of little benefit for slowing disease progression.

A later multicenter placebo-controlled trial of 127 patients with RRMS found that IVIG treatment conferred no benefit for reducing relapses or new lesions on MRI [149].

Laquinimod — Laquinimod is a synthetic immunomodulatory compound with high oral bioavailability [150,151]. The effectiveness of oral laquinimod was evaluated in two large randomized controlled trials.

In the multicenter ALLEGRO trial, 1106 patients with RRMS were randomly assigned to oral laquinimod (0.6 mg daily) or to placebo [152]. At 24 months, oral laquinimod treatment led to a statistically significant though modest reductions in the annual relapse rate (0.30, versus 0.39 for placebo; risk ratio 0.77, 95% CI 0.65-0.91) and the risk of confirmed disability progression (11.1 versus 15.7 percent, hazard ratio 0.64, 95% CI 0.45-0.91). Laquinimod was generally well-tolerated, but transient reversible liver enzyme elevations were two-fold more frequent in the laquinimod group. The trial had a relatively high dropout rate (22 percent), which limits the strength of the findings [153].

The multicenter BRAVO trial enrolled 1331 patients with RRMS and randomly assigned them to either laquinimod (0.6 mg daily), interferon beta-1a (30 mcg weekly), or placebo in a 1:1:1 ratio [154]. Preliminary findings show that laquinimod treatment at 24 months resulted in a trend towards a reduction in the annualized relapse rate that missed statistical significance in the unadjusted analysis (0.28, versus 0.34 with placebo, risk ratio [RR] 0.82, 95% CI 0.66-1.02) [155]. In contrast, the reduction in annualized relapse rate with interferon beta-1a treatment compared with placebo was significant. However, in a prespecified analysis that adjusted for baseline imbalances on brain MRI T2 lesion volume and the number of gadolinium-enhancing lesions, laquinimod treatment led to a statistically significant reduction in annualized relapse rate (0.29 versus 0.37 for placebo, RR 0.78, 95% CI 0.64-0.97) and disability progression (hazard ratio 0.67, 95% CI 0.45-0.99). The trial was not designed to compare laquinimod with interferon beta-1a.

These trials suggest that laquinimod is modestly effective for reducing the relapse rate and disability progression for patients with RRMS.

Ocrelizumab — Ocrelizumab is a recombinant human anti-CD20 monoclonal antibody that binds to a different, but overlapping, CD20 epitope than rituximab. It was designed to optimize B cell depletion by modification of the Fc region, which enhances antibody-dependent cell-mediated cytotoxicity and reduces complement-dependent cytotoxicity compared with rituximab.

A phase 2 randomized trial of over 200 patients with RRMS demonstrated that ocrelizumab, compared with placebo, reduced the appearance of gadolinium-enhancing brain lesions on MRI by approximately 90 percent and reduced the annualized relapse rate by 70 to 80 percent [156]. In addition, ocrelizumab was better than interferon beta-1a for reducing the appearance of new gadolinium-enhancing lesions on brain MRI and the annualized relapse rate. No opportunistic infections were observed. However, the development of ocrelizumab for use in rheumatoid arthritis was halted because of safety concerns raised in clinical trials by the occurrence of opportunistic infections, including fatal infections. (See "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Ocrelizumab'.)

Rituximab — Rituximab is a monoclonal antibody directed against the CD20 antigen on B lymphocytes that causes B cell depletion. In a preliminary randomized trial of 104 adult patients with RRMS, treatment with intravenous rituximab (1000 mg) given on days 1 and 15 was associated with a significant reduction in both total and new gadolinium-enhancing lesions on brain MRI at 24 weeks when compared with placebo [157]. In addition, rituximab treatment was associated with a significant reduction in the proportion of patients who had a clinical relapse by week 24.

While these results are promising, further clinical trials are needed to establish the long-term effectiveness and safety of rituximab for RRMS [158]. Rare cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with rituximab. However, it is unknown if rituximab increases the risk of PML, since rituximab is often used to treat patients who have an underlying risk factor for PML. (See "Progressive multifocal leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis".)

Statins — Statins have immunomodulatory effects that may be beneficial in MS [159-161], but are also known to have proinflammatory effects [162]. Available clinical data regarding statins in the treatment of RRMS are not entirely consistent, but most of the studies showed no benefit [163].

The largest trial of 307 patients with RRMS found no benefit at 12 months for simvastatin as add-on therapy to interferon beta-1a [164].

A post hoc analysis of data from the SENTINEL trial found no effect of statins in patients with RRMS assigned to intramuscular interferon beta-1a monotherapy [165]. The study compared subgroups of patients taking statins (n = 40) and those not taking statins (n = 542) and found no significant differences in annualized relapse rates, disability progression, or MRI lesion burden.

A preliminary study enrolled 30 patients with active RRMS [166]. Patients were treated with open-label simvastatin 80 mg daily. Brain MRI scans obtained after four, five, and six months of treatment showed a significant decrease in the number of gadolinium-enhancing lesions compared with pretreatment brain MRI scans. These results must be interpreted cautiously because the study had no placebo group.

A small double-blind trial of patients with clinically stable RRMS receiving interferon beta-1a therapy found that the addition of atorvastatin resulted in increased clinical and MRI disease activity compared with placebo [167].

Given these findings, off-label use of statins for MS treatment is not recommended.

The evidence regarding statins for progressive forms of MS is reviewed elsewhere. (See "Treatment of progressive multiple sclerosis in adults", section on 'Simvastatin'.)

Stem cell transplantation — Autologous hematopoietic stem cell transplantation (HSCT) has been evaluated for patients with refractory RRMS in several uncontrolled studies. The goal is eliminating and replacing the patient’s pathogenic immune system to achieve long-term remission of MS [168]. The process involves mobilizing and harvesting hematopoietic stem cells from the patient’s peripheral blood or bone marrow, followed by a conditioning regimen of chemotherapy, sometimes with immune-depleting biologic agents or radiation therapy, to partially or totally ablate the patient’s immune system. The last step is infusing the harvested stem cells to regenerate the immune system.

In one case series of 156 adults with MS, mainly RRMS (n = 123), treatment with nonmyeloablative HSCT was associated with improvement in disability and other clinical outcomes at two years and four years of follow-up [169]. However, the results must be interpreted with caution due to methodologic limitations of the study; as examples, there was no control group, most patients were treated off protocol, disability assessment was not blinded, and the drop-out rate was high, with follow-up available for only 82 patients at two years and 36 patients at four years [170].

In an open-label study (HALT-MS) of 24 patients with refractory RRMS, myeloablation with high-dose immunotherapy followed by HSCT was associated at three years with a high rate of event-free survival (78 percent) and improvements in neurologic function. Adverse events included two deaths, one from MS progression and one from worsening asthma [171].

These reports illustrate the potential benefits and perils of HSCT. More long-term data, preferably from randomized controlled trials, are needed to assess the efficacy and safety of this intervention for the treatment of highly active RRMS [172].

Stem cell transplantation is also under investigation as a treatment for patients with progressive forms of MS. This approach is discussed separately. (See "Treatment of progressive multiple sclerosis in adults", section on 'Stem cell transplantation'.)

MONITORING RESPONSE TO THERAPY — There is no consensus about how often a patient with MS should undergo a brain MRI while stable on treatment.

Since disease-modifying treatments are only partially effective, many MS experts recommend more aggressive treatment when acute or progressive disease activity is seen on MRI, even when the patient is on a specific treatment and appears to be doing well clinically. From this perspective, a conservative approach is to repeat the brain MRI once a year. More frequent neuroimaging may be desirable, but is impractical due to financial constraints.

However, this view is not universally shared, and other experts do not recommend repeat or serial brain MRIs for patients with MS who are clinically stable on treatment.

Refractory disease — Some patients with relapsing-remitting multiple sclerosis (RRMS) have disease activity that is refractory to initial disease-modifying therapy with interferon beta (IFNB) drugs or glatiramer acetate. In this situation, we suggest the following options:

Switching to an oral disease modifying agent such as dimethyl fumarate or teriflunomide (see 'Dimethyl fumarate' above and 'Teriflunomide' above)

Adding intravenous (IV) methylprednisolone 1000 mg monthly bolus (see 'Glucocorticoids in combination therapy' above)

Natalizumab 300 mg by IV infusion every four weeks as monotherapy only (see "Natalizumab for relapsing-remitting multiple sclerosis in adults")

Alemtuzumab as monotherapy (see 'Alemtuzumab' above)

For patients with RRMS who are poor responders to IFNB agents, glatiramer, natalizumab, and methylprednisolone, and who develop accumulating disability despite therapy, we suggest the following options:

IV pulse cyclophosphamide combined with pulse methylprednisolone. The dose regimen for this treatment is discussed separately. (See "Treatment of progressive multiple sclerosis in adults", section on 'Cyclophosphamide'.)

IV mitoxantrone 4 to 12 mg/m2 every three months up to a maximum lifetime cumulative dose of 140 mg/m2. (See 'Mitoxantrone' above.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient information: Multiple sclerosis in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS — A number of medications are available as disease modifying therapy of relapsing-remitting multiple sclerosis (RRMS). These include interferon beta-1a, interferon beta-1b, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, alemtuzumab, and mitoxantrone. There are no consensus guidelines, with the exception that mitoxantrone should be reserved for patients with rapidly advancing disease who have failed other therapies [110].

After making a diagnosis of definite MS, it is important to present the data in summary form to the patient and to discuss the risks and benefits of each treatment. One of the most important points is to remind the patient that these therapies slow the disease, but they do not stop it or make the patient feel better.

It is reasonable to start newly diagnosed patients with RRMS on one of the following disease modifying agents:

Interferon beta-1a (Avonex) 30 mcg intramuscular injection weekly

Glatiramer acetate 20 mg subcutaneous injection daily

Interferon beta-1b (Betaseron) 0.25 mg (1 mL) subcutaneously every other day

Interferon beta-1a (Rebif) 22 or 44 mcg subcutaneously three times a week

Pegylated interferon beta-1a 125 mg subcutaneously once every two weeks

Dimethyl fumarate delayed-release capsules 120 mg twice daily for one week, then 240 mg twice daily

Teriflunomide (7 or 14 mg tablet) once daily

Based upon clinical experience, the available clinical data, neutralizing antibody formation, side effect profile, route of administration, and MRI data, we suggest Avonex or glatiramer acetate as agents of first choice for patients with RRMS, depending upon the patient's lifestyle and laboratory data. These drugs are typically continued indefinitely unless side effects are intolerable or the patient begins to fail in terms of response, after which use of another agent can be considered. For patients with highly active RRMS who have a poor response to beta interferons, glatiramer acetate, and the oral agents (dimethyl fumarate and teriflunomide) or intolerance of these immunomodulators, we suggest adding either intravenous methylprednisolone monthly bolus, treatment with natalizumab monotherapy, or treatment with alemtuzumab monotherapy. (See 'Refractory disease' above.)

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