Multiple Sclerosis

Treatment of relapsing-remitting multiple sclerosis in adultsAuthorMichael J Olek, DOSection EditorFrancisco Gonzalez-Scarano, MDDeputy EditorJohn F Dashe, MD, PhDDisclosures

Last literature review version 19.2: May 2011 | This topic last updated: May 17, 2011 (More)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 and temporary minor improvements allowed.

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

• Progressive-relapsing MS (PRMS) is characterized by progressive disease from onset, with clear acute relapses, with or without full recovery. Progression continues during the periods between disease relapses.

The relapsing form of MS is generally associated with a better prognosis than progressive disease [2]. Measures of disease progression and prognosis are discussed in greater detail separately. (See "Epidemiology and clinical features of multiple sclerosis in adults".)

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 clinical aspects of MS are discussed separately. (See "Epidemiology and clinical features of multiple sclerosis in adults" and "Diagnosis of multiple sclerosis in adults" and "Comorbid problems associated with 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-1a, interferon beta-1b, glatiramer acetate, and natalizumab, have shown several important beneficial effects for patients with relapsing-remitting multiple sclerosis (RRMS):

• A decreased relapse rate• A reduced progression of disability• A slower accumulation of lesions on magnetic resonance imaging (MRI)

Thus, everyone with a diagnosis of definite RRMS should begin disease modifying therapy with interferon or glatiramer acetate.

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 [3-5], while others have not [6,7].

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.

Thus, 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 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 medication approved by the US Food and Drug Administration (FDA) 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 [8].

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 one of the following groups: Betaseron 1.6 million international units (MIU) every other day; Betaseron 8 MIU every other day; or placebo [9]. After two years, the annual exacerbation rate was significantly lower for both 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 Betaseron groups, respectively.

At five-year follow-up, the incidence of disease progression was lower in the 8 MIU interferon beta-1b group compared with the placebo group (35 versus 46 percent) [10]. There was also a 30 percent decrease in the annual exacerbation rate in the treated group over five years. Although this was not statistically significant, the treatment benefit trend was maintained. There was no significant increase in the median magnetic resonance imaging (MRI) lesion burden (3.6 percent) in the interferon beta-1b patients, while the placebo patients had a 30 percent increase in median MRI lesion burden over five years.

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 and optic-spinal MS'.)

In a randomized clinical trial of 205 Japanese patients with RRMS that was not placebo controlled, treatment with interferon beta-1b 250 mcg SC 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 SC once weekly with subcutaneous interferon beta-1b (Betaseron) 250 mcg SC 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 RR disease 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].

Rebif received approval from the US FDA based upon a head to head comparison study (the EVIDENCE trial), in which 677 patients 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.

Long term benefit — The benefit of long-term treatment with IFNB preparations for RRMS is unproven. As discussed above, randomized controlled trials of these agents provide evidence of benefit only for the relatively short duration (generally two years) of the trials. A meta-analysis of trials published between 1993 and 2002 concluded that the effectiveness of recombinant interferons on exacerbations was modest after one year of treatment, and that

existing data were inadequate for evaluation of efficacy at two years [25].

As already discussed, results from a number of clinical trial extension studies suggest that there is continued benefit of IFNB treatment beyond two years [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 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 [26].

Long-term observational studies are more practical, and these can be analyzed by applying propensity score weighting, a statistical method proposed to reduce the effects of bias in observational studies [27-29]. This approach 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 [30]. 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 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).

While this study provides additional supportive evidence that IFNB treatment prevents long-term progression of disability in RRMS [30], further research is needed to confirm such benefit.

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 [31]. 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 [32]. 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 [33]. 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. However, the US FDA announced in March 2005 that several cases of severe hepatic injury, including some cases of hepatic failure, had been reported among the 130,000 patients taking interferon beta-1a (Avonex). The Avonex drug label was changed to reflect this information by upgrading liver damage from a "precaution" to a stronger "warning." The FDA recommended that 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 [34].

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 (3 to 5 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 interferon beta (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 MS (SPMS) found that older age and longer disease duration were associated with responsiveness [35]. 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 [35].

Potential biologic [36-41] and radiologic [40,42] 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 IFNB as measured by MRI activity, relapses, and disease progression [43-47]. All of the interferons are capable of stimulating the production of NAbs, which reduce the bioavailability of interferon [48].

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 [49,50]:

• 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) [49].

• 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 [50]. 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 [7]. 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 [50].

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 [51].

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 [52].

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 [53,54]. 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 [47].

• 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 [55]. 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 [56]:

• 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 [57]. 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 demonstrate the effectiveness of glatiramer in RRMS:

• The benefit of glatiramer acetate was first established in a double-blind trial of 251 patients with RRMS [58]. 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) [58]. Furthermore, over 140 weeks, a significantly larger proportion of patients in the placebo group experienced increased disability by ≥1.5 EDSS steps compared with the treatment group (41 versus 22 percent) [59].

• 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 [60].

Side effects of glatiramer — 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 were not detected in the trial cited above [58], but have been detected in other studies; their clinical significance is unknown [61]. Desensitization to glatiramer acetate has been successfully performed in patients with either systemic allergic reactions or recurrent local reactions [62].

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 glucocorticoids.

Trials comparing interferons with glatiramer — The available evidence from controlled trials suggests that interferons and glatiramer have similar clinical utility [63].

• 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) [64]. 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.

• An open-label randomized trial (the REGARD study) of 764 patients with RRMS compared interferon beta-1a (Rebif) with glatiramer acetate [65]. There was no significant difference between treatment groups in the primary outcome of time to first relapse [65]. Relapse rates were low in both groups.

• Another open-label trial (the BECOME study) of 75 patients with RRMS or clinically isolated syndromes compared interferon beta-1b with glatiramer acetate [66]. Over two years, there were no differences between treatment groups in new lesions or clinical relapses [66].

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 [67]. There is evidence from two large controlled trials that fingolimod is effective for reducing the relapse rate in patients with 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 [68]. 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 [69]. 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 [70]. 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 herpes virus infections, potentially fatal, and tumor development. Further trials are needed to determine both the risk profile and the optimal dose of oral fingolimod for RRMS.

Clinical use of fingolimod — In late September 2010, the manufacturer received regulatory approval from the FDA for marketing oral fingolimod 0.5 mg daily for the treatment of RRMS. While there is no consensus yet among experts, the use of fingolimod is likely to be limited in most cases to treat newly diagnosed patients who have active relapsing MS and prefer oral administration despite the increased risks associated with this agent. However, fingolimod may be also be used to treat patients with active RRMS who are intolerant of beta interferons and glatiramer acetate.

Since the trials of fingolimod excluded patients with diabetes, we suggest not using fingolimod to treat patients with MS who have diabetes.

The most common side effects associated with fingolimod include headache, influenza, diarrhea, back pain, elevated liver enzymes, and cough [71]. Less common but potentially serious adverse events associated with fingolimod include bradyarrhythmia and atrioventricular block (potentially fatal), macular edema, diminished respiratory function, and tumor development.

Before starting fingolimod, patients should have the following [71]:

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

• Electrocardiogram for those who use antiarrhythmics or have a history of arrhythmia or heart disease

• 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.

At treatment initiation, baseline pulse and blood pressure should be measured and the patient observed for six hours after the first dose for signs of bradycardia or atrioventricular block [71]. During fingolimod treatment,

patients should report symptoms of infection and avoid live attenuated vaccines. 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 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 [72]. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults" and 'Refractory disease' below.)

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 [73]. In addition, mitoxantrone treatment is associated with a low risk of developing therapy-related acute leukemia [74]. (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 [75].

OTHER AGENTS

Alemtuzumab — Alemtuzumab is a humanized monoclonal antibody that causes depletion of CD52-expressing T cells, natural killer cells, and monocytes. Preliminary data suggest that alemtuzumab is more effective than interferon beta-1a for the treatment of early RRMS, but this benefit is offset by a risk of potentially fatal immune thrombocytopenic purpura (ITP) [76]. (See "Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults", section on 'Alemtuzumab'.)

Supporting evidence comes from a rater-blind trial of over 300 patients with early RRMS and no prior disease-modifying therapy who were randomly assigned to either subcutaneous interferon beta-1a (Rebif) or to intravenous alemtuzumab [76]. Alemtuzumab therapy was associated with significant reductions in the rate of sustained accumulation of disability at 36 months (9 versus 26 percent with interferon beta-1a, hazard ratio [HR] 0.29, 95% CI

0.16-0.54), the annualized rate of relapse (0.10 versus 0.36 percent, HR 0.26, 95% CI 0.16-0.41), and brain lesion volume on T2-weighted MRI.

The trial was terminated early when three patients treated with alemtuzumab developed ITP and one died [76]. At 36 months, the rate of ITP in the alemtuzumab group was 3 percent, compared with 1 percent in the interferon beta-1a group. The alemtuzumab group also had a significantly higher rate of thyroid autoimmunity (23 versus 3 percent).

Larger phase III trials are planned to determine the safety and confirm the effectiveness of alemtuzumab for early RRMS. Given the risk of ITP and the unknown risk of opportunistic infections with this agent [77,78], alemtuzumab should NOT be used to treat MS outside of these clinical trials.

Azathioprine — Early trials of azathioprine for MS were small and conflicting [79-81]. 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 [82]. Approximately 55 percent of the pooled patients included in the meta-analysis had 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 [83]. The benefit and tolerability of azathioprine for patients with RRMS requires confirmation in larger blinded, randomized trials.

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 [84]. 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 [85]. 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 [86,87]. 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 [87]. 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 clinical data from a phase 2 randomized controlled trial [88] and small open label studies [89,90] in patients with RRMS and secondary progressive MS suggest that daclizumab treatment is well tolerated and is associated with reductions in MRI evidence of disease activity.

Fumarate — Fumarates may have neuroprotective and immunomodulatory properties. In two preliminary studies, an oral formulation of dimethyl fumarate (BG00012) reduced the development of new gadolinium-enhancing brain MRI lesions in patients with active MS [91,92], but its benefit for lowering the rate of clinical relapses or disability has not been established.

The larger of these studies was a multicenter, double-blind trial that enrolled 257 adults with RRMS and evaluated BG00012 at three doses (120 mg once daily, 120 mg three times daily, and 240 mg three times daily) [92]. Compared with placebo, the highest dose (240 mg three times daily) of BG00012

significantly reduced the number of new gadolinium-enhancing brain MRI lesions from weeks 12 to 24 (1.4 versus 4.5 new lesions). In addition, this dose of BG00012 nonsignificantly reduced the annualized relapse rate, but the study was not powered to detect differences in clinical outcome. Flushing and abdominal pain were significantly more common with BG00012 than with placebo.

Larger trials are underway to evaluate the safety and effectiveness of BG00012 for reducing clinical relapses in patients with RRMS.

Glucocorticoids in combination therapy — Monthly intravenous 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 [93]. 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), intravenous methylprednisolone (1000 mg daily for three days every other month), or both [94]. At one year, there was no statistically significant benefit for either adjunctive therapy, although there were trends suggesting modest benefit for intravenous 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 [95]. 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 [96-99], but not all [100] 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 [101].

• The 2002 AAN guidelines [102], looking at essentially the same data [96-98], noted that trials of IVIG generally involved small numbers of patients, lacked complete data on clinical and MRI outcomes, or used questionable methodology [102]. 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 [103].

Laquinimod — Laquinimod is a synthetic immunomodulatory compound with high oral bioavailability [104,105]. In animal studies, laquinimod inhibited development and relapses of experimental autoimmune encephalomyelitis [104]. In patients with RRMS, laquinimod appears to reduce new MRI lesions, but its utility for reducing clinical relapses or disability is unknown.

• Using a per-protocol analysis of 189 patients with relapsing MS, a preliminary randomized clinical trial found that oral laquinimod (0.3 mg daily) treatment was associated with significantly fewer active brain lesions on MRI scan over 24 weeks (the primary outcome measure) than placebo [106]. However, this finding did not achieve statistical significance on the intention-to-treat analysis. The detection of small lesions on MRI in this study was probably increased by the use of triple-dose gadolinium.

• A later multicenter randomized clinical trial, using an intention-to-treat analysis of 306 patients with relapsing MS, found that laquinimod (0.6 mg daily) led to a statistically significant reduction in gadolinium-enhancing brain MRI lesions from weeks 24 to 36 compared with placebo (2.6 versus 4.2) [107]. However, the lower dose of laquinimod (0.3 mg daily) that was beneficial in the earlier trial showed no significant benefit in this one

(3.9 versus 4.2). Unlike the earlier trial, this trial used single-dose gadolinium.

Laquinimod was generally well-tolerated, but asymptomatic liver enzyme elevations were more common in the laquinimod group [107]. In addition, one patient in the laquinimod group with an underlying hypercoagulable state developed a thrombotic venous outflow obstruction of the liver (Budd-Chiari syndrome).

Neither trial provided convincing evidence that laquinimod reduces clinical relapses or disability. Further study in larger trials is needed to establish whether laquinimod treatment is safe and clinically effective for RRMS.

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 [108]. 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. 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 [109-111], but are also known to have proinflammatory effects [112]. Available clinical data regarding statins in the treatment of MS are limited and conflicting.

• A small double-blind trial of patients with clinically stable RRMS receiving interferon beta-1a therapy found that the addition of atorvastatin (40 or 80 mg daily) resulted in increased clinical and MRI disease activity compared with placebo [113].

• 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 [114]. 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 confirmed by gadolinium-enhancing lesions on brain MRI [115]. 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.

More data from larger randomized controlled trials are needed to clarify the role of statins in the treatment of MS [116]. Currently, off-label use of statins for MS treatment is not recommended.

Teriflunomide — The oral immunomodulator teriflunomide is the active metabolite of leflunomide that inhibits pyrimidine biosynthesis and disrupts the interaction of T cells with antigen presenting cells [117]. In a preliminary randomized controlled trial involving 179 patients with RRMS or SPMS, teriflunomide was effective in reducing MRI lesions compared with placebo and was well tolerated [118]. Larger trials are needed to demonstrate whether this agent is effective for reducing MS relapses.

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 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:

• Adding intravenous methylprednisolone 1000 mg monthly bolus.• Natalizumab 300 mg by intravenous infusion every four weeks as

monotherapy only. Natalizumab should be reserved for patients with highly active RRMS who are either poor responders to both beta interferons and glatiramer acetate or are intolerant of these immunomodulators. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults".)

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:

• Intravenous 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'.)

• Intravenous 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 (The Basics)")

SUMMARY AND RECOMMENDATIONS — A number of medications are available as disease modifying therapy of relapsing-remitting multiple sclerosis (RRMS). These include three interferon beta (IFNB) drugs (Avonex, Rebif, Betaseron), glatiramer acetate, fingolimod, and mitoxantrone. Natalizumab is approved as monotherapy only. There are no consensus guidelines, with the exception that mitoxantrone should be reserved for patients with rapidly advancing disease who have failed other therapies [73].

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 any one of the approved disease modifying agents. These are:

• Interferon beta-1a (Avonex) 30 mcg intramuscular (IM) injection weekly• Glatiramer acetate 20 mg subcutaneous (SC) injection daily• Interferon beta-1b (Betaseron) 0.25 mg (1 mL) SC every other day• Interferon beta-1a (Rebif) 22 or 44 mcg SC three times a week• Fingolimod 0.5 mg orally 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 both beta interferons and glatiramer acetate, or intolerance of these immunomodulators, we suggest adding intravenous methylprednisolone monthly bolus or treatment with natalizumab. (See 'Refractory disease' above.)

However, natalizumab therapy is associated with a risk of progressive multifocal leukoencephalopathy. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults".)

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