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Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults
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Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults
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Literature review current through: Jul 2017. | This topic last updated: Jul 06, 2017.

INTRODUCTION — Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system (CNS) that is a leading cause of disability in young adults.

The treatment of relapsing forms of MS is reviewed here, primarily focused on disease-modifying therapies. 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".)

STARTING DISEASE-MODIFYING THERAPY — A number of immunomodulatory agents, including interferon beta preparations, glatiramer acetate, natalizumab, alemtuzumab, ocrelizumab, dimethyl fumarate, teriflunomide, and fingolimod, have 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 (DMT). However, these therapies are not a cure; they are only partially effective for reducing the relapse rate, and whether all or any reduce disability progression is still under investigation. However, some observational studies have found evidence suggesting that the use of DMTs for patients with MS is associated with a lower long-term risk of disease progression [1,2].

We recommend disease-modifying therapy (DMT) with one of the effective agents for all patients with RRMS starting as soon as possible. The choice of a specific agent should be individualized according to disease activity and patient values and preferences. Our suggested approach to initial treatment is as follows (algorithm 1):

Infusion therapy with natalizumab for patients with more active disease and for those who value effectiveness above safety and convenience. The evidence that natalizumab is more effective than interferons, glatiramer, or oral DMTs for patients with RRMS is based upon cross-trial comparisons and clinical experience [3].

Injection therapy (interferons or glatiramer) for patients who value safety more than effectiveness and convenience. Among these, we prefer intramuscular interferon beta-1a 30 mcg weekly or glatiramer acetate.

Oral therapy (dimethyl fumarate, teriflunomide, or fingolimod) for patients who value convenience. We prefer dimethyl fumarate in this setting because it may be more effective and have a better safety profile than the other two agents, though the evidence is indirect and inconclusive [4-6]. In addition, the potential teratogenicity of teriflunomide limits its use for a disease where a substantial portion of patients are of child-bearing age.

Most DMTs are continued indefinitely in clinically stable patients with RRMS unless side effects are intolerable. Exceptions include natalizumab therapy, where the risk of progressive multifocal leukoencephalopathy increases with the duration of treatment, and pregnancy, where the risk of possible adverse effects of DMTs on the fetus must be weighed against DMT discontinuation and increased risk of maternal disease relapses.

MONITORING RESPONSE TO THERAPY — The response to disease-modifying therapy can be monitored by clinical follow-up with careful attention to possible manifestations of MS disease activity including acute attacks (relapses) and onset or progression of sustained disability. Many or most experienced clinicians supplement the clinical information with periodic neuroimaging (MRI) studies to monitor the development of new asymptomatic lesions. Our preferred protocol is to assess patients with the Expanded Disability Status Scale (table 1) every 3 months and a brain MRI every 12 months.

A range of symptomatic problems can occur in patients with MS. Cognitive dysfunction, depression, fatigue, and mood swings are increasingly common with disease progression. Paroxysmal symptoms, spasticity, tremor, seizures, sphincter dysfunction, and sexual dysfunction may also complicate disease progression. The management of these issues is discussed in detail separately. (See "Symptom management of multiple sclerosis in adults".)

Acute attacks 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".)

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 reasonable approach is to repeat the brain MRI annually. More frequent neuroimaging may be desirable, but is impractical due to financial constraints. Less frequent imaging may be reasonable for individuals with years of clinically and radiologically stable disease.

REFRACTORY DISEASE — Some patients with RRMS have disease activity that is refractory to initial disease-modifying therapy (DMT). Although refractory disease is hard to define, the frequency and severity of clinical relapses and MRI lesion activity on therapy are the crucial factors. A single relapse of mild severity or a single new MRI lesion within six months of starting DMT is concerning but is usually insufficient to demand a change in therapy. However, any serious relapse (ie, more than sensory involvement), multiple relapses regardless of severity, or a pronounced increase in MRI activity with multiple contrast-enhancing lesions should prompt a review of treatment options with a predisposition to change the DMT [7]. While there is no standard protocol for changing treatment in patients with either relapses or clinically silent MRI lesions, our suggested approach is outlined below (algorithm 2). The overall goal is to balance the risks posed by the medications to the risks posed by the disease, though prognosticating long-term outcomes in MS is difficult.

For patients initially treated with interferon beta (IFNB) drugs or glatiramer acetate who have an inadequate response, we suggest the following options (algorithm 2):

Switch to an oral disease-modifying agent such as dimethyl fumarate, teriflunomide, or fingolimod (see 'Dimethyl fumarate' below and 'Teriflunomide' below and 'Fingolimod' below)

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

For patients initially treated with natalizumab who have an inadequate response, or who become seropositive for anti-JC virus antibodies, we suggest stopping natalizumab and starting one of the following options (algorithm 2):

Dimethyl fumarate (see 'Dimethyl fumarate' below)

Fingolimod monotherapy (see 'Fingolimod' below)

Teriflunomide (see 'Teriflunomide' below)

For patients initially treated with an oral agent who have an inadequate response, we suggest the following options (algorithm 2):

Switch to a different oral agent (see 'Oral therapies' below)

Switch to injection therapy with an IFNB or glatiramer (see 'Injectable therapies' below)

Switch to infusion therapy with natalizumab (see 'Natalizumab' below)

For patients with RRMS who are poor responders to all first-line treatments, and who develop accumulating disability despite therapy, the following options are available:

Add intravenous (IV) methylprednisolone 1000 mg monthly bolus (see 'Glucocorticoids in combination therapy' below)

Switch to fingolimod (see 'Fingolimod' below)

Switch to alemtuzumab monotherapy (see 'Alemtuzumab' below)

Intravenous immune globulin (see 'Intravenous immune globulin' below)

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')

PREGNANCY — For women with MS who are planning a pregnancy or who become pregnant, we suggest stopping treatment with disease-modifying therapy. However, there is no clear consensus about this approach. The treatment of MS in pregnancy is discussed in detail separately. (See "Neurologic disorders complicating pregnancy", section on 'Multiple sclerosis'.)

INJECTABLE THERAPIES — Injectable (intramuscular and subcutaneous) disease-modifying therapies for RRMS include the interferon beta (IFNB) preparations and glatiramer acetate. These are the oldest treatments for RRMS, the first being approved in 1993. They are sometimes called the "platform" therapies for this reason. The available evidence from controlled trials suggests that interferons and glatiramer have similar clinical utility [8].

Daclizumab, another self-administered injection therapy, was approved for treating RRMS in 2016 [9].

Interferons — A number of different IFNB preparations are effective for the treatment of RRMS, as presented below.

Interferon beta-1b — The first disease-modifying medication approved for use in MS was recombinant interferon beta-1b. The drug is a cytokine that modulates immune responsiveness through various mechanisms [10].

The efficacy of subcutaneous 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 [11].

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 [11].

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) [12]. 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) [13]. 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 is administered at 0.25 mg (1 mL) 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 [14]. (See 'Neutralizing antibodies and response markers' below.)

The INCOMIN study compared subcutaneous interferon beta-1b 0.25 mg every other day with intramuscular interferon beta-1a 30 mcg once weekly in 188 patients with RRMS and found the former to be more effective on both clinical and MRI outcomes [15]. 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).

In contrast to the INCOMIN results, a multicenter open-label randomized Danish trial involving 310 patients with RRMS compared subcutaneous interferon beta-1a 22 mcg once a week with subcutaneous interferon beta-1b 250 mcg every other day and found that the annual relapse rates were nearly equal in the two treatment groups [16].

Interferon beta-1a — Interferon beta-1a is available in several different formulations, including intramuscular, subcutaneous, and pegylated preparations.

The efficacy of intramuscular interferon beta-1a in patients with RRMS was demonstrated in a randomized, double-blind study of 301 patients [17]. Weekly intramuscular injections of 6 million units (30 mcg) of interferon beta-1a or placebo were administered [17]. Over two years, treatment with intramuscular interferon beta-1a 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 intramuscular interferon beta-1a (60 mcg per week) was not superior to 30 mcg [18].

The benefit of subcutaneous interferon beta-1a was established by the double-blind PRISMS trial that randomly assigned 560 patients with RRMS to placebo, 22 mcg, or 44 mcg of subcutaneous interferon beta-1a three times per week for two years [14]. 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).

A head to head comparison study (the EVIDENCE trial) enrolled 677 patients who were randomly assigned to receive subcutaneous interferon beta-1a 44 mcg three times weekly or intramuscular interferon beta-1a 30 mcg once a week [19]. Relapse was less frequent with subcutaneous interferon beta-1a (25 versus 37 percent), and the mean number of active MRI lesions per patient per scan was fewer (0.17 versus 0.33). However, treatment with subcutaneous interferon beta-1a 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 patients assigned to subcutaneous interferon beta-1a who developed 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 [20,21].

In an extension of the EVIDENCE trial, patients who changed from low-dose intramuscular interferon beta-1a (30 mcg once weekly injection) to high-dose subcutaneous 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 [22]. The higher dose of interferon beta-1a was associated with an increased rate of adverse effects.

Pegylated interferon beta-1a is formed by attaching a polyethylene glycol (PEG) group to the N terminus of interferon beta-1a [23]. Pegylation can improve some pharmacodynamic properties, including a longer half-life and consequently a reduced dosing frequency [23,24]. Peginterferon beta-1a was evaluated in 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 [25]. 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 of interferons — The benefit of long-term treatment with 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 [13,26,27]. 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. Most of these studies too suggest that IFNB treatment for MS does not prevent long-term disability [29-31], though a minority suggests otherwise [32].

Side effects of interferons — Injection site reactions are common with IFNB therapy and can include injection site necrosis. Flu-like symptoms are also common and may be treated with ibuprofen, acetaminophen, and glucocorticoids [33]. 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. However, for some patients they remain intolerable.

There is a high prevalence of mainly asymptomatic liver dysfunction associated with IFNB therapy [34,35]. However, serious hepatotoxicity associated with IFNB is rare. Nevertheless, the potential risk of using intramuscular interferon beta-1a 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 suicidal ideation. A partially reversible polyneuropathy was described in a small series of patients with MS who were treated with IFNB therapy [36]. In addition, rare cases of thrombotic microangiopathy have been linked to the use of IFNB therapy [37-39]. The relationship appears to be dose-dependent, suggesting a toxicity mechanism [39]. IFNB treatment should be stopped immediately for patients who develop thrombotic microangiopathy. (See "Drug-induced thrombotic microangiopathy", section on 'Immunosuppressive agents'.)

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.

Neutralizing antibodies and response markers — Potential biologic [40-45] and radiologic [44,46] markers of IFNB responsiveness have been examined, including neutralizing antibodies (NAbs) and myxovirus resistance protein A (MxA). While the clinical utility of these markers remains to be proven, there is evidence that the development of NAbs can limit the effectiveness of interferons as measured by MRI activity, relapses, and disease progression [47-51]. All of the interferons are capable of stimulating the production of NAbs, which reduce the bioavailability of interferon [52]. The rate of NAb formation varies with the type of interferon, the dosing regimen, and duration of IFNB therapy [53].  

In our view, trials establishing the utility of NAb or MxA testing for patients receiving IFNB therapy are needed before the routine use of these markers can be recommended. However, the negative impact of NAbs on relapses and disease progression led some experts to call for NAb testing in clinical practice [54-56]. Our approach has been that, in the setting of high disease activity, therapy should be changed independent of Nab or MxA results, though neutralizing antibody testing can inform the selection of ensuing treatment. For patients who have NAb titers, a switch to a non-IFNB therapy would be indicated [56].

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 anti-inflammatory cytokines.

The following trials demonstrated the effectiveness of glatiramer in RRMS [58]:

The benefit of glatiramer acetate was first established in a double-blind trial of 251 patients with RRMS [59]. 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) [59]. 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) [60].

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 [61].

Dosing and side effects of glatiramer — Glatiramer acetate is administered by subcutaneous injection at 20 mg daily or 40 mg three times a week [62].

Side effects of glatiramer acetate include local injection site reactions and, less commonly, 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 [63]. Desensitization to glatiramer acetate has been successfully performed in patients with either systemic allergic reactions or recurrent local reactions [64].

Serious adverse effects due to glatiramer are uncommon, but cases of possible hepatotoxicity have been reported [65,66].

Daclizumab — Daclizumab is a humanized monoclonal antibody that has specific binding activity for the alpha chain component of the high-affinity interleukin 2 receptor. Daclizumab is effective for reducing relapse rates in RRMS, as supported by the following randomized controlled trials:

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 [67]. The daclizumab high-yield process (HYP) 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 DECIDE trial randomly assigned more than 1800 adults with RRMS to subcutaneous daclizumab HYP (150 mg every four weeks) or intramuscular interferon beta-1a (30 mcg once a week) for up to 144 weeks [68]. Patients assigned to daclizumab HYP had a significantly lower annualized relapse rate compared with those assigned to interferon beta-1a (0.22 versus 0.39), corresponding to a 45 percent reduction, and (at 96 weeks) a significantly lower number of new or newly enlarged brain lesions on T2-weighted MRI (4.3 versus 9.4). However, there was no significant difference in the estimated rate of sustained disability progression (16 versus 20 percent). Serious adverse events were more common in the daclizumab HYP group compared with the interferon beta-1a group (15 versus 10 percent), including rates of infection (4 versus 2 percent). Cutaneous adverse events (rash and eczema) and elevated liver aminotransferase levels were also more common with daclizumab.

The findings of these trials are promising, particularly those suggesting that daclizumab reduces disability progression compared with placebo in patients with RRMS. However, the clinical utility of daclizumab is likely to be limited by the risk of serious adverse events, making it a second- or third-line agent for patients who have had an inadequate response to two or more disease-modifying agents for RRMS [9].

Daclizumab was approved by the FDA for treating RRMS in 2016 [9]. The dose of daclizumab is 150 mg given subcutaneously once a month. Because of safety risks, which include hepatotoxicity and serious infection, daclizumab will be available in the United States only through a restricted distribution program. Patients should have baseline liver function testing before starting daclizumab, with testing repeated every month before each dose, and continuing for up to six months after the last dose.

INFUSION THERAPIES — Infusion therapies for RRMS include natalizumab, alemtuzumab, ocrelizumab, and mitoxantrone. Observational data suggest that natalizumab and alemtuzumab have similar benefit for reducing relapse rates [3,69]. Mitoxantrone is seldom used because of cardiac toxicity and limited evidence of benefit [70].

Natalizumab — Natalizumab is a highly effective drug for the treatment of RRMS. However, its use is associated with the development of progressive multifocal leukoencephalopathy (PML), a potentially disabling and fatal complication. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults" and 'Refractory disease' above.)

The reduction in the annualized relapse rate for RRMS seen with natalizumab therapy in randomized trials (54 to 68 percent) compares favorably with the reduction seen with interferon beta drugs or glatiramer acetate in other randomized trials (about 33 percent). However, there are no trials comparing natalizumab directly with other disease-modifying agents. Thus, the relative effectiveness of natalizumab compared with other disease-modifying agents for RRMS cannot be defined confidently. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults", section on 'Effectiveness'.)

The overall risk of PML with natalizumab therapy is estimated to be approximately 4.1 in 1000, but this estimate can be refined based upon well-established risk factors (table 2). The risk of PML is increased with the duration of natalizumab therapy, prior immunosuppressant treatment, and seropositivity for anti-JC virus antibodies prior to natalizumab treatment. For patients who are seronegative for JC virus and have no prior history of immunosuppression, the risk of PML in the first 24 months of natalizumab therapy is very low (less than 1:10,000).

We suggest testing for anti-JC virus antibodies after one year of natalizumab therapy and discontinuing natalizumab for patients who are seropositive (see "Natalizumab for relapsing-remitting multiple sclerosis in adults", section on 'PML risk stratification'). The rationale for testing at one year is that PML is rare in the first year of natalizumab therapy even among those who are seropositive at baseline for JC virus antibodies. For patients who are JC virus antibody-positive, screening for PML with brain MRI every three to four months is advisable. For patients who are negative for JC virus antibodies at one year, we suggest checking titers two to three times per year thereafter, with reconsideration of natalizumab in patients who seroconvert. However, in patients with a negative or low JC virus antibody level, 97 percent remain low over an 18-month period. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults", section on 'Risk of PML' and "Natalizumab for relapsing-remitting multiple sclerosis in adults", section on 'PML risk stratification'.)

Natalizumab is given as a 300 mg intravenous (IV) infusion every four weeks. Side effects include infusion-related symptoms (headache, flushing, erythema, nausea, and dizziness), fatigue, allergic reactions, anxiety, infections (mainly urinary tract infection and pneumonia), pharyngitis, sinus congestion, and peripheral edema. Given its efficacy, natalizumab is reasonable as a starting medication for patients with aggressive disease, especially if they are negative for the JC virus antibody. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults", section on 'Other side effects'.)

Alemtuzumab — Alemtuzumab is a humanized monoclonal antibody that causes depletion of CD52-expressing T cells, B cells, natural killer cells, and monocytes [71]. Data from randomized controlled trials show that alemtuzumab is more effective than interferon beta-1a for reducing the relapse rate in RRMS [72]. 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 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]. ITP developed in 1 percent of patients at two years [74,75], and in 3 percent at three years [73,76]. This included one patient who suffered a fatal intracerebral hemorrhage in a phase II study of alemtuzumab. All subsequent ITP cases were detected through a monitoring program and successfully treated [77]. Another report described three cases of acute acalculous cholecystitis during treatment with alemtuzumab for RRMS [78].

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 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). Premedication with glucocorticoids (1 g of methylprednisolone) for the first three days of therapy is indicated. Alemtuzumab therapy requires monitoring (for infusion reactions, symptoms of ITP, and symptoms of nephropathy) and prophylaxis for herpes virus infections (oral acyclovir 200 mg twice daily) during treatment and for several weeks after treatment. Patients should be educated about the symptoms of ITP and to report them immediately if they develop.

Prolonged surveillance (for 48 months after the last dose) for bone marrow suppression, infections, and autoimmune disorders such as ITP is also necessary.

Ocrelizumab — Ocrelizumab is a recombinant human anti-CD20 (a B-cell marker) 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. Evidence from randomized trials shows that ocrelizumab is more effective than interferon beta-1a for reducing relapses and may slow disability progression.

Two identical randomized, controlled trials (OPERA I and OPERA II) of 821 and 825 adults with relapsing multiple sclerosis compared intravenous ocrelizumab (600 mg every 24 weeks) with subcutaneous interferon beta-1a (44 mcg three times weekly) for 96 weeks [80]. All patients were pretreated with one dose of intravenous methylprednisolone (100 mg) before each infusion. The following observations were reported:

In both trials, treatment with ocrelizumab compared with interferon beta-1a significantly reduced the annualized relapse rate (0.16 versus 0.29, absolute risk reduction [ARR] 0.13).

Ocrelizumab treatment significantly reduced the mean number of gadolinium-enhancing lesions per MRI scan in OPERA I (0.02 versus 0.29, ARR 0.27) and in OPERA II (0.02 versus 0.42, ARR 0.40).

In a prespecified pooled analysis, ocrelizumab led to a significant reduction in the proportion of subjects with confirmed disability progression at 24 weeks (6.9 versus 10.5 percent, hazard ratio 0.60, 95% CI 0.43-0.84, ARR 3.6 percent).

Ocrelizumab treatment was associated with infusion reactions in 34 percent, serious infections in 1 percent, and neoplasms in 0.5 percent of patients.

An earlier 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 [81]. 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.

These randomized trial findings confirmed the effectiveness of ocrelizumab. In March 2017, The US Food and Drug Administration (FDA) approved ocrelizumab for both relapsing MS and for primary progressive MS [82]. The role of this agent in the treatment of RRMS remains to be clarified pending further safety data on rates of infection and neoplasm.

The evidence for ocrelizumab in primary progressive MS is reviewed elsewhere. (See "Treatment of progressive multiple sclerosis in adults", section on 'Ocrelizumab'.)

The initial dose of ocrelizumab is a 300 mg intravenous (IV) infusion, followed two weeks later by a second 300 mg IV infusion [83]. Subsequently, ocrelizumab is given as 600 mg IV infusion every six months. The drug should be given under close medical supervision with access to medical support should severe infusion reactions develop. Premedication is recommended with both methylprednisolone 100 mg IV (or equivalent glucocorticoid) approximately 30 minutes prior to each ocrelizumab infusion and with an antihistamine (eg, diphenhydramine) approximately 30 to 60 minutes prior to each ocrelizumab infusion to reduce the frequency and severity of infusion reactions; an antipyretic (eg, acetaminophen) can be added as well. Infusions should be delayed, if there is active infection, until the infection resolves.

Ocrelizumab is contraindicated in patients with active hepatitis B virus infection [83]. Therefore, patients must be screened for hepatitis B virus before starting ocrelizumab (see "Diagnosis of hepatitis B virus infection"). In addition, patients should receive all necessary immunizations at least six weeks prior to starting ocrelizumab; live-attenuated and live vaccines are not recommended during ocrelizumab treatment or after discontinuation until B-cell repletion occurs.

There are no data regarding the risk of fetal harm associated with ocrelizumab treatment for pregnant women, but animal data suggest harm with observations of increased perinatal mortality and renal, bone marrow, and testicular toxicity [83].

Mitoxantrone — Mitoxantrone is approved for use in both relapsing-remitting and progressive forms of MS. However, 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 [84]. In addition, mitoxantrone treatment is associated with a low risk of developing therapy-related acute leukemia [85-88]. Due to these potential side effects, there is a maximum lifetime dose. (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 [89].

ORAL THERAPIES — Approved oral disease-modifying therapies for RRMS are dimethyl fumarate, teriflunomide, and fingolimod.

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 [90-92], and results from one of these trials suggest that BG-12 reduces the rate of disability progression [91].

The CONFIRM trial randomly assigned over 1400 adults with 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 [90]. 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, respectively, 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 [91]. 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 were flushing and gastrointestinal symptoms, including diarrhea, nausea, and abdominal pain. Taking the medication with food can decrease the rate of gastrointestinal upset.

The starting dose for oral dimethyl fumarate is 120 mg given twice daily. After seven days, the dose should be increased to 240 mg given twice daily. It is available in 120 and 240 mg preparations.

Treatment with dimethyl fumarate may decrease lymphocyte counts, so patients should have a complete blood count obtained before starting the medication, at no longer than six months after starting, and at least annually or as clinically indicated during the course of treatment. Dimethyl fumarate should be discontinued if lymphocytopenia develops. Dimethyl fumarate has not been studied in patients with pre-existing low lymphocyte counts. Another concern associated with dimethyl fumarate is liver injury manifested by elevated serum aminotransferase and bilirubin levels, with onset from a few days to several months after starting treatment [93]. Therefore, serum aminotransferase, alkaline phosphatase, and total bilirubin levels should be obtained prior to and during treatment as clinically indicated; the drug should be discontinued if clinically significant liver injury occurs.

There are case reports of patients taking dimethyl fumarates for MS or psoriasis who developed progressive multifocal leukoencephalopathy (PML), including those with and without lymphocytopenia [94-97]. (See "Treatment of psoriasis", section on 'Fumaric acid esters' and "Progressive multifocal leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis".)

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 [98]. The effectiveness of teriflunomide for the treatment of RRMS was demonstrated in several randomized controlled trials:

The TEMSO 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 [99]. 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 of approximately 20 percent [100].

In the TOWER trial of over 1100 adults (ages 18 to 55) with relapsing forms of MS, both doses of teriflunomide (7 mg or 14 mg once daily, with a median treatment duration of more than 550 days) were superior to placebo for reducing the annualized relapse rate, and teriflunomide 14 mg daily (but not 7 mg daily) barely achieved statistical significance for reducing sustained accumulation of disability compared with placebo (hazard ratio 0.68, 95% CI 0.47-1.0) [101]. This trial too had a high dropout rate of approximately 30 percent [100].

The most common adverse effects of teriflunomide were diarrhea, nausea, hair thinning, and elevated alanine aminotransferase (ALT) levels [99,102,103].

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.

Patients should be brought up to date with all immunizations before initiating therapy with teriflunomide. Live vaccines should not be given concurrently.

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 [104]. Thus, women who become pregnant and 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. Despite this, no evidence of fetal harm was found in pregnancy registries of babies born to men or women taking the medication [105].

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 [106]. There is evidence from several randomized controlled trials that fingolimod is effective in reducing the relapse rate in patients with RRMS [107]. However, this benefit is associated with a small increased risk of infection, atrioventricular block, and possibly basal cell carcinoma. The largest trials reported the following observations:

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 [108]. At 24 months, the following observations were reported:

The annualized relapse rate 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 was similar in the fingolimod and placebo groups.

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

In the open-label FREEDOMS extension trial, long-term fingolimod treatment was associated with reduced relapse rates and disability progression [109].

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 [110]. 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 was significantly reduced in both the high and low dose fingolimod groups compared with 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).

Results from the extension phase of the TRANSFORMS trial supported a long-term benefit of fingolimod for maintaining a reduced relapse rate [111].

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

Additional varicella-zoster virus (VZV) infections [112,113]. 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 [114].

Paradoxical worsening of MS disease activity with severe MS relapses (some following cessation of natalizumab) or the development of tumefactive MS lesions during fingolimod treatment [115-117].

Reports of MS rebound after stopping fingolimod treatment. In one retrospective study of 46 patients who stopped fingolimod, severe MS relapses within 4 to 16 weeks were observed in 5 patients (11 percent) [118]. In another case, marked exacerbation of MS activity was observed after fingolimod was withdrawn due to the development of severe herpes zoster infection [112].

Rare cases of progressive multifocal leukoencephalopathy (PML) in patients with and without prior immunosuppressant treatment [119,120].

Case reports of cryptococcal meningoencephalitis [121] and disseminated cryptococcus [122].

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 and fungal 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 [123,124]. A preliminary review by the US Food and Drug Administration (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 [125].

Clinical use of fingolimod — The most common side effects associated with fingolimod include headache, influenza, diarrhea, back pain, elevated liver enzymes, and cough [126]. Less common but potentially serious adverse events associated with fingolimod include bradyarrhythmia and atrioventricular block (potentially fatal), macular edema [127], diminished respiratory function, and tumor development. There were no published reports of fatalities during the first-dose administration of fingolimod, though cases of prolonged bradycardia were reported [128].

Contraindications to fingolimod include patients with recent (within six months) myocardial infarction, unstable angina, stroke, transient ischemic attack (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, and treatment with anti-arrhythmic drugs [125,126]. We suggest not using fingolimod to treat patients who have diabetes because they are at increased risk for macular edema, which has been reported in association with fingolimod treatment. In addition, the trials of fingolimod excluded patients with diabetes.

Before starting fingolimod, patients should have the following [126]:

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; however, a higher rate of fetal abnormalities was not detected among women who took fingolimod in pregnancy registries [129]

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 [125,126]. 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 [114,126]. 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 a possible teratogen and should be stopped two months prior to conception [130].

OTHER TREATMENTS

Azathioprine — Early trials of azathioprine for MS were small and conflicting [131-133]. 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 [134]. 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 [135]. 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'.)

Invasive treatments for CCSVI are not beneficial, and there are reports of harm with such treatments [136-140]. Therefore, we do not recommend using endovascular venoplasty or stenting procedures to treat patients with MS for presumed CCSVI [141].

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 and tumor development. Supporting evidence comes from the CLARITY trial of 1326 adults with RRMS [142]. 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 annualized relapse rate 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 [142]. 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).

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 [143]. 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 [144,145]. 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 [145]. 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.

Dalfampridine — Dalfampridine, 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 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 [146]. All patients were started on intramuscular interferon beta-1a treatment 30 mcg once a week 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 [147]. 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 [148]. 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 [149-152], but not all [153] early clinical trials reported beneficial effects for IVIG in RRMS. However, these trials generally involved small numbers of patients, lacked complete data on clinical and MRI outcomes, or used questionable methodology [154]. 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 [155].

Laquinimod — Laquinimod is a synthetic immunomodulatory compound with high oral bioavailability [156,157]. 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 [158]. 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 in 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 twofold more frequent in the laquinimod group. The trial had a relatively high dropout rate (22 percent), which limits the strength of the findings [159].

The multicenter BRAVO trial enrolled 1331 patients with RRMS and randomly assigned them to either laquinimod (0.6 mg daily), intramuscular interferon beta-1a (30 mcg weekly), or placebo in a 1:1:1 ratio [160]. 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). In contrast, the reduction in annualized relapse rate with interferon beta-1a treatment compared with placebo was significant. However, in a post hoc 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. 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.

Rituximab — Rituximab is a monoclonal antibody directed against the CD20 antigen on B lymphocytes that causes B cell reduction. Limited data suggest the effectiveness of rituximab for RRMS:

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 [161]. In addition, rituximab treatment was associated with a significant reduction in the proportion of patients who had a clinical relapse by week 24.

In an observational study of 256 patients with stable RRMS who switched to rituximab or fingolimod after stopping natalizumab due to JC virus antibody positivity, the rituximab group had lower rates of clinical relapse, adverse events, and treatment discontinuation compared with the fingolimod group [162].

A retrospective report analyzed data from 822 Swedish patients with MS, including 557 with RRMS, who were treated with intravenous rituximab (500 or 1000 mg every 6 to 12 months) [163]. During rituximab treatment (mean duration of approximately 22 months), patients with RRMS had a low mean annualized relapse rate (0.04) and their median disability status remained unchanged. The most common noninfusion-related adverse events were infections.

While these results are promising, further clinical trials are needed to establish the long-term effectiveness and safety of rituximab for RRMS [164]. Rare cases of PML have been reported in patients treated with rituximab for other indications. 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".)

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 [165]. 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 a 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 [166]. 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 [167].

In an open-label study (HALT-MS) of 24 patients with refractory RRMS, myeloablation with high-dose immunotherapy followed by HSCT was associated with a high rate of event-free survival at three and five years (78 and 69 percent, respectively) and improvements in neurologic function [168,169]. Adverse events included three deaths, all in patients with MS progression; none of the deaths were attributed to transplant.

In another open label study, 24 adults with refractory MS, early disability, and ongoing disease activity were treated with immunoablation followed by autologous HSCT [170]. Complications of transplantation caused one death. Among survivors, there were no relapses and no evidence of new MRI gadolinium-enhancing lesions or new T2 lesions. With a median follow-up of 6.7 years, the rate of MS clinical disease activity-free survival at three years after transplantation was 70 percent.

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 [171].

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'.)

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 education: Multiple sclerosis in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

For patients with relapsing-remitting multiple sclerosis (RRMS), we recommend initial therapy with one of the disease-modifying agents listed below (Grade 1A):

Intramuscular interferon beta-1a, 30 mcg once a week

Subcutaneous interferon beta-1a, 22 or 44 mcg three times a week

Subcutaneous pegylated interferon beta-1a, 125 mg once every two weeks

Subcutaneous interferon beta-1b, 0.25 mg (1 mL) every other day

Subcutaneous glatiramer acetate, 20 mg daily

Intravenous natalizumab, 300 mg infusion over one hour every four weeks

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

Oral teriflunomide, 7 or 14 mg tablet once daily

The initial choice of a specific agent should be individualized according to disease activity and patient values and preferences (algorithm 1). We suggest infusion therapy with natalizumab for patients with more active disease and for those who value effectiveness above safety and convenience (Grade 2C). We suggest injection therapy with one of the interferon beta preparations or glatiramer for patients who value safety more than effectiveness and convenience (Grade 2C). Among these, we prefer intramuscular interferon beta-1a 30 mcg weekly or subcutaneous glatiramer acetate 20 mg daily. We suggest oral therapy with dimethyl fumarate for patients who value convenience (Grade 2C). (See 'Starting disease-modifying therapy' above.)

The response to disease-modifying therapy can be monitored by clinical follow-up with careful attention to possible manifestations of MS disease activity including acute attacks (relapses), new or contrast-enhancing lesions on MRI, and onset or progression of sustained disability. (See 'Monitoring response to therapy' above.)

Some patients with RRMS have disease activity that is refractory to initial disease-modifying therapy. In such cases, switching to another first-line disease-modifying agent may be helpful (algorithm 2). (See 'Refractory disease' above.)

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