Version May 2024
INTRODUCTION — Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system that is a leading cause of disability in young adults. The disease-modifying therapies (DMTs) for MS are reviewed here.
CHOOSING THERAPY — The treatment strategy and choice of disease-modifying therapy (DMT) for MS are discussed in separate topic reviews:
●(See "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis".)
●(See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)
●(See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis".)
●(See "Treatment of secondary progressive multiple sclerosis in adults".)
●(See "Treatment of primary progressive multiple sclerosis in adults".)
●(See "Multiple sclerosis: Pregnancy planning".)
●(See "Multiple sclerosis: Pregnancy and postpartum care".)
The treatment of acute MS exacerbations is also reviewed separately. (See "Treatment of acute exacerbations of multiple sclerosis in adults".)
Note that clinical trials of DMTs in MS have been performed in many populations, but mainly involving individuals of White European ancestry. In some countries, areas, and situations, this ethnicity may not reflect the composition of the population being treated. Treatment decisions should therefore be individualized.
MONOCLONAL ANTIBODIES — Monoclonal antibodies for MS include natalizumab, ocrelizumab, rituximab, ofatumumab, alemtuzumab, and ublituximab. These disease-modifying therapies (DMTs) may be preferred for patients with more active disease and for those who place a high value on efficacy and are risk-tolerant (algorithm 1). (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)
However, serious safety issues, including infections, are possible adverse effects of several of these medications. The indications, efficacy, dose, administration, monitoring, and adverse effects of the monoclonal antibody DMTs for MS are discussed in detail separately. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis".)
ORAL AGENTS — Approved oral disease-modifying therapies (DMTs) for MS include fumarates (dimethyl fumarate, diroximel fumarate, monomethyl fumarate), sphingosine 1-phosphate receptor (S1PR) modulators (fingolimod, siponimod, ozanimod, ponesimod), a pyrimidine synthesis inhibitor (teriflunomide), and an antimetabolite purine nucleoside analog (cladribine).
Oral DMTs may be preferred for patients who value a self-administered oral medication over medications requiring injections and infusions or who largely prefer an escalation approach to therapy (algorithm 1). (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)
These medications are reviewed in detail elsewhere. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis".)
INJECTION THERAPIES
Platform therapies — Injectable (intramuscular and subcutaneous) forms of disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS) include the interferon beta (IFNB) preparations and glatiramer acetate. The interferons and glatiramer acetate were the earliest DMTs for RRMS, with the first approved in 1993; they are sometimes called the "platform" therapies for this reason. The available evidence from controlled trials suggests that interferons and glatiramer acetate have similar clinical utility [1].
These older DMTs may be preferred for patients who value safety and are less concerned about convenience or who are comfortable utilizing an escalation approach to treatment (algorithm 1). (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)
Interferons — Interferons are cytokines that modulate immune responsiveness through various mechanisms [2-4]. Several interferon IFNB preparations are effective for the treatment of RRMS, as presented below.
Indications — IFNBs are indicated for the treatment of relapsing forms of MS, including clinically isolated syndrome (CIS), RRMS, and active secondary progressive multiple sclerosis (SPMS). IFNBs are contraindicated for patients with a history of hypersensitivity to IFNB or other components of the formulations.
Dose and administration — Dosing of the different interferon beta drugs differs according to the formulation and route of administration. Coadministration of analgesics and/or antipyretics on treatment days may help to minimize flu-like symptoms [5].
●Interferon beta-1b – Recombinant human interferon beta-1b is administered at 0.25 mg (1 mL) every other day subcutaneously by self-injection [6]. Generally, the drug is started at 0.0625 mg (0.25 mL) every other day and increased over a six-week period to 0.25 mg (1 mL) every other day. One dose titration schedule begins at 0.0625 mg (0.25 mL) every other day for the first two weeks of therapy and is increased to 0.125 mg (0.5 mL) every other day for weeks 3 and 4, to 0.185 mg (0.75 mL) every other day for weeks 5 and 6, and to the final dose of 0.25 mg (1 mL) every other day beginning at week 7 and thereafter [6].
●Intramuscular interferon beta-1a – Intramuscular recombinant human interferon beta-1a is dosed at 30 mcg once weekly. To minimize flu-like symptoms, one strategy is to start with 7.5 mcg (week 1) then increase dose in increments of 7.5 mcg once weekly (during weeks 2, 3, and 4) up to the recommended dose (30 mcg once weekly) [7].
●Subcutaneous interferon beta-1a – Subcutaneous recombinant human interferon beta-1a is given as a dose of 22 mcg three times weekly or 44 mcg three times weekly [8]. The lower dose is generally used for patients who do not tolerate the higher dose. Dose titration schedules for each target dose follow:
Target dose 44 mcg three times weekly:
•Initial dose 8 mcg three times weekly for weeks 1 and 2
•Increase to 22 mcg three times weekly for weeks 3 and 4
•Increase to 44 mcg three times weekly for week 5 and thereafter
Target dose 22 mcg three times weekly:
•Initial dose 4.4 mcg three times weekly for weeks 1 and 2
•Increase to 11 mcg three times weekly for weeks 3 and 4
•Increase to 22 mcg three times weekly for week 5 and thereafter
●Pegylated interferon beta-1a – Pegylated recombinant human interferon beta-1a is given by subcutaneous or intramuscular injection. The recommended target dose is 125 mcg every 14 days. The dose is titrated, beginning with 63 mcg on day 1, 94 mcg on day 15, and 125 mcg (the full dose) on day 29 [5].
Adverse effects — Injection site reactions are common with IFNB therapy and may include injection site abscess, cellulitis, or necrosis [5-8]. Flu-like symptoms are also common and may be treated with ibuprofen, acetaminophen, and glucocorticoids [9]. The routine use of acetaminophen should probably be avoided as it may increase the risk of liver dysfunction associated with IFNB use. Flu-like symptoms tend to diminish with time. However, for some patients they remain intolerable. Although depression has been reported as a possible adverse effect of IFNB therapy, the association has not been confirmed [10-12], and a 2010 meta-analysis of placebo-controlled randomized trials on the efficacy and/or tolerability of IFNB in MS found no increase in depression with IFNB therapy [13].
There is a relatively high prevalence of mainly asymptomatic liver dysfunction (transaminitis) associated with IFNB therapy [14,15]. However, serious hepatotoxicity associated with IFNB is rare. Nevertheless, the potential risk of using IFNB in combination with known hepatotoxic drugs or other products (eg, alcohol) should be considered prior to IFNB administration, or when adding new agents to the regimen of patients already on an IFNB.
Rare but potentially life-threatening cases of pulmonary artery hypertension have been reported with IFNB [16,17], as have rare cases of thrombotic microangiopathy [18-20]. The relationship with thrombotic microangiopathy appears to be dose-dependent, suggesting a toxicity mechanism [20]. IFNB treatment should be stopped immediately for patients who develop pulmonary artery hypertension or thrombotic microangiopathy. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Immunosuppressive agents'.)
Other adverse reactions possibly related to IFNB therapy include leukopenia and anemia, anaphylaxis and other allergic reactions, congestive heart failure, seizures, and drug-induced lupus erythematosus. A partially reversible polyneuropathy was described in a small series of patients with MS who were treated with IFNB therapy [21].
Monitoring
●Laboratory abnormalities – Periodic monitoring is recommended to include complete blood count and differential, platelet count, blood chemistries, and liver function tests at one, three, and six months following the start of IFNB therapy, and periodically thereafter; thyroid function testing is also suggested for patients on IFNB therapy [5-8]. However, 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 (or months 1, 2, 3, and 6), and thereafter repeat the liver function tests and complete blood count every six months.
In the past, we suggested decreasing the IFNB dose by 50 percent if leukopenia develops or if transaminases are persistently elevated (eg, illness, a new medication, or alcohol intake); monitoring should then be continued for another six months. However, a dose reduction of this magnitude may lower the effectiveness of IFNB therapy; with the availability of many other options, this possibility should prompt a discussion with the patient about switching to another DMT.
●Neutralizing antibodies and response markers – The development of neutralizing antibodies (NAbs) may limit the effectiveness of interferons as measured by magnetic resonance imaging (MRI) activity, relapses, and disease progression [22-26]. All of the interferons are capable of stimulating the production of NAbs, which reduce the bioavailability of interferon [27]. The rate of NAb formation varies with the type of interferon, the dosing regimen, and duration of IFNB therapy [28]. In one study, 34 percent of patients taking interferon beta-1b developed NAbs [29].
In our view, trials establishing the utility of NAb or myxovirus resistance protein A (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 [30-32]. 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 [32].
Efficacy
●Interferon beta-1b – The first disease-modifying medication approved for use in MS was recombinant human interferon beta-1b.
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 [33]. 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 [33].
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) [34]. There was no significant increase in the median brain MRI lesion burden 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) [35]. Patients in this extension study received the assigned treatment for up to five years, and subsequent use of DMT 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-1a – Recombinant human interferon beta-1a is available in several different formulations, including intramuscular, subcutaneous, and pegylated preparations.
•Intramuscular interferon beta-1a – A double-blind trial randomly assigned 301 patients with RRMS to intramuscular interferon beta-1a 6 million units (30 mcg) once a week or to placebo [36]. Over two years, treatment with intramuscular interferon beta-1a led to 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 [37].
•Subcutaneous interferon beta-1a – The double-blind PRISMS trial 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 [29]. 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 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 [38]. 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 NAbs (25 versus 2 percent). The percentage of relapse-free patients, the primary outcome measure, was lower in the group assigned to subcutaneous interferon beta-1a who developed NAbs.
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 assessed as an outcome measure, and different doses, frequencies, and routes of administration were compared [39,40].
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 [41]. The higher dose of interferon beta-1a was associated with an increased rate of adverse effects.
•Pegylated interferon beta-1a – Pegylation is a process of drug modification that attaches a polyethylene glycol (PEG) group to the N terminus of interferon beta-1a [42]. Pegylation can improve some pharmacodynamic properties, including a longer half-life and consequently a reduced dosing frequency [42,43]. 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 [44]. 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 improvement on several 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 IFNB formulations. However, there are no data directly comparing pegylated with nonpegylated formulations, and longer-term studies are needed to confirm the benefit and safety of peginterferon beyond the first year.
●Studies comparing interferon beta-1b with beta-1a – 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 [45]. 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, 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).
●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 [35,46,47]. 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 [48].
Long-term observational studies are more practical but are similarly limited by nonrandomized retrospective methodology and other issues, including potential confounding by indication and inability to assess treatment strategy or account for treatment adherence. Most of these studies too suggest that IFNB treatment for MS does not prevent long-term disability [49-51], though a minority suggests otherwise [52].
Glatiramer acetate — 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 acetate involves binding to major histocompatibility complex molecules and consequent competition with various myelin antigens for their presentation to T cells [53]. In addition, glatiramer acetate 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.
Indications — Glatiramer acetate is indicated for the treatment of relapsing forms of MS, including CIS, RRMS, and active SPMS.
Dose and administration — Glatiramer acetate is administered by subcutaneous injection. There are two different doses, which are not interchangeable [54]:
●20 mg daily
or
●40 mg three times a week and at least 48 hours apart
Adverse effects — Side effects of glatiramer acetate include local injection site reactions and, less commonly, transient systemic postinjection reactions such as chest pain, flushing, dyspnea, palpitations, tachycardia, urticaria, and/or anxiety [54]. Other potential adverse effects include lipoatrophy and skin necrosis. Desensitization to glatiramer acetate has been successfully performed in patients with either systemic allergic reactions or recurrent local reactions [55].
Serious adverse effects due to glatiramer acetate are uncommon, but cases of hepatotoxicity, some severe, have been reported [56-58].
NAbs to glatiramer acetate have been detected in some studies, but their clinical significance is unknown [59].
Monitoring — No laboratory monitoring is necessary.
Efficacy — A number of randomized trials have demonstrated the effectiveness of glatiramer acetate in RRMS [60]. The benefit of glatiramer acetate was first established in a double-blind trial of 251 patients with RRMS [61]. 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). Furthermore, over 140 weeks, a significantly larger proportion of patients in the placebo group experienced increased disability by ≥1.5 steps on the EDSS compared with the treatment group (41 versus 22 percent) [62]. In another trial, glatiramer acetate was given at 40 mg three times a week and led to a reduction in confirmed relapses of 34 percent compared with placebo (mean annualized relapse rate, 0.33 versus 0.51) and to a lower rate of gadolinium-enhancing lesions and new or enlarging T2 lesions on MRI [63].
Ofatumumab — Ofatumumab, while given by subcutaneous injection, is a monoclonal antibody that was approved in 2020 and is discussed with the other monoclonal antibodies. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Ofatumumab'.)
OTHER IMMUNE MODULATING AGENTS — Before the approval of injection therapies (interferons and glatiramer acetate), and based on limited evidence, several immunosuppressive agents were used to treat MS, including azathioprine, cyclophosphamide, glucocorticoids, intravenous immune globulin (IVIG), and mitoxantrone. However, these agents are less often used for MS now that disease-modifying therapies (DMTs) with proven efficacy are available [64].
Azathioprine — Early trials of azathioprine for MS were small and conflicting [65-67]. 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 [68]. Approximately 55 percent of the pooled patients included in the meta-analysis had relapsing-remitting multiple sclerosis (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 [69]. The benefit and tolerability of azathioprine for patients with RRMS requires confirmation in larger blinded, randomized trials.
Cyclophosphamide — Limited observational evidence supports the use of pulse (eg, monthly) intravenous (IV) cyclophosphamide for RRMS [70]. There is more experience with pulse cyclophosphamide for progressive forms of MS, but data are conflicting regarding benefit. (See "Treatment of secondary progressive multiple sclerosis in adults", section on 'Other treatments'.)
Another option employs high-dose cyclophosphamide as immunoablative treatment without bone marrow transplantation [71,72]. 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 [72]. 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.
Glucocorticoids — Monthly IV glucocorticoid boluses, typically 1000 mg of methylprednisolone, were once 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 inconclusive regarding any benefit of glucocorticoids in combination with interferon beta (IFNB) preparations for RRMS [73-75]. Thus, the role of glucocorticoids combined with beta interferons or other agents for the treatment of RRMS remains uncertain.
Intravenous immune globulin — Although data are equivocal, there is no compelling evidence that IVIG is effective for patients with RRMS. Some [76-79] but not all [80] 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 [81]. 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 [82].
Mitoxantrone — Mitoxantrone is approved for use in both relapsing-remitting and progressive forms of MS. However, because of cardiac toxicity, an increased risk of ovarian failure, male infertility, chromosomal aberrations, and promyelocytic leukemia, mitoxantrone should not be used to treat MS unless potential benefits greatly outweigh the risks [83,84]. Thus, mitoxantrone is considered only as a last resort for patients with rapidly advancing disease who have failed other therapies [85]. Due to these potential adverse effects, there is a maximum lifetime dose.
The usual dose of mitoxantrone is 12 mg/m2 by IV administration every three months up to a maximum cumulative lifetime dose of 140 mg/m2 [86]. The left ventricular ejection fraction (LVEF) should be evaluated before initiating mitoxantrone and prior to each subsequent dose and should be maintained at ≥50 percent. In addition, annual cardiac testing should continue after completion of mitoxantrone therapy because of concern for delayed cardiotoxicity. In patients with MS treated with mitoxantrone, a systematic review published in 2010 estimated that the risks of developing systolic dysfunction, heart failure, and acute leukemia were 12, 0.4, and 0.8 percent, respectively [86]. In patients with cancer who were treated with mitoxantrone, the rate of heart failure was estimated to be approximately 3 percent.
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 or any DMT than patients without these characteristics [87].
STEM CELL TRANSPLANTATION — The goal of autologous hematopoietic stem cell transplantation (HSCT) is eliminating and replacing the patient's pathogenic immune system to achieve long-term remission of MS [88]. 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.
●Relapsing forms of MS – The open-label MIST trial randomly assigned 110 patients with highly active relapsing-remitting multiple sclerosis (RRMS) on disease-modifying therapy (DMT) to nonmyeloablative HSCT with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) or to another DMT of higher efficacy or different class than the DMT they were taking at baseline [89]. At a median follow-up of two years, disease progression, defined as an increase of one point on the Expanded Disability Status Scale (EDSS), occurred in 5 percent in the HSCT group and 62 percent in the DMT group; median time to disease progression could not be calculated in the HSCT group due to an insufficient number of events and was 24 months in the DMT group (hazard ratio 0.07, 95% CI 0.02-0.24). Compared with the DMT group, the HSCT group had a lower relapse rate, an improvement in MRI lesion volume, and a greater proportion of patients with no evidence of disease activity at follow-up. There were no deaths and no disabling or potential life-threatening adverse events among the patients who received HSCT.
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 [90,91]. 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 [92]. 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 and other reports illustrate the potential benefits and perils of HSCT [93-98]. More long-term data from randomized controlled trials are needed to assess the efficacy and safety of this intervention for the treatment of highly active RRMS [99].
●Progressive forms of MS – HSCT has been evaluated in uncontrolled studies of patients with progressive forms of MS [100-103]. A 2011 systematic review of autologous HSCT in patients with progressive MS refractory to conventional medical treatment identified eight case series with 161 patients (most with secondary progressive multiple sclerosis [SPMS]) that reported progression-free survival, which ranged from 33 to 95 percent at median follow-up times of 24 to 42 months [104]. There was substantial heterogeneity among these studies, which appeared to be due mainly to the intensity of the immunoablative conditioning regimen employed prior to HSCT.
Among 15 studies that reported adverse events, the most frequent complications occurring within six months of autologous HSCT were fever, engraftment syndrome, enteritis, and transient neurologic deterioration [104]. Among 13 case series with posttreatment follow-up, seven patients died from treatment-related causes, mainly infection, and six patients died from nontreatment-related causes, mainly disease progression. Overall mortality was approximately 3 percent. Transplant-related mortality was as high as 8 percent in older studies [105,106] but appears to be lower since the year 2000 [97,100,104].
In addition to HSCT, mesenchymal stem cell therapy for MS is being explored, with inconsistent results in small studies [107-111]. Larger controlled trials are awaited to evaluate the risk/benefit ratio of stem cell therapies and their appropriate indications for the treatment of MS.
COVID-19 AND DMTs
●COVID vaccinations in patients with MS – We advise coronavirus disease 2019 (COVID-19) vaccination and boosters for all patients with MS, in accordance with local availability and allocation priorities [112,113]. (See "COVID-19: Vaccines".)
Note that COVID-19 vaccination, and likely other vaccinations, may be less effective in patients being treated with anti-CD20 or sphingosine 1-phosphate receptor (S1PR) modulator disease-modifying therapies (DMTs) due to attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody response [114,115].
For patients starting B-cell depleting DMTs, COVID vaccines should be given prior to commencing therapy when possible. In instances when COVID vaccination has to be given after therapy has been instituted, timing should be arranged for a cycle in the treatment when the immune response is likely to be maximal, which is generally as long after the most recent DMT infusion as possible but approximately two weeks prior to next expected dose (for infused anti-CD20 therapies) [116].
●DMTs that may increase the risk of severe COVID-19 – There are concerns about DMTs (eg, ocrelizumab, rituximab, ofatumumab, alemtuzumab, cladribine, and others) that cause B cell or lymphocyte depletion, which theoretically may increase the risk of developing severe COVID-19 [117,118].
Observational data suggest that anti-CD20 DMTs for MS increase the risk for more severe COVID-19 illness [118-122]. As an example, a multinational cohort study that included 1683 patients with MS and confirmed COVID-19 found that the risk of hospitalization was increased for patients taking either ocrelizumab (adjusted odds ratio [aOR] 1.75, 95% CI 1.29-2.38) or rituximab (aOR 2.76, 95% CI 1.87-4.07) compared with those taking other DMTs [121]. Both ocrelizumab and rituximab were also associated with higher risk of intensive care unit admission, but neither was associated with an increased risk of death.
Note that several DMTs, including alemtuzumab and cladribine, are not well studied for their impact on the severity of COVID-19.
●DMTs unlikely to increase the risk of more severe COVID-19 – Observational evidence suggests that there is no increased risk of severe COVID-19 infection associated with DMTs for patients using natalizumab, teriflunomide, fumarates (dimethyl fumarate, diroximel fumarate, monomethyl fumarate), or S1PR modulators (fingolimod, siponimod, ozanimod, and ponesimod), although not all of these agents have been specifically evaluated [117,118,121,123]. In addition, the platform DMTs (the interferons and glatiramer acetate) have not been associated with increased severity of COVID-19 [122].
●Individualized approach for patients at risk for severe COVID-19 – We advise an individualized approach for the use of DMTs that considers MS disease activity, lymphocyte count, and the presence of comorbid conditions, in addition to MS itself, which may increase the risk associated with COVID-19 (table 1) [124]. Depending upon the degree of inflammatory MS activity, it may be reasonable to delay dosing or starting anti-CD20 DMTs (ocrelizumab, rituximab, ofatumumab) to allow time for the patient to be fully vaccinated against COVID-19 (eg, for two to eight weeks depending upon which vaccine is used and how quickly it can be given), but there is no high-quality evidence to guide these decisions.
●Patients who develop COVID-19 – Clinicians should advise patients with MS who develop symptoms suggestive of COVID-19 or test positive for COVID-19 to contact their MS health care professional for advice about DMT management [125].
For patients who develop severe COVID-19, it may be reasonable to stop monoclonal antibody DMTs (natalizumab and anti-CD20 therapies) until the recovery phase of the disease [117], but evidence is limited. Another approach is to treat with nirmatrelvir-ritonavir for adults of any age, given the immunocompromised state associated with DMTs for MS. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Nirmatrelvir-ritonavir as preferred therapy'.)
If DMTs are stopped, some experts advise restarting treatment with natalizumab within eight weeks, circumstances permitting, to avoid rebound disease [117].
The management of COVID-19 is discussed in several UpToDate topic reviews. (See "COVID-19: Management in nursing homes" and "COVID-19: Management in hospitalized adults" and "COVID-19: Management of adults with acute illness in the outpatient setting".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)
SUMMARY
●Monoclonal antibody DMTs – Monoclonal antibody disease-modifying therapies (DMTs) for multiple sclerosis (MS) include natalizumab and biosimilars, several anti-CD20 agents (ocrelizumab, rituximab, ofatumumab, ublituximab), and alemtuzumab. These DMTs are highly efficacious and may be preferred for patients with more active disease and for those who place a high value on efficacy and are risk-tolerant (algorithm 1). However, serious safety issues, including infections, are possible adverse effects of several of these medications. The monoclonal antibody DMTs are reviewed in detail elsewhere. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis".)
●Oral DMTs for MS – Oral DMTs for MS include fumarates (dimethyl fumarate, diroximel fumarate, monomethyl fumarate), sphingosine 1-phosphate receptor (S1PR) modulators (fingolimod, siponimod, ozanimod, and ponesimod), cladribine, and teriflunomide. These DMTs may be preferred for patients with MS who value a self-administered oral medication over medications requiring injections and infusions (algorithm 1). They are discussed in detail separately. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis".)
●Platform injection therapies – Older injectable (intramuscular and subcutaneous) DMTs include the interferon beta agents (recombinant human interferon beta-1b and recombinant human interferon beta-1a) and glatiramer acetate. These DMTs may be preferred by patients who place the highest value on safety and are willing to accept lower effectiveness (algorithm 1). The dose, administration, and monitoring of these agents are described above. (See 'Interferons' above and 'Glatiramer acetate' above.)
●Other immune modulating agents – Before the approval of injection therapies (interferons and glatiramer acetate), and based on limited evidence, several immunosuppressive agents were used to treat MS, including azathioprine, cyclophosphamide, glucocorticoids, intravenous immune globulin, and mitoxantrone. However, these agents are less often used for MS now that DMTs with proven efficacy are available. (See 'Other immune modulating agents' above.)
●Stem cell transplantation – Hematopoietic and mesenchymal stem cell therapy are promising investigational therapies for MS, but long-term data from randomized controlled trials are needed to assess the efficacy and safety of these therapies. (See 'Stem cell transplantation' above.)
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