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. The use of DMTs for different clinical forms of MS and the symptom management of MS are discussed in separate topic reviews:
●(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".)
The management of symptoms caused by MS is also reviewed separately:
●(See "Symptom management of multiple sclerosis in adults".)
MONOCLONAL ANTIBODIES — Monoclonal antibodies for relapsing-remitting multiple sclerosis (RRMS) include natalizumab, ocrelizumab, rituximab (off-label), ofatumumab, and alemtuzumab. Observational data suggest that natalizumab and alemtuzumab have similar benefit for reducing relapse rates [1,2]. It is likely that rituximab and ocrelizumab reduce relapse rates to the same extent as natalizumab and alemtuzumab, although comparative data are sparse.
Natalizumab — Natalizumab is a recombinant monoclonal antibody directed against the alpha-4 subunit of integrin molecules, thereby blocking integrin association with vascular receptors and limiting adhesion and transmigration of leukocytes. In patients with MS, natalizumab treatment is associated with a diminished migratory capacity of immune cells and a prolonged decrease in lymphocyte counts in the cerebrospinal fluid (CSF) [3,4].
Indications and efficacy — Natalizumab is one of several disease-modifying therapies (DMTs) that effectively reduce the relapse rate for patients with RRMS. Natalizumab is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndromes, RRMS, and active secondary progressive multiple sclerosis (SPMS).
The choice of a specific agent for patients with MS should be individualized according to disease activity and patient values and preferences (algorithm 1), as discussed in detail elsewhere. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults" and "Indications for switching or stopping disease-modifying therapy for multiple sclerosis".)
●Randomized trials – In a 2011 systematic review of trials evaluating natalizumab for relapsing forms of MS, pooled efficacy data from two randomized controlled trials, AFFIRM [5] and SENTINEL [6], showed that natalizumab significantly reduced the risk for having a relapse during two years of treatment (relative risk [RR] 0.57, 95% CI 0.47-0.69) [7]. In addition, natalizumab significantly reduced the risk for experiencing progression at two years (RR 0.74, 95% CI 0.62-0.89). The number needed to treat (NNT) to prevent one new exacerbation at two years was 4 (95% CI 3-5) and the NNT to prevent progression at two years was 10 (95% CI 7-23).
In the AFFIRM trial, 942 patients with relapsing MS were randomly assigned to receive either monotherapy with natalizumab 300 mg (n = 627), or placebo (n = 315) by intravenous (IV) infusion every four weeks for two years [5]. Natalizumab treatment was associated with a statistically significant 68 percent reduction in annualized relapse rate compared with placebo treatment at one year (0.26 versus 0.81), a reduction that was maintained at two years, and with a significant reduction in the cumulative probability of sustained disability progression at two years (17 versus 29 percent).
In the SENTINEL trial, 1171 patients with relapsing MS who continued to experience disease activity despite interferon beta-1a treatment were randomly assigned to also receive natalizumab 300 mg (n = 589) or placebo (n = 582) by IV infusion every four weeks [6]. All patients continued to receive interferon beta-1a throughout the trial. The study was stopped approximately one month early because two patients developed progressive multifocal leukoencephalopathy. Combination therapy (natalizumab plus interferon beta-1a) was associated with a statistically significant 54 percent reduction in annualized relapse rate compared with placebo at one year (0.38 versus 0.82), a difference that was maintained at two years, and with a significant reduction in the risk of sustained disability progression at two years (23 versus 29 percent).
Natalizumab was beneficial in all analyses of primary and secondary endpoints in both the AFFIRM and SENTINEL trials, indicating the robust nature of the results [5,6]. As an example, natalizumab treatment as monotherapy (in AFFIRM) or combination therapy (in SENTINEL) was associated with an 83 percent reduction in the number of new or enlarging hyperintense lesions on T2-weighted magnetic resonance imaging (MRI). Finally, natalizumab treatment was associated with improved health-related quality of life compared with placebo [8].
●Comparative efficacy – Natalizumab appears to be more effective than many other MS disease-modifying treatments, particularly the injectable and oral therapies, based upon clinical experience and long-term observational data [1,9-12]. The reduction in the annualized relapse rate seen with natalizumab in these trials (54 to 68 percent) compares favorably with the reduction seen with interferon beta or glatiramer acetate treatment in clinical trials (approximately 33 percent) [13]. However, indirect comparisons of effectiveness across trials do not provide compelling evidence of an advantage for natalizumab, and there are no randomized trials comparing natalizumab monotherapy directly with other disease-modifying agents.
Adverse effects — Natalizumab treatment is associated with a risk of developing progressive multifocal leukoencephalopathy (PML), a rare, potentially fatal neurologic disease caused by reactivation of JC virus (JCV) infection. (See 'Surveillance for PML' below and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.)
The most frequent adverse events associated with natalizumab treatment include infusion-related symptoms (headache, flushing, erythema, nausea, and dizziness), fatigue, infections (mainly urinary tract and lower respiratory tract infections), arthralgia, gastroenteritis, vaginitis, extremity pain, depression, and rash [14,15]. Other than PML, opportunistic infections are rarely associated with natalizumab therapy; they have included cases of herpes zoster, herpes meningitis, herpes simplex virus encephalitis, and tuberculosis [14,16,17]. Hepatoxicity, including clinically significant liver injury, and thrombocytopenia have been reported in postmarketing data [18,19]. Neonatal thrombocytopenia has been reported in newborns exposed to natalizumab in utero [15].
Natalizumab is contraindicated in patients who have or have had PML, and in patients with a previous hypersensitivity reaction to natalizumab. Because of the risk of PML, natalizumab should not be used for patients who may have impaired immunity, such as hematologic or rheumatologic conditions associated with compromised cell-mediated immunity [20,21].
As of March 2020, there were 832 cases of natalizumab-associated PML reported worldwide, for an overall incidence of 3.99 per 1000 patients (95% CI 3.73-4.27) [22]. The risk of natalizumab-associated PML for an individual patient varies according to the following factors (table 1) [23-27]:
●Anti-JCV antibody status
●Prior immunosuppressant treatment
●Duration of natalizumab exposure
Detailed PML risks are provided in the figure (figure 1) [28]. The estimated risk of PML is low (<1:10,000) for patients who are seronegative for anti-JCV antibodies, but increases with seroconversion, the strength of the seropositive response, and the duration of natalizumab exposure for seropositive patients. (See 'Surveillance for PML' below.)
In postmarketing data as of June 2017, the number of natalizumab doses received before the diagnosis of PML ranged from 8 to 136 (mean approximately 49) [29]. In the United States, the number of prior natalizumab infusions for an individual patient can be determined by contacting the TOUCH program.
Dosing and monitoring
Administration — Natalizumab is given as a 300 mg IV infusion over one hour, every four weeks. In the United States, infusions are given in centers registered under the TOUCH program. Patients should be observed for any signs or symptoms consistent with hypersensitivity reaction during the infusion and for one hour after the infusion is complete. Natalizumab should be discontinued in patients who develop hypersensitivity reactions.
Among patients treated with natalizumab who are seropositive for JCV antibody, the risk of PML may be reduced by converting the dosing interval to every six or eight weeks rather than every four weeks, without a loss in efficacy. (See 'Extended interval dosing' below.)
When there is suspicion for PML, natalizumab should be discontinued [23]. The management of natalizumab-related PML is discussed elsewhere. (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis", section on 'Natalizumab-associated PML'.)
●Before starting – Leukocyte and neutrophil counts should be within or close to the normal range. We suggest stopping glucocorticoids and other immunomodulators for at least one month prior to starting natalizumab. Cholestyramine may be used to accelerate the removal of teriflunomide. A longer washout period (up to three months or more) is suggested for azathioprine, methotrexate, mycophenolate, mitoxantrone, and cyclophosphamide [20]. A baseline brain MRI scan should be obtained prior to initiating therapy with natalizumab, since it is useful in comparison with later MRI scans for detecting changes suggestive of PML.
●Risk management program – For patients treated with natalizumab, rigorous clinical and neuroimaging follow-up is essential in order to detect the onset of symptoms and signs related to PML as opposed to those related to MS [23]. Natalizumab is available in the United States through a risk management program (the TOUCH risk minimization action plan) that requires enrollment by prescribers, specialty pharmacies, and infusion centers that dispense the drug [30]. Clinicians must evaluate patients at three and six months after natalizumab treatment is started, and at least every six months thereafter. Patients receiving natalizumab must enroll in a mandatory registry and complete a checklist that asks about medications and new symptoms suggestive of PML prior to monthly infusions. Monitoring programs and registries for natalizumab prescribing are in place in several other countries as well.
●Antibodies to natalizumab – Antibodies to natalizumab are not routinely obtained in clinical practice, but limited data suggest they may be useful in select patients with infusion reactions or poor response to natalizumab. However, it is more common in these scenarios to switch to a different DMT rather than obtain natalizumab antibody studies. Antibodies to natalizumab developed in approximately 9 percent of patients in the AFFIRM and SENTINEL trials, and were persistently positive in approximately 6 percent [31]. When compared with antibody negativity, persistent anti-natalizumab antibody positivity was associated with reduced clinical effectiveness of natalizumab treatment and with an increased incidence of infusion reactions. The authors of the study suggest testing for antibodies after six months of natalizumab therapy in patients who have continued clinical MS activity or persistent infusion reactions and stopping natalizumab if antibody positivity is confirmed by retesting after three more months [31].
Surveillance for PML — PML is rare in the first year of natalizumab therapy even among those who are seropositive at baseline for anti-JCV antibodies. In patients with a negative or low JCV antibody level, most studies suggest that approximately 97 percent remain low over an 18-month period. However, the risk increases with in patients who are seropositive for anti-JCV antibodies and longer duration of natalizumab therapy.
●JCV antibody testing – We suggest testing for anti-JCV antibodies at baseline and every six months while on natalizumab therapy (table 2). For patients who are seropositive and without prior immunosuppressive treatment, determination of anti-JCV antibody levels, as measured by the anti-JCV antibody index, may improve the accuracy of PML risk stratification [26]. The index allows quantification of anti-JCV antibody levels for individual patients, and is calculated by normalizing the optical density of the anti-JCV antibody serum sample with a calibrator [32].
In contrast to testing for anti-JCV antibodies, testing for JCV DNA in blood or urine appears to have no utility for determining the risk of PML. The authors have noted with some frequency that despite ordering JCV antibody testing, some commercial labs have erroneously run the JCV polymerase chain reaction (PCR) instead. Therefore, it is important to verify that the correct test (the anti-JCV antibody assay) was done when results come in.
●JCV antibody status – The JCV antibody status, JCV antibody index, history of prior immunosuppressant exposure, and duration of natalizumab exposure can be used to estimate the risk of PML and to guide decisions concerning natalizumab therapy (figure 1) [26,32,33].
•For patients who remain seronegative for anti-JCV antibodies, the estimated risk of PML is <1:10,000, suggesting relative safety of continuing natalizumab as indicated for MS. However, vigilance for PML is still required, as illustrated by a case report of a patient who had a negative anti-JCV antibody test two weeks prior to being diagnosed with PML [28]. Suggested monitoring involves repeating the anti-JCV antibody test every six months and a brain MRI every 12 months of natalizumab exposure. Although a negative JCV antibody test is often used to signify safety of therapy for indefinite periods of time, there is limited documented experience with long-term (more than six years) natalizumab therapy [22].
•For patients who are seropositive or seroconvert to positive anti-JCV status, and have with no prior use of immunosuppressant medications, the estimated risk of PML varies with the strength of the seropositive response or the antibody index; higher antibody levels are associated with a higher risk.
-With an anti-JCV antibody index <0.9, the estimated risk of PML is <1:10,000 for months 1 to 24 and 1:748 for >24 months of natalizumab exposure (table 2) [26,32,33]. Suggested monitoring involves repeating the anti-JCV antibody index every six months and a brain MRI every 12 months of natalizumab exposure. At a minimum, clinicians should counsel the patient about the risks of continuing natalizumab therapy beyond 24 months, although it should be cautioned that PML risk is cumulative rather than only beginning at the 24-month period.
-With an anti-JCV antibody index of ≥0.9, the estimated risk of PML is <1:1062 for months 1 to 24 and 1:101 for >24 months of natalizumab exposure (table 2). Suggested monitoring involves repeating the MRI scan at 12 months and then every 6 months beginning at 18 months of natalizumab exposure. For patients with an index of ≥0.9, we suggest stopping natalizumab after 24 months of treatment and transitioning to another DMT because of the mounting risk of PML.
Some experts, including one author of this topic (EM), do not use natalizumab for patients who are anti-JCV antibody positive at baseline. They also favor switching from natalizumab to another DMT as soon as possible if patients seroconvert to positive anti-JCV antibody status during natalizumab treatment, particularly if they have a high titer, with appropriate counselling about the pros and cons of doing so.
The rationale for switching to another DMT immediately upon seroconversion is that the risk of PML is cumulative with natalizumab treatment; continued natalizumab exposure drives up risk, which may theoretically be compounded by the potential for a short period of heightened PML risk when switching to the next DMT. However, reducing PML risk by simply stopping natalizumab for a washout period carries an unacceptable risk of MS rebound. It is reasonable to obtain a brain MRI scan prior to starting the next therapy (to exclude signs of PML) and discuss the utility of CSF JCV PCR testing.
Extended interval dosing of natalizumab, which has been associated with a reduced risk of PML in observational studies, is an alternative to switching DMT for patients who seroconvert. (See 'Extended interval dosing' below.)
•For patients with a history of prior immunosuppressant use (eg, azathioprine, cyclophosphamide, methotrexate, mitoxantrone, mycophenolate, or a combination) who are seropositive for anti-JCV antibodies, or who seroconvert from negative to positive during subsequent testing, the estimated risk of PML is relatively high even in the first 24 months (1:330) and increases thereafter to 1:31. Therefore, we suggest stopping natalizumab and transitioning to another DMT after 12 months of treatment (or sooner) for most of these patients because of the mounting risk of PML.
Importantly, the JCV antibody status may change over time among natalizumab-treated patients with MS [34-37]. In a retrospective study of German patients with serologic follow-up over approximately eight months, conversion from anti-JCV seronegative to seropositive status occurred in 19 of 194 (10 percent), while conversion from seropositive to seronegative status occurred in 13 of 276 (5 percent) [34]. Anti-JCV antibody levels were low in both groups, suggesting that fluctuations around the cut points of the assay could lead to alternating positive and negative test results. A study of 165 patients from France reported a higher rate of seroconversion after one year of treatment with natalizumab, but the study used a more sensitive anti-JCV assay, which complicates the analysis [35].
●Neurologic assessment – Clinical vigilance and neurologic follow-up is an important aspect of monitoring for the signs and symptoms of PML. In general, MS relapses are characterized by subacute onset, typically occurring over hours to days, with eventual stabilization and resolution, and typical presentations that include diplopia, optic neuritis, and myelopathy. By contrast, PML is characterized by even slower onset over several weeks to months, progressive disease, and presentations that include aphasia, behavioral and neuropsychiatric abnormalities, cortical visual deficits, hemiparesis, and seizures.
●MRI monitoring – Some PML cases have been discovered prior to any symptoms, and imaging (ie, brain MRI) follow-up is very important. A baseline brain MRI scan should be obtained prior to initiating therapy with natalizumab. For patients who are JCV antibody-positive, screening for PML with brain MRI more frequently, as often as every three to four months, may be advised, although practice preferences vary widely among MS experts. For patients who are negative for JCV antibodies at baseline and at one year, we suggest repeating the MRI scan every 12 months for PML monitoring (table 2).
●New MRI lesion – Any anti-JCV positive patient on natalizumab who develops a new MRI lesion while should be evaluated for the possibility of PML. Important issues are the specific characteristics of the lesion and the length of time on natalizumab. Radiologists must be informed that patients are on natalizumab and at risk for PML, as the initial lesions of PML may be indistinguishable from a new demyelinating lesion due to MS. However, the presence of punctate hyperintense T2 lesions and cortical gray matter involvement suggest PML rather than new MS-related lesions, while periventricular location and focal appearance (as opposed to a diffuse, confluent irregular, or infiltrative appearance) suggest new MS-related lesions rather than PML [38]. Cerebrospinal fluid analysis for JCV polymerase chain reaction (PCR) DNA is mandatory in these patients, though different laboratories have different sensitivities, and the PCR may be negative in early case of PML. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)
Extended interval dosing — Observational data suggest that dosing natalizumab every five to eight weeks rather than every four weeks may reduce the risk of PML without reducing efficacy [39-44], but this approach is not yet proven. In a retrospective cohort study that analyzed over 35,000 patients from the TOUCH database who were seropositive for the anti-JCV antibody, natalizumab extended interval dosing was associated with a lower risk of PML than standard interval dosing [43]. A later study from the same investigators, published in abstract form, updated data from the TOUCH program and also found that extended interval dosing was associated with a lower risk of PML [41]. In addition, a small study found there was no significant difference in neurofilament light serum levels, a proposed biomarker of MS disease activity, for patients who switched to extended interval dosing compared with patients who remained on standard interval dosing [42].
In a subsequent prospective study of 61 patients with RRMS who were free of disease activity on natalizumab for at least one year, natalizumab treatment intervals were personalized according to natalizumab trough levels [40]. The dosing interval was increased by one week if the natalizumab trough level was ≥15 mcg/mL, targeting a natalizumab trough level of 10 mcg/mL. This method extended the dosing interval to five to seven weeks for 51 patients and retained the standard four-week dosing interval for 10 patients. For patients on extended interval dosing who completed one year of follow-up (n = 48) and a one-year extension phase (n = 24), none developed relapses or new or enlarging MRI lesions.
The utility of extended interval dosing needs confirmation, ideally in a larger clinical trial, but such extended interval dosing is a potential option when natalizumab is continued despite conversion to seropositivity for the JCV.
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, another anti B cell monoclonal antibody. 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; the latter has shown efficacy in small trials (see 'Rituximab' below) and has been widely used in some MS centers for years.
Indications and efficacy — Ocrelizumab is indicated for relapsing forms of MS including, RRMS, clinically isolated syndrome (CIS), and active SPMS; it is also indicated for primary progressive MS [45].
Two identical randomized, controlled trials (OPERA I and OPERA II) of 821 and 825 adults with relapsing multiple sclerosis compared IV ocrelizumab (600 mg every 24 weeks) with subcutaneous interferon beta-1a (44 micrograms three times weekly) for 96 weeks [46]. All patients were pretreated with one dose of IV methylprednisolone (100 mg) before each infusion. 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 also 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).
In the placebo-controlled ORATORIO trial, which enrolled 732 adult patients with primary progressive MS, ocrelizumab modestly reduced confirmed disability progression at 12 and 24 weeks. The evidence for ocrelizumab in primary progressive MS is reviewed in greater detail elsewhere. (See "Treatment of primary progressive multiple sclerosis in adults", section on 'Ocrelizumab'.)
Adverse effects — The most common adverse effects of ocrelizumab are infusion reactions, upper and lower respiratory tract infections, and skin infections [47].
In the postmarketing setting, the following infections and immune-mediated conditions have been reported in patients treated with ocrelizumab [47-49]:
●Serious infections caused by herpes simplex virus and varicella zoster virus (VZV)
●Hepatitis B reactivation
●PML that developed in patients on ocrelizumab who had not received natalizumab or prior immunomodulatory medications, and who did not have conditions resulting in compromised immune system function
●Immune-mediated colitis
There may be an increased risk of malignancy, including breast cancer, with ocrelizumab. In randomized trials, ocrelizumab treatment was associated with infusion reactions in 34 percent, serious infections in 1 percent, and neoplasms in 0.5 percent of patients [46,50].
Longer-term risks associated with rituximab use (see 'Rituximab' below) are theoretically also similar for ocrelizumab, and we suggest counseling patients accordingly [51].
There are no data regarding the risk of fetal harm associated with ocrelizumab treatment during pregnancy, but animal data suggest harm with observations of increased perinatal mortality and renal, bone marrow, and testicular toxicity [47].
Ocrelizumab is contraindicated in patients with active hepatitis B virus infection and those with a history of life-threatening infusion reaction to ocrelizumab [47].
Dosing — The initial dose of ocrelizumab is a 300 mg IV infusion, followed two weeks later by a second 300 mg IV infusion [47]. Subsequently, ocrelizumab is given as 600 mg IV infusion every six months, beginning six months after the first 300 mg dose. 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. Some mild infusion reactions can be treated with additional doses of methylprednisolone and/or antihistamine.
Quantitative levels of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) should be obtained at baseline; the label recommends consulting with immunology experts for patients with low immunoglobulin levels before starting ocrelizumab [47]. Patients must be screened for hepatitis B virus before starting ocrelizumab (see "Hepatitis B virus: Screening and diagnosis"). We also screen at baseline for hepatitis C, tuberculosis, HIV, and obtain a complete blood count, lymphocyte subsets, and a metabolic panel. Repeat screening for these factors depends upon individual patient characteristics, such as hepatitis risk factors, prior vaccination, and level of hepatitis B surface antibody (anti-HBs) as a positive response to vaccination. (See "Hepatitis B virus immunization in adults".)
Patients should receive all necessary live or live-attenuated vaccines at least four weeks before starting ocrelizumab and non-live vaccines at least two weeks before starting ocrelizumab [47]. Live-attenuated and live vaccines are not recommended during ocrelizumab treatment or after discontinuation until B-cell repletion occurs.
Rituximab — Rituximab is a monoclonal antibody directed against the CD20 antigen on B lymphocytes that causes B cell reduction; its mechanism of action is similar to that of ocrelizumab.
Indications and efficacy — Rituximab has been widely used off-label to treat MS in some centers for years. Data from randomized controlled trials supporting the effectiveness of rituximab for RRMS are limited but convincing, and nonrandomized studies and the positive trials for ocrelizumab increase confidence that rituximab is beneficial [52].
In a rater-blind trial, adult patients (n = 200) in Sweden with RRMS or CIS were randomly assigned in a 1:1 ratio to treatment with intravenous rituximab (1000 mg, followed by 500 mg every six months) or oral dimethyl fumarate (240 mg twice daily) [53]. At 24 months of follow-up, relapses were less frequent in the rituximab group compared with the dimethyl fumarate group (3 versus 16 percent, risk ratio [RR] 0.19, 95% CI 0.06-0.62). In an earlier randomized trial of 104 adult patients with RRMS, treatment with IV rituximab (1000 mg) given on days 1 and 15 reduced both total and new gadolinium-enhancing lesions on brain MRI at 24 weeks when compared with placebo [54]. In addition, rituximab treatment reduced 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 JCV antibody positivity, the rituximab group had lower rates of clinical relapse, adverse events, and treatment discontinuation compared with the fingolimod group [55]. In another observational study of 494 patients diagnosed with RRMS identified from a Swedish MS registry, rituximab treatment was associated with a lower discontinuation rate compared with other disease-modifying therapies, including interferons, glatiramer acetate, dimethyl fumarate, fingolimod, and natalizumab [56]. In addition, rituximab treatment was associated with a lower rate of clinical relapses and MRI measures of disease activity compared with interferons, glatiramer acetate, and dimethyl fumarate. However, the same investigators published a registry-based cohort study of over 6400 patients with RRMS from Sweden that examined the risk of infection associated with exposure to rituximab, natalizumab, fingolimod, interferon beta, and glatiramer acetate [51]. Among these, treatment with rituximab was associated with the highest rate of serious infections.
Adverse effects — Potential adverse effects include infusion reactions, hypogammaglobulinemia, infection, reactivation of hepatitis B, and neutropenia.
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 (PML): Epidemiology, clinical manifestations, and diagnosis".)
Dosing and monitoring — Patients must be screened for hepatitis B virus before starting rituximab (see "Hepatitis B virus: Screening and diagnosis"). We also screen at baseline for hepatitis C, tuberculosis, HIV, and obtain a complete blood count, lymphocyte subsets, levels of IgG, IgA, and IgM, and a metabolic panel. In addition, patients should ideally receive all necessary immunizations at least six weeks prior to starting rituximab.
Immunoglobulin levels should be monitored prior to each infusion cycle.
Rituximab dosing varies among UpToDate MS experts, with the following different regimens employed [52,57]:
●Induction with two 1 g infusions separated by a two-week interval, followed by 1 g infusion given every six months
●1 g infusion given every six months with a reduction in the dose and/or infusion frequency after one or two years
●500 mg infusion given every six months
Rituximab should be given under close medical supervision with access to medical support to manage possible severe infusion reactions. Premedication is recommended using both methylprednisolone 100 or 125 mg IV (or equivalent glucocorticoid) approximately 30 minutes prior to each rituximab infusion, and with an antihistamine (eg, diphenhydramine) approximately 30 to 60 minutes prior to each rituximab 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.
Ofatumumab — Ofatumumab is a monoclonal antibody that targets CD20 (a protein expressed on the surface of normal B lymphocytes) and causes selective B cell depletion.
Indications and efficacy — Ofatumumab was approved in August 2020 by the US Food and Drug Administration (FDA) for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
Efficacy was established in two controlled trials (ASCLEPIOS I and II) of identical design that enrolled a combined total of over 1800 adults with relapsing MS [58]. Patients were randomly assigned in a 1:1 ratio to treatment with subcutaneous ofatumumab and oral placebo or oral teriflunomide and subcutaneous placebo for up to 30 months. At a median follow-up of 1.6 years, ofatumumab compared with teriflunomide reduced the annualized relapse rate in ASCLEPIOS I (0.11 versus 0.22, absolute risk reduction [ARR] -0.11, 95% CI -0.16 to -0.06) and ASCLEPIOS II (0.10 versus 0.25, ARR -0.15, 95% CI -0.20 to -0.09). In pooled data from the two trials, ofatumumab reduced the number of patients with disability worsening confirmed at six months (8.1 percent, versus 12.0 with teriflunomide, hazard ratio 0.68, 95% CI 0.50-0.92, ARR 4.1 percent). In both trials, ofatumumab reduced the mean number of gadolinium-enhancing lesions per T1-weighted MRI scan and the annualized rate of new or enlarged lesions on T2-weighted MRI.
Adverse effects — The most common adverse effects observed with ofatumumab are upper respiratory tract infection, headache, injection-related reactions, and local injection site reactions [59]. The potential for reduction in immunoglobulins may increase the risk of recurrent infections or opportunistic infections.
Ofatumumab is contraindicated in patients with active hepatitis B virus infection. Animal data suggest a risk of fetal harm. The label recommends use of an effective method of contraception during ofatumumab treatment and for six months after discontinuation [59].
Dosing and monitoring — Ofatumumab is given by subcutaneous injection, starting with 20 mg administered at weeks zero, one, and two. Subsequently, the dose is 20 mg per month starting at week four [59]. Before the first dose, patients should be screened for hepatitis B virus and tested for quantitative serum immunoglobulins. Patients should receive all recommended immunizations at least four weeks before starting ofatumumab. Administration should be delayed in patients with active infection until the infection resolves. Live or live-attenuated vaccines are not recommended during treatment and after stopping treatment until B cell repletion occurs.
Alemtuzumab — Alemtuzumab is a humanized monoclonal antibody that causes depletion of CD52-expressing T cells, B cells, natural killer cells, and monocytes [60].
Indications and efficacy — Alemtuzumab is indicated for the treatment of relapsing forms of MS, including RRMS and active SPMS. Because of its safety profile, alemtuzumab is not recommended for the treatment of clinically isolated syndromes. Alemtuzumab is generally reserved in the United States for patients with highly active RRMS who have had an inadequate response to two or more DMTs, or where other DMTs cannot be used. Furthermore, the European Medicines Agency recommends that alemtuzumab should only be used for the treatment of RRMS if the disease is highly active despite treatment with at least one DMT or if the disease is worsening rapidly [61]. The drug is contraindicated in patients with HIV infection, active infection, or known hypersensitivity to alemtuzumab [62].
Data from randomized controlled trials show that alemtuzumab is more effective than interferon beta-1a for reducing the relapse rate in RRMS [63]. This benefit is associated with a small increased risk of potentially serious infections and autoimmune disorders, including immune thrombocytopenia (ITP) [64-66].
CARE-MS I was a rater-blind trial that evaluated over 550 adults with RRMS, low disability levels, and no prior DMT [65]. 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 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 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 [66]. At two years, alemtuzumab reduced the proportion of patients with any relapse (35 percent, versus 53 percent for interferon beta-1a, rate ratio 0.51, 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. Notably, the CARE-MS II trial design may have magnified the treatment effect of alemtuzumab, as some patients were randomly assigned to the same treatment (interferon beta-1a) on which they had disease activity prior to enrollment. Modern treatment paradigms usually do not continue a therapy that has been associated with breakthrough disease.
Adverse effects — The main side effects of alemtuzumab are infusion reactions, infections, and autoimmune disorders [64-67]. Infusion reactions occur in approximately 90 percent of patients and are 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 [65,66]. Thyroid autoimmunity was seen in 16 to 18 percent of patients at two years after alemtuzumab treatment [65,66], and in 30 percent with longer follow-up [67]. ITP developed in 1 percent of patients at two years [65,66], and in 3 percent at three years [64,67]. 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 [68].
The prescribing label warns of an increased risk of autoimmunity (ITP, thrombotic thrombocytopenic purpura [TTP], antiglomerular basement membrane disease, autoimmune encephalitis), infusion reactions, thyroid disorders, hemophagocytic lymphohistiocytosis, adult-onset Still disease, acquired hemophilia A, infections, and malignancies (thyroid cancer, melanoma, lymphoproliferative disorders) [62].
Other reports described three cases of acute acalculous cholecystitis [69] and two cases of neutropenia [70] during treatment with alemtuzumab for RRMS. Announcements from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have warned of cases of ischemic stroke, hemorrhagic stroke, arterial dissection, and myocardial infarction that occurred shortly after starting treatment with alemtuzumab [61,71,72].
Dosing and monitoring — Necessary immunizations must be completed at least six weeks before the start of treatment with alemtuzumab [62]. Patients without a history of VZV infection or vaccination for VZV should be tested for antibodies to VZV, and VZV vaccination should be considered for patients who are antibody-negative, with postponing alemtuzumab treatment for six weeks after VZV vaccination. Patients should be screened for tuberculosis and advised to avoid potential sources of Listeria monocytogenes. (See "Treatment and prevention of Listeria monocytogenes infection", section on 'Prevention of foodborne infection'.)
To monitor for early signs of potentially serious adverse events, laboratory testing is recommended at baseline and periodically thereafter until 48 months after the last treatment course of alemtuzumab for the following [62]:
●Urine protein to creatinine ratio prior to initiation of treatment
●Complete blood count (CBC) with differential prior to treatment and at monthly intervals thereafter
●Serum creatinine levels prior to treatment and at monthly intervals thereafter
●Urinalysis with urine cell counts prior to treatment and at monthly intervals thereafter
●Thyroid function testing (eg, thyroid stimulating hormone level [TSH]) prior to treatment and every three months thereafter
●Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin levels prior to initiation and periodically thereafter
Baseline and yearly skin examination are recommended to monitor for melanoma [62].
Alemtuzumab is administered via IV infusion at 12 mg daily for five consecutive days (total 60 mg) at the start of treatment followed 12 months later by 12 mg daily for three consecutive days (total 36 mg) [62]. Subsequent treatments (12 mg daily for three consecutive days, total dose 36 mg) are given as needed at least 12 months after the last dose of a previous treatment course. Premedication with glucocorticoids (1 g of methylprednisolone) for the first three days of therapy is indicated. Infusions should be administered in a medical setting capable of managing anaphylaxis, serious infusion reactions, and myocardial, cerebrovascular, or pulmonary adverse reactions, and patients should be observed for at least two hours after each infusion.
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 continuing for at least two months after completion of a treatment course, or until the CD4+ count is >200 cells/microL, whichever occurs later [62]. Prolonged surveillance (for 48 months after the last dose) for bone marrow suppression, infections, and autoimmune disorders such as ITP is also necessary. Patients should be educated about the symptoms of ITP and should report them immediately if they develop.
Treatment with alemtuzumab in the United States requires special registration through a restricted distribution program (the Lemtrada Risk Evaluation and Mitigation Strategy or REMS) for both the center and patient in order to ensure adequate follow-up [73].
ORAL THERAPIES — Approved oral disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) are dimethyl fumarate, diroximel fumarate, monomethyl fumarate, teriflunomide, fingolimod, siponimod, ozanimod, ponesimod, and cladribine [74].
Fumarates — Fumarates may have neuroprotective and immunomodulatory properties through activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, the exact mechanism of therapeutic effect in MS is uncertain.
Dimethyl fumarate — Dimethyl fumarate is an oral fumarate that is metabolized to monomethyl fumarate, its active metabolite.
Indications and efficacy — Dimethyl fumarate is indicated for the treatment of relapsing forms of MS, including clinically isolated syndromes, RRMS, and active secondary progressive multiple sclerosis (SPMS).
In the CONFIRM and DEFINE 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 [75-77], and results from the DEFINE trial suggest that BG-12 reduces the rate of disability progression [76].
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 [75]. 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 [76]. 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.
Adverse effects — The most common side effects of dimethyl fumarate were flushing and gastrointestinal symptoms, including diarrhea, nausea, and abdominal pain.
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 [78-81]. Other reported adverse events include anaphylaxis and angioedema, herpes zoster and other serious opportunistic infections, hepatotoxicity, and lymphopenia [82]. (See "Treatment of psoriasis in adults", section on 'Fumaric acid esters' and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
Dimethyl fumarate is contraindicated for patients with known hypersensitivity to dimethyl fumarate.
Dosing and monitoring — 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 every six months or as clinically indicated during the course of treatment. Dimethyl fumarate should be discontinued if lymphocytopenia develops, although the exact cutpoint that defines an unacceptably low count is not established. However, lymphocyte counts <0.8 x 109/L may raise concern despite the uncertainty of the cutpoint. 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 [83]. 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.
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. Taking the medication with food may decrease the rate of gastrointestinal upset.
Diroximel fumarate — Diroximel fumarate is an oral fumarate and bioequivalent to dimethyl fumarate; it is rapidly metabolized to monomethyl fumarate, its major active metabolite.
●Indications and efficacy – Diroximel fumarate was approved by the US Food and Drug Administration (FDA) in late 2019 for the treatment of relapsing forms of multiple sclerosis including clinically isolated syndrome, RRMS, and active secondary SPMS [84,85]. The approval of diroximel fumarate was based mainly upon bioequivalence, safety, and efficacy data for dimethyl fumarate; both are metabolized to monomethyl fumarate [84]. (See 'Dimethyl fumarate' above.)
●Adverse effects – The adverse effect profile of diroximel fumarate is similar to that of dimethyl fumarate, which has the same active metabolite (see 'Dimethyl fumarate' above). The most common adverse effects are flushing, abdominal pain, diarrhea, and nausea. Uncommon but serious adverse effects may include anaphylaxis, angioedema, opportunistic infections (eg, PML, herpes zoster virus), lymphopenia, and liver injury.
Diroximel fumarate is postulated to have fewer gastrointestinal symptoms compared with dimethyl fumarate. In a five-week randomized trial of patients with RRMS comparing diroximel fumarate with dimethyl fumarate, the group assigned to diroximel fumarate had lower rates of gastrointestinal adverse events (35 percent versus 49 percent) [86].
●Dosing and monitoring – Before starting diroximel fumarate, patients should have baseline tests to include complete blood count with lymphocyte count, serum aminotransferase, alkaline phosphatase, and total bilirubin levels [84].
Oral diroximel fumarate is started at 231 mg twice daily for seven days, and then increased to the maintenance dose of 462 mg twice daily. During therapy, patients should have a complete blood cell count, including lymphocyte count, six months after starting diroximel fumarate and every 6 to 12 months thereafter, as clinically indicated. Serum aminotransferase, alkaline phosphatase, and total bilirubin levels are monitored during treatment as clinically indicated.
Monomethyl fumarate — Monomethyl fumarate is another bioequivalent alternative to dimethyl fumarate.
●Indications and efficacy – Monomethyl fumarate received FDA approval in April 2020 for the treatment of relapsing forms of multiple sclerosis including clinically isolated syndrome, RRMS, and active secondary progressive disease. The approval was based upon bioequivalence, safety, and efficacy data for dimethyl fumarate, which is metabolized to monomethyl fumarate [87]. (See 'Dimethyl fumarate' above.)
●Adverse effects – The adverse effect profile of monomethyl fumarate is the same as that of dimethyl fumarate, the prodrug of monomethyl fumarate (see 'Dimethyl fumarate' above) [88]. The most common adverse effects are flushing, abdominal pain, diarrhea, and nausea. Uncommon but serious adverse effects may include anaphylaxis, angioedema, opportunistic infections (eg, PML, herpes zoster virus), lymphopenia, and liver injury.
●Dosing and monitoring – Before starting monomethyl fumarate, patients should have baseline tests to include complete blood count with lymphocyte count, serum aminotransferase, alkaline phosphatase, and total bilirubin levels [88].
Monomethyl fumarate is started at 95 mg twice daily for seven days, and then increased to the maintenance dose of 190 mg twice daily. During therapy, patients should have a complete blood cell count, including lymphocyte count, six months after starting monomethyl fumarate and every 6 to 12 months thereafter, as clinically indicated. Serum aminotransferase, alkaline phosphatase, and total bilirubin levels are monitored during treatment as clinically indicated.
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 [89].
Indications and efficacy — Teriflunomide is indicated for the treatment of relapsing forms of MS, including clinically isolated syndromes, RRMS, and active SPMS.
The effectiveness of teriflunomide for the treatment of RRMS was demonstrated in the TEMSO and TOWER trials [90,91]. 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 [90]. 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 [92].
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) [91]. This trial too had a high dropout rate of approximately 30 percent [92].
Adverse effects — The most common adverse effects of teriflunomide were headache, diarrhea, nausea, hair thinning, and elevated alanine aminotransferase (ALT) levels [90,93,94]. Uncommon but potentially serious adverse effects include hepatotoxicity, bone marrow suppression, immunosuppression, infections, hypersensitivity and serious skin reactions, peripheral neuropathy, increased blood pressure, and interstitial lung disease [95].
Teriflunomide is contraindicated in patients with severe hepatic impairment, pregnancy, hypersensitivity to teriflunomide, or current leflunomide treatment.
Dosing and monitoring — Patients should be brought up to date with all immunizations before initiating therapy with teriflunomide. Live vaccines should not be given concurrently [95]. Before starting teriflunomide, patients should be screened for latent tuberculosis infection. Blood pressure should be monitored before starting treatment and periodically thereafter.
The recommended dose of oral teriflunomide is 7 mg or 14 mg once daily [95].
Recommended laboratory testing includes transaminase and bilirubin levels at baseline, and ALT levels monthly for at least six months after starting treatment. A complete blood cell count (CBC) should be obtained within six months before starting treatment; further CBCs should be done if signs and symptoms of infection develop. Some experts repeat the CBC and a comprehensive metabolic panel (which includes liver and kidney function) every six months during therapy.
Due to the risk of teratogenicity, teriflunomide is contraindicated for females who are pregnant or trying to conceive, and females of childbearing age must have a negative pregnancy test before starting the drug. Teriflunomide is also found in semen [96]. Thus, females who become pregnant and males and females 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 two 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 couples taking the medication [97].
S1PR modulators — Fingolimod, siponimod, ozanimod, and ponesimod are sphingosine 1-phosphate receptor (S1PR) modulators used for the treatment of MS [98].
Fingolimod — Fingolimod is sphingosine analogue that modulates the S1PR and thereby alters lymphocyte migration, resulting in sequestration of lymphocytes in lymph nodes [99].
Indications and efficacy — Fingolimod is indicated for the treatment of relapsing forms of MS, including clinically isolated syndromes, RRMS, and active SPMS.
There is evidence from several randomized controlled trials that fingolimod is effective in reducing the relapse rate in patients with RRMS [100]. 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 [101]. At 24 months, 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. In the open-label FREEDOMS extension trial, long-term fingolimod treatment was associated with reduced relapse rates and disability progression [102].
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 [103]. At 12 months, 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. Results from the extension phase of the TRANSFORMS trial supported a long-term benefit of fingolimod for maintaining a reduced relapse rate [104].
Adverse effects — The most common adverse effects associated with fingolimod are headache, elevated liver enzymes, diarrhea, cough, flu, sinusitis, back pain, abdominal pain, and pain in the arms or legs [105]. Fingolimod treatment has been associated with an increased risk of bradyarrhythmia and atrioventricular block (potentially fatal), macular edema, liver injury, diminished respiratory function, tumor development, and opportunistic infections [101,103,106,107]. The immunomodulating and lymphocytopenic effects of fingolimod increase the risk of viral and fungal infection, including varicella zoster virus (VZV) infections [108-110], cryptococcal meningoencephalitis [111], and disseminated cryptococcus [112]. Rare cases of PML have been reported patients with and without prior immunosuppressant treatment [113-115]. All reported cases occurred after 19 months of fingolimod treatment.
Fingolimod is contraindicated in 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 sinus node dysfunction (unless treated with a pacemaker), a prolonged QT interval ≥500 milliseconds at baseline, and treatment with anti-arrhythmic drugs [105,116]. 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.
There is observational evidence that fingolimod may cause or contribute to paradoxical worsening of MS disease activity, including reports of MS rebound or severe worsening after stopping fingolimod treatment [117,118]. 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 [119-121].
Dosing and monitoring — Before starting fingolimod, patients should have the following [116]:
●Complete blood count and liver function test results within six months
●Electrocardiogram (ECG)
●Ophthalmologic examination
●Varicella serology, and VZV vaccination if antibody negative, for patients without a confirmed history of chicken pox or prior vaccination; fingolimod should not be started until one month after vaccination
●Females of childbearing potential should be informed of risk for adverse fetal outcomes; however, a higher rate of fetal abnormalities was not detected among infants exposed to fingolimod in pregnancy registries [122]
In addition, we suggest a skin examination at baseline to screen for evidence of precancerous skin lesions.
The dose of oral fingolimod is 0.5 mg once daily. The first dose, and doses following therapy interruption longer than 14 days, should be given in a setting where symptomatic bradycardia can be managed [105,116]. 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 [105,108]. 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 liver function tests 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 [123]. This has been associated, in our experience, with rebound of MS in some patients, so appropriate counseling and management should be provided before cessation of medication.
Siponimod — Siponimod is a S1PR modulator that is similar to but more selective than fingolimod.
Indications and efficacy — Siponimod is approved in the United States by the FDA for the treatment of adults with RRMS, active SPMS, and clinically isolated syndromes [124]. In the six-month dose-finding BOLD trial of 297 patients with RRMS, treatment with siponimod led to reductions in MRI lesion activity [125]. In the EXPAND trial of 1651 subjects with SPMS, oral siponimod compared with placebo reduced the risk of confirmed disability progression at three months, relapse rates at 12 and 24 months, and reduced the volume of brain lesions identified by T2-weighted MRI [126].
Adverse effects — The most common adverse reactions with siponimod are headache, hypertension, and increased transaminase levels [127]. Siponimod cause a dose-dependent decrease in peripheral lymphocyte counts by approximately 20 to 30 percent. Potential adverse effects include infections, macular edema, bradyarrhythmia, decreased pulmonary function, liver toxicity, cutaneous malignancies, increased blood pressure, and fetal harm [127]. Although not yet reported with siponimod, rare cases of posterior reversible encephalopathy syndrome (PRES) have been associated with other S1PR modulators.
Siponimod is contraindicated for patients with a CYP2C9*3/*3 genotype (which causes substantially elevated siponimod plasma levels), or those with recent myocardial infarction, unstable angina, stroke, TIA, or advanced heart failure [127]. It is also contraindicated for patients with Mobitz type II second-degree or third-degree atrioventricular block, or sick sinus syndrome unless patient has a functioning pacemaker. Caution is suggested for concomitant use with other anti-neoplastic, immune-modulating, or immunosuppressive therapies. The label advises against starting siponimod treatment after alemtuzumab.
Animal data suggest that siponimod may cause fetal harm; females of childbearing potential should avoid pregnancy during siponimod treatment' and for 10 days after stopping siponimod [127].
Dosing and monitoring — Prior to starting treatment, patients should be tested for CYP2C9 genotype, complete blood count, liver function, and presence of antibodies to VZV; antibody-negative patients should receive varicella vaccination [127]. In addition, patients should have baseline ophthalmic evaluation of the fundus and cardiac evaluation, including ECG, to look for conduction system abnormalities. A skin examination at baseline and periodically thereafter is recommended to monitor for precancerous skin lesions.
The starting dose of siponimod is 0.25 mg daily [127]. The first dose should be monitored for patients with sinus bradycardia, first- or second-degree (Mobitz type I) atrioventricular block, or a history of myocardial infarction or heart failure. For patients with a CYP2C9*1/*3 or *2/*3 genotype, the drug is titrated over a five-day period up to the maintenance dose of 1 mg daily; for patients with a CYP2C9*1/*1, *1/*2, or *2/*2 genotype, the drug is titrated over a six-day period to the maintenance dose of 2 mg daily. Liver function and blood pressure should be monitored during treatment.
Ozanimod — Ozanimod is an oral S1PR modulator, a class of drugs that includes fingolimod (see 'Fingolimod' above) and siponimod (see 'Siponimod' above). Ozanimod was approved in March 2020 by the FDA for the treatment in adults of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
Indications and efficacy — Two double-blind controlled trials (SUNBEAM [128] and RADIANCE [129]) randomly assigned patients with relapsing MS to oral ozanimod (0.5 or 1 mg daily) or to intramuscular interferon beta-1a (30 mcg weekly). In each trial, both doses of ozanimod were more effective than interferon beta-1a for reducing both the annualized relapse rate and the development of brain lesions on MRI. In the longer of the two trials (RADIANCE), the annualized relapse rates over 24 months for patients assigned to ozanimod 1 mg, ozanimod 0.5 mg, or interferon beta-1a were 0.17, 0.22, and 0.28, respectively [129]. Compared with interferon beta-1a, the risk of relapse was reduced with ozanimod 1 mg (rate ratio [RR] 0.62, 95% CI 0.51-0.77) and ozanimod 0.5 mg (RR 0.79, 95% CI 0.65-0.96).
Adverse effects — In the randomized trials, adverse events resulting in treatment discontinuation were uncommon with ozanimod; infections were similar for the ozanimod and beta interferon 1-a groups [128,129]. The most common adverse reactions with ozanimod are upper respiratory infection, elevated hepatic transaminase levels, orthostatic hypotension, urinary tract infection, back pain, and hypertension [130]. Serious adverse effects include infection, bradyarrhythmia, cardiac conduction delay, liver injury, fetal risk, hypertension, and macular edema. Females of childbearing potential should use contraception during ozanimod treatment and for three months after stopping treatment.
Ozanimod is contraindicated in patients with myocardial infarction, unstable angina, stroke, TIA, or heart failure in the last six months. Additional contraindications include patients with Mobitz type II second- or third-degree atrioventricular block, sick sinus syndrome, or sinoatrial block (unless the patient has a functioning pacemaker), and severe untreated sleep apnea. It is also contraindicated for patients taking a monoamine oxidase inhibitor.
Dosing and monitoring — Before starting ozanimod, patients should be assessed with a complete blood count, cardiac evaluation, and liver function tests [130]. All patients should have an ECG, and those with pre-existing heart conditions should have a cardiology evaluation. Patients with a history of uveitis or macular edema should have an ophthalmic evaluation. Current or prior medications should be reviewed for potential additive immunosuppressant effects and for drugs that could slow the heart rate or affect atrioventricular conduction. Patients without a history of chickenpox confirmed by a health care professional or without documentation of a full course of vaccination against VZV should also be tested for antibodies to VZV, and seronegative patients should have VZV vaccination.
Ozanimod is titrated slowly over the first week [130]. The recommended starting dose of ozanimod is 0.23 mg once daily on days 1 to 4, 0.46 mg once daily on days 5 to 7, and 0.92 mg once daily on day 8 and thereafter.
Ponesimod — Ponesimod is an oral S1PR modulator.
Indications and efficacy — Ponesimod was approved by the FDA in March 2021 for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, RRMS, and active SPMS. Efficacy was established in a controlled trial that randomly assigned 1133 patients with relapsing forms of MS to treatment with ponesimod 20 mg daily or teriflunomide 14 mg daily [131]. Over a treatment period of 108 weeks, patients in the ponesimod treatment group had a lower annualized relapse rate during the study period compared with those in the teriflunomide group (0.202 versus 0.290, relative risk reduction 31 percent, absolute risk reduction 0.088), and a lower number of new or enlarging T2 lesions and a lower number of gadolinium enhancing lesions on brain MRI [132].
Adverse effects — The most common adverse reactions with ponesimod are upper respiratory tract infections, hepatic transaminase elevations, and hypertension [132]. Serious adverse effects include infections, bradyarrhythmia, cardiac conduction delay, pulmonary effects, liver injury, fetal risk, hypertension, and macular edema.
Ponesimod is contraindicated for patients with a recent (within six months) history of myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure [132]. Additional contraindications include patients with Mobitz type II second- or third-degree atrioventricular block, or sick sinus syndrome (unless the patient has a functioning pacemaker).
Dosing and monitoring — Before starting ponesimod, patients require a complete blood count including lymphocyte count, ECG, liver function tests, and ophthalmic evaluation. Patients with pre-existing heart conditions should have a cardiology evaluation. Patients should also be tested for antibodies to VZV, and seronegative patients should have VZV vaccination. Current or prior medications should be reviewed for potential additive immunosuppressant effects and for drugs that could slow the heart rate or affect atrioventricular conduction. Ponesimod should not be started in patients with active infection.
The dose of oral ponesimod is started at 2 mg daily and slowly titrated (using a starter pack) over 15 days to a recommended maintenance dose of 20 mg once daily. Patients with sinus bradycardia or certain heart conditions should have four-hour cardiac monitoring with the first dose. Patients should be monitored for infection during treatment and for one to two weeks after stopping treatment. In addition, patients on treatment require periodic skin examinations to monitor for cutaneous malignancies, and females of childbearing potential are recommended to use effective contraception during treatment and for one week after stopping treatment.
Cladribine — Cladribine, an immunosuppressive purine antimetabolite agent that targets lymphocyte subtypes, appears to reduce the relapse rate in patients with RRMS. Cladribine was previously available in many countries, including the European Union, Canada, and Australia, before approval in the United States.
Indications and efficacy — Cladribine is approved in the United States by the FDA for the treatment of adults with relapsing forms of MS, including RRMS and active SPMS [133]. Because of its adverse effect profile, cladribine is generally reserved for patients who do not tolerate or have inadequate response to other drugs for MS [134].
Cladribine is beneficial for patients with relapsing forms of MS, as shown by the CLARITY trial of 1326 adults with RRMS [135]. 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 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.
Adverse effects — The most common adverse reactions with cladribine are upper respiratory tract infections, headache, and lymphocytopenia [134]. There is also an increased risk of life-threatening infection and tumor development. 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) in the CLARITY trial [135].
Cladribine is contraindicated in patients with malignancy and active chronic infections. It is contraindicated in pregnancy, breastfeeding, and for females and males of reproductive potential who do not plan to use effective contraception during treatment and for six months after the last dose in each treatment course.
Dosing and monitoring — Prior to starting cladribine, patients must be screened to exclude infections, malignancy, and pregnancy, and a baseline brain MRI should be obtained [134]. Zoster vaccination is recommended before treatment for patients who are seronegative for VZV. Vaccination with the recombinant zoster vaccine is recommended before or during treatment for patients who are seropositive for VZV.
The recommended cumulative dosage of oral cladribine is 3.5 mg/kg of body weight divided into two yearly treatment courses (1.75 mg/kg per treatment course) [134]. Each treatment course is divided into two treatment cycles of four or five days separated by approximately four weeks. Lymphocyte counts must be monitored before, during, and after treatment.
PLATFORM INJECTION THERAPIES — Older 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 have similar clinical utility [136].
Ofatumumab, a monoclonal antibody that was approved in 2020, is given by subcutaneous injection and is discussed with the other monoclonal antibodies. (See 'Ofatumumab' above.)
Interferons — Interferons are cytokines that modulate immune responsiveness through various mechanisms [137-139].
Indications and efficacy — A number of different IFNB preparations are effective for the treatment of RRMS, as presented below. All are indicated for the treatment of relapsing forms of MS, including clinically isolated syndromes, RRMS, and active secondary progressive multiple sclerosis (SPMS).
●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 [140]. 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 [140].
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) [141]. 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) [142]. Patients in this trial 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 [143]. 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 [144].
•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 [145]. 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 [146]. 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 lower in the group 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 assessed as an outcome measure, and different doses, frequencies, and routes of administration were compared [147,148].
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 [149]. 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 [150]. Pegylation can improve some pharmacodynamic properties, including a longer half-life and consequently a reduced dosing frequency [150,151]. 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 [152]. 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 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.
●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 [153]. 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 [142,154,155]. 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 [156].
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 [157-159], though a minority suggests otherwise [160].
Adverse effects of interferons — Injection site reactions are common with IFNB therapy and may include injection site abscess, cellulitis, or necrosis [161-164]. Flu-like symptoms are also common and may be treated with ibuprofen, acetaminophen, and glucocorticoids [165]. 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 [166-168], 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 [169].
There is a relatively high prevalence of mainly asymptomatic liver dysfunction (transaminitis) associated with IFNB therapy [170,171]. 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 and anemia. A partially reversible polyneuropathy was described in a small series of patients with MS who were treated with IFNB therapy [172]. In addition, rare cases of thrombotic microangiopathy have been linked to the use of IFNB therapy [173-175]. The relationship appears to be dose-dependent, suggesting a toxicity mechanism [175]. IFNB treatment should be stopped immediately for patients who develop thrombotic microangiopathy. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Immunosuppressive agents'.)
Dosing and monitoring interferons — Dosing of the different interferon-beta drugs differs according to the formulation and route of administration.
●Interferon beta-1b – Recombinant human interferon beta-1b is administered at 0.25 mg (1 mL) every other day subcutaneously by self-injection [161]. 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.
●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) [162].
●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 [163]. 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 [164].
Co-administration of analgesics and/or antipyretics on treatment days may help to minimize flu-like symptoms [164].
●Monitoring – 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, and thereafter repeat the liver function tests and complete blood count every six months. 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. However, a dose reduction of this magnitude may lower the effectiveness of IFNB therapy; 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 MRI activity, relapses, and disease progression [176-180]. All of the interferons are capable of stimulating the production of NAbs, which reduce the bioavailability of interferon [181]. The rate of NAb formation varies with the type of interferon, the dosing regimen, and duration of IFNB therapy [182]. In one study, 34 percent of patients taking interferon beta-1b developed neutralizing antibodies [145].
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 [183-185]. 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 [185].
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 [186]. 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.
Indications and efficacy — Glatiramer acetate is indicated for the treatment of relapsing forms of MS, including clinically isolated syndromes, RRMS, and active SPMS.
A number of randomized trials have demonstrated the effectiveness of glatiramer in RRMS [187]. The benefit of glatiramer acetate was first established in a double-blind trial of 251 patients with RRMS [188]. 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) [189]. In another trial, glatiramer 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 [190].
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, and/or anxiety [191]. Neutralizing antibodies to glatiramer acetate have been detected in some studies but their clinical significance is unknown [192]. Desensitization to glatiramer acetate has been successfully performed in patients with either systemic allergic reactions or recurrent local reactions [193].
Serious adverse effects due to glatiramer are uncommon, but cases of hepatotoxicity, some severe, have been reported [194-196].
Dosing and monitoring — Glatiramer acetate is administered by subcutaneous injection. There are two different doses, which are not interchangeable [191]:
●20 mg daily or
●40 mg three times a week
No laboratory monitoring is necessary.
OTHER TREATMENTS
Azathioprine — Early trials of azathioprine for MS were small and conflicting [197-199]. 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 [200]. 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 [201]. 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 [202]. 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 [203,204]. 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 [204]. 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, was 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 preparations for RRMS [205-207]. 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 [208-211], but not all [212] 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 [213]. 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 [214].
Laquinimod — Laquinimod is a synthetic immunomodulatory compound – a selective aryl hydrocarbon receptor inhibitor – with high oral bioavailability [215,216]. In the multicenter ALLEGRO trial of 1106 patients with RRMS 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) [217]. The trial had a relatively high dropout rate (22 percent), which limits the strength of the findings [218]. In the multicenter BRAVO trial of 1331 patients with RRMS, 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 0.82, 95% CI 0.66-1.02) [219]. While these trials suggest that laquinimod is modestly effective for reducing the relapse rate and disability progression for patients with RRMS, others such as CONCERTO did not meet their primary endpoint [220], and this drug is no longer being considered for approval for treatment in MS.
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, along with the limited evidence of benefit, mitoxantrone should not be used to treat MS unless potential benefits greatly outweigh the risks [221,222]. Thus, mitoxantrone is considered only as a last resort for patients with rapidly advancing disease who have failed other therapies [223]. 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 [224]. The left ventricular ejection fraction (LVEF) should be evaluated before initiating mitoxantrone and prior to each subsequent dose and 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 [224]. 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 than patients without these characteristics [225].
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 [226]. 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 RRMS on disease-modifying therapy (DMT) to nonmyeloablative HSCT with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) or to a another DMT of higher efficacy or different class than the DMT they were taking at baseline [227]. At a median follow-up of two years, disease progression, defined as an increase of one point on the 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 [228,229]. 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 [230]. 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 [231-235]. 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 [236].
●Progressive forms of MS – Hematopoietic stem cell transplantation (HSCT) has shown promise in uncontrolled studies of patients with progressive forms of MS [237-240]. 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 SPMS) that reported progression-free survival, which ranged from 33 to 95 percent at median follow-up times of 24 to 42 months [241]. 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 [241]. Among 13 case series with post-treatment 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 [242,243], but appears to be lower since the year 2000 [235,237,241].
In addition to HSCT, mesenchymal stem cell therapy for MS is being explored, with inconsistent results in small studies [244-248]. Larger controlled trials are awaited to evaluate the risk/benefit ratio of stem cell therapies for the treatment of MS.
COVID-19 PANDEMIC 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 [249,250]. (See "COVID-19: Vaccines".)
Note that COVID-19 vaccination 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 [251,252].
For patients starting B-cell depleting disease-modifying therapies, 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 [253].
Pre-exposure prophylaxis for COVID-19 with monoclonal antibodies is suggested for select individuals, including those taking immunosuppressive or immunomodulatory agents such as DMTs for MD. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Pre-exposure prophylaxis for selected individuals'.)
●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 [254,255].
Although not entirely consistent, observational data suggest that anti-CD20 DMTs for MS increase the risk for more severe COVID-19 illness [255-259]. 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 [258]. 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 [254,255,258,260]. In addition, the platform DMTs (the interferons and glatiramer acetate) have not been associated with increased severity of COVID-19 [259].
●Guidance for use of DMTs during the pandemic – Most patients already on DMT for MS should continue treatment during the pandemic, and that most newly diagnosed patients with MS should be started on DMT as appropriate [254,261].
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 3) [262]. 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 2 to 8 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 healthcare professional for advice about DMT management [261].
For patients who develop severe COVID-19, it may be reasonable to stop oral DMTs and monoclonal antibody DMTs until the recovery phase of the disease [254]. Some experts advise restarting treatment with S1PR modulators (eg, fingolimod) and natalizumab within eight weeks, circumstances permitting, in order to avoid rebound disease [254].
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 disease-modifying therapies (DMTs) for multiple sclerosis (MS) include:
•Natalizumab (see 'Natalizumab' above)
•Ocrelizumab (see 'Ocrelizumab' above)
•Rituximab (off label) (see 'Rituximab' above)
•Ofatumumab (see 'Ofatumumab' above)
•Alemtuzumab (see 'Alemtuzumab' above)
●Oral DMTs for MS include:
•Fumarates:
-Dimethyl fumarate (see 'Dimethyl fumarate' above)
-Diroximel fumarate (see 'Diroximel fumarate' above)
-Monomethyl fumarate (see 'Monomethyl fumarate' above)
•Teriflunomide (see 'Teriflunomide' above)
•Sphingosine 1-phosphate receptor modulators:
-Fingolimod (see 'Fingolimod' above)
-Siponimod (see 'Siponimod' above)
-Ozanimod (see 'Ozanimod' above)
-Ponesimod (see 'Ponesimod' above)
•Cladribine (see 'Cladribine' above)
●Platform injection DMTs for MS include:
•Interferons: recombinant human interferon beta-1b and recombinant human interferon beta-1a (see 'Interferons' above)
•Glatiramer acetate (see 'Glatiramer' above)
33 : Natalizumab-associated PML: Challenges with incidence, resulting risk, and risk stratification.
111 : Cryptococcal Meningoencephalitis in a Patient With Multiple Sclerosis Treated With Fingolimod.
177 : Neutralizing antibodies reduce the efficacy of betaIFN during treatment of multiple sclerosis.
