Version May 2024
INTRODUCTION — Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system that is a leading cause of disability in young adults. Disease-modifying therapies (DMTs) for MS are drugs that effectively reduce the relapse rate for patients with MS.
The indications, efficacy, dose, administration, monitoring, and adverse effects of oral DMTs for MS are discussed in this topic review. Other DMTs for MS are reviewed elsewhere:
●Monoclonal antibodies for MS (see "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis")
●Platform injection therapies (see "Overview of disease-modifying therapies for multiple sclerosis", section on 'Platform therapies')
CHOOSING THERAPY — There are multiple disease-modifying therapies (DMTs) for MS, including older platform injection therapies, monoclonal antibodies, and oral agents.
Oral DMTs for MS include fumarates (dimethyl fumarate, diroximel fumarate, and monomethyl fumarate), sphingosine 1-phosphate receptor (S1PR) modulators (fingolimod, siponimod, ozanimod, and ponesimod), a purine nucleoside analog (cladribine), and a pyrimidine synthesis inhibitor (teriflunomide) [1]. In general, oral DMTs may be preferred for patients with less active disease and for patients who value convenience using a self-administered oral medication compared with medications requiring injections or infusions, although efficacy appears to vary amongst them, and definitive benefit for using higher-efficacy therapies instead of an escalation approach remains to be established.
Thus, there is no uniform method for choosing the best DMT for an individual patient. The choice of a specific agent for patients with MS should be individualized according to disease activity, comorbid conditions, and patient values and preferences (algorithm 1).
The use of DMTs for specific clinical situations is discussed in separate topic reviews:
●(See "Management of clinically and radiologically isolated syndromes suggestive of multiple sclerosis".)
●(See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)
●(See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis".)
●(See "Treatment of secondary progressive multiple sclerosis in adults".)
●(See "Treatment of primary progressive multiple sclerosis in adults".)
●(See "Multiple sclerosis: Pregnancy planning".)
●(See "Multiple sclerosis: Pregnancy and postpartum care".)
The treatment of acute MS exacerbations is also reviewed separately. (See "Treatment of acute exacerbations of multiple sclerosis in adults".)
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 – Dimethyl fumarate is indicated for the treatment of relapsing forms of MS, including clinically isolated syndromes (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS). It is contraindicated for patients with known hypersensitivity to dimethyl fumarate.
●Dose and administration – 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.
●Adverse effects – The most common side effects of dimethyl fumarate are 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, although lymphocytopenia is considered the major risk factor for PML beyond JC polyomavirus (JCV) serostatus [2-6]. Other reported adverse events include anaphylaxis and angioedema, herpes zoster and other serious opportunistic infections, hepatotoxicity, and serious gastrointestinal reactions including perforation, ulceration, hemorrhage, and obstruction [6]. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
Liver injury associated with dimethyl fumarate is manifested by elevated serum aminotransferase and bilirubin levels, with onset from a few days to several months after starting treatment [7].
●Screening and monitoring – Treatment with dimethyl fumarate may decrease lymphocyte counts, so patients should have a complete blood count obtained before starting the medication, no longer than six months after starting treatment (eg, months 1, 2, 3, and 6 after starting treatment), and at least every six months or as clinically indicated during 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 risk has not been specifically studied in patients with pre-existing low lymphocyte counts.
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.
●Efficacy – In the CONFIRM and DEFINE trials, an oral formulation of dimethyl fumarate (called BG-12 at the time of these trials) significantly reduced relapse rates and the development of new brain lesions on magnetic resonance imaging (MRI) in patients with active MS [8-10], and results from the DEFINE trial suggest that dimethyl fumarate reduces the rate of disability progression [9].
The CONFIRM trial randomly assigned over 1400 adults with RRMS to treatment with oral dimethyl fumarate at 480 mg daily in two divided doses, oral dimethyl fumarate at 720 mg daily in three divided doses, subcutaneous glatiramer acetate 20 mg daily, or placebo in a 1:1:1:1 ratio [8]. At two years compared with placebo, the annualized relapse rate was significantly lower in groups assigned to dimethyl fumarate 480 mg daily, dimethyl fumarate 720 mg daily, and glatiramer acetate (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 dimethyl fumarate and to glatiramer acetate compared with placebo. There was a trend towards lower rates of disability progression with dimethyl fumarate and glatiramer acetate treatment, but the differences compared with placebo were not statistically significant. In post hoc analyses comparing dimethyl fumarate with glatiramer acetate, there were no significant differences in relapse rates or MRI outcomes.
The DEFINE trial randomly assigned over 1200 adults with RRMS to oral dimethyl fumarate at 480 mg daily in two divided doses, oral dimethyl fumarate at 720 mg daily in three divided doses, or placebo [9]. At two years, treatment with dimethyl fumarate 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). Dimethyl fumarate treatment also significantly reduced the number of new brain lesions on MRI.
Diroximel fumarate — Diroximel fumarate is an oral fumarate and bioequivalent to dimethyl fumarate; it is rapidly metabolized to monomethyl fumarate, its major active metabolite. The approval of diroximel fumarate was based mainly upon bioequivalence, safety, and efficacy data for dimethyl fumarate; both are metabolized to monomethyl fumarate [11]. (See 'Dimethyl fumarate' above.)
●Indications – Diroximel fumarate is indicated for the treatment of relapsing forms of MS, including CIS, RRMS, and active SPMS [11,12].
●Dose and administration – 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 [11]. The drug should not be taken with a high-fat, high-calorie meal or snack.
●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) [11]. 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, liver injury, and gastrointestinal reactions including perforation, ulceration, hemorrhage, and obstruction [11].
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) [13], possibly because the moiety attached to monomethyl fumarate (the active ingredient) is less enterotoxic in this form of the medication.
●Screening 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 [11].
During therapy, patients should have a complete blood cell count, including lymphocyte count, six months after starting diroximel fumarate (or months 1, 2, 3, and 6 after starting treatment) and every six months thereafter. 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. The approval was based upon bioequivalence, safety, and efficacy data for dimethyl fumarate, which is metabolized to monomethyl fumarate [14]. (See 'Dimethyl fumarate' above.)
●Indications – Monomethyl fumarate is indicated for the treatment of relapsing forms of MS, including CIS, RRMS, and active SPMS [15].
●Dose and administration – Monomethyl fumarate is started at 95 mg twice daily orally for seven days, and then increased to the maintenance dose of 190 mg twice daily [15].
●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) [15]. 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; serious gastrointestinal reactions including perforation, ulceration, hemorrhage, and obstruction have been reported with other fumarates [15].
●Screening 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 [15].
During therapy, patients should have a complete blood count, including lymphocyte count, within six months after starting monomethyl fumarate (or months 1, 2, 3, and 6 after starting treatment) and every six months thereafter, as clinically indicated. Serum aminotransferase, alkaline phosphatase, and total bilirubin levels are monitored during treatment as clinically indicated.
S1PR MODULATORS — Fingolimod, siponimod, ozanimod, and ponesimod are sphingosine 1-phosphate receptor (S1PR) modulators used for the treatment of MS [16]. These drugs work by preventing lymphocyte egress from lymph nodes, which is thought to limit migration of inflammatory cells into the central nervous system.
Fingolimod — Fingolimod is a sphingosine analog that modulates the S1PR and thereby alters lymphocyte migration, resulting in sequestration of lymphocytes in lymph nodes [17].
●Indications – Fingolimod is indicated for the treatment of relapsing forms of MS, including clinically isolated syndromes (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS), in patients age 10 years and older [18,19].
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 antiarrhythmic drugs [18]. 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.
●Dose and administration – For adults and children (age 10 years and older) weighing more than 40 kg, the dose of oral fingolimod is 0.5 mg once daily [18]. For children age ≥10 years weighing ≤40 kg, the dose is 0.25 mg orally, 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 [18]. 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 electrocardiogram (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.
●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 [18,19]. Fingolimod treatment has been associated with an increased risk of bradyarrhythmia and atrioventricular block (potentially fatal), increased blood pressure, macular edema, liver injury, diminished respiratory function, tumor development, and opportunistic infections [20-23]. The immunomodulating and lymphocytopenic effects of fingolimod increase the risk of viral and fungal infection, including varicella zoster virus (VZV) infections [24-26], cryptococcal meningoencephalitis [27], and disseminated cryptococcus [28]. Rare cases of progressive multifocal leukoencephalopathy (PML) and PML with immune reconstitution inflammatory syndrome (PML-IRIS) have been reported in patients with and without prior immunosuppressant treatment [29-31]. All reported PML cases occurred after 19 months of fingolimod treatment.
There is observational evidence that paradoxical worsening of MS disease activity can occur after stopping fingolimod treatment [32,33]. In addition, paradoxical worsening of MS disease activity (some following cessation of natalizumab) or the development of tumefactive MS lesions has been reported during fingolimod treatment [34-36].
●Screening and monitoring – Before starting fingolimod, patients should have the following baseline studies [18,19]:
•Complete blood count and liver function test results within six months
•ECG
•Ophthalmologic examination
•Varicella serology, and VZV vaccination if antibody negative, for patients without a confirmed history of VZV infection or prior vaccination; fingolimod should not be started until one month after vaccination
•Skin examination
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 [37].
With fingolimod treatment, the following tests and practices are recommended [18]:
•Monitor for infection during and for two months after stopping fingolimod treatment; patients with subacute new or worsening symptoms should be evaluated for possible PML with brain MRI and polymerase chain reaction (PCR) analysis of cerebrospinal fluid for the presence of JC polyomavirus (JCV) deoxyribonucleic acid (DNA).
•We check a complete blood count with differential including lymphocyte count before starting treatment and every six months during treatment. Fingolimod is expected to lower the lymphocyte count by its mechanism of action. Many experts suggest consideration of therapy switch if the lymphocyte count decreases below 200 cells/microL or even 400 cells/microL.
•Live attenuated vaccines should be avoided during and for two months after stopping fingolimod treatment [18,24].
•Ophthalmologic examination should be repeated three to four months after starting fingolimod, and routinely in patients with diabetes mellitus or a history of uveitis.
•A skin examination at baseline and periodically during treatment is recommended to screen for evidence of cancerous or precancerous skin lesions.
•Pulmonary function tests with spirometry and diffusion lung capacity for carbon monoxide (DLCO) should be obtained if indicated clinically.
•Liver function tests should be monitored for patients with symptoms suggestive of hepatic dysfunction; some experts monitor every six months during treatment even in the absence of symptoms.
•Monitor blood pressure during treatment.
•Fingolimod is a possible teratogen and should be stopped two months prior to conception, with consideration of switching to an anti-CD20 monoclonal antibody disease-modifying therapy (DMT) two or more months before attempts to conceive to avoid MS rebound [38]. (See "Multiple sclerosis: Pregnancy planning", section on 'Preconception planning and care'.)
•Stopping fingolimod 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.
●Efficacy – There is evidence from several randomized controlled trials that fingolimod is effective in reducing the relapse rate in patients with RRMS [39]. 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 [20]. 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 [40].
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 [21]. 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 [41].
Siponimod — Siponimod is a S1PR modulator that is similar to but more selective than fingolimod.
●Indications – Siponimod is approved in the United States by the Food and Drug Administration (FDA) for the treatment of adults with CIS, RRMS, and active SPMS [42].
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 [43]. It is also contraindicated for patients with Mobitz type II second-degree atrioventricular (AV) block, third-degree AV block, or sick sinus syndrome, unless the patient has a functioning pacemaker. Caution is suggested for concomitant use with other antineoplastic, immune-modulating, or immunosuppressive therapies. The label advises against starting siponimod treatment after alemtuzumab.
●Dose and administration – The starting dose of siponimod is 0.25 mg daily [43]. 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.
●Adverse effects – The most common adverse reactions with siponimod are headache, hypertension, and increased transaminase levels [43]. Siponimod causes 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 [43]. Although not yet reported with siponimod, rare cases of posterior reversible encephalopathy syndrome (PRES) have been associated with other S1PR modulators. Rare cases of PML and PML-IRIS have been reported in patients treated with S1PR modulators.
●Screening and monitoring – Before starting siponimod, patients should have the following baseline studies [43]:
•CYP2C9 genotype
•Complete blood count and liver function test
•Ophthalmologic examination
•Varicella serology, and VZV vaccination if antibody negative for patients without a confirmed history of VZV or prior vaccination
•Cardiac evaluation, including ECG, to look for conduction system abnormalities
•Skin examination
With siponimod treatment, the following tests and practices are recommended [43]:
•Monitor for symptoms and signs of infection. Patients with subacute new or worsening symptoms should be evaluated for possible PML with brain MRI and PCR analysis of cerebrospinal fluid for the presence of JCV DNA.
•We check a complete blood count with differential including lymphocyte count before starting treatment and every six months during treatment. S1PR modulators are expected to lower the lymphocyte count by their mechanism of action. Many experts suggest consideration of therapy switch if the lymphocyte count decreases below 200 cells/microL or even 400 cells/microL.
•Live attenuated vaccines should be avoided during and for four weeks after stopping siponimod.
•Ophthalmologic examination should be repeated if there is any change in vision, and done routinely in patients with diabetes mellitus or a history of uveitis.
•A skin examination periodically during treatment to screen for evidence of cancerous or precancerous skin lesions.
•Pulmonary function tests with spirometry and DLCO, if indicated clinically.
•Liver function tests for patients with symptoms suggestive of hepatic dysfunction; some experts monitor every six months during treatment even in the absence of symptoms.
•Blood pressure monitoring.
•Females of childbearing potential should avoid pregnancy during siponimod treatment and for 10 days after stopping siponimod [43]. (See "Multiple sclerosis: Pregnancy planning", section on 'Preconception planning and care'.)
•Stopping siponimod has been associated with rebound of MS in some patients [44], so appropriate counseling and management should be provided before cessation of medication.
●Efficacy – In the six-month dose-finding BOLD trial of 297 patients with RRMS, treatment with siponimod led to reductions in MRI lesion activity [45]. 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 the volume of brain lesions identified by T2-weighted MRI [46].
Ozanimod — Ozanimod is an oral S1PR modulator, a class of drugs that includes fingolimod (see 'Fingolimod' above) and siponimod (see 'Siponimod' above).
●Indications – Ozanimod is indicated for the treatment of adults with relapsing forms of MS, including CIS, RRMS, and active SPMS.
Ozanimod is contraindicated in patients with myocardial infarction, unstable angina, stroke, TIA, or heart failure in the last six months [47]. Additional contraindications include patients with Mobitz type II second-degree AV block, third-degree AV block, sick sinus syndrome or sinoatrial block (unless the patient has a functioning pacemaker), severe untreated sleep apnea, and concomitant use of a monamine oxidase inhibitor.
●Dose and administration – Ozanimod is titrated slowly over the first week [47]. The recommended starting dose of ozanimod is 0.23 mg once daily orally 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.
For patients with mild or moderate chronic hepatic impairment, the maintenance dose is 0.92 mg once every other day.
●Adverse effects – In the randomized trials, adverse events resulting in treatment discontinuation were uncommon with ozanimod; infections were similar for the ozanimod and interferon beta-1a groups [48,49]. The most common adverse reactions with ozanimod are upper respiratory infection, elevated hepatic transaminase levels, orthostatic hypotension, urinary tract infection, back pain, and hypertension [47]. 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. Rare cases of PML and PML-IRIS have been reported in patients treated with S1PR modulators.
●Screening and monitoring – Before starting ozanimod, patients should have the following baseline studies [47]:
•Complete blood count and liver function tests
•Ophthalmologic examination for patients with a history of uveitis or macular edema
•Varicella serology, and VZV vaccination if antibody negative, for patients without a confirmed history of VZV or prior vaccination
•ECG; patients with pre-existing heart conditions should have a cardiology evaluation
•Periodic skin examination is reasonable since treatment with other S1PR modulators is associated with a risk of cutaneous lesions
With ozanimod treatment, the following tests and practices are recommended [47]:
•Monitor for infection during and for three months after ozanimod treatment. Patients with subacute new or worsening symptoms should be evaluated for possible PML with brain MRI and PCR analysis of cerebrospinal fluid for the presence of JCV DNA.
•We check a complete blood count with differential including lymphocyte count before starting treatment and every six months during treatment. S1PR modulators are expected to lower the lymphocyte count by their mechanism of action. Many experts suggest consideration of therapy switch if the lymphocyte count decreases below 200 cells/microL or even 400 cells/microL.
•Live attenuated vaccines should be avoided during and for up to three months after stopping ozanimod.
•Ophthalmologic examination should be repeated if there is any change in vision, and done routinely in patients with diabetes mellitus or a history of uveitis.
•Pulmonary function tests with spirometry and DLCO, if indicated clinically.
•Monitor liver function tests every six months during treatment.
•Monitor blood pressure during treatment.
•Females of childbearing potential should avoid pregnancy during ozanimod treatment and for three months after stopping siponimod [47]. (See "Multiple sclerosis: Pregnancy planning", section on 'Preconception planning and care'.)
•Stopping ozanimod may be associated with rebound of MS in some patients as occurs with other S1PR modulators, so appropriate counseling and management should be provided before cessation of medication.
●Efficacy – Two double-blind controlled trials (SUNBEAM [48] and RADIANCE [49]) 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 [49]. 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).
Ponesimod — Ponesimod is an oral S1PR modulator.
●Indications – Ponesimod is indicated for the treatment of adults with relapsing forms of MS, including CIS, RRMS, and active SPMS [50].
Ponesimod is contraindicated for patients with a recent (within six months) history of myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure [50]. Additional contraindications include patients with Mobitz type II second-degree AV block, third-degree AV block, or sick sinus syndrome (unless the patient has a functioning pacemaker).
●Dose and administration – 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.
●Adverse effects – The most common adverse reactions with ponesimod are upper respiratory tract infections, hepatic transaminase elevations, and hypertension [50]. Serious adverse effects include infections, bradyarrhythmia, cardiac conduction delay, pulmonary effects, liver injury, fetal risk, hypertension, and macular edema. Rare cases of PML and PML-IRIS have been reported in patients treated with S1PR modulators.
●Screening and monitoring – Before starting ponesimod, patients should have the following [50]:
•Complete blood count including lymphocyte count
•Liver function tests
•ECG; patients with pre-existing heart conditions should have a cardiology evaluation
•Ophthalmologic evaluation
•Antibodies to VZV; seronegative patients should have VZV vaccination
•Skin examination
•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.
With ponesimod treatment, the following tests and practices are advised [50]:
•Monitor for infection during ponesimod treatment and for two weeks after stopping treatment. Patients with subacute new or worsening symptoms should be evaluated for possible PML with brain MRI and PCR analysis of cerebrospinal fluid for the presence of JCV DNA.
•We check a complete blood count with differential including lymphocyte count before starting treatment and every six months during treatment. S1PR modulators are expected to lower the lymphocyte count by their mechanism of action. Many experts suggest consideration of therapy switch if the lymphocyte count decreases below 200 cells/microL or even 400 cells/microL.
•Live attenuated vaccines should be avoided during and for one to two weeks after stopping ponesimod.
•Ophthalmologic examination should be repeated if there is any change in vision, and done routinely in patients with diabetes mellitus or a history of uveitis.
•Periodic skin examination to screen for evidence of cancerous or precancerous skin lesions.
•Monitor liver function tests every six months during treatment.
•Pulmonary function tests with spirometry and DLCO, if indicated clinically.
•Monitor blood pressure.
•Females of childbearing potential should avoid pregnancy during ponesimod treatment and for one week after stopping ponesimod. (See "Multiple sclerosis: Pregnancy planning", section on 'Preconception planning and care'.)
•Stopping ponesimod may be associated with rebound of MS in some patients [50], so appropriate counseling and management should be provided before cessation of medication.
●Efficacy – Efficacy of ponesimod 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 [51]. 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 [50].
OTHER IMMUNOSUPPRESSANTS
Cladribine — Cladribine, an immunosuppressive purine antimetabolite agent that targets lymphocyte subtypes, appears to reduce the relapse rate in patients with relapsing-remitting multiple sclerosis (RRMS). Cladribine was previously available in many countries, including the European Union, Canada, and Australia, before approval in the United States.
●Indications – Cladribine is indicated for the treatment of adults with RRMS and active secondary progressive multiple sclerosis (SPMS) [52]. 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 [53]. For the same reason, cladribine is not recommended for patients with clinically isolated syndromes (CIS) [53].
Cladribine is contraindicated in patients with malignancy, human immunodeficiency virus (HIV), or active chronic infections. It is also 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.
●Dose and administration – The recommended cumulative dose of oral cladribine is 3.5 mg/kg of body weight divided into two yearly treatment courses (1.75 mg/kg per treatment course) [53]. 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 and must be within normal limits before starting treatment and at least 800 cells/microL before starting the second treatment course.
●Adverse effects – The most common adverse reactions with cladribine are upper respiratory tract infections, headache, and lymphocytopenia [53]. There is also an increased risk of life-threatening infection, malignancy, and teratogenicity. 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 [54].
●Screening and monitoring – Before starting cladribine, patients should have the following [53]:
•Screening to exclude infections (HIV, tuberculosis, hepatitis B and C, acute infection), malignancy, and pregnancy
•Complete blood count with differential including lymphocyte count
•Zoster vaccination for patients who are seronegative for varicella zoster virus (VZV)
•Recombinant zoster vaccine is recommended before or during treatment for patients who are seropositive for VZV
•All recommended immunizations; live attenuated or live vaccines should be given at least four to six weeks before starting cladribine
•Baseline brain MRI, due to the risk of progressive multifocal leukoencephalopathy (PML)
With cladribine treatment, the following tests and practices are recommended [53]:
•Complete blood count and lymphocyte counts
•Anti-herpes prophylaxis for patients with lymphocyte counts <200 cells/microL
•Monitor for infections
•Liver function tests prior to each treatment course
•Follow cancer screening guidelines
•Exclude pregnancy before each treatment course; provide counseling for patients planning conception
•Effective contraception during treatment and for at least six months after the last dose of each treatment course
•Diagnostic evaluation (including brain MRI) if symptoms or signs suggestive of PML
•Irradiation of cellular blood components for patients who require blood transfusion, due to the risk of graft-versus-host disease
●Efficacy – Cladribine is beneficial for patients with relapsing forms of MS, as shown by the CLARITY trial of 1326 adults with RRMS [54]. 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.
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 [55].
●Indications – Teriflunomide is indicated for the treatment of relapsing forms of MS, including CIS, RRMS, and active SPMS.
Teriflunomide is contraindicated in patients with severe hepatic impairment, pregnancy, hypersensitivity to teriflunomide, or current leflunomide treatment.
●Dose and administration – The recommended dose of oral teriflunomide is 7 mg or 14 mg once daily [56].
●Adverse effects – The most common adverse effects of teriflunomide are headache, diarrhea, nausea, hair thinning, and elevated alanine aminotransferase (ALT) levels [57-59]. 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 [56]. Teriflunomide is associated with teratogenicity and embryofetal toxicity in animal studies. Teriflunomide is also found in semen [60]. However, no evidence of fetal harm was found in pregnancy registries of babies born to couples taking the medication [61].
●Screening and monitoring – Before starting teriflunomide, patients should have the following [56]:
•Liver function tests (transaminase, bilirubin) within the previous six months
•Complete blood count within the previous six months
•Screen for latent tuberculosis
•Bring patient up-to-date with all immunizations before initiating therapy with teriflunomide
•Exclude pregnancy in females of reproductive potential
•Blood pressure check
With teriflunomide treatment, the following tests and practices are recommended:
•Complete blood count if signs or symptoms of infection, or if signs or symptoms of bone marrow suppression; some experts repeat the complete blood count and a comprehensive metabolic panel (which includes liver and kidney function) every six months during therapy.
•Live vaccines should not be given concurrently [56].
•Monitor ALT levels at least monthly for six months after starting teriflunomide; stop treatment if transaminase increase is more than three times the upper limit of normal or if symptoms develop that are suggestive of hepatic dysfunction.
•Monitor blood pressure periodically.
•Effective contraception during teriflunomide treatment, followed by an accelerated drug elimination procedure after treatment.
•Due to the risk of teratogenicity, 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. Some practitioners avoid teriflunomide in partners of childbearing age.
●Efficacy – The effectiveness of teriflunomide for the treatment of RRMS was demonstrated in the TEMSO and TOWER trials [57,62]. 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 [57]. 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 [63].
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) [62]. This trial also had a high dropout rate of approximately 30 percent [63].
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
●Role of oral disease-modifying therapies (DMTs) for multiple sclerosis (MS) – There are multiple DMTs for MS, including older platform injection therapies, monoclonal antibodies, and oral agents. In general, oral DMTs are moderately effective for reducing the relapse rate and development of new brain lesions on MRI (see "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults", section on 'Comparative efficacy'); they may be preferred for patients with less active disease and for patients who value convenience using a self-administered oral medication compared with medications requiring injections or infusions. However, there is no uniform method for choosing the best DMT for an individual patient. The choice of a specific agent for patients with MS should be individualized according to disease activity, comorbid conditions, and patient values and preferences (algorithm 1). (See 'Choosing therapy' above.)
●Fumarates – The oral fumarate DMTs include dimethyl fumarate (see 'Dimethyl fumarate' above) and bioequivalents diroximel fumarate (see 'Diroximel fumarate' above) and monomethyl fumarate (see 'Monomethyl fumarate' above). These DMTS are indicated for the treatment of relapsing forms of MS including clinically isolated syndromes (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS). The most common adverse effects of these medications are flushing and gastrointestinal symptoms. Uncommon but serious adverse effects may include anaphylaxis, angioedema, opportunistic infections, lymphopenia, and liver injury. The dose, administration, and recommended patient screening and monitoring for use of fumarates are described above. (See 'Fumarates' above.)
●S1PR modulators – The oral sphingosine 1-phosphate receptor (S1PR) modulators are fingolimod (see 'Fingolimod' above), siponimod (see 'Siponimod' above), ozanimod (see 'Ozanimod' above), and ponesimod (see 'Ponesimod' above). They are indicated for the treatment of relapsing forms of MS including CIS, RRMS, and active SPMS. The most common adverse effects associated with S1PR modulators are headache, elevated liver enzymes, diarrhea, cough, flu, sinusitis, back pain, abdominal pain, and limb pain. More serious adverse effects include cardiac arrhythmias, increased blood pressure, macular edema, liver injury, diminished respiratory function, tumor development, and opportunistic infections. The dose, administration, and recommended patient screening and monitoring for use of S1PR modulators are described above. (See 'S1PR modulators' above.)
●Cladribine – Cladribine, an immunosuppressive purine antimetabolite agent that targets lymphocyte subtypes, is indicated for the treatment of adults with RRMS and active SPMS. 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; cladribine is not recommended for patients with CIS. The most common adverse reactions with cladribine are upper respiratory tract infections, headache, and lymphocytopenia. There is also an increased risk of life-threatening infection, malignancy, and teratogenicity. The dose, administration, and recommended patient screening and monitoring for use of cladribine are described above. (See 'Cladribine' above.)
●Teriflunomide – Teriflunomide inhibits pyrimidine biosynthesis and disrupts the interaction of T cells with antigen presenting cells. It is indicated for the treatment of CIS, RRMS, and active SPMS. The most common adverse effects of teriflunomide are headache, diarrhea, nausea, hair thinning, and elevated alanine aminotransferase (ALT) levels. Teriflunomide is teratogenic. 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. The dose, administration, and recommended patient screening and monitoring for use of teriflunomide are described above. (See 'Teriflunomide' above.)
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