Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
immunomodulators
Disease-modifying therapy should be offered to all patients with relapsing-remitting MS (RRMS).[15][59] However, some patients may have a benign course or be in an age group where the benefits of disease-modifying therapy may be less clear.
Interferon beta preparations, glatiramer, dimethyl fumarate, diroximel fumarate, and teriflunomide are generally considered to be first-line agents.[60][61][62][63][64]
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[Evidence B] In the US, fingolimod and siponimod may also be used as first-line agents. However, fingolimod, siponimod, natalizumab, ocrelizumab, cladribine, and alemtuzumab are more commonly reserved for patients who have more aggressive disease and/or have not tolerated or responded to previous disease-modifying agents.[60][61][65][66][67][68][69]
Clinically significant cases of liver injury in patients treated with dimethyl fumarate have been reported.[87] The onset ranged from a few days to several months after initiation of treatment. Liver function tests should be obtained at baseline and considered at 6- to 12-month intervals. Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients on dimethyl fumarate; persistent lymphopenia appears to be a risk factor.[86] Monitoring of lymphocyte counts every 6 months while on therapy is advised.
Diroximel fumarate is similar to dimethyl fumarate (both drugs have the same active metabolite, monomethyl fumarate). It has comparable efficacy but lower rates of gastrointestinal adverse events.[88][89] Risk of clinically significant cases of liver injury should be considered in patients on diroximel fumarate; liver function tests should be monitored during treatment.
Teriflunomide is a potential teratogen; pregnancy should be excluded before starting treatment, and contraception must be used during treatment. A drug elimination procedure must be undertaken before trying to conceive.
Fingolimod can cause persistent bradycardia, which can increase the risk of serious cardiac arrhythmias. The UK Medicines and Healthcare products Regulatory Agency (MHRA) stipulates a number of contraindications relating to fingolimod use in patients with pre-existing cardiac disorders.[93] Severe worsening of MS after stopping fingolimod has been reported, which, although rare, can result in permanent disability.[95] Cases of PML and cases of basal cell carcinoma have also been reported in patients taking fingolimod. The European Medicines Agency (EMA) recommends that, because of the risk of major congenital malformations, fingolimod must not be used in pregnant women or in women of childbearing age who are not using effective contraception. If a woman becomes pregnant while using fingolimod, the medicine must be stopped and the pregnancy should be closely monitored.[121]
Siponimod is associated with a lower risk of adverse events than fingolimod.
Natalizumab is associated with an increased risk of PML. John Cunningham virus (JCV) testing should be carried out for risk stratification, and natalizumab should be continued only if benefits outweigh the risks in patients at higher risk for PML.[100][101][162] Expert panel recommendations regarding the stratification and ongoing monitoring of natalizumab-associated PML risk have been published.[102]
Ocrelizumab is approved by the Food and Drug Administration (FDA) and the EMA for the treatment of relapsing forms of MS.[104][105] Ocrelizumab can cause infusion-related reactions, which can be severe, and increase risk of infection. It may also increase the risk for malignancies, particularly breast cancer.
Rituximab is used off-label for the management of MS in some countries.[108] There is evidence for the efficacy and safety of rituximab in patients with RRMS.[109][110]
Oral cladribine is approved by the FDA for the treatment of relapsing forms of MS in adults, including RRMS. It is licensed by the EMA for the treatment of adult patients with highly active relapsing MS. Cladribine may increase the risk of malignancy and of fetal harm; it must not be used by patients with current malignancy, or by women and men of reproductive potential who do not plan to use effective contraception.
Alemtuzumab has been associated with rare, serious adverse effects, some fatal, within 3 days of infusion, including myocardial ischemia, myocardial infarction, cerebral hemorrhage, cervicocephalic arterial dissection, pulmonary alveolar hemorrhage, and thrombocytopenia.[115] Immune-mediated conditions can occur many months after treatment. A risk of serious and life-threatening infusion reactions, infections, and an increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders, have also been reported.[114]
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Serious cases of stroke and tears in the lining of arteries in the head and neck (cervicocephalic arterial dissection) have been reported in patients soon after alemtuzumab treatment (usually within 1 day). These can result in permanent disability and even death.[116] Healthcare professionals should consider stopping alemtuzumab in patients who develop signs of any of these conditions.
Alemtuzumab should be given in a hospital with ready access to intensive care facilities and specialists who can manage serious adverse reactions. Vital signs should be monitored before and during each infusion, liver function tests should be performed before and during treatment, and patients should be monitored for signs of pathological immune activation. Patients should be informed of the signs and symptoms of these conditions at each infusion, and advised to seek immediate medical attention if they experience symptoms.[117] Because of its safety profile, alemtuzumab is approved by the FDA for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS. In Europe, the use of alemtuzumab is restricted to patients with RRMS that is highly active despite adequate treatment with at least one disease-modifying therapy or if the disease is worsening rapidly, with a minimum of two disabling relapses in 1 year and brain imaging showing new damage. Alemtuzumab must not be used in patients with certain heart, circulation, or bleeding disorders.[117]
There is uncertainty regarding the potential harms to neonates from the use of disease-modifying drugs preconception and during pregnancy. For all drugs, the risk of potential harm to the neonate must be weighed against the risk of relapse in individual patients.[59] Guidelines from the Association of British Neurologists outline considerations with specific medications and circumstances.[118]
Primary options
interferon beta 1a: 30 micrograms intramuscularly once weekly; or 44 micrograms subcutaneously three times weekly
MoreOR
interferon beta 1b: 250 micrograms subcutaneously once daily on alternate days
OR
peginterferon beta 1a: 63 micrograms subcutaneously once daily initially on day 1, increase to 94 micrograms once daily on day 15, then 125 micrograms every 2 weeks thereafter
OR
glatiramer: (20 mg/ml solution) 20 mg subcutaneously once daily; (40 mg/ml solution): 40 mg subcutaneously three times weekly
OR
teriflunomide: 7-14 mg orally once daily
OR
dimethyl fumarate: 120-240 mg orally twice daily
OR
diroximel fumarate: 231 mg orally twice daily initially for 7 days, then increase to 462 mg twice daily; may temporarily decrease dose to initial dose if patient does not tolerate maintenance dose and then increase again within 4 weeks
Secondary options
fingolimod: 0.5 mg orally once daily
OR
siponimod: consult specialist for guidance on dose; dose depends on CYP2C9 genotype
OR
natalizumab: 300 mg intravenously once every 4 weeks
OR
ocrelizumab: 300 mg intravenously as a single dose initially, followed by 300 mg as a single dose 2 weeks later, then 600 mg every 6 months
OR
rituximab: consult specialist for guidance on dose
Tertiary options
cladribine: consult specialist for guidance on oral dose
OR
alemtuzumab: 12 mg intravenously daily for 5 consecutive days for the first treatment course, then 12 mg intravenously daily for 3 consecutive days given 12 months later
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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer
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