Multiple Sclerosis Disease Modifying Therapies

Disease modifying therapies for multiple sclerosis reduce relapses, new lesions and disability progression by modulating or depleting immune cells. Early treatment of relapsing disease prevents accumulation of disability, and efficacy rises with risk.

Classification. Moderate efficacy: interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate. Higher efficacy: sphingosine-1-phosphate modulators (fingolimod, siponimod, ozanimod, ponesimod), cladribine, natalizumab, anti-CD20 antibodies (ocrelizumab, ofatumumab, rituximab), alemtuzumab.

• Interferon beta-1a 30 microgram intramuscularly weekly, or 22 to 44 microgram subcutaneously three times weekly; interferon beta-1b 250 microgram subcutaneously on alternate days.
• Glatiramer acetate 20 mg subcutaneously daily or 40 mg three times weekly.
• Dimethyl fumarate 120 mg twice daily for 7 days, then 240 mg twice daily.
• Teriflunomide 14 mg once daily.
• Fingolimod 0.5 mg once daily.
• Cladribine tablets 3.5 mg/kg over 2 years (1.75 mg/kg in each year).
• Natalizumab 300 mg intravenously every 4 weeks.
• Ocrelizumab 600 mg intravenously every 6 months (300 mg twice, 2 weeks apart, initially); ofatumumab 20 mg subcutaneously at weeks 0, 1 and 2, then monthly; rituximab 500 to 1,000 mg every 6 months (off label).
• Alemtuzumab 12 mg daily intravenously for 5 days, then 3 days a year later.

Differences. Higher-efficacy drugs carry more serious risk. Anti-CD20 antibodies and natalizumab give the greatest relapse reduction.

• Acute relapse: methylprednisolone 1 g intravenously daily for 3 to 5 days (or high-dose oral); plasma exchange if there is no response.
• Starting treatment: relapsing-remitting disease or active secondary progressive disease; ocrelizumab for primary progressive disease.
• Before starting: confirm the diagnosis. Neuromyelitis optica spectrum disorder is more common in people of African ancestry; test AQP4-IgG and MOG-IgG, because interferon beta, fingolimod and natalizumab can worsen it. Consider mimics such as HIV and HTLV-1 myelopathy, neurosyphilis and neurosarcoidosis.
• Screening: tuberculosis, hepatitis B and C, HIV, varicella immunity, pregnancy test, and JC virus antibody for natalizumab.
• Symptomatic treatment: fampridine 10 mg twice daily for walking; baclofen for spasticity.
• Regional: availability of disease modifying drugs is limited; rituximab, interferon beta and generic oral drugs are the most accessible.

Selection. Switch when there are relapses or new lesions despite adherence.

Contraindications. Active serious infection, pregnancy (teriflunomide, cladribine, fingolimod), malignancy, severe immunodeficiency. Fingolimod in recent myocardial infarction, heart block or QT prolongation. Natalizumab with prior immunosuppression and a high JC virus index.

Adverse effects. Interferons: flu-like symptoms, liver enzyme rise, depression. Glatiramer: injection reactions. Dimethyl fumarate: flushing, diarrhoea, lymphopenia. Teriflunomide: hair thinning, hepatotoxicity, hypertension. Fingolimod: bradycardia, macular oedema, infection. Cladribine: lymphopenia and herpes zoster. Natalizumab: progressive multifocal leukoencephalopathy. Anti-CD20 antibodies: infusion reactions, hypogammaglobulinaemia, hepatitis B reactivation. Alemtuzumab: autoimmune thyroid disease, immune thrombocytopenia, anti-GBM disease.

Interactions. Live vaccines are contraindicated during treatment. Teriflunomide washout uses cholestyramine 8 g three times daily for 11 days.

Special groups.

• Pregnancy: interferon beta and glatiramer can continue; plan stopping other drugs (fingolimod 2 months, teriflunomide washout, cladribine 6 months) before conception.
• Breastfeeding: interferon beta and glatiramer acceptable.
• Older adults: lower efficacy and higher infection risk; consider stopping after 60 to 65 if stable.
• Kidney impairment: avoid fampridine at creatinine clearance 50 mL/min or less.
• Liver impairment: avoid teriflunomide.

Monitoring. MRI yearly, full blood count and liver enzymes, lymphocyte counts, thyroid function (alemtuzumab), immunoglobulins with anti-CD20 treatment, and JC virus antibody every 6 months with natalizumab.

Referral and escalation. All patients need neurologist care. New neurological symptoms on natalizumab (progressive multifocal leukoencephalopathy), serious infection, or pregnancy on a teratogenic drug.