What are the therapeutic classes, mechanisms of action, and example medications (with typical dosing) used to treat multiple sclerosis?

Multiple Sclerosis Medication Classes and Mechanisms of Action

For relapsing-remitting MS, initiate high-efficacy disease-modifying therapies immediately at diagnosis—specifically ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine—rather than using traditional stepped escalation approaches, as early aggressive treatment prevents irreversible neurological damage and yields superior long-term outcomes. 1

Disease-Modifying Therapy Classes

Immunomodulators

• Interferons (IFN-β): Shift immune balance toward anti-inflammatory responses by modulating cytokine production, reducing T-cell activation, and decreasing blood-brain barrier permeability 2, 3

  • Examples: Interferon beta-1a (Avonex, Rebif), interferon beta-1b (Betaseron)
  • Dosing: Interferon beta-1a 30 mcg IM weekly (Avonex) or 44 mcg SC three times weekly (Rebif); interferon beta-1b 250 mcg SC every other day 3
  • Reduce annualized relapse rates by approximately 29-34% compared to placebo 3

• Glatiramer acetate: Induces antigen-specific suppressor T-cells and promotes anti-inflammatory Th2 responses 2, 4

  • Dosing: 20 mg SC daily or 40 mg SC three times weekly 3
  • Reduces relapse rates by approximately 29% 3

Sphingosine 1-Phosphate (S1P) Receptor Modulators

• Mechanism: Sequester lymphocytes in lymph nodes by blocking S1P-mediated egress, preventing inflammatory CNS infiltration; may also directly affect CNS-resident cells 5, 6
• Examples:
  • Fingolimod: 0.5 mg oral daily 3
  • Siponimod, ozanimod, ponesimod (newer agents with improved selectivity) 6
• Efficacy: Reduce annualized relapse rates by 48-54% compared to placebo 3
• Key monitoring: Baseline ECG and cardiac monitoring for first dose (bradycardia/heart block risk), ophthalmologic exams for macular edema 3

Fumarates

• Mechanism: Activate Nrf2 antioxidant pathway, reduce inflammatory cytokines, and shift toward anti-inflammatory immune responses 2, 3
• Dimethyl fumarate: 240 mg oral twice daily 3
• Diroximel fumarate: 462 mg oral twice daily (improved GI tolerability) 3
• Efficacy: Reduce relapse rates by approximately 44-53% 3

Monoclonal Antibodies (High-Efficacy)

Anti-CD20 B-Cell Depleting Agents

• Mechanism: Lyse CD20-expressing B-cells, eliminating antigen presentation and pro-inflammatory cytokine production 2, 4
• Ocrelizumab: 300 mg IV infusion twice (2 weeks apart) initially, then 600 mg IV every 6 months 1, 3
  • Only approved therapy for primary progressive MS 7
• Ofatumumab: 20 mg SC monthly (self-administered) 1, 7
• Efficacy: Reduce annualized relapse rates by approximately 46-47% compared to interferon beta-1a 3
• Monitoring: Hepatitis B screening before initiation, immunoglobulin levels every 6 months, watch for respiratory infections 1

Anti-α4 Integrin

• Natalizumab: Blocks α4β1 integrin on lymphocytes, preventing CNS infiltration by inhibiting adhesion to vascular endothelium 5, 2
  • Dosing: 300 mg IV every 4 weeks 3
  • Efficacy: Reduces relapse rates by approximately 68% 3
  • Critical safety concern: Progressive multifocal leukoencephalopathy (PML) risk, especially in JC virus antibody-positive patients; requires JC virus testing and MRI monitoring every 3-4 months if positive 1, 7, 3

Anti-CD52

• Alemtuzumab: Depletes T-cells and B-cells by targeting CD52 surface marker 5, 2
  • Dosing: 12 mg IV daily for 5 days, then 12 mg IV daily for 3 days one year later 3
  • Efficacy: Reduces relapse rates by approximately 49-55% compared to interferon beta-1a 3
  • Intensive monitoring required: Monthly CBC, serum creatinine, urinalysis for 48 months; thyroid function tests every 3 months for 48 months; screen for secondary autoimmunity (thyroid disease, immune thrombocytopenia, nephropathies) 1

Pyrimidine Synthesis Inhibitors

• Teriflunomide: Inhibits dihydroorotate dehydrogenase, reducing proliferation of activated lymphocytes 2, 3
  • Dosing: 7 mg or 14 mg oral daily 3
  • Reduces relapse rates by approximately 31-36% 3

Purine Analogs

• Cladribine: Selectively depletes lymphocytes through disruption of DNA synthesis and repair 1, 2
  • Dosing: 3.5 mg/kg cumulative dose over 2 years (given as short treatment courses) 3
  • High-efficacy agent with pulsed dosing strategy 1

Treatment Algorithm for Newly Diagnosed RRMS

Immediate First-Line Strategy

• For treatment-naïve patients with highly active or aggressive disease: Initiate high-efficacy DMT immediately (ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine) without trial of moderate-efficacy therapy 1
• Aggressive disease markers: Frequent relapses, incomplete recovery, high frequency of new MRI lesions, rapid disability onset, multiple gadolinium-enhancing lesions 1

Monitoring Protocol

• Clinical follow-up: Every 3-6 months with EDSS assessment 1
• MRI surveillance: Brain MRI at least annually with T2-weighted, T2-FLAIR, and gadolinium-enhanced T1-weighted sequences 1, 7
• High-risk patients: Increase MRI frequency to every 3-4 months 1, 7

Defining Treatment Failure

• Breakthrough disease activity on high-efficacy DMT includes: ≥1 clinical relapse, ≥2 new or enlarging T2 lesions on MRI, or ≥1 gadolinium-enhancing lesion 1
• Allow 6-12 months on high-efficacy DMT before declaring treatment failure, as some agents require this period for maximal efficacy 1

Escalation to AHSCT

• For highly active disease failing first high-efficacy DMT: Refer immediately for autologous hematopoietic stem cell transplantation (AHSCT) evaluation 1
• AHSCT outcomes: ~90% progression-free survival at 5 years versus ~25% with continued DMTs; ~78% achieve NEDA-3 (no evidence of disease activity) at 5 years versus ~3% with DMTs 1
• Favorable AHSCT criteria: Age <45 years, disease duration <10 years, EDSS <4.0, high focal inflammation on MRI with gadolinium-enhancing lesions 1

Critical Safety Considerations

Vaccination Timing

• Administer all indicated vaccines (COVID-19, influenza, pneumococcal, varicella-zoster) at least 4-6 weeks before starting immunosuppressive DMTs, or wait 4-6 months after last immune-reconstitution therapy 1

Washout Periods

• Keep washout periods as short as safely possible when switching DMTs to minimize disease reactivation risk 1
• Specific washout durations depend on mechanism and half-life of prior agent 1

Common Pitfalls

• Pseudoatrophy effect: Brain volume loss may initially increase after starting high-efficacy DMT due to resolution of inflammation-related edema; this does not represent true disease progression 1
• Delayed escalation: Do not delay switching to higher-efficacy DMT or AHSCT referral, as this prevents irreversible disability accumulation 1
• Inadequate monitoring: Failure to perform agent-specific safety monitoring (e.g., JC virus testing for natalizumab, autoimmunity screening for alemtuzumab) increases serious adverse event risk 1, 3

Infection Prophylaxis

• For patients on high-dose immunosuppression: Consider Pneumocystis jirovecii pneumonia prophylaxis with trimethoprim-sulfamethoxazole 1
• Universal recommendations: Herpes simplex and varicella zoster virus prophylaxis for certain agents; hepatitis B screening for all patients 8

Rehabilitation Strategy

• Initiate intensive rehabilitation immediately after starting high-efficacy DMT (especially post-AHSCT) to exploit neuroplasticity during complete inflammatory suppression 1
• Phases include pre-habilitation, acute inpatient rehabilitation (weeks 0-8), sub-acute intensive rehabilitation (weeks 8-12), and community-based rehabilitation with vocational reintegration (weeks 12-26) 1