What is the treatment for Multiple Sclerosis (MS)?

Treatment of Multiple Sclerosis

For relapsing-remitting MS, initiate high-efficacy disease-modifying therapies (DMTs) early in the disease course—specifically ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine—rather than moderate-efficacy options, as this approach yields superior long-term outcomes. 1

Treatment Strategy by MS Subtype

Relapsing-Remitting MS (RRMS)

High-efficacy DMTs should be started immediately upon diagnosis rather than following traditional escalation approaches. 1, 2

• First-line high-efficacy options include:

  • Ocrelizumab (monoclonal antibody targeting CD20+ B cells) 1
  • Ofatumumab (monoclonal antibody targeting CD20+ B cells) 1
  • Natalizumab (monoclonal antibody; FDA-approved for relapsing forms including clinically isolated syndrome, RRMS, and active secondary progressive disease) 3
  • Alemtuzumab (monoclonal antibody) 1
  • Cladribine (oral purine analog) 1

• Moderate-efficacy options (now considered suboptimal for initial therapy):

  • Interferon beta-1a (intramuscular or subcutaneous; FDA-approved for relapsing forms) 4, 5
  • Glatiramer acetate (subcutaneous) 5
  • Teriflunomide (oral) 5, 6
  • Dimethyl fumarate (oral) 5
  • Fingolimod (oral sphingosine 1-phosphate receptor modulator) 5, 6

Treatment-Refractory RRMS

For patients failing high-efficacy DMTs (defined as ≥1 clinical relapse occurring ≥3 months after treatment initiation, new MRI activity, or incomplete recovery from relapses), autologous haematopoietic stem cell transplantation (AHSCT) should be considered as the most effective escalation therapy. 7, 1

• AHSCT demonstrates 90% progression-free survival at 5 years versus 25% with standard DMTs, and 78% achieve NEDA-3 (no relapses, no disability increase, no new MRI lesions) at 5 years versus 3% with DMTs. 7

• Optimal AHSCT candidate profile:

  • Age <45 years 7, 1
  • Disease duration <10 years 7, 1
  • EDSS score <4.0 7, 1
  • High focal inflammation present on MRI 7, 1
  • Failed ≥1 high-efficacy DMT after meaningful treatment period 7, 1
  • Relapsing-remitting disease subtype 7, 1

• AHSCT protocols: BEAM-ATG (carmustine, etoposide, cytarabine, melphalan with anti-thymocyte globulin) or cyclophosphamide-ATG are most commonly used, with transplant-related mortality of only 1.4% in experienced centers. 7, 1

Secondary Progressive MS (SPMS)

AHSCT should only be considered for young patients (<45 years) with early SPMS of short disease duration who demonstrate well-documented clinical and radiological evidence of inflammatory activity within the past 12 months. 7, 1

• Critical requirement: MRI or clinical evidence of inflammatory activity within past 12 months is mandatory; AHSCT is not supported for non-inflammatory progressive disease. 7, 1

• EDSS must be <6.0 for AHSCT consideration in SPMS. 7, 1

• Registry data shows AHSCT (BEAM-ATG protocol) significantly slows disability progression and increases likelihood of sustained disability improvement compared to standard immunotherapy in active SPMS. 7

Primary Progressive MS (PPMS)

Ocrelizumab is the only FDA-approved DMT specifically indicated for primary progressive MS, though its efficacy is primarily limited to slowing disability progression rather than halting it. 1, 8

• AHSCT may be considered only for early inflammatory active PPMS with EDSS <6.0, age <45 years, and documented inflammatory activity within past 12 months. 1

Absolute Contraindications for AHSCT

AHSCT is not recommended when the following adverse factors are prevalent: 7

• Age >55 years 7, 1
• EDSS score >6.0 7, 1
• Absence of focal inflammation on MRI 7, 1
• No clinical or MRI inflammatory activity within past 12 months 7, 1
• Long-standing disease with severe disability 7
• Multiple medical comorbidities 7
• Active infections 7
• Poor performance status 7

Rapidly Evolving Severe MS

AHSCT as first-line therapy should only be considered for individuals with rapidly evolving, severe MS with poor prognosis, and must be offered within a clinical trial or observational research study. 7, 1

Monitoring Protocol

High-risk patients (highly active disease, recent treatment change) require MRI surveillance every 3-4 months; standard monitoring is every 6 months in the first year, then annually if stable. 1, 9

• MRI sequences must include: T2-weighted, T2-FLAIR, and gadolinium-enhanced T1-weighted sequences with consistent protocols for serial comparison. 1

• Critical pitfall to avoid: Pseudoatrophy effect (excessive brain volume decrease within first 6-12 months of treatment due to resolution of inflammation) should not be mistaken for disease progression. 9, 10

Treatment Algorithm Summary

1. Confirm MS subtype (RRMS, SPMS, PPMS) with MRI and EDSS scoring 9

2. For RRMS: Initiate high-efficacy DMT immediately (ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine) 1

3. If breakthrough disease on first high-efficacy DMT with aggressive features: Refer for AHSCT evaluation 1

4. For active SPMS with inflammatory activity, EDSS <6.0, age <45: Consider AHSCT 1

5. For PPMS: Initiate ocrelizumab; consider AHSCT only if early inflammatory active disease with EDSS <6.0 and age <45 1

6. For patients >55 years with stable disease >20 years: Consider treatment discontinuation as risks may outweigh benefits 9

Special Considerations

Natalizumab carries a boxed warning for progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection with risk factors including anti-JCV antibodies, treatment duration >2 years, and prior immunosuppressant use. 3

• Natalizumab requires enrollment in the TOUCH Prescribing Program REMS and should not be combined with other immunosuppressants. 3

For patients starting AHSCT, rehabilitation must begin immediately post-transplant to exploit neuroplasticity during complete inflammatory suppression, with phased approach including pre-habilitation, early mobilization, intensive outpatient rehabilitation, and maintenance rehabilitation. 9

Long-term AHSCT outcomes show 87% progression-free survival at 10 years in optimal candidates, representing a paradigm shift from last-resort therapy to standard of care for treatment-refractory disease. 1