What are the treatment options for multiple sclerosis (MS)?

Treatment Options for Multiple Sclerosis

For relapsing-remitting MS, initiate high-efficacy disease-modifying therapies (DMTs) early in the disease course rather than using a stepped escalation approach, as this strategy prevents irreversible neurological damage and improves long-term outcomes. 1

Disease-Modifying Therapies by MS Subtype

Relapsing-Remitting MS (RRMS)

High-efficacy DMTs should be started early and include monoclonal antibodies (alemtuzumab, natalizumab, ocrelizumab, ofatumumab) and in some classifications, cladribine. 1 These agents are more effective when treatment is initiated early rather than after disease progression has occurred. 1, 2

FDA-approved first-line options for relapsing forms of MS include:

• Interferon beta-1b for relapsing forms including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease 3
• Natalizumab (300 mg IV every 4 weeks) as monotherapy for relapsing forms of MS, though it carries significant PML risk requiring enrollment in the TOUCH Prescribing Program 4
• Additional DMTs include interferons, glatiramer acetate, teriflunomide, sphingosine 1-phosphate receptor modulators, fumarates, and cladribine, which reduce annual relapse rates by 29-68% compared with placebo 5

Highly Active or Aggressive MS

For patients with markers of aggressive disease (frequent relapses, incomplete recovery from relapses, high frequency of new MRI lesions, rapid onset of disability), AHSCT can be considered after failure of a single high-efficacy DMT after a meaningful treatment period. 1

AHSCT is most suitable for patients who meet ALL of the following criteria: 1

• Age <45 years
• Disease duration <10 years
• High focal inflammation present
• EDSS score <4.0
• Relapsing-remitting MS subtype
• No major cognitive impairment
• Excellent performance status
• No active infections or multiple medical comorbidities

AHSCT should be considered as appropriate escalation therapy for highly active MS that has failed high-efficacy DMT, and patients meeting these criteria should be referred as early as possible for AHSCT consideration. 1, 2

Rapidly Evolving, Severe MS (Treatment-Naïve)

AHSCT as first-line therapy should only be considered for individuals with rapidly evolving, severe MS with poor prognosis, and must be offered as part of a clinical trial or observational longitudinal research study. 1, 2

Progressive MS

For primary progressive MS, ocrelizumab is the specific FDA-approved treatment, though its efficacy is primarily limited to slowing disability progression rather than halting it. 2

AHSCT can be considered for young individuals (<45 years) with early progressive MS only if they have: 1, 2

• Short disease duration
• Well-documented clinical evidence of inflammatory disease
• Radiological evidence of inflammatory activity on MRI

AHSCT is NOT recommended for progressive MS without detectable inflammatory lesion activity due to lack of evidence of benefit. 1

AHSCT is contraindicated in patients with: 1

• Age >55 years
• Disease duration >20 years
• Absence of focal inflammation
• EDSS score >6.0
• Long-standing, advanced forms of MS with severe disability

Secondary Progressive MS with Activity

For secondary progressive MS with ongoing inflammatory activity, AHSCT (typically using BEAM-ATG protocol) significantly slows disability progression and increases likelihood of sustained disability improvement compared with standard immunotherapy. 1

Treatment Monitoring

MRI follow-up should be conducted within 3-12 months depending on disease characteristics and treatment. 2 For patients on natalizumab with high PML risk (anti-JCV antibody positive, duration >2 years, prior immunosuppressant use), MRI should be performed every 3-4 months. 4

Key monitoring parameters include:

• New T2 lesions or gadolinium-enhancing lesions on MRI 5
• Clinical relapses and EDSS progression 5
• For AHSCT patients: progression-free survival was 87% at 10 years in relapsing-remitting MS cohorts 1

Critical Treatment Pitfalls to Avoid

Pseudoatrophy can cause excessive brain volume decrease within the first 6-12 months of DMT initiation due to resolution of inflammation, which should not be mistaken for disease progression. 2

Natalizumab carries a boxed warning for progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection usually leading to death or severe disability. 4 Risk factors include anti-JCV antibodies, duration of therapy >2 years, and prior immunosuppressant use. 4

Do not combine natalizumab with other immunosuppressants, as this substantially increases PML risk. 4

AHSCT has a transplant-related mortality risk that was 2.8% in earlier cohorts with advanced progressive MS but has decreased to 1.4% in more recent cohorts and 0% in optimally selected relapsing-remitting MS patients. 1

Age-Specific Considerations

Patients <45 years with disease duration <10 years are optimal candidates for intensive treatments including AHSCT if indicated. 2

For patients >55 years with stable disease, discontinuation of DMT may be considered, as benefits of continuing immunosuppressive therapy may be outweighed by increased infection risk and other adverse effects. 6

Patients >55 years with disease duration >20 years and absence of focal inflammation are not candidates for AHSCT and require more conservative approaches. 2