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

Treatment Options for Multiple Sclerosis

Disease-Modifying Therapies by MS Subtype

For relapsing-remitting MS, high-efficacy disease-modifying therapies (DMTs) should be initiated early in the disease course, with autologous haematopoietic stem cell transplantation (AHSCT) reserved as the most effective escalation therapy for treatment-refractory disease, demonstrating 87% progression-free survival at 10 years in optimal candidates. 1, 2

First-Line Treatment Options for Relapsing-Remitting MS

High-Efficacy DMTs (Preferred Initial Approach):

• Monoclonal antibodies: ocrelizumab, ofatumumab, natalizumab 3, alemtuzumab 4, 2
• Oral agents: fingolimod, cladribine 4, 2
• These agents reduce annualized relapse rates by 49-68% compared to placebo 5

Moderate-Efficacy DMTs (Alternative Options):

• Injectable interferons: IFN β-1a (intramuscular or subcutaneous) 6, IFN β-1b 6
• Glatiramer acetate 7
• Oral agents: teriflunomide, dimethyl fumarate 7
• These agents reduce relapse rates by 29-43% compared to placebo 5

Treatment Strategy: Early Escalation vs. Traditional Stepped Approach

Current evidence strongly favors early escalation and induction strategies over traditional stepped approaches. 4, 8 The traditional model of starting with moderate-efficacy DMTs and escalating only after breakthrough activity is being replaced by initiating high-efficacy DMTs from disease onset, particularly in patients with aggressive disease markers 4, 2.

Markers indicating need for high-efficacy DMTs from onset: 4, 2

• Frequent relapses (≥2 in past year)
• Incomplete recovery from relapses
• High burden of new T2 or gadolinium-enhancing lesions on MRI
• Rapid onset of disability accumulation

Autologous Haematopoietic Stem Cell Transplantation (AHSCT)

AHSCT represents a paradigm shift and is now endorsed as standard of care for treatment-refractory relapsing-remitting MS rather than a last resort. 1, 2

Optimal Candidate Profile for AHSCT: 1, 4, 2

• Age <45 years
• Disease duration <10 years
• EDSS score <4.0
• High focal inflammation on MRI
• Failed ≥1 high-efficacy DMT after meaningful treatment period
• Clinical or MRI inflammatory activity within past 12 months

AHSCT as First-Line Therapy: AHSCT should only be considered as first-line treatment for rapidly evolving, severe MS with poor prognosis, and must be offered within a clinical trial or observational study. 1, 4

Outcomes with AHSCT: 1, 2

• 87% progression-free survival at 10 years in relapsing-remitting MS (Swedish cohorts)
• 71% progression-free survival at 10 years (Italian BMT-MS Study Group)
• 1.4% transplant-related mortality in recent cohorts
• Superior to alemtuzumab and other high-efficacy DMTs in comparative studies

Treatment for Progressive Forms of MS

Secondary Progressive MS with Active Inflammation:

• AHSCT can be considered for young individuals (<45 years) with early progressive MS, short disease duration, and documented clinical and radiological inflammatory activity 1, 4, 2
• High-efficacy DMTs (ocrelizumab, ofatumumab) may slow progression in active disease 2

Primary Progressive MS:

• Ocrelizumab is the only FDA-approved DMT specifically indicated for primary progressive MS, though efficacy is limited to slowing disability progression 4, 2
• AHSCT may be considered only in early inflammatory active disease with EDSS <6.0 2

Critical Exclusion Criteria for AHSCT in Progressive MS: 1, 2

• Age >55 years
• EDSS >6.0
• Absence of focal inflammation on MRI
• No inflammatory activity in past 12 months
• Long-standing, advanced disease with severe disability

Specific DMT Indications and Mechanisms

Natalizumab (Tysabri): 3

• Indicated as monotherapy for relapsing forms of MS (300 mg IV every 4 weeks)
• Critical Warning: Increases risk of progressive multifocal leukoencephalopathy (PML)
• Risk factors for PML: anti-JCV antibody positivity, duration of therapy >2 years, prior immunosuppressant use
• Requires enrollment in TOUCH® Prescribing Program
• Patients at high PML risk require MRI surveillance every 3-4 months 9

Interferon Beta-1b (Betaseron): 6

• Indicated for relapsing forms of MS including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease

Comparative Efficacy Rankings (by relapse rate reduction): 5

1. Alemtuzumab, ocrelizumab, mitoxantrone, natalizumab (49-51% reduction vs placebo)
2. Fingolimod (57% reduction)
3. Dimethyl fumarate (65% reduction)
4. Glatiramer acetate, interferons (80-87% reduction)

Treatment Monitoring Protocol

MRI Surveillance Schedule: 2, 9

• High-risk patients (highly active disease, recent treatment change): every 3-4 months
• Standard monitoring: every 6 months in first year, then annually if stable
• Required sequences: T2-weighted, T2-FLAIR, gadolinium-enhanced T1-weighted

Clinical Monitoring:

• EDSS assessment at each visit to track disability progression 1
• Evaluate for incomplete recovery after relapses as trigger for DMT adjustment 4

Treatment Algorithm for Relapsing-Remitting MS

Step 1: Initial Assessment

• Determine presence of aggressive disease markers (frequent relapses, high lesion burden, rapid disability accumulation) 4, 2

Step 2: Treatment Selection

• If aggressive markers present: Initiate high-efficacy DMT immediately 4, 2
• If no aggressive markers: Consider high-efficacy DMT (preferred) or moderate-efficacy DMT 2

Step 3: Breakthrough Disease on First High-Efficacy DMT

• If age <45, disease duration <10 years, EDSS <4.0, ongoing inflammation: Refer for AHSCT evaluation 1, 2
• If not AHSCT candidate: Switch to alternative high-efficacy DMT 2

Step 4: Failure of Multiple High-Efficacy DMTs

• If AHSCT candidate criteria met: Proceed with AHSCT 1, 2
• If not candidate: Consider clinical trial enrollment 1

Critical Pitfalls to Avoid

Pseudoatrophy Effect: Excessive brain volume decrease within first 6-12 months of DMT treatment due to resolution of inflammation should not be mistaken for disease progression. 4

Inappropriate Washout Periods: Inadequate washout between different DMTs can lead to complications from carryover effects, particularly when switching from natalizumab or fingolimod. 4

Delayed AHSCT Referral: Waiting until EDSS >6.0 or disease duration >10 years significantly reduces AHSCT efficacy and increases transplant-related mortality risk. 1, 2

Combining Immunosuppressants: Natalizumab should not be used with other immunosuppressants or TNF-α inhibitors due to increased PML risk. 3

Age-Specific Considerations

Patients <45 Years:

• Optimal candidates for intensive treatments including AHSCT if indicated 1, 4, 2
• Should receive high-efficacy DMTs early in disease course 4, 2

Patients >55 Years with Stable Disease:

• Consider treatment discontinuation if disease duration >20 years and absence of focal inflammation 4, 9
• Benefits of continuing immunosuppression may be outweighed by infection risk 9

Patients >55 Years with Active Disease:

• Not candidates for AHSCT 1, 2
• Continue or optimize high-efficacy DMT therapy 2