What is the recommended treatment plan for multiple sclerosis (MS)?

Treatment Plan for Multiple Sclerosis

For relapsing-remitting MS with highly active disease that has failed high-efficacy disease-modifying therapy, autologous haematopoietic stem cell transplantation (AHSCT) should be considered as the most effective escalation therapy, demonstrating 87% progression-free survival at 10 years in optimal candidates. 1, 2

Initial Disease Classification and Baseline Assessment

• Determine MS subtype (relapsing-remitting, secondary progressive, or primary progressive) through clinical history and MRI findings, as this dictates available treatment options 2, 3
• Obtain baseline brain MRI with T2-weighted, T2-FLAIR, and gadolinium-enhanced T1-weighted sequences to assess lesion burden and inflammatory activity 2, 3
• Calculate Expanded Disability Status Scale (EDSS) score at baseline, as this determines eligibility for specific therapies and predicts treatment response 1, 2

Treatment Strategy for Relapsing-Remitting MS

First-Line High-Efficacy DMTs

Start with high-efficacy DMTs (ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine) rather than moderate-efficacy options, as early aggressive treatment yields superior long-term outcomes. 2

• Interferon beta-1a is FDA-approved for relapsing forms of MS including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease 4
• Natalizumab (300 mg IV every 4 weeks) is indicated as monotherapy for relapsing forms of MS but carries PML risk requiring REMS program enrollment 5
• These DMTs reduce annualized relapse rates by 29-68% compared to placebo or active comparators 6

Defining Treatment Failure

Treatment failure warranting escalation occurs when patients experience: 1, 2

• ≥1 clinical relapse occurring ≥3 months after DMT initiation
• New MRI activity (≥1 gadolinium-enhancing lesion OR ≥3 new/enlarging T2 lesions) within the past 12 months
• Incomplete recovery from relapses
• Rapid onset of disability progression

AHSCT as Escalation Therapy

Optimal Candidate Profile

AHSCT should be considered for patients meeting ALL of the following criteria: 1, 2

• Age <45 years (though biologically fit older patients may be considered individually)
• Disease duration <10 years
• EDSS score <4.0
• High focal inflammation present on MRI
• Failed ≥1 high-efficacy DMT after meaningful treatment period (typically ≥6 months)
• No major cognitive impairment
• Excellent performance status with no active infections or multiple medical comorbidities

Rapidly Evolving Severe MS

For treatment-naive patients with rapidly evolving severe MS and poor prognostic factors (frequent relapses, incomplete recovery, high MRI lesion frequency, rapid disability onset): 1, 2

• AHSCT can be considered as first-line therapy ONLY within a clinical trial or observational research study
• This represents a paradigm shift from traditional escalation approaches but requires specialized multidisciplinary assessment

Absolute Contraindications to AHSCT

Do NOT offer AHSCT when: 1, 2

• Age >55 years
• EDSS score >6.0
• Disease duration >20 years
• Absence of focal inflammation on MRI
• Major cognitive impairment present
• Poor performance status or multiple comorbidities
• Active infections
• Long-standing, advanced MS with severe disability

Treatment for Progressive MS

Secondary Progressive MS

AHSCT can be considered ONLY for young patients (<45 years) with early secondary progressive MS who have: 1, 2

• Short disease duration
• Well-documented clinical AND radiological evidence of inflammatory disease activity within past 12 months
• EDSS score <6.0

Without inflammatory activity, AHSCT is not supported due to lack of evidence. 1

Primary Progressive MS

Ocrelizumab is the only FDA-approved DMT specifically for primary progressive MS and should be the standard treatment. 2

AHSCT may be considered only if: 1, 2

• Early inflammatory active disease present
• EDSS score <6.0
• Age <45 years
• Clinical or MRI inflammatory activity within past 12 months

Monitoring Protocol

MRI Surveillance Schedule

For high-risk patients (highly active disease, recent treatment change): 2, 3

• MRI every 3-4 months initially
• Include T2-weighted, T2-FLAIR, and gadolinium-enhanced T1-weighted sequences
• Maintain consistent protocols for serial comparison

For stable patients: 2, 3

• MRI every 6 months in first year
• Then annually if stable
• Watch for pseudoatrophy effect (excessive brain volume decrease within first 6-12 months due to inflammation resolution, not true progression) 3

Clinical Monitoring

Combine EDSS with Multiple Sclerosis Functional Composite (MSFC) for more sensitive disability assessment, as EDSS alone has low sensitivity especially with baseline scores near 6.0 1

Separate disability accrual into: 1

• Relapse-associated worsening
• Progression independent of relapse activity (PIRA)

AHSCT Rehabilitation Protocol

Four-Phase Approach

Phase 1 (Weeks -4 to 0): Pre-habilitation 1

• Optimize physical, social, and emotional functioning before AHSCT
• Breathing and cardiovascular exercises
• Management of spasticity, fatigue, and pain
• Cognitive rehabilitation

Phase 2 (Weeks 0-4): Acute Rehabilitation 1

• Gentle mobilization to prevent hospitalization-related complications
• Optimize respiratory function
• Adapt exercise intensity to platelet counts (contraindicated if <20 × 10⁹/L)
• Strict infection control measures

Phase 3 (Weeks 8-12): Subacute Rehabilitation 1

• Intense inpatient or outpatient rehabilitation when medically stable
• Optimize physical fitness and independence
• Treat neurological problems and disabilities

Phase 4 (Weeks 12-26): Community Rehabilitation 1

• Integration back into home life
• Promote independence
• Vocational rehabilitation

Critical Pitfalls to Avoid

• Do not delay AHSCT referral in patients with highly active, treatment-refractory MS, as younger age and fewer previous DMTs associate with better long-term outcomes 1
• Do not offer AHSCT for progressive MS without documented inflammatory activity in the past 12 months 1, 2
• Do not combine natalizumab with immunosuppressants due to increased PML risk 5
• Do not mistake pseudoatrophy (inflammation resolution) for true disease progression in first 6-12 months of DMT treatment 3
• Do not continue DMT in patients >55 years with stable disease, as infection risks may outweigh benefits 3