What are the recommended treatments for managing multiple sclerosis?

Management of Multiple Sclerosis

For relapsing-remitting MS, initiate high-efficacy disease-modifying therapies (DMTs) early in the disease course, with autologous haematopoietic stem cell transplantation (AHSCT) reserved for patients with aggressive disease refractory to high-efficacy DMTs. 1

Disease-Modifying Therapy Selection

First-Line Treatment Options

High-efficacy DMTs should be prioritized over traditional escalation approaches, particularly in patients with markers of aggressive disease. 2, 3

• Monoclonal antibodies (natalizumab, alemtuzumab, ocrelizumab, ofatumumab) provide annualized relapse rate reductions of 47-68% compared to placebo or active comparators 4, 5
• Oral therapies (fingolimod, teriflunomide, dimethyl fumarate, cladribine) offer efficacy rates of 29-54% with convenient administration 4, 5
• Injectable therapies (interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a) reduce annual relapse rates by 29-32% with established long-term safety profiles 6, 7, 5

Treatment Failure Criteria

Switch to higher efficacy DMT when patients experience: 2, 3

• ≥1 clinical relapse occurring ≥3 months after DMT initiation
• New or enlarging T2 lesions on MRI (≥1 gadolinium-enhancing or ≥1 new T2 lesion)
• Sustained EDSS progression
• Incomplete recovery from relapses

Autologous Haematopoietic Stem Cell Transplantation

Optimal Eligibility Criteria

AHSCT is recommended for relapsing-remitting MS refractory to high-efficacy DMTs, with optimal candidates being: 1, 3

• Age <45 years
• Disease duration <10 years
• EDSS score <4.0
• High focal inflammation on MRI
• Active disease despite high-efficacy DMT (≥1 relapse and MRI activity in previous 12 months)

Conditioning Regimens

Two standard protocols are used: 1, 2

• Cyclophosphamide + anti-thymocyte globulin (ATG)
• BEAM (carmustine, etoposide, cytarabine, melphalan) + ATG

Pre-Transplant Assessment

Required screening includes: 1, 2

• Liver function, bone marrow, and viral profiles
• Glomerular filtration rate measurement
• Lung function testing and chest radiography
• Cardiac assessment (ECG, echocardiography)
• Dental evaluation
• Fertility counseling and preservation options
• HSCT comorbidity index calculation

DMT washout periods must balance MS relapse risk against treatment complications, with particular caution after alemtuzumab or multiple therapy lines. 1

Progressive Multiple Sclerosis

Primary Progressive MS

Ocrelizumab is the only approved DMT for primary progressive MS, though efficacy is limited to slowing disability progression rather than halting it. 3

Secondary Progressive MS

AHSCT may be considered for young patients (<45 years) with early secondary progressive MS of short duration and documented inflammatory activity (clinical relapses and MRI lesions). 1, 3

Monitoring Protocol

MRI Surveillance

Baseline MRI should use minimum 1.5T field strength, slice thickness ≤3mm, and in-plane resolution 1×1mm, with sequences including T2-weighted, T2-FLAIR, and gadolinium-enhanced T1-weighted images. 2

Follow-up intervals: 2, 3

• High-risk patients: Every 3-4 months (particularly those on natalizumab ≥18 months)
• Standard monitoring: Every 6 months in first year, then annually if stable
• Post-AHSCT: Every 3-12 months depending on patient characteristics

Cognitive Assessment

Symbol Digit Modalities Test (SDMT) should be performed at baseline and every 6 months. 2

Natalizumab-Specific Safety Monitoring

Due to progressive multifocal leukoencephalopathy (PML) risk, natalizumab requires: 8

• JC virus antibody testing before initiation and every 6 months 2, 8
• Brain MRI every 3-4 months if treatment duration ≥18 months 2, 8
• Immediate discontinuation at first sign or symptom suggestive of PML 8
• Gadolinium-enhanced MRI and cerebrospinal fluid JC viral DNA testing when PML suspected 8

Risk factors for PML include: 8

• Anti-JCV antibody positivity
• Treatment duration >2 years
• Prior immunosuppressant use

Rehabilitation Strategy

Four-phase rehabilitation protocol for AHSCT patients: 1

1. Pre-habilitation (weeks before transplant): Breathing exercises, cardiovascular training, spasticity management, fatigue and pain control, cognitive rehabilitation 1

2. Acute phase (weeks 0-4): Gentle mobilization, respiratory optimization, exercise contraindicated if platelets <20×10⁹/L, strict infection control 1

3. Subacute phase (weeks 8-12): Intensive inpatient/outpatient rehabilitation to optimize physical fitness and independence 1

4. Community phase (weeks 12-26): Home-based recovery, vocational rehabilitation, integration into daily activities 1

Critical Pitfalls to Avoid

• Never prolong DMT withdrawal unnecessarily before AHSCT, as this increases MS relapse risk 2
• Do not underestimate carryover effects of alemtuzumab or other long-acting lymphodepleting agents before AHSCT 1, 2
• Maintain consistent MRI protocols to facilitate serial comparison 2
• Distinguish between disease progression and treatment complications rather than attributing all changes to MS 2
• Do not mistake pseudoatrophy (excessive brain volume decrease in first 6-12 months from inflammation resolution) for disease progression 3

Treatment Discontinuation Considerations

Patients >55 years with stable disease should consider stopping DMT, as infection risks may outweigh benefits 3

Patients <45 years with disease duration <10 years or history of highly active disease should continue therapy even if currently stable. 3