What are the treatment options for multiple sclerosis?

Treatment of Multiple Sclerosis

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 for aggressive disease that fails high-efficacy DMTs, demonstrating 87% progression-free survival at 10 years in optimal candidates. 1, 2

Disease-Modifying Therapies by MS Subtype

Relapsing-Remitting MS (RRMS)

First-Line High-Efficacy DMTs:

• Monoclonal antibodies: ocrelizumab, ofatumumab, natalizumab, alemtuzumab 2, 3
• Oral agents: cladribine, fingolimod 3, 4
• These agents reduce annualized relapse rates by 29-68% compared with placebo 3

Moderate-Efficacy DMTs (now considered suboptimal as first-line):

• Interferons (IFN-β-1a intramuscular, IFN-β-1a subcutaneous, IFN-β-1b subcutaneous, peginterferon beta-1a) 5, 3
• Glatiramer acetate 3, 6
• Teriflunomide, dimethyl fumarate (fumarates) 7, 3

Active Secondary Progressive MS

• Same high-efficacy DMTs as RRMS if inflammatory activity is documented 8
• AHSCT may be considered only if age <45 years, EDSS <6.0, disease duration <10 years, and documented inflammatory activity within past 12 months 2

Primary Progressive MS

• Ocrelizumab is the only FDA-approved DMT specifically indicated, though efficacy is limited to slowing disability progression 9, 2
• AHSCT may be considered only in early inflammatory active disease with EDSS <6.0 2

Autologous Haematopoietic Stem Cell Transplantation (AHSCT)

AHSCT represents a paradigm shift from last-resort therapy to standard of care for treatment-refractory disease. 1, 2

Optimal Candidate Criteria for AHSCT:

• Age <45 years 1, 9
• Disease duration <10 years 1, 9
• EDSS score <4.0 1, 9
• High focal inflammation present on MRI 1
• Failed ≥1 high-efficacy DMT after meaningful treatment period 2
• Relapsing-remitting MS subtype 1

Indications for AHSCT:

• Standard indication: Highly active RRMS refractory to high-efficacy DMTs 1
• First-line consideration (only in clinical trials): Rapidly evolving severe MS with poor prognosis 1, 9, 10
• Not recommended: Age >55 years, EDSS >6.0, absence of focal inflammation, no inflammatory activity in past 12 months 2

AHSCT Conditioning Regimens:

• Cyclophosphamide + anti-thymocyte globulin (Cy + ATG) 1
• BEAM (carmustine, etoposide, cytarabine, melphalan) + ATG 1

AHSCT Outcomes:

• 87% progression-free survival at 10 years in optimal candidates 2
• 71% progression-free survival at 10 years for RRMS with 1.4% transplant-related mortality 2
• Highly effective at suppressing clinical and MRI-detected disease activity 1

Treatment Algorithm

Step 1: Determine MS Subtype and Disease Activity

• Obtain baseline brain MRI with T2/FLAIR and gadolinium-enhanced T1 sequences 9
• Calculate EDSS score 9
• Document clinical relapses and MRI activity in past 12 months 1

Step 2: Initial Treatment Selection

For newly diagnosed RRMS with aggressive features (≥2 relapses in past year, high lesion load, incomplete recovery):

• Initiate high-efficacy DMT (ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine) 2, 3
• Consider AHSCT evaluation if rapidly evolving severe disease with poor prognosis (only within clinical trial) 1, 10

For newly diagnosed RRMS without aggressive features:

• Initiate high-efficacy DMT rather than moderate-efficacy options 2
• Early aggressive treatment yields better long-term outcomes 2

Step 3: Define Treatment Failure

Treatment failure criteria include:

• ≥1 clinical relapse occurring ≥3 months after DMT initiation 9
• New MRI activity (≥1 gadolinium-enhancing lesion or ≥1 new T2 lesion) 1
• Incomplete recovery from relapses 10

Step 4: Escalation Strategy

After first high-efficacy DMT failure with aggressive features:

• Refer for AHSCT evaluation if patient meets optimal candidate criteria 2
• Alternative: Switch to different high-efficacy DMT 3

After second high-efficacy DMT failure:

• AHSCT is the appropriate escalation therapy 10, 2

Monitoring Protocol

MRI Surveillance:

• High-risk patients (highly active disease, recent treatment change): Every 3-4 months 2
• Standard monitoring: Every 6 months in first year, then annually if stable 9, 2
• Required sequences: T2-weighted, T2-FLAIR, gadolinium-enhanced T1-weighted 2

Clinical Monitoring:

• EDSS score at each visit 1
• Consider Multiple Sclerosis Functional Composite (MSFC) for more sensitive assessment 1
• Separate disability accrual into relapse-associated worsening versus progression independent of relapse activity (PIRA) 1

Rehabilitation for AHSCT Patients

Rehabilitation must begin immediately after AHSCT to exploit brain reorganization capacity during complete inflammatory suppression. 9

Four-Phase Rehabilitation Protocol:

Phase 1 (Pre-AHSCT): Pre-habilitation to enhance neuromuscular and respiratory function, manage spasticity, fatigue, pain 1

Phase 2 (Weeks 0-4): Acute inpatient rehabilitation with gentle mobilization, respiratory optimization; exercise contraindicated if platelets <20 × 10⁹/L 1

Phase 3 (Weeks 8-12): Subacute intensive rehabilitation to optimize physical fitness and independence 1

Phase 4 (Weeks 12-26): Community rehabilitation including vocational rehabilitation 1

Special Considerations and Pitfalls

Natalizumab-Specific Warnings:

• Black Box Warning: Increases risk of progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection usually leading to death or severe disability 8
• Risk factors: anti-JCV antibodies, duration of therapy, prior immunosuppressant use 8
• Available only through TOUCH® Prescribing Program REMS 8
• Indicated as monotherapy for relapsing forms of MS 8

Common Pitfalls:

• Pseudoatrophy effect: Excessive brain volume decrease within first 6-12 months of treatment due to inflammation resolution should not be mistaken for disease progression 9, 10
• Inappropriate washout periods: Between different DMTs can lead to carryover effect complications 10
• Delaying AHSCT referral: Patients who meet optimal candidate criteria should be referred early, not after multiple DMT failures when EDSS has progressed 1

Age-Specific Treatment Decisions:

Patients <45 years with disease duration <10 years:

• Optimal candidates for intensive treatments including AHSCT if indicated 10
• Should continue therapy even if stable, given history of highly active disease 9

Patients >55 years with stable disease:

• Consider treatment discontinuation, as risks of immunosuppression may outweigh benefits 9
• AHSCT not recommended if disease duration >20 years and absence of focal inflammation 10

Adverse Effects of DMTs

Common adverse effects across DMT classes: 3

• Infections (all immunosuppressive agents)
• Bradycardia and heart blocks (sphingosine 1-phosphate receptor modulators)
• Macular edema (fingolimod)
• Infusion reactions (monoclonal antibodies)
• Injection-site reactions and flu-like symptoms (interferons, glatiramer acetate) 5
• Secondary autoimmune effects including autoimmune thyroid disease 3