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 traditional escalation approach, as this strategy yields superior long-term outcomes with better control of inflammatory activity and disability progression. 1, 2, 3

Disease-Modifying Therapies by MS Subtype

Relapsing-Remitting MS (RRMS)

High-efficacy DMTs should be considered as first-line treatment, particularly for patients with markers of aggressive disease including frequent relapses, incomplete recovery, high lesion burden on MRI, or rapid disability onset. 2, 3

Available high-efficacy DMTs include:

• Monoclonal antibodies: Ocrelizumab, ofatumumab, natalizumab, and alemtuzumab 2, 3
• Oral agents: Cladribine and fingolimod 4
• Injectable agents: Interferon beta-1a (IM), interferon beta-1b (SC), and glatiramer acetate for moderate-efficacy options 5, 4

Natalizumab (300 mg IV every 4 weeks) is indicated for relapsing forms of MS but carries significant risk of progressive multifocal leukoencephalopathy (PML), particularly with anti-JCV antibody positivity, prolonged treatment duration, and prior immunosuppressant use. 6 Patients on natalizumab require MRI monitoring every 3-4 months if at high risk for PML. 7

Secondary Progressive MS (SPMS)

AHSCT should only be considered for young individuals (<45 years) with early progressive MS who have short disease duration and well-documented clinical and radiological evidence of inflammatory disease. 1, 2 Patients must demonstrate clinical or MRI inflammatory activity within the past 12 months. 3

Critical exclusion criteria for AHSCT in progressive MS include:

• Age >55 years 3
• EDSS score >6.0 3
• Absence of focal inflammation 3
• No inflammatory activity in past 12 months 3

Primary Progressive MS (PPMS)

Ocrelizumab is the only FDA-approved DMT specifically indicated for primary progressive MS, though its efficacy is primarily limited to slowing disability progression. 2, 3 AHSCT may be considered only in early inflammatory active disease with EDSS <6.0 and age <45 years. 3

Autologous Haematopoietic Stem Cell Transplantation (AHSCT)

AHSCT represents the most effective escalation therapy for treatment-refractory relapsing-remitting MS, demonstrating 87% progression-free survival at 10 years in optimal candidates. 3 The Italian BMT-MS Study Group reported 71% progression-free survival at 10 years for relapsing-remitting MS with only 1.4% transplant-related mortality. 1, 3

Optimal Candidate Profile for AHSCT

Patients most suitable for AHSCT have the following characteristics:

• Age <45 years 1, 2, 3
• Disease duration <10 years 1, 2, 3
• EDSS score <4.0 2, 3
• High focal inflammation present 2, 3
• Failed ≥1 high-efficacy DMT after meaningful treatment period 3
• Relapsing-remitting MS subtype 1, 2

AHSCT as First-Line Therapy

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 study. 1, 2 This represents a paradigm shift from viewing AHSCT as a last resort to recognizing it as standard of care for treatment-refractory disease. 3

AHSCT in Progressive MS

For progressive MS, AHSCT is not recommended for patients with:

• Long-standing, advanced forms with severe disability 1
• Age >55 years with disease duration >20 years 2
• Absence of inflammatory lesion activity 1

AHSCT can be considered for active secondary progressive MS with inflammatory activity if EDSS <6.0 and age <45 years. 3

Treatment Algorithm for Relapsing-Remitting MS

Step 1: Initial Assessment

• Determine MS subtype, disease activity, and patient age 2
• Obtain baseline MRI with T2-weighted, T2-FLAIR, and gadolinium-enhanced T1-weighted sequences 7, 3
• Assess disability using EDSS scale 7

Step 2: Risk Stratification

• Aggressive disease markers: Frequent relapses, incomplete recovery, high MRI lesion burden, rapid disability onset 2
• Standard disease: Infrequent relapses, complete recovery, low lesion burden 4

Step 3: Treatment Selection

• Aggressive disease: Initiate high-efficacy DMT (ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine) 2, 3
• Standard disease: Consider high-efficacy DMT given evidence favoring early aggressive treatment over escalation approach 2, 7

Step 4: Monitoring Protocol

• High-risk patients (highly active disease, recent treatment change): MRI every 3-4 months 3
• Standard monitoring: Every 6 months in first year, then annually if stable 3

Step 5: Treatment Escalation

• Breakthrough disease on first high-efficacy DMT with aggressive features: Refer for AHSCT evaluation 3
• Incomplete response: Switch to alternative high-efficacy DMT before considering AHSCT 1

Monitoring and Treatment Adjustment

MRI surveillance should include T2-weighted, T2-FLAIR, and gadolinium-enhanced T1-weighted sequences with consistent protocols for serial comparison. 3 High-risk patients require MRI every 3-4 months, while stable patients need annual imaging after the first year. 3

For patients with incomplete recovery after relapses, evaluate for DMT adjustment. 2 The presence of new T2 lesions or gadolinium-enhancing lesions indicates breakthrough disease activity requiring treatment modification. 4

Common Pitfalls and Caveats

Pseudoatrophy effect can cause excessive decrease in brain volume within the first 6-12 months of treatment due to resolution of inflammation, which should not be mistaken for disease progression. 2 This is particularly common with high-efficacy DMTs and requires careful interpretation of volumetric MRI data.

Inappropriate washout periods between different DMTs can lead to complications from carryover effects. 2 Specific washout periods depend on the mechanism of action and half-life of the discontinued medication, with particular caution needed when switching from lymphocyte-depleting therapies.

Natalizumab requires careful risk stratification for PML, with consideration of anti-JCV antibody status, treatment duration, and prior immunosuppressant exposure. 6 Patients with all three risk factors have substantially elevated PML risk and require enhanced monitoring or alternative therapy.

AHSCT is not appropriate for patients with long-standing, advanced MS with severe disability, as outcomes are poor and transplant-related risks outweigh potential benefits. 1 The procedure should be reserved for patients meeting strict eligibility criteria regarding age, disease duration, disability level, and inflammatory activity.

Age-Specific Considerations

Patients under 45 years with disease duration less than 10 years are optimal candidates for intensive treatments, including AHSCT if indicated. 2 This age group demonstrates the best response to aggressive immunosuppression and has the lowest transplant-related mortality.

For patients over 55 years with disease duration greater than 20 years and absence of focal inflammation, AHSCT is not recommended and more conservative approaches are required. 2 In stable older patients, discontinuation of DMT may be considered as benefits of continued immunosuppression may be outweighed by infection risk. 7

Young patients (<45 years) with short disease duration (<10 years) or history of highly active disease before stabilization should continue current therapy even if stable, as the risk of disease reactivation remains substantial. 7