What is the approach to treating multiple sclerosis (MS)?

Approach to Multiple Sclerosis

Initial Classification and Risk Stratification

For newly diagnosed MS, immediately classify the disease subtype (relapsing-remitting, secondary progressive, or primary progressive) using clinical history, MRI with gadolinium-enhanced T1 and T2/FLAIR sequences, and EDSS scoring, as this classification dictates all subsequent treatment decisions 1, 2.

• Obtain baseline brain MRI with specific attention to focal inflammatory lesions, lesion burden, and gadolinium enhancement to establish disease activity 3, 1
• Document EDSS score, disease duration, relapse frequency, and recovery completeness from prior relapses 3
• Assess for aggressive disease markers: frequent relapses (≥2/year), incomplete recovery, high frequency of new MRI lesions, and rapid disability onset 3, 2

Treatment Strategy for Relapsing-Remitting MS

Initiate high-efficacy disease-modifying therapies (DMTs) immediately rather than using a stepped escalation approach, as early aggressive treatment yields superior long-term outcomes 3, 4.

First-Line High-Efficacy DMTs

• Start with ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine as initial therapy for treatment-naive relapsing-remitting MS 4
• Natalizumab is FDA-approved for relapsing forms of MS including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease 5
• Interferon beta-1a is also FDA-approved for relapsing forms of MS but represents lower efficacy compared to monoclonal antibodies 6

Defining Treatment Failure

Treatment failure requiring escalation occurs when patients experience 1:

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

Autologous Hematopoietic Stem Cell Transplantation (AHSCT)

AHSCT represents the most effective escalation therapy for highly active relapsing-remitting MS that has failed high-efficacy DMTs, with 87% progression-free survival at 10 years in optimal candidates 4.

Optimal Candidate Profile for AHSCT

AHSCT should be considered for patients meeting these criteria 3, 4:

• 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 (typically 6-12 months)
• No major cognitive impairment
• Excellent performance status
• No active infections or multiple medical comorbidities

Timing of AHSCT Referral

• Refer patients with highly active, treatment-refractory MS immediately after failure of first high-efficacy DMT if aggressive disease features are present 3, 4
• For rapidly evolving severe MS with poor prognosis, AHSCT as first-line therapy should only be considered within a clinical trial 3
• Early referral is critical as younger age and shorter disease duration correlate with better outcomes 3

Absolute Contraindications for AHSCT

Do not offer AHSCT to patients with 3:

• Age >55 years (unless biologically fit on individual basis)
• Disease duration >20 years
• EDSS score >6.0
• Absence of focal inflammation on MRI
• No clinical or MRI inflammatory activity within past 12 months
• Long-standing advanced MS with severe disability

Treatment of Progressive MS

Secondary Progressive MS

• AHSCT can be considered only for young patients (<45 years) with early secondary progressive MS of short duration who have well-documented clinical and radiological evidence of active inflammatory disease 3, 4
• Patients must demonstrate inflammatory activity (clinical relapses or gadolinium-enhancing lesions) within the past 12 months 3, 4
• AHSCT is not supported for secondary progressive MS without detectable inflammatory lesion activity 3

Primary Progressive MS

• Ocrelizumab is the only FDA-approved DMT specifically indicated for primary progressive MS, though efficacy is limited to slowing disability progression 1, 2, 4
• AHSCT may be considered only in early inflammatory active primary progressive MS with EDSS <6.0 and age <45 years 4
• Most patients with primary progressive MS are not candidates for AHSCT due to lack of inflammatory activity 3

MRI Monitoring Protocol

Perform brain MRI at least annually for stable patients, but increase frequency to every 3-4 months for high-risk patients including those with highly active disease, recent treatment changes, or those on natalizumab 3, 1, 4.

Standard Monitoring Sequences

Include the following sequences 3, 1:

• T2-weighted and T2-FLAIR for detecting new or enlarging lesions
• Gadolinium-enhanced T1-weighted sequences (minimum 5 minutes post-contrast) to identify active inflammatory lesions
• Maintain consistent slice thickness (≤5mm), positioning, and timing for serial comparisons

Enhanced Surveillance Situations

Perform MRI every 3-4 months for 3, 1, 5:

• Patients switching from natalizumab to other therapeutics (fingolimod, alemtuzumab, dimethyl fumarate) for up to 12 months
• Natalizumab-treated patients at high risk for progressive multifocal leukoencephalopathy (PML)
• Patients with breakthrough disease activity on current DMT

Age-Based Treatment Considerations

Younger Patients (<45 years)

• Continue aggressive DMT even if clinically stable, particularly if disease duration <10 years or history of highly active disease before stabilization 1, 2
• These patients remain optimal candidates for treatment intensification including AHSCT if needed 3

Older Patients (>55 years)

• Consider discontinuing DMT in patients >55 years with stable disease, as infection risks and other adverse effects may outweigh benefits of continued immunosuppression 1, 2
• Exceptions may be made for biologically fit individuals on case-by-case basis 3

Critical Safety Monitoring

Natalizumab-Specific Precautions

Natalizumab carries significant PML risk requiring 5:

• Assessment of anti-JCV antibody status before initiation
• Risk stratification based on JCV antibody presence, treatment duration, and prior immunosuppressant use
• Immediate discontinuation at first sign or symptom suggestive of PML
• Gadolinium-enhanced MRI and CSF analysis for JC viral DNA when PML suspected
• Enrollment in TOUCH® Prescribing Program REMS

Post-AHSCT Rehabilitation

• Begin intensive rehabilitation immediately after AHSCT to exploit neuroplasticity during complete inflammatory suppression, using a phased approach including pre-habilitation, early mobilization, intensive outpatient rehabilitation, and maintenance rehabilitation 1