What is the recommended treatment for a patient with multiple sclerosis?

Treatment of Multiple Sclerosis

Immediate Treatment Strategy for Relapsing-Remitting MS

For newly diagnosed relapsing-remitting MS, initiate high-efficacy disease-modifying therapies (DMTs) immediately—specifically ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine—rather than using moderate-efficacy agents or a stepped escalation approach, as early aggressive treatment yields superior long-term disability outcomes. 1, 2

• The traditional paradigm of starting with moderate-efficacy therapies (interferons, glatiramer acetate) and escalating only after failure has been abandoned by major guideline bodies 1, 2
• Real-world evidence demonstrates that delayed initiation of high-efficacy therapy results in worse long-term disability outcomes 2
• Moderate-efficacy DMTs reduce annualized relapse rates by only 29-50% compared to placebo, whereas high-efficacy agents achieve 50-68% reduction 3

Escalation to Autologous Hematopoietic Stem Cell Transplantation (AHSCT)

For highly active relapsing-remitting MS that fails a first high-efficacy DMT, refer immediately for AHSCT evaluation if the patient meets eligibility criteria, as AHSCT demonstrates 87% progression-free survival at 10 years and represents the most effective escalation therapy available. 4, 1

Specific AHSCT Eligibility Criteria:

• Age <45 years 1, 2, 5
• Disease duration <10 years 1, 2, 5
• EDSS score <4.0 1, 5
• High focal inflammation on MRI with gadolinium-enhancing lesions 1, 5
• Failed ≥1 high-efficacy DMT after meaningful treatment period (typically 6-12 months) 1, 5
• Frequent relapses (≥2 per year) or incomplete recovery from relapses 1

AHSCT Evidence Base:

• The MIST randomized trial demonstrated AHSCT superiority over FDA-approved DMTs: 90% vs 25% progression-free survival at 5 years, 85% vs 15% relapse-free survival, and 78% vs 3% achieving NEDA-3 4
• Long-term registry data shows 71% progression-free survival at 10 years with only 1.4% transplant-related mortality 5
• AHSCT achieves complete suppression of inflammatory activity in most patients, with NEDA rates of 83% at 2 years and 67% at 5 years 4

Critical Timing Consideration:

• Refer for AHSCT evaluation immediately after failure of the first high-efficacy DMT if aggressive disease features are present (frequent relapses, incomplete recovery, rapid disability accumulation) 1, 2
• Do not wait for failure of multiple high-efficacy DMTs, as outcomes worsen with higher baseline EDSS scores and longer disease duration 1, 5

Treatment of Secondary Progressive MS

For secondary progressive MS, consider AHSCT only in patients <45 years with early disease of short duration (<10 years), EDSS <6.0, and well-documented clinical and radiological evidence of active inflammatory disease within the past 12 months. 4, 2, 5

• Active inflammatory disease must be demonstrated by either clinical relapses or new gadolinium-enhancing lesions on MRI within 12 months 5
• AHSCT in active secondary progressive MS significantly slows disability progression compared to standard immunotherapy 4
• Exclude patients with EDSS >6.0, age >55 years, or absence of inflammatory activity, as outcomes are poor in this population 5

Treatment of Primary Progressive MS

For primary progressive MS, initiate ocrelizumab as the only FDA-approved DMT specifically indicated for this phenotype, though efficacy is limited to slowing disability progression rather than halting it. 1, 5, 6

• AHSCT may be considered only for early inflammatory active primary progressive MS with EDSS <6.0, age <45 years, and documented inflammatory activity 5
• Most primary progressive MS patients lack sufficient inflammatory activity to benefit from AHSCT 5

MRI Monitoring Protocol

Perform brain MRI with gadolinium-enhanced T1 and T2/FLAIR sequences every 3-4 months for high-risk patients (highly active disease, recent treatment changes, or natalizumab therapy), and at least annually for stable patients. 4, 1, 2

High-Risk Patients Requiring Frequent Monitoring:

• Patients on natalizumab due to progressive multifocal leukoencephalopathy (PML) risk 1, 2, 6
• Patients with breakthrough disease activity on current therapy 1, 2
• Patients within first year of new DMT initiation 5

MRI Sequences Required:

• T2-weighted and T2-FLAIR sequences to detect new or enlarging lesions 4, 1
• Gadolinium-enhanced T1-weighted sequences to identify active inflammatory lesions 4, 1
• Maintain consistent protocols across serial scans for accurate comparison 5

Natalizumab-Specific Safety Monitoring

For patients receiving natalizumab, assess anti-JCV antibody status before initiation and perform MRI surveillance every 3-4 months if JCV-positive, as PML risk increases with treatment duration, prior immunosuppressant use, and JCV antibody positivity. 6

• Natalizumab is FDA-approved as monotherapy for relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease 6
• PML is an opportunistic viral brain infection that usually leads to death or severe disability 6
• Withhold natalizumab dosing immediately at first sign or symptom suggestive of PML 6

Age-Based Treatment Modifications

Continue aggressive DMT in patients <55 years even if clinically stable, particularly if disease duration is <10 years or there is history of highly active disease before stabilization. 1, 2

• For patients >55 years with stable disease for >2 years and no inflammatory activity on MRI, consider discontinuing DMT, as infection risks and other adverse effects may outweigh benefits of continued immunosuppression 1, 2
• Patients >55 years with disease duration >20 years and absence of focal inflammation are generally not candidates for AHSCT 2

Rehabilitation Protocol for AHSCT Patients

Implement a four-phase rehabilitation protocol beginning with pre-habilitation before stem cell mobilization and continuing through 26 weeks post-transplant to optimize neurological outcomes during the period of complete inflammatory suppression. 4

Four Rehabilitation Phases:

• Phase 1 (Pre-habilitation): Enhance neuromuscular and respiratory function through breathing exercises, cardiovascular training, spasticity management, and cognitive rehabilitation 4
• Phase 2 (Weeks 0-4, Inpatient): Gentle mobilization adapted to platelet counts (contraindicated if platelets <20 × 10⁹/L) with strict infection control 4
• Phase 3 (Weeks 8-12, Outpatient): Intensive rehabilitation to optimize physical fitness, independence, and treat neurological disabilities 4
• Phase 4 (Weeks 12-26, Community): Vocational rehabilitation and reintegration into home life and work activities 4

Management of MS Reactivation After AHSCT

For MS reactivations occurring between mobilization and conditioning, do not resume DMTs, as these events relate to the time gap between procedures and previous treatment; for reactivations after completion of AHSCT protocol, manage on an individual case basis with consideration of re-initiating high-efficacy DMTs. 4

• MS reactivation rates after AHSCT are low, occurring in <10-15% of patients 4
• Few data exist regarding optimal DMT selection and safety after AHSCT failure 4