What are the recommended first-line and second-line treatments for multiple sclerosis (MS)?

First-Line and Second-Line Treatments for Multiple Sclerosis

Direct Answer

For relapsing-remitting MS, high-efficacy disease-modifying therapies (DMTs) including ocrelizumab, natalizumab, alemtuzumab, and ofatumumab should be initiated early in the disease course rather than starting with traditional first-line agents like interferons or glatiramer acetate. 1, 2 Current evidence strongly favors early escalation or induction strategies over the outdated stepwise approach. 1, 2

First-Line Treatment Strategy

High-Efficacy DMTs as Preferred Initial Therapy

• High-efficacy DMTs (monoclonal antibodies including alemtuzumab, natalizumab, ocrelizumab, and ofatumumab) are most effective when initiated early in the disease course. 2

• Patients with markers of aggressive disease—including frequent relapses, incomplete recovery from relapses, high frequency of new MRI lesions, and rapid onset of disability—should receive high-efficacy DMTs from the outset. 2, 3

• The traditional stepwise approach has been replaced by early escalation and induction strategies based on current evidence from the European Academy of Neurology-ECTRIMS guidelines. 2

Traditional First-Line Agents (Now Secondary Options)

• Interferon-beta (subcutaneous IFNβ-1b or IFNβ-1a given multiple times weekly) and glatiramer acetate remain valid options primarily due to their long-term safety profile and cost-effectiveness, though they are only modestly efficient in reducing annualized relapse rates. 4, 5

• These agents reduce relapse rates by 29-68% compared to placebo but are less effective than high-efficacy DMTs. 6

• Weekly intramuscular IFNβ-1a is inferior to subcutaneous formulations given multiple times per week and to glatiramer acetate. 7

Second-Line Treatment Strategy

When to Escalate Therapy

• Treatment failure is defined as ≥1 clinical relapse occurring ≥3 months after DMT initiation, new MRI activity, or incomplete recovery from relapses. 1

• When breakthrough disease activity occurs on first-line therapy, escalate to natalizumab if JC virus antibody-negative, or consider alemtuzumab, ocrelizumab, or fingolimod. 3

Switching Between First-Line Agents

• For patients failing initial interferon therapy, switching from one interferon to another interferon formulation can be effective, with 67% of patients remaining relapse-free at 24 months on the second interferon compared to 41% on the initial interferon. 8

• Switching from glatiramer acetate to interferon-beta shows superior outcomes, with 87% relapse-free at 24 months on interferon versus 12% on glatiramer acetate. 8

Autologous Hematopoietic Stem Cell Transplantation (AHSCT)

• For aggressive relapsing-remitting MS refractory to high-efficacy DMTs, AHSCT using intermediate-intensity conditioning achieves superior disease control compared to continued DMT escalation. 9, 3

• Optimal eligibility criteria for AHSCT include: age <45 years, disease duration <10 years, EDSS score <4.0 (or 0.0-6.0 per some guidelines), and high focal inflammation. 1, 3

• In contemporary studies of relapsing-remitting MS patients treated with AHSCT, progression-free survival rates reach 80-100% with NEDA (no evidence of disease activity) rates of 70-80%. 9

• Long-term outcomes show 87% progression-free survival at 10 years in relapsing-remitting MS patients, with no transplant-related mortality in recent Swedish case series. 9

• AHSCT as first-line therapy should only be considered for patients with rapidly evolving, severe MS with poor prognosis, ideally within a clinical trial. 1

Treatment for Progressive Forms

Primary Progressive MS

• Ocrelizumab is the specific indicated treatment for primary progressive MS, though its efficacy is primarily limited to slowing disability progression. 1, 2

Secondary Progressive MS

• AHSCT may be considered for young patients (<45 years) with early secondary progressive MS of short duration and well-documented clinical and radiological evidence of active inflammatory disease. 1

• AHSCT is not indicated for advanced progressive MS forms. 2

Monitoring Requirements

• Brain MRI follow-up should be performed at least annually for stable patients, but patients at risk of serious treatment-related adverse events require monitoring every 3-4 months. 1, 2

• MRI sequences must include T2/FLAIR and gadolinium-enhanced T1-weighted images to detect new or expanding lesions. 1, 2

• For natalizumab-treated patients at high risk for progressive multifocal leukoencephalopathy, brain MRI every 3-4 months is recommended. 2

Critical Age and Disease Duration Considerations

• Patients >55 years with stable disease should consider treatment discontinuation, as benefits of continuing immunosuppressive therapy may be outweighed by increased infection risk and other adverse effects. 1, 2

• Young patients (<45 years) with disease duration <10 years or history of highly active disease before stabilization should continue current therapy even if stable. 1, 2

Common Pitfalls to Avoid

• Do not unnecessarily prolong DMT withdrawal before AHSCT, as this increases relapse risk. 3

• Do not underestimate carryover effects of alemtuzumab before AHSCT. 3

• Do not mistake pseudoatrophy (excessive brain volume decrease within the first 6-12 months of treatment due to resolution of inflammation) for disease progression. 1

• Rehabilitation should begin immediately post-AHSCT to exploit the brain's reorganizational capacity during complete inflammatory suppression, with a phased approach including pre-habilitation, early mobilization, intensive outpatient rehabilitation, and maintenance rehabilitation. 1, 3