What is the recommended initial treatment approach for a patient diagnosed with relapsing-remitting multiple sclerosis (RRMS)?

Initial Treatment Approach for Relapsing-Remitting Multiple Sclerosis

Immediate High-Efficacy Disease-Modifying Therapy as First-Line Treatment

For treatment-naïve patients with relapsing-remitting multiple sclerosis, initiate high-efficacy disease-modifying therapies (DMTs) immediately rather than using a stepped escalation approach, as early aggressive treatment yields superior long-term outcomes and prevents irreversible neurological damage. 1, 2

The traditional escalation strategy—starting with moderate-efficacy agents and escalating only after breakthrough activity—has been superseded by evidence demonstrating that delayed initiation of high-efficacy therapy results in worse long-term disability outcomes. 3

Specific High-Efficacy DMT Options for First-Line Use

The following high-efficacy DMTs are recommended for initial therapy in treatment-naïve RRMS:

• Ocrelizumab (anti-CD20 monoclonal antibody): Reduces annualized relapse rate by 46-47% compared to interferon beta-1a, with 40% risk reduction in 12-week confirmed disability progression 4
• Ofatumumab (anti-CD20 monoclonal antibody) 1, 2
• Natalizumab (anti-α4 integrin monoclonal antibody) 1, 2, 5
• Alemtuzumab (anti-CD52 monoclonal antibody) 1, 2, 5
• Cladribine (purine nucleoside analog) 1, 2, 5

Among these options, the anti-CD20 therapies (ocrelizumab, ofatumumab) and natalizumab have demonstrated superiority in randomized controlled trials and observational studies compared to older injectable therapies and some oral therapies. 5 Alemtuzumab shows excellent efficacy but carries potentially severe side effects that limit its use. 5 Cladribine, while grouped with high-efficacy DMTs, may be slightly less effective than the other agents. 5

Baseline Assessment and Risk Stratification

Before initiating treatment, perform the following assessments to establish disease activity and identify aggressive disease markers:

• Brain MRI with gadolinium-enhanced T1 and T2/FLAIR sequences to document focal inflammatory lesions, lesion burden, and gadolinium enhancement 2
• EDSS scoring to establish baseline disability 2
• Document disease duration, relapse frequency, and recovery completeness from prior relapses 2
• Identify aggressive disease markers: ≥2 relapses per year, incomplete recovery from relapses, high frequency of new MRI lesions, rapid disability onset 2

Treatment Algorithm for Highly Active or Aggressive Disease

For patients presenting with aggressive disease features at diagnosis:

1. Initiate high-efficacy DMT immediately (ocrelizumab, ofatumumab, natalizumab, alemtuzumab, or cladribine) 1, 2
2. Perform brain MRI every 3-4 months during the first year to detect breakthrough activity early 1, 2
3. If breakthrough activity occurs on first high-efficacy DMT (new relapses, new/enlarging T2 lesions, or gadolinium-enhancing lesions), refer immediately for autologous hematopoietic stem cell transplantation (AHSCT) evaluation 1, 2

Autologous Hematopoietic Stem Cell Transplantation as Escalation Therapy

AHSCT represents the most effective escalation therapy for highly active RRMS that fails high-efficacy DMTs, with 90% progression-free survival at 5 years versus 25% with DMTs, and 78% achieving no evidence of disease activity (NEDA-3) at 5 years versus 3% with DMTs. 6, 1

Optimal Candidate Criteria for AHSCT:

• Age <45 years 1, 2
• Disease duration <10 years 1, 2
• EDSS score <4.0 1, 2
• High focal inflammation on MRI with gadolinium-enhancing lesions 1, 2
• Failed ≥1 high-efficacy DMT 1, 2

AHSCT Timing Considerations:

The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and European Society for Blood and Marrow Transplantation (EBMT) recommend referring patients with highly active, treatment-refractory MS immediately after failure of first high-efficacy DMT if aggressive disease features are present. 6, 1, 2 This recommendation reflects the critical importance of intervening within the window of opportunity before irreversible disability develops. 6

In the MIST randomized controlled trial, AHSCT with cyclophosphamide-ATG protocol demonstrated superiority over FDA-approved DMTs (excluding alemtuzumab) with 90% versus 25% progression-free survival at 5 years, 85% versus 15% relapse-free survival, and 78% versus 3% NEDA-3 achievement. 6 A limitation of this trial was that only approximately half the control group received high-efficacy DMTs (natalizumab or mitoxantrone), with the remainder receiving moderate-efficacy agents. 6

Ongoing Monitoring Protocol

For Stable Patients:

• Brain MRI at least annually with T2-weighted, T2-FLAIR sequences for new/enlarging lesions and gadolinium-enhanced T1-weighted sequences for active inflammatory lesions 1, 2

For High-Risk Patients:

• Increase MRI frequency to every 3-4 months for patients with highly active disease, recent treatment changes, or those on natalizumab (due to progressive multifocal leukoencephalopathy risk) 1, 2, 3

Critical Safety Considerations

Common Pitfall: Pseudoatrophy Effect

Be aware that high-efficacy DMTs, particularly anti-CD20 therapies, can cause apparent brain volume loss in the first year of treatment due to resolution of inflammation rather than true neurodegeneration. 1 This pseudoatrophy should not be misinterpreted as treatment failure.

Agent-Specific Adverse Effects:

• Natalizumab: Progressive multifocal leukoencephalopathy risk, particularly in JC virus-positive patients 7, 8
• Alemtuzumab: Secondary autoimmune diseases (thyroiditis, immune thrombocytopenic purpura, autoimmune hemolytic anemia) 6, 5
• Anti-CD20 therapies: Infusion reactions, infections, hypogammaglobulinemia 8
• Cladribine: Lymphopenia, infections 8

Vaccination Timing:

Administer vaccines at least 4-6 weeks before starting immunosuppressive therapies or at least 4-6 months after the last treatment course. 1 After AHSCT, offer revaccination according to ECIL7 recommendations. 6

Washout Periods:

Implement appropriate washout periods between different DMTs to avoid complications from carryover effects or rebound inflammatory activity. 1 The specific duration depends on the mechanism of action and half-life of the prior agent.

Age-Based Treatment Modifications

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, 3 These patients have the most to gain from sustained inflammatory suppression to prevent long-term disability accumulation.

Older Patients (>55 years):

Consider discontinuing DMT in patients with stable disease, as infection risks and other adverse effects may outweigh benefits of continued immunosuppression. 1, 2, 3 This decision should account for disease duration (typically >20 years) and absence of focal inflammation on recent MRI.

Post-AHSCT Rehabilitation Strategy

For patients undergoing AHSCT, begin intensive rehabilitation immediately after transplantation to exploit neuroplasticity during complete inflammatory suppression. 1, 2 Use a phased approach including:

• Pre-habilitation before AHSCT 6
• Early mobilization during recovery 6
• Intensive outpatient rehabilitation in the first 6-12 months 2
• Maintenance rehabilitation for sustained functional gains 2

Ongoing Clinical Trials Comparing Treatment Strategies

Two major randomized controlled trials are currently comparing escalation versus early aggressive approaches:

• RAM-MS trial: Comparing AHSCT (cyclophosphamide-ATG) versus alemtuzumab, cladribine, or ocrelizumab, with NEDA-3 as primary endpoint 6
• BEAT-MS trial: Comparing AHSCT (BEAM-ATG) versus alemtuzumab, cladribine, natalizumab, ocrelizumab, ofatumumab, or ublituximab, with relapse-free survival as primary endpoint 6
• STAR-MS trial: Comparing AHSCT (cyclophosphamide-ATG) versus alemtuzumab, cladribine, ocrelizumab, or ofatumumab in UK patients 6
• NET-MS trial: Comparing AHSCT (BEAM-ATG) versus alemtuzumab, natalizumab, ocrelizumab, or ofatumumab in Italian patients 6

These trials will provide definitive evidence on optimal positioning of AHSCT in the treatment algorithm and may further refine recommendations for early aggressive therapy. 6