What are the treatment options for multiple sclerosis (MS)?

Multiple Sclerosis Treatment

For relapsing-remitting MS, initiate high-efficacy disease-modifying therapies (DMTs) immediately rather than using traditional step-up approaches, and for aggressive disease refractory to high-efficacy DMTs, escalate to autologous haematopoietic stem cell transplantation (AHSCT) which achieves 87% progression-free survival at 10 years. 1, 2

Initial Disease Classification and Risk Assessment

Before selecting treatment, determine the MS subtype as this dictates all therapeutic options 2:

• Relapsing-remitting MS (RR-MS): Relapses at onset with stable neurologic disability between episodes 3
• Secondary progressive MS (SP-MS): Steadily increasing neurologic disability following a relapsing course 3
• Primary progressive MS (PP-MS): Progressive disability from onset without distinct relapses 2

Obtain baseline brain MRI with gadolinium-enhanced T1 and T2/FLAIR sequences to establish disease activity, lesion burden, and focal inflammatory lesions 2. Document EDSS score (0-10 scale measuring disability), disease duration, relapse frequency, and recovery completeness from prior relapses 2.

Identify aggressive disease markers that warrant immediate high-efficacy therapy 2:

• Frequent relapses (≥2 per year) 2
• Incomplete recovery from relapses 2
• High frequency of new MRI lesions 2
• Rapid disability onset 2

First-Line Treatment for Relapsing-Remitting MS

Start with high-efficacy DMTs as initial therapy rather than traditional escalation from moderate-efficacy agents, as early aggressive treatment yields superior long-term outcomes 1, 2. The most effective first-line options include 2:

• Ocrelizumab (anti-CD20 monoclonal antibody)
• Ofatumumab (anti-CD20 monoclonal antibody)
• Natalizumab (anti-α4 integrin monoclonal antibody) - if JC virus antibody-negative 1, 4
• Alemtuzumab (anti-CD52 monoclonal antibody)
• Cladribine (purine nucleoside analogue)

These agents reduce annualized relapse rates by 29-68% compared with placebo or active comparators 3.

Moderate-Efficacy Alternatives

For patients with milder disease or contraindications to high-efficacy agents 5, 6:

• Interferon beta preparations (IFNβ-1a intramuscular, IFNβ-1a subcutaneous, IFNβ-1b subcutaneous, peginterferon beta-1a) 5, 6
• Glatiramer acetate 7
• Teriflunomide 3
• Fumarates (dimethyl fumarate, diroximel fumarate) 3
• Sphingosine 1-phosphate receptor modulators (fingolimod, siponimod, ozanimod, ponesimod) 3

Escalation to AHSCT for Refractory Disease

AHSCT represents the most effective escalation therapy for highly active RR-MS that has failed high-efficacy DMTs, achieving superior disease control compared to continued DMT escalation 8, 1, 2. AHSCT using intermediate-intensity conditioning (cyclophosphamide + anti-thymocyte globulin or BEAM + anti-thymocyte globulin) is recommended 8.

Optimal AHSCT Eligibility Criteria

Refer patients immediately after failure of first high-efficacy DMT if they meet these criteria 1, 2:

• Age <45 years (preferably 18-55 years) 8, 1, 2
• Disease duration <10 years 1, 2
• EDSS score 0.0-6.0 (preferably <4.0) 8, 1, 2
• High focal inflammation on MRI 2
• Failed ≥1 high-efficacy DMT for ≥6 months 1
• Active disease: ≥1 clinical relapse or MRI activity (≥1 gadolinium-enhancing lesion or ≥1 new T2 lesion) in the previous 12 months 8

First-Line AHSCT Consideration

AHSCT as first-line therapy should only be considered for rapidly evolving severe MS with poor prognosis, ideally within a clinical trial 9. This applies to treatment-naive patients with aggressive disease features including multiple severe relapses with incomplete recovery and extensive MRI activity within the first year 8, 9.

Pre-AHSCT Requirements

Before proceeding with AHSCT, comprehensive screening is mandatory 8, 1:

• Haematological assessment: Liver function, bone marrow evaluation, viral profiles (HIV, hepatitis B/C, CMV, EBV, VZV), glomerular filtration rate 8
• Cardiac evaluation: Electrocardiography, echocardiography; additional cardiological work-up for patients >40 years or with cardiac risk factors 8
• Respiratory assessment: Lung function tests, chest radiography; chest CT if abnormalities detected 8
• Dental examination 8
• Fertility preservation discussion 8
• HSCT comorbidity index assessment 8

Critical washout period consideration: Balance MS relapse risk during DMT withdrawal against complications from treatment carryover effects, particularly after alemtuzumab or cytotoxic agents 8, 1. Keep DMT withdrawal as short as possible 8.

Treatment of Progressive MS

Secondary Progressive MS

Consider AHSCT only for young patients (<45 years) with early SP-MS of short duration who have well-documented clinical and radiological evidence of active inflammatory disease 9, 2. AHSCT has limited efficacy once the progressive phase is established without ongoing inflammation 8.

Primary Progressive MS

Ocrelizumab is the only FDA-approved DMT specifically indicated for PP-MS, though efficacy is limited to slowing disability progression rather than halting it 9, 2. No other DMTs have demonstrated benefit in PP-MS 8.

MRI Surveillance 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 (due to PML risk) 1, 2.

Required MRI sequences 9, 2:

• T2-weighted and T2-FLAIR sequences for detecting new or enlarging lesions
• Gadolinium-enhanced T1-weighted sequences to identify active inflammatory lesions

Monitor for pseudoatrophy effect: Excessive brain volume decrease within the first 6-12 months of treatment due to resolution of inflammation should not be mistaken for disease progression 9.

Rehabilitation After AHSCT

Begin intensive rehabilitation immediately after AHSCT to exploit neuroplasticity during complete inflammatory suppression 1, 2. The phased approach includes 8, 1:

1. Pre-habilitation (before AHSCT): Enhance neuromuscular systems, respiratory function, breathing exercises, cardiovascular exercises, spasticity management 8

2. Acute rehabilitation (weeks 0-4, inpatient): Gentle mobilization, respiratory function optimization; exercise contraindicated if platelet counts <20 × 10⁹/L 8

3. Subacute rehabilitation (weeks 8-12, outpatient): Intensive inpatient or outpatient rehabilitation to optimize physical fitness and independence 8

4. Community rehabilitation (weeks 12-26, outpatient): Integration back into home life, promote independence, vocational rehabilitation 8

Age-Based Treatment Decisions

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 9, 2. These patients remain at risk for future inflammatory activity 2.

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 9, 2. Stable disease is defined as no relapses and no new MRI activity for ≥2 years 2.

Management of Breakthrough Disease Activity

When patients experience breakthrough disease activity on first-line therapy, defined as ≥1 relapse occurring ≥3 months after DMT initiation or new MRI activity 1, 9:

• Escalate to natalizumab if JC virus antibody-negative 1, 4
• Consider alemtuzumab, ocrelizumab, or fingolimod 1
• If breakthrough occurs on high-efficacy DMT, proceed to AHSCT evaluation 1, 2

Critical Safety Considerations

Natalizumab-Specific Warnings

Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral brain infection usually leading to death or severe disability 4. Risk factors include 4:

• Presence of anti-JC virus antibodies
• Duration of therapy (risk increases after 2 years)
• Prior use of immunosuppressants

Monitor patients on natalizumab for any new neurological sign or symptom suggestive of PML; withhold dosing immediately and obtain gadolinium-enhanced brain MRI and cerebrospinal fluid analysis for JC viral DNA if PML is suspected 4.

AHSCT-Specific Risks

AHSCT involves higher acute risk than approved DMTs, including treatment-related mortality (historically 1-2%, now <0.3% in experienced centers), infections during neutropenia, and potential long-term complications 8. However, for appropriate candidates with refractory aggressive disease, the long-term benefit-risk ratio favors AHSCT over continued DMT escalation 8, 2.

Common Pitfalls to Avoid

• Do not unnecessarily prolong DMT withdrawal before AHSCT, as this increases relapse risk 1
• Do not underestimate carryover effects of alemtuzumab or cytotoxic agents before AHSCT, which can complicate mobilization and conditioning 8, 1
• Do not use AHSCT in established progressive MS without documented inflammatory activity, as efficacy is minimal 8, 9, 2
• Do not combine natalizumab with other immunosuppressants, as this increases PML risk 4

Ongoing Clinical Trials

Four major randomized controlled trials are comparing AHSCT to high-efficacy DMTs in RR-MS 8:

• RAM-MS (Norway, Denmark, Sweden, Netherlands): AHSCT vs alemtuzumab/cladribine/ocrelizumab
• BEAT-MS (USA): AHSCT vs alemtuzumab/cladribine/natalizumab/ocrelizumab/ofatumumab/ublituximab
• STAR-MS (UK): AHSCT vs alemtuzumab/cladribine/ocrelizumab/ofatumumab
• NET-MS (Italy): AHSCT vs alemtuzumab/natalizumab/ocrelizumab/ofatumumab

These trials will provide definitive evidence on optimal AHSCT positioning in the treatment algorithm 8.