What are the indications for disease-modifying drugs (DMDs) in adults with relapsing-remitting multiple sclerosis (MS) or progressive multiple sclerosis (MS)?

Indications for Disease-Modifying Drugs in Multiple Sclerosis

Disease-modifying therapies (DMTs) are indicated for all adults with relapsing forms of multiple sclerosis—including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease—and should be initiated early to maximize efficacy and prevent disability progression. 1

Relapsing-Remitting Multiple Sclerosis (RRMS)

Standard Indications for DMT Initiation

• All patients with RRMS should receive DMT treatment, as these medications reduce annual relapse rates by 29-68% compared to placebo and decrease MRI lesion accumulation 2

• DMTs are FDA-approved for relapsing forms of MS, which encompasses clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults 1

• Treatment should begin at diagnosis rather than waiting for disease progression, as early initiation is associated with better long-term outcomes 3, 2

High-Efficacy DMT Indications

For patients with markers of aggressive disease—including frequent relapses, incomplete recovery from relapses, high frequency of new MRI lesions, or rapid onset of disability—high-efficacy DMTs (natalizumab, ocrelizumab, ofatumumab, alemtuzumab, cladribine) should be considered as first-line treatment. 4

• Current evidence favors early escalation and induction treatment strategies over traditional stepped approaches for patients with highly active disease 4, 3

• High-efficacy DMTs are more effective when initiated early in the disease course 5

• After failure of a single high-efficacy DMT for a meaningful treatment period, autologous haematopoietic stem cell transplantation (AHSCT) can be considered within a specialized multidisciplinary assessment pathway for patients with markers of aggressive disease 5

Treatment-Refractory Disease

• AHSCT should be considered as an appropriate escalation therapy for people with highly active MS in whom high-efficacy DMT has failed, and patients should be referred as early as possible 5

• For treatment-refractory RRMS, AHSCT demonstrated 90% progression-free survival at 5 years versus 25% with DMTs, and 78% achieved NEDA-3 at 5 years versus 3% with DMTs 5

Progressive Multiple Sclerosis

Secondary Progressive MS with Activity

• DMTs are indicated for active secondary progressive MS, defined as steadily increasing neurologic disability following a relapsing course with evidence of ongoing inflammatory activity 2

• AHSCT is only indicated for people with secondary progressive MS who have early disease, short disease duration, and well-documented clinical and radiological evidence of inflammatory disease activity 5

• Offering AHSCT for progressive MS without detectable inflammatory lesion activity is not supported due to lack of evidence 5

Primary Progressive MS

• Ocrelizumab is the only DMT approved for primary progressive MS 3, 2

• AHSCT can be considered for young patients (<45 years) with early primary progressive MS, short disease duration, and well-documented clinical and radiological evidence of inflammatory disease 5

Specific Patient Selection Criteria for AHSCT

Favorable Characteristics for AHSCT

• Age <45 years 5
• Disease duration <10 years 5
• EDSS score <4.0 5
• High focal inflammation on MRI 5
• Absence of cognitive impairment 5
• Treatment failure with ≥1 high-efficacy DMT plus poor prognostic factors, or ≥1 high-efficacy DMT plus ≥1 moderate-efficacy DMT 5

Contraindications for AHSCT

• Age >55 years (though could be considered in biologically fit individuals) 5
• Disease duration >20 years 5
• EDSS score >6.0 5
• Absence of focal inflammation 5
• Major cognitive impairment 5
• Multiple medical comorbidities 5
• Active infections 5
• Poor performance status 5

Available DMT Classes and Mechanisms

Moderate-Efficacy DMTs

• Interferon beta formulations reduce brain atrophy by 30% in clinically isolated syndromes compared to placebo 3
• Glatiramer acetate shows positive effects when initiated early 3
• Dimethyl fumarate reduces brain atrophy compared to placebo 3, 1
• Teriflunomide is approved for relapsing forms 2

High-Efficacy DMTs

• Fingolimod (sphingosine 1-phosphate receptor modulator) reduces brain atrophy compared to placebo 3
• Alemtuzumab reduces brain atrophy compared to subcutaneous interferon beta-1a 3
• Ocrelizumab reduces brain atrophy compared to subcutaneous interferon beta-1a and is approved for both relapsing MS and primary progressive MS 3
• Ofatumumab achieved 78% NEDA-3 at 5 years versus 3% with teriflunomide 6
• Cladribine reduces brain atrophy compared to placebo 3
• Natalizumab is a high-efficacy monoclonal antibody option 4, 2

Common Pitfalls to Avoid

• Do not delay DMT initiation while pursuing perfect diagnostic certainty—early treatment is associated with better outcomes 3, 2

• Do not mistake pseudoatrophy effect for disease progression—excessive brain volume decrease within the first 6-12 months of treatment can occur due to resolution of inflammation and edema 3

• Ensure appropriate washout periods between different DMTs to avoid complications from carryover effects or disease reactivation 3

• Do not apply Alzheimer's disease treatment criteria when seeking insurance authorization for MS DMTs—this leads to inappropriate denials 4

• For patients on high-efficacy DMTs, do not delay treatment while waiting for perfect hepatitis B immunity if the patient has aggressive MS—implement appropriate monitoring or prophylaxis protocols instead 4

• Administer vaccines at least 4-6 weeks before starting immunosuppressive therapies like ocrelizumab, or at least 4-6 months after the last treatment course 3