What alternative treatments are available for a patient with relapsing-remitting Multiple Sclerosis (MS) if preferred disease-modifying therapies (DMTs) such as fingolimod, dimethyl fumarate, teriflunomide, or cladribine are not available?

Alternative DMTs for Relapsing-Remitting MS When Preferred Oral Agents Are Unavailable

If fingolimod, dimethyl fumarate, teriflunomide, or cladribine are not available, use injectable disease-modifying therapies including interferon-beta preparations (intramuscular or subcutaneous) or glatiramer acetate as first-line alternatives, or escalate to high-efficacy monoclonal antibodies (ocrelizumab, natalizumab, or alemtuzumab) if the patient has highly active disease. 1, 2, 3

Injectable First-Line Alternatives

Interferon-Beta and Glatiramer Acetate

• Interferon-beta preparations (IFNβ-1a intramuscular, IFNβ-1a subcutaneous, or IFNβ-1b) and glatiramer acetate represent well-established first-line therapies with proven efficacy in reducing relapse rates and MRI activity in RRMS. 1, 4, 5

• These agents have well-established safety profiles with no major safety concerns after decades of clinical use, making them appropriate alternatives when oral agents are unavailable. 5, 6

• Both interferon-beta and glatiramer acetate allow for unrestricted vaccination schedules, including live attenuated vaccines, without timing restrictions—a significant practical advantage. 7

• The primary limitation is injection-related adverse events and potentially lower patient compliance compared to oral therapies, but these remain acceptable first-line options. 4

High-Efficacy Monoclonal Antibody Alternatives

When to Escalate Beyond Injectable First-Line Agents

• For patients with highly aggressive MS characterized by frequent relapses (≥2 relapses in the past year), multiple active MRI lesions (≥3 new demyelinating lesions), or tumefactive demyelinating lesions, immediately escalate to high-efficacy monoclonal antibody therapy rather than using injectable first-line agents. 1, 2, 3

Ocrelizumab

• Ocrelizumab is a preferred high-efficacy alternative, demonstrating 61% reduction in relapse rate and 40% reduction in disability progression in RRMS patients. 2

• Administered as intravenous infusions every 6 months after initial dosing, providing convenient dosing schedule. 2

• Requires vaccination 4-6 weeks before starting therapy or 4-6 months after last infusion—critical timing consideration that differs from oral agents. 7

• Monitoring requirements include clinical assessment and MRI surveillance per American Academy of Neurology recommendations. 2

Natalizumab

• Natalizumab represents another high-efficacy monoclonal antibody option with established efficacy in reducing relapse rates and MRI activity. 1, 8, 9

• Administered as monthly intravenous infusions. 9

• Carries risk of progressive multifocal leukoencephalopathy (PML), requiring JC virus antibody testing and ongoing monitoring—this rare but serious adverse event must be discussed with patients. 5

• Vaccination can be administered without interruption of therapy, unlike ocrelizumab. 7

Alemtuzumab

• Alemtuzumab demonstrates superior efficacy compared to interferon-beta, with significant reductions in brain atrophy and disability progression. 1

• Administered as two annual treatment courses (5 consecutive days initially, then 3 consecutive days 12 months later), providing long-lasting immune effects. 8

• Requires specific timing considerations for vaccination and carries autoimmune risks requiring long-term monitoring. 7, 8

Treatment Selection Algorithm

Step 1: Assess Disease Activity Level

• Mild-to-moderate disease activity (≤1 relapse in past year, minimal MRI activity): Use injectable first-line agents (interferon-beta or glatiramer acetate). 1, 5

• Highly active disease (≥2 relapses in past year, multiple active MRI lesions, or tumefactive lesions): Proceed directly to high-efficacy monoclonal antibodies. 1, 3

Step 2: Consider Patient-Specific Factors

• Young patients with early disease and high inflammatory activity: Prioritize high-efficacy therapy (ocrelizumab, natalizumab, or alemtuzumab) to maximize benefit during optimal treatment window. 2, 3

• Patients requiring flexible vaccination schedules: Prefer interferon-beta, glatiramer acetate, or natalizumab over ocrelizumab or alemtuzumab. 7

• Patients with JC virus positivity: Avoid natalizumab due to PML risk; use ocrelizumab or alemtuzumab instead. 5

Step 3: Implement Appropriate Washout Periods

• When transitioning from unavailable oral DMTs, implement appropriate washout periods to balance MS relapse risk against complications from sequential treatments—this is particularly critical after lymphodepleting agents. 1

• Keep DMT withdrawal as short as possible to avoid MS disease activity during the transition period. 1

Critical Monitoring Considerations

• Pseudoatrophy effect: Powerful anti-inflammatory drugs (including natalizumab and ocrelizumab) may cause initial increases in brain volume loss during the first year due to resolution of inflammation and edema, followed by beneficial effects in subsequent years—this should not be misinterpreted as treatment failure. 1

• All alternative DMTs require ongoing clinical assessment and MRI surveillance to monitor treatment response and safety. 1, 2

• Long-term safety monitoring through registries and cohort studies remains essential, as rare adverse events may not be identified in pivotal trials. 5, 6