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Disease-Modifying Therapies (DMTs) for Multiple Sclerosis (MS) are medications that aim to alter the course of the disease by reducing the frequency of relapses, delaying disability progression, and limiting new lesion formation on MRI. DMTs are not curative but are critical in long-term MS management.
📌 Classes of DMTs for MS
1. Interferon Beta Preparations
These are among the earliest DMTs used.
- Examples: Interferon beta-1a (Avonex®, Rebif®) Interferon beta-1b (Betaseron®, Extavia®)
- Mechanism: Modulates immune response and reduces inflammatory activity in the CNS.
- Route: Intramuscular (IM) or subcutaneous (SC)
- Side Effects: Flu-like symptoms, injection site reactions, elevated liver enzymes
2. Glatiramer Acetate
- Example: Copaxone®, Glatopa®
- Mechanism: Mimics myelin basic protein, shifts immune response from pro-inflammatory to anti-inflammatory.
- Route: SC
- Side Effects: Injection site reactions, transient chest pain, lipoatrophy
3. Oral Therapies
These offer greater convenience compared to injectables.
- Examples: Fingolimod (Gilenya®) – Sphingosine-1-phosphate receptor modulator Dimethyl fumarate (Tecfidera®) – Anti-inflammatory and neuroprotective Teriflunomide (Aubagio®) – Pyrimidine synthesis inhibitor Siponimod, Ozanimod – Newer sphingosine-1-phosphate modulators Cladribine (Mavenclad®) – Purine analog, lymphocyte depletion
- Side Effects: Vary by agent (e.g., bradycardia with fingolimod, lymphopenia, GI upset, liver toxicity)
4. Monoclonal Antibodies
Highly effective, used in more aggressive or refractory cases.
- Examples: Natalizumab (Tysabri®) – Blocks leukocyte migration across the blood-brain barrier Ocrelizumab (Ocrevus®) – Anti-CD20, B-cell depleting Ofatumumab (Kesimpta®) – SC anti-CD20 monoclonal antibody Alemtuzumab (Lemtrada®) – Anti-CD52, profound lymphocyte depletion Ublituximab – Newer anti-CD20
- Side Effects: Natalizumab: Risk of PML (progressive multifocal leukoencephalopathy) Ocrelizumab/Alemtuzumab: Infections, infusion reactions, secondary autoimmunity
✅ Choosing a DMT
Factors considered include:
- Disease subtype (RRMS vs. PPMS vs. SPMS)
- Disease severity and activity
- Patient preference (oral vs. injectable)
- Safety profile and monitoring requirements
- Comorbidities, pregnancy plans
1. Injectable Therapies (First-Line DMTs)
– Interferon Beta (IFN-β)
– Examples: Interferon beta-1a (Avonex, Rebif), Interferon beta-1b (Betaseron, Extavia)
– Mechanism: Immunomodulatory—reduces inflammation & T-cell activation.
– Side Effects: Flu-like symptoms, injection-site reactions, liver enzyme elevation.
– Glatiramer Acetate (Copaxone, Glatopa):
– Mechanism: Mimics myelin protein, modulates immune response.
– Side Effects: Injection-site reactions, flushing, chest tightness.
2. Oral Therapies
– Fumarates:
– Examples: Dimethyl fumarate (Tecfidera), Diroximel fumarate (Vumerity)
– Mechanism: Activates Nrf2 pathway, reducing oxidative stress & inflammation.
– Side Effects: Flushing, GI upset, lymphopenia.
– Sphingosine-1-Phosphate (S1P) Receptor Modulators**:
– Examples: Fingolimod (Gilenya), Siponimod (Mayzent), Ozanimod (Zeposia)
– Mechanism: Traps lymphocytes in lymph nodes, preventing CNS infiltration.
– Side Effects: Bradycardia (first dose), macular edema, infections.
– Teriflunomide (Aubagio):
– Mechanism: Inhibits pyrimidine synthesis, reducing immune cell proliferation.
– Side Effects: Hepatotoxicity, hair thinning, teratogenic.
3. Infusion Therapies (High-Efficacy DMTs)
– Monoclonal Antibodies:
– Natalizumab (Tysabri):
– Target: α4-integrin (blocks lymphocyte entry into CNS).
– Risk: Progressive multifocal leukoencephalopathy (PML) (JC virus+ patients).
– Ocrelizumab (Ocrevus):
– Target: CD20+ B-cells (depletes B-cells).
– Used for: Relapsing & primary progressive MS (PPMS).
– Side Effects: Infusion reactions, infections.
– Alemtuzumab (Lemtrada):
– Target: CD52 (depletes T & B cells).
– Side Effects: Autoimmune disorders (thyroid, ITP), severe infusion reactions.
– Ofatumumab (Kesimpta):
– Target: CD20 (subcutaneous anti-B-cell therapy).
– Advantage: Self-administered, fewer infusions.
4. Other High-Efficacy DMTs
– Cladribine (Mavenclad):
– Mechanism: Purine analog, selectively depletes lymphocytes.
– Dosing: Short courses over 2 years.
– Side Effects: Lymphopenia, infection risk.
Key Considerations for DMT Selection
– Efficacy vs. Risk: High-efficacy DMTs (e.g., ocrelizumab, natalizumab) for aggressive MS.
– Safety Monitoring: Regular blood tests (lymphopenia, liver function), MRI, PML risk assessment.
– Pregnancy: Avoid teratogenic DMTs (e.g., fingolimod, teriflunomide).
Emerging Therapies
– Bruton’s Tyrosine Kinase (BTK) Inhibitors** (e.g., evobrutinib)—target B-cells & microglia.
– Stem Cell Therapy (HSCT) for refractory MS.
DMT choice depends on disease activity, comorbidities, and patient preference. Early initiation improves long-term outcomes.
Here is a summarized comparison chart of common Disease-Modifying Therapies (DMTs) for Multiple Sclerosis:
Interferons
IFN-β1a (Avonex®, Rebif®) IFN-β1b (Betaseron®, Extavia®)
Immunomodulation, reduces inflammation
Flu-like symptoms, liver dysfunction, injection site reactions
First-line in mild to moderate MS
Glatiramer Acetate
Copaxone®, Glatopa®
Mimics myelin basic protein
Chest pain, injection site reactions
Safe in pregnancy
Oral Therapies
Fingolimod (Gilenya®) Dimethyl fumarate (Tecfidera®) Teriflunomide (Aubagio®) Cladribine (Mavenclad®)
S1P modulator NRF2 pathway activation Pyrimidine synthesis inhibitor Purine analog
Bradycardia, lymphopenia, GI upset, liver toxicity, teratogenicity
Convenient; moderate efficacy
Monoclonal Antibodies
Natalizumab (Tysabri®) Ocrelizumab (Ocrevus®) Ofatumumab (Kesimpta®) Alemtuzumab (Lemtrada®)
IV (Natalizumab, Ocrelizumab, Alemtuzumab) SC (Ofatumumab)
Anti-VLA-4 (natalizumab) Anti-CD20 (ocrelizumab/ofatumumab) Anti-CD52 (alemtuzumab)
PML (natalizumab), infusion reactions, autoimmune diseases (alemtuzumab), infection risk
High efficacy; used in active or refractory MS
General Treatment Algorithm for Relapsing MS
- Mild to Moderate Disease → Interferons or Glatiramer Acetate → Consider oral DMTs if preference favors convenience
- Moderate to Severe Disease or High MRI Activity → Oral agents (Fingolimod, Dimethyl Fumarate, Cladribine) → Consider monoclonal antibodies early (Ocrelizumab, Natalizumab)
- Highly Active or Rapidly Progressive MS → Monoclonal Antibodies (Ocrelizumab, Alemtuzumab) → Escalate from injectables/orals if frequent relapses or new lesions.
