Comparing types of treatments for NMO

This is article no. 12 in a series on rare diseases. Next article coming soon. Previous article: CEDS: a break in cell death.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare and disabling autoimmune condition of the central nervous system that primarily attacks the optic nerves and spinal cord (see previous article for more). Symptoms include eye pain, blurred vision, weakness or paralysis in the limbs, muscle spasms, bowel disruptions etc. Before 2019, treatment options were limited to acute relapse management and off-label broad immunosuppression. This is done by stopping acute inflammatory attacks and using targeted maintenance therapies, such as monoclonal antibodies, to prevent relapses. However, the approval of targeted monoclonal antibodies starting in 2019 established a new standard of care for long-term relapse prevention.

What are monoclonal antibodies? How does monoclonal antibody therapy work for NMOSD?

Monoclonal antibodies (mAbs) are specialised, laboratory-engineered proteins designed to bind to precise cell surface receptors or soluble immune molecules, thereby interrupting specific pathogenic pathways responsible for driving neuroinflammation and tissue injury.

In NMOSD, aquaporin-4 autoantibodies (AQP4-IgG) bind directly to astrocytes in the optic nerves and spinal cord, triggering severe localised inflammation, complement protein activation, and irreversible cell damage. Monoclonal antibody therapies block this destructive cascade through three distinct immunological mechanisms:

1. Agents, such as inebilizumab and rituximab, target and deplete B-cell populations responsible for generating AQP4-IgG autoantibodies, thereby lowering circulating pathogenic antibody titers. 

2. Drugs like satralizumab and tocilizumab inhibit interleukin-6 (IL-6) receptors, stopping downstream inflammatory cascades that recruit damaging immune cells to central nervous system tissue. 

3. Terminal complement inhibitors, such as eculizumab and ravulizumab, block the C5 complement protein cascade, preventing antibody-mediated destruction of astrocytes and surrounding tissues. 

See Table 1 on the types of monoclonal antibody treatment for NMOSD, including mechanisms and efficacy.

As of now, the above four monoclonal antibodies (apart from rituximab) (Table 1) have received U.S. Food and Drug Administration (FDA) approval for treating anti-aquaporin-4 (AQP4) antibody-positive NMOSD. Inebilizumab (Uplizna) is a humanized monoclonal antibody targeting CD19 on B cells, delivering broad depletion across early and mature B-cell populations. Satralizumab (Enspryng) acts as an interleukin-6 receptor antagonist that suppresses pro-inflammatory cytokine signaling networks. Complement inhibitors eculizumab (Soliris) and ravulizumab (Ultomiris) target the terminal complement C5 protein to stop the assembly of the membrane attack complex. Additionally, rituximab is a chimeric anti-CD20 monoclonal antibody widely prescribed off-label as a first-line preventive therapy due to extensive long-term clinical experience and documented real-world efficacy.

When evaluating clinical efficacy and safety considerations, these targeted monoclonal therapies display their highest certainty of clinical benefit in patients who test positive for AQP4-IgG autoantibodies, though they are also utilised across the broader NMOSD spectrum. The primary safety concern associated with these biologic therapies is an increased risk of severe infections; notably, patients initiating complement inhibitor therapy require mandatory prior vaccination against meningococcal infection. Ultimately, selecting an appropriate monoclonal antibody depends on individual patient safety profiles, route and frequency of administration, drug availability, and cost factors.

Future directions

Despite the growing hope for the NMOSD community, it is necessary to be cautiously optimistic when interpreting these treatment options, as all currently approved monoclonal antibody therapies were tested and validated specifically for anti-aquaporin-4 antibody-positive (AQP4-IgG+) NMOSD. Broadly speaking, patients presenting with NMOSD-like syndromes fall into three distinct diagnostic categories based on autoantibody status. Approximately 70% to 80% of patients test positive for AQP4-IgG, representing a distinct astrocytopathy that responds exceptionally well to targeted complement and B-cell blockade. Another 10% to 20% of individuals with NMOSD-like presentations test positive for myelin oligodendrocyte glycoprotein antibodies (MOGAD), an entity involving primary oligodendrocyte damage that shows lower responsiveness to standard B-cell therapies. The remaining 10% to 20% are classified as double-seronegative NMOSD, a heterogeneous group lacking definitive biomarkers where monoclonal antibodies exhibit significantly reduced relative efficacy compared to AQP4-positive cases.

While biologics have transformed care for AQP4-IgG positive disease, we still have a long way to go in uncovering the underlying mechanisms and developing targeted therapies for non-AQP4+ NMOSD.

Written by Chloe Kam

Related article: Introduction to NMO

REFERENCES

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