Natalizumab Treatment for Multiple Sclerosis: Understanding Benefits, Risks, and Monitoring

Table of Contents

• Introduction: Understanding Multiple Sclerosis and Natalizumab
• How Natalizumab Works: Mechanisms of Action
• PML Complication: Understanding the Risks
• Drug Monitoring: Measuring Effectiveness and Safety
• Anti-Drug Antibodies: When Treatment Stops Working
• Conclusion: Balancing Benefits and Risks
• Source Information

Introduction: Understanding Multiple Sclerosis and Natalizumab

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that affects the central nervous system (brain and spinal cord), causing damage to the protective myelin sheath around nerves. The most common form is relapsing-remitting MS (RRMS), where patients experience periods of symptoms (relapses) followed by recovery periods. Over time, some patients may develop secondary progressive MS (SPMS) with continuous worsening without recovery.

Natalizumab (brand name Tysabri®) is a disease-modifying therapy that has dramatically changed RRMS treatment. It's a humanized monoclonal antibody that targets the alpha-4 chain (CD49d) of the VLA-4 integrin, a protein that helps immune cells migrate into tissues including the brain. By blocking this migration, Natalizumab significantly reduces MS relapses and active brain lesions seen on MRI scans.

However, this powerful treatment comes with a serious risk: progressive multifocal leukoencephalitis (PML), a rare but often fatal brain infection caused by the John Cunningham virus (JCV). This article explains everything patients need to know about how Natalizumab works, its benefits and risks, and how doctors monitor treatment to maximize safety and effectiveness.

How Natalizumab Works: Mechanisms of Action

Natalizumab works by preventing immune cells from crossing the blood-brain barrier and entering the central nervous system where they cause damage in MS. The drug blocks the VLA-4 integrin on immune cells, which normally interacts with VCAM-1 on blood vessel walls to enable migration into tissues.

The treatment causes significant changes in the immune system:

• Blood cell increases: B lymphocytes increase more than 3 times pre-treatment levels, natural killer (NK) cells increase 2 times, and T lymphocytes increase 1.8 times
• Brain cell decreases: T lymphocytes (especially CD4+ cells) and B cells decrease in the cerebrospinal fluid and brain tissue
• Antibody reduction: Immunoglobulin levels (IgM, IgG) decrease in the cerebrospinal fluid, including oligoclonal bands
• No change in regulatory T cells: The important regulatory T cells that help control immune responses maintain their function despite treatment

These effects begin quickly after starting treatment and can take up to 6 months to reverse after stopping the medication. The accumulation of potentially activated immune cells in the bloodstream explains why approximately one-third of patients experience disease recurrence after stopping Natalizumab, sometimes with more severe relapses than before treatment.

PML Complication: Understanding the Risks

Progressive multifocal leukoencephalitis (PML) is the most serious risk associated with Natalizumab treatment. PML is a rare brain infection caused by the John Cunningham virus (JCV), which typically remains dormant in healthy people but can reactivate in immunocompromised individuals.

The risk factors for developing PML include:

• Treatment duration: Risk increases significantly after 18-24 months of treatment
• Prior immunosuppression: Patients who previously used immunosuppressive drugs
• JCV antibody status: Patients who test positive for JCV antibodies
• Extended treatment: Risk is approximately 1 in 1000 patients after 18 months of treatment

The mechanism behind PML risk involves multiple factors. Natalizumab causes accumulation of hematopoietic precursors and B cells in circulation, which may serve as reservoirs for JCV. The drug also upregulates transcription regulators (POU2AF1 and Spi-B) in B cells that may facilitate viral reactivation and replication.

Interestingly, the anti-viral Th1 immune cells that normally control JCV are retained in the circulation under Natalizumab treatment, hampering viral elimination from the brain. This combination of factors creates an environment where JCV can reactivate and cause PML while the immune system cannot effectively respond.

Drug Monitoring: Measuring Effectiveness and Safety

Regular monitoring is essential for patients receiving Natalizumab treatment. Doctors use several methods to ensure the drug is working properly and to assess potential risks.

Drug level monitoring: Natalizumab concentrations in blood show high variability among patients (from less than 4 μg/ml to over 100-200 μg/ml), though most patients (over 90%) maintain levels above 10 μg/ml. These levels reach a stable plateau quickly and remain consistent with continued treatment. In the cerebrospinal fluid, drug levels are approximately 100 times lower (45-110 ng/ml).

Receptor saturation monitoring: Doctors can measure how completely Natalizumab saturates the CD49d receptors on immune cells. Under standard 4-week dosing, receptor saturation reaches 76-84%. With extended interval dosing (6-8 weeks), saturation decreases to 54-62% but remains effective for most patients.

CD49d expression monitoring: Natalizumab treatment causes approximately a 50% decrease in CD49d expression on immune cells, which contributes to the drug's effect. This reduced expression remains stable throughout treatment unless patients develop antibodies against the drug.

Research shows that extended interval dosing (every 6-8 weeks instead of 4 weeks) maintains clinical effectiveness while potentially reducing PML risk. Studies found no worsening of clinical status with extended dosing, making this an important option for long-term treatment management.

Anti-Drug Antibodies: When Treatment Stops Working

Approximately 9% of patients develop antibodies against Natalizumab, with 6% developing permanent antibodies that neutralize the drug's effects. This immunization can cause the treatment to stop working and may lead to disease relapse.

Signs of immunization include:

• Return of CD49d expression to normal levels (loss of the typical 50% decrease)
• Complete disappearance of circulating Natalizumab
• Clinical relapses or return of disease activity
• Injection-related side effects in some patients

Patients typically undergo systematic screening for antibodies at 6 months of treatment. Those with high antibody levels usually need to switch to another therapy. Research has identified specific regions of the Natalizumab molecule that trigger immune responses, leading to development of "deimmunized" antibodies that might help treated patients who develop immunity.

For patients who need to stop Natalizumab quickly (such as when PML is suspected), plasma exchange can eliminate approximately 90% of circulating drug within one week. However, this rapid elimination carries risks, including disease reactivation and immune reconstitution inflammatory syndrome (IRIS) in PML patients, which can worsen outcomes.

Conclusion: Balancing Benefits and Risks

Natalizumab remains one of the most effective treatments for relapsing-remitting multiple sclerosis, providing a 68% reduction in relapse rates and an 83% reduction in new brain lesions. However, the risk of progressive multifocal leukoencephalitis requires careful patient selection and ongoing monitoring.

The development of extended interval dosing protocols (every 6-8 weeks instead of 4 weeks) represents an important advancement that maintains clinical effectiveness while potentially reducing PML risk. Regular monitoring of drug levels, receptor saturation, and CD49d expression helps doctors optimize treatment for each individual patient.

For patients considering Natalizumab treatment, understanding both the significant benefits and serious risks is essential. Working closely with neurologists to implement appropriate monitoring and consider extended interval dosing after the initial treatment period can help maximize safety while maintaining the excellent disease control that Natalizumab provides.

Source Information

Original Article Title: "Natalizumab in Multiple Sclerosis Treatment: From Biological Effects to Immune Monitoring"

Authors: Kathy Khoy, Delphine Mariotte, Gilles Defer, Gautier Petit, Olivier Toutirais, Brigitte Le Mauff

Publication: Frontiers in Immunology, September 24, 2020

DOI: 10.3389/fimmu.2020.549842

This patient-friendly article is based on peer-reviewed research and maintains all original data, statistics, and findings from the scientific publication.