Can Rituximab (rituximab) treatment lead to permanent elimination of memory B cells, negatively affecting humoral immunity?

Rituximab's Impact on Memory B Cells and Humoral Immunity

Yes, rituximab treatment can lead to permanent elimination of some memory B cells, negatively affecting humoral immunity in certain patients. 1, 2

Mechanism of B-Cell Depletion

Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen expressed on:

• Pre-B cells
• Mature B cells
• Memory B cells
• Autoantigen-specific B cells 1

Upon binding to CD20, rituximab mediates B-cell lysis through:

• Complement-dependent cytotoxicity (CDC)
• Antibody-dependent cell-mediated cytotoxicity (ADCC) 1

Pattern of B-Cell Depletion and Recovery

Initial Depletion

• Rituximab causes rapid and profound depletion of circulating B cells within 2-3 weeks of administration 1, 2
• Depletion is maintained for at least 6-12 months in most patients 2

Recovery Pattern

• B-cell recovery typically begins at approximately 6 months post-treatment 1
• Median B-cell levels generally return to normal by 12 months following treatment completion 1
• However, a small proportion (~4%) of patients experience prolonged peripheral B-cell depletion lasting more than 3 years after a single course of treatment 1

Impact on Memory B Cells

Memory B cells are particularly affected by rituximab treatment:

• In lymph nodes, rituximab alters the composition of remaining B cells, with a higher percentage of switched memory B cells (IgD-CD27+) 3
• However, some memory B cells can be permanently eliminated, as evidenced by incomplete recovery patterns 2, 4
• Flow cytometry studies show that memory B cell populations (IgD-CD38+/-) can be used as biomarkers to predict clinical response and relapse 4

Effects on Immunoglobulin Levels

Rituximab treatment leads to:

• Sustained and statistically significant reductions in both IgM and IgG serum levels from 5-11 months post-administration 1
• 14% of patients develop IgM and/or IgG serum levels below the normal range 1
• In RA patients with repeated rituximab treatment, 23.3%, 5.5%, and 0.5% of patients experience decreases in IgM, IgG, and IgA concentrations below lower limit of normal, respectively 1

Factors Affecting Permanent B-Cell Depletion

Several factors influence whether memory B cells are permanently eliminated:

1. Number of treatment cycles - Repeated courses increase risk of prolonged depletion 5
2. Pre-existing hypogammaglobulinemia - Associated with increased risk of persistent reduction in IgG levels 5
3. Concomitant immunosuppressive therapy - Particularly cyclophosphamide, increases risk of developing hypogammaglobulinemia 5
4. Completeness of initial B-cell depletion - Failure to achieve complete depletion of CD19+ cells, naïve B cells, or memory B cells is associated with higher relapse rates but potentially less permanent impact 6

Clinical Consequences

Vaccine Response Impairment

• Rituximab significantly reduces responses to vaccines, including:
  • SARS-CoV-2 vaccines (only 39% seroconversion compared to 100% in controls) 2
  • Tetanus vaccine (only 9% of rituximab-treated patients had a ≥4-fold rise in antibody titers) 2
  • Influenza vaccines (impaired immune response associated with persistent memory B-cell depletion) 2

Risk factors for poor vaccine response

• Shorter duration between rituximab dose and vaccination
• Lack of B-cell reconstitution 2
• Patients vaccinated 6 months after rituximab had ~20% seropositivity rate
• Patients vaccinated 1 year after rituximab had ~50% seropositivity rate 2

Infection Risk

• Rituximab causes profound B-cell depletion leading to increased infection risk 7
• Some patients develop persistent B-cell dysfunction requiring immunoglobulin replacement therapy (IGRT) 8
• B-cell phenotyping after rituximab shows predominantly naïve B cells with significant decrease in switched and memory B cells 8

Monitoring Recommendations

To identify patients at risk of permanent memory B-cell depletion:

1. Obtain baseline B-cell numbers and serum immunoglobulin levels before starting therapy 5
2. Monitor immunoglobulin levels periodically during and after treatment 5
3. Consider B-cell phenotyping to identify patients who may develop persistent immune dysfunction 8, 4
4. Monitor for signs of infection 7

Conclusion

While most patients recover B-cell populations within 12 months after rituximab treatment, a subset of patients experience permanent elimination of some memory B cells, resulting in long-term impairment of humoral immunity. This can lead to hypogammaglobulinemia, increased infection risk, and poor vaccine responses, potentially requiring immunoglobulin replacement therapy in severe cases.