Random Dermatology MCQ - Rituximab's Mechanism of Action

A 55-year-old woman with refractory pemphigus vulgaris is started on a monoclonal antibody therapy. This drug leads to a rapid and sustained depletion of CD20-positive B cells from the peripheral blood. Which of the following best describes the mechanism of action of this medication?

A) Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) targeting CD20 on B cells
B) Inhibition of B-cell activation by blocking CD40 ligand
C) Binding to and neutralizing B-cell activating factor (BAFF)
D) Inhibition of the Bruton tyrosine kinase (BTK) signaling pathway
E) Blockade of the B-cell receptor (BCR) complex

Correct Answer: A) Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) targeting CD20 on B cells

Explanation

The drug described is rituximab, a chimeric monoclonal antibody that targets the CD20 antigen on the surface of B cells.

Mechanism of Action of Rituximab:

1. Target: The CD20 antigen is expressed on the surface of pre-B cells, mature B cells, and memory B cells, but not on plasma cells, pro-B cells, or stem cells.

2. Primary Mechanisms of Cell Lysis:

   • Antibody-Dependent Cellular Cytotoxicity (ADCC): The Fc portion of rituximab binds to Fcγ receptors on immune effector cells (primarily natural killer (NK) cells), which then lyse the targeted B cell.

   • Complement-Dependent Cytotoxicity (CDC): The Fc portion of rituximab activates the classical complement pathway, leading to the formation of the membrane attack complex (MAC) and B-cell lysis.

3. Secondary Mechanisms:

   • Direct Induction of Apoptosis: Cross-linking of CD20 by the antibody can trigger intracellular signals that lead to programmed cell death.

   • Inhibition of B-Cell Proliferation.

Clinical Correlation in Pemphigus Vulgaris:

• Pemphigus vulgaris is driven by pathogenic autoantibodies (anti-desmoglein) produced by B cells and plasma cells.

• Rituximab depletes the precursor B-cell pool, preventing the generation of new autoantibody-producing plasma cells. This leads to a gradual decline in pathogenic autoantibody titers and clinical improvement.

Why Not the Other Options?

• (B) Inhibition of B-cell activation by blocking CD40 ligand: This describes the mechanism of an investigational drug, not rituximab.

• (C) Binding to and neutralizing B-cell activating factor (BAFF): This is the mechanism of belimumab, used in systemic lupus erythematosus.

• (D) Inhibition of the Bruton tyrosine kinase (BTK) signaling pathway: This is the mechanism of small molecule inhibitors like ibrutinib, used in B-cell malignancies.

• (E) Blockade of the B-cell receptor (BCR) complex: This is not the mechanism of rituximab.

Clinical Use in Dermatology:

• Refractory pemphigus vulgaris and foliaceus

• Bullous pemphigoid

• Cutaneous B-cell lymphomas

• SLE

Adverse Effects:

• Infusion reactions

• Increased risk of infections (especially HBV reactivation)

• Progressive multifocal leukoencephalopathy (PML) - rare

Note: Rituximab's efficacy in autoimmune blistering diseases stems from its ability to deplete the B-cell lineage responsible for autoantibody production. The key to its mechanism is the dual lysis pathway of ADCC and CDC directed at the CD20 antigen.