A 24-year-old woman with relapsing-remitting multiple sclerosis (RRMS) has had 2 clinical relapses in 2 years and new T2 lesions on MRI. She is currently on interferon-beta 1a. Her neurologist considers switching to a high-efficacy therapy. The mechanism of action of natalizumab in MS is:
- A Depletes circulating B-cells by targeting CD20 on B-lymphocytes
- B Inhibits sphingosine-1-phosphate (S1P) receptors, sequestering lymphocytes in lymph nodes
- C Activates Nrf2 pathway, reducing oxidative stress in demyelinating lesions
- D Blocks integrin α4β1 (VLA-4), preventing lymphocyte migration across the blood-brain barrier ✓
Explanation
Natalizumab (Tysabri) is a humanized monoclonal antibody against α4-integrin (VLA-4), which mediates lymphocyte adhesion to VCAM-1 on brain endothelium. By blocking VLA-4 binding, natalizumab prevents activated T-lymphocytes from crossing the blood-brain barrier, thereby reducing CNS inflammation. It reduces relapse rate by ~68% and new MRI lesions by ~83% (AFFIRM trial). The major risk is JC virus reactivation causing PML (progressive multifocal leukoencephalopathy), particularly in JC antibody-positive patients after >24 months of therapy. Ocrelizumab/rituximab target CD20 (B-cells); fingolimod/siponimod act via S1P receptors; dimethyl fumarate activates Nrf2.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.