A 40-year-old woman with relapsing-remitting MS is being considered for high-efficacy disease-modifying therapy. Which of the following is associated with the highest risk of progressive multifocal leukoencephalopathy (PML) due to JC virus reactivation?
- A Interferon beta-1a (Avonex)
- B Fingolimod (sphingosine-1-phosphate receptor modulator)
- C Natalizumab (anti-VLA-4 antibody) ✓
- D Dimethyl fumarate (BG-12)
Correct answer: C. Natalizumab (anti-VLA-4 antibody)
Explanation
Natalizumab prevents lymphocyte trafficking into the CNS by blocking VLA-4 (α4-integrin). While highly effective for RRMS, it substantially increases the risk of PML (caused by JC virus reactivation in immunocompromised CNS) — particularly in patients positive for anti-JCV antibodies, with higher antibody index, and with >24 months of natalizumab use. Risk stratification using JCV antibody index guides treatment decisions. Fingolimod and dimethyl fumarate have very rare PML reports. Interferon beta has no PML risk.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
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Written and medically reviewed by the StethoPrep medical team.