Re-evaluating the incidence of natalizumab-associated progressive multifocal leukoencephalopathy

Area of Science:

• Neuroimmunology
• Pharmacovigilance
• Infectious Disease Epidemiology

Background:

• Natalalizumab is an effective therapy for multiple sclerosis and Crohn's disease.
• Progressive multifocal leukoencephalopathy (PML) is a rare but serious adverse event associated with natalizumab treatment.
• Risk factors for PML include John Cunningham virus (JCV) seropositivity and prior immunosuppressant (IS) use.

Purpose of the Study:

• To provide more accurate estimates of the prospective risk of developing PML in JCV-seropositive patients treated with natalizumab.
• To identify patient subgroups with a significantly elevated risk of PML.

Main Methods:

• Analysis of postmarketing surveillance data for natalizumab.
• Quantification of PML incidence using Kaplan-Meier estimation and relevant formulas.
• Stratification of risk based on prior immunosuppressant use and JCV index levels.

Main Results:

• The incidence of PML during months 25-48 of natalizumab therapy is approximately 19.5 per thousand in JCV-seropositive patients with prior IS use.
• Without prior IS use, the incidence during months 25-48 is 7.4 per thousand, and during months 49-72, it is 10.8 per thousand.
• Patients with a JCV index >1.5 face a higher PML risk (17.0 per thousand during months 49-72) compared to those with an index of 0.9-1.5 (6.2 per thousand).

Conclusions:

• Published estimates of PML risk with natalizumab systematically underestimate the true incidence.
• The long-term risk of PML is nearly double previous estimates, with some patient groups facing risks up to nine times higher.
• Incorporating markers like L-selectin and CSF lipid-specific IgM bands into risk-stratification algorithms can enhance the safety of natalizumab therapy.