A panel of neurologists from the U.K. and Ireland recently developed practical consensus guidelines for monitoring multiple sclerosis (MS) patients on natalizumab (Tysabri) therapy for the risk of developing progressive multifocal leukoencephalopathy (PML), a life-threatening viral infection caused by the John Cunningham (JC) virus.
The panel was summoned by Biogen but worked independently of the company, and members did not receive financial reimbursement for their work. They analyzed available data from clinical trials and real-life use. Their findings were published in the article“Stratification and monitoring of natalizumab associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group,” which appeared in the Journal of Neurology, Neurosurgery & Psychiatry.
Natalizumab, used for the treatment of highly active relapsing-remitting MS (RRMS) in patients, has been associated with the development of PML. Before the age of immunomodulating biological drugs, PML was associated with immunosuppression but not with autoimmune diseases such as MS. The JC virus is common and usually benign, and infects an estimated 60 percent of the European population. But the type causing PML is a mutated form that can enter into the brain, and researchers are puzzled as to why the virus mutates in MS patients on natalizumab.
Active monitoring during treatment is necessary to reduce the risks of PML, but until now, there has been no consensus on best monitoring practices.
Known risk factors for developing PML are previous immunosuppressive therapy, as well as treatment with natalizumab for more than 25 months. A patient’s overall risk of developing PML is 1 in 1,667 during treatment of up to two years (24 months), and that risk increases to 1 in 192 patients for treatment durations of 25–48 months.
Also, the presence of antibodies against the virus before symptoms occur has been detected in the majority of patients developing PML. The Committee for Medicinal Products for Human Use currently recommends anti-JCV antibody testing every six months to identify early patients whose antibody status has changed from negative to positive. The levels of antibodies against the virus — known as the anti-JCV antibody index — has also been associated with the development of PML in patients without previous immunosuppressant therapy. This test is sensitive in predicting PML infection, but the specificity is low since many patients with high antibody levels never develop PML.
The consensus group suggested that patients should be stratified into two risk groups based on their antibody levels and other risk factors: low-risk patients in the group having an anti-JCV index equal or less than 1.5, and high-risk patients with an index above 1.5. Patients in the low-risk group are recommended to repeat antibody testing at six-month intervals, as only 1 in 5,882 MS patients with an index of 1.5 or lower and natalizumab treatment of less than two years has developed PML.
This risk subsequently increases with both treatment time and antibody levels, and an index value of 0.9 or less carries a risk of 1 in 1,961, rising to 1 in 885 if index values increase to 1.5 during years two to four of natalizumab treatment. Longer exposure further increases the risk somewhat, to 1 in 1,724 for index 0.9 or lower, and to 1 in 730 for index 1.5 during months 49-72.
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