PML, a Rare Side Effect of Tysabri, Found to Worsen Long-Term Disability in Patients with MS


Progressive multifocal leukoencephalopathy (PML) is caused by John Cunningham virus (JCV). A recently published study suggests that the number of cases of PML related to Tysabri (natalizumab) have been decreasing perhaps as a result of increased monitoring.

Tysabri (natalizumab) is an integrin receptor antagonist indicated for treating relapsing forms of multiple sclerosis (MS) and to induce and maintain remission in Crohn’s disease in adults. This monoclonal antibody, marketed by Biogen in Cambridge, Massachusetts, works by blocking the alpha4-beta 1 integrin receptor on lymphocytes, which prevents the movement of these white blood cells from the blood vessels into the brain and spinal cord. In doing so, Tysabri reduces inflammation and slows MS disease activity.

Tysabri now carries a boxed warning for the increased risk of developing progressive multifocal leukoencephalopathy (PML). PML is a rare, opportunistic brain infection caused by human polyomavirus 2, commonly known as John Cunningham virus (JCV). PML is a serious and potentially fatal infection.

Risk factors for developing PML during Tysabri treatment include prior treatment with immunosuppressants, the presence of anti-JCV antibodies, and a longer duration of therapy with Tysabri.

To prescribe Tysabri as an MS treatment, clinicians must be registered in the MS TOUCH Prescribing Program. The program alerts prescribers of the risks associated with Tysabri therapy and ensures they are able to detect and manage PML if it occurs.

In an effort to understand the long-term effects of PML, Tobias Moser and colleagues from the Department of Neurology at the Christian Doppler University Hospital in Salzburg, Austria, conducted a retrospective study based on a review of medical records within the Austrian MS Treatment Registry. The results were published last month in the Journal of Neurology.

Using records from 2006 up to December 2022, the researchers identified 15 patients who had developed PML during Tysabri treatment. They discovered that 80% of PML cases occurred between 2010 and 2015. Only three cases were reported after 2016, when increased monitoring for PML began.

After a median follow-up of 76 months, the study results showed an overall mortality rate of 20%. Overall disability scores, measured by the Expanded Disability Status Scale (EDSS), increased by 3 points after PML diagnosis. A majority of patients (55%) had long-term continuing worsening disability, and 20% of patients went on to develop secondary progressive MS.

The researchers note that, although PML diagnoses have been decreasing, partly due to increased monitoring, this condition is associated with increased long-term neurological disability in patients with MS. They concluded, “Whether our findings may suggest a modification of MS course beyond natural course needs to be investigated in larger cohorts enabling adjustment for confounders.”

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