Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal viral brain infection characterised by progressive damage to the white matter of the brain. It is caused by the JC virus (JCV), which is present in about half of the general population, but only manifests in people whose immune system has been suppressed.
This includes those on immune-modifying medication and PML has been identified as a relatively rare risk for people with MS treated by natalizumab (Tysabri). As part of their ongoing monitoring, the pharmaceutical sponsor of natalizumab, Biogen Idec, has reported that there have been 395 PML cases in people on natalizumab up to 6th August 2013*. Over 118,100 people have been treated with natalizumab, giving an overall risk of PML of 3.28 in 1000.
Certain factors can change a person’s risk of developing PML including whether there are JCV antibodies detected in blood, the length of time a patient is treated (especially for longer than two years), and whether there is a history of immune suppression. Screening patients for these factors and limiting the length of time a person is on natalizumab will reduce the risk of PML in individual cases.
Natalizumab can be very effective in the treatment of MS, with up to 81% reduction in relapse rates and 64% reduction in disability progression. As such, further refining the identification of who may be most at risk of PML so that treatment can be targeted to those at lowest risk of this serious adverse event is a major goal of research.
Research presented in June at the European Neurological Society Congress showed that increased amounts of JCV antibodies in a person’s system increases the likelihood that a person will develop PML. They first looked at how JCV antibody levels interacted with the two other known risk factors of PML and then updated risk values based on high or low levels of JCV antibody.
Using data from natalizumab patients, 71 of whom went on to develop PML and 2522 people who did not, they found that in people with MS who have low JCV antibody index, the risk of PML is several-fold lower than the risk currently attributed to all JCV antibody positive patients.
A Swedish study published in the Journal of Neurology, Neurosurgery and Psychiatry has also looked at ways to predict PML in people treated with natalizumab using anti-JCV antibodies. They looked at serum samples which had been stored from 1157 people with MS including five cases of PML. They found before treatment JCV antibodies were stable, and during treatment these antibodies went slightly down. In the people who developed PML, the antibodies increased slightly at the time of PML diagnosis and possibly before PML was diagnosed.
While further research is needed these studies suggest that JCV antibody levels may help to determine natalizumab treatment options more accurately for people with MS and may assist with the early diagnosis of PML. It also highlights the need to regularly check JCV antibody levels in people with MS undergoing natalizumab treatment.
Another recent study has identified a biomarker to predict whether a person may develop PML. Biomarkers are targets for testing, in this case in the blood, which would allow risk of PML to be tracked over time. The study looked at the blood of 16 people with PML, 8 of which had been collected prior to PML developing. They were compared with PML cases that were unrelated to natalizumab and healthy controls.
They found the percentage of specific immune cells (CD4 positive T cells) with a molecule called l-selectin on their surface was significantly lower in long term natalizumab treated patients (40.2%) compared with in people with MS not receiving natalizumab (47.2%) and in healthy controls (61%). However, in patients who went on to develop PML, this percentage dropped to 4.6%. L-selectin is a ‘homing’ molecule involved in immune cell activation and migration through the body. While these results will need to be confirmed in a larger study, the researchers suggest that bi-yearly testing for l-selectin in people taking natalizumab with a cut-off of 15% could be useful in the clinical setting.
*Biogen Idec provides a monthly update of information on PML cases to registered neurologists.