Information that sheds some light on the mechanism by which the multiple sclerosis drug natalizumab (Tysabri, Biogen) increases the risk for potentially fatal progressive multifocal leukoencephalopathy (PML) has been reported in a new study, which may help with risk stratification of patients taking this medication.
Researchers have found that the rate of seroconversion to JC virus (JCV) positivity is much higher — about 10-fold higher — in patients receiving natalizumab than in the general population and that the index value of antibody levels at the time of seroconversion is generally high.
The study, published in the January 27 online issue of Neurology: Neuroimmunology and Neuroinflammation, was led by Nicholas Schwab, PhD, University of Münster, Germany.
"PML risk with natalizumab is a very complex issue," he explained to Medscape Medical News. "We know that natalizumab is associated with PML and we know this is related to the John Cunningham virus (JCV) and that patients have to be JCV antibody positive to develop PML. But we haven't before had detailed information about how natalizumab influences JCV seroconversion and antibody index levels. So our results are providing key new data on this."
Dr Schwab elaborated: "Biogen has previously suggested that PML develops in patients on natalizumab who are already JCV positive, so that if a patient is JCV negative they are not at risk. Additionally it has been thought that if patients seroconvert on natalizumab they generally will have low levels of JCV antibodies to start with and be at low risk of developing PML. But our data suggest that is not the case — that patients on natalizumab are at increased risk of seroconversion and that they often seroconvert to high antibody index value signaling increased PML risk."
"At least this appears to be the case in Germany and France — it may not be the same everywhere. Other smaller studies in other populations have shown lower risks so host genetics and environmental factors probably also play a role."
Dr Schwab said the new findings underlined the importance of regular JCV tests for patients taking natalizumab.
"We need to monitor JCV serology more closely. At present many patients just have the occasional test for JCV antibodies. But because the seroconversion rate appears to be much higher than we thought when taking natalizumab, more frequent tests are advisable."
"Because we have shown that the levels of antibody titers, which are related to PML risk, can vary over time, patients with relatively low antibody levels may still be at risk. It is not all right to get a positive antibody index in the low range — 0.5 or 0.6 — and think there is no reason for worry. This antibody level can rise and with it the risk of PML. So regular tests are necessary — at least twice a year. Current recommendations do advise this, but they are not always followed in clinical practice, especially in nonspecialist centers."
Risk Still Low
In an accompanying editorial, Adil Javed, MD, and Anthony T. Reder, MD, University of Chicago, Illinois, point out that the risks of developing PML while receiving natalizumab are still very low.
"Risk is relative. Despite a higher JCV replication state, an increase in JCV-Ab index does not necessarily mean that PML infection is imminent," they write. "Our risk of death from driving to work in Illinois is 1/10,000 per year; the risk of PML in JCV+ natalizumab-treated patients without prior immunosuppressant therapy is 1:1,000 per year; the risk of an MS attack in untreated patients is 1/2 per year."
However, they acknowledge that "markers that quantify risk can give an edge in life's gambles." They note that the JCV index appears to be a valid serum marker of risk for PML, with an index below 0.9 signifying minimal risk and a value over 1.5 suggestive of increased risk.
The editorialists conclude that: "Schwab et al extend growing observations that JCV-Ab index values need to be monitored and that seroconversion or rising JCV-Ab titers alter the risk of PML in patients treated with natalizumab."
For the study, the researchers analyzed JCV serology in 1921 patients in Germany and 1259 patients in France, all of whom were talking natalizumab for MS. In the German group, 525 patients were followed longitudinally over an average of 14.8 months; in the French group, 711 patients had longitudinal follow-up over an average of 24 months.
Results showed an annual rate of seroconversion was 10.3% in the German group and 8.5% in the French patients. This compared to rates of around 0.5% to 1% for the general population or for patients with MS not treated with natalizumab, Dr Schwab said.
In patients who were anti-JCV positive already at the beginning of the study, their level of antibodies also rose over time. Treatment with natalizumab was associated with a 13% annual rise in the level of anti-JCV antibodies.
"Our data suggests that natalizumab appears to increase JCV activity," Dr Schwab commented. "While the exact mechanism of how the virus brings about PML is not known, it is believed that the virus has to mutate as the first step and the more active the virus the more likely it is to mutate."
The researchers conclude: "JCV positive patients should check their JCV index values until they have reached the highest risk category, after which JCV serology loses some of its usefulness. The fact that treatment with natalizumab is associated with a very high rate of seroconversion and rising index values does not diminish its clinical efficacy, but calls for more elaborate strategies for PML risk stratification."
Dr Schwab received travel funding from Biogen and speaker honoraria from Novartis, and he holds a patent for usage of L-selectin as a predictive marker for PML. Dr Javed has consulted for Bayer, Biogen, Questcor, Novartis, and Teva. Dr. Reder served on the scientific advisory boards, consulted for, and received travel funding and/or speaker honoraria from Abbott, ImmunoScience, Questcor/Malinkrodt, AstraZeneca, Merck Serono, Athena Diagnostics, Sanofi-Aventis, Bayer, Biogen Idec, BioMS Medical, Blue Cross–Blue Shield, Boehringer Ingelheim, Caremark, Centocor Ortho Biotech Inc, Cephalon Inc, Connetics Corp, Cro-Medica Global, Eli Lilly, Elan, Genentech, Genzyme, GlaxoSmithKline, Hoechst MarionRoussel Canada Research, Roche, Immunex, Johnson & Johnson, Neurocrine Biosciences, Novartis, Parke-Davis, Pfizer, Pharmacia & Upjohn, Protein Design Labs, Quantum Biotechnologies, Quintiles, EMD Serono, Sention, SmithKline- Beecham, Specialized Therapeutics, Takeda, and Teva.
Neurol Neuroimmunol Neuroinflamm. Published online January 27, 2016. Full text Editorial
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Cite this: Natalizumab Ups JCV Seroconversion, Antibody Index in MS - Medscape - Jan 29, 2016.