Study confirms value of watching JCV serology during natalizumab treatment

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More reasons to watch for JCV index changes

Dr. Schwab and his colleagues’ study showing high rates of seroconversion, rising seroprevalence, and increasing John Cunningham virus (JCV) index values add to growing evidence for the need to monitor JCV index values and seroconversion to determine patients’ risk for progressive multifocal leukoencephalopathy while taking natalizumab.

Their data extend earlier paired, longitudinal studies of natalizumab-treated patients with similar high rates of seroconversion (8%-27% per year) and rises in titers.

However, the higher replication rate of JCV implicated by rising anti-JCV titers does not mean that PML is imminent; the risk of PML in JCV-positive natalizumab-treated patients without prior immunosuppressant therapy is 1 in 1,000 per year, whereas the risk of an MS attack in untreated patients is 1 in 2 per year.

It will be important to combine JCV index with other predictive markers for PML in the future, including potential blood markers involving L-selectin expression on T cells, human leukocyte antigen subtypes, viral DNA content in circulating B cells, and numbers of cytolytic T cells, interleukin-10–positive T cells, or anti-JCV effector memory T cells.

Dr. Adil Javed and Dr. Anthony T. Reder are with the University of Chicago. This commentary summarized their editorial accompanying the study by Dr. Schwab and his colleagues (Neurol Neuroimmunol Neuroinflamm. 2016;3:e199. doi: 10.1212/NXI.0000000000000199). The authors disclosed financial ties to many companies that market drugs for MS, including Biogen, which manufactures natalizumab.




New analyses of multiple sclerosis patients taking natalizumab reemphasize the need to monitor John Cunningham virus (JCV) seroconversion and the level of anti-JCV antibody titers via JCV index values, according to a study of a pair of German and French cohorts.

Longitudinal data available for 525 German patients and 711 French patients with relapsing-remitting multiple sclerosis (MS) revealed seroconversion rates of 8.5%-10.3% per year, seroprevalence increases of 5%-6% during 15-24 months of follow-up, and increases in JCV index values of 0.091 units (12.9%) per year, which “clearly support the facilitation [of progressive multifocal leukoencephalopathy (PML)] by treatment with natalizumab [Tysabri]” and are “at least 8 to 10 times as much as would be expected by age,” reported Nicholas Schwab, Ph.D., of the University of Münster (Germany) and his colleagues (Neurol Neuroimmunol Neuroinflamm. 2016;3:e195. doi: 10.1212/NXI.0000000000000195).

Of the longitudinally followed German patients, 186 (35.4%) were initially seropositive and 43 (12.7%) became seropositive during a mean follow-up duration of 14.8 months, or 10.3% per year. The group of 711 longitudinally followed French patients included 468 (65.8%) who were initially JCV positive. A total of 20 (8.2%) patients who were initially JCV negative seroconverted in the first year, and another 21 (8.6%) did so in the second year, for an overall rate of 8.5% per year.

A total of 525 patients had changes in the level of anti-JCV antibodies in serum (and therefore had changes in JCV index value) during the observation period. Patients with a JCV index value less than 0.4 (very low PML risk) declined from 65.1% to 61.3%, and those with values 0.4-0.9 (low risk) declined from 8.0% to 7.8%. The proportion grew from 4.6% to 5.9% for values 0.9-1.5 (medium risk) and from 22.3% to 25.0% for values greater than 1.5 (high risk). In addition to reflecting the patients’ change in serostatus, the change in PML risk levels “suggested that patients who changed serostatus directly presented with high anti-JCV antibody titers afterward, as the groups of low and medium risk did not grow substantially over time,” the researchers wrote.

A group of 201 patients who were followed over time after becoming seropositive had a mean JCV index value that rose significantly from 2.046 to 2.158 and was not attributable to aging. Rises in JCV index values of more than 30% over the course of 14.8 months occurred in 17% of the patients, compared with stable values in 80% and decreases of more than 30% in 3%. Altogether, the index value of all 201 patients rose by a mean of 0.091 units (12.9%) per year.

“Because as yet there are no studies on the influence of other treatments on JCV index values ... we cannot be certain that it was the treatment with natalizumab that led to the rising index values in our study,” the investigators wrote, although they noted that a recent study of more than 7,000 control patients with MS showed that the duration of non–natalizumab MS treatment did not influence JCV seroprevalence after adjustment for age, sex, and country of origin.

Also, even though the mean index value for JCV-positive patients was greater than 2, putting them in the highest PML risk category, the investigators noted that very few of these patients will ultimately develop PML, so “JCV serology should not be the only PML risk biomarker used in the stratification of patients treated with natalizumab.”

The study was funded by various German and French institutional and governmental grants. Many authors reported financial ties to companies marketing MS drugs, including Biogen, the manufacturer of natalizumab.