BOSTON—In addition to John Cunningham virus (JCV) index, L-selectin level can help neurologists make treatment decisions for individuals with multiple sclerosis (MS), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The two biomarkers can help neurologists determine which patients are at highest risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML).

More than 40% of patients with MS can be considered at high risk of PML if JCV index alone is taken into account. If only L-selectin level is considered, then between 5% and 15% of patients with MS are at high risk of PML. Taking both JCV index and L-selectin level into account results in a rate of approximately 4% of patients with MS who are at high risk of PML. “That is a further stratification of patients being at risk, with all the advantages and disadvantages that biomarkers and serial assessments would have,” said Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.

Compared with JCV index, L-selectin may have disadvantages as a biomarker. For example, a patient’s JCV index generally is stable, but his or her L-selectin level may fluctuate. Furthermore, it is easier to measure JCV index than L-selectin level, which must be assessed in fragile peripheral blood mononucleated cells.

Yet data indicate that the two biomarkers have comparable sensitivity (98% for JCV index and 91% for L-selectin). An advantage of L-selectin is that it can provide information about all patients, while JCV index only is informative in patients who have not previously had immune suppression, said Dr. Wiendl.

L-Selectin May Indicate PML Risk in Various Disorders
In a 2013 study of patients with MS without previous immune suppression, Plavina et al concluded that individuals with a JCV index greater than 0.9 are at higher risk of developing PML. In the same year, Schwab and colleagues found that patients with MS and an L-selectin value lower than 21.6 are at higher risk of developing PML.

These findings prompted Dr. Wiendl and colleagues to ask whether L-selectin was associated only with natalizumab. They examined 10 patients with HIV who previously had developed PML and found that nine had a low L-selectin value. The group concluded that L-selectin might have a connection to the development of PML in various disorders.

L-Selectin Decreases During Natalizumab Treatment
Dr. Wiendl’s group recruited 2,300 patients with MS to further investigate JCV index and L-selectin. Approximately 55% of the patients had JCV antibodies, and this result is consistent with the literature. Approximately 41% of the cohort had a JCV index greater than 0.9 and were thus at higher risk of developing PML, said Dr. Wiendl.

In analyses of all patients and of only patients who had JCV antibodies, JCV index did not change during treatment with natalizumab. “This [finding] is rather good news for a biomarker because it’s pretty stable all the time,” said Dr. Wiendl. The investigators also found a clear correlation of JCV index with age, “which is a phenomenon that is mainly to be explained by seroconversion.”

The researchers also assessed patients’ L-selectin values. Early in the study, they found that 10 of 11 patients who later developed PML had low L-selectin values. The investigators went on to measure each patient as many as six times. After Dr. Wiendl’s group had screened approximately 800 patients, they calculated that with current protocols and cohorts, L-selectin had a specificity of approximately 89% and a sensitivity of approximately 91% for indicating risk of PML.

By examining the series of measurements for individual patients, the investigators gained additional information about both biomarkers. In one patient who previously had immune suppression and later developed PML, JCV index was low. The result indicates that JCV index is not a reliable indicator of PML risk among patients with previous immune suppression, said Dr. Wiendl.

Another patient had a normal L-selectin value that later decreased, and the patient subsequently developed PML. This patient’s JCV index was consistently high throughout all measurements. One patient with high L-selectin values and high JC index developed PML.

L-Selectin in Clinical Practice
The data indicate that a single measurement of a low L-selectin level confers a higher risk of PML. A patient’s L-selectin level will not necessarily stay low, however; it may recover. This fluctuation underscores the importance of repeated assessments, said Dr. Wiendl. L-selectin is “a dynamic marker that can change,” he added.

In addition, JCV index seems to correlate with L-selectin expression levels. Patients with high JCV index are likely to have a low L-selectin level, but the two biomarkers may not be correlated biologically, said Dr. Wiendl.

Treatment decisions are influenced by unchangeable factors, such as previous immune suppression, and dynamic biomarkers, such as treatment duration and JCV antibody seropositivity. “Then you have two additional parameters that might be helpful for individual treatment decisions: JCV index and L-selectin,” concluded Dr. Wiendl.

—Erik Greb

L-Selectin Level May Help Stratify Patients at Risk of PML