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. 2014 Dec;76(6):802-12.
doi: 10.1002/ana.24286. Epub 2014 Oct 24.

Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy

Tatiana Plavina  1 , Meena Subramanyam, Gary Bloomgren, Sandra Richman, Amy Pace, Sophia Lee, Brian Schlain, Denise Campagnolo, Shibeshih Belachew, Barry Ticho
Affiliations
Free PMC article

Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy

Tatiana Plavina et al. Ann Neurol. 2014 Dec.
Free PMC article

Abstract

Objective: The increased risk of progressive multifocal leukoencephalopathy (PML) with natalizumab treatment is associated with the presence of anti-JC virus (JCV) antibodies. We analyzed whether anti-JCV antibody levels, measured as index, may further define PML risk in seropositive patients.

Methods: The association between serum or plasma anti-JCV antibody levels and PML risk was examined in anti-JCV antibody-positive multiple sclerosis (MS) patients from natalizumab clinical studies and postmarketing sources. For PML and non-PML patients, the probabilities of having an index below and above a range of anti-JCV antibody index thresholds were calculated using all available data and applied to the PML risk stratification algorithm. Longitudinal stability of anti-JCV antibody index was also evaluated.

Results: Anti-JCV antibody index data were available for serum/plasma samples collected >6 months prior to PML diagnosis from 71 natalizumab-treated PML patients and 2,522 non-PML anti-JCV antibody-positive patients. In patients with no prior immunosuppressant use, anti-JCV antibody index distribution was significantly higher in PML patients than in non-PML patients (p < 0.0001). Among patients who were anti-JCV antibody negative at baseline in the AFFIRM and STRATIFY-1 trials, 97% remained consistently negative or below an index threshold of 1.5 over 18 months. Retrospective analyses of pre-PML samples collected longitudinally from PML patients displayed sustained higher anti-JCV antibody index over time.

Interpretation: Anti-JCV antibody levels in serum/plasma, measured as index, may differentiate PML risk in anti-JCV antibody-positive MS patients with no prior immunosuppressant use. Continued evaluation of anti-JCV antibody index and PML risk is warranted.

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Figures

Figure 1
Figure 1
Anti–JC virus (JCV) antibody index in non–progressive multifocal leukoencephalopathy (PML) and PML patients. (A) Test data set includes lowest index for 1,039 non-PML patients who tested anti-JCV antibody–positive and 45 PML patients with pre-PML samples >6 months prior to PML diagnosis, as of September 2012. (B) Verification data set includes samples from 1,483 non-PML patients who tested anti-JCV antibody–positive at baseline of STRATIFY-2 and pre-PML samples (>6 months prior to PML diagnosis) from 26 patients who developed PML in STRATIFY-2. For the non-PML group in the verification data set, optical densities >3.0 used to calculate anti-JCV antibody index were reported as 3.0 by the testing laboratory. The lowest index value was used for patients who had multiple samples available. Box = interquartile range; thick black horizontal line = median; horizontal bars = range; x = mean.
Figure 2
Figure 2
Association between (A) natalizumab treatment duration or (B) prior immunosuppressant (IS) use and index in the combined non–progressive multifocal leukoencephalopathy (PML) and PML population for the test and verification data sets. The test data set includes the combined population of 1,039 non-PML patients who tested anti–JC virus (JCV) antibody–positive and 45 PML patients with samples available >6 months prior to PML diagnosis, as of September 2012. The verification data set includes the combined population of 1,483 non-PML patients who tested anti-JCV antibody–positive and 26 PML patients with samples available >6 months prior to PML diagnosis, as of September 2012. The lowest index value was used for patients who had multiple samples available. Box = interquartile range; thick black horizontal line = median; horizontal bars = range; x = mean.
Figure 3
Figure 3
Anti–JC virus (JCV) antibody index in non–progressive multifocal leukoencephalopathy (PML) and PML patients by prior immunosuppressant (IS) use for the (A) test and (B) verification data sets. The test data set includes 993 non-PML patients who tested anti-JCV antibody–positive and 44 PML patients (with samples available >6 months prior to PML diagnosis) who had information available on prior IS use, as of September 2012. The verification data set includes 1,425 non-PML patients who tested anti-JCV antibody–positive and 26 PML patients (with samples available >6 months prior to PML diagnosis) who had information available on prior IS use, as of September 2012. The lowest index value was used for patients who had multiple samples available. Box = interquartile range; thick black horizontal line = median; horizontal bars = range; x = mean.
Figure 4
Figure 4
Anti–JC virus (JCV) antibody index in anti-JCV antibody–positive non–progressive multifocal leukoencephalopathy (PML) and PML patients with or without prior immunosuppressant (IS) use. (A) Results based on combined test and verification data sets including 2,522 non-PML and 71 PML patients, stratified based on prior IS use. Interaction p value tests difference in association between anti-JCV antibody index and PML risk by prior IS use. (B) Results based on data for 2,242 non-PML and 51 PML patients who had no prior IS use and who tested anti-JCV antibody–positive as of September 2012; 104 non-PML patients and 1 PML patient were missing prior IS use information and were excluded from analyses. Optical densities >3.0 used to calculate anti-JCV antibody index for the non-PML group in the verification data set were reported as 3.0 by the testing laboratory. The lowest index value was used for patients who had multiple samples available. Horizontal line = median; horizontal dashed lines = index at 0.9, 1.1, 1.3, and 1.5. CI = confidence interval.
Figure 5
Figure 5
Longitudinal pre–progressive multifocal leukoencephalopathy (PML) samples generally demonstrate consistently high anti–JC virus (JCV) antibody index over time: examples of individual cases. Longitudinal scatter JC plot data are given from 7 individual case examples (A–G) out of 25 PML patients with no prior immunosuppressant use who had at least 2 pre-PML samples available >6 months prior to PML diagnosis.
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