Stability and predictive value of anti-JCV antibody index in multiple sclerosis: A 6-year longitudinal study

Abstract

Background: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies.

Objective: To investigate the longitudinal evolution of anti-JCV antibody index and to determine the predictive value of baseline anti-JCV antibody index for long-term stability of anti-JCV antibody status.

Methods: MS patients from the MS centre of Medical University of Innsbruck, who had serum sampling for a time period of 4-6 years at intervals of 6±3 months, were included in this retrospective, longitudinal study. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay.

Results: 154 patients were included in this study. Median follow-up time was 63.7 months, with median 11 samples available per patient. At baseline, 111 (72.1%) patients were anti-JCV antibody positive. Baseline anti-JCV antibody index significantly correlated with age (R = 0.22, p = 0.005); there was no difference with respect to sex, disease duration or previously used disease-modifying treatment. During follow-up anti-JCV antibody status changed from negative to positive or vice versa in 17% of patients. In seronegative patients at baseline, baseline anti-JCV antibody index was significantly lower in those remaining seronegative at follow-up compared to those converting to seropositivity (median 0.16 vs. 0.24, p = 0.002). In seropositive patients at baseline, index was higher in those remaining seropositive compared to those reverting to seronegativity (2.6 vs. 0.45, p<10-7). Baseline anti-JCV antibody index >0.90 predicted stable positive serostatus (sensitivity 88.7%, specificity 96.5%) and <0.20 stable negative serostatus (sensitivity 61.3%, specificity 97.6%).

Conclusions: Anti-JCV antibody index remained relatively stable over 6-year follow-up with annual serostatus change of ~3%. Baseline anti-JCV antibody index predicted stable negative and stable positive JCV serostatus.

Fig 1. Spearman correlation between anti-JCV antibody index and patients’ age.

The correlation between the rank of patient's age and the rank of anti-JVC antibody index is visualized, i.e. the Spearman correlation coefficient with its significance.

Fig 2. Evolution of anti-JCV antibody index.

Anti-JCV antibody indices are displayed in seronegative and seropositive patients at the different time points during follow-up. At each visit, the total number of patients, the number of anti-JCV antibody positive patients and their distribution among different index categories are shown. JCV, John Cunningham virus.

Fig 3. Longitudinal change of anti-JCV serostatus.

Frequency of conversion and reversion of anti-JCV serostatus from baseline throughout follow-up.

Fig 4. Predictive value of baseline anti-JCV antibody index.

(A) Anti-JCV antibody index in seronegative patients at baseline according to seroconversion status at follow-up. Predictive value of different anti-JCV antibody index levels at baseline for prediction of stable seronegative status at follow-up (AUC: 0.986, p<10⁻²³). (B) Anti-JCV antibody index in seropositive patients at baseline according to seroreversion status at follow-up. Predictive value of different anti-JCV antibody index levels at baseline for prediction of stable seropositive status at follow-up (AUC: 0.976, p<10⁻¹⁵). (C) Anti-JCV antibody index in patients with baseline values ≤0.9 according to the change to a higher index category (>0.9) at follow-up. Predictive value of different anti-JCV antibody index levels at baseline for prediction of stable JCV index ≤0.9 at follow-up (AUC: 0.962, p<10⁻²⁰). (D) Anti-JCV antibody index in patients with baseline values ≤1.5 according to the change to a higher index category (>1.5) at follow-up. Predictive value of different anti-JCV antibody index levels at baseline for prediction of stable JCV index ≤1.5 at follow-up (AUC: 0.948, p<10⁻²⁰). Ab, antibody; AUC, area under the curve; BL, baseline; JCV, John Cunningham virus; NPV, negative predictive value; PPV, positive predictive value; ROC, receiver operating characteristic; **, *** indicate statistical significance at a P-value <0.01 and <0.001, respectively.

Fig 5. Percentages of patients switching between different anti-JCV antibody index categories.

(A) Percentage of patients with anti-JCV antibody index ≤0.9 at baseline (n = 66) switching to higher index categories at least once during follow-up. (B) Percentage of patients with positive anti-JCV serostatus and antibody index ≤0.9 at baseline (n = 23) switching to higher index categories at least once during follow-up. (C) Percentage of patients with anti-JCV antibody index >0.9 and ≤1.5 at baseline (n = 19) switching to higher or lower index categories at least once during follow-up. There was no patient remaining within the baseline index category during follow-up. (D) Percentage of patients with anti-JCV antibody index >1.5 at baseline (n = 69) switching to lower index categories at least once during follow-up.