Interpreting the anti-JCV antibody index is more complicated than you think. #NeuroSpeak #ClinicSpeak
PML seems to raise its ugly head whenever a new MS therapy emerges. A large number of us have gotten used to using JCV serostatus as risk mitigation tool. We use positvie or negative JCV serostatus to assess whether or not our patients are infected with the virus. If they are JCV seropositive we assume they are still infected with the virus, however, this may not be correct. Some people who are JCV seropositive may not be infected with the virus, i.e. their immune systems have cleared the JC virus, and therefore may not be at risk of developing PML in the future. I suspect a proportion of people who have a low and a stable anti-JCV antibody index fall into this category. On the other hand in people with a high index, or an increasing index, or in those who become seropositive with a high index, the virus must be stimulating their immune systems to produce antibody. These are the people who are at highest risk of developing PML. There is a caveat. If you go onto treatments that interfere with the immune system, particularly immunosuppressive drugs, then the immune response to the JC virus cannot be used to assess risk. This is why we need to be very careful about extrapolating the knowledge we have acquired concerning anti-JCV index and PML risk from natalizumab-treated patients to other DMTs. Natalizumab, to the best of my knowledge, does not affect the humoral or antibody responses to viruses. All that we can do is rely on the baseline anti-JCV serostatus for the other immunosuppressive drugs and not the index.
The study below on the stability of the anti-JCV antibody index is helpful. I am surprised by the high number of annual seroconverters (~3%) this has not been my personal experience. I think it is also important to differentiate low-index from high-index seroconverters; the low-index ones are likely to be false-positives based on the sensitivity of the assay. In comparison, the high-index seroconverters are likely to be true convertes and have unfortunately been infected with the virus.
You may be intrerested in one of our older posts on the topic of derisking natalizumab in relation to PML. The issues discussed then are as relevant today.
Hegen et al. Stability and predictive value of anti-JCV antibody index in multiple sclerosis: A 6-year longitudinal study. PLoS One. 2017 Mar 20;12(3):e0174005. doi: 10.1371/journal.pone.0174005.
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.