JCV index and the effect of DMTs


JCV STRATIFY (anti-JCV antibody) test has been utilized for more than decade to de-risk natalizumab treatment and other DMTs for risk of PML (Progressive Multifocal Leukoencephalopathy). Cases of PML have occurred predominantly in natalizumab, but less commonly with fingolimod (Gilenya), dimethylfumerate (Tecfidera) and rituximab.

A high JCV antibody index value indicates that the risk of developing PML is significantly raised. It is a test based around the antibodies that your own body produces against JCV either to prevent the primary infection or to keep control of the already present infection (JCV resides dormant in the brain, bone marrow and the kidney after infection).

So it is with great interest that I read the article by Farley et al. (see below for the abstract), who studied the influence of certain DMTs, namely rituximab, and fingolimod, and dimethylfumerate, on the JCV antibody index. With both rituximab and fingolimod there was a trend for a decrease in index values over time, but not dimethylfumerate (see Figure 1 below). They formulate that these rituximab and fingolimod may impair the the body’s antibody response to JCV. This effect was unrelated to the absolute reduction in lymphocyte counts that occurred on treatment, although we are not provided with data on the sub-types of lymphocytes involved i.e. CD4+ and CD8+ levels.

Figure 1: Changes in anti-JC index value with time.

This of course a worrying development in the DMT saga, and in my mind further support for induction strategies, or other strategies that don’t rely on continuous immunosuppression for efficacy. Ocrelizumab with its hypogammaglobulinaemia (reduction in antibody levels) and nearly undetectable CD20+ B cells would also be a strong contender for this.


Surg Neurol Int. 2019 Apr 24;10:59. doi: 10.25259/SNI-4-2019. eCollection 2019.

Anti-John Cunningham virus antibody index levels in multiple sclerosis patients treated with rituximab, fingolimod, and dimethyl fumarate.

Farley S, Gottesman MH, Friedman-Urevich S, Ye J, Shen M, Grueneberg D, Martone L, Calixte R.


Progressive multifocal leukoencephalopathy (PML), a potentially fatal demyelinating disease caused by the John Cunningham virus (JCV), can occur as a complication of treatment with rituximab, fingolimod, and dimethyl fumarate. The primary objective of this study was to determine changes in anti-JCV antibody index values in multiple sclerosis (MS) patients treated with these three medications. Second, we explored the relationship between absolute lymphocyte count (ALC), anti-JCV antibody index values, and various patient characteristics.


In this retrospective chart review, we evaluated changes in JCV serology and ALC in 172 MS patients treated with fingolimod, rituximab, or dimethyl fumarate (2013-2016). Only those with known anti-JCV antibody and ALC values before starting the study medications were included. Subsequent values were obtained on an ad hoc basis throughout the study.


There was a significant decrease in anti-JCV antibody index values in patients treated with fingolimod and rituximab (P = 0.03 and P = 0.014, respectively). A non-significant decreasing trend in anti-JCV antibody index values occurred in patients treated with dimethyl fumarate. Notably, there was no relationship between ALC and anti-JCV antibody index values for patients treated with rituximab, fingolimod, or dimethyl fumarate.


Anti-JCV antibody index values significantly decreased in MS patients treated with fingolimod and rituximab; however, this did not occur with dimethyl fumarate. Fingolimod and rituximab may impair the humoral response to the JCV. Nevertheless, a declining anti-JCV antibody index in MS patients treated with fingolimod or rituximab should not necessarily be interpreted as correlating with a decreased risk for PML.

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Neuro Doc Gnanapavan


  • Interesting post. Amazing that natalizumab is not included as well since there is where it all started. I need a microbiology lesson. The thought process for rituximab and fingolimod is that antibodies can simply not be made as the cells that make the antibodies have been wiped out by the DMT? IF that is the case why is ALC not a significant variable? While the analyzed data shows a significance the actual graphs look awful random especially as there appears to be far less data for longer time periods.

    I seroconverted after 10 yrs on natalizumab. My titer levels have always been high (way above 1.5). I struggle to understand how after 5 yrs on extended dosing, I am unable to bring those levels down. While your explanation makes sense in theory, there must be something else going on or the test only makes sense over a given time period. Or the test has cross reactivity with another virus in my system.

    I welcome any understanding and insight.

    As always, the blog is my first read in the morning and always a good read.


    • Yes Debbie, there is a lot to consider here. The JCV stratify test is not an index test one normally understands by an index. In biochemistry terms and index value is generally between the relative quantities of a protein in CSF versus the blood controlling for the blood brain barrier. The JCV stratify test is calculated by dividing the optical density value from an ELISA for patient sample divided by the optical density of a control sample collected from pooled blood from anti-JCV positive healthy volunteers (no PML). >0.40 is anti-JCV antibody positivity while index <0.20 is anti-JCV antibody negativity. So in the truest sense this is a proportionate assessment and not a true index that gives you an idea of what’s happening in the brain, which is your area of primary interest.

      The risk from natalizumab for PML comes from not allowing immune cells to enter the brain as part of their normal immune surveillance function. Fingolimod similarly prevents the egress of immune cells from lymph nodes so they’re stuck. But we know now that the brain has a lymphatic system so they’re not completely excluded from there. But not many people are aware of the work that fingolimod the B cell subtype (produces antibodies) distribution changes. There is a decrease in the proportion of memory B cells and an increase in the proportion of naive and double negative B cells. Memory B cells produce antibodies directed at target antigens but also self antigens and are also able to migrate into the brain and enhance the immune response. The mouse data therefore demonstrates after fingolimod there is a decrease in high affinity class-switched antibodies and vaccination studies in healthy volunteers has shown mild-moderate decrease in immunoglobulin (Ig) G and Ig M antibody levels towards some antigens. And therein lies the problem.

      So it is not always about the absolute lymphocyte count measured in the blood. The interaction between the immune cells and the JCV infection also needs to be considered.

      To be absolutely certain about JCV you need to look at the source - the best surrogate is the CSF where viral copy numbers can be quantified. As far as natalizumab is concerned if you take the breaks off by extending the dosing intervals then technically you reduce the risk. In my opinion the data on stratify between non PML and PML cases shows considerable overlap - the relative index values are therefore not valuable. What contributes to the greatest risk is if you’ antibody positive and have had continuous infusion beyond 2y (of course the latex data with extended dosing changes this risk). The latter achievement has nothing to do with the index value, but everything to do with targeting the mechanism of the drug that increases the likelihood of developing PML.

      • You are so kind to take your time to respond in such great detail. I had no idea how the Eliza test worked let alone it was a ratio against a pooled positive group. So while I am beginning to understand the nataluzimab piece, can you further explain the articles conclusions? Simply: the titers go down because the cells that make the antibodies are no longer there? It would seem then that the current test is not a good one for JCV in this population.

        I agree with the testing in CSF. I just need to be brave enough to have the test!

        Thank you,


        • No problem Debbie. The authors implying that the antibody production targeted against JCV is going down in the individuals on fingolimod and rituximab. Of course, this work needs to be repeated, but if this were true then we will need to look closely at the implications of this. Are these treatments affecting the hosts ability to keep the acquired JCV infection under control? Assuming this was the case we will need to monitor these individuals more closely – with testing their CSF or frequent MRI head scans. So the JCV test becomes useful rather than less ironically!!

          • Thank you. All research which enlightens any hazards of the therapy is so important for PwMS as we tend to remain on these DMT for a very long time. I hope the authors heed your words.

  • I read this with slight alarm. I’m 58 and have been on Fingolimod for almost 4 years. So far, its done what it’s made for and I haven’t relapsed since I started taking it. However, I’ve had shingles, a minor skin cancer scare and so many viruses I’ve lost count. These, of course might not be linked to Fingolimod but it’s always worried me that I’ll still be taking Fingolimod when I go into my sixties, assuming I remain RRMS.
    I asked for a JCV test before I started on Fingo and I’m JCV positive with a high titre.
    I know you cannot give us advice but I have a neuro appointment next month and I would like to broach the PML risk with him, given my age and length of use. What would be the most pertinent question to ask?

    • Suzanne, always ask the question what would you do if you were in my position? I would also recommend that you give advanced warning about topics such as these, as they take time to consider and confer with others. The data on fingolimod is 15 confirmed cases, estimated risk of 0.069 per 1000 patients; very small.

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