ClinicSpeak StatsSpeak: JCV antibody index before PML

Should I be monitoring by JCV antibody index? #ClinicSpeak #MSBlog #MSResearch #StatsSpeak

“The case reports below are very important; they show that in 4 MSers who developed PML on natalizumab their JCV-index was high and stayed persistently high before they were diagnosed with PML. The paper reports the median anti-JCV antibody index before and during natalizumab therapy in these four MSers was 3.04 with a range of 2.04–3.59. Why is the paper important? It is important because there is some preliminary data suggesting that a rising JCV-index is another risk factor for the development of PML. This paper would suggest that this may only apply to MSers with a low index as once you have a high index the assay is saturated and can’t detect a rising level of antibody. 

This paper reinforces the risks associated with staying on natalizumab if you are JCV positive, particularly if you have a high JCV antibody index. How good is the index at stratifying risk? It depends which side of the fence you sitting on. As far as lab assays go it not very good; we have a statistical test called a receiver operating curve, or ROC, analysis that we apply to diagnostic or predictive tests. When you apply a ROC analysis, setting the cutoffs for sensitivity and specificity at 80%, the assay does not pass muster. Although the cut-offs are quite sensitive (>90%) they are not specific (<45%). Why an 80% cut-off? This is the traditional thresholds that has been set by laboratry scientists for allowing an assay into routine clinical practice. Can I make this simpler to understand? Yes, 1 in 10 cases of PML developed in MSers with an index less than 1.5, 1 in 13 with an index less than 1.3, 1 in 23 with an index less 1.1, 1 in 59 with an index less than 0.9 and 1 in 167 with an index less than 0.7. Even simpler, if you are JCV positive on natalizumab you should seriously consider other options. Hopefully we will be able to derisk natalizumab therapy in the future.

StatsSpeak: Please note that a median value is used in this paper instead of an average or mean to describe the JCV-index; the median describes the value above and below which 50% of the population values lie. It is often used instead of an average or mean when there a very few samples or if the samples are not normally or symmetrically distributed. The mode refers to the commonest value and is not relevant to this paper. I will do a more detailed post on ROC analysis in the future.”

Background: The presence of anti-John Cunningham Virus (JCV) antibodies is a risk factor for the development of progressive multifocal leukoencephalopathy (PML) in MSers treated with natalizumab. It has been suggested that an increase in serum anti-JCV antibody index precedes the development of PML. 

Case reports: We here describe extensive longitudinal serum anti-JCV antibody indexes of four MSers who developed PML. Anti-JCV antibodies were measured using the STRATIFY JCV™DxSelect™ test. All four MSers had rather stable high anti-JCV antibody indexes in all samples obtained before developing PML. Possibly caused by reaching the saturation level of the assay, no increase in anti-JCV antibody indexes was seen just before the diagnosis of PML. 

Conclusion: This study confirms that high serum anti-JCV antibody indexes precede natalizumab-associated PML.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • This whole thing must make George Scangos, CEO of Biogen, very uncomfortable. If he's a guy who actually wants to help people, he's had a drug that's useful but very seriously risky for many years now with no improvement. MS already makes people live in fear and when they finally get drug that works, they live in fear of the drug. If he's a money guy, which he's kind of required to be as CEO, he's missed out on the opportunity to basically have close to 100% of MS patients using his very expensive drug. And now people are basically recommending patients move away from the most effective MS drug.

    Failing to materialize that kind of opportunity should have the board questioning whether he's the best person for the job. If you can't make a known winner succeed you have no business being a CEO.

  • Extending time between doses appears to mitigate PML risk. The hypothesis behind extending time is dose “adequate to exclude autoreactive T cells from entry into CNS (MS-protective) but nevertheless sufficiently permissive to enable CNS lymphocyte scavenging of JC virus to occur (PML protective).”

    Poster #287 at last year’s Boston Conference presented no cases of PML in an Extended Dosing (ED) cohort (n-684) with 861 patient-years of JCV-antibody positive person-years. There were 2 cases of PML in the Standard Dosing (SD) cohort (n-674).
    Quote, “we calculated that 1,248 JCV-antibody positive person-years of natalizumab exposure and no cases of PML in the ED cohort are required to demonstrate statistically significant decrease in PML incidence at p=0.05 level.”

    Hopefully, within the next few months we will learn if dose extension reduces PML significantly. Also, dosing according to weight may achieve a reduction of PML risk. Lower weight individuals are at higher risk of PML, as we have seen.

    I’m sure Biogen is quite interested, as is a good number of MS patients in methods to reduce PML risk. Including trials my wife has received 146 natalizumab infusions dating back to early 2002. MS progression has stopped almost entirely, clinically and on MRI. Last week she was timed 4.9 seconds in the 25’ walk; considerably better than in 2002.

    Yes, being JCV positive is a huge risk. Comparing my wife’s MS before Tysabri to now… well, just let me say MS is one hell of a risk, also. BTW, she is on dose extension. I think we have found something extremely valuable to staying healthy… extending dose.

  • Note to moderators. I'm the person who posted the details about my Tysabri dose extension and switch to gilenya. I just realized Biogen could probably identify me by all the stats I gave. I just realized I also made some factual mistakes as typos. (Dose extension duration for me did NOT appear to be related to the index. It fluctuated high at times at longer extensions.) maybe it's best to remove the comment if you don't mind. Obviosly you don't probably know if I'm really that person but regardless the identifying health info is probably bad for a comment.

By Prof G



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