Tuesday, 24 October 2017

JCV index in Natalizumabers - does anyone realy understand this?

J Neurol. 2017 Oct 16. doi: 10.1007/s00415-017-8643-4. [Epub ahead of print]

Natalizumab therapy is associated with changes in serum JC virus antibody indices over time.

Peters J, Williamson E.


Abstract


To examine changes in anti-JC Virus (JCV) index measurements over time in multiple sclerosis (MS) patients to better understand this test, which is used in assessing risk of progressive multifocal leukoencephalopathy (PML) with natalizumab. We aim to describe and compare seroconversion rates, variability of JCV antibody index values, and changes in index values over time between patients on natalizumab therapy and patients naïve to natalizumab. Anti-JCV index values are used to help decide whether to start, continue, or stop treatment. Assessing how index values vary over time is interpreted to allow a patient's risk of PML to be better characterized. Retrospective analysis was conducted using records of patients with multiple JCV antibody index measurements exposed to therapy with natalizumab (N = 150) or not (N = 145). Rates of seroconversion, variability of indices, and changes in index values over time were calculated and compared. Patients on natalizumab who were initially JCV antibody negative seroconverted at a significantly higher rate than patients naïve to natalizumab (23.9 vs. 9.1%, p < 0.01). Variability of anti-JCV indices was also found to be significantly higher for patients on natalizumab (p < 0.05). Patients on natalizumab additionally trended towards a larger increase in index values over time. Therapy with natalizumab was associated with higher rates of seroconversion and greater anti-JCV index variability, suggesting that therapy with natalizumab may influence this test used to assess risk of treatment with it.



Biogen's (BIIB) market performance has been outstanding this year (12.4% share price rise vs. 12.4% growth of the Medical-Biomed/Genetics over the same time frame; source: Zacks Equity Research); and is expected to beat expectations further when it reports its Q3 earnings today (Oct 24th). In the MS field, Biogen's name is synonymous with Tysabri (Natalizumab), one of the best drugs available in its class. However, Tysabri has a murky past, and was withdrawn following the first few cases of PML (progressive multifocal leukoencephalothy, secondary to JCV infection). Following a review of safety information by regulatory authorities, the drug was returned to the US and EU market with contingencies. The updated risk estimates for PML on Tysabri are believed to be small, and lower than previously estimated for JCV antibody index values of 0.9 or less. The JCV antibody index test is therefore invaluable, the advantage for Biogen is the value of the JCV antibody test vis-à-vis other drugs, which lack an objective stratification test.

The test, however, is not without its grating flaws - the biggest being that you cannot reliably predict the long term risk of PML at an individual level. Longitudinal evaluation of individual longitudinal JCV antibody index values will undoubtedly provide more information, particularly about the presumed cut off's of 0.9 and 1.5 utilised in the test. And then there is the unknown, known; the seroconversion rate from negative to positive result of 13% (at 18 months follow up) and rarely vice versa - prompting the EMA to suggest frequent testing. Over the past two years, there have also been concerning data about a significant increase in JCV antibody index over time on treatment. The clinical relevance of this finding is as yet unknown.

Peters et al., above aimed to characterize changes in the JCV antibody index overtime from the University of Pennysylvania (USA; previous similar work have come from Europe) in natalizumabers versus those not on treatment. The bottom line is that the rate of seroconversion (those going from negative to positive) was higher in those receiving Tysabri than not (24% vs 9%), with annualized rates of conversion of 17% on Tysabri vs 7% not on Tysabri. Moreover, the percentage of higher order magnitude change (>0.5) between sequential tests was seen in those on Tysabri vs those not on it.

The key here is that as the authors point out, clinical decisions are often based on these results and it would be difficult to contemplate a scenario where a positive JCV result will not influence treatment decision making. But the big questions are whether the changes in JCV antibody index values over time also increase the risk of PML, and what are the mechanisms whereby Tysabri leads to this change in index values? I believe it is in the best interests of the MS community to get to grip with this problem as soon as possible. For a while, it seemed these findings were a peculiarity of certain countries but it is now clear that this may be a global phenomenon.

Monday, 23 October 2017

MS in the news today

You may have seen this BBC news article today about two pwMS. One of which had a well-planned trip to Switzerland to end his life. After meeting a local woman with MS he appears to have a new outlook and has postponed his trip to Switzerland indefinitely.

Programmed Death 1 disappears and leaves EBV to trigger Activity

Now that we know what PD-1 is, it's time to look at this paper

Sunday, 22 October 2017

What is programmed death 1?

This is about a protein expressed by the immune system. It is a protein involved in limiting the immune response.


Temperature

Twists and turns in the MS research trails


Saturday, 21 October 2017

Tackling progressive MS

Tackling Progressive MS is a priority. ECTRIMS had a meeting on this subject and they have done a special issue on this.

Here's a list of several papers on this subject.

Friday, 20 October 2017

Does MS affect peripheral nerves?

There are few things that all MSologists agree on. 

Perhaps one of the least controversial statements you can make about MS is that it is a disease of the Central Nervous System - i.e. the brain, brainstem, cerebellum, and spinal cord - and that it does not affect the peripheral nerves.


Plus ca change.



Thursday, 19 October 2017

Remyelination....a reality


Good news from repair studies! 

A few years ago Jonah Chan and his team developed a neat screening assay to show myelination (making myelin) by myelin-forming cells (oligodendrocytes).