Sunday, 25 January 2015

ClinicSpeak: spinal fluid cells on natalizumab (Tysabri)

How much more do we have to learn about natalizumab? De-risking natalizumab. #MSBlog #MResearch #ClinicSpeak

"The study below shows that natalizumab (Tysabri) does not have the same effect on the immune system in everyone on the drug. It shows that levels of the drug vary between individuals and the effect on immune surveillance of the central nervous system differs depending on levels of natalizumab on the surface of cells. Should we be surprised? No. There is only one certainty about nature and it is that it is highly variable; so I am not surprised that a fixed dose of a drug, i.e. 300mg intravenously per month, will have different effects on different people. This study is important as it may tell us that there are a proportion of MSers on natalizumab who may have relatively intact CNS immune surveillance and are therefore at low risk of getting PML."

"What is CNS immune surveillance? There are several subsets of immune cells that literally go walk-about all over the body looking for infections and  cancers. The immunological equivalent of reconnaissance commandos in the military. If they find something amiss they will start fighting it and at the same time send signals to call in the army. Natalizumab is designed to stop trafficking of autoimmune cells into the CNS and because the autoimmune cells and surveillance cells use the same mechanism of trafficking natalizumab stops the vital function of immune surveillance. Imagine an army without surveillance or intelligence? This is why MSers on natalizumab are at high risk of PML and other CNS infections."

"Please note if you are on natalizumab and get another viral infection of the brain, for example herpes encephalitis, you will also be in trouble; PML is not the only infectious risk on natalizumab. Natalizumab-associated herpes encephalitis is very different to typical herpes encephalitis; the condition is initially more indolent and progresses slowly and mimics a tumour. This is why MSologists have to be very vigilant for atypical manifestation of other CNS infections in MSers on natalizumab."

"What this study shows that a proportion of MSers on natalizumab have higher CD8+ T-cells in their spinal fluid that is associated with lower levels of natalizumab on their surface. These cells are the ones that survey for infections and fight them. I suspect these MSers will have a lower risk of PML. The downside of this is these MSers may have a greater chance of breakthrough MS disease activity."


"Other observations and musings: I have been aware for sometime now that a subset of MSers (~20%) on natalizumab are aware when the natalizumab wears off before the next dose. These MSers describe non-specific symptoms of MS returning, particularly fatigue and feeling out of sorts, in the week or 2 before their next infusion. It's as if the immune system is trafficking back into the brain and setting-off a low grade immune response that is triggering sickness behaviour. Sickness behaviour is the brain's response to inflammation. Typical symptoms of sickness behaviour include fatigue, raised temperature, sleepiness, reduced appetite, low mood, poor concentration and attention and a mild systemic inflammatory response. Sickness behaviour is what it feels like when you have flu or another viral infection. Getting to the point of the argument; I would be interested to know if the small group of MSers who feel natalizumab wearing off are the ones with lower natalizumab saturation levels on their CD8+ T cells and are the ones at lower risk of PML."

"Why are these observation important? If the MSers with wearing-off have a lower, or no, risk of PML, but still have a excellent, or good, therapeutic response to natalizumab may be we could optimise the dose of natalizumab to de-risk natalizumab and prevent PML. You may be interested in reading my previous post on other strategies to de-risk natalizumab."

"For those of you interested in natalizumab and PML risk we have created a new app. We would appreciate your feedback on the app. Thanks."


Epub: Harrer et al. High interindividual variability in the CD4/CD8 T cell ratio and natalizumab concentration levels in the cerebrospinal fluid of patients with multiple sclerosis. Clin Exp Immunol. 2015 Jan. doi: 10.1111/cei.12590. .

Background: Strongly decreased leukocyte counts and a reduced CD4/CD8 T cell ratio in the cerebrospinal fluid (CSF) of natalizumab (NZB)-treated MSers may have implications on central nervous (CNS) immune surveillance.

Aims: With regard to NZB-associated progressive multifocal leukoencephalopathy we aimed at delineating a relationship between free NZB, cell-bound NZB, adhesion molecule (AM) expression, and the treatment-associated shift in the CSF T cell ratio. 

Methods: Peripheral blood (PB) and CSF T cells from fifteen NZB-treated MSers, and CSF T cells from ten patients with non-inflammatory neurological diseases and five newly diagnosed MSers were studied. Intercellular adhesion molecule-1 (ICAM-1), leukocyte function antigen-1 (LFA-1), very late activation antigen-4 (VLA-4), NZB saturation levels, and T cell ratios were analyzed by flow cytometry. NZB concentrations were measured by ELISA. 

Results: Lower NZB saturation levels (P <.02) and a higher surface expression of ICAM-1 and LFA-1 (P <.001) were observed on CSF CD8 T cells. CSF T cell ratios (0.3-2.1) and NZB concentrations (0.01-0.42 µg/ml) showed a pronounced interindividual variance. A correlation between free NZB, cell-bound NZB, or AM expression levels and the CSF T cell ratio was not found. Extremely low NZB concentrations and a normalized CSF T cell ratio were observed in one case. 

Conclusion: The differential NZB saturation and AM expression of CSF CD8 T cells may contribute to their relative enrichment in the CSF. The reduced CSF T cell ratio appeared sensitive to steady-state NZB levels as normalization occurred quickly. Latter may be important concerning a fast reconstitution of CNS immune surveillance.

CoI: multiple

4 comments:

  1. Has Tysabri had its day? While it appears to be an effective DMT, it comes with so many issues. We now have Lemtrada which given early enough delivers long term remission for many. On the horizon are the B cell depleting treatments. Looks to me like Biogen know their days are numbered with Tysabri. By 2020 I would hope that the current injectibles are no longer being prescribed. Protecting the MS brain starts with highly effective treatments with a neuroprotective drug. How far are we away from this Prof G? Is the drug being tested in the Charcot Project a disease modifying drug or a neuroprotective drug or both (I don't want a wait for the data answer), but an if it all works as intended answer.

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  2. "have been aware for sometime now that a subset of MSers (~20%) on natalizumab are aware when the natalizumab wears off before the next dose. These MSers describe non-specific symptoms of MS returning, particularly fatigue and feeling out of sorts, in the week or 2 before their next infusion"

    I'm more than curious about this as it happens to me (though more than solely fatigue). Looking at other studies, there could be a relationship between higher body weight and faster clearance. But I'm at the low end of the healthy body weight range for my height, so that can't be the reason in my case. So wondering if you have seen any noticeable weight correlation with Tysabri users you observe and having this problem?

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    Replies
    1. one MSer called it their coke as they could tell when they
      needed the next hit

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    2. Haha, I wish it was that simple for me, it takes at least 3-4 days after the infusion that I feel better. Essentially I have only around 2 weeks of the 4 week cycle when I'm functioning normally. So I'm trying to find out why that is, but it can't just be body higher body weight as other research states for faster clearance 'cos I'm slim/slender.

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