Thursday, 18 May 2017

Active EBV cause Attacks?

Serafini B, Scorsi E, Rosicarelli B, Rigau V, Thouvenot E, Aloisi F. Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal.J Neuroimmunol. 2017 Jun 15;307:14-17

Rebound of disease activity in multiple sclerosis patients after natalizumab withdrawal is a potentially life-threatening event. To verify whether highly destructive inflammation after natalizumab withdrawal is associated with Epstein-Barr virus (EBV) reactivation in central nervous system infiltrating B-lineage cells and cytotoxic immunity, we analyzed post-mortem brain tissue from a patient who died during a fulminating MS relapse following natalizumab withdrawal. Numerous EBV infected B cells/plasma cells and CD8+ T cells infiltrated all white matter lesions; the highest frequency of EBV lytically infected cells and granzyme B+ CD8+ T cells was observed in actively demyelinating lesions. These results may encourage switching to B-cell depleting therapy after natalizumab discontinuation.


When you select a drug, you may consider things like safety and side-effects, efficacy (which is often inversely related to safety), convenience (route and how often you take drugs but also what screening for problems), however you have to also think what next as we know no MS drug is infallible. Even relapses occur after HSCT.

One problem that is evident is the migration inhibition drugs (natalizumab and to some extent fingolimod). The damaging cells are not killed but kept out of the brain. They are there ready to go if the brakes are removed. This is removed when you stop the drug and then there is a time bomb waiting. 

Can you get them under control before the damaging cells pile into the brain to cause rebound damage.  

This is why you need to plan the exit before you start the entry. 

Following fingolimod much needs to be defined, how best to switch, as it is not just a migration blocker but a depleter too.
Do you wait until blood levels increase, but do you risk damaging cells surging out of the lymph glands and bone marrow to cause a rebound.

The transition from Natalizumab is more defined, but occassionally things go wrong, as in this case. 

However, in these cases we know disease has been held in check for some time and so when an attack occurs what ever is driving the attack is present. 

In this individual there were loads of B cells and these were EBV infected and the virus was not latent but lytic and CD8 T cells were there presumably killing the virus infected cell. Is the trigger for the attack viral reactivation or does the virus activate because the B cells are activated and dividing?

The study infers that a switch to a B cell depleting therapy is needed, but before you accuse me of giving ocrelizumab a plug. I will remind you that we have shown that all MS drugs are memory B cell depleters, some are better than others at this.

20 comments:

  1. Until Ocrelizumab is available in UK, what to prescribe in these cases - off-label Rituximab? Privately funded as not possible on NHS in England and Wales. Scotland??

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    1. I think MD is saying you can use any effective dmt as hunt down Bmem cells is what they all do ;-)

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    2. Hey! Good the MS research world is waking up to B cells and ebv :-) at least the world as shared here seems to be, sometimes wonder how many papers are published everyday relating to MS? And how much fluff has to be weeded out as not worthy of wasting time on ;-)

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    3. Ta Judy

      Galatea
      If you know me you know what I could say like off-label generic *********, I'm told I sound like a mouthpiece for *****.

      Fluff yes it seems we spend out life in the proverbial belly-button

      P.S. Hey Judy, just so you know we had a positive chat with you know who, about getting a view to you know what data.

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    4. MD 12.11 very good news re he who shall not be named :-)
      Ps you would be proud of me, handed a copy of your B cell paper to a very nice haematologist ;-) one step closer to generic **********

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    5. lol here is more medical tourism: it is cheaper to buy return flights and fly to mexico or russia (or really anywhere) for a dose of rituximab, then it is to pay out of pocket for a dose of rituximab in australia.

      Return trip to Mexico - $1,500 plus $300 for rituximab and hospital admission.

      Cost of rituximab in Australia - $4,500 to $6000 per dose.

      Yeh.

      I know that Americans travel to Mexico for cheap (pharma) drugs all the time and that they even have rules against this (haha). So someone just needs to point out to that Mexican doctor person that he should set up a space for rituximab seekers and he'll be busy running a rituximab/ocrelizumab infusion centre for americans without insurance (or rejected by insurance) and for anyone else who can't afford treatment in their own countries... sigh, hey

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  2. How would a transition fron natalizumab to ocrelizumab work? Does one need a wash-out period? if so, what disease reactivation in that period?

    Last, will ocrelizumab be effective in hunting down those B cells natalizumab kept at bay (without killing) in the years preceeding the switch?

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    1. All relevant questions, but I have never seen ProfB respond to comments. So good luck with that!

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    2. We'll need to see a measured repond to those questions first and then indulge in the irrelevant exercise of guesswork.

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    3. Same as Rituximab? Wash out of 2 months as per Malucchi et al?
      Multiple Sclerosis and Demyelinating Disorders (2016) 1:11
      DOI 10.1186/s40893-016-0013-z

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    4. Will ocrelizumab hunt the B cells...yes.

      How would transition work...by all accounts it could work well, we would be guided by the experience with rituximab.

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  3. "The damaging cells are not killed but kept out of the brain. They are there ready to go if the brakes are removed. This is removed when you stop the drug and then there is a time bomb waiting."

    Surely this explains reactivation, but not the excessive force of a rebound effect. Why is the immune system so furious after drug removal? What is building up in the background, according to you?

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    1. It's like a dam VV. Break it and the bad guys that want to get into the CNS come flooding back (see what I did there). It's not reactivation, the cells are already activated they are merely stopped from going where they want to go by natalizumab not depleted.

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    2. The dam analogy implies water building up. Are you saying that activated (but confined) cells increase in numbers while on the the drug? If not, then drug discontinuation should let the disease continue from where it was when the drug was initiated.

      But this clearly not the case. The disease comes back worse than before. To me it is clear than brain damage is going on (only less detected by the immune system) while on the drug, and that is exactly the reason for rebound.

      Do you agree?

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    3. The cells are constantly being generated, so there is a steady stream of them, they are unable to home to where they want to go (the CNS in this case)so the actual numbers of disease causing cells in the blood builds up over time during natalizumab. So, when treatment is discontinued, there is a larger disease causing population that is now able to enter the CNS, so a rebound relapse is likely to be more severe.
      I don't think this is too difficult to understand.

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    4. "In conclusion natalizumab treatment selectively increased the effector memory T-cell pool but not the activation state of T-cells in the blood compartment. Myelin-reactive T-cells were not selectively increased in natalizumab treated MS."
      source: https://www.ncbi.nlm.nih.gov/pubmed/23226199

      So, if you are right, then rebound effect is due to effector memory T-cells, not myelin-reactive T-cells. Sounds like anti-dogma.

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    5. I think worse than before because it is a coordinated attack

      You have been away too long VV we are beating the memory B cell drum Read our ebiomedine paper come up with some reasons why it is pants and we can have a look..

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    6. T or B cells, it doesn't really matter. The question is:

      Can you prove they attack on healthy brain tissue?

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    7. The response to therapy is the best I can do.

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    8. Just finished your ebiomedine paper. Two immune-compartment model caught my eye, steps 2 and 6.

      Step 6: How is this damaging force confined? Why doesn't it culminate to full CNS damage?

      Step 2: How do they select their entrance point? Is it random? Do they all come out of the same vein, or from a bunch of local venules? Remember that MS lesions have a distinct topology and shape.

      And another thing: If EBV is causing damage to the brain, what keeps it from doing so in natalizumab treated patients? I mean JC virus destroys everything if left unattended.

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