Sunday, 8 October 2017

#ClinicSpeak & #ResearchSpeak: how close are we to pinning down EBV as being the cause of MS?

Causation theory is essential to frame the EBV problem in MS. #ClinicSpeak #ResearchSpeak

Summary: This post sets the scene for revisiting the Bradford-Hill criteria around EBV being the cause of MS. 



Are we any closer to proving EBV is the cause of MS? I have posted on this topic many times before, but one of the Bradford-Hill criteria we use for establishing causation is 'Coherence with Biological Background and Previous Knowledge'. We now have at least nine classes of DMTs that have been shown to work in MS. Over the last few months, we have been making the case that they work via B-cells in particular memory B-cells. It may be a coincidence that the memory B cell is the main cell where EBV resides in a latent state. The challenge now is how to work this knowledge into what we know about the pathogenesis of MS and the other factors that are in the causal pathway, for example, smoking, vD and UVB sunlight exposure, female sex and the genetic pathways identified from the whole genome association studies. We have so much to do and so little time. Regardless of this work, we need to start our proposed infectious mononucleosis and EBV vaccination studies sooner than later. Causation will only be proved when we show that preventing, or treating infectious mononucleosis or preventing EBV infection reduces the incidence of MS. 

The British Statistician, Sir Austin Bradford-Hill, has formulated more general and appropriate criteria of causation; the following are the Bradford-Hill criteria:




1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS

2. STRENGTH OF ASSOCIATION

3. TEMPORAL SEQUENCE

4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP)

5. SPECIFICITY

6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE

7. BIOLOGICAL PLAUSIBILITY

8. REASONING BY ANALOGY

9. EXPERIMENTAL EVIDENCE

If you are interested in reading about these criteria I suggest the following references:

Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1965; 58:295-300.

Bradford-Hills Criteria

Bradford-Hill's criteria have been modified to apply them to the problem of MS. I coauthored the following paper over 10 years ago. I think it is time to update it with new knowledge that has been acquired since then. The case now is more compelling than ever. 

Giovannoni et al. Infectious causes of multiple sclerosis.Lancet Neurol. 2006 Oct;5(10):887-94.

CoI: multiple and I am convinced EBV is the cause of MS.
    


ProfG    

43 comments:

  1. Yes please! It is too late for us patients, but it is much more important than we though. Cancer is another reason for this vaccine.

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  2. It would seem EBV is associated with higher risk of other autoimmune disorders too especially dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome.

    Autoimmune disease: A role for new anti-viral therapies?
    Autoimmunity Reviews, Volume 11, Issue 2, Pages 88-97
    David H. Dreyfus. 2011.

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    Replies
    1. I agree EBV may well be a rather generic contributor to risk of several "auto-immune" diseases. Our steep learning curve about the role of memory B cells in MS certainly suggests this: http://www.sciencedirect.com/science/article/pii/S2352396417300452?via%3Dihub

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    2. Dr. Schmierer, or Dr. Baker, is there any evidence for cladribine trials for progressive MS that cladribine is killing these EBV-controlled memory cells in follicles in the brain that may control MS relapses and progression?

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    3. Not yet. There is a suggestion that cladribine can influence OCB in some studies. However these studies need doing and we will try to do them.

      As for evidence that cladribine blocks relapsing disease in relapsing and advanced MS. I would say yes is the answer.

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  3. "Conclusions
    While these findings confirm the association of EBV infection with early MS, neither EBNA-1 nor VCA IgG antibodies in serum nor EBV DNA load in saliva were associated with radiological or clinical disease activity in patients with CIS/early RRMS. These data are compatible with the concept that EBV may be a trigger for MS acting very early during the development of the disease."

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175279.

    If ebv infected B cells are the bad guys and

    Leflunomide/teriflunomide is very good at killing those

    infected b cell ,why its only 30% efficacy in ms (mainly relapses reduction )?

    Along with your reasoning Leflunomide/teriflunomide should be 2the

    mother of all Dmds"

    Am I missing something?

    https://www.ncbi.nlm.nih.gov/pubmed/28574826
    https://www.ncbi.nlm.nih.gov/pubmed/16534472
    https://www.ncbi.nlm.nih.gov/pubmed/27494108

    http://www.nejm.org/doi/full/10.1056/NEJMoa1014656#t=article


    Obrigado Luis

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  4. If you believe, Dr. G, that these EBV controlled memory B-cells in the follicles in the brain are directing MS relapses and progression and not one treatment currently is proven to destroy them then isn't every current therapy DMD treating a downstream effect (i.e. peripheral B or T-cells) and not the cause of relapses and progression of MS? Hence maybe why every current treatment have a far less than perfect NEDA outcome?

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    Replies
    1. I am not sure the relapses are caused by the B feel follicles. The fact that the ms drugs that block relapse but don't get into the brain argues against this.

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    2. "isn't every current therapy DMD treating a downstream effect (i.e. peripheral B or T-cells) and not the cause of relapses and progression of MS"

      ... Yes. And that's why DMDs don't work. All the evidence over decades of dmd's, entirely fits your above thought

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  5. Are any virologists on board? Are you out there?

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  6. Simply put leflunomide is not good at killing the memory B and there lies it's efficacy I think.. I have seen a poster on this.

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    Replies
    1. "EBV infects cells in both latent and lytic
      forms. EBV-infected humans sustain life-long latent
      viral infection within the memory B cell compartment,
      and periodically shed infectious viral particles into the
      saliva [2]"

      In summary, our investigations here, using both in
      vitro as well as in vivo systems to model the effects of
      the FDA-approved leflunomide metabolite teriflunomide
      on latent and lytic EBV B-cell infection, suggest that
      these drugs may be surprisingly effective for treating
      both latent and lytic EBV infection in humans

      I found this study here on the blog and it says that Ebv infects memory B cells, and Teri/leflunomide are good at killing those infected memory b cells

      https://www.ncbi.nlm.nih.gov/pubmed/28574826

      Obrigado
      Luis

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    2. Wonder if this is why it is better as a second lie treat

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    3. Based on paper you sent us...EBV becomes active once the B cells differentiate to become plamsa cells

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    4. As someone commented there is a similarity with Lupus and arthritis etc
      What drives the tissue specificity

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    5. This one:1. The virus will enter any resting B cell and cause it to proliferate, guaranteeing efficient access of
      the virus to the B cell pool and amplifying the viral genome copy number. In doing so, it uses a set of
      genes that recapitulates what is necessary to cause a B cell to become a blast on the way to
      differentiating to a plasma or memory cell.
      2. The virus will infect any resting B cell, but in vivo it ends up in a very specific subset, the resting
      memory B cell - precisely the best place to be for long term persistence. When there, it shuts off gene
      expression so the cells cannot be immunosurveilled. Instead the cells are maintained at stable levels
      for long periods of time as though they were normal memory B cells - precisely the state required for
      benign, long term persistence in a healthy host.
      3. The memory cells appear to go through an activated state when they enter mucosal epithelium where
      they express only the minimal viral information necessary for survival, the LMPl/Th surrogate, the
      LMP2a/BCR surrogate and EBNAl(Qp) to be sure the viral genome is maintained.
      4. When the cells become activated in the mucosal epithelium they behave like normal memory B cells
      in a secondary response. Most of the cells produced undergo terminal differentiation to become plasma cells. The virus responds by reactivating and producing infectious virus so that it can be released into
      the saliva.
      https://www.ncbi.nlm.nih.gov/pubmed/10530796

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  7. "...that are in the causal pathway, for example, smoking, vD and UVB sunlight exposure"

    There is at least a link: IL-6 levels.
    Did you notice that all well working DMTs also target IL-6?
    IL-6 knock out mice can't develop EAE...
    IL-6 elevated mixe have more severe EAE symptomes

    EBV enhances the secretion of IL-6 and so on.

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    Replies
    1. IL-6 B cell growth and differntiation factor?

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    2. In Cambridge they are working on the IL-6

      "Neurodegenerative diseases are often preceded by inflammation. Inflammation perturbs the normal dynamic equilibrium of the neuron altering its environment and causing adverse metabolic changes. When the inflammation becomes chronic, a vicious cycle of inflammatory damage predisposes to death of neurons as their ability to function correctly is compromised, leading to neurodegeneration. We know that both LIF and IL-6 play key roles in the CNS, appearing to act in concert to maintain the healthy environment of the brain. However, too much IL-6 - as may occur in inflammation - may suppress LIF. To recover the normal dynamic equilibrium between LIF and IL-6, delivery of LIF via LIFNano therapy may break the vicious cycle of chronic inflammation within the CNS. "

      They start from degeneration but if the immune system is not corrected the problem will still be there I guess. The idea has not been tested on human.

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    3. I can't comment on this, but I am familiar with the idea and the data

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    4. "Causation will only be proved when we show that preventing, or treating infectious mononucleosis or preventing EBV infection reduces the incidence of MS."

      EBV vaccination study would take how many decades..?
      If you treat PPMS for EBV and it stops progression
      and removes brain lesions in one year you'd know the score.

      All these drugs and not one can clear lesions or stop
      progressive ms.

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    5. "If you treat PPMS for EBV and it stops progression
      and removes brain lesions in one year you'd know the score." This assumes it is the virus acting directly and not something the virus accidentally modifies, acting indirectly. If you do not remove what it changed when you kill the virus it will not work. Some sub types of Hodgkin's Lymphoma are caused by EBV but killing the virus would be unlikely to cure the Lymphoma. It would, however, stop it happening in the first place.

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  8. Prof. Michael Pender could give a light and show how EBV can act in MS and how a pwMS with PPMS can be treated in fact by EM in combating EBV.

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    Replies
    1. "can be treated in fact by EM in combating EBV."

      Cinara EM = Electron Microscopy..don't think this is what you meant though..?

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    2. Sorry Adam Bomb, actually meant "MS" for "multiple Sclerosis", the acronym in english of multiple sclerosis, and not "EM" of "esclerose múltipla" (multiple sclerosis) in portuguese.

      I was just talking to someone else in portuguese when I wrote this blog comment.

      A thousand apologies.

      From time to time when the "brain" gives a "bug"...

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  9. Could MS be caused by number of virus and bacteria infections? Dr David wheldon thinks the cause maybe chlamydia pneumoniae? His wife was sick with 2nd progressive MS. After years course of antibiotics she recovered, including lost function. That should not happen right?

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    Replies
    1. I would view any n=1 "study" with extreme caution, proper studies would need to be done before any firm conclusion could be drawn.

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    2. Yes agreed. You cannot extrapolate the results based on sample of 1. But this is never going to be done as proper study because pharma never see a return and will be to expensive for government to fund. However Redhill biopharma is also showing positive results with their patented antibiotic treatment for ms!. Does this not at least intrigue you as researchers?

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    3. Plus the effect of monocyclene in Canadian research and growing evidence of role gut bacteria.

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    4. Does this intrigue me as researchers.
      Personally,I have a hundred and one things to think of and anti-biotic treatment is not currently high on my agenda. You can only do so much. We can let the company do the studies but to get anywhere they will have to do it the pharma way and if they can't it goes no where and my intervention of work on the project will not change this.

      As to minocycline and the gut bacteria, you are buying the hype I suspect.

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    5. I would expect a more firm answer from the MDs... Is it possible that MS could be a chronic bacterial infection like Lymes? Then we would need to throw all the research that has been done on MS in the garbage.
      There are a tone of reasons why those two are condradicting and a long term use of anti-biotics wouldn't fix MS (even if we would love to).
      There are a few papers that correlate Chlamydia Pneumonie with the occurance of MS, but they are old and not very important.
      Could there be cases of misdiagnosed MS instead of bacterial infections? Sure. But if only you give these patients cortisone you could very soon have an answer.
      And minocycline (which is known to have antiinflammatory properties) has very minimal improvements on MS.

      Unless there are things we don't know yet as usual.
      Bacterial infections can follow viral infections but it is probably irrelevant.

      And yes, this is a recent research that I personally didn't took into account
      https://www.technologynetworks.com/neuroscience/news/research-team-finds-bacterial-biofilms-may-play-role-lupus-ms-other-auto-immune-283383

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    6. we have reported on chlamydia numerous times

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    7. Thanks all for your replies. I wasn't pushing the idea of bacteria being cause of MS. Just asking why it's not a valid stream of research?. Strangely, Whilst having my alemtuzumab course a patient came in for MS diagnose. He/She was in their 70s. Looking after spouse with ms for last 30 years. Doesn't that sound like a infection jumping from one person to another?

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    8. quebecdailyexaminer.com/pr/ny-scientists-first-to-discover-that-neurodegenerative-diseases-can-be-caused-by-bacterial-viruses/25089

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    9. They could be kissing a lot when they were young :P
      EBV doesn't cause autoimmunity to everyone that has had it and more importantly a.i. does not occur within a reasonable time after infection, so this is why this post exist, because it is so hard to prove. Also, there are patients that never had EBV and have a.i. diseases so this makes it even more comlicated (possible genetic mutations). In Canada it is so often to have a.i. diseases that there are couples that both have MS. How lucky!
      This is why a vaccine could possibly decrease the number of a.i. cases but not eliminate them.

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  10. What role do you think HERV-K18-encoded superantigen has in all of this?

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  11. iaino
    That's interesting, EBV can trigger HERV-K18 superantigen in B cells after infection http://www.jimmunol.org/content/177/4/2056 expression of this superantigen may not only ensure persistence of infected B cells but may also non-specifically activate T cells as well perhaps leading to autoimmunity.
    https://virologyj.biomedcentral.com/articles/10.1186/s12985-017-0719-3
    Certainly something that needs further study.

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  12. You might be super interested (I will) to hear the talk by a researcher from GeNeuro at ECTRIMS Paris, the 28th of October at 9h30. She/he will present their results about the phase 2b of their antibody targeting an HERV virus.

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    Replies
    1. Why super interested? The results are on the web. I am sure ProfG knows them already as he has a direct line to GeNeuro

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    2. Do he has the result of the Phase IIb? I remember reading some stuff about the CHANGE-MS trial on this blog. But nothing that hit me, it seems they are all-in for this 'viral theory' of MS.

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    3. A rapid search on this made me found the disappointing result of the Phase IIB CHANGE-MS trial. I should have looked before posting... Keep up with your great work anyway.

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  13. BTW the EBV also infects epithelial cells. Why not oligodendrocyte (kind of epithelial cells)?

    I am doing my Don Quichotte here (but you might understand me with your EBV windmills) and I am going to keep repeating this question and the associated comment (perseverance, perseverance the two first qualities of a researcher).

    It would make sense for a virus to infect both immune cells AND their new favorite target the oligodendrocyte (who are full of working virus because previously infected). At least you could tell me why this is stupid (step 2 of the genesis of a different idea).

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    Replies
    1. I think lack of evidence for the oligodendrocyte infection and lack of co-receptors for infection but I will keep an open mind it is only absent until you find it.

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