Thursday, 11 October 2012

Education:Interpreting EAE

Because of the Failure of Immunosuppressive Drugs to Stop Progressive MS other ideas of what maybe happening in MS cam e to light. Progression is currently though to result from nerve damage.

Now, virtually every paper on EAE says that their drug exhibits neuroprotection (protects nerves from damage). This creates false hope to progressive MSers. Why because the EAEers are often over interpreting their data. They are also still of a mind set that MS is all about autoimmunity.

That nerve lost was a feature of MS was seemingly forgotten until 1998, when some pathologists brought it back to the attention of the World. So if you search the academic literature with the terms   "neuroprotection" and "EAE" before 1998 you get zero hits. Since 1998 it has been increasing year on year and now virtually every EAE paper claims neuroprotection. But do they every show it? 

I say not hitting yourself over the head with a hammer saves nerves. Of course this is obvious but EAEers fail to see this over and over again!!!!.

It should be obvious that if a damaging immune response never reaches the brain, it is clear that there will be no brain damage. Unfortunately most EAEers do not see this. They dip their heads in the sand and think that immunology is the cause and the solution of MS. However, progression in MS has yet to respond to immunosuppressive drugs. This should tell them that they need to remove the blinkers. This indicates that we have to think n a different way to save nerves in MS. So to find nerve protecting drugs we need to deal with the consequences of disease so...
So the development of disease is a cascade if you do not have one event you will not get the next event so if you do not become sensitized then immune cells will not accumulate in the CNS (infiltration) this will not cause neurological disease and it will not cause nerve damage and this will not leave you with a neurological deficit.....simples. 
So if you do not get immune attack of the CNS, then there will be no clinical disease and you will not get nerve damage.

However a different approach needs to be used for clinical treatment of progressive MS. The damage is occurring in MS. We need to deal with it so we have to target the consequence of disease, rather than always focusing on the cause. Therefore where the animal recovers to is important, especially when the drug has no effect on the severity of disease. Therefore the deficit after the attack is the important endpoint.            
So if you look at the neurological profile of an EAE study (below) and you see a delay in onset and//or a reduction in the severity of disease. The treatment is immunosuppressive!!!! This is invariably the case even if the author is claiming otherwise. Therefore you should expect to see less infiltrate and less immunological events, such as less cytokine produced. We have seen this time and time again and when you think the drug is an immunosuppressive that is OK, but when you think it is a repair drug you can be misled. For example early stem cell studies were attributed to repair, but subsequently (often years later) shown to be due to immunosuppression.  If use this guide for interpretation it was obvious from the start.
If the drug does not eliminate the clinical disease and they show pictures, where their are no white blood cells etc in the CNS, they are selecting unrepresentative areas as you do not get disease without something happening in the CNS. These drugs are better candidates as neuroprotective agents for MS

As clinical disease resolves there is likewise a drop in the white blood cell activity in the CNS. This way you get recovery from neurological insult. However, if a drug is neuroprotective, without immunosuppressive activity, you do not see the drug stopping the disease from occurring or reaching its peak, but neuroprotective events are seen with a failure to accumulate of residual deficit.  This has been shown for a few drugs.
We can go even further and  show using EAE that neurological progression can occur even if the drug is immunosuppressive, but the EAE model needs to be used differently from the way most people use it.

However, if you use this simple approach and view the clinical data before you read what the author is telling you to see, then you may be more sceptical about the claims. So "Cure of the Week" that occurs in EAE every week can be put into better perspective. It is possible to completely eliminate relapsing EAE is the drug showing a marked effect or just a marginal change in disease course.

Using this approach ask yourself are some of the drugs claimed to be neuroprotective, just plain old simple immunosuppressives agents or are are some of the repair agents actually being immunosuppressive and just allowing the natural recovery processes to act. Maybe I'm just being cynical.

7 comments:

  1. Therefore, its a lot more difficult to prove a drug is neuroprotective- if you continue to relapse and presumably have MRI activity, but don't get any worse measured by your EDSS score, then that drug is neuroprotective. How would you construct a trial for it?
    Trust me- you'll still relapse, but once you've recovered you won't be any worse than before (we think). It doesn't have the wow factor of the immunosuppresives.

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  2. I wish everyone claiming neuroprotection in their EAE studies when in the vast majority of cases it is just immunosuppression would read this before making such claims.

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  3. "It doesn't have the wow factor of the immunosuppresives".

    Although I see where you are coming from you have kind of missed the point.

    Whilst neuroprotection is important to RRMSers the major challenge to find treatments for PPMSers/SPMSers.

    The trial design that you use for an immunosuppressive in RRMS is of no use to someone with progressive MS because they are not gadolinium enhancing and having relapses and giving them immunosuppressives does not stop their progression we need a different approach.

    If you are having the two above you should be taking a DMT or change your DMT so that you are not having relapses. Therefore your comments about having a relapse and accumulating no damage is kind of irrelevant, because there are tools to do something about relapses.

    Once these tools become established and the immune arm is dealt with funders will be less and less interested in this and the funding streams open to EAEers will become less and less, particularly as there are more humane ways of studying immune function than working with paralysed animals

    We need a different approach to find treatments for progressive MS and we need new tools to find agents to treat MS. The point of this post is to help you to see through the mountains of false claims that create false hope. If you are a researcher reading this post then do not make the false claims that create the false hope.

    Using this approach to monitoring EAE some new targets have arisen one such is ameliroide. Look at the original EAE papers and see how it fits with clinical profile in the EAE studies it is not an immunosuppressive. Time will tell if it a neuroprotective.

    In the long run to treat someone with MS we will need immunosuppressives, neuroprotectives and repair agents as DMT this could be different treatments or one drug may do all.

    Maybe if we can stop MS from taking hold then we won't need to bother about neuroprotection and repair and if we can prevent MS from starting who will be bothered about immunosuppressives either. Let's hope.

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  4. You'll have to wait an entire generation before we can claim no more kids will go on to develop MS.

    I'm curious, has the rate of individuals going on to develop SPMS actually dropped during the noughties as a result of potent DMTs? Is SPMS statistically peetering out because of new therapies?

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  5. That's a good question anon 6:16pm. Is SPMS dying out because of DMTs? This means that MS will finally have treatments that are as good as a cure. Are you seeing less cases of SPMS?

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  6. We have seen some data with the interferons which has been open to discussion. Maybe someone access the data but has it been collected in a systematic way probably not in the UK. (Dr ram here's another job for you!) Maybe the VA in the states could get the answer for service men and women. The Canadians could maybe have another look at there data.

    However, I would not call the nineties early noughties drugs potent, remember only a thirty% drop in relapse rate. The late noughies early teenies drugs are at least twice as effective. I would call them potent.

    This has been discussed before, there has been a number of years since trysabri was introduced, did we ever see the data of conversion to SPMS..I think not and the alemtuzumab 5 year data is on the blog.

    Not sure we can rely of historic data as things change over the past decade and it is not just drugs.

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  7. Is SPMS dying out I hopes so but at least it should be delayed by the new potent DMT.

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