Friday, 6 July 2012

Grand Challenges in MS (2): early aggressive therapy

In response to yesterday's discussion on whether or not MS is a primary neurodegenerative disease or a primary inflammatory or autoimmune disease. 


"One way of testing this is with very aggressive induction immunotherapy, i.e. an immune system rebooter, early in the course of the disease." 


"Aggressive early treatment that gets rid of autoimmunity will have a short term impact on the disease by suppressing focal MRI activity and relapses, but will have little long-term impact if the disease was neurodegenerative. In other words this treatment strategy should convert relapsing MS into the primary progressive type or more correctly non-relapsing SPMS. As an MSers with early disease and little disability it would take several years for the progressive disease to emerge." 


"This strategy is currently been tested with autologous bone marrow transplantation and alemetuzumab treatment. How long should we wait to declare a victory? 10 years, 15 years, 20 years or longer? The debate on length of follow-up is not trivial, in fact it is very important as it will be used to define a cure.  In other words if an MSer with RRMS is treated with a bone marrow transplantation, or alemtuzumab, and remains free of disease activity (no new MRI lesions, no excess brain atrophy, no relapses and no disease progression) for 20 years or more they would be cured of having MS. If on the other hand they remain free of disease activity for a period of time and then present with progressive disease they clearly will not be cured and MS would be confirmed as being a primary neurodegenerative disease."


"My money is on the former scenario, which is why I classify myself as a promoter of aggressive treatment strategies. The other extreme is therapeutic nihilism, i.e. not treating MS with anti-inflammatory strategies, until you have evidence that anti-inflammatory treatments impact on the long-term prognosis. My problem with therapeutic nihilism is that I don't have the disease and what if the nihilist is wrong? Surely an intelligent MSer armed with the facts, or lack of facts, can make the call? What do you think? I don't want to have regrets."


"Please note that not all MSers will respond to BMT or alemtuzumab; in other words these treatments may or may get rid of autoimmunity. This fraction may not be small, which is why we need large number of MSers in trials and prolonged follow-up."


"Please note all of the above may be wrong and MS could be due to a virus; the virus is what is responsible for causing the damage and if your immune system sees the virus it results in focal inflammation and cause an MRI lesion and possibly a relapse. This is why we have launched The Charcot Project, to test the hypothesis that MS is due to a virus. If you read this blog you will note that we favour EBV and HERVs as being the leading contenders. We may be wrong, we may be right! The only way to find out is to treat MS with targeted anti-virals." 

Finally, I would like to point out the twin that is described in this small series of MSers that underwent a BMT:

Mandalfino P, Rice G, Smith A, Klein JL, Rystedt L, Ebers GC. Bone marrow transplantation in multiple sclerosis. J Neurol. 2000 Sep;247(9):691-5. 

There is strong circumstantial evidence that MS is an autoimmune disease. Nonspecific immunosuppressive therapy has not been successful in altering the natural course of the illness. Bone marrow transplantation has heretofore been a radical therapy used in patients with life-threatening malignancies but has potential as a treatment for human autoimmunity. In MS there have been no controlled studies. We report here four patients with MS undergoing bone marrow transplantation with 6-48 months of follow-up. In three this was carried out for co-existing malignancy and in one as an experimental treatment for MS using the patient's unaffected identical twin as a donor. The limited outcome that can be evaluated in these patients supports further experimentation into this treatment modality in MS patients with poor prognostic indications.



"George Ebers told me that initially this twin did very well; her disability improved and she stabilised without any relapses - she appeared to have burnt out MS. Was she cured? Unfortunately not, about 7 years after her BMT she developed SPMS. This observation would support MS as being a primary neurodegenerative disease. What do you think?"

"This case is not a good example; as she has quite advanced disease and had already acquired a lot of damage she was destined to develop progressive disease. Why should someone with a damaged nervous system be primed for progression? That is another story, possibly another grand challenge."

"I hope this post in not confusing; if it is I will try and simplify the concepts!"

CoI: multiple

27 comments:

  1. I'm having a little bit of difficulty understanding. I may have misspoke in my previous comment on the previous post.

    When I look closer at those charts, they appear to show that things "go back" to an SPMS course for RRMSers after each relapse.

    Empirically relapses seem to pretty clearly cause lasting disability above and beyond any progressive course and stopping relapses seems important.

    However, I think there might also be progressive element to RRMS, but for that I have little evidence, in fact I can think of ways I could be wrong. I have enough lesions that disability could have accumulated through many undetectable relapses (going as far back as my childhood) before the relapses became obvious enough to feel.

    One thing I'm pretty sure of is that relapses are bad, cause lasting disability above and beyond any potential progressive course, and stopping them aggressively is a good thing.

    Where I'm confused is where that puts me in your two scenarios. Every time I post a comment I usually end up learning something and changing my mind at least little, usually a lot. It's hard to have stable opinions when I'm learning so fast.

    Two things I know:

    - I have lots of weakness and other issues in my childhood that look like progression of "something" however I don't know whether it's progression or unfelt relapses or totally not related to MS.

    - relapses are bad, bad, bad and have lasting effects

    It's these two experiences that I'm always trying to reconcile with the various theories.

    I have a suggestion, could you post in the following format for the two theories (my ignorance will be shown in my attempt to provide an example)

    1. "primarily progressive" option beliefs (<-- in quotes is the name of the theory we should use when referring to it in discussion)
    - relapses have no lasting effect
    - idea 2
    - idea 3
    - ...

    2. "autoimmune" option beliefs
    - relapses are everything
    - there is no progressive course along with RRMS
    - ...

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  2. Re: "Empirically relapses seem to pretty clearly cause lasting disability above and beyond any progressive course and stopping relapses seems important."

    I agree with you, bu tall MSologists buy into this. This is based on natural hisotry data that show relapses correlate poorly with longterm disease outcomes. The exception being early relapses, i.e. those occurring within the first 2 years.

    This position is based on natural history studies and not MSers on DMTs. I think relapses on DMTs are much more ominous that relapses on no treatment. Relapses on DMTs indicate that the individual is a non-responder. In this context it may not be the relapse that is important by the pathological process underlying the relapse; for example viral replication.

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  3. Re: "I think there might also be progressive element to RRMS."

    You are correct; there are MRI studies showing progressive whole brain and gray matter atrophy in RRMS regardless of whether or not there are relapses.

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  4. Re: "primary progressive"

    The notion is that PPMS is not inflammatory is simply wrong. Pathologically PPMS is full of inflammatory cells and has a prominent B cell response that is identical to RRMS and SPMS.

    ~5-20% of PPMSers will go onto have relapses. We should use PPMS to support MS as being a neurodegenerative disease; there are a several other observations that are more compelling.

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  5. Let's make things a bit more personal:

    Let's look at the scenario where your son/daughter (nature forbid) contracted RRMS few years ago.

    conventional MS course: a couple of light relapses, optic neuritis....
    They started off with a CRAB and had another relapse (and new lesions).
    They are now on Tysabri and all of you can sleep well at night as they are JCV negative. It has been a couple of years without new clinical symptoms.

    What would you do in this situation: keep them on Tysabri (best licensed drug in the market), with the empirical comfort of a disease slow down (but degeneration after all)

    OR

    advise them to look into one of the aggressive induction therapies discussed in this post?


    Does the risk/reward of induction therapy out run a lifelong treatment with Tysabri? (reward defined hereby as a better outcome, not necessarily a total cure)

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  6. Re: "Does the risk/reward of induction therapy out run a lifelong treatment with Tysabri?"

    I have no idea; this is why we do clinical trials. We are planning a head-2-head study in the UK to address this question. We may have answer for you in 15 to 20 years time.

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  7. Why are we still testing theories?

    - an Vit D prevention trial is just starting in Australia to test the theory that Vit D supplementation might prevent MS;

    - the Charcot project (maybe) will test the theory as to whether EBV is the cause / trigger of MS;

    - BMT and Alemtuzumab will test the theory as to whether MS is a an inflammatory disease whcih causes neuro-degeneration or a primary neuro-degenerative disease.

    For the latter it will be another 15-20 yeas before there is an answer.

    Am I right to feel pissed off, that in 2012 we are still dealing in theorie / that the testing of these theories will take decades?

    Most research provides incremental increases in knowledge / understanding i.e. after 5 years we know more than 5 years ago. Why is MS different. All MS research does is raise further questions, identify more theories, but never provides answers.

    MouseDr has slaughtered '000s of our fluffy friends - for what? Prof G has produced '00s of peer-reviewed researh papers - for what? What has been learned given there are no definitve answers?

    I've had MS for 9 years. It's 2012 - 40 years after they put a man on the moon. The best I hear is that it will be 20 years before there is an answer to the primary inflammation or primary neuro-degeneration question!

    Surely repair is the answer. Regrowing axons, nerve cells etc. Repair will be benefi all types of MS. But I'm guessing this is 30-50 years away.

    I'm advising my son to become an MS researcher - job for life, you don't need to answer any fundamental questions about the disease etc etc.

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  8. When you say 'immune system rebooter, early in the course of the disease', what does 'early' mean? How late is too late?

    Is cyclophosphomide also used for aggressive induction therapy?

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  9. By reading this blog I have come to believe progression is an independent process and it will probably happen even after aggressive induction therapy. But I think aggressive induction therapy will be very good.

    If it stops relapses there will at least be slower progression, which is good enough to start with. If it becomes really slow, that is almost as good as no progression.

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  10. "after 5 years we know more than 5 years ago.Why is MS different".

    5 years ago we did not know about Gilenya, BG12, Lemtrada, Teriflunomide, Dacluzimab, Sativex, Fampridine, etc etc etc.

    Why does it take 15-20 years to show things...because the course of MS is slow. Thats a good thing.

    Why test theories...
    Until you have the right solution you trial things becuase you want an anwer to a theory. An answer
    always leads to another question

    "Surely repair is the answer"..that is one answer but stopping MS in the first place would be a better answer.

    However if you cannot stop the damaging process you are fighting a loosing battle. You can now start to think about repair because some form of brake can be put on the damaging side.

    For what?...Perhaps drugs that have some value for MSers?.....A place where you can let off some steam?:-)

    If you think it is a easy life to be an (MS) researcher tell that to people on the Dole queue. Advise your son against this. Science is very a tough business to be in, especially in the current climate..no funds...no theories......no nothing.

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  11. "I have no idea; this is why we do clinical trials. We are planning a head-2-head study in the UK to address this question. We may have answer for you in 15 to 20 years time."

    Funny you say that when you posted

    "My money is on the former scenario, which is why I classify myself as a promoter of aggressive treatment strategies"

    so you are willing to bet your money but not your child's disease course?

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  12. But NICE guidelines don't factor in such aggressive responses, do they?

    I asked for some aggressive therapies when I was first diagnosed with CIS and the neurologist looked at me like I was an idiot.

    What do do, Prof G? Refuse to you leave the surgery until your neuro gives us Campath?

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  13. Anon 11.40 how nasty can you get

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  14. This comment has been removed by the author.

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  15. Re: "My money is on the former scenario, which is why I classify myself as a promoter of aggressive treatment strategies"

    We don't have long-term Alemtuzumab data so all we can talk about is what happens at 5 years. The person who has to take the risk of getting Grave's disease, or ITP, or Goodpasture's disease and have to come in monthly for monitoring is not me, but the person with the disease. If they understand that we don't have a complete picture and that Alemtuzumab may be offering a proportion of MSers a cure, or it may not, then the decision should be up to them and not me.

    If my daughter had MS I would hope that was being treated by a like-minded neurologist. On the other hand if she was risk averse I would respect that decision. We can't and shouldn't second guess what risks people with MS are prepared to take. Perceived risks change depending a lot of factors.

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  16. Re - "Why does it take 15-20 years to show things...because the course of MS is slow. Thats a good thing."

    Erm, I've had PPMS for 7 years and am now in a wheelchair. That's a pretty short timeframe Prof G, nothing "good" about that.

    As I read this blog it's clear that the MS research field is comprised of headless chickens banging into walls. Progression is not being taken seriously enough.

    Keep up the good work.

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  17. "As I read this blog it's clear that the MS research field is comprised of headless chickens banging into walls. Progression is not being taken seriously enough."

    Some of us chickens have knocked bricks out of the wall and have emerged into the garden of enlightenment. We take progression and our research into slowing it down very very seriously.

    "Keep up the good work."

    You're understandably bitter but really sarcasm isn't the way to go.

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  18. "Some of us chickens have knocked bricks out of the wall and have emerged into the garden of enlightenment. We take progression and our research into slowing it down very very seriously."

    I don't doubt that you are all working very hard. But there's a massive chasm between the progress researchers think they are making and what is actually available for people with MS. Team G has been around for several years, but I can't think of one example of benefit to patients i.e. What's available NOW - to stop progression, to encourage repair. After 15-20 years with this disease you are likely to be in a poor way. The timescales are too long for many of us. There must be someway to cut the red tape, be more agile. If not, I and others are being left to rot.

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  19. Easy, guys, easy. We are not left to rot - quite the contrary. If you take a drug like BG12 as an example you can see how much has changed even in the last 2-3 years when I got my diagnosis. If BG12 had been available then I would not have wasted a year without any DMT due to fear of needles and side-effects.

    Also, see what the Australians are doing as I have done the other day - plenty of projects on the very topics raised here.

    The only people who can really vent here are PPMS-ers - I could, of course, vent too, but in all honesty, all I have now is just a bit of vertigo and a huge fear of the future but Team G is not to blame for that.

    Btw, speaking of vertigo - are any drugs in the pipline for that? It's difficult to treat but a nasty symptom.

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  20. Perhaps your recent post on modafinil suggests it might slow progression...

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  21. I just hope that MSers get some choice with DMDs, that NICE doesn't tie up the use of the new ones so whether you are willing to take risks doesn't matter as you can't get them anyway

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  22. Re: "I just hope that MSers get some choice with DMDs, that NICE doesn't tie up the use of the new ones so whether you are willing to take risks doesn't matter as you can't get them anyway."

    That is the risk; NICE need data and cost-effectiveness data. So you are right we may not be able to give you a choice. We are trying to get the NHS to fund a national study to allow us to test the more effective agents head-2-head to answer some of the questions that will not be answered by Pharma sponsored trials. We may need your help to lobby for this. This may be one way of getting early access to these more effective treatments. The other is to convince the Commissioners to allow us to use off patent drugs that have a reasonable evidence base, but cost substantially less than licensed drugs. This may be a can of worms but at least it will allow us to offer more aggressive therapies earlier on.

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  23. Off patent drugs- is that IV cladribine? The old revimmune in the US has been re packaged as Cyrevia, but I thought it was cyclophosphamide by another name. What are the aggressive off patent drugs?

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  24. Re: "Off patent drugs"

    Cladribine is one and the other would be off license use of Rituximab. These would need to be included as part of a study; we can't use off license drugs outside of clinical trials when there are licensed therapies available to treat MS.

    In the EU it is is illegal to use off license drugs when there are licensed drugs for the indication. An example of this is the legal case Novartis brought against several NHS trusts using Avastin instead of Lucentis for age-related macular degeneration.

    We have to practice neurology within the confines of European law. Legal handcuffs at whose expense?

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  25. Why not do some NHS-funded trials break the handcuffs?

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  26. Re: "In the EU it is is illegal to use off license drugs when there are licensed drugs for the indication."

    At a macro-economic level this legislation is very important to incentivise Pharma to develop drugs for orphan indications and to repurpose drugs that target an unmet need.

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  27. Re: "Why not do some NHS-funded trials break the handcuffs?"

    We are planning to submit a grant; but you need to remember that a trial will only allow a small number of people to access early aggressive treatments. For the majority of MSers they will have to go via the 1st line therapies.

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