Sunday, 1 June 2014

NEDA vs.end-organ damage are we missing something important?

Will NEDA give us a false sense of security? How big is the problem of slow burn? #MSBlog #MSResearch 

"We ran a teaching course for trainee neurologists and clinical nurse specialists this week. I gave a talk stressing that treating-2-target of no evident disease activity (NEDA) may not be good enough. I used an example of a patient of mine of treatment who had NEDA, but her serial MRI scans over 4 years showed progressive brain atrophy. This young woman had no relapses, her physical disability was stable (I can't comment about her cognition because we don't routinely measure it) and her MRI has shown no new lesions. She was being treated-2-target of NEDA and yet were not addressing end-organ damage. In other words something was continuing to shred her brain. May be it was the inflammation that she had prior to starting her DMT and been rendered as having NEDA? This is possible as she had highly-active MS and has a high lesion load"

"One of the smart young registrars in the audience was worried about this patient and said that he had concerns about some of the low to moderate efficacy drugs that would result in a proportion of MSers being rendered NEDA, but did as these drugs have no impact on brain atrophy, or end-organ damage, we were being lulled into a false sense of security and that over time this group of MSers will do worse than if they were elevated, or started early, on a more effective DMT that slows are normalises brain volume loss. I agreed with him and made the case for us to get brain atrophy measurements and spinal fluid neurofilament levels into clinical practice as soon as possible. Both these biomarkers will hopefully allow us to escalate, or switch, treatment earlier and will allow us to monitor MSers to see if we need to change our current definition of NEDA."

"When we switched using the term DAF (disease-activity free) to NEDA (no evident disease activity) one of the reasons for doing this was to allow us to evolve the definition overtime as advances occurred in the field. I don't think we are there yet. There are a lot of problems incorporating brain atrophy measurements into clinical practice at present. However, I am confident that we will overcome the problems in the near future. What we need is to develop standard methods to get rid of, or at least minimize, the influence of day-to-day factors that affect brain atrophy, for example alcohol use, dehydration, medications, etc. We also need better metrics with lower variability; I think the latter is possible. One of the things hampering the field at the moment is that all the MRI units working on this want to champion their own methods and not work towards validating and using the best method. This is not an insurmountable problem and could be changed by a global research initiative similar to the one in Alzheimer's disease (ADNI). I think routine spinal fluid neurofilament measurements may be easier to standardise; but will this be enough and will it be sensitive enough to detect and monitor slow burn?"


"On reflection, I agree that having large numbers of MSers on drugs that suppress macroscopic inflammation, inflammation associated with relapses and focal MRI activity, but are not sufficient to suppress microscopic foci of inflammation, and the slow burn we see in progressive MS, may be a bigger problem than we realise. This is why we need better tools and markers to define and investigate this problem."

33 comments:

  1. While measuring all these aspects is important, measuring is only of use if there is treatment to address continuing disease activity. I am currently NEDA (I'm an Alemtuzumab recipient) - no new lesions, stable EDSS etc. However, I'm not monitored for brain atrophy nor neurofilament levels. If I was tested through these monitoring approaches, what could be done? More Alemtuzumab? Perhaps, but my neuro would say my MRI shows no inflammation. What else is there? Priority of research teams is to find highly effective treatments for slow burn. But then we end up going round the same buoy where drugs will be out of patent and the issue of no pharma company prepared to fund Phase III trials. BPA isn't a solution, nor is MSers protesting on the streets. We need neuros who based on good evidence are prepared to prescribe drugs not licensed for MS e.g. Simvastin. Are you prepared to do this for the benefit of your patients? Time is brain you have said. However, 20 years to get Alemtuzumab to market and almost unsurmountable barriers to get any of the neuroprotective treatments, which have been identified, to market shows how absurd the whole system is. I'm going to be much more radical and put my health first. If the Charcot project shows some promise, i will be ordering the drug on the internet. I will also be doing the same for simvastin. This is my brain and life and the internet gives me choice (once I've assessed the risks). I'm guessing that you would advice against this, but without giving me an alternative, i have to act on my own.

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    1. So are you going to start simvastatin yourself? This is the problem with the way it has been left - no phase 3 studies and no previous dosing studies to see if 80mg is really required.

      These sorts of trials would seem to be a priority as the MS-STAT trial itself seemed to suggest a stunning effect on brain atrophy - this would surely seem an absolute priority to sort out.

      I wonder if the charities have enough money to fund that sort of research, as it would seem to be an ideal target. Is the money spread over to many bodies/countries requiring a level of cooperation that would never be possibile to get this off the ground?

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    2. Like you I was impressed by simvastin and Dr Chattaway seems a nice guy. But we are alway left in the lurch i.e. They announce positive observations from the early trial which gives us hope, then take the hope away by saying it won't get licensed. As it is a drug which is widely used and I'm a guy in my 40s, what have I got to loose? A friend did something similar with minocycline in the US. This has a comparable effect as the injectibles. The drug being used in the charcot project is used in HIV patients - it has a known safety record. If the early charcot project is positive I wil look at obtaining this. All three drugs I have mentioned are cheap and have a well known safety records. I'm prepared to sign a form to sat that I take full responsibility ie there is no risk to the doctor who prescribes the drug. The trials too long for us - I'd happily put my name forward for one of the drugs targetting repair e.g. Antilingo. Its unlikely I'd be lucky enough to get on the trial, but I'd be happy to pay for the drug as I can't wait another 10 years. As patients we need to take care of ourseleves. Remember - research teams are academic who interest in publishing papers.

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  2. Prof G,

    With regard to your pyramid, what is the order of the various events? Will the drug being used for the Charcot project address all / some of the different events happening in MS?


    There seems to be a recognition that the immune system outside the CNS causes relapses (as the immune cells enter the brain) and the immune system within the CNS is responsible for slow burn / progression. I'm guessing the latter comes first. Is Team G active in identifying therapies to address the slow burn? Is this the same as the hot microglia?

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  3. I agree with anon above (first). I haven't got time to wait another 10-15 years for a neuro-protection treatment to hit the streets. I too, will be looking at options on the internet such as simvastin and minocycline. What can I loose? You've already acknowledged that the brains of MSers are being shredded. You guys hide behind safety and the need for larger trials etc etc. Thanks, but no thanks. I can't operate to your snails pace approach, I won't have any brain left. And in 15 years time, when the big simvastin trial reports good results, i can tell myself that I did the right thing. The worse thing you can do is wait for MS researchers to deliver the goods. I see MS as a war - a war to preserve the brain I have left and a reasonable quality of life. I have to fight this disease on my own and on my terms - including buying drugs on the internet. I'm a statistic to research teams - a point on the EDSS or a number of enhancing lesions. I'm also a dad, husband etc. It's a shame you can't acknowledge the latter - if you could, you wouldn't have a system for indentifyinf, trialling, kicensing treatments which take decades.

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    1. Well said.

      Whilst we still have the brains to come to our own decision we should be in a position to decide for ourselves if the benefits outweigh the risks. Statins are fairly safe and the side effects are very well known. It would be nice to know if 80mg is really required though.

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    2. I have been taking 80mg statins for half a year last year - got an awful lot of relapses cos no other DMTs.

      I will be starting statins next month but a low dosis in addition to a DMT - will report how I am doing.

      However, it would be great to know if a low dosage is also okay and to have the atrophy actually measured.

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    3. Can I ask, has your GP or Neuro prescribed this level of statin? As someone on the active drug on the trial, I am very disappointed not to be able to continue with this medication.

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  4. The fact that people some patients are still apparently accruing brain damage (on-going atrophy) in the absence of NEDA should raise more questions than simply saying we need to improve the tools used to measure disease. Does the on-going atrophy actually tell us that a different disease progress is occurring and relapses are merely superimposed on top. Maybe we are supressing the bodies physiological response to the disease but not actually dealing with the underlying pathology?

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    1. I concur with your comment. You have to wonder why after 50 years of MS research the most fundamental questions about the disease can't be answered. I put the blame on: (i) EAE and (ii) the focus on the immune response e.g. relapses (easy option in terms of measuring). Prof G himself states that the rebound after stopping Tysabri shows that what is causing the disease is still in the brain i.e. the immune response is just responding to a target in the brain. This isn't part of the wretched EAE model which is just an inflammatory autoimmune model which is easy to cure (unlike MS).

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    2. If you treat EAE with tysabri like drug and it stops disease then you stop treatment and disease comes back so there is no difference with MS.

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    3. Prof Compston stated many times that by transferring some immune cells from EAE animal to a healthy one they can induce disease in latter. What cells he was talked about?

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    4. There is growing evidence that T cells provide what has been coined "protective autoimmunity"

      http://wws.weizmann.ac.il/neurobiology/labs/schwartz/research/theory-%E2%80%9Cprotective-autoimmunity%E2%80%9D-integrated-view-brain%E2%80%99s-maintenance-immune-system

      Im sure no one on this blog gives a second thought to this, but It seems restricting your immune system from the CNS may be a bad idea.

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    5. Yep well aware of this theory....the theory of inflammation which ends in repair has been likewise around for years. So we have a balance of good verses bad.

      Based on response to treatment with say Alemtuzumab and Bone Marrow transplantation there is not sufficient evidence that people get worse but seems that people get better.
      So where is the balance?

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    6. http://www.ncbi.nlm.nih.gov/pubmed/15949502

      Schwartz M, Kipnis J. Protective autoimmunity and neuroprotection in inflammatory and noninflammatory neurodegenerative diseases. Autoimmune diseases are traditionally viewed as an outcome of a malfunctioning of the immune system, in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis (MS), a disease of the white matter of the central nervous system (CNS), the attack is directed against myelin proteins. In this article we summarize a paradigm shift proposed by us in the perception of autoimmune disease. Observations by our group indicating that an autoimmune response is the body's mechanism for coping with CNS damage led us to suggest that all individuals are apparently endowed with a purposeful autoimmune response to CNS injuries, but have only limited inherent ability to control this response so that its effect will be beneficial. In animals susceptible to autoimmune diseases, the same autoimmune T cells are responsible both for neuroprotection and for disease development; the timing and strength of their activity will determine which of these effects is expressed. Individuals with non-inflammatory neurodegenerative diseases need a heightened autoimmunity. We discovered that autoimmunity could be boosted without risk of disease induction, even in susceptible strains, by the use of Copolymer-1 (Copaxone(R)), a weak agonist of a wide range of self-reactive T cells. Here we summarize the basic findings that led us to formulate the concept of protective autoimmunity, the mechanisms underlying its constitutive presence and its on/off regulation, and its therapeutic implications.

      Another use for glaterimer acetate

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    7. Well, I can agree with Lemtrada or bone marrow transplant, but prescribing Tysabri to someone knowing that protective autoimmunity is something that this agent would prevent is simply irresponsible. It certainly would bother my conscience if I was prescribing this drug. I would be curious what therapy this person is on that is NEDA yet has atrophy. My guess is Tysabri.

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    8. Also, saying that it is a balancing act with Tysabri is really not telling the whole story. Induction therapy with Mitoxantron seems like it is more effective:

      http://www.ncbi.nlm.nih.gov/pubmed/18424479

      I suppose this route is seldom used as Mitoxantron is generic.

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    9. Actually, the Mitioxantrone induction trial I posted is for three monthly infusions of 12 mg/m^2 folowed by daily GA maintenance therapy. This is well below the lifetime limit of 140 mg/m^2. I think the occurance of cancer was about 0.2% but this was with the full lifetime limit dosing.

      This is for people with active disease who fail first line therapy.

      I know of someone who had this induction therapy followed by GA maintenabce and they have been NEDA for about 5 years.

      If i had highly active disease this would be my choice as it seems the least problematic of all the available treatments.

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    10. The idea of mitoxantrone induction was developed I believe in the UK

      Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis. Ramtahal J, Jacob A, Das K, Boggild M.
      J Neurol. 2006 Sep;253(9):1160-4

      The post you mention is interesting. It is surprising that TEVA as a generic drug and glaterimer manufacturer did not try to develop this.

      Mitoxantrone carriers a risk of cancers http://www.ncbi.nlm.nih.gov/pubmed/19251838 and may increase your risk to PML if you subsequently take tysabri and we had too stop our immune tolerance trial because few would be willing to take it. In the US Mixoantrone is licenced treatment, it is not in the UK. If you have failed beta interferons there are still alternatives so it is not clear if this combination would be easy to get

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    11. "Tysabri to someone knowing that protective autoimmunity is something that this agent would prevent is simply irresponsible".

      Of protective autoimmunity being stopped by tysabri, where is the evidence?

      If you are prescribed Tysabri, based on neurofilament levels the evidence is that on balance it slows down loss of nerves, not the reverse that the protective autoimmunity story would predict.

      http://www.ncbi.nlm.nih.gov/pubmed/21280078
      http://www.ncbi.nlm.nih.gov/pubmed/23763388
      http://www.ncbi.nlm.nih.gov/pubmed/24515731

      Does Tysabri stop progression. We will see following publication of ASCEND....I predict the answer will be no in people that are progressive,

      Will it slow the rate of progression based on one published study it may change the rate of accumulation of deficit.

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    12. I think it is not natural to prevent t cells from entering the CNS such as what Tysabri is suggested to do.

      http://www.ncbi.nlm.nih.gov/pubmed/22903150

      Personally I would leave it as a last option.

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    13. Would you care to tell us what this paper says.

      The anatomical and cellular basis of immune surveillance in the central nervous system
      "A new model to explain how antigen-specific T cell responses occur in the CNS"

      The abstract says little, and not all the readers have a personal subscription to Nature Reviews......So maybe you are a scientist.....so remember Junk the Jargon.when yougive your lay summary.

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  5. MD / Prof G,

    surely it wouldn't require a study of 1000s of people to work out if some of the drugs such as simvastatin decrease the activity of these hot microglia?

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  6. Estriol is another case where the question is who would fund stage three trials? We need a cheaper regulatory process or government funding, or maybe a change in the rules to allow licensure and profit for the entity that shows medical benefit even if technically non patentable. Something. Or else, yes we will seek self help based on what limited knowledge is available.

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  7. BBC reports that the potential side effects of statins include:

    Type-2 diabetes
    Muscle pain
    Headache
    Nausea
    Insomnia
    Liver inflammation
    Kidney problems
    Blurred vision
    Nerve damage

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    1. The side effects of progressive ms includes death - edss 10. I'd rather take a risk with simvastin than the risk which comes from progressive ms.

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    2. Side effects of life include death.

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    3. Life is a sexually transmitted disease with 100% mortality ;-)

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    4. There's death and there's death. Nice little heart attack at 75 = no problem. EDSS of 8 or 9 assessed by MSers as worse than death.

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  8. Hi.
    Is it OK to use Your pyramide illustration? Who has the copyright, and who should be given as reference?

    Jenny Nordfalk, neurologist/researcher

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    1. I suspect this is one of ProfGs. Write to him on his email.

      I am sure he would not mind you unsing it,for a presentation, but if you want to publish it, then my advice is why not simply redraw it yourself rather than copy it. Then it is yours to do what you like, it will only take a few minutes. I have no idea about the source of the MRI but are they needed?

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