Sunday, 3 June 2018

Managing expectations: can we cure MS?

When I was at the ANZAN meeting in Darwin I was shown the results of a recent survey of Australian people with MS regarding their research priorities. The number one unmet need was for researchers 'to find a cure for MS via repair and regeneration of cells'. This is easier said than done. I also have problems linking 'an MS cure' with the concepts of 'repair and regeneration'. In this post, I try and explain why.




Although a large part of this post is repetitive from past posts, sometimes it is helpful to repeat oneself. 
How will we know if we have cured MS?

The current thinking is that MS is an autoimmune disease of the central nervous system that is driven by MS lesions. We think the MS lesion is responsible for both acute (now) and delayed (in the future) neuronal loss. The permanent loss of neurological function (impairment or disability) is due to neuronal loss, which can be measured clinically (neurological examination and cognitive testing), electrically with evoked potentials, using MRI (brain atrophy or loss of brain volume) and/or biochemically using spinal fluid neurofilament levels. 


Acute Neuronal Loss (the Shredder or Scissors): Inflammation in the active MS lesion transects neuronal processes, or axons, acutely that results in loss of function. If the lesion is an eloquent site it causes a relapse. Loss of function is then restored by the surviving axons taking over the function of the lost axons, or other areas of the brain taking on new functions, we call this axonal and cortical plasticity, respectively. Recovery can only occur if there is sufficient reserve capacity. The accumulation of damage and ageing reduces reserve capacity, which explains why recovery from relapses tends to fail with more advanced disease and with advancing age. This is why it is important to treat MS early so as to protect reserve capacity.

Delayed Neuronal Loss (Slow Burn): Neuronal processes (axons) that survive being transected are compromised and never recover fully. They may remain demyelinated, or if they are remyelinated the myelin sheath never gets back to what it was in health. In addition, the so-called microenvironment within the chronic MS lesion is stressful to the axon. All these processes program the previously damaged axons to die off over time. This is why anti-inflammatory therapies that switch off the development of new focal MS lesions may not prevent the delayed neuronal loss that characterises progressive MS. Even if we were able to cure MS as an autoimmune disease we may not be able to stop, or prevent, progressive disease from occurring in the future as it may already be programmed to occur from previous damage that has accumulated in the past. 


In other words, progressive MS is like a ticking ‘time bomb’ in people who have acquire d a lot of damage from MS in the past.

Premature ageing: We also seem to forget that as we get older we lose brain; this is what we call age-related cognitive, or neuronal, decline. From the age of 35 our brains start to shrink and our neuronal systems start to fail. The manifestations of this are not that subtle; how often do you battle to find the right word, or remember an important fact, only to find that your memory has failed you. Similarly, your balance is just not as good as it once was; you realise that you can’t put on your trousers standing-up unsupported and you have to resort to sitting down, or holding onto to a piece of furniture, for balance. If we all lived long enough we would all dement from natural ageing. Evolution never designed our brains to function for as long as we are living today. 


What protects us from the ageing process is brain reserve; the more brain reserve we have the later we will present with our dementia. As MS reduces brain reserve we hypothesise that people with MS (pwMS) will notice age-related cognitive decline earlier than their peers in the general population. So even if we cure you of your MS you may still get a drop off in neuronal function earlier than expected that is simply due to ageing. This early drop-off in your neuronal function will probably be interpreted as MS-related, and not age-related decline.

The insights above highlight some of the reasons why we started the ‘Brain Health: Time is Brain’ campaign and why it is going to be so hard to prove that we have cured MS. However, if we don’t define what a cure looks like we won’t find it.

Defining a cure in MS: Based on what I have said above you may be cured of our MS, but still, have progressive disease. The difference between progressive disease, which is due to previous MS damage and that which is due to premature ageing is that the former should burn-out, i.e. after a period of time, your worsening disability should stop (flat-lining). In comparison, premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier would be easier. 


I hope you can see that this definition of a cure is incompatible with the terms 'repair' and 'regeneration'. The latter are separate processes that are independent of a cure. We clearly need repair and regeneration agents to treat pwMS who have accumulated a significant amount of damage to their nervous systems. In comparison, in pwMS who have been cured of their MS and have not had any significant damage will not need to undergo treatments to repair and/or regenerate their nervous systems. 

Importantly, a cure can only really occur in relation to IRTs (immune reconstitution therapies; e.g. alemtuzumab, cladribine & HSCT), i.e. treatments that are given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity tends to return. 

Let’s say we have treated a group of pwMS early in the course of their disease with an IRT and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 15, 20 or 25 years? In the past, I have proposed defining a cure as NEDA at 15 years post-treatment as a starting point. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that should be accepted by the wider community; this may be wishful thinking many in the field are saying that we can’t cure MS, therefore, we should not be having this discussion. 


In addition, the average time to the onset of secondary progressive MS is ~14-15 years so one would expect to see a significant proportion of people manifesting with SPMS in this timeframe. If we had got the autoimmune hypothesis wrong and the IRTs don't work then I would estimate at least a third should have SPMS if our hypothesis is wrong. The problem with 15 years is that it is too long to wait; some pwMS want to know 'now' if an IRT offers a cure, therefore we need data to convince the naysayers to support the ‘cure hypothesis’. Hopefully, convincing data will change their minds and get them to at least offer IRTs to more of their patients.

Deep phenotyping: We are therefore proposing a deep phenotyping project to look at pwMS who are NEDA-2 post-IRT to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. We propose interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term to interrogate brain and spinal cord integrity in a lot of anatomical and functional detail to see if an IRT has stopped ongoing damage and protected reserve capacity. At the same time, we plan to look for evidence of ongoing inflammation in the spinal fluid. 


One of the problems I am finding with pwMS who have had an IRT and are now in long-term remission is that they forget that they have MS and simply get on with their lives. They disengage from the MS community; they stop reading MS blogs and stop coming to MS research meetings. In short, these people act as if their MS has gone away. They act differently and start to believe they have been cured of MS. Therefore, I see the biggest problem of doing this study will be difficult recruiting subjects; who will want to take a day off work and come into a research unit to be interrogated in detail? 

Deep phenotyping will include quantitative neurological examinations, multiple questionnaires (PROMS), multidimensional MRI scans, a full set of sensory evoked potentials and central motor conduction times, detailed neuropsychological testing, a large number of blood tests and a lumbar puncture. The latter is to make sure spinal neurofilament levels are normal and to see if the oligoclonal bands (antibodies) have disappeared. I am hoping they will have disappeared. If we can show that the majority of the subjects in an IRT cohort has stabilised with no evidence of progressive disease compared to the maintenance DMT group we may convince the field of the value of IRTs. 

What do you think? Will you be convinced?  


ProfG    

42 comments:

  1. This is one of the best pieces I have read. I Have/had MS for 22 years, my neurologist withheld the fact I had MS as 'I was was terifeied of it" I am bitter as he played god. I would have taken a DMT, I often wonder now had I had option would I be better? I am now on Ocrevus as I pushed for it. I think this study is so important. Thank you for all you do. One thing I have learned, I have to take care of me.

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    Replies
    1. How long have you been on Ocrevus? Have you noticed any change in your condition? Do you have RRMS or SPMS?

      Delete
  2. Subjects with no evidence of disease activity (NEDA) by clinical
    and MRI criteria during the first 2 years had long-term outcomes that were no different from those of the cohort as
    a whole.

    Interpretation: Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural
    history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call
    into question the utility of annual MRI assessments as a treat-to-target approach for MS care.

    These observations challenge
    the concept that NEDA represents remission. Although
    NEDA may be a useful measure for assessing relative
    therapeutic efficacy, many patients who meet NEDA criteria
    over 2 years go on to develop clinically significant
    disability.


    ANN NEUROL 2016;80:499–510

    Obrigado

    ReplyDelete
    Replies
    1. NEDA represents three outcomes if you look at the forth outcome you may not be NEDA...it is only as good as what you look for.

      Delete

    2. This study was open-label observational and patients were not necessarily treated to a target of NEDA.

      In the blinded trial data sets those who are NEDA have much better outcomes than non-NEDA

      At the end of the day it is up to your neurologist or you to make a decision about the treatment target.

      What would you prefer being NEDA or non-NEDA?

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  3. Thanks very much ProfG for taking the time and trouble to provide neat summaries of information already available on the blog.

    With my husband away, a friend is accompanying me to my appointment with my neuro and she is working hard to bring herself up-to-speed, so to speak. This and the post 'What is HSCT?' last month are very helpful.

    I wish there was more time and space available to you to put them out on social media - YouTube etc. The summaries by those such as Aaron Boster would be enhanced and complimented by yours.

    Another friend who is an occupational therapist is making patients with ms aware of the Blog. Sadly, I think it's true that there are too many who don't know of it or who can't, perhaps, see past the science.

    Personally I've found some of the science accessible, interesting and of value. But for many these accessible summaries would be incredibly beneficial - after all there's a lot of bolderdash out there!!

    Thanks again.

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    1. Thank you for the compliment. We can put them out there on YouTube. What format do you want them in? A 30-45 minute long lecture, a 15 min TED type talk on the main issue or a short 2-3 minute short summary video?

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    2. Yes please!

      (Any format that's appropriate!)

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    3. I'm really pleased you're able to put out valuable summaries like this on You Tube.

      I'd like to echo James reply, except for wanting to see any broad brush coverage to provide advice on where to go for more detailed information (this Blog of course!)
      Or maybe Aaron style - four separate YT films on Alemtuzumab.

      Am chuffed that PwMS doing YT searches will, in future, find your summaries to watch!

      Delete
    4. Can one of the YouTube posts focus, on diet and exercise?
      Something to weed out the BS, and give clear practical advice to those with MS. I

      I think there’s also room for the topic of stress to be discussed. It seems common place after diagnosis, that we are told to avoid stress, as it can make things worse. But that’s about it.. and that can be quite stressful.

      I think I’ve learnt since then, that it’s more the symptoms of stress, and lifestyle choices that might come as a consequence; such as smoking (heavily), drinking alchohol( heavily), depression, over eating etc.
      I think your blog, has become a stable diet( excuse the pun) for many people with MS, and having focus on things that compliment the other material would go a long way.

      Delete
  4. For someone diagnosed in the age of IRTs, is there hope to have a life without any disabilities?
    Are we able now to control MS from scratch?

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    Replies
    1. Yes, you need to look at the long-term alemtuzumab and HSCT follow-up. However, it is not 100%. Unfortunately, there are people who despite these treatments who end up with disabilities. What we still don't know is what happens after 15, 20, 25, 30 and more years after treatment.

      This is not only an IRT issue; you can do well on maintenance therapies as well.

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    2. Thinking about the prospect of having to stay on maintenance therapies long term - what happens in older age when you reach your 50's,60's and 70's with the increasing chance of other health problems and the scary risk of MS rebound activity if a maintenance therapy is stopped? At what age to you personally recommend stopping treatment in older patients and just how many problems have you encountered in those older patients that do stop? Do you reckon that Alemtuzumab, HSCT and Cladribine are far too risky treatments for someone above 50 years of age?

      Delete
    3. Thursday, 1 February 2018
      Does your age predict how well you respond to DMTs?.......something to ponder from earlier post on this blog.

      Delete
  5. Replies
    1. By definition benign MS is a retrospective diagnosis. NEDA refers to the here and now and has nothing to do with benign MS. However, in reality we hope pwMS rendered NEDA and maintained NEDA will end up having benign MS.

      Delete
  6. One question, Professor. Gionavonni

    Why would dmts such as Tysabri and the like, continue to be prescribed, it the only true “cure” like state of remission, can only be achieved using one of the IRTs?

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    Replies
    1. The IRTs are risky and irreversible. Some pwMS don't want the risks and some neurologists don't believe we can potentially cure MS.

      Delete
    2. Surely Cladribine is the DMT to favour as it seems considerably less risky than Tysabri or Alemtuzumab?

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    3. But cladribine, in my opinion, is being underdose and hence is less effective than alemtuzumab and HSCT. We did this deliberately to make the drug safer.

      Delete
    4. There was no difference between doses in CLARITY, nor in CLARITY extension, though there seemed to be a difference in an earlier phase II study by Rice, et al. Neurology 2000.

      Delete
    5. In response to your comment Prof G: what dose of Cladribine do you think should and could be safely used to make it more effective?

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    6. There was a difference in MRI outcomes; the higher dose was slightly more effective than the lower dose. In addition, those treated for 2-years followed by placebo start to breakthrough earlier than those give additional courses.

      Cladribine unfortunately doesn't bat in the same league as HSCT, alemtuzumab and natalizumab when it comes to a reduction in brain volume loss. All these factors tell me we haven't reached its true potential at the current dose. Can we get more of cladribine without compromising its safety?

      I think we can but that a story for another time.

      Delete
    7. That is why we call it alemtuzumab-light in Germany; it is simply a light-weight compared to the heavy hitters above it.

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    8. So will ocrelizumab be considered a hard hitter in the same league as natalizumab alemtuzumab and hsct?

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    9. But cladribine won't?

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  7. What are the options for a PPMS patient who never had active lesions and was progressive from the get-go?

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    Replies
    1. Check diagnosis. Test neurofilament level. Participate in trial.

      Delete
  8. Another awesome article Prof G! Again, thank you for the hard work and dedication. Without the work that this website has done, I don't even want to know how much less informed and worse off I would be. Because of you, I am exercising, eating right, rarely drink, and am no longer overweight. So thanks!

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  9. Thank you!! Great lecture for all of us who are treating patients with the best that we can do in our far countries. I'm sure that this kind of articles that are the mirror of your self clinical experience are the most important for us the neurologist who are trying to treat our patients with the best knowledge that we can learn.
    ( sorry my english!! Saludos desde Chile)

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  10. Really good article clearly outlining what can and cannot be expected. If explained to Nice would they take this onboard and therefore approve more drugs for those more advanced people or do they still expect miracles quickly in order to approve anything.

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    1. Unlikely. In general NICE only respond to licensed DMTs and the data that led to the license being granted by the EMA. We need to do better trials and generate the evidence to support a NICE extension to prescribing. It is all about cost-effectiveness; does the effectiveness justify the cost of the treatment?

      Delete
  11. When do you think you may be recruiting for this proposed deep phenotyping and what are likely to be the principal selection criteria?

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  12. I am on tysabri and currently stable, but this post, makes me question whether the decision was correct. Versus Lemtrada.

    having to attend a monthly infusion every month, does become tiresome, and the picture painted of life feeling like you don't have MS, sounds very appealing. I don't feel I ever, really forget I have MS.

    what I don't get in you say these people act like they have been cured of their MS. and in some sense, you are saying they may be. so isn't their reaction, the correct one?

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    Replies
    1. We don't know if they are cured, which is why we want to do the deep phenotyping study.

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    2. same here - yet the author does not recommend the switch if you are JCV- (unless female and wanting kids). Read his previous posts.

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  13. Great article. I have had MS 33+ years and have a very high lesion load even on my first MRI. This explains why even the most aggressive therapies (intrathecal methotrexate, immune ablation) and currently Ocrevus have not stopped my progression. I wish my neurologist had explained this to me.

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    1. So sorry to hear you have worsened despite aggressive treatment. Do you mind me asking when you started taking DMT's and how recently you took the most potent therapies? Being nearly fifty years old, I'm wondering if it's really worth trying Alemtuzumab (or Ocrelizumab if it becomes available in UK) with all the accompanying risks. Very best wishes.

      Delete
    2. This may be long:
      diagnosed in 85' at 20. Too many lesions to count at diagnosis. Dozens of attacks and new lesions over the next 5 years: no permanent disability. From 90' to 05 no new attacks and EDSS was still 0. Fatigue remained severe and continued to progress. Started copaxone in 00'. 2006-dosease became aggressive relapsing progressive-switched to interferon to no avail and numerous IV pred infusions. 06-08 disability went from 0-6 on disability scale. Had total immune ablation with cyclophosphamide at Hopkins. Could walk without can for 1/4 to 1/2 mile for 9 mos. and attacks stopped for good. After 9 mos. I was just progressive. Had intrathecal methotrexate from 2013-2016 with no effect on progression. Started Ocrevus at MD's insistence in 4/18. MRI's have been stable for 10 years, but I am no longer walking.

      Delete
  14. Excellent news. No hope of reversal of disability and virtually everyone progresses to disability. Love this disease. I’m in my forties and there will not be a cure in my lifetime.

    ReplyDelete
    Replies
    1. 3 people with progressive disease have stopped progression
      and gone down in EDSS. Possibly Patient 1 & 2 & 5 are the only people in 2,000 years of history to have done so.

      SPMS/PPMS 6.5-6.0 and 5.0-3.5 and Look Mom..No Therapeutic Lag either all done in a year.

      https://i.imgur.com/niGAJWi.jpg

      Of course Neuros here won't admit about progression..it's
      a dirty hidden secret here..not to be talked about or admitted.
      Too busy thinking about managing expectations from
      all the overpromises made about anti-inflammation drugs.

      Delete

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