Thursday, 26 May 2016

ResearchSpeak: reflections on the ABN

My pod-casting experiment from the ABN #ResearchSpeak #ABN2016 #MSBlog 

I spent most of last week at the annual Association of British Neurologists (ABN) meeting in Brighton. I chaired two debates, presented 4 posters and was co-presenter on another 2 posters. I also networked and met many young neurologists and saw some old friends.

The debates:

Debate 1: ‘Was the NICE mandate that pwMS should have annual cognitive assessments appropriate or not?’


Professor Dawn Langdon made the case for annual cognitive assessments arguing that knowing if someone with MS had cognitive impairment would affect how you manage them. Cognitive impairment is associated with poor drug adherence and difficulties with following self-management strategies. For example, pwMS who have cognitive impairment are more likely to get recurrent urinary tract infections. I suspect that this may not be causal, but simply an association; i.e. people with cognitive impairment may simply have a greater chance of associated bladder problems. She was implying that they were less likely to follow medical advice on how to manage their bladders and adhere to their treatments. She also stressed that annual cognitive assessments does not mean full neuropsychometric testing, but could simply be done using a rapid screening battery such as BICAMS (Brief Cognitive Assessment in MS). She slipped in that BICAMS takes 15 minutes to do and needs to be done by a healthcare professional. At our centre with 1200+ MSers on our books that is 400 hours of testing per year. Dr Brenner, a good friend of mine, argued against the motion. He focused on the NHS resources it would require, and consume, implement annual cognitive assessments across the UK; resources he felt would be better used on more pressing problems. He made the point that as we have no treatment for MS-related cognitive impairment it was unethical to do the tests. Do pwMS want to know they are cognitively impaired? He assumed that pwMS wouldn’t want to know about an MS complication they could do littke about. I am not sure we can make any assumptions, this is a question that needs to be answered by you people with MS.

There were too few voters to really assess which way this debate went, but the debate generated lively discussions. I concluded that this debate needs a larger audience and should include people with the disease. I wonder if NICE asked MSers their opinion before recommending annual cognitive assessments?



Debate 2: ‘To manage MS properly we need a new MS disease activity score or DAS’


As chairman I set the scene drawing on the experience of rheumatolgists who have been using the RA DAS (disease activity scale) for decades. In RA a DAS score is used as a metric to treat-2-target. The RA-DAS semi-objectively measures how active RA is and allows rheumatologists to assess how effective their DMARDs (disease-modifying antirheumatic drugs) are at controlling RA. The RA-DAS has been instrumental the paradigm of treating-2-target that underpins what we are trying to copy and promote in MS.

Dr Leonora Fisniku, from Haywards Heath, argued for a new MS-DAS. She opened the debate by reviewing the treatment landscape and made the argument that because most of the inflammatory disease activity in MS occurs below the surface, i.e. the iceberg analogy, we need to use biomarkers (MRI) to quantify MS disease activity. She made a strong theoretical argument for a MS-DAS without actually defining what components should would include in her score. Dr Waqar Rashid, from Brighton, countered her argument with a pragmatic approach telling us to shy away from perfectionism and to use what we have already and what we have been trained to do in the clinic. He argued that there is no reason to reinvent the wheel and that we should simply use what we collect routinely in clinic to make an assessment of whether the patient is active or not. In other words the clinician's acumen. He stressed the difficulties we would face with having to validate a new MS-DAS and that it is unlikely to capture all aspects of the disease. Both debaters covered the EDSS and mentioned its failings, but neither were brave enough to confine it to history. I was surprised that the vote went against the MS-DAS. I suspect what won the day was that Dr Rashid managed to exploit neurologists fears of a new unvalidated MS-DAS consuming valuable clinic time and forcing neurologists to change the way they practice clinical neurology. Neurologists don’t like change; they have been examining the nervous system the same way for over 100 years, why change the way we do things with better tools? This debate generated a lot of discussion from the floor, a lot of which focused on a prognostic scoring systems rather than the issue at hand.

I am of the opinion that a new MS-DAS is essential; we need it to get wide adoption of the treat-2-target approach of NEDA. Its development would clearly need careful consideration and multi-stakeholder input if it had any chance of being adopted. I personally would argue for it to include a PROM (patient-related outcome measure). A PROM will at least get the individual with MS engaged with the process of monitoring their own disease activity. The latter aspect may be why the RA-DAS has been so successful as a change agent in the management of RA. As I have said before patient-engagement is a no-brainer and one of the most underused therapeutic interventions we have. A MS-DAS could also be used as a driver of quality. If your neurologist refused to use the MS-DAS you may be tempted to find another neurologist who did. Now wouldn’t that be something worth talking about? I am aware from comments on this blog that some of you have done this already and moved neurologists simply to get annual MRI scans.

The posters:

Although the posters were up for most of the meeting we had just over an hour to stand by the posters to field questions from the attendees. This caused me problems although I had three posters in a row the fourth poster was in another location so I had to split my time between the two locations. It was a pity because the data in all my posters was worth talking about. The isolated poster showed that disability improvement on alemtuzumab occurs across most functional systems of the EDSS and is not simply limited to one functional system. On reflections isn’t amazing that with the more effective DMTs we can now expect disability improvement? Interestingly, we are seeing disability improvement occurring in years 3 and 4 and not just in year 1 and 2 post-alemtuzumab. This challenges the dogma about recovery mechanisms in the central nervous system and finally buries the dogma that the EDSS progression is a one-way street. Disability improvement, or the promise of disability improvement, is in itself proof of how far we have come with the treatment of MS. For the cynics and nihilists out there ‘eat your hat’.





Another ground-shifting poster was the ORATORIO study results (ocrelizumab in PPMS). This study is the first study to show a DMT slowing the rate of disability progression in PPMS. This is has to be one of the most significant things to happen in the field of MS in the last 10 years. Despite this I am concerned that NICE may not view ocrelizumab as a treatment for PPMS very favourably. NICE always assesses cost-effectiveness using an incremental cost model. For PPMS the cost-effectiveness of ocrelizumab will be compared to what is out there already, i.e. best supportive care. The latter will cause problems because ocrelizumab will presumably be licensed for RRMS where the comparison will be with existing DMTs that are high-cost. So the cost per QALY for treating RRMS will command a higher price than that for PPMS. Will this be the opportunity for NICE to demand differential pricing? Will the NHS pay less for ocrelizumab in PPMS compared to RRMS? Differential pricing of this nature is called value-based pricing whereby healthcare payers pay for what they get. In reality this is the system that airlines use for booking flights and what Uber use in the APP with surge pricing. Why shouldn't we bring value-based, or surge, pricing to the field of MS? Comments; I am particularly interested to hear Pharma’s perspective on this.




I also presented two posters on daclizumab. One was on NEDA rates in the phase 3 study and the other the effectiveness of daclizumab in study subjects in the extension study of the phase 2b, SELECT-SELECTION, study, appropriately called the SELECTED study. Please note that although I sat on the steering committee of the SELECT and SELECTION studies I had nothing to do with their names. There is a whole field dedicated to the naming of clinical trials; if you get the acronym right the study develops a life of its own. Not unexpectedly in the phase 3 ??? study the chances of NEDA were higher on daclizumab than interferon-beta. In the extension, or SELECTED, study the relapse rate appeared to continue to go down, hinting that the efficacy of daclizumab may increase with time. We actually saw the evidence for the ramping up of efficacy in the original SELECT study on MRI. Despite the daclizumab efficacy data, I spent most of my time at the daclizumab posters enthusing over daclizumab’s mode of action or MOA. Dac’s MOA challenges the core immunological dogma around the pathogenesis of MS. As I have said many times before daclizumab is not an immunosuppressive drug and it works by subtly changing the IL2 (interleukin 2) signaling pathways diverting IL2 away from activated T cells and T-reg cells towards the CD56-bright NK cell population. The expansion of this latter cell population seems to be closely linked to Dac’s efficacy. What is more the number of T-reg cells go down; this contrary to what we have been told by immunologists that MS is a immune mediated disease that is linked to abnormally regulated T-cells. An interesting discussion will be where Dac fits into the current treatment paradigm; I have thoughts on this but this will be a discussion for another time. 







My ABN highlight:

The real highlight of the meeting was Prof. Compston’s ABN gold medal acceptance speech. It was about his medical life from the time he entered medical school up until the present and his current retirement plans writing historical books. He summarised his career as a neurologist covering his research into the genetics and treatment of MS, his time as an editor of Brain (one of the premier neurology journals, or argubly the premier neurology journal) and his legacy - a large number of his trainees now head-up neurology departments across the UK. He voice broke a few times during his talk as it was clearly very emotional speech. Getting to an end of such a glittering career and reflecting on it must be very nostalgic. I personally find nostalgia one of the most powerful of emotions; it is not necessarily a sad, or happy, emotion, but it somehow brings tears to my eyes. At the end of the talk he was given a standing ovation; the first time I have experienced this at an ABN gold medal ceremony.


Some reflections after the meeting:

Many times we the community are criticised for not making progress in MS research. The problem is we tend to look at what happens from year to year. When you look at it from Professor Compston’s perspective and take a 40-year view of the field you realise that so much has changed. It is simply quite incredible what has happened to MS in the last 40 years. We now have treatments that render MSers with NEDA, i.e. putting some of them into long-term remission with the promise of a cure in a proportion of them. With ocrelizumab we now have a DMT that has been shown to be effective in PPMS. We have refined our diagnostic criteria and are better at excluding MS mimics from being inappropriately diagnosed as having MS. We know so much more about the causal pathway of MS and are beginning to use this knowledge to discuss and design MS prevention studies. Are there really some humbugs out there who still think we have made so little progress in MS research? If there are I suggest they take a 40 year helicopter view of the field rather than a very short-sighted one, or two, year view of the field. Another option who be to spend an afternoon discussing MS research with Professor Compston.

CoI: multiple

59 comments:

  1. Re: annual cognition testing

    My cognition can be variable and dependent on many factors such as time of day, if I have eaten enough or not, if I am hydrated, if I am stressed, if I am anxious, if I am sleep deprived, if I have an infection or still recovering from one, if I consume caffeine, if I have had some exercise such as a walk.

    I know my cognition is best first thing in the morning. So if I was to have an annual cognition test at 9am after a good nights sleep, sufficient breakfast, no stress or anxiety, well hydrated and after a walk I am sure my results would be better than after a big lunch or at 3pm in the afternoon, feeling dehydrated and sitting around waiting for some time. All things for me to keep in mind daily.

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    1. To add to these factors pain can cause cognitive issues as the pain takes away ability to focus on other things. Then there is drug induced cognitive impairment linked to some pain killers such as opiates. Other drugs such as benzodiazepines, tricyclic antidepressants and anticonvulsants.

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    2. I agree; I know my cognitive ability is variable, as you say, and my neurologist is often disinterested in my reports of the variability and the effects on my day to day life. Testing would at least validate the changes that I know are occurring, and possibly help focus on the strategies that are available to help cope, even if many of them are impractical for the requirements of my daily life.

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  2. Many thanks for your feedback on the conference. While I agree that MS research has made some huge strides over the past 40 years (I am in long term remission from Alemtuzumab), i think more progress could have and should have been made. The unbeliveable changes in technology should have seen bigger and more frequent breakthroughs and advances in MS research. A key reason for the slow progress has been the inability to turn many research breakthroughs into available treatment (I know you will blame the cost of trials etc). I've lost count of the research which identifies potential repair therapies (Prof Scolding, Profs Ffrench Constant and Franklin) and potential treatments for neuroprotection (Prof Kapoor, Dr Chattaway). And then we enter the black hole phase of MS research - things disappear and are never seen again. Your take on MS research is from a researcher's perspective. I imagine that a 65 year old woman diagnosed in 1985 and now using an electric wheelchair would have a different / personal perspective on the progress made.

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    1. MSers should try and imaging what it is like from the perspective of someone with motor neurone disease or ALS, Parkinson's disease, Alzheimer's, etc. MS is way ahead of the other neurodegenerative diseases; we should celebrate successes and not complain about slow progress.

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    2. i believe it's appropriate to both celebrate successes and know what a long way there is still to go. it can even be done in the same breath and the two are not mutually exclusive. it's possible for progress to be both fast and slow at the same time, depending on the perspective

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    3. Celebrate. Tom Williams a young neurologist in the won the ABN poster prize for the work associated with VSN16R.

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    4. It's been said that MS research has made gains at a rate of 3:1 over other chronic diseases including cancer and a good deal of this has been due to the patient associations.

      That all said researchers getting access to state of the art technologies represents a significant wall towards better understanding the complexities of CNS function, immune function and malfunctions thereof.

      In my community Rochester NY there is some state of the art equipment. For example last year in research they discovered keys to immune response towards injuries and more. Essentially similar to ants that leave a pheromone trail for other ants to follow (they pee!).

      Our immune system "first responders" also leave a trail for immune cells to follow. It takes time to muster all this to bare. Now imagine if an early cancer diagnosis, infection perhaps and one can create that trail resulting in a much faster response. The full weight of the immune system which is an amazingly powerful machine can be brought to bare post haste before tumor cells get a real opportunity to take hold.

      This sort of equipment costs big money and the universities need get it paid for on often a pay to play basis.

      In my foray into all of this which began some 9 months back... I am just completely astonished by all the complexity, how all these various systems work, the amounts of money and the incredible dedication and minds that work on all of this stuff.

      Now I dont know about celebrating success but I am truly grateful for both the dedication and brilliance that is at hand in understanding the complex machine that is the human being.

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    5. "Celebrate. Tom Williams a young neurologist in the won the ABN poster prize for the work associated with VSN16R."

      Yay, nice one Tom!

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    6. You celebrate the progress that has made into DMTs for MS. Some of these even produce a 'cure'. This is almost exclusively for RRMS. There are a huge number suffering from SPMS, what progress has been made to help them over the last 40 years? None has been made as far as I can see

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    7. Yes some of us have had MS for 40 years, but there was nothing other than ACTH. We had to get on with our lives and not wait around for DMTs and treatments. The MRI scanners were still being researched for MS. We have come a long way since the seventies, too late for me, but knowing so much research is being done is comforting. Forty years ago more people died of cancer. Rome wasn't built in a day.

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  3. What a fascinating read. Thank you so much!

    My "fly" on all of this:

    1. Towards cognition testing, yes. The argument that nothing can be done about cognitive impairment is simple incorrect. I am living proof. While little exists in the way of approved mechanisms by the medical community / insurers at large research does show gains can be made. Cognitive behavioral therapy (CBT) has undergone research and showed many patients do experience gains and came from stroke therapy. Strategy video gaming has shown gains in research towards cognition but we are not going to see broadband clinical trials on this. I dont imagine insurer's are going to pay for a new computer capable of playing Simcity Mars or Civilization 6.

    All fun aside, self-assessing cognitive and even memory loss is difficult and whilst therapies such as CBT, Gaming, Music therapies have anecdotal forms of results we might say the same of DMT's. Strategy gaming has helped my cognition, no donuts about it. I can tell. For others it may not. Interferon works for some, not for others. So we should just scrap assessments? Many of the DMD's in fact most are a "We think it works by ____". Cognition is about brain-gain is about neuroplasticity. We know this exists in healthy people, MSer's and stroke to name a few. By this method of thought stroke patients who experience cognitive and memory damage should just not engage therapy.

    How come stroke seems to be further ahead of the cognitive / memory (and then some) curve .vs. MS. Could it be that MS deficits are not often as "Bam.... welcome to brain damage?" and as such, let just keep money out of this one?

    Whilst the "systems" may not be able to prescribe approved therapies if a person who endures MS is monitored and aware of loss perhaps they take it as "time to try do something about it".... Like what? Well apparently if MS patients have a stroke they can get access to cognitive and memory oriented therapies.

    Oye.

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  4. 2. Towards DAS again, yes. Again, no secrets here. The better the assessment the more options become available to try and locate best long term outcomes, quality of life, fostering need of perhaps more granular research aspects in whole.

    Here we are in an era when we send automaton's to other planets. We have phones that have more power than that which put men on the moon. We have mapped the human genome. We have found and research cells that can turn into any types of other cells. But when it comes to MS?

    Where do you fit on this scant point disability scale based on really really scant criteria? Can you do the peg test? Lets see if you can walk 25 feet?

    Mice in research get a better assessment than the human being who endures the disease. I dont know how you do cognitive/memory assessment in mice? The cheese maze? Thats more advanced than a peg test. If a person has physical tremors, motor function matters can see it. No peg test needed. For cognition? No. A game of yahtzee is more telling or better yet... As I recall children do go to school, they go through different grades of school. They are presented information they cognitively learn and hopefully retain.

    Math problems both numeric and logic. Cynthia has twelve lesions in three MS flare ups that occurred over nine years. She took Tecfidera and had two more relapses and 4 new lesions appeared and two existing lesions we impacted over 4 years. How many lesions does she have over how many years? Given 8 more years time at the same rate how many lesions will she have at year 8?

    "Here are twelve words, please write 6 sentences using only these 12 words"

    "Thes santance has splelling erors in it. Pleze correct awl erors in the santance"

    "Here are the names of all the planets in the solar system, please review them for one minute.... Now write them back down on paper. Please try represent their sizes, position to the sun".

    Not to be too ghastly about all this... The MS assessments appear to be from a very different century and I dont mean the last one.

    Sure sure... Time is money. Right on the money.

    That is to say, time spent properly assessing and attempting help people is money. At the sametime neglecting it results in more money later down the road whilst also perhaps poorer quality of life and poorer long term outcomes.

    Pay me now or pay me later?

    Oye Vey

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  5. Is prof Compston ok? I thought he had cancer? What a true legend

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    1. On the mend hopefully and thanks to the NHS. Fingers crossed.

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    2. BTW please use a name or a pseudonym if you want to keep your identity secret) when posting a comment in future, many others are now doing so and it's more likely your comments will be uploaded.
      Thanks!

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  6. Daclizumab vs Alemtuzumab? Given that the secondary AI diseases associated with Alemtuzumab respond to timely treatment, why would anyone choose Daclizumab when statistically Alemtuzumab offers a greater chance of achieving NEDA?

    Does it not pose the same secondary malignancy risks since it does not utilise an immunosuppressive MOA?

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    1. Please refer to my comment above regarding anonymous comments.

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  7. What does this mean for PPMS sufferers? If we've had the disease for years and are wheelchair users, would we still qualify for the drug? Are we too far gone?

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  8. many thanks for this conference update, it the sort of article I really want to read and I can't get this information elsewhere.
    NB. I note the 6am posting. PwMS are constantly told to pace ourselves, can we offer our neurologists the same advice?

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    1. Scheduled posting! Be more concerned when it's 4:37:36, then it's more likely from the hip:-)

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    2. Ain't that the truth ;-) though there were mitigating circumstances.

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  9. Do the pod-casts add anything to this type of post?

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    1. I like it, though it could be jazzed up a bit and made livelier. Perhaps you could do podcasts debates on things happening with others in Team G. You can discuss MS research and political issues affecting MSers. You can even invite students and researchers. It'd be grand because there is nothing out there like that.

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    2. I listened to the podcasts and found them interesting. It is hard to read the posters even with zooming in.

      The podcast does indeed add valued information to the subject matter.

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    3. No not really. Just repeating facts already stated in the article. Now if it was a longer discussion, it would be more valuable

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    4. No. Can we get prof Compston to do a guest post? Would love to hear this lecture

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    5. Re: "It is hard to read the posters even with zooming in."

      If you open the posters in SlideShare you can download them to read more clearly.

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    6. Yes the podcast is less exhausting to listen then to read for pwMS. Thank you.

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    7. Information wise, it doesn't. But as a french guy who loves the english accent (My GF and I just started watching the Downton Abbey TV series, and love it), it's a pleasure to listen to those casts ;)
      If it is not too time consumming, I wish you could keep posting some

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    8. We love the French accent over here. Let's hope the UK is still in the EU on June 24th!

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  10. “… take a 40 year helicopter view of the field ...”

    As a pwMS since 1973, I have already taken that helicopter ride, and I can attest that so much has changed, the field of MS treatment seems unrecognizable. I was, by the way, being treated then by top university neurologists in New York and Chicago. Some highlights of the MS landscape then were:

    • DMTs, as they are currently offered, did not exist. It was steroids, ACTH or bust.

    • MRIs were not yet in general use. Lumbar punctures and clinical observations were pretty much it.

    • The advisability of optimizing healthy diet and exercise were not granted much credibility.

    • The brain, once damaged, was believed to be irreparable.

    • An MS diagnosis was, in effect, a death sentence.

    • Most importantly, the internet did not exist. I cannot over-emphasize how transformative the internet has been. It has had an enormously positive impact on a pwMS’s quality of life, social and physical well-being, information availability, support and, not least, health delivery. This blog, for example, would not have existed, and all MS communities, whether patient, research or treatment, would have been much poorer for its absence.

    So much has changed, indeed, that I am certain I have forgotten something because the current landscape has allowed me to forget. I thank all the remarkable researchers who, believing there could be progress, remained dedicated to finding solutions, however incomplete they may have felt at the time (and still are). And, thank you, the Barts team, for creating this unique blog, an outstanding medium for facilitating future progress for patients, their communities, and those engaged in treatment and research.

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  11. Daclizumab vs Alemtuzumab? Given that the secondary AI diseases associated with Alemtuzumab respond to timely treatment, why would anyone choose Daclizumab when statistically Alemtuzumab offers a greater chance of achieving NEDA?

    Does it not pose the same secondary malignancy risks since it does not utilise an immunosuppressive MOA?

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    1. Re: "Daclizumab vs Alemtuzumab?"

      I will need to do a special pod-cast or post on this. What would you prefer?

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    2. I'd prefer post :) Much appreciated.

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    3. I'm interested.

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    4. When I'm at home, I like to read the articles, but when I'm on the go, and that's not practical, I'm already diggin' the new podcasts! My phone's screen is too small for my reading anymore (eyeballs aren't what they used to be), and the bouncing around on the bus makes that harder. At times like that, it's nice to just listen in. But I'll be happy with whatever is easiest for you guys. Either way, I'll make it work!

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  12. Is MSARD the top ms journal? Will you get this award soon g?

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    1. No MSARD is what we call a tier two journal. At present the top MS journal is the 'Multiple Sclerosis Journal', however, I predict MSARDS will overtake it in a few years time.

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  13. Thank you for updating, these are my favorite posts on this blog.

    I have many questions about the alemtuzumab poster, as I am mid-alemtuzumab treatment.

    1. Are you continuing in the ten year study?

    2. What kind of functional improvements are you seeing in yr 3/4? Is this including retreated patients or just in those who are 2-years and done? How does the improvement show, does it slow down indicating people are relearning or retraining their CNS the hard way, or is it fast, like the body is contributing repair?

    3. In the audio, you highlight that brainstem and bladder function doesn't seem to recover as well/very much at all. Any theory why? Are these patients less likely to get to NEDA?

    4. I had a lot of questions about the dropoff rate in the ten years study from Wales. Can you give any sense why, since most people who needed retreatment in this study went on for a third round? Is this more because of patient satisfaction with alemtuzumab or because there's very little to escalate to at the moment?

    As a patient, I am of course hoping to achieve NEDA but I'm worried my heavy brainstem leisons mean that I'll be less of a responder. There seems to be a real lack of information about what you should do AFTER alemtuzumab, maybe because no one was expecting to see improvements, and I'm hoping someone will work on a best practices for the recovery.

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  14. Cladribine or Alemtumab: How do they compare in efficacy and potential side effects?

    This isn't an academic question. Alemtuzumab would require me to sink a big chunk of my savings (not easy in late middle age). Cladribine would require me to convince the neurologist. Or maybe find a new doctor who is willing to prescribe the oncology drug off-label

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    1. Anon 3:54: I'm no doctor, but if I had to hazard a guess, it would be that they'd recommend Cladribine. It's easier to apply, is also an induction treatment, it has little to no serious side effects (including none of the AI issues that Alem has), and a similar malignancy profile. About the only real 'bad' thing that it does is permanently depress your immune system, though the amount by which it does so is very little for most people. It would also likely be much cheaper. Something that you indicated as important in your post above.

      You said that you're in late middle age. You understand that neither of these two treatments are likely to help much if you're progressive, correct?

      Remember - I'm no doctor. If they don't respond to your question, I'd recommend that you find a neuro who's willing to consider both choices.

      Best of luck to you!

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    2. Thank you so much Unonymous (Anon 3.54 again, I picked a moniker)

      I don't think I'm progressive. The MS revealed itself quite recently (maybe linked to menopause). My symptoms have been very minor and most cleared quite soon. But I may be in my first proper relapse at the moment.


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    3. UnonymousFriday, May 27, 2016 6:47:00 pm

      "You understand that neither of these two treatments are likely to help much if you're progressive, correct?"

      This is an unresolved question, certainly for Cladribine. The trial by Rice, et al. (Cladribine and progressive MS. Clinical and MRI outcomes of a multicenter controlled trial. Neurology 2000;54:1145–55.) was too short - 1 year - to be conclusive on clinical endpoints, however was positive on MRI outcome. Unlike monoclonal antibodies, Cladribine is not CNS excluded. We therefore believe that "if" the inflammation one can see on pathology in advanced MS is relevant for disease progression (and I cannot see why it should be beneficial), then there is clearly a rationale to test whether Cladribine works in advanced MS. We are working on a respective trial design, but it is quite tedious getting this off the ground in the current funding climate, where you are often asked to provide data before submitting an application to produce data (dog chasing tail scenario). We’ll keep pushing forward with this regardless!

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    4. Please explain something about what makes cladribine an induction treatment

      Prof G once said that alemtuzumab 'reboots' the immune system. What does cladribine do?

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    5. It does the same thing but unlike alemtuzumab it does not cause secondary autoimmunities. You give the drug for a few days and then the same again for one year then if no disease you do nothing but monitor progress.

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    6. Dr. Schmierer:

      Thank you for the correction. I'm actually a big fan of what you're doing with Clad, and I genuinely hope that you get your funding!

      You mentioned that "if the inflammation one can see on pathology in advanced MS is relevant for disease progression, then there is clearly a rational to test Clad".

      Isn't the hallmark of advanced/progressive MS the fact that there's either very little, or no inflammation at all? If progressives tend to have fewer lesions - or no lesions - on successive annual MRI's, wouldn't that rule most of them out for benefit from Cladribine?

      I want to believe in Clad for the progressive types (if anyone needs a break, it's them), but I'm not sure that I see the mechanism by which it will help them very much if there isn't a lot of inflammation. (Not knocking Clad for RR types, however. For those folks, it may be the best choice of all)

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    7. UnonymousTuesday, May 31, 2016 4:26:00 am

      I realise I have to write a post on this topic, which has several facets including, among others, B/T cell clusters and 'smouldering' lesions described in post mortem MS brains, meningeal inflammation (potentially detectable with more recent MRI & PET techniques), and the realisation that the classification of MS into (i) relapsing = inflammatory lesions, and (ii) progressive = no inflammation but degenerative mechanisms, is too simplistic. For example, one of my patients participating in INFORMS (Fingolimod in PPMS) literally fell 'off the cliff' (EDSS 6.5 > 8) about 3 months after the drug was stopped following the overall negative trial outcome. MRI showed >30 Gd-enhancing lesions whilst on drug about one year earlier there were none. This case illustrates how 'inflammatory' PPMS can be. Am currently marking a BSc thesis, and there’s plenty more on the plate of my day job, but once I’ve finished I’ll draft a post...

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    8. Such confusion...most advice is HSTC won't help any progressive MS but some patients say if you have low EDSS you have better chance of stopping progression with HSTC.

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    9. Dr Schmierer,

      When you have the time, please also try to do a post comparing alemtuzumab with sub-cutaneous cladribine

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    10. Annualized relapse rates about 0.1-0.15 in both; gadolium lesion reduction about the same NEDA at 2 year about 40% Alem and 45% CLAD. CNS excluded verses CNS penetrant; administration in hospital verses hospitalisation not necessary. CNS PML very low both, secondary autoimmunity about 50% ALEM verses 0% CLAD, cost for 2years about £80,000 for drug plus much more such as monitoring and side effect management verses abut £1000-1500. Monitoring once a month for 4 years or get on with your life.

      But Licenced for MS verses everything possible stacked against it being available, with little support by establishment.

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    11. Dr. Schmierer:

      I appreciate the follow-up post. Sounds like you're up to your eyeballs in work over there. No rush on the Clad post, but when you do have a little time, that sounds like a very interesting/informative read. Obviously, your folks' opinion on this topic carries quite a bit more weight with many of us than most of the opinions that we tend to get around the web.

      At this point I don't know who's busier - you with all this paperwork, Dr. G, who probably has more frequent flier miles than the entire population of France, or MD, with his relentless efforts to teach mice calculus.

      Thank you all, for all that you do!

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  15. The current May MS Journal the article titled A useful annual review of cognition in relapsing MS is beyond most neurologists - Yes.
    Discusses BICAMS in more detail.
    I wonder about pwMS on higher doses of baclofen and it's possible impact on cognitive performance.

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    1. Yes, Baclofen, particularly at higher doses will have a likely negative impact on cognition ie the dreaded brain fog.

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  16. I fail to understand the amount of enthusiasm for Ocrelizumab in the treatment of PPMS. The trial was loaded with patients who were prescreened to be very likely to respond, based on the much earlier Rituxamab PPMS trials. Of course, the Rituxamab trials were deemed a failure, but later sifting through the results revealed a population of primary progressive patients who did seem to respond, namely those who were younger, less disabled, and more likely to display enhancing lesions.

    While it's encouraging that such a subpopulation was identified, only about 15% of PPMS patients display enhancing lesions, and the higher proportion of such patients included in the Ocrelizumab study does not reflect a true sample of the PPMS population at large. Why should we expect Ocrelizumab to be any more successful treating the majority of PPMS folks who don't have enhancing lesions and who are suffering from more progressed disease than those who "failed" in the Rituxamab trial. After all, the two drugs share a nearly identical mechanism of action, targeting CD20 cells. In fact, Rituxamab seems to be the much more benign drug, with a very robust safety profile built over decades of use, while Ocrelizumab trials in lupus and rheumatoid arthritis were halted because of patient deaths. The MS trials were only allowed to proceed because it was perceived that MS patients had a high tolerance for risk.

    Let's not forget, also, that the only reason Ocrelizumab was developed was because Rituxamab was due to go off patent in 2015, meaning Genentech wouldn't stand to reap the tremendous profits it now expect to gain given a probable FDA approval of Ocrelizumab for PPMS and an almost definite approval for RRMS. Call me a cynic, but to me this borders on the scandalous. A perfect example of the unholy marriage of medicine and the profit motive.

    So, to sum up, why the level of excitement over Ocrelizumab for PPMS when the drug probably won't be very useful in treating the majority of PPMS patients? Though the Ocrelizumab study hinted at an effect for patients without enhancing lesions, the study was underpowered in this regard so no real conclusions can be drawn. Judging by the Rituxamab results, though, it seems clear that nonenhancing patients will likely see little or no benefit. And why not prescribe Rituxamab over Ocrelizumab, given that the two drugs share an identical mechanism of action and Rituxamab would seem to have a much higher safety profile?

    Honestly, not trying to cause trouble or do any "trolling", just would love to get some honest answers. BTW, my own neurologist, a well-known MS researcher himself, tends to agree with me on all of these points. Just trying to get another perspective…

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    1. You need to read my length-dependent axonopathy hypothesis. It predicts that it simply takes longer to see the effects in progressive MSers. Therefore the effects of ocrelizumab are likely to get better with time. I will repost on this.

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    2. Thanks for the reply, Dr. G. I do understand that many of the studies on progressive MS have not been of long enough duration to detect positive effect, but I don't understand why immunosuppressive agents that work on the peripheral nervous system would be of value in progressive MS when it appears that in the vast majority of patients the peripheral immune system plays little if any part in driving disease progression.

      Certainly, especially in patients with SPMS, tertiary lymphatic tissues within the CNS could very well be playing a significant role in driving progression, but we've no evidence that agents that suppress peripheral immune cells have any effect on immune activity compartmentalized within the CNS. Certainly, the recently failed intrathecal Rituxan trials would argue that an agent like Ocrelizumab, even given intrathecally, would not disrupt immune activity contained solely within the CNS.

      Again, I can understand how Ocrelizumab and rituximab could be effective in PPMS patients with evidence of peripheral immune cell infiltration (enhancing lesions), but find it hard to envision a mechanism of action which would dampen disease progression not directly caused by the action of peripheral B cells.

      I hope you don't find my comments to be endlessly argumentative, as I said previously, just trying to gain some clarity on the issue.

      On a completely different note (and please feel free to edit this part of the comment out when/if you decide to publish it) is it possible to communicate with you via email? I have some questions on some very interesting test results I recently received on my own very atypical case of neurodegenerative disease, involving the presence of areas of hot microglia infiltration in the CNS tissues of mice injected with my CSF. This, despite the fact that the mice did not seem to develop lesions, as was seen in other mice injected with the CSF of typical PPMS patients (I've long been labeled "atypical PPMS"). I know that there have been many posts on this blog regarding the role of microglia in MS disease progression, and was wondering if you had any thoughts on how this process might be disrupted. You can contact me at wheelchairkamikaze@Gmail.com. I would tremendously appreciate any input you might have on this matter, and would be happy to provide you with further details of this rather interesting research project in which I was involved. Again, please feel free to edit this last paragraph out of the response you publish for the general audience. I also understand if you decline any personal interactions, as I do realize you are already burdened with numerous responsibilities.

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    3. I share you sceptisism concerning anti B cell in PPMS based on the published results, ProfG is a glass half full person.

      Sure you can send me some questions offlinewe have put CSF/Ab into mice.

      many thought of how to block microglia

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    4. Hi MD, I've been putting together an email to send to you regarding my test results, but can't find an email address to send it to. Should I just send it to Dr. G, or can you supply an email address? You can reply to me directly at wheelchairkamikaze@Gmail.com.

      Thanks…M.D.,

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