ClinicSpeak: explaining the theory behind progressive MS

A new infographic to explain progressive MS. #ClinicSpeak #MSBlog #MSResearch

“Some readers  have taken to asking me questions by email; I would prefer it if you asked via the comments box. You may have noticed I am very poor at responding to emails; I get too many. However, I will give this one a go. This post is in response to the following question.”

Ocrelizumab in relapsing MS results; very good efficacy with a very favourable safety profile. Ocrelizumab will allow us to flip the pyramid and use highly effective treatments very early in the disease in the majority of MSers. However, my initial enthusiasm for ocrelizumab has been dampened by Steve Hauser’s comments that a large number of their patients with relapsing MS who have been treated for 10+ years on rituximab have now developed SPMS. If this is correct then anti-CD20 B-cell depletion will not be a panacea.” 

Question: Can you elaborate a bit more about this issue in your blog, it would be most appreciated by your readers, including me?

“People with MS and those of us who treat the disease want a cure. However, we may have a cure in hand and yet we don’t reverse or prevent progressive disease. How can this be? I have tried to capture all the issues in this infographic; it is a work in progress so if you don’t understand it please let me know and I will adapt it.”

“Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or it can damage nerves and leave them functioning, but the resulting damage primes them to die off in the future; so called delayed neurodegeneration. The mechanisms that result in delayed neurodegeneration of nerves are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals, premature ageing, etc. Clearly anti-inflammatory drugs that prevent new lesions formation, such as ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that has damaged many nerve fibres, even if you go onto a highly effective DMT such as ocrelizumab, that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future.”

“What protects you from entering the clinically-apparent secondary progressive phase of the disease is reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I therefore suspect that those patients of Steve Hauser, who have been treated with rituximab and have now become secondary progressive, had a low reserve capacity and a large number of damage nerve fibres that had been primed to die off in the future. In other words they were treated with rituximab too late to prevent SPMS.”

“Please note that Steve Hauser’s observations, and the above theoretical explanation, are not new and have been noted with with other high efficacy DMTs, i.e. mitoxantrone, HSCT, natalizumab and alemtuzumab. There are two conclusions to be drawn from the above observations and theory; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, or (2) we need additional add-on neuroprotective therapies to target the delayed neurodegenerative processes referred to above. The latter includes avoiding or reversing factors that prematurely age the nervous system. The latter is what underpins our Brain Health campaign.”

“So unless you get treated with ocrelizumab, or another high efficacy DMT, early in the course of your disease it may not prevent you entering the progressive phase of the disease, i.e. it will not be a panacea.”

“There is one caveat to the last paragraph. There is an alternative hypothesis that the progressive phase of MS is driven by antibodies produced within the central nervous system. Although ocrelizumab targets B cells it doesn’t target long-lived plasma cells within the brain and spinal cord of MSers. None of the current crop of DMTs has been convincingly shown to target the so called intrathecal plasma cells. In fact plasma cells are very difficult to target biologically, particularly within the CNS. Please watch this space; I suspect there is going to be a flurry of activity around plasma cell targeting as a potential treatment for MS. I did mention in my talk at ECTRIMS that there are some reports that MSers on long-term natalizumab seem to lose  their OCBs (oligoclonal bands or antibody bands); it now emerges that plasma cells live in a ‘niche’ or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this is the case natalizumab may have the edge on the other DMTs in this regard. However, the data on natalizumab and OCBs needs confirming and to be studied in more detail. Already a German consortium of investigators’ have not confirmed the earlier reports.”

“Finally, those of you interested in animal models will find the two studies below of interest. They try and model the early and late effects of inflammation in driving neurodegeneration. In other words there is animal data to support the delayed neurodegeneration theory; it is not simply a thumb suck.”

Animal model 1: Mindur et al. Early treatment with anti-VLA-4 mAb can prevent the infiltration and/or development of pathogenic CD11b+CD4+ T cells in the CNS during progressive EAE. PLoS One. 2014 Jun 4;9(6):e99068. doi: 10.1371/journal.pone.0099068.

Background: Natalizumab is a humanized monoclonal antibody against the leukocyte adhesion molecule very late antigen (VLA)-4, and is currently an approved therapy for patients with relapsing-remitting multiple sclerosis (RRMS). However, it is unknown whether natalizumab is beneficial for progressive forms of MS.

Objectives & Methods: Therefore, we assessed the effects of anti-VLA-4 monoclonal antibody (mAb) therapy in a progressive experimental autoimmune encephalomyelitis (EAE) mouse model. 

Results: Notably, we found that early therapy could significantly reduce the severity of progressive EAE, while treatment initiated at an advanced stage was less efficient. Furthermore, we observed the accumulation of a novel subset of GM-CSF-producing CD11b+CD4+ T cells in the CNS throughout disease progression. Importantly, early therapeutic anti-VLA-4 mAb treatment suppressed the accumulation of these GM-CSF-producing CD11b+CD4+ T cells in the CNS along with activated microglia/macrophages populations, and also conferred a protective effect against inflammation-mediated neurodegeneration, including demyelination and axonal loss. 

Conclusion: Collectively, our data suggest that early treatment with anti-VLA-4 mAb can provide neuroprotection against progressive CNS autoimmune disease by preventing the accumulation of pathogenic GM-CSF-producing CD11b+CD4+ T cells in the CNS.

Animal model 2: Hampton et al. Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis. Acta Neuropathol Commun. 2013 Dec 23;1:84. doi: 10.1186/2051-5960-1-84.

BACKGOUND: Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration.

OBJECTIVES: To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.

RESULTS: By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.

CONCLUSIONS: These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis.

CoI: multiple

83 thoughts on “ClinicSpeak: explaining the theory behind progressive MS”

  1. Thank you, once again, for taking the time to dwell on this difficult topic. "but the resulting damage primes them to die off in the future"From your clinical experience with highly active RRMSers on a high efficacy DMD early on post diagnosis: what is the delayed neurodegeneration time lag or how long would it take for the damaged nerves to die-off post NEDA-3 ?And would you envisage a plateau after this event?With my regards,Tony Fonda

    1. I am interested in this answer too, i have seen suggestions that it is anywhere between 2 and 4 years.

    2. Re: "And would you envisage a plateau after this event?"If a plateau occurs within the zone where you have reserve then you would expect MSers to flatline or improve; this is what we see. If you have lost reserve and outside the window then we see continued progression and possibly a delay in reaching a plateau. There is a hint that this occurs in RRMS, but we don't have the data yet from progressive MS as we have not had a licensed therapy for the disease with long-term follow-up.

  2. Prof G, do you regard the total absence of licensed medicines for progressive MS to be the single biggest failure of modern research?You get the sense from this post that those with progressive MS are seriously screwed.

    1. interesting you are singling out MS in your question…how about the 000s other diseases?No failure whatsoever – progress takes time

    2. Re: "You get the sense from this post that those with progressive MS are seriously screwed."Not all we now know how to do trials, which is why we are planning a trial in progressive MSers in wheelchairs. Watch this space; DrK is leading on the design.

  3. I thought at some points when reading this publication, points these that mostly the Team G has already been emphasizing for some time: 1) education and awareness of neuros compared to early treatment with highly effective DMTs from the start of MS ; 2) The need for neuroprotection, while the Big Pharma does not wake up to this will not have an effective treatment for MS, especially the progressive forms. If Big Pharma wants those who have RRMS eg still continue to use Interferons and/ or Glatiramer she has to act in pursuit of a joint processing aimed at neuroprotection; 3) the need for an effective vaccine or drug against JC Virus to "bring peace" to neuros so that they prescribe for example Natalizumab from the initial course of MS. That's what I hear from many neuros "Natalizumab is a very effective drug is very dangerous but also risk Lemp"; 5) Cladribine is approved for use in treatment of MS since the beginning …

  4. If "Steve Hauser's observations and the theoretical explanation are not new and have been noted with with other high efficacy DMTs" then why did they dampen your enthusiasm for Ocrelizumab?

  5. "they were treated with rituximab too late to prevent SPMS"How confident are you that early treatment will prevent SPMS?And how late is "too late" ?

    1. Re: "How confident are you that early treatment will prevent SPMS? And how late is "too late" ?"Confident; please read: too late; it depends on which system you are referring to. I call this the asynchrnous progressive MS hypothesis. Even if you are in wheelchair we should try and prevent loss of upper limb and bulbar (swallowing and speech) function.

  6. What I would like to hear is what happens in Transverse Myelitis cases – is there evidence that after the inflammatory moment there is a slow burn progression? And if not, then is there a different in the spinal fluid between TM and CIS?

    1. Re: What I…. happens in Transverse Myelitis cases …"Wonderful question; in NMO cases there is no secondary progression and they don't have OCBs. But you could also argue there is no multiple hits along the pathway in TM/NMO, before and after the sentinel TM event. So using TM as an argument against the hypothesis works and it doesn't work.

    2. Is it also possible that NMO inflammatory events simply cause more complete nerve death than MS inflammatory events? There is greater acute disability, and less recovery, following NMO relapses. This suggests that there may be more complete destruction of nerves during NMO relapses, and therefore less room for secondary neurodegeneration: the nerves that would later die during MS progression, are already dead following an NMO relapse.

  7. I was diagnosed with PPMS which became noticeable for the first time in my early twenties. But nothing much happened for a decade or so after that. Or so it seemed. And little things that I recall suggest to me now that MS was very possibly active in my body during my teens already. But there were no symptoms to warrant investigation. I do wonder how early MS activity might begin typically, even in PPMS, how it might be detected in future, and when therapies will begin. In an ideal world. At any rate, I am very thankful for researchers like Prof. Giovannoni who do not write off people with progressive MS, who seek therapies for those that have dealt with MS for a long time already. Perhaps longer than they realise.

  8. The one thing that I don't understand about these hypothesis is why we can't answer these questions. Alemtuzumab has been in trails since the early 2000's and so there is minimum 15 year data, Natalizumab as was approved in 2004 which means there will be trial data going back 15 years or more. Surely it can't be too difficult with the various extension trails or neuro personal experiences to answer a) percentage by year of how long people were relapse free (or NEDA) and how many people now have progressive disease. My gut feeling is that the drug companies don't complete or publish data on such long term follow ups because they just aren't positive. If any drug company could even publish that their drug was still suppressing/treating PwMS 15/20 years on (I.e x% were still NEDA) why wouldn't they?? (You could then extrapolate 'benign MS' vs drug success)I have spoken to 3 separate neuros who have all send that none of the current drugs stop RRMS progressing eventually, they may slow it down. Which is based on their own experiences. Do any neuros have any better stories to tell 15/20 years on?

    1. I am beginning to sound like a stuck gramaphone: problem with extension studies is selective drop-out and enrichment for responders; all extension studies show what you want them to show. I have been in the field of MS long enough now to see the transformation high-efficacy therapies have to done to RRMS. The challenge is what to do in MSers who have missed the boat.

    2. Sorry Prof G, I don't see an answer to the above. In fact, just more questions..1) this is 7 year data. You yourself say average progression to SPMS is 10 years, the NHS website says 15. So still no answer on whether it reduces or slows progression to SPMS. (Unless it is written in the full paper)2) I also find it interesting that you say extension studies show what you want them to show? How is that different to the initial study? Pick patients that are most likely to respond etc etc..So can you answer this question. What RRMS patient have you seen with the longest period of NEDA for Natalizumab and Alemtuzumab? Can you claim 15 or 20 year NEDA? As that would be deemed as impressive in my book…

  9. Thank you very much for this post. This blog has been an important part of my therapy. I feel like I know more about the disease and the understand the mechanisms of the treatments used for it, and that has helped me come to terms with my disease. I am able to have a more intelligent conversation with my neurologist and be an advocate for my health.

  10. Could you please explain your thoughts on 'over-treating'? There is a large population of patients who have definite ms but who have mild disease (according to low MRI lesion load & low EDSS).Should such patients be trying CRAB drugs or the oral therapies? Surely receiving a highly effective therapy at such an early stage can equate to a cure for a large percentage of these patients. But in doing this are we assigning unacceptable & potentially unnecessary risks to such patients, who could potentially continue to have mild disease on a safer drug?

    1. This thinking will be soon be outdated hopefully once very safe highly effectives drugs make it to the market (Ocreluzimab) 🙂

    2. the Team G approach to have everyone on the most (highly) effective therapy of their choice is laudable.Fixed that for you 😉

    3. Not sure where you get this message from! Our approach is about having a choice. Alemtuzumab is simply too risky for some people and not all MSers would be eligible for alemtuzumab. You have to have active MS to be eligible for a DMT, which excludes a large number or MSers. Then there are large number or MSers who are NEDA on platform therapies, why would we change their treatment?

    4. The message Team G is sending is that since you don't know how well you will do on the less effective therapies, it would be ideal to have everyone on one of your highly effective therapies.You have ranted time and time again that time is brain, so unless you use the most potent immunosuppressive agent, you cannot guarantee how you will don on a different therapy.You've painted yourselves in this corner so you have to own it.

    5. Re: "You have ranted time and time again that time is brain, so unless you use the most potent immunosuppressive agent, you cannot guarantee how you will don on a different therapy."Time is brain only if the shredder is on; some MSers turn out to have benign disease. This is why you have to be monitored. It is very difficult to call a prognosis up front; even if you tick all the good prognostic boxes you could still become disabled. This is why try and monitor our patients; however, there are some patients who choose not to be monitored and there are those who select to stay on treatment x despite having ongoing disease activity, because they are satisfied with a partial therapeutic response, or they want to fall pregnant, or the other drugs are too risky, etc. At the end of the day it is about informed choice. Let's hope you are informed.

    6. If you read the paper above "NEDA" Is an evaluation of how well a person does on a particular drug. In fact if a person has been on a therapy over a year and has a minor relapse, the recommendation is to sat on the current therapy.According to the Team G mantra this person should be escalated to a more potent immunosuppressive. The Team G mantra is a literal interpretation of No Evidence of Disease Activity.If a person is on a less effective DMD and has a minor relapse after one year, you can't afford to waste time finding a DMD to halt relapses. You havs to escalate full bore without consideration.This is why people with an EDSS of 0 are getting HSCT overseas. Team G is partly rsponsible for this mind set.

    7. I've been NEDA on Rebif since diagnosis 18 months ago. But there's no way I have benign ms due to the presence of 8 brain lesions & OCBs in CSF.So how do you know the 'shredder' is off? I'm looking at pulling the cord to make sure of that! (Lemtrada). Being a first-line therapy in Australia, the mere diagnosis of definite ms allows that.

    8. To Anon 5:50pm…I am one of the people who went overseas for HSCT as a first line treatment. Team G were in no way responsible for my mindset. I own that myself, thanks – on the back of a ton of research and conversations with docs around the world.If you read the posts on here at the time, you could hardly say Team G endorsed it. Quite the opposite in fact.Nevertheless, I absolutely agree with their view that everyone should be offered the opportunity for early effective treatment.The counterargument seems ridiculous to me, in effectively suggesting that some disease activity could in some way be preferable to no disease activity.Yes there are some risks associated with these therapies, but I for one feel that those risks are worth taking for a better prospect of avoiding reducing an otherwise high probability of disability, financial destitution, reduced quality of life, impact on relationships etc.You may feel differently – and I respect that. It's a personal choice for everyone.But I am personally of the view that if this blog encourages more people to take ownership of their own lives and seek the most efficacious treatments available (in the UK, or wherever), that's a pretty good result. Particularly given that, in the absence of any reliable measure of subclinical disease activity, you're essentially shooting in the dark.

    9. Once you ablate your immune system you don't magically regenerate a new one, but rely on memory cells to rebuild the repertoire. One thing that Team G or anyone doing HSCT won't tell you is that your immune system is vital for cancer surveilance. This is the reason why cancer becomes prevalent with age since your immune system can no longer regenerate itself. So, chopping out large chunks when you are young is not a good idea.Sure, you may be cancer free 5, 10, 15 years down the road but no one can tell you what HSCT will do in the longterm. Hopefully you weighed this in your treatment choice, but I suspect this is doubtful.

    10. Anon 11:09pm:I'll still take on the 'potential' risks associated with HSCT over a virtual certain progression of disability. You're right, we don't know the consequences of HSCT in the long term, maybe nothing other than a cessation of ms progression. But we can certainly predict the future with ms, not necessarily the exact type of systems affected, but the fact that there will be progression.

    11. The falacy perpetuated by Team G and others is that without the use of the most dangerous immunosuppressive agent, your MS is going to progress. Fortunately the rest of the MS scientific community knows this is not the case.

    12. I guess this is why Anon Wednesday, November 11, 2015 6:16:00 p.m. who is NEDA on interferon is opting to go on Lemtrada.Is this a consequence of reading this blog? Most definitely.Team G are marketers masquerading as scientists.

    13. Anon Thursday 12th Nov 2:34pm:I've been NEDA-3 on Rebif since diagnosis nearly 2 years ago. But am I NEDA-4? Probably not based on what we know about interferons & brain atrophy.My decision to go on Lemtrada has been based on much research & extensive consultations with neurologists & haematologists. I'll take what I see as a wise calculated risk in order to stop all damage NOW, including subclinical damage. I'd hardly base such an important decision on a single blog, no matter how informative. Odds are almost inevitable that I'll progress. Benign ms is very rare & my neurologists have assured me based on lesion load that I don't have this. Everything I've read from multiple sources says treat effectively early. Interferon is better than nothing, but it barely qualifies as effective. Not effective enough anyway if the intention is to aim for NEDA.So your assumption that my decision is 'most definitely' a result of reading this blog is very very incorrect. Our opinions may differ but I can assure you that mine is based on extensive research & consideration about what is right for me.

    14. I'm glad to hear that your decision is based on sound judgments with your neurologist. Hopefully others aren't relying on the hype perpetuated by Team G.

    15. Unfortunately your blog is pretty one sided and biased in my view. It would be interesting to get some views from those in the mainstream MS community that have opposing views to Team G. I suspect this would not be welcome by Team G as it would be a threat to your propoganda machine. Hopefully another research MS will become available but it's not likely as these other scientist are busy trying to cure ms.

    16. Thanks for your input. You're free to set up your own site should you choose to do so as you're obviously unhappy with ours, though you seem to be a very regular visitor. We're all trying to cure MS, we are in the minority in that we seek to engage with the public in addition to our research/clinical activities, if more researchers did this it would be a good thing.

    17. Our site contains our opinions. They may follow dogma and they may not and of course you should seek alternative views. YYou make opions of us based on what we write, just as we and other will make an opinion of you based on what you write. Is this correct or not?. Are you a troll?Of course we are biased. We select content and so that is biased. We publish research news otherwise we would be publishing the latest fad of the month, but in terms of bias what are you refering too specifically and we can take note when we are proved right or wrong. In some aspects we are very happy not to follow the mainstream MS community. There is a herding mentality but unless you follow the trend you may not get funded.Yesterday, the MS society had a session of prevention. So vitamin D was brought up quite rightly so. But when is vitamin D important after Onset of MS..lets do a trial, during adolescence…lets do a trial, during pregnancy lets do a trial. This all costs money that could be spent elsewhere. But how many people are asking the same question in other conditions diabetes, lupus etc. Yesterday it was shown that in diabetes the disease kicks in maybe 9 months from birth, so would MS be any different in when vitamin D is influenceing the immune system.However we create the hype and you demand studies, but do we want ten underpowered studies done in ten differnt countries that don't give an answer of one joint one that gives an answer. Search Vitamin D on clinical and MS you get 33 hits, vitamin D alone you get 2348 studies of other people doing the same thing in a different condition. There is still no consensus of Vitamin D supplementation.Smoking you should all stop if you smoke, but where does it effect MS, is it because some people thing the immune system is programmed in the lungs?You want opposing views…which views do you want and whose views do you want.Name some names and maybe we can ask them to do a guess post…but maybe they are not willing to spend the time as you seem to question. They are too busy to talk to you. This is indeed the case we have have asked people who haven't produced anything all we ask of them is for a biography a picture, a conflict of interest statement and then they are free to say what they want.However give people an public audience and sometimes the lion becomes a mouseMaybe scientists/neuros think if they put their head above the parapet that people like you will will be sniping at them, saying why are you so blinkered and biased because Team G has educated me to realise that you are talking mushroom food:-).There are many blogs where you can get different views such as the MS Societies there is MS translate, MS Discovery forum etc.however do they allow anonymus comments . However, we do what we do voluntarily and so may not have to like it but if you read it you do have to lump-it 🙂

    18. To Anon of 13-11 at 11.39pm.It's really very simple – you make the decision to visit this site and you have control over whether you read what is on this blog or not. No one is forcing you to read it, so if you don't like it's content, then don't visit the site.

    19. I see we are dealing with MS conformists who like to be spoonfed information and will believe what they want and don't like anyone to challenge what is being told to them.I guess this might be a consequence of their disease but most likely it is an indication of their level of intellegence or lack thereof.I like reading this blog and posting information from the mainstream scientific community that counters Team G's point of view. But this is not very productive because Team G and their followers take this as an insult. I guest the same can be said of those who visit the CCSVI alliance.But reading what is on this blog and comparing it to what is coming out of the mainstream MS scientific community is a good thing as it helps you establish what is valid and what is not. Those die hard Team G supporters should try it sometime.

    20. Anon 11:09I'm curious. What is your stake in this? Are you an MS’er yourself, a neuro, a pharma rep, or just trolling?"Once you ablate your immune system you don't magically regenerate a new one, but rely on memory cells to rebuild the repertoire. ".And yet, in the only study examining immune reconstitution following HSCT in MS patients… "Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients"“One thing that anyone doing HSCT won’t tell you is that your immune system is vital for cancer surveillance”.Based on what – your personal experience? Presumably the last time you spoke to an HSCT consultant would be….never. This is unsubstantiated drivel."No one can tell you what HSCT will do in the longterm"It's hardly a novel treatment outside of MS. Millions of patients treated with HSCT, dating back to the 1960s – substantially longer than most, if not all, MS pharmaceutical interventions. Chronic lifelong suppression of the immune system with maintenance therapies carries it's own risks to immune surveillance – balanced against a much lower success rate at inducing and sustaining NEDA.

    21. Anon 1.33 "I like reading this blog and posting information from the mainstream scientific community that counters Team G's point of view. But this is not very productive because Team G and their followers take this as an insult."Glad you like reading the blog. If the tone of your posts is insulting, we take it as an insult 😉 To accuse us of hyping particular pruducts, being marketers for drugs or hyping drugs is just that. There's lots of information out there, this blog is just one (the best IMO) pwMS should read around as widely as possible.

    22. Matt P, obviously you don't know much about HSCT or the immune system or what cancer immunoediting is. I guess this might have been something to consider prior to undergoing HSCT, but you won't find this on Facebook pages. Good luck anyway.To the mouses, It seems you know everything their is about MS and you come across as nit pickers of other scientists work. I guess this is fine when they cannot respond but it seems highly unprofessional. Especially because clearly you two are not at the forefront of MS research but I suppose in your minds you are. Keep up the good work.

    23. Thanks for the kind wishes. I'll leave it to our peers to judge whether we're at the forefront of MS research or not, in the meantime, we'll keep up the good work.All the best MD2

    24. True. If only I'd had the opportunity to consult with you beforehand – the anonymous keyboard-warrior on the internet. What a legend. Makes me regret hiring a haemo-oncologist at all really. Ah well. Best of luck with the trolling.

    25. "I like reading this blog and posting information from the mainstream scientific community that counters Team G's point of view". Not sure what you have ever posted as you are anonymous and can be anyone one of a thousand people or you maybe a cyborg collective:-)Get yourself a persona (doesn't have to be your real name e.g. Mr angry oh that's taken). You can become our nemesis if you like and you will get your supporters.However, if it looks like an insult, sounds like an insult then it probably is an insult. Maybe, you are afraid that you will trip yourself up saying something that is wrongand then the nit picking may come your way, so be careful who you slag off they may know more than you thinkNit pickers or constructive comments….but you want content. We can be the gushy that's great and super type of people that you get every where on the blog. Your view it may depend if you are on the receiving end. If someone wants to disagree we can be contacted and corrected. Maybe you want to do a post each week Correcting TeamGs wrongs….We had a laugh today about a lab going ballistic about a comment MD2 once made……maybe they simply need to address the comment, as it was a constructive one.We cannot read the context of any posts are you joking are you serious. That is the problem of the internet. However having asked some questions…there were no constructive answers.

    26. What is the mainstream Community coming out with that you want to know so we can give it a special mention:-)

    27. So Matt P, how is your name any more specific than using an anonymous tag? Why not use your full name?But I guess the concern with HSCT and many other immunosuppressive treatments is that your T cells never come back to baseline. What are the implications for this?Here is a video by Dr. James Bowen who is an expert on HSCT that explains this. Hopefully in this format it will hold your attention: after consulting with all of your HSCT experts overseas I guess this is not a concern, at least in the short term. I think your "experts" are interested in convincing you to become a medical tourist and want your money. 20 years down the road it is none of their concern what happens to you.

    28. As it is unprofessional friday I wonder if your name is John Thomas as I think you are behaving like one:-). Maybe I am not reading the tone correctly and I apologise.MattP does not have to use their full name but if you are a regulatr reader of the blog then you will know with responable probability what it is. However , they have the courage to use a name and so have a personality, even if it just a web personality. Hiding behind anonymous means that you never have to stand behind your what you write.As to the video maybe Matt will have 30 minutes to spare ( I don't today) and will say thank you for the insight or maybe he will watch and say thanks I know this already and this presentation was made seven years ago when the mortality rate data and approach was different from what it is today.Maybe MattP may say they know that HSCT is not infallible and many people are not NEDA and maybe they will talk about the efficacy compared to some current DMT. Maybe MattP will not be bothered to comment and this will be the end of it

    29. Yes, the BEAM conditioning regimen is still used today for myoblation HSCT so Dr. Bowers presentation is still quite valid. But I guess you wouldn't know this, as you are not up to speed on HSCT and probably most things of interest in multiple sclerosis. Your quite right, it is getting tiresome but I imagine I must have struck a nerve since you seem to be on the edge of your seat with your rebuttals. This leaves me to wonder, does anything get done in the mouse doctors lab?

    30. You make the assumption that I watched the video. If you read the comment I didn't.As to being on my seat, it is 1.00 am so am not at work at present but am posting on the new PML case because it of interest and yes I do know what the letters stand for.As for getting stuff done…maybe we waste too much time dealing with pointless comments:-)But please do educate me what is of interest in MS?

    31. I don't have 30 mins tonight either, but I've seen it before. You've got your references mixed up though dude. The data on immune reconstitution is taken from a decade old paper (2004) based on a high intensity protocol using Total Body Irradiation + chemo. Nobody uses TBI today in HSCT for AI disease. So not valid at all, really. Interesting paper though – talks about thymic hypertrophy and de novo generation of a diverse T cell repertoire post HSCT through thymopoiesis. You should bother to read it next time – you'd enjoy it greatly, I'm sure.MD has eloquently answered your point re anonymity. My identity is no secret.What was your 3rd question again? Oh yeah, "experts". My haemo/oncologist is based in the UK, and is the regional director of the BMT unit. Pretty qualified, I'd say. He has zero connection to HSCT for MS, medical tourism, or any financial interest in me pursuing the treatment whatsoever – so I'm afraid you're just spouting more presumptuous drivel here.I'm outta this convo – it's going nowhere and I can see I'm just fanning the flames of your trolling by giving you the attention you crave. Irritate someone else for a bit.

    32. I guess your idea is a troll is anyone who questions the logic of Team G. Very interesting, you should probably restrict yourself to the HSCT facebook pages if you want conformaty. But one little piece of information to those who care and to bring this post back onto the subject. HSCT does not halt neurodegeneration as confirmed by researchers looking at post mortem subjects who underwent HSCT: should say many of these researchers have impeccable reputations in the MS field and I await Teat G's response.So it seems intense immune suppression as marketed by Team G and the overseas HSCT clinics is not going to halt progression no matter how many anecdotal stories you hear on Facebook.

    33. A troll is someone who is insulting and destructive, if you want to question TeamG you can do so eloquently as MattP has done in the past as well as others.But it helps if you do your reading before you open your mouth. It is clear you have not done any reading about our views and you are not telling us anything we are not aware of therefore it is pointless address you further bye.Hugs & kisses….Be nice saturday!

    34. Impeccable pathologists…who only missed the existence and significance of nerve loss and grey matter lesions for years and years and years

    35. LoL. Science is about discovery and evolution of ideas and not everyone agrees with everything. When I first started MS research i years ago MS was a demyelinating disease of the white matter. However when you see some dissections it is easily possible to see grey matter lesions with the naked eye, but pathologists were so convinced they was no myelin in grey matter they used to get their technicians to remove the luxol fast blue myelin staining from the grey matter. It was only when they started doing immunostaining for myelin that the grey matter lesions were evident. MRIers missed the grey matter lesions because of inabilities in their machines.

    36. Ah Anon – I was hoping you'd go bug someone else. Alas, no.Look. You guess wrong. Nobody would object to you "questioning the logic" of Team G – including Team G themselves. That's why they set up an open comments section that allows you your voice in the first place, no? Unfortunately, your logic is about as sound as a square circle.Here's an example of one of your intellectually stimulating arguments: "I see we are dealing with MS conformists who like to be spoonfed information… I guess this might be a consequence of their disease but most likely it is an indication of their level of intellegence or lack thereof.".Wow. It's like Socrates has been reincarnated (as a moron).Just so we're clear, my definition of a troll is one who, as far as I can tell, doesn't actually have a point, beyond firing out a scatter-gun array of semi-researched google/wikipedia hits, and attempting to get attention/reaction by belittling and insulting anyone who does not share your poorly evidenced, bitter/angry conspiracy theories.Compounding matters, you seem to have deluded yourself that you are better researched and have superior knowledge and understanding of MS therapies/studies than everyone else – resident experts included.Unfortunately for you, you've consistently demonstrated the exact opposite – posting nonsense remarks with little to no basis in educated fact nor reality, and a level of understanding that's about as deep as a bowl of soup.

    37. Let's have a recap.1) You told us the reason patients are going overseas for HSCT at EDSS 0 is down to Team G. Back in the real world, if you'd read the blog, you'd see Team G have repeatedly posted against "health tourism" and warned against HSCT until further studies are complete (a position I personally don't necessarily agree with, but respect the good intetions of nonetheless).2) You then spoke on behalf of another patient/commentator, who you suggest is switching from interferon to Lemtrada due to Team G. "Is this a consequence of reading this blog? Most definitely!", you exclaim. Unfortunately for you, this MS'er also calls bullshit and sets you straight that this was not the case and that you don't speak for them. Oops!3) You go on to make some claims about what HSCT doctors will/will not tell you about associated risks. It subsequently emerges you've never spoken to an HSCT doctor and thus have no idea what you are talking about. Another baseless claim.4) You claim that Team G are marketers masquerading as scientists, on the basis that they believe in early effective treatment. Despite the fact that they have put their names to page upon page of commentary and evidence on this blog to substantiate their views on EET, no substantiation or coherent reasoning is offered by you in support of your claims – and it becomes clear that you're not even prepared to put a name to your own remarks.5) Next, you tell us that you can't generate a de novo immune system post HSCT due to thymic involution, telling everyone who disagrees how stupid they are. The evidence makes a mug of you once again, with the paper from Muraro et al concluding the exact opposite. On being presented with this evidence, you provide no counter-argument.6) Next up, you cherry pick a quote from a decade old symposium video on YouTube about immune reconstitution after HSCT. Despite attempting to belittle everyone else's knowledge as coming from Facebook (a position you repeatedly fall back on when getting spanked), it turns out that you've actually not read the paper it's based on. Embarassingly, unlike you, all of the people you're attempting to belittle as being ill-informed have actually read the paper. Lols!7) Continuing your run of highly entertaining form, you then (wrongly) make condescending remarks that the immune reconstitution study you've posted relates to BEAM – claiming , and I quote "I guess you wouldn't know this, as you are not up to speed on HSCT". Sadly for you, within minutes this is debunked, and we see that it is in fact you that is not up to speed with HSCT, with the data in your video instead relating to a high intensity protocol with TBI. *Cringe*

    38. So, that brings us up to today's google-search-of-the-day from you, which you claim disproves the efficacy of early effective treatment. Spoiler alert: it doesn't.It's a paper from 2007, published in the journal Brain. I highly doubt you've looked below the headline, so here's the lowdown. All 5 of these patients had late progressive disease. Three were SPMS, two were PPMS (with one being progressive/relapsing) – and all had advanced disease with a mean duration of 13.2 years since dx, and EDSS from 5.5. to 8. Hardly a strong target cohort from which to draw conclusions on early effective treatment.Find below link to a factual, evidence based rebuttal of the conclusions reached by Metz et al in the paper you posted, which was published in the journal Brain (same journal who published the original article) shortly thereafter. Incidentally, you may recognise one of the authors of this rebuttal as a certain James D Bowen – who you may remember you were waxing lyrical about yesterday as a leading "HSCT expert". I wonder, does your opinion of Dr Bowen only hold true when you're cherry picking the soundbites that fit your agenda? conclusion, if you're going to ride in on your high horse, be careful you don't fall off.On that note, I'll leave you to enjoy your Sunday lunch. What's on the menu? I recommend the humble pie.

    39. Anon said It's somewhat likely that anon is………..which case this is sad more than anything else. …….. But given how obnoxiously ill-informed ……has been at every turn, Matt P's response is also rather satisfying. I have a strong suspicion that this is the same idiot who got into an argument about albuterol a couple months ago. I wish I had written Matt P's response then.

  11. I started early treatment with Finoglimod at CIS , however I had a high lesion load (around 20). I have been stable for 2 years. But does the high lesion load mean I might have missed the window to prevent progressive disease ?

    1. Re: "Dr. Ebers explains the data, relapse rate and lesion load have no effect on progression. "Yes, Dr Ebers is right but he is referring to natural history and placebo data. However, in trials when you are on a DMT relapses and lesions are highly predictive. What this is telling is that relapses and lesions on MRI are not the disease and are in response to the disease. If you are not modifying the disease then the inflammation tells us this. I spoke on the disconnect between natural history studies and treatment trials many times; I use this observation to support my field hypothesis of MS. am really missing Dr Eber's contribution to this debate; he does acknowledge the difference between placebo and treatment arms. He is an author on the original betaferon/betaseron trial that showed this.

  12. So if you're an RRMSer who has done alemtuzumab but you suspect you're way down on this chart, what can you do to get the most from the treatment? Or do we also have to wait and pray? I'm popping biotin in the morning, what else is there?

  13. Here's a favourite story – GETTING THE HORSE TO FLY:A king condemned a man to death. When the king finished reading the sentence, the condemned man said: ‘You are a wise man, Your Majesty. When I was a child, my grandfather taught me how to make a white horse fly. Since there is no one else in the whole kingdom who knows how to do this, my life should be spared.’The king immediately ordered a white horse to be brought.‘I need to spend two years with this animal,’ said the condemned man.‘All right, you will have two years,’ replied the king, already somewhat suspicious. ‘But if this horse does not learn to fly, you will be hanged.’Overjoyed, the man left with the horse. ‘Are you mad?’ his family and friends cried. ‘How can you make a horse fly?’‘Don’t worry. Two years is a long time. In two years the king might die. Or the horse might die and then I’ll get another two years to teach the new horse. Or the king might have a change of heart. Not to mention the possibility of revolutions, coups d’état and general amnesties.And of course, no one has ever tried to teach a horse to fly. Who knows, the horse might well fly!And even if everything remains exactly as it is, I will still have gained two years of life. Does that seem little to you?’Lesson is obvious: SPMS could turn up 10/20/30 years after starting something like ocrelizumab or alemtuzumab. But those 10/20/30 years are not a little thing. And who knows, a black swan might turn up and make the horse fly

  14. Ok, so I understand the theory that inflammation primes axons to die in the future, leading to progressive disease, but can you explain why there has been some success stabilizing progression with rituxab and presumably ocrielizumab? Is the theory that these drugs dampen inflammation to such a degree to permit natural repair or otherwise stimulate remylination of damaged axons?

    1. Rituximab stops the inflammation Inflammation that primes the progressive aspect and slows it however I do not think they are hitting the core problem of progression once it is set in motion

  15. I might be the only one but my first MS symptoms were mild, almost invisible. This was long before my first attack. The delayed neuro-degeneration occured before the acute degeneration. You could say that I had attacks and that I did not noticed them and the apparent progressiveness comes from that. But it seems that in my case the delayed neurodegeneration made more damages than the acute one. How does it fit?

    1. I was 29 at my first real attack (in last year June). I started with bladder problem at 28 (December). Initially, I thought they were not MS related. I started a blog called MS and ME. My first posts are about these first symptoms.

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