Unrelated Blogger Comments December

U



Some times you want say some thing that is unrelated to a thread.


This is the place for you

About the author

MouseDoctor

89 comments

  • Just watched the new movie Dallas Buyers Club here in the U.S. It looks like it's not in the UK until Feb. 7. It is about AIDs patients fighting the FDA and Pharma to access treatments in the mid-1980s. Fascinating from an MSer's perspective. In the past, you've written on this blog that we need to be the kind of activists AIDs patients were back then. This really dramatizes your point.

    At the same time, part of me wonders if they didn't just get lucky. You'll see some scenes and wonder how anybody could know who had the effective treatments and who were profiteering off desperate people.

    Anyway, I hope we'll talk about it here when it's more widely available. Interferon gets a cameo appearance too!

    • Sounds interesting – maybe as you say it will help to inspire some campaigning amongst the MS community – I will look out for it hitting our cinemas in the UK

  • Induction and maintenance…

    Hi Prof G, Mouse.

    I have long followed your blog and views re: early, aggressive treatment and induction therapy. I agree. What I'm interested in is what you recommend as 'maintenance' for MS? The usual principle of induction therapy, from other medical fields, is hit hard, early (eg Alemtuzumab where MS is concerned) and then take some kind of on-going therapy as a maintenance drug. What are your views about an appropriate maintenance approach? BG-12? Laquinimod? Injectables? Nothing? I realise it is a stab in the dark as there's no research but, if you had to choose something, based on your knowledge of mechanism of action of the different drugs, what would you do?

    I wonder if I might ask a second question. Under your 'NEDA' approach, you (rightly) point out that disease activity under a DMT is bad. However, following induction, you say it is not – just an indication to retreat. I don't understand the distinction – can you explain? If I've had Alemtuzumab and I continue relapsing or having MRI activity – how can it not be that this is bad? Surely the point of the Alemtuzumab is to stop this activity and by not doing so, it has failed in it's purpose i.e. I'm a 'non' or a 'poor' responder? How does this differ from other DMTs in this respect?

    Many thanks.

    • Yes I have views but unless there is data I feel they are best kept to myself. Furthermore I am not prescribing anything

      However be aware that all drugs come with risks and this may be exaggerated when you mix them, for example one drug may make liver enzymes that destroy the other or magnify potential side-effects.

      I would say if you are having disease activity then this is never likely to be good and I think that you and you neuro should think what actions can be taken to prevent this whether this is retreating drug switching etc.

    • "Yes I have views but unless there is data I feel they are best kept to myself."

      I'm never one to criticise this blog as I think it is, frankly, a wonderful source of guidance and information but that feels a bit unfair to MSers who follow this blog. There probably will never be the right data because it is unlikely that different drugs companies will work together to test their drugs in this way. Even if they do, it'll be years before there's enough data. We MSers have to take calculated risks on treatment choices all the time – including unexpected side effects. One of the over-arching themes of the whole site – especially from Prof G – is (repeated in a post only the other day): (a) early treatment, (b) highly effective treatment and (c) induction therapy. It seems a reasonable question to ask what the blog authors think is the current 'best bet' for proper induction therapy. i.e. once induction therapy has taken place early in the disease – let's assume with Alemtuzumab – what maintainence therapy should follow? My personal best guess would be that Tecfidera, perhaps starting some months after the 2nd dose of Alemtuzumab, would make a lot of sense but I have barely a tiny fraction of your understanding of drug mechanisms etc and I'd really appreciate yours and Prof G's views (with all the disclaimers about lack of data, risk of combination drug side effects etc). Please?!

    • I think a problem with BG12 after alem might be that it has some immunosuppressive action I believe. So not a good idea to follow a hard hitting immunosuppressive with another one, even if it is only minor. Laquinimod might be a better bet (and I'm not from Teva)

    • It appears unclear whether BG12 is actually immunosuppresive or not. However, to be fair to Prof G, it appears he's recently answered this question here: http://multiple-sclerosis-research.blogspot.co.uk/2013/09/is-laquinimod-new-wonder-drug-that.html when he says: "Hence my enthusiasm for combing LAQ with an induction agent.". Is the above why you prefer LAQ to BG12 Prof? As soon as LAQ is EMA approved, I'm going to look with my neuro at adding that to my therapy along with the Alem I've already taken and potentially I'll feel like I've covered as many bases as I currently can.

    • Induction followed by maintenance therapy? Maintenance therapy is only required if you can't be retreated with the induction therapy. This is the case with mitoxantrone and why it often followed by IFNbeta and GA. However, with alemtuzumab, cladribine and anti-CD20 therapy further courses can be given relatively safely. You only need to be retreated if your disease becomes active. Although NEDA is the target if your disease becomes active you get retreated. What are lot of you are alluding to is the dual treatment strategy that I refer to in the treatment pyramid; i.e. anti-inflammatory and a neuroprotective agent. With regard to the latter the best data we have to date is for laquinimod. However, before promoting this as a treatment option we need to do a clinical trial. We need class 1 evidence. There is no way the payers will allow us to use two expensive MS therapies in series without evidence. I suspect however, that some of you may push for this anyway.

    • " I'd really appreciate yours and Prof G's views (with all the disclaimers about lack of data, risk of combination drug side effects etc). Please?!"
      .
      If I suggested that drug X will combined well with drug Y and you do it and then it causes you to get cancer, who is going to take the responsibility?….Whilst you should be responsible for your own actions,unfortunately there will be someone who will try to hold us responsible for this advice……..therefore it is better to keep quiet. Hope you understand but there are litigious people out there. We have a global readership and we are not lawyers. Maybe if we had a legal team monitoring what was posted we could be more adventurous….We could do with some now.

      because it is unlikely that different drugs companies will work together to test their drugs in this way. Even if they do, it'll be years before there's enough data.

    • Fair point MD – sad that those taking their time to provide an information service to individuals feel at risk in this way. I think you could express a view (as Prof G has above about LAQ) without any real risk provided you made clear it was based on purely theoretical thinking and you weren't advocating it but I appreciate your position.

    • Unfortunately lips are sealed, If you got to see some of the abuse and other things that we are subject to (but you wont as comments are now moderated) then I hope you can understand our caution. Likewise if ProfG made a recommendation, then some pharma bod may also take issues.

  • I was in Detroit last week and caught the movie too. I also saw How to Survive a Plague, which documents how gay communities in the early ‘80s mobilised America’s government to expedite effective treatments for HIV sufferers. Both are noble films, though I still feel MS is a different ballgame.

    The AIDS situation of 30 years back was basically a pandemic. It was spreading from person to person and no-one really knew how or why. The gay community – a group consisting of professionals, business men, entertainers and academics – took the law into their own hands and made such a roar that it couldn’t be ignored. MS is not a cinematic disease in that way. It’s not killing people at an exponential rate, and those living with it are keen not to be labelled or thought of disabled, that is until they actually are. Even then, most MSers get through life without their disease becoming too notable.

    It’s disappointing how the few movies about MS are more to do with people at the top of their game succumbing to physical degeneration and ultimately death. There is a reason for that. The disease remains an unknown quantity and there really isn’t a drug to effectively combat it. If you want movies based on MS sufferers acquiring effective medicines then that will only come about if remyelination and restorative drugs are discovered. That will make for a happier ending than speculative new DMTs that still remains a grey area.

    • "Even then, most MSers get through life without their disease becoming too notable."

      Are you sure about your facts? The majority of MSers end up disabled.

    • Dr Dre, your right. The HIV community had a much greater sense of urgency than MSers do. They were facing a death sentence, while we may not be so obviously. Most of them would have risked PML or a lost thyroid rather than near-certain death. For MSers, there's always a chance that maybe nothing bad will happen if we do nothing….

    • It's certainly NOT true that "most MSers get through life without their disease becoming too notable." It's not true even for the benign cases.

      Imagine somebody who has had MS for 30 years without getting disabled and is now in her 60s. Remember that most people of that age are active, with relaxed semi-retired lives. The children have grown up and moved away to different cities. The spouse has never needed to be a caretaker or housekeeper.

      And then serious disability hits you. Yes, you were much luckier than people who got disabled young, but it is still difficult.

  • My journey to gettting a diagnosis was extreme but I hear lots of stories of similar difficulties. Most of us get brushed off as emotional women. I had lots of symptoms but they were consistently ignored and not even documented in medical records. Obviously, this delays diagnosis and treatment for years. I wish I had gone to a private MRI facility as I could have unofficially diagnosed myself with the help of the radiologist instead of wasting time with a neurologist — supposedly one of the best in town — who did nothing for me.

    I would love it if 'somebody' did a study on that. I had MS for at least 8 years before I was diagnosed.

    Perhaps with your influence in the international neurology community, you could help educate doctors who neglect their patients or choose not to listen to them.

  • In battlefield situations, progesterone is used to help soldiers with limb damage to help regenerate nerves. There are also several PubMed articles where progesterone and nesterone are used on damaged mice nerves to promote repair. (Mostly peripheral nerves)
    Is anything happening in MS research along these lines for humans?

    • As you say this is peripheral nerve, and CNS nerves are a different beast as there are mechanisms that stop CNS nerves growing.

  • Dr Giovannoni,
    I watched the Medscape educational program -2013 A key year in RRMS- in which you said:

    In terms of the real-life experience, we have seen incredibly low event rates in terms of relapses across the board. With routine MRI monitoring I have seen a large number of patients that appear to have freedom of disease activity, which was not my experience 10 years ago. Either the drugs are more effective, we are treating a more appropriate population, or the disease is getting more benign. But overall things are improving.

    Is it possible that vitamin D could be involved in this? I have noticed that many MSrs take vitamin D supplements nowadays which was not the case in 2003 (at least here in Sweden).

  • Anybody see today's Telegraph? Article on health- Do these supplements help us keep healthy in the winter? Dr Mullen lecturer in nutrition sciences re Vit D- a key vitamin but too early to say if supplement could prevent common infections. More than 25mcg daily could be harmful says the NHS.
    How much is that re iu's? Is it a load of tosh?

  • I completely agree that MSers should be treated as early as possible, however I have to question if it is advisable to put someone on one of the "highly effective" drugs without the patient weighing all of the risks.

    The fact of the matter is many of these new drugs are effective because they suppress the immune system in some way and nobody knows what this will do to cancer rates down the road. Your immune system is vital for eliminating cancer as well as maintaining a state of equilibrium in which cancer is held at bay by the immune system. Once your immune system starts to decline in older age by mechanisms such as thymic involution, cancer becomes more prevelant.

    So, I think these risks should be communicated to a patient even though the short term trials do not convey these concerns. I don't think I am alone on this either:

    http://m.bloodjournal.hematologylibrary.org/content/119/9/2176.full

    • I agree with you; but this is no reason to limit the use of these effective agents to second or third-line. At the end of the day it is up to the MSer to decide whether or not they want to take the risks or not.

    • It is right that peope are made aware of the longer-term possible risks but, equally, that it is then their decision whether to accept them. When taking Alem, I accepted a number of risks evidenced in the trials as well as a number of unknown longer-term risks not yet known – including quite probably an increased risk of cancer longer-term. For me, those are risks I was more than willing to take when weighed against the risks of having MS and the chances of shifting the odds in favour of a mild, or, less likely but possible, even a long-term stable disease course. At the end of the day, it's a numbers game and depends on your attitude to risk, life etc. I have young children and am hopeful my treatment regime will ensure i remain fully functioning throughout their childhood – that's what motivates my treatment approach. If, 20 years hence, the price I have to pay for that is cancer then I'm okay with that. I realise it might not achieve what I hope and I might suffer serious side effects sooner but, again, I am okay with that – I might also get run over tomorrow. It's all about playing the hand you've been dealt in the best way for you and your life – there is no 'right' answer, but patient choice should, in my view, prevail in all but the most dangerously irrational cases.

    • Well, I agree with you that if you have highly active disease you should not be forced to go on a first line therapy because it is not likely to do much to halt damage as quickly as possible.

      However, I know some people who were stable on a first line drugs who decided to undergo HSCT overseas because they believe this will permanantly cease thier disease activity and they will not be burdened with injections. They think it is more effective. But I believe these people have no idea what impact immune suppressive therapy has on them and do not understand how this may impact cancer imunoediting down the road.

    • There is a need for someone to investigate how many MS patients have developed cancer without having had any treatment. In thirty years time. it will be assumed we have cancer due to the drugs. The research needs to be done now, while some of us are still alive that have never had treatments. The information should collected now before it is too late.

    • Good idea, but many lifestyles have changed over the past few years, even in short terms studies I think the cancer risk is about 0.5% based on many trials.

  • I have a question re: Alemtuzumab. All the stats support the good chances of stable disease on this treatment given early enough. The one stat from all the trials I don't understand is that new/enlarging T2 lesions are found in c. 50% of those treated which seems in stark contrast to the concept of NEDA, stability etc? Am I missing something or is it felt the T2 lesions are somehow less important or maybe occur due to processes in train before treatment commenced? If I have an MRI then Alem and then a year later have new/enlarging T2 lesions I would be disappointed based on the flat-lining theory, yet from the data it seems I'm at least 50% likely to be in this situation? Just to confuse matters more, the data also show a reduction of between 1 and 9% in T2 lesion volume – how does that fit with new lesions forming?

    • A bit related to this question, I have a question about GD+ lesions: i.e. what is the significance of Ganolinium enhancing lesions on MRI? They appear to be used as a marker for prognosis, activity and severity in both trials and clinical practice. Yet, as I understand it, whether a lesion enhances is just a matter of whether you catch it at the right time in its formation? i.e. all lesions enhance at one time or another – it just depends if your MRI is early enough in the lesion's 'lifecycle'. Eg if I have an MRI, then 6 months later I have another which shows new or enlarging T2 lesions, but they don't enhance – why is the lack of enhancement considered a 'good' thing? It seems to me that it doesn't really matter whether they enhance or not – they've formed at some point in the past 6 months and would have enhanced if I'd had my MRI at some different time? Equally, in trials, if 'new T2 hyperintense lesions' are tracked – what's the point in separately tracking GD+ lesions? All are just new lesions (i.e. bad) and of the same significance as I understand it? I've seen trials rave about their ability to suppress GD+ lesions but then still show significant new T2 lesions as if that's not really that significant in comparison.

      Am I confusing something? Do not all T2 lesions enhance at some point in their life? Does enhancement somehow mean 'worse' inflammation or greater severity to the lesion?

    • Gadolinium is a small molecule that can be picked up by MRI. When the lesion is active and their is blood brain barrier dysfunction then gadolinium can penetrate into the brain. This is equated to active inflammation and in the rare occurrence when someone has died just after an MRI they were able to go back to the same spot and show white blood cells entering the brain. From my perspective I think it is a marker of fluid movement across the the barrier rather than cells. Why do I say this well we did some time course analysis and gadolinium leaks into the brain before substantial numbers of cells go in and two when you see the extent of gadolinium leak in an animal it is far more extensive than the amount of cell infiltrate.

      However, whatever the scenario it shows the lesion is active and active usually means it is getting bigger and causing damage in the process. If it is not active then it is less likely that damage is being done. Therefore we do not want to see active lesions that are gadolinium enhancing. This is why this is a desirable outcome to inhibit gadolinium enhancing lesions. If drugs can stop Gadolinium enhancing lesions there is a chance it can stop relapsing disease. However it is not an absolute correlation. Beta interferon is pretty good at having a positive MRI effect but is less good from a clinical perspective.

      However lesions have a limited lifespan before the regulatory processes kick in and this leaves a lesion to either repair and remyelinate or become gliotic and scarred. These are what T1 and T2 lesions can be so they are perhaps burnt out and not enhancing so there is not active damage and so this is a good thing.

      I am no imager but I am still not 100% sure what a T1 or T2 lesions really is from a histological perspective as they are usually described from analysis of living people and without the power to do post mortem histology, some of the MRI outcomes are theoretical. e.g NAA was supposed to be and is a measure of nerve loss, however in some cases NAA levels can increase but is unlikely to be nerve regrowth so it is not always simple. MRI measures the movement of protons under a magnetic field and detects how they relax after the magnetic field is removed. T1/T2 are are marker of lesion load and so it is better to have as few as possible. As you say they probably will have gadolinium enhanced in the past.

    • Thanks for the reply MouseDoc – although I'm still confused!

      Take the following example:

      MRI 1 = 4 T2 lesions, no GD+.
      MRI 2, 6 months later = 6 T2 lesions, no GD+.

      So, in that 6 months, 2 new 'T2 lesions' have formed. My assumption is that the 2 'new' lesions didn't enhance because they formed long enough ago in that period to have now resolved. I don't take that as any better than a hypothetical MRI3 which showed 4 T2 and 2 GD+ lesions – in this example the 2 new lesions have just formed a little later and still haven't resolved. If there was another scan in a few weeks, it would then be 6 T2 as the 2 GD+ resolve.

      Now, something must be wrong in my analysis above – because everyone seems to treat MRI3 result as much worse than MRI2 result – both clinically and in trials. You say that "if you can stop enhancing lesions you can stop rrms" – but surely not if the T2 lesions keep rising? i.e. if I never, ever have a GD+ on serial MRIs but my T2 lesion numbers continually increase, then my MS must be active and progressing, no?

    • Lesions only enhance for 2-4 weeks. This is the reason why in the optic neuritis people are being recruited within two weeks of symptom onset as we want to treat during lesion formation.

      In a 6 monthly scan there is time for new lesions to appear and go quiet. Also did they upgrade their scanner between scans and finally who was reading and calling the scans.

      The ProfGs are doing a trial I think with monthly scans and so we may be able to address your point. I am sure it has been published already but I don't follow the scanning literature as closely as perhaps I should.

      No enhancing lesions and that should stop RRMS, not necessarily because lesions in the spinal cord are missed if only the brain is scanned. Likewise you get T1/T2 lesions in progressive MS and this not show itself with gadolinium, so increasing T2 in my mind in not a good thing

      So the question again, what really is a T2 lesion. Maybe ProfG can shed light on what he thinks are good and bad prognostic indicators from MRI

    • Anon, with regards to your queries about MR in MS, my take on the lesions is similar to yours. I'm almost certain that every T2 lesion will have enhanced once (at formation) or more in the past. This can range from a very tiny area of enhancement in a small lesion to larger, typically broken ring enhancement. Enhancement is said to typically last for 4 to 6 weeks, but can last longer. Lesions can and often do get smaller some months after their formation. Enhancing lesions will also be T2 hyperintense. Small lesions can then disappear with time on conventional MR sequences, so that they're not obvious on T2 – I'd assume there would be remaining abnormality if you could examine the region histologically.

      This is why enhancing lesions seem an unreasonable criterion for starting a DMT – unless you're scanning people once a month which isn't going to happen, especially not in the UK.

  • Just to confuse the Alemtuzumab/lesions question further – the paper on the original Campath treated MSers says this about the SMPSers who went on to progress anyway: "MRI scans on patients treated 7 years earlier showed no new lesion formation". Yet, the more recent trials show the stats quoted above – c. 50% still have new or enlarging T2 lesions. What's your view on this Prof G? And how is the clinical relapse rate for 5 years as low as it is (0.11 I believe for months 0-60) if 50% are still accruing new lesions? Confused… :-/

    • In early MS studies people with SPMS were studied and they have few enhancing lesions and lesions accumulate slowly, in some of the more recent trials people were selected to be very active in terms of their lesion load so you are comparing apples and oranges. Furthermore some of the immunomodulatory drugs may take abit of time to work and so lesions may continue to form even after onset of treatment and you could pick this up by MRI

    • Even considering that people were chosen for a highly active lesion load – is 50% of people continuing to have lesions post-treatment not really high for such a knock-out treatment? Much of the talk is of a majority of people experiencing a 'long-term remission' following treatment but surely new T2 lesions on MRI is contrary to a long-term remission. Is there any data to suggest most of these new T2 lesions occur early-on post-treatment and, say, from years 2-3 there's much fewer people with new lesions? Or do they develop less lesions than they did before (eg from 10 per year to 1 or 2)?

      I presume Prof G's NEDA approach includes radiological measures? I certainly take the aim of my treatment regime as being to stop all new MRI activity, as much as to stop tangible symptoms, the absence or presence of which I view as simply good/bad luck if there remains MRI activity. I just find this particular piece of data highly incongruous with the general views of the efficacy of Alemtuzumab and hope someone can put it into context?!

    • Sorry – partially answering my own question – but I do wonder if this is largely a delay in treatment effect? Looking at Prof G's slides for the Cleveland Clinic on NEDA it is interesting to see that for Tysabri, years 0-1 had only 60% radiologically disease free but in years 1-2 it rose to over 90%. The cummulative number of people with complete NEDA on the CARE MS1 trial was only 39% (51% being free of radiologically active disease) but I wonder if that would have been much higher has they excluded, say, the first 6 month MRI. Otherwise, Alemtuzumab doesn't show any better NEDA than Fingolmod, for example, and much worse than Tysabri – although I realise you can't necessarily compare from different trials (even IFN was 27% in the Care MS1 which, while statistically worse than 39%, it's not exactly different league given Alem's risk profile).

      Prof G – would you comment on this?

    • Yes he can reply as he is closer to the data than me and I would need to read before answering and he knows the ins and outs of treatment failures too.

    • Prof G? Can you reply/comment? I'm hoping you can provide some reassurance as to the efficacy of Alemtuzumab on a T2T-NEDA/radiological basis?

    • The data on which to base those thoughts are out there, Prof G has been incredibly busy too much travelling and meetings and other stuff.

    • Re: "NEDA"

      It is difficult to compare NEDA rates until we have rebaselined subjects after the drug starts working. With natalizumab it is probably 6 months and with alemtuzumab maybe 18 months, i.e. 6 months after the 2nd course. NEDA also means different things if you are on a maintenance or induction therapy. For a maintenance therapy break through disease activity is an indicator of a lack of, or suboptimal, response in comparison for an induction therapy this indicates that it is time to retreat. These differences are not subtle and need to be communicated to the wider audience.

    • "For a maintenance therapy break through disease activity is an indicator of a lack of, or suboptimal, response in comparison for an induction therapy this indicates that it is time to retreat."

      Can you explain this? Why?

      "with alemtuzumab maybe 18 months, i.e. 6 months after the 2nd course"

      Really? I thought it immediately depleted the relevant parts of the immune system – why doesn't it therefore start making its impact immediately? As someone who has recently received the first dose, another 18 months of MS 'damage' rather worries me?

    • I normally don't answer the clinical stuff but

      If you are on a constant treatment (maintainence) and disease is occurring it means that drug has stopped working such as because there are neutralising antibodies blocking the drug or the drug is not strong enough so you need to switch to a more powerful drug. e.g beta interferon switching to gilenya.

      However, with an induction therapy you give a short course of treatment that has a long lasting effect but it may not last forever, so disease may return as seen by new relapses or MRI lesions, but rather than switch drugs it may mean you just need another course of drug so it is re-treat (i.e. treat again), rather than retreat and run backwards

      Alemtuzumab depletes cells in the blood immediately and lasts for many years. It is less clear what it does immediately to immune cells already in the CNS, because it is an antibody a lot of it is kept out of the brain and most of the cells are macrophages that are less susceptible to the actions of alemtuzumab so it these lesions may continue to grumble for a short time until they burn out (I don't know the data for alemtuzumab off the top of my head but with others it takes a short while for optimal effect) and the drug then kicks in by stopping further lesions.

      So you get a course of drug and another one a year later then it is a waiting game because disease may not come back…..maybe at least 15 years for some people I am led to believe.

      If you are on alemtuzumab you are going to be monitored every month for 5 years to check if the autoimmunity side effect occurs, so I suspect you will see a health care professional regularly, if you feel you have active disease then you must say something. As part of your health MOT you should be asking for a scan, I think profG tries to do this yearly. Lack of MRI activity on a scan should be re-assuring.

      Hope this answers your queries

  • FYI on 12/05/2013 the NMSS aired a web cast on Repair, Restoration and Neuro-protection in MS.http://www.media-server.com/m/p/hb2kaege/
    Dr. Barres at Stanford School of Medicine gave a short synopsis of his reseaerch. He said something interesting regarding myelin formation and the role of synapses. Oligodendrocytes are primed to myelinate axons but it seems their control is in part dependent on electrical activity in the axon. Newly formed synaptic connections, as in development, are more likely to be properly myelinated while axons that have lost their myelin and exhibit synapse loss, as in MS, are less likely to re-myelinate properly due to impaired electrical stimulus. This basic research into myelin repair is needed to understand and develop therapies for myelin repair. Interesting discussion.

  • I think i deleted a post by mistake concerning a paper in Nature neuroscience review. We routinely do not post on reviews they are the views of other scientists about the state of the art. We focus on new work. The review was focusing on laquinimod and neuroprotection. When the bloogger search feature gets repaired you will see we have posted o this aspect.

  • I re-post ( since MD said the post was deleted by mistake ) so the interested readers of the blog can judge themselves.

    As understand impact-factor is related to quality. Don't you think? That's why I found the paper in N.R.Neurology interesting.

    __

    Profs,

    Have you missed this? ( Brück, W. & Vollmer, T. Nat. Rev. Neurol. 9, 664–665 (2013); published online 26 November 2013; doi:10.1038/nrneurol.2013.234 )

    Would nice to have your comments. As I understand they are the #1 impact-factor peer review journal with regards to clinical neurology ( the Lancet neurology rated 1/191 is broader )

    " Laquinimod may,—be the first of a new class of MS drugs with a predominant CNS-intrinsic
    mechanism of action that helps to slow clinical disease progression and preserve brain
    tissue. "

    Sounds promissing to me.

  • Would you please comment on an article in The Times Fri 6 December re BCG injections and (the positive effect on) MS?

    Thank you

    • Looks really interesting. Small study but adds weight – if any were needed – to the immune hypothesis. It almost doubled (form 30% to 58%) the chance of not converting from CIS to MS in the first 5 years after the first attack which is quite remarkable. I wonder if it is being trialled for early MS (on the basis that early MS/CIS is a very blurred distinction in any event). I have to say, there's few side effects of a BCG, I'd be tempted to try and find a travel clinic somewhere and have an injection privately…

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735452/ (interesting 2008 study on BCG impact on EAE and TH17 responses)
      http://www.neurology.org/content/early/2013/12/04/01.wnl.0000438216.93319.ab

    • i will have a look when i get proper access to the internet.
      rember virtually everyone in the uk had bcg vaccination until recently and we are ms central.
      As for bcg and eae rember mycobacterium are the cornerstone of eae induction M.bovis in BCG and M tuberculosis butyrium in EAE.

    • My generation all had the BCG vaccination and we still got MS. Prof McDonald's words are still relevant. Don't believe everything you read in the newspapers.

    • I don't think this is suggesting BCG as a preventative vaccine for MS – it is saying that if the BCG is given at point of CIS, it reduced conversion to MS. I assume – although it's not clear – that these people had already had the childhoold BCG and this was given additionally as a specific MS treatment.

    • If you have already had BCG then you would probably get a massive reaction if you gave it again. The idea is you get life long immunity

      If you are mantoux test positive (the prick test on your wrist) then you will not get the BCG and get an xray to check you have not got tuberculosis.

      It would not make sense to do it twice….I'll have a read

    • Yes this an very interesting first step we reported on this study on July 7 2013 done in rats

      http://multiple-sclerosis-research.blogspot.co.uk/2013/07/imaging-remyelination.html

      I feel that 2014 is a year for myelin repair and the strides that have been made in the past couple of years will see a number of studies aimed at promoting repair start in ernest in MS…maybe we won't get the results in the same year frame. Maybe the intial trials will fail as Neuros workout how to detect positive effects. One of the roadblocks to investigating myelin repair is finding a method that actually monitors this. A myelin labelling agent is something that is needed. This study identifies a PET agent which is a molecule that emits low level radioactivity that is detected by the PET machine and in this case binds to myelin. This is a first study in rats the next stages will be to determine whether this can be translated into humans. A promising move forward.

  • I would like to hear you POV on IL-6 as a strong trigger in MS.
    I know that IL-6 plays a main role all over the bodies immune response. but:

    – IL-6 controls the permability of BBB (more IL-6 -> increased permability)
    – Vit D3 inhibits / lowers IL-6
    – Cannabinoids lower IL-6 level via the Endocannabinoidsystem
    – IL-6 regulates TNF-a (more IL-6 less TNF; with reagrds to recent reasearch which indicates that TNF-a is more on the positive side when it comes to MS)
    – EGCG downregulates IL-6
    – Methyprednisolon downregulates IL-6
    – Smoking increases IL-6
    – Sleeping and solitude lowers IL-6 (maybe the reason why MSers who have retired have a decreased activity?)
    – Simvastatin regulates IL-6
    – Curcumin inhibits IL-6
    – A lot of other medicines influence IL-6 direct or indirect.
    – IL-6-Deficient Mice Are Resistant to Experimental Autoimmune Encephalomyelitis
    – Rituximab has a stron influence on IL-6 expression
    – EBV infected B-cells produce IL-6 as a growth factor!!!
    – IL-6 is upregulated in warm enviroments (which may indicate, why ppl around the equator are less vulnerable to MS, because their bodies have adapted to higher IL-6 levels)

    So why has no one ever thought of testing IL-6 inhibitors in MS patients? With Tocilizumab there is already an IL-6 inhibitor on the market. And maybe there are a lot of other IL- inhibitors available of which I don't have any information.

    Maybe there is als a very good reason for NOT testing it. If so, please feed me info.

    feed me feed me, need more input xD

    • You forgot to mention proliferating astrocytes and IL-6.:-)..Obviously IL-6 has many functions outside the CNS and this all carries side-effect potential. For many years IL-6 was considered to be pro-inflammatory now IL-6 has been reported to promote anti-inflammatory effects. Which part of immunology dogma will prevail?

      One would need to ask Roche. What is the fate of Tociluzumab in MS?
      Would they want to compete with Ocreluzimab?

      However demyelinating polyneuropathy was reported rarely in RA trials and MS is a risk factor with use of this antibody, and so there is caution note about using ACTEMRA in demyelinating conditions, just as anti-TNF has been found to increase risk of demyelinating complications. TNF regulates IL-1 and IL-6

    • Maybe it's a dosage problem?
      Or a application problem (Intrathecal <> intravenous)?

      IL-6 (to my understanding) has also an "auto-amplifing-process" (is this the right term)? So more IL-6 generates more IL-6. Maybe this gets out of control?

      E.g. because a natural inhibiting factor (like TNF-a) doesn't work or isn't strong enough?

      So I guess anti-TNF would be a bad idea as TNF-A regulates IL-6 (more TNF, less IL-6).

      I also read about the anti-inflammatory effects. But I think it's more or less a 80/20 thing.

      I only have catched a few studies on IL-6 and MS (less than 10). But some promising in-vitro studies with Luteolin, Andrographolide and Resveratrol (which may act estrogen-like in MS). I know that a lot of these studies aim for money to get them started.

      But it seems to me that there are a lot of factors which correlate more with MS than, lets say, CCSVI.
      Especially if you look at medicines which are already in use for years. And they all have IL-6 inhibition in common (I don't find exact values for it, most studies only say "inhibits IL-6" or "inhibits IL-6 via xy-pathway)

  • Should people with MS be bombarding NICE's alemtuzumab appraisal website with comments while there's still time?

    I think we probably should be, but not sure it would meet the fairly narrow criteria they've requested.

  • Profs,

    Any chance of a quick review of 2013 i.e. your thoughts on top 3 research stories and your thoughts on what we might see in 2014 ?

    Another suggestion – why not shut blog down fron 24/12/13 to 2/1/14. Give yourselves a break.

    • Prof G may have time for reflection
      But in terms of highlights for 2013 it has to be choice………. this year we have seen the approval of more MS drugs which can only be a good thing.

      As for 2014 the trials with finoglimod in primary progressive should be finished, so watch for the markets as they release info to the financial sector.

      CCSVI trials could be completed…who will need to eat words?

      It will be a year for repair…I suspect we will see trials start doubt we will get results

    • I do not think there are any optimally-designed CCSVI trials due for completion in 2014.
      Is fingolimod likely to be effective in primary progressive?

  • Whatever happened to the promised response to this post?

    multiple-sclerosis-research.blogspot.co.uk/2012/02/alasdair-coles-guest-spotlong-term.htm

    "A couple of months" we were told – which was 6-12 months for us actually seeing it but….nothing…. Was it just an evasion of the question or am I being too cynical? We all no the earliest SPMS treatments were not positive in terms of progression but what of the earliest treated RRMSers? Does the lack of reply suggest the data on the early RRMSers treated is not good in terms of progress to SPMS and so someone (Sanofi) doesn't want it out in the open? Can someone repeat this question to Revd Coles to see what he has to say? We all hear anecdotes of long-term remission with Alemtuzumab of 10, 15 years but to hear real data, even if that itself is only fairly anecdotal, on those very earliest treated MSers, some of whom must be c. 20 years post treatment by now, would be incredibly informative and valuable. Prof G/MouseDoc – over to you?

    • Just giving this a 'bump' – I think, given the previous promise, we are owed a reply/comment on this. If the data is out there – even if just based on small numbers/anecdotal – I think it should be shared, as it was suggested it would be. Even Prof G must now have some treated Alemtuzumab patients who have been treated for more years than the 5 year extension study? Maybe some in the 10 year mark perhaps? What is your clinical experience of those treated early with Alemtuzumab?

  • "Top comments", which used to be available on the left panel (above the list of recent blog posts in the ""blog archive" panel), disappeared recently. Was it intentional? if not, can it be fixed?

    • The gadget enabling this appears to be broken. if you click on the subscribe to comments and select atom from the menu you can get the recent comments that way. Apologies.

    • The size depends on how you view them MRI lesion look bigger than histological kesion Some are much bigger that 1mm.

  • I read a comment about the trial comparing Lemtrada vs. Interferons. It seems this trial did not exclude those who had neutralizing antibodies to interferon which may skew the data in favor of Lemtrada:

    http://m.neurology.org/content/78/14/1069/reply

    I can see this point of view, and I don't really think the trial results are valid since you should be monitored by nabs when on interferon if you have a good neurologist. Any comments?

  • Lets hope so i cant see the paper on my phone but first we have toremeber this is the lowest efficacy DMT in MS
    That it did better than expected in atrophy may indicate a neuroprotective effect. GREAT
    Is lacqunimod rubbish in eae too?
    If not are the right experiment being done
    i will have a look

  • Did you already post about this paper?
    http://www.ncbi.nlm.nih.gov/pubmed/24364862

    I think it's suggesting that no matter how well I respond to my DMD early on, even the most aggressive drugs, I'm probably still going to get progression and need a second neuroprotective drug. (understanding that human experiences don't always mirror mice experiences.)

    • No i will post on this in the bext couple of dayss team g areco authirs. Weare aware ofthis no it does notnecessariky saythat progressionis an invariable consequnce but some. Tracts are affcted

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives