Tuesday, 27 January 2015

ClinicSpeak: Helicobacter pylori infection might prove the hygiene hypothesis in MS

How convinced are you by the hygiene hypothesis? #MSBlog #MSResearch #ClinicSpeak

"There is a theory that MS, and other putative autoimmune diseases, are due to excessive hygiene. The cleaner the environment you grow up in, the less infections you get as a child, the less your immune system gets educated by infections, the more likely it is your immune system will go awry when you are older, the more likely you are to get MS. The hygiene hypothesis has its many proponents; I am yet to be convinced as the data is inconsistent. The study below shows that MSers are less likely to be infected with the bacteria Helicobacter, which causes peptic (high acid) ulcers in the stomach and duodenum (upper small intestine). This study supports the hygiene hypothesis."

"A large component of the hygiene hypothesis relates to parasitic infections; there is data showing that the prevalence of MS is inversely proportional to prevalence of parasite infections in the population. This and other data have led to several clinical trials of worm therapy in MS; if you are infected with worms it changes your immune function that suppresses MS disease activity."

"Is it not amazing that we can go from bone marrow transplantation, or haemopoietic stem cell transplantation (HSCT), one day as means of rebooting your immune system to deliberate parasitic infections to subtly tweak your immune system as treatments for MS? How disparate can these two scenarios be. The difference with the parasite infection lobby is that they are doing randomised, double-blind, placebo-controlled trials to generate data to prove or disprove their hypothesis (Trichuris Suis Ova (TSO) in Recurrent Remittent Multiple Sclerosis and Clinically Isolated Syndrome (TRIOMS); NCT01413243). In comparison, the HSCT lobby simply want us to accept the evidence based on open-label observational studies that this treatment works and everyone should have access to the treatment because they know best and are prepared to take the risk. Either we accept the scientific process or we don't. If we don't set a very high-bar of scientific evidence for HSCT we are going to have all the same problems we have seen with other fringe therapies in MS and it will end-up condemning HSCT as a potentially very effective treatment for MS and open it up to abuse from unscrupulous clinics and clinicians wanting to make money out of desperate MSers and their families. It is important that the HSCT lobby take the MS community along with them; the only way this will be achieved is by a deliberate and well thought out public engagement campaign underpinned by due scientific process."

"Is anyone out there keen to help design a clinical trial to raise the level of evidence for HSCT above what it is at the moment? It is not just about whether HSCT works, but about its safety and durability and how it stacks up against existing licensed therapies."

"Back to this post. What is Helicobacter? It is a bacteria which infects up to 50% of the human population. Some strains of this bacterium cause disease in particular peptic ulcers, chronic gastritis, duodenitis, and stomach cancer. Helicobacter species are able to thrive in the very acidic mammalian stomach by producing large quantities of the enzyme urease, which locally raises the pH from about 2 to a more compatible range of 6 to 7. Helicobacter are usually susceptible to antibiotics. There is an amazing story behind the discovery of Helicobacter as a cause of peptic ulcer disease that eventually led to a Nobel prize. I would recommend reading about how Marshall and Warren came to win the 2005 Nobel Prize in Medicine; science does not get more inspiring than this. The Helicobacter story is not too dissimilar to countless others, whenever there is a paradigm shift in a field the community rejects it. I touched on this a few weeks ago when I discussed Zur Hausen, HPV and cervical cancer. I would not be surprised if a similar story is waiting in the wings for MS. Please remember Arthur Schopenhauer’s Dictum; all truth passes through three stages: (1) It is ridiculed, (2) it is violently opposed and (3) it is finally accepted as self-evident. Are we anywhere near this with the autoimmune MS theory or is there a black swan circling?"


Epub: Fabis et al. Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females.J Neurol Neurosurg Psychiatry. 2015 Jan 19. pii: jnnp-2014-309495. doi: 10.1136/jnnp-2014-309495.

BACKGROUND: In recent years, a relationship between Helicobacter pylori and many disease conditions has been reported, however, studies in its relationship with multiple sclerosis (MS) have had contradictory results.

OBJECTIVE: To determine the association between the H. pylori infection and MS.

METHODS: 550 MSers were included in the study and were matched by gender and year of birth to 299 controls. MSers were assessed for clinical and demographic parameters. An enzyme immunoassay was used to detect the presence of specific IgG antibodies against H. pylori in the serum sample of both groups.

RESULTS: H. pylori seropositivity was found to be lower in MSers than in controls (16% vs 21%) with the decrease pertaining to females (14% vs 22%, p=0.027) but not males (19% vs 20%, p=1.0). When adjusted for age at onset, year of birth and disease duration, H. pylori seropositive females presented with a lower disability score than seronegative females (p=0.049), while among males the reverse was true (p=0.025). There was no significant association between H. pylori seropositivity and relapse rate.

CONCLUSIONS: Our results could reflect a protective role of H. pylori in the disease development. However, it may be that H. pylori infection is a surrogate marker for the 'hygiene hypothesis', a theory which postulates that early life infections are essential to prime the immune system and thus prevent allergic and autoimmune conditions later in life.

54 comments:

  1. I think (and hope!) that either Charcot Project or HSCT turns out to be the Black Swan.
    And brings MS and all the old MS therapies to an end

    Worms don't seem as promising. But mine is an uninformed opinion


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  2. Thanks for your post. Your 'is there a black swan circling'is on par with Mouse's 'knights' and MD2's 'watch this space'. Is 2015 going to be the year when a breakthrough to benefit MSers will announced? A yes or no will suffice.

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    1. Maybe,who knows what is round the corner :-)

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    2. I asked for a yes or no response. We pay you guys well so please provide us with a good service!

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    3. I say "yes" there will be breakthroughs but will they translate to universal human benefit is the problem? I'm glass half full are thee readers too

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    4. "We pay you guys well so please provide us with a good service!"

      You're not paying me (or MD) anything like enough :-(
      My glass is half full of the milk of human kindness.

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  3. Don Giovannoni , what the heck is going on here?

    Your customers are going crackers, all of a sudden demanding access to some untested bone marrow transplantation that 48-hours previously they hadn’t even heard of. These MSers is crazy, blud. They’re like the ultimate Evel Knievel, totally willing to jump in at the deep end if a so-called ‘professional’ (a.k.a. neurologist) suggests it may cure their hitherto incurable disease. The last time I checked, you geezers don’t even know why MS happens.

    And now we come to Helicobacter: something else to fill these blog pages full of random suppositions. Blimey, the more you blokes clutch haphazard propositions out of the air, the more I wonder if Barts and The London is some kind of Dead Poets Society collective where pages are torn out of text books and med students jump onto table tops to declare the next pathetic hypothesises pertaining to the origins and fixtures of multiple sclerosis.

    Hey, did you old dudes hear about Nytol, Benadryl, Ditropan and Piriton being among the medications identified by scientists as raising likelihood of dementia in today’s press? Mate, these are over-the-counter pharmaceuticals you can buy without a prescription that, according to The Telegraph, “can increase the chance of getting Alzheimer’s disease by more than 60 per cent.” And these are innocuous medicines that have been available for decades.

    It all makes you wonder what kind of damage the even more dangerous DMT crap you folks are advocating on this blog is doing to clueless MSers seeking quick fixes. In the words of Johnny Rotten: “You’ve all been had”.

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    1. Bone marrow transplants for MS were in the news in the year 2000, http://news.bbc.co.uk/1/hi/health/894219.stm , not 48 hours ago.

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    2. So true, Dre I read about this. It's all over news broadcasts. It's alright for these people to encourage us to experiment with dangerous drugs, but they don't even know what is happening to us or why. If we get more ill they'll just say that they thought they were on the right tracks at the time.

      God knows what these DMTs are doing to the human body. So irresponsible.

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    3. You make a good point. The long term effects of DMTs might be seriously devastating. No one can even say why MS happens let alone cure it. It's scary. Not interested in HSCT.

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    4. Looks like you've being overdoing the Nytol, dear Dre ;-)

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    5. It's easy to mock Dre but his potential predictions could be possible. You hear about stuff like that all the time.

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    6. Of course these drugs are dangerous and carry risks they are beating seven bells out of the immune system, but then the disease is doing the same to the brain. It is the devil and the deep blue sea. Its like cancer do you want to die of the disease or risk dying from the treatment. I chose the treatment, I almost died but in the end failed to do so.

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    7. Re: "Nytol, Benadryl, Ditropan and Piriton..."

      Common to all these drugs is that they have central anti-cholinergic effects. I have been lobbying for years to get Ditropan (oxybutynin) off the shelf for MSers. Being on these drugs reduces your IQ by about a half a standard deviation, i.e. 7.5 IQ points. This will be enough to bring forward the diagnosis of dementia. Please if you have bladder problems and are on oxybutynin can you please see your GP or neurologist to change it to one of the newer generation drugs that does not cross the blood brain barrier.

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    8. "In the words of Johnny Rotten: “You’ve all been had”.

      In the words of Johnny Rotten "Buy Anchor butter".

      Delete
  4. Why no mention of reverse causality? The H pylori does not modify the immune system it colonises people with certain types of immune system.

    And does this make the good people of Queensland an unclean bunch while those of Tasmania are much too clean. Looks more like noise to me.

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  5. Hopefully the black swans swoop down soon :)

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  6. Prof G - last comment from me then I'm going to pipe down for a bit! :)
    The HSCT lobby, as you call it, do not say that "everyone should have access to it because we know best and are prepared to take the risk". That is entirely unfair, and totally untrue - and it is precisely this kind of childish statement that is at the heart of the problem.
    As you well know, what you've said above is fundamentally untrue. Non-myeloblative HSCT is already in a randomised, controlled, partially blinded trial MIST Phase III). The UK is participating in that trial, at Hallamshire hospital. It is head to head with Tysabri (2nd line treatment in the UK). By comparison, the anti-CD20s - which you are telling us is the future for MS - are in trial against lowly Interferon Beta. Not Alemtuzumab. Not Tysabri. Interferon Beta. Unsurprisingly, I've not heard you complaining so loudly (or at all) about that.
    According to your recent posts, HSCT must be trialled against the efficacy of Alemtuzumab for it to be relevant, but you don't apply the same standard to Ocrelizumab (which is against If-B). On top of this, when results were published for HSCT (albeit open label), the results showed it to be MORE THAN TWICE as effective at inducing NEDA (80%), versus Alemtuzumab (39%). Your response? "Stem cell transplantation results are very similar to Alemtuzumab". That is simply not correct and is not an evidence-based statement. If the results for another drug reported these same results I highly suspect you'd be trumpeting it as a "paradigm shift".
    Then, in defence of that, you have suggested this view is based upon repeated treatments of Alemtuzumab. Do you believe that comparing a single hit of HSCT (one induction therapy) versus multiple annual doses of Alemtuzumab (another induction therapy), is a fair, like-for-like unbiased trial of effectiveness of one protocol versus the other? By the same logic, for Ocrelizumab to get through, perhaps we should test one dose of that against a year of annual Tysabri infusions?
    Of course, there is no comparitor trial of multiple hits of Alemtuzumab vs. multiple hits of HSCT (or even multiple hits of Alemtuzumab vs a single hit of HSCT) to back up your claim, but apparently the requirement for comparitor trials only applies to arguments which oppose yours.

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  7. What the HSCT lobby would like is a fair appraisal of the treatment, and an end to posts on well-read research blogs which (misleadingly) talk about a 2-5% mortality rate, the use of Total Body Irradiation and dismiss any results published with disdain and misleading facts (such as those outlined above). There is an element of plucking stats to fit a picture that suits your pre-established view of the world, also known as "bias".

    We would all like to see more RCTs for HSCT, but since there is no profit/patent at the end of it, the likelihood of getting that funded (much to all of our frustration) is very small. If you have a solution to this or the influence to make these trials happen, we would all like to hear it and be very grateful. However, if you are so close-minded as to think that any MS treatment is that it is not backed by the deep pockets of pharma to fund an RCT should be disregarded, then you're effectively introducing financial bias.

    The fact that neurologists - including yourself, I'm afraid - regularly spout mortality stats that are over a decade out of date (<0.5% maximum these days) reinforces this view that HSCT is outlandishly dangerous, when in fact it is quite clearly not. The simple fact it is that deaths in non-myeloablative HSCT are exceptionally rare these days - even in cancer patients, let alone relatively healthy MS patients. Patients die on Alemtuzumab and Tysabri also, but when HSCT comes up, you exorbitantly emphasise the mortality rate and late risks of that therapy, whilst downplaying or downright ignoring those of the treatments to which you're comparing it (Ocrelizumab, Alemtuzumab, Tysabri).

    I love your blog, and I think we’re all on the same side, but I do wish you would pick up the phone to your colleagues in the UK and overseas who are involved in the HSCT research to make sure that, if you’re commenting on it, you’re giving a fair, unbiased and informed opinion – as you generally do so brilliantly for pharma treatments.

    To sum up, I'd like to leave you with your own favourite quote; all truth passes through three stages: (1) It is ridiculed, (2) it is violently opposed and (3) it is finally accepted as self-evident. I'd say with HSCT we're about mid-way through #2! :)

    And on that note, I shall shut up for a while :)

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    1. OK.thanks.. as it is beginning to sound like a Lobby. Maybe we will get some guest posts

      It is important that this does not become another CCSVI as it is clear people are starting to go for medical tourism.

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    2. oh no don't let it be another CCSVI and do caution the MSers quick smart. Are you for real ? You wouldn't get away with your attitude in any other discipline. Anyone, yourself included is going to try anything once function is lost . The choice is the latest miracle cure or the quack neuro with his/her bag of tricks. Caution your ego.

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    3. You might find crystal therapy helpful, whatever floats your boat and it won't do you any harm.
      All we are doing is trying to stop people trying non-recommended therapies that may do nothing except induce anorexia of the wallet. There will be lot of quacks springing up on the back of HSCT.

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  8. God bless the charcot project

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  9. As a newly diagnosed MSer I feel I have no choice but to jump on the health tourist bandwagon as my MS is at present to "mild" to get on any of the stronger stuff in the UK. First lines are all I qualify for. I'd choose Lemtrada right now but as the cost of this abroad is the same as HSCT I may as well plump for HSCT.

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    1. I am not a neuro but look at the NICE guidelines is says simply 'active' MS for first line Alem, this could be interpreted as a very low hanging fruit compared to the activity needed for first line Natalizumab, obviously I don't know your circumstance and am not a neuro

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    2. I agree with you MD but the guidelines still refer to active as a clinical relapse :-(

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    3. "Alemtuzumab is recommended as an option, within its marketing authorisation, for treating adults with active relapsing remitting multiple sclerosis."

      LEMTRADA [alemtuzumab] is indicated for adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features."

      http://multiple-sclerosis-research.blogspot.com/2014/04/nice-approves-alemtuzumab-lemtrada.html

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    4. Thanks for that. The MS Trust website refers to active in the context of Lemtrada as normally two clinical relapses within two years hence my confusion.

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    5. One could think this could be one of the easiest drugs to access based on the interpretation. You should talk to your neuro, before going on medical holiday.

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  10. MINDY SAID
    "Is anyone out there keen to help design a clinical trial to raise the level of evidence for HSCT above what it is at the moment? It is not just about whether HSCT works, but about its safety and durability and how it stacks up against existing licensed therapies." Yes, I would like to be involved. EMAIL REMOVED

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  11. "HSCT lobby simply want us to accept the evidence based on open-label observational studies that this treatment works and everyone should have access to the treatment because they know best and are prepared to take the risk"

    I think this comment is a bit unfair. Over and over you've drummed into us time is brain and the need to hit hard and early. You've encouraged MSers to get a voice, take control of our own health and become informed. Now you've achieved this you don't seem comfortable with the feedback.

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    1. Re: " Now you've achieved this you don't seem comfortable with the feedback."

      I am comfortable with the feedback; I just don't think MSers should be travelling to different countries to have HSCT at great expense. I think we need to take a breath and ask the question what needs to be done to get HSCT licensed in the UK and other countries so that healthcare systems will pay for this treatment. If we don't do the latter then unscrupulous practitioners will continue to take money off vulnerable MSers. At a healthcare systems level it is against EU law to prescribe off-label treatments for a disease when licensed treatments are available. These are just two reasons to get HSCT licensed; this will also give neurologist confidence to prescribe it.

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    2. Dear Professor,

      I can see your points. Despite having my MS stopped by HSCT, I am pretty sure that this treatment will not become mainstream. First, there won't be enough clinical trial result in the next 20 years for this to happen and secondly, haematological units do currently not have those capacities. Even when Dr. Burts Phase III trial will be completed (2022?), health authorities might ask for another Phase-III study...then we will have 2030 and by then the mono-clonals will most likely be optimized to treat patients with the first sign of disease and very little risk.

      You know this already and hence look for other options.

      However, I would like you to think about your own life and things you want to achieve in a lifetime. From a neutral perspective, you already know that as a community, neurologists have failed to use their lifetime to make a positive difference. I am not only talking about failure of implementing HSCT as a curative option for MS and lobotomy, but most strikingly, I find what you posted a couple of days ago: Maybe simple sunlight (or UV-B) therapy could, on the long term, not only delay disease onset to after death, but it might be actually good enough to stop inflammation.

      All this in mind, how can a neurologist believe he/she will go to neurologists-heaven after all? Do you think god will fall for the excuse "we have to treat according to scientific evidence"?

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    3. Do you think neurologists should treat where scientific evidence is lacking or incomplete?

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    4. We all know that morphine can inhibit pain, but you are asking us to support going to score some street heroin as a solution.

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    5. "Do you think neurologists should treat where scientific evidence is lacking or incomplete?"

      I think that is exactly what neurologists have been doing in the last decades. For example, most of the time neurologist prescribe steroids for relapses, but what evidence is there for doing this? None, absolutely none! Maybe steroids even increase the conversion rate to SPMS...

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    6. "We all know that morphine can inhibit pain, but you are asking us to support going to score some street heroin as a solution."

      Sorry, that I would not ask you to do...morphine is better!

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    7. "For example, most of the time neurologist prescribe steroids for relapses, but what evidence is there for doing this? None, absolutely none! Maybe steroids even increase the conversion rate to SPMS..."

      I have to say I do tend to agree with you on this point. I seem to remember that a study showed that for head trauma steroids actually made outcomes worse.

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    8. " I think we need to take a breath and ask the question what needs to be done to get HSCT licensed in the UK and other countries so that healthcare systems will pay for this treatment. If we don't do the latter then unscrupulous practitioners will continue to take money off vulnerable MSers. At a healthcare systems level it is against EU law to prescribe off-label treatments for a disease when licensed treatments are available. These are just two reasons to get HSCT licensed; this will also give neurologist confidence to prescribe it."

      I agree with you. I thought a few cases had been done on the NHS already? Would this be from a trial? The NHS England clinical commissioning policy for HSCT lists MS but refers to BSBMT 2012 indicators. What does this mean please?

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  12. "Is anyone out there keen to help design a clinical trial to raise the level of evidence for HSCT above what it is at the moment? It is not just about whether HSCT works, but about its safety and durability and how it stacks up against existing licensed therapies."

    It seems this is exactly what Dr. Burt is doing in his phase 3 trial. Below is a link to the trial description. Please explain what you see wrong with this as it is sanctioned by the NIH?

    https://clinicaltrials.gov/ct2/show/NCT00273364

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    1. We are well aware of the existence of the trial thanks and destructive comments do you no favours and end up in the bin.....spammed
      I bet many of you could critique the trial , is it perfect? Of course not...which ones are?

      You can see it is an open trial and this is compared with what's there. Can it beat beta interferon...I suspect it can...would it beat another induction therapy? Health tourisms is occurring based on the hype,

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    2. We may need to do more analysis but for non-gadolium progressive MS, the evidence is much weaker and suggests a relative lack of efficacy in PPMS/SPMS, hence it is an exclusion criteria in some trials, een in some of the medical tourist destrinations

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    3. Hi MouseDoctor... are you associated with the author of this article? I can't tell from your comments.

      Bojana

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    4. MD: I did not write any of the comments posted above. But I am failing to find which one/s you find destructive? It appears that educated MSers are being their own advocates now, they are doing their research & the bias towards DMTs is so heavily influenced by financial incentives (to both physicians & pharmaceutical companies) it clearly apparent. Trial results supporting the effacity of HSCT are starting to speak very very loudly, people a cross the globe are listening (& acting). "Stem-cell" therapies (without chemo) are absolutely creating medical tourism. HSCT is not that, it's not experimental & it's getting results. Granted we don't know the long term durability, but it's certainly looking far better than anything else currently available!

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    5. Hi MouseDoctor... are you associated with the author of this article? No

      MD: I did not write any of the comments posted above. But I am failing to find which one/s you find destructive?

      The ones in spam in relation to this comment that I haven't posted, but the person posting them will come back to see if I have responded to them. Therefore they can read a response or part of a response.

      It is better than anything else available? Is it appropriate for your stage of disease? Will the phase III trial lead to approval? Should be anything but a third line? etc
      s lead I can see the them and us starting and the tourism

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  13. Prof G - I agree that in order to prove treatments are effective you need to have clinical trials with controlled results. However, tell me if Alemtuzumab and Natalizumab are now the most effective treatments on the market, why are other drugs being put into trial vs Interferon or Copaxone? That I am afraid is not gold standard, it is basically saying there are 10 drugs on the market, my new drug is better that the least effective so here is another choice but its not that effective..

    I am also curious, for a treatment like HSCT, how do you do blinded/controlled trials vs another drug? As Hair loss from Chemo is hard to not notice?

    Also in another post regarding HSCT you said we hear you loud and clear? What does that mean? Are you going to consider how you can make this an option? Start really looking/understanding/analyzing the data? MD talks about avoiding medical tourism, but if it turns out that HSCT is the most effective treatment, as an MS Specialist do you worry about missing the boat for your PATIENTS?

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  14. I've a question not directly related to HSCT (yay, I hear you say!).
    On this blog you've published a league table suggesting the UK has some of the worst access to MS care in Europe.
    You've also published that in countries like Australia they wouldn't participate in your trial as they considered not treating with Tysabri first-line to be unethical.
    You've also hammered home "time is brain".
    So to recap, care in the UK is substandard, it's better overseas, and if we don't act we'll lose brain and prime future degeneration and progressive disease.
    You also say UK neuro's are too conservative and MS'ers need to own their disease and treatment.
    Yet you're remarks on health tourism are so disparaging... I'm struggling to reconcile what your views actually are.
    Are you saying the care is sub-standard in the UK, it's better elsewhere, and our advice is that you stay put, suck it up and lose brain?

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    1. The comments on "health tourism" are not meant to be disparaging. They are merely meant to caution MSers that there are numerous unscrupulous practioners out there that will gladly empty your wallet for treatments that can be dubious, to say the least. This has happened with "stem cell therapy" and CCSVI which are the two that spring immediately to mind. If HSCT is really as good as people say, it will be reflected in clinical outcomes from properly conducted trials, then it should be recommended as a treatment in the UK.
      At the moment it is too early for proper conclusions to be drawn.

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    2. Health Tourism...can be the pay day for scammers so it can be buyers beware.
      As I have said we all know that morphine can inhibit pain, but should should not be asking us to support going to score some street heroin as a solution.

      Delete
  15. I'm glad that Matt has had a good outcome with HSCT, and I agree it should be trialed against alemtuzumab . However, as both of them are hopefully going to work in the long term, it could take 10-20 years to get the data. I would also like to state that chemo does not easily cross the blood brain barrier- some do; in some only a small amount crosses; some don't. Not all chemo causes hair loss. HSCT in itself for auto immune dieases (ADs) can cause further ADs- see article in bloodjournal.org for August 11 2011- secondary ADs occurring after HSCT for AD; a retrospective study of the EBMT AD working party. Saying that, I'd much rather the choice was between alemtuzumab and HSCT, rather than alemtuzumab and nataluzimab, a real russian roulette drug.

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  16. Looking at the BSBMT, HSCT is a clinical option for "severe resistant" MS so is it not already approved in England? Just trying to get my head around it.

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    1. Some places that so HSCT, may try HSCT when other things have failed, however at present it is licensed and so not generally available.

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