1. Patients launch a $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
9th Invest in ME International ME Conference, 2014 - Part 2: Pathogens and the Gut
Mark Berry continues his series of articles on the 9th Invest in ME International ME Conference in London, with the emphasis shifting from autoimmunity to pathogens and the gut ...
Discuss the article on the Forums.

Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

Discussion in 'General ME/CFS News' started by Sasha, Jul 30, 2013.

  1. froufox

    froufox Senior Member

    Messages:
    396
    Likes:
    65
    Hi Legendrew, thanks for sharing. Yes as you say its difficult to work out what is causing what sometimes. My ME was triggered by vaccines too - Hep B in my case...it was following my 4th jab/booster that I caught a viral ear infection, which led onto ME...I never recovered and that was 20yrs ago! I only tried abx the last few yrs since testing positive to various infections eg lyme, cpn and I have to say that they have been the most helpful treatment overall that Ive tried, though as I said the side effects became difficult to tolerate so I decided to stop. Though the fact that I experienced significant improvement does seem to suggest that I have various chronic infections....I dont know if this means the infections are at the root of the illness or as Prof Edwards says maybe as a result of immune dysregulation. I know that vaccines can trigger immune dysfunction and i wonder if either they are contaminated themselves, or disturb the body's ecology, and/or reactivate dormant infections? Who knows. There is some research that suggests that the Hep B vaccine in particular, can trigger demyelinating diseases via molecular mimicry.
    Kati likes this.
  2. Graham

    Graham Senior Moment

    Messages:
    776
    Likes:
    1,831
    Sussex, UK
    Hi there! I'm the friend that Bob mentioned that was on steroids - prednisolone (or prednisone in the US), a cortiscosteroid. I went down with ME in 1999 after an infection following a sinus operation, then went down with PolyMyalgic Rheumatica in 2005 (inflammation of the arteries and veins). On 10 mg a day, I am pretty much as I was with ME before getting PMR: I can wean off, very very slowly (half a mg a month) but by the time I hit 7.5mg my energies are at dropping fast.

    I have looked online a lot about this, and the picture is very mixed, but it does appear that I am in a small but significant minority. I did read an account by one doctor in the US who found that a low dose of 5 to 10 mg helped a proportion of his patients, but I cannot find the link any more.

    It seems to me that there are two possibilities. The first, as suggested most recently by Stephen Holgate, and by many many good researchers before him, is that there may well be many different subsets within the broad label of ME, some may have an adrenal problem, but it may be dangerous to generalise. The second is that I haven't got ME at all but an adrenal problem: we all know how reluctant doctors are to test properly for adrenal insufficiency - they assert that the standard test is sufficient.

    My sister, in Canada, wonders what my ME specialist makes of it. I just laugh. The only way to get a referral around here to a specialist is to cross their palms with large quantities of silver. An ME specialist diagnoses you, passes you back to a GP who then decides that there is no treatment or medication that is appropriate.

    Cynical - moi?
  3. lansbergen

    lansbergen Senior Member

    Messages:
    949
    Likes:
    408
    Could the increased IL-10 production be a result of B10 cells involvement ?

    http://arthritis-research.com/content/15/S1/S1

    Review
    IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

    Ioannis Kalampokis, Ayumi Yoshizaki and Thomas F Tedder*
    froufox likes this.
  4. voner

    voner Senior Member

    Messages:
    219
    Likes:
    102
    Prof. Edwards,

    Thank you for your enlightening replies about the subject of biomarkers. Prospecting for gold is actually done in with a very similar mindset. The analogy works for me.

    I think what confused me is that when us patients meet with researchers and organizations like CFIDS of America (One of the major ME Associations in the United States), They keep hammering the point that the researchers need to find biomarkers. But the biomarkers that these researchers were talking about are biomarkers that will proclaim this is a real disease and biomarkers that will separate different patient groups into subsets.

    You seem to be looking at it from the standpoint of that there are patients we can treat successfully and there's a biomarker that will help us identify them And hopefully we can also use that to further flesh out the story of what is happening is within these patients.

    When I used to look for gold, what you're doing right now was the part of the gold prospecting process I think I enjoyed the most. This was in the days before the Internet was prominent. I would do research and pinpoint areas that had clues that indicated there might be gold. I would haunt libraries, County assessor offices looking at records, Pour through old journals and ancient records and all sorts of oddball locations and talk to all sorts of people. Many of the people I would talk to would live in the middle of nowhere and not really like being Sociable, But I always found the give-and-take with these folks to be entertaining, and sometimes enlightening. I would Hunt & poke into every corner I could think of, and then within the given time frame put together a plan and try it out.

    I would consult with talk and to other people who do the similar jobs as I did, and I was always amazed at how the vast majority of them just did not do this pondering, early phase of work. Most would doggedly stick to the model they were using without ever questioning it even though it wasn't working very well. Many would run down along avenues that just were obviously not pragmatic and needlessly spend Their funders money. I guess they just did not have it in them to step back and wonder "what's going on here and why".

    Of course, that's what a lot of us chronically sick people spend our days wondering, "what's going on here and why".

    anyway, thanks for the Discussion.
    rosie26 and Marco like this.
  5. Dolphin

    Dolphin Senior Member

    Messages:
    6,472
    Likes:
    4,755
    I recall reading that the drug itself cost the NHS a price less than £1000 (I can't remember exact figure - high 3 figures). There would then be extra infusion costs. However, this is in the range of costs that not a tiny number might even be able to pay for privately.

    I then recall hearing a figure of $70,000 being quoted for the US. These are in two different ball parks, even if the $70,000 for the US is presumably for more than one infusion.

    Anyone know anything more?
  6. rosie26

    rosie26 moderate ME

    Messages:
    929
    Likes:
    1,072
    NZ
    Whatever causes, starts the ball rolling with ME, seems to make us extremely vulnerable, to viruses (flu etc), these viruses seem to finish the job and ultimately knock us down completely into the chasm of full on ME.

    It certainly seems to me that there is some over reaction going on in ME, absurd amounts. Outrageous sensitivities to noise, temperature, visual sensory, exertion PEM which requires absurd amounts of rest to try and recover from. Inflammation intensifies and rages at slightest amount exertion causing stomach problems, headaches, sinusitis, facial bone pain, muscle ache and pain, joint discomfort, glands ache and in severe ME there is also the unbearable poisonous feeling circulating in the blood vessels. Multitudes of symptoms to deal with in a very weakened state.

    btw, I was given Prednisone in the first year of ME, I had to stop taking it immediately. I found it utterly intolerable.

    I noticed someone else mentioned Interferon, I pondered this one a lot in the first years of my ME, perhaps another sign of the over reaction. ? What ever causes ME may make the immune system think a flu virus is a catastrophic fatal danger and over react. ?

    In the Severe years, ME feels like it is trying to kill you. It keeps hitting hard.
    aimossy, Gemini, froufox and 2 others like this.
  7. Firestormm

    Firestormm Senior Member

    Messages:
    5,817
    Likes:
    5,919
    Cornwall England
    Thanks for the reply :)

    So does it then follow, from what you said, and speaking plainly, that people with a diagnosis of ME, should display B-cell abnormalities prior to being treated with Rituximab? And is this something you can test for and better define your cohort - thus perhaps leading to an improved response rate?

    Or, given the random nature of generation (of which I understand very little), are antibodies always likely to be present? Could they be present one day and not the next? And how might this be allowed for with any test to determine suitability?

    I realise that part of what I am asking is perhaps what is missing and not known in ME; but perhaps Norway were able to observe pre and post treatment changes from their initial work and have been better able to account for this in their current trial.
    aimossy, voner and rosie26 like this.
  8. Marco

    Marco Old blackguard

    Messages:
    1,138
    Likes:
    743
    Near Cognac, France

    For what its worth many compounds have physiological effects beyond and often unrelated to their original purpose and assumed therapeutic pathway (e.g. SSRI anti-depressants typically take a few weeks to work while serotonin levels rise almost immediately suggesting their anti-depressant effects may be due to other actions).

    When I was looking for existing drugs that might target 'neuroinflammation' I found that Doxycycline (and other tetracycline antibiotics such as Minocycline) has been shown to reduce glutamate excitotoxicity and may be effective in treating pain via inhibitory effects on TNF-alpha. Similarly beta lactam type antibiotics (which include penicillin derived antibiotics) activate the EAAT2 glutamate transporter protein and in an animal model one such antibiotic, ceftriaxone, increased glutamate re-uptake thereby reducing excitotoxicity and providing neuroprotection.

    The EAAT2 glutamate transporter has been implicated in neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS) and in relapsing/remitting MS.

    Not that this is necessarily relevant to any improvements you experienced. These antibiotics may have other very different documented physiological effects which a different search might have turned up.

    Difficult to say when many drug effects are 'messy'.
    froufox and voner like this.
  9. Ecoclimber

    Ecoclimber Senior Member

    Messages:
    595
    Likes:
    929
    Mercer Island Wa
    I thought this was interestng as the rearch is still conintuing.

    https://www.ncbi.nlm.nih.gov/pubmed/21383843
    PLoS One. 2011 Feb 23;6(2):e17287. doi: 10.1371/journal.pone.0017287.
    Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome.
    Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, Camp DG, Holland BK, Bergquist J, Coyle PK, Smith RD, Fallon BA, Natelson BH.
    Schutzer, Natelson et.al came up with a biomraker that distinguish between chronic fatigue and Lyme disease. The procedure is not userful as a bio-marker because of the lumbar puntucre procedure.

    You are have theLght gound breaking stury on the Dorsal Root Ganglia. They
    proposes that a varicella-zoster infection of the dorsal root ganglia or other peripheral ganglia could readily account for a number of factors in CFS the acute onset, the wide variety of symptoms, the high misery/low fatality index and the post-exertional relapse found.

    You are have peope who are predisposition, upon receiving the HINI flu, all there hyprocretin wipes away.
    his article indicates that a pathogen H1N1 or an influenza vaccination is a cause of an autoimmune disease. It could be a subset of ME patients or it could lead to a dead end but I thought it would be worth exploring before posting a thread on it. It could be controversial.
    http://forums.phoenixrising.me/inde...e-cause-of-m-e-c-f-s.21737/page-4#post-341425

    Research had found that narcolepsy is an autoimmune disease that destroys the neuropeptide Hypocretin located in the Hypothalamus within the brain. Hypocretin and/or receptors OXi1 and Oxi2 control the entire body's asleep and awake state as well as circadian rhythms. Furthermore, it down regulates the HPA Axis, muscle... olfactory, inability to adjust to temperature extremes, severe insomnia, brain fog and memory issues, POTS, blood pressure volume, cardiovascular issues basically the human homeostasis...Occam's razor!

    It is caused by a gene mutation through an exposure to an influenza pathogen. This can be passed on genetically to other generations. Not every one that has this mutated gene develops this condition but 90% of the people who do have narcolepsy vs. controls have this gene mutation in the HLA ( Human Leukocyte Antigen) It is near the same location as a mutated gene expression for MS!

    What if the immune system targets this pathogen but also mistakes proteins in the brain that regulate sleep/awake cycles as a pathogen and take them out as well? Research has shown that this is what exactly occurs in narcoleptic patients?

    Dr. I would be interested in yout feeback? Would this make a possible challnge for you, to took outside the box.? Who knows, maybe chronic illensses and diseases are conncted in somewau.

    Eco
  10. Snow Leopard

    Snow Leopard Senior Member

    Messages:
    2,206
    Likes:
    1,543
    Australia
    It is really about following leads. Yes, we would like to find biomarkers, but how? You need some leads to follow and this is one of those leads. As I said on a previous thread, when Maria was just starting her crowd funding campaign, this drug is not necessarily the end solution, but rather a potential clue, at least in the long run. If these studies (Mela/Fluge and Edwards) demonstrate an effect, then it sends a message out there "please explain". It will bring a lot of new people into the field and perhaps we will no longer be in the catch-22 funding situation. (eg scientists don't spend a lot of effort applying for grants that will be knocked back and funding agencies say they can't fund more as they need more high quality proposals). Perhaps in time ME/CFS will no longer be funded a magnitude of order lower than every other disease category in the NIH and NHMRC (Aus.) lists, when comparing societal disease burden (DALYs)...........
    MeSci, biophile, Kati and 1 other person like this.
  11. froufox

    froufox Senior Member

    Messages:
    396
    Likes:
    65
    Hi Marco, thanks yes I completely agree about the multiple, and also perhaps unknown actions of some antibiotics/drugs in general, and that some of the improvements I experienced may well, at least partly, be explained by that. However, would that also explain herxing/die-off reactions too? I mean once the inflammation pathways are under control, I wonder if that could lead to some kind of normalisation of the immune response, which in turn allows it to fight off whatever pathogens we are harbouring?? Also just to add to that, I have responded to anti-virals aswell in the past eg famvir....again short-term improvements that did not last, but very definite improvements in functionality/energy. Ive also have also had some quite dramatic improvements at times from other pathogen killing treatments eg drugs/herbs for worms/parasites. Again, all temporary. So, all the evidence seems to suggest, at least in my case multiple pathogens, whether that is due to either a dysregulated or a suppressed immune system, I don't know, but with all the horrific symptoms that Rosie26 describes so well eg a constant feeling of being poisoned.

    Re steroids, I also took hydrocortisone for 6 months (averaging 15mg)) and although I never really felt worse as such whilst I was on it, although not much better either, it was clear to me that my body became dependent on it pretty quickly, no doubt due to an alreadyhypersensitive and dysfunctional HPA axis....I'd already been struggling with severe adrenal dysfunction for yrs prior to that. It felt like the h/c interfered with that delicate feedback mechanism that was already right on the edge in my case. When I weaned off the h/c, my adrenals tanked pretty badly and my cortisol levels nosedived and I also experienced a big exacerbation in inflammation. I have never really been the same since (that was 7yrs ago), although my adrenals/HPA axis are thankfully a bit stronger these days.

    rosie26 likes this.
  12. froufox

    froufox Senior Member

    Messages:
    396
    Likes:
    65
    Thanks lansbergen, thats interesting. Ive had IL-10 tested a few times, and its always been high, the last time a few months ago it was 101 (10-80).

  13. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    267
    Likes:
    1,442
    A course of two Igm rituximab infusions, which tends to need repeating every 8-12 months, cost the NHS £4,000 not long ago. Infusion services tend to charge around £1,000 per infusion but this may more than cover local costs. So a course will cost the NHS around £6,000 now. Fluge and Mella used the oncologists' dose by body surface area rule and gave what on average would be about 1.5gm total so that would be £5,000 for the two infusion course. Once off patent (November 2013) the cost ought to come down but nobody knows whether it will in practice.
    Firestormm, Dolphin and voner like this.
  14. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    267
    Likes:
    1,442
    You have a habit of getting to the crux of the matter Firestormm. That is the line I personally think is worth following. If there are relevant antibodies they will not go up and down that much - maybe over months or years a bit but only in degree. other B cell markers may indeed be more temperamental. The problem as I see it is a more subtle one. To give an example: when we first started treating RA it was our impression that the best responses occurred in patients with moderate levels of rheumatoid factor antibodies (RF). It became fairly clear that patients with no antibodies did not respond much. It also looked as if patients with very high RF antibody levels did not get the best (or longest) responses because their disease was just too tough to get on top of. I am not sure that this latter point ever proved true in statistical analysis of the bigger studies but it seemed to hold up in our clinic. The point is that any given B cell misbehaviour marker might turn out to predict response to rituximab or it might mark 'the tip of a very big iceberg' in cases too tough to respond. It might be a negative predictor. There will be a small number of people with ME with high levels on one of any number of B cell markers (ANA for instance). The problem is making a sensible choice on how to try to validate the predictive value of markers and which ones. To say more would be to speak on behalf of a team of other people who will actually conduct a study and it is not for me to do that.
    aimossy, Esther12, MeSci and 4 others like this.
  15. Jonathan Edwards

    Jonathan Edwards Senior Member

    Messages:
    267
    Likes:
    1,442
    Thanks for mentioning this. I was aware that narcolepsy was associated with the MHC DR1 haplotype (gene variation). I had not yet heard that this has been linked to an autoimmune response to hypocretin. I will read further. This would clearly be a good analogy for ME (or a subset) - an autoimmune reaction that simply presents as impairment of neurological function with no other standard signs of inflammatory disease. What I am unclear about is where the flu comes in, or maybe the adjuvant in the flu jab (which would be a quite different mechanism). The story sounds like the old molecular mimicry idea that all immunologists seem to believe in for no very good reason. Maybe this is the good reason at last, or maybe somebody has got a bit overenthusiastic in the storytelling in the journals or newspapers?

    Fascinating, thanks.
  16. Ecoclimber

    Ecoclimber Senior Member

    Messages:
    595
    Likes:
    929
    Mercer Island Wa
    The abstracts to the research are published here:

    Hypocretin deficiency develops during onset of human narcolepsy with cataplexy.
    https://www.ncbi.nlm.nih.gov/pubmed/23288981

    Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A.
    https://www.ncbi.nlm.nih.gov/pubmed/23773727

    Genetic association, seasonal infections and autoimmune basis of narcolepsy
    https://www.ncbi.nlm.nih.gov/pubmed/23497937

    A patient with both narcolepsy and multiple sclerosis in association with Pandemrix vaccination.
    https://www.ncbi.nlm.nih.gov/pubmed/22841884

    Finding could lead to new treatments, better understanding of other autoimmune diseases
    https://news.stanford.edu/news/1999/august11/narcolepsy-811.html


    Note: this would only apply to a subset of patients who have a predisposition to the specific gene. HLA-DQB1*0602

    Thanks for your input!
    rosie26 and voner like this.
  17. Dolphin

    Dolphin Senior Member

    Messages:
    6,472
    Likes:
    4,755
    Cheers. I presume the figure I saw was for 1gm.
    Those sorts of figures are still very different to the $70000 I have heard people mention for the US (anyone able to confirm/deny that figure).
  18. Kati

    Kati Patient in training

    Messages:
    1,823
    Likes:
    883
    I have been told the cost of one dose varies between 6000$ and 6700$ in the US. The cost of infusion in the US is definitely not 1000 £. Thankfully, patients have been able to get pharmaceutical fnancial assistance, so the cost to them patients is not 70 000$, much much less.

    Dr Edwards would be best consulting Dr F, M and K as to what protocol to use. i don't feel it is up to patients to tell him what protocol they are on. It has put people like me in serious trouble in the past. There are groups of people, doctors and scientists preying on situations like these.
    garcia, Firestormm and Ecoclimber like this.
  19. Dolphin

    Dolphin Senior Member

    Messages:
    6,472
    Likes:
    4,755
    More or less?
    Thanks for the reply.
    Here is where I came across the $70,000 figure for the US. No idea why they were so far off:

    http://www.whchronicle.com/tag/myalgic-encephalomyelitis/




    Think they may have mentioned the $70,000 figure in one or more MECFS Alert videos
    Kati likes this.
  20. Kati

    Kati Patient in training

    Messages:
    1,823
    Likes:
    883

    Infusion costs are much much less. You pay for the IV supply, and the time of the nurse to infuse, do the vital signs, etc. The first infusion requires much monitoring and 1:1 time, is more expensive, and the subsequent ones are cheaper.

    70 000$ figure represents if you had to pay for everything, including intercontinental travel to get such infusion.
    My own costs have been a fraction of that.

    I have been fairly open to such information in the past, however like I mentioned before, this forum is open to the public, and there are people who will take this information and use to cause obstacles to such treatments so I am threading much more conservatively now.
    Valentijn, Firestormm, Purple and 2 others like this.

See more popular forum discussions.

Share This Page