1. Patients launch $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!
A disease with two faces? Re-naming ME/CFS
Persuasion Smith covers the bases on the misleading and disreputable name for our disease we've all been saddled with ...
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. MeSci

    MeSci ME/CFS since 1995; activity level 6

    Messages:
    3,826
    Likes:
    4,587
    Cornwall, UK
    Are you sure it was a cold? To me it just sounds like a bad case of 'standard ME symptoms'! People with ME often think they are getting frequent colds and flu because that's what the symptoms are like. But that is also what ME symptoms are like! As Jonathan Edwards said, symptoms of infection are mostly due to our immune reactions. And the symptoms of ME are also largely due to persistent (auto)immune activity, at least in a significant subset.

    In my experience, such worsenings occur after over-exertion and/or excessive carbohydrate consumption.
     
  2. Legendrew

    Legendrew Content team

    Messages:
    535
    Likes:
    692
    UK

    Yeah in this case my whole family was infected and feeling lousy - i just felt that little bit more lousy! I understand where you're coming from, I often worry i'm coming down with another cold only to wake up the next day feeling fine (ME aside that is!)
     
    Firestormm likes this.
  3. Firestormm

    Firestormm Guest

    Messages:
    5,824
    Likes:
    5,982
    Cornwall England
    One major difference between ME and a cold: NO SNOT! :D

    Funny mood. Sorry. Need bed!
     
    madietodd and heapsreal like this.
  4. Ember

    Ember Senior Member

    Messages:
    1,741
    Likes:
    1,818
    Post-exercise malaise is described differently in different case definitions. The NICE criteria define PEM in such a way as to make optional “general malaise or 'flu-like' symptoms,” as well as “physical or mental exertion makes symptoms worse.” But PEM as defined in the CCC involves the "tendency for other associated symptoms within the patient's cluster of symptoms to worsen:”
    The ICC, a more strict and coherent definition, describes PENE as the cardinal feature of ME, “a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions.”
     
  5. Bob

    Bob

    Messages:
    8,840
    Likes:
    12,312
    South of England
    I won't post any thing else about this subject, as I don't want to distract the thread, but I just want to clarify some details about the NICE critieria, that Firestormm posted above...

    Post-exertional malaise is discussed in the NICE guidelines, but it is not a requirement for a diagnosis.

    Quote from the NICE guidelines (my emphasis):
    Note the use of the word 'or'.

    The guidelines then go on to say (my emphasis):
    Note the use of the word 'reconsidered', which is not the same as 'disregarded'.
    The last extract seems to add some ambiguity, as it seems to suggest the inclusion of post-exertional malaise or fatigue is at the clinician's discretion, which doesn't seem to fit with the previous quoted extract.
    This perhaps might be explained by NICE guidelines being exactly that: 'guidelines', and not rules.

    So, it seems that post-exertional malaise or fatigue are at least recommended inclusionary criteria. But it is not a requirement that the post-exertional symptoms are delayed or have slow recovery. And post-exertional malaise is not a requirement. So NICE does not seem to require the sort of post-exertional symptoms that many of us associate with ME. (i.e. a delayed and prolonged post-exertional symptomatic flare-up that is not relieved by rest.) This, in my opinion, makes NICE inadequate at distinguishing CFS/ME from chronic fatigue.

    So, to clarify, NICE does not require post-exertional malaise.

    Professor Edwards has said, that we don't know if patients with post-exertional malaise would respond to treatment with Rituximab, so it's perhaps not necessarily a good thing to only include patients with post-exertional malaise. (I think I am showing my biases, whereas Prof Edwards is approaching it with an open and scientific mind.)
     
    Valentijn likes this.
  6. Bob

    Bob

    Messages:
    8,840
    Likes:
    12,312
    South of England
    I'm demonstrating my long-held biases, and you're approaching it all with an open and scientific mind, thankfully. In our experience, not all scientists approach the field with this sort of openess, and inquisitiveness, so it's very refreshing! Thank you.
     
    Gemini, MeSci and Marco like this.
  7. MeSci

    MeSci ME/CFS since 1995; activity level 6

    Messages:
    3,826
    Likes:
    4,587
    Cornwall, UK
    Speak for yourself! I do get snotty sometimes, often sneeze a lot, get nasal congestion, etc., with PEM.
     
  8. Legendrew

    Legendrew Content team

    Messages:
    535
    Likes:
    692
    UK
    Is it possible for an autoimmune response to bind to an extracellular proteins or enzyme and set off a chain of reaction meaning, instead of reducing or completely stopping the action of the protein - cause an upregulation in the production of the product from an enzyme - whether that be directly by increasing the catabollic rate of the enzyme or indirectly through a complex set of interractions.

    I bring this up because i've recently been reading into nitric oxide which has been implicated several times through the history of ME. As you may very well know Nitric Oxide has many different roles in the body - acting as an intracellular messenger, being a major EDRF and also plays a role in the immune system - being produced by phagocytes (i believe the current theory is that it acts as a toxin to pathogens due to its status as a free radical being able to damage pathogen DNA). It certainly has to potential to explain the wide ranging systemic involvement apparent in ME despite the lack of evidence indicating any observable damage. Certainly Nitric oxide synthases have been implicated in autoimmunity before and could prove to be a potential target.

    The following link discusses the potential for overproduction of nitric oxide through a fairly complex uncoupling of the Nitric Oxide synthase enzyme which could theoretically be achieved by an autoantibody. http://www.cfids-cab.org/rc/Pall-1.pdf

    while this link http://www.sciencedirect.com/science/article/pii/S0301008209001580 discusses the role of Nitric Oxide with the nervous system which I believe you seem to consider being adversly effected with ME.

    I also thought you'd find the following link quite interesting considering the attention you gave the study suggesting visual disturbance as a potential marker of ME http://www.udc.es/dep/medicina/neurocom/revistas/tins.pdf

    Finally here's one linking together Nitric oxide and natural killer cells - for all those nk cell lovers out there =)
    http://www.ncbi.nlm.nih.gov/pubmed/11515816

    I certainly think this area deserves some thought.
     
    NK17 and voner like this.
  9. Jonathan Edwards

    Jonathan Edwards Board Member

    Messages:
    1,110
    Likes:
    5,094
    That all sounds perfectly feasible Andrew. However, Oystein Fluge has staked a litre of best Norwegian lager on nitric oxide being crucial and I feel I should put my pint of Adnam's on something a bit different. He may be right but one has to have a little friendly competition going on! I will have to read up on your citations - sounds interesting.
     
    NK17, aimossy, MeSci and 2 others like this.
  10. Snow Leopard

    Snow Leopard Senior Member

    Messages:
    2,411
    Likes:
    2,059
    Australia
    I've said things along the same lines - eg the fatigue associated with MS, RA, HIV-AIDS, post-cancer treatment, is all medically unexplained. No one understands how those conditions can cause the fatigue as it is experienced by patients.

    Yet those people get even less treatment and research than CFS patients. Or worse, they just effectively say "It is due to the psychosocial stress of the illness, so we will treat the psychosocial aspects it with CBT and other non-pharmacological treatments etc. and it will magically go away". Of course just like in CFS, there is no objective improvements in activity levels or neuropsychological testing, something that should be considered very important in non double-blinded RCTs.

    Interesting. The problem is that without a large amount of luck/serendipity, the field may continue to be a backwater and continue to receive a magnitude of order less research funding than its disease burden mandates. It is very much a chicken and egg question, I would very much like to see more catalysts for action for research into chronically fatiguing conditions.

    I do have another question: How do you conceptually deal with the fact that about 10-20% of patients spontaneously recover, or at least have remission for 5 years. Are those patients not likely to have an autoimmune condition?

    I guess I am still worried that the Rituximab research may turn out to be yet another dead end. Or even if it is useful, those who do not respond will still be stuck with the same old assumptions and still not get the focus they deserve...
     
    Sasha and heapsreal like this.
  11. Jonathan Edwards

    Jonathan Edwards Board Member

    Messages:
    1,110
    Likes:
    5,094
    I am interested in the frustration sensed by people within the ME community over funding. Diseases do not in general 'not receive funding' because of some deliberate decision by anybody. Research is a free for all. If a researcher thinks he or she has a good idea they can ask for support. I am not sure that there is any particular bias against diseases. The real problem with large funding bodies is bias against anything unfamiliar or new, so a lot of original research has to be done on a shoestring until its worth has been proven. And new ideas are hard to come by. Until 1985, when monoclonal antibody technology and gene cloning got going, it took years to isolate a single protein. With pathways involving fifty proteins there was never any hope of working out mechanisms - all that changed. Work was naturally first applied to situations where there were molecular leads - which mostly came from studying structural changes in tissues. So conditions without any structural change have by and large not seen much headway. But much more subtle leads can now be pursued.

    Trouble is, even where there are leads, new ideas are thin on the ground. As a result vast amounts of funding are poured into testing the same old ideas with the most marginal benefit. Huge amounts of funding have gone into heart disease when what was needed was for people to eat better food, stop smoking and do more exercise. Heart attacks in young middle aged men had almost disappeared in 2000, as compared to when I was a houseman on the ward in 1975. But they will be back now that everybody is getting fat. Money mostly down the drain. Useful original research very often occurs when one particular person has a particular idea about something that interests them and has the determination to pursue it. I am not impressed by initiatives to 'tackle disease X' with big new institutes and lavish funding. If nobody has a good new idea it will all be wasted. If they did have a good new idea then why not just fund it without all the hoo-hah.

    Funding also depends on charities and the support they get. Cancer charities get a lot of money because cancer is very common and a lot of rich people get cancer and their estates help to set up big foundations that have momentum, I suspect. But a lot of other common diseases get much less funding. Each disease community has to rely on the man and woman in the street to be sympathetic. If the money for ME is less, the questions is why, and I am not sure I know the answer better than anyone else.

    But I am actually very optimistic here for ME. There are clearly a few people (you only need a few) who seriously want to sort out what is going on. There are a number of new leads emerging. Scientific meetings specifically on ME are now being held. There is a community with a commitment to getting funds together once a lead looks promising. The problem is not actually money, I think, it is having goods leads and a few people wanting to pursue them. It's a bit like saying 'Why haven't you invented the wheel this week?' 'Oh, because we can never get the funding.' The reality is that inventing the wheel is a bit tricky.

    What remains frustrating is that it takes so long to put things in to practice. Laboratory science is a slow business if it is to be done well enough not to leave a meaningless mess of unreliable results. But it doesn't take forever.

    I think we did cover this - a small proportion of cases of several autoimmune diseases recover spontaneously. That can be explained by B cell loops drifting in such a way that they exhaust themselves and 'burn out'.
     
    NK17, aimossy, currer and 7 others like this.
  12. Sasha

    Sasha Fine, thank you

    Messages:
    8,749
    Likes:
    8,093
    UK

    Is there anything that can be done to encourage that process?
     
    NK17 likes this.
  13. Jonathan Edwards

    Jonathan Edwards Board Member

    Messages:
    1,110
    Likes:
    5,094
    I fear not in the foreseeable future. It would require a level of detail of understanding of the individual immune system's repertoire that is way beyond anything possible at present and may always be unrealistic. Blocking a loop is fairly easy to see how one might do, but encouraging a loop to run so fast round and round the tree it turns into butter, like the tiger in the children's story, is a bit too clever for any of us I think. Maybe one day...
     
    NK17 and Sasha like this.
  14. Snow Leopard

    Snow Leopard Senior Member

    Messages:
    2,411
    Likes:
    2,059
    Australia
    I will reply to the other issue later, but this is very interesting. I must have missed when it was first mentioned. But I am curious as to how common this is in any otehr particular disease? Can it explain 10-30% of spontaneous remission within about 10 years (after which the likelihood of spontaneous recovery flattens out close to zero, I have tried to model this as best as I can with all of the published data on long term outcomes...). If not, for what reason could or would ME be special, or are most of those recoveries likely to be in patients without an autoimmune condition? This is purely speculative I know, but I'm still trying to wrap my head around it.
    I am still leaning towards something along the lines of the speculative paper (by the Italian authors) I linked earlier which discussed B Cell loops, but not necessarily classic autoimmunity.
     
    MeSci likes this.
  15. Ember

    Ember Senior Member

    Messages:
    1,741
    Likes:
    1,818
    Given your wariness of “post-exercise malaise” and its narrative, do you think that you're tracking ME here or could it be a different GIMIF that's responding to rituximab?
     
  16. Jonathan Edwards

    Jonathan Edwards Board Member

    Messages:
    1,110
    Likes:
    5,094
    I think almost anything could fit with a B cell loop. Short lived autoimmunity sometimes occurs when B cells are returning after something like bone marrow transpantation. Some autoimmune diseases, like immune thrombocytopenia remit in quite a good proportion of cases spontaneously. Lupus quite often stops giving major problems after initial episodes have been controlled. All sorts of patterns seem to be possible. That is perhaps not too helpful for theorising because it doesn't narrow things down, but that's the way it is I think.
     
  17. Jonathan Edwards

    Jonathan Edwards Board Member

    Messages:
    1,110
    Likes:
    5,094
    I am not particularly wary of post exercise malaise, I just think we should not change criteria on a hunch - any hunch.
     
  18. Ember

    Ember Senior Member

    Messages:
    1,741
    Likes:
    1,818
    Would the exclusive use of the CCC, with its PEM requirement, represent a change of criteria in upcoming studies, considering that all but two of the subjects met these criteria (as well as the broader Fukuda criteria) in the 2011 study?
     
  19. Jonathan Edwards

    Jonathan Edwards Board Member

    Messages:
    1,110
    Likes:
    5,094
    You have to be extremely careful about using different sampling criteria on a new population that may be significantly skewed in its subsets in relation to the first one. It is probably too complicated to explain here because it has to do with the complex uncertainties involved which give rise to statistical formulae that give even me a headache. It is likely that there would be no big problem, but if patients referred differently in a different healthcare system arrive in different subsets in different proportions all sorts of problems just might arise.
     
    ukxmrv, Marco and Ember like this.
  20. Esther12

    Esther12 Senior Member

    Messages:
    5,378
    Likes:
    5,870
    I think that I, and perhaps other patients, were given unrealistic expectations as a result of how CFS is often treated. It is quite normal for doctors to take it upon themselves to treat CFS patients with 'positive' thinking, 'reassurance' and exaggerated claims about the understanding they have of CFS and the efficacy of treatments. It was only after being ill for half a decade that I realised none of the forms of graded exercise were leading to the recovery I was told to expect, and then another couple of years before I realised that ME/CFS could be a serious problem I might not recover from (which is still not something I've truly accepted to be honest).

    The fact that people can be given reassuring claims about recovery, and then come to realise that these claims were not supported by the evidence but were actually psychosocial management performed without consent, makes it harder to then also accept that there is little money being spent on trying to really understanding the cause of one's health problems.

    Also, funding for ME/CFS is low when compared to other conditions with equivalent economic impact or effect on QOL.

    (Only a brief post on a complicated matter, but I don't want to take things too off topic.)
     
    Sidereal, irwinsturtle, MeSci and 4 others like this.

See more popular forum discussions.

Share This Page