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

[Forbin]

That is not quite what was said. The severity of the illness, rather than the severity of the infection was the key predictor. Eg those who were bedbound, suddenly couldn't walk etc. were the ones who were likely to have a CFS like condition at the follow ups, whereas those with more mild fatigue were more likely to claim to be recovered at the follow up.

Thanks for the correction. It was indeed incorrect to use the phrase “severity of the infection.”

The paper says, “The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors.”

During the acute illness, the severity of the symptoms was also strongly correlated with the ex vivo production of the pro-inflammatory cytokines interleukin 1β and interleukin 6.

However, the severity of the symptoms was not correlated with viral load or antiviral immune responses [though only the EBV cohort was checked for this].

http://www.bmj.com/content/333/7568/575

 

[Jonathan Edwards]

The issue is that corticosteroids can cause us immense long term relapse. I'm not talking about huge doses either, I'm talking about anything from a physiological replacement dose (say 20mg hydrocortisone), down to 1mg or lower. Immune suppression seems to be one of the worst things to do in ME. Obviously this doesn't prove infectious aetiology, but at least strongly suggests it, to my mind at least.

This is what I'm saying happens. By giving immunosuppresive therapy such as corticosteroids, ME patients are generally made much worse.

I agree that we have to keep options open in terms of models that include viruses and those that do not. I am a bit worried, though, about a blanket fear of 'immunosuppression'. My point about immunosuppression was that if a virus was present at least some sorts of immunosuppressive therapy should make the presence of the virus more obvious. That would not necessarily have any implications for whether or not the person felt better or worse. I am doubtful that worsening following the use of drugs that might have an immunosuppressive effect is itself reliable evidence for infection. What is puzzling about the steroid situation is that the doses you mention are not really immunosuppressive. If anything I would tend to regard them as the sorts of levels normally found in an active immune response. When the body is stressed by infection steroid levels go up by this sort of amount and if they do not the infection may be much more dangerous. At low doses steroids are in effect 'immunopermissive' or 'immunonecessary'. One of their problems, though is that shifting levels artificially by medication can upset the progress of a lot of diseases so for many of the conditions like RA, for which they were originally developed, we now think they may be more trouble than they are worth.

These debates are useful, but I think one has to be careful about the detail and not lump a lot of things together under an umbrella term like immunosuppression. I am aware that a story of immunodeficiency relating to NK cells has been popular, but so far I cannot make a simple analysis along those lines add up.

 

[Jonathan Edwards]

Professor you bring to mind my favorite 2012 paper involving infectious triggers. Researchers monitoring the immune system's interaction with the environment in a 54-yr old man over a 14 month period unexpectedly on Day 289 caught a respiratory syncytial viral infection (RSV) apparently trigger Type 2 diabetes to which he was genetically predisposed. They had been tracking 40,000 variables including his [Michael Snyder's] autoantibodies : "Snyder also exhibited increased levels of autoantibodies, or antibodies that reacted with his own proteins, after viral infection. Although autoantibody production can be a normal, temporary reaction to illness, the researchers were interested to note that one in particular targeted an insulin receptor binding protein." The researchers concluded: "We speculate that perhaps RSV triggered aberrant glucose metabolism through activation of a viral inflammation response in conjunction with a predisposition toward T2D."

A confounding mystery in this story to me is that Snyder experienced a second viral illness during the experiment a human rhinovirus (HRV) on Day 0 which did not trigger his autoimmune disease. Would you suppose the generation of his insulin receptor binding protein autoantibody was random, or is it possible that some unique characteristic of RSV but not HRV played a role? Bringing it back to ME, I wonder if some "unique" characteristic of the enteroviruses and other viruses/vaccines mentioned over the years as triggers might provoke an overly strong immune response leading the interferon pathway to protectively switch to immune supression mode setting off a cascade of immune and neurological symptoms?

I am a bit uncertain about this report, partly because autoimmune diabetes is, at least as far as I understand it, defined as Type 1. Type 2 is insulin resistance. I am also a bit surprised by the claim that an infection led to lots of autoantibodies. I know of no other consistent evidence of this sort of thing. There is a problem that if people not used to the need for careful controls in interpreting antibody data go off and measure some antibodies they will find all sorts of things that get misinterpreted. For instance I would expect after an infection for everybody's antibodies to everything to go up a bit, but we ignore that as non-soecific.

Generation of antibodies is always random - there is no other way to make them. But a rise in level after infection does not necessarily mean generation of a new antibody. B cell dynamics are complicated. I do think that certain specific sorts of virus might stimulate the immune system to amplify a loop that causes ME symptoms but the question would be where the machinery for the loop came from and had it been set up at random in the few weeks or months before the infection arrived. In RA the loop is set up quite a long time before it causes symptoms.

It is all very difficult to disentangle, which is why my feeling is that maybe the best line of research is to try to pin down what the signals in the loops are. Antibodies may be in there, interferon may be in there, TNF in the brain may be in there but we need to know exactly how they interrelate, which means getting the detail of the mechanisms right.

 

[user9876]

I agree that we have to keep options open in terms of models that include viruses and those that do not. I am a bit worried, though, about a blanket fear of 'immunosuppression'. My point about immunosuppression was that if a virus was present at least some sorts of immunosuppressive therapy should make the presence of the virus more obvious.

A friend who had severe ME symptoms although was diagnosed with fibromyalga had treatment for Leaukemia (chemo that wiped out the bone marrow followed by a bone marrow transplant). She didn't get any viral infection after her immune system was wiped although at various points inflamation markers shot up followed identifiable bacterial infections. Its hard to tell during the treatment but afterwards the pain went and the nature of fatigue changed - the delayed prolonged fatigue (PEM) associated with ME seemed to go.

 

[Jonathan Edwards]

Well for us that have been reading medical research papers for years, there have been all sorts of "blood test biomarkers", But the caveat seems to often come along with the question of patient selection subsets, etc. Kind of a chicken and egg. How do you get around that?

For me, the exercise gene expression studies done by Alan Light, et. al. Certainly shown the most dramatic evidence of illness/Dysfunction. Their test Involved Moderate exercise, Which still could be problematic for some or many.

Prof Edwards .... Can you give a couple examples of blood tests that are done in autoimmune diseases? Would you be looking for antibodies?

I think what may underlie this problem is that a biomarker tends to be useful in the long term if it fits in to a mechanistic story. If you cannot understand what caused the biomarker to be like that then you don't have a lead as to how a treatment might help. For B cells we have the lead from Fluge and Mella but maybe not yet the biomarker - but at least it makes sense to look for B cell biomarkers. The exercise studies are interesting but it may not be clear why the particular molecules that go up do so, so it is difficult to know whether they are marking specific disease processes or not. Muscle changes might be secondary to other things. On the other hand if they are part of a loop that feeds back on to the cause then maybe they will be very useful in terms of suggesting treatment approaches.

The most specific markers in autoimmune disease are antibodies, but there are also markers of effects like c-reactive protein level, TSH level in thyroid disease, histological patterns like lupus nephritis or signs of endothelial dysfunction. So on that basis I guess you want B cell markers that link to the cause that is influenced by rituximab and also effect markers, maybe like the exercise studies and a way of putting them together in a story.

 

[Firestormm]

Jonathan Edwards

Professor can I ask if you are able to determine before treatment with Rituximab which patients with a diagnosis of Rheumatoid Arthritis are most likely to respond? And if so, how? And, finally, if a similar determining factor could be applied to people with a diagnosis of ME?

I am thinking that you can't, but would like to know more about selection of people for treatment who have RA or other autoimmune conditions; as from what I have read it seems Rituximab is considered pretty much if other things have failed or do not provide the relief they once did.

Thanks

 

[lansbergen]

It is all very difficult to disentangle, which is why my feeling is that maybe the best line of research is to try to pin down what the signals in the loops are. Antibodies may be in there, interferon may be in there, TNF in the brain may be in there but we need to know exactly how they interrelate, which means getting the detail of the mechanisms right.

I wonder what will happen when the innate response stays to long in the interferon type1 producing fase.

 

[Jonathan Edwards]

Professor can I ask if you are able to determine before treatment with Rituximab which patients with a diagnosis of Rheumatoid Arthritis are most likely to respond? And if so, how? And, finally, if a similar determining factor could be applied to people with a diagnosis of ME?

I am thinking that you can't, but would like to know more about selection of people for treatment who have RA or other autoimmune conditions; as from what I have read it seems Rituximab is considered pretty much if other things have failed or do not provide the relief they once did.

The answer is, I think, in some ways yes and in other ways no. It is fairly well established by large trials that RA patients are more likely to respond well if they have the typical autoantibodies - rheumatoid factors. The experience in my own unit has been that responses tend to be good even if there are less clear cut antibody abnormalities but that patients with entirely normal antibody profiles tend not to respond. This all makes sense since the treatment is supposed to work on antibodies and as far as we know diseases without antibodies like psoriasis get no benefit or may even be made worse. We separated off a subset of inflammatory arthritis into psoriasis-related and so on about forty years ago. I suspect there is another smaller subset with no antibodies still hidden under the diagnostic criteria for 'RA' that needs to be separated off, but the separation may be messier and may involve overlaps.

We know that rituximab benefits inflammation but not cartilage damage, so patients with a lot of inflammation and no damage will do better, but one of the surprises was how much better people with cartilage damage could function once their inflammation settled. There have recently been some papers suggesting a statistical basis for predicting response on the basis of either genetics or gene expression patterns (these ar quite different things and sometimes seem to get muddled together under 'genotype'). I am not sure these are yet clinically useful but they may be.

Beyond this there is still considerable uncertainty, but one thing we have found is that rituximab may not work on its own but if another drug is given in sequence and rituximab tried again it may work very well. This suggests that some people respond poorly not because they have the wrong disease but because their disease is just too aggressive to deal with in one go.

Rituximab is used last in line of a series of options purely because it was the last to be licensed and licenses are usually given for treatment of people who do not respond to other drugs first. This has caused a lot of confusion but I think now we are at the stage where rituximab can be used before other drugs if it seems sensible. It takes longer to work, which is one reason for not necessarily trying it first. For a number of rare neurological autoimmune diseases rituximab is about the only thing that helps so would be used straight away I think. Rituximab is used a lot in countries with low budgets because it is cheaper, and also countries with a lot of TB, which gets reactivated with some other drugs (for instance in South America and Mexico). It is not used so much in the USA because physicians do not get so many fees for infusions given every year rather than every month! (This problem was pointed out by an eminent US rheumatologist at one of the early advisory boards on development of rituximab for RA - 'they won't touch it' he said.)

I am thinking that in ME we should expect people responding to rituximab to show some B cell or antibody changes. That I think is important to pursue in lots of different approaches. As far as I know there is little evidence for permanent structural damage in ME so that should not be so much of an issue.

 

[lansbergen]

What is puzzling about the steroid situation is that the doses you mention are not really immunosuppressive. If anything I would tend to regard them as the sorts of levels normally found in an active immune response

I saw dexamethasone worsen symptoms. Could supersensitivity explain it?

http://www.cfids-cab.org/cfs-inform/Cytokines/visser.etal01.txt
http://www.ncbi.nlm.nih.gov/pubmed/11585638
LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone

http://www.ncbi.nlm.nih.gov/pubmed/11288761
Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors.

http://www.ncbi.nlm.nih.gov/pubmed/11268418
Altered glucocorticoid regulation of the immune response in the chronic fatigue syndrome.

 

[Purple]

Rituximab is used last in line of a series of options purely because it was the last to be licensed and licenses are usually given for treatment of people who do not respond to other drugs first. This has caused a lot of confusion but I think now we are at the stage where rituximab can be used before other drugs if it seems sensible. It takes longer to work, which is one reason for not necessarily trying it first. For a number of rare neurological autoimmune diseases rituximab is about the only thing that helps so would be used straight away I think. Rituximab is used a lot in countries with low budgets because it is cheaper, and also countries with a lot of TB, which gets reactivated with some other drugs (for instance in South America and Mexico). It is not used so much in the USA because physicians do not get so many fees for infusions given every year rather than every month! (This problem was pointed out by an eminent US rheumatologist at one of the early advisory boards on development of rituximab for RA - 'they won't touch it' he said.)

Would you be able to expand more on which rare neurological autoimmune diseases these would be?

Also, I am under the impression that Rituximab is an expensive drug and especially since it has to be given by infusion - so I am surprised this would be considered cheaper - what would be more expensive options? Or is there different pricing/cost of Rituximab in different countries?

Also, it is quite a surprise to hear Rituximab would be used so that TB does NOT get reactivated (presumably this would be useful in AIDS where TB is a problem).

 

[voner]

I think what may underlie this problem is that a biomarker tends to be useful in the long term if it fits in to a mechanistic story. If you cannot understand what caused the biomarker to be like that then you don't have a lead as to how a treatment might help. For B cells we have the lead from Fluge and Mella but maybe not yet the biomarker - but at least it makes sense to look for B cell biomarkers. The exercise studies are interesting but it may not be clear why the particular molecules that go up do so, so it is difficult to know whether they are marking specific disease processes or not. Muscle changes might be secondary to other things. On the other hand if they are part of a loop that feeds back on to the cause then maybe they will be very useful in terms of suggesting treatment approaches.

The most specific markers in autoimmune disease are antibodies, but there are also markers of effects like c-reactive protein level, TSH level in thyroid disease, histological patterns like lupus nephritis or signs of endothelial dysfunction. So on that basis I guess you want B cell markers that link to the cause that is influenced by rituximab and also effect markers, maybe like the exercise studies and a way of putting them together in a story.

Prof. Edwards,

Thanks so much. I finally understand... I think.... a biomarker has to be linked to a causation story line? Just because you have a well-defined patient group and Anomalous biochemical markers, Those markers have to be linked to a good storyline in order to convince the rest of the medical community?

And in reality, a treatment (Like Rituximab) does not necessarily have to be linked to that story line, although it helps immensely if it is. I'm just thinking that there's all sorts of pharmaceutical drugs are used as treatments, however how they work and affect a Particular disease is not clear.

As far as the gene expression studies by Light, etc. and their connection to B cells, That's where I'm hoping there some speculation going on in your mind. Their gene expression results may be secondary to causation, but I can assure you hear they're pretty reflective of primary symptoms. I guess the question would be how do they (B cells and Light's results) connect how are they related, If at all? Good luck on that one!!

 

[Legendrew]

How many independent trials of the drug would be needed for licensing of Rituximab as an ME treatment - I'd guess there is no exact number but if further trials continue the current trend what would be a good guess?I realise we are very early on such a road and the effects need to be verified and tested thoroughly but if these trials go well, how far in the future could patients be receiving the treatment? I expect that this won't happen in just a couple of years but I would hope that in 4-5 years time we'd be close to such a situation. Hopefully before then a few simpler biomarkers can be identified to help with patient selection and diagnostics. However in the absence of this; one concern I would have is whether any qualifying critera would be applied to the drug - I hope that the situation doesn't arise where a lesser severity of illness would exclude people from being treated.

Would you be able to expand more on which rare neurological autoimmune diseases these would be?

I found this article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002645/ from 2010 which may be worth a read. It discusses the use of Rituximab in quite a few autoimmune neurological diseases and has paragraphs later down dedicated to specific diseases and the effects observed with rituximab treatment. It may be slightly out of date but it shows the uses in lots of different diseases.

 

[Jonathan Edwards]

Would you be able to expand more on which rare neurological autoimmune diseases these would be?

Also, I am under the impression that Rituximab is an expensive drug and especially since it has to be given by infusion - so I am surprised this would be considered cheaper - what would be more expensive options? Or is there different pricing/cost of Rituximab in different countries?

Also, it is quite a surprise to hear Rituximab would be used so that TB does NOT get reactivated (presumably this would be useful in AIDS where TB is a problem).

I am not an expert on the rare autoimmune neurological states but my understanding is that neurologists have had success with conditions such as 'stiff person syndrome' and various forms of neuropathy. The review cited above looks a good one.

Rituximab is expensive but about half the price of the other biologic treatments for RA - mostly anti-TNF drugs. That is why it is used in South America. Anti-TNF drugs reactivate TB rather reliably and so are not much good for places where silent TB is common. We have no reason to think that rituximab makes TB reactivate, probably because antibodies are not that much involved in immunity to TB, although this remains speculative.

 

[Jonathan Edwards]

Prof. Edwards,

Thanks so much. I finally understand... I think.... a biomarker has to be linked to a causation story line? Those markers have to be linked to a good storyline in order to convince the rest of the medical community?

Not to convince the medical community - that is always tough! More to base a logical research strategy on I was thinking.

And in reality, a treatment (Like Rituximab) does not necessarily have to be linked to that story line, although it helps immensely if it is. I'm just thinking that there's all sorts of pharmaceutical drugs are used as treatments, however how they work and affect a Particular disease is not clear.

Yes, lots. If we knew how gold helps RA we might have a great research lead but all we have as a blank page.

As far as the gene expression studies by Light, etc. and their connection to B cells, That's where I'm hoping there some speculation going on in your mind. Their gene expression results may be secondary to causation, but I can assure you hear they're pretty reflective of primary symptoms. I guess the question would be how do they (B cells and Light's results) connect how are they related, If at all? Good luck on that one!!

Yes, I am finding all these citations of references very helpful. The Light programme looks a useful line. It sort of suggests that an antibody might be interfering with muscle homeostasis but I am not yet quite sure how to read the data. They seem to be doing gene expression studies on blood cells, which would change as a knock on effect in some way I guess. I need to scratch my head about this.

 

[voner]

Not to convince the medical community - that is always tough! More to base a logical research strategy on I was thinking.



Yes, lots. If we knew how gold helps RA we might have a great research lead but all we have as a blank page.



Yes, I am finding all these citations of references very helpful. The Light programme looks a useful line. It sort of suggests that an antibody might be interfering with muscle homeostasis but I am not yet quite sure how to read the data. They seem to be doing gene expression studies on blood cells, which would change as a knock on effect in some way I guess. I need to scratch my head about this.

Prof. Edwards,

The Light group is involved in follow up studies... Dr. Alan Light is a real decent and accessible chap.

I think I'm starting to beat a dead horse here, but so you're trying think about a Plausible B cell story line and then also what potential biomarkers might you search for that would fit that storyline?

Eventually, you're going to have to convince a certain amount of medical community that your biomarker is the proper one to use. Every month it seems that there's some research paper published where they say that either a fibromyalgia or ME/CFS Biomarker has been found. And they may well have been found, but nothing is done with that information, Beyond a press release in the paper.

Respectfully, I guess since you're a bigwig in the world of B cells and autoimmunity, and a very successful And well designed rituximab trial by you carries weight In the medical community.......so your research claims will carry more weight? What I'm getting at is,...... "what will distinguish your research's Claim of biomarkers, if you're successful?"

I'm really not trying to be combative here I'm just trying to sort through what would distinguish your research from all the other research that claims that they have biomarkers? Your (hopefully) clinical trial successes?

here is some sympathy towards you and your profession. I can't imagine the amount of bureaucracy and paperwork etc. that's involved in trying to put together any kind of trials nowadays.

off subject, but Gold as a treament...... Intriguing! I wonder what the history of the use of it is.... sounds like it my go all the way back to the blood letting days and the days when they gave out mercury as a treatment. I used to be in the gold prospecting business and have studied the properties of gold pretty minutely. An amazing element. Relatively Chemically inert.... At least in the world of nonbiological physical chemistry...

 

[froufox]

Apologies if this has been asked before, or the topic has been covered, I havent managed to read all of the posts on this thread (or understand all of them either ). Professor Edwards, I just wondered what your or anyone else's thoughts re those of us who respond to antibiotics (various ones including rifampicin, plus tetracyclines, macrolides) eg herxing/die-off reactions, followed by improvements. Although they have not been a cure as such, they have definitely helped for sure.

Unfortunately, the improvements either peter out or the side effects from the drugs usually become intolerable. I know that abx have immunomodulatory & anti-inflammatory actions too, but my question is, is it possible that any improvements from the antibiotics could be attributed to infected B-cells being killed off? ps. treatment was based on positive test results to various infections eg lyme, bartonella, chlamydia pneumoniae. thanks.

 

[Jonathan Edwards]

I just wondered what your or anyone else's thoughts re those of us who respond to antibiotics (various ones including rifampicin, plus tetracyclines, macrolides) eg herxing/die-off reactions, followed by improvements. Although they have not been a cure as such, they have definitely helped for sure.

...my question is, is it possible that any improvements from the antibiotics could be attributed to infected B-cells being killed off?

I am not sure I have an informed answer to this but we may all be harbouring a certain amount of bacterial junk, for instance as low grade dental sepsis, and feel better after a broad spectrum antibiotic like rifampicin or tetracycline, and I can imagine this effect being more obvious if immune signalling is dysregulated in various ways. But as you say it does not seem to be a long term answer to the problem. I do not think antibiotics would kill B cells and B cells are not infected with bacteria, only viruses, as far as I know and viruses do not respond to antibiotics.

 

[Bob]

However most patients have a negative effect from hydrocortisone and other corticosteroids, many (like me) a profoundly negative effect.

Hi Garcia, are you certain that applies to 'most' patients?
Are you basing that conclusion on any research evidence?
I know an ME patient who thrives on a low dose of steroid, and cannot stop taking it without a long-term flare up in symptoms. (I'm not certain which type of steroid it is though, so it might not be a corticosteroid.)

Edit: Graham's provided the details on the next page of this thread.

 

[Jonathan Edwards]

I think I'm starting to beat a dead horse here, but so you're trying think about a Plausible B cell story line and then also what potential biomarkers might you search for that would fit that storyline? Eventually, you're going to have to convince a certain amount of medical community that your biomarker is the proper one to use. Every month it seems that there's some research paper published where they say that either a fibromyalgia or ME/CFS Biomarker has been found. And they may well have been found, but nothing is done with that information, Beyond a press release in the paper. Respectfully, I guess since you're a bigwig in the world of B cells and autoimmunity, and a well designed rituximab trial by you carries weight In the medical community.......so your research claims will carry more weight? What I'm getting at is,...... "what will distinguish your research's Claim of biomarkers, if you're successful?"

A very reasonable analysis but I am more optimistic. I have looked through a lot of claimed markers and have a hundred more to look at but the majority of them I would drop in the wastebin on two counts - the data are presented in a way that does not look reliable and the story they are designed to support is based on some old chestnut that does not make sense in the bigger perspective. I may not be Usain Bolt but most of these look like the Hillbilly County Junior Team. In contrast there are maybe four or five groups who look like serious medal contenders and Dr Light may well be one of them. I am not going to be the one who finds the biomarker but I am interested in encouraging support for those who may be on the right track. We do not need anything very dramatic-sounding or highly specific, just something that seems to fit with the implications of Fluge and Mella's study and takes things a step forward.

But the next step is not convincing the medical community. That takes 15 years. And they usually get it half wrong. All you need is to convince a few people to help put in place an experiment that gives the pay off. So we showed that rituximab worked for RA long before the 'medical community' had any idea what was going on. If finding a biomarker gets us to discovering who with ME will really benefit from rituximab then we do not need anybody to take an interest in the biomarker first. We just need to get on and make use of it. Once it has been shown to be useful then the medical community will use it, just as they use rituximab for RA. I fully realise that anyone can play this game and end up chasing moonbeams. All I can say is that over a period of thirty years I think I learnt to tell moonbeams from 24 carat ingots. There are certain ways of telling. If the Norwegian study can be confirmed we know there is gold in this particular hill. All I can see at the moment are some glints but I feel reasonably confident after mining for 15 years on the RA field that I know which people know what they should be looking for.

 

[froufox]

I am not sure I have an informed answer to this but we may all be harbouring a certain amount of bacterial junk, for instance as low grade dental sepsis, and feel better after a broad spectrum antibiotic like rifampicin or tetracycline, and I can imagine this effect being more obvious if immune signalling is dysregulated in various ways. But as you say it does not seem to be a long term answer to the problem. I do not think antibiotics would kill B cells and B cells are not infected with bacteria, only viruses, as far as I know and viruses do not respond to antibiotics.

Thanks for replying. Could you explain a little bit more about what you meant when you said: "and I can imagine this effect being more obvious if immune signalling is dysregulated in various ways". Thanks!