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

[Bob]

I do not know it is autoimmune but I have no doubt in my case there is an immune reaction when overdoing and it hurts like hell.

Yep, I agree that there seems to be an immune reaction when over-exerting.

Dr Nancy Klimas is supposed to be having some success in her clinic with Imunovir (inosine pranobex), which is an immune modulator or immuno-stimulant (with anti-viral properties).

 

[Sasha]

I agree with Dolphin I also think that when UCL have confirmed a Trial as being worthwhile and produced a proposal, and said proposal meets the separate charities (or a collaboration thereof) peer review: THEN you might see some momentum.

Possibly, but the MEA have pledged already, subject to their peer review, and AfME are considering it. It's possible to pledge with those strings attached and that's very valuable.

Individual charities are unlikely to invest with IiME fundraising pot until such time as this is produced - their is also the issue of ownership to be resolved or raised. IiME cannot take funds from a separate charity and expect to control them; or to hold onto them in the event of this UCL venture not proceeding for any reason. Their literature thus far produced claims that in such a situation the funding would be reallocated to the general 'biomedical' fund.

I don't think it makes any sense for any charity to hand money to IiME rather than give it directly to the research team. As you say, if the trial didn't for some reason go ahead, any charity that had donated to IiME would have robbed their own research fund to give to IiME's research fund, which is not what the people who gave them that money intended. It's common for research to be funded by multiple donors and they give to the research team, not to one of the other donors.

Personally, though, I still think you'll be hard pressed to reach £400k before the Norwegian Trial has been completed. If I had the money, I would I think at this point, hold fire until I saw what that revealed.

The Haukeland trial isn't starting until January 2014 and is estimated to take two years to complete. I think that's too long to wait. Better to do an independent study in parallel.

But it depends also on what comes out of UCL by way of a proposal - and if that proposal is good enough - you might see an application to the MRC being honoured; which could change the landscape.

I agree - that could get this trial done fast. But support from multiple charities would be a big signal to the MRC that this is an important trial. I'd really like to see as many of the charities on board as possible, as soon as possible.

 

[Firestormm]

Sasha Lots on Facebook in case you don't peruse as much as I from those supporting IiME and constantly questioning the other charity's commitment. Indeed I have grown rather sick of some of it.

Thanks for the reply. I agree. Hope you do get the money up together in a short space of time; but I can't help feeling the way I do. It's a lot of cash that won't be available for anything else.

Anyway:

Dr Charles Shepherd:
"Am pleased to report that as of this afternoon we now have 6 support or research funding charities discussing some form of collaboration in relation to fundraising for a clinical trial of Rituximab at UCL once the preliminary steps are finalised and a protocol has been approved by the Clinical Trials Unit at UCL. So this type of inter-charity collaboration is now taking place."

 

[Firestormm]

Bob Interesting thoughts re: hypothesizing. I wonder if it's worth considering the other diseases that are treated with Rituximab and looking at what symptoms are resolved as a result in them? I would certainly like to consider that in more detail. I think Prof. Edwards mentioned a couple of treated diseases that we hadn't talked about before - on this thread previously. Might help to review them.

I am also thinking if it is worth considering what possible reasons there could have been for Rituximab seeming to help someone with ME - other than them having some problem relating to B-cells and autoimmunity. Is such as situation likely? If Rituximab is seen to have had a positive effect - does it always mean that autoimmunity was the problem? Could there be another explanation? What of inflammation generally or inflammatory muscle disease? Do we know at this point that autoimmunity is the only explanation? Is it necessary to rule out other possible explanations.

American College of Rheumatology gives some alternate explanations I think. And a very quick look at Myasthenia Gravis and a yet to be published Clinical Trial carried this narrative:

Myasthenia gravis is a disease that happens because the immune system attacks the nervous system. The damage is caused by antibodies produced by B lymphocytes. These antibodies damage a special part of the muscle that helps transmit impulses from nerves to muscles to allow muscles to work properly. This damage results in symptoms of myasthenia gravis. Participants are being asked to participate in this research study because their myasthenia gravis has either failed to respond to treatments commonly used in the disease, or they have had bad side-effects from such treatments.

May have absolutely no parallels with processes within some folk with our diagnosis of course. But Rituximab treatment may well help in resolving things that I certainly had not before been aware of and might help in the treatment of diseases I hadn't considered.

There will be I am sure, symptoms that we are most familiar with now, that could be impacted by Rituximab, or might not. For example, cognitive dysfunction: might that be helped with Ritux or might it be accounted for by e.g. resolving sleep problems? Might sleep problems be resolved by Ritux? Etc. Thing is - not all our additional symptoms are shared by all of us.

Though I do agree, Bob. It would be very interesting to learn if/how Ritux might account for Post-Exertional Malaise. I think it can but I'd like to hear from Prof. Edwards. My thinking would be along the lines of treating lymphoma (maybe even leukemia) with Ritux. Our PEM has been compared to the similar symptoms experienced by people with certain forms of cancer.

Disappointing that the Macmillan source I used there doesn't actually say what the likely improvements are from even the patients point of view. Be good to find something like that even from people who have been treated for their Rheumatoid Arthritis I think.

Edited

 

[Sasha]

Sasha Lots on Facebook in case you don't peruse as much as I from those supporting IiME and constantly questioning the other charity's commitment. Indeed I have grown rather sick of some of it.

Conflict is exactly the sort of thing to drive donors away. I hope that people can learn from Maria's MEandYou campaign. She said that it was hugely important that her campaign was positive and feelgood. Every time we post something on the net about the trial we should each ask ourselves, 'Is what I'm about to say going to make it more likely or less likely that people will donate?'

We've got to not let other patients down. I really hope that we can all welcome people in and encourage donors by a positive attitude. Nothing is more important than getting this trial funded.

Thanks for the reply. I agree. Hope you do get the money up together in a short space of time; but I can't help feeling the way I do. It's a lot of cash that won't be available for anything else.

I don't think it's a zero-sum game. Think of Norway. People in Norway weren't donating £280,000 a year before the Rituximab trial - that sum wasn't diverted from other ME research, it was generated by creating such excitement about the trial and such awareness outside the ME community in Norway that people who hadn't donated to ME research before - which probably included most people with ME - started donating. And now that that base has been established, those people will be more likely to donate to ME research in future. The entire funding base in Norway has taken a major step up. I think that the Rituximab trial has the potential to do that in the UK, if we run a positive and inclusive campaign.

Dr Charles Shepherd:​

"Am pleased to report that as of this afternoon we now have 6 support or research funding charities discussing some form of collaboration in relation to fundraising for a clinical trial of Rituximab at UCL once the preliminary steps are finalised and a protocol has been approved by the Clinical Trials Unit at UCL. So this type of inter-charity collaboration is now taking place."​

That's excellent news!

 

[Snow Leopard]

I am very upbeat about this and very much hope it goes ahead. An independent replication by a team with a lot of experience with the drug is a big deal.

Secondly, even if this drug is not the panacea we may want it to be, further research on how this drug affects patients may well one of the key leads to understanding this disease.

ME seems gradually to improve in most cases. .

This is not necessarily the case long-term. There have been about 5 or so long term (5 year+ studies). It is worth reading all of these in my opinion. A few of them are published in the Journal of CFS by the way, which I believe isn't indexed in pub med at the moment. There also seem to be a significant number of 'exclusions' for various reasons over time. Eg patients that seem to later develop signs for Lupus, cancers or RA, even though there was no sign during the inital screening. Is this also a coincidence?

Most of the improvement is in the first year or two and then the illness is either stable, or relapse/remitting. Long term, about 10-30% recover, which is interesting in itself, but almost all of those do so within the first few years. On the other hand, the shorter term studies reporting higher levels of recovery can be in error, as patients can later relapse again.

If I could make one key proposal regarding the trial methodology, use an objective outcome! I do not believe that questionnaires truly capture what we should be trying to measure. On the other hand, actigraphy would lead to greater confidence in the results, as it would show that patents were not only reporting less fatigue, but actually able to do more as a result.

Apart from that, my opinion is that it is clear is that ME/CFS does not fit our current models of autoimmunity, but then again, the same could have be said about other diseases including RA until we had a magnitude of order more research done than has been done for ME/CFS currently.

My personal case was that I became very ill straight after an oral polio immunisation, and indeed a minority of patients also report onset after immunisation. This has long suggested to me that at least a proportion of cases are due to dysregulation of the immune system rather than a chronic viral infection.

I am sympathetic to the hypothesis that a number of different triggers can lead to a variety of different metastable states of the immune system leading to chronic nonspecific activation. The following paper explores this from a modelling perspective, and focuses on EBV as a trigger, but it is an interesting paper all the same:
http://www.ncbi.nlm.nih.gov/pubmed/22873615

 

[Firestormm]

Sasha my bad. I should have been more specific. I meant the 'ring-fenced' funding some charity's are segregating from their existing research funds; not the amount that will I am sure continue to pour in from individuals. The other charities may also of course lend their support to IiME; endorsing that effort. At the end of the day - it matters little where the money comes from: just that it comes. And it will. I am in no doubt on that score I just have some personal reservations is all x

 

[Sasha]

Sasha my bad. I should have been more specific. I meant the 'ring-fenced' funding some charity's are segregating from their existing research funds; not the amount that will I am sure continue to pour in from individuals. The other charities may also of course lend their support to IiME; endorsing that effort. At the end of the day - it matters little where the money comes from: just that it comes. And it will. I am in no doubt on that score I just have some personal reservations is all x

That's what I understood you to mean - that the charities wouldn't get that ring-fenced money back but that's what I was addressing with my 'not zero-sum' argument. People will donate more to ME research, not just Rituximab research, once Rituximab raises awareness and that trial is funded. There'll be more all round.

All medical charities start small and get bigger as awareness grows. I think we're at the beginning of that process.

 

[Legendrew]

I'm open minded to the idea that ME is an autoimmune disease, but I wonder if the illness can be as simple as the production of an auto-antibody.

The main reason that I question it is because of post-exertional malaise.

Post-exertional malaise is a very specific reaction to exertion. Simply put, when we exert ourselves (i.e. use energy) all of our symptoms increase, often with a delayed reaction of 12 to 24 hours, and our illness deteriorates.

I wonder how and why the symptoms would increase in reaction to exertion, if it's an autoimmune disease.

If looking at it from the point of view of autoimmunity, what happens when we use energy, that would provoke an autoimmune response? And then why would the reaction be long-lasting once we stopped exercising?

Exploring the issue hypothetically, let's say that a unique molecule is produced (or enters our bloodstream) when we use energy, and that provokes an auto-immune response. Then why doesn't the autoimmune response diminish once we stop exerting ourselves, or why is there a long-lasting reaction? Post-exertional malaise can last for months, or longer, after we over-exert ourselves. Symptoms do not increase and decrease in direct proportion to energy used.

If auto-antibodies are produced in reaction to exertion, how long can they last in the body? Can they last a very long time after they are produced? Could this be an explanation for long-lasting reaction to exertion? Or can dysfunctional B-cells last for a very long time after they are created?

I'm out of my depth here, scientifically, but I can't help feeling that it's more complex than an auto-antibody at play, and that we have a more complex immune dysfunction.

Hypothetically, again, perhaps there is some sort of destructive biological loop at play, and an auto-antibody is targeted at a part of the immune system. So that when an auto-immune response is provoked or triggered, by exertion, the auto-antibody attacks a part of the immune system which makes the immune system dysfunctional. And perhaps this immune dysfunction causes, or allows, the auto-immune response to take place in the first place. So it's a destructive feedback loop.

I'm sure I'm talking absolute nonsense, in terms of actual science, but I'm just trying to get my head around the possibilities.


Another thought is Julia Newton's recent (as yet unpublished) research in which she found that muscle tissue taken from ME patients produces 20 times as much (lactic?) acid as muscle tissue from healthy people. How would this come about in terms of auto-immunity? I imagine that there might be an interplay between auto-antibodies and something within the cellular mechanism that produces energy (i.e. related to the mitochondria.) Are the mitochondria an integral part of the immune system? Could this explain a possible destructive feedback loop? (Dysfunctional mitochondria could potentially explain both the profound fatigue/exhaustion, and the post-exertional malaise in ME patients.)

Here's an interesting article about the relationship between the immune system and mitochondria, which discusses how mitochondria can mediate/trigger a systemic inflammatory immune response to 'trauma'. (The article doesn't mention ME, but perhaps ME could be described as a systemic inflammatory immune response to 'trauma' or 'stress'?):
http://www.nature.com/scitable/topicpage/mitochondria-and-the-immune-response-14266967


I wonder if Jonathan Edwards has any thoughts about any of this at all, if it makes any sense?

I think the majority of symptoms from the autoimmune disease would come from the damage to the tissue instead of the autoimmune response itself (I can only think that symptoms such as swollen lymph nodes and sore throat are a direct symptom from the immune reaction).

You then get into the realm of wondering what tissue could be under attack - some people have made the link with sensory nerves (as I believe Fluge and Mella are proposing) leading to action potentials being fired when there is no stimulus or not being fired when they should which could explain all the pain type symptoms, muscle aches, headaches etc and would also go some way to explaining why lactic acid may build up (muscles seen to be working much harder than usual due to 'misfiring' therefore more aerobic respiration than usual at times of rest depleting vital components of the Krebs cycle meaning none left for aerobic resp, therefore upon exertion the body has no choice but to go into anaerobic respiration - this could also explain post excersise malaise somewhat as in desperate need for energy the body sometimes shuttles the other phosphate from ADP producing a little energy but leaving AMP which is much harder to then reconvert to ATP.)
Another theory i've heard thrown about it damage to the vagus nerve which also explains a few stranger symptoms such as the gastro type ones which could be due to the vagus nerve linking the central and enteric nervous systems.
Andrew

EDIT: I also forgot to mention that the vagus nerve itself is able to control/effect the immune response directly and as such is something of an immuno-privileged sit therefore any damage to this could theoretically lead to the self-perpetuating loop that you mentioned.

 

[MeSci]

I'm open minded to the idea that ME is an autoimmune disease, but I wonder if the illness can be as simple as the production of an auto-antibody.

The main reason that I question it is because of post-exertional malaise.

Post-exertional malaise is a very specific reaction to exertion. Simply put, when we exert ourselves (i.e. use energy) all of our symptoms increase, often with a delayed reaction of 12 to 24 hours, and our illness deteriorates.

I wonder how and why the symptoms would increase in reaction to exertion, if it's an autoimmune disease.

If looking at it from the point of view of autoimmunity, what happens when we use energy, that would provoke an autoimmune response? And then why would the reaction be long-lasting once we stopped exercising?

Exploring the issue hypothetically, let's say that a unique molecule is produced (or enters our bloodstream) when we use energy, and that provokes an auto-immune response. Then why doesn't the autoimmune response diminish once we stop exerting ourselves, or why is there a long-lasting reaction? Post-exertional malaise can last for months, or longer, after we over-exert ourselves. Symptoms do not increase and decrease in direct proportion to energy used.

If auto-antibodies are produced in reaction to exertion, how long can they last in the body? Can they last a very long time after they are produced? Could this be an explanation for long-lasting reaction to exertion? Or can dysfunctional B-cells last for a very long time after they are created?

I'm out of my depth here, scientifically, but I can't help feeling that it's more complex than an auto-antibody at play, and that we have a more complex immune dysfunction.

Hypothetically, again, perhaps there is some sort of destructive biological loop at play, and an auto-antibody is targeted at a part of the immune system. So that when an auto-immune response is provoked or triggered, by exertion, the auto-antibody attacks a part of the immune system which makes the immune system dysfunctional. And perhaps this immune dysfunction causes, or allows, the auto-immune response to take place in the first place. So it's a destructive feedback loop.

I'm sure I'm talking absolute nonsense, in terms of actual science, but I'm just trying to get my head around the possibilities.


Another thought is Julia Newton's recent (as yet unpublished) research in which she found that muscle tissue taken from ME patients produces 20 times as much (lactic?) acid as muscle tissue from healthy people. How would this come about in terms of auto-immunity? I imagine that there might be an interplay between auto-antibodies and something within the cellular mechanism that produces energy (i.e. related to the mitochondria.) Are the mitochondria an integral part of the immune system? Could this explain a possible destructive feedback loop? (Dysfunctional mitochondria could potentially explain both the profound fatigue/exhaustion, and the post-exertional malaise in ME patients.)

Here's an interesting article about the relationship between the immune system and mitochondria, which discusses how mitochondria can mediate/trigger a systemic inflammatory immune response to 'trauma'. (The article doesn't mention ME, but perhaps ME could be described as a systemic inflammatory immune response to 'trauma' or 'stress'?):
http://www.nature.com/scitable/topicpage/mitochondria-and-the-immune-response-14266967


I wonder if Jonathan Edwards has any thoughts about any of this at all, if it makes any sense?

The leaky gut-autoimmunity mechanism could provide a plausible hypothetical explanation as follows:

1. Leaky gut (likely involving some kind of acidosis, perhaps d-lactic, perhaps involving abnormal carbohydrate metabolism) leads to autoimmunity
2. This autoimmunity (whether innate/non-specific or adaptive/antibody-based) is directed at some aspect(s) of the energy-production system, so that capacity to produce ATP via oxidative phosphorylation is severely limited
3. Exertion or stress therefore produces excessive quantities of lactic acid in muscles and/or neurons
4. This hyperlactaemia recreates/perpetuates excessively acidic conditions in the gut
5. The gut wall therefore stays leaky/becomes leaky again each time there is over-exertion/ stress

Whilst the overall sequence is hypothetical, most of the individual components are not.

Why does the PEM last a certain length of time? Several possibilities including:

• Liver function. The liver has to deal with the hyperlactaemia, and any reduction in liver function would make this take longer
• Downstream effects of hyperlactaemia or liver overload
• Continuing damage to gut wall due to wrong diet, wrong gut flora, etc.

I think that autoantibodies can last for years, but I'm sure Jonathan can help here.

Re an autoantibody against an aspect of the immune system, I recall reading one or more messages about that on PR in the past couple of days. I think they can be produced against just about anything.

That article you link to about mitochondria and immune response is intriguing. I'd forgotten about the external origins of mitochondria.

 

[Jonathan Edwards]

re concerns about a small trial: ...

Dear Esther,
Good questions about reasons for doing a trial. This is going to be long and a bit rambling, but I think it is something we all want to thrash out. It looks as if the Norwegian multicentre trial will go ahead soon. So the real question is whether we need any other trial. I will come to that, but if we do think a trial is worth doing my view is that we do not want it any bigger than needed. Bigger would be more expensive, take longer, and if the whole thing proves a mistake more people will have had treatment for no good reason.

You might say, on the other hand, at least if there is a large trial and it works, more people will have benefited. So maybe a justification for a trial is to give some people in the UK a chance to be treated. That is not going to be fair and reasonable as a primary justification for a trial but I do not discount it. If various people in the UK get involved in terms of raising money, being treated, or, from the medical side, getting experience in treating, and we assiduously report all the positive and negative aspects and all gain confidence in the treatment that will not be time wasted. However, as I say, a trial has to focus on a scientific objective and the knock on benefits of starting to treat patients in the UK will come with 20-30 patients in one centre at this stage. More will add little and multicentre studies run into problems with quality control, particularly with rituximab. (Fluge and Mella will be able to minimize these because they have focused in on ME/ritux-specific practicalities for years, people in the UK need to bring expertise together.)

So we are wanting to keep a trial as small as will give an answer. If we do a mini-Norway study and the real response rate is 60% it should show. If the response rate is lower I think we begin to run into problems. Responses in rheumatoid arthritis were about 70%. We had good markers to do everything objectively and we understood what we thought was happening. However, the responses were almost all short to medium term and long term repeat rituximab therapy begins to produce problems with antibody stores. Rituximab is good but there is a risk/benefit analysis to be done. If the total response rate for unselected ME turned out to be 40% (or less), taken with all the uncertainties about objective monitoring I think regulatory authorities would be very cagy about licensing until there was other information to help the case. For this sort of reason my view is that we should try very hard to find a different sort of trial design.

One of my reasons for getting involved in this is that I can see things are tricky and I have weaved my way through this stuff before. There are too many unknowns. So one of my main thoughts about design is not to do a mini-Norway. It would be much better if we could find a way of testing whether rituximab works for some people with ME from a different angle and one that might get at least one step further towards finding out who those people might be and why they respond. I would like to explain this in more detail but there are reasons for not saying much more at least at this stage. They have to do with fairness to people involved and the interests of patients. Nobody has any financial interest in keeping anything quiet and as soon as there are results these would be made public in full just as we did for our first 22 rheumatoid patients. We have particular expertise in the UK in B cell dynamics in autoimmunity and ME with Dr Cambridge and Dr Bansal and what I would like to see is a focus on the longer term objective of making sense of a B cell story for some of ME. In that sense I agree with a lot of other people’s comments, especially Firestormm. If the big Norway study is a bit disappointing we want to make sure the real value of a B cell approach, if there is one, is not lost. In five years time there may not be the same mix of people in a position to collaborate.

One good argument put to me is that whatever extra we could study in the UK the Norwegians could add on to their study. However, the more you add on to a study beyond a certain point the more unwieldy it gets and the more people cut corners. Since there is a strong argument for independent confirmation in another healthcare population and we have specific expertise I think the case for doing different things carefully in parallel is strong.

So to come back to your specific queries; a small study would be quicker, yes, but I think it is overoptimistic to think that once one more study is done things are sorted. What I think is a more realistic way of looking at it for people desperate to have a chance of a new treatment is that as more studies get done confidence will improve enough for the further studies needed to be funded and set up with options for being included in studies, or even compassionate off label usage, expanding. That is how it worked in RA and with a bit of fighting we got people treated as soon as we had an sound basis for doing so.

I would not say the reasons for setting up a UK trial are political but because of the difficulty in measuring things in ME confidence is a big issue. Confidence will increase if we know that results that fit together can be obtained in different countries with different health care referral systems. There might even be a difference in NK cell receptor ligands in Norway and the UK (a bit like Turkey for Behcet’s syndrome). And truly independent confirmation is a golden rule. I personally have total confidence in Fluge and Mella as scientists, but personal confidence does not count in science. You have to be able to convince Mr Spock from Star Trek. You say ‘Maybe just having different groups working on this in slightly different ways increases the chances of something useful turning up?’ and I think that is the close to the truth but we also want to be as logical, and also as creative, about complementing each other as we can, which is why I am going to visit Bergen next month.

 

[lansbergen]

The leaky gut-autoimmunity mechanism could provide a plausible hypothetical explanation as follows:

1. Leaky gut (likely involving some kind of acidosis, perhaps d-lactic, perhaps involving abnormal carbohydrate

• Continuing damage to gut wall due to wrong diet, wrong gut flora, etc.

.

That would exclude patients who do not have "leaky gut" and can eat anything they want,

 

[MeSci]

That would exclude patients who do not have "leaky gut" and can eat anything they want,

True - some sufferers may have something different going on and causing symptoms, although a high percentage of ME sufferers have IBS, with one study reporting it to be 92%. Without testing for leaky gut no one can be sure whether or not they have it.

 

[Firestormm]

True - some sufferers may have something different going on and causing symptoms, although a high percentage of ME sufferers have IBS, with one study reporting it to be 92%. Without testing for leaky gut no one can be sure whether or not they have it.

Perhaps, again, MeSci it would help to consider if in those other diseases which are treated with, or are being studied for treatment with, Rituximab - there are similar reported symptoms e.g. IBS-like ones? Again, it would be interesting to pursue this from a symptom-resolution point of view I think (as well as from a disease-hypothesis and biological one). As we are patients after-all

 

[Jonathan Edwards]

In response to Bob’s thoughts about PEM and autoimmunity:

With autoantibodies any physiological mechanism can be disrupted. After exercise there are various mechanisms that repair muscle, increase muscle bulk as in training, and also systemic effects on sleep, appetite etc. All these mechanisms must have mediators that are operating in the time window. An autoantibody that interacts with such mediators directly or indirectly can then turn their effects into other things in that time frame.

In rheumatoid arthritis if joints are rested strictly then inflammation tends to subside. If activity is increased there is often no major problem during the activity or later that day but first thing the next morning the patient is as stiff as a block of cement. This is not the same as post-exercise malaise but it shows how similar things can occur.

If the problem is antibody related then the PEM is not going to be due to antibodies being made overnight. The antibodies are there all the time but only cause trouble when the mediators they target are released. So the exercise does not provoke the autoimmune response; that arises according to its own rules and swings in to play when exercise related mediators are released. Once autoantibodies have been produced in quantities large enough to produce symptoms they are likely to hang around for weeks at a minimum, and in most cases life long, because the cycle that gets them started carries on. Having said that, there are a variety of mechanisms whereby the autoantibody levels can go up or down. An irrelevant infection can produce what is known as an anamnestic response – a boost in antibodies to everything. A surge of cortisol from stress could upset the cycling mechanism. There may be what is known as clonal drift – which in the Samurai analogy is when one lot of old Samurai masters die and another lot take over their place.

Bob: I'm out of my depth here, scientifically, but I can't help feeling that it's more complex than an auto-antibody at play, and that we have a more complex immune dysfunction.

Jo: We are all out of our depth here and I have been turning over exactly the same questions with colleagues. Autoantibody production is as complicated as the inside of a Swiss watch, so maybe no need to look further – but equally that does not mean it must be the right explanation. I agree that a loop seems likely. Moreover, the model that Jo Cambridge and I work with has as a central tenet that all autoantibodies are directed at molecules that themselves regulate immune responses in some way. Some of the ways are very surprising, but most of the diseases we know about fit the pattern. So your suggestion is in no way nonsense – at least not to my mind.

I have not looked at the detail of the muscle lactate studies but the simple answer is that autoantibodies can potentially do whatever you like to physiological processes. They can pretend to be hormones. They can block neuromuscular transmission. They can fur up filters. They can probably interfere with both cell division and protein synthesis. An antibody is a protein with a segment that can be any shape you like, so that segment can act as an enzyme, a hormone, a receptor blocker or whatever.

And the story gets more subtle as you go deeper in. I have talked in terms of autoantibodies but I try to stick to the more general idea of a vicious cycle of unwanted antibody production. In multiple sclerosis there are antibodies in the cerebrospinal fluid that should not be there. But we do not know whether they are autoantibodies, they may just cause trouble by being antibodies in the wrong place. One of the major antibody types in rheumatoid is against proteins with arginine is oxidized to citrulline. These need not be self proteins – any protein will do. So this is not strictly an autoantibody. And in lupus antibodies are against any DNA. And so it goes on. So I agree with Firestormm that a benefit from rituximab does not prove that the problem is strictly autoimmune. But I think it does prove that B cells are involved and if the response pattern is as usually seen, that antibody cycles are involved. The loop might not relate to one specific antibody, it could perhaps engage for a whole class of antibodies, although it is hard to build models without sneaking a specific sort-of-autoantibody in the chain somewhere.

One of the recurring themes is that these abnormal antibodies are against some outcome of degradation, like cell death or oxidation. That might fit with PEM.

Sjogren’s syndrome seems a bit like ME in some ways. There is often a lot of fatigue and although there are effects on salivary and tear glands there is often otherwise not much to find. We know what the antibody is against – something called Ro. It turns out that part of Ro is a protein that has an immune regulatory function to do with antibodies and viruses. Maybe we are looking for something a bit like that.

And then again there is the caveat that all this talk is very likely to be only about some sorts of ME. Maybe not, but if we lump everything together wrongly nothing will become clear.

And following Snow Leopard’s point, when we started treating RA everyone else was quite sure it had nothing to do with antibodies at all – except maybe Jacob Natvig in Oslo and one or two others. The clues were there but had to be pieced together. For ME the only reliable clues, apart from the Norwegian study, seem to be symptoms, but that’s a start.

 

[Firestormm]

Thank you once again Professor for taking the time to do this for us. I think we all greatly appreciate your explanations and are learning a great deal - particularly me. This last contribution especially. Brilliant

 

[Bob]

Jonathan Edwards, thank you very much for that explanation. I'm afraid to admit that I had no idea that auto-immunity was such a fascinating area of science, until now. The level of complexity seems huge. And the possibilities, in terms of auto-antibodies and targets, seems quite mind-blowing.

Thanks again, for all of the interesting and helpful info, which all makes sense to me. I'll now take some time to digest it.

On this forum, we're always saying that defining subsets is essential for meaningful research results in the field of ME. So, if you can find a way to define any subsets before or after the Rituximab trial results, that would be a huge step forwards in ME research.

 

[Marco]

I am also thinking if it is worth considering what possible reasons there could have been for Rituximab seeming to help someone with ME - other than them having some problem relating to B-cells and autoimmunity. Is such as situation likely? If Rituximab is seen to have had a positive effect - does it always mean that autoimmunity was the problem? Could there be another explanation? What of inflammation generally or inflammatory muscle disease? Do we know at this point that autoimmunity is the only explanation? Is it necessary to rule out other possible explanations.

I've been thinking along the same lines for some time and I have a feeling that elevated pro-inflammatory cytokines (IL1b, IL6, TNF-a - particularly TNF-a) in serum or CSF can explain most if not all of the symptoms of ME/CFS.

That doesn't preclude and autoimmune connection but neither does it require one. We may just (sic) have a predisposition to develop a (neuro) inflammatory state when we encounter a wide range of stressors.

 

[MeSci]

Perhaps, again, MeSci it would help to consider if in those other diseases which are treated with, or are being studied for treatment with, Rituximab - there are similar reported symptoms e.g. IBS-like ones? Again, it would be interesting to pursue this from a symptom-resolution point of view I think (as well as from a disease-hypothesis and biological one). As we are patients after-all

Maybe only relates to autoimmune diseases, so not the cancers that rituximab is used for.

Did a quick search and found this re gut and RA:

http://www.sciencedaily.com/releases/2012/06/120611193342.htm

 

[Jonathan Edwards]

I've been thinking along the same lines for some time and I have a feeling that elevated pro-inflammatory cytokines (IL1b, IL6, TNF-a - particularly TNF-a) in serum or CSF can explain most if not all of the symptoms of ME/CFS.

That doesn't preclude and autoimmune connection but neither does it require one. We may just (sic) have a predisposition to develop a (neuro) inflammatory state when we encounter a wide range of stressors.

This is an interesting line to argue. IL-1, TNF and IL-6 could explain the symptoms. But we have two knock-on arguments. Why would these cytokines go down gradually over a period of months after rituximab is given unless they were being produced in response to antibody-based interactions? There are maybe possible answers but they are a bit contrived, I think. And if the symptoms are due to these cytokines why is the C-reactive protein level not raised consistently when people have the symptoms? IL-6 reliably raises CRP, and TNF feeds in to the same pathway (pretty sure IL-1b does but I forget). ME patients, who as far as I know have CRP levels less than 5, feel even worse than RA patients who have a CRP of 100. It might be a matter of where the cytokines are being made but I don't think that will work well enough. I came to the conclusion that it must be some other cytokine that makes you feel 'lousy with flu' but does not put CRP up. That to me whiffs of interferons but I am out of my area of direct experience. Fluge thinks in terms of something like nitric oxide altering blood vessel function. I wonder about things like acetaldehyde giving you a hangover. It would not be acetaldehyde but that probably works through some endogenous signal pathway too. TNF in RA does not make you hate noise and light but typhoid vaccine or flu can do that. (Maybe there's more circulating TNF then but I am not sure it fits.) In lupus people hide under the bedclothes when neurological crisis is coming and CRP does not go up. I don't know the answer but maybe the pieces are ready to fit together.