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

[Jonathan Edwards]

Staying on the theme of 'stress' just for a little longer ...

I also find it fascinating that two of the key symptoms of narcolepsy are hypnagogic hallucinations (night-time auditory, visual or somatosensory hallucinations) and sleep paralysis. In the early years post 'onset' I experienced both of these on a nightly basis which lasted for hours on end. Thankfully after a year or so they disappeared – not pleasant.

Intuitively I feel we may be on the right lines here. Unfortunately intuition doesn't cut it so a working model that coherently pulls together all the pieces would be nice to see.

I think intuition goes quite a long way if you beat the hell out of it and it still pops up smiling. As you point out, one way to beat the hell out of ideas is to look carefully at time course and anatomical domain. Narcopleptic cataplexy must be a modified neural reflex rather than something to do with blood vessels. My friend Eric would sit down as soon as he saw someone was about to tell a good joke because he wouldn't have time to do so once he started laughing.

Your experience with hypnagogic states seems to me very telling. This is the sort of detail that a really good model, like Gail Trimble of Corpus Christi, will have an answer to before you have finished the question. And that model is not going to be 'believing you have a disease called ME'. I have a lot to learn but this is a good way to do it. I like to stand my ground a bit but MeSci has put me on the spot today - I'll admit!

 

[MeSci]

I think intuition goes quite a long way if you beat the hell out of it and it still pops up smiling. As you point out, one way to beat the hell out of ideas is to look carefully at time course and anatomical domain. Narcopleptic cataplexy must be a modified neural reflex rather than something to do with blood vessels. My friend Eric would sit down as soon as he saw someone was about to tell a good joke because he wouldn't have time to do so once he started laughing.

Your experience with hypnagogic states seems to me very telling. This is the sort of detail that a really good model, like Gail Trimble of Corpus Christi, will have an answer to before you have finished the question. And that model is not going to be 'believing you have a disease called ME'. I have a lot to learn but this is a good way to do it. I like to stand my ground a bit but MeSci has put me on the spot today - I'll admit!

Is that good or bad? Apologies if the latter. I do have a tendency to ask awkward questions and then worry at them like a dog with a bone (notwithstanding the sweet feline avatar)!

OTOH you did say earlier in the thread:

What helps a lot is everyone thinking of awkward questions

 

[Jonathan Edwards]

Is that good or bad? Apologies if the latter. I do have a tendency to ask awkward questions and then worry at them like a dog with a bone (notwithstanding the sweet feline avatar)!

OTOH you did say earlier in the thread:

What helps a lot is everyone thinking of awkward questions

Absolutely. I guess dogs don't really know it's a bone they're chewing on, they just chew (often it's plastic these days). Cats are altogether more particular and rational about their persistence so I think you've got the right picture!

 

[Gemini]

It is interesting that exercise to exhaustion makes a brain protein appear in the circulation, but maybe not so surprising. When I have exercised to exhaustion I have been pretty nearly unconscious, and on one or two occasions actually passed out, as seems to happen from time to time on the Olympic track!

Professor, so glad you've brought exercise into the conversation. A while back I happened upon the sub-specialty "Exercise Immunology." Studies in this field sugggest exercise is an immune modulator that can cause a +/- 15-25% change in cell numbers & other measures of immunity, not significant for those whose immune systems function at 100%, but possibly problematic for those whose systems are deficient or overactive. In those cases this literature indicates the body may invoke a "safety net" mechanism & I was wondering what your thoughts are regards that & PEM/PENE in ME? Also are you aware by any chance of the impact of exercise on antibody production (their literature indicates antibody levels remain the same or are increased post-exercise)? And thinking about the physical aspects of antibodies, do they in numbers increase the viscosity of blood & possibly affect blood flow & circulation? You are a runner I see, so I'm most interested in hearing your thoughts about this field.

http://www.ncbi.nlm.nih.gov/pubmed/21446352

 

[Legendrew]

The thing that interests me more than anything is that in the preliminary studies, patients not only improved transiently but some recovered, seemingly completely without further ongoing treatment. To me that heavily implies that there is little to no permanent damage done and is very positive in terms of potential treatment (as I believe was discussed a few pages back). This would fall in line with the ideas Prof. Edwards was theorising about antibodies not damaging anything directly. but binding to other proteins; receptors, channels etc and disrupting normal function. One question this does raise is whether in all cases these long lived bone marrow plasma cells are at work. Perhaps they are and the remission is only temporary and these patients will all relapse eventually but it does raise the question of whether there is another thing perpetuating the illness in these patients who experience this seeming full remission. Could the autoimmune process proposed occur without these long lived plasma cells behind the scenes? Hopefully in the UK trial we can see whether B-cell profiles could help to predict not only good response but also these really good responses.

I know that Maria Gjerpe is currently in good health and hasn't had any infusion for quite a while now and I recently contacted one of the original pilot study participants to ask how they were doing (i'm writing an informal article/blog thing on the whole CFS/rituximab saga and thought their insight would be an interesting addition) and it seems they're now living a normal ME free life!

 

[Sasha]

I know that Maria Gjerpe is currently in good health and hasn't had any infusion for quite a while now and I recently contacted one of the original pilot study participants to ask how they were doing (i'm writing an informal article/blog thing on the whole CFS/rituximab saga and thought their insight would be an interesting addition) and it seems they're now living a normal ME free life!

That's great to know!

Jonathan Edwards - I'm not the only one on these forums to have had a severe initial illness (several years bedbound) and then a substantial, spontaneous remission for some years (working full-time, going to the gym, full social life, though with many short episodes of ill health) and then a big relapse (mostly housebound now).

I'm wondering how/whether the mechanism you're considering for B-cells allows for such remissions occurring spontaneously? Many people with ME do of course undergo gradual improvement without treatment, even if not to full health. I understand in broad terms your suggestion about how randomness might operate in setting up the disease but not in how the body might fix that on its own.

 

[MeSci]

That's great to know!

Jonathan Edwards - I'm not the only one on these forums to have had a severe initial illness (several years bedbound) and then a substantial, spontaneous remission for some years (working full-time, going to the gym, full social life, though with many short episodes of ill health) and then a big relapse (mostly housebound now).

I'm wondering how/whether the mechanism you're considering for B-cells allows for such remissions occurring spontaneously? Many people with ME do of course undergo gradual improvement without treatment, even if not to full health. I understand in broad terms your suggestion about how randomness might operate in setting up the disease but not in how the body might fix that on its own.

Apologies for not being Jonathan Edwards but I thought that antibody production died down over time (typically years) unless there was a continuous or repeated process triggering their production, hence the need for booster vaccines, for example. I can't remember if Jonathan answered this point when I raised it earlier in the thread (post 69). I know that he is much more au fait with the different stages of antibody production than I am and I managed to absorb the fact that there are longer-term stages and shorter-term stages but my brain has not retained the finer detail. Wish I had time to study this better!

 

[Sasha]

Apologies for not being Jonathan Edwards but I thought that antibody production died down over time (typically years) unless there was a continuous or repeated process triggering their production, hence the need for booster vaccines, for example. I can't remember if Jonathan answered this point when I raised it earlier in the thread (post 69). I know that he is much more au fait with the different stages of antibody production than I am and I managed to absorb the fact that there are longer-term stages and shorter-term stages but my brain has not retained the finer detail. Wish I had time to study this better!

Thanks - I'll look for that post (it's been a long thread!).

 

[MeSci]

Staying on the theme of 'stress' just for a little longer (wasn't Selye's original conception of stress as anything that caused physiological stress which did include psychological stress but in common parlance is now shorthand for psychological stress?) it occurred to me that 'stress' may play a major role in several of the disorders discussed on this thread.

A key aspect of ME/CFS is the worsening of symptoms in response to physical or cognitive challenge and emotional or psychological stress. Stiff person syndrome and narcloepsy (both proposed to be autoimmune mediated conditions) also show adverse reactions to stressors. In SPS external stimuli (sudden loud noises, light, touch, volitional movement, emotional distress etc) trigger the characteristic painful spasms while narcolpesy seems to be triggered by strong emotions (including surprise, laughter, anger).

These reactions tend to be very rapid (instantaneous in SPS and narcolepsy and with whatever variant of ME/CFS I have) or within minutes to hours. I may be wrong but the speed of response doesn't seem to me to be likely to reflect disease activity related to autoimmunity which suggests that brain mechanisms (perhaps impaired by an autoimmune insult) relating to arousal and the processing of stimuli may be to blame.

As I mentioned previously, sensory gating is a neurological measure often used to test deficits in the processing of sensory information. In rodent models (again) isolation rearing (an entirely non- physical stress) has been found to induce sensory gating deficits (isolation results in increased levels of oxidative stress including increased superoxide dismutase activity, decreased oxidized: reduced glutathione ratio and increased lipid peroxidation in brain regions).

I also wonder whether narcloepsy or stiff person syndrome (or both) might be appropriate analogues for ME/CFS. For those of us who would self-describe as 'wired and tired' the muscle stiffness and spasms of SPS may be familiar while cataplexy (sudden loss of voluntary muscle tone) in narcolepsy may be more appropriate to others.

I also find it fascinating that two of the key symptoms of narcolepsy are hypnagogic hallucinations (night-time auditory, visual or somatosensory hallucinations) and sleep paralysis. In the early years post 'onset' I experienced both of these on a nightly basis which lasted for hours on end. Thankfully after a year or so they disappeared – not pleasant.

Intuitively I feel we may be on the right lines here. Unfortunately intuition doesn't cut it so a working model that coherently pulls together all the pieces would be nice to see.

I think that the rapid effects of stress/exertion involve different mechanisms from the initial development of the disease(s). The disease is largely characterised by these rapid reactions, but the underlying abnormality/abnormalities may be the presence of autoantibodies, and result from a process that has initiated the creation of autoantibodies. If I have followed Jonathan Edwards and others' arguments correctly, these autoantibodies may bind to proteins that are released by exertion/stress, etc., and this binding leads to the rapid post-exertional effects (and perhaps the delayed PEM too).

Maybe one or more aspects of the autoantibody binding are what leads to the over-production of lactic acid that results from mitochondrial abnormalities, or at least abnormalities in ATP production.

I wonder whether this 2012 paper on different types of mitochondrial abnormality in ME/CFS could help to complete the story with regard to the acute effects of stress/exertion and suggest possible binding sites for autoantibodies.

 

[Jonathan Edwards]

A while back I happened upon the sub-specialty "Exercise Immunology." Studies in this field sugggest exercise is an immune modulator that can cause a +/- 15-25% change in cell numbers & other measures of immunity. I was wondering what your thoughts are regards that & PEM/PENE in ME? Also are you aware by any chance of the impact of exercise on antibody production? And thinking about the physical aspects of antibodies, do they in numbers increase the viscosity of blood & possibly affect blood flow & circulation?

I am not sure that the immediate effects of exercise on cell numbers are that interesting. Remember that cell numbers are a bit like the number of cars on the M25, they can go up and down quite quickly as traffic shifts without that meaning much about how many people have cars. Exercise probably speeds up traffic of cells in certain directions, in or out of the circulation. That traffic might be controlled by mediators that themselves get caught up in an autoimmune story though. One of the things I am thinking that distinguishes ME from narcolepsy is that effects of stimuli (like PEM) seem to take longer, as if some messenger RNA synthesis or cell traffic outside the brain is involved. Maybe the target mediator is not so much a brain neurotransmitter/receptor as something out in the muscle? Not sure how that ties in to sensitivity to noise and light though. Its puzzling. Lots of other people in the forum are making good points on this and I am not sure I can add much. I discovered today about Tom Gordon's amazing work on narcolepsy sera affecting gut motility, from Jo Cambridge. That looks like a peripheral autonomic nervous effect. Maybe that's why I get tummyache at night! Its all fascinating but a bit bewildering.

To get back to your questions. Exercise can also have a long term effect on immunity, or at least hormones, as in the amenorrhoea of athletes and dancers but that is high level stuff. Antibody levels do not change much over time - what changes is the range of binding specificities as new microbes come and go. High levels of antibody cause blood to increase viscosity but levels are not necessarily high in autoimmunity. They can be in RA and Sjogren's but they can also be low or more often normal.

 

[Jonathan Edwards]

Could the autoimmune process proposed occur without these long lived plasma cells behind the scenes?

I see no reason why perpetuation should not be due to short lived plasma cells engaging further short lived plasma cells and cycling on without the long lived ones. This might be what happens in immune thrombocytopenia. In such a situation shutting down B cell recruitment for six months could break the cycle.

A word of caution about interpretation of the long remissions so far is that in RA we had remissions of up to five years on one course of treatment but all of them finally relapsed. This is not a huge problem because another course tended to produce a further long remission, but it is disappointing for everyone when the relapse occurs all the same. I think it likely that the long remissions in Norway will hold up, but in terms of drawing conclusions about mechanism we may need to wait for ten years before that is clear.

 

[Jonathan Edwards]

Jonathan Edwards - I'm not the only one on these forums to have had a severe initial illness (several years bedbound) and then a substantial, spontaneous remission for some years (working full-time, going to the gym, full social life, though with many short episodes of ill health) and then a big relapse (mostly housebound now).

I'm wondering how/whether the mechanism you're considering for B-cells allows for such remissions occurring spontaneously? Many people with ME do of course undergo gradual improvement without treatment, even if not to full health. I understand in broad terms your suggestion about how randomness might operate in setting up the disease but not in how the body might fix that on its own.

The autoimmune cycle mechanism can readily cope with spontaneous remission. The cycle can theoretically 'burn itself out'. This is not easy to explain in detail but for instance, it might happen if the cycle depended on antibodies binding not too weakly but not too strongly. Too weak might not cycle. Too strong might engage a control mechanism. Cycling may cause the binding strength to drift up and down (a bit like global warming and ice ages may be) but might also lead to the cycle spinning itself out of existence.

What I find much harder to explain is how you can have a long period of remission and then a crash. I am not sure I know of autoimmune diseases that do that - anyone got ideas? RA can remit and relapse and so can lupus but it usually seems more of a fluctuation of degree I think. There are models within the approach that could work but I am intrigued by this.

 

[Ember]

One of the things I am thinking that distinguishes ME from narcolepsy is that effects of stimuli (like PEM) seem to take longer, as if some messenger RNA synthesis or cell traffic outside the brain is involved. Maybe the target mediator is not so much a brain neurotransmitter/receptor as something out in the muscle? Not sure how that ties in to sensitivity to noise and light though. Its puzzling.

When I first experienced ME (but was still relatively healthy), my muscles would suddenly lapse into a kind of paralysis in the context of jogging. The symptom was alarming, but transient--so strange that I never mentioned it to a doctor. Then maybe six to eight hours later, the neuroimmune exhaustion would begin. I always experience PENE as a global, not a muscular, dysfunction.

 

[rosie26]

I have never experienced remission, just snail like slow improvement last 12 years. If I went into remission, I certainly wouldn't believe I was cured, I know the rage of this illness and it's nasty streak, it is ready and waiting to wake up again. I don't trust it one bit.

 

[Firestormm]

...What I find much harder to explain is how you can have a long period of remission and then a crash. I am not sure I know of autoimmune diseases that do that - anyone got ideas? RA can remit and relapse and so can lupus but it usually seems more of a fluctuation of degree I think. There are models within the approach that could work but I am intrigued by this.

Yeah this gets me every time I try and think about it. I like the 'fluctuation of degree'. That could fit within my own experience; but as a layperson each and every time I am knocked from my perch it's by a nastier than normal virus. So in my naive mind it was the virus doing the pushing. At least until I grasped the concept that I had in fact reached an accommodation of coping with my condition - and this accounted for the remission.

I have enjoyed periods of a year or more where I have been in what I would term 'remission'. Bumps along the way, of course, but nothing like the feeling I experience when some nasty virus knocks me down and I can't get up: and I experience a relapse.

Maybe, maybe, maybe, my body itself reaches the accommodation after a fashion and it's not controlled by me learning better management skills and getting more help - or maybe it's a little of both. It's a funny thing to think that I have managed three remissions in 15 years all on my own - but that maybe there is a model that can account for it and a drug that might allow it to happen.

What is hard is trying to think of a model that fits my own experience: but then I am assuming the same things that are wrong with me also comply with a model encompassing autoimmunity. One thing is for sure - never once in my periods of remission was I ever totally free of this incapacity. I was however, able to ignore it for a while: we'd reached that accommodation - and that was rather nice while it lasted

 

[Marco]

One of the things I am thinking that distinguishes ME from narcolepsy is that effects of stimuli (like PEM) seem to take longer, as if some messenger RNA synthesis or cell traffic outside the brain is involved. Maybe the target mediator is not so much a brain neurotransmitter/receptor as something out in the muscle? Not sure how that ties in to sensitivity to noise and light though. Its puzzling. Lots of other people in the forum are making good points on this and I am not sure I can add much. I discovered today about Tom Gordon's amazing work on narcolepsy sera affecting gut motility, from Jo Cambridge. That looks like a peripheral autonomic nervous effect. Maybe that's why I get tummyache at night! Its all fascinating but a bit bewildering.

I've a feeling that peripheral and autonomic neuropathy may play a big part in this disorder.

As for the delay in the response to stimuli - (mine are almost instantaneous - but I take the point - in most PWME the effects are long lasting - up to 48 hours if the crash doesn't cause a sustained relapse) - heat shock proteins, or the lack of, might fit the timescale. HSPs are produced to maintain cellular integrity against the physiological effects of stressors which include oxidative stress. Normally HSP production peaks at 48 hours post 'the stressor' which might suggest this also coincides with peak oxidative stress. If the HSP response is deficient then HSP protection will be deficient during the peak period of oxidative stress. Elevated oxidative stress and autonomic dysfunction are among the few consistent findings in ME/CFS.

Just a thought.

 

[Sasha]

The autoimmune cycle mechanism can readily cope with spontaneous remission. The cycle can theoretically 'burn itself out'. This is not easy to explain in detail but for instance, it might happen if the cycle depended on antibodies binding not too weakly but not too strongly. Too weak might not cycle. Too strong might engage a control mechanism. Cycling may cause the binding strength to drift up and down (a bit like global warming and ice ages may be) but might also lead to the cycle spinning itself out of existence.

Very interesting!

What I find much harder to explain is how you can have a long period of remission and then a crash. I am not sure I know of autoimmune diseases that do that - anyone got ideas? RA can remit and relapse and so can lupus but it usually seems more of a fluctuation of degree I think. There are models within the approach that could work but I am intrigued by this.

My experience of remission was quite strange. I actually thought I'd fully recovered except for what I thought was a kind of immune-damage legacy of frequent 'colds', which I now suspect might have been repeated viral reactivations (I was told so by an immunologist). I had about 15-20 such episodes a year for ten years, each putting me in bed for a couple of days and resolving over the course of a week or ten days until they became longer and more frequent and, eventually, one long relapse which has now lasted six years.

I suppose it's possible that I'm not in the autoimmune subset of ME, if there is one, but rather one with a reactivating virus such as HHV-6, or perhaps one with some kind of other immune system damage. Maybe that kind of pattern will be one way of identifying non-responders (sadly, for me!).

 

[Legendrew]

Very interesting!



My experience of remission was quite strange. I actually thought I'd fully recovered except for what I thought was a kind of immune-damage legacy of frequent 'colds', which I now suspect might have been repeated viral reactivations (I was told so by an immunologist). I had about 15-20 such episodes a year for ten years, each putting me in bed for a couple of days and resolving over the course of a week or ten days until they became longer and more frequent and, eventually, one long relapse which has now lasted six years.

I suppose it's possible that I'm not in the autoimmune subset of ME, if there is one, but rather one with a reactivating virus such as HHV-6, or perhaps one with some kind of other immune system damage. Maybe that kind of pattern will be one way of identifying non-responders (sadly, for me!).

That pattern could be accounted for by a clonal shift towards a stronger binding auto-antibody but with lower specificity. In your periods where you were feeling well only a small number of autoantibodies were bound but over several days/weeks this could slowly build up until you came down with what would appear to be an acute illness. These would remain bound for several days/weeks before eventually coming unbound (or the cellular receptors were destroyed and replaced) leaving you feeling better again only for the same process to repeat. I'm not saying this is what happened but it could account for the unusual pattern.

 

[Jill]

Thank you Dr Edwards for all that you are doing and all the thought you are putting into ME. I'd also like to thank your family , as this all must be taking time from your retirement!!! It is good to read that someone is thinking about this illness , out of their own sub- speciality and want to have our input.
My experience is that as I child I got unusually heavy colds, seemed to catch every flu going, and then after I had what they thought was glandular fever (age 14), I never caught anything much again and have had ME/CFS since.
My only experiences of remission were twice -
1 .(age 28) has been after emergency surgery for a ruptured appendix. I felt completely different and had the best 3 months ever!! ( I've had other surgeries and they'v all helped for shorter times). I had assumed it was the antibiotics (metrinidosole etc), but now think it was the anthesthetic. I know other people with ME relapse after surgery and so I think i'm possibly at the FM end of the continuum ?? (who knows)
2. when I first started Gabapentin. The effects were great - but it wore off over about 3 months.

I've also had help from Immunovir and LDN

Not sure if this useful, but thought I'd add my 2 cents worth.

 

[rosie26]

Jonathan Edwards you said regarding remissions- "fluctuation by degree" I would agree there.! would seem answer as relapse seems to occur again for some with ME. Remissions could be a level/degree of the illness. This feels out of my depth though so leave it here. Many thanks Prof. Edwards for all your thoughts, it is interesting and insightful.