Science at the UK CMRC Conference, 1-2 Sept 2014

[Jonathan Edwards]

Peter White: PACE trial

I think I can only describe Dr White’s presentation as out of place. He presented a single slide of outcomes in the PACE study and claimed that it showed clearly that two treatments worked. He then spent the rest of his talk saying how unreasonable it was that patients did not gratefully accept this conclusion, indicating that this was an attack on science (if I remember rightly).

I have not scrutinised the PACE trial in detail but my understanding is that it was an unblinded trial and that, indeed, for such treatments it could only be unblinded. What Dr White seemed not to understand is that a simple reason for not accepting the conclusion is that an unblinded trial in a situation where endpoints are subjective is valueless. Even where there is traditional double blinding you have to be very careful. My old boss at UCL who is a clinical trials expert, immediately pointed out to me in a recent discussion that the crucial weakness even of a randomised double blind placebo controlled trial of something like rituximab in ME is that if either the researchers or the patients get a hint as to what treatment they have (from some minor side effects maybe) the whole thing becomes uninterpretable. Methodological problems for ME trials are almost insuperable. Open efficacy studies are not worth embarking on.

I think it was unfortunate that Dr White suggested that people were being unreasonable over the interpretation of the PACE study. Fortunately nobody seemed to take offence.

 

[Jonathan Edwards]

Invited Lectures


Andrew Lloyd: Acute infection and post infective fatigue as a model for CFS

As soon as Dr Lloyd began his presentation I realised we were being entertained by a hugely charming smoothie Australian showman. I turned up my scepticism receptors. But a few minutes later I also realised that the charming exterior concealed a critical mind with a level of intellectual honesty that matched the best scientists I have come across. His presentation centred around the Dubbo study of post infective fatigue that many people on PR may be familiar with. I had not seen the data in detail before. Every bit of it made sense. Importantly, a lot of the findings were not what the researchers expected, which is always a good sign.

The first point was that fatigue clearly persists despite either elimination or reduction of levels of pathogen in some people and not others. It is not due just to persistent organisms. The second point was that persistent fatigue correlated well with severity of initial symptoms, suggesting that it was some sort of ‘thermostat getting stuck’ response to a major initial reaction. The pattern of persistent fatigue seemed to be the same for very different organisms, and even where the organism turned out not to be one of the three under study, again suggesting that the organism itself was not what mattered. Nevertheless, it is interesting that persistent fatigue seems to relate almost always to intracellular organisms. This for me ties in with Reiter’s fatigue always being after intracellular infection.

And again, Dr Lloyd indicated that persistent fatigue did not seem to relate to persistent blood cytokine levels, even if production from cultured white blood cells may do.

Dr Lloyd found that cytokine related genes could explain part of the persistent fatigue response – related to interferon gamma and IL-10. He also found a correlation with variants of the P2X7 gene, which is implicated in the central nervous system. However, the genes identified did not account for a high proportion of risk (stochastic factor again?).

His final conclusion was that persistent fatigue was not due to persistence of the organism or indeed persistence of a systemic host inflammatory response (as judged by blood cytokines) so must be due to some resetting of a regulatory mechanism within the central nervous system. He did not enlarge but microglia might have been in his mind.

There was a lot of discussion amongst delegates about where Dr Lloyd ‘put his money’. A number of people raised the possibility that there might still be a systemic immune response involved but that blood cytokine might simply be the wrong thing to measure. That would certainly be true for lupus, where cytokines are likely to be normal but antibodies will show what is going on.

I had a particularly interesting discussion on this with Dr Hugh Perry, trying to see how Dr Lloyd’s view could be compatible with a benefit from rituximab. It turned out that we had come to the same conclusion – that there was a role for Fc receptors on microglia and perhaps in particular FcRI, which I put at the centre of my ME5 mechanism on the thread about MEs causing CFS. Dr Jessica Teeling has apparently published on the potential role of Fc receptors. The nice thing about this aspect is that it provides a way that low affinity antibody, that may not show up as classical autoantibody, can contribute, on an optional basis, to persistent microglial activation. So some people’s persistent fatigue might be due to microglial activation getting stuck right at the start and others might be continually ‘topped up’ by rather hidden antibody populations. And the cytokine events would be very local and likely to involve interferons, perhaps with less obvious involvement of the usual suspects.

So all in all I came away thinking that there was a way of making sense, albeit on a complex mix and match basis, of the whole ME story. Importantly that would involve pathways we have tended to ignore in the past but which could be studied now.

 

[Jonathan Edwards]

Ian Lipkin: Microbiology and immunology of CFS/ME and other challenging disorders


Dr Lipkin gave a very wide ranging talk about the role of infectious agents and post infectious reactions in conditions including Sydenham’s chorea, AIDS, and herpesvirus infections. I actually think that many PR members will have accessed a video version of a similar presentation and will be familiar with Dr Lipkin’s work anyway. He mentioned the work on mice with PANDA like symptoms. He reviewed Dr Hornig’s recent studies on cytokines in early and late CFS/ME groups. It is certainly interesting that there seems to be a difference between patients with less than 3 years disease and those with longer disease for interferon gamma (again) and IL-17. Nevertheless, across the board the patients are not much different from controls so it seems pretty clear that the presence of any one of these cytokines in the blood cannot be held directly responsible for symptoms. CSF findings were also interesting in that IFN gamma and IL-17a tended to be lower.


Dr Lipkin discussed the importance of the microbiome and his plans for a large crowdfunded study. He also mentioned that some ‘hot data’ were coming out from Dr Hornig’s lab but said no more about this.

 

[Jonathan Edwards]

Pain/Adolescent Session


Maria Fitzgerald: Understanding pain mechanisms

Dr Fitzgerald was billed to talk about children specifically but changed to a more general overview of the phenomenon of ‘central sensitisation’ to pain, with the implication that this might be relevant to fatigue as well. She gave a detailed account of the way in which neurons can be made to increase their responsiveness by repeated stimulation. She emphasised that there are well established mechanisms for generating a persistent nociceptor response within both brain and spinal cord based on neurochemistry, with the implication that there was nothing ‘beyond the biophysical’ we need to search for.

And in the middle of this potentiation or sensitisation she showed us vast swathes of microglia clustering around both input and output areas in the spinal cord. Microglia are clearly very curious ‘hybrid function’ cells in that they look very much like the macrophages that clear up damage in other tissues but they are also intimately involved in the responsiveness of neurons to electrical signals. Moreover, they seem to be recruited not just by immunological insults but also by others forms of stimuli. Again, it makes me think that talking of inflammation is not helping us here. It is too charged with anthropomorphic overtones. We need to focus on the precise biological mechanisms.

Having Dr Fitzgerald’s (deliberately rejigged) presentation at the end seemed to me to bring the whole programme and discussion together in a very impressive way. Maybe one can get too hooked on microglia, but they look to me to be where the money really is.

Jon Tobias and Roberto Nuevo: I must apologise to these last two speakers for not being able to hear their presentations on adolescent CFS. I also missed Hugh Perry’s final summary. I will be interested to see if it was on the same lines as mine!

END

 

[A.B.]

The first point was that fatigue clearly persists despite either elimination or reduction of levels of pathogen in some people and not others. It is not due just to persistent organisms.

My CFS doctor seemed to believe that some pathogens retreat into CSF or other areas where they can no longer be detected via the usual tests. I'm not sure whether this is merely a suspicion or a proven phenomenon. In the case of Sophia Mirza at least, there was infection of the spinal cord.

 

[lansbergen]

CSF findings were also interesting in that IFN gamma and IL-17a tended to be lower.

Only in the CSF? I am very interested in interferon gamma. I have been saying to myself: come on levamisole ypu can raise it, hurry up. I think it has started some time ago but I can only rely on clinical picture.

 

[Sasha]

I have not scrutinised the PACE trial in detail but my understanding is that it was an unblinded trial and that, indeed, for such treatments it could only be unblinded. What Dr White seemed not to understand is that a simple reason for not accepting the conclusion is that an unblinded trial in a situation where endpoints are subjective is valueless. Even where there is traditional double blinding you have to be very careful. My old boss at UCL who is a clinical trials expert, immediately pointed out to me in a recent discussion that the crucial weakness even of a randomised double blind placebo controlled trial of something like rituximab in ME is that if either the researchers or the patients get a hint as to what treatment they have (from some minor side effects maybe) the whole thing becomes uninterpretable. Methodological problems for ME trials are almost insuperable. Open efficacy studies are not worth embarking on.

This issue about the extent to which we can trust nonblind outcomes, especially in PWME, is an interesting one. I have no doubt that any patient with any disease can be pushed or can deceive themselves into thinking that they have improved when their symptoms and functional abilities have in fact stayed the same. However, I've seen it said by many (surprisingly, also by Prof Wessely) that ME seems to be remarkly resistant to a true placebo effect (biological response in the absence of physical intervention), as opposed to the "misdescription" effect I've just described (I forget its technical name).

I read a book a year or two ago that put the case that the placebo effect only operates on the acute response of the innate immune system (I think) and nothing else (but don't trust my memory on this - also I'm no biologist and this stuff just gets jumbled up in my head). I recall a Cochrane review a while back (2002 - here it is) looking at RCTs in which a non-treatment arm had been included as well as a placebo arm in intervention studies and evidence for a genuine placebo effect was surprisingly weak. I'm not up-to-date on this, though.

Anyway, this kind of 'misdescription' issue is why it's critically important to have actimeters in ME trials but I think the role of placebo effects (or lack thereof) in ME is potentially a very interesting one. Personally, I've tried all sorts of stuff over the decades and the lack of a placebo effect has been quite extraordinary.

I think it was unfortunate that Dr White suggested that people were being unreasonable over the interpretation of the PACE study. Fortunately nobody seemed to take offence.

What questions from the floor did Dr White get? And how did he respond?

 

[Sasha]

Even where there is traditional double blinding you have to be very careful. My old boss at UCL who is a clinical trials expert, immediately pointed out to me in a recent discussion that the crucial weakness even of a randomised double blind placebo controlled trial of something like rituximab in ME is that if either the researchers or the patients get a hint as to what treatment they have (from some minor side effects maybe) the whole thing becomes uninterpretable.

There was some discussion of this about ten years ago in RCT methodology circles and people were starting to talk about having a questionnaire for patients as standard practice, asking them (possibly at several points, including well before the beneficial effects of the intervention could have kicked in but side effects could have) whether they thought they were on the active intervention or the placebo.

I think that that knowledge could have a much bigger effect on certain kinds of trial outcome than anticipated, particularly where the outcomes are based on self-reporting. At least if you ask the question you're forced to confront the issue and not just pretend it's not there because you haven't measured it.

I don't know whether that initiative ever took off.

 

[Snow Leopard]

@Jonathan Edwards

Thanks for all the summaries.

Too many posts to 'like' at this point!

 

[Jonathan Edwards]

I was wondering how consistent a picture we would expect from these 29 papers. For example, are all cytokines known or is there potential for new ones associated with fatigue to be found. Also if there are multiple different diseases and cytokines are involved would you expect them to be the same ones or a mixture of different ones? I'm guessing if the answer to the last question is that different cytokines could be involved this could lead to confused results particularly with small studies - my guess is there could be clusters in larger studies.

Good points. We may be mixing up different situations. However, I think the answer is probably simpler - that cytokines are not intended to work in free solution blood, even if that is where they were first found. They will be billions of times more potent acting locally in tissues. That may not be universally true but my experience has always been that looking for cytokines in blood tells you nothing much.

 

[Sasha]

Thanks so much for such a fantastic summary, @Jonathan Edwards - almost as good as being there. I'm sure you can imagine what it's like to be desperate to know what was going on at the conference and yet to be too sick to get there and you've filled that knowledge gap, and so speedily! I'm hugely grateful.

 

[Jonathan Edwards]

I have no doubt that any patient with any disease can be pushed or can deceive themselves into thinking that they have improved when their symptoms and functional abilities have in fact stayed the same. However, I've seen it said by many (surprisingly, also by Prof Wessely) that ME seems to be remarkly resistant to a true placebo effect (biological response in the absence of physical intervention), as opposed to the "misdescription" effect I've just described (I forget its technical name).

I read a book a year or two ago that put the case that the placebo effect only operates on the acute response of the innate immune system (I think) and nothing else. I recall a Cochrane review a while back (2002 - here it is) looking at RCTs in which a non-treatment arm had been included as well as a placebo arm in intervention studies and evidence for a genuine placebo effect was surprisingly weak. I'm not up-to-date on this, though.

What questions from the floor did Dr White get? And how did he respond?

As you say, Sasha, the true placebo effect is probably the least of our problems in trials. There is regression to mean when there is temporal variation in disease. There are misdescription effects as you say. But to my mind the biggest effect is ikely to be what has been called the reverse placebo effect - the patient trying to please the doctor. I suspect that a high proportion of 'placebo' responses are the patient trying not to offend the therapist. If you think it is important to the therapist's ego that their treatment is appreciated then you will score 'their treatment' higher than 'the ordinary one'. It is worse than that because patients are frightened of upsetting their therapists because they think they may be sent away from the clinic if they do not 'help'. There was a rheumatologist in the 1970s who ran trials with a group of patients who always preferred the real treatment because they wanted to stay in his clinic - and they were the ones in the clinic for that reason. The whole situation with open trials with subjective outcomes is hopeless.

 

[user9876]

Invited Lectures

The nice thing about this aspect is that it provides a way that low affinity antibody, that may not show up as classical autoantibody, can contribute, on an optional basis, to persistent microglial activation. So some people’s persistent fatigue might be due to microglial activation getting stuck right at the start and others might be continually ‘topped up’ by rather hidden antibody populations. And the cytokine events would be very local and likely to involve interferons, perhaps with less obvious involvement of the usual suspects.

Would there be a process where 'topping up' would relate to over excursion which could then relate to PEM?

 

[aimossy]

I won't tag Jonathan Edwards he will get a million alerts. You said it @Sasha
I appreciated Jonathan's analysis and thoughts as well. Too much to comment on and amazed at Jonathan's memory!!
I really enjoyed the Andrew Lloyd information in particular and find it really interesting. I have become familiar with Dubbo studies not that long ago thanks to @Simon (after a bit of reading I became very annoyed that this research was not followed up on as it seemed like there was gold in them ). The other thing I am excited about is Mady Hornig beavering away on her work and hopefully her finding's will be hot and have some nice gold in them too. I'm a bit tired for more thoughts - except thanks to Jonathan it is sincerely appreciated.

 

[Jonathan Edwards]

Would there be a process where 'topping up' would relate to over excursion which could then relate to PEM?

I think that would be in a different time frame. Continued antibody production could keep microglia 'primed' as a baseline. Exertion might then trigger a short term loop of signalling permitted by the baseline priming. The fact that mental exertion can trigger crashes too tends to suggest to me that the crashes are a response to the nerves being busy rather than the muscles but it may not be that simple.

 

[Esther12]

Thanks for all the summaries. Pleased to hear that people are feeling generally positive about it.

Although tbh, White's claims sound offensive, so I'm not sure how great the lack of offense to them is!

But to my mind the biggest effect is ikely to be what has been called the reverse placebo effect - the patient trying to please the doctor. I suspect that a high proportion of 'placebo' responses are the patient trying not to offend the therapist. If you think it is important to the therapist's ego that their treatment is appreciated then you will score 'their treatment' higher than 'the ordinary one'. It is worse than that because patients are frightened of upsetting their therapists because they think they may be sent away from the clinic if they do not 'help'.

When people talk about a placebo response, I tend to assume that they are referring to the above. I can't tell to what extent some researchers and therapists can fail to recognise the danger here, and to what extent they just want to take credit for any self-reported improvement, regardless of it's illusory nature.

 

[Sasha]

When people talk about a placebo response, I tend to assume that they are referring to the above [pleasing the doctor].

That's interesting because I tend to assume the exact opposite - my impression is that they're assuming it's all genuine biological effects of a sham therapy. I guess we won't know until someone does a survey (there's an interesting research project).

 

[Valentijn]

Resveratrol comes from the skins of red grapes and some other fruits and is in red wine and (yippee!) chocolate. You can buy it as a food supplement. I think a few PR members have tried it but I don't know what kind of results they've had.

A normal dose of resveratrol gives me a crippling headache

 

[Nielk]

Thank you @Jonathan Edwards -

We are truly lucky to have you here as an active member on PR. Having you report back to us is even better than being there myself. We get to see the information through your knowledgeable, intellectual prism.

 

[worldbackwards]

I think I can only describe Dr White’s presentation as out of place. He presented a single slide of outcomes in the PACE study and claimed that it showed clearly that two treatments worked. He then spent the rest of his talk saying how unreasonable it was that patients did not gratefully accept this conclusion, indicating that this was an attack on science (if I remember rightly).

Nice to see that ole' White charm still working for him.