NICE ME/CFS Guideline stakeholder scoping workshop, Fri 25th May 2018

Jonathan Edwards said:
However, the truth is that we have nothing that provides firm evidence for a pathological mechanism in ME.
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While there are no firm evidences for a mechanism, there have been many studies that tend to show that there is something abnormal happening (I'm thinking about metabolomics or exercise studies...). We don't know yet the importance of these abnormalities, the role they play, if they discriminate from other pathological states etc, but they are nonetheless there.

I do not think they should be presentend as "firm evidences", but I do not think they should be discarded either, on the ground that the pathophysiology is not yet understood.
 
Cheshire said:
there have been many studies that tend to show that there is something abnormal happening
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Tending to show is not enough, though. There are tens of thousands of papers tending to show this or that in any number of diseases and the great majority of them never turn out to mean anything useful. Peter Barry works in intensive care paediatrics. He will be used to sifting out the studies that show from those that tend to show, because it matters to responsible care.

I think it is a pity that PWME have been encouraged to think that firm evidence of pathology has been found. It may be good to be optimistic but not to be unrealistic. Pointing Peter Barry and his committee to a vast list of papers that in the end come to no very definite conclusion is not going to help and I think distracts from the real arguments.
 
@Jonathan Edwards - in Dr Komaroff's webinar this week, he referred to an old study of his showing big differences on three tests between PWME and healthy controls but in response to a question about why these weren't being used as biomarkers, he said (in essence) that they weren't sensitive/specific enough for that use.

But do the big (and they were big) statistical differences between PWME and healthies in this and other studies indicate disease, or have this and similar studies failed to replicate (or to have replication tested)?
 
As I understand it, the role of NICE is to inform doctors about definition, diagnostic tests, differential diagnosis, which treatments are evidence based and approved for use, and to outline appropriate care pathways for patients diagnosed with a condition.

Does its remit also include judging on the evidence for the cause and biological mechanisms of a disease?
 
Sasha said:
But do the big (and they were big) statistical differences between PWME and healthies in this and other studies indicate disease, or have this and similar studies failed to replicate (or to have replication tested)?
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I am not sure what big differences are being referred to. I have not seen anything that has stood up to replication well and am not actually aware of anything major from Komaroff. Is there a link to this?
 
Jonathan Edwards said:
I am not sure what big differences are being referred to. I have not seen anything that has stood up to replication well and am not actually aware of anything major from Komaroff. Is there a link to this?
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A recording of the presentation is not yet available on YouTube. Going from memory, he found statistically significant differences in IgG, something related to lymphocytes (lymphocyte counts maybe?), and something else (also related to immune function).
 
Jonathan Edwards said:
I am not sure what big differences are being referred to. I have not seen anything that has stood up to replication well and am not actually aware of anything major from Komaroff. Is there a link to this?
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IIRC it was a fairly large (hundreds of patients?) study that he'd been involved with quite a few years ago. He had a slide in his talk summarising the findings, and one of the odds ratios was over 20, I think, but I can't remember more than that. Looks like we'll have to wait for the webinar going uup on YouTube.
 
This one maybe? 203 cases and 203 controls.
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic illness that is often disabling. This paper introduces the Chronic Fatigue Initiative, which conducted a large multi-center study to more fully characterize ME/CFS and ultimately to describe and understand the underlying mechanisms and pathogenesis of this illness.

Methods: A total of 203 patients with ME/CFS (cases) and 202 matched healthy controls (HCs) were enrolled from 5 geographically different expert clinical sites to create a well-characterized population linked to a national biorepository. ME/CFS subjects were compared to a one-to-one matched HC population for analyses of symptoms and illness severity. Cases were further evaluated for frequency and severity of symptoms and symptom clusters, and the effects of illness duration and acute vs. gradual onset.

Results: This study collected more than 4000 pieces of data from each subject in the study. Marked impairment was demonstrated for cases vs. controls. Symptoms of fatigue were identified, but also, nearly as frequent and severe, were symptoms of cognitive dysfunction, inflammation, pain and autonomic dysfunction. Potential subgrouping strategies were suggested by these identified symptom clusters: sleep, neurocognitive, autonomic, inflammatory, neuroinflammatory, gastrointestinal and endocrine symptoms.

Conclusions: Clearly, ME/CFS is not simply a state of chronic fatigue. These data indicate that fatigue severity is matched by cognitive, autonomic, pain, inflammatory and neuroinflammatory symptoms as the predominant clinical features. These findings may assist in the clarification and validation of case definitions. In addition, the data can aid clinicians in recognizing and understanding the overall illness presentation. Framing ME/CFS as a multisystem disorder may assist in developing therapies targeting the multifaceted domains of illness.
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Paywalled at https://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1023652?journalCode=rftg20
 
Andy said:
Exactly this. Arguing that attendance at an ME self-help group is a cause of worse outcomes is the same as arguing that attendance at an Alcoholics Anonymous meeting is the cause of those people drinking more.
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Or, indeed, that seeing a psychiatrist is the cause of mental health problems (which may well be true in some cases).

Jonathan Edwards said:
There was also a lot of support for paying less attention to evidence from trials and taking personal experience into account more - with the suggestion that different patients responded to different treatments. At the summing up our facilitator took this as the main message from stakeholders. But of course it plays directly into the hands of those wanting to keep CBT and GET on the books - the new guideline will say that these may be good for some and not others. What the guidelines should be saying is that there is no evidence for them being any good for anyone - based on formal trials. The only way to get CBT and GET removed from any actual recommendation is to say nothing is allowed unless there is solid evidence - which is the position for all other illnesses and should be the position for NHS provision.
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I have mixed feeling about this. Do you think we should distinguish between treatments which have been trialled and shown to be ineffective (eg CBT, GET and Rituximab), and treatments which have not yet been adequately tested for which there is anecdotal evidence of benefit and very little risk of harm (eg B12, Q10)? Is that what Charles is suggesting?

Jonathan Edwards said:
The trouble with that is that it may lead to the idea that they should be 'inclusive' and allow lots of different options, even if with a weak evidence base. That of course allows the psychiatrists right back in (having never actually left) and we are back to square one. My position has been that the only way to keep unproven and troublesome treatments out of the picture is to stick to the normal NICE policy of requiring a good evidence base.

And that makes it hard to have a 'biomedical basis cast in stone' because it isn't cast in any stone in the literature. We cannot say to NICE 'we have decided that ME is biomedical and you have to agree'. All we can say is that there is no evidence that the psychiatrists either have any coherent theories or trial based evidence for their approach being of any value. In a court of law the relatives are not allowed to tell the judge that the defendant has to be acquitted because they say so. The judge has to decide on evidence. The problem we have is that the psychiatry people have been doing this. If we use the same tactic we have a very weak position.
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I know you’re not, but I think it is important not to differentiate between biomedical and psychiatric illnesses. The question of whether ME is perpetuated by pathology (biomedical) is completely separate from the argument about whether or not it is psychiatric. My understanding/belief is that all genuine psychiatric illnesses are biomedical. When biomarkers are discovered for psychiatric illnesses, it may change their names and the way they are treated, but it won’t necessarily change how they are classified. The classification is a reflection symptoms more than aetiology.

Of course, Wessely et al do not suggest that “CFS/ME” is psychiatric or biomedical. Quite what they believe becomes harder to understand the more you listen to them, and does not always appear to be consistent. But I think I’m right in saying that they believe there is no underlying pathology which prevents recovery, that the illness is perpetuated my patients’ unhelpful beliefs and deconditioning, and that it can be reversed through psychological and behavioural interventions (despite evidence to the contrary).

Ironically, the difficulty in discrediting the BPS creed seems to be partly due to its unfalsifiability – which ought to have prevented it from being taken seriously in the first place.
 
Robert 1973 said:
Do you think we should distinguish between treatments which have been trialled and shown to be ineffective (eg CBT, GET and Rituximab), and treatments which have not yet been adequately tested for which there is anecdotal evidence of benefit and very little risk of harm (eg B12, Q10)? Is that what Charles is suggesting?
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No, I think not. B12 has been used for decades as the panacea placebo and I would bet my shirt that is all it is. It is the perfect placebo - being a vitamin sounds healthy and natural and being an injection makes it powerful. Q10 is pretty similar. I can think of no plausible scientific reason why these should make a difference to ME.

I think there are two further specific arguments for not suggesting things like this. Firstly, any physician can use options like this if they want anyway. There is no need to tempt patients into thinking they help by mentioning them specifically. The second is that it is all too easy to give the impression a real treatment is being given which may raise false hopes and delay attention to important problems. If anyone genuinely thinks B12 or Q10 help ME there should be a decent double blind trial. Then if they do something we actually have some facts. The reason nobody does such a trial is that they know in their heart of hearts that it will not show much.

I keep banging on about this but we need to impress Peter Barry that the patient community know their stuff and are not going in for wishy washy argument. It is interesting that he quipped that they had forgotten to separate Charles and I. Presumably he has not yet worked out that Charles and I have quite big differences in approach.
 
Jonathan Edwards said:
I think there are two further specific arguments for not suggesting things like this. Firstly, any physician can use options like this if they want anyway. There is no need to tempt patients into thinking they help by mentioning them specifically. The second is that it is all too easy to give the impression a real treatment is being given which may raise false hopes and delay attention to important problems.

I keep banging on about this but we need to impress Peter Barry that the patient community know their stuff and are not going in for wishy washy argument.
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The only reason I was uncertain was that I hadn’t appreciated your first point – that physicians can prescribe these things anyway. Given that, I think you’re absolutely right.
 
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sorry to repeat myself but I just want to get my understanding clear about off label prescribing

NelliePledge said:
o if there is a clinic that has a specialist medic who has been educated in what’s current known about ME based on biomedical research findings and experienced doctors knowledge. There doesn’t need to be a specific treatment in the guidelines. There needs to be proper comprehensive testing to rule out other issues. The doctor needs to be allowed to treat symptoms using available resources and their best judgment on individual patients needs which may be medications used in adjacent conditions. This doesn’t mean everyone would be getting random medications everyone on antivrals for eg as the specialist would have to be able to justify use of the medication in each case.
But it could mean if someone has bad muscle weakness they maybe have access to Mestinon. If they have problems with sleep they maybe have melatonin.

Or would strict evidence based requirement needed in order to exclude GET mean the specialist wouldn’t be able to use their judgment in this way?
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Jonathan Edwards said:
Firstly, any physician can use options like this if they want anyway. There is no need to tempt patients into thinking they help by mentioning them specifically.
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NelliePledge said:
sorry to repeat myself but I just want to get my understanding clear about off label prescribing
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There is a difference between putting something in the guideline as a positive suggestion and what physicians are free to use if they wish. I don't think mestinon should be suggested specifically but if a physician feels they are justified in using it they can now and will still be able to. There might be an issue about costing but if it a cost issue I think we have to fall in line with the general NHS rule that funding of drugs is tied to reliable proof of efficacy. Without that one gets chaos with the budget as constrained as it is. And unless rules like that are in force nobody is ever motivated to do proper trials.
 
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