Pressure grows on Lancet to review “flawed” PACE trial
BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k3621 (Published 22 August 2018) Cite this as: BMJ 2018;362:k3621
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Now that the biopsychosocial treatments, cognitive behavioural therapy (CBT) and graded exercise therapy (GET), are correctly recognised to be ineffective and even harmful (in the case of GET), it seems appropriate to reconsider what we can offer CFS/ME patients in terms of real benefit.
We can identify some disease subtypes for which effective treatments already exist. Psychological stress has been shown to weaken cellular immunity leading to reactivation of endogenous Epstein-Barr virus (EBV) with expression of EBV dUTPase which creates a pro-inflammatory state which if prolonged can lead to development of CFS/ME (1,2). Clinical benefit in EBV-induced CFS/ME patients has been achieved using valganciclovir (3). We can identify this important and treatable CFS/ME subtype (up to 50% CFS/ME patients) by detection of antibodies to EBV dUTPase and DNApol (4) and/or by detection of the EBV induced gene 2 (EBI2), which is upregulated in peripheral blood mononuclear cells (PMBC) (5).
Parvovirus B19 has also been shown to trigger CFS/ME. B19-CFS/ME maybe identified by a characteristic viral illness at the onset of CFS/ME with serum anti-B19 IgM positivity, and persisting B19 DNA positivity. B19-CFS/ME has been cured in several cases using intravenous immunoglobulin (IVIG), the specific treatment for parvovirus B19 (6).
Acute Q-fever may also trigger CFS/ME and Q-CFS/ME has been shown to respond to tetracyclines (7). These approaches actually work and their widespread implementation, along with other more general supportive treatments, would be a respectful clinical service to CFS/ME patients.
References
1. Glaser R, et al. Psychoneuroendocrinology 1994;19:765-72.
2. Padgett DA, et al. J Med Virol 2004;74:442-8.
3. Montoya JG, et al. J Med Virol 2013;85:2101-9.
4. Lerner AM, et al. PLoS One 2012;7:e47891.
5. Kerr JR, et al. J Infect Dis 2008;197:1171-84.
6. Kerr JR, et al. Clin Infect Dis 2003;36:e100–6.
7. Arashima Y, et al. Intern Med 2004;43:49–54.
Email: jonathan@ssl-mail.com
Competing interests: No competing interests
It also bears pointing out that the PACE study used diagnostic criteria (the Oxford criteria) which are known not to exclude patients with psychiatric illness. So again it can be seen that CBT and GET were given the maximum opportunity to demonstrate efficacy in the PACE study; but the results were nil or negligible.
It is ridiculous therefore to argue that PACE showed efficacy for CBT and GET in ME/CFS. That is simply not a rationally tenable position to adopt and I would urge Professor Sharpe to reconsider his entire outlook in this matter.
Competing interests: No competing interests
Even though PACE did not control for placebo and therapist effects it still did not manage to provide evidence of significant benefit from CBT and GET. So even under the most favourable conditions - conditions which meant the study was not constrained by appropriate scientific methodology - it failed to demonstrate significant effects.
The only conclusions one can draw from PACE are that (a) in all probability CBT and GET are not effective treatments for ME/CFS, and (b) given the size of the study it would be an irresponsible waste of scarce resources to continue to research these treatments for ME/CFS.
Competing interests: No competing interests
With all due respect, I would like to remind Professor Sharpe that his own study [1] found "There was little evidence of differences in outcomes between the randomised treatment groups at long-term follow-up."
I suggest we ought to take those results at face value, and look for treatments that might actually work.
Competing interests: No competing interests
Professor Michael Sharpe claims patients resist research into ME/CFS; nothing could be further from the truth. Individuals as well as organisations such as the ME Association and Millions Missing have fought long and hard to see real research into the condition. We now know about its impact on the mitochondria, immune system, HPA axis, heart, brain, and gut.
Scientific research should be valid and reliable, avoiding bias by being blinded and having objective measurements which can be replicated.
The PACE trial doesn't meet any of those criteria, and the more REAL research into the biological processes involved gives us a clearer picture of the condition, the more risible the PACE trial looks.
Competing interests: No competing interests
The PACE trial does not exist in a vacuum and was the much publicised crystallisation of years of effort to psychologise a poorly understood neurological illness myalgic encephalomyelitis (ME). I was diagnosed with ME/severe postviral fatigue syndrome by a consultant neurologist in 1984, after a Coxsackie B4 infection in late 1982 in west of Scotland. I had muscle biopsy and EMG to confirm this diagnosis, both abnormal. I had never heard of ME before my own diagnosis, aged twenty. I remain ill today.
I have lived through the politics of the illness being played out - in UK in late eighties/early nineties ME was reframed as chronic fatigue syndrome (CFS), a nebulous syndrome which bears little resemblance to the illness I and thousands of others in UK experience. In fact, it has been recommended by the *Agency of Research and Healthcare Quality (ARHQ) in USA that the Oxford Criteria, which underpinned this reframing, be retired as research using them is simply unreliable.
ME utterly derails and destroys lives - there have tragically been two recorded deaths in UK as a result of ME - and patients have undoubtedly suffered further as the result of treatments like graded exercise therapy (GET) and cognitive behavioural therapy (CBT ) being touted as curative.
In reality, many ME patients have been made worse by graded exercise, which is unsurprising as exertion intolerance is at the core of ME. Symptoms are exacerbated by both physical and mental exertion. It can take days to recover from minor exertion. The mechanism of this disrupted energy remains elusive, but it is simply impossible to exercise one’s way out.
Unfortunately, those who supported the PACE trial have compounded the suffering of ME patients by refusing to listen. PACE and its subsequent trumpeting by media as tackling ‘fear of exercise’ was an insult and catastrophe for patients all over the world. Carol Monaghan MP is correct to state that when full details are known that PACE will go down as one of the biggest medical scandals of 21st century.
* AHRQ evidence review (2014)
https://www.meresearch.org.uk/news/ahrq-review/
Competing interests: No competing interests
As others have noted [1,2] scientific criticism of the methodology of the PACE trial [for example: 3,4,5] is independent of disagreement about the causes and mechanisms of ME/CFS.
From a patient’s perspective, the main issue with the PACE trial is not that it implies that ME is "all in the mind" but that it recommends treatments which don't work and are potentially harmful [7].The unhelpful belief, perpetuated by the trial, that ME can be “reversed” by teaching patients to think differently and/or gradually increase exercise has not only led to the mistreatment of patients but it has also inhibited biomedical research which may have led to diagnostic tests and effective treatments.
As someone who has been severely disabled by ME for more than 26 years, I would be delighted if my illness could be cured, or my symptoms alleviated, by PACE-type cognitive behavioural therapy and/or graded exercise therapy. But the sad truth, based on the scientific evidence as well as my own painful experience, is that it cannot. That so many have been persuaded otherwise, at such cost to patients, by such profoundly flawed research suggests that the problems with psychological medicine may run far deeper than just one study.
1. Edwards JCW. Re: Pressure grows on Lancet to review “flawed” PACE trial. BMJ 2018;362:k3621https://doi.org/10.1136/bmj.k3621
2. Kewley AJ. Please do not misunderstand patients views. BMJ 2018;362:k3621https://doi.org/10.1136/bmj.k3621
3. Wilshere CE et al. Rethinking the treatment of chronic fatigue syndrome – a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology. March 2018: https://doi.org/10.1186/s40359-018-0218-3
4. Journal of Health Psychology special Issue: The PACE trial. Vol 22. Issue 9. August 2017. http://journals.sagepub.com/toc/hpqa/22/9
5. Racaniello VR et al, Open letter to The Lancet version 3.0, Virology Blog, August 2018.
http://www.virology.ws/2018/08/13/trial-by-error-open-letter-to-the-lanc...
7. Geraghty K et al. Journal of Health Psychology. August 2017.
https://doi.org/10.1177/1359105317726152
Competing interests: No competing interests
I feel I need to respond to inaccurate remarks from Professor Sharpe.
The only thing unwelcome about PACE was the interpretation, which was unfounded, not the findings. More specifically, none of the authors of the letter to the Lancet has ever expressed a desire to stop research into treatment of ME/CFS. This allegation is untrue. The authors have expressed their desire to see research of an adequate standard. None of the authors of the letter to the Lancet, as far as I am aware, has any objection to the study of psychological or exercise therapies if competently performed. The implication that for some reason the type of research was unwelcome to them is a fabrication.
Professor Sharpe says that the PACE trial had extensive review before publishing. This remark may be misleading. It is a quotation from Richard Horton. It transpires that the trial was indeed subject to multiple peer review during planning. However, Horton also made clear that the publication of the results and interpretation was fast tracked. My information is that fast-tracking includes giving the authors an opportunity to choose at least one sympathetic referee. So it seems fairly certain that the publication may not have received extensive peer review.
Professor Sharpe says that all further reviews of the trial have found its conclusions to be sound. This is not the case. An entire volume of the Journal of Health Psychology (August 2017) was devoted to reviewing the trial and the majority of papers found it totally unsatisfactory. These papers also pointed out that the 'other studies' noted by Dr Sharpe had similar flaws. As indicated in my previous comment, it was the patient scientists who brought the problems of PACE to the attention of academics outside the field of liaison psychiatry, where peer review appears to fall below standard. Unblinded trials of therapist-delivered treatments with subjective outcomes are not considered valid evidence in any other field as far as I am aware.
Competing interests: No competing interests
Another aspect that may be behind a smoke screen is that of fully informed consent. Presumably the participants in the PACE trial gave this prior to participation. But if the parameters for recovery and/or improvement were changed after the data was collected, wouldn’t this render previous informed consent null and void and, therefore, negate the trial results a priori?
Competing interests: No competing interests
Re: Pressure grows on Lancet to review “flawed” PACE trial
PACE proponents, straw men and bricks.
After reading Professor Sharpe’s letter to the Times on the PACE Trial, I have followed the BMJ comments submitted by learned and informed people. I am not learned, but as a carer for some 20 plus years, I am reasonably informed.
Perhaps it would be helpful to look at the divergence of opinion on PACE again, this time metaphorically?
What I see in the PACE proponents’ arguments are “strawmen’, “clutching at proverbial straws.”
Neither is the strawman approach helpful, nor clutching at straws advised.
Neither have have any place in reasoned, scientific argument.
Finally, the "proof of the pudding is in the eating."
If PACE were to have been the "best thing since sliced bread", patients and their families would be embracing it, not rejecting it! No one wants to remain ill and most will do anything to improve their situation.
The only "benefits" coming out of the PACE trial are to the DWP (central Government ideology) and the Insurance Industry.
FYI
Straw man
noun
noun: straw man; plural noun: straw men; noun: strawman; plural noun: strawmen
1. 1.
an intentionally misrepresented proposition that is set up because it is easier to defeat than an opponent's real argument.
"her familiar procedure of creating a straw man by exaggerating their approach"
2. 2.
a person regarded as having no substance or integrity.
Clutching at Straws.......
“We drift down time, clutching at straws. But what good's a brick to a drowning man?”
Tom Stoppard, Rosencrantz and Guildenstern Are Dead
"Hamlet told from the worm's-eye view of two minor characters, bewildered Rosencrantz and Guildenstern. Echoes of Waiting for Godot resound, reality and illusion mix, and where fate leads heroes to a tragic but inevitable end.............."
Competing interests: No competing interests