PACE trial claims of recovery are not justified by the data: a rejoinder to Sharpe, Chalder, Johnson, Goldsmith & White

Posted on 03/23/2017 by wames

Following a response from the PACE trial researchers to their re-analysis from the PACE trial researchers Wilshire et al have published a reply:

Article abstract: 

BACKGROUND: Recently, we critically evaluated the claim from the PACE trial that cognitive behavioural therapy (CBT) and graded exercise therapy (GET) can lead to recovery from chronic fatigue syndrome.

We showed that the trial’s definition of recovery was so loose it failed to capture the term’s core meaning. Also, this definition was substantially loosened very late in the trial, in ways that favoured the study hypotheses. The investigators do not acknowledge any of these criticisms and stand by their original analyses.

PURPOSE: To examine the arguments advanced in defence of PACE’s recovery claims.

METHODS: Drawing on various sources of evidence, we consider three major arguments raised in defence of PACE’s recovery claims: 1) that since there is no agreed definition of recovery, it comes down to a matter of opinion; 2) that the original definition was “too stringent”; and 3) the revised definition generates results that align with previous studies.

RESULTS: We find that: 1) “recovery” is a strong claim, which implies evidence a return to health, and that the trial’s final definition did not preserve this core meaning; 2) there is no evidence to suggest that the original protocol-specified definition was “too stringent”; 3) absolute recovery rates from other studies are not a legitimate source of support for the recovery definition used.

CONCLUSIONS: The PACE trial provides no evidence that CBT and GET can lead to recovery from CFS. The recovery claims made in the PACE trial are therefore misleading for patients and clinicians.

PACE trial claims of recovery are not justified by the data: A Rejoinder to Sharpe, Chalder, Johnson, Goldsmith and White, by Carolyn Wilshire Tom Kindlon and Simon McGrath,  [Published: 22 March 2017] Full text available on open access

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The full independent re-analysis of the PACE Trial now available on open access

Posted on 03/23/2017 by wames

ME Association blog post, 22 March 2017: Thanks to the MEA, you can now read the whole independent re-analysis of the PACE Trial recovery paper, 22 March 2017

The independent re-analysis of the PACE Trial recovery paper emerged from behind the publisher’s paywall today – after the ME Association paid US$2,000 for the paper to be switched to Open Access so that academics and clinicians can read it in full.

We used funds in our Medical Education Programme to enable this exercise in transparency to take place.    Read more from the MEA.

Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial, by Carolyn Wilshire, Tom Kindlon Irish ME/CFS Association, Dublin, Alem Matthees & Simon McGrath in Journal Fatigue: Biomedicine, Health & Behavior [Published online: 14 Dec 2016]

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Clinically proven mtDNA mutations are not common in CFS

Posted on 03/22/2017 by wames

Research abstract:

Background:
Chronic Fatigue Syndrome (CFS) is a prevalent debilitating condition tat affects approximately 250,000 people in the UK. There is growing interest in the role of mitochondrial function and mitochondrial DNA (mtDNA) variation in CFS. It is now known that fatigue is common and often severe in patients with mitochondrial disease irrespective of their age, gender or mtDNA genotype. More recently, it has been
suggested that some CFS patients harbour clinically proven mtDNA mutations.

Methods:
MtDNA sequencing of 93 CFS patients from the United Kingdom (UK) and South Africa (RSA) was performed using an Ion Torrent Personal Genome Machine. The sequence data was examined for any evidence of clinically proven mutations, currently; more than 200 clinically proven mtDNA mutations point mutations have been identified.

Results:
e report the complete mtDNA sequence of 93 CFS patients from the UK and RSA, without finding evidence of clinically proven mtDNA mutations. This finding demonstrates that clinically proven mtDNA mutations are not a common element in the aetiology of disease in CFS patients. That is patients having a clinically proven mtDNA mutation and subsequently being misdiagnosed with CFS are likely to be rare.

Conclusion:
The work supports the assertion that CFS should not be considered to fall within the spectrum of mtDNA disease. However, the current study cannot exclude a role for nuclear genes with a mitochondrial function, nor a role of mtDNA population variants in susceptibility to disease. This study highlights the need for more to be done to understand the pathophysiology of CFS.

Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome by Elizna M. Schoeman, Francois H. Van Der Westhuizen, Elardus
Erasmus, Etresia van Dyk, Charlotte V. Y. Knowles, Shereen Al-Ali, Wan-Fai Ng, Robert W. Taylor, Julia L. Newton, Joanna L. Elson in BMC Medical Genetics Vol. 18, #1, p 29 [Published: 16 March 2017]

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Bodily distress syndrome – the latest ‘term’ for CFS, FM, IBS etc.

Posted on 03/22/2017 by wames

Mail online article, by Roger Dobson, 20 March 2017:  Why doctors can no longer dismiss symptoms as ‘all in the mind’: Experts reveal medically unexplained conditions can still have a physical cause

  • In as many one fifth of cases, doctors find no explanation for patients’ symptoms
  • Though the symptoms are real, they often end up being told it’s all in their mind
  • Now, experts reveal these are signs of a new condition, bodily distress syndrome

For patients who have no obvious physical cause for their symptoms, trying to get a diagnosis or effective treatment can be a nightmare.

It’s a common problem: in as many as one in five cases, doctors find no explanation for a patient’s symptoms or for their severity.

Though the symptoms are real, patients can end up being told it’s all in their mind.

This will ring all too true for many with conditions such as chronic fatigue, fibro-myalgia (characterised by widespread pain and fatigue), irritable bowel syndrome, unexplained chest pain or interstitial cystitis (not caused by infection).

Not only do these problems, known as functional disorders, cause misery, but they cost the NHS a fortune.

Treating medically unexplained symptoms cost £3.1 billion a year, more than stroke or heart disease.

But research suggests these different diagnoses are all types of a single illness, bodily distress syndrome (BDS) — a new condition that’s just been included in the draft of the next World Health Organisation’s International Classification of Diseases, the diagnostic bible for doctors.

A study in the British Journal of General Practice last year, based on 1,400 patients, found around 17 per cent would meet the criteria for BDS.

The term is used to describe medically unexplained symptoms, and recognises illness has roots in the body and mind, paving the way for new treatments for many patients who may have been told symptoms were ‘in their heads’.

Read more

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Activin B – a potential biomarker for CFS/ME?

Posted on 03/21/2017 by wames

Research abstract:

Background: Investigations of activin family proteins as serum biomarkers for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). CFS/ME is a disease with complex, wide-ranging symptoms, featuring persistent fatigue of 6 months or longer, particularly post exertion. No definitive biomarkers are available.

Methods: A cross-sectional, observational study of CFS/ME patients fulfilling the 2003 Canadian Consensus Criteria, in parallel with healthy non-fatigued controls, was conducted. Comparisons with a previously defined activin reference population were also performed.

For the total study cohort the age range was 18–65 years with a female: male participant ratio of greater than 3:1. All participants were assessed via a primary care community clinic. Blood samples were collected for pathology testing after physical examination and orthostatic intolerance assessment. Cytokines, activin A, activin B and follistatin were also measured in sera from these samples. All data were compared between the CFS/ME and control cohorts, with the activins and follistatin also compared with previously defined reference intervals.

Results: Serum activin B levels for CFS/ME participants were significantly elevated when compared to the study controls, as well as the established reference interval. Serum activin A and follistatin were within their normal ranges. All routine and special pathology markers were within the normal laboratory reference intervals for the total study cohort, with no significant differences detected between CFS/ME and control groups. Also, no significant differences were detected for IL-2, IL-4, IL-6, IL-10, IL-17A, TNF or IFN-gamma.

Conclusion: Elevated activin B levels together with normal activin A levels identified patients with the diagnostic symptoms of CFS/ME, thus providing a novel serum based test. The activins have multiple physiological roles and capture the diverse array of symptoms experienced by CFS/ME patients.

Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study, by Brett A. Lidbury, Badia Kita,
Donald P. Lewis, Susan Hayward, Helen Ludlow, Mark P. Hedger and David M  de Kretser in Journal of Translational Medicine 2017 15:60 [Published: 16 March 2017]

Comment:

ME Action blog post, by Sasho Nimmo: Australian scientists publish study showing potential biomarker for ME/CFS

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New York Times: Getting it wrong on CFS

Posted on 03/20/2017 by wames

New York Times article, by Julie Rehmeyer and David Tuller, 18 March 2017: Getting It wrong on Chronic Fatigue Syndrome

What are some of the treatment regimens that sufferers of chronic fatigue syndrome should follow? Many major medical organizations cite two: psychotherapy and a steady increase in exercise. There’s just one problem. The main study that has been cited as proof that patients can recover with those treatments overstated some of its results. In reality, the claim that patients can recover from these treatments is not justified by the data.

That’s the finding of a peer-reviewed preliminary re-analysis of previously unpublished data from the clinical trial, the largest ever for chronic fatigue syndrome. Nicknamed the PACE trial, the core findings of the British study appeared in The Lancet in 2011 and Psychological Medicine in 2013. Patients battled for years to obtain the underlying data, and last spring, a legal tribunal in Britain, the General Regulatory Chamber, directed the release of some of the study’s information.

The impact of the trial on treatment options for the estimated one million chronic fatigue patients in the United States has been profound. The Mayo Clinic, Kaiser Permanente, WebMD, the American Academy of Family Physicians and others recommend psychotherapy and a steady increase in exercise.

But this approach can be harmful. According to a 2015 report from the Institute of Medicine, now the National Academy of Medicine, even minimal activity can cause patients prolonged exhaustion, muscle pain, cognitive problems and more. In severe cases, a short conversation or a trip to the bathroom can deplete patients for hours, days or more. In surveys, patients routinely report deterioration after a program of graded exercise. The psychotherapeutic intervention also encourages patients to increase their activity levels.

Many patients (including one of us) have remained ill for years or decades with chronic fatigue syndrome, also known as myalgic encephalomyelitis, or ME/CFS. It can be triggered by a viral infection, resulting in continuing or recurring immunological and neurological dysfunction. The Institute of Medicine dismissed any notion that it is a psychiatric illness.

Read the full article

The article concludes:

In short, this episode has damaged public trust in science.

Doctors and medical organizations must stop recommending these two therapies for ME/CFS as treatment options. Next, the disputed findings must be retracted. Finally, health agencies must ramp up funding for medical research to develop accurate diagnostic tests and pharmacological treatments.

A million Americans are waiting

Health rising blog post, by Cort Johnson, 2o March 2017: New York Times Opinion Piece Slams PACE Trial and Lancet

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Woman’s Hour features a woman with ME’s experience of being cared for

Posted on 03/17/2017 by wames

BBC Radio 4: Woman’s Hour, 15 March 2017 Anastasia, a woman with ME in her early 30s, talks about what its’ like to be cared for by her mother and how hard it is to ask for what she needs.

 

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A recumbent isometric yoga program for patients with severe CFS/ME

Posted on 03/17/2017 by wames

Research abstract:

BACKGROUND:

Our previous randomized controlled trial demonstrated that isometric yoga in a sitting position reduces fatigue in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). However, some patients experience difficulties sitting or practicing isometric yoga in a sitting position for long periods. To date, therapeutic interventions for patients with severe symptoms have not been established. Therefore, we developed a recumbent isometric yoga program, which takes approximately 20 min to complete, designed to reduce fatigue in patients with severe CFS/ME. The aim of this pilot study was to assess the feasibility, safety, and usefulness of this program.

METHODS

This pilot study included 12 adult patients with CFS/ME. Six patients were reluctant to practice isometric yoga in a sitting position because of the severity of their fatigue (group 1). The remaining six patients had previously practiced isometric yoga in a sitting position (group 2). For 3 months, the patients of both groups practiced recumbent isometric yoga every 2 to 4 weeks with a yoga instructor and at home on other days if they could. The short-term effects of isometric yoga on fatigue were assessed using the Profile of Mood Status (POMS) questionnaire immediately before and after their final session with the yoga instructor. The long-term effects of isometric yoga on fatigue were assessed using the Chalder Fatigue Scale (FS) questionnaire before and after the intervention period. Adverse events, satisfaction with the program, and preference of yoga position (sitting or recumbent) were also recorded.

RESULTS

All subjects completed the intervention. In both groups, the POMS fatigue score was significantly decreased after practicing the 20-min yoga program and the Chalder FS score was decreased significantly after the 3-month intervention period. There were no serious adverse events. All subjects in group 2 preferred the recumbent isometric yoga program over a sitting yoga program.

CONCLUSIONS

This study suggests that recumbent isometric yoga is a feasible and acceptable treatment for patients with CFS/ME, even for patients who experience difficulty practicing isometric yoga in the sitting position.

Development of a recumbent isometric yoga program for patients with severe chronic fatigue syndrome/myalgic encephalomyelitis: a pilot study to assess feasibility and efficacy, by Takakazu Oka, Hisako Wakita , Keishin Kimura in BioPsychoSocial Medicine 3 March 2017

 

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People with ME/CFS don’t trust their GP to give them info on their condition

Posted on 03/17/2017 by wames

Healthwatch Trafford press release 17 March 2017: More than half of people in the UK with ME/CFS said they wouldn’t trust their GP to give them information on their condition

A revealing new report released today by Healthwatch Trafford shows the findings of a survey of people with Myalgic Encephalomyelitis(ME), also known as Chronic Fatigue Syndrome(CFS), to find out what their experience of the NHS was like.

The report ‘Tired of explaining : Experiences of services for ME/CFS patients in Trafford and Greater Manchester’ highlights the issues that people with the condition are finding and how that impacts upon them.

Key findings included:

  • More than a third of people in the UK diagnosed with ME/CFS get no information from the NHS (and 40% that did receive some information said it wasn’t useful)
  • Less than 10% of respondents in Greater Manchester felt inpatient hospital facilities were suitable for them
  • More than half in Greater Manchester said they wouldn’t trust their GP to provide them with information about the condition
  • 5% of people across the UK waited more than 2 years for a diagnosis, with a quarter in Greater Manchester waiting more than 5 years
  • 9% of respondents in Greater Manchester are unable to work or study because of their condition
  • 77% have had ME/CFS of 5 years or more, with 34.7% having had it for 15+

The survey had more than a thousand responses and attracted responses from people around the UK. Many people with the condition observe they are experiencing poor treatment, often making their condition worse.

ME/CFS as a condition has a number of issues that make its effective treatment very difficult. Chief amongst these is the fact that it isn’t really understood, and so many medical professionals and professional bodies cannot agree on what it is, its cause and what to do about it. This has lead to huge variation in its treatment, with some medical professionals treating it purely as a psychological problem, meaning the physical aspects are not addressed and vice versa.

A core issue is that many feel their GPs knowledge of the condition and treatment options is not adequate and often their attitudes towards it have been a major problem, with levels of trust in their GP amongst those with ME/CFS being low.

Adam Webb, the report’s author and Communications and Information officer for Healthwatch Trafford, said:

“We created this survey after hearing reports of people with the condition receiving poor treatment and aimed it at our local area. We didn’t expect there to be such a large response to it, but the strength of feeling expressed by the respondents shows there is a real issue with their treatment across the whole of the UK.

“Addressing the recommendations made in the report would go a long way to improve the lives and treatment of a large number of people who have felt misunderstood for so long.”

ME/CFS is thought to affects around 250,000[1] people in the UK and around 85% of respondents were women, largely reflecting the general incidence of the condition (four females to every one male[2]).

Andrew Latham, Chief Officer of Healthwatch Trafford said :

“This report highlights some of the very real issues that people with ME/CFS face on a daily basis, from initial diagnosis through to living with the condition for many years. The report shows that there are multiple issues to be addressed and that whilst our initial focus is on patients within Trafford, the high response rate to our survey shows that these are nationwide problems that cannot not be ignored.

“Healthwatch Trafford is committed to making sure that the issues people have told us about get heard by the people with the power to act on the recommendations made, both locally and nationally. We will share this data with providers and commissioners in Trafford and urge our colleagues in local Healthwatch throughout Greater Manchester and the rest of England to do the same. We hope that this can have a positive impact on how patients with ME/CFS access services and the treatment that they receive.”
Adam added :

“We are extremely grateful for the assistance of Manchester Metropolitan University in analysing the survey results”

Find the summary report here

Find the full report here

Notes:

[1] NHS Choices, http://www.nhs.uk/conditions/Chronic-fatigue-syndrome/Pages/Introduction.aspx

[2] ME Research UK, http://www.meresearch.org.uk/news/sex-differences-in-mecfs/

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Study shows that clinicians often overestimate potential benefits & underestimate harms

Posted on 03/16/2017 by wames

This review looked at the work of clinicians in general, not specifically in relation to ME or CFS.

Key Points:

Question:  Do clinicians have accurate expectations of the benefits and harms of treatments, tests, and screening tests?

Findings:  In this systematic review of 48 studies (13 011 clinicians), most participants correctly estimated 13% of the 69 harm expectation outcomes and 11% of the 28 benefit expectations. The majority of participants overestimated benefit for 32% of outcomes, underestimated benefit for 9%, underestimated harm for 34%, and overestimated harm for 5% of outcomes.

Meaning:  Clinicians rarely had accurate expectations of benefits or harms, with inaccuracies in both directions, but more often underestimated harms and overestimated benefits.

Review abstract:

Importance:   Inaccurate clinician expectations of the benefits and harms of interventions can profoundly influence decision making and may be contributing to increasing intervention overuse.

Objective:    To systematically review all studies that have quantitatively assessed clinicians’ expectations of the benefits and/or harms of any treatment, test, or screening test.

Evidence Review:    A comprehensive search strategy of 4 databases (MEDLINE, EMBASE, Cumulative Index of Nursing and Allied Health Literature, and PsycINFO) from the start years to March 17-20, 2015, with no language or study type restriction, was performed. Searches were also conducted on cited references of the included studies, and experts and study authors were contacted. Two researchers independently evaluated methodologic quality and extracted participants’ estimates of benefit and harms and authors’ contemporaneous estimates.

Findings:    Of the 8166 records screened, 48 articles (13 011 clinicians) were eligible. Twenty studies focused on treatment, 20 on medical imaging, and 8 on screening. Of the 48 studies, 30 (67%) assessed only harm expectations, 9 (20%) evaluated only benefit expectations, and 6 (13%) assessed both benefit and harm expectations. Among the studies comparing benefit expectations with a correct answer (total of 28 outcomes), most participants provided correct estimation for only 3 outcomes (11%). Of the studies comparing expectations of harm with a correct answer (total of 69 outcomes), a majority of participants correctly estimated harm for 9 outcomes (13%). Where overestimation or underestimation data were provided, most participants overestimated benefit for 7 (32%) and underestimated benefit for 2 (9%) of the 22 outcomes, and underestimated harm for 20 (34%) and overestimated harm for 3 (5%) of the 58 outcomes.

Conclusions and Relevance:    Clinicians rarely had accurate expectations of benefits or harms, with inaccuracies in both directions. However, clinicians more often underestimated rather than overestimated harms and overestimated rather than underestimated benefits. Inaccurate perceptions about the benefits and harms of interventions are likely to result in suboptimal clinical management choices.

Clinicians’ Expectations of the Benefits and Harms of Treatments, Screening, and Tests: a Systematic Review, by Tammy C. Hoffmann, PhD; Chris Del Mar, MD, FRACGP
in JAMA Intern Med. 2017;177(3):407-419

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