PACE Trial reanalysis in the news – Findings of £5m ME chronic fatigue study ‘worthless’

Posted on 03/22/2018 by wames

Times article, by Tom Whipple, Science Editor, 22 March 2018: Findings of £5m ME chronic fatigue study ‘worthless’ [register for free to read 2 articles a week]

Scientists have questioned the robustness of a study that recommended exercise and cognitive behavioural therapy for ME sufferers.

 BBC news article, by 22 March 2018: Chronic fatigue trial results ‘not robust’, new study says

Fresh analysis of a controversial study, which recommended exercise and psychological therapy for people with chronic fatigue syndrome, suggests their impact is more modest than first thought.

The PACE trial found the treatments to be “moderately effective”, leading to recovery in a fifth of patients. But this new analysis finds “no long-term benefits at all”.

The authors of the original trial in 2007 said they stood by their findings.

That randomised trial was designed to examine the effectiveness of graded exercise therapy (GET) and cognitive behavioural therapy (CBT) for chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis, or ME.

Its findings were positive, but patient groups like the ME Association have always been critical of the way the trial was designed and the way the results were reported.

Goalposts ‘moved’
There has also been controversy over the release of data from the trial, with some arguing it should be made available to all researchers for further analysis.

The PACE trial reported that 59% of patients who received CBT and 61% who had exercise therapy had improved overall, compared with 45% in a control group.

When the results were re-examined, after data was obtained under a Freedom of Information request, researchers found that just 20% of CBT patients and 21% of GET patients improved, along with 10% of control patients.

Figures for those who recovered were originally reported as 22% for patients in each of the CBT and GET groups, but this reduced to 8% in the latest re-analysis.

Writing in the journal BMC Psychology, lead author Dr Carolyn Wilshire, from the University of Wellington in New Zealand, said the PACE trial moved the goalposts by changing the way treatment success was measured after the trial had begun.

She added: “Until there is positive evidence to suggest otherwise, the conclusion we must draw is that PACE’s treatment effects are not sustained over the long term, not even on self-report measures.

“CBT and GET have no long-term benefits at all. Patients do just as well with good basic medical care.”

Modestly effective treatment
The ME Association, which part-funded the new study, said it was no surprise that “impressive claims for recovery following CBT and GET are not statistically reliable”.

Dr Jon Stone, consultant neurologist at the Western General Hospital in Edinburgh, said better treatments for chronic fatigue syndrome were needed, or more effective forms of rehabilitation.

“Until we have these, the question is whether it is better to offer a modestly effective treatment supported by data from many other trials, with a realistic discussion of its pros and cons, than none at all.”

The three authors of the original PACE trial – Prof Michael Sharpe, from the University of Oxford, and Prof Trudie Chalder and Dr Kimberley Goldsmith, from King’s College London, said the new analysis had used only part of the data from the trial.

They also said many other trials and meta-analyses had replicated the findings of the PACE trial.

“In conclusion, we find little of substance in this critique and stand by our original reports.”

NICE is currently updating its guidance on the diagnosis and management of chronic fatigue syndrome.

 

ME association press release, 22 March 2018: Reanalysis of the PACE trial finds impressive claims for recovery following CBT and GET are ‘not statistically reliable’ 

The ME Association believes that it is very important to encourage research data sharing and, where appropriate, independent reanalysis – which is why we made a significant financial contribution towards the processing fee for publication of this paper.

“The message is clear – CBT and GET are not effective ways of treating a serious neuroimmune disease. The sooner this message gets across to health professionals the better.”

The Herald, 26 March: ME sufferers welcome ‘unreliable’ stamp on exercise report

The Canary, 22 March 2018: The mainstream medical community just declared war on people living with ME

AfME, 22 March 2018: PACE update: latest analysis and comment

Daily Mail, 22 March 2018: Findings of chronic fatigue study `not reliable´

ME/CFS Research review by Simon McGrath, 22 March 2018: PACE trial’s findings fundamentally challenged by a new study

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A metabolic ‘trap’ hypothesis for ME/CFS?

Posted on 03/21/2018 by wames

Open Medicine Foundation blog post, 14 March 2018: OMF-funded research: a metabolic ‘trap’ hypothesis for ME/CFS

On this #OMFScienceWednesday we highlight a new project that OMF is funding, which proposes a new metabolic ‘trap’ hypothesis for ME/CFS. This project is just getting started under the direction of Dr. Robert Phair, Chief Science Officer of Integrative Bioinformatics, Inc., an expert in computational modelling of biological processes. Dr. Phair has been collaborating with Dr. Ron Davis’ team at Stanford for nearly 2 years on investigating mechanisms behind ME/CFS. In this project, they will test a new hypothesis that could help to explain some of the genetic and metabolic characteristics of ME/CFS patients.

The big data study of severely ill ME/CFS patients that we funded identified several genes that carry damaging mutations. Dr. Phair’s hypothesis, based on computational predictions, suggests that some of these mutations may slow down enzymes that process important metabolites required for our energy, brain function, and immune system. If this is true, it could explain some of the symptoms of ME/CFS. Identifying interesting mutations is the (relatively) easy part, though – experimental evidence is needed to confirm their impact.

During this project, the team will test how cells with these mutations carry out the relevant metabolic reactions, using special ‘tracer’ metabolites that can be easily followed as they are processed by the cells. These experiments will determine whether the mutations are indeed creating a metabolic ‘trap’ that could lead to the neurological and/or immunological symptoms of ME/CFS. We’ll be happy to share more details as the results provide more evidence. Stay tuned!

Read more about the metabolic trap hypothesis

Read more about Dr. Phair and his research

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Low mood, poor quality of life & high symptom impact in adolescents attending a tertiary service for CFS/ME

Posted on 03/20/2018 by wames

Research abstract:

Prevalence and correlates of low mood, poor quality of life and high symptom impact in adolescents attending a tertiary service for chronic fatigue syndrome/myalgic encephalomyelitis, by FK Neale, TY Segal, DS Hargreaves in Archives of Disease in Childhood Vol 103, Suppl 1, G13, March 2018

Background:
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a condition characterised by persistent fatigue that reduces activity and affects everyday life. It is associated with mood disorders, such as depression and anxiety, and a reduction in quality of life.

Aims:
This project describes the demographic of adolescents with CFS/ME being treated at a specialist service and their mood, quality of life and symptom impact. It assesses whether sex, age, Body Mass Index, household income and illness duration are associated with low mood, poor quality of life and greater symptom impact. It investigates the similarity
between the adolescents’ and their parents’ views of the impact of CFS/ME.

Methods:
69 adolescents, (10.4-18.0 years), were assessed at their initial clinic appointment using a three-part questionnaire. Their parents received one part of this questionnaire separately. The questionnaire was comprised of three survey instruments which had been previously validated for use in adolescents. Additional data about the adolescents was collected from
their clinic assessment form.

Results:
69.6% of the adolescents were female, 13.0% were obese or very obese and mean illness duration was 25.3 months. 36.2% of the adolescents came from a household within the 10% most affluent in the country. Moderate, severe or extreme anxiety or depression symptoms were reported by 39.1%, severe levels of worry by 43.5% and high or very high symptom impact by 69.1%. Long illness duration was significantly associated with low mood (p=0.006) but no other associations were significant. There was minimal  agreement between the adolescents’ and parents’ answers (mean kappa score=0.373) with the parents reporting CFS/ME to cause greater difficulties.

Conclusions:
Adolescents from high-income backgrounds are over-represented amongst adolescents attending this specialist clinic. This may represent higher prevalence or greater access to specialist services in high-income families. More than a third of adolescents attending this clinic reported significantly reduced quality of life and/or low or anxious mood symptoms; more than two thirds reported that the condition has a major impact on their daily life. Parents report CFS/ME to cause greater difficulties than their children do.

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Immunoadsorption to remove ß2 adrenergic receptor antibodies in CFS/ME

Posted on 03/19/2018 by wames

Research abstract:

Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME, by Carmen Scheibenbogen, Madlen Loebel, Helma Freitag, Anne Krueger, Sandra Bauer, Michaela Antelmann, Wolfram Doehner, Nadja Scherbakov, Harald Heidecke, Petra Reinke, Hans-Dieter Volk, Patricia Grabowski in PLoS One. 2018 Mar 15;13(3):e0193672

INTRODUCTION:
Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2 adrenergic receptors, and muscarinic 3 and 4 acetylcholine receptors in a subset of patients. Immunoadsorption (IA) was shown to be effective in removing autoantibodies and improve outcome in various autoimmune diseases.

METHODS:
10 patients with post-infectious CFS/ME and elevated ß2 autoantibodies were treated with IA with an IgG-binding column for 5 days. We assessed severity of symptoms as outcome parameter by disease specific scores. Antibodies were determined by ELISA and B cell phenotype by flow cytometry.

RESULTS:
IgG levels dropped to median 0.73 g/l (normal 7-16 g/l) after the 4th cycle of IA, while IgA and IgM levels remained unchanged. Similarly, elevated ß2 IgG antibodies rapidly decreased during IA in 9 of 10 patients. Also 6 months later ß2 autoantibodies were significantly lower compared to pretreatment. Frequency of memory B cells significantly decreased and frequency of plasma cells increased after the 4th IA cycle. A rapid improvement of symptoms was reported by 7 patients during the IA. 3 of these patients had long lasting moderate to marked improvement for 6-12+ months, 2 patients had short improvement only and 2 patients improved for several months following initial worsening.

CONCLUSIONS:
IA can remove autoantibodies against ß2 adrenergic receptor and lead to clinical improvement. B cell phenotyping provides evidence for an effect of IA on memory B cell development. Data from our pilot trial warrants further studies in CFS/ME.

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On CFS & nosological categories (historical review of CFS & relationship to other conditions)

Posted on 03/16/2018 by wames

Research abstract:

On chronic fatigue syndrome and nosological categories, by Sharif K, Watad A, Bragazzi NL, Lichtbroun M, Martini M, Perricone C, Amital H, Shoenfeld Y. in Clin Rheumatol. 2018 Feb 7.  [Epub ahead of print]

Chronic fatigue syndrome (CFS) is a heterogeneous disease which presents with pronounced disabling fatigue, sleep disturbances, and cognitive impairment that negatively affects patients’ functional capability. CFS remains a poorly defined entity and its etiology is still in question. CFS is neither a novel diagnosis nor a new medical condition. From as early as the eighteenth century, a constellation of perplexing symptoms was observed that resembled symptoms of CFS.

Commencing with “febricula” and ending with CFS, many names for the disease were proposed including neurocirculatory asthenia, atypical poliomyelitis, Royal Free disease, effort syndrome, Akureyri disease, Tapanui disease, chronic Epstein-Barr virus syndrome, and myalgic encephalitis. To date, it remains unclear whether CFS has an autoimmune component or is a condition that precedes a full-blown autoimmune disease.

Research suggests that CFS may overlap with other diseases including postural orthostatic tachycardia syndrome (POTS), autoimmune syndrome induced by adjuvants (ASIA), and Sjögren’s syndrome. Additionally, it has been postulated that the earliest manifestations of some autoimmune diseases can present with vague non-specific symptoms similar to CFS.

Sometimes only when exposed to a secondary stimulus (e.g., antigen) which could accelerate the natural course of the disease would an individual develop the classic autoimmune disease. Due to the similarity of symptoms, it has been postulated that CFS could simply be an early manifestation of an autoimmune disease. This paper will provide a historical background review of this disease and a discussion of CFS as an entity overlapping with multiple other conditions.

Read the full article

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Functional status & well-being in people with ME/CFS compared with people with MS & healthy controls

Posted on 03/15/2018 by wames

Research abstract:

Functional Status and Well-Being in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Compared with People with Multiple Sclerosis and Healthy Controls, by Caroline C. Kingdon, Erinna W. Bowman, Hayley Curran, Luis Nacul, Eliana M. Lacerda in PharmacoEconomics Open 2018 pp 1-12  [Online: 13 March 2018]

Background:
People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) continue to struggle to have their condition recognised as disabling in the face of public and professional prejudice and discrimination.

Objective:
The aim of this study was to compare the functional status and well-being of people with well-characterised ME/CFS with people with multiple sclerosis (PWMS), as well as healthy controls (HCs).

Methods:
In this cross-sectional study, we used data collected as part of the UK ME/CFS Biobank to compare actual participant scores from the Medical Outcomes Survey Short Form-36 v2™ (SF-36v2™) between groups, as a proxy for impact of disability, and from a bespoke questionnaire seeking data on employment and income.

Results:
People with ME/CFS scored significantly lower than PWMS or HCs in almost all SF-36v2™ areas. Prominent were lower scores for people with ME/CFS in the Physical Component Summary and Role Physical and Social Function domains, while the smallest differences were seen in the Mental Health domain. Responses to the bespoke questionnaire indicated that people with ME/CFS in this study work fewer hours and have lower incomes compared with people in the other two groups.

Conclusions:
Using SF-36v2™ scores as a proxy, people with ME/CFS were measurably more disabled than PWMS or HCs in this study population. Furthermore, employment and income data are consistent with loss of functional status. These findings should encourage the health community to recognise the disabling effects of ME/CFS, to advocate for the needs of people with ME/CFS, and to investigate strategies to address the cost of the disease to both individuals and society.

Key Points for Decision Makers:

  • This study suggests that at a group level people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are more disabled than people affected by multiple sclerosis (MS), as measured by the SF-36v2™.
  • ME/CFS is associated with a reduction in time spent at work and lower income, compared with people affected by MS.
  • Further efforts should be made to identify and address the impact of ME/CFS to individuals and society.
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Treating patients suffering from (ME/CFS) with sodium dichloroacetate: a pilot trial

Posted on 03/14/2018 by wames

Research abstract:

Treating patients suffering from myalgic encephalopathy/chronic fatigue syndrome ME/CFS) with sodium dichloroacetate: An open-label, proof-of-principle pilot trial, by Frank Comhaire in Medical hypotheses May 2018 Vol 114, Pp 45–48

Twenty-two consecutive patients suffering from refractory myalgic encephalitis/chronic fatigue syndrome (ME/CFS) were treated with an innovative nutriceutical containing sodium dichloroacetate in a proof-of-principle, pilot, open-label prospective cohort trial.

Ten patients experienced significant improvement of their health condition with reduction to almost half of their score in the fatigue severity scale. In twelve patients treatment failed to exert any beneficial effect. In the latter patients several other diseases have commonly been revealed by extensive biological and imaging investigations.

These preliminary findings sustain the hypothetical role of mitochondrial hypo-metabolism due to inhibition of the activity of the pyruvate dehydrogenase in the pathogenesis of primary ME/CFS, and suggest a possible benefit of nutriceutical treatment by sodium dichloroacetate.

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Managing fatigue in postural tachycardia syndrome (PoTS): The Newcastle approach

Posted on 03/13/2018 by wames

Managing fatigue in postural tachycardia syndrome (PoTS): The Newcastle approach, Victoria Strassheim, Jenny Welford, Rob Ballantine, Julia L Newton in Auton Neurosci. 2018 Feb 22. pii: S1566-0702(17)30328-4 [Epub ahead of print]

Highlights:

  • Fatigue is a common symptom described by those with PoTS.
  • Chronic Fatigue Syndrome is often co-diagnosed with PoTS.
  • Management of fatigue in PoTS is best delivered as a multidisciplinary approach.

Research abstract:

Fatigue is a significant symptom that is frequently reported by those with postural tachycardia syndrome (PoTS). There are a variety of reasons why those with PoTS might experience fatigue and as a consequence an individualised approach to management is most appropriate.

In this chapter we will examine the prevalence of fatigue in those with PoTS, its overlap with conditions such as chronic fatigue syndrome and describe a clinical approach to the management of fatigue in those with PoTS.

Extract:

Managing fatigue
Managing fatigue is possible, but it is not easy. It takes commitment, persistence, trial and error with no immediate quick fix. There is no medication that will cure fatigue in general, or specifically in those with PoTS and a multi-disciplinary approach is needed to aid its management.

First, it is important to find a stable start point. In our fatigue clinic, in Newcastle UK (Hackett et al., 2016; Lambson et al., 2015) we frequently ask people to complete activity diaries and to grade whether their activities are high, medium or low, defining periods when they are resting or asleep. When people do this, they can often see patterns in their activity that highlight how they may be booming and busting, or pacing their activity appropriately.

The management booklet that we use in Newcastle is available via http://www.ncl.ac.uk/medicalsciences/research/centres/fatigue/, and the components of our multidisciplinary approach shown in Fig. 2.

When managing fatigue in PoTS patients, much of the advice that we use in our clinical practice is generic and some extrapolated from information available in the CFS literature (Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (Encephalopathy); Diagnosis and Management, NICE 2007). However, by understanding the mechanisms that might lead to symptoms in PoTS, exacerbations can be avoided in order to help find a stable base line from which to manage and improve.

We consider fatigue management as being a package of advice that we provide for PoTS patients, it is unlikely that one thing alone will make the difference people want, it is most likely that approaching management of fatigue from multiple perspectives will have the best result.

It is our group’s experience that once PoTS physiology improves, people with CFS/ME are then able to exercise, suggesting that it is the orthostatic intolerance keeping PoTS patients less active rather than an unwillingness to exercise in the first place.

Read the full article

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This is brain awareness week 12-16 March 2018

Posted on 03/13/2018 by wames

There are more than 350 different conditions of the brain and spine and together they affect more than 12 million people in the UK. #BrainAwarenessWeek

Over 13,000 people in Wales could have ME and over 240,000 in the UK.

Find out more about research into the ME brain:

WAMES booklet: The ME brain

Health rising articles

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Does the microbiome & virome contribute to ME/CFS?

Posted on 03/12/2018 by wames

Review abstract:

Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome? by Fiona Newberry, Shen-Yuan Hsieh, Tom Wileman, Simon R. Carding in Clinical Science Vol 135, #5, pp 523-542 [Published online March 9, 2018]

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease characterized by various inflammatory, immune, viral, neurological and endocrine symptoms.

Several microbiome studies have described alterations in the bacterial component of the microbiome (dysbiosis) consistent with a possible role in disease development.  However, in focusing on the bacterial components of the microbiome, these studies have neglected the viral constituent known as the virome.

Viruses, particularly those infecting bacteria (bacteriophages), have the potential to alter the function and structure of the microbiome via gene transfer and host lysis. Viral-induced microbiome changes can directly and indirectly influence host health and disease. The contribution of viruses towards disease pathogenesis is therefore an important area for research in ME/CFS. Recent advancements in sequencing technology and bioinformatics now allow more comprehensive and inclusive investigations of human microbiomes.

However, as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies.

This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the pitfalls and challenges associated with microbiome studies are discussed.

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