Rituximab impedes natural killer cell function in CFS/ME patients

Posted on 03/28/2018 by wames

Research abstract:

Rituximab impedes natural killer cell function in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients: A pilot in vitro investigation by Natalie Eaton, Hélène Cabanas, Cassandra Balinas, Anne Klein, Donald Staines and Sonya Marshall-Gradisnik in BMC Pharmacology and Toxicology 2018 19:12 [Published: 27 March 2018]

Background:

A recent in vitro pilot investigation reported Rituximab significantly reduced natural killer (NK) cell cytotoxicity in healthy donors.

Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) is a debilitating disorder of unknown etiology. A consistent finding is a significant reduction in NK cell cytotoxicity. Rituximab has been reported having questionable potential therapeutic benefits for the treatment of CFS/ME, however, the potential effects of Rituximab on NK cell cytotoxicity in CFS/ME patients are yet to be determined.

Methods:

A total of eight CFS/ME patients (48.63 ± 15.69 years) and nine non-fatigued controls (NFC) (37.56 ± 11.06 years) were included using the Fukuda case definition. Apoptotic function, lytic proteins and degranulation markers were measured on isolated NK cells using flow cytometry following overnight incubation with Rituximab at 10 μg/ml and 100 μg/ml.

Results:

There was a significant reduction in NK cell lysis between CFS/ME patients and NFC following incubation with Rituximab at 100 μg/ml at

12.5:1 and 6.25:1 effecter-target (E:T) ratios (p < 0.05). However, there was no significant difference for NFC following incubation with Rituximab at 10 μg/ml and 100 μg/ml.

There was no significant difference between CFS/ME patients and NFC for granzyme A and granzyme B prior to incubation with Rituximab and following overnight incubation with Rituximab at 10 μg/ml. There was a significant decrease in granzyme B in CFS/ME patients compared to NFC with 100 μg/ml of Rituximab prior to K562 cells stimulation (p < 0.05).

There was a significant increase in CD107a (p < 0.05) and CD107b expression (p < 0.01) in NFC after stimulation with K562 cells prior to incubation with Rituximab. There was a significant increase in CD107b expression between CFS/ME patients and NFC prior to incubation with Rituximab and without stimulation of K562 cells (p < 0.01).

Importantly, there was a significant increase in CD107b following overnight incubation with 100 μg/ml of Rituximab in NFC prior to K562 cells stimulation (p < 0.01).

Conclusion:

This study reports significant decreases in NK cell lysis and a significant increase in NK cell degranulation following Rituximab incubation in vitro in CFS/ME patients, suggesting Rituximab may be toxic for NK cells. Caution should be observed in clinical trials until further investigations in a safe and controlled in vitro setting are completed.

Griffith news blog post by Louise Durack, March 27, 2018 : Drug hoped to treat CFS causes impaired immune function, Griffith study says

… the use of Rituximab in CFS patients could incur problems with their immune cells and is not beneficial as a potential treatment. The Natural Killer (NK) cells have vital functions in fighting viruses, bacteria and tumours.

“We found that these functions were significantly impaired when exposed to Rituximab in CFS patients,” says Scientific Co-Director of NCNED, Professor Sonya Marshall-Gradisnik.

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Dutch report on CFS downgrades CBT & GET, calls for more research

Posted on 03/27/2018 by wames

The Dutch Health Council  report to their Parliament in the Hague on CFS, 19 March 2018.

Report in Dutch          Summary in Dutch        Background

Google translation of Report into English     Google translation of Summary into English 

Google translation of Background into English

The Report’s conclusions and recommendations:

  • Scientific research into ME / CFS is necessary to help patients better.
  • In the meantime it is essential that the diagnosis ME / CFS is put into practice, that the symptoms of patients are taken seriously and treated as well as possible.
  • Their functional limitations must also be fully recognized when assessing entitlements to income and other provisions.
  • The Minister of Health, Welfare and Sport gives ZonMw the assignment for a long-term and substantial research program for ME / CFS.
  • The research should mainly focus on substantiating the diagnosis, the development of the disease and the treatment of ME / CFS.
  • Those responsible for training and further training of health care providers ensure that in education and training attention is paid to the severe, chronic multisystem disease ME / CFS and to what caregivers can mean for the patients with this disease.
  • The Dutch Federation of University Medical Centers (NFU) and health insurers appoint a number of university medical centers that – in collaboration with patient representatives, other hospitals, general practitioners, rehabilitation centers, sleep centers and other health care providers in the region – open an outpatient clinic for ME / CFS. associated care networks and research groups.
  • Medical assessors in the context of occupational disability insurance, the Social Support Act, the Long-term Care Act and the Participation Act recognize that ME / CFS is a serious illness that is accompanied by substantial functional limitations and do not consider a patient’s choice not to do CBT or exercise therapy as’ not adequate recovery behavior ‘.

Cort Johnson blogs about the surprising conclusions from a country  that has long supported CBT and GET as treatments for CFS:

The Dutch Surprise: Federal Report Calls for More ME/CFS Research – Less CBT/GET

A Serious Disease 
It became clear the Committee was on a mission to convince its readers that chronic fatigue syndrome (ME/CFS) is a “serious chronic disease” which substantially limits functioning. One recommendation was that the government institute health care provider training which “highlight(s) the serious, chronic, multisystem (nature of the) disease ME/CFS.”

Prof David Tuller comments on the draft report: Trial By Error: The Dutch Review; My Trip; Bristol’s Silence

The draft stated flatly that, based on the evidence, “the committee sees no reason” for GET to be used in the Netherlands. As for CBT, the draft noted that “a small majority” of committee members believed it could be helpful for some patients. But those in this group also acknowledged that patients also reported having been harmed by the approach, and they suggested that the treatment should be pursued with care. The other committee members objected to any use of the kind of CBT designed for ME/CFS, in part given the therapy’s reliance on the theory of misguided illness beliefs. In any event, this split decision was hardly a full-throated endorsement of CBT.

ME Action blog post, 23 March 2018: Dutch Health Council Downgrades GET for ME/CFS

The report stated that patients must be free to decide whether or not to undergo Cognitive Behavioural Therapy (CBT) and/or GET, and that choosing to decline these treatments should not invalidate patients’ insurance or disability claims.

“The choice to refrain from CBT or GET should not lead to the judgment that the patient misses his chance of recovery, does not cooperate in his or her recovery or acts culpably,” the report stated.

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Cortene – a new drug trial & disease hypothesis for ME/CFS

Posted on 03/26/2018 by wames

Cortene

In his blog, Health Rising, Cort Johnson introduces a new drug trial and hypothesis for ME/CFS.

With the help of Dr Lucinda Bateman and Dr Suzanne Vernon a small drug company, Cortene, will be conducting a small proof-of-concept trial of a new drug, at the Bateman Horne Center in the US.

Their hypothesis is that a maladaptation within the limbic system, which shapes our response to stress, may underlie ME/CFS.  Specifically that a receptor called CRF2, which triggers neurons to release serotonin, has become unusually prevalent in parts of ME/CFS patients’ brains. Cortene believes that the elevated release of serotonin – in response to even small levels of stress – in turn causes ME/CFS.

 

Read more:

The Cortene Way: New Drug to Be Trialed in Chronic Fatigue Syndrome (ME/CFS) Soon – Pt. I

Cortene II: A New Drug & A New Hypothesis For Chronic Fatigue Syndrome (ME/CFS)

The Cortene Way: New Drug to Be Trialed in Chronic Fatigue Syndrome (ME/CFS) Soon – Pt. I

Cortene – A New Drug for Chronic Fatigue Syndrome (ME/CFS) Pt III: The Clinical Trial

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Forward ME Group writes to the Times: patients are ‘not simply deconditioned’

Posted on 03/23/2018 by wames

Times online letter, 22 March 2018: TREATMENT FOR PATIENTS WITH ME

Sir, The article by Tom Whipple, (“Findings of £5m ME chronic fatigue study ‘worthless’,” Mar 22) highlights a long-standing problem.

The National Institute for Health and Care Excellence (Nice) is in the process of replacing its guideline for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but this will take time.

Patients with ME/CFS in this country continue to receive damaging treatment in the form of graded exercise therapy (GET). Despite evidence of disabling metabolic abnormalities in their muscles, patients are advised to “exercise back to fitness”. They are not simply “deconditioned” as claimed by many psychiatrists. Forced exercise above very low levels characteristically incapacitates most patients. The “exercise will make you better doctrine” applied to ME/CFS is profoundly incorrect and has no scientific evidence base.

The human cost is enormous, with many sufferers from ME/CFS rendered worse by inappropriate medical management. Even worse, such management is inflicted compulsorily on some patients, both adults and children, with their informed consent being bypassed via the use of mental health and child protection legislation.

Countess of Mar, Forward-ME; Dr William Weir, infectious disease consultant;
Dr Nigel Speight, paediatrician; Dr Charles Shepherd, ME association;
Dr Vance Spence, ME research UK; Jonathan Davies, ME research UK;
Dr Gareth Tuckwell, ME trust; Dr Paul Worthley, ME trust; Jane Colby, Tymes trust;
Helen Brownlie, 25 per cent ME group; Tanya and Christine Harrison, Brame;
William and Janice Kent, Remember; Hannah Clifton, ME trust;
Clare Ogden, Action for ME

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Rethinking the treatment of CFS – a reanalysis of the PACE trial

Posted on 03/22/2018 by wames

Research abstract:

Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT by Carolyn E. Wilshire, Tom Kindlon, Robert Courtney, Alem Matthees, David Tuller, Keith Geraghty and Bruce Levin in BMC Psychology BMC series  2018 6:6 [Published: 22 March 2018]

 

Background:

The PACE trial was a well-powered randomised trial designed to examine the efficacy of graded exercise therapy (GET) and cognitive behavioural therapy (CBT) for chronic fatigue syndrome.

Reports concluded that both treatments were moderately effective, each leading to recovery in over a fifth of patients. However, the reported analyses did not consistently follow the procedures set out in the published protocol, and it is unclear whether the conclusions are fully justified by the evidence.

Methods:

Here, we present results based on the original protocol-specified procedures. Data from a recent Freedom of Information request enabled us to closely approximate these procedures. We also evaluate the conclusions from the trial as a whole.

Results:

On the original protocol-specified primary outcome measure – overall improvement rates – there was a significant effect of treatment group. However, the groups receiving CBT or GET did not significantly outperform the Control group after correcting for the number of comparisons specified in the trial protocol. Also, rates of recovery were consistently low and not significantly different across treatment groups. Finally, on secondary measures, significant effects were almost entirely confined to self-report measures. These effects did not endure beyond two years.

Conclusions:

These findings raise serious concerns about the robustness of the claims made about the efficacy of CBT and GET. The modest treatment effects obtained on self-report measures in the PACE trial do not exceed what could be reasonably accounted for by participant reporting biases.

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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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