Mainstreaming ME Research: The 8th Invest in ME International ME Conference, 2013

June 2, 2013

Mark Berry reports from London on the 8th Invest in ME International ME Conference.

DVD-2013wgifThis was only my second year at the Invest in ME conference, but already I feel right at home! The presentations you’re about to read about are only half the story; the opportunity to mingle and network with a family (yes it really does feel like a family!) of top researchers, physicians, campaigners and patients from all over the world, is absolutely priceless. And this year, the new spirit of hope and togetherness in the air was a joy to behold.

The title this year was “Mainstreaming ME Research: Infections, Immunity and Myalgic Encephalomyelitis”, and the twin themes – an emerging consensus around a ‘paradigm shift’ to thinking about ME as an autoimmune disorder, and a focus on strategies for effective research and a breakthrough into the scientific mainstream – fit together perfectly. For it’s the growing recognition that immune treatments like Rituximab and Ampligen are having dramatic effects on many patients who were once bedbound and without hope, together with two decades of often confusing but highly suggestive research findings of immune dysfunction in ME patients, that is now threatening to propel ME from the backwaters of science right into the limelight.

A key part of that process has been Invest in ME’s Clinical Autoimmunity Working Group, formed last year – a group of researchers which meets before the main conference to discuss the latest scientific developments. The creation of international collaborative networks is surely valuable in any field of science, but in a field that has been so neglected and so under-resourced for so long, it’s even more important to maximize resources.

Once the working group has done its thing, next comes the pre-conference dinner – the Patient Advocate reports on Linda Tannenbaum’s pre-conference dinner presentation here.

And then it’s on with the main event: time for conference-goers to pick up their copy of the Conference Journal, mingle and chat with old friends over coffee for a while, and settle down for the first item on the Agenda….

Of course, sadly many of us can’t hope to make it to a day like this, and I’m acutely aware of that and wish for the day when they can, so for those who’ve been relying on Jorgen Jelstad and his excellent conference tweets, here’s my summary of the day…as a teaser for the far more comprehensive conference DVD

Conference Highlights

  • Dr Ian Gibson announces new PhD studentship in Norwich looking at gut bacteria. “Things are beginning to pop, across the nation and across the world…There’s a new spirit loose, I think, in the ME field”.
  • Dr Peterson keynote: “It’s time to stop querying patients and begin developing new diagnostics”. We need both clear endpoints and clear populations for successful research.
  • Dr Kogelnik: Medicine is at a crossroads, and ME will be “key disease” in coming “health/disease revolution”: technology enables the ‘Quantified Self’ and personalized medicine. Govt agencies “not the enemy”, it’s “their ignorance and our lack of data” – our job is to bring them the data so it can’t be ignored.
  • Dr Rakib Rayhan: In Gulf War Illness, Baraniuk et al believe their brain scans after exercise challenge produced a “quite robust biomarker”, and they want to extend to ME/CFS. New study out in a couple of weeks finds 2 subgroups for pain and fatigue post-exercise.
  • Professor Greg Towers puts XMRV saga to bed: valuable lessons learned mean this kind of situation should never happen again.
  • Professor Mady Hornig: Final analysis of cerebrospinal fluid now underway; possible finding of ‘different patterns of cytokine associative networks’ and ‘potential novel candidate’ in CSF still needs to be confirmed.
  • Dr Clare Gerada steps into the lions’ den and “tells it straight” – attempts to “build a bridge between the largest Royal College and a very important problem” – hopes to “be better able to work with you to improve the care you receive from my profession”.
  • Dr Donald Staines stands in for Professor Sonya Marshall-Gradisnik. Publications expected in next weeks and months; still finding “sustained, demonstrable, significant impairment in NK cell function”, “highly confident” of up-regulation of T-reg cells; “clear derangement in the immune system…it’s irrefutable”, and “anyone who suggests that this might be fixed by exercise therapy should probably be de-registered I think”.
  • Dr Amolak Bansal senses a “paradigm shift” towards model of subtle form of autoimmunity in ME; suspects patients’ B cells are failing to mature properly and producing low avidity antibodies; lasting response to B-cell depletion therapy may require clearing the viruses responsible in addition to ‘rebooting’ the B cells.
  • Norwegian ME Association presents awards to Invest in ME founders Richard and Pia Simpson, and to Professor Malcolm Hooper for “untiring and exceptional contribution to the ME cause”. Hooper accepts with his shortest ever speech.
  • Carmen Scheibenbogen and her team at Charite are finding similar immune dysfunction and share many of the same theories as Bansal, Fluge and Mella. They’re trying to develop a diagnostic test, investigating EBV infections in depth, and seeing 3 immune subtypes of CFS. Hoping for solid data in about 6 months.
  • Professor Mella and Dr Fluge are closing in on publication of their follow-up study on Rituximab therapy. Some details were presented, along with a fascinating hypothesis, but that’s all embargoed awaiting publication, so if you’re curious about that, you’d better order the conference DVD right away…my lips are sealed!

Dr Ian Gibson: Welcome

Dr Ian Gibson

Dr Ian Gibson

Ian Gibson welcomed conference-goers back to 1 Birdcage Walk – the home of Invest in ME’s annual conference since 2006 – by joking that he “dreams about this place”. But really, said Gibson, the idea is to stop people dreaming…”because the thing about dreams is, then you wake up!”. Gibson seemed to feel the same sense of hope and excitement that many of the people I spoke to at the conference expressed: “Things are beginning to pop,” he enthused, “across the nation and across the world”. The sort of positive developments we’ve seen recently “don’t just happen”, he added, hinting at the hours of hard work and lobbying behind the scenes that slowly but surely result in progress.

Gibson then announced the funding of a new PhD studentship in Norwich that will be looking at gut bacteria in ME/CFS (presumably in connection with IiME’s foundation biomedical research project for ME, which will be carried out at the University of East Anglia). He reminded delegates that in science there’s no telling where the next major development might come from. “Somebody is going to make a breakthrough which shatters us all,” he predicted, and that makes all the work that went before look irrelevant.

Encouraging the audience to persevere and think broadly and open-mindedly, he acknowledged that political campaigning and lobbying can be a frustrating business, but suggested that local projects might provide more easily achievable objectives that can make a big difference – “politicians…they don’t quite understand the issues…we keep on at them, but what happened in Norwich can happen anywhere, and we want to build that elsewhere too”.

Gibson was upbeat and sensed a ‘paradigm shift’: “There’s a new spirit loose, I think, in the ME field” and people say to him “Do you remember what it was like 10 years ago?” – a helpful reminder, when road-blocks cause frustration, to think back and realize that the progress made is very real, even if it doesn’t always come as quickly as we might like.

He finished by setting the scene for the exchange of information and ideas that was to come: he always told people, he said: “do your own thing, but talk to other people too”…sometimes in science you do ‘go down the wrong road’, so continued communication is very important. And with that positive introduction, the presentations began…

Dr Daniel Peterson: Key Note Speech: “The Mainstreaming of ME Research”

Dr Daniel Peterson

Dr. Peterson began by reflecting on the past history of ME/CFS. He said that, in his view, there is now a need for a single set of diagnostic criteria accepted worldwide by researchers and clinicians and to “forget nomenclature”, seemingly suggesting that we may be reaching a turning point where the emerging scientific consensus enables us all to put the multiple sets of criteria and arguments over names behind us.

Peterson’s short race through history began in the 1980s, with a series of outbreaks of disease; in the 80s and 90s, the focus was on fatigue, resulting in the definitions at that time. Since then, however, the focus of research has been on neurological, endocrine and immune dysfunction, and on Post-Exertional Malaise (PEM) – aspects of the illness which most researchers consider critical to diagnosis. The old criteria, he pointed out, have been around for 25 years: it’s “time to stop querying patients and begin developing new diagnostics”.

Outlining the scale of the problem, he noted that the prevalence of ME/CFS in the US is around 1 million – ‘not rare by any means’. Looking at the picture worldwide, he added, one finds a similar story for all patients: they are in a position of enormous socioeconomic disadvantage, with unmet medical and social needs. The direct financial cost of the disease in the US is estimated at $9 billion, and with indirect costs included the estimate rises to $51 billion. Considering the scale of the problem “sometimes brings us all to a paralyzed state”.

Problems with Diagnosis

Showing a brief model of disease progression, where genetic predisposition followed by triggers (including infection, trauma, stress, toxins, and immunization) provokes a complex range of mediators to induce chronic illness (ME/CFS), Peterson considered why this pattern is problematic for traditional medical diagnosis. The US FDA, he said, uses the four steps of traditional differential diagnosis (gather information and create a symptoms list; make a list of all possible causes; prioritize the list with the most urgently dangerous condition at the top; and work down the list of causes treating or ruling them out with tests). This model doesn’t fit well with ME/CFS, he explained, because we have a heterogeneous population, there are no clear-cut validated biomarkers, there are multiple clinical definitions, no drug is licensed for treatment, and there is no universal surrogate marker. Symptomatic therapy can alleviate symptoms and improve quality of life, he said, but it has never returned a patient to full cognitive and physical functioning.

FDA Stakeholders Meeting

Turning to a review of the FDA Stakeholders Meeting, Peterson noted that the FDA had been completely unenlightened with respect to the nature of ME/CFS, the extent of the problem, the lack of treatments, and the amount of research being carried out. But for him, the take-home message from the workshop was a positive one: drug approval does not require a biomarker if there are other means to define endpoints. Drug development, however, typically takes 8-15 years, and it’s driven by market potential. For the FDA’s purposes, it needs validated, reproducible endpoints, which can be surrogate markers.

A Look Ahead

Having outlined the background, Peterson brought up an Invest in ME slide and said: “Along comes my favorite small charity with a big cause”. Looking ahead at the presentations to come, he highlighted some key headings. Computational analysis and bioinformatics, he said, is a new and exciting advancement, and the CFIDS Association had used these tools to help in its drug re-purposing project (suggesting a way around that 8-15 year drug development timeframe). Looking ahead to Mady Hornig’s presentation, Columbia Center for Infection and Immunity’s pathogen discovery project had started in 2012, the final analysis of the study of spinal fluid in 60 ME patients and 60 controls is now under way, and they now have a large repository of samples and data to work with. Immune biomarkers are critical to diagnosis, they can define subsets, and Natural Killer (NK) cell function and enumeration is his favorite biomarker for ME/CFS: there’s a large literature on NK cells and it’s a field with lots of agreement around the world.

Enabling Drug Development and Approval

Peterson continued his focus on issues critical to drug development and approval. Endpoint evaluation is a key issue: in January 2013 the FDA had declined to approve Ampligen, largely because of the lack of availability of objective endpoints that could be used. The PACE trial had used the 6 minute walking test to define an endpoint, but this was not a good candidate: it’s not generally considered to be an objective endpoint and would be rejected in the US. VO2 max or Cardio-pulmonary exercise testing (CPET) could be acceptable though. Finally, large numbers of patients are needed for useful and meaningful studies; smaller studies are only useful if there is a very homogeneous population being studied. So we need both clear endpoints and clear populations for successful research.

So: to drive drug development and conduct effective clinical trials, we need large multi-site clinical studies, with clear endpoints, studying a well-defined population – and an appropriate level of funding is of course essential for this.

Peterson summed up: Worldwide collaboration is necessary, to define subsets based on accepted biomarkers, to define the exact pathogenesis, to design interventional strategies, and to create centers of excellence.

Dr Andreas Kogelnik: Key Note Speech: “Making ME Mainstream: Strategies for ME Research and Collaboration”

Dr Andreas Kogelnik

Dr. Kogelnik is founder and director of the Open Medicine Institute (look out for a Phoenix Rising article on the OMI in a couple of weeks). Kogelnik’s exciting key note presentation introduced “The Changing World of Medicine”, where the IT revolution, the Social Information revolution, and the Biotechnology revolution are all leading, Kogelnik predicted, to a Health/Disease revolution. ME, he suggested, is now coming to the point where it will be a key disease in moving that process forward.

Kogelnik illustrated the dramatic changes that are taking place, building on the huge growth in processing power and storage capacity by developing personal technology solutions that enable the concept of the “Quantified Self”. Gadgets that turn your mobile phone into an ECG, quantify sleep, continuously measure activity levels and enable you to monitor your vital signs to see what changes when you try a particular drug or treatment, are just as important to the individual as to the physician or researcher, he said. Costs of full genome sequencing are dropping at a spectacular rate: 5 years ago it cost a billion dollars to sequence the human genome for the first time; now you can sequence your own for about $2,000 and that price is set to drop below $500 very soon.

Medicine is at a crossroads, Kogelnik believes, and he predicts that we will transition from a paradigm of generic ‘evidence-based’ guidelines to a model of medicine driven by genomics and personalized, precision medicine. Evidence will still be important, but the kind of evidence has changed.

ME/CFS has been easy to ignore while there hasn’t been enough data, Kogelnik explained; researchers have been gathering that data in order to gain leverage. Agencies like the FDA are “not an enemy” – it’s more an issue of “their ignorance and our lack of data”: our job is to bring that data to them so that it can’t be ignored. So in order to mainstream ME/CFS, we need broad and deep measurement, and we need to encourage greater engagement of people.

Kogelnik also quickly summarized the OMI-Merit (ME Roundtable on Immunology and Treatment) Priority Projects: you can see those 10 projects listed in more detail here.

The Open Medicine Institute’s Open MedNet project – an ME/CFS patient data repository which you can now pre-register for – is due to go online in the next month or two, and when it does we’ll be urging all our members and readers to help it reach its target of tens of thousands of individuals. I’m also hoping to report on Kogelnik’s inspiring presentation in more detail later this week.

Dr Rakib Rayhan: “The Role of the Brain and ME”

Dr Rakib Rayhan

Dr Rakib Rayhan

Rakib Rayhan is a colleague of Professor James Baraniuk, who was unable to attend the Invest in ME conference this year, but sent his regards. Rayhan’s presentation focused mainly on Gulf War Illness, covering some of its history, some subjective analysis, markers of the disease, and some of his recent research findings with Baraniuk’s group.

About 30% of the troops in the first Gulf War have now registered in the American Legion gulf war illness database, and those stricken with the illness have had a tough time getting acceptance of their illness. With no diagnostic code, and skepticism from physicians, many are still fighting for benefits after 10-15 years.

There are so many potential causes of GWI – oil wells, smoke, combustion, vaccinations, etc – that 20 years later, the exact causal relationships may be difficult to find, Rayhan said – but he offered to shed light on the pathophysiological mechanisms in his presentation. He focused attention on the huge munitions dump in Khamisiyah where sarin gas and other nerve toxins are thought to have been released into the atmosphere when it was destroyed. Sarin is a potent acetylcholinesterase inhibitor, he noted, with similar mechanisms to various kinds of insecticides.

The Post-Traumatic Stress Disorder (PTSD) theories have been done away with, he argued, and pointed to a study by Steele, Sastre, Gerkovich and Cook which shows associations with other factors that put veterans at risk, such as taking bromide pills, periods of less than 4 hours sleep, being near pesticides, and wearing treated uniforms – maybe all these factors worked in combination.

Reminiscent of the ME/CFS history, Rayhan noted that there are many definitions for GWI as well, including the Fukuda and Kansus definitions, and he spoke of the potential for a new consensus criteria for GWI. Baraniuk is not alone in noting the similarities between GWI and ME/CFS, and he has hypothesized that central nervous system (CNS) dysfunction could cause all the symptoms we see in both. The group have been measuring VO2 max and conducting brain scans before and after exercise stress tests, looking for blood flow and structural changes, in an attempt to see what the brain is doing when PEM occurs (veterans complain about that too as a a prominent part of their disease state).

CNS Dysfunction

Baranuik and Rayahn have used a new technology (Diffusion Tensor Imaging) to enhance standard fMRI techniques, so that they can probe the functioning of bundles of nerve fibers. With this technique, they found anomalies in the nerve fibers that interpret pain signals in Gulf War veterans.

They are particularly excited by the details because their brain imaging work is highlighting a pathway that connects 2 regions of the brain associated with pain and fatigue processing and pain and fatigue perception. They’ve found other potential biomarkers in other areas of the brain as well.

They believe, Rayhan said, that this work has produced a “quite robust biomarker” to distinguish GWI patients from controls, and their findings indicate “some kind of central nervous system dysfunction”.

Studying veterans using fMRI and cardiovascular indices before and after 2 bicycle exercise tests, they found the veterans showed either increased or decreased working memory scores, while the controls were unaffected, and later found that the ‘increasers’ had lower cerebral lactate (associated with mitochondrial dysfunction, leading to the hypothesis that the brain may have used lactate rather than glucose as an alternate sugar source) whereas the ‘decreasers’ had a higher glutamine/glutamate ratio.

Piece de Resistance

Rayhan then moved on to the group’s ‘piece de resistance’, which should be out in the next couple of weeks, he said. They’ve been looking at the change in heart rate following exercise, and they’re finding two subgroups. One group, with increased tachycardia throughout the two exercises which went away after 4 nights of rest, they are terming the “Stress Test Associated Reversible Tachycardia Phenotype” (START). The other saw an increase in pain perception, which they’re terming “Stress Test Originated Phantom Perception (STOPP). They are also seeing different areas of compensatory brain activity in the two groups. We’ll be reporting in more detail when that study is published.

Summarizing, Rayhan concluded that exposure to acetylcholine may have led to damage to the central nervous system, and suggested that their approach to exercise stress-testing offered a potential model to study overlapping syndromes, which may be of use in the case of ME/CFS.

Questions

Ian Gibson now invited questions from the audience on the presentations so far.

Dr Peterson was asked for advice about vertigo and some other symptoms by a severely affected patient. Peterson said that he tended to have all-day meetings with patients such as this, and there was no simple answer. They are an overlooked group of people who largely can’t access care, he said; in the old days they used to be looked after in hospital, but sadly that’s no longer economic.

Charles Shepherd was pleased to see the PEM study, and asked Rayhan how far along they were in conducting similar studies on ME/CFS. Answer: they haven’t started yet; it’s a difficult funding environment but they’re hoping to do it.

Malcolm Hooper asked Rayhan whether the vets they had studied were deployed or non-deployed; hearing that all but 2 were non-deployed, Hooper cautioned that the two groups’ circumstances were quite different, and reminded him to look at that: the non-deployed veterans didn’t get the chemical exposures, just the vaccines.

A questioner from the audience wanted to highlight hypo-pituitary syndrome, which can arise after brain injury damages the pituitary gland: between 500,000 and 1 million with this condition are believed to be undiagnosed in the UK today, and she was wondering why people with ME aren’t tested for that. The ME experts said it’s well known that the pituitary is turned down in ME, and there are many other causes for that so it’s important to exclude such people. It’s quite an involved process to diagnose HPS, using imaging and dynamic tests, but good endocrinologists won’t miss pituitary dysfunction. Correct diagnosis of ME does indeed involve excluding such conditions, and that’s very important.

Another questioner felt that there was an important category missing in the study of ME/CFS: people who have had diagnosed ME, with full symptoms, who are now fully recovered. This might be an interesting subgroup to study; these stories might be valuable for research. Kogelnik was very positive in response to that: he sees that as “the low-hanging fruit”, and said that the MedLine database will allow patients to diarise their symptoms then, now, and next, and tell their stories from a medical perspective – he invited past patients to do that, and add their medical history under the healthy control section.

A final question asked the speakers about the accepted criteria. The CCC and ICC exist. And why is it so hard for physicians to co-ordinate different specialties for a patient; why do we have to do that for them? Answer: At the heart of the problem: we don’t agree about what it is. Dr Peterson lamented: “CFSAC has just voted to put off the clinical and research definition question for 2 more years…why would you ever use 25-year old outdated useless criteria?”

 

Time for a short Refreshment Break!

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Professor Greg Towers: “Retroviruses and ME”

Professor Greg Towers

After a short break for refreshments, Professor Greg Towers reprised the XMRV saga. Retrovirologists weren’t paying much attention to XMRV, he said, until the Mikovits paper came out, but that paper caught their attention. Firstly because ME was clearly hard to diagnose, but with XMRV, it wouldn’t be, and vaccination and treatment would have been feasible. Secondly, the study had suggested that many (maybe 4% of the general population) may have the virus without symptoms, and it may lead to prostate cancer. So it seemed very important to sort this out as quickly as possible.

But the situation got confusing quickly: the positive studies slacked off, and the negative studies began. The important question remained: is XMRV circulating in the population?

I’ll cut a long story short here – followers of the XMRV saga are familiar with the discovery of XMRV in the 22rv1 cell line; the revelation that it has been known for some time that novel combination retroviruses are commonly created inadvertently in laboratories by the repeated passage of cell lines through mice; the comparison of ancestral genetic sequences that found patterns of variation suggestive of a common laboratory source rather than an actively circulating virus; and the discovery of common integration sites that further suggested a contamination explanation.

One revelation was new to me, though: when tracking down this detective mystery, the team had hit a wall when they tried to get hold of samples of the 22Rv1 plasmid used in Cleveland. This problem was circumvented, Towers explained, when they discovered that Vinnie Pathak’s brother in law happened to know somebody who worked in the Cleveland lab; they called him up and got hold of the necessary samples! They were then able to show the XMRV sequence there to be a recombinant of 2 others in the mouse genome – ‘preX1′ and ‘preX2′. The final closure came with the Lipkin study, when he sent samples blinded to Lo, and to Ruscetti, and they didn’t detect any viruses with their method. That study puts this story to bed, said Towers.

Valuable lessons had been learned along the way though. PCR is very sensitive – that was well known, and this investigation confirmed just how sensitive it can be. But retrovirologists learned that it is essential to manage it in such a way that you are able to fully understand the possible sources of contamination. They didn’t think before that it mattered, but now they know that you mustn’t prepare a virus-encoding plasmid in the same laboratory that contains the samples you’re testing against; if you do, you can’t test sensitively without a risk of contamination. This situation should never happen again, said Towers: the papers published since should show how to prevent this kind of situation happening in future.

Professor Mady Hornig: “Pathogen discovery in ME”

Professor Mady Hornig

Professor Mady Hornig is Director of Translational Research at Ian Lipkin’s Center for Infection and Immunity (CII), Columbia University, and her goal is to understand illnesses where brain and immunity are believed to take centre stage. This is an ideal fit for ME/CFS, given that most researchers suspect that the brain and/or immunity play a central role in the illness.

Hopes for a sneak peak at some early findings from the world’s largest ever ME/CFS biomedical study were largely dashed…there were a couple of bits of very preliminary news, but we’re going to have to wait a little longer for the findings. The hunt by Mady Hornig, Ian Lipkin and colleagues for a virus or other pathogen that may cause our illness, and their investigation of signs of immune abnormalities (as opposed to specific pathogens) has already been described here on Phoenix Rising, in Simon McGrath’s articles Lipkin & Hornig go hunting for ME/CFS pathogens and Mady Hornig: How do you solve a problem like CFS? Hornig’s presentation at Invest in ME covered very similar ground, and I can’t hope to describe it as well as Simon did!

She did mention an additional study of some ‘unusual cases’ provided by Dr Peterson though, and offered a glimpse of the type of data they are collecting in their cerebrospinal fluid work: a promising slide showed very different patterns of cytokine associative networks in the ME/CFS patients as compared with controls, with the cytokines in the patients more tightly associated. They are perhaps beginning to see here how the immune system functions in a very different way to the controls, but we’ll have to wait a little longer for these findings to be confirmed.

We got a few clues as to how far they have progressed: they’ve completed the initial peripheral blood work, and she estimates they’re about 80% through the lab work on that. The bioinformatics work is ongoing, and they think they may have found a ‘potential novel candidate’ in the spinal fluid, though that needs to be confirmed (is that the network association, or something else? We’ll just have to wait and see…) The other studies (including the microbiome investigation) are just gearing up now. This is painstaking work, and science of the highest caliber: although we must wait a little longer, the up side is that the results of this study are sure to be very widely respected, and we have good reason to hope that, when they are published, they will take the field of ME/CFS research forward significantly.

Mady threw in a couple of fine quotes as well. Her opening slide cited Esquirol on Insanity: “Many authors assure us that mental alienation is epidemic. It is certain that there are years, when, independently of moral causes, insanity seems suddenly to extend to a great number of individuals”. At times, she added in her introduction, the approach has seemed “almost as if we’ve had a decapitated body” – where the head has been thought to function independently of biology and physics. I think we can be confident from this that Hornig leans rather more towards the biomedical than to the biopsychosocial…

And to emphasize the ever-changing nature of science at the frontier, she ended again with her great Einstein quote:

Student: Dr. Einstein, Aren’t these the same questions as last year’s [physics] final exam?
Dr. Einstein: Yes; But this year the answers are different.

 

 

Lunch Time!

Yum! That looks delicious!

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Dr Clare Gerada: “Govt NHS Reforms: Implications for long term chronic conditions such as ME – for GPs and Patients”

Dr Clare Gerada

Nobody wanted to be back late from lunch! We started the afternoon “with a highlight of the conference,” said Ian Gibson, introducing Dr Clare Gerada, “I enjoy listening to Clare because she tells it straight”. The audience applauded warmly as Gerada stepped bravely into the lions’ den…

Dr Clare Gerada was elected to lead the Royal College of General Practitioners in 2011, and now represents over 40,000 doctors; she recently announced that she will be stepping down from the position in November. She trained in psychiatry and maintains an interest in the treatment of patients with addiction problems.

Following her father into general practice, her career as a GP began in 1991 at the Hurley Clinic, Lambeth. She has been concerned with improving the support available to drug-users from their GPs and in 2000 she was awarded an MBE for services to medicine and the wellbeing of drug-users. She has served as Director of Primary Care for the National Clinical Governance Team and Senior Medical Advisor to the Department of Health.

She also happens to be married to Simon Wessely.

A Controversial Choice

The decision to invite Gerada to the Invest in ME conference raised more than a few eyebrows; her strong biopsychosocial views and her appearance in a training video advising GPs how to treat ME patients (playing the role of a GP advising a patient that ‘exercise has been shown to be safe’) made her a controversial and surprising choice to say the least. But Invest in ME defended their decision to invite her robustly, and their call for the audience “to use this opportunity wisely and politely to move the ME cause forward” was very much heeded: no demonstrations, cat-calling or walkouts here.

Building a Bridge

Indeed, Gerada was applauded as warmly when she left the lecture theatre as she was when she was introduced, and while the questioning at the end of her talk was intense, the conversation was enlightening and constructive. The bravery of Gerada’s attempt to “build a bridge between the largest royal college and a very important problem” won respect from the audience, as did her robust and forthright defence of GPs “under strain…blamed for problems in everything from dementia to Accident and Emergency…battered by political leaders, the press, and sometimes the patients we serve…bearing the brunt of cuts, and the inability to deliver personalised care at supermarket prices…”.

The audience were treated to an insight into the realities of general practice which put the experience of ME patients in the UK into some context, as she spoke of the huge problems with “models of care for chronic illnesses” in general and defended GPs’ admitted ignorance of ME by insisting that general practitioners, as generalists, “cannot know a lot about everything” and when faced with a “chronic disease with such levels of disability” can only refer their patients to a specialist. GPs simply cannot provide the care that ME patients need, she explained, “That takes skills, and resources, and where are the experts? How, if there are no specialists” can GPs provide for the needs of ME patients?

“I’m not disputing whether it’s physical, neurological, or jelly…I want to move on from that…”, she said: the patients’ disability needs to be managed with kindness but “we need specialist services: we need you to lobby for that”. And when challenged with stories of GPs advising patients to “go to a gym”, or stating that they “don’t believe in ME”, she was clear that while she did not expect a GP to understand the complexities of ME, she “would expect him not to make such comments”. “I don’t know what causes motor neurone disease, but I can still treat those patients with compassion” – she doesn’t know the cause of illness for many or most patients, but for the GP the important thing is the “ability to handle patients kindly, with compassion – that’s the point”.

NHS Re-organisation

Gerada’s talk focused not on ME, but on the challenges and problems the NHS is now facing, with a minimum of £20bn more cuts to come in the next 4 years; she warned that the re-organisation in the last few years has “dismantled every existing structure on social care that we had” and rebuilt them at breakneck speed while losing 16% of the staff, and she explained the importance for patients of lobbying the new commissioning groups to answer “what they are doing, and when, for ME – otherwise you will be left out”.

Two Conflicting Paradigms

Clare Gerada’s appearance at an Invest in ME conference was never going to resolve the differences between what an audience member called “two conflicting paradigms” – but it did show that respectful and worthwhile communication is possible across that divide. I, for one, learned a great deal about the current transformation of the NHS, the pressures faced by general practitioners, and the reality of where the gaping hole in provision for ME patients should properly be filled. While I, like most of those present, remain convinced that the guidance being provided to GPs is still inappropriate and frequently harmful to ME patients, and that remains a huge problem, I gained a greater appreciation that this situation is not the fault of GPs.

Common Ground?

There was even one point on which all those present appeared to find common ground: the real gap in provision is the complete lack of specialist care for ME, and the way forward for ME care has to come from the provision of integrative, specialist services. So in the end, we communicated, we learned, we expressed our concerns, we were respectful and we applauded Gerada’s passion and her bravery in speaking to us, and we can only hope that Gerada learned something in the process as well. We even found what looked like points of agreement, and as a football fan (that’s soccer, for you Americans), trying to remain objective, I saw the match as a game played in a positive spirit ending in a score draw. Whether a bridge was built, as Gerada hoped, only time will tell, but there is at least a glimmer of a chance that Gerada will get her wish to “be better able to work with you to improve the care you receive from my profession”.

Coming soon on Phoenix Rising, we’ll have a full report on Dr. Clare Gerada’s talk.

Dr. Donald Staines: “Current Knowledge of Immunological Biomarkers”

Dr Donald Staines

Dr Donald Staines

Dr. Don Staines was standing in for Professor Sonya Marshall-Gradisnik, who was unfortunately unable to attend due to ill health. (A get well soon card for one of the world’s most important ME/CFS researchers may perhaps be in order!). Stains is a member of Marshall-Gradisnik’s research team at Griffith University in Queensland, Australia.

Staines introduced himself as a public health physician, responsible for supporting GPs in understanding disease outbreaks and how to deal with them in the community. Addressing first some of the issues raised in the previous debate, he said he had some perspective on prevalence and incidence. Part of the design of the research unit at Griffith University, he said, was a dedicated clinical and research capacity, with a dedicated 3-bed unit with 24-hour care, enabling them to observe patients over a period of time. It was a very integrated system, he said, and a “really simple idea”, and he didn’t know why it’s “not picking up momentum here as well”.

As a primary care physician, said Staines, it was “very important to find immunological and molecular markers”. Clearly, he continued, there are factors in ME/CFS throughout the body, but they are focusing on the immunological factors, and in particular the bridge between the innate and adaptive (acquired) immune system.

Natural Killer Cells and CD8 Cell Lysis

Starting with what is already known regarding NK cells and CD8 cell lysis, he explained that NK cells release granzymes, which attack target cells; in ME/CFS, a consistent reduction in NK cell lysis (the breaking down of cells by granzymes) has been found by them and by others. This observation is “not a flash in the pan”, it’s a “sustained, demonstrable, significant impairment in NK cell function”. They see CD107a degranulation, and big differences in expression. Staines showed how granzymes do their work to assassinate cells. In their studies, they find that this job breaks down in the granzyme B group (not so much in granzyme A or perforin). In CD56 glycoproteins (binding glycoproteins expressed on the surface of NK cells), they find that a specific subset is affected, the CD56 ‘bright’ and not the CD56 ‘dim’. In the NK cell receptors, they see a change in the KIR3DL receptor. All of these are responsible for attacking and immobilizing an invading infection, and so there are several aspects of impaired function.

Looking at the CD8 transmembrane glycoprotein (a co-receptor for the T cell receptor), they see consistent changes over time: they have studied this at several time points through the year and find that the CD8 itself is compromised. Staines next explained the function of neutrophils, a type of phagocyte (white blood cells that protect the body by ingesting foreign particles) – an essential part of the innate immune system. They migrate through the bloodstream towards sites of inflammation, target the cells they want to immobilize, and trigger several pathways to create a toxic environment within the targeted cell, and are therefore very important in defending the body from invaders. In ME, when they look at the respiratory burst, they find that it is profoundly reduced. This is a significant abnormality, and they are finding that the human neutrophil antigens HNA-2 and HNA-5 are abnormal. More strength for these results would be required to provide an exclusive diagnosis, however.

MicroRNAs, T-regs and pDCs

Turning to MicroRNAs, Staines explained that they are made in the nucleus, exported to the cytoplasm, and work from then on as ‘messenger RNAs’. There are about 2000 of them in humans, of which only 200 are known, and still less is understood about them. They have found quite a number of MicroRNAs with significant differences in ME/CFS patients, but they will need to perform studies with other conditions before they can say whether these differences are unique to ME/CFS, or shared with other conditions.

In the adaptive immune system, as they reported at Invest in ME 2012, they have found subsets of T-regulatory cells which are up-regulated, in particular, FOXP3, which is seen as a ‘master regulator’ in the development of T-regulatory cells. The up-regulation of these cells is probably in order to suppress some inflammatory mechanism and they are “highly confident” of this up-regulation.

They’ve looked at gamma and delta T-cells, which straddle the adaptive and innate immune systems, but although they observed something there, it wasn’t statistically significant. Looking at subtypes of B cells, they found deficits in immature cells, and an increase in memory and plasma cells (but the latter finding has also not yet been found at statistically significant levels). They have also found high levels of plasmocytoid dendritic cells (pDCs).

Summary

Summing up, Staines went through the immune defence process: a pathogen enters the body, recognition starts, and innate and adaptive immune responses then begin. In ME/CFS patients, they find that the innate immune response shows changes in neutrophils, NK cells, gdT, pDC, and nitric oxide. In the adaptive response, they find disorder in B cells, T cells (including T-reg cells), CD4, granzymes, micro RNAs, CD8 and more. They conclude, then, that in ME/CFS, dysregulation is initiated and maintained throughout NK and CD8 cells, B and T cells, T-regulatory cells, and Th1 and Th2 response.

These findings, says Staines, suggest the potential hallmarks of autoimmunity, and “anyone who suggests that this might be fixed by exercise therapy should probably be de-registered I think”.

Questions

Challenged that these findings wouldn’t differentiate between the “biologic” and “psychiatric”, Staines accepted that his phrasing was a “shorthand paradigm” – the key thing, though, was that there was “clear derangement in the immune system, in so many compartments – it’s irrefutable”.

A researcher from Spain (IrsiCaixa?) said his research group had tried to correlate their similar findings with severity, but have not yet found any clear association. Did they find any association with severity?

An excellent question, said Staines: they did look at this. The severely affected group are very abandoned. In any other illness, the more severely patients are affected, the more care they receive; with ME, the opposite seems to be the case. So they went into their homes, they took blood samples, and carried out a number of other tests as well, especially with flu vaccines. They found differences both in the response to flu and in the response to flu vaccines. His recommendation based on their findings would be that this makes it especially important for severely ME patients to get the vaccine. But anyway, no they didn’t really find differences in the markers between the moderate and severe patients. But maybe we shouldn’t expect there to be, he mused – there are many other systems of the body affected as well in ME/CFS (suggesting that the severity of disease provoked by the immune disorder may be determined by other factors). The short answer, Staines concluded, was that they can’t yet explain this, but will be interested to research it further.

Dr Amolak Bansal: “Clinical Immunology and Research on B-cell abnormalities in ME Patients”

Dr Amolak Bansal

Dr Amolak Bansal

Dr Bansal began by joking that he was glad he hadn’t begun his presentation with a photo of St Helier Hospital (in the London borough of Sutton); it wouldn’t compare well with Griffith University!

But he thinks “we have a hypothesis here”, and a “paradigm shift” towards autoimmunity in ME…he would begin by taking a step back and trying to “bring everything together”, starting with a look at the evidence for immune dysfunction.

Predisposing Factors

It’s well known, said Bansal, that certain predisposing factors are associated with CFS, and people with these kinds of immune and autoimmune conditions (such as EDS) have a very high incidence of CFS, and even if they don’t have CFS, they too have chronic fatigue. We know that CFS affects women more than men – just like most other autoimmune conditions. There’s a slight tendency for it to run in families, though that could be due to environmental factors. It has been associated with certain personality traits, and black Americans, American Indians, and other groups, are at higher risk. It has also been associated with higher than average IQ, lower social class, and lower income.

We know too, he added, that any form of severe stress causes stress on the immune system – so maybe stress leaves you susceptible to CFS?

Infectious Triggers

Bansal looked quickly at a number of potential infectious triggers. Regarding infections, he noted that EBV, while it may not be ‘the cause’, has proteins that may encourage autoimmunity. Regarding spirochetes, he said they are not really a significant problem in this country. He didn’t seem to think that fungal triggers are particularly important either, but on vaccinations, he seemed more open, as that does seem feasible. He listed other triggers, including stress, organophosphates, sleep and mood disorders, over- or under-activity, multiple infections, illness beliefs, etc etc…and in the end, he thinks it all comes back to stress.

He finds the known delayed reaction to mental over-exertion, in particular, very hard to explain. Speculating, he wondered whether leaking adenosine and ATP might be acting on prurinergic receptors.

Stress and Immune State

But persistent stress, Bansal re-iterated, does have an adverse effect on the immune system, and he thinks that’s very important. So his suspicion is that persistent stress can provoke a shift to a type of immune state which promotes autoimmunity and also impairs immune function. And cognitive dysfunction and ANS dysfunction could perhaps be explained by the auto-antibodies binding to one or more CNS sites or neurotransmitters.

So Bansal produced a model: a cyclical graph in which stress causes fatigue and lowered Th1 immune response, leading to increased susceptibility to viral infections, causing worry and more stress, which further reduces Th1 response and impacts on T-regs, which induces more viral illnesses, which causes further stress, and so on back round the cycle. In this way, stress, he suggested, prevents the immune system from regulating itself.

Viral and Immune Observations

Considering the viral and immune observations in CFS patients, very few get rashes, pneumonia, or similar classic consequences of an impaired immune system, so it seems there is a very subtle immune dysregulation involved here. We need to look in much more detail in order to find that, and that’s why we haven’t found it before, he suggested.

Bansal turned next to cytokines: we’ve seen some are increased, and some are decreased, and a lot has been written about this. To work all that out, it all comes back to autoimmunity. But in CFS, we don’t find anything on routine tests for autoimmunity – the standard tests have all showed up negative there: IgG, IgG subclasses, ANCA, C, C4, TPO abs…nothing. A few have increased levels of atypical lymphocytes. There are conflicting reports regarding levels of cytokines, he pointed out.

His research hasn’t found reduced functioning or numbers of NK cells, whereas others have. Why? Well, he speculated that this may be due to different case definitions, different test protocols…they may be affected by something like taking samples at different times of day…in the early HIV work, he noted, results from blood taken early in the day looked different to blood taken in the evening.

But we have failed to ask, he said: What is the role of exaggerated receptor solubilisation and cytokine/cytokine receptor autoimmunity? Could it be that patients are making antibodies against cytokines, maybe?

Altered Functional B Cell Subsets

Bansal moved on to discussing his own recent study. Most of his patients were classed as moderate, two were severe. All fulfilled the CCC. All were negative for routine antibodies and none had gluten sensitivity. All were seen at the same time of day; all were assessed in serum for a wide range of exotic antibodies seen in neurological problems: all those tests were negative.

But when they studied B-cell gating, what they found was that levels of transitional B cells were increased in CFS. B cells are produced in the bone marrow, and migrate via secondary lymphoid tissues (such as the spleen and the lymph nodes) where they are called transitional B cells, some of which differentiate into mature B lymphocytes. Bansal thinks what may be happening is that some problem in the transition of these cells means that they haven’t been through the same ‘checkpoints’ as normal B cells, meaning that the B cells in CFS patients are more likely to produce low avidity antibodies – antibodies which bind weakly with the antigens they are supposed to attack, perhaps because some of their antigen-binding sites are not functioning properly.

[Interestingly, this hypothesis may connect somehow with the recently-discovered mechanism of Rituximab reported in Cancer last month: Rituximab binds to one side of a diseased B-cell and dramatically increases the success rate of NK cells in destroying the diseased cell. Could Rituximab be assisting somehow with the faulty binding of these low avidity antibodies?]

Bansal also finds that naïve B cells are a higher percentage of all B cells in the CFS patients he studied – these are the cells that haven’t undergone the ‘checkpoints’. He noted that other results show lowered levels of IL 21,12, and 27 – all of which are involved in the correct maturation of B cells. So it would make sense to him that the B cells aren’t undergoing the correct checkpoint analysis. But then looking at T cells, a number of abnormalities have been reported. The end result: an abnormal interaction between T and B cells, and the B cells are not regulated properly. As the interaction proceeds, Bansal warned, these responses will mature, the avidity gets higher, and the process becomes harder to reverse, which would make early diagnosis particularly important.

Summarising his findings, Bansel re-iterated that he believes he is seeing impaired maturation of B cells, less anti-viral cytokines and especially less of those involved in B cell regulation, resulting in impaired T-Lymphocyte homing receptors.

Conclusions

Bansal therefore proposes that the initial problem in CFS may involve B cell dysregulation, perhaps after a series of viral infections, and especially if the patient is under stress as well at the time of infection. In some people, the B cells then start to make auto-antibodies against neural receptors in the CNS and the periphery. These auto-antibodies contribute to worsened arousal mechanisms, causing sleep dysregulation and autonomic dysfunction. Some may also target mitochondrial proteins and produce delayed PEM.

In perhaps one of the most important take-home messages of the day, Bansal suggested that while removing these auto-antibodies has been found to reduce symptoms, for a lasting response it may also be necessary to suppress the action of certain viruses which encourage the survival of auto-reactive B cells. So we may not only need to ‘reboot’ the B cells; we may also need to get rid of those viruses as well.

In summary: it’s a very complex disease, he said, but he believes we are now entering a ‘paradigm shift’. In Bansal’s opinion, it is very likely there is a subtle autoimmune phenomenon here, with antibodies targeting CNS proteins.

Questions

I asked Dr Bansal whether this need to clear viruses as well as rebooting the B cells is the reason for the  ‘combination treatment’ arm mentioned in Dr Peterson’s proposed multi-site Rituximab + Valcyte study; he confirmed that’s the rationale.

Somebody asked where the gut might fit in with all of this. If you have gut inflammation, he answered, that will disrupt digestion in the gut. The initial trauma maybe encourages a loss of tolerance, and thus you end up with increased auto-reactive B cells (this may occur due to food poisoning, salmonella, or with typhoid). Maybe the initial infection targeted T cells, causing a diminished ability to regulate B cells, and then the cycle is underway…

 

 

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Award Winners!

Ellen Piro, founder of the Norwegian ME Association (celebrating its 25th year) called forward Richard and Pia Simpson to receive a special award from the Norwegian MEA.

Invest in ME was officially founded in 2006, Ellen explained – and it was those two who were behind it. They created IiME because of their frustration at the lack of progress. They have worked tirelessly, always successful in their choices of topics and speakers, and IiME conferences have always been exciting and surprising, always at the frontline of research, and an important source for updates and information.

Through this conference, said Ellen, an international network of professionals and communities has been established. Richard and Pia are down to earth, forthright and friendly. They have two children with ME, and they have poured their time and funds into this organization. Without IiME, there would be no ME conference in Europe, and Invest in ME has earned great respect worldwide; they have always been very appreciative of the Norwegian MEA. So on behalf of the Norwegian MEA, Ellen presented the ME Award to Richard and Pia Simpson.

All those present at the conference who were physically able to do so rose to their feet for a round of appreciative applause – and Richard was obliged to say a few words. “You’re all doing great work by what you’re doing,” he said graciously, “here and elsewhere”. He praised the “frontline research” in Norway, making “great inroads into a very difficult area,” and added that everything that has been achieved is built on the backs of many campaigners and researchers. If researchers and people like Dr Peterson had given up, he asked, where would we be now? “This is the easy part,” claimed Richard, “it should actually be us honoring you”.

Ellen wasn’t done yet though – time for Professor Malcolm Hooper to step forward, to more rapturous applause. Hooper needed no introduction: “A real warrior” in the frontline for years. “He has no personal involvement in this,” Ellen pointed out, and yet he’s fighting for us. Lecturing, writing, publishing, speaking out about opponents, an active part of Invest in ME and its professional supporter, the Norwegian MEA had often approached him for advice and benefited from his support. So Ellen presented Professor Hooper with the ME award for his “untiring and exceptional contribution to the ME cause”.

“Thank you very much,” said Hooper.

“The shortest speech I’ve ever heard him make,” remarked Ian Gibson. “Thank you guys, I’ll come and see the Northern Lights. Although, you can seem them better in Scotland actually…”

Professor Carmen Scheibenbogen: “Immunological Basis of ME”

Professor Carmen Scheibenbogen

Professor Scheibenbogen, from the Charite Institute for Medical Immunology in Berlin, has also noticed that there has been “much progress in recent years”. In Germany, she said, they call it “CFS”; her work is in immune deficiency and she shares many of the same theories as Bansal, Fluge and Mella. It has become obvious that we need to develop a diagnostic test, and this is what she is trying to do.

Scheibenbogen showed a simple venn diagram of symptoms, somewhat reminiscent of the findings presented by Rakib Rayhan earlier in the day, with Fatigue and Pain either side, and CNS symptoms overlapping with both in the middle. She then reviewed the evidence for ME as an immune-mediated condition.

Firstly, the clinical picture. ME often starts with an infection, and in some patients there is evidence of an ongoing infection; many report ongoing ‘flu-like’ symptoms. The immune function seems to have changed, with patients experiencing either more or less infections. Secondly, the immune dysfunction is confirmed by the laboratory findings; immune phenotype studies are controversial, but there are clearly elevated T-regs and reduced NK cell cytotoxicity. And thirdly, immunological treatments are now working.

Charite’s Immune Diagnosis Study

At Charite, their immune diagnosis study has been looking at T-cell activation, T-cell phenotype, T-cell cytokines, and immunoglobulin elevation.

They found elevated T cell function in about half their patients, divided into three types. They used flow cytometry to analyse the surface of cells and they found some patients with Th1 dominance, more with Th2 dominance, and others with low cytokines, so this again looks like 3 different subtypes to them.

They found polyclonal immunoglobulin elevation is a quarter of the patients (n=286), and think that’s a response to ongoing immune activation. Another quarter have immunoglobulin deficiency, and again they think that’s a consequence and not a cause.

They also found complete deficiency in MBL (mannan-binding lectin) in 15% of their patients and 7% of healthy controls, which is associated with increased risk of infections and that seems to be confirmed from what the patients say, but that’s just one piece of the story…

Herpesviruses

They have been looking really closely at herpesviruses and hope to have solid data in about 6 months time, but Scheibenbogen presented some preliminary results. In the subset of patients with EBV infection, who tend to suffer from recurring herpes lesions, they find they generally improve with valacyclovir, and typically recommend trying that for 8 weeks. HHV1-3, she said, is easy to diagnose from symptoms, whereas EBV is much harder: patients typically get it later in life, EBV copies stay in their blood, and after about a year they are diagnosed with CFS. They don’t know yet whether it is the EBV infection that is ongoing or the immune response; nobody can answer this yet.

The data on EBV infection is controversial, with both enhanced and diminished EBV antibodies reported. They are finding some elevated antibody response, but suspect this is just the ‘tip of an iceberg’. They have been trying to make a more sensitive assay for antibodies against EBV, evaluating against more than 2000 overlapping peptide libraries; they have support from local government to develop a test based on that. They think they have found some EBV structures that people do or don’t respond against. They’re now running a study with a multiple sclerosis control group, and hope for clear data on all this in about 6 months time.

Summary

Scheibenbogen summarized their findings so far: they find evidence for immune activation, T cell activation, enhanced antibody production, immune dysfunction and dysregulation, a T cell type 2 shift, antibody and complement deficiency, and altered EBV specific response. Overall, they see chronic immune activation, and think that the infection is not always active but the T cells remain active, perhaps triggered by B cells.

Finally, she presented a diagram summarizing the picture they are seeing: 3 distinct entities, which can be either infection-triggered or adjuvant-triggered:

  • Immune activation CFS
  • Immune deficiency CFS
  • Non-immune CFS (triggered by other agents)

Professor Olav Mella: “B-cell Depletion Therapy Using Rituximab in ME/CFS – Part I”

Dr Oystein Fluge: “B-cell Depletion Therapy Using Rituximab in ME/CFS – Part II”

Professor Olav Mella (left) and Dr Oystein Fluge

Professor Olav Mella (left) and Dr Oystein Fluge

Saving the best for last (and ensuring that an exhausted audience remained glued to their seats), the last act of the day was the Fluge and Mella show. Unfortunately for you, dear reader, the material presented in this section of the conference has not yet been published, and we are asked not to disclose it in order not to jeopardize the publication process. I most certainly do not want to be the one to do that!

Norwegian journalist Jorgen Jelstad, however, has a good handle on what to say and what not to say, so I’ll refer you to his tweets from the conference, and you’ll just have to wait for the follow up to Fluge and Mella’s 2011 Plos One Rituximab study. I will say, though, that the picture is encouraging, and the new hypothesis that Fluge presented is indeed fascinating, just as Jorgen says.

As the first study showed, and as some members of the Phoenix Rising forums have found, not everybody is responding to Rituximab, but the progress on exploring the reasons for that – and possible solutions – is encouraging. In particular, see Dr Bansal’s comments above regarding the necessity of identifying and clearing any underlying viral infection as well as ‘rebooting’ the B cells. That’s the basis for the proposal for a trial with Valcyte alongside Rituximab, so that theory has clearly been seriously considered for a while, and it makes a lot of sense to me.

On the downside, Bansal also noted that the longer a patient has been ill, the harder it will be to reverse the kind of immune dysregulation he’s theorizing, but that’s not a reason to give up hope in my opinion. It is still very early days for B cell depletion therapy, and the work on developing therapeutic strategies using Rituximab – and other similar treatments – has only just begun. Assuming it all pans out, the effectiveness of the treatment will surely improve as more studies are done.

Speaking of which, one part of Mella’s presentation is no secret: they are pushing hard now to fund a bigger study nationally, and they need to raise enough money for a 140-patient multi-site study. If you’re impatient for treatments and possible cures – and who isn’t? – then the best thing for you to do, in my opinion, would be to join the small but dedicated army of volunteers who are raising funds for this and other vital research. Starting with the appropriately-named MEandYou

 

 

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69 comments

{ 69 comments… read them below or add one }

Firestormm June 2, 2013 at 11:54 pm

Burning the midnight oil again Mark?! :) Nice job. Thanks. Am going to read through slowly…

Here are some comments posted on IiME Facebook:

Rosie Cox
Notes made by Dr William Weir at the 8th Invest in ME Conference, May 2013.

Permission to repost.

INVEST IN ME

Synopsis of proceedings of 8th International Conference held on 31st May 2013. Dr William Weir FRCP (Lond) FRCP (Edin)

The main theme of this conference focused on the three burning questions which all ME sufferers want answered, namely what causes ME, what is being done to discover this cause and what treatments might be effective?

What was very encouraging was the impressive cast of speakers from around the world whose scientific credentials could not be challenged.

Happily, none of them were psychiatrists, as gradually the psychiatric, biopsychosocial theory of ME causation is being consigned to the dustbin of history.

There is now far too much high quality scientific evidence indicating that ME is due to immunological dysfunction and many of the speakers stated this principle very forcefully.

There were four main categories of speaker. Firstly there were those who talked about the organization of studies, which included the collection and computerisation of data (such as case histories) and biological material (such as blood and other body fluid samples).

Clearly, in the USA at least, work of this nature is now getting off the ground and a large effort is being made to establish a “biobank” of biological materials from patients which will be made available to researchers.

Here in the UK a biobank has already been set up, based at the London School of Hygiene and Tropical Medicine to where blood samples are being sent for cold storage.

Secondly there were the immunologists who described the immunological abnormalities seen in ME patients.

One of the frustrations with ME is that, although there are always across-the-board abnormalities, those seen are never as consistent as they are, for example in AIDS where one particular type of immunologically active cell is consistently reduced.

However one of the speakers came out with the opinion that: “if any doctor now thinks that these abnormalities are due to psychological disorder and that exercise is the cure, he/she should be deregistered” (He was from Australia).

One phenomenon which is now well recognised is the “cytokine flare” which follows physical (and mental) exercise. Cytokines are substances produced by the immune system as part of a normal immune response to the presence of an invading bug, be it a virus or bacterium (or other, such as a malaria parasite).

Interferon is the one most people have heard of. They make you feel ill as part of the body’s normal defence against infection. In ME however they appear to be produced inappropriately, and go on being produced in the apparent absence of a recognisable infection.

Furthermore there is an abnormal increase – “flare” – after exercise which now explains the problem of post exertional malaise. Here, at last, is direct evidence that Graded Exercise Therapy (GET) is very likely to be harmful.

Thirdly the issue of a possible virus infection was addressed. This would provide a logical explanation for the ongoing immunological activity – finally identifying the metaphorical fire from which all the immunological smoke was coming.

The XMRV story was reviewed and provided real insights into the complexities of identifying a “new” virus. The term “new” meaning hitherto undiscovered, as it is fully appreciated that there are probably very many undiscovered viruses out there in the biological ecosystem, often being carried silently (ie without illness) by a large range of animals, including humans.

The disease-causing potential of these viruses is unknown and may have very long incubation periods with infection preceding the development of disease by many years. For example It has been suggested that Parkinson’s disease is due to such a virus, and the same may be true of ME.

As many will know, XMRV was finally recognised as a contaminant of the cultures in which attempts were being made to grow a new virus from samples taken from ME patients.
The initial excitement over the discovery of XMRV was dampened when this was realized, but has not deterred the search for other viruses.

To apply historical perspective, when influenza was first researched, a number of bacteria and viruses were initially but incorrectly proposed as the cause before the real villain was identified.

Some very sophisticated techniques are now being used in the search for the real ME villain, one candidate being a form of retrovirus known as a “human endogenous retrovirus” (HERV).

These are viruses which are already present in human genes, and usually inactive (ie not replicating). Nonetheless they probably can be turned on again and they have been postulated as causes of a wide range of diseases, including cancer and autoimmune disease. Thus ME may well be due to a HERV.

Finally there was a presentation of the Norwegian study of rituximab therapy which shows promise in the treatment of ME. Twenty of twenty eight patients improved significantly although there was a lag period of two to three months before improvement occurred.

Rituximab specifically targets the CD20 lymphocytes, taking them out of circulation but well before symptomatic improvement – suggesting that it is antibodies produced by the CD20 cells which cause the symptoms, but which require the 2-3 month period to clear from the body.

This study on its own supports the immunological hypothesis of causation, further diminishing the psychiatric attribution of an “abnormal illness belief”.

Rituximab does however have its drawbacks. It is potentially very toxic, also very expensive and no UK doctor would be able to prescribe it for ME at present. Further studies are in progress.

Watch this space!

Enid June 3, 2013 at 1:03 am

Oh Wow, thanks Mark, what can one say except it's been a long twelve years to reach this stage. Richard and Pia deserve a hundred medals for their persistence over all these years in the face of the ridicule and nay-sayers UK. Now serious work/discoveries go on unhindered. To my mind Rituximab findings the crux pointing the way to immune abnormalities. Happiness (well you know what I mean) all round.

Kati June 3, 2013 at 1:16 am

Thank you for this, Mark, it made for good reading and great hope for many publications in the next few months.

Enid June 3, 2013 at 1:18 am

Must add – I much appreciated the invitation and acceptance by Dr Gerada to attend this conference, and think she spoke very well – another mainstreaming so to speak for us.

maryb June 3, 2013 at 3:03 am

Thank you so much Mark for your efforts, its really appreciated, hard for those of us who can't focus for too long but are desperate for news. Super info from all the speakers, looks like things are moving faster, we can only hope change is really achievible in the not too distant future.
Hope that Dr Gerada also learnt quite a lot from this conference too. And has much to discuss in the future – who knows even help change the ways GP's view ME? Pity she's retiring.
As I've seen 2 consultants in the past year who both recommended excercise there's a long way to go. But my respect to her for attending.

Valentijn June 3, 2013 at 3:15 am
maryb

Hope that Dr Gerada also learnt quite a lot from this conference too. And has much to discuss in the future – who knows even help change the ways GP's view ME? Pity she's retiring.

In addition to the horrible CFS videos she starred in, she's also gotten involved in strongly urging Scottish authorities not to adopt the CCC within the past few years: http://www.cathcartmesupportgroup.org.uk/resources/ClareGeradaLETTER.pdf

In that letter she is strongly opposed to neurological symptoms being accepted as part of it, and pretty much any treatment that isn't recommended by NICE. Her stepping down is an opportunity for progress, if anything.

alex3619 June 3, 2013 at 3:29 am
  • "Dr Donald Staines stands in for Professor Sonya Marshall-Gradisnik. Publications expected in next weeks and months; still finding “sustained, demonstrable, significant impairment in NK cell function”, "highly confident" of up-regulation of T-reg cells; "clear derangement in the immune system…it's irrefutable", and “anyone who suggests that this might be fixed by exercise therapy should probably be de-registered I think”.
  • Dr Amolak Bansal senses a "paradigm shift" towards model of subtle form of autoimmunity in ME; suspects patients' B cells are failing to mature properly and producing low avidity antibodies; lasting response to B-cell depletion therapy may require clearing the viruses responsible in addition to 'rebooting' the B cells."

Wow. Wish I was there, I would have questions. First, a direct attack on psychobabble and unproven exercise hypotheses, and stronger immune findings. Second, the suggestion by Bansal cannot be overestimated I think.

Avidity refers to the property of something, often an antibody, to bind to multiple target points at the same time. High avidity is linked to high specificity. If we have LOW avidity then our antibodies will not be specific … they will target a huge range of targets, attacking almost everything in a way, resulting in the equivalent of many many simultaneous weak autoimmune disorders, all at once. This fits with Maes' research. Its very very interesting. It also explains our huge range of symptoms. As I said, this could prove very very interesting.

The Bansal hypothesis could potentially explain just about all the findings, including why Rituximab works. However it needs much more development, more studies, more funding.

Sasha June 3, 2013 at 3:42 am

Absolutely superb article, Mark – very exciting to hear not only about this major advances but also how hopeful the researchers feel about everything.

And I liked your cheeky intermission requests for support! They have a serious purpose, of course – the conference cost Invest in ME a ton of money and Phoenix Rising needs to cover its costs to bring you this kind of reporting and keep the forums running.

If you haven't donated yet and you can afford to, you really should… :cool:

And if you're interested in volunteering, I can recommend it! You won't be under any pressure to do more than you can very easily cope with and it feels good to be contributing to the community, and to be part of the effort towards getting treatments and a cure.

alex3619 June 3, 2013 at 3:51 am

I agree with the general sentiment that a change in attitude about ME research is in the air. I have been sensing that for over a year now. Things are changing, huge advances might be in the near future, the potential for positive change has never been this good.

Sasha June 3, 2013 at 3:51 am
alex3619

I agree with the general sentiment that a change in attitude about ME research is in the air. I have been sensing that for over a year now. Things are changing, huge advances might be in the near future, the potential for positive change has never been this good.

And, ironically, all off the back of XMRV. What a story.

alex3619 June 3, 2013 at 3:58 am
Sasha

And, ironically, all off the back of XMRV. What a story.

Almost mythic. ;)

It also doesn't escape my attention that it was the WPI who first noted that we have too many immature B cells.

snowathlete June 3, 2013 at 4:13 am

Mark – fantastic article. Thank you so much for attending and then reporting all this in such clear detail. I still have a fair amount of it to read but a few things struck me already.

Hornig's ‘potential novel candidate’: if this is the exact term she used, then reading into it (perhaps too much) the language suggests that the candidate might be a new strain or member of an existing species of a known group of pathogens. I would imagine that if you find something completely novel that you would know very quickly that it is something completley novel. But if you find a new strain or member of a group, then it is less immediately obvious that it is a novel strain, or species. I could be reading too much into it though – they could easily be saying it like this as they want to be cautious and check its a real finding and not something like contamination.

The PHD studentship at Norwich is excellent news. We need this. Dr Enlander is doing fellowships in the US at Mt. Sinai and Dr. Newton is working hard to get young people interested in the disease up in Newcastle, UK. I personally see this as vitally important as it not only brings new ideas and youth to the field, but it helps to mainstream the disease. Important to get behind it and encourage more of the same elsewhere.

Gibsons comment “do your own thing, but talk to other people too” is a very good one. Collaborating even at the level of just talking with other researchers on a regular basis is oh so valuable. I think our doctors are getting much better at this lately and we are seeing benefits.

Dr Bansal's theory of B-cells failing to mature is an interesting idea. Look forward to hearing/reading more on that in the future.

Thanks again Mark. I know the work that goes into putting something like this together. It was clearly a monumental effort on your part, from which we all benefit!

Nielk June 3, 2013 at 6:52 am

Thank you, Mark for being our eyes, ears, note taker, transcriber, writer, reporter. Reading this article makes me feel like I was there myself. It is always a unique opportunity at these type of meetings that bring our experts together to get a glimpse of what has been going on in the background. I will take my time to read through this treasure trove carefully.

Thank you!

natasa778 June 3, 2013 at 7:59 am
alex3619
  • Dr Amolak Bansal senses a "paradigm shift" towards model of subtle form of autoimmunity in ME; suspects patients' B cells are failing to mature properly and producing low avidity antibodies; lasting response to B-cell depletion therapy may require clearing the viruses responsible in addition to 'rebooting' the B cells."

Wow. Wish I was there, I would have questions. First, a direct attack on psychobabble and unproven exercise hypotheses, and stronger immune findings. Second, the suggestion by Bansal cannot be overestimated I think.

Avidity refers to the property of something, often an antibody, to bind to multiple target points at the same time. High avidity is linked to high specificity. If we have LOW avidity then our antibodies will not be specific … they will target a huge range of targets, attacking almost everything in a way, resulting in the equivalent of many many simultaneous weak autoimmune disorders, all at once. This fits with Maes' research. Its very very interesting. It also explains our huge range of symptoms. As I said, this could prove very very interesting.

The Bansal hypothesis could potentially explain just about all the findings, including why Rituximab works. However it needs much more development, more studies, more funding.

What about blood monocyte/macrophage maturation in ME, any research on that? I wonder if these two things could be related somehow … going out on a limb but want to mention in case you or someone here has any ideas. What I have in mind here is the research by Michal Schwartz and her group at Weizman institute on blood monocyte maturation/differentiation and their recruitment to CNS for repair of damaged/inflamed tissue. If this this process is impaired for whatever reason (including impaired differentiation/maturation of monocytes) there will be neurological dysfunction, possible ongoing gliosis etc …

Mark June 3, 2013 at 8:09 am
Enid

Oh Wow, thanks Mark, what can one say except it's been a long twelve years to reach this stage. Richard and Pia deserve a hundred medals for their persistence over all these years in the face of the ridicule and nay-sayers UK. Now serious work/discoveries go on unhindered. To my mind Rituximab findings the crux pointing the way to immune abnormalities. Happiness (well you know what I mean) all round.

Amen to all of that!

It was an absolute pleasure to meet Richard and Pia at the conference and I can what was said of them when they received their well-deserved award: down-to-earth and friendly for sure! :) So many wonderful people there.

And yes, I agree that Rituximab looks to me like the crux pointing at a key detail, maybe the key detail, of the immune dysfunction.

Mark June 3, 2013 at 8:15 am
Enid

Must add – I much appreciated the invitation and acceptance by Dr Gerada to attend this conference, and think she spoke very well – another mainstreaming so to speak for us.

Indeed: the problems people will have with her associations and previous stance on ME issues are obvious, but putting all that aside for a moment there's no question she's a superb speaker, with some passionately held core values which I wholeheartedly agree with. Yes, this was definitely a key part of the 'mainstreaming' theme and I think it was a massive gamble and a huge success.

Mark June 3, 2013 at 8:19 am
Kati

Thank you for this, Mark, it made for good reading and great hope for many publications in the next few months.

Thanks Kati, you're most welcome – I really enjoyed writing it and learned a lot along the way. Looking forward to all those publications as well…

Mark June 3, 2013 at 8:27 am
maryb

Thank you so much Mark for your efforts, its really appreciated, hard for those of us who can't focus for too long but are desperate for news. Super info from all the speakers, looks like things are moving faster, we can only hope change is really achievible in the not too distant future.
Hope that Dr Gerada also learnt quite a lot from this conference too. And has much to discuss in the future – who knows even help change the ways GP's view ME? Pity she's retiring.
As I've seen 2 consultants in the past year who both recommended excercise there's a long way to go. But my respect to her for attending.

As above: I really enjoyed it, so you're welcome. :) I know people out there are really hungry for news and it really does get to me when I think about some of the people who just aren't physically able to attend; I know some people who would get far more out of it than me, understand everything better, and just deserve to be there more than me somehow. It's really good to be able to share with them. Still very sad for those who can't even hope to read through a long article like this, but we do what we can…

As to the whole thing about recommending exercise…I don't know if anything that was said on that subject got through to Dr Gerada, but all I know is that all communication is two way and you have to at least try to listen to what somebody is telling you before you can hope or expect that they listen to you as well. I think it was at least a start, and I learned a lot from her like I said, so it has to be seen as a success.

Mark June 3, 2013 at 8:31 am
Valentijn

In addition to the horrible CFS videos she starred in, she's also gotten involved in strongly urging Scottish authorities not to adopt the CCC within the past few years: http://www.cathcartmesupportgroup.org.uk/resources/ClareGeradaLETTER.pdf

In that letter she is strongly opposed to neurological symptoms being accepted as part of it, and pretty much any treatment that isn't recommended by NICE. Her stepping down is an opportunity for progress, if anything.

I don't mean to gloss over the negative issues, I agree these are important problems for sure, but I felt it was important to support Invest in ME's brave decision to invite her and emphasise the positives as well.

Sasha June 3, 2013 at 8:32 am
Mark

I know people out there are really hungry for news and it really does get to me when I think about some of the people who just aren't physically able to attend.

As one of those people, it really got to me too! I've ordered the DVD but it was frustrating not to see it live-streamed as we've got used to seeing the FDA etc. do.

I gather that IiME subsidise the cost of the DVDs so that patients can afford them but would it be cheaper to upload the content to YouTube? And better for IiME in terms of exposure? And for doctors in terms of education? Could livestreaming be a possibility? I've no clue about what's involved or what that costs.

Sasha June 3, 2013 at 8:38 am
Mark

I don't mean to gloss over the negative issues, I agree these are important problems for sure, but I felt it was important to support Invest in ME's brave decision to invite her and emphasise the positives as well.

I agree. My impression – having heard her on Question Time or something (big UK political debate radio show) was that she's extremely politically astute. I can't read her mind and don't know her motivations but whatever the case, if our researchers and advocates and charities have now got things to the point where the smart thing politically would be to jump on the biomedical bandwagon, then the more she's brought into the fold to see that, the better. She has influence and it would be good if she could see the benefits to herself, as well as to us, of recognising that things are changing and acting accordingly.

Valentijn June 3, 2013 at 8:48 am
Mark

I don't mean to gloss over the negative issues, I agree these are important problems for sure, but I felt it was important to support Invest in ME's brave decision to invite her and emphasise the positives as well.

I agree … I just think some people are interpreting her presence to mean that she's on our side.

But practitioners who are strong or long-time believers in psychosomatic theories regarding medically unexplained symptoms have never shown any capability of changing their views that I've ever seen. So I wouldn't read much into her appearance there, and it sounds like she did her best to avoid being contaminated by opposing views with her early departure :alien:

Mark June 3, 2013 at 9:00 am
alex3619
  • "Dr Donald Staines stands in for Professor Sonya Marshall-Gradisnik. Publications expected in next weeks and months; still finding “sustained, demonstrable, significant impairment in NK cell function”, "highly confident" of up-regulation of T-reg cells; "clear derangement in the immune system…it's irrefutable", and “anyone who suggests that this might be fixed by exercise therapy should probably be de-registered I think”.
  • Dr Amolak Bansal senses a "paradigm shift" towards model of subtle form of autoimmunity in ME; suspects patients' B cells are failing to mature properly and producing low avidity antibodies; lasting response to B-cell depletion therapy may require clearing the viruses responsible in addition to 'rebooting' the B cells."

Wow. Wish I was there, I would have questions. First, a direct attack on psychobabble and unproven exercise hypotheses, and stronger immune findings. Second, the suggestion by Bansal cannot be overestimated I think.

Avidity refers to the property of something, often an antibody, to bind to multiple target points at the same time. High avidity is linked to high specificity. If we have LOW avidity then our antibodies will not be specific … they will target a huge range of targets, attacking almost everything in a way, resulting in the equivalent of many many simultaneous weak autoimmune disorders, all at once. This fits with Maes' research. Its very very interesting. It also explains our huge range of symptoms. As I said, this could prove very very interesting.

The Bansal hypothesis could potentially explain just about all the findings, including why Rituximab works. However it needs much more development, more studies, more funding.

I wish you were there too Alex! Big time! :)

Staines' last sentence got a good reaction from the audience of course. :)

I think you're spot on in focusing on Bansal's suggestion/hypothesis/theory. That was probably the biggest light-bulb moment of the conference, for me (with the possible exception of the exciting embargoed hypothesis of Fluge which takes the whole thing to another level…), and I think Bansal's work in general may be a really key component in taking all this forward. I thought so at the time, but when I came to going through my notes to write up the article and looked up 'avidity', I got even more excited…as you say, that hypothesis could potentially explain sooo much, including why Rituximab works.

One more detail to add to what you explained above: the idea is that known T-cell deficiencies could cause the failure in the maturation of the B cells, because (if I understand this right) one of their jobs is to manage these 'checkpoints' in the development of those cells, and (reading between the lines) if that fails, you end up with B cells that are missing some of their binding sites (paratopes). So they have lower avidity (less strength of binding to multiple target points) because some of those binding sites are missing or defective.

At the time, I didn't quite understand why this might cause autoimmune antibodies, but (this may be an amateur's misunderstanding) it may be because the defective binding sites then start binding to the wrong things rather than binding to everything as you suggest (maybe it's both). The other part I wasn't 100% on is that I think he was saying that the dodgy B cells may then be attacking certain T-cells or T-cell components themselves (I think that may be related to the comment about cytokine/cytokine receptor autoimmunity) – so there can then be a vicious cycle whereby the malformed B cells cause problems for the T-cells that are supposed to provide the 'checkpoints' on maturing cells…that undermines the T-cells further leading to more malformed B-cells and the avidity gets lower and lower and becomes more and more ingrained.

As you know, I'm only pretending to understand any of this :D but I'm certainly fascinated by immunology now!

And amen to more studies and more funding…:)

Mark June 3, 2013 at 9:02 am
Sasha

Absolutely superb article, Mark – very exciting to hear not only about this major advances but also how hopeful the researchers feel about everything.

And I liked your cheeky intermission requests for support! They have a serious purpose, of course – the conference cost Invest in ME a ton of money and Phoenix Rising needs to cover its costs to bring you this kind of reporting and keep the forums running.

If you haven't donated yet and you can afford to, you really should… :cool:

And if you're interested in volunteering, I can recommend it! You won't be under any pressure to do more than you can very easily cope with and it feels good to be contributing to the community, and to be part of the effort towards getting treatments and a cure.

Indeed, thanks Sasha…the more volunteers we have to write, proof-read, edit, administer etc, the more articles like this we can do…we do work round people's limitations, and many hands make like work…

Mark June 3, 2013 at 9:03 am
alex3619

Almost mythic. ;)

It also doesn't escape my attention that it was the WPI who first noted that we have too many immature B cells.

Wow, I must have missed that…did they ever publish on that, or do you have a reference on them saying so?

alex3619 June 3, 2013 at 9:10 am

Hi Mark, each individual antibody from an immature B cell can be expected to bind only to one or two things, or none, or a few, but the low specificity means they can be our own proteins. However if many such antibody types are being made, then many may bind to a few targets. Many times a few is still many. So each will have some limited specificity, but if this is a generalized problem then there will be so many being made, with so many targets accordingly. Its an intriguing hypothesis, though it needs more evidence.

I have not read much on B cell maturation in a a long time, nor the current science on T cell involvement. It seems I might have some more reading to do … like I need more reading but this is welcome information. :)

Bye, Alex.

Esther12 June 3, 2013 at 9:11 am

Thanks Mark.

re Gerada: So long as increased funding for specialist services is likely to help Chalder/White/Crawly/etc, I'd rather have money go to those patients with conditions that the NHS can really treat. For ME/CFS, give the money to patients imo. They'd make better use of it.

I'm sure that a lot of the dishonest spin around PACE stems from a recognition that, if they were honest about the impact of their 'treatments', they would not be able to get funding. These cutbacks should be seen as a great opportunity to cut the quackery from the NHS. I think funding was increased too rapidly in the past, and along with some poor research and spun meta-analyses, this led to the NHS spending money on nonsense. Better to have nothing than be 'cared for' by those following the work of Chalder and White.

Gerada is a good politician.

Firestormm June 3, 2013 at 9:18 am
Sasha

As one of those people, it really got to me too! I've ordered the DVD but it was frustrating not to see it live-streamed as we've got used to seeing the FDA etc. do.

I gather that IiME subsidise the cost of the DVDs so that patients can afford them but would it be cheaper to upload the content to YouTube? And better for IiME in terms of exposure? And for doctors in terms of education? Could livestreaming be a possibility? I've no clue about what's involved or what that costs.

I agree with the frustration you express here Sasha. America is setting the bar high for us here in little olde UK to follow. I think though that IiME depend on this revenue stream – I might be wrong – but yes when you hear about things being 'embargoed' or said only to the audience and not expressed outside of the conference: it does rather add to the frustration when waiting for a DVD to be produced. Rather an olde school approach to modernity.

Dolphin made a point on Facebook that some of the Rituximab comments might have been restricted or something – in relation to Dr Weir's comments above. I don't believe they were – but clearly something was. Presumably when the DVD is published such comments will be more widely circulated – so I'm not sure how things can be embargoed?

Sorry if that doesn't make sense. I am rather shattered.

Mark June 3, 2013 at 9:33 am
snowathlete

fantastic article. Thank you so much for attending and then reporting all this in such clear detail. I still have a fair amount of it to read but a few things struck me already.

Thanks…and sure, there's a lot there, and it's going to take a while to digest!

Hornig's ‘potential novel candidate’: if this is the exact term she used, then reading into it (perhaps too much) the language suggests that the candidate might be a new strain or member of an existing species of a known group of pathogens. I would imagine that if you find something completely novel that you would know very quickly that it is something completley novel. But if you find a new strain or member of a group, then it is less immediately obvious that it is a novel strain, or species. I could be reading too much into it though – they could easily be saying it like this as they want to be cautious and check its a real finding and not something like contamination.

I think that 'potential novel candidate' were the exact words…that's what I typed anyway but it may have been slight shorthand. When I came back and went through it all, I found myself wondering if it might have been more like 'potential candidate novel phenomenon', in other words referring to the different associative cytokine network rather than a novel entity. At the time, I thought she was referring to a possible novel entity, but on reflection I'm not certain of that. In any case, this is all preliminary and has yet to be confirmed.

But to be honest, it wouldn't surprise me at all if they find novel strains/species along the way…I'm hoping for something like the suttarrella they found in autism, but the caution here is that even if they do find such things, it'll still be possible they are side-shows, like opportunistic infections or things which just happen to have never been found before. There's such an unimaginably vast complexity to the biome in particular, that there must be masses of stuff out there to be discovered and some of it may turn out to be rather incidental. There will also be a big question mark over chicken-and-egg issues with such things: are they just taking advantage of an autoimmune condition, or are they the pathogen that triggered it? Or both…

We'll have to wait and see, but for me, a breakthrough from those studies that explains the whole thing is only in my wildest dreams: the main thing for me is to see ME/CFS being studied by such a heavyweight team with such mainstream respect: I feel confident that they will find something because I'm sure there is plenty there to be found, and I feel hopeful that when they do so it will really draw attention and respect from other researchers and cause new people to really look more closely at ME/CFS and start researching it.

The PHD studentship at Norwich is excellent news. We need this. Dr Enlander is doing fellowships in the US at Mt. Sinai and Dr. Newton is working hard to get young people interested in the disease up in Newcastle, UK. I personally see this as vitally important as it not only brings new ideas and youth to the field, but it helps to mainstream the disease. Important to get behind it and encourage more of the same elsewhere.

Good point: the fellowships and studentships are really important. I also think the focus on gut bacteria is very forward-looking, because I think that's a frontier area of research that will become more and more important in the coming years. I have this suspicion that as the autoimmunity work proceeds there may come a point where the focus starts to shift towards studying the interactions with gut bacteria…it seems like it might be the next logical step in the hunt. I also have it in my mind that the University of East Anglia is something of a center of excellence in gut bacteria, though not sure if I've misremembered that…anyway it's great to have ME being studied in such contexts.

Thanks again Mark. I know the work that goes into putting something like this together. It was clearly a monumental effort on your part, from which we all benefit!

It certainly has been a pretty epic undertaking! I've got a week's holiday ahead and expecting to spent most of it horizontal. :) I feel I should note at this point that I've had a lot of help from Simon along the way. Anyway, I really, really enjoyed it and I wanted to do it for my own enjoyment as much as anything; it was a bit of self-indulgence really so if people appreciate it, that's a bonus.

Mark June 3, 2013 at 9:35 am
Nielk

Thank you, Mark for being our eyes, ears, note taker, transcriber, writer, reporter. Reading this article makes me feel like I was there myself. It is always a unique opportunity at these type of meetings that bring our experts together to get a glimpse of what has been going on in the background. I will take my time to read through this treasure trove carefully.

Thank you!

More than welcome Gabby – and by the way, some of the things you did in your recent work on the FDA articles were a significant inspiration to me while I was writing this; you really made me think about some issues of writing style and I incorporated a lot of those things here.

Sasha June 3, 2013 at 9:37 am
Firestormm

I agree with the frustration you express here Sasha. America is setting the bar high for us here in little olde UK to follow. I think though that IiME depend on this revenue stream

I thought that too but I think I remember reading on their site that they subsidise the cost. I did a quick search on their site and could only find that in relation to their 2011 DVD:

http://www.investinme.org/IiME Conference 2011/IIME 2011 DVD Production Status Aug11 2.htm​
Another important factor is, of course, that IiME subsidise the cost of the DVD production in order to make it accessible to as many people as possible.

Dolphin made a point on Facebook that some of the Rituximab comments might have been restricted or something – in relation to Dr Weir's comments above. I don't believe they were – but clearly something was. Presumably when the DVD is published such comments will be more widely circulated – so I'm not sure how things can be embargoed?

Here's something from that same page:

This year as well we have the new research from the Haukeland University Hospital, Norway. Before the conference the Norwegian presenters, Professor Olav Mella and Dr Øystein Fluge, discussed with us the amount of data that they could present regarding their exciting new research. They wished to present as much as possible but did not wish to compromise the publication of their imminent paper. IiME promised that we would not distribute the DVD (including their presentation) until the Norwegian researchers gave the go-ahead due to the magnitude and implications of their research. In return Professor Mella and Dr Fluge were very open in their presentation and gave as much information as they could.​
We do not wish to jeopardise their research publication so we are now awaiting news of their imminent publication before beginning the distribution of the DVD. ​

If they were livestreaming they could surely just stop for a bit; and if they were putting the conference up on Youtube they could just not upload the embargoed lecture until later.

Mark June 3, 2013 at 9:45 am
natasa778

What about blood monocyte/macrophage maturation in ME, any research on that? I wonder if these two things could be related somehow … going out on a limb but want to mention in case you or someone here has any ideas. What I have in mind here is the research by Michal Schwartz and her group at Weizman institute on blood monocyte maturation/differentiation and their recruitment to CNS for repair of damaged/inflamed tissue. If this this process is impaired for whatever reason (including impaired differentiation/maturation of monocytes) there will be neurological dysfunction, possible ongoing gliosis etc …

Honestly don't know about this one…I don't think anything was mentioned and they seemed very much focused on B cell maturation specifically, but they don't seem to know very much about precisely what's causing the problems with B cell maturation or what's getting the problem started – I guess that's one of the frontiers and it sounds quite feasible to me that it might turn out that there are problems with the maturation of other cells as well. Hopefully somebody else on here can answer that – who's our immunology expert? :D

Mark June 3, 2013 at 9:51 am
alex3619

Hi Mark, each individual antibody from an immature B cell can be expected to bind only to one or two things, or none, or a few, but the low specificity means they can be our own proteins. However if many such antibody types are being made, then many may bind to a few targets. Many times a few is still many. So each will have some limited specificity, but if this is a generalized problem then there will be so many being made, with so many targets accordingly. Its an intriguing hypothesis, though it needs more evidence.

I have not read much on B cell maturation in a a long time, nor the current science on T cell involvement. It seems I might have some more reading to do … like I need more reading but this is welcome information. :)

Bye, Alex.

Thanks Alex, that makes good sense.

While you're looking into the involvement of T cells in B cell maturation, you might want to have particular reference to IL 21,12, and 27 which were mentioned in Bansal's talk – and also anything else observed to be low in ME/CFS which is involved in B cell maturation.

alex3619 June 3, 2013 at 9:51 am
Mark

Wow, I must have missed that…did they ever publish on that, or do you have a reference on them saying so?

It came up somwehere in all that discussion of XMRV, particularly when they were looking at immune markers. I don't know that it was ever published in a paper, and I dimly recall it might have been Mikovits who discussed it during a presentation. At the time they did not know what it might mean, it was only an observation. Now we realize it may be the smoke from the crime, and pointing us toward the gun.

We could probably find out by contacting Mikovits or the WPI.

alex3619 June 3, 2013 at 9:57 am
Mark

Thanks Alex, that makes good sense.

While you're looking into the involvement of T cells in B cell maturation, you might want to have particular reference to IL 21,12, and 27 which were mentioned in Bansal's talk – and also anything else observed to be low in ME/CFS which is involved in B cell maturation.

One thing I was going to blog on but is now delayed for some months is gamma delta T cells. They are an innate form of T cell similar to a Treg, and it was again the WPI who got me to looking at them by a comment that we appear to have too many with signs of polyclonal expansion. This ties into other work by Maes on LPS, which is why I was going to blog on it. Now perhaps I need to expand my parameters. I am not an immunologist, there is so much I do not know.

Essentially what I was working on was alternate enteroviral life cycles and gut function. It now appears they increase translocation of gut bacterial products to the blood stream. In various paths that might or might not be relevant this can be shown to induce some of our problems … if the path is significant. There are multiple ways to get to many things in the way the body works.

In case anybody is not aware, lipopolysaccharide or LPS is a family of bacterial product, part of the bacteria's outer defence, and it can massively induce an immune response … a generalized immune response. Its called a superantigen. Some gamma delta T cells are hard wired to detect LPS in the blood, and it sends them nuts so they alert the rest of the immune system.

Mark June 3, 2013 at 10:01 am
Esther12

Thanks Mark.

re Gerada: So long as increased funding for specialist services is likely to help Chalder/White/Crawly/etc, I'd rather have money go to those patients with conditions that the NHS can really treat. For ME/CFS, give the money to patients imo. They'd make better use of it.

I'm sure that a lot of the dishonest spin around PACE stems from a recognition that, if they were honest about the impact of their 'treatments', they would not be able to get funding. These cutbacks should be seen as a great opportunity to cut the quackery from the NHS. I think funding was increased too rapidly in the past, and along with some poor research and spun meta-analyses, this led to the NHS spending money on nonsense. Better to have nothing than be 'cared for' by those following the work of Chalder and White.

Gerada is a good politician.

This is the really sharp question for us I think. We're in a bind because we're all afraid to campaign for what we need most, fearing that "specialist treatment centres" will get translated into "more psychotherapy". The problem is how to campaign for the services we need without ending up producing more services that are harmful to ME patients. It's a real problem, but I think the answer lies in multi-disciplinary teams. That's what we need: teams of immunologists, neurologists, dieticians, specialists in sleep and exercise, and yes, the odd psychologist or psychotherapist as part of the mix, all in one centre so that patients can see the range of specialists they need for their own particular problems. One thought I have on this is that maybe such centres may be more achievable if we think about what other conditions need the same kind of range of specialists as us, and combine a couple of other conditions in what we're campaigning for. This kind of model does seem the obvious way forward in dealing with chronic illness though. And I do think, for sure, that if we're going to ask for something we need to be pretty specific in exactly what it is we want; a definite case of 'be careful what you ask for…'

Mark June 3, 2013 at 10:06 am
Firestormm

I agree with the frustration you express here Sasha. America is setting the bar high for us here in little olde UK to follow. I think though that IiME depend on this revenue stream – I might be wrong – but yes when you hear about things being 'embargoed' or said only to the audience and not expressed outside of the conference: it does rather add to the frustration when waiting for a DVD to be produced. Rather an olde school approach to modernity.

Dolphin made a point on Facebook that some of the Rituximab comments might have been restricted or something – in relation to Dr Weir's comments above. I don't believe they were – but clearly something was. Presumably when the DVD is published such comments will be more widely circulated – so I'm not sure how things can be embargoed?

Sorry if that doesn't make sense. I am rather shattered.

The point here is that conference-goers often get a sneak peek of results that are shortly going to be published. If too much of that news leaks out, the researchers may have more difficulty in getting it published at all. Nobody wants to publish old news. It's good for conference-goers to get some little teasers and bits of advance news, it makes the conference more attractive, and it's bad for all of us if the news leaks out. This is pretty much the norm in research rather than 'olde school' I think…I'd love to see a different model but until the entire research publishing system is dismantled, it's just the reality.

alex3619 June 3, 2013 at 10:13 am
Mark

This is the really sharp question for us I think. We're in a bind because we're all afraid to campaign for what we need most, fearing that "specialist treatment centres" will get translated into "more psychotherapy". The problem is how to campaign for the services we need without ending up producing more services that are harmful to ME patients. It's a real problem, but I think the answer lies in multi-disciplinary teams. That's what we need: teams of immunologists, neurologists, dieticians, specialists in sleep and exercise, and yes, the odd psychologist or psychotherapist as part of the mix, all in one centre so that patients can see the range of specialists they need for their own particular problems. One thought I have on this is that maybe such centres may be more achievable if we think about what other conditions need the same kind of range of specialists as us, and combine a couple of other conditions in what we're campaigning for. This kind of model does seem the obvious way forward in dealing with chronic illness though. And I do think, for sure, that if we're going to ask for something we need to be pretty specific in exactly what it is we want; a definite case of 'be careful what you ask for…'

Combining with other similar groups to achieve limited goals is something I am big on. I think this can be done.

Sasha June 3, 2013 at 10:19 am
Mark

The point here is that conference-goers often get a sneak peek of results that are shortly going to be published. If too much of that news leaks out, the researchers may have more difficulty in getting it published at all. Nobody wants to publish old news. It's good for conference-goers to get some little teasers and bits of advance news, it makes the conference more attractive, and it's bad for all of us if the news leaks out. This is pretty much the norm in research rather than 'olde school' I think…I'd love to see a different model but until the entire research publishing system is dismantled, it's just the reality.

I wonder if they'd at least consider putting the conference up on Youtube as individual presentations when each presenter gives them the OK – or livestream the keynote speeches or something.

Nielk June 3, 2013 at 10:23 am

I thought that they will have cd's ready for purchase.

Esther12 June 3, 2013 at 10:27 am
Mark

This is the really sharp question for us I think. We're in a bind because we're all afraid to campaign for what we need most, fearing that "specialist treatment centres" will get translated into "more psychotherapy". The problem is how to campaign for the services we need without ending up producing more services that are harmful to ME patients. It's a real problem, but I think the answer lies in multi-disciplinary teams. That's what we need: teams of immunologists, neurologists, dieticians, specialists in sleep and exercise, and yes, the odd psychologist or psychotherapist as part of the mix, all in one centre so that patients can see the range of specialists they need for their own particular problems. One thought I have on this is that maybe such centres may be more achievable if we think about what other conditions need the same kind of range of specialists as us, and combine a couple of other conditions in what we're campaigning for. This kind of model does seem the obvious way forward in dealing with chronic illness though. And I do think, for sure, that if we're going to ask for something we need to be pretty specific in exactly what it is we want; a definite case of 'be careful what you ask for…'

Other than for research, I'm not sure that there's much value in having a specialist centre with immunologists, neurologists, dieticians, psychiatrists etc. Also, I don't think it's realistic to expect the NHS t pay for lots of centres with this range of experts, given how little value they are able to provide. If there were infinite resources for the NHS, and a good system of accountability to ensure that problems with how patients are treated will be identified and lead to disciplinary action, then that sort of set-up could be a good idea. In the current reality that we face with CFS in the NHS, I don't think it would be a good idea.

Gerada has actually been critical of proposals for a statutory Duty of Candour, and excitedly linked (all in CAPS) to a poor blog post which claimed to show that there were no excess death at Mid Staffordshire hospital. I do not think that we should be pushing for more 'care' from this organisation, given how poor the evidence is that there are effective treatments available for 'CFS'. Testing for alternative diagnoses could be handled by GPs, or specialist centres limited to this role.

If people want lifestyle/emotional/diet advice and help, I think it would be better if they were provided with money that would allow them to get this for themselves. Or pay for a friend/relative to help them out. Or just let them access research papers for themselves. The NHS does some things very well, and some things very poorly. CFS 'management' does not play to it's strengths, and this has led to quackery being inflicted upon patients. Until there is some accountability for this, I'd much rather starve the beast than pour more money in and hope it will work out better next time.

Valentijn June 3, 2013 at 10:30 am
Mark

The problem is how to campaign for the services we need without ending up producing more services that are harmful to ME patients. It's a real problem, but I think the answer lies in multi-disciplinary teams. That's what we need: teams of immunologists, neurologists, dieticians, specialists in sleep and exercise, and yes, the odd psychologist or psychotherapist as part of the mix, all in one centre so that patients can see the range of specialists they need for their own particular problems.

Even with these teams there's the risk that you end up with 4 or 5 different therapists working together to administer stealth-CBT/GET. It's the approach I experienced in Lelystad, and it sounds like some of the less hard-core BPS clinics in the UK do the same.

But even when the multidisciplinary team concept is abused in this manner, it's still probably a better result than what comes from the pure psych teams. They at least pretend to treat ME seriously, which does help with the public perception, and with a wider variety of backgrounds and knowledge there's a better chance of biological issues being taken seriously and addressed somewhat.

How about multidisciplinary teams AND a law firing all doctors and other therapists who substantially mislead patients regarding their beliefs and approaches to treating an illness? :D

SOC June 3, 2013 at 10:52 am
Valentijn

I agree … I just think some people are interpreting her presence to mean that she's on our side.

But practitioners who are strong or long-time believers in psychosomatic theories regarding medically unexplained symptoms have never shown any capability of changing their views that I've ever seen. So I wouldn't read much into her appearance there, and it sounds like she did her best to avoid being contaminated by opposing views with her early departure :alien:

There is still the issue of plausible deniability. ;) She now has less credibility when trying to argue that she didn't know about the clear immune abnormalities. She may argue that she doesn't believe the research, or interpret it as somehow psychologically based, but she can't argue she hasn't heard hard evidence. That's a start. :D

SOC June 3, 2013 at 11:10 am
alex3619

Hi Mark, each individual antibody from an immature B cell can be expected to bind only to one or two things, or none, or a few, but the low specificity means they can be our own proteins. However if many such antibody types are being made, then many may bind to a few targets. Many times a few is still many. So each will have some limited specificity, but if this is a generalized problem then there will be so many being made, with so many targets accordingly. Its an intriguing hypothesis, though it needs more evidence.

I have not read much on B cell maturation in a a long time, nor the current science on T cell involvement. It seems I might have some more reading to do … like I need more reading but this is welcome information. :)

Bye, Alex.

Any ideas how this would related to ANA (anti-nuclear antibody) titres? ANA tests are the go-to test for GPs (in the US anyway) to determine the existence of autoimmune disorders. I tried reading up on ANA and the tests, but my brain exploded. :alien:

I would guess that many low-avidity antibodies would show up in an ANA test as a high ANA titre. However, since most of us do not have high ANA titres, I'm guessing that's not true. Are ANA tests specific to certain autoantibodies, or are they supposed to pick up any autoantibodies? This immune stuff is going way, way over my head, I'm afraid. :ill:

Simon June 3, 2013 at 11:49 am

Fine, fine article Mark, clearly a labour of love and thanks for bringing back new from the frontline to all of us unable to make it.

Re embargo, on the Invest in ME website is the latest issue (Vol 7, no. 1) of their Journal with abstracts from the IiME 2013 Conference, including details of the new Rituximab maintenance study. Interestingly, some of this info was tweeted by Jorgen Jelstad, the Norwegian journalist who knows Fluge & Mella well, so I'm assuming he knew this was ok to tweet.

I'm not going to quote from the IiME journal here, in case it is sensitve (there is more than was tweeted), but here's the tweet:

Jørgen Jelstad@DeBortgjemte 31 May
#InvestME Mella presents data from maintenance study on 28 patients – all have been observed at least 28 months now.

#InvestME Definitely positive results from maintenance study on Rituximab. Details have to wait until publication of study.

alex3619 June 3, 2013 at 12:33 pm
SOC

Any ideas how this would related to ANA (anti-nuclear antibody) titres? ANA tests are the go-to test for GPs (in the US anyway) to determine the existence of autoimmune disorders. I tried reading up on ANA and the tests, but my brain exploded. :alien:

I would guess that many low-avidity antibodies would show up in an ANA test as a high ANA titre. However, since most of us do not have high ANA titres, I'm guessing that's not true. Are ANA tests specific to certain autoantibodies, or are they supposed to pick up any autoantibodies? This immune stuff is going way, way over my head, I'm afraid. :ill:

I would need to know the details of the tests to be sure. My guess though is that instead of picking up one anti-ANA antibody, they will pick up many and think its only one, because thats the presumption I think. The thing about this model of autoimmunity is what antibodies we have will be random … possibly explaining why we have the appearence of so many subgroups. However the Rituximab research (so far, I have not looked at what was said in this conference, I need the DVD or the publication) indicates that upwards of 70% might have this problem. We still don't know what is wrong with the other nearly 30%.

Bob June 3, 2013 at 12:50 pm

Action for ME mention the conference very briefly, and provide a link to Mark's conference summary:
http://www.actionforme.org.uk/get-informed/news/our-news/invest-in-me-conference-highlights

Mark June 3, 2013 at 1:07 pm
Firestormm

I agree with the frustration you express here Sasha. America is setting the bar high for us here in little olde UK to follow. I think though that IiME depend on this revenue stream – I might be wrong – but yes when you hear about things being 'embargoed' or said only to the audience and not expressed outside of the conference: it does rather add to the frustration when waiting for a DVD to be produced. Rather an olde school approach to modernity.

Dolphin made a point on Facebook that some of the Rituximab comments might have been restricted or something – in relation to Dr Weir's comments above. I don't believe they were – but clearly something was. Presumably when the DVD is published such comments will be more widely circulated – so I'm not sure how things can be embargoed?

Sorry if that doesn't make sense. I am rather shattered.

I didn't report a couple of the things Dr Weir mentioned because we were asked not to. All will be revealed when the DVD is published, which is normally after the embargoed material is published, which is why the DVD comes out a few months after the conference. There's a genuine risk that research may have a more difficult time finding a good publisher if everybody already knows what it says.

Mark June 3, 2013 at 1:14 pm
alex3619

One thing I was going to blog on but is now delayed for some months is gamma delta T cells. They are an innate form of T cell similar to a Treg, and it was again the WPI who got me to looking at them by a comment that we appear to have too many with signs of polyclonal expansion. This ties into other work by Maes on LPS, which is why I was going to blog on it. Now perhaps I need to expand my parameters. I am not an immunologist, there is so much I do not know.

Essentially what I was working on was alternate enteroviral life cycles and gut function. It now appears they increase translocation of gut bacterial products to the blood stream. In various paths that might or might not be relevant this can be shown to induce some of our problems … if the path is significant. There are multiple ways to get to many things in the way the body works.

In case anybody is not aware, lipopolysaccharide or LPS is a family of bacterial product, part of the bacteria's outer defence, and it can massively induce an immune response … a generalized immune response. Its called a superantigen. Some gamma delta T cells are hard wired to detect LPS in the blood, and it sends them nuts so they alert the rest of the immune system.

Staines mentioned gamma/delta T, I think he said they straddle the adaptive and innate immune systems, and I think he said they have found an 'observation' there but not statistically significant.

Mark June 3, 2013 at 1:22 pm
SOC

Any ideas how this would related to ANA (anti-nuclear antibody) titres? ANA tests are the go-to test for GPs (in the US anyway) to determine the existence of autoimmune disorders. I tried reading up on ANA and the tests, but my brain exploded. :alien:

I would guess that many low-avidity antibodies would show up in an ANA test as a high ANA titre. However, since most of us do not have high ANA titres, I'm guessing that's not true. Are ANA tests specific to certain autoantibodies, or are they supposed to pick up any autoantibodies? This immune stuff is going way, way over my head, I'm afraid. :ill:

All I know on this is that Bansal noted that all the standard immune tests come back negative; I got down some of the ones he mentioned and I have one as 'ANCA' but maybe that should have been ANA. Anyway, from what he said I would assume that they come back negative (that's why he described this kind of autoimmunity as 'subtle'), but I don't know if there might be potential for more specific autoantibody tests once you know what you're looking for. Assuming that's feasible, I would think that sounds like a good candidate for a future definitive blood test for ME, assuming also that this autoimmune theory is correct of course.

Mark June 3, 2013 at 2:54 pm
Simon

Fine, fine article Mark, clearly a labour of love and thanks for bringing back new from the frontline to all of us unable to make it.

Re embargo, on the Invest in ME website is the latest issue (Vol 7, no. 1) of their Journal with abstracts from the IiME 2013 Conference, including details of the new Rituximab maintenance study. Interestingly, some of this info was tweeted by Jorgen Jelstad, the Norwegian journalist who knows Fluge & Mella well, so I'm assuming he knew this was ok to tweet.

Thanks Simon, and thanks for all your help with it.

I'm checking on the situation with the embargo, but I'm sure it's fine, I'll let you all know here when I have confirmation this is OK.

Mark June 3, 2013 at 3:15 pm
alex3619

I would need to know the details of the tests to be sure. My guess though is that instead of picking up one anti-ANA antibody, they will pick up many and think its only one, because thats the presumption I think. The thing about this model of autoimmunity is what antibodies we have will be random … possibly explaining why we have the appearence of so many subgroups. However the Rituximab research (so far, I have not looked at what was said in this conference, I need the DVD or the publication) indicates that upwards of 70% might have this problem. We still don't know what is wrong with the other nearly 30%.

Actually, I get the impression that they think that (many or all of) the non-responders do also have this b-cell problem but maybe worse or more ingrained than the ones that respond. From Bansal's comment about the importance of early diagnosis, I think that may be a factor. Also the details of co-infections or triggers may define subgroups in terms of the response patterns, particularly re: who responds and who doesn't; hence the idea now of treating with appropriate type of antivirals as well at the same time – that issue may be significant for those who respond but then relapse. There's clearly a lot more science to be done to work all that out.

snowathlete June 3, 2013 at 4:49 pm
alex3619

It came up somwehere in all that discussion of XMRV, particularly when they were looking at immune markers. I don't know that it was ever published in a paper, and I dimly recall it might have been Mikovits who discussed it during a presentation. At the time they did not know what it might mean, it was only an observation. Now we realize it may be the smoke from the crime, and pointing us toward the gun.

We could probably find out by contacting Mikovits or the WPI.

I believe that came from the Spanish HIV doctors that we recently published an ariticle about – Mikovits went over and showed them some stuff and got them involved. They took an initial look and found irregular B-cells, but in their recent paper they mentioned that their initial observation didnt show itself in their larger study, though they pointed out some reasons why that may be the case, and clearly havent shut the book on there being B-cell abnormalities.

Valentijn June 3, 2013 at 9:54 pm
Mark

All I know on this is that Bansal noted that all the standard immune tests come back negative; I got down some of the ones he mentioned and I have one as 'ANCA' but maybe that should have been ANA.

It could very well be ANCA – it is an autoantibody and at least one specialist tests for it routinely.

Bob June 4, 2013 at 3:40 am

Invest in ME website, Conference Report by Dr Ros Vallings:
http://www.investinme.org/IiME Conference 2013/IIMEC8 Conference Report.htm

alex3619 June 4, 2013 at 7:39 am

The thing about antibody producing B cells is that they can replicate. A long term patient may have many more problem causing B cells, a higher percentage. This is all still hypothetical though, my mantra as always is we need more research.

jimells June 4, 2013 at 11:29 am

Hi Mark, another great article for our front page.

"Dr Donald Staines … still finding “sustained, demonstrable, significant impairment in NK cell function”, "highly confident" of up-regulation of T-reg cells; "clear derangement in the immune system…it's irrefutable", and “anyone who suggests that this might be fixed by exercise therapy should probably be de-registered I think”.

I love this quote. I'm going to send this to a rheumatologist who wrote in his report that "chronic fatigue" is a psychological condition. When the FDA finally approves a treatment, will doctors like this be open to malpractice lawsuits?

Bob June 4, 2013 at 4:40 pm

Well, I've just read it, and goodness knows how you managed that amazing feat, Mark! The mind boggles!
It took me three days just to read it!
Thanks very much Mark. It's a really helpful and fascinating record of events.

There really is so much meaningful research being carried out at the moment. The research field has totally transformed over the past 10 years.
I got ill about 9 years ago, just before IiME started holding their conferences, and I think I've seen every conference (on DVD) that they've held.
In the early days of my illness, they were the best/only source of information for me with regards to ME, as I knew absolutely nothing about ME, and I hadn't discovered any internet forums.

The conferences have always been excellent, but there really didn't seem to be a great deal of research being carried out when the early conferences were held.
Now the conference is packed with dynamic scientists carrying out enormous cutting-edge research trials, looking deep into the complex workings of the body at a cellular level, using technology that's never been available before.
Things have transformed, and it seems to be accelerating.

A few years ago, who'd have thought that a scientist with the status of Lipkin would be looking at Dr Peterson's patients' spinal fluid and hinting that they "think they may have found a 'potential novel candidate' in the spinal fluid…"

SpecialK82 June 4, 2013 at 5:18 pm

Absolutely amazing article Mark! :thumbsup: I have to take a break before I can read the rest and make sense of all of it. I'm so appreciative of your efforts and of course all the researchers and doctors who took part.

Michelle June 5, 2013 at 2:16 am

Quick comment regarding WPI/Mikovits and PWME having lots of immature B-cells. At last year's press conference for the negative XMRV study, Dr. Lipkin mentioned that when he was working on the Borna virus-CFS paper in 1999*, he noticed "there was an enormous amount of immuno-reactivity that appeared to be non-specific in these individuals. So at a time when people were saying this was a psychosomatic disorder I said '2/3-3/4 of individuals whom we've studied have polyclonal B-cell activation. They are sick.'" Clearly people have been noticing B-cell issues in ME/CFS for awhile now.

That said, when I read Mark's review of Dr Bansal's presentation, it was the one report that made me "ohhhh" out loud, mostly because it was the most original (imho). And then I got goosebumps when IiME referred to the "magnitude" of Fluge/Mella's newest findings. Thanks for the hard work, Mark!

*Absence of evidence of Borna disease virus infection in Swedish patients with Chronic Fatigue Syndrome. Evengård B, Briese T, Lindh G, Lee S, Lipkin WI. J Neurovirol. 1999 Oct;5(5):495-9.

(Also interesting to note that Brigitta Evengard worked with him on the 1999 paper and a 1997 Borna virus paper.)

Michelle June 5, 2013 at 1:40 pm

While feeling my patella pop back into its groove this morning while turning over in bed, I remembered a little nitpick with regards to EDS. It is not an immune or autoimmune disease. It is an inherited (or in my case a de novo mutation) genetic disorder in which the body is not producing enough collagen for certain types of tissue, depending on the form of it that one has. I do, however, agree with Dr. Bansal regarding why those with EDS might have such a high prevalence of ME/CFS: stress resulting from constant trauma in which the immune system is being called upon to repair injured tissue over and over again. Moreover, fatigue is inevitable as, say, muscles are tasked with, above and beyond their own job, compensating for ligaments and tendons that cannot do their job very well. For those with Type 3 Hypermobility form, developing Fibromyalgia is almost a given as the brain becomes more and more "efficient" at reading pain signals from all of these injuries. A model of ME/CFS in which the immune system becomes dysfunctional as a result of it being stressed is eminently compatible with the orthopedic, dermatological, and gastroenterological traumas that occur in EDS.

Bob June 6, 2013 at 6:48 am

I'm not sure if this has been posted yet. It's a conference summary by CFS Patient Advocate:
http://cfspatientadvocate.blogspot.ie/2013/06/invest-in-me-conference-2013.html

Snow Leopard June 8, 2013 at 4:24 am

Thanks for the summary.

"Hooper accepts with his shortest ever speech." Nice one!

Snow Leopard June 8, 2013 at 4:26 am
jimells

Hi Mark, another great article for our front page.

"Dr Donald Staines … still finding “sustained, demonstrable, significant impairment in NK cell function”, "highly confident" of up-regulation of T-reg cells; "clear derangement in the immune system…it's irrefutable", and “anyone who suggests that this might be fixed by exercise therapy should probably be de-registered I think”.

I love this quote. I'm going to send this to a rheumatologist who wrote in his report that "chronic fatigue" is a psychological condition. When the FDA finally approves a treatment, will doctors like this be open to malpractice lawsuits?

I doubt much will go through, because it is judged on the 'art' at the time, but if the medical practitioner treated you badly for other reasons as well, then you might still have a case.

Bob June 8, 2013 at 4:49 am

Latest blog by CFS Patient Advocate
Friday, June 7, 2013
Text of Linda Tannenbaum's Pre Conference Dinner Speech for Invest In ME Conference
http://cfspatientadvocate.blogspot.co.uk/2013/06/text-of-linda-tannenbaums-pre.html

(It's very inspiring, and worth reading. It's mainly about the OMI-MERIT initiative.)

————————————————————————————————————

From this article, I've finally found out what "OMI-MERIT" means!
> The Open Medicine Institute-Myalgic Encephalomyelitis Roundtable in Immunology and Treatment.

The OMI-MERIT flyer in the IiME journal is on page 35:
http://investinme.org/Documents/Journals/Journal of IiME Vol 7 Issue 1.pdf

Pre-register for OpenMedNet, here:
https://www.openmednet.org/registration/MECFS

Sign up to the Open Medicine Foundation newsletter, here:
https://app.etapestry.com/onlineforms/OMF/contact1.html

See the full list of OMI-MERIT research proposals, here:
http://openmedicineinstitute.org/research-initiatives/mecfs-merit/

Firestormm June 24, 2013 at 11:37 pm

5.4 Janice Kent reported on a presentation given by Dr Amolak Bansal at reMEmember’s ME Awareness Week Conference. He looked carefully at the work done on Rituximab and had found that only those who had received chemotherapy had suffered ill effects. He would be publishing a paper on this subject in September. It was agreed that Forward-ME should invite Dr Bansal to speak to them after the paper had been published.

Forward ME Meeting 14 May 2013

Not sure if this date and info. had come out of the conference discussion previously on this thread :)

Bob June 25, 2013 at 5:14 am

5.4 Janice Kent reported on a presentation given by Dr Amolak Bansal at reMEmember’s ME Awareness Week Conference. He looked carefully at the work done on Rituximab and had found that only those who had received chemotherapy had suffered ill effects.

Ah, that's important information. I'd read a suggestion that serious ill-effects might only be experienced by cancer patients, but I hadn't seen this specific info before. Thanku Firestormm.

Sasha July 20, 2013 at 4:49 am

They're shipping the conference DVD next week – presumably that means all the embargos are off:

https://www.facebook.com/events/215349901946162/permalink/222238914590594/

Looking forward to getting my copy!

Sasha July 20, 2013 at 4:53 am

Oh! I should read stuff before I post it:

Unfortunately we have had a request from Dr Øystein Fluge and Professor Olav Mella to hold off from including Dr Fluge's presentation in the DVD at this time.

This is because the Norwegian researchers have still not finalised their hypotheses for symptom maintenance in ME and do not feel comfortable with having this material distributed at this time. We are therefore bound to honour our agreement with Professor Mella and Dr Fluge.

However, the DVD still holds a great deal of education. It was the best conference yet.

We will retain the presentation from Dr Fluge and hope to come to an agreement on when it can be released at some point in the future.

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