Two days in Newcastle | reflections on ways forward for global ME/CFS research| 22 October 2015


Dr Charles Shepherd reports and reflects on the second UK CFS/ME Research Collaborative conference held in Newcastle on 13 and 14 October, 2015.


Following on from our conference at Bristol University in 2014, Professor Julia Newton and the multidisciplinary research group at Newcastle University hosted this year’s event.

Once again, the conference attracted a large number of researchers from here and abroad, clinicians, medical students – four of whom were funded by the MEA – and charity representatives. The presentations, workshops and discussions concentrated on neuropathology, autonomic nervous system dysfunction, clinical trials, including Rituximab, patient-reported outcomes and sleep.

Especially encouraging was the high standard of research being presented, as well as the way in which we are moving forward with a biomedical model of causation that involves infection, immune system dysfunction – including cytokine involvement, and resulting in low-level neuroinflammation. This type of neuroimmune model of causation could explain some of the key symptoms in ME/CFS and in turn lead to effective forms of treatment.

Please note that several of the presentations contain pre-publication research findings – so it is not possible to report on them in any detail at this stage.


TUESDAY MORNING: Conference Opening and Plenary Session on Neuropathology


header-stephen-holgate-1170x410

Professor Stephen Holgate, Southampton University (pictured), opened the conference with some encouraging news about the Wellcome Trust (a major funder of medical research) and Arthritis Research UK (another research funder that is interested in some of the overlaps between inflammatory arthritis and ME/CFS) joining the collaborative and making a substantial financial contribution.

Professor Holgate referred to some of the key conclusions and recommendations relating to nomenclature, definition, and the need to make ME/CFS an inclusive diagnosis that were contained in the Institute of Medicine (IoM) report. He also welcomed the sometimes critical but constructive analysis of ME/CFS research strategy that was contained in the National Institutes of Health Pathways to Prevention report.

Taking this forward in the form of a ‘Grand Challenge’, Professor Holgate set out a number of research priorities which all key stakeholders involved in ME/CFS research must now address:

• Agreeing on a case definition for ME/CFS

• Subgrouping (phenotyping in medical jargon) people who come under the ME/CFS umbrella in order to develop what is now referred to as personalized medicine. Professor Holgate compared the situation in ME/CFS to asthma, which used to be regarded as one homogenous disease with one basic cause and treatment. Asthma is now recognized to be a very heterogeneous condition that involves at least six different molecular and cellular pathways, with differing phenotypes responding (or not responding) to different forms of treatment (mast cell stabilization for example).

• Collecting and banking biological samples – blood, post-mortem tissue etc

• Identifying preventable and therapeutic targets for each subgroup

José Montoya

Professor Jose Montoya, Stanford University, USA, opened the first plenary session on neuropathology with an outstanding presentation that commenced with a one-minute silent tribute to his close colleague and friend Dr Martin Lerner, who had recently died. Martin Lerner had worked with Professor Montoya on a number of research studies, including the use of antiviral treatment.

Professor Montoya also referred positively to the impact of the Institute of Medicine (IoM) report and is a supporter of the new IoM diagnostic definition for ME/CFS (or systemic exertion intolerance disease/SEID as is being recommended in the report) because he believes that clinicians need a simple and accurate way of making a diagnosis. He believes that the new IoM definition, which emphasises post-exertional malaise and orthostatic intolerance, is preferable to the options – eg Canadian, Fukuda – that are currently available. Work from the Stanford group indicates that there is a strong (90%) concordance between Canadian, Fukuda and IoM definitions.

He then said that people with ME/CFS had been ignored and humiliated by the very people who were supposed to be helping them – the medical profession. In his own words….“I have a wish and a dream that medical and scientific research societies in the US apologise to their ME/CFS patients”.

Turning to treatment, Professor Montoya described how the publication of a flawed clinical trial involving acyclovir back in 1988 had led to the view that ME/CFS was not caused by EBV infection and that antiviral drugs do not have any role in the treatment of ME/CFS. Despite this, he has been involved in a number of the clinical trials that have assessed the efficacy and safety of the antiviral drug valganciclovir. This is a treatment option – involving a lower dose than is normally used in other situations and over a prolonged period of time, at least 6 months, possibly much longer – that he now uses for some ME/CFS patients with considerable success. In addition to antiviral activity and reduction of latent HHV-6 replication, he believes that this drug may have immunomodulatory effects in ME/CFS as well (as it can decrease the level of white blood cells called monocytes and reduce microglia activation in mice).

[CS note: During the discussion that followed I pointed out that here in the UK antiviral treatment is not recommended by NICE – so antiviral drugs are seldom used in ME/CFS and very little interest has been shown in further research or clinical trials involving antiviral treatment. The ME Assoxciation has met with Roche, the pharmaceutical company that makes this drug, but we did not have any success in trying to set up a UK clinical trial. We clearly need an independent randomiaed placebo-controlled trial to assess the value of valganciclovir in ME/CFS.]

Professor Montoya then described some of the other research that his multidisciplinary group at Stanford are carrying out on a large group of ME/CFS patients, along with healthy controls, with the help of a $5 million anonymous donation. In particular:

• Immune function studies that are looking at the response to infection with various organisms. In particular, the role of immune system chemicals called cytokines, how the cytokine pattern changes over time (less or more than 3 years – the Hornig/Lipkin study), as well as daily fluctuations in cytokines relating to activity levels. To do so they can measure over 50 individual cytokines and have access to a cohort of around 200 ME/CFS patients and 400 controls. Proposed research at Stanford will also involve a detailed study of the role of NK cell status and function in ME/CFS.

• Virology studies examining the role of latent herpes viruses including EBV and HHV-6 and how low NK function may be maintaining HHV-6 activation in ME/CFS. Professor Montoya also referred to research involving Torque viruses. CS note: Torque teno virus is considered to be a relatively new global marker of immune function and the more immunosuppression occurs, the higher the level of torque viruses. Professor Montoya pointed out that torque viruses have been found to be lower in ME/CFS – adding further support to the role of immune system activation in ME/CFS.

• Neuroimaging studies looking at both grey and white matter in the brain – one of which has used diffusion tensor imaging, an MRI based technique that can visualize location, orientation and anisotropy of white matter tracts in the brain. This study has recently been published and described a very significant structural abnormality involving the right arcuate fasciculus. This structure contains fibres which connect different areas of the brain. The fibres are thicker in ME/CFS than in healthy controls and the inference is that nerve fibre transmission is therefore affected. The abnormality could turn out to be a diagnostic marker for ME/CFS.

• Genetic studies examining HLA characteristics in ME/CFS and a genetic predisposition to ME/CFS

Key references:

Immunology: cytokine status and illness duration www.ncbi.nlm.nih.gov/pubmed/26079000

Neuroimaging: right arcuate fasciculus abnormality http://pubs.rsna.org/doi/abs/10.1148/radiol.14141079

Valganciclovir clinical trials:

Kogelnick 2006:
www.ncbi.nlm.nih.gov/pubmed/17276366

Lerner et al, 2002:
www.ncbi.nlm.nih.gov/pubmed/12582420

Lerner et al: 2004:
www.ncbi.nlm.nih.gov/pubmed/12582420

Montoya et al 2013:
www.ncbi.nlm.nih.gov/pubmed/23959519

In this trial Montoya et al randomized (2:1) 30 ME/CFS patients with elevated IgG antibody titres against HHV-6 and EBV to receive valganciclovir (VGCV) or placebo for 6 months in a double-blind, placebo-controlled trial. Statistically significant differences between groups were observed in mental fatigue sub-scores and cognitive function. The VGCV patients experienced improvements within the first three months and maintained that benefit for the remaining 9 months. In the VGCV arm monocyte counts decreased, neutrophil counts increased, and cytokines were more likely to evolve towards a Th-1 profile.]

Watt et al, 2012
www.ncbi.nlm.nih.gov/pubmed/23080504

Valganciclovir reduces inflammation in HIV:http://hivandhepatitis.com/recent/2011/0426_2011_c.html

All patients treated with valganciclovir had undetectable CMV viral load after 8 weeks of treatment, while 44% of those in the placebo group still had detectable CMV. In addition, valganciclovir-treated participants had significantly greater reductions in CD8 T-cell activation (defined as CD38+HLA-DR+ marker profile) compared with placebo recipients at weeks 8 and 12 — a reduction of about 20%. Patients in the valganciclovir arm also had reduced levels of high-sensitivity C-reactive protein (CRP), a blood biomarker of inflammation.]

Virology: Torque viruses: http://jid.oxfordjournals.org/content/early/2014/05/05/infdis.jiu210.full<

YouTube video of opening remarks from Professor Stephen Holgate and presentation from Professor Jose Montoya:

www.youtube.com/watch?v=69Jz43kSQX0

Whitney General, Bristol University, described some of the sometimes conflicting neuroimaging findings relating to grey and white matter volumes in the brain in ME/CFS. She reported on a new magnetic resonance imaging (MRI) study that has assessed grey matter volume in the brain in ME/CFS patients and healthy controls (grey matter is the part of the brain that processes information) and whether abnormalities in specific regions of the brain could be linked to symptoms, including cognitive dysfunction. She pointed out that in order to increase our knowledge from this type of investigation, we need much larger sample sizes, longitudinal studies, and the use of structural MRI studies alongside functional ones.

Andreas Finkelmeyer, Newcastle University, reported on another neuroimaging study which is reassessing the significance of a previously reported finding involving what are called white matter hyperintensities in the brain in ME/CFS.

Over lunch we had an opportunity to visit the wide ranging exhibition of poster research, including one from by Erinna Bowman from the ME/CFS Biobank.

This described the work of the ME/CFS Biobank – which is now being solely funded by the MEA Ramsay Research Fund – and what has been achieved so far in relation to blood sample collection.

The ME/CFS biobank now has over 25,000 samples/aliquots from over 500 participants. The three groups comprise of:

(a) people with ME/CFS (diagnosed by a physician and compliant with Fukuda and Canadian criteria and compliance available for four other criteria) including a cohort with severe ME/CFS and samples that are being collected longitudinally at 6 monthly intervals

(b) healthy controls

(c) a further cohort of people with multiple sclerosis.

The blood samples comprise of whole blood; serum, plasma, red blood cells, peripheral blood mononuclear cells (PBMCs), blood for RNA extraction.

Associated data available includes

(a) baseline standard laboratory tests to exclude other causes of fatigue

(b) detailed clinical data and symptom assessment

(c) demographic information

(e) standardised instruments of fatigue severity and functional impairment

The ME/CFS Biobank aims to open for the supply of samples to research groups in early 2016. Fees, which are currently being calculated, will be based on cost recovery only.

Researchers who wish to register an interest in sample supply should do so via: mecfsbiobank@LSHTM.ac.uk

ME/CFS Biobank website:
www.lshtm.ac.uk/itd/crd/research/cure-me/ukmecfsbiobank/


TUESDAY AFTERNOON: Research Workshops


Repeating the very successful format of the 2015 conference, delegates and speakers spent the afternoon by splitting into small groups that attended expert-led workshops. The workshops covered autonomic dysfunction (Dr James Frith, Newcastle University), clinical trials (Dr Esther Crawley, Bristol University), fatigue (Professor Julia Newton, Newcastle University), neuropathology (Richard Reynolds, Professor of Cellular Neuroscience, Imperial College, London), patient-reported outcome measures (Dr Kirstie Haywood, Warwick University).

Along with Professor Montoya, Professor Norman Booth, experts in neurology, neuropathology and neuroimaging, and two of the medical students the MEA sponsored to attend the conference, I attended a two hour neuropathology workshop.

Topics discussed included linking neuropathology to symptoms; the findings of dorsal root ganglionitis that have been reported from the UK post mortem research group; brain banking; lumbar punctures; are abnormalities in the brain focal or general?; and where do we go next in relation to investigating the neuropathology of ME/CFS with neuroimaging etc.

This group also briefly discussed the role of cytokine-mediated neuroinflammation and the new clinical trial involving a drug called anakinra that inhibits the pro-inflammatory cytokine IL-1. A member of the clinical trials group from The Netherlands had also joined this workshop.

Key reference:

Cytokine inhibition in ME/CFS – new clinical trial: www.ncbi.nlm.nih.gov/pubmed/26438161


TUESDAY AFTERNOON/EVENING


The final session started with a lecture from Professor Liz Perkins, Liverpool University, on Health and Social Policy Research and ME/CFS

New research funding announcement from the MRC

This was followed by an important research funding announcement from the Medical Research Council relating to a new functional neuroimaging study (fMRI) study that should help to increase our understanding of what causes the most important clinical and diagnosis feature of ME/CFS: post-exertional malaise (PEM).

Post-exertional malaise (PEM), or post-exertional symptom exacerbation, describes a delayed and significant exacerbation of ME/CFS symptoms that always follows physical activity and often follows cognitive activity. PEM is a highly characteristic clinical and diagnostic feature of ME/CFS. And in some respects, PEM is an illness within an illness

The cause of PEM remains uncertain. However, clues are starting to emerge. So gaining a better understanding of the underlying pathophysiological mechanisms involved could help to improve at least one aspect of ME/CFS management

Researchers involved in this study include Dr Mark Edwards, a neurologist from University College London, Dr Neil Harrison, from the University of Sussex and who reported on cytokine-mediated neuroinflammation at the 2014 conference and Dr James Kilner (Institute of Neurology, Imperial College, London). Dr Edwards outlined the background and key points to this research:

On the first day, 20 people with Canadian criteria defined ME/CFS and 20 aged and sex matched controls will have a baseline fMRI scan and blood samples taken. They will then have an exercise challenge to induce PEM.

On the second day, the fMRI scans and blood tests will be repeated.

More details on this study can be found on the MEA website coverage of the conference:
www.meassociation.org.uk/2015/10/post-exertional-malaise-in-mecfs-medical-research-council-announces-new-neuroimaging-research-16-october-2015/

Reference: Experimental research from Neil Harrison et al on the role of inflammatory cytokines and sickness behavior:

www.ncbi.nlm.nih.gov/pmc/articles/PMC2885492/

We than had an update from all the UK research groups who have received MRC funding as a result of the recommendations produced by the MRC Expert Group on ME/CFS research:

• Epidemiology of fatigue in children: Prevalence at different ages; sex ratios; what happens over the course of time; schooling; prognosis etc – Dr Esther Crawley, Bristol University

• Identifying biological fingerprints of fatigue, the study that also involves blood samples from people with Sjogren’s syndrome – Dr Fai Ng, Newcastle University

• Persistent fatigue induced by interferon alpha: an immunological model for ME/CFS – Dr Alice Russell (standing in for Professor Carmine Pariante), Kings College Hospital, London

• Determination of mitochondrial function and cytokine production in patients with ME/CFS – Professor Anne McArdle, Liverpool University who was unfortunately unable to attend. This study is almost finished and has been co-funded by the MEA RRF. Report on preliminary findings: www.meassociation.org.uk/2015/04/mitochondrial-dysfunction-and-the-role-of-cytokines-in-mecfs-preliminary-results-from-research-being-funded-by-the-mea-ramsay-research-fund-and-the-medical-research-council-2-april-2015/

• Pathogenesis of autonomic dysfunction in ME/CFS and its relationship to cognitive impairment – Professor Julia Newton, Newcastle University

Tuesday evening closed with a drinks reception where it was good to catch up with former MEA medical adviser Dr Anne Macintyre and research colleagues I hadn’t seen for some time.


WEDNESDAY MORNING: Second Plenary Session on autonomic nervous system


Professor jo Nijs

Wednesday morning opened with another excellent keynote presentation from Professor Jo Nijs, Vrije Universiteit, Brussels, who has been carrying out an MEA funded study into the pathophysiology of post-exertional malaise in ME/CFS and the role of the autonomic nervous system (ANS).

Professor Nijs explained how current knowledge indicates that post-exertional malaise involves a complex interaction involving immune system responses to activity (as exercise causes a low grade inflammatory response and the production of certain cytokines: I-L1, I-L6 and TNF-alpha) and ANS dysfunction (with new information on the role of the parasympathetic response to exercise due to be reported) contribute to this unique clinical feature of ME/CFS.

Professor Julia Newton

Professor Julia Newton, Newcastle University, spoke about current findings from two new ANS function studies.

The first is looking at heart size in ME/CFS (do people with ME/CFS have smaller volume hearts?) as well as plasma volume and red cell mass (as there is some evidence to indicate that people with ME/CFS have low plasma volumes and that intravenous saline infusions can be of benefit in some cases), whether there are any other cardiac abnormalities in ME/CFS, and whether any of these abnormalities are being caused by deconditioning (probably not as there does not appear to be any relationship to length of disease).

The second study involves the use of a complex investigative technique called cardiac iodine 123 meta iodo benzylguanidine (MIBG) uptake to investigate the role of the sympathetic nervous system in ME/CFS and whether this is linked to fatigue.

Both of these studies could have implications for management and during the discussion that followed the importance of maintaining a good fluid intake was emphasised, especially in people who have evidence of autonomic dysfunction. The discussion also covered a controversial approach, which is more popular in the USA, of treating people with saline infusions (to increase plasma volume) and the use of a drug called EPO, which increases red cell mass.

The second Plenary Session on Wednesday covered clinical trials

Oystein Fluge

Dr Øystein Fluge, University of Bergen, Norway gave a very thorough presentation covering the history of Rituximab in ME/CFS starting from how his group were first alerted to the possibility that this could be an effective form of treatment for at least a sub-group of people with ME/CFS back in 2004 right up to the completed and published phase 2 trial, and the phase 3 multicentre clinical trial (150 patients across 5 centres) that is now fully recruited and underway.

As previously reported, Rituximab appears to be a safe form of treatment in ME/CFS – the side-effects reported so far being upper airways infections, late-onset neutropenia, allergic reactions, and in some cases a worsening of ME/CFS symptoms.

Dr Fluge also spoke about the other clinical trial they are carrying out involving the immunosuppressive drug cyclophosphamide and some of the research they are doing looking at endothelial dysfunction in blood vessels in ME/CFS (endothelium is part of the blood vessel wall).

One of the poster presentations from Jopson et al at the University of Newcastle described the clinical trial of Rituximab in primary biliary cirrhosis – which also causes debilitating fatigue – that they are undertaking.

Key references:

Phase 3 clinical trial of Rituximab in ME/CFS: https://clinicaltrials.gov/ct2/show/NCT02229942

Autoimmunity in relation to Rituximab response: www.meassociation.org.uk/2015/09/new-study-sheds-more-light-on-why-some-people-with-mecfs-may-respond-to-rituximab-26-september-2015/<

Clinical trial of Rituximab in primary biliary cirrhosis: https://clinicaltrials.gov/ct2/show/NCT02376335

Dr Caroline Strachan, Leeds Partnership NHS Trust, described research that is looking at mechanisms involved in the production of fatigue that is seen in cancer patients during and after treatment with surgery, chemotherapy and radiotherapy. Cancer fatigue can persist long after treatment is completed and there may be common causative factors, especially involving pro-inflammatory immune system responses to those found in ME/CFS fatigue. This research includes looking at immune system function, B cell status in particular, in a group of patients with ME/CFS – B cells are a key part of the immune system that are destroyed by the drug Rituximab. To gain a better understanding of how B cells might produce fatigue in ME/CFS, they are currently assessing the production of B cell cytokines following in-vitro stimulation.

More information on the study into immune function and fatigue in people with ME/CFS and cancer that is taking place in Leeds can be found here:

www.leedsandyorkpft.nhs.uk/news/archive_news/1/688

Dr Simon Collin

Dr Simon Collin, Bristol University, reported on a new epidemiological study – The Collaborative on Fatigue Following Infection – he is helping to set up that will investigate fatigue following infection. This is a very large collaborative study involving 10 cohorts of patients collected from America (including the Katz/Jason study of glandular fever in college students), Australia (the impressive Dubbo cohort from Professor Andrew Lloyd), New Zealand, and Norway.


TUESDAY AFTERNOON: Fourth Plenary session on Sleep


Professor Jim Horne

Professor Jim Horne, Loughborough University, concentrated on the importance of sleep for the brain and what we know (and don’t know) about various components of normal sleep, ways of assessing sleep – eg Epworth Sleep Score and the Pittsburg Sleep Quality Index, and the management of sleep disturbance.

Professor Horne considered the various sleep problems that can occur – insomnia, sleep apnoea, hypopnea (shallow breathing and decreased oxygenation of the blood), restless legs syndrome and ‘worn out syndrome’ – when normal sleep and circadian (body clock) rhythms malfunction.

In purely practical terms, Professor Horne advised that regular short daytime naps can be helpful – but keep them short. Irregular periods of longer daytime napping/sleeping are often unhelpful. Melatonin might be worth trying in some cases but it should be noted that this drug works by synchronizing the body clock. It is not a hypnotic drug in the sense that it is sleep-producing.

Professor Horne finished his presentation by looking at some of the research findings relating to sleep disturbance in ME/CFS, which have produced conflicting results. He also referred to the recent work on sleep disturbance in ME/CFS that has been carried out by Dr Zoe Gotts et al at the University of Northumbria with funding from the MEA Ramsay Research Fund.

References:

Research on sleep specific phenotypes in ME/CFS – Gotts et al: >www.ncbi.nlm.nih.gov/pubmed/23794547

Pittsburg Sleep Quality Index: http://consultgerirn.org/uploads/File/trythis/try_this_6_1.pdf

Rebecca Lambson, University of Newcastle, spoke about her research into the incidence and impact of fatigue in people with Sjögren’s Syndrome (SS) – an autoimmune condition that can cause debilitating fatigue and which has a number of common features (including the presence of dorsal root ganglionitis) with ME/CFS. Around 55% of people with SS have significant fatigue once identifiable causes of fatigue (eg anaemia, low thyroid function) have been excluded.

Eva Stormorken, Oslo University, spoke about her research involving people who had developed an ME/CFS like illness following an outbreak of giardia infection from contaminated water in Bergen in 2004.


ANNE FAULKNER MEMORIAL LECTURE


ALSPAC @ 21st Conference

ALSPAC @ 21st Conference

The final presentation came from Professor George Davey Smith, an epidemiologist at Bristol University, who spoke about the increasing use of what is called ‘big data’ in researching conditions like ME/CFS and how research using small numbers of patients can easily produce statistically flawed data, inaccurate conclusions, and even false positive findings.

Professor Davey Smith covered the way in which new and emerging ways of investigating disease – including genomics, immunologics, microbiomics (the human biome), proteomics and metabolomics (the study of small metabolic molecules) – are likely to play an increasing role in the investigation of diseases like ME/CFS.

Professor Stephen Holgate closed what had been a successful, stimulating and highly enjoyable meeting.

Taking forward his plan for a Grand Challenge, and incorporating some of the key points made by Professor Davey Smith about the need to collect ‘big data’ from large cohorts of patients, this will analyse and stratify information on gene expression, immunology, proteins etc in ME/CFS into clinical and pathological subgroups. The Grand Challenge will bring together key stakeholders (researchers, funders, charities) in a meeting that the collaborative aims to hold early in 2016.

The next Research Collaborative conference is provisionally due to take place in Southampton on 12 and 13 October 2016.


Dr Charles Shepherd represents The ME Association on the Board of the UK CFS/ME Research Collaborative.


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