Research: State of the Art Professor Derek Pheby Slide 2 Where
are we starting from? (1) What we know: ME is a syndrome (defined
by its symptoms, not underlying pathology) Characterised by
multi-system dysfunction Varies in severity and duration Acute or
insidious onset Range of trigger factors, frequently viral Most
common in women, particularly young adults (though occurs at all
ages) Slide 3 Where are we starting from? (2) What we dont know
Underlying pathology one disease or several? How to treat it Slide
4 Where are we starting from? (3) Common myths: It doesnt exist! If
it does exist, its a psychological condition NICE has had the last
word on the subject Graded exercise and cognitive behaviour therapy
are effective treatments Slide 5 The Pathophysiology of ME Cause or
Effect? Hypothalamic-pituitary dysfunction Neuromuscular
abnormalities Abnormal serum cortisol Abnormal patterns of cytokine
expression Abnormal patterns of gene expression Mitochondrial
dysfunction Oxidative stress Slide 6 Research Activity (1)
Published scientific papers: US 50% UK 30% Rest of world 20% - but
it doesnt really amount to a coherent corpus of scientific
knowledge Slide 7 Research Activity (2) Why has all this work not
advanced knowledge further? Vicissitudes of funding No coherent
strategy No supportive infrastructure Slide 8 The Observatory
project (1) Funded for three years by the Big Lottery Fund
Sponsored by Action for ME Academic collaboration of three
universities: London School of Hygiene and Tropical Medicine
University of Hull University of East Anglia Slide 9 The
Observatory project (2) Purpose: Fill gaps in knowledge
Epidemiology Qualitative social research Create range of
infrastructure facilities to support research Slide 10 The
Observatory project (3) Output to date: Six scientific papers
published Disease Register Services Directory Slide 11 The
Observatory project (4) New projects: Biobank Post Mortem tissue
archive Slide 12 The Biobank Aims : To develop a key resource for
biomedical research, especially the investigation of biomarkers for
diagnosis and prognosis. Slide 13 The Biobank (2) Specific main
objectives: to establish a biobank for the study of ME/CFS, as a
resource for high quality and ethically approved biomedical
research studies benefiting from well catalogued blood samples,
which are linkable to clinical and risk factors data; to
investigate risk factors for severity; to correlate clinical
phenotype with disease severity. Slide 14 The Biobank (3)
Subsequently: to disseminate the resource to the research community
to plan high throughput studies, benefiting from sample collections
and rapid advancing sequencing (e.g. whole genome sequencing,) and
other molecular techniques, such as those investigating immune and
genetic biomarkers to link the Biobank to the planned post- mortem
tissue bank for the study of ME/CFS. Slide 15 The Biobank (4)
Outcomes full implementation of the ME/CFS Biobank, including:
recruitment of well characterised cases with ME/CFS and controls,
blood sample collections and storage. Slide 16 The Biobank (5)
Other Research Possibilities Linkage of data from stored biological
samples with longitudinal clinical data from the Disease Register
will enable identification of clinical and pathological factors
associated with particular adverse outcomes of interest. e.g. what
clinical and pathological factors may be associated with disease
severity? This will contribute to the development of prevention
strategies Slide 17 The Biobank (6) $1.5 million awarded by
National Institutes of Health, Washington DC Making possible a very
large increase in the scale of the project Slide 18 The Biobank
(7): The NIH Project Aims (i) i)to investigate risk factors for
disease severity; ii)to correlate clinical phenotype with disease
severity; iii)to disseminate the resource to researchers and others
iv)to plan high throughput studies. Slide 19 The Biobank (8): The
NIH Project Aims (ii) High throughput studies will benefit from:-
sample collections; rapidly advancing molecular techniques, e.g.
investigating immune and genetic biomarkers; expansion of the
Disease Register; link to post-mortem tissue bank for the study of
ME/CFS. Slide 20 More Information http://www.lshtm.ac.uk/itd/crd/
research/cure-me/index.html Slide 21 Post Mortem Tissue Archive
Pros & Cons Rationale To create an opportunity to study
neurological and other tissues from people with ME, in order to
investigate underlying disease processes. Post mortem tissue
archives have been established and function effectively in other
neurodegenerative diseases, and one for ME exists in the US Slide
22 Post Mortem Tissue Archive Pros & Cons Problems Logistics of
specimen handling Cost Time Slide 23 Post Mortem Tissue Archive
Feasibility Study ME has rarely been studied in post-mortem
examinations, despite evidence of abnormalities from neuroimaging.
Aim: To ascertain the feasibility of developing a national
post-mortem ME/CFS tissue bank in the UK. Method: Case study,
involving key informant interviews, focus group of PWME, workshop
with experts Results suggested that post-mortem tissue bank was
desirable, feasible, and acceptable to possible donors. Lacerda EM,
Nacul L, Pheby D, Shepherd C, Spencer P. Exploring the feasibility
of establishing a disease-specific post-mortem tissue bank in the
UK: a case study in ME/CFS. J Clin Pathol (2010); 63: 1032-1034.
Slide 24 Other Initiatives: MRC Euromene US Department of Defense
Slide 25 The MRC Initiative 1.6 million allocated, following work
of Expert Group, for call entitled: Understanding the Mechanisms of
CFS/ME Closing date 7 June 2011. Slide 26 MRC (2) - Aims Support
high-quality, innovative research that increases the CFS/ME
knowledge base; Address the mechanisms underlying chronic changes
in CFS/ME, particularly: Autonomic dysfunction Cognitive symptoms
Fatigue Immune dysregulation Pain Sleep disorders Slide 27 MRC (3)
Aims (continued) Enhance understanding through study of
cross-disease symptomology Address lack of capacity in CFS/ME
research, and need for multidisciplinary teams Involve partnerships
between CFS/ME researchers and leading investigators in other
fields. Slide 28 MRC (4) - The Five Funded Projects Identifying the
biological fingerprints of fatigue Dr Wan Ng, Newcastle University
Understanding the pathogenesis of autonomic dysfunction in chronic
fatigue syndrome and its relationship with cognitive impairment
Professor Julia Newton, Newcastle University Modulation of aberrant
mitochondrial function and cytokine production in skeletal muscle
of patients with CFS by supplementary polyphenols Professor Anne
McArdle, Universities of Liverpool & Leeds Can enhancing slow
wave sleep SWS improve daytime function in patients with CFS?
Professor David Nutt, Imperial College London Persistent fatigue
induced by interferon-alpha: a new immunological model for chronic
fatigue syndrome Dr Carmine Pariante, Kings College London Slide 29
MRC (5) - Identifying the biological fingerprints of fatigue Aims:
To improve understanding of the mechanisms of fatigue by: analysing
the immune systems of > 500 patients with primary Sjgren
syndrome identifying immune system abnormalities in these patients
in order to help identify the biological fingerprints of fatigue,
hopefully leading to: new treatments. a clinical diagnostic test
for CFS/ME. Slide 30 MRC (6) - Understanding the pathogenesis of
autonomic dysfunction in CFS and its relationship with cognitive
impairment Aims: To explore the causes of autonomic nervous system
dysfunction ( dizziness and light- headedness in 90% of PWME),
using fMRI to measure changes in brain blood flow to the brain
relating this to cognition and nervous system dysfunction, in order
to lay the foundations for: new diagnostic tools better
understanding of nervous system abnormalities development of
targeted treatments Slide 31 MRC (7) Modulation of aberrant
mitochondrial function and cytokine production in skeletal muscle
of patients with CFS by supplementary polyphenols Aim: To use a
newly-developed technique to study muscle mitochondria, in order
to: learn more about how CFS/ME develops and becomes chronic Slide
32 MRC (8) - Can enhancing slow wave sleep improve daytime function
in patients with CFS? Aims: To study sleep disturbance in CFS/ME.
To measure the effect of drug-induced deep restorative sleep in
CFS/ME patients on brain function while awake. To increase
understanding of the impact of sleep disturbance CFS/ME sufferers,
in order to develop new treatments. Slide 33 MRC (9) - Persistent
fatigue induced by interferon-alpha: a new immunological model for
CFS Aims: To study patients undergoing IFN-alpha treatment for
Hepatitis C [NB IFN-alpha induces fatigue] To identify resultant
biological changes, hopefully leading to: a check-list of blood
measures to predict who will develop CFS/ME identification of new
targets for therapy. Slide 34 MRC (10) - Conclusions Common Themes:
Analogies with other illnesses Start with symptoms Explore
underlying disease mechanisms Based on improved understanding of
pathology, develop new diagnostic tests &/or treatments Slide
35 EUROMENE 30+ participating centres in 15 countries; Just
submitted proposal to EU for 6 million to support collaborative
research as part of the Horizon 2020 programme; Title:
Understanding ME/CFS: elucidating determinants, risk factors and
pathways, in order to develop personalised preventive, diagnostic
and therapeutic strategies Slide 36 EUROMENE (2): Aims of the
proposed project Increasing understanding of ME/CFS by:- mapping
knowledge in a systems medicine model, enriched with novel
nanoanalytical, new generation sequencing, proteome analysis data,
and PET studies; developing an integrated translational platform
incorporating new and existing knowledge, and well characterised
patient cohorts in seven EU countries; leading to new diagnostic
and therapeutic products, and optimal prevention and treatment
strategies. Slide 37 Rituximab (1) A monoclonal antibody against
the protein CD20, found on the surface of B lymphocytes. Function
Rituximab destroys normal and malignant B cells that have CD20 on
their surfaces. Slide 38 Rituximab (2) Uses To treat diseases with
excessive numbers, overactive or dysfunctional B cells, e.g.
leukaemias, lymphomas, including Hodgkin's disease, also autoimmune
diseases, e.g. rheumatoid arthritis, lupus, autoimmune haemolytic
anaemia, in patients not responding to anti-TNF-alpha therapy.
Slide 39 Rituximab (3) Pilot Study A CFS patient undergoing
chemotherapy for Hodgkin's disease experienced transient CFS
recovery, thought to be related to methotrexate, which induces
immunomodulation partly through B-cell depletion. Subsequently,
this patient and two others were B-cell depleted by rituximab
infusion All three showed improvement of all CFS symptoms. Fluge
O., Mella O. Clinical impact of B-cell depletion with the anti-CD20
antibody rituximab in chronic fatigue syndrome: A preliminary case
series. 2009 BMC Neurology 9 Slide 40 Red Herrings! PACE XMRV Slide
41 PACE: Definitely not the last word (1) Significant weaknesses
admitted: Only studied people with mild and moderate illness:
Oxford case definition Extended criteria to improve recruitment
Standard medical care inadequate. No objective or consistent
outcome assessment Slide 42 PACE: Definitely not the last word (2)
Other weaknesses: Intention to treat analysis poorly applied
Exaggerated claims regarding outcomes Improvements marginal for all
therapies Many showed no improvement However, adverse consequences
were rare. Slide 43 Xenotropic Murine Leukemia VirusRelated Virus
(XMRV) 2009: Lombardi et al (Whittemore-Peterson Institute
University of Nevada, Reno, NV) report XMRV, a gammaretrovirus in
67% of patients (67%) compared to 3.7% of healthy controls.
Numerous subsequent studies fail to replicate this finding
Meanwhile, Mikovits et al (Whittemore-Peterson Institute) cast
doubt on their own analyses. Consensus emerges that DNA or RNA
contamination of test kits is very likely. Slide 44 Action for ME
Pilot Studies (May 2012) Dr Phil Manning and Prof Julia Newton,
Newcastle University. Understanding muscle dysfunction in M.E./CFS:
developing a drug pre-testing system Understanding muscle
dysfunction in M.E./CFS: developing a drug pre-testing system Dr
Jason Ellis, Northumbria University: A case controlled study
exploring the qualitative experience of sleep, the roles of sleep
architecture and diurnal patterns of salivary cortisol in M.E./CFS
A case controlled study exploring the qualitative experience of
sleep, the roles of sleep architecture and diurnal patterns of
salivary cortisol in M.E./CFS Prof Annalena Venneri, University of
Sheffield: Uncovering the biological correlates of cognitive
impairment associated with fatigue in M.E./ CFS: a pilot study of
cognition and functional connectivity pre and post-exertional
malaise. Uncovering the biological correlates of cognitive
impairment associated with fatigue in M.E./ CFS: a pilot study of
cognition and functional connectivity pre and post-exertional
malaise Slide 45 What next for ME research? Slide 46 Thank you for
listening Any questions, or points for discussion? Slide 47 Chronic
Fatigue Syndrome Research Foundation
