Transcript Risk Factors for Severe ME/CFS: A Pilot Survey

Research: State of the
Art
Professor Derek Pheby
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)
Where are we starting
from? (2)
What we don’t know
• Underlying pathology – one
disease or several?
• How to treat it
Where are we starting
from? (3)
Common myths:
• It doesn’t exist!
• If it does exist, it’s a psychological
condition
• NICE has had the last word on the
subject
• Graded exercise and cognitive behaviour
therapy are effective treatments
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
Research Activity (1)
Published scientific papers:
• US 50%
• UK 30%
• Rest of world 20%
- but it doesn’t really amount to a coherent
corpus of scientific knowledge
Research Activity (2)
Why has all this work not
advanced knowledge further?
• Vicissitudes of funding
• No coherent strategy
• No supportive infrastructure
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
The Observatory project (2)
Purpose:
• Fill gaps in knowledge
•Epidemiology
•Qualitative social research
• Create range of infrastructure
facilities to support research
The Observatory project (3)
Output to date:
• Six scientific papers published
• Disease Register
• Services Directory
The Observatory project (4)
New projects:
• Biobank
• Post Mortem tissue archive
The Biobank
Aims :
• To develop a key resource for
biomedical research, especially
the investigation of biomarkers
for diagnosis and prognosis.
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.
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 ‘postmortem’ tissue bank for the study of
ME/CFS.
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.
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
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
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.
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.
More Information
• http://www.lshtm.ac.uk/itd/crd/
research/cure-me/index.html
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
Post Mortem Tissue
Archive – Pros & Cons
Problems
• Logistics of specimen
handling
• Cost
• Time
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.
Other Initiatives:
• MRC
• Euromene
• US Department of Defense
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.
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
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.
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, King’s College London
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 Sjögren 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.
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 lightheadedness 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
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
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.
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.
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
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”
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.
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.
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.
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
Red Herrings!
•PACE
•XMRV
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
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.
Xenotropic Murine Leukemia
Virus–Related 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.
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
• 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
• 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.
What next for ME research?
Thank you for listening
• Any questions, or points for
discussion?
Chronic Fatigue Syndrome
Research Foundation