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 ‘post-mortem’ 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) • to investigate risk factors for disease severity; • to correlate clinical phenotype with disease severity; • to disseminate the resource to researchers and others • 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 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
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.
XenotropicMurineLeukemia 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.
Thank you for listening • Any questions, or points for discussion?
Chronic Fatigue Syndrome Research Foundation CFS/ME Research Collaborative