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Patient Support DayNottingham March 2012
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Contibutors
• Dr Gisli Jenkins• Dr Vidya Navaratnam• Professor Simon Johnson• Carole Mallia• David Cashman• Dr Sanjay Agrawal• Geraldine Burge• Dr Helen Parfrey• Annette Duck• British Lung Foundation.
• All funding from the Nottingham Respiratory Biomedical Research Unit
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Program
• The Science of IPF– How much IPF is there and how bad is it?– Why does IPF happen?– What have clinical trials in IPF taught us?
• Practical Management of IPF– Lung Transplantation– Best Supportive/Palliative Care– Oxygen Therapy– Travelling, flying and exercising with IPF
• The Future for IPF– Developing an IPF support network– Potential New Clinical Trials– Lung Tissue Research Proposals
• Question Time
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Aims of Today
• To inform patients of what we know.
• To offer practical advice.• To answer questions.• To find out what’s
important to you.• To develop a strategy to
improve the care of people with IPF throughout the UK
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What is IPF?
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It's a new killer baffling doctors. And the only warning sign is feeling out of breath...Read more: http://www.dailymail.co.uk/health/article-1385311/New-killer-baffling-doctors-And-warning-sign-feeling-breath-.html#ixzz1oNbdwE00
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Interstitial Lung Diseases
Idiopathic Pulmonary Fibrosis• Average age > 60• Male > Female• No Known Cause• No proven therapy• Median survival 3 years• Also known as Cryptogenic
Fibrosing Alveolitis
Other Stuff• Sarcoidosis• Connective Tissue Disease• Asbestosis• Hypersensitivity Pneumonitis• Non Specific Interstitial Pneumonitis• Desquamative Interstitial Pneumonitis• Respiratory Bronchiolitis ILD• Cryptogenic Organising Pneumonia• Acute Interstitial Pneumonitis• Idiopathic Pleuroparenchymal Fibrosing
Elastosis• LAM• HX
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ILD Olympics
IPF Sarcoidosis
AsbestosisCTD
HSPDrugs
NSIP
The rest
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Why do people get Idiopathic Pulmonary Fibrosis?
• It is NOT infectious• It is genetic in a small
minority of cases
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Causes of IPF• Idiopathic (and cryptogenic)
means “we don’t know”• Genetics plays a role
– Surfactant protein D– Muc5b– Telomerase
• Other hypotheses include:– Viral infection– Gastro-Oesophageal Reflux
Disease– Inhaled dust/smoke– Immune system going wrong
• Problem is distinguishing cause from association
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What about pulmonary fibrosis generally?
• Immune reaction to birds
• Immune reaction to drugs
• Inhaled dusts leading to injury of the lung
• Inhaled chemicals injuring the lung
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Interstitial Lung Disease Unit
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Goodwin and Jenkins Biochem Soc Trans 2009
Interstitial Lung Disease Unit
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Wrong place, wrong time, and then some, hypothesis
• If you have the wrong genes (?Muc5b polymorphism)
• If you have the wrong exposure (?Metal dust)
• And then your repair process breaks down! (epigenetics)
• You develop IPF
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What happens when your cell gets injured?
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Cell dies (apoptosis)
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Neighboring cell divides
• Risky time for cells• DNA taken apart and
then put back together• This can lead to the
introduction of genetic mistakes
• This can lead to reprogramming of cells
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Sometimes just the DNA gets damaged
• Again risky time for cells
• Complex repair process can lead to errors
• Even small mistake can have profound consequences
• Average gene contains thousands of DNA molecules
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Just one mistake can lead to an amino acid change which can completely change the
function of a protein
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Complex disease pathogenesis• You need to be on the road
to have a RTA• BUT NOT ALL ROAD USERS
WILL HAVE AN RTA.• The more you use the road
the higher your chance of an RTA
• A car is more likely to kill a pedestrian than a cyclist
• A motorcyclist is more likely to die in RTA than any other road user
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Complex disease pathogenesis
• The more often your cells divide the more likely they are to acquire errors
• The more often your cells get injured the more likely they are to acquire errors
• Some things will injure certain cells/genes over others
• Certain cells/genes are more prone to injury than others
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So why do people get lung fibrosis?
• They get older (more cell divisions)
• Their lungs get injured (cigarette smoke, gastroesophageal reflux.)
• They have susceptible genes
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Lung transplantation
http://www.uktransplant.org.uk/ukt/
Interstitial Lung Disease Unit
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IPF is the second commonest indication for lung transplantation
COPD 34-38%IPF 17-
23% CF 17-
19% Alpha1-AT deficiency 9%
Registry DataISHLT lung transplantation 22nd report 2005.LAIA 2002
Interstitial Lung Disease Unit
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ISHLT Guidelines for lung transplant in people with IPF
Referral• Histologic or radiographic evidence of UIP irrespective of vital
capacity.• Absence of major CI
Transplantation- Histologic or radiographic evidence of UIP and any of the following: - A DLco of less than 39% predicted.- 10% or > FVC during 6/12 follow-up.- O2 Sats < 88% during a 6-MWT.- Honeycombing on HRCT (fibrosis score of > 2).
JHLT, July 2006Interstitial Lung Disease Unit
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Lung transplant leads to improved survival in IPF
Thaboot et al 2003
Interstitial Lung Disease Unit
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The number of patients with IPF being transplanted are increasing.
Interstitial Lung Disease Unit
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The downside?
High operative mortality (15% in first 3 months)
No. of donor organs available<< recipients.– median waiting period for the single lung transplantation
• UK= 351 days (CI 293 to 427 days ) • USA=3 months.
Large number of contraindications.
Interstitial Lung Disease Unit
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Suitable organs• Age (donor<65)• Minimal smoking history
(<5 pack years)• Clear CXR• No evidence of sepsis• No PMH of
malignancy/chronic lung disease/ Hep B/C HIV
• Acceptable bronchoscopic and visual findings
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Bridging to Transplant on ECMO
• IPF, is a progressive diseases without effective therapy.
• Transplant is often “only chance”.
• ECMO is a bridge to transplant.
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Research in IPF
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Vancheri ERJ 2010 35(3):496-504
.
5 year survival rates from IPF compared with various cancers.
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Interstitial Lung Disease Unit
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CRUK
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CRUK
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Spending on cancer research by cancer type
CRUK
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1971-1975 1976-1980 1981-1985 1986-1990 1991-1995 1996-2000*0
10
20
30
40
50
60
70
80
90
100
Period of diagnosis
% survival
Figure 3.1: Age standardised relative survival (%) at one, five, ten and twenty years since diagnosis, female breast cancer, England and Wales, 1971-2003
* England only
Figure 3.3: Ten-year relative survival rate, female breast cancer, England and Wales, 1971-2000
CRUK
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UK IPF research budgets
Interstitial Lung Disease Unit
Maybe £2,000,000
British Lung Foundation £260,000 in 2012
However the profile is rising
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Two Broad Approaches 1) Choose available drug2) See if it works
1) Define molecular pathogenesis2) Design drug targeting offending molecule3) Check drug engages mechanism4) See if it works
Interstitial Lung Disease Unit
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Chronic Myeloid Leukaemia
• 5 year survival figures• Busulphan 34.2%• Hydroxyurea 46.5%• Interferon 54.6%• Imatinib 89%
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What do we need to study disease and discover new treatments
• Imagination• Persistence• Translation• Priorities
– Specific– Relevant– Achievable
• Money • Tissue
– Blood– Bronchoalveolar Lavage– Bits of lung
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Randomised Clinical Trials in IPF
• Raghu et al 2004• Demendts et al 2005• Tashkin et al 2006• King et al 2009• Daniels et al 2010• Zisman et al 2010• Richeldi et al 2011• Noble et al 2011
Pre-2000 Post-2000
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Numerous therapies currently in clinical trials
• BIBF-1120 (Boehringher)• IL13 antibody (Novartis)• Integrin antibody (Stromedix)• IL13 and IL4 antibody (Sanofi-Aventis)• PI3K antibody (Gilead)• Around 40 drugs currently being trialled
worldwide
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Thankyou!