Patient Support Day
Nottingham March 2012
Contibutors
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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
Program
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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?
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Practical Management of IPF
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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
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Question Time
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
What is IPF?
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-killerbaffling-doctors-And-warning-sign-feeling-breath-.html#ixzz1oNbdwE00
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
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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
ILD Olympics
CTD
Asbestosis
Sarcoidosis
IPF
NSIP
HSP
Drugs
The rest
Why do people get Idiopathic
Pulmonary Fibrosis?
• It is NOT infectious
• It is genetic in a small
minority of cases
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
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
Interstitial Lung Disease Unit
Goodwin and Jenkins Biochem Soc Trans 2009
Interstitial Lung Disease Unit
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
What happens when your cell gets
injured?
Cell dies (apoptosis)
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
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
Just one mistake can lead to an amino acid
change which can completely change the
function of a protein
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
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
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
Lung transplantation
http://www.uktransplant.org.uk/ukt/
Interstitial Lung Disease Unit
IPF is the second commonest indication for lung
transplantation
COPD
IPF
CF
Alpha1-AT deficiency
34-38%
17-23%
17-19%
9%
Registry Data
ISHLT lung transplantation 22nd report 2005.
LAIA 2002
Interstitial Lung Disease Unit
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 2006
Interstitial Lung Disease Unit
Lung transplant leads to improved survival
in IPF
Thaboot et al 2003
Interstitial Lung Disease Unit
The number of patients with IPF being
transplanted are increasing.
Interstitial Lung Disease Unit
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
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
Bridging to Transplant on ECMO
• IPF, is a progressive
diseases without effective
therapy.
• Transplant is often “only
chance”.
• ECMO is a bridge to
transplant.
Research in IPF
5 year survival rates from IPF compared with
various cancers.
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Vancheri ERJ 2010 35(3):496-504
Interstitial Lung Disease Unit
CRUK
CRUK
Spending on cancer research by cancer type
CRUK
Figure 3.3: Ten-year relative survival rate, female breast cancer,
England and Wales, 1971-2000
100
90
80
70
% survival
60
50
40
30
20
10
0
1971-1975
1976-1980
1981-1985
1986-1990
1991-1995
Period of diagnosis
1996-2000*
* England only
CRUK
UK IPF research budgets
Maybe £2,000,000
British Lung Foundation
£260,000 in 2012
However the profile is
rising
Interstitial Lung Disease Unit
Two Broad Approaches
1) Choose available drug
2) See if it works
1) Define molecular pathogenesis
2) Design drug targeting offending molecule
3) Check drug engages mechanism
4) See if it works
Interstitial Lung Disease Unit
Chronic Myeloid Leukaemia
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5 year survival figures
Busulphan 34.2%
Hydroxyurea 46.5%
Interferon  54.6%
Imatinib 89%
What do we need to study disease and
discover new treatments
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Imagination
Persistence
Translation
Priorities
– Specific
– Relevant
– Achievable
• Money
• Tissue
– Blood
– Bronchoalveolar Lavage
– Bits of lung
Randomised Clinical Trials in IPF
Pre-2000
Post-2000
• 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
Numerous therapies currently in clinical
trials
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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
Thankyou!