educational materialthe main result of this study was that b2ar genotype (arg16 homozygotes)...
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ERS Annual Congress Amsterdam
26–30 September 2015
EDUCATIONAL MATERIAL
Meet the expert 4
Asthma susceptibility
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INDG1X0280_Onbrez JournalAd_ERJ_r17.indd 1 7/9/12 2:48 PM
Supported by
Asthma susceptibility: from pathophysiology to personalised medicine
Prof. Dr Gerard Koppelman
Groningen Research Institute for Asthma and COPD
University Medical Center Groningen
Beatrix Children's Hospital
Hanzeplein 1
PO Box 30001
9700 RB Groningen
NETHERLANDS
Interviewer:
Ms. Carmen Veith
Maastricht University
Department of Toxicology
Universiteitssingel 50
6229 ER Maastricht
NETHERLANDS
AIMS: To explain asthma susceptibility by presenting the results of basic science in relation to
clinical observations. This will promote the development of personalised therapy on the basis of
pathophysiology.
TARGET AUDIENCE: Pulmonologists, paediatricians, respiratory therapists, basic scientists,
trainees, and anyone with an interest in asthma
AIMS
The aims of this session are to:
Define personalized and precision medicine in the context of asthma
Review the heterogeneity of treatment response in asthma
Analyse tools for precision medicine in asthma
Discuss evidence that this could work in clinical practice
SUMMARY
Despite progress in asthma research and management, asthma outcomes are still suboptimal. The
number of hospitalizations and number of deaths from asthma have stalled. Patients experience
insufficient asthma control in real life. [1] There are many reasons for this that include doctor related
factors (medical care that is suboptimal and not according to recent guidelines); patient related factors
(problems with inhalation technique, adherence, and personal factors that limit asthma control) and
finally disease related factors (therapy resistant asthma).
In the past, we have treated our patients as if they were the mean of a group of patients from a clinical
trial. However, it has become increasingly clear that there is a marked variability in response to
asthma treatment. Recent developments in understanding asthma pathophysiology now start to make
it possible to make asthma treatment choice more personal, called personalized medicine.
Personalized medicine is a medical model that proposes the customization of healthcare - with
4
medical decisions, practices, and/or products being tailored to the individual patient. The word
“personalized” could be misinterpreted to imply that treatments and preventions are being developed
uniquely for each individual. Therefore, new concepts have been proposed, and currently perhaps the
better term ‘Precision Medicine’ is used instead.
In asthma, there is a marked heterogeneity of the disease, as well as heterogeneity in response to
asthma medication. For example, Sfezler and co-workers showed that in childhood asthma, response
to either inhaled corticosteroids and/or montelukast (defined by an improvement of FEV1 > 7.5 %)
was limited: 55 % did not improve to either drug, whereas 23 % improved after ICS and 5% to
Montelukast, and 17 % to both drugs. [2]
The question in precision medicine is if we could improve targeted treatment of asthma by
preselecting responders. Different tools could potentially be used: Genomics (DNA variation),
epigenomics, transcriptomics (mRNA expression profile), proteomics / metabolomics, phenomics
(based on a certain phenotype), exposomics, and humanomics. These tools coincide with genomic
tools that have improved our understanding of asthma pathophysiology. In this meet the professor
session, we will focus on genomic and transcriptomic tools.
Genomics: In asthma, several studies have been performed to relate the beta2 receptor (B2AR)
genotype at amino acid position 16 to the response to bronchodilators. One example is the Barge
study [3], a prospective, randomized, double blind trial, stratified on B2AR genotype. 4 times a day
salbutamol vs as needed in a 6 weeks, cross over design. The primary outcome was morning
peakflow. The main result of this study was that B2AR genotype (Arg16 homozygotes) negatively
affects lung function when salbutamol is used on a regular basis (no ICS), compared to placebo.
Follow up studies showed no effect of genotype on lung function when using combination therapy
LABA/ICS.
Transcriptomics: Another approach is to define subgroups of based on the transcriptome. Woodruff et
al defined a gene expression signature in airway epithelial cells of three genes that are upregulated by
Th2 cytokine IL13: ‘Th2 high’ pattern. These three genes are Periostin (POSTN), Chloride Channel
Regulator 1 (CLCA1) and Serpin peptidase inhibitor, B2 (SERPINB2). [4] In a study of 42 adult
patients with mild to moderate asthma and 28 healthy controls, gene expression signature in epithelial
brushes were related to clinical characteristics, parameters from airway wall biopsies and treatment
response to 8 weeks of inhaled corticosteroids. One of the most important findings of this study was
that ICS responders were amongst the Th2 high group. Also, novel biologicals in asthma, such as anti
IL13, may be efficacious in Th2 high asthma patients, as defined by high serum periostin levels. [5]
In conclusion, the time has come to make asthma treatment more precise. The first examples of
genomic and transcriptomic biomarkers that could be used to select patients for certain treatments
have been published. What is needed are real life studies that show that this ‘precise’ approach is
better than traditional approaches. Despite how biologically effective our treatment choices are, we
should always consider the ‘human’ factor: improve the quality of our clinical care, improving
adherence and involve out patients in making the best management decisions for themselves or their
children with asthma. [1]
REFERENCES
1. Thomas, M. Prim Care Resp J 2015 (25). 15004; 2. Szefler et al, J Allergy Clin Immunol 2005;
115:233-42.; 3. Israel E, et al. Lancet. 2004; 364:1505-1512; 4. Woodruff et al, AJRCCM 2009;
180:388-395; 5. Corren et al, N Engl J Med. 2011 Sep 22;365(12):1088-98
5
EVALUATION
1. Asthma is a heterogeneous disease. In the GINA guidelines, the following patient related factors
are suggested to personalize treatment choices
a. The genotype at position 16 ( Arg / Gly) of the beta 2 adrenergic receptor gene
b. The presence of airway hyperresponsiveness
c. The level of serum periostin
d. Patient preference; practical issues inhaler technique, adherence, and cost
2. About 30 asthma genes have been discovered. Which statement is true?
a. The 17q12-21 (ORMDL3/GSDMB) genetic variants are associated with childhood onset
asthma
b. The 17q12-21 (ORMDL3/GSDMB) genetic variants are associated with adult onset asthma
c. IL1RL1 gene variants are associated with transient non atopic wheeze in early childhood
d. IL1RL1 gene variants predict treatment response to anti-IL4R antagonist
3. Genetic testing using a panel of well replicated asthma genetic variants
a. Is almost as good as flipping a coin
b. Can be implemented in clinical practice soon
c. Can distinguish between transient wheezers and persistent asthma in childhood
d. Has been FDA approved for direct to consumer genetic testing companies
4. Th2 high gene expression signature is defined based on
a. Gene expression of three genes POSTN, CLCA1 and SERPINB2 in blood
b. Gene expression of three genes POSTN, CLCA1 and SERPINB2 in nasal epithelium
c. Gene expression of three genes POSTN, CLCA1 and SERPINB2 in bronchial epithelium
d. Gene expression of three genes POSTN, CLCA1 and SERPINB2 in induced sputum
5. New therapeutic options, such as biologicals, have been developed for the following asthma
characteristics
a. Eosinophilic asthma
b. Neutrophilic asthma
c. Airway remodelling
6
Asthma susceptibility From pathophysiology to
personalised medicine
Gerard H. Koppelman, MD PhD
Pediatric Pulmonology and Pediatric Allergology, Beatix Children’s Hospital, University MedicalCenter Groningen, the Netherlands
Groningen Research Institute for Asthma and COPD
7
Conflict of interest
• No real or perceived conflict of interest relating to this presentation
• Grant support – Netherlands Lung Foundation, – Ubbo Emmius Foundation, – TEVA Pharmaceuticals, – Stichting Astma Bestrijding
8
The problem
• Despite progress in asthma research and management, asthma outcomes are still suboptimal• Hospitalizations, deaths from asthma have
stalled• Insufficient asthma control in real life
• Reasons?
Mike Thomas, Why aren’t we doing better in asthma: time for
personalised medicine? Prim Care Resp J 2015 (25). 15004 9
One size fits all medicine?
10
Time to make asthma management
more personal!
New!
11
What is it?
• Personalised medicine is a medical model that proposes the customisation of healthcare - with medical decisions, practices, and/or products being tailored to the individual patient.
• First context: geneticsNow broadened to encompass all sorts of personalisation measures.
12
Is it a good term?
• The word “personalized” could be misinterpreted to imply that treatments and preventions are being developed uniquely for each individual
• Therefore, new concepts have been proposed: – Precision Medicine – Stratified Medicine– Genomic medicine
Momentum grows to make 'personalized' medicine more 'precise';
Alla Katsnelson; Nature Medicine 19, 249 (2013) ;
doi:10.1038/nm0313-24913
Expectations are high
“Tonight, I'm launching a new Precision
Medicine Initiative to bring us closer to curing diseases like cancer and diabetes — and to give all of us access to the personalized information we need to keep ourselves and our families healthier.” State of the Union 2015
14
A new initiative on precision medicine
• “..approaches for detecting, measuring, and
analyzing a wide range of biomedical information — including molecular, genomic, cellular, clinical, behavioral, physiological, and environmental parameters..”
• Powered by omics techology, and large datasets handling
• Will start with cancer, but also be applied to chronic non-communicable diseases
Francis S. Collins, and Harold Varmus, N Engl J Med 2015;
372:793-795 15
Traditional approach
16
Precision medicine
a test
17
This presentation
• Defining precision medicine in asthma• Review heterogeneity of asthma –
treatment response• Analyse tools for precision medicine in
asthma• Discuss evidence that this could work
18
Precision medicine in asthma
• What does it mean?
19
Precision medicine in asthma
• Use of patients characteristics to direct the best asthma management advices to this specific(group of) patient(s)
• Which characteristics?– Genomics– Epigenomics– Transcriptomics– Proteomics / Metabolomics– Phenomics– Exposomics– Humanomics
20
Asthma is a heterogenous
disease
“ Asthma is a heterogeneous disease, usually characterized by chronic
airway inflammation..” Global Initiative for Asthma (GINA) –Guidelines Update 2015
21
Asthma management guidelines do not take this into account
Reddel et al, ERJ Express. Published on July 23, 201522
Not really, but ….
• Treatment choices– Population-level decisions: efficacy,
effectiveness, safety, cost, regulations– Patient-level decisions for tailoring treatment:
also discuss patient characteristics (phenotype) that predict response or risk;
– patient preference; practical issues inhaler technique, adherence, and cost;
– treat modifiable risk factors; use non-pharmacological strategies where appropriate
Reddel et al, ERJ Express. Published on July 23, 201523
Treatment response in asthma is variable
Distribution of FEV1 response in 895 asthmatic patients aged 15 to 85 years treated with either
beclomethasone or montelukast for 12 weeks.
Data from Malmstrom et al., Ann Intern Med 1999;130,487-495
Larj and Bleecker,Chest. 2004;126(2_suppl_1):138S-149S. 24
Non response is significant
Larj and Bleecker,Chest. 2004;126(2_suppl_1):138S-149S. 25
Treatment response in childhood asthma
Szefler et al, J Allergy Clin Immunol 2005;115:233-42. 26
Fev1 response to ICS or LTRA in childhood is variable
Szefler et al, J Allergy Clin Immunol 2005;115:233-42.
17 %5 %
55 % 23 %
27
Strategies to improve
precision
• Genomics• Epigenomics• Transcriptomics• Proteomics / Metabolomics• Phenomics• Exposomics• Humanomics
28
genes
Multifactorial:
Asthmaenvironment environment
Monogenic:
CF
CFTR
Genomics:
Asthma is a multifactorial disease
29
Asthma genetic variation
Moffatt et al, N Engl J Med 2010;363:1211-21
IL18R1 /
IL1RL117q 21 locus
IL33
30
Asthma GWAS Loci
Meyers et al, Lancet Respir Med 2014; 2: 405-15.
• 30 Loci identified by GWAS
• Some loci are ethnic specific
Afr Am / Japanese
• Only small risk increases
• Explains < 5 % of asthma
• Risk alleles are common
31
Disease subtypes: Chr 17q21 SNPs predict childhood onset
asthma
Bouzigon et al N Engl J Med 2008; 359:1985-1994
Age at onset asthma
32
IL33-IL1RL1 pathway: from epithelial
damage to immune activation
Grotenboer NS et al. JACI 2013 Mar;131(3):856-6533
• Study populations
PIAMA (Netherlands) & ALSPAC (UK)
• SNPs
91 SNPs in both cohorts
• Outcome
Wheezing phenotypes by latent class analysisAsthma at age 8
IL33-IL1RL1 pathway SNPs in wheezing
phenotypes and asthma
Savenije OEM et al., J Allergy Clin Immunol. 2014
Jul;134(1):170-734
Savenije OE/ Granell R et al., JACI 2011; 127(6):1505-12
Association of IL33-IL1RL1 pathway with
wheezing phenotypes
35
Association of IL33-IL1RL1 pathway with
wheezing phenotypes and asthma
Intermediate onset wheeze is strongly associated with variants in the IL33-IL1RL1 pathway (stronger effects than outcome asthma)
Gene
(nr
SNPs)
IL33
(20)
IL1RL
1
(12)
IL1RA
P
(42)
MYD8
8
(2)
TIRA
P
(8)
IRAK
4
(3)
TRAF
6
(4)
NW ref. ref. ref. ref. ref. ref. ref.TEW 2IOW 6 5 1LOW 1 2PW 1 1Asthma8 yr
3 4
Savenije et al., J Allergy Clin Immunol. 2014 Jul;134(1):170-7 36
Genomics
• Multiple SNPs• Some SNPs predict specific asthma
phenotypes– 17q12-21 SNPs and childhood onset asthma– IL33/IL1RL1 SNPs and wheezing phenotypes
• How good can we predict asthma withthese SNPs?
37
Genetic risk score
A truly useless test (one no better at identifying true positives than flipping a coin) has an area of 0.5. A perfect test (one that has zero false positives and zero false negatives) has an area of 1.00.
38
Fereira et al, Lancet, 2011; 378 (9795): 1006-14
Genetic risk score
39
Genomics
• Multiple SNPs• Some SNPs predict specific asthma
phenotypes– 17q12-21 SNPs and childhood onset asthma– IL33/IL1RL1 SNPs and wheezing phenotypes
• How good can we predict asthma withthese SNPs?
• Can SNPs predict treatment response?
40
Beta mimetics and bronchodilation
Salbutamol binds to the 2-
Adrenoceptor
41
2-Adrenoceptor (2-AR)
genetic variation
Reishaus et al., 1993. AJRCMB; 8:334–339
COOH
Arg 16 Gly
Gln 27 Glu
Val 34 Met
Thr 164 Ile
NH2
Cell
membrane
42
BARGE Beta-adrenergic response
by genotype
• Prospective, randomized, double blind trial,stratified on B2AR genotype
• B2AR –16 Arg Arg vs Gly Gly• 4 dgs salbutamol vs as needed• 6 weeks, cross over design• Primary outcome: Morning Peakflow
Israel E, et al. Lancet. 2004;364:1505-1512. 43
BARGE: Patients
• Patients with mild asthma, no ICS– Mean age = 31 years– Mean FEV1 = 90% of predicted
• Patients were mathced in pairs for FEV1 and B2AR genotype
• Arg/Arg (n = 37)*
• Gly/Gly (n = 41) genotype
Israel E, et al. Lancet. 2004;364:1505-1512.44
BARGE: AM PEF en B2AR Genotype
Israel E, et al. Lancet. 2004;364:1505-1512.
Albuterol modelledAlbuterol raw meansPlacebo modelledPlacebo raw means
P=0.0175
Treatment Washout
Time (weeks)
Gly/Gly
0 5 10 15 20
20
10
0
-10
-20
Mo
rnin
g P
EF
R (
L/m
in)
*
P=0.029
Treatment Washout
Time (weeks)
Arg/Arg
0 5 10 15 20
20
10
0
-10
-20
Mo
rnin
g P
EF
R (
L/m
in)
†
45
Conclusions BARGE
• B2AR genotype effects PEF response when salbutamol is used on a regular basis (no ICS)
• Asthma patients with B2AR Arg/Arggenotype (~1/6) : only salbutamol as needed
• Follow up studies: No effect of genotype on combination therapy LABA/ICS on lung function (retrospective studies in adults)
46
Treatment choice in B2AR Arg 16
homozygotes
•A pragmatic trial in children with asthma on inhaled corticosteroids (ICS)•1 year, 3 monthly visits, 62 children•Salmeterol SL (n=34) / Montelukast ML (n=28)•Outcome: School abcenses•Secundary: QOL, FEV1, Salbutamol use
Lipworth et al, Clin Science 2013: 124; 521-847
ML reduces school absences in
B2AR Arg 16 homozygotes
Lipworth et al, Clin Science 2013: 124; 521-8
0 = no absences1 = 1-2 days2=> 2 days – 1 week3= > 1 week
48
ML improves bronchodilator use,
but not FEV1 in B2AR Arg 16
Lipworth et al, Clin Science 2013: 124; 521-8
Salbutamol use
FEV1
49
Making therapy more precise
By understanding disease pathopysiology and targeting types of asthma, defined by transcriptomics
50
T helper 2 mediated
inflammation• Woodruff et al defined a gene expression signature in airway epithelial cells of three genes that are upregulated by Th2 cytokine IL13: ‘Th2 high’ pattern
•Three genes: • Periostin (POSTN), • Chloride Channel Regulator 1 (CLCA1) • Serpin peptidase inhibitor, B2 (SERPINB2)
Woodruff et al, AJRCCM 2009; 180:388-39551
Th2 high
• 42 adult patients with mild to moderate asthma• 28 healthy controls• Gene expression signature in epithelial brushes related to
•Clinical characteristics• Parameters from airway wall biopsies•Treatment response to 8 weeks of ICS (fluticsone 500 mcg bid
Woodruff et al, AJRCCM 2009; 180:388-39552
Th2 high defines a subroups
of asthmatics
Woodruff et al, AJRCCM 2009; 180:388-39553
Th2 high: similar FEV1 and
reversibility, more severe AHR
Woodruff et al, AJRCCM 2009; 180:388-39554
Th2 high: defines group of ICS
responders
Woodruff et al, AJRCCM 2009; 180:388-39555
Kian Fan Chung,
J Int Med 201556
Kian Fan Chung,
J Int Med 201557
Understanding disease:
tailored treatment• Asthma
•Eosinophilis- Th2 type inflammation•Neutrophilic inflammation• Remodeling, repair
• Targeted treatment with biologicals(anti-IgE, IL4, IL5, IL13, etc)
58
Understanding disease:
tailored treatment• Asthma
• Anti-IL13 antibody in adult asthma, not well controlled on ICS/LABA• Efficacy in
•All patients•Subgroup of Th2 high, defined as high serum periostin
Corren et al, N Engl J Med. 2011 Sep 22;365(12):1088-9859
Anti-IL13 in asthma
Corren et al, N Engl J Med. 2011 Sep 22;365(12):1088-9860
Anti-IL13: and serum Periostin
Corren et al, N Engl J Med. 2011 Sep 22;365(12):1088-9861
Anti IL4R and IL4RA genotype
• Anti –IL4R antagonistand asthma exacerbations• Carriers of IL4RA risk alleleReduction in exacerbations
• Not seen in carriers non-riskallele
Slager et al, JACI 2012: 130:516-22
Meyers et al, Lancet Respir Med 2014; 2: 405-15. 62
Conclusion
• Asthma is a heterogeneous disease, and so is treatment response to asthma medication
•Personalised medicine holds promise for•Using genetic riks profiles, transcriptomics or biomarkers to select patient subgroups
•Most developments in eosinphilic asthma, not so much in neutrophil asthma / remodelling
63
Conclusion
• We are not there!
• Searching for missing heritability (Genetics/ Epigenetics
• Using Th2 type biomarkers in clinical care
• Trials comparing traditional versus personalised approach
64
Ready for Precision Medicine ?
“… We would be better off directing more resources to
understanding what it takes to solve messy problems about how humans behave as individuals and in groups. Ultimately, we almost certainly have more control over how much we exercise, eat, drink and smoke than we do over our genomes …”
Michael J. Joyner, Mayo Clinic, USA, New York Times
Jan 29, 2015
65
Future
• Improve our understanding of therapy resistent asthma
• ‘Omics methods help”
- Do not forget- improving quality of our clinical care- improving adherence - patient related factors
Mike Thomas, Why aren’t we doing better in asthma: time for personalised medicine?
Prim Care Resp J 2015 (25). 15004 66
Faculty disclosures
Prof. Dr Gerard Koppelman receives unrestricted grants from Dutch Lung Foundation, Stichting,
Astma Bestrijding and TEVA Pharmaceuticals for research projects non - related to this seminar.
68
Answers to evaluation questions
Please find all correct answers in bold below
Asthma susceptibility: from pathophysiology to personalised medicine - Prof. Dr Gerard
Koppelman
1. Asthma is a heterogeneous disease. In the GINA guidelines, the following patient related factors
are suggested to personalize treatment choices
a. The genotype at position 16 ( Arg / Gly) of the beta 2 adrenergic receptor gene
b. The presence of airway hyperresponsiveness
c. The level of serum periostin
d. Patient preference; practical issues inhaler technique, adherence, and cost
2. About 30 asthma genes have been discovered. Which statement is true?
a. The 17q12-21 (ORMDL3/GSDMB) genetic variants are associated with childhood onset
asthma
b. The 17q12-21 (ORMDL3/GSDMB) genetic variants are associated with adult onset asthma
c. IL1RL1 gene variants are associated with transient non atopic wheeze in early childhood
d. IL1RL1 gene variants predict treatment response to anti-IL4R antagonist
3. Genetic testing using a panel of well replicated asthma genetic variants
a. Is almost as good as flipping a coin
b. Can be implemented in clinical practice soon
c. Can distinguish between transient wheezers and persistent asthma in childhood
d. Has been FDA approved for direct to consumer genetic testing companies
4. Th2 high gene expression signature is defined based on
a. Gene expression of three genes POSTN, CLCA1 and SERPINB2 in blood
b. Gene expression of three genes POSTN, CLCA1 and SERPINB2 in nasal epithelium
c. Gene expression of three genes POSTN, CLCA1 and SERPINB2 in bronchial
epithelium
d. Gene expression of three genes POSTN, CLCA1 and SERPINB2 in induced sputum
5. New therapeutic options, such as biologicals, have been developed for the following asthma
characteristics
a. Eosinophilic asthma
b. Neutrophilic asthma
c. Airway remodelling