Transcript Modena - Progetto LIBRA

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Phenotyping the patient with
Rhinitis and Asthma
Sergio Bonini
Guido Rasi
Professor of Medicine
Second University of Naples
IFT-CNR, Rome
Professor of Microbiology
University Tor Vergata, Rome
General Director AIFA
Modena March 1, 2011
From EBM to EBM
Experience
Based
Medicine
Evidence
Based
Medicine
Approach
Target
Product
Empirical
Individual
Textbooks
RCT
Population
Guidelines
Evidence of superiority
does not mean it works for all
P < 0.05
Outcome
Threshold of clinical
relevance
Drug
Comparator
Sublingual immunotherapy for hazelnut food
allergy: A randomized, double-blind, placebocontrolled study with a standardized hazelnut
extract
Enrique E et al. JACI 2005
0.02
0.014
30
30
NS
24
24
18
18
12
12
6
6
SLIT (n= 14)
BEFORE
PLACEBO (n= 12)
AFTER
BEFORE
AFTER
Distribution of FEV1 response in 895 asthmatic patients aged
15 to 85 years treated with either beclomethasone or
montelukast for 12 weeks
Larj, M. J. et al. Chest 2004;126:138S-149S
Reasons for different responses to drugs
in patients with rhinitis and/or asthma
Different genotypes
Different phenotypes
• Beta-2 agonists
• Age, race, gender
(ADRB2, ARG1)
• Anti-leucotrienies
• Duration of the disease
• Corticosteroids
• Co-morbidities
(ALOX5, MRP1, LTC4S,CYSLTR1,2)
(CRHHR1, NR3CI, STIP1)
Phenotype-targeted therapy (PTT)
An individualized/mass treatment, a compromise
between EBM and a more patient-tailored
approach, made actual and accepted from the
industry by the increasing trend of regulatory
bodies to “pay per response”
Accessed, February 2010
710
No. of papers
383
120
Approaches used to define phenotypes
Pre-defined
• Resulting from a classificatory dissection of the
disease or from demographic features of patients
• Endotypes
Experimental
• Resulting from drug response in RCT
• Factor analysis
• Cluster analysis
Requirements for defining a phenotype
• Well-established genetic, biological,
functional or clinical markers
• Epidemiologically defined
Approaches used to define phenotypes
Pre-defined
• Resulting from a classificatory dissection of the
disease or from demographic features of patients
• Endotypes
Experimental
• Resulting from drug response in RCT
• Factor analysis
• Cluster analysis
Phenotyping of Rhinitis
Non infectious
Rhinitis
Infectious
Rhinitis
Allergic
IgE-mediated
Viral
Allergic
Non IgE-mediated
Bacterial
Non allergic
Parasitic
Asthma Phenotypes
• Age (adult, children)
• Time of onset (early, late)
• Triggers (allergic, occupational, ASA,
menses, exercise)
• Co-morbidities (Obesity, GER)
• Pathology (eosinophilic., neutrophilic,
pauci-granulocytic)
• Severity (exacerbation-prone, with
chronic airflow obstruction, severe)
Fixed
obstruction
Exacerbation-prone
Severe
Excercise-induced
Eosinophilic
corticosteroid responsive
Early/childhood onset
phenotypes
Allergic
PMA
Late/adult onset
phenotypes
Allergic
Non-allergic
Approaches used to define phenotypes
Pre-defined
• Resulting from a classificatory dissection of the
disease or from demographic features of patients
• Endotypes
Experimental
• Resulting from drug response in RCT
• Factor analysis
• Cluster analysis
PRACTALL Endotypes
1. Aspirine sensitive asthma
2. Allergic bronchopulmonary mycosis
3. Allergic asthma (adults)
4. Pre-school weezers at high risk for asthma
5. Severe late-onset eosinophilic
6. Asthma in country-skiers
Lotvall J et al. J Allergy Clin Immunol 2011,127:355-360
Hallmarks of allergic diseases
• Specific IgE response
• Allergic inflammation
(high total IgE, eosinophils, mast cells and basophils, etc.)
• Hyperreactivity of target organs
(lung, nose, skin, eye)
The Spectrum of Allergic Disease
Bonini S, Rasi G et al. Ann Allergy Asthma Immunoll 2001;87 Suppl.3:48-51
HLA genes and
allergen exposure
Genetic and environmental influences on
inflammatory genes overexpression
Neural and
tissue factor (?)
Cytokines
INFLAMMATION
Enhanced specific
IgE response
I
High total IgE Upregulation of inflammatory cells
Increased number
Eosinophilic
and releasability of
Neutrophilic
MC and basophils
II
Allergic
III
IV
ASA intolerance , Pollutants, Hormones
Clinical phenotypes
Tissue
hyperreactivity
V
EIA,GER, Stress
How to distinguish different
allergy phenotypes?
• Markers of sensitization
• Skin tests, IgE tests
• Markers of inflammation
• Total IgE
• Eosinophil and eosinophil
products
• Th2 profile
• Markers of tissue
hyperreactivity
• Non specific provocation tests
• New markers?
Asthma
Rhinitis
Conjunctivitis
Type I
Late-phase IgE Eos/Neutrophilic
Target
Hypersensitivity dependent
inflammation
organ
inflammation without sIgE
hyperreactivity
Pollenosis
Hyposensitisation
Antihistamines
SCUAD
Topical steroids
Antileukotrienes
EIB , CR
ß2 agonists
Anticolinergics
Approaches used to define phenotypes
Pre-defined
• Resulting from a classificatory dissection of the
disease or from demographic features of patients
• Endotypes
Experimental
• Resulting from drug response in RCT
• Factor analysis
• Cluster analysis
Phenotypes resulting from drug
response in RCT
Population Intervention
Outcome
Analysis
Responders
Unselected
RCT
Phenotyping
Non-responders
Sub-group analysis should be defined in advance, and not
resulting from the most favorable post-hoc analysis
WHO Classification of severe asthma
• Untreated
• Difficult-to-treat
• Treatment resistant
– Uncontrolled (Refractory, Corticoid-resistant)
– Controlled with the highest level of treatment
Bousquet J et al. J Allergy Clin Immunol 2010;126:926-938
Approaches used to define phenotypes
Pre-defined
• Resulting from a classificatory dissection of the
disease or from demographic features of patients
• Endotypes
Experimental
• Resulting from drug response in RCT
• Factor analysis
• Cluster analysis
GAIN Phenotypes
Factor analysis
1. FEV1 and FVC
2. SPT sensitization
3. Self-reported allergies
4. Rhinitis symptoms
5. Asthma symptoms
Pillon SG et al. Clin exp Allergy 2008,38:421-429
Approaches used to define phenotypes
Pre-defined
• Resulting from a classificatory dissection of the
disease or from demographic features of patients
• Endotypes
Experimental
• Resulting from drug response in RCT
• Factor analysis
• Cluster analysis
SARP Phenotypes
Cluster Analysis
1.
2.
3.
4.
5.
Early-onset atopic asthma, mild
15%
Early-onset atopic asthma, moderate 44%
Obese women, late-onset, non atopic
8%
Severe airflow obstruction*
16.5%
Severe airflow obstruction*
16.5%
* Differing for lung function, age of onset, atopic status, response to steroids
Moore WC et al. AJRCCM 2010,181:315-323
Discordant
Symptoms
Summary
Primary Care Asthma
Concordant
disease
EARLY SYMPTOM
PREDOMINANT
Non-eosinophilic
Normal BMI
High symptom expression
Symptoms
Symptoms
Refractory Asthma
OBESE FEMALE NON
EOSINOPHILIC
High symptom expression
BENIGN ASTHMA
Mixed middle aged cohort
Few symptoms
No airway inflammation
Little airway dysfunction
Discordant
Inflammation
Eosinophilic Inflammation
INFLAMMATION PREDOMINANT
Late onset
Greater proportion of males
Few daily symptoms
Haldar et al, AJRCCM 2008:178:218
Future of phenotyping: ‘Systems Medicine’
Patient reported
Clinical
Functional
Cellular
Molecular
From E. Bel
Auffray et al. Genome Med 2009;1:2
The usefulness of phenotyping the patient
with asthma and/or rhinitis
Conclusions
• Phenotyping of asthma and rhinitis represents a step
forward vs guidelines, since it reduces the heterogeneity
of these diseases and the variable response to drugs in
individual patients
• Phenotyping of asthma and rhinitis is at present not
satisfactory. Phenotyping should be based on well defined
clinical criteria and biomarkers relevant to the disease
course, severity and response to therapy
• Phenotyping is essential in future clinical trials of existing
and new treatments of asthma and rhinitis, in order to
document their effectiveness (and not only their efficacy!)