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Phenotyping the patient with Rhinitis and Asthma

Sergio Bonini Guido RasiProfessor of Medicine Professor of MicrobiologySecond University of Naples University Tor Vergata, RomeIFT-CNR, Rome General Director AIFA

Modena March 1, 2011

From EBM to EBM

Approach Target ProductExperienceBased Empirical Individual TextbooksMedicine

EvidenceBased RCT Population GuidelinesMedicine

Evidence of superiority does not mean it works for all

Drug Comparator

P < 0.05Outcome

Threshold of clinical relevance

Sublingual immunotherapy for hazelnut food allergy: A randomized, double-blind, placebo-controlled study with a standardized hazelnut extract

Enrique E et al. JACI 2005

BEFORE AFTER

SLIT (n= 14) PLACEBO (n= 12)

6

30

24

18

12

BEFORE AFTER

6

30

24

18

12

0.02

0.014NS

Larj, M. J. et al. Chest 2004;126:138S-149S

Distribution of FEV1 response in 895 asthmatic patients aged 15 to 85 years treated with either beclomethasone or

montelukast for 12 weeks

Reasons for different responses to drugs in patients with rhinitis and/or asthma

Different genotypes

• Beta-2 agonists (ADRB2, ARG1)

• Anti-leucotrienies (ALOX5, MRP1, LTC4S,CYSLTR1,2)

• Corticosteroids (CRHHR1, NR3CI, STIP1)

Different phenotypes

• Age, race, gender

• Duration of the disease

• Co-morbidities

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”

No. of papers

383

710

120

Accessed, February 2010

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

Infectious Rhinitis

Viral

Bacterial

Parasitic

Non infectiousRhinitis

AllergicIgE-mediated

AllergicNon IgE-mediated

Non allergic

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)

Eosinophilic

corticosteroid responsiveExcercise-induced

Allergic

Fixedobstruction

Severe

Exacerbation-prone

Allergic

Occupat

ional

Non-allergic

Aspirin-sensitive

Eosinophilic corticosteroid responsive

PMA

Severe

Early/childhood onset phenotypes

Late/adult onsetphenotypes

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)

HLA genes and allergen exposure

Genetic and environmental influences on inflammatory genes overexpression

Neural and tissue factor (?)

Cytokines

Enhanced specific IgE response High total IgE Upregulation of inflammatory cells

Increased number Eosinophilic and releasability of NeutrophilicMC and basophils

Tissue hyperreactivity

I II III IV V

Allergic ASA intolerance , Pollutants, Hormones EIA,GER, Stress

Clinical phenotypes

The Spectrum of Allergic DiseaseBonini S, Rasi G et al. Ann Allergy Asthma Immunoll 2001;87 Suppl.3:48-51

INFLAMMATION

How to distinguish differentallergy phenotypes?

• Markers of sensitization

• Markers of inflammation

• Markers of tissue hyperreactivity

• Skin tests, IgE tests

• Total IgE• Eosinophil and eosinophil

products• Th2 profile

• Non specific provocation tests• New markers?

Asthma

Rhinitis

Conjunctivitis

Type I Late-phase IgE Eos/Neutrophilic TargetHypersensitivity dependent inflammation organ

inflammation without sIgE hyperreactivity

Hyposensitisation Topical steroids ß2 agonists Antihistamines Antileukotrienes Anticolinergics

Pollenosis SCUAD EIB , CR

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 notresulting 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 PhenotypesFactor 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 PhenotypesCluster Analysis

1. Early-onset atopic asthma, mild 15%2. Early-onset atopic asthma, moderate 44%3. Obese women, late-onset, non atopic 8%4. Severe airflow obstruction* 16.5%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

Summary

INFLAMMATION PREDOMINANT Late onset

Greater proportion of malesFew daily symptoms

Concordant disease

Discordant Inflammation

Discordant Symptoms

OBESE FEMALE NON EOSINOPHILIC

High symptom expression

EARLY SYMPTOM PREDOMINANTNon-eosinophilic

Normal BMIHigh symptom expression

EARLY ONSET ATOPIC

Concordant symptoms, in

flammation & airw

ay dysfunction

BENIGN ASTHMAMixed middle aged cohort

Few symptomsNo airway inflammationLittle airway dysfunction

Primary Care Asthma Refractory AsthmaS

ymp

tom

s

Haldar et al, AJRCCM 2008:178:218

Sym

ptom

s

Eosinophilic Inflammation

From E. Bel Auffray et al. Genome Med 2009;1:2

Patient reported

Clinical

Functional

Cellular

Molecular

Future of phenotyping: ‘Systems Medicine’

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!)