Phenotyping the patient with Rhinitis and Asthma

1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra.Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

2. Phenotyping the patient with Rhinitis and Asthma Sergio BoniniGuido Rasi Professor of Medicine Professor of Microbiology Second University of Naples University Tor Vergata, Rome IFT-CNR, Rome General Director AIFA Modena March 1, 2011

3. FromEBMtoEBM ApproachTarget Product Experience BasedEmpiricalIndividualTextbooks Medicine Evidence Based RCT PopulationGuidelines Medicine

4. Evidence of superiority does not meanit works for all Outcome P < 0.05 Threshold of clinical relevance Drug Comparator

5. Sublingual immunotherapy for hazelnut food allergy: A randomized, double-blind, placebo-controlled study with a standardized hazelnut extract Enrique E et al. JACI 2005

6. 0.02 0.014 30 30 NS 24 24 18 18 12 12 6 6 SLIT (n= 14) PLACEBO (n= 12) AFTER AFTER BEFORE BEFORE

7. 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

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

10. Phenotype-targetedtherapy (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”

11. Accessed, February 2010 710 No. of papers 383 120

12. Approachesusedtodefinephenotypes Pre-defined • Resultingfrom a classificatorydissectionof the disease or fromdemographicfeaturesofpatients • Endotypes Experimental • Resultingfromdrugresponse in RCT • Factoranalysis • Cluster analysis

13. Requirementsfordefining a phenotype • Well-established genetic, biological, functional or clinical markers • Epidemiologically defined

14. Approachesusedtodefinephenotypes Pre-defined • Resultingfrom a classificatorydissectionof the disease or fromdemographicfeaturesofpatients • Endotypes Experimental • Resultingfromdrugresponse in RCT • Factoranalysis • Cluster analysis

15. Infectious Rhinitis Non infectious Rhinitis Allergic IgE-mediated Viral Allergic Non IgE-mediated Bacterial Non allergic Parasitic Phenotyping of Rhinitis

16. 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)

17. Fixed obstruction Allergic Severe Eosinophilic corticosteroid responsive Exacerbation-prone Early/childhood onset phenotypes Excercise-induced Occupational PMA Aspirin-sensitive Severe Non-allergic Eosinophilic corticosteroid responsive Allergic Late/adult onset phenotypes

18. Approachesusedtodefinephenotypes Pre-defined • Resultingfrom a classificatorydissectionof the disease or fromdemographicfeaturesofpatients • Endotypes Experimental • Resultingfromdrugresponse in RCT • Factoranalysis • Cluster analysis

19. PRACTALL Endotypes • Aspirine sensitive asthma • Allergicbronchopulmonarymycosis • Allergicasthma (adults) • Pre-schoolweezers at high riskforasthma • Severe late-onseteosinophilic • Asthma in country-skiers Lotvall J et al. J AllergyClinImmunol 2011,127:355-360

20. Hallmarksofallergicdiseases • Specific IgE response • Allergic inflammation • (high total IgE, eosinophils, mast cells and basophils, etc.) • Hyperreactivity of target organs • (lung, nose, skin, eye)

21. The SpectrumofAllergicDisease Bonini S, Rasi G et al. AnnAllergyAsthmaImmunoll 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 High total IgE Upregulation of inflammatory cells Increased number Eosinophilic and releasability of Neutrophilic MC and basophils Tissue hyperreactivity I IIIII IVV Allergic ASA intolerance , Pollutants, Hormones EIA,GER, Stress Clinical phenotypes

22. Howtodistinguishdifferentallergyphenotypes? • Markers of sensitization • Markers of inflammation • Markers of tissue hyperreactivity • Skintests, IgEtests • Total IgE • Eosinophil and eosinophilproducts • Th2 profile • Non specificprovocationtests • New markers?

23. Asthma Rhinitis Conjunctivitis Type I Late-phase IgE Eos/Neutrophilic Target Hypersensitivity dependent inflammation organ inflammation without sIgE hyperreactivity Pollenosis SCUAD EIB , CR HyposensitisationTopicalsteroidsß2 agonists AntihistaminesAntileukotrienesAnticolinergics

24. Approachesusedtodefinephenotypes Pre-defined • Resultingfrom a classificatorydissectionof the disease or fromdemographicfeaturesofpatients • Endotypes Experimental • Resultingfromdrugresponse in RCT • Factoranalysis • Cluster analysis

25. 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

26. 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

27. Approachesusedtodefinephenotypes Pre-defined • Resultingfrom a classificatorydissectionof the disease or fromdemographicfeaturesofpatients • Endotypes Experimental • Resultingfromdrugresponse in RCT • Factoranalysis • Cluster analysis

28. GAIN PhenotypesFactoranalysis • FEV1 and FVC • SPT sensitization • Self-reportedallergies • Rhinitissymptoms • Asthmasymptoms Pillon SG et al. ClinexpAllergy 2008,38:421-429

29. Approachesusedtodefinephenotypes Pre-defined • Resultingfrom a classificatorydissectionof the disease or fromdemographicfeaturesofpatients • Endotypes Experimental • Resultingfromdrugresponse in RCT • Factoranalysis • Cluster analysis

30. SARP PhenotypesCluster Analysis • Early-onsetatopicasthma, mild 15% • Early-onsetatopicasthma, moderate 44% • Obese women, late-onset, non atopic 8% • Severe airflowobstruction* 16.5% • Severe airflowobstruction* 16.5% * Differingforlungfunction, ageofonset, atopic status, responsetosteroids Moore WC et al. AJRCCM 2010,181:315-323

31. Summary Discordant Symptoms Primary Care Asthma Refractory Asthma Concordant disease EARLY SYMPTOM PREDOMINANT Non-eosinophilicNormal BMIHigh symptom expression OBESE FEMALE NON EOSINOPHILIC High symptom expression Symptoms INFLAMMATION PREDOMINANT Late onset Greater proportion of malesFew daily symptoms BENIGN ASTHMAMixed middle aged cohortFew symptomsNo airway inflammationLittle airway dysfunction EARLY ONSET ATOPIC Concordant symptoms, inflammation & airway dysfunction Discordant Inflammation Symptoms Eosinophilic Inflammation Haldar et al, AJRCCM 2008:178:218

32. Future of phenotyping: ‘Systems Medicine’ Patient reported Clinical Functional Cellular Molecular From E. Bel Auffrayet al. Genome Med 2009;1:2

33. The usefulness of phenotyping the patient with asthma and/or rhinitisConclusions • 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!)