Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà

Presentazione sul tema: "Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà"— Transcript della presentazione:

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

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

3 From EBM to EBM Approach Target Product Experience Based Empirical Individual Textbooks Medicine Evidence Based RCT Population Guidelines Medicine

4 Evidence of superiority does not mean it works for all DrugComparator P < 0.05 Outcome Threshold of clinical relevance

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

7 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

8

9 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

10 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

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

12 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

13 Requirements for defining a phenotype Well-established genetic, biological, functional or clinical markers Epidemiologically defined

14 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

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

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

18 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

19 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

20 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)

21 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 numberEosinophilic and releasability ofNeutrophilic MC and basophils Tissue hyperreactivity IIIIIIIVV Allergic ASA intolerance, Pollutants, Hormones EIA,GER, Stress Clinical phenotypes The Spectrum of Allergic Disease Bonini S, Rasi G et al. Ann Allergy Asthma Immunoll 2001;87 Suppl.3:48-51 INFLAMMATION

22 How to distinguish different allergy 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?

23 Asthma Rhinitis Conjunctivitis Type ILate-phase IgEEos/Neutrophilic Target Hypersensitivitydependentinflammation organ inflammationwithout sIgE hyperreactivity Hyposensitisation Topical steroids ß2 agonists Antihistamines Antileukotrienes Anticolinergics Pollenosis SCUAD EIB, CR

24 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

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 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

28 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

29 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

30 SARP Phenotypes Cluster 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

31 Summary INFLAMMATION PREDOMINANT Late onset Greater proportion of males Few daily symptoms Concordant disease Discordant Inflammation Discordant Symptoms OBESE FEMALE NON EOSINOPHILIC High symptom expression EARLY SYMPTOM PREDOMINANT Non-eosinophilic Normal BMI High symptom expression EARLY ONSET ATOPIC Concordant symptoms, inflammation & airway dysfunction BENIGN ASTHMA Mixed middle aged cohort Few symptoms No airway inflammation Little airway dysfunction Primary Care AsthmaRefractory Asthma Symptoms Haldar et al, AJRCCM 2008:178:218 Symptoms Eosinophilic Inflammation

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

33 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!)