I Fenotipi dell Asma. Angelo G. Corsico. Università di Pavia. IRCCS Fondazione Policlinico S.Matteo

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1 Università di Pavia IRCCS Fondazione Policlinico S.Matteo Angelo G. Corsico SC Pneumologia Dipartimento di Medicina Interna e Terapia Medica I Fenotipi dell Asma

2 Definition of asthma Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation. NEW! GINA 2014 Global Initiative for Asthma

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4 (468 subjects with physician-diagnosed current asthma using ICS in the last 12 months) (ECRHS II; ) 49% 15% 36% Controlled Partially controlled Uncontrolled JACI 2007;120:1360-7

5 DISTRIBUTION OF THE COST COMPONENTS ACCORDING PHARMACOLOGICAL TO THE DEGREE OF DISEASE CONTROL TREATMENT 88% 12% * * 30% 60% 8% 16% EUR % EUR 625 EUR 2,032 * 64% 12% HOSPITAL SERVICES * DOCTOR VISITS CLINICAL AND LAB. TESTS INDIRECT COSTS CONTROLLED (n = 32) PARTLY CONTROLLED (n = 175) UNCONTROLLED (n = 255) Drugs Visits + clinical & Lab. tests Indirect costs Hospital services Accordini S, Corsico AG, et al. Int Arch Allergy Immunol. 2013;160:93.

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8 Difficult-to-treat asthma, severe/refractory asthma 5 10% of asthmatics whose asthma cannot be controlled with a combination of high-dose ICS together with LABA Intensive comorbid investigation and multiple re-evaluations are necessary to ensure that asthma is the correct diagnosis. The pathophysiology of severe/refractory asthma is likely to be different from that of the mild to moderate form. The immune mechanisms underlying the inflammatory process are not purely Th2.

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10 Fenotipo = genotipo + ambiente Fenotipo = caratteristiche visibili di un organismo che risultano dall interazione tra il suo corredo genetico e l ambiente.

11 Asma approccio clinico: categorie fenotipiche Aspetti clinici o fisiopatologici Gravità Frequenti esacerbazioni Ostruzione fissa Resistente ai trattamenti Età di insorgenza Trigger Aspirina o FANS Allergeni ambientali Sostanze occupazionali o irritanti Ciclo mestruale Esercizio Infiammazione Eosinofila Neutrofila Paucigranulocitica Comorbidità Obesità Reflusso gastro-esofageo BPCO

12 Different Asthma Phenotypes Hypothetical yearly peak prevalence of wheezing according to phenotype in childhood Martinez, F. D. Pediatrics 2002;109:

13 Early/childhood onset phenotypes

14 Late/adult onset

15 Distribution of sputum cellular phenotypes in severe asthma Schleich F. Respiratory Medicine (2014) 108, 1723e1732

16 Classification of SA according to: sputum eosinophil count (>or <3%) FENO levels (>or <27 ppb) blood eosinophil count (>or <188/mm3) Schleich F. Respiratory Medicine (2014) 108, 1723e1732

17 Conclusion: Approximately 60% of elderly subjects with asthma had rhinitis, mainly allergic and often untreated, whose onset preceded asthma symptoms by a mean of approximately 10 years. Nonallergic asthma was better controlled than allergic asthma. HDM sensitization was greater in subjects with asthma with features resembling chronic obstructive pulmonary disease (39% vs 28%). When restricting analysis to this group, the negative role of HDM in overall asthma control (forced expiratory volume in first second and Asthma Control Test) was significant. Ann Allergy Asthma Immunol 116 (2016) 206e211

18 Cluster analisys Analisi multivariata che consente di raggruppare i pazienti in cluster (gruppi fenotipici), che presentano differenze clinicamente rilevanti, utilizzando diverse variabili impiegate come misure di similarità.

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20 Symptoms Eosinophilic inflammation Haldar et al. Am J Respir Crit Care Med 2008;178:

21 Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program Cluster 1= early onset atopic asthma with normal lung function treated with two or fewer controller medications (82%) and minimal health care utilization. Cluster 2 = early-onset atopic asthma and preserved lung function but increased medication requirements (29% on three or more medications) and health care utilization. Cluster 3 = mostly older obese women with late-onset nonatopic asthma, moderate reductions in FEV1, and frequent oral corticosteroid use to manage exacerbations. Clusters 4 & 5 = severe airflow obstruction with bronchodilator responsiveness but differ in to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids Moore. AJRCCM 2010;181:

22 SARP: Tree performance Mild Atopic Asthma Mild-Moderate Atopic Asthma Late onset Non-atopic Asthma Severe Atopic Asthma Severe Asthma with Fixed Obstruction Using only pre and post-bronchodilator FEV1% pred. and age of onset, 80% were correctly assigned. %= of subjects from that cluster correcly assigned. N = 728 Moore. AJRCCM 2010;181:

23 Endotipo E un sottotipo definito da un particolare meccanismo funzionale o biologico. Deve essere distinto dal fenotipo che è una caratteristica osservabile o un aspetto di una una malattia, ad esempio un tratto morfologico, di sviluppo, una proprietà biochimica o fisiologica, un aspetto comportamentale, senza alcuna implicazione rispetto ai suoi meccanismi. E previsto che pazienti con uno specifico endotipo si presentino in particolari cluster di malattia.

24 From clinical/statistical to molecular phenotypes S.E. Wenzel / Pulmonary Pharmacology & Therapeutics (2013) in press

25 Brusselle G. Ann Am Thorac Soc Vol 11, Supplement 5, pp S322 S328, 2014

26 Varricchi G. Curr Opin Allergy Clin Immunol 2016, 16:

27 Omalizumab blocca le IgE libere BLOCCARE LE IgE porta ad un effetto MULTI-TARGET! Un anti-ige induce ad effetti diretti e indiretti agendo su molte componenti cellulari legate alla risposta immune Th2 mediata Le IgE sono un attore chiave nell induzione e nel mantenimento della risposta allergica (infiammazione) Impatto su T-lymphocytes e B-lymphocytes 5 Lega le IgE libere e downregola i recettori per le IgE su mastociti basofili e cellule dendritiche RIDUZIONE di IL-2, IL-4, IL-5, IL-13 e GM-CSF 1 4 RIDUZIONE DI EOSINOFILI periferici, nello sputo e a livello della sottomucosa Modificato da Humbert et al. JACI Pract. 2014

28 Varricchi G. Curr Opin Allergy Clin Immunol 2016, 16:

29 Specifiche terapie per specifici target immunoflogistici dell asma Thomson, BMC Medicine 2011

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32 Probability Asthma control maintained on lower ICS dose FAS= Full Analysis Set SQ HDM SLIT-tablet Reduced risk of exacerbations during ICS reduction 15% reduction 42% reduction Time to first moderate or severe asthma exacerbation -81 µg p= Placebo 6 SQ-HDM 12 SQ-HDM % ICS reduction Hazard Ratio (% risk reduction) 12 SQ-HDM: 0.66 (34%), p= SQ-HDM : 0.69 (31%), p= % ICS reduction 0.00 Treatment (12 SQ-HDM, 6 SQ-HDM or placebo) Time (days) 9% reduction ~100 days ~170 days ~180 days 63% reduction Virchow et al. JAMA 2016;315(16): µg p= Mosbech H et al. J Allergy Clin Immunol. 2014;134(3): de Blay F et al. Respir Med. 2014;108(10):1430-7

33 Annual decline in FEV1 (95% CI) according to the level of total IgE and to the ICS use during the follow-up Elevated (>100 ku/l) total IgE levels were present in 47% of the subjects JACI 2007;119:611-7 included in the analysis.

34 Responsiveness of TH2-high asthma to ICSs Woodruff PG.. Am J Respir Crit Care Med 2009;180:

35 IL-13 and Non IL- 13 Inflammatory Pathways in Asthma Inhaled allergen activates mast cells Allergens are processed by dendritic cells Dendritic cells then attract and activate Th2 Th2 secrete IL-5, which is necessary for the development and survival of eosinophils; and IL-9, which activates mast cells. Th2 secrete IL-4 and IL-13, which induce B cells to produce IgE. IL-13 promotes the survival and migration of IL-13 also has direct eosinophils effects on airway smooth muscle Kraft M. NEJM 2011

36 Moore WC. J Allergy Clin Immunol 2014;133: Moore WC. J Allergy Clin Immunol 2014;133:

37 Maes T. J Allergy Clin Immunol 2016;137:

38 Surrogate biomarkers for inflammatory phenotypes defined by induced sputum cell counts in severe asthma Schleich F. Current Topics in Medicinal Chemistry, 2016,16, 1561.

39 Personalized Respiratory Medicine: Exploring the Horizon, Addressing the Issues Agusti et al.ajrccm 2015

40 The White House Office of the Press Secretary For Immediate Release January 30, 2015 FACT SHEET: President Obama s Precision Medicine Initiative Building on President Obama s announcement in his State of the Union Address, today the Administration is unveiling details about the Precision Medicine Initiative, a bold new research effort to revolutionize how we improve health and treat disease. Launched with a $215 million investment in the President s 2016 Budget, the Precision Medicine Initiative will pioneer a new model of patient-powered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients. Most medical treatments have been designed for the average patient. As a result of this one-size-fits-all-approach, treatments can be very successful for some patients but not for others. This is changing with the emergence of precision medicine, an innovative approach to disease prevention and treatment that takes into account individual differences in people s genes, environments, and lifestyles. Precision medicine gives clinicians tools to better understand the complex mechanisms underlying a patient s health, disease, or condition, and to better predict which treatments will be most effective.

41 PATIENTS ARE NOT ALL THE SAME!