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VERSO UN TRATTAMENTO PERSONALIZZATO DELL’ASMA. Valore del farmaco nell’ASMA Controllo della malattia.

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Presentation on theme: "VERSO UN TRATTAMENTO PERSONALIZZATO DELL’ASMA. Valore del farmaco nell’ASMA Controllo della malattia."— Presentation transcript:

1 VERSO UN TRATTAMENTO PERSONALIZZATO DELL’ASMA

2 Valore del farmaco nell’ASMA Controllo della malattia

3 panel a first four days of treatment panel b four days of the following week panel c the last four days before the fatal attack mucous plug thickening of the basement membrane Saetta M et al. ERJ 1989;2:

4 Dissociation between Airway Inflammation and Airway hyperresponsiveness in Allergic Asthma Crimi E et al. Am J Respir Crit Care Med 1998; 157:4-9

5 Effects of Inhaled Corticosteroids Bronchial Function Bronchial Submucosa Asthmaticsymptoms Severity PC20 methacholine (mg/ml) mg/ml number of cells/mm 2 of submucosa eosinophil s T lymphocytes mast cells Pre-BD 6 wk Pre-BD Pr e-BD 6 wk Djukanovic et al, Am Rev Respir Dis 1992;145:669-74

6 Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroids AP Greening, PW Ind, M Northfield, G Shaw Lancet 1994; 344:

7 A substantial body of evidence from randomized controlled trials indicates that addition of a LABA to existing ICS therapy is clinically more effective than increasing the dose of ICS monotherapy

8  L’obiettivo principale del trattamento è ottenere il “buon controllo” dell’asma  Tale indice composito include tutte le principali misure cliniche e funzionali, ed è realisticamente raggiungibile in una alta percentuale di pazienti  Il solo controllo delle riacutizzazioni, senza tener conto dei sintomi quotidiani e del livello di funzione polmonare, non è sufficiente  La rivalutazione periodica dell’ottenuto controllo permette di adeguare la terapia sia in step-up che in step-down Controllo dell’Asma

9 Sintomi diurni nessuno Uso farmaci al bisogno nessuno PEF del mattino > 80% predetto Risvegli notturni nessuno Riacutizzazione di qualsiasi gravità nessuna Visite di emergenza nessuna Eventi avversi dovuti al trattamento nessuno Definizioni di “controllo” Controllo Totale dell’asma

10 Il CONTROLLO TOTALE dell’asma migliora con il trattamento prolungato Settimane Salm/FP Fluticasone % di pazienti controllati ogni settimana = Total Control Asthma Weeks Bateman et al, GOAL study, ARJCCM 2004

11 Controllo dell’asma Nonostante la larga diffusione delle Linee Guida, il controllo dell’asma è ancora insoddisfacente La gestione del paziente asmatico

12 J Allergy Clin Immunol 2007;120:1360-7

13 Adherence Different Phenotypes

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15 A major reason of the poor control of asthma is that patients fail to adhere to their treatment. The aim of this study was to identify factors affecting changes in asthma treatment adherence in an international court

16  Among the 428 non-adherent subjects in ECRHS-I, the only predictors of increased adherence among the variables considered were having regular appointments for asthma or not thinking that it is bad to take medicine all the time.  Gender, age at baseline, duration of the disease, smoking habit, educational level, having written instruction from a doctor, having a personal PEF meter and having had spirometry during the previous 12 months were not significant determinants for the improvement or the persistence of adherence to antiasthmatic treatment.

17 Adherence Different Phenotypes

18 Nonatopic/Intrinsic Traditionally asthma has been categorized as… Atopic/Extrinsic Allergen exposures, Progressive allergic inflammation, Hyperresponsiveness and symptoms in the airways Adult onset form of the disease Absence of family history. More severe symptoms and nasal polyps, and persistent airflow limitation in men. Atopic asthma often starts in childhood, Family history Response to treatment against anti T- helper cell type 2 (anti-Th2) inflammation Hyperresponsiveness and symptoms in the airways

19 Complexity of asthma mechanisms

20 Clinical or physiological phenotypes Severity- defined Exacerbation-prone Defined by chronic restriction Treatment-resistant Defined by age at onset Phenotypes related to the following triggers Aspirin or on-steroidal anti-inflammatory drugs Enviromental allergens Occupational allergens or irritants Menses Exercise Inflammatory phenotypes Eosinophilic Neutrophilic Pauci-granulocytic

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22 Volume 132, Issue 2Volume 132, Issue 2, Pages The majority of patients with severe adult-onset asthma are nonatopic and have persistent eosinophilic airway inflammation.

23 Wenzel S, Lancet 2006;386: Eosinophilic steroid-responsive Exacerbation prone Severe Fixed obstruction Allergic Exercise-induced Early/childhood onset phenotypes

24 Wenzel SE. Lancet 2006; 368: 804–13 Allergic Severe Occupational Non-Allergic Aspirin-sensitive Eosinophilic corticosteroid responsive PMA Late/adult onset

25 Clinical or physiological phenotypes Severity- defined Exacerbation-prone Defined by chronic restriction Treatment-resistant Defined by age at onset Phenotypes related to the following triggers Aspirin or on-steroidal anti-inflammatory drugs Enviromental allergens Occupational allergens or irritants Menses Exercise Inflammatory phenotypes Eosinophilic Neutrophilic Pauci-granulocytic

26 Eosinophilic asthma Neutrophilic asthma Paucigranulocytic asthma EG2 + Neutrophil elastase + Haldar e Pavord JACI 2007 Inflammatory Phenotypes

27 Eosinophilic asthma EG2 + Haldar e Pavord JACI 2007 Inflammatory Phenotypes

28 Comparison of two methods of processing induced sputum: selected versus entire sputum A Spanevello et al. AJRCCM 1998; 157: Selected Sputum Entire Sputum Eosinophils (%) asthmatics normals

29 Sputum eosinophils are higher in asthmatics than in controls and their amount in sputum increases with the severity of the disease

30 Sputum eosinophil count predicts response to corticosteroids Meijer et al Clin Exp Med 2002;32:

31 Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial Ruth H Green, Christopher E Brightling, Susan McKenna, Beverley Hargadon, Debbie Parker, Peter Bradding, Andrew J Wardlaw, lan D Pavord Lancet 2002;360:

32 Effects of Anti-IgE Omalizumab on Inflammation in Asthma Djukanovic et al Am J Respir Crit Care Med 2004:170 p

33 Targeted therapy with anti IL-5 in asthma Patients with sputum eosinophils > 3% despite steroid treatment Haldar et al. NEJM 2009;360: placebo 250 mg 75 mg 750 mg Eosinophilic asthma placebo 75 mg 250 mg 750 mg exacerbations Sputum eos Pavord et al. 2012

34 Benralizumab targets eosinophils by binding IL-5 receptor α, inducing apoptosis through antibody-dependent cell-mediated cytotoxicity. Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood. Laviolette M., et al.

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36 Wenzel S., et al Patients with persistent, moderate-to-severe asthma and elevated eosinophil levels human monoclonal antibody to the alpha subunit of the interleukin-4 receptor

37 Neutrophilic asthma Neutrophil elastase + Haldar e Pavord JACI 2007 Inflammatory Phenotypes

38 Neutrophilic Inflammation in severe persistent asthma. A Jatakanon et al. AJRCCM 1999; 160:

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40 Paucigranulocytic asthma Haldar e Pavord JACI 2007 Inflammatory Phenotypes

41 Phenotypes Clinical sputum database from January samples 297 patients AO + AHR + Eosinophils AO + AHR + Neutrophils (infective) AO + AHR + Neutrophils (non-infective) AO + AHR + Eosinophils + Neutrophils no AO + AHR + eosinophils no AO + AHR, no cellular inflammation no AO + no AHR + eosinophils Data submitted

42 Paucigranulocytic asthma Severe asthma No inflammatory cells No biological markers identified Steroid-resistant

43 Assessment of Airway Inflammation Indirect Indices Blood inflammatory cells

44 The inflammatory marker serum eosinophil cationic protein (ECP) compared with PEF as a tool to decide inhaled corticosteroid dose in asthmatic patients Lowhagen O et al. Respir Med 2002; 96: The objective of this study was to compare the inflammatory marker eosinophil cationic protein (ECP) with peak expiratory flow (PEF) in determining the therapeutic needs of inhaled corticosteroids in asthma patients assessed as asthma symptoms None of the used algorithms for ECP and PEF led to improvement in symptom scores, in spite of increased doses of inhaled corticosteroids. In the respect, both methods were equivalent and insufficient

45 AJRCC 2009

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49 Lebrikizumab  IgG4 humanized monoclonal antibody that binds to IL-13 Stratifying patients into a high Th2 phenotype using serum periostin, which is upregulated in lung epithelial cells by IL-13, may identify individuals responsive to blockade of IL-13. Corren J et al.

50 TAKE HOME MESSAGES

51 Where are we now? Asthma is treated empirically Cont.Uncont. Step 1 SABA PRN Step 2 Low-dose ICS Step 3 Low-dose ICS + LABA, or Medium-dose ICS Step 4 Medium-dose ICS + LABA Step 5 High-dose ICS + LABA Step 6 High-dose ICS + LABA + oral corticosteroid High-Need (severe) NHLBI Guidelines for the Diagnosis and Management of Asthma, Oct 2007 Standard of care guidelines: asthma is treated empirically according to clinical severity and response to treatment, not according to underlying biology

52 Treatment A Treatment B Treatment C Treatment D Asthma Treatment Where do we need to go? Personalized Medicine

53 Personalized Medicine for Asthma Getting there Improved understanding of the molecular mechanism of different clinical phenotypes of asthma. Non-invasive (preferably blood-based) biomarkers that identify molecular phenotypes to guide treatment.

54 Cont.Uncont. Step 1 SABA PRN Step 2 Low-dose ICS Step 3 Low-dose ICS + LABA, or Medium-dose ICS Step 4 Medium-dose ICS + LABA Step 5 High-dose ICS + LABA Step 6 High-dose ICS + LABA + oral corticosteroid High-Need (severe) NHLBI Guidelines for the Diagnosis and Management of Asthma, Oct 2007 OK!!!!

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