VERSO UN TRATTAMENTO PERSONALIZZATO DELL’ASMA

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;2:1008-1012

4. DissociationbetweenAirwayInflammation and Airwayhyperresponsiveness in AllergicAsthma Crimi E et al. Am J RespirCrit Care Med 1998; 157:4-9

5. mast cells 760 720 240 200 160 120 80 40 0 Pre-BD 6 wk Pre-BD 6 wk Pre-BD 6 wk EffectsofInhaledCorticosteroids Bronchial Function Bronchial Submucosa PC20 methacholine (mg/ml) Asthmatic symptoms eosinophils T lymphocytes numberofcells/mm2ofsubmucosa Severity mg/ml Djukanovicet al, Am RevRespirDis 1992;145:669-74

6. Addedsalmeterol versus higher-dose corticosteroid in asthmapatients with symptoms on existinginhaledcorticosteroids AP Greening, PW Ind, M Northfield, G Shaw Lancet 1994; 344:219-224

7. A substantial body of evidence from randomizedcontrolled trials indicatesthataddition of a LABA to existing ICS therapyisclinically more effectivethanincreasing the dose of ICS monotherapy

8. Controllo dell’Asma • 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

9. Definizioni di “controllo” ControlloTotaledell’asma Sintomidiurninessuno Usofarmaci al bisognonessuno PEF del mattino> 80% predetto Risveglinotturninessuno Riacutizzazione di qualsiasigravitànessuna Visitedi emergenzanessuna Eventiavversidovuti al trattamentonessuno

10. Il CONTROLLO TOTALE dell’asmamigliora con iltrattamentoprolungato 100 Salm/FP Fluticasone 80 60 % di pazienti controllati ogni settimana = Total Control Asthma Weeks 40 20 0 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Settimane Bateman et al , GOAL study, ARJCCM 2004

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

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

13. Adherence DifferentPhenotypes

15. The aim of thisstudywas to identifyfactorsaffectingchanges in asthma treatment adherence in an international court A major reason of the poor control of asthmaisthatpatientsfail to adhere to their treatment.

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 • DifferentPhenotypes

18. Traditionallyasthmahasbeencategorizedas… Atopic/Extrinsic Nonatopic/Intrinsic Allergenexposures, Progressive allergicinflammation, Hyperresponsivenessand symptoms in the airways Hyperresponsivenessand symptoms in the airways • Atopic asthma often starts in childhood, • Family history • Response to treatment against anti T-helper cell type 2 (anti-Th2) inflammation • Adult onset form of the disease • Absence of family history. • More severe symptoms and nasal polyps, and persistent airflow limitation in men.

19. Complexityofasthmamechanisms

20. Clinical or physiologicalphenotypes Severity- defined Exacerbation-prone Defined by chronicrestriction Treatment-resistant Defined by ageatonset Phenotypesrelated to the followingtriggers Aspirin or on-steroidal anti-inflammatorydrugs Enviromentalallergens Occupationalallergens or irritants Menses Exercise Inflammatoryphenotypes Eosinophilic Neutrophilic Pauci-granulocytic

22. Volume 132, Issue 2 , Pages 336-341 The majority of patients with severe adult-onset asthma are nonatopicand have persistent eosinophilicairway inflammation.

23. Early/childhoodonsetphenotypes Fixed obstruction Exacerbation prone Severe Exercise-induced Eosinophilic steroid-responsive Allergic Wenzel S, Lancet 2006;386:804-813

24. PMA Aspirin-sensitive Allergic Eosinophiliccorticosteroid responsive Severe Occupational Non-Allergic Late/adultonset Wenzel SE. Lancet 2006; 368: 804–13

25. Clinical or physiologicalphenotypes Severity- defined Exacerbation-prone Defined by chronicrestriction Treatment-resistant Defined by ageatonset Phenotypesrelated to the followingtriggers Aspirin or on-steroidal anti-inflammatorydrugs Enviromentalallergens Occupationalallergens or irritants Menses Exercise Inflammatoryphenotypes Eosinophilic Neutrophilic Pauci-granulocytic

26. Inflammatory Phenotypes Eosinophilicasthma Neutrophilicasthma EG2 + Paucigranulocyticasthma Neutrophilelastase + Haldar e Pavord JACI 2007

27. InflammatoryPhenotypes Eosinophilicasthma Haldar e Pavord JACI 2007 EG2 +

28. 30 25 20 15 10 5 0 asthmatics normals Eosinophils (%) Entire Sputum Selected Sputum Comparison of two methods of processing induced sputum: selected versus entire sputum A Spanevello et al. AJRCCM 1998; 157: 665-668

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;32:1096-1103

31. Asthmaexacerbations and sputumeosinophilcounts: a randomisedcontrolled trial Ruth H Green, Christopher E Brightling, Susan McKenna, BeverleyHargadon, Debbie Parker, Peter Bradding, Andrew J Wardlaw, lan D Pavord Lancet 2002;360: 1715-21

32. Effects of Anti-IgEOmalizumab on Inflammation in Asthma Djukanovic et al Am J Respir Crit Care Med 2004:170 p583-593

33. Eosinophilic asthma Targeted therapy with anti IL-5 in asthmaPatients with sputum eosinophils > 3% despite steroid treatment Pavord et al. 2012 Haldar et al. NEJM 2009;360:973-984 exacerbations exacerbations placebo 250 mg 75 mg 750 mg Sputum eos Sputum eos placebo 75 mg 250 mg 750 mg

34. Laviolette M., et al. Benralizumab targets eosinophils by binding IL-5 receptorα, inducingapoptosisthroughantibody-dependentcell-mediatedcytotoxicity. Single-dose intravenous and multiple-dose subcutaneousbenralizumabreducedeosinophilcounts in airway mucosa/submucosaand sputum and suppressedeosinophilcountsin bone marrow and peripheralblood.

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

37. InflammatoryPhenotypes Neutrophilicasthma Neutrophilelastase + Haldar e Pavord JACI 2007

38. NeutrophilicInflammation in severe persistentasthma. A Jatakanon et al. AJRCCM 1999; 160: 1532-1539

40. InflammatoryPhenotypes Paucigranulocyticasthma Haldar e Pavord JACI 2007

41. Phenotypes Clinicalsputum database from January 2005 388 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 cellularinflammation no AO + no AHR + eosinophils Data submitted

42. Paucigranulocyticasthma • Severe asthma • No inflammatorycells • No biologicalmarkersidentified • Steroid-resistant

43. Assessment of AirwayInflammation IndirectIndices Blood inflammatorycells

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; 96:95-101 The objective of thisstudywas to compare the inflammatory marker eosinophilcationicprotein (ECP) with peakexpiratory flow (PEF) in determining the therapeuticneeds of inhaledcorticosteroids in asthmapatientsassessedasasthmasymptoms None of the usedalgorithms for ECP and PEF led to improvement in symptomscores, in spite of increaseddoses of inhaledcorticosteroids. In the respect, bothmethodswereequivalent and insufficient

45. AJRCC 2009

46. AJRCC 2009

48. AJRCC 2009

49. Corren J et al. 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.

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