Linee Guida Italiane – Aggiornamento 2004 G IN A lobal itiative for Sthma Linee Guida Italiane – Aggiornamento

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9 Linee Guida Italiane – Aggiornamento 2004
G IN A lobal itiative for Sthma Linee Guida Italiane – Aggiornamento 2004

10 Asma bronchiale: definizione
L’asma è una malattia infiammatoria cronica delle vie aeree caratterizzata da: Episodi ricorrenti di dispnea, respiro sibilante, tosse e senso di costrizione toracica Ostruzione bronchiale (di solito reversibile spontaneamente o dopo trattamento farmacologico) Iperreattività bronchiale Infiltrazione di cellule infiammatorie, rilascio di mediatori e rimodellamento strutturale delle vie aeree

11 Asthma Definition ASTHMA. Asthma is a heterogeneous disease, usually characterized by airway inflammation, that is defined by the presence 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. [GINA 2016]

12 Airway inflammation Normal Asthma Mauad T et al 2004 AJRCCM

13 Variable expiratory airflow limitation is variation that is outside the normal range for healthy individuals. For example: “bronchodilator reversibility”: increase in FEV1 of >12% and >200 mL (children: >12% predicted), min after administration of a rapid-acting β2-agonist bronchial provocation test: in adults, decrease in FEV1 of ≥20% with direct challenge agents (methacholine, histamine) or ≥15% with indirect challenge agents (hypertonic saline, eucapnic hyperventilation, mannitol) or, with exercise challenge, decrease of >10% and >200 mL in adults or >12% predicted in children. It should be confirmed that FEV1/FVC has also decreased, to avoid false-positives (variable inspiration; upper airway dysfunction) average within-day variability of peak expiratory flow (PEF) expressed as amplitude percent mean of >10% (>13% in children).

14 Epidemiologia dell’asma
L’asma è una delle patologie più diffuse al mondo L’asma è diffusa in tutti i paesi ma varia in modo considerevole da nazione a nazione e può mostrare variazioni anche all’interno della stessa nazione La variazione geografica è confermata anche dalla distribuzione dell’atopia e della reattivita’ bronchiale La variazione geografica è simile per bambini e adulti In Italia la prevalenza di asma è più bassa rispetto a quella di molte altre nazioni, soprattutto dei paesi anglosassoni, sia nella popolazione infantile sia negli adulti

15 Distribuzione geografica della prevalenza dell’asma in atto - ECRHS
ECRHS – Eur Respir J 1996; 9:

16 Prevalenza di sibili e asma in bambini ed adolescenti italiani
Studio SIDRIA ( ) % 6 - 7 anni anni SIDRIA Collaborative Group - Eur Respir J 1997; Eur Respir J 1999

17 Epidemiologia dell’asma
Negli ultimi 20 anni la prevalenza di asma è aumentata considerevolmente in molti paesi, soprattutto nei bambini

18 Epidemiologia dell’asma
Alcune evidenze, anche italiane, sembrerebbero documentare che la prevalenza di asma e delle manifestazioni asmatiche non e’ attualmente in ulteriore aumento La stabilizzazione della prevalenza della sintomatologia asmatica, secondo alcuni studi, anche italiani, essere associata sembra all’incremento dei trattamenti antiasmatici

19 Epidemiologia dell’asma
L’attuale prevalenza di asma in Italia, benché inferiore a quella di molte altre nazioni, rappresenta una notevole fonte di costi sia sociali sia umani

20 Componenti del costo medio annuale di un paziente adulto asmatico in Italia (studio ISAYA)
Fonte: ISAYA

21 Fattori di rischio di asma
Fattori individuali: predispongono l’individuo all’asma Fattori ambientali: - influenzano la possibilità di sviluppare asma in soggetti predisposti, - scatenano le riacutizzazioni e/o causano la persistenza dei sintomi

22 ASMA = MALATTIA GENETICA COMPLESSA
Iperreattività bronchiale Sintomi VEMS ? Allergeni Infezioni ? ? GENOTIPO AMBIENTE = + FENOTIPO ? ? IgE totali ? IgE specifiche + prove cutanee Inquinanti atmosferici Sforzo fisico Eosinofili

23 Fattori di rischio di asma
Fattori individuali Predisposizione genetica Atopia Iperresponsività delle vie aeree Sesso Razza/etnia Fattori ambientali Allergeni Sensibilizzanti professionali Fumo di tabacco Inquinamento atmosferico Infezioni delle vie respiratorie Fattori socio-economici Dimensioni del nucleo familiare Additivi alimentari e farmaci Obesità Infezioni parassitarie

24 Fattori in grado di indurre riacutizzazioni asmatiche
Infezioni delle vie respiratorie Allergeni Inquinanti atmosferici interni (fumo, ecc..) ed esterni (urbani, industriali, ecc..) Esercizio fisico Fattori meteorologici Farmaci Alimenti

25 Riacutizzazioni asmatiche e virus respiratori
Le infezioni virali sono causa frequente di riacutizzazioni asmatiche I soggetti asmatici sono più suscettibili all’infezione da rinovirus E’ dimostrato un sinergismo tra infezioni virali ed esposizione ad allergeni nell’indurre le riacutizzazioni e nel determinare la gravità delle riacutizzazioni Frase 2: Lancet ’02 Frase 3: BMJ ’02 (sinergismo), Lancet ’03 (infezioni virali che determinano la gravità di riacutizzazioni)

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31 Rapporto del Gruppo di Lavoro del GINA
Argomenti: Definizione Epidemiologia ed impatto socio- economico dell’asma Fattori di rischio Patogenesi Diagnosi e Classificazione Educazione del paziente e somministrazione delle cure Programma di trattamento dell’asma in sei parti Raccomandazioni per la ricerca

32 BRONCOPNEUMOPATIA CRONICA OSTRUTTIVA OSTRUZIONE BRONCHIALE
FEV1 FEV1 = valore normale D = VARIAZIONE DI FEV1 PRE-BRONCODILATATORE POST-BRONCODILATATORE OSTRUZIONE BRONCHIALE reversibile

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35 Classificazione di Gravità
CLASSIFICAZIONE DI GRAVITA’ Caratteristiche cliniche in assenza di terapia Sintomi notturni Sintomi FEV1 o PEF Continui Attività fisica limitata STEP 4 Grave Persistente £ 60% predetto Variabilità > 30% Frequenti STEP 3 Moderato Persistente % predetto Variabilità > 30% Quotidiani Attacchi che limitano L’attività 1 volta Alla settimana STEP 2 Lieve Persistente > 2 volte al mese ³ 80% predetto Variabilità % > 1 volta/settimana ma < 1 volta / giorno < 1 volta/settimana Asintomatico e con normale PEF tra gli attacchi STEP 1 Intermittente ³ 80% predetto Variabilita < 20% £ 2 volte al mese La presenza di almeno uno dei criteri di gravità è sufficiente per classificare un paziente in un determinato livello di gravità

36 Levels of Asthma Control
Characteristic Controlled (All of the following) Partly controlled (Any present in any week) Uncontrolled Daytime symptoms None (2 or less / week) More than twice / week 3 or more features of partly controlled asthma present in any week Limitations of activities None Any Nocturnal symptoms / awakening Need for rescue / “reliever” treatment More than twice / week Lung function (PEF or FEV1) Normal < 80% predicted or personal best (if known) on any day Exacerbation One or more / year in any week

37 1 2 3 4 5 LEVEL OF CONTROL TREATMENT OF ACTION TREATMENT STEPS REDUCE
controlled partly controlled uncontrolled exacerbation LEVEL OF CONTROL maintain and find lowest controlling step consider stepping up to gain control step up until controlled treat as exacerbation TREATMENT OF ACTION INCREASE TREATMENT STEPS REDUCE INCREASE STEP 1 2 3 4 5

38 Stepwise management - pharmacotherapy
Low-dose inhaled corticosteroid (ICS) Consider low-dose ICS Leukotriene receptor antagonists (LTRA) Low-dose theophylline* Med/high-dose ICS Low-dose ICS+LTRA (or + theoph*) As-needed short-acting beta2-agonist (SABA) Low-dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium, omali- zumab, mepoli- zumab* Add tiotropium High-dose ICS + LTRA (or + theoph*) Add low- dose OCS As-needed SABA or low-dose ICS/formoterol# *† *Not for children <12 years. **For children 6–11 years, preferred Step 3 treatment is medium dose ICS. #Low-dose ICS/FORM is the reliever medication for patients prescribed low-dose BUD/FORM or low-dose BDP/FORM maintenance and reliever therapy. †Tiotropium by mist inhaler is an add-on treatment for patients with a history of exacerbations; it is not indicated in children <12 years. Global Initiative for Asthma (GINA). GINA Report (accessed July 2016)

39 Early symptom predominant Inflammation Predominant
Where is the need? Not in mild/moderate asthma “ A symptom based approach would be effective for mild to moderate asthma,… where concordance was observed between inflammation and symptoms” Haldar P, AJRCCM 2008 Discordant Symptoms Monitoring inflammation allows down-titration of corticosteroids Primary Care Asthma Secondary Care Asthma Symptoms Early symptom predominant Concordant Disease Early onset Atopic Asthma Benign Asthma Symptom-based approach to therapy titration may be sufficient Obese Non-eosinophilic Monitoring inflammation allows targeted corticosteroids to lower exacerbation frequency Discordant Inflammation Inflammation Predominant Eosinophilic Inflammation 40

40 Empirical treatment appropriate
Biomarker-guided management

41 ERS/ATS definition of severe asthma
‘Asthma which requires treatment with guidelines suggested medications for GINA steps 4−5 asthma (high-dose inhaled corticosteroids and long-acting β2-agonists or leukotriene modifier/theophylline) for the previous year or systemic corticosteroids for ≥50% of the previous year to prevent it from becoming “uncontrolled” or which remains “uncontrolled” despite this therapy’ Note: among patients aged 6 years and older Chung KF et al. Eur Respir J 2014;43:343−73

42 Patient has severe refractory asthma
Patient has uncontrolled asthma and/or Frequent (≥2/yr) asthma exacerbations * High intensity asthma treatment is defined as: • 1000 mcg/day fluticasone equivalent combined with long acting beta-2- agonists or other controllers (adults) Yes Patient has prescription of NO high dose inhaled corticosteroids* Increase dose of inhaled corticosteroids and with or without systemic corticosteroids long-acting beta agonists to maximal daily dose Patient has a confirmed diagnosis of asthma # NO Demonstrate variable airflow limitation (PEF, spirometry, methacholine challenge, tapering)) Yes Yes Patient is using inhalers correctly and has received NO adequate asthma education Provide information and check inhaler technique Yes Patient is compliant with asthma treatment NO Check pharmacy records, powder inhalations, plasma cortisol or prednisolone levels Alternative or overlapping diagnoses as primary NO conditions are excluded Exclude alternative diagnoses, Yes Yes Exposure to sensitizing and non-sensitizing NO substances in school/workplace or home are excluded Check environmental exposure at school/work/home, Drugs that may cause bonchoconstriction are NO are discontinued Discontinuee NSAIDs, beta-blockers, hormone replacement therapy, if possible, Yes Yes Co-morbidities are optimally treated NO Address and optimally treat rhinosinusitis, gastric reflux, obesity, depression and anxiety, Yes Patient has been followed and reassessed for at NO least 6 months Repeat diagnostic steps and reassess patient Patient has severe refractory asthma

43 The use of Omalizumab in the treatment of severe allergic asthma.
The Wave of Personalized Medicine in asthma “Biomarker-Driven Therapy Is Ready for the Clinic” The use of Omalizumab in the treatment of severe allergic asthma. Holgate ST, Resp Med 2009 44

44 Therapeutic antibodies entered clinical development
Cytokines released by immune-inflammatory and airway structural cells contribute to asthma inflammation1 Research has identified several potential cytokine targets for anti-asthma therapy2–4 Therapeutic antibody Target Infliximab TNF-α Mepolizumab IL-5 Golimumab Benralizumab IL-5R Etanercept Reslizumab Daclizumab IL-2R (CD25) QAX5764 IL-13 Secukinumab IL-17A Tralokinumab Brodalumab IL-17 Lebrikizumab Dupilumab4 IL-4R/IL-13R 1. Lambrecht BN & Hammad H. Nat Immunol 2015; 16:45‒56; 2. Gallelli L, et al. Biomed Res Int 2013; 2013:104315; 3. Menzella F, et al. Multidiscip Respir Med 2015;10:1; 4.

45 Targeting sputum eosinophilia and severe exacerbations of asthma
120 100 80 60 40 20 1 2 3 5 4 12 9 10 11 6 7 8 Severe exacerbations (n) Time (months) 6 patients admitted BTS guidelines 1 patient admitted *p=0.01 109* 35 Green et al, Lancet 2002; 360: Asthma Sputum guided

46 Mepolizumab: effect on severe exacerbations
Haldar et al. NEJM 2009;360:973-84 Pavord et al. Lancet 2012;380:651-9.

47 Studies 3082 and 3083: Reslizumab consistently reduced clinical exacerbation rates compared with placebo Study 30821 Study 30831 Pooled data1 Annual exacerbation rate* (events/patient/year) 50% reduction vs placebo; p < 59% reduction vs placebo; p < 54% reduction vs placebo; p < Reslizumab significantly reduced the annual exacerbation rate in patients with inadequately controlled asthma and active eosinophilic airway inflammation1 * Exacerbations were defined as worsening asthma resulting in any of the following: use of systemic corticosteroids in steroid-naïve patients, a two-fold increase in the dose of either ICS or systemic corticosteroids for ≥ 3 days, the need for asthma-related emergency treatment. 1. Castro M, et al. Lancet Respir Med 2015; 3:355‒366.

48 Annual asthma exacerbation rate reduction with benralizumab
Blood eosinophils ≥300 cells/µLa –45% –51% Annual exacerbation rate estimate (95% CI) Q4W 0.55 (0.42 to 0.71) p<0.0001 Q8W 0.49 (0.37 to 0.64) Annual exacerbation rate ratio vs. placebob (1.12 to 1.58) (0.60 to 0.89) (0.53 to 0.80) aAdolescents represented 4%, 3%, and 4% of the placebo, Q4W, and Q8W cohorts, respectively. bEstimates calculated by a negative binomial model with adjustment for treatment, region, oral corticosteroid use, and prior exacerbations. 95% CI: confidence interval.

49 Profile: Anti-IL 5 treatments
The magnitude of benefit for exacerbation reduction is greater in individuals with a higher number of exacerbations in the previous year and higher blood eosinophil counts. However, improvements, especially in symptoms, remain slight. Mepolizumab and Benralizumab also enabled prednisolone-dependent people with asthma to successfully withdraw oral corticosteroid treatment. Antiinterleukin- 5 receptor strategies have successfully identified a target group, patients with eosinophilic inflammation, and an important outcome, exacerbation reduction. Phase 3 trials demonstrated similar reductions in exacerbation frequency with modest effects on lung function and asthma control..

50 ADJUSTED ANNUALISED SEVERE EXACERBATION EVENT RATES ESTIMATED
FROM THE 24-WEEK TREATMENT PERIOD 769 severe asthmatics not controlled by inhaled LABA/highICS Treated with dupilumab mg sc every 2 or 4 weeks for 12 months Powered on FEV1 Dupilumab improves lung functions and reduces severe exacerbations irrespective of baseline eosinophil count Blood Eos >300/uL <300/uL Wenzel S et al., Lancet Apr 26

51 Impact on the treatment pathway «TYPE 2»
Fevipiprant – CRTH2 antag Before any mABs? Intermittent: viral – seasonal? Dupilumab Not only exacerbations High + low eos? Comorbidities Tralokinumab ? High Periostin/DPP4? Anti TSLP ? Intremittent - seasonal Azithromycin? Treatment for the poor?