Dott.V.N.Valerio. U.O.Malattie dell Apparato Respiratorio Universitaria direttore Prof.O.Resta Ospedale Policlinico Consorziale BARI

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1 Dott.V.N.Valerio U.O.Malattie dell Apparato Respiratorio Universitaria direttore Prof.O.Resta Ospedale Policlinico Consorziale BARI

2 Inhaled corticosteroids (ICSs) are used extensively in the treatment of asthma and chronic obstructive pulmonary disease (COPD) due to their broad antiinflammatory effects. They improve lung function, symptoms, and quality of life and reduce exacerbations in both conditions but do not alter the progression of disease. They decrease mortality in asthma but not COPD.

3 MECHANISM OF ACTION The corticosteroid enters the cell cytoplasm and binds with the inactive glucocorticoid receptor complex. Consequently, the activated glucocorticoid receptor binds to DNA at the glucocorticoid response element sequence and promotes synthesis of antiinflammatory proteins (transactivation) and inhibits transcription and synthesis of many proinflammatory cytokines (transrepression). Corticosteroids also reduce the number of T lymphocytes, dendritic cells, eosinophils, and mast cells in airways and reduce inducible nitric oxide production.

4 CSI nell Asma Il riconoscimento della presenza di processi infiammatori cronici persino nelle vie aeree di pazienti con asma lieve, e che tali processi possono contribuire alla ipereattività bronchiale, al restringimento ed al rimodellamento delle vie aeree, ha portato ad un uso crescente di agenti anti-infiammatori come trattamento di prima linea. Sin dalla loro introduzione nella pratica clinica nei primi anni settanta, gli steroidi inalatori sono diventati il principale sostegno nel trattamento dell asma persistente. I corticosteroidi inalatori hanno dimostrato di migliorare l infiammazione delle vie aeree, la iperreattività bronchiale, l ostruzione bronchiale ed i sintomi negli asmatici. Questa evidenza è stata usata come razionale per suggerire che per quasi tutti i pazienti, sia adulti che pediatrici, gli steroidi inalatori sono il trattamento di scelta per l asma persistente.

5 Stepwise management - pharmacotherapy *For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS **For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy GINA 2014, Box 3-5 (upper part) Global Initiative for Asthma

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7 Terapia farmacologica DOSI QUOTIDIANE (in mcg) COMPARATIVE DI CORTICOSTEROIDI PER VIA INALATORIA $ ADULTI FARMACO Dose bassa Dose intermedia Dose alta Mometasone furoato Beclometasone dipropionato extrafine > > Budesonide > > Flunisolide > >2000 Fluticasone propionato > > Ciclesonide $ confronto basato sui dati di efficacia 2013 PROGETTO LIBRA PROGETTO LIBRA 7

8 Corticosteroide LABA RG + + Recettore-ß2 SUPERIORE EFFETTO ANTINFIAMMATORIO la traslocazione di RG il legame di RG a GRE (elemento di risposta ai gc) MIGLIORE BRONCODILATAZIONE l espressione dei recettori β2 accoppiamento dei recettori β2 down regulation dei recettori β2

9 Although ICSs are the preferred agents for managing persistent asthma in all ages, their benefit in COPD is more controversial.

10 CSI nella BPCO

11 Why Do ICS Not Work in COPD? The reason for the extreme corticosteroid resistance in COPD may be due to a marked reduction in the nuclear enzyme histone deacetylase-2 (HDAC2), which is required for corticosteroids to switch off activated inflammatory genes that are associated with histone acetylation. The reduction in HDAC2 activity and expression appears to be secondary to oxidative stress. The corticosteroid resistance persists even after smoking cessation, as the inflammatory response and oxidative stress continue and HDAC2 is just as reduced in ex-smokers as in smokers. In asthmatics who smoke there is a marked reduction in responsiveness to corticosteroids and this may also be explained by the oxidative stress of cigarette smoking reducing the anti-inflammatory effects of corticosteroids through a similar molecular mechanism involving HDAC2.

12 Are There Any COPD Patients Who May Benefit from ICS? COPD is a heterogeneous disease with several different pathological mechanisms, including emphysema, small airway disease and mucous hypersecretion, so it is possible that corticosteroids might work more effectively on some components of disease compared to others. COPD patients who have some of the clinical features of asthma, with greater reversibility of airways obstruction, may have increased sputum eosinophils and an increase in exhaled nitric oxide concentration, which are characteristics of asthmatic airway inflammation. These COPD patients probably have coexistent asthma. COPD patients with increased sputum eosinophils show a reduction in sputum eosinophils with oral steroids and a management strategy that increased ICS dose or added oral steroids with increased sputum eosinophils reduced exacerbations, as had previously been observed in patients with asthma.

13 Chronic Bronchitis Emphysema COPD Asthma Airflow obstruction AJRCCM ATS-COPD 1995

14 It is recognised that COPD is a very heterogeneous disease and not all patients respond to all drugs available for treatment. The identification of responders to therapies is crucial in chronic diseases to provide the most appropriate treatment and avoid unnecessary medications. The classically defined phenotypes of chronic bronchitis and emphysema, together with the newly described phenotypes of overlap COPD-asthma and frequent exacerbator, allow a simple classification of patients that share clinical characteristics and outcomes and, more importantly, similar responses to existing treatments. These clinical phenotypes can help clinicians identify patients that respond to specific pharmacological interventions.

15 The proposed phenotypes are: (A) infrequent exacerbators with either chronic bronchitis or emphysema; (B) overlap COPD-asthma; (C) frequent exacerbators with emphysema predominant; (D) frequent exacerbators with chronic bronchitis predominant

16 No exacerbator Overlap COPDasthma Exacerbator with emphysema Exacerbator with chronic bronchitis Long acting bronchodilators Inhaled corticosteroids Mucolytics PDE4 inhibitors Macrolides

17 Patients with overlap COPDasthma phenotype show an enhanced response to inhaled corticosteroids. Therefore, these patients should be prescribed inhaled corticosteroids together with long-acting bronchodilators irrespective of the severity of the airflow obstruction.

18 The major criteria selected were: very positive bronchodilator test (increase in FEV1 15% and 400 ml over baseline value), eosinophilia in sputum and personal history of asthma. The minor criteria were: total high IgE, personal history of atopy and positive bronchodilator test (increase in FEV1 12% and 200 ml over baseline value) on 2 or more occasions. In addition, it was agreed upon that it would be necessary for there to be 2 major criteria or 1 major and 2 minor criteria to correctly diagnose this clinical entity.

19 GINA GINA , Box 5-4 Global Initiative for Asthma

20 GINA 2014 Global Initiative for Asthma

21 Design: Post hoc cluster analys randomised clinical trials of salmeterol/fluticasone propionate (SFC) and salmeterol (SAL) that had primary endpoints of moderate/severe exacerbation rates. Participants: 1543 COPD patients were studied. Interventions: SFC 50/250 μg or SAL 50 μg, twice daily.

22 Long-term treatment with ICSs is recommended by the GOLD guidelines for patients with an FEV1 <50% predicted and/or frequent exacerbations and whose symptoms are not adequately controlled on long-acting bronchodilators, although long-term monotherapy with ICS is not recommended. No clinical factors have been identified that can predict ICS responsiveness and long-term safety, and ultimate dosing is unknown. Regular treatment with ICSs in patients with COPD improves symptoms, lung function, and quality of life measures and reduces exacerbations in patients with FEV1 <60% compared with placebo.

23 Riacutizzaioni/anno Progetto strategico mondiale per la diagnosi, trattamento e prevenzione della BPCO: Trattamento della BPCO stabile: Trattamento farmacologico Prima scelta GOLD 4 GOLD 3 C ICS + LABA o LAMA D ICS + LABA e/o LAMA > 2 o > 1 con ospedalizzazione GOLD 2 GOLD 1 A SAMA prn o SABA prn B LABA o LAMA 1 senza ospedalizzazione) 0 CAT < 10 mmrc 0-1 CAT > 10 mmrc > Global Initiative for Chronic Obstructive Lung Disease

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25 Methods: 914 COPD patients, on maintenance therapy with bronchodilators and ICS, FEV1>50% predicted, and <2 exacerbations/year were recruited. Results: FEV1, CAT and exacerbations history were similar in the two groups (ICS and no ICS). Conclusions: We conclude that the withdrawal of ICS, in COPD patients at low risk of exacerbation, can be safe provided that patients are left on maintenance treatment with long-acting bronchodilators. The primary objective was met, with a mean treatment difference of 9 ml (FEV1). There were no significant differences between treatments in terms of breathlessness (transition dyspnoea index) or health status (Saint George s Respiratory Questionnaire) at weeks 12 or 26, or rescue medication use or COPD exacerbation rates over 26 weeks. This study demonstrated that patients with moderate COPD and no exacerbations in the previous year can be switched from SFC to indacaterol 150 mg with no efficacy loss.

26 Take home message Esiste sufficiente evidenza per consigliare la terapia con steroidi inalatori anche nella BPCO in particolare nei pazienti con: - Quota di reversibilità dell ostruzione bronchiale - Infiammazione eosinofilica - Elevata frequenza di riacutizzazioni - Accellerato declino della funzione polmonare - Comorbidità cardiologiche? Gli steroidi inalatori sono sovra utilizzati La BPCO è una malattia eterogenea quindi è importante fenotipizzare i pazienti per individuare i responders a specifici trattamenti

27 Grazie per l attenzione

28 Mechanism of dyspnoea relief and improved exercise after furosemide inhalation in COPD. Jensen D et al. Thorax 2008;63: Effects of inhaled furosemide on exertional dyspnea in chronic obstructive pulmonary disease. Ong KC et al Am J Respir Crit Care Med 2004;169: Prevention of exercise-induced asthma in children using low doses of inhaled furosemide. Roger A et al. J Invest Allergol Clin Immunol 1993;3: Comparative efficacy of inhaled furosemide and disodium cromoglycate in the treatment of exercise-induced asthma in children. Melo RE, Sole D, Naspitz CK. J Allergy Clin Immunol 1997;99:204 9 The preventative effect and duration of action of two doses of inhaled furosemide on exercise-induced asthma in children. Novembre E et al. J Allergy Clin Immunol 1995;96:906 9.

29 Step 3 - Spirometry Spirometric variable Asthma COPD ACOS Normal FEV 1 /FVC pre - or post - BD FEV 1 =80% predicted Compatible with asthma Not compatible with diagnosis (GOLD) Post - BD FEV 1 /FVC <0.7 Indicates airflow limitation; may improve Compatible with asthma (good control, or interval between symptoms) Required for diagnosis by GOLD criteria C ompatible with GOLD category A or B if post - BD FEV 1 /FVC <0.7 Not compatible unless other evidence of chronic airflow limitation Usual in ACOS Compatible with mild ACOS FEV 1 <80% predicted Compatible with asthma. A risk factor for exacerbations Indicates severity of airflow limitation and risk of exacerbations and mortality Indicates severity of airflow limitation and risk of exacerbations and mortality Post - BD increase in FEV 1 >12% and 200mL from baseline (reversible airflow limitation) Usual at some time in course of asthma; not always present Common in COPD and more likely when FEV 1 is low, but consider ACOS Common in ACOS, and more likely when FEV 1 is low Post - BD increase in FEV 1 >12% and 400mL from baseline High probability of asthma Unusual in COPD. Consider ACOS Compatible with diagnosis of ACOS GINA 2014, Box 5-3 Global Initiative for Asthma

30 A metaanalysis of 13,000 patients with COPD found no effect of ICSs on the rate of decline in FEV1 or in mortality; however, they have been shown to reduce exacerbation rate by 25%. However, these studies used high-dose ICSs (1,000 mg/d FP or comparable) that would expose the patients to increased risk of systemic adverse effects.

31 Terapia della BPCO in base allo stadio di gravità in prima visita - GOLD anteriori al 2011 I: Lieve II: Moderato III: Grave IV: Molto Grave VEMS/CVF < 0.7 VEMS/CVF < 0.7 VEMS > 80% del predetto VEMS/CVF < % < VEMS < 80% del predetto VEMS/CVF < % < VEMS < 50% del predetto VEMS < 30% del predetto o VEMS < 50% del predetto più insufficienza respiratoria cronica Smettere di fumare.riduzione attiva degli altri fattori di rischio.vaccinazione antinfluenzale e antipneumococcica Aggiungere broncodilatatori a breve durata d azione (quando necessario) Aggiungere un trattamento regolare con 1 o + broncodilatatori a lunga durata d azione; Aggiungere riabilitazione Aggiungere glucocorticosteroidi inalatori* Aggiungere ossigeno-terapia a lungo termine in caso di insufficienza respiratoria Prendere in cosiderazione la terapia chirurgica * Le autorità regolatorie Europea (EMEA) e Italiana (AIFA) hanno approvato l uso della combinazione salmeterolo fluticasone in pazienti sintomatici con VEMS pre-broncodilatatore <60% PROGETTO LIBRA 31

32 When used appropriately, ICSs have few adverse events a low and medium doses, but risk increases with high-dose ICSs. The local side effects result from the deposition of the ICS in the oropharynx and include hoarseness, candidiasis, cough, and dysphonia. Potential systemic side effects of ICSs include suppression of the hypothalamus-pituitaryadrenal (HPA) axis, Cushing syndrome, osteoporosis, cataracts, dermal thinning and bruising, adrenal insufficiency, and growth suppression in children. Additionally, ICS therapy increases the risk of pneumonia in patients with COPD.

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36 Molecular mechanisms of glucocorticoid resistance

37 Budesonide and fluticasone, delivered alone or in combination with a LABA, are associated with increased risk of serious adverse pneumonia events, but neither significantly affected mortality compared with controls. The safety concerns highlighted in this review should be balanced with recent cohort data and established randomised evidence of efficacy regarding exacerbations and quality of life. Comparison of the two drugs revealed no statistically significant difference in serious pneumonias, mortality or serious adverse events. Fluticasone was associated with higher risk of any pneumonia when compared with budesonide (i.e. less serious cases dealt with in the community), but variation in the definitions used by the respective manufacturers is a potential confounding factor in their comparison

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39 APPROCCIO PROGRESSIVO ALLA TERAPIA DELL ASMA NELL ADULTO STEP 1 STEP 2 STEP 3 STEP 4 STEP 5 Scegliere uno: Scegliere uno: Aggiungere uno o più: Aggiungere in pr0gressione: Opzione principale β 2 -agonisti a breve azione al bisogno CSI a bassa dose CSI a bassa dose + LABA CSI a media dose + LABA CSI a alta dose + LABA Altre opzioni (in ordine decrescente di efficacia) Anti-leucotrieni * Cromoni CSI a bassa dose + anti-leucotrieni * CSI a dose medioalta Anti-leucotrieni Teofilline-LR Anti-leucotrieni Anti-IgE (omalizumab) ** Teofilline-LR CS orali Termoplastica β 2 -agonisti a rapida azione al bisogno *** Programma personalizzato di educazione Controllo ambientale, Immunoterapia specifica,trattamento delle comorbilità 2013 PROGETTO LIBRA CSI = corticosteroidi inalatori; LABA = long-acting β 2 -agonisti; LR = a lento rilascio * i pazienti con asma e rinite rispondono bene agli anti-leucotrieni ** nei pazienti allergici ad allergeni perenni e con livelli di IgE totali sieriche compresi tra 30 e 1500 U/ml *** le combinazioni Budesonide/Formoterolo e Beclometasone/Formoterolo possono essere usate anche al bisogno in aggiunta al trattamento regolare con la stessa combinazione

40 Effetti antinfiammatori dei corticosteroidi e dei β2 agonisti a lunga durata d azione nel trattamento delle riacutizzazioni asmatiche β2 stimolanti long acting sono principalmente broncodilatatori ma possono avere alcune proprietà anti-infiammatorie che possono essere addittive a quelle degli steroidi inalatori. Barnes PJ Eur Respir J 2007; 29:

41 Progetto strategico mondiale per la diagnosi, trattamento e prevenzione della BPCO: opzioni terapeutiche: steroidi inalatori Il trattamento regolare con steroidi inalatori migliora I sintomi, la funzionalità respiratoria e la qualità di vita, e riduce la frequenza di riacutizzazioni in pazienti con BPCO e VEMS inferiore al 60% del teorico Il trattamento regolare con steroidi inalatori aumenta il rischio di polmonite La sospensione del trattamento con steroidi inalatori può comportare il rischio di riacutizzazioni in alcuni pazienti 2014 Global Initiative for Chronic Obstructive Lung Disease

42 Progetto strategico mondiale per la diagnosi, trattamento e prevenzione della BPCO: opzioni terapeutiche: terapia combinata Il trattamento regolare con steroidi inalatori combinati con broncodilatatori beta2 agonisti a lunga durata d azione è più efficace dei singoli componenti nel migliorare la funzionalità respiratoria e la qualità di vita, e nel ridurre la frequenza di riacutizzazioni in pazienti con BPCO moderato-grave Il trattamento regolare combinato con steroidi inalatori broncodilatatori beta2 agonisti a lunga durata d azione aumenta il rischio di polmonite L aggiunta a un trattamento regolare con steroidi inalatori + broncodilatatori beta2 agonisti a lunga durata d azione di un anticolinergico (tiotropio) sembra portare ulteriori benefici 2014 Global Initiative for Chronic Obstructive Lung Disease