Aggiornamento Linee Guida GINA /4/2004 Sala Congressi Hotel Michelangelo Sassuolo Prof. Leonardo M. Fabbri Clinica di Malattie dellApparato Respiratorio Università degli Studi di Modena e Reggio Emilia, Modena ATTUALITA ED EVOLUZIONE NELLA GESTIONE CLINICA DELLASMA

G lobal IN itiative for A sthma

Executive Committee Chair: Paul OByrne, MD Dissemination Committee Chair: Tan Wan-Cheng, MD GINA Structure ScienceCommittee Chair: Eric Bateman, MD GINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the World Health Organization.

G lobal Initiative for Chronic O bstructive O bstructive L ung L ung D isease D isease

Global Initiative on Obstructive Lung Disease EXECUTIVE COMMITTEE Chair: Romain Pauwels S.Buist, US P.Calverley, UK B.Celli, US L.Fabbri, Italy Y.Fukuchi, Japan L.Grouse, US S.Hurd, US C.Jenkins, Australia C.Lenfant, US J.Luna, Guatemala W.McNee, UK E.Nizankowska-Mogilnicka, Poland K.Rabe, NL R.Rodriguez Roisin, E P.Van Der Molen, NL N.Zhong, China

Global Initiative on Obstructive Lung Disease SCIENTIFIC COMMITTEE Chair: Leonardo M. Fabbri P. Barnes, UK S. Buist, US P. Calverley, UK Y. Fukuchi, Giappone W. McNee, UK R. Pauwels, Belgium K. Rabe, Germany Roberto Rodrigues Roisin, Spain N. Zielinski, Poland

Third Quarter, 2000: Publication Date from 2000/07/01 to 2000/09/30 Search COPD NOT ASTHMA: All Fields. Limits: All Adult: 19+ years, only items with abstracts, English, Clinical Trial, Human Sort by: Authors (20 citations) No star = Clinical Trial, One * = Randomized Clinical Trials (15 citations) Two ** = Randomized Clinical Trials and Core Clinical Journals (7 citations) ASSIGNMENTS, REVIEWER, PUBLICATION NUMBER Peter Barnes, 8 Sonia Buist, 16, 17 Leo Fabbri, 14, 20, 10, 19 Yoshi Fukuchi, 5, 7, 10, 12, 19, 20 Bill MacNee, 1, 5, 8, 15 Romain Pauwels, 16, 17 Klaus Rabe, 2, 3, 4, 11, 14 Roberto Rodriguez-Roisin, 2, 3, 4, 11, 13, 18 Jan Zielinski, 1, 7, 10, 15, 19

GOLD REPORT – Section 4 Page 32, left column, end of para 2, ORIGINAL TEXT …. tract inflammation It is likely that indoor air pollution derived from the burning of biomass fuels will prove to have similar effects. SUGGESTED REVISION …. tract inflammation It is likely that indoor air pollution derived from the burning of biomass fuels will prove to have similar effects. Also bacterial colonization contributes to the airway inflammation in patients with stable COPD. The degree of inflammation also relating to the bacterial load and to the bacterial species (Hill at et al, 2000). Consequences of such colonization and enhanced inflammation on morbidity and lung function is not clear Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am J Med 2000 Sep;109(4):288-95

PATIENTS AT HIGH RISK OF DEATH AFTER LUNG-VOLUME–REDUCTION SURGERY N Engl J Med 2001; 345: to be published on October 11 National Emphysema Treatment Trial Research Group

New Engl J Med 2001; to be published next Oct 11 Probability of death Months since Randomization Medical therapy Surgery Patients at High Risk of Death after Lung-Volume-Reduction Surgery P < NATIONAL EMPHISEMA TREATMENT TRIAL RESEARCH GROUP

Levels of evidence LevelSource A Randomized clinical trials (RCT). Several, consistent B Randomized clinical trials (RCT). Few, inconsistent C Non-randomized clinical trials. Small and/or observational studies D Opinion of experts

INSTITUTE OF SCIENTIFIC INFORMATION (ISI) ISI JOURNAL CITATION REPORTS Impact Factor Number of Citations in 2002 Number of articles

IMPACT FACTOR 2002 Medicine, General & Internal: 1) New Engl J Med ) JAMA – J Am Med Assoc ) Lancet ) Ann Intern Med ) Annu Rev Med ) Brit Med J ) Arch Intern Med ) Medicine 5.18

IMPACT FACTOR 2002 Respiratory System 1) Am J Resp Crit Care6.56 2) Am J Resp Cell Mol4.17 3) Thorax4.08 4) Am J Physiol-Lung C3.90 5) Chest2.97 6) Eur Respir J2.94 7) J Thorac Cardiov Sur2.84 8) Sarcoidosis Vasc Dif2.83

Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: Asma grave/BPCO Nuovi farmaci antiasmatici

Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: Asma grave/BPCO Nuovi farmaci antiasmatici

G lobal IN itiative for A sthma

Executive Committee Chair: Paul OByrne, MD Dissemination Committee Chair: Tan Chen Wan, MD GINA Structure ScienceCommittee Chair: Eric Bateman, MD GINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the World Health Organization.

Science Committee E. Bateman, South Africa, Chair P. Barnes, UK S. Holgate, UK J. Bousquet, France J. Kips, Belgium W. Busse, USAP. OByrne, Canada J. Drazen, USA K. Ohta, Japan M. FitzGerald, Canada S. Pedersen, Denmark P. Gibson, Australia E. von Mutius,Germany E. Bateman, South Africa, Chair P. Barnes, UK S. Holgate, UK J. Bousquet, France J. Kips, Belgium W. Busse, USAP. OByrne, Canada J. Drazen, USA K. Ohta, Japan M. FitzGerald, Canada S. Pedersen, Denmark P. Gibson, Australia E. von Mutius,Germany

Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: Asma grave/BPCO Nuovi farmaci antiasmatici

Management of asthma: updating the GINA guidelines Systemic steroids Asthma severity MildIntermittent MildPersistent ModeratePersistent ModeratePersistent(Severe?) SeverePersistent (Very severe?) Combination with higher doses inhaled corticosteroids, theophylline, antileukotrienes Avoidance of risk factors, immunotherapy Short-acting beta-2 agonists as needed Low-dose inhaled steroids Combination of long-acting beta2 agonists with low dose inhaled steroids

Stepwise Approach to Asthma Therapy Controlled by inhaled short-acting beta-2 agonists prn Controller Not requiredNot requiredReliever Inhaled beta2-agonistInhaled beta2-agonist prn <3-4x a day prn <3-4x a day Inhaled beta2-agonist or Cromolyn or Leukotriene modifier prior to exercise or exposure to antigen Inhaled beta2-agonist or Cromolyn or Leukotriene modifier prior to exercise or exposure to antigen Step 1: Mild Intermittent Asthma Avoid or Control Triggers

Year Visit START – study outline Adults Children (6–10 yrs) Budesonide 200 g once daily + usual asthma therapy Budesonide 400 g once daily + usual asthma therapy Part B Adults and Children Placebo once daily + usual asthma therapy Part A – Budesonide therapy Adults Children (6–10 yrs) Budesonide 400 g once daily + usual asthma therapy Budesonide 200 g once daily + usual asthma therapy Part A – Reference therapy Pauwels R et a. Lancet 2003; 371:

Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations by 44% and improves asthma control compared with placebo in patients with recent onset, mild persistent asthma.Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations by 44% and improves asthma control compared with placebo in patients with recent onset, mild persistent asthma. STARTConclusions Pauwels R et a. Lancet 2003; 371:

Stepwise Approach to Asthma Therapy Controlled by low-dose inhaled steroids Controller Daily inhaled cortico-Daily inhaled cortico- steroid ( mcg) steroid ( mcg) Cromolyn, Nedocromil,Cromolyn, Nedocromil, sustained release sustained release Theophylline Theophylline Consider LeukotrieneConsider Leukotriene Modifiers Modifiers Reliever Inhaled beta2-agonistInhaled beta2-agonist prn <3-4x a day prn <3-4x a day Inhaled beta2-agonist or Cromolyn or Leukotriene modifier prior to exercise or exposure to antigen Inhaled beta2-agonist or Cromolyn or Leukotriene modifier prior to exercise or exposure to antigen Step 2: Mild Persistent Asthma Avoid or Control Triggers

Effects of Inhaled Beclomethasone Dipropionate in Clinical Asthma Bronchial Function Bronchial Submucosa Asthmatic symptoms Severity PC20 methacholine (mg/ml) mg/ml number of cells/mm 2 of submucosa eosinophilsT lymphocytes mast cells Pre-BD6 wk Pre-BD6 wkPre-BD6 wk Djukanovic et al, Am Rev Respir Dis 1992 Mar;145(3):669-74

JAMA 2001; 285: LONG-ACTING 2-AGONIST MONOTHERAPY VS CONTINUED THERAPY WITH INHALED CORTICOSTEROIDS IN PATIENTS WITH PERSISTENT ASTHMA A Randomized Controlled Trial Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control. Lazarus SC et al.

Low-dose Fluticasone is More Effective of Montelukast in Mild Persistent Asthma Busse W et al., J Allergy Clin Immunol 2001; 107: Treatment week EndpointBaseline Mean % change from baseline in FEV1 * * * * * * * *

OByrne et al. Am. J. Respir. Crit. Care Med. 2001; Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma. The OPTIMA Randomized Trial Paul M. OByrne, Peter J. Barnes, Roberto Rodriguez-roisin, Eva Runnerstrom,Thomas Sandstrom, Klas Svensson, and Anne Tattersfield

Placebo Budesonide 200 Budesonide Formoterol 34/226 44/227 79/237 Time to first severe exacerbation Proportion Days OByrne et al. Am. J. Respir. Crit. Care Med. 2001;

Rate for poorly controlled days Placebo Budesonide 200 Budesonide + Formoterol Rate OByrne et al. Am. J. Respir. Crit. Care Med. 2001;

Mometasone furoate administered once daily is as effective as twice-daily administration for treatment of mild-to-moderate persistent asthma This is the first study demonstrating that a total daily dose of 400 g of mometasone furoate (MF) administered by dry powder inhaler is an effective treatment for patients with mild-to- moderate persistent asthma previously taking only 2-agonists _________________________________________________ Kemp et al, J Allergy Clin Immunol Sep;106(3):485-92

Stepwise Approach to Asthma Therapy Controlled by inhaled steroids plus long-acting bronchodilators Controller Add long acting broncho-Add long acting broncho- dilators to low dose inhaled dilators to low dose inhaled steroids steroids Increase the dose of inhaled corticosteroids 800-2,000 gIncrease the dose of inhaled corticosteroids 800-2,000 g Add leukotriene modifiers if control is not achieved Add leukotriene modifiers if control is not achievedReliever Inhaled beta2-agonist prnInhaled beta2-agonist prn <3-4x a day <3-4x a day Inhaled beta2-agonist or Cromolyn or Leukotriene modifier prior to exercise or Inhaled beta2-agonist or Cromolyn or Leukotriene modifier prior to exercise or exposure to antigen exposure to antigen Step 3: Moderate Persistent Asthma Avoid or Control Triggers

Time (weeks) Salmeterol 50 g bid + BDP 200 g bid BDP 500 g bid *** ** * *p<0.05, **p<0.01, ***p<0.001 vs BDP Addition of salmeterol to inhaled BDP is superior to increased dose of BDP in persistent asthma Greening et al. Lancet 1994 Mean change from baseline in morning PEF (L/min) BDP, beclomethasone dipropionate; ICS, inhaled corticosteroid PEF, peak expiratory flow

Weeks of treatment Addition of salmeterol to inhaled BDP is superior to increased dose of BDP in moderate/severe asthma Change in FEV 1 (% predicted) Woolcock et al. Am J Respir Crit Care Med 1996 Adapted with permission Salmeterol 50 g bid + BDP 500 g bid BDP 1000 g bid BDP, beclomethasone dipropionate ** * * *p<0.001, **p<0.05

Pauwels RA et al., N Engl J Med 1997 Higher-dose budesonide plus formoterol Lower-dose budesonide plus formoterol Higher-dose budesonide Lower-dose budesonide Changes in FEV 1 during the study Month FEV 1 (% of predicted) FACET

Estimates of severe exacerbation rates BUD200h=0.91BUD800h=0.46BUD200+Fh=0.67BUD800+Fh=0.34 FORM: - 26% (p=0.014) p=0.031 Pauwels RA et al., N Engl J Med 1997 BUDH: - 49% (p<0.001)

Estimates of mild exacerbation rates BUD200h=35.4BUD800h=22.3BUD200+Fh=21.3BUD800+Fh=13.4 FORM: - 40% (p=0.001) p=0.76 FACET BUDH: - 37% (p<0.001) Pauwels RA et al., N Engl J Med 1997

Classification of Asthma Severity CLASSIFY SEVERITY Clinical Features Before Treatment Symptoms STEP 4 Severe Persistent Continuous Limited physical activity Frequent 60% predicted Variability >30% Nighttime SymptomsPEF STEP 3 Moderate Persistent Daily Use 2-agonist daily Attacks limit activity >1 time week 60-80% predicted Variability >30% STEP 2 Mild Persistent 1 time a week but <1 time a day >2times a months 80% predicted Variability 20-30% STEP 1 Intermittent <1 time a week Asymptomatic and normal PEF between attacks 2 times a month 80% predicted Variability <20% One of the features of severity is sufficient to place a patient in that category Intensity of treatment Treatment

Management of Asthma Long-acting bronchodilators and/or LTRA Inhaled steroids Short-acting 2 agonists prn PREVENTION Severity of asthma Oral steroids IMMUNOTHERAPY ?

Treatment Options for Patients Not Controlled on Inhaled Steroids Patients not controlled on inhaled steroids Increase the dose of inhaled steroid Add leukotriene receptorantagonists Add long-acting beta2-agonists Addtheophylline

Montelukast + Budesonide vs higher-dose budesonide Days relative to start of trial Montelukast + budesonide 800 µg (n=433) Budesonide 1600 µg (n=425) AM PEF (L/min) p=0.367 between groups during the last 10 weeks of the 12-week treatment period Run-in Price et al., Thorax 2003

Busse WW et al. J Allergy Clin Immunol 1999; 103: COMPARISON OF INHALED SALMETEROL AND ORAL ZAFIRLUKAST IN PATIENTS WITH ASTHMA In patients with persistent asthma, most of whom currently using inhaled corticosteroids, treatment with inhaled salmeterol provided significantly greater improvement that oral zafirlukast in overall clinical control over the 4-week treatment period

Biermer L t al. BMJ 2003; in press A ONE-YEAR COMPARATIVE TRIAL OF MONTELUKAST AND FLUTICASONE VS SALMETEROL AND FLUTICASONE IN PROTECTING AGAINST ASTHMA ATTACKS The study demonstrates the equal clinical benefit of including montelukast or salmeterol in asthma therapy for protection against asthma exacerbations of patients inadequately controlled by inhaled corticosteroids.

ADDITION OF LEUKOTRIENE ANTAGONISTS TO THERAPY IN CHRONIC PERSISTENT ASTHMA: A RANDOMISED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL Used as additional therapy in a hospital outpatient clinic setting, montelukast did not provide such additional benefit in patients with moderate or severe asthma Robinson DS et al Lancet 2001; 357:

Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: Asma grave/BPCO Nuovi farmaci antiasmatici

Differences between asthma and COPD ASTHMA Sensitizing agent COPD Noxious agent Asthmatic airway inflammation CD4+ T-lymphocytes Eosinophils COPD airway inflammation CD8+ T-lymphocytes MarcrophagesNeutrophils Airflow limitation Completelyreversible Completelyirreversible

Asthma A B C B D COPD Fabbri LM et al Am J Respir Crit Care Med 2003;

ASTHMA COPD Mild Intermittent 2 prn Mild 2 prn Mild persistentiGCS Moderate LABA Moderate persistent Combination Severe Combination LABA+iGCS LABA+iGCS LABA+iGCS LABA+iGCS Severe persistent Oral GCS Very Oxygen, Sx severe Surgery severe Surgery Management of COPD and asthma: GOLD and GINA guidelines

Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: Asma grave/BPCO Nuovi farmaci antiasmatici

TREATMENT OPTIONS IN ASTHMA CURRENT OPTIONS Inhaled corticosteroids Long acting beta2-agonists Leukotriene receptor antagonists FUTURE OPTIONS Better corticosteroids and bronchodilators Phosphodiesterase inhibitors Anti-IgE FUTURISTIC OPTIONS Mediator antagonists Non-steroidal antiinflammatory agents Chemokine and chemokine receptor antagonists Gene therapy Modified by P.J. Barnes, 2003

Y Y IgE Y Y Y IL-4, IL-13 B lymphocyte Y Y Y HistamineCys-LTs PGD 2 Fc RI Mast cell Y Y Y Y Y Y Y Chronicinflammation Y Y Fc RII (CD23) Macrophage T lymphocyte Eosinophil rhuMAb-E25,omalizumab IgE AND ITS INHIBITION IN ATOPY Modified by P.J. Barnes, 2003

L L % Patients Placebo Anti-IgE (low dose) Anti-IgE (high dose) Milgrom H et al: NEJM 1999 >50% reductionDiscontinuing omalizumab: iv. 2x weekly x 12 weeks then reduction over 8 weeks ANTI-IgE IN STEROID-DEPENDENT ASTHMA Oral steroids

Median BDP dose reduction (%) Omalizumab sc 28wks Placebo Complete BDP withdrawal (%)p<0.001p<0.001 Soler M et al: Eur Respir J 2001 Moderate to severe allergic asthma EFFECT OF ANTI-IgE IN ASTHMA FEV 1, PEF FEV 1, PEF Exacerbations (58%) Exacerbations (58%)

POSITION OF ANTI-IgE IN THE TREATMENT OF ASTHMA Patients with more severe asthma steroid-dependent, steroid-resistant, brittle Patients with severe concomitant allergic diseases Poor compliance with existing therapy ? Cover for immunotherapy ? Modified by P.J. Barnes, 2003

Management of asthma: updating the GINA guidelines Systemic steroids Asthma severity MildIntermittent MildPersistent ModeratePersistent ModeratePersistent(Severe?) SeverePersistent (Very severe?) Combination with higher doses inhaled corticosteroids, theophylline, antileukotrienes Avoidance of risk factors, immunotherapy Short-acting beta-2 agonists as needed Low-dose inhaled steroids Combination of long-acting beta2 agonists with low dose inhaled steroids

Le linee guida GINA in Italia: passare dalla teoria ai fatti Prof. L.M. Fabbri Processo di aggiornamento delle linee guida Trattamento farmacologico: Asma grave/BPCO Nuovi farmaci antiasmatici

Aggiornamento Linee Guida GINA 2003 Prof. Leonardo M. Fabbri Clinica di Malattie dellApparato Respiratorio Università degli Studi di Modena e Reggio Emilia, Modena ATTUALITA ED EVOLUZIONE NELLA GESTIONE CLINICA DELLASMA