Aggiornamento Linee Guida GINA 2003
1/4/2004Sala Congressi Hotel Michelangelo
Sassuolo
Prof. Leonardo M. FabbriClinica di Malattie dell’Apparato Respiratorio
Università degli Studi di Modena e Reggio Emilia, Modena
ATTUALITA’ ED EVOLUZIONE NELLA GESTIONE CLINICA DELL’ASMA
GGloballobalININitiative foritiative forAAsthma 2003sthma 2003
www.ginasthma.comwww.ginasthma.com
Executive CommitteeExecutive CommitteeChair: Paul O’Byrne, MDChair: Paul O’Byrne, MDExecutive CommitteeExecutive CommitteeChair: Paul O’Byrne, MDChair: Paul O’Byrne, MD
Dissemination Dissemination CommitteeCommittee
Chair: Tan Chair: Tan Wan-ChengWan-Cheng, MD, MD
GINA StructureGINA Structure
Science Science CommitteeCommittee
Chair: Eric Bateman, MDChair: Eric Bateman, MD
GINA reports prepared during workshops conducted in cooperation with GINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the World the U.S. National Heart, Lung, and Blood Institute, NIH and the World
Health Organization.Health Organization.
GINA reports prepared during workshops conducted in cooperation with GINA reports prepared during workshops conducted in cooperation with the U.S. National Heart, Lung, and Blood Institute, NIH and the World the U.S. National Heart, Lung, and Blood Institute, NIH and the World
Health Organization.Health Organization.
G G lobal Initiative for Chroniclobal Initiative for Chronic
O O bstructivebstructive
L L ungung
D D iseaseisease
www.goldcopd.comwww.goldcopd.com
Global Initiative on Obstructive Global Initiative on Obstructive Lung DiseaseLung Disease
EXECUTIVE COMMITTEEEXECUTIVE COMMITTEEChair: Romain PauwelsChair: Romain Pauwels
S.Buist, USS.Buist, USP.Calverley, UKP.Calverley, UKB.Celli, USB.Celli, USL.Fabbri, ItalyL.Fabbri, ItalyY.Fukuchi, JapanY.Fukuchi, JapanL.Grouse, USL.Grouse, USS.Hurd, USS.Hurd, USC.Jenkins, AustraliaC.Jenkins, Australia
C.Lenfant, USC.Lenfant, USJ.Luna, GuatemalaJ.Luna, GuatemalaW.McNee, UKW.McNee, UKE.Nizankowska-Mogilnicka, E.Nizankowska-Mogilnicka,
PolandPolandK.Rabe, NLK.Rabe, NLR.Rodriguez Roisin, ER.Rodriguez Roisin, EP.Van Der Molen, NLP.Van Der Molen, NLN.Zhong, ChinaN.Zhong, China
Global Initiative on Obstructive Lung DiseaseGlobal Initiative on Obstructive Lung Disease
SCIENTIFIC COMMITTEESCIENTIFIC COMMITTEEChair: Leonardo M. FabbriChair: Leonardo M. Fabbri
P. Barnes, UKP. Barnes, UKS. Buist, USS. Buist, US
P. Calverley, UKP. Calverley, UKY. Fukuchi, GiapponeY. Fukuchi, Giappone
W. McNee, UKW. McNee, UKR. Pauwels, BelgiumR. Pauwels, Belgium
K. Rabe, GermanyK. Rabe, GermanyRoberto Rodrigues Roisin, SpainRoberto Rodrigues Roisin, Spain
N. Zielinski, PolandN. Zielinski, Poland
Third Quarter, 2000: Publication Date from 2000/07/01 to 2000/09/30Search 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, 8Sonia Buist, 16, 17
Leo Fabbri, 14, 20, 10, 19Yoshi Fukuchi, 5, 7, 10, 12, 19, 20
Bill MacNee, 1, 5, 8, 15Romain Pauwels, 16, 17
Klaus Rabe, 2, 3, 4, 11, 14Roberto Rodriguez-Roisin, 2, 3, 4, 11, 13, 18
Jan Zielinski, 1, 7, 10, 15, 19
GOLD REPORT – Section 4Page 32, left column, end of para 2,
ORIGINAL TEXT…. tract inflammation57-61. It is likely that
indoor air pollution derived from the burning of biomass fuels will prove to
have similar effects.
SUGGESTED REVISION…. tract inflammation57-61. 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 PATIENTS AT HIGH RISK OF DEATH AFTER LUNG-VOLUME–REDUCTION SURGERYAFTER LUNG-VOLUME–REDUCTION SURGERY
N Engl J Med 2001; 345: to be published on October 11N Engl J Med 2001; 345: to be published on October 11
National Emphysema Treatment Trial Research GroupNational Emphysema Treatment Trial Research Group
New Engl J Med 2001; to be published next Oct 11New Engl J Med 2001; to be published next Oct 11
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 6 12 18 24 30 36 42
Pro
bab
ility
of
dea
thP
rob
abili
ty o
f d
eath
Months since RandomizationMonths since Randomization
Medical therapyMedical therapy
SurgerySurgery
Patients at High Risk of Death after Patients at High Risk of Death after Lung-Volume-Reduction SurgeryLung-Volume-Reduction Surgery
P < 0.001P < 0.001
NATIONAL EMPHISEMA TREATMENT TRIAL RESEARCH GROUPNATIONAL EMPHISEMA TREATMENT TRIAL RESEARCH GROUP
Levels of evidenceLevels of evidenceLevelLevel SourceSource
AA Randomized clinical trials Randomized clinical trials (RCT). Several, consistent(RCT). Several, consistent
BB Randomized clinical trials Randomized clinical trials (RCT). Few, inconsistent(RCT). Few, inconsistent
CC Non-randomized clinical Non-randomized clinical trials. Small and/or trials. Small and/or observational studiesobservational studies
DD Opinion of expertsOpinion of experts
INSTITUTE OF SCIENTIFIC INSTITUTE OF SCIENTIFIC INFORMATION (ISI)INFORMATION (ISI)
ISI JOURNAL CITATION REPORTSISI JOURNAL CITATION REPORTShttp://jcrweb.com/http://jcrweb.com/
Impact Factor Impact Factor Number of Citations in 2002Number of Citations in 2002Number of articles 2000-2001Number of articles 2000-2001
IMPACT FACTOR 2002IMPACT FACTOR 2002
Medicine, General & Internal:Medicine, General & Internal:
1) New Engl J Med1) New Engl J Med 31.7431.742) JAMA – J Am Med Assoc2) JAMA – J Am Med Assoc 16.7816.783) Lancet3) Lancet 15.3915.394) Ann Intern Med 4) Ann Intern Med 11.4111.415) Annu Rev Med5) Annu Rev Med 7.95 7.956) Brit Med J 6) Brit Med J 7.58 7.587) Arch Intern Med7) Arch Intern Med 6.74 6.748) Medicine8) Medicine 5.18 5.18
IMPACT FACTOR 2002IMPACT FACTOR 2002
Respiratory SystemRespiratory System
1) Am J Resp Crit Care1) Am J Resp Crit Care 6.566.562) Am J Resp Cell Mol2) Am J Resp Cell Mol 4.174.173) Thorax3) Thorax 4.084.084) Am J Physiol-Lung C4) Am J Physiol-Lung C 3.903.905) Chest5) Chest 2.972.976) Eur Respir J6) Eur Respir J 2.942.947) J Thorac Cardiov Sur7) J Thorac Cardiov Sur 2.842.848) Sarcoidosis Vasc Dif8) Sarcoidosis Vasc Dif 2.832.83
Le linee guida GINA in Italia:passare dalla teoria ai fatti
Prof. L.M. Fabbri
Processo di aggiornamento delle linee guida
Trattamento farmacologico: 2003-2004
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: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
GGloballobalININitiative foritiative forAAsthma 2003sthma 2003
www.ginasthma.comwww.ginasthma.com
Executive CommitteeExecutive CommitteeChair: Paul O’Byrne, MDChair: Paul O’Byrne, MDExecutive CommitteeExecutive CommitteeChair: Paul O’Byrne, MDChair: Paul O’Byrne, MD
Dissemination Dissemination CommitteeCommittee
Chair: Tan Chair: Tan Chen WanChen Wan, MD, MD
GINA StructureGINA Structure
Science Science CommitteeCommittee
Chair: Eric Bateman, MDChair: 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.
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 CommitteeScience CommitteeScience CommitteeScience Committee
E. Bateman, E. Bateman, South AfricaSouth Africa, , ChairChair
P. Barnes, P. Barnes, UKUK S. Holgate, S. Holgate, UKUK
J. Bousquet, J. Bousquet, FranceFrance J. Kips, J. Kips, BelgiumBelgium
W. Busse, W. Busse, USAUSA P. O’Byrne, P. O’Byrne, CanadaCanada
J. Drazen, J. Drazen, USAUSA K. Ohta, K. Ohta, JapanJapan
M. FitzGerald, M. FitzGerald, CanadaCanada S. Pedersen, S. Pedersen, DenmarkDenmark
P. Gibson, P. Gibson, AustraliaAustralia E. von E. von Mutius,Mutius,GermanyGermany
E. Bateman, E. Bateman, South AfricaSouth Africa, , ChairChair
P. Barnes, P. Barnes, UKUK S. Holgate, S. Holgate, UKUK
J. Bousquet, J. Bousquet, FranceFrance J. Kips, J. Kips, BelgiumBelgium
W. Busse, W. Busse, USAUSA P. O’Byrne, P. O’Byrne, CanadaCanada
J. Drazen, J. Drazen, USAUSA K. Ohta, K. Ohta, JapanJapan
M. FitzGerald, M. FitzGerald, CanadaCanada S. Pedersen, S. Pedersen, DenmarkDenmark
P. Gibson, P. Gibson, AustraliaAustralia E. von E. von Mutius,Mutius,GermanyGermany
Le linee guida GINA in Italia:passare dalla teoria ai fatti
Prof. L.M. Fabbri
Processo di aggiornamento delle linee guida
Trattamento farmacologico: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
Management of asthma:Management of asthma:updating the GINA guidelinesupdating the GINA guidelines
Systemic Systemic steroidssteroids
Ast
hm
a se
ver i
t yA
sth
ma
seve
rit y
MildMildIntermittentIntermittent
Mild Mild PersistentPersistent
Moderate Moderate PersistentPersistent
ModerateModeratePersistentPersistent(Severe?)(Severe?)SevereSevere
PersistentPersistent(Very severe?)(Very severe?)
Combination with higher Combination with higher doses inhaled corticosteroids, doses inhaled corticosteroids, theophylline, antileukotrienestheophylline, antileukotrienes
Avoidance of risk factors, immunotherapyAvoidance of risk factors, immunotherapyShort-acting beta-2 agonists as neededShort-acting beta-2 agonists as needed
Low-dose inhaled steroidsLow-dose inhaled steroids
Combination of long-acting beta2 agonists Combination of long-acting beta2 agonists with low dose inhaled steroidswith low dose inhaled steroids
Stepwise Approach to Asthma TherapyStepwise Approach to Asthma Therapy
Controlled by inhaledControlled by inhaledshort-acting beta-2 agonists prnshort-acting beta-2 agonists prn
ControllerController•• Not requiredNot required
RelieverReliever•• Inhaled beta2-agonistInhaled beta2-agonist
prn <3-4x a dayprn <3-4x a day
• • Inhaled beta2-agonist or Inhaled beta2-agonist or Cromolyn or Leukotriene Cromolyn or Leukotriene modifier prior to exercisemodifier prior to exercise or exposure to antigenor exposure to antigen
Step 1: Mild Intermittent Asthma
Avoid or Control Triggers
YearYear 11 22 33 44 55
VisitVisit
00
11 22 33 44 55
START – study outlineSTART – study outline
AdultsAdults
ChildrenChildren (6 (6––10 yrs)10 yrs)Budesonide 200 Budesonide 200 g g once dailyonce daily
+ usual + usual asthma asthma therapytherapy
Budesonide 400 Budesonide 400 g g once dailyonce daily+ usual + usual asthma asthma therapytherapy
Part BPart B
66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717 1818 1919 2020 2121 2222
Adults and Adults and CChildrenhildrenPlaceboPlacebo once daily once daily
+ usual + usual asthma asthma therapytherapy
Part APart A – Budesonide therapy – Budesonide therapyAdultsAdults
ChildrenChildren (6 (6––10 yrs)10 yrs)
Budesonide 400 Budesonide 400 g g once dailyonce daily+ usual + usual asthma asthma therapytherapy
Budesonide Budesonide 2200 00 g g once dailyonce daily+ usual + usual asthma asthma therapytherapy
Part APart A – Reference therapy – Reference therapy
Pauwels R et a. Lancet 2003; 371: 1071-1076
• Long-term, once-daily treatment Long-term, once-daily treatment with low-dose budesonide with low-dose budesonide
decreases the risk of severe decreases the risk of severe exacerbations by 44% and improves exacerbations by 44% and improves
asthma control compared with asthma control compared with placebo in patients with recent placebo in patients with recent onset, mild persistent asthma.onset, mild persistent asthma.
START START ConclusionsConclusions
Pauwels R et a. Lancet 2003; 371: 1071-1076
Stepwise Approach to Asthma TherapyStepwise Approach to Asthma Therapy
Controlled by low-doseControlled by low-doseinhaled steroidsinhaled steroids
ControllerController•• Daily inhaled cortico-Daily inhaled cortico-
steroid (200-500 mcg)steroid (200-500 mcg)
•• Cromolyn, Nedocromil, Cromolyn, Nedocromil,
sustained release sustained release
TheophyllineTheophylline
•• Consider LeukotrieneConsider Leukotriene
ModifiersModifiers
RelieverReliever•• Inhaled beta2-agonistInhaled beta2-agonist
prn <3-4x a dayprn <3-4x a day
• • Inhaled beta2-agonist or Inhaled beta2-agonist or Cromolyn or Leukotriene Cromolyn or Leukotriene modifier prior to exercise modifier prior to exercise or exposure to antigenor exposure to antigen
Step 2: Mild Persistent AsthmaStep 2: Mild Persistent Asthma
Avoid or Control TriggersAvoid or Control Triggers
0
2
4
6
Pre-BD 6 wk
Effects of Inhaled BeclomethasoneEffects of Inhaled BeclomethasoneDipropionate in Clinical AsthmaDipropionate in Clinical Asthma
Bronchial FunctionBronchial Function Bronchial SubmucosaBronchial Submucosa
Asthmaticsymptoms
Sev
erit
y
0,01
0,1
1
10
100
Pre-BD 6 wk
PC20 methacholine
(mg/ml)m
g/m
l
nu
mb
er o
f ce
lls/m
m2
of
sub
mu
cosa eosinophilsT lymphocytesmast cells
0
40
80
120
160
200
240
720
760
Pre-BD6 wk Pre-BD6 wk Pre-BD6 wk
Djukanovic et al, Am Rev Respir Dis 1992 Mar;145(3):669-74
JAMA 2001; 285: 2583-2593JAMA 2001; 285: 2583-2593
LONG-ACTING LONG-ACTING 2-AGONIST 2-AGONIST MONOTHERAPY MONOTHERAPY VSVS CONTINUED CONTINUED THERAPY WITH INHALED THERAPY WITH INHALED CORTICOSTEROIDS IN PATIENTS CORTICOSTEROIDS IN PATIENTS WITH PERSISTENT ASTHMAWITH PERSISTENT ASTHMAA Randomized Controlled TrialA Randomized Controlled Trial
Patients with persistent asthma well controlled by low doses of Patients with persistent asthma well controlled by low doses of triamcinolone cannot be switched to salmeterol monotherapy triamcinolone cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.without risk of clinically significant loss of asthma control.
Lazarus SC et al.Lazarus SC et al.
0
5
10
15
20
25
30
4 8 12 16 20 24
FP 88 µg BID
MON 10 mg BID
Low-dose Fluticasone is More Effective of Low-dose Fluticasone is More Effective of Montelukast in Mild Persistent AsthmaMontelukast in Mild Persistent Asthma
Busse W et al., J Allergy Clin Immunol 2001; 107: 461-468Busse W et al., J Allergy Clin Immunol 2001; 107: 461-468
Treatment week
EndpointBaseline
Mea
n %
ch
ang
e fr
om
bas
elin
e
in F
EV
1
** *
* * * **
O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397
Low Dose Inhaled Budesonide and Formoterol Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma . The OPTIMA in Mild Persistent Asthma . The OPTIMA
Randomized TrialRandomized Trial
Paul M. O‘Byrne, Peter J. Barnes, Roberto Rodriguez-roisin,Paul M. O‘Byrne, Peter J. Barnes, Roberto Rodriguez-roisin,
Eva Runnerstrom,Thomas Sandstrom, Klas Svensson, Eva Runnerstrom,Thomas Sandstrom, Klas Svensson,
and Anne Tattersfieldand Anne Tattersfield
Placebo
Budesonide200
Budesonide 200+ Formoterol
34/226
44/227
79/237
Time to first severe exacerbationTime to first severe exacerbationP
rop
ort
ion
Days
O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397
Rate for poorly controlled days
Rate for poorly controlled days
Placebo Budesonide200
Budesonide +Formoterol
Rate
0.00
0.05
0.10
0.150.144
0.0730.083
O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397O’Byrne et al. Am. J. Respir. Crit. Care Med. 2001;164 1392-1397
Mometasone furoate administered once daily Mometasone furoate administered once daily is as effective as twice-daily administration for is as effective as twice-daily administration for treatment of mild-to-moderate persistent treatment of mild-to-moderate persistent asthmaasthma
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. 2000 Sep;106(3):485-92
Stepwise Approach to Asthma TherapyStepwise Approach to Asthma Therapy
Controlled by inhaled steroidsControlled by inhaled steroidsplus long-acting bronchodilatorsplus long-acting bronchodilators
ControllerController
•• Add long acting broncho-Add long acting broncho- dilators to low dose inhaled dilators to low dose inhaled steroidssteroids
•• Increase the dose of inhaled Increase the dose of inhaled corticosteroids 800-2,000corticosteroids 800-2,000gg
• • Add leukotriene modifiers if Add leukotriene modifiers if control is not achievedcontrol is not achieved
RelieverReliever
•• Inhaled beta2-agonist prnInhaled beta2-agonist prn <3-4x a day<3-4x a day
• • Inhaled beta2-agonist or Inhaled beta2-agonist or Cromolyn or Leukotriene Cromolyn or Leukotriene modifier prior to exercise ormodifier prior to exercise or
exposure to antigenexposure to antigen
Step 3: Moderate Persistent AsthmaStep 3: Moderate Persistent Asthma
Avoid or Control TriggersAvoid or Control Triggers
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 21
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
Mea
n c
han
ge
fro
m b
asel
ine
in m
orn
ing
PE
F (
L/m
in)
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
0
1
2
3
4
5
6
7
8
9
10
0 2 8 16 24
Ch
ang
e in
FE
V1 (%
pre
dic
ted
)
Woolcock et al. Am J Respir Crit Care Med 1996Adapted 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 1997Pauwels RA et al., N Engl J Med 1997
Higher-dose budesonide plus formoterolLower-dose budesonide plus formoterolHigher-dose budesonideLower-dose budesonide
Changes in FEVChanges in FEV1 1 during the study during the study
90
85
80
75
-1 0 1 2 3 6 9 12
Month
FE
V1
(% o
f p
red
icte
d)
FACET
Estimates of severe exacerbation ratesEstimates of severe exacerbation rates
BUD200BUD200
h=0.91h=0.91
BUD800BUD800
h=0.46h=0.46
BUD200+FBUD200+F
h=0.67h=0.67
BUD800+FBUD800+F
h=0.34h=0.34
FORM: - 26% FORM: - 26% (p=0.014)(p=0.014)p=0.031p=0.031
Pauwels RA et al., N Engl J Med 1997Pauwels RA et al., N Engl J Med 1997
BUDH:BUDH:- 49%- 49%(p<0.001)(p<0.001)
Estimates of mild exacerbation ratesEstimates of mild exacerbation rates
BUD200BUD200
h=35.4h=35.4
BUD800BUD800
h=22.3h=22.3
BUD200+FBUD200+F
h=21.3h=21.3
BUD800+FBUD800+F
h=13.4h=13.4
FORM: - 40% FORM: - 40% (p=0.001)(p=0.001) p=0.76p=0.76
FACET
BUDH:BUDH:- 37%- 37%(p<0.001)(p<0.001)
Pauwels RA et al., N Engl J Med 1997Pauwels RA et al., N Engl J Med 1997
Classification of Asthma SeverityClassification of Asthma Severity
CLASSIFY SEVERITYClinical Features Before Treatment
Symptoms
STEP 4SeverePersistent
ContinuousLimited physicalactivity
Frequent≤60% predictedVariability >30%
Nighttime Symptoms PEF
STEP 3ModeratePersistent
Daily
Use 2-agonist dailyAttacks limit activity
>1 time week 60-80% predictedVariability >30%
STEP 2MildPersistent
≥1 time a weekbut <1 time a day >2times a months
≥80% predictedVariability 20-30%
STEP 1Intermittent
<1 time a week
Asymptomatic andnormal PEF betweenattacks
≤2 times a month≥80% predictedVariability <20%
One of the features of severity is sufficient to place a patient in that category
Inten
sity of treatm
ent
Inten
sity of treatm
ent
TreatmentTreatment
Management of AsthmaManagement of Asthma
Long-acting bronchodilators and/or LTRALong-acting bronchodilators and/or LTRA
Inhaled steroidsInhaled steroids
Short-acting Short-acting 2 agonists prn2 agonists prn
PREVENTIONPREVENTION
Severity of asthmaSeverity of asthma
Oral steroidsOral steroids
IMMUNOTHERAPY ?IMMUNOTHERAPY ?
Treatment Options for PatientsTreatment Options for PatientsNot Controlled on Inhaled SteroidsNot Controlled on Inhaled Steroids
Patients not controlled on inhaled steroidsPatients not controlled on inhaled steroidsPatients not controlled on inhaled steroidsPatients not controlled on inhaled steroids
Increase theIncrease thedose of inhaleddose of inhaled
steroidsteroid
Add leukotrieneAdd leukotrienereceptor receptor
antagonistsantagonistsAdd long-actingAdd long-actingbeta2-agonistsbeta2-agonists
Add Add theophyllinetheophylline
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)
440
390
400
410
420
430
-14 -7 0 7 14 21 28 35 42 48 56 63 70 77 84
p=0.367between groups
during the last 10 weeks of the 12-week treatment period
Run-inPrice et al., Thorax 2003
Busse WW et al.Busse WW et al. J Allergy Clin Immunol 1999; 103: 1075-80 J Allergy Clin Immunol 1999; 103: 1075-80
COMPARISON OF INHALED SALMETEROL COMPARISON OF INHALED SALMETEROL AND ORAL ZAFIRLUKAST IN PATIENTS AND ORAL ZAFIRLUKAST IN PATIENTS
WITH ASTHMAWITH ASTHMA
In patients with persistent asthma, most of whom currently In patients with persistent asthma, most of whom currently using inhaled corticosteroids, treatment with inhaled using inhaled corticosteroids, treatment with inhaled
salmeterol provided significantly greater improvement that salmeterol provided significantly greater improvement that oral zafirlukast in overall clinical control over the 4-week oral zafirlukast in overall clinical control over the 4-week
treatment periodtreatment period
Biermer L t al.Biermer L t al. BMJ 2003; in press BMJ 2003; in press
A ONE-YEAR COMPARATIVE TRIAL OF A ONE-YEAR COMPARATIVE TRIAL OF MONTELUKAST AND FLUTICASONE VS MONTELUKAST AND FLUTICASONE VS SALMETEROL AND FLUTICASONE IN SALMETEROL AND FLUTICASONE IN
PROTECTING AGAINST ASTHMA ATTACKSPROTECTING AGAINST ASTHMA ATTACKS
The study demonstrates the equal clinical benefit of The study demonstrates the equal clinical benefit of including montelukast or salmeterol in asthma therapy for including montelukast or salmeterol in asthma therapy for
protection against asthma exacerbations of patients protection against asthma exacerbations of patients inadequately controlled by inhaled corticosteroids.inadequately controlled by inhaled corticosteroids.
ADDITION OF LEUKOTRIENE ANTAGONISTS ADDITION OF LEUKOTRIENE ANTAGONISTS TO THERAPY IN CHRONIC PERSISTENT TO THERAPY IN CHRONIC PERSISTENT
ASTHMA: A RANDOMISED DOUBLE-BLINDASTHMA: A RANDOMISED DOUBLE-BLINDPLACEBO-CONTROLLED TRIAL PLACEBO-CONTROLLED TRIAL
Used as additional therapy in a hospital outpatient clinic setting, Used as additional therapy in a hospital outpatient clinic setting, montelukast did not provide such additional benefit in patientsmontelukast did not provide such additional benefit in patients
with moderate or severe asthmawith moderate or severe asthma
Robinson DS et al Lancet 2001; 357: 2007-11Robinson DS et al Lancet 2001; 357: 2007-11
Le linee guida GINA in Italia:passare dalla teoria ai fatti
Prof. L.M. Fabbri
Processo di aggiornamento delle linee guida
Trattamento farmacologico: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
Differences between asthma and COPDDifferences between asthma and COPD
ASTHMAASTHMASensitizing agentSensitizing agent
COPDCOPDNoxious agentNoxious agent
Asthmatic airwayAsthmatic airwayinflammationinflammation
CD4+ T-lymphocytesCD4+ T-lymphocytes
EosinophilsEosinophils
COPD airway inflammationCOPD airway inflammationCD8+ T-lymphocytesCD8+ T-lymphocytes
MarcrophagesMarcrophages
NeutrophilsNeutrophils
Airflow limitationAirflow limitationCompletelyCompletelyreversiblereversible
CompletelyCompletelyirreversibleirreversibleAirflow limitationAirflow limitation
AsthmaAsthmaA
B
C
B
D
COPDCOPD
Fabbri LM et al Am J Respir Crit Care Med Fabbri LM et al Am J Respir Crit Care Med 2003;167 418-4242003;167 418-424
ASTHMAASTHMA COPDCOPD
Mild Intermittent Mild Intermittent 2 prn 2 prn MildMild 2 prn 2 prn
Mild persistentMild persistent iGCS iGCS Moderate LABAModerate LABA
Moderate persistent Combination Severe Moderate persistent Combination Severe CombinationCombination
LABA+iGCS LABA+iGCS LABA+iGCSLABA+iGCS
Severe persistent Oral GCS Very Oxygen, SxSevere persistent Oral GCS Very Oxygen, Sx severesevere SurgerySurgery
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: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
TREATMENT OPTIONS IN ASTHMATREATMENT OPTIONS IN ASTHMA
CURRENT OPTIONSCURRENT OPTIONSInhaled corticosteroidsInhaled corticosteroids
Long acting beta2-agonistsLong acting beta2-agonistsLeukotriene receptor antagonistsLeukotriene receptor antagonists
FUTURE OPTIONSFUTURE OPTIONSBetter corticosteroids and bronchodilatorsBetter corticosteroids and bronchodilators
Phosphodiesterase inhibitorsPhosphodiesterase inhibitorsAnti-IgEAnti-IgE
FUTURISTIC OPTIONSFUTURISTIC OPTIONSMediator antagonistsMediator antagonists
Non-steroidal antiinflammatory agentsNon-steroidal antiinflammatory agentsChemokine and chemokine receptor antagonistsChemokine and chemokine receptor antagonists
Gene therapyGene therapy
Modified by P.J. Barnes, 2003Modified by P.J. Barnes, 2003
YYYYIgEIgE
YY
YY
YY
IL-4, IL-13IL-4, IL-13
B lymphocyteB lymphocyte
YYYY
YY HistamineHistamineCys-LTsCys-LTsPGDPGD22
FcFcRIRI
Mast cellMast cell
YYYY
YY
YYYY
YY
YY
ChronicChronicinflammationinflammation
YYYY
FcFcRII (CD23)RII (CD23)
MacrophageMacrophage
T lymphocyteT lymphocyte
EosinophilEosinophil
rhuMAb-E25,rhuMAb-E25,omalizumabomalizumab
IgE AND ITS INHIBITION IN ATOPYIgE AND ITS INHIBITION IN ATOPY
Modified by P.J. Barnes, 2003Modified by P.J. Barnes, 2003
L 0
20
40
60
80
L
% P
atie
nts
Placebo
Anti-IgE (low dose)
Anti-IgE (high dose)
Milgrom H et al: NEJM 1999
>50% reduction Discontinuing
omalizumab: iv. 2x weekly x 12 weeks then reduction over 8 weeks
ANTI-IgE IN STEROID-DEPENDENT ASTHMAANTI-IgE IN STEROID-DEPENDENT ASTHMA
Oral steroids
0
20
40
60
80
100
Median BDP dosereduction (%)
Omalizumab sc 28wks
Placebo
Complete BDPwithdrawal (%)
p<0.001p<0.001
p<0.001p<0.001
Soler M et al: Eur Respir J 2001
Moderate to severe allergic asthmaModerate to severe allergic asthma
EFFECT OF ANTI-IgE IN EFFECT OF ANTI-IgE IN ASTHMAASTHMA
FEVFEV11, PEF, PEF
Exacerbations (58%)Exacerbations (58%)
POSITION OFPOSITION OF ANTI-IgE ANTI-IgE IN THE IN THE TREATMENT OF ASTHMATREATMENT 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 ?Cover for immunotherapy ? Modified by P.J. Barnes, 2003Modified by P.J. Barnes, 2003
Management of asthma:Management of asthma:updating the GINA guidelinesupdating the GINA guidelines
Systemic Systemic steroidssteroids
Ast
hm
a se
ver i
t yA
sth
ma
seve
rit y
MildMildIntermittentIntermittent
Mild Mild PersistentPersistent
Moderate Moderate PersistentPersistent
ModerateModeratePersistentPersistent(Severe?)(Severe?)SevereSevere
PersistentPersistent(Very severe?)(Very severe?)
Combination with higher Combination with higher doses inhaled corticosteroids, doses inhaled corticosteroids, theophylline, antileukotrienestheophylline, antileukotrienes
Avoidance of risk factors, immunotherapyAvoidance of risk factors, immunotherapyShort-acting beta-2 agonists as neededShort-acting beta-2 agonists as needed
Low-dose inhaled steroidsLow-dose inhaled steroids
Combination of long-acting beta2 agonists Combination of long-acting beta2 agonists with low dose inhaled steroidswith 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: 2003-2004
Asma grave/BPCO
Nuovi farmaci antiasmatici
Aggiornamento Linee Guida GINA 2003
Prof. Leonardo M. FabbriClinica di Malattie dell’Apparato Respiratorio
Università degli Studi di Modena e Reggio Emilia, Modena
ATTUALITA’ ED EVOLUZIONE NELLA GESTIONE CLINICA DELL’ASMA